HPHS Journal Watch:  July/Aug 2023

American Journal of Clinical Pathology

Histologic and Clinical Outcomes of Patients Developing Post-Liver Transplant Plasma Cell-Rich Rejection

Ozturk NB, Schiano TD, Fiel MI. Am J Clin Pathol. 2023 July 5;160(1):49-57.


In this study, the authors present the histologic and clinical outcomes of patients who develop post-liver transplant plasma cell-rich rejection (PCRR) and evaluate the possibility that PCRR falls within the spectrum of antibody-mediated rejection (AMR) using immunohistochemical staining for C4d and correlation with donor-specific antibodies (DSA), in a single institution cohort spanning years 2000-2020. A total of 35 patients (all >18 years of age) were included in the study, all of whom developed PCRR and had at least one follow-up biopsy. All biopsies were performed for-cause. 40% of patients developed PCRR within 2 years of liver transplant, with most (65.7%) having at least one episode of T-cell-mediated rejection prior to the diagnosis of PCRR. Most (68.5%) had negative outcomes, with progression to cirrhosis or chronic ductopenic-type rejection (CDR). 10 patients required re-transplant (6 with cirrhosis, 3 with CDR, 1 with PCRR alone). Of those who developed cirrhosis (n=13), 4 patients died due to allograft failure (all with original diagnosis of HCV), 3 of whom had been re-transplanted prior to death. Of those who developed CDR (n=11), 4 died due to allograft failure (1 patient each with original diagnosis of HCV, PSC, sarcoidosis (re-transplanted), and drug-induced liver injury). Patients originally transplanted for HCV were more likely to develop cirrhosis versus CDR after a diagnosis of PCRR and those who developed cirrhosis were more likely to need re-transplant or died than those with PCRR alone. Thus, development of PCRR was associated with negative outcomes in this study. DSAs were positive in 84% (n=19) and C4d immunostain was positive in 90% (n=10), supporting PCRR to be within the histologic spectrum of AMR.

American Journal of Gastroenterology

Exercise Training Is Associated With Treatment Response in Liver Fat Content by Magnetic Resonance Imaging Independent of Clinically Significant Body Weight Loss in Patients With Nonalcoholic Fatty Liver Disease: A Systematic Review and Meta-Analysis

Stine JG, DiJoseph K, Pattison Z, et al. Am J Gastroenterol. 2023 Jul 1;118(7):1204-1213. 


Exercise training is crucial in non-alcoholic fatty liver disease management; however, whether it can achieve clinically meaningful improvement in liver fat is unclear, especially without modest weight loss. The authors investigated the association between exercise training and the achievement of validated thresholds of MRI-measured treatment response. The study is essentially a systematic review and meta-analysis to assess the evidence for MRI-measured liver reduction in response to exercise training, including whether a ≥30% relative reduction can be achieved across different doses of exercise. Exercise training subjects were more likely to achieve ≥30% relative reduction in MRI-measured liver fat (odds ratio 3.51, 95% confidence interval 1.49–8.23, P 5 0.004) than those in the control condition. An exercise dose of ≥750 metabolic equivalents of task min/wk (e.g., 150 min/wk of brisk walking) resulted in significant treatment response (MRI response odds ratio 3.73, 95% confidence interval 1.34–10.41, P 5 0.010), but lesser doses of exercise did not. The treatment response was independent of clinically significant body weight loss (>5%). The results provide further support the benefit of prescribing exercise as medicine to all patients with NAFLD, including those with NASH who are most in need of disease-modifying therapies.

American Journal of Surgical Pathology

Unique Morphologic Findings in the Liver After Stereotactic Radiation Cholangiocarcinoma

Soon GST, Yasir S, Wu TT, et al. Am J Surg Pathol. 2023 Jul 1;47(7):792-800.


The purpose of the study was to better characterize morphologic changes to the liver after stereotactic radiotherapy.  To that end, the authors identified 21 patients with hilar cholangiocarcinoma treated with chemotherapy and radiation who ultimately underwent liver transplantation. Sections of radiated liver adjacent to the tumor bed and background, non-targeted liver parenchyma were selected for analysis. The authors found that sinusoidal congestion and edema, hepatocellular atrophy or drop-out, and partial/complete occlusion of central veins were the most common histologic features in the irradiated liver. In most cases (86%) these features were limited to the irradiated area, which was well circumscribed.

Spectrum of Liver Pathology in Dyskeratosis Congenita

Putra J, Agarwal S, Al-Ibraheemi A, et al. Am J Surg Pathol. 2023 Aug 1;47(8):869-877.


The authors of this study report on the heterogeneous liver histology present in patients with dyskeratosis congenita (DC). DC is a rare heritable disorder in which affected patients have shortened germline telomeres. The diagnostic triad consists of abnormal nails, reticular skin pigmentation, and oral leukoplakia. Bone marrow failure is also common, including anaplastic anemia and MDS. Liver disorders are much less common. In the eleven patients with liver tissue for review in this study, the findings were nonspecific and included nodular regenerative hyperplasia, chronic passive congestion, and sinusoidal fibrosis.

Archives of Pathology & Laboratory Medicine

Liver Explants of Biliary Atresia Patients Transplanted in Adulthood Show Features of Obliterative Portal Venopathy: Case Series and Guidelines for Pathologic Reporting of Adult Explants

Patel KR, Sadhna D, Goss J. Arch Pathol Lab Med. 2023 Aug 1;147(8):925-932.


This study describes three patients diagnosed with biliary atresia as children and treated with a successful Kasai portoenterostomy, followed by liver transplantation in adulthood. Despite transplants occurring after age 25 for all three, each patient had experienced complications from portal hypertension beginning in childhood. The three explant livers showed heterogeneous pathology, with one having diffuse biliary cirrhosis and severe cholestasis, while another had portal fibrous expansion (stage 1-2). The livers were similar, however, in the changes found in the intra- and extrahepatic portal veins. The portal venous system showed intimal fibromyxoid hyperplasia, variable luminal occlusion, evidence of recanalization, and arterialization. The authors hypothesize that the obliterative portal venopathy may be a driving cause for portal hypertension and the need for adult transplantation after a successful childhood Kasai procedure.

Clinical Gastroenterology and Hepatology

Pathophysiology of Hepatorenal Syndrome – Acute Kidney Injury

Adebayo D, Wong F. Clin Gastroenterol Hepatol. 2023 Sep;21(10S):S1-S10. 


This review article reviews the pathophysiology and pathogenesis of hepatorenal syndrome–acute kidney injury (HRS-AKI) in decompensated cirrhosis. Relevant discussion to liver pathologists includes the inflammatory cascade in portal hypertension and cirrhotic cardiomyopathy. The authors discuss future developments in metabolomics and treatment strategies.  

Contemporary Changes in Etiology for Hepatocellular Carcinoma in Liver Transplantation 

Goff C, Shaikh A, Goli K, et al; Liver Cancer Investigator Working Group. Clin Gastroenterol Hepatol. 2023 Aug;21(9):2410-2412.e1. 


This retrospective study utilized data from the United Network for Organ Sharing transplant registry and evaluated changes in etiology of hepatocellular carcinoma (HCC) in patients undergoing liver transplantation. The authors found an overall decrease in liver transplantation between 2015 to 2021, with an increase in alcohol-related liver disease (ARLD) and NASH-related HCC in patients undergoing liver transplantation. Transplantation due to HCV-related HCC declined by 50% over 5 years likely related to availability of DAA therapy and stricter inclusion criteria for HCC MELD. 

Artificial Intelligence Applications in Hepatology 

Schattenberg JM, Chalasani N, Alkhouri N. Clin Gastroenterol Hepatol. 2023 Jul;21(8):2015-2025. 


This review article discusses the implementation of AI models in various hepatology applications including liver imaging, interpretation of liver histopathology, noninvasive tests, and prediction models. In one section, the authors review use of AI in the diagnosis of NASH, including the quantitative measurement of macrosteatosis, ballooning, inflammation, and fibrosis. The paper also discusses the development of an AI-based Deep Learning Treatment Assessment (DELTA) Liver Fibrosis score which showed correlation with other noninvasive fibrosis markers, such as the enhanced liver fibrosis score and liver stiffness by transient elastography, as well as an ML score to predict hepatic vein pressure gradient (ML-HVPG score).


Fibrosis Progression Rate in Biopsy-Proven Nonalcoholic Fatty Liver Disease Among People With Diabetes Versus People Without Diabetes: A Multicenter Study 

Huang DQ, Wilson LA, Behling C, et al. Gastroenterology. 2023 Aug;165(2):463-472.e5. 


The authors of this multi-institutional study evaluated how fibrosis in steatohepatitis progresses in patients with and without type 2 diabetes mellitus (T2DM). A total of 447 participants (208 with T2DM, and 239 without T2DM) from eight sites across the United States were included. Each participant had liver biopsies performed at baseline and at time points determined clinically. The authors found that participants with T2DM had a faster progression of fibrosis than those without diabetes. The 4-year (24% vs. 20%), 8-year (60% vs. 50%), and 12-year (93% vs. 76%) cumulative incidences of fibrosis progression were significantly higher in participants with T2DM compared to those without the disease.


Diagnostic accuracy of FibroScan-AST (FAST) score for the non-invasive identification of patients with fibrotic non-alcoholic steatohepatitis: a systematic review and meta-analysis

Ravaioli F, Dajti E, Mantovani A, et al. Gut. 2023 Jul;72(7):1399-1409. doi: 10.1136/gutjnl-2022-328689.


In 2020, Newsome et al developed a simple score that combined FibroScan, controlled attenuation parameter (CAP), and serum aspartate aminotransferase (AST) level, which was designated as FibroScan-AST(FAST) score, to non-invasively identify those patients who have NASH with elevated NAFLD Activity Score (NAS ≥4) and advanced fibrosis (stage 2 or higher (F≥2)). The authors performed a systematic review and meta-analysis of published studies between 3 February 2020 and 30 April 2022 and that the FAST score has good performance for non-invasive diagnosis of fibrotic NASH. Therefore, this score can be used to efficiently identify patients who should be referred for a conclusive liver biopsy and/or consideration of treatment with emerging pharmacotherapies. 

Isoformic PD-1-mediated immunosuppression underlies resistance to PD-1 blockade in hepatocellular carcinoma patients

Tan Z, Chiu MS, Yang X, et al. Gut. 2023 Aug;72(8):1568-1580


Here, the author elucidated the role of a programmed cell death protein 1 (PD-1) isoform,

Δ42PD-1, in HCC progression and resistance to nivolumab Immune Checkpoint blockade (ICB) by investigating 74 HCC patients in three cohorts, including 41 untreated, 28 treated with nivolumab, and five treated with pembrolizumab. The study implies that Δ42PD-1 may serve as a novel drug target against HCC or other relevant cancers and may warrant the clinical development of a humanized anti- Δ42PD-1 antibody for treatment against HCC and other Δ42PD-1-mediated cancers.


Lean Individuals with NAFLD have more severe liver disease and poorer clinical outcomes (NASH-CO study)

Nabi O, Lapidus N, Boursier J, et al. Hepatology 2023;78:272-283.


There has been much information on patients with lean NAFLD, and how they compare to both healthy individuals and to obese patients with NAFLD. In this longitudinal study, the authors used data from the Constances (French population) cohort between 2012 and 2019. The presence of NAFLD was determined by the fatty liver index (FLI), which describes the likelihood of a subject having fatty liver, rather than histology or radiology. The Forns Index (FI) was used as a surrogate marker of liver fibrosis. Patients with a history of excess alcohol use or viral hepatitis were excluded.  From this cohort, 25,753 patients had NAFLD, including 3664 with lean NAFLD. The prevalence of NAFLD in lean, overweight, and obese subjects was 5.3%, 28.5%, and 79.2%, respectively, but the prevalence of NAFLD in lean subjects increased in patients with metabolic risk factors (reaching 25.1% in those with type 2 diabetes). Compared to patients with non-lean NAFLD, patients with lean NAFLD more often had elevated ALT (34.3% vs. 21%) and advanced fibrosis (3.6% vs. 1.7%).  Patients with lean NAFLD had a significantly increased risk of liver-related events (hazard ratio 5.84) and mortality (HR=3.01). These parameters were more pronounced among patients with advanced fibrosis.  On multivariate analysis, lean status was associated with advanced fibrosis, independent of demographics, risk factors, and lifestyle; this is in contrast to data from biopsy-proven NAFLD patients. The authors conclude that screening for NAFLD in lean subjects should target patients with metabolic abnormalities and that given the relatively poor prognosis, they should be encouraged to join clinical trials.

Hepatology Communications

A gut bacterial signature in blood and liver tissue characterizes cirrhosis and hepatocellular carcinoma  

Effenberger M, Waschina S, Bronowski C, et al. Hepatol Commun. 2023 Jun 14;7(7):e00182.  


The authors of this study profiled the microbiome of patients with HCC by 16S rRNA sequencing and compared profiles to nonmalignant cirrhotic and noncirrhotic NAFLD patients to evaluate the role of dysbiosis in disease progression. The authors performed real-time PCR amplification using 16S universal primers on feces, blood, and liver tissue from patients with noncirrhotic NAFLD (n = 21), cirrhosis of various etiologies (n = 27), and HCC (n = 111) patients. The authors demonstrate a gradual increase in host-microbe perturbation in patients with cirrhosis and HCC (compared to NAFLD). 

Human Pathology

The role of routine biopsy of the background liver in the management of hepatocellular carcinoma

Lee S, Ahmed M, Taddei T, Jain D. Hum Pathol. 2023 Aug;138:18-23. 


The diagnosis of hepatocellular carcinoma (HCC) often does not rely on tissue biopsy given characteristic features on imaging studies. In contrast, the features of the non-tumoral background liver can be more difficult to assess by imaging studies alone, and yet are important in guiding surgical management of HCC. The authors of this retrospective study included 104 patients with HCC who had a paired biopsy of background liver in addition to a biopsy of the tumor. This study shows that biopsies of background liver can reveal clinically unsuspected cirrhosis and disprove clinical suspicion of cirrhosis. In the study cohort, 40.0% of patients who had uncertain cirrhosis status were confirmed to have cirrhosis on biopsy, and suspected cirrhosis was disproven in 4 patients due to biopsy findings; one patient who was not clinically suspected of having advanced liver disease was found to have stage 3 fibrosis. Overall, treatment was altered in 5% of the study patients due to the findings in the background liver on biopsy. 

Clinicopathologic characterization of hepatocellular adenomas in men: a multicenter experience

González IA, Torbenson M, Sharifai N, et al. Hum Pathol. 2023 Aug;138:24-33. 


Hepatocellular adenomas (HCAs) are typically diagnosed in reproductive-age female patients and are rare in men. This study examines the clinical and pathologic features of a cohort of 27 HCAs in men across multiple institutions. The most common HCA subtype identified was inflammatory HCA (IHCA; 10 cases, 37.0%) followed by unclassified HCA (UHCA; 7 cases, 25.9%), HNF1A-inactivated HCA (H-HCA; 6 cases, 22.2%), β-catenin-activated IHCA (b-IHCA; 3 cases, 11.1%), and β-catenin-activated HCA (b-HCA; 1 case, 3.7%). The authors also evaluated 6 cases diagnosed as hepatocellular neoplasm of uncertain malignant potential (HUMP). Overall, 15% of cases in the cohort of HCA and HUMP showed concomitant HCC, while none of the 7 biopsy cases showed any malignant transformation on follow-up (range, 22-160 months; mean, 61.8 months). The significance of androgen receptor immunohistochemistry in the lesions is also described.

Liver Transplantation

Development and validation of a REcurrent Liver cAncer Prediction ScorE (RELAPSE) following liver transplantation in patients with hepatocellular carcinoma: Analysis of the US Multicenter HCC Transplant Consortium

Tran BV, Moris D, Markovic D, et al. Liver Transpl. 2023 Jul 1;29(7):683-697.


HCC recurrence following liver transplantation (LT) is highly morbid and occurs despite strict patient selection criteria. Based on the clinicoradiologic and pathologic data of 4981 patients with HCC undergoing LT, the US Multicenter HCC Transplant Consortium (UMHTC) developed a REcurrent Liver cAncer Prediction ScorE (RELAPSE). Overall and recurrence-free survival at 1, 3, and 5 years was 89.7%, 78.6%, and 69.8% and 86.8%, 74.9%, and 66.7%, respectively, with a 5-year incidence of HCC recurrence of 12.5% (median 16 months) and non-HCC mortality of 20.8%. A multivariable model identified maximum alpha-fetoprotein (HR = 1.35 per-log SD, 95% CI,1.22-1.50, p < 0.001), neutrophil-lymphocyte ratio (HR = 1.16 per-log SD, 95% CI,1.04-1.28, p < 0.006), pathologic maximum tumor diameter (HR = 1.53 per-log SD, 95% CI, 1.35-1.73, p < 0.001), microvascular (HR = 2.37, 95%-CI, 1.87-2.99, p < 0.001) and macrovascular (HR = 3.38, 95% CI, 2.41-4.75, p < 0.001) invasion, and tumor differentiation (moderate HR = 1.75, 95% CI, 1.29-2.37, p < 0.001; poor HR = 2.62, 95% CI, 1.54-3.32, p < 0.001) as independent variables predicting post-LT HCC recurrence (C-statistic = 0.78). Machine learning algorithms incorporating additional covariates improved prediction of recurrence (Random Survival Forest C-statistic = 0.81).  RELAPSE was externally validated in 1160 HCC LT recipients from the European Hepatocellular Cancer Liver Transplant study group.  Despite significant differences in European Hepatocellular Cancer Liver Transplant recipient radiologic, treatment, and pathologic characteristics, external validation of RELAPSE demonstrated consistent 2- and 5-year recurrence risk discrimination (AUCs 0.77 and 0.75, respectively).

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

Joseph Misdraji, MD; Yale School of Medicine

Meredith Pittman, MD; Maimonides Medical Center

Daniel Roberts, MD; Cleveland Clinic

Xuefeng Zhang, MD; Cleveland Clinic

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