The latest medical research on Hepatology

The research magnet gathers the latest research from around the web, based on your specialty area. Below you will find a sample of some of the most recent articles from reputable medical journals about hepatology gathered by our medical AI research bot.

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Dietary management of adults with IBD - the emerging role of dietary therapy.

Nat Rev Gastroenterol

Historically, dietitians played a minor part in the management of inflammatory bowel disease (IBD), including Crohn's disease and ulcerative coliti...

Genetics, pathobiology and therapeutic opportunities of polycystic liver disease.

Nat Rev Gastroenterol

Polycystic liver diseases (PLDs) are inherited genetic disorders characterized by progressive development of intrahepatic, fluid-filled biliary cys...

Liver injury after SARS-CoV-2 vaccination: Features of immune-mediated hepatitis, role of corticosteroid therapy and outcome.


A few case reports of autoimmune hepatitis like liver injury have been reported after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination. We evaluated clinical features, treatment response and outcomes of liver injury following SARS-CoV-2 vaccination in a large case series.

We collected data from cases in 18 countries. The type of liver injury was assessed with the R-value. The study population was categorized according to features of immune-mediated hepatitis (positive autoantibodies and elevated immunoglobulin-G levels) and corticosteroid therapy for the liver injury. We identified 87 patients (63%, female), median age 48 (range:18-79) years at presentation. Liver injury was diagnosed a median 15 (range:3-65) days after vaccination. Fifty-one cases (59%) were attributed to the Pfizer-BioNTech (BNT162b2) vaccine, 20 (23%) cases to the Oxford-AstraZeneca (ChAdOX1 nCoV-19) vaccine and 16 (18%) cases to the Moderna (mRNA-1273) vaccine. The liver injury was predominantly hepatocellular (84%) and 57% of patients showed features of immune-mediated hepatitis. Corticosteroids were given to 46 (53%) patients, more often for grade 3-4 liver injury than for grade 1-2 liver injury (88.9% vs 43.5%, p=0.001) and more often for patients with than without immune mediated-hepatitis (71.1% vs 38.2%, p=0.003). All patients showed resolution of liver injury except for one man (1.1%) who developed liver failure and underwent liver transplantation. Steroid therapy was withdrawn during the observation period in 12 (26%) patients after complete biochemical resolution. None had a relapse during follow-up.

SARS-CoV-2 vaccination can be associated with liver injury. Corticosteroid therapy may be beneficial in those with immune-mediated features or severe hepatitis. Outcome was generally favorable, but vaccine associated liver injury led to fulminant liver failure in one patient.

Multiomics identifies the link between intratumor steatosis and the exhausted tumor immune microenvironment in hepatocellular carcinoma.


Immunotherapy has become the standard-of-care treatment for hepatocellular carcinoma (HCC), but its efficacy remains limited. To identify immunotherapy-susceptible HCC, we profiled the molecular abnormalities and tumor immune microenvironment (TIME) of rapidly increasing nonviral HCC.

We performed RNA-seq of tumor tissues in 113 nonviral HCC patients and cancer genome sequencing of 69 genes with recurrent genetic alterations reported in HCC. Unsupervised hierarchical clustering classified nonviral HCCs into 3 molecular classes (Class I, II, III), which stratified patient prognosis. Class I, with the poorest prognosis, was associated with TP53 mutations, whereas class III, with the best prognosis, was associated with CTNNB1 mutations. Thirty-eight percent of nonviral HCC was defined as an immune class characterized by a high frequency of intratumoral steatosis and a low frequency of CTNNB1 mutations. Steatotic HCC, which accounts for 23% of nonviral HCC cases, presented an immune-enriched but immune-exhausted TIME characterized by T-cell exhaustion, M2 macrophage and cancer-associated fibroblast (CAF) infiltration, high PD-L1 expression, and TGF-β signaling activation. Spatial transcriptome analysis suggested that M2 macrophages and CAFs may be in close proximity to exhausted CD8+ T cells in steatotic HCC. An in vitro study showed that palmitic acid-induced lipid accumulation in HCC cells upregulated PD-L1 expression and promoted immunosuppressive phenotypes of cocultured macrophages and fibroblasts. Steatotic HCC patients, confirmed by chemical-shift MR imaging, had significantly longer PFS with combined immunotherapy using anti-PD-L1 and anti-VEGF antibodies.

Multiomics stratified nonviral HCCs according to prognosis or TIME. We identified the link between intratumoral steatosis and immune-exhausted immunotherapy-susceptible TIME.

Genetic modifiers of penetrance to liver endpoints in HFE hemochromatosis: associations in a large community cohort.


The iron overload condition Hereditary Heamochromatosis (HH) can cause liver cirrhosis and cancer, diabetes and arthritis. Male HFE p.C282Y homozygotes have greatest risk, yet only a minority develop these conditions. We aimed to determine whether common genetic variants influencing iron levels or liver disease risk in the general population also modify clinical penetrance in HFE p.C282Y and p.H63D carriers.

We studied 1,294 male and 1,596 female UK Biobank European-ancestry HFE p.C282Y homozygous participants with medical records up to 14 years after baseline assessment. Polygenic scores quantified genetic effects of blood iron biomarkers and relevant diseases (identified in the general population). Analyses were also performed in other HFE p.C282Y/p.H63D genotype groups.

In male p.C282Y homozygotes, higher iron polygenic score increased risk of liver fibrosis or cirrhosis diagnoses (Odds Ratio for top 20% of iron polygenic score vs bottom 20%=4.90: 95% Confidence Intervals 1.63 to 14.73, p=0.005), liver cancer, and osteoarthritis, but not diabetes. A liver cirrhosis polygenic score was associated with liver cancer diagnoses. In female p.C282Y homozygotes, osteoarthritis polygenic score was associated with increased osteoarthritis diagnoses, and type-2 diabetes polygenic score with diabetes. However, the iron polygenic score was not robustly associated with diagnoses in p.C282Y homozygote females, or in other p.C282Y/p.H63D genotypes.

HFE p.C282Y homozygote penetrance to clinical disease in a large community cohort was partly explained by common genetic variants that influence iron and risks of related diagnoses in the general population. Including polygenic scores in HH screening and diagnosis may help in estimating prognosis and treatment planning.

Nonalcoholic Fatty Liver Disease Risk and Histologic Severity are Associated with Genetic Polymorphisms in Children.


Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in children. Large pediatric studies identifying single nucleotide polymorphisms (SNPs) associated with risk and histologic severity of NAFLD are limited. Study aims included investigating SNPs associated with risk for NAFLD using family trios and association of candidate alleles with histologic severity.

Children with biopsy-confirmed NAFLD were enrolled from the NASH Clinical Research Network. The Expert Pathology Committee reviewed liver histology. Genotyping was conducted with allele specific primers for 60 candidate SNPs. Parents were enrolled for trio analysis. To assess risk for NAFLD, the transmission disequilibrium test was conducted in trios. Among cases, regression analysis assessed associations with histologic severity. 822 children with NAFLD had mean age 13.2 years (SD 2.7) and mean ALT 101 U/L (SD 90). PNPLA3 (rs738409) demonstrated the strongest risk (p = 2.24x10-14 ) for NAFLD. Among children with NAFLD, stratifying by PNPLA3 s738409 genotype, the variant genotype associated with steatosis (p=0.005), lobular (p=0.03) and portal inflammation (p=0.002). Steatosis grade associated with TM6SF2 (p=0.0009), GCKR (p=0.0032), PNPLA3 rs738409 (p=0.0053), and MTTP (p=0.0051). Fibrosis stage associated with PARVB rs6006473 (p=0.0001), NR1I2 (p=0.0021), ADIPOR2 (p=0.0038), and OXTR (p=0.0065). PNPLA3 rs738409 (p=0.0002) associated with borderline zone 1 NASH.

This study demonstrated novel disease-associated SNPs in children with NAFLD. In particular, rs6006473 was highly associated with severity of fibrosis. These hypothesis-generating results support future mechanistic studies of development of adverse outcomes such as fibrosis and generation of therapeutic targets for NAFLD in children.

Lipocalin-2 Activates Hepatic stellate cells and Promotes Non-alcoholic Steatohepatitis in High-Fat Diet-Fed ob/ob mice.


In obesity and type 2 diabetes mellitus, leptin promotes insulin resistance and contributes to the progression of non-alcoholic steatohepatitis (NASH) via activation of hepatic stellate cells (HSCs). However, the pathogenic mechanisms that trigger HSC activation in leptin-deficient obesity are still unknown. This study aimed to determine how HSC-targeting lipocalin-2 (LCN2) mediates the transition from simple steatosis to NASH.

Male wild-type (WT) and ob/ob mice were fed a high-fat diet (HFD) for 20 weeks to establish an animal model of NASH with fibrosis. Ob/ob mice were subject to caloric restriction or recombinant leptin treatment. Double knockout (DKO) mice lacking both leptin and lcn2 were also fed an HFD for 20 weeks. In addition, HFD-fed ob/ob mice were treated with gadolinium trichloride to deplete Kupffer cells. Human LX-2 cells and primary HSCs from ob/ob mice were used to investigate the effects of LCN2 on HSC activation. Serum and hepatic LCN2 expression levels were prominently increased in HFD-fed ob/ob mice compared with normal diet-fed ob/ob mice or HFD-fed WT mice, and these changes were closely linked to liver fibrosis and increased hepatic α-SMA/MMP9/STAT3 protein levels. HFD-fed DKO mice showed a marked reduction of α-SMA protein compared with HFD-fed ob/ob mice. In particular, the co-localization of LCN2 and α-SMA was increased in HSCs from HFD-fed ob/ob mice. In primary HSCs from ob/ob mice, exogenous LCN2 treatment-induced HSC activation and MMP9 secretion. By contrast, LCN2 receptor 24p3R deficiency or a STAT3 inhibitor reduced the activation and migration of primary HSCs.

LCN2 acts as a key mediator of HSC activation in leptin-deficient obesity via α-SMA/MMP9/STAT3 signaling, thereby exacerbating NASH.

Impact of Bacterial Infections and SBP Prophylaxis on Phage-Bacterial Dynamics in Cirrhosis.


Gut microbiota, including bacteria and phages are altered in cirrhosis, but their role during infections and SBP prophylaxis is unclear. Aim: Deter...

Metabolic reprogramming of the intestinal microbiome with functional bile acid changes underlie the development of NAFLD.


Bile acids are hepatic metabolites and have many properties considered to be relevant to the pathophysiology of nonalcoholic fatty liver disease (NAFLD). Circulating levels of the intestinal microbiome-modified bile acid deoxycholate are increased in cirrhosis.

To further elucidate the role of bile acids and intestinal microbiota linked to bile acids in progressively severe NAFLD, a multi-omic study of feces including 16s rRNA sequencing, microbial transcriptomics and metabolomics was performed in a cohort with varying phenotypes of NAFLD.

Several bile acids of microbial origin derived from deoxycholic acid (DCA) (glycodeoxycholate, 7-ketodeoxycholic acid, dehydrocholic acid) increased with disease activity and fibrosis stage. These were linked to increased expression of microbial bile salt hydrolase, bile acid operon (BaiCD) and hydroxysteroid dehydrogenases (hdhA) required for DCA and downstream metabolite synthesis providing a mechanistic basis for altered bile acid profiles with disease progression. Bacteroidetes and several genera of Lachnospiraceae family containing DCA generating genes increased with increasing disease severity, while several potentially beneficial microbes sensitive to antibacterial effects of DCA e.g. Ruminococcaceae were decreased. The clinical relevance of these data was confirmed in an independent cohort enrolled in a clinical trial for non-alcoholic steatohepatitis (NASH) where at entry DCA and its conjugates were associated with advanced fibrosis. In placebo treated patients, DCA declined in those with fibrosis regression and increased in those with fibrosis progression. DCA rose further in those with compensated cirrhosis when they experienced decompensation.

These novel findings demonstrate a role for bile acids and the bile acid dependent microbiome in the development and progression of NAFLD and set the stage to leverage these findings for NASH biomarker development and for therapeutics.

Endoplasmic Reticulum Stress in Liver Diseases.


The endoplasmic reticulum (ER) is an intracellular organelle that fosters the correct folding of linear polypeptides and proteins, a process tightl...

NAFLD improves risk prediction of type 2 diabetes: with effect modification by sex and menopausal status.


The effects of sex and menopausal status on the association between NAFLD and incident type 2 diabetes (T2D) remain unclear. We investigated the effect modification by sex and menopause in the association between NAFLD and T2D; also, added predictive ability of NAFLD for the risk of T2D was assessed.

This cohort study comprised 245,054 adults without diabetes (109,810 premenopausal women; 4,958 postmenopausal women; 130,286 men). Cox proportional hazard models were used to estimate hazard ratios (HRs; 95% confidence intervals [CIs]) for incident T2D according to NAFLD status. The incremental predictive role of NAFLD for incident T2D was assessed using the area under the receiver operating characteristic curve, net reclassification improvement, and integrated discrimination improvement. A total of 8,381 participants developed T2D (crude incidence rate/103 person-years: 2.9 premenopausal women; 12.2 postmenopausal women; 9.3 men) during median follow-up of 5.3 years. NAFLD was positively associated with incident T2D in all groups. After adjustment for potential confounders, the multivariable-adjusted HRs (95% CIs) for incident T2D comparing NAFLD to no NAFLD were 4.63 (4.17-5.14), 2.65 (2.02-3.48), and 2.16 (2.04-2.29) in premenopausal women, postmenopausal women and men, respectively. The risks of T2D increased with NAFLD severity as assessed by serum fibrosis markers, and the highest relative excess risks were observed in premenopausal women. The addition of NAFLD to conventional risk factors improved risk prediction for incident T2D in both sexes, with a greater improvement in women than men.

NAFLD, including more severe NAFLD, is a stronger risk factor for incident T2D in premenopausal women than in post-menopausal women or men; protection against T2D is lost in pre-menopausal women with NAFLD.

Pharmaceutical Shp2 inhibition suppresses primary and metastasized liver tumors by provoking hepatic innate immunity.


Shp2 is the first identified pro-oncogenic tyrosine phosphatase that acts downstream of receptor tyrosine kinases (RTK) to promote Ras-Erk signaling. However, this phosphatase was also shown to be anti-tumorigenic in hepatocellular cancer (HCC). This study is aimed at deciphering paradoxical Shp2 functions and mechanisms in hepatocarcinogenesis and also at exploring its value as a pharmaceutical target in HCC therapy.

We took both genetic and pharmaceutical approaches, to examine the effects of Shp2 inhibition on primary liver cancers driven by various oncogenes and also on metastasized liver tumors. We show here that the catalytic activity of Shp2 was essential for relay of oncogenic signals from RTK in HCC and that chemical inhibition of Shp2 robustly suppressed HCC driven by RTK. However, in contrast to a tumor-promoting hepatic niche generated by genetically deleting Shp2 in hepatocytes, treatment with a specific Shp2 inhibitor had a tumor-suppressing effect on metastasized liver tumor progression. Mechanistically, the Shp2 inhibitor enhanced anti-tumor innate immunity by downregulating inflammatory cytokines, suppressing the CCR5 signaling axis but upregulating interferon-β secretion.

These results unveil complex mechanisms for the tumor-suppressing effect of pharmaceutical Shp2 inhibition in the liver immune environment. We provide a proof of principle for clinical trial with specific Shp2 inhibitors in primary and metastasized liver cancer patients.