Hepatology

A transmembrane glycoprotein labeled neuropilin-1 may be a diagnostic biomarker for hepatocellular carcinoma.

In a series of experiments using HCC tissues and cell lines, as well as serum samples from patients with other malignancies or hepatitis, Jiafei Lin, MD, from Shanghai Jiaotong University, Shanghai, China, and colleagues found that neuropilin-1 (NRP1) was up-regulated in hepatocellular carcinoma (HCC) and promotes tumor growth.

“Notably, the concentrations of serum NRP1 in the HCC patients were much higher than those of hepatitis B, hepatitis C, cirrhosis, breast cancer, colon cancer, gastric cancer, and lung cancer patients,” they wrote in the journal Clinica Chimica Acta.

They also found that NRP1 has a high degree of sensitivity and specificity for HCC, and suggested that NRP1 could replace alpha fetoprotein (AFP) for early clinical diagnosis of HCC.

They first showed that NRP1 was directly regulated by TEAD, a family of transcription factors essential for developmental processes. The experiments in HCC cell lines showed that messenger RNA levels of NRP1 were increased when TEAD was overexpressed, and decreased when TEAD was knocked down. The experiments also suggested that TEAD binds directly to the promoter of NRP1 to stimulate its transcription in HCC cells.

The investigators then sought to demonstrate that NRP1 promotes tumor development and growth in HCC by testing expression of the protein in both normal liver and HCC tissue samples.

“NRP1 was found highly up-regulated in HCC tissues compared to normal tissues. Moreover, NRP1 was recruited to the membrane in HCC tissues, whereas this protein was not detected in normal tissues,” they wrote.

Furthermore, when they zeroed in on NRP1 using two different short hairpin RNAs to silence its expression, they found that knocking down NRP1 suppressed the viability of tumor cells and inhibited colony formation while also ramping up programmed cell death. Taken together, the data indicate that NRP1 is highly expressed in HCC and promotes tumorigenesis.

They then showed that NRP1 serum concentrations were significantly higher in samples from patients with HCC than in those from healthy individuals or patients with hepatitis B, hepatitis C, cirrhosis, breast cancer, colon cancer, gastric cancer, or lung cancer. In addition, higher NRP1 concentrations were significantly associated with higher HCC tumor stages.

The investigators then looked at the relationship between serum NRP1 and standard liver function markers in HCC, and found that NRP1 serum levels significantly correlated with gamma-glutamyltransferase, albumin, bile acid, ALT, AST, AFP, and prealbumin levels, but not total bilirubin or total protein levels.

Finally, they demonstrated that serum NRP1 is a better diagnostic marker than AFP, with an area under the receiver operating characteristic curve of 0.971, compared with 0.862 for AFP. At an NRP1 cutoff of 68 pg/mL, NRP1 had a sensitivity of 93.7%, and a specificity of 98.7%. Combining NRP1 with AFP only slightly improved the diagnostic accuracy.

“These results indicate that the single use of NRP1 is a promising choice for the diagnosis of HCC,” the investigators wrote.

They noted that the most of the study subjects were of Han Chinese origin, and that the results need to be validated in people of other ethnicities.

The study was supported by the National Natural Science Foundation of China. Potential conflicts of interest were not reported.

SOURCE: Lin J et al. Clin Chim Acta. 2018;485:158-65.

A transmembrane glycoprotein labeled neuropilin-1 may be a diagnostic biomarker for hepatocellular carcinoma.

In a series of experiments using HCC tissues and cell lines, as well as serum samples from patients with other malignancies or hepatitis, Jiafei Lin, MD, from Shanghai Jiaotong University, Shanghai, China, and colleagues found that neuropilin-1 (NRP1) was up-regulated in hepatocellular carcinoma (HCC) and promotes tumor growth.

“Notably, the concentrations of serum NRP1 in the HCC patients were much higher than those of hepatitis B, hepatitis C, cirrhosis, breast cancer, colon cancer, gastric cancer, and lung cancer patients,” they wrote in the journal Clinica Chimica Acta.

They also found that NRP1 has a high degree of sensitivity and specificity for HCC, and suggested that NRP1 could replace alpha fetoprotein (AFP) for early clinical diagnosis of HCC.

They first showed that NRP1 was directly regulated by TEAD, a family of transcription factors essential for developmental processes. The experiments in HCC cell lines showed that messenger RNA levels of NRP1 were increased when TEAD was overexpressed, and decreased when TEAD was knocked down. The experiments also suggested that TEAD binds directly to the promoter of NRP1 to stimulate its transcription in HCC cells.

The investigators then sought to demonstrate that NRP1 promotes tumor development and growth in HCC by testing expression of the protein in both normal liver and HCC tissue samples.

“NRP1 was found highly up-regulated in HCC tissues compared to normal tissues. Moreover, NRP1 was recruited to the membrane in HCC tissues, whereas this protein was not detected in normal tissues,” they wrote.

Furthermore, when they zeroed in on NRP1 using two different short hairpin RNAs to silence its expression, they found that knocking down NRP1 suppressed the viability of tumor cells and inhibited colony formation while also ramping up programmed cell death. Taken together, the data indicate that NRP1 is highly expressed in HCC and promotes tumorigenesis.

They then showed that NRP1 serum concentrations were significantly higher in samples from patients with HCC than in those from healthy individuals or patients with hepatitis B, hepatitis C, cirrhosis, breast cancer, colon cancer, gastric cancer, or lung cancer. In addition, higher NRP1 concentrations were significantly associated with higher HCC tumor stages.

The investigators then looked at the relationship between serum NRP1 and standard liver function markers in HCC, and found that NRP1 serum levels significantly correlated with gamma-glutamyltransferase, albumin, bile acid, ALT, AST, AFP, and prealbumin levels, but not total bilirubin or total protein levels.

Finally, they demonstrated that serum NRP1 is a better diagnostic marker than AFP, with an area under the receiver operating characteristic curve of 0.971, compared with 0.862 for AFP. At an NRP1 cutoff of 68 pg/mL, NRP1 had a sensitivity of 93.7%, and a specificity of 98.7%. Combining NRP1 with AFP only slightly improved the diagnostic accuracy.

“These results indicate that the single use of NRP1 is a promising choice for the diagnosis of HCC,” the investigators wrote.

They noted that the most of the study subjects were of Han Chinese origin, and that the results need to be validated in people of other ethnicities.

The study was supported by the National Natural Science Foundation of China. Potential conflicts of interest were not reported.

SOURCE: Lin J et al. Clin Chim Acta. 2018;485:158-65.

A transmembrane glycoprotein labeled neuropilin-1 may be a diagnostic biomarker for hepatocellular carcinoma.

In a series of experiments using HCC tissues and cell lines, as well as serum samples from patients with other malignancies or hepatitis, Jiafei Lin, MD, from Shanghai Jiaotong University, Shanghai, China, and colleagues found that neuropilin-1 (NRP1) was up-regulated in hepatocellular carcinoma (HCC) and promotes tumor growth.

“Notably, the concentrations of serum NRP1 in the HCC patients were much higher than those of hepatitis B, hepatitis C, cirrhosis, breast cancer, colon cancer, gastric cancer, and lung cancer patients,” they wrote in the journal Clinica Chimica Acta.

They also found that NRP1 has a high degree of sensitivity and specificity for HCC, and suggested that NRP1 could replace alpha fetoprotein (AFP) for early clinical diagnosis of HCC.

They first showed that NRP1 was directly regulated by TEAD, a family of transcription factors essential for developmental processes. The experiments in HCC cell lines showed that messenger RNA levels of NRP1 were increased when TEAD was overexpressed, and decreased when TEAD was knocked down. The experiments also suggested that TEAD binds directly to the promoter of NRP1 to stimulate its transcription in HCC cells.

The investigators then sought to demonstrate that NRP1 promotes tumor development and growth in HCC by testing expression of the protein in both normal liver and HCC tissue samples.

“NRP1 was found highly up-regulated in HCC tissues compared to normal tissues. Moreover, NRP1 was recruited to the membrane in HCC tissues, whereas this protein was not detected in normal tissues,” they wrote.

Furthermore, when they zeroed in on NRP1 using two different short hairpin RNAs to silence its expression, they found that knocking down NRP1 suppressed the viability of tumor cells and inhibited colony formation while also ramping up programmed cell death. Taken together, the data indicate that NRP1 is highly expressed in HCC and promotes tumorigenesis.

They then showed that NRP1 serum concentrations were significantly higher in samples from patients with HCC than in those from healthy individuals or patients with hepatitis B, hepatitis C, cirrhosis, breast cancer, colon cancer, gastric cancer, or lung cancer. In addition, higher NRP1 concentrations were significantly associated with higher HCC tumor stages.

The investigators then looked at the relationship between serum NRP1 and standard liver function markers in HCC, and found that NRP1 serum levels significantly correlated with gamma-glutamyltransferase, albumin, bile acid, ALT, AST, AFP, and prealbumin levels, but not total bilirubin or total protein levels.

Finally, they demonstrated that serum NRP1 is a better diagnostic marker than AFP, with an area under the receiver operating characteristic curve of 0.971, compared with 0.862 for AFP. At an NRP1 cutoff of 68 pg/mL, NRP1 had a sensitivity of 93.7%, and a specificity of 98.7%. Combining NRP1 with AFP only slightly improved the diagnostic accuracy.

“These results indicate that the single use of NRP1 is a promising choice for the diagnosis of HCC,” the investigators wrote.

They noted that the most of the study subjects were of Han Chinese origin, and that the results need to be validated in people of other ethnicities.

The study was supported by the National Natural Science Foundation of China. Potential conflicts of interest were not reported.

SOURCE: Lin J et al. Clin Chim Acta. 2018;485:158-65.

CASE

A 44-year-old nurse describes persistent fatigue and itching over the last 2 months. She is taking ramipril 5 mg/d for hypertension and has a family history of rheumatic disease. Lab tests reveal a recurrent moderate elevation of gamma glutamyl-transpeptidase (gGT; 75 U/L) associated with, on some occasions, mild elevation of alanine aminotransferase (ALT) levels (100 U/L) of unknown origin. She has no history of hepatitis virus infection, hepatotoxic medications, or alcohol intake. She is overweight with a body mass index of 28.5 kg/m² and a waist circumference of 99 cm (39 inches). Liver ultrasonography detects an enlarged liver with diffuse echostructure dishomogeneity, but no signs of cirrhosis or portal hypertension. The patient’s biliary tree is not dilated.

How would you proceed with the care of this patient?

Cholestasis is characterized by the alteration of bile flow through any part of the biliary system, from the hepatocyte basocellular membrane to the duodenum. The condition is classified as intrahepatic when the cause is a defect of hepatocellular function or obstruction of the biliary tree within the liver. The extrahepatic form includes all conditions obstructing bile flow in the main biliary tract (choledochus, common bile duct).

Suspect intrahepatic cholestasis in a patient with chronic itching, normal transaminases, and mildly elevated gamma glutamyl-transpeptidase.

The key to successfully managing cholestasis lies in the early identification of subtle signs and symptoms before serious complications can arise. In the review that follows, we provide guidance for evaluating laboratory and imaging results that are vital to the accurate diagnosis of intrahepatic and extrahepatic cholestasis. We also detail treatment recommendations.

Clues—subtle and otherwise—of cholestasis

Clinical features of cholestasis include fatigue and itching all over the skin. The latter likely is caused by induction of the enzyme autotaxin, which produces the neuronal activator lysophosphatidic acid. Retention of pruritogenic substances that normally are excreted into bile might contribute to pruritus as well.¹ Jaundice, dark urine, and pale and fatty stools occur with advanced disease. However, a cholestatic condition can be detected in asymptomatic patients with elevated biochemical markers.

Continue to: Mildly elevated gGT and/or alkaline phosphatase (ALP)

Mildly elevated gGT and/or alkaline phosphatase (ALP) (0.5-2.5 times the upper normal limit [UNL] or 19-95 U/L and 60-300 U/L, respectively²) in the presence of normal transaminase levels (<20 U/L) in an asymptomatic patient can indicate chronic liver disease. Signs suggestive of significant liver disease have been reported in many patients with gGT or ALP elevation with good sensitivity (65%) and specificity (83%) for a diagnosis of intrahepatic cholestasis.³ However, because abnormal gGT values are common and often resolve spontaneously, family physicians (FPs) may pay little attention to this finding, thus missing an opportunity for early identification and treatment.

Patient’s history can provide important clues

A thorough patient history is especially important when cholestasis is suspected. Details about the patient’s occupation, environment, and lifestyle are key, as are the specifics of prescribed or over-the-counter medications and supplements that could be hepatotoxic (TABLE 4¹⁰). A number of exogenous substances can cause liver injury, and the use of some herbal products (senna, black cohosh, greater celandine, kava) have been linked to hepatitis and cholestasis.¹¹ Ask patients about alcohol use and history of conditions associated with liver disease, such as diabetes, hyperlipidemia, and thyroid disorders.

Continue to: Indicators pointing to cholestasis? It's time for ultrasonography

Abdominal ultrasonography is a first-line diagnostic tool for cholestasis.

While biopsy is considered the gold standard for diagnosing and staging chronic cholestatic liver disease and can exclude an extrahepatic obstruction, it should be employed only if blood tests have been confirmed, second-level tests have been performed, and ultrasound is inconclusive.¹² (More on biopsy in a bit.)

Ultrasonography is a low-cost, widely available, noninvasive test that allows easy identification of extrahepatic dilatation of the biliary tree and sometimes the underlying cause, as well. Ultrasonography identifies extrahepatic cholestasis by allowing visualization of an enlarged choledochus (>7 mm) or common hepatic duct (>5 mm) and an intrahepatic bile duct diameter that is more than 40% larger than adjacent branches of the portal vein.¹³ However, ultrasonography has a low diagnostic sensitivity for many conditions (eg, 15% to 89% for detecting common bile duct stones),¹⁴ requiring other diagnostic procedures, such as endoscopic retrograde cholangiopancreatography (ERCP) or magnetic resonance cholangiopancreatography (MRCP), before reaching a diagnosis.

For asymptomatic patients with cirrhosis or those at an early stage of liver disease, ultrasound at 6-month intervals combined with serum liver function tests can be useful to track disease progression and screen for hepatocellular carcinoma or cholangiocarcinoma.^15,16

New noninvasive methods. Noninvasive tools for evaluating the presence and severity of liver fibrosis and for differentiating cirrhosis from noncirrhotic conditions have positive predictive values >85% to 90% for some chronic liver diseases.¹⁷ Transient elastography, which assesses liver stiffness, is one such method. Although it is often used successfully, morbid obesity, small intercostal spaces, and ascites limit its diagnostic capability.¹⁸ Recently, some questions about the validity of elastography to assess the extent of fibrosis in patients with chronic cholestatic conditions have been reported.^19,20

Suspect intrahepatic cholestasis? Your next steps

If imaging techniques do not show bile duct obstruction and you suspect the intrahepatic form, second-level tests could have strategic importance. This is where antimitochondrial antibodies (AMAs) come in. AMAs are immunoglobulins (IgG and IgM) directed against mitochondrial antigens. They are important markers for PBC, which is a T-lymphocyte-mediated attack on small intralobular bile ducts resulting in their gradual destruction and eventual disappearance. The sustained loss of intralobular bile ducts leads to signs and symptoms of cholestasis and eventually results in cirrhosis and liver failure.

AMA serum levels show high sensitivity and specificity (90% and 95%, respectively) for PBC.²¹ Some PBC patients (<5%) show histologic confirmation of the disease, but have negative AMA tests (AMA negative PBC or autoimmune cholangitis).²² Therefore, according to the American Association for the Study of Liver Diseases, diagnosis of PBC is guided by the combination of serologic, biochemical, and histologic criteria.²³ Many PBC patients with or without a positive AMA (≥1:40) also have positive circulating antinuclear antibodies (ANA; ≥1:80). The recent availability of lab tests for antibodies (anti-M2, anti-gp120, anti-sp100) has allowed identification of subgroups of patients who have a more aggressive form of PBC. Patients with PBC often have elevated levels of circulating IgM (>280 mg/dL).

Continue to: Other circulating antibodies

Other circulating antibodies can help discriminate among cholestatic disorders. In particular, positive tests for perinuclear anti-neutrophil cytoplasmic antibodies (pANCA) are found in 25% to 95% of patients with primary sclerosing cholangitis (PSC), a chronic progressive disorder of unknown etiology that is characterized by inflammation, fibrosis, and stricturing of medium and large ducts of the intrahepatic and extrahepatic biliary tree.²⁴ Anti-smooth muscle antibodies (SMA) can be observed in both PSC and autoimmune hepatitis.

Alkaline phosphatase levels are useful for monitoring evolution of primary biliary cholangitis disease.

Finally, there are syndromes with serologic and histologic overlap that are characterized by the simultaneous presence of PBC with autoimmune hepatitis or PSC or overlap of PSC with autoimmune hepatitis.

Liver biopsy fills in the rest of the diagnostic picture

Unfortunately, blood tests reveal little about organ integrity and are not useful for disease staging. The decision to perform a liver biopsy should be based on several factors, including the patient’s age, serum parameters, the need to stage the disease, therapy choices, and prognosis.¹² One should also consider that biopsy is a costly procedure with potentially serious adverse effects; it should not be repeated frequently. However, when a biopsy is done, it provides critical information, including damage to medium-sized intrahepatic bile ducts with neoductular formation or bile duct scars and strictures.

Treating intrahepatic cholestasis

Although FPs often can provide most—or even all—of the care for patients with stable conditions, a specialist consultation might recommend further testing to identify the underlying disease, which is essential to establish the most appropriate treatment.

Treatment of patients with PBC is based on administering hydrophilic secondary bile salt ursodeoxycholic acid (UDCA) 15 mg/kg/d, which is used to equilibrate the ratio between hydrophilic and hydrophobic bile salts in the liver and bile,²⁵ and is the only treatment approved by the US Food and Drug Administration (FDA) for PBC.⁴ Tauroursodeoxycholate is better absorbed than UDCA, and, although partially deconjugated and reconjugated with glycine, it undergoes reduced biotransformation to more hydrophobic metabolites and has benefits, including antioxidant, immunomodulation, and neuroprotective effects over UDCA—especially for long-term therapy in PBC.²⁶ However, it is not used often in clinical practice.

Continue to: Bile acid administration counters the cytotoxic effect...

Bile acid administration counters the cytotoxic effect of hydrophobic bile salts. Although it seems that UDCA might improve biochemical and histologic features of the disease at earlier stages (I-II), it fails in patients with more advanced disease.²⁷ In addition, monitoring and defining response to UDCA is inconsistent, partly because of variations in guideline criteria.^28,29

Despite progress in diagnostic techniques, life expectancy and quality of life for patients with advanced cholestatic conditions remain poor.

Recently a new molecule, obeticholic acid (OCA), has been approved by the FDA. A farnesoid X receptor agonist, OCA is indicated for treating patients who do not tolerate UDCA or as an adjunct to UDCA in those with a partial response to UDCA, defined as lowering ALP levels by <1.5 times the baseline value after 12 months of treatment.

Treating PSC is more complex. Combination therapy with prednisone and azathioprine is recommended only when there is an overlap syndrome between PSC and autoimmune hepatitis.⁴ UDCA at a high dosage (15-20 mg/kg/d) is used to facilitate long-lasting biochemical remission. These patients also need to be monitored for inflammatory bowel diseases, which affect up to 75% of patients,³⁰ and for cholangiocarcinoma, which is a life-limiting complication because of a lack of therapy options. Finally, these patients might need endoscopic-guided dilatation of the biliary tree when they have evidence of dominant fibrotic strictures of the greater bile ducts.^14,31

Addressing the systemic effects of intrahepatic cholestasis

Pruritus. A number of potential pruritogens, including bile salts, endogenous opioids, histamine, serotonin, and lisophosphatidic acid (LPA), can be targeted to relieve pruritus.

• Bile acid resin binders such as cholestyramine are the first step for treating pruritus. UDCA also can be useful, mainly for intrahepatic cholestasis during pregnancy. Rifampicin, 300 mg/d, improves cholestatic pruritus, but is associated with hepatotoxicity and a number of severe reactions, such as nausea, loss of appetite, hemolytic anemia, and thrombocytopenia.³¹
• Most evidence favors a role for opioids in relieving itch, and micro-opioid receptor antagonists (naltrexone, naloxone, nalmefene) that exert an antipruritic effect can be effective.
• Sertraline (a selective serotonin reuptake inhibitor), 50 to 75 mg/d, usually is well tolerated in patients with chronic cholestasis and exerts a beneficial effect on pruritus in approximately 40% of patients.³²
• Extracorporeal albumin dialysis removes albumin-bound pruritogens and has been found to be effective in patients with liver failure. Steroids and UV light also can be used in select patients.
• The potent neuronal activator LPA and its converting enzyme autotaxin have been identified in the serum of patients with cholestatic pruritus; experimental modalities using LPA antagonists are ongoing for treating pruritus in patients who do not respond to other medications.³³

Continue to: Malnutrition

Malnutrition. Many patients with cholestasis are at risk for malnutrition, which can be exacerbated in those with cirrhosis. Causes of malnutrition include poor oral intake, malabsorption, or dental problems that prevent the patient from chewing. Assess the nutritional status of every patient with chronic cholestasis, and stress the importance of multivitamin supplementation to reverse systemic alterations caused by malnutrition.³⁴

When the patient has advanced disease

Despite progress in diagnostic techniques, life expectancy and quality of life for patients with advanced cholestatic conditions remain poor. Patients routinely experience fatigue, pruritus, and complications of cirrhosis including ascites, encephalopathy, and bleeding. Cholestasis also carries the risk of life-threatening complications, partly because of comorbidities such as osteoporosis and malabsorption.

ERCP is widely employed for diagnosing and treating pancreatobiliary diseases; however, its use has dropped over the last 10 years because of the risk of complications.

Liver transplantation can improve the life expectancy of patients with advanced disease, but because of long waiting lists, candidates for transplant often die before an organ becomes available. For many patients who are not in end-stage condition, targeted therapy is crucial to slow disease progression and is recommended along with hepatitis A and B vaccinations and nutritional counseling.³⁵

Extrahepatic cholestasis is suspected? How to proceed

Computer tomography (CT) is recommended for better identification of neoplastic causes of biliary obstruction and for staging purposes. MRCP is an excellent noninvasive imaging technique for evaluating biliary ducts.³⁶

MRCP has 92% to 93% sensitivity and 97% to 98% specificity for diagnosing biliary duct stones.³⁷ MRCP also is the first-choice modality for evaluating bile ducts in patients with suspected PSC. If performed in expert centers, the diagnostic accuracy reaches that of ERCP. A meta-analysis of studies from 2000 to 2006 has shown a sensitivity of 86% and specificity of 94% for diagnosing PSC.³⁸

Endoscopic ultrasonography, which uses an ultrasonographic probe, allows clinicians to evaluate the integrity of the biliary and pancreatic ducts and is effective for diagnosing and staging cancer of the ampulla of Vater (sensitivity 93% vs 7% for abdominal ultrasonography and 29% for CT), and identifying biliary stones and biliary tree strictures.

Continue to: ERCP

ERCP is widely employed for diagnosing and treating pancreatobiliary diseases; however, its use has dropped over the last 10 years because of the risk of complications. ERCP is nearly exclusively used as a therapeutic procedure for pancreatic sphincterotomy, biliary dilatations, and removing biliary stones. It also has a diagnostic role in dominant stenosis or suspected biliary malignancy using brushing cytology and sampling biopsies of the bile ducts.

Treating extrahepatic cholestasis

Treatment of the different underlying conditions that cause extrahepatic cholestasis is surgical. Thus, the potential surgical techniques that can resolve or improve an extrahepatic cholestatic condition are guided by the surgeon and beyond the scope of this article.

Treating osteopenia: A concern for intra- and extrahepatic cholestasis

Vitamin D deficiency as a consequence of reduced intestinal absorption (poor availability of bile salts) or decreased hepatic activation to 25,OH-cholecalcipherol in both intrahepatic and extrahepatic cholestasis can lead to reduced bone formation.³⁹ However, osteopenia can occur even in early stages of the disease. Prescribing bisphosphonates, in combination with calcium and vitamin D3_, to improve bone mineral density is a good practice.⁴⁰

CASE

Blood tests and ultrasound imaging suggest the presence of a chronic liver disease. Other lab tests indicate that the patient has an ALP level 3 times normal. This finding, together with the other tests, points to a likely diagnosis of intrahepatic cholestatic liver disease. Serology confirms positivity for ANA (1:160) and AMA (1:640). The clinician suspects PBC, so the patient is referred to a liver specialist for further evaluation and to determine whether a liver biopsy is needed.

The liver specialist confirms the diagnosis of PBC, performs a transient elastographym, which indicates a low-grade liver fibrosis (F1 out of 4), and starts therapy with UDCA.

CORRESPONDENCE
Ignazio Grattagliano, MD, Italian College of General Practitioners and Primary Care, Via del Sansovino 179, 50142, Florence, Italy; [email protected].

CASE

A 44-year-old nurse describes persistent fatigue and itching over the last 2 months. She is taking ramipril 5 mg/d for hypertension and has a family history of rheumatic disease. Lab tests reveal a recurrent moderate elevation of gamma glutamyl-transpeptidase (gGT; 75 U/L) associated with, on some occasions, mild elevation of alanine aminotransferase (ALT) levels (100 U/L) of unknown origin. She has no history of hepatitis virus infection, hepatotoxic medications, or alcohol intake. She is overweight with a body mass index of 28.5 kg/m² and a waist circumference of 99 cm (39 inches). Liver ultrasonography detects an enlarged liver with diffuse echostructure dishomogeneity, but no signs of cirrhosis or portal hypertension. The patient’s biliary tree is not dilated.

How would you proceed with the care of this patient?

Cholestasis is characterized by the alteration of bile flow through any part of the biliary system, from the hepatocyte basocellular membrane to the duodenum. The condition is classified as intrahepatic when the cause is a defect of hepatocellular function or obstruction of the biliary tree within the liver. The extrahepatic form includes all conditions obstructing bile flow in the main biliary tract (choledochus, common bile duct).

Suspect intrahepatic cholestasis in a patient with chronic itching, normal transaminases, and mildly elevated gamma glutamyl-transpeptidase.

The key to successfully managing cholestasis lies in the early identification of subtle signs and symptoms before serious complications can arise. In the review that follows, we provide guidance for evaluating laboratory and imaging results that are vital to the accurate diagnosis of intrahepatic and extrahepatic cholestasis. We also detail treatment recommendations.

Clues—subtle and otherwise—of cholestasis

Clinical features of cholestasis include fatigue and itching all over the skin. The latter likely is caused by induction of the enzyme autotaxin, which produces the neuronal activator lysophosphatidic acid. Retention of pruritogenic substances that normally are excreted into bile might contribute to pruritus as well.¹ Jaundice, dark urine, and pale and fatty stools occur with advanced disease. However, a cholestatic condition can be detected in asymptomatic patients with elevated biochemical markers.

Continue to: Mildly elevated gGT and/or alkaline phosphatase (ALP)

Mildly elevated gGT and/or alkaline phosphatase (ALP) (0.5-2.5 times the upper normal limit [UNL] or 19-95 U/L and 60-300 U/L, respectively²) in the presence of normal transaminase levels (<20 U/L) in an asymptomatic patient can indicate chronic liver disease. Signs suggestive of significant liver disease have been reported in many patients with gGT or ALP elevation with good sensitivity (65%) and specificity (83%) for a diagnosis of intrahepatic cholestasis.³ However, because abnormal gGT values are common and often resolve spontaneously, family physicians (FPs) may pay little attention to this finding, thus missing an opportunity for early identification and treatment.

Patient’s history can provide important clues

A thorough patient history is especially important when cholestasis is suspected. Details about the patient’s occupation, environment, and lifestyle are key, as are the specifics of prescribed or over-the-counter medications and supplements that could be hepatotoxic (TABLE 4¹⁰). A number of exogenous substances can cause liver injury, and the use of some herbal products (senna, black cohosh, greater celandine, kava) have been linked to hepatitis and cholestasis.¹¹ Ask patients about alcohol use and history of conditions associated with liver disease, such as diabetes, hyperlipidemia, and thyroid disorders.

Continue to: Indicators pointing to cholestasis? It's time for ultrasonography

Abdominal ultrasonography is a first-line diagnostic tool for cholestasis.

While biopsy is considered the gold standard for diagnosing and staging chronic cholestatic liver disease and can exclude an extrahepatic obstruction, it should be employed only if blood tests have been confirmed, second-level tests have been performed, and ultrasound is inconclusive.¹² (More on biopsy in a bit.)

Ultrasonography is a low-cost, widely available, noninvasive test that allows easy identification of extrahepatic dilatation of the biliary tree and sometimes the underlying cause, as well. Ultrasonography identifies extrahepatic cholestasis by allowing visualization of an enlarged choledochus (>7 mm) or common hepatic duct (>5 mm) and an intrahepatic bile duct diameter that is more than 40% larger than adjacent branches of the portal vein.¹³ However, ultrasonography has a low diagnostic sensitivity for many conditions (eg, 15% to 89% for detecting common bile duct stones),¹⁴ requiring other diagnostic procedures, such as endoscopic retrograde cholangiopancreatography (ERCP) or magnetic resonance cholangiopancreatography (MRCP), before reaching a diagnosis.

For asymptomatic patients with cirrhosis or those at an early stage of liver disease, ultrasound at 6-month intervals combined with serum liver function tests can be useful to track disease progression and screen for hepatocellular carcinoma or cholangiocarcinoma.^15,16

New noninvasive methods. Noninvasive tools for evaluating the presence and severity of liver fibrosis and for differentiating cirrhosis from noncirrhotic conditions have positive predictive values >85% to 90% for some chronic liver diseases.¹⁷ Transient elastography, which assesses liver stiffness, is one such method. Although it is often used successfully, morbid obesity, small intercostal spaces, and ascites limit its diagnostic capability.¹⁸ Recently, some questions about the validity of elastography to assess the extent of fibrosis in patients with chronic cholestatic conditions have been reported.^19,20

Suspect intrahepatic cholestasis? Your next steps

If imaging techniques do not show bile duct obstruction and you suspect the intrahepatic form, second-level tests could have strategic importance. This is where antimitochondrial antibodies (AMAs) come in. AMAs are immunoglobulins (IgG and IgM) directed against mitochondrial antigens. They are important markers for PBC, which is a T-lymphocyte-mediated attack on small intralobular bile ducts resulting in their gradual destruction and eventual disappearance. The sustained loss of intralobular bile ducts leads to signs and symptoms of cholestasis and eventually results in cirrhosis and liver failure.

AMA serum levels show high sensitivity and specificity (90% and 95%, respectively) for PBC.²¹ Some PBC patients (<5%) show histologic confirmation of the disease, but have negative AMA tests (AMA negative PBC or autoimmune cholangitis).²² Therefore, according to the American Association for the Study of Liver Diseases, diagnosis of PBC is guided by the combination of serologic, biochemical, and histologic criteria.²³ Many PBC patients with or without a positive AMA (≥1:40) also have positive circulating antinuclear antibodies (ANA; ≥1:80). The recent availability of lab tests for antibodies (anti-M2, anti-gp120, anti-sp100) has allowed identification of subgroups of patients who have a more aggressive form of PBC. Patients with PBC often have elevated levels of circulating IgM (>280 mg/dL).

Continue to: Other circulating antibodies

Other circulating antibodies can help discriminate among cholestatic disorders. In particular, positive tests for perinuclear anti-neutrophil cytoplasmic antibodies (pANCA) are found in 25% to 95% of patients with primary sclerosing cholangitis (PSC), a chronic progressive disorder of unknown etiology that is characterized by inflammation, fibrosis, and stricturing of medium and large ducts of the intrahepatic and extrahepatic biliary tree.²⁴ Anti-smooth muscle antibodies (SMA) can be observed in both PSC and autoimmune hepatitis.

Alkaline phosphatase levels are useful for monitoring evolution of primary biliary cholangitis disease.

Finally, there are syndromes with serologic and histologic overlap that are characterized by the simultaneous presence of PBC with autoimmune hepatitis or PSC or overlap of PSC with autoimmune hepatitis.

Liver biopsy fills in the rest of the diagnostic picture

Unfortunately, blood tests reveal little about organ integrity and are not useful for disease staging. The decision to perform a liver biopsy should be based on several factors, including the patient’s age, serum parameters, the need to stage the disease, therapy choices, and prognosis.¹² One should also consider that biopsy is a costly procedure with potentially serious adverse effects; it should not be repeated frequently. However, when a biopsy is done, it provides critical information, including damage to medium-sized intrahepatic bile ducts with neoductular formation or bile duct scars and strictures.

Treating intrahepatic cholestasis

Although FPs often can provide most—or even all—of the care for patients with stable conditions, a specialist consultation might recommend further testing to identify the underlying disease, which is essential to establish the most appropriate treatment.

Treatment of patients with PBC is based on administering hydrophilic secondary bile salt ursodeoxycholic acid (UDCA) 15 mg/kg/d, which is used to equilibrate the ratio between hydrophilic and hydrophobic bile salts in the liver and bile,²⁵ and is the only treatment approved by the US Food and Drug Administration (FDA) for PBC.⁴ Tauroursodeoxycholate is better absorbed than UDCA, and, although partially deconjugated and reconjugated with glycine, it undergoes reduced biotransformation to more hydrophobic metabolites and has benefits, including antioxidant, immunomodulation, and neuroprotective effects over UDCA—especially for long-term therapy in PBC.²⁶ However, it is not used often in clinical practice.

Continue to: Bile acid administration counters the cytotoxic effect...

Bile acid administration counters the cytotoxic effect of hydrophobic bile salts. Although it seems that UDCA might improve biochemical and histologic features of the disease at earlier stages (I-II), it fails in patients with more advanced disease.²⁷ In addition, monitoring and defining response to UDCA is inconsistent, partly because of variations in guideline criteria.^28,29

Despite progress in diagnostic techniques, life expectancy and quality of life for patients with advanced cholestatic conditions remain poor.

Recently a new molecule, obeticholic acid (OCA), has been approved by the FDA. A farnesoid X receptor agonist, OCA is indicated for treating patients who do not tolerate UDCA or as an adjunct to UDCA in those with a partial response to UDCA, defined as lowering ALP levels by <1.5 times the baseline value after 12 months of treatment.

Treating PSC is more complex. Combination therapy with prednisone and azathioprine is recommended only when there is an overlap syndrome between PSC and autoimmune hepatitis.⁴ UDCA at a high dosage (15-20 mg/kg/d) is used to facilitate long-lasting biochemical remission. These patients also need to be monitored for inflammatory bowel diseases, which affect up to 75% of patients,³⁰ and for cholangiocarcinoma, which is a life-limiting complication because of a lack of therapy options. Finally, these patients might need endoscopic-guided dilatation of the biliary tree when they have evidence of dominant fibrotic strictures of the greater bile ducts.^14,31

Addressing the systemic effects of intrahepatic cholestasis

Pruritus. A number of potential pruritogens, including bile salts, endogenous opioids, histamine, serotonin, and lisophosphatidic acid (LPA), can be targeted to relieve pruritus.

• Bile acid resin binders such as cholestyramine are the first step for treating pruritus. UDCA also can be useful, mainly for intrahepatic cholestasis during pregnancy. Rifampicin, 300 mg/d, improves cholestatic pruritus, but is associated with hepatotoxicity and a number of severe reactions, such as nausea, loss of appetite, hemolytic anemia, and thrombocytopenia.³¹
• Most evidence favors a role for opioids in relieving itch, and micro-opioid receptor antagonists (naltrexone, naloxone, nalmefene) that exert an antipruritic effect can be effective.
• Sertraline (a selective serotonin reuptake inhibitor), 50 to 75 mg/d, usually is well tolerated in patients with chronic cholestasis and exerts a beneficial effect on pruritus in approximately 40% of patients.³²
• Extracorporeal albumin dialysis removes albumin-bound pruritogens and has been found to be effective in patients with liver failure. Steroids and UV light also can be used in select patients.
• The potent neuronal activator LPA and its converting enzyme autotaxin have been identified in the serum of patients with cholestatic pruritus; experimental modalities using LPA antagonists are ongoing for treating pruritus in patients who do not respond to other medications.³³

Continue to: Malnutrition

Malnutrition. Many patients with cholestasis are at risk for malnutrition, which can be exacerbated in those with cirrhosis. Causes of malnutrition include poor oral intake, malabsorption, or dental problems that prevent the patient from chewing. Assess the nutritional status of every patient with chronic cholestasis, and stress the importance of multivitamin supplementation to reverse systemic alterations caused by malnutrition.³⁴

When the patient has advanced disease

Despite progress in diagnostic techniques, life expectancy and quality of life for patients with advanced cholestatic conditions remain poor. Patients routinely experience fatigue, pruritus, and complications of cirrhosis including ascites, encephalopathy, and bleeding. Cholestasis also carries the risk of life-threatening complications, partly because of comorbidities such as osteoporosis and malabsorption.

ERCP is widely employed for diagnosing and treating pancreatobiliary diseases; however, its use has dropped over the last 10 years because of the risk of complications.

Liver transplantation can improve the life expectancy of patients with advanced disease, but because of long waiting lists, candidates for transplant often die before an organ becomes available. For many patients who are not in end-stage condition, targeted therapy is crucial to slow disease progression and is recommended along with hepatitis A and B vaccinations and nutritional counseling.³⁵

Extrahepatic cholestasis is suspected? How to proceed

Computer tomography (CT) is recommended for better identification of neoplastic causes of biliary obstruction and for staging purposes. MRCP is an excellent noninvasive imaging technique for evaluating biliary ducts.³⁶

MRCP has 92% to 93% sensitivity and 97% to 98% specificity for diagnosing biliary duct stones.³⁷ MRCP also is the first-choice modality for evaluating bile ducts in patients with suspected PSC. If performed in expert centers, the diagnostic accuracy reaches that of ERCP. A meta-analysis of studies from 2000 to 2006 has shown a sensitivity of 86% and specificity of 94% for diagnosing PSC.³⁸

Endoscopic ultrasonography, which uses an ultrasonographic probe, allows clinicians to evaluate the integrity of the biliary and pancreatic ducts and is effective for diagnosing and staging cancer of the ampulla of Vater (sensitivity 93% vs 7% for abdominal ultrasonography and 29% for CT), and identifying biliary stones and biliary tree strictures.

Continue to: ERCP

ERCP is widely employed for diagnosing and treating pancreatobiliary diseases; however, its use has dropped over the last 10 years because of the risk of complications. ERCP is nearly exclusively used as a therapeutic procedure for pancreatic sphincterotomy, biliary dilatations, and removing biliary stones. It also has a diagnostic role in dominant stenosis or suspected biliary malignancy using brushing cytology and sampling biopsies of the bile ducts.

Treating extrahepatic cholestasis

Treatment of the different underlying conditions that cause extrahepatic cholestasis is surgical. Thus, the potential surgical techniques that can resolve or improve an extrahepatic cholestatic condition are guided by the surgeon and beyond the scope of this article.

Treating osteopenia: A concern for intra- and extrahepatic cholestasis

Vitamin D deficiency as a consequence of reduced intestinal absorption (poor availability of bile salts) or decreased hepatic activation to 25,OH-cholecalcipherol in both intrahepatic and extrahepatic cholestasis can lead to reduced bone formation.³⁹ However, osteopenia can occur even in early stages of the disease. Prescribing bisphosphonates, in combination with calcium and vitamin D3_, to improve bone mineral density is a good practice.⁴⁰

CASE

Blood tests and ultrasound imaging suggest the presence of a chronic liver disease. Other lab tests indicate that the patient has an ALP level 3 times normal. This finding, together with the other tests, points to a likely diagnosis of intrahepatic cholestatic liver disease. Serology confirms positivity for ANA (1:160) and AMA (1:640). The clinician suspects PBC, so the patient is referred to a liver specialist for further evaluation and to determine whether a liver biopsy is needed.

The liver specialist confirms the diagnosis of PBC, performs a transient elastographym, which indicates a low-grade liver fibrosis (F1 out of 4), and starts therapy with UDCA.

CORRESPONDENCE
Ignazio Grattagliano, MD, Italian College of General Practitioners and Primary Care, Via del Sansovino 179, 50142, Florence, Italy; [email protected].

CASE

A 44-year-old nurse describes persistent fatigue and itching over the last 2 months. She is taking ramipril 5 mg/d for hypertension and has a family history of rheumatic disease. Lab tests reveal a recurrent moderate elevation of gamma glutamyl-transpeptidase (gGT; 75 U/L) associated with, on some occasions, mild elevation of alanine aminotransferase (ALT) levels (100 U/L) of unknown origin. She has no history of hepatitis virus infection, hepatotoxic medications, or alcohol intake. She is overweight with a body mass index of 28.5 kg/m² and a waist circumference of 99 cm (39 inches). Liver ultrasonography detects an enlarged liver with diffuse echostructure dishomogeneity, but no signs of cirrhosis or portal hypertension. The patient’s biliary tree is not dilated.

How would you proceed with the care of this patient?

Cholestasis is characterized by the alteration of bile flow through any part of the biliary system, from the hepatocyte basocellular membrane to the duodenum. The condition is classified as intrahepatic when the cause is a defect of hepatocellular function or obstruction of the biliary tree within the liver. The extrahepatic form includes all conditions obstructing bile flow in the main biliary tract (choledochus, common bile duct).

Suspect intrahepatic cholestasis in a patient with chronic itching, normal transaminases, and mildly elevated gamma glutamyl-transpeptidase.

The key to successfully managing cholestasis lies in the early identification of subtle signs and symptoms before serious complications can arise. In the review that follows, we provide guidance for evaluating laboratory and imaging results that are vital to the accurate diagnosis of intrahepatic and extrahepatic cholestasis. We also detail treatment recommendations.

Clues—subtle and otherwise—of cholestasis

Clinical features of cholestasis include fatigue and itching all over the skin. The latter likely is caused by induction of the enzyme autotaxin, which produces the neuronal activator lysophosphatidic acid. Retention of pruritogenic substances that normally are excreted into bile might contribute to pruritus as well.¹ Jaundice, dark urine, and pale and fatty stools occur with advanced disease. However, a cholestatic condition can be detected in asymptomatic patients with elevated biochemical markers.

Continue to: Mildly elevated gGT and/or alkaline phosphatase (ALP)

Mildly elevated gGT and/or alkaline phosphatase (ALP) (0.5-2.5 times the upper normal limit [UNL] or 19-95 U/L and 60-300 U/L, respectively²) in the presence of normal transaminase levels (<20 U/L) in an asymptomatic patient can indicate chronic liver disease. Signs suggestive of significant liver disease have been reported in many patients with gGT or ALP elevation with good sensitivity (65%) and specificity (83%) for a diagnosis of intrahepatic cholestasis.³ However, because abnormal gGT values are common and often resolve spontaneously, family physicians (FPs) may pay little attention to this finding, thus missing an opportunity for early identification and treatment.

Patient’s history can provide important clues

A thorough patient history is especially important when cholestasis is suspected. Details about the patient’s occupation, environment, and lifestyle are key, as are the specifics of prescribed or over-the-counter medications and supplements that could be hepatotoxic (TABLE 4¹⁰). A number of exogenous substances can cause liver injury, and the use of some herbal products (senna, black cohosh, greater celandine, kava) have been linked to hepatitis and cholestasis.¹¹ Ask patients about alcohol use and history of conditions associated with liver disease, such as diabetes, hyperlipidemia, and thyroid disorders.

Continue to: Indicators pointing to cholestasis? It's time for ultrasonography

Abdominal ultrasonography is a first-line diagnostic tool for cholestasis.

While biopsy is considered the gold standard for diagnosing and staging chronic cholestatic liver disease and can exclude an extrahepatic obstruction, it should be employed only if blood tests have been confirmed, second-level tests have been performed, and ultrasound is inconclusive.¹² (More on biopsy in a bit.)

Ultrasonography is a low-cost, widely available, noninvasive test that allows easy identification of extrahepatic dilatation of the biliary tree and sometimes the underlying cause, as well. Ultrasonography identifies extrahepatic cholestasis by allowing visualization of an enlarged choledochus (>7 mm) or common hepatic duct (>5 mm) and an intrahepatic bile duct diameter that is more than 40% larger than adjacent branches of the portal vein.¹³ However, ultrasonography has a low diagnostic sensitivity for many conditions (eg, 15% to 89% for detecting common bile duct stones),¹⁴ requiring other diagnostic procedures, such as endoscopic retrograde cholangiopancreatography (ERCP) or magnetic resonance cholangiopancreatography (MRCP), before reaching a diagnosis.

For asymptomatic patients with cirrhosis or those at an early stage of liver disease, ultrasound at 6-month intervals combined with serum liver function tests can be useful to track disease progression and screen for hepatocellular carcinoma or cholangiocarcinoma.^15,16

New noninvasive methods. Noninvasive tools for evaluating the presence and severity of liver fibrosis and for differentiating cirrhosis from noncirrhotic conditions have positive predictive values >85% to 90% for some chronic liver diseases.¹⁷ Transient elastography, which assesses liver stiffness, is one such method. Although it is often used successfully, morbid obesity, small intercostal spaces, and ascites limit its diagnostic capability.¹⁸ Recently, some questions about the validity of elastography to assess the extent of fibrosis in patients with chronic cholestatic conditions have been reported.^19,20

Suspect intrahepatic cholestasis? Your next steps

If imaging techniques do not show bile duct obstruction and you suspect the intrahepatic form, second-level tests could have strategic importance. This is where antimitochondrial antibodies (AMAs) come in. AMAs are immunoglobulins (IgG and IgM) directed against mitochondrial antigens. They are important markers for PBC, which is a T-lymphocyte-mediated attack on small intralobular bile ducts resulting in their gradual destruction and eventual disappearance. The sustained loss of intralobular bile ducts leads to signs and symptoms of cholestasis and eventually results in cirrhosis and liver failure.

AMA serum levels show high sensitivity and specificity (90% and 95%, respectively) for PBC.²¹ Some PBC patients (<5%) show histologic confirmation of the disease, but have negative AMA tests (AMA negative PBC or autoimmune cholangitis).²² Therefore, according to the American Association for the Study of Liver Diseases, diagnosis of PBC is guided by the combination of serologic, biochemical, and histologic criteria.²³ Many PBC patients with or without a positive AMA (≥1:40) also have positive circulating antinuclear antibodies (ANA; ≥1:80). The recent availability of lab tests for antibodies (anti-M2, anti-gp120, anti-sp100) has allowed identification of subgroups of patients who have a more aggressive form of PBC. Patients with PBC often have elevated levels of circulating IgM (>280 mg/dL).

Continue to: Other circulating antibodies

Other circulating antibodies can help discriminate among cholestatic disorders. In particular, positive tests for perinuclear anti-neutrophil cytoplasmic antibodies (pANCA) are found in 25% to 95% of patients with primary sclerosing cholangitis (PSC), a chronic progressive disorder of unknown etiology that is characterized by inflammation, fibrosis, and stricturing of medium and large ducts of the intrahepatic and extrahepatic biliary tree.²⁴ Anti-smooth muscle antibodies (SMA) can be observed in both PSC and autoimmune hepatitis.

Alkaline phosphatase levels are useful for monitoring evolution of primary biliary cholangitis disease.

Finally, there are syndromes with serologic and histologic overlap that are characterized by the simultaneous presence of PBC with autoimmune hepatitis or PSC or overlap of PSC with autoimmune hepatitis.

Liver biopsy fills in the rest of the diagnostic picture

Unfortunately, blood tests reveal little about organ integrity and are not useful for disease staging. The decision to perform a liver biopsy should be based on several factors, including the patient’s age, serum parameters, the need to stage the disease, therapy choices, and prognosis.¹² One should also consider that biopsy is a costly procedure with potentially serious adverse effects; it should not be repeated frequently. However, when a biopsy is done, it provides critical information, including damage to medium-sized intrahepatic bile ducts with neoductular formation or bile duct scars and strictures.

Treating intrahepatic cholestasis

Although FPs often can provide most—or even all—of the care for patients with stable conditions, a specialist consultation might recommend further testing to identify the underlying disease, which is essential to establish the most appropriate treatment.

Treatment of patients with PBC is based on administering hydrophilic secondary bile salt ursodeoxycholic acid (UDCA) 15 mg/kg/d, which is used to equilibrate the ratio between hydrophilic and hydrophobic bile salts in the liver and bile,²⁵ and is the only treatment approved by the US Food and Drug Administration (FDA) for PBC.⁴ Tauroursodeoxycholate is better absorbed than UDCA, and, although partially deconjugated and reconjugated with glycine, it undergoes reduced biotransformation to more hydrophobic metabolites and has benefits, including antioxidant, immunomodulation, and neuroprotective effects over UDCA—especially for long-term therapy in PBC.²⁶ However, it is not used often in clinical practice.

Continue to: Bile acid administration counters the cytotoxic effect...

Bile acid administration counters the cytotoxic effect of hydrophobic bile salts. Although it seems that UDCA might improve biochemical and histologic features of the disease at earlier stages (I-II), it fails in patients with more advanced disease.²⁷ In addition, monitoring and defining response to UDCA is inconsistent, partly because of variations in guideline criteria.^28,29

Despite progress in diagnostic techniques, life expectancy and quality of life for patients with advanced cholestatic conditions remain poor.

Recently a new molecule, obeticholic acid (OCA), has been approved by the FDA. A farnesoid X receptor agonist, OCA is indicated for treating patients who do not tolerate UDCA or as an adjunct to UDCA in those with a partial response to UDCA, defined as lowering ALP levels by <1.5 times the baseline value after 12 months of treatment.

Treating PSC is more complex. Combination therapy with prednisone and azathioprine is recommended only when there is an overlap syndrome between PSC and autoimmune hepatitis.⁴ UDCA at a high dosage (15-20 mg/kg/d) is used to facilitate long-lasting biochemical remission. These patients also need to be monitored for inflammatory bowel diseases, which affect up to 75% of patients,³⁰ and for cholangiocarcinoma, which is a life-limiting complication because of a lack of therapy options. Finally, these patients might need endoscopic-guided dilatation of the biliary tree when they have evidence of dominant fibrotic strictures of the greater bile ducts.^14,31

Addressing the systemic effects of intrahepatic cholestasis

Pruritus. A number of potential pruritogens, including bile salts, endogenous opioids, histamine, serotonin, and lisophosphatidic acid (LPA), can be targeted to relieve pruritus.

• Bile acid resin binders such as cholestyramine are the first step for treating pruritus. UDCA also can be useful, mainly for intrahepatic cholestasis during pregnancy. Rifampicin, 300 mg/d, improves cholestatic pruritus, but is associated with hepatotoxicity and a number of severe reactions, such as nausea, loss of appetite, hemolytic anemia, and thrombocytopenia.³¹
• Most evidence favors a role for opioids in relieving itch, and micro-opioid receptor antagonists (naltrexone, naloxone, nalmefene) that exert an antipruritic effect can be effective.
• Sertraline (a selective serotonin reuptake inhibitor), 50 to 75 mg/d, usually is well tolerated in patients with chronic cholestasis and exerts a beneficial effect on pruritus in approximately 40% of patients.³²
• Extracorporeal albumin dialysis removes albumin-bound pruritogens and has been found to be effective in patients with liver failure. Steroids and UV light also can be used in select patients.
• The potent neuronal activator LPA and its converting enzyme autotaxin have been identified in the serum of patients with cholestatic pruritus; experimental modalities using LPA antagonists are ongoing for treating pruritus in patients who do not respond to other medications.³³

Continue to: Malnutrition

Malnutrition. Many patients with cholestasis are at risk for malnutrition, which can be exacerbated in those with cirrhosis. Causes of malnutrition include poor oral intake, malabsorption, or dental problems that prevent the patient from chewing. Assess the nutritional status of every patient with chronic cholestasis, and stress the importance of multivitamin supplementation to reverse systemic alterations caused by malnutrition.³⁴

When the patient has advanced disease

Despite progress in diagnostic techniques, life expectancy and quality of life for patients with advanced cholestatic conditions remain poor. Patients routinely experience fatigue, pruritus, and complications of cirrhosis including ascites, encephalopathy, and bleeding. Cholestasis also carries the risk of life-threatening complications, partly because of comorbidities such as osteoporosis and malabsorption.

ERCP is widely employed for diagnosing and treating pancreatobiliary diseases; however, its use has dropped over the last 10 years because of the risk of complications.

Liver transplantation can improve the life expectancy of patients with advanced disease, but because of long waiting lists, candidates for transplant often die before an organ becomes available. For many patients who are not in end-stage condition, targeted therapy is crucial to slow disease progression and is recommended along with hepatitis A and B vaccinations and nutritional counseling.³⁵

Extrahepatic cholestasis is suspected? How to proceed

Computer tomography (CT) is recommended for better identification of neoplastic causes of biliary obstruction and for staging purposes. MRCP is an excellent noninvasive imaging technique for evaluating biliary ducts.³⁶

MRCP has 92% to 93% sensitivity and 97% to 98% specificity for diagnosing biliary duct stones.³⁷ MRCP also is the first-choice modality for evaluating bile ducts in patients with suspected PSC. If performed in expert centers, the diagnostic accuracy reaches that of ERCP. A meta-analysis of studies from 2000 to 2006 has shown a sensitivity of 86% and specificity of 94% for diagnosing PSC.³⁸

Endoscopic ultrasonography, which uses an ultrasonographic probe, allows clinicians to evaluate the integrity of the biliary and pancreatic ducts and is effective for diagnosing and staging cancer of the ampulla of Vater (sensitivity 93% vs 7% for abdominal ultrasonography and 29% for CT), and identifying biliary stones and biliary tree strictures.

Continue to: ERCP

ERCP is widely employed for diagnosing and treating pancreatobiliary diseases; however, its use has dropped over the last 10 years because of the risk of complications. ERCP is nearly exclusively used as a therapeutic procedure for pancreatic sphincterotomy, biliary dilatations, and removing biliary stones. It also has a diagnostic role in dominant stenosis or suspected biliary malignancy using brushing cytology and sampling biopsies of the bile ducts.

Treating extrahepatic cholestasis

Treatment of the different underlying conditions that cause extrahepatic cholestasis is surgical. Thus, the potential surgical techniques that can resolve or improve an extrahepatic cholestatic condition are guided by the surgeon and beyond the scope of this article.

Treating osteopenia: A concern for intra- and extrahepatic cholestasis

Vitamin D deficiency as a consequence of reduced intestinal absorption (poor availability of bile salts) or decreased hepatic activation to 25,OH-cholecalcipherol in both intrahepatic and extrahepatic cholestasis can lead to reduced bone formation.³⁹ However, osteopenia can occur even in early stages of the disease. Prescribing bisphosphonates, in combination with calcium and vitamin D3_, to improve bone mineral density is a good practice.⁴⁰

CASE

Blood tests and ultrasound imaging suggest the presence of a chronic liver disease. Other lab tests indicate that the patient has an ALP level 3 times normal. This finding, together with the other tests, points to a likely diagnosis of intrahepatic cholestatic liver disease. Serology confirms positivity for ANA (1:160) and AMA (1:640). The clinician suspects PBC, so the patient is referred to a liver specialist for further evaluation and to determine whether a liver biopsy is needed.

The liver specialist confirms the diagnosis of PBC, performs a transient elastographym, which indicates a low-grade liver fibrosis (F1 out of 4), and starts therapy with UDCA.

CORRESPONDENCE
Ignazio Grattagliano, MD, Italian College of General Practitioners and Primary Care, Via del Sansovino 179, 50142, Florence, Italy; [email protected].

Insurance denials of direct-acting antiviral (DAA) prescriptions remain high and have increased over time, according to a prospective cohort study.

About one in three patients had lack of fill approval by insurers, contributing to a continued lack of access to hepatitis C virus (HCV) therapy across insurance types, despite availability of new, highly effective regimens and relaxation of restrictions on reimbursement, according to Charitha Gowda, MD, of Ohio State University, Columbus, and her coauthors.

“To achieve the goal of HCV elimination, access to antiviral treatment must be improved,” they wrote.

The study by Dr. Gowda and colleagues included 9,025 patients in 45 states who had a DAA prescription submitted to one large, independent pharmacy provider between January 2016 and April 2017. Of those patients, most (4,702) were covered by Medicaid, while 2,502 were covered commercially, and 1,821 were covered by Medicare.

Over the 16-month study period, 3,200 patients (35.5%) had an absolute denial of treatment, defined as lack of fill approval by the insurer.

Absolute denials were significantly more frequent in patients with commercial insurance (52.4%), as compared with Medicaid (34.5%) and Medicare (14.7%).

Absolute denials increased significantly over the 16-month study period, from 27.7% in the first quarter evaluated to 43.8% in the last, researchers noted, adding that each insurance type had a significant increase in absolute denials over time.

While DAAs are associated with very high cure rates, their high costs have led to restrictions to access by both private and public insurers. However, over the past few years, restrictions in DAA reimbursement have been relaxed in a variety of settings because of advocacy efforts, greater price competition, and class action lawsuits/threats of legal action, Dr. Gowda and colleagues noted.

“The reason for this higher than expected denial rate is unclear, but may be due to attempts to treat chronic HCV-infected patients who have less advanced liver fibrosis, have not met sobriety restrictions, or have not had consultation with a specialist,” Dr. Gowda and colleagues wrote in their report.

The study was supported by the Penn Center for AIDS Research and the National Institutes of Health. Dr. Gowda had no conflicts of interest to report. Two coauthors reported grant support and/or advisory board fees from Gilead.

SOURCE: Gowda C et al. Open Forum Infect Dis. 2018 Jun 7 doi: 10.1093/ofid/ofy076.

Insurance denials of direct-acting antiviral (DAA) prescriptions remain high and have increased over time, according to a prospective cohort study.

About one in three patients had lack of fill approval by insurers, contributing to a continued lack of access to hepatitis C virus (HCV) therapy across insurance types, despite availability of new, highly effective regimens and relaxation of restrictions on reimbursement, according to Charitha Gowda, MD, of Ohio State University, Columbus, and her coauthors.

“To achieve the goal of HCV elimination, access to antiviral treatment must be improved,” they wrote.

The study by Dr. Gowda and colleagues included 9,025 patients in 45 states who had a DAA prescription submitted to one large, independent pharmacy provider between January 2016 and April 2017. Of those patients, most (4,702) were covered by Medicaid, while 2,502 were covered commercially, and 1,821 were covered by Medicare.

Over the 16-month study period, 3,200 patients (35.5%) had an absolute denial of treatment, defined as lack of fill approval by the insurer.

Absolute denials were significantly more frequent in patients with commercial insurance (52.4%), as compared with Medicaid (34.5%) and Medicare (14.7%).

Absolute denials increased significantly over the 16-month study period, from 27.7% in the first quarter evaluated to 43.8% in the last, researchers noted, adding that each insurance type had a significant increase in absolute denials over time.

While DAAs are associated with very high cure rates, their high costs have led to restrictions to access by both private and public insurers. However, over the past few years, restrictions in DAA reimbursement have been relaxed in a variety of settings because of advocacy efforts, greater price competition, and class action lawsuits/threats of legal action, Dr. Gowda and colleagues noted.

“The reason for this higher than expected denial rate is unclear, but may be due to attempts to treat chronic HCV-infected patients who have less advanced liver fibrosis, have not met sobriety restrictions, or have not had consultation with a specialist,” Dr. Gowda and colleagues wrote in their report.

The study was supported by the Penn Center for AIDS Research and the National Institutes of Health. Dr. Gowda had no conflicts of interest to report. Two coauthors reported grant support and/or advisory board fees from Gilead.

SOURCE: Gowda C et al. Open Forum Infect Dis. 2018 Jun 7 doi: 10.1093/ofid/ofy076.

Insurance denials of direct-acting antiviral (DAA) prescriptions remain high and have increased over time, according to a prospective cohort study.

About one in three patients had lack of fill approval by insurers, contributing to a continued lack of access to hepatitis C virus (HCV) therapy across insurance types, despite availability of new, highly effective regimens and relaxation of restrictions on reimbursement, according to Charitha Gowda, MD, of Ohio State University, Columbus, and her coauthors.

“To achieve the goal of HCV elimination, access to antiviral treatment must be improved,” they wrote.

The study by Dr. Gowda and colleagues included 9,025 patients in 45 states who had a DAA prescription submitted to one large, independent pharmacy provider between January 2016 and April 2017. Of those patients, most (4,702) were covered by Medicaid, while 2,502 were covered commercially, and 1,821 were covered by Medicare.

Over the 16-month study period, 3,200 patients (35.5%) had an absolute denial of treatment, defined as lack of fill approval by the insurer.

Absolute denials were significantly more frequent in patients with commercial insurance (52.4%), as compared with Medicaid (34.5%) and Medicare (14.7%).

Absolute denials increased significantly over the 16-month study period, from 27.7% in the first quarter evaluated to 43.8% in the last, researchers noted, adding that each insurance type had a significant increase in absolute denials over time.

While DAAs are associated with very high cure rates, their high costs have led to restrictions to access by both private and public insurers. However, over the past few years, restrictions in DAA reimbursement have been relaxed in a variety of settings because of advocacy efforts, greater price competition, and class action lawsuits/threats of legal action, Dr. Gowda and colleagues noted.

“The reason for this higher than expected denial rate is unclear, but may be due to attempts to treat chronic HCV-infected patients who have less advanced liver fibrosis, have not met sobriety restrictions, or have not had consultation with a specialist,” Dr. Gowda and colleagues wrote in their report.

The study was supported by the Penn Center for AIDS Research and the National Institutes of Health. Dr. Gowda had no conflicts of interest to report. Two coauthors reported grant support and/or advisory board fees from Gilead.

SOURCE: Gowda C et al. Open Forum Infect Dis. 2018 Jun 7 doi: 10.1093/ofid/ofy076.

The liver enzyme autotaxin may be a useful noninvasive marker of disease progression in people with primary biliary cholangitis (PBC), new research has suggested.

Satoru Joshita, MD, from the gastroenterology and hepatology department at Shinshu University in Matsumoto, Japan, and colleagues noted that the liver-specific autoimmune disease PBC is characterized by the destruction of bile ducts, leading to cirrhosis and liver failure, and is more often seen in women.

Symptoms at diagnosis, a lack of response to gold standard treatment with ursodeoxycholic acid, and more advanced histologic phase are linked to worse patient outcomes, the research team explained in Scientific Reports.

While liver biopsy could give vital information on the severity of disease, it is an invasive procedure that is limited by sampling error and interobserver disparity. “As advanced histological stage is associated with a worse prognosis in PBC patients, it is important for clinicians to know clinical stage noninvasively when deciding appropriate therapies,” they wrote.

Noninvasive measures of liver fibrosis and PBC progression are available, such as Wisteria floribunda agglutinin–positive Mac-2 binding protein, hyaluronic acid, and type IV collagen 7S, but the authors said their “diagnostic abilities remain under scrutiny” because of their “moderate” accuracy.

Previous research had described autotaxin (ATX), a secreted enzyme metabolized by liver sinusoidal endothelial cells, as a prognostic factor for overall survival in cirrhosis patients, which suggested “an important role of ATX in the progression of liver disease,” the researchers noted.

They therefore set out to assess its utility as a marker of primary biliary cholangitis disease progression by measuring the serum ATX values of 128 treatment-naive, histologically assessed PBC patients, 108 of whom were female and 20 were male. Their ATX levels were then compared with 80 healthy controls.

Results showed that the ATX levels of patients with PBC were significantly higher than those of controls (median, 0.97 mg/L vs. 0.76 mg/L, respectively; P less than .0001).

Autotaxin results were validated by biopsy-proven histologic assessment: Patients with PBC that was classified as Nakanuma’s stage I, II, III, and IV had median ATX concentrations of 0.70, 0.80, 0.87, 1.03, and 1.70 mg/L, respectively, which demonstrated significant increases in concentration of ATX with disease stage (r = 0.53; P less than .0001). The researchers confirmed this finding using Scheuer’s classification of the disease (r = 0.43; P less than .0001).

The researchers noted that their findings were also “well correlated with other established noninvasive fibrosis markers, indicating ATX to be a reliable clinical surrogate marker to predict disease progression in patients with PBC.”

For example, autotaxin levels correlated with W. floribunda agglutinin–positive Mac-2 binding protein (r = 0.51; P less than .0001) and the fibrosis index based on four factors index (r = 0.51; P less than .0001).

Interestingly, the researchers found a sex difference in ATX levels: Not only were ATX values in female patients significantly higher than those in female controls (median, 1.00 mg/L vs. 0.82 mg/L, respectively; P less than .001) but they also were higher than those of male patients (median, 0.78 mg/L; P = .005).

According to the authors, these findings highlighted a need for sex-specific benchmarks, as well as more research to clarify why the sex disparity existed.

A further longitudinal study conducted by the authors involving 29 patients seen at their clinic showed that ATX levels increased slowly but significantly over an 18-year period, with a median increase rate of 0.03 mg/L per year (P less than .00001).

Patients who died from their disease had a significantly higher autotaxin increase rate than did survivors (0.05 mg/L per year vs. 0.02 mg/L per year, respectively; P less than .01).

Based on their findings, the researchers concluded that serum ATX levels “represent an accurate, noninvasive biomarker for estimating disease progression in patients with PBC.”

However, they said a longer longitudinal study of patients with PBC looking at ATX levels and clinical features, as well as long-term prognosis and complicating hepatocellular carcinoma, was warranted.

Two coauthors are employees of TOSOH corporation and Inova Diagnostics. The remaining authors had no conflicts to declare related to this study.

SOURCE: Joshita S et al. Scientific Reports. 2018 May 25. doi: 10.1038/s41598-018-26531-0.

The liver enzyme autotaxin may be a useful noninvasive marker of disease progression in people with primary biliary cholangitis (PBC), new research has suggested.

Satoru Joshita, MD, from the gastroenterology and hepatology department at Shinshu University in Matsumoto, Japan, and colleagues noted that the liver-specific autoimmune disease PBC is characterized by the destruction of bile ducts, leading to cirrhosis and liver failure, and is more often seen in women.

Symptoms at diagnosis, a lack of response to gold standard treatment with ursodeoxycholic acid, and more advanced histologic phase are linked to worse patient outcomes, the research team explained in Scientific Reports.

While liver biopsy could give vital information on the severity of disease, it is an invasive procedure that is limited by sampling error and interobserver disparity. “As advanced histological stage is associated with a worse prognosis in PBC patients, it is important for clinicians to know clinical stage noninvasively when deciding appropriate therapies,” they wrote.

Noninvasive measures of liver fibrosis and PBC progression are available, such as Wisteria floribunda agglutinin–positive Mac-2 binding protein, hyaluronic acid, and type IV collagen 7S, but the authors said their “diagnostic abilities remain under scrutiny” because of their “moderate” accuracy.

Previous research had described autotaxin (ATX), a secreted enzyme metabolized by liver sinusoidal endothelial cells, as a prognostic factor for overall survival in cirrhosis patients, which suggested “an important role of ATX in the progression of liver disease,” the researchers noted.

They therefore set out to assess its utility as a marker of primary biliary cholangitis disease progression by measuring the serum ATX values of 128 treatment-naive, histologically assessed PBC patients, 108 of whom were female and 20 were male. Their ATX levels were then compared with 80 healthy controls.

Results showed that the ATX levels of patients with PBC were significantly higher than those of controls (median, 0.97 mg/L vs. 0.76 mg/L, respectively; P less than .0001).

Autotaxin results were validated by biopsy-proven histologic assessment: Patients with PBC that was classified as Nakanuma’s stage I, II, III, and IV had median ATX concentrations of 0.70, 0.80, 0.87, 1.03, and 1.70 mg/L, respectively, which demonstrated significant increases in concentration of ATX with disease stage (r = 0.53; P less than .0001). The researchers confirmed this finding using Scheuer’s classification of the disease (r = 0.43; P less than .0001).

The researchers noted that their findings were also “well correlated with other established noninvasive fibrosis markers, indicating ATX to be a reliable clinical surrogate marker to predict disease progression in patients with PBC.”

For example, autotaxin levels correlated with W. floribunda agglutinin–positive Mac-2 binding protein (r = 0.51; P less than .0001) and the fibrosis index based on four factors index (r = 0.51; P less than .0001).

Interestingly, the researchers found a sex difference in ATX levels: Not only were ATX values in female patients significantly higher than those in female controls (median, 1.00 mg/L vs. 0.82 mg/L, respectively; P less than .001) but they also were higher than those of male patients (median, 0.78 mg/L; P = .005).

According to the authors, these findings highlighted a need for sex-specific benchmarks, as well as more research to clarify why the sex disparity existed.

A further longitudinal study conducted by the authors involving 29 patients seen at their clinic showed that ATX levels increased slowly but significantly over an 18-year period, with a median increase rate of 0.03 mg/L per year (P less than .00001).

Patients who died from their disease had a significantly higher autotaxin increase rate than did survivors (0.05 mg/L per year vs. 0.02 mg/L per year, respectively; P less than .01).

Based on their findings, the researchers concluded that serum ATX levels “represent an accurate, noninvasive biomarker for estimating disease progression in patients with PBC.”

However, they said a longer longitudinal study of patients with PBC looking at ATX levels and clinical features, as well as long-term prognosis and complicating hepatocellular carcinoma, was warranted.

Two coauthors are employees of TOSOH corporation and Inova Diagnostics. The remaining authors had no conflicts to declare related to this study.

SOURCE: Joshita S et al. Scientific Reports. 2018 May 25. doi: 10.1038/s41598-018-26531-0.

The liver enzyme autotaxin may be a useful noninvasive marker of disease progression in people with primary biliary cholangitis (PBC), new research has suggested.

Satoru Joshita, MD, from the gastroenterology and hepatology department at Shinshu University in Matsumoto, Japan, and colleagues noted that the liver-specific autoimmune disease PBC is characterized by the destruction of bile ducts, leading to cirrhosis and liver failure, and is more often seen in women.

Symptoms at diagnosis, a lack of response to gold standard treatment with ursodeoxycholic acid, and more advanced histologic phase are linked to worse patient outcomes, the research team explained in Scientific Reports.

While liver biopsy could give vital information on the severity of disease, it is an invasive procedure that is limited by sampling error and interobserver disparity. “As advanced histological stage is associated with a worse prognosis in PBC patients, it is important for clinicians to know clinical stage noninvasively when deciding appropriate therapies,” they wrote.

Noninvasive measures of liver fibrosis and PBC progression are available, such as Wisteria floribunda agglutinin–positive Mac-2 binding protein, hyaluronic acid, and type IV collagen 7S, but the authors said their “diagnostic abilities remain under scrutiny” because of their “moderate” accuracy.

Previous research had described autotaxin (ATX), a secreted enzyme metabolized by liver sinusoidal endothelial cells, as a prognostic factor for overall survival in cirrhosis patients, which suggested “an important role of ATX in the progression of liver disease,” the researchers noted.

They therefore set out to assess its utility as a marker of primary biliary cholangitis disease progression by measuring the serum ATX values of 128 treatment-naive, histologically assessed PBC patients, 108 of whom were female and 20 were male. Their ATX levels were then compared with 80 healthy controls.

Results showed that the ATX levels of patients with PBC were significantly higher than those of controls (median, 0.97 mg/L vs. 0.76 mg/L, respectively; P less than .0001).

Autotaxin results were validated by biopsy-proven histologic assessment: Patients with PBC that was classified as Nakanuma’s stage I, II, III, and IV had median ATX concentrations of 0.70, 0.80, 0.87, 1.03, and 1.70 mg/L, respectively, which demonstrated significant increases in concentration of ATX with disease stage (r = 0.53; P less than .0001). The researchers confirmed this finding using Scheuer’s classification of the disease (r = 0.43; P less than .0001).

The researchers noted that their findings were also “well correlated with other established noninvasive fibrosis markers, indicating ATX to be a reliable clinical surrogate marker to predict disease progression in patients with PBC.”

For example, autotaxin levels correlated with W. floribunda agglutinin–positive Mac-2 binding protein (r = 0.51; P less than .0001) and the fibrosis index based on four factors index (r = 0.51; P less than .0001).

Interestingly, the researchers found a sex difference in ATX levels: Not only were ATX values in female patients significantly higher than those in female controls (median, 1.00 mg/L vs. 0.82 mg/L, respectively; P less than .001) but they also were higher than those of male patients (median, 0.78 mg/L; P = .005).

According to the authors, these findings highlighted a need for sex-specific benchmarks, as well as more research to clarify why the sex disparity existed.

A further longitudinal study conducted by the authors involving 29 patients seen at their clinic showed that ATX levels increased slowly but significantly over an 18-year period, with a median increase rate of 0.03 mg/L per year (P less than .00001).

Patients who died from their disease had a significantly higher autotaxin increase rate than did survivors (0.05 mg/L per year vs. 0.02 mg/L per year, respectively; P less than .01).

Based on their findings, the researchers concluded that serum ATX levels “represent an accurate, noninvasive biomarker for estimating disease progression in patients with PBC.”

However, they said a longer longitudinal study of patients with PBC looking at ATX levels and clinical features, as well as long-term prognosis and complicating hepatocellular carcinoma, was warranted.

Two coauthors are employees of TOSOH corporation and Inova Diagnostics. The remaining authors had no conflicts to declare related to this study.

SOURCE: Joshita S et al. Scientific Reports. 2018 May 25. doi: 10.1038/s41598-018-26531-0.

WASHINGTON – Treatment of hepatitis C infection with a direct-acting antiviral drug strongly linked with a rapid, 14% drop in the incidence of all nonhepatic cancers, based on analysis of data from more than 30,000 U.S. patients.

The data also showed statistically significant drops in the incidence rates of several specific nonliver cancers among hepatitis C–infected patients treated with a direct-acting antiviral (DAA) drug, compared with infected patients who had been treated with an interferon-based regimen during the period immediately preceding the availability of DAAs in late 2013. This included a 45% cut in lung cancers, a 49% cut in bladder cancer, a 62% relative risk reduction in leukemia, and a 29% drop in prostate cancer, Michael B. Charlton, MD, said at the annual Digestive Disease Week.^®

The relative reductions in nonhepatic cancer incidence appeared soon after DAA treatment. The data Dr. Charlton reported reflected a median follow-up of 1 year for DAA-treated patients and 2.6 years for the hepatitis C–infected patients who had received interferon and did not get a DAA. A major difference between these two regimens is their efficacy, with DAA regimens producing sustained virologic response rates of 90% or better, while the interferon regimens produced substantially lower eradication rates.

“The most obvious hypothesis” to explain the observed effects is that “hepatitis C is a potent carcinogen,” possibly acting by inhibiting immune surveillance for new cancers in infected people, Dr. Charlton said in a video interview.

The study he reported used insurance-claims data from more than 146 million U.S. residents during 2007-2017 in the IQVIA PharMetrics Plus database, which included more than 367,000 adults infected with hepatitis C. Dr. Charlton and his associates pulled from this claims data on 10,989 of the infected patients who received interferon during January 2007-May 2011 (and followed through November 2013), and 22,894 infected patients treated with any type of DAA during December 2013 through March 2017. They used these two discrete time windows to completely separate the patients who received a DAA from those who did not.

The primary analysis calculated a hazard ratio for the development of any nonhepatic cancer after adjustment for a number of demographic and clinical covariates including age, smoking history, and weight, and also applied propensity-score weighting to the data. The Kaplan-Meier analysis of the data showed clear separation of the cancer-free survival curves of the two subgroups by 6 months of follow-up, and then showed steady further separation over time suggesting an ongoing carcinogenic effect from continued hepatitis C infection in patients who had received the less effective antiviral regimen. The analysis was able to reveal this effect because it had data from many thousands of treated hepatitis C patients, far more than had been enrolled in the pivotal trials for the DAAs, noted Dr. Charlton, professor and director of the Center for Liver Diseases at the University of Chicago.

The Centers for Disease Control and Prevention estimates that 3.5 million Americans have a chronic hepatitis C infection. Dr. Charlton believed the number today might be more like 1-2 million remaining chronic U.S. cases because of the strong impact of DAA treatment. These chronic infections largely remain because hepatitis C is mostly silent and many clinicians fail to act on screening recommendations. The new findings provide even greater incentive for more rigorous screening and treatment, Dr. Charlton suggested.

“As if you needed another reason to get rid of hepatitis C, lowering your cancer risk is now added to the list,” he said.

[email protected]

WASHINGTON – Treatment of hepatitis C infection with a direct-acting antiviral drug strongly linked with a rapid, 14% drop in the incidence of all nonhepatic cancers, based on analysis of data from more than 30,000 U.S. patients.

The data also showed statistically significant drops in the incidence rates of several specific nonliver cancers among hepatitis C–infected patients treated with a direct-acting antiviral (DAA) drug, compared with infected patients who had been treated with an interferon-based regimen during the period immediately preceding the availability of DAAs in late 2013. This included a 45% cut in lung cancers, a 49% cut in bladder cancer, a 62% relative risk reduction in leukemia, and a 29% drop in prostate cancer, Michael B. Charlton, MD, said at the annual Digestive Disease Week.^®

The relative reductions in nonhepatic cancer incidence appeared soon after DAA treatment. The data Dr. Charlton reported reflected a median follow-up of 1 year for DAA-treated patients and 2.6 years for the hepatitis C–infected patients who had received interferon and did not get a DAA. A major difference between these two regimens is their efficacy, with DAA regimens producing sustained virologic response rates of 90% or better, while the interferon regimens produced substantially lower eradication rates.

“The most obvious hypothesis” to explain the observed effects is that “hepatitis C is a potent carcinogen,” possibly acting by inhibiting immune surveillance for new cancers in infected people, Dr. Charlton said in a video interview.

The study he reported used insurance-claims data from more than 146 million U.S. residents during 2007-2017 in the IQVIA PharMetrics Plus database, which included more than 367,000 adults infected with hepatitis C. Dr. Charlton and his associates pulled from this claims data on 10,989 of the infected patients who received interferon during January 2007-May 2011 (and followed through November 2013), and 22,894 infected patients treated with any type of DAA during December 2013 through March 2017. They used these two discrete time windows to completely separate the patients who received a DAA from those who did not.

The primary analysis calculated a hazard ratio for the development of any nonhepatic cancer after adjustment for a number of demographic and clinical covariates including age, smoking history, and weight, and also applied propensity-score weighting to the data. The Kaplan-Meier analysis of the data showed clear separation of the cancer-free survival curves of the two subgroups by 6 months of follow-up, and then showed steady further separation over time suggesting an ongoing carcinogenic effect from continued hepatitis C infection in patients who had received the less effective antiviral regimen. The analysis was able to reveal this effect because it had data from many thousands of treated hepatitis C patients, far more than had been enrolled in the pivotal trials for the DAAs, noted Dr. Charlton, professor and director of the Center for Liver Diseases at the University of Chicago.

The Centers for Disease Control and Prevention estimates that 3.5 million Americans have a chronic hepatitis C infection. Dr. Charlton believed the number today might be more like 1-2 million remaining chronic U.S. cases because of the strong impact of DAA treatment. These chronic infections largely remain because hepatitis C is mostly silent and many clinicians fail to act on screening recommendations. The new findings provide even greater incentive for more rigorous screening and treatment, Dr. Charlton suggested.

“As if you needed another reason to get rid of hepatitis C, lowering your cancer risk is now added to the list,” he said.

[email protected]

WASHINGTON – Treatment of hepatitis C infection with a direct-acting antiviral drug strongly linked with a rapid, 14% drop in the incidence of all nonhepatic cancers, based on analysis of data from more than 30,000 U.S. patients.

The data also showed statistically significant drops in the incidence rates of several specific nonliver cancers among hepatitis C–infected patients treated with a direct-acting antiviral (DAA) drug, compared with infected patients who had been treated with an interferon-based regimen during the period immediately preceding the availability of DAAs in late 2013. This included a 45% cut in lung cancers, a 49% cut in bladder cancer, a 62% relative risk reduction in leukemia, and a 29% drop in prostate cancer, Michael B. Charlton, MD, said at the annual Digestive Disease Week.^®

The relative reductions in nonhepatic cancer incidence appeared soon after DAA treatment. The data Dr. Charlton reported reflected a median follow-up of 1 year for DAA-treated patients and 2.6 years for the hepatitis C–infected patients who had received interferon and did not get a DAA. A major difference between these two regimens is their efficacy, with DAA regimens producing sustained virologic response rates of 90% or better, while the interferon regimens produced substantially lower eradication rates.

“The most obvious hypothesis” to explain the observed effects is that “hepatitis C is a potent carcinogen,” possibly acting by inhibiting immune surveillance for new cancers in infected people, Dr. Charlton said in a video interview.

The study he reported used insurance-claims data from more than 146 million U.S. residents during 2007-2017 in the IQVIA PharMetrics Plus database, which included more than 367,000 adults infected with hepatitis C. Dr. Charlton and his associates pulled from this claims data on 10,989 of the infected patients who received interferon during January 2007-May 2011 (and followed through November 2013), and 22,894 infected patients treated with any type of DAA during December 2013 through March 2017. They used these two discrete time windows to completely separate the patients who received a DAA from those who did not.

The primary analysis calculated a hazard ratio for the development of any nonhepatic cancer after adjustment for a number of demographic and clinical covariates including age, smoking history, and weight, and also applied propensity-score weighting to the data. The Kaplan-Meier analysis of the data showed clear separation of the cancer-free survival curves of the two subgroups by 6 months of follow-up, and then showed steady further separation over time suggesting an ongoing carcinogenic effect from continued hepatitis C infection in patients who had received the less effective antiviral regimen. The analysis was able to reveal this effect because it had data from many thousands of treated hepatitis C patients, far more than had been enrolled in the pivotal trials for the DAAs, noted Dr. Charlton, professor and director of the Center for Liver Diseases at the University of Chicago.

The Centers for Disease Control and Prevention estimates that 3.5 million Americans have a chronic hepatitis C infection. Dr. Charlton believed the number today might be more like 1-2 million remaining chronic U.S. cases because of the strong impact of DAA treatment. These chronic infections largely remain because hepatitis C is mostly silent and many clinicians fail to act on screening recommendations. The new findings provide even greater incentive for more rigorous screening and treatment, Dr. Charlton suggested.

“As if you needed another reason to get rid of hepatitis C, lowering your cancer risk is now added to the list,” he said.

[email protected]

WASHINGTON – Several potential treatments for nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) currently in phase 3 trials show promise in treating these complex disorders.

“When we talk emerging treatments in NASH, focusing on phase 3s [trials], there are really four drugs,” said Stephen Harrison, MD, the medical director of Pinnacle Clinical Research at the annual Digestive Disease Week^®. “There’s elafibranor, obeticholic acid (OCA), selonsertib, and cenicriviroc. Each of these have there own phase 3.”

The phase 3 trials for these drugs have different primary endpoints, an important factor to consider, according to Dr. Harrison.

OCA is one of the promising drugs to treat NASH. It is already approved by the Food and Drug Administration to treat primary biliary cholangitis. In FLINT (The Farnesoid X Receptor Ligand Obeticholic Acid in NASH Treatment Trial), a phase 2 study, OCA showed promise in treating NASH. In this double-blind, randomized, controlled trial, 141 patients received 25 mg of OCA daily for 72 weeks while another 142 received placebo. By the end of the study, 45% of 110 patients in the OCA group had improved their liver histology, compared with only 21% of patients receiving placebo.

Currently, the REGENERATE trial is evaluating the effects of obeticholic acid on histologic improvement and liver related outcomes in NASH patients. Patients have been randomized to receive either 10 mg of OCA, 25 mg of OCA, or placebo. As of yet, no results have been posted.

Much as he did for trials involving OCA, Dr. Harrison also detailed the results of a phase 2b elafibranor study that led to a registration trial that is currently underway. In Golden 505 (Phase IIb Study to Evaluate the Efficacy and Safety of GFT505 Versus Placebo in Patients With Non-Alcoholic Steatohepatitis), patients were randomized to receive either GFT505 80 mg, GFT505 120 mg, or placebo. The aim of the study was to identify the percentage of responders with disappearance of steatohepatitis without worsening of fibrosis. Unfortunately, there was no difference between placebo and the treatment groups for this outcome, although a post hoc analysis did reveal that NASH resolved in a higher proportion of the 120-mg elafibranor group, compared with the placebo group (19% vs. 12%, respectively). This also translated into a reduction of 0.65 in liver fibrosis stages in responders, compared with a 0.10 increase in nonresponders (P less than .001).

Now, elafibranor is being further examined in RESOLVE-IT (Phase 3 Study to Evaluate the Efficacy and Safety of Elafibranor Versus Placebo in Patients With Nonalcoholic Steatohepatitis), but no results have been posted at press time.

Cenicriviroc has followed a similar path, with a phase 2b leading to a phase 3 study.

[email protected]

SOURCE: Harrison S. DDW 2018, Presentation 2230.

WASHINGTON – Several potential treatments for nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) currently in phase 3 trials show promise in treating these complex disorders.

“When we talk emerging treatments in NASH, focusing on phase 3s [trials], there are really four drugs,” said Stephen Harrison, MD, the medical director of Pinnacle Clinical Research at the annual Digestive Disease Week^®. “There’s elafibranor, obeticholic acid (OCA), selonsertib, and cenicriviroc. Each of these have there own phase 3.”

The phase 3 trials for these drugs have different primary endpoints, an important factor to consider, according to Dr. Harrison.

OCA is one of the promising drugs to treat NASH. It is already approved by the Food and Drug Administration to treat primary biliary cholangitis. In FLINT (The Farnesoid X Receptor Ligand Obeticholic Acid in NASH Treatment Trial), a phase 2 study, OCA showed promise in treating NASH. In this double-blind, randomized, controlled trial, 141 patients received 25 mg of OCA daily for 72 weeks while another 142 received placebo. By the end of the study, 45% of 110 patients in the OCA group had improved their liver histology, compared with only 21% of patients receiving placebo.

Currently, the REGENERATE trial is evaluating the effects of obeticholic acid on histologic improvement and liver related outcomes in NASH patients. Patients have been randomized to receive either 10 mg of OCA, 25 mg of OCA, or placebo. As of yet, no results have been posted.

Much as he did for trials involving OCA, Dr. Harrison also detailed the results of a phase 2b elafibranor study that led to a registration trial that is currently underway. In Golden 505 (Phase IIb Study to Evaluate the Efficacy and Safety of GFT505 Versus Placebo in Patients With Non-Alcoholic Steatohepatitis), patients were randomized to receive either GFT505 80 mg, GFT505 120 mg, or placebo. The aim of the study was to identify the percentage of responders with disappearance of steatohepatitis without worsening of fibrosis. Unfortunately, there was no difference between placebo and the treatment groups for this outcome, although a post hoc analysis did reveal that NASH resolved in a higher proportion of the 120-mg elafibranor group, compared with the placebo group (19% vs. 12%, respectively). This also translated into a reduction of 0.65 in liver fibrosis stages in responders, compared with a 0.10 increase in nonresponders (P less than .001).

Now, elafibranor is being further examined in RESOLVE-IT (Phase 3 Study to Evaluate the Efficacy and Safety of Elafibranor Versus Placebo in Patients With Nonalcoholic Steatohepatitis), but no results have been posted at press time.

Cenicriviroc has followed a similar path, with a phase 2b leading to a phase 3 study.

[email protected]

SOURCE: Harrison S. DDW 2018, Presentation 2230.

WASHINGTON – Several potential treatments for nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) currently in phase 3 trials show promise in treating these complex disorders.

“When we talk emerging treatments in NASH, focusing on phase 3s [trials], there are really four drugs,” said Stephen Harrison, MD, the medical director of Pinnacle Clinical Research at the annual Digestive Disease Week^®. “There’s elafibranor, obeticholic acid (OCA), selonsertib, and cenicriviroc. Each of these have there own phase 3.”

The phase 3 trials for these drugs have different primary endpoints, an important factor to consider, according to Dr. Harrison.

OCA is one of the promising drugs to treat NASH. It is already approved by the Food and Drug Administration to treat primary biliary cholangitis. In FLINT (The Farnesoid X Receptor Ligand Obeticholic Acid in NASH Treatment Trial), a phase 2 study, OCA showed promise in treating NASH. In this double-blind, randomized, controlled trial, 141 patients received 25 mg of OCA daily for 72 weeks while another 142 received placebo. By the end of the study, 45% of 110 patients in the OCA group had improved their liver histology, compared with only 21% of patients receiving placebo.

Currently, the REGENERATE trial is evaluating the effects of obeticholic acid on histologic improvement and liver related outcomes in NASH patients. Patients have been randomized to receive either 10 mg of OCA, 25 mg of OCA, or placebo. As of yet, no results have been posted.

Much as he did for trials involving OCA, Dr. Harrison also detailed the results of a phase 2b elafibranor study that led to a registration trial that is currently underway. In Golden 505 (Phase IIb Study to Evaluate the Efficacy and Safety of GFT505 Versus Placebo in Patients With Non-Alcoholic Steatohepatitis), patients were randomized to receive either GFT505 80 mg, GFT505 120 mg, or placebo. The aim of the study was to identify the percentage of responders with disappearance of steatohepatitis without worsening of fibrosis. Unfortunately, there was no difference between placebo and the treatment groups for this outcome, although a post hoc analysis did reveal that NASH resolved in a higher proportion of the 120-mg elafibranor group, compared with the placebo group (19% vs. 12%, respectively). This also translated into a reduction of 0.65 in liver fibrosis stages in responders, compared with a 0.10 increase in nonresponders (P less than .001).

Now, elafibranor is being further examined in RESOLVE-IT (Phase 3 Study to Evaluate the Efficacy and Safety of Elafibranor Versus Placebo in Patients With Nonalcoholic Steatohepatitis), but no results have been posted at press time.

Cenicriviroc has followed a similar path, with a phase 2b leading to a phase 3 study.

[email protected]

SOURCE: Harrison S. DDW 2018, Presentation 2230.

WASHINGTON – Though the liver safety of statins in patients with low-level liver enzyme elevations has long been established, some providers still hesitate to prescribe them to the patients with the conditions for which they are indicated.

Nonalcoholic fatty liver disease (NAFLD), hyperlipidemia, metabolic syndrome, and diabetes, which often co-occur, are also involved in cardiovascular disease. Cardiovascular disease is the most common cause of mortality in NAFLD, before liver disease.

Sonal Kumar, MD, MPH, of New York–Presbyterian Hospital described in a video interview at the annual Digestive Disease Week^® a study she and her colleagues conducted to evaluate statin use in patients with hyperlipidemia by using data from the National Health and Nutrition Examination Survey during 2005-2014 (NHANES). Adult patients aged over 18 years were included if they did not have viral hepatitis, did not excessively consume alcohol, were not pregnant, and did not have transaminase levels over 500 IU/L.

Statin use was assessed in 136,833,627 participants by NHANES interviewers. Of these participants, 74.6% had hyperlipidemia (defined as LDL cholesterol greater than 130 mg/dL) and 93.5% were taking a statin. Patients with hyperlipidemia with abnormal alanine aminotransferase values were significantly less likely to be taking a statin (86.3% vs. 89.1%, P = .001). With multivariate analysis, abnormal ALT significantly decreased the odds of patients receiving a statin if they had diabetes (odds ratio, 0.75; 95% confidence interval, 0.57-0.99) when sex and age were controlled for.

Statins are underutilized in patients with NAFLD and diabetes, patient groups in whom they could help control cardiovascular disease risk factors, said Dr. Kumar. Providers need to be educated on the safety of statins in these patients to improve cardiovascular outcomes.

Dr. Kumar reported receiving support from Gilead and AbbVie.

[email protected]

WASHINGTON – Though the liver safety of statins in patients with low-level liver enzyme elevations has long been established, some providers still hesitate to prescribe them to the patients with the conditions for which they are indicated.

Nonalcoholic fatty liver disease (NAFLD), hyperlipidemia, metabolic syndrome, and diabetes, which often co-occur, are also involved in cardiovascular disease. Cardiovascular disease is the most common cause of mortality in NAFLD, before liver disease.

Sonal Kumar, MD, MPH, of New York–Presbyterian Hospital described in a video interview at the annual Digestive Disease Week^® a study she and her colleagues conducted to evaluate statin use in patients with hyperlipidemia by using data from the National Health and Nutrition Examination Survey during 2005-2014 (NHANES). Adult patients aged over 18 years were included if they did not have viral hepatitis, did not excessively consume alcohol, were not pregnant, and did not have transaminase levels over 500 IU/L.

Statin use was assessed in 136,833,627 participants by NHANES interviewers. Of these participants, 74.6% had hyperlipidemia (defined as LDL cholesterol greater than 130 mg/dL) and 93.5% were taking a statin. Patients with hyperlipidemia with abnormal alanine aminotransferase values were significantly less likely to be taking a statin (86.3% vs. 89.1%, P = .001). With multivariate analysis, abnormal ALT significantly decreased the odds of patients receiving a statin if they had diabetes (odds ratio, 0.75; 95% confidence interval, 0.57-0.99) when sex and age were controlled for.

Statins are underutilized in patients with NAFLD and diabetes, patient groups in whom they could help control cardiovascular disease risk factors, said Dr. Kumar. Providers need to be educated on the safety of statins in these patients to improve cardiovascular outcomes.

Dr. Kumar reported receiving support from Gilead and AbbVie.

[email protected]

WASHINGTON – Though the liver safety of statins in patients with low-level liver enzyme elevations has long been established, some providers still hesitate to prescribe them to the patients with the conditions for which they are indicated.

Nonalcoholic fatty liver disease (NAFLD), hyperlipidemia, metabolic syndrome, and diabetes, which often co-occur, are also involved in cardiovascular disease. Cardiovascular disease is the most common cause of mortality in NAFLD, before liver disease.

Sonal Kumar, MD, MPH, of New York–Presbyterian Hospital described in a video interview at the annual Digestive Disease Week^® a study she and her colleagues conducted to evaluate statin use in patients with hyperlipidemia by using data from the National Health and Nutrition Examination Survey during 2005-2014 (NHANES). Adult patients aged over 18 years were included if they did not have viral hepatitis, did not excessively consume alcohol, were not pregnant, and did not have transaminase levels over 500 IU/L.

Statin use was assessed in 136,833,627 participants by NHANES interviewers. Of these participants, 74.6% had hyperlipidemia (defined as LDL cholesterol greater than 130 mg/dL) and 93.5% were taking a statin. Patients with hyperlipidemia with abnormal alanine aminotransferase values were significantly less likely to be taking a statin (86.3% vs. 89.1%, P = .001). With multivariate analysis, abnormal ALT significantly decreased the odds of patients receiving a statin if they had diabetes (odds ratio, 0.75; 95% confidence interval, 0.57-0.99) when sex and age were controlled for.

Statins are underutilized in patients with NAFLD and diabetes, patient groups in whom they could help control cardiovascular disease risk factors, said Dr. Kumar. Providers need to be educated on the safety of statins in these patients to improve cardiovascular outcomes.

Dr. Kumar reported receiving support from Gilead and AbbVie.

[email protected]

A new scoring system predicted which patients with decompensated cirrhosis caused by hepatitis C virus (HCV) infection were most likely to experience meaningful benefits from direct-acting antiviral (DAA) therapy.

Dubbed BEA3, their scoring system assigns one point each for body mass index under 25 kg/m², absence of encephalopathy, absence of ascites, ALT more than 1.5 times the upper limit of normal, and albumin above 3.5 g/dL. Patients who scored 4 or 5 were more than 50 times more likely to improve to Child-Pugh Turcotte (CPT) class A (compensated) cirrhosis with DAA therapy than were patients who scored 0 (hazard ratio, 52.3; 95% confidence interval, 15.2-179.7; P less than .001), wrote Omar El-Sherif, MB, BCh, of St. James’s Hospital, Dublin, together with his associates in the June issue of Gastroenterology.

Eradicating HCV does not necessarily improve the odds of transplant-free survival in the setting of decompensated cirrhosis, the researchers noted. Patients can end up in “MELD [Model for End-Stage Liver Disease] purgatory,” meaning they are still decompensated despite achieving sustained virologic response and improved MELD scores. Such patients can face longer waits for liver transplantation than if they had foregone DAA therapy. “There is an urgent need for data to refine our understanding of the reversibility of hepatic decompensation with viral eradication, and, ultimately, define the “point of no return,” the degree of liver dysfunction at which HCV therapy does not yield any meaningful clinical benefit, the researchers wrote.

Their study included 622 patients from the SOLAR-1, SOLAR-2, ASTRAL-4, and GS-US-334-0125 trials, which evaluated interferon-free sofosbuvir-based DAA therapy in patients with chronic hepatitis C virus infection and advanced liver disease. Patients received 12 or 24 weeks of therapy with ledipasvir, sofosbuvir, and ribavirin or velpatasvir, sofosbuvir, and/or ribavirin, or 48 weeks of treatment with sofosbuvir and ribavirin.

A total of 32% of patients with CPT class B cirrhosis improved to class A, as did 12% of patients with class C cirrhosis. Each factor in the scoring system independently affected the chances of reaching CPT class A cirrhosis, even after accounting for SVR.

Notably, patients with intermediate BEA3 scores of 1, 2, or 3 were significantly more likely to reach CPT class A cirrhosis than were patients with scores of 0, with hazard ratios ranging from 4.2 (for a score of 1) to 21.2 (for a score of 3). Most patients had scores of 0 (106 individuals), 1 (219 individuals), or 2 (180 individuals), and only 23 patients scored a 4 or a 5.

CPT score reflects prothrombin time, serum albumin and bilirubin, and the presence or severity of ascites. The investigators called the new scoring system “a tool that can enhance shared decision making at the point of care, quantifying the potential benefits of DAA therapy for patients with decompensated cirrhosis in the pretransplant setting.”Dr. El-Sherif disclosed ties to Gilead Sciences, Bristol-Myers Squibb, and the Health Research Board of Ireland. Four coinvestigators disclosed employment with Gilead, and several other coinvestigators disclosed ties to Gilead, BMS, AbbVie, and other companies.
 

SOURCE: El-Sherif O et al. Gastroenterology. 2018 Mar 10. doi: 10.1053/j.gastro.2018.03.022.

A new scoring system predicted which patients with decompensated cirrhosis caused by hepatitis C virus (HCV) infection were most likely to experience meaningful benefits from direct-acting antiviral (DAA) therapy.

Dubbed BEA3, their scoring system assigns one point each for body mass index under 25 kg/m², absence of encephalopathy, absence of ascites, ALT more than 1.5 times the upper limit of normal, and albumin above 3.5 g/dL. Patients who scored 4 or 5 were more than 50 times more likely to improve to Child-Pugh Turcotte (CPT) class A (compensated) cirrhosis with DAA therapy than were patients who scored 0 (hazard ratio, 52.3; 95% confidence interval, 15.2-179.7; P less than .001), wrote Omar El-Sherif, MB, BCh, of St. James’s Hospital, Dublin, together with his associates in the June issue of Gastroenterology.

Eradicating HCV does not necessarily improve the odds of transplant-free survival in the setting of decompensated cirrhosis, the researchers noted. Patients can end up in “MELD [Model for End-Stage Liver Disease] purgatory,” meaning they are still decompensated despite achieving sustained virologic response and improved MELD scores. Such patients can face longer waits for liver transplantation than if they had foregone DAA therapy. “There is an urgent need for data to refine our understanding of the reversibility of hepatic decompensation with viral eradication, and, ultimately, define the “point of no return,” the degree of liver dysfunction at which HCV therapy does not yield any meaningful clinical benefit, the researchers wrote.

Their study included 622 patients from the SOLAR-1, SOLAR-2, ASTRAL-4, and GS-US-334-0125 trials, which evaluated interferon-free sofosbuvir-based DAA therapy in patients with chronic hepatitis C virus infection and advanced liver disease. Patients received 12 or 24 weeks of therapy with ledipasvir, sofosbuvir, and ribavirin or velpatasvir, sofosbuvir, and/or ribavirin, or 48 weeks of treatment with sofosbuvir and ribavirin.

A total of 32% of patients with CPT class B cirrhosis improved to class A, as did 12% of patients with class C cirrhosis. Each factor in the scoring system independently affected the chances of reaching CPT class A cirrhosis, even after accounting for SVR.

Notably, patients with intermediate BEA3 scores of 1, 2, or 3 were significantly more likely to reach CPT class A cirrhosis than were patients with scores of 0, with hazard ratios ranging from 4.2 (for a score of 1) to 21.2 (for a score of 3). Most patients had scores of 0 (106 individuals), 1 (219 individuals), or 2 (180 individuals), and only 23 patients scored a 4 or a 5.

CPT score reflects prothrombin time, serum albumin and bilirubin, and the presence or severity of ascites. The investigators called the new scoring system “a tool that can enhance shared decision making at the point of care, quantifying the potential benefits of DAA therapy for patients with decompensated cirrhosis in the pretransplant setting.”Dr. El-Sherif disclosed ties to Gilead Sciences, Bristol-Myers Squibb, and the Health Research Board of Ireland. Four coinvestigators disclosed employment with Gilead, and several other coinvestigators disclosed ties to Gilead, BMS, AbbVie, and other companies.
 

SOURCE: El-Sherif O et al. Gastroenterology. 2018 Mar 10. doi: 10.1053/j.gastro.2018.03.022.

A new scoring system predicted which patients with decompensated cirrhosis caused by hepatitis C virus (HCV) infection were most likely to experience meaningful benefits from direct-acting antiviral (DAA) therapy.

Dubbed BEA3, their scoring system assigns one point each for body mass index under 25 kg/m², absence of encephalopathy, absence of ascites, ALT more than 1.5 times the upper limit of normal, and albumin above 3.5 g/dL. Patients who scored 4 or 5 were more than 50 times more likely to improve to Child-Pugh Turcotte (CPT) class A (compensated) cirrhosis with DAA therapy than were patients who scored 0 (hazard ratio, 52.3; 95% confidence interval, 15.2-179.7; P less than .001), wrote Omar El-Sherif, MB, BCh, of St. James’s Hospital, Dublin, together with his associates in the June issue of Gastroenterology.

Eradicating HCV does not necessarily improve the odds of transplant-free survival in the setting of decompensated cirrhosis, the researchers noted. Patients can end up in “MELD [Model for End-Stage Liver Disease] purgatory,” meaning they are still decompensated despite achieving sustained virologic response and improved MELD scores. Such patients can face longer waits for liver transplantation than if they had foregone DAA therapy. “There is an urgent need for data to refine our understanding of the reversibility of hepatic decompensation with viral eradication, and, ultimately, define the “point of no return,” the degree of liver dysfunction at which HCV therapy does not yield any meaningful clinical benefit, the researchers wrote.

Their study included 622 patients from the SOLAR-1, SOLAR-2, ASTRAL-4, and GS-US-334-0125 trials, which evaluated interferon-free sofosbuvir-based DAA therapy in patients with chronic hepatitis C virus infection and advanced liver disease. Patients received 12 or 24 weeks of therapy with ledipasvir, sofosbuvir, and ribavirin or velpatasvir, sofosbuvir, and/or ribavirin, or 48 weeks of treatment with sofosbuvir and ribavirin.

A total of 32% of patients with CPT class B cirrhosis improved to class A, as did 12% of patients with class C cirrhosis. Each factor in the scoring system independently affected the chances of reaching CPT class A cirrhosis, even after accounting for SVR.

Notably, patients with intermediate BEA3 scores of 1, 2, or 3 were significantly more likely to reach CPT class A cirrhosis than were patients with scores of 0, with hazard ratios ranging from 4.2 (for a score of 1) to 21.2 (for a score of 3). Most patients had scores of 0 (106 individuals), 1 (219 individuals), or 2 (180 individuals), and only 23 patients scored a 4 or a 5.

CPT score reflects prothrombin time, serum albumin and bilirubin, and the presence or severity of ascites. The investigators called the new scoring system “a tool that can enhance shared decision making at the point of care, quantifying the potential benefits of DAA therapy for patients with decompensated cirrhosis in the pretransplant setting.”Dr. El-Sherif disclosed ties to Gilead Sciences, Bristol-Myers Squibb, and the Health Research Board of Ireland. Four coinvestigators disclosed employment with Gilead, and several other coinvestigators disclosed ties to Gilead, BMS, AbbVie, and other companies.
 

SOURCE: El-Sherif O et al. Gastroenterology. 2018 Mar 10. doi: 10.1053/j.gastro.2018.03.022.

More transplant centers are offering liver transplantation as a viable therapeutic option for patients with severe alcoholic hepatitis who do not respond to steroid treatment.

“Alcoholic hepatitis is a disease caused by drinking alcohol. Excessive alcohol consumption causes fat to build up in your liver cells, as well as inflammation and scarring of the liver,” stated Saroja Bangaru, MD, chief resident at the University of Texas, Dallas. “Severe alcoholic hepatitis has an extremely high mortality and steroids are really the mainstay of therapy. Some alcoholic hepatitis patients do not respond to steroids and a significant percentage of them will die within 3 months. For these patients, liver transplantation is a therapeutic option.”

Dr. Bangaru and her colleagues conducted a survey that gathered data from 45 transplant centers in the United States and found that an increasing number have changed this practice and now offer liver transplantation to patients with severe alcoholic hepatitis.

The survey revealed that 51.1% of the 45 clinics offered liver transplantation to patients who had not yet been sober for 6 months, and 47.8% of transplant centers reported performing at least one liver transplant for severe alcoholic hepatitis. Just over a third (34.8%) of these centers had conducted three to five liver transplants, while only 8.9% of clinics performed at least six transplants. It is of note that most clinics have transplanted livers in fewer than five patients with severe alcoholic hepatitis, Dr. Bangaru said at the annual Digestive Disease Week^®.

Patients experienced positive outcomes from these transplants, with almost 75% of surveyed clinics reporting 1-year survival rates of more than 90%, and 15% reporting 1-year survival rates of 80%-90%.

A factor that may have contributed to such positive outcomes was good patient selection based on liver transplant criteria for severe alcoholic hepatitis. More than 85% of center directors believed that liver transplant candidates should have a strong social support system, absence of severe psychiatric disorders, and a completed psychosocial evaluation, among other criteria.

Dr. Bangaru pointed out that the change in treating patients who have not abstained from alcohol is a break from traditional medical practice. “Historically, transplant centers would not consider a liver transplantation as an option unless a patient had abstained from drinking alcohol for 6 months. This rule was due to a concern that the patient would return to drinking after transplant as well as a perceived high risk that patients who continued drinking would miss medical appointments, fail to take their immunosuppressants and medications, and that this would lead to eventual graft failure.”

Another compounding issue was that patients were not counseled on their alcohol consumption habits, leading to further issues with transplantation. “Not infrequently, patients receive a diagnosis of severe alcoholic hepatitis during their initial visit and no one had previously told them to stop drinking. Since their presentation was preceded by active alcohol consumption, they would essentially be rendered ineligible for a transplant at that time,” she said.

Despite the history surrounding liver transplants in patients with severe alcoholic hepatitis, Dr. Bangaru hopes the shift in practice will improve the lives of more patients. “Because this practice of transplantation is being increasingly accepted and demonstrating positive outcomes, the hope is that more patients will be evaluated for transplantation and that transplant centers will improve their posttransplant support to ensure patients have great success after transplantation.”

Digestive Disease Week^® is jointly sponsored by the American Association for the Study of Liver Diseases (AASLD), the American Gastroenterological Association (AGA) Institute, the American Society for Gastrointestinal Endoscopy (ASGE), and the Society for Surgery of the Alimentary Tract (SSAT).

[email protected]

More transplant centers are offering liver transplantation as a viable therapeutic option for patients with severe alcoholic hepatitis who do not respond to steroid treatment.

“Alcoholic hepatitis is a disease caused by drinking alcohol. Excessive alcohol consumption causes fat to build up in your liver cells, as well as inflammation and scarring of the liver,” stated Saroja Bangaru, MD, chief resident at the University of Texas, Dallas. “Severe alcoholic hepatitis has an extremely high mortality and steroids are really the mainstay of therapy. Some alcoholic hepatitis patients do not respond to steroids and a significant percentage of them will die within 3 months. For these patients, liver transplantation is a therapeutic option.”

Dr. Bangaru and her colleagues conducted a survey that gathered data from 45 transplant centers in the United States and found that an increasing number have changed this practice and now offer liver transplantation to patients with severe alcoholic hepatitis.

The survey revealed that 51.1% of the 45 clinics offered liver transplantation to patients who had not yet been sober for 6 months, and 47.8% of transplant centers reported performing at least one liver transplant for severe alcoholic hepatitis. Just over a third (34.8%) of these centers had conducted three to five liver transplants, while only 8.9% of clinics performed at least six transplants. It is of note that most clinics have transplanted livers in fewer than five patients with severe alcoholic hepatitis, Dr. Bangaru said at the annual Digestive Disease Week^®.

Patients experienced positive outcomes from these transplants, with almost 75% of surveyed clinics reporting 1-year survival rates of more than 90%, and 15% reporting 1-year survival rates of 80%-90%.

A factor that may have contributed to such positive outcomes was good patient selection based on liver transplant criteria for severe alcoholic hepatitis. More than 85% of center directors believed that liver transplant candidates should have a strong social support system, absence of severe psychiatric disorders, and a completed psychosocial evaluation, among other criteria.

Dr. Bangaru pointed out that the change in treating patients who have not abstained from alcohol is a break from traditional medical practice. “Historically, transplant centers would not consider a liver transplantation as an option unless a patient had abstained from drinking alcohol for 6 months. This rule was due to a concern that the patient would return to drinking after transplant as well as a perceived high risk that patients who continued drinking would miss medical appointments, fail to take their immunosuppressants and medications, and that this would lead to eventual graft failure.”

Another compounding issue was that patients were not counseled on their alcohol consumption habits, leading to further issues with transplantation. “Not infrequently, patients receive a diagnosis of severe alcoholic hepatitis during their initial visit and no one had previously told them to stop drinking. Since their presentation was preceded by active alcohol consumption, they would essentially be rendered ineligible for a transplant at that time,” she said.

Despite the history surrounding liver transplants in patients with severe alcoholic hepatitis, Dr. Bangaru hopes the shift in practice will improve the lives of more patients. “Because this practice of transplantation is being increasingly accepted and demonstrating positive outcomes, the hope is that more patients will be evaluated for transplantation and that transplant centers will improve their posttransplant support to ensure patients have great success after transplantation.”

Digestive Disease Week^® is jointly sponsored by the American Association for the Study of Liver Diseases (AASLD), the American Gastroenterological Association (AGA) Institute, the American Society for Gastrointestinal Endoscopy (ASGE), and the Society for Surgery of the Alimentary Tract (SSAT).

[email protected]

More transplant centers are offering liver transplantation as a viable therapeutic option for patients with severe alcoholic hepatitis who do not respond to steroid treatment.

“Alcoholic hepatitis is a disease caused by drinking alcohol. Excessive alcohol consumption causes fat to build up in your liver cells, as well as inflammation and scarring of the liver,” stated Saroja Bangaru, MD, chief resident at the University of Texas, Dallas. “Severe alcoholic hepatitis has an extremely high mortality and steroids are really the mainstay of therapy. Some alcoholic hepatitis patients do not respond to steroids and a significant percentage of them will die within 3 months. For these patients, liver transplantation is a therapeutic option.”

Dr. Bangaru and her colleagues conducted a survey that gathered data from 45 transplant centers in the United States and found that an increasing number have changed this practice and now offer liver transplantation to patients with severe alcoholic hepatitis.

The survey revealed that 51.1% of the 45 clinics offered liver transplantation to patients who had not yet been sober for 6 months, and 47.8% of transplant centers reported performing at least one liver transplant for severe alcoholic hepatitis. Just over a third (34.8%) of these centers had conducted three to five liver transplants, while only 8.9% of clinics performed at least six transplants. It is of note that most clinics have transplanted livers in fewer than five patients with severe alcoholic hepatitis, Dr. Bangaru said at the annual Digestive Disease Week^®.

Patients experienced positive outcomes from these transplants, with almost 75% of surveyed clinics reporting 1-year survival rates of more than 90%, and 15% reporting 1-year survival rates of 80%-90%.

A factor that may have contributed to such positive outcomes was good patient selection based on liver transplant criteria for severe alcoholic hepatitis. More than 85% of center directors believed that liver transplant candidates should have a strong social support system, absence of severe psychiatric disorders, and a completed psychosocial evaluation, among other criteria.

Dr. Bangaru pointed out that the change in treating patients who have not abstained from alcohol is a break from traditional medical practice. “Historically, transplant centers would not consider a liver transplantation as an option unless a patient had abstained from drinking alcohol for 6 months. This rule was due to a concern that the patient would return to drinking after transplant as well as a perceived high risk that patients who continued drinking would miss medical appointments, fail to take their immunosuppressants and medications, and that this would lead to eventual graft failure.”

Another compounding issue was that patients were not counseled on their alcohol consumption habits, leading to further issues with transplantation. “Not infrequently, patients receive a diagnosis of severe alcoholic hepatitis during their initial visit and no one had previously told them to stop drinking. Since their presentation was preceded by active alcohol consumption, they would essentially be rendered ineligible for a transplant at that time,” she said.

Despite the history surrounding liver transplants in patients with severe alcoholic hepatitis, Dr. Bangaru hopes the shift in practice will improve the lives of more patients. “Because this practice of transplantation is being increasingly accepted and demonstrating positive outcomes, the hope is that more patients will be evaluated for transplantation and that transplant centers will improve their posttransplant support to ensure patients have great success after transplantation.”

Digestive Disease Week^® is jointly sponsored by the American Association for the Study of Liver Diseases (AASLD), the American Gastroenterological Association (AGA) Institute, the American Society for Gastrointestinal Endoscopy (ASGE), and the Society for Surgery of the Alimentary Tract (SSAT).

[email protected]