HPHS Journal Watch: March/April 2021

Advances in Anatomic Pathology

The Differential Diagnosis of Intrahepatic Ductular Reaction in Medical Liver Biopsy

Jain R, Clark I. Adv Anat Pathol. 2021 Mar 1;28(2):72-80.


This comprehensive review article discusses the differential diagnoses for intrahepatic bile ductular reactions in medical liver biopsies.  It also provides a useful algorithm that can be used by the practicing pathologist while working up these cases.

American Journal of Clinical Pathology

Recurrent Autoimmune hepatitis and De Novo Autoimmune Hepatitis in the Liver Allograft

Gonzalez IA, Hartley CP, Nalbantoglu I. Am J Clin Pathol. 2021;155(3):435-445.


This study compares the clinicopathologic features of recurrent autoimmune hepatitis (RAIH; n = 11) and de novo AIH (DNAIH; n = 22) in patients after orthotopic liver transplantation. In summary, statistically significant (P <0.05) differences were noted in 5-year disease-specific graft survival (GS) as well as overall GS, both of which were worse in patients with RAIH. Histologically, moderate portal inflammation was more common in patients with RAIH; while there were trends toward more severe portal inflammation, hepatocyte rosetting, and submassive necrosis in DNAIH, and more advanced fibrosis in RAIH, these differences did not reach statistical significance. C4d immunohistochemistry showed positivity in 2 patients with RAIH and 3 with DNAIH, but there was no correlation with GS or other parameters. The authors conclude that RAIH appears to have a more aggressive clinical course than DNAIH and should receive closer clinical follow-up and more aggressive treatment.

American Journal of Gastroenterology

Impact of Body Weight Gain on the Incidence of Nonalcoholic Fatty Liver Disease in Nonobese Japanese Individuals

Yamada G, Hagiwara Y, Kimura T, et al. Am J Gastroenterol. 2021 Apr;116(4):733-740.


In a longitudinal study, 27,064 non-alcoholic fatty liver disease (NAFLD) free, non-obese (Body mass index < 25 kg/m2) Japanese individuals were followed with ultra-sonographic (U/S) examination of the liver to find the incidence of new-onset non-alcoholic fatty liver disorders. Correlation with annual health checkup data and retrospective information on weight change from the age of 20 years was performed. A weight gain from age 20 years to baseline, BMI of 23.0–24.9 kg/m2, current smoking, and dyslipidemia were associated with the development of NAFLD in nonobese men and women. Weight gain, even if recent and short-term or within nonobese patients, is a risk factor for NAFLD. This highlights the importance of monitoring weight gain, even in nonobese individuals, to prevent progression to NAFLD. The strength of this study is that it is a longitudinal study of a large number of male and female participants, and it was adjusted for important covariates associated with the development of NAFLD in non-obese individuals. The limitations are that only U/S examination was carried out to detect fatty liver, which can miss mild fatty change, and there was no confirmation by liver biopsy to exclude other causes of fatty change. Other limitations are that this cohort was restricted to healthy Japanese office workers who lived in an urban area, did not exclude all medication intake, and did not consider the effect of lifestyle components (e.g. diet and exercise) in the overall risk for NAFLD.

Noninvasive Diagnosis of Portal Hypertension in Patients with Compensated Advanced Chronic Liver Disease

Pons M, Augustin S, Scheiner B, et al. Am J Gastroenterol. 2021 Apr;116(4):723-732.


The new term “compensated advanced chronic liver disease (cACLD)” is defined as patients with chronic liver disease detected by noninvasive methods that have never decompensated. Liver stiffness measurements (LSM) of 10 kPa rule out cACLD but values of >15 kPa are highly suggestive of cACLD in patients with known causes of chronic liver disease. cACLD patients are at risk of developing clinically significant portal hypertension (CSPH). The aims of the present study are to analyze the prevalence of portal hypertension in the main etiologies of cACLD, to validate the ANTICIPATE models for CSPH, and to develop simple classification rules based on LSM to diagnose or exclude CSPH. The data from different international cohorts with patients of different etiologies of chronic liver disease were analyzed with the inclusion criteria of LSM ≥10 kPa (suggestive of cACLD), normal liver function (equivalent to Child-Pugh class A), no previous decompensation, and no prior β-blocker therapy for varices. Paired data on LSM and hepatic venous pressure gradient (HVPG) were obtained within 3 months. The present study demonstrated that LSM alone is useful to select patients with chronic liver disease at risk of having portal hypertension and CSPH for most etiologies, including ALD, HCV, and HBV. In patients with NASH, particularly obese patients with NASH, LSM-based rules behave differently from other etiologies, in part because of the association between LSM and HVPG changes with BMI in patients with NASH. LSM>25 kPa is sufficient to rule in CSPH in ALD, HBV, HCV, and nonobese patients with NASH (PPV higher than 90%) without the need of additional noninvasive parameters.

Burden of Future Liver Abnormalities in Patients with Intrahepatic Cholestasis of Pregnancy

Monrose E, Bui A, Rosenbluth E, et al. Am J Gastroenterol. 2021 Mar 1;116(3):568-575.


There are limited data on long-term liver morbidity among patients with intrahepatic cholestasis of pregnancy (ICP). Using data from a cohort of women in a hospital with increased prevalence of ICP (2.5%), the authors have investigated incidence, predictors, and time to occurrence of future liver abnormalities to analyze the long-term effects of ICP (as opposed to persistently elevated LT elevation after pregnancy).  Women returning for care with liver function tests at a minimum of 6 months postpartum were included in the analysis. Two hundred fifty-five patients of 475 (53.7%) returned to care during the follow-up period and served as the cases in this analytic cohort.  A total of Sixty (24%) ICP patients and 20 (15%) non-ICP women were diagnosed with liver disease, the most common being NAFLD with ICP patients having more postpartum liver imaging. Women with ICP developed liver disease earlier than those without.

American Journal of Surgical Pathology

Predictive Patterns of Glutamine Synthetase Immunohistochemical Staining in CTNN1B-mutated Hepatocellular Adenomas

Sempoux, C, Gouw A, Dunet V, et al. Am J Surg Pathol. 2021 Apr;45:477–487.


Mutations in CTNN1B confer variable risk of malignant transformation in a hepatocellular adenoma depending on the particular mutation. The authors propose using patterns of glutamine synthetase (GS) staining to differentiate exon 3 (high risk) from exon 7/8 (low risk) mutations without the need for costly molecular analysis. Immunohistochemical staining for GS, CD34, and beta-catenin was performed on 93 adenomas (33 CTNN1B-mutated inflammatory adenomas, 30 CTNN1B-mutated adenomas, and 30 non-mutated inflammatory adenomas). A “diffuse heterogeneous” or “starry-sky” pattern of intratumoral GS staining with strong GS/negative CD34 at the periphery was seen in all 20 of the adenomas with a CTNN1B exon 3 S45 mutation. A “diffuse homogenous” pattern of intratumoral staining was seen in most of the CTNN1B exon 3 non-S45 mutated adenomas (sensitivity ~80%), and focal, patchy intratumoral GS was evident in most CTNN1B exon 7/8 mutated adenomas. Only 4 of the 30 non-mutated adenomas were incorrectly identified using GS/CD34 staining. The authors conclude that a panel of GS and CD34 can aid in risk stratification in CTNN1B mutated adenomas.

Archives of Pathology & Laboratory Medicine

Liver Pathologic Changes after Direct-Acting Antiviral Agent Therapy and Sustained Virologic Response in the Setting of Chronic Hepatitis C Virus Infection

Celli R, Saffo S, Kamili S, et al. Arch Path Lab Med. 2021 Apr;145(4):419-27.


The ability to cure Hepatitis C using direct-acting antiviral agents (DAA) has dramatically changed the practice of hepatology in the past decade. Even so, patients with a sustained viral response (SVR) after therapy may still have significant liver fibrosis or develop hepatocellular carcinoma. In order to systematically investigate the impact of DAA treatment on liver histology, the authors compared liver biopsies and/or resections from 65 patients with untreated Hepatitis C to 31 patients with Hepatitis C who had completed DAA therapy.  None of the post-treatment liver specimens were found to have occult HCV by tissue PCR.  Nevertheless, they found that DAA-treated livers may still show significant portal inflammation, although paired pre-and post-treatment liver biopsies showed an overall qualitative decrease in inflammation. Likewise, advanced fibrosis was seen in similar proportions of patients with and without DAA treatment, with patients with HCC being the most likely to have cirrhosis, regardless of therapy status. The authors speculate that the presence of HCC after DAA therapy could partially be explained by tissue damage sustained prior to DAA therapy, and they suggest that DAA therapy earlier in the course of Hepatitis C may mitigate these factors.

Clinical Gastroenterology and Hepatology

Trends in Incidence of Autoimmune Liver Diseases and Increasing Incidence of Autoimmune Hepatitis

Lamba M, Ngu JH, Stedman CAM. Clin Gastroenterol Hepatol. 2021 Mar;19(3):573-579.e1.


This population-based, prospective study looked at trends in incidences of AIH, PBC, and PSC in Canterbury, New Zealand.  They found that AIH incidence was significantly higher in the time period of 2014 to 2016 than from 2008 to 2010.  PBC and PSC incidence was not different between these two time periods.

Nonalcoholic Steatohepatitis Is the Most Rapidly Increasing Indication for Liver Transplantation in the United States

Younossi ZM, Stepanova M, Ong J, et al. Clin Gastroenterol Hepatol. 2021 Mar;19(3):580-589.e5.


This study evaluated the causes of liver transplantation by comparing 2002 to 2019 in the US. It found that NASH was the most rapidly increasing cause in 2019.  In 2019, for patients without HCC, the main causes were ALD (#1) and NASH (#2).  In patients with HCC the main causes were HCV (#1), NASH (#2), and ALD (#3).

Role for Biochemical Assays and Kayser-Fleischer Rings in Diagnosis of Wilson’s Disease

Dong Y, Wang RM, Yang GM, et al. Clin Gastroenterol Hepatol. 2021 Mar;19(3):590-596.


This study evaluated 715 patients with Wilson’s disease to determine the most useful tests/clinical manifestations to diagnose the disease.  They showed that serum levels of ceruloplasmin, 24-hour urinary copper excretion, and Kayser-Fleisher rings were the most useful.  Children with urinary copper excretion above 40 μg and serum levels of ceruloplasmin below 120 mg/L and should undergo genetic testing.

Associations Between Nonalcoholic Fatty Liver Disease and Cancers in a Large Cohort in China

Wang Z, Zhao X, Chen S, et al. Clin Gastroenterol Hepatol. 2021 Apr;19(4):788-796.e4.


There is quite a bit of controversy regarding whether it is fatty liver disease or actually alcohol and other risk factors that lead to HCC (see the letter to the Editor in this issue).  A recent cohort study showed that men in China with NAFLD have a higher risk of extrahepatic cancers, including thyroid and lung cancer.  Men with NASH and higher ALT had a higher risk of thyroid and hepatocellular cancer. NAFLD/NASH increased risk of colorectal and lung cancer only in smokers.


Protective Role of Tacrolimus, Deleterious Role of Age and Comorbidities in Liver Transplant Recipients With Covid-19: Results From the ELITA/ELTR Multi-center European Study

Belli LS, Fondevila C, Cortesi PA, et al. Gastroenterology. 2021 Mar;160(4):1151-1163.e3.


While the rates of COVID-19 infection in solid organ transplant recipients appear to be higher than the general population, there is limited data on how co-morbidities, immunosuppressive therapies, and aging impact the risk of mortality from SARS-CoV-2 in liver transplant (LT) recipients. This study, the largest of its kind to date, collected data on 243 adult patients with symptomatic COVID-19 from 36 centers in nine countries over a 4-month period. Overall, 25% of LT patients who required hospitalization died, and patients over the age of 70 years with comorbidities had the greatest risk of mortality – these findings have been observed in the general population as well. The most important (and unexpected) finding in the study was that patients on tacrolimus had a significantly lower risk of death (HR, 0.55; 95% CI, 0.31–0.99). The potential mechanisms underlying this positive effect are explored and include inhibition of viral replication and suppression of cytokines.

Fibrosis Regression After Eradication of Hepatitis C Virus: From Bench to Bedside
Rockey DC, Friedman SL. 2021 Apr;160(5):1502-1520.e1.

This review article discusses what we know about the mechanisms of fibrosis regression, and in particular, focuses upon regression in patients with hepatitis C virus who achieve sustained virologic response from direct-acting antiviral drugs.


Alpha-1 antitrypsin governs alcohol-related liver disease in mice and humans

Grander C, Schaefer B, Schwärzler J, et al. Gut. 2021 Mar;70(3):585-594.


This study looked at alpha-1 antitrypsin (AAT) in a patient cohort with and without alcohol-related liver disease (ALD) and examined the effects of AAT in experimental mouse models of ALD. A total of 512 individual cirrhotic patients with SERPINA1 genotyping data and available AAT serum concentration were included in the study. AAT concentrations less than 120 mg/dL were associated with poor survival in patients with alcoholic liver cirrhosis. Ethanol-fed wild-type mice displayed decreased hepatic AAT levels. Mice genetically changed to produce human AAT and mice treated with AAT had significantly less liver injury when fed an ethanol-containing diet. The impact of this study would be that AAT can potentially serve as a new therapeutic agent for ALD in the future.

Dietary cholesterol drives fatty liver-associated liver cancer by modulating gut microbiota and metabolites

Zhang X, Coker OO, Chu ES, et al. Gut. 2021 Apr;70(4):761-774.


The prevalence of non-alcoholic fatty liver disease (NAFLD)-associated hepatocellular carcinoma (HCC) has increased fourfold in the last decade compared with 2.5-fold for hepatitis, making it the most rapidly growing indication for liver transplantation. Among hepatic lipid species, cholesterol is considered a major lipotoxic molecule in NASH development. Abnormalities in hepatic cholesterol homeostasis have been demonstrated in both human and experimental models of NASH. This group has found that squalene epoxidase, a rate-limiting enzyme in cholesterol biosynthesis, drives NAFLD–HCC development. The intestinal microbiota has a symbiotic relationship with its host and contributes nutrients and energy by metabolizing dietary components including cholesterol in the large intestine. It has been suggested that the gut microbiome represents an environmental factor contributing to the development of NAFLD and its progression to NAFLD–HCC. However, whether gut microbiota dysbiosis is the cause or effect of dietary cholesterol-induced NASH and NAFLD–HCC progression remains unclear. The present study was performed to determine the role and the associated molecular mechanisms of dietary cholesterol in the development of NAFLD–HCC. A high-fat high-cholesterol diet (HFHC) spontaneously and sequentially induced fatty liver, steatohepatitis, fibrosis, and NAFLD–HCC development, while a high-fat low-cholesterol diet induced only hepatic steatosis in male mice. Dietary cholesterol-induced NAFLD–HCC formation was associated with gut microbiota dysbiosis. The microbiota composition changed along stages of NAFLD–HCC formation: Mucispirillum, Desulfovibrio, Anaerotruncus, and Desulfovibrionaceae were sequentially increased, while Bifidobacterium and Bacteroides were depleted in HFHC-fed mice, which was corroborated in human hypercholesteremia patients. Gut bacterial metabolite alteration including increased serum taurocholic acid (TCA) and depleted 3-indolepropionic acid (IPA) was found in NAFLD–HCC. IPA inhibited cholesterol-induced lipid accumulation and cell proliferation, while TCA aggravated cholesterol-induced triglyceride accumulation in a human normal immortalized hepatocyte cell line. Anticholesterol treatment restored dietary cholesterol-induced gut microbiota dysbiosis and completely prevented NAFLD–HCC formation. Cholesterol inhibitory therapy and gut microbiota manipulation may be effective strategies for NAFLD–HCC prevention.

Liver injury is independently associated with adverse clinical outcomes in patients with COVID-19

Yip TC, Lui GC, Wong VW, et al. Gut. 2021 Apr;70(4):733-742.


Liver injury, in the form of hepatitis, cholestasis, or both has been observed in patients infected by different human coronaviruses (HCoVs), including severe acute respiratory syndrome (SARS)-CoV (SARS) and the more recent SARS-CoV-2 (COVID-19). Liver injury is possibly caused by systemic inflammation and adverse drug reactions in COVID-19 patients who have been receiving different medical treatments. The study aims to compare the serial liver biochemistries of patients in Hong Kong infected by various HCoVs, with a special focus on their prognostic role. ALT/AST elevation occurred in 50.3% of SARS patients, 22.5% of COVID-19 patients, and 36.0% of other HCoV patients. For COVID-19 patients, 53 (5.1%) were admitted to ICU, 22 (2.1%) received invasive mechanical ventilation, and 4 (0.4%) died. ALT/ AST elevation was independently associated with primary end point (adjusted OR (aOR) 7.92, 95% CI 4.14 to 15.14, p<0.001) after adjusting for albumin, diabetes, and hypertension. Vigilant monitoring of liver biochemistries is important given its dynamic change during infection and association with adverse clinical outcomes in COVID-19 patients. The author advised an extremely cautious use of appropriate medications with the least hepatotoxicity. Use of lopinavir-ritonavir ±ribavirin + interferon beta and corticosteroids was independently associated with ALT/AST elevation in COVID-19 patients. Thorough review of medical history and detailed investigation for concomitant liver diseases are crucial to improve patient outcomes.

MicroRNAs as regulators, biomarkers and therapeutic targets in liver diseases

Wang X, He Y, Mackowiak B, et al. Gut. 2021 Apr;70(4):784-795.


Hepatic miRNA profiles play an important role in the pathogenesis of liver diseases by regulating liver metabolism, injury, fibrosis, and tumor development. Additionally, in preclinical studies, miRNA mimics/anti-miRs have been found to have some therapeutic benefits. The authors reviewed some recent advances regarding the regulation and function of miRNAs in liver diseases with a major focus on miRNAs that are specifically expressed or enriched in hepatocytes (miR-122, miR-194/192), neutrophils (miR-223), hepatic stellate cells (miR-29), immune cells (miR-155), and in circulation (miR-21). miR-122 is a highly abundant, liver-specific miRNA that accounts for approximately 70% and 52% of the whole hepatic miRNome in adult mice and humans, respectively, with negligible expression in other cell types; hence, it is considered a hepatocyte-specific miRNA. miR-122 is expressed at high levels in mature liver but is markedly downregulated in HCC closely correlated with hepatocarcinogenesis, poor prognosis, and metastasis in HCC. Hepatic miR-122 levels are decreased in patients with non-alcoholic steatohepatitis (NASH) and alcohol-associated liver disease (ALD) compared with healthy controls; alternatively, serum miR-122 levels are elevated in patients with non-alcoholic fatty liver disease (NAFLD) and are even higher in patients with NASH. The dynamic regulation of both the liver expression and release of miR-122 into circulation may explain these opposing changes. It has been observed that miR-122 inhibition by antagomiR-122 worsens fatty liver in high-fat diet (HFD)-fed mice by reducing β-oxidation. The different miRNAs may have synergistic/additive functions or opposing functions, such as miR-21, miR-29, miR-214, and miR-223 have been reported to exert profibrotic or antifibrotic functions while deletion of all miRNAs in HSC-specific Dicer KO mice revealed no significant effects on HSC activation and liver fibrosis. Importantly, some dysregulated miRNAs promote liver disease progression, but some act as defensive responses. For example, miR-122 has been shown to exert anti-NASH functions. The same miRNA may play different or even opposite roles in different liver diseases. miRNAs have the potential to act as promising biomarkers and therapeutic strategies for the treatment of liver diseases. Many miRNAs have been or are currently being evaluated in preclinical studies or clinical trials for their potential as diagnostic, prognostic, and treatment-response biomarkers for liver diseases.


Alanine Aminotransferase and Gamma-Glutamyl Transpeptidase Predict Histologic Improvement in Pediatric Nonalcoholic Steatohepatitis

Newton KP, Lavine JE, Wilson L, et al. Hepatology. 2021 Mar;73(3):937-951.


This study from the Nonalcoholic Steatohepatitis Clinical Research Network (NASH CRN) evaluated the relationship between liver chemistries and liver pathology using data from a clinical trial. The study included 146 children with NASH. Multivariate analysis was conducted at 52 weeks for improvement in 1) liver pathology, 2) borderline zone 1 NASH, and 3) fibrosis. Improvement in liver histology occurred in 43 participants (30%). There were 46 participants with borderline zone 1 NASH, with resolution in 12 of 46 children (28%). Dynamic changes in ALT and GGT were associated with a change in liver histology and were powerful indicators of histologic response. GGT appeared to best address improvement in activity score, and ALT appeared to best address improvement in borderline zone 1 NASH and fibrosis.

Hepatology Communications

Clinical Presentation and Gene Expression of Acute Alcohol-Induced Microvesicular Steatosis Mimicking Alcoholic Hepatitis

Spahr L, Lanthier N, Tihy M, et al. Hepatol Commun. 2021 Jan 9;5(4):618-628.


Acute alcoholic microvesicular steatosis (MIC) was compared to alcoholic hepatitis (AH) and whole transcriptome analysis was performed on frozen liver tissue from a total of 36 patients. They determined that MIC appeared to be acute, noninflammatory, potentially severe alcoholic liver injury, mimicking ASH.  However, the cases of MIC that had severe microvesicular steatosis involved lipid metabolism and mitochondrial-related pathways.  MIC was also associated with a lower fibrosis stage and has a distinct gene expression profile.

Human Pathology

An immunostaining panel of C-reactive protein, N-cadherin, and S100 calcium binding protein P is useful for intrahepatic cholangiocarcinoma subtyping

Akita M, Sawada R, Komatsu M, et al. Hum Pathol. 2021 Mar;109:45-52.

The 5th Ed WHO Classification of Digestive System Tumours stratifies intrahepatic cholangiocarcinoma (iCCAs) into small duct and large duct types. This study builds upon prior studies in evaluating whether five immunostains (C-reactive protein (CRP), N-cadherin, tubulin beta-III (TUBB3), neural cell adhesion molecule (NCAM), and S100 calcium binding protein P (S100P)) can be used to aid in iCCA subclassification. A total of 50 iCCAs were evaluated, including 31 small duct and 19 large duct types. Tissue microarrays were created from a paraffin block on each case to simulate small liver biopsies. The optimal markers of small-duct iCCAs were CRP (97% sensitivity, 95% specificity) and N-cadherin (87% sensitivity, 84% specificity), whereas S100P was more commonly expressed in large-duct iCCA (95% vs. 29% in small-duct iCCA, P < 0.001). The authors, therefore, propose utilization of CRP, N-cadherin, and S100P in iCCA subclassification.

Pathological findings in the postmortem liver of patients with coronavirus disease 2019 (COVID-19)

Zhao CL, Rapkiewicz A, Maghsoodi-Deerwester M, et al. 2021 Mar;109:59-68.

We know that COVID-19 infections are not only associated with fever and respiratory symptoms, but also with gastrointestinal symptoms including diarrhea, vomiting, and abdominal pain.  This autopsy study evaluates the histopathologic changes in the livers of 17 fatal COVID-19 cases. The main pathologic findings included extensive platelet-fibrin microthrombi present in sinusoids, central vein or portal vein (12/17 cases, 71%), rare megakaryocytes (11/13 cases, 85%), histiocytic hyperplasia (5/17 cases, 29%; of note, these foci are similar in morphologic appearance to lipogranulomas and are highlighted by the authors with a CD68 stain), ischemic-type hepatic necrosis, and centrizonal hemorrhage (8/17 cases, 47%). A COVID-19 immunostain showed staining in portal-based histiocytes in 5 of 17 cases (29%). The overall findings may represent secondary effects of COVID-19 from hypoxia, multiorgan failure, and various drugs.

Journal of Gastroenterology and Hepatology

Modest alcohol intake not associated with significant hepatic steatosis or more severe liver disease among patients with diabetes mellitus

Tan EZ, Lai LL, Vethakkan SR, et al. J Gastroenterol Hepatol. 2021 Mar;36(3):751-757.


The effect of modest alcohol intake on the prevalence of significant hepatic steatosis and severity of liver disease in patients with type 2 diabetes mellitus (T2DM) is unclear. This paper found that modest alcohol intake is not associated with a higher prevalence of significant hepatic steatosis or more severe liver disease among patients with T2DM.

Oxidative stress and Liver X Receptor agonist induce hepatocellular carcinoma in Non‐alcoholic steatohepatitis model

Shimizu Y, Tamura T, Kemmochi A, et al. J Gastroenterol Hepatol. 2021 Mar;36(3):800-810.


The incidence of non‐alcoholic steatohepatitis (NASH)‐related hepatocellular carcinoma (HCC) is progressively increasing. However, the pathophysiology and etiology of NASH progression to HCC are unknown. The authors hypothesized that steatosis was the key factor in NASH‐related hepatocarcinogenesis and aimed to evaluate the effects of long‐term liver X receptor (LXR) agonist stimulation on hepatic steatosis induced by a high‐fat diet and oxidative stress.

Prediction of the prognosis of advanced hepatocellular carcinoma by TERT promoter mutations in circulating tumor DNA

Hirai M, Kinugasa H, Nouso K, et al. J Gastroenterol Hepatol. 2021 Apr;36(4):1118-1125.


Human telomerase reverse transcriptase (TERT) promoter mutations are the most prevalent mutations in hepatocellular carcinoma (HCC). The goal of this study was to detect the mutations with plasma circulating tumor DNA (ctDNA) in patients with advanced HCC and elucidate their clinical utility. They found that TERT promoter mutations in ctDNA are associated with a short survival and may be a valuable biomarker for prognosis in patients with advanced HCC.

Journal of Hepatology

Clinicopathologic features, tumor immune microenvironment and genomic landscape of Epstein-Barr virus-associated intrahepatic cholangiocarcinoma

Huang Y-H, Zhang CZ-Y, Huang Q-S, et al. J Hepatol. 2021 Apr;74(4):838-849.


Epstein-Barr virus (EBV)-associated intrahepatic cholangiocarcinoma (EBVaICC) is a rare variant of cholangiocarcinoma with the majority of cases to date reported in Asia in patients of Chinese descent. This study is a single-institution (China) retrospective consecutive cohort study of 303 patients with ICC. Notable findings included the first report of prevalence of EBVaICC (6.6%), with a significantly higher percentage of lymphoepithelioma-like (LEL) subtype (45%) compared to non-EBVaICC. However, 55% of patients were of conventional type ICC, implying EBVaICC may be underdiagnosed if testing for EBV is not routinely performed in ICC. Patients with EBVaICC were more often female, younger, with solitary tumors, and higher HBV infection rates, but with less frequent cirrhosis. EBVaICC LEL subtype was associated with higher 2-year overall survival rates compared to conventional EBVaICC and non-EBVaICC. EBVaICC showed high PD-L1 expression in tumor cells with high CD8+ tumor infiltrating lymphocytes (TILs) suggesting the possible utility of immune checkpoint inhibitors in these patients. EBVaICCs also demonstrated a distinct genomic profile from non-EBVaICCs.

Liver Transplantation

Clinicopathologic Characteristics of Centrilobular Injury in Pediatric Liver Transplantation

González IA, Lu HC, Alipour Z, et al. 2021 March;27(3):416-424.


Centrilobular injury (CLI) is defined as the presence of perivenular mononuclear inflammation, hepatocyte dropout, and extravasated erythrocytes. In pediatric liver allografts, CLI has been associated with advanced fibrosis and chronic rejection (CR). The aim of this study was to better characterize the clinicopathologic features of CLI in the setting of T cell-mediated rejection (TCMR) and its association with complement component 4d (C4d) deposition. The authors evaluated a total of 206 posttransplant pediatric patients (491 allograft liver biopsies) from 2000 to 2018, of which 63 patients (102 biopsies) showed evidence of TCMR and were included in the study. Of the patients, 35 (55.6%) had CLI on their initial episode of TCMR; those patients with CLI were significantly associated with the type of immunosuppression treatment (P = 0.03), severity of TCMR (P < 0.001), higher gamma-glutamyltransferase (P = 0.01), and advanced fibrosis (P = 0.03). There was a trend to shorter time interval from transplantation to presentation of CLI compared with those without CLI (P = 0.06). No difference was observed in graft or overall survival in the patients with CLI. In 20 patients with CLI, additional biopsies were available; in 45% of these patients, CLI was a persistent/recurrent finding. C4d deposition was noted in 12% of all biopsies (6 patients) with CLI. No significant correlation was noted in C4d deposition and CLI, CR, or graft/overall survival. The authors conclude that CLI, although not significantly associated with worse graft survival, was significantly associated with severe TCMR and degree of fibrosis, which highlights the importance of active clinical management and follow-up for these patients.

Modern Pathology

Key histopathologic features in idiopathic noncirrhotic portal hypertension: an interobserver agreement study and proposal for diagnostic criteria

Liang J, Shi C, Dupont WD, et al. Mod Pathol. 2021 Mar;34(3):592-602.


There is currently no consensus on diagnostic criteria for histologic features of idiopathic noncirrhotic portal hypertension (INCPH). This paper proposes a three-tiered classification with diagnostic criteria to facilitate the histologic assignment of obliterative portal venopathy (OPV) status for the evaluation of INCPH.

Prognostic impact of tumor microvessels in intrahepatic cholangiocarcinoma: association with tumor-infiltrating lymphocytes

Yugawa K, Itoh S, Yoshizumi T, et al. Mod Pathol. 2021 Apr;34(4):798-807.


Tumor microvessel density (MVD) is a prognostic factor for patients with intrahepatic cholangiocarcinoma (ICC). Tumor-infiltrating lymphocytes (TILs) are also key components of the tumor microenvironment that play important roles in ICC progression. This study aimed to clarify the relationships between the MVD and immune status and prognosis in patients with ICC.

A large-scale internal validation study of unsupervised virtual trichrome staining technologies on nonalcoholic steatohepatitis liver biopsies

Levy JJ, Azizgolshani N, Andersen MJ Jr, et al. Mod Pathol. 2021 Apr;34(4):808-822.


The paper focuses on describing methods to computationally transform H&E stain into trichrome for evaluation of fibrosis on digital whole slide images (WSI) in order to lessen the need for additional physical staining besides H&E, reducing personnel, equipment, and time costs.

Morphology of tumor and nontumor tissue in liver resection specimens for hepatocellular carcinoma following nivolumab therapy

Simoes CC, Thung SN, Fiel MI, et al. Mod Pathol. 2021 Apr;34(4):823-833.


This paper describes the morphologic changes to tumor and nontumor liver after Nivolumab treatment in 20 well-characterized HCC patients.

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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