HPHS Journal Watch: September/October 2021

American Journal of Gastroenterology

Fibrosis-4 Index vs Nonalcoholic Fatty Liver Disease Fibrosis Score in Identifying Advanced Fibrosis in Subjects With Nonalcoholic Fatty Liver Disease: A Meta-Analysis

Castellana M, Donghia R, Guerra V, et al. Am J Gastroenterol. 2021 Sep 1;116(9):1833-1841.


This meta-analysis compared the efficacy of two common non-invasive tools (NIT) – fibrosis-4 index (FIB-4) and NAFLD fibrosis scores (NFS) – in subjects with confirmed advanced fibrosis (AF) by liver biopsy. A total of eighteen studies included 4,289 subjects with and 8,315 subjects without AF. This meta-analysis showed FIB-4 to be associated with higher performance in ruling in and NFS in ruling out AF in the single threshold approach. With a dual threshold approach, a lower prevalence of indeterminate findings was found for FIB-4. In a single threshold approach, subjects scoring below the lower cut-off are unlikely to be affected by AF and should be monitored every 2 years; the higher cut-offs are likely to have AF. In a dual threshold approach, the risk of AF cannot be adequately stratified in those subjects scoring between the lower and the higher cut-offs (i.e., indeterminate); a liver biopsy may be considered in these subjects only.

The Changing Epidemiology of Liver Disease Among US Children and Adolescents From 1999 to 2016

Li J, Le MH, Barakat MT, et al. Am J Gastroenterol. 2021 Oct 1;116(10):2068-2078.


The authors included data from the National Health and Nutrition Examination Survey (NHANES) of 6,647 patients between 6–21 years of age from 1999 to 2016. Results showed a significant reduction of HBV infection, but the prevalence of HCV infection increased after 2011. The prevalence of possible NAFLD among US adolescents has increased substantially over the past 2 decades, especially after 2005, in female individuals, in Mexican Americans, and children and adolescents aged 12–13 and 14–17 years. There is a need for public health efforts to get seek further understanding of the driving factors of this increase so that age-appropriate interventions can be developed and implemented.

American Journal of Surgical Pathology

Steatotic and Steatohepatitic Hepatocellular Carcinomas

Aykutlu U, Argon A, Orman M, et al. Am J Surg Pathol. 2021 September; 45(9):1252-1263.


The aim of this retrospective study was to correlate pathologic features of steatohepatitic HCC with clinical findings and to investigate the expression of SAA and CRP within this subtype of hepatocellular carcinoma. To that end, the authors reviewed 150 resected hepatocellular carcinomas with clinical data and stains. They found that of “typical” steatohepatitic HCC cases (n=13), where more than 50% of the tumor had features of steatohepatitis, 77% occurred in patients with a history of viral hepatitis. Of “classic” HCC (n=102) cases, 84% occurred in patients with viral hepatitis, and patients with only steatosis in their HCC (n=13) had a history of viral hepatitis in 85% of cases. The authors also found that these three groups of tumors had similar overall and disease-free survival. Immunostains for CRP and SAA did not provide diagnostic or prognostic data. Overall, the authors provide clinicopathologic data for steatotic and steatohepatitic HCC but show that these subtypes do not appear to have prognostic implications.

Fibrohistiocytic Variant of Hepatic Pseudotumor: An Antibiotic Responsive Tumefactive Lesion

Arora KS, Anderson MA, Neyaz A, et al. Am J Surg Pathol. 2021. October; 45(10):1314-1323.


The authors of this multicenter study present 30 patients with the fibrohistiocytic variant of hepatic pseudotumor. Most patients presented with abdominal pain and were found to have solitary liver lesions where a neoplastic or metastatic process was favored. On histology, the lesions usually had prominent histiocytes with lymphoplasmacytic inflammation. Less than half had neutrophils, microabscesses, or eosinophils. Fibrosis was a prominent feature of 7 of the cases. Interestingly, sixteen patients were treated with antibiotics, and 12 (75%) of those treated resolved on imaging. Six patients who did not receive specific therapy also had resolution of the lesion. Overall, the authors suggest that the fibrohistiocytic variant of hepatic pseudotumor is a non-neoplastic lesion that may have an underlying infectious etiology and which can mimic a neoplasm by imaging.

Clinical Gastroenterology and Hepatology

Recent Advances in Hepatocellular Carcinoma Treatment

Parikh ND, Pillai A. Clin Gastroenterol Hepatol. 2021 Oct;19(10):2020-2024.


This review article written by Parikh and Pillai discusses the current treatment approaches for hepatocellular carcinoma (HCC).  The article focuses on four main areas: 1) Extended transplantation for patients with tumors outside of the Milan criteria, 2) locoregional therapies, 3) combination of multimodal therapies to treat patients with intermediate to advanced stages of HCC, and 4) combinations of systemic therapies for patients with unresectable HCCs.


Evidence-Based Management of Hepatocellular Carcinoma: Systematic Review and Meta-analysis of Randomized Controlled Trials (2002-2020)

Haber PK, Puigvehí M, Castet F, et al. 2021 Sep;161(3):879-898.


For those interested in a review of hepatocellular carcinoma therapies, particularly with respect to the emergence of immunotherapies, this systematic review and meta-analysis evaluate 49 high-quality phase III randomized controlled trials conducted over the past 20 years.

Preparing for the NASH Epidemic: A Call to Action

Kanwal F, Shubrook JH, Younossi Z, et al. 2021 Sep;161(3):1030-1042.e8.


To help guide a single global strategy for the management of NAFLD and NASH, the American Gastroenterological Association, in collaboration with 7 professional associations, convened an international conference comprising 32 experts in gastroenterology, hepatology, endocrinology, and primary care providers from the United States, Europe, Asia, and Australia. Highlighted in the conference was a role for artificial intelligence to improve the accuracy and reliability of liver histologic interpretation using quantitative scoring systems for NAFLD/NASH radiologic and histopathologic features. The participants also clarified the role of liver biopsy, particularly to assess disease activity, aid in cases in which there is a “diagnostic doubt,” as part of phase 2 or 3 clinical trials, and in excluding co-existent liver diseases. The participants reviewed and discussed published literature on the global burden, screening, risk stratification, diagnosis, and management of individuals with NAFLD, including those with NASH, and called for a unified, international public health response to NAFLD and NASH.


Amelioration of systemic inflammation in advanced chronic liver disease upon beta-blocker therapy translates into improved clinical outcomes

Jachs M, Hartl L, Schaufler D, et al. Gut. 2021 Sep;70(9):1758-1767.


Systemic inflammation promotes the development of clinical events in the form of decompensation and acute-on-chronic liver failure in cirrhosis. The authors tried to assess whether non-selective beta-blocker (NSBB) treatment initiation has any impact on the biomarkers of systemic inflammation (white blood cell count (WBC), C reactive protein (CRP), interleukin-6 (IL-6), and procalcitonin (PCT)) and whether these changes in systemic inflammation can predict complications and mortality. These biomarkers were assessed at sequential hepatic venous pressure gradient (HVPG) measurements without NSBB and under stable NSBB intake. This study incorporated 307 stable patients with advanced chronic liver disease (Child-A: 77 (25.1%), Child-B: 161 (52.4%), Child-C: 69 (22.5%), median HVPG: 20 (IQR 17–24) mm Hg) including 231 (75.2%) with decompensated disease. NSBB therapy had a systemic anti-inflammatory activity with reductions of WBC and CRP levels. The effect was most pronounced in Child-C and irrespective of hepatic venous pressure gradient. A reduction of WBC of ≥15% following NSBB therapy had a decreased risk of further decompensation and death. The main limitations of this study are its retrospective design and lack of any control arm.

MRE combined with FIB-4 (MEFIB) index in detection of candidates for pharmacological treatment of NASH-related fibrosis

Jung J, Loomba RR, Imajo K, et al. Gut. 2021 Oct;70(10):1946-1953.


A cross-sectional analysis of a prospective cohort of 238 consecutive patients of  University of California at San Diego (UCSD)-NAFLD with simultaneous Magnetic Resonance elastography (MRE) and biopsy-proven NAFLD was done. The goal was to examine the diagnostic accuracy of MR elastography (MRE) combined with fibrosis-4 (FIB-4) in diagnosing ≥stage 2 fibrosis as these patients are candidates for pharmacological treatment. The diagnostic accuracy was compared between MRE and FIB-4 in diagnosing ≥stage 2 fibrosis in UCSD-NAFLD (training) Cohort and Japan-NAFLD (validation) Cohort. In both the training and validation cohorts, MRE outperformed FIB-4 in assessing fibrosis stage. Additionally, a combined MRE with FIB-4 (MRE ≥3.3 kPa and FIB-4 ≥1.6) has been shown to develop a clinical prediction to rule in ≥stage 2 fibrosis patients in both cohorts with a positive predictive value (PPV) of 97.1% (p<0.02) in the UCSD-NAFLD cohort (AUROC of 0.90 (95% CI 0.85 to 0.95)) and remained significant at PPV of 91.0% (p<0.003) in the Japan-NAFLD Cohort (AUROC of 0.84 (95% CI 0.78 to 0.89).

ATF4 activation promotes hepatic mitochondrial dysfunction by repressing NRF1–TFAM signalling in alcoholic steatohepatitis

Hao L, Zhong W, Dong H, et al. Gut. 2021 Oct;70(10):1933-1945.


Hepatic activating transcription factor 4 (ATF4) activation was associated with mitochondrial dysfunction in Alcoholic Liver disease (ALD). This study was aimed to investigate the function and mechanism of ATF4 in alcohol-induced hepatic mitochondrial dysfunction in hepatocyte-specific ATF4 knockout mice and mitochondrial transcription factor A (TFAM) in liver-specific TFAM overexpression mice, respectively. In this experimental study, it has been observed that the hepatocyte-specific deletion of ATF4 alleviates alcohol-induced liver injury and prevents alcohol-induced mitochondrial dysfunction in mice. ATF4 negatively regulates TFAM expression in hepatocytes and deletion of hepatocyte-specific ATF4 leads to overexpression of hepatocyte-specific TFAM; thereby preventing alcohol-induced mitochondrial dysfunction in mice. Even, experimentally induced hepatocyte-specific TFAM overexpression attenuates alcoholic steatohepatitis. Therefore, targeting ATF4 or downstream NRF1–TFAM signals may be potential strategies for the prevention and treatment of ALD.


Proteomic Profiling of Hepatocellular Adenomas Paves the Way to Diagnostic and Prognostic Approaches

Dourthe C, Julien C, Di Tommaso S, et al. Hepatology. 2021 Sept;74(3):1595-1610.


The authors selected 52 typical cases of all the different hepatocellular adenoma (HCA) subgroups and built a reference HCA proteomics database. They defined a specific proteomic profile for each of the HCA subgroups. They then built a matching algorithm and applied it to test cases. Proteomic profiles allowed for HCA classification even in complex cases, in which immunohistochemical and genomic analysis could not reveal a definite conclusion. This work proposes a proteomic-based, machine-learning tool for HCA classification.


Comparing the clinicopathological characteristics of combined hepatocellular-cholangiocarcinoma with those of other primary liver cancers by use of the updated World Health Organization classification

Yen CC, Yen CJ, Shan YS, et al. Histopathology. 2021 Oct;79(4):556-572.


The authors investigate the characteristics of combined hepatocellular-cholangiocarcinoma (cHCC-CCA) in comparison with those of other primary liver cancers by utilizing the updated WHO classification. They retrospectively analyzed 64 cHCC-CCA patients and 55 HCC with stem cell/progenitor features (HCCscf) patients from December 2007 to May 2018. Propensity score matching was conducted to compare these with HCC and intrahepatic cholangiocarcinoma (iCCA) patients. Clinicopathological characteristics, event-free survival, and overall survival were evaluated with multivariate Cox proportional hazard regression. During a median follow-up of 55.9 months, cHCC-CCA patients had significantly poorer survival than HCCscf patients and survival intermediate between that of HCC patients and that of iCCA patients. Hepatitis B virus (HBV) infection and high levels of tumor-infiltrating lymphocytes (TILs) were associated with favorable survival in cHCC-CCA patients. In the multivariate analysis, poor hepatic reserve, absence of HBV infection, stage IV disease, and low levels of TILs were significant negative prognostic factors in cHCC-CCA patients. After being pooled with other primary liver cancers, cHCC-CCA and iCCA resulted in worse survival. cHCC-CCA patients have survival intermediate between that of HCC patients and iCCA patients, and HBV infection and high levels of TILs predict favorable survival. This study provides clinical correlations for the new 2019 WHO classification.

Human Pathology

Inhibin-positive hepatic carcinoma: proposal for a solid-tubulocystic variant of intrahepatic cholangiocarcinoma

Wen KW, Joseph NM, Srivastava A, et al. 2021 Oct;116:82-93.


This case series describes the clinicopathologic and molecular features of six cases of inhibin-positive hepatic carcinoma, a rare primary liver tumor that occurs in young women and morphologically resembles sex cord-stromal tumors. The tumors in the case series demonstrate similar albumin expression and clinicoradiographic and immunohistochemical features that contrast with conventional intrahepatic cholangiocarcinoma. No predictive genomic changes were identified in the inhibin-positive hepatic carcinoma cases, but the tumors lacked a mutational profile characteristic of intrahepatic cholangiocarcinoma and hepatocellular carcinoma. The overall findings support that inhibin-positive hepatic carcinoma is a distinct variant of intrahepatic cholangiocarcinoma, and the study authors propose the terminology “solid-tubulocystic variant.”

Primary hepatic neoplasms arising in cirrhotic livers can have a variable spectrum of neuroendocrine differentiation

Shi C, Jug R, Bean SM, et al. 2021 Oct;116:63-72.


This study describes the morphologic features and immunophenotype of four cases of primary hepatic tumors with neuroendocrine differentiation, all of which arose in cirrhotic livers; next-generation sequencing (NGS) was additionally performed in two cases. Case 1 is characterized as amphicrine carcinoma and arose in a 74-year-old M with multiple small liver nodules; synaptophysin, chromogranin, GPC3, and AFP stains were positive and Ki67 index >80%; HepPar1 and arginase stains were negative. Case 2 is a neuroendocrine carcinoma, small cell type (synaptophysin and cytokeratin positive; chromogranin, HepPar1, arginase, GPC3 stains negative) diagnosed in a 52-year-old M with 8.5 cm tumor and multiple satellite lesions. NGS detected NOTCH3 and BRD4 amplification. Case 3 is described as a mixed hepatocellular-neuroendocrine carcinoma (small cell type) and arose in a 64-year-old female with a dominant liver mass and multiple large liver masses. The small cell component was highlighted by a synaptophysin stain and had Ki67 of >75%, while the HCC component displayed patchy HepPar1 with a Ki67 of 40%. NGS detected mutations in CDKN1A and CTNNB1. Finally, case 4 was described as a neuroendocrine tumor, WHO grade 3, and was diagnosed in a 52-year-old female incidentally found to have a large mass in the left hepatic lobe during screening for abdominal aortic aneurysm. The study authors conclude that primary hepatic tumors arising in cirrhotic liver can have variable neuroendocrine differentiation and likely follow molecular pathways similar to those of conventional hepatocellular carcinoma.

Journal of Gastroenterology and Hepatology

Programmed cell death-ligand 1 expression in hepatocellular carcinoma and its correlation with clinicopathological characteristics

Mou H, Yang QA, Yu L, et al. J Gastroenterol Hepatol. 2021 Sep;36(9):2601-2609.


Higher PD-L1 expression as measured by combined positive score (CPS) was associated with increased Edmondson–Steiner grade (grade III vs II, P = 0.041) and TP53 mutations (P = 0.021). PD-L1 CPS had no correlation with tumor mutational burden (Spearman’s correlation coefficient 0.067). PD-L1 CPS was not significantly associated with hepatitis B virus infection.

TA allele of rs2070673 in the CYP2E1 gene is associated with lobular inflammation and nonalcoholic steatohepatitis in patients with biopsy-proven nonalcoholic fatty liver disease

Ma HL, Chen SD, Zheng KI, et al. J Gastroenterol Hepatol. 2021 Oct;36(10):2925-2934.


Cytochrome P450 2E1 (CYP2E1) plays a role in lipid metabolism, and by increasing hepatic oxidative stress and inflammation. The upregulation of CYP2E1 is involved in the development of nonalcoholic steatohepatitis (NASH). The study aimed to explore the relationship between CYP2E1-333A>T (rs2070673) and the histological severity of nonalcoholic fatty liver disease (NAFLD). The TA allele of rs2070673 is strongly associated with lobular inflammation and NASH, and this effect appears to be largely mediated by serum IP-10 levels.

Journal of Hepatology

Ceruloplasmin gene variants are associated with hyperferritinemia and increased liver iron in patients with NAFLD

Corradini E, Buzzetti E, Dongiovanni P, et al. J Hepatol. 2021 Sep;75(3):506-513.


Hyperferritinemia and altered iron metabolism are known to be associated with worse outcomes in patients with non-alcoholic fatty liver disease (NAFLD). To evaluate the genetic determinants of hyperferritinemia and iron overload in patients with NAFLD, from a cohort of 328 patients with NAFLD in Italy, the authors studied 23 patients with high ferritin (>750 ng/ml) and positive iron staining compared to 25 controls with normal ferritin and absent iron staining. Patients with increased transferrin saturation and known causes of hyperferritinemia were excluded from the study. A panel of 32 genes related to iron metabolism was sequenced. Patients with hyperferritinemia had a higher prevalence of potentially pathogenic variants, most commonly in the ceruloplasmin gene. These variants were associated with hyperferritinemia, higher iron stores, and more severe liver fibrosis. Thus, carriers of these variants, particularly in ceruloplasmin, are at risk for more severe liver disease in the setting of NAFLD.

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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