Table 1.
Principal clinical studies examining the association between hypothyroidism and NAFLD.
| Reference | Study Design | Study Sample | Diagnosis of NAFLD | Definition of Hypothyroidism | Main Findings |
|---|---|---|---|---|---|
| Liangpunsakul et al. 2003 [55] | Cross-sectional case-control study | 174 patients with NASH and 442 controls | Biopsy (all cases had NASH) | Self-reported use of levothyroxin | Hypothyroidism was independently associated with NASH (OR 2.30, 95% CI 1.20–4.20) |
| Reddy et al. 2007 [56] | Case-control study | 54 patients with HCC of unknown etiology and 2 groups of controls (57 HCC patients with HCV and 49 HCC patients with alcoholic liver disease) | Biopsy or clinical and imaging criteria | TSH > 5 mIU/L, history of hypothyroidism | Hypothyroidism is significantly higher prevalent in subjects with HCC of unknown etiology compared to controls with viral or alcoholic HCC |
| Silveira et al. 2009 [57] | Cross-sectional study | 97 patients with NAFLD | Biopsy | TSH > 5 mIU/L or < 0.3 mIU/L Total T4 > 12.5 μg/dL or < 5 μg/dL History of hyper/hypothyroidism |
The prevalence of hypothyroidism in patients with NAFLD was 20% |
| Xu et al. 2011 [58] | Cross-sectional study | 227 patients with NAFLD and 651 controls | Ultrasound | TSH > 4.5 mIU/L or < 0.5 mIU/L FT4 > 14.4 pmol/L or < 7.85 pmol/L |
Patients with hypothyroidism are more likely to develop NAFLD (p < 0.001), FT4 is a risk factor for NAFLD (OR = 0.847, 95% CI: 0.743–0.966) |
| Chung et al. 2012 [59] | Cross-sectional study | 2324 patients with hypothyroidism and 2324 controls | Ultrasound | Subclinical hypothyroidism: TSH > 4.1 mIU/L and normal FT4 Overt hypothyroidism: TSH > 4.1 mIU/L and FT4 < 0.7 ng/dL |
Hypothyroidism is an independent risk factor for NAFLD (OR = 1.38, 95% CI: 1.17–1.67) |
| Pagadala et al. 2012 [60] | Cross-sectional study | 233 patients with NAFLD and 430 controls | Biopsy | Clinical diagnosis and on thyroid replacement therapy | Prevalence of hypothyroidism was higher in NAFLD patients (21.1% vs. 9.5%, p < 0.001) |
| Xu et al. 2012 [61] | Prospective case-control study | 327 patients with subclinical hypothyroidism and 327 controls | Ultrasound (15% developed NAFLD after 4.9 years median follow-up) | TSH > 4.5 mIU/L and normal FT4 levels | Subclinical hypothyroidism was independently associated with risk of developing NAFLD (HR 2.21, 95% CI: 1.42–3.44) |
| Itterman et al. 2012 [62] | Population-based study | 3661 individuals without a self-reported history of thyroid or liver disease | Ultrasound (16.1% had NAFLD) | Subclinical hypothyroidism: TSH > 3 mIU/L and normal FT4 Overt hypothyroidism: TSH > 3 mIU/L and FT4 < 7 pmol/L |
Hypothyroidism was not independently associated with NAFLD. FT4 levels were inversely associated with NAFLD in men (OR 0.04, 95% CI: 0.01–0.17]) and in women (OR 0.06, 95% CI:0.01–0.42) |
| Eshraghian et al. 2013 [63] | Cross-sectional study | 832 individuals | Ultrasound (15.3% had NAFLD) | Subclinical hypothyroidism: TSH > 5.2 mIU/L and normal FT4 levels Overt hypothyroidism: TSH > 5.2 mIU/L and FT4 < 11.5 pmol/L |
Subclinical hypothyroidism was not associated with NAFLD (OR 1.12, 95% CI: 0.51–2.46). Overt hypothyroidism was not associated with NAFLD (OR 0.87, 95% CI: 0.33–2.28) |
| Posadas-Romero et al. 2014 [64] | Cross-sectional study | 753 adults | Computed tomography (31.1% with NAFLD) | Subclinical hypothyroidism: TSH > 4.5 mIU/L and normal FT4 | Subclinical hypothyroidism was not associated with NAFLD (OR 0.83, 95% CI: 0.55–1.25) |
| Lee et al. 2015 [65] | Retrospective cohort study | 18,544 individuals | Ultrasound | Subclinical hypothyroidism: TSH > 4.2 mIU/L, normal FT4 Overt hypothyroidism: TSH > 4.2 mIU/L, FT4 < 10.97 ng/dL |
NAFLD incidence did not differ significantly with thyroid hormonal status (Subclinical hypothyroidism: HR = 0.965, 95% CI = 0.814–1.143, p = 0.67; Overt hypothyroidism group: HR = 1.255, 95% CI = 0.830–1.899, p = 0.28) |
| Parikh et al. 2015 [66] | Case-control study | 500 patients with NAFLD and 300 controls | Ultrasound | Subclinical hypothyroidism: TSH > 5.5 IU/mL and <10 IU/mL) Overt hypothyroidism: TSH > 10 IU/mL) |
NAFLD was statistically significantly associated with hypothyroidism (OR: 14.94, 95% CI: 3.5–62.6) |
| Ludwig et al. 2015 [67] | Cross-sectional, population-based study | 1276 individuals | Ultrasound (24.7% with NAFLD) | Subclinical hypothyroidism: TSH > 3.4 mIU/L and normal total T4 Overt hypothyroidism: TSH > 3.4 mIU/L and total T4 < 12.8 pmol/L |
Hypothyroidism was not associated with NAFLD (OR 1.19 95% CI: 0.65–2.17) |
| Bano et al. 2016 [68] | Longitudinal prospective cohort study | 9419 euthyroid adults | Ultrasound (12.9% developed incident NAFLD after 10 years of median follow-up) | Subclinical hypothyroidism: TSH > 4.0 mIU/L and normal FT4 Overt hypothyroidism: TSH > 4.0 mIU/L and FT4 < 10.9 pmol/L |
Hypothyroidism was associated with a 1.24-fold higher NAFLD risk (95% CI: 1.01–1.53). NAFLD risk decreased gradually from hypothyroidism to hyperthyroidism (p for trend = 0.003). |
| Kim et al. 2018 [69] | Cross-sectional study | 425 patients with NAFLD | Biopsy | Subclinical hypothyroidism: TSH > 4.5 mIU/L and normal FT4 | Subclinical hypothyroidism was independently associated with NASH (OR 1.61, 95% CI: 1.04–2.50) and advanced fibrosis (OR 2.23 95% CI: 1.18–4.23). |
| Martinez Escude et al. 2020 [70] | Cross-sectional, retrospective population study |
10,116 adults | Ultrasound | Subclinical hypothyroidism: TSH > 4.94 UI/mL and normal T4 Overt hypothyroidism: elevated TSH and decreased T4 |
Hypothyroidism is not associated with NAFLD (p = 0.631) |
NAFLD: nonalcoholic fatty liver disease, NASH: nonalcoholic steatohepatitis, OR: odds ratio, CI: confidence intervals, HCC: hepatocellular carcinoma.