Thyroid Hormones - Endocrinology Slides PDF

Thyroid Hormones Jason Ryan, MD, MPH Thyroid Hormones Produced by the thyroid gland Triiodothyronine (T3) and thyroxine (T4) Tyrosine Both synthesized from tyrosine and iodine Triiodothyronine (T3) Thyroxine (T4) Thyroid Hormones Contain the el...

Thyroid Hormones Jason Ryan, MD, MPH Thyroid Hormones Produced by the thyroid gland Triiodothyronine (T3) and thyroxine (T4) Tyrosine Both synthesized from tyrosine and iodine Triiodothyronine (T3) Thyroxine (T4) Thyroid Hormones Contain the element iodine Iodized salt Table salt (NaCl) mixed with small minute amount of iodine Done in many countries to prevent iodine deficiency Added to salt in US in 1924 For thyroid hormone, iodine in our diet needs to be: Oxidized to I2 (“oxidation”) Added to organic/carbon structures (“organification”) TPO Thyroid Peroxidase Multifunctional enzyme Catalyzes several steps in thyroid hormone synthesis Oxidation of iodine Organification of iodine into MIT/DIT Coupling of MIT/DIT into T3/T4 TPO antibodies common in autoimmune thyroid disease Thyroid Peroxidase TPO Monoiodotyrosine (MIT) Tyrosine Triiodothyronine (T3) TPO TPO + Iodine (I2) TPO I- I- Diiodotyrosine (DIT) Thyroxine (T4) Thyroglobulin Protein produced by thyroid follicular cells Contains numerous tyrosine molecules Tyrosine → MIT/DIT → T3/T4 Thyroglobulin antibodies in autoimmune thyroid disease Tyrosine Tyrosine Tyrosine Tyrosine Tyrosine Thyroglobulin Thyroid Hormones Thyroxine (T4) is major hormone produced by thyroid gland Over 90% of thyroid hormone produced is T4 Triiodothyronine (T3) more potent hormone 5’ deiodinase converts T4 → T3 Most conversion occurs in peripheral tissues Iodine 5’-deiodinase Thyroxine (T4) Triiodothyronine (T3) Wolff-Chaikoff Effect Excessive iodine in diet could lead to hyperthyroidism Thyroid protects itself via Wolff-Chaikoff Effect Iodine inhibits synthesis of thyroid hormone Organification inhibited by ↑ iodine Less synthesis of MIT/DIT Normal patients “escape” with time Wolff-Chaikoff Effect “Failure to escape” Iodine → prolonged ↓ hormone → hypothyroidism Occurs in amiodarone-induced hypothyroidism May also occur in autoimmune thyroid disease Jod-Basedow phenomenon Lack of Wolff-Chaikoff effect Excess iodine → hyperthyroidism Occurs in patients with toxic adenomas Thyroid Hormone Regulation Hypothalamus releases thyroid releasing hormone (TRH) Anterior pituitary releases thyrotropin (TSH) Thyroid gland releases T3 and T4 Feedback on pituitary and hypothalamus Shutterstock TBG Thyroxine-Binding Globulin Thyroid hormones poorly soluble in water Circulates bound to TBG (produced in liver) Most plasma thyroid hormone is T4 Almost all T4 is bound to TBG Bound T4 does not exert hormone effects Small amount of “free T4” produces hormone effects Thyroid Panel Four standard measurements to assess thyroid Test Normal Value TSH 0.5 to 5.0 mU/L Total T4 60 to 145 nmol/L Total T3 1.1 to 3 nmol/L Free T4 0.01-0.03nmol/L Note: T4 > T3 Total T4 >> Free T4 (most bound to TBG) TBG Thyroxine-Binding Globulin Increased production due to estrogen Occurs in pregnancy Contraceptives or hormone replacement Raise total T4 TSH and free T4 will be normal Classic findings high estrogen states Elevated total T4 Normal TSH and free T4 Does not indicate thyroid disease Thyroid Hormones Pregnancy Rise in TBG levels (estrogen) Rise in total T4 level hCG stimulates thyroid (same alpha unit as TSH) Raises free T4 → lower TSH Thyroid Hormone Effects Major regulator of metabolic activity and growth Glucose and lipid metabolism Cardiac function Bone growth CNS development Thyroid Hormone Metabolic Effects ↑ carbohydrate metabolism ↑ glycogenolysis, gluconeogenesis ↑ serum glucose ↑ lipid metabolism ↓ concentrations of cholesterol, triglycerides Hypothyroid patients: ↑ cholesterol Check TSH in hyperlipidemic patients Hyperthyroid patients: hyperglycemia Cholesterol Thyroid Hormone Metabolic Effects ↑ basal metabolic rate Basal rate of energy use per time Amount of energy burned if you slept all day ↑ Na/K ATPase pumps More pumps = more ATP consumed ↑ oxygen demand to replenish ATP ↑ respiratory rate ↑ body temperature Hypothyroid patients: weight gain Hyperthyroid patients: weight loss Wikipedia/Public Domain McDonough AA, et al. Thyroid hormone coordinately regulates Na+-K+-ATPase alpha- and beta-subunit mRNA levels in kidney. Am J Physiol. 1988 Feb;254(2 Pt 1):C323-9. Thyroid Hormone Cardiac Effects ↑ β1 receptors in heart ↑ cardiac output and heart rate Hypothyroid patients: bradycardia Hyperthyroid patients: tachycardia or arrhythmias Tachycardia Thyroid Hormone Bone effects Thyroid hormones increase bone turnover Stimulates bone resorption Hyperthyroidism: osteoporosis and hypercalcemia Wikipedia/Public Domain Thyroid Hormone CNS and Bone Development TH required for normal bone growth/CNS maturation Childhood hypothyroidism → cretinism Stunted growth Intellectual disability Large tongue Umbilical hernia Causes Iodine deficiency Congenital thyroid disease Wellcome Images/Wikipedia Hypothyroidism Jason Ryan, MD, MPH Hypothyroidism Underproduction of thyroid hormone by thyroid gland Metabolism SLOWS DOWN Highly variable clinical features Symptoms can be subtle Some patients have minimal symptoms Pixabay.com Hypothyroidism Clinical Features Lethargy and fatigue Weakness Cold intolerance Weight gain with loss of appetite Constipation Hyporeflexia Dry, cool skin Sinus Bradycardia Coarse, brittle hair Bradycardia Hypothyroidism Clinical Features Hyperlipidemia ↑ total cholesterol ↑ LDL cholesterol TSH often checked in hyperlipidemia Myopathy Muscle symptoms common in hypothyroid Weakness, cramps, myalgias ↑ serum creatine kinase (CK) common (up to 90%) Hyponatremia High levels of ADH (SIADH) Wikipedia/Public Domain Hypothyroidism Clinical Features Infertility Associated with increased prolactin Low FSH/LH Disruption of menstrual cycle Low sperm count Cognitive impairment Depression Hypertension Causes aortic stiffness Shutterstock Myxedema Thyroid dermopathy Non-pitting edema of the skin from hypothyroidism Hyaluronic acid deposits in dermis Draws water out → swelling Usually facial/periorbital swelling Pretibial myxedema Special form of myxedema over shin Seen in Grave’s disease (hyperthyroidism) Myxedema coma = coma from hypothyroidism Herbert L. Fred, MD and Hendrik A. van Dijk Hypothyroidism Subtypes Primary hypothyroidism Most common form Failure of thyroid gland function due to disease or iodine deficiency TSH will be high Central hypothyroidism: rare Failure of pituitary gland or hypothalamus Same causes as hypopituitarism Usually occurs with deficiency of other pituitary hormones Workup usually involves MRI of brain TSH will be low or inappropriately normal Shutterstock Hypothyroidism Lab Findings Test Normal Value Primary Central TSH 0.5 to 5.0 mU/L HIGH LOW or NL Total T4 60 to 145 nmol/L Low Low Total T3 1.1 to 3 nmol/L Low Low Free T4 0.01-0.03nmol/L Low Low Goiter Enlarged thyroid Mild forms detected on physical exam Normal thyroid = 15 to 25 grams Caused by excess stimulation of thyroid gland Primary hypothyroidism High TSH, inability to produce T3/T4 Hyperthyroidism due to Grave’s disease Thyroid stimulating antibodies Wikipedia/Public Domain Subclinical Hypothyroidism Normal free T4 Increased TSH Generally asymptomatic Often identified on routine lab work Same causes as overt hypothyroidism Treated only if TSH > 10 mU/L High risk of and progression to symptoms Also risk of atherosclerosis and myocardial infarction Thyroid Function in Illness Euthyroid Sick Syndrome Thyroid hormone levels often abnormal in critically-ill patients Related to underlying illness with no treatment required Levels only checked if strong suspicion of thyroid disease Low T3: low conversion T4 → T3 (cortisol, cytokines) May also see low TSH → Low T3/T4 Early: low T3; low-normal TSH and T4 Late: Low TSH, T3 and T4 Shutterstock Thyroid Function in Illness Euthyroid Sick Syndrome Key test: reverse T3 (rT3) Isomer of T3 Level rises in critical illness due to impaired clearance Critically ill patient with low TSH/T4/T3 Check rT3 Low → central hypothyroidism High → sick euthyroid syndrome (no treatment) Primary Hypothyroidism Causes, demographics and workup Most common cause worldwide: iodine deficiency Rare in US due to iodized salt Most common cause US: autoimmune thyroiditis Prevalence increases with age More common in women Diagnosis by lab testing (TSH, T3, T4) Additional testing usually not performed Antibody testing or nuclear scans only used in select cases Primary Hypothyroidism Treatment Levothyroxine Synthetic T4 Check TSH in 6 weeks Titrate dose to normal TSH (0.5 to 5.0 mU/L) Treat all symptomatic patients Subclinical patients: TSH concentrations >10 mU/L Primary Hypothyroidism Treatment Higher dosages required with higher TBG levels Occurs in high estrogen states Pregnancy Hormone replacement therapy Øyvind Holmstad/Wikipedia Myxedema Coma Severe hypothyroidism Altered mental status, hypothermia and organ dysfunction Hypoventilation, bradycardia Hyponatremia May be due to severe, longstanding hypothyroidism Or caused by an acute event in poorly-controlled hypothyroidism Infection, myocardial infarction, surgery Administration of sedatives (e.g., opioids) Myxedema Coma Diagnosis and Treatment Diagnosis: TSH and thyroid hormone levels Intravenous combined therapy: T4 (levothyroxine) and T3 (liothyronine) Stress-dose glucocorticoids Often IV hydrocortisone 100 mg every eight hours Mechanical ventilation Intravenous fluids Hydrocortisone Primary Hypothyroidism Causes Chronic lymphocytic thyroiditis Other forms of thyroiditis Iodine deficiency Drugs Thyroiditis Thyroid gland inflammation Painful when caused by infection, radiation or trauma Painless when caused by autoimmune disease or medications May initially cause hyperthyroidism → hypothyroidism Most common form: chronic lymphocytic thyroiditis Chronic Lymphocytic Thyroiditis Hashimoto’s Thyroiditis Most common cause of hypothyroidism in the US Infiltration of thyroid gland by lymphocytes Lymphocyte Autoimmune disorder HLA-DR3, HLA-DR5 and others Antibodies produced Anti-TPO Anti-thyroglobulin Not required to begin treatment Can be used to confirm the diagnosis Chronic Lymphocytic Thyroiditis Hashimoto’s Thyroiditis Primarily occurs in older women Enlarged non-tender thyroid gland Gradual loss of thyroid function → symptoms Symptoms and labs consistent with hypothyroidism Treatment: thyroid hormone replacement Increased risk of non-Hodgkin B cell lymphoma Dr. Ryan’s Grandmother Subacute Thyroiditis de Quervain’s Thyroiditis/Granulomatous Thyroiditis Post-viral inflammation of thyroid Most common cause of thyroid pain Occurs in young women Tender, enlarged thyroid gland Variable lab findings Hyperthyroid → euthyroid → hypothyroid Thyroid symptoms usually mild (no treatment) Elevated ESR and CRP Shutterstock Subacute Thyroiditis de Quervain’s Thyroiditis/Granulomatous Thyroiditis Radioactive Iodine Uptake Scan Clinical diagnosis Neck pain with tender, enlarged thyroid Low thyroid radioiodine uptake Usually less than 1 to 3 percent Inflammation interferes with uptake Treatment: Anti-inflammatories (aspirin, NSAIDs, steroids) Usually resolves in few weeks Subacute Lymphocytic Thyroiditis Painless Thyroiditis Variant of Hashimoto’s Lymphocytic infiltration of thyroid gland Transient mild hyperthyroidism Resembles Grave’s disease without eye/skin findings Serum thyroid stimulating immunoglobulins not elevated Radioiodine uptake low when hyperthyroid Contrast with Grave’s disease: upper normal or high Rarely can be followed by hypothyroidism Usually self-limited – resolves over weeks Postpartum Thyroiditis Similar to painless thyroiditis By definition occurs within one year after pregnancy Delivery of baby or after spontaneous/induced abortion Self-limited PxHere.com Fibrous Thyroiditis Riedel’s Thyroiditis Fibroblast activation and proliferation Fibrous tissue (collagen) deposition in thyroid “Rock hard” thyroid Often extends beyond the thyroid Parathyroid glands → hypoparathyroidism Recurrent laryngeal nerves → hoarseness Trachea compression → difficulty breathing Shutterstock Fibrous Thyroiditis Riedel’s Thyroiditis Associated with IgG4 plasma cells IgG4 plasma cells identified in biopsy specimens Diagnosis: biopsy Treatment: thyroid hormone replacement Surgery often required to relieve thoracic compression Plasma Cell Infiltrative Thyroid Disease Amyloidosis Fibrous thyroiditis Amyloidosis Sarcoidosis Hereditary hemochromatosis Ed Uthman, MD Iodine Deficiency Constant elevation of TSH → enlarged thyroid “Endemic goiter” Goiter in regions with widespread iodine deficiency Wellcome Images Goitrogens Substances that inhibit thyroid hormone production Lithium (inhibits release of thyroid hormone) Amiodarone Amiodarone Antiarrhythmic drug May cause hypothyroidism Excess iodine → Wolff-Chaikoff Effect Normal patients “escape” in few weeks Pre-existing subclinical thyroid disease → “failure to escape” Also inhibits conversion of T4 → T3 May also cause hyperthyroidism Increased iodine → increase hormone synthesis May also cause thyroiditis → hyperthyroidism Must check TSH prior to starting therapy Amiodarone Iatrogenic Hypothyroidism Thyroid surgery Treatment for Grave’s or malignancy Radioiodine therapy I131 administered orally as solution or capsule Beta-emissions → tissue damage Ablation of thyroid function over weeks Treatment for Grave’s or malignancy Neck radiation Hodgkin’s lymphoma Head and neck cancer Public Domain Hyperthyroidism Jason Ryan, MD, MPH Hyperthyroidism Overproduction of thyroid hormone by thyroid gland Metabolism SPEEDS UP Hyperactivity Heat intolerance Weight loss with increased appetite Diarrhea Hyperreflexia Warm, moist skin Fine hair Tachycardia (atrial fibrillation) Shutterstock Hyperthyroidism Subtypes Primary hyperthyroidism Most common form Overactivity of thyroid gland not due to high TSH Low TSH with high T3/T4 Central hyperthyroidism: rare Excess TSH from pituitary gland High TSH and high T3/T4 Neoplastic: pituitary tumor (TSHoma) Non-neoplastic: pituitary resistance to thyroid hormone Shutterstock Hyperthyroidism Lab Findings Test Normal Value Primary Central TSH 0.5 to 5.0 mU/L LOW NL or HIGH Total T4 60 to 145 nmol/L High High Total T3 1.1 to 3 nmol/L High High Free T4 0.01-0.03nmol/L High High Primary Hyperthyroidism Causes Grave’s disease (most common) Multinodular goiter Toxic adenoma Iodine-induced Amiodarone Thyroiditis Levothyroxine Grave’s Disease Autoimmune disease Thyroid stimulating antibodies produced Symptoms of hyperthyroidism occur Large non-nodular thyroid Shutterstock Grave’s Disease Special features Exophthalmos (bulging eyes) Proptosis (protrusion of eye) and periorbital edema Retroocular fibroblast and adipocyte activation Pretibial myxedema (shins) Fibroblasts contain TSH receptor Stimulation → secretion of glycosaminoglycans Draws in water → swelling Herbert L. Fred, MD and Hendrik A. van Dijk Jonathan Trobe, M.D./Wikipedia Grave’s Disease Diagnosis Often clinical: hyperthyroid symptoms and labs, goiter plus exophthalmos TSH receptor antibodies Radioactive Iodine Uptake Scan Thyrotropin receptor antibodies (TRAb) Also called TSIs: “Thyroid stimulating immunoglobulins” Radioactive iodine uptake Increased due to overactive thyroid Grave’s Disease Treatment Symptom control: beta blockers Used for initial treatment of symptoms Improves tachycardia Usually atenolol – once daily dosing Decrease thyroid hormone synthesis Thionamides Radioiodine thyroid ablation Surgery Public Domain Thionamides Inhibit production of thyroid hormone Used initially to improve moderate to severe symptoms Methimazole Most commonly used drug Once daily dosing - usually well tolerated Propylthiouracil Main use is 1st trimester of pregnancy Lower risk of adverse fetal effects Also used in thyroid storm Public Domain Thionamides Agranulocytosis Adverse Effects Agranulocytosis Rare drop in WBC May present as fever, infection after starting drug WBC improves with stopping drug Aplastic anemia cases reported Hepatotoxicity Baseline testing: CBC and LFTs Monitoring WBC: controversial Not recommended by American Thyroid Association guidelines Most clinicians advise patients to report any signs of infection Signs of infection → stop drug → check CBC Grave’s Disease Treatment Radioiodine ablation Usually given as oral capsule Concentrated in thyroid → ablation Requires lifelong replacement therapy Associated with increase in TRAb May lead to worsening orbitopathy Surgery (thyroidectomy) May cause hypoparathyroidism May cause recurrent laryngeal nerve damage Associated with a fall in TRAb Does not worsen orbitopathy Shutterstock Thyroidectomy Post-operative hypocalcemia Common complications of thyroidectomy Paresthesias of lips, mouth, hands and feet Muscle twitches or cramps Rarely trismus (lockjaw) or tetany Reduced serum calcium Treatment: IV calcium gluconate Grave’s Orbitopathy Can cause irritation, excessive tearing or eye pain Symptoms often worsened by cold air, wind or bright lights Immune-mediated process Mainstay of treatment when severe: glucocorticoids Other immunosuppressants may be used Also treated with radiation or surgery Jonathan Trobe, M.D./Wikipedia Toxic Adenomas Multinodular Goiter Thyroid nodules Function independently Usually contain mutated TSH receptor No response to TSH One nodule: toxic adenoma Multiple: toxic multinodular goiter Findings: Palpable nodule(s) or nodular goiter Hyperthyroidism symptoms/labs Increased uptake of radioiodine in nodule(s) Public Domain Toxic Adenomas Treatment Initial symptom control: beta blockers and thionamides Preferred therapy for most patients: radioiodine ablation Accumulates in hyperfunctioning nodules Underactive surrounding tissue not affected Patient may become euthryoid and avoid thyroid replacement Surgery in select patients Large, obstructive goiters Coexisting thyroid malignancy Shutterstock Iodine-Induced Hyperthyroidism Jod-Basedow Phenomenon Wolff-Chaikoff effect: excess iodine → decreased hormone production Some patients “escape” the Wolff-Chaikoff effect Called the Jod-Basedow Phenomenon Excess iodine → hyperthyroidism Iodine-Induced Hyperthyroidism Jod-Basedow Phenomenon Often occurs in regions of iodine deficiency Introduction of iodine → hyperthyroidism Often occurs in patients with toxic adenomas Drugs administered with high iodine content Expectorants (potassium iodide), CT contrast dye Amiodarone Amiodarone Hyperthyroidism Type I Occurs in patients with pre-existing thyroid disease Grave’s or Multi-nodular goiter Amiodarone provides iodine → excess hormone production Increased radioiodine uptake Type II Amiodarone Destructive thyroiditis Excess release T4/ T3 (no ↑ hormone synthesis) Direct toxic effect of drug Can occur in patients without pre-existing thyroid illness Decreased radioiodine uptake Amiodarone Hyperthyroidism Management Stop amiodarone if possible Radioiodine uptake test to distinguish type I from type II Type I: beta blockers, thionamides, ablation or surgery Type II (thyroiditis): glucocorticoids Amiodarone Hyperthyroidism Other Causes Early thyroiditis Low radioiodine uptake High serum thyroglobulin concentration Exogenous hyperthyroidism Excess levothyroxine Supplements with thyroid hormone Low radioiodine uptake Low serum thyroglobulin concentration Hyperthyroidism Workup Thyroid Storm Life-threatening hyperthyroidism Usually precipitated by acute event Patient with pre-existing hyperthyroid disease Grave’s or toxic multinodular goiter Surgery, trauma, infection Massive catecholamine surge Acute increase in thyroid hormone levels Pixabay.com Thyroid Storm Clinical Features Fever (up to 106⁰F) Delirium Tachycardia with possible death from arrhythmia Warm skin Tremor Hyperglycemia (catecholamines/thyroid hormone) Hypercalcemia (bone turnover) Diagnosis: increased free T4 and T3; low TSH Thyroid Storm Iodine Treatment Propranolol Beta blocker → improves symptoms Also blocks T4 → T3 conversion Thyroxine (T4) Propylthiouracil Preferred over methimazole Decreases T4 → T3 conversion 5’-deiodinase Peripheral Tissues Glucocorticoids Decreases T4 → T3 conversion Reduces inflammation if Graves' disease present Triiodothyronine (T3) – More Potent Thyroid Storm Treatment Iodine Potassium iodide-iodine (Lugol’s) solution Blocks release of T4 and T3 from thyroid gland ICU level care Public Domain Thyroid Nodules Jason Ryan, MD, MPH Thyroid Nodules Identified by patients or detected on physical exam by clinician Incidental finding on imaging Carotid ultrasound Neck or chest CT May have benign cause Cyst, adenoma Major clinical concern: thyroid cancer Cause of about 5 to 10% nodules Shutterstock Thyroid Nodules Workup TSH Thyroid ultrasound Radioactive iodine uptake scan Fine needle aspiration Thyroid Nodules TSH Measurement Low TSH Overt or subclinical hyperthyroidism Suggests hyperfunctioning nodule Also T3/T4 measurement for hyperthyroidism Risk of malignancy low Normal or high TSH Possibly malignant nodule Higher TSH = higher likelihood cancer Thyroid Nodules Radioactive iodine scan Hyperfunctioning (“hot”) nodule Greater uptake than surrounding tissue Evaluate for hyperthyroidism Risk of malignancy low FNA not required Normal Nonfunctioning (“cold”) nodule Less uptake than surrounding tissue Follow-up testing with ultrasound May require FNA Cold Nodule Hot Nodule Thyroid Nodules Thyroid Ultrasound Purely cystic lesions are almost always benign Suspicious lesions followed by FNA Large nodules (≥ 2 cm) Micro calcifications Irregular margins Extrathyroidal invasion Public Domain Thyroid Nodules Workup Thyroid Nodules Fine Needle Aspiration Usually performed under US guidance Six categories of results based on Bethesda classification system Class Description Follow-up I Non-diagnostic Repeat FNA II Benign Reassurance and periodic US follow-up III Atypia of undetermined significance Variable IV Suspicious for follicular neoplasm Variable V Suspicious for malignancy Surgery VI Malignant Surgery Thyroid Cancer Papillary Follicular Medullary Anaplastic Lymphoma Papillary Carcinoma Most common form thyroid cancer (~ 80%) Increased risk with prior radiation exposure Childhood chest radiation for mediastinal malignancy Papillary Carcinoma Survivors of atomic bomb detonation (Japan) Nuclear power plant accidents (Chernobyl) Median age at diagnosis is 51 years Presents as thyroid nodule Sometimes identified on imaging (CT/MRI) Diagnosis made after fine needle aspiration (FNA) KGH/Wikipedia Papillary Carcinoma Excellent prognosis Treated with surgery Total thyroidectomy or lobectomy Based on size and degree of spread Post-operative T4 (levothyroxine) Prevent hypothyroidism Prevent TSH rise → cancer growth Radioactive iodine ablation Based on patient risk category Ablate residual normal thyroid tissue Eliminate metastatic cells Public Domain Follicular Carcinoma Malignancy of follicular epithelial cells Similar to follicular adenoma Breaks through (“invades”) fibrous capsule FNA cannot distinguish between adenomas/cancer Follicular Carcinoma Many similarities with papillary carcinoma Similar age and risk factors Treatment similar to papillary carcinoma Thyroidectomy Radioiodine ablation of remaining tissue or metastasis Nephron/Wikipedia Medullary Carcinoma Cancer of parafollicular cells (C cells) Produces calcitonin Medullary Carcinoma Lowers serum calcium Normally minimal effect on calcium levels Used for monitoring Amyloid protein deposits in thyroid Treatment: total thyroidectomy Most patients have bilateral disease Serial calcitonin monitoring Nephron/Wikipedia MEN Syndromes Multiple Endocrine Neoplasia Gene mutations that run in families Cause multiple endocrine tumors MEN 2A and 2B associated with medullary carcinoma Caused by RET oncogene mutation Some patients have elective thyroidectomy Sometimes at a young age Mikael Häggström Anaplastic Carcinoma Undifferentiated Carcinoma Occurs in elderly Highly malignant - invades local tissues Dysphagia (esophagus) Hoarseness (recurrent laryngeal nerve) Dyspnea (trachea) Don’t confuse with Riedel’s (“rock hard” thyroid/young pt) Poor prognosis Treatment: surgery (local disease only), chemotherapy and radiation Primary Thyroid Lymphoma Rare B-cell lymphoma arising in thyroid gland Associated with chronic lymphocytic thyroiditis (Hashimoto’s) Shutterstock Hyperaldosteronism Jason Ryan, MD, MPH Primary Hyperaldosteronism Excessive levels of aldosterone secretion Not due to increased activity of RAAS Adrenal adenoma (Conn’s syndrome) Bilateral idiopathic adrenal hyperplasia Rarely adrenal carcinoma (~1%) Wikipedia /Public Domain Primary Hyperaldosteronism ↑ Na reabsorption distal nephron ↑ circulating volume → hypertension ↑ K excretion → hypokalemia ↑ H+ excretion → metabolic alkalosis High serum bicarbonate Acid (H+) Potassium (K+) BLOOD URINE Sodium (Na+) Aldosterone Escape Excess aldosterone does not lead to volume overload Usually no pitting edema, rales, increased JVP Na and water retention → hypertension Compensatory mechanisms activated Increased ANP Increased sodium and free water excretion Result: diuresis → normal volume status Pixabay Primary Hyperaldosteronism Clinical Features Resistant hypertension Possible hypokalemia Inconsistent finding Less than 30% in some studies Normal volume status on physical exam Shutterstock Primary Hyperaldosteronism Diagnosis Renin-independent aldosterone secretion Plasma renin activity (PRA) Low in primary hyperaldosteronism Usually than 1 ng/mL per hour Plasma aldosterone concentration (PAC) High in primary hyperaldosteronism Greater than 15 ng/dL Ratio of PAC:PRA Greater than 20 suggest primary hyperaldosteronism Primary Hyperaldosteronism Confirmatory Testing Demonstration of inappropriate aldosterone secretion Oral sodium load or sodium infusion Should suppress aldosterone release Measure urinary aldosterone excretion or plasma aldosterone concentration Increased aldosterone after sodium load = positive test Primary Hyperaldosteronism Determination of cause Abdominal CT scan Adrenal mass Bilateral adrenal enlargement Adrenal vein sampling Interventional radiology procedure Separate blood sample from each vein Measurement of aldosterone in samples Distinguishes unilateral from bilateral disease Metastatic adenocarcinoma within a functioning adrenal adenoma: A case report - Scientific Figure on ResearchGate. https://www.researchgate.net/figure/Abdominal-CT-scan-arrow-depicts-right-adrenal-mass_fig5_38012436 [accessed 21 Jan, 2021] Primary Hyperaldosteronism Treatment Unilateral disease: surgical adrenalectomy Bilateral disease: medical therapy Drugs of choice: spironolactone/eplerenone Aldosterone antagonists Spironolactone ACE inhibitors and ARBs: no effect AII levels already very low (↓ RAAS activity) Aldosterone release not dependent on AII stimulation Eplerenone SAME Syndrome of Apparent Mineralocorticoid Excess Cortisol binds to renal aldosterone receptors Cortisol → cortisone by renal cells Enzyme: 11-β-hydroxysteroid dehydrogenase SAME: deficiency 11-β-hydroxysteroid dehydrogenase Cortisol produces aldosterone effects 11-β-hydroxysteroid Cortisol dehydrogenase Cortisone SAME Syndrome of Apparent Mineralocorticoid Excess Presents in children/adolescents Similar clinical syndrome to hyperaldosteronism Hypertension Hypokalemia Metabolic alkalosis Low plasma renin activity Low plasma aldosterone levels Treatment: potassium-sparing diuretics Amiloride, spironolactone Inhibit mineralocorticoid effects Licorice Contains glycyrrhetinic acid (a steroid) Weak mineralocorticoid effect Inhibits renal 11-beta-hydroxysteroid dehydrogenase Large amounts may cause disease Hypertension, hypokalemia, metabolic alkalosis Low plasma renin activity Low plasma aldosterone levels Pikaluk/Flikr Secondary Hyperaldosteronism Hyperreninemic hyperaldosteronism Elevated plasma renin activity Limited renal perfusion Renal artery stenosis Heart failure Cirrhosis Renin-secreting tumor (rare) Public Domain Cushing’s Syndrome Jason Ryan, MD, MPH Cushing’s Syndrome Hypercortisolism Clinical syndrome of excess effects of cortisol Cortisol: steroid hormone “Glucocorticoid:” raises serum glucose Synthesized by adrenal glands Cortisol Wikipedia /Public Domain Pituitary-Adrenal Axis Controls cortisol secretion Hypothalamus: CRH Corticotropin releasing hormone Acts of pituitary gland Anterior pituitary: ACTH Adrenocorticotropic hormone Acts on adrenal gland Adrenal: cortisol Drosenbach/Wikipedia Excess Cortisol Major Effects Immunosuppression Hyperglycemia Hypertension Fat deposition Muscle, bone and skin changes Reproductive effects Cortisol Cortisol Immunosuppressive Effects Reduces T and B cell levels in plasma Sequesters lymphocytes in spleen/nodes Neutrophils Impairs neutrophils Blocks neutrophil migration Increases peripheral neutrophil count Raises the white blood cell count Mast cells: blocks histamine release Reduces eosinophil counts Basis for corticosteroids as immunosuppressive therapy Dr Graham Beards/Wikipedia Corticosteroid Drugs “Steroids” or “Glucocorticoids” Cortisol Dexamethasone Prednisone Cortisone Hydrocortisone Triamcinolone Betamethasone Methylprednisolone Cortisol Glucose Effects Increases liver gluconeogenesis More glucose produced by liver May cause insulin resistance Increases serum glucose Cortisol excess: hyperglycemia May worsen diabetes Shutterstock Cortisol Blood Pressure Effects Maintains blood pressure Modifies vascular smooth muscle tone ↑ cortisol: hypertension (Cushing’s syndrome) ↓ cortisol: hypotension (adrenal insufficiency) Shutterstock Cortisol Lipid Effects Activation of lipolysis in adipocytes Can increase total cholesterol and triglycerides Stimulate adipocyte growth Key effect: fat deposition Face (“Moon face”) Trunk Upper back (“Buffalo hump”) Shutterstock Cortisol Muscle, Skin and Bone Effects Muscle atrophy Thin arms and legs Striae Thin skin Easy bruising Striae Osteopenia and osteoporosis Inhibits osteoblasts Shutterstock Cortisol Reproductive Effects Supresses GnRH release → ↓ LH and FSH Hypogonadotropic hypogonadism Women: irregular menses Men: low testosterone Cushing’s Syndrome Common Clinical Features Weight gain Hypertension Hyperglycemia Round face Menstrual irregularities Thin skin Bruising and striae Shutterstock Cushing’s Syndrome Special Clinical Features Skin hyperpigmentation Only occurs in ACTH-dependent Cushing’s syndrome Caused by ↑ ACTH not cortisol ↑ ACTH → ↑ MSH Also seen in adrenal insufficiency Loss of cortisol → ↑ ACTH Wikipedia/Public Domain Cushing’s Syndrome Special Clinical Features Androgen excess Occurs in some adrenal carcinomas Hirsutism Tumor secretes cortisol and androgens May cause acne Women: hirsutism Shutterstock Cushing’s Syndrome Causes Most common cause: exogenous glucocorticoids Commonly oral prednisone Administered for immunosuppressive effects Many indications Rare causes: Overproduction of ACTH by pituitary (Cushing’s disease) Ectopic ACTH syndrome (tumor) Adrenal adenoma Wikipedia /Public Domain Cushing’s Syndrome Causes ACTH-dependent High ACTH level → hypercortisolism Cushing’s disease Ectopic ACTH syndrome ACTH-independent Low ACTH level Adrenal adenoma Wikipedia /Public Domain Cushing’s Syndrome Workup Step 1: exclude exogenous glucocorticoids Step 2: diagnosis of hypercortisolism Twenty-four-hour urinary cortisol excretion Late-night salivary cortisol Late-night serum cortisol Low-dose dexamethasone suppression test If clinical suspicion high, sometimes 2 tests done (false negatives) Step 3: plasma ACTH Cushing’s Syndrome Low dose dexamethasone suppression test Screening test for hypercortisolism 1mg dexamethasone (“low dose”) administered at bedtime Suppresses normal pituitary ACTH release Morning blood test → cortisol level should be low (suppressed) Cushing’s syndrome: cortisol will be high ACTH production not suppressed from pituitary adenomas or ectopic tumors Cortisol production not suppressed from adrenal adenomas Cushing’s Syndrome Plasma ACTH Low plasma ACTH concentration ACTH-independent disease Suggests adrenal tumor Next best test: CT scan of adrenal glands Normal or high ACTH concentration ACTH-dependent disease Pituitary tumor or ectopic production Next best test: determine source of ACTH production High dose dexamethasone test CRH stimulation test Petrosal vein sampling Cushing’s Syndrome Source of ACTH production High dose dexamethasone test (8mg) Differentiates causes of high ACTH Cushing’s syndrome Will suppress cortisol in pituitary adenomas Will not suppress cortisol from ACTH tumors AM Cortisol After Dexamethasone Low Dose High Dose Normal ↓ ↓ Pituitary Adenoma -- ↓ ACTH Tumor -- -- Cushing’s Syndrome Source of ACTH production CRH stimulation test Pituitary tumor: ACTH and cortisol increases after CRH administration Pituitary cells actively synthesizing ACTH Release can be increased by surge of CRH Ectopic tumors: no response Pituitary cells NOT synthesizing ACTH Pituitary cells inactive Minimal or no response to surge in CRH Cushing’s Syndrome Source of ACTH production Petrosal venous sampling Petrosal venous sinus drains pituitary gland Venous blood sample obtained via catheter Gradient of central to peripheral ACTH measured Pituitary ACTH source: high central-to-peripheral ACTH gradient Cushing’s Syndrome Workup Cushing’s Disease Pituitary ACTH Release Usually caused by benign pituitary adenomas Usually microadenomas (< 10 mm in diameter) May be too small to identify by MRI Treatment: transsphenoidal surgery Main complication: diabetes insipidus (rarely permanent) Radiation if surgery unsuccessful Shutterstock Cushing’s Syndrome Ectopic ACTH Release Small cell lung cancer Carcinoid tumors of lung Islet cell tumors of pancreas Medullary thyroid carcinoma Thymus gland tumors Treatment: surgical resection of tumor Public Domain Cushing’s Syndrome Adrenal Adenoma Treatment Unilateral adrenalectomy Refractory disease (any cause): bilateral adrenalectomy Lifelong glucocorticoid and mineralocorticoid replacement Wikipedia /Public Domain Cushing’s Disease Cabergoline ACTH Medical Treatments Used if surgery unsuccessful or not possible Cabergoline Dopamine agonist Used to treat hyperprolactinemia Also suppresses ACTH release Pasireotide Somatostatin analogue Blocks the release of ACTH Adrenal Insufficiency Jason Ryan, MD, MPH Adrenal Insufficiency Loss of adrenal function Loss of one or more adrenal hormones Glucocorticoids: cortisol Mineralocorticoids: aldosterone Androgens: dehydroepiandrosterone (DHEA) Wikipedia /Public Domain Adrenal Insufficiency Types Primary adrenal insufficiency “Addison’s disease” Destruction of adrenal gland tissue Loss of cortisol, aldosterone and androgens Secondary or tertiary (central) Loss of ACTH from pituitary (secondary) Loss of CRH from hypothalamus (tertiary) Loss of cortisol only Glucocorticoid Deficiency Clinical Features Fatigue Weight loss Gastrointestinal symptoms Usually nausea Sometimes vomiting, abdominal pain or diarrhea Hypotension +/- syncope Cortisol maintains vascular tone Often orthostatic hypotension Muscle and joint pain Cortisol Hyponatremia (↑ ADH release) Mineralocorticoid Deficiency Clinical Features Hypovolemia “Salt wasting” – patient may crave salty foods Loss of sodium and water in urine May lead to hypovolemic shock Hyponatremia High ADH from hypovolemia Retention of free water Hyperkalemia Aldosterone Decreased urinary potassium Metabolic acidosis Acid (H+) Decreased urinary acid excretion Potassium (K+) BLOOD URINE Sodium (Na+) Androgen Deficiency Clinical Features No significant impact in males (testes) Decreased axillary and pubic hair in females Dehydroepiandrosterone (DHEA) Primary Adrenal Insufficiency Clinical Presentation Fatigue Eosinophil Weight loss Nausea, vomiting and abdominal pain Muscle and joint pain Postural hypotension Salt craving Hyponatremia Hyperkalemia Eosinophilia Bobjgalindo/Wikipedia Primary Adrenal Insufficiency Skin Hyperpigmentation ACTH is high in primary adrenal insufficiency ↑ melanocyte stimulating hormone (MSH) Common precursor in pituitary with ACTH Proopiomelanocortin (POMC) ↑ ACTH → ↑ MSH → ↑ melanin synthesis Most obvious in sun-exposed areas Face, neck, backs of hands May also occur on mucous membranes Wikipedia/Public Domain Primary Adrenal Insufficiency Diagnosis Morning cortisol Cortisol concentration higher in early morning Low value at this time suggests adrenal insufficiency Plasma ACTH Low cortisol + high ACTH = primary disease Low cortisol + low ACTH = central disease Cosyntropin stimulation test Used to quickly exclude adrenal insufficiency Shutterstock Cosyntropin Stimulation Test Cosyntropin: synthetic ACTH Standard high-dose test: 250 mcg Normal response: rise in serum cortisol Measured after 30 or 60 minutes Should peak at ≥ 18 to 20 mcg/dL Normal response rules out primary adrenal insufficiency Rules out most forms of central adrenal insufficiency Abnormal response = adrenal insufficiency Primary disease: blunted rise due to adrenal pathology Central disease: blunted rise due to adrenal atrophy Primary Adrenal Insufficiency Causes Autoimmune adrenalitis Suggested by other autoimmune disorders Infectious adrenalitis Neisseria Meningitis Tuberculosis, HIV Disseminated fungal infections Hemorrhagic infarction Associated with meningococcemia Waterhouse-Friderichsen syndrome Increased risk with anticoagulant use Metastatic cancer CDC/Public Domain Primary Adrenal Insufficiency Determination of cause Cause may be evident from history and exam CT Abdomen Tuberculosis, HIV or meningococcemia Antibodies against 21-hydroxylase Autoimmune adrenalitis CT abdomen Infection, hemorrhage or malignancy CT-directed fine needle aspiration Infection or malignancy Primary Adrenal Insufficiency Treatment Corticosteroids Dexamethasone, prednisone or hydrocortisone Mineralocorticoids Fludrocortisone Fludricortisone Central Adrenal Insufficiency Clinical Features Weakness and fatigue Muscle and joint pain Hypotension (less prominent) Decreased vascular tone only No loss of mineralocorticoids Hypothalamus and Pituitary Gland Hyponatremia (but less common) Intact mineralocorticoids Low cortisol →↑ ADH No skin hyperpigmentation (low ACTH) Diagnostic testing consistent with central disease Shutterstock Central Adrenal Insufficiency Evaluation and Treatment Head MRI Head MRI CRH stimulation test Differentiates 2∘ from 3∘ No cortisol rise after CRH: 2∘ (pituitary failure) Cortisol rise after CRH: 3∘ (hypothalamic failure) Treatment: glucocorticoids Public Domain Adrenal Insufficiency Workup Central Adrenal Insufficiency Patients on Chronic Glucocorticoids Suppression of HPA axis ↓ CRH and ↓ ACTH Adrenal atrophy Impaired ability to produce cortisol Cortisol effects entirely from endogenous drugs Mineralocorticoids intact from RAAS Patient dependent on endogenous glucocorticoids Cessation or underdosing → deficiency state Drosenbach/Wikipedia Central Adrenal Insufficiency Patients on Chronic Glucocorticoids Longer duration therapy requires tapering of dose (“weaning”) Various regimens to prevent symptoms of adrenal insufficiency Usually a small decrease in dose every one to two weeks Suppression of HPA axis unlikely if treatment under three weeks Wikipedia /Public Domain Adrenal Crisis Acute-onset, life-threatening condition Shock due to sudden loss of adrenal hormones Poorly-responsive to fluids alone Resolves with glucocorticoid administration Consider in any hypotensive patient Picpedia/Public Domain Adrenal Crisis Causes Occurs with underlying adrenal disease and acute stressor Chronic primary adrenal insufficiency (possible initial presentation) Chronic glucocorticoid therapy and adrenal atrophy Adrenal function unable to increase in response to stressor Stressors: trauma, surgery or major illness Also occurs with acute-onset adrenal gland destruction Bilateral hemorrhage Picpedia/Public Domain Adrenal Crisis Treatment and Prevention “Stress dose steroids” Hydrocortisone intravenous bolus Regular intravenous doses every few hours or infusion Prevention: stress dose steroids in patients on chronic glucocorticoids High daily dose for more than 3 weeks Prior to major surgery After trauma During major illness Not necessary for minor surgical procedures or low daily doses Diabetes Mellitus Jason Ryan, MD, MPH Diabetes Mellitus Chronic disorder of elevated blood glucose levels Lack of insulin or poor response to insulin (“insulin resistance”) Can lead to symptoms of hyperglycemia Many long-term complications Vascular disease Kidney disease Blindness Diabetes Mellitus Symptoms May be asymptomatic “Silent killer” No symptoms until complications develop Basis for screening Classic hyperglycemia symptoms Polyuria (osmotic diuresis from glucose) Polydipsia (thirst to replace lost fluids) Can present with diabetic ketoacidosis Shutterstock Diabetes Mellitus Diagnosis Symptomatic (polyuria, polydipsia, DKA) Symptoms plus glucose > 200 mg/dl = diabetes Asymptomatic Fasting blood glucose level (no food for 8 hours) Hemoglobin A1c > 6.5% Two-hour plasma glucose ≥ 200 mg/dL after 75 g oral glucose tolerance test State Fasting plasma glucose Normal < 100 mgl/dl Pre-diabetes 100 to 125 mg/dl Diabetes >= 126 mg/dl Diabetes Mellitus Stress hyperglycemia Occurs in normal individuals without diabetes Infection, trauma, surgery, burns Cortisol, epinephrine Does not indicate diabetes Diagnosis not usually done during in illness/stress Shutterstock Hemoglobin A1C Hemoglobin Small fraction of hemoglobin is “glycated” Glucose combines with alpha/beta chains Amount of HbA1c measured in diabetes Reflects average glucose over past 3 months Normal < 5.7% Pre-diabetes: 5.7 to 6.4% Diabetes: >= 6.5% Used for diagnosis and monitoring therapy Hemoglobin A1C Treatment Goals Lower value = better control of blood sugar Type I diabetes: < 7.0% Type II diabetes: < 7.0% for average adult patient Higher goal (< 8.0%) for older patients Avoid hypoglycemia Limited life expectancy for complications Shutterstock Glucose Tolerance Test Oral glucose load administered Plasma glucose measured 1-3 hours later High glucose indicates diabetes Often used to screen for gestational diabetes Some insulin resistance normal in pregnancy Fasting glucose and A1c not reliable Need to study response to glucose load for diagnosis Pixabay.com Type 1 Diabetes Autoimmune disorder Type IV hypersensitivity reaction Immune-mediated destruction of beta cells Loss of insulin Multifactorial etiology Genetics, environment Only major risk factor: family history Shutterstock Type 1 Diabetes Mostly a childhood disorder Bimodal distribution Peak at 4-6 years 2nd peak 10 to 14 years of age Presents with hyperglycemia symptoms Polyuria Polydipsia Glucose in urine Diabetic ketoacidosis Wikipedia/Public Domain Type 1 Diabetes Diagnosis and treatment No standard screening Diagnosis usually made when symptoms occur Treatment: insulin Shutterstock Type 2 Diabetes Complex disorder of insulin resistance Reduced response to insulin → hyperglycemia Pancreas initially responds with ↑ insulin Eventually pancreas can fail → ↓ insulin Most common form of diabetes Common in adults Also becoming more common among children Type 2 Diabetes Risk Factors Major risk factor: obesity Central or abdominal obesity carries greatest risk Weight loss improves glucose levels Family history Strong genetic component (more than type I) Any first degree relative with T2DM: ↑ 2-3x risk Sedentary lifestyle Smoking Shutterstock Type 2 Diabetes Screening Guidelines vary slightly by expert groups American Diabetes Association Screening for most patients beginning age 45 Earlier screening in high-risk groups Repeat screening every 3 years US Preventive Services Task Force Patients 40 to 70 who are overweight or obese Repeat screening every 3 years Picpedia Type I versus Type II Diagnosis Usually distinguished by clinical features Type I: Childhood onset Rapid onset with severe hyperglycemia Obesity less likely (~ 20%) Type II: Puberty or adulthood Often insidious onset (screening, polyuria/polydipsia) Family history more likely Obesity common (~ 80%) Islet-specific pancreatic autoantibodies in some cases of type I (not reliable) Type 2 Diabetes Management All patients: maintain healthy weight and exercise Can be done prior to medical therapy in select cases For highly motivated patients with A1C near target Usually 3- to 6-month trial of lifestyle modification Most common initial therapy: metformin May add additional agents to achieve target A1c After failure of two or more agents consider insulin If severely elevated A1c (> 9.5%) consider insulin Shutterstock Bariatric Surgery Indicated for obese patients with type II diabetes Long-term remission up to 60% in some studies Reduced risk of diabetes complications Indicated for any patient with diabetes and BMI > 35 Or 30 to 34.9 if hyperglycemia inadequately controlled Public Domain Acanthosis Nigricans Hyperpigmented plaques on skin Intertriginous sites (folds) Classically neck and axillae Associated with insulin resistance Often seen in obesity, diabetes Much more common type II Rarely associated with malignancy Gastric adenocarcinoma most common Madhero88/Dermnet.com Diabetes Complications Jason Ryan, MD, MPH Diabetes Mellitus Complications Chronic hyperglycemia → complications Vascular disease Kidney disease Neuropathy Ocular disease (blindness) Shutterstock Diabetic Macroangiopathy Atherosclerosis Coronary artery disease Most common cause of death in diabetes Stroke and TIA Peripheral vascular disease BruceBlaus/Wikipedia Diabetic Macroangiopathy Atherosclerosis Screening lipid panel At time of diagnosis At least every five years thereafter Statin therapy US Preventive Services Task Force guidelines Diabetes + age > 40 + 10-year risk > 10% Regardless of LDL level Routine EKG, stress test, imaging not indicated BruceBlaus/Wikipedia Diabetic Kidney Disease Diabetic Microangiopathy Damage to glomeruli and arterioles Efferent arteriole glycosylation Hyperfiltration Basement membrane damage Mesangial and glomeruli sclerosis Causes albuminuria May lead to end-stage kidney disease Public Domain Diabetic Kidney Disease Screening and Prevention Annual urine albumin-to-creatinine ratio Measurement correlated to 24-hour urine values (mg/day) Normal rate: less than 30 mg/day Above 30 mg/day indicates diabetic nephropathy ACE inhibitors and ARBs Indicated for albuminuria Even if blood pressure is not elevated Shown to reduce progression to ESRD Slows progression of nephropathy Hypertension goal: < 130/80 mmHg Public Domain Diabetic Peripheral Neuropathy Most common form of diabetic neuropathy “Distal symmetric polyneuropathy” “Stocking-glove" sensory loss Progressive loss of sensation: distal → proximal Severe cases: motor weakness Large Myelinated Fibers Small Myelinated Fibers Function Proprioception/Pressure Pain Symptoms Numbness, loss of balance Burning, electric shocks Reduced ankle reflexes Loss of pinprick Exam Findings Reduced vibration Loss of hot/cold Reduced proprioception discrimination Diabetic Peripheral Neuropathy Foot Ulcers Common problem in diabetes Loss of sensation → tissue damage Vascular disease → impaired healing May be painless Patients should check feet daily Annual foot exam and sensory testing Monofilament testing (pressure) Vibratory testing Pinprick testing Ankle reflexes Shutterstock Diabetic Peripheral Neuropathy Management Generally not reversible Glucose control slows progression Pain in feet (burning or stabbing) SNRIs: duloxetine or venlafaxine TCAs: amitriptyline, desipramine or nortriptyline AEDs: pregabalin or gabapentin Shutterstock Diabetic Autonomic Neuropathy Abnormal function of autonomic nerves GU system: bladder dysfunction, erectile dysfunction GI: gastroparesis CV: orthostatic hypotension, silent ischemia Diabetic Eye Disease Cataracts Glaucoma Diabetic retinopathy Diabetic macular edema Annual screening for prevention Dilated fundus examination by trained specialist Usually ophthalmologist or optometrist Petr Novák, Wikipedia Diabetic Eye Disease Cataracts Increased risk with diabetes Sorbitol accumulates in lens Increased osmolarity Fluid into lens Opacification over time Rakesh Ahuja, MD/Wikipedia Diabetic Eye Disease Retinopathy Can cause blindness Nonproliferative retinopathy Cotton Wool Spots Microaneurysms or hemorrhages Exudates: leakage of proteins and lipids Cotton-wool spots (nerve infarctions) Proliferative retinopathy Retinal ischemia → new vessel growth “Neovascularization” Treated with photocoagulation (laser) Also intraocular anti-VEGF agents Public Domain Diabetes Mellitus Benefits of lowering blood glucose Several large, randomized trials of intensive glycemic control Comparisons of lower versus higher A1c targets Type 2 diabetes Lower risk of microvascular complications Mostly retinopathy and nephropathy Little impact on macrovascular disease (MI, stroke) ACCORD trial: A1c 6.0 to 6.5% → increased mortality Type 1 diabetes Lower risk of most complications Microvascular and macrovascular Diabetic Ketoacidosis Jason Ryan, MD, MPH Diabetic Ketoacidosis DKA Life-threatening complication of diabetes Biochemical derangement: hyperglycemia, acidosis Requires very low insulin effects More common in type 1 Common type 1 initial presentation Often precipitated by infection or trauma (↑ epinephrine) Can occur with missed insulin dose in type 1 diabetes (↓ insulin) Epinephrine Insulin Diabetic Ketoacidosis DKA ↑ epinephrine or ↓ insulin → increased glucose Very low insulin effects → liver ketone synthesis Net result: hyperglycemia + ketones Osmotic diuresis (glucose) → volume depletion Hyperglycemia High ketones = anion gap metabolic acidosis Low bicarbonate Acidosis → hyperkalemia Hyperkalemia Volume depletion Diabetic Ketoacidosis Clinical Presentation Abdominal pain, nausea and vomiting Volume depletion Dry mucous membranes Low blood pressure Hyperglycemia Low bicarbonate Hyperkalemia Shutterstock Diabetic Ketoacidosis Metabolic Acidosis Bicarbonate Clinical Presentation Elevated plasma and urine ketones Glucose in urine Anion gap metabolic acidosis (↓ bicarbonate) Kussmaul breathing: deep, labored breathing Hyperventilation to blow off CO2 and raise pH Fruity smell on breath (acetone) Diabetic Ketoacidosis Phosphate Risk of hypophosphatemia Phosphaturia caused by osmotic diuresis Loss of ATP Muscle weakness (respiratory failure) Heart failure (↓ contractility) Diabetic Ketoacidosis Other features Arrhythmias (hyperkalemia) Cerebral edema Mechanism poorly understood Common cause of death in children with DKA _DJ_/Wikipedia Diabetic Ketoacidosis Diagnostic Criteria Triad: hyperglycemia, anion gap acidosis and ketones Measurement Criteria Glucose > 250 mg/dL Arterial pH < 7.30 Bicarbonate < 18 mEq/L Urine ketones Positive Serum ketones Positive Diabetic Ketoacidosis Treatment IV Fluids Volume replacement Usually normal saline Usually infused continuously IV Insulin Lowers blood glucose levels Inhibits liver production of ketones Shifts potassium into cells Bolus plus continuous drip Diabetic Ketoacidosis Treatment - Potassium Total body potassium is low from loss of potassium in urine Hyperkalemia presents initially due to acidosis/low insulin Potassium shifted out of cells into plasma Hypokalemia may develop from insulin infusion Add potassium to IV fluids when potassium less than 5.3 mEq/L Normal potassium: 3.6 to 5.2 mEq/L Diabetic Ketoacidosis Treatment – other electrolytes Monitor magnesium, calcium and phosphate Levels may fall due to loss in urine Replete as needed Diabetic Ketoacidosis Treatment - bicarbonate infusion Usually not necessary Arterial pH will increase with DKA treatment Only indicated with pH < 6.9 (impaired cardiac function) Diabetic Ketoacidosis Treatment monitoring Close monitoring of serum glucose and electrolytes When glucose approaches 200 mg/dL add 5% dextrose to saline infusion Allows continued insulin infusion to suppress ketones Avoids hypoglycemia Can also decrease insulin infusion rate DKA resolves when: Anion gap normalizes (less than 12 mEq/L) Beta-hydroxybutyrate absent (if available) Patient can eat HHS Hyperglycemic Hyperosmolar Syndrome Life-threatening complication of diabetes More common in type 2 Markedly elevated glucose (can be >1000) High glucose → diuresis and volume depletion High osmolarity → CNS dysfunction Usually no acidosis Shutterstock HHS Hyperglycemic Hyperosmolar Syndrome Very high serum osmolarity → CNS dysfunction Caused by very high glucose (can be > 1000) Normal plasma osmolarity: less than 300 mOsm/kg HHS: usually above 320 mOsm/kg Few or no ketone bodies (insulin present) Usually no acidosis Different from DKA Shutterstock HHS Clinical features and diagnosis Polyuria, polydipsia Volume depletion Mental status changes Confusion, even coma Diagnosis: serum glucose Shutterstock HHS Treatment Similar to DKA Insulin, fluids Resolved when: Plasma osmolality below 315 mOsmol/kg Patients alert and able to eat Insulin Jason Ryan, MD, MPH Type 1 and Type 2 Type 1 diabetes treated mainly with insulin Type 2 diabetes: oral or SQ drugs +/- insulin Initial stages: oral and/or SQ drugs Advanced disease: insulin Insulin Many different types available for diabetes therapy All vary by time to peak and duration of action Also vary by peak effect Rapid Regular NPH Acting Basal Insulins Insulin Insulin Insulin Fast Peak Slow Peak Short Duration Long Duration Insulin Hexamers Insulin forms hexamers in the body Six insulin molecules linked together Stable structure Insulin usually administered subcutaneously Activity related to speed of absorption Insulin hexamers → slower onset of action Insulin monomers → faster onset of action Isaac Yonemoto /Wikipedia Rapid-acting Insulin Lispro, Aspart, and Glulisine Modified human insulin Insulin with modified amino acids Reduced hexamer/polymer formation Rapid absorption, fast action, short duration Onset: 15 minutes Peak: 1 hour Duration: 2 to 4 hours Often used pre-meal Pixabay Insulin Rapid 2 4 6 8 10 12 14 16 18 20 22 24 Hours After Administration Regular Insulin Synthetic analog of human insulin Made by recombinant DNA techniques Onset: 30 minutes Peak: 2 to 4 hours Duration: 3 to 6 hours Regular Insulin Only type of insulin that is given IV IV regular insulin used in DKA/HHS Used to treat hyperkalemia Given IV with glucose to prevent hypoglycemia Wikipedia/Public Domain NPH Insulin Neutral Protamine Hagedorn Regular insulin combined with neutral protamine Slows absorption Peak: ~ 8 hours Duration: 12-16 hours Basal insulin analogs Glargine, Detemir, Degludec Insulin with modified chemical structure Provide low, continuous insulin effects Onset: ~ 2 hours Duration: up to 24 hours or more Glargine and Detemir: up to 24 hours Degludec: > 40 hours Often given once daily Insulin Administration Subcutaneous (SQ) Continuous infusion Infusion pump Rapid-acting insulin Shutterstock Hypoglycemia Major adverse effect of all insulin regimens Tremor, palpitations, sweating, anxiety If severe: seizure, coma Always check blood sugar in unconscious patients Dosages, frequency adjusted to avoid low glucose Shutterstock Weight Gain Occurs in most patients on insulin Insulin promotes fatty acid and protein synthesis Wikipedia/Public Domain Insulin Hypersensitivity Reactions Immediate IgE-mediated type I hypersensitivity reactions Occur within 1 hour of injection Local skin reactions: erythema, wheals, pruritus Systemic reactions: generalized urticaria and angioedema Treatment: antihistamines, glucocorticoids; epinephrine if anaphylaxis Delayed More than one hour after injection Induration and nodules at injection sites Contact dermatitis Treatment: topical corticosteroids Insulin Subcutaneous fat changes Lipohypertrophy: swelling of fatty tissue at injection sites Insulin alters fatty tissue growth Lipoatrophy: loss of fatty tissue Lipohypertrophy Lipoatrophy Prevention: rotate injection sites Mokta JK, Mokta KK, Panda P. Insulin lipodystrophy and lipohypertrophy. Indian J Endocrinol Metab. 2013 Jul;17(4):773-4. Diabetes Treatment Jason Ryan, MD, MPH Type 1 and Type 2 Treatment Type 1 diabetes treated mainly with insulin Type 2 diabetes: oral or SQ drugs +/- insulin Most common initial therapy: metformin Advanced disease: insulin Hemoglobin A1C Treatment Goals Type I diabetes: < 7.0% Type II diabetes: < 7.0% for average adult patient Higher goal (< 8.0%) for older patients Lower value = lower average blood glucose levels Reduced risk of diabetes complications Type I: most complications Type II: microvascular complications Especially retinopathy and nephropathy May not reduce risk of macrovascular complications Shutterstock Antidiabetic Agents Oral or Subcutaneous Biguanides (Metformin) Sulfonylureas Glitazones Glucosidase Inhibitors GLP-1 Analogs DPP-4 Inhibitors SGLT2 inhibitors Metformin Biguanide Oral medication Exact mechanism unknown Multiple metabolic effects ↓ hepatic glucose production Inhibits gluconeogenesis ↑ insulin effects ↑ insulin sensitivity Metformin Metformin Benefits and Adverse Effects Usually first line in type 2 diabetes Associated with weight loss Rarely causes hypoglycemia Does not depend on beta cells Can be used in advanced diabetes Most common adverse effect is GI upset Nausea, abdominal pain Can cause a metallic taste in the mouth Shutterstock Metformin Lactic Acidosis Rare, life-threatening adverse effect of metformin Exact mechanism unclear/controversial Metformin can increase conversion of glucose to lactate Beneficial for lowering glucose levels Too much → lactic acidosis Can be life threatening Lactic Acid Metformin Lactic Acidosis Almost always occurs associated with other illness Renal insufficiency Liver disease or heavy alcohol use Acute heart failure Hypoxia Serious acute illness Metformin not used in patients with low GFR Often “held” when patients acutely ill Also held during IV contrast tests Public Domain Sulfonylureas ↑ insulin release Bind to sulfonylurea receptor in pancreas Close K+ channels in beta cells Beta cells more sensitive to glucose/amino acids Urea “Insulin secretagogues” Used when metformin contraindicated (renal failure) Or side effects on metformin (GI upset) Can be added to metformin Sulfonylurea Sulfonylureas Oral medications Each generation more potent ↓ dosage used → ↓ side effects First generation: tolbutamide, chlorpropamide, tolazamide Second generation: glyburide, glipizide Third generation: glimepiride Needpix.com Sulfonylureas Adverse Effects Hypoglycemia Most common adverse effect Sweating, palpitations May occur with exercise or skipping meals Can also cause weight gain More insulin release Insulin causes weight gain Wikipedia/Public Domain Sulfonylureas Adverse Effects - Chlorpropamide Flushing with alcohol consumption Inhibits acetaldehyde dehydrogenase (disulfiram effect) Hyponatremia (↑ADH activity) Meglitinides Repaglinide, Nateglinide Oral medications Similar mechanism but different chemical structure from sulfonylureas Close K+ channels → ↑ insulin secretion Short acting → given prior to meals Major side effect is hypoglycemia No sulfa group → can be used in sulfa allergy Added to metformin if sulfa allergy Repaglinide Thiazolidinediones Pioglitazone, Rosiglitazone Oral medications Decrease insulin resistance Act on PPAR-γ receptors Highest levels in adipose tissue Also found in muscle, liver, other tissues Modulate expression of genes Thiazolidinediones Pulmonary Edema Adverse Effects Weight gain Proliferation of adipocytes plus fluid retention Risk of hepatotoxicity Troglitazone removed from market due to liver failure Edema Occurs in ~ 5% patients Due to PPAR-γ effects in nephron → ↑ Na retention Risk of pulmonary edema Not used in patients with advanced heart failure Pioglitazone not used with active bladder cancer Potential small increased risk of bladder cancer Glucosidase Inhibitors Acarbose, Miglitol, Voglibose Competitive inhibitors of intestinal α-glucosidases Enzymes of brush border of intestinal cells Hydrolyze starches, oligosaccharides, disaccharides Slows and limits absorption of glucose Taken orally before meals Less increase in glucose after meals Main side effect: GI upset Especially flatulence Diarrhea Shutterstock GLP-1 Analogs Exenatide, Liraglutide, Dulaglutide GLP-1 (glucagon-like peptide-1) Produced by L-cells of small intestine Secreted after meals Stimulates insulin release Also blunts glucagon release, slows gastric emptying Subcutaneous drugs Exenatide: twice daily or weekly Liraglutide: once daily Dulaglutide: once weekly GLP-1 Analogs Exenatide, Liraglutide, Dulaglutide Usually not used as initial therapy Add-on therapy in multi-drug regimens Do not usually cause hypoglycemia Associated with weight loss Reduce mortality in patients with cardiovascular disease GI side effects: nausea, vomiting, diarrhea Pixabay DPP-4 Inhibitors Sitagliptin, Linagliptin, Saxagliptin DPP-4: Dipeptidyl peptidase 4 Enzyme expressed on many cells Inhibits release GLP-1 Inhibition → ↑ GLP-1 Oral drugs Side effects: infections May depress immune function ↑ risk nasopharyngitis and respiratory infections Weight neutral; not associated with hypoglycemia Shutterstock SGLT2 Inhibitors Canagliflozin, Dapagliflozin SGLT2: renal glucose transporter Expressed in proximal tubule Reabsorbs sodium and glucose Reabsorbs ~ 90% percent filtered glucose Glucose Inhibition → loss of glucose in urine SGLT2 Lowers glucose levels Also causes mild osmotic diuresis SGLT2 Inhibitors Canagliflozin, Dapagliflozin Oral medications Lead to mild weight loss Adverse effects Vulvovaginal candidiasis UTIs May lead to volume depletion Not used advanced renal disease (low GFR) Shown to improve outcomes in systolic heart failure Shutterstock Diabetes Therapy Helpful Tips Renal failure: avoid metformin May cause lactic acidosis Advanced heart failure Avoid glitazones (fluid retention) Avoid metformin (lactic acidosis) Insulin generally safe with any comorbidity Patients with cardiovascular disease GLP-1 agonists (reduce mortality) SGLT2 inhibitors (systolic heart failure) Shutterstock Diabetes Therapy Helpful Tips Hospitalized patients Oral antidiabetic agents often held/avoided Most patients treated with insulin Most oral agents decrease A1c by 0.5 to 1.5% Metformin 1 to 1.5% Markedly elevated A1c % usually requires insulin Insulin used at diagnosis when Hgb A1c > 9.5% Shutterstock Pituitary Gland Jason Ryan, MD, MPH Pituitary Gland “Master gland” Controls other endocrine organs Located at base of brain Sits in small cavity of sphenoid bone: sella turcica Shutterstock Pituitary Gland Posterior pituitary Antidiuretic hormone (ADH; vasopressin) Oxytocin Anterior pituitary Adrenocorticotropic hormone (ACTH) Follicle-stimulating hormone (FSH) Luteinizing hormone (LH) Growth hormone (GH) Thyroid-stimulating hormone (TSH) Prolactin Shutterstock Hypothalamus Controls anterior pituitary gland Delivers releasing/inhibiting hormones via hypothalamic portal system Hypothalamus Pituitary Corticotropin-releasing hormone (CRH) ACTH Thyrotropin-releasing hormone (TRH) TSH Gonadotropin-releasing hormone (GnRH) LH/FSH Growth hormone–releasing hormone (GHRH) GH Dopamine Prolactin Somatostatin GH, TSH Pituitary Adenomas Benign tumors of the anterior pituitary May produce hormones → hormone excess syndromes May compress nearby CNS structures → neurologic symptoms Classified by cell type of origin and size Microadenoma: < 10 mm in size Macroadenoma: > 10 mm in size Shutterstock Pituitary Adenomas Cell types Cell Type Hormone Adenoma Lactotrophs Prolactin Hyperprolactinemia Corticotrophs Adrenocorticotropic hormone (ACTH) Cushing’s disease Thyrotrophs Thyroid-stimulating hormone (TSH) Central hyperthyroidism Somatotrophs Growth hormone (GH) Acromegaly Luteinizing hormone (LH) Gonadotrophs Usually non-functioning Follicle-stimulating hormone (FSH) Pituitary Adenomas Clinical presentation Most patients present with features of hormone hypersecretion Hyperprolactinemia, hypercortisolism, growth hormone excess, etc. Non-functioning adenomas: about 30% of adenomas Do not produce hormones Usually gonadotroph adenomas Usually identified as macroadenomas Present with neurologic symptoms from mass effect Or incidental finding on imaging May grow large enough to cause hypopituitarism Shutterstock Pituitary Adenomas Mass effect symptoms Headaches Classic cause of bitemporal hemianopsia Compression of optic chiasm JFW/Wikipedia Prolactinoma Most common functional pituitary adenoma Excess pituitary production of prolactin Normal: less than 20 ng/mL Small prolactinoma < 1 cm: up to 200 Large prolactinoma over 2 cm: > 1000 Hypogonadism Prolactin → ↓ LH/FSH Women: amenorrhea Men: low testosterone Galactorrhea (uncommon) Shutterstock Hyperprolactinemia Clinical features and diagnosis Postmenopausal women: usually no symptoms from high prolactin Diagnosis: serum prolactin level Premenopausal Women Men Fatigue Oligomenorrhea Loss of libido Amenorrhea Decreased muscle mass Infertility Decreased body hair Decreased bone density Infertility Galactorrhea Galactorrhea* *less common due to less breast tissue Hyperprolactinemia Differential diagnosis Prolactinoma Dopamine-blocking drugs Antipsychotic drugs Usually mild and asymptomatic Usually no treatment required Procedureready/Wikipedia Hyperprolactinemia Differential diagnosis Primary hypothyroidism Increases TSH and TRH Chronic renal failure Decreased clearance Hypothalamic disease Tumors Infiltrative disease (sarcoid) Damage to pituitary stalk (trauma) Pregnancy or stress (physiologic) Procedureready/Wikipedia Hyperprolactinemia Workup History Symptoms and medication review Exam Visual field defects Signs of hypothyroidism Lab testing Thyroid: TSH Renal: BUN/Cr Pituitary MRI Shutterstock Prolactinoma Management Small, asymptomatic adenomas → observation Cabergoline or bromocriptine Treat symptoms of hyperprolactinemia Hypogonadism or galactorrhea Dopamine agonists Will decrease prolactin release Transsphenoidal surgical resection If medical management fails Large adenomas with neurologic symptoms Cabergoline Somatotroph Adenoma Causes excess growth hormone Children: gigantism Adults: acromegaly Growth hormone → IGF-1 secretion Insulin-like growth factor 1 Secreted by liver Causes many clinical manifestations Acromegaly Clinical features Clinical syndrome of growth hormone excess Insidious onset Average duration symptoms → diagnosis = 12 years Enlarged jaw Coarse facial features Enlargement of nose, frontal bones Enlarged hands and feet Increasing glove or shoe size Rings that no longer fit Philippe Chanson and Sylvie Salenave Acromegaly Insulin effects Growth hormone oppose insulin effects Insulin resistance → diabetes Diabetes in 10-15% of patients Abnormal glucose tolerance in 50% of patients Insulin Glucagon Cortisol Epinephrine Growth Hormone Acromegaly Other clinical features Visceral organ enlargement Thyroid, heart, liver, lungs, kidneys, prostate Synovial tissue/cartilage enlargement Joint pain in knees, ankles, hips, spine Common presenting complaint is joint pain Cardiovascular disease Hypertension, left ventricular hypertrophy Diastolic dysfunction and arrhythmias Mortality increased in acromegaly due to CV disease Acromegaly Diagnosis Serum IGF-1 concentration IGF-1 level is constant (contrast with GH) Oral glucose tolerance testing Glucose should suppress growth hormone levels Normal subjects: GH falls within two hours Acromegaly: GH levels not supressed CNS imaging (MRI) Acromegaly Treatment Preferred treatment: surgery Medical therapy less effective Octreotide and lanreotide Analog of somatostatin Suppress somatotroph growth Suppress release of growth hormone Monitoring: IGF-1 Goal level within reference range Bony abnormalities do not regress Joint symptoms often continue Shutterstock Pituitary Incidentaloma Common testing Prolactin Cortisol testing IGF-1 TSH and free T4 LH and FSH Testosterone (men) Estradiol (women) Hypopituitarism Decreased secretion of pituitary hormones Hormone Clinical Features Adrenocorticotropic hormone (ACTH) Adrenal insufficiency Thyroid-stimulating hormone (TSH) Hypothyroidism Luteinizing hormone (LH) Hypogonadism Follicle-stimulating hormone (FSH) Short stature in children Growth hormone (GH) Adults: ↓ lean mass ↑ fat mass Prolactin Inability to lactate postpartum Hypopituitarism Diagnostic testing Hormone Testing Adrenocorticotropic hormone (ACTH) Measuring serum cortisol Thyroid-stimulating hormone (TSH) Free T4 or total T4 Luteinizing hormone (LH) Testosterone (males) Follicle-stimulating hormone (FSH) Estradiol (females) Growth hormone (GH) IGF-1 Prolactin Levels variable Hypopituitarism Causes Hypothalamic disease Tumors, trauma, stroke Pituitary disease Mass lesions especially macroadenomas Radiation Damage to hypothalamus or pituitary gland Pituitary infarction Pituitary apoplexy Shutterstock Pituitary Infarction Sheehan syndrome Ischemia and infarction of pituitary gland Occurs after postpartum hemorrhage Pituitary gland increases in size during pregnancy Estrogen stimulates lactotrophs growth (prolactin) Postpartum hemorrhage/shock → infarction Shutterstock Pituitary Infarction Clinical features Variable based on degree of infarction Lethargy, anorexia and weight loss (cortisol, thyroid) Inability to lactate (prolactin) Failure to resume menses (LH/FSH) Anton Nossik/Wikipedia Pituitary Apoplexy Sudden hemorrhage into pituitary gland Most often into a pituitary adenoma Abrupt onset of severe headache, visual loss and diplopia Pituitary Apoplexy Hypopituitarism: usually laboratory evidence only Diagnosis: head MRI or CT Treatment: surgical decompression of pituitary Case courtesy of Assoc Prof Frank Gaillard, Radiopaedia.org, rID: 17664 Hypopituitarism Treatment Deficient Hormone Treatment Adrenocorticotropic hormone (ACTH) Glucocorticoids Thyroid-stimulating hormone (TSH) Levothyroxine Luteinizing hormone (LH) Testosterone (males) Follicle-stimulating hormone (FSH) Estrogens and progestins (females) Replacement in children Growth hormone (GH) Usually no replacement in adults Prolactin No replacement Hyperparathyroidism Jason Ryan, MD, MPH Parathyroid Glands Four endocrine glands Located behind thyroid Secrete parathyroid hormone (PTH) Important for calcium and phosphate balance Wikipedia/Public Domain Parathyroid Hormone Net effects ↑ plasma Ca2+ ↓ plasma P043- Some effects due to direct action PTH Some due to activation of vitamin D (indirect) Parathyroid Hormone Stimuli for secretion Major stimulus: ↓ plasma Ca2+ ↑ plasma P043- ↓ 1,25-(0H)2 vitamin D Parathyroid Hormone Systemic effects Kidney ↑ Ca2+ reabsorption (less urinary calcium) ↓ P043- reabsorption (more urinary phosphate) ↑ 1,25-(0H)2 vitamin D production GI tract ↑ Ca2+ and P043- absorption (via vitamin D) Bone ↑ Ca2+ and P043- reabsorption (direct and via vitamin D) Shutterstock Hyperparathyroidism Excess release of PTH Primary: overactive glands Secondary: caused by hypocalcemia Tertiary: occurs in chronic kidney disease Shutterstock Primary Hyperparathyroidism Inappropriate secretion of PTH not due to low calcium ↑ PTH → ↑ Ca Most common cause of outpatient hypercalcemia Malignancy most common cause in hospitalized patients Most common in postmenopausal women Diagnosis: serum calcium and PTH Must have hypercalcemia PTH may be elevated PTH may be inappropriately normal for high calcium Primary Hyperparathyroidism Causes Parathyroid Adenoma Most common cause: adenoma (85% of cases) Hypertrophy of all four glands Multiple adenomas Rarely parathyroid carcinoma BruceBlaus/Wikipedia Primary Hyperparathyroidism Signs and symptoms Often incidental finding when asymptomatic Recurrent kidney stones “Stones, bones, groans, and psychiatric overtones” Largely historical Kidney Stones Modern era, most patients diagnosed early Shutterstock Osteitis Fibrosa Cystica Classic bone disease of hyperparathyroidism Clinical features: bone pain and fractures Brown Tumors Subperiosteal bone resorption Brown Tumors Commonly seen in bones of fingers Irregular or indented edges to bones Brown tumors (osteoclastoma) Appear as black spaces in bone on x ray Frank Gaillard/Wikipedia Primary Hyperparathyroidism Diagnosis and workup Diagnosis: calcium and PTH 24-hour urinary calcium excretion Maye be high, normal or low Not required for diagnosis Used to estimate risk of renal complications Elevated urinary calcium excludes FHH Familial Hypocalciuric Hypercalcemia Disorder of excess renal resorption of calcium Also causes hypercalcemia but low urinary calcium Wikipedia/Public Domain Primary Hyperparathyroidism Localization studies Parathyroid MIBI Scan Used to identify hyperfunctioning tissue Done only if surgery being planned Not used for diagnosis Sestamibi scintigraphy Technetium-99m-sestamibi (MIBI) Concentrates in parathyroid glands Alternatives: ultrasound or CT-scan Public Domain Primary Hyperparathyroidism Treatment Definitive treatment: parathyroidectomy Pre-op nuclear imaging often done to identify hyperfunctioning tissue Focused parathyroidectomy: remove adenoma only Bilateral hyperplasia: remove 3.5 glands Or remove 4 glands and implant tissue in arm Resolves symptoms of hypercalcemia (if present) Decreases risk of kidney stones Improves bone mineral density Public Domain Primary Hyperparathyroidism Parathyroidectomy indications Indicated for all symptomatic patients Asymptomatic patients*: Age less than 50 years (lower surgical risk; more likely to progress) Calcium more than 1.0 mg/dL above normal (~ 11.5 or higher) Osteoporosis by DXA scan GFR < 60 mL/min Many patients are older and asymptomatic Often do not require surgery * Fourth International Workshop on Asymptomatic Primary Hyperparathyroidism 2014 guidelines Primary Hyperparathyroidism Parathyroidectomy complications Risks of recurrent laryngeal nerve damage May result in hoarseness Post-op hypocalcemia Remaining parathyroid glands may be suppressed Numbness or tingling in fingertips, toes, hands If severe: twitching or cramping of muscles Treat with calcium supplementation Shutterstock Primary Hyperparathyroidism Medical therapy Used in poor surgical candidates with symptoms Bisphosphonates Cinacalcet “Calcimimetic” Activate calcium receptor in parathyroid glands Inhibits PTH secretion Secondary Hyperparathyroidism Occurs in chronic kidney disease Chronically low serum calcium → ↑ PTH No symptoms of hypercalcemia Results in renal osteodystrophy Bone pain (predominant symptom) Fractures (weak bones 2° chronic high PTH levels) If severe, untreated can lead to osteitis fibrosa cystica ↑PTH ↓Ca Public Domain Secondary Hyperparathyroidism Chronic Kidney Disease ↑ Phosphate ↓ 1,25-OH2 Vitamin D ↓ Ca from plasma ↓ Ca from gut Hypocalcemia ↑PTH Secondary Hyperparathyroidism Monitoring, treatment and prevention Standard monitoring in patients with low GFR Calcium and phosphate Vitamin D PTH level Hyperphosphatemia: phosphate binders Calcium-containing binders: calcium carbonate and acetate Non-calcium-containing binders: sevelamer and lanthanum Treat vitamin D deficiency with supplementation Persistently elevated PTH: calcitriol Public Domain Tertiary Hyperparathyroidism Consequence of chronic kidney disease Chronically low calcium → chronically ↑ PTH Parathyroid hyperplasia Parathyroid gland becomes autonomous VERY high PTH levels Calcium may become elevated Often requires parathyroidectomy