Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0020473 (hyperlipidemia)
 15,891 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hypothyroidism is associated with an increased risk of coronary artery disease. This observation may in part be related to the lipid abnormalities in patients with this condition. The lipid profiles of 268 patients with primary hypothyroidism and 27 with secondary hypothyroidism, who were examined in the Thyroid Clinic at the Mayo Clinic during a 1-year period, were reviewed. Hyperlipidemia was commonly associated with both primary and secondary hypothyroidism. The lipid values decreased with treatment of hypothyroidism. Type IIa hyperlipidemia was the most common lipid abnormality in patients with primary hypothyroidism, whereas type IIb was the most common in those with secondary hypothyroidism. Total/high-density lipoprotein cholesterol and low-density lipoprotein/high-density lipoprotein cholesterol ratios were increased in both male and female patients with primary and secondary hypothyroidism, and they decreased with restitution of the euthyroid state, although this decrease achieved statistical significance only in female patients. Significant associations with total thyroxine were noted for total cholesterol and triglycerides and with thyroid-stimulating hormone (thyrotropin) for total cholesterol and low-density lipoprotein cholesterol. Thus, both primary and secondary hypothyroidism are commonly associated with an atherogenic lipid profile, which improves with replacement of thyroid hormone. Even after restitution of the euthyroid state, however, the lipid profile remains atherogenic in male patients. In comparison with primary hypothyroidism, the lipid profile is more atherogenic in secondary hypothyroidism because of the lower high-density lipoprotein cholesterol levels associated with this condition.
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PMID:Hyperlipidemia in patients with primary and secondary hypothyroidism. 837 4

Abnormalities of thyroid function are associated with hyperlipidemia, a risk factor for coronary artery disease that starts in childhood. We investigated the age-, race-, and sex-related differences in thyroid function and its relation to serum lipoprotein levels in children (n = 363) aged 6 to 18 years from the biracial (black/white) community of Bogalusa, Louisiana, using an ultrasensitive thyroid-stimulating hormone (TSH) assay. Serum levels of lipoprotein cholesterol fractions, triglycerides, triiodothyronine (T3), thyroxine (T4), and the Tanner stage of sexual development were determined. Serum T3 (P < 0.0001), T4 (P < 0.0001), and TSH (P < 0.0020) levels decreased significantly with Tanner stage. Serum T4 levels were significantly higher (P < 0.0001) in both black and white females than their male counterparts. An unexpected finding was a significantly increased mean serum TSH in whites (2.09 + 0.91; mean + standard error of mean) when compared to blacks (1.74 + 0.10; P = 0.0185). Overall, no significant correlation was noted between serum lipoprotein variables and TSH. However, those with the highest low-density lipoprotein to very low-density lipoprotein cholesterol fractions had a higher T4 and a T4/TSH ratio than those with the lowest low-density lipoprotein to very low-density lipoprotein cholesterol fractions. In summary, it is concluded that there is no simple relationship between lipoproteins and TSH or thyroid hormone levels in children.
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PMID:Thyroid function in children with different lipoprotein profiles: observations in a biracial (black/white) population--the Bogalusa Heart Study. 903 Jun 72

A thyroid hormone analog with organ-selective effects could have therapeutic application for disorders such as hyperlipidemia and osteoporosis. We performed a randomized clinical trial to determine the specific thyromimetic effects of tiratricol. Twenty-four athyreotic patients underwent detailed metabolic and physiological evaluation after a 2-month baseline period, taking TSH-suppressive doses of L-T4. They were then randomized to blinded treatment with either tiratricol (24 micrograms/kg twice daily) or L-T4 (1.9 micrograms/kg daily). The dose of hormone was increased until the TSH level was less than 0.1 mU/L, and the metabolic and physiological testing was repeated. Comparing the change from baseline to the study drug periods, when serum TSH levels were equivalently suppressed, there were no significant differences between the two groups in resting metabolic rate, weight, urea nitrogen excretion, or symptom score. Plasma total and low density lipoprotein cholesterol levels declined 13 +/- 4% and 23 +/- 6% in the tiratricol group compared with 2 +/- 2% and 5 +/- 3% in the L-T4 group (P = 0.015 and P = 0.0066, respectively). Serum sex hormone-binding globulin levels increased 55 +/- 13% with tiratricol compared with a 1.7 +/- 4% decline with L-T4 (P = 0.0006), indicating an augmented hepatic response to tiratricol. Skeletal metabolic activity was enhanced, with increased levels of serum osteocalcin and urinary excretion of calcium and pyridinium cross-links. Tiratricol and L-T4 had comparable effects on cardiovascular function. Tiratricol has distinct augmented hepatic and skeletal thyromimetic actions of potential therapeutic value.
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PMID:Augmented hepatic and skeletal thyromimetic effects of tiratricol in comparison with levothyroxine. 921 87

A patient is described with type III hyperlipidaemia and primary hypothyroidism who had a unique clinical course of hyperlipidaemia. The patient was a 65-year-old man with primary hypothyroidism. His plasma total cholesterol, triglyceride and high density lipoprotein-cholesterol concentrations 1 year after starting thyroid hormone replacement therapy were 7.98, 4.04 and 0.72 mmol/l, respectively. His plasma apolipoprotein (apo) E level was 0.29 g/l and its phenotype was E2/2. Remarkably, this patient had no hyperlipidaemia before starting thyroid hormone replacement therapy but it became overt only after the hypothyroidism had been treated. Although we have not confirmed the mechanism for this, we speculate that a decrease in enzyme activities responsible for cholesterol production may have been sufficient to surpass the effect of apolipoprotein E2/2 and the decrease in enzyme activities involved in degrading and excreting plasma cholesterol, resulting in normolipidaemia.
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PMID:Type III hyperlipidaemia with primary hypothyroidism: a unique clinical course of hyperlipidaemia during replacement therapy of thyroid hormone. 923 Oct 59

Thyroid hormone directly affects the heart and peripheral vascular system. The hormone can increase myocardial inotropy and heart rate and dilate peripheral arteries to increase cardiac output. An excessive deficiency of thyroid hormone can cause cardiovascular disease and aggravate many preexisting conditions. In severe systemic illness and after major surgical procedures changes in thyroid function can occur, leading to the "euthyroid sick syndrome." Patients will have normal or decreased levels of T4, decreased free and total T3, and usually normal levels of thyroid stimulating hormone. This syndrome may be an adaptive response to systemic illness that usually will revert to normal without hormone supplementation as the illness subsides. Recently, however, many investigators have explored the benefits of thyroid hormone supplementation in those diseases associated with euthyroid sick syndrome. Thyroid hormone's effects on the cardiovascular system make it an attractive therapy for those patients with impaired hemodynamics and low T3. Thyroid hormone has also been considered a treatment for patients with congestive heart failure, for patients undergoing cardiopulmonary bypass and heart transplantation, and for patients with hyperlipidemia. At present there is no evidence suggesting a favorable treatment outcome using thyroid hormone supplementation for any systemic condition except in those patients with documented hypothyroidism.
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PMID:Thyroid hormone and cardiovascular disease. 948 64

The development of sensitive assays for thyrotropin (TSH) has led to the discovery that many older patients have abnormal TSH levels without other alterations in serum thyroid hormone levels, conditions termed subclinical hypothyroidism (isolated elevation of TSH levels) and subclinical hyperthyroidism (isolated suppression of TSH levels). Subclinical hypothyroidism occurs in 5% to 10% of elderly subjects, and is especially prevalent in elderly women. Subclinical hyperthyroidism is less common, affecting less than 2% of the elderly population. The causes of subclinical thyroid disease in the elderly are similar to those of thyroid disease in the general population, although medications and iodine-containing compounds may play an increased role. Potential risks of subclinical hypothyroidism in the elderly include progression to overt hypothyroidism, cardiovascular effects, hyperlipidemia, and neurological and neuropsychiatric effects. Potential risks of subclinical hyperthyroidism in the elderly include progression to overt hyperthyroidism, cardiovascular effects (especially atrial fibrillation), and osteoporosis. Decisions to treat elderly subjects with subclinical thyroid disease should be based on a careful assessment of these risks in the individual patient.
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PMID:Subclinical thyroid disease in the elderly. 977 54

Thyroid hormones influence all major metabolic pathways. Their most obvious and well-known action is an increase in basal energy expenditure obtained acting on protein, carbohydrate and lipid metabolism. With specific regard to lipid metabolism, thyroid hormones affect synthesis, mobilization and degradation of lipids, although degradation is influenced more than synthesis. The main and best-known effects on lipid metabolism include: (a) enhanced utilization of lipid substrates; (b) increase in the synthesis and mobilization of triglycerides stored in adipose tissue; (c) increase in the concentration of non-esterified fatty acids (NEFA); and (d) increase of lipoprotein-lipase activity. While severe hypothyroidism is usually associated with an increased serum concentration of total cholesterol and atherogenic lipoproteins, the occurrence of acute myocardial infarction (AMI) in hypothyroid patients is not frequent. However, hypothyroid patients appear to have an increased incidence of residual myocardial ischemia following AMI. Even in subclinical hypothyroidism, which is characterized by raised serum TSH levels with normal serum thyroid hormone concentrations, mild hyperlipidemia is present and may contribute to an increased risk of atherogenesis. Prudent substitution therapy with L-thyroxine is indicated in patients with both overt and subclinical hypothyroidism, with or without angina, to counteract the cardiovascular risk resulting from hyper-dyslipidemia.
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PMID:Thyroid and lipid metabolism. 1099 23

The wide range of phenotypic abnormalities seen in the leptin-deficient ob/ob mouse and their reversibility by leptin administration provide compelling evidence for the existence of multiple physiological functions of this hormone in rodents. In contrast, information regarding the roles of this hormone in humans is limited. Three morbidly obese children, who were congenitally deficient in leptin, were treated with daily subcutaneous injections of recombinant human leptin for up to 4 years with sustained, beneficial effects on appetite, fat mass, hyperinsulinemia, and hyperlipidemia. Leptin therapy resulted in a rapid and sustained increase in plasma thyroid hormone levels and, through its age-dependent effects on gonadotropin secretion, facilitated appropriately timed pubertal development. Leptin deficiency was associated with reduced numbers of circulating CD4(+) T cells and impaired T cell proliferation and cytokine release, all of which were reversed by recombinant human leptin administration. The subcutaneous administration of recombinant human leptin has major and sustained beneficial effects on the multiple phenotypic abnormalities associated with congenital human leptin deficiency.
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PMID:Beneficial effects of leptin on obesity, T cell hyporesponsiveness, and neuroendocrine/metabolic dysfunction of human congenital leptin deficiency. 1239 45

Endogenous thyroid receptor hormones 3,5,3',5'-tetraiodo-l-thyronine (T(4), 1) and 3,5,3'-triiodo-l-thyronine (T(3), 2) exert a significant effects on growth, development, and homeostasis in mammals. They regulate important genes in intestinal, skeletal, and cardiac muscles, the liver, and the central nervous system, influence overall metabolic rate, cholesterol and triglyceride levels, and heart rate, and affect mood and overall sense of well being. The literature suggests many or most effects of thyroid hormones on the heart, in particular on the heart rate and rhythm, are mediated through the TRalpha(1) isoform, while most actions of the hormones on the liver and other tissues are mediated more through the TRbeta(1) isoform of the receptor. Some effects of thyroid hormones may be therapeutically useful in nonthyroid disorders if adverse effects can be minimized or eliminated. These potentially useful features include weight reduction for the treatment of obesity, cholesterol lowering for treating hyperlipidemia, amelioration of depression, and stimulation of bone formation in osteoporosis. Prior attempts to utilize thyroid hormones pharmacologically to treat these disorders have been limited by manifestations of hyperthyroidism and, in particular, cardiovascular toxicity. Consequently, development of thyroid hormone receptor agonists that are selective for the beta-isoform could lead to safe therapies for these common disorders while avoiding cardiotoxicity. We describe here the synthesis and evaluation of a series of novel TR ligands, which are selective for TRbeta(1) over TRalpha(1). These ligands could potentially be useful for treatment of various disorders as outlined above. From a series of homologous R(1)-substituted carboxylic acid derivatives, increasing chain length was found to have a profound effect on affinity and selectivity in a radioreceptor binding assay for the human thyroid hormone receptors alpha(1) and beta(1) (TRalpha(1) and TRbeta(2)) as well as a reporter cell assay employing CHOK1-cells (Chinese hamster ovary cells) stably transfected with hTRalpha(1) or hTRbeta(1) and an alkaline phosphatase reporter-gene downstream thyroid response element (TRAFalpha(1) and TRAFbeta(1)). Affinity increases in the order formic, acetic, and propionic acid, while beta-selectivity is highest when the R(1) position is substituted with acetic acid. Within this series 3,5-dibromo-4-[(4-hydroxy-3-isopropylphenoxy)phenyl]acetic acid (11a) and 3,5-dichloro-4-[(4-hydroxy-3-isopropylphenoxy)phenyl]acetic acid (15) were found to reveal the most promising in vitro data based on isoform selectivity and were selected for further in vivo studies. The effect of 2, 11a, and 15 in a cholesterol-fed rat model was monitored including potencies for heart rate (ED(15)), cholesterol (ED(50)), and TSH (ED(50)). Potency for tachycardia was significantly reduced for the TRbeta selective compounds 11a and 15 compared with 2, while both 11a and 15 retained the cholesterol-lowering potency of 2. This left an approximately 10-fold therapeutic window between heart rate and cholesterol, which is consistent with the action of ligands that are approximately 10-fold more selective for TRbeta(1). We also report the X-ray crystallographic structures of the ligand binding domains of TRalpha and TRbeta in complex with 15. These structures reveal that the single amino acid difference in the ligand binding pocket (Ser277 in TRalpha or Asn331 in TRbeta) results in a slightly different hydrogen bonding pattern that may explain the increased beta-selectivity of 15.
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PMID:Thyroid receptor ligands. 1. Agonist ligands selective for the thyroid receptor beta1. 1269 76

Subclinical and overt hypothyroidism are relatively common disorders in the general population. Thyroid hormone is known to play a role in regulating the synthesis, metabolism, and mobilization of lipids. In patients with overt hypothyroidism there is an increase in serum total cholesterol, low-density lipoprotein (LDL) cholesterol, apolipoprotein B, lipoprotein(a) levels, and possibly triglyceride levels. The effects of subclinical hypothyroidism on serum lipid values are less clear. The preponderance of evidence suggests that total cholesterol, LDL cholesterol, and possibly triglycerides are increased in patients with subclinical hypothyroidism, whereas high-density lipoprotein (HDL) cholesterol and Lp(a) remain unchanged. Most lipid abnormalities in patients with overt hypothyroidism will resolve with thyroid hormone replacement therapy. However, clinical trials to date have not shown a beneficial effect of thyroid hormone treatment on serum lipid levels in patients with subclinical hypothyroidism. The lipid-altering effects of thyroid hormone make it an appealing target for drug development. The development of specifically targeted thyroid hormone analogues that could potentially treat hyperlipidemia without causing systemic thyrotoxicosis is currently ongoing.
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PMID:Hypothyroidism and dyslipidemia: modern concepts and approaches. 1548 7


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