Hepatology Highlights
Authors: Jean-François Dufour
Journal: Hepatology (2013)

In 1978 and 1979, more than 2,000 women were infected with hepatitis C virus (HCV) while receiving anti-D immunoglobulins in East Germany. In a subsequent analysis of this cohort, 25 years after infection, slow fibrosis was evident. In this issue, Wiese et al. report on the findings of the 35-year follow-up. In this recent analysis, data were collected on 718 patients, 25% of whom were not included in the previous analyses. The data show that 15% of women had progressed to cirrhosis 35 years after infection. A comparison of data at 25 and 35 years postinfection in women who had data at both time points revealed a sharp increase (>10-fold) in cirrhosis at 35 years. However, it should be noted that, overall, only a minority of these women progressed to cirrhosis. Except for interleukin (IL)−28, no genetic testing was performed, so we do not know whether recent gene polymorphisms associated with fibrosis progression could also have been identified in this cohort. However, the researchers found that being overweight was associated with progression to cirrhosis and decreased survival. Once again, if infected with HCV, it is better to stay lean. (Hepatology 2014;59:49-57.) HCV enjoys fat, as supported by an abundance of literature that describes how HCV hijacks fat metabolism in hepatocytes for its own gain. Singaravelu et al. shed new light on the responsible mechanism by elegantly showing that expression of either HCV core protein or nonstructural protein 4B in vitro leads to production of microRNA (miR)−27 in a phosphoinositide 3-kinase–dependent manner. They go on to show that miR-27 decreases expression of peroxisome proliferator-activated receptor (PPAR)-α and angiopoietin-like protein 3, explaining its steatogenic effects. They reiterated key observations in an animal model of HCV infection. However, the negative effect of miR-27 on replication of HCV genotype 1b was unexpected. This opens up the possibility of new therapeutic targets—but, first, we need to fully understand the mechanism. (Hepatology 2014;59:98-108.) With the new antiviral drugs, we will interpret HCV genotypes differently. We are quite familiar with the contrast in responses to conventional dual therapy for genotype 1 to genotypes 2 and 3. Currently, with direct-acting antiviral agents demonstrating pan-genotypic effects, these differences in response between the genotypes are fading, and more subtle differences associated with barriers to resistance are appearing in daily practice. In this context, the taxonomic effort of the group of Peter Simmonds is timely, especially because the proliferation of publications in this field has led to a confused nomenclature of HCV sequences. This descriptive work argues the case for a solid framework based on seven genotypes and 67 subtypes. Not surprisingly, within genotypes there are groups with less-evident geographic distribution than the parent genotypes. However, the significance of sequence differences, in terms of evolution and functions, remains speculative. (Hepatology 2014;59:318-327.) There are eight genotypes of hepatitis B virus (HBV), which amounts to one more than with HCV. HBV genotypes demonstrate a clear geographic distribution and influence not only in response to interferon, but also the course of chronic hepatitis B (CHB) infection. So, what about the course of acute hepatitis B (AHB) infection? In a large, multicenter study, Ito et al. examined the effect of genotype on clearance of HBV surface antigen (HBsAg). In Japan, there is no universal program of vaccination for HBV, and the investigators identified 212 cases of AHB. Of those patients, approximately half were infected with genotype A. The course of AHB in the case of genotype A differed from the course of AHB with other genotypes: Clearance of HBsAg was slower, the peak of serum alanine aminotransferase levels lower, and HBV viremia higher. Multivariate analysis revealed that this genotype was associated with viral persistence. From a clinical perspective, this work challenges the 6-month rule used to define CHB, in that patients infected with genotype A exhibit a prolonged clearance of HBsAg. (Hepatology 2014;59:89-97.) Biomarkers do not have to be fancy and expensive, they simply need to be effective. Sometimes, the predictive significance of an already well-established test might not have been realized. According to Nagai et al. the absolute lymphocyte count at the time of transplantation predicts not only hepatitis C recurrence, but also survival—if validated, this would be impressively simple. Their work is based on a single-center, retrospective analysis of 289 liver transplantations (LTs). Severe pretransplant lymphopenia reduced survival by 20%, which was already evident in the months after transplantation and was not related to HCV recurrence, suggesting that lymphopenia is a biomarker of more general significance. Regarding HCV, fibrosis (defined as >F2) occurred earlier in cases of lymphopenia pre- or post-LT, but the difference tended to disappear at 5 years post–LT. Patients with advanced HCV-related fibrosis had lower lymphocyte counts pre- and post-transplantation. It is surprising that a nonfunctional test that simply takes into account the number of a heterogeneous population of circulating cells has such a strong significance. We await validation of this observation. (Hepatology 2014;59:35-45.) As a consequence of progress in the management of pediatric diseases, adult hepatologists are seeing an increasing number of adolescents with congenital diseases, and not only congenital liver disease. Univentricular congenital heart disease is treated by the Fontan procedure, which diverts the venous atrial blood flow directly into the pulmonary arteries, bypassing the ventricle, and this results in increased hepatic afterload. In this unique series, 41 patients who underwent a Fontan procedure were compared to 65 healthy controls. Shear wave elastography (SWE) measurements were significantly higher in Fontan patients than in controls, and the flow in the portal vein was decreased. In patients who had a right heart catheterization, SWE correlated with pulmonary artery wedge pressure. Finally, 20% of the Fontan patients had cirrhosis, and patients with more fibrosis on liver biopsy also had higher SWE values, although this was expected. This research indicates that patients who have a Fontan procedure might be more likely to develop hepatic fibrosis and should therefore be regularly managed by hepatologists. (Hepatology 2014;59:251-260.) Hepatic stellate cells (SCs) store vitamin A and retinol esters when quiescent and are fibrogenic when activated. After conducting a particularly thorough set of experiments, Tomita et al. describe how nutritional cholesterol triggers a cycle of events whereby it sensitizes SCs to transforming growth factor (TGF)-β-mediated activation, which drives activated SCs to accumulate more cholesterol. Mechanistically, cholesterol increased expression of Toll-like receptor 4 and decreased that of the TGF-β pseudoreceptor, Bambi. Moreover, in activated SCs, PPAR-γ was down-regulated, leading to enhanced expression of sterol-regulatory element-binding protein 2 and low-density lipoprotein receptor. In vivo, nutritional cholesterol increased hepatic fibrosis in two animal models of dietary nonalcoholic steatohepatitis (NASH) independently of hepatocellular injury and Kupffer cell (KC) activation. This work outlines a novel mechanism for cholesterol in hepatic fibrogenesis and paves the way for its pharmacologic targeting. (Hepatology 2014;59:154-169.) KCs come in two “colors”: M1 polarized KCs, which promote inflammation, and M2 polarized KCs, which promote inflammation resolution and tissue repair. The balance between the two populations influences the progression of liver diseases. Wan et al. present experiments that demonstrated that M2 KCs induce apoptosis of M1 KCs. M2 KCs release IL-10, which activates arginase in M1 KCs and triggers their demise. This mechanism depletes the M1 population of KCs, favoring the protective M2 KCs. They report on an interesting difference between two different mouse strains, with C57BL6/J mice showing an “M1 response,” whereas BALB/c mice showed an “M2 response,” which was, in fact, the result of an obliteration of the M1 population of KCs. They suggest that resveratrol and adiponectin might be hepatoprotective by promoting M2-induced M1 apoptosis. The investigators confirmed their observation in a small set of clinical samples: In active alcohol drinkers and in morbidly obese patients, high M2 marker expression was associated with limited liver injury. (Hepatology 2014;59:130-142.) Steatosis in patients with nonalcoholic fatty liver disease is considered a cardiovascular risk factor. Numerous epidemiologic studies have reported increased cardiovascular mortality in these patients. Multiple mechanisms may underlie this association, which may be grouped into three categories: inflammatory (increased IL-6 and C-reactive protein); metabolic (increased triglycerides and decreased high-density lipoprotein cholesterol); and prothrombotic (increased fibrinogen and factor VIII). Verrijken et al. performed an extensive analysis of coagulation parameters in 273 obese patients who had a liver biopsy. The only coagulation parameter that correlated with hepatic histology was plasminogen activator inhibitor 1 (PAI-1). In short, PAI-1 inhibits fibrinolysis. Circulating PAI-1 levels correlated with steatosis, lobular inflammation, and NASH activity score, and hepatic PAI-1 expression was increased in NASH. This work contributes to a growing body of evidence that links coagulation and liver diseases. (Hepatology 2014;59:121-129.) Primary sclerosing cholangitis (PSC) affects mainly the large intrahepatic bile ducts. This inflammatory and scarring process progresses into secondary cirrhosis, which places patients at risk of recurrent cholangitis and cholangiocarcinoma. However, the factors that influence progression of PSC are poorly defined. Ruiz et al. systematically quantified the radiologic findings observed on magnetic resonance imaging and three-dimensional magnetic resonance cholangiopancreatography in 64 patients with PSC. The investigators developed a descriptive score that helped to predict radiologic progression. Interestingly, this score took into account parenchymal changes (dysmorphy). It will be particularly relevant to investigate whether this score is also predictive of clinical outcomes and how it compares with the Mayo PSC score. (Hepatology 2014;59:242-250.)