Thyroid Hormone for Nonalcoholic Steatohepatitis

Overseen By Jennifer A Atherton

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: VA Office of Research and Development

Must be taking: Antidiabetics, Vitamin E

Must not be taking: Antidepressants, Ketamine

Disqualifiers: Hepatitis, Cirrhosis, Hypertension, Heart failure, others

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 3 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

128 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial examines the effectiveness of low-dose thyroid hormone as a treatment for nonalcoholic steatohepatitis (NASH), a serious liver condition that can lead to liver disease and cancer. The research investigates whether the hormone improves fat breakdown in the liver's mitochondria, the energy-producing parts of cells. Participants will receive either a placebo or varying doses of a thyroid hormone treatment called Synthroid (also known as Levothyroxine or T4). This trial targets Veterans who are overweight or obese, have type 2 diabetes, and meet specific health criteria related to metabolic syndrome, which includes conditions like high blood pressure and high blood sugar. As a Phase 2 trial, the research measures the treatment's effectiveness in an initial, smaller group of people.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop all current medications, but if you are on tricyclic or tetracyclic antidepressants or ketamine, you must stop them before joining. If you are on digitalis or amiodarone, you can continue them with your cardiologist's guidance.

Is there any evidence suggesting that this treatment is likely to be safe for humans?

Research is exploring the use of low-dose Synthroid (Levothyroxine) for treating nonalcoholic fatty liver disease, which is associated with nonalcoholic steatohepatitis (NASH). Although specific safety information on Synthroid for NASH is limited, this medication is commonly used for thyroid issues and is generally well-tolerated. The FDA has approved it for thyroid problems, indicating its safety in humans is well-established.

Most individuals do not experience serious side effects, especially at low doses. However, like any medication, it can cause side effects such as changes in heart rate or mood, so monitoring these is crucial during a clinical trial. Since this study is in Phase 2, early evidence suggests it is safe, but further research is necessary to fully understand its effects on people with NASH. Participants should always consult the study team with any questions or concerns. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for NASH?

Researchers are excited about using Synthroid (Levothyroxine) for treating nonalcoholic steatohepatitis (NASH) because it introduces a novel approach for managing this liver condition. Unlike most current treatments that focus on lifestyle changes or drugs targeting liver inflammation directly, Synthroid works by influencing thyroid hormone levels, which may play a role in liver metabolism. This unique mechanism offers a new angle for potentially improving liver health, making it a promising candidate to complement existing therapies.

What evidence suggests that this treatment might be an effective treatment for NASH?

Research shows that the thyroid hormone, specifically Synthroid (Levothyroxine), might help treat nonalcoholic steatohepatitis (NASH) by aiding the liver in breaking down fat. Previous studies have found that Levothyroxine can effectively reduce fat buildup in similar liver issues. This is important because excessive fat in the liver can cause damage. Studies also suggest that people with thyroid problems often have liver issues, so using thyroid hormone might address both conditions. In this trial, participants in the study group will receive Synthroid, while those in the placebo group will receive placebo tablets. Although more research is needed, these findings offer hope that Levothyroxine could be a helpful treatment for those with NASH. ^{3 6 7 8 9}

Who Is on the Research Team?

Jamal A Ibdah, MD PhD

Principal Investigator

Harry S. Truman Memorial, Columbia, MO

Are You a Good Fit for This Trial?

Veterans with nonalcoholic steatohepatitis (NASH) who are overweight or obese, may have type 2 diabetes on stable medication, and exhibit features of metabolic syndrome. They must not drink more than a small amount of alcohol daily and agree to use effective birth control if applicable. Those with certain heart conditions, uncontrolled blood pressure, recent severe cardiovascular events, other liver diseases or cirrhosis are excluded.

Inclusion Criteria

My BMI is 25.9 or higher, indicating I am overweight or obese.

I am scheduled for a liver biopsy for diagnosis.

I am not pregnant, breastfeeding, or planning to become pregnant and will use birth control, or I cannot become pregnant.

Exclusion Criteria

Evidence of Portal hypertension

I have had dangerously high blood pressure.

I have a serious heart block without a pacemaker.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment Stage 1

Proof-of-concept stage where 32 Veterans with biopsy-proven NASH are randomized to receive either low dose thyroid hormone or placebo for 52 weeks

52 weeks

Baseline and end of treatment liver biopsies

Interim Analysis

Interim analysis to determine the probability of achieving statistically significant findings in the primary outcome

End of year 2

Treatment Stage 2

Continuation of the study with additional recruitment for a full 6-year clinical trial if interim analysis supports continuation

6 years

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Placebo
• Synthroid

Trial Overview The trial is testing low dose thyroid hormone (Synthroid) against a placebo to see if it helps break down fat in the liver for Veterans with NASH. The study has two stages: an initial proof of concept followed by interim analysis which will determine whether the trial continues into stage two.

How Is the Trial Designed?

Group I: Study group Active Control 1 Intervention

Study group will receive Synthroid (Levothyroxine) 25, 50, or 75 mcg daily

Group II: Placebo group Placebo Group 1 Intervention

Placebo group will receive placebo tablets

Synthroid is already approved in United States, Canada, European Union for the following indications:

Approved in United States as Synthroid for:

• Hypothyroidism
• Goiter
• Thyroid nodules
• Thyroid cancer

Approved in Canada as Eltroxin for:

• Hypothyroidism
• Goiter
• Thyroid nodules
• Thyroid cancer

Approved in European Union as Evotrox for:

• Hypothyroidism
• Goiter
• Thyroid nodules
• Thyroid cancer

Who Is Running the Clinical Trial?

VA Office of Research and Development

Lead Sponsor

Trials

1,691

Recruited

3,759,000+

Published Research Related to This Trial

In a study of 137 obese individuals, those taking Levothyroxine had a significantly higher prevalence of liver fibrosis (30.6%) compared to those not on the medication (2.3%), suggesting a potential link between Levothyroxine use and liver damage.

The study also found that liver stiffness values were higher in Levothyroxine users, indicating increased liver fibrosis, although no significant differences were observed in medication dosage or treatment duration among those with and without liver fibrosis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Liver Stiffness in Obese Hypothyroid Patients Taking Levothyroxine. Pujia, R., Mazza, E., Montalcini, T., et al.[2023]

Thyroxine, a hormone that regulates metabolism, has shown promise in reducing liver fat in animal models of nonalcoholic fatty liver disease (NAFLD), but its use is limited by cardiac side effects.

TRβ-specific agonists, which target a subtype of the thyroid hormone receptor primarily found in the liver, have demonstrated positive effects in treating NAFLD without the adverse cardiac effects associated with thyroxine, and some of these agonists are currently in clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Thyroid Hormone Receptor-β Agonists in NAFLD Therapy: Possibilities and Challenges. Li, L., Song, Y., Shi, Y., et al.[2023]

In significant subclinical hypothyroidism (SCH) patients, levothyroxine (LT4) therapy significantly reduced the prevalence of nonalcoholic fatty liver disease (NAFLD) from 48.5% to 24.2% after 15 months, indicating its efficacy in this group.

For mild SCH patients with dyslipidemia, LT4 treatment also led to a decrease in NAFLD prevalence and serum ALT levels, while those not receiving treatment showed no significant changes, suggesting that LT4 can be beneficial for specific subgroups.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Benefits of Levothyroxine Replacement Therapy on Nonalcoholic Fatty Liver Disease in Subclinical Hypothyroidism Patients. Liu, L., Yu, Y., Zhao, M., et al.[2022]

In a study of 52 patients with non-alcoholic fatty liver disease (NAFLD), hypothyroidism was found to be common and associated with increased NAFLD activity scores, suggesting a potential link between thyroid dysfunction and the progression of liver disease.

However, hypothyroidism did not show a significant association with the severity of liver fibrosis or steatosis, indicating that while thyroid dysfunction may influence NAFLD activity, it may not directly impact the severity of liver damage.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The relationship between liver histology and thyroid function tests in patients with non-alcoholic fatty liver disease (NAFLD). D'Ambrosio, R., Campi, I., Maggioni, M., et al.[2021]

The thyroid hormone triiodothyronine (T3) can completely prevent and even reverse fatty liver and steatohepatitis in rats induced by a choline-methionine deficient diet, highlighting its potential as a therapeutic approach for nonalcoholic fatty liver disease.

The TRbeta agonist GC-1 also effectively prevented and reversed fat accumulation in the liver without significant side effects, suggesting that targeting thyroid hormone receptors could be a promising strategy for treating liver diseases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Thyroid hormone (T3) and TRbeta agonist GC-1 inhibit/reverse nonalcoholic fatty liver in rats. Perra, A., Simbula, G., Simbula, M., et al.[2013]

Non-alcoholic fatty liver disease (NAFLD) is rapidly increasing, and while thyroid hormone signaling has shown promise in improving metabolic symptoms and liver injury, no drugs are currently approved for treating NASH, a severe form of NAFLD.

To minimize side effects like cardiotoxicity from non-selective thyroid hormone treatments, researchers are focusing on developing TRβ-selective thyromimetics, which could provide safer and more effective options for treating NAFLD in the future.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Development of Thyroid Hormones and Synthetic Thyromimetics in Non-Alcoholic Fatty Liver Disease. Zhao, M., Xie, H., Shan, H., et al.[2023]

In a study of 7,946 euthyroid participants, both the FT3/FT4 ratio and visceral adiposity index (VAI) were identified as significant predictors of non-alcoholic fatty liver disease (NAFLD), with 35.36% of participants diagnosed with NAFLD.

The VAI was found to partially mediate the relationship between the FT3/FT4 ratio and NAFLD prevalence, accounting for 42.75% of the total effect, indicating that higher FT3/FT4 ratios may increase NAFLD risk through their association with increased visceral fat.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Mediating effect analysis of visceral adiposity index on free triiodothyronine to free thyroxine ratio and non-alcoholic fatty liver disease in euthyroid population. Liu, HX., Ren, YY., Meng, CQ., et al.[2022]

Levothyroxine, a common treatment for hypothyroidism, can rarely cause liver injury, as demonstrated in a case involving a 34-year-old woman who experienced this adverse effect after starting the medication.

The liver injury was self-limiting and resolved completely after stopping levothyroxine, highlighting the importance of monitoring liver function in patients beginning treatment with this drug.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Levothyroxine-induced liver injury followed by complete recovery upon cessation of the drug: a case report. Hlaihel, AF., Al-Khairalla, MZH.[2020]

A 49-year-old woman with hypothyroidism experienced liver dysfunction after increasing her levothyroxine dose, which was resolved after stopping the medication, indicating a case of levothyroxine-induced liver injury.

Switching to a different levothyroxine formulation (Letrox®) without lactose and gradually increasing the dose helped maintain normal liver enzyme levels, suggesting that careful dosing and formulation choice are important in preventing drug-induced liver injury.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Liver dysfunction induced by Levothyroxine Sodium Tablets (Euthyrox®) in a hypothyroid patient with Hashimoto's thyroiditis: case report and literature review. Yu, H., Zhang, W., Shen, C., et al.[2020]

In a study of over 10,000 patients treated with levothyroxine (LT4), the use of statins increased significantly after starting LT4 therapy, indicating a potential link between thyroid hormone normalization and lipid management.

Patients on LT4 had higher rates of statin prescriptions compared to those not on LT4, with odds ratios indicating a strong association, suggesting that LT4 treatment may influence lipid metabolism and necessitate further investigation into this relationship.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Use of Statins Among Patients Taking Levothyroxine: an Observational Drug Utilization Study Across Sites. Idrees, T., Prieto, WH., Casula, S., et al.[2022]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11862249/

Exploring the nexus between hypothyroidism and metabolic ... Is hypothyroidism a risk factor for non-alcoholic steatohepatitis? J. Clin. Gastroenterol.37, 340–343. 10.1097/00004836-200310000-00014 ...

2. clinicaltrials.gov clinicaltrials.gov/study/NCT03281083

Levothyroxine for Non-Alcoholic Fatty Liver Disease (NAFLD) Background: Non-alcoholic fatty liver disease (NAFLD) is a spectrum of disorders characterized by lipid accumulation in hepatocytes.

3. link.springer.com link.springer.com/article/10.1007/s12020-025-04451-0

Repurposing levothyroxine for managing metabolic ... The terms MASLD and MASH have largely replaced the older terms 'non-alcoholic fatty liver disease' (NAFLD) and 'non-alcoholic steatohepatitis' ( ...

4. bmcendocrdisord.biomedcentral.com bmcendocrdisord.biomedcentral.com/articles/10.1186/s12902-025-01977-2

Evidence on the link between hypothyroidism and non ... Numerous studies have investigated the relationship between hypothyroidism and non-alcoholic fatty liver disease (NAFLD), while the underlying ...

5. ejim.springeropen.com ejim.springeropen.com/articles/10.1186/s43162-025-00415-y

Influence of levothyroxine replacement on metabolic ... These findings support the clinical use of thyroxine for managing MASLD and dyslipidemia in SCH patients. Introduction. Non-alcoholic fatty ...

6. sciencedirect.com sciencedirect.com/science/article/pii/S1043276022001606

Review NAFLD and thyroid function: pathophysiological ... This review aims at summarizing the most updated information on the relationships between abnormal thyroid function and NAFLD.

7. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/38324483/

A Phase 3, Randomized, Controlled Trial of Resmetirom in ... NASH resolution with no worsening of fibrosis was achieved in 25.9% of the patients in the 80-mg resmetirom group and 29.9% of those in the 100- ...

8. nature.com nature.com/articles/s41598-024-70242-8

Efficacy and safety of Resmetirom, a selective thyroid ... Resmetirom treatment showed modest efficacy in treating MASLD with reduction in MRI-PDFF, LDL-c, triglyceride, lipoproteins, liver enzymes and NASH biomarkers

9. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC7460638/

Hypothyroidism-Induced Nonalcoholic Fatty Liver Disease (HIN) Data showed that children with obesity and dysregulation of TH levels have a higher risk of developing hepatic steatosis [34].