Journal Watch July-August 2015

American Journal of Gastroenterology, July-August 2015

Long-Term Prognostic Significance of Persisting Histological Activity Despite Biochemical Remission in Autoimmune Hepatitis.
Harpreet K et al.  Am J Gastro 2015;2110:993-9

The clinical significance of persistent histologic activity despite biochemical remission in patients with autoimmune hepatitis is unknown.  The authors studied 120 patients with autoimmune hepatitis who received immunosuppression and underwent liver biopsy at least 6 months after sustained biochemical remission (normal ALT and serum globulins).  Despite having biochemical remission, 55/120 (46%) had persistent histologic activity (defined as HAI ≥4).  No differences were seen in patients who achieved histologic remission compared to those who did not with regard to pretreatment clinical, laboratory, or histologic parameters.  No differences in treatment and time to biochemical remission was observed between these two groups.  However, serum ALT and AST were lower in those who achieved histologic remission.  The presence of HAI ≥4 on follow-up biopsy was associated with decreased fibrosis regression (60% versus 32%, p=0.004).  Finally, patients who did not achieve histologic remission had reduced transplant-free and overall survival.

American Journal of Surgical Pathology, July-August 2015

One Hundred Thirteen Consecutive Transgastric Liver Biopsies for Hepatic Parenchymal Diseases: A Single-institution Study.
Nakanishi, Y et al.  Am J Surg Pathol 2015;39:968-76

In this study, the authors present their results from 113 transgastric liver biopsies performed at a single institution (using QuickCore needle, ProCore needle, and Flex needle).  The transgastric biopsies were compared to 100 percutaneous and 100 transjugular biopsies.  The main reason for obtaining transgastric liver biopsies was assessment of fatty liver disease (43%) followed by elevated LFTs (25%).  In contrast percutaneous liver biopsies were performed mainly for grading and staging chronic hepatitis (45%).  The main indication for transjugular liver biopsy was to evaluate for cirrhosis.  In contrast to transjugular and percutaneous biopsies, transgastric biopsies were often quite fragmented and contained >10 tissue fragments with a median fragment length of 4 mm.  Most transgastric biopsies yielded less complete portal tracts; although biopsies obtained from the Flex needle performed as well as transjugular and percutaneous biopsies. Using the QuickCore neede a median of 2 complete portal tracts was obtained whereas 9 and 12 portal tracts were obtained using the ProCore and Flex needle respectively.  Transgastric biopsies were less likely to be adequate for staging and diagnosis as only 42%, 75% and 85% of the QuickCore, ProCore and Flex needle biopsies, respectively were deemed.  All transgastric biopsies contained gastric mucosa.

Ipilimumab-associated Hepatitis: Clinicopathologic Characterization in a Series of 11 Cases.
Johncilla, M et al.  Am J Surg Pathol 2015;39:1075-84

Ipilimumab is a monoclonal antibody directed against CTLA4 on T-cells and is most often used to treat metastatic melanoma.  Ipilimumab has been associated with a wide variety of immune-mediated side effects including colitis, enteritis, pancreatitis, nephritis and generalized lymphadenopathy.  The authors study 11 cases of ipilimumab associated hepatitis.  No patient had preexisting liver disease and 10 patients had normal LFTs before ipilimumab treatment.  Two patterns of hepatitis were observed, panlobular hepatitis and zone 3 hepatitis.  Three patients with panlobular hepatitis also had zone 3 necrosis and central vein endotheliitis was commonly seen. The inflammatory cell infiltrate consisted mostly of lymphocytes and histiocytic aggregates whereas plasma cells were usually rare, although in 3 patients they were more prominent.  In one patient steatohepatitis was identified and another showed cholangitis.  Discontinuation of ipilimumab resulted in improvement of LFTs in all patients.  All patients were also treated with steroids.

Archives of Pathology and Laboratory Medicine, July-August 2015

Comparison of 5 Immunohistochemical Markers of Hepatocellular Differentiation for the Diagnosis of Hepatocellular Carcinoma.
Nguyen, T et al Arch Pathol Lab Med.  2014;139:1028-34

The authors compare the efficacy of 5 hepatocellular markers (arginase-1, hep par1, glypican-3, polyclonal CEA, and bile salt export pump transporter) in the diagnosis of hepatocellular carcinoma.  The authors included well differentiated, moderately differentiated and poorly differentiated hepatocellular carcinoma.  Of the 79 HCC cases, only 1 case failed to stain with arginase-1 (a poorly differentiated HCC).  Importantly, hep-par1 failed to stain 14/39 poorly differentiated HCC.  Polyclonal CEA and BSEP also performed poorly in high-grade tumors.  Gylpican 3 staining increased with increasing tumor grade.  Arginase 1 and glypican 3 immunohistochemistry may be most useful in the diagnosis of poorly differentiated hepatocellular carcinoma.

Clinical Gastroenterology and Hepatology, July-August 2015

Identification and Characterization of Cefazolin-induced Liver Injury.
Alqahtani SA et al. Clin Gastroenterol Hepatol. 2015;13(7):1328-1336

Cefazolin is a commonly used first generation Cephalosporins, for which drug induced liver injury (DILI) is generally considered rare. A recent ongoing prospective study from the United States, Drug Induced Liver Injury Network (DILIN), identified 19 out of 1212 (2%) patients with DILI attributed to Cefazolin, making Cefazolin the sixth most common single agent in the data set.  Cefazolin induced liver injury has a latency period of about 20 days (1-3 weeks), and shows a self-limited moderate to severe clinical course characterized by a cholestatic biochemical and histologic pattern. The study also identified 14 more patients with DILI attributed to other Cephalosporins, a few of them were associated with severe injury and death. For the first time, the authors describe the clinical presentations, laboratory tests and histopathology of cephazolin induced DILI, and identify Cephalosporins as a relative common cause of antibiotic-associated liver injury.

Gut, July-August 2015

A genomic and clinical prognostic index for hepatitis C-related early-stage cirrhosis that predicts clinical deterioration.
King Y et al.  Gut 2015;64:1296-1302

Cirrhosis due to HCV is increasing.  While eradication of the virus decreases the risk of disease progression, it does not eliminate the risk.  In a prior study, the authors developed a 186-gene expression panel that can risk stratify patients with HCV.  In this study the authors implemented the 186-gene signature using an FDA-approved clinical diagnostic assay platform.  The authors of this study developed a prognostic gene expression signature in an attempt to risk stratify HCV patients with cirrhosis.  Using RNA isolated from FFPE samples, the authors validate this gene signature using a training cohort.  A 145 patient validation cohort was appropriately risk stratified using this gene panel as the high-risk group experienced more frequent hepatic decompensation (HR=7.36), overall death (HR=3.57), and liver-related death (HR=6.49).  Importantly, the prognostic association remained statistically significant in Child-Turcotte-Pugh class A patients (n = 121) indicating that it will be useful in patients with “early cirrhosis”.

Gastroenterology, July-August 2015

Liver Fibrosis, but No Other Histologic Features, Is Associated With Long-term Outcomes of Patients With Nonalcoholic Fatty Liver Disease.
Angulo P, et al. Gastroenterology. 2015;149(2):389-397.

Editorial: The Hierarchical Model of NAFLD: Prognostic Significance of Histologic Features in NASH.
Loomba R, et al. Gastroenterology. 2015;149(2):278-81.

This study examines prognostic significance of histologic features in 619 NAFLD cases. Older age, diabetes, current smoking and presence of fibrosis (as well as stage of fibrosis) were associated with death or liver transplantation. Ballooning and portal inflammation were significant associations, but not in multivariate analysis. Stage 3 and stage 4 fibrosis were the only features associated with liver-related events (defined as variceal bleeding, HCC, liver-related death, liver transplant). Steatosis grade, lobular inflammation and NAFLD score were not associated with overall mortality or liver-related events.

Hepatology, May 2015

Fibrosis stage is the strongest predictor for disease-specific mortality in NAFLD after up to 33 years of follow-up.
Ekstedt M, et al. Hepatology. 2015;61(5):1547-54.

The outcome in 229 biopsy-proven NAFLD with mean available follow-up of 26.4 years was compared to a reference population. NAFLD patients had higher risk of cardiovascular disease, hepatocellular carcinoma, infections and cirrhosis. NAFLD patients with stage 3 and stage 4 fibrosis had increased mortality, but not those with no fibrosis or lower stage of fibrosis.

Journal of Gastroenterology and Hepatology, July-August 2015

Usefulness of endoscopic ultrasound-guided sampling using core biopsy needle as a percutaneous biopsy rescue for diagnosis of solid liver mass: Combined histological-cytological analysis.
Lee YN. Et al. J Gastroenterology and Hepatology. July, 2015; 30(7):1161-1166.

In this study, the diagnostic accuracy of EUS-guided fine needle biopsy (EUS-FNB) was studied. Twenty-one patients underwent EUS-FNB after the failure of a percutaneous biopsy for liver solid mass. The median number of needle passes was 2.0 (range, 1-5). On-site cytology and cytology with Papanicolaou stain showed malignancy in 16 (76.2%) and 17 patients (81.0%), respectively. In histology with H&E stain, 19 patients (90.5%) were diagnosed malignancy and optimal to IHC stain. The overall diagnostic accuracy for malignancy and specific tumor type were 90.5% and 85.7%, respectively. No complications were seen. In summary, EUS-FNB with core biopsy needle may be helpful in the management of patients who are unable to diagnose using percutaneous liver biopsy.

Journal of Hepatology, July-August 2015

Targeting cyclin dependent kinase 5 in hepatocellular carcinoma – A novel therapeutic approach.
Ehrlich SM et al.  Journal of Hepatology 2015; 63: 102-13.

Recently, dysregulation of cyclin dependent kinase 5 (Cdk5) has been linked to malignancy, including cancers of the prostate, pancreas, thyroid, lung, cervix, myeloma, and breast. In the study, the role of Cdk5 in HCC progression was investigated. Increased expression of Cdk5 and its activator P35 were seen in HCC compared to normal liver tissues. Overexpression of Cdk5 promoted HCC cell growth in vitro. Genetic (siRNA and shRNA) or pharmacologic (roscovitine) inhibition of Cdk5 expression reduced HCC cell proliferation and tumor growth in a xenograft mouse model. Furthermore, HCC cell line and xenografts were treated with CDK5 inhibition plus DNA-damage-inducing chemotherapeutics to examine the effect on cancer cell proliferation and tumor growth. Data showed that down regulation of Cdk5 expression enhanced the sensitivity of various DNA damaging agents in HCC. The study suggested that CDK5 might be a novel treatment target, and combination of CDK5 inhibition and DNA-damaging agent could serve as an effective therapeutic approach for HCC.

Breast tumor kinase/protein tyrosine kinase 6 (Brk/PTK6) activity in normal and neoplastic biliary epithelia.
Mizuguchi Y et al. Journal of Hepatology 2015; 63:399-407

In this article, using immunohistochemistry, the authors found BRK protein was expressed at low level in normal intrahepatic bile ducts. The expression of BRK was significantly higher in CC cell lines and a majority of CC compared to normal tissues. High expression of BRK in CC was associated with extrahepatic location and well differentiation. Studies in vitro revealed BRK co-localized with EGFR and ErbB2/neu, and promoted tumor growth. Knock down BRK by siRNA significantly reduced tumor cell proliferation. The data indicated the important role of BRK in HCC progression, suggesting that BRK might serve as a target for HCC treatment.

Modern Pathology, July-August 2015

The liver in heart failure: a biopsy and explant series of the histopathologic and laboratory findings with a particular focus on pre-cardiac transplant evaluation.
Louie CY., et al. Modern Pathology July 31st, 2015 (28):932-943

Liver biopsies are commonly obtained as part of the work up before heart transplantation in patients with longstanding right heart failure, particularly if ascites, abnormal liver function tests or abnormal abdominal imaging are noted as part of the pre-transplant evaluation. In these cases, the liver biopsy findings may be used to further risk stratify patients for isolated heart or combined heart and liver transplantation. Thus, it is important to be able to correlate the histologic changes with post-transplant outcomes.  In this report, the pathologic and clinical findings in liver explants from six patients who underwent combined heart-liver transplantation and preoperative liver biopsies from 21 patients who underwent heart transplantation without simultaneous liver transplantation were studied. The changes related to chronic passive congestion were staged as follows: stage 0-no fibrosis; stage I-pericellular fibrosis; stage II-bridging fibrosis; and stage III-regenerative nodules. Thirteen biopsies showed bridging fibrosis in 13 and 6 had regenerative nodules. Fifteen patients were alive at 1 year post transplant. Only three patients had a postoperative course that was characterized by signs and symptoms of chronic liver disease. Pre-transplant liver biopsies from these 3 patients all showed at least stage II fibrosis. These 3 patients survived for 3, 6, and 10 months after cardiac transplant. It appears that the presence of bridging fibrosis was not significantly associated with postoperative survival (P=0.336) or postoperative liver failure (P=0.257). In conclusion, patients with bridging fibrosis may still be considered viable candidates for isolated heart transplantation.

Infiltrative (sinusoidal) and hepatitic patterns of injury in acute cellular rejection in liver
allograft with clinical implications
Siddiqui A. et al. Modern Pathology July 31st, 2015 (28) 1275–1281

Two patterns of acute cellular rejection (ACR), sinusoidal infiltrative and hepatitic, were described in this study. Twenty-eight cases of ACR with rejection activity index 5 or above were included. Among them, 15 (54%) had typical, 6 (21%) hepatitic and 7 (25%) sinusoidal infiltrative ACR. Sinusoidal infiltrative ACR occurred later (124 versus 50 days; P=0.032) and had a higher rise in baseline AST compared with the conventional one (289 vs 109 U/l; P=0.046). Only one out of seven patients with sinusoidal infiltrative ACR (14% versus 40% in typical ACR) failed Solu-Medrol boluses and required thymoglobulin. Patients with hepatitic ACR had similar AST (P=0.12) but higher bilirubinemia than typical one (160 vs 35 mol/l; P=0.039) and required thymoglobulin in four out of six (67% vs 40%) instances. Patients with sinusoidal infiltrative ACR had higher AST than the typical one but better Solu-Medrol response compared with both the typical and hepatic ACR.

Nature July-August 2015

Self-renewing diploid Axin2+ cells fuel homeostatic renewal of the liver.
Wang B, et al. Nature 2015 Aug 13;524(7564):180-185.

This report revolutionizes how we think about liver regeneration and hepatocytes renewal and shifts emphasis away from the Canals of Hering to the perivenular zone. The authors, using the wnt-responsive Axin2 gene lineage-traced renewal of hepatocytes by diploid, Axin2-expressing, cells in the perivenular zone of mice liver. This study demonstrate the presence of diploid Axin2 cells ONLY around hepatic veins, and that these cells differ from hepatocytes which are almost always non-diploid (having 4N-32N polyploidy). The authors surmised that being polyploid was a disadvantage to hepatocytes’ ability to self-renew. The lineage tracing in this study showed ability of these diploid Axin2 cells to replace all hepatocytes all the way to periportal hepatocytes over one year. They also demonstrate that like glutamine synthetase, Axin2 also responds to wnt signaling in an autocrine manner; that wnt signal originated from the hepatic vein endothelial cells, and that hepatocytes renewed by these Axin2 cells lost Axin2 expression as they migrated away from the hepatic vein vicinity towards hepatocytes, in the manner that they lost glutamine synthetase. The renewed hepatocytes take up carbamoyl-phosphate synthase 1, which replace GS and Axin2. Lastly the authors proved that Axin2 truly self-renewed and not preplaced by new Axin2 cells by using other cell labelling methods; i.e. “..while Axin2+ cells can give rise to all the hepatocytes along the lobule, they are not replaced by unlabeled Axin2− cells”. Other findings include Tbx3 gene dependence of Axin2 cells renewability. This study clearly revolutionizes traditional thinking about liver regeneration.

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; University of Rochester
Jingmei Lin, MD, PhD; Indiana University
Oyedele Adeyi, MD; University of Toronto
Charles Lassman, MD; University of California, Los Angeles

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, Nature

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