Impact of subclinical hypothyroidism on the development of non-alcoholic fatty liver disease: A prospective case-control study
Authors: Lei Xu, Han Ma, Min Miao, Youming Li
Journal: Journal of Hepatology (2012)

Non-alcoholic fatty liver disease across the spectrum of hypothyroidismJournal of HepatologyVol. 57Issue 1PreviewThe aim of this study was to characterize the relationship between the broad spectrum of hypothyroidism and NAFLD. Full-Text PDF We read with great interest the article by Chung et al. [[1]Chung G.E. Kim D. Kim W. Yim J.Y. Park M.J. Kim Y.J. et al.Non-alcoholic fatty liver disease across the spectrum of hypothyroidism.J Hepatol. 2012; 57: 150-156Abstract Full Text Full Text PDF PubMed Scopus (205) Google Scholar] showing that subclinical hypothyroidism, even in the range of upper normal thyroid stimulating hormone (TSH) levels, was closely associated with non-alcoholic fatty liver disease (NAFLD) in a dose-dependent manner. Their results indeed provided important evidence, confirming the close relationship between these two diseases. However, as mentioned by the authors, the causal relationship between hypothyroidism and NAFLD could not be identified by their cross-sectional study. Recently, we have performed a prospective case-control study to evaluate the impact of subclinical hypothyroidism on the development of NAFLD in a Chinese population. The study was conducted among the employees of Zhenhai Refining & Chemical Company Ltd., Ningbo, China, since 2006. The study population was described in detail in our previous studies [2Xu C. Yu C. Xu L. Miao M. Li Y. High serum uric acid increases the risk for nonalcoholic Fatty liver disease: a prospective observational study.PLoS One. 2010; 5: e11578Crossref PubMed Scopus (124) Google Scholar, 3Yu C. Xu C. Xu L. Yu J. Miao M. Li Y. Serum proteomic analysis revealed diagnostic value of hemoglobin for nonalcoholicfatty liver disease.J Hepatol. 2012; 56: 241-247Abstract Full Text Full Text PDF PubMed Scopus (75) Google Scholar]. A total of 327 subclinical hypothyroidism subjects were enrolled. Age, gender, and body mass index (BMI) are three major factors that may influence the development of NAFLD. To reduce the influence of these variables, we randomly selected 327 age, gender, and BMI matched euthyroid subjects as controls. All the subjects were free of NAFLD at baseline, and did not have a history of excessive alcohol consumption or liver disease. Subclinical hypothyroidism was defined as a TSH level of 4.5 mIU/L or greater, after excluding subjects with an abnormal thyroxine level [4Surks M.I. Ortiz E. Daniels G.H. Sawin C.T. Col N.F. Cobin R.H. et al.Subclinical thyroid disease: scientific review and guidelines for diagnosis and management.JAMA. 2004; 291: 228-238Crossref PubMed Scopus (1546) Google Scholar, 5Rodondi N. Newman A.B. Vittinghoff E. de Rekeneire N. Satterfield S. Harris T.B. et al.Subclinical hypothyroidism and the risk of heart failure, other cardiovascularevents, and death.Arch Intern Med. 2005; 165: 2460-2466Crossref PubMed Scopus (410) Google Scholar]. NAFLD was diagnosed based on the results of abdominal ultrasonography, after exclusion of alcohol consumption, viral, or autoimmune liver disease [6Bedogni G. Miglioli L. Masutti F. Tiribelli C. Marchesini G. Bellentani S. Prevalence of and risk factors for nonalcoholic fatty liver disease: the Dionysos nutrition and liver study.Hepatology. 2005; 42: 44-52Crossref PubMed Scopus (1058) Google Scholar, 7Cerda C. Perez-Ayuso R.M. Riquelme A. Soza A. Villaseca P. Sir-Petermann T. et al.Nonalcoholic fatty liver disease in women with polycystic ovary syndrome.J Hepatol. 2007; 47: 412-417Abstract Full Text Full Text PDF PubMed Scopus (170) Google Scholar]. The development of NAFLD was evaluated annually during follow-up by ultrasound examination, using a Toshiba Nemio 20 sonography machine with a 3.5-MHz probe (Toshiba, Tokyo, Japan). Ultrasound studies were carried out by experienced ultrasonographists who were blinded to the clinical and laboratory data. A total of 63 subclinical hypothyroidism subjects and 35 euthyroid subjects developed NAFLD during a median follow-up of 4.92 years. Compared to the euthyroid subjects, the incidence of NAFLD for 1000 person-years of follow-up was significantly higher in the subjects with subclinical hypothyroidism (38.3 vs. 21.8; p <0.05). Subclinical hypothyroidism subjects were further classified into three subgroups according to their TSH levels: 4.5–6.9 mIU/L (mild elevation), 7.0–9.9 mIU/L (moderate elevation), and 10.0 mIU/L or greater (severe elevation). The incidence of NAFLD showed an increased trend with increasing TSH levels. The incidence of NAFLD per 1000 person-years of follow-up was 21.8, 34.2, 48.3 and 52.5 for the euthyroid, mild, moderate and severe elevation subgroup, respectively (p <0.05 for trend). This observation indicated that subjects with higher baseline TSH levels are more likely to develop NAFLD during the follow-up period. Cox proportional hazards regression analyses were used to estimate hazard ratios for incident NAFLD for subclinical hypothyroidism over the follow-up period. Our analysis showed that subclinical hypothyroidism was a risk factor for the development of NAFLD in the unadjusted model, the hazard ratio (95% CI) was 1.77 (1.17–2.67). The metabolic syndrome is a major mediating variable for the studied relationship. Therefore, we further adjusted the indicators of the metabolic syndrome in the Cox proportional hazards regression analysis. Our result showed that the relationship of subclinical hypothyroidism with incident NAFLD remained significant even after further adjustment for the indicators of the metabolic syndrome, including waist circumference, systolic blood pressure, diastolic blood pressure, triglyceride, HDL cholesterol and fasting plasma glucose, the adjusted hazard ratio (95% CI) was 2.21 (1.42–3.44). These results indicated that subclinical hypothyroidism is an independent factor that predicts the development of NAFLD. A limitation of this study is that ultrasound examination is not sensitive enough to detect mild steatosis. However, ultrasonography is the most commonly used in epidemiological surveys of NAFLD. Ultrasonography has the advantage of being non-invasive, safe, widely available, and sensitivity for detecting hepatic steatosis is acceptable. Another limitation is that the causal relationship between subclinical hypothyroidism and development of NAFLD could not been drawn by this study. Further evidence is needed to clarify this issue. Taken together, our prospective case-control study provided evidence that subclinical hypothyroidism is a significant factor associated with NAFLD development. This finding may have important clinical implications for disease therapy and prevention. The authors who have taken part in this study declared that they do not have anything to disclose regarding conflict of interest with respect to this manuscript. This study was supported by National Natural Science Foundation of China (Nos. 31070315, 81170378, and 81100278), National Science and Technology Support Plan Project (No. 2012BAI06B04), and National Key Basic Research Development Program (No. 2012CB524905).