PNPLA3-Associated Steatohepatitis: Toward a Gene-Based Classification of Fatty Liver Disease

Department of Medicine II, Saarland University Medical Center, Homburg, Germany.
Seminars in Liver Disease (Impact Factor: 4.95). 11/2013; 33(4):369-79. DOI: 10.1055/s-0033-1358525
Source: PubMed


Nonalcoholic fatty liver disease is one of the most common hepatic disorders worldwide. Given the high-calorie nutrition of children and adults, nonalcoholic fatty liver disease (NAFLD) is expected to become a major cause of cirrhosis and eventually liver transplantation. Familial clustering and ethnic differences indicate that genetic factors contribute to NAFLD. Recently, the common variant p.I148M of the enzyme adiponutrin (PNPLA3) has emerged as a major genetic determinant of hepatic steatosis and nonalcoholic steatohepatitis as well as its pathobiological sequelae fibrosis, cirrhosis, and hepatocellular cancer. PNPLA3 encodes a lipid droplet-associated, carbohydrate-regulated lipogenic and/or lipolytic enzyme. Homozygous carriers of the PNPLA3 variant are prone to develop cirrhosis in the absence of other risk factors such as alcohol or viral hepatitis. Here we review the plethora of studies that unraveled the association between PNPLA3 and NAFLD in children and adults, discuss its distinct effects on liver and metabolic traits, and introduce the term PNPLA3-associated steatohepatitis (PASH) as a novel gene-based liver disease. Given the prevalence of the risk allele in 40 to 50% of Europeans, the authors conclude that PNPLA3 should be considered in the diagnostic workup of fatty liver disease and that homozygous risk allele carriers might benefit from careful cancer surveillance.

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    ABSTRACT: The common PNPLA3 (adiponutrin) variant p.I148M represents a major genetic driver of progression in non-alcoholic fatty liver disease (NAFLD). NAFLD is commonly associated with traits of the metabolic syndrome, therefore it is mostly suspected in obese individuals. Here, we investigate the association between the PNPLA3 variant and anthropometric traits in a cohort of healthy individuals. We recruited 1,000 (500 females; age 18 - 66 years) healthy blood donors. The PNPLA3 variant was genotyped using TaqMan assays. All individuals were phenotyped with respect to anthropometric characteristics. We also determined the percentage of total fat (F%) and active tissue (TA%) of body weight. Healthy carriers of the PNPLA3 [IM] and [MM] genotypes, although not differing in height from individuals with the genotype [II], displayed significantly lower body weight and lower BMI (both P = 0.005), higher TA% (P = 0.03) but lower F% (P = 0.03) and smaller waist, chest and shin circumferences (all P < 0.05). Separate analysis for males and females demonstrated an association between the [IM] and [MM] genotypes and higher TA% but lower F% (P = 0.04) in females. In males, BMI and total weight were significantly (P = 0.04) lower among carriers of the [M] allele. Healthy individuals carrying the prosteatotic PNPLA3 allele p.I48M may be leaner as compared to the carriers of the common allele. Hence in clinical practice they might be overlooked since they do not necessarily present with the anthropometric characteristics commonly associated with severe hepatic steatosis.
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    ABSTRACT: Background The distinction between definitive nonalcoholic steatohepatitis (NASH) and other histological patterns of nonalcoholic fatty liver disease (NAFLD) continues to rely on liver biopsy, which has risks and limitations. Objectives We explored the usefulness of a Bayesian approach to establish the likelihood ratios (LRs) of different noninvasive diagnostic modalities (circulating cytokeratin-18 fragment levels, hydrogen breath test, transient elastography) for distinguishing definitive NASH from other forms of NAFLD. Patients and methods From a series of 235 consecutive patients with biopsy-proven NAFLD enrolled at a tertiary referral hepatology clinic, we identified 135 patients with definitive NASH and 100 with other forms of NAFLD. Bayesian probabilities in the form of LRs were estimated for predicting definitive NASH. Results In conditional logistic regression models, the probability of having definitive NASH was associated with diabetes mellitus [ odds ratio (OR) 2.89; 95% confidence interval (CI) 1.71-4.85], positive transient elastography results (OR 2.11; 95% CI 1.08-4.09), and apoptosis marker M30 (OR 2.57; 95% CI 1.78-3.93). We then estimated the LRs for variables independently related to definitive NASH, which were as follows: diabetes(+) LR = 2.42; M30(+) LR = 2.12; and transient elastography(+) LR = 1.77. On the basis of the LR form of Bayes' theorem, the prediction model that took into account diabetes, M30 measurements, and the results of transient elastography at a tertiary hospital determined an 81% probability of distinguishing definitive NASH from other forms of NAFLD. Conclusion A Bayesian approach combining clinical, laboratory, and imaging data may be useful for identifying patients with the highest probability of having definitive NASH. (C) 2014 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins.
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