HPHS JOURNAL WATCH: July – August 2017

De Marco L, Pellicano R. Gastroenterology. 2017 Jul;153(1):327.
This communication is in response to an article published by Elmasry et al (Gastroenterology 2017)regarding elevated ALT levels in patients with occult hepatitis C virus (HCV) infection (OCI) who had achieved sustained virologic response (SVR), after therapy with direct-acting antiviral (DAA). The authors point out 3 forms of OCI: (1) Undetectable HCV-RNA in serum and normal transaminases, but positive HCV-RNA in peripheral blood mononuclear cells or liver, (2) HCV-RNA undetectable in serum and persistent elevation of transaminases. In the study by Elmasry et al, 9 cases with SVR and elevated ALT had OCI, which led to the suggestion that these patients should receive additional antiviral therapy. IN this communication, the authors emphasize that evaluation for OCI and possibly additional treatment should also be considered for patients who have been treated for HCV prior to liver transplantation, and this can potentially reduce recurrent hepatitis C in the allograft liver. These reports to not mention liver histology, but the increasing recognition of OCI is interesting as persistent inflammation in the liver has been reported in many studies after SVR for hepatitis C. The correlation of histology with OCI is not fully understood as inflammatory changes are seen more often than detection of HCV-RNA in liver.
American Journal of Gastroenterology
Bugianese, E, et al. Am J Gastroenterol2017;112:1277-1286.
The authors analyzed 288 consecutive Caucasian Italian overweight/obese children to determine any associations between clinical parameters and histologic features.  12.2% of this cohort was small for gestational age and this was associated with severe steatosis, portal inflammation, and NAS score ≥5.  Lobular inflammation and ballooning were similar between groups.  Children who were large for gestational age were more likely to have type 1 NAFLD (steatosis, ballooning, and/or perisinusoidal fibrosis without portal inflammation or periportal fibrosis) compared to children who were small for gestational age or appropriate for gestational age.
Journal of Hepatology
Urban TJ, Nicoletti P, et al. J Hepatol. 2017 (67); 137-144.
Minocycline drug-induced liver injury (DILI) can present with prominent autoimmune features. To determine the genetic characters of minocycline DILI, the authors studied 25 Caucasian patients with genome-wide genotyping and compared to unexposed population controls. HLA-B35:02 was identified as a potential genetic risk factor for minocycline DILI: 16% carrier rate in DILI compared to 0.6% in population control. This data was confirmed with sequence based genotyping. In addition, HLA docking study suggested that minocycline had the potential to bind HLA-B*35:02 antigen binding cleft. HLA-B35:02 may be useful diagnostic maker of minocycline DILI.
Patouraux S, Rousseau D, et al. J Hepatol. 2017 (67); 328-338.
The roles of CD44 in hepatic inflammation and fibrosis were studied in a mouse model of steatohepatitis and human tissues. Compared to wild type mice on methionine- and choline deficient diet (MCDD), CD44-/- mice showed significantly less liver inflammatory infiltrates (macrophages and neutrophils), CCL2/CCR2 expression, hepatocyte injury and fibrosis.  CD44 silencing strongly enhanced M2 macrophage polarization and decreased the expression of pro-inflammatory cytokines such as IL-6 and TNFα. Neutralization of CD44 corrected hepatic inflammation and liver injury induced by MCDD. In obesity patients, hepatic CD44 expression was upregulated and strongly correlated with macrophage recruitment and markers of inflammation including TNFα, IL1β, MCP1 and CCR2. Correction of NASH with Bariatric surgery was associated with less hepatic CD44 positive cells. Serum levels of CD44 increased with the severity of steatosis and NAFLD. The study suggests CD44 is a key player in NASH and a potential therapeutic target.
American Journal of Pathology
Labgaa I, Stueck A, Ward S. American Journal of Pathology 2017; 187(7): 1438-1444.
This is an excellent review and summary of the literature on both lymphoepithelioma-like hepatocellular carcinoma and lymphoepithelioma-like cholangiocarcinoma.
American Journal of Surgical Pathology
Yang Z, Klimstra DS, Hruban RH, Tang LH. Am J Surg Pathol. 2017 Jul;41(7):915-922.
The treatment of neuroendocrine tumors (NETs) can differ depending on the primary site of the tumor.  Therefore, identifying the site of origin for metastatic NETs can be important.  In patients with distant metastases, the liver is the most common site to be involved.  The authors compiled 85 cases of metastatic well-differentiated NETs to the liver and assessed the effectiveness of a panel of immunostains (TTF1, CDX2, ISL1, NKX2.2, PDX1) in predicting the site of origin.  Tissue from microarrays (42 cases) and whole sections (43 cases) were used in this study that included NETs from the pancreas (35%), small bowel (32%), rectum (8%), stomach (2%), bile duct (1%), lung (9%), and unknown origin (12%); the sites of origin were determined based on previous or concurrent pathologic specimens in 74% and the remainder were based on radiologic findings or clinical history.  The use of a 3-marker panel composed of TTF1, CDX2, and ISL1 gave a sensitivity of 63-89%, specificity of 94-100%, positive predictive value of 89-100%, and a negative predictive value of 84-96% in differentiating among sites of origin when grouped as small bowel, lung, and pancreas/rectum.  In examining the 12% of tumors of unknown origin, over half of the cases showed staining for at least one of these 3 markers and was suggestive of small bowel or pancreas/rectum as the primary site.  In conclusion, the authors propose using this 3-marker panel along with any clinical findings for predicting the site of origin of well-differentiated NETs to the liver.  NKX2.2 and PDX1 did not add any additional information regarding site of origin when used in conjunction with the proposed 3-marker panel. 
Clinical Gastroenterology and Hepatology
Freeman AJ, Ng VL, Harpavat S, et al. Clin Gastroenterol Hepatol. 2017 Jul;15(7):1133-1135.
The authors evaluate the utility of gamma glutamyltransferase (GGT) as a potential marker of disease progression for patients affected by biliary atresia who survive without liver transplant. Thrombocytopenia is a recognized surrogate marker for disease progression and portal hypertension. The authors find that a GGT level ≥100 U/L at 2 years of age correlated with progressive decline in platelet counts at 4, 5, and 6 years of age. In comparison, having a GGT level < 100 U/L predicted a low risk of developing subsequent thrombocytopenia. The potential ramifications of this finding is that GGT levels obtained at age 2 may predict the development of thrombocytopenia, a feature of portal hypertension. If these findings are validated with further long term studies, such patients may need additional monitoring or closer follow up in consideration of therapeutic intervention.
Jacobson IM, Washington MK, Buti M, et al. Clin Gastroenterol Hepatol. 2017 Jul;15(7):1087-1094.e2.
Some chronic hepatitis B patients continue to have abnormal levels of alanine aminotransferase (ALT) despite antiviral therapy. This study of chronic hepatitis B patients treated with tenofovir showed 18% to continue to have increased ALT level at year 5, despite long term tenofovir disoproxil fumarate treatment. Grade 1 steatosis (34% to <66%), pretreatment HBeAg seropositivity, and younger age were the main factors associated with increased ALT at year 5. Compared to patients who achieve normalized ALT levels (n=384), those with persistently elevated ALT (n=18) were less likely to achieve virologic suppression and less likely to have cirrhosis regression at year 5 (80% vs 47%). In addition, in the group with persistently elevated ALT, HBeAg+ patients with steatosis on baseline biopsy had a higher frequency of progressing in steatosis over 5 years. The correlation between ALT abnormality and steatosis was not related to PNPLA3 genotype status.
Whitcomb E, Choi W, Jerome K, et al. Clin Gastroenterol Hepatol. 2017 Aug;15(8):1279-1285.
Hepatitis C infection is now curable, as defined by the absence of detectable serum HCV RNA after treatment completion. This study evaluated liver biopsies from patients who received liver transplant for chronic hepatitis C. Even after sustained virologic response (SVR) to antiviral therapy, ~70% of liver biopsies showed histologic features of active HCV infection, posing a potential pitfall of misdiagnosis to pathologists unaware of treatment status. PCR results, however, were negative for HCV in the liver tissue after sustained virological response, despite the histologic findings of hepatitis C infection. Of interest, approximately 30% of the patients had an increase in fibrosis stage in subsequent biopsy. This study characterizes the persistent histologic features of HCV in post-SVR allograft liver biopsies, although PCR is negative for hepatitis C virus in the tissue. Pathologists should avoid incorrect diagnosis of recurrent or persistent HCV in these patients who have completed therapy successfully. Nevertheless, the progression of fibrosis in a subset of these patients raises the question of what may be causing increase in disease stage, whether it be low but undetectable levels of persistent virus or other mechanisms such as idiopathic post-transplant hepatitis.
Kim YJ, Rhee H, Yoo JE, et al. Histopathology. 2017 Aug;71(2):217-226.
The authors use immunohistochemistry including keratins and markers of stemness (K19, K7, EpCAM, and NCAM), inflammation and inflammatory signaling (CD163, CD68, and pSTAT3), proliferation (Ki-67), and fibroblast activation protein (FAP) to mark cancer-associated fibroblasts (CAFs) on 17 scirrhous HCCs and 6 fibrolamellar carcinomas to evaluate differences in the supporting stroma/tumor microenvironment.
Liver Transplantation
Bajaj JS, Fagan A, Sikaroodi M et al.Liver Transpl. 2017 Jul;23(7):907-914.
The effects of liver transplantation on the gut microbial composition were evaluated and correlated with cognitive function and health-related quality of life measures in patients with cirrhosis.
Perito ER, Vase T, Ramachandran R et al. Liver Transpl. 2017 Jul;23(7):957-967.
The prevalence, persistence and association of post-transplant steatosis and chronic liver damage were evaluated in children in this single center study with long-term follow up.
Kasahara M, Sakamoto S, Sasaki K et al. Liver Transpl. 2017 Aug;23(8):1051-1057.
In this study, the authors report their experience with 12 children <3 months of age who underwent liver transplantation at a single center. The overall cumulative 10-year patient and graft survival rates were both excellent at 90.9%.
Prepared by:
Daniela Allende, MD (Editor), Cleveland Clinic 
Wenqing Cao, MD; New York University
Cynthia Guy, MD; Duke University
Sanjay Kakar, MD; University of California, San Francisco
Jingmei Lin, MD, PhD; Indiana University
Rish Pai, MD, PhD; Mayo Clinic Arizona
Nafis Shafizadeh, MD; Southern California Permanente Medical Group
Eric Yee, MD; University of Arkansas for Medical Sciences
Maria Westerhoff, MD; University of Michigan 

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