MINISTRY OF HEALTH PROTECTION OF UKRAINE Vynnitsa national medical university named after M.I.Pyrogov «CONFIRM» on methodical meeting of endocrinology department A chief of endocrinology department, prof. Vlasenko M.V. _________________ “_31_”_august___ 2012 y METHODOLOGICAL RECOMМENDATIONS FOR INDEPENDENT WORK OF STUDENTS BY PREPARATION FOR PRACTICAL CLASSES Scientific discipline Мodule № 1 substantial module №1 Topic Course Faculty Internal medicine Basis of Internal medicine “Diagnostic, treatment and prophylactic basis of main endocrinology diseases” Topic №14: Diseases of parathyroid gland. Hyperparathyroidism: etiology, pathogenesis, classification, clinics, differential diagnosis, treatment. Hypoparathyroidism: etiology, pathogenesis, classification, clinics, diagnostic, treatment. 4 Medical № 1 Vynnitsa – 2012 METHODOLOGICAL RECOMМENDATIONS for the students of 4-th course of medical faculty for preparation to the practical classes from endocrinology 1.Тopic №14: Diseases of parathyroid gland. Hyperparathyroidism: etiology, pathogenesis, classification, clinics, differential diagnosis, treatment. Hypoparathyroidism: etiology, pathogenesis, classification, clinics, diagnostic, treatment. 2. Relevance of topic: Parathyroid disorders are characterized by impairment of their function or structure. They occur rarely, but according to diffcult early diagnosis, consequences of wrong diagnosis and treatment, they are recommended to learn for students of higher medical school. Graduates of medical faculty of higher medical school commonly work as a general practice doctors, who must be able primary reveal endocrine pathology. Hypoparathyroidism (a tendency to hypocalcemia, often associated with chronic tetany, resulting from hormone deficiency, characterized chemically by low serum calcium and high phosphorus levels) occurs permanently in 3 % of expartly performed thyroidectomies. Hypoparathyroidism is a generalized disorder resulting from excessive secretion of parathyroid hormone by one or more parathyroid glands and it is usually characterised by hypercalcemia, hypophosphatemia, and exessive bone resorption. It occurs with increased frequency in women and with aging. Hyperparathyroidism (is characterized by hypercalcemia, associated with damaging of the bones, kidneys and gastrointestinal tract) occurs in 0,15 – 0,52 % of adults. 3. Aim of lesson: - to know etiology, pathogenesis, main clinical manifestations, special features of parathyroid deseases - to examine a patient with suspicion on parathyroid disease - to carry out the diagnosis on a basis of clinical and laboratory fndings; - to make up differential diagnosis and determine management; - to give the frst aid in a case of hypoparathyroid crisis. - to know phosphorus and calcium homeostasis. - to know etiology, pathogenesis of hyper- and hypoparathyroidism. - to know classifcation of hyper- and hypoparathyroidism. - to know clinical presentation of these diseases. - to know early diagnostics on a basis of laboratory and instrumental examination fndings. - to know differential diagnostics between hyperparathyroidism and other diseases, incl. endocrine (thyrotoxicosis, acromegalia, pheochromocytoma, chronic adrenal insuffciency) and hypercalcinemic states. - to know differential diagnostics between hypoparathyroidism and other causes of hypocalcinemia and convulsive syndrome. - to know the treatment of hyper- and hypoparathyroidism, frst aid in a case of acute form of hypocalcinemic tetania. 4. References 4.1. Main literature 1. Endocrinology. Textbook/Study Guide for the Practical Classes. Ed. By Petro M. Bodnar: Vinnytsya: Nova Knyha Publishers, 2008.-496 p. 2. Basіc & Clіnіcal Endocrіnology. Seventh edіtіon. Edіted by Francіs S. Greenspan, Davіd G. Gardner. – Mc Grew – Hіll Companіes, USA, 2004. – 976p. 3. Harrison‘s Endocrinology. Edited J.Larry Jameson. Mc Grew – Hill, USA,2006. – 563p. 4. Endocrinology. 6th edition by Mac Hadley, Jon E. Levine Benjamin Cummings.2006. – 608p. 5. Oxford Handbook of Endocrinology and Diabetes. Edited by Helen E. Turner, John A. H. Wass. Oxford, University press,2006. – 1005p. 4.2. Additional literature 6. Endocrinology (A Logical Approach for Clinicians (Second Edition)). William Jubiz.-New York: WC Graw-Hill Book, 1985. - P. 232-236. Pediatric Endocrinology. 5th edition. – 2006. – 536p. 7. Thyroid Disordes (Aclevelend Clinic Guide) by Mario Skugor, Jesse Bryant Wilder Clevelend Press,2006. – 224p. Basic Level. Students must know: 1. Anatomy and physiology of parathyroid glands. 2. Main functions of сalcitonin and parathyroid hormone. 3. Biological effects of calcium on organism. 4. Laboratory and instrumental methods which can be used in patients with diseases of parathyroid glands. Students should be able to: 1. Examine patient. 2. Interpritate data of laboratory and instrumental methods of examination. Students’ Independent Study Program. You should prepare for the practical class using the existing text books and lectures. Special attention should be paid to the following: 1. Anatomy, physiology of parathyroid glands. 2. Regulation of calcium-phosphorus homeostasis. 3. Hypoparathyroidism: etiology and pathogenesis. 4. Classification of hypoparathyroidism. 5. What are the main diagnostic criteria of hypoparathyroidism? 6. Early diagnostics on a basis of laboratory and instrumental examination fndings. 7. Differential diagnostics between hypoparathyroidism and other causes of hypocalcinemia and convulsive syndrome. 8. What does treatment of hypoparathyroidism include? 9. What are the main causes and signs of hypocalcemic crisis? 10. What does emergency treatment of hypocalcemic crisis include? 11. Hyperparathyroidism: etiology and pathogenesis. 12. Classification of hyperparathyroidism. 13. What are the main diagnostic criteria of hyperparathyroidism? 14. Differential diagnostics between hyperparathyroidism and other diseases, incl. endocrine (thyrotoxicosis, acromegalia, pheochromocytoma, chronic adrenal insuffciency) and hypercalcinemic states. 15. What does treatment of hyperparathyroidism include? 16. What are the main causes and signs of hypercalcemic crisis? 17. What does emergency treatment of hypercalcemic crisis include? Short content of the theme. Normal serum calcium (Ca) levels range between 2, 25 – 2,75 mmol/l (8.8 – 10.4 mg/100 ml. Approximately 40 % of the total blood Ca is bound to serum proteins while the remaining 50 % is ultrafilterable and includes ionized Ca plus Ca comlexed with phosphate and citrate. The ionized Ca fraction (about 50 % of the total blood Ca) is influenced by pH changes. Acidosis is associated with decreased protein - binding and increased ionized Ca and alkalosis with a fall of ionized Ca due to increased protein – binding. These pH – induced changes in ionized Ca occur independently of any change in total blood Ca concentration. In the laboratory determination of serum Ca, only total serum Ca is usually measured. Maintenance of the blood Ca level is partially dependent upon dietary Ca intake (0,5 – 1,0 gm/day), gastro-intestinal absorption of Ca, and renal Ca excretion. The major factor preserving the constancy of blood Ca concentration is the bone Ca reservoir. About 99 % of body Ca is in bone, of which 1 % is freely exchangeable with ECF. Parathyroid hormone (PTH) is secreted by the parathyroid glands. PTH and vitamin D are the principle regulators of Ca and phosphorus (P) homeostasis; their metabolic actions are interrelated. PTH promotes renal formation of the active metabolite of vitamin D. Conversely, with a deficiency of the vitamin or any resistance to its action, some of the effects of the hormone are blunted. The most important actions of PTH are: 1) increasing the rate of bone resorption with mobilization of Ca and P from bone; 2) increasing intestinal absorption of Ca (mediated by an action on the metabolism of vitamin D); 3) stimulation of Ca resorption in the distal tubule of the kidney; 4) decreasing renal tubular reabsorption of phosphate (PO4). These actions account for most of the important clinical manifestations of PTH excess or deficiency. (Calcitonin is synthesized in the C cells of the thyroid gland. The major regulator of calcitonin secretion is the serum Ca concentration. In contrast to their effect on PTH, hypercalcemia stimulates and hypocalcemia suppresses calcitonin secretion. A number of gastrointestinal hormones including gastrin, glucagon, and cholecystokinin are pharmacologic secretegogues for calcitonin, but gastrin is the most potent. Physiologic actions: - inhibiting osteoclastic bone resorption; - decreasing renal tubular calcium reabsorption and others.) HYPOPARATHYROIDISM it is a disease resulting from PTH deficiency, characterized chemically by low serum calcium and high serum phosphorus levels, often associated with chronic tetany. (Pseudohypoparathyroidism is a congenital condition in which there is tissue resistance to the effects of parathyroid hormone. It presents with skeletal abnormalities, elevated levels of serum parathyroid hormone and normal serum calcium.) Etiology. 1) accidental removal of or damage to several parathyroid glands during thyroidectomy (2 %); 2) radioactive iodine therapy of the hyperthyroidism or X-ray therapy of the neck organs; 3) it is also occurs as a part of a genetic syndrome of type I (hypoparathyroidism, Addison’s disease, mucucutaneous candidiasis); 4) congenital deficiency (DiGeorge syndrome), agenesis or aplasia of parathyroid glands; 5) hemorrhages, infarctions, infections of the glands; 6) severe hypomagnesemia; 7) autoimmune processes. Classification. 1. Congenital hypoparathyroidism (aplasia of parathyroid glands). 2. Idiopathic hypoparathyroidism (autoimmune): isolated or type I autoimmune polyglandular syndrome. 3. Post operative hypoparathyroidism. 4. Secondary hypoparathyroidism due to: - irradiation; X-ray therapy; treatment of the thyroid gland by radioactive iodine; - infectious damaging of the glands; - hemochromatosis, granulomatous disease of parathyroids; - disturbances of the innervation or vascularization. Due to duration: 1. Manifest hypoparathyroidism (acute and chronic). 2. Latent hypoparathyroidism. Clinical presentation. Patients may be asymptomatic 1. The most characteristic syndrome is tetany, resulting from severe hypocalcemia or a reduction in the serum ionized Ca fraction without marked hypocalcemia (e.g., in respiratory or metabolic alkalosis). Tetany is characterized by: 1) sensory symptoms consisting of paresthesias of the lips, tongue, fingers and feet: 2) carpopedal spasm (the hands incarpal spasm adopt a characteristic position, the metacarpophalangeal joints are flexed, the interphalangeal joints of fingers & thumb are extended and there is opposition of the thumb), which may be prolonged or painful; 3) generalized muscle aching; 4) spasm of facial musculature; 5) laryngeal stridor. Tetany may be overt (spontaneous symptoms) or latent. In latent tetany the neuromuscular instability frequently is brought out by provocative tests. Trousseau’s sign is carpopedal spasm caused by reduction of the blood supply to the hand when a tourniquet or blood pressure cuff above systolic pressure is applied to the forearm for 3 min. Chvostek’s sign is contraction of the facial muscles, elicited by a light tapping of the facial nerve. Erba’s sign is dyspnea which develops after hyperventilation. 2. Changes of other organs and systems. 1. The clinical manifestations of hypocalcemia may be primarily neurologic. Slowly developing, insidious hypocalcemia may produce mild, diffuse encephalopathy and thus should be suspected in any patient with unexplained dementia, depression, or psychosis. 2. Trophic changes: - papilledema occasionally may be present and cataracts may develop after prolonged hypocalcemia: - changes of the skin and hair. 3. Respiratory system: - dyspnea; - laryngospasm. 4. Cardiovascular system: - pain in the region of the heart like angina; - the ECG typically shows prolongation of the Q – T. 5. Gastrointestinal tract: - spastic constipation or diarrhea. Laboratory findings. 1. The level of total Ca < 2,2 mmol/l, ionized Ca , 1,0 mmol/l. 2. High serum PO4. 3. Low or absent urinary Ca. Differential diagnosis have to be made with other causes of hypocalcemia: 1) increased phosphate (chronic renal failure; phosphate therapy); 2) drugs (calcitonin; diphosphanates); 3) acute pancreatitis; citrated blood in massive transfusion; 4) pseudohypoparathyroidism (resistance to PTH); 5) deficiency or resistance to vitamin D; and tetany: 1) infectious diseases (tetanus); 2) alkalosis (repeated vomiting of gastric juice; hyperventilation). Treatment of Acute severe hypocalcemic tetany. 1. It is treated initially with IV infusion of Ca salts. 10 – 50 ml of 10 % solution of Ca gluconate or Ca chloride may be given IV over 15 – 30 min, but the effect lasts for only a few hours. (side effects: thrombophlebitis, IM injection can cause local necrosis). 2. Magnesium repletion. 3. Parathyroidin 1 – 2 ml IM 2 times a day. 4. Sedative preparations and spasmolitics. Treatment of chronic hypocalcemia: 1. Diet with increased quantity of calcium and vitamin D. 2. Preparations of Ca and vitamin D, which have to be given orally (Calcium-D3 nicomed, Calcemin). 3. Surgery (transplantation of a special bone into the muscles of the abdomen or back. The efficacy is about 8 – 12 month). HYPERPARATHYROIDISM. It is a generalized disorder resulting from excessive secretion of parathyroid hormone by one or more parathyroid glands; it is usually characterized by hypercalcemia, hypophosphatemia, and abnormal bone metabolism. Classification due to etiology. 1. Primary (due to parathyroid glands): - adenoma of a single gland (80 %), multiple adenomata (5 %); - hyperplasia of parathyroid glands (15 %); - carcinoma of a gland (< 5 %); - associated with syndromes of familial endocrine neoplasia (MEN-types I and II). 2. Secondary (due to increased physiological demand of hormone in response to low serum Ca in chronic renal failure, malabsorption, rickets and osteomalacia): - renal; - intestinal; - vitamin D insufficiency. 3. Tertiary (due to development of parathyroid tumor against a background of prolonged secondary hyperparathyroidism). Classifcation of Hyperparathyroidism I. Primary hyperparathyroidism 1. Solitary adenoma (80 %), multiple adenomas (5 %). 2. Hyperplasia of parathyroid glands (15 %). 3. Parathyroid carcinoma (<5 %). 4. Primary hyperparathyroidism at multiple endocrine neoplasia types 1 and 2 syndrome (MEN-1 and MEN-2). II. Secondary hyperparathyroidism 1. Renal secondary hyperparathyroidism. 2. Secondary hyperparathyroidism with normal renal function: a) malabsorption syndrome with calcium absorption disorder; b) hepatic pathology: cirrhosis (formation of 25-[OH]-D3 from cholecalciferol disorder), cholestasis (resorption of calciferol disorder). 2. Vitamin D defcit (insuffcient sunlight exposure). III. Tertiary hyperparathyroidism Clinical forms of hyperparathyroidism. 1. Bone: - osteoporosis; - osteodystrofya. 2. Visceropatic: - dyspeptic; - gastrointestinal; - nephrotic; - pancreatic. 3. Mixed: - myopathy; - mixed damaging of organs and systems Clinical presentation. Many patients with mild hypercalcemia are asymptomatic, and the condition is discovered accidentally during routine laboratory screening. Onset is usually gradual with bone pain or swelling, rarely sudden with fracture or renal colic. The clinical manifestations of hypercalcemia include constipation, anorexia, nausea, vomiting with abdominal pain and ileus, weight loss.. More severe elevation of serum calcium is associated with emotional lability, confusion, delirium, psychosis, stupor and coma. Myopathy may cause prominent skeletal muscle weakness. Seizures are rare. Reversible impairment of the renal concentrating mechanism leads to polyuria, nocturia and polydipsia. Hypercalciuria with nephrolithiasis or urolithiasis is common. Less often, prolonged and severe hypercalcemia may produce reversible acute renal failure or irreversible renal damage, due to precipitation of Ca salts within the kidney parenchyma (nephrocalcinosis). Renal damage may result in azotemia and hypertension. Peptic ulcers and pancreatitis may also be associated with hyperparathyroidism. Osteitis fibrosa cystica, in which increased osteoclastic activity causes rarefying osteitis with fibrous degeneration, the formation of cysts, and the development of fibrous nodules in the affected bone, may develop in patients severe hyperparathyroidism. Other bony manifestations include bone pain, tenderness, fracture, deformity, swelling of mandible due to cyst formation (rarely), falling of teeth. Cardiovascular disorders are presented as hypertension, arrhythmia, left ventricle hypertrophy. Investigations. 1. Increased level of serum Ca. 2. A low serum phosphate level. 3. Elevated serum parathyroid hormone. 4. Increased alkaline phosphatase. 5. Hypercalciuria, hyperphosphaturia. 6. X-ray: cortical erosions most marked in phalanges especially radial side of middle phalanx; destructive bone lesions; Ca deposition on kidney. 7. Ultrasound and CT scan: localizing of the parathyroid tumor. Differential diagnosis. Polyarthritis, radiculitis, tumors of the bones, diabetes insipidus and others. Treatment. 1. Surgery. It is indicated if the disease is symptomatic or progressive. Chances of cure depend on successful removal of all excess functioning tissue and on reversibility of renal damage; renal insufficiency may progress despite cure of the underlying disease. Abnormally functioning parathyroid glands may be found in unusual locations and experience is required to find them. Preoperative localization of abnormally functioning parathyroid tissue is possible by immunoassay of the thyroid venous drainage. When hyperparathyroidism is mild, no special postoperative precautions are required. In patients with severe osteitis fibrosa cystica, prolonged symptomatic hypocalcemia may occur and require large doses of Ca together with vitamin D, usually for 1 to 3 month. 2. Conservative treatment include (may be used in patients with hypercacemic crisis, which is medical emergency and characterized by dehydration, hypotension, abdominal pain, vomiting, fever and altered consciousness): - rehydration 2 – 6 l of sodium chloride solution and furosemid 40 – 160 mg; - calcitonine 1 – 4 units/kg; - prednisolone 40 – 60 mg/day. Tests and Assignments for Self-assessment. Multiple Choice. Choose the correct answer/statement: 1. A 24-year-old woman is referred to you by an ophthalmologist who discovered bilateral cataracts. Patient is product of normal pregnancy and delivery. Childhood was uncomplicated, and she has done well at school. During the past 5 years, she has been complaining of decreased visual acuity, tingling and numbness of hands and legs, and constipation. The patient married at age 21, and she had a normal child at age 22. During pregnancy, tingling and numbness of the extremities worsened, and she had several seizure episodes necessitating intravenous calcium administration. Two sisters have been treated for hypocalcemia with vitamin D. The patient takes no medications. The physical examination is unremarkable. Laboratory: the complete blood count, urinanalysis and examination of the stools for ova and parasites are normal; serum calcium is decreased, serum phosphate is increased, serum alkaline phosphatase is normal. 1. What is your diagnosis? A. Inappropriate PTH secretion. B. Osteomalacia. C. Vitamin D deficiency. D. Hypoparathyroidism. E. Vitamin D intoxication. 2. Which is the most important test to evaluate the mechanism of the hypocalcemia? A. Bone X-rays. B. Serum magnesium concentration. C. Plasma PTH concentration. D. Plasma 25-(OH)D. E. Urinary calcium. 3. How would you treat this patient? A. Intramuscular PTH. B. Subcutaneous calcitonin. C. Oral phosphates. D. Vitamin D. E. Thiazide diuretics. 4. A patient, 35 years old, a week later after thyroidectomy for thyroid gland cancer has paraesthesia, muscle fbrillations, convulsions in extremities.What is the possible diagnosis? A. Primary hypoparathyroidism B. Secondary hypoparathyroidism C. Hypothyroidism D. Myeloma E. Distant metastases 5. A patient, 59 years old, consult a doctor with complaints of fast fatigue, muscular weakness, pain in muscles, spine, thirst, poliuria, loss of teeth. A leg fracture has occurred 10 months ago after damage and bad synostosis. The patient has gastric ulcer and nodular goiter in her life history. Menopause has been obtained at 53 years. Complete blood count: erythrocytes - 3x1012/L, Hb - 100 g/L, leucocytes - 4,4x109/L, ESR - 28 mm/h, serum calcium - 2,9 mmol/L, serum phosphate - 0,4 mmol/L. Bone X-ray examination: systemic osteoporosis, subperiosteal resorption of bones, cysts, spine deformation.Determine possible diagnosis. A. Primary hyperparathyroidism B. Secondary hyperparathyroidism C. Postmenopausal osteoporosis D. Thyroid cancer with metastases in bones E. Pedjet disease 6. A patient 40 years old, having urolithiasis for 10 years, has coral calculus in right kidney and multiple calculi in left kidney. Laboratory fndings: serum calcium - 2,85 mmol/L, serum phosphate 0,3 mmol/L, creatinine, urea are normal.What is the diagnosis? A. Primary hyperparathyroidism B. Secondary hyperparathyroidism C. Tertiary hyperparathyroidism D. Pseudohyperparathyroidism E. Primary hypoparathyroidism 7. A patient, 52 years old, consult a doctor with complaints of general weakness, insomnia, decreasing memory, vertigo, cardiac pain, palpitation, periodic vomiting, diarrhea, following constipation, paraes-thesia, muscle fbrillations, turning to cramps in upper extremities. Cramps occur after stress, infectious diseases. There are no endocrine diseases in family history. Laboratory fndings: glycemia - 4,8 mmol/L, serum calcium - 2,0 mmol/L, serum phosphates - 1,1 mmol/L. ECG: prolongation of QT interval. X-ray: increased density of bones.What is the diagnosis? A. Hypoparathyroidism B. Pseudohypoparathyroidism C. Insulinoma D. Epilepsy E. Malabsorption syndrome 8. A 38-years-old patient M. has been operated on for toxic multinodular goiter, II gr. For 2 weeks after the operation cramps in upper extremities had appeared, which persisted for 1-2 min. and accompanied with numbness in face. Cramps occur 1-2 times a day, commonly at a daytime. Pulse is 82 st/min, rhythmic; blood pressure is 110/70 mmHg. Visceral organs are not damaged. Trousseau’s, Hvostek’s I symptoms are positive.What is the diagnosis? A. Post-operative hypoparathyroidism B. Post-operative hypothyroidism C. Pseudohypoparathyroidism D. Epilepsy E. Insulinoma Case 6. A patient Z., 47 years old has been consulted different specialists for 4 years with complaints of weakness in extremities, constant pain in muscles of legs and back. X-ray: osteoporosis, cysts and pathologic fractures. Serum calcium level is increased. What is the correct diagnosis? F. *Primary hyperparathyroidism G. Myeloma H. Osteoblastoma I. Secondary hyperparathyroidism J. Hypoparathyroidism 9. A patient D., 38 years old, is treated for recurrent urolithiasis for 7 years. At examination increased serum calcium and urinary calcium and low serum phosphate. Serum creatinine is normal. What is the preliminary diagnosis? A. Primary hyperparathyroidism, renal form B. Urolithiasis, secondary hyperparathyroidism C. Urolithiasis, threefold hyperparathyroidism D. Pseudohyperparathyroidism E. Primary hyperparathyroidism, bone form 10. A 7-years-old child with cramps has hypocalcemia and radiologic signs of osteoporosis. Parathyroid hormone blood level is increased. Hyperphosphatemia is revealed. The child has signs of physical and mental retardation. A treatment with parathyroid hormone was not effective. What is the preliminary diagnosis? A. Pseudohypoparathyroidism B. Pseudohyperparathyroidism C. Pseudoidiopathic hypoparathyroidism D. Idiopathic hypoparathyroidism E. Primary hyperparathyroidism Answer: 1 – D. 2 – C. 3 – D. 4 – A. 5 – A. 6 – A. 7 – A. 8 – A. 9 – A.10 – A. Real-life situations to be solved: As a part of a general check-up hypercalcemia is discovered in 46-yearoold female. The patient has no complaints. What is your previous diagnosis? Answer: This a typical presentation of primary hyperparathyroidism. Patients complains on polydipsia, polyuria, general weakness, weight loss. Three years age stones in kidneys were found. What is your previous diagnosis? Make a plan of investigations. Answer: Hyperparathyroidim. The level of serum calcium, phosphate, alkaline phosphatase, examination of kidneys function, bones X-rays. Students Practical Activities. Work 1 : Students’ group is divided into 2 sub-groups, that work near the patients’ bed: ask the patients on organs and systems, take anamnesis of the disease , anamnesis of life, make objective exam. With the teacher’s presence. In the class-room they discuss the patients, learn data of laboratory and instrumental exam. of these patients. 1.To group the symptoms into the syndromes. 2.To find out the leading syndrome and make differential diagnosis. 3.To formulate the diagnosis. 4.To make a plan of treatment. Methodological recommendation prepared assistant, c.m.s. Chernobrova O.I. It is discussed and confirm on endocrinology department meeting " 31 " august 2012 y. Protocol № 1.