HPHS JOURNAL WATCH:  Nov/Dec 2023

American Journal of Gastroenterology

History of Gestational Diabetes and Incident Nonalcoholic Fatty Liver Disease: The Kangbuk Samsung Health Study 

Cho Y, Chang Y, Ryu S, et al. Am J Gastroenterol 2023;118:1980–1988.

https://pubmed.ncbi.nlm.nih.gov/36940424/

In this retrospective study, the authors investigated the association between gestational diabetes mellitus (pGDM) and the development of NAFLD as assessed by liver ultrasonography. The authors found a 2-fold increased risk of developing moderate-to-severe NAFLD after about 4 years of follow-up. Diabetes and insulin resistance (Homeostatic Model Assessment for Insulin Resistance) each mediated <10% of the association between pGDM and overall NAFLD development. The authors conclude that gestational diabetes mellitus is an independent risk factor for NAFLD development.

CS-iCCA, A New Clinically Based Staging System for Intrahepatic Cholangiocarcinoma: Establishment and External Validation.

Lozada ME, Zhang N, Jin W et al Am J Gastroenterol 2023;118:2173–2183.

https://pubmed.ncbi.nlm.nih.gov/36940423/

The authors aimed to develop a staging system for both resectable and non-resectable cases of intrahepatic cholangiocarcinoma (iCCA) based on clinical variables ascertained at the time of diagnosis, with the aim to provide a tool to stratify non-surgical participants in clinical trials. The study included used a derivation cohort of 436 patients and a validation cohort of 249 patients. Univariate Cox proportional hazards analysis was performed to identify prognostic predictors of all-cause mortality. The proposed Clinical Staging for iCCA (CS-iCCA) uses nonhistopathologic patient and tumor characteristics including ECOG PS, albumin and CA 19-9 levels, tumor multiplicity, tumor diameter, and regional or distant metastasis to allocate patients into 1 of 4 stages.

American Journal of Surgical Pathology

Genomic Analysis in the Categorization of Poorly Differentiated Primary Liver Carcinomas

Kikuchi AT, Umetsu S, Joseph N, et al. Am J Surg Pathol. (2023) 47(11):1207-1218.

https://pubmed.ncbi.nlm.nih.gov/37661782/

In this retrospective study, the authors evaluated the role of genomic analysis to characterize poorly differentiated primary liver carcinoma. Molecular testing of 16 cases included a capture-based next-generation sequencing assay targeting all coding regions of 529 cancer-related genes and the TERT promoter and PCR amplification of the IDH1 gene. The paper neatly outlines the morphologic and immunohistochemical findings in each tumor, as well as the subsequent genomic alterations and final diagnosis. The authors were able to use the addition of genomic analysis to support either HCC or iCCA in 14 (88%) of the originally unclassified tumors. These included 9 tumors finally classified as HCC due to the presence of TERT promoter mutations with or without concurrent TP53 mutations, and 5 tumors classified as iCCA because of IDH1, FGFR2, BAP1, PBRM1, or ERBB2 mutations. The authors conclude that genomic testing in these ambiguous cases may be helpful to determine surgical approach and chemotherapeutic regimen.  

Clinical Gastroenterology and Hepatology

aMAP Score and Its Combination With Liver Stiffness Measurement Accurately Assess Liver Fibrosis in Chronic Hepatitis B Patients

Fan R, Li G, Yu N, et al. Clin Gastroenterol Hepatol. 2023 Nov;21(12):3070-3079.e13.

https://pubmed.ncbi.nlm.nih.gov/36933605/

This study evaluated the utility of the noninvasive age-male-albumin-bilirubin-platelets (aMAP) score to diagnose advanced fibrosis and cirrhosis. Using a cohort of chronic hepatitis B (CHB) patients, the authors compared the aMAP score along with other measures to paired liver biopsies taken before and after CHB treatment. The aMAP score is comparable to other currently used noninvasive methods (fibrosis index based on 4 factors (FIB-4) and aspartate aminotransferase-platelet ratio (APRI)). Combination with liver stiffness measurement (LSM) further improved performance and could diagnose advanced fibrosis and cirrhosis in CHB patients with satisfactory accuracy (approximately 80%). The authors estimate that application of aMAP and LSM could decrease the need for liver biopsy to diagnosis cirrhosis in CHB patients by approximately 70%.

Gastroenterology

Deep Learning-Enabled Diagnosis of Liver Adenocarcinoma

Albrecht T, Rossberg A, Albrecht JD, et al. Gastroenterology. 2023 Nov;165(5):1262-1275.

https://pubmed.ncbi.nlm.nih.gov/37562657/

The study authors evaluated the accuracy of a deep learning model (HEPNET) in distinguishing intrahepatic cholangiocarcinoma from colorectal liver metastasis using H&E-stained whole-slide images. HEPNET was trained on over 7000,000 image tiles from 456 patients who underwent either surgical resection or biopsy. HEPNET achieved an accuracy of 98% (95% CI, 96.907%-100.000%), surpassing the performance of resident and senior pathologists. The authors contend that this tool has the potential to support routine diagnostic pathology workflow in the discrimination between metastatic colorectal adenocarcinoma and intrahepatic cholangiocarcinoma.

Gut

From clinical variables to multiomics analysis: a margin morphology-based gross classification system for hepatocellular carcinoma stratification.

Fan Z, Jin M, Zhang L, et al. Gut. 2023; 72:2149–2163.

https://pubmed.ncbi.nlm.nih.gov/37549980/

The authors investigated the molecular and pathological characteristics as well as prognosis among different gross subtypes of HCC. The authors define a margin morphology classification (MMC) system (type I: single nodule with distinct margin, type II: single nodule with extranodular growth, type III: a unifocal lesion composed of confluent multiple nodules and type IV: infiltrative nodule). Types II and III HCC were demonstrated to have worse overall and recurrence-free survival than type I, while type IV HCC presented the worst prognosis. Histopathological features including vascular invasion, micrometastasis or tumor size increased in severity in the order of type I, type II/III to type IV. Type IV HCC presented with the highest frequency of TP53 mutations and molecular features reminiscent of the recently identified ICC-like subtype. The authors proposed that gross classification, which can be easily obtained by radiological examinations, can serve as a foundation for refined stratified management of HCC.

Global prevalence of non-alcoholic fatty liver disease in type 2 diabetes mellitus: an updated systematic review and meta-analysis.

En Li Cho E, Ang CZ, Quek J, et al. Gut  2023; 72: 2138–2148.          

https://pubmed.ncbi.nlm.nih.gov/37491159/

This systematic review and meta-analysis aimed to quantify the prevalence of NAFLD and advanced fibrosis in people with T2DM. A total of 156 studies were included from MEDLINE and Embase database search. The prevalence rates of NAFLD, significant fibrosis and advanced fibrosis in T2DM were 65%, 36% and 15%, respectively. This study highlights the association between NAFLD, fibrosis and T2DM and underscores the need for improved surveillance strategies and therapies for people with T2DM and NAFLD.

Quest for immunological biomarkers in the management of CHB patients.

Bertoletti A, Le Bert N. Gut 2023;72:2012–2014.

https://pubmed.ncbi.nlm.nih.gov/36922017/

In this correspondence, the authors discuss the use of immunological biomarkers in the clinical management of patients with chronic HBV infection (CHB), including when to start or stop nucleos(t)ide analogue (NA) therapy, and/or to identify patients who would benefit from novel therapeutic strategies designed to modify host–virus interaction. The authors discuss the utility of phenotypic analysis of total circulating CD8T cells which can predict HBV-specific CD8 T cell response to immuno-modulatory compounds.

Clinical care pathway to detect advanced liver disease in patients with type 2 diabetes through automated fibrosis score calculation and electronic reminder messages: a randomised controlled trial.

Zhang X, Yip TC-F, Wong GL-H, et al. Gut 2023;72:2364–2371.

https://pubmed.ncbi.nlm.nih.gov/37549979/

As the majority of patients with NAFLD and metabolic risk factors are seen in primary care and non-hepatology settings, the authors developed a care model based on automated fibrosis score calculation and electronic reminder messages in patients with type 2 diabetes in order to increase the detection of advanced liver disease in patients with type 2 diabetes. The care model increased referral to hepatologists or further specific liver assessments for liver fibrosis within 1 year of the baseline visit (33.3% patients with increased fibrosis scores in the intervention group compared to 3.1%patients in the control group); however, less than 20% of patients with abnormal fibrosis scores were confirmed to have advanced liver fibrosis.

Hepatology

Progression of liver disease and portal hypertension in dyskeratosis congenita and related telomere biology disorders

Vittal A, Niewisch MR, Bhala S, et al. Hepatology. 2023 Dec 1;78(6):1777-1787.

https://pubmed.ncbi.nlm.nih.gov/37184208/

Dyskeratosis congenita and related telomere disorders is a group of premature aging disorders whose common underpinning is short telomeres. About 5-10% of patients have some form of liver disease. In this longitudinal cohort study, all patients with dyskeratosis congenita/telomere biology disorders who were evaluated at the NIH Clinical Center between January 2002 and November 2019 were assessed for liver disease and liver-related complications. In total 58 patients were included, 42 of whom (72.4%) had either elevated liver enzymes or imaging abnormalities (18 had liver enzyme abnormalities [9 cholestatic, 4 hepatocellular, 5 mixed]; 34 patients had heterogeneous coarsened liver echotexture or increased echogenicity). During 8 years of follow up, 10 patients had an MRI of the liver: 4 had advanced fibrosis or cirrhosis; 2 had hemosiderosis. Ten patients developed portal hypertension, which was associated with a history of vascular disease. Histology was available for 11 patients, 4 of whom had stage 1 fibrosis, 1 had cirrhosis, and 2 hemosiderosis. One patient died, and the autopsy showed obliterative portal venopathy and NRH. Two liver explants showed NRH. Of the 23 patients who died during follow up, 3 (13%) were attributed to liver disease.

Antiviral therapy substantially reduces HCC risk in patients with chronic hepatitis B infection in the indeterminate phase.

Huang DQ, Tran A, Yeh ML, et al. Hepatology. 2023 Nov 1;78(5):1558-1568.

https://pubmed.ncbi.nlm.nih.gov/37184202/

Hepatitis B is a leading cause of HCC worldwide. Simplistically, chronic HBV infection is often classified as immune-tolerant, immune-active, and inactive; however, patients who do not meet criteria for any of the defined stages are described as being in indeterminate phase. It is well known that treating patients with antiviral therapy in the immune-active phase reduces risk of HCC. In this retrospective study, the authors study a large cohort of patients in indeterminate phase HBV infection based on ALT level, HBV DNA quantification, and HBeAg status. Patients with co-infection with HCV/HIV, cirrhosis, other malignancy, HCC within 6 months of follow up, or liver transplant were excluded. In total 855 patients met inclusion criteria, including 405 treated and 450 untreated patients. Ultimately, the 5-, 10-, and 15-year HCC incidence was 2.5%, 3.9%, and 9.4% among the antiviral-treated patients compared with 2.7%, 14.7%, and 19.1% among untreated patients. Treatment with antiviral therapy was associated with reduced risk of HCC (HR=0.4) whereas male sex, age > 45 years, and positive HBeAg were associated with increased risk. In summary, in this multi-institutional study, antiviral therapy was associated with a 70% reduction in the incidence of HCC.

A multisociety Delphi consensus statement on new fatty liver disease nomenclature.

Rinella MR, Lazarus JV, Ratziu V, et al. Hepatology 2023;78:1966-1986.

https://pubmed.ncbi.nlm.nih.gov/37364816/

The terms for fatty liver disease have received increased scrutiny for a variety of reasons, including the fact that the term “nonalcoholic” does not describe etiology of disease, and several of the terms such as “fatty” are stigmatizing. This paper describes a multi-stakeholder modified Delphi survey under the auspices of AASLD, EASL, and the Asociacion Latinoamericana para el Estudio del Higado (ALEH), in which participants from multiple specialties arrive at consensus terminology for fatty liver disease. To summarize, the over-arching term Steatotic Liver Disease (SLD) replaces Fatty Liver disease. Under SLD, patients who meet cardiometabolic criteria are described as having Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) or, if they have steatohepatitis, Metabolic Dysfunction-Associated Steatohepatitis (MASH). Patients whose liver disease is related to alcohol are classified as Alcohol-Associated Liver disease (ALD). Patients who have features of both metabolic and alcohol related liver disease are described as “MASLD and increased alcohol intake” (MetALD); their disease may be MASLD predominant or ALD predominant, and that might change over time. Patients with specific etiologies for liver disease are classified according to the disease, which may be particularly relevant for the pediatric population with monogenic diseases and patients with DILI. Finally, cryptogenic SLD describes patients whose SLD is of uncertain etiology.

Histopathology

Metallothionein: a game changer in histopathological diagnosis of Wilson disease

Wiethoff H, Mohr I, Fichtner A, et al. Histopathology. 2023 Dec;83(6):936-948.

https://pubmed.ncbi.nlm.nih.gov/37661783/

In this study, metallothionein (MT) immunohistochemistry was proposed as a diagnostic marker for Wilson disease (WD).  MT immunohistochemistry was performed on liver specimens of WD patients (n = 64) and control cases (n = 160) including acute liver failure, steatotic liver disease, autoimmune hepatitis, normal liver, primary biliary cholangitis, primary and secondary sclerosing cholangitis, and progressive familial intrahepatic cholestasis.  At least moderate staining in >50% of hepatocytes was observed in 81% of analyzed liver specimens (n = 56/69) of WD patients. Some control cases showed periportal (27/160), periseptal (34/160), or perivenular (31/160) staining, but only five control cases showed moderate staining in >50% of hepatocytes. The sensitivity, specificity, and accuracy for a new diagnosis of WD were 85.7%, 96.9%, and 94.9%, respectively. Sensitivity in nonfibrotic patients was 70.6% and this MT pattern was robust in small biopsies. The hepatic copper concentration was similar between WD patients with MT-positive and MT-negative liver samples (P > 0.05). Zinc treatment may induce hepatocellular MT expression. Kayser-Fleischer rings (50% versus 15%) and neurologic disorders (50% versus 13%) were significantly more prevalent in MT-negative compared to MT-positive WD patients, respectively.

Human Pathology

Hepatic graft-versus-host disease: what we know, when to biopsy, and how to diagnose.

Stueck AE, Fiel MI. Hum Pathol. 2023 Nov;141:170-182.

https://pubmed.ncbi.nlm.nih.gov/37541449/

In this detailed review of hepatic graft-versus-host disease (hGVHD), the authors describe the pathogenesis, clinical, laboratory, imaging, and histopathologic features of acute and chronic GVHD. While the historical definition of acute GVHD defines the disease as arising in the first 100 days post-transplant, and chronic GVHD occurring greater than 100 days post-transplant, there are newer criteria that integrate clinical, laboratory and histopathologic characteristics. Both acute and chronic GVHD present with elevated bilirubin and ALP, but an acute hepatitis form should also be recognized, and tissue biopsies are more frequently performed in this setting. There is currently no standardized histologic grading scheme for acute and chronic hGVHD, and the pathologic changes do not correspond to clinical time-based criteria for acute and chronic hGVHD; however, there are two recognized histologic patterns, hepatitic and classical. Features of classical hGVHD include injury to the interlobular bile ducts (ex. withering, luminal debris, irregular contours, epithelial cell swelling and vacuolization) while the hepatitic pattern displays lobular disarray, hepatocellular necrosis and variable endothelialitis. The features can be further studied in this excellent review.

Ancillary tests for hepatobiliary neoplasms: what we know and what we need to know.

Zhang SL, Wang HL. Hum Pathol. 2023 Nov;141:183-200.

https://pubmed.ncbi.nlm.nih.gov/36775105/

The authors of this comprehensive review discuss the utility of established and emerging immunohistochemical stains in differentiating between hepatocellular neoplasms (ie. well differentiated hepatocellular carcinoma, hepatocellular adenoma, high grade dysplastic nodule). An overview of the molecular and immunophenotypic characterization of hepatocellular adenomas is also provided. Then the authors discuss the utility of a 3-marker panel (IMP3, S100P, SMAD4) for differentiating benign/reactive from malignant bile ducts and for challenging pancreas biopsies. Optimal immunostain panels are provided for detecting cell of origin in metastatic neoplasms. Finally, the utility of therapeutic/prognostic biomarkers (ex. MMR, PD-1, HER2) for hepatobiliary carcinomas is described.

Liver fibrosis: the good, the bad, and the patchy-an update

Guindi M. Hum Pathol. 2023 Nov;141:201-211.

https://pubmed.ncbi.nlm.nih.gov/36702358/

In this comprehensive review of hepatic fibrosis, Guindi discusses the historical evolution of fibrosis staging systems (including systems that address the severity of cirrhosis), the histologic features of fibrosis regression, and staging schemes that incorporate fibrosis regression. The article discusses the challenging area of assessing fibrosis in congestive liver disease and provides valuable recommendations on fibrosis reporting.

Fatty liver disease that is neither metabolic nor alcoholic

Allende DS, Kleiner DE. Hum Pathol. 2023 Nov;141:212-221.

https://pubmed.ncbi.nlm.nih.gov/36702356/

The classic risk factors of obesity, metabolic syndrome, dyslipidemia, and diabetes for nonalcoholic fatty liver disease (now referred to as metabolic dysfunction-associated steatotic liver disease) have been well-defined. However, this review draws important attention to a broad spectrum of underlying diseases (genetic, drug-mediated, and immune mediated) that can also result in steatosis and identical features of steatohepatitis.

Focal nodular hyperplasia-like nodules arising in the setting of hepatic vascular disorders with portosystemic shunting show β-catenin activation

Umetsu SE, Joseph NM, Cho SJ, et al. Hum Pathol. 2023 Dec;142:20-26.

https://pubmed.ncbi.nlm.nih.gov/37806391/

Hepatocellular nodules such as focal nodular hyperplasia (FNH) are well-known to arise in a background of vascular flow alterations in the liver but can be difficult to accurately define by imaging studies alone. The detailed pathologic and molecular characteristics of hepatocellular nodules that develop in the clinical setting of surgical portosystemic shunts and Abernethy malformation (also referred to as extrahepatic congenital portosystemic shunt) have not been well-characterized. This study examines hepatocellular nodules in 6 patients with portosystemic shunts (5 patients with Abernethy malformation and 1 patient with tetralogy of Fallot) ranging in age from 9 to 30 years. The number of nodules in each patient varied from 1 to over 70, and most were categorized as FNH-like lesions (features suggestive of FNH, but lacking map-like glutamine synthetase (GS) staining), followed by hepatocellular adenoma. Interestingly, the authors found that 6 FNH-like nodules showed diffuse patterns of GS staining without cytologic atypia or reticulin loss, and 4 of 4 of these cases tested for molecular alterations harbored CTNNB1 mutations. Thus, FNH-like lesions arising in the setting of surgical portosystemic shunts or Abernethy malformation have malignant potential. As a result, GS and B-catenin stains should be performed to evaluate for evidence of an atypical hepatocellular neoplasm with B-catenin activation, and sequencing analysis for CTNNB1 mutations should be done when the GS staining pattern is diffuse heterogeneous or indeterminate.

Prepared by:
Dana Balitzer, MD (Editor); 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

Joseph Misdraji, MD; Yale School of Medicine

Meredith Pittman, MD; Maimonides Medical Center

Daniel Roberts, MD; Cleveland Clinic

Lindsey Westbrook, MD; University of Colorado

Xuefeng Zhang, MD; Cleveland Clinic