Risk for Graves' Disease Nearly Tripled in Vietnam Vets Exposed to Agent Orange

Katherine Kahn, DVM

April 27, 2010

April 27, 2010 (Boston, Massachusetts) — Vietnam veterans who report being exposed to Agent Orange have a markedly increased prevalence of Graves' disease, compared with those with no exposure, a new study finds. Lead investigator Ajay Varanasi, MD, a fellow at the State University of New York, Buffalo, presented results of this research here at the American Association of Clinical Endocrinologists (AACE) 19th Annual Meeting.

The study was 1 of 6 abstracts chosen for the Fellows-in-Training and Residents Oral Abstracts Competition, based on scientific merit and interest.

"Environmental factors are believed to contribute to the increased prevalence of some autoimmune diseases," Dr. Varanasi told attendees. "During the Vietnam war, nearly 20% of the surface of Vietnam was sprayed with Agent Orange between 1962 and 1971, mainly for deforestation and crop destruction," Dr. Varanasi explained.

"Much of the concern over the widespread use of Agent Orange stems from the dioxin 2,3,7,8-tetrachlordibenzo-p-dioxin, or TCDD, which is a contaminant in the Agent Orange production process," Dr. Varanasi told meeting attendees. "It lasts in the soil for decades and remains in the body for many years. TCDD has similar properties to triiodothyronine (T3) and thyroxine (T4)."

"TCDD can interfere with thyroid function and metabolism, [and can bind] to thyroid transport proteins and [induce] thyroid metabolizing enzymes," he noted.

Dr. Varanasi and colleagues assessed the prevalence of major thyroid diagnoses in the Veterans Administration (VA) electronic medical record database for upstate New York veterans born between 1925 and 1963. They compared the frequency of diagnoses of thyroid cancer, nodules, hypothyroidism, and Graves' disease in veterans who identified themselves as being exposed to Agent Orange (n = 23,939) or not exposed to Agent Orange (n =200,109).

In both groups, the average age of veterans was approximately 62 years. Nearly all veterans in both groups were male (~90%) and had a history of smoking (~93%). Approximately 22% of both groups were African American. In the group exposed to Agent Orange, 24% had diabetes, whereas in the nonexposed group, nearly 14% did (P = .01). The VA acknowledges type 2 diabetes as a presumptive disease associated with exposure to herbicides, including Agent Orange.

Analyzing data on thyroid conditions, researchers found no difference in the prevalence of thyroid nodules or cancers between the exposed and nonexposed groups. Graves' disease, however, was 3 times more prevalent in the exposed group (odds ratio [OR], 3.05; 95% confidence interval [CI], 2.17 - 4.5; P < .001). Interestingly, hypothyroidism was less common in the exposed group (OR, 0.85; 95% CI, 0.79 - 0.92; P > .001), Dr. Varanasi reported.

In a multivariate analysis, smoking, diabetes, and race were not independently associated with a risk of developing Graves' disease. However, exposure to Agent Orange was independently associated, with an OR of 2.76 (95% CI, 2.22 - 3.81; P < .001). "When you look at the multivariate analysis — including smoking, which has been reported to cause a higher incidence of thyroiditis — we didn't find any of these confounding factors to be associated with Graves' disease," Dr. Varanasi told Medscape Diabetes & Endocrinology.

When conducting a retrospective review of the literature, investigators found evidence of a possible mechanism by which TCDD exposure leads to Graves' disease, he said. Previous research has shown that TCDD binds tightly to the aryl hydrocarbon receptor (AhR), which plays a role in normal immune pathways. In particular, T helper 17 (Th17) cells express high levels of AhR. TCDD, along with endogenous AhR, has been shown to promote Th17 cell growth.

High levels of Th17 cells have been linked to autoimmune disorders, including Graves' disease, Dr. Varanasi explained. "Most studies on TCDD and thyroid function, however, have provided little and inconsistent evidence of long-term TCDD effects on the human thyroid," he said.

K.M. Mohamed Shakir, MD, AACE chair of the Abstract Review Subcommittee, spoke with Medscape Diabetes & Endocrinology about the study. "It would have been interesting to know which of these patients had lymphoma, but the study didn't look at that. Otherwise, this is something new," Dr. Shakir said. "If a patient comes with a thyroid issue, of course Graves' disease should be considered, especially in the VA setting. We should be asking that question."

"We have some limitations [because of it] being a cross-sectional study, but looking at the immune-modulating effects of Agent Orange — specifically the contaminant TCDD, by binding to the aryl hydrocarbon receptors and leading to autoimmune phenomena — it needs further investigation," Dr. Varanasi told Medscape Diabetes & Endocrinology.

The study was independently funded. Drs. Varanasi and Shakir have disclosed no relevant financial relationships.

American Association of Clinical Endocrinologists (AACE) 19th Annual Meeting: Abstract 1046. Presented April 23, 2010.

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