Non-Autoimmune Primary Hypothyroidism in Diabetic and Non-Diabetic Chronic Renal Dysfunction

Summary

The aim of this study was to investigate the frequency and mechanisms of hypothyroidism observed in diabetic patients with advanced diabetic nephropathy, including outcomes of management for this condition. A controlled study was designed using 32 diabetic and 31 non-diabetic patients not receiving hemodialysis or continuous ambulatory peritoneal dialysis (CAPD) who excreted mean urinary protein greater than 0.5 g/day examined on three consecutive days during admission to our hospital. Thyroid hormones in both serum and urine, anti-thyroid antibodies, renal function and iodine concentrations in serum were measured during admission in all patients included. In particular, in patients who showed overt hypothyroidism, further studies including large-needle biopsies of the thyroid and iodine-perchlorate discharge tests were performed. All patients in the two groups revealed negative antithyroid antibody titers, and the mean serum total iodine levels did not significantly differ between the two groups. Mean serum FT4 levels significantly decreased, and the TSH level was significantly elevated in the diabetic group compared to those in the non-diabetic group (p < 0.005, p < 0.02, respectively). The frequency of overt hypothyroidism in the diabetic group (22%; 7/32) was significantly higher (p < 0.05) than that in the non-diabetic group (3.2%; 1/31). The daily urinary thyroid hormone excretion in both groups did not show any significant correlation with serum thyroid hormone levels. Seven patients who revealed overt hypothyroidism in the diabetic group showed elevated serum total iodine levels during hypothyroidal status, ranging between 177 and 561 μg/l. Also, the iodine-perchlorate discharge tests carried out in six of these patients all showed a positive discharge. After management based on iodine restriction, normalization of serum thyroid hormone levels in accordance with definite decreases in the serum total iodine level was achieved, accompanied by a significant weight reduction. In conclusion, we found a significantly high prevalence of non-autoimmune primary hypothyroidism in patients with advanced diabetic nephropathy compared to those with non-diabetic chronic renal dysfunction, which may partly relate to earlier development of oedematous status. Clinical and laboratory findings suggest that impaired renal handling of iodine resulting in an elevation of serum iodine levels, rather than autoimmune mechanism or urinary hormone loss, may play a principal role in the development of these conditions, probably through a prolongation of the Wolff-Chaikoff effect. The mechanisms by which this phenomenon develops more frequently in diabetic than in non-diabetic renal dysfunction remain to be elucidated.

Key words:

Hypothyroidism - Advanced diabetic nephropathy - Wolff-Chaikoff effect

References

• 1 Afrasiabi M A, Vaziri N D, Gwinup G, Mays D M, Barton C H, Ness R L, Valenta L J. Thyroid function studies in the nephrotic syndrome.  Annals of Internal Medicine. 1979;  9 335-338
• 2 Allen H C, Goodwin W E. The scintillation counter as an instrument for in vivo determination of thyroid weight.  Radiology. 1952;  58 68-79
• 3 Chang F Y, Shaio M F. Respiratory burst activity of monocytes from patients with non-insulin-dependent diabetes mellitus.  Diabetes Research and Clinical Practice. 1995;  29 121-127
• 4 Corvilain B, Van Sande J, Dumont J E. Inhibition by iodide binding to proteins: the “Wolff-Chaikoff” effect is caused by inhibition of H₂O₂ generation.  Biochem Biophys Res Commun. 1988;  154 1287-1292
• 5 Corvilain B, Laurent E, Lecomte M, Vansande J, Dumont J E. Role of the cyclic adenosine 3′,5′-monophosphate and the phosphatidylinositol-Ca²⁺ cascade in mediating the effects of thyrotropin and iodine on hormone synthesis and secretion in human thyroid slices.  J Clin Endocrinol Metab. 1994;  79 152-159
• 6 DeGroot L J, Larsen P R, Hennemann G. Adult hypothyroidism. In: The Thyroid and Its Diseases. Ninth Edition Churchill Livingstone Inc, New York 1996: 323-370
• 7 Doi K, Siomi T, Nagai S, Hasegawa K, Kojima J. Fundamental and clinical evaluation on Amerlite Free T4 and Free T3.  Journal of Medicine & Pharmaceutical Science. 27 ((in Japanese)) 1992;  312-315
• 8 Early Treatment Diabetic Retinopathy Study Research Group . Fundus photographic risk factors for progression of diabetic retinopathy: ETDRS report number 12.  Ophthalmology. 98 ((Suppl 5)) 1991;  823-833
• 9 Eng P H, Cardona G R, Fang S L, Previti M C, Alex S, Carrasco N, Chin W W, Braverman L E. Escape from the acute Wolff-Chaikoff effect is associated with a decrease in thyroid sodium/iodine symporter messenger ribonuclic acid and protein.  Endocrinology. 1999;  140 404-3410
• 10 Hardy M J, Ragbeer S S, Mascimento L. Pituitary-thyroid function in chronic renal failure assessed by a highly sensitive thyrotropin assay.  Journal of Clinical Endocrinology and Metabolism. 1988;  66 233-236
• 11 Hatch F E, Parrish A E. Apparent remission of a severe diabetic on developing the Kimmelstiel-Wilson syndrome.  Annals of Internal Medicine. 1961;  54 544-549
• 12 Inoue S, Lan Y, Muran J, Tsuji M. Reduced hydrogen peroxide production in neutrophils from patients with diabetes.  Diabetes Research and Clinical Practice. 1996;  33 119-127
• 13 Itoh S, Kano K, Ando T, Ichimura T. Thyroid function in children with nephrotic syndrome.  Pediatr Nephrol 1994. 8 412-415
• 14 Kabadi U M. Impaired pituitary thyrotroph function in uncontrolled type 2 Diabetes mellitus: normalization on recovery.  J Clin Endocrinol Metab. 1984;  59 521-525
• 15 Kabadi U M. Serum T3 and reverse T3 concentrations: indices of metabolic control in diabetes mellitus.  Diabetes Res. 1986;  3 417-421
• 16 Kaptein E M, Quion-Verde H, Chooljian C J, Tang W W, Friedman P E, Rodriguez H J, Massry S G. The thyroid function in endo-stage renal failure.  Medicine. 1988;  67 187-197
• 17 Kaptein E M. Thyroid hormone metabolism and thyroid diseases in chronic renal failure.  Endocrine Reviews. 1996;  17 45-63
• 18 Larsen P R. Salicylate-induced increases in free triiodothyronin in human serum: evidence of inhibition of triiodothyronin binding to thyroxine-binding globulin and thyroxine-binding prealbumin.  Journal of Clinical Investigation. 1972;  51 1125-1134
• 19 Lim V S, Fang V S, Katz A I, Refetoff S. Thyroid dysfunction in chronic renal failure: a study of pituitary-thyroid axis and peripheral turnover kinetics of thyroxine and triiodothyronine.  Journal of Clinical Investigation. 1977;  60 522-534
• 20 McLean R H, Kennedy T L, Rosoulpour M, Ratzan S K, Siegel N J, Kauschansky A, Genel M. Hypothyroidism in the congenital nephrotic syndrome.  Journal of Pediatrics. 1982;  101 72-75
• 21 Nicollof J T, Fisher D A, Appleman M D. The role of glucocorticoids in the regulation of thyroid function in man.  Journal of Clinical Investigation. 1970;  49 1922-1929
• 22 Ramiretz G, O'Neill W, Jubiz W, Bloomer H A. Thyroid dysfunction in uremia: evidence for thyroid and hypophyseal abnormalities.  Annals of Internal Medicine. 1976;  84 672-676
• 23 Sato R, Ban Y, Taniyama M, Hara H, Nagakura H, Umihara M, Morita Y, Enomoto S, Sugita E. Fundamental and clinical evaluation on Amerlite-MAB Free T4 using enhanced chemiluminescent immunoassay.  Journal of Medicine & Pharmaceutical Science. 30 ((in Japanese)) 1993;  825-837
• 24 Sato K, Okamura K, Yoshinari M, Kuroda T, Ikenoue H, Okazawa K, Mizokami T, Onoyama K, Fujishima M. Reversible primary hypothyroidism and elevated serum iodine level in patients with renal dysfunction.  Acta Endocrinologica (Copenhagen). 1992;  126 253-259
• 25 Schwartz H L, Schadlow A R, Faierman D, Surks M I, Oppenheimer J H. Heparin administration appears to decrease cellular binding of thyroxine.  Journal of Clinical Endocrinology and Metabolism. 1973;  36 598-600
• 26 Stanley M M. The direct estimation of the rate of thyroid hormone formation in man. The effect of the iodine ion on thyroid iodine utilization.  Journal of Clinical Endocrinology and Metabolism. 1949;  9 941-954
• 27 Takeda S, Michigishi T, Takazakura E. Iodine-induced hypothyroidism in patients on regular dialysis treatment.  Nephron. 1993;  65 51-55
• 28 Warady B A, Howard C P, Hellerstein S, Alon U, Grune J A. Congenital nephrosis in association with hypothyroidism and hypoadrenocortism.  Pediatr Nephrol. 1993;  7 79-80
• 29 Watkins P J, Blainey J D, Brewer D B, Fitzgerald M G, Malins J M, O'Sullivan D J, Wolff J, Chaikoff I L. Plasma inorganic iodine as a homeostatic regulator of thyroid function.  J Biol Chem. 1948;  174 555-564
• 30 Wilson J D, Braunwald E, Isselbacher K J, Petersdorf R G, Martin J B, Fauci A S, Root R K. Harrison's principles of internal medicine. Twelfth Edition. McGraw-Hill Inc, New York 1991: 1173
• 31 Wolff J, Chaikoff I L. Plasma inorganic iodine, a chemical regulator of normal thyroid function.  Endocrinology. 1948;  42 468-471
• 32 World Health Organization .Definition, diagnosis and Classification of Diabetes Mellitus and Its Complications: Report of a WHO Consultation. Part 1. Diagnosis and Classification of Diabetes Mellitus (WHO/NCD/NCS/99.2) World Health Org, Geneva 1999
• 33 World Health Organization - International Society of Hypertention Guidelines for the Management of Hypertention . Guidelines Subcommittee.  J Hypertens. 1999;  17 151-183
• 34 Yoshinaga J, Morita M. Determination of iodine in biological fluids by ICP-MS (in Japanese with English abstract).  Biomedical Research of Trace Elements. 1991;  2 143-144