HPHS Journal Watch: May/June 2021

American Journal of Clinical Pathology

Liver Pathology and SARS-CoV-2 Detection in Formalin-Fixed Tissue of Patients with COVID-19

Chornenkyy Y, Mejia-Bautista M, Brucal M, et al. Am J Clin Pathol. 2021 May18;155(6):802-814.


This study evaluated whether the SARS-CoV-2 viral RNA could be detected in formalin-fixed paraffin embedded (FFPE) tissue blocks of the liver from 8 patients who died of COVID-19 and documented the patterns of liver injury in these patients. Viral RNA was detected in 44% (4/9) liver FFPE blocks compared to 100% of bronchioalveolar cell blocks (12/12) and lung FFPE blocks (8/8). The main histologic findings in the liver were minimal to focal mild portal tract chronic inflammation (88%) and mild focal lobular activity (6/8). Peak values of liver enzymes and bilirubin were higher in patients with COVID-19 compared to the control group, but the differences were not significant.

American Journal of Gastroenterology

Impact of the Association Between PNPLA3 Genetic Variation and Dietary Intake on the Risk of Significant Fibrosis in Patients With NAFLD

Vilar-Gomez E, Jose PC, Sookoian S, et al. Am J Gastroenterol. 2021 May 1;116(5):994-1006.


This article discusses the relationship between genetic and dietary factors in the pathogenesis and progression of nonalcoholic fatty liver disease (NAFLD) through exploring the role between patatin-like phospholipase domain-containing 3 gene (PNPLA3  rs738409), nutrient intake, and liver histology severity in patients with NAFLD. PNPLA3-rs738409 variant was genotyped in 452 non-Hispanic whites with histologically confirmed NAFLD that had completed a Food Frequency Questionnaire regarding dietary intake within 6 months of their liver biopsy. The genotypes in this cohort were identified as CC (28%), CG (46%), and GG (25%). High-carbohydrate intake was positively associated with increased risk of significant fibrosis (stage of fibrosis ≥2), whereas higher n-3 polyunsaturated fatty acids (n-3 PUFAs) (g/d), isoflavones (mg/d), methionine (mg/d), and choline (mg/d) intakes were inversely associated. Their findings suggest that PNPLA3 rs738409 G-allele may modulate effects of these dietary factors on risk of fibrosis in NAFLD patients as these dietary nutrients tended to have a significant effect on fibrosis severity amongst G-allele carriers.

Post–COVID-19 Cholangiopathy: A Novel Entity

Roth NC, Kim A, Vitkovski T, et al. Am J Gastroenterol. 2021 May 1;116(5):1077-82.


Angiotensin converting enzyme-2 (ACE2), the host receptor for SARS-CoV-2, is expressed in cholangiocytes and may lead to cholangiocyte injury via direct viral effects and possibly eventual chronic liver disease. Roth et al described the liver biopsy features in three young adults who presented with prolonged and severe cholestasis during the recovery period from critical COVID-19 without any history of pre-existing liver disease. The liver biopsy of all cases showed extensive degenerative cholangiocyte injury in the form of prominent vacuolization and regenerative changes with evidence of apoptosis, and necrosis of the cholangiocytes of the terminal bile ducts and marginal ductules. Portal and peri-portal fibrosis could be appreciated in all three cases with portal-portal bridging and focal fibrotic obliteration of the terminal hepatic venules in one case. Peri-portal ductular metaplasia of the hepatocytes was seen in one case. All cases showed endothelial swelling with luminal narrowing of the hepatic arteries and endophlebitis of the portal veins. One case exhibited features of sinusoidal obstruction syndrome with evidence of perivenular confluent necrosis. According to the authors, the post–COVID-19 cholangiopathy described in this article likely represents a confluence of secondary sclerosing cholangitis of the critically ill patient (SSC-CIP) and direct hepatic injury from COVID-19.

Childhood and Adulthood Passive Smoking and Nonalcoholic Fatty Liver in Midlife: A 31-year Cohort Study

Wu F, Pahkala K, Juonala M, et al. Am J Gastroenterol. 2021 Jun 1;116(6):1256-63.


The authors tried to examine the association between childhood and adulthood passive smoking with fatty liver in midlife. The authors attempted to identify early life risk factors in a longitudinal 31-year prospective cohort study of 1,315 participants in relation to childhood passive smoking (parental smoking) collected in 1980 (aged 3– 18 years) and 1983 and adulthood passive smoking in 2001, 2007, and 2011. Fatty liver was determined by ultrasound in 2011 (aged 34– 49 years). 24% of patients who were exposed to passive smoking had fatty liver on ultrasonography in the adult life as compared to 7.7% who do not have any such history. Both childhood and adulthood passive smoking were associated with an increased risk of fatty liver in adulthood. This was partly mediated through adult body mass index, waist circumference, and serum triglyceride levels, but individuals with persistent exposure to passive smoking between childhood and adulthood had the highest risk of adult fatty liver. The main strength of this study is the long-term prospective follow-up of a large population-based cohort, but the limitation is the lack of assessment of fatty liver in childhood and the reliance of the assessment of fatty liver by ultrasonography only. Even a small cohort of patients with the confirmation by liver biopsy would have strengthened the study further. One curiosity is that the authors published their findings 10 years after the completion of the study.

Archives of Pathology & Laboratory Medicine

Recent Advances in Digestive Tract Tumors: Updates from the 5th Edition of the World Health Organization “Blue Book”

Gonzalez RS, Raza A, Propst R, et al. Arch Path Lab Med. 2021 May;145(5):607-26.


The authors provide a comprehensive report on the changes in nomenclature and reporting in the WHO blue book as they relate to hepatocellular and intrahepatic biliary tumors. In particular, the 5th edition describes the molecular pathogenesis of hepatocellular adenoma and carcinoma and recognizes variants of hepatocellular carcinoma, although the significance of some of these variants remains under investigation. This edition also provides updates to the known molecular alterations of intrahepatic cholangiocarcinoma, introduces sections on biliary adenofibroma and primary hepatic neuroendocrine neoplasms, and expands on cystic liver lesions.

Pathologic Manifestations of Gastrointestinal and Hepatobiliary Injury in Immune Checkpoint Inhibitor Therapy

Patil PA, Zhang X. Arch Path Lab Med. 2021 May;145(5):571-582.


This is a review article covering the reported patterns of injury associated with immune checkpoint inhibitors. The manifestations of injury in the luminal gastrointestinal tract can be rather nonspecific and range from minimal inflammation to active ulcerating disease. Finding increased apoptotic debris can be a helpful clue to the diagnosis. In the liver, both panlobular hepatitis and bile duct injury have been reported. The authors provide a differential diagnosis for each organ covered.

The 8th Edition American Joint Committee on Cancer Staging for Hepato-pancreato-biliary Cancer: A Review and Update

Liao X, Zhang D. Arch Path Lab Med. 2021 May;145(5):543-553.


The authors of this report provide details on the changes in tumor staging from the 7th to the 8th edition of the AJCC. In addition, the authors include data from validation studies that have taken place since the guidelines went into effect in 2018.

Clinical Gastroenterology and Hepatology

Electronic Image of the month: A Brilliant Blue Liver

Bong SH, Soon GS, Huang DQ. Clin Gastroenterol Hepatol. 2021 May;19(5):e47.



Squalene Epoxidase Induces Nonalcoholic Steatohepatitis Via Binding to Carbonic Anhydrase III and is a Therapeutic Target.
Liu D, Wong CC, Zhou Y, et al. Gastroenterology. 2021 Jun;160(7):2467-2482.e3.

Squalene epoxidase (SQLE) catalyzes the first oxygenation step in cholesterol synthesis and serves as an important rate-limiting enzyme in the pathway. In this study, SQLE overexpression transgenic mice developed spontaneous insulin resistance, hepatic steatosis, liver injury and accelerated diet-induced NASH development. SQLE was found to drive NASH development through its direct interaction with carbonic anhydrase-3 (CA3), which promoted the accumulation of cholesterol and triglycerides in hepatocytes and inflammation in the liver. In addition, the authors discovered that simultaneously inhibiting SQLE with terbinafine and CA3 with acetazolamide attenuated steatohepatitis and fibrosis in the transgenic mice (more so than terbinafine alone). The study also showed that SQLE is upregulated in the serum of patients with NAFLD as compared to healthy controls.


Non-alcoholic fatty liver disease and risk of incident diabetes mellitus: an updated meta-analysis of  501022 adult individuals

Mantovani A, Petracca G, Beatrice G, et al. Gut. 2021 May;70(5):962-969.


Non-alcoholic fatty liver disease (NAFLD) is associated with an increased incidence of diabetes, but it is not certain whether the risk changes with increasing severity of NAFLD. Type 2 diabetes and NAFLD are two pathological conditions that frequently coexist and act synergistically to increase risk of adverse clinical outcomes. Type 2 diabetes is one of the strongest clinical risk factors for faster progression of NAFLD to non-alcoholic steatohepatitis (NASH), cirrhosis, or hepatocellular carcinoma. The aim was to gauge the nature and magnitude of the relationship between NAFLD and risk of new-onset diabetes. An updated systematic review and meta-analysis of observational cohort studies was to examine the association between NAFLD (as detected by liver biopsy or imaging methods) and the risk of developing diabetes. This updated meta-analysis of 501,022 middle-aged individuals of different countries provides strong evidence that NAFLD is associated with a 2.2-fold increased risk of developing diabetes. This risk parallels the underlying severity of NAFLD, especially fibrosis stage. All risks were independent of age, sex, adiposity measures, and other common metabolic risk factors.

Exploring prognostic indicators in the pathological images of hepatocellular carcinoma based on deep learning

Shi JY, Wang X, Ding GY, et al. Gut. 2021 May;70(5):951-961.


Extreme heterogenous nature of hepatocellular carcinoma (HCC) at the histological, molecular, and genetic levels makes it extremely difficult in risk stratification and personalised management. Although genetic, transcriptomic, and proteomic profiles are increasingly attempted to predict tumor aggressiveness, tumor histology remains essential in prognostic stratification. The importance of numerous phenotypic features requires an in-depth analysis to translate the histopathological features of HCC into prognostic and predictive algorithms to improve patient stratification and clinical management. The study is based on a deep learning framework for predicting HCC patient prognosis by pathological images from the Zhongshan cohort and the Cancer Genome Atlas (TCGA) HCC cohort. Initial haematoxylin and eosin (H&E) images were taken as learning materials to train tissue category-based local sampling as prior knowledge to prune the feature space. Next, the ‘tumor risk score’ (TRS) based on weakly supervised deep learning was established using sampled tiles from tumor tissue as inputs and patient outcomes as labels. Finally, they explored the TRS-related features by risk activation mapping and the relevance of TRS to tumor immune infiltration and gene mutations using the Cancer Genome Atlas (TCGA) HCC data. A total of 1125 HCC patients with 2550 pathological slides were randomly selected from patients who had received curative hepatectomy for HCC without distant metastasis or any prior anti-cancer treatments between 2009 and 2013 at Zhongshan Hospital of Fudan University. A total of 2451 slides were captured and scanned as whole-slide images (WSIs). In addition, 260 WSIs of 96 patients were randomly selected for manual annotation. All 2191 WSIs of 1029 patients were randomly divided into a training set and a validation set. They have collected 376 HCC patients from the TCGA data base via the Genomic Data Commons with prognostic information and qualified pathological images as an independent cohort. Finally, this data set included 320 HCC patients; however, the patients of this cohort lacked recurrence information, so the overall survival was used as the major index in survival analysis. The histological features associated with a high TRS were discerned as sinusoidal capillarization, prominent nucleoli and karyotheca, a high nucleus/cytoplasm ratio, and the absence of tumor-infiltrating immune cells. This prognostic network based on weakly supervised deep learning is an effective and labour-saving method to improve patient stratification and clinical management in HCC. TRS, featured by tumor angiogenesis, cell morphology, and immune infiltration, may serve as an innovative determinant of the response to combinational immune, cellular function, and anti-angiogenic therapy in HCC.


NAFLD: Reporting Histologic Findings in Clinical Practice

Bunt EM, Kleiner DE, Carpenter DH, et al. Hepatology. 2021 May;73(5):2028-2038.


This article, sponsored by the American Association for the Study of Liver Disease NASH Task Force, is a focused review of liver biopsy evaluation in fatty liver disease patients for practicing pathologists. The paper provides specific recommendations for reporting the histopathologic elements of NASH, distinguishing NASH from nonalcoholic fatty liver without steatohepatitis, and from alcohol-associated steatohepatitis when possible. Other issues addressed include NASH in advanced fibrosis or cirrhosis, NASH in pediatric patients, and semiquantitative methods for addressing disease activity and fibrosis.

Hepatology Communications

The Growing Burden of Disability Related to Chronic Liver Disease in the United States: Data From the Global Burden of Disease Study 2007-2017

Paik JM, Golabi P, Younossi Y, et al. Hepatol Commun. 2021 Jan 14;5(5):749-759.


This paper describes data from the Global Burden of Disease Study 2007-2017.  The main conclusion of the study was that the burden from chronic liver disease (CLD) is increasing in most U.S. states and this is occurring at an alarming rate.  They present differences in liver cancer and cirrhosis by determining differences in disability-adjusted life years and CLD-related mortality.

Human Pathology

Increasing tumor budding in cholangiocarcinoma is associated with decreased disease-specific survival.
Agostini-Vulaj D, Cates JMM, Bratton LE, et al. Hum Pathol. 2021 May;111:75-83.

This study evaluated the association between survival and tumor budding in a cohort of 112 cholangiocarcinoma (CC) patients (54 (48%) extrahepatic and 58 (52%) intrahepatic CCs). Budding was quantified using the International Tumor Budding Consensus Conference recommendations for colorectal cancer. Tumor budding was more commonly seen in higher-grade lesions, males, extrahepatic cholangiocarcinomas, PNI, LVI, and in cases with a positive resection margin. Increased budding was associated with worse patient survival.

Hans Popper Hepatopathology Society: mini-symposium

Kakar, S. Hum Pathol. 2021 Jun;112:84.

The June issue of Human Pathology features 5 review articles that are based on presentations from the Hans Popper Hepatopathology Society companion session at the 2020 USCAP annual meeting and are listed below.

Cystic biliary tumors of the liver: diagnostic criteria and common pitfalls.
Shyu S, Singhi AD. Hum Pathol. 2021 Jun;112:70-83.

This review article discusses the nomenclature, pathogenesis and pathologic features of intraductal papillary neoplasm of the bile duct (IPNB) and mucinous cystic neoplasm of the liver, as well as molecular characteristics, management and prognosis of these tumors.

Hepatocellular carcinoma: making sense of morphological heterogeneity, growth patterns, and subtypes.
Torbenson MS. Hum Pathol. 2021 Jun;112:86-101.


Dr. Torbenson describes the criteria used to define a morphologic hepatocellular carcinoma (HCC) subtype and discusses the pathologic features and molecular correlates of the 13 existing HCC subtypes. In addition, he highlights challenging aspects of classification, and methods on how to apply definitional HCC subtyping to help improve research.

Dialogs in the assessment of neonatal cholestatic liver disease.
Cho SJ, Perito ER, Shafizadeh N, et al. Hum Pathol. 2021 Jun;112:102-115.

This review describes the clinical, pathologic and ultrastructural features of non-biliary atresia etiologies of neonatal cholestasis, including infectious, genetic, and metabolic entities.  The importance of communication with clinical colleagues prior to liver biopsy and throughout the ensuing workup is highlighted, and direct insight from a gastroenterologist is provided through a pathologist and gastroenterologist Q&A.

Mimics of hepatocellular carcinoma: a review and an approach to avoiding histopathological diagnostic missteps.
Arif D, Mettler T, Adeyi OA. Hum Pathol. 2021 Jun;112:116-127.

This review highlights notable tumors that overlap morphologically, clinically, and  radiographically with hepatocellular carcinoma to help practicing pathologists avoid misdiagnosis.

Hepatocellular adenomas: review of pathological and molecular features.
Beaufrère A, Paradis V.  Hum Pathol. 2021 Jun;112:128-137.

This review describes the pathologic and molecular features of five hepatocellular adenoma subtypes: HNF1A inactivated HCA, inflammatory HCA, β-catenin mutated HCA, sonic hedgehog HCA, and unclassified HCA. 

Journal of Hepatology

SARS-CoV-2 infection in patients with autoimmune hepatitis

Marjot T, Buescher G, Sebode M, et al. J Hepatol. 2021 Jun;74(6):1335-1343.


This study combined data spanning March 25th-October 24th, 2020 from 3 large international registries to evaluate the relationship between autoimmune hepatitis (AIH) and SARS-CoV-2 infection. 932 patients with chronic liver disease and SARS-CoV-2 infection were identified, with 70 patients with AIH. Despite immunosuppressive treatment (83% of patients with AIH were taking one or more immunosuppressive drugs), patients with AIH were not at increased risk of adverse outcomes (hospitalization, intensive care unit admission, death) compared to other causes of chronic liver disease. Even compared to matched cases without liver disease, patients with AIH had increased risk of hospitalization, but no difference in other outcomes, including death.

Prepared by:
Lindsey Westbrook, MD (Editor); University of Colorado
Vishal Chandan, MBBS; University of California Irvine
Soo-Jin Cho, MD, PhD; University of California San Francisco
Ashim Das, MD; Post Graduate Institute of Medical Education and Research, India
Gillian Hale, MD, MPH; University of Utah
Mojgan Hosseini, MD; University of California San Diego
Meredith Pittman, MD; Maimonides Medical Center
Nafis Shafizadeh, MD; Southern California Permanente Medical Group
Heather Stevenson-Lerner, MD, PhD; University of Texas

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