1. Clinical aspects of common mineral disorders

2. hypocalcemia Normal [Ca2+] total = 8.5-10.5 mg/dl (2.12-2.62 mmol/L) Normal [Ca2+] ion = 4.65-5.25 mg/dL (1.16-1.31 mmol/L)

3. hypercalcemia Normal [Ca2+] total = 8.5-10.5 mg/dl (2.12-2.62 mmol/L) Normal [Ca2+] ion = 4.65-5.25 mg/dL (1.16-1.31 mmol/L)

4. hypophosphatemia Normal [P] = 2.5-4.5 mg/dl (0.75- 1.45 mmol/L)

5. hyperphosphatemia Normal [P] = 2.5-4.5 mg/dl (0.75- 1.45 mmol/L) ? acute phosphate nephropathy increased cardiovascular calcifications and associated morbidity and mortality

6. Calcium Homeostasis [Ca ICF ]~100nM [Ca ECF ]~1.2mM total serum Ca 2.2-2.6 mM (8.5-10.5 mg%) 5% passive absorption 20-70% (OH) 2 D –extremes?

7. Causes of hypercalcemia –1° hyperparathyroidism –malignancy-related –vitamin D-related: intoxication, sarcoid, etc. –high bone turnover: hyperthyroid, immobility –associated with renal failure: tertiary hyperparathyroidism aluminum and adynamic bone disease milk-alkali syndrome 90%

8. Primary hyperparathyroidism –solitary adenoma –parathyroid hyperplasia –multiple endocrine neoplasia (MEN) MEN1; MENIN tumor suppressor MEN2A, MEN2B; RET proto-oncogene FHH – CaSR mutations

9. Hypercalcemia of malignancy –humoral; tumor secretes PTHrP squamous cell carcinoma renal tumors many others –direct bone marrow invasion – bone resorption and local destruction by cytokines –1,25(OH) 2 D

11. Clinical features of hypercalcemia –fatigue –depression –confusion –anorexia, nausea, vomiting, constipation –polyuria –calcifications, renal failure –coma –cardiac arrest

12. Stones refers to kidney stones, nephrocalcinosis, and DI insipidus Bones refers to bone-related complications. The classic bone disease Abdominal groans refers to gastrointestinal symptoms of constipation, anorexia, nausea and vomiting. Hypercalcemia can lead to peptic ulcers and acute pancreatitis. Psychiatric moans refers to effects on the central nervous system; lethargy, fatigue, depression, memory loss, psychosis, ataxia, delirium, coma

14. phosphate?

16. Indications for surgery in 1° HPTH: –serum Ca > 2.9 mmol/l –urine Ca > 400 mg/d –creatinine clearance reduced 30% –age < 50 –osteoporosis

17. Calcium Homeostasis [Ca ICF ]~100nM [Ca ECF ]~1.2mM total serum Ca 2.2-2.6 mM (8.5-10.5 mg%) 5% passive absorption 20-70% (OH) 2 D –extremes?

18. Mechanisms of hypocalcemia: –PTH absent: hereditary, acquired, ↓Mg –PTH ineffective: CRF, vit. D deficiency or resistance, pseudohypoparathyroidism –PTH overwhelmed: severe acute hyperphosphatemia, hungry bone (osteitis fibrosa after parathyroidectomy)

21. Phosphorus Homeostasis 600 g phosphorus 85% in bone [P ICF ]~[P ECF ] [P ECF ] = 0.75-1.45 mM (2.5-4.5 mg/dl) Diet: 0.5-1 g/d Absorption 65% -> 90% with 1,25(OH) 2 D Torres et al. KI 2011

22. HYPERPHOSPHATEMIA

23. Phosphate intake above 4 g/day causes only small elevations in serum phosphate concentrations as long as the intake is distributed over the course of the day. An acute phosphate load given over several hours causes transient hyperphosphatemia. Thus, the diagnostic approach to hyperphos- phatemia involves identification of the reason that phosphate entry into the extracellular fluid exceeds the rate at which it can be excreted.

24. There are three general circumstances in which this occurs: –massive acute phosphate load –primary increase in proximal phosphate reabsorption –renal failure (decreased filtration)

25. Phosphate load: –tumor lysis syndrome –rhabdomyolysis –crush injury –hyperthermia –fulminant hepatitis –hemolysis –acidosis –exogenous administration

26. Increased phosphate reabsorption –hypoparathyroidism –parathyroid suppression hypercalcemia –vitamin D or vitamin A intoxication –sarcoidosis, granulomatous diseases –immobilization, osteolytic metastases hypomagnesemia and hypermagnesemia –pseudohypoparathyroidism –acromegaly –tumoral calcinosis –heparin therapy

27. Clinical findings in acute ↑ P: –calcium phosphate precipitates –hypocalcemia Treatment of acute ↑ P: –volume expansion –aluminum hydroxide, sevelamer –hemodialysis

28. HYPOPHOSPHATEMIA

29. 600 g phosphorus 85% in bone [P ECF ]~[P ICF ] [P ECF ] = 0.75-1.45 mmol/l (2.5-4.5 mg/dl) Diet: 0.5-1 g/d Absorption 65% -> 90% with 1,25(OH) 2 D Torres et al. KI 2011

30. Mechanisms of hypophosphatemia: –Impaired intestinal absorption –Reduced renal phosphate reabsorption PTH/PTHrP-dependent PTH/PTHrP-independent –Shifts into cells –Accelerated bone formation

31. Decreased intestinal absorption –Inadequate intake –Antacids containing aluminum or magnesium –Steatorrhea and chronic diarrhea –Vitamin D deficiency or resistance

32. Increased urinary excretion –Primary hyperparathyroidism and FHH –2° HPTH incl. vit D deficiency or resistance –Hereditary hypophosphatemic rickets –PTHrP-dependent hypercalcemia –Oncogenic osteomalacia –Fanconi syndrome –Other - osmotic diuresis, acetazolamide, acute volume expansion

33. Internal redistribution –Increased insulin secretion, particularly during refeeding –Acute respiratory alkalosis –Hungry bone syndrome following parathyroidectomy osteoblastic metastases

34. Clinical findings of hypophosphatemia –neuromuscular weakness confusion hallucinations oculomotor palsies ataxia paralysis seizures coma rhabdomylysis –respiratory failure, cardiac dysfunction –hemolysis, defective leukocyte and platelet function

35. Treatment of acute hypophosphatemia –correct hypocalcemia first –intravenous phosphate over 6 hours avoid high Ca×P products –oral phosphate Management of chronic hypophosphatemia –vit D with calcium for vit D deficiency –oral phosphate and 1,25(OH) 2 D for blocks –resection of tumor in TIO