Hepatology highlights


  • Potential conflict of interest: Nothing to report.

Digging Deeper Into Hepatitis C Virus/Human Immunodeficiency Virus Coinfection

Patients coinfected with human immunodeficiency virus and hepatitis C virus (HCV) are at increased risk for progressive liver disease. In a prospective study with 282 coinfected patients who had multiple liver biopsies, Konerman et al. examine the factors influencing fibrosis progression. After review of 435 liver biopsy pairs, they report that one third of the patients had histologic progression of the fibrosis. Not surprisingly, baseline metabolic parameters, such as high body mass index, diabetes, and steatosis, were associated with fibrosis progression. Interestingly, an aspartate aminotransferase level above 100 IU/L, which was associated with alcohol abuse and failure to be on antiretroviral therapy, identified individuals at greater risk of progression. Of note, this study included mostly African-American patients infected with genotype 1. (Hepatology 2014;59:767–775.)

Linking Interferon-Stimulated Genes and HCV Replication

Up-regulation of hepatic interferon-stimulated genes (ISGs) is associated with lower response rate to therapy and with the unfavorable interleukin (IL)28B genotype. Honda et al. performed laser-capture microdissection and immunohistochemistry on tissue samples from 146 patients treated with pegylated interferon and ribavirin. They report an impaired infiltration of immune cells into liver lobules of patients with the unfavorable IL28B genotype. Nevertheless, the ISGs were up-regulated in these livers. They identified WNT5A as a factor positively regulating expression of the hepatic ISGs. Moreover, they found that WNT5A increased HCV replication. This work links up-regulation of ISGs with stimulation of HCV replication. (Hepatology 2014;59:828–838.)

It Is a Question of Tracer

18F-fluoro-deoxy-glucose positron emission tomography/computerized tomography (PET/CT) is used routinely in oncologic workup. However, its accuracy in hepatocellular carcinoma (HCC) is limited and this test has not been endorsed by guidelines. This lack of accuracy suggests that HCC relies less on glycolysis than other tumors. It is then possible that another metabolite might be an adequate tracer. In a pilot study, Bieze et al. tested 18F-methyl-choline PET/CT as an alternative tracer in 29 patients. This test displayed a sensitivity of 88% and a specificity of 100%. 18F-methyl-choline PET/CT revealed lesions that affected management in 15 patients. This is an important observation, which should revive the interest for PET/CT within the HCC community. (Hepatology 2014;59:996–1006.)

At the Heart of Ascites

A serum-ascites albumin gradient greater than 11 g/L generally suggests cirrhosis-induced ascites, with the most frequent exception being heart failure. Then, a protein concentration higher than 25 mg/L in ascites favors heart failure over cirrhosis. In an impressive clinical study, Farias et al. propose serum B-type natriuretic peptide (BNP) as a better marker for ascites resulting from heart failure. They compared serum-ascites albumin gradient, protein concentration in ascites, serum BNP, and ascites BNP in a prospective group of patients with new ascites resulting from heart failure, cirrhosis, and peritoneal disease. Serum BNP was the most accurate measure for ascites related to heart failure: A value >364 pg/mL rules in heart failure and a value ≤182 rules out heart failure as the cause of ascites. This finding was confirmed in a validation cohort. Patients with a serum creatinine value above 2.5 mg/dL were excluded from this study, indicating that the value of serum BNP determination in patients with renal insufficiency remains to be investigated. In clinical practice, a diagnostic paracentesis likely remains indicated. (Hepatology 2014;59:1043–1051.)

Alfa-Fetoprotein Refuses to Go Away

Alfa-fetoprotein (AFP) was already pronounced dead as a biomarker for HCC; obituaries have been written! Data from the HALT-C trial showed that AFP was not elevated in the months preceding the diagnosis of HCC in patients treated for chronic hepatitis C. Following a similar approach, Wong et al. report that AFP starts to increase 6 months before the diagnosis of HCC in a cohort of 1,531 entecavir-treated hepatitis B virus (HBV)-infected patients, followed for more than 4 years, among whom 57 patients developed HCC. Of note, surveillance sonography was done less frequently than the recommended 6-month interval. Even if AFP appears to be a better marker in patients treated for HBV than in those infected with HCV, the sensitivity and specificity reported are rather low. This research indicates that AFP may remain a helpful, albeit suboptimal, marker. (Hepatology 2014;59:986–995.)

Hemochromatosis: One Last Piece to the Puzzle

Hereditary hemochromatosis is presently one of the best understood liver diseases. Since the identification of the most common gene mutation, an abundance of literature has nearly completed the puzzle. If the pathophysiology is clear with an unbalanced intestinal absorption of iron resulting from a hepatocellular defect in hepcidin secretion, one last piece was to show the curative effect of liver transplantation (LT). Experimental work aimed at this curiously preceded the clinical proof. Bardou-Jacquet et al. have finally demonstrated the correction of the iron overload after LT with normalization of serum hepcidin levels in a small series of well-characterized patients. Therefore, we can conclude that the liver controls iron homeostasis and that hereditary hemochromatosis is a liver disease. (Hepatology 2014;59:839–847.)

T Party for Autoimmune Hepatitis

When patients ask for explanations, we can provide them with extensive detailed information for many liver diseases, for example, viral hepatitis, hemochromatosis, and Wilson's disease. For autoimmune hepatitis (AIH), we can describe clinical presentation and treatment, but not the mechanism. The work of Grant et al. will help us to better answer this question. They quantitatively and qualitatively characterized circulating CD39pos (positive) regulatory T cells in 41 young patients with AIH. They found that patients with AIH have fewer CD39pos regulatory T cells than patients with other liver diseases and healthy subjects. Moreover, in patients with AIH, these cells harbor a defect in their ectonucleotidase activity and CD4 T-cell suppressive function. These data provide the beginning of an answer. (Hepatology 2014;59:1007–1015.)

Isoniazid Hepatitis Is No Longer Idiosyncratic

Isoniazid remains an essential drug in the treatment of tuberculosis. However, isoniazid hepatotoxicity can be fulminant and lethal without transplantation. Metabolic idiosyncrasy takes into account the lack of evidence for immunologic mechanism and the suspicion of a mechanism involving the metabolism of isoniazid in its hepatotoxicity. Metushi et al. challenged the concept of metabolic idiosyncrasy and looked carefully for the presence of antibodies against isoniazid adducts in 19 patients with isoniazid-induced liver insufficiency. They were able to detect autoantibodies against cytochrome 2E1 modified in vitro to have isoniazid adducts in 14 of these 19 patients. The binding was specific because it could be prevented by the addition of isoniazid. This observation suggests that indeed isoniazid hepatotoxicity may be immune mediated in more than two thirds of the patients. Consequently, textbooks will have to be revised! (Hepatology 2014;59:1084–1093.)

Adducts Drive Nonalcoholic Steatohepatitis

Understanding the mechanisms governing the transition from steatosis to steatohepatitis is of paramount importance in modern hepatology. Building on previous results showing that the presence of immunoglobulin G against oxidative stress-derived antigens is associated with more severe nonalcoholic steatohepatitis (NASH), Sutti et al. devised mechanistic experiments in the methionine-choline deficient (MCD) model of NASH. Immunization with malonyldialdehyde-adducted bovine serum albumin before the deficient diet worsened all severity parameters examined in animals subjected to this model, except for hepatic triglyceride content. In immunized MCD animals, there was a recruitment of T lymphocytes and natural killer T cells in the liver with an increased hepatic content of IL-15 and osteopontin. Furthermore, the researchers showed that depletion of CD4+ T lymphocytes improved the lesions in immunized animals. This work complements remarkably the clinical observations and suggests that NASH might be an immunologic disease. (Hepatology 2014;59:886–897.)

Mapping Liver Metastases

Liver metastases of nonliver tumors often do not catch the attention of hepatologists. However, they are much more frequent than primary liver cancer and are an underexplored field of research. In an astonishing article, Turtoi et al. performed matrix-assisted laser desorption/ionization image-guided proteomic analysis of colorectal cancer liver metastases. The reaserchers consistently observed a different distribution of proteins in three spatially distinct zones: the center of the metastasis; the rim of the metastasis; and the peritumoral region. They identified several extracellular proteins expressed only in the tumoral stroma, which have potential as therapeutic targets. These results are based on a small number of lesions, but they illustrate the potential of this approach; still currently very sophisticated, this technology will become more accessible and widely used. (Hepatology 2014;59:924–934.)