Michael M. Kaplan

Prevalence of abnormal thyroid function test results in patients with acute medical illnesses

We measured serum total and free thyroxine (T4) and triiodothyronine (T3) concentrations, free T4 and T3 indexes, thyroid-stimulating hormone (TSH), thyroxine-binding globulin (TBG) and thyroxine-binding prealbumin (TBPA) concentrations in 98 patients hospitalized for acute medical illnesses. The free thyroxine index (FT4I) or TSH level was abnormal in 16 percent, but only 3 percent had thyroid disease. Serum fre T4 measurements by equilibrium dialysis were abnormal in 25 percent, but no additional patients who initially had abnormal concentrations of serum free T4 were subsequently proved to have thyroid disease. Patients with supranormal serum free T4 concentrations (21 percent) ahd higher serum T4, lower serum T3, and higher serum reverse T3 (rT3) concentrations than other patients, but the measured changes in serum T4, TBG and TBPA levels could only partly account for the magnitude of the free T4 elevation. In these acutely ill patients, an accurate diagnosis of thyroid disease could be achieved by determination of FT4I and TSH level and a history of medication usage. We conclude that other tests are rarely necessary for this purpose in a patient population such as this.

Reduced Tissue Thyroid Hormone Levels in Fatal Illness

Patients with severe nonthyroidal illnesses (NTIs) frequently have decreased serum concentrations of triiodothyronine (T3) and less often of thyroxine (T4) without clear evidence of hypothyroidism. To determine whether T3 and T4 levels are also reduced in the tissues, we analyzed autopsy samples from 12 patients dying of NTI and 10 previously healthy individuals dying suddenly from trauma. Mean serum T3, T4, and free T4 index values were lower by 79%, 71%, and 49%, respectively, in the NTI group than in controls, but serum thyrotropin (TSH) values did not differ significantly. Mean T3 concentrations in cerebral cortex, hypothalamus, pituitary, liver, kidney, and lung were lower in the NTI group than in controls by 43% to 76%, but mean values in heart and skeletal muscle did not differ significantly between the groups. The mean liver T4 concentration was 66% lower in the NTI group, but mean T4 concentrations in the cerebral cortex were similar in the two groups. These results indicate that many tissues may be deficient in thyroid hormones in patients with fatal NTI, although the severity of the reduction in thyroid hormone concentrations may vary from one organ to another.

Risk factors for thyroid abnormalities after neck irradiation for childhood cancer

Thyroid evaluations were performed in 95 patients who received radiotherapy to the neck region for childhood cancer five to 34 years earlier. Fifty-six patients (61 percent) had at least one abnormality of serum free thyroxine index, serum thyroid-stimulating hormone (thyrotropin), or thyroid palpation. Seven had subnormal free thyroxine index and 40 had elevated thyrotropin concentrations. Thyroidal radiation doses of 3,000 or more rads and lymphangiography independently increased the risk (p less than or equal to 0.01) of an elevated serum thyrotropin concentration (present in 11 percent of patients with neither risk factor, 50 percent of those who underwent lymphangiography and received less than 3,000 rads, 46 percent of those who had 3,000 or more rads and no lymphangiography, and 76 percent of those with both), but duration of follow-up did not. Twenty-six patients had thyroid nodules and six others had diffuse thyroid enlargement. The frequency of palpable abnormalities increased with the follow-up time after radiation (30 percent of patients followed up less than 10 years had abnormalities versus 43 percent of those followed up 10 or more years, p = 0.03), but was not related to the serum thyrotropin level, radiation dose, or lymphangiography. Among 10 patients who had surgery for nodules, three had localized papillary thyroid carcinomas.

Partial peripheral resistance to thyroid hormone

A 33 year old partially thyroidectomized woman was euthyroid when ingesting 500 microgram of L-triiodothyronine (T3) daily. Her condition was evaluated during therapy with daily T3 doses between 50 and 500 microgram. She was hypothyroid and had a markedly subnormal oxygen consumption rate when taking 50 to 100 microgram T3 daily, and oxygen consumption did not increase greatly above predicted normal values despite serum T3 concentrations up to 3,200 ng/dl. Her pulse rate, blood pressure, systolic time intervals and exercise tolerance changed minimally and remained within the normal range during the different dosage schedules. Urinary creatine and hydroxyproline, indices of muscle and skeletal protein catabolism, increased normally with higher T3 doses, but serum cholesterol, creatine phosphokinase, calcium and alkaline phosphatase did not change substantially. Basal and thyrotropin-releasing hormone (TRH) stimulated thyrotropin secretion were suppressed during all T3 doses. The prolactin response to TRH was normal at 50 microgram T3/day and was reduced by higher doses of T3. Absorption of T3, serum T3 protein binding and T3 metabolic clearance rates were all within normal limits. The findings in this patient are compared to clinical and biochemical findings in 17 previously described patients. The manifestations of peripheral thyroid hormone resistance are quite variable in the organ systems involved and in the degree of involvement. The molecular basis of the abnormality in our patient remains undefined.

Thyroid nodularity after childhood irradiation for lymphoid hyperplasia: a comparison of questionnaire and clinical findings

Ionizing radiation is a well-established cause of thyroid cancer and nodularity, however, important questions relating to the magnitude of the risk following low-dose medical exposures remain unresolved. To address these issues, we conducted a follow-up study of 1590 individuals treated between 1938 and 1969 with X-rays for childhood lymphoid hyperplasia (av. thyroid dose = 24 cGy) and 1499 individuals treated with surgery only. Thyroid nodularity was determined from self-administered questionnaires completed by 1195 irradiated and 1063 surgically-treated subjects and from clinical examinations of 602 irradiated and 457 non-irradiated subjects. A much higher relative risk (RR) for radiation-induced thyroid nodules was estimated from the questionnaire than from the clinical examination data, 15.8 and 2.7, respectively. (The corresponding estimates of excess RR per cGy were 64 and 7%). Analysis of the examination data revealed a strong dose-response relationship, similar excess RR/cGy for males and females, and an inverse relationship with age at exposure. Although the thyroid gland is one of the most sensitive organs to the neoplastic effects of radiation, the radiation-induced risk of thyroid nodularity reported from questionnaire studies may over-estimate the true risk.

Comparison of thyroxine and 3,3′,5′-triiodothyronine metabolism in rat kidney and liver homogenates

Abstract The effects of agents added in vitro, in vivo PTU treatment, and fasting for 72 hr on T 4 -T 3 conversion rates and rT 3 degradation rates in rat kidney and liver homogenates were compared. In kidney homogenates, 5 m M DTT stimulated both reactions, whereas 0.3 m M diamide, 0.1 μ M iopanoic acid, 17 μ M PTU and 1 m M 2,4-dinitrophenol inhibited both reactions; 25 μ M methimazole had no effect. DTT also stimulated both of these reactions in liver homogenates. Diamide was a less potent inhibitor in liver than in kidney homogenates. Kinetic analysis showed that the k m for T 4 in kidney and liver homogenates were similar, but not identical, and that the k m for rT 3 in kidney and liver homogenates were again similar, but not precisely the same. When a particulate fraction of the homogenates was employed, the k m for T 4 in two kidney preparations was 0.8 and 1.0 μ M , and in two liver preparations it was 2.9 and 5.5 μ M . PTU administered in vivo reduced the T 4 -T 3 conversion rates and rT 3 degradation rates in kidney and liver homogenates to 3 concentration to 3 concentration to nine times control, but did not alter the mean serum T 4 concentration or the hepatic glutathione content. A 72-hr fast had no effect on T 4 -T 3 conversion or rT 3 degradation rates in kidney homogenates and had no effect on renal glutathione content, but fasting had the expected inhibitory effect on T 4 -T 3 conversion in liver homogenates and lowered the hepatic glutathione content to 79% of control. These results, along with previous findings from this and other laboratories, strongly suggest that there is a single iodothyronine 5′-monodeio-dinase in rat kidney that metabolizes both T 4 and rT 3 . The results are also compatible with the hypothesis that the iodothyronine 5′-monodeiodinases in rat kidney and liver are the same enzyme.