Hepatology highlights
Authors: Jean-François Dufour
Journal: Hepatology (2014)

Hepatitis delta remains a therapeutic challenge. Interferon-alpha (IFN-α) is the sole therapeutic option for patients with chronic hepatitis delta, but results are suboptimal. Less than 30% of patients treated for 48 weeks with pegylated IFN-α (Peg-IFN-α) have a negative viremia 24 weeks after the end of treatment. Heidrich et al. report on the long-term outcome of patients treated in the HIDIT-1 trial. Their assessment is humbling. More than 50% of the patients with a negative viremia 24 weeks after treatment have late relapse, and Peg-IFN-α therapy was not associated with a reduction of hepatic events until year 5 of follow-up. On a positive note, none of the patients with a negative viremia at 24 weeks post-treatment experienced a clinical event. This article delivers two messages: (1) A negative viremia 24 weeks post-treatment should not be considered a sustained virological response (SVR) in hepatitis delta and (2) better treatments are required. (Hepatology 2014;60:87-97.) There is no doubt that the best way to avoid problems with hepatitis B virus (HBV) is to vaccinate at birth. Since the implementation of programs aiming at vaccinating every newborn, the effect of HBV decreased substantially, especially in countries with high prevalence. But, how important is it to have the multiple shots that a complete vaccination against HBV implies? To answer this question, Chien et al. stratified 3.8 million Taiwanese subjects, according to their complete or incomplete vaccination status, and investigated whether an incomplete vaccination could be associated with liver-related outcomes (i.e., chronic liver disease, hepatocellular carcinoma [HCC], or fulminant liver failure). All of these outcomes were significantly more frequent in individuals who did not receive a complete vaccination, in comparison with those who had a complete vaccination. To implement general vaccination against hepatitis B is excellent, but to be sure that the complete vaccination is performed is even better. (Hepatology 2014;60:125-132.) Patients with cirrhosis are prone to develop infections, and infections in these patients can lead to severe, potentially lethal complications, such as acute-on-chronic liver failure (ACLF). It is essential to identify patients at high risk as early as possible. Bajaj et al., for the North American Consortium for the Study of End-stage Liver Disease, studied 507 patients with cirrhosis hospitalized with an infection. The determinants of the development of infection-related ACLF (I-ACLF), defined as ≥2 organ failures, and the determinants of the 30-day mortality were identified using multivariable logistic regression. Urinary tract infections and spontaneous bacterial peritonitis were the most frequent infections. Model for End-Stage Liver Disease (MELD) score and nosocomial first infection were predictive of I-ACLF. The 30-day mortality reached 23%. MELD score, I-ACLF, white blood cell count, and second infection were predictive of mortality. As already reported by the Chronic Liver Failure (CLIF) Consortium, the higher the number of organ failures, the worse the prognosis. (Hepatology 2014;60:250-256.) To maintain cellular energy levels, cells can break down their own components in a complex catabolic process called autophagy. Autophagy protein 5 (ATG5) is an E3 ubiquitin ligase that is important for the formation of the autophagosome. In a previous Highlights article, we commented on ATG5 mediating the caffeine-induced reduction in intracellular lipids. In this issue of Hepatology, the work of Toshima et al. is reported on, whereby they used mice lacking hepatocellular ATG5 to investigate the role of autophagy during liver regeneration. They found that liver regeneration activates autophagy, and that autophagy is necessary to maintain β-oxidation and adenosine triphosphate production in mitochondria. Absence of ATG5 did not compromise the increase in liver weight after partial hepatectomy; on the contrary, it was higher in genetically modified mice. However, the absence of ATG5 impaired the postoperative mitotic response of hepatocytes, which became senescent and hypertrophic. This work identifies autophagy as an important recycling source of energy for normal liver regeneration. (Hepatology 2014;60:290-300.) Evaluation of elevated bilirubin levels in a patient treated in the intensive care unit (ICU) is a classic consultation for hepatologists. Invariably, not one cause, but several potential causes are found, for example, sepsis, transfusions, and drugs. The role of parenteral nutrition is often debated. Vanwijngaerden et al. used the data of the randomized, controlled EPaNIC trial, which was designed to test the effect of early (within 48 hours) versus late (after day 8) parenteral nutrition on the outcome of critical illness. They report that circulating levels of total bilirubin were higher in the ICU patients randomized to receive late parenteral nutrition during the week without this support. The values became identical in the two groups when both received parenteral nutrition. In contrast, levels of alanine aminotransferase (ALT), alkaline phosphatase, and gamma-glutamyltranspeptidase (GGT) were lower in the late parenteral nutrition group, and fewer patients developed sludge in this group. These data confirm that hyperbilirubinemia in ICU patients is not necessarily a result of cholestasis, but instead suggest that it can be related to caloric deficit resulting from withholding parenteral nutrition. (Hepatology 2014;60:202-210.) The natural history of chronic hepatitis B is not only about progression to cirrhosis and development of HCC. A substantial fraction of patients spontaneously clear hepatitis B e antigen (HBeAg) and have no more detectable levels of circulating HBV DNA. What are the clinical predictors for these favorable outcomes? Liu et al. investigated more than 2,000 hepatitis B surface antigen (HBsAg)-seropositive, untreated patients without cirrhosis enrolled in the REVEAL-HBV study. Baseline HBV DNA was the most important predictor of HBeAg seroclearance. Serum HBsAg levels were the most significant predictor of HBV DNA undetectability. Serum HBsAg levels are considered to reflect the translation of messenger RNA from the covalently closed circular DNA template, and quantitative determinations of HBsAg levels have been reported to be also predictive of response to treatment. Therefore, evolution of HBsAg levels over time with or without treatment has an important clinical significance. HBsAg levels are worth quantifying. (Hepatology 2014;60:77-86.) Unlike liver biopsies, liver stiffness measurement and noninvasive fibrosis scores, such as the fibrosis index based on the four factors (FIB-4) and aspartate aminotransferase (AST)/platelet ratio index (APRI), are easy to repeat, and their evolution over time can have prognostic significance. Vergniol et al. prospectively followed 1,025 patients with chronic hepatitis C (CHC) and repeated these tests with a 3-year interval. Liver stiffness measurement and the FIB-4 score, which combines platelets, AST, ALT, and age, were equally accurate for the prediction of death and performed better than the APRI score. Baseline and delta liver stiffness measurements, as well as baseline and delta FIB-4 measurements, categorized patients in groups with different prognosis. This work emphasizes the value of repeating noninvasive assessment of liver fibrosis in the management of patients with CHC. This concept is likely to be applicable to other liver diseases as well. (Hepatology 2014;60:65-76.) Hepatitis C virus (HCV) has seven different genotypes, and genotyping is necessary in daily practice because antiviral treatment is still tailored according to genotype. Until recently, it was thought that the natural history of CHC infection was not affected by genotype. Then, data suggested that infection with genotype 3 might progress more rapidly. In a very large study based on the U.S. veterans HCV Registry, Kanwal et al. assembled more than 110,000 patients with positive HCV viremia, of whom 80% were infected with genotype 1, 12% with genotype 2, and 8% with genotype 3. Patients infected with genotype 3 demonstrated a higher risk for developing cirrhosis and HCC, in comparison with patients infected with genotype 1, even after taking into account confounding factors, such as age, diabetes, body mass index, and antiviral treatment. HCV genotype 3 is known to have specific metabolic effects. It remains to be determined whether it is the bad guy because it is more steatogenic. (Hepatology 2014;60:98-105.) Rare diseases are instructive about specific pathophysiological mechanisms. Microvillous inclusion disease is a rare entity leading to intestinal failure. This disease can be associated with a cholestatic liver disease resembling progressive familial intrahepatic cholestasis (PFIC). It is thought that microvillous inclusion disease is caused by mutations in the MYO5B gene, which encodes a motor protein involved in the targeting of proteins to the apical membrane. In a series of 28 patients with microvillous inclusion disease, Girard et al. show that 8 patients with cholestasis have elevated serum direct bilirubin, serum bile acids, and normal GGT activity. In contrast to enterocytes, no inclusion bodies were observed in hepatocytes. Immunohistochemistry revealed abnormal staining for MYO5B and the bile salt export pump in liver of patients with cholestasis, suggesting an impaired sorting of the bile salt transporter. Interestingly, cholestasis symptoms may worsen after intestinal transplantation, because of implantation of the superior mesenteric vein directly in the inferior vena cava, and improve after interruption of the enterohepatic cycling of bile acids by biliary drainage. This is a PFIC-like situation without transporter mutation, but with a defect in the ride of the transporter to the canalicular membrane. (Hepatology 2014;60:301-310.) Physicians select a therapeutic option primarily for its efficacy and safety. Price becomes a selection criterion when competitive options with comparable efficacy and safety exist. With multiple direct-acting antiviral agents (DAAs) arriving on the market and numerous combinations of them possible, treatment price becomes an issue when selecting a treatment with DAAs. Hagan et al. performed a detailed cost-effectiveness analysis of a 24-week course of sofosbuvir/ribavirin (SOF/RBV) or a 12-week course of sofosbuvir/simeprevir (SOF/SMV) for patients who were interferon ineligible/intolerant and infected with HCV genotype 1. The investigators took into account not only the cost of the drugs, but also the cost of treatment-related care, the cost of retreatment, and the cost of continuing CHC in patients who did not achieve SVR. They found the 12-week course with SOF/SMV to be more cost-effective than the 24-week course with SOF/RBV. Despite the limitations inherent to every Markov model and the fact that some of the key numbers in the model are derived from rather small clinical trials, this article offers timely and precious guidance. (Hepatology 2014;60:37-45.)