Non-alcoholic fatty liver disease (NAFLD) is the hepatic manifestation of metabolic syndrome and the leading cause of chronic liver disease in the Western world. Twenty per cent of NAFLD individuals develop chronic hepatic inflammation (non-alcoholic steatohepatitis, NASH) associated with cirrhosis, portal hypertension and hepatocellular carcinoma, yet the causes of progression from NAFLD to NASH remain obscure. Here, we show that the NLRP6 and NLRP3 inflammasomes and the effector protein IL-18 negatively regulate NAFLD/NASH progression, as well as multiple aspects of metabolic syndrome via modulation of the gut microbiota. Different mouse models reveal that inflammasome-deficiency-associated changes in the configuration of the gut microbiota are associated with exacerbated hepatic steatosis and inflammation through influx of TLR4 and TLR9 agonists into the portal circulation, leading to enhanced hepatic tumour-necrosis factor (TNF)-α expression that drives NASH progression. Furthermore, co-housing of inflammasome-deficient mice with wild-type mice results in exacerbation of hepatic steatosis and obesity. Thus, altered interactions between the gut microbiota and the host, produced by defective NLRP3 and NLRP6 inflammasome sensing, may govern the rate of progression of multiple metabolic syndrome-associated abnormalities, highlighting the central role of the microbiota in the pathogenesis of heretofore seemingly unrelated systemic auto-inflammatory and metabolic disorders. An expansion of Porphyromonadaceae in the gut is linked to the pathogenesis and progression of non-alcoholic fatty liver disease/non-alcoholic steatohepatitis in the mouse. Using a mouse model, Richard Flavell and co-workers study the inflammatory processes associated with progression from non-alcoholic fatty liver disease — the leading cause of chronic liver disease in developed countries — to the more severe non-alcoholic steatohepatitis, which often leads to cirrhosis and hepatocellular carcinoma. They find that alterations of the intestinal microbiota associated with the NLRP6 and NLRP3 inflammasomes enhance disease in mice with diet-induced non-alcoholic fatty liver syndrome. These findings highlight the pivotal role of the microbiota in the development of autoinflammatory and metabolic disorders, and point to the manipulation of host–microflora interactions as a focus for new therapies.

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Inflammasome-mediated dysbiosis regulates progression of NAFLD and obesity

Background An increasing proportion of deaths among human immunodeficiency virus (HIV)-infected persons with access to combination antiretroviral therapy (cART) are due to complications of liver diseases. Methods We investigated the frequency of and risk factors associated with liver-related deaths in the Data Collection on Adverse Events of Anti-HIV Drugs study, which prospectively evaluated 76 893 person-years of follow-up in 23 441 HIV-infected persons. Multivariable Poisson regression analyses identified factors associated with liver-related, AIDS-related, and other causes of death. Results There were 1246 deaths (5.3%; 1.6 per 100 person-years); 14.5% were from liver-related causes. Of these, 16.9% had active hepatitis B virus (HBV), 66.1% had hepatitis C virus (HCV), and 7.1% had dual viral hepatitis co-infections. Predictors of liver-related deaths were latest CD4 cell count (adjusted relative rate [RR], 16.1; 95% confidence interval [CI], 8.1-31.7 for or =500/microL), age (RR, 1.3; 95% CI, 1.2-1.4 per 5 years older), intravenous drug use (RR, 2.0; 95% CI, 1.2-3.4), HCV infection (RR, 6.7; 95% CI, 4.0-11.2), and active HBV infection (RR, 3.7; 95% CI, 2.4-5.9). Univariable analyses showed no relationship between cumulative years patients were receiving cART and liver-related death (RR, 1.00; 95% CI, 0.93-1.07). Adjustment for the most recent CD4 cell count and patient characteristics resulted in an increased risk of liver-related mortality per year of mono or dual antiretroviral therapy before cART (RR, 1.09; 95% CI, 1.02-1.16; P = .008) and per year of cART (RR, 1.11; 95% CI, 1.02-1.21; P = .02). Conclusions Liver-related death was the most frequent cause of non-AIDS-related death. We found a strong association between immunodeficiency and risk of liver-related death. Longer follow-up is required to investigate whether clinically significant treatment-associated liver-related mortality will develop.

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Liver-related deaths in persons infected with the human immunodeficiency virus: the D:A:D study

https://aasldpubs.onlinelibrary.wiley.com/doi/pdf/10.1002/hep.24452

Diagnostic accuracy and reliability of ultrasonography for the detection of fatty liver: A meta‐analysis

https://www.gastrojournal.org/article/S0016-5085(02)60385-3/pdf

The association between hepatitis C infection and survival after orthotopic liver transplantation.

https://www.journal-of-hepatology.eu/article/S0168-8278(00)80231-7/pdf

HCV-related fibrosis progression following liver transplantation: increase in recent years

https://aasldpubs.onlinelibrary.wiley.com/doi/epdf/10.1002/hep.510280333

Predictors of patient and graft survival following liver transplantation for hepatitis C

TT‐virus infection in north american blood donors, patients with fulminant hepatic failure, and cryptogenic cirrhosis

https://aasldpubs.onlinelibrary.wiley.com/doi/pdf/10.1002/hep.22246

Michael Charlton

Papers

Predictors of patient and graft survival following liver transplantation for hepatitis C

TT‐virus infection in north american blood donors, patients with fulminant hepatic failure, and cryptogenic cirrhosis

Cirrhosis and liver failure in nonalcoholic fatty liver disease: Molehill or mountain?

Boceprevir (Victrelis) for HCV: V is for victory and very complex.

Medical hurricane: health care reform and hepatology.