HPHS Journal Watch: September/October 2022

American Journal of Gastroenterology

Incidence of Hepatitis E Infection in American Patients With Suspected Drug-Induced Liver Injury Is Low and Declining: The DILIN Prospective Study

Fontana RJ, Engle RE, Hayashi PH, et al. Am J Gastroenterol. 2022 Sep 1;117(9):1462-1470.


Acute Hepatitis E virus (HEV) infection is a rare cause of acute viral hepatitis in the general US population. However, recent European studies have suggested that up to 10% of patients with suspected idiosyncratic drug-induced liver injury (DILI) may have undiagnosed acute HEV. The study is to find the incidence, presentation, and outcome of acute and previous HEV infection in a large cohort of patients with suspected drug-induced liver injury (DILI). The serum samples from 2012 patients enrolled in the DILI Network were tested for anti-HEV immunoglobulin G (IgG). Those with detectable anti-HEV IgG underwent testing for anti-HEV IgM; those with detectable anti-HEV immunoglobulin m (IgM) were tested for HEV RNA. Anti-HEV IgG was detected in 407 (20%) patients and associated with increasing age and earlier year of enrollment. The median age of seropositive subjects was more than a decade higher than seronegative subjects (59.8 vs 48.7 years). The overall prevalence of anti-HEV declined from 22% (2004-2011) to 18% (2012-2019), suggestive of a cohort effect. The frequency of acute HEV (median ALT 5 1231 IU/L) also decreased from 3% (2004-2008) to 1.2% (2009-2013) to 0.6% (2014-2019). These results suggest that acute HEV infection is usually subclinical and was much more frequent in this cohort before 2004. Acute HEV infection accounts for less than 1% of suspected American DILI cases and is more frequent in older men. Previous HEV infection is also most commonly seen in older individuals. Clinicians should consider testing for unsuspected acute HEV infection in older adult patients with acute hepatocellular DILI and jaundice.

American Journal of Surgical Pathology

Hepatic Cysts: Reappraisal of the Classification, Terminology, Differential Diagnosis, and Clinicopathologic Characteristics in 258 Cases

Armutlu A, Quigley B, Choi H, et al. Am J Surg Pathol. 2022 Sep 1;46(9):1219-1233.


The authors of this multi-site study reviewed the histology of 258 resected hepatic cysts. They found that only 34 (13%) cases qualified as true neoplastic cysts. The majority (n=27) of the neoplastic cysts were mucinous cystic neoplasms (MCN) with mucinous epithelium and ovarian-like stroma. All MCN were identified in women. The remaining neoplastic cysts were intraductal non-invasive neoplasms (n=4), a cystic cholangiocarcinoma (n=1), and metastatic adenocarcinoma (n=2). The vast majority of the reviewed hepatic cystic lesions were ductal plate malformation-related (n=163, 63%). These were lined by biliary-type epithelium, and most were easily classified as cystic bile duct hamartomas. Another 32 (12.4%) cases were infectious/inflammatory, 18 (7%) were congenital, and 11 (4%) fell into a miscellaneous category that included mesenchymal hamartomas and hematomas. Overall, the authors found that most cystic lesions of the liver are non-neoplastic, and very few of these show invasive malignancy.

Prominent Pseudoacini in Focal Nodular Hyperplasia

Wang D, Gonzalez IA, Russo PA, et al. Am J Surg Pathol. 2022 Oct 1;46(10):1380-1385.


Pseudoacinar growth is often taken as a sign of hepatocellular carcinoma in the setting of a mass. The authors investigated the frequency of pseudoacini in focal nodular hyperplasia (FNH) by reviewing 55 resected and 40 biopsied FNH for a total of 95 cases. They found that 88% of FNH were identified in women, and 77% had a central scar identified histologically. Prominent pseudoacinar changes were found in only 12 (12.6%) cases. The pseudoacinar hepatocytes co-expressed Hep-Par1 and CK7, suggesting that chronic cholestasis within FNH may contribute to this morphologic finding. The authors conclude that the finding of pseudoacinar growth in an otherwise typical FNA should not deter one from making a diagnosis of FNH.

Archives of Pathology & Laboratory Medicine

Persistent Cholestatic Injury and Secondary Sclerosing Cholangitis in COVID-19 Patients

Shih AR, Hatipoglu D, Wilechansky R, et al. Arch Pathol Lab Med. 2022 Oct 1;146(10):1184-1193.


The understanding of cholestatic liver disease in patients with COVID-19 has been confounded by the often complex disease course of many of these patients, some of whom have various co-morbidities and combinations of drug therapies pre- and post-infection. The authors of this study review the clinical and histologic features of 7 patients who recovered from severe COVID-19 but who had persistent elevations in liver enzymes. All patients were hospitalized for more than one month, all required intubation, and all had acute kidney injury. Four (57%) also had ventilator-associated pneumonia. The elevated LFTs for all patients were mixed hepatocellular and cholestatic injury, but elevations in alkaline phosphatase predominated. Four (57%) patients were found to have “beading” of bile ducts by MRCP. Core liver biopsy was performed in 6 (86%) patients 2-6 months after COVID-19 diagnosis. All six had features of cholestatic injury, and 2 (33%) of these had features of severe obstructive biliary disease. The authors conclude that a subset of patients with severe COVID-19 develop cholestatic injury and/or secondary sclerosing cholangitis.

Clinical Gastroenterology and Hepatology

Nonalcoholic Fatty Liver Disease in Children: Where Are We?

Li J, Cheung R. Clin Gastroenterol Hepatol. 2022 Oct;20(10):2210-2215.


This editorial focused on pediatric nonalcoholic fatty liver disease (NAFLD) and summarizes the clinical and histologic features of NASH presenting in children younger than 12 years of age. The conclusions of major randomized control trials are summarized including the use of vitamin E and omega-3 fatty acids (specifically docosahexaenoic acid) plus vitamin D treatment.

Trends in Etiology-based Mortality From Chronic Liver Disease Before and During COVID-19 Pandemic in the United States

Kim D, Alshuwaykh O, Dennis BB, et al. Clin Gastroenterol Hepatol. 2022 Oct;20(10):2307-2316.e3


This study used United States national mortality records to compare the cause of death according to the etiology of chronic liver disease before and during the COVID-19 pandemic. This study found a sharp increase in all-cause mortality for alcoholic liver disease and an increase in all-cause mortality for NAFLD, which the authors contribute to pandemic-related mental health barriers as well as unhealthy lifestyles including alcohol consumption during the lockdown.


Clinical, histological and molecular profiling of different stages of alcohol-related liver disease

Ventura-Cots M, Argemi J, Jones PD, et al. Gut. 2022 Sep;71(9):1856-1866.


This study is essentially a comprehensive multicentre international effort to compare the clinical, histological, and molecular characteristics of never decompensated forms of alcoholic liver disease (ndALD) and the life-threatening alcoholic hepatitis (AH) as the clinical outcomes were very different between these two phenotypes. A few studies are only available regarding the early stages of ALD. Hence, this study is intended to elucidate critical biomarkers and pathways of disease progression in facilitating early diagnosis and identifying novel drug targets. This study has incorporated two large cohorts of patients involving multiple centers; one is a retrospective cohort of patients with ndALD (n=110) and another is the prospective cohort of patients with AH (n=225) with respect to clinical, analytical, immunohistochemical, and hepatic RNA microarray analysis of both disease phenotypes. The survival status among these two groups was different as the patients with AH showed 62% survival at 2 years compared to 10% in patients with ndALD. The presence of advanced fibrosis and continued alcohol consumption are the main parameters associated with early mortality in patients with compensated forms of ALD. AH patients had greater AST/ALT ratio and lower GGT levels than in ndALD. Histologically, steatosis grade, ballooning, and pericellular fibrosis were similar in both groups, while advanced fibrosis, Mallory-Denk bodies, bilirubinostasis, severe neutrophil infiltration, and ductular reaction were more frequent among AH patients. Transcriptome analysis revealed a profound gene dysregulation within both phenotypes when compared to controls. While ndALD was characterized by deregulated expression of genes involved in matrisome and immune response, the development of AH resulted in marked deregulation of genes involved in hepatocyte reprogramming and bile acid metabolism.

Non-alcoholic fatty liver disease and incident major adverse cardiovascular events: results from a nationwide histology cohort

Simon TG, Roelstraete B, Hagström H, et al. Gut. 2022 Sep;71(9):1867-1875.


The study is based on a population-based cohort of all Swedish adults with histologically confirmed non-alcoholic fatty liver disease (NAFLD) and without cardiovascular disease (CVD) at baseline (1966–2016, n=10 422). NAFLD was categorized prospectively as simple steatosis, non-fibrotic steatohepatitis, non-cirrhotic fibrosis, and cirrhosis histologically. Patients with NAFLD were matched to ≤5 population controls without NAFLD or CVD, by age, sex, calendar year, and county (n=46 517). Using Cox proportional hazards modeling, the authors calculated multivariable-adjusted HRs (aHRs) and 95% CIs for major adverse cardiovascular events (MACE) outcomes like ischaemic heart disease (IHD), stroke, congestive heart failure (CHF) or cardiovascular (CV) mortality. Compared with matched population controls, patients with biopsy-proven NAFLD had a significantly higher incidence of MACE. NAFLD was associated with significantly higher rates of both fatal and non-fatal MACE outcomes. Compared with controls, patients with NAFLD had a 63% higher relative risk of developing MACE. The rates of both fatal and non-fatal CV events increased with worsening NAFLD histological severity, particularly among patients with progressive fibrosis. The limitations of this study include: a retrospective study with NAFLD defined histologically, the possibility that the controls could include patients with undiagnosed NAFLD, detailed laboratory data (information regarding smoking, precise alcohol consumption, or body mass index) was lacking, and the Swedish population is primarily Caucasian (need additional research in more diverse, large-scale histology cohorts).


Reliability of histologic assessment for NAFLD and development of an expanded NAFLD activity score

Pai RK, Jairath V, Hogan M, et al. Hepatology. 2022 Oct;76(4):1150-1163.


In this study, four liver pathologists, after standardized training and multiple discussions, scored histologic measures of NAFLD for 40 liver biopsies twice, > 2 weeks apart. Steatosis measures correlated poorly with disease activity. Correlation with disease activity was largest for hepatocyte ballooning and Mallory-Denk bodies. The authors demonstrate improved reliability of multiple existing histologic NAFLD indices and fibrosis staging systems.

Hepatology Communications

Immune-mediated liver injury following COVID-19 vaccination: A systematic review

Roy A, Verma N, Singh S, et al. Hepatol Commun. 2022 Sep;6(9):2513-2522.


This systematic review evaluated the clinicopathologic features of immune-mediated liver injury (ILI) following coronavirus disease 2019 (COVID-19) vaccination. This systematic review found that the biochemical and histologic features were consistent with ILI resembling AIH, including frequent autoantibody positivity (ANA and ASMA were positive in 56.5% and 35.5% of the cases), frequent portal-based lymphoplasmacytic infiltrate in the majority of cases, and an eosinophilic infiltrate in approximately one-third of patients. More than half of patients had a complete response to steroids.

Polycystic ovary syndrome is associated with nonalcoholic steatohepatitis in women of reproductive age

Maldonado SS, Grab J, Wang CW, et al. Hepatol Commun. 2022 Oct;6(10):2634-2639.


This study utilized a large national database (US National Inpatient Sample) to evaluate the association of polycystic ovary syndrome (PCOS) with the presence of nonalcoholic steatohepatitis (NASH) in reproductive-age women (18–50 years old). The authors identified more than 20% higher odds of prevalent NASH among reproductive-age women with NAFLD and PCOS, despite these women being on average 7 years younger than women without PCOS. This NASH risk was independent of coexisting metabolic comorbidities, including diabetes, obesity, and dyslipidemia. The authors recommend that hepatology providers routinely inquire about PCOS-related symptoms and raise consideration for NAFLD/NASH screening in women with PCOS.


Simple biliary cysts of the liver can be lined by mucinous epithelium

Wong NACS, Abdalkoddus M, Al-Khafaji N, et al. Histopathology. 2022 Sep;81(3):402-406.


Simple biliary cysts of the liver are described to be lined by biliary epithelium and may be managed nonsurgically or by de-roofing only. By contrast, its important differential diagnosis – mucinous cystic neoplasm (MCN) – is at least focally lined by mucinous epithelium, has malignant potential, and therefore should be resected. The authors reviewed 21 simple biliary cysts devoid of ovarian-like stroma. The lining epithelium of seven cysts showed focal supranuclear/apical mucin, as confirmed with Alcian blue and PASD stains. Cysts with mucinous epithelium were generally larger and more often showed histological evidence of previous hemorrhage than cysts without this epithelium. There were no other statistically significant differences in clinicoradiologic features between cysts with and without mucinous epithelium, including at postoperative radiological follow-up. In conclusion, the mucinous epithelium may be metaplastic and should not be misinterpreted to indicate a diagnosis of MCN but, apart from this, appears to have no clinical significance. Ovarian-like stroma may therefore be the only histological feature that reliably distinguishes MCN from simple biliary cyst.

Human Pathology

Acute Antibody-mediated rejection in liver transplantation: Impact and applicability of the Banff working group on liver allograft pathology 2016 criteria

Maurice JB, Nwaogu A, Gouda M, et al. Hum Pathol. 2022 Sep;127:67-77.


In 2016, the Banff working group published updated consensus criteria for the diagnosis of liver transplant antibody-mediated rejection. This study aimed to evaluate the clinical utility and impact of the 2016 Banff criteria for acute antibody-mediated rejection (acute AMR) in liver transplant patients. The study population included adult patients with donor-specific antibody (DSA) assays performed between 2015 and 2020, a proven DSA (mean fluorescent index >2000), and a matched liver biopsy. There were 55 total patients identified, and of those, 28 (51%) had class I DSA, 45 (82%) had class II DSA and 18 (33%) had both. Mild, moderate, and severe microvasculitis were observed in 11 (20%), 2 (4%), and 1 (2%) case(s), respectively. Diffuse immunoreactivity to C4d (using a rabbit monoclonal antibody that does not produce diffuse high background) on portal microvascular endothelia was confirmed in 5 cases (9%), which met the criteria of definite (n = 2) or suspicious for acute AMR (n = 3). The study found that cases of acute AMR more commonly had class I DSA (100% vs. 46%; p = 0.027) or both class I and II DSA (80% vs. 28%; p = 0.018) than cases of non-acute AMR. In four cases, transplant patients had features of both acute AMR and T cell-mediated rejection (TCMR), and two of those patients progressed to ductopenic rejection within 3 weeks. Overall, 9% (5/55) of DSA-positive patients met the Banff criteria for acute AMR. Interestingly, combined acute AMR/TCMR was more common than isolated acute AMR, and additional AMR in TCMR cases may be associated with rapid progression to ductopenic rejection. Pure acute AMR was notably rare.

SUOX and GLUT1 are biomarkers for the prognosis in large duct type intrahepatic cholangiocarcinoma

Kinjo Y, Naito Y, Akiba J, et al. Hum Pathol. 2022 Oct;128:11-19.


Intrahepatic cholangiocarcinoma (iCCA) accounts for approximately 15% of primary liver tumors and has a poor prognosis, with a 5-year survival rate of ~30%. This study examined the biology of cholangiocarcinoma in an attempt to identify prognostic biomarkers. The authors selected glucose transporter 1 (GLUT1), a factor in energy metabolism that has previously been shown to be associated with iCCA prognosis, and metalloenzyme sulfite oxidase (SUOX), which is thought to be important in ATP production. The expression of SUOX and GLUT1 was evaluated by immunohistochemistry in 96 large duct type iCCA cases. The expression of SUOX and GLUT1 in tumor cells (cytoplasmic staining) was evaluated by a population score (PS) depending on their respective staining ratio (PS0: 0%, PS1: 0-1%, PS2: 1-10%, PS3: 10-33%, PS4: 33-66%, PS5: 66-100%). Overall, 73 iCCA cases (76.0%) showed low SUOX expression and 66 (68.8%) showed high GLUT1 expression. The authors found that the 5-year survival rate of iCCA with low SUOX expression was significantly shorter than that of iCCA with high SUOX expression (p = 0.001). In contrast, the 5-year survival rate of iCCA with high GLUT1 expression was significantly shorter than that of iCCA with low GLUT1 expression (p = 0.005). There was no correlation between SUOX and GLUT1. The most common pattern of expression in 51 of 96 cases (53.1%) was the combination of low SUOX and high GLUT1 expression and the overall survival was significantly shorter than that of patients with other expression patterns. Finally, SUOX was shown to be an independent prognostic factor together with GLUT1, which could indicate that SUOX in combination with GLUT1 can predict the prognosis of large duct type iCCA.

Journal of Hepatology

Hepatoblastomas with carcinoma features represent a biological spectrum of aggressive neoplasms in children and young adults

Sumazin P, Peter TL, Sarabia SF, et al. J Hepatol. 2022 Oct;77(4):1026-1037.


In this study, the authors present a molecular characterization of tumors with mixed histologic features of hepatoblastoma (HB) and hepatocellular carcinoma (HCC), currently classified in the provisional category of hepatocellular neoplasm, not otherwise specified (HCN-NOS) following the 2014 consensus classification of pediatric liver tumors. This is the largest cohort of HCN-NOS studied to date and includes cases the authors noted as “biphasic” HCN-NOS (with distinct HB or HCC features, n=13) and cases of “equivocal” HCN-NOS (with cytological features and growth pattern intermediate between HC and HCC, n=12). The authors compared the molecular features of HCN-NOS, including copy number alterations, mutations, and gene expression profiles, with those of HBs, HCCs, as well as HBs with focal atypia or pleomorphism (HB FPAs, <8 years of age, n=10) and HBs diagnosed in older children (>8 years of age, n=5) and found that the molecular profiles of HCN-NOS and HB FPAs show common underlying biological features previously seen in HCCs, including high mutation rates and enrichment of alterations in key cancer genes and pathways as well as recurrent large-scale chromosomal gains, including 2q, 6p, and 20p. HCN-NOS and HB FPAs were thus designated HB with HCC features (HBCs). HBCs were overall associated with poor clinical outcomes irrespective of patient age. Transplanted patients were most likely to have good outcomes than those treated with chemotherapy and surgery alone. This is the largest study of HCN-NOS to date and provides biological insights into this group of tumors.

Bi-allelic hydroxymethylbilane synthase inactivation defines a homogenous clinico-molecular subtype of hepatocellular carcinoma

Molina L, Zhu J, Trepo E, et al. J Hepatol. 2022 Oct;77(4):1038-1046.


In this study, the authors identify a distinct set of hepatocellular carcinomas (HCCs) characterized by bi-allelic inactivation of HMBS (hydroxymethylbilane synthetase). Mutations in HMBS are seen in patients with acute intermittent porphyria (AIP). Patients with AIP are known to be at increased risk for HCCs, with germline and subsequent second somatic HMBS alteration. HCCs in patients with AIP show a female predominance, and the authors have now also identified bi-allelic HMBS inactivation in a subset of sporadic HCCs, again with female predominance; these HCCs occur in the absence of fibrosis and classical HCC risk factors. Bi-allelic inactivation of HMBS results in accumulation of toxic intermediates, and synergies with CTNNB1-activating mutations, leading to the development of well-differentiated HCCs with a transcriptomic signature of Wnt/beta-catenin pathway activation and a DNA methylation signature related to aging. The authors conclude that HMBS, beyond its role in the pathogenesis of AIP, functions as a tumor suppressor whose bi-allelic inactivation functions as a rare driver of HCC development.

Journal of Pathology

Molecular deciphering of primary liver neuroendocrine neoplasms confirms their distinct existence with foregut-like profile

Mestier LD, Nicolle R, Pote N, et al. J Pathol. 2022 Sep;258(1):58-68.


The authors assembled a retrospective cohort of patients managed for hepatic localization of neuroendocrine tumors (NET) without extra-hepatic primary tumor after exhaustive clinical, imaging, and immunohistochemical characterization. Whole-exome sequencing with mutational and copy number analysis was performed, which showed ‘foregut-like’ genomic profiles with frequent alterations of DNA repair, histone modifiers, adherens junctions, and cell cycle control. The most frequently involved genes were KMT2A, ATM, CDH1, CDKN2C, FANCF, and MEN1. Transcriptomic profiles were compared with pancreatic, small-bowel, and lung NETs, which showed hepatic NETS to cluster closer to foregut NETs than to midgut while remaining a distinct entity with a specific profile.

Liver Transplantation

Standardizing the histological assessment of late posttransplantation biopsies from pediatric liver allograft recipients

Hübscher SG, Feng S, Gouw ASH, et al. Liver Transpl. 2022 Sep;28(9):1475-1489.


Excellent short-term survival after pediatric liver transplantation (LT) has shifted attention toward the optimization of long-term outcomes. In >12-month post-LT protocol biopsies from pediatric LT recipients, histological abnormalities such as unexplained graft inflammation (idiopathic posttransplantation hepatitis) and graft fibrosis are very common, while the majority of children studied had normal or near-normal liver biochemistry. Therefore, liver biopsies continue to be required to monitor allograft health and to titrate immunosuppression. This study formulated a list of histopathological features relevant to the assessment of long-surviving liver allograft health and developed an approach for assessing the presence and severity of these features in a standardized manner. Weighted interobserver kappa statistics showed a high level of agreement for various parameters of inflammation, interface activity, fibrosis, and microvascular injury. Intraobserver agreement for these features was even more substantial. The results of this study will help to standardize the assessment of biopsies from long-surviving liver allografts, aid the recognition of important histological features, and facilitate international comparisons and clinical trials aiming to improve outcomes for children undergoing LT.

Heterogeneity of hepatic steatosis definitions and reporting of donor liver frozen sections among pathologists: A multicenter survey.

Ho S, Kuo E, Allende D, et al. Liver Transpl. 2022 Sep;28(9):1540-1542.


This survey-based study on the evaluation of graft hepatic steatosis by intraoperative frozen section included responses from 28 pathologists in 25 academic pathology departments across the United States. The results demonstrated significant variation in how subspecialty-trained liver pathologists define, assess, calculate, and report donor liver steatosis during intraoperative consultation. These findings call for unified definitions of steatosis types and subtypes and consistent methods for determining and reporting the presence of steatosis in donor livers. The implementation of recently published Banff consensus recommendations for the determination and reporting of “large-droplet fat” (https://pubmed.ncbi.nlm.nih.gov/34676901/) may help to achieve this goal.

Prepared by:
Lindsey Westbrook, MD (Editor); University of Colorado
Dana Balitzer, MD; University of California San Francisco
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
Meredith Pittman, MD; Maimonides Medical Center
Daniel Roberts, MD; Cleveland Clinic
Nafis Shafizadeh, MD; Southern California Permanente Medical Group
Xuefeng Zhang, MD; Cleveland Clinic

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