Hepatology Highlights
Authors: Jean‐François Dufour
Journal: Hepatology (2014)

No doubt that the burden of liver diseases worldwide is significant, but China has a greater burden than other countries. In an “eye-opening” article, Wang et al. provide numbers on the disproportionate contribution from China to global liver disease. The numbers are astonishing. Half of the global incidence for hepatocellular carcinoma (HCC) occurs in China, where this cancer kills approximately 383,000 individuals every year. If more than one quarter of the hepatitis B serum antigen (HBsAg)-positive individuals live in China (93 million), the contribution of China to chronic hepatitis C is no less than 13 million people. Last, but not least, nonalcoholic fatty liver disease (NAFLD) is estimated to affect 200 million Chinese. Substantial efforts are under way, as shown by the positive effects of the hepatitis B virus (HBV) vaccination. (HEPATOLOGY 2014;60:2099-2108) HCCs are heterogeneous, and several molecular classifications have been proposed. Identification of mutations occurring early in the hepatocarcinogenic process would highlight diagnostic, as well as therapeutic, targets. Understandably, it is difficult to separate histologically early HCC from high-grade dysplasia given that this is a continuous process. Building on their recent publication, which identified telomerase reverse transcriptase (TERT) promoter mutations as one of the most frequent somatic genetic alterations in HCC, Nault et al. quantified the appearance of mutations in TERT promoter in well-characterized low-grade dysplastic nodules, high-grade dysplastic nodules, early HCCs, and small HCCs. Their results reveal a jump in the proportion of TERT promoter mutations from 19% for high-grade dysplasia to 61% for early HCC. Therefore, TERT seems to function as a gatekeeper in the hepatocarcinogenic process. (HEPATOLOGY 2014;60:1983-1992) Prediction of HCC recurrence after resection permits triage of those who are at risk toward a more aggressive management strategy. Molecular signatures associated with survival after liver resection have been published. Ahn et al. performed whole-exome sequencing and copy number analysis in 231 HCCs that were resected. This was a Korean population with predominantly chronic hepatitis B (CHB) as the underlying liver disease. The investigators confirmed the importance of genetic aberrations in the Wnt and p53 pathways. They identified a novel subtype of HCC characterized by amplification of FGF19, suggesting a therapeutic target. Moreover, their analysis revealed that mutations in the RB1 gene were independent predictors of early recurrence after resection. They were able to detect this effect because the mutation rate of RB1 is higher in HBV-related HCC. These interesting findings still have to be translated in the clinic. (HEPATOLOGY 2014;60:1972-1982) HCC is an excellent indication for liver transplantation (LT) when patients are selected properly. Waiting time on the list should be short in order to avoid tumor progression and delisting. Halazun et al. compared the outcome of LT for HCC in regions with long waiting times (median time 7.6 months, which, in many parts of the world, is a short time) with regions with short waiting times (1.6 months, which is an incredibly short time). Surprisingly, survival was significantly better in the regions with a long waiting time than in the regions with a short waiting time. This observation of better survival was robust because it was observed in three different analyses: comparing the survival of patients listed transplanted or not; comparing the survival of patients after transplantation; and, finally, comparing the survival of patients listed and transplanted. Fast tracking patients with HCC to transplantation results in a short observation time, which means that patients with aggressive tumors are transplanted rather than delisted. This work suggests that optimal selection of patients with HCC for transplantation should factor in a certain amount of observation time. (HEPATOLOGY 2014;60:1957-1962) Since the Model for End-Stage Liver Disease (MELD) score was introduced to prioritize patients on the waiting list for LT, the number of transplanted patients with poor renal function has increased dramatically. This is explained by the weight of creatinine in the calculation of the score. As a consequence, many patients are now considered for combined LT/kidney transplantation (KT) or require KT soon after LT. In this context, predicting tools to identify patients with reversible acute kidney injury (rAKI) and those with irreversible kidney injury (iAKI) are urgently needed. Levitsky et al. took a candidate approach measuring several plasma and urine proteins in 18 patients with rAKI and 13 with iAKI. Plasma levels of osteopontin and tissue inhibitor of metalloproteinase 1 were higher in rAKI and, when combined with diabetes and age, accurately identified patients with reversible kidney damage. This interesting work has to be confirmed and extended. (HEPATOLOGY 2014;60:2017-2026) Administration of albumin is the standard therapy in patients with cirrhosis with hepatorenal syndrome, in patients with cirrhosis at risk of hepatorenal syndrome resulting from spontaneous bacterial peritonitis, and in patients with ascites after paracentesis to preserve the fragile hemodynamics of these patients. The rationale is based on the oncotic properties of albumin, the most abundant circulating protein. However, albumin has other functions, which depend on its structural integrity. Domenicali et al. measured seven damaged albumin isoforms in 168 patients with cirrhosis and 94 healthy controls. Intact albumin levels were reduced in patients with cirrhosis and correlated negatively with Child-Pugh and MELD scores. Abundance of the N-truncated isoform was predictive of poor survival and was independently associated with ascites, renal dysfunction, and bacterial infection. Albumin administration is not only a question of quantity, but also a question of quality. (HEPATOLOGY 2014;60:1851-1860) The incidence of biliary cancers is rising. Chronic inflammation of the bile ducts and cirrhosis have been reported to be predisposing factors. Furthermore, animal studies linked Helicobacter spp. infections with biliary tract tumors. But we need to gain a greater understanding of these tumors. Murphy et al. performed a nested case-control study investigating positive serology with increased risk of biliary tract cancer. They selected 410 participants for the Alpha-Tocopherol Beta-carotene Cancer Prevention (ATBC) study. Of this cohort of Finnish, male smokers, 186 individuals developed hepatobiliary cancer during 22 years of follow-up and 224 were matched controls. The investigators found that seropositivity for H. pylori tested with a validated multiplex serology panel in baseline samples was significantly associated with biliary cancer. This observation should be duplicated in other populations. (HEPATOLOGY 2014;60:1963-1971) We learnt that metformin may cause lactic acidosis when administered to patients with cirrhosis. Given the gravity of this possible complication, many physicians stop metformin in patients with cirrhosis. However, recent publications outline benefits for patients with cirrhosis receiving metformin, in particular, a reduced risk of HCC. To assess the benefit-risk profile of metformin in patients with cirrhosis, Zhang et al. undertook a retrospective analysis of 250 diabetics who were receiving metformin and diagnosed with cirrhosis between 2000 and 2010. Of those, 78 patients discontinued metformin, whereas 172 continued. Survival was twice as long in those who continued metformin (12 vs. 6 years). The researchers adjusted for several variables and metformin remained an independent predictor of better survival. Importantly, there were no cases of lactic acidosis. Another piece of evidence in favor of metformin. (HEPATOLOGY 2014;60:2008-2016) As with other liver diseases, accurate assessment of fibrosis is essential in the management of patients with NAFLD. These patients are often obese, which decreases the success rate of transient elastography. Moreover, high hepatic fat content may interfere with the results from this technique, which means that fibrosis may not be accurately represented. Magnetic resonance (MR) elastography does not have these limitations. Loomba et al. prospectively measured fibrosis with this noninvasive tool in 117 consecutive patients with a histology-proven NAFLD. The accuracy of this method in identifying patients with advanced fibrosis (F3-F4) is remarkable (0.92), with little overlap in the values between F0-F2 and F3-F4. This carefully performed study sets the stage for further evaluations of MR elastography in NAFLD and other liver diseases. (HEPATOLOGY 2014;60:1920-1928) It is estimated that approximately 20 million individuals worldwide are infected with hepatitis D virus (HDV). The only available treatment for these patients is interferon (IFN), which is only successful in less than 25% of cases. Optimization of this treatment requires better understanding of its mechanisms of action. Guedj et al. took a mathematical approach. They developed a model that fits the HDV-RNA and HBsAg kinetics in 10 patients treated with IFN. HDV-RNA decline was biphasic. The first rapid phase was assumed to represent inhibition of HDV production by IFN. The second slower phase, which paralleled the HBsAg kinetics, was assumed to represent the clearance of infected hepatocytes. Treatment failure was associated with a flat second phase. This work provides interesting tools to evaluate future treatments against hepatitis D. (HEPATOLOGY 2014;60:1902-1910) Stratification of patients according to their risk of developing complications caused by HBV-induced cirrhosis is an important area of research in order to optimize attribution of resources. The degree of fibrosis is the most important parameter in such stratification. It may itself require significant resources if it assessed by liver biopsy. Kim et al. considered several tools, such as liver stiffness, and established a combination of biochemical parameters to predict outcomes in a homogenous population of 170 patients with CHB. The enhanced liver fibrosis (ELF) test was the most accurate test, and it could be used to categorize patients into three groups with low, intermediate, and high risk for decompensation, HCC, and liver-related death. This noninvasive test was actually more accurate than liver biopsy. This approach used a simple test, which can be easily implemented. (HEPATOLOGY 2014;60:1911-1919)