There is increasing evidence for the role of gut microbial composition in the pathogenesis of nonalcoholic fatty liver disease (NAFLD). Nonalcoholic steatohepatitis (NASH) is the most serious form of NAFLD where inflammation causes liver damage that can progress to cirrhosis. We have characterized the gut microbiome composition in UK patients with biopsy-proven NASH (n = 65) and compared it to that in healthy controls (n = 76). We report a 7% lower Shannon alpha diversity in NASH patients without cirrhosis (n = 40) compared to controls (p = 2.7x 10 −4) and a 14% drop in NASH patients with cirrhosis (n = 25, p = 5.0x 10 −4). Beta diversity (Unweighted UniFrac distance) was also significantly reduced in both NASH (p = 5.6x 10 −25) and NASH-cirrhosis (p = 8.1x 10 −7) groups. The genus most strongly associated with NASH in this study was Collinsella (0.29% abundance in controls, 3.45% in NASH without cirrhosis (False Discovery Rate (FDR) p = .008), and 4.38% in NASH with cirrhosis (FDR p = .02)). This genus, which has been linked previously to obesity and atherosclerosis, was also positively correlated with fasting levels of triglycerides (p = .01) and total cholesterol (p = 1.2x 10 −4) and negatively correlated with high-density lipoprotein cholesterol (p = 2.8x 10 −6) suggesting that some of the pathways present in this microbial genus may influence lipid metabolism in the host. In patients, we also found decreased abundance of some of the Ruminococcaceae which are known to produce high levels of short-chain fatty acids which can lower inflammation. This may thus contribute to pathology associated with NASH.
Background & Aims: No multi-national prospective study of drug-induced liver injury (DILI) has originated from Europe. The design of a prospective European DILI registry, clinica l features and short-term outcomes of the cases and controls is reported.Methods: Patients with suspected DILI were prospectively enrolled in the United Kingdom,
Background
Zanubrutinib is a Bruton’s tyrosine kinase inhibitor that has been recently licensed in refractory mantle cell lymphoma and under assessment in phase 3 clinical trials for other B cell malignancies. To date, there are no reported cases of hepatotoxicity secondary to zanubrutinib. We report the first case of severe liver injury due to zanubrutinib.
Case presentation
A 56-year-old Caucasian male with a history of relapsed lymphoplasmacytic lymphoma was admitted to the hospital with new-onset jaundice, choluria, and pruritus for 10 days. He had been on zanubrutinib as part of a clinical trial for 30 months. His blood profile showed a severe hepatocellular injury with jaundice (alanine transaminase 2474 IU/L and total bilirubin 141 umol/L with mild coagulopathy). He had an extensive work-up including virology, autoimmune, and metabolic profiles in addition to abdominal ultrasound with no alternative explanation found for his liver injury. Zanubrutinib-induced liver injury was suspected, and causality assessment by the updated Roussel Uclaf Causality Assessment Method score showed a probable causal relationship with zanubrutinib. His liver histology was also consistent with drug-induced liver injury. His liver biochemistry improved following cessation of zanubrutinib and normalised after 8 weeks.
Conclusion
We report the first case of severe liver injury secondary to zanubrutinib after 30 months of treatment. This case raises clinical awareness regarding zanubrutinib-induced liver toxicity and the importance of drug withdrawal in the event of liver injury.
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