Dysregulation of serum bile acids and FGF19 in alcoholic hepatitis.

BACKGROUND & AIMS: The degree of cholestasis is an important disease driver in alcoholic hepatitis, a severe clinical condition that needs new biomarkers and targeted therapies. We aimed to identify the largely unknown mechanisms and biomarkers linked to cholestasis in alcoholic hepatitis. METHODS: Herein, we analyzed a well characterized cohort of patients with alcoholic hepatitis and correlated clinical and histological parameters and outcomes with serum bile acids and fibroblast growth factor 19 (FGF19), a major regulator of bile acid synthesis. RESULTS: We found that total and conjugated bile acids were significantly increased in patients with alcoholic hepatitis compared with controls. Serum FGF19 levels were strongly increased and gene expression of FGF19 was induced in biliary epithelial cells and ductular cells of patients with alcoholic hepatitis. De novo bile acid synthesis (CYP7A1 gene expression and C4 serum levels) was significantly decreased in patients with alcoholic hepatitis. Importantly, total and conjugated bile acids correlated positively with FGF19 and with disease severity (model for end-stage liver disease score). FGF19 correlated best with conjugated cholic acid, and model for end-stage liver disease score best with taurine-conjugated chenodeoxycholic acid. Univariate analysis demonstrated significant associations between FGF19 and bilirubin as well as gamma glutamyl transferase, and negative correlations between FGF19 and fibrosis stage as well as polymorphonuclear leukocyte infiltration, in all patients with alcoholic hepatitis. CONCLUSION: Serum FGF19 and bile acids are significantly increased in patients with alcoholic hepatitis, while de novo bile acid synthesis is suppressed. Modulation of bile acid metabolism or signaling could represent a promising target for treatment of alcoholic hepatitis in humans. LAY SUMMARY: Understanding the underlying mechanisms that drive alcoholic hepatitis is important for the development of new biomarkers and targeted therapies. Herein, we describe a molecule that is increased in patients with alcoholic hepatitis. Modulating the molecular pathway of this molecule might lead to promising targets for the treatment of alcoholic hepatitis.

Time-Restricted Feeding Attenuates Metabolic Dysfunction-Associated Steatohepatitis and Hepatocellular Carcinoma in Obese Male Mice.

Metabolic dysfunction-associated steatotic liver disease (MASLD) has surpassed the hepatitis B virus and hepatitis C virus as the leading cause of chronic liver disease in most parts of the Western world. MASLD (formerly known as NAFLD) encompasses both simple steatosis and more aggressive metabolic dysfunction-associated steatohepatitis (MASH), which is accompanied by inflammation, fibrosis, and cirrhosis, and ultimately can lead to hepatocellular carcinoma (HCC). There are currently very few approved therapies for MASH. Weight loss strategies such as caloric restriction can ameliorate the harmful metabolic effect of MASH and inhibit HCC; however, it is difficult to implement and maintain in daily life, especially in individuals diagnosed with HCC. In this study, we tested a time-restricted feeding (TRF) nutritional intervention in mouse models of MASH and HCC. We show that TRF abrogated metabolic dysregulation induced by a Western diet without any calorie restriction or weight loss. TRF improved insulin sensitivity and reduced hyperinsulinemia, liver steatosis, inflammation, and fibrosis. Importantly, TRF inhibited liver tumors in two mouse models of obesity-driven HCC. Our data suggest that TRF is likely to be effective in abrogating MASH and HCC and warrant further studies of time-restricted eating in humans with MASH who are at higher risk of developing HCC.

Primary extrahepatic biliary neuroendocrine tumor: a case report.

Extrahepatic biliary neuroendocrine tumors (EBNETs) are extremely rare and difficult to diagnose. The vast majority are diagnosed postoperatively on histological evaluation of surgical specimens. Workup and treatment principles are largely based on retrospective series and case reports. Complete surgical resection is the gold standard treatment for these lesions. Here we present a case of a 77-year-old male with a biopsy-proven EBNET incidentally discovered during evaluation for fatty liver disease. Further workup did not show any other suspicious lesions. Resection of the tumor and multiple Roux-en-Y hepaticojejunostomy was performed. Final pathology revealed grade 1, well-differentiated neuroendocrine tumor. This is the third case reported in the literature with a confirmed preoperative EBNET diagnosis based on endoscopic biopsy results. This case highlights the feasibility of preoperative diagnosis of EBNETs and emphasizes the importance of complete surgical resection.

ASK1 inhibition reduces cell death and hepatic fibrosis in an Nlrp3 mutant liver injury model.

Hepatic inflammasome activation is considered a major contributor to liver fibrosis in NASH. Apoptosis signal-regulating kinase 1 (ASK1) is an apical mitogen-activated protein kinase that activates hepatic JNK and p38 to promote apoptosis, inflammation, and fibrosis. The aim of the current study was to investigate whether pharmacologic inhibition of ASK1 could attenuate hepatic fibrosis driven by inflammasome activation using gain-of-function NOD-like receptor protein 3 (Nlrp3) mutant mice. Tamoxifen-inducible Nlrp3 knock-in (Nlrp3A350V/+CreT-KI) mice and WT mice were administered either control chow diet or diet containing the selective ASK1 inhibitor GS-444217 for 6 weeks. Livers of Nlrp3-KI mice had increased inflammation, cell death, and fibrosis and increased phosphorylation of ASK1, p38, and c-Jun. GS-444217 reduced ASK1 pathway activation, liver cell death, and liver fibrosis. ASK1 inhibition resulted in a significant downregulation of genes involved in collagen production and extracellular matrix deposition, as well as in a reduced hepatic TNF-α expression. ASK1 inhibition also directly reduced LPS-induced gene expression of Collagen 1A1 (Col1a1) in hepatic stellate cells isolated from Nlrp3-KI mice. In conclusion, ASK1 inhibition reduced liver cell death and fibrosis downstream of inflammatory signaling induced by NLRP3. These data provide mechanistic insight into the antifibrotic mechanisms of ASK1 inhibition.

Hodgkin's lymphoma with unusual pulmonary presentations: Reporting two cases.

Classical Hodgkin's lymphoma (CHL) presenting with exclusively pulmonary symptoms is very unusual. We report two cases of CHL with atypical clinical presentations mimicking pulmonary infections. The first case represents a stage IV CHL with secondary lung involvement, and the second case demonstrates a very rare case of CHL with isolated lung involvement, also known as primary pulmonary Hodgkin's lymphoma. The second patient was initially misdiagnosed and treated with six months of antibiotics before the correct diagnosis was made by a lung biopsy. Both patients received chemotherapy; one patient achieved complete remission and the other achieved near-complete remission.

Anaplastic Transformation of Papillary Thyroid Cancer in the Retroperitoneum.

Anaplastic thyroid carcinoma is an aggressive variant of thyroid cancer that in most cases arises from anaplastic transformation of terminally differentiated thyroid carcinomas. This process usually occurs in the thyroid or cervical lymph nodes. Anaplastic transformation in distant metastatic sites is exceedingly rare, only previously documented in a few case reports. We report a rare case of anaplastic transformation of papillary thyroid carcinoma within a large retroperitoneal metastasis in a 64-year-old male 30 years after the initial diagnosis.

Noninvasive determination of endothelial cell function in the microcirculation in Kawasaki syndrome.

The aim of the study was to noninvasively assess endothelial cell (EC) function in the microcirculation using laser Doppler fluximetry (LDF) in acute and convalescent Kawasaki syndrome (KS) patients and healthy controls. KS is an acute, self-limited vasculitis of childhood that affects the EC of medium-sized arteries. No studies have addressed EC function in the peripheral microcirculation. LDF preacetylcholine and postacetylcholine (ACh) iontophoresis estimates microcirculation EC nitric oxide production leading to smooth muscle relaxation and vasodilatation, which are blunted in EC dysfunction. We studied a total of 97 subjects: 36 acute and 27 convalescent KS patients and 34 normal children. Change in blood flow was measured by LDF for 10 min post-ACh iontophoresis. Acute KS patients had significantly lower average flux when compared to convalescent KS patients and controls in the first 5 min postiontophoresis. However, there was no difference in flux or area under the curve (AUC) between convalescent KS patients and healthy controls. Despite a reduced response of the microvascular EC to ACh in acute KS patients, convalescent patients with and without coronary aneurysms had microvascular EC function similar to normal controls. This suggests that the EC injury in KS is confined to the endothelium of medium-sized arteries and that microvascular EC function is normal after acute KS.