Haematologica 2002; 87:(04)ELT20
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Autoimmune hypothyroidism and retinoic acid
Pierangelo Spedini, Monica Tajana
Divisione di Medicina 2, Sezione di Ematologia, Istituti Ospitalieri di Cremona, Italy.

Correspondence: P. Spedini, Divisione di Medicina 2, Sezione di Ematologia, Istituti Ospitalieri di Cremona, Italy. Phone: +39.0372.405248. Fax: +39.0372.405655.
A 49-year-old man was referred to our hospital because of pancytopenia. After bone marrow biopsy, a diagnosis of acute promyelocytic leukemia (M3-FAB) was made. He was started on chemotherapy according to the GIMEMA protocol1 AIDA 2000 with retinoic acid. Before enrollment, there was no history of previous or actual thyroid disease, neck irradiation, virus infections and autoimmune diseases; physical examination before the chemotherapy showed no goiter or signs of thyroid dysfunction. At diagnosis, serum FT3, FT4 and TSH were normal. Two weeks after the end of consolidation phase the patient developed symptoms of hypothyroidism (cold intolerance, bradycardia, easy fatigability, edema of legs with weight gain of 10 Kg, constipation, hoarseness, impaired cognition and depression). Routine laboratory tests showed only elevated serum level of cholesterol (550 mg/mL). This parameter is known to be a typical feature of primary hypothyroidism. The thyroid's dysfunction was documented by a rapid and marked decrease in serum FT4 and FT3 concentrations and a compensatory hypersecretion of thyrotropin (Table 1). The search for antibodies directed against thyroglobulin was negative while antibodies directed against thyroid' peroxidase was highly positive (antibody titers to thyroid peroxidase was > 3000 U/mL, normal range < 30 U/mL). The patient was started on replacement therapy with thyroxine and his metabolic state increased slowly towards normal. Since no additional drugs known to be able to induce hypothyroidism2 were used during the weeks before thyroid dysfunction, we supposed that the therapy with retinoic acid was involved in the development of autoimmune hypothyroidism. In the literature, some reports3 have investigated the effect of retinoic acid on thyroid peroxidase and thyroglobulin gene expression in cultured human thyrocytes and demonstrated that retinoic acid inhibits the expression of the two genes. Other studies in animals have suggested that pharmacologic amounts of retinoids may decrease serum thyrotropin concentrations Ref 4. Recently, retinoic acid has been associated with autoimmune diseases such as arthralgia, myalgia, and vasculitis Ref 5. The etiology of autoimmune disorders associated with retinoids is unknown; it is presumed that immunomodulation induced by an alteration of the cytokine balance could be responsible for the autoimmune disorders. To our knowledge, this is the first report of autoimmune hypothyroidism following treatment with retinoic acid in acute promyelocytic leukemia.

Table 1.

FT4 (total pg/mL) = 0.8

FT3 (total pg/mL) = 0,7

TSH (microIU/mL) = >150

normal range (4.7-12)

normal range (4.7-12)

normal range (0.1-4.2)

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References
  1. Mandelli F, Diverio D, Avvisati G et al. Molecular remission in PML/RARa-positive acute promyelocytic leukemia by combined all-trans retinoic acid and idarubicin (AIDA) therapy. Blood, 1997 90: 1014; .
  2. Hansen B, Johnsen HE, Hippe E. Autoimmune hypothyroidism and granulocyte-macrophage colony-stimulating factor. Eur J Haematol, 50: 183; 1993.
  3. Namba H, Yamashita S, Morita S et al. Retinoic acid inhibits human thyroid peroxidase and thyroglobulin gene expression in cultured human thyrocytes. J Endocrinol Invest, 16: 87; 1996.
  4. Sherman SI, Gopal J, Haugen B. Central hypothyroidism associated with retinoid X receptor-selective ligands. New Eng j Med, 340: 1075; 1999.
  5. Leibovitch I, Amital H, Levy Y et al. Isotretinoin-induced adult onset Still's disease. Clin Exp Rheumatol 18: 616; 2000.