Association between thyroid function and nonalcoholic fatty liver disease: a dose-response meta-analysis.

Frontiers in endocrinology. 2024;15:1399517
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Plain language summary

Non-alcoholic fatty liver disease (NAFLD) affects about a quarter of the world’s population. Thyroid hormones, including thyroxine (T4), 3-iodothyronine (T3) and thyroid-stimulating hormone (TSH), are essential for lipid metabolism in the liver. The aim of this meta-analysis of observational studies was to evaluate the association between thyroid hormones and NAFLD. 7 cohort and 3 case-control studies with a total of 38,425 individuals were included in the meta-analysis. When comparing high versus low levels of thyroid hormones, no significant association with risk of NAFLD was found for T4 or TSH whilst high levels of T3 were associated with a 58% increased risk of NAFLD (based on 2 studies, 7442 participants). Higher levels of TSH were associated with a higher risk of liver fibrosis, whilst there was no correlation between T4 or T3 and liver fibrosis (based on 5 articles, 2508 participants). In dose-response analysis for TSH and T4, a U-shaped relationship between the thyroid hormones and NAFLD was found. There was no dose-response relationship between TSH or T4 and fibrosis. There was insufficient data for a dose-response analysis for T3.

Expert Review


Conflicts of interest: None

Take Home Message:
  • Thyroid hormones are closely associated with non-alcoholic fatty liver disease and play an important role in lipogenesis, beta-oxidation, cholesterol metabolism and carbohydrate metabolism.
  • Therefore, monitoring of thyroid levels may be useful for nutrition practitioners when considering NAFLD.

Evidence Category:
  • X A: Meta-analyses, position-stands, randomized-controlled trials (RCTs)
  • B: Systematic reviews including RCTs of limited number
  • C: Non-randomized trials, observational studies, narrative reviews
  • D: Case-reports, evidence-based clinical findings
  • E: Opinion piece, other

Summary Review:
Introduction

This dose-response meta-analysis of observational studies investigated the dosage-dependent correlation between thyroid hormone (TH) levels and non-alcoholic fatty liver disease (NAFLD).

Methods

The meta-analysis followed the PRISMA guidelines and was registered on PROSPERO. PubMed, Web of Science, Cochrane Library and Embase databases were searched from inception to February 2023.

10 studies published between 2015 and 2022 were included in the meta-analysis of 38,425 individual, with a follow-up period between 1 and 10 years. On the Newcastle-Ottawa Scale assessment all studies were of high quality.

Results

Analysis used combined risk ratios (ORs) with 95% CIs, a random effects model and a robust-error meta-regression (REMR) model to achieve an “average” dose-response relationship between thyroid hormones and NAFLD. Cochrane Q statistic and the I2 statistic evaluated heterogeneity among the studies. Key findings were as follows:

  • High levels of free triiodothyronine (FT3) were associated with a high risk of NAFLD, and a nonlinear inverse association was found between elevated free thyroxine (FT4) and incidence of NAFLD (OR=1.580, 95%CI 1.370 to 1.830, I2= 0.0%, p<0.001).
  • High serum thyroid stimulating hormone (TSH) levels (OR=0.670, 95%CI 0.336–1.341, I2 = 96.6%, P=0.259), and high FT4 (OR=1.190, 95%CI 0.540 to 2.590, I2= 95.5%, p=0.666) were not related with NAFLD risk.
  • For FT4 levels above 1.019 ng/ dL, every 1 ng/dL increase in FT4 lead to a 10.56% reduction in the relative risk of NAFLD (p=0.003).
  • The result of a random-effects model looking at TSH level and liver fibrosis, suggests that the incidence of liver fibrosis is significantly higher with high TSH levels than with low TSH levels (SMD 1.320, 95%CI 0.660 to 1.970, p<0.001).

Limitations

  • Heterogeneity could not be explained even with subgroup analysis.
  • As the article included a limited number of studies, the authors highlighted that the potential for “false positives” should also be recognised.

Conclusion

Despite limitations, this review provides further consideration of subclinical hypothyroidism (SH) as a risk factor for NAFLD.

Clinical practice applications:
  • Awareness or monitoring of subclinical hypothyroidism may be worth considering as a risk factor for NAFLD.
  • While a nonlinear inverse association exists between elevated FT4 and incidence of NAFLD, indicators of liver fibrosis have been shown to be higher in individuals with high TSH hormone levels.

Considerations for future research:
  • More comprehensive prospective studies with larger samples are needed to clarify the relationship between thyroid-related hormones and NAFLD and to achieve more clinically meaningful evidence.

Abstract

BACKGROUND Thyroid hormones (THs) have been found that it is closely associated with the onset and progression of non-alcoholic fatty liver disease (NAFLD). However, the current study could not verify the intrinsic relationship between thyroid hormones and NAFLD, which requires further research. METHODS The searches of studies reported both TH level in serum and NAFLD were performed in PubMed, Web of Science, Cochrane Library, and Embase databases. We combined an overall meta-analysis with a dose-response meta-analysis to assess the correlation and dose-response relationship between thyroid function levels and the risk of NAFLD. RESULTS Overall, 10 studies were included with a total of 38,425 individuals. We found that the non-linear dose-response model showed that for every 1 ng/dL increase in FT4, the risk of NAFLD was reduced by 10.56% (p=0.003). The odds ratios (ORs) for NAFLD with high free triiodothyronine (FT3) exposure compared to those with low FT3 were 1.580 (95% CI 1.370 to 1.830, I2 = 0.0%, p<0.001) in the overall meta-analysis. The continuous variable meta-analysis indicated that individuals with high levels of TSH (SMD=1.32, 95% CI 0.660 to 1.970, p<0.001) had significantly higher levels of liver fibrosis than those with low levels. CONCLUSIONS Our findings only validate that there is a correlation between the occurrence of NAFLD and abnormal levels of THs, and it is expected that more observational studies will still be conducted in the future to further demonstrate the relationship between thyroid hormones and NAFLD. TRIAL REGISTRATION Registered number in PROSPERO CRD42023405052.

Lifestyle medicine

Fundamental Clinical Imbalances : Hormonal ; Detoxification and biotransformational
Patient Centred Factors : Mediators/Thyroid function
Environmental Inputs : Diet
Personal Lifestyle Factors : Not applicable
Functional Laboratory Testing : Blood

Methodological quality

Jadad score : Not applicable
Allocation concealment : Not applicable
Publication Type : Journal Article ; Meta-Analysis

Metadata

Nutrition Evidence keywords : Thyroid-stimulating hormone ; Thyroxine ; 3-iodothyronine