Endocrinology- Thyroid Function Tests.

1. Endocrinology- Thyroid Function Tests. GROUP C: Wedyan Meshreky Helen Naguib Sharon Naguib

2. Ms MS, aged 40 years, has been taking Lithium carbonate therapy (1000mg/d) for the last 6 weeks as a mood stabiliser. She also takes the following medications on a regular basis: Hydrochlorothiazide 50mg d Verapamil 240mg d What effect does lithium have on thyroid function? What clinical chemistry tests should be performed and why? Explain any concerns you might have. Describe analytical protocols for evaluation of the hypothalamic and pituitary control of the thyroid gland. Describe the clinical application of the results of these investigations.

3. Lithium - Background • DOC in the treatment of bipolar manic-depressive disorder. • Low therapeutic index • Recommended therapeutic plasma lithium concentration is 1.0-1.5mmol/L1 in acute mania and 0.6 to 1.2 mmol/L1 during long term control. • Serum levels should not exceed 2mmol/L • Lithium is highly concentrated in the thyroid gland, probably by active transport • Lithium inhibits the secretion of T4 and T3 by poorly understood mechanisms. This results in an increase in pituitary secretion of TSH.

4. Lithium and Thyroid Function • Lithium can cause: –   Goiter –   Hypothyroidism –   Chronic autoimmune thyroiditis - Hyperthyroidism

5. Goiter • Generally it presents as a smooth enlargement of the thyroid gland and requires no further intervention. • Can occur within several weeks of initiation of lithium therapy; although, in most cases, it may take months to several years for a goiter to occur. • Euthyroid goiter occurs in 4-12% of patients.

6. Hypothyroidism • Occurs in Approximately 10% of Lithium – treated patients, predominantly female. • Can be with or without goiter. • Usually sub clinical • Responds to treatment with thyroxine; generally not necessary to stop lithium treatment. • Observed more frequently in patients with prior history of a damaged thyroid gland. • Few patients may have overt hypothyroidism with all of its usual signs and symptoms.

7. Chronic Autoimmune Thyroiditis • Inflammation of the Thyroid. • Rare - occurs in approximately 0.7%. • Cause is not clear. Some authors have speculated that lithium may directly stimulate autoimmune reactions. • Possibility that these patients have underlying chronic autoimmune thyroiditis.

8. Hyperthyroidism • In a recent retrospective analysis, the incidence of hyperthyroidism in patients treated with lithium was more than three times greater than the incidence of thyrotoxicosis in the general population. • However, there have been suggestions that this hyperthyroidism is random and not due to lithium.2

9. What clinical chemistry tests should be performed and why • Thyroid function tests should be run routinely whenever a person is suspected of having bipolar disorder, since a misbehaving thyroid gland can produce symptoms of mania or depression.

10. …cont • Before starting Lithium, patients should have a careful thyroid physical examination and TFT’s including T4, T3 test, TSH, free T4 index and antithyroid antibodies. • If a patient is hypothyroid before Lithium treatment, Thyroxine may be started. • Patients with normal thyroid function, need to have TFT’s every 3-6 months. If there are changes in thyroid function, there is a possibility thatthyroid function tests may normalize over 6 months to 2 years with continuous lithium treatment.

11. Other tests… • Renal function tests. (dose must be reduced) • Complete blood counts periodically. • Periodic electrocardiograms. • Lithium serum levels (greater than 2 mmol/L, although toxic symptoms may occur at levels greater than 1.5 mmol/L).

12. Explain any concerns you might have… • DRUG INTERACTIONS: • Lithium & HCT: concurrent use can lead to d Li conc.  Li toxicity (weakness, tremor, excessive thirst, confusion..) • Mechanism: reabsorption of Na and Li ions at proximal renal tubule  Li retention • Concomitant use should be avoided • Li levels should be monitored within the first week: lower Li doses may be needed

13. Concerns.. • Li & Verapamil:concurrent use can result in decreases in Li conc, leading to exacerbation of manic psychosis • Serum Li levels should be monitored periodically • Px’s should be followed closely for signs of manic psychosis, & any symptoms of neurotoxicity (ataxia, tremors, tinnitus, nausea, vomiting or diarrhoea)

14. TSH • 1st generation assays using RIA had poor sensitivity (limit of 1mU/L) • Disadv: cross reactivity with gonadotrophins (eg LH, FSH, hCG) sharing with TSH a common ‘a’ subunit • Newer TSH assays using immunometric assay more sensitive and accurate

15. TSH immunometric assay • One Ab directed against the ‘a’ subunit serves to anchor the TSH molecule • Another Ab usually a monoclonal Ab directed at the ‘b’ subunit is either • Radioiodinated: Immunoradiometric assay (IRMA) • Conjugated: with – an enzyme : Immunoenzymometric assay (IEMA) - a chemiluminescent compound: Chemiluminescent assay (ICMA)

16. Principle • TSH serves as the link between an immobilised Ab binding TSH at one epitope & a monoclonal Ab directed at a 2nd part of the molecule • Eg. IEMA: one Ab is attached to magnetic particles and the other is labelled with Alkaline Phosphastase. There are 4 stages to the assay,  uses spectrophometry and abs measured at 550nm or 492nm

17. Principle.. • Signal is directly related to amount TSH • Greater sensitivity and decreased interference from related compounds • 2nd, 3rd and 4th generation assays have higher sensitivity (~0.005-0.01mU/L)

18. TRH • TRH test: administering 500mcg IV synthetic TRH to measure the increase of pituitary TSH in serum • Normally: rapid rise in TSH levels, peaks in 30min, decreasing to normal by 120min • In primary hypothyroidism: rise is exaggerated

19. TRH.. • Useful in distinguishing pituitary from hypothalamic hypothyroidism • 20 to pituitary deficiency: absent/impaired TSH response to TRH • Hypothalamic disorder: normal amounts of TSH..delayed peak and prolonged elevation • Hyperthyroidism: TSH release remains suppressed • TRH test rarely used now to diagnose thyroid dysfunction due to the availability of newer TSH assays

20. Thyroid Gland • Secretes thyroid hormones (TH) which control our metabolic rate in 2 ways: • Stimulates every tissue in body to produce proteins • Increases amount of O2 that cells use.

21. Thyroid Hormones • Gland requires Iodine to produce thyroid hormones. • TH affect heart rate, resp. rate, growth, heat production, fertility, digestion, rate at which we burn calories etc. • The two hormones are: • T4- Thyroxine • T3- Triiodothyronine • T4 is the major hormone produced but it is converted to T3 in the liver and other tissues. • T3 is the more active hormone.

22. Controlling the level of TH • Firstly the hypothalamus secretes TRH which causes the pituitary gland to produce TSH. • TSH then goes on to stimulate the gland to produce TH.

23. What is the clinical application of these investigations? • By measuring TSH and the level of TH, thyroid dysfunction (hyperthyroidism or hypothyroidism) and the cause can be determined.

24. Hyperthyroidism • Excessive thyroid hormone activity. • Causes: • Grave’s disease • Toxic multinodular goiter or adenoma • Silent thyroiditis • Iodine induced hyperthyroidism (eg amiodarone, lithium) • Excessive pituitary TSH • Excessive ingestion of thyroid hormone

25. Signs & Symptoms • Nervousness & Irritability • Palpitations & tachycardia • Heat intolerance & increased sweating • Tremor • Frequent bowel movements (diarrhoea) • Weight loss (or gain) • Fatigue or muscle weakness

27. Diagnosis of Hyperthyroidism • Hyperthyroidism of any cause results in a low levels of TSH and high levels of free T4. • If TSH is low and FT4 is normal, serum T3 should be measured. If elevated this condition is called T3 toxicosis. • If TSH, T3 and T4 are elevated, then diagnosis for a TSH-secreting tumour is confirmed. • During severe illness, TSH, T4, & T3 levels often fall outside normal ref. Ranges so, clinical assessment should be made in conjunction with laboratory assessment.

28. Treatment of Hyperthyroidism • Surgical intervention • Antithyroid drugs • Radioactive iodine

29. Hypothyroidism • Results from under-secretion of TH from the thyroid gland. • Most common causes: • Hashimoto’s disease (chronic autoimmune thyroiditis) • Surgical removal of thyroid gland, thyroid gland ablation with radioactive iodine etc • Secondary causes: pituitary or hypothalamic disease.

30. Sign & Symptoms • Fatigue • Weight gain from fluid retention • Dry skin and cold intolerance • Coarseness or loss of hair • Goitre • Constipation • Depression • Hyperlipidaemia • Bradycardia • Hypothermia

32. Diagnosis of 1o hypothyroidism • Elevated TSH levels with low to normal FT4. • Presence of antithyroid peroxidase antibodies are present in almost all patients with Hashimoto’s. • 2o Hypothyroidism: due to dysfunction of hypothalamic-pituitary axis: Eg. low TSH and T4 may be due to deficient secretion of TRH from the hypothalamus or secretion of TSH from the pituitary.

33. Additional testing • May be necessary in rare cases in which a doctor cannot determine whether the problem lies in the thyroid or in the pituitary gland. • One of these tests involves injecting TRH IV and then measuring the level of TSH in the blood to determine the pituitary gland's response. • If cancer of the thyroid gland is suspected, a biopsy is performed. • When medullary thyroid cancer is suspected, blood levels of calcitonin are checked, because these cancers always secrete calcitonin.

34. Cont… • Ultrasound scan uses sound waves to measure the size of the gland and to determine whether the growth is solid or filled with fluid (cystic). • Uses radioactive iodine or technetium and a device to produce a picture of the thyroid gland that will show any physical abnormalities. • Thyroid scanning can also help determine whether the functioning of a specific area of the thyroid is normal, overactive, or underactive compared with the rest of the gland.

35. Summary • Hyperthyroidism: • PRIMARY:  T4 and TSH • SECONDARY: T4 and  TSH • Hypothyroidism: • PRIMARY:  T4 and  TSH • SECONDARY:  TSH and  T4