HPHS Journal Watch September-October 2024

American Journal of Clinical Pathology

Artificial intelligence–aided steatosis assessment in donor livers according to the Banff consensus recommendations.

Jiao J, Tang H, Sun N, Zhang X. Am J Clin Pathol. 2024 Oct 3;162(4):401-407.

https://pubmed.ncbi.nlm.nih.gov/38716796

The Banff Working Group on Liver Allograft Pathology has proposed recommendations for steatosis assessment in donor liver biopsy specimens, including a consensus definition for “large droplet fat” (LDF) and a 3-step algorithmic approach. This evaluation follows three steps: (1) assessing the overall percentage of the biopsy affected by steatosis (standout white) under low power (LP%), (2) determining the proportion of cells in the standout steatosis area containing LDF under high power (HP%), and (3) adjusting LP% by HP% to calculate LDF% as HP% × LP%. The authors also used a computer-assisted, manual quantification protocol developed on QuPath (an open-source software for morphometry analysis) and a recently developed AI-aided algorithm for LDF detection that integrates the segment-anything model, to evaluate donor livers. The results show high correlation coefficients between pathologist and computer-assisted manual quantification, between computer-assisted manual quantification and the AI model, and between the AI model and pathologist were 0.94, 0.88, and 0.81, respectively. The authors concluded that the two most common challenges in evaluating donor liver steatosis—the lack of a uniform definition for steatosis type and quantification strategy, as well as the presence of freezing artifacts—can be mitigated through the implementation of the Banff consensus recommendations and AI-aided algorithms. The ongoing development of AI-aided algorithms holds promise for facilitating rapid and objective assessments of donor liver steatosis.

American Journal of Surgical Pathology

Clinical and Histopathologic Characteristics of Acute Severe Hepatitis Associated With Human Herpesvirus 6 Infection

Wang H, Vannilam A, Hafberg ET, et al. Am J Surg Pathol. 2024 Sep 1;48(9):1117-1130.

https://pubmed.ncbi.nlm.nih.gov/38907627

Human herpesvirus 6 (HHV-6) is detected in most children within the first two years of life. While generally mild and self-limited, in rare instances HHV-6 has been linked with severe acute hepatitis and acute liver failure. This retrospective study describes the clinical course and histologic features of 5 previously healthy pediatric patients (mean age of 8.8 years, range 4-14 years) with indeterminate acute severe hepatitis found to have hepatic HHV-6 infection. Four patients developed acute liver failure (ALF) and three patients received liver transplantation. Histologic sections from the explanted livers and biopsies showed a centrilobular pattern of necroinflammation with perivenulitis, confluent centrilobular to panlobular necrosis, and relatively mild portal inflammation. Immunohistochemical staining with a monoclonal antibody targeting envelope glycoprotein H, a late structural protein of HHV-6, was positive in all cases, primarily in bile duct epithelial cells. The authors conclude that HHV-6 may manifest in acute liver failure in immunocompetent children, is associated with prominent centrilobular necroinflammatory activity and appears to involve an immune-mediated process driven by CD8-positive T cell activation.

Crystalline Hepatopathy Associated With Bietti Crystalline Dystrophy: A Striking Manifestation of Disordered Fatty Acid Metabolism

Dulken BW, Bahceci D, Leung LS, et al. Am J Surg Pathol. 2024 Sep 1;48(9):1138-1145.

https://pubmed.ncbi.nlm.nih.gov/38802997

Bietti crystalline dystrophy (BCD) is a heritable ophthalmic disease caused by variants in CYP4V2 (which encodes a cytochrome P450 hemethiolate protein superfamily member), which leads to crystal deposition in the posterior pole of the retina, atrophy, and a progressive decrease in visual acuity. In this study, the authors report granulomatous hepatitis associated with abundant diffuse crystalline clefts in the hepatic parenchyma in a cohort of 3 patients with genetically confirmed BCD (n=2) or crystalline retinal dystrophy resembling BCD (n=1). All three patients showed AST and ALT abnormalities and had elevated serum cholesterol and LDL. One patient developed advanced liver fibrosis that was identified in a repeat liver biopsy performed 3 years following the initial biopsy. The authors suggest that this case series may represent the first report of extraocular manifestations of BCD.

Clinical Gastroenterology and Hepatology

Chronic Hepatitis C Related Steatotic Liver Disease Is More Than “Miscellaneous Steatotic Liver Disease”

Huang CF, Yeh ML, Dai CY, et al. Clin Gastroenterol Hepatol . 2024 Oct;22(10):2137-2139.e2.

https://pubmed.ncbi.nlm.nih.gov/38729391

This prospective study used a nationwide Hepatitis C virus (HCV) registry in Taiwan to compare liver disease severity and cardiovascular risks in patients with steatotic liver disease (SLD) in the setting of HCV. The study included over 28000 chronic HCV patients, of which 46.9% had SLD. Among patients with SLD, 12,462 (93.4%) expressed at least 1 cardiometabolic risk factor and were defined as having HCV-MASLD. Compared with patients without HCV-MASLD, HCV-MASLD patients had higher Fibrosis-4 Index (FIB-4) score (3.0 vs 2.2; P < .001) and higher cardiovascular risk calculated by the Framingham Risk Score (FRS) (8.1% vs 5.2%; P < .001). Logistic regression analysis showed that HCV-MASLD patients had a higher risk of significant liver fibrosis than HCV patients with SLD without cardiometabolic risk factors. The authors conclude that the risk of liver fibrosis/cardiovascular disease in chronic HCV-SLD is similar to those of other MASLD cohorts. As such, steatotic chronic HCV patients with cardiometabolic risk factors should be classified as HCV-MASLD.

Gastroenterology

Fazirsiran for Adults With Alpha-1 Antitrypsin Deficiency Liver Disease: A Phase 2 Placebo Controlled Trial (SEQUOIA)

Clark VC, Strange C, Strnad P, et al. Gastroenterology. 2024;167:1008-1018

https://pubmed.ncbi.nlm.nih.gov/38964420

Alpha-1 antitrypsin (AAT) deficiency is associated with progressive liver dysfunction and fibrosis. This paper discusses an ongoing phase 2 study of fazirsiran, an investigational RNA interference therapy that targets hepatocytes to degrade Z-AAT messenger RNA, resulting in a reduction of harmful protein production. Forty patients were randomized to receive either a placebo or fazirsiran (25, 100, or 200 mg) subcutaneously. The study found that fazirsiran reduced Z-AAT accumulation in the liver, achieving a 93% reduction in Z-AAT levels and notable decreases in liver damage markers, including globule burden, inflammation, and scarring, compared to placebo. Patients with baseline fibrosis on fazirsiran also demonstrated significant histologic improvements in inflammation and fibrosis scores, while such improvements were minimal in the placebo group. These findings are relevant to liver pathologists, as new therapies may lead to increased evaluation of post-treatment biopsies in AAT deficiency patients. However, given the limited sample size in each dosing group, further studies with larger populations will be valuable to confirm these findings.

Gut

PARP-1 selectively impairs KRAS-driven phenotypic and molecular features in intrahepatic cholangiocarcinoma

El-Serag H, Kanwal F, Ning J, et al Gut 2024;73:1000-1007

https://pubmed.ncbi.nlm.nih.gov/38857989

KRAS mutations are associated with poor treatment response and clinical outcome in intrahepatic cholangiocarcinoma (iCCA). In KRAS-mutant cancers, Poly (ADP-ribose) polymerase 1 (PARP-1) has recently been found to play a significant role, although its function specifically in iCCA and cholangiocarcinogenesis is not entirely clear. In this study, the authors targeted PARP-1 in patient-derived and established iCCA cells using RNAi, CRISPR/Cas9 and pharmacological inhibition in KRAS-mutant, non-mutant cells. PARP-1-based interventions were shown to preferentially impair cell viability and tumorigenic potential in KRAS-mutant iCCA cell lines, compared to non-mutant cells. Parp-1 knockout mice, when combined with iCCA induction by hydrodynamic tail vein injection, showed a distinct phenotypic response, with a pronounced effect on Kras/Tp53-induced iCCA as opposed to Akt/Nicd-induced iCCA. Importantly, loss of PARP-1 completely abolished Kras-dependent cholangiocarcinogenesis, highlighting the critical role of PARP-1 in KRAS-driven cancer development. The findings suggest that PARP-1 could be a promising therapeutic target in KRAS-mutant iCCA.

Hepatology

Hepatology Communications: Vol 8, Issue 10-11

Cholestatic insult triggers alcohol-associated hepatitis in mice

Yan S, Lin Z, Ma M, Arasteh A, Yin XM. Hepatol Commun . 2024 Oct 24;8(11):e0566.

https://pubmed.ncbi.nlm.nih.gov/39445893

This animal model study investigates the association between cholestasis and alcohol-associated hepatitis (AH). Many patients with AH show biliary dysfunction and cholestatic injury, and oftentimes have a poorer prognosis, but the nature of this relationship is unknown. The authors investigate the interaction by using chronic ethanol-fed (EtOH) mice and challenging them with α-naphthylisothiocyanate (ANIT), which is a well-known cholestasis inducer. The results showed that ANIT increased liver injury in EtOH mice with increased ALT, AST, and total bile acids in a dose-dependent manner. Histology revealed that these mice showed significant necrosis and portal inflammation in a manner similar to AH in humans. RNAseq analysis showed activation of pathways associated with the innate immune response, including leukocyte migration and chemotaxis. The most frequently suppressed pathways were related to lipid metabolism. Depletion of neutrophils reduced cholestatic liver injury and inflammation, suggesting that neutrophils as part of the liver inflammation are a significant contributor to AH mice, which evidence that they contribute through the release of neutrophil extracellular traps (NETs) by investigating response to DNase I. The authors conclude that cholestasis in the setting of chronic alcohol exposure may instigate AH via the formation of NETs, but the exact mechanism by which alcohol increases susceptibility of cholestatic injury is not yet known.

Histopathology

Severe acute liver disease in adults: Contemporary role of histopathology

Clouston AD, Gouw ASH, Tiniakos D, et al. Histopathology. 2024 Oct;85(4):549-561.

https://pubmed.ncbi.nlm.nih.gov/38773813

This review article provided a framework for pathologists faced with biopsies from patients with acute liver diseases, such as acute liver failure (ALF), acute-on-chronic liver failure (ACLF) and acute hepatitis, including acute liver injury (ALI). This overview provides an insight into the contemporary role of biopsies (as well as explant and autopsy material) in diagnosing acute liver disease. It outlined up-to-date clinical definitions of liver injury and recent recommendations for the diagnosis of AIH and drug-induced, autoimmune-like hepatitis (DI-AIH).

Human Pathology

Gradual telomere shortening in the tumorigenesis of pancreatic and hepatic mucinous cystic neoplasms

Sung YN, Stojanova M, Shin S, et al. Human Pathology. 2024;152:105653.

https://pubmed.ncbi.nlm.nih.gov/39214240

Mucinous cystic neoplasms (MCNs) are epithelial tumors with mucin-secreting columnar cells and ovarian-type stroma, with potential progression to pancreatic ductal adenocarcinoma or intrahepatic cholangiocarcinoma. The authors investigated telomere shortening in MCN tumorigenesis, measuring telomere lengths in lesion components via telomere-specific FISH. A progressive telomere length decrease was observed across normal ductal epithelium, ovarian-type stroma, non-mucinous and mucinous epithelia, and adenocarcinoma in pancreatic (n=30) and hepatic (n=15) cohorts (45 women, mean age 46.2 years). Pancreatic and hepatic MCNs were analyzed jointly due to their shared clinical, pathological, and molecular features. Significant pairwise differences between components suggest gradual telomere shortening in MCN tumorigenesis. Notably, high-grade dysplasia was absent from the analysis and only one hepatic MCN case included a cancer component, limiting the strength of conclusions regarding hepatic MCN progression.

Liver Transplantation

Incidence, epidemiology, and outcomes of acute allograft rejection following liver transplantation in Australia

Tang LCY, Chetwood JD, Lai MSM, et al. Liver Transpl. 2024 Oct 1;30(10):1039-1049.

https://pubmed.ncbi.nlm.nih.gov/38647419

In this retrospective study, the authors evaluated the incidence, epidemiology, and outcomes of acute allograft rejection in adult s(n=770) who underwent deceased donor liver transplant at a single medical center in Australia between 2010 and 2020. Biopsy-proven rejection occurred in 34.9% of liver transplants. The median time to the first episode of rejection was 71 days after LT: 2.2% hyperacute, 50.4% early (≤90 d), and 47.5% late rejection (>90 d). Independent risk factors for rejection were younger recipient age at transplant (aHR 0.98 per year increase, 95% CI: 0.97-1.00, p =0.01), and ABO-incompatible grafts (aHR 2.55 vs. ABO-compatible, 95% CI: 1.27-5.09, p <0.01) while simultaneous multiorgan transplants were protective (aHR 0.21 vs. LT only, 95% CI: 0.08-0.58, p <0.01). Development of acute rejection (both early and late) was independently associated with significantly reduced graft (aHR 3.13, 95% CI: 2.21-4.42, p <0.001) and patient survival (aHR 3.42, 95% CI: 2.35-4.98, p <0.001).

Modern Pathology

Comprehensive Characterization of Intraductal Oncocytic Papillary Neoplasm of the Pancreas: A Systematic and Critical Review

Paolino G, Basturk O, Esposito I et al. Mod Pathol. 2024 Sep;37(9):100554.. https://pubmed.ncbi.nlm.nih.gov/38950698/

The authors sought to characterize the intraductal oncocytic papillary neoplasm (IOPN) of the pancreas via review of published literature and reference molecular cohorts such as the Cancer Genome Atlas. They found a slight male predominance (1.5:1 male to female ratio), site predilection for the pancreatic head, and associated invasive carcinoma in half of all cases. IHC for MUC5AC and MUC6 was expressed in 98.2% and 92.8%, respectively. Fusions involving PRKACA and PRKACB were present in all cases tested, the most common of which being PRKACB::ATP1B1 (39.7% of examined cases), PRKACA::ATP1B1 (30.9%) and PRKACA::DNAJB1 (29.4%).

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