Hepatology

Study participants with nonalcoholic fatty liver disease (NAFLD) who were obese or gained weight were at an increased risk of fibrosis progression, while participants who lost weight had a reduced risk, according to recent research published in Clinical Gastroenterology and Hepatology.

Nephron/Wikimedia/Creative Commons License

Researchers evaluated 40,700 Korean adults (minimum age, 18 years) with NAFLD who underwent health screenings during 2002-2016 with a median 6-year follow-up. Patients were categorized and placed into weight quintiles based on whether they lost weight (quintile 1, 2.3-kg or greater weight loss; quintile 2, 2.2-kg to 0.6-kg weight loss), gained weight (quintile 4, 0.7- to 2.1-kg weight gain; quintile 5, at least 2.2-kg or greater weight gain) or whether their weight remained stable (quintile 3, 0.5-kg weight loss to 0.6-kg weight gain). Researchers followed patients from baseline to fibrosis progression or last visit, calculated as person-years, and used the aspartate aminotransferase to platelet ratio index (APRI) to measure outcomes. They defined body mass index based on criteria specific to Asian populations, with underweight categorized as less than 18.5 kg/m², normal weight as 18.5-23 kg/m², overweight as 23-25 kg/m², and obese as at least 25 kg/m².

“Our findings from mostly asymptomatic, relatively young individuals with ultrasonographically detected steatosis, possibly reflecting low-risk NAFLD patients, are less likely to be affected by survivor bias and biases related to comorbidities, compared with previous findings from cohorts of high-risk groups that underwent liver biopsy,” Seungho Ryu, MD, PhD, from Kangbuk Samsung Hospital in Seoul, South Korea, and colleagues wrote in the study.

There were 5,454 participants who progressed from a low APRI to an intermediate or high APRI within 275,451.5 person-years, researchers said. Compared with the stable-weight group, hazard ratios for APRI progression in the first weight-change quintile were 0.68 (95% confidence interval, 0.62-0.74) and 0.86 in the second weight-change quintile (95% CI, 0.78-0.94). In the weight-gain groups, an increase in weight was associated with APRI progression in the fourth quintile (HR, 1.17; 95% CI, 1.07-1.28) and fifth quintile (HR, 1.71; 95% CI, 1.58-1.85) groups.

After multivariable adjustment, there was an increase in APRI progression among patients with BMIs between 23 and 24.9 kg/m² (HR, 1.13; 95% CI, 1.02-1.26), between 25 and 29.9 kg/m² (HR, 1.41; 95% CI, 1.28-1.55), and greater than or equal to 30 kg/m² (HR, 2.09; 95% CI, 1.86-2.36) compared with patients with a BMI between 18.5 and 22.9 kg/m²,.

Limitations of the study included the use of ultrasonography in place of liver biopsy for diagnosing NAFLD and the use of APRI to predict fibrosis in individuals with NAFLD, researchers said.

“APRI has demonstrated a reasonable utility as a noninvasive method for the prediction of histologically confirmed advanced fibrosis,” Dr. Ryu and colleagues wrote. “Nonetheless, we acknowledge that there is no currently available longitudinal data to support the use of worsening noninvasive fibrosis markers as an indicator of histological progression of fibrosis stage over time.”

Other limitations included the study’s retrospective design, lack of availability of medication use and dietary intake, and lack of generalization based on a young, healthy population of mostly Korean employees who were employed by companies or local government. However, researchers said clinicians should encourage their patients with NAFLD to maintain a healthy weight to avoid progression of fibrosis.

The authors reported no relevant financial disclosures.

SOURCE: Kim Y et al. Clin Gastroenterol Hepatol. 2018. doi: 10.1016/j.cgh.2018.07.006.

Study participants with nonalcoholic fatty liver disease (NAFLD) who were obese or gained weight were at an increased risk of fibrosis progression, while participants who lost weight had a reduced risk, according to recent research published in Clinical Gastroenterology and Hepatology.

Nephron/Wikimedia/Creative Commons License

Researchers evaluated 40,700 Korean adults (minimum age, 18 years) with NAFLD who underwent health screenings during 2002-2016 with a median 6-year follow-up. Patients were categorized and placed into weight quintiles based on whether they lost weight (quintile 1, 2.3-kg or greater weight loss; quintile 2, 2.2-kg to 0.6-kg weight loss), gained weight (quintile 4, 0.7- to 2.1-kg weight gain; quintile 5, at least 2.2-kg or greater weight gain) or whether their weight remained stable (quintile 3, 0.5-kg weight loss to 0.6-kg weight gain). Researchers followed patients from baseline to fibrosis progression or last visit, calculated as person-years, and used the aspartate aminotransferase to platelet ratio index (APRI) to measure outcomes. They defined body mass index based on criteria specific to Asian populations, with underweight categorized as less than 18.5 kg/m², normal weight as 18.5-23 kg/m², overweight as 23-25 kg/m², and obese as at least 25 kg/m².

“Our findings from mostly asymptomatic, relatively young individuals with ultrasonographically detected steatosis, possibly reflecting low-risk NAFLD patients, are less likely to be affected by survivor bias and biases related to comorbidities, compared with previous findings from cohorts of high-risk groups that underwent liver biopsy,” Seungho Ryu, MD, PhD, from Kangbuk Samsung Hospital in Seoul, South Korea, and colleagues wrote in the study.

There were 5,454 participants who progressed from a low APRI to an intermediate or high APRI within 275,451.5 person-years, researchers said. Compared with the stable-weight group, hazard ratios for APRI progression in the first weight-change quintile were 0.68 (95% confidence interval, 0.62-0.74) and 0.86 in the second weight-change quintile (95% CI, 0.78-0.94). In the weight-gain groups, an increase in weight was associated with APRI progression in the fourth quintile (HR, 1.17; 95% CI, 1.07-1.28) and fifth quintile (HR, 1.71; 95% CI, 1.58-1.85) groups.

After multivariable adjustment, there was an increase in APRI progression among patients with BMIs between 23 and 24.9 kg/m² (HR, 1.13; 95% CI, 1.02-1.26), between 25 and 29.9 kg/m² (HR, 1.41; 95% CI, 1.28-1.55), and greater than or equal to 30 kg/m² (HR, 2.09; 95% CI, 1.86-2.36) compared with patients with a BMI between 18.5 and 22.9 kg/m²,.

Limitations of the study included the use of ultrasonography in place of liver biopsy for diagnosing NAFLD and the use of APRI to predict fibrosis in individuals with NAFLD, researchers said.

“APRI has demonstrated a reasonable utility as a noninvasive method for the prediction of histologically confirmed advanced fibrosis,” Dr. Ryu and colleagues wrote. “Nonetheless, we acknowledge that there is no currently available longitudinal data to support the use of worsening noninvasive fibrosis markers as an indicator of histological progression of fibrosis stage over time.”

Other limitations included the study’s retrospective design, lack of availability of medication use and dietary intake, and lack of generalization based on a young, healthy population of mostly Korean employees who were employed by companies or local government. However, researchers said clinicians should encourage their patients with NAFLD to maintain a healthy weight to avoid progression of fibrosis.

The authors reported no relevant financial disclosures.

SOURCE: Kim Y et al. Clin Gastroenterol Hepatol. 2018. doi: 10.1016/j.cgh.2018.07.006.

Study participants with nonalcoholic fatty liver disease (NAFLD) who were obese or gained weight were at an increased risk of fibrosis progression, while participants who lost weight had a reduced risk, according to recent research published in Clinical Gastroenterology and Hepatology.

Nephron/Wikimedia/Creative Commons License

Researchers evaluated 40,700 Korean adults (minimum age, 18 years) with NAFLD who underwent health screenings during 2002-2016 with a median 6-year follow-up. Patients were categorized and placed into weight quintiles based on whether they lost weight (quintile 1, 2.3-kg or greater weight loss; quintile 2, 2.2-kg to 0.6-kg weight loss), gained weight (quintile 4, 0.7- to 2.1-kg weight gain; quintile 5, at least 2.2-kg or greater weight gain) or whether their weight remained stable (quintile 3, 0.5-kg weight loss to 0.6-kg weight gain). Researchers followed patients from baseline to fibrosis progression or last visit, calculated as person-years, and used the aspartate aminotransferase to platelet ratio index (APRI) to measure outcomes. They defined body mass index based on criteria specific to Asian populations, with underweight categorized as less than 18.5 kg/m², normal weight as 18.5-23 kg/m², overweight as 23-25 kg/m², and obese as at least 25 kg/m².

“Our findings from mostly asymptomatic, relatively young individuals with ultrasonographically detected steatosis, possibly reflecting low-risk NAFLD patients, are less likely to be affected by survivor bias and biases related to comorbidities, compared with previous findings from cohorts of high-risk groups that underwent liver biopsy,” Seungho Ryu, MD, PhD, from Kangbuk Samsung Hospital in Seoul, South Korea, and colleagues wrote in the study.

There were 5,454 participants who progressed from a low APRI to an intermediate or high APRI within 275,451.5 person-years, researchers said. Compared with the stable-weight group, hazard ratios for APRI progression in the first weight-change quintile were 0.68 (95% confidence interval, 0.62-0.74) and 0.86 in the second weight-change quintile (95% CI, 0.78-0.94). In the weight-gain groups, an increase in weight was associated with APRI progression in the fourth quintile (HR, 1.17; 95% CI, 1.07-1.28) and fifth quintile (HR, 1.71; 95% CI, 1.58-1.85) groups.

After multivariable adjustment, there was an increase in APRI progression among patients with BMIs between 23 and 24.9 kg/m² (HR, 1.13; 95% CI, 1.02-1.26), between 25 and 29.9 kg/m² (HR, 1.41; 95% CI, 1.28-1.55), and greater than or equal to 30 kg/m² (HR, 2.09; 95% CI, 1.86-2.36) compared with patients with a BMI between 18.5 and 22.9 kg/m²,.

Limitations of the study included the use of ultrasonography in place of liver biopsy for diagnosing NAFLD and the use of APRI to predict fibrosis in individuals with NAFLD, researchers said.

“APRI has demonstrated a reasonable utility as a noninvasive method for the prediction of histologically confirmed advanced fibrosis,” Dr. Ryu and colleagues wrote. “Nonetheless, we acknowledge that there is no currently available longitudinal data to support the use of worsening noninvasive fibrosis markers as an indicator of histological progression of fibrosis stage over time.”

Other limitations included the study’s retrospective design, lack of availability of medication use and dietary intake, and lack of generalization based on a young, healthy population of mostly Korean employees who were employed by companies or local government. However, researchers said clinicians should encourage their patients with NAFLD to maintain a healthy weight to avoid progression of fibrosis.

The authors reported no relevant financial disclosures.

SOURCE: Kim Y et al. Clin Gastroenterol Hepatol. 2018. doi: 10.1016/j.cgh.2018.07.006.

Elevated levels of circulating enzymes that are frequently of hepatic origin (aminotransferases and alkaline phosphatase) and bilirubin in the absence of symptoms are common in clinical practice. A dogmatic but true statement holds that there are no trivial elevations in these substances. All persistent elevations of liver enzymes need a methodical evaluation and an appropriate working diagnosis.¹

Here, we outline a framework for the workup and treatment of common causes of liver enzyme elevations.

PATTERN OF ELEVATION: CHOLESTATIC OR HEPATOCELLULAR

Based on the pattern of elevation, causes of elevated liver enzymes can be sorted into disorders of cholestasis and disorders of hepatocellular injury (Table 1).¹

Cholestatic disorders tend to cause elevations in alkaline phosphatase, bilirubin, and gamma-glutamyl transferase (GGT).

Hepatocellular injury raises levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST).

HOW SHOULD ABNORMAL RESULTS BE EVALUATED?

When approaching liver enzyme elevations, the clinician should develop a working differential diagnosis based on the medical and social history and physical examination.

Think about alcohol, drugs, and fat

The most common causes of liver enzyme elevation are alcohol toxicity, medication overdose, and fatty liver disease.

Alcohol intake should be ascertained. “Significant” consumption is defined as more than 21 drinks per week in men or more than 14 drinks per week in women, over a period of at least 2 years.²

The exact pathogenesis of alcoholic hepatitis is incompletely understood, but alcohol is primarily metabolized by the liver, and damage likely occurs during metabolism of the ingested alcohol. AST elevations tend to be higher than ALT elevations; the reason is ascribed to hepatic deficiency of pyridoxal 5´-phosphate, a cofactor of the enzymatic activity of ALT, which leads to a lesser increase in ALT than in AST.

Alcoholic liver disease can be difficult to diagnose, as many people are initially reluctant to fully disclose how much they drink, but it should be suspected when the ratio of AST to ALT is 2 or greater.

In a classic study, a ratio greater than 2 was found in 70% of patients with alcoholic hepatitis and cirrhosis, compared with 26% of patients with postnecrotic cirrhosis, 8% with chronic hepatitis, 4% with viral hepatitis, and none with obstructive jaundice.³ Importantly, the disorder is often correctable if the patient is able to remain abstinent from alcohol over time.

A detailed medication history is important and should focus especially on recently added medications, dosage changes, medication overuse, and use of nonprescription drugs and herbal supplements. Common medications that affect liver enzyme levels include statins, which cause hepatic dysfunction primarily during the first 3 months of therapy, nonsteroidal anti-inflammatory drugs, antiep­ileptic drugs, antibiotics, anabolic steroids, and acetaminophen (Table 2).¹ Use of illicit drugs and herbal remedies should be discussed, as they may cause toxin-mediated hepatitis.

Although inflammation from drug toxicity will resolve if the offending agent is discontinued, complete recovery may take weeks to months.⁴

A pertinent social history includes exposure to environmental hepatotoxins such as amatoxin (contained in some wild mushrooms) and occupational hazards (eg, vinyl chloride). Risk factors for viral hepatitis should be evaluated, including intravenous drug use, blood transfusions, unprotected sexual contact, organ transplant, perinatal transmission, and a history of work in healthcare facilities or travel to regions in which hepatitis A or E is endemic.

The medical and family history should include details of associated conditions, such as:

• Right heart failure (a cause of congestive hepatopathy)
• Metabolic syndrome (associated with fatty liver disease)
• Inflammatory bowel disease and primary sclerosing cholangitis
• Early-onset emphysema and alpha-1 antitrypsin deficiency.

The physical examination should be thorough, with emphasis on the abdomen, and search for stigmata of advanced liver disease such as hepatomegaly, splenomegaly, ascites, edema, spider angiomata, jaundice, and asterixis. Any patient with evidence of chronic liver disease should be referred to a subspecialist for further evaluation.

Abnormal liver enzyme findings or physical examination findings should direct the subsequent diagnostic workup with laboratory testing and imaging.⁵

For cholestasis. If laboratory data are consistent with cholestasis or abnormal bile flow, it should be further characterized as extrahepatic or intrahepatic. Common causes of extrahepatic cholestasis include biliary tree obstruction due to stones or malignancy, often visualized as intraductal biliary dilation on ultrasonography of the right upper quadrant. Common causes of intrahepatic cholestasis include viral and alcoholic hepatitis, nonalcoholic steatohepatitis, certain drugs and toxins such as alkylated steroids and herbal medications, infiltrative diseases such as amyloid, sarcoid, lymphoma, and tuberculosis, and primary biliary cholangitis.

Abnormal findings on ultrasonography should be further pursued with advanced imaging, ie, computed tomography or magnetic resonance cholangiopancreatography (MRCP). The confirmation of a lesion on imaging is often followed by endoscopic retrograde cholangiopancreatography (ERCP) in an attempt to obtain biopsy samples, remove obstructions, and place therapeutic stents. In instances when endoscopic attempts fail to relieve the obstruction, surgical referral may be appropriate.

For nonhepatobiliary problems. Depending on clinical presentation, it may also be important to consider nonhepatobiliary causes of elevated liver enzymes.

Alkaline phosphatase is found in many other tissue types, including bone, kidney, and the placenta, and can be elevated during pregnancy, adolescence, and even after fatty meals due to intestinal release.⁶ After screening for the aforementioned physiologic conditions, isolated elevated alkaline phosphatase should be further evaluated by obtaining GGT or 5-nucleotidase levels, which are more specifically of hepatic origin. If these levels are within normal limits, further evaluation for conditions of bone growth and cellular turnover such as Paget disease, hyperparathyroidism, and malignancy should be considered. Specifically, Stauffer syndrome should be considered when there is a paraneoplastic rise in the alkaline phosphatase level in the setting of renal cell carcinoma without liver metastases.

AST and ALT levels may also be elevated in clinical situations and syndromes unrelated to liver disease. Rhabdomyolysis, for instance, may be associated with elevations of AST in more than 90% of cases, and ALT in more than 75%.⁷ Markers of muscle injury including serum creatine kinase should be obtained in the setting of heat stroke, muscle weakness, strenuous activity, or seizures, as related elevations in AST and ALT may not always be clinically indicative of liver injury.

Given the many conditions that may cause elevated liver enzymes, evaluation and treatment should focus on identifying and removing offending agents and targeting the underlying process with appropriate medical therapy.

FATTY LIVER

With rates of obesity and type 2 diabetes on the rise in the general population, identifying and treating nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) require increased awareness and close coordination between primary care providers and subspecialists.

According to current estimates, up to one-third of the US population (100 million people) may have NAFLD, and 1% to 3% of the population (4–6 million people) likely have NASH, defined as steatosis with inflammation. Development of NASH places patients at a significantly higher risk of fibrosis, hepatocellular injury, and cancer.⁸

NAFLD is more common in men than in women. It is present in around 80% to 90% of obese adults, two-thirds of adults with type 2 diabetes, and many people with hyperlipidemia. It is also becoming more common in children, with 40% to 70% of obese children likely having some element of NAFLD.

Diagnosis of fatty liver

Although liver enzymes are more likely to be abnormal in individuals with NAFLD, many individuals with underlying NAFLD may have normal laboratory evaluations. ALT may be elevated in only up to 20% of cases and does not likely correlate with the level of underlying liver damage, although increasing GGT may serve as a marker of fibrosis over time.^9–11 In contrast to alcohol injury, however, the AST-ALT ratio is usually less than 1.0.

Noninvasive tools for diagnosing NAFLD include the NAFLD fibrosis score, which incorporates age, hyperglycemia, body mass index, platelet count, albumin level, and AST-ALT ratio. This and related scoring algorithms may be useful in differentiating patients with minimal fibrosis from those with advanced fibrosis.^12,13

Ultrasonography is a first-line diagnostic test for steatosis, although it may demonstrate fatty infiltration only around 60% of the time. Computed tomography and magnetic resonance imaging are more sensitive, but costlier. Transient elastography (FibroScan; Echosens, Paris, France) has become more popular and has been shown to correlate with findings on liver biopsy in diagnosing or excluding advanced liver fibrosis.^14,15

The gold standard for diagnosing NAFLD and NASH is identifying fat-laden hepatocytes or portal inflammation on biopsy; however, biopsy is generally reserved for cases in which the diagnosis remains uncertain.

Behavioral treatment

The primary treatment for NAFLD consists of behavioral modification including weight loss, exercise, and adherence to a low-fat diet, in addition to tight glycemic control and treatment of any underlying lipid abnormalities. Studies have shown that a reduction of 7% to 10% of body weight is associated with a decrease in the inflammation of NAFLD, though no strict guidelines have been established.¹⁶

Given the prevalence of NAFLD and the need for longitudinal treatment, primary care physicians will play a significant role in long-term monitoring and management of patients with fatty liver disease.

Hereditary hemochromatosis

Hereditary hemochromatosis is the most common inherited liver disorder in adults of European descent,¹⁷ and can be effectively treated if discovered early. But its clinical diagnosis can be challenging, as many patients have no symptoms at presentation despite abnormal liver enzyme levels. Early symptoms may include severe fatigue, arthralgias, and, in men, impotence, before the appearance of the classic triad of “bronze diabetes” with cirrhosis, diabetes, and darkening of the skin.¹⁸

If hemochromatosis is suspected, laboratory tests should include a calculation of percent transferrin saturation, with saturation greater than 45% warranting serum ferritin measurement to evaluate for iron overload (ferritin > 200–300 ng/mL in men, > 150–200 ng/mL in women).¹⁹ If iron overload is confirmed, referral to a gastroenterologist is recommended.

Genetic evaluation is often pursued, but patients may ultimately require liver biopsy regardless of the findings, as some patients homozygous for the HFE mutation C282Y may not have clinical hemochromatosis, whereas others with hereditary hemochromatosis may not have the HFE mutation.

Therapeutic phlebotomy is the treatment of choice, and most patients tolerate it well.

Chronic hepatitis B virus and hepatitis C virus infections

Chronic hepatitis B virus (HBV) and hepatitis C virus (HCV) infections are common in the United States, with HBV affecting more than 1 million people and HCV affecting an estimated 3.5 million.

Chronic HCV infection. Direct-acting antiviral drugs have revolutionized HCV treatment and have led to a sustained viral response and presumed cure at 12 weeks in more than 95% of cases across all HCV genotypes.²⁰ Given the recent development of effective and well-tolerated treatments, primary care physicians have assumed a pivotal role in screening for HCV.

The American Association for the Study of Liver Diseases and the Infectious Diseases Society of America²¹ recommend screening for HCV in people who have risk factors for it, ie:

• HCV exposure
• HIV infection
• Behavioral or environmental risks for contracting the virus such as intravenous drug use or incarceration
• Birth between 1945 and 1965 (one-time testing).

If HCV antibody screening is positive, HCV RNA should be obtained to quantify the viral load and confirm active infection, and genotype testing should be performed to guide treatment. Among the 6 most common HCV genotypes, genotype 1 is the most common in North America, accounting for over 70% of cases in the United States.

Although recommendations and therapies are constantly evolving, the selection of a treatment regimen and the duration of therapy are determined by viral genotype, history of prior treatment, stage of liver fibrosis, potential drug interactions, and frequently, medication cost and insurance coverage.

HBV infection. The treatment for acute HBV infection is generally supportive, though viral suppression with tenofovir or entecavir may be required for those who develop coagulopathy, bilirubinemia, or liver failure. Treatment of chronic HBV infection may not be required and is generally considered for those with elevated ALT, high viral load, or evidence of liver fibrosis on noninvasive measurements such as transient elastography.

Autoimmune hepatitis

Autoimmune causes of liver enzyme elevations should also be considered during initial screening. Positive antinuclear antibody and positive antismooth muscle antibody tests are common in cases of autoimmune hepatitis.²² Autoimmune hepatitis affects women more often than men, with a ratio of 4:1. The peaks of incidence occur during adolescence and between ages 30 and 45.²³

Primary biliary cholangitis

Additionally, an elevated alkaline phosphatase level should raise concern for underlying primary biliary cholangitis (formerly called primary biliary cirrhosis), an autoimmune disorder that affects the small and medium intrahepatic bile ducts. Diagnosis of primary biliary cholangitis can be assisted by a positive test for antimitochondrial antibody, present in almost 90% of patients.²⁴

Primary sclerosing cholangitis

Elevated alkaline phosphatase is also the hallmark of primary sclerosing cholangitis, which is associated with inflammatory bowel disease.²⁵ Primary sclerosing cholangitis is characterized by inflammation and fibrosis of the intrahepatic and extrahepatic bile ducts, which are visualized on MRCP and confirmed by biopsy if needed.

REFERRAL

Subspecialty referral should be considered if the cause remains ambiguous or unknown, if there is concern for a rare hepatic disorder such as an autoimmune condition, Wilson disease, or alpha-1 antitrypsin deficiency, or if there is evidence of advanced or chronic liver disease.

Primary care physicians are at the forefront of detecting and diagnosing liver disease, and close coordination with subspecialists will remain crucial in delivering patient care.

Elevated levels of circulating enzymes that are frequently of hepatic origin (aminotransferases and alkaline phosphatase) and bilirubin in the absence of symptoms are common in clinical practice. A dogmatic but true statement holds that there are no trivial elevations in these substances. All persistent elevations of liver enzymes need a methodical evaluation and an appropriate working diagnosis.¹

Here, we outline a framework for the workup and treatment of common causes of liver enzyme elevations.

PATTERN OF ELEVATION: CHOLESTATIC OR HEPATOCELLULAR

Based on the pattern of elevation, causes of elevated liver enzymes can be sorted into disorders of cholestasis and disorders of hepatocellular injury (Table 1).¹

Cholestatic disorders tend to cause elevations in alkaline phosphatase, bilirubin, and gamma-glutamyl transferase (GGT).

Hepatocellular injury raises levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST).

HOW SHOULD ABNORMAL RESULTS BE EVALUATED?

When approaching liver enzyme elevations, the clinician should develop a working differential diagnosis based on the medical and social history and physical examination.

Think about alcohol, drugs, and fat

The most common causes of liver enzyme elevation are alcohol toxicity, medication overdose, and fatty liver disease.

Alcohol intake should be ascertained. “Significant” consumption is defined as more than 21 drinks per week in men or more than 14 drinks per week in women, over a period of at least 2 years.²

The exact pathogenesis of alcoholic hepatitis is incompletely understood, but alcohol is primarily metabolized by the liver, and damage likely occurs during metabolism of the ingested alcohol. AST elevations tend to be higher than ALT elevations; the reason is ascribed to hepatic deficiency of pyridoxal 5´-phosphate, a cofactor of the enzymatic activity of ALT, which leads to a lesser increase in ALT than in AST.

Alcoholic liver disease can be difficult to diagnose, as many people are initially reluctant to fully disclose how much they drink, but it should be suspected when the ratio of AST to ALT is 2 or greater.

In a classic study, a ratio greater than 2 was found in 70% of patients with alcoholic hepatitis and cirrhosis, compared with 26% of patients with postnecrotic cirrhosis, 8% with chronic hepatitis, 4% with viral hepatitis, and none with obstructive jaundice.³ Importantly, the disorder is often correctable if the patient is able to remain abstinent from alcohol over time.

A detailed medication history is important and should focus especially on recently added medications, dosage changes, medication overuse, and use of nonprescription drugs and herbal supplements. Common medications that affect liver enzyme levels include statins, which cause hepatic dysfunction primarily during the first 3 months of therapy, nonsteroidal anti-inflammatory drugs, antiep­ileptic drugs, antibiotics, anabolic steroids, and acetaminophen (Table 2).¹ Use of illicit drugs and herbal remedies should be discussed, as they may cause toxin-mediated hepatitis.

Although inflammation from drug toxicity will resolve if the offending agent is discontinued, complete recovery may take weeks to months.⁴

A pertinent social history includes exposure to environmental hepatotoxins such as amatoxin (contained in some wild mushrooms) and occupational hazards (eg, vinyl chloride). Risk factors for viral hepatitis should be evaluated, including intravenous drug use, blood transfusions, unprotected sexual contact, organ transplant, perinatal transmission, and a history of work in healthcare facilities or travel to regions in which hepatitis A or E is endemic.

The medical and family history should include details of associated conditions, such as:

• Right heart failure (a cause of congestive hepatopathy)
• Metabolic syndrome (associated with fatty liver disease)
• Inflammatory bowel disease and primary sclerosing cholangitis
• Early-onset emphysema and alpha-1 antitrypsin deficiency.

The physical examination should be thorough, with emphasis on the abdomen, and search for stigmata of advanced liver disease such as hepatomegaly, splenomegaly, ascites, edema, spider angiomata, jaundice, and asterixis. Any patient with evidence of chronic liver disease should be referred to a subspecialist for further evaluation.

Abnormal liver enzyme findings or physical examination findings should direct the subsequent diagnostic workup with laboratory testing and imaging.⁵

For cholestasis. If laboratory data are consistent with cholestasis or abnormal bile flow, it should be further characterized as extrahepatic or intrahepatic. Common causes of extrahepatic cholestasis include biliary tree obstruction due to stones or malignancy, often visualized as intraductal biliary dilation on ultrasonography of the right upper quadrant. Common causes of intrahepatic cholestasis include viral and alcoholic hepatitis, nonalcoholic steatohepatitis, certain drugs and toxins such as alkylated steroids and herbal medications, infiltrative diseases such as amyloid, sarcoid, lymphoma, and tuberculosis, and primary biliary cholangitis.

Abnormal findings on ultrasonography should be further pursued with advanced imaging, ie, computed tomography or magnetic resonance cholangiopancreatography (MRCP). The confirmation of a lesion on imaging is often followed by endoscopic retrograde cholangiopancreatography (ERCP) in an attempt to obtain biopsy samples, remove obstructions, and place therapeutic stents. In instances when endoscopic attempts fail to relieve the obstruction, surgical referral may be appropriate.

For nonhepatobiliary problems. Depending on clinical presentation, it may also be important to consider nonhepatobiliary causes of elevated liver enzymes.

Alkaline phosphatase is found in many other tissue types, including bone, kidney, and the placenta, and can be elevated during pregnancy, adolescence, and even after fatty meals due to intestinal release.⁶ After screening for the aforementioned physiologic conditions, isolated elevated alkaline phosphatase should be further evaluated by obtaining GGT or 5-nucleotidase levels, which are more specifically of hepatic origin. If these levels are within normal limits, further evaluation for conditions of bone growth and cellular turnover such as Paget disease, hyperparathyroidism, and malignancy should be considered. Specifically, Stauffer syndrome should be considered when there is a paraneoplastic rise in the alkaline phosphatase level in the setting of renal cell carcinoma without liver metastases.

AST and ALT levels may also be elevated in clinical situations and syndromes unrelated to liver disease. Rhabdomyolysis, for instance, may be associated with elevations of AST in more than 90% of cases, and ALT in more than 75%.⁷ Markers of muscle injury including serum creatine kinase should be obtained in the setting of heat stroke, muscle weakness, strenuous activity, or seizures, as related elevations in AST and ALT may not always be clinically indicative of liver injury.

Given the many conditions that may cause elevated liver enzymes, evaluation and treatment should focus on identifying and removing offending agents and targeting the underlying process with appropriate medical therapy.

FATTY LIVER

With rates of obesity and type 2 diabetes on the rise in the general population, identifying and treating nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) require increased awareness and close coordination between primary care providers and subspecialists.

According to current estimates, up to one-third of the US population (100 million people) may have NAFLD, and 1% to 3% of the population (4–6 million people) likely have NASH, defined as steatosis with inflammation. Development of NASH places patients at a significantly higher risk of fibrosis, hepatocellular injury, and cancer.⁸

NAFLD is more common in men than in women. It is present in around 80% to 90% of obese adults, two-thirds of adults with type 2 diabetes, and many people with hyperlipidemia. It is also becoming more common in children, with 40% to 70% of obese children likely having some element of NAFLD.

Diagnosis of fatty liver

Although liver enzymes are more likely to be abnormal in individuals with NAFLD, many individuals with underlying NAFLD may have normal laboratory evaluations. ALT may be elevated in only up to 20% of cases and does not likely correlate with the level of underlying liver damage, although increasing GGT may serve as a marker of fibrosis over time.^9–11 In contrast to alcohol injury, however, the AST-ALT ratio is usually less than 1.0.

Noninvasive tools for diagnosing NAFLD include the NAFLD fibrosis score, which incorporates age, hyperglycemia, body mass index, platelet count, albumin level, and AST-ALT ratio. This and related scoring algorithms may be useful in differentiating patients with minimal fibrosis from those with advanced fibrosis.^12,13

Ultrasonography is a first-line diagnostic test for steatosis, although it may demonstrate fatty infiltration only around 60% of the time. Computed tomography and magnetic resonance imaging are more sensitive, but costlier. Transient elastography (FibroScan; Echosens, Paris, France) has become more popular and has been shown to correlate with findings on liver biopsy in diagnosing or excluding advanced liver fibrosis.^14,15

The gold standard for diagnosing NAFLD and NASH is identifying fat-laden hepatocytes or portal inflammation on biopsy; however, biopsy is generally reserved for cases in which the diagnosis remains uncertain.

Behavioral treatment

The primary treatment for NAFLD consists of behavioral modification including weight loss, exercise, and adherence to a low-fat diet, in addition to tight glycemic control and treatment of any underlying lipid abnormalities. Studies have shown that a reduction of 7% to 10% of body weight is associated with a decrease in the inflammation of NAFLD, though no strict guidelines have been established.¹⁶

Given the prevalence of NAFLD and the need for longitudinal treatment, primary care physicians will play a significant role in long-term monitoring and management of patients with fatty liver disease.

Hereditary hemochromatosis

Hereditary hemochromatosis is the most common inherited liver disorder in adults of European descent,¹⁷ and can be effectively treated if discovered early. But its clinical diagnosis can be challenging, as many patients have no symptoms at presentation despite abnormal liver enzyme levels. Early symptoms may include severe fatigue, arthralgias, and, in men, impotence, before the appearance of the classic triad of “bronze diabetes” with cirrhosis, diabetes, and darkening of the skin.¹⁸

If hemochromatosis is suspected, laboratory tests should include a calculation of percent transferrin saturation, with saturation greater than 45% warranting serum ferritin measurement to evaluate for iron overload (ferritin > 200–300 ng/mL in men, > 150–200 ng/mL in women).¹⁹ If iron overload is confirmed, referral to a gastroenterologist is recommended.

Genetic evaluation is often pursued, but patients may ultimately require liver biopsy regardless of the findings, as some patients homozygous for the HFE mutation C282Y may not have clinical hemochromatosis, whereas others with hereditary hemochromatosis may not have the HFE mutation.

Therapeutic phlebotomy is the treatment of choice, and most patients tolerate it well.

Chronic hepatitis B virus and hepatitis C virus infections

Chronic hepatitis B virus (HBV) and hepatitis C virus (HCV) infections are common in the United States, with HBV affecting more than 1 million people and HCV affecting an estimated 3.5 million.

Chronic HCV infection. Direct-acting antiviral drugs have revolutionized HCV treatment and have led to a sustained viral response and presumed cure at 12 weeks in more than 95% of cases across all HCV genotypes.²⁰ Given the recent development of effective and well-tolerated treatments, primary care physicians have assumed a pivotal role in screening for HCV.

The American Association for the Study of Liver Diseases and the Infectious Diseases Society of America²¹ recommend screening for HCV in people who have risk factors for it, ie:

• HCV exposure
• HIV infection
• Behavioral or environmental risks for contracting the virus such as intravenous drug use or incarceration
• Birth between 1945 and 1965 (one-time testing).

If HCV antibody screening is positive, HCV RNA should be obtained to quantify the viral load and confirm active infection, and genotype testing should be performed to guide treatment. Among the 6 most common HCV genotypes, genotype 1 is the most common in North America, accounting for over 70% of cases in the United States.

Although recommendations and therapies are constantly evolving, the selection of a treatment regimen and the duration of therapy are determined by viral genotype, history of prior treatment, stage of liver fibrosis, potential drug interactions, and frequently, medication cost and insurance coverage.

HBV infection. The treatment for acute HBV infection is generally supportive, though viral suppression with tenofovir or entecavir may be required for those who develop coagulopathy, bilirubinemia, or liver failure. Treatment of chronic HBV infection may not be required and is generally considered for those with elevated ALT, high viral load, or evidence of liver fibrosis on noninvasive measurements such as transient elastography.

Autoimmune hepatitis

Autoimmune causes of liver enzyme elevations should also be considered during initial screening. Positive antinuclear antibody and positive antismooth muscle antibody tests are common in cases of autoimmune hepatitis.²² Autoimmune hepatitis affects women more often than men, with a ratio of 4:1. The peaks of incidence occur during adolescence and between ages 30 and 45.²³

Primary biliary cholangitis

Additionally, an elevated alkaline phosphatase level should raise concern for underlying primary biliary cholangitis (formerly called primary biliary cirrhosis), an autoimmune disorder that affects the small and medium intrahepatic bile ducts. Diagnosis of primary biliary cholangitis can be assisted by a positive test for antimitochondrial antibody, present in almost 90% of patients.²⁴

Primary sclerosing cholangitis

Elevated alkaline phosphatase is also the hallmark of primary sclerosing cholangitis, which is associated with inflammatory bowel disease.²⁵ Primary sclerosing cholangitis is characterized by inflammation and fibrosis of the intrahepatic and extrahepatic bile ducts, which are visualized on MRCP and confirmed by biopsy if needed.

REFERRAL

Subspecialty referral should be considered if the cause remains ambiguous or unknown, if there is concern for a rare hepatic disorder such as an autoimmune condition, Wilson disease, or alpha-1 antitrypsin deficiency, or if there is evidence of advanced or chronic liver disease.

Primary care physicians are at the forefront of detecting and diagnosing liver disease, and close coordination with subspecialists will remain crucial in delivering patient care.

Elevated levels of circulating enzymes that are frequently of hepatic origin (aminotransferases and alkaline phosphatase) and bilirubin in the absence of symptoms are common in clinical practice. A dogmatic but true statement holds that there are no trivial elevations in these substances. All persistent elevations of liver enzymes need a methodical evaluation and an appropriate working diagnosis.¹

Here, we outline a framework for the workup and treatment of common causes of liver enzyme elevations.

PATTERN OF ELEVATION: CHOLESTATIC OR HEPATOCELLULAR

Based on the pattern of elevation, causes of elevated liver enzymes can be sorted into disorders of cholestasis and disorders of hepatocellular injury (Table 1).¹

Cholestatic disorders tend to cause elevations in alkaline phosphatase, bilirubin, and gamma-glutamyl transferase (GGT).

Hepatocellular injury raises levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST).

HOW SHOULD ABNORMAL RESULTS BE EVALUATED?

When approaching liver enzyme elevations, the clinician should develop a working differential diagnosis based on the medical and social history and physical examination.

Think about alcohol, drugs, and fat

The most common causes of liver enzyme elevation are alcohol toxicity, medication overdose, and fatty liver disease.

Alcohol intake should be ascertained. “Significant” consumption is defined as more than 21 drinks per week in men or more than 14 drinks per week in women, over a period of at least 2 years.²

The exact pathogenesis of alcoholic hepatitis is incompletely understood, but alcohol is primarily metabolized by the liver, and damage likely occurs during metabolism of the ingested alcohol. AST elevations tend to be higher than ALT elevations; the reason is ascribed to hepatic deficiency of pyridoxal 5´-phosphate, a cofactor of the enzymatic activity of ALT, which leads to a lesser increase in ALT than in AST.

Alcoholic liver disease can be difficult to diagnose, as many people are initially reluctant to fully disclose how much they drink, but it should be suspected when the ratio of AST to ALT is 2 or greater.

In a classic study, a ratio greater than 2 was found in 70% of patients with alcoholic hepatitis and cirrhosis, compared with 26% of patients with postnecrotic cirrhosis, 8% with chronic hepatitis, 4% with viral hepatitis, and none with obstructive jaundice.³ Importantly, the disorder is often correctable if the patient is able to remain abstinent from alcohol over time.

A detailed medication history is important and should focus especially on recently added medications, dosage changes, medication overuse, and use of nonprescription drugs and herbal supplements. Common medications that affect liver enzyme levels include statins, which cause hepatic dysfunction primarily during the first 3 months of therapy, nonsteroidal anti-inflammatory drugs, antiep­ileptic drugs, antibiotics, anabolic steroids, and acetaminophen (Table 2).¹ Use of illicit drugs and herbal remedies should be discussed, as they may cause toxin-mediated hepatitis.

Although inflammation from drug toxicity will resolve if the offending agent is discontinued, complete recovery may take weeks to months.⁴

A pertinent social history includes exposure to environmental hepatotoxins such as amatoxin (contained in some wild mushrooms) and occupational hazards (eg, vinyl chloride). Risk factors for viral hepatitis should be evaluated, including intravenous drug use, blood transfusions, unprotected sexual contact, organ transplant, perinatal transmission, and a history of work in healthcare facilities or travel to regions in which hepatitis A or E is endemic.

The medical and family history should include details of associated conditions, such as:

• Right heart failure (a cause of congestive hepatopathy)
• Metabolic syndrome (associated with fatty liver disease)
• Inflammatory bowel disease and primary sclerosing cholangitis
• Early-onset emphysema and alpha-1 antitrypsin deficiency.

The physical examination should be thorough, with emphasis on the abdomen, and search for stigmata of advanced liver disease such as hepatomegaly, splenomegaly, ascites, edema, spider angiomata, jaundice, and asterixis. Any patient with evidence of chronic liver disease should be referred to a subspecialist for further evaluation.

Abnormal liver enzyme findings or physical examination findings should direct the subsequent diagnostic workup with laboratory testing and imaging.⁵

For cholestasis. If laboratory data are consistent with cholestasis or abnormal bile flow, it should be further characterized as extrahepatic or intrahepatic. Common causes of extrahepatic cholestasis include biliary tree obstruction due to stones or malignancy, often visualized as intraductal biliary dilation on ultrasonography of the right upper quadrant. Common causes of intrahepatic cholestasis include viral and alcoholic hepatitis, nonalcoholic steatohepatitis, certain drugs and toxins such as alkylated steroids and herbal medications, infiltrative diseases such as amyloid, sarcoid, lymphoma, and tuberculosis, and primary biliary cholangitis.

Abnormal findings on ultrasonography should be further pursued with advanced imaging, ie, computed tomography or magnetic resonance cholangiopancreatography (MRCP). The confirmation of a lesion on imaging is often followed by endoscopic retrograde cholangiopancreatography (ERCP) in an attempt to obtain biopsy samples, remove obstructions, and place therapeutic stents. In instances when endoscopic attempts fail to relieve the obstruction, surgical referral may be appropriate.

For nonhepatobiliary problems. Depending on clinical presentation, it may also be important to consider nonhepatobiliary causes of elevated liver enzymes.

Alkaline phosphatase is found in many other tissue types, including bone, kidney, and the placenta, and can be elevated during pregnancy, adolescence, and even after fatty meals due to intestinal release.⁶ After screening for the aforementioned physiologic conditions, isolated elevated alkaline phosphatase should be further evaluated by obtaining GGT or 5-nucleotidase levels, which are more specifically of hepatic origin. If these levels are within normal limits, further evaluation for conditions of bone growth and cellular turnover such as Paget disease, hyperparathyroidism, and malignancy should be considered. Specifically, Stauffer syndrome should be considered when there is a paraneoplastic rise in the alkaline phosphatase level in the setting of renal cell carcinoma without liver metastases.

AST and ALT levels may also be elevated in clinical situations and syndromes unrelated to liver disease. Rhabdomyolysis, for instance, may be associated with elevations of AST in more than 90% of cases, and ALT in more than 75%.⁷ Markers of muscle injury including serum creatine kinase should be obtained in the setting of heat stroke, muscle weakness, strenuous activity, or seizures, as related elevations in AST and ALT may not always be clinically indicative of liver injury.

Given the many conditions that may cause elevated liver enzymes, evaluation and treatment should focus on identifying and removing offending agents and targeting the underlying process with appropriate medical therapy.

FATTY LIVER

With rates of obesity and type 2 diabetes on the rise in the general population, identifying and treating nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) require increased awareness and close coordination between primary care providers and subspecialists.

According to current estimates, up to one-third of the US population (100 million people) may have NAFLD, and 1% to 3% of the population (4–6 million people) likely have NASH, defined as steatosis with inflammation. Development of NASH places patients at a significantly higher risk of fibrosis, hepatocellular injury, and cancer.⁸

NAFLD is more common in men than in women. It is present in around 80% to 90% of obese adults, two-thirds of adults with type 2 diabetes, and many people with hyperlipidemia. It is also becoming more common in children, with 40% to 70% of obese children likely having some element of NAFLD.

Diagnosis of fatty liver

Although liver enzymes are more likely to be abnormal in individuals with NAFLD, many individuals with underlying NAFLD may have normal laboratory evaluations. ALT may be elevated in only up to 20% of cases and does not likely correlate with the level of underlying liver damage, although increasing GGT may serve as a marker of fibrosis over time.^9–11 In contrast to alcohol injury, however, the AST-ALT ratio is usually less than 1.0.

Noninvasive tools for diagnosing NAFLD include the NAFLD fibrosis score, which incorporates age, hyperglycemia, body mass index, platelet count, albumin level, and AST-ALT ratio. This and related scoring algorithms may be useful in differentiating patients with minimal fibrosis from those with advanced fibrosis.^12,13

Ultrasonography is a first-line diagnostic test for steatosis, although it may demonstrate fatty infiltration only around 60% of the time. Computed tomography and magnetic resonance imaging are more sensitive, but costlier. Transient elastography (FibroScan; Echosens, Paris, France) has become more popular and has been shown to correlate with findings on liver biopsy in diagnosing or excluding advanced liver fibrosis.^14,15

The gold standard for diagnosing NAFLD and NASH is identifying fat-laden hepatocytes or portal inflammation on biopsy; however, biopsy is generally reserved for cases in which the diagnosis remains uncertain.

Behavioral treatment

The primary treatment for NAFLD consists of behavioral modification including weight loss, exercise, and adherence to a low-fat diet, in addition to tight glycemic control and treatment of any underlying lipid abnormalities. Studies have shown that a reduction of 7% to 10% of body weight is associated with a decrease in the inflammation of NAFLD, though no strict guidelines have been established.¹⁶

Given the prevalence of NAFLD and the need for longitudinal treatment, primary care physicians will play a significant role in long-term monitoring and management of patients with fatty liver disease.

Hereditary hemochromatosis

Hereditary hemochromatosis is the most common inherited liver disorder in adults of European descent,¹⁷ and can be effectively treated if discovered early. But its clinical diagnosis can be challenging, as many patients have no symptoms at presentation despite abnormal liver enzyme levels. Early symptoms may include severe fatigue, arthralgias, and, in men, impotence, before the appearance of the classic triad of “bronze diabetes” with cirrhosis, diabetes, and darkening of the skin.¹⁸

If hemochromatosis is suspected, laboratory tests should include a calculation of percent transferrin saturation, with saturation greater than 45% warranting serum ferritin measurement to evaluate for iron overload (ferritin > 200–300 ng/mL in men, > 150–200 ng/mL in women).¹⁹ If iron overload is confirmed, referral to a gastroenterologist is recommended.

Genetic evaluation is often pursued, but patients may ultimately require liver biopsy regardless of the findings, as some patients homozygous for the HFE mutation C282Y may not have clinical hemochromatosis, whereas others with hereditary hemochromatosis may not have the HFE mutation.

Therapeutic phlebotomy is the treatment of choice, and most patients tolerate it well.

Chronic hepatitis B virus and hepatitis C virus infections

Chronic hepatitis B virus (HBV) and hepatitis C virus (HCV) infections are common in the United States, with HBV affecting more than 1 million people and HCV affecting an estimated 3.5 million.

Chronic HCV infection. Direct-acting antiviral drugs have revolutionized HCV treatment and have led to a sustained viral response and presumed cure at 12 weeks in more than 95% of cases across all HCV genotypes.²⁰ Given the recent development of effective and well-tolerated treatments, primary care physicians have assumed a pivotal role in screening for HCV.

The American Association for the Study of Liver Diseases and the Infectious Diseases Society of America²¹ recommend screening for HCV in people who have risk factors for it, ie:

• HCV exposure
• HIV infection
• Behavioral or environmental risks for contracting the virus such as intravenous drug use or incarceration
• Birth between 1945 and 1965 (one-time testing).

If HCV antibody screening is positive, HCV RNA should be obtained to quantify the viral load and confirm active infection, and genotype testing should be performed to guide treatment. Among the 6 most common HCV genotypes, genotype 1 is the most common in North America, accounting for over 70% of cases in the United States.

Although recommendations and therapies are constantly evolving, the selection of a treatment regimen and the duration of therapy are determined by viral genotype, history of prior treatment, stage of liver fibrosis, potential drug interactions, and frequently, medication cost and insurance coverage.

HBV infection. The treatment for acute HBV infection is generally supportive, though viral suppression with tenofovir or entecavir may be required for those who develop coagulopathy, bilirubinemia, or liver failure. Treatment of chronic HBV infection may not be required and is generally considered for those with elevated ALT, high viral load, or evidence of liver fibrosis on noninvasive measurements such as transient elastography.

Autoimmune hepatitis

Autoimmune causes of liver enzyme elevations should also be considered during initial screening. Positive antinuclear antibody and positive antismooth muscle antibody tests are common in cases of autoimmune hepatitis.²² Autoimmune hepatitis affects women more often than men, with a ratio of 4:1. The peaks of incidence occur during adolescence and between ages 30 and 45.²³

Primary biliary cholangitis

Additionally, an elevated alkaline phosphatase level should raise concern for underlying primary biliary cholangitis (formerly called primary biliary cirrhosis), an autoimmune disorder that affects the small and medium intrahepatic bile ducts. Diagnosis of primary biliary cholangitis can be assisted by a positive test for antimitochondrial antibody, present in almost 90% of patients.²⁴

Primary sclerosing cholangitis

Elevated alkaline phosphatase is also the hallmark of primary sclerosing cholangitis, which is associated with inflammatory bowel disease.²⁵ Primary sclerosing cholangitis is characterized by inflammation and fibrosis of the intrahepatic and extrahepatic bile ducts, which are visualized on MRCP and confirmed by biopsy if needed.

REFERRAL

Subspecialty referral should be considered if the cause remains ambiguous or unknown, if there is concern for a rare hepatic disorder such as an autoimmune condition, Wilson disease, or alpha-1 antitrypsin deficiency, or if there is evidence of advanced or chronic liver disease.

Primary care physicians are at the forefront of detecting and diagnosing liver disease, and close coordination with subspecialists will remain crucial in delivering patient care.

In the current sociopolitical environment in the United States, the slogan “words matter” has become a battle cry for several groups and causes, emphasizing that our choice of words can influence the way we assess a specific person or situation. We are not immune to the subliminal bias of words, even as we evaluate such seemingly objective components of clinical management as laboratory test results.

Several years ago, I was supervising teaching rounds on a general medicine service. It was the first rounds of the month, and the patients were relatively new to the residents and totally unknown to me. One patient was an elderly man with weight loss, fatigue, weakness, and a history of excessive alcohol ingestion. His family had corroborated the last detail, but he had stopped drinking a long time before his admission. He had normal creatinine, minimal anemia, and markedly elevated and unexplained “liver function tests.” Liver biopsy was planned.

As we entered his room, we saw a gaunt man struggle to rise from the bedside chair to get back into bed. He rocked several times and then pushed himself up from the chair using his arms. Then, after a few short steps, he plopped back into bed and greeted us. His breakfast tray was untouched at the bedside. I introduced myself, we chatted for a short while as I examined him in front of our team, and we left.

In the hallway I asked, “Who would like to get an additional blood test before we do a liver biopsy?” Without waiting for a response I asked a second question, “What exactly are liver function tests?”

Words do matter, and they influence the way we analyze clinical scenarios. It could be argued that a complete and careful history would have established that our patient’s fatigue and weakness were due to proximal muscle weakness and not general asthenia, and that detailed questioning would have revealed that his weight loss was mainly from difficulty in swallowing without a sense of choking and coughing. But faced with an elderly man, a likely explanation for liver disease, and markedly elevated aspartate and alanine aminotransferase (AST and ALT) levels, there was premature closure of the diagnosis, and the decision was made to obtain a liver biopsy—which our hepatology consultants surely would not have done. I believe that a major contributor to the premature diagnosis was the choice of the words “liver function tests” and the default assumption that elevated serum levels of these enzymes always reflect liver disease.

Aminotransferases are fairly ubiquitous, likely present in various concentrations in all cells in our body. AST exists in mitochondrial and cytosolic forms, and ALT in the cytosol. The concentration of ALT is higher in the liver than in other organs, and its enzymatic activity is suppressed by hepatic exposure to alcohol. Both enzymes are present in muscle, and although AST is more abundant in cells other than hepatocytes, the longer serum half-life of ALT may result in roughly equal serum levels in the setting of chronic muscle injury such as myositis (the true diagnosis in our weak patient).

While a meticulous history and examination would indeed have led to the diagnosis of muscle disease in this man, they alone could not have determined whether he had coexistent liver and muscle disease. And this is a real challenge when acute muscle toxicity and liver toxicity are equally possible (eg, statin or immune checkpoint autoimmune tissue damage, or after significant trauma).

There are many nuances in the interpretation of even the most common laboratory tests. In this issue of the Journal, Agganis et al discuss liver enzymes (a term slightly more acceptable to me than liver function tests). In future issues, we will address the interpretation of other laboratory tests.

In the current sociopolitical environment in the United States, the slogan “words matter” has become a battle cry for several groups and causes, emphasizing that our choice of words can influence the way we assess a specific person or situation. We are not immune to the subliminal bias of words, even as we evaluate such seemingly objective components of clinical management as laboratory test results.

Several years ago, I was supervising teaching rounds on a general medicine service. It was the first rounds of the month, and the patients were relatively new to the residents and totally unknown to me. One patient was an elderly man with weight loss, fatigue, weakness, and a history of excessive alcohol ingestion. His family had corroborated the last detail, but he had stopped drinking a long time before his admission. He had normal creatinine, minimal anemia, and markedly elevated and unexplained “liver function tests.” Liver biopsy was planned.

As we entered his room, we saw a gaunt man struggle to rise from the bedside chair to get back into bed. He rocked several times and then pushed himself up from the chair using his arms. Then, after a few short steps, he plopped back into bed and greeted us. His breakfast tray was untouched at the bedside. I introduced myself, we chatted for a short while as I examined him in front of our team, and we left.

In the hallway I asked, “Who would like to get an additional blood test before we do a liver biopsy?” Without waiting for a response I asked a second question, “What exactly are liver function tests?”

Words do matter, and they influence the way we analyze clinical scenarios. It could be argued that a complete and careful history would have established that our patient’s fatigue and weakness were due to proximal muscle weakness and not general asthenia, and that detailed questioning would have revealed that his weight loss was mainly from difficulty in swallowing without a sense of choking and coughing. But faced with an elderly man, a likely explanation for liver disease, and markedly elevated aspartate and alanine aminotransferase (AST and ALT) levels, there was premature closure of the diagnosis, and the decision was made to obtain a liver biopsy—which our hepatology consultants surely would not have done. I believe that a major contributor to the premature diagnosis was the choice of the words “liver function tests” and the default assumption that elevated serum levels of these enzymes always reflect liver disease.

Aminotransferases are fairly ubiquitous, likely present in various concentrations in all cells in our body. AST exists in mitochondrial and cytosolic forms, and ALT in the cytosol. The concentration of ALT is higher in the liver than in other organs, and its enzymatic activity is suppressed by hepatic exposure to alcohol. Both enzymes are present in muscle, and although AST is more abundant in cells other than hepatocytes, the longer serum half-life of ALT may result in roughly equal serum levels in the setting of chronic muscle injury such as myositis (the true diagnosis in our weak patient).

While a meticulous history and examination would indeed have led to the diagnosis of muscle disease in this man, they alone could not have determined whether he had coexistent liver and muscle disease. And this is a real challenge when acute muscle toxicity and liver toxicity are equally possible (eg, statin or immune checkpoint autoimmune tissue damage, or after significant trauma).

There are many nuances in the interpretation of even the most common laboratory tests. In this issue of the Journal, Agganis et al discuss liver enzymes (a term slightly more acceptable to me than liver function tests). In future issues, we will address the interpretation of other laboratory tests.

In the current sociopolitical environment in the United States, the slogan “words matter” has become a battle cry for several groups and causes, emphasizing that our choice of words can influence the way we assess a specific person or situation. We are not immune to the subliminal bias of words, even as we evaluate such seemingly objective components of clinical management as laboratory test results.

Several years ago, I was supervising teaching rounds on a general medicine service. It was the first rounds of the month, and the patients were relatively new to the residents and totally unknown to me. One patient was an elderly man with weight loss, fatigue, weakness, and a history of excessive alcohol ingestion. His family had corroborated the last detail, but he had stopped drinking a long time before his admission. He had normal creatinine, minimal anemia, and markedly elevated and unexplained “liver function tests.” Liver biopsy was planned.

As we entered his room, we saw a gaunt man struggle to rise from the bedside chair to get back into bed. He rocked several times and then pushed himself up from the chair using his arms. Then, after a few short steps, he plopped back into bed and greeted us. His breakfast tray was untouched at the bedside. I introduced myself, we chatted for a short while as I examined him in front of our team, and we left.

In the hallway I asked, “Who would like to get an additional blood test before we do a liver biopsy?” Without waiting for a response I asked a second question, “What exactly are liver function tests?”

Words do matter, and they influence the way we analyze clinical scenarios. It could be argued that a complete and careful history would have established that our patient’s fatigue and weakness were due to proximal muscle weakness and not general asthenia, and that detailed questioning would have revealed that his weight loss was mainly from difficulty in swallowing without a sense of choking and coughing. But faced with an elderly man, a likely explanation for liver disease, and markedly elevated aspartate and alanine aminotransferase (AST and ALT) levels, there was premature closure of the diagnosis, and the decision was made to obtain a liver biopsy—which our hepatology consultants surely would not have done. I believe that a major contributor to the premature diagnosis was the choice of the words “liver function tests” and the default assumption that elevated serum levels of these enzymes always reflect liver disease.

Aminotransferases are fairly ubiquitous, likely present in various concentrations in all cells in our body. AST exists in mitochondrial and cytosolic forms, and ALT in the cytosol. The concentration of ALT is higher in the liver than in other organs, and its enzymatic activity is suppressed by hepatic exposure to alcohol. Both enzymes are present in muscle, and although AST is more abundant in cells other than hepatocytes, the longer serum half-life of ALT may result in roughly equal serum levels in the setting of chronic muscle injury such as myositis (the true diagnosis in our weak patient).

While a meticulous history and examination would indeed have led to the diagnosis of muscle disease in this man, they alone could not have determined whether he had coexistent liver and muscle disease. And this is a real challenge when acute muscle toxicity and liver toxicity are equally possible (eg, statin or immune checkpoint autoimmune tissue damage, or after significant trauma).

There are many nuances in the interpretation of even the most common laboratory tests. In this issue of the Journal, Agganis et al discuss liver enzymes (a term slightly more acceptable to me than liver function tests). In future issues, we will address the interpretation of other laboratory tests.

A 51-year-old man with type 2 diabetes was referred to our hospital because of liver dysfunction and nonpruritic exanthema, with papulosquamous, scaly, papular and macular lesions on his trunk and extremities, including his palms (Figure 1) and soles. Also noted were tiny grayish mucus patches on the oral mucosa. Axillary and inguinal superficial lymph nodes were palpable.

Laboratory testing revealed elevated serum levels of markers of liver disease, ie:

• Total bilirubin 9.8 mg/dL (reference range 0.2–1.3)
• Direct bilirubin 8.0 mg/dL (< 0.2)
• Aspartate aminotransferase 57 IU/L (13–35)
• Alanine aminotransferase 90 IU/L (10–54)
• Alkaline phosphatase 4,446 IU/L (36–108).

Possible causes of liver dysfunction such as legal and illicit drugs, alcohol abuse, obstructive biliary tract or liver disease, viral hepatitis, and primary biliary cirrhosis were ruled out by history, serologic testing, abdominal ultrasonography, and computed tomography.

Secondary syphilis was suspected in view of the characteristic distribution of exanthema involving the trunk and extremities, especially the palms and soles. On questioning, the patient admitted to having had unprotected sex with a female sex worker, which also raised the probability of syphilis infection.

The rapid plasma reagin test was positive at a titer of 1:16, and the Treponema pallidum agglutination test was positive at a signal-to-cutoff ratio of 27.02. Antibody testing for human immunodeficiency virus (HIV) was negative.

The patient was started on penicillin G, but 4 hours later, he developed a fever with a temperature of 100.2°F (37.9°C), which was assumed to be a Jarisch-Herxheimer reaction. The fever resolved by the next morning without further treatment.

His course was otherwise uneventful. The exanthema resolved within 3 months, and his liver function returned to normal. Five months later, the rapid plasma reagin test was repeated on an outpatient basis, and the result was normal.

SYPHILIS IS NOT A DISEASE OF THE PAST

Syphilis is caused by T pallidum and is mainly transmitted by sexual contact.¹

The incidence of syphilis has substantially increased in recent years in Japan^2,3 and worldwide.⁴ The typical patient is a young man who has sex with men, is infected with HIV, and has a history of syphilis infection.³ However, the rapid increase in syphilis infections in Japan in recent years is largely because of an increase in heterosexual transmission.³

Infectious in its early stages

Syphilis is potentially infectious in its early (primary, secondary, and early latent) stages.^1,5 The secondary stage generally begins 6 to 8 weeks after the primary infection¹ and presents with diverse symptoms, including arthralgia, condylomata lata, generalized lymphaden­opathy, maculopapular and papulosquamous exanthema, myalgia, and pharyngitis.¹

Liver dysfunction in secondary syphilis

Liver dysfunction is common in secondary syphilis, occurring in 25% to 50% of cases.⁵ The liver enzyme pattern in most cases is a disproportionate increase in the alkaline phosphatase level compared with modest elevations of aminotransferases and bilirubin.^2,5 However, some cases may show predominant hepatocellular damage (with prominent elevations in aminotransferase levels), and others may present with severe cholestasis (with prominent elevations in alkaline phosphatase and bilirubin) or even fulminant hepatic failure.^2,5

The diagnostic criteria for syphilitic hepatitis are abnormal liver enzyme levels, serologic evidence of syphilis in conjunction with acute clinical presentation of secondary syphilis, exclusion of alternative causes of liver dysfunction, and prompt recovery of liver function after antimicrobial therapy.^2,5

Pathogenic mechanisms in syphilitic hepatitis include direct portal venous inoculation and immune complex-mediated disease.² However, direct hepatotoxicity of the microorganism seems unlikely, as spirochetes are rarely detected in liver specimens.^2,5

Jarisch-Herxheimer reaction

The Jarisch-Herxheimer reaction is an acute febrile illness during the first 24 hours of antimicrobial treatment.^1,6 It is assumed to be due to lysis of large numbers of spirochetes, releasing lipopolysaccharides (endotoxins) that further incite the release of a range of cytokines, resulting in symptoms such as fever, chills, myalgias, headache, tachycardia, hyperventilation, vasodilation with flushing, and mild hypotension.^6,7

The frequency of Jarisch-Herxheimer reaction in syphilis and other spirochetal infections has varied widely in different reports.⁸ It is common in primary and secondary syphilis but usually does not occur in latent syphilis.⁶

Consider the diagnosis

Physicians should consider secondary syphilis in patients who present with characteristic generalized reddish macules and papules with papulosquamous lesions, including on the palms and soles as in our patient, and also in patients who have had unprotected sexual contact. Syphilis is not a disease of the past.

Acknowledgment: The authors thank Dr. Joel Branch, Shonan Kamakura General Hospital, Japan, for his editorial assistance.

A 51-year-old man with type 2 diabetes was referred to our hospital because of liver dysfunction and nonpruritic exanthema, with papulosquamous, scaly, papular and macular lesions on his trunk and extremities, including his palms (Figure 1) and soles. Also noted were tiny grayish mucus patches on the oral mucosa. Axillary and inguinal superficial lymph nodes were palpable.

Laboratory testing revealed elevated serum levels of markers of liver disease, ie:

• Total bilirubin 9.8 mg/dL (reference range 0.2–1.3)
• Direct bilirubin 8.0 mg/dL (< 0.2)
• Aspartate aminotransferase 57 IU/L (13–35)
• Alanine aminotransferase 90 IU/L (10–54)
• Alkaline phosphatase 4,446 IU/L (36–108).

Possible causes of liver dysfunction such as legal and illicit drugs, alcohol abuse, obstructive biliary tract or liver disease, viral hepatitis, and primary biliary cirrhosis were ruled out by history, serologic testing, abdominal ultrasonography, and computed tomography.

Secondary syphilis was suspected in view of the characteristic distribution of exanthema involving the trunk and extremities, especially the palms and soles. On questioning, the patient admitted to having had unprotected sex with a female sex worker, which also raised the probability of syphilis infection.

The rapid plasma reagin test was positive at a titer of 1:16, and the Treponema pallidum agglutination test was positive at a signal-to-cutoff ratio of 27.02. Antibody testing for human immunodeficiency virus (HIV) was negative.

The patient was started on penicillin G, but 4 hours later, he developed a fever with a temperature of 100.2°F (37.9°C), which was assumed to be a Jarisch-Herxheimer reaction. The fever resolved by the next morning without further treatment.

His course was otherwise uneventful. The exanthema resolved within 3 months, and his liver function returned to normal. Five months later, the rapid plasma reagin test was repeated on an outpatient basis, and the result was normal.

SYPHILIS IS NOT A DISEASE OF THE PAST

Syphilis is caused by T pallidum and is mainly transmitted by sexual contact.¹

The incidence of syphilis has substantially increased in recent years in Japan^2,3 and worldwide.⁴ The typical patient is a young man who has sex with men, is infected with HIV, and has a history of syphilis infection.³ However, the rapid increase in syphilis infections in Japan in recent years is largely because of an increase in heterosexual transmission.³

Infectious in its early stages

Syphilis is potentially infectious in its early (primary, secondary, and early latent) stages.^1,5 The secondary stage generally begins 6 to 8 weeks after the primary infection¹ and presents with diverse symptoms, including arthralgia, condylomata lata, generalized lymphaden­opathy, maculopapular and papulosquamous exanthema, myalgia, and pharyngitis.¹

Liver dysfunction in secondary syphilis

Liver dysfunction is common in secondary syphilis, occurring in 25% to 50% of cases.⁵ The liver enzyme pattern in most cases is a disproportionate increase in the alkaline phosphatase level compared with modest elevations of aminotransferases and bilirubin.^2,5 However, some cases may show predominant hepatocellular damage (with prominent elevations in aminotransferase levels), and others may present with severe cholestasis (with prominent elevations in alkaline phosphatase and bilirubin) or even fulminant hepatic failure.^2,5

The diagnostic criteria for syphilitic hepatitis are abnormal liver enzyme levels, serologic evidence of syphilis in conjunction with acute clinical presentation of secondary syphilis, exclusion of alternative causes of liver dysfunction, and prompt recovery of liver function after antimicrobial therapy.^2,5

Pathogenic mechanisms in syphilitic hepatitis include direct portal venous inoculation and immune complex-mediated disease.² However, direct hepatotoxicity of the microorganism seems unlikely, as spirochetes are rarely detected in liver specimens.^2,5

Jarisch-Herxheimer reaction

The Jarisch-Herxheimer reaction is an acute febrile illness during the first 24 hours of antimicrobial treatment.^1,6 It is assumed to be due to lysis of large numbers of spirochetes, releasing lipopolysaccharides (endotoxins) that further incite the release of a range of cytokines, resulting in symptoms such as fever, chills, myalgias, headache, tachycardia, hyperventilation, vasodilation with flushing, and mild hypotension.^6,7

The frequency of Jarisch-Herxheimer reaction in syphilis and other spirochetal infections has varied widely in different reports.⁸ It is common in primary and secondary syphilis but usually does not occur in latent syphilis.⁶

Consider the diagnosis

Physicians should consider secondary syphilis in patients who present with characteristic generalized reddish macules and papules with papulosquamous lesions, including on the palms and soles as in our patient, and also in patients who have had unprotected sexual contact. Syphilis is not a disease of the past.

Acknowledgment: The authors thank Dr. Joel Branch, Shonan Kamakura General Hospital, Japan, for his editorial assistance.

A 51-year-old man with type 2 diabetes was referred to our hospital because of liver dysfunction and nonpruritic exanthema, with papulosquamous, scaly, papular and macular lesions on his trunk and extremities, including his palms (Figure 1) and soles. Also noted were tiny grayish mucus patches on the oral mucosa. Axillary and inguinal superficial lymph nodes were palpable.

Laboratory testing revealed elevated serum levels of markers of liver disease, ie:

• Total bilirubin 9.8 mg/dL (reference range 0.2–1.3)
• Direct bilirubin 8.0 mg/dL (< 0.2)
• Aspartate aminotransferase 57 IU/L (13–35)
• Alanine aminotransferase 90 IU/L (10–54)
• Alkaline phosphatase 4,446 IU/L (36–108).

Possible causes of liver dysfunction such as legal and illicit drugs, alcohol abuse, obstructive biliary tract or liver disease, viral hepatitis, and primary biliary cirrhosis were ruled out by history, serologic testing, abdominal ultrasonography, and computed tomography.

Secondary syphilis was suspected in view of the characteristic distribution of exanthema involving the trunk and extremities, especially the palms and soles. On questioning, the patient admitted to having had unprotected sex with a female sex worker, which also raised the probability of syphilis infection.

The rapid plasma reagin test was positive at a titer of 1:16, and the Treponema pallidum agglutination test was positive at a signal-to-cutoff ratio of 27.02. Antibody testing for human immunodeficiency virus (HIV) was negative.

The patient was started on penicillin G, but 4 hours later, he developed a fever with a temperature of 100.2°F (37.9°C), which was assumed to be a Jarisch-Herxheimer reaction. The fever resolved by the next morning without further treatment.

His course was otherwise uneventful. The exanthema resolved within 3 months, and his liver function returned to normal. Five months later, the rapid plasma reagin test was repeated on an outpatient basis, and the result was normal.

SYPHILIS IS NOT A DISEASE OF THE PAST

Syphilis is caused by T pallidum and is mainly transmitted by sexual contact.¹

The incidence of syphilis has substantially increased in recent years in Japan^2,3 and worldwide.⁴ The typical patient is a young man who has sex with men, is infected with HIV, and has a history of syphilis infection.³ However, the rapid increase in syphilis infections in Japan in recent years is largely because of an increase in heterosexual transmission.³

Infectious in its early stages

Syphilis is potentially infectious in its early (primary, secondary, and early latent) stages.^1,5 The secondary stage generally begins 6 to 8 weeks after the primary infection¹ and presents with diverse symptoms, including arthralgia, condylomata lata, generalized lymphaden­opathy, maculopapular and papulosquamous exanthema, myalgia, and pharyngitis.¹

Liver dysfunction in secondary syphilis

Liver dysfunction is common in secondary syphilis, occurring in 25% to 50% of cases.⁵ The liver enzyme pattern in most cases is a disproportionate increase in the alkaline phosphatase level compared with modest elevations of aminotransferases and bilirubin.^2,5 However, some cases may show predominant hepatocellular damage (with prominent elevations in aminotransferase levels), and others may present with severe cholestasis (with prominent elevations in alkaline phosphatase and bilirubin) or even fulminant hepatic failure.^2,5

The diagnostic criteria for syphilitic hepatitis are abnormal liver enzyme levels, serologic evidence of syphilis in conjunction with acute clinical presentation of secondary syphilis, exclusion of alternative causes of liver dysfunction, and prompt recovery of liver function after antimicrobial therapy.^2,5

Pathogenic mechanisms in syphilitic hepatitis include direct portal venous inoculation and immune complex-mediated disease.² However, direct hepatotoxicity of the microorganism seems unlikely, as spirochetes are rarely detected in liver specimens.^2,5

Jarisch-Herxheimer reaction

The Jarisch-Herxheimer reaction is an acute febrile illness during the first 24 hours of antimicrobial treatment.^1,6 It is assumed to be due to lysis of large numbers of spirochetes, releasing lipopolysaccharides (endotoxins) that further incite the release of a range of cytokines, resulting in symptoms such as fever, chills, myalgias, headache, tachycardia, hyperventilation, vasodilation with flushing, and mild hypotension.^6,7

The frequency of Jarisch-Herxheimer reaction in syphilis and other spirochetal infections has varied widely in different reports.⁸ It is common in primary and secondary syphilis but usually does not occur in latent syphilis.⁶

Consider the diagnosis

Physicians should consider secondary syphilis in patients who present with characteristic generalized reddish macules and papules with papulosquamous lesions, including on the palms and soles as in our patient, and also in patients who have had unprotected sexual contact. Syphilis is not a disease of the past.

Acknowledgment: The authors thank Dr. Joel Branch, Shonan Kamakura General Hospital, Japan, for his editorial assistance.

Among patients hospitalized with gastrointestinal and liver diseases, a clearly identifiable subset uses significantly more health care resources, which incurs significantly greater costs, according to the results of a national database analysis published in the August issue of Clinical Gastroenterology and Hepatology.

Compared with otherwise similar inpatients, these “high-need, high-cost” individuals are significantly more likely to be enrolled in Medicare or Medicaid, to have lower income, to initially be admitted to a large, rural hospital, to have multiple comorbidities, to be obese, or to be hospitalized for infection, said Nghia Nguyen, MD, and his associates. “[A] small fraction of high-need, high-cost patients contribute disproportionately to hospitalization costs,” they wrote. “Population health management directed toward these patients would facilitate high-value care.”

Gastrointestinal and liver diseases incur more than $100 billion in health care expenses annually in the United States, of which more than 60% is related to inpatient care, the researchers noted. However, few studies have comprehensively evaluated the annual burden and costs of hospitalization in patients with chronic gastrointestinal and liver diseases. Therefore, using the Nationwide Readmissions Database, the investigators studied patients with inflammatory bowel disease (IBD), chronic liver disease, functional gastrointestinal disorders, gastrointestinal hemorrhage, or pancreatic diseases who were hospitalized at least once during the first 6 months of 2013. All patients were diagnosed with IBD, chronic liver diseases, functional gastrointestinal disorders, gastrointestinal hemorrhage, or pancreatic diseases and followed for at least 6 months. The researchers stratified hospital days and costs and characterized the subset of patients who fell into the highest decile of days spent in the hospital per month.

The most common reason for hospitalization was chronic liver disease (nearly 377,000 patients), followed by functional gastrointestinal disorders (more than 351,000 patients), gastrointestinal hemorrhage (nearly 191,000 patients), pancreatic diseases (more than 98,000 patients), and IBD (more than 47,000 patients). Patients spent a median of 6-7 days in the hospital per year, with an interquartile range of 3-14 days. Compared with patients in the lowest decile for annual hospital stay (median, 0.13-0.14 days per month), patients in the highest decile spent a median of 3.7-5.1 days in the hospital per month. In this high-cost, high-need subset of patients, the costs of each hospitalization ranged from $7,438 per month to $11,425 per month, and they were typically hospitalized once every 2 months.

“Gastrointestinal diseases, infections, and cardiopulmonary causes were leading reasons for hospitalization of these patients,” the researchers wrote. “At a patient level, modifiable risk factors may include tackling the obesity epidemic and mental health issues and minimizing risk of iatrogenic or health care–associated infections, whereas at a health system level, interventions may include better access to care and connectivity between rural and specialty hospitals.”

Funders included the American College of Gastroenterology, the Crohn’s and Colitis Foundation, and the National Institutes of Health. Senior author Siddharth Singh disclosed unrelated grant funding from Pifzer and AbbVie. The other investigators reported having no conflicts of interest.

SOURCE: Nguyen NH et al. Clin Gastroenterol Hepatol. 2018 Feb 20. doi: 10.1016/j.cgh.2018.02.015.

Among patients hospitalized with gastrointestinal and liver diseases, a clearly identifiable subset uses significantly more health care resources, which incurs significantly greater costs, according to the results of a national database analysis published in the August issue of Clinical Gastroenterology and Hepatology.

Compared with otherwise similar inpatients, these “high-need, high-cost” individuals are significantly more likely to be enrolled in Medicare or Medicaid, to have lower income, to initially be admitted to a large, rural hospital, to have multiple comorbidities, to be obese, or to be hospitalized for infection, said Nghia Nguyen, MD, and his associates. “[A] small fraction of high-need, high-cost patients contribute disproportionately to hospitalization costs,” they wrote. “Population health management directed toward these patients would facilitate high-value care.”

Gastrointestinal and liver diseases incur more than $100 billion in health care expenses annually in the United States, of which more than 60% is related to inpatient care, the researchers noted. However, few studies have comprehensively evaluated the annual burden and costs of hospitalization in patients with chronic gastrointestinal and liver diseases. Therefore, using the Nationwide Readmissions Database, the investigators studied patients with inflammatory bowel disease (IBD), chronic liver disease, functional gastrointestinal disorders, gastrointestinal hemorrhage, or pancreatic diseases who were hospitalized at least once during the first 6 months of 2013. All patients were diagnosed with IBD, chronic liver diseases, functional gastrointestinal disorders, gastrointestinal hemorrhage, or pancreatic diseases and followed for at least 6 months. The researchers stratified hospital days and costs and characterized the subset of patients who fell into the highest decile of days spent in the hospital per month.

The most common reason for hospitalization was chronic liver disease (nearly 377,000 patients), followed by functional gastrointestinal disorders (more than 351,000 patients), gastrointestinal hemorrhage (nearly 191,000 patients), pancreatic diseases (more than 98,000 patients), and IBD (more than 47,000 patients). Patients spent a median of 6-7 days in the hospital per year, with an interquartile range of 3-14 days. Compared with patients in the lowest decile for annual hospital stay (median, 0.13-0.14 days per month), patients in the highest decile spent a median of 3.7-5.1 days in the hospital per month. In this high-cost, high-need subset of patients, the costs of each hospitalization ranged from $7,438 per month to $11,425 per month, and they were typically hospitalized once every 2 months.

“Gastrointestinal diseases, infections, and cardiopulmonary causes were leading reasons for hospitalization of these patients,” the researchers wrote. “At a patient level, modifiable risk factors may include tackling the obesity epidemic and mental health issues and minimizing risk of iatrogenic or health care–associated infections, whereas at a health system level, interventions may include better access to care and connectivity between rural and specialty hospitals.”

Funders included the American College of Gastroenterology, the Crohn’s and Colitis Foundation, and the National Institutes of Health. Senior author Siddharth Singh disclosed unrelated grant funding from Pifzer and AbbVie. The other investigators reported having no conflicts of interest.

SOURCE: Nguyen NH et al. Clin Gastroenterol Hepatol. 2018 Feb 20. doi: 10.1016/j.cgh.2018.02.015.

Among patients hospitalized with gastrointestinal and liver diseases, a clearly identifiable subset uses significantly more health care resources, which incurs significantly greater costs, according to the results of a national database analysis published in the August issue of Clinical Gastroenterology and Hepatology.

Compared with otherwise similar inpatients, these “high-need, high-cost” individuals are significantly more likely to be enrolled in Medicare or Medicaid, to have lower income, to initially be admitted to a large, rural hospital, to have multiple comorbidities, to be obese, or to be hospitalized for infection, said Nghia Nguyen, MD, and his associates. “[A] small fraction of high-need, high-cost patients contribute disproportionately to hospitalization costs,” they wrote. “Population health management directed toward these patients would facilitate high-value care.”

Gastrointestinal and liver diseases incur more than $100 billion in health care expenses annually in the United States, of which more than 60% is related to inpatient care, the researchers noted. However, few studies have comprehensively evaluated the annual burden and costs of hospitalization in patients with chronic gastrointestinal and liver diseases. Therefore, using the Nationwide Readmissions Database, the investigators studied patients with inflammatory bowel disease (IBD), chronic liver disease, functional gastrointestinal disorders, gastrointestinal hemorrhage, or pancreatic diseases who were hospitalized at least once during the first 6 months of 2013. All patients were diagnosed with IBD, chronic liver diseases, functional gastrointestinal disorders, gastrointestinal hemorrhage, or pancreatic diseases and followed for at least 6 months. The researchers stratified hospital days and costs and characterized the subset of patients who fell into the highest decile of days spent in the hospital per month.

The most common reason for hospitalization was chronic liver disease (nearly 377,000 patients), followed by functional gastrointestinal disorders (more than 351,000 patients), gastrointestinal hemorrhage (nearly 191,000 patients), pancreatic diseases (more than 98,000 patients), and IBD (more than 47,000 patients). Patients spent a median of 6-7 days in the hospital per year, with an interquartile range of 3-14 days. Compared with patients in the lowest decile for annual hospital stay (median, 0.13-0.14 days per month), patients in the highest decile spent a median of 3.7-5.1 days in the hospital per month. In this high-cost, high-need subset of patients, the costs of each hospitalization ranged from $7,438 per month to $11,425 per month, and they were typically hospitalized once every 2 months.

“Gastrointestinal diseases, infections, and cardiopulmonary causes were leading reasons for hospitalization of these patients,” the researchers wrote. “At a patient level, modifiable risk factors may include tackling the obesity epidemic and mental health issues and minimizing risk of iatrogenic or health care–associated infections, whereas at a health system level, interventions may include better access to care and connectivity between rural and specialty hospitals.”

Funders included the American College of Gastroenterology, the Crohn’s and Colitis Foundation, and the National Institutes of Health. Senior author Siddharth Singh disclosed unrelated grant funding from Pifzer and AbbVie. The other investigators reported having no conflicts of interest.

SOURCE: Nguyen NH et al. Clin Gastroenterol Hepatol. 2018 Feb 20. doi: 10.1016/j.cgh.2018.02.015.

Liver cancer death rates are dropping for Asians/Pacific Islanders, but that is the exception to a larger trend, according to the National Center for Health Statistics.

The age-adjusted death rate for liver cancer is down 22% among Asian or Pacific Islander adults aged 25 years and older since the turn of the century, falling from 17.5 per 100,000 population in 2000 – when it was the highest of the four racial/ethnic groups included in the report – to 13.6 per 100,000 in 2016, by which time it was just middle of the pack, the NCHS reported.

That shift resulted as much from increases for the other groups as from the decreased rate for Asians/Pacific Islanders. White adults were dying of liver cancer at a 48% higher rate in 2016 (9.0 per 100,000) than they were in 2000 (6.1), blacks saw their death rate go from 9.5 to 13.6 – a 43% increase – and the rate for Hispanics rose by 27% from 2000 (11.5) to 2016 (14.6), said Jiaquan Xu, MD, of the NCHS mortality statistics branch.

The adjusted death rate from liver cancer for all adults went from 7.2 per 100,000 in 2000 to 10.3 in 2016 for an increase of 43%. Over that period, the rate for men was always at least twice as high as it was for women: It rose from 10.5 per 100,000 for men and 4.9 for women in 2000 to 15.0 for men and 6.3 for women in 2016, Dr. Xu said based on data from the mortality files of the National Vital Statistics System.

Geographically, the District of Columbia had the highest rate at 16.8 per 100,000 in 2016, followed by Louisiana (13.8), Hawaii (12.7), and Mississippi and New Mexico (12.4 each). Vermont’s rate of 6.0 was the lowest in the country, with Maine second at 7.4, Montana third at 7.7, and Utah and Nebraska tied for fourth at 7.8, according to Dr. Xu.

[email protected]

Liver cancer death rates are dropping for Asians/Pacific Islanders, but that is the exception to a larger trend, according to the National Center for Health Statistics.

The age-adjusted death rate for liver cancer is down 22% among Asian or Pacific Islander adults aged 25 years and older since the turn of the century, falling from 17.5 per 100,000 population in 2000 – when it was the highest of the four racial/ethnic groups included in the report – to 13.6 per 100,000 in 2016, by which time it was just middle of the pack, the NCHS reported.

That shift resulted as much from increases for the other groups as from the decreased rate for Asians/Pacific Islanders. White adults were dying of liver cancer at a 48% higher rate in 2016 (9.0 per 100,000) than they were in 2000 (6.1), blacks saw their death rate go from 9.5 to 13.6 – a 43% increase – and the rate for Hispanics rose by 27% from 2000 (11.5) to 2016 (14.6), said Jiaquan Xu, MD, of the NCHS mortality statistics branch.

The adjusted death rate from liver cancer for all adults went from 7.2 per 100,000 in 2000 to 10.3 in 2016 for an increase of 43%. Over that period, the rate for men was always at least twice as high as it was for women: It rose from 10.5 per 100,000 for men and 4.9 for women in 2000 to 15.0 for men and 6.3 for women in 2016, Dr. Xu said based on data from the mortality files of the National Vital Statistics System.

Geographically, the District of Columbia had the highest rate at 16.8 per 100,000 in 2016, followed by Louisiana (13.8), Hawaii (12.7), and Mississippi and New Mexico (12.4 each). Vermont’s rate of 6.0 was the lowest in the country, with Maine second at 7.4, Montana third at 7.7, and Utah and Nebraska tied for fourth at 7.8, according to Dr. Xu.

[email protected]

Liver cancer death rates are dropping for Asians/Pacific Islanders, but that is the exception to a larger trend, according to the National Center for Health Statistics.

The age-adjusted death rate for liver cancer is down 22% among Asian or Pacific Islander adults aged 25 years and older since the turn of the century, falling from 17.5 per 100,000 population in 2000 – when it was the highest of the four racial/ethnic groups included in the report – to 13.6 per 100,000 in 2016, by which time it was just middle of the pack, the NCHS reported.

That shift resulted as much from increases for the other groups as from the decreased rate for Asians/Pacific Islanders. White adults were dying of liver cancer at a 48% higher rate in 2016 (9.0 per 100,000) than they were in 2000 (6.1), blacks saw their death rate go from 9.5 to 13.6 – a 43% increase – and the rate for Hispanics rose by 27% from 2000 (11.5) to 2016 (14.6), said Jiaquan Xu, MD, of the NCHS mortality statistics branch.

The adjusted death rate from liver cancer for all adults went from 7.2 per 100,000 in 2000 to 10.3 in 2016 for an increase of 43%. Over that period, the rate for men was always at least twice as high as it was for women: It rose from 10.5 per 100,000 for men and 4.9 for women in 2000 to 15.0 for men and 6.3 for women in 2016, Dr. Xu said based on data from the mortality files of the National Vital Statistics System.

Geographically, the District of Columbia had the highest rate at 16.8 per 100,000 in 2016, followed by Louisiana (13.8), Hawaii (12.7), and Mississippi and New Mexico (12.4 each). Vermont’s rate of 6.0 was the lowest in the country, with Maine second at 7.4, Montana third at 7.7, and Utah and Nebraska tied for fourth at 7.8, according to Dr. Xu.

[email protected]

Deaths from cirrhosis of the liver in the United States increased by 65% during 1999-2016, while deaths from hepatocellular carcinoma more than doubled.

Cirrhosis mortality showed a sharp rise beginning in 2009, with a 3.6% annual increase driven entirely by a surge in alcoholic cirrhosis among young people aged 25-34 years, Elliot B. Tapper, MD, and Neehar D. Parikh, MD, reported in the BMJ. The uptick in hepatocellular carcinoma, however, was gradual and consistent, with a 2% annual increase felt mostly in older people, wrote Dr. Tapper and Dr. Parikh, both at the University of Michigan, Ann Arbor.

“The increasing mortality due to cirrhosis and hepatocellular carcinoma speaks to the expanding socioeconomic impact of liver disease,” the colleagues wrote. “Adverse trends in liver-related mortality are particularly unfortunate given that in most cases the liver disease is preventable. Understanding the factors associated with mortality due to these conditions will inform how best to allocate resources.”

The study extracted its data from the Vital Statistic Cooperative and the Centers for Disease Control and Prevention. The investigators not only examined raw mortality numbers, but analyzed them for demographic and geographic trends, in analyses that controlled for age.

Cirrhosis

During the study period, 460,760 patients died from cirrhosis (20,661 in 1999 and 34,174 in 2016, an increase of 65.4%).

Men were twice as likely to die from cirrhosis. Young people aged 25-34 years had the highest rate of increase (3.7% over the entire period and 10.5% from 2009 to 2016). This was directly driven by parallel increases in both alcohol use disorder and alcohol-related liver diseases, which increased by about 16% and 10%, respectively, in this group.

Native Americans had the highest mortality rate (25.8 per 100,000) followed by whites (12.7 per 100,000). “Notably, by 2016, cirrhosis accounted for 6.3% [up from 4.3% in 2009] and 7% [up from 5.8% in 2009] of deaths for Native Americans aged 25-34 and 35 or more, respectively,” and 2.3% of all deaths among adults aged 25-34 years, the authors wrote.

The increases were largely felt in the southern and western states (about 13 per 100,000 in each region). The greatest increases occurred in Kentucky (6.8%), New Mexico (6%), Arkansas (5.7%), Indiana (5%), and Alabama (5%). There was a statistically significant 1.2% decrease in deaths from cirrhosis in Maryland.

Hepatocellular carcinoma

Hepatocellular carcinoma accounted for 136,442 deaths during the study period (5,112 in 1999 and 11,073 in 2016 – an increase of 116.6%). This represented an average annual increase of 2%.

Men were four times more likely to die from hepatocellular carcinoma. The increase manifested mostly in older people, decreasing in those younger than 55 years. Mortality was highest among Asians and Pacific Islanders (6 per 100,000), followed by blacks (4.94 per 100,000).

The increases were largely felt in western states, with an overall increase of 4.2 per 100,000.

“Many of the same states with worsening cirrhosis-related mortality also experienced worsening mortality from hepatocellular carcinoma, including Oregon and Iowa,” the authors wrote. But mortality from the disease also increased significantly in Arizona (5.1%), Kansas (4.3%), Kentucky (4%), and Washington (3.9%).

“Potential explanations supported by these data include increasing early detection of hepatocellular carcinoma, application of curative or locoregional therapies, and, because hepatitis B is the principal cause of hepatocellular carcinoma worldwide and among Asian Americans, effectiveness of vaccination programs and the efficacy of antiviral therapy for hepatitis B in preventing the development of hepatocellular carcinoma.”

However, they noted, “it is unclear how these trends are, or will be, affected by direct-acting antivirals for hepatitis C virus ... eradication of hepatitis C virus will prevent the development of cirrhosis and its complications, potentially changing these trends in the next 5-10 years. However, therapy for hepatitis C viral infection cannot modify the statistically significant trends observed related to alcohol or the expected increase in the burden of nonalcoholic fatty liver disease.”

Neither author had any financial disclosure relevant to the work.

[email protected]

SOURCE: Tapper EB et al. BMJ 2018;362:k2817.

Deaths from cirrhosis of the liver in the United States increased by 65% during 1999-2016, while deaths from hepatocellular carcinoma more than doubled.

Cirrhosis mortality showed a sharp rise beginning in 2009, with a 3.6% annual increase driven entirely by a surge in alcoholic cirrhosis among young people aged 25-34 years, Elliot B. Tapper, MD, and Neehar D. Parikh, MD, reported in the BMJ. The uptick in hepatocellular carcinoma, however, was gradual and consistent, with a 2% annual increase felt mostly in older people, wrote Dr. Tapper and Dr. Parikh, both at the University of Michigan, Ann Arbor.

“The increasing mortality due to cirrhosis and hepatocellular carcinoma speaks to the expanding socioeconomic impact of liver disease,” the colleagues wrote. “Adverse trends in liver-related mortality are particularly unfortunate given that in most cases the liver disease is preventable. Understanding the factors associated with mortality due to these conditions will inform how best to allocate resources.”

The study extracted its data from the Vital Statistic Cooperative and the Centers for Disease Control and Prevention. The investigators not only examined raw mortality numbers, but analyzed them for demographic and geographic trends, in analyses that controlled for age.

Cirrhosis

During the study period, 460,760 patients died from cirrhosis (20,661 in 1999 and 34,174 in 2016, an increase of 65.4%).

Men were twice as likely to die from cirrhosis. Young people aged 25-34 years had the highest rate of increase (3.7% over the entire period and 10.5% from 2009 to 2016). This was directly driven by parallel increases in both alcohol use disorder and alcohol-related liver diseases, which increased by about 16% and 10%, respectively, in this group.

Native Americans had the highest mortality rate (25.8 per 100,000) followed by whites (12.7 per 100,000). “Notably, by 2016, cirrhosis accounted for 6.3% [up from 4.3% in 2009] and 7% [up from 5.8% in 2009] of deaths for Native Americans aged 25-34 and 35 or more, respectively,” and 2.3% of all deaths among adults aged 25-34 years, the authors wrote.

The increases were largely felt in the southern and western states (about 13 per 100,000 in each region). The greatest increases occurred in Kentucky (6.8%), New Mexico (6%), Arkansas (5.7%), Indiana (5%), and Alabama (5%). There was a statistically significant 1.2% decrease in deaths from cirrhosis in Maryland.

Hepatocellular carcinoma

Hepatocellular carcinoma accounted for 136,442 deaths during the study period (5,112 in 1999 and 11,073 in 2016 – an increase of 116.6%). This represented an average annual increase of 2%.

Men were four times more likely to die from hepatocellular carcinoma. The increase manifested mostly in older people, decreasing in those younger than 55 years. Mortality was highest among Asians and Pacific Islanders (6 per 100,000), followed by blacks (4.94 per 100,000).

The increases were largely felt in western states, with an overall increase of 4.2 per 100,000.

“Many of the same states with worsening cirrhosis-related mortality also experienced worsening mortality from hepatocellular carcinoma, including Oregon and Iowa,” the authors wrote. But mortality from the disease also increased significantly in Arizona (5.1%), Kansas (4.3%), Kentucky (4%), and Washington (3.9%).

“Potential explanations supported by these data include increasing early detection of hepatocellular carcinoma, application of curative or locoregional therapies, and, because hepatitis B is the principal cause of hepatocellular carcinoma worldwide and among Asian Americans, effectiveness of vaccination programs and the efficacy of antiviral therapy for hepatitis B in preventing the development of hepatocellular carcinoma.”

However, they noted, “it is unclear how these trends are, or will be, affected by direct-acting antivirals for hepatitis C virus ... eradication of hepatitis C virus will prevent the development of cirrhosis and its complications, potentially changing these trends in the next 5-10 years. However, therapy for hepatitis C viral infection cannot modify the statistically significant trends observed related to alcohol or the expected increase in the burden of nonalcoholic fatty liver disease.”

Neither author had any financial disclosure relevant to the work.

[email protected]

SOURCE: Tapper EB et al. BMJ 2018;362:k2817.

Deaths from cirrhosis of the liver in the United States increased by 65% during 1999-2016, while deaths from hepatocellular carcinoma more than doubled.

Cirrhosis mortality showed a sharp rise beginning in 2009, with a 3.6% annual increase driven entirely by a surge in alcoholic cirrhosis among young people aged 25-34 years, Elliot B. Tapper, MD, and Neehar D. Parikh, MD, reported in the BMJ. The uptick in hepatocellular carcinoma, however, was gradual and consistent, with a 2% annual increase felt mostly in older people, wrote Dr. Tapper and Dr. Parikh, both at the University of Michigan, Ann Arbor.

“The increasing mortality due to cirrhosis and hepatocellular carcinoma speaks to the expanding socioeconomic impact of liver disease,” the colleagues wrote. “Adverse trends in liver-related mortality are particularly unfortunate given that in most cases the liver disease is preventable. Understanding the factors associated with mortality due to these conditions will inform how best to allocate resources.”

The study extracted its data from the Vital Statistic Cooperative and the Centers for Disease Control and Prevention. The investigators not only examined raw mortality numbers, but analyzed them for demographic and geographic trends, in analyses that controlled for age.

Cirrhosis

During the study period, 460,760 patients died from cirrhosis (20,661 in 1999 and 34,174 in 2016, an increase of 65.4%).

Men were twice as likely to die from cirrhosis. Young people aged 25-34 years had the highest rate of increase (3.7% over the entire period and 10.5% from 2009 to 2016). This was directly driven by parallel increases in both alcohol use disorder and alcohol-related liver diseases, which increased by about 16% and 10%, respectively, in this group.

Native Americans had the highest mortality rate (25.8 per 100,000) followed by whites (12.7 per 100,000). “Notably, by 2016, cirrhosis accounted for 6.3% [up from 4.3% in 2009] and 7% [up from 5.8% in 2009] of deaths for Native Americans aged 25-34 and 35 or more, respectively,” and 2.3% of all deaths among adults aged 25-34 years, the authors wrote.

The increases were largely felt in the southern and western states (about 13 per 100,000 in each region). The greatest increases occurred in Kentucky (6.8%), New Mexico (6%), Arkansas (5.7%), Indiana (5%), and Alabama (5%). There was a statistically significant 1.2% decrease in deaths from cirrhosis in Maryland.

Hepatocellular carcinoma

Hepatocellular carcinoma accounted for 136,442 deaths during the study period (5,112 in 1999 and 11,073 in 2016 – an increase of 116.6%). This represented an average annual increase of 2%.

Men were four times more likely to die from hepatocellular carcinoma. The increase manifested mostly in older people, decreasing in those younger than 55 years. Mortality was highest among Asians and Pacific Islanders (6 per 100,000), followed by blacks (4.94 per 100,000).

The increases were largely felt in western states, with an overall increase of 4.2 per 100,000.

“Many of the same states with worsening cirrhosis-related mortality also experienced worsening mortality from hepatocellular carcinoma, including Oregon and Iowa,” the authors wrote. But mortality from the disease also increased significantly in Arizona (5.1%), Kansas (4.3%), Kentucky (4%), and Washington (3.9%).

“Potential explanations supported by these data include increasing early detection of hepatocellular carcinoma, application of curative or locoregional therapies, and, because hepatitis B is the principal cause of hepatocellular carcinoma worldwide and among Asian Americans, effectiveness of vaccination programs and the efficacy of antiviral therapy for hepatitis B in preventing the development of hepatocellular carcinoma.”

However, they noted, “it is unclear how these trends are, or will be, affected by direct-acting antivirals for hepatitis C virus ... eradication of hepatitis C virus will prevent the development of cirrhosis and its complications, potentially changing these trends in the next 5-10 years. However, therapy for hepatitis C viral infection cannot modify the statistically significant trends observed related to alcohol or the expected increase in the burden of nonalcoholic fatty liver disease.”

Neither author had any financial disclosure relevant to the work.

[email protected]

SOURCE: Tapper EB et al. BMJ 2018;362:k2817.

ORLANDO – Obese black children are less likely than others to develop nonalcoholic fatty liver disease (NAFLD), but more likely to suffer its consequences if they do,according to a review of 503 adolescents at the Yale University pediatric obesity clinic in New Haven, Conn.

M. Alexander Otto/MDedge News

*This story was updated on 7/20/2018.

[email protected]

SOURCE: Trico D et al. ADA 2018, Abstract 313-OR.

ORLANDO – Obese black children are less likely than others to develop nonalcoholic fatty liver disease (NAFLD), but more likely to suffer its consequences if they do,according to a review of 503 adolescents at the Yale University pediatric obesity clinic in New Haven, Conn.

M. Alexander Otto/MDedge News

*This story was updated on 7/20/2018.

[email protected]

SOURCE: Trico D et al. ADA 2018, Abstract 313-OR.

ORLANDO – Obese black children are less likely than others to develop nonalcoholic fatty liver disease (NAFLD), but more likely to suffer its consequences if they do,according to a review of 503 adolescents at the Yale University pediatric obesity clinic in New Haven, Conn.

M. Alexander Otto/MDedge News

*This story was updated on 7/20/2018.

[email protected]

SOURCE: Trico D et al. ADA 2018, Abstract 313-OR.

Lipid-lowering agents are safe and effective in patients with most liver diseases and should be used when indicated to reduce the risk of cardiovascular disease.

The medications are only contraindicated in patients with decompensated cirrhosis and statin-induced liver injury, Elizabeth Speliotes, MD, PhD, MPH, and her colleagues wrote in an expert review published in Clinical Gastroenterology and Hepatology. In these patients, statin treatment can compound liver damage and should be avoided, wrote Dr. Speliotes and her coauthors.

Because the liver plays a central role in cholesterol production, many clinicians shy away from treating hyperlipidemia in patients with liver disease. But studies consistently show that lipid-lowering drugs improve dyslipidemia in these patients, which significantly improves both high- and low-density lipoproteins and thereby reduces the long-term risk of cardiovascular disease, the authors wrote.

“Furthermore, the liver plays a role in the metabolism of many drugs, including those that are used to treat dyslipidemia,” wrote Dr. Speliotes of the University of Michigan, Ann Arbor. “It is not surprising, therefore, that many practitioners are hesitant to prescribe medicines to treat dyslipidemia in the setting of liver disease.”

Cholesterol targets described in the 2013 American College of Cardiology/American Heart Association guidelines can safely be applied to patients with liver disease. “The guidelines recommend that adults with cardiovascular disease or LDL of 190 mg/dL or higher be treated with high-intensity statins with the goal of reducing LDL levels by 50%,” they said. Patients whose LDL is 189 mg/dL or lower will benefit from moderate-intensity statins, with a target of a 30%-50% decrease in LDL.

The authors described best practice advice for dyslipidemia treatment in six liver diseases: drug-induced liver injury (DILI), nonalcoholic fatty liver disease (NAFLD), viral hepatitis B and C (HBV and HCV), primary biliary cholangitis (PBC), cirrhosis, and posttransplant dyslipidemia.
 

DILI

DILI is characterized by elevations of threefold or more in serum alanine aminotransferase (ALT) or aspartate aminotransferase and at least a doubling of total serum bilirubin with no other identifiable cause of these aberrations except the suspect drug. Statins rarely cause a DILI (1 in 100,000 patients), but can cause transient, benign ALT elevations. Statins should be discontinued if ALT or aspartate aminotransferase levels exceed a tripling of the upper limit of normal with concomitant bilirubin elevations. They should not be prescribed to patients with acute liver failure or decompensated liver disease, but otherwise they are safe for most patients with liver disease.

NAFLD

Many patients with NAFLD also have dyslipidemia. All NAFLD patients have an increased risk of cardiovascular disease, although NAFLD and nonalcoholic steatohepatitis are not traditional cardiovascular risk factors. Nevertheless, statins and the accompanying improvement in dyslipidemia have been shown to decrease cardiovascular mortality in these patients. The IDEAL study, for example, showed that moderate statin treatment with 80 mg atorvastatin was associated with a 44% decreased risk in secondary cardiovascular events. Other studies show similar results.

NAFLD patients with elevated LDL may benefit from ezetimibe as primary or add-on therapy. However, none of the drugs used to treat dyslipidemia will improve NAFLD or nonalcoholic steatohepatitis histology.
 

Viral hepatitis

Hepatitis C virus

Patients with HCV infection often experience decreased serum LDL and total cholesterol. However, these are virally mediated and don’t confer cardiovascular protection. In fact, HCV infections are associated with an increased risk of myocardial infarction. If the patient spontaneously clears the virus, lipids may rebound, so levels should be regularly monitored even if the patient does not need statin therapy.

Hepatitis B virus

HBV also interacts with lipid metabolism and can lead to hyperlipidemia. The American College of Cardiology/American Heart Association guidelines for cardiovascular risk assessment and statin therapy apply to these patients. Statins are safe in patients with either HCV or HBV, who tolerate them well.

PBC

PBC is a chronic autoimmune inflammatory cholestatic disease that is associated with dyslipidemia. These patients exhibit increased serum triglyceride and HDL levels that vary according to PBC stage. About 10% have a significant risk of cardiovascular disease. PBC patients with compensated liver disease can safely tolerate statin treatment, but the drugs should not be given to PBC patients with decompensated liver disease.

Obeticholic acid (OCA) is sometimes used as second-line therapy for PBC; it affects genes that regulate bile acid synthesis, transport, and action. However, the POISE study showed that, while OCA improved PBC symptoms, it was associated with an increase in LDL and total cholesterol and a decrease in HDL. No follow-up studies have determined cardiovascular implications of that change, but OCA should be avoided in patients with active cardiovascular disease or with cardiovascular risk factors.
 

Cirrhosis

Recent work suggests that patients with cirrhosis may face a higher risk of coronary artery disease than was previously thought, although that risk varies widely according to the etiology of the cirrhosis.

Statins are safe and effective in patients with Child-Pugh class A cirrhosis; there are few data on their safety in patients with decompensated cirrhosis. Some guidance for these patients exists in the 2014 recommendations of the Liver Expert Panel, which advised against statin use in patients with Child-Pugh class B or C cirrhosis.

There’s some evidence that statins reduce portal pressure and may reduce the risk of decompensation in patients whose cirrhosis is caused by HCV or HBV infections, but they should not be used for this purpose.
 

Posttransplant dyslipidemia

After liver transplant, more than 60% of patients will develop dyslipidemia; these patients often have obesity or diabetes.

Statins are safe for patients with liver transplant. Concomitant use of calcineurin inhibitors and statins that are metabolized by cytochrome P450 may increase the risk of statin-associated myopathy. Pravastatin and fluvastatin are preferable, because they are metabolized by cytochrome P450 34A.



Neither Dr. Speliotes nor her coauthors had any financial disclosures.

[email protected]

SOURCE: Speliotes EK et al. Clin Gastroenterol Hepatol. 2018 Apr 21. doi: 10.1016/j.cgh.2018.04.023.

Lipid-lowering agents are safe and effective in patients with most liver diseases and should be used when indicated to reduce the risk of cardiovascular disease.

The medications are only contraindicated in patients with decompensated cirrhosis and statin-induced liver injury, Elizabeth Speliotes, MD, PhD, MPH, and her colleagues wrote in an expert review published in Clinical Gastroenterology and Hepatology. In these patients, statin treatment can compound liver damage and should be avoided, wrote Dr. Speliotes and her coauthors.

Because the liver plays a central role in cholesterol production, many clinicians shy away from treating hyperlipidemia in patients with liver disease. But studies consistently show that lipid-lowering drugs improve dyslipidemia in these patients, which significantly improves both high- and low-density lipoproteins and thereby reduces the long-term risk of cardiovascular disease, the authors wrote.

“Furthermore, the liver plays a role in the metabolism of many drugs, including those that are used to treat dyslipidemia,” wrote Dr. Speliotes of the University of Michigan, Ann Arbor. “It is not surprising, therefore, that many practitioners are hesitant to prescribe medicines to treat dyslipidemia in the setting of liver disease.”

Cholesterol targets described in the 2013 American College of Cardiology/American Heart Association guidelines can safely be applied to patients with liver disease. “The guidelines recommend that adults with cardiovascular disease or LDL of 190 mg/dL or higher be treated with high-intensity statins with the goal of reducing LDL levels by 50%,” they said. Patients whose LDL is 189 mg/dL or lower will benefit from moderate-intensity statins, with a target of a 30%-50% decrease in LDL.

The authors described best practice advice for dyslipidemia treatment in six liver diseases: drug-induced liver injury (DILI), nonalcoholic fatty liver disease (NAFLD), viral hepatitis B and C (HBV and HCV), primary biliary cholangitis (PBC), cirrhosis, and posttransplant dyslipidemia.
 

DILI

DILI is characterized by elevations of threefold or more in serum alanine aminotransferase (ALT) or aspartate aminotransferase and at least a doubling of total serum bilirubin with no other identifiable cause of these aberrations except the suspect drug. Statins rarely cause a DILI (1 in 100,000 patients), but can cause transient, benign ALT elevations. Statins should be discontinued if ALT or aspartate aminotransferase levels exceed a tripling of the upper limit of normal with concomitant bilirubin elevations. They should not be prescribed to patients with acute liver failure or decompensated liver disease, but otherwise they are safe for most patients with liver disease.

NAFLD

Many patients with NAFLD also have dyslipidemia. All NAFLD patients have an increased risk of cardiovascular disease, although NAFLD and nonalcoholic steatohepatitis are not traditional cardiovascular risk factors. Nevertheless, statins and the accompanying improvement in dyslipidemia have been shown to decrease cardiovascular mortality in these patients. The IDEAL study, for example, showed that moderate statin treatment with 80 mg atorvastatin was associated with a 44% decreased risk in secondary cardiovascular events. Other studies show similar results.

NAFLD patients with elevated LDL may benefit from ezetimibe as primary or add-on therapy. However, none of the drugs used to treat dyslipidemia will improve NAFLD or nonalcoholic steatohepatitis histology.
 

Viral hepatitis

Hepatitis C virus

Patients with HCV infection often experience decreased serum LDL and total cholesterol. However, these are virally mediated and don’t confer cardiovascular protection. In fact, HCV infections are associated with an increased risk of myocardial infarction. If the patient spontaneously clears the virus, lipids may rebound, so levels should be regularly monitored even if the patient does not need statin therapy.

Hepatitis B virus

HBV also interacts with lipid metabolism and can lead to hyperlipidemia. The American College of Cardiology/American Heart Association guidelines for cardiovascular risk assessment and statin therapy apply to these patients. Statins are safe in patients with either HCV or HBV, who tolerate them well.

PBC

PBC is a chronic autoimmune inflammatory cholestatic disease that is associated with dyslipidemia. These patients exhibit increased serum triglyceride and HDL levels that vary according to PBC stage. About 10% have a significant risk of cardiovascular disease. PBC patients with compensated liver disease can safely tolerate statin treatment, but the drugs should not be given to PBC patients with decompensated liver disease.

Obeticholic acid (OCA) is sometimes used as second-line therapy for PBC; it affects genes that regulate bile acid synthesis, transport, and action. However, the POISE study showed that, while OCA improved PBC symptoms, it was associated with an increase in LDL and total cholesterol and a decrease in HDL. No follow-up studies have determined cardiovascular implications of that change, but OCA should be avoided in patients with active cardiovascular disease or with cardiovascular risk factors.
 

Cirrhosis

Recent work suggests that patients with cirrhosis may face a higher risk of coronary artery disease than was previously thought, although that risk varies widely according to the etiology of the cirrhosis.

Statins are safe and effective in patients with Child-Pugh class A cirrhosis; there are few data on their safety in patients with decompensated cirrhosis. Some guidance for these patients exists in the 2014 recommendations of the Liver Expert Panel, which advised against statin use in patients with Child-Pugh class B or C cirrhosis.

There’s some evidence that statins reduce portal pressure and may reduce the risk of decompensation in patients whose cirrhosis is caused by HCV or HBV infections, but they should not be used for this purpose.
 

Posttransplant dyslipidemia

After liver transplant, more than 60% of patients will develop dyslipidemia; these patients often have obesity or diabetes.

Statins are safe for patients with liver transplant. Concomitant use of calcineurin inhibitors and statins that are metabolized by cytochrome P450 may increase the risk of statin-associated myopathy. Pravastatin and fluvastatin are preferable, because they are metabolized by cytochrome P450 34A.



Neither Dr. Speliotes nor her coauthors had any financial disclosures.

[email protected]

SOURCE: Speliotes EK et al. Clin Gastroenterol Hepatol. 2018 Apr 21. doi: 10.1016/j.cgh.2018.04.023.

Lipid-lowering agents are safe and effective in patients with most liver diseases and should be used when indicated to reduce the risk of cardiovascular disease.

The medications are only contraindicated in patients with decompensated cirrhosis and statin-induced liver injury, Elizabeth Speliotes, MD, PhD, MPH, and her colleagues wrote in an expert review published in Clinical Gastroenterology and Hepatology. In these patients, statin treatment can compound liver damage and should be avoided, wrote Dr. Speliotes and her coauthors.

Because the liver plays a central role in cholesterol production, many clinicians shy away from treating hyperlipidemia in patients with liver disease. But studies consistently show that lipid-lowering drugs improve dyslipidemia in these patients, which significantly improves both high- and low-density lipoproteins and thereby reduces the long-term risk of cardiovascular disease, the authors wrote.

“Furthermore, the liver plays a role in the metabolism of many drugs, including those that are used to treat dyslipidemia,” wrote Dr. Speliotes of the University of Michigan, Ann Arbor. “It is not surprising, therefore, that many practitioners are hesitant to prescribe medicines to treat dyslipidemia in the setting of liver disease.”

Cholesterol targets described in the 2013 American College of Cardiology/American Heart Association guidelines can safely be applied to patients with liver disease. “The guidelines recommend that adults with cardiovascular disease or LDL of 190 mg/dL or higher be treated with high-intensity statins with the goal of reducing LDL levels by 50%,” they said. Patients whose LDL is 189 mg/dL or lower will benefit from moderate-intensity statins, with a target of a 30%-50% decrease in LDL.

The authors described best practice advice for dyslipidemia treatment in six liver diseases: drug-induced liver injury (DILI), nonalcoholic fatty liver disease (NAFLD), viral hepatitis B and C (HBV and HCV), primary biliary cholangitis (PBC), cirrhosis, and posttransplant dyslipidemia.
 

DILI

DILI is characterized by elevations of threefold or more in serum alanine aminotransferase (ALT) or aspartate aminotransferase and at least a doubling of total serum bilirubin with no other identifiable cause of these aberrations except the suspect drug. Statins rarely cause a DILI (1 in 100,000 patients), but can cause transient, benign ALT elevations. Statins should be discontinued if ALT or aspartate aminotransferase levels exceed a tripling of the upper limit of normal with concomitant bilirubin elevations. They should not be prescribed to patients with acute liver failure or decompensated liver disease, but otherwise they are safe for most patients with liver disease.

NAFLD

Many patients with NAFLD also have dyslipidemia. All NAFLD patients have an increased risk of cardiovascular disease, although NAFLD and nonalcoholic steatohepatitis are not traditional cardiovascular risk factors. Nevertheless, statins and the accompanying improvement in dyslipidemia have been shown to decrease cardiovascular mortality in these patients. The IDEAL study, for example, showed that moderate statin treatment with 80 mg atorvastatin was associated with a 44% decreased risk in secondary cardiovascular events. Other studies show similar results.

NAFLD patients with elevated LDL may benefit from ezetimibe as primary or add-on therapy. However, none of the drugs used to treat dyslipidemia will improve NAFLD or nonalcoholic steatohepatitis histology.
 

Viral hepatitis

Hepatitis C virus

Patients with HCV infection often experience decreased serum LDL and total cholesterol. However, these are virally mediated and don’t confer cardiovascular protection. In fact, HCV infections are associated with an increased risk of myocardial infarction. If the patient spontaneously clears the virus, lipids may rebound, so levels should be regularly monitored even if the patient does not need statin therapy.

Hepatitis B virus

HBV also interacts with lipid metabolism and can lead to hyperlipidemia. The American College of Cardiology/American Heart Association guidelines for cardiovascular risk assessment and statin therapy apply to these patients. Statins are safe in patients with either HCV or HBV, who tolerate them well.

PBC

PBC is a chronic autoimmune inflammatory cholestatic disease that is associated with dyslipidemia. These patients exhibit increased serum triglyceride and HDL levels that vary according to PBC stage. About 10% have a significant risk of cardiovascular disease. PBC patients with compensated liver disease can safely tolerate statin treatment, but the drugs should not be given to PBC patients with decompensated liver disease.

Obeticholic acid (OCA) is sometimes used as second-line therapy for PBC; it affects genes that regulate bile acid synthesis, transport, and action. However, the POISE study showed that, while OCA improved PBC symptoms, it was associated with an increase in LDL and total cholesterol and a decrease in HDL. No follow-up studies have determined cardiovascular implications of that change, but OCA should be avoided in patients with active cardiovascular disease or with cardiovascular risk factors.
 

Cirrhosis

Recent work suggests that patients with cirrhosis may face a higher risk of coronary artery disease than was previously thought, although that risk varies widely according to the etiology of the cirrhosis.

Statins are safe and effective in patients with Child-Pugh class A cirrhosis; there are few data on their safety in patients with decompensated cirrhosis. Some guidance for these patients exists in the 2014 recommendations of the Liver Expert Panel, which advised against statin use in patients with Child-Pugh class B or C cirrhosis.

There’s some evidence that statins reduce portal pressure and may reduce the risk of decompensation in patients whose cirrhosis is caused by HCV or HBV infections, but they should not be used for this purpose.
 

Posttransplant dyslipidemia

After liver transplant, more than 60% of patients will develop dyslipidemia; these patients often have obesity or diabetes.

Statins are safe for patients with liver transplant. Concomitant use of calcineurin inhibitors and statins that are metabolized by cytochrome P450 may increase the risk of statin-associated myopathy. Pravastatin and fluvastatin are preferable, because they are metabolized by cytochrome P450 34A.



Neither Dr. Speliotes nor her coauthors had any financial disclosures.

[email protected]

SOURCE: Speliotes EK et al. Clin Gastroenterol Hepatol. 2018 Apr 21. doi: 10.1016/j.cgh.2018.04.023.

WASHINGTON – Patients with cirrhosis who received secondary prophylaxis for spontaneous bacterial peritonitis had better outcomes than patients who received primary prophylaxis in a review of more than 300 patients at 14 North American centers.

The mortality rate during follow-up of cirrhotic patients hospitalized while on primary prophylaxis against spontaneous bacterial peritonitis (SBP) was 19%, compared with a 9% death rate among cirrhotic patients hospitalized while on secondary prophylaxis, Jasmohan S. Bajaj, MD, said at the annual Digestive Disease Week^®.

Although the findings raised questions about the value of primary prophylaxis with an antibiotic in cirrhotic patients for preventing a first episode of SBP, secondary prophylaxis remains an important precaution.

“There is clear benefit from secondary prophylaxis; please use it. The data supporting it are robust,” said Dr. Bajaj, a hepatologist at Virginia Commonwealth University, Richmond. In contrast, the evidence supporting benefits from primary prophylaxis is weaker, he said. The findings were also counterintuitive, because patients who experience repeat episodes of SBP might be expected to fare worse than those hit by SBP just once.

Dr. Bajaj also acknowledged the substantial confounding that distinguishes patients with cirrhosis receiving primary or secondary prophylaxis, and the difficulty of fully adjusting for all this confounding by statistical analyses. “There is selective bias for secondary prevention, and there is no way to correct for this,” he explained. Patients who need secondary prophylaxis have “weathered the storm” of a first episode of SBP, which might have exerted selection pressure, and might have triggered important immunologic changes, Dr. Bajaj suggested.

The findings also raised concerns about the appropriateness of existing antibiotic prophylaxis for SBP. The patients included in the study all received similar regimens regardless of whether they were on primary or secondary prophylaxis. Three-quarters of primary prophylaxis patients received a fluoroquinolone, as did 81% on secondary prophylaxis. All other patients received trimethoprim-sulfamethoxazole. These regimens are aimed at preventing gram-negative infections; however, an increasing number of SBP episodes are caused by either gram-positive pathogens or strains of gram-negative bacteria or fungi resistant to standard antibiotics.

Clinicians “absolutely” need to rethink their approach to both primary and secondary prophylaxis, Dr. Bajaj said. “As fast as treatment evolves, bacteria evolve 20 times faster. We need to find ways to prevent infections without antibiotic prophylaxis, whatever that might be.”

The study used data collected prospectively from patients with cirrhosis at any of 12 U.S. and 2 Canadian centers that belonged to the North American Consortium for the Study of End-Stage Liver Disease. Among 2,731 cirrhotic patients admitted nonelectively, 492 (18%) were on antibiotic prophylaxis at the time of their admission, 305 for primary prophylaxis and 187 for secondary prophylaxis. Dr. Bajaj and his associates used both the baseline model for end-stage liver disease score and serum albumin level of each patient to focus on a group of 154 primary prophylaxis and 154 secondary prophylaxis patients who were similar by these two criteria. Despite this matching, the two subgroups showed statistically significant differences at the time of their index hospitalization for several important clinical measures.

The secondary prophylaxis patients were significantly more likely to have been hospitalized within the previous 6 months, significantly more likely to be on treatment for hepatic encephalopathy at the time of their index admission, and significantly less likely to have systemic inflammatory response syndrome on admission.

Also, at the time of admission, secondary prophylaxis patients were significantly more likely to have an infection of any type at a rate of 40%, compared with 24% among those on primary prophylaxis, as well as a significantly higher rate of SBP at 16%, compared with a 9% rate among the primary prophylaxis patients. During hospitalization, nosocomial SBP occurred significantly more often among the secondary prophylaxis patients at a rate of 6%, compared with a 0.5% rate among those on primary prophylaxis.

Despite these between-group differences, the average duration of hospitalization, and the average incidence of acute-on-chronic liver failure during follow-up out to 30 days post discharge was similar in the two subgroups. And the patients on secondary prophylaxis showed better outcomes by two important parameters: mortality during hospitalization and 30 days post discharge; and the incidence of ICU admission during hospitalization, which was significantly greater for primary prophylaxis patients at 31%, compared with 21% among the secondary prophylaxis patients, Dr. Bajaj reported.

Dr. Bajaj has been a consultant for Norgine and Salix Pharmaceuticals and has received research support from Grifols and Salix Pharmaceuticals.

[email protected]

WASHINGTON – Patients with cirrhosis who received secondary prophylaxis for spontaneous bacterial peritonitis had better outcomes than patients who received primary prophylaxis in a review of more than 300 patients at 14 North American centers.

The mortality rate during follow-up of cirrhotic patients hospitalized while on primary prophylaxis against spontaneous bacterial peritonitis (SBP) was 19%, compared with a 9% death rate among cirrhotic patients hospitalized while on secondary prophylaxis, Jasmohan S. Bajaj, MD, said at the annual Digestive Disease Week^®.

Although the findings raised questions about the value of primary prophylaxis with an antibiotic in cirrhotic patients for preventing a first episode of SBP, secondary prophylaxis remains an important precaution.

“There is clear benefit from secondary prophylaxis; please use it. The data supporting it are robust,” said Dr. Bajaj, a hepatologist at Virginia Commonwealth University, Richmond. In contrast, the evidence supporting benefits from primary prophylaxis is weaker, he said. The findings were also counterintuitive, because patients who experience repeat episodes of SBP might be expected to fare worse than those hit by SBP just once.

Dr. Bajaj also acknowledged the substantial confounding that distinguishes patients with cirrhosis receiving primary or secondary prophylaxis, and the difficulty of fully adjusting for all this confounding by statistical analyses. “There is selective bias for secondary prevention, and there is no way to correct for this,” he explained. Patients who need secondary prophylaxis have “weathered the storm” of a first episode of SBP, which might have exerted selection pressure, and might have triggered important immunologic changes, Dr. Bajaj suggested.

The findings also raised concerns about the appropriateness of existing antibiotic prophylaxis for SBP. The patients included in the study all received similar regimens regardless of whether they were on primary or secondary prophylaxis. Three-quarters of primary prophylaxis patients received a fluoroquinolone, as did 81% on secondary prophylaxis. All other patients received trimethoprim-sulfamethoxazole. These regimens are aimed at preventing gram-negative infections; however, an increasing number of SBP episodes are caused by either gram-positive pathogens or strains of gram-negative bacteria or fungi resistant to standard antibiotics.

Clinicians “absolutely” need to rethink their approach to both primary and secondary prophylaxis, Dr. Bajaj said. “As fast as treatment evolves, bacteria evolve 20 times faster. We need to find ways to prevent infections without antibiotic prophylaxis, whatever that might be.”

The study used data collected prospectively from patients with cirrhosis at any of 12 U.S. and 2 Canadian centers that belonged to the North American Consortium for the Study of End-Stage Liver Disease. Among 2,731 cirrhotic patients admitted nonelectively, 492 (18%) were on antibiotic prophylaxis at the time of their admission, 305 for primary prophylaxis and 187 for secondary prophylaxis. Dr. Bajaj and his associates used both the baseline model for end-stage liver disease score and serum albumin level of each patient to focus on a group of 154 primary prophylaxis and 154 secondary prophylaxis patients who were similar by these two criteria. Despite this matching, the two subgroups showed statistically significant differences at the time of their index hospitalization for several important clinical measures.

The secondary prophylaxis patients were significantly more likely to have been hospitalized within the previous 6 months, significantly more likely to be on treatment for hepatic encephalopathy at the time of their index admission, and significantly less likely to have systemic inflammatory response syndrome on admission.

Also, at the time of admission, secondary prophylaxis patients were significantly more likely to have an infection of any type at a rate of 40%, compared with 24% among those on primary prophylaxis, as well as a significantly higher rate of SBP at 16%, compared with a 9% rate among the primary prophylaxis patients. During hospitalization, nosocomial SBP occurred significantly more often among the secondary prophylaxis patients at a rate of 6%, compared with a 0.5% rate among those on primary prophylaxis.

Despite these between-group differences, the average duration of hospitalization, and the average incidence of acute-on-chronic liver failure during follow-up out to 30 days post discharge was similar in the two subgroups. And the patients on secondary prophylaxis showed better outcomes by two important parameters: mortality during hospitalization and 30 days post discharge; and the incidence of ICU admission during hospitalization, which was significantly greater for primary prophylaxis patients at 31%, compared with 21% among the secondary prophylaxis patients, Dr. Bajaj reported.

Dr. Bajaj has been a consultant for Norgine and Salix Pharmaceuticals and has received research support from Grifols and Salix Pharmaceuticals.

[email protected]

WASHINGTON – Patients with cirrhosis who received secondary prophylaxis for spontaneous bacterial peritonitis had better outcomes than patients who received primary prophylaxis in a review of more than 300 patients at 14 North American centers.

The mortality rate during follow-up of cirrhotic patients hospitalized while on primary prophylaxis against spontaneous bacterial peritonitis (SBP) was 19%, compared with a 9% death rate among cirrhotic patients hospitalized while on secondary prophylaxis, Jasmohan S. Bajaj, MD, said at the annual Digestive Disease Week^®.

Although the findings raised questions about the value of primary prophylaxis with an antibiotic in cirrhotic patients for preventing a first episode of SBP, secondary prophylaxis remains an important precaution.

“There is clear benefit from secondary prophylaxis; please use it. The data supporting it are robust,” said Dr. Bajaj, a hepatologist at Virginia Commonwealth University, Richmond. In contrast, the evidence supporting benefits from primary prophylaxis is weaker, he said. The findings were also counterintuitive, because patients who experience repeat episodes of SBP might be expected to fare worse than those hit by SBP just once.

Dr. Bajaj also acknowledged the substantial confounding that distinguishes patients with cirrhosis receiving primary or secondary prophylaxis, and the difficulty of fully adjusting for all this confounding by statistical analyses. “There is selective bias for secondary prevention, and there is no way to correct for this,” he explained. Patients who need secondary prophylaxis have “weathered the storm” of a first episode of SBP, which might have exerted selection pressure, and might have triggered important immunologic changes, Dr. Bajaj suggested.

The findings also raised concerns about the appropriateness of existing antibiotic prophylaxis for SBP. The patients included in the study all received similar regimens regardless of whether they were on primary or secondary prophylaxis. Three-quarters of primary prophylaxis patients received a fluoroquinolone, as did 81% on secondary prophylaxis. All other patients received trimethoprim-sulfamethoxazole. These regimens are aimed at preventing gram-negative infections; however, an increasing number of SBP episodes are caused by either gram-positive pathogens or strains of gram-negative bacteria or fungi resistant to standard antibiotics.

Clinicians “absolutely” need to rethink their approach to both primary and secondary prophylaxis, Dr. Bajaj said. “As fast as treatment evolves, bacteria evolve 20 times faster. We need to find ways to prevent infections without antibiotic prophylaxis, whatever that might be.”

The study used data collected prospectively from patients with cirrhosis at any of 12 U.S. and 2 Canadian centers that belonged to the North American Consortium for the Study of End-Stage Liver Disease. Among 2,731 cirrhotic patients admitted nonelectively, 492 (18%) were on antibiotic prophylaxis at the time of their admission, 305 for primary prophylaxis and 187 for secondary prophylaxis. Dr. Bajaj and his associates used both the baseline model for end-stage liver disease score and serum albumin level of each patient to focus on a group of 154 primary prophylaxis and 154 secondary prophylaxis patients who were similar by these two criteria. Despite this matching, the two subgroups showed statistically significant differences at the time of their index hospitalization for several important clinical measures.

The secondary prophylaxis patients were significantly more likely to have been hospitalized within the previous 6 months, significantly more likely to be on treatment for hepatic encephalopathy at the time of their index admission, and significantly less likely to have systemic inflammatory response syndrome on admission.

Also, at the time of admission, secondary prophylaxis patients were significantly more likely to have an infection of any type at a rate of 40%, compared with 24% among those on primary prophylaxis, as well as a significantly higher rate of SBP at 16%, compared with a 9% rate among the primary prophylaxis patients. During hospitalization, nosocomial SBP occurred significantly more often among the secondary prophylaxis patients at a rate of 6%, compared with a 0.5% rate among those on primary prophylaxis.

Despite these between-group differences, the average duration of hospitalization, and the average incidence of acute-on-chronic liver failure during follow-up out to 30 days post discharge was similar in the two subgroups. And the patients on secondary prophylaxis showed better outcomes by two important parameters: mortality during hospitalization and 30 days post discharge; and the incidence of ICU admission during hospitalization, which was significantly greater for primary prophylaxis patients at 31%, compared with 21% among the secondary prophylaxis patients, Dr. Bajaj reported.

Dr. Bajaj has been a consultant for Norgine and Salix Pharmaceuticals and has received research support from Grifols and Salix Pharmaceuticals.

[email protected]