Background and Aims: We previously identified subsets of patients with NAFLD with different metabolic phenotypes. Here we align metabolomic signatures with cardiovascular disease (CVD) and genetic risk factors. Approach and Results: We analyzed serum metabolome from 1154 individuals with biopsy-proven NAFLD, and from four mouse models of NAFLD with impaired VLDL-triglyceride (TG) secretion, and one with normal VLDL-TG secretion. We identified three metabolic subtypes: A (47%), B (27%), and C (26%). Subtype A phenocopied the metabolome of mice with impaired VLDL-TG secretion; subtype C phenocopied the metabolome of mice with normal VLDL-TG; and subtype B showed an intermediate signature. The percent of patients with NASH and fibrosis was comparable among subtypes, although subtypes B and C exhibited higher liver enzymes. Serum VLDL-TG levels and secretion rate were lower among subtype A compared with subtypes B and C. Subtype A VLDL-TG and VLDL-apolipoprotein B concentrations were independent of steatosis, whereas subtypes B and C showed an association with these parameters. Serum TG, cholesterol, VLDL, small dense LDL 5,6 , and remnant lipoprotein cholesterol were lower among subtype A compared with subtypes B and C. The 10-year high risk of CVD, measured with the Framingham risk score, and the frequency of patatin-like phospholipase domain-containing protein 3 NAFLD risk allele were lower in subtype A. Conclusions: Metabolomic signatures identify three NAFLD subgroups, independent of histological disease severity. These signatures align with known CVD and genetic risk factors, with subtype A exhibiting a lower CVD risk profile. This may account for the variation in hepatic versus cardiovascular outcomes, offering clinically relevant risk stratification.
This case stresses the fact that an adequate and detailed history on concomitant medication is mandatory in patients who present with cryptic hepatitis. Though severe hepatic adverse effects of phenprocoumon are rare, physicians should consider coumarin derivatives as a potential source of hepatitis.
Alcohol consumption represents a major factor of morbidity and mortality, with a wide range of adverse medical implications that practically affect every organ system. It is the fifth major cause of deaths in men and women and causes up to 139 million disability-adjusted life years. Solid evidence places the risk as undoubtedly correlated to the length of time and amount of alcohol consumption. While alcohol-related liver disease represents one of the most studied and well-known consequences of alcohol use, the term itself embodies a wide spectrum of progressive disease stages that are responsible for almost half of the liver-related mortality worldwide. We discuss the staged alcohol-related fatty liver, alcohol-related steatohepatitis and, finally, fibrosis and cirrhosis, which ultimately may end up in a hepatocellular carcinoma. Other comorbidities such as acute and chronic pancreatitis; central nervous system; cardiovascular, respiratory and endocrine system; renal disease; urological pathologies; type 2 diabetes mellitus and even infectious diseases are reviewed in their relation to alcohol consumption. This article reviews the impact of alcohol use on different systems and organs, summarizing available evidence regarding its medical implications. It examines current basic and clinical data regarding mechanisms to highlight factors and processes that may be targetable to improve patient outcomes. Although alcohol use is a part of many cultural and social practices, as healthcare providers we must identify populations at high risk of alcohol abuse, educate patients about the potential alcohol-related harm and provide appropriate treatment.
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