HPHS JOURNAL WATCH:  March/April 2023

American Journal of Clinical Pathology

Late-Onset Rejection in Liver Allograft Biopsies: An Analysis of Process, Pattern, and Clinical Implications

Bateman J, Anugwom C, Zhou Y, et al. Am J Clin Pathol. 2023 Mar 13; 159(3):283-292.


In this study, the authors present the histopathologic spectrum and clinical features of late-onset (defined >6 months post-transplant) rejection (LOR) in liver allograft biopsies in a single-institution cohort of 160 patients (122 adults, 38 children) seen between 2014 and 2019. Alloimmune forms of rejection included acute cellular rejection (typical and atypical (plasma cell-rich rejection, isolated central perivenulitis, nonspecific hepatitis, and sinusoidal)) while nonalloimmune forms included recurrent liver disease, de novo liver disease, vascular injury, or biliary tract disease. 233 total liver biopsies (all for-cause) were reviewed, with 123 (53%) showing some form of LOR: typical ACR 22%, atypical ACR 21% (nonspecific hepatitis 10%, plasma cell-rich rejection 8%, isolated central perivenulitis 1%, and sinusoidal 1%). Ductopenic rejection was seen in 10% and was associated with the highest rate of graft failure; rates of graft failure were otherwise similar between typical and atypical ACR as well as between alloimmune and nonalloimmune liver injury groups. Overall, 14% of patients progressed to graft failure (20 adults, 2 pediatric). Advanced fibrosis was present with similar frequency between the LOR and nonalloimmune groups and highest in biopsies with plasma cell-rich rejection. The overall incidence as well as response to treatment (as measured by changes in liver tests) was similar between typical ACR and other LORs. Biopsies from adults versus children showed overall similar rates of rejection, but atypical ACR was more frequently seen in children, including nonspecific hepatitis pattern.

Archives of Pathology & Laboratory Medicine

Uncommon Benign Neoplasms and Pseudotumors of the Liver

Assarzadegan N, Montgomery E. Arch Pathol Lab Med. 2023. April;147:390-402.


This review article, part of a series of “emerging topics in anatomic pathology” presented by the journal, covers a variety of hepatic lesions: segmental atrophy, IgG4-related sclerosing disease, Rosai-Dorfman disease, inflammatory pseudotumor-like follicular/fibroblastic dendritic cell sarcoma, syphilitic pseudotumor, echinococcosis, angiomyolipoma, mesenchymal hamartoma, and types of hemangioma.  With clear pictures and descriptions, the authors introduce these predominately non-epithelial lesions to remind pathologists to include them in the differential diagnosis of a sampled mass with unusual morphology.


Integrated Multi-Omics Landscape of Liver Metastases. Gastroenterology

Yang S, Qian L, Li Z, et al. Gastroenterology. 2023 Mar;164(3):407-423.e17.


Immunotherapy has emerged as an important component of comprehensive cancer therapy that includes surgery and chemoradiation. Immune checkpoint inhibitors have shown efficacy against some cancers; however, these therapies provide little to no benefit to patients with liver metastases. This study explored the immune microenvironment (T-cell characteristics) associated with a variety of primary liver tumors and tumor metastases to help identify potential immunomodulatory targets. The authors discovered 5 immune microenvironment subtypes in their evaluation of 100 liver metastases and 50 primary liver cancers using mass cytometry together with transcriptomic and whole-exome sequencing. One key molecule, SLC2A1, was identified that induced immune suppression and escape in both primary liver tumors and metastatic lesions. The authors suggest that targeting SLC2A1 and related signaling pathways could provide a systemic immunoregulatory strategy for liver metastases.


Liver stiffness thresholds to predict disease progression and clinical outcomes in bridging fibrosis and cirrhosis

Loomba R, Huang DQ, Sanyal AJ, et al. Gut. 2023 Mar;72(3):581-589.


The risk of liver-related mortality and decompensation in NASH increases in parallel with fibrosis stage. The histological staging of fibrosis is the reference standard but the liver biopsy is limited because of its invasive nature and associated with complications with sampling variability. The authors utilized data from two well-controlled recent phase three placebo-controlled trials of selonsertib, a selective inhibitor of apoptosis signal-regulating kinase 1 (ASK1), and two phase 2b placebo-controlled trials of simtuzumab, a humanized monoclonal antibody directed against lysyl oxidase-like 2. These studies are associated with the prospectively collected data with serial liver biopsies and provide a unique opportunity to study the association between baseline Liver stiffness (LS) by vibration-controlled transient elastography (VCTE)  and disease progression. The primary aim of this study was to establish thresholds of LS that prognosticate the risk of clinical outcomes in participants with bridging fibrosis and cirrhosis due to NASH. In this analysis of four large, randomized placebo-controlled trials of participants with NASH and biopsy-proven advanced fibrosis (F3–F4), clinical disease progression was associated with higher LS by VCTE at baseline. The optimal LS thresholds for predicting progression to cirrhosis among patients with bridging fibrosis (F3) and development of liver-related events among patients with cirrhosis were ≥16.6 kPa and ≥30.7 kPa, respectively. A ≥5 kPA (and ≥20%) increase in LS by VCTE was associated with an increased risk of progression to cirrhosis among participants with baseline bridging (F3) fibrosis. The LS thresholds identified in this study may be useful for risk stratification of patients with NASH in clinical trials and clinical practice and lend further support to the use of non-invasive surrogates rather than liver histology to predict the risk of clinically meaningful outcomes.

Novel microenvironment-based classification of intrahepatic cholangiocarcinoma with therapeutic implications

Martin-Serrano MA, Kepecs B, Torres-Martin M, et al. Gut. 2023 Apr;72(4):736-748.


Through virtual deconvolution of transcriptomic data from intrahepatic cholangiocarcinomas (iCCAs) and the subsequent creation of murine models, five tumor microenvironment (TME)-based classes (called stroma, tumor, immune microenvironment or STIM) of iCCA, encompassing both inflamed and non-inflamed profiles, were identified. This novel STIM classification provides insights into the rational design of therapeutic strategies targeting both the cancer cells and the surrounding TME, and the authors propose that it could be used for personalized treatment approaches using existing drugs.


Metabolic dysfunction-associated fatty liver disease and excessive alcohol consumption are both independent risk factors for mortality

van Kleef LA, de Knegt RJ, Brouwer WP. Hepatology. 2023 Mar 1;77(3):942-948.


Non-alcoholic fatty liver disease (NAFLD) refers to fatty liver disease in the absence of alcohol use, which refers largely to patients with metabolic syndrome but also to patients with fatty liver disease for myriad reasons other than alcohol. The recently introduced term metabolic dysfunction-associated fatty liver disease is a term for fatty liver disease specifically in patients with metabolic syndrome. Patients with MAFLD can also have other causes of fatty liver disease, including alcohol. Whether the prognosis of patients with MAFLD and concurrent excessive alcohol consumption is related to metabolic dysfunction or to alcohol abuse is unclear. In this study from the Netherlands, participants in the National Health and Nutrition Examination Survey (NHANES) were included if they had ultrasound evidence of steatosis and information on alcohol use.  Excessive alcohol use was defined using two thresholds (one more stringent). Patients were classified as having MAFLD if they met various metabolic criteria. 12,656 participants were included for analysis. MAFLD and excessive alcohol consumption were independently and simultaneously associated with increased mortality. MAFLD increased mortality in patients with and without excessive alcohol use. Using the more stringent threshold for alcohol use, the mortality risk for excess alcohol use was more pronounced whereas the effect of MAFLD was stable. The authors conclude that both MAFLD and excessive alcohol consumption contribute to increased mortality risk. The effect appeared to be additive rather than synergistic. The authors suggest that patients with both MAFLD and excessive alcohol use constitute a specific subgroup within MAFLD.

A shared mucosal gut microbiota signature in primary sclerosing cholangitis before and after liver transplantation

Hole MJ, Jørgensen KK, Holm K, et al. Hepatology. 2023 Mar 1;77(3):715-728.


Gut microbiota has been studied largely from fecal samples in patients with PSC; the most consistent finding is loss of intraindividual microbial diversity. Several taxa have also been associated with PSC, including Veillonella. There has been little data on microbiota in PSC patients with IBD, or on whether liver transplant normalizes the microbiota in these patients. The authors designed a study to explore the ileocolonic mucosal (rather than fecal) microbiota in non-transplanted and transplanted PSC patients to investigate the effect of liver transplant, concomitant IBD, and the relationship to disease severity. 84 PSC patients and 51 PSC-liver transplant (PSC-LT) patients who underwent ileocolonoscopy from 2005-2008 at Riskhospitalet in Oslo were included.  40 healthy controls were included. Mucosal biopsies were subjected to DNA extraction and tested by PCR using a DNA library targeting the hypervariable regions of the 16S rRNA. Results: Microbial diversity was reduced in PSC and PSC-LT compared to controls, but was similar between PSC and PSC-LT. Eight genera were increased in PSC/PSC-LT. In contrast, short-chain fatty acid producers were reduced in PSC/PSC-LT. PSC-IBD was significantly different from PSC without IBD, irrespective of LT status. Mucosal signatures overlapped between patients with PSC and recurrent PSC in the LT group. The authors conclude that 1. LT did not normalize the microbiota in PSC; 2. Concomitant IBD is associated with altered microbiota; 3. Five genera are associated with PSC, before and after LT; 4. The presence of Klebsiella was associated with worse outcomes in PSC. The findings suggest that liver disease is not the primary driver of reduced diversity and expansion of PSC-associated genera. The authors note that 2 of the 3 reduced genera in PSC are short-chain fatty acid producers and this may influence mucosal barrier and immune cell regulation in the gut. K. pneumoniae has been shown to impair the intestinal barrier and promote liver inflammation, explaining why its presence may be associated with reduced LT-free survival.

Hepatology Communications

A series of homeopathic remedies-related severe drug-induced liver injury from South India

Theruvath AH, Raveendran R, Philips CA, et al. Hepatol Commun. 2023 Feb 9;7(3):e0064.


This study identified 9 patients with liver injury attributed to homeopathic formulations. The authors excluded other potentially hepatotoxic agents, significant alcohol consumption, acute and chronic viral hepatitis, and classic autoimmune hepatitis. The most common presentation was acute hepatitis (n=5, 55.6%) with an absence of autoimmune hepatitis-related antibodies. Biopsies demonstrated necrosis including 60% with confluent/bridging necrosis. Toxicology analysis identified 156 unique compounds, including heavy metals, industrial solvents, alcohols, steroids, antimicrobials, sedatives, and bioactive plant compounds, such as diterpenes, isoquinolines, furanoids, terpenes, glycosides, and sterols, even in supposedly “ultra-diluted” formulations. The authors conclude that homeopathic remedies could play a central role in promoting severe liver injury.

Acute severe hepatitis as a presenting symptom in clinically stable patients admitted with SARS-CoV-2 Omicron infection

Swain LA, Ambasta A, Munhoz EP, et al. Hepatol Commun. 2023 Mar 30;7(4):e0115.


This study describes two cases of severe hepatitis in association with the Omicron variant of acute COVID-19 infection in vaccinated individuals who had only mild respiratory symptoms. Both patients were not critically ill and did not receive any hepatotoxic therapy. Liver biopsy from one patient demonstrated lobular cholestasis with diffuse bile duct injury, moderate macrovesicular steatosis, and lobular/interface inflammation, with positive immunohistochemistry for SAR-CoV2 spike protein found associated with inflammatory infiltrates within the portal areas and hepatic lobules and in the biliary epithelium. Evaluation of a deidentified database containing patients admitted for SARS-CoV-2 infection found that severe liver injury (ALT >10 times upper limit of normal or 300 IU/L) was observed at an incidence rate of 0.42% with Omicron versus 0.30% with pre-Omicron variants. The authors conclude that the Omicron variant of SARS-CoV-2 should be considered in the differential diagnosis of severe acute liver injury.


Genetic and epigenetic analysis of hepatocellular adenomas with atypical morphological features

Haefliger S, Hench J, O’Rourke CJ, et al. Histopathology. 2023 Apr;82(5):722-730.


Hepatocellular adenoma (HCA) can have atypical morphological features such as cytological atypia, pseudoglandular architecture, and altered reticulin framework. Little is known about the genetic and epigenetic alterations of such HCAs and whether they show the alterations classically found in hepatocellular carcinoma (HCC) or in HCA without atypical morphology. The authors analyzed five HCAs with atypical morphological features and one HCA with transition to HCC. Subtyping of the five HCAs with atypical features revealed two β-catenin mutated HCA (b-HCA), two β-catenin mutated inflammatory HCA (b-IHCA), and one sonic hedgehog activated HCA (shHCA). None of them showed mutations typically found in HCC, such as TERT or TP53 mutations. The epigenomic pattern of HCAs with atypical morphological features clustered with reference data for HCAs without atypical morphological features but not with HCC. Similarly, phyloepigenetic trees using the DNA methylation data reproducibly showed that HCAs with morphological atypia are much more similar to nonmalignant samples than to malignant samples. Finally, atypical HCAs showed no relevant copy number variations (CNV). The HCC arising in an HCA showed a pathogenic nonsense mutation in BRD7 in exon 12 in the HCC part. However, no BRD7 or other mutations, including HNF1A, were found in the classical adenoma area of that tumor, even though the tissue derived from close to the HCC. The data supported a relationship between atypical HCAs with nonatypical HCAs rather than with HCCs. Therefore, in cases with difficult differential diagnoses between HCC and HCA, it might be advisable to perform targeted sequencing and/or combined methylation/copy number profiling.

Liver Transplantation

Digital imaging software versus the “eyeball” method in quantifying steatosis in a liver biopsy

Long, JJ, Nijhar, K, Jenkins, RT, et al. Liver Transplantation. 29(3):268-278.


Digital imaging software (DIS) may better standardize definitions of steatosis to study posttransplant outcomes. Using HALO, a DIS, the authors analyzed 63 liver biopsies, from 3 transplant centers, transplanted between 2016 and 2018, and compared macrovesicular steatosis percentage (%MaS) as estimated by the transplant center, donor hospital, and DIS. Transplant centers and donor hospitals overestimated %MaS compared with DIS, with better agreement at lower %MaS and less agreement for higher %MaS. No DIS-analyzed liver biopsies were calculated to be >20% %MaS; however, 40% of liver biopsies read by transplant center pathologists were read to be >30%. Percent MaS read by HALO was positively associated with peak aspartate aminotransferase (regression coefficient= 1.04 1.08 1.12, p <0.001), peak alanine aminotransferase (regression coefficient = 1.04 1.08 1.12, p <0.001), and early allograft dysfunction (OR= 1.10 1.40 1.78, p =0.006). There was no association between HALO %MaS and total bilirubin on postoperative day 7 (regression coefficient = 0.99 1.01 1.04, p =0.3). DIS provides reproducible quantification of steatosis that could standardize MaS definitions and identify phenotypes associated with good clinical outcomes to increase the utilization of steatotic livers.

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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