HPHS Journal Watch: July/August 2020

Archives of Pathology and Laboratory Medicine

COVID-19-Associated Hepatitis Complicating Recent Living Donor Liver Transplantation

Lagana SM, De Michele S, Lee MJ, et al. Arch Pathol Lab Med 2020; 144: 929-932.


This case report provides the first detailed description of histopathologic findings of likely COVID-19 hepatitis. The patient, a six-month old female with biliary atresia and failed Kasai, tested positive for COVID-19 on post-operative day (POD) 4 after receiving a living donor liver allograft. Liver enzymes significantly increased in a hepatitic pattern on POD 6. Liver biopsy showed typical features of acute cellular rejection (rejection activity index of 5). Additionally, the biopsy showed a moderate acute hepatitis with prominent clusters of apoptotic hepatocytes, which were termed here “crumbling hepatocytes”. Endotheliitis of the sinusoids and central veins with prominent Kupffer cells was seen, which may be related to COVID-19 as it has been reported in MERS hepatitis. Mild small and large droplet macrovesicular steatosis was present; however, the possible role of COVID-19 in this finding requires further elucidation given short time from transplant. Overall, the authors felt that COVID-19 hepatitis likely presents as a moderate acute hepatitis with “crumbling” apoptotic hepatocytes possibly with lymphohistiocytic inflammation of sinusoidal and central vein endothelium.


BRAF‐associated bile duct adenomatosis: a new entity?

Augustin J, Calderaro J, Pujals A. Histopathology. 2020 July;77(1):160-161.


Bile duct adenomas (BDAs) are benign intrahepatic biliary proliferations consisting of bile ducts arranged in small and tortuous tubules and embedded in a dense fibrous stroma. Recurrent BRAF V600E mutations are identified in these lesions, supporting the hypothesis that they are true neoplasms. The authors report the case of a 62 year old patient in which five BDAs were identified, all of them harboring BRAF V600E mutations. All the lesions were screened for the BRAF V600E mutation by immunohistochemistry with an anti‐BRAF V600E mouse monoclonal antibody. Cytoplasmic staining was observed in all cases. An allele‐specific polymerase chain reaction assay was performed on extracted DNA from the largest lesion, and the existence of the BRAF V600E mutation was confirmed. This intriguing case raises questions regarding the occurrence within a single liver of these multiple BRAF V600E‐mutated biliary neoplasms. The authors suggest that further studies including patients with multiple BDAs are warranted to identify the potential risk factors leading to this particular phenotype, which may be designated “BRAF‐associated bile duct adenomatosis.”

Journal of Hepatology

Molecular targeted therapies: Ready for “prime time” in biliary tract cancer 

Lamarca A, Barriuso J, McNamara MG, Valle JW. Journal of Hepatology 2020 Jul;73(1):170–185.


The incidence of biliary tract cancers (cholangiocarcinoma and gallbladder cancer) is on the rise and its outcomes is poor.  Most tumors are advanced at diagnosis and treatment options are limited to palliative approaches.  Novel molecular treatment options are vastly reshaping the field.  Among these are fibroblast growth factor receptor (FGFR) fusions and isocitrate dehydrogenase (IDH)-1 and -2 mutations, each present in 10–20% of patients with intrahepatic cholangiocarcinoma.  Other options include human epidermal growth factor receptor (HER) family members, the Wnt pathway, neurotropic tyrosine kinase receptor (NTRK) fusions and BRAF mutations.  This article provides an excellent overview of the status of targeted therapies in biliary tract cancers.

Journal of Gastroenterology and Hepatology

Dengue hepatitis with acute liver failure: Clinical, biochemical, histopathological characteristics and predictors of outcome.

Devarbhavi H, Ganga D, Menon M, et al. J Gastroenterol Hepatol. 2020;35(7):1223-1228.


This paper is a clinicopathologic review of Dengue hepatitis in 36 patients.

Risk factors for histological progression of non-alcoholic steatohepatitis analyzed from repeated biopsy cases.

Daijo K, Nakahara T, Inagaki Y, et al. J Gastroenterol Hepatol. 2020;35(8):1412-1419.


The aim of this study was to examine the clinical parameters involved in pathological progression in NASH patients who underwent repeated liver biopsy and to analyze the response to treatment with respect to NASH-related single nucleotide polymorphisms (SNPs). TNF‐α‐related SNP (rs1799964) was recognized as having a significant association with histological progression as an independent factor. ALT and HbA1c were risk factors predicting histological progression.


Diagnosis and Management of Autoimmune Hepatitis in Adults and Children: 2019 Practice Guidance and Guidelines From the American Association for the Study of Liver Diseases.

Mack CL, Adams D, Assis DN, et al. Hepatology. 2020;72(2):671-722.


The study presents an update to the AIH guidelines published in 2010 by the American Association for the Study of Liver Diseases. The article includes histologic features along with the association between AIH and NAFLD, diagnostic scoring systems and immune mediated injury in the setting of check-point inhibitors.

Hepatotoxicity From Immune Checkpoint Inhibitors: A Systematic Review and Management Recommendation.

Peeraphatdit TB, Wang J, Odenwald MA, et al. Hepatology. 2020;72(1):315-329.


This is a review article on hepatotoxicity associated with immune checkpoint inhibitors. The authors describe the pathogenesis, clinical manifestations, and histopathologic findings described to date. Histologic findings are heterogenous and can include lobular hepatitis, periportal activity, centrilobular necrosis, and microgranulomas. As opposed to autoimmune hepatitis, immune mediated hepatotoxicity: 1. Does not have female predominance.

2. Only 50% of patients have ANA positivity (in low titers <1:80).

3. Show very few to no plasma cells.

4. Has fewer CD20 positive and CD4 positive lymphocytes.

5. Typically resolves when the medication is withheld or resolves with a short course of steroids.

Lymphoepithelioma-Like Carcinomas: A Rare Variant of Cholangiocarcinoma.

Lin A, Alpert L, Hart J, Chapman C, Pillai AA. Hepatology. 2020;72(1):353-355.


This article reports cases of lymphoepithelioma-like carcinoma with cholangiocarcinoma features in two African-American individuals. Given the high rate of EBV positivity in these tumors (approximately 70% with EBER in situ hybridization), the authors suggest that EBER staining could be helpful in identifying this variant of cholangiocarcinoma. 

Journal of Pathology

Three-dimensional analysis of extrahepatic cholangiocarcinoma and tumor budding.

Yoshizawa T, Hong SM, Jung D, et al. J Pathol. 2020;251(4):400-410.


High-grade tumor budding is associated with poor prognosis in various cancers. This study analyzed the 3D structure of tumor budding and E-cadherin expression in 31 extrahepatic cholangiocarcinomas (27 hilar and 4 distal). Based on the standard (2D) pathological criteria: 18 tumors showed high-grade and 13 low grade tumor budding. 3D analysis revealed:

1. Neoplastic cells in tumor buds of adenocarcinoma were tips of attenuated protrusions connected to the main tumor.

2. Low-grade tumor budding tumors were composed predominantly of tubules with focal cords at the periphery and high-grade tumor budding predominantly formed cords in both centers and peripheries of the tumors.

3. Low-grade tumor budding was characterized by a few short protrusions with few branches, whereas adenocarcinoma with high-grade tumor budding was characterized by longer protrusions with more branching.

4. E-cadherin expression was stronger in the center of the adenocarcinoma but decreased at the tips of protrusions and E-cadherin loss was more extensive in the protrusions of high-grade tumor budding than in the protrusions of low-grade tumor budding.

In summary, the study suggests that tumor buds as seen in 2D are, in fact, cross-sections of attenuated but contiguous protrusions extending from the main tumor.

Clinical Gastroenterology and Hepatology

Alcohol Use Is Associated With Hepatic Steatosis Among Persons With Presumed Nonalcoholic Fatty Liver Disease.

Long M, Massaro JM, Hoffmann U, et al. 2020 Jul;18(8):1831-1841.


The authors completed a cross-sectional study of participants in the Framingham heart study that had hepatic steatosis.  They report an association between alcohol use and NAFLD and suggest that even moderate alcohol use may contribute to the development of hepatic fat.

Regression of Fibrosis Stage With Treatment Reduces Long-Term Risk of Liver Cancer in Patients With Hemochromatosis Caused by Mutation in HFE.

Bardou-Jacquet E, Morandeau E, Anderson GJ, et al. 2020 Jul;18(8):1851-1857.


In a retrospective analysis of patients with hemochromatosis caused by the C282Y mutation in HFE, the authors determined that advanced hepatic fibrosis can regress with treatment. This reduced the risk of hepatocellular carcinoma development.

Keratin 18 Is a Diagnostic and Prognostic Factor for Acute Alcoholic Hepatitis

Vatsalya V, Cave MC, Kong M, et al. 2020 Aug;18(9):2046-2054.


The authors analyzed data from 173 participants in a large trial performed at 4 medical centers.  They evaluated differences in the levels of serum CK18 in patients with severe acute alcoholic hepatitis and correlated these levels with patient outcome. Patients with higher levels of CK18 in the serum had higher 90-day mortality.

High-Throughput, Machine Learning–Based Quantification of Steatosis, Inflammation, Ballooning, and Fibrosis in Biopsies From Patients With Nonalcoholic Fatty Liver Disease

Forlano R, Mullish BH, Giannakeas N, et al. 2020 Aug;18(9):2081-2090.


The authors used machine learning to develop fully automated software for quantification of steatosis, inflammation, ballooning, and fibrosis in biopsy specimens from patients with NAFLD. The results from the software correlate with those from histopathologists, with high levels of interobserver and intraobserver agreement and the approach was also validated using a separate set of biopsies.  The authors suggest that this may be a tool to evaluate these biopsies and to assess for differences after life-style modifications and treatment.

Hepatology Communications

#LiverTwitter: An Emerging Tool for Liver Education and Research

Mikolajczyk AE, Ufere N, Breu AC, et al. 2020 5;4(8):1229-1233.


This article summarizes material presented at the 2019 Liver Meeting. It discusses topics related to teaching, mentoring, sharing journal articles, and offers tips to get more involved in this social media platform.

Prevalence and Profile of Nonalcoholic Fatty Liver Disease in Lean Adults: Systematic Review and Meta-Analysis.

Young S, Tariq R, Provenza J, et al. 2020 21;4(7): 953-972.


The authors compared “lean” NAFLD to “obese” NAFLD and found differences in several parameters when comparing these two groups.  Lean NAFLD was defined as patients that had NAFLD diagnosed by biopsy with normal BMIs. They reported that lean NAFLD is a distinct entity with metabolic, biochemical, and inflammatory abnormalities compared to healthy subjects and that it has a more favorable profile, including liver histology of steatohepatitis and fibrosis stage. They suggested the importance of larger studies to determine differences in clinical outcomes between these two groups.

The Hepatic Sinusoid in Aging and Disease: Update and Advances From the 20th Liver Sinusoid Meeting

Ortega-Ribera M, Hunt NH, Gracia-Sancho J, Cogger VC. 2020 27;4(7):1087-1098.


This is a meeting report of the 2019 Liver Sinusoid Meeting, 20th International Symposium on Cells of the Hepatic Sinusoid, held in Sydney, Australia, in September 2019.  It focuses on several of the key cellular players that occupy the hepatic sinusoid (e.g., liver sinusoidal endothelial cells and hepatic stellate cells).  It also discusses the sinusoids role in fibrosis progression in diseases such as NAFLD. 

Prepared by:
Nafis Shafizadeh MD (Editor); Southern California Permanente Medical Group

Daniela Allende MD; Cleveland Clinic
Vishal Chandan MBBS; University of California Irvine
Robert Goldin MD; Imperial College, London
Bella Goyal MD; California Pacific Pathology Medical Group
Grace Guzman MD; University of Illinois
Mojgan Hosseini MD; University of California San Diego
Heather Stevenson-Lerner MD PhD; University of Texas
Lindsey Westbrook MD; University of Colorado

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