Hypothyroidism --a clinical perspective

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  • Let’s start off with a clinical presentation. Ayesha is a 70-year-old woman, who was apparently healthy when she went for her routine visit to doctor. However, she complained of mild fatigue, dry skin, and difficulty in losing weight since last 2 years. The past medical and surgical history had been uneventful. There was also no reported family history of diabetes, hypertension, or ischemic heart disease. Physical examination results were normal including a non- palpable thyroid gland. ECG was normal. Fasting and postprandial blood sugar and complete blood count were within normal limits. Laboratory investigations for serum levels of TSH, free T4, total cholesterol, HDL and LDL cholesterol, triglycerides, and thyroperoxidase antibodies were carried out and the results are shown in the table. Serum TSH and free T4 tests were repeated 2 weeks after the first visit and were found to be 8.1 mIU/L and 1.4 ng/dL, respectively. Considering the mildness of symptoms, insignificant findings on physical examination, persistently high TSH levels and normal T4 level, and presence of thyroperoxidase antibodies, her doctor diagnosed her with subclinical hypothyroidism; the most likely etiology being Hashimoto’s thyroiditis.
  • Hypothyroidism is a condition where there is a reduced production of thyroid hormone. 1 (/p1/para1) Hypothyroidism is categorized as primary and secondary on the basis of its cause. Primary hypothyroidism occurs due to the improper functioning of the thyroid gland. It may be further classified as overt and subclinical hypothyroidism on the basis of the level of severity. 2 (/p793/col2/para2) ,3 (/p1700/col2/para3) Subclinical hypothyroidism is characterized by no or minimal symptoms and moderately elevated TSH but normal free T4 levels. 3 (/p1700/col2/para3) ,4 (/p464/col2/para4) Clinical or overt hypothyroidism is characterized by apparent symptoms with elevated TSH (>10 mIU/L) and lower free T4 levels. 3 (/p1700/col2/para3) ,2 (/p797/col1/para2) Primary hypothyroidism affects approximately 5% of individuals, with elderly women being the most commonly affected. 3 (/p1701/col1/para1) Secondary hypothyroidism occurs due to inadequate stimulation of thyroid gland by thyroid stimulating hormone (TSH). This could be because of either decreased TSH levels or ineffective TSH caused by congenital or acquired pituitary or hypothalamic disorders. This form of hypothyroidism is rare and occurs in less than 1% of individuals. 3 (/p1700/col2/para3) We will discuss the etiology of both the above mentioned conditions in the subsequent frames. References Hypothyroidism, Medline Plus. http://www.nlm.nih.gov/medlineplus/ency/article/000353.htm ; 2011:1-7. Accessed 01 March,2011. Roberts CGP, Ladenson PW. Hypothyroidism. Lancet . 2004;363: 793-803. Ladenson P, Kim M. Thyroid. In: Cecil RL, Goldman L, Ausiello DA, eds. Cecil medicine . 23 rd ed. Philadelphia: Saunders Elsevier; 2008:1698-1713. AACE medical guidelines for clinical practice for the evaluation and treatment of hyperthyroidism and hypothyroidism. American College of Endocrinology.8, 6. 1-13.Available at: http://www.aace.com/pub/pdf/guidelines/hypo_hyper.pdf . Accessed March 1, 2011.
  • Let’s look at the etiological factors of primary hypothyroidism. Primary hypothyroidism may be caused due to either thyroid dysfunction or impaired synthesis of thyroid hormone. Absence of or defects in the thyroid gland and abnormal thyroid hormone synthesis during birth may lead to congenital hypothyroidism.(/p1701/col1/para4) Thyroid dysfunction: Iodine deficiency is the most common cause for hypothyroidism. In the United States and most of the developed countries, thyroid dysfunction is most commonly caused by a condition characterized by autoimmune-mediated destruction of thyroid gland called Hashimoto’s thyroiditis. In this condition, there is alteration in the T cell–mediated immunity that leads to inflammation of the thyroid gland. This can be diagnosed by detecting antithyroid antibodies targeted against thyroid peroxidase and thyroglobulin, which act as important markers, present in the circulation.(/p1701/col1/para2) Surgical removal of thyroid gland to treat thyroid disorders and cancers of the head and neck may also lead to hypothyroidism.(/p1701/col1/para3) In addition, radioactive iodine irradiation for the treatment of hyperthyroidism, and other radiation therapy to treat head and neck cancer, are also known to cause hypothyroidism. Infiltrative disorders such as hemochromatosis, amyloidosis, systemic sclerosis, and invasive fibrous thyroiditis are also known to destroy the thyroid tissue and cause hypothyroidism.(/p1701/col1/para4) Impaired synthesis of thyroid hormone: This can be due to iodine deficiency in the diet which is still considered the primary cause of hypothyroidism in some underdeveloped countries.(/p1701/col1/para2) Treatment with drugs containing large amounts of iodine such as amiodarone, lithium, and aminoglutethimide can also lead to primary hypothyroidism.(/p1701/col1/para3) Reference Ladenson P, Kim M. Thyroid. In: Cecil RL, Goldman L, Ausiello DA, eds. Cecil medicine . 23rd ed. Philadelphia: Saunders Elsevier; 2008:1698-1713.
  • Secondary hypothyroidism may be caused due to the disorders of the hypothalamus or pituitary gland. Hypothalamic disorders may interfere with the secretion of thyrotropin-releasing hormone (TRH), which is responsible for the release of TSH from the pituitary gland. These disorders include tumors such as lymphoma, germinoma, or glioma (/p1700/table244-3), and infiltrative conditions such as sarcoidosis, hemochromatosis, or histocytosis. In case of pituitary gland disorders, such as pituitary adenomas and other tumors of the sella turcica, the secretion and synthesis of TSH may inhibited because of compression of the thyrotrophic cells by the overgrown tissue. Surgical removal of pituitary adenomas and radiation therapy are also known to destroy the thyrotropic tissues. Sheehan’s syndrome (infarction caused by hemorrhage during labor in women) and lymphocytic hypophysis are some of the other known disorders associated with secondary hypothyroidism.(/p1701/col1/para5)(/p1700/table244-3) Let’s now review the clinical manifestations of hypothyroidism. Reference Ladenson P, Kim M. Thyroid. In: Cecil RL, Goldman L, Ausiello DA, eds. Cecil medicine . 23rd ed. Philadelphia: Saunders Elsevier; 2008:1698-1713.
  • In order to understand the disease better, let’s now review the clinical manifestations of hypothyroidism. Hypothyroidism progresses with few or no symptoms, making it difficult to recognize the disease in the initial stages. 1 (/p1701/col2/para1) The symptoms include tiredness, dry skin, intolerance to cold, hair loss, difficulty in concentration, constipation, weight gain in spite of having poor appetite, breathlessness, hoarseness of voice, paresthesia, and hearing impairment. 1 (/p1701/col2/para1) ,2 (/p2230/col1/335-5) In women, precocious puberty, menorrhagia, amenorrhea, and galactorrhea are the common symptoms associated with hypothyroidism. 1 (/p1701/col2/para1) Depression, lack of initiative, and sociability are also noted in these patients. The range of cognitive defects are wide and may vary from mild memory loss to even seizures and coma. 1 (/p1701/col2/para1) References Ladenson P, Kim M. Thyroid. In: Cecil RL, Goldman L, Ausiello DA, eds. Cecil medicine . 23rd ed. Philadelphia: Saunders Elsevier; 2008:1698-1713. Jameson JL, Weetman AP. Disorders of the thyroid gland. In: Braunwald E, Fauci AS, Kasper DL, Hauser SL, Longo DL, Jameson JL eds. Harrison´s Principles of Internal Medicine . 17th ed. 2008: 2224-2247.
  • The physical findings that hint toward hypothyroidism include cold extremities due to peripheral vasoconstriction; dry, coarse, and yellow skin; puffiness of face and extremities; brittle nails, hair loss, diffuse thinning of scalp hair, and mild hypothermia. 1 (/p1701/col2/para2) ,2 (/p2231/col1/para4) Cardiovascular signs include bradycardia, diastolic hypertension, and distant heart sounds. 1 (/p1701/col2/para2) Neurological examination may reveal slowing of tendon reflexes associated with a delay in the terminal relaxation phase. 1 (/p1701/col2/para2) Peripheral edema and the effusions of the serous cavities are also common signs seen in hypothyroid patients. 1 (/p1701/col2/para2), 2 (/p2231/col1/para6) The thyroid gland may be normal in size or it can be enlarged. In some cases, the gland may be atrophied to an extent that it would be difficult to detect it on palpation. On examination, the texture of the gland may vary from being soft and smooth to firm and irregular. 1 (/p1701/col2/para3) In children with hypothyroidism, delayed growth in spite of weight gain may be seen associated with delayed onset of puberty and pseudo hypertrophy of the muscles. 1 (/p1701/col2/para2) References Ladenson P, Kim M. Thyroid. In: Cecil RL, Goldman L, Ausiello DA, eds. Cecil medicine . 23rd ed. Philadelphia: Saunders Elsevier; 2008:1698-1713. Jameson JL, Weetman AP. Disorders of the thyroid gland. In: Braunwald E, Fauci AS, Kasper DL, Hauser SL, Longo DL, Jameson JL eds. Harrison´s Principles of Internal Medicine . 17th ed. 2008: 2224-2247.
  • The most important test recommended to arrive at a diagnosis of primary hypothyroidism is the measurement of TSH levels.(/p464/col1/para1) Other recommended tests include estimation of free T 3 and T 4 hormone levels and test for thyroid antibodies such as antithyroid peroxidase and antithyroglobulin autoantibodies.(/p464/col1/para2) Thyroid scan, ultrasonography, or sometimes both may be required in case of doubtful structural thyroid defects.(/p464/col1/para2) The principal defining criteria for patients with overt and subclinical hypothyroidism are the laboratory test values of free T 3 and T 4 estimates and TSH levels. In patients with overt hypothyroidism, free T 3 andT 4 levels are reduced accompanied by an increase in TSH levels. In patients with subclinical hypothyroidism, levels of free T 3 and T 4 hormone are normal, whereas TSH levels are moderately higher.(/p464/col1/para4) Reference AACE medical guidelines for clinical practice for the evaluation and treatment of hyperthyroidism and hypothyroidism. American College of Endocrinology.8, 6. 1-13.Available at: http://www.aace.com/pub/pdf/guidelines/hypo_hyper.pdf . Accessed March 1, 2011.
  • After having discussed about the diagnosis of hypothyroidism, let us now have an overview of the management of the disease. The treatment goal for the management of hypothyroidism is to mimic normal, physiological levels of thyroid hormone and alleviate signs, symptoms, and biochemical abnormalities. The treatment must be adapted to the needs of the individual patient.(/p464/col1/para5) The treatment of choice for most patients with hypothyroidism is thyroid hormone replacement therapy using levothyroxine (LT4).(/p464/col1/para5) There is no definite treatment of choice for subclinical hypothyroidism. However, treatment with LT4 is advised for patients whose TSH levels are above 10 mIU/mL. Based on the AACE, 2006 guidelines, LT4 treatment is also recommended in patients with TSH between 5 and 10 mIU/mL when they have associated goiter or in the presence of antithyroid antibodies.(/p465/col1/para3) Desiccated thyroid hormone or a combination of T 3 and T 4 hormones is not recommended by the AACE guidelines because of the insufficient evidence available for their use in the management of hypothyroidism.(/p464/col1/para6;/col2/para3) Reference AACE medical guidelines for clinical practice for the evaluation and treatment of hyperthyroidism and hypothyroidism. American College of Endocrinology.8, 6. 1-13.Available at: http://www.aace.com/pub/pdf/guidelines/hypo_hyper.pdf . Accessed March 1, 2011.
  • Going back to the Ayesha’s case, recall that she was diagnosed with subclinical hypothyroidism. In the next few slides, we will be discussing subclinical hyperthyroidism , its treatment options, and also see how Ayesha was treated and how she responded to her treatment. The main diagnostic criteria that define subclinical hyperthyroidism are slightly elevated levels of serum TSH and levels of FT 4 and T 3 within the reference range.(/p464/col2/para4) It affects 1% to 10% of adults and with higher prevalence seen in women. The chief cause of subclinical hyperthyroidism is autoimmune thyroiditis, also called as Hashimoto’s disease.(/p464/col1/para1) The main predisposing factors include advancing age and people with higher iodine consumption.(/p464/col2/para4) Though subclinical hyperthyroidism represents early thyroid failure, it is commonly asymptomatic.(/p464/col2/para4) Reference AACE medical guidelines for clinical practice for the evaluation and treatment of hyperthyroidism and hypothyroidism. American College of Endocrinology.8, 6. 1-13.Available at: http://www.aace.com/pub/pdf/guidelines/hypo_hyper.pdf . Accessed March 1, 2011.
  • The flowchart in this slide depicts the treatment algorithm for subclinical hyperthyroidism as suggested by American Medical Association. When the laboratory results show higher TSH levels with normal T4 levels, the test is repeated twice after an interval of 6 weeks. If the laboratory values show that the levels of TSH is greater than 10 mIU per mL, then testing for antithyroid antibodies is recommended. When the result for antithyroid antibodies is positive, therapy with LT4 is initiated. When the laboratory results show absence of antithyroid antibodies, therapy is initiated even if the patient is asymptomatic. If the TSH values are between 4.5 to 10 and is accompanied by low FT4 Rule out hypopituitarism before starting levothyroxine because starting levothyropxine treatment can precipitate adrenal crisis in case patient has adrenal insufficency also. If the TSH values are between 5 and 10 mIU/mL, testing for antithyroid antibodies is recommended. If the result for antithyroid antibodies is positive, treatment is initiated. If the result for antithyroid antibodies is negative, the patient is put on observation and retested every 6 months. 1 (/p240/figure1) Treatment is also initiated in women who are attempting for pregnancy, in order to avoid obstetric and fetal complications due to reduced TSH. 2 (/p234/col1/para1) References Col NF, Surks MI, Daniels GH. Subclinical thyroid disease: clinical applications. JAMA . 2004; 291:239-243. Surks MI, Ortiz E, Daniels DH, Sawin CT, Col NF, Cobin RH, et al. Subclinical thyroid disease. Scientific review and guidelines for diagnosis and management. Scientific review and clinical applications. JAMA . 2004;291:228-238.
  • The recommended initial dosage of LT4 is 25 to 50 mcg/day. 1 (/p465/col1/para3) The initial dose of LT4 should be reduced in elderly patients and in patients with coronary artery disease. 2 (/p21/col2/para4) The serum TSH levels should be monitored every 6 to 8 weeks after initiation of LT4 therapy and the dosage should be adjusted accordingly. 1 (/p465/col1/para3) The target TSH level in subclinical hyperthyroidism should be between 0.3 and 3.0 µ IU/mL. 1 (/p465/col1/para3) After achieving stable TSH levels through therapy, annual follow-up is recommended. 1 (/p465/col1/para3) Progression to overt hypothyroidism is seen in 3% to 20% of patients.(/p465/col1/para1) In patients with goiter and antithyroid antibodies (or both), the risk of progression is comparatively higher. 1 (/p465/col1/para1) The associated risks of subclinical hyperthyroidism include, progression to overt hypothyroidism, cardiovascular effects, hyperlipidemia, and neuropsychiatric effects. 1 (/p465/col1/para2) References AACE medical guidelines for clinical practice for the evaluation and treatment of hyperthyroidism and hypothyroidism. American College of Endocrinology.8, 6. 1-13.Available at: http://www.aace.com/pub/pdf/guidelines/hypo_hyper.pdf . Accessed March 1, 2011. Shah SN, Joshi SR. Indian Thyroid Guidelines 2011. JAPI. 2011;59(Suppl):1-68.
  • Let’s now come back to the case we started with. To recapitulate, Ayesha was diagnosed with subclinical hypothyroidism due to Hashimoto’s thyroiditis; thereafter, she was put on LT4 therapy based on the following findings: Increased TSH Positive antithyroid antibodies Dyslipidemia Dosage administered was 30 mcg/day. She was asked to visit again for follow-up after 8 weeks.
  • Now let ‘s discuss in detail about LT4, its indications, dosing, and drug interactions. Levothyroxine, or LT4, is a synthetic form of T4 and is similar to the naturally produced hormone in the thyroid gland of humans.(/p1/para1) It is mainly indicated for hypothyroidism and pituitary TSH suppression. All categories of hypothyroidism, including congenital, acquired, primary, secondary, and subclinical can be treated with LT4.(/p3/para1) LT4 can be used to treat and prevent various euthyroid goiters such as thyroid nodules, subacute or chronic lymphocytic thyroiditis (Hashimoto’s thyroiditis) and those caused by pituitary TSH suppression. It is also indicated in the treatment of thyroid cancer as an adjunct to surgery and iodine irradiation therapy.(/p3/para2) Reference Synthroid Prescribing Information. Abbott Laboratories, North Chicago, USA. Revised March 2008.
  • It is important to know some important, unique facts of LT4, which would help us in our practice. LT4 is a molecule with a narrow therapeutic index with very less difference between the therapeutic and toxic doses.(/p464/col2/para2). A very less change in dose administered may change an euthyroid patient into hypo or hyperthyroid state. Hence, careful dose titration of LT4 is required in case of absorption variability or drug interactions. This would prevent the consequences of over- or under-treatment.(/p464/col2/para2) AACE recommends the use of high-quality brand of LT4, since the bioequivalence of LT4 is not the same as therapeutic equivalence. The bioequivalence is also based on total T4 levels and not on the TSH levels. Also the commercially available LT4 products are compared against another brand (innovator brand) and not against LT4 standard. This leads to the possibility of minor changes in dose administered to the patient, if the brands of LT4 are changed during the course of the treatment. In order to avoid this, AACE recommends that the patients should receive the same brand of LT4 throughout the treatment duration.(/p464/col1/para6) REFERENCE: AACE medical guidelines for clinical practice for the evaluation and treatment of hyperthyroidism and hypothyroidism. American College of Endocrinology.8, 6. 1-13.Available at: http://www.aace.com/pub/pdf/guidelines/hypo_hyper.pdf . Accessed March 1, 2011.
  • Let’s see in detail the dosing and monitoring requirements during the treatment with LT4. The mean daily dose of LT4 recommended for hormone replacement therapy is 1.6 mcg/kg of body weight. However, the dosage may vary among patients, tailored to their individual needs.(/p464/col1/para6) The patient can start with an initial daily dose ranging from 12.5 mcg to a full replacement therapy. Further, based on patient factors, such as age, weight, and cardiac status, and disease factors, such as severity and duration of hypothyroidism, the dose of full replacement therapy may vary.(/p464/col1/para6;/col2/para1) Patients are advised to reassess their hormone levels after at least 6 weeks following therapy initiation, a dose change, or a change in the brand of LT4.(/p464/col2/para1) Once normal levels of TSH is achieved, follow-up after 6 months and thereafter annually is recommended.(/p464/col2/para1) Absorption of LT4 is affected in malabsorptive states and dose adjustments are required in case of absorption variability and drug interactions.(/p464/col2/para2) If the dose titration is not appropriate, then the cost of treatment may increase due to additional follow-up visits and laboratory tests.(/p464/col2/para2) Reference AACE medical guidelines for clinical practice for the evaluation and treatment of hyperthyroidism and hypothyroidism. American College of Endocrinology.8, 6. 1-13.Available at: http://www.aace.com/pub/pdf/guidelines/hypo_hyper.pdf . Accessed March 1, 2011.
  • Thyroid hormone is highly protein bound and hence the drugs that compete for binding affect the amount of free T4 hormone in the blood. The dose of LT4 when coadministered with such drugs must be altered in order to exert optimum effect. 1 (/p1722/col2/para2) Also, there are a few drugs that alter the production, absorption, and metabolism of thyroxine. Hence, the dose of LT4 should be increased when administered with such drugs. Drugs that reduce thyroxine production include lithium, iodine-containing drugs, and amiodarone. Drugs that reduce thyroxine absorption include sucralfate, ferrous sulfate, cholestyramine, colestipol, aluminum-containing antacids, and calcium supplements. Drugs that increase thyroxine metabolism include rifampin, phenobarbital, carbamazepine, warfarin, and oral hypoglycemic agents. Dose of LT4 should be decreased when administered with drugs that displace thyroxine from binding proteins, such as furosemide, mefenamic acid, and salicylates. 1 (/p1723/col1/table4) ,2 (/p464/col2/para2) References Hueston WJ, Treatment of hypothyroidism. Am Fam Physician. 2001;64:1717-24. AACE medical guidelines for clinical practice for the evaluation and treatment of hyperthyroidism and hypothyroidism. American College of Endocrinology.8, 6. 1-13.Available at: http://www.aace.com/pub/pdf/guidelines/hypo_hyper.pdf . Accessed March 1, 2011.
  • Coming back to Ayesha’s case, let’s see how she had responded to treatment. To recapitulate, Ayesha was diagnosed with subclinical hypothyroidism due to Hashimoto’s thyroiditis; thereafter, she was put on LT4 therapy. Dosage administered was 30 mcg/day. She was asked to revisit for follow-up after 8 weeks of commencing the treatment. Serum TSH measurement was repeated. Her TSH levels had fallen to 1.2 mIU/mL, but remained within the normal range of 1 to 1.5 mIU/mL on consecutive visits. She was asked to stay on the treatment and follow up after 1 year. After 1 year of treatment, she had lost weight and was asymptomatic. On investigation, her serum cholesterol and low-density lipoprotein (LDL) cholesterol levels were 190 and 100 mg/dL, respectively.
  • Now we shall see another clinical case. This case is about a pregnant woman and the baby that she delivers subsequently. Shobha, a 32-week pregnant, 30-year-old woman presents premature labor. She complains of inappropriate weight gain for gestational age and cold intolerance during past few months. In past, she was diagnosed with hypothyroidism at the age of 20. She was put on LT4 therapy. The last dose modification was 2 years back after which she continued to take the same dose.
  • On physical examination, Shobha weighed 100 kg. Her pulse rate were 68 per minute. Systemic blood pressure was 140/90 mm Hg in right arm in supine position. Her face was puffy. Skin was cold and dry. Slow relaxation was seen when deep tendon reflexes such as bicep reflex, supinator reflex, knee jerk, and ankle jerk were elicited. Considering her symptoms and past history, thyroid function tests were performed. Serum TSH and free T4 levels were 11 mIU/L and 1.2 pmol/L, respectively. Can hyperlink this slide to slide #27 which gives reference values for all three trimesters. Further, on fetal monitoring, fetal distress was diagnosed. Considering gestational age, fetal maturity, and the amount of dilation and effacement of the cervix, fetal distress labor was allowed to continue. She delivered a preterm and low birth weight male child. To get an insight on Shobha’s condition, let’s see some details about maternal hypothyroidism.
  • Maternal hypothyroidism is one of the common hormonal disorders encountered during pregnancy. 1 (/p215/col2/para2) The prevalence of overt hypothyroidism in pregnancy is 1.3 per 1000 females and that of subclinical hypothyroidism is 23 per 1000. 1 (/p215/col2/para2) The most common cause of maternal hypothyroidism is endemic iodine deficiency. 2 (/p8/para2) Hypothyroidism in women may result in increased incidence of infertility, miscarriage rates, and risk for obstetric and fetal complications. 1 (/p215/col2/para2) The obstetric complications include anemia, preeclampsia, cardiac dysfunction, placental abruption, and postpartum hemorrhage. 1 (/p215/col2/para2) The fetal complications include premature birth, low-birth weight, fetal distress in labor, fetal death, perinatal death, and congenital hypothyroidism. 1 (/p215/col2/para2) Studies have shown that even mild, untreated maternal hypothyroidism may impair the cognitive function of the offspring. This can be prevented by administering thyroid hormone replacement therapy during pregnancy. 3 (/p464/col1/para4) References Sahu MT, et al. Overt and subclinical thyroid dysfunction among Indian pregnant women and its effect on maternal and fetal outcome. Arch Gynaecol Obstet . 2010;218:215-220. Lazaras JH. Thyroid function in pregnancy. Br Med Bull . 2010;1-12. AACE medical guidelines for clinical practice for the evaluation and treatment of hyperthyroidism and hypothyroidism. American College of Endocrinology.8, 6. 1-13.Available at: http://www.aace.com/pub/pdf/guidelines/hypo_hyper.pdf . Accessed March 1, 2011.
  • The flowchart on this slide is a schematic representation of thyroid regulation during pregnancy. The mechanism of regulation of thyroid hormone synthesis slightly differs during gestation under the influence of various gestation-related physiological changes in women. Many of the processes here are interlinked. Influence of placenta on thyroid physiology starts during the first trimester of pregnancy with elevated human chorionic gonadotropin (hCG) production. As already discussed in detail, since hCG can act as a functional agonist of TSH on TSH receptor, it stimulated TSH receptor mediated thyroid hormone production in the thyroid gland leading to increased thyroid hormone in circulation. Apart from these, placental production of type 3 deiodinase leads to elevated peripheral degradation of thyroid hormones, which again stimulated the thyroid for the production of thyroid hormones. In addition to these factors, increased placental transport of T4 also reduces maternal T4 in circulation, stimulating maternal thyroid gland to produce more and more thyroid hormones. Gestational period is also characterized by increase in estrogen production. Estrogen stimulates increased hepatic production of thyroxin-binding globulin (TBG) as well as increase in the half life of serum TBG. This results in increased serum concentration of TBG, which leads to decreased free thyroid hormone in circulation. This stimulates hypothalamic pituitary axis to produce TSH, which in turn stimulates thyroid for further production of thyroid hormone. This overall increase in thyroid hormone reduces serum TSH. Increased stimulation of thyroid gland can result in thyroid hypertrophy/goiter mainly in iodine-deficient area or in case of iodine deficiency in the pregnant woman. 1 (p1847/col1/para2,3;/col2/para1) 2 (/p173/para3)(/p174/para1,2). This calls for a need to establish gestational reference range for thyroid hormones. References Galofre JC, Davies TF. Autoimmune thyroid disease in pregnancy: a review. J Womens Health (Larchmt). 2009;18(11):1847-1856. Fitzpatrick DL, Russel MA. Diagnosis and management of thyroid disease in pregnancy. Obstet Gynecol Clin N Am. 37 (2010) 173-193.
  • Normally T 3 and T 4 occur in two forms: bound with TBG and unbound or free (active) form. 1 (/p2226/col2/para3) Thyroid hormone levels vary in pregnancy based on the trimester. The upper graph (A) depicts the levels of HCG and TSH against weeks of gestation. Lower graph (B), (C) depicts TBG, total T 4 , free T 3 , and free T 4 levels with respect to the gestational week. There is a rise in total T 3 and total T 4 levels during the first trimester of pregnancy, which reaches a plateau by mid-gestation until delivery. Similarly, FT 3 and FT 4 levels also increase during the first trimester, which decrease to reach a plateau in second and third trimesters of pregnancy. In a normal pregnancy, there is increase in estrogen and progesterone levels as weeks of pregnancy progress. Level of TSH shows an inverse relationship with hCG concentration and, hence, during the first trimester of pregnancy, levels of TSH decrease with increase in hCG concentrations. An increase in circulating TBG is also reported during the first trimester of pregnancy, which reaches a plateau during midgestation. Half life of TBG is reported to increase as a result of altered glycosylation by estrogen during gestation. 2 (/p2/para2)(/p3/fig1)(/p4/fig1) ,3 (/p1847/col1/para2)(/p1848/fig 2) This calls for a need to establish gestational reference range for thyroid hormones, which is discussed in the next slide. References Jameson JL, Weetman AP. Disorders of the thyroid gland. In: Kasper DL, Fauci AS, Longo DL, Braunwald E, Hauser SL, Jameson JL, eds. Harrison's Principles of Internal Medicine . 17th ed. New York: McGraw-Hill Medical; 2008:2224-2247. Lazarus JH. Thyroid function in pregnancy. Br Med Bull. 2010;1-12. Galofre JC, Davies TF. Autoimmune thyroid disease in pregnancy: a review. J Womens Health (Larchmt). 2009;18(11):1847-1856.
  • The table here details the referral values for thyroid function tests in pregnant Indian women as reported by Marwaha (2008). 1 (/p604/table2) 2 (/p1-6) Reference 1. Marwaha RK, Chopra S, Gopalakrishnan S, et al. Establishment of reference range for thyroid hormones in normal pregnant Indian women. BJOG. 2008;115(5):602-606. 2. SI Units for Clinical Data. University of North Carolina. Available at: http://www.unc.edu/~rowlett/units/scales/clinical_data.html. Accessed March 22, 2011.
  • Since thyroid disorders are common during pregnancy, the AACE recommends that thyroid hormone tests should be routinely performed before pregnancy or during the screening performed in the first semester. The obstetric and fetal complications due to hypothyroidism can be avoided by thyroid hormone replacement therapy. LT4 is found to be safe during pregnancy and it can be administered for both overt and subclinical hypothyroidism. (/p465/col1/para4) The serum TSH levels should be monitored every 6 weeks during pregnancy and based on the results, appropriate dose adjustments for LT4 should be made to meet the requirements.(/p465/col2/para1) In pregnant patients with moderate to severe hypothyroidism, the dosage of LT4 should be increased appropriately.(/p465/col2/para1) Reference AACE medical guidelines for clinical practice for the evaluation and treatment of hyperthyroidism and hypothyroidism. American College of Endocrinology.8, 6. 1-13.Available at: http://www.aace.com/pub/pdf/guidelines/hypo_hyper.pdf . Accessed March 1, 2011.
  • Let’s now review some of the important aspects of thyroxine treatment during pregnancy During preconception phase, the dose of LT4 should be optimized in patients with preexisting hypothyroidism in order to avoid infertility issues. Once the pregnancy is confirmed, the dose of LT4 should be increased by 30% to 50% of the preconception dose. The TSH levels are checked early in first trimester and should be aimed at less than 2.5 mIU/L. During the later stages of pregnancy, the TSH levels should be less than 3 mIU/L. After delivery, the dose of LT4 should be reduced to preconception dose. After 6 weeks of delivery, the thyroid function should be reassessed. Post-ablative and post-surgical hypothyroidism require higher doses of LT4.(/p9/table3) Reference Lazaras JH. Thyroid function in pregnancy. Br Med Bull . 2010;1-12.
  • Now that we have discussed maternal hypothyroidism and its complications, let’s return to Shoba’s case. The baby delivered by Shobha was apparently normal. Findings on neonatal examination are within normal limits, except for low birth weight. Neonatal screening for congenital hypothyroidism was carried out on the third day using cord blood . TSH and serum free T4 were 38 mIU/L and 0.5 ng/dL, respectively. Considering the laboratory test results, he was diagnosed with congenital hypothyroidism. In the next few slides we will have an overview of congenital hypothyroidism and it’s diagnosis and management.
  • Congenital hypothyroidism occurs due to the agenesis or dysgenesis of thyroid gland and defect in the biosynthesis of the thyroid hormones. The prevalence rate of congenital hypothyroidism is 1 in 4000 of new born infants in regions of sufficient daily intake of iodine. Incidence in female infants is twice more that of males. The major cause for congenital hypothyroidism is endemic iodine deficiency. Other causes in neonates include genetic mutation and hemangiomas.(/p794/col2/para2) Most of the affected infants do not show obvious clinical manifestations, hence the practice of routine screening for thyroid function is recommended for all the newborn infants.(/p797/col1/para4) Congenital hypothyroidism when left untreated results in a syndrome known as Cretinism. Do not delay diagnosis of congenital hypothyroidism until physical manifestations are seen which is characterized by mental retardation, deafness, short stature, and facial deformities.(/p794/col1/para1) Reference Roberts CGP, Ladenson PW. Hypothyroidism. Lancet . 2004;363:793-803.
  • In infants, congenital hypothyroidism is present with hypothermia, poor feeding, bradycardia, jaundice, enlarged posterior fontanel, and umbilical hernia. In children and adolescents with congenital hypothyroidism, the clinical manifestations include growth failure with delayed bone maturation, delay in the eruption of permanent teeth, pseudo hypertrophy of muscles, enlargement of pituitary gland, galactorrhoea, and delayed or precocious puberty.(/p797/col1/para4) Reference Roberts CGP, Ladenson PW. Hypothyroidism. Lancet . 2004;363:793-803.
  • The flowchart in this slide represents the diagnostic algorithm for evaluating congenital hypothyroidism. If the screening results of the newborn show increased values for TSH or if the values for initial T 4 is less than 10% of the normal range, then measurement of serum TSH and free T 4 is recommended. The above tests are also recommended when there is a clinical suspicion of hypothyroidism. If the TSH levels recorded are greater than 9 mIU/L or if the free T 4 values are lesser than 0.6 ng/dL, diagnosis of primary congenital hypothyroidism is confirmed. In order to determine the etiology of the disease, additional optional tests such as radionuclide uptake and scan, ultrasonography, tests for serum thyroglobulin, maternal antithyroid antibodies, and urinary iodine are recommended. If the TSH levels recorded are reduced or normal, and less than 9 mIU/L, and if the free T 4 values are less than 0.6 ng/dL, secondary hypothyroidism is suspected. Additional tests to confirm the diagnosis include gene analysis, evaluation for other pituitary hormone deficiencies, MRI of brain, and eye check-up for optic nerve hypoplasia.(/p10/figure4) Reference Rastogi, LaFranchi. Congenital hypothyroidism. Orphanet J Rare Diseases. 2010,5:17;1-22.
  • Lets now see how Shobha’s child was doing in the initial phase. Shobha’s child was referred to a paediatric endocrinologist. Thyroid ultrasonography showed a normal thyroid gland. Maternal antithyroid antibodies were absent. The baby was started on LT4 at an initial daily dose of 50 mcg. The serum T4 normalized in 3 days. TSH normalized by end of 2 weeks. Shobha was asked to follow-up along with her new born on a monthly basis.
  • The goal of therapy in the management of congenital hypothyroidism is to normalize TSH values, and maintain T4 and free T4 hormone levels in the upper half of the reference range. Permanence of congenital hypothyroidism can be assessed by the presence of ectopic or absence of thyroid gland in the thyroid scan. If the initial TSH values are less than 50 mIU/L, with no rise in TSH values after newborn period, off therapy is tried at 3 years. If TSH increases during the off-therapy period, the condition may be considered as permanent congenital hypothyroidism. During the phase of initial work-up, detailed history and physical examination of the child is recorded. This is followed by referring the patient to pediatric endocrinologist. The serum TSH and FT4 values are reassessed, followed by thyroid ultrasonography and/or thyroid scan to confirm the diagnosis of congenital hypothyroidism. Congenital hypothyroidism can be managed by administering oral, once daily, LT4 at a dose of 10 to 15 mcg/day. T4 and TSH levels are monitored 2 to 4 weeks after initiation of the treatment. During the first 6 months, monitoring hormone levels every 1 to 2 months, and between 6 months and 3 years of age, monitoring hormone levels every 3 to 4 months is recommended. From 3 years of age to end of growth period, monitoring every 6 to 12 months is recommended.(/p2297/col1/table1) Reference Rose SR, Brown RS. Update of newborn screening and therapy for congenital hypothyroidism. Pediatric s. 2006;117(6):2290-2303.
  • Now, let’s discuss the major comorbid conditions associated with hypothyroidism. The major comorbid conditions include autoimmune disorders, infertility, depression, and hyperlipidemia. 1 (/p465/col2/para3,4)2(/p27/col1/para1) The autoimmune diseases that occur concurrently with hypothyroidism are diabetes mellitus, vitiligo, rheumatoid arthritis, Addison’s disease, and pernicious anemia. Autoimmune diseases are associated with autoimmune thyroiditis. 1 (/p463/col2/para4)   References AACE medical guidelines for clinical practice for the evaluation and treatment of hyperthyroidism and hypothyroidism. American College of Endocrinology.8, 6. 1-13.Available at: http://www.aace.com/pub/pdf/guidelines/hypo_hyper.pdf . Accessed March 1, 2011. Duntas LH, Biondi B. New insights into subclinical hypothyroidism and cardiovascular risk. Semin Thromb Hemost . 2011;37(1):27-34.
  • Let’s now have a look at the effect of the above-mentioned comorbid conditions on hypothyroidism. Diabetes mellitus Hashimoto’s thyroiditis may be associated with 10% patients of type 1 diabetes mellitus. Approximately one-fourth of female patients with type 1 diabetes mellitus develop postpartum thyroiditis. The AACE recommends that patients with diabetes mellitus should be examined for goiter development and should assess TSH levels regularly in the presence of a goiter or other autoimmune disorders.(/p465/col2/para2) Infertility In some patients, it is found that infertility and menstrual irregularities have underlying thyroid disorder. Chronic thyroiditis can be confirmed by physical examination and laboratory evaluation. Treatment with LT4 replacement therapy restores normal menstrual cycle and fertility.(/p465/col2/para3) Reference AACE medical guidelines for clinical practice for the evaluation and treatment of hyperthyroidism and hypothyroidism. American College of Endocrinology.8, 6. 1-13.Available at: http://www.aace.com/pub/pdf/guidelines/hypo_hyper.pdf . Accessed March 1, 2011.
  • Depression According to the AACE recommendations, in every patient with depression, diagnosis of overt or subclinical hypothyroidism should be considered. Periodic evaluation for thyroid function should be performed in patients receiving lithium therapy, because lithium is known to induce goiter and hypothyroidism. LT4 replacement therapy is used in the management of depression associated with hypothyroidism. It is indicated occasionally in combination with antidepressants in euthyroid patients with depression.(/p465/col2/para5) Reference AACE medical guidelines for clinical practice for the evaluation and treatment of hyperthyroidism and hypothyroidism. American College of Endocrinology.8, 6. 1-13.Available at: http://www.aace.com/pub/pdf/guidelines/hypo_hyper.pdf . Accessed March 1, 2011.
  • When overt hypothyroidism coexists with dyslipidemia, the blood levels of total and LDL cholesterols are increased.(/p30/col2/para4) The mechanisms associated with dyslipidemia include impaired production of total cholesterol and decreased expression of LDL receptor. Severe cardiovascular disease and premature atherosclerosis, left untreated, can lead to the development of pericardial effusion, congestive heart failure, and coronary artery disease.(/p28/col2/para3) Reference Duntas LH, Biondi B. New insights into subclinical hypothyroidism and cardiovascular risk. Semin Thromb Hemost . 2011;37(1):27-34.
  • In middle-aged patients with subclinical hyperthyroidism , impaired diastolic function and reduced left ventricular systolic function at rest and during physical exertion are noted.(/p29/col1/para1) Studies reveal that subclinical hyperthyroidism is also associated with atherosclerosis and myocardial infarction.(/p29/col1/para4) Meta-analysis of high-quality studies reveal that total and cardiovascular-related mortality was noted only in patients who had subclinical hyperthyroidism and were less than 65 years of age.(/p29/col2/para4) Subclinical hyperthyroidism is associated with proatherogenic mechanisms leading to low-grade inflammation and this may also suggest cardiovascular disease.(/p30/col2/para4) Subclinical hyperthyroidism is known to be linked to a hypercoagulable state, but the degree of impact is yet to be studied.(/p32/col1/para1) LT4 therapy for subclinical hyperthyroidism reverses cardiovascular alterations, reduces risk factors, improves dyslipidaemia, and minimizes neurobehavioral changes.(/p31/col1/para1) Reference Duntas LH, Biondi B. New insights into subclinical hypothyroidism and cardiovascular risk. Semin Thromb Hemost . 2011;37(1):27-34.
  • Hypothyroidism --a clinical perspective

    1. 1. Clinician’s Perspective to Hypothyroidism Module 2 Copyright © 2011 Abbott India Limited. All rights reserved
    2. 2. <ul><li>&quot;The thyroid gland regulates the metabolic functions of the body in virtually every cell,“ . &quot;Everything from the brain to the skin is affected by the hormone made by the thyroid gland.“ </li></ul><ul><li>Hypothyroidism &quot;It slows you down,It makes you lethargic and fatigued Your hair becomes brittle, and your skin becomes dry. You become cold much easier than the average person. </li></ul>
    3. 3. Case Presentation 1 <ul><li>During her routine visit to doctor, Ayesha, an apparently healthy 70-year-old woman complained of mild fatigue, dry skin, and difficulty in losing weight since last 2 years. </li></ul><ul><li>The past medical and surgical history were uneventful. </li></ul><ul><li>There was no reported family history of DM/HTN/IHD. </li></ul><ul><li>Physical examination results were normal including a non- palpable thyroid gland. </li></ul><ul><li>ECG was normal. Fasting and postprandial blood sugar and CBC were within normal limits. </li></ul><ul><li>Serum TSH and FT4 tests were repeated 2 weeks after the first visit and were found to be 8.1 mIU/L and 1.4 ng/dL, respectively. </li></ul><ul><li>Diagnosis: Subclinical hypothyroidism (Hashimoto’s thyroiditis) </li></ul>Serum TSH 8.0 mlU/L(0.3-5.5) Serum free T4 1.3 ng/dL(0.7-2) Serum total cholesterol 220 mg/dL(150-200) Serum HDL cholesterol 46 mg/dL(30-60) Serum LDL cholesterol 150 mg/dl(80-150) Serum triglycerides 80 mg/dL(75-150) Thyroperoxidase antibodies Positive
    4. 4. Hypothyroidism: Overview, Manifestations and Treatment
    5. 5. Hypothyroidism <ul><li>Condition where there is a reduced production of thyroid hormone 1 </li></ul><ul><li>Categorized as primary and secondary on the basis of its cause </li></ul><ul><li>Primary hypothyroidism occurs due to improper functioning of the thyroid gland </li></ul><ul><ul><li>May be further classified as overt and subclinical hypothyroidism 2,3 </li></ul></ul><ul><ul><li>Affects approximately 5% of individuals with elderly women being most commonly affected 3 </li></ul></ul><ul><li>Secondary hypothyroidism occurs due to inadequate stimulation of thyroid gland by thyroid stimulating hormone (TSH) </li></ul><ul><li>May be due to congenital or acquired defects in the pituitary or hypothalamus </li></ul><ul><li>Rare and occurs in less than 1% of individuals 3 </li></ul>Thyroid gland <ul><li>Hypothyroidism, Medline Plus. Available at: http://www.nlm.nih.gov/medlineplus/ency/article/000353.htm ; 2011:1-7. </li></ul><ul><li>Roberts CGP. Lancet . 2004;363: 793-803. </li></ul><ul><li>Ladenson P. Cecil Medicine. 2008:1698-1713. </li></ul><ul><li>AACE medical guidelines for clinical practice for the evaluation and treatment of hyperthyroidism and hypothyroidism, 2006:1-13 http://www.aace.com/pub/pdf/guidelines/hypo_hyper.pdf . </li></ul>
    6. 6. Primary Hypothyroidism: Etiology <ul><li>Thyroid dysfunction </li></ul><ul><ul><li>Autoimmune thyroiditis (Hashimoto’s thyroiditis) </li></ul></ul><ul><ul><li>Congenital absence or defect in the thyroid tissue </li></ul></ul><ul><ul><li>Thyroid removal by surgery </li></ul></ul><ul><ul><li>Radio ablation by radio active iodine or irradiation </li></ul></ul><ul><ul><li>Destruction of thyroid tissue caused by infiltrative disorders(amyloidosis,sarcoidosis) </li></ul></ul><ul><li>Impaired synthesis of thyroid hormone </li></ul><ul><ul><li>Iodine deficiency----MOST COMMON CAUSE </li></ul></ul><ul><ul><li>Congenital enzymatic defects </li></ul></ul><ul><ul><li>Drug-mediated: thionamides, amiodarone, lithium, aminoglutethimide,carbemazole </li></ul></ul>Ladenson P, Kim M. Cecil Medicine. 2008:1698-1713.
    7. 7. Secondary Hypothyroidism: Etiology <ul><li>Reduced secretion of TRH or TSH </li></ul><ul><ul><li>Hypothalamic disorders </li></ul></ul><ul><ul><ul><li>Tumor (lymphoma, germinoma, glioma) </li></ul></ul></ul><ul><ul><ul><li>Infiltrative disorders (sarcoidosis, hemochromatosis, and histiocytosis) </li></ul></ul></ul><ul><ul><li>Hypopituitarism </li></ul></ul><ul><ul><ul><li>Mass lesions </li></ul></ul></ul><ul><ul><ul><li>Pituitary surgery </li></ul></ul></ul><ul><ul><ul><li>Pituitary irradiation </li></ul></ul></ul><ul><ul><ul><li>Hemorrhagic apoplexy (Sheehan’s syndrome) </li></ul></ul></ul><ul><ul><ul><li>Lymphocytic hypophysitis </li></ul></ul></ul>Ladenson P, Kim M. Cecil Medicine. 2008:1698-1713.
    8. 8. Clinical Manifestations: Symptoms <ul><li>Symptoms 1,2 </li></ul><ul><ul><li>Tiredness/ weakness </li></ul></ul><ul><ul><li>Weight gain with poor appetite </li></ul></ul><ul><ul><li>Dry skin </li></ul></ul><ul><ul><li>Cold sensation </li></ul></ul><ul><ul><li>Hair loss(diffuse alopecia) </li></ul></ul><ul><ul><li>Nail growth is retarded </li></ul></ul><ul><ul><li>Poor concentration/memory loss </li></ul></ul><ul><ul><li>Constipation </li></ul></ul><ul><ul><li>Dyspnea </li></ul></ul><ul><ul><li>Hoarseness of voice </li></ul></ul><ul><ul><li>Hearing Impairment </li></ul></ul><ul><ul><li>Carpal tunnel syndrome </li></ul></ul><ul><ul><li>Menorrhagia(miscarriage) </li></ul></ul><ul><ul><li>Paresthesia </li></ul></ul><ul><li>Ladenson P and Kim M. Cecil Medicine. 2008:1698-1713. </li></ul><ul><li>Jameson JL, et al. Harrison's Principles of Internal Medicine . 2008: 2224-2247. </li></ul>
    9. 9. Clinical Manifestations: Signs <ul><li>Signs 1,2 </li></ul><ul><ul><li>Cold peripheral extremities </li></ul></ul><ul><ul><li>Dry, coarse and yellow skin </li></ul></ul><ul><ul><li>Puffiness of face, hands and feet </li></ul></ul><ul><ul><li>Pre tibial non pitting edema </li></ul></ul><ul><ul><li>Hair loss and brittle nails </li></ul></ul><ul><ul><li>Bradycardia/ diastolic hypertension </li></ul></ul><ul><ul><li>Slow relaxation of tendon reflex (woltmans sign) </li></ul></ul><ul><ul><li>Serous cavity effusions </li></ul></ul><ul><ul><li>Normal/enlarged/atrophied thyroid gland </li></ul></ul><ul><li>Hypothyroidism in children </li></ul><ul><ul><li>Delayed growth in children and delayed appearance of permanent teeth </li></ul></ul><ul><ul><li>Delayed or precocious puberty </li></ul></ul><ul><ul><li>Pseudohypertrophy of muscles </li></ul></ul><ul><li>Ladenson P and Kim M. Cecil Medicine. 2008:1698-1713. </li></ul><ul><li>Jameson JL et al. Harrison's Principles of Internal Medicine . 2008: 2224-2247. </li></ul>
    10. 10. Laboratory Diagnosis <ul><li>TSH assay: Primary test to establish the diagnosis </li></ul><ul><li>Additional tests: </li></ul><ul><ul><li>Estimation of free T 3 and T 4 </li></ul></ul><ul><ul><li>Test for thyroid autoantibodies </li></ul></ul><ul><ul><li>Thyroid scan/ultrasonography </li></ul></ul><ul><ul><li>Serum cholesterol-  in hypothyroidism </li></ul></ul>T 3 /T 4 Subclinical hypothyroidism Overt hypothyroidism TSH TSH AACE medical guidelines for clinical practice for the evaluation and treatment of hyperthyroidism and hypothyroidism, 2006:1-13 http://www.aace.com/pub/pdf/guidelines/hypo_hyper.pdf . T 3 /T 4
    11. 11. Treatment Overview <ul><li>Goal: To mimic normal, physiological levels and alleviate signs, symptoms, and biochemical abnormalities </li></ul><ul><li>Treatment should be tailored to individual needs </li></ul><ul><li>Treatment of choice: Levothyroxine (LT4) replacement therapy </li></ul><ul><li>Desiccated thyroid hormone and T 3 +T 4 mixture: Insufficient evidence and not recommended for replacement therapy by the AACE guidelines </li></ul>AACE medical guidelines for clinical practice for the evaluation and treatment of hyperthyroidism and hypothyroidism, 2006:1-13 http://www.aace.com/pub/pdf/guidelines/hypo_hyper.pdf .
    12. 12. Subclinical Hypothyroidism
    13. 13. Subclinical Hypothyroidism: Ayesha’s Case <ul><li>Criteria defining subclinical hyperthyroidism: </li></ul><ul><ul><li>Slightly elevated serum TSH levels </li></ul></ul><ul><ul><li>FT4 and T 3 levels within the reference range </li></ul></ul><ul><li>Affects 1-10% of adults, with greater prevalence in women </li></ul><ul><li>Most common cause: autoimmune thyroiditis (Hashimoto’s disease) </li></ul><ul><li>Predisposing factors </li></ul><ul><ul><li>Advancing age </li></ul></ul><ul><ul><li>Greater iodine consumption </li></ul></ul><ul><li>Often asymptomatic </li></ul><ul><li>May represent early thyroid failure </li></ul>AACE medical guidelines for clinical practice for the evaluation and treatment of hyperthyroidism and hypothyroidism, 2006:1-13 http://www.aace.com/pub/pdf/guidelines/hypo_hyper.pdf .
    14. 14. Subclinical Hypothyroidism: Management Algorithm <ul><li>Col NF, et al. JAMA 2004; 291:239-243. </li></ul><ul><li>Surks MI, et al. JAMA 2004;291:228-238. </li></ul>Algorithm for the management of subclinical hypothyroidism (T 4 = thyroxine: TSH = thyrotropin-stimulating hormone) Serum TSH >4.5 mU/L Repeat Serum TSH Measurement with FT 4 Measurement 2 to 12 Weeks Later Serum TSH Level within Reference Range (0.45 to 4.5 mlU/L)? Serum TSH Level 4.5 to 10mlU/L Monitor Every 6 to 12 mo for Several Years Serum TSH Level > 10mlU/L Signs or Symptoms Consistent with Hypothyroidism? FT 4 Level Decreased (<0.8 ng/dL)? Treat with Levothyroxine* Pregnant or Contemplating Pregnancy? Consider Levothyroxine Treatment with Periodic Monitoring Monitor Serum TSH Every 6 to 12 mo FT 4 Level Decreased (<0.8 ng/dL)? Treat with Levothyroxine* Pregnant or Contemplating Pregnancy? Consider Levothyroxine Treatment in Appropriate Clinical Settings Yes No Yes No Yes No No Yes Yes No No Yes <ul><li>TSH: Thyroid stimulating hormone </li></ul><ul><li>FT4: Free Thyroxine </li></ul><ul><li>Mo: Months </li></ul>Rule out hypopituitarism
    15. 15. Subclinical Hypothyroidism <ul><li>Dosing and Monitoring 1,2 </li></ul><ul><ul><li>Always start with a small dose to prevent risk of Atrial Fibrillation </li></ul></ul><ul><ul><li>Dose of LT4: 25-50 mcg/day (reduced dose in elderly and in patients with heart disease) </li></ul></ul><ul><ul><li>Adjustment in dosage is made in 12.5-25µg inc or dec </li></ul></ul><ul><ul><li>Serum TSH levels to be measured 6-8 weeks after starting treatment or after a change in the dosage </li></ul></ul><ul><ul><li>Target TSH levels: 0.3-3.0 µIU/mL </li></ul></ul><ul><ul><li>Annual examination after achieving stable TSH levels </li></ul></ul><ul><li>Progression to overt hypothyroidism 1 </li></ul><ul><ul><li>Occurs in 3-20% patients </li></ul></ul><ul><ul><li>Patients with goiter and thyroid antibodies at higher risk for progression </li></ul></ul><ul><li>Associated risks 1 </li></ul><ul><ul><li>Progression to overt hypothyroidism </li></ul></ul><ul><ul><li>Cardiovascular effects </li></ul></ul><ul><ul><li>Hyperlipidemia </li></ul></ul><ul><ul><li>Neuropsychiatric effects </li></ul></ul><ul><li>AACE medical guidelines for clinical practice for the evaluation and treatment of hyperthyroidism and hypothyroidism, 2006:1-13. </li></ul><ul><li>http://www.aace.com/pub/pdf/guidelines/hypo_hyper.pdf . </li></ul><ul><li>2. Shah SN, Joshi SR. Journal of the Association of Physicians of India. 2011;59(Supplement):1-68. </li></ul>
    16. 16. Learning Activity
    17. 17. Learning Activity <ul><li>All of the following statements related to subclinical hypothyroidism are true, EXCEPT: </li></ul><ul><ul><li>The most common cause of subclinical hypothyroidism is Hashimoto’s disease. </li></ul></ul><ul><ul><li>Subclinical hypothyroidism is more common in women. </li></ul></ul><ul><ul><li>Subclinical hypothyroidism is characterized by elevated levels of TSH and free T4. </li></ul></ul><ul><ul><li>Subclinical hypothyroidism may represent early thyroid failure. </li></ul></ul>
    18. 18. Case Study
    19. 19. Ayesha's Case: Management <ul><li>Ayesha was put on LT4 therapy based on the following findings: </li></ul><ul><ul><li>Increased TSH </li></ul></ul><ul><ul><li>Positive antithyroid antibodies </li></ul></ul><ul><ul><li>Dyslipidemia </li></ul></ul><ul><li>Dosage administered was 30 mcg/day. </li></ul><ul><li>She was asked to visit again for follow-up after 8 weeks </li></ul>
    20. 20. Levothyroxine
    21. 21. Levothyroxine <ul><li>Synthetic T4 identical to that produced in the human thyroid gland </li></ul><ul><li>Indications: </li></ul><ul><ul><li>Hypothyroidism: All types </li></ul></ul><ul><ul><li>Pituitary TSH suppression </li></ul></ul><ul><ul><ul><li>Euthyroid goiters </li></ul></ul></ul><ul><ul><ul><ul><li>Thyroid nodules </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Subacute or chronic lymphocytic thyroiditis (Hashimoto’s thyroiditis) </li></ul></ul></ul></ul><ul><ul><ul><li>Adjunct to surgery and radioiodine therapy in the management of thyroid cancer </li></ul></ul></ul>Synthroid PI,Abbott. 2008
    22. 22. Levothyroxine: Important Facts <ul><li>Levothyroxine sodium has a narrow therapeutic range </li></ul><ul><ul><li>Regardless of indication of use, careful dose titration is necessary to avoid consequences of over- or under- treatment </li></ul></ul><ul><ul><li>Even small changes in the dose of LT4 can shift a patient from a euthyroid to a hyperthyroid or hypothyroid state. </li></ul></ul><ul><li>The AACE recommends the use of a high-quality brand preparation of levothyroxine </li></ul><ul><li>Same brand of LT4 should be received throughout treatment </li></ul>AACE medical guidelines for clinical practice for the evaluation and treatment of hyperthyroidism and hypothyroidism, 2006:1-13 http://www.aace.com/pub/pdf/guidelines/hypo_hyper.pdf .
    23. 23. Levothyroxine: Dosing <ul><li>Recommended mean daily dose of LT4 therapy: 1.6 mcg/kg of body weight </li></ul><ul><li>Initiate with 12.5 mcg daily to a full replacement dose of LT4 depending on age, weight, and cardiac status </li></ul><ul><li>Reassess TSH and/or free T4 after 6 weeks </li></ul><ul><li>Follow up after 6 months and thereafter annually, once TSH is in normal range </li></ul><ul><li>Adjust doses as appropriate in case of absorption variability and drug interactions </li></ul><ul><li>Keep in mind that inappropriate dose adjustments can lead to increased costs due to additional patient visits and laboratory tests </li></ul>AACE medical guidelines for clinical practice for the evaluation and treatment of hyperthyroidism and hypothyroidism, 2006:1-13 http://www.aace.com/pub/pdf/guidelines/hypo_hyper.pdf .
    24. 24. Levothyroxine: Drug Interactions <ul><li>Increase LT4 dose with </li></ul><ul><ul><li>Drugs that reduce thyroxine production: lithium, iodine-containing drugs, and amiodarone </li></ul></ul><ul><ul><li>Drugs that reduce thyroxine absorption: sucralfate, ferrous sulfate, cholestyramine, colestipol, aluminum-containing antacids, and calcium supplements </li></ul></ul><ul><ul><li>Drugs that increase thyroxine metabolism: rifampin, phenobarbital, carbamazepine, warfarin, and oral hypoglycemic agents </li></ul></ul><ul><li>Decrease LT4 dose with </li></ul><ul><ul><li>Drugs that displace thyroxine from binding proteins: furosemide, mefenamic acid, salicylates, vitamin C </li></ul></ul><ul><li>Hueston WJ. Treatment of Hypothyroidism. American family physician. 64(10): 1717-1724. </li></ul><ul><li>AACE medical guidelines for clinical practice for the evaluation and treatment of hyperthyroidism and hypothyroidism, 2006:1-13 </li></ul><ul><li>http://www.aace.com/pub/pdf/guidelines/hypo_hyper.pdf . </li></ul>
    25. 25. Learning Activity
    26. 26. Learning Activity <ul><li>Which of the following agents increase the absorption of LT4? </li></ul><ul><ul><li>Calcium </li></ul></ul><ul><ul><li>Furosemide </li></ul></ul><ul><ul><li>Ferrous sulfate </li></ul></ul><ul><ul><li>Rifampin </li></ul></ul>
    27. 27. Case Study 1
    28. 28. Ayesha's Case: Therapy and Follow-up <ul><li>Follow-up </li></ul><ul><ul><li>Serum TSH measurement was repeated after 8 weeks of commencing the treatment. They had fallen to 1.2 mIU/mL and remained within the range of 1 to 1.5 mIU/mL on consecutive visits. </li></ul></ul><ul><ul><li>She was asked to stay on the treatment and follow up after 1 year. </li></ul></ul><ul><ul><li>After 1 year of treatment, she had lost weight and was asymptomatic. On investigation, her serum cholesterol and low-density lipoprotein (LDL) cholesterol levels were 190 and 100 mg/dL, respectively. </li></ul></ul>
    29. 29. Case Study 2
    30. 30. Case Presentation: 2 <ul><li>Patient </li></ul><ul><ul><li>Shobha, a 32-week pregnant 30-year-old woman presents premature labor </li></ul></ul><ul><ul><li>Inappropriate weight gain for gestational age </li></ul></ul><ul><ul><li>Cold intolerance during past few months </li></ul></ul><ul><li>Past medical history </li></ul><ul><ul><li>She was diagnosed with hypothyroidism at the age of 20 </li></ul></ul><ul><ul><li>She was on LT4 therapy </li></ul></ul><ul><ul><li>Last dose modification was 2 years back after which she continued on same dose. </li></ul></ul>
    31. 31. Case Presentation: 2 (Continued) <ul><li>Physical Examination </li></ul><ul><ul><li>Weight : 100 kg </li></ul></ul><ul><ul><li>Pulse Rate: 68 per minute </li></ul></ul><ul><ul><li>BP: 140/90 mm Hg </li></ul></ul><ul><ul><li>Facial puffiness </li></ul></ul><ul><ul><li>Skin: Cold, Dry </li></ul></ul><ul><ul><li>Deep tendon reflexes,: Slow relaxation </li></ul></ul><ul><li>Thyroid Function Tests </li></ul><ul><ul><li>Serum TSH: 11 mIU/L </li></ul></ul><ul><ul><li>Free T4: 1.2 pmol/L </li></ul></ul><ul><li>Fetal Examination </li></ul><ul><ul><li>Fetal distress in labour </li></ul></ul><ul><li>Outcome of Pregnancy </li></ul><ul><ul><li>She delivered a preterm low birth weight male. </li></ul></ul>
    32. 32. Maternal Hypothyroidism
    33. 33. Maternal Hypothyroidism <ul><li>One of the most common endocrine disorders in pregnancy 1 </li></ul><ul><li>Overt hypothyroidism found in 1.3 per 1000 pregnant women and subclinical hypothyroidism in 23 per 1000 pregnant women 1 </li></ul><ul><li>Most common cause: endemic iodine deficiency 2 </li></ul><ul><li>Women with hypothyroidism carry an increased risk of infertility, miscarriage, and obstetric complications 1 </li></ul><ul><li>Foetal complications: p remature birth, low-birth weight (LBW), fetal distress in labor, fetal death, perinatal death, and c ongenital hypothyroidism 1 </li></ul><ul><li>Even an untreated subclinical hypothyroidism during pregnancy can lead to cognitive impairment in the offspring. 3 </li></ul><ul><li>Sahu MT, et al. Arch.Gynaecol. Obstet . 2010;218:215-220. </li></ul><ul><li>Lazaras JH. British Medical Bulletin . 2010;1-12. </li></ul><ul><li>AACE medical guidelines for clinical practice for the evaluation and treatment of hyperthyroidism and hypothyroidism, 2006:1-13 http://www.aace.com/pub/pdf/guidelines/hypo_hyper.pdf . </li></ul>
    34. 34. Thyroid Physiology in Pregnancy Decreased TSH Placenta hCG Increased TH degradation Thyroid stimulation for increased TH Production Estrogen Increased serum TBG Increased hepatic production of TBG Increased half life of TBG Type 3 deiodinase Stimulates TSH receptor Decreased free TH Stimulation of hypothalamic pituitary axis Increased serum TH hCG: Human chorionic gonadotropin TSH: Thyroid stimulating hormone TH: Thyroid hormone TBG: Thyroxine-binding globulin
    35. 35. Thyroid Physiology in Pregnancy Increased oestrogen in pregnancy Two- to threefold increase in TBG Decrease Free T 3 and T 4 Similar structure of hCG and TSH hCG stimulates release of T 3 and T 4 Transient TSH decrease in weeks 8 to 14 Increased peripheral metabolism of T 3 and T 4 Decrease Free T 3 and T 4 <ul><li>Jameson JL. Harrison's Principles of Internal Medicine . 2008:2224-2247. </li></ul><ul><li>Lazarus JH. Br Med Bull. 2010;1-12. </li></ul><ul><li>Galofre JC, Davies TF. J Womens Health (Larchmt). 2009;18(11):1847-1856. . </li></ul>0 50 75 100 125 150 0 0.5 1.5 2.5 3.5 4.5 4 0 8 12 16 20 24 28 32 36 40 TSH (mU/L) hCG (IU/mL Weeks of gestation 0.2 0.6 1.0 1.4 1.8 160 220 280 340 400 4 0 8 12 16 20 24 28 32 36 40 FT3 (pg/dL) FT4 (ng/dL) Weeks of gestation A B C TBG: Thyroxine- binding globulin TSH: Thyroid stimulating hormone HCG: Human chorionic gonadotropin TT4: Total thyroxine FT3: Free triiodothyronine FT4: Free thyroxine hCG TSH 0 1.5 2.0 2.5 3.0 3.5 0 5 10 15 20 25 4 0 8 12 16 20 24 28 32 36 40 TT4 (mcg/dL) TBG (mg/dL) TBG Total T4 Weeks of gestation Free T4 Free T3
    36. 36. Thyroid Function Tests in Pregnancy FT4, Free thyroxine; FT3, Free triiodothyronine; TSH, Thyroid stimulating hormone 1. Marwaha RK. BJOG. 2008;115(5):602-606. 2. SI Units for Clinical Data. University of North Carolina. Referral Values for TFT in Pregnant Indian Women 1,2 Thyroid Hormone Normal Values in Nonpregnant Trimester Range (5 th -95 th Percentile) FT 3 3.7-7.2 pM/L(240.26-467.53 pg/dL) I 1.92-5.86 pM/L (124.68-380.51 pg/dL) II 3.2-5.73 pM/L (207.8-372 pg/dL) III 3.3-5.18 pM/L (214.3-336.36 pg/dL) FT 4 12-23 pM/L (0.93-1.79 ng/dL) I 12-19.45 pM/L (0.93-1.51 ng/dL) II 9.48-19.58 pM/L (0.74-1.521 ng/dL) III 11.32-17.7 pM/L (0.88-1.38 ng/dL) TSH 0.27-4.2 µIU/mL I 0.6-5.0 µIU/mL II 0.44-5.78 µIU/mL III 0.74-5.7 µIU/mL
    37. 37. Maternal Hypothyroidism <ul><li>AACE recommendations </li></ul><ul><ul><li>Carry out TSH assay routinely before pregnancy or during the first trimester to rule out thyroid disorder </li></ul></ul><ul><ul><li>Avoid complications by administering thyroid hormone replacement therapy </li></ul></ul><ul><ul><li>Both mild as well as overt hypothyroidism are managed by administering levothyroxine therapy which can be safely administered during pregnancy </li></ul></ul><ul><ul><li>Assess TSH levels every 6 weeks during pregnancy for appropriate dose adjustments </li></ul></ul><ul><ul><li>Increase the dose of thyroid hormone in pregnant women with moderate to severe hypothyroidism </li></ul></ul>AACE medical guidelines for clinical practice for the evaluation and treatment of hyperthyroidism and hypothyroidism, 2006:1-13 http://www.aace.com/pub/pdf/guidelines/hypo_hyper.pdf .
    38. 38. Maternal Hypothyroidism <ul><li>Preconception: Optimize therapy in patients with preexisting disease </li></ul><ul><li>Pregnancy confirmed: Increase dose by 30-50% of preconception dose </li></ul><ul><li>Target levels </li></ul><ul><ul><li>TSH<2.5 mIU/L in the first trimester </li></ul></ul><ul><ul><li>TSH<3 mIU/L in later pregnancy </li></ul></ul><ul><li>After delivery, reduce dose to preconception dose </li></ul><ul><li>Assess thyroid function at 6 weeks postpartum </li></ul><ul><li>Post-ablative and post-surgical hypothyroidism require higher dose </li></ul>Lazaras JH. British Medical Bulletin . 2010;1-12.
    39. 39. Learning Activity <ul><li>Women with hypothyroidism carry an increased risk of ______. </li></ul><ul><ul><li>Infertility </li></ul></ul><ul><ul><li>Miscarriage/spontaneous abortion </li></ul></ul><ul><ul><li>Maternal hypertension </li></ul></ul><ul><ul><li>All of the above </li></ul></ul>
    40. 40. Case Presentation II: Congenital Hypothyroidism <ul><li>The baby delivered by Shobha was apparently normal. </li></ul><ul><li>Findings on neonatal examination are within normal limits </li></ul><ul><li>Neonatal screening for congenital hypothyroidism on the 3rd day by cord blood </li></ul><ul><ul><li>TSH: 38 mIU/L </li></ul></ul><ul><ul><li>Serum free T4: 0.5 ng/dL </li></ul></ul><ul><li>Diagnosis: Congenital Hypothyroidism </li></ul>
    41. 41. Congenital Hypothyroidism
    42. 42. Congenital Hypothyroidism <ul><li>Abnormality in the development of thyroid gland (dysgenesis or agenesis) and defect in the biosynthesis of thyroid hormones </li></ul><ul><li>Prevalence rate 1 in 4000 newborn infants in regions of sufficient daily iodine intake </li></ul><ul><li>2:1 incidence in females compared with males </li></ul><ul><li>Causes: Endemic iodine deficiency, genetic mutation, and hemangiomas </li></ul><ul><li>Routine thyroid function screening in neonates is recommended since no apparent clinical manifestation </li></ul><ul><li>Untreated congenital hypothyroidism results in development of cretinism </li></ul><ul><li>Do not delay diagnosis of congenital hypothyroidism until physical manifestations are seen </li></ul><ul><ul><li>Mental retardation </li></ul></ul><ul><ul><li>Deafness </li></ul></ul><ul><ul><li>Short stature </li></ul></ul><ul><ul><li>Characteristic facial deformities </li></ul></ul>Roberts CGP et al. Lancet. 2004;363: 793-803.
    43. 43. Congenital Hypothyroidism: Clinical Features Roberts CGP et al. Lancet. 2004;363: 793-803. <ul><ul><li>Infants </li></ul></ul>Children and Adolescents Hypothermia <ul><ul><li>Growth failure </li></ul></ul>Poor feeding <ul><ul><li>Markedly delayed bone maturation </li></ul></ul>Bradycardia <ul><ul><li>Delayed eruption of permanent teeth </li></ul></ul>Jaundice <ul><ul><li>Muscle pseudohypertrophy </li></ul></ul>Enlarged posterior fontanel Delayed or precocious puberty Umbilical hernia Pituitary enlargement <ul><ul><li>Galactorrhoea </li></ul></ul>
    44. 44. Diagnosis Of Congenital Hypothyroidism Rastogi and LaFranchi. Orphanet Journal of Rare Diseases 2010,5:17;1-22. DIAGNOSTIC ALGORITHM Screen the newborn for hypothyroidism: Initial T4 <10%, TSH ↑ Or Initial TSH ↑ Clinical suspicion of hypothyroidism Measure serum TSH and free T4 (or T 4 and T 3 resin uptake) TSH ↑(>9 mU/L) Free T 4 ↓ (<0.6 ng/dL) Diagnosis primary CH confirmed TSH ↓ or normal (<9 mU/L) Free T 4 ↓ (<0.6 ng/dL) Diagnosis likely secondary (central) hypothyroidism <ul><li>Other diagnostic tests to </li></ul><ul><li>determine etiology (optional): </li></ul><ul><li>Radionuclide uptake and scan </li></ul><ul><li>Ultrasonography </li></ul><ul><li>Serum thyroglobulin </li></ul><ul><li>Maternal antithyroid antibodies </li></ul><ul><li>Urinary iodine </li></ul><ul><li>Isolated: TSH β gene analysis </li></ul><ul><li>Evaluate for other pituitary hormone deficiencies </li></ul><ul><li>MRI of brain </li></ul><ul><li>Eye exam to check for optic nerve hypoplasia </li></ul>TSH: Thyroid stimulating hormone T4: Thyroxine T3: Triiodothyronine Free T4: Free thyroxine TSH β : Thyroid stimulating hormone beta
    45. 45. Congenital Hypothyroidism Case: Follow Up <ul><li>Initial work-up for Shobha’s child </li></ul><ul><ul><li>The baby was referred to pediatric endocrinologist </li></ul></ul><ul><ul><li>Thyroid ultrasonography showed a normal thyroid gland. </li></ul></ul><ul><li>Management </li></ul><ul><ul><li>The baby was started on LT4 at an initial daily dose of 50 mcg </li></ul></ul><ul><ul><li>The serum T4 normalized in 3 days </li></ul></ul><ul><ul><li>TSH normalized by end of 2 weeks </li></ul></ul><ul><ul><li>The mother was asked to follow-up with the baby on monthly basis. </li></ul></ul>
    46. 46. Management of Congenital Hypothyroidism <ul><li>Goal: To normalize T4 within 2 weeks and TSH within 1 month </li></ul><ul><li>Assess permanence of congenital hypothyroidism </li></ul><ul><ul><li>If initial thyroid scan shows ectopic/absent gland, congenital hypothyroidism is permanent </li></ul></ul><ul><ul><li>If initial TSH is <50 mIU/L and there is no increase in TSH after newborn period, off- therapy period is recommended at 3 years of age </li></ul></ul><ul><ul><li>If TSH increases during the off-therapy period, consider the condition as permanent congenital hypothyroidism </li></ul></ul><ul><li>Medications: LT4: 10-15  g/kg by mouth once-daily </li></ul><ul><li>Monitoring: Recheck T4 and TSH </li></ul><ul><ul><li>At 2-4 weeks after initiation of LT4 treatment </li></ul></ul><ul><ul><li>Every 1-2 months in the first 6 months </li></ul></ul><ul><ul><li>Every 3-4 months between 6 months and 3 years of age </li></ul></ul><ul><ul><li>Every 6-12 months from 3 years of age to end of growth </li></ul></ul>Rose SR and Brown RS. Pediatric s. 2006;117(6):2290-2303.
    47. 47. Learning Activity <ul><li>All of the following signs represent congenital hypothyroidism, EXCEPT </li></ul><ul><li>Tachycardia </li></ul><ul><li>Jaundice </li></ul><ul><li>Enlarged posterior fontanel </li></ul><ul><li>Umbilical hernia </li></ul>
    48. 48. Comorbid Conditions
    49. 49. Comorbid Conditions 1. AACE medical guidelines for clinical practice for the evaluation and treatment of hyperthyroidism and hypothyroidism, 2006:1-13 http://www.aace.com/pub/pdf/guidelines/hypo_hyper.pdf . 2. Duntas LH, Biondi B. Semin Thromb Hemost . 2011;37(1):27-34.
    50. 50. Comorbid Conditions (Contd.) <ul><li>Diabetes mellitus </li></ul><ul><li>Hashimoto’s thyroiditis may be associated with 10% patients of type 1 diabetes mellitus </li></ul><ul><li>Approximately one-fourth of female patients with type 1 diabetes mellitus develop postpartum thyroiditis </li></ul><ul><li>AACE recommendations for patients with diabetes mellitus </li></ul><ul><ul><li>Examine for goiter </li></ul></ul><ul><ul><li>Assess TSH levels regularly especially in the presence of a goiter or other autoimmune disorders </li></ul></ul><ul><li>Infertility </li></ul><ul><li>Hypothyroidism due to chronic thyroiditis may cause infertility, miscarriage, and menstrual irregularities </li></ul><ul><ul><li>Treatment with LT4 replacement therapy restores normal menstrual cycle and fertility </li></ul></ul>AACE medical guidelines for clinical practice for the evaluation and treatment of hyperthyroidism and hypothyroidism, 2006:1-13 http://www.aace.com/pub/pdf/guidelines/hypo_hyper.pdf .
    51. 51. Comorbid Conditions (Contd.) <ul><li>Depression </li></ul><ul><li>In every patient with depression, diagnosis of overt or subclinical hypothyroidism should be considered </li></ul><ul><li>Periodic evaluation for thyroid function should be performed in patients receiving lithium therapy </li></ul><ul><ul><li>Treatment is with LT4 replacement therapy </li></ul></ul><ul><ul><li>LT4 is indicated occasionally in combination with antidepressants in euthyroid patients with depression </li></ul></ul>AACE medical guidelines for clinical practice for the evaluation and treatment of hyperthyroidism and hypothyroidism, 2006:1-13 http://www.aace.com/pub/pdf/guidelines/hypo_hyper.pdf .
    52. 52. Comorbid Conditions (Contd.) <ul><li>Dyslipidemia and cardiovascular sequelae comorbid with overt hypothyroidism </li></ul><ul><li>Overt hypothyroidism with dyslipidemia is characterized by </li></ul><ul><ul><li>Increased levels of total cholesterol </li></ul></ul><ul><ul><li>Increased LDL cholesterol </li></ul></ul><ul><li>Mechanisms for dyslipidemia </li></ul><ul><ul><li>Impaired production of TC and </li></ul></ul><ul><ul><li>Decreased expression of the LDL receptors </li></ul></ul><ul><li>Severe cardiovascular disease and premature atherosclerosis, if untreated, lead to </li></ul><ul><ul><li>Pericardial effusion </li></ul></ul><ul><ul><li>Congestive heart failure </li></ul></ul><ul><ul><li>Coronary artery disease </li></ul></ul>Duntas LH, Biondi B. Semin Thromb Hemost. 2011;37(1):27-34
    53. 53. Comorbid Conditions (Contd.) <ul><li>Cardiovascular sequelae comorbid with subclinical hypothyroidism </li></ul><ul><li>Subclinical hypothyroidism is associated with </li></ul><ul><ul><ul><li>Impaired diastolic function and depressed left ventricular systolic function in middle-aged patients </li></ul></ul></ul><ul><ul><ul><li>Increased risks of atherosclerosis and myocardial infarction </li></ul></ul></ul><ul><ul><ul><li>Mortality in patients less than 65 years of age due to cardiovascular events </li></ul></ul></ul><ul><ul><ul><li>Proatherogenic mechanisms that leads to low-grade inflammation and may suggest CVD </li></ul></ul></ul><ul><ul><ul><li>Hypercoagulable state </li></ul></ul></ul><ul><li>LT4 therapy for subclinical hypothyroidism </li></ul><ul><ul><ul><li>Reverses cardiovascular alterations </li></ul></ul></ul><ul><ul><ul><li>Reduces cardiovascular risk factors </li></ul></ul></ul><ul><ul><ul><li>Improves dyslipidaemia </li></ul></ul></ul><ul><ul><ul><li>Minimizes neurobehavioral changes </li></ul></ul></ul>Duntas LH, Biondi B. Semin Thromb Hemost. 2011;37(1):27-34 CVD: Cardiovascular disease The Cycle of Disease Subclinical Hypothyroidism Emerging Risk Factors CVD Endothelial Dysfunction Cardiac Alterations Blood Pressure Hyperlipidemia Hemostatic Balance Obesity
    54. 54. Learning Activity
    55. 55. Learning Activity <ul><li>Which of the following statements are TRUE regarding LT4 therapy in hypothyroidism? (Select all that apply.) </li></ul><ul><li>Congenital hypothyroidism is treated with LT4 at a dose of 50-100 mcg/kg orally once-daily. </li></ul><ul><li>LT4 therapy for subclinical hypothyroidism reverses cardiovascular alterations. </li></ul><ul><li>LT4 is contraindicated in combination with antidepressants in euthyroid patients with depression. </li></ul><ul><li>Both mild as well as overt hypothyroidism are managed by administering levothyroxine therapy. </li></ul>
    56. 56. Thank You Copyright © 2011 Abbott India Limited. All rights reserved

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