HPHS Journal Watch January/February 2025

American Journal of Clinical Pathology

Nodular regenerative hyperplasia: The role of the CK7 immunohistochemistry pattern of expression in diagnosis

Bartow BB, Dhall D, Lee G, et al. Am J Clin Pathol. 2025 Feb 12;163(2):196-204.

https://pubmed.ncbi.nlm.nih.gov/39213447

Nodular regenerative hyperplasia (NRH) is a challenging diagnosis in biopsy specimens, yet biopsy remains the gold standard. This study utilized cytokeratin 7 (CK7) immunohistochemistry (IHC) to aid in the diagnosis and characterization of NRH and NRH-like changes. The location of CK7 staining (centrilobular hepatic progenitor cells vs. periportal/bile ductular reaction) and its distribution pattern (patchy vs. diffuse) were analyzed. In NRH, CK7 expression in centrizonal areas is variable and may reflect either an adaptive hepatocytic response to ischemia or the activation of hepatic progenitor cells. CK7 can help distinguish primary NRH from secondary NRH-like changes. In challenging cases, CK7 positivity in centrilobular hepatic progenitor cells supports an NRH diagnosis, whereas CK7 negativity is characteristic of NRH-like changes associated with conditions such as congestive hepatopathy and portal vein thrombosis. These findings reinforce NRH as a distinct entity with a unique pathophysiology compared to NRH-like changes. In patients with portal hypertension without an alternative cause, CK7 staining can help support an NRH diagnosis.

Clinical Gastroenterology and Hepatology

Drug-induced Liver Injury in Latin America: 10-year Experience of the Latin American DILI (LATINDILI) Network.

Bessone F, Hernandez N, Medina-Caliz I, et al. Clin Gastroenterol Hepatol. 2025 Jan;23(1):89-102.

https://pubmed.ncbi.nlm.nih.gov/38992407

This prospective study analyzed the clinical presentation, histology, and outcomes of drug-induced liver injury (DILI) cases in the Latin American DILI (LATINDILI) Network. The 10-year experience involved review of clinical presentation and outcome of 468 idiosyncratic DILI patients. These patients presented most commonly with hepatocellular injury (62%) and jaundice (60% patients); 42% were hospitalized, with 4.1% fatality. 88% were caused by a single drug and included 1.9% drug-induced autoimmune hepatitis and 5.1% had eosinophilia and systemic symptoms. The most common drug classes identified as causative agents included antimicrobials (31%), musculoskeletal agents (12%), anti-neoplastic and immunomodulating agents (11%), and herbal/dietary supplements (9%). Of the 17% of patients with liver biopsy or pathologic evaluation of an explant, the most common findings was cholestatic hepatitis (25%) followed by acute cholestasis (13%) and acute hepatitis (13%). 9 patients had zonal necrosis, and 5 patients had massive necrosis. None of the patients with DILI associated with antibacterials or immunosuppressants were fatal, whereas anti-tuberculosis drugs, nimesulide, and herbal and dietary supplements were associated with the worst outcome.

Hepatology

A genetic basis of mitochondrial DNAJA3 in nonalcoholic steatohepatitis-related hepatocellular carcinoma

Chang CW, Chen YS, Huang CH, et al. Hepatology. 2025 Jan 1;81(1):60-76.

https://pubmed.ncbi.nlm.nih.gov/37870291

In this study, the authors used a database of body fat distribution–related variants associated with non-alcoholic steatohepatitis-related hepatocellular carcinoma (NASH-related HCC) and generated a genetically engineered mouse model to identify genetic risk genes that drive NASH and NASH-related HCC. A single nucleotide polymorphism (SNP) array was used to analyze the National Cancer Institute – University of Maryland (NCI- UMD) cohort, which includes 484 healthy volunteers, 499 individuals without NASH (non-NASH, either with chronic liver diseases due to other etiologies or with HCC), and 26 individuals with confirmed NASH (including at-risk and HCC). The authors identified 4 coding variants (rs3747579, rs8052655, rs3764002, and rs897453) strongly associated with NASH. The rs3747579 variant showed the strongest association with NASH, and was associated with clinical features of NASH such increased cholesterol and triglycerides. This variant is linked to the reduced expression of mitochondrial chaperone Hsp40, also known as DnaJ Heat Shock Protein Family, (Hsp40) Member A3 (DNAJA3). Mice with a conditional knockout of Dnaja3 in hepatocytes progressively developed fatty liver, NASH, and cirrhosis/HCC phenotypes. The authors conclude that a metabolic syndrome-related rs3747579-TT variant may serve as the risk allele linked to reduced expression of DNAJA3 in NASH-related HCC.

Macrophage hitchhiking for systematic suppression in postablative multifocal HCC.

Li X, Zhang Y, Li S, et al.. Hepatology. 2025 Jan 1;81(1):44-59.

https://pubmed.ncbi.nlm.nih.gov/38683582

In this study, the authors designed a novel method of therapeutic delivery of lenvatinib (LEN) after microinvasive ablation of HCC using monocytes. The authors constructed LEN-loaded macrophages through the phagocytosis of EM vesicles (derived from Escherichia coli membrane)-coated LEN-loaded nanoparticles. These LEN-loaded macrophages were used in a technique the authors describe as the “microinvasive ablation–guided MΦ hitchhiking (MAMH) strategy” in which the LEN-loaded macrophages are administered via IV after tumor ablation. The LEN-loaded macrophages respond to the gradient of inflammatory factors and migrate toward the ablated tumor site. The authors show that in a hydrodynamic tail vein injection multifocal HCC mouse model and the orthotopic xenograft HCC rabbit model, systematically inhibiting residual tumor progression after ablation and prolonging the median survival of tumor-bearing mice.

Cell metabolism-based therapy for liver fibrosis, repair, and hepatocellular carcinoma

Gilgenkrantz H, Paradis V, Lotersztajn S. Hepatology. 2025 Jan 1;81(1):269-287.

https://pubmed.ncbi.nlm.nih.gov/37212145

In this comprehensive review, the authors explain the delicate balance between fibrogenesis, regeneration, and cancer and discuss how modulating the metabolism of key liver cells may disrupt the pathogenic sequence from chronic liver injury to hepatocellular carcinoma (HCC). The authors highlight that intrinsic metabolic reprogramming is undoubtedly a characteristic feature of the fibrosis/regeneration/HCC sequence. In conclusion, the authors discuss how synergistic effects could be achieved with existing kinase inhibitors or immunotherapy will be the challenge of future studies.

Bile metabolic fingerprints distinguish biliary tract cancer from benign biliary diseases

Yang S, Fu J, Qin W, et al. Hepatology. 2025 Feb 1;81(2):476-490.

https://pubmed.ncbi.nlm.nih.gov/38861680

In this study, the authors develop and validated a bile metabolite–based platform for precise discrimination between malignant and benign biliary diseases (“BileMet assay”). This novel diagnostic tool uses nanoparticle-enhanced laser desorption/ionization mass spectrometry (MS) to capture detailed metabolic fingerprints from bile. Samples were collected from 336 patients with biliary tract cancer or benign biliary diseases across 3 independent cohorts. Untargeted metabolic fingerprinting was performed on 300 bile samples using novel nanoparticle-enhanced laser desorption/ionization MS. A BileMet assay was developed combining the 6 metabolites to construct the final classification model with an accuracy of 82.90% (95% CI: 82.70%–83.10%), sensitivity of 83.48% (95% CI: 83.28%–83.69%), and specificity of 82.04% (95% CI: 81.68%–82.40%) to distinguish biliary tract cancers (BTCs) from benign diseases (BDs). The authors conclude that this metabolomics-based diagnostic assay may be helpful to improve BTC detection.

Utility of methylated DNA markers for the diagnosis of malignant biliary strictures

Cooley MA, Schneider AR, Barr Fritcher EG, et al. Hepatology. 2025 Feb 1;81(2):453-464

https://pubmed.ncbi.nlm.nih.gov/38905442

In this study the primary goal was to identify the top-performing candidate methylated DNA markers (MDMs) for the detection of malignancy using biliary brushings obtained during endoscopic retrograde cholangiopancreatography (ERCP). The secondary aim was to compare the performance characteristics of these MDMs with cytology and PB-FISH (Pancreatobiliary Fluorescence In Situ Hybridization). DNA was extracted from biliary brushing samples, quantified, bisulfite-converted, and then subjected to methylation-specific droplet digital polymerase chain reaction. Patients were considered to have no malignancy if the sampling was negative and there was no evidence of malignancy after 1 year or definitive negative surgical histopathology. As a result, the study identified and validated four markers (TWIST1, HOXA1, VSTM2B, and CLEC11A) for the detection of malignant biliary strictures (MBSs). The use of all 4 markers in combination demonstrated a higher diagnostic power than the individual markers (AUC = 0.86); however, the highest performing combination was the 3-marker MDM panel, TWIST1/HOXA1/ VSTM2B (AUC = 0.86, sensitivity = 73.4%, and specificity = 92.9%). The authors conclude that the measurement of aberrant DNA methylation markers in biliary brushings can improve the detection of malignant biliary strictures (MBSs)

Hepatology Communications

Genome-wide meta-analysis associates donor-recipient non-HLA genetic mismatch with acute cellular rejection post-liver transplantation.

Nieuwenhuis LM, Li Y, Liza BL, et al. Hepatology Communications 9(1):e0601, January 2025

https://pubmed.ncbi.nlm.nih.gov/39670865

This international multi-center case-control genome-wide association study evaluated the association of non-human leukocyte antigen (non-HLA) mismatches in acute cellular rejection (ACR) in liver transplantation. This association has been demonstrated in kidney transplants as having a profound effect on graft patency and rejection, and the authors sought to identify associations in liver transplantation. The authors studied a total of 1846 donor-recipient liver transplant pairs, assessing genetic mismatch burden based on single-nucleotide polymorphism (SNP) mismatch based on non-HLA functional SNPs, and subsequently analyzed the mismatch scores with a clinical diagnosis of ACR by a multivariable regression model. Diagnosis of ACR was confirmed on biopsy as Banff grade 2 or grade 3. Weighted meta-analysis showed an association between a higher mismatch in functional non-HLA SNPs and increased incidence of ACR at 1 year (HR 5.99). There was also an increased risk of 5 year graft loss for all functional non-HLA SNPs (HR 6.75) and transmembrane/secreted proteins (HR 3.97). Interestingly there were 27 related living donor transplants within this cohort, in which non-HLA mismatch was significantly correlated to HLA mismatch (but not in the non-related groups), but only 1 recipient of a related donor experienced clinically relevant ACR and no recipients of a related donor experienced graft loss within 5 years. The authors believe that identifying these high-risk features may help in personalizing immunosuppressive therapy but further studies are needed to validate these findings.

The evolving role of liver biopsy: Current applications and future prospects.

Gopal P, Hu X, Robert ME, Zhang X. Hepatol Commun. 2025 Jan 7;9(1):e0628.

https://pubmed.ncbi.nlm.nih.gov/39774070

This review article discusses the role of liver biopsy as a mainstay in evaluation and management of liver disease. The role of histology in the diagnosis of autoimmune hepatitis, primary biliary cholangitis, and other medical liver diseases are also discussed. The authors point to a study demonstrating that in 383 patients who underwent liver biopsy for unexplained abnormal LFTs, histologic evaluation was able to provide a clinical diagnosis in 87% (most commonly autoimmune hepatitis, metabolic-associated steatotic liver disease, and drug-induced liver injury). Patients with early or mid-stage metabolic dysfunction-associated steatohepatitis (MASH) may have a major fibrosis discrepancy between elastography and biopsy. The biopsy of neoplastic lesions provides prognostic information and possible molecular diagnostics for targetable mutations.

Histopathology

Turmeric supplement-associated hepatitis: a clinicopathological series of 11 cases highlighting pan-lobular and zone 3 injury

Papke DJ Jr, Viveiros K, Zota V, et al. Histopathology. 2025 Feb;86(3):410-422.

Although turmeric is commonly ingested and well tolerated, there is increasing evidence that over-the-counter turmeric supplements can cause drug-induced liver injury. This article reported 11 patients for whom liver injury was attributed clinically to turmeric supplements: 10 females (91%) and one male, with a median age of 58 years (range = 37-66 years). Six patients (55%) were asymptomatic with abnormal liver function tests, while five patients (45%) presented with malaise and/or jaundice. Ten patients (91%) showed predominant transaminase abnormalities, while one exhibited predominant alkaline phosphatase elevation. Histologically, biopsies showed acute hepatitis (eight cases, 73%, including five pan-lobular and three zone 3-predominant inflammation), scattered lobular aggregates of histiocytes (two; 18%) and a chronic hepatitis pattern of injury (one; 9%). Mild bile duct injury was present in five biopsies (45%). All patients stopped ingesting turmeric supplements after presenting with liver injury, and four patients additionally received steroid therapy; liver function tests normalized in all patients. Roussel Uclaf causality assessment method (RUCAM) analysis estimated the likelihood of turmeric supplement-associated liver injury to be probable (eight cases) and possible (three). Histological features in the ‘possible’ cases were consistent with drug-induced injury, highlighting the added benefit of histological analysis relative to RUCAM analysis isolation. This study underscores the need to obtain a full history of over-the-counter medications and supplements when investigating etiologies for liver injury, including supplements purportedly containing innocuous compounds such as turmeric.

Gastroenterology

Longitudinal Evaluation of Individuals with Severe Alpha-1 Antitrypsin Deficiency (Pi∗ZZ Genotype)

Fromme M, Payancé A, Mandorfer M, et al. Gastroenterology. 2025;168:367-381

https://pubmed.ncbi.nlm.nih.gov/39414159

This multinational, longitudinal study examines disease progression in patients with alpha-1-antitrypsin deficiency (Pi*ZZ genotype), analyzing 737 adults over 2,634 follow-up years. The findings highlight liver and lung diseases as the primary causes of death, each accounting for approximately 40% of observed fatalities. The study also evaluates surrogates for liver- and lung-related endpoints. Noninvasive liver fibrosis markers, including liver stiffness measurement (LSM) via vibration-controlled transient elastography (VCTE), aspartate aminotransferase-to-platelet ratio index (APRI), and fibrosis-4 index (FIB-4), accurately predict liver-related outcomes such as decompensated cirrhosis, liver transplant, and liver-related death. In contrast, lung-related surrogates demonstrated only moderate predictive performance, with low FEV1 values emerging as the strongest, though still limited, predictor of pulmonary endpoints. Fibrosis progression in patients with no or mild liver fibrosis at baseline was primarily observed in those with preexisting risk factors. The study underscores the clinical utility of simple, widely available biomarkers for liver fibrosis in high-risk populations such as Pi*ZZ individuals, aiding both clinical management and patient selection for clinical trials.

Liver Transplantation

Porto-sinusoidal vascular disorder in surgical candidates for liver metastases: Prevalence, noninvasive diagnosis, and burden on surgical outcomes

Dajti E, Serenari M, Malvi D, et al. Liver Transpl. 2025 Jan 1;31(1):58-69.

https://pubmed.ncbi.nlm.nih.gov/39311847

Chemotherapy can cause vascular and metabolic liver injury in patients with liver metastases, but scarce data are available. This article described the prevalence of porto-sinusoidal vascular disorder (PSVD) among patients undergoing resection for liver metastases, and assessed whether liver stiffness measurement (LSM) and spleen stiffness measurement could diagnose PSVD and predict postoperative complications. This prospective single-center study enrolled 68 consecutive patients undergoing hepatic resection for metastases at a tertiary center. Sixty patients (88%) had received chemotherapy. Twenty-nine (44%) patients had PSVD. Spleen stiffness measurements <21 kPa (negative predictive value 87%) and >40 kPa (positive predictive value 100%) could accurately diagnose PSVD. PSVD significantly increased the risk of post-hepatectomy liver failure (22% vs. 45%) and major complications (11% vs. 31%). Preoperative LSM was associated with postoperative morbidity. The cutoff LSMs <4.5 and >8 kPa predicted the risk of clinically significant post-hepatectomy liver failure (0%, 11%, and 33% in LSM <4.5, 4.5-8, and >8 kPa, respectively) and major complications (0%, 25%, 44% in LSM <4.5, 4.5-8, and >8 kPa, respectively). PSVD is very common among patients undergoing liver surgery for metastases, and it is associated with increased morbidity. LSM and spleen stiffness measurement can correctly identify patients with PSVD and those at risk of clinically relevant postoperative complications.

Prepared by:

Dana Balitzer, MD (Editor); University of California San Francisco

Clifton Fulmer, MD, PhD; Cleveland Clinic

Nigar Anjuman Khurram, MD; University of Pittsburgh

Yuanxin Liang, MD, PhD; Yale School of Medicine

Juan Putra, MD; Boston Children’s Hospital

Daniel Roberts MD; Cleveland Clinic

Camila Simoes MD; UAMS College of Medicine

Angela R. Shih, MD; Massachusetts General Hospital

Xuefeng Zhang, MD; Cleveland Clinic