Lithium hypothyroidism with

Leutgeb U. Ambient iodine and lithium associated with clinical hypothyroidism. Br J Psychiatry 2000 176 495-6. 

Treatment of Manic—Depressive Illness. Siace the 1960s, lithium carbonate [10377-37-4] and other lithium salts have represented the standard treatment of mild-to-moderate manic-depressive disorders (175). It is effective ia about 60—80% of all acute manic episodes within one to three weeks of adrninistration. Lithium ions can reduce the frequency of manic or depressive episodes ia bipolar patients providing a mood-stabilising effect. Patients ate maintained on low, stabilising doses of lithium salts indefinitely as a prophylaxis. However, the therapeutic iadex is low, thus requiring monitoring of semm concentration. Adverse effects iaclude tremor, diarrhea, problems with eyes (adaptation to darkness), hypothyroidism, and cardiac problems (bradycardia—tachycardia syndrome). 

Lithium is concentrated in the thyroid gland and can impair thyroid hormone synthesis. Although goiter is uncommon, as many as 30% of patients develop at least transiently elevated thyroid-stimulating hormone values. Lithium-induced hypothyroidism is not usually an indication to discontinue the drug. Patients can be supplemented with levothyroxine if continuation of lithium is desired.30... 

Lithium is associated with hypothyroidism in up to 34% of patients, and hypothyroidism may occur after years of therapy. Lithium appears to inhibit thyroid hormone synthesis and secretion. Patients with underlying autoimmune thyroiditis are more likely to develop lithium-induced hypothyroidism. Patients may require LT4 replacement even if lithium is discontinued. 

Other causes include magnesium-containing antacids in patients with renal insufficiency, enteral or parenteral nutrition in patients with multiorgan system failure, magnesium for treatment of eclampsia, lithium therapy, hypothyroidism, and Addison s disease. 

Thyroid Hormone (Thyroxine, Synthroid). The most common use of thyroxine in bipolar patients is the treatment of lithium-induced hypothyroidism. Approximately 5% of patients receiving long-term lithium treatment ultimately develop hypothyroidism. When this occurs, the patient with bipolar disorder may present with symptoms of a depressive episode. Therefore, periodic thyroid axis monitoring, that is, a serum thyroid stimulating hormone (TSH) test, is required for all patients taking lithium and should always be performed when the bipolar patient experiences a depressive episode. 

When laboratory testing indicates that a patient with BPAD is clinically hypothyroid, even if lithium is the readily apparent cause, we recommend starting thyroid hormone replacement. Lithium should not be discontinued, particularly if it has otherwise managed the BPAD well. Thyroxine should be started at 50 ag/day. TSH levels can then be checked 6-8 weeks later. The daily dose of thyroxine can be increased in 25 g increments every 1-2 months until TSH levels have normalized. 

The next step in the management of the depressed bipolar patient is to evaluate thyroid function. This is especially important for patients treated with lithium in order to rule out lithium-induced hypothyroidism. When this occurs, the addition of thyroid hormone replacement may relieve the depressive symptoms without any additional changes to the bipolar treatment regimen. 

Hypothyroidism Hypothyroidism may occur with long-term lithium administration. Patients may develop enlargement of thyroid gland and increased thyroid-stimulating hormone levels. 

Aggravation of the extrapyramidal effects of antipsychotic agents have been described and it has been reported that the use of lithium in combination with haloperidol may result in irreversible neurological toxicity. Lithium can increase the hypothyroid effects of antithyroid agents or iodides. 

Biosynthetic defects in thyroid hormonogenesis may also result in an inability of the thyroid gland to produce sufficient hormone and may be due to inherited enzymatic deficiencies or the ingestion of natural or therapeutically administered antithyroid agents. An example in the latter category is lithium, widely used to treat psychiatric disorders and associated with the development of hypothyroidism and goiter. It is concentrated by the thyroid, where it inhibits thyroidal I uptake, incorpora-... 

Lithium should not be administered to patients with fluctuating or unstable renal function. Because hthium may affect functioning of the cardiac sinus node, patients with sinus node dysfunction (e.g., sick sinus syndrome) should not receive hthium. Although hthium also has acute and chronic effects on the thyroid, patients with hypothyroidism may receive hthium if the thyroid disease is adequately treated and monitored. Laboratory tests that should be performed before initiation of hthium are listed in Table 5-1. 

A common mistake is to treat bipolar depression in the same manner that one treats unipolar depression, overlooking the need for a mood stabilizer. In bipolar depression, the first pharmacological intervention should be to start or optimize treatment with a mood stabilizer rather than to start administering an antidepressant medication. In addition, thyroid function should be evaluated, particularly if the patient is taking lithium. Subclinical hypothyroidism, manifested as an increased thyroid-stimulating hormone level and normal triiodothyronine and thyroxine levels, may present as depression in affectively predisposed individuals. In such cases, the addition of thyroid hormones may be beneficial, even if there is no other evidence of hypothyroidism. 

Lithium Plus Thyroid Supplementation. Treatment-resistant and rapid-cycling bipolar patients may have an increased frequency of thyroid dysfunction. Further, some patients suffer from subclinical hypothyroidism and improve with the addition of thyroid supplementation. In this context, several case reports involving this population found that high doses of the thyroid hormone levothyroxine sodium (T ) were clinically beneficial (122,123 and 124). Kusalic (1.25) found that 6 of 10 rapid cyclers had hypothyroidism, based on their thyrotropin-releasing hormone stimulation tests. Further, the average number of mood episodes per year decreased by more than 75% (i.e., from 9.7 to 2.2) after thyroxine was added to the treatment regimen. 

Hypothyroidism, a condition in which the circulating concentrations of thyroid hormones are too low, is the most prevalent thyroid disease. Primary hypothyroidism, the commonest form, is an autoimmune disease (Hashimoto s thyroiditis) often associated with goitre. Like other autoimmune diseases, it is more prevalent in women (4 per 1000) than in men (1 per 1000). Other causes include thyroidectomy, radioac tive ablation and, in some countries, iodine deficiency. Hypothyroidism can also be caused by several drugs, including lithium, interleukin-2 and interferon. Secondary hypothyroidism is a disease caused by decreased secretion of TSH by the pituitary. 

Inhibition of thyroid hormone synthesis or release with the induction of hypothyroidism (or occasionally hyperthyroidism) Iodides (including amiodarone), lithium, aminoglutethimide, thioamides, ethionamide... 

Induction of autoimmune thyroid disease with hypothyroidism or hyperthyroidism Interferon-a, interleukin-2, interferon-B, lithium, amiodarone... 

Long-term side effects of lithium treatment include weight gain. The treatment is associated with development of hypothyroidism in about 10-15% of cases. There is an association with kidney disease. Birch has expressed the general view that Li may interact with magnesium-dependent processes, and theoretical chemistry supports this view. Despite the widespread clinical significance of Li, there is presently no consensus on its mode of action. One postulate for the mechanism is termed hyperpolarization . Li affects the conductivity in cell transport channels. Other explanations include modulation of neurotransmitter concentrations and inhibition of Na+/K+/Mg2+/ Ca2+ ATPases. 

Lithium-induced hypothyroidism has been briefly reviewed (626). Some patients develop more persistent subclinical hypothyroidism (TSH over 5 mU/1, free thyroxine normal) and others overt hypothyroidism (higher risk in women, in those with pre-existing thyroid dysfunction, and those with a family history of hypothyroidism). Since subclinical hypothyroidism is not necessarily asymptomatic, treatment with thyroxine may be necessary in this group (627), as well as in those with more obvious hypothyroidism (628). 

In 1705 patients, aged 65 years or over, who had recently started to take lithium, identified from the 1.3 million adults in Ontario receiving universal health care coverage, the rate of treatment with thyroxine was 5.65 per 100 person-years, significantly higher that the rate of 2.70/100 person-years found in 2406 new users of valproate (629). Of 46 adults taking lithium in a psychiatric clinic, 17% developed overt hypothyroidism while 35% had subclinical hypothyroidism (raised concentrations of thyroid stimulating hormone, TSH) (630). 

The prevalence of thyroperoxidase antibodies was higher in 226 bipolar patients (28%) than in population-and psychiatric-control groups (3-18%). While there was no association with lithium exposure, the presence of antibodies increased the risk of lithium-induced hypothyroidism (632). 

In a review of lithium-induced subclinical hypothyroidism (TSH over 5 mU/1, free thyroxine normal), a prevalence of up to 23% in lithium patients was contrasted with up to 10% in the general population. It was stressed that subclinical hypothyroidism from any cause can be associated with subtle neuropsychiatric symptoms, such as depression, impaired memory and concentration, and mental slowing and lethargy, as well as with other somatic symptoms. Management guidelines were discussed (628). 

An abstract reported that 23% of 61 children and adolescents taking lithium and divalproex sodium for up to 20 weeks had a TSH concentration over 10 mU/1 (reference range 0.2-6.0) however, no clinical information was provided (635). Another abstract reported that the prevalence of thyroperoxidase antibodies was higher in bipolar outpatients (28% of 226) than in psychiatric inpatients with any diagnosis (10% of 2782) or healthy controls (14% of 225), but this was not related to lithium exposure on the other hand, hypothyroidism was associated with lithium exposure, especially in the presence of antithyroid antibodies (636). 

The observation that Canada, with ample nutritional iodine, has a relatively high rate of lithium-related hypothyroidism compared with relatively low rates in iodine-deficient countries such as Italy, Spain,... 

Euthyroid or hypothyroid goiter can also complicate lithium therapy, although the goiter is seldom of clinical importance and tends to resolve on withdrawal or with thyroxine treatment. In one ultrasound study, there was a... 

Henry C. Lithium side-effects and predictors of hypothyroidism in patients with bipolar disorder sex differences. J Psychiatry Neurosci 2002 27(2) 104-7. 

Many of the adverse effects of lithium can be ascribed to the action of lithium on adenylate cyclase, the key enzyme that links many hormones and neurotransmitters with their intracellular actions. Thus antidiuretic hormone and thyroid-stimulating-hormone-sensitive adenylate cyclases are inhibited by therapeutic concentrations of the drug, which frequently leads to enhanced diuresis, hypothyroidism and even goitre. Aldosterone synthesis is increased following chronic lithium treatment and is probably a secondary consequence of the enhanced diuresis caused by the inhibition of antidiuretic-hormone-sensitive adenylate cyclase in the kidney. There is also evidence that chronic lithium treatment causes an increase in serum parathyroid hormone levels and, with this, a rise in calcium and magnesium concentrations. A decrease in plasma phosphate and in bone mineralization can also be attributed to the effects of the drug on parathyroid activity. Whether these changes are of any clinical consequence is unclear. 

A very uncommon adverse effect involves sinus node dysfunction (extreme bradycardia, sinus arrest, sinoatrial block), which can be associated with syncopal episodes, perhaps due to hypothyroidism (119,120). In such cases, lithium must either be withdrawn or continued in the presence of a pacemaker. At therapeutic concentrations, other cardiac conduction disturbances have been reported, sometimes in conjunction with hypercalcemia (121), but are uncommon. 

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