Low-Normal Thyroid Function as Potential Sign of Advanced Fibrosis

Given the rising rates of nonalcoholic fatty liver disease, and the comorbidity of cardiovascular disease, a team from Stanford examined the role of low thyroid function and fibrosis for a possible connection.

With Terry Davies, MD

Concern about the rising rates of nonalcoholic fatty liver disease (NAFLD) has grown with an increasing prevalence of type 2 diabetes, obesity, and metabolic syndrome, and by extension cardiovascular disease. This trend tipped off a team of investigators from Division of Gastroenterology and Hepatology at Stanford University in California, to assess the potential for advanced fibrosis in patients with low-normal thyroid function.1,2

To ascertain possible adverse implications in patients presenting with low-normal thyroid levels, Aijaz Ahmed, MD, professor of Medicine at Stanford University School of Medicine in Stanford, California, and colleagues focused the prevalence of advanced fibrosis,2 and their findings were published in the journal, Clinical Gastroenterology, and Hepatology.

Researchers looked at low thyroid hormone levels for risk of fatty liver disease.

Examining the Association between Thyroid Status and Liver Disease

It is known that thyroid dysfunction (hyper- or hypothyroidism) is associated with greater risk of adverse outcomes and that patients with end-stage renal disease have a higher risk of thyroid disease compared with patients who do not have kidney disease.3 In addition, a higher rate of subclinical hypothyroidism and low-normal thyroid function in patients with biopsy-confirmed nonalcoholic fatty liver disease(NAFLD)has been reported.1,4

For example, in a retrospective study of 1,154 patients with chronic hepatitis B, the authors found a 23% incidence of NAFLD, and a serum thyroid-stimulating hormone (TSH) level that was significantly higher than that in patients without NAFLD (P < 0.05).4 These patients also exhibited an elevated TSH level which was associated with greater odds of having fatty liver.4

Similarly, in an earlier Stanford research study,1 425 patients with NAFLD were evaluated. There was a significantly higher percentage of patients with low thyroid function had nonalcoholic steatohepatitis (NASH) and advanced fibrosis compared with patients with strict-normal thyroid function (52.4% vs 37.2% for NASH; 21.0% vs 10.6% for advanced fibrosis; P < 0.01). In addition, a significantly greater number of patients with subclinical hypothyroidism had NASH and advanced fibrosis when compared with patients with low-normal thyroid function (57.6% vs 48.8% for NASH; 25.4% vs 17.9% for advanced fibrosis; P < 0.01).1

Do Low-Normal Thyroid Hormone Levels Portend Risk of Fibrosis?

At present, any medical consequences related to a persistent low-normal thyroid level are uncertain. Using data from the National Health and Nutrition Examination Survey (NHANES)  for 2007-2012, the investigators sought to examine whether low-normal thyroid was associated with advanced fibrosis.2

Ahmed et al focused on patients with low-normal thyroid hormone levels—defined as a “higher level of thyroid-stimulating hormone (TSH) within the euthyroid reference range”— which may appear comparable to that of overt and subclinical hypothyroidism.5-7 and for which there is an apparent dose-dependent response.1

In this fibrosis analysis,2 the study sample consisted of 7,259 adults at least 21 years old (out of an original sample of 8,779 subjects) who had available thyroid function laboratory data and sufficient results of at least three non-invasive fibrosis markers: BMI, impaired fasting glycemia or diabetes, aspartate aminotransferase [AST]/alanine aminotransferase [ALT] ratio, platelet, and albumin levels.

Patients were excluded from the study if they had known significant alcohol consumption, viral hepatitis, steatogenic medications, pregnancy; were missing data regarding body mass index (BMI), serum aminotransferase, platelet, or albumin; anyone who received thyroid medications, or had overt thyroid disease (ie, hypothyroidism, hyperthyroidism).2

The investigators defined thyroid function as follows:

  • Subclinical hypothyroidism — TSH level > 4.5 µIU/L with a normal free thyroxine (T4) level
  • Low-normal thyroid function — TSH level 2.5 to 4.5 µIU/L and/or lower free T4 level within the euthyroid reference range (0.45 to 4.5 µIU/mL for TSH; 0.6 to 1.6 ng/dL for T4

The NAFLD fibrosis score (NFS) was calculated based on a formula that incorporated available data for age, body mass index, whether or not the patient had impaired fasting glycemia or diabetes, the aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ration, platelet count, and albumin level. Subjects with NAFLD were categorized into three groups: including those with high probability (NFS > 0.676), intermediate probability (NFS 0.676 to -1.455) and low probability for advanced fibrosis (NFS < -1.455).2

As with prior research, there was a greater prevalence of advanced fibrosis in subjects with low thyroid hormone function, which encompassed patients with both low-normal and subclinical hypothyroidism, than subjects with strict-normal thyroid function.

The number of individuals with advanced fibrosis was not significantly different in those with subclinical and low-normal thyroid function (5.4% vs 6.0%, P = 0.759). Of note, subjects with low-thyroid function were 2.0-fold more likely to have advanced fibrosis than those with strict normal thyroid function, according to the authors.2

Study Falls Short in Establishing an Association between Thyroid Status and Liver Function

In an interview with EndocrineWeb, Terry Davies, MD, Co-director of the Thyroid Center at Mount Sinai Union Square, and professor of medicine at the Icahn School of Medicine at Mount Sinai in New York said, “this study didn’t actually measure fibrosis but rather examined various indices that indicate fibrosis.”

In addition, Dr. Davies said that obesity (based on a higher body mass index) increases the risk of fatty liver disease, which, in turn, leads to a greater development of fibrosis in these patients. The fix for this is relatively straightforward—encourage weight loss to facilitate improvement in liver function and reduce fibrosis.

Most importantly, Dr. Davies told EndocrineWeb, “our patients with low thyroid are not dying of liver disease, and fibrosis is not causing major pathology in this patient population.”

While the study investigators concluded that “targeted therapy to improve thyroid function may provide a novel opportunity to prevent NAFLD-related advanced fibrosis,”2 findings from a systematic review and meta-analysis of 21 studies involving nearly 2,200 adults indicated that use of thyroid hormone therapy was “not associated with improvements in general quality of life or thyroid-related symptoms,” suggesting that the “research does not support the routine use of thyroid hormone therapy in adults with subclinical hypothyroidism.”8

EndocrineWeb reached out to Aijaz Ahmed, MD, Division of Gastroenterology and Hepatology at Stanford University School of Medicine in Palo Alto, CA, corresponding author of the study, on multiple occasions for comment on the study findings and the critique of the study report; he was aware of these requests but did not make an effort to respond.

There were not reported financial conflicts related to this research

Continue Reading:
Half of Patients With Type 2 Diabetes Have Nonalcoholic Fatty Liver Disease
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