With Diagnosis of Hypothyroidism, Assessment of NAFLD Should Follow

A closer look at new data supports a strong association between low thyroid function and liver disease with likelihood of non-alcoholic fatty liver disease tied to degree of hypothyroidism.

With Christos S. Mantzoros, MD, DSc, Naga Chalasani, MD, Kenneth Cusi, MD

While findings over the past decade or so have introduced a credible case for the role of hypothyroidism in the development of nonalcoholic fatty liver disease (NAFLD),1-3 the precise relationship has remained unconfirmed.

Yet, the prevalence of NAFLD has been increasing steadily, such that an estimated 30% of adults in the United States as of 2015 have been diagnosed, and some experts suggest that the rise may be driven, at least in part, by the increase in obesity.3    

 Non-alcoholic fatty liver disease more common in people with hypothyroidism.  from 123RF. Degree of hypothyroidism related to risk for non-alcoholic fatty liver disease.

When patients are diagnosed with hypothyroidism—whether subclinical or overt—the evidence may have reached a tipping point in favor of the need for a more concerted effort to at least consider the risk for nonalcoholic fatty liver disease (NAFLD) in treatment planning.4

Systematic Review of NAFLD and Hypothyroidism Research Over Nearly Two Decades 

In a systematic review,4 researchers examined 15 published studies that were conducted from 2000 to 2018, and included more than 44,000 people. Mantovani et al found that a clinical history of hypothyroidism raised the risk of NALFD by 42%, with a diagnosis confirmed with imaging or biopsy.  

"The lower [patients’] thyroid levels were, the more likely a presence of NAFLD," said Christos Mantzoros, MD, DSc, professor of medicine and director of the Human Nutrition Unit at Harvard Medical School, who was a co-author of the study.1

The researchers evaluated 12 cross-sectional studies and 3 longitudinal trials to determine whether there was a valid association over time.4 All of these studies were included given consideration of the risk, if any, of an increased risk for NAFLD when hypothyroidism was present.

Overall, the possibility that a person with existing hypothyroidism would develop NAFLD increased across different definitions used for diagnosing hypothyroidism, said Dr. Manozoros, sometimes increasing as much as 2.7 times.4

The definitions included:

  •  Self-reported diagnosis backed by levothyroxine replacement therapy
  • Newly-diagnosed overt hypothyroid
  • Newly-diagnosed subclinical (mild) hypothyroidism.

However, in three of the studies, when the hypothyroidism was subclinical (given mildly elevated thyroid-stimulating hormone (TSH) levels no link to NAFLD was found over a median follow up of five years.4

Among the limitations of this systematic analysis, the researchers wrote that none of the studies looked at the effect of levothyroxine replacement on NAFLD.4 However, in one reanalysis done after the original study results were published, the researchers confirmed that giving levothyroxine replacement for 15 months helped improve liver enzyme levels.

However, the findings from this review of the literature substantiated the findings of at least one study published in 2012;5 these investigators compared about 2,300 participants with hypothyroidism and about 2,300 without a diagnosis of liver disease. While 30% of the patients with hypothyroidism had NAFLD, 19% of those having thyroid function levels in the normal thyroid group had a dual diagnosis.5

These researchers, too, found that the worse the hypothyroidism, the more likely the participants were to have NAFLD.5

Plausible Link Between Thyroid Function and Onset of Liver Disease

Why does low thyroid function seem to increase the risk of NAFLD?  The researchers wrote about several possible mechanisms.4 For example, depressed thyroid function may induce NAFLD through such means as low-grade inflammation or increased oxidative stress.  

Dr. Mantzoros told EndocrineWeb: "We know that with lower thyroid levels, our metabolic function declines so calories taken in are not burned efficiently but stored as fat.”

“These calories, when stored in the liver instead of adipose tissue, lead to the development of non-alcoholic fatty liver disease and related complications, such as steatohepatitis, and possibly with time and in extreme situations, cirrhosis or liver failure," he said.

As such, said Dr. Mantzoros, “it becomes important to determine if doses of thyroid replacement therapy have the capability to reverse the NAFLD or whether that intervention alone is not enough.”

Experts Assess Validation of Relationship Between Hypothyroidism and NAFLD  

This systematic analysis was a good summary of the evidence amassed from various studies exploring the association between hypothyroidism and NAFLD, according to Naga Chalasani, MD, the David W. Crabb Professor and Associate Dean for Clinical Research at the Indiana University School of Medicine, who reviewed the study findings at the request of EndocrineWeb.  

The observed link, he said, "highlights the benefit gained in evaluating for hypothyroidism in patients with newly diagnosed NAFLD if they had not already received a diagnosis of hypothyroidism."

Given the nature of this literature analysis, it cannot prove a causal link, he said, “but does offer evidence for a strong association.” In his own research, he had found a similar association as far back as 2003.6

"Although this review of the literature does not prove causality, there is good reason to believe that hypothyroidism may cause steatosis primarily by impairing fatty acid oxidation in the hepatocytes," said Dr. Chalasani.

Other research has shown that treating these patients with thyroid hormone can help improve the liver issues,7 he added.

Another expert who reviewed the paper told EndocrineWeb the new analysis has some problems. Kenneth Cusi, MD, FACP, FACE, professor of medicine and chief of endocrinology, diabetes, and metabolism at the University of Florida, Gainesville, said some of the studies analyzed were often of poor quality, which would have impacted the findings. Case in point, in his own research, he has found that hypothyroidism correlated with the presence and severity of liver fat but not with the severity of NASH.8

In Dr. Cusi's opinion, the research strongly suggests that physicians must be on the lookout and consider the link between hypothyroidism and NAFLD, more specifically in patients with overweight or obesity.

Neither Dr. Mantzoros nor Dr. Cusi had any relevant financial conflicts to disclose. Dr. Chalasani is a consultant to Madrigal Therapeutics, which is developing a therapeutic to treat thyroid hormone B receptor for NASH.  

Continue Reading:
Closing in on Better Treatment for Non-Alcoholic Fatty Liver Disease
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