Journal Watch November-December 2015

Clinical Gastroenterology and Hepatology, Nov-Dec 2015

The art and Science of Diagnosing and Managing Drug-induced Liver Injury in 2015 and Beyond 
James H. Lewis  Clin Gastroenterol Hepatol. 2015;13:2173-2189.

In this review article, the author summarizes the key advances in the clinical diagnosis and management of idiosyncratic drug induced liver injury (DILI) during the last decade. It is estimated that about half of the cases of acute liver failure (ALF) occurring annually in the United States are due to DILI, especially from acetaminophen (40%), but also other drugs (11%) such as herbal compounds and dietary supplements (HDS). The classic host risk factors for DILI are age (>65 years), gender (female), use of alcohol and obesity. Daily drug doses of 50-100mg are more hepatotoxic than <10mg.  Three main biochemical injury patterns have been recognized: hepatocellular, cholestatic and mixed. The diagnosis of DILI is clinically challenging as DILI can mimic all known causes of acute and chronic liver diseases. Liver biopsy findings may be supportive for DILI but most helpful in excluding other possible causes. Recently, substantial progresses have been made in identifying predictive biomarkers (microRNA 122, high mobility group box-1 and keratin 18) and genetic risk factors (HLA and cytochrome phenotypic alterations) for DILI.  Preventing DILI is limited to liver associated biochemistry (ALT) monitoring and restricting access to certain drugs.  Liver transplantation remains an important treatment procedure for irreversible ALF. The first published guidelines on the diagnosis and management of DILI has been offered by the American college of Gastroenterology. In addition, a LiverTox Web site ( has been launched recently.

Journal of Hepatology, Nov-Dec 2015

Progenitor cell markers predict outcome of patients with hepatocellular carcinoma beyond Milan criteria undergoing liver transplantation
Miltiadous O, Sia D et al. Journal of Hepatology 2015; 63: 1368-1377. 

Liver transplantation (LT) is an effective treatment option for patients with HCC within Milan criteria. The concept of a modest expansion beyond the Milan criteria has been proposed without gaining global acceptance. The current study explored the possibility of using gene signatures to identify patients with HCC beyond Milan criteria who nevertheless may have acceptable outcomes with LT. 132 patients with HCC beyond Milan criteria underwent LT at two medical centers were included in the study. Explant tumors were analyzed for genomic signatures and Immunohistochemical markers, and then correlated with patient outcome. At a median follow up of 88 months, the 5-year survival and recurrent rates were 57% and 35%, respectively. In the multivariate analysis, S2 gene signature (HR = 3.18, p = 0.001), tumor diameter >5 cm (HR=5.06, p<0.001), and outside up-to-7 rule (HR=2.50, p= 0.002) were independently associated with 5 year survival. CK19 (HR = 2.91, p = 0.001), tumor diameter >5 cm (HR=3.37, p=0.023) and satellites (HR = 2.98, p <0.001) were independent predictors of recurrence. Combination of progenitor signatures (CK19 and S2) improves prediction both OS and recurrence.  Patients with one and/or both signatures had a 45% 5-year OS and 53% recurrence vs. 67% 5-year OS and 19% recurrence when neither signature was present. These results suggested that the gene signatures of progenitor cell (CK19/S2) may be potential makers for stratifying patients with HCC in high and low risk for both recurrence and survival.

Histopathology, Nov-Dec 2015

CAMTA1 is a useful immunohistochemical marker for diagnosing epithelioid haemangioendothelioma. 
Shibuya R, Atsuji A, Eisuke S, Hiroshi H, Kei Y, Masanori H. Histopathology 2015;67(6):827-835.
Molecular characterization of epithelioid haemangioendotheliomas identifies novel WWTR1–CAMTA1 fusion variants. 
Patel NR, Salim AA, Sayeed H, Sarabia SF, et al. Histopathology 2015;67(5):699-708.

Epithelioid hemangioendothelioma is an intermediate grade endothelial neoplasm that could be primary in or metastatic to the liver. The WWTR1–CAMTA1 translocation leading to CAMTA-1 overexpression had been found to be very specific for majority of EHE, while the remaining lesions carry the alternative YAP1–TFE3 translocation. Until now the way to demonstrate these translocations had been by PCR for the fusion gene transcript and/or FISH methods. However the first study, Shibuya R et al report successful use of CAMTA1 antibody by immunohistochemistry with a sensitivity of 87.5% and specificity of 99.6%. Only one false positive case in a breast ductal carcinoma was reported.
The second study Patel NR et al reported successful use of RT-PCR and direct gene sequencing in epithelioid hemangioendothelioma, majority of their cases arising from or involving the liver.  In addition to detecting the WWTR1–CAMTA1 transcript in 14 of 18 cases, 4 cases, when directly sequenced also showed novel in-frame fusion transcripts. Only 1 of 18 cases demonstrated YAP1–TFE3 fusion transcript and this case also showed strong nuclear TFE3 immunostain. Other degrees of TFE3 stain were found in 5 other cases, 3 of which had no YAP1–TFE3 fusion transcript; the remaining 2 failed RT-PCR. The use of TFE3 immunostain required a specific (strong nuclear) staining pattern for specificity in cases harboring the YAP1–TFE3 translocation.

Journal of Gastroenterology and Hepatology, Nov-Dec 2015

Intimate association of visceral obesity with non-alcoholic fatty liver disease in healthy Asians: A case-control study.
Ha Y et al. Journal of Gastroenterology and Hepatology. Nov. 2015, 30 (11):1666-72.

The study was to identify factors associated with non-alcoholic fatty liver disease (NAFLD) in Asian subjects. Potential living liver donors without hepatic steatosis (< 5%: n = 1353, group 1) were considered as controls, and subjects with mild (5-33%: n = 724, group 2) and moderate/severe (> 33%: n = 116, group 3) steatosis were defined as study groups. Age and gender were matched, which resulted in 83 matched subjects in each of the three groups. The area of abdominal (visceral and subcutaneous) fat was measured in all subjects by unenhanced computed tomography. Serum AST, ALT, gamma-glutamyltranspeptidase, total cholesterol and triglyceride levels, and visceral fat amount were found directly correlated with the grade of steatosis, while high-density lipoprotein cholesterol levels were inversely correlated. In a multivariate model, visceral fat amount was significantly correlated with both mild and moderate/severe NAFLD groups (P < 0.05). Body mass index (BMI), ALT, and subcutaneous fat were significant predictors of only moderate/severe NAFLD group (P < 0.05).The findings indicate that visceral adiposity makes non-obese subjects more susceptible to NAFLD, compared with subcutaneous fat and BMI.

American Journal of Pathology, Nov-Dec 2015

Mice with Hepatic Loss of the Desmosomal Protein ϒ-catenin are Prone to Cholestatic Injury and Chemical Carcinogenesis
Zhou L et al.  Am J of Pathol 2015;185:3274-3289.

The role of β-catenin as an important component of the adherens junction and canonical Wnt signaling is fairly well understood. In this paper, however, the authors explore the role of ϒ-catenin, an important component of desmosomes, in liver pathobiology. This study used conditional knockout (KO) mice, bile duct ligation (BDL) and a model of chemical carcinogenesis (CC, diethylnitrosamine). KO mice at baseline showed a significant change in the desmosome composition, although the desmosome structure and function were maintained. However, KO mice subjected to BDL showed increased injury and fibrosis, and KO mice subjected to CC showed enhanced tumorigenesis via Wnt signaling. The authors conclude that ϒ-catenin appears to have a tumor suppressor function which could have therapeutic implications.

Hepatology, Nov-Dec 2015

CX3CR1 is a Gatekeeper for Intestinal Barrier Integrity in Mice: Limiting Steatohepatitis by Maintaining Intestinal Homeostasis
Schneider KM et al. Hepatology 2015;62:1405-1416.

CX3CR1 is G protein-coupled chemokine receptor expressed on macrophages that is involved in maintaining intestinal homeostasis in addition to playing a role in several of the manifestations of the metabolic syndrome. Since diet induced intestinal dysbiosis is a driver for NASH, the authors studied wild type and CX3CR1 deficient mice exposed to 2 diet-induced models of NASH (high fat diet or MCD diet). CX3CR1 protected mice from excessive liver steatosis and inflammation, as well as systemic glucose intolerance. Lack of CX3CR1 altered the intestinal microbiota composition, was linked to an impaired mucosal barrier and a greater amount of bacterial translocation. Nonabsorbable antibiotic treatment showed a marked improvement in steatohepatitis. The authors conclude microbiota-mediated activation of the innate immune responses through CX3CR1 is crucial for controlling NASH progression. With regards to the gut-liver axis, CX3CR1 is an essential gatekeeper and maintains the intestinal mucosal barrier.

A Novel Noninvasive Diagnostic Method for Nonalcoholic Steatohepatitis Using Two Glycobiomarkers
Kamada Y et al. Hepatology 2015;1433-1443.

Two glycobiomarkers, fucosylated haptoglobin (Fuc-Hpt) and Mac-2 binding protein (Mac2bp), were used to predict the degree of NASH ballooning and fibrosis, respectively. By combining the 2 serum markers together and using logistic regression analysis, the authors developed a prediction model for the diagnosis of NASH. This model was then validated using 382 biopsy proven NAFLD patients. Furthermore, the utility of this model was tested in a larger population of 803 NAFLD patients undergoing medical health checkups. The authors conclude that this serologic test-based glycobiomarker model is a novel NASH diagnostic modality that could replace liver biopsy.

Association of Nonalcoholic Fatty Liver Disease with Hepatocellular Carcinoma in the United States from 2004 to 2009
Younossi ZM et al. Hepatology 2015;62:1723-1730.

The SEER registries from 2004-2009 along with Medicare-linkage files and ICD codes were used to assess the prevalence and mortality of patients with NALFD-HCC in comparison with other chronic liver diseases such as HCV, HBV and alcoholic liver disease. Almost 5,000 cases of HCC and almost 15,000 controls without HCC were identified for statistical analysis. During the 6 year period NAFLD-HCC showed a 9% annual increase. NAFLD-HCC patients were older, had shorter survival time, more heart disease and were more likely to die from their primary liver cancer (all P < 0.0001). In multivariate analysis, NAFLD increased the risk of 1-year mortality. The authors conclude that NAFLD is becoming a major cause of HCC in the United States and that NAFLD-HCC is associated with a shorter survival time, more advanced stage and lower possibility of receiving a liver transplant.

Prospective Evaluation of the Diagnostic Accuracy of Hepatic Copper Content as Determined Using the Entire Core of a Liver Biopsy Sample
Yang Xu et al. Hepatology 2015;62:1731-1741.

Hepatic copper determination is an important tool for establishing the diagnosis of Wilson disease (WD), however, the methodology has not been standardized, the diagnostic accuracy prospectively validated and the optimum cut off value established. This is a prospective study of 3,350 consecutive patients who underwent core liver biopsy; 691 of those patients underwent liver biopsy with two passes, of which 178 were diagnosed with WD using a clinical and laboratory values based WD score (e.g., neuropsychiatric symptoms, Kayser-Fleischer rings, serum ceruloplasmin, urinary copper excretion, ATP7B mutation analysis etc) in combination with clinical follow up. ROC analysis supported a hepatic copper content cut off of 209 µg/g dry weight for the diagnosis of WD, if PBC and PSC have been excluded, instead of the two commonly cited but widely divergent cut off values of 250 µg/g dry weight and 75 µg/g dry weight. Copper deposition is unevenly distributed in the liver parenchyma and sample size is very important. Stringent study methodology was used to conclude that two passes of liver biopsy should be performed and a dedicated entire core of liver should be used for copper determination. The authors reiterate that histochemical staining is often negative when copper is diffusely distributed in the hepatocyte cytoplasm and histochemistry is more accurate only when copper is sequestered into lysosomes.

Human Pathology, November 2015

Immunohistochemical characterization of the regenerative compartment in biliary atresia: a comparison between Kasai procedure and transplant cases.
Kuo FY, et al. Hum Pathol. 2015;46(11):1633-9. 

This study examines immunohistochemical expression of CD56, CK7 and CK19 in relatively early biliary atresia (BA) patients (those undergoing Kasai procedure, n=24) vs, those with relatively late disease (those undergoing liver transplantation, n=64). The degree of ductular reaction and CK19 staining was similar on both groups. CD56 staining was seen significantly more often in liver transplant group. The authors suggest that the regenerative compartment shows more expansion in BA patients undergoing transplant and that there is more active regeneration in livers with advanced-stage BA.

Diagnostic value of maspin in distinguishing adenocarcinoma from benign biliary epithelium on endoscopic bile duct biopsy.
Chen L, et al. Hum Pathol. 2015;46(11):1647-54. 

The authors have shown in their previous studies that immunohistochemistry for insulin-like growth factor II mRNA-binding protein 3, S100P, and the von Hippel-Lindau gene product
(pVHL) can help to distinguish benign vs. malignant biliary epithelium. This study examines maspin (a serine protease inhibitor) expression by immunohistochemistry in 134 endoscopic bile duct biopsies (adenocarcinoma 45, atypical 31, and benign 58). Positive staining with maspin was seen more often in malignant cases, with diffuse nuclear and cytoplasmic staining of intermediate to strong intensity. Maspin was positive in 67% of atypical cases, which was consistent with an adenocarcinoma diagnosis made on follow-up. Maspin+/S100P+/pVHL- phenotype was present in 75% of malignant cases, while no benign biopsy showed this pattern.

Gastroenterology, Nov-Dec 2015

Liver Histology and Clinical Trials for Nonalcoholic Steatohepatitis-Perspectives From 2 Pathologists
Kleiner DE, Bedossa P. Gastroenterology. 2015 Nov;149(6):1305-8.

This is a very thoughtful commentary on various aspects of steatohepatitis by two experienced and widely respected hepatopathologists. The authors highlight the following points and diagnostic challenges:
(1) NAFL and NASH are considered as a dichotomous concept from the viewpoint of clinical trials. This is an oversimplification and does not allow proper categorization of cases with intermediate features. The NASH CRN has used the term ‘borderline NASH’ for these cases. For binary analysis in clinical trials, the NASH CRN has included these cases with cases showing definite NASH. The author state that further work is needed to clarify the utility of a more detailed histologic classification of NAFLD.
(2) Since binary classification into NAFL and NASH somewhat artificial, the authors advocate the concept that NAFLD is a chronic liver disease with a continuous spectrum, both in terms of disease activity and fibrosis.
(3)Histologic activity in NAFLD is reflected by features that are used to diagnose NASH: ballooning and lobular inflammation). European FLIP (Fatty Liver Inhibition of Progression) consortium has proposed the SAF (steatosis, activity, fibrosis) score. This involves semiquantitative evaluation of steatosis, activity (ballooning, inflammation), and fibrosis. This score does not include steatosis as part of disease activity, which is different from the NAFLD activity score (NAS).
(4) Fibrosis is a histologic marker of disease stage, and is more strongly associated with adverse clinical outcomes than histologic activity. Fibrosis has much higher reproducibility between pathologists compared to disease activity, and is an excellent indicator of adequacy of the biopsy (recommended 2 cm core using at least a 16-G needle). Hence regression of fibrosis may be the best marker to test drug efficacy. However, fibrosis regression is likely to take more time compared to markers of disease activity, and need a more generous biopsy. Despite these challenges, fibrosis regression is a goal that can be achieved for clinical trials as has been demonstrated in the FLINT study over a 72-week period. An expanded semiquantitative fibrosis staging system (from 0 to 6, similar to Ishak scheme for chronic viral hepatitis) or morphometric techniques may help in assessing fibrosis regression in shorter trials.
(5) Defining resolution of NASH is difficult, but is often required for clinical trials. The authors suggest that this should be defined as loss of ballooning (to a score of 0), with at least a 1-point decrement in lobular inflammation, without worsening of fibrosis.

Extrahepatic Morbidity and Mortality of Chronic Hepatitis C
Negro F, et al. Gastroenterology. 2015;149(6):1345-60. 

Extrahepatic manifestations associated with chronic hepatitis C includes mixed cryoglobulinemia which can manifest as cutaneous/visceral vasculitis, glomerulonephritis and B-cell lymphoma. Insulin resistance, diabetes, and atherosclerosis are common in hepatitis C cases and can lead to increased cardiovascular disease. Fatigue and cognitive impairment can also occur as part of neurological manifestations. The multisystem disease may be related to endocrine disturbances, viral replication in extrahepatic tissue, or an aberrant systemic immune reaction. Treatment with interferon alfa and ribavirin can improve the extrahepatic effects and the use of new interferon-free regimens may lead to greater improvements in extrahepatic manifestations. It is possible that extrahepatic manifestations can become an indication for treatment even if significant liver disease is not present.

American Journal Gastroenterology, Nov-Dec 2015

Changing Nomenclature for PBC: From ‘Cirrhosis’ to ‘Cholangitis’
Beuers U, Gershwin ME, Gish RG, et al. Am J Gastroenterol. 2015 Nov;110(11):1536-8.

In this position paper sponsored by the European Association for the Study of Liver Diseases of the authors describe the history of the nomenclature of primary biliary cirrhosis and propose an alternative name given that many patients with this disease do not present with cirrhosis.  A survey was sent out to expert in the fields and “primary biliary cholangitis” had the broadest support.  The authors contend that this change will have critical implications for patients by removing the stigma of cirrhosis.

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