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Choice of Treatment in Graves Disease
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Various Drugs Used in the treatment of Hyperthyroidism
- Beta blockers: alone are usually sufficient during the thyrotoxic phase of silent or painless thyroiditis
- Potassium iodide: inhibits thyroid hormone synthesis and release. It is used mainly in preparation for thyroidectomy in Graves disease and for treating thyroid storm.
- Systemic glucocorticoids: are used for thyroid storm, type 2 amiodarone induced thyrotoxicosis, and severe cases of subacute (de Ouervain) thyroiditis.
- Thyroidectomy: is preferred over RAI in some patients with Graves hyperthyroidism, especially those with a large goiter or a coexisting thyroid nodule suspicious for cancer.
- Thyroidectomy is also advised for patients with severe Graves ophthalmopathy in whom RAI is contraindicated.
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Subacute Thyroiditis
- Clinical Features: Primary hyperthyroidism (elevated free T4, suppressed TSH), fever, neck pain, tender goiter, and elevated erythrocyte sedimentation rate, this is most likely due to subacute thyroiditis.
- It is thought to be due to a postviral inflammatory process and is often preceded by an upper respiratory illness.
- Thyrotoxicosis in subacute thyroiditis resolves spontaneously within a few weeks and may be followed by a hypothyroid phase lasting a few months.
- Most patients eventually recover to a euthyroid state.
- Treatment: is symptomatic with beta blockers to control thyrotoxic symptoms and nonsteroidal anti inflammatory drugs (NSAIDs) for pain relief. Glucocorticoids are used for severe thyroid pain not responding to NSAIDs.
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Radioactive iodine uptake (RAIU)
- Patients with undiagnosed hyperthyroidism may be evaluated further with RAIU Scan.
- A high RAIU suggests de novo hormone synthesis due to Graves' disease (diffusely increased uptake) or toxic nodular disease (nodular uptake).
- A low RAIU suggests either release of preformed thyroid hormone (ie, thyroiditis) or exogenous thyroid hormone intake.
- In such cases, the serum thyroglobulin level can make the distinction: elevated thyroglobulin is consistent with endogenous thyroid hormone release whereas decreased thyroglobulin suggests exogenous or factitious thyrotoxicosis.
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Evaluation of Thyrotoxicosis
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Primary hyperthyroidism
- It can result from:
- • Overproduction of thyroid hormone (eg, Graves disease, toxic nodular goiter)
- • Release of preformed hormone (eg, painless thyroiditis, subacute thyroiditis)
- These etiologies can be distinguished with radioactive iodine uptake (RAIU) scintigraphy, which will be increased in cases of hormone overproduction and low or undetectable in cases of release of preformed hormone.
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Painless thyroiditis
- It is associated with thyroid peroxidase autoantibodies and is considered a variant of chronic lymphocytic (Hashimoto) thyroiditis.
- It is similar to postpartum thyroiditis but by definition excludes patients within a year of pregnancy.
- Following a self-limited hyperthyroid phase, patients often develop a hypothyroid phase, which may persist or return to a euthyroid state.
- Painless thyroiditis does not require specific therapy. However, as hyperthyroidism causes adrenergic overstimulation, a beta blocker (eg, propranolol) may be prescribed to control symptoms, especially palpitations or tremulousness
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Central Hyperthyroidism
- Most TSH-secreting pituitary adenomas are macroadenomas.
- Patients with this condition typically have a goiter due to the effect of TSH on growth of he thyroid follicles. However, they do not have the extrathyroidal manifestations of Graves disease such as infiltrative ophthalmopathy or pretibial myxedema.
- Laboratory testing shows a high concentration of circulating thyroid hormone with an elevated or inappropriately normal TSH.
- Most TSH-secreting tumors are macroadenomas and can be associated with mass effect symptoms including headache, visual field defects, and impaired function of surrounding pituitary tissue.
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Clinical Features Of Graves Disease
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Graves ophthalmopathy.
- Proptosis , impaired extraocular motion (decreased convergence, diplopia), irritation (eg, gritty or sandy sensation), redness, photophobia, pain, and tearing. Risk factors: include female sex, advancing age, and smoking.
- In Graves disease, thyrotropin (TSH) receptor autoantibodies (TRAB) stimulate thyroid hormone production, resulting in hyperthyroidism.
- Thyroid hormone increases sensitivity to catecholamines, and thyrotoxicosis of any etiology may cause lid lag and retraction due to sympathetic activation and contraction of the superior tarsal muscle.
- However, true exophthalmos with impaired extraocular motion is seen only in Graves disease and is due to T cell activation and stimulation of orbital fibroblasts and adipocytes by TRAB, resulting in orbital tissue expansion and lymphocytic infiltration.
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Cardiovascular Effects Of Thyrotoxicosis
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Why Angina in Thyrotoxicosis?
- Increased oxygen demand in thyrotoxicosis is due to increased cardiac output and increased systemic oxygen consumption; this can lead to anginal symptoms in patients with underlying coronary atherosclerosis. Angina may also occur due to coronary vasospasm (especially in young female patients).
- Thyrotoxicosis may also cause newonset heart failure or decompensation of pre-existing heart failure.
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Why HTN in Thyroid Disorder?
- Systemic hypertension may be seen in both hyper- and hypothyroidism.
- Hyperthyroidism causes a decrease in systemic vascular resistance, but blood pressure (primarily systolic) rises due to positive inotropic and chronotropic effects.
- In contrast, hypothyroidism causes hypertension due to an increase in systemic vascular resistance.
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Mechanism of Thyroid Storm
- Proposed mechanisms include a rapid increase in blood thyroid hormone levels, increased cellular response to thyroid hormones, and an exaggerated response to catecholamines.
- Thyroid storm can lead to cardiac arrhythmias, congestive heart failure, seizures, hypotension, and shock.
- Diagnosis is based on clinical evaluation.
- Thyroid storm is usually seen in patients with undiagnosed or inadequately treated hyperthyroidism, as in this patient who is at risk for autoimmune thyroid disease (eg, Graves disease) in light of her type 1 diabetes.
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Hypomagnesemia and Hypocalcemia
- Hypomagnesemia is very common in hospitalized alcoholics and can cause hypocalcemia by inducing resistance to parathyroid hormone (PTH) as well as by decreasing PTH secretion.
- The cause of hypomagnesemia in alcoholics is multifactorial, and may include urinary losses, malnutrition, acute pancreatitis, and diarrhea.
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Treatment of Hypocalcemia due to Hypomagnesemia
- Hypocalcemia due to hypomagnesemia is typically refractory to treatment with calcium unless magnesium is replaced as well.
- Although PTH levels increase rapidly after magnesium replacement, hypocalcemia takes longer to improve because PTH resistance persists despite improvement in magnesium levels.
- Despite PTH deficiency, phosphorus levels are normal or low in magnesium deficiency; this is possibly due to intracellular phosphorus depletion.
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Acute hypocalcemia
- Causes:
- • Neck surgery (parathyroidectomy)
- • Pancreatitis
- • Sepsis
- • Tumor lysis syndrome
- • Acute alkalosis
- • Chelation: Blood (citrate) transfusion, EDTA, lactate, foscarnet
- Clinical features:
- • Muscle cramps
- • Chvostek & Trousseau signs
- • Paresthesias
- • Hyperreflexia/tetany
- • Seizures, encephalopathy, laryngospasm, Heart failure
- • Prolongation of QT interval
- Treatment:
- • IV calcium gluconate/chloride
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Causes of primary hypoparathyroidism include:
- 1. Post-surgical (most common cause)
- 2. Autoimmune
- 3. Congenital absence or maldevelopment of the parathyroid glands (eg, DiGeorge syndrome)
- 4. Defective calcium-sensing receptor on the parathyroid glands
- 5. Non-autoimmune destruction of the parathyroid gland due to infiltrative diseases such as hemochromatosis, Wilson disease, and neck irradiation
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Evaluation of Hypoglycemia
- Helpful tests used in the evaluation of hypoglycemic patients are measurements of c-peptide, proinsulin and sulfonylurea levels.
- Hypoglycemia secondary to insulinoma is associated with elevated insulin, c-peptide and proinsulin levels.
- Exogenous insulin-induced hypoglycemia is associated with very high serum insulin levels combined with low c-peptide levels
- Patients with sulfonylurea-induced hypoglycemia are sometimes difficult to differentiate from those with insulinoma because increased insulin and c-peptide levels are seen in both groups.Measure serum Sulphonylurea level in these patients
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Secondary hypogonadism
- Causes: mass lesions in the hypothalamus or pituitary, hyperprolactinemia (due to suppression of gonadotropin-releasing hormone), long-term use of glucocorticoids or opiates, or severe systemic illness.
- It is also more common in individuals with obesity or type 2 DM.
- Patients with secondary hypogonadism should have measurement of serum prolactin and other pituitary hormone deficiencies (eg, TSH).
- In men with prolactinoma, gynecomastia is present and galactorrhea is uncommon. Visual field defects are present only when the tumor impinges on the optic chiasm.
- Indications of MRI: patients with elevated prolactin, mass-effect symptoms (eg, visual field defects), very low (<150 ng/dl) testosterone levels, or disruptions in other pituitary hormones.
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Clinical features ot hypopituitarism
- Pituitary causes
- • Primary (eg, adenoma) or metastatic mass
- • Infiltration (eg, hemochromatosis, lymphocytic hypophysitis)
- • Hemorrhage (pituitary apoplexy) or infarction (Sheehan syndrome)
- Hypothalamic causes
- • Mass lesions
- • Radiation therapy
- • Infiltration (sarcoidosis)
- • Trauma to skull base
- • Infections (tuberculosis meningitis)
- Clinical Features
- ACTH deficiency (secondary adrenal insufficiency)
- • Postural hypotension, tachycardia, fatigue, weight loss, hypoglycemia, hyponatremia, eosinophilia
- Hypothyroidism (low or inappropriately normal TSH, low free T4)
- • Fatigue, cold intolerance, constipation, dry skin, bradycardia, slowed deep-tendon reflexes
- Gonadotropins(low/normal FSH and LH, low testosterone)
- • Women: Amenorrhea, infertility
- • Men: Infertility, loss of libido
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Clinical Features of Hypopituitarism
- Hyponatremia may be present due to an inappropriate increase in antidiuretic hormone or from cortisol deficiency.
- Hypoglycemia is commonly seen due to deficiencies of cortisol and growth hormone.
- Patients also typically have pale skin due to low ACTH and melanocyte-stimulating hormone levels.
- Testes are soft and small due to chronic gonadotropin deficiency
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Glucocorticoid Induced Adrenal Insufficiency
- Glucocorticoids suppress the secretion of corticotropin-releasing hormone from the hypothalamus and ACTH secretion from the pituitary.
- Suppression of adrenal function is likely to develop in patients receiving corticosteroids for a prolonged period
- Patients treated with corticosteroids for <3 weeks are less likely to develop HPA suppression.
- In addition, patients with a Cushingoid appearance are more likely to have a suppressed HPA axis. Normal HPA axis function after corticosteroid use may not fully recover for up to 6-12 months after discontinuation of the medication.
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Pituitary apoplexy
- refers to spontaneous hemorrhage into the pituitary gland, a potential complication of a pituitary adenoma.
- In addition to hypopituitarism (eg, ACTH deficiency), the sudden pituitary enlargement (due to bleeding) can compress the oculomotor nerves and cause acute headache, diplopia, and vision loss.
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Postpartum thyroiditis
- is an autoimmune-mediated destruction of the thyroid occurring within one year of delivery.
- It usually presents initially with hyperthyroidism symptoms (eg, fatigue, weight loss, palpitations, tremor) followed by hypothyroid symptoms (eg, cold intolerance, constipation, dry skin).
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Metabolic abnormalities in Hypothyroidism
- Hypothyroidism can cause metalbolic abnormalities such as hyperlipidemia, hyponatremia and asymptomatic elevations of creatinine kinase (usually less than 10 times normal) and serum transaminases
- Hypercholesteremia with high low-density lipoprotein (LDL) is due primarily to decreased surface LDL receptors (type 2a hyperlipidemia) and/or decreased LDL receptor activity.
- Hypothyroidism can also decrease lipoprotein lipase activity to cause hypertriglyceridemia.
- The lipid abnormalities may take months to resolve despite adequate treatment of hypothyroidism.
- Statins can increase the risk of myopathy in poorly controlled hypothyroidism and should be given with caution in these patients.
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Congenital Hypothyroidism
- Congenital hypothyroidism is associated with neurodevelopmental injury if not recognized and treated early
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Myopathy in Hypothyroidism
- Myopathy occurs in over one third of patients with hypothyroidism, and can range from an asymptomatic elevation in CK to myalgias, muscle hypertrophy, proximal myopathy, and rhabdomyolysis.
- Serum CK can be elevated for years before a patient develops clinical symptoms of hypothyroidism, and there is no clear correlation between the degree of CK elevation and severity of muscle disease.
- Inflammatory markers (eg, erythrocyte sedimentation rate, C-reactive protein) may be normal or mildly elevated.
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Causes of recurrent Pregnancy loss
- Antithyroid peroxidase (anti-TPO) antibodies are present in more than 90% of patients with Hashimoto thyroiditis, and high titers of anti-TPO are associated with an increased risk of progression to overt hypothyroidism.
- High titers of anti-TPO are also associated with increased risk of miscarriage in both euthyroid and hypothyroid women.
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Euthyroid Sick Syndrome
- ESS encompasses a variety of alterations in thyroid physiology, the most common of which is termed "low T3 syndrome" and is thought to be the result of decreased conversion of T4 to T3.
- Factors in acute illness that inhibit peripheral deiodination include high endogenous cortisol levels, inflammatory cytokines (eg, tumor necrosis factor), starvation, and certain medications (eg, glucocorticoids, amiodarone ).
- TSH and T4 levels are often normal in ESS, although they also may fall in severe or prolonged cases; thus, ESS may represent a transient central hypothyroidism rather than a true euthyroid state
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Metabolic Syndrome
- Insulin resistance is associated with several other systemic effects (e.g., dyslipidemia, endothelial dysfunction, procoagulable state, increased sympathetic activity, increased markers of inflammation, decreased uric acid excretion, increased sodium absorption, disordered breathing and increased testosterone production from the ovaries
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Multiple Endocrine Neoplasia
- MEN2A and MEN2B are caused by gain of function of mutations involving the RET proto-oncogene on chromosome 10.
- Patients with Medullary Thyroid Cancer should be tested for RET mutations and pheochromocytoma with a plasma fractionated metanephrine assay.
- Pheochromocytoma can cause severe hypertensive crisis during surgical resection of the thyroid mass. If found, pheochromocytoma should be resected prior to thyroidectomy.
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Ehlers-Danlos syndrome and Marfan Syndrome
- is characterized by joint hypermobility with recurrent joint dislocations, easy bruisability, and poor wound healing leading to wide scars.
- Marfan syndrome is characterized by tall stature with disproportionately long extremities, joint hypermobility, and skeletal abnormalities (eg, kyphoscoliosis, pectus carinatum).
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Diabetic Foot Ulcer
- Risk factors
- • Diabetic neuropathy (loss of protective sensation, small muscle atrophy, abnormal vascular tone, decreased sweating with fissures)
- • Arterial insufficiency
- • End-stage renal disease in a patient on dialysis
- • Smoking
- Location
- • Plantar surface, areas under pressure points (eg, bony prominences)
- Management
- • Mechanical offloading
- • Debridement
- • Wound dressings
- • Antibiotics if infection
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Arterial and venous ulcers
- Arterial ulcer include location at the tips of the digits, diminished pulses, skin pallor, loss of hair, and intermittent claudication
- Venous ulcers typically occur on the medial aspect of the leg above the malleolus; they are usually associated with edema and stasis dermatitis.
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Pheochromocytoma
- Paroxysms of severe hypertension can be precipitated by increases in intra-abdominal pressure (eg, tumor palpation, positional changes), surgical procedures, and a number of medications, particularly anesthetic agents.
- In addition, nonselective beta blockers can cause a state of unopposed alpha adrenergic stimulation leading to vasoconstriction and paradoxical hypertension.
- For this reason, alpha adrenergic blockers (eg, phenoxybenzamine) should be administered prior to beta blockers in patients with pheochromocytoma.
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Polycystic Ovarian Syndrome
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Mechanism of OCPs in PCOS
- Combined oral contraceptives contain progesterone to stimulate endometrial differentiation and estrogen to stabilize the uterine lining, which restores normal cycles.
- In addition, combined oral contraceptives reduce hirsutism by blocking adrenal androgen secretion and increasing production of sex hormone-binding globulin, which binds and decreases free testosterone.
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Management of Prolactinoma in Premenopausal women
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Prolactinoma
- Significant elevations in the prolactin level (eg, serum prolactin level >200 ng/ml or repeat level >100 ng/ml ) suggest a prolactin-secreting tumor (prolactinoma).
- Elevated prolactin levels suppress gonadotropin-releasing hormone, LH, and estradiol, leading to oligo-amenorrhea in premenopausal females.
- Men and postmenopausal women often have minimal early symptoms and are more likely to seek evaluation when a large tumor (>1 cm, macroadenoma) causes mass-effect symptoms (eg, headache, visual field defects).
- Patients with macroprolactinomas or symptomatic tumors of any size should be treated with dopaminergic agonists (eg, cabergoline, bromocriptine), which can normalize prolactin levels and reduce tumor size.
- Patients who fail to respond or who have very large tumors (>3 cm) should be referred for transsphenoidal resection
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Papillary carcinoma thyroid
- Surgical resection is the primary treatment for papillary thyroid cancer.
- Small tumors (less than 1-2 cm) without evidence of lymph node involvement or contralateral thyroid abnormalities can usually be managed with partial thyroidectomy/lobectomy
- Larger tumors usually warrant total thyroidectomy.
- Regional lymph node or central compartment lymph node dissection is usually performed for papillary cancer with lymph node metastasis or extrathyroidal invasion.
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Indication of Radioactive ablation in Papillary Cancer
- Following surgery, adjuvant therapy with radioiodine ablation is warranted for patients with increased risk of tumor recurrence (eg, large tumors, extrathyroidal invasion, lymph node metastasis, incomplete resection)
- TSH can stimulate growth of occult residual or metastatic disease. For this reason, patients at increased risk of recurrence should also receive adequate doses of thyroid replacement to suppress TSH secretion.
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Evaluation of thyroid nodule
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Follicular Carcinoma of Thyroid
- It is the second most common thyroid epithelial malignancy
- Peak incidence at age 40-60.
- It presents with a firm thyroid nodule and is often discovered incidentally on examination or imaging for other purposes.
- Thyroid scintigraphy usually shows a nonmetabolically active ("cold") nodule.
- Diagnosis of FTC based on a limited tissue sample (eg, fine-needle biopsy) is not possible as the cytologic findings (large numbers of follicular cells arranged in microfollicles, clusters, and clumps, often categorized as "follicular neoplasm") are similar in both FTC and benign follicular adenomas.
- However, in contrast to benign adenomas, FTC is characterized by invasion of the tumor capsule and/or blood vessels, a finding that is typically made on examination of a surgically excised nodule.
- It has hematogenous spread to distant tissues ( eg, bone, lung).
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