Hepatology highlights

In the four phase III clinical trials, Neutrino, Positron, Fusion, and Fission, 224 of 982 patients failed a sofosbuvir (SOF)-based treatment. Most of these patients experienced relapse, and 78% were infected with genotype 3. The manufacturer of SOF, Gilead Sciences Inc., investigated resistance by next-generation sequencing, a relatively novel technology for which methodological standards are still lacking. In the present report, Donaldson et al., from the U.S. Food and Drug Administration, performed an independent analysis of these data. In only 11 of the patients infected with genotype 3, possible relevant treatment-emergent substitutions could be detected at positions 159 and 321. A baseline polymorphism at position 316 might be unfavorable for a treatment response in patients with genotype 1b. However, in the vast majority of the patients, no resistance-associated substitution in the polymerase gene could be identified, leaving the reasons for treatment failure open. (Hepatology 2015;61:56-65) When starting a treatment against chronic hepatitis C, it is always important to explain to patients that a negative viremia at the end of treatment is not proof of success. Only a negative viremia several weeks after the end of treatment guarantees absence of relapse. The question is how many weeks? Patients are impatient to know. It was previously thought that 24 weeks was required, but, more recently, a window of 12 weeks was accepted. What about 4 weeks? Yoshida et al. evaluated this in 863 patients with hepatitis C virus (HCV) who received an SOF-based treatment. The investigators found that 22% of patients who experienced a relapse had a negative viremia 4 weeks after the end of treatment. However, 99.7% of patients with a negative viremia 12 weeks after the end of treatment still had a negative viremia 24 weeks after the end of treatment. So, it would appear that being patient for 12 weeks is needed to be sure of being “HCV free.” (Hepatology 2015;61:41-45) Farnesoid X receptor (FXR)—the master transcriptional regulator of bile-acid homeostasis—is expressed in the liver as well as in the intestine. Aging FXR knockout (KO) mice develop hepatocellular carcinoma (HCC). In order to delineate the role of intestinal FXR, Degirolamo et al. expressed FXR in the intestines of FXR KO mice. With this sophisticated model, the investigators were able to show that selective intestinal FXR reactivation restores the fibroblast growth factor (FGF) 15 enterohepatic axis and protects against the development of HCC. Interleukin-6, tumor necrosis factor alpha, and interferon-gamma were down-regulated in livers of transgenic mice. With pharmacological tools to manipulate FXR already in clinical trials, these results emphasize the role of this nuclear receptor in crosstalk between the gut and the liver. (Hepatology 2015;61:161-170) Conjugated bile salts returning from the intestine are specifically taken up into hepatocytes by the sodium taurocholate cotransporting polypeptide, SLC10A1, which is also known as NTCP. This transporter is essential to the enterohepatic circulation of bile salts. Vaz et al. provide the first clinical description of a patient with a genetic deficiency in this enzyme. Despite the massive elevation (100×) of plasma bile salts, this young patient exhibited no pruritus, no jaundice, and normal liver function. Moreover, hepatic bile-salt synthesis seemed to be unaffected and FGF19 levels were normal. This patient had a homozygous point mutation, which resulted in poor expression of the transporter at the plasma membrane. Theoretically, such a patient should be partially protected against hepatitis B virus infection, which employs SLC10A1 as a receptor. With a surprisingly mild phenotype, it is possible that mutations in this transporter are overlooked and are not so rare. (Hepatology 2015;61:260-267) Hedgehog pathway is a complex signaling pathway that is important during embryogenesis for the interactions between epithelial and stromal cells. Ballooned hepatocytes, a hallmark of nonalcoholic steatohepatitis (NASH), produce and release sonic hedgehog ligands. It has already been shown, by Guy et al., that activation of this pathway parallels the histological severity of NASH. The same researchers also investigated whether amelioration of NASH is associated with decreased markers of this pathway. Using immunohistochemistry, they studied the liver biopsies of 30 patients assigned to vitamin E and 29 assigned to placebo in the PIVENS trial. Decreases in cells positive for sonic hedgehog correlated with a decrease in hepatocyte ballooning, ductular reaction, and even hepatic fibrosis. This work emphasizes this morphogen pathway as a potential therapeutic target. (Hepatology 2015;61:98-107) The specific I148M polymorphism in patatin-like phospholipid domain-containing protein 3 (PNPLA3) has been repeatedly associated with steatosis, steatohepatitis, fibrosis, and HCC. How this polymorphism affects the function of the PNPLA3 enzyme is hotly debated, and several mechanisms have been proposed. Smagris et al. opted for the closest animal model to the human situation. They engineered mice in which residue 148 of the endogenous PNPLA3 gene is changed from an isoleucine to a methionine. Using the same strategy, they developed mice in which the catalytic serine was replaced by alanine. Both strains developed steatosis only when exposed to a high-sucrose diet. Moreover, PNPLA3 protein abundance increased massively on lipid droplets. This work, which shows, for the first time, that physiological expression of the PNPLA3-I148M variant causes steatosis, advances the field significantly, but still does not crack the mechanism of this enzyme. (Hepatology 2015;61:108-118) Our assessment of patients with nonalcoholic fatty liver disease is far from perfect. Elevation of alanine aminotransferase (ALT) is frequently used as the main indicator to select patients for further investigations, such as liver biopsy, because it is considered a marker for parenchymal damage—wrongly, according to Maximos et al. These researchers studied 222 patients who had biopsy-proven NASH, one quarter of whom had normal ALT levels. There was no difference in the extent of inflammation, hepatocyte ballooning, and fibrosis between patients with elevated ALT levels and those with normal ALT levels. Hepatic triglyceride content, measured histologically and by proton magnetic resonance spectroscopy, was significantly higher in patients with elevated ALT levels. Moreover, patients with elevated ALT levels had worse adipose tissue (but not hepatic) insulin resistance. Contrary to the expectations in patients with NASH, ALT seems to be a metabolic marker. (Hepatology 2015;61:153-160) The first sentences of articles on HCC usually refer to the high number of patients dying from this cancer worldwide and its increasing incidence. Is this trend continuing? Using the Surveillance, Epidemiology and End Results data, Njei et al. examined the incidence and incidence-based mortality in HCC from 1973 to 2011. HCC incidence quadrupled from 1.51 in 100,000 in 1973 to 6.2 in 100,000 in 2011. The researchers observed a slowing in the rate of this increase since 2006, suggesting that if this deceleration continues, HCC incidence may actually decrease after 2017. Similar trends were observed for incidence-based mortality, with no increase since 2009. The HCC forecast predicts a brighter outlook, with the storm fading away. (Hepatology 2015;61:191-199) The Model of End-Stage Liver Disease (MELD) allocation system prioritizes patients on the waiting list according to their risk of death without transplantation. It was immediately recognized that several indications for liver transplantation (LT) are not fairly taken into account, and a parallel allocation system with exception MELD score was integrated. Northup et al. investigated how these two systems evolved over the years in the competitive access to the limited resource of liver donation. The findings are clearer than anticipated. There was an inflation of the mean MELD score at the time of death or transplantation, which increased from 23 in 2005 to 27.5 in 2012. The percentage of patients listed with MELD exception increased from 16.6% to 22.4%; among these patients, those with HCC were predominant. The proportion of patients dying on the waiting list and the proportion of those undergoing LT were 5× lower and twice as high, respectively, in the group listed with exception versus those listed without exception. There is no perfect system, but is this exception system still fair? (Hepatology 2015;61:285-291) Following on from the previous highlight, favoring resection over transplantation in eligible patients with HCC may decrease MELD inflation. But is this strategy cost-effective? Lim et al. created a Markov model to compare the costs of resection against the cost of transplantation in a simulated cohort of 55-year-old patients within Milan criteria and with Child-Pugh A or B. Unsurprisingly, the most sensitive parameters were survival after transplantation, HCC recurrence rate after resection, and cost of transplantation. The 5-year cumulative survival after transplantation had to be outstanding and above 88% for this strategy to be cost-effective in the United States. Otherwise, liver resection is more cost-effective, providing another reason to consider it. (Hepatology 2015;61:227-237)