Severely Hypothyroid Research Articles

Prediction-based prompt levothyroxine replacement to prevent a hypothyroid state after immune-related adverse events involving the thyroid gland.

Immune checkpoint inhibitors (ICIs) are used for various malignancies, although they frequently cause immune-related adverse events involving the thyroid gland (thyroid irAEs). We conducted a retrospective cohort study to elucidate thyroid function outcomes. Fifty of 639 patients who received PD-1 blockade therapy met criteria and were divided into the following groups: thyrotoxicosis with subsequent hypothyroidism (Toxic-Hypo, n = 21); thyrotoxicosis without subsequent hypothyroidism (Toxic, n = 9); and hypothyroidism without prior thyrotoxicosis (Hypo, n = 20). The Toxic-Hypo group developed thyroid irAEs earlier than the Toxic group (26 vs. 91 days; p < 0.001), and had higher serum free T4 levels (3.210 vs. 1.880 ng/dL; p = 0.011). In addition, positive anti-thyroglobulin antibodies (TgAbs) at thyroid irAE onset were more common in the Toxic-Hypo group (93.3%) than in the Toxic group (0.0%; p = 0.005) and Hypo group (44.4%; p = 0.007). The Toxic-Hypo group developed severe hypothyroidism and required larger levothyroxine (LT4) doses than the Hypo group (75 vs. 25 μg/day; p = 0.007). We predicted that patients with positive TgAbs who developed severe thyrotoxicosis within 4 weeks after the first ICI administration would develop subsequent hypothyroidism. We treated 4 such patients with prompt LT4 replacement, characterized by LT4 initiation after thyrotoxicosis improvement and quick dose titration. Their euthyroid state was successfully maintained, in contrast with patients receiving conventional replacement. In conclusion, rapid-onset severe thyrotoxicosis in patients with TgAbs correlated with a high likelihood of subsequent hypothyroidism. Accordingly, prompt LT4 replacement is suggested to prevent a severely hypothyroid state.

SAT-563 Nonshivering Thermogenesis as a Compensatory Mechanism for Reduced Metabolism in Severely Hypothyroid Mice

ABSTRACT The rate of obesity is steadily increasing in the United States and around the world. This is a major health concern, as obesity is associated with multiple leading causes of death, including heart disease, stroke, type 2 diabetes, and a subset of cancers [1]. Reduced thermogenesis causes fat and weight gain, whereas increased thermogenesis promotes weight and fat loss [2-5]. Therefore, stimulating adaptive thermogenesis is a promising approach to treating the obesity epidemic. However, current avenues of research have yet to identify a thermogenic target that could be used to efficaciously promote weight loss. The sodium/iodide symporter (NIS) is the key plasma membrane protein that mediates the sodium-dependent active transport of iodide into the thyroid follicular cells, the first step in the biosynthesis of the thyroid hormones (THs) [6]. Using a drug-free model of severe hypothyroidism (mice that are knockouts for NIS placed on a low-iodide diet), we found that these mice do not gain weight and exhibit a trend towards higher energy expenditure than is exhibited by a model of mild hypothyroidism (wild-type mice on a low-iodide diet). Severely hypothyroid mice exhibit significantly increased expression of markers of adipose tissue and skeletal muscle adaptive thermogenesis at room temperature (22°C). These mice may upregulate thermogenic mechanisms to compensate for reduced basal metabolism. This hypothesis is supported by the fact that severely hypothyroid mice are cold intolerant when transferred from thermoneutrality to a 4°C cold challenge, despite increased levels of thermogenic markers. Our results are consistent with the hypothesis that severely hypothyroid mice upregulate thermogenic mechanisms to maintain homeostasis, which ultimately protects them from weight gain.

Generic and Brand-Namel-Thyroxine Are Not Bioequivalent for Children With Severe Congenital Hypothyroidism

In the United States, generic substitution of levothyroxine (L-T(4)) by pharmacists is permitted if the formulations are deemed to be bioequivalent by the Federal Drug Administration, but there is widespread concern that the pharmacokinetic standard used is too insensitive. We aimed to evaluate the bioequivalence of a brand-name L-T(4) (Synthroid) and an AB-rated generic formulation (Sandoz, Princeton, NJ) in children with severe hypothyroidism. This was a prospective randomized crossover study in which patients received 8 weeks of one L-T(4) formulation followed by 8 weeks of the other. The setting was an academic medical center. Of 31 children with an initial serum TSH concentration >100 mU/L, 20 had congenital hypothyroidism (CH), and 11 had autoimmune thyroiditis. The primary endpoint was the serum TSH concentration. Secondary endpoints were the free T(4) and total T(3) concentrations. The serum TSH concentration was significantly lower after 8 weeks of Synthroid than after generic drug (P = .002), but thyroid hormone levels did not differ significantly. Subgroup analysis revealed that the difference in TSH was restricted to patients with CH (P = .0005). Patients with CH required a higher L-T(4) dose (P < .0004) and were younger (P = .003) but were not resistant to thyroid hormone; 15 of 16 CH patients had severe thyroid dysgenesis or agenesis on imaging. The response to generic vs brand-name preparation remained significant when adjusted for age. Synthroid and an AB-rated generic L-T(4) are not bioequivalent for patients with severe hypothyroidism due to CH, probably because of diminished thyroid reserve. It would therefore seem prudent not to substitute L-T(4) formulations in patients with severe CH, particularly in those <3 yr of age. Our results may have important implications for other severely hypothyroid patients in whom precise titration of L-T(4) is necessary.

Osborn waves in a patient with hypothermia due to severe hypothyroidism

An 88-year-old female with history of hypothyroidism was brought to our emergency department with acute change in mental status. Her vital signs were significant for a core body temperature of 88°F (31°C). She was found to be severely hypothyroid (serum TSH—7.14 mU/l, Free T4—0.5 ng/dl) …

Mice Deficient in Dual Oxidase Maturation Factors Are Severely Hypothyroid

Dual oxidases (DUOX1 and DUOX2) are evolutionary conserved reduced nicotinamide adenine dinucleotide phosphate oxidases responsible for regulated hydrogen peroxide (H(2)O(2)) release of epithelial cells. Specific maturation factors (DUOXA1 and DUOXA2) are required for targeting of functional DUOX enzymes to the cell surface. Mutations in the single-copy Duox and Duoxa genes of invertebrates cause developmental defects with reduced survival, whereas knockdown in later life impairs intestinal epithelial immune homeostasis. In humans, mutations in both DUOX2 and DUOXA2 can cause congenital hypothyroidism with partial iodide organification defects compatible with a role of DUOX2-generated H(2)O(2) in driving thyroid peroxidase activity. The DUOX1/DUOXA1 system may account for residual iodide organification in patients with loss of DUOX2, but its physiological function is less clear. To provide a murine model recapitulating complete DUOX deficiency, we simultaneously targeted both Duoxa genes by homologous recombination. Knockout of Duoxa genes (Duoxa(-/-) mice) led to a maturation defect of DUOX proteins lacking Golgi processing of N-glycans and to loss of H(2)O(2) release from thyroid tissue. Postnatally, Duoxa(-/-) mice developed severe goitreous congenital hypothyroidism with undetectable serum T4 and maximally disinhibited TSH levels. Heterozygous mice had normal thyroid function parameters. (125)I uptake and discharge studies and probing of iodinated TG epitopes corroborated the iodide organification defect in Duoxa(-/-) mice. Duoxa(-/-) mice on continuous T4 replacement from P6 showed normal growth without an overt phenotype. Our results confirm in vivo the requirement of DUOXA for functional expression of DUOX-based reduced nicotinamide adenine dinucleotide phosphate oxidases and the role of DUOX isoenzymes as sole source of hormonogenic H(2)O(2).

Hypothyroidism causing paralytic ileus and acute kidney injury - case report

We present a patient with severe hypothyroidism complicated by paralytic ileus and acute kidney injury. A 65 year old male patient, diagnosed with hypothyroidism one year ago was transferred to our unit in a state of drowsiness and confusion. He was severely hypothyroid and had paralytic ileus and impaired renal function at the time of transfer. Hypokalaemia was present, and was likely to have contributed to the paralytic ileus and this together with dehydration was likely to have contributed to renal injury. Nonetheless, hypothyroidism is very likely to have been the principal precipitant of both these complications, and both paralytic ileus and acute kidney injury improved with thyroxine replacement. Unfortunately, the patient died unexpectedly eight days after admission to the unit.Hypothyroidism may induce de novo acute kidney injury or it may exacerbate ongoing chronic kidney disease. This rare complication is assumed to be due to the hypodynamic circulatory state created by thyroid hormone deficiency. Paralytic ileus is an even rarer fatal manifestation of hypothyroidism and is thought to be due to an autonomic neuropathy affecting the intestines that is reversible with thyroxine replacement. To our knowledge, both these complications have not been observed in a single patient so far.It is important that clinicians are aware of these rare manifestations of hypothyroidism as in most occasions, thyroxine deficiency may be missed, and treatment can reverse the complications.

The Impaired Hypothyroid Patient: Ethical Considerations and Obligations

Analyze the ethical duties and dilemmas involved in treating the severely hypothyroid patient. A critical review of the literature was conducted with respect to clinical ethics issues pertaining to severe hypothyroidism; legal and ethical guidelines for consent and capacity in the context of severe hypothyroidism; health case law involving the duty to warn third parties; and comparable clinical conditions resulting in impaired driving and the performance of critical tasks. Neuropsychological studies and accepted clinical experiences verify the variable degrees of intellectual and neurological impairment consequent to severe hypothyroidism. Thus, severely hypothyroid patients are considered impaired in the performance of specific tasks, such as driving. Consequent to that, they may be agents of harm as a result of their impairment if they are not warned against driving or performing other duties affecting public safety. Severely hypothyroid patients may lack the capacity to make an informed decision, even when warned against driving or other tasks, and some may ignore such warnings. The legal and ethical "duty to warn" may trump confidentiality and HIPAA in cases where the activity of impaired patients seriously affects public safety. Not only do health care providers have a clear duty to warn patients not to drive, but in some extreme cases, may have a duty to warn third parties when a patient's driving or occupational duties place the public in harm's way.

Type 3 Deiodinase Deficiency Results in Functional Abnormalities at Multiple Levels of the Thyroid Axis

The type 3 deiodinase (D3) is a selenoenzyme that inactivates thyroid hormones and is highly expressed during development and in the adult central nervous system. We have recently observed that mice lacking D3 activity (D3KO mice) develop perinatal thyrotoxicosis followed in adulthood by a pattern of hormonal levels that is suggestive of central hypothyroidism. In this report we describe the results of additional studies designed to investigate the regulation of the thyroid axis in this unique animal model. Our results demonstrate that the thyroid and pituitary glands of D3KO mice do not respond appropriately to TSH and TRH stimulation, respectively. Furthermore, after induction of severe hypothyroidism by antithyroid treatment, the rise in serum TSH in D3KO mice is only 15% of that observed in wild-type mice. In addition, D3KO animals rendered severely hypothyroid fail to show the expected increase in prepro-TRH mRNA in the paraventricular nucleus of the hypothalamus. Finally, treatment with T(3) results in a serum T(3) level in D3KO mice that is much higher than that in wild-type mice. This is accompanied by significant weight loss and lethality in mutant animals. In conclusion, the absence of D3 activity results in impaired clearance of T(3) and significant defects in the mechanisms regulating the thyroid axis at all levels: hypothalamus, pituitary, and thyroid.

Elevated serum creatinine levels in infants with congenital hypothyroidism: reflection of decreased renal function?

UNLABELLED The effects of hypothyroid status on renal function have been poorly studied in children. We assessed the renal function of hypothyroid infants detected during neonatal mass screening for congenital hypothyroidism (CH). Eighty hypothyroid infants and 20 age-matched normal infants for controls were enrolled. The 80 patients, aged 1 mo, were divided into two groups based on the initial thyroid stimulating hormone (TSH) and free thyroxine (FT4) values: a mild-moderately hypothyroid (MHT) group (n = 64, 31M and 33F) and a severely hypothyroid (SHT) group (n = 16, 3M and 13F). Serum creatinine (SCr), TSH, FT4 and other chemicals were compared before and 2 mo after L-thyroxine (LT4) substitution therapy. The following results were obtained: SCr levels were significantly higher in the SHT group (33.2+/-10.0 micromol/L, p < 0.001) compared with the MHT group (20.6+/-6.4 micromol/L) and normal control group (21.0+/-4.4 micromol/L). Two months after the LT4 replacement therapy, the elevated SCr levels in the SHT group decreased by 41.3% to the level (19.5+/-6.0 micromol/L) very close to that in the MHT group (18.8+/-5.1 micromol/L). No significant differences were noted among BUN levels in the three groups. Although serum creatinine kinase levels were significantly higher in the SHT group (230.3+/-102.3 U/L, p < 0.001) than in the MHT group (121.1+/-60.8 U/L), rhabdomyolysis was not considered to be responsible for the impaired renal function. CONCLUSION From these results we conclude that serum creatinine levels are elevated in congenitally hypothyroid infants. This is a reversible change with thyroid hormone replacement therapy. The possibility of impaired renal functions should be kept in mind when treating hypothyroid infants.

Severe and mild neonatal hypothyroidism mediate opposite effects on Leydig cells of rats.

The effects of neonatal hypothyroidism on the number of Leydig cells were studied in neonatal Wistar rats. Moderate or severe hypothyroidism were induced during neonatal life by giving different amounts of methimazole (MMI; 0.05% or 0.1%) in the drinking water of pregnant and lactating dams. Rats were sacrificed on day 21 of postnatal life. Severely hypothyroid rats had approximately 45-fold higher serum thyrotropin (TSH) values and demonstrated approximately a 65% decrease in testes weight (p < 0.05) and the number of Leydig cells. However, in moderately hypothyroid rats, in which serum TSH was only approximately 16-fold higher, testicular weight was normal and the number of Leydig cells almost doubled (p < 0.01). There were no significant differences between the serum-free testosterone levels of the moderately and severely hypothyroid rats versus controls. Serum levels of 3alpha-androstanediol glucuronide, although decreased to less than 10% in severely hypothyroid rats (p < 0.01), were not changed by mild hypothyroidism. The number of Sertoli cells was increased in moderately hypothyroid rats versus controls (p < 0.05) and even further increased in severely hypothyroid rats (p < 0.05). We conclude that (1) severe neonatal hypothyroidism impairs the development and function of the testes and (2) moderate neonatal hypothyroidism stimulates the proliferation of Leydig cells.

Elevated serum creatinine levels in infants with congenital hypothyroidism: reflection of decreased renal function?

The effects of hypothyroid status on renal function have been poorly studied in children. We assessed the renal function of hypothyroid infants detected during neonatal mass screening for congenital hypothyroidism (CH). Eighty hypothyroid infants and 20 age-matched normal infants for controls were enrolled. The 80 patients, aged 1 mo, were divided into two groups based on the initial thyroid stimulating hormone (TSH) and free thyroxine (FT4) values: a mild-moderately hypothyroid (MHT) group (n = 64, 31M and 33F) and a severely hypothyroid (SHT) group (n = 16, 3M and 13F). Serum creatinine (SCr), TSH, FT4 and other chemicals were compared before and 2 mo after L-thyroxine (LT4) substitution therapy. The following results were obtained: SCr levels were significantly higher in the SHT group (33.2+/-10.0 micromol/L, p < 0.001) compared with the MHT group (20.6+/-6.4 micromol/L) and normal control group (21.0+/-4.4 micromol/L). Two months after the LT4 replacement therapy, the elevated SCr levels in the SHT group decreased by 41.3% to the level (19.5+/-6.0 micromol/L) very close to that in the MHT group (18.8+/-5.1 micromol/L). No significant differences were noted among BUN levels in the three groups. Although serum creatinine kinase levels were significantly higher in the SHT group (230.3+/-102.3 U/L, p < 0.001) than in the MHT group (121.1+/-60.8 U/L), rhabdomyolysis was not considered to be responsible for the impaired renal function. From these results we conclude that serum creatinine levels are elevated in congenitally hypothyroid infants. This is a reversible change with thyroid hormone replacement therapy. The possibility of impaired renal functions should be kept in mind when treating hypothyroid infants.

Diverse effects of mild and potent goitrogens on blood-brain barrier nutrient transport

Populations living in goitre endemic areas consume foods rich in a variety of goitrogens of different potencies and some are severely hypothyroid. Recently we observed in Wistar:NIN rats that chronic feeding of KSCN to dams produced only a moderate hypothyroidism and decreased the transport of 2-deoxy-D-glucose (2-DG) across the blood-brain barrier (BBB) in the offspring. The present studies were conducted to assess whether severe hypothyroidism would have greater effect on BBB nutrient transport. It has now been observed that weaning the pups of KSCN fed dams on to KSCN diet for four weeks had no further effect either on their thyroid status or the BBB 2-DG transport. However, feeding KSCN to rats through two generations produced somewhat severe hypothyroidism in F2 pups than that in F1 pups. Interestingly, unlike in F1 pups, the BBB transport of all the three nutrients tested (2-DG, Leu and Tyr) was significantly decreased in F2 pups, albeit to a small extent (10–15%). On the other hand the potent goitrogen: methyl mercaptoimidazole (MMI) even on short term feeding to pregnant dams produced very severe hypothyroidism in the offspring Serum T 4 :0.55±30.09 μg:dl vs 4.96±30.85 in controls . Surprisingly, the BBB transport of 2-DG, Leu, Tyr and also sucrose, the background marker, was significantly increased in these pups (20–30%). The diverse effects of goitrogen-induced moderate and severe hypothyroidism observed here on the BBB nutrient transport probably suggest different mechanisms for iodine deficiency disorders of different aetiologies and hence the need for discrete approaches for their management.

Clues to a possible new variant of thyroid hormone resistance.

Clues to a possible new variant of thyroid hormone resistance.

Effect of Chronic and Acute Thyroid Hormone Reduction on Perioperative Outcome

Effect of Chronic and Acute Thyroid Hormone Reduction on Perioperative Outcome

Effects of thyroid hormone treatment on 31P-NMR spectroscopy of muscle and on nerve conduction studies in a patient with long-standing severe hypothyroidism

Hypothyroidism exerts a significant effect on several body systems, including the functioning of muscle and nerve. Described here is the case of a severely hypothyroid patient with weakness and numbness of the legs who showed marked clinical improvement with thyroid hormone treatment. Concurrently obtained phosphorus 31-nuclear magnetic resonance (NRM) spectra and nerve conduction studies showed changes in muscle phosphorus metabolism with increases in conduction velocities. Phosphorus 31-NMR spectroscopy is useful for evaluating metabolism in muscle in hypothyroid patients.

Perinatal Consequences of Maternal Hypothyroidism in Early Pregnancy and Inadequate Replacement

Summary Maternal hypothyroidism may be associated with a variety of pregnancy complications. OBJECTIVE We have evaluated the perinatal consequences of maternal hypothyroidism in early and late gestation. DESIGN Retrospective study of pregnant women, with quasi-experimental design comparing different subjects. SUBJECTS Forty-three pregnancies In 42 women with hypothyroidism - either biochemically hypothyroid or with a history of hypothyroidism on adequate replacement - and no other preexisting medical conditions. MEASUREMENT Free thyroxine index (FTI), TSH, and haematocrit at Initial antepartum presentation and near term gestation. Pregnancy outcome variables Including: rate of Caesarean section performed for fetal distress in labour, neonatal weight percentile, and gestational age at birth. RESULTS Of 42 hypothyroid pregnancies, six were complicated by fetal distress In labour leading to Caesarean section. Five of these six were severely hypothyroid (defined as FTI ≤ 0.6 (normal range 1.1–4.4)) on initial antepartum presentation. In contrast, of the 36 pregnancies without fetal distress, only four initially presented severely hypothyroid (P<0.001). Conversely, 56% (5/9) of pregnancies which Initially presented severely hypothyroid were subsequently complicated by Caesarean section for fetal distress in labour. This compared to 3% (1/33) among those who presented either mildly hypothyroid or euthyroid on replacement (P<0.0001). Fetal distress correlated with low FTI (P<0.001) and high TSH at Initial presentation. However, It was independent of FTI near term. A relation between fetal distress and TSH near term did not reach statistical significance. Fetal distress also correlated with low maternal haematocrit on admission to labour and delivery (P<0.05), but was Independent of haematocrit and gestational age at Initial presentation, neonatal weight percentile, and gestational age at birth. CONCLUSIONS Severe maternal hypothyroidism early in gestation Is strongly associated with fetal distress in labour. This suggests that (1) Inadequate maternal replacement leads to fetal distress and (2) maternal thyroid status in early gestation may exert Irreversible effects on the fetus, the placenta, and/or on subsequent maternal adaptations to pregnancy. Early adequate replacement therapy Is especially prudent in pregnant women presenting with severe hypothyroidism.

Perinatal consequences of maternal hypothyroidism in early pregnancy and inadequate replacement.

Maternal hypothyroidism may be associated with a variety of pregnancy complications. We have evaluated the perinatal consequences of maternal hypothyroidism in early and late gestation. Retrospective study of pregnant women, with quasi-experimental design comparing different subjects. Forty-three pregnancies in 42 women with hypothyroidism--either biochemically hypothyroid or with a history of hypothyroidism on adequate replacement--and no other preexisting medical conditions. Free thyroxine index (FTI), TSH, and haematocrit at initial antepartum presentation and near term gestation. Pregnancy outcome variables including: rate of Caesarean section performed for fetal distress in labour, neonatal weight percentile, and gestational age at birth. Of 42 hypothyroid pregnancies, six were complicated by fetal distress in labour leading to Caesarean section. Five of these six were severely hypothyroid (defined as FTI < or = 0.6 (normal range 1.1-4.4)) on initial antepartum presentation. In contrast, of the 36 pregnancies without fetal distress, only four initially presented severely hypothyroid (P < 0.001). Conversely, 56% (5/9) of pregnancies which initially presented severely hypothyroid were subsequently complicated by Caesarean section for fetal distress in labour. This compared to 3% (1/33) among those who presented either mildly hypothyroid or euthyroid on replacement (P < 0.0001). Fetal distress correlated with low FTI (P < 0.001) and high TSH at initial presentation. However, it was independent of FTI near term. A relation between fetal distress and TSH near term did not reach statistical significance. Fetal distress also correlated with low maternal haematocrit on admission to labour and delivery (P < 0.05), but was independent of haematocrit and gestational age at initial presentation, neonatal weight percentile, and gestational age at birth. Severe maternal hypothyroidism early in gestation is strongly associated with fetal distress in labour. This suggests that (1) inadequate maternal replacement leads to fetal distress and (2) maternal thyroid status in early gestation may exert irreversible effects on the fetus, the placenta, and/or on subsequent maternal adaptations to pregnancy. Early adequate replacement therapy is especially prudent in pregnant women presenting with severe hypothyroidism.

Cardiac left ventricular function before and during early thyroxine treatment in severe hypothyroidism

In some patients with severe hypothyroidism, thyroxine replacement therapy precipitates or aggravates angina pectoris, whereas in other patients angina pectoris is ameliorated or even cured. Cardiac function in eight severely hypothyroid patients was studied by means of radionuclide ventriculography (RNV) at rest and during supine bicycle exercise before thyroxine treatment, and repeated during treatment before and after administration of 160 mg of oral verapamil. There was an exercise-induced fall in left ventricular ejection fraction (LVEF) in two patients before therapy, and in two additional subjects after 17 d on suboptimal doses of thyroxine. Verapamil attenuated the fall and induced a significant increase in LVEF during exercise (P less than 0.014). No abnormal regional cardiac wall movement (RWM) was observed. After 2 months of thyroxine treatment, LVEF increased significantly during exercise both before and after verapamil (P less than 0.012 and P less than 0.005). These findings are indicative of reversible coronary artery dysfunction. We recommend that, if feasible, thyroxine should be supplemented with verapamil during the early phase of treatment.

Parasympathetic nervous system activity in hypothyroidism determined by R‐R interval variations on electrocardiogram

Little is known about the relationship between hypothyroidism and the parasympathetic nervous system. R-R interval variations revealed by electrocardiogram (ECG) are known to be a useful clinical indicator of abnormalities of parasympathetic nervous system activity. Studies were conducted in hypothyroid patients, and significant reductions in R-R interval variations were observed in patients with primary severe hypothyroidism due to Hashimoto's thyroiditis, and in patients with Graves' disease who became severely hypothyroid during antithyroid drug therapy. R-R interval variations were restored to normal levels in both groups of patients after treatment. The present investigation suggests that in marked hypothyroidism there are hypofunctional abnormalities in the parasympathetic nervous system in association with a reduction in the levels of serum T4 and T3.

Are iodine-deficient rats euthyroid?

Inhabitants of many severe endemic goiter areas have low serum T4 and high circulating TSH, despite normal levels of T3. This situation may be produced experimentally chronically feeding rats a low iodine diet (LID). We fed rats a Remington-type LID and gave them 1% NaClO4 in their drinking water for 2 days. After this, the animals were divided into three groups. One group was fed LID, supplemented with 5 micrograms I/rat.day and was used as the control group. Another group was fed LID alone. The third group was fed LID and given 1% NaClO4 to drink. The latter treatment was used to induce severe hypothyroidism. Animals were killed 1, 2, 3, and 5 weeks after the onset of these treatment schedules. The following measurements were made on some or all groups of animals: body and thyroid weights; thyroidal I content; soluble labeled iodoprotein profile; thyroidal labeled iodoamino acid distribution pattern; plasma T4, T3, and TSH; pituitary GH content; and liver intramitochondrial alpha-glycerophosphate dehydrogenase and cytosolic malic enzyme activities. T4 and T3 concentrations were also measured in liver nuclei of the animals killed 5 weeks after the onset of treatment. As assessed from various indices of thyroid function, the LID rats became iodine deficient, although not as markedly as those given LID and ClO4-, The plasma T4 decreased to undetectable levels, and plasma TSH increased, whereas circulating T3 remained normal throughout in the LID rats. In rats given LID and ClO4-, plasma T4 decreased sooner than in rats given LID alone; plasma T3 levels also became undetectable, and TSH increased more markedly and sooner than in rats given LID alone. As measured at the end of 5 weeks of treatment, pituitary GH content, and liver alpha-glycerophosphate dehydrogenase and malic enzyme activities were lower in rats given LID than in the euthyroid LID- and I--treated controls. They were not, however, as markedly reduced as in the severely hypothyroid LID- and ClO4--treated rats. In spite of normal plasma T3 levels, the concentration of T3 in liver nuclei of the rats given LID alone was significantly lower than that of the LID- and I--treated controls. The results show that the thyrotrophs, somatotrophs, and livers of rats given LID alone are not like those of euthyroid rats despite normal circulating T3 levels. In iodine-deficient rats, there is a discrepancy between the measured indices of thyroid hormone action in the liver and the circulating T3 level, but not between biological activity and liver nuclear T3 concentration. It remains to be seen whether the same is true in the anterior pituitary.