The association of metabolic syndrome severity with outcomes and survival in non-alcoholic fatty liver disease: a population study of adults in the United States

Background: Non-Alcoholic Fatty Liver Disease (NAFLD) is the most common cause of chronic liver disease. The current global prevalence of NAFLD is 25%, while 26% of adults in the United States (US) are estimated to have NAFLD. At Present, NAFLD related fibrosis is projected to be the leading cause of liver transplantation in the coming years. NAFLD patients have a 1.7-fold increased risk of mortality, yet there are no pharmacologic or other modalities of treatment for this disease. Due to the primary function obesity-induced insulin resistance plays in promoting liver steatosis, NAFLD is regarded as the hepatic manifestation of Metabolic Syndrome (MetS). Despite knowledge of the association between MetS related metabolic abnormalities and NAFLD, it is not known why only some MetS patients develop NAFLD. It is also unknown as to why some NAFLD patients progress to more severe hepatic manifestation, while others do not. Furthermore, the impacts of MetS severity on the risk of mortality in NAFLD are not fully explained. Previously conducted research has solely focused on recognizing the presence of MetS as a risk factor for disease progression without accounting for the effects of its severity on the increased risk of morbidity and mortality in NAFLD. The limitations of the dichotomous definition of MetS in relation to outcomes in NAFLD could be fully addressed by using a continuous measure of MetS severity that encapsulates the effects of all five metabolic features in one summary risk score. Specific Aims: The main objectives of this dissertation were to utilize the MetS severity score, a validated gender-race specific Z-score, to assess the association between MetS severity and 1) the odds of NAFLD occurrence, 2) the odds of advanced fibrosis presence in NAFLD, and the risks of all-cause mortality, heart disease-related mortality, diabetes-related mortality and hypertension-related mortality in NAFLD. Methods and Materials: The study included 10,605 adults ages 20 to 74 years who participated in the Third National Health and Nutrition Examination Survey and met all inclusion and exclusion criteria. All five metabolic features (i.e., high-density lipoprotein, systolic blood pressure, waist circumference, triglycerides, and blood glucose) were used to calculate gender-race specific MetS severity Z-scores, which were then transformed into four percentiles-based categories [mild (0th-50th), moderate (>50th-75th), high (>75th-90th), very high (>90th+)]. NAFLD was defined as mild, moderate, or severe hepatic steatosis on ultrasound in the absence of hepatitis B virus, hepatitis C virus, iron overload, and excessive alcohol intake. The Nonalcoholic Fatty Liver Disease Fibrosis Score (NFS) was used to estimate the probability of advanced fibrosis presence. An individual NFS value of ≥ -1.455 was used to define an intermediate to high advanced fibrosis probability, while a score of >0.676 was classified as a high probability of advanced fibrosis. A validated matching algorithm was used to link participants’ baseline characteristics with mortality outcomes obtained from the National Death Index database. Both adjusted multivariable logistic regression models and Cox proportional hazard models were used to examine the associations between MetS severity and the odds of NAFLD, odds of advanced fibrosis in NAFLD, and the risk of mortality in NAFLD. Results: At baseline, the prevalence of NAFLD was 26.7% (95% CI; 24.3% ⎯ 29.1%). Stratified by race/ethnicity, NAFLD prevalence was 26.7%, 23.3%, and 33.7% amongst White non-Hispanics, Black non-Hispanics, and Mexican Americans, respectively. We observed racial/ethnic disparities in age adjusted prevalence of all five metabolic abnormalities for both male and female patients with NAFLD. The prevalence of the traditionally defined MetS was higher in NAFLD patients compared to those without NAFLD (44.0% vs. 20.4%; P-value <0.001). Both the mean and median MetS severity scores were significantly higher in NAFLD relative to those without [mean MetS severity Z-score (percentile), 0.48 (61st) vs. -0.14 (46th); median MetS severity Z-score (percentile), 0.48 (69th) vs. -0.23 (41st)]. In those with mild, moderate, high, and very high MetS severity, the age adjusted NAFLD prevalence was 17.4%, 25.7%, 42.5, and 54.9% (P-trend