Journal Watch September-October 2016

Clinical Gastroenterology and Hepatology

Noninvasive Detection of Nonalcoholic Steatohepatitis Using Clinical Markers and Circulating Levels of Lipids and Metabolites
Zhou Y, Oresic M, Leivonen M, et al. Clin Gastroenterol Hepatol. 2016;14:1463-1472.

Clinical factors such as age, sex, liver enzymes, components of the metabolic syndrome, as well as circulating markers of inflammation, fibrosis, apoptosis, and extracellular matrix components are associated with NASH. Genetic factors, especially the I148M variant in patatin-like phospholipase domain containing protein 3 (PNPLA3), also confers susceptibility to NASH. In this study, using mass spectrometry (MS)-based methods, the authors identified a set of lipids and metabolites that significantly associated with NASH in a liver biopsy cohort of 318 patients. They subsequently developed models based on 1) clinical parameters and the PNPLA3 genotype alone (NASH Clin Score); 2) MS-based profiling (NASH Met Score); and 3) all data (NASH ClinLipMet Score). They found that the NASH ClinLipMet Score identified patients with NASH with significantly higher accuracy than the NASH Clin Score or NASH Met Score. A score based on MS (glutamate, isoleucine, glycine, lysophosphatidylcholine 16:0, phosphoethanolamine 40:6) and knowledge of AST, fasting insulin, and PNPLA3 genotype may be a useful tool to improve noninvasive diagnosis of NASH.

Journal of Hepatology

Definition and Risk Factors for Chronicity Following Acute Idiosyncratic Drug-induced Liver Injury
Medina-Caliz I, Robles-Diaz M, Garcia-Muñoz B,et al. J Hepatol. 2016; 65:57-65.

The best definition of DILI chronicity remains a matter of debate. This study prospective, long-term follow-up study analyzed 298 out of 850 patients in the Spanish DILI registry and concluded one year is the best cutoff point to define chronic DILI. In this cohort, 28 patients (8%) were chronic DILI. Risk factors for chronicity include old age, dyslipidemia, and severe DILI.  Compare to acute DILI, chronic DILI group had significantly higher mean values of alanine aminotransferase (ALT), alkaline phosphatase (ALP) and total bilirubin (TB). In addition, elevated ALP and TB in second month from DILI onset may predict chronicity. Main drug classes associated with chronic DILI were statins, and anti-infective.


Prevalence of Sclerosing Cholangitis Detected by Magnetic Resonance Cholangiography in Patients With Long-term Inflammatory Bowel Disease.
Lunder AK, Hov JR, Borthne A, et al. Gastroenterol. 2016;151(4):660-669.

This study examines MRCP findings in 756 patients with IBD 20 years after initial diagnosis to examine the prevalence of primary sclerosing cholangitis (PSC). Findings of PSC were seen on imaging in 26 cases (8.1%), of which only 7 (2.2%). PSC-related findings correlated with extensive colitis, history of colectomy, and persistent symptoms. In asymptomatic cases with PSC-like changes, the MRCP findings increased on follow-up. In this study, prevalence of PSC was 3-fold higher compared to that detected based on symptoms. Subclinical PSC and no biochemical abnormalities were seen in 65% of cases.

Shifting Paradigms: What Is the True Prevalence and Clinical Course of Primary Sclerosing Cholangitis?
Weersma RK, Lindor KD. Gastroenterol. 2016;151(4):590-3.

This is an editorial that accompanies the previous article. The review highlights the important findings of the paper:
-Biochemical abnormalities are not always present in PSC.
-Severe colitis and prior colectomy are risk factors for subclinical PSC.
-The natural history of subclinical PSC detected by MRCP will requires longer follow-up studies; the present data indicates that these cases progress in a subset of cases.

Human Pathology

Arginase-1 is frequently positive in hepatoid adenocarcinomas.
Chandan VS, Shah SS, Torbenson MS, et al. Hum Pathol. 2016; 55:11-6.

The morphology and immunohistochemical findings in hepatoid adenocarcinomas are similar to hepatocellular carcinoma (HCC). This study performed immunohistochemistry for Arginase-1, Hepar-1, Glypican-3, CK7, CK20, CK19, polyclonal carcinoembryonic antigen, ɑ-fetoprotein, CDX2, and TTF-1 in 8 cases, and albumin in situ hybridization in 4 of cases of hepatoid adenocarcinoma. Arginase-1 was positive in 5 (62.5%) cases, 2 of which had diffuse staining. Hepar-1 was positive in all 8 cases; glypican-3, CK7 and AFP were each positive in 4 (50%), CK19 in 3 (37.5%); polyclonal carcinoembryonic antigen (canalicular staining) in 3 (37.5%) and albumin in situ hybridization was positive in 3 (75%); CDX2 in 2 (25%); CK20 in 1 (12.5%); TTF-1 was negative in all cases.  Arginase-1 cannot be used to distinguish HCC from hepatoid adenocarcinoma.

Quantitative fibrosis estimation by image analysis predicts development of decompensation, composite events and defines event-free survival in chronic hepatitis B patients.
Bihari C, Rastogi A, Sen B, et al. Hum Pathol. 2016; 55: 63-71.

Fibrosis quantification was done in 964 cases of chronic hepatitis B by image analysis on Masson’s trichrome-stained sections. Median quantitative fibrosis (QF) was F0, 1%; F1, 3.03%; F2, 7.1%; F3, 12.7%; F4, 26.9%. METAVIR stage, liver stiffness measurement, and hepatic vein pressure gradient correlated with QF. After adjusting for stage, QF, albumin and ALT were predictors of outcome.

Hepatocyte differentiation markers in adenocarcinoma of the prostate: hepatocyte paraffin 1 but not arginase-1 is specifically expressed in a subset of prostatic adenocarcinoma.
Giedl J, Büttner-Herold M, Wach S, et al. Hum Pathol. 2016; 55: 101-7.

Prostate adenocarcinoma and hepatocellular carcinoma (HCC) can present with bone metastasis and typically negative for both CK7 and CK20. This study performed immunohistochemistry for arginase-1 and HepPar-1 using tissue microarrays in 557 cases of prostatic adenocarcinoma. Positive staining with HepPar-1 was seen in 64 (11.5%) cases showed with variable expression (1-75%) in tumor cells. HepPar-1 staining in >10% of tumor cells was present in 13 (2.3%) cases. Arginase-1 showed nonspecific cytoplasmic staining in 19 (3.4%), which was different from combined nucleocytoplasmic staining seen in normal liver and HCC. This pattern with Arg-1 was used with one antibody lot, but not the other. Nucleocytoplasmic pattern was seen in Arg-1 only 1 case. In conclusion, HepPar-1 is common in prostatic adenocarcinomas and Arg-1 expression is more reliable for distinction of HCC and prostatic adenocarcinoma.

American Journal of Surgical Pathology

Clearance of Hepatic Spingomyelin by Olipudase Alfa is Associated with Improvement in Lipid Profiles in Acid Spingomyelinase Deficiency
Thurberg BL, Wasserstein MP, Jones SA, et al. Am J Surg Pathol. 2016; 40(9):1232-42.

Acid spingomeylinase deficiency/Niemann-Pick disease (ASMD/NPD) is a lysosomal storage disorder due to abnormal intracellular accumulation of spingomyelin (SM).  In NPD type B, SM accumulation within Kupffer cells and hepatocytes eventually leads to hepatomegaly, a significant cause of morbidity and mortality.  In addition to abnormal LFTs, most patients also have abnormal lipid profiles (high LDL-C, low HDL-C), known risk factors for atherosclerosis and coronary artery disease.  In this study, the investigators demonstrate the effects of escalating doses of olipudase alfa (OA), a recombinant human ASM that has shown promise as enzyme replacement therapy in previous phase 1 trial data.  Histomorphologic (including MetaMorph digital analysis), biochemical and electron microscopic parameters were evaluated after 26 weeks of therapy.  Compared to baseline, 4 out of 5 patients (tissue insufficient for analysis in 1 subject) showed significant reductions in SM by all 3 methods of measurement, and normalization of AST/ALT.  Additionally, all patients showed decreases in LDL-C and increases in HDL-C.  OA continues to show promise but therapy is still investigational and effects on long-term outcomes remain unknown.

Archives of Pathology and Laboratory Medicine

Practical Applications in Immunohistochemistry: Evaluation of Rejection and Infection in Organ Transplantation
Troxell ML, Lanciault C. Arch Pathol Lab Med 2016; 140(9): 910-925.

This review article summarizes applications and limitations of C4d and other infectious organism immunostains in the setting of solid organ transplant.  With regards to the liver and ABO-compatible grafts, recipients with preformed lymphocytotoxic donor-specific antibodies (DSA) are at increased risk for developing antibody-mediated rejection (ABMR).  Microscopic changes suggestive of ABMR include bile ductular reaction, periductal neutrophilic infiltrates, portal edema, fibrin deposition around or within vessels, lobular neutrophils, and sinusoidal injury with parenchymal hemorrhage in severe cases.  When C4d immunohistochemistry is performed to assess for ABMR, staining of portal veins/capillaries and/or sinusoids is considered supportive of ABMR; however, staining of the sinusoids is thought to be more specific.  C4d immunohistochemistry result reporting should indicate if there is positive staining and which compartment stains; more than 50% staining is termed diffuse and has the highest correlation with ABMR.  However, C4d immunohistochemistry must be interpreted in context with histologic changes, DSA titers and the clinical situation, as C4d staining alone is not specific and can be seen in approximately 50% of cases with cellular rejection as well as conditions not related to rejection (chronic hepatitis, vascular injury, biliary injury).  Likewise, when performing immunostains for infectious agents, we are reminded that a negative stain does not exclude infection (organisms can be patchy, false-negative sampling, some antibody clones may react with only a limited range of viral serotypes) and more than one infectious agent may coexist in a case.

American Journal of Pathology

Pathogenesis of Kupffer Cells in Cholestatic Liver Injury
Sato K, Hall C, Glaser S, et al. Am J Pathol 2016; 186: 2238-2247.

This is a detailed review of the pathogenic role of Kupffer cells in chronic liver inflammatory injury, with a focus on chronic cholestatic disease.


Albumin expression distinguishes bile duct adenomas from metastatic adenocarcinoma.
Moy AP, Arora K, Deshpande V. Histopathol. 2016;69(3):423-430

AIMS: Bile duct adenomas may be difficult to distinguish from metastatic carcinomas, particularly well-differentiated pancreatic ductal adenocarcinoma. Prior studies have evaluated the utility of various immunohistochemical markers, although these markers are notable for low sensitivity and/or specificity. The aim of this study was to investigate the utility of albumin and BRAFV600E expression in distinguishing between metastatic pancreatic adenocarcinoma and bile duct adenoma.
METHODS AND RESULTS: We studied 26 bile duct adenomas, three bile duct hamartomas, and 158 pancreatic ductal adenocarcinomas. Branched-chain in-situ hybridization (bISH) for albumin was performed; bISH is based on the branched DNA technology, wherein signal amplification is achieved via a series of sequential steps. Additionally, BRAFV600E immunohistochemistry (IHC) was performed on a subset of cases. Twenty-three of 25 (92%) bile duct adenomas were positive for albumin; 18 (72%) showed diffuse staining, and five showed focal staining (20%), including two challenging examples. Two bile duct hamartomas also stained positively. All pancreatic adenocarcinomas were negative for albumin. Seven of 16 (44%) bile duct adenomas and five of 106 (5%) pancreatic ductal adenocarcinomas were positive for BRAFV600E by IHC. The sensitivity and specificity of expression of albumin, as detected by bISH, for distinguishing bile duct adenomas from metastatic pancreatic adenocarcinomas were 92% and 100%, respectively; the sensitivity and specificity of BRAFV600E IHC for distinguishing bile duct adenomas from metastatic pancreatic adenocarcinomas were 43.8% and 95.3%, respectively.
CONCLUSIONS: Diagnostically challenging examples of bile duct adenoma may be distinguished from metastatic pancreatic adenocarcinoma by the use of albumin bISH.

Treatment with Optifast reduces hepatic steatosis and increases candidacy rates for living donor liver transplantation.
Doyle A, Adeyi O, Khalili K, et al. Liver Transpl. 2016; 22(9):1295-1300

This study used paired liver biopsies to document improvements in steatosis levels in liver living donors, who subsequently successfully donated portions of their liver. Optifast is shown as a viable intervention for improving donor liver pool.

Prepared by:
Editor, Daniela Allende, MD, Cleveland Clinic
Oyedele Adeyi, MD; University of Toronto
Wenqing Cao, MD; New York University
Cindy 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
Eric Yee, MD; University of Oklahoma
Nafis Shafizadeh, MD, Southern California Permanente Medical Group

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