Graves disease: an increasingly recognized immune reconstitution syndrome

Abstract

Since the advent of HAART in 1995, multiple immune reconstitution syndromes (IRS) have been described; IRS-related autoimmune conditions remain uncommon. We report five cases of IRS-related Graves' disease and review the medical literature. Case 1 A 38-year-old woman began a new antiretroviral regimen (zidovudine, lamivudine, lopinavir/ritonavir, and amprenavir) after 10 years of immunological and virological failure on multiple earlier regimens. Her CD4 cell count at the time was 25 cells/μl. Seventeen months later, the CD4 cell count had increased to 196 cells/μl. She then developed anxiety, tremors, palpitations, heat intolerance, and weight loss (20 lb). Physical examination revealed left upper eyelid retraction, tremor, and a 25 g thyroid. Thyroid-stimulating hormone (TSH) was less than 0.01 MIU/ml, free thyroxine (FT4) was 3.2 ng/dl, and 3,5,3′-triiodo-L-thyronine (T3) was 1.7 ng/ml. Antithyroid antibodies were positive, and a thyroid scan showed increased homogenous uptake. The patient was treated for Graves disease with atenolol and methimazole; all symptoms resolved, but she had persistent left eye proptosis. Case 2 A 40-year-old woman had a CD4 cell nadir of 5 cells/μl. She began tenofovir, lamivudine, atazanavir/ritonavir, fosamprenavir, and enfuvirtide; her CD4 cell count increased to 300 cells/μl 15 months later. She developed abdominal pain, diarrhea, fever, an 18 lb weight loss, and insomnia. On physical examination, the thyroid gland was enlarged, pulsatile, and tender to palpation. Bilateral hand tremor and diffuse weakness were noted. Her TSH was less than 0.01 MIU/ml, FT4 was 10.18 ng/dl, T3 was greater than 8.0 ng/dl and thyroglobulin level was greater than 2500 ng/ml. The patient was treated with propranolol and propylthiouracil followed by methimazole. All symptoms and examination findings resolved within 2 weeks. Case 3 A 52-year-old man had a CD4 cell count of 9 cells/μl. He was treated with stavudine, didanosine, and indinavir/ritonavir; the CD4 cell count increased to 138 cells/μl within 20 months. He then developed palpitations, heat intolerance, tremors, and a 20 lb weight loss. The thyroid gland appeared normal and was not tender to palpation. Thyroid tests revealed an undetectable TSH and an elevated FT4 of 4.3 ng/dl. Thyroid scintigraphy demonstrated the elevated uptake of I-123. Graves disease was managed with atenolol and propylthiouracil followed by a total thyroidectomy. Case 4 A 55-year-old man had a nadir CD4 cell count of 6 cells/μl; the patient was subsequently treated with zidovudine, lamivudine, and nelfinavir. Twenty-five months later, he reported insomnia, anxiety, anorexia, and a 14 lb weight loss. Examination was remarkable for tachycardia. His CD4 cell count was 321 cells/μl. FT4 was 3.9 ng/dl, with an undetectable TSH; a thyroglobulin antibody test was negative. The uptake of I-123 was increased. The patient was treated with propranolol followed by thyroid ablation. Case 5 A 33-year-old woman had a CD4 cell count of 472 cells/μl at the time of HIV diagnosis; she was started on zidovudine, lamivudine, and abacavir. Within 6 months, she reported weight loss, palpitations, and hot, moist skin. Over the following 6 months, she developed exopthalmos, proptosis, and decreased extraocular movements; her CD4 cell count was 533 cells/μl. TSH was 0.02 MIU/ml, FT4 was 1.30 ng/dl, and total T3 was 105 ng/dl. Despite methimazole, she developed optic nerve compression necessitating treatment with solumedrol. She had an improvement of her vision on a steroid taper. A Medline search (1981–2005) found 23 additional cases of IRS-related Graves disease (Table 1) [1–6]. Among the 28 cases, the mean age was 39.1 years; 16 cases (57.1%) were female. The most common symptoms were tremor, weight loss, tachycardia, asthenia, insomnia, and ophthalmological symptoms. The mean CD4 cell count increase from nadir to the development of Graves disease was 355 cells/μl (range 44–840), and the mean time from starting HAART to the diagnosis of Graves disease was 20.7 months (range 9–48).Table 1: Additional cases of immune reconstitution syndrome-related Graves disease from search of Medline database (1981–2005).Table 1: (Continued)Graves disease is an increasingly recognized IRS among HIV-infected patients. Cases of Graves disease among HIV-infected individuals do not seem coincidental, but rather related to immune restoration. Like other IRS, Graves disease typically occurs after a dramatic rise in the CD4 cell count; it differs by its late presentation (9–48 months) after HAART. IRS that present shortly (days to weeks) after a new HAART regimen, such as mycobacterial adenitis, are probably caused by memory CD4 cells. Later occurring IRS, such as Graves disease, may be the result of the second phase of CD4 cell increase as naive CD4 cells migrate from the thymus [2]. The reasons why only a few HIV-infected individuals develop IRS-related Graves disease remain unknown, but those with dramatic an