Leonard Wartofsky

Alterations in thyroid iodine release and the peripheral metabolism of thyroxine during acute falciparum malaria in man

Previous studies of thyroid function during various infections have yielded conflicting results, but most have suggested an acceleration of peripheral thyroxine (T(4)) turnover during the acute infectious illness. In the present studies, thyroid function was examined by a method allowing simultaneous analysis of both endogenous thyroidal release and peripheral T(4) disposal in normal volunteers after induction of acute falciparum malaria. Subjects received iodide-(125)I, followed in 5-7 days by (131)I-T(4) intravenously. 4 days later, infection was induced by the injection of parasitized red blood cells. Bidaily measurements of serum protein-bound (125)I and protein-bound (131)I, and urinary (125)I and (131)I, together with frequent estimates of serum (127)I-T(4) (Murphy-Pattee) and free T(4) (FT(4)), were made during a control period, during acute illness, and during convalescence. Alterations in the peripheral metabolism of (131)I-T(4) during infection included significant decreases in the fractional disappearance rate for T(4) [(k)], and in the clearance and daily disposal of T(4), all of which returned to control values during convalescence. Total serum (127)I-T(4) increased late in the infected period to become greater during convalescence than either before or during infection, while FT(4) did not increase significantly until convalescence. An analysis of serum (131)I-T(4)/(127)I-T(4) and (131)I-T(4)/PB(125)I ratios confirmed these observations. The slope with time of ratios for urinary (125)I/(131)I, a reflection of thyroidal iodine release, was decreased during infection, but rebounded to control values during the convalescent period. The observed increments in serum (127)I-T(4) concentration in the convalescent phase may reflect in part the slowing of (k), but together with the rising ratios of urine (125)I/(131)I suggests enhanced thyroidal T(4) secretion immediately after the acute illness. Thus, with malarial infection, there appears to be an initial depression followed by a rebound in rates of thyroidal iodine release. In contradistinction to other infections, fractional turnover and daily disposal of hormone is decreased in malaria, perhaps due to hepatic dysfunction and the consequent impairment in cellular deiodinative processes.

The response of the thyroid gland and thyroid hormone metabolism to infectious disease.

A review is presented of the current state of knowledge of responses of the hypothalamic-pituitary-thyroid axis and peripheral thyroxine metabolism to infectious disease. The effects of various infect

Thyrotropin Modulates Receptors for Atrial Natriuretic Peptide on Intact Human Thyroid Cells

Interest in the mechanism of impaired salt and water metabolism in hypothyroidism has led to growing evidence of an interaction between atrial natriuretic peptide (ANP) and the thyroid, which includes reports of direct effects of thyroid hormone on ANP synthesis and circulating ANP levels, and of the presence of specific ANP receptors in human thyroid tissue, which may act to inhibit thyroglobulin (Tg) secretion. The authors questioned whether or not thyrotropin (TSH) has a role in this interaction. They used 125I-ANP to study the effect of TSH on ANP binding to human thyroid cells in primary culture. Binding competition by increasing concentrations of unlabeled ANP in the presence or absence of TSH was assessed by Scatchard analysis. At lower temperatures of 4 degrees C or 23 degrees C, TSH had no effect either on the ANP receptor equilibrium dissociation constant (Kd) or number of binding sites. However, at 37 degrees C, bovine TSH at 1 mU/ml reduced measurable binding sites by about 50% without affecting receptor affinity (Kd = 0.2 nM). Prolonged (6 days) coincubation of TSH with thyroid cells decreased the assayable ANP receptor. The effects of TSH appear to be specific because human luteinizing hormone, follicle-stimulatory hormone, growth hormone, human chorionic gonadotropin and iodide had no effect on ANP binding. Thus, human thyroid cells possess a single class of high-affinity, specific receptors for ANP with binding activity that is temperature dependent and modulated by TSH at physiologic temperature. TSH-mediated reduction of binding at 37 degrees C but not at 4 degrees C suggests an energy-dependent process that acts possibly by activating an ANP degradative enzyme or by changing the rate of receptor internalization and subsequent degradation.

Deiodination of 131I-Labeled Thyroxine in the Fetal Rat

Summary In vitro deiodination of 131I-T4 as an index of T4 to T3 conversion, was assessed in homogenates of fetal and adult rat liver and kidney, to explore whether differences existed which might account for the low fetal concentrations of serum T3 observed by others. The deiodination rate per milligram of protein was greater for both kidney and liver homogenates in the fetus than in adult rats. These results suggest that fetal T4 deiodination is not decreased in comparison to the neonatal or adult rat. Thus, the mechanism for the low serum T3 concentration in the fetus does not appear to be a decreased production of T3 from T4, insofar as in vitro T4 deiodination may reflect in vivo T4 to T3 conversion.

Therapy of Graves’ Ophthalmopathy

As described in Chapter 18, the characteristic ophthalmopathy of Graves’ disease is marked by impaired eye muscle movement, periorbital edema, with or without actual proptosis. The exophthalmos may be unilateral early but usually becomes bilateral with time. With moderate to advancing severity, the proptosis will be accompanied by varying degrees of ophthalmoplegia and congestive oculopathy characterized by Chemosis, conjunctivitis, and periorbital swelling. The most dreaded potential complications are corneal ulceration, optic neuritis, and optic atrophy. When exophthalmos becomes more severe and progresses rapidly to this point, it has been termed “malignant exophthalmos”. The term exophthalmic ophthalmoplegia refers to the ocular muscle weakness that results in impaired upward gaze and convergence and strabismus with varying degrees of diplopia. Progressive ophthalmopathy is the most difficult component of Graves’ disease to treat successfully. Given four fixed bony orbital walls, the increased intraorbital contents (enlarged external ocular muscles due to lymphocytic infiltration and edema, increased retrobulbar fat) cause the globe to protrude outward causing proptosis. With limits to outward proptosis, pressure can be directed posteriorly on the optic nerve in its course between the bodies of the eye muscles causing ischemia and blindness. In its later stages, the external eye muscles and the levator palpebrae become fibrotic with resultant restricted movement leading to blurred vision, diplopia, and lid retraction. A consequence of lid retraction may be corneal drying and exposure keratitis and ulceration.