Hyperthyroidism - A Subtle Disorder

Sachdev Yadav

Thyroid gland is an endocrine gland located in neck, anterior to trachea.  It has two lobes one on each side of trachea. The lobes are connected by a thin band of tissue. The thyroid gland takes iodine from the blood and uses it to make two hormones

Thyroxine-T4

Triiodotthyronine-T3

These hormones regulate growth and metabolism. Disorders result from autoimmune processes that stimulate either overproduction (hyperthyroidism) or underproduction (hypothyroidism) of thyroid hormones. Dietary iodine deficiency is an important cause of thyroid disease as it is an essential requirement for thyroid hormone synthesis¹.

Under active thyroid², called hypothyroidism, is a defect that results in a reduced production of thyroid hormones. This deficiency causes an overall decrease in both physical and mental activity.

Overactive thyroid, called HYPERTHYROIDISM, results in an overproduction of thyroid hormones. It occurs in almost 1 in 100 people and affects women predominantly being 10 times more common in them. Hyperthyroidism is a common clinical entity that responds favorably to a number of treatment options; drugs remain preferred treatment in India.

Graves’ disease is the most common form of hyperthyroidism. The elevated level of thyroid hormones ranges from mild and manageable to severely toxic. Though, thyrotoxicosis is not fatal; thyroid storm, a condition characterized by massive increase in thyroid hormones can be fatal in every 5^th case².

Hyperthyroidism may be treated with antithyroid drugs, ¹³¹I, or subtotal thyroidectomy, the type of treatment being determined by the form of hyperthyroidism, the age of patient, the size of goiter, and the presence of coexisting conditions³.

Indian Scenario

Indian studies⁴ have shown that the profile of thyroid disorders encountered especially in paediatric and adolescent age groups in India is similar to that seen in most parts of the world except for the prevalence of iodine deficiency disorders in certain endemic regions of this country. Though hyperthyroidism is more common in India, cases with hyperthyroidism have a more gratifying treatment response as many treatment modalities are present.

World-over⁵, approximately 1.1% population suffers from Hyperthyroidism. However in India according to the industry estimates only 4 Lac patients get treated. Generally speaking incidence of hyperthyroidism is more common in females then males in the ratio of 4:1 (Female: Male).

Hyperthyriodism - Etiopathogenesis

Hyperthyroidism may be the result of increased synthesis and secretion of thyroid hormones   (T4 and T3) from the thyroid glands, caused by thyroid gland stimulators in the blood or autonomous thyroid hyperfunction. It can also be caused by excessive release of from thyroid hormones from the thyroid gland into the peripheral circulation without increased synthesis of the hormones. This is commonly caused by the destructive changes in the thyroid secondary to the various causes of thyroiditis⁶.

Hyperthyroidism may be caused by a variety of disorders:

Three common causes⁷(Account for 99% of cases)

1.Graves’ Disease

2.Toxic Multinodular Goiter

3.Toxic Adenoma (Plummer’s Disease)

Uncommon causes⁷

1.Acute and Subacute Thyroidities

2.Iodine Induced Hyperthyroidism

3.Iatrogenic (Exogenous) Hyperthyroidism

Graves’ disease, the most common form is an autoimmune disease.²

A number of other precipitating factors have been identified. These include stress, pregnancy, glucocorticoid withdrawal, treatment with large doses of iodine and lithium therapy. Bacterial and viral infections have also been associated with an increased risk². Drugs are an important causes of Hyperthyroidism among which amiodarone is common. It is estimated that 3% of all hyperthyroidism occur due to this drug. Clinician should consider drugs in the in the differential diagnosis of thyrotoxicosis.

Clinical Presentation

Clinical presentation depends on⁸

·Severity of disease

·Duration of the disease

·Age of the patient

Symptoms and Signs^{8, 9}

·Unexplained Weight Loss inspite of increased appetite

·Sweating, Heat intolerance

·Palpitation / Tachycardia

·Anxiety / Nervousness

·Tremors

·Muscular Weakness / Fatigue

·Menstrual Irregularities

·Diarrhoea

·Enlarged Thyroid Gland

·Exopthalmos / Bulging Eyes

·Decrease in Bone Density

“An anxious, lean, staring individual, who eats like a glutton and offers you a warm, moist trembling hand, can be a patient with thyrotoxicosis.”

Laboratory Evaluation

1. Thyroid Function Test (TFT)

The TFT’s are done to measure total T4, Free T4, Total T3, Free T3 and TSH. Generally T3, T4 and TSH are investigated to confirm the diagnosis.

The current emerging trend^{8, 11} being adapted in west is to use TSH to distinguish between hyperthyroidism, hypothyroidism and euthyroidism.

2. Radioiodine uptake and Thyroid scanning¹¹

·Thyroid gland selectively transports radioisotopes of iodine.

·Toxic adenomas appear as focal areas of increase uptake.

·In toxic multinodular goitre, there are multiple areas of relatively increased or decreased tracer utake.

·Subacute thyroiditis is associated with very low uptake.

·Thyroid scanning is used in follow-up studies of thyroid cancer.

3. Thyroid Ultrasound¹¹

·Used to assist in diagnosis of nodular thyroid disease.

·Useful for monitoring nodule size, for guiding FNA biopsies and for aspiration of cystic lesions.

·Ultrasound is also used in evaluation of recurrent thyroid cancer, including possible spread to cervical lymph nodes.

4. Fine needle Thyroid biopsy⁸

Aspiration of thyroid tissue with a fine needle (25 guage) is helpful in the diagnosis of thyroid disorders, especially nodular lesions. This technique has become the preferred approach to the diagnosis of thyroid masses.

Management of thyroid disorders usually requires prolonged, and often lifelong, courses of treatment. Hence adequate compliance is needed to achieve euthyroidism.

Normal Pathway For Formation Of T3 And T4

Treatment¹²
Antithyroid Drugs
Thionamides^2,6

Antithyroid drugs decrease the organification of iodine and impair the coupling reaction,three antithyroid drugs propylthiouracil, carbimazole and methimazole block synthesis of thyroid hormone by inhibiting thyroid peroxidase, which is necessary for the synthesis of T₄.

Methylthiouracil and Propylthiouracil blocks the binding of iodine with tyrosine. The absorption of inorganic iodine by the gland takes place normally, but it is not converted into di-iodotyrosine or thyroxine. They are very toxic and hence can not be given as maintenance therapy for prolonged periods. The toxic reactions are agranulocytosis, drug fever and skin rashes. In large doses, propylthiouracil also inhibits the peripheral tissue conversion of thyroxin to triiodothyrominine.

Methimazole is used in preference to propylthiouracil, because it has a longer inhibitory effect on glandular hormone synthesis and can therefore be taken as a single daily dose, improving compliance. Moreover in doses up to 30 mg/d, methimazole may carry a lower risk of agranulocytosis.

Carbimazole in-vivo is metabolized to the active drug methimazole which is responsible for its clinical activity. It acts by; ^14,15

·Preventing formation of monoiodotyrosine (MIT).

·Preventing coupling of Iodotyrosine.

·Preventing conversion of MIT and Diiodotyrosine(DIT) to T3 and T4.

It has been documented to be safe and effective for pregnant women with hyperthyroidism^{17, 18, 19, 20}. It is also well tolerated; overall incidences of adverse effects are lower than the incidence observed with others^{21, 22}.

Radioiodine^3,13

¹³¹I is the treatment of choice for patients with Grave’s hyperthyroidism who relapse after long-term antithyroid therapy, for patient with severe thyrocardiac disease, for most patients with toxic multinodular or uninodular goitre, and for the patients with the major adverse reaction to antithyroid drugs. ¹³¹I therapy is contraindicated during pregnancy or breastfeeding.

Subtotal Thyroidectomy³

Subtotal thyroidectomy is indicated in pregnant patients and children who have a major adverse reaction to propylthiouracil or methimazole. It is also appropriate therapy for patients with large goitre that extend retrosternally and lead to compressive manifestations and for patients with thyroid carcinoma compliancing a toxic goitre.

Summary

Conditions of the thyroid, usually the result of overproduction or underproduction of thyroid hormone, are often seen by primary care practitioners and are far more common among the women then in men. Pregnancy and advancing age may be the contributing factors in thyroid dysfunction. Thyroid function can best be evaluated by measuring levels of TSH; Free T4 and T3 levels contribute to the clinical picture.

Because the clinical presentation of hyperthyroidism may be overt or subtle, the primary care provider must maintain a high index of suspicion and screen for potential thyroid dysfunction. Management of hyperthyroidism usually requires prolonged, and often lifelong, course of treatment. Hence adequate compliance is needed to achieve and maintain euthyroidism. For patients with sustained forms of hyperthyroidism, such as Graves’ disease or toxic nodular goitre, anti thyroid medications are often used. The goal with this form of drug therapy is to prevent the thyroid from producing excessive hormones. Thionamides are common drugs in this category. Carbimazole ia an effective antithyroid agent, which gives rapid and effective control of thyrotoxicosis. It has been proved to be safe with minimal side effects compared with other anti thyroid agents.

References

1.Menon PS, API-Text book of medicine-7^th edn,2003, Disorders of the thyroid gland, Chapter 6, 1051-1061.

2.Dhikav V, Ajmani A.K., Medicine update, 2003, 11 (7): 59-63.

3.Woeber KA, Update on the Management of Hyperthyroidism and Hypothyroidism, Arch Fam Med. 2000; 9: 743-747.

4.Virmani A, Menon PS, Karmarkar MG, Gopinath PG,Pandhy AK. Profile of thyroid disorders in a referral centre in north India. Indian Pediatr.1989, Mar; 26(3): 265-269.

5.Adapted from the Pharmaceutical Journal; Vol 265 No 7109; 240-244.

6.The Merck Manual of Diagnosis and Therapy, Chapter 8. Thyroid Disorders.

7.The Endocrine System, Chapter 26, Robbins Pathological basis of disease, 6th edn,1999, 1130-1147.

8.Harrisons Principles of Internal Medicine, 15th edn 2001. Jameson J et al, Chapter 330, Disorders of the thyroid gland, 2060-2084.

9.Larsen PR et al, Williams Textbook of Endocrinology, 9th edn 1998, Chapter11, The thyroid gland, 389-515.

10. Harrisons Principles of Internal Medicine, 15th edn 2001.Appendix.

11. Adapted from Clinical Medicine- Kumar 4th edn 1998.

12.Franklin JA.The management of hyperthyroidism. New Eng J Med 1994; 330: 1731-1738.

13. Bartalena L, Marcocci C, Bogazzi F,et al. Relation between the therapy for hyperthyroidism and the course of Graves’opthalmopathy. New Eng J Med.1998; 338: 73-78.

14. MICROMEDEX HEALTHCARE SERIES, Vol 120.

15. Gilman AG, Rall TW, NiesAS et al (Eds); Goodman and Gillman’s The Pharmacological Basis of Therapeutics, 8th edn. Pergamon Press, New York, NY,1990.

16. Modebe O, Experience with carbimazole in the drug treatment of the hyperythyroidism of Graves’ disease in Nigerians. East Afr Med J. 1992 Mar; 69(3):153-156.

17. Sherif IH, Oyan WT, Bosairi S, Carrascal SM. Treatment of hyperthyroidism in pregnancy. Acta Obstet Gynecol Scand.1991; 70(6): 461-463

18. Shahid R. Pregnancy with hyperthyroidism. J Coll PhysiciansSurg Park. 2003 May; 13(5) 255-9.

19. Lim BH, Raman S, Sivanesaratnam V, Ngan A., Thyrotoxicosis in pregnancy-a six year review. Singapore Med J. 1989 Dec; 30(6): 539-541.

20. Sugrue D, Drury MI. Hyperthyroidism complicating pregnancy: results of treatment by antithyroid drugs in 77 pregnancies. Br J Obstet Gynaecol. 1980 Nov; 87(11): 970-975.

21. VanderLaan WP & Storrie VM: A survey of the factors controlling thyroid function, with special reference to newer views on antithyroid substances. Pharmacol Rev 1955;7: 301-334.

22. Eigtved A, Bregengard C, Poulsen S., Severe adverse effects of low –dose carbimazole treatment in hyperthyroidism. A retrospective study of 476 patients, Ugeskr Laeger. 1989 Jan 2; 151(1) : 23-25.

About Authors:

Sachdev Yadav

M.Pharm. (Pharmacology), Senior Lecturer, Department of Pharmacology,  Rajiv Academy for Pharmacy, Mathura, Delhi-Mathura Highway, Chhattikara. 281006, India
Corresponding Author – sachdev_y@yahoo.com, Phone Number - (+919410446348), Fax Number – 0565 -2530766