Saturday, September 23, 2017

President's Message September 2017

Dear Friends and Colleagues:

In this president’s message we will consider one of the major functions of the office of the President—organizing the Hans Popper Hepatopathology companion meeting.

The President proposes topics and speakers to the Executive Committee, who provide feedback and additional suggestions before the agenda is finalized.  The topics are usually organized around a central theme.  For 2018, the theme will be Major challenges in liver pathology, with topics selected because they pose ongoing challenges, even to those with a lot of experience in diagnostic liver pathology.  Speakers are chosen because they have demonstrable expertise by way of experience and publications.  In many cases, there are multiple excellent speaker candidates, so other factors might be considered, such as geographic variation and if/when an individual spoke at the last Hans Popper companion meeting.  With the new SOPs, we try to hear a wider range of expert voices, selecting whenever possible speakers who have not given talks at the companion within the last three years.  Is there a topic you would be interested in?  Feel free to propose a topic or speaker by sending an email to the president.

Many of the speakers attend the annual Hans Popper Reception, which takes place on Saturday night before the companion meeting, and this is a great place to meet them informally. They are fun and interesting people!  If you get the chance, please take the opportunity to thank the speakers.  They do not receive honorarium or travel expenses with the new SOPs, but agree to speak because of their interest, expertise, and passion for liver pathology.

In the table below are the topics and speakers for the 2018 meeting.  I believe it will be an excellent session and hope you can attend.  

Please don’t forget to mark your calendars for the Hans Popper Reception in Vancouver (Saturday night)—location will be announced later.

Finally, at the reception we raffle off a handful of liver pathology books.  If you would like to donate a book, please send me an email (and the book) and I will get it to the reception.  It can be a book you wrote, or even one that you like a lot and think it would be a good addition to the raffle.


Michael Torbenson, MD
President, Hans Popper Society

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 Gastroenterol 2017;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 

Interesting Case September 2017

Clinical History:
The patient is a 27-year-old male with a history of right lower extremity osteosarcoma, status post above-knee amputation and chemotherapy that resulted in severe cardiomyopathy requiring a cardiac transplant.  Subsequently, he developed monomorphic post-transplant lymphoproliferative disorder (PTLD), diffuse large B-cell type, involving the GI tract, bone, and lymph nodes which had been in remission for the past 4 years. He was also being followed for a small lesion in the left lobe of the liver. He presented to the hospital for acute onset of jaundice with a peak bilirubin of 10.0. Due to concern for a recurrence of PTLD, a biopsy of the liver lesion was performed.

Imaging Findings:
MRI of the abdomen initially demonstrated a T2 hyperintense round lesion (1.0 cm) with thin peripheral enhancement. A CT abdomen performed a year later showed that the lesion had slowly increased in size measuring 1.7 x 1.4 x 1.4 cm. The findings were nonspecific and a wide clinical differential was considered, including a simple cyst, infection, metastatic disease, and PTLD.

Figure 1: H&E 100x 
Figure 2: H&E 200x

Figure 3: Smooth muscle actin 100x

Figure 4: Desmin 100x

Figure 5: EBER 100x

Liver Biopsy Findings:
The liver biopsy showed spindled tumor cells arranged in short intersecting fascicles. The tumor cells were bland, demonstrating elongated nuclei with blunted ends and abundant eosinophilic cytoplasm. No significant cytologic atypia was identified. Mitotic activity and tumor necrosis were not conspicuous. The background liver was unremarkable.
Immunohistochemical stains demonstrated that tumor cells were diffusely positive for smooth muscle actin (SMA) and patchy positive for desmin. In situ hybridization for Epstein-Barr virus encoded RNA (EBER) was strongly and diffusely positive in the tumor cells. 

EBV-associated smooth muscle tumor

Epstein-Barr virus (EBV)-associated smooth muscle tumor is a rare neoplasm that is most commonly seen in immunocompromised patients, including those with organ transplants, HIV/AIDS, and congenital immunodeficiency1. The lesions can involve a variety of anatomic sites and multifocal tumors are thought to be due to multiple infections rather than metastatic disease2. In post-transplant recipients, the most common locations of tumor occurrence are the liver, lungs, larynx, pharynx, gastrointestinal tract, spleen, kidneys and central nervous system.  Histopathologic features may vary in terms of cellular atypia, mitotic activity, and necrosis, however unlike conventional smooth muscle tumors, these features do not correlate well with tumor behavior.
Local surgical resection, reduced immunosuppression, and chemotherapeutic approaches have been used in the treatment of these tumors. Most patients succumb to infectious complications or underlying disease rather than tumor progression, however HIV associated tumors and tumors of the CNS have been reported to have the worst prognoses. 
Histologic features
The histologic features of these tumors include spindled cells arranged in fascicles. Tumor cells have eosinophilic cytoplasm with elongated, blunt-ended nuclei. Two unique histologic features have been described, which include a variable number of intratumoral lymphocytes and occasional primitive round cell areas. Histopathologic features may vary in terms of cellular atypia, mitotic activity, and necrosis. 
Ancillary testing
The critical ancillary diagnostic finding is positive in situ hybridization for EBER. The tumor cells are positive for SMA and may be positive for desmin. They are negative for S100, HMB45, CD34, CD117, and HHV-8. 
Differential diagnosis
These tumors demonstrate a relatively bland spindle cell proliferation, and the morphologic differential diagnosis includes mesenchymal tumors such as solitary fibrous tumor, leiomyoma, schwannoma, neurofibroma, angiomyolipoma, gastrointestinal stromal tumor, and inflammatory myofibroblastic tumor3.  Due to the patient’s clinical history of post-organ transplant immunosuppression, Kaposi sarcoma and mycobacterial spindle cell pseudotumor may also be considered. In this case, the tumor cells were diffusely and strongly positive for EBER and SMA, which confirmed the diagnosis. 
In conclusion, EBV-associated smooth muscle tumor is a rare lesion that can occur in the liver of immunocompromised patients. In situ hybridization for EBER confirms the diagnosis. The patient has undergone partial left liver resection of the lesion and is currently doing well. His hyperbilirubinemia resolved without elucidation of a definitive etiology, but it was thought not to be related to the tumor.

1. Dekate J, Chetty R. Epstein-Barr virus-associated smooth muscle tumor. Arch Pathol Lab Med. 2016;140(7):718-22.
2. Deyrup AT, Lee VK, Hill CE, et al. Epstein-Barr virus-associated smooth muscle tumors are distinctive mesenchymal tumors reflecting multiple infection events: a clinicopathologic and molecular analysis of 29 tumors from 19 patients. Am J Surg Pathol. 2006;30(1):75-82.
3. Burt A, Portman B, Ferrell L. MacSween’s Pathology of the Liver. 6th ed. Edinburgh: Churchill Livingston Elsevier; 2012. Chapter 14, Tumours and tumour-like lesions of the liver; p. 818-819.

This case was submitted by:
Katherine E. Boylan, MD, Resident, Department of Pathology, University of Utah, Salt Lake City, UT
Mazdak Khalighi, MD, Assistant Professor, Department of Pathology, University of Utah, Salt Lake City, UT
Eric Swanson, MD,  Assistant Professor,  Department of Pathology, University of Utah, Salt Lake City, UT

Wednesday, September 6, 2017

In Memoriam Lina Popper

Lina Popper passed away on August 15, 2017 in her Manhattan home at age 100. She was the wife of the eminent physician Dr. Hans Popper, the pathologist who is credited with originating modern liver research and who was a founder and the first academic dean of Mount Sinai Hospital's Medical School, now the Icahn School of Medicine at Mount Sinai. Long revered in the medical community, Lina traveled with her husband to medical meetings all over the world and was a constant and respected presence in the research community long after his 1988 death. She was born in Vienna, Austria to Paul Billig and Rosa Dym Billig on July 4, 1917. She fled the Nazis in 1938 for Chicago. There she met and married Hans, a fellow Viennese immigrant. She was President of the local PTA every year their children were in school in Chicago. They moved in 1957 to New York City, where she lived the rest of her life. She was an early volunteer at the Transplant Living Center at Mount Sinai. Her love of the arts made her a strong supporter and patron of New York's cultural offerings, including opera, classical music, art, education, environmental issues, and Jewish activities. Her day was never complete until she had attended a cultural event with a friend, and she finished The New York Times crossword puzzles every day in pen well into her 90's. Her loving family survives: sons Frank, a Rutgers University and Princeton University professor of city planning, and Charles, a psychiatrist at McLean Hospital and Harvard University Medical School; daughter-in-law and partner Deborah Popper and Leland Perry; grandchildren Joanna and Nicholas, married to Amy Haley; and great- grandchildren Hazel and Celia. The family would appreciate donations to the Visiting Doctors Program at Mount Sinai, a valuable service that provided medical care for Lina at home in the final years.

Wednesday, August 16, 2017

GI/Liver Pathology Fellowship

University of California, Davis School of Medicine (Sacramento, CA)

The University of California, Davis, Department of Pathology and Laboratory Medicine is seeking candidates for its non-ACGME-certified Surgical Pathology Fellowship for the 2018-19 and 2019-2020 academic years.  Sub-specialty emphasis in either GI or GYN pathology is available (limited to one each per year).

UC Davis offers a one-year Surgical Pathology fellowship program which is designed to prepare the fellow as a diagnostic expert in the interpretation of surgical pathology specimens. Expertise will include; intra-operative consultations (frozen section interpretation), gross examination, biopsy diagnosis/interpretation and appropriate work-up of cancer resections. The fellow in Surgical Pathology will develop an analytical approach to diagnoses, which include the appropriate use of ancillary techniques  (electron microscopy, immunohistochemistry and molecular pathology). Training in this program will encompass consultation to health care staff, residents, pathologists and clinicians including tumor boards and other conferences. Participation in a research project, or in a LEAN/ CQI project is expected. The fellow will also participate in departmental teaching activities for residents and medical students. At completion, the successful fellow should be able to demonstrate the knowledge, poise, maturity and communication skills to effectively function at the level of junior staff/faculty.

The Program Director will select from resident applicants who have preferably had four or more years of training with two years anatomic pathology and two years clinical pathology experience.  Completed applications consist of the following and must be free of gaps of time, whether professional or personal: CV/Resume/CAP standardized form; personal statement, three letters of recommendation (one must be from your Residency Program Director), please address to John Bishop, M.D., Director, Surgical Pathology Fellowship; and your letter of interest or intent. Applicants must be licensed in California in the spring prior to their start date.  Please submit application materials to Residency & Fellowship Program Coordinator, Anna Gutierrez at

For additional information, please visit our website at  

John W. Bishop, M.D.
HSC Professor of Pathology and Vice Chair for Clinical Services
UCDMC Pathology
4400 V St, Suite 1116
Sacramento, CA 95817


Wednesday, July 26, 2017


Human Pathology

Shah SS, et al. Hum Pathol. 2017;64:13-18.

This study shows that 5.2% (9/172) resected HCCs were positive for CDX-2, while all 6 resected fibrolamellar carcinomas (FLCs) were negative. CDX2 expression was seen in 5/16 poorly differentiated, and 2.5% (4/156) in well and moderately differentiated HCC. These results show that CDX2 expression does not exclude a diagnosis of HCC.

Chen J, et al. Hum Pathol. 2017;64:118-127.

This study compares the characteristics of 23 cholangiolocellular carcinoma (referred to as combined hepatocellular-cholangiocarcinoma, cholangiolocellular subtype) and 79 conventional intrahepatic cholangiocarcinoma (ICC). Cholangiolocellular carcinoma showed less invasive growth, less involvement of liver capsule and absence of mucous production compared to ICC. Mutations of isocitrate dehydrogenase 1 (IDH1) or IDH2 were higher (35%) in cholangiolocellular carcinoma than in mass-forming ICC (4%) or non-mass forming ICC. The 5-year postresection survival was significantly better in cholangiolocellular carcinoma (52%) compared to mass forming ICC (40%) and non-mass forming ICC (0).


Goeppert B, Roessler S, Becker N, et al. Histopathology. 2017 Jun;70(7):1064-1071.

Expression patterns of deleted in malignant brain tumors 1 (DMBT1) was analyzed in 157 biliary tract cancer patients, including intrahepatic and extrahepatic cholangiocarcinoma, adenocarcinomas of the gallbladder, and BilIN 3. DMBT1 expression was high in BiLN3 compared to normal biliary epithelium and BTC (both p<0.0001). However, BTCs showed no significantly different expression levels compared to non-neoplastic biliary tissue (p=0.315). Absent DMBT1 expression in non-neoplastic biliary tissue in BTC patients was associated with poor survival. The authors conclude that DMBT1 expression is elevated in BilIN 3, but expression levels of DMBT1 in BTC declines to levels comparable to non-neoplastic biliary epithelium. Absent DMBT1 expression in non-neoplastic biliary tissues of BTC patients correlates with poor patient survival (p=0.027), and the aggregate findings suggest a tumor-suppressor role for DMBT1.

Liver Transplantation

Tan A, Florman SS, and Schiano TD. Liver Transpl. 2017 May;23(5):663-678.

This is a nice review article delineating several genetic disorders (including inherited cholestatic disorders, urea cycle disorders and hereditary hemochromatosis) which can potentially be transmitted following liver transplantation.

Haga H. Yan IK, Borrelli DA et al. Liver Transpl. 2017 Jun;23(6):791-803.
Hepatic ischemia/reperfusion injury (IRI) is associated with significant liver dysfunction and complications following liver surgery and transplantation. These authors studied the effects of systemically administered extracellular vesicles from mesenchymal stem cells (MSC-EV) in an experimental mouse model of hepatic IRI. Compared to controls, intravenous administration of MSC-EVs dramatically reduced the extent of tissue necrosis, decreased caspase-3-positive and apoptotic cells, reduced serum aminotransferase levels, and reduced RNA expression of several inflammatory cytokines such as IL6. MSC-EV increased cell viability and suppressed oxidative injury and nuclear factor kappa B activity in murine hepatocytes in vitro. The authors conclude that administration of extracellular vesicles from bone marrow derived MSCs may improve IRI by reducing hepatic injury through tempering the inflammatory response.

Journal of Hepatology

Moeini A, Sia D et al. J Hepatol. 2017; 952-961.

Molecular characterization of mixed HCC-CCA was studied including histologic features, whole genome expression profile, single-nucleotide polymorphism array and whole exome sequencing. In classic type, clonality analysis revealed HCC-like and iCC-like components were derived from same clone. Exome sequencing revealed an average of 63 non-synonymous mutations per tumor, among which TP53 was the most frequently mutated gene. Stem cell subclass tumors were characterized by SALL4 positivity, showed enrichment of progenitor like signatures (CK19, EpCAM), activation of MYC and IGF oncogenic pathways, and associate with poor prognosis. In contrast, cholangiolocellular carcinoma (CLC) showed NCAM positivity, chromosomal stability and enrichment of TGF-β and immune related signaling. The data suggest that CLC stands alone as an independent biliary-derived entity, not sharing any molecular traits of HCC.

Vesterhus M, Holm A, et al. J Hepatol. 2017; 1214-1222.

Biomarkers to predict prognosis of primary sclerosing cholangitis are lacking. Using a bead-based array targeting 63 proteins related to inflammation and fibrosis, the authors studied bile samples from 55 PSC patients and 20 controls, and identified 13 proteins that showed significant difference between PSC and control, and 18 proteins that showed significant difference between mild and advanced PSC. Further studies identified ICAM-1, MMP7, S100A4 and S100 A12 as the group of markers that collectively best distinguished PSC from controls, and Calprotectin alone as the protein best capturing the difference between mild and advanced PSC. In addition, serum analyses were performed in two independent cohorts. IL-8 was identified as the best predictor of transplant-free survival in PSC, and correlated with the ELF score and Mayo score.

Schaberg KB, Kambham N, Sibley RK, et al. Am J Surg Pathol. 2017 Jun;41(6):810-819.

Adenovirus can lead to severe infection, including hepatitis, in immunocompromised patients.  The authors searched the archives from a single institution to compile the largest series to date (12 cases including biopsies as well as autopsies) of adenovirus hepatitis and review the histopathologic and clinical features.  All patients were immunocompromised and adenovirus hepatitis was fatal in all 4 adult patients and 5 of the 8 pediatric patients.  All patients presented with fever and had a hepatitic-dominant elevation in liver enzymes (mean AST 5879 U/L, mean ALT 1894 U/L, mean Alk Phos 453 U/L, mean total bilirubin 3.8 mg/dL).  Coagulative necrosis was seen in all cases, but the extent varied from focal to massive.  Necrosis was usually nonzonal, but half of cases showed an apparent accentuation of necrosis in periportal regions on biopsies.  Over half of cases were paucy inflammatory, but when inflammation was present, it tended to be focal, lymphohistiocytic and periportal.  All cases showed characteristic viral cytopathic effect (smudgy, glassy, predominantly basophilic intranuclear inclusions), most often in hepatocytes surrounding areas of necrosis.  Rarely, portal tract granulomas and viral inclusions were seen in biliary epithelium.  The minority of patients who survived their infection showed limited necrosis on initial biopsy and comparatively mild elevations in liver enzymes; these findings may be predictive of patients who are more likely to survive.  In conclusion, the authors remind us that adenovirus hepatitis is a serious and often fatal infection in immunocompromised hosts, more often seen in pediatric patients. 


Sun Y, Theise ND, You H, Jia J, et al. Hepatology 2017; 65(5): 1438-1450.

This study evaluated the utility of applying some of the histologic features of fibrosis regression, coined by Ian Wanless and colleagues as the hepatic repair complex (HRC). The authors examined 71 paired liver biopsies of chronic hepatitis B patients before and after entecavir-based therapy for 78 weeks. Fibrosis was categorized into one of three groups:

1.       Predominantly progressive: defined as more than 50% fibroseptal stroma showing wide/broad, loosely aggregated collagen fibers, often a mix of light and dark staining fibers on trichrome, which are moderately to markedly cellular containing, variably, inflammatory cells, macrophages, and ductular reactions.

2.       Predominantly regressive: defined as more than 50% fibroseptal stroma showing features of hepatic repair complex, namely thin, densely compacted stroma, largely darkly staining on trichrome, which are largely acellular.

3.       Indeterminate: defined as an uncertain mix/balance between progressive and regressive scarring.

Progressive, indeterminate, and regressive scarring was observed in 58%, 29%, and 13% of patients before treatment versus 11%, 11%, and 78% after treatment. Of the 55 patients who showed predominantly regressive changes on posttreatment liver biopsy, 53% has fibrosis improvement of at least one Ishak stage and 45% had improvement in terms of Laennec substage, collagen percentage area, and liver stiffness despite remaining in the same Ishak stage. The authors propose a “Beijing Classification” for liver biopsy assessment, which includes both the degree of fibrosis and the presence of progressive, indeterminate, or regressive features, in order to reflect the directionality of the fibrosis. In the same Hepatology issue, there is an editorial (pg. 1432-1434) on the study by Dr. David Kleiner.

Modern Pathology

Balitzer D, et al. Modern Pathology 2017; May (30): 773-783

Simplified criteria for diagnosis of autoimmune hepatitis are based on autoantibodies, serum immunoglobulin G, histologic features, and negative viral serology. A score of 6 points is necessary for the designation of probable autoimmune hepatitis and 7 points or more for definite autoimmune hepatitis. The presence of three histologic features (interface hepatitis, emperipolesis, and rosettes) is required for categorizing a case as typical (2 points). In the absence of all three features, a chronic hepatitis picture is considered compatible (1 point). This study used the modified histologic criteria (interface/lobular activity, number of plasma cells, and presence of biliary features) and compared the validity for the diagnosis of autoimmune hepatitis. Clinical data and liver biopsies were reviewed for 88 cases of autoimmune hepatitis, 20 primary biliary cholangitis, and 13 non-autoimmune acute hepatitis. Interface/lobular activity, number of plasma cells, copper/CK7 stains, and presence of biliary features were assessed. Using the modified histologic features, histologic score of 2 increased from 8 to 77%, and the total simplified score of >6 increased from 69 to 86%. There was no increase in total simplified score for primary biliary cholangitis or non-autoimmune acute hepatitis. Rosettes and emperipolesis are difficult to interpret, and lack sensitivity and sensitivity for autoimmune hepatitis diagnosis. The current histologic criteria used in the current simplified score lead to underscoring of autoimmune hepatitis cases. The modified histologic criteria increased the histologic score and led to a probable/definite diagnosis of autoimmune hepatitis in 17% of cases that would have otherwise been classified as non- autoimmune hepatitis by simplified score.

Tsai JH, et al. Modern Pathology 2017; June (30): 834-842
Non-alcoholic steatohepatitis is a slowly progressive disease, although patients may rarely present in acute liver failure. This study characterizes clinicopathologic features of 6 patients who had aggressive non-alcoholic steatohepatitis following rapid weight loss (4) or malnutrition (2) and developed severe hepatic dysfunction. Four patients either died or received an urgent liver transplant. Pathologic findings were characterized by advanced alcoholic steatohepatitis-like features, including severe centrizonal pericellular fibrosis, central scar with perivenular sclerosis/veno-occlusion with superimposed hepatocellular dropout, prominent hepatocyte ballooning, and numerous Mallory–Denk bodies, although any of them had a history of excess alcohol consumption. The mechanism of liver injury in aggressive steatohepatitis is unclear, but rapid fat mobilization may be a potential cause of oxidative stress in the liver injury.

Gastroenterology and Hepatology

Bonacini M, Shetler K, Yu I, Osorio RC, Osorio RW. Clin Gastroenterol Hepatol. 2017; May;15(5):776-779.
This brief report of acute liver failure due to toxic mushroom exposure aimed to evaluate mortality due to mushroom poisoning and factors associated with survival without liver transplantation. Twenty-seven patients presented within 24 hours after ingesting toxic mushrooms. Amanita phalloides was the cause in 41% and Amanita ocreata was the cause in 11%. All patients had elevated liver transaminases, with a median alanine aminotransferase of 2185 IU/L. Of these patients, 3 died, 1 received liver transplant, and the remaining survived without transplant. Overall, the probability of poor outcome (transplant or death) due to Amanita hepatotoxicity was 17% in those who have a peak total bilirubin >2 mg/dL (signifying hepatocellular jaundice). Patients who have bilirubin >2 mg/dL or AST >4000 IU/L at presentation or follow up need to be evaluated for transplant.

Tanaka A, Tazuma S, Okazaki K, Nakazawa T, Inui K, Chiba T, Takikawa H. Clin Gastroenterol Hepatol. 2017; Jun;15(6):920-926.

IgG-4 related sclerosing cholangitis is clinically distinct from primary sclerosing cholangitis and found often in association with autoimmune pancreatitis. This article showcases the largest case series of IgG-4 related sclerosing cholangitis (527 patients) and describes the clinical features in detail. The majority of patients were male (83%) and the median age at presentation was 66 years. The presenting symptoms included jaundice (35%), pruritus (13%), abdominal pain (11%), and cholangitis (10%). Eighty-four percent had elevated IgG4 levels. Even though 28% were asymptomatic (28%), 95% of these patients had evidence of other IgG4-related organ involvement. Sixty-three patients had pathologic samples, but the findings were not described in this paper. Diagnoses were based on Japanese criteria. There was an excellent response to prednisolone in 90% of patients. Death from hepatobiliary disease was rare in a 5–10 year period, none of the patients required liver transplant was not required in any of the patients, and cholangiocarcinoma was seen in less than 1%. Based upon this large data set, it appears that IgG-4 related sclerosing cholangitis is a generally benign condition with excellent response to treatment with corticosteroids, and overall good prognosis over a 10-year period. It is noted, however, that there is the possibility that IgG4-sclerosing cholangitis might be able to progress to cryptogenic cirrhosis, in which any diagnostic evidence such as elevated IgG-4 levels or typical radiographic findings are no longer present.

Mukewar S, Sharma A, Lackore KA, Enders FT, Torbenson MS, Kamath PS, Roberts
LR, Kudva YC. Clin Gastroenterol Hepatol. 2017; Jun;15(6):927-933.

This is the largest study of glycogenic hepatopathy in diabetes type 1 patients. It is also a case control study comparing type 1 diabetic patients with and without glycogenic hepatopathy. The purpose was to determine whether type 1 diabetics with glycogenic hepatopathy have more frequent diabetic ketoacidosis (DKA) episodes and evidence of poor glycemic control. The study shows that over half of the patients with glycogenic hepatopathy more frequently had recurrent DKA and elevated HbA 1c levels compared with type 1 diabetics with normal liver enzymes.  Glycogenic hepatopathy did not lead to adverse long-term outcomes and the liver enzymes eventually normalized in most patients on follow-up.

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 Oklahoma
Maria Westerhoff, MD; University of Washington