Subclinical and clinical hypothyroidism and non-alcoholic fatty liver disease: a cross-sectional study of a random population sample aged 18 to 65 years

Over the past decade, beginning with a study by Liangpunsakul and Chalasani in 2003 [14], the association between thyroid dysfunction and non-alcoholic fatty liver disease (NAFLD) has increasingly become a focus of research. After some controversial reports [24, 25], numerous studies have confirmed an association between thyroid function and NAFLD [13, 15, 26, 27]. Unfortunately, most studies have been characterized by either a relatively small or selected study collective, or by a gender imbalance [6, 14, 15, 28‐30]. In addition, study subjects were in many cases patients rather than being a collective representative of the general population [14, 29, 30]. By contrast, the present study, like those of Chung et al., Ittermann et al. und Zhang et al., is characterized by a balanced gender distribution and its large study collective representative of the general population [13, 27, 31]. In addition, with a mean age of 40.7 ± 12.7 years, our collective is one of the younger populations studied, and includes the age group with the highest prevalence of NAFLD [5, 6].

The findings of the present study agree in general with those reported from the cross-sectional study of Ittermann et al. In both studies, a significant inverse association between the FT4 concentration of NAFLD could be demonstrated, while no significant association could be identified for TT3 or TSH [31]. This underscores the importance of the TT4 or FT4 concentration as a marker for hepatic steatosis in the general population. By contrast, the TT3 concentration, both in the present study and in those of Ittermann et al. and Xu et al., had no identified value as a marker [6, 31]. This finding could related to an inhibition of the conversion of TT4 to TT3, possibly explaining the subordinate diagnostic role of the TT3 or FT3. Even the study of Chung et al., which presented clear evidence of the association between hypothyroidism and NAFLD, did not ascribe any diagnostic value to the TT3 concentration [13].

Beside the inverse association with FT4, Chung et al. and Xu et al. identified a positive association between NAFLD and TSH [6, 13]. This association was observed in other studies [28, 29]. The difference between these studies and the present investigation may be the result of a divergent classification of study subjects regarding thyroid function or differences in recruitment of subjects from population-based sources or from a patient collective. Data reported by Carulli et al. and Pagadala et al. suggest, in addition, that the TSH concentration is associated with the severity of the hepatic steatosis [15, 28].

The above observations point to a possible correlation between thyroid dysfunction and NAFLD. This correlation may be explained, on the one hand, by a significant association between thyroid dysfunction, a hypothyroid metabolic state and the metabolic syndrome [28, 32, 33]. Metabolic syndrome, in turn, is associated with NAFLD [1, 7, 9] and would point indirectly to a possible correlation between thyroid dysfunction and NAFLD. On the other hand, the correlation may be grounded in the association of reduced TT4 levels with hypertriglyceridemia and overweight. Beside studies which confirm the association between thyroid dysfunction, especially the hypothyroid metabolic state, and metabolic syndrome, there are studies with controversial findings [34, 35]. These studies highlight the correlation between NAFLD and thyroid dysfunction. For example, the study by Roos et al. shows a correlation between the FT4 level and triglycerides [33]. Our study would confirm this finding, as our data show a significant association between the TT4 level and triglycerides (p = 0.0027). These observations agree with the findings of other studies that suggest a correlation between hypothyroidism and hyperlipidemia [33, 36]. The increase in triglycerides in patients with hypothyroidism is explained by the reduced hepatic activity of triglyceride lipase [32, 33] and increased fatty acid oxidation. Loria et al. come to the conclusion that hepatic steatosis may develop from hypothyroidism-induced hyperlipidemia and overweight [17]. The development of hepatic steatosis may be explained by an increase influx of triglycerides and an imbalance between the in- and outflow of other lipids in the liver.

Because thyroid dysfunction, especially the hypothyroid metabolic state, affects the overall metabolism and may contribute to the development of hepatic steatosis and more serious forms of NAFLD, future interventional studies, similar to that of Ineck et al. should focus on treatment of thyroid dysfunction [18].

The present study has some limitations. Because of the choice of study design, it was possible to investigate associations but not causalities. While liver biopsy represents the gold standard for diagnosis of NAFLD [1], the diagnosis of hepatic steatosis in our study was made using ultrasonography. Also, because serum insulin levels were not determined in fasting subjects and thus could not be used, insulin resistance was not assessed in this study as a possible factor impacting the association between thyroid dysfunction and NAFLD.