Non-alcoholic fatty liver disease and thyroid dysfunction: A systematic review

Table 1 Main characteristics and findings of the studies

Study	Design	Number	Method for diagnosis of NAFLD/NASH	Definition of thyroid dysfunction	Main Findings
Chung et al[13]	Cross-sectional	4648 (2324 Hypothyroidism vs 2324 euthyroidism)	Ultrasonography	Subclinical hypothyroidism: TSH > 4.1 mIU/L and normal fT	Prevalence of NAFLD increased with severity of hypothyroidism (subclinical: 29.9%, overt: 36.3%)
				Overt hypothyroidism: TSH > 4.1 mIU/L and fT4 < 0.7 ng/Dl	Prevalence of NAFLD plus elevated ALT was higher in patients with hypothyroidism (P < 0.001)
					Hypothyroidism is an independent risk factor for increased prevalence of NAFLD (OR = 1.38, 95%CI: 1.17-1.67)
Liangpunsakul et al[14]	Case-control	174 NASH patients compared with 442 controls	Liver biopsy Liver biopsy	Previous history of hypothyroidism on T4 replacement therapy	Prevalence of hypothyroidism was 15 % compared to 7.2% in controls (P < 0.001)
					In multivariate analysis, hypothyroidism was more prevalent than controls (OR = 2.3, 95%CI: 1.2-4.2, P = 0.008)
Silveira et al[15]	Cross-sectional	97 patients with NAFLD Compared with 67 PBC, and 79PSC	Liver biopsy	TSH > 5 mIU/L or < 0.3 mIU/L	The prevalence of hypothyroidism in patients with NAFLD was 20%
				Total thyroxine> 12.5 μg/dL or < 5 μg/dL	Five patients had hyperthyroidism in NAFLD group
				History of hyper/hypo thyroidism	The prevalence of thyroid dysfunction was not different in three group
Pagadala et al[16]	Cross-sectional	233 patients with NAFLD Compared to 430 controls	Liver biopsy	Clinical diagnosis of hypothyroidism and on thyroid replacement therapy	The prevalence of hypothyroidism was higher in NAFLD patients compared to controls (21.1% vs 9.5%, P < 0.001)
					Hypothyroidism was more common in NASH compared to patients without NASH (P = 0.03)
Xu et al[17]	Cross-sectional	227 patients with NAFLD Compared with 651 controls	Ultrasonography	TSH > 4.5 mIU/L or < 0.5 mIU/L	Patients with lower FT4 or higher TSH are more likely to develop NAFLD (P < 0.001)
				fT4 > 14.4 pmol/L or < 7.85 pmol/L	in logistic regression analysis Ft4 was a risk factor for NAFLD (OR = 0.847, 95%CI: 0.743-0.966)
Mazo et al[18]	Retrospective	33 patients with steatosis Compared with 70 NASH patients	Liver biopsy	History of hypothyroidism on thyroid replacement therapy	Prevalence of hypothyroidism was 15.5% in NAFLD (15.2% in steatosis and 15.7% in NASH)
					In multivariate analysis insulin, HOMA index and AST were correlated with hypothyroidism
					No direct association between NASH and hypothyroidism
Moustafa et al[19]	Cross-sectional	90 patients with NASH, Chronic HCV, HCV cirrhosis compared to 20 healthy controls	Ultrasonography	Only determined thyroid hormone without normal range	The serum TSH level in NASH patients was higher than healthy controls (2.1 ± 0.75 μIU/mL vs 1.75 ± 0.9 μIU/mL
Carulli et al[20]	Cross-sectional	69 NAFLD, 25 steatosis, 44 NASH	Liver biopsy	Normal range: TSH: 0.35-4.5 μIU/mL	TSH level was significantly higher in NASH compared to steatosis group
				FT4: 6.1-16.6 pg/mL; FT3: 1.7-4.2 pg/mL	TSH level was an independent positive risk factor for NASH in logistic regression analysis (OR = 2.34, 95%CI: 1.15-4.776)
Zhang et al[21]	Cross-sectional	1322 participants including 266 patients with NAFLD	Ultrasonography	Normal TSH range: 0.71-6.25 mIU/mL	In female patient with NAFLD serum TSH level was significantly higher than controls (P < 0.05)
					In logistic regression analysis TSH level was not an independent risk factor for NAFLD
Ittermann et al[22]	Cross-sectional	3661 healthy appearing participants	Ultrasonography	Thyroid hormone and TSH below or Above normal range	Low FT4 concentrations are associated with hepatic steatosis
					No consistent association between TSH and hepatic steatosis
					No association between hyper- or hypothyroidism and hepatic steatosis
Eshraghian et al[23]	Cross-sectional	832 healthy appearing participants	Ultrasonography	Normal TSH range: 0.2- 5.2 mIU/mL	No association between hyper- or hypothyroidism and NAFLD
				-FT4: 11.5-23 pmol/L	No association between thyroid autoimmunity and NAFLD
					The diagnosis of NAFLD was higher among low TSH group
					The thyroid hormone abnormalities may be due to sick euthyroid syndrome

TSH: Thyroid stimulating hormone; NAFLD: Nonalcoholic fatty liver disease; NASH: Nonalcoholic steatohepatitis, ALT: Alanine aminotransferase; PSC: Primary sclerosing cholangitis; PBC: Primary biliary cirrhosis; HCV: Hepatitis C virus; AST: Aspartate aminotransferase.