Journal Watch January – February 2016

Histopathology Jan-Feb 2016

Low expression of B-cell-associated protein 31 in human primary hepatocellular carcinoma correlates with poor prognosis. 
Tan, N, et al. Histopathology 2016, 68, 221–229.

Based on the hypothesis that endoplasmic reticulum (ER) stress was associated with hepatocellular carcinogenesis, and that BAP31 regulates the export of secreted membrane proteins from the ER to the downstream secretory pathway, the authors investigated BAP31 as potential correlate of tumor biology, and hence prognosis. The study utilized paraffin-embedded tissue microarrays on a training, and a validation, cohort of HCC patients. The outcome indicates poor survival and higher tumor recurrence rate post-operatively correlated with low expression of BAP31 in tumor cells. Tumors that expressed this protein had a mean overall survival of 46.3 months versus 33.6 months in low expressor (p=0.021) among the validation cohort.  Also mean time to recurrence of 36.8 versus 26. 5 months was found in the validation cohort in high versus low expressing tumors respectively, although this did not reach statistical significance (p= 0.13). How BAP31 expression correlates with other measures of tumor biology was also analyzed.

Liver transplantation Jan-Feb 2016

Contribution of alloantigens to hepatic ischemia/reperfusion injury: Roles of natural killer cells and innate immune recognition of nonself. 
Kimura S, et al. Liver Transpl. 2016;22(1):80-90

Overactivation of the nuclear factor (erythroid-derived 2)-like 2-antioxidant response element pathway in hepatocytes decreases hepatic ischemia/reperfusion injury in mice. 
Lee LY, et al. Liver Transpl. 2016;22(1):91-102.

Subnormothermic ex vivo liver perfusion is a safe alternative to cold static storage for preserving standard criteria grafts. 
Spetzler VN, et al. Liver Transpl. 2016;22(1):111-9

The January 2016 issue of Liver Transplantation published three articles around ischemia-reperfusion and preservation injury of transplanted grafts.  A role for alloantigens and Natural Killer Cells is proposed by the Pittsburgh group (Kimura S et al), because depleting NK cells reduced significantly reperfusion injury. A second paper proposed mediating the antioxidant response influenced reperfusion injury in a mouse model. Lee LY et al demonstrated that “Over-activation of the Nuclear Factor (Erythroid-Derived 2)–Like 2–Antioxidant Response Element Pathway in Hepatocytes Decreases Hepatic Ischemia/Reperfusion Injury in Mice”. A third paper utilized an ex vivo warm preservation method at just subnormothermic temperature to demonstrate superior outcome to the traditional cold storage of standard criteria cadaveric organs in humans.  This paper by Spetzler VN et al from Toronto, Canada  demonstrated histologically and biochemically that parenchymal, endothelial, and biliary epithelial cells were better preserved using subnormothermic ex vivo than cold preservation.

Excellent outcomes of liver transplantation using severely steatotic grafts from brain-dead donors. 
Wong, T et al. Liver Transpl 2016;22:226-236

This paper challenges the traditional view that steatosis was a contraindication to organ acceptance for transplantation. Between 1991 and 2013 19 patients received grafts with more than 60% macrovesicular steatosis. Compared with a control of 354 recipients of less steatotic grafts, the short-term and long-term outcomes were not clinically or statistically significant. The outcome parameters measured are primary non-function; post-operative hospital stay duration; early allograft dysfunction; 30-day mortality and 1-year and 3-year overall survival rates.

Gut, Jan-Feb 2016

Stratification of hepatocellular carcinoma risk in primary biliary cirrhosis: a multicenter international study. 
Trivedi PJ, et al; Global PBC Study Group. Gut. 2016 Feb;65(2):321-9.

Hepatocellular carcinoma is a rare event in patients with primary biliary cirrhosis/cholangitis.  In this study of 4565 patients with PBC, 123 developed HCC (incidence rate of 3.4 cases/1000 patient-years).  The authors attempt to define the risk factors for the development of HCC in this cohort.  In univariate analysis male sex, elevated aspartate aminotransferase, thrombocytopenia, advanced biochemical disease, and hepatic decompensation were significantly associated with HCC development.  Advanced fibrosis (stage III/IV according to Batts and Ludwig) was also predictive but many patients did not have a baseline liver biopsy.  The strongest predictor of HCC development was lack of biochemical response (measured by Paris-I criteria) to ursodeoxycholic acid.  Lack of response to urso predicted development of HCC in patients with all stages of disease.  On multivariate analysis lack of biochemical response was the most significant factor predictive of HCC (hazard ratio 3.44).

Modern Pathology, Jan-Feb 2016

Inflammatory hepatocellular adenomas developed in the setting of chronic liver disease and cirrhosis.
Calderaro J; et al. Modern Pathology, 2016;26(1):43-50.

Hepatocellular adenoma, a heterogeneous entity, often occurs in non-fibrotic livers. The most common subtype of hepatocellular adenoma is inflammatory adenoma that harbors somatic mutations of genes involving in interleukin-6 pathway leading to elevated C-reactive protein and serum amyloid A expression. In this study, 10 benign hepatocellular neoplasms from three patients with cirrhosis were assessed using immunohistochemistry and molecular methods, including PCR and sequencing for CTNNB1, HNF1A, IL6ST, GNAS, STAT3, and TERT (promoter) mutations. A group of 32 cirrhotic livers that were caused by various etiologies was used as controls. The etiologies of cirrhosis of the three study patients included metabolic syndrome and/or alcohol liver disease. Two of them had a single tumor, and one developed more than 30 lesions. Microscopic examination revealed well-differentiated neoplasms that shared morphological features of inflammatory adenoma including inflammatory infiltrates, sinusoidal dilatation, and dystrophic vessels. Sequencing analysis demonstrated somatic mutations of IL6ST (n=8), STAT3 (n=1) and GNAS (n=1), the typical hotspots in IL-6/JAK/STAT pathway. Additionally, two lesions were immunoreactive for serum amyloid A and/or C-reactive protein. In summary, the findings support the existence of rare inflammatory type hepatocellular adenoma in patients with cirrhosis.

Gastroenterology, Jan-Feb 2016

Time to Replace Assessment of Liver Histology With MR-Based Imaging Tests to Assess Efficacy of Interventions for Nonalcoholic Fatty Liver Disease. 
Byrne C, Targher G. Gastroenterology. 2016;150(1):7-10.

This commentary is likely a response to the views expressed by Drs. Kleiner and Bedossa in the previous issue regarding histologic end points for NASH trials (covered in previous J watch).  The authors argue that the FDA requirement of improvement of the histologically derived NAFLD Activity Score by 2 points for drug approval for NASH should be changed. The authors believe liver fat content is an early marker of disease, and should be used for evaluation of treatment. This is also relevant as patients with steatosis have increased risk of cardiovascular disease and it is also important to ensure that therapy for NAFLD prevents harm beyond the liver as well. The authors also cite a few small studies that show that there is no difference in disease progression in simple steatosis vs. steatohepatitis.

End Points Must Be Clinically Meaningful for Drug Development in Nonalcoholic Fatty Liver Disease.
Sanyal AJ, et al. Gastroenterology. 2016;150(1):7-10.

In a competing opinion, these authors state that there is no compelling evidence that improvement of steatosis will lead to “clinically meaningful benefit,” as intended by the FDA. Hence improvement in steatosis alone by MR or other techniques does not meet regulatory standards to be accepted as the surrogate for drug approval for NASH.

Am J Pathology, Jan-Feb 2016

Diet-Induced Obesity Enhances Progression of Hepatocellular Carcinoma through Tenascin-C/Toll-Like Receptor 4 Signaling
Benbow JH et al. Am J Pathol 2016 Jan;186(1):145-158.

Tenascin-C is an extracellular matrix protein known to play a role in fibrogenesis and tumorigenesis. The authors developed a diet-induced obesity HCC mouse model and used it along with other tools to determine the cellular mechanism by which TnC signaling is involved in the promotion of inflammation, hepatocyte epithelial-to-mesenchymal transition (EMT), hepatocyte migration and carcinogenesis. Patients’ plasma TnC levels were also measured; obese patients with cirrhosis alone and in combination with HCC showed significant increases compared to healthy volunteers and patients with less severe liver injury. The authors conclude that hepatic stellate cell-derived TnC is elevated in obesity-associated HCC and that TnC can initiate an inflammatory response and EMT through TLR4 signaling. TnC is potentially a candidate as an early HCC biomarker and may also be a therapeutic target.

Serum miR-30e and miR-223 as Novel Noninvasive Biomarkers for Hepatocellular Carcinoma
Bhattacharya S et al. Am J Pathol 2016 Feb;186(2):242-247.

Limited noninvasive biomarkers for HCC detection are available, but early detection is key for improving outcomes. MiRNAs are single stranded, noncoding RNAs which regulate gene silencing by targeting mRNA directly for degradation or by inhibiting translation. 70 serum samples were utilized for miRNA-specific qRT-PCR. The authors found that miR-30e and miR-223 were expressed in significantly lower levels in the sera of HCC patients compared with healthy volunteers and chronic liver disease patients. These miRNAs may be candidates for useful HCC biomarkers.

Hepatology Jan-Feb 2016

Circulating Tumor Cells are Associated with Poor Overall Survival in Patients with Cholangiocarcinoma
Yang JD et al. Hepatology 2016;63:148-158.

The incidence of intrahepatic cholangiocarcinoma (iCCA) appears to be increasing and the prognosis remains dismal due to late detection. As a tumor proliferates, some tumor cells are released into the bloodstream to generate circulating tumor cells (CTCs). CTCs can be detected by tools such as the CellSearch System which uses EpCAM antibody-coated magnetic beads. These authors prospectively studied 88 iCCA patients and found that CTCs were associated with more aggressive tumor characteristics (including more extensive tumor burden, larger tumor size, multifocal disease, lymph node involvement and metastatic disease) and independently associated with survival after adjusting for known predictors of survival. The detection of CTCs could be useful for patient management decisions and as a predictor of recurrent disease s/p resection or as a predictor of unresectability.

Risk Stratification in Autoimmune Cholestatic Liver Diseases: Opportunities for Clinicians and Trialists
Trivedi PJ et al. Hepatology 2016;63:644-659.

Renewed interest in and understanding of the mechanistic and biologic pathways involved in primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC) have spurned the desire for additional therapies beyond ursodeoxycholic acid. The newer therapies would be aimed at both slowing the disease progression and improving quality of life. Also, there is now a better understanding of disease heterogeneity and therefore an opportunity to provide patients with a more individualized assessment. These factors have led to a new approach to patient care that focuses on risk stratification. This article reviews the applicability and validity of risk stratification in autoimmune cholestatic liver disease.

Clinical Gastroenterology and Hepatology Jan-Feb 2016

The Epidemiology of Liver Disease Unique to Pregnancy in a US Community: A Population-Based Study
Allen AM, Kim WR et al.  Clin Gastroenterol Hepatol. 2016;14:287-294.

The epidemiology of liver diseases of pregnancy (LDoP) including intrahepatic cholestasis of pregnancy (ICP), acute fatty liver of pregnancy (AFLP), HEELP (hemolysis, elevated liver enzyme, and low platelets), hyperemesis gravidarum (HG) and preeclampsia (PE) with liver dysfunction, in the US population is largely unknown. This first population based study of LDoP in the US identified 247 subjects with LDoP from 35,101 pregnancies in 21,857 subjects in Olmsted County, Minnesota between 1996 and 2010 using the Rochester Epidemiology Project database.  The overall incidence of LDoP was 0.77% of pregnancies, lower than that reported from Europe or US tertiary referral centers. PE with liver dysfunction was the most common (0.4%) followed by HELLP (0.23%) and ICP (0.1%), whereas HG with liver dysfunction (0.05%) and AFLP (one patient) were very rare. The overall fetal motility rate was 4% in patients with PE, 3% in patients HELLP, and 100% in the one case with AFLP. In the median of 7 years follow-up, the recurrence rate in subsequent pregnancies was 64% in HG, 63% in ICP and 17% in HELLP. Subsequent hepatobiliary diseases and other medical conditions were not common in the study.

Journal of Hepatology Jan-Feb 2016

Morphophenotypic changes in human multistep hepatocarcinogenesis with translational implications.
Sciarra A, Tommaso LD et al. Journal of Hepatology 2016; 64:87-93. 

The multistep Human hepatocarcinogenesis from low to high grade dysplastic nodules (LGDN and HGDN), to early and progressed hepatocellular carcinoma (eHCC and pHCC) is still controversial. The authors studied the morphophenotypic changes (vascular profile, ductular reaction/stromal invasion) and overexpression of five biomarkers (GPC3, HSP70, GS, CHC and EZH2), in a series of 100 resected nodules (13 LGDN, 16 HGDN, 42 eHCC and 29 pHCC). The data suggested that the earliest alteration was the vascular remodeling of the nodules, detectable in LGDN, but did not linearly develop in the sequence. As the disease progresses, there is significantly increased biomarker overexpression and decreased DR. The mean value of cumulative semi-quantitative score (CK7/CD34/5 biomarkers) was significantly different among the four diagnostic categories. For diagnosis, using traditional 3M panel (HPS70, GS and GPC3), eHCC was detected in 52% of the cases. When applying 4M panel (HPS70, GS, GPC3, and CHC) and 5M panel, eHCC was documented in 76% and 93% of the cases respectively. The study support the multistep nature of hepatocarcinogenesis. Additional biomarkers may increase the sensitivity and specificity of diagnosing eHCC.

FibroGENE: A gene-based model for staging liver fibrosis.
Eslam M, Hashem AM et al. Journal of Hepatology 2016; 64:390-398. 

Several non-invasive methods based on panels of serum markers, or the measurement of liver stiffness by elastograph have been established and widely used as surrogate measures. But the concerns about reproducibility and over- or under-estimation of fibrosis stage in these methods, particularly for non- CHC (chronic hepatitis C) diseases such as CHB and NAFLD, are problematic. The recent findings from the study group indicated that single-nucleotide polymorphisms (rs12979860) in the intronic region of the interferon-k4 (IFNL4) gene modulate liver inflammation and fibrosis, in an etiology independent manner. The authors in the current study sought to incorporate the invariant genetic marker of liver fibrosis risk to algorithms for fibrosis prediction, in combination with routinely available clinical and laboratory data. After analysis of two cohorts 3234 patients with liver fibrosis of different etiologies, data suggest that the novel non-invasive decision tree model (FibroGENE-DT) reliably estimates the risk of fast fibrosis progression, significant fibrosis and cirrhosis. FibroGENE-DT also performs well in NAFLD and CHB with AUROCs (area under the receiver operating characteristic curve) of 0.791, and 0.726, respectively. In addition, FibroGENE-DT excludes cirrhosis with a negative predictive value (NPV) of > 0.96 in CHC, CHB and NAFLD. FibroGENE-DT model may be an effective clinical tool for prediction of fibrosis risk in chronic liver diseases and assessment of liver fibrosis stage to aid clinical decision making.

Prepared by:
Rish Pai, MD, PhD; Mayo Clinic Arizona
Sanjay Kakar, MD; University of California, San Francisco
Cindy Guy, MD; Duke University
Wenqing Cao, MD; New York University
Jingmei Lin, MD, PhD; Indiana University
Oyedele Adeyi, MD; University of Toronto

Journals Reviewed
American Journal of Surgical Pathology, Modern Pathology, Histopathology, Human Pathology, American Journal of Clinical Pathology, Journal of Pathology, Archives of Pathology and Laboratory Medicine, Advances in Anatomic Pathology, Hepatology, Journal of Hepatology, Liver Transplantation, Gastroenterology, Gut, Clinical Gastroenterology and Hepatology, Journal of Gastroenterology and Hepatology, American Journal of Gastroenterology

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