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

Direct measurement of portal pressure (PP) is too invasive to be of clinical use. The most accurate, clinically acceptable measure of PP is by catheterization of the hepatic vein and determination of the intrahepatic wedge pressure gradient, which represents, under certain simple assumptions, the pressure in the portal vein (PV). In this issue, Lisotti et al. propose a pharmacologic approach for measurement of PP. Indocyanine green (ICG) is taken up into hepatocytes and excreted into the bile. They measured ICG blood levels 5, 10, and 15 minutes after injection of a specified amount. They hypothesized that in the case of portal hypertension (PH) and the presence of collaterals, retention of ICG will be higher. They prospectively enrolled 96 consecutive patients with Child A cirrhosis and reported an excellent correlation between the hepatic venous pressure gradient and ICG retention at 15 minutes. Moreover, they identified values for this parameter that are predictive for the presence and absence of esophageal varices. The approach is original, but, nevertheless, less practical than transient elastometry, which has been shown to be useful not only to identify patients with cirrhosis, but also patients with PH. (Hepatology 2014;59:643-650.) Autoimmune hepatitis (AIH) is characterized by the presence of autoantibodies (autoAbs), which are useful for its diagnosis and classification. The evolution of autoAb titers during therapy could provide guidance on when to stop treatment. In a retrospective analysis of 95 patients with AIH type 1, Couto et al. report that the persistence of anti-smooth muscle autoAbs and of anti-actin autoAbs was significantly associated with persistence of elevated aminotransferase levels and with persistence of histologic activity. In contrast, persistence of antinuclear autoAbs was not. In this series, decision to stop treatment was based on biochemical and histologic remission, which occurred in only 47% of patients. This work highlights that current biomarkers in the assessment of AIH are not sufficient. Another related future area of interest would be the role of total immunoglobulin G levels. (Hepatology 2014;59:592-600.) Medical students learn that, in virology, resistance is just a matter of time. The case of tenofovir and hepatitis B virus (HBV) may disprove this adage. Kitrinos et al. searched for HBV resistance among 585 patients who received tenofovir for 6 years in an open-label extension of phase III studies. The researchers performed a detailed analysis of patients with viremia during the treatment: This included sequencing of the HBV polymerase/reverse-transcriptase gene and tenofovir treatment of HepG2 cells transiently transfected with recombinant HBV containing patients' quasispecies. They could not find evidence for resistance. In cases of relapse, patient nonadherence, rather than treatment failure, was the problem. This is an impressive work that provides remarkable results! (Hepatology 2014;59:434-442.) At the end of the 1990s, amantadine was tested in clinical studies against hepatitis C virus (HCV). The results were modest. Fifteen years later, Foster et al. have resolved the structure of the amantadine target, the HCV protein, P7. P7 forms an ion channel, which is essential for viral replication. This channel probably protects acid-labile virions by dissipating the pH gradient in secretory vesicles during exocytosis. Following a structure-guided approach, the investigators could select inhibitory small molecules with a much higher potency than amantadine. This work paves the way to a new class of direct-acting antiviral agents. (Hepatology 2014;59:408-422.) HCV lifecycle has been extensively investigated. Nevertheless, its regulation still offers interesting and unexpected surprises. Rowe et al. describe a new paracrine pathway that regulates HCV replication. They discovered that the conditioned media of endothelial cells (ECs) stimulates HCV replication. In contrast, it did not stimulate HBV replication. When the ECs, but not the hepatocytes, were exposed to vascular endothelial growth factor (VEGF)-A, the replication of HCV was no longer stimulated. The investigators went on to identify the factor responsible for this effect—bone morphogenetic protein (BMP)−4—whose secretion by ECs is diminished by VEGF-A in a VEGF receptor 2– and p38 mitogen-activated protein kinase–dependent manner. This elegant work unveils a new aspect of HCV life cycle, which seems to take advantage of elevated BMP-4 levels in the inflamed liver. In particular, the investigators reported elevated BMP-4 levels in alcoholic cirrhosis, providing a novel explanation for the worsening of chronic hepatitis C by alcohol. (Hepatology 2014;59:375-384.) Transjugular intrahepatic portosystemic shunt (TIPS) is an established therapeutic option for refractory ascites and variceal bleeding. However, it is associated with the risk of hepatic encephalopathy. Selection based on identified risk factors, such as age, pre-TIPS encephalopathy, and Child-Pugh class C, does not guarantee absence of post-TIPS encephalopathy. Berlioux et al. investigated the predictive value of a visual test—the critical flicker frequency test—which has been validated for diagnosing minimal encephalopathy. In a cohort of 54 consecutive patients who received a nonemergency TIPS, they found that this test could identify patients who will not develop post-TIPS encephalopathy. Before TIPS, 39% of patients had minimal encephalopathy, and after TIPS, 35% developed overt encephalopathy. A critical flicker frequency test excluding minimal encephalopathy and the absence of overt encephalopathy pre-TIPS were associated with no recurrent encephalopathy post-TIPS. For this purpose, this straightforward test outperformed psychometric tests. (Hepatology 2014;59:622-629.) Drug-induced liver injury (DILI) can mimic any liver disease. So, DILI should always be included in the differential diagnosis of a liver disease and is often retained as the final diagnosis when all others have been ruled out. This process requires a liver biopsy, in most cases. If not pathognomonic, the findings can provide predictive information. In their article, Kleiner et al., from the DILI Network, systematically classified the histologic findings of 249 patients with suspected DILI. Among the 18 patterns, cholestatic hepatitis was the most frequent (29%). Eosinophils and granulomas were associated with better outcome, whereas necrosis, fibrosis, microvesicular steatosis, and ductular reaction were associated with poorer outcome. One of the most intriguing lessons of this work is the lack of correlation between histologic pattern and biochemical categorization. (Hepatology 2014;59:661-670.) In the despair of acute liver failure (ALF), a “nothing to lose attitude” may lead to the prescription of steroids. Whether or not this treatment offers a survival advantage remains unknown. In an impressive study, Karkhanis et al. analyzed 361 patients who had ALF resulting from AIH, DILI, or an indeterminate cause. Of those, 62 received steroids. Spontaneous survival (without transplant) was only marginally improved by administration of steroids. This trend was apparent, but not statistically significant, across the three categories of ALF. Moreover, administration of steroids to patients with a high Model for End-Stage Liver Disease score (>40) was associated with diminished survival. Although this cautions against indiscriminate use of steroids in ALF, it is possible that a subgroup, which is yet to be characterized, may profit from steroid treatment. (Hepatology 2014;59:612-621.) Patatin-like phospholipase domain-containing protein 3 gene polymorphism has established itself in recent years as one of the most robust genetic markers in hepatology: It is a marker for steatosis, fibrosis, and hepatocellular carcinoma (HCC) risk. This gene encodes for adiponutrin, an enzyme involved in triglyceride metabolism, and it is likely that its presence in hepatocytes is responsible for its effects on the progression of liver disease. To demonstrate this, Dunn et al. investigated 101 HCV patients who underwent liver transplantation (LT), which creates an iatrogenic chimeric situation. The CC variant of the rs738409 polymorphism was present in 56% of donors and 57% of recipients. Time to stage >2 fibrosis or HCV-related mortality/graft loss was assessed as the primary endpoint. Recipient genotype was not associated with this endpoint, whereas the donor CC polymorphism was significantly associated with this endpoint. These results may have been even more convincing if the hepatic histology of the graft at time of transplantation had been taken into account. (Hepatology 2014;59:453-460.) LT patients are subjected to numerous radiologic investigations, which expose them to ionizing radiation, while on the waiting list for, as well as after, LT. This is particularly the case for patients transplanted for HCC. It has not been established how much harm this type of investigation is causing to this population of patients. Lee et al., from the Presbyterian Hospital in New York, set out to quantify exposure to ionizing radiation retrospectively in 74 patients. Fifty-one percent had an exposure above 50 mSv per year. Patients with HCC had a 4-fold higher exposure than those without HCC. The researchers put these findings into perspective: Background radiation is approximately 3 mSv per year, and nuclear power plant workers are limited to an annual exposure of 20 mSv. Then, as stated by the researchers in the title, this is a matter for potential concern. Thus far, this exposure has not been linked to specific outcomes, but it would be prudent to consider magnetic resonance imaging and sonography ahead of the more harmful radiologic investigations, where possible. (Hepatology 2014;59:496-504.)