Subclinical Hypothyroid State Research Articles

Response of Leucine Metabolism to Hyperinsulinemia in Hypothyroid Patients before and after Thyroxine Replacement1

We have investigated the effect of hypothyroidism and insulin on protein metabolism in humans. Six hypothyroid patients were studied in a postabsorptive state before and after 5 months of regular treatment for hypothyroidism (153 +/- 17 microg/day of L-T4). The effect of insulin was assessed under hyperinsulinemic euglycemic and eukalemic conditions. Insulin was infused for 140 min at 0.0063 +/- 0.0002 nmol/kg x min. An amino acid infusion was used to blunt insulin-induced hypoaminoacidemia. Whole body protein turnover was measured using L-[1-13C] leucine. When compared to L-T4-induced subclinical thyrotoxic state, hypothyroidism induced a significant decrease (P < 0.05) in leucine endogenous appearance rate (a reflection of proteolysis; 0.89 +/- 0.09 vs. 1.33 +/- 0.05 micromol/kg x min), oxidation (0.19 +/- 0.02 vs. 0.25 +/- 0.03 micromol/kg x min), and nonoxidative disposal (a reflection of protein synthesis; 0.87 +/- 0.11 vs. 1.30 +/- 0.05 micromol/ kg x min). Insulin lowered proteolysis during both the subclinical thyrotoxic and hypothyroid states. Hypothyroidism impaired the antiproteolytic effects of insulin. Thyroid hormones are, therefore, essential for the normal antiproteolytic action of insulin.

The diagnosis and treatment of subclinical hypothyroid states in depressed patients

The diagnosis and treatment of subclinical hypothyroidism in mood-disordered patients is complex and somewhat controversial. The psychiatrist must recognize that such subclinical states may contribute to depression, mood cycling, or delayed response to treatment if undetected. Autoimmune thyroiditis, which may ultimately lead to various grades of hyporhyroidism, may also be seen in depressed populations, particularly in postpartum females. The author discusses these issues by means of a clinical vignette, then proposes an algorithm for the diagnosis and treatment of hypothyroid states in mood disordered populations.

Cardiac systolic and diastolic function at rest and exercise in subclinical hypothyroidism: effect of thyroid hormone therapy.

Cardiac atrial and ventricular parameters were determined by Doppler two-dimensional echocardiography at rest and exercise in 8 patients with subclinical hypothyroidism (SCH) (6 women and 2 men; age range: 28-48 years) before and 3 months after achievement of a euthyroid state with incremental adjustment of L-thyroxine therapy. None of the patients had known heart disease. At 3 months of L-thyroxine therapy, TSH levels decreased from 14.8 +/- 9.4 mIU/L to 3.0 +/- 1.5 mIU/L and FTI increased from 7.1 +/- 1.8 to 8.1 +/- 1.9. The cardiac studies were performed at rest, and during incremental exercise load (50, 100, 150 W workload) on a Quinton exercise bicycle. No significant differences were found between the subclinical hypothyroid and euthyroid states in systolic blood pressure at rest (104.8 +/- 12.3 vs 105 +/- 10.1 mm Hg) and exercise (158 +/- 24.9 vs 158.5 +/- 20.9 mm Hg) or diastolic blood pressure at rest (70 +/- 4.7 vs 69 +/- 5.7 mm Hg) and exercise (86 +/- 11.4 vs 89.2 +/- 7.3 mm Hg). All echocardiographic atrial and ventricular parameters were similar before and during L-thyroxine therapy with the exception of a small but significant change in left ventricular diastolic dimension (4.5 +/- 0.3 vs 4.8 +/- 0.4 cm; p < 0.05). All Doppler parameters were not significantly affected by L-thyroxine therapy with the exception of preejection period at stage III exercise (51 +/- 17 vs 39 +/- 13 msec; p < 0.05). Preejection period at other stages of exercise showed trends toward similar differences between subclinical hypothyroidism and euthyroidism, but the differences were not statistically significant. We conclude that the cardiac structure and function overall remains for practical purposes normal in subclinical hypothyroidism. However, the latter may be responsible for a mild prolongation of the preejection period during exercise and a slightly smaller left ventricular diastolic dimension at rest, changes that may not be of clinical significance in patients without underlying heart disease.

Lipoprotein(a) concentration in subclinical hypothyroidism before and after levo-thyroxine therapy.

Subclinical hypothyroidism is a frequent disorder in populations and has been shown to be a risk factor for coronary heart disease (CHD). Less is known about the contribution of lipoprotein (a) [Lp(a)] to the development of CHD in this disorder. Therefore this study was designed to evaluate Lp(a) and other lipoprotein concentrations before and after L-T4 therapy in 20 patients with subclinical hypothyroidism and 20 normal healthy subjects matched for sex, age and BMI. In the basal state of subclinical hypothyroidism, a significant increase in total cholesterol, LDL-cholesterol and apolipoprotein (apo) B concentrations was observed in patients compared with those in the control group. The mean Lp(a) concentration before treatment was 163 +/- 15 mg/L. This is slightly but not significantly higher than those in the control group (131 +/- 15 mg/L). Treatment of subclinical hypothyroidism with a low dose of L-T4 (25 micrograms daily) for 3 months after restoration of euthyroidism led to decreases in levels of Lp(a) from 163 mg/L to 126 mg/L (23% reduction, P < 0.001), total cholesterol from 5.5 mmol/L to 5.1 mmol/L (7% reduction, P < 0.001), LDL-cholesterol from 4.14 mmol/L to 3.63 mmol/L (12%, P < 0.001), and apo B from 98 mg/dL to 86 mg/dL (12% reduction, P < 0.05), but triglyceride, HDL-cholesterol and apo A-I concentrations were unchanged. These data suggest that L-T4 replacement therapy in patients with subclinical hypothyroidism has beneficial effects on the lipid profile since L-T4 replacement therapy lowered the concentrations of Lp(a) and other atherogenic lipid particles.

Lipoprotein and Apolipoprotein Levels in Subclinical Hypothyroidism

To assess whether subclinical hypothyroidism is associated with changes in lipoprotein fractions, 13 patients maintained in a stable state of subclinical hypothyroidism for at least 3 months were studied prior to and 2 and 4 months following restoration of a euthyroid state with incremental levothyroxine sodium therapy. Thyrotropin levels ( +/- SEM) had decreased from 16.6 +/- 3.2 mU/L to 3.1 +/- 0.7 mU/L and 3.2 +/- 0.7 mU/L at 2 months and 4 months. At 2 months, levothyroxine treatment led to a decrease in levels of total cholesterol from 5.5 +/- 0.3 mmol/L (213 +/- 12 mg/dL) to 4.8 +/- 0.3 mmol/L (186 +/- 12 mg/dL), in low-density lipoprotein cholesterol (LDL-C) from 3.7 +/- 0.3 mmol/L (143 +/- 12 mg/dL) to 2.9 +/- 0.3 mmol/L (112 +/- 12 mg/dL), and in apolipoprotein B from 91 +/- 8 mg/dL to 74 +/- 7 mg/dL. At 4 months, levels of LDL-C and apolipoprotein B remained significantly lower than pretreatment values (2.9 +/- 0.2 mmol/L [112 +/- 8 mg/dL] and 75 +/- 6 mg/dL, respectively). While high-density lipoprotein cholesterol (HDL-C), HDL3-C, and apolipoprotein A-I were not significantly affected by levothyroxine therapy, there was a slight trend of increase in HDL2-C during levothyroxine substitution. There was also a tendency for a decrease in triglyceride levels from 1.3 +/- 0.2 mmol/L (115 +/- 18 mg/dL) to 0.9 +/- 0.1 mmol/L (80 +/- 9 mg/dL) at 4 months of levothyroxine therapy. Levels of HDL-C tended to decrease from 4.8 +/- 0.4 mmol/L (186 +/- 15 mg/dL) to 4.5 +/- 0.5 mmol/L (174 +/- 19 mg/dL) at 2 months and to 3.9 +/- 0.4 mmol/L (151 +/- 15 mg/dL) at 4 months. The LDL-C/HDL-C ratio also decreased from 3.3 +/- 0.3 mmol/L (128 +/- 12 mg/dL) to 2.9 +/- 0.5 mmol/L (112 +/- 19 mg/dL) and 2.5 +/- 0.3 mmol/L (97 +/- 12 mg/dL) at 2 months and 4 months, respectively. These results suggest that long-term levothyroxine therapy in patients with subclinical hypothyroidism is associated with a decrease in LDL-C and apolipoprotein B levels that are reflected in a trend of decreases in cholesterol/HDL-C and LDL-C/HDL-C ratios known to have a relationship with coronary artery disease.

Transient Subclinical Hypothyroidism in Early Pregnancy.

In the present study, a new clinical state of transient subclinical hypothyroidism in 12 early pregnant women is documented. The incidence of transient subclinical hypothyroidism was 18 (0.19%) among 9,453 pregnant women examined in this series in Sapporo. The characteristics of transient subclinical early gestational hypothyroidism in our study may be summarized as follows: temporarily increased TSH in the blood (11.7 +/- 6.3 microU/ml; mean +/- S.D.) in early pregnant women at 8.5 +/- 2.4 weeks of gestation, accompanied with or without reduced FT4 which spontaneously return to normal at 17.9 +/- 7.1 weeks; no subjective complaints and no previous history of thyroid disease; small struma; positive titers of antimicrosome antibody and antithyroglobulin antibody; normal serum hCG; negative results for TSH receptor antibody. None of the infants show any physical abnormality such as struma and none of the patients had neck pain or fever suggesting subacute thyroiditis. The presence of autoantibody to the thyroid gland and echographical findings strongly suggest the existence of Hashimoto's thyroiditis in early pregnant women with transient subclinical hypothyroidism, although the cause of transient subclinical early gestational hypothyroidism remains obscure.

Thyroid functions before and after maintenance hemodialysis in patients with chronic renal failure.

To study the factors involved in the low thyroid hormone levels in patients with chronic renal failure (CRF), we investigated thyroid functions just before and after hemodialyses (HD) in 32 such patients who were on maintenance HD. In addition, we measured serum thyroid hormone binding inhibitor activities (THBI) in another set of 37 patients. None of the patients had been suspected of having thyroid diseases. HD duration and aging did not have a significant effect on the results of the thyroid function tests. Before each HD, the serum concentrations of T3, T4, FT3, FT4, rT3, PBI, FT3I, FT4I, FT3/T3, FT4/T4, T4/TBG, T4/TSH and FT4/TSH were lower, and those of TSH, TBG, and thyroglobulin (Tg) were higher in the patients than in normal controls. The thyroid hormone concentrations were negatively correlated with the BUN and creatinine levels. The Tg levels were positively correlated with the BUN levels. After each HD, almost all the thyroid function tests including T4/TBG ratio showed improvements, which indicated that hemodilution and a decrease in the T4-binding affinity of TBG with thyroid hormones were the major factors in the low thyroid hormone levels in CRF patients. However, even after HD, T3, FT3, rT3, T4/TSH and FT4/TSH were still lower and TSH and Tg were still higher in the patients. These data suggested that the CRF patients were in a subclinical hypothyroid state. THBI was high in patients with CRF and did not change following HD. NEFA did not seem to contribute to the high THBI before HD, because they were in the normal range. However, as NEFA became very high after HD and possessed THBI, we calculated the corrected THBI (C-THBI) by subtracting the effect of NEFA from total THBI. C-THBI was high before HD and decreased after HD. Therefore, it was suggested that this C-THBI contributed to the abnormalities in the affinity of TBG with thyroid hormones. From these studies, it is concluded that (1) the patients with CRF may be in a subclinical hypothyroid state, although hemodilution was seen to have a strong effect on the thyroid hormone concentrations, and (2) C-THBI may have an effect on the affinity of TBG with thyroid hormones and play an additional role in low thyroid hormone levels in these patients. The mechanisms of hypothyroidism and the nature of C-THBI remain to be clarified.

Decreased serum thyroglobulin levels in the late stage of pregnancy.

Serum thyroglobulin levels were serially measured in 25 normal pregnant women to evaluate thyroidal activity during normal pregnancy. Measurements included serum T3, T4, free T4, TBG, and TSH. Tg and FT4 levels were found to be decreased in the third trimester when compared with those of the first trimester and with those of normal non-pregnant individuals (P less than 0.01). TSH levels were higher than normal in pregnant women at all stages of pregnancy, with a significant rise at the third trimester. These findings suggest the presence of a subclinical hypothyroid state in the late stage of normal pregnancy.

Left Ventricular Performance in Subclinical Hypothyroidism

Normal plasma thyroid hormones with elevation of thyrotrophin levels in asymptomatic patients is known as subclinical hypothyroidism. Radionuclide angiography was used to study left ventricular function in 10 such patients before and after establishment of normal thyrotrophin levels with thyroxine. Resting left ventricular ejection fraction was similar in both states but exercise left ventricular ejection fraction was less in the subclinical hypothyroid (61 +/- 3 per cent) compared with the euthyroid (68 +/- 3 per cent; p less than 0.025) state. Sodium nitroprusside caused similar increases in resting cardiac output but in subclinical hypothyroidism this resulted from a large increase in heart rate (26 +/- 4 beats/min) and reduction in stroke volume (11 +/- 4 per cent) whereas in the euthyroid state, the heart rate increment was less (14 +/- beats/min) and stroke volume was unchanged. Analysis of left ventricular pressure-volume relationships at end-systole during exercise showed a steeper pressure-volume slope in the euthyroid compared with the subclinical hypothyroid state (p less than 0.05). Subtle impairment of left ventricular function is detectable in subclinical hypothyroidism and may justify use of hormone replacement.

Subclinical hypothyroidism in Addison's disease.

Fourteen patients with Idiopathic Addison's disease (IAD) were studied in order to detect a possible subclinical hypothyroid state. All were clinically euthyroid with normal serum thyroxine (T4) and serum 3,5',5'-triiodothyronine (T3). Eleven had circulating thyroid microsomal antibodies in blood. The mean basal serum TSH was significantly higher than that of the control group but only three patients had values above the upper normal range. The mean value of serum T4 was decreased as compared to that of the normal persons, while serum 3,3',5'-triiodothyronine was elevated. 7.5 mU bovine thyrotrophin per kilogram body weight injected intravenously caused a rise in serum T3 not different from the response in normals. However, as well increasing serum TSH as increasing microsomal antibody titer correlated significantly to decreasing thyroidal release of T3. Our results suggest that clinically euthyroid patients suffering from IAD might have a beginning thyroidal insufficiency because of a progressive immunological damage of the thyroid.

Clinical studeis on the regulatory system of thyroid hormone secretion and serum triiodothyronine. Part III. Studies on thyroid hormone change and its relationship when TSH in cases with subclinical hypothyroidism (Hashimoto's thyroiditis and 131I treated Graves' disease)

Changes in thyroid hormone levels and their relationship with TSH in cases with Hashimoto's thyroiditis and 131I treated Graves' disease in subclinical hypothyroid state were investigated: 1) In 34 cases with Hashimoto's thyroiditis, TSH levels was 14.7 +/- 26.8 muU/ml (mean +/- s.d.), T3 144.5 +/- 33.6 Rg/100 ml; T4 6.7 +/- 2.4 MUG/100 ML; T3RU 25.4 +/- 3.2%; F.T.I. 2.0g +/- O.89; T3/T4 2.46+/- 1.04%. It was noted that TSH levels revealed significant positive correlation with T3/T4 (r=0.77); significant inverse correlation with F.T.I. (r= - 0.51); and non-significant inverse correlation with T3 levels (r= - 0.06). These results indicate that T3 might play a more important role than T4 in maintaining normal thyroid function (so-called T3 euthyroidism). This is probably based on metabolic disturbance of iodine which is common in Hashimoto's thyroid. In several cases with rather high normal basal T3 levels, no significant elevation in T3 was observed in spite of elevated TSH level following TRH administration. This might indicate that the thyroid is fully functioning and that no more reserve is left for the thyroid to respond further to elevated TSH. 2) In 30 cases with 131I treated Graves' disease, TSH concentration was 22.3 +/- 29.8 muU/ml (mean +/- s.d.); T3 100.7 +/- 35.4 ng/100 ml: T4 6.2 +/- 2.9 MUG/100 ML; T3RU 25.6 +/- 2.3%; F.T.I. 1.87 +/- 0.85; T3/T4 1.80 +/- 0.64. Significant inverse correlation was noted between TSH levels and F.T.I. as well as T3 levels. Although TSH levels showed significant positive correlation with T3/T4 (r=0.44), its degree of correlation was not as good as that with F.T.I. (r= - 0.71) and T3 (r= - 0.53). These results indicate that there is no preference in T3 production. From the responsiveness of thyroid and pituitary following TRH administration, assumption can be drawn that 131I treated Graves' patients, who became euthyroid, may in fact be on the way to hypothyroidism.