Thyroid Hormones Influence Fat Accumulation in the Liver

Type 2 diabetes is not the only precursor to nonalcoholic fatty liver disease, patients with thyroid disease also appear at elevated risk.

with Arun J. Sanyal, MD

Non-alcoholic fatty liver disease (NAFLD) has garnered increased attention given the widening persistence of metabolic comorbidities including obesity, type 2 diabetes and cardiovascular disease.1 Given that NAFLD encompasses a range of lipid-related conditions, there has been greater attention regarding the influence of thyroid hormones in fat accumulation in the liver.

A closer look at thyroid hormones finds a significant role for these substances in the onset of non-alcoholic fatty liver disease as well as in lipid metabolism through regulation of lipoproteins, triglycerides (TGs), and hepatic fat storage and metabolism,2 according to findings reported in the journal, Thyroid.   

alcoholic Fatty liver disease is driven by thyroid hormone levels.

Thyroid Hormones in Hyperlipidemia of the Liver

Beyond thyroid function levels, clinicians may look for the following inverse, cardiovascular-related changes: In patients with hyperthyroidism—These individuals have lower serum low density lipoprotein cholesterol (LDL-C) and TG levels, along with greater weight loss—whereas individuals with hypothyroidism have discernably higher serum LDL-C and TG levels as well as weight gain.2

“In this incredibly thorough and informative review of the roles of thyroid hormones, metabolites and agonists on non-alcoholic fatty liver disease (NAFLD) and hypercholesterolemia, the authors outline the potential benefits of thyroid-based therapies for the treatment of NAFLD and hypercholesterolemia,” Arun J. Sanyal, MD, professor of medicine in the division of gastroenterology, hepatology and nutrition at Virginia Commonwealth University in Richmond, who reviewed the study for EndocrineWeb.

The authors found that hepatic triglyceride metabolism is influenced by regulation of thyroid hormones on hepatic autophagy and mitrochondrial metabolism, offering a mechanistic understanding of the effects on cholesterol synthesis, LDL clearance and reverse cholesterol transport result in decreased serum cholesterol.2

The major biologically active thyroid hormones include thyroxine (T4) and tri-iodothyronine (T3); however, there are numerous additional thyroid metabolites that may be exerting biological activity. As Dr. Sanyal said, “Since thyroid hormones bind in both the heart and liver; it is important to facilitate selective activity that only targets the liver.”

Relationship of Thyroid Disease and NAFLD

Examining the association between hypothyroidism and NAFLD has been studied extensively. In a meta-analysis of 13 studies,3 a strong independent relationship was found with both subclinical and overt hypothyroidism (95% CI 1.30–2.52, P < 0.001 and 1.63 (95% CI 1.19–2.24, P = 0.002, respectively), suggesting that patients with hypothyroidism are at increased risk for NAFLD than euthyroid individuals.

Consequently, TH analogs are under development that may have specific actions in the liver.4 Yet, this area of research has been slow to develop. For example, the thyroxine receptor β (THRβ) isoform is the most abundant isoform in the liver, and THRβ analog agents appear to act directly in the liver, thereby imposing minimal risk of cardiac toxicity and other side effects associated with natural TH, according to Dr. Sanyal.

THRβ analogs may function to clear fat from the liver and decrease the inflammation associated with steatohepatitis. However, it is not, as yet, known if these agents will successfully prevent progression of non-alcoholic fatty liver disease to the level of cirrhosis. Currently, THRβ analogs are undergoing proof of concept investigations for management of both NAFLD and hypercholesterolemia, he said.

In a four-month, interventional open-label, single arm study, LT4 was given to men (n=29) with type 2 diabetes who were diagnosed with NAFLD from six medical centers across Singapore to ascertain whether low dose levothyroxine therapy may reduce liver fat accumulation by at least 3%, as determined by functional magnetic resonance imaging; unfortunately, the study was terminated before completion due to insufficient funding.5

NAFLD has been most often observed in patients with obesity and/or hypercholesterolemia, and is also commonly seen in patients with type 2 diabetes (T2D).6 However, recent research has led to a greater understanding of the role of altered intracellular action of thyroid hormones.7 Consequently, there has been interest in the potential role of THs, TH mimetic and TH metabolites as lipid-modifying agents.

Evolving Therapies for Non-Alcoholic Fatty Liver DIsease

“As noted in this article, a variety of TH-based therapies show clinical promise as potential therapies for the treatment of NAFLD and hypercholesterolemia. However, because TH-based therapies can affect both cardiac and hepatic functioning, strategies for addressing and managing unwanted side effects of TH must first be identified and implemented,” said Dr. Sanyal.

Regardless of the precipitating factors, treatment of NAFLD will depend on the severity of scarring in the liver; adjustments to diet and lifestyle interventions remain the most appropriate management approach for less severe liver involvement, and consideration of medications for moderate to severe scarring,8,9 he said.

The focus on weight loss remains an essential management strategy. In fact, encouraging patients to follow a Mediterranean style diet may be the most effective suggestion for any patient at risk for NAFLD, particularly those with obesity, thyroid disease, diabetes, cardiovascular disease, or metabolic syndrome.

“Two of the key take-away messages from this data are: (1) clinicians need to consider and screen for possible hypothyroidism in patients with nonalcoholic fatty liver disease; and (2) clinicians need to consider and screen for possible NAFLD in appropriate patients with hyperthyroidism,” said Dr. Sanyal.

Going along with this, Dr. Sanyal added that in patients with high LDL-C who do not respond favorably to treatment with statins, check their thyroid levels. He noted that this is only the beginning of research into TH and lipid metabolism, as a number of TH-related analogs are currently in preclinical, phase 1, or phase 2 trials.

In addition to insulin resistance, which is one of the most commonly recognized risk factors for non-alcoholic fatty liver disease, and thyroid dysfunction, other suspected risk factors include: hypopituitarism, hypogonadism, polycystic ovary syndrome, and obstructive sleep apnea.1

Dr. Sunyal has no financial disclosures with regard to this paper. EndocrineWeb was unsuccessful in their attempts to contact the authors, who are based in Singapore.

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