Abstract

Hypothyroidism is a common condition, often mediated by autoimmune processes, characterized by a deficiency in thyroid hormone.  Untreated hypothyroidism can lead to significant clinical consequences, as thyroid hormones play a critical role in various physiological processes.  For instance, hypothyroidism is closely associated with metabolic dysfunction-associated steatotic liver disease (MASLD) and hypercholesterolemia.

The current standard treatment, primarily based on levothyroxine (T4) supplementation, is effective in most patients.  However, a subset of patients continues to experience persistent residual symptoms despite achieving biochemical euthyroidism.  This lack of response may be due to reduced activity of the enzyme deiodinase (DIO), which is essential for converting T4 into the active hormone T3.

Although still debated, the combination of T3 and T4 has shown favorable results in a small group of patients.  In the near future, a personalized approach based on individual DIO activity may help identify those who would benefit from T3 supplementation.  Ultimately, the use of thyroid organoids in treatment may offer a definitive cure for hypothyroidism.

This mini review will summarize thyroid hormone physiology, the metabolic consequences of hypothyroidism, and the limitations of current treatment, as well as emerging developments on the horizon.

Thyroid hormone: The Key Hormone in Metabolism

Thyroid hormone is critical for bodily functions.  Thyroid glands, in response to thyroid stimulating hormone (TSH) from pituitary glands, synthesize and secrete thyroid hormones.  Tetraiodothyronine (T4) with four iodine residues serves as a pro-hormone, which is converted to potent and active hormone trioiodothyronine (T3) in the peripheral tissue by de-iodinase (DIO).  In humans, T4 and T3 are secreted at a ratio of approximately 12:1 to 16:1; therefore, the concentration of T3 in systemic circulation is kept stable and readily available for the use.  Thyroid hormone receptors are located in the nucleus, and present in two different types: thyroid hormone receptor α and β (TRα and TRβ).  For example, brain, bone and heart express TRα while pituitary glands and liver expresses TRβ.  This tissue specificity was utilized for treating fatty liver by thyroid hormone action (See below).  There are three types of DIO in human (type 1, 2 and 3). DIO1 and DIO2 mainly convert T4 into an active T3, whereas DIO3 converts T4 into inactive reverse T3 (rT3).  Interestingly, these enzymes have distinct tissue expression profiles, with DIO1 predominantly expressed in the liver and kidney, and DIO2 in the periphery tissues such as muscles, and in the pituitary gland and hypothalamus. (Fig1)

Hypothyroidism: Metabolic Consequence

Hypothyroidism, characterized by underactive thyroid function, is a common condition.  In the United States, approximately 0.3% of the population is affected by overt hypothyroidism, and around 4.3% have subclinical hypothyroidism, which can progress to overt hypothyroidism (1).  Similarly, in Korea, 0.7% of the population has overt hypothyroidism, and over 3% have subclinical hypothyroidism. (2, 3)  About 90% of non-iatrogenic hypothyroidism in iodine-sufficient areas is caused by autoimmune-mediated inflammation, so-called Hashimoto disease (4).

Hypothyroidism can affect all organ systems, and these manifestations depend on the degree of hormone deficiency, although severe hypothyroidism is rarely seen nowadays.  Among the broad spectrum of clinical consequence of hypothyroidism, the metabolic complications will be focused on here.

Overt and subclinical hypothyroidism is associated with increased levels of low-density lipoprotein (LDL), although predominantly less atherogenic large LDL particles (5).  A subset of young male patients with hypothyroidism showed elevated serum triglyceride and C-reactive protein as well (5).  Thyroid hormone plays a key role in lipid synthesis and degradation, the latter is significantly reduced in hypothyroidism (6).  Therefore, plasma free fatty acid levels are decreased and mobilization of free fatty acids in response to fasting, catecholamines, and growth hormone is impaired greatly (7).  However, the hypothyroidism as a risk factor for cardiovascular disease is not well understood because of inconsistent findings from the studies (8-10).

Recent interest in fatty liver, now officially named metabolic dysfunction-associated steatotic liver disease (MASLD) is closely related to the action of thyroid hormone.  This condition is commonly seen in patients with diabetes and obesity, but also hypothyroidism.  The prevalence of MASLD is 1.6 times higher in individuals with hypothyroidism, almost 40% higher compared with normal thyroid function (11, 12).  Subclinical hypothyroidism has been identified as an independent risk factor for MASLD (12), and elevated TSH levels have been associated with a 1.8 to 2.3-fold increased risk of liver fibrosis (13).  It is known that T3 action in hepatocytes regulates lipogenesis, β-oxidation of fatty acids, mitophagy, and cholesterol synthesis (14).  Thus, lower T3 levels are linked to decreased lipolysis and reduced cholesterol clearance.  Moreover, this regulatory system appears to be disrupted in damaged liver tissue.  The recent development of the first FDA-approved thyroid receptor β (TRβ) agonist, Resimetron, for MASLD highlights the critical role of thyroid hormone effect in hepatic lipid metabolism (15, 16).

Hypothyroidism: Current Management

Treatment of hypothyroidism is generally straightforward, as patients typically respond well and show improvement with thyroid hormone supplements.  For example, elevated LDL associated with hypothyroidism often decreases by about 5-10% of baseline levels after starting treatment.  The mainstay of treatment is levothyroxine (T4), which takes advantage of the body’s ability to convert T4 into the active T3 required by tissues, a process that is physiologically regulated.(17)

Before synthetic thyroid hormone was available, desiccated animal thyroid tissue extracts including T4 and T3 was the only feasible option.  Once Synthroid, the first synthetic thyroid hormone, came to the market, it quickly became the standard of care, followed by many other brand names and generics (levothyroxine) after single-dose bioequivalence studies.  The saga involving the comparative trial of Synthroid between investigators and sponsor is worth reading for a better understanding of the current landscape of hypothyroidism treatment (18).

Levothyroxine, the mainstay treatment, has a 7 day half-life, and about 80% of the hormone is absorbed relatively slowly over hours and it equilibrates rapidly in its extracellular distribution volume, therefore avoiding large postabsorptive fluctuation in free thyroxine (T4) levels (19).

The monitoring of response to the treatment of assessment of proper thyroid hormone supplementation is predominantly based on laboratory tests in addition to clinical assessment.  Thyroid stimulating hormone (TSH) which is a tropic hormone from pituitary glands has reciprocal relationship with thyroid hormones (T4 and T3) and is believed to be the most reliable marker.  As a matter of fact, TSH levels were used as a clinical endpoint for pharmacodynamic studies of the thyroid hormones.  By and large, most of the patients with hypothyroidism respond well to levothyroxine and improve their symptoms.

The limitation of T4-based Treatment

In humans, approximately 20% of T3 is secreted directly by the thyroid gland, helping to maintain stable plasma T3 levels.  Therefore, T4-based supplementation is a compromise, relying on the peripheral conversion of the remaining 80% of T3 from T4 (17).

T4 has an independent mechanism for TSH suppression independently of T3, due to intracellular conversion to T3 in the pituitary gland.  Thus, TSH levels might not correctly indicate T3 availability in the tissue.  For example, the ratio of T3 to T4 in the serum of a patient receiving levothyroxine as the only source of T3 is about 20% lower than that in normal individuals.  Also, the quantity of levothyroxine required to normalize TSH in an athyreotic patient (i.e., patients after thyroidectomy) results in a slightly higher serum T4 concentration (20, 21).  In animal studies, it was not possible to normalize T3 in all tissues by intravenous T4 infusion, which may not be directly applicable to humans.(22)

More importantly, there is a subset of patents who persistently have symptoms of hypothyroidism even after achieving biochemical euthyroid (23).  Up to 15% of patients report residual symptoms impairing quality of life and psychological well-being (i.e., mental fogginess, weight gain, lack of focus, memory loss, or fatigue) (24, 25).  For both clinicians and patients, it is difficult to reconcile these symptoms when thyroid function appears to be in the normal range.  The addition of thyroid supplements containing T3 remains a topic of debate for patients, as there is no clear evidence of long-term symptom relief (23).  The lack of superiority of combination therapy over T4-only treatment may be due to the characteristics of study participants.  These studies should have focused specifically on patients with persistent symptoms despite T4 treatment, rather than including all patients with hypothyroidism.

Hypothyroidism: Future Direction

Recent evidence from GWAS studies provides plausible explanations for why some individuals do not respond well to T4-only treatment.  In a Dutch population, as to DIO1 gene, carriers of D1a-T allele (rs11206244) had higher T4 and lower T3 while the D1b-G allele (rs12095080) was associated with higher T3 levels (26).  An analysis using data from the Weston Area T3/T4 Study (WATTS), the Exeter Family Study of Childhood Health (EFSOCH), and the Invecchiare in Chianti (InCHIANTI) study showed that subjects with the C-allele (rs2235544) in the DIO1 gene were associated with increased DIO1 function.  This led to elevated T3 levels, decreased T4 levels, and a higher T3/T4 ratio (27).  Additionally, a polymorphism in the 5′-UTR of the DIO2 gene was found to be associated with variations in serum T3 and T4 levels (28).  These findings suggest that genetic variations in deiodinase (DIO), the enzyme crucial for converting T4 to T3, may impair its function, potentially limiting the ability of some patients to efficiently convert T4 to T3. 

The association does not necessarily imply causality, and these findings need to be validated through functional assays.  However, measuring DIO activity is challenging, and a reliable assay is not yet available.  Despite this, several commercial genetic testing platforms already offer testing for DIO SNP variants.

Finally, there has been an effort to develop thyroid organoids, which could potentially provide a definitive cure for hypothyroidism.  Dr. Terry Davies’ lab at Mount Sinai has used hypoimmune stem cells to differentiate them into functional thyroid follicles (29, 30).  Although this is a promising development, many challenges remain.  Further work is needed to characterize the homogeneity of cell composition and to assess the feasibility and safety of this approach in hypothyroid and immunodeficient mouse models first. 

Conclusion

Hypothyroidism is often managed effectively, with good clinical outcomes in most cases.  However, non-responders who continue to experience persistent residual symptoms may be at risk of untreated metabolic consequences.  It is not physiologically ideal for athyreotic patients to be treated solely with T4 supplementation, and the debate over the best approach for these patients is still ongoing.  With advancements in technology, we will soon be able to treat patients using a personalized approach based on their genotypes and the functionality of their DIO enzymes.  Although still in its infancy, thyroid organoid transplantation could eventually offer a cure for hypothyroidism.