This lecture was conducted during the Nephrology Unit Grand Ground by Medical Student rotated under Nephrology Division under the supervision and administration of Prof. Jamal Al Wakeel, Head of Nephrology Unit, Department of Medicine and Dr. Abdulkareem Al Suwaida, Chairman of Department of Medicine. Nephrology Division is not responsible for the content of the presentation for it is intended for learning and /or education purpose only.

HYPERTHYROIDISM Presented by: Muteb Al-Rowaili Medical Student August 2008

What is Hyperthyroidism? “Hyperthyroidism” refers to overactivity of the thyroid gland leading to excessive synthesis of thyroid hormones and accelerated metabolism in the peripheral tissues. The secretion of thyroid hormone is no longer under the regulatory control of the hypothalamic-pituitary center. Prevalence Women 2% Men 0.2% 15% of cases occur in patients older than 60 years of age

Clinical Symptoms Older patient presents with lack of clinical signs and symptoms, which makes diagnosis more difficult Thyroid storm is a rare presentation, occurs after stressful illness in under treated or untreated patient. Characteristics -Delirium -Dehydration -Severe tachycardia -Vomiting -Fever -Diarrhea

Clinical symptoms Skin -Warm -May be erythematous (due to increased blood flow) -Smooth- due to decrease in keratin -Sweaty and heat intolerance -Onycholysis –softening of nails and loosening of nail beds

Clinical symptoms Hyperpigmentation -Due the patient increase ACTH secretion Pruritis -mainly in graves disease Thinning of hair Vitilago and alopecia areata -mainly due to autoimmune disease Infilterative dermopathy -Graves disease, most common on shins

Clinical symptoms Eyes Stare Lid lag *Due to sympathetic over activity *Only Grave’s disease has ophthalmopathy -Inflammation of extraocular muscles, orbital fat and connective tissue. -This results in exopthalmos -More common in smokers

Clinical symptoms Eyes Impaired eye muscle function (Diplopia) Periorbital and conjunctival edema Gritty feeling or pain in the eyes Corneal ulceration due to lid lag and proptosis Optic neuritis and even blindness

Clinical symptoms Cardiovascular System Increased cardiac output (due to increased oxygen demand and increased cardiac contractibility. Tachycardia Widened pulse pressure High output – heart failure

Clinical symptoms Cardiovascular System Atrial fibrillation, 10-20% of patients. More common in elderly Atrial ectopy 60% of A-fib will convert to normal sinus rhythm with treatment (4-months of becoming euthyroid) Mitral valve problems LVH and cardiomyopathy

Serum Lipids Low total cholesterol Low HDL Low total cholesterol/HDL ratio

Respiratory System Dyspnea on rest and with exertion Oxygen consumpation and CO2 production increases. Hypoxemia and hypercapnea, which stimulates ventilation Respiratory muscle weakness Decreased exercise capacity Tracheal obstruction May exacerbate asthma Increased pulmonary arterial pressure

GI System -Weight loss due to increased calorigenesis -Malabsorption -Steatorrhea -Celiac Disease (in Grave’s Disease) -Hyperphagia (weight gain in younger patient) -Anorexia- weight loss in elderly -Dysphagia -Abnormal LFT especially phosphate

Hematological System Normochromic normocytic anemia Serum ferritin may be high Grave’s disese ITP Pernicious anemia Anti-neutrophiliac antibody

GU System Urinary frequency and nocturia Enuresis is common in children Women High serum estradiol Low free estradiol High LH Oligomenorrhea and amenorrhea Anovulatory infertility

GU System…cont Men High total testosterone Low free testosterone High serum LH High serum estradiol Gynecomastia Decreased libido Decreased or abnormal sperm

Clinical symptoms Skeletal System Bone resorption Increased porosity of cortical bone Reduced volume of trabecular bone Serum alkaline phosphate is increased Increased osteoblasts Inhibit PTH secretions Decreased calcium absorption and increased excretion Osteoporosis, Fractures

Skeletal System Grave’s disease is associated with : -Clubbing of nails -Periosteal bone formation in metacarpal bone or phalanges

Neuromuscular System Tremors-outstretched hand and tongue Hyperactive tendon reflexes

Psychiatric Hyperactivity Emotional lability Anxiety Decreased concentration Insomnia

Muscle Weakness Proximal muscle weakness in 50% pts. Decreased muscle mass and strength May take up to six months after euthyroid state to gain strength Myesthenia Gravis, especially in Grave’s disease.

Endocrine Increased sensitivity of pancreatic beta cells to glucose Increased insulin secretion Antagonism to peripheral action of insulin Latter effects usually predominate leading to intolerance.

Etiology 1 Grave’s disease Autoimmune disease caused by antibodies to TSH receptors Can be familial and associated with other autoimmune diseases 2 Toxic multi-nodular goiter 5% of all cases 10 times more common in iodine deficient area Typically occurs in older than 40 with long standing goiter

More common in young patients Autonomically functioning nodule Etiology 3 Toxic adenoma More common in young patients Autonomically functioning nodule

Etiology 4 Thyroiditis Subacute Abrupt onset due to leakage of hormones Follows viral infection Resolves within eight months Can re-occur Lymphatic and postpartum Transient inflammation Postpartum can occur in 5-10% cases in the first 3-6 months Transient hypothyroidism occurs before resolution

Etiology 5 Treatment Induced Hyperthyroidism Iodine Induced Excess iodine indirect Exposure to radiographic contrast media Medication Excess iodine increases synthesis and release of thyroid hormone in iodine deficient and older patients with pre-existing goiters

Etiology Amiodarone Induced Thyroiditis Up to 12% of patients, especially in iodine deficient cases Most common cause of iodine excess in US. Amiodarone contains 37% iodine.

Etiology Thyroid Hormone Induced Factitious hyperthyroidism in accidental or intentional ingestion to lose weight Tumors -Metastatic thyroid cancer -Ovarian tumor that produces thyriod hormone (struma ovarii) -Trophoblastic tumor -TSH secreting tumor

Secondary hyperthyroidism Signs and symptoms of hyperthyroid TSH level Low TSH High TSH (rare) Measure T4 High Secondary hyperthyroidism Image pituitary gland

Low TSH (> 0.1mu/ml ) Measure Free T4 Level Normal High Primary hyperthyroidism Thyroid uptake Measure Free T3 Level High Normal -Subclinical hyperthyroidism -Resolving Hyperthyroidism -Medication -Pregnancy -New thyroid illness T3 Toxicosis Low High Measure thyroglobulin DIffuse Nodular decreased Increased Graves Multiple areas One “hot” area disease Exogenous hormone Thyroiditis Toxic adenoma Toxic multinodular goiter Iodide exposure Exrtraglandular production

Etiology Hyperthyroidism with high RIU - Grave’s disease - Toxic adenoma - Toxic multinodular goiter - TSH- producing pituitary adenoma

Etiology Hyperthyroidism with low RIU - Subacute thyroiditis - Exogenous harmone intake - Ectopic ovarii - Metastatic follicular thyroid CA - Radiation thyroiditis - palpation thyroiditis - Amiodarone induced

Treatment Treatment depends upon -Cause and severity of disease -Patients age -Goiter size -Comorbid condition -Treatment desired

Treatment The goal of therapy is to correct hyper-metabaolic state with fewest side effects and lowest incidence of hypothyroidism.

Options Anti-thyroid drugs Radioactive iodine Surgery Beta-blocker and iodides are adjuncts to above treatment

Beta Blockers Prompt relief of adrenergic symptoms: such as palpitation , tremor , and anxiety Propranolol widely used Increase progressively until symptoms are controlled Most cases 80-320 mg qd is sufficient Ca-CB can be used if beta blocker not tolerated or contraindicated. Verapamil cab be used to control tachycardia in pt with CI to β-adrenergic antagonists.

Iodides Iodide blocks peripheral conversion of T4 to T3 and inhibits hormone release. These are used as adjunct therapy Before emergency non-thyroid surgery Beta blockers cannot curtail symptoms Decrease vascularity before surgery for Grave’s disease

Iodides Iodides are not used for routine treatment because of paradoxical increase of hormone release with prolonged use Commonly used: Radiograph contrast agents -Iopanoic acid -Ipodate sodium Potassium iodide (SSKI) Dose 1 gram/ 12 weeks

Anti-thyroid Drugs Thionamides : They interfere with organification of iodine—suppress thyroid hormone levels Thionamides : two agents: - (methimazole) -PTU (propylthiauracil)

Anti-thyroid Drugs Remission rate: 60% when therapy continued for two years Relapse in 50% of cases. Relapse more common in -smokers -elevated TS antibodies at end of therapy

Anti-thyroid Drugs Methimazole Drug of choice for non-pregnant patients because of : Low cost Long half life Lower incidence of side effects Can be given in conjunction with beta-blocker Beta-blockers can be tapered off after 4-8 weeks of therapy Dose 15-30 mg/day

Anti-thyroid Drugs Methimazole: Starting dose: 10-40 mg PO daily Monthly evaluation of * clinical finding. * plasma T4 . until euthyroid. then the dose adjusted to maintain plasma T4 within the normal range. Maintenance dose 5-10 mg/day TSH levels may remain undetectable for months after euthyroid and not to be used to monitor the therapy

Anti-thyroid Drugs Methimazole At one year if patient is clinically and biochemically euthyroid and TS antibodies are not detectable, therapy can be discontinued Monitor every three months for first year then annually Relapses are more common in the first year but can occur years later If relapse occurs, iodide or surgery although anti-thyroid drugs can be restarted

Anti-thyroid Drugs PTU Prefered for pregnant patients Methimazole is associated with rare genetic abnormalities Dose 100 mg t.i.d Maintenance 100-200 mg/day Goal: Keep Free T4 at upper level of normal

Anti-thyroid Drugs Complications Agranulocytosis up to 0.5% minor S/E: rash , urticaria , arthralgias , transient leukopenia. High with PTU Can occur suddenly Mostly reversible with supportive Tx Routine WBC monitoring controversial Some people monitor WBC every two weeks for first month then monthly Advised to stop drug immediately if they develop (sudden fever , chills or sore throat)

Radioactive Iodine Treatment of choice for Grave’s disease and toxic nodular goiter Inexpensive Highly effective Easy to administer Safe Dose depends on estimated weight of gland Higher dose increases success rate but higher chance of hypothyroidism Some studies have shown increase of hypothyroidism irrespective of dose

Radioactive Iodine Follow up: Usually , several months are needed to restore euthyroidism . Patients are evaluated at 4-6 week interval , with assessment of clinical finding and plasma free T4 If thyroid function stabilizes within the normal range, the interval between follow up visits is gradually increased to annual intervals If symptomatic HYPOthyroidism develops, thyroxine Rx is started. If symptomatic HYPERthyroidism persists after 6 months, RAI treatment is repeated.

Radioactive Iodine Higher dose is favored in older patient A pregnancy test is done immediately before therapy in potentially fertile women. A 24-hour RAIU is usually measured and used to calculate the dose. Thionamides interfere with RAI therapy and should be stopped 3 days before Rx.

Radioactive Iodine Side effects 50% of Grave’s ophthalmology can develop or worsen by use of radioactive iodine Use 40-50 mg Prednisone for at least three months can prevent or improve severe eye disease in 2/3 of patients Use lower dose in ophthalmology because post Tx hypothyroidism may be associated with exacerbation of eye disease Smoking makes ophthalmopathy worse.

Surgery Radioactive iodine has replaced surgery for Tx of hyperthyroidism Subtotal thyroidectomy is most common This limits incidence of hypothyroidism to 25% Total thyroidectomy in large goiter or severe disease The pts should be prepared for surgry by: * a Thionamide which given until the pt is nearly euthyroid. * supersaturated KI (SSKI) 40-80mg PO BID both drugs are stopped postoperatively. * atenolol (50-100 mg daily) is started 1-2 weeks before surgry. if needed, increase the dose to reduce the resting H.R. below 90 bpm & continued 5-7 days postop

New Treatment Endoscopic subtotal thyroidectomy Embolization of thyroid arteries Plasmaphoresis Percutaneous ethanol injection into toxic nodule L-Carnitine supplementation may improve symptoms and may prevent bone loss

Thank you