Disorders of calcium metabolism

calcium metabolism and disorders associated with it

1. DISORDERS OF CALCIUM METABOLISM DR OGECHUKWU MBANU FAMILY MEDICINE DEPARTMENT AKTH ,KANO 15 TH DECEMBER 2017

2. Clinical scenrio 1 a 59 year old woman with a past medical history significant for hypertension who comes for a routine clinic visit. She initially states that she has no symptomatic complaints, but later in the interview describes chronic fatigue and a mildly depressed mood. Her exam is unremarkable. She used thiazide diuretics as treatment for hypertension, Labs results showed: Calcium (total) – 11.9 mg/ dL (normal ~ 8.5-10.2 mg/ dL ) Phosphate – 1.8 mg/ dL (normal ~ 2.0-4.3 mg/ dL ) Albumin – 3.8 g/ dL (normal ~ 3.5-5.0 g/ dL ) PTH – 124 pg/mL (normal ~ 10-60 pg/mL) Creatinine – 1.2 mg/ dL

3. Clinical scenario 2 A 9-year-old boy presents to the emergency department with diffuse abdominal pain, nausea, and vomiting 2 hours after sustaining blunt trauma to the abdomen when he fell off his bike and hit the handlebars . Laboratory studies show elevated amylase , lipase, and hypocalcemia. He is diagnosed with acute pancreatitis and admitted for intravenous fluid hydration and management. Which of the following findings is expected to be seen as a result of the hypocalcemia? A. Decreased QT interval on electrocardiography B. Normal or slightly decreased phosphorus C. Positive Trousseau sign D. Rigidity of fingers (cannot be bent) E. Hypophosphatemia

4. OUTLINE Introduction Different forms of calcium Functions of calcium Calcium homeostasis Regulation of Ca metabolism Calcium metabolism disorders Conclusion References

5. INTRODUCTION Element number 20 in the periodic table Makes up 3% of the Earths crust Calcium ion: Ca2+ , Divalent cation Most Abundant Mineral In The Body Its about 1-2 kg ,of which 99% in bones and teeth , Rest of it is present in ECF Normal level of calcium is 9-11 mg/dl of blood Dietary sources includes Milk and milk products(good source) ,Boned fish, green leafy veg , beans BODY REQUIREMENT Adult – 700 mg/day Children-1.2gm/day Pregnancy and lactation-1.5 gm/day

6. DIFFERENT FORMS OF CALCIUM Most of the calcium in the body exists as the mineral hydroxyapatite, Ca 10 (PO 4 ) 6 (OH) 2 . Calcium in the plasma: 45 % in ionized form (the physiologically active form) 45 % bound to proteins (predominantly albumin) 10 % complexed with anions (citrate, sulfate, phosphate) Total calcium(usually measured in the lab): ionized calcium + protein bound + anion bound; should be 2.2 to 2.6 mmol /L Corrected calcium: when the albumin is low, protein-bound calcium will also be low; however the levels of ionized calcium remain unchanged Corrected calcium is what the total calcium WOULD BE if the patient had a normal albumin level. To estimate the physiologic levels of ionized calcium in states of hypoalbuminemia: [ Ca +2 ] Corrected = [Ca +2 ] Measured + [ 0.8 (4 – Albumin) ] OR corrected [Ca] in mmol /L = measured total [Ca] ( mmol /L) + 0.02 x (40 – serum albumin in g/L )

7. DIFFERENT FORMS OF CALCIUM CONT’D Normal Range of Total Serum Calcium 8.5 to 10.5 mg/dl ( or 9-11 mg/dl of blood or 2.2-2.6 mmol /l (total) Normal Range of Ionized Serum Calcium 1.17 to 1.33 mmol /l serum Phosphate ( HPO 4 2- ):- 0.7-1.4 mmol /l

8. FUNCTIONS OF CALCIUM Muscle contraction - caused by Ca++ efflux from sarcoplasmic reticulum Neurotransmitter release - caused by Ca++ influx into presynaptic terminal Conduction system of the heart - Uses Ca++ instead of Na+ to depolarise Myocardial contraction - Ca ++ influx is responsible for the plateau phase of the action potential Clotting cascade - Ca ++ is a cofactor required at most factor activation steps, that’s why blood bank purple top tubes contain a calcium chelator ( EDTA) Bone integrity Cell signaling ,enzymatic co-factor

9. Calcium homeostasis

10. CALCIUM HOMEOSTASIS CONT’D RENAL CALCIUM EXCRETION 10,000 mg Ca filtered through glomerulus per day Urinary calcium excretion is approx. 200 mg per day Only 2% of filtered Ca is normally excreted

11. CALCIUM HOMEOSTASIS CONT’D CAUSES OF INCREASED CALCIUM ABSORPTION  RENAL 1,25 –VIT D3 PRODUCTION Growth Pregnancy Lactation Primary hyperparathyroidism Idiopathic hypercalciuria  EXTRARENAL 1,25 VIT D3 Sarcoidosis Granulomatous disorders e.g. Tb,leprosy B – cell lymphoma Causes of decreased calcium absorption  1,25 –VITD3 PRODUCTION Hypoparathyroidism Vit. D deficiency Vit. D deficiency rickets type 1 Chronic renal insufficiency Aging NORMAL 1,25 –VIT D3 PRODUCTION Glucocorticoid excess Thyroid hormone excess Intestinal malabsorption syndrome Renal 1,25 – Vit d3 production Low dietary Ca intake

12. REGULATION OF CALCIUM METABOLISM Organ systems that play an import role in Ca 2+ metabolism Skeleton GI tract Kidney CALCITROPIC HORMONES Parathyroid hormone (PTH) Calcitonin (CT) Vitamin D (1,25 dihydroxycholecalciferol) Parathyroid hormone related protein ( PTHrP ) Calcium receptors: are present in the parathyroid gland, kidney , brain and other organs

13. REGULATION OF CA METAB. CONT’D:- VITAMIN D Lipid soluble vitamin Precursors: - Cholecalciferol in the skin (produced by UV radioation ) – Vitamin D3 Ergocalciferol from diet – Vitamin D2 Both get hydrolysed in the liver to 25-hydroxyvitamin D2 Then, in the kidney, get hydrolysed again to 1,25-hydroxyvitamin D3( active form ) Production in the kidney is catalyzed by 1 a-hydroxylase 1 A-HYDROXYLASE ACTIVITY IS INCREASED BY :  serum Ca2+  PTH level  serum phosphate VITAMIN D ACTIVITY: Increased gut absorption of calcium and phosphate Increased reabsorption of calcium and phosphate from the kidney Vitamin D increases Ca ++ resorption from the bone Decreases hydroxylation of Vit D

14. REGULATION OF CA METAB. CONT’D:- VITAMIN D

15. REGULATION OF CA METAB. CONT’D:- CALCITONIN Produced by parafollicular (C) cells in the thyroid gland Release stimulated by rising ionized calcium levels Action: directly inhibits osteoclast activity Increases renal excretion of calcium by inhibiting resorption Calcitonin causes a decrease in plasma Ca ++ . Calcitonin is a physiological antagonist to PTH with regard to Ca ++ homeostasis

16. REGULATION OF CA METAB. CONT’D:- PARATHYROID HORMONE it is an 84-amino-acid hormone. SECRETION: from the chief cells of the parathyroid glands. FUNCTION:- increase renal phosphate excretion , and increases plasma calcium by: osteoclastic resorption of bone (occurring rapidly). Intestinal absorption of calcium (a slower response). Synthesis of 1,25-(OH)2D3 (stimulating GIT absorption). Renal tubular reabsorption of calcium Serum phosphate

17. PTH, Calcium & Phosphate REGULATION OF Ca MTETABOLISM CONT’D

18. Calcium metabolism disorders: Disorders of calcium metabolism includes: Hypercalcemia Hypocalcemia Hyperparathyrodism Hypoparathyroidism

19. Neuronal hyper excitability or irritability due to neuronal membrane understabilization Paresthesias Tetany (carpopedal spasm) abnormal reflexes eg Trousseau’s, Chvostek’s signs Seizures QT prolongation Hyperactive Deep tendon reflex HYPOCALCEMIA : CLINICAL SIGNS

20. HYPOCALCEMIA : CLINICAL SIGNS

21. HYPOCALCEMIA : CLINICAL SIGNS TROUSSEAU’S SIGN

22. ETIOLOGY OF HYPERCALCEMIA T Thiazide, other drugs - Lithium R Rhabdomyolysis A AIDS P Paget’s disease, Parental nutrition, Pheochromocytoma, Parathyroid disease Approx. 80% of all cases are caused by Malignancy or Primary Hyperparathyroidism V Vitamins I Immobilization T Thyrotoxicosis A Addison’s disease M Milk- alkali syndrome I Inflammatory disorders N Neoplastic related disease S Sarcoidosis

23. HYPERCALCEMIA:- CLINICAL SIGNS There is neuronal hypoactivity , membrane over – stabilization GI: Nausea, vomiting, abdominal pain Constipation Renal: Polyuria, dehydration Renal failure Nephrolithiasis Neurological Fatigue Confusion Depression Stupor, coma

24. Neuromuscular Muscle weakness, hypotonia ,poor deep tendon reflex Cardiovascular Hypertension Short QT interval Skeletal Bone pain and tenderness Spontaneous fracture EYE(Band keratopathy) Corneal opacities Calcium deposition begins near the limbus at the 3 & 9 o’clock position HYPERCALCEMIA: – CLINICAL SIGNS CONT’D

25. MANAGEMENT OF SEVERE HYPERCALCEMIA GOALS: Decrease bone resorption Increase calcium excretion Expand ECF volume Then, deal with the primary pathology, if possible INDICATIONS FOR THERAPY Symptoms of hypercalcemia Plasma [Ca] >15 mg/dl

26. HYPERPARATHYROIDISM Hyperparathyroidism is a metabolic disorder with excessive secretion of Parathyroid hormone (PTH ) above the normal level ( 12-70pg/mL )(2) , HPT is characterized by ↑ PTH, PTH induced bone resorption H hypercalcemia 3 Types Primary HPT Secondary HPT Tertiary HPT

27. PRIMARY H YPERPARATHYROIDISM E xcessive , relatively uncontrolled secretion of PTH O ne or more hyper functioning parathyroid glands. Hypercalcemia, the biochemical hallmark Most patients today are relatively asymptomatic. Symptoms remarkably varied and vague.

28. EPIDEMIOLOGY Incidence :0.1-0.3%. 1 case per 1000 men 2-3 cases per 1000 women. 25/100000 population Incidence increases above age 40 Most patients with sporadic primary hyperparathyroidism are postmenopausal women with an average age of 55 years Female to male ratio is 2-3:1

29. ETIOLOGY AND PATHOGENESIS Primary hyperparathyroidism is caused by Parathyroid adenoma – 80% P arathyroid hyperplasia – 15% P arathyroid carcinoma – 1-2% Approximately 10% are caused by “double a denoma ” It can occur as part of at least three familial endocrinopathies MEN 1 MEN 2A .Isolated familial hyperparathyroidism

30. SYMPTOMS AND S IGNS Renal hypercalciuria nephrolithiasis nephrocalcinosis polyuria and polydipsia renal insufficiency Neuromuscular weakness m yalgia Skeletal Bone pain Osteoporosis Pathologic Neurologic and psychiatric - Memory loss - Confusion Depression - Lethargy Psychosis - Fatigue - P aresthesias Peptic ulcer Zollinger -Ellison Syndrome ( MEN 1 ):- gastrinomas Chronic pancreatitis

31. LABORATORY F INDINGS Hypercalcemia is universal (>10.6 mg/dL) Serum phosphorus is low normal (<3.5 mg/dl) or low (<2.5 mg/dl) Mild hyperchloremic metabolic acidosis PTH is elevated or high normal  Alkaline phosphatase urine calcium Serum chloride : phosphate ratio >33 Urinary ph Serum chloride

32. MEDICAL MANAGEMENT PRIMARY HPT Estrogen Dose required is high SERMs (selective estrogen receptor modulators) Reduction in serum calcium and markers of bone turnover after 4 weeks Bisphosphonates Studies have shown increase in lumbar spine and femoral neck mineral density Calcium/Vitamin D Calcimimetic agents ( Cinacalcet ) Under investigation for primary HPT

33. SECONDARY HYPERPARATHYROIDISM the parathyroid glands are stimulated to produce increased amounts of hormones to correct abnormally low serum calcium levels in different conditions like renal failure , Intestinal malabsorption syndrome decrease of Vitamin D production this results in parathyroid hyperplasia FINDINGS secretion of PTH Impaired absorption of Ca Impaired excretion of phosphates   phosphates(renal cause)  serum phosphate in other causes Impaired production of 1,25 –Vit D3

34. TERTIARY HYPERPARATHYROIDISM Tertiary When long-standing secondary hyperplasia becomes autonomous in spite of correction of the underlying stimulant ( renal transplant , dialysis) There is minimal Vit D production and little excretion of phosphates FINDINGS increased gut absorption of Ca bone resorption of Ca Impaired excretion of phosphates  phosphates Impaired production of 1,25-VitD3 but enough for absorption of Ca

35. HYPOPARATHYROIDISM Hypoparathyroidism is a metabolic disorder characterized by low serum calcium and high serum phosphate concentrations due to a deficiency or absence of PTH secretion TYPES Primary hypoparathyroidism pseudohypoparathyroidism

36. TYPES OF HYPOPARATHYROIDISM PRIMARY HYPOPARATHYROIDISM :- parathyroid gland is either not present or atrophied or do not function normally or damage to parathyroid gland after surgical excision (acquired hypoparathyroidism). FINDING S  serum PTH concentration PSEUDOHYPOPARATHYROIDISM (PHP) parathyroid gland function is normal , but kidneys fail to respond to PTH due to deficient receptor. As a result, the parathyroid glands secretes PTH in excess, and serum-PTH is increased.

37. ETIOLOGY Some causes of hypoparathyroidism includes Injury to or removal of the parathyroid glands DiGeorge syndrome Autoimmune diseases Cancer radiation Low magnesium levels

38. SIGNS AND SYMPTOMS • Tingling or burning ( paresthesias ) Muscle aches or cramps Twitching or spasms of the muscles Fatigue or weakness Painful menstruation Patchy hair loss, such as thinning of your eyebrows Dry , coarse skin Brittle nails Headaches , seizures Depression , mood swings Memory problems

39. DIAGNOSIS PRIMARY HYPOPARATHYROIDISM :- serum calcium PTH  serum phosphate Normal alkaline phosphate PSEUDOHYPOPARATHYROIDISM Serum calcium  or normal PTH

40. TREATMENT Dietary calcium and oral supplements Vitamin D3 Magnesium supplement Phosphate binders

41. CONCLUSION Disorders of calcium metabolism can have devastating effects on the health of patients and the well being of the entire family A good understanding of calcium metabolism and associated disorders is very important as there are diverse causes affecting different age groups within the family Early diagnosis and treatment are keys to good management of this conditions and will help to control symptoms and decrease the risk of other related complex problems

42. Thank you for listening

43. References Oral Manifestations of Parathyroid Disorders and Its Dental Management Sanjeev Mittal, Deepak Gupta1 , Sahil Sekhri, Shivali Goyal . Department of Prosthodontics, MM college of Dental Sciences and Research, Mullana , Ambala , Haryana, 1 Department of Orthodontics, HS Judge Dental College, Panjab University, Chandigarh, India. Primary Hyperparathyroidism Presented as Central Giant Cell Granuloma of Jaw Bones. A Report of Three Cases Ibrahim Saeed Gataa1 BDS , FICMS Faraedon M. Zardawi2* BDS, MSc, PhD Hyperparathyroidism-jaw tumour syndrome detected by aggressive generalized osteitis fibrosa cystica Alae Guerrouani, Abdelkader Rzin, and Karim El Khatib Endocrine Physiology, 3 rd ed. P.E. Molina; Chapter 5 (Via CIAP ) Guyton & Hall Textbook of Medical physiology, 11 th ed.; J.E.Hall ; Chapter 79 Oh’s Intensive Care Manual, 6 th ed. B. Venkatesh; Chapter 54 Acute Calcium Disorders

44. References Hypocalceamia presentation by Shaila Sukthankar Calcium metabolism and hypercalceamia presentation by alex yartsev Calcium metabolism and its disorders Dr Amir Babike MBBS, FRCPCH (UK), CCT (UK), Msc in Endocrinology and Diabetes Queen Mary University, London(UK) Consultant Paediatric Endocrinologist (KKUH) Assistant Professor (KSU, KSA) Disorders of Calcium Metabolism: Hypercalcemia Steven Chessler , MD,Ph.D . March , 2015 Internal Medicine noon conference Disorders of Parathyroid Gland by Dr Irum siddiquie PGR Pediatrics Disorders of Parathyroid glands By : Garmyan Yawar University Of Sulaimani Faculty Of Medical Sciences School Of Dentistry Oral Diagnosis Department Disorders of Parathyroid Gland Dr . Jeetendra K Singh PARATHYROID GLAND By : Steph and Lindsey Calcium metablolism presentation by Dr Krishnasamy Calcium homeostasis presentation by Dr Lederer