Reviews

Thanks to advances in medical science and our understanding of inherited and acquired liver disease, many more children with acquired or congenital liver disease survive into adulthood than they did 2 decades ago. Improvements in immunosuppression and surgery have increased the chances of pediatric liver transplant recipients reaching adulthood, with a survival rate of 75% at 15 to 20 years.¹

With the growing number of adult patients with pediatric-onset liver disease, internists and adult hepatologists need to be aware of these liver diseases and develop expertise to manage this challenging group of patients. Moreover, young adults with pediatric-onset chronic liver disease pose distinct challenges such as pregnancy, adherence to medical regimens, and psychosocial changes in life.

These patients need a “transition of care” rather than a “transfer of care.” Transition of care is a multifaceted process that takes the medical, educational, and psychosocial needs of the patient into consideration before switching their care to adult care physicians, whereas transfer of care is simply an administrative process of change to adult care without previous knowledge of the patients.²

BILIARY ATRESIA

Biliary atresia is a progressive inflammatory fibrosclerosing cholangiopathy of unknown cause. Its prevalence varies with geographic location, ranging from 1 in 6,000 to 1 in 19,000, with the highest prevalence in Taiwan.³

Biliary atresia usually presents within the first few weeks of life, with progressive cholestasis leading to failure to thrive and to fat-soluble vitamin deficiency. Approximately 20% of patients have congenital splenic, gastrointestinal, genitourinary, cardiac, and venous malformations.^4,5 Untreated, biliary atresia progresses to end-stage liver disease and death within 2 years.

The first-line treatment for biliary atresia is to establish biliary outflow with the Kasai procedure (hepatic portoenterostomy), in which a jejunal limb is anastomosed in a Roux-en-Y with the liver. The outcomes of the Kasai procedure depend on the timing of surgery, so timely diagnosis of biliary atresia is crucial. When the Kasai procedure is performed within 60 days of birth, biliary flow is achieved in up to 70% of patients; but if performed after 90 days, biliary flow is achieved in fewer than 25%.⁶

Long-term outcomes of biliary atresia in patients with their native liver have been reported in a few studies.

In a French study,⁷ 743 patients with biliary atresia underwent the Kasai procedure at a median age of 60 days. Survival rates were 57.1% at 2 years, 37.9% at 5 years, 32.4% at 10 years, and 28.5% at 15 years. In other studies,^4–9 the 20-year transplant-free survival rate ranged from 23% to 46%. Therefore, at least one-third of children with biliary atresia survive to adulthood with their native liver.

Implications of biliary atresia in adulthood

Although the Kasai procedure improves biliary outflow, up to 70% of patients develop complications of biliary atresia such as progressive fibrosis, cirrhosis, portal hypertension, cholangitis, and hepatocellular carcinoma, even after a successful Kasai procedure.¹⁰

Portal hypertension with evidence of splenomegaly, thrombocytopenia, or ascites is found in two-thirds of long-term survivors of biliary atresia with a native liver, with variceal hemorrhage occurring in 30%.¹¹ Therefore, patients with biliary atresia who have evidence of portal hypertension should be screened for varices with upper endoscopy on an annual basis. Management of variceal hemorrhage in these patients includes the use of octreotide, antibiotics, variceal ligation, and sclerotherapy; primary prophylaxis can be achieved with beta-blockers and endoscopic variceal ligation.¹²

Cholangitis is frequent, occurring in 40% to 60% of biliary atresia patients after the Kasai procedure, and about one-fourth of these patients have multiple episodes.¹³ The number of episodes of cholangitis negatively affects transplant-free survival.¹⁴ Patients with cholangitis should be adequately treated with oral or intravenous antibiotics depending on the severity of presentation. The role of prophylaxis with antibiotics remains unclear.¹⁵

Pulmonary complications such as hepato­pulmonary syndrome and portopulmonary hypertension can also occur in biliary atresia patients with a native liver. It is important for physicians to be aware of these complications and to screen for them, for example, with agitated saline echocardiography for hepatopulmonary syndrome and with echocardiography for portopulmonary hypertension. Timely screening is crucial, as the outcome of liver transplant depends on the severity at the time of transplant in these conditions, especially portopulmonary hypertension.

Hepatocellular carcinoma has been rarely reported in children with biliary atresia,¹⁶ so well-defined guidelines for screening in young adults with biliary atresia are lacking. Most centers recommend screening with ultrasonography of the abdomen and alpha-fetoprotein measurement every 6 months or annually starting soon after the Kasai procedure, since hepatocellular carcinoma has been reported in children as young as age 2.¹⁶

Transplant. Adult hepatologists are faced with the challenging task of deciding when it is time for transplant, balancing the long-term complications of biliary atresia with the risk of long-term immunosuppression after transplant. In addition, young adults with these complications may have preserved synthetic function, resulting in low Model for End-Stage Liver Disease (MELD) scores, which may complicate the process of listing for transplant.

Neurocognitive deficits are reported in children with biliary atresia,¹⁷ but young adults with biliary atresia generally have reasonable cognitive function and prospects for education and employment.

Pregnancy with successful outcomes has been reported.⁸

Alagille syndrome is an autosomal-dominant multisystemic disease caused by mutations in the JAG1 gene (accounting for > 95% of cases) and the NOTCH2 gene, with highly variable expression.¹⁸

Extrahepatic manifestations include butterfly vertebral defects, facial dysmorphism (eg, deep-set and low-set eyes, with characteristic “triangular” facies), posterior embryotoxon (a congenital defect of the eye characterized by an opaque ring around the margin of the cornea), peripheral pulmonary stenosis, renal abnormalities, and vascular malformations.

Hepatic manifestations vary from asymptomatic laboratory abnormalities to progressive cholestasis starting in early infancy with intractable pruritus, xanthomas, failure to thrive, and end-stage liver disease requiring liver transplant in childhood in 15% to 20% of patients.¹⁹

Implications of Alagille syndrome in adulthood

Transplant. Interestingly, the phenotype of hepatic disease is already established in childhood, with minimal or no progression in adulthood. Most children with minimal liver disease experience spontaneous resolution, whereas those with significant cholestasis might ultimately develop progressive liver fibrosis or cirrhosis requiring liver transplant in childhood. Only a small subset of children with minimal cholestasis progress to end-stage liver disease in late childhood or early adulthood.²⁰ Therefore, liver transplant for progressive liver disease from significant cholestasis almost always occurs in childhood, usually between ages 1 and 4.²¹

In a retrospective study comparing posttransplant outcomes in children with Alagille syndrome and biliary atresia, 1-year patient survival was excellent overall in children with Alagille syndrome, although slightly lower than in children with biliary atresia, most likely owing to extrahepatic morbidities of Alagille syndrome and especially the use of immunosuppression in those with renal disease.²¹ Similarly, 1- and 5-year patient and graft survival outcomes of liver transplant in adults with Alagille syndrome were also excellent compared with those who received a liver transplant in childhood for Alagille syndrome or in adulthood for biliary atresia.²²

Hepatocellular carcinoma has occurred in these patients in the absence of cirrhosis, which makes implementation of prognostic and surveillance strategies almost impossible to design for them. Annual ultrasonography with alpha-fetoprotein testing might be applicable in Alagille syndrome patients. However, deciding which patients should undergo this testing and when it should start will be challenging, given the paucity of data.

Cardiovascular disease. Cardiac phenotype is also mostly established in childhood, with the pulmonary vasculature being most commonly involved.¹⁹ In contrast, renal and other vascular abnormalities can manifest in adulthood. Renal manifestations vary and include structural anomalies such as hyperechoic kidneys or renal cysts, which can manifest in childhood, and some abnormalities such as hypertension and renal artery stenosis that can manifest in adulthood.^23,24

Vasculopathy is reported to involve the intracranial, renal, and intra-abdominal blood vessels.²⁵ Neurovascular accidents such as stroke and intracranial hemorrhage can occur at any age, with significant rates of morbidity and death.²⁶ Therefore, some experts recommend magnetic resonance angiography every 5 years and before any major intervention to prevent these devastating complications.²⁰

Pregnancy. Successful pregnancies have been reported. Preexisting cardiac and hepatic disease can complicate pregnancy depending on the severity of the disease. Because of the autosomal-dominant pattern of inheritance, infants have a 50% risk of the disease, so genetic counseling should be seriously considered before conception.²⁷ Prenatal diagnosis is possible, but the lack of genotype-phenotype correlation precludes its use in clinical practice.

PROGRESSIVE FAMILIAL INTRAHEPATIC CHOLESTASIS

Progressive familial intrahepatic cholestasis (PFIC) is a heterogeneous group of autosomal-recessive conditions associated with disruption of bile formation causing cholestatic liver disease in infants and young children. Three types have been described, depending on the genetic mutation in the hepatobiliary transport pathway:

• PFIC 1 (Byler disease) is caused by impaired bile salt secretion due to mutations in the ATP8B1 gene encoding for the familial intrahepatic cholestasis 1 (FIC 1) protein
• PFIC 2 is caused by impaired bile salt secretion due to mutations in the ABCB11 gene encoding for the bile salt export pump (BSEP) protein
• PFIC 3 is caused by impaired biliary phospholipid secretion due to a defect in ABCB4 encoding for multidrug resistance 3 (MDR3) protein.²⁸

PFIC 1 and 2 manifest with low gamma-glutamyl transferase (GGT) cholestasis, whereas PFIC 3 presents with high GGT cholestasis.

PFIC 1 and PFIC 2 usually cause cholestasis in early infancy, but PFIC 3 can cause cholestasis in late infancy, childhood, and even adulthood.

Because ATP8B1 is expressed in other tissues, PFIC 1 is characterized by extrahepatic manifestations such as sensorineural hearing loss, growth failure, severe diarrhea, and pancreatic insufficiency.

PFIC 1 and 2 (low-GGT cholestasis) are usually progressive and often lead to end-stage liver disease and cirrhosis before adulthood. Therefore, almost all patients with PFIC 1 and 2 undergo liver transplant or at least a biliary diversion procedure before reaching adulthood. Intractable pruritus is one of the most challenging clinical manifestations in patients with PFIC.

First-line management is pharmacologic and includes ursodeoxycholic acid, antihistamines (eg, hydroxyzine), bile acid sequestrants (eg, cholestyramine, colestipol), naltrexone, and rifampin, but these have limited efficacy.¹⁰

Most patients, especially those with PFIC 1 and 2, undergo a biliary diversion procedure such as partial external biliary diversion (cholecystojejunocutaneostomy), ileal exclusion, or partial internal biliary diversion (cholecystojejunocolic anastomosis) to decrease enterohepatic circulation of bile salts. The efficacy of these procedures is very limited in patients with established cirrhosis. Excessive losses of bile can occur through the biliary stoma, leading to dehydration in patients with external biliary diversion. In patients who are not candidates for biliary diversion, endoscopic nasobiliary drainage of pancreatobiliary secretions could be achieved by placing a catheter in the common bile duct; this has been reported to be effective in relieving cholestasis in a few cases.²⁹

Liver transplant is needed in patients with progressive liver disease and intractable pruritus despite medical management and biliary diversion. Unlike in biliary atresia, liver transplant is not curative in PFIC 1, due to extrahepatic manifestations: patients with PFIC 1 can still have intractable diarrhea and pancreatitis after liver transplant. More importantly, allograft steatohepatitis with further progression to cirrhosis can occur after liver transplant in patients with PFIC 1. Interestingly, biliary diversion has been reported to improve graft steatosis and diarrhea after liver transplant.³⁰

Although graft survival after transplant is good in patients with PFIC 2, recurrence of low-GGT cholestasis has been reported and is believed to be due to the formation of anti-bile salt export pump (anti-BSEP) antibodies by the host immune system in response to exposure to new proteins from the transplant graft.³¹

Cancer. The risk of malignancy, especially hepatocellular carcinoma, is also increased in PFIC 2, affecting nearly 15% of patients. Therefore, standard hepatocellular carcinoma surveillance with ultrasonography or alpha-fetoprotein testing or both is recommended in patients with PFIC 2. Cholangiocarcinoma and pancreatic adenocarcinoma have also been reported in patients with PFIC 2.²⁰

Incomplete penetrance of mutations in ATP8B1 and ABCB11 can cause recurrent episodes of cholestasis and pruritus with asymptomatic periods between episodes, referred to as benign recurrent intrahepatic cholestasis. Prognosis is usually good, with no progression to cirrhosis.³²

Pregnancy. In contrast to FIC 1 and BSEP deficiency, MDR3 defects lead to a wide phenotypic spectrum depending on the type of mutation. Heterozygous mutation is associated with increased risk of development of cholestasis during pregnancy, which typically presents with generalized pruritus in the third trimester and is associated with adverse fetal outcomes. Intrahepatic cholestasis of pregnancy is usually treated with ursodeoxycholic acid, with reported improvement in pruritus, liver function, and pregnancy outcomes.³³

In adults, drug-induced liver injury and idiopathic cirrhosis have also been described with MDR3 defects. Intrahepatic lithiasis and cholesterol gallstones can also occur with MDR3 defects as a result of impaired secretion of biliary phospholipid.³² Despite intrahepatic cholestasis of pregnancy, successful outcomes have been reported in women with PFIC.²⁰

OTHER CHILDHOOD-ONSET INHERITED CHOLESTATIC DISEASES

Cystic fibrosis-associated liver disease

Nearly 40% of patients with cystic fibrosis develop liver disease.³⁴ Cystic fibrosis-associated liver disease encompasses a broad clinical spectrum including asymptomatic elevation of aminotransferases, neonatal cholestasis, hepatic steatosis, focal biliary cirrhosis, and multilobar cirrhosis. Cirrhosis and portal hypertension can occur in 5% to 10% of patients and is the third-leading cause of death in patients with cystic fibrosis.³⁵

Risk factors for cystic fibrosis-associated liver disease include male sex, meconium ileus, and severe CFTR gene mutation (class I–III) with pancreatic insufficiency. Cystic fibrosis-related cirrhosis is more frequent in children and adolescents, whereas noncirrhotic portal hypertension and intrahepatic cholangiopathies are more common in adults.³⁶

Limited available studies support treatment with ursodeoxycholic acid in patients with cholestasis to delay the progression of liver disease, but the impact of this drug on long-term outcome is unknown.²⁹

Most patients remain in compensated cirrhosis for many years before progressing to decompensated cirrhosis requiring liver transplant. Other indications for liver transplant include recurrent intractable variceal bleeding, hepatopulmonary syndrome, and portopulmonary hypertension. Combined liver and lung transplant may be considered in patients with advanced liver and lung disease. Outcomes after isolated liver or liver-lung transplant in cystic fibrosis patients have been comparable to those in patients with other liver diseases.³⁷

Defects in bile acid synthesis

Inherited defects of enzymes required for the synthesis of primary bile acids from cholesterol can cause cholestasis from impaired bile flow and production of hepatotoxic aberrant bile acids. The clinical presentation varies depending on the enzymatic defect and can range from liver disease of varying severity to neurologic manifestations. Idiopathic late-onset cholestasis and cirrhosis of unknown etiology have been reported in adults with bile acid synthesis defects.^38,39 Therefore, this diagnosis should be considered in cases of cryptogenic cirrhosis and other cholestatic features.

Treatment with primary bile acids (cholic acid) has been effective in most patients with defective bile acid synthesis.

Primary sclerosing cholangitis

Primary sclerosing cholangitis is characterized by progressive obliteration of intrahepatic and extrahepatic bile ducts and is most commonly seen in patients with inflammatory bowel disease. Sclerosing cholangitis can also be secondary to other diseases in children such as immunodeficiency syndromes, Langerhans cell histiocytosis, cystic fibrosis, or sickle cell anemia.⁴⁰ Neonatal sclerosing cholangitis is a rare autosomal-recessive disease characterized by a severe form of cholangiopathy in neonates and young infants requiring transplant. It can be associated with Kabuki syndrome and neonatal ichthyosis-sclerosing cholangitis syndrome.

Treatment options are limited. Ursodeoxycholic acid and oral vancomycin have variable efficacy. Liver transplant is needed in patients with decompensated cirrhosis. Patients with primary sclerosing cholangitis, especially adults, are at higher risk of developing cholangiocarcinoma, and therefore screening with ultrasonography or magnetic resonance imaging every 6 to 12 months is recommended.

The risk of preterm and cesarean deliveries may be elevated in women with primary sclerosing cholangitis, though data are limited.³³

Adolescent rebellion poses risks

Outcomes of liver transplant in children and adolescents have improved tremendously in the past 2 decades with advances in surgical techniques, pre- and postoperative management, organ preservation, and immunosuppression. Now, most pediatric liver transplant recipients survive into adulthood, creating a unique challenge for internists and adult  care hepatologists.⁴¹

In rebellious adolescents and young adults, risk-taking behavior, nonadherence to immunosuppressive medications, alcohol intake, and substance abuse increase the risk of graft rejection and loss. Current immunosuppressive drugs such as calcineurin inhibitors (tacrolimus, cyclosporine), mycophenolate mofetil, sirolimus, and corticosteroids have drastically decreased rejection rates in compliant patients.⁴¹ Educating patients on the importance of taking their medications and avoiding alcohol and drug abuse is especially important for adolescents and young adults, as rates of nonadherence are high in these age groups.

Although pregnancy is usually successful after liver transplant, it should be considered high-risk due to reported complications such as graft rejection, diabetes, preeclampsia, sepsis, prematurity, and low birth weight. Conception should be avoided for at least 1 year after transplant.⁴² Appropriate counseling with regard to pregnancy and contraception is important.

There is no consensus on breastfeeding, but it is considered safe in women on low-dose calcineurin inhibitors.⁴³

Life is better with a new liver, but patients have special needs

Liver transplant is life-saving and improves quality of life. However, long-term pediatric liver transplant recipients face challenges such as strict adherence to medications and follow-up visits, avoiding exposure to infections, and fear of graft rejection.

Chronic liver disease in children leads to failure to thrive, growth failure, and even delayed puberty, which resolve in most patients after liver transplant before adulthood in the absence of other comorbidities.⁴⁴ However, these patients are reported to have lower psychosocial functioning and more psychiatric disorders such as anxiety or posttraumatic disorder.^41,44

Therefore, a psychologist or other mental health professional should be part of the management team from the time of pretransplant assessment to identify mental health problems and the need for adjustments before liver transplant. Ongoing psychosocial assessment after liver transplant is equally important to identify risks such as drug or alcohol abuse, depression, posttraumatic stress disorder, and medication nonadherence, all of which can negatively affect posttransplant outcome.⁴⁵

In addition, assessment of family functioning and structure is important for good long-term outcomes posttransplant; therefore, a social worker should also be a part of the transplant team. Psyschosocial assessment tools can identify high-risk candidates who would benefit from earlier intervention to avoid any negative impact posttransplant.

Neurocognitive development can be delayed in children with chronic liver disease, and the delay may persist even after liver transplant, with reported impairments in intellectual ability, language, verbal, and visuospatial functioning skills.⁴¹ In spite of this, a recent study found that more than half the study patients were employed at a median follow-up of 24 years from liver transplant and a median age of 27.⁴⁶

Remarkably, pediatric liver transplant recipients have reported quality of life comparable to that in the general population,⁴⁷ and even better than in patients with other chronic illnesses.⁴⁸

Long-term medical comorbidities in pediatric liver transplant recipients

Favorable outcomes such as long-term survival and good quality of life in pediatric liver transplant recipients are lessened by late complications such as portal vein thrombosis or biliary strictures needing interventions, chronic graft rejection, adverse effects of immunosuppression, and recurrence of the disease.

Split-liver transplant—splitting a deceased-donor allograft to provide grafts for 2 recipients—has revolutionized liver transplant by increasing the donor pool and thereby decreasing waitlist mortality rates, especially in pediatric candidates. Despite this advantage, split-liver transplant is technically challenging and associated with increased perioperative complications compared with whole-liver transplant, especially in adult recipients. Recently, experienced centers have reported favorable outcomes with split-liver transplant comparable to those with whole-liver transplant; therefore, split-liver transplant should be considered after careful evaluation of donor organ and recipient clinical status.⁴⁹

Old age in the recipient can also adversely affect liver transplant outcomes.⁵⁰

Interestingly, even in patients whose clinical course is unremarkable and biochemical values are normal, graft hepatitis or fibrosis of unknown cause with progression to cirrhosis has been described in the decade after transplant.⁴¹

Chronic rejection with eventual graft loss may be related to nonadherence in adolescents and can be reduced with use of an additional immunosuppressant such as sirolimus or mycophenolate. Chronic kidney disease can occur in about one-third of liver transplant recipients secondary to renal disease associated with primary disease (like Alagille syndrome), hepatorenal syndrome, and most importantly, use of calcineurin inhibitors.⁴⁵

Components of the metabolic syndrome such as type 2 diabetes, obesity, nonalcoholic fatty liver disease, hypertension, and dyslipidemia are also seen in long-term pediatric liver transplant survivors. Internists are advised to screen for these comorbidities so that interventions can be applied early to improve long-term health outcomes and graft survival.

Of importance, multiple studies have shown a 2-fold increase in the rates of de novo malignancy in liver transplant recipients, including solid-organ and lymphoproliferative cancers, probably due to long-term immunosuppression. Posttransplant lymphoproliferative disorder occurs at lower rates than with other solid-organ transplants; its incidence is greatest in pediatric patients and in the first 12 to 18 months after transplant.⁵¹

While the number of patients with childhood-onset liver disease and pediatric liver transplant recipients who survive into adulthood is increasing, there are no established guidelines or formal models for transitioning these patients into adult care. Consequently, studies on transitional process have examined various issues such as patient and parent frustration, poor medical knowledge among patients during transition, lack of parental facilitation, and inadequate knowledge on disease process among adult-care hepatologists.^52–54

A prolonged period of transition up to age 25 is preferred in complicated cases. Distinctive consideration for transition should include those with neurocognitive developmental delay from underlying disease or hepatic encephalopathy before transplant. These patients need additional support and time to achieve independence in health management before transition.⁵⁷ Validated questionnaires are available to assess readiness to transition into adult care,⁵⁸ implying that the decision to transition should not be based solely on age. 

Thanks to advances in medical science and our understanding of inherited and acquired liver disease, many more children with acquired or congenital liver disease survive into adulthood than they did 2 decades ago. Improvements in immunosuppression and surgery have increased the chances of pediatric liver transplant recipients reaching adulthood, with a survival rate of 75% at 15 to 20 years.¹

With the growing number of adult patients with pediatric-onset liver disease, internists and adult hepatologists need to be aware of these liver diseases and develop expertise to manage this challenging group of patients. Moreover, young adults with pediatric-onset chronic liver disease pose distinct challenges such as pregnancy, adherence to medical regimens, and psychosocial changes in life.

These patients need a “transition of care” rather than a “transfer of care.” Transition of care is a multifaceted process that takes the medical, educational, and psychosocial needs of the patient into consideration before switching their care to adult care physicians, whereas transfer of care is simply an administrative process of change to adult care without previous knowledge of the patients.²

BILIARY ATRESIA

Biliary atresia is a progressive inflammatory fibrosclerosing cholangiopathy of unknown cause. Its prevalence varies with geographic location, ranging from 1 in 6,000 to 1 in 19,000, with the highest prevalence in Taiwan.³

Biliary atresia usually presents within the first few weeks of life, with progressive cholestasis leading to failure to thrive and to fat-soluble vitamin deficiency. Approximately 20% of patients have congenital splenic, gastrointestinal, genitourinary, cardiac, and venous malformations.^4,5 Untreated, biliary atresia progresses to end-stage liver disease and death within 2 years.

The first-line treatment for biliary atresia is to establish biliary outflow with the Kasai procedure (hepatic portoenterostomy), in which a jejunal limb is anastomosed in a Roux-en-Y with the liver. The outcomes of the Kasai procedure depend on the timing of surgery, so timely diagnosis of biliary atresia is crucial. When the Kasai procedure is performed within 60 days of birth, biliary flow is achieved in up to 70% of patients; but if performed after 90 days, biliary flow is achieved in fewer than 25%.⁶

Long-term outcomes of biliary atresia in patients with their native liver have been reported in a few studies.

In a French study,⁷ 743 patients with biliary atresia underwent the Kasai procedure at a median age of 60 days. Survival rates were 57.1% at 2 years, 37.9% at 5 years, 32.4% at 10 years, and 28.5% at 15 years. In other studies,^4–9 the 20-year transplant-free survival rate ranged from 23% to 46%. Therefore, at least one-third of children with biliary atresia survive to adulthood with their native liver.

Implications of biliary atresia in adulthood

Although the Kasai procedure improves biliary outflow, up to 70% of patients develop complications of biliary atresia such as progressive fibrosis, cirrhosis, portal hypertension, cholangitis, and hepatocellular carcinoma, even after a successful Kasai procedure.¹⁰

Portal hypertension with evidence of splenomegaly, thrombocytopenia, or ascites is found in two-thirds of long-term survivors of biliary atresia with a native liver, with variceal hemorrhage occurring in 30%.¹¹ Therefore, patients with biliary atresia who have evidence of portal hypertension should be screened for varices with upper endoscopy on an annual basis. Management of variceal hemorrhage in these patients includes the use of octreotide, antibiotics, variceal ligation, and sclerotherapy; primary prophylaxis can be achieved with beta-blockers and endoscopic variceal ligation.¹²

Cholangitis is frequent, occurring in 40% to 60% of biliary atresia patients after the Kasai procedure, and about one-fourth of these patients have multiple episodes.¹³ The number of episodes of cholangitis negatively affects transplant-free survival.¹⁴ Patients with cholangitis should be adequately treated with oral or intravenous antibiotics depending on the severity of presentation. The role of prophylaxis with antibiotics remains unclear.¹⁵

Pulmonary complications such as hepato­pulmonary syndrome and portopulmonary hypertension can also occur in biliary atresia patients with a native liver. It is important for physicians to be aware of these complications and to screen for them, for example, with agitated saline echocardiography for hepatopulmonary syndrome and with echocardiography for portopulmonary hypertension. Timely screening is crucial, as the outcome of liver transplant depends on the severity at the time of transplant in these conditions, especially portopulmonary hypertension.

Hepatocellular carcinoma has been rarely reported in children with biliary atresia,¹⁶ so well-defined guidelines for screening in young adults with biliary atresia are lacking. Most centers recommend screening with ultrasonography of the abdomen and alpha-fetoprotein measurement every 6 months or annually starting soon after the Kasai procedure, since hepatocellular carcinoma has been reported in children as young as age 2.¹⁶

Transplant. Adult hepatologists are faced with the challenging task of deciding when it is time for transplant, balancing the long-term complications of biliary atresia with the risk of long-term immunosuppression after transplant. In addition, young adults with these complications may have preserved synthetic function, resulting in low Model for End-Stage Liver Disease (MELD) scores, which may complicate the process of listing for transplant.

Neurocognitive deficits are reported in children with biliary atresia,¹⁷ but young adults with biliary atresia generally have reasonable cognitive function and prospects for education and employment.

Pregnancy with successful outcomes has been reported.⁸

Alagille syndrome is an autosomal-dominant multisystemic disease caused by mutations in the JAG1 gene (accounting for > 95% of cases) and the NOTCH2 gene, with highly variable expression.¹⁸

Extrahepatic manifestations include butterfly vertebral defects, facial dysmorphism (eg, deep-set and low-set eyes, with characteristic “triangular” facies), posterior embryotoxon (a congenital defect of the eye characterized by an opaque ring around the margin of the cornea), peripheral pulmonary stenosis, renal abnormalities, and vascular malformations.

Hepatic manifestations vary from asymptomatic laboratory abnormalities to progressive cholestasis starting in early infancy with intractable pruritus, xanthomas, failure to thrive, and end-stage liver disease requiring liver transplant in childhood in 15% to 20% of patients.¹⁹

Implications of Alagille syndrome in adulthood

Transplant. Interestingly, the phenotype of hepatic disease is already established in childhood, with minimal or no progression in adulthood. Most children with minimal liver disease experience spontaneous resolution, whereas those with significant cholestasis might ultimately develop progressive liver fibrosis or cirrhosis requiring liver transplant in childhood. Only a small subset of children with minimal cholestasis progress to end-stage liver disease in late childhood or early adulthood.²⁰ Therefore, liver transplant for progressive liver disease from significant cholestasis almost always occurs in childhood, usually between ages 1 and 4.²¹

In a retrospective study comparing posttransplant outcomes in children with Alagille syndrome and biliary atresia, 1-year patient survival was excellent overall in children with Alagille syndrome, although slightly lower than in children with biliary atresia, most likely owing to extrahepatic morbidities of Alagille syndrome and especially the use of immunosuppression in those with renal disease.²¹ Similarly, 1- and 5-year patient and graft survival outcomes of liver transplant in adults with Alagille syndrome were also excellent compared with those who received a liver transplant in childhood for Alagille syndrome or in adulthood for biliary atresia.²²

Hepatocellular carcinoma has occurred in these patients in the absence of cirrhosis, which makes implementation of prognostic and surveillance strategies almost impossible to design for them. Annual ultrasonography with alpha-fetoprotein testing might be applicable in Alagille syndrome patients. However, deciding which patients should undergo this testing and when it should start will be challenging, given the paucity of data.

Cardiovascular disease. Cardiac phenotype is also mostly established in childhood, with the pulmonary vasculature being most commonly involved.¹⁹ In contrast, renal and other vascular abnormalities can manifest in adulthood. Renal manifestations vary and include structural anomalies such as hyperechoic kidneys or renal cysts, which can manifest in childhood, and some abnormalities such as hypertension and renal artery stenosis that can manifest in adulthood.^23,24

Vasculopathy is reported to involve the intracranial, renal, and intra-abdominal blood vessels.²⁵ Neurovascular accidents such as stroke and intracranial hemorrhage can occur at any age, with significant rates of morbidity and death.²⁶ Therefore, some experts recommend magnetic resonance angiography every 5 years and before any major intervention to prevent these devastating complications.²⁰

Pregnancy. Successful pregnancies have been reported. Preexisting cardiac and hepatic disease can complicate pregnancy depending on the severity of the disease. Because of the autosomal-dominant pattern of inheritance, infants have a 50% risk of the disease, so genetic counseling should be seriously considered before conception.²⁷ Prenatal diagnosis is possible, but the lack of genotype-phenotype correlation precludes its use in clinical practice.

PROGRESSIVE FAMILIAL INTRAHEPATIC CHOLESTASIS

Progressive familial intrahepatic cholestasis (PFIC) is a heterogeneous group of autosomal-recessive conditions associated with disruption of bile formation causing cholestatic liver disease in infants and young children. Three types have been described, depending on the genetic mutation in the hepatobiliary transport pathway:

• PFIC 1 (Byler disease) is caused by impaired bile salt secretion due to mutations in the ATP8B1 gene encoding for the familial intrahepatic cholestasis 1 (FIC 1) protein
• PFIC 2 is caused by impaired bile salt secretion due to mutations in the ABCB11 gene encoding for the bile salt export pump (BSEP) protein
• PFIC 3 is caused by impaired biliary phospholipid secretion due to a defect in ABCB4 encoding for multidrug resistance 3 (MDR3) protein.²⁸

PFIC 1 and 2 manifest with low gamma-glutamyl transferase (GGT) cholestasis, whereas PFIC 3 presents with high GGT cholestasis.

PFIC 1 and PFIC 2 usually cause cholestasis in early infancy, but PFIC 3 can cause cholestasis in late infancy, childhood, and even adulthood.

Because ATP8B1 is expressed in other tissues, PFIC 1 is characterized by extrahepatic manifestations such as sensorineural hearing loss, growth failure, severe diarrhea, and pancreatic insufficiency.

PFIC 1 and 2 (low-GGT cholestasis) are usually progressive and often lead to end-stage liver disease and cirrhosis before adulthood. Therefore, almost all patients with PFIC 1 and 2 undergo liver transplant or at least a biliary diversion procedure before reaching adulthood. Intractable pruritus is one of the most challenging clinical manifestations in patients with PFIC.

First-line management is pharmacologic and includes ursodeoxycholic acid, antihistamines (eg, hydroxyzine), bile acid sequestrants (eg, cholestyramine, colestipol), naltrexone, and rifampin, but these have limited efficacy.¹⁰

Most patients, especially those with PFIC 1 and 2, undergo a biliary diversion procedure such as partial external biliary diversion (cholecystojejunocutaneostomy), ileal exclusion, or partial internal biliary diversion (cholecystojejunocolic anastomosis) to decrease enterohepatic circulation of bile salts. The efficacy of these procedures is very limited in patients with established cirrhosis. Excessive losses of bile can occur through the biliary stoma, leading to dehydration in patients with external biliary diversion. In patients who are not candidates for biliary diversion, endoscopic nasobiliary drainage of pancreatobiliary secretions could be achieved by placing a catheter in the common bile duct; this has been reported to be effective in relieving cholestasis in a few cases.²⁹

Liver transplant is needed in patients with progressive liver disease and intractable pruritus despite medical management and biliary diversion. Unlike in biliary atresia, liver transplant is not curative in PFIC 1, due to extrahepatic manifestations: patients with PFIC 1 can still have intractable diarrhea and pancreatitis after liver transplant. More importantly, allograft steatohepatitis with further progression to cirrhosis can occur after liver transplant in patients with PFIC 1. Interestingly, biliary diversion has been reported to improve graft steatosis and diarrhea after liver transplant.³⁰

Although graft survival after transplant is good in patients with PFIC 2, recurrence of low-GGT cholestasis has been reported and is believed to be due to the formation of anti-bile salt export pump (anti-BSEP) antibodies by the host immune system in response to exposure to new proteins from the transplant graft.³¹

Cancer. The risk of malignancy, especially hepatocellular carcinoma, is also increased in PFIC 2, affecting nearly 15% of patients. Therefore, standard hepatocellular carcinoma surveillance with ultrasonography or alpha-fetoprotein testing or both is recommended in patients with PFIC 2. Cholangiocarcinoma and pancreatic adenocarcinoma have also been reported in patients with PFIC 2.²⁰

Incomplete penetrance of mutations in ATP8B1 and ABCB11 can cause recurrent episodes of cholestasis and pruritus with asymptomatic periods between episodes, referred to as benign recurrent intrahepatic cholestasis. Prognosis is usually good, with no progression to cirrhosis.³²

Pregnancy. In contrast to FIC 1 and BSEP deficiency, MDR3 defects lead to a wide phenotypic spectrum depending on the type of mutation. Heterozygous mutation is associated with increased risk of development of cholestasis during pregnancy, which typically presents with generalized pruritus in the third trimester and is associated with adverse fetal outcomes. Intrahepatic cholestasis of pregnancy is usually treated with ursodeoxycholic acid, with reported improvement in pruritus, liver function, and pregnancy outcomes.³³

In adults, drug-induced liver injury and idiopathic cirrhosis have also been described with MDR3 defects. Intrahepatic lithiasis and cholesterol gallstones can also occur with MDR3 defects as a result of impaired secretion of biliary phospholipid.³² Despite intrahepatic cholestasis of pregnancy, successful outcomes have been reported in women with PFIC.²⁰

OTHER CHILDHOOD-ONSET INHERITED CHOLESTATIC DISEASES

Cystic fibrosis-associated liver disease

Nearly 40% of patients with cystic fibrosis develop liver disease.³⁴ Cystic fibrosis-associated liver disease encompasses a broad clinical spectrum including asymptomatic elevation of aminotransferases, neonatal cholestasis, hepatic steatosis, focal biliary cirrhosis, and multilobar cirrhosis. Cirrhosis and portal hypertension can occur in 5% to 10% of patients and is the third-leading cause of death in patients with cystic fibrosis.³⁵

Risk factors for cystic fibrosis-associated liver disease include male sex, meconium ileus, and severe CFTR gene mutation (class I–III) with pancreatic insufficiency. Cystic fibrosis-related cirrhosis is more frequent in children and adolescents, whereas noncirrhotic portal hypertension and intrahepatic cholangiopathies are more common in adults.³⁶

Limited available studies support treatment with ursodeoxycholic acid in patients with cholestasis to delay the progression of liver disease, but the impact of this drug on long-term outcome is unknown.²⁹

Most patients remain in compensated cirrhosis for many years before progressing to decompensated cirrhosis requiring liver transplant. Other indications for liver transplant include recurrent intractable variceal bleeding, hepatopulmonary syndrome, and portopulmonary hypertension. Combined liver and lung transplant may be considered in patients with advanced liver and lung disease. Outcomes after isolated liver or liver-lung transplant in cystic fibrosis patients have been comparable to those in patients with other liver diseases.³⁷

Defects in bile acid synthesis

Inherited defects of enzymes required for the synthesis of primary bile acids from cholesterol can cause cholestasis from impaired bile flow and production of hepatotoxic aberrant bile acids. The clinical presentation varies depending on the enzymatic defect and can range from liver disease of varying severity to neurologic manifestations. Idiopathic late-onset cholestasis and cirrhosis of unknown etiology have been reported in adults with bile acid synthesis defects.^38,39 Therefore, this diagnosis should be considered in cases of cryptogenic cirrhosis and other cholestatic features.

Treatment with primary bile acids (cholic acid) has been effective in most patients with defective bile acid synthesis.

Primary sclerosing cholangitis

Primary sclerosing cholangitis is characterized by progressive obliteration of intrahepatic and extrahepatic bile ducts and is most commonly seen in patients with inflammatory bowel disease. Sclerosing cholangitis can also be secondary to other diseases in children such as immunodeficiency syndromes, Langerhans cell histiocytosis, cystic fibrosis, or sickle cell anemia.⁴⁰ Neonatal sclerosing cholangitis is a rare autosomal-recessive disease characterized by a severe form of cholangiopathy in neonates and young infants requiring transplant. It can be associated with Kabuki syndrome and neonatal ichthyosis-sclerosing cholangitis syndrome.

Treatment options are limited. Ursodeoxycholic acid and oral vancomycin have variable efficacy. Liver transplant is needed in patients with decompensated cirrhosis. Patients with primary sclerosing cholangitis, especially adults, are at higher risk of developing cholangiocarcinoma, and therefore screening with ultrasonography or magnetic resonance imaging every 6 to 12 months is recommended.

The risk of preterm and cesarean deliveries may be elevated in women with primary sclerosing cholangitis, though data are limited.³³

Adolescent rebellion poses risks

Outcomes of liver transplant in children and adolescents have improved tremendously in the past 2 decades with advances in surgical techniques, pre- and postoperative management, organ preservation, and immunosuppression. Now, most pediatric liver transplant recipients survive into adulthood, creating a unique challenge for internists and adult  care hepatologists.⁴¹

In rebellious adolescents and young adults, risk-taking behavior, nonadherence to immunosuppressive medications, alcohol intake, and substance abuse increase the risk of graft rejection and loss. Current immunosuppressive drugs such as calcineurin inhibitors (tacrolimus, cyclosporine), mycophenolate mofetil, sirolimus, and corticosteroids have drastically decreased rejection rates in compliant patients.⁴¹ Educating patients on the importance of taking their medications and avoiding alcohol and drug abuse is especially important for adolescents and young adults, as rates of nonadherence are high in these age groups.

Although pregnancy is usually successful after liver transplant, it should be considered high-risk due to reported complications such as graft rejection, diabetes, preeclampsia, sepsis, prematurity, and low birth weight. Conception should be avoided for at least 1 year after transplant.⁴² Appropriate counseling with regard to pregnancy and contraception is important.

There is no consensus on breastfeeding, but it is considered safe in women on low-dose calcineurin inhibitors.⁴³

Life is better with a new liver, but patients have special needs

Liver transplant is life-saving and improves quality of life. However, long-term pediatric liver transplant recipients face challenges such as strict adherence to medications and follow-up visits, avoiding exposure to infections, and fear of graft rejection.

Chronic liver disease in children leads to failure to thrive, growth failure, and even delayed puberty, which resolve in most patients after liver transplant before adulthood in the absence of other comorbidities.⁴⁴ However, these patients are reported to have lower psychosocial functioning and more psychiatric disorders such as anxiety or posttraumatic disorder.^41,44

Therefore, a psychologist or other mental health professional should be part of the management team from the time of pretransplant assessment to identify mental health problems and the need for adjustments before liver transplant. Ongoing psychosocial assessment after liver transplant is equally important to identify risks such as drug or alcohol abuse, depression, posttraumatic stress disorder, and medication nonadherence, all of which can negatively affect posttransplant outcome.⁴⁵

In addition, assessment of family functioning and structure is important for good long-term outcomes posttransplant; therefore, a social worker should also be a part of the transplant team. Psyschosocial assessment tools can identify high-risk candidates who would benefit from earlier intervention to avoid any negative impact posttransplant.

Neurocognitive development can be delayed in children with chronic liver disease, and the delay may persist even after liver transplant, with reported impairments in intellectual ability, language, verbal, and visuospatial functioning skills.⁴¹ In spite of this, a recent study found that more than half the study patients were employed at a median follow-up of 24 years from liver transplant and a median age of 27.⁴⁶

Remarkably, pediatric liver transplant recipients have reported quality of life comparable to that in the general population,⁴⁷ and even better than in patients with other chronic illnesses.⁴⁸

Long-term medical comorbidities in pediatric liver transplant recipients

Favorable outcomes such as long-term survival and good quality of life in pediatric liver transplant recipients are lessened by late complications such as portal vein thrombosis or biliary strictures needing interventions, chronic graft rejection, adverse effects of immunosuppression, and recurrence of the disease.

Split-liver transplant—splitting a deceased-donor allograft to provide grafts for 2 recipients—has revolutionized liver transplant by increasing the donor pool and thereby decreasing waitlist mortality rates, especially in pediatric candidates. Despite this advantage, split-liver transplant is technically challenging and associated with increased perioperative complications compared with whole-liver transplant, especially in adult recipients. Recently, experienced centers have reported favorable outcomes with split-liver transplant comparable to those with whole-liver transplant; therefore, split-liver transplant should be considered after careful evaluation of donor organ and recipient clinical status.⁴⁹

Old age in the recipient can also adversely affect liver transplant outcomes.⁵⁰

Interestingly, even in patients whose clinical course is unremarkable and biochemical values are normal, graft hepatitis or fibrosis of unknown cause with progression to cirrhosis has been described in the decade after transplant.⁴¹

Chronic rejection with eventual graft loss may be related to nonadherence in adolescents and can be reduced with use of an additional immunosuppressant such as sirolimus or mycophenolate. Chronic kidney disease can occur in about one-third of liver transplant recipients secondary to renal disease associated with primary disease (like Alagille syndrome), hepatorenal syndrome, and most importantly, use of calcineurin inhibitors.⁴⁵

Components of the metabolic syndrome such as type 2 diabetes, obesity, nonalcoholic fatty liver disease, hypertension, and dyslipidemia are also seen in long-term pediatric liver transplant survivors. Internists are advised to screen for these comorbidities so that interventions can be applied early to improve long-term health outcomes and graft survival.

Of importance, multiple studies have shown a 2-fold increase in the rates of de novo malignancy in liver transplant recipients, including solid-organ and lymphoproliferative cancers, probably due to long-term immunosuppression. Posttransplant lymphoproliferative disorder occurs at lower rates than with other solid-organ transplants; its incidence is greatest in pediatric patients and in the first 12 to 18 months after transplant.⁵¹

While the number of patients with childhood-onset liver disease and pediatric liver transplant recipients who survive into adulthood is increasing, there are no established guidelines or formal models for transitioning these patients into adult care. Consequently, studies on transitional process have examined various issues such as patient and parent frustration, poor medical knowledge among patients during transition, lack of parental facilitation, and inadequate knowledge on disease process among adult-care hepatologists.^52–54

A prolonged period of transition up to age 25 is preferred in complicated cases. Distinctive consideration for transition should include those with neurocognitive developmental delay from underlying disease or hepatic encephalopathy before transplant. These patients need additional support and time to achieve independence in health management before transition.⁵⁷ Validated questionnaires are available to assess readiness to transition into adult care,⁵⁸ implying that the decision to transition should not be based solely on age. 

Thanks to advances in medical science and our understanding of inherited and acquired liver disease, many more children with acquired or congenital liver disease survive into adulthood than they did 2 decades ago. Improvements in immunosuppression and surgery have increased the chances of pediatric liver transplant recipients reaching adulthood, with a survival rate of 75% at 15 to 20 years.¹

With the growing number of adult patients with pediatric-onset liver disease, internists and adult hepatologists need to be aware of these liver diseases and develop expertise to manage this challenging group of patients. Moreover, young adults with pediatric-onset chronic liver disease pose distinct challenges such as pregnancy, adherence to medical regimens, and psychosocial changes in life.

These patients need a “transition of care” rather than a “transfer of care.” Transition of care is a multifaceted process that takes the medical, educational, and psychosocial needs of the patient into consideration before switching their care to adult care physicians, whereas transfer of care is simply an administrative process of change to adult care without previous knowledge of the patients.²

BILIARY ATRESIA

Biliary atresia is a progressive inflammatory fibrosclerosing cholangiopathy of unknown cause. Its prevalence varies with geographic location, ranging from 1 in 6,000 to 1 in 19,000, with the highest prevalence in Taiwan.³

Biliary atresia usually presents within the first few weeks of life, with progressive cholestasis leading to failure to thrive and to fat-soluble vitamin deficiency. Approximately 20% of patients have congenital splenic, gastrointestinal, genitourinary, cardiac, and venous malformations.^4,5 Untreated, biliary atresia progresses to end-stage liver disease and death within 2 years.

The first-line treatment for biliary atresia is to establish biliary outflow with the Kasai procedure (hepatic portoenterostomy), in which a jejunal limb is anastomosed in a Roux-en-Y with the liver. The outcomes of the Kasai procedure depend on the timing of surgery, so timely diagnosis of biliary atresia is crucial. When the Kasai procedure is performed within 60 days of birth, biliary flow is achieved in up to 70% of patients; but if performed after 90 days, biliary flow is achieved in fewer than 25%.⁶

Long-term outcomes of biliary atresia in patients with their native liver have been reported in a few studies.

In a French study,⁷ 743 patients with biliary atresia underwent the Kasai procedure at a median age of 60 days. Survival rates were 57.1% at 2 years, 37.9% at 5 years, 32.4% at 10 years, and 28.5% at 15 years. In other studies,^4–9 the 20-year transplant-free survival rate ranged from 23% to 46%. Therefore, at least one-third of children with biliary atresia survive to adulthood with their native liver.

Implications of biliary atresia in adulthood

Although the Kasai procedure improves biliary outflow, up to 70% of patients develop complications of biliary atresia such as progressive fibrosis, cirrhosis, portal hypertension, cholangitis, and hepatocellular carcinoma, even after a successful Kasai procedure.¹⁰

Portal hypertension with evidence of splenomegaly, thrombocytopenia, or ascites is found in two-thirds of long-term survivors of biliary atresia with a native liver, with variceal hemorrhage occurring in 30%.¹¹ Therefore, patients with biliary atresia who have evidence of portal hypertension should be screened for varices with upper endoscopy on an annual basis. Management of variceal hemorrhage in these patients includes the use of octreotide, antibiotics, variceal ligation, and sclerotherapy; primary prophylaxis can be achieved with beta-blockers and endoscopic variceal ligation.¹²

Cholangitis is frequent, occurring in 40% to 60% of biliary atresia patients after the Kasai procedure, and about one-fourth of these patients have multiple episodes.¹³ The number of episodes of cholangitis negatively affects transplant-free survival.¹⁴ Patients with cholangitis should be adequately treated with oral or intravenous antibiotics depending on the severity of presentation. The role of prophylaxis with antibiotics remains unclear.¹⁵

Pulmonary complications such as hepato­pulmonary syndrome and portopulmonary hypertension can also occur in biliary atresia patients with a native liver. It is important for physicians to be aware of these complications and to screen for them, for example, with agitated saline echocardiography for hepatopulmonary syndrome and with echocardiography for portopulmonary hypertension. Timely screening is crucial, as the outcome of liver transplant depends on the severity at the time of transplant in these conditions, especially portopulmonary hypertension.

Hepatocellular carcinoma has been rarely reported in children with biliary atresia,¹⁶ so well-defined guidelines for screening in young adults with biliary atresia are lacking. Most centers recommend screening with ultrasonography of the abdomen and alpha-fetoprotein measurement every 6 months or annually starting soon after the Kasai procedure, since hepatocellular carcinoma has been reported in children as young as age 2.¹⁶

Transplant. Adult hepatologists are faced with the challenging task of deciding when it is time for transplant, balancing the long-term complications of biliary atresia with the risk of long-term immunosuppression after transplant. In addition, young adults with these complications may have preserved synthetic function, resulting in low Model for End-Stage Liver Disease (MELD) scores, which may complicate the process of listing for transplant.

Neurocognitive deficits are reported in children with biliary atresia,¹⁷ but young adults with biliary atresia generally have reasonable cognitive function and prospects for education and employment.

Pregnancy with successful outcomes has been reported.⁸

Alagille syndrome is an autosomal-dominant multisystemic disease caused by mutations in the JAG1 gene (accounting for > 95% of cases) and the NOTCH2 gene, with highly variable expression.¹⁸

Extrahepatic manifestations include butterfly vertebral defects, facial dysmorphism (eg, deep-set and low-set eyes, with characteristic “triangular” facies), posterior embryotoxon (a congenital defect of the eye characterized by an opaque ring around the margin of the cornea), peripheral pulmonary stenosis, renal abnormalities, and vascular malformations.

Hepatic manifestations vary from asymptomatic laboratory abnormalities to progressive cholestasis starting in early infancy with intractable pruritus, xanthomas, failure to thrive, and end-stage liver disease requiring liver transplant in childhood in 15% to 20% of patients.¹⁹

Implications of Alagille syndrome in adulthood

Transplant. Interestingly, the phenotype of hepatic disease is already established in childhood, with minimal or no progression in adulthood. Most children with minimal liver disease experience spontaneous resolution, whereas those with significant cholestasis might ultimately develop progressive liver fibrosis or cirrhosis requiring liver transplant in childhood. Only a small subset of children with minimal cholestasis progress to end-stage liver disease in late childhood or early adulthood.²⁰ Therefore, liver transplant for progressive liver disease from significant cholestasis almost always occurs in childhood, usually between ages 1 and 4.²¹

In a retrospective study comparing posttransplant outcomes in children with Alagille syndrome and biliary atresia, 1-year patient survival was excellent overall in children with Alagille syndrome, although slightly lower than in children with biliary atresia, most likely owing to extrahepatic morbidities of Alagille syndrome and especially the use of immunosuppression in those with renal disease.²¹ Similarly, 1- and 5-year patient and graft survival outcomes of liver transplant in adults with Alagille syndrome were also excellent compared with those who received a liver transplant in childhood for Alagille syndrome or in adulthood for biliary atresia.²²

Hepatocellular carcinoma has occurred in these patients in the absence of cirrhosis, which makes implementation of prognostic and surveillance strategies almost impossible to design for them. Annual ultrasonography with alpha-fetoprotein testing might be applicable in Alagille syndrome patients. However, deciding which patients should undergo this testing and when it should start will be challenging, given the paucity of data.

Cardiovascular disease. Cardiac phenotype is also mostly established in childhood, with the pulmonary vasculature being most commonly involved.¹⁹ In contrast, renal and other vascular abnormalities can manifest in adulthood. Renal manifestations vary and include structural anomalies such as hyperechoic kidneys or renal cysts, which can manifest in childhood, and some abnormalities such as hypertension and renal artery stenosis that can manifest in adulthood.^23,24

Vasculopathy is reported to involve the intracranial, renal, and intra-abdominal blood vessels.²⁵ Neurovascular accidents such as stroke and intracranial hemorrhage can occur at any age, with significant rates of morbidity and death.²⁶ Therefore, some experts recommend magnetic resonance angiography every 5 years and before any major intervention to prevent these devastating complications.²⁰

Pregnancy. Successful pregnancies have been reported. Preexisting cardiac and hepatic disease can complicate pregnancy depending on the severity of the disease. Because of the autosomal-dominant pattern of inheritance, infants have a 50% risk of the disease, so genetic counseling should be seriously considered before conception.²⁷ Prenatal diagnosis is possible, but the lack of genotype-phenotype correlation precludes its use in clinical practice.

PROGRESSIVE FAMILIAL INTRAHEPATIC CHOLESTASIS

Progressive familial intrahepatic cholestasis (PFIC) is a heterogeneous group of autosomal-recessive conditions associated with disruption of bile formation causing cholestatic liver disease in infants and young children. Three types have been described, depending on the genetic mutation in the hepatobiliary transport pathway:

• PFIC 1 (Byler disease) is caused by impaired bile salt secretion due to mutations in the ATP8B1 gene encoding for the familial intrahepatic cholestasis 1 (FIC 1) protein
• PFIC 2 is caused by impaired bile salt secretion due to mutations in the ABCB11 gene encoding for the bile salt export pump (BSEP) protein
• PFIC 3 is caused by impaired biliary phospholipid secretion due to a defect in ABCB4 encoding for multidrug resistance 3 (MDR3) protein.²⁸

PFIC 1 and 2 manifest with low gamma-glutamyl transferase (GGT) cholestasis, whereas PFIC 3 presents with high GGT cholestasis.

PFIC 1 and PFIC 2 usually cause cholestasis in early infancy, but PFIC 3 can cause cholestasis in late infancy, childhood, and even adulthood.

Because ATP8B1 is expressed in other tissues, PFIC 1 is characterized by extrahepatic manifestations such as sensorineural hearing loss, growth failure, severe diarrhea, and pancreatic insufficiency.

PFIC 1 and 2 (low-GGT cholestasis) are usually progressive and often lead to end-stage liver disease and cirrhosis before adulthood. Therefore, almost all patients with PFIC 1 and 2 undergo liver transplant or at least a biliary diversion procedure before reaching adulthood. Intractable pruritus is one of the most challenging clinical manifestations in patients with PFIC.

First-line management is pharmacologic and includes ursodeoxycholic acid, antihistamines (eg, hydroxyzine), bile acid sequestrants (eg, cholestyramine, colestipol), naltrexone, and rifampin, but these have limited efficacy.¹⁰

Most patients, especially those with PFIC 1 and 2, undergo a biliary diversion procedure such as partial external biliary diversion (cholecystojejunocutaneostomy), ileal exclusion, or partial internal biliary diversion (cholecystojejunocolic anastomosis) to decrease enterohepatic circulation of bile salts. The efficacy of these procedures is very limited in patients with established cirrhosis. Excessive losses of bile can occur through the biliary stoma, leading to dehydration in patients with external biliary diversion. In patients who are not candidates for biliary diversion, endoscopic nasobiliary drainage of pancreatobiliary secretions could be achieved by placing a catheter in the common bile duct; this has been reported to be effective in relieving cholestasis in a few cases.²⁹

Liver transplant is needed in patients with progressive liver disease and intractable pruritus despite medical management and biliary diversion. Unlike in biliary atresia, liver transplant is not curative in PFIC 1, due to extrahepatic manifestations: patients with PFIC 1 can still have intractable diarrhea and pancreatitis after liver transplant. More importantly, allograft steatohepatitis with further progression to cirrhosis can occur after liver transplant in patients with PFIC 1. Interestingly, biliary diversion has been reported to improve graft steatosis and diarrhea after liver transplant.³⁰

Although graft survival after transplant is good in patients with PFIC 2, recurrence of low-GGT cholestasis has been reported and is believed to be due to the formation of anti-bile salt export pump (anti-BSEP) antibodies by the host immune system in response to exposure to new proteins from the transplant graft.³¹

Cancer. The risk of malignancy, especially hepatocellular carcinoma, is also increased in PFIC 2, affecting nearly 15% of patients. Therefore, standard hepatocellular carcinoma surveillance with ultrasonography or alpha-fetoprotein testing or both is recommended in patients with PFIC 2. Cholangiocarcinoma and pancreatic adenocarcinoma have also been reported in patients with PFIC 2.²⁰

Incomplete penetrance of mutations in ATP8B1 and ABCB11 can cause recurrent episodes of cholestasis and pruritus with asymptomatic periods between episodes, referred to as benign recurrent intrahepatic cholestasis. Prognosis is usually good, with no progression to cirrhosis.³²

Pregnancy. In contrast to FIC 1 and BSEP deficiency, MDR3 defects lead to a wide phenotypic spectrum depending on the type of mutation. Heterozygous mutation is associated with increased risk of development of cholestasis during pregnancy, which typically presents with generalized pruritus in the third trimester and is associated with adverse fetal outcomes. Intrahepatic cholestasis of pregnancy is usually treated with ursodeoxycholic acid, with reported improvement in pruritus, liver function, and pregnancy outcomes.³³

In adults, drug-induced liver injury and idiopathic cirrhosis have also been described with MDR3 defects. Intrahepatic lithiasis and cholesterol gallstones can also occur with MDR3 defects as a result of impaired secretion of biliary phospholipid.³² Despite intrahepatic cholestasis of pregnancy, successful outcomes have been reported in women with PFIC.²⁰

OTHER CHILDHOOD-ONSET INHERITED CHOLESTATIC DISEASES

Cystic fibrosis-associated liver disease

Nearly 40% of patients with cystic fibrosis develop liver disease.³⁴ Cystic fibrosis-associated liver disease encompasses a broad clinical spectrum including asymptomatic elevation of aminotransferases, neonatal cholestasis, hepatic steatosis, focal biliary cirrhosis, and multilobar cirrhosis. Cirrhosis and portal hypertension can occur in 5% to 10% of patients and is the third-leading cause of death in patients with cystic fibrosis.³⁵

Risk factors for cystic fibrosis-associated liver disease include male sex, meconium ileus, and severe CFTR gene mutation (class I–III) with pancreatic insufficiency. Cystic fibrosis-related cirrhosis is more frequent in children and adolescents, whereas noncirrhotic portal hypertension and intrahepatic cholangiopathies are more common in adults.³⁶

Limited available studies support treatment with ursodeoxycholic acid in patients with cholestasis to delay the progression of liver disease, but the impact of this drug on long-term outcome is unknown.²⁹

Most patients remain in compensated cirrhosis for many years before progressing to decompensated cirrhosis requiring liver transplant. Other indications for liver transplant include recurrent intractable variceal bleeding, hepatopulmonary syndrome, and portopulmonary hypertension. Combined liver and lung transplant may be considered in patients with advanced liver and lung disease. Outcomes after isolated liver or liver-lung transplant in cystic fibrosis patients have been comparable to those in patients with other liver diseases.³⁷

Defects in bile acid synthesis

Inherited defects of enzymes required for the synthesis of primary bile acids from cholesterol can cause cholestasis from impaired bile flow and production of hepatotoxic aberrant bile acids. The clinical presentation varies depending on the enzymatic defect and can range from liver disease of varying severity to neurologic manifestations. Idiopathic late-onset cholestasis and cirrhosis of unknown etiology have been reported in adults with bile acid synthesis defects.^38,39 Therefore, this diagnosis should be considered in cases of cryptogenic cirrhosis and other cholestatic features.

Treatment with primary bile acids (cholic acid) has been effective in most patients with defective bile acid synthesis.

Primary sclerosing cholangitis

Primary sclerosing cholangitis is characterized by progressive obliteration of intrahepatic and extrahepatic bile ducts and is most commonly seen in patients with inflammatory bowel disease. Sclerosing cholangitis can also be secondary to other diseases in children such as immunodeficiency syndromes, Langerhans cell histiocytosis, cystic fibrosis, or sickle cell anemia.⁴⁰ Neonatal sclerosing cholangitis is a rare autosomal-recessive disease characterized by a severe form of cholangiopathy in neonates and young infants requiring transplant. It can be associated with Kabuki syndrome and neonatal ichthyosis-sclerosing cholangitis syndrome.

Treatment options are limited. Ursodeoxycholic acid and oral vancomycin have variable efficacy. Liver transplant is needed in patients with decompensated cirrhosis. Patients with primary sclerosing cholangitis, especially adults, are at higher risk of developing cholangiocarcinoma, and therefore screening with ultrasonography or magnetic resonance imaging every 6 to 12 months is recommended.

The risk of preterm and cesarean deliveries may be elevated in women with primary sclerosing cholangitis, though data are limited.³³

Adolescent rebellion poses risks

Outcomes of liver transplant in children and adolescents have improved tremendously in the past 2 decades with advances in surgical techniques, pre- and postoperative management, organ preservation, and immunosuppression. Now, most pediatric liver transplant recipients survive into adulthood, creating a unique challenge for internists and adult  care hepatologists.⁴¹

In rebellious adolescents and young adults, risk-taking behavior, nonadherence to immunosuppressive medications, alcohol intake, and substance abuse increase the risk of graft rejection and loss. Current immunosuppressive drugs such as calcineurin inhibitors (tacrolimus, cyclosporine), mycophenolate mofetil, sirolimus, and corticosteroids have drastically decreased rejection rates in compliant patients.⁴¹ Educating patients on the importance of taking their medications and avoiding alcohol and drug abuse is especially important for adolescents and young adults, as rates of nonadherence are high in these age groups.

Although pregnancy is usually successful after liver transplant, it should be considered high-risk due to reported complications such as graft rejection, diabetes, preeclampsia, sepsis, prematurity, and low birth weight. Conception should be avoided for at least 1 year after transplant.⁴² Appropriate counseling with regard to pregnancy and contraception is important.

There is no consensus on breastfeeding, but it is considered safe in women on low-dose calcineurin inhibitors.⁴³

Life is better with a new liver, but patients have special needs

Liver transplant is life-saving and improves quality of life. However, long-term pediatric liver transplant recipients face challenges such as strict adherence to medications and follow-up visits, avoiding exposure to infections, and fear of graft rejection.

Chronic liver disease in children leads to failure to thrive, growth failure, and even delayed puberty, which resolve in most patients after liver transplant before adulthood in the absence of other comorbidities.⁴⁴ However, these patients are reported to have lower psychosocial functioning and more psychiatric disorders such as anxiety or posttraumatic disorder.^41,44

Therefore, a psychologist or other mental health professional should be part of the management team from the time of pretransplant assessment to identify mental health problems and the need for adjustments before liver transplant. Ongoing psychosocial assessment after liver transplant is equally important to identify risks such as drug or alcohol abuse, depression, posttraumatic stress disorder, and medication nonadherence, all of which can negatively affect posttransplant outcome.⁴⁵

In addition, assessment of family functioning and structure is important for good long-term outcomes posttransplant; therefore, a social worker should also be a part of the transplant team. Psyschosocial assessment tools can identify high-risk candidates who would benefit from earlier intervention to avoid any negative impact posttransplant.

Neurocognitive development can be delayed in children with chronic liver disease, and the delay may persist even after liver transplant, with reported impairments in intellectual ability, language, verbal, and visuospatial functioning skills.⁴¹ In spite of this, a recent study found that more than half the study patients were employed at a median follow-up of 24 years from liver transplant and a median age of 27.⁴⁶

Remarkably, pediatric liver transplant recipients have reported quality of life comparable to that in the general population,⁴⁷ and even better than in patients with other chronic illnesses.⁴⁸

Long-term medical comorbidities in pediatric liver transplant recipients

Favorable outcomes such as long-term survival and good quality of life in pediatric liver transplant recipients are lessened by late complications such as portal vein thrombosis or biliary strictures needing interventions, chronic graft rejection, adverse effects of immunosuppression, and recurrence of the disease.

Split-liver transplant—splitting a deceased-donor allograft to provide grafts for 2 recipients—has revolutionized liver transplant by increasing the donor pool and thereby decreasing waitlist mortality rates, especially in pediatric candidates. Despite this advantage, split-liver transplant is technically challenging and associated with increased perioperative complications compared with whole-liver transplant, especially in adult recipients. Recently, experienced centers have reported favorable outcomes with split-liver transplant comparable to those with whole-liver transplant; therefore, split-liver transplant should be considered after careful evaluation of donor organ and recipient clinical status.⁴⁹

Old age in the recipient can also adversely affect liver transplant outcomes.⁵⁰

Interestingly, even in patients whose clinical course is unremarkable and biochemical values are normal, graft hepatitis or fibrosis of unknown cause with progression to cirrhosis has been described in the decade after transplant.⁴¹

Chronic rejection with eventual graft loss may be related to nonadherence in adolescents and can be reduced with use of an additional immunosuppressant such as sirolimus or mycophenolate. Chronic kidney disease can occur in about one-third of liver transplant recipients secondary to renal disease associated with primary disease (like Alagille syndrome), hepatorenal syndrome, and most importantly, use of calcineurin inhibitors.⁴⁵

Components of the metabolic syndrome such as type 2 diabetes, obesity, nonalcoholic fatty liver disease, hypertension, and dyslipidemia are also seen in long-term pediatric liver transplant survivors. Internists are advised to screen for these comorbidities so that interventions can be applied early to improve long-term health outcomes and graft survival.

Of importance, multiple studies have shown a 2-fold increase in the rates of de novo malignancy in liver transplant recipients, including solid-organ and lymphoproliferative cancers, probably due to long-term immunosuppression. Posttransplant lymphoproliferative disorder occurs at lower rates than with other solid-organ transplants; its incidence is greatest in pediatric patients and in the first 12 to 18 months after transplant.⁵¹

While the number of patients with childhood-onset liver disease and pediatric liver transplant recipients who survive into adulthood is increasing, there are no established guidelines or formal models for transitioning these patients into adult care. Consequently, studies on transitional process have examined various issues such as patient and parent frustration, poor medical knowledge among patients during transition, lack of parental facilitation, and inadequate knowledge on disease process among adult-care hepatologists.^52–54

A prolonged period of transition up to age 25 is preferred in complicated cases. Distinctive consideration for transition should include those with neurocognitive developmental delay from underlying disease or hepatic encephalopathy before transplant. These patients need additional support and time to achieve independence in health management before transition.⁵⁷ Validated questionnaires are available to assess readiness to transition into adult care,⁵⁸ implying that the decision to transition should not be based solely on age. 

Giant cell arteritis (GCA) is a systemic vasculitis involving medium-sized and large arteries, most commonly the temporal, ophthalmic, occipital, vertebral, posterior ciliary, and proximal vertebral arteries. Moreover, involvement of the ophthalmic artery and its branches results in loss of vision. GCA can also involve the aorta and its proximal branches, especially in the upper extremities.

GCA is the most common systemic vasculitis in adults. It occurs almost exclusively in patients over age 50 and affects women more than men. It is most frequent in populations of northern European ancestry, especially Scandinavian. In a retrospective cohort study in Norway, the average annual cumulative incidence rate of GCA was 16.7 per 100,000 people over age 50.¹ Risk factors include older age, history of smoking, current smoking, early menopause, and, possibly, stress-related disorders.²

PATHOGENESIS IS NOT COMPLETELY UNDERSTOOD

The pathogenesis of GCA is not completely understood, but there is evidence of immune activation in the arterial wall leading to activation of macrophages and formation of multinucleated giant cells (which may not always be present in biopsies).

The most relevant cytokines in the ongoing pathogenesis are still being defined, but the presence of interferon gamma and interleukin 6 (IL-6) seem to be critical for the expression of the disease. The primary immunogenic triggers for the elaboration of these cytokines and the arteritis remain elusive.

A SPECTRUM OF PRESENTATIONS

The initial symptoms of GCA may be vague, such as malaise, fever, and night sweats, and are likely due to systemic inflammation. Features of vascular involvement include headache, scalp tenderness, and jaw claudication (cramping pain in the jaw while chewing).

A less common but serious feature associated with GCA is partial or complete vision loss affecting 1 or both eyes.³ Some patients suddenly go completely blind without any visual prodrome.

Overlapping GCA phenotypes exist, with a spectrum of presentations that include classic cranial arteritis, extracranial GCA (also called large-vessel GCA), and polymyalgia rheumatica.²

Cranial GCA, the best-characterized clinical presentation, causes symptoms such as headache or signs such as tenderness of the temporal artery. On examination, the temporal arteries may be tender or nodular, and the pulses may be felt above the zygomatic arch, above and in front of the tragus of the ear. About two-thirds of patients with cranial GCA present with new-onset headache, most often in the temporal area, but possibly anywhere throughout the head.

Visual disturbance, jaw claudication, and tongue pain are less common but, if present, increase the likelihood of this diagnosis.²

Large-vessel involvement in GCA is common and refers to involvement of the aorta and its proximal branches. Imaging methods used in diagnosing large-vessel GCA include color Doppler ultrasonography, computed tomography with angiography, magnetic resonance imaging with angiography, and positron emission tomography. In some centers, such imaging is performed in all patients diagnosed with GCA to survey for large-vessel involvement.

Depending on the imaging study, large-vessel involvement has been found in 30% to 80% of cases of GCA.^4,5 It is often associated with nonspecific symptoms such as fever, weight loss, chills, and malaise, but it can also cause more specific symptoms such as unilateral extremity claudication. In contrast to patients with cranial GCA, patients with large-vessel GCA were younger at onset, less likely to have headaches, and more likely to have arm claudication at presentation.⁶ Aortitis of the ascending aorta can occur with a histopathologic pattern of GCA but without the clinical stigmata of GCA.

The finding of aortitis should prompt the clinician to question the patient about other symptoms of GCA and to order imaging of the whole vascular tree. Ultrasonography and biopsy of the temporal arteries can be considered. Whether idiopathic aortitis is part of the GCA spectrum remains to be seen.

Laboratory tests often show anemia, leukocytosis, and thrombocytosis. Acute-phase reactants such as C-reactive protein and the erythrocyte sedimentation rate are often elevated. The sedimentation rate often exceeds 50 mm/hour and sometimes 100 mm/hour.

In 2 retrospective studies, the number of patients with GCA whose sedimentation rate was less than 50 mm/hour ranged between 5% and 11%.^7,8 However, a small percentage of patients with GCA have normal inflammatory markers. Therefore, if the suspicion for GCA is high, treatment should be started and biopsy pursued.⁹ In patients with paraproteinemia or other causes of a spuriously elevated or low erythrocyte sedimentation rate, C-reactive protein is a more reliable test.

Polymyalgia rheumatica is another rheumatologic condition that can occur independently or in conjunction with GCA. It is characterized by stiffness and pain in the proximal joints such as the hips and shoulders, typically worse in the morning and better with activity. Although the patient may subjectively feel weak, a close neurologic examination will reveal normal muscle strength.

Polymyalgia rheumatica is observed in 40% to 60% of patients with GCA at the time of diagnosis; 16% to 21% of patients with polymyalgia rheumatica may develop GCA, especially if untreated.^2,10

Differential diagnosis

Other vasculitides (eg, Takayasu arteritis) can also present with unexplained fever, anemia, and constitutional symptoms.

Infection should be considered if fever is present. An infectious disease accompanied by fever, headache, and elevated inflammatory markers can mimic GCA.

Nonarteritic anterior ischemic optic neuropathy can present with sudden vision loss, prompting concern for underlying GCA. Risk factors include hypertension and diabetes mellitus; other features of GCA, including elevated inflammatory markers, are generally absent.

Temporal artery biopsy remains the standard to confirm the diagnosis. However, because inflammation in the temporal arteries can affect some segments but not others, biopsy results on conventional hematoxylin and eosin staining can be falsely negative in patients with GCA. In one study,¹¹ the mean sensitivity of unilateral temporal artery biopsy was 86.9%.

Typical positive histologic findings are inflammation with panarteritis, CD4-positive lymphocytes, macrophages, giant cells, and fragmentation of the internal elastic lamina.¹²

When GCA is suspected, treatment with glucocorticoids should be started immediately and biopsy performed as soon as possible. Delaying biopsy for 14 days or more may not affect the accuracy of biopsy study.¹³ Treatment should never be withheld while awaiting the results of biopsy study.

Biopsy is usually performed unilaterally, on the same side as the symptoms or abnormal findings on examination. Bilateral temporal artery biopsy is also performed and compared with unilateral biopsy; this approach increases the diagnostic yield by about 5%.¹⁴

IMAGING

In patients with suspected GCA, imaging is recommended early to complement the clinical criteria for the diagnosis of GCA.¹⁵ Positron emission tomography, computed tomography angiography, magnetic resonance angiography, or Doppler ultrasonography can reveal inflammation of the arteries in the proximal upper or lower limbs or the aorta.²

In patients with suspected cranial GCA, ultrasonography of the temporal and axillary arteries is recommended first. If ultrasonography is not available or is inconclusive, high-resolution magnetic resonance imaging of the cranial arteries can be used as an alternative. Computed tomography and positron emission tomography of the cranial arteries are not recommended.

In patients with suspected large-vessel GCA, ultrasonography, positron emission tomography, computed tomography, and magnetic resonance imaging may be used to screen for vessel wall inflammation, edema, and luminal narrowing in extracranial arteries. Ultrasonography is of limited value in assessing aortitis.

Color duplex ultrasonography can be applied to assess for vascular inflammation of the temporal or large arteries. The typical finding of the “halo” sign, a hypoechoic ring around the arterial lumen, represents the inflammation-induced thickening of the arterial wall. The “compression sign,” the persistence of the “halo” during compression of the vessel lumen by the ultrasound probe, has high specificity for the diagnosis.¹⁶

Ultrasonography of suspected GCA has yielded sensitivities of 55% to 100% and specificities of 78% to 100%. However, its sensitivity depends on the user’s level of expertise, so it should be done only in medical centers with a high number of GCA cases and with highly experienced sonographers. High-resolution magnetic resonance imaging is an alternative to ultrasonography and has shown similar sensitivity and specificity.³

TREATMENT WITH GLUCOCORTICOIDS

Glucocorticoids remain the standard for treatment of GCA. The therapeutic effect of glucocorticoids in GCA has been established by years of clinical experience, but has never been proven in a placebo-controlled trial. When started appropriately and expeditiously, glucocorticoids produce exquisite resolution of signs and symptoms and prevent the serious complication of vision loss. Rapid resolution of symptoms is so typical of GCA that if the patient’s symptoms persist more than a few days after starting a glucocorticoid, the diagnosis of GCA should be reconsidered.

In a retrospective study of 245 patients with biopsy-proven GCA treated with glucocorticoids, 34 had permanent loss of sight.¹⁷ In 32 (94%) of the 34, the vision loss occurred before glucocorticoids were started. Of the remaining 2 patients, 1 lost vision 8 days into treatment, and the other lost vision 3 years after diagnosis and 1 year after discontinuation of glucocorticoids.

In a series of 144 patients with biopsy-proven GCA, 51 had no vision loss at presentation and no vision loss after starting glucocorticoids, and 93 had vision loss at presentation. In the latter group, symptoms worsened within 5 days of starting glucocorticoids in 9 patients.¹⁸ If vision was intact at the time of presentation, prompt initiation of glucocorticoids reduced the risk of vision loss to less than 1%.

High doses, slowly tapered

The European League Against Rheumatism recommends early initiation of high-dose glucocorticoids for patients with large-vessel vasculitis,¹⁹ and it also recommends glucocorticoids for patients with polymyalgia rheumatica.²⁰ The optimal initial and tapering dosage has never been formally evaluated, but regimens have been devised on the basis of expert opinion.²¹

For patients with GCA who do not have vision loss at the time of diagnosis, the initial dose is prednisone 1 mg/kg or its equivalent daily for 2 to 4 weeks, after which it is tapered.²¹ If the initial dosage is prednisone 60 mg orally daily for 2 to 4 weeks, our practice is to taper it to 50 mg daily for 2 weeks, then 40 mg daily for 2 weeks. Then, it  is decreased by 5 mg every 2 weeks until it is 20 mg daily, and then by 2.5 mg every 2 weeks until it is 10 mg orally daily. Thereafter, the dosage is decreased by 1 mg every 2 to 4 weeks.

For patients with GCA who experience transient vision loss or diplopia at the time of diagnosis, intravenous pulse glucocorticoid therapy should be initiated to reduce the risk of vision loss as rapidly as possible.²² A typical pulse regimen is methylprednisolone 1 g intravenously daily for 3 days. Though not rigorously validated in studies, such an approach is used to avoid vision impairment due to GCA, which is rarely reversible.

Suspect a relapse of GCA if the patient’s initial symptoms recur, if inflammatory markers become elevated, or if classic symptoms of GCA or polymyalgia rheumatica occur. Elevations in inflammatory markers do not definitely indicate a flare of GCA, but they should trigger close monitoring of the patient’s symptoms.

Relapse is treated by increasing the glucocorticoid dosage as appropriate to the nature of the relapse. If vision is affected or the patient has symptoms of GCA, then increments of 30 to 60 mg of prednisone are warranted, whereas if the patient has symptoms of polymyalgia rheumatica, then increments of 5 to 10 mg of prednisone are usually used.

The incidence of relapses of GCA in multiple tertiary care centers has been reported to vary between 34% and 75%.^23,24 Most relapses occur at prednisone dosages of less than 20 mg orally daily and within the first year after diagnosis. The most common symptoms are limb ischemia, jaw claudication, constitutional symptoms, headaches, and polymyalgia rheumatica. In a review of 286 patients,²⁵ 213 (74%) had at least 1 relapse. The first relapse occurred in the first year in 50%, by 2 years in 68%, and by 5 years in 79%.

ADVERSE EFFECTS OF GLUCOCORTICOIDS

In high doses, glucocorticoids have well-known adverse effects. In a population-based study of 120 patients, each patient treated with glucocorticoids experienced at least 1 adverse effect (cataract, fracture, infection, osteonecrosis, diabetes, hypertension, weight gain, capillary fragility, or hair loss).²⁶ The effects were related to aging and cumulative dosage of prednisone but not to the initial dosage.

Glucocorticoids can affect many organs and systems:

• Eyes (cataracts, increased intraocular pressure, exophthalmos)
• Heart (premature atherosclerotic disease, hypertension, fluid retention, hyperlipidemia, arrhythmias)
• Gastrointestinal system (ulcer, gastrointestinal bleeding, gastritis, visceral perforation, hepatic steatosis, acute pancreatitis)
• Bone and muscle (osteopenia, osteoporosis, osteonecrosis, myopathy)
• Brain (mood disorder, psychosis, memory impairment)
• Endocrine system (hyperglycemia, hypothalamic-pituitary-adrenal axis suppression)
• Immune system (immunosuppression, leading to infection and leukocytosis).

Patients receiving a glucocorticoid dose equivalent to 20 mg or more of prednisone daily for 1 month or more who also have another cause of immunocompromise need prophylaxis against Pneumocystis jirovecii pneumonia.²⁷ They should also receive appropriate immunizations before starting glucocorticoids. Live-virus vaccines should not be given to these patients until they have been off glucocorticoids for 1 month.

Glucocorticoids and bone loss

Glucocorticoids are associated with bone loss and fracture, which can occur within the first few months of use and with dosages as low as 2.5 to 7.5 mg orally daily.²⁸ Therefore, glucocorticoid-induced bone loss has to be treated aggressively, particularly in patients who are older and have a history of fragility fracture.

For patients with GCA who need glucocorticoids in doses greater than 5 mg orally daily for more than 3 months, the following measures are advised to decrease the risk of bone loss:

• Weight-bearing exercise
• Smoking cessation
• Moderation in alcohol intake
• Measures to prevent falls²⁹
• Supplementation with 1,200 mg of calcium and 800 IU of vitamin D.³⁰

Pharmacologic therapy should be initiated in men over age 50 who have established osteoporosis and in postmenopausal women with established osteoporosis or osteopenia. For men over age 50 with established osteopenia, risk assessment with the glucocorticoid-corrected FRAX score (www.sheffield.ac.uk/FRAX) should be performed to identify those at high risk in whom pharmacologic therapy is warranted.³¹

Bisphosphonates are the first-line therapy for glucocorticoid-induced osteoporosis.³²

Teriparatide is the second-line therapy and is used in patients who cannot tolerate bis­phosphonates or other osteoporosis therapies, and in those who have severe osteoporosis, with T scores of –3.5 and below if they have not had a fracture, and –2.5 and below if they have had a fragility fracture.³³

Denosumab, a monoclonal antibody to an osteoclast differentiating factor, may be beneficial for some patients with glucocorticoid-induced osteoporosis.³⁴

To assess the efficacy of therapy, measuring bone mineral density at baseline and at 1 year of therapy is recommended. If density is stable or improved, then repeating the measurement at 2- to 3-year intervals is suggested.

Due to the adverse effects of long-term use of glucocorticoids and high rates of relapse, there is a pressing need for medications that are more efficacious and less toxic to treat GCA.

The European League Against Rheumatism, in its 2009 management guidelines for large-vessel vasculitis, recommend using an adjunctive immunosuppressant agent.¹⁹ In the case of GCA, they recommend using methotrexate 10 to 15 mg/week, which has shown modest evidence of reducing the relapse rate and lowering the cumulative doses of glucocorticoids needed.^35,36

Studies of tumor necrosis factor inhibitors and abatacept have not yielded significant reductions in the relapse rate or decreased cumulative doses of prednisone.^37,38

Advances in treatment for GCA have stagnated, but recent trials^39,40 have evaluated the IL-6 receptor alpha inhibitor tocilizumab, given the central role of IL-6 in the pathogenesis of GCA. Case reports have revealed rapid induction and maintenance of remission in GCA using tocilizumab.^41,42

Villiger et al³⁹ performed a randomized, placebo-controlled trial to study the efficacy and safety of tocilizumab in induction and maintenance of disease remission in 30 patients with newly diagnosed GCA. The primary outcome, complete remission at 12 weeks, was achieved in 85% of patients who received tocilizumab plus tapered prednisolone, compared with 40% of patients who received placebo plus tapering prednisolone. The tocilizumab group also had favorable results in secondary outcomes including relapse-free survival at 52 weeks, time to first relapse after induction of remission, and cumulative dose of prednisolone.

The GiACTA trial. Stone et al⁴⁰ studied the effect of tocilizumab on rates of relapse during glucocorticoid tapering in 251 GCA patients over the course of 52 weeks. Patients were randomized in a 2:1:1:1 ratio to 4 treatment groups:

• Tocilizumab weekly plus prednisone, with prednisone tapered over 26 weeks
• Tocilizumab every other week plus prednisone tapered over 26 weeks
• Placebo plus prednisone tapered over 26 weeks
• Placebo plus prednisone tapered over 52 weeks.

The primary outcome was the rate of sustained glucocorticoid-free remission at 52 weeks. Secondary outcomes included the remission rate, the cumulative glucocorticoid dose, and safety measures. At 52 weeks, the rates of sustained remission were:

• 56% with tocilizumab weekly
• 53% with tocilizumab every other week
• 14% with placebo plus 26-week prednisone taper
• 18% with placebo plus 52-week taper.

Differences between the active treatment groups and the placebo groups were statistically significant (P < .001).

The cumulative dose of prednisone in tocilizumab recipients was significantly less than in placebo recipients. Rates of adverse events were similar. Ultimately, the study showed that tocilizumab, either weekly or every other week, was more effective than prednisone alone at sustaining glucocorticoid-free remission in patients with GCA.

However, the study also raised questions about tocilizumab’s toxic effect profile and its  long-term efficacy, as well as who are the optimal candidates for this therapy. Data on long-term use of tocilizumab are primarily taken from its use in rheumatoid arthritis.⁴³ As of this writing, Stone et al are conducting an open-label trial to help provide long-term safety and efficacy data in patients with GCA. In the meantime, we must extrapolate data from the long-term use of tocilizumab in rheumatoid arthritis.

Tocilizumab and lower gastrointestinal tract perforation

One of the major adverse effects of long-term use of tocilizumab is lower gastrointestinal tract perforation.

Xie et al,⁴⁴ in 2016, reported that the risk of perforation in patients on tocilizumab for rheumatoid arthritis was more than 2 times higher than in patients taking a tumor necrosis factor inhibitor. However, the absolute rates of perforation were low overall,  roughly 1 to 3 per 1,000 patient-years in the tocilizumab group. Risk factors for perforation included older age, history of diverticulitis or other gastrointestinal tract condition, and prednisone doses of 7.5 mg or more a day.

Does tocilizumab prevent blindness?

Another consideration is that tocilizumab may not prevent optic neuropathy. In the GiACTA trial, 1 patient in the group receiving tocilizumab every other week developed optic neuropathy.⁴⁰ Prednisone had been completely tapered off at the time, and the condition resolved when glucocorticoids were restarted. Thus, it is unknown if tocilizumab would be effective on its own without concomitant use of glucocorticoids.

Vision loss is one of the most severe complications of GCA, and it is still unclear whether tocilizumab can prevent vision loss in GCA. Also, we still have no data on the effect of tocilizumab on histopathologic findings, and whether biopsy yield diminishes over time. We hope future studies will help guide us in this regard.

No guidelines on tocilizumab yet

Clinical guidelines on the appropriate use of tocilizumab in GCA are lacking. The American College of Rheumatology and the European League Against Rheumatism have yet to publish updated guidelines with comments on use of tocilizumab. Therefore, it is unclear if tocilizumab is a first-line treatment in GCA, as its efficacy alone without glucocorticoids and its long-term safety in GCA patients have not been studied.

Treatment with tocilizumab should be individualized; it should be considered in patients who have had adverse effects from glucocorticoids, and in patients who experience a flare or cannot have their glucocorticoid dose lowered to an appropriate range.

The optimal duration of tocilizumab therapy is also unknown. However, using the GiACTA study as a rough guide, we try to limit its use to 1 year until additional data are available.

Patients on IL-6 inhibition may have suppressed C-reactive protein regardless of disease activity.⁴³ Therefore, this laboratory value may not be reliable in determining active disease in patients on tocilizumab.

The GiACTA trial has shown an impressive improvement in the relapse-free remission period in patients with GCA taking tocilizumab. However, much work needs to be done to define the safety of this medication and determine which patients should be started on it. In the meantime, we recommend starting high-dose glucocorticoid therapy as soon as the diagnosis of GCA is suspected. In patients who do not tolerate glucocorticoids or whose disease flares during glucocorticoid taper, we recommend starting treatment with tocilizumab either once a week or every other week for at least 1 year.

Giant cell arteritis (GCA) is a systemic vasculitis involving medium-sized and large arteries, most commonly the temporal, ophthalmic, occipital, vertebral, posterior ciliary, and proximal vertebral arteries. Moreover, involvement of the ophthalmic artery and its branches results in loss of vision. GCA can also involve the aorta and its proximal branches, especially in the upper extremities.

GCA is the most common systemic vasculitis in adults. It occurs almost exclusively in patients over age 50 and affects women more than men. It is most frequent in populations of northern European ancestry, especially Scandinavian. In a retrospective cohort study in Norway, the average annual cumulative incidence rate of GCA was 16.7 per 100,000 people over age 50.¹ Risk factors include older age, history of smoking, current smoking, early menopause, and, possibly, stress-related disorders.²

PATHOGENESIS IS NOT COMPLETELY UNDERSTOOD

The pathogenesis of GCA is not completely understood, but there is evidence of immune activation in the arterial wall leading to activation of macrophages and formation of multinucleated giant cells (which may not always be present in biopsies).

The most relevant cytokines in the ongoing pathogenesis are still being defined, but the presence of interferon gamma and interleukin 6 (IL-6) seem to be critical for the expression of the disease. The primary immunogenic triggers for the elaboration of these cytokines and the arteritis remain elusive.

A SPECTRUM OF PRESENTATIONS

The initial symptoms of GCA may be vague, such as malaise, fever, and night sweats, and are likely due to systemic inflammation. Features of vascular involvement include headache, scalp tenderness, and jaw claudication (cramping pain in the jaw while chewing).

A less common but serious feature associated with GCA is partial or complete vision loss affecting 1 or both eyes.³ Some patients suddenly go completely blind without any visual prodrome.

Overlapping GCA phenotypes exist, with a spectrum of presentations that include classic cranial arteritis, extracranial GCA (also called large-vessel GCA), and polymyalgia rheumatica.²

Cranial GCA, the best-characterized clinical presentation, causes symptoms such as headache or signs such as tenderness of the temporal artery. On examination, the temporal arteries may be tender or nodular, and the pulses may be felt above the zygomatic arch, above and in front of the tragus of the ear. About two-thirds of patients with cranial GCA present with new-onset headache, most often in the temporal area, but possibly anywhere throughout the head.

Visual disturbance, jaw claudication, and tongue pain are less common but, if present, increase the likelihood of this diagnosis.²

Large-vessel involvement in GCA is common and refers to involvement of the aorta and its proximal branches. Imaging methods used in diagnosing large-vessel GCA include color Doppler ultrasonography, computed tomography with angiography, magnetic resonance imaging with angiography, and positron emission tomography. In some centers, such imaging is performed in all patients diagnosed with GCA to survey for large-vessel involvement.

Depending on the imaging study, large-vessel involvement has been found in 30% to 80% of cases of GCA.^4,5 It is often associated with nonspecific symptoms such as fever, weight loss, chills, and malaise, but it can also cause more specific symptoms such as unilateral extremity claudication. In contrast to patients with cranial GCA, patients with large-vessel GCA were younger at onset, less likely to have headaches, and more likely to have arm claudication at presentation.⁶ Aortitis of the ascending aorta can occur with a histopathologic pattern of GCA but without the clinical stigmata of GCA.

The finding of aortitis should prompt the clinician to question the patient about other symptoms of GCA and to order imaging of the whole vascular tree. Ultrasonography and biopsy of the temporal arteries can be considered. Whether idiopathic aortitis is part of the GCA spectrum remains to be seen.

Laboratory tests often show anemia, leukocytosis, and thrombocytosis. Acute-phase reactants such as C-reactive protein and the erythrocyte sedimentation rate are often elevated. The sedimentation rate often exceeds 50 mm/hour and sometimes 100 mm/hour.

In 2 retrospective studies, the number of patients with GCA whose sedimentation rate was less than 50 mm/hour ranged between 5% and 11%.^7,8 However, a small percentage of patients with GCA have normal inflammatory markers. Therefore, if the suspicion for GCA is high, treatment should be started and biopsy pursued.⁹ In patients with paraproteinemia or other causes of a spuriously elevated or low erythrocyte sedimentation rate, C-reactive protein is a more reliable test.

Polymyalgia rheumatica is another rheumatologic condition that can occur independently or in conjunction with GCA. It is characterized by stiffness and pain in the proximal joints such as the hips and shoulders, typically worse in the morning and better with activity. Although the patient may subjectively feel weak, a close neurologic examination will reveal normal muscle strength.

Polymyalgia rheumatica is observed in 40% to 60% of patients with GCA at the time of diagnosis; 16% to 21% of patients with polymyalgia rheumatica may develop GCA, especially if untreated.^2,10

Differential diagnosis

Other vasculitides (eg, Takayasu arteritis) can also present with unexplained fever, anemia, and constitutional symptoms.

Infection should be considered if fever is present. An infectious disease accompanied by fever, headache, and elevated inflammatory markers can mimic GCA.

Nonarteritic anterior ischemic optic neuropathy can present with sudden vision loss, prompting concern for underlying GCA. Risk factors include hypertension and diabetes mellitus; other features of GCA, including elevated inflammatory markers, are generally absent.

Temporal artery biopsy remains the standard to confirm the diagnosis. However, because inflammation in the temporal arteries can affect some segments but not others, biopsy results on conventional hematoxylin and eosin staining can be falsely negative in patients with GCA. In one study,¹¹ the mean sensitivity of unilateral temporal artery biopsy was 86.9%.

Typical positive histologic findings are inflammation with panarteritis, CD4-positive lymphocytes, macrophages, giant cells, and fragmentation of the internal elastic lamina.¹²

When GCA is suspected, treatment with glucocorticoids should be started immediately and biopsy performed as soon as possible. Delaying biopsy for 14 days or more may not affect the accuracy of biopsy study.¹³ Treatment should never be withheld while awaiting the results of biopsy study.

Biopsy is usually performed unilaterally, on the same side as the symptoms or abnormal findings on examination. Bilateral temporal artery biopsy is also performed and compared with unilateral biopsy; this approach increases the diagnostic yield by about 5%.¹⁴

IMAGING

In patients with suspected GCA, imaging is recommended early to complement the clinical criteria for the diagnosis of GCA.¹⁵ Positron emission tomography, computed tomography angiography, magnetic resonance angiography, or Doppler ultrasonography can reveal inflammation of the arteries in the proximal upper or lower limbs or the aorta.²

In patients with suspected cranial GCA, ultrasonography of the temporal and axillary arteries is recommended first. If ultrasonography is not available or is inconclusive, high-resolution magnetic resonance imaging of the cranial arteries can be used as an alternative. Computed tomography and positron emission tomography of the cranial arteries are not recommended.

In patients with suspected large-vessel GCA, ultrasonography, positron emission tomography, computed tomography, and magnetic resonance imaging may be used to screen for vessel wall inflammation, edema, and luminal narrowing in extracranial arteries. Ultrasonography is of limited value in assessing aortitis.

Color duplex ultrasonography can be applied to assess for vascular inflammation of the temporal or large arteries. The typical finding of the “halo” sign, a hypoechoic ring around the arterial lumen, represents the inflammation-induced thickening of the arterial wall. The “compression sign,” the persistence of the “halo” during compression of the vessel lumen by the ultrasound probe, has high specificity for the diagnosis.¹⁶

Ultrasonography of suspected GCA has yielded sensitivities of 55% to 100% and specificities of 78% to 100%. However, its sensitivity depends on the user’s level of expertise, so it should be done only in medical centers with a high number of GCA cases and with highly experienced sonographers. High-resolution magnetic resonance imaging is an alternative to ultrasonography and has shown similar sensitivity and specificity.³

TREATMENT WITH GLUCOCORTICOIDS

Glucocorticoids remain the standard for treatment of GCA. The therapeutic effect of glucocorticoids in GCA has been established by years of clinical experience, but has never been proven in a placebo-controlled trial. When started appropriately and expeditiously, glucocorticoids produce exquisite resolution of signs and symptoms and prevent the serious complication of vision loss. Rapid resolution of symptoms is so typical of GCA that if the patient’s symptoms persist more than a few days after starting a glucocorticoid, the diagnosis of GCA should be reconsidered.

In a retrospective study of 245 patients with biopsy-proven GCA treated with glucocorticoids, 34 had permanent loss of sight.¹⁷ In 32 (94%) of the 34, the vision loss occurred before glucocorticoids were started. Of the remaining 2 patients, 1 lost vision 8 days into treatment, and the other lost vision 3 years after diagnosis and 1 year after discontinuation of glucocorticoids.

In a series of 144 patients with biopsy-proven GCA, 51 had no vision loss at presentation and no vision loss after starting glucocorticoids, and 93 had vision loss at presentation. In the latter group, symptoms worsened within 5 days of starting glucocorticoids in 9 patients.¹⁸ If vision was intact at the time of presentation, prompt initiation of glucocorticoids reduced the risk of vision loss to less than 1%.

High doses, slowly tapered

The European League Against Rheumatism recommends early initiation of high-dose glucocorticoids for patients with large-vessel vasculitis,¹⁹ and it also recommends glucocorticoids for patients with polymyalgia rheumatica.²⁰ The optimal initial and tapering dosage has never been formally evaluated, but regimens have been devised on the basis of expert opinion.²¹

For patients with GCA who do not have vision loss at the time of diagnosis, the initial dose is prednisone 1 mg/kg or its equivalent daily for 2 to 4 weeks, after which it is tapered.²¹ If the initial dosage is prednisone 60 mg orally daily for 2 to 4 weeks, our practice is to taper it to 50 mg daily for 2 weeks, then 40 mg daily for 2 weeks. Then, it  is decreased by 5 mg every 2 weeks until it is 20 mg daily, and then by 2.5 mg every 2 weeks until it is 10 mg orally daily. Thereafter, the dosage is decreased by 1 mg every 2 to 4 weeks.

For patients with GCA who experience transient vision loss or diplopia at the time of diagnosis, intravenous pulse glucocorticoid therapy should be initiated to reduce the risk of vision loss as rapidly as possible.²² A typical pulse regimen is methylprednisolone 1 g intravenously daily for 3 days. Though not rigorously validated in studies, such an approach is used to avoid vision impairment due to GCA, which is rarely reversible.

Suspect a relapse of GCA if the patient’s initial symptoms recur, if inflammatory markers become elevated, or if classic symptoms of GCA or polymyalgia rheumatica occur. Elevations in inflammatory markers do not definitely indicate a flare of GCA, but they should trigger close monitoring of the patient’s symptoms.

Relapse is treated by increasing the glucocorticoid dosage as appropriate to the nature of the relapse. If vision is affected or the patient has symptoms of GCA, then increments of 30 to 60 mg of prednisone are warranted, whereas if the patient has symptoms of polymyalgia rheumatica, then increments of 5 to 10 mg of prednisone are usually used.

The incidence of relapses of GCA in multiple tertiary care centers has been reported to vary between 34% and 75%.^23,24 Most relapses occur at prednisone dosages of less than 20 mg orally daily and within the first year after diagnosis. The most common symptoms are limb ischemia, jaw claudication, constitutional symptoms, headaches, and polymyalgia rheumatica. In a review of 286 patients,²⁵ 213 (74%) had at least 1 relapse. The first relapse occurred in the first year in 50%, by 2 years in 68%, and by 5 years in 79%.

ADVERSE EFFECTS OF GLUCOCORTICOIDS

In high doses, glucocorticoids have well-known adverse effects. In a population-based study of 120 patients, each patient treated with glucocorticoids experienced at least 1 adverse effect (cataract, fracture, infection, osteonecrosis, diabetes, hypertension, weight gain, capillary fragility, or hair loss).²⁶ The effects were related to aging and cumulative dosage of prednisone but not to the initial dosage.

Glucocorticoids can affect many organs and systems:

• Eyes (cataracts, increased intraocular pressure, exophthalmos)
• Heart (premature atherosclerotic disease, hypertension, fluid retention, hyperlipidemia, arrhythmias)
• Gastrointestinal system (ulcer, gastrointestinal bleeding, gastritis, visceral perforation, hepatic steatosis, acute pancreatitis)
• Bone and muscle (osteopenia, osteoporosis, osteonecrosis, myopathy)
• Brain (mood disorder, psychosis, memory impairment)
• Endocrine system (hyperglycemia, hypothalamic-pituitary-adrenal axis suppression)
• Immune system (immunosuppression, leading to infection and leukocytosis).

Patients receiving a glucocorticoid dose equivalent to 20 mg or more of prednisone daily for 1 month or more who also have another cause of immunocompromise need prophylaxis against Pneumocystis jirovecii pneumonia.²⁷ They should also receive appropriate immunizations before starting glucocorticoids. Live-virus vaccines should not be given to these patients until they have been off glucocorticoids for 1 month.

Glucocorticoids and bone loss

Glucocorticoids are associated with bone loss and fracture, which can occur within the first few months of use and with dosages as low as 2.5 to 7.5 mg orally daily.²⁸ Therefore, glucocorticoid-induced bone loss has to be treated aggressively, particularly in patients who are older and have a history of fragility fracture.

For patients with GCA who need glucocorticoids in doses greater than 5 mg orally daily for more than 3 months, the following measures are advised to decrease the risk of bone loss:

• Weight-bearing exercise
• Smoking cessation
• Moderation in alcohol intake
• Measures to prevent falls²⁹
• Supplementation with 1,200 mg of calcium and 800 IU of vitamin D.³⁰

Pharmacologic therapy should be initiated in men over age 50 who have established osteoporosis and in postmenopausal women with established osteoporosis or osteopenia. For men over age 50 with established osteopenia, risk assessment with the glucocorticoid-corrected FRAX score (www.sheffield.ac.uk/FRAX) should be performed to identify those at high risk in whom pharmacologic therapy is warranted.³¹

Bisphosphonates are the first-line therapy for glucocorticoid-induced osteoporosis.³²

Teriparatide is the second-line therapy and is used in patients who cannot tolerate bis­phosphonates or other osteoporosis therapies, and in those who have severe osteoporosis, with T scores of –3.5 and below if they have not had a fracture, and –2.5 and below if they have had a fragility fracture.³³

Denosumab, a monoclonal antibody to an osteoclast differentiating factor, may be beneficial for some patients with glucocorticoid-induced osteoporosis.³⁴

To assess the efficacy of therapy, measuring bone mineral density at baseline and at 1 year of therapy is recommended. If density is stable or improved, then repeating the measurement at 2- to 3-year intervals is suggested.

Due to the adverse effects of long-term use of glucocorticoids and high rates of relapse, there is a pressing need for medications that are more efficacious and less toxic to treat GCA.

The European League Against Rheumatism, in its 2009 management guidelines for large-vessel vasculitis, recommend using an adjunctive immunosuppressant agent.¹⁹ In the case of GCA, they recommend using methotrexate 10 to 15 mg/week, which has shown modest evidence of reducing the relapse rate and lowering the cumulative doses of glucocorticoids needed.^35,36

Studies of tumor necrosis factor inhibitors and abatacept have not yielded significant reductions in the relapse rate or decreased cumulative doses of prednisone.^37,38

Advances in treatment for GCA have stagnated, but recent trials^39,40 have evaluated the IL-6 receptor alpha inhibitor tocilizumab, given the central role of IL-6 in the pathogenesis of GCA. Case reports have revealed rapid induction and maintenance of remission in GCA using tocilizumab.^41,42

Villiger et al³⁹ performed a randomized, placebo-controlled trial to study the efficacy and safety of tocilizumab in induction and maintenance of disease remission in 30 patients with newly diagnosed GCA. The primary outcome, complete remission at 12 weeks, was achieved in 85% of patients who received tocilizumab plus tapered prednisolone, compared with 40% of patients who received placebo plus tapering prednisolone. The tocilizumab group also had favorable results in secondary outcomes including relapse-free survival at 52 weeks, time to first relapse after induction of remission, and cumulative dose of prednisolone.

The GiACTA trial. Stone et al⁴⁰ studied the effect of tocilizumab on rates of relapse during glucocorticoid tapering in 251 GCA patients over the course of 52 weeks. Patients were randomized in a 2:1:1:1 ratio to 4 treatment groups:

• Tocilizumab weekly plus prednisone, with prednisone tapered over 26 weeks
• Tocilizumab every other week plus prednisone tapered over 26 weeks
• Placebo plus prednisone tapered over 26 weeks
• Placebo plus prednisone tapered over 52 weeks.

The primary outcome was the rate of sustained glucocorticoid-free remission at 52 weeks. Secondary outcomes included the remission rate, the cumulative glucocorticoid dose, and safety measures. At 52 weeks, the rates of sustained remission were:

• 56% with tocilizumab weekly
• 53% with tocilizumab every other week
• 14% with placebo plus 26-week prednisone taper
• 18% with placebo plus 52-week taper.

Differences between the active treatment groups and the placebo groups were statistically significant (P < .001).

The cumulative dose of prednisone in tocilizumab recipients was significantly less than in placebo recipients. Rates of adverse events were similar. Ultimately, the study showed that tocilizumab, either weekly or every other week, was more effective than prednisone alone at sustaining glucocorticoid-free remission in patients with GCA.

However, the study also raised questions about tocilizumab’s toxic effect profile and its  long-term efficacy, as well as who are the optimal candidates for this therapy. Data on long-term use of tocilizumab are primarily taken from its use in rheumatoid arthritis.⁴³ As of this writing, Stone et al are conducting an open-label trial to help provide long-term safety and efficacy data in patients with GCA. In the meantime, we must extrapolate data from the long-term use of tocilizumab in rheumatoid arthritis.

Tocilizumab and lower gastrointestinal tract perforation

One of the major adverse effects of long-term use of tocilizumab is lower gastrointestinal tract perforation.

Xie et al,⁴⁴ in 2016, reported that the risk of perforation in patients on tocilizumab for rheumatoid arthritis was more than 2 times higher than in patients taking a tumor necrosis factor inhibitor. However, the absolute rates of perforation were low overall,  roughly 1 to 3 per 1,000 patient-years in the tocilizumab group. Risk factors for perforation included older age, history of diverticulitis or other gastrointestinal tract condition, and prednisone doses of 7.5 mg or more a day.

Does tocilizumab prevent blindness?

Another consideration is that tocilizumab may not prevent optic neuropathy. In the GiACTA trial, 1 patient in the group receiving tocilizumab every other week developed optic neuropathy.⁴⁰ Prednisone had been completely tapered off at the time, and the condition resolved when glucocorticoids were restarted. Thus, it is unknown if tocilizumab would be effective on its own without concomitant use of glucocorticoids.

Vision loss is one of the most severe complications of GCA, and it is still unclear whether tocilizumab can prevent vision loss in GCA. Also, we still have no data on the effect of tocilizumab on histopathologic findings, and whether biopsy yield diminishes over time. We hope future studies will help guide us in this regard.

No guidelines on tocilizumab yet

Clinical guidelines on the appropriate use of tocilizumab in GCA are lacking. The American College of Rheumatology and the European League Against Rheumatism have yet to publish updated guidelines with comments on use of tocilizumab. Therefore, it is unclear if tocilizumab is a first-line treatment in GCA, as its efficacy alone without glucocorticoids and its long-term safety in GCA patients have not been studied.

Treatment with tocilizumab should be individualized; it should be considered in patients who have had adverse effects from glucocorticoids, and in patients who experience a flare or cannot have their glucocorticoid dose lowered to an appropriate range.

The optimal duration of tocilizumab therapy is also unknown. However, using the GiACTA study as a rough guide, we try to limit its use to 1 year until additional data are available.

Patients on IL-6 inhibition may have suppressed C-reactive protein regardless of disease activity.⁴³ Therefore, this laboratory value may not be reliable in determining active disease in patients on tocilizumab.

The GiACTA trial has shown an impressive improvement in the relapse-free remission period in patients with GCA taking tocilizumab. However, much work needs to be done to define the safety of this medication and determine which patients should be started on it. In the meantime, we recommend starting high-dose glucocorticoid therapy as soon as the diagnosis of GCA is suspected. In patients who do not tolerate glucocorticoids or whose disease flares during glucocorticoid taper, we recommend starting treatment with tocilizumab either once a week or every other week for at least 1 year.

Giant cell arteritis (GCA) is a systemic vasculitis involving medium-sized and large arteries, most commonly the temporal, ophthalmic, occipital, vertebral, posterior ciliary, and proximal vertebral arteries. Moreover, involvement of the ophthalmic artery and its branches results in loss of vision. GCA can also involve the aorta and its proximal branches, especially in the upper extremities.

GCA is the most common systemic vasculitis in adults. It occurs almost exclusively in patients over age 50 and affects women more than men. It is most frequent in populations of northern European ancestry, especially Scandinavian. In a retrospective cohort study in Norway, the average annual cumulative incidence rate of GCA was 16.7 per 100,000 people over age 50.¹ Risk factors include older age, history of smoking, current smoking, early menopause, and, possibly, stress-related disorders.²

PATHOGENESIS IS NOT COMPLETELY UNDERSTOOD

The pathogenesis of GCA is not completely understood, but there is evidence of immune activation in the arterial wall leading to activation of macrophages and formation of multinucleated giant cells (which may not always be present in biopsies).

The most relevant cytokines in the ongoing pathogenesis are still being defined, but the presence of interferon gamma and interleukin 6 (IL-6) seem to be critical for the expression of the disease. The primary immunogenic triggers for the elaboration of these cytokines and the arteritis remain elusive.

A SPECTRUM OF PRESENTATIONS

The initial symptoms of GCA may be vague, such as malaise, fever, and night sweats, and are likely due to systemic inflammation. Features of vascular involvement include headache, scalp tenderness, and jaw claudication (cramping pain in the jaw while chewing).

A less common but serious feature associated with GCA is partial or complete vision loss affecting 1 or both eyes.³ Some patients suddenly go completely blind without any visual prodrome.

Overlapping GCA phenotypes exist, with a spectrum of presentations that include classic cranial arteritis, extracranial GCA (also called large-vessel GCA), and polymyalgia rheumatica.²

Cranial GCA, the best-characterized clinical presentation, causes symptoms such as headache or signs such as tenderness of the temporal artery. On examination, the temporal arteries may be tender or nodular, and the pulses may be felt above the zygomatic arch, above and in front of the tragus of the ear. About two-thirds of patients with cranial GCA present with new-onset headache, most often in the temporal area, but possibly anywhere throughout the head.

Visual disturbance, jaw claudication, and tongue pain are less common but, if present, increase the likelihood of this diagnosis.²

Large-vessel involvement in GCA is common and refers to involvement of the aorta and its proximal branches. Imaging methods used in diagnosing large-vessel GCA include color Doppler ultrasonography, computed tomography with angiography, magnetic resonance imaging with angiography, and positron emission tomography. In some centers, such imaging is performed in all patients diagnosed with GCA to survey for large-vessel involvement.

Depending on the imaging study, large-vessel involvement has been found in 30% to 80% of cases of GCA.^4,5 It is often associated with nonspecific symptoms such as fever, weight loss, chills, and malaise, but it can also cause more specific symptoms such as unilateral extremity claudication. In contrast to patients with cranial GCA, patients with large-vessel GCA were younger at onset, less likely to have headaches, and more likely to have arm claudication at presentation.⁶ Aortitis of the ascending aorta can occur with a histopathologic pattern of GCA but without the clinical stigmata of GCA.

The finding of aortitis should prompt the clinician to question the patient about other symptoms of GCA and to order imaging of the whole vascular tree. Ultrasonography and biopsy of the temporal arteries can be considered. Whether idiopathic aortitis is part of the GCA spectrum remains to be seen.

Laboratory tests often show anemia, leukocytosis, and thrombocytosis. Acute-phase reactants such as C-reactive protein and the erythrocyte sedimentation rate are often elevated. The sedimentation rate often exceeds 50 mm/hour and sometimes 100 mm/hour.

In 2 retrospective studies, the number of patients with GCA whose sedimentation rate was less than 50 mm/hour ranged between 5% and 11%.^7,8 However, a small percentage of patients with GCA have normal inflammatory markers. Therefore, if the suspicion for GCA is high, treatment should be started and biopsy pursued.⁹ In patients with paraproteinemia or other causes of a spuriously elevated or low erythrocyte sedimentation rate, C-reactive protein is a more reliable test.

Polymyalgia rheumatica is another rheumatologic condition that can occur independently or in conjunction with GCA. It is characterized by stiffness and pain in the proximal joints such as the hips and shoulders, typically worse in the morning and better with activity. Although the patient may subjectively feel weak, a close neurologic examination will reveal normal muscle strength.

Polymyalgia rheumatica is observed in 40% to 60% of patients with GCA at the time of diagnosis; 16% to 21% of patients with polymyalgia rheumatica may develop GCA, especially if untreated.^2,10

Differential diagnosis

Other vasculitides (eg, Takayasu arteritis) can also present with unexplained fever, anemia, and constitutional symptoms.

Infection should be considered if fever is present. An infectious disease accompanied by fever, headache, and elevated inflammatory markers can mimic GCA.

Nonarteritic anterior ischemic optic neuropathy can present with sudden vision loss, prompting concern for underlying GCA. Risk factors include hypertension and diabetes mellitus; other features of GCA, including elevated inflammatory markers, are generally absent.

Temporal artery biopsy remains the standard to confirm the diagnosis. However, because inflammation in the temporal arteries can affect some segments but not others, biopsy results on conventional hematoxylin and eosin staining can be falsely negative in patients with GCA. In one study,¹¹ the mean sensitivity of unilateral temporal artery biopsy was 86.9%.

Typical positive histologic findings are inflammation with panarteritis, CD4-positive lymphocytes, macrophages, giant cells, and fragmentation of the internal elastic lamina.¹²

When GCA is suspected, treatment with glucocorticoids should be started immediately and biopsy performed as soon as possible. Delaying biopsy for 14 days or more may not affect the accuracy of biopsy study.¹³ Treatment should never be withheld while awaiting the results of biopsy study.

Biopsy is usually performed unilaterally, on the same side as the symptoms or abnormal findings on examination. Bilateral temporal artery biopsy is also performed and compared with unilateral biopsy; this approach increases the diagnostic yield by about 5%.¹⁴

IMAGING

In patients with suspected GCA, imaging is recommended early to complement the clinical criteria for the diagnosis of GCA.¹⁵ Positron emission tomography, computed tomography angiography, magnetic resonance angiography, or Doppler ultrasonography can reveal inflammation of the arteries in the proximal upper or lower limbs or the aorta.²

In patients with suspected cranial GCA, ultrasonography of the temporal and axillary arteries is recommended first. If ultrasonography is not available or is inconclusive, high-resolution magnetic resonance imaging of the cranial arteries can be used as an alternative. Computed tomography and positron emission tomography of the cranial arteries are not recommended.

In patients with suspected large-vessel GCA, ultrasonography, positron emission tomography, computed tomography, and magnetic resonance imaging may be used to screen for vessel wall inflammation, edema, and luminal narrowing in extracranial arteries. Ultrasonography is of limited value in assessing aortitis.

Color duplex ultrasonography can be applied to assess for vascular inflammation of the temporal or large arteries. The typical finding of the “halo” sign, a hypoechoic ring around the arterial lumen, represents the inflammation-induced thickening of the arterial wall. The “compression sign,” the persistence of the “halo” during compression of the vessel lumen by the ultrasound probe, has high specificity for the diagnosis.¹⁶

Ultrasonography of suspected GCA has yielded sensitivities of 55% to 100% and specificities of 78% to 100%. However, its sensitivity depends on the user’s level of expertise, so it should be done only in medical centers with a high number of GCA cases and with highly experienced sonographers. High-resolution magnetic resonance imaging is an alternative to ultrasonography and has shown similar sensitivity and specificity.³

TREATMENT WITH GLUCOCORTICOIDS

Glucocorticoids remain the standard for treatment of GCA. The therapeutic effect of glucocorticoids in GCA has been established by years of clinical experience, but has never been proven in a placebo-controlled trial. When started appropriately and expeditiously, glucocorticoids produce exquisite resolution of signs and symptoms and prevent the serious complication of vision loss. Rapid resolution of symptoms is so typical of GCA that if the patient’s symptoms persist more than a few days after starting a glucocorticoid, the diagnosis of GCA should be reconsidered.

In a retrospective study of 245 patients with biopsy-proven GCA treated with glucocorticoids, 34 had permanent loss of sight.¹⁷ In 32 (94%) of the 34, the vision loss occurred before glucocorticoids were started. Of the remaining 2 patients, 1 lost vision 8 days into treatment, and the other lost vision 3 years after diagnosis and 1 year after discontinuation of glucocorticoids.

In a series of 144 patients with biopsy-proven GCA, 51 had no vision loss at presentation and no vision loss after starting glucocorticoids, and 93 had vision loss at presentation. In the latter group, symptoms worsened within 5 days of starting glucocorticoids in 9 patients.¹⁸ If vision was intact at the time of presentation, prompt initiation of glucocorticoids reduced the risk of vision loss to less than 1%.

High doses, slowly tapered

The European League Against Rheumatism recommends early initiation of high-dose glucocorticoids for patients with large-vessel vasculitis,¹⁹ and it also recommends glucocorticoids for patients with polymyalgia rheumatica.²⁰ The optimal initial and tapering dosage has never been formally evaluated, but regimens have been devised on the basis of expert opinion.²¹

For patients with GCA who do not have vision loss at the time of diagnosis, the initial dose is prednisone 1 mg/kg or its equivalent daily for 2 to 4 weeks, after which it is tapered.²¹ If the initial dosage is prednisone 60 mg orally daily for 2 to 4 weeks, our practice is to taper it to 50 mg daily for 2 weeks, then 40 mg daily for 2 weeks. Then, it  is decreased by 5 mg every 2 weeks until it is 20 mg daily, and then by 2.5 mg every 2 weeks until it is 10 mg orally daily. Thereafter, the dosage is decreased by 1 mg every 2 to 4 weeks.

For patients with GCA who experience transient vision loss or diplopia at the time of diagnosis, intravenous pulse glucocorticoid therapy should be initiated to reduce the risk of vision loss as rapidly as possible.²² A typical pulse regimen is methylprednisolone 1 g intravenously daily for 3 days. Though not rigorously validated in studies, such an approach is used to avoid vision impairment due to GCA, which is rarely reversible.

Suspect a relapse of GCA if the patient’s initial symptoms recur, if inflammatory markers become elevated, or if classic symptoms of GCA or polymyalgia rheumatica occur. Elevations in inflammatory markers do not definitely indicate a flare of GCA, but they should trigger close monitoring of the patient’s symptoms.

Relapse is treated by increasing the glucocorticoid dosage as appropriate to the nature of the relapse. If vision is affected or the patient has symptoms of GCA, then increments of 30 to 60 mg of prednisone are warranted, whereas if the patient has symptoms of polymyalgia rheumatica, then increments of 5 to 10 mg of prednisone are usually used.

The incidence of relapses of GCA in multiple tertiary care centers has been reported to vary between 34% and 75%.^23,24 Most relapses occur at prednisone dosages of less than 20 mg orally daily and within the first year after diagnosis. The most common symptoms are limb ischemia, jaw claudication, constitutional symptoms, headaches, and polymyalgia rheumatica. In a review of 286 patients,²⁵ 213 (74%) had at least 1 relapse. The first relapse occurred in the first year in 50%, by 2 years in 68%, and by 5 years in 79%.

ADVERSE EFFECTS OF GLUCOCORTICOIDS

In high doses, glucocorticoids have well-known adverse effects. In a population-based study of 120 patients, each patient treated with glucocorticoids experienced at least 1 adverse effect (cataract, fracture, infection, osteonecrosis, diabetes, hypertension, weight gain, capillary fragility, or hair loss).²⁶ The effects were related to aging and cumulative dosage of prednisone but not to the initial dosage.

Glucocorticoids can affect many organs and systems:

• Eyes (cataracts, increased intraocular pressure, exophthalmos)
• Heart (premature atherosclerotic disease, hypertension, fluid retention, hyperlipidemia, arrhythmias)
• Gastrointestinal system (ulcer, gastrointestinal bleeding, gastritis, visceral perforation, hepatic steatosis, acute pancreatitis)
• Bone and muscle (osteopenia, osteoporosis, osteonecrosis, myopathy)
• Brain (mood disorder, psychosis, memory impairment)
• Endocrine system (hyperglycemia, hypothalamic-pituitary-adrenal axis suppression)
• Immune system (immunosuppression, leading to infection and leukocytosis).

Patients receiving a glucocorticoid dose equivalent to 20 mg or more of prednisone daily for 1 month or more who also have another cause of immunocompromise need prophylaxis against Pneumocystis jirovecii pneumonia.²⁷ They should also receive appropriate immunizations before starting glucocorticoids. Live-virus vaccines should not be given to these patients until they have been off glucocorticoids for 1 month.

Glucocorticoids and bone loss

Glucocorticoids are associated with bone loss and fracture, which can occur within the first few months of use and with dosages as low as 2.5 to 7.5 mg orally daily.²⁸ Therefore, glucocorticoid-induced bone loss has to be treated aggressively, particularly in patients who are older and have a history of fragility fracture.

For patients with GCA who need glucocorticoids in doses greater than 5 mg orally daily for more than 3 months, the following measures are advised to decrease the risk of bone loss:

• Weight-bearing exercise
• Smoking cessation
• Moderation in alcohol intake
• Measures to prevent falls²⁹
• Supplementation with 1,200 mg of calcium and 800 IU of vitamin D.³⁰

Pharmacologic therapy should be initiated in men over age 50 who have established osteoporosis and in postmenopausal women with established osteoporosis or osteopenia. For men over age 50 with established osteopenia, risk assessment with the glucocorticoid-corrected FRAX score (www.sheffield.ac.uk/FRAX) should be performed to identify those at high risk in whom pharmacologic therapy is warranted.³¹

Bisphosphonates are the first-line therapy for glucocorticoid-induced osteoporosis.³²

Teriparatide is the second-line therapy and is used in patients who cannot tolerate bis­phosphonates or other osteoporosis therapies, and in those who have severe osteoporosis, with T scores of –3.5 and below if they have not had a fracture, and –2.5 and below if they have had a fragility fracture.³³

Denosumab, a monoclonal antibody to an osteoclast differentiating factor, may be beneficial for some patients with glucocorticoid-induced osteoporosis.³⁴

To assess the efficacy of therapy, measuring bone mineral density at baseline and at 1 year of therapy is recommended. If density is stable or improved, then repeating the measurement at 2- to 3-year intervals is suggested.

Due to the adverse effects of long-term use of glucocorticoids and high rates of relapse, there is a pressing need for medications that are more efficacious and less toxic to treat GCA.

The European League Against Rheumatism, in its 2009 management guidelines for large-vessel vasculitis, recommend using an adjunctive immunosuppressant agent.¹⁹ In the case of GCA, they recommend using methotrexate 10 to 15 mg/week, which has shown modest evidence of reducing the relapse rate and lowering the cumulative doses of glucocorticoids needed.^35,36

Studies of tumor necrosis factor inhibitors and abatacept have not yielded significant reductions in the relapse rate or decreased cumulative doses of prednisone.^37,38

Advances in treatment for GCA have stagnated, but recent trials^39,40 have evaluated the IL-6 receptor alpha inhibitor tocilizumab, given the central role of IL-6 in the pathogenesis of GCA. Case reports have revealed rapid induction and maintenance of remission in GCA using tocilizumab.^41,42

Villiger et al³⁹ performed a randomized, placebo-controlled trial to study the efficacy and safety of tocilizumab in induction and maintenance of disease remission in 30 patients with newly diagnosed GCA. The primary outcome, complete remission at 12 weeks, was achieved in 85% of patients who received tocilizumab plus tapered prednisolone, compared with 40% of patients who received placebo plus tapering prednisolone. The tocilizumab group also had favorable results in secondary outcomes including relapse-free survival at 52 weeks, time to first relapse after induction of remission, and cumulative dose of prednisolone.

The GiACTA trial. Stone et al⁴⁰ studied the effect of tocilizumab on rates of relapse during glucocorticoid tapering in 251 GCA patients over the course of 52 weeks. Patients were randomized in a 2:1:1:1 ratio to 4 treatment groups:

• Tocilizumab weekly plus prednisone, with prednisone tapered over 26 weeks
• Tocilizumab every other week plus prednisone tapered over 26 weeks
• Placebo plus prednisone tapered over 26 weeks
• Placebo plus prednisone tapered over 52 weeks.

The primary outcome was the rate of sustained glucocorticoid-free remission at 52 weeks. Secondary outcomes included the remission rate, the cumulative glucocorticoid dose, and safety measures. At 52 weeks, the rates of sustained remission were:

• 56% with tocilizumab weekly
• 53% with tocilizumab every other week
• 14% with placebo plus 26-week prednisone taper
• 18% with placebo plus 52-week taper.

Differences between the active treatment groups and the placebo groups were statistically significant (P < .001).

The cumulative dose of prednisone in tocilizumab recipients was significantly less than in placebo recipients. Rates of adverse events were similar. Ultimately, the study showed that tocilizumab, either weekly or every other week, was more effective than prednisone alone at sustaining glucocorticoid-free remission in patients with GCA.

However, the study also raised questions about tocilizumab’s toxic effect profile and its  long-term efficacy, as well as who are the optimal candidates for this therapy. Data on long-term use of tocilizumab are primarily taken from its use in rheumatoid arthritis.⁴³ As of this writing, Stone et al are conducting an open-label trial to help provide long-term safety and efficacy data in patients with GCA. In the meantime, we must extrapolate data from the long-term use of tocilizumab in rheumatoid arthritis.

Tocilizumab and lower gastrointestinal tract perforation

One of the major adverse effects of long-term use of tocilizumab is lower gastrointestinal tract perforation.

Xie et al,⁴⁴ in 2016, reported that the risk of perforation in patients on tocilizumab for rheumatoid arthritis was more than 2 times higher than in patients taking a tumor necrosis factor inhibitor. However, the absolute rates of perforation were low overall,  roughly 1 to 3 per 1,000 patient-years in the tocilizumab group. Risk factors for perforation included older age, history of diverticulitis or other gastrointestinal tract condition, and prednisone doses of 7.5 mg or more a day.

Does tocilizumab prevent blindness?

Another consideration is that tocilizumab may not prevent optic neuropathy. In the GiACTA trial, 1 patient in the group receiving tocilizumab every other week developed optic neuropathy.⁴⁰ Prednisone had been completely tapered off at the time, and the condition resolved when glucocorticoids were restarted. Thus, it is unknown if tocilizumab would be effective on its own without concomitant use of glucocorticoids.

Vision loss is one of the most severe complications of GCA, and it is still unclear whether tocilizumab can prevent vision loss in GCA. Also, we still have no data on the effect of tocilizumab on histopathologic findings, and whether biopsy yield diminishes over time. We hope future studies will help guide us in this regard.

No guidelines on tocilizumab yet

Clinical guidelines on the appropriate use of tocilizumab in GCA are lacking. The American College of Rheumatology and the European League Against Rheumatism have yet to publish updated guidelines with comments on use of tocilizumab. Therefore, it is unclear if tocilizumab is a first-line treatment in GCA, as its efficacy alone without glucocorticoids and its long-term safety in GCA patients have not been studied.

Treatment with tocilizumab should be individualized; it should be considered in patients who have had adverse effects from glucocorticoids, and in patients who experience a flare or cannot have their glucocorticoid dose lowered to an appropriate range.

The optimal duration of tocilizumab therapy is also unknown. However, using the GiACTA study as a rough guide, we try to limit its use to 1 year until additional data are available.

Patients on IL-6 inhibition may have suppressed C-reactive protein regardless of disease activity.⁴³ Therefore, this laboratory value may not be reliable in determining active disease in patients on tocilizumab.

The GiACTA trial has shown an impressive improvement in the relapse-free remission period in patients with GCA taking tocilizumab. However, much work needs to be done to define the safety of this medication and determine which patients should be started on it. In the meantime, we recommend starting high-dose glucocorticoid therapy as soon as the diagnosis of GCA is suspected. In patients who do not tolerate glucocorticoids or whose disease flares during glucocorticoid taper, we recommend starting treatment with tocilizumab either once a week or every other week for at least 1 year.

For millions of couples, a primary care physician may be the first point of contact for fertility concerns. Statistics from the US Centers for Disease Control and Prevention indicate that 12% of women ages 15 to 44 received fertility services from 2006 to 2010.¹ Despite seeking services, most couples requested only advice or testing rather than treatments such as ovulation-inducing medications, surgery, or, rarely, assisted reproductive technologies including in vitro fertilization. Based on these data, primary care physicians are in a unique position to offer guidance and provide fertility services in most circumstances without the need for referral.

This article reviews the answers to questions patients frequently ask, and outlines a practical framework for the evaluation and management of the infertile couple.

MANY PATIENTS SEEK INFORMATION

At least 1 million medical visits per year are for women seeking help in becoming pregnant, with the number increasing over the last several decades.¹ Reasons for the increase include delayed childbearing and the effects of aging on the female reproductive system (“female reproductive aging”), as well as the availability of increasingly effective treatments for infertility.

While the prevalence of infertility in US couples is widely quoted as 10% to 15%,² there is no estimate for the number of fertility-related questions patients routinely pose to care providers. These questions often relate to coital timing, use of lubricants, positioning, and the use of fertility trackers and ovulation predictors.

A 2017 study of women with 12 months of infertility found that only 8% sought subspecialist care vs care from a general physician or provider, indicating that generalists are most often the first point of contact.³ The majority (92%) of women responding to a survey regarding fertility-awareness education indicated a preference for immediate counseling from their general practitioner.⁴

Although some healthcare providers may consider infertility simply a quality-of-life issue, the World Health Organization classifies it as a disease, and as such it warrants identification, assessment, and intervention.⁵ Further, patients with infertility are known to experience considerable psychological distress related to their condition. In a comparison study, women with infertility experienced levels of psychological distress similar to the level in patients with cancer and patients with chronic medical illness.⁶

In the current era, general practitioners and women’s health specialists may also now address patients’ questions about reproductive aging and egg-freezing, which is now an established technology.⁷

FAILURE TO CONCEIVE AFTER 1 YEAR

As women approach age 40, the potential for fertility decreases rapidly and significantly. Women in their later 30s have only half the fertility of women in their early 20s.¹⁰ Misperceptions of aging and female fertility have been fueled by widely publicized celebrity births from women in their 40s and even 50s, without disclosing the use of frozen or donor eggs. This unfortunate fact affects women actively trying to conceive as well as women who wish to delay childbearing due to lack of a partner or for personal or professional reasons. Primary care physicians should be able to provide counseling relevant to female reproductive aging and make suitable and timely referrals for fertility preservation if indicated.

AN EMOTIONAL ISSUE

In approaching the couple with infertility, it is important to proceed with great sensitivity for the socioemotional context of this diagnosis. For both the male and female partner, infertility can be highly stigmatizing, and can be viewed as a personal or relationship failure.

Couples should be encouraged to ask embarrassing or uncomfortable questions. Although this may not be feasible in many circumstances, interviews should ideally be conducted with both partners individually as well as together, to allow sensitive issues to be shared. In some cases, a partner may be unaware of a history of a sexually transmitted infection, a prior abortion, the use of testosterone supplements or medications to enhance male sexual performance, or a vasectomy or tubal ligation during a previous relationship.

It is not unusual that the anxiety of infertility can cause decreased libido and sexual and erectile dysfunction. These issues can further complicate the problem of conceiving, and couples counseling is not uncommonly required.11 Patients are often reassured to know that they are not alone in their diagnosis.

Before embarking on a series of tests, the primary care physician can carefully evaluate for clues that may guide the diagnostic evaluation. The approach can be individualized based on the patient’s age, duration of subfertility (ie, how long they have been trying to become pregnant), and risk factors. But as a general rule, regardless of age, couples who have been trying to conceive for more than 1 year should be encouraged to pursue additional testing.

Because each month presents a new cycle of hope (often followed by intense disappointment), the prevailing sentiment to “just give it a little more time” must be countered by education and counseling. The primary care physician must increase awareness that lack of pregnancy in the stated time periods is a compelling reason for evaluation.

History-taking in the infertile couple should include a complete gynecologic and menstrual history. A history of sexually transmitted diseases that can cause tubal disease, such as gonorrhea and Chlamydia, is significant. Both partners should be assessed for a history of prior conceptions, past medical or surgical problems, medications, and exposures to environmental toxins including alcohol, tobacco, and drugs.

A detailed physical examination can provide clues to the cause of subfertility, especially if signs of obesity, androgen excess, or insulin resistance are present.

QUESTIONS OFTEN ASKED BY COUPLES TRYING TO CONCEIVE

Clinicians are frequently asked questions related to sexual practices and lifestyle in relation to fertility and should be comfortable responding to questions in these areas.

Does frequent ejaculation ‘use up’ my sperm?

Men should be reassured that frequent ejaculations do not decrease sperm counts; even daily ejaculation does not deplete the concentration of sperm. Male partners can be reassured that “saving up” is not an effective strategy; in fact, abstinence periods of greater than 5 days can adversely affect semen parameters.¹²

How often should we have sex?

Infrequent intercourse (< 1 time per week) reduces the monthly chance of conceiving.¹³ There does not seem to be a significant improvement in fecundity with daily intercourse vs intercourse on alternate days. Strict schedules surrounding intercourse may increase stress, and reassurance should be offered that intercourse need not be regimented. Every 1 to 2 days should suffice.

Are any sexual positions better for conception?

There is no evidence that particular coital positioning or remaining supine after intercourse improves fertility. Sperm can be found within the endocervix within seconds of ejaculation, irrespective of sexual position.

What is the window of fertility?

There is good evidence that the fertile window lasts approximately 6 days and closes after ovulation.^13,14 Women with regular cycles can determine their typical day of ovulation based on menstrual tracking. Intercourse should begin about 6 days before ovulation and should continue every 1 to 2 days for 1 week to fully capture this window.

Should we change our lifestyle?

Couples seeking pregnancy should be advised to limit alcohol and caffeine use, completely abstain from cigarette smoking or illicit drug use, and maintain a healthy body mass index.

Very few data exist to support particular diets or supplements to promote fertility, including antioxidants and herbal remedies. Folic acid supplementation is recommended in all women attempting to conceive to reduce the incidence of birth defects.

Do lubricants reduce fertility?

Although there seem to be no differences in fecundity rates in couples using commercial lubricants, most water-based lubricants are best avoided in couples with infertility, as adverse effects on sperm have been demonstrated in vitro.¹⁵ If lubrication is needed, couples may try mineral oil, canola oil, or hydroxyetyl­cellulose-based lubricants (eg, Pre-seed).

Do fertility trackers work?

Many couples with primary infertility perceive that coital timing is critical and worry that their infertility is due to poorly timed intercourse; in fact, this is seldom the case.

Despite widespread marketing of urinary luteinizing hormone (LH) detection kits and electronic trackers and monitors, there is no clear evidence that these methods improve monthly rates of conception.

Women with a regular menstrual cycle should be encouraged to take notice when their cervical mucus appears clear and slippery (a sign of ovulation). Not all women are able to detect these fluctuations; however, for those who can, observing cervical mucus changes appears to be equivalent or superior to predictor kits in predicting conception.¹⁶

A PRACTICAL FRAMEWORK FOR EVALUATING THE INFERTILE COUPLE

To assess for the common factors identified in Table 1, the essential investigation of the infertile couple includes:

• Semen analysis
• Confirmation of ovulation
• Hysterosalpingography.

Consideration can also be given to ovarian reserve testing in women at risk of diminished ovarian reserve. The above investigation can be performed simultaneously to allow for prompt identification of any issues. Further, infertility is often a combination of problems (eg, anovulation in the woman together with a problem in the man), so an incomplete evaluation may overlook a coexisting diagnosis and lead to delays in treatment and pregnancy.

Tests that are no longer typically used in clinical practice are outlined in Table 2.

Ovarian reserve refers to the number of fertilizable oocytes that remain in the ovary. This reserve changes over time, and changes occur rapidly as women approach and enter their 30s. Though not the case in men, the age of the female partner is an independent risk factor for infertility. This discrepancy is due to loss of ovarian reserve, chromosome abnormalities in embryos, and the development of medical conditions with age that affect fertility.

Testing for ovarian reserve does not necessarily predict an overall inability to achieve a live birth,¹⁷ but it can predict response to exogenous gonadotropins and, to some degree, the chance for successful pregnancy with assisted reproductive technology.¹⁸

The ASRM states that testing for diminished ovarian reserve may provide useful information in women who have had a previous poor response to gonadotropins and in women planning assisted reproductive technology.¹⁹ The ASRM also indicates that the following are risk factors for diminished ovarian reserve, and clinicians may target the assessment accordingly¹⁹:

• Age 35 or older
• History of exposure to chemotherapy or pelvic radiation
• Family history of early menopause (age < 40)
• History of ovarian surgery
• Unexplained or idiopathic fertility.

Although several tests of ovarian reserve exist, either an antimullerian hormone (AMH) test or a combined cycle day-3 follicle-stimulating hormone (FSH) and estradiol level are the 2 tests commonly used in clinical practice. Antral follicle counts are an ultrasonographic measure used by infertility specialists but rarely by primary care physicians. Assays such as inhibin are rarely ordered and have limited clinical utility.

The AMH test

Many reproductive endocrinologists rely on the AMH level as a single test of ovarian reserve as it is easy to obtain, has a relatively low cost, and offers stable results. AMH is produced by the granulosa cells of the ovarian antral follicles and is readily detected in serum samples.

Conveniently for the clinician, levels of this hormone remain stable throughout the menstrual cycle and therefore can be tested on any day and at any time of day. Lower serum AMH levels (< 1 ng/mL) have been shown to correspond to diminished ovarian stimulation with gonadotropins as well as decreased embryo quality and poor pregnancy outcomes with assisted reproductive technology.¹⁹

Nevertheless, despite overall stability, AMH levels can be falsely lowered in women using exogenous hormones or with a diagnosis of hypogonadotropic hypogonadism. Levels may be higher than expected in women with polycystic ovary syndrome due to higher numbers of antral and preantral follicles in the polycystic ovary.

The day-3 follicle-stimulating hormone test

FSH and 17-beta estradiol testing can be ordered in combination to assess function of the hypothalamic-pituitary-ovarian axis on day 3 of the menstrual cycle. There is some flexibility, however, and testing obtained on cycle day 2, 3, or 4 yields equivalent results.

Although there are no strict cutoffs, FSH levels that appear elevated (> 10–20 IU/L) are associated with lower chances of conceiving with in vitro fertilization in multiple studies.²⁰

The test is limited by levels that may fluctuate cycle to cycle, and reassuring test results do not necessarily indicate that a woman will achieve a pregnancy. Although a serum estradiol value alone is not a useful test, it can be used in combination with day-3 FSH to screen for diminished ovarian reserve.

As premature recruitment of a follicle can cause an early follicular rise in estradiol, FSH may be falsely suppressed on day 3. For example, a “normal” day-3 FSH combined with an elevated day-3 17-beta estradiol level of 60 to 80 pg/mL is associated with a poor response to medical treatments for infertility.

Female reproductive aging

Aging of the female reproductive system is a central threat to fertility, and prompt assessment and referral are warranted for women age 35 or older who have been trying to conceive for more than 6 months. The ASRM recommends that women over age 40 be evaluated immediately.²¹

A prevailing misconception is that regular menstrual cycles correspond with normal fertility. In reality, women lose their ability to achieve a healthy live birth in the 5 to 10 years preceding menopause. Although all women who do not desire pregnancy should still use appropriate contraception to avoid unintended pregnancy, women who do desire pregnancy should be aware of these physiologic changes.

Classic age-related changes in ovarian reserve are accompanied by a steep rise in aneuploidy and miscarriage risk.²² This is particularly relevant as women increasingly delay childbearing in modern society. Loss of fertility begins at 32 and abruptly accelerates at age 37²¹; this fact is poorly communicated to and understood by patients. In a 2018 study of highly educated women, most respondents failed to identify that 45-year-old women can only rarely achieve a successful pregnancy.²³

In recent decades, the percentage of women who delay childbearing until after age 35 has steadily increased. There is a widespread misconception that fertility treatments and assisted reproductive technology can compensate for female reproductive aging. Primary care physicians can play a central role in reminding couples that age remains the single greatest predictor of natural fertility and the chance of success with assisted reproduction.

Further, for women who desire future fertility and are without a partner, primary care physicians can counsel them regarding the availability of donor insemination or egg freezing. Studies confirm that women want clinicians to initiate information on reproductive health, and 80% of women undergoing elective egg-freezing for fertility preservation wished that they had done so at an earlier age.^24,25

Women with endometriosis, fibroids, or a history of tubal disease have impaired fecundity. Pelvic imaging is an essential component of their evaluation. Although hysterosalpingography is the mainstay of tubal assessment, in select cases ultrasonography or hysteroscopy may be indicated.

Tubal disease and hysterosalpingography

Tubal disease remains one of the most common causes of infertility in the US females. In most cases, tubal damage is secondary to pelvic inflammatory disease from infection with gonorrhea or Chlamydia, or both.

Rates of confirmed tubal-factor infertility have been shown to increase with both the severity of the infection and the number of past infections.²⁶ In a landmark study, 1 episode of pelvic inflammatory disease was associated with a 12% risk of tubal-factor infertility, whereas 3 infections carried a risk as high as 54%. Pelvic inflammatory disease is also known to increase the risk of ectopic pregnancy.

To assess tubal patency, hysterosalpingography, a radiographic procedure, is typically performed using fluoroscopy and injected contrast material. Some centers may offer sonohysterography as a radiation-free alternative, depending on sonographic skill and experience. Both tests are best scheduled in the window between the end of menstrual bleeding and ovulation. In practice, patients with regular cycles can typically schedule hysterosalpingography between cycle days 5 and 12.

In patients with known hydrosalpinx (a distended fallopian tube due to blockage) or a history of pelvic infection, doxycycline should be given before the procedure.²⁷ Patients with demonstrated hydrosalpinx on hysterosalpingography should receive doxycycline 100 mg twice daily for 5 days to prevent posthysterosalpingography pelvic inflammatory disease.²⁷ Patients with active pelvic or cervical infection should not undergo hysterosalpingography .

Women with confirmed hydrosalpinx or tubal obstruction can be referred for laparoscopy. Gynecologic surgeons will plan their approach based on whether the obstruction is proximal (near the uterus) or distal (near the ovary) as well as whether hydrosalpinx, abnormal tubal architecture, salpingitis isthmica nodosa, or peritubal adhesions are noted. Tubal surgery can be effective in mild cases of tubal disease; however, as in vitro fertilization is becoming more effective, patients with moderate or severe tubal disease are increasingly being referred directly for assisted reproductive technology. Before undergoing assisted reproductive technology, hydrosalpinx will need to be addressed, as it can decrease clinical pregnancy rates with in vitro fertilization.

Endometriosis

Endometriosis is found in 21% to 47% of women with subfertility²⁸ and commonly causes pain, ovarian cysts, and tubal disease. There is often a delay of 7 to 8 years for diagnosis due to the misapprehension that severe dysmenorrhea is normal. Women with an affected first-degree family member are at substantially increased risk.

Although endometriosis is commonly thought to result from reflux of endometrial tissue into the peritoneal cavity with menses, there are multiple proposed mechanisms for the disease.²⁹ The pathogenesis of endometriosis is enigmatic, and there are likely as yet undetermined immunologic and genetic predispositions that confer increased risk.

Common symptoms of endometriosis are dysmenorrhea, dyspareunia, and pelvic pain, and these are sometimes accompanied by bowel and bladder symptoms. Pelvic examination classically demonstrates an immobile uterus and uterosacral nodularity; palpation of these nodules can elicit pain. On laparoscopy, endometriosis can range from minimal to severe; however, stage of endometriosis correlates poorly with reported symptoms.³⁰

Consideration of surgery is based on clinical history, results of the pelvic examination, and possible findings on ultrasonography or hysterosalpingography. Although positive findings on imaging can support a plan for intervention, endometriosis is largely a peritoneal disease, and evidence of tubal damage or ovarian cysts is rarely evident on ultrasonography. In women with menstrual complaints (eg, dysmenorrhea, heavy menstrual bleeding, abnormal uterine bleeding) and a history of infertility, ultrasonography may be useful in determining the presence of uterine pathology such as ovarian cyst or endometrioma, large hydrosalpinx, polyp, or substantial fibroid burden—any of which may have a significant impact on female fertility.

In the absence of a reliable blood test or imaging study, the gold standard for the diagnosis of endometriosis continues to be laparoscopic surgery. Hormonal treatments for endometriosis symptoms are not effective in improving infertility and will preclude pregnancy. Laparoscopic surgery is more successful in improving pregnancy rates in women with advanced disease: pregnancy rates after surgery can be as high as 60% in women with ovarian endometriomas but are significantly lower in women with removal of minimal to mild disease.^30,31 Women over age 35 or who present with low ovarian reserve and whose male partner has semen abnormalities should consider moving directly to assisted reproductive technology rather than pursuing endometriosis surgery.

Although male partners are often highly engaged in and supportive of the fertility evaluation, some are reluctant to undergo testing, and some wish to undergo semen analysis only after female factors have been ruled out. Our practice is to evaluate male factors immediately, due to the high contribution of male factors (up to 40% of cases) either alone or in combination with female factors.³²

Men at particularly increased risk of semen abnormalities include those with a history of chemotherapy or radiation or exposure to toxins (eg, environmental exposures, alcohol, tobacco, illicit substances) and prescribed medications.

At a minimum, for the male partner, a reproductive history should be taken and a semen analysis ordered. Men should be directly queried about testosterone use, as this often-used anabolic steroid hormone can severely impair sperm production.

Men who have low sperm counts, motility, or morphology scores based on World Health Organization criteria should not be deemed “infertile,” as there is significant variation from one analysis to the next, and normal fertility has been reported in men with notably low sperm counts. Particular caution should be exercised in interpreting low morphology scores in men with normal counts and motility, as this parameter appears to have the least prognostic value in this context. Men with abnormal semen analyses should be referred to a specialist for further urologic evaluation and treatment.

Treatments for male factor infertility include surgery, steroid hormones, and possibly intrauterine insemination or assisted reproductive technology. In even the most challenging cases, male infertility is now largely treatable with intracytoplasmic sperm injection with assisted reproductive technology. While most advances in in vitro fertilization have been evolutionary, intracytoplasmic sperm injection was revolutionary. This breakthrough technology allows a single sperm to be injected directly into the oocyte. Sperm for this procedure can be obtained either from the ejaculate or from microsurgical testicular sperm extraction.

ANOVULATION

A thorough menstrual history can be informative, as most females of reproductive age have a fairly predictable 25-to-35-day monthly menstrual cycle. Women presenting with menstrual charting with this pattern do not require laboratory confirmation of ovulation. Basal body temperatures are rarely used currently, as they are time-consuming, can induce stress, and are confirmatory rather than predictive of ovulation. Endometrial biopsy for endometrial “dating” is no longer performed in infertile women.

If laboratory confirmation is desired, LH kit testing with a commercially available test or a luteal phase serum progesterone obtained 7 days after suspected ovulation can be obtained. A serum progesterone level higher than 3 ng/mL is indicative of ovulation.¹⁹ Due to the notable fluctuations in ovulatory-appearing progesterone levels over several hours, caution must be taken in interpreting a lower-normal level as indicative of a luteal phase insufficiency.

Polycystic ovary syndrome

Polycystic ovary syndrome is important to understand because it is a metabolic condition that predisposes patients to a variety of health risks. Along with gynecologic consequences such as infertility, abnormal uterine bleeding, and endometrial pathology, it is often accompanied by alterations in glucose and lipid metabolism, obesity, hypertension, and cardiovascular disease.³⁵

Despite its name, the syndrome does not involve the presence of classic ovarian cysts. In fact, the cysts associated with polycystic ovary syndrome are dense accumulations of antral follicles arranged peripherally in the ovarian cortex; they should not be removed surgically as they represent the ovarian reserve.

Although ovaries that appear polycystic on transvaginal ultrasonography are often associated with the syndrome, they are not invariably present and are not absolutely required for the diagnosis of polycystic ovary syndrome based on the most commonly used criteria.³⁵ Several diagnostic criteria have been proposed for polycystic ovary syndrome and its phenotypes. The 2003 revised Rotterdam criteria require 2 out of the following 3 features:

• Oligo-ovulation or anovulation
• Evidence of hyperandrogenism, whether clinical (eg, acne or hirsutism) or based on laboratory testing
• Polycystic-appearing ovaries on ultrasonography.

There is no single test that can diagnose the disease. Although polycystic ovary syndrome is often characterized by elevated LH levels, LH–FSH ratios, and fasting insulin levels, these are not diagnostic criteria. The diagnosis hinges on excluding other causes of anovulation such as thyroid disease, hyperprolactinemia, 21-hydroxylase deficiency, androgen-producing neoplasms, and Cushing syndrome. In addition to checking serum testosterone levels, irregular menstrual cycles and infertility should be assessed at minimum with measurement of TSH, prolactin, and day-3 FSH. Obese women should be screened for metabolic syndrome, which should include an assessment of impaired glucose tolerance with a 2-hour oral glucose tolerance test.³⁶

Women with polycystic ovary syndrome are known to have insulin resistance, which is difficult to assess and is independent of their body mass index.³⁷ They often report a family history of diabetes or a personal history of gestational diabetes or giving birth to infants who are large for gestational age. Although most women diagnosed with insulin resistance and anovulatory infertility will not yet have a diagnosis of diabetes, women with polycystic ovary syndrome are 3 to 7 times more likely to develop type 2 diabetes later in life³⁷ and are at increased risk of lipid abnormalities, cardiovascular disease, and stroke. Therefore, interventions to address the compounding influences of polycystic ovary syndrome and obesity can improve fertility outcomes and help prevent long-term sequelae that accompany the syndrome.

Treatment for women with polycystic ovary syndrome attempting conception includes lifestyle modifications, medications for ovulation induction, and possible use of insulin sensitizers. Metformin alone is not effective as a single agent for achieving pregnancy.³⁸ Diet, weight loss, and exercise can have dramatic effects on ovulation and pregnancy and should be highly encouraged.

Ovulation induction is often required in anovulatory women, either in combination with lifestyle modifications or used subsequently if modifications are not successful. Letrozole is advised as the initial agent in women with obesity and anovulatory infertility rather than clomiphene citrate; a side-by-side comparison demonstrated increased rates of ovulation and live birth with letrozole.³⁹

Once-daily letrozole 2.5 mg or clomiphene 50 mg can be prescribed for 5 days, from cycle days 3 through 7 to cycle days 5 through 9. If this initial dosing fails to result in ovulation, the dose can be increased. Known adverse effects are hot flashes, headaches, ovarian cysts, and increased risk of multiple gestation.

Metformin should be considered as an adjunct to fertility treatments in women with polycystic ovary syndrome, especially those with obesity or impaired glucose tolerance, or if there is no response to standard ovulation induction.

Ovarian hyperstimulation syndrome (cystic enlargement of the ovaries with potentially dangerous fluid and electrolyte imbalances) can occur in women with polycystic ovary syndrome; however, it rarely occurs with oral medications.

For millions of couples, a primary care physician may be the first point of contact for fertility concerns. Statistics from the US Centers for Disease Control and Prevention indicate that 12% of women ages 15 to 44 received fertility services from 2006 to 2010.¹ Despite seeking services, most couples requested only advice or testing rather than treatments such as ovulation-inducing medications, surgery, or, rarely, assisted reproductive technologies including in vitro fertilization. Based on these data, primary care physicians are in a unique position to offer guidance and provide fertility services in most circumstances without the need for referral.

This article reviews the answers to questions patients frequently ask, and outlines a practical framework for the evaluation and management of the infertile couple.

MANY PATIENTS SEEK INFORMATION

At least 1 million medical visits per year are for women seeking help in becoming pregnant, with the number increasing over the last several decades.¹ Reasons for the increase include delayed childbearing and the effects of aging on the female reproductive system (“female reproductive aging”), as well as the availability of increasingly effective treatments for infertility.

While the prevalence of infertility in US couples is widely quoted as 10% to 15%,² there is no estimate for the number of fertility-related questions patients routinely pose to care providers. These questions often relate to coital timing, use of lubricants, positioning, and the use of fertility trackers and ovulation predictors.

A 2017 study of women with 12 months of infertility found that only 8% sought subspecialist care vs care from a general physician or provider, indicating that generalists are most often the first point of contact.³ The majority (92%) of women responding to a survey regarding fertility-awareness education indicated a preference for immediate counseling from their general practitioner.⁴

Although some healthcare providers may consider infertility simply a quality-of-life issue, the World Health Organization classifies it as a disease, and as such it warrants identification, assessment, and intervention.⁵ Further, patients with infertility are known to experience considerable psychological distress related to their condition. In a comparison study, women with infertility experienced levels of psychological distress similar to the level in patients with cancer and patients with chronic medical illness.⁶

In the current era, general practitioners and women’s health specialists may also now address patients’ questions about reproductive aging and egg-freezing, which is now an established technology.⁷

FAILURE TO CONCEIVE AFTER 1 YEAR

As women approach age 40, the potential for fertility decreases rapidly and significantly. Women in their later 30s have only half the fertility of women in their early 20s.¹⁰ Misperceptions of aging and female fertility have been fueled by widely publicized celebrity births from women in their 40s and even 50s, without disclosing the use of frozen or donor eggs. This unfortunate fact affects women actively trying to conceive as well as women who wish to delay childbearing due to lack of a partner or for personal or professional reasons. Primary care physicians should be able to provide counseling relevant to female reproductive aging and make suitable and timely referrals for fertility preservation if indicated.

AN EMOTIONAL ISSUE

In approaching the couple with infertility, it is important to proceed with great sensitivity for the socioemotional context of this diagnosis. For both the male and female partner, infertility can be highly stigmatizing, and can be viewed as a personal or relationship failure.

Couples should be encouraged to ask embarrassing or uncomfortable questions. Although this may not be feasible in many circumstances, interviews should ideally be conducted with both partners individually as well as together, to allow sensitive issues to be shared. In some cases, a partner may be unaware of a history of a sexually transmitted infection, a prior abortion, the use of testosterone supplements or medications to enhance male sexual performance, or a vasectomy or tubal ligation during a previous relationship.

It is not unusual that the anxiety of infertility can cause decreased libido and sexual and erectile dysfunction. These issues can further complicate the problem of conceiving, and couples counseling is not uncommonly required.11 Patients are often reassured to know that they are not alone in their diagnosis.

Before embarking on a series of tests, the primary care physician can carefully evaluate for clues that may guide the diagnostic evaluation. The approach can be individualized based on the patient’s age, duration of subfertility (ie, how long they have been trying to become pregnant), and risk factors. But as a general rule, regardless of age, couples who have been trying to conceive for more than 1 year should be encouraged to pursue additional testing.

Because each month presents a new cycle of hope (often followed by intense disappointment), the prevailing sentiment to “just give it a little more time” must be countered by education and counseling. The primary care physician must increase awareness that lack of pregnancy in the stated time periods is a compelling reason for evaluation.

History-taking in the infertile couple should include a complete gynecologic and menstrual history. A history of sexually transmitted diseases that can cause tubal disease, such as gonorrhea and Chlamydia, is significant. Both partners should be assessed for a history of prior conceptions, past medical or surgical problems, medications, and exposures to environmental toxins including alcohol, tobacco, and drugs.

A detailed physical examination can provide clues to the cause of subfertility, especially if signs of obesity, androgen excess, or insulin resistance are present.

QUESTIONS OFTEN ASKED BY COUPLES TRYING TO CONCEIVE

Clinicians are frequently asked questions related to sexual practices and lifestyle in relation to fertility and should be comfortable responding to questions in these areas.

Does frequent ejaculation ‘use up’ my sperm?

Men should be reassured that frequent ejaculations do not decrease sperm counts; even daily ejaculation does not deplete the concentration of sperm. Male partners can be reassured that “saving up” is not an effective strategy; in fact, abstinence periods of greater than 5 days can adversely affect semen parameters.¹²

How often should we have sex?

Infrequent intercourse (< 1 time per week) reduces the monthly chance of conceiving.¹³ There does not seem to be a significant improvement in fecundity with daily intercourse vs intercourse on alternate days. Strict schedules surrounding intercourse may increase stress, and reassurance should be offered that intercourse need not be regimented. Every 1 to 2 days should suffice.

Are any sexual positions better for conception?

There is no evidence that particular coital positioning or remaining supine after intercourse improves fertility. Sperm can be found within the endocervix within seconds of ejaculation, irrespective of sexual position.

What is the window of fertility?

There is good evidence that the fertile window lasts approximately 6 days and closes after ovulation.^13,14 Women with regular cycles can determine their typical day of ovulation based on menstrual tracking. Intercourse should begin about 6 days before ovulation and should continue every 1 to 2 days for 1 week to fully capture this window.

Should we change our lifestyle?

Couples seeking pregnancy should be advised to limit alcohol and caffeine use, completely abstain from cigarette smoking or illicit drug use, and maintain a healthy body mass index.

Very few data exist to support particular diets or supplements to promote fertility, including antioxidants and herbal remedies. Folic acid supplementation is recommended in all women attempting to conceive to reduce the incidence of birth defects.

Do lubricants reduce fertility?

Although there seem to be no differences in fecundity rates in couples using commercial lubricants, most water-based lubricants are best avoided in couples with infertility, as adverse effects on sperm have been demonstrated in vitro.¹⁵ If lubrication is needed, couples may try mineral oil, canola oil, or hydroxyetyl­cellulose-based lubricants (eg, Pre-seed).

Do fertility trackers work?

Many couples with primary infertility perceive that coital timing is critical and worry that their infertility is due to poorly timed intercourse; in fact, this is seldom the case.

Despite widespread marketing of urinary luteinizing hormone (LH) detection kits and electronic trackers and monitors, there is no clear evidence that these methods improve monthly rates of conception.

Women with a regular menstrual cycle should be encouraged to take notice when their cervical mucus appears clear and slippery (a sign of ovulation). Not all women are able to detect these fluctuations; however, for those who can, observing cervical mucus changes appears to be equivalent or superior to predictor kits in predicting conception.¹⁶

A PRACTICAL FRAMEWORK FOR EVALUATING THE INFERTILE COUPLE

To assess for the common factors identified in Table 1, the essential investigation of the infertile couple includes:

• Semen analysis
• Confirmation of ovulation
• Hysterosalpingography.

Consideration can also be given to ovarian reserve testing in women at risk of diminished ovarian reserve. The above investigation can be performed simultaneously to allow for prompt identification of any issues. Further, infertility is often a combination of problems (eg, anovulation in the woman together with a problem in the man), so an incomplete evaluation may overlook a coexisting diagnosis and lead to delays in treatment and pregnancy.

Tests that are no longer typically used in clinical practice are outlined in Table 2.

Ovarian reserve refers to the number of fertilizable oocytes that remain in the ovary. This reserve changes over time, and changes occur rapidly as women approach and enter their 30s. Though not the case in men, the age of the female partner is an independent risk factor for infertility. This discrepancy is due to loss of ovarian reserve, chromosome abnormalities in embryos, and the development of medical conditions with age that affect fertility.

Testing for ovarian reserve does not necessarily predict an overall inability to achieve a live birth,¹⁷ but it can predict response to exogenous gonadotropins and, to some degree, the chance for successful pregnancy with assisted reproductive technology.¹⁸

The ASRM states that testing for diminished ovarian reserve may provide useful information in women who have had a previous poor response to gonadotropins and in women planning assisted reproductive technology.¹⁹ The ASRM also indicates that the following are risk factors for diminished ovarian reserve, and clinicians may target the assessment accordingly¹⁹:

• Age 35 or older
• History of exposure to chemotherapy or pelvic radiation
• Family history of early menopause (age < 40)
• History of ovarian surgery
• Unexplained or idiopathic fertility.

Although several tests of ovarian reserve exist, either an antimullerian hormone (AMH) test or a combined cycle day-3 follicle-stimulating hormone (FSH) and estradiol level are the 2 tests commonly used in clinical practice. Antral follicle counts are an ultrasonographic measure used by infertility specialists but rarely by primary care physicians. Assays such as inhibin are rarely ordered and have limited clinical utility.

The AMH test

Many reproductive endocrinologists rely on the AMH level as a single test of ovarian reserve as it is easy to obtain, has a relatively low cost, and offers stable results. AMH is produced by the granulosa cells of the ovarian antral follicles and is readily detected in serum samples.

Conveniently for the clinician, levels of this hormone remain stable throughout the menstrual cycle and therefore can be tested on any day and at any time of day. Lower serum AMH levels (< 1 ng/mL) have been shown to correspond to diminished ovarian stimulation with gonadotropins as well as decreased embryo quality and poor pregnancy outcomes with assisted reproductive technology.¹⁹

Nevertheless, despite overall stability, AMH levels can be falsely lowered in women using exogenous hormones or with a diagnosis of hypogonadotropic hypogonadism. Levels may be higher than expected in women with polycystic ovary syndrome due to higher numbers of antral and preantral follicles in the polycystic ovary.

The day-3 follicle-stimulating hormone test

FSH and 17-beta estradiol testing can be ordered in combination to assess function of the hypothalamic-pituitary-ovarian axis on day 3 of the menstrual cycle. There is some flexibility, however, and testing obtained on cycle day 2, 3, or 4 yields equivalent results.

Although there are no strict cutoffs, FSH levels that appear elevated (> 10–20 IU/L) are associated with lower chances of conceiving with in vitro fertilization in multiple studies.²⁰

The test is limited by levels that may fluctuate cycle to cycle, and reassuring test results do not necessarily indicate that a woman will achieve a pregnancy. Although a serum estradiol value alone is not a useful test, it can be used in combination with day-3 FSH to screen for diminished ovarian reserve.

As premature recruitment of a follicle can cause an early follicular rise in estradiol, FSH may be falsely suppressed on day 3. For example, a “normal” day-3 FSH combined with an elevated day-3 17-beta estradiol level of 60 to 80 pg/mL is associated with a poor response to medical treatments for infertility.

Female reproductive aging

Aging of the female reproductive system is a central threat to fertility, and prompt assessment and referral are warranted for women age 35 or older who have been trying to conceive for more than 6 months. The ASRM recommends that women over age 40 be evaluated immediately.²¹

A prevailing misconception is that regular menstrual cycles correspond with normal fertility. In reality, women lose their ability to achieve a healthy live birth in the 5 to 10 years preceding menopause. Although all women who do not desire pregnancy should still use appropriate contraception to avoid unintended pregnancy, women who do desire pregnancy should be aware of these physiologic changes.

Classic age-related changes in ovarian reserve are accompanied by a steep rise in aneuploidy and miscarriage risk.²² This is particularly relevant as women increasingly delay childbearing in modern society. Loss of fertility begins at 32 and abruptly accelerates at age 37²¹; this fact is poorly communicated to and understood by patients. In a 2018 study of highly educated women, most respondents failed to identify that 45-year-old women can only rarely achieve a successful pregnancy.²³

In recent decades, the percentage of women who delay childbearing until after age 35 has steadily increased. There is a widespread misconception that fertility treatments and assisted reproductive technology can compensate for female reproductive aging. Primary care physicians can play a central role in reminding couples that age remains the single greatest predictor of natural fertility and the chance of success with assisted reproduction.

Further, for women who desire future fertility and are without a partner, primary care physicians can counsel them regarding the availability of donor insemination or egg freezing. Studies confirm that women want clinicians to initiate information on reproductive health, and 80% of women undergoing elective egg-freezing for fertility preservation wished that they had done so at an earlier age.^24,25

Women with endometriosis, fibroids, or a history of tubal disease have impaired fecundity. Pelvic imaging is an essential component of their evaluation. Although hysterosalpingography is the mainstay of tubal assessment, in select cases ultrasonography or hysteroscopy may be indicated.

Tubal disease and hysterosalpingography

Tubal disease remains one of the most common causes of infertility in the US females. In most cases, tubal damage is secondary to pelvic inflammatory disease from infection with gonorrhea or Chlamydia, or both.

Rates of confirmed tubal-factor infertility have been shown to increase with both the severity of the infection and the number of past infections.²⁶ In a landmark study, 1 episode of pelvic inflammatory disease was associated with a 12% risk of tubal-factor infertility, whereas 3 infections carried a risk as high as 54%. Pelvic inflammatory disease is also known to increase the risk of ectopic pregnancy.

To assess tubal patency, hysterosalpingography, a radiographic procedure, is typically performed using fluoroscopy and injected contrast material. Some centers may offer sonohysterography as a radiation-free alternative, depending on sonographic skill and experience. Both tests are best scheduled in the window between the end of menstrual bleeding and ovulation. In practice, patients with regular cycles can typically schedule hysterosalpingography between cycle days 5 and 12.

In patients with known hydrosalpinx (a distended fallopian tube due to blockage) or a history of pelvic infection, doxycycline should be given before the procedure.²⁷ Patients with demonstrated hydrosalpinx on hysterosalpingography should receive doxycycline 100 mg twice daily for 5 days to prevent posthysterosalpingography pelvic inflammatory disease.²⁷ Patients with active pelvic or cervical infection should not undergo hysterosalpingography .

Women with confirmed hydrosalpinx or tubal obstruction can be referred for laparoscopy. Gynecologic surgeons will plan their approach based on whether the obstruction is proximal (near the uterus) or distal (near the ovary) as well as whether hydrosalpinx, abnormal tubal architecture, salpingitis isthmica nodosa, or peritubal adhesions are noted. Tubal surgery can be effective in mild cases of tubal disease; however, as in vitro fertilization is becoming more effective, patients with moderate or severe tubal disease are increasingly being referred directly for assisted reproductive technology. Before undergoing assisted reproductive technology, hydrosalpinx will need to be addressed, as it can decrease clinical pregnancy rates with in vitro fertilization.

Endometriosis

Endometriosis is found in 21% to 47% of women with subfertility²⁸ and commonly causes pain, ovarian cysts, and tubal disease. There is often a delay of 7 to 8 years for diagnosis due to the misapprehension that severe dysmenorrhea is normal. Women with an affected first-degree family member are at substantially increased risk.

Although endometriosis is commonly thought to result from reflux of endometrial tissue into the peritoneal cavity with menses, there are multiple proposed mechanisms for the disease.²⁹ The pathogenesis of endometriosis is enigmatic, and there are likely as yet undetermined immunologic and genetic predispositions that confer increased risk.

Common symptoms of endometriosis are dysmenorrhea, dyspareunia, and pelvic pain, and these are sometimes accompanied by bowel and bladder symptoms. Pelvic examination classically demonstrates an immobile uterus and uterosacral nodularity; palpation of these nodules can elicit pain. On laparoscopy, endometriosis can range from minimal to severe; however, stage of endometriosis correlates poorly with reported symptoms.³⁰

Consideration of surgery is based on clinical history, results of the pelvic examination, and possible findings on ultrasonography or hysterosalpingography. Although positive findings on imaging can support a plan for intervention, endometriosis is largely a peritoneal disease, and evidence of tubal damage or ovarian cysts is rarely evident on ultrasonography. In women with menstrual complaints (eg, dysmenorrhea, heavy menstrual bleeding, abnormal uterine bleeding) and a history of infertility, ultrasonography may be useful in determining the presence of uterine pathology such as ovarian cyst or endometrioma, large hydrosalpinx, polyp, or substantial fibroid burden—any of which may have a significant impact on female fertility.

In the absence of a reliable blood test or imaging study, the gold standard for the diagnosis of endometriosis continues to be laparoscopic surgery. Hormonal treatments for endometriosis symptoms are not effective in improving infertility and will preclude pregnancy. Laparoscopic surgery is more successful in improving pregnancy rates in women with advanced disease: pregnancy rates after surgery can be as high as 60% in women with ovarian endometriomas but are significantly lower in women with removal of minimal to mild disease.^30,31 Women over age 35 or who present with low ovarian reserve and whose male partner has semen abnormalities should consider moving directly to assisted reproductive technology rather than pursuing endometriosis surgery.

Although male partners are often highly engaged in and supportive of the fertility evaluation, some are reluctant to undergo testing, and some wish to undergo semen analysis only after female factors have been ruled out. Our practice is to evaluate male factors immediately, due to the high contribution of male factors (up to 40% of cases) either alone or in combination with female factors.³²

Men at particularly increased risk of semen abnormalities include those with a history of chemotherapy or radiation or exposure to toxins (eg, environmental exposures, alcohol, tobacco, illicit substances) and prescribed medications.

At a minimum, for the male partner, a reproductive history should be taken and a semen analysis ordered. Men should be directly queried about testosterone use, as this often-used anabolic steroid hormone can severely impair sperm production.

Men who have low sperm counts, motility, or morphology scores based on World Health Organization criteria should not be deemed “infertile,” as there is significant variation from one analysis to the next, and normal fertility has been reported in men with notably low sperm counts. Particular caution should be exercised in interpreting low morphology scores in men with normal counts and motility, as this parameter appears to have the least prognostic value in this context. Men with abnormal semen analyses should be referred to a specialist for further urologic evaluation and treatment.

Treatments for male factor infertility include surgery, steroid hormones, and possibly intrauterine insemination or assisted reproductive technology. In even the most challenging cases, male infertility is now largely treatable with intracytoplasmic sperm injection with assisted reproductive technology. While most advances in in vitro fertilization have been evolutionary, intracytoplasmic sperm injection was revolutionary. This breakthrough technology allows a single sperm to be injected directly into the oocyte. Sperm for this procedure can be obtained either from the ejaculate or from microsurgical testicular sperm extraction.

ANOVULATION

A thorough menstrual history can be informative, as most females of reproductive age have a fairly predictable 25-to-35-day monthly menstrual cycle. Women presenting with menstrual charting with this pattern do not require laboratory confirmation of ovulation. Basal body temperatures are rarely used currently, as they are time-consuming, can induce stress, and are confirmatory rather than predictive of ovulation. Endometrial biopsy for endometrial “dating” is no longer performed in infertile women.

If laboratory confirmation is desired, LH kit testing with a commercially available test or a luteal phase serum progesterone obtained 7 days after suspected ovulation can be obtained. A serum progesterone level higher than 3 ng/mL is indicative of ovulation.¹⁹ Due to the notable fluctuations in ovulatory-appearing progesterone levels over several hours, caution must be taken in interpreting a lower-normal level as indicative of a luteal phase insufficiency.

Polycystic ovary syndrome

Polycystic ovary syndrome is important to understand because it is a metabolic condition that predisposes patients to a variety of health risks. Along with gynecologic consequences such as infertility, abnormal uterine bleeding, and endometrial pathology, it is often accompanied by alterations in glucose and lipid metabolism, obesity, hypertension, and cardiovascular disease.³⁵

Despite its name, the syndrome does not involve the presence of classic ovarian cysts. In fact, the cysts associated with polycystic ovary syndrome are dense accumulations of antral follicles arranged peripherally in the ovarian cortex; they should not be removed surgically as they represent the ovarian reserve.

Although ovaries that appear polycystic on transvaginal ultrasonography are often associated with the syndrome, they are not invariably present and are not absolutely required for the diagnosis of polycystic ovary syndrome based on the most commonly used criteria.³⁵ Several diagnostic criteria have been proposed for polycystic ovary syndrome and its phenotypes. The 2003 revised Rotterdam criteria require 2 out of the following 3 features:

• Oligo-ovulation or anovulation
• Evidence of hyperandrogenism, whether clinical (eg, acne or hirsutism) or based on laboratory testing
• Polycystic-appearing ovaries on ultrasonography.

There is no single test that can diagnose the disease. Although polycystic ovary syndrome is often characterized by elevated LH levels, LH–FSH ratios, and fasting insulin levels, these are not diagnostic criteria. The diagnosis hinges on excluding other causes of anovulation such as thyroid disease, hyperprolactinemia, 21-hydroxylase deficiency, androgen-producing neoplasms, and Cushing syndrome. In addition to checking serum testosterone levels, irregular menstrual cycles and infertility should be assessed at minimum with measurement of TSH, prolactin, and day-3 FSH. Obese women should be screened for metabolic syndrome, which should include an assessment of impaired glucose tolerance with a 2-hour oral glucose tolerance test.³⁶

Women with polycystic ovary syndrome are known to have insulin resistance, which is difficult to assess and is independent of their body mass index.³⁷ They often report a family history of diabetes or a personal history of gestational diabetes or giving birth to infants who are large for gestational age. Although most women diagnosed with insulin resistance and anovulatory infertility will not yet have a diagnosis of diabetes, women with polycystic ovary syndrome are 3 to 7 times more likely to develop type 2 diabetes later in life³⁷ and are at increased risk of lipid abnormalities, cardiovascular disease, and stroke. Therefore, interventions to address the compounding influences of polycystic ovary syndrome and obesity can improve fertility outcomes and help prevent long-term sequelae that accompany the syndrome.

Treatment for women with polycystic ovary syndrome attempting conception includes lifestyle modifications, medications for ovulation induction, and possible use of insulin sensitizers. Metformin alone is not effective as a single agent for achieving pregnancy.³⁸ Diet, weight loss, and exercise can have dramatic effects on ovulation and pregnancy and should be highly encouraged.

Ovulation induction is often required in anovulatory women, either in combination with lifestyle modifications or used subsequently if modifications are not successful. Letrozole is advised as the initial agent in women with obesity and anovulatory infertility rather than clomiphene citrate; a side-by-side comparison demonstrated increased rates of ovulation and live birth with letrozole.³⁹

Once-daily letrozole 2.5 mg or clomiphene 50 mg can be prescribed for 5 days, from cycle days 3 through 7 to cycle days 5 through 9. If this initial dosing fails to result in ovulation, the dose can be increased. Known adverse effects are hot flashes, headaches, ovarian cysts, and increased risk of multiple gestation.

Metformin should be considered as an adjunct to fertility treatments in women with polycystic ovary syndrome, especially those with obesity or impaired glucose tolerance, or if there is no response to standard ovulation induction.

Ovarian hyperstimulation syndrome (cystic enlargement of the ovaries with potentially dangerous fluid and electrolyte imbalances) can occur in women with polycystic ovary syndrome; however, it rarely occurs with oral medications.

For millions of couples, a primary care physician may be the first point of contact for fertility concerns. Statistics from the US Centers for Disease Control and Prevention indicate that 12% of women ages 15 to 44 received fertility services from 2006 to 2010.¹ Despite seeking services, most couples requested only advice or testing rather than treatments such as ovulation-inducing medications, surgery, or, rarely, assisted reproductive technologies including in vitro fertilization. Based on these data, primary care physicians are in a unique position to offer guidance and provide fertility services in most circumstances without the need for referral.

This article reviews the answers to questions patients frequently ask, and outlines a practical framework for the evaluation and management of the infertile couple.

MANY PATIENTS SEEK INFORMATION

At least 1 million medical visits per year are for women seeking help in becoming pregnant, with the number increasing over the last several decades.¹ Reasons for the increase include delayed childbearing and the effects of aging on the female reproductive system (“female reproductive aging”), as well as the availability of increasingly effective treatments for infertility.

While the prevalence of infertility in US couples is widely quoted as 10% to 15%,² there is no estimate for the number of fertility-related questions patients routinely pose to care providers. These questions often relate to coital timing, use of lubricants, positioning, and the use of fertility trackers and ovulation predictors.

A 2017 study of women with 12 months of infertility found that only 8% sought subspecialist care vs care from a general physician or provider, indicating that generalists are most often the first point of contact.³ The majority (92%) of women responding to a survey regarding fertility-awareness education indicated a preference for immediate counseling from their general practitioner.⁴

Although some healthcare providers may consider infertility simply a quality-of-life issue, the World Health Organization classifies it as a disease, and as such it warrants identification, assessment, and intervention.⁵ Further, patients with infertility are known to experience considerable psychological distress related to their condition. In a comparison study, women with infertility experienced levels of psychological distress similar to the level in patients with cancer and patients with chronic medical illness.⁶

In the current era, general practitioners and women’s health specialists may also now address patients’ questions about reproductive aging and egg-freezing, which is now an established technology.⁷

FAILURE TO CONCEIVE AFTER 1 YEAR

As women approach age 40, the potential for fertility decreases rapidly and significantly. Women in their later 30s have only half the fertility of women in their early 20s.¹⁰ Misperceptions of aging and female fertility have been fueled by widely publicized celebrity births from women in their 40s and even 50s, without disclosing the use of frozen or donor eggs. This unfortunate fact affects women actively trying to conceive as well as women who wish to delay childbearing due to lack of a partner or for personal or professional reasons. Primary care physicians should be able to provide counseling relevant to female reproductive aging and make suitable and timely referrals for fertility preservation if indicated.

AN EMOTIONAL ISSUE

In approaching the couple with infertility, it is important to proceed with great sensitivity for the socioemotional context of this diagnosis. For both the male and female partner, infertility can be highly stigmatizing, and can be viewed as a personal or relationship failure.

Couples should be encouraged to ask embarrassing or uncomfortable questions. Although this may not be feasible in many circumstances, interviews should ideally be conducted with both partners individually as well as together, to allow sensitive issues to be shared. In some cases, a partner may be unaware of a history of a sexually transmitted infection, a prior abortion, the use of testosterone supplements or medications to enhance male sexual performance, or a vasectomy or tubal ligation during a previous relationship.

It is not unusual that the anxiety of infertility can cause decreased libido and sexual and erectile dysfunction. These issues can further complicate the problem of conceiving, and couples counseling is not uncommonly required.11 Patients are often reassured to know that they are not alone in their diagnosis.

Before embarking on a series of tests, the primary care physician can carefully evaluate for clues that may guide the diagnostic evaluation. The approach can be individualized based on the patient’s age, duration of subfertility (ie, how long they have been trying to become pregnant), and risk factors. But as a general rule, regardless of age, couples who have been trying to conceive for more than 1 year should be encouraged to pursue additional testing.

Because each month presents a new cycle of hope (often followed by intense disappointment), the prevailing sentiment to “just give it a little more time” must be countered by education and counseling. The primary care physician must increase awareness that lack of pregnancy in the stated time periods is a compelling reason for evaluation.

History-taking in the infertile couple should include a complete gynecologic and menstrual history. A history of sexually transmitted diseases that can cause tubal disease, such as gonorrhea and Chlamydia, is significant. Both partners should be assessed for a history of prior conceptions, past medical or surgical problems, medications, and exposures to environmental toxins including alcohol, tobacco, and drugs.

A detailed physical examination can provide clues to the cause of subfertility, especially if signs of obesity, androgen excess, or insulin resistance are present.

QUESTIONS OFTEN ASKED BY COUPLES TRYING TO CONCEIVE

Clinicians are frequently asked questions related to sexual practices and lifestyle in relation to fertility and should be comfortable responding to questions in these areas.

Does frequent ejaculation ‘use up’ my sperm?

Men should be reassured that frequent ejaculations do not decrease sperm counts; even daily ejaculation does not deplete the concentration of sperm. Male partners can be reassured that “saving up” is not an effective strategy; in fact, abstinence periods of greater than 5 days can adversely affect semen parameters.¹²

How often should we have sex?

Infrequent intercourse (< 1 time per week) reduces the monthly chance of conceiving.¹³ There does not seem to be a significant improvement in fecundity with daily intercourse vs intercourse on alternate days. Strict schedules surrounding intercourse may increase stress, and reassurance should be offered that intercourse need not be regimented. Every 1 to 2 days should suffice.

Are any sexual positions better for conception?

There is no evidence that particular coital positioning or remaining supine after intercourse improves fertility. Sperm can be found within the endocervix within seconds of ejaculation, irrespective of sexual position.

What is the window of fertility?

There is good evidence that the fertile window lasts approximately 6 days and closes after ovulation.^13,14 Women with regular cycles can determine their typical day of ovulation based on menstrual tracking. Intercourse should begin about 6 days before ovulation and should continue every 1 to 2 days for 1 week to fully capture this window.

Should we change our lifestyle?

Couples seeking pregnancy should be advised to limit alcohol and caffeine use, completely abstain from cigarette smoking or illicit drug use, and maintain a healthy body mass index.

Very few data exist to support particular diets or supplements to promote fertility, including antioxidants and herbal remedies. Folic acid supplementation is recommended in all women attempting to conceive to reduce the incidence of birth defects.

Do lubricants reduce fertility?

Although there seem to be no differences in fecundity rates in couples using commercial lubricants, most water-based lubricants are best avoided in couples with infertility, as adverse effects on sperm have been demonstrated in vitro.¹⁵ If lubrication is needed, couples may try mineral oil, canola oil, or hydroxyetyl­cellulose-based lubricants (eg, Pre-seed).

Do fertility trackers work?

Many couples with primary infertility perceive that coital timing is critical and worry that their infertility is due to poorly timed intercourse; in fact, this is seldom the case.

Despite widespread marketing of urinary luteinizing hormone (LH) detection kits and electronic trackers and monitors, there is no clear evidence that these methods improve monthly rates of conception.

Women with a regular menstrual cycle should be encouraged to take notice when their cervical mucus appears clear and slippery (a sign of ovulation). Not all women are able to detect these fluctuations; however, for those who can, observing cervical mucus changes appears to be equivalent or superior to predictor kits in predicting conception.¹⁶

A PRACTICAL FRAMEWORK FOR EVALUATING THE INFERTILE COUPLE

To assess for the common factors identified in Table 1, the essential investigation of the infertile couple includes:

• Semen analysis
• Confirmation of ovulation
• Hysterosalpingography.

Consideration can also be given to ovarian reserve testing in women at risk of diminished ovarian reserve. The above investigation can be performed simultaneously to allow for prompt identification of any issues. Further, infertility is often a combination of problems (eg, anovulation in the woman together with a problem in the man), so an incomplete evaluation may overlook a coexisting diagnosis and lead to delays in treatment and pregnancy.

Tests that are no longer typically used in clinical practice are outlined in Table 2.

Ovarian reserve refers to the number of fertilizable oocytes that remain in the ovary. This reserve changes over time, and changes occur rapidly as women approach and enter their 30s. Though not the case in men, the age of the female partner is an independent risk factor for infertility. This discrepancy is due to loss of ovarian reserve, chromosome abnormalities in embryos, and the development of medical conditions with age that affect fertility.

Testing for ovarian reserve does not necessarily predict an overall inability to achieve a live birth,¹⁷ but it can predict response to exogenous gonadotropins and, to some degree, the chance for successful pregnancy with assisted reproductive technology.¹⁸

The ASRM states that testing for diminished ovarian reserve may provide useful information in women who have had a previous poor response to gonadotropins and in women planning assisted reproductive technology.¹⁹ The ASRM also indicates that the following are risk factors for diminished ovarian reserve, and clinicians may target the assessment accordingly¹⁹:

• Age 35 or older
• History of exposure to chemotherapy or pelvic radiation
• Family history of early menopause (age < 40)
• History of ovarian surgery
• Unexplained or idiopathic fertility.

Although several tests of ovarian reserve exist, either an antimullerian hormone (AMH) test or a combined cycle day-3 follicle-stimulating hormone (FSH) and estradiol level are the 2 tests commonly used in clinical practice. Antral follicle counts are an ultrasonographic measure used by infertility specialists but rarely by primary care physicians. Assays such as inhibin are rarely ordered and have limited clinical utility.

The AMH test

Many reproductive endocrinologists rely on the AMH level as a single test of ovarian reserve as it is easy to obtain, has a relatively low cost, and offers stable results. AMH is produced by the granulosa cells of the ovarian antral follicles and is readily detected in serum samples.

Conveniently for the clinician, levels of this hormone remain stable throughout the menstrual cycle and therefore can be tested on any day and at any time of day. Lower serum AMH levels (< 1 ng/mL) have been shown to correspond to diminished ovarian stimulation with gonadotropins as well as decreased embryo quality and poor pregnancy outcomes with assisted reproductive technology.¹⁹

Nevertheless, despite overall stability, AMH levels can be falsely lowered in women using exogenous hormones or with a diagnosis of hypogonadotropic hypogonadism. Levels may be higher than expected in women with polycystic ovary syndrome due to higher numbers of antral and preantral follicles in the polycystic ovary.

The day-3 follicle-stimulating hormone test

FSH and 17-beta estradiol testing can be ordered in combination to assess function of the hypothalamic-pituitary-ovarian axis on day 3 of the menstrual cycle. There is some flexibility, however, and testing obtained on cycle day 2, 3, or 4 yields equivalent results.

Although there are no strict cutoffs, FSH levels that appear elevated (> 10–20 IU/L) are associated with lower chances of conceiving with in vitro fertilization in multiple studies.²⁰

The test is limited by levels that may fluctuate cycle to cycle, and reassuring test results do not necessarily indicate that a woman will achieve a pregnancy. Although a serum estradiol value alone is not a useful test, it can be used in combination with day-3 FSH to screen for diminished ovarian reserve.

As premature recruitment of a follicle can cause an early follicular rise in estradiol, FSH may be falsely suppressed on day 3. For example, a “normal” day-3 FSH combined with an elevated day-3 17-beta estradiol level of 60 to 80 pg/mL is associated with a poor response to medical treatments for infertility.

Female reproductive aging

Aging of the female reproductive system is a central threat to fertility, and prompt assessment and referral are warranted for women age 35 or older who have been trying to conceive for more than 6 months. The ASRM recommends that women over age 40 be evaluated immediately.²¹

A prevailing misconception is that regular menstrual cycles correspond with normal fertility. In reality, women lose their ability to achieve a healthy live birth in the 5 to 10 years preceding menopause. Although all women who do not desire pregnancy should still use appropriate contraception to avoid unintended pregnancy, women who do desire pregnancy should be aware of these physiologic changes.

Classic age-related changes in ovarian reserve are accompanied by a steep rise in aneuploidy and miscarriage risk.²² This is particularly relevant as women increasingly delay childbearing in modern society. Loss of fertility begins at 32 and abruptly accelerates at age 37²¹; this fact is poorly communicated to and understood by patients. In a 2018 study of highly educated women, most respondents failed to identify that 45-year-old women can only rarely achieve a successful pregnancy.²³

In recent decades, the percentage of women who delay childbearing until after age 35 has steadily increased. There is a widespread misconception that fertility treatments and assisted reproductive technology can compensate for female reproductive aging. Primary care physicians can play a central role in reminding couples that age remains the single greatest predictor of natural fertility and the chance of success with assisted reproduction.

Further, for women who desire future fertility and are without a partner, primary care physicians can counsel them regarding the availability of donor insemination or egg freezing. Studies confirm that women want clinicians to initiate information on reproductive health, and 80% of women undergoing elective egg-freezing for fertility preservation wished that they had done so at an earlier age.^24,25

Women with endometriosis, fibroids, or a history of tubal disease have impaired fecundity. Pelvic imaging is an essential component of their evaluation. Although hysterosalpingography is the mainstay of tubal assessment, in select cases ultrasonography or hysteroscopy may be indicated.

Tubal disease and hysterosalpingography

Tubal disease remains one of the most common causes of infertility in the US females. In most cases, tubal damage is secondary to pelvic inflammatory disease from infection with gonorrhea or Chlamydia, or both.

Rates of confirmed tubal-factor infertility have been shown to increase with both the severity of the infection and the number of past infections.²⁶ In a landmark study, 1 episode of pelvic inflammatory disease was associated with a 12% risk of tubal-factor infertility, whereas 3 infections carried a risk as high as 54%. Pelvic inflammatory disease is also known to increase the risk of ectopic pregnancy.

To assess tubal patency, hysterosalpingography, a radiographic procedure, is typically performed using fluoroscopy and injected contrast material. Some centers may offer sonohysterography as a radiation-free alternative, depending on sonographic skill and experience. Both tests are best scheduled in the window between the end of menstrual bleeding and ovulation. In practice, patients with regular cycles can typically schedule hysterosalpingography between cycle days 5 and 12.

In patients with known hydrosalpinx (a distended fallopian tube due to blockage) or a history of pelvic infection, doxycycline should be given before the procedure.²⁷ Patients with demonstrated hydrosalpinx on hysterosalpingography should receive doxycycline 100 mg twice daily for 5 days to prevent posthysterosalpingography pelvic inflammatory disease.²⁷ Patients with active pelvic or cervical infection should not undergo hysterosalpingography .

Women with confirmed hydrosalpinx or tubal obstruction can be referred for laparoscopy. Gynecologic surgeons will plan their approach based on whether the obstruction is proximal (near the uterus) or distal (near the ovary) as well as whether hydrosalpinx, abnormal tubal architecture, salpingitis isthmica nodosa, or peritubal adhesions are noted. Tubal surgery can be effective in mild cases of tubal disease; however, as in vitro fertilization is becoming more effective, patients with moderate or severe tubal disease are increasingly being referred directly for assisted reproductive technology. Before undergoing assisted reproductive technology, hydrosalpinx will need to be addressed, as it can decrease clinical pregnancy rates with in vitro fertilization.

Endometriosis

Endometriosis is found in 21% to 47% of women with subfertility²⁸ and commonly causes pain, ovarian cysts, and tubal disease. There is often a delay of 7 to 8 years for diagnosis due to the misapprehension that severe dysmenorrhea is normal. Women with an affected first-degree family member are at substantially increased risk.

Although endometriosis is commonly thought to result from reflux of endometrial tissue into the peritoneal cavity with menses, there are multiple proposed mechanisms for the disease.²⁹ The pathogenesis of endometriosis is enigmatic, and there are likely as yet undetermined immunologic and genetic predispositions that confer increased risk.

Common symptoms of endometriosis are dysmenorrhea, dyspareunia, and pelvic pain, and these are sometimes accompanied by bowel and bladder symptoms. Pelvic examination classically demonstrates an immobile uterus and uterosacral nodularity; palpation of these nodules can elicit pain. On laparoscopy, endometriosis can range from minimal to severe; however, stage of endometriosis correlates poorly with reported symptoms.³⁰

Consideration of surgery is based on clinical history, results of the pelvic examination, and possible findings on ultrasonography or hysterosalpingography. Although positive findings on imaging can support a plan for intervention, endometriosis is largely a peritoneal disease, and evidence of tubal damage or ovarian cysts is rarely evident on ultrasonography. In women with menstrual complaints (eg, dysmenorrhea, heavy menstrual bleeding, abnormal uterine bleeding) and a history of infertility, ultrasonography may be useful in determining the presence of uterine pathology such as ovarian cyst or endometrioma, large hydrosalpinx, polyp, or substantial fibroid burden—any of which may have a significant impact on female fertility.

In the absence of a reliable blood test or imaging study, the gold standard for the diagnosis of endometriosis continues to be laparoscopic surgery. Hormonal treatments for endometriosis symptoms are not effective in improving infertility and will preclude pregnancy. Laparoscopic surgery is more successful in improving pregnancy rates in women with advanced disease: pregnancy rates after surgery can be as high as 60% in women with ovarian endometriomas but are significantly lower in women with removal of minimal to mild disease.^30,31 Women over age 35 or who present with low ovarian reserve and whose male partner has semen abnormalities should consider moving directly to assisted reproductive technology rather than pursuing endometriosis surgery.

Although male partners are often highly engaged in and supportive of the fertility evaluation, some are reluctant to undergo testing, and some wish to undergo semen analysis only after female factors have been ruled out. Our practice is to evaluate male factors immediately, due to the high contribution of male factors (up to 40% of cases) either alone or in combination with female factors.³²

Men at particularly increased risk of semen abnormalities include those with a history of chemotherapy or radiation or exposure to toxins (eg, environmental exposures, alcohol, tobacco, illicit substances) and prescribed medications.

At a minimum, for the male partner, a reproductive history should be taken and a semen analysis ordered. Men should be directly queried about testosterone use, as this often-used anabolic steroid hormone can severely impair sperm production.

Men who have low sperm counts, motility, or morphology scores based on World Health Organization criteria should not be deemed “infertile,” as there is significant variation from one analysis to the next, and normal fertility has been reported in men with notably low sperm counts. Particular caution should be exercised in interpreting low morphology scores in men with normal counts and motility, as this parameter appears to have the least prognostic value in this context. Men with abnormal semen analyses should be referred to a specialist for further urologic evaluation and treatment.

Treatments for male factor infertility include surgery, steroid hormones, and possibly intrauterine insemination or assisted reproductive technology. In even the most challenging cases, male infertility is now largely treatable with intracytoplasmic sperm injection with assisted reproductive technology. While most advances in in vitro fertilization have been evolutionary, intracytoplasmic sperm injection was revolutionary. This breakthrough technology allows a single sperm to be injected directly into the oocyte. Sperm for this procedure can be obtained either from the ejaculate or from microsurgical testicular sperm extraction.

ANOVULATION

A thorough menstrual history can be informative, as most females of reproductive age have a fairly predictable 25-to-35-day monthly menstrual cycle. Women presenting with menstrual charting with this pattern do not require laboratory confirmation of ovulation. Basal body temperatures are rarely used currently, as they are time-consuming, can induce stress, and are confirmatory rather than predictive of ovulation. Endometrial biopsy for endometrial “dating” is no longer performed in infertile women.

If laboratory confirmation is desired, LH kit testing with a commercially available test or a luteal phase serum progesterone obtained 7 days after suspected ovulation can be obtained. A serum progesterone level higher than 3 ng/mL is indicative of ovulation.¹⁹ Due to the notable fluctuations in ovulatory-appearing progesterone levels over several hours, caution must be taken in interpreting a lower-normal level as indicative of a luteal phase insufficiency.

Polycystic ovary syndrome

Polycystic ovary syndrome is important to understand because it is a metabolic condition that predisposes patients to a variety of health risks. Along with gynecologic consequences such as infertility, abnormal uterine bleeding, and endometrial pathology, it is often accompanied by alterations in glucose and lipid metabolism, obesity, hypertension, and cardiovascular disease.³⁵

Despite its name, the syndrome does not involve the presence of classic ovarian cysts. In fact, the cysts associated with polycystic ovary syndrome are dense accumulations of antral follicles arranged peripherally in the ovarian cortex; they should not be removed surgically as they represent the ovarian reserve.

Although ovaries that appear polycystic on transvaginal ultrasonography are often associated with the syndrome, they are not invariably present and are not absolutely required for the diagnosis of polycystic ovary syndrome based on the most commonly used criteria.³⁵ Several diagnostic criteria have been proposed for polycystic ovary syndrome and its phenotypes. The 2003 revised Rotterdam criteria require 2 out of the following 3 features:

• Oligo-ovulation or anovulation
• Evidence of hyperandrogenism, whether clinical (eg, acne or hirsutism) or based on laboratory testing
• Polycystic-appearing ovaries on ultrasonography.

There is no single test that can diagnose the disease. Although polycystic ovary syndrome is often characterized by elevated LH levels, LH–FSH ratios, and fasting insulin levels, these are not diagnostic criteria. The diagnosis hinges on excluding other causes of anovulation such as thyroid disease, hyperprolactinemia, 21-hydroxylase deficiency, androgen-producing neoplasms, and Cushing syndrome. In addition to checking serum testosterone levels, irregular menstrual cycles and infertility should be assessed at minimum with measurement of TSH, prolactin, and day-3 FSH. Obese women should be screened for metabolic syndrome, which should include an assessment of impaired glucose tolerance with a 2-hour oral glucose tolerance test.³⁶

Women with polycystic ovary syndrome are known to have insulin resistance, which is difficult to assess and is independent of their body mass index.³⁷ They often report a family history of diabetes or a personal history of gestational diabetes or giving birth to infants who are large for gestational age. Although most women diagnosed with insulin resistance and anovulatory infertility will not yet have a diagnosis of diabetes, women with polycystic ovary syndrome are 3 to 7 times more likely to develop type 2 diabetes later in life³⁷ and are at increased risk of lipid abnormalities, cardiovascular disease, and stroke. Therefore, interventions to address the compounding influences of polycystic ovary syndrome and obesity can improve fertility outcomes and help prevent long-term sequelae that accompany the syndrome.

Treatment for women with polycystic ovary syndrome attempting conception includes lifestyle modifications, medications for ovulation induction, and possible use of insulin sensitizers. Metformin alone is not effective as a single agent for achieving pregnancy.³⁸ Diet, weight loss, and exercise can have dramatic effects on ovulation and pregnancy and should be highly encouraged.

Ovulation induction is often required in anovulatory women, either in combination with lifestyle modifications or used subsequently if modifications are not successful. Letrozole is advised as the initial agent in women with obesity and anovulatory infertility rather than clomiphene citrate; a side-by-side comparison demonstrated increased rates of ovulation and live birth with letrozole.³⁹

Once-daily letrozole 2.5 mg or clomiphene 50 mg can be prescribed for 5 days, from cycle days 3 through 7 to cycle days 5 through 9. If this initial dosing fails to result in ovulation, the dose can be increased. Known adverse effects are hot flashes, headaches, ovarian cysts, and increased risk of multiple gestation.

Metformin should be considered as an adjunct to fertility treatments in women with polycystic ovary syndrome, especially those with obesity or impaired glucose tolerance, or if there is no response to standard ovulation induction.

Ovarian hyperstimulation syndrome (cystic enlargement of the ovaries with potentially dangerous fluid and electrolyte imbalances) can occur in women with polycystic ovary syndrome; however, it rarely occurs with oral medications.

A mbulatory electrocardiography (ECG) began in 1949 when Norman “Jeff” Holter developed a monitor that could wirelessly transmit electrophysiologic data.¹ His original device used vacuum tubes, weighed 85 pounds, and had to be carried in a backpack. Furthermore, it could send a signal a distance of only 1 block.²

At the time, it was uncertain if this technology would have any clinical utility. However, in 1952, Holter published the first tracing of abnormal cardiac electrical activity in a patient who had suffered a posterior myocardial infarction.³ By the 1960s, Holter monitoring systems were in full production and use.⁴

Since then, advances in technology have led to small, lightweight devices that enable clinicians to evaluate patients for arrhythmias in a real-world context for extended times, often with the ability to respond in real time.

Many ambulatory devices are available, and choosing the optimal one requires an understanding of which features they have and which are the most appropriate for the specific clinical context. This article reviews the features, indications, advantages, and disadvantages of current devices, and their best use in clinical practice.

INDICATIONS FOR AMBULATORY ECG MONITORING

Diagnosis

The most common diagnostic role of monitoring is to correlate unexplained symptoms, including palpitations, presyncope, and syncope, with a transient cardiac arrhythmia. Monitoring can be considered successful if findings on ECG identify risks for serious arrhythmia and either correlate symptoms with those findings or demonstrate no arrhythmia when symptoms occur.

A range of arrhythmias can cause symptoms. Some, such as premature atrial contractions and premature ventricular contractions, may be benign in many clinical contexts. Others, such as atrial fibrillation, are more serious, and some, such as third-degree heart block and ventricular tachycardia, can be lethal.

Arrhythmia symptoms can vary in frequency and cause differing degrees of debility. The patient’s symptoms, family history, and baseline ECG findings can suggest a more serious or a less serious underlying rhythm. These factors are important when determining which device is most appropriate.

Ambulatory ECG can also be useful in looking for a cause of cryptogenic stroke, ie, an ischemic stroke with an unexplained cause, even after a thorough initial workup. Paroxysmal atrial fibrillation is a frequent cause of cryptogenic stroke, and because it is transient, short-term inpatient telemetry may not be sufficient to detect it. Extended cardiac monitoring, lasting weeks or even months, is often needed for clinicians to make this diagnosis and initiate appropriate secondary prevention.

Prognosis: Identifying patients at risk

In a patient with known structural or electrical heart disease, ambulatory ECG can be used to stratify risk. This is particularly true in evaluating conditions associated with sudden cardiac death.

For example, hypertrophic cardiomyopathy and arrhythmogenic right ventricular dysplasia or cardiomyopathy are 2 cardiomyopathies that can manifest clinically with ventricular arrhythmias and sudden cardiac death. Ambulatory ECG can detect premature ventricular contractions and ventricular tachycardia and identify their frequency, duration, and anatomic origin. This information is useful in assessing risk of sudden cardiac death and determining the need for an implantable cardioverter-defibrillator.

Similarly, Wolff-Parkinson-White syndrome, involving rapid conduction through an accessory pathway, is associated with increased risk of ventricular fibrillation and sudden cardiac death. Ambulatory ECG monitoring can identify patients who have electrical features that portend the development of ventricular fibrillation.

Also associated with sudden cardiac death are the inherited channelopathies, a heterogeneous group of primary arrhythmic disorders without accompanying structural pathology. Ambulatory ECG monitoring can detect transient electrical changes and nonsustained ventricular arrhythmias that would indicate the patient is at high risk of these disorders.

Assessing arrhythmia treatment

Arrhythmia monitoring using an ambulatory ECG device can also provide data to assess the efficacy of treatment under several circumstances.

The “pill-in-the-pocket” approach to treating atrial fibrillation, for example, involves self-administering a single dose of an antiarrhythmic drug when symptoms occur. Patients with infrequent but bothersome episodes can use an ambulatory ECG device to detect when they are having atrial fibrillation, take their prescribed drug, and see whether it terminates the arrhythmia, all without going to the hospital.

Ambulatory ECG also is useful for assessing pharmacologic or ablative therapy in patients with atrial fibrillation or ventricular tachycardia. Monitoring for several weeks can help clinicians assess the burden of atrial fibrillation when using a rhythm-control strategy; assessing the ventricular rate in real-world situations is useful to determine the success of a rate-control strategy. Shortly after ablation of either atrial fibrillation or ventricular tachycardia, ECG home monitoring for 24 to 48 hours can detect asymptomatic recurrence and treatment failure.

Some antiarrhythmic drugs can prolong the QT interval. Ambulatory ECG devices that feature real-time monitoring can be used during drug initiation, enabling the clinician to monitor the QT interval without admitting the patient to the hospital.

Ultimately, ambulatory ECG monitoring is most commonly used to evaluate symptoms. Because arrhythmias and specific symptoms are unpredictable and transient, extended monitoring in a real-world setting allows for a more comprehensive evaluation than a standard 10-second ECG recording.

Continuous external monitoring: The Holter monitor

Recording is typically done continuously for 24 to 48 hours, although some newer devices can record for longer. Patients can press a button to note when they are experiencing symptoms, allowing for potential correlation with ECG abnormalities. The data are stored on a flash drive that can be uploaded for analysis after recording is complete.

What is its best use? Given its relatively short duration of monitoring, the Holter device is typically used to evaluate symptoms that occur daily or nearly daily. An advantage of the Holter monitor is its ability to record continuously, without requiring the patient to interact with the device. This feature provides “full disclosure,” which is the ability to see arrhythmia data from the entire recording period.

These features make Holter monitoring useful to identify suspected frequently occurring silent arrhythmias or to assess the overall arrhythmia burden. A typical Holter report can contain information on the heart rate (maximum, minimum, and average), ectopic beats, and tachy- and bradyarrhythmias, as well as representative samples.

The Holter device is familiar to most practitioners and remains an effective choice for ambulatory ECG monitoring. However, its use has largely been replaced by newer devices that overcome the Holter’s drawbacks, particularly its short duration of monitoring and the need for postmonitoring analysis. Additionally, although newer Holter devices are more ergonomic, some patients find the wires and gel electrodes uncomfortable or inconvenient.

Intermittent monitoring: Event recorders

Unlike the continuous monitors, intermittent recording devices (also called event recorders), capture and store tracings only during an event.

Intermittent recording monitors are of 2 general types: post-event recorders and loop recorders. These devices can extend the overall duration of observation, which can be especially useful for those whose symptoms and arrhythmias are infrequent.

Post-event recorders are small and self-contained, not requiring electrodes (Figure 1). The device is carried by the patient but not worn continuously. When the patient experiences symptoms, he or she places the device against the chest and presses a button to begin recording. These tracings are stored on the device and can be transmitted by telephone to a data center for analysis. Although post-event recorders allow for monitoring periods typically up to 30 days, they are limited by requiring the patient to act to record an event.

What is its best use? These devices are best used in patients who have infrequent symptoms and are at low risk. Transient or debilitating symptoms, including syncope, can limit the possibility of capturing an event.

Intermittent monitoring: Loop recorders

Loop recorders monitor continuously but record only intermittently. The name refers to the device’s looping memory: ie, to extend how long it can be used and make the most of its limited storage, the device records over previously captured data, saving only the most important data. The device saves the data whenever it detects an abnormal rhythm or the patient experiences symptoms and pushes a button. Data are recorded for a specified time before and after the activation, typically 30 seconds.

Loop recorders come in 2 types: external and implantable.

External loop recorders

External loop recorders look like Holter monitors (Figure 1), but they have the advantage of a much longer observation period—typically up to 1 month. The newest devices have even greater storage capacity and can provide “backward” memory, saving data that were captured just before the patient pushed the button.

In studies of patients with palpitations, presyncope, or syncope, external loop recorders had greater diagnostic yield than traditional 24-hour Holter monitors.^7,8 This finding was supported by a clinical trial that found 30-day monitoring with an external loop recorder led to a 5-fold increase in detecting atrial fibrillation in patients with cryptogenic stroke.⁹

Disadvantages of external loop recorders are limited memory storage, a considerable reliance on patient activation of the device, and wires and electrodes that need to be worn continuously.

What is their best use? External loop recorders are most effective when used to detect an arrhythmia or to correlate infrequent symptoms with an arrhythmia. They are most appropriately used in patients whose symptoms occur more often than every 4 weeks. They are less useful in assessing very infrequent symptoms, overall arrhythmia burden, or responsiveness to therapy.¹⁰

Implantable loop recorders are small devices that contain a pair of sensing electrodes housed within an outer shell (Figure 1). They are implanted subcutaneously, usually in the left parasternal region, using local anesthesia. The subcutaneous location eliminates many of the drawbacks of the skin-electrode interface of external loop recorders.

Similar to the external loop recorder, this device monitors continuously and can be activated to record either by the patient by pressing a button on a separate device, or automatically when an arrhythmia is detected using a preprogrammed algorithm.

In contrast to external devices, many internal loop recorders have a battery life and monitoring capability of up to 3 years. This extended monitoring period has been shown to increase the likelihood of diagnosing syncope or infrequent palpitations.^11,12 Given that paroxysmal atrial fibrillation can be sporadic and reveal itself months after a stroke, internal loop recorders may also have a role in evaluating cryptogenic stroke.^13,14

The most important drawbacks of internal loop recorders are the surgical procedure for insertion, their limited memory storage, and high upfront cost.¹⁵ Furthermore, even though they allow for extended monitoring, there may be diminishing returns for prolonged observation.

What is their best use? For patients with palpitations, intermittent event monitoring has been shown to be cost-effective for the first 2 weeks, but after 3 weeks, the cost per diagnosis increases dramatically.¹⁶ As a result, internal loop recorders are reserved primarily for scenarios in which prolonged external monitoring has not revealed a source of arrhythmia despite a high degree of suspicion.

Mobile cardiac telemetry

Mobile cardiac telemetry builds on other ECG monitoring systems by adding real-time communication and technician evaluation.

Physically, these devices resemble either hand-held event records, with a single-channel sensing unit embedded in the case, or a traditional Holter monitor, with 3 channels, wires, and electrodes  (Figure 1).

The sensor wirelessly communicates with a nearby portable monitor, which continuously observes and analyzes the patient’s heart rhythm. When an abnormal rhythm is detected or when the patient marks the presence of symptoms, data are recorded and sent in real time via a cellular network to a monitoring center; the newest monitors can send data via any Wi-Fi system. The rhythm is then either evaluated by a trained technician or relayed to a physician. If necessary, the patient can be contacted immediately.

Mobile cardiac telemetry is typically used for up to 30 days, which  allows for evaluation of less-frequent symptoms. As a result, it may have a higher diagnostic yield for palpitations, syncope, and presyncope than the 24-hour Holter monitor.¹⁷

Further, perhaps because mobile cardiac telemetry relies less on stored information and requires less patient-device interaction than external loop recorders, it is more effective at symptom evaluation.¹⁸

Mobile cardiac telemetry also has a diagnostic role in evaluating patients with cryptogenic stroke. This is based on studies showing it has a high rate of atrial fibrillation detection in this patient population and is more effective at determining overall atrial fibrillation burden than loop recorders.^18,19

What is its best use? The key advantage of mobile cardiac telemetry is its ability to make rhythm assessments and communicate with technicians in real time. This allows high-risk patients to be immediately alerted to a life-threatening arrhythmia. It also gives providers an opportunity to initiate anticoagulation or titrate antiarrhythmic therapy in the outpatient setting without a delay in obtaining information. This intensive monitoring, however, requires significant manpower, which translates to higher cost, averaging 3 times that of other standard external monitors.¹⁵

Patch monitors

These ultraportable devices are a relatively unobtrusive and easy-to-use alternative for short-term ambulatory ECG monitoring. They monitor continuously with full disclosure, outpatient telemetry, and post-event recording features.

Patch monitors are small, leadless, wireless, and water-resistant (Figure 1). They are affixed to the left pectoral region with a waterproof adhesive and can be worn for 14 to 28 days. Recording is usually done continuously; however, these devices have an event marker button that can be pressed when the user experiences symptoms. They acquire a single channel of data, and each manufacturer has a proprietary algorithm for automated rhythm detection and analysis.²⁰

Several manufacturers produce ECG patch monitors. Two notable devices are the Zio patch (iRhythm Technologies, San Francisco, CA) and the Mobile Cardiac Outpatient Telemetry patch (BioTelemetry, Inc, Malvern, PA).

The Zio patch is a continuous external monitor with full disclosure. It is comparable to the Holter monitor, but has a longer recording period. After completing a 2-week monitoring period, the device is returned for comprehensive rhythm analysis. A typical Zio report contains information on atrial fibrillation burden, ectopic rhythm burden, symptom and rhythm correlation, heart rate trends, and relevant rhythm strips.

The Mobile Cardiac Outpatient Telemetry patch collects data continuously and communicates wirelessly by Bluetooth to send its ECG data to a monitoring center for evaluation.

A principal advantage of patch monitors—and a major selling point for manufacturers—is their low-profile, ergonomic, and patient-friendly design. Patients do not have to manage wires or batteries and are able to shower with their devices. Studies show that these features increase patient satisfaction and compliance, resulting in increased diagnostic yield.^21,22 Additionally, patch monitors have the advantage of a longer continuous monitoring period than traditional Holter devices (2 weeks vs 1 or 2 days), affording an opportunity to capture events that occur less frequently.

Validation studies have reinforced their efficacy and utility in clinical scenarios.^22,23 In large part because of the extended monitoring period, patch monitors have been shown to have greater diagnostic yield than the 24-hour Holter monitor in symptomatic patients undergoing workup for suspected arrhythmia.

The role of patch monitors in evaluating atrial fibrillation is also being established. For patients with cryptogenic stroke, patch monitors have shown better atrial fibrillation detection than the 24-hour Holter monitor.²⁴ Compared with traditional loop monitors, patch monitors have the added advantage of assessing total atrial fibrillation burden. Further, although screening for atrial fibrillation with a traditional 12-lead ECG monitor has not been shown to be effective, clinical studies have found that the patch monitor may be a useful screening tool for high-risk patients.^25,26

Nevertheless, patch monitors have drawbacks. They are not capable of long-term monitoring, owing to battery and adhesive limitations.²⁰ More important, they have  been able to offer only single-channel acquisition, which makes it more difficult to detect an arrhythmia that is characterized by a change in QRS axis or change in QRS width, or to distinguish an arrhythmia from an artifact. This appears to be changing, however, as several manufacturers have recently developed multilead ECG patch monitors or attachments and are attempting to merge this technology with fully capable remote telemetry.

Recent improvements in battery life, memory, detection algorithms, wireless transmission, cellular communication, and adhesives have enabled multiple features to be combined into a single device. Patch monitors, for example, are small devices that now offer full-disclosure recording, extended monitoring, and telemetry transmitting. Automated arrhythmia recognition that triggers recording is central to all modern devices, regardless of type.

As a result of these trends, the traditional features used to differentiate devices may become less applicable. The classic Holter monitor may become obsolete as its advantages (full disclosure, continuous recording) are being incorporated into smaller devices that can record longer. Similarly, external monitors that have the capacity for full disclosure and continuous recording are no longer loop recorders in that they do not record into a circular memory.

It may be preferable to describe all non-Holter devices as event monitors or ambulatory monitors, with the main distinguishing features being the ability to transmit data (telemetry), full disclosure vs patient- or arrhythmia-activated recording, and single-channel or multichannel recording (single-lead or 3-lead ECG).

The following are the main distinguishing features that should influence the choice of device for a given clinical context.

Real-time data evaluation provided by mobile telemetry makes this feature ideal to monitor patients with suspected high-risk arrhythmias and their response to antiarrhythmic therapy.

Full-disclosure recording is necessary to assess the overall burden of an arrhythmia, which is frequently important in making treatment decisions, risk-stratifying, and assessing response to therapy. In contrast, patient- or arrhythmia-activated devices are best used when the goal is simply to establish the presence of an arrhythmia.

Multichannel recording may be better than single-channel recording, as it is needed to determine the anatomic origin of an arrhythmia, as might be the case in risk-stratification in a patient with a ventricular tachycardia.

Long duration. The clinician must have a reasonable estimate of how often the symptoms or arrhythmia occur to determine which device will offer a monitoring duration sufficient to detect an arrhythmia.

NEWER TECHNOLOGIES

The newest ambulatory ECG devices build on the foundational concepts of the older ones. However, with miniaturized electronic circuits, Bluetooth, Wi-Fi, and smartphones, these new devices can capture ECG tracings and diagnose offending arrhythmias on more consumer-friendly devices.

Smartphones and smartwatches have become increasingly powerful. Some have the ability to capture, display, and record the cardiac waveform. One manufacturer to capitalize on these technologies, AliveCor (Mountain View, CA), has developed 2 products capable of generating a single-lead ECG recording using either a smartphone (KardiaMobile) or an Apple watch (KardiaBand).

KardiaMobile has a 2-electrode band that can be carried in a pocket or attached to the back of a smartphone (Figure 1). The user places 1 or 2 fingers from each hand on the electrodes, and the device sends an ultrasound signal that is picked up by the smartphone’s microphone. The signal is digitized to produce a 30-second ECG tracing on the phone’s screen. A proprietary algorithm analyzes the rhythm and generates a description of “normal” or “possible atrial fibrillation.” The ECG is then uploaded to a cloud-based storage system for later access or transmission. KardiaMobile is compatible with both iOS and Android devices.

The KardiaBand is a specialized Apple watch band that has an electrode embedded in it. The user places a thumb on the electrode for 30 seconds, and an ECG tracing is displayed on the watch screen.

The Kardia devices were developed (and advertised) predominantly to assess atrial fibrillation. Studies have validated the accuracy of their algorithm. One study showed that, compared with physician-interpreted ECGs, the algorithm had a 96.6% sensitivity and 94.1% specificity for detecting atrial fibrillation.²⁷ They have been found useful for detecting and evaluating atrial fibrillation in several clinical scenarios, including discharge monitoring in patients after ablation or cardiac surgery.^28,29 In a longer study of patients at risk of stroke, twice-weekly ECG screening using a Kardia device for 1 year was more likely to detect incident atrial fibrillation than routine care alone.³⁰

Also, the Kardia devices can effectively function as post-event recorders when activated by patients when they experience symptoms. In a small study of outpatients with palpitations and a prior nondiagnostic workup, the KardiaMobile device was found to be noninferior to external loop recorders for detecting arrhythmias.³¹ Additional studies are assessing Kardia’s utility in other scenarios, including the evaluation of ST-segment elevation myocardial infarction^32,33 and QT interval for patients receiving antiarrhythmic therapy.³⁴

Cardiio Inc. (Cambridge, MA) has developed technology to screen for atrial fibrillation using an app that requires no additional external hardware. Instead, the app uses a smartphone’s camera and flashlight to perform photo­plethysmography to detect pulsatile changes in blood volume and generate a waveform. Based on waveform variability, a proprietary algorithm attempts to determine whether the user is in atrial fibrillation. It does not produce an ECG tracing. Initial studies suggest it has good diagnostic accuracy and potential utility as a population-based screening tool,^35,36 but it has not been fully validated.

Recently, Apple entered the arena of ambulatory cardiac monitoring with the release of its fourth-generation watch (Apple Watch Series 4 model). This watch has built-in electrodes that can generate a single-lead ECG on the watch screen. Its algorithm can discriminate between atrial fibrillation and sinus rhythm, but it has not been assessed for its ability to evaluate other arrhythmias. Even though it has been “cleared” by the US Food and Drug Administration, it is approved only for informational use, not to make a medical diagnosis.

Integration of ambulatory ECG technology with smartphone and watch technology is an exciting new wearable option for arrhythmia detection. The patient-centered and controlled nature of these devices have the potential to help patients with palpitations or other symptoms determine if their cardiac rhythms are normal.

This technology, however, is still in its infancy and has many limitations. For example, even though these devices can function as post-event recorders, they depend on user-device interactions. Plus, they cannot yet perform continuous arrhythmia monitoring like modern loop recorders.

Additionally, automated analysis has largely been limited to distinguishing atrial fibrillation from normal sinus rhythm. It is uncertain how effective the devices may be in evaluating other arrhythmias. Single-lead ECG recordings, as discussed, have limited interpretability and value. And even though studies have shown utility in certain clinical scenarios, large-scale validation studies are lacking. This technology will likely continue to be developed and its clinical value improved; however, its clinical use requires careful consideration and collaborative physician-patient decision-making.

The development of smartphone and watch ECG technology has led to a rise in direct-to-consumer healthcare delivery. By devising technology that is appealing, useful, and affordable, companies can bypass the insurer and practitioner by targeting increasingly health-literate consumers. For many companies, there is great motivation to enter this healthcare space. Wearable devices are immensely popular and, as a result, generate substantial revenue. One analysis estimates that 1 in 10 Americans (nearly 30 million) owns a wearable, smart-technology device.³⁷

This direct-to-consumer approach has specific implications for cardiology and, more broadly, for healthcare overall. By directly selling to consumers, companies have an opportunity to reach many more people. The Apple Watch Series 4 has taken this a step further: by including this technology in the watch, consumers not necessarily seeking an ambulatory cardiac monitor will have one with a watch purchase. This could lead to increases in monitoring and could alert people to previously undiagnosed disorders.

For consumers, this technology can empower them to choose how and when to be monitored. Further, it gives them personal control of their healthcare data, and helps move the point of care out of hospitals and clinics and into the home.

But wearable medical technology and direct-to-consumer healthcare have risks. First, in the absence of appropriate regulation, patients have to distinguish between products that are well validated and those that are unproven. Consumers also may inappropriately use devices for indications or in scenarios for which the value is uncertain.

Also, there is potential for confusion and misunderstanding of results, including false-positive readings, which could lead to excessive and costly use of unnecessary diagnostic workups. Instead of providing peace of mind, these devices could cause greater worry. This may be especially true with the newest Apple watch, as this product will introduce ambulatory ECG to a younger and healthier segment of the population who are less likely to have true disease.

Further, these devices have algorithms that detect atrial fibrillation, but is it the same as that detected by traditional methods? Sometimes termed “subclinical” atrial fibrillation, it poses uncertainties: ie, Do patients need anticoagulation, pharmacologic therapy, and ablation? The optimal management of subclinical atrial fibrillation, as well as its similarities to and differences from atrial fibrillation diagnosed by traditional methods, are topics that need further study.

Wearable technology is still developing and will continue to do so. Medical practice will have to adapt to it.

FUTURE DIRECTIONS

Changes in technology have led to remarkable advances in the convenience and accuracy of ambulatory ECG monitoring. Ongoing research is expected to lead to even more improvements. Devices will become more ergonomic and technically capable, and they may expand monitoring to include other biologic parameters beyond ECG.

Comfort is important to ensure patient adherence. Newer, flexible electronics embedded in ultrathin materials can potentially improve the wearability of devices that require gel electrodes or adhesive patches.³⁸ Wireless technology may obviate the need for on-skin attachments. Future recording systems may be embedded into clothing or incorporated into wearable vests capable of wirelessly transmitting ECG signals to separate recording stations.³⁹

In addition to becoming smaller and more comfortable, future devices will be more technically capable, leading to a merging of technologies that will further blur the distinctions among devices. Eventually, the features of full disclosure, extended monitoring duration, and telemetric communication will all be present together. Perhaps more important is that ambulatory ECG devices may become fully capable biosensor monitors. These devices would have the potential to monitor respiratory frequency, peripheral oxygen saturation, potassium levels, and arterial pulse pressure.^39,40

A mbulatory electrocardiography (ECG) began in 1949 when Norman “Jeff” Holter developed a monitor that could wirelessly transmit electrophysiologic data.¹ His original device used vacuum tubes, weighed 85 pounds, and had to be carried in a backpack. Furthermore, it could send a signal a distance of only 1 block.²

At the time, it was uncertain if this technology would have any clinical utility. However, in 1952, Holter published the first tracing of abnormal cardiac electrical activity in a patient who had suffered a posterior myocardial infarction.³ By the 1960s, Holter monitoring systems were in full production and use.⁴

Since then, advances in technology have led to small, lightweight devices that enable clinicians to evaluate patients for arrhythmias in a real-world context for extended times, often with the ability to respond in real time.

Many ambulatory devices are available, and choosing the optimal one requires an understanding of which features they have and which are the most appropriate for the specific clinical context. This article reviews the features, indications, advantages, and disadvantages of current devices, and their best use in clinical practice.

INDICATIONS FOR AMBULATORY ECG MONITORING

Diagnosis

The most common diagnostic role of monitoring is to correlate unexplained symptoms, including palpitations, presyncope, and syncope, with a transient cardiac arrhythmia. Monitoring can be considered successful if findings on ECG identify risks for serious arrhythmia and either correlate symptoms with those findings or demonstrate no arrhythmia when symptoms occur.

A range of arrhythmias can cause symptoms. Some, such as premature atrial contractions and premature ventricular contractions, may be benign in many clinical contexts. Others, such as atrial fibrillation, are more serious, and some, such as third-degree heart block and ventricular tachycardia, can be lethal.

Arrhythmia symptoms can vary in frequency and cause differing degrees of debility. The patient’s symptoms, family history, and baseline ECG findings can suggest a more serious or a less serious underlying rhythm. These factors are important when determining which device is most appropriate.

Ambulatory ECG can also be useful in looking for a cause of cryptogenic stroke, ie, an ischemic stroke with an unexplained cause, even after a thorough initial workup. Paroxysmal atrial fibrillation is a frequent cause of cryptogenic stroke, and because it is transient, short-term inpatient telemetry may not be sufficient to detect it. Extended cardiac monitoring, lasting weeks or even months, is often needed for clinicians to make this diagnosis and initiate appropriate secondary prevention.

Prognosis: Identifying patients at risk

In a patient with known structural or electrical heart disease, ambulatory ECG can be used to stratify risk. This is particularly true in evaluating conditions associated with sudden cardiac death.

For example, hypertrophic cardiomyopathy and arrhythmogenic right ventricular dysplasia or cardiomyopathy are 2 cardiomyopathies that can manifest clinically with ventricular arrhythmias and sudden cardiac death. Ambulatory ECG can detect premature ventricular contractions and ventricular tachycardia and identify their frequency, duration, and anatomic origin. This information is useful in assessing risk of sudden cardiac death and determining the need for an implantable cardioverter-defibrillator.

Similarly, Wolff-Parkinson-White syndrome, involving rapid conduction through an accessory pathway, is associated with increased risk of ventricular fibrillation and sudden cardiac death. Ambulatory ECG monitoring can identify patients who have electrical features that portend the development of ventricular fibrillation.

Also associated with sudden cardiac death are the inherited channelopathies, a heterogeneous group of primary arrhythmic disorders without accompanying structural pathology. Ambulatory ECG monitoring can detect transient electrical changes and nonsustained ventricular arrhythmias that would indicate the patient is at high risk of these disorders.

Assessing arrhythmia treatment

Arrhythmia monitoring using an ambulatory ECG device can also provide data to assess the efficacy of treatment under several circumstances.

The “pill-in-the-pocket” approach to treating atrial fibrillation, for example, involves self-administering a single dose of an antiarrhythmic drug when symptoms occur. Patients with infrequent but bothersome episodes can use an ambulatory ECG device to detect when they are having atrial fibrillation, take their prescribed drug, and see whether it terminates the arrhythmia, all without going to the hospital.

Ambulatory ECG also is useful for assessing pharmacologic or ablative therapy in patients with atrial fibrillation or ventricular tachycardia. Monitoring for several weeks can help clinicians assess the burden of atrial fibrillation when using a rhythm-control strategy; assessing the ventricular rate in real-world situations is useful to determine the success of a rate-control strategy. Shortly after ablation of either atrial fibrillation or ventricular tachycardia, ECG home monitoring for 24 to 48 hours can detect asymptomatic recurrence and treatment failure.

Some antiarrhythmic drugs can prolong the QT interval. Ambulatory ECG devices that feature real-time monitoring can be used during drug initiation, enabling the clinician to monitor the QT interval without admitting the patient to the hospital.

Ultimately, ambulatory ECG monitoring is most commonly used to evaluate symptoms. Because arrhythmias and specific symptoms are unpredictable and transient, extended monitoring in a real-world setting allows for a more comprehensive evaluation than a standard 10-second ECG recording.

Continuous external monitoring: The Holter monitor

Recording is typically done continuously for 24 to 48 hours, although some newer devices can record for longer. Patients can press a button to note when they are experiencing symptoms, allowing for potential correlation with ECG abnormalities. The data are stored on a flash drive that can be uploaded for analysis after recording is complete.

What is its best use? Given its relatively short duration of monitoring, the Holter device is typically used to evaluate symptoms that occur daily or nearly daily. An advantage of the Holter monitor is its ability to record continuously, without requiring the patient to interact with the device. This feature provides “full disclosure,” which is the ability to see arrhythmia data from the entire recording period.

These features make Holter monitoring useful to identify suspected frequently occurring silent arrhythmias or to assess the overall arrhythmia burden. A typical Holter report can contain information on the heart rate (maximum, minimum, and average), ectopic beats, and tachy- and bradyarrhythmias, as well as representative samples.

The Holter device is familiar to most practitioners and remains an effective choice for ambulatory ECG monitoring. However, its use has largely been replaced by newer devices that overcome the Holter’s drawbacks, particularly its short duration of monitoring and the need for postmonitoring analysis. Additionally, although newer Holter devices are more ergonomic, some patients find the wires and gel electrodes uncomfortable or inconvenient.

Intermittent monitoring: Event recorders

Unlike the continuous monitors, intermittent recording devices (also called event recorders), capture and store tracings only during an event.

Intermittent recording monitors are of 2 general types: post-event recorders and loop recorders. These devices can extend the overall duration of observation, which can be especially useful for those whose symptoms and arrhythmias are infrequent.

Post-event recorders are small and self-contained, not requiring electrodes (Figure 1). The device is carried by the patient but not worn continuously. When the patient experiences symptoms, he or she places the device against the chest and presses a button to begin recording. These tracings are stored on the device and can be transmitted by telephone to a data center for analysis. Although post-event recorders allow for monitoring periods typically up to 30 days, they are limited by requiring the patient to act to record an event.

What is its best use? These devices are best used in patients who have infrequent symptoms and are at low risk. Transient or debilitating symptoms, including syncope, can limit the possibility of capturing an event.

Intermittent monitoring: Loop recorders

Loop recorders monitor continuously but record only intermittently. The name refers to the device’s looping memory: ie, to extend how long it can be used and make the most of its limited storage, the device records over previously captured data, saving only the most important data. The device saves the data whenever it detects an abnormal rhythm or the patient experiences symptoms and pushes a button. Data are recorded for a specified time before and after the activation, typically 30 seconds.

Loop recorders come in 2 types: external and implantable.

External loop recorders

External loop recorders look like Holter monitors (Figure 1), but they have the advantage of a much longer observation period—typically up to 1 month. The newest devices have even greater storage capacity and can provide “backward” memory, saving data that were captured just before the patient pushed the button.

In studies of patients with palpitations, presyncope, or syncope, external loop recorders had greater diagnostic yield than traditional 24-hour Holter monitors.^7,8 This finding was supported by a clinical trial that found 30-day monitoring with an external loop recorder led to a 5-fold increase in detecting atrial fibrillation in patients with cryptogenic stroke.⁹

Disadvantages of external loop recorders are limited memory storage, a considerable reliance on patient activation of the device, and wires and electrodes that need to be worn continuously.

What is their best use? External loop recorders are most effective when used to detect an arrhythmia or to correlate infrequent symptoms with an arrhythmia. They are most appropriately used in patients whose symptoms occur more often than every 4 weeks. They are less useful in assessing very infrequent symptoms, overall arrhythmia burden, or responsiveness to therapy.¹⁰

Implantable loop recorders are small devices that contain a pair of sensing electrodes housed within an outer shell (Figure 1). They are implanted subcutaneously, usually in the left parasternal region, using local anesthesia. The subcutaneous location eliminates many of the drawbacks of the skin-electrode interface of external loop recorders.

Similar to the external loop recorder, this device monitors continuously and can be activated to record either by the patient by pressing a button on a separate device, or automatically when an arrhythmia is detected using a preprogrammed algorithm.

In contrast to external devices, many internal loop recorders have a battery life and monitoring capability of up to 3 years. This extended monitoring period has been shown to increase the likelihood of diagnosing syncope or infrequent palpitations.^11,12 Given that paroxysmal atrial fibrillation can be sporadic and reveal itself months after a stroke, internal loop recorders may also have a role in evaluating cryptogenic stroke.^13,14

The most important drawbacks of internal loop recorders are the surgical procedure for insertion, their limited memory storage, and high upfront cost.¹⁵ Furthermore, even though they allow for extended monitoring, there may be diminishing returns for prolonged observation.

What is their best use? For patients with palpitations, intermittent event monitoring has been shown to be cost-effective for the first 2 weeks, but after 3 weeks, the cost per diagnosis increases dramatically.¹⁶ As a result, internal loop recorders are reserved primarily for scenarios in which prolonged external monitoring has not revealed a source of arrhythmia despite a high degree of suspicion.

Mobile cardiac telemetry

Mobile cardiac telemetry builds on other ECG monitoring systems by adding real-time communication and technician evaluation.

Physically, these devices resemble either hand-held event records, with a single-channel sensing unit embedded in the case, or a traditional Holter monitor, with 3 channels, wires, and electrodes  (Figure 1).

The sensor wirelessly communicates with a nearby portable monitor, which continuously observes and analyzes the patient’s heart rhythm. When an abnormal rhythm is detected or when the patient marks the presence of symptoms, data are recorded and sent in real time via a cellular network to a monitoring center; the newest monitors can send data via any Wi-Fi system. The rhythm is then either evaluated by a trained technician or relayed to a physician. If necessary, the patient can be contacted immediately.

Mobile cardiac telemetry is typically used for up to 30 days, which  allows for evaluation of less-frequent symptoms. As a result, it may have a higher diagnostic yield for palpitations, syncope, and presyncope than the 24-hour Holter monitor.¹⁷

Further, perhaps because mobile cardiac telemetry relies less on stored information and requires less patient-device interaction than external loop recorders, it is more effective at symptom evaluation.¹⁸

Mobile cardiac telemetry also has a diagnostic role in evaluating patients with cryptogenic stroke. This is based on studies showing it has a high rate of atrial fibrillation detection in this patient population and is more effective at determining overall atrial fibrillation burden than loop recorders.^18,19

What is its best use? The key advantage of mobile cardiac telemetry is its ability to make rhythm assessments and communicate with technicians in real time. This allows high-risk patients to be immediately alerted to a life-threatening arrhythmia. It also gives providers an opportunity to initiate anticoagulation or titrate antiarrhythmic therapy in the outpatient setting without a delay in obtaining information. This intensive monitoring, however, requires significant manpower, which translates to higher cost, averaging 3 times that of other standard external monitors.¹⁵

Patch monitors

These ultraportable devices are a relatively unobtrusive and easy-to-use alternative for short-term ambulatory ECG monitoring. They monitor continuously with full disclosure, outpatient telemetry, and post-event recording features.

Patch monitors are small, leadless, wireless, and water-resistant (Figure 1). They are affixed to the left pectoral region with a waterproof adhesive and can be worn for 14 to 28 days. Recording is usually done continuously; however, these devices have an event marker button that can be pressed when the user experiences symptoms. They acquire a single channel of data, and each manufacturer has a proprietary algorithm for automated rhythm detection and analysis.²⁰

Several manufacturers produce ECG patch monitors. Two notable devices are the Zio patch (iRhythm Technologies, San Francisco, CA) and the Mobile Cardiac Outpatient Telemetry patch (BioTelemetry, Inc, Malvern, PA).

The Zio patch is a continuous external monitor with full disclosure. It is comparable to the Holter monitor, but has a longer recording period. After completing a 2-week monitoring period, the device is returned for comprehensive rhythm analysis. A typical Zio report contains information on atrial fibrillation burden, ectopic rhythm burden, symptom and rhythm correlation, heart rate trends, and relevant rhythm strips.

The Mobile Cardiac Outpatient Telemetry patch collects data continuously and communicates wirelessly by Bluetooth to send its ECG data to a monitoring center for evaluation.

A principal advantage of patch monitors—and a major selling point for manufacturers—is their low-profile, ergonomic, and patient-friendly design. Patients do not have to manage wires or batteries and are able to shower with their devices. Studies show that these features increase patient satisfaction and compliance, resulting in increased diagnostic yield.^21,22 Additionally, patch monitors have the advantage of a longer continuous monitoring period than traditional Holter devices (2 weeks vs 1 or 2 days), affording an opportunity to capture events that occur less frequently.

Validation studies have reinforced their efficacy and utility in clinical scenarios.^22,23 In large part because of the extended monitoring period, patch monitors have been shown to have greater diagnostic yield than the 24-hour Holter monitor in symptomatic patients undergoing workup for suspected arrhythmia.

The role of patch monitors in evaluating atrial fibrillation is also being established. For patients with cryptogenic stroke, patch monitors have shown better atrial fibrillation detection than the 24-hour Holter monitor.²⁴ Compared with traditional loop monitors, patch monitors have the added advantage of assessing total atrial fibrillation burden. Further, although screening for atrial fibrillation with a traditional 12-lead ECG monitor has not been shown to be effective, clinical studies have found that the patch monitor may be a useful screening tool for high-risk patients.^25,26

Nevertheless, patch monitors have drawbacks. They are not capable of long-term monitoring, owing to battery and adhesive limitations.²⁰ More important, they have  been able to offer only single-channel acquisition, which makes it more difficult to detect an arrhythmia that is characterized by a change in QRS axis or change in QRS width, or to distinguish an arrhythmia from an artifact. This appears to be changing, however, as several manufacturers have recently developed multilead ECG patch monitors or attachments and are attempting to merge this technology with fully capable remote telemetry.

Recent improvements in battery life, memory, detection algorithms, wireless transmission, cellular communication, and adhesives have enabled multiple features to be combined into a single device. Patch monitors, for example, are small devices that now offer full-disclosure recording, extended monitoring, and telemetry transmitting. Automated arrhythmia recognition that triggers recording is central to all modern devices, regardless of type.

As a result of these trends, the traditional features used to differentiate devices may become less applicable. The classic Holter monitor may become obsolete as its advantages (full disclosure, continuous recording) are being incorporated into smaller devices that can record longer. Similarly, external monitors that have the capacity for full disclosure and continuous recording are no longer loop recorders in that they do not record into a circular memory.

It may be preferable to describe all non-Holter devices as event monitors or ambulatory monitors, with the main distinguishing features being the ability to transmit data (telemetry), full disclosure vs patient- or arrhythmia-activated recording, and single-channel or multichannel recording (single-lead or 3-lead ECG).

The following are the main distinguishing features that should influence the choice of device for a given clinical context.

Real-time data evaluation provided by mobile telemetry makes this feature ideal to monitor patients with suspected high-risk arrhythmias and their response to antiarrhythmic therapy.

Full-disclosure recording is necessary to assess the overall burden of an arrhythmia, which is frequently important in making treatment decisions, risk-stratifying, and assessing response to therapy. In contrast, patient- or arrhythmia-activated devices are best used when the goal is simply to establish the presence of an arrhythmia.

Multichannel recording may be better than single-channel recording, as it is needed to determine the anatomic origin of an arrhythmia, as might be the case in risk-stratification in a patient with a ventricular tachycardia.

Long duration. The clinician must have a reasonable estimate of how often the symptoms or arrhythmia occur to determine which device will offer a monitoring duration sufficient to detect an arrhythmia.

NEWER TECHNOLOGIES

The newest ambulatory ECG devices build on the foundational concepts of the older ones. However, with miniaturized electronic circuits, Bluetooth, Wi-Fi, and smartphones, these new devices can capture ECG tracings and diagnose offending arrhythmias on more consumer-friendly devices.

Smartphones and smartwatches have become increasingly powerful. Some have the ability to capture, display, and record the cardiac waveform. One manufacturer to capitalize on these technologies, AliveCor (Mountain View, CA), has developed 2 products capable of generating a single-lead ECG recording using either a smartphone (KardiaMobile) or an Apple watch (KardiaBand).

KardiaMobile has a 2-electrode band that can be carried in a pocket or attached to the back of a smartphone (Figure 1). The user places 1 or 2 fingers from each hand on the electrodes, and the device sends an ultrasound signal that is picked up by the smartphone’s microphone. The signal is digitized to produce a 30-second ECG tracing on the phone’s screen. A proprietary algorithm analyzes the rhythm and generates a description of “normal” or “possible atrial fibrillation.” The ECG is then uploaded to a cloud-based storage system for later access or transmission. KardiaMobile is compatible with both iOS and Android devices.

The KardiaBand is a specialized Apple watch band that has an electrode embedded in it. The user places a thumb on the electrode for 30 seconds, and an ECG tracing is displayed on the watch screen.

The Kardia devices were developed (and advertised) predominantly to assess atrial fibrillation. Studies have validated the accuracy of their algorithm. One study showed that, compared with physician-interpreted ECGs, the algorithm had a 96.6% sensitivity and 94.1% specificity for detecting atrial fibrillation.²⁷ They have been found useful for detecting and evaluating atrial fibrillation in several clinical scenarios, including discharge monitoring in patients after ablation or cardiac surgery.^28,29 In a longer study of patients at risk of stroke, twice-weekly ECG screening using a Kardia device for 1 year was more likely to detect incident atrial fibrillation than routine care alone.³⁰

Also, the Kardia devices can effectively function as post-event recorders when activated by patients when they experience symptoms. In a small study of outpatients with palpitations and a prior nondiagnostic workup, the KardiaMobile device was found to be noninferior to external loop recorders for detecting arrhythmias.³¹ Additional studies are assessing Kardia’s utility in other scenarios, including the evaluation of ST-segment elevation myocardial infarction^32,33 and QT interval for patients receiving antiarrhythmic therapy.³⁴

Cardiio Inc. (Cambridge, MA) has developed technology to screen for atrial fibrillation using an app that requires no additional external hardware. Instead, the app uses a smartphone’s camera and flashlight to perform photo­plethysmography to detect pulsatile changes in blood volume and generate a waveform. Based on waveform variability, a proprietary algorithm attempts to determine whether the user is in atrial fibrillation. It does not produce an ECG tracing. Initial studies suggest it has good diagnostic accuracy and potential utility as a population-based screening tool,^35,36 but it has not been fully validated.

Recently, Apple entered the arena of ambulatory cardiac monitoring with the release of its fourth-generation watch (Apple Watch Series 4 model). This watch has built-in electrodes that can generate a single-lead ECG on the watch screen. Its algorithm can discriminate between atrial fibrillation and sinus rhythm, but it has not been assessed for its ability to evaluate other arrhythmias. Even though it has been “cleared” by the US Food and Drug Administration, it is approved only for informational use, not to make a medical diagnosis.

Integration of ambulatory ECG technology with smartphone and watch technology is an exciting new wearable option for arrhythmia detection. The patient-centered and controlled nature of these devices have the potential to help patients with palpitations or other symptoms determine if their cardiac rhythms are normal.

This technology, however, is still in its infancy and has many limitations. For example, even though these devices can function as post-event recorders, they depend on user-device interactions. Plus, they cannot yet perform continuous arrhythmia monitoring like modern loop recorders.

Additionally, automated analysis has largely been limited to distinguishing atrial fibrillation from normal sinus rhythm. It is uncertain how effective the devices may be in evaluating other arrhythmias. Single-lead ECG recordings, as discussed, have limited interpretability and value. And even though studies have shown utility in certain clinical scenarios, large-scale validation studies are lacking. This technology will likely continue to be developed and its clinical value improved; however, its clinical use requires careful consideration and collaborative physician-patient decision-making.

The development of smartphone and watch ECG technology has led to a rise in direct-to-consumer healthcare delivery. By devising technology that is appealing, useful, and affordable, companies can bypass the insurer and practitioner by targeting increasingly health-literate consumers. For many companies, there is great motivation to enter this healthcare space. Wearable devices are immensely popular and, as a result, generate substantial revenue. One analysis estimates that 1 in 10 Americans (nearly 30 million) owns a wearable, smart-technology device.³⁷

This direct-to-consumer approach has specific implications for cardiology and, more broadly, for healthcare overall. By directly selling to consumers, companies have an opportunity to reach many more people. The Apple Watch Series 4 has taken this a step further: by including this technology in the watch, consumers not necessarily seeking an ambulatory cardiac monitor will have one with a watch purchase. This could lead to increases in monitoring and could alert people to previously undiagnosed disorders.

For consumers, this technology can empower them to choose how and when to be monitored. Further, it gives them personal control of their healthcare data, and helps move the point of care out of hospitals and clinics and into the home.

But wearable medical technology and direct-to-consumer healthcare have risks. First, in the absence of appropriate regulation, patients have to distinguish between products that are well validated and those that are unproven. Consumers also may inappropriately use devices for indications or in scenarios for which the value is uncertain.

Also, there is potential for confusion and misunderstanding of results, including false-positive readings, which could lead to excessive and costly use of unnecessary diagnostic workups. Instead of providing peace of mind, these devices could cause greater worry. This may be especially true with the newest Apple watch, as this product will introduce ambulatory ECG to a younger and healthier segment of the population who are less likely to have true disease.

Further, these devices have algorithms that detect atrial fibrillation, but is it the same as that detected by traditional methods? Sometimes termed “subclinical” atrial fibrillation, it poses uncertainties: ie, Do patients need anticoagulation, pharmacologic therapy, and ablation? The optimal management of subclinical atrial fibrillation, as well as its similarities to and differences from atrial fibrillation diagnosed by traditional methods, are topics that need further study.

Wearable technology is still developing and will continue to do so. Medical practice will have to adapt to it.

FUTURE DIRECTIONS

Changes in technology have led to remarkable advances in the convenience and accuracy of ambulatory ECG monitoring. Ongoing research is expected to lead to even more improvements. Devices will become more ergonomic and technically capable, and they may expand monitoring to include other biologic parameters beyond ECG.

Comfort is important to ensure patient adherence. Newer, flexible electronics embedded in ultrathin materials can potentially improve the wearability of devices that require gel electrodes or adhesive patches.³⁸ Wireless technology may obviate the need for on-skin attachments. Future recording systems may be embedded into clothing or incorporated into wearable vests capable of wirelessly transmitting ECG signals to separate recording stations.³⁹

In addition to becoming smaller and more comfortable, future devices will be more technically capable, leading to a merging of technologies that will further blur the distinctions among devices. Eventually, the features of full disclosure, extended monitoring duration, and telemetric communication will all be present together. Perhaps more important is that ambulatory ECG devices may become fully capable biosensor monitors. These devices would have the potential to monitor respiratory frequency, peripheral oxygen saturation, potassium levels, and arterial pulse pressure.^39,40

A mbulatory electrocardiography (ECG) began in 1949 when Norman “Jeff” Holter developed a monitor that could wirelessly transmit electrophysiologic data.¹ His original device used vacuum tubes, weighed 85 pounds, and had to be carried in a backpack. Furthermore, it could send a signal a distance of only 1 block.²

At the time, it was uncertain if this technology would have any clinical utility. However, in 1952, Holter published the first tracing of abnormal cardiac electrical activity in a patient who had suffered a posterior myocardial infarction.³ By the 1960s, Holter monitoring systems were in full production and use.⁴

Since then, advances in technology have led to small, lightweight devices that enable clinicians to evaluate patients for arrhythmias in a real-world context for extended times, often with the ability to respond in real time.

Many ambulatory devices are available, and choosing the optimal one requires an understanding of which features they have and which are the most appropriate for the specific clinical context. This article reviews the features, indications, advantages, and disadvantages of current devices, and their best use in clinical practice.

INDICATIONS FOR AMBULATORY ECG MONITORING

Diagnosis

The most common diagnostic role of monitoring is to correlate unexplained symptoms, including palpitations, presyncope, and syncope, with a transient cardiac arrhythmia. Monitoring can be considered successful if findings on ECG identify risks for serious arrhythmia and either correlate symptoms with those findings or demonstrate no arrhythmia when symptoms occur.

A range of arrhythmias can cause symptoms. Some, such as premature atrial contractions and premature ventricular contractions, may be benign in many clinical contexts. Others, such as atrial fibrillation, are more serious, and some, such as third-degree heart block and ventricular tachycardia, can be lethal.

Arrhythmia symptoms can vary in frequency and cause differing degrees of debility. The patient’s symptoms, family history, and baseline ECG findings can suggest a more serious or a less serious underlying rhythm. These factors are important when determining which device is most appropriate.

Ambulatory ECG can also be useful in looking for a cause of cryptogenic stroke, ie, an ischemic stroke with an unexplained cause, even after a thorough initial workup. Paroxysmal atrial fibrillation is a frequent cause of cryptogenic stroke, and because it is transient, short-term inpatient telemetry may not be sufficient to detect it. Extended cardiac monitoring, lasting weeks or even months, is often needed for clinicians to make this diagnosis and initiate appropriate secondary prevention.

Prognosis: Identifying patients at risk

In a patient with known structural or electrical heart disease, ambulatory ECG can be used to stratify risk. This is particularly true in evaluating conditions associated with sudden cardiac death.

For example, hypertrophic cardiomyopathy and arrhythmogenic right ventricular dysplasia or cardiomyopathy are 2 cardiomyopathies that can manifest clinically with ventricular arrhythmias and sudden cardiac death. Ambulatory ECG can detect premature ventricular contractions and ventricular tachycardia and identify their frequency, duration, and anatomic origin. This information is useful in assessing risk of sudden cardiac death and determining the need for an implantable cardioverter-defibrillator.

Similarly, Wolff-Parkinson-White syndrome, involving rapid conduction through an accessory pathway, is associated with increased risk of ventricular fibrillation and sudden cardiac death. Ambulatory ECG monitoring can identify patients who have electrical features that portend the development of ventricular fibrillation.

Also associated with sudden cardiac death are the inherited channelopathies, a heterogeneous group of primary arrhythmic disorders without accompanying structural pathology. Ambulatory ECG monitoring can detect transient electrical changes and nonsustained ventricular arrhythmias that would indicate the patient is at high risk of these disorders.

Assessing arrhythmia treatment

Arrhythmia monitoring using an ambulatory ECG device can also provide data to assess the efficacy of treatment under several circumstances.

The “pill-in-the-pocket” approach to treating atrial fibrillation, for example, involves self-administering a single dose of an antiarrhythmic drug when symptoms occur. Patients with infrequent but bothersome episodes can use an ambulatory ECG device to detect when they are having atrial fibrillation, take their prescribed drug, and see whether it terminates the arrhythmia, all without going to the hospital.

Ambulatory ECG also is useful for assessing pharmacologic or ablative therapy in patients with atrial fibrillation or ventricular tachycardia. Monitoring for several weeks can help clinicians assess the burden of atrial fibrillation when using a rhythm-control strategy; assessing the ventricular rate in real-world situations is useful to determine the success of a rate-control strategy. Shortly after ablation of either atrial fibrillation or ventricular tachycardia, ECG home monitoring for 24 to 48 hours can detect asymptomatic recurrence and treatment failure.

Some antiarrhythmic drugs can prolong the QT interval. Ambulatory ECG devices that feature real-time monitoring can be used during drug initiation, enabling the clinician to monitor the QT interval without admitting the patient to the hospital.

Ultimately, ambulatory ECG monitoring is most commonly used to evaluate symptoms. Because arrhythmias and specific symptoms are unpredictable and transient, extended monitoring in a real-world setting allows for a more comprehensive evaluation than a standard 10-second ECG recording.

Continuous external monitoring: The Holter monitor

Recording is typically done continuously for 24 to 48 hours, although some newer devices can record for longer. Patients can press a button to note when they are experiencing symptoms, allowing for potential correlation with ECG abnormalities. The data are stored on a flash drive that can be uploaded for analysis after recording is complete.

What is its best use? Given its relatively short duration of monitoring, the Holter device is typically used to evaluate symptoms that occur daily or nearly daily. An advantage of the Holter monitor is its ability to record continuously, without requiring the patient to interact with the device. This feature provides “full disclosure,” which is the ability to see arrhythmia data from the entire recording period.

These features make Holter monitoring useful to identify suspected frequently occurring silent arrhythmias or to assess the overall arrhythmia burden. A typical Holter report can contain information on the heart rate (maximum, minimum, and average), ectopic beats, and tachy- and bradyarrhythmias, as well as representative samples.

The Holter device is familiar to most practitioners and remains an effective choice for ambulatory ECG monitoring. However, its use has largely been replaced by newer devices that overcome the Holter’s drawbacks, particularly its short duration of monitoring and the need for postmonitoring analysis. Additionally, although newer Holter devices are more ergonomic, some patients find the wires and gel electrodes uncomfortable or inconvenient.

Intermittent monitoring: Event recorders

Unlike the continuous monitors, intermittent recording devices (also called event recorders), capture and store tracings only during an event.

Intermittent recording monitors are of 2 general types: post-event recorders and loop recorders. These devices can extend the overall duration of observation, which can be especially useful for those whose symptoms and arrhythmias are infrequent.

Post-event recorders are small and self-contained, not requiring electrodes (Figure 1). The device is carried by the patient but not worn continuously. When the patient experiences symptoms, he or she places the device against the chest and presses a button to begin recording. These tracings are stored on the device and can be transmitted by telephone to a data center for analysis. Although post-event recorders allow for monitoring periods typically up to 30 days, they are limited by requiring the patient to act to record an event.

What is its best use? These devices are best used in patients who have infrequent symptoms and are at low risk. Transient or debilitating symptoms, including syncope, can limit the possibility of capturing an event.

Intermittent monitoring: Loop recorders

Loop recorders monitor continuously but record only intermittently. The name refers to the device’s looping memory: ie, to extend how long it can be used and make the most of its limited storage, the device records over previously captured data, saving only the most important data. The device saves the data whenever it detects an abnormal rhythm or the patient experiences symptoms and pushes a button. Data are recorded for a specified time before and after the activation, typically 30 seconds.

Loop recorders come in 2 types: external and implantable.

External loop recorders

External loop recorders look like Holter monitors (Figure 1), but they have the advantage of a much longer observation period—typically up to 1 month. The newest devices have even greater storage capacity and can provide “backward” memory, saving data that were captured just before the patient pushed the button.

In studies of patients with palpitations, presyncope, or syncope, external loop recorders had greater diagnostic yield than traditional 24-hour Holter monitors.^7,8 This finding was supported by a clinical trial that found 30-day monitoring with an external loop recorder led to a 5-fold increase in detecting atrial fibrillation in patients with cryptogenic stroke.⁹

Disadvantages of external loop recorders are limited memory storage, a considerable reliance on patient activation of the device, and wires and electrodes that need to be worn continuously.

What is their best use? External loop recorders are most effective when used to detect an arrhythmia or to correlate infrequent symptoms with an arrhythmia. They are most appropriately used in patients whose symptoms occur more often than every 4 weeks. They are less useful in assessing very infrequent symptoms, overall arrhythmia burden, or responsiveness to therapy.¹⁰

Implantable loop recorders are small devices that contain a pair of sensing electrodes housed within an outer shell (Figure 1). They are implanted subcutaneously, usually in the left parasternal region, using local anesthesia. The subcutaneous location eliminates many of the drawbacks of the skin-electrode interface of external loop recorders.

Similar to the external loop recorder, this device monitors continuously and can be activated to record either by the patient by pressing a button on a separate device, or automatically when an arrhythmia is detected using a preprogrammed algorithm.

In contrast to external devices, many internal loop recorders have a battery life and monitoring capability of up to 3 years. This extended monitoring period has been shown to increase the likelihood of diagnosing syncope or infrequent palpitations.^11,12 Given that paroxysmal atrial fibrillation can be sporadic and reveal itself months after a stroke, internal loop recorders may also have a role in evaluating cryptogenic stroke.^13,14

The most important drawbacks of internal loop recorders are the surgical procedure for insertion, their limited memory storage, and high upfront cost.¹⁵ Furthermore, even though they allow for extended monitoring, there may be diminishing returns for prolonged observation.

What is their best use? For patients with palpitations, intermittent event monitoring has been shown to be cost-effective for the first 2 weeks, but after 3 weeks, the cost per diagnosis increases dramatically.¹⁶ As a result, internal loop recorders are reserved primarily for scenarios in which prolonged external monitoring has not revealed a source of arrhythmia despite a high degree of suspicion.

Mobile cardiac telemetry

Mobile cardiac telemetry builds on other ECG monitoring systems by adding real-time communication and technician evaluation.

Physically, these devices resemble either hand-held event records, with a single-channel sensing unit embedded in the case, or a traditional Holter monitor, with 3 channels, wires, and electrodes  (Figure 1).

The sensor wirelessly communicates with a nearby portable monitor, which continuously observes and analyzes the patient’s heart rhythm. When an abnormal rhythm is detected or when the patient marks the presence of symptoms, data are recorded and sent in real time via a cellular network to a monitoring center; the newest monitors can send data via any Wi-Fi system. The rhythm is then either evaluated by a trained technician or relayed to a physician. If necessary, the patient can be contacted immediately.

Mobile cardiac telemetry is typically used for up to 30 days, which  allows for evaluation of less-frequent symptoms. As a result, it may have a higher diagnostic yield for palpitations, syncope, and presyncope than the 24-hour Holter monitor.¹⁷

Further, perhaps because mobile cardiac telemetry relies less on stored information and requires less patient-device interaction than external loop recorders, it is more effective at symptom evaluation.¹⁸

Mobile cardiac telemetry also has a diagnostic role in evaluating patients with cryptogenic stroke. This is based on studies showing it has a high rate of atrial fibrillation detection in this patient population and is more effective at determining overall atrial fibrillation burden than loop recorders.^18,19

What is its best use? The key advantage of mobile cardiac telemetry is its ability to make rhythm assessments and communicate with technicians in real time. This allows high-risk patients to be immediately alerted to a life-threatening arrhythmia. It also gives providers an opportunity to initiate anticoagulation or titrate antiarrhythmic therapy in the outpatient setting without a delay in obtaining information. This intensive monitoring, however, requires significant manpower, which translates to higher cost, averaging 3 times that of other standard external monitors.¹⁵

Patch monitors

These ultraportable devices are a relatively unobtrusive and easy-to-use alternative for short-term ambulatory ECG monitoring. They monitor continuously with full disclosure, outpatient telemetry, and post-event recording features.

Patch monitors are small, leadless, wireless, and water-resistant (Figure 1). They are affixed to the left pectoral region with a waterproof adhesive and can be worn for 14 to 28 days. Recording is usually done continuously; however, these devices have an event marker button that can be pressed when the user experiences symptoms. They acquire a single channel of data, and each manufacturer has a proprietary algorithm for automated rhythm detection and analysis.²⁰

Several manufacturers produce ECG patch monitors. Two notable devices are the Zio patch (iRhythm Technologies, San Francisco, CA) and the Mobile Cardiac Outpatient Telemetry patch (BioTelemetry, Inc, Malvern, PA).

The Zio patch is a continuous external monitor with full disclosure. It is comparable to the Holter monitor, but has a longer recording period. After completing a 2-week monitoring period, the device is returned for comprehensive rhythm analysis. A typical Zio report contains information on atrial fibrillation burden, ectopic rhythm burden, symptom and rhythm correlation, heart rate trends, and relevant rhythm strips.

The Mobile Cardiac Outpatient Telemetry patch collects data continuously and communicates wirelessly by Bluetooth to send its ECG data to a monitoring center for evaluation.

A principal advantage of patch monitors—and a major selling point for manufacturers—is their low-profile, ergonomic, and patient-friendly design. Patients do not have to manage wires or batteries and are able to shower with their devices. Studies show that these features increase patient satisfaction and compliance, resulting in increased diagnostic yield.^21,22 Additionally, patch monitors have the advantage of a longer continuous monitoring period than traditional Holter devices (2 weeks vs 1 or 2 days), affording an opportunity to capture events that occur less frequently.

Validation studies have reinforced their efficacy and utility in clinical scenarios.^22,23 In large part because of the extended monitoring period, patch monitors have been shown to have greater diagnostic yield than the 24-hour Holter monitor in symptomatic patients undergoing workup for suspected arrhythmia.

The role of patch monitors in evaluating atrial fibrillation is also being established. For patients with cryptogenic stroke, patch monitors have shown better atrial fibrillation detection than the 24-hour Holter monitor.²⁴ Compared with traditional loop monitors, patch monitors have the added advantage of assessing total atrial fibrillation burden. Further, although screening for atrial fibrillation with a traditional 12-lead ECG monitor has not been shown to be effective, clinical studies have found that the patch monitor may be a useful screening tool for high-risk patients.^25,26

Nevertheless, patch monitors have drawbacks. They are not capable of long-term monitoring, owing to battery and adhesive limitations.²⁰ More important, they have  been able to offer only single-channel acquisition, which makes it more difficult to detect an arrhythmia that is characterized by a change in QRS axis or change in QRS width, or to distinguish an arrhythmia from an artifact. This appears to be changing, however, as several manufacturers have recently developed multilead ECG patch monitors or attachments and are attempting to merge this technology with fully capable remote telemetry.

Recent improvements in battery life, memory, detection algorithms, wireless transmission, cellular communication, and adhesives have enabled multiple features to be combined into a single device. Patch monitors, for example, are small devices that now offer full-disclosure recording, extended monitoring, and telemetry transmitting. Automated arrhythmia recognition that triggers recording is central to all modern devices, regardless of type.

As a result of these trends, the traditional features used to differentiate devices may become less applicable. The classic Holter monitor may become obsolete as its advantages (full disclosure, continuous recording) are being incorporated into smaller devices that can record longer. Similarly, external monitors that have the capacity for full disclosure and continuous recording are no longer loop recorders in that they do not record into a circular memory.

It may be preferable to describe all non-Holter devices as event monitors or ambulatory monitors, with the main distinguishing features being the ability to transmit data (telemetry), full disclosure vs patient- or arrhythmia-activated recording, and single-channel or multichannel recording (single-lead or 3-lead ECG).

The following are the main distinguishing features that should influence the choice of device for a given clinical context.

Real-time data evaluation provided by mobile telemetry makes this feature ideal to monitor patients with suspected high-risk arrhythmias and their response to antiarrhythmic therapy.

Full-disclosure recording is necessary to assess the overall burden of an arrhythmia, which is frequently important in making treatment decisions, risk-stratifying, and assessing response to therapy. In contrast, patient- or arrhythmia-activated devices are best used when the goal is simply to establish the presence of an arrhythmia.

Multichannel recording may be better than single-channel recording, as it is needed to determine the anatomic origin of an arrhythmia, as might be the case in risk-stratification in a patient with a ventricular tachycardia.

Long duration. The clinician must have a reasonable estimate of how often the symptoms or arrhythmia occur to determine which device will offer a monitoring duration sufficient to detect an arrhythmia.

NEWER TECHNOLOGIES

The newest ambulatory ECG devices build on the foundational concepts of the older ones. However, with miniaturized electronic circuits, Bluetooth, Wi-Fi, and smartphones, these new devices can capture ECG tracings and diagnose offending arrhythmias on more consumer-friendly devices.

Smartphones and smartwatches have become increasingly powerful. Some have the ability to capture, display, and record the cardiac waveform. One manufacturer to capitalize on these technologies, AliveCor (Mountain View, CA), has developed 2 products capable of generating a single-lead ECG recording using either a smartphone (KardiaMobile) or an Apple watch (KardiaBand).

KardiaMobile has a 2-electrode band that can be carried in a pocket or attached to the back of a smartphone (Figure 1). The user places 1 or 2 fingers from each hand on the electrodes, and the device sends an ultrasound signal that is picked up by the smartphone’s microphone. The signal is digitized to produce a 30-second ECG tracing on the phone’s screen. A proprietary algorithm analyzes the rhythm and generates a description of “normal” or “possible atrial fibrillation.” The ECG is then uploaded to a cloud-based storage system for later access or transmission. KardiaMobile is compatible with both iOS and Android devices.

The KardiaBand is a specialized Apple watch band that has an electrode embedded in it. The user places a thumb on the electrode for 30 seconds, and an ECG tracing is displayed on the watch screen.

The Kardia devices were developed (and advertised) predominantly to assess atrial fibrillation. Studies have validated the accuracy of their algorithm. One study showed that, compared with physician-interpreted ECGs, the algorithm had a 96.6% sensitivity and 94.1% specificity for detecting atrial fibrillation.²⁷ They have been found useful for detecting and evaluating atrial fibrillation in several clinical scenarios, including discharge monitoring in patients after ablation or cardiac surgery.^28,29 In a longer study of patients at risk of stroke, twice-weekly ECG screening using a Kardia device for 1 year was more likely to detect incident atrial fibrillation than routine care alone.³⁰

Also, the Kardia devices can effectively function as post-event recorders when activated by patients when they experience symptoms. In a small study of outpatients with palpitations and a prior nondiagnostic workup, the KardiaMobile device was found to be noninferior to external loop recorders for detecting arrhythmias.³¹ Additional studies are assessing Kardia’s utility in other scenarios, including the evaluation of ST-segment elevation myocardial infarction^32,33 and QT interval for patients receiving antiarrhythmic therapy.³⁴

Cardiio Inc. (Cambridge, MA) has developed technology to screen for atrial fibrillation using an app that requires no additional external hardware. Instead, the app uses a smartphone’s camera and flashlight to perform photo­plethysmography to detect pulsatile changes in blood volume and generate a waveform. Based on waveform variability, a proprietary algorithm attempts to determine whether the user is in atrial fibrillation. It does not produce an ECG tracing. Initial studies suggest it has good diagnostic accuracy and potential utility as a population-based screening tool,^35,36 but it has not been fully validated.

Recently, Apple entered the arena of ambulatory cardiac monitoring with the release of its fourth-generation watch (Apple Watch Series 4 model). This watch has built-in electrodes that can generate a single-lead ECG on the watch screen. Its algorithm can discriminate between atrial fibrillation and sinus rhythm, but it has not been assessed for its ability to evaluate other arrhythmias. Even though it has been “cleared” by the US Food and Drug Administration, it is approved only for informational use, not to make a medical diagnosis.

Integration of ambulatory ECG technology with smartphone and watch technology is an exciting new wearable option for arrhythmia detection. The patient-centered and controlled nature of these devices have the potential to help patients with palpitations or other symptoms determine if their cardiac rhythms are normal.

This technology, however, is still in its infancy and has many limitations. For example, even though these devices can function as post-event recorders, they depend on user-device interactions. Plus, they cannot yet perform continuous arrhythmia monitoring like modern loop recorders.

Additionally, automated analysis has largely been limited to distinguishing atrial fibrillation from normal sinus rhythm. It is uncertain how effective the devices may be in evaluating other arrhythmias. Single-lead ECG recordings, as discussed, have limited interpretability and value. And even though studies have shown utility in certain clinical scenarios, large-scale validation studies are lacking. This technology will likely continue to be developed and its clinical value improved; however, its clinical use requires careful consideration and collaborative physician-patient decision-making.

The development of smartphone and watch ECG technology has led to a rise in direct-to-consumer healthcare delivery. By devising technology that is appealing, useful, and affordable, companies can bypass the insurer and practitioner by targeting increasingly health-literate consumers. For many companies, there is great motivation to enter this healthcare space. Wearable devices are immensely popular and, as a result, generate substantial revenue. One analysis estimates that 1 in 10 Americans (nearly 30 million) owns a wearable, smart-technology device.³⁷

This direct-to-consumer approach has specific implications for cardiology and, more broadly, for healthcare overall. By directly selling to consumers, companies have an opportunity to reach many more people. The Apple Watch Series 4 has taken this a step further: by including this technology in the watch, consumers not necessarily seeking an ambulatory cardiac monitor will have one with a watch purchase. This could lead to increases in monitoring and could alert people to previously undiagnosed disorders.

For consumers, this technology can empower them to choose how and when to be monitored. Further, it gives them personal control of their healthcare data, and helps move the point of care out of hospitals and clinics and into the home.

But wearable medical technology and direct-to-consumer healthcare have risks. First, in the absence of appropriate regulation, patients have to distinguish between products that are well validated and those that are unproven. Consumers also may inappropriately use devices for indications or in scenarios for which the value is uncertain.

Also, there is potential for confusion and misunderstanding of results, including false-positive readings, which could lead to excessive and costly use of unnecessary diagnostic workups. Instead of providing peace of mind, these devices could cause greater worry. This may be especially true with the newest Apple watch, as this product will introduce ambulatory ECG to a younger and healthier segment of the population who are less likely to have true disease.

Further, these devices have algorithms that detect atrial fibrillation, but is it the same as that detected by traditional methods? Sometimes termed “subclinical” atrial fibrillation, it poses uncertainties: ie, Do patients need anticoagulation, pharmacologic therapy, and ablation? The optimal management of subclinical atrial fibrillation, as well as its similarities to and differences from atrial fibrillation diagnosed by traditional methods, are topics that need further study.

Wearable technology is still developing and will continue to do so. Medical practice will have to adapt to it.

FUTURE DIRECTIONS

Changes in technology have led to remarkable advances in the convenience and accuracy of ambulatory ECG monitoring. Ongoing research is expected to lead to even more improvements. Devices will become more ergonomic and technically capable, and they may expand monitoring to include other biologic parameters beyond ECG.

Comfort is important to ensure patient adherence. Newer, flexible electronics embedded in ultrathin materials can potentially improve the wearability of devices that require gel electrodes or adhesive patches.³⁸ Wireless technology may obviate the need for on-skin attachments. Future recording systems may be embedded into clothing or incorporated into wearable vests capable of wirelessly transmitting ECG signals to separate recording stations.³⁹

In addition to becoming smaller and more comfortable, future devices will be more technically capable, leading to a merging of technologies that will further blur the distinctions among devices. Eventually, the features of full disclosure, extended monitoring duration, and telemetric communication will all be present together. Perhaps more important is that ambulatory ECG devices may become fully capable biosensor monitors. These devices would have the potential to monitor respiratory frequency, peripheral oxygen saturation, potassium levels, and arterial pulse pressure.^39,40

Insights from basic and clinical research are changing the way we treat diabetes mellitus. In 2016, several key diabetes organizations, ie, the American Diabetes Association (ADA), the Juvenile Diabetes Research Foundation (JDRF), the European Association for the Study of Diabetes (EASD), and the American Association of Clinical Endocrinologists (AACE), called for bringing therapeutic approaches in line with our updated understanding of disease pathophysiology, replacing “one-size-fits-all” management with a tailored approach.¹ This message has since been reiterated.²

Here, we review advances in our understanding of diabetes and how these inform a new model of diabetes treatment.

BETA CELLS ARE KEY

High levels of glucose and lipids damage and eventually kill beta cells through mechanisms including that of oxidative stress, so that glucose control deteriorates over time. The same processes are active in the target-organ damage seen in diabetes.^3,4 These 2 insights—that the disease arises from combinatorial, nondiscrete pressures and that it proceeds through common processes of cell damage—leads us to a more unified understanding of the mechanism of diabetes, and may eventually replace current classifications of type 1, type 2, or latent autoimmune diabetes in adults, as well as nomenclature such as “microvascular” and “macrovascular” disease.³

FIRST-LINE LIFESTYLE INTERVENTIONS

Lifestyle interventions are the first-line therapy for elevated blood glucose. Achieving and maintaining a healthy body mass index is essential to help correct insulin resistance and minimize beta-cell dysfunction.

Lifestyle modifications for overweight or obese patients with diabetes mellitus include optimal caloric intake, decreased intake of simple carbohydrates, increased physical activity, and a 3% to 5% reduction in body weight.⁵ Weight-loss drugs may be indicated in obese patients. Normalization of lipids and hypertension should be an early goal.

RIGHT MEDICATIONS, RIGHT PATIENTS

While all of the drugs approved for treating diabetes lower glucose levels, some are more beneficial than others, possessing actions beyond their effect on plasma glucose levels, both good and bad.

The AACE guideline for use of various antidiabetic medications⁶ grades factors such as risks of hypoglycemia, ketoacidosis, weight gain, cardiovascular events, and renal, gastrointestinal, and bone concerns. This represents a much-needed first step toward guidance on selecting the right medications for the right patients. Risk factors (such as heart failure) and comorbidities (such as nonalcoholic fatty liver disease and nonalcoholic steatohepatitis) are among the considerations for choosing treatment.

Two principles

We propose 2 principles when choosing treatment:

Use “gentle” agents, ie, those that are least likely to exhaust beta cells or damage the organs involved in diabetes-related complications. Since the disease course depends on the health of the beta cells, give preference to agents that appear to best support beta cells—ie, agents that create the least oxidative stress or wear-and-tear—as will be outlined in this article.

Diabetes is associated with risks of cardiovascular disease, cardiac events, heart failure, and accelerated renal decompensation. Thus, it is equally important to prevent damage to the cardiovascular system, kidneys, and other tissues subject to damage through glucolipotoxicity.

Balancing glycemic control and risk

The hemoglobin A_1c level is the chief target of care and an important barometer of risk of diabetes-related complications. In 2018, the American College of Physicians (ACP) relaxed its target for hemoglobin A_1c from 7% to 8%.⁸ This move was apparently to give physicians greater “wiggle room” for achieving goals in hypoglycemia-prone patients. This, however, may take a toll.

Hypoglycemia is closely tied to cardiovascular disease. Even mild and asymptomatic hypoglycemia that goes undiagnosed and unnoticed by patients has been found to be associated with higher rates of all-cause mortality, prolonged QT interval, angina, arrhythmias, myocardial dysfunction, disturbances in autonomic balance, and sudden death.^9–11

However, the ADA, AACE, American Association of Diabetes Educators (AADE), and the Endocrine Society jointly issued a strong indictment of the ACP recommendation.¹² They argue that tight glucose control and its well-documented “legacy effects” on long-term outcomes should not be sacrificed.^12,13 Indeed, there is no need to abandon evidence-based best practices in care when at least 8 of the 11 classes of antidiabetes agents do not introduce the same level of risk for hypoglycemia.

Current guidelines argue for tight glucose control but generally stop short of discriminating or stratifying the mechanisms of action of the individual classes of drugs. These guidelines also do not stress targeting the particular pathways of hyperglycemia present in any given patient. However, the 2016 ADA joint statement acknowledges the need to “characterize the many paths to beta-cell dysfunction or demise and identify therapeutic approaches that best target each path.”¹

The sections below highlight some of the recent data on the profiles of most of the currently available agents.

Metformin: Still the first-line treatment

Current guidelines from the ACP, ADA, and AACE keep metformin¹⁴ as the backbone of treatment, although debate continues as to whether newer agents such as GLP-1 receptor agonists are superior for first-line therapy.

Pathways affected. Metformin improves insulin resistance in the liver, increases endogenous GLP-1 levels via the gut, and appears to modulate gut flora composition, which is increasingly suspected to contribute to dysmetabolism. 

Advantages, benefits. Metformin is easy to use and does not cause hypoglycemia. It was found to modestly reduce the number of cardiovascular events and deaths in a number of clinical outcome studies.^15–19

Disadvantages, adverse effects. In some patients, tolerability restricts the use of this drug at higher doses. The most common adverse effects of metformin are gastrointestinal symptoms (diarrhea, nausea, vomiting, flatulence); other risks include lactic acidosis in patients with impaired kidney function, heart failure, hypoxemia, alcoholism, cirrhosis, contrast exposure, sepsis, and shock.

GLP-1 receptor agonists

GLP-1 receptor agonists^20–25 are injectable medications approved for adults with type 2 diabetes. Exenatide and liraglutide lower hemoglobin A_1c by 1 to 1.5 absolute percentage points and reduce body weight; these effects persist over the long term.²⁶ Newer once-weekly GLP-1 receptor agonists (albiglutide,²⁰ dulaglutide,²¹ and semaglutide²⁵) have similar benefits. In 2019, new drug applications were submitted to the FDA for the first-in-kind oral GLP-1 receptor agonists, which would improve convenience and adherence and make this class even more attractive.

Pathways affected. GLP-1 receptor agonists address multiple pathways of hyperglycemia. They increase insulin production and release, promote weight loss, and reduce insulin resistance, glucagon secretion, and inflammation. They also increase amylin, help overcome GLP-1 resistance, slow gastric emptying, and favorably modify gut flora.²⁷

Advantages, benefits. The cardioprotective actions of GLP-1 receptor agonists include reducing inflammation and dysfunction in endothelial and myocardial cells; slowing atherosclerosis; reducing oxidative stress-induced injury and scavenging of reactive oxygen species in coronary endothelial, smooth muscle, and other cells; and enhancing endogenous antioxidant defenses.²⁷ GLP-1 receptor agonism has also been found to inhibit apoptosis in cardiomyocytes, as well as in beta cells.

Several large-scale studies have shown improved outcomes with GLP-1 receptor agonists. The Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEADER) trial²⁶ found that liraglutide reduced major adverse cardiovascular events by 13% and myocardial infarctions by 22% in more than 9,000 adults with type 2 diabetes who were at high risk of major adverse cardiovascular events compared with placebo. Rates of microvascular outcomes were also reduced.

A retrospective database analysis of 39,275 patients with type 2 diabetes who were treated with exenatide reported a lower incidence of cardiovascular events than in patients not treated with exenatide.²⁸

However, no effect on cardiovascular outcomes was found with a third GLP-1 agent, lixisenatide, in a large-scale trial in high-risk patients with diabetes.²⁹

The most recently evaluated GLP-1 receptor agonist is semaglutide. The Trial to Evaluate Cardiovascular and Other Long-term Outcomes With Semaglutide in Subjects With Type 2 Diabetes (SUSTAIN-6) demonstrated a reduced risk of major adverse cardiovascular events.³⁰

Disadvantages, adverse effects. The most common adverse effects in this class include nausea, hypoglycemia, diarrhea, constipation, vomiting, headache, decreased appetite, dyspepsia, fatigue, dizziness, abdominal pain, and increased lipase. The nausea can be mitigated by advising patients to stop eating at first sensation of stomach fullness.

DPP-4 inhibitors

Dipeptidyl peptidase 4 (DPP-4) is a ubiquitous enzyme that rapidly degrades GLP-1 and other endogenous peptides.³¹ Saxagliptin,³² sitagliptin,³³ linagliptin,³⁴ and alogliptin³⁵ are approved for use in the United States, and vildagliptin36 is available in Europe.

Pathways affected. These agents modify 3 pathways of hyperglycemia: they increase insulin secretion, decrease glucagon levels, and help overcome GLP-1 resistance.

Advantages, benefits. DPP-4 inhibitors have been used safely and effectively in clinically challenging populations of patients with long-standing type 2 diabetes (> 10 years).

Disadvantages, adverse effects. As this class increases GLP-1 levels only 2- to 4-fold, their efficacy is more modest than that of GLP-1 receptor agonists (hemoglobin A_1c reductions of 0.5% to 1%; neutral effects on weight).³⁷

Outcome trials have largely been neutral. Saxagliptin has been associated with an increase in admissions for heart failure. There have been a very small but statistically significant number of drug-related cases of acute pancreatitis.³⁸

The most common adverse effects with this class include headache, nasopharyngitis, urinary tract infection, upper respiratory tract infection, and elevated liver enzymes.

Drugs of this class currently available in the United States are canagliflozin,³⁹ dapagliflozin,⁴⁰ empagliflozin,⁴¹ and ertugliflozin.⁴²

Pathways affected. SGLT2 inhibitors lower the glucose reabsorption threshold in the kidney so that more glucose is excreted in the urine; they also decrease insulin resistance in muscle, liver, and fat cells (via weight loss) and possibly preserve beta-cell function by reducing glucotoxicity. A nonrenal mechanism—delayed gut absorption reducing postprandial glucose excursion—has been proposed to contribute to the glucose-lowering effects of canagliflozin.⁴³

Advantages, benefits. These agents reduce hemoglobin A_1c by about 0.5% to 1.0% from a baseline of about 8%. Because their action is independent of insulin, they can be used at any stage of type 2 diabetes, even after insulin secretion has significantly waned. Additional potential advantages include weight loss (up to 3.5% of body mass index) and lowering of systolic blood pressure (2–4 mm Hg) and diastolic blood pressure (1–2 mm Hg).^39–42

Canagliflozin was shown in the Canagliflozin Cardiovascular Assessment Study (CANVAS)⁴⁴ to significantly reduce the overall risk of cardiovascular disease by 14% and risk of heart failure hospitalization by 33% while significantly slowing the progression of renal disease.

In the BI 10773 (Empagliflozin) Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients (EMPA-REG OUTCOME),⁴⁵ empagliflozin reduced heart failure hospitalizations by 35%, cardiovascular deaths by 38%, and all-cause mortality by about 32%. These benefits are thought to be due to less arterial stiffness, lower sympathetic tone, and decreased arrhythmias. Notably, these dramatic benefits accrued in only about 3 years with use of add-on therapy, even though the reduction in hemoglobin A_1c was modest (0.6%), suggesting that pleiotropic effects are at work.

Disadvantages, adverse effects. The most common adverse effects of this class include urinary tract infections, yeast infections, dehydration, and hypovolemic symptoms; these can often be prevented. A trend toward increased incidence of amputations in earlier studies was not borne out in a 2018 meta-analysis of 4 observational databases.⁴⁶

Thiazolidinediones

There are currently 2 approved thiazolidine­diones in the United States, pioglitazone⁴⁷ and rosiglitazone.⁴⁸ Only pioglitazone is in common use, as rosiglitazone is associated with safety issues.⁴⁹

Pathways affected. Pioglitazone reduces insulin resistance in muscle, liver, and adipose tissue.

Advantages, benefits. Decreased levels of low-density lipoprotein cholesterol and triglycerides and increased high-density lipoprotein cholesterol levels⁴⁹ could plausibly account for the cardiovascular benefits reported in the Prospective Pioglitazone Clinical Trial in Macrovascular Events.⁵⁰ Pioglitazone has also been found to improve insulin secretion, endothelial function, and diastolic dysfunction; reduce inflammation; decrease plasminogen activator inhibitor 1; reverse lipotoxicity; and help correct nonalcoholic fatty liver disease and steatohepatitis.

Pioglitazone has also been found to reduce plaque in carotid and coronary arteries⁵¹; improve outcomes in patients with heart failure and myocardial infarction compared with insulin-sensitizing drugs⁵²; and reduce stroke and myocardial infarction in patients with insulin resistance (but not diabetes) and a recent history of ischemic stroke or transient ischemic attack (in the Insulin Resistance Intervention After Stroke trial).⁵³ It may also help maintain beta-cell function; the Actos Now for the Prevention of Diabetes Study found that pioglitazone reduced the risk of conversion of impaired glucose tolerance to frank diabetes by 72%.⁵⁴

Disadvantages, adverse effects. The most common adverse effects seen with this class include weight gain and salt retention, swelling, edema,⁵⁵ and related cardiovascular consequences in certain patients. While this may be mitigatable with lifestyle changes or use in combination with a GLP-1 receptor agonist or SGLT2 inhibitor,⁵⁶ pioglitazone is contraindicated in patients with heart failure, hemodynamic instability, or hepatic dysfunction.

Concerns that pioglitazone might increase the risk of bladder cancer seem to have been put to rest when a study in nearly 200,000 patients found no statistically significant association,⁵⁷ but the warning remains in the US label.

Long-term use of this class of drugs has been associated with an increased risk of bone fractures,⁵⁸ which warrants a risk-benefit assessment in each patient.

Injected insulin: Less safe than thought

Recent research suggests that injected insulin has a less favorable safety profile than previously thought.^15–19,59 Studies of the long-term safety of insulin therapy have had inconsistent results but suggest that injected insulin is associated with poorer cardiovascular and renal outcomes (in some of the same studies that showed metformin or other agents to improve outcomes),^17–19 and the association was dose-dependent. Several studies attempted to cancel out the poorer outcomes by adjusting for hemoglobin A_1c levels, stage of disease,^{17–19,26,27} or severe hypoglycemic episodes.⁶⁰ However, it may be inappropriate to reduce the impact of these variables, as these may themselves be the mediators of any deleterious effects of exogenous insulin.

When exogenous insulin is introduced into the peripheral circulation it causes a state of persistent iatrogenic hyperinsulinemia, which leads to insulin resistance and also appears to compromise the cardiovascular system. In contrast, endogenous insulin is released into the portal system in tightly controlled amounts.^5,61 This suggests that the same insulin peptide may not be equivalently beneficial when introduced in an artificial manner.

Before starting insulin therapy, consider its side effects such as weight gain and hypoglycemia. Most (about 85%) episodes of hypoglycemia occur with basal-bolus insulin regimens.⁶² Moreover, iatrogenic hyperinsulinemia can damage the vascular system.^63,64

We recommend. Insulin therapy is used early in the course of the disease as a short-term intervention for glucolipotoxicity. However, this can be accomplished without attendant risks of hypoglycemia and weight gain by using agents such as SGLT2 inhibitors and incretins. When insulin therapy is necessary, using it as add-on therapy might be considered instead of drug-switching. We have found alternate pharmacologic approaches successful in avoiding or delaying bolus insulin therapy. And in some patients taking insulin, we have had success in progressively introducing a noninsulin agent and were ultimately able to eliminate insulin altogether.

Bromocriptine-QR (quick release)⁶⁵ is a short-acting dopamine agonist that mimics the morning dopamine surge in the suprachiasmatic nucleus—the biologic clock.

Pathways affected. Bromocriptine addresses part of the brain contribution to hyperglycemia, with resultant reductions in both peripheral insulin resistance and sympathetic tone. This reduces muscle, liver, and adipose insulin resistance. It is moderately effective in glucose-lowering, especially in patients with significant insulin resistance.⁶⁶

Advantages, benefits. A 1-year clinical trial reported that bromocriptine reduced cardiovascular adverse outcomes by 39%, and the composite end point of myocardial infarction, stroke, and cardiovascular death by 52% compared with placebo.⁶⁷

Disadvantages, adverse effects. The most common adverse effects are nausea, rhinitis, headache, asthenia, dizziness, constipation, and sinusitis.

Alpha-glucosidase inhibitors

Alpha-glucosidase inhibitors (acarbose,⁶⁸ miglitol⁶⁹) work by decreasing the rate of absorption of glucose from the gastrointestinal tract.

Advantages, benefits. These drugs decrease hemoglobin A_1c by 0.5% to 0.8%.70 They are weight-neutral and do not pose a risk of hypoglycemia. Clinical studies suggest that they may delay or prevent diabetes progression. They were also found to reduce cardiovascular events, acute myocardial infarction, and the onset of hypertension.⁶⁹

Disadvantages, adverse effects. Their use remains limited due to gastrointestinal adverse effects. They may be contraindicated in patients with inflammatory bowel disease, partial bowel obstruction, or severe renal or hepatic disease.

Pramlintide

Pramlintide⁷¹ is an injectable amylin analogue. It is used as monotherapy or in combination with a sulfonylurea, metformin, or insulin glargine.

Pathways affected. Pramlintide decreases appetite, reduces glucagon levels, and minimizes absorption of glucose in the gut.

Disadvantages, adverse effects. Common side effects include mild to moderate hypoglycemia and nausea. Nausea may help explain the ability of pramlintide to confer weight loss when used in combination with insulin.

Sulfonylureas and meglitinides

These classes are still widely used in the treatment of type 2 diabetes, although the AACE⁶ and ADA⁷² guidelines de-emphasize their use based on associated risks of hypoglycemia, weight gain, morbidity, mortality, and loss of effect over time.

Pathways affected. Sulfonylureas stimulate insulin secretion from beta cells.

Disadvantages, adverse effects. Sulfonylureas and glinides are associated with poorer outcomes than newer agents in clinical trials^{15–19,59,60} and may be generally less beta-cell friendly.⁷³ Their harmful effects are difficult to measure in vivo, but these drugs sometimes appear to be associated with more rapid beta-cell failure and progression to insulin dependence compared with newer ones. Several large-scale registry studies have found sulfonylureas and glinides to be associated with poorer outcomes (reviewed by Herman et al).⁷⁴

Adverse effects include asthenia, headache, dizziness, nausea, diarrhea, epigastric fullness, and heartburn. Although they are often selected based on their low cost, other factors may offset their cost-effectiveness, such as need for glucose monitoring and hospital charges due to sulfonylurea-induced hypoglycemia. Their utility is also limited by dependence on beta-cell function.

Colesevelam

Colesevelam⁷⁵ is a bile acid sequestrant and low-density lipoprotein cholesterol-reducing agent that has been approved for use in diabetes. The mode of action of colesevelam in this capacity is under investigation. Its effect on hemoglobin A_1c is modest. It is associated with gastrointestinal adverse effects, particularly constipation.

Ranolazine

Ranolazine⁷⁶ is an antianginal drug that also lowers glucose by increasing insulin release. It also possesses cardioprotective properties. In patients with diabetes and non-ST-segment elevation acute coronary syndromes, ranolazine reduced hemoglobin A_1c by 1.2% and appeared to be weight-neutral.⁷⁶ Ranolazine is under clinical development for use in diabetes. Adverse effects include dizziness, headache, constipation, and nausea.


Rational combinations of agents

The ideal strategy would use combinations of agents that mechanistically complement one another and address each path of hyperglycemia present in a patient. This approach should supplant the former approaches of adding-on agents only after treatment failure or sequentially trying first-, second-, and third-line treatments.

Examples of synergistic combinations include those that target fasting plasma glucose and postprandial glucose, reduce reliance on insulin with add-on therapies, or manage hyperglycemia in specific patient groups, such as renal-impaired patients.

Large-scale long-term clinical studies are needed to determine the safety, efficacy, and outcomes of various combinations and whether they confer additive benefits. Some studies have begun to explore possible combinations.

Combined metformin, pioglitazone, and exenatide was reported to delay progression of diabetes in early dysglycemia.^77,78 Notably, this combination addresses multiple mediating pathways of hyperglycemia (Table 1).

A GLP-1 receptor agonist with an SGLT2 inhibitor would be another intriguing combination, as the mechanisms of action of these 2 classes complement one another. In limited clinical trials—the DURATION-8 study (lasting 26 weeks),⁷⁹ the Canagliflozin Cardiovascular Assessment Study (18 weeks),⁸⁰ and a 24-week study in nondiabetic obese patients⁸¹—additive benefits were also seen in systolic blood pressure, body weight, and cardiac risk factors by adding an SGLT2 inhibitor to a GLP-1 receptor agonist, compared with either agent alone. In theory, these improvements might slow or reverse cardiorenal compromise. Lower doses of 1 or more may be possible, and the regimen could prove cost-effective and life-sparing should it slow the progression of the disease and the onset of its complications. A clinical study of this combination is under way (Ralph DeFronzo, personal communication, July 2018). Similarly, the combination of metformin, saxagliptin and dapagliflozin has been shown to be effective.⁸²

CONCLUSION

Care for diabetes mellitus can be particularly challenging for the primary care physician. The progressive nature of diabetes, with worsening hyperglycemia over the course of the disease, further complicates disease management.

Best practices for care nonetheless need to evolve with well-evidenced data, and without years of delay for “trickle-down” education from the specialties to primary care. We have arrived at a juncture to leverage therapies that address the 11 mediating pathways of hyperglycemia, optimally protect beta cells, minimize hypoglycemia, manage risk factors associated with diabetes, and improve diabetes-related outcomes.

Insights from basic and clinical research are changing the way we treat diabetes mellitus. In 2016, several key diabetes organizations, ie, the American Diabetes Association (ADA), the Juvenile Diabetes Research Foundation (JDRF), the European Association for the Study of Diabetes (EASD), and the American Association of Clinical Endocrinologists (AACE), called for bringing therapeutic approaches in line with our updated understanding of disease pathophysiology, replacing “one-size-fits-all” management with a tailored approach.¹ This message has since been reiterated.²

Here, we review advances in our understanding of diabetes and how these inform a new model of diabetes treatment.

BETA CELLS ARE KEY

High levels of glucose and lipids damage and eventually kill beta cells through mechanisms including that of oxidative stress, so that glucose control deteriorates over time. The same processes are active in the target-organ damage seen in diabetes.^3,4 These 2 insights—that the disease arises from combinatorial, nondiscrete pressures and that it proceeds through common processes of cell damage—leads us to a more unified understanding of the mechanism of diabetes, and may eventually replace current classifications of type 1, type 2, or latent autoimmune diabetes in adults, as well as nomenclature such as “microvascular” and “macrovascular” disease.³

FIRST-LINE LIFESTYLE INTERVENTIONS

Lifestyle interventions are the first-line therapy for elevated blood glucose. Achieving and maintaining a healthy body mass index is essential to help correct insulin resistance and minimize beta-cell dysfunction.

Lifestyle modifications for overweight or obese patients with diabetes mellitus include optimal caloric intake, decreased intake of simple carbohydrates, increased physical activity, and a 3% to 5% reduction in body weight.⁵ Weight-loss drugs may be indicated in obese patients. Normalization of lipids and hypertension should be an early goal.

RIGHT MEDICATIONS, RIGHT PATIENTS

While all of the drugs approved for treating diabetes lower glucose levels, some are more beneficial than others, possessing actions beyond their effect on plasma glucose levels, both good and bad.

The AACE guideline for use of various antidiabetic medications⁶ grades factors such as risks of hypoglycemia, ketoacidosis, weight gain, cardiovascular events, and renal, gastrointestinal, and bone concerns. This represents a much-needed first step toward guidance on selecting the right medications for the right patients. Risk factors (such as heart failure) and comorbidities (such as nonalcoholic fatty liver disease and nonalcoholic steatohepatitis) are among the considerations for choosing treatment.

Two principles

We propose 2 principles when choosing treatment:

Use “gentle” agents, ie, those that are least likely to exhaust beta cells or damage the organs involved in diabetes-related complications. Since the disease course depends on the health of the beta cells, give preference to agents that appear to best support beta cells—ie, agents that create the least oxidative stress or wear-and-tear—as will be outlined in this article.

Diabetes is associated with risks of cardiovascular disease, cardiac events, heart failure, and accelerated renal decompensation. Thus, it is equally important to prevent damage to the cardiovascular system, kidneys, and other tissues subject to damage through glucolipotoxicity.

Balancing glycemic control and risk

The hemoglobin A_1c level is the chief target of care and an important barometer of risk of diabetes-related complications. In 2018, the American College of Physicians (ACP) relaxed its target for hemoglobin A_1c from 7% to 8%.⁸ This move was apparently to give physicians greater “wiggle room” for achieving goals in hypoglycemia-prone patients. This, however, may take a toll.

Hypoglycemia is closely tied to cardiovascular disease. Even mild and asymptomatic hypoglycemia that goes undiagnosed and unnoticed by patients has been found to be associated with higher rates of all-cause mortality, prolonged QT interval, angina, arrhythmias, myocardial dysfunction, disturbances in autonomic balance, and sudden death.^9–11

However, the ADA, AACE, American Association of Diabetes Educators (AADE), and the Endocrine Society jointly issued a strong indictment of the ACP recommendation.¹² They argue that tight glucose control and its well-documented “legacy effects” on long-term outcomes should not be sacrificed.^12,13 Indeed, there is no need to abandon evidence-based best practices in care when at least 8 of the 11 classes of antidiabetes agents do not introduce the same level of risk for hypoglycemia.

Current guidelines argue for tight glucose control but generally stop short of discriminating or stratifying the mechanisms of action of the individual classes of drugs. These guidelines also do not stress targeting the particular pathways of hyperglycemia present in any given patient. However, the 2016 ADA joint statement acknowledges the need to “characterize the many paths to beta-cell dysfunction or demise and identify therapeutic approaches that best target each path.”¹

The sections below highlight some of the recent data on the profiles of most of the currently available agents.

Metformin: Still the first-line treatment

Current guidelines from the ACP, ADA, and AACE keep metformin¹⁴ as the backbone of treatment, although debate continues as to whether newer agents such as GLP-1 receptor agonists are superior for first-line therapy.

Pathways affected. Metformin improves insulin resistance in the liver, increases endogenous GLP-1 levels via the gut, and appears to modulate gut flora composition, which is increasingly suspected to contribute to dysmetabolism. 

Advantages, benefits. Metformin is easy to use and does not cause hypoglycemia. It was found to modestly reduce the number of cardiovascular events and deaths in a number of clinical outcome studies.^15–19

Disadvantages, adverse effects. In some patients, tolerability restricts the use of this drug at higher doses. The most common adverse effects of metformin are gastrointestinal symptoms (diarrhea, nausea, vomiting, flatulence); other risks include lactic acidosis in patients with impaired kidney function, heart failure, hypoxemia, alcoholism, cirrhosis, contrast exposure, sepsis, and shock.

GLP-1 receptor agonists

GLP-1 receptor agonists^20–25 are injectable medications approved for adults with type 2 diabetes. Exenatide and liraglutide lower hemoglobin A_1c by 1 to 1.5 absolute percentage points and reduce body weight; these effects persist over the long term.²⁶ Newer once-weekly GLP-1 receptor agonists (albiglutide,²⁰ dulaglutide,²¹ and semaglutide²⁵) have similar benefits. In 2019, new drug applications were submitted to the FDA for the first-in-kind oral GLP-1 receptor agonists, which would improve convenience and adherence and make this class even more attractive.

Pathways affected. GLP-1 receptor agonists address multiple pathways of hyperglycemia. They increase insulin production and release, promote weight loss, and reduce insulin resistance, glucagon secretion, and inflammation. They also increase amylin, help overcome GLP-1 resistance, slow gastric emptying, and favorably modify gut flora.²⁷

Advantages, benefits. The cardioprotective actions of GLP-1 receptor agonists include reducing inflammation and dysfunction in endothelial and myocardial cells; slowing atherosclerosis; reducing oxidative stress-induced injury and scavenging of reactive oxygen species in coronary endothelial, smooth muscle, and other cells; and enhancing endogenous antioxidant defenses.²⁷ GLP-1 receptor agonism has also been found to inhibit apoptosis in cardiomyocytes, as well as in beta cells.

Several large-scale studies have shown improved outcomes with GLP-1 receptor agonists. The Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEADER) trial²⁶ found that liraglutide reduced major adverse cardiovascular events by 13% and myocardial infarctions by 22% in more than 9,000 adults with type 2 diabetes who were at high risk of major adverse cardiovascular events compared with placebo. Rates of microvascular outcomes were also reduced.

A retrospective database analysis of 39,275 patients with type 2 diabetes who were treated with exenatide reported a lower incidence of cardiovascular events than in patients not treated with exenatide.²⁸

However, no effect on cardiovascular outcomes was found with a third GLP-1 agent, lixisenatide, in a large-scale trial in high-risk patients with diabetes.²⁹

The most recently evaluated GLP-1 receptor agonist is semaglutide. The Trial to Evaluate Cardiovascular and Other Long-term Outcomes With Semaglutide in Subjects With Type 2 Diabetes (SUSTAIN-6) demonstrated a reduced risk of major adverse cardiovascular events.³⁰

Disadvantages, adverse effects. The most common adverse effects in this class include nausea, hypoglycemia, diarrhea, constipation, vomiting, headache, decreased appetite, dyspepsia, fatigue, dizziness, abdominal pain, and increased lipase. The nausea can be mitigated by advising patients to stop eating at first sensation of stomach fullness.

DPP-4 inhibitors

Dipeptidyl peptidase 4 (DPP-4) is a ubiquitous enzyme that rapidly degrades GLP-1 and other endogenous peptides.³¹ Saxagliptin,³² sitagliptin,³³ linagliptin,³⁴ and alogliptin³⁵ are approved for use in the United States, and vildagliptin36 is available in Europe.

Pathways affected. These agents modify 3 pathways of hyperglycemia: they increase insulin secretion, decrease glucagon levels, and help overcome GLP-1 resistance.

Advantages, benefits. DPP-4 inhibitors have been used safely and effectively in clinically challenging populations of patients with long-standing type 2 diabetes (> 10 years).

Disadvantages, adverse effects. As this class increases GLP-1 levels only 2- to 4-fold, their efficacy is more modest than that of GLP-1 receptor agonists (hemoglobin A_1c reductions of 0.5% to 1%; neutral effects on weight).³⁷

Outcome trials have largely been neutral. Saxagliptin has been associated with an increase in admissions for heart failure. There have been a very small but statistically significant number of drug-related cases of acute pancreatitis.³⁸

The most common adverse effects with this class include headache, nasopharyngitis, urinary tract infection, upper respiratory tract infection, and elevated liver enzymes.

Drugs of this class currently available in the United States are canagliflozin,³⁹ dapagliflozin,⁴⁰ empagliflozin,⁴¹ and ertugliflozin.⁴²

Pathways affected. SGLT2 inhibitors lower the glucose reabsorption threshold in the kidney so that more glucose is excreted in the urine; they also decrease insulin resistance in muscle, liver, and fat cells (via weight loss) and possibly preserve beta-cell function by reducing glucotoxicity. A nonrenal mechanism—delayed gut absorption reducing postprandial glucose excursion—has been proposed to contribute to the glucose-lowering effects of canagliflozin.⁴³

Advantages, benefits. These agents reduce hemoglobin A_1c by about 0.5% to 1.0% from a baseline of about 8%. Because their action is independent of insulin, they can be used at any stage of type 2 diabetes, even after insulin secretion has significantly waned. Additional potential advantages include weight loss (up to 3.5% of body mass index) and lowering of systolic blood pressure (2–4 mm Hg) and diastolic blood pressure (1–2 mm Hg).^39–42

Canagliflozin was shown in the Canagliflozin Cardiovascular Assessment Study (CANVAS)⁴⁴ to significantly reduce the overall risk of cardiovascular disease by 14% and risk of heart failure hospitalization by 33% while significantly slowing the progression of renal disease.

In the BI 10773 (Empagliflozin) Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients (EMPA-REG OUTCOME),⁴⁵ empagliflozin reduced heart failure hospitalizations by 35%, cardiovascular deaths by 38%, and all-cause mortality by about 32%. These benefits are thought to be due to less arterial stiffness, lower sympathetic tone, and decreased arrhythmias. Notably, these dramatic benefits accrued in only about 3 years with use of add-on therapy, even though the reduction in hemoglobin A_1c was modest (0.6%), suggesting that pleiotropic effects are at work.

Disadvantages, adverse effects. The most common adverse effects of this class include urinary tract infections, yeast infections, dehydration, and hypovolemic symptoms; these can often be prevented. A trend toward increased incidence of amputations in earlier studies was not borne out in a 2018 meta-analysis of 4 observational databases.⁴⁶

Thiazolidinediones

There are currently 2 approved thiazolidine­diones in the United States, pioglitazone⁴⁷ and rosiglitazone.⁴⁸ Only pioglitazone is in common use, as rosiglitazone is associated with safety issues.⁴⁹

Pathways affected. Pioglitazone reduces insulin resistance in muscle, liver, and adipose tissue.

Advantages, benefits. Decreased levels of low-density lipoprotein cholesterol and triglycerides and increased high-density lipoprotein cholesterol levels⁴⁹ could plausibly account for the cardiovascular benefits reported in the Prospective Pioglitazone Clinical Trial in Macrovascular Events.⁵⁰ Pioglitazone has also been found to improve insulin secretion, endothelial function, and diastolic dysfunction; reduce inflammation; decrease plasminogen activator inhibitor 1; reverse lipotoxicity; and help correct nonalcoholic fatty liver disease and steatohepatitis.

Pioglitazone has also been found to reduce plaque in carotid and coronary arteries⁵¹; improve outcomes in patients with heart failure and myocardial infarction compared with insulin-sensitizing drugs⁵²; and reduce stroke and myocardial infarction in patients with insulin resistance (but not diabetes) and a recent history of ischemic stroke or transient ischemic attack (in the Insulin Resistance Intervention After Stroke trial).⁵³ It may also help maintain beta-cell function; the Actos Now for the Prevention of Diabetes Study found that pioglitazone reduced the risk of conversion of impaired glucose tolerance to frank diabetes by 72%.⁵⁴

Disadvantages, adverse effects. The most common adverse effects seen with this class include weight gain and salt retention, swelling, edema,⁵⁵ and related cardiovascular consequences in certain patients. While this may be mitigatable with lifestyle changes or use in combination with a GLP-1 receptor agonist or SGLT2 inhibitor,⁵⁶ pioglitazone is contraindicated in patients with heart failure, hemodynamic instability, or hepatic dysfunction.

Concerns that pioglitazone might increase the risk of bladder cancer seem to have been put to rest when a study in nearly 200,000 patients found no statistically significant association,⁵⁷ but the warning remains in the US label.

Long-term use of this class of drugs has been associated with an increased risk of bone fractures,⁵⁸ which warrants a risk-benefit assessment in each patient.

Injected insulin: Less safe than thought

Recent research suggests that injected insulin has a less favorable safety profile than previously thought.^15–19,59 Studies of the long-term safety of insulin therapy have had inconsistent results but suggest that injected insulin is associated with poorer cardiovascular and renal outcomes (in some of the same studies that showed metformin or other agents to improve outcomes),^17–19 and the association was dose-dependent. Several studies attempted to cancel out the poorer outcomes by adjusting for hemoglobin A_1c levels, stage of disease,^{17–19,26,27} or severe hypoglycemic episodes.⁶⁰ However, it may be inappropriate to reduce the impact of these variables, as these may themselves be the mediators of any deleterious effects of exogenous insulin.

When exogenous insulin is introduced into the peripheral circulation it causes a state of persistent iatrogenic hyperinsulinemia, which leads to insulin resistance and also appears to compromise the cardiovascular system. In contrast, endogenous insulin is released into the portal system in tightly controlled amounts.^5,61 This suggests that the same insulin peptide may not be equivalently beneficial when introduced in an artificial manner.

Before starting insulin therapy, consider its side effects such as weight gain and hypoglycemia. Most (about 85%) episodes of hypoglycemia occur with basal-bolus insulin regimens.⁶² Moreover, iatrogenic hyperinsulinemia can damage the vascular system.^63,64

We recommend. Insulin therapy is used early in the course of the disease as a short-term intervention for glucolipotoxicity. However, this can be accomplished without attendant risks of hypoglycemia and weight gain by using agents such as SGLT2 inhibitors and incretins. When insulin therapy is necessary, using it as add-on therapy might be considered instead of drug-switching. We have found alternate pharmacologic approaches successful in avoiding or delaying bolus insulin therapy. And in some patients taking insulin, we have had success in progressively introducing a noninsulin agent and were ultimately able to eliminate insulin altogether.

Bromocriptine-QR (quick release)⁶⁵ is a short-acting dopamine agonist that mimics the morning dopamine surge in the suprachiasmatic nucleus—the biologic clock.

Pathways affected. Bromocriptine addresses part of the brain contribution to hyperglycemia, with resultant reductions in both peripheral insulin resistance and sympathetic tone. This reduces muscle, liver, and adipose insulin resistance. It is moderately effective in glucose-lowering, especially in patients with significant insulin resistance.⁶⁶

Advantages, benefits. A 1-year clinical trial reported that bromocriptine reduced cardiovascular adverse outcomes by 39%, and the composite end point of myocardial infarction, stroke, and cardiovascular death by 52% compared with placebo.⁶⁷

Disadvantages, adverse effects. The most common adverse effects are nausea, rhinitis, headache, asthenia, dizziness, constipation, and sinusitis.

Alpha-glucosidase inhibitors

Alpha-glucosidase inhibitors (acarbose,⁶⁸ miglitol⁶⁹) work by decreasing the rate of absorption of glucose from the gastrointestinal tract.

Advantages, benefits. These drugs decrease hemoglobin A_1c by 0.5% to 0.8%.70 They are weight-neutral and do not pose a risk of hypoglycemia. Clinical studies suggest that they may delay or prevent diabetes progression. They were also found to reduce cardiovascular events, acute myocardial infarction, and the onset of hypertension.⁶⁹

Disadvantages, adverse effects. Their use remains limited due to gastrointestinal adverse effects. They may be contraindicated in patients with inflammatory bowel disease, partial bowel obstruction, or severe renal or hepatic disease.

Pramlintide

Pramlintide⁷¹ is an injectable amylin analogue. It is used as monotherapy or in combination with a sulfonylurea, metformin, or insulin glargine.

Pathways affected. Pramlintide decreases appetite, reduces glucagon levels, and minimizes absorption of glucose in the gut.

Disadvantages, adverse effects. Common side effects include mild to moderate hypoglycemia and nausea. Nausea may help explain the ability of pramlintide to confer weight loss when used in combination with insulin.

Sulfonylureas and meglitinides

These classes are still widely used in the treatment of type 2 diabetes, although the AACE⁶ and ADA⁷² guidelines de-emphasize their use based on associated risks of hypoglycemia, weight gain, morbidity, mortality, and loss of effect over time.

Pathways affected. Sulfonylureas stimulate insulin secretion from beta cells.

Disadvantages, adverse effects. Sulfonylureas and glinides are associated with poorer outcomes than newer agents in clinical trials^{15–19,59,60} and may be generally less beta-cell friendly.⁷³ Their harmful effects are difficult to measure in vivo, but these drugs sometimes appear to be associated with more rapid beta-cell failure and progression to insulin dependence compared with newer ones. Several large-scale registry studies have found sulfonylureas and glinides to be associated with poorer outcomes (reviewed by Herman et al).⁷⁴

Adverse effects include asthenia, headache, dizziness, nausea, diarrhea, epigastric fullness, and heartburn. Although they are often selected based on their low cost, other factors may offset their cost-effectiveness, such as need for glucose monitoring and hospital charges due to sulfonylurea-induced hypoglycemia. Their utility is also limited by dependence on beta-cell function.

Colesevelam

Colesevelam⁷⁵ is a bile acid sequestrant and low-density lipoprotein cholesterol-reducing agent that has been approved for use in diabetes. The mode of action of colesevelam in this capacity is under investigation. Its effect on hemoglobin A_1c is modest. It is associated with gastrointestinal adverse effects, particularly constipation.

Ranolazine

Ranolazine⁷⁶ is an antianginal drug that also lowers glucose by increasing insulin release. It also possesses cardioprotective properties. In patients with diabetes and non-ST-segment elevation acute coronary syndromes, ranolazine reduced hemoglobin A_1c by 1.2% and appeared to be weight-neutral.⁷⁶ Ranolazine is under clinical development for use in diabetes. Adverse effects include dizziness, headache, constipation, and nausea.


Rational combinations of agents

The ideal strategy would use combinations of agents that mechanistically complement one another and address each path of hyperglycemia present in a patient. This approach should supplant the former approaches of adding-on agents only after treatment failure or sequentially trying first-, second-, and third-line treatments.

Examples of synergistic combinations include those that target fasting plasma glucose and postprandial glucose, reduce reliance on insulin with add-on therapies, or manage hyperglycemia in specific patient groups, such as renal-impaired patients.

Large-scale long-term clinical studies are needed to determine the safety, efficacy, and outcomes of various combinations and whether they confer additive benefits. Some studies have begun to explore possible combinations.

Combined metformin, pioglitazone, and exenatide was reported to delay progression of diabetes in early dysglycemia.^77,78 Notably, this combination addresses multiple mediating pathways of hyperglycemia (Table 1).

A GLP-1 receptor agonist with an SGLT2 inhibitor would be another intriguing combination, as the mechanisms of action of these 2 classes complement one another. In limited clinical trials—the DURATION-8 study (lasting 26 weeks),⁷⁹ the Canagliflozin Cardiovascular Assessment Study (18 weeks),⁸⁰ and a 24-week study in nondiabetic obese patients⁸¹—additive benefits were also seen in systolic blood pressure, body weight, and cardiac risk factors by adding an SGLT2 inhibitor to a GLP-1 receptor agonist, compared with either agent alone. In theory, these improvements might slow or reverse cardiorenal compromise. Lower doses of 1 or more may be possible, and the regimen could prove cost-effective and life-sparing should it slow the progression of the disease and the onset of its complications. A clinical study of this combination is under way (Ralph DeFronzo, personal communication, July 2018). Similarly, the combination of metformin, saxagliptin and dapagliflozin has been shown to be effective.⁸²

CONCLUSION

Care for diabetes mellitus can be particularly challenging for the primary care physician. The progressive nature of diabetes, with worsening hyperglycemia over the course of the disease, further complicates disease management.

Best practices for care nonetheless need to evolve with well-evidenced data, and without years of delay for “trickle-down” education from the specialties to primary care. We have arrived at a juncture to leverage therapies that address the 11 mediating pathways of hyperglycemia, optimally protect beta cells, minimize hypoglycemia, manage risk factors associated with diabetes, and improve diabetes-related outcomes.

Insights from basic and clinical research are changing the way we treat diabetes mellitus. In 2016, several key diabetes organizations, ie, the American Diabetes Association (ADA), the Juvenile Diabetes Research Foundation (JDRF), the European Association for the Study of Diabetes (EASD), and the American Association of Clinical Endocrinologists (AACE), called for bringing therapeutic approaches in line with our updated understanding of disease pathophysiology, replacing “one-size-fits-all” management with a tailored approach.¹ This message has since been reiterated.²

Here, we review advances in our understanding of diabetes and how these inform a new model of diabetes treatment.

BETA CELLS ARE KEY

High levels of glucose and lipids damage and eventually kill beta cells through mechanisms including that of oxidative stress, so that glucose control deteriorates over time. The same processes are active in the target-organ damage seen in diabetes.^3,4 These 2 insights—that the disease arises from combinatorial, nondiscrete pressures and that it proceeds through common processes of cell damage—leads us to a more unified understanding of the mechanism of diabetes, and may eventually replace current classifications of type 1, type 2, or latent autoimmune diabetes in adults, as well as nomenclature such as “microvascular” and “macrovascular” disease.³

FIRST-LINE LIFESTYLE INTERVENTIONS

Lifestyle interventions are the first-line therapy for elevated blood glucose. Achieving and maintaining a healthy body mass index is essential to help correct insulin resistance and minimize beta-cell dysfunction.

Lifestyle modifications for overweight or obese patients with diabetes mellitus include optimal caloric intake, decreased intake of simple carbohydrates, increased physical activity, and a 3% to 5% reduction in body weight.⁵ Weight-loss drugs may be indicated in obese patients. Normalization of lipids and hypertension should be an early goal.

RIGHT MEDICATIONS, RIGHT PATIENTS

While all of the drugs approved for treating diabetes lower glucose levels, some are more beneficial than others, possessing actions beyond their effect on plasma glucose levels, both good and bad.

The AACE guideline for use of various antidiabetic medications⁶ grades factors such as risks of hypoglycemia, ketoacidosis, weight gain, cardiovascular events, and renal, gastrointestinal, and bone concerns. This represents a much-needed first step toward guidance on selecting the right medications for the right patients. Risk factors (such as heart failure) and comorbidities (such as nonalcoholic fatty liver disease and nonalcoholic steatohepatitis) are among the considerations for choosing treatment.

Two principles

We propose 2 principles when choosing treatment:

Use “gentle” agents, ie, those that are least likely to exhaust beta cells or damage the organs involved in diabetes-related complications. Since the disease course depends on the health of the beta cells, give preference to agents that appear to best support beta cells—ie, agents that create the least oxidative stress or wear-and-tear—as will be outlined in this article.

Diabetes is associated with risks of cardiovascular disease, cardiac events, heart failure, and accelerated renal decompensation. Thus, it is equally important to prevent damage to the cardiovascular system, kidneys, and other tissues subject to damage through glucolipotoxicity.

Balancing glycemic control and risk

The hemoglobin A_1c level is the chief target of care and an important barometer of risk of diabetes-related complications. In 2018, the American College of Physicians (ACP) relaxed its target for hemoglobin A_1c from 7% to 8%.⁸ This move was apparently to give physicians greater “wiggle room” for achieving goals in hypoglycemia-prone patients. This, however, may take a toll.

Hypoglycemia is closely tied to cardiovascular disease. Even mild and asymptomatic hypoglycemia that goes undiagnosed and unnoticed by patients has been found to be associated with higher rates of all-cause mortality, prolonged QT interval, angina, arrhythmias, myocardial dysfunction, disturbances in autonomic balance, and sudden death.^9–11

However, the ADA, AACE, American Association of Diabetes Educators (AADE), and the Endocrine Society jointly issued a strong indictment of the ACP recommendation.¹² They argue that tight glucose control and its well-documented “legacy effects” on long-term outcomes should not be sacrificed.^12,13 Indeed, there is no need to abandon evidence-based best practices in care when at least 8 of the 11 classes of antidiabetes agents do not introduce the same level of risk for hypoglycemia.

Current guidelines argue for tight glucose control but generally stop short of discriminating or stratifying the mechanisms of action of the individual classes of drugs. These guidelines also do not stress targeting the particular pathways of hyperglycemia present in any given patient. However, the 2016 ADA joint statement acknowledges the need to “characterize the many paths to beta-cell dysfunction or demise and identify therapeutic approaches that best target each path.”¹

The sections below highlight some of the recent data on the profiles of most of the currently available agents.

Metformin: Still the first-line treatment

Current guidelines from the ACP, ADA, and AACE keep metformin¹⁴ as the backbone of treatment, although debate continues as to whether newer agents such as GLP-1 receptor agonists are superior for first-line therapy.

Pathways affected. Metformin improves insulin resistance in the liver, increases endogenous GLP-1 levels via the gut, and appears to modulate gut flora composition, which is increasingly suspected to contribute to dysmetabolism. 

Advantages, benefits. Metformin is easy to use and does not cause hypoglycemia. It was found to modestly reduce the number of cardiovascular events and deaths in a number of clinical outcome studies.^15–19

Disadvantages, adverse effects. In some patients, tolerability restricts the use of this drug at higher doses. The most common adverse effects of metformin are gastrointestinal symptoms (diarrhea, nausea, vomiting, flatulence); other risks include lactic acidosis in patients with impaired kidney function, heart failure, hypoxemia, alcoholism, cirrhosis, contrast exposure, sepsis, and shock.

GLP-1 receptor agonists

GLP-1 receptor agonists^20–25 are injectable medications approved for adults with type 2 diabetes. Exenatide and liraglutide lower hemoglobin A_1c by 1 to 1.5 absolute percentage points and reduce body weight; these effects persist over the long term.²⁶ Newer once-weekly GLP-1 receptor agonists (albiglutide,²⁰ dulaglutide,²¹ and semaglutide²⁵) have similar benefits. In 2019, new drug applications were submitted to the FDA for the first-in-kind oral GLP-1 receptor agonists, which would improve convenience and adherence and make this class even more attractive.

Pathways affected. GLP-1 receptor agonists address multiple pathways of hyperglycemia. They increase insulin production and release, promote weight loss, and reduce insulin resistance, glucagon secretion, and inflammation. They also increase amylin, help overcome GLP-1 resistance, slow gastric emptying, and favorably modify gut flora.²⁷

Advantages, benefits. The cardioprotective actions of GLP-1 receptor agonists include reducing inflammation and dysfunction in endothelial and myocardial cells; slowing atherosclerosis; reducing oxidative stress-induced injury and scavenging of reactive oxygen species in coronary endothelial, smooth muscle, and other cells; and enhancing endogenous antioxidant defenses.²⁷ GLP-1 receptor agonism has also been found to inhibit apoptosis in cardiomyocytes, as well as in beta cells.

Several large-scale studies have shown improved outcomes with GLP-1 receptor agonists. The Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEADER) trial²⁶ found that liraglutide reduced major adverse cardiovascular events by 13% and myocardial infarctions by 22% in more than 9,000 adults with type 2 diabetes who were at high risk of major adverse cardiovascular events compared with placebo. Rates of microvascular outcomes were also reduced.

A retrospective database analysis of 39,275 patients with type 2 diabetes who were treated with exenatide reported a lower incidence of cardiovascular events than in patients not treated with exenatide.²⁸

However, no effect on cardiovascular outcomes was found with a third GLP-1 agent, lixisenatide, in a large-scale trial in high-risk patients with diabetes.²⁹

The most recently evaluated GLP-1 receptor agonist is semaglutide. The Trial to Evaluate Cardiovascular and Other Long-term Outcomes With Semaglutide in Subjects With Type 2 Diabetes (SUSTAIN-6) demonstrated a reduced risk of major adverse cardiovascular events.³⁰

Disadvantages, adverse effects. The most common adverse effects in this class include nausea, hypoglycemia, diarrhea, constipation, vomiting, headache, decreased appetite, dyspepsia, fatigue, dizziness, abdominal pain, and increased lipase. The nausea can be mitigated by advising patients to stop eating at first sensation of stomach fullness.

DPP-4 inhibitors

Dipeptidyl peptidase 4 (DPP-4) is a ubiquitous enzyme that rapidly degrades GLP-1 and other endogenous peptides.³¹ Saxagliptin,³² sitagliptin,³³ linagliptin,³⁴ and alogliptin³⁵ are approved for use in the United States, and vildagliptin36 is available in Europe.

Pathways affected. These agents modify 3 pathways of hyperglycemia: they increase insulin secretion, decrease glucagon levels, and help overcome GLP-1 resistance.

Advantages, benefits. DPP-4 inhibitors have been used safely and effectively in clinically challenging populations of patients with long-standing type 2 diabetes (> 10 years).

Disadvantages, adverse effects. As this class increases GLP-1 levels only 2- to 4-fold, their efficacy is more modest than that of GLP-1 receptor agonists (hemoglobin A_1c reductions of 0.5% to 1%; neutral effects on weight).³⁷

Outcome trials have largely been neutral. Saxagliptin has been associated with an increase in admissions for heart failure. There have been a very small but statistically significant number of drug-related cases of acute pancreatitis.³⁸

The most common adverse effects with this class include headache, nasopharyngitis, urinary tract infection, upper respiratory tract infection, and elevated liver enzymes.

Drugs of this class currently available in the United States are canagliflozin,³⁹ dapagliflozin,⁴⁰ empagliflozin,⁴¹ and ertugliflozin.⁴²

Pathways affected. SGLT2 inhibitors lower the glucose reabsorption threshold in the kidney so that more glucose is excreted in the urine; they also decrease insulin resistance in muscle, liver, and fat cells (via weight loss) and possibly preserve beta-cell function by reducing glucotoxicity. A nonrenal mechanism—delayed gut absorption reducing postprandial glucose excursion—has been proposed to contribute to the glucose-lowering effects of canagliflozin.⁴³

Advantages, benefits. These agents reduce hemoglobin A_1c by about 0.5% to 1.0% from a baseline of about 8%. Because their action is independent of insulin, they can be used at any stage of type 2 diabetes, even after insulin secretion has significantly waned. Additional potential advantages include weight loss (up to 3.5% of body mass index) and lowering of systolic blood pressure (2–4 mm Hg) and diastolic blood pressure (1–2 mm Hg).^39–42

Canagliflozin was shown in the Canagliflozin Cardiovascular Assessment Study (CANVAS)⁴⁴ to significantly reduce the overall risk of cardiovascular disease by 14% and risk of heart failure hospitalization by 33% while significantly slowing the progression of renal disease.

In the BI 10773 (Empagliflozin) Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients (EMPA-REG OUTCOME),⁴⁵ empagliflozin reduced heart failure hospitalizations by 35%, cardiovascular deaths by 38%, and all-cause mortality by about 32%. These benefits are thought to be due to less arterial stiffness, lower sympathetic tone, and decreased arrhythmias. Notably, these dramatic benefits accrued in only about 3 years with use of add-on therapy, even though the reduction in hemoglobin A_1c was modest (0.6%), suggesting that pleiotropic effects are at work.

Disadvantages, adverse effects. The most common adverse effects of this class include urinary tract infections, yeast infections, dehydration, and hypovolemic symptoms; these can often be prevented. A trend toward increased incidence of amputations in earlier studies was not borne out in a 2018 meta-analysis of 4 observational databases.⁴⁶

Thiazolidinediones

There are currently 2 approved thiazolidine­diones in the United States, pioglitazone⁴⁷ and rosiglitazone.⁴⁸ Only pioglitazone is in common use, as rosiglitazone is associated with safety issues.⁴⁹

Pathways affected. Pioglitazone reduces insulin resistance in muscle, liver, and adipose tissue.

Advantages, benefits. Decreased levels of low-density lipoprotein cholesterol and triglycerides and increased high-density lipoprotein cholesterol levels⁴⁹ could plausibly account for the cardiovascular benefits reported in the Prospective Pioglitazone Clinical Trial in Macrovascular Events.⁵⁰ Pioglitazone has also been found to improve insulin secretion, endothelial function, and diastolic dysfunction; reduce inflammation; decrease plasminogen activator inhibitor 1; reverse lipotoxicity; and help correct nonalcoholic fatty liver disease and steatohepatitis.

Pioglitazone has also been found to reduce plaque in carotid and coronary arteries⁵¹; improve outcomes in patients with heart failure and myocardial infarction compared with insulin-sensitizing drugs⁵²; and reduce stroke and myocardial infarction in patients with insulin resistance (but not diabetes) and a recent history of ischemic stroke or transient ischemic attack (in the Insulin Resistance Intervention After Stroke trial).⁵³ It may also help maintain beta-cell function; the Actos Now for the Prevention of Diabetes Study found that pioglitazone reduced the risk of conversion of impaired glucose tolerance to frank diabetes by 72%.⁵⁴

Disadvantages, adverse effects. The most common adverse effects seen with this class include weight gain and salt retention, swelling, edema,⁵⁵ and related cardiovascular consequences in certain patients. While this may be mitigatable with lifestyle changes or use in combination with a GLP-1 receptor agonist or SGLT2 inhibitor,⁵⁶ pioglitazone is contraindicated in patients with heart failure, hemodynamic instability, or hepatic dysfunction.

Concerns that pioglitazone might increase the risk of bladder cancer seem to have been put to rest when a study in nearly 200,000 patients found no statistically significant association,⁵⁷ but the warning remains in the US label.

Long-term use of this class of drugs has been associated with an increased risk of bone fractures,⁵⁸ which warrants a risk-benefit assessment in each patient.

Injected insulin: Less safe than thought

Recent research suggests that injected insulin has a less favorable safety profile than previously thought.^15–19,59 Studies of the long-term safety of insulin therapy have had inconsistent results but suggest that injected insulin is associated with poorer cardiovascular and renal outcomes (in some of the same studies that showed metformin or other agents to improve outcomes),^17–19 and the association was dose-dependent. Several studies attempted to cancel out the poorer outcomes by adjusting for hemoglobin A_1c levels, stage of disease,^{17–19,26,27} or severe hypoglycemic episodes.⁶⁰ However, it may be inappropriate to reduce the impact of these variables, as these may themselves be the mediators of any deleterious effects of exogenous insulin.

When exogenous insulin is introduced into the peripheral circulation it causes a state of persistent iatrogenic hyperinsulinemia, which leads to insulin resistance and also appears to compromise the cardiovascular system. In contrast, endogenous insulin is released into the portal system in tightly controlled amounts.^5,61 This suggests that the same insulin peptide may not be equivalently beneficial when introduced in an artificial manner.

Before starting insulin therapy, consider its side effects such as weight gain and hypoglycemia. Most (about 85%) episodes of hypoglycemia occur with basal-bolus insulin regimens.⁶² Moreover, iatrogenic hyperinsulinemia can damage the vascular system.^63,64

We recommend. Insulin therapy is used early in the course of the disease as a short-term intervention for glucolipotoxicity. However, this can be accomplished without attendant risks of hypoglycemia and weight gain by using agents such as SGLT2 inhibitors and incretins. When insulin therapy is necessary, using it as add-on therapy might be considered instead of drug-switching. We have found alternate pharmacologic approaches successful in avoiding or delaying bolus insulin therapy. And in some patients taking insulin, we have had success in progressively introducing a noninsulin agent and were ultimately able to eliminate insulin altogether.

Bromocriptine-QR (quick release)⁶⁵ is a short-acting dopamine agonist that mimics the morning dopamine surge in the suprachiasmatic nucleus—the biologic clock.

Pathways affected. Bromocriptine addresses part of the brain contribution to hyperglycemia, with resultant reductions in both peripheral insulin resistance and sympathetic tone. This reduces muscle, liver, and adipose insulin resistance. It is moderately effective in glucose-lowering, especially in patients with significant insulin resistance.⁶⁶

Advantages, benefits. A 1-year clinical trial reported that bromocriptine reduced cardiovascular adverse outcomes by 39%, and the composite end point of myocardial infarction, stroke, and cardiovascular death by 52% compared with placebo.⁶⁷

Disadvantages, adverse effects. The most common adverse effects are nausea, rhinitis, headache, asthenia, dizziness, constipation, and sinusitis.

Alpha-glucosidase inhibitors

Alpha-glucosidase inhibitors (acarbose,⁶⁸ miglitol⁶⁹) work by decreasing the rate of absorption of glucose from the gastrointestinal tract.

Advantages, benefits. These drugs decrease hemoglobin A_1c by 0.5% to 0.8%.70 They are weight-neutral and do not pose a risk of hypoglycemia. Clinical studies suggest that they may delay or prevent diabetes progression. They were also found to reduce cardiovascular events, acute myocardial infarction, and the onset of hypertension.⁶⁹

Disadvantages, adverse effects. Their use remains limited due to gastrointestinal adverse effects. They may be contraindicated in patients with inflammatory bowel disease, partial bowel obstruction, or severe renal or hepatic disease.

Pramlintide

Pramlintide⁷¹ is an injectable amylin analogue. It is used as monotherapy or in combination with a sulfonylurea, metformin, or insulin glargine.

Pathways affected. Pramlintide decreases appetite, reduces glucagon levels, and minimizes absorption of glucose in the gut.

Disadvantages, adverse effects. Common side effects include mild to moderate hypoglycemia and nausea. Nausea may help explain the ability of pramlintide to confer weight loss when used in combination with insulin.

Sulfonylureas and meglitinides

These classes are still widely used in the treatment of type 2 diabetes, although the AACE⁶ and ADA⁷² guidelines de-emphasize their use based on associated risks of hypoglycemia, weight gain, morbidity, mortality, and loss of effect over time.

Pathways affected. Sulfonylureas stimulate insulin secretion from beta cells.

Disadvantages, adverse effects. Sulfonylureas and glinides are associated with poorer outcomes than newer agents in clinical trials^{15–19,59,60} and may be generally less beta-cell friendly.⁷³ Their harmful effects are difficult to measure in vivo, but these drugs sometimes appear to be associated with more rapid beta-cell failure and progression to insulin dependence compared with newer ones. Several large-scale registry studies have found sulfonylureas and glinides to be associated with poorer outcomes (reviewed by Herman et al).⁷⁴

Adverse effects include asthenia, headache, dizziness, nausea, diarrhea, epigastric fullness, and heartburn. Although they are often selected based on their low cost, other factors may offset their cost-effectiveness, such as need for glucose monitoring and hospital charges due to sulfonylurea-induced hypoglycemia. Their utility is also limited by dependence on beta-cell function.

Colesevelam

Colesevelam⁷⁵ is a bile acid sequestrant and low-density lipoprotein cholesterol-reducing agent that has been approved for use in diabetes. The mode of action of colesevelam in this capacity is under investigation. Its effect on hemoglobin A_1c is modest. It is associated with gastrointestinal adverse effects, particularly constipation.

Ranolazine

Ranolazine⁷⁶ is an antianginal drug that also lowers glucose by increasing insulin release. It also possesses cardioprotective properties. In patients with diabetes and non-ST-segment elevation acute coronary syndromes, ranolazine reduced hemoglobin A_1c by 1.2% and appeared to be weight-neutral.⁷⁶ Ranolazine is under clinical development for use in diabetes. Adverse effects include dizziness, headache, constipation, and nausea.


Rational combinations of agents

The ideal strategy would use combinations of agents that mechanistically complement one another and address each path of hyperglycemia present in a patient. This approach should supplant the former approaches of adding-on agents only after treatment failure or sequentially trying first-, second-, and third-line treatments.

Examples of synergistic combinations include those that target fasting plasma glucose and postprandial glucose, reduce reliance on insulin with add-on therapies, or manage hyperglycemia in specific patient groups, such as renal-impaired patients.

Large-scale long-term clinical studies are needed to determine the safety, efficacy, and outcomes of various combinations and whether they confer additive benefits. Some studies have begun to explore possible combinations.

Combined metformin, pioglitazone, and exenatide was reported to delay progression of diabetes in early dysglycemia.^77,78 Notably, this combination addresses multiple mediating pathways of hyperglycemia (Table 1).

A GLP-1 receptor agonist with an SGLT2 inhibitor would be another intriguing combination, as the mechanisms of action of these 2 classes complement one another. In limited clinical trials—the DURATION-8 study (lasting 26 weeks),⁷⁹ the Canagliflozin Cardiovascular Assessment Study (18 weeks),⁸⁰ and a 24-week study in nondiabetic obese patients⁸¹—additive benefits were also seen in systolic blood pressure, body weight, and cardiac risk factors by adding an SGLT2 inhibitor to a GLP-1 receptor agonist, compared with either agent alone. In theory, these improvements might slow or reverse cardiorenal compromise. Lower doses of 1 or more may be possible, and the regimen could prove cost-effective and life-sparing should it slow the progression of the disease and the onset of its complications. A clinical study of this combination is under way (Ralph DeFronzo, personal communication, July 2018). Similarly, the combination of metformin, saxagliptin and dapagliflozin has been shown to be effective.⁸²

CONCLUSION

Care for diabetes mellitus can be particularly challenging for the primary care physician. The progressive nature of diabetes, with worsening hyperglycemia over the course of the disease, further complicates disease management.

Best practices for care nonetheless need to evolve with well-evidenced data, and without years of delay for “trickle-down” education from the specialties to primary care. We have arrived at a juncture to leverage therapies that address the 11 mediating pathways of hyperglycemia, optimally protect beta cells, minimize hypoglycemia, manage risk factors associated with diabetes, and improve diabetes-related outcomes.

Establishing a diagnosis of hypersomnia—recurrent episodes of excessive daytime sleepiness (EDS) or prolonged nighttime sleep—requires a stepwise assessment. We describe a complex case of an older adult who presented with multiple potential causes of hypersomnolence.

CASE REPORT

Persistent daytime sleepiness

Mr. W, age 63, is a veteran with a medical history significant for severe obstructive sleep apnea (OSA), insomnia, restless leg syndrome, hypertension, and major depressive disorder. He reported long-standing EDS that was causing functional and social impairment. Mr. W’s EDS persisted despite the use of continuous positive airway pressure (CPAP) therapy. A download of his CPAP compliance summary revealed both optimal CPAP adherence (>7-hour usage for 95%) and control of OSA (Apnea Hypopnea Index <5). His Epworth Sleepiness Scale (ESS) score remained at 20 out of 24. Another clinician had previously prescribed modafinil to treat Mr. W’s EDS, which was presumed to be related to sleep apnea. At the time of assessment, Mr. W was taking modafinil, 200 mg every morning, without significant relief of his daytime somnolence. Laboratory results revealed normal liver function tests, electrolytes, and hormonal levels, and a urine toxicology was negative. Mr. W said he constantly rubbed his legs to ease his bilateral leg movement. He reported both sensory and motor components, and relief with movement and absence of sensations in the morning.¹ Gabapentin was initiated and titrated to a therapeutic dose to stabilize these symptoms.

Further contemplation led the treating clinician to investigate sleep deprivation or insomnia as potential causes of Mr. W’s daytime somnolence. Mr. W also reported occasional insomnia symptoms. To probe for the culprit of daytime sleepiness, actigraphy wrist monitoring was performed and showed no persistent insomnia or circadian rhythm disturbances.² Medication reconciliation revealed Mr. W was taking 2 medications (fluoxetine and modafinil) that made him alert, but because he took these in the morning, it was unlikely that they were affecting his sleep. Upon review of his sleep habits, Mr. W’s naps were rare and unrefreshing during the day and he was not drinking excessive amounts of caffeinated beverages.

The diagnostic uncertainty led the treating clinician to order a polysomnography sleep study (PSG) with Multiple Sleep Latency Test (MSLT), which revealed a mean sleep latency of 4.1 minutes with no rapid eye movement (REM) periods during his PSG nor next-day napping.³ The PSG showed sleep fragmentation with a sleep efficiency of 90%. The results indicated residual sleepiness secondary to OSA.

Next, the clinician prescribed dextroamphetamine, 25 mg/d, which lowered Mr. W’s ESS score by 2 points (18 out of 24). The clinician presumed that if the stimulant worked, the diagnosis would more likely fit the criteria for residual sleepiness from OSA, rather than idiopathic hypersomnia (IH). Due to a lack of efficacy and adverse effects, the patient was tapered off this medication.

Mr. W reported that he experienced sleepiness during his service in the military at age 23. He also said he did not feel refreshed if he napped during the day.

To address the hypersomnia, he was prescribed off-label sodium oxybate. Sodium oxybate was efficacious and well tolerated; it was slowly titrated up to 9 g/d. After taking sodium oxybate for 2 months, Mr. W’s ESS score diminished to 6. Currently, he reports no functional impairment. A repeat actigraphy showed minimal sleep fragmentation and a strong normal circadian rhythm.

Continue to: Identifying hypersomnia

Identifying hypersomnia

Idiopathic hypersomnia should be considered when a patient’s excessive sleep or EDS are not better explained by another sleep disorder, other medical or psychiatric disorders, or the use of illicit drugs or medications.⁴ Idiopathic hypersomnia is characterized by EDS that occurs in the absence of cataplexy and is accompanied by no more than 1 sleep-onset REM (SOREM) period on an MSLT and the preceding PSG combined. The differential diagnosis includes narcolepsy, sleep apnea, and other conditions; most importantly, insufficient sleep syndrome must be carefully considered and excluded.

In IH, evidence of hypersomnia must be demonstrated by an MSLT showing a mean sleep latency of <8 minutes or by PSG or wrist actigraphy showing a total 24-hour sleep time of >660 minutes.⁴ A prolonged and severe form of sleep inertia, consisting of prolonged difficulty waking up with repeated returns to sleep, irritability, automatic behavior, and confusion, often occurs in IH but is not pathognomonic.⁴

Naps are long—often 60 minutes—and described as unrefreshing by 46% to 78% of patients.⁴ Sleep efficiency on polysomnography is usually high (mean 90% to 94%). Self-reported total sleep time is longer than in controls and is >10 hours in at least 30% of patients.⁴ Unfortunately, symptoms and certain objective findings of IH are not unique to the disorder and are considered ubiquitous.

For Mr. W, a diagnosis of narcolepsy was unlikely due to his MSLT results. Patients with narcolepsy have cataplexy (REM dissociation) and/or at least 2 SOREM periods on MLST, or at least 1 SOREM period on MLST in conjunction with a SOREM on the preceding PSG,⁴ which Mr. W did not exhibit. Patients with narcolepsy typically take refreshing naps lasting 15 to 30 minutes. Although not unique to narcolepsy, common findings include hypnagogic hallucinations and sleep paralysis. Patients with narcolepsy typically do not have sleep inertia but, when seemingly awake, have lapses in vigilance sometimes in combination with automatic behavior, such as writing gibberish or interrupting a conversation with a completely different topic. Another characteristic PSG finding is moderate to severe sleep fragmentation, which may be due to associated periodic limb movements or instability in sleep/wake transitions.⁵ Mr. W had no history of traumatic brain injury that would suggest hypersomnolence secondary to a brain injury.

Among medical conditions, OSA is the predominant cause of EDS, but this, too, was unlikely for Mr. W because the CPAP therapy reports indicated excellent chronic use and effect. His apnea/hypopnea index was low, and the lowest oxygen saturation recorded on his pre-MSLT PSG using CPAP was 93%. Subjectively, Mr. W reported no choking, gasping, or snoring while receiving CPAP therapy.

Continue to: Restless leg syndrome...

Restless leg syndrome was excluded because after receiving gabapentin, both Mr. W and his wife reported improvement in his leg movements.

Although patients with mood disorders such as depression have normal MSLT results, Mr. W reported no excessive time lying in bed awake, which patients with depression often describe as fatigue and sleepiness. In addition, Mr. W’s score on the Clinically Useful Depression Outcome Scale indicated he was not depressed.

Mr. W’s clinician prescribed off-label sodium oxybate to address his EDS. Its potential benefit in this case may be related to its activity on gamma-aminobutyric acid (GABA_B) receptors and its effects in prolonging slow-wave sleep, which has restorative properties. This treatment’s effectiveness in this patient was surprising and without precedent. Because the causes of IH often are not precisely defined, we do not recommend administering a trial of this medication without stepwise exclusion of other causes of sleepiness as demonstrated in Pagel’s algorithm “Diagnosis and Management of Conditions That Cause Excessive Daytime Sleepiness,”⁶ available at www.aafp.org/afp/2009/0301/p391.html.

Establishing a diagnosis of hypersomnia—recurrent episodes of excessive daytime sleepiness (EDS) or prolonged nighttime sleep—requires a stepwise assessment. We describe a complex case of an older adult who presented with multiple potential causes of hypersomnolence.

CASE REPORT

Persistent daytime sleepiness

Mr. W, age 63, is a veteran with a medical history significant for severe obstructive sleep apnea (OSA), insomnia, restless leg syndrome, hypertension, and major depressive disorder. He reported long-standing EDS that was causing functional and social impairment. Mr. W’s EDS persisted despite the use of continuous positive airway pressure (CPAP) therapy. A download of his CPAP compliance summary revealed both optimal CPAP adherence (>7-hour usage for 95%) and control of OSA (Apnea Hypopnea Index <5). His Epworth Sleepiness Scale (ESS) score remained at 20 out of 24. Another clinician had previously prescribed modafinil to treat Mr. W’s EDS, which was presumed to be related to sleep apnea. At the time of assessment, Mr. W was taking modafinil, 200 mg every morning, without significant relief of his daytime somnolence. Laboratory results revealed normal liver function tests, electrolytes, and hormonal levels, and a urine toxicology was negative. Mr. W said he constantly rubbed his legs to ease his bilateral leg movement. He reported both sensory and motor components, and relief with movement and absence of sensations in the morning.¹ Gabapentin was initiated and titrated to a therapeutic dose to stabilize these symptoms.

Further contemplation led the treating clinician to investigate sleep deprivation or insomnia as potential causes of Mr. W’s daytime somnolence. Mr. W also reported occasional insomnia symptoms. To probe for the culprit of daytime sleepiness, actigraphy wrist monitoring was performed and showed no persistent insomnia or circadian rhythm disturbances.² Medication reconciliation revealed Mr. W was taking 2 medications (fluoxetine and modafinil) that made him alert, but because he took these in the morning, it was unlikely that they were affecting his sleep. Upon review of his sleep habits, Mr. W’s naps were rare and unrefreshing during the day and he was not drinking excessive amounts of caffeinated beverages.

The diagnostic uncertainty led the treating clinician to order a polysomnography sleep study (PSG) with Multiple Sleep Latency Test (MSLT), which revealed a mean sleep latency of 4.1 minutes with no rapid eye movement (REM) periods during his PSG nor next-day napping.³ The PSG showed sleep fragmentation with a sleep efficiency of 90%. The results indicated residual sleepiness secondary to OSA.

Next, the clinician prescribed dextroamphetamine, 25 mg/d, which lowered Mr. W’s ESS score by 2 points (18 out of 24). The clinician presumed that if the stimulant worked, the diagnosis would more likely fit the criteria for residual sleepiness from OSA, rather than idiopathic hypersomnia (IH). Due to a lack of efficacy and adverse effects, the patient was tapered off this medication.

Mr. W reported that he experienced sleepiness during his service in the military at age 23. He also said he did not feel refreshed if he napped during the day.

To address the hypersomnia, he was prescribed off-label sodium oxybate. Sodium oxybate was efficacious and well tolerated; it was slowly titrated up to 9 g/d. After taking sodium oxybate for 2 months, Mr. W’s ESS score diminished to 6. Currently, he reports no functional impairment. A repeat actigraphy showed minimal sleep fragmentation and a strong normal circadian rhythm.

Continue to: Identifying hypersomnia

Identifying hypersomnia

Idiopathic hypersomnia should be considered when a patient’s excessive sleep or EDS are not better explained by another sleep disorder, other medical or psychiatric disorders, or the use of illicit drugs or medications.⁴ Idiopathic hypersomnia is characterized by EDS that occurs in the absence of cataplexy and is accompanied by no more than 1 sleep-onset REM (SOREM) period on an MSLT and the preceding PSG combined. The differential diagnosis includes narcolepsy, sleep apnea, and other conditions; most importantly, insufficient sleep syndrome must be carefully considered and excluded.

In IH, evidence of hypersomnia must be demonstrated by an MSLT showing a mean sleep latency of <8 minutes or by PSG or wrist actigraphy showing a total 24-hour sleep time of >660 minutes.⁴ A prolonged and severe form of sleep inertia, consisting of prolonged difficulty waking up with repeated returns to sleep, irritability, automatic behavior, and confusion, often occurs in IH but is not pathognomonic.⁴

Naps are long—often 60 minutes—and described as unrefreshing by 46% to 78% of patients.⁴ Sleep efficiency on polysomnography is usually high (mean 90% to 94%). Self-reported total sleep time is longer than in controls and is >10 hours in at least 30% of patients.⁴ Unfortunately, symptoms and certain objective findings of IH are not unique to the disorder and are considered ubiquitous.

For Mr. W, a diagnosis of narcolepsy was unlikely due to his MSLT results. Patients with narcolepsy have cataplexy (REM dissociation) and/or at least 2 SOREM periods on MLST, or at least 1 SOREM period on MLST in conjunction with a SOREM on the preceding PSG,⁴ which Mr. W did not exhibit. Patients with narcolepsy typically take refreshing naps lasting 15 to 30 minutes. Although not unique to narcolepsy, common findings include hypnagogic hallucinations and sleep paralysis. Patients with narcolepsy typically do not have sleep inertia but, when seemingly awake, have lapses in vigilance sometimes in combination with automatic behavior, such as writing gibberish or interrupting a conversation with a completely different topic. Another characteristic PSG finding is moderate to severe sleep fragmentation, which may be due to associated periodic limb movements or instability in sleep/wake transitions.⁵ Mr. W had no history of traumatic brain injury that would suggest hypersomnolence secondary to a brain injury.

Among medical conditions, OSA is the predominant cause of EDS, but this, too, was unlikely for Mr. W because the CPAP therapy reports indicated excellent chronic use and effect. His apnea/hypopnea index was low, and the lowest oxygen saturation recorded on his pre-MSLT PSG using CPAP was 93%. Subjectively, Mr. W reported no choking, gasping, or snoring while receiving CPAP therapy.

Continue to: Restless leg syndrome...

Restless leg syndrome was excluded because after receiving gabapentin, both Mr. W and his wife reported improvement in his leg movements.

Although patients with mood disorders such as depression have normal MSLT results, Mr. W reported no excessive time lying in bed awake, which patients with depression often describe as fatigue and sleepiness. In addition, Mr. W’s score on the Clinically Useful Depression Outcome Scale indicated he was not depressed.

Mr. W’s clinician prescribed off-label sodium oxybate to address his EDS. Its potential benefit in this case may be related to its activity on gamma-aminobutyric acid (GABA_B) receptors and its effects in prolonging slow-wave sleep, which has restorative properties. This treatment’s effectiveness in this patient was surprising and without precedent. Because the causes of IH often are not precisely defined, we do not recommend administering a trial of this medication without stepwise exclusion of other causes of sleepiness as demonstrated in Pagel’s algorithm “Diagnosis and Management of Conditions That Cause Excessive Daytime Sleepiness,”⁶ available at www.aafp.org/afp/2009/0301/p391.html.

Establishing a diagnosis of hypersomnia—recurrent episodes of excessive daytime sleepiness (EDS) or prolonged nighttime sleep—requires a stepwise assessment. We describe a complex case of an older adult who presented with multiple potential causes of hypersomnolence.

CASE REPORT

Persistent daytime sleepiness

Mr. W, age 63, is a veteran with a medical history significant for severe obstructive sleep apnea (OSA), insomnia, restless leg syndrome, hypertension, and major depressive disorder. He reported long-standing EDS that was causing functional and social impairment. Mr. W’s EDS persisted despite the use of continuous positive airway pressure (CPAP) therapy. A download of his CPAP compliance summary revealed both optimal CPAP adherence (>7-hour usage for 95%) and control of OSA (Apnea Hypopnea Index <5). His Epworth Sleepiness Scale (ESS) score remained at 20 out of 24. Another clinician had previously prescribed modafinil to treat Mr. W’s EDS, which was presumed to be related to sleep apnea. At the time of assessment, Mr. W was taking modafinil, 200 mg every morning, without significant relief of his daytime somnolence. Laboratory results revealed normal liver function tests, electrolytes, and hormonal levels, and a urine toxicology was negative. Mr. W said he constantly rubbed his legs to ease his bilateral leg movement. He reported both sensory and motor components, and relief with movement and absence of sensations in the morning.¹ Gabapentin was initiated and titrated to a therapeutic dose to stabilize these symptoms.

Further contemplation led the treating clinician to investigate sleep deprivation or insomnia as potential causes of Mr. W’s daytime somnolence. Mr. W also reported occasional insomnia symptoms. To probe for the culprit of daytime sleepiness, actigraphy wrist monitoring was performed and showed no persistent insomnia or circadian rhythm disturbances.² Medication reconciliation revealed Mr. W was taking 2 medications (fluoxetine and modafinil) that made him alert, but because he took these in the morning, it was unlikely that they were affecting his sleep. Upon review of his sleep habits, Mr. W’s naps were rare and unrefreshing during the day and he was not drinking excessive amounts of caffeinated beverages.

The diagnostic uncertainty led the treating clinician to order a polysomnography sleep study (PSG) with Multiple Sleep Latency Test (MSLT), which revealed a mean sleep latency of 4.1 minutes with no rapid eye movement (REM) periods during his PSG nor next-day napping.³ The PSG showed sleep fragmentation with a sleep efficiency of 90%. The results indicated residual sleepiness secondary to OSA.

Next, the clinician prescribed dextroamphetamine, 25 mg/d, which lowered Mr. W’s ESS score by 2 points (18 out of 24). The clinician presumed that if the stimulant worked, the diagnosis would more likely fit the criteria for residual sleepiness from OSA, rather than idiopathic hypersomnia (IH). Due to a lack of efficacy and adverse effects, the patient was tapered off this medication.

Mr. W reported that he experienced sleepiness during his service in the military at age 23. He also said he did not feel refreshed if he napped during the day.

To address the hypersomnia, he was prescribed off-label sodium oxybate. Sodium oxybate was efficacious and well tolerated; it was slowly titrated up to 9 g/d. After taking sodium oxybate for 2 months, Mr. W’s ESS score diminished to 6. Currently, he reports no functional impairment. A repeat actigraphy showed minimal sleep fragmentation and a strong normal circadian rhythm.

Continue to: Identifying hypersomnia

Identifying hypersomnia

Idiopathic hypersomnia should be considered when a patient’s excessive sleep or EDS are not better explained by another sleep disorder, other medical or psychiatric disorders, or the use of illicit drugs or medications.⁴ Idiopathic hypersomnia is characterized by EDS that occurs in the absence of cataplexy and is accompanied by no more than 1 sleep-onset REM (SOREM) period on an MSLT and the preceding PSG combined. The differential diagnosis includes narcolepsy, sleep apnea, and other conditions; most importantly, insufficient sleep syndrome must be carefully considered and excluded.

In IH, evidence of hypersomnia must be demonstrated by an MSLT showing a mean sleep latency of <8 minutes or by PSG or wrist actigraphy showing a total 24-hour sleep time of >660 minutes.⁴ A prolonged and severe form of sleep inertia, consisting of prolonged difficulty waking up with repeated returns to sleep, irritability, automatic behavior, and confusion, often occurs in IH but is not pathognomonic.⁴

Naps are long—often 60 minutes—and described as unrefreshing by 46% to 78% of patients.⁴ Sleep efficiency on polysomnography is usually high (mean 90% to 94%). Self-reported total sleep time is longer than in controls and is >10 hours in at least 30% of patients.⁴ Unfortunately, symptoms and certain objective findings of IH are not unique to the disorder and are considered ubiquitous.

For Mr. W, a diagnosis of narcolepsy was unlikely due to his MSLT results. Patients with narcolepsy have cataplexy (REM dissociation) and/or at least 2 SOREM periods on MLST, or at least 1 SOREM period on MLST in conjunction with a SOREM on the preceding PSG,⁴ which Mr. W did not exhibit. Patients with narcolepsy typically take refreshing naps lasting 15 to 30 minutes. Although not unique to narcolepsy, common findings include hypnagogic hallucinations and sleep paralysis. Patients with narcolepsy typically do not have sleep inertia but, when seemingly awake, have lapses in vigilance sometimes in combination with automatic behavior, such as writing gibberish or interrupting a conversation with a completely different topic. Another characteristic PSG finding is moderate to severe sleep fragmentation, which may be due to associated periodic limb movements or instability in sleep/wake transitions.⁵ Mr. W had no history of traumatic brain injury that would suggest hypersomnolence secondary to a brain injury.

Among medical conditions, OSA is the predominant cause of EDS, but this, too, was unlikely for Mr. W because the CPAP therapy reports indicated excellent chronic use and effect. His apnea/hypopnea index was low, and the lowest oxygen saturation recorded on his pre-MSLT PSG using CPAP was 93%. Subjectively, Mr. W reported no choking, gasping, or snoring while receiving CPAP therapy.

Continue to: Restless leg syndrome...

Restless leg syndrome was excluded because after receiving gabapentin, both Mr. W and his wife reported improvement in his leg movements.

Although patients with mood disorders such as depression have normal MSLT results, Mr. W reported no excessive time lying in bed awake, which patients with depression often describe as fatigue and sleepiness. In addition, Mr. W’s score on the Clinically Useful Depression Outcome Scale indicated he was not depressed.

Mr. W’s clinician prescribed off-label sodium oxybate to address his EDS. Its potential benefit in this case may be related to its activity on gamma-aminobutyric acid (GABA_B) receptors and its effects in prolonging slow-wave sleep, which has restorative properties. This treatment’s effectiveness in this patient was surprising and without precedent. Because the causes of IH often are not precisely defined, we do not recommend administering a trial of this medication without stepwise exclusion of other causes of sleepiness as demonstrated in Pagel’s algorithm “Diagnosis and Management of Conditions That Cause Excessive Daytime Sleepiness,”⁶ available at www.aafp.org/afp/2009/0301/p391.html.

Polypharmacy is often defined as the simultaneous prescription of multiple medications (usually ≥5) to a single patient for a single condition or multiple conditions.¹ Patients with psychiatric illnesses may easily be prescribed multiple psychotropic medications regardless of how many other medications they may already take for nonpsychiatric comorbidities. According to 2011-2014 Centers for Disease Control and Prevention data, 11.9% of the US population used ≥5 medications in the past 30 days.² Risks of polypharmacy include higher rates of adverse effects as well as treatment noncompliance.³

There are, however, many patients for whom a combination of psychotropic agents can be beneficial. It is important to carefully assess your patient’s regimen, and to document the rationale for prescribing multiple medications. Here I describe some factors that can help you to determine whether a multi-medication regimen might be warranted for your patient.

Accepted medication pairings. This describes a medication combination that has been recognized as generally safe and may provide more benefits than either single agent alone. Examples of clinically accepted medication combinations include^4,5:

• a selective serotonin reuptake inhibitor (SSRI) or serotonin-norepinephrine reuptake inhibitor (SNRI) plus bupropion
• an SSRI or SNRI plus mirtazapine
• ziprasidone as an adjunct to valproate or lithium for treating bipolar disorder
• aripiprazole as an adjunctive treatment for major depressive disorder (MDD).

Comorbid diagnoses. Each of a patient’s psychiatric comorbidities may require a different medication to address specific symptoms.³ Psychiatric comorbidities that might be appropriate for multiple medications include attention-deficit/hyperactivity disorder and bipolar disorder, MDD and generalized anxiety disorder, and a mood disorder and a substance use disorder.

Treatment resistance. The patient has demonstrated poor or no response to prior trials with simpler medication regimens, and/or there is a history of decompensation or hospitalization when medications were pared down.

Severe acute symptoms. The patient has been experiencing acute symptoms that do not respond to one medication class. For example, a patient with bipolar disorder who has acute mania and psychosis may require significant doses of both a mood stabilizer and an antipsychotic.

Amelioration of adverse effects. One medication may be prescribed to address the adverse effects of other medications. For example, propranolol may be added to address akathisia from aripiprazole or tremors from lithium. In these cases, it is important to determine if the medication that’s causing adverse effects continues to provide benefits, in order to justify continuing it as well as adding a new agent.³

Continue to: After reviewing...

After reviewing your patient’s medication regimen, if one of these scenarios does not clearly exist, consider a “deprescribing” approach—reducing or stopping medications—to address unnecessary and potentially detrimental polypharmacy. For more information on deprescribing, see “6 Steps to deprescribing: A practical approach,” (Current Psychiatry, June 2017, p. 36-37).

Polypharmacy is often defined as the simultaneous prescription of multiple medications (usually ≥5) to a single patient for a single condition or multiple conditions.¹ Patients with psychiatric illnesses may easily be prescribed multiple psychotropic medications regardless of how many other medications they may already take for nonpsychiatric comorbidities. According to 2011-2014 Centers for Disease Control and Prevention data, 11.9% of the US population used ≥5 medications in the past 30 days.² Risks of polypharmacy include higher rates of adverse effects as well as treatment noncompliance.³

There are, however, many patients for whom a combination of psychotropic agents can be beneficial. It is important to carefully assess your patient’s regimen, and to document the rationale for prescribing multiple medications. Here I describe some factors that can help you to determine whether a multi-medication regimen might be warranted for your patient.

Accepted medication pairings. This describes a medication combination that has been recognized as generally safe and may provide more benefits than either single agent alone. Examples of clinically accepted medication combinations include^4,5:

• a selective serotonin reuptake inhibitor (SSRI) or serotonin-norepinephrine reuptake inhibitor (SNRI) plus bupropion
• an SSRI or SNRI plus mirtazapine
• ziprasidone as an adjunct to valproate or lithium for treating bipolar disorder
• aripiprazole as an adjunctive treatment for major depressive disorder (MDD).

Comorbid diagnoses. Each of a patient’s psychiatric comorbidities may require a different medication to address specific symptoms.³ Psychiatric comorbidities that might be appropriate for multiple medications include attention-deficit/hyperactivity disorder and bipolar disorder, MDD and generalized anxiety disorder, and a mood disorder and a substance use disorder.

Treatment resistance. The patient has demonstrated poor or no response to prior trials with simpler medication regimens, and/or there is a history of decompensation or hospitalization when medications were pared down.

Severe acute symptoms. The patient has been experiencing acute symptoms that do not respond to one medication class. For example, a patient with bipolar disorder who has acute mania and psychosis may require significant doses of both a mood stabilizer and an antipsychotic.

Amelioration of adverse effects. One medication may be prescribed to address the adverse effects of other medications. For example, propranolol may be added to address akathisia from aripiprazole or tremors from lithium. In these cases, it is important to determine if the medication that’s causing adverse effects continues to provide benefits, in order to justify continuing it as well as adding a new agent.³

Continue to: After reviewing...

After reviewing your patient’s medication regimen, if one of these scenarios does not clearly exist, consider a “deprescribing” approach—reducing or stopping medications—to address unnecessary and potentially detrimental polypharmacy. For more information on deprescribing, see “6 Steps to deprescribing: A practical approach,” (Current Psychiatry, June 2017, p. 36-37).

Polypharmacy is often defined as the simultaneous prescription of multiple medications (usually ≥5) to a single patient for a single condition or multiple conditions.¹ Patients with psychiatric illnesses may easily be prescribed multiple psychotropic medications regardless of how many other medications they may already take for nonpsychiatric comorbidities. According to 2011-2014 Centers for Disease Control and Prevention data, 11.9% of the US population used ≥5 medications in the past 30 days.² Risks of polypharmacy include higher rates of adverse effects as well as treatment noncompliance.³

There are, however, many patients for whom a combination of psychotropic agents can be beneficial. It is important to carefully assess your patient’s regimen, and to document the rationale for prescribing multiple medications. Here I describe some factors that can help you to determine whether a multi-medication regimen might be warranted for your patient.

Accepted medication pairings. This describes a medication combination that has been recognized as generally safe and may provide more benefits than either single agent alone. Examples of clinically accepted medication combinations include^4,5:

• a selective serotonin reuptake inhibitor (SSRI) or serotonin-norepinephrine reuptake inhibitor (SNRI) plus bupropion
• an SSRI or SNRI plus mirtazapine
• ziprasidone as an adjunct to valproate or lithium for treating bipolar disorder
• aripiprazole as an adjunctive treatment for major depressive disorder (MDD).

Comorbid diagnoses. Each of a patient’s psychiatric comorbidities may require a different medication to address specific symptoms.³ Psychiatric comorbidities that might be appropriate for multiple medications include attention-deficit/hyperactivity disorder and bipolar disorder, MDD and generalized anxiety disorder, and a mood disorder and a substance use disorder.

Treatment resistance. The patient has demonstrated poor or no response to prior trials with simpler medication regimens, and/or there is a history of decompensation or hospitalization when medications were pared down.

Severe acute symptoms. The patient has been experiencing acute symptoms that do not respond to one medication class. For example, a patient with bipolar disorder who has acute mania and psychosis may require significant doses of both a mood stabilizer and an antipsychotic.

Amelioration of adverse effects. One medication may be prescribed to address the adverse effects of other medications. For example, propranolol may be added to address akathisia from aripiprazole or tremors from lithium. In these cases, it is important to determine if the medication that’s causing adverse effects continues to provide benefits, in order to justify continuing it as well as adding a new agent.³

Continue to: After reviewing...

After reviewing your patient’s medication regimen, if one of these scenarios does not clearly exist, consider a “deprescribing” approach—reducing or stopping medications—to address unnecessary and potentially detrimental polypharmacy. For more information on deprescribing, see “6 Steps to deprescribing: A practical approach,” (Current Psychiatry, June 2017, p. 36-37).

Delirium is defined as a disturbance in attention, awareness, and cognition that develops over hours to days as a direct physiological consequence of an underlying medical condition and is not better explained by another neurocognitive disorder.¹ This condition is found in up to 31% of general medical patients and up to 87% of critically ill medical patients. Delirium is commonly seen in patients who have undergone surgery, those who are in palliative care, and patients with cancer.² It is associated with increased morbidity and mortality. Compared with those who do not develop delirium, patients who are hospitalized who develop delirium have a higher risk of longer hospital stays, post-hospitalization nursing facility placement, persistent cognitive dysfunction, and death.³

Thus far, the management and treatment of delirium have been complicated by an incomplete understanding of the pathophysiology of this condition. However, prevailing theories suggest a dysregulation of neurotransmitter synthesis, function, or availability.² Recent literature reflects this theory; researchers have investigated agents that target dopamine or acetylcholine. Below we review some of this recent literature on treating delirium; these studies are summarized in the Table.^4-6

1. Burry L, Mehta S, Perreault MM, et al. Antipsychotics for treatment of delirium in hospitalized non-ICU patients. Cochrane Database Syst Rev. 2018;6:CD005594.

An extensive literature review identified randomized or quasi-randomized trials on the treatment of delirium among non-critically ill hospitalized patients in which antipsychotics were compared with nonantipsychotic medications or placebo, or in which a first-generation antipsychotic (FGA) was compared with a second-generation antipsychotic (SGA).⁴

Study design

• Researchers conducted a literature review of 9 trials that included 727 hospitalized but not critically ill patients (ie, they were not in an ICU) who developed delirium.
• Four trials compared an antipsychotic with a medication from another drug class or with placebo.
• Seven trials compared a FGA with an SGA.

Outcomes

• Although the intended primary outcome was the duration of delirium, none of the included studies reported on duration of delirium. Secondary outcomes were delirium severity and resolution, mortality, hospital length of stay, discharge disposition, health-related quality of life, and adverse effects.
• Among the secondary outcomes, no statistical difference was observed between delirium severity, delirium resolution, or mortality.
• None of the included studies reported on hospital length of stay, discharge disposition, or health-related quality of life.
• Evidence related to adverse effects was determined to be very low quality due to potential bias, inconsistency, and imprecision.

Conclusion

• A review of 9 randomized trials did not find any evidence supporting the use of antipsychotics for treating delirium. However, most of the studies included were of lower quality because they were single-center trials with insufficient sample sizes, heterogeneous study populations, and risk of bias.

Continue to: 2...

Study design

• Researchers used the Confusion Assessment Method for the Intensive Care Unit (CAM-ICU) to assess 1,183 patients with acute respiratory failure or shock in 16 medical centers in the United States.⁵
• Overall, 566 patients developed delirium and were randomized in a double-blind fashion to receive IV haloperidol, ziprasidone, or placebo.
• Haloperidol was started at 2.5 mg (age <70) or 1.25 mg (age ≥70) every 12 hours and titrated to a maximum dose of 20 mg/d as tolerated.
• Ziprasidone was started at 5 mg (age <70) or 2.5 mg (age ≥70) every 12 hours and titrated to a maximum dose of 40 mg/d as tolerated.

Outcomes

• The primary endpoint was days alive without delirium or coma. Secondary endpoints included duration of delirium, time to freedom from mechanical ventilation, time to final successful ICU discharge, time to ICU readmission, time to successful hospital discharge, 30-day survival, and 90-day survival.
• Neither ziprasidone nor haloperidol had an impact on number of days alive without delirium or coma.
• There was also no statistically significant difference in 30-day survival, 90-day survival, time to freedom from mechanical ventilation, ICU discharge, ICU readmission, or hospital discharge.

Conclusion

• This study found no evidence supporting haloperidol or ziprasidone for the treatment of delirium. Because all patients in this study were critically ill, it is unclear if these results would be generalizable to other hospitalized patient populations.

3. Yu A, Wu S, Zhang Z, et al. Cholinesterase inhibitors for the treatment of delirium in non-ICU settings. Cochrane Database Syst Rev. 2018;6:CD012494.

Continue to: Study design

• A literature review identified published and unpublished randomized controlled trials in English and Chinese in which cholinesterase inhibitors were compared with placebo or another drug for treating delirium in non-critically ill patients.⁶
• Only one study met the criteria to be included in the review. It included 15 participants treated with rivastigmine or placebo.

Outcomes

• The intended primary outcomes were severity of delirium and duration of delirium. However, the included study did not report on the severity of delirium. It also lacked statistical power to determine a difference in duration of delirium between the rivastigmine and placebo groups.
• Secondary outcomes included use of a rescue medication, persistent cognitive impairment, length of hospitalization, institutionalization, mortality, cost of intervention, early departure from the study, and quality of life.
• There was no clear difference between the rivastigmine group and the placebo group in terms of the use of rescue medications, mortality, or early departure from the study. The included study did not report on persistent cognitive impairment, length of hospitalization, institutionalization, cost of intervention, or quality of life.

Conclusion

• This literature review did not find any evidence to support the use of cholinesterase inhibitors for treating delirium. However, because this review included only a single small study, limited conclusions can be drawn from this research.

In summary, delirium is common, especially among patients who are acutely medically ill, and it is associated with poor physical and cognitive clinical outcomes. Because of these poor outcomes, it is important to identify delirium early and intervene aggressively. Clearly, there is a need for further research into short- and long-term treatments for delirium.

Delirium is defined as a disturbance in attention, awareness, and cognition that develops over hours to days as a direct physiological consequence of an underlying medical condition and is not better explained by another neurocognitive disorder.¹ This condition is found in up to 31% of general medical patients and up to 87% of critically ill medical patients. Delirium is commonly seen in patients who have undergone surgery, those who are in palliative care, and patients with cancer.² It is associated with increased morbidity and mortality. Compared with those who do not develop delirium, patients who are hospitalized who develop delirium have a higher risk of longer hospital stays, post-hospitalization nursing facility placement, persistent cognitive dysfunction, and death.³

Thus far, the management and treatment of delirium have been complicated by an incomplete understanding of the pathophysiology of this condition. However, prevailing theories suggest a dysregulation of neurotransmitter synthesis, function, or availability.² Recent literature reflects this theory; researchers have investigated agents that target dopamine or acetylcholine. Below we review some of this recent literature on treating delirium; these studies are summarized in the Table.^4-6

1. Burry L, Mehta S, Perreault MM, et al. Antipsychotics for treatment of delirium in hospitalized non-ICU patients. Cochrane Database Syst Rev. 2018;6:CD005594.

An extensive literature review identified randomized or quasi-randomized trials on the treatment of delirium among non-critically ill hospitalized patients in which antipsychotics were compared with nonantipsychotic medications or placebo, or in which a first-generation antipsychotic (FGA) was compared with a second-generation antipsychotic (SGA).⁴

Study design

• Researchers conducted a literature review of 9 trials that included 727 hospitalized but not critically ill patients (ie, they were not in an ICU) who developed delirium.
• Four trials compared an antipsychotic with a medication from another drug class or with placebo.
• Seven trials compared a FGA with an SGA.

Outcomes

• Although the intended primary outcome was the duration of delirium, none of the included studies reported on duration of delirium. Secondary outcomes were delirium severity and resolution, mortality, hospital length of stay, discharge disposition, health-related quality of life, and adverse effects.
• Among the secondary outcomes, no statistical difference was observed between delirium severity, delirium resolution, or mortality.
• None of the included studies reported on hospital length of stay, discharge disposition, or health-related quality of life.
• Evidence related to adverse effects was determined to be very low quality due to potential bias, inconsistency, and imprecision.

Conclusion

• A review of 9 randomized trials did not find any evidence supporting the use of antipsychotics for treating delirium. However, most of the studies included were of lower quality because they were single-center trials with insufficient sample sizes, heterogeneous study populations, and risk of bias.

Continue to: 2...

Study design

• Researchers used the Confusion Assessment Method for the Intensive Care Unit (CAM-ICU) to assess 1,183 patients with acute respiratory failure or shock in 16 medical centers in the United States.⁵
• Overall, 566 patients developed delirium and were randomized in a double-blind fashion to receive IV haloperidol, ziprasidone, or placebo.
• Haloperidol was started at 2.5 mg (age <70) or 1.25 mg (age ≥70) every 12 hours and titrated to a maximum dose of 20 mg/d as tolerated.
• Ziprasidone was started at 5 mg (age <70) or 2.5 mg (age ≥70) every 12 hours and titrated to a maximum dose of 40 mg/d as tolerated.

Outcomes

• The primary endpoint was days alive without delirium or coma. Secondary endpoints included duration of delirium, time to freedom from mechanical ventilation, time to final successful ICU discharge, time to ICU readmission, time to successful hospital discharge, 30-day survival, and 90-day survival.
• Neither ziprasidone nor haloperidol had an impact on number of days alive without delirium or coma.
• There was also no statistically significant difference in 30-day survival, 90-day survival, time to freedom from mechanical ventilation, ICU discharge, ICU readmission, or hospital discharge.

Conclusion

• This study found no evidence supporting haloperidol or ziprasidone for the treatment of delirium. Because all patients in this study were critically ill, it is unclear if these results would be generalizable to other hospitalized patient populations.

3. Yu A, Wu S, Zhang Z, et al. Cholinesterase inhibitors for the treatment of delirium in non-ICU settings. Cochrane Database Syst Rev. 2018;6:CD012494.

Continue to: Study design

• A literature review identified published and unpublished randomized controlled trials in English and Chinese in which cholinesterase inhibitors were compared with placebo or another drug for treating delirium in non-critically ill patients.⁶
• Only one study met the criteria to be included in the review. It included 15 participants treated with rivastigmine or placebo.

Outcomes

• The intended primary outcomes were severity of delirium and duration of delirium. However, the included study did not report on the severity of delirium. It also lacked statistical power to determine a difference in duration of delirium between the rivastigmine and placebo groups.
• Secondary outcomes included use of a rescue medication, persistent cognitive impairment, length of hospitalization, institutionalization, mortality, cost of intervention, early departure from the study, and quality of life.
• There was no clear difference between the rivastigmine group and the placebo group in terms of the use of rescue medications, mortality, or early departure from the study. The included study did not report on persistent cognitive impairment, length of hospitalization, institutionalization, cost of intervention, or quality of life.

Conclusion

• This literature review did not find any evidence to support the use of cholinesterase inhibitors for treating delirium. However, because this review included only a single small study, limited conclusions can be drawn from this research.

In summary, delirium is common, especially among patients who are acutely medically ill, and it is associated with poor physical and cognitive clinical outcomes. Because of these poor outcomes, it is important to identify delirium early and intervene aggressively. Clearly, there is a need for further research into short- and long-term treatments for delirium.

Delirium is defined as a disturbance in attention, awareness, and cognition that develops over hours to days as a direct physiological consequence of an underlying medical condition and is not better explained by another neurocognitive disorder.¹ This condition is found in up to 31% of general medical patients and up to 87% of critically ill medical patients. Delirium is commonly seen in patients who have undergone surgery, those who are in palliative care, and patients with cancer.² It is associated with increased morbidity and mortality. Compared with those who do not develop delirium, patients who are hospitalized who develop delirium have a higher risk of longer hospital stays, post-hospitalization nursing facility placement, persistent cognitive dysfunction, and death.³

Thus far, the management and treatment of delirium have been complicated by an incomplete understanding of the pathophysiology of this condition. However, prevailing theories suggest a dysregulation of neurotransmitter synthesis, function, or availability.² Recent literature reflects this theory; researchers have investigated agents that target dopamine or acetylcholine. Below we review some of this recent literature on treating delirium; these studies are summarized in the Table.^4-6

1. Burry L, Mehta S, Perreault MM, et al. Antipsychotics for treatment of delirium in hospitalized non-ICU patients. Cochrane Database Syst Rev. 2018;6:CD005594.

An extensive literature review identified randomized or quasi-randomized trials on the treatment of delirium among non-critically ill hospitalized patients in which antipsychotics were compared with nonantipsychotic medications or placebo, or in which a first-generation antipsychotic (FGA) was compared with a second-generation antipsychotic (SGA).⁴

Study design

• Researchers conducted a literature review of 9 trials that included 727 hospitalized but not critically ill patients (ie, they were not in an ICU) who developed delirium.
• Four trials compared an antipsychotic with a medication from another drug class or with placebo.
• Seven trials compared a FGA with an SGA.

Outcomes

• Although the intended primary outcome was the duration of delirium, none of the included studies reported on duration of delirium. Secondary outcomes were delirium severity and resolution, mortality, hospital length of stay, discharge disposition, health-related quality of life, and adverse effects.
• Among the secondary outcomes, no statistical difference was observed between delirium severity, delirium resolution, or mortality.
• None of the included studies reported on hospital length of stay, discharge disposition, or health-related quality of life.
• Evidence related to adverse effects was determined to be very low quality due to potential bias, inconsistency, and imprecision.

Conclusion

• A review of 9 randomized trials did not find any evidence supporting the use of antipsychotics for treating delirium. However, most of the studies included were of lower quality because they were single-center trials with insufficient sample sizes, heterogeneous study populations, and risk of bias.

Continue to: 2...

Study design

• Researchers used the Confusion Assessment Method for the Intensive Care Unit (CAM-ICU) to assess 1,183 patients with acute respiratory failure or shock in 16 medical centers in the United States.⁵
• Overall, 566 patients developed delirium and were randomized in a double-blind fashion to receive IV haloperidol, ziprasidone, or placebo.
• Haloperidol was started at 2.5 mg (age <70) or 1.25 mg (age ≥70) every 12 hours and titrated to a maximum dose of 20 mg/d as tolerated.
• Ziprasidone was started at 5 mg (age <70) or 2.5 mg (age ≥70) every 12 hours and titrated to a maximum dose of 40 mg/d as tolerated.

Outcomes

• The primary endpoint was days alive without delirium or coma. Secondary endpoints included duration of delirium, time to freedom from mechanical ventilation, time to final successful ICU discharge, time to ICU readmission, time to successful hospital discharge, 30-day survival, and 90-day survival.
• Neither ziprasidone nor haloperidol had an impact on number of days alive without delirium or coma.
• There was also no statistically significant difference in 30-day survival, 90-day survival, time to freedom from mechanical ventilation, ICU discharge, ICU readmission, or hospital discharge.

Conclusion

• This study found no evidence supporting haloperidol or ziprasidone for the treatment of delirium. Because all patients in this study were critically ill, it is unclear if these results would be generalizable to other hospitalized patient populations.

3. Yu A, Wu S, Zhang Z, et al. Cholinesterase inhibitors for the treatment of delirium in non-ICU settings. Cochrane Database Syst Rev. 2018;6:CD012494.

Continue to: Study design

• A literature review identified published and unpublished randomized controlled trials in English and Chinese in which cholinesterase inhibitors were compared with placebo or another drug for treating delirium in non-critically ill patients.⁶
• Only one study met the criteria to be included in the review. It included 15 participants treated with rivastigmine or placebo.

Outcomes

• The intended primary outcomes were severity of delirium and duration of delirium. However, the included study did not report on the severity of delirium. It also lacked statistical power to determine a difference in duration of delirium between the rivastigmine and placebo groups.
• Secondary outcomes included use of a rescue medication, persistent cognitive impairment, length of hospitalization, institutionalization, mortality, cost of intervention, early departure from the study, and quality of life.
• There was no clear difference between the rivastigmine group and the placebo group in terms of the use of rescue medications, mortality, or early departure from the study. The included study did not report on persistent cognitive impairment, length of hospitalization, institutionalization, cost of intervention, or quality of life.

Conclusion

• This literature review did not find any evidence to support the use of cholinesterase inhibitors for treating delirium. However, because this review included only a single small study, limited conclusions can be drawn from this research.

In summary, delirium is common, especially among patients who are acutely medically ill, and it is associated with poor physical and cognitive clinical outcomes. Because of these poor outcomes, it is important to identify delirium early and intervene aggressively. Clearly, there is a need for further research into short- and long-term treatments for delirium.

Acute upper respiratory infections (URIs) often lead to mild illnesses, but they can be severely destabilizing for individuals with mood disorders. Additionally, the medications patients often take to target symptoms of the common cold or influenza can interact with psychiatric medications to produce dangerous adverse events or induce further mood symptoms. In this article, we describe the relationship between URIs and mood disorders, the psychiatric diagnostic challenges that arise when evaluating a patient with a URI, and treatment approaches that emphasize psycho­education and watchful waiting, when appropriate.

A bidirectional relationship

Acute upper respiratory infections are the most common human illnesses, affecting almost 25 million people annually in the United States.¹ The common cold is caused by >200 different viruses; rhinovirus and coronavirus are the most common. Influenza, which also attacks the upper respiratory tract, is caused by strains of influenza A, B, or C virus.² The common cold may present initially with mild symptoms of headache, sneezing, chills, and sore throat, and then progress to nasal discharge, congestion, cough, and malaise. When influenza strikes, patients may have a sudden onset of fever, headache, cough, sore throat, myalgia, congestion, weakness, anorexia, and gastrointestinal (GI) symptoms. Production of URI symptoms results from viral cytopathic activity along with immune activation of inflammatory pathways.^2,3 The incidence of colds is inversely correlated with age; adults average 2 to 4 colds per year.^4,5 Cold symptoms peak at 1 to 3 days and typically last 7 to 10 days, but can persist up to 3 weeks.⁶ With influenza, fever and other systemic symptoms last for 3 days but can persist up to 8 days, while cough and lethargy can persist for another 2 weeks.⁷

Upper respiratory infections have the potential to disrupt mood. Large studies of psychiatrically-healthy undergraduate students have found that compared with healthy controls, participants with URIs endorsed a negative affect within the first week of viral illness,⁸ and that the number and intensity of URI symptoms caused by cold viruses were correlated with the degree of their negative affect.⁹ A few case reports have documented instances of individuals with no previous personal or family psychiatric history developing full manic episodes in the setting of influenza.^10-12 One case report described an influenza-induced manic episode in a patient with pre-existing psychiatric illness.¹³ There are no published case reports of common cold viruses inducing a full depressive or manic episode. If cold symptom severity correlates with negative affect among individuals with no psychiatric illness, and if influenza can induce manic episodes, then it is reasonable to expect that patients with pre-existing mood disorders could have an elevated risk for mood disturbances when they experience a URI (Box).

Box

Mood disorders may also be a risk factor for contracting URIs. Patients with mood disorders are more likely than healthy controls to be seropositive for markers of influenza A, influenza B, and coronavirus, and those with a history of suicide attempts are more likely to be seropositive for markers of influenza B.¹⁴ In a community sample of German adults age 18 to 65, those with mood disorders had a 35% higher likelihood of having had a cold within the last 12 months compared with those without a mood disorder.¹⁵ A survey of Korean employees found the odds of having had a cold in the last 4 months were up to 2.5 times greater for individuals with elevated scores on a depression symptom severity scale compared with those with lower scores.¹⁶ Because these studies were retrospective, recall bias may have impacted the results, as patients who are depressed are more likely to recall negative recent events.¹⁷

Proposed mechanisms

Researchers have proposed several mechanisms to explain the association of URIs with mood episodes. Mood disorders, such as bipolar disorder and major depressive disorder (MDD), are associated with chronic dysregulation of the innate immune system, which leads to elevated levels of cortisol and pro-inflammatory cytokines.^18,19 Men with chronic low-grade inflammation are more vulnerable to all types of infection, including those that cause respiratory illnesses.²⁰ High levels of stress,²¹ a negative affective style,²² and depression²³ have all been associated with reduced antibody response and/or cellular-mediated immunity following vaccination, which suggests a possible mechanism for the vulnerability to infection found in individuals with mood disorders. On the other hand, after influenza vaccination, patients with depression produce a greater and more prolonged release of the cytokine interleukin 6, which perpetuates the state of chronic low-grade inflammation.²⁴ Additionally, patients with mood disorders may engage in behaviors that reduce immune functioning, such as using illicit substances, drinking alcohol, smoking cigarettes, consuming an unhealthy diet, or living a sedentary lifestyle.

Conversely, there are several mechanisms by which a URI could induce a mood episode in a patient with a mood disorder. Animal studies have shown that a non-CNS viral infection can lead to depressive behavior by inducing peripheral interferon-beta release. This signaling protein binds to a receptor on the endothelial cells of the blood-brain barrier, inducing the release of additional cytokines that affect neuronal functioning.²⁵ Among patients receiving interferon treatments for hepatitis C, a history of depression increased their likelihood of becoming depressed during their treatment course, which suggests people with mood disorders have a sensitivity to peripheral cytokines.²⁶

Sleep interruptions from nighttime coughing or nasal congestion can increase the risk of a recurrence of hypomania or mania in patients with bipolar disorder,²⁷ or a recurrence of depression in a patient with MDD.²⁸ The stress that comes with missed work days or the inability to take care of other personal responsibilities due to a URI may increase the risk of becoming depressed in a patient with bipolar disorder or MDD. When present, GI symptoms such as vomiting and diarrhea can reduce the absorption of psychotropic medications and increase the risk of a mood recurrence. Finally, the treatments used for URIs may also contribute to mood instability. Case reports have described instances where patients with URIs developed mania or depression when exposed to medications such as intranasal corticosteroids,²⁹ nasal decongestants,^30,31 and anti-influenza treatments.^32,33

Continue to: A diagnostic challenge

Making the diagnosis of a major depressive episode can be challenging in patients who present with a URI, particularly in those who are highly vigilant for relapse and seek care soon after mood symptoms emerge. Many symptoms overlap between the conditions, including insomnia, hypersomnia, reduced interest, anhedonia, fatigue, impaired concentration, and anorexia. Symptoms that are more specific for a major depressive episode include depressed mood, pathologic guilt, worthlessness, and suicidal ideation. Of course, a major depressive episode and a URI are not mutually exclusive and can occur simultaneously. However, incorrectly diagnosing recurrence of a major depressive episode in a euthymic patient who has a URI could lead to unnecessary changes to psychiatric treatment.

Psychoeducation is key

Teach patients about the bidirectional relationship between URIs and mood symptoms to reduce anxiety and confusion about the cause of the return of mood symptoms. Telling patients that they can expect their mood symptoms to be of short duration and self-limiting due to the URI can provide helpful reassurance.

Because it is possible that the mood symptoms will be transient, increasing psychotropic doses or adding a new psychotropic medication may not be necessary. The decision to initiate such changes should be made collaboratively with patients and should be based on the severity and duration of the patient’s mood symptoms. Symptoms that may warrant a medication change include psychosis, suicidal ideation, or mania. If a patient taking lithium becomes dehydrated because of excessive vomiting, diarrhea, or anorexia, temporarily reducing the dose or stopping the medication until the patient is hydrated may be appropriate.

When a patient presents with a URI, make basic URI treatment recommendations, including rest, hydration, and the use of over-the-counter (OTC) anti-cold medications and zinc.³⁴ Encourage patients with suspected influenza to visit their primary care physician so that they may receive an anti-influenza medication. However, also remind patients about the psychiatric risks associated with some of these treatments and their potential interactions with psychotropics (Table). For example, many OTC cold formulations contain dextromethorphan or chlorpheniramine, both of which have weak serotonin reuptake properties and should not be combined with a monoamine oxidase inhibitor. Such cold formulations may also contain non-steroidal anti-inflammatory agents, which could elevate lithium levels. Codeine, which is often prescribed to suppress the coughing reflex, can lead a patient with a history of substance use to relapse on their drug of choice.

Also recommend lifestyle modifications to help patients reduce their risk of infection. These includes frequent hand washing, avoiding or limiting alcohol use, avoiding cigarettes, exercising regularly, consuming a Mediterranean diet, and receiving scheduled immunizations. To avoid contracting a URI and infecting patients, wash your hands or use an alcohol-based cleanser after shaking hands with patients. Finally, if a patient does not have a primary care physician, encourage him/her to find one to help manage subsequent infections.

Continue to: Bottom Line

Patients with mood disorders may have an increased risk of developing an upper respiratory infection (URI), which can worsen their mood. Clinicians must make psychotropic treatment changes cautiously and guide patients to select safe over-the-counter medications for relief of URI symptoms.

Related Resources

• Centers for Disease Control and Prevention. Cold versus flu. www.cdc.gov/flu/about/qa/coldflu.htm.
• Centers for Disease Control and Prevention. Nonspecific upper respiratory tract infection. www.cdc.gov/getsmart/community/materials-references/print-materials/hcp/adult-tract-infection.pdf.

Drug Brand Names

Clonazepam • Klonopin
Ipratropium • Atrovent
Lamotrigine • Lamictal
Lithium • Eskalith, Lithobid
Lurasidone • Latuda
Oseltamivir • Tamiflu
Paroxetine • Paxil