HPHS JOURNAL WATCH March/April 2024

American Journal of Clinical Pathology

Microvascular invasion is associated with poor survival in patients with dual-phenotype hepatocellular carcinoma.

Ouyang X, Yan Y, Zhang S, et al. Am J Clin Pathol. 2024 Mar 1;161(3):245-255.

https://pubmed.ncbi.nlm.nih.gov/37947176

The authors investigated the impact of Microvascular Invasion (MVI) on the survival of 900 patients diagnosed with Dual-Phenotype Hepatocellular Carcinoma (DPHCC) in China. The inclusion criteria for DPHCC required more than 15% of tumor cells to diffusely express at least one hepatocyte marker (e.g., Hepatocyte Paraffin 1 [HepPar-1], Arginase 1 [Arg-1]) and one cholangiocyte marker (e.g., CK19, MUC-1). Statistical analysis revealed that Microvascular Invasion (MVI) was a risk factor contributing to postoperative recurrence in patients with DPHCC. The authors suggested that MVI may correlate with the survival of patients with DPHCC and could potentially serve as a prognostic predictor of survival.

Clinical Gastroenterology and Hepatology

Longitudinal Outcomes Associated With Metabolic Dysfunction-Associated Steatotic Liver Disease: A Meta-analysis of 129 Studies

Chan KE, Ong EYH, Cung CH, et al. Clin Gastroenterol Hepatol . 2024 Mar;22(3):488-498.e14.

https://pubmed.ncbi.nlm.nih.gov/37775028

In this meta-analysis of 129 studies of metabolic dysfunction-associated steatotic liver disease (MASLD), the authors find that MASLD is associated with an increased risk of cardiovascular disease, metabolic disease, diabetes, chronic kidney disease, and cancer. In particular, the association between MASLD and hepatocellular carcinoma was high (hazard ratio: 4.37). There are no statistically significant differences in associated risks when stratified by sex. This meta-analysis confirms the multisystemic longitudinal effects of MASLD and the need for treatment targets in MASLD to prevent non-hepatic end organ complications.

Incidence of Etiology-specific Hepatocellular Carcinoma: Diverging Trends and Significant Heterogeneity by Race and Ethnicity

Pinheiro PS, Jones PD, Medina H, et al. Clin Gastroenterol Hepatol . 2024 Mar;22(3):562-571.e8.

https://pubmed.ncbi.nlm.nih.gov/37678486

In this retrospective cohort study based on the hepatocellular carcinoma (HCC) cohort in the Florida statewide cancer registry, the authors evaluate the dominant etiology for patients diagnosed between 2010 and 2018 with a focus on race/ethnicity. The study finds that HCV-HCC is the most common etiology, followed by NAFLD-HCC. The authors conclude that HCV is the leading cause of HCC in men and is particularly high in minorities (Puerto Rican, African American, and US-born Mexican men), whereas NAFLD is currently the leading cause among women and a subset of other minorities (Hispanics, Filipinos). There has been a rapid decline of HCV-HCC rates since 2015, likely due to the discovery of direct-acting anti-viral agents, but there has been an increase in ALD-HCC and NAFLD-HCC, particularly in Hispanic populations.

Metabolic Dysfunction-Associated Steatotic Liver Disease Facilitates Hepatitis B Surface Antigen Seroclearance and Seroconversion

Huang SC, Su TH, Tseng TC, et al. Clin Gastroenterol Hepatol . 2024 Mar;22(3):581-590.e6

https://pubmed.ncbi.nlm.nih.gov/37871842

In this prospective cohort study, the authors evaluate the impact of metabolic dysfunction-associated steatotic liver disease (MASLD) on hepatitis B surface antigen (HBsAg) seroclearance, as seroclearance is associated with lower risks of adverse liver outcomes. In an evaluation of 4084 treatment naïve hepatitis B e antigen (HBeAg)-negative chronic hepatitis B patients, the 887 patients with concurrent MASLD had significantly lower levels of HBsAg and HBV DNA compared to the non-MASLD patients. MASLD was independently associated with a higher likelihood of HBsAg seroclearance, which increased even higher with the addition of other metabolic dysfunctions. The authors conclude that MASLD is a predictive marker for HBsAg seroclearance and seroconversion.

Statins Are Associated With a Decreased Risk of Severe Liver Disease in Individuals With Noncirrhotic Chronic Liver Disease

Sharma R, Simon TG, Hagstrom H, et al. Clin Gastroenterol Hepatol . 2024 Apr;22(4):749-759.e19.

https://pubmed.ncbi.nlm.nih.gov/37121528

This nationwide case control study evaluates the impact of statin use on the progression of chronic liver disease to severe liver disease. In this Swedish cohort, 3862 non-cirrhotic patients with chronic liver disease on statins were matched with patients with chronic liver disease but statin non-users. In the follow up period, 6.1% statins users vs 7.1% statin non-users developed severe liver disease. Overall, statins were associated with a sustained decreased risk when the etiology was alcohol and fatty liver disease, but not viral hepatitis or autoimmune hepatitis. Statin use was associated with lower rates of progression to cirrhosis, hepatocellular carcinoma, and liver-related mortality when used in both pre-fibrotic and fibrotic clinical settings. The authors conclude that statin use may have disease-modifying role in non-cirrhotic chronic liver disease.

Alcoholic Foamy Degeneration, an Entity Resembling Alcohol-Associated Hepatitis: Diagnosis, Prognosis, and Molecular Profiling

Gratacós-Ginés J, Avitaabile E, Montironi C, et al. Clin Gastroenterol Hepatol . 2024 Apr;22(4):768-777.e8.

https://pubmed.ncbi.nlm.nih.gov/38065374

This study included a cohort of patients with clinically suspected alcohol-associated hepatitis who underwent liver biopsy. Histology was classified as alcoholic foamy degeneration (AFD) (defined as microvesicular fatty degeneration in the absence/minimal features of steatohepatitis) or alcohol-associated hepatitis (AH) (defined as steatosis with hepatocyte degenerative changes and lobular inflammation). Patients with histologic finding of AFD presented with less severe impairment of liver function tests, higher serum triglyceride level and high survival rate of 100%, despite similar alcohol consumption in the two groups. RNA sequencing showed different gene expression patterns, in which pathways of fibrosis, stellate cell activation, mesenchymal cell activation, interleukin signaling pathways, and other inflammatory pathways were downregulated in AFD. AFD showed upregulation of mitochondrial function, lipid metabolism, and cholesterol/triglyceride biosynthesis. The authors argue that AFD should be differentiated from AH due to its excellent prognosis without the need for steroid treatment, and that serum triglyceride levels can be helpful in identifying AFD from AH.

Gastroenterology

Cholangiocytes Modulate CD100 Expression in the Liver and Facilitate Pathogenic T-Helper 17 Cell Differentiation

Jiang X, Otterdal K, Chung BK, Maucourant C, Rønneberg JD, Zimmer CL, Øgaard J, Boichuk Y, Holm S, Geanon D, Schneditz G, Bergquist A, Björkström NK, Melum E. Gatsroenterology 2024;166:667-679.

https://pubmed.ncbi.nlm.nih.gov/37995866

In their study, Jiang et al. explored how cholangiocytes influence CD100 expression in livers affected by primary sclerosing cholangitis. They found that CD100 plays a crucial part in bile duct inflammation by facilitating communication between cholangiocytes and immune cells, underscoring the proinflammatory nature of cholangiocytes. The study also uncovered a new role for CD100 mutations in a specific biliary pathogenic process, wherein cholangiocytes promote the differentiation of pathogenic T-helper 17 (Th17) cells from CD4 T cells. These findings emphasize the importance of mutation-specific tools in identifying key molecules involved in biliary inflammation, which could serve as potential targets for treatment.

Gut

MASH Resolution Index: development and validation of a non-invasive score to detect histological resolution of MASH.

Loomba R, Amangurbanova M, Bettencourt R, Madamba E et.al Gut. 2024 Feb 28: gutjnl-2023-331401.

https://pubmed.ncbi.nlm.nih.gov/38418210

The primary objective of this study was non-invasive determination of metabolic dysfunction-associated steatohepatitis (MASH) resolution in precise and reproducible manner. A decline in alanine aminotransferase (ALT) and a decline in MRI proton-density-fat-fraction (MRI-PDFF) are known to be strongly associated with MASH resolution. The authors propose a MASH Resolution Index) included MRI-PDFF, ALT and aspartate aminotransferase. This study included a derivation cohort of 95 consecutive eligible participants (67% female) with MASH who underwent paired liver biopsies and MRI-PDFF assessments at two time points, as well as a validation cohort comprised of 163 participants from a randomized trial. The MASH Resolution Index outperformed ALT response, MRI-PDFF-response, combined in both validation and derivation cohorts. Non-invasive assessment of MASH resolution represents a critical unmet need, and this study fills this important knowledge gap.

Hepatology

Telomere length and risk of cirrhosis, hepatocellular carcinoma, and cholangiocarcinoma in 63,272 individuals from a general population

Gellert-Kristensen H, Bojesen SE, Hanten AT, Stender S.  Hepatology 2024 Apr; 79(4):857-868.

https://pubmed.ncbi.nlm.nih.gov/37732945

Telomere length is associated with various human conditions. In the liver, TERT promoter mutations increase the activity of the telomerase enzyme, leading to elongation of the telomeres; this mutation is present in 60% of HCC. In this population study, approximately 63,000 Danish individuals from two large cohorts were studied. Telomere length was measured in DNA isolated from blood leukocytes. There was a negative correlation between telomere length and age. The authors report an inverse linear association between telomere length and cirrhosis risk. Regarding HCC risk, there was a non-linear association with telomere length: individuals with both shorter than average and longer than average telomeres had increased HCC risk (higher in short telomere individuals). Finally, there was an inverse linear association between telomere length and the risk of extrahepatic (but not intrahepatic) cholangiocarcinoma. The authors hypothesize that short telomeres may predispose to fibrosing liver disease by impairing the liver’s regenerative capacity. The risk of HCC may be related to the risk of cirrhosis, but there may be other factors involved.

Lack of complete biochemical response in autoimmune hepatitis leads to adverse outcome: First report of the IAIHG retrospective registry.

Slooter CD, ven den Brand FF, Lleo A, et al. Hepatology 2024 Mar: 79(3):538-550.

https://pubmed.ncbi.nlm.nih.gov/37676683

The International Autoimmune Hepatitis Group (IAIHG) developed a registry to generate a web-based platform with a large number of clinically well-phenotypes autoimmune hepatitis (AIH) cases. This observational study used data collected from this registry. Patients were diagnosed based on the simplified AIH diagnostic criteria. Overlap patients were included. Complete biochemical response was defined as normalization of aminotransferase and IgG serum levels within 6 months. A total of 2559 patients were included. Females represented 75% of patients and the median age was 48. A liver biopsy was performed at diagnosis in 84%, and cirrhosis was reported in 20.9% and another 2.2% had clinical evidence of cirrhosis. The vast majority of patients were white. PBC and PSC overlap was reported in 11% and 7%, respectively. Liver-related death and liver transplantation was associated with non-white ethnicity, cirrhosis at diagnosis, PSC, and of aminotransferase normalization within 6 months. Of the 205 patients with cirrhosis, 54% achieved complete biochemical response; survival was impaired in those who did not achieve complete biochemical response.  The authors conclude that cirrhosis at diagnosis adversely affect outcome, and complete biochemical response is more difficult to achieve in this patient group. However, 17% of the patients who did not achieve complete response by 6 months did so by 1 year, and this was prognostically significant as well; therefore, lack of complete response at 6 months does not mandate a therapeutic change. Survival was reduce din patient with AIH-PSC, and the risk of cirrhosis was higher as well. The worse outcome in non-white individuals may be explained by inherent genetic and immunologic differences between ethnic groups, but access to care cannot be ruled out. Finally, the authors note that in 16% of cases, a liver biopsy was not performed, despite this being an essential part of the diagnostic evaluation for AIH.  Patients who did not have a liver biopsy were more often younger, had LKM1 antibody, and were followed in higher proportion at transplant centers. The authors reiterate the importance of an initial liver biopsy to establish a diagnosis of AIH, especially since diagnostic uncertainty is more difficult to address after instituting immunosuppressive therapy

Hepatology Communications

HBV DNA polymerase regulates tumor cell glycogen to enhance the malignancy of HCC cells

Zhao X, Wang C, Zhao L, et al. Hepatol Commun . 2024 Feb 14;8(3):e0387.

https://pubmed.ncbi.nlm.nih.gov/38358372

In this basic science study, the authors evaluate the contribution of HBV DNA polymerase (HBV-DNA-Pol) to the development of hepatocellular carcinoma, specifically the relationship of HBV-DNA-Pol to glycogen phosphorylase L (PYGL – which is known to regulate glycogenolysis and is involved in tumorigenesis). Both in vitro and in vivo experiments showed that overexpression of HBV-DNA-Pol promotes HCC progression by increasing viability, proliferation, migration, invasion, tumor growth rate, and metastatic rate. The mechanism acts through HBV-DNA-Pol inhibiting PYGL ubiquitination, thereby increasing PYGL protein levels. Upregulation of PYGL increases glycolysis, a metabolic alteration that provides a selective advantage for growth, proliferation, and survival that promotes HCC tumorigenesis. The authors conclude that HBV-DNA-Pol may function as an oncogenic protein in hepatocarcinogenesis.

Increased type-I interferon level is associated with liver damage and fibrosis in primary sclerosing cholangitis

Salzmann RJS, Krotz C, Mocan T, et al. Hepatol Commun . 2024 Feb 14;8(3):e0380.

https://pubmed.ncbi.nlm.nih.gov/38358371

In this study, the authors evaluate type I interferon (IFN) levels in the progression of primary sclerosing cholangitis (PSC). The study compares patient serum from PSC patients with healthy participants and primary biliary cholangitis patients. Bioactive type I IFN levels were elevated in PSC compared to healthy patients and correlated with elevated alkaline phosphatase, alanine transaminase, and gamma-glutamyl transpeptidase, but not serum bilirubin. PBC patients had type I IFN levels mostly similar to the healthy cohort. IFN levels in all cohorts showed a gender bias towards men. PSC patients with advanced fibrosis showed higher type I IFN levels (specifically the IFNω subtype). There is no association with IBD. The authors conclude that type I IFN may have a role in the development of liver damage in PSC and may be a pharmacologic target in the future.

Genetics of liver disease in adults

Knokwo C, Chowdhury S, Vilarinho S. Hepatol Commun . 2024 Mar 29;8(4):e0408.

https://pubmed.ncbi.nlm.nih.gov/38551385

In this review, the authors discuss the role of genomic information in the diagnosis and management of chronic liver disease. Genetic variants driving metabolic-associated steatotic liver disease (MASLD) include variants in PNPLA3 (p.I148M), GCKR (p.P446L), and TM6SF2 (p.E167K), as well as others; the association of many genetic variants with MASLD has led to the development of polygenic risk scores (which are not currently ready for clinical practice). Novel genetic causes of Porto-Sinusoidal Vascular Disease (PSVD) are being discovered in children and adults. The authors suggest that translating these genomic discoveries into patient care involves a multidisciplinary approach.

Granulomatous liver diseases

Mironova M, Gopalakrishma H, Franco GR, et al. Hepatol Commun. 2024 Mar 18;8(4):e0392.

https://pubmed.ncbi.nlm.nih.gov/38497932

In this review, the authors discuss the pathogenesis of hepatic granulomas and describe histologic features and common etiologies. Histologic type of granulomas can include microgranulomas (non-specific); lipogranuloma (associated with steatotic liver disease and hepatitis C); fibrin-ring granulomas (associated with Q fever, leishmaniasis, toxoplasmosis, Hodgkin disease, and immune checkpoint inhibitors); epithelioid necrotizing granulomas (associated with TB, nocardia, and fungal infections); and epithelioid non-necrotizing granulomas (associated with sarcoidosis, hepatitis C, PBC, and drug reaction). Granulomas are commonly found in liver biopsies, and it is critical for pathologists to understand the common etiologies of granulomatous liver disease for appropriate diagnosis and treatment.

NGS of brush cytology samples improves the detection of high-grade dysplasia and cholangiocarcinoma in patients with primary sclerosing cholangitis: A retrospective and prospective study

Boyd S, Mustamäki T, Sjöblom N, et al. Hepatol Commun . 2024 Mar 29;8(4):e0415.

https://pubmed.ncbi.nlm.nih.gov/38551383

In this sequencing study, the authors analyzed archival liver explant and cholangiocarcinoma samples to identify oncogenic mutations which occur in the setting of primary sclerosing cholangitis (PSC). The authors identified mutations in KRAS, GNAS, GLT3, RNF43, TP53, ATRX, and SMAD4 in archival tissue with diagnoses of high-grade dysplasia and cholangiocarcinoma. Prospectively collected brush cytology (BC) identified KRAS, GNAS, TP53, CDKN2A, FBXW7, BRAF, and ATM mutations. The combination of BC and NGS improved diagnostic sensitivity and specificity.

Histopathology

Histologic manifestations of ocrelizumab-associated intestinal and hepatic injury in patients with multiple sclerosis

Challa B and Esnakula AK. Histopathology. 2024 Apr;84(5):765-775.

https://pubmed.ncbi.nlm.nih.gov/38114289

Ocrelizumab is a humanized anti-CD20-monoclonal antibody for the treatment of certain types of multiple sclerosis. This study included six patients with suspected or clinically confirmed ocrelizumab-associated intestinal injury and one patient with hepatic injury. Histologic patterns of initial colonic injury included acute colitis/proctitis (n = 5), and chronic active colitis (n = 1). The liver biopsy from the patient with a marked hepatic pattern of liver enzyme elevation showed an acute hepatitis pattern of injury with prominent centrilobular necrosis, which resolved upon discontinuation of the drug and treatment with steroids and azathioprine.

Human Pathology

Comparative histologic features among liver biopsies with biliary-pattern injury and confirmed clinical diagnoses

Yu S, Vidal B, Peric M, Rosenbaum MW, Cates JMM, Gonzalez RS. Hum Pathol 2024;146:8-14.

https://pubmed.ncbi.nlm.nih.gov/38479481

The authors examined distinctive pathological features to aid in the diagnosis of liver biopsies with biliary-pattern injury. Their cohort comprised 121 cases, including primary biliary cholangitis (PBC; 52), primary sclerosing cholangitis (PSC; 44), chronic large duct obstruction (LDO; 6), and drug-induced liver injury (DILI; 19). The study confirmed the high specificity of classic findings, such as florid duct lesions for PBC and onion-skin fibrosis for PSC. Other findings supporting a specific diagnosis included cholestasis and feathery degeneration, which were more common in LDO and DILI, and ductular reaction lacking neutrophils in PBC.

Morphological findings in different subtypes of hepatic amyloid

Yasir S, Chen ZE, Hartley C, Zhang L, Torbenson M. Hum Pathol 2024;7:35-42.

https://pubmed.ncbi.nlm.nih.gov/38460799

This study characterized histologic findings of hepatic amyloid in 58 middle-aged patients. The authors evaluated various subtypes, including 17 light chain lambda, 15 light chain kappa, 15 transthyretin, 4 serum amyloid A, 4 apolipoprotein A1, 2 fibrinogen alpha, and 1 LECT2. There was significant histologic overlap between subtypes, with amyloid deposits predominantly found in the liver vasculature, including hepatic arteries, portal veins, and sinusoids. Light chain amyloid showed sinusoidal predominance, while transthyretin mainly targeted larger hepatic arteries. Only LECT2 amyloid exhibited hepatocyte involvement (globular deposits). Due to these overlaps, morphological analysis alone is insufficient for amyloid subtyping.

Journal of Hepatology

Improved assessment of donor liver steatosis using Banff consensus recommendations and deep learning algorithms.

Gambella A, Salvi M, Molinaro L, et al. J Hepatol. 2024 Mar;80(3):495-504.

https://pubmed.ncbi.nlm.nih.gov/38036009

The Banff Liver Working Group recently published consensus recommendations for assessing steatosis in donor liver biopsy. Large droplet macrovesicular steatosis (LDMS) is defined as a fat droplet larger than a nearby non-steatotic hepatocyte, displacing the nucleus to the periphery of the containing hepatocyte. Fat droplets not meeting these criteria are termed small droplet macrovesicular steatosis (SDMS) but are not considered relevant in overall organ steatosis assessment due to biological and pathophysiological factors. The Banff approach involves initially using low power to score the percentage of steatosis, then using high power to determine the exact percentage of LDMS, and finally adjusting the low power score with the high power score to determine the LDMS percentage. This study evaluated the Banff recommendations by comparing pathologists’ scores with those generated by AI. A total of 292 allograft liver needle biopsies were collected, showing significantly improved agreement between pathologists and AI models using the Banff approach. Based on these findings, the authors recommend adopting the Banff recommendations in daily practice.

Liver Transplantation

Overcoming the hurdles of steatotic grafts in liver transplantation: Insights into survival and prognostic factors

Akabane M, Imaoka Y, Esquivel CO, et al. Liver Transpl. 2024 Apr 1;30(4):376-385.

https://pubmed.ncbi.nlm.nih.gov/37616509

This article analyzed adult liver transplantation (LT) recipient data (2002-2022) from the United Network for Organ Sharing database, and compared outcomes of LT using steatotic (≥30% macrosteatosis) and nonsteatotic donor livers, donors after circulatory death, and standard-risk older donors (age 45-50). Fatty liver showed inferior graft survival (GS) during the initial 30-day postoperative period; however, the GS discrepancy between fatty and nonfatty livers subsided over time (p = 0.10 at 5 y). Long-term GS outcomes showed comparable or even superior results in fatty livers relative to nonsteatotic livers. Young (<40 y) fatty donors showed a high BSA ratio, diabetes, and intensive care unit hospitalization as significant indicators of a worse prognosis (p < 0.01). The study emphasizes the initial postoperative 30-day survival challenge in LT using fatty livers. However, with careful donor-recipient matching, for example, avoiding the use of steatotic donors with long cold ischemic time and high BSA ratios for recipients in the intensive care unit, it is possible to enhance immediate GS, and in a longer time, outcomes comparable to those using nonfatty livers, donors after circulatory death livers, or standard-risk older donors can be anticipated.

Autoimmune hepatitis recurrence after liver transplantation: “Les jeux sont faits”

Chouik Y, Corpechot C, Francoz C, et al. Liver Transpl. 2024 Apr 1;30(4):395-411.

https://pubmed.ncbi.nlm.nih.gov/37788303

This study evaluated the incidence and risk factors for recurrent autoimmune hepatitis (rAIH) after liver transplantation (LT) in a multicenter retrospective French nationwide study. Seventy-six patients (22.1%) developed recurrence in a median time of 53.6 months (IQR, 14.1-93.2). In multivariate analysis, the strongest risk factor for rAIH was cytomegalovirus D+/R- mismatch status (HR=2.0; 95% CI: 1.1-3.6; p =0.03), followed by associated autoimmune condition. Independent risk factors for severe forms of rAIH were young age at LT, IgG levels >20.7 g/L, and LT in the context of (sub)fulminant hepatitis. Immunosuppression, especially long-term maintenance of corticosteroid therapy, was not significantly associated with rAIH. In summary, recurrence of AIH after LT is frequent and may lead to graft loss. Recurrence is more frequent in young patients with active disease at the time of LT, yet systematic corticosteroid therapy does not prevent it.