Disorders of calcium homeostasis. FRACP part 1 lecture 2012 Peter Simm

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1 Disorders of calcium homeostasis FRACP part 1 lecture 2012 Peter Simm

2 Calcium metabolism PTH bone osteoclast (resorption) Ca kidney 1 hydroxylation of Vitamin D Ca absorption from gut 25 OH Vit D Ca from bone P, Na, HCO3, c AMP excretion PTH calcium calcitonin PTH

3 Parathyroid Hormone PTH gene on 11p exons encoding 115 aa s first 31 aa s for processing & secretion PTH 84 aa peptide 1st 34 aa s at NH2 end essential for action For PTH action Stored in cell vesicles Release stimulated by plasma Ca within seconds 1. Hormone binds to receptors on membrane of target cells 2.PTH / PTHrP receptor coupled by Gs,, to signal effector molecules on inner surface of plasma membrane 3. C AMP or Ca action Parathyroids from 3 rd & 4 th branchial arches PTH release regulated by: Ca sensing receptor Mg calcitriol

4 The Parathyroid Axis

5 Vitamin D Production Sunlight exposure (> 80%) Intake< 20% via diet, Minimal in breast milk (25 IU/L) Hydroxylation Kidney Ca &P reabsorption Inhibits 1 Hydroxylase activity Action in Bone Stimulates osteoblast activity bone mineralisation Intestine Stimulates Ca & P absorption in small intestine

6 Calcium Sensing Receptor Cell surface receptor present on Parathyroid chief cells, Renal tubular cells, C-cells of Thyroid Ligand Calcium, Magnesium Acts as the Calciostat by: (1) regulating PTH & Calcitonin secretion (2)Renal tubular calcium reabsorption

7 Clinical features of hypocalcaemia Fitting apnoea weakness & tiredness carpopedal spasm stridor irritability and other behaviour problems prolonged QT interval Cardiac failure Soft tissue and basal ganglia calcification with longer standing hypoparathyroidism or pseudohypoparathyroidism Trousseau s sign: sensitive & specific clinical sign of Hypocalcaemia (1% false positive rate) Chvostek s sign

8 Neonatal Hypocalcaemia Undetectable or low PTH Hypoparathyroidism Hypomagnesaemia Normal PTH Abnormal Calcium Sensing Receptor High PTH Vitamin D deficiency/impaired metabolism Pseudohypoparathyroidism Renal Failure Hypoparathyroidism transient premature, growth retarded 30-90% infant of diabetic mother +/_ Mg infant of Vit D deficient mother permanent 1 hypoparathyroidism Di George q HDR: (with deafness/renal dysplasia) GATA 3 gene on 10p15 J Med Genet 2000;37:33-37

9 MAJOR DIFFERENTIAL DIAGNOSES OF HYPOCALCAEMIA (1) Related to vitamin D abnormalities : COMMON: Vitamin D deficiency Suspect in darker skinned infants presenting aged 6-12 months or maternal/child history of sun avoidance or malabsorption. NB. May occur in younger children where mother wears covering clothing and is also vitamin D deficient (these infants are born without vitamin D stores and can present in as early as 3 months) RARE: VDDR type 1 1 hydroxylase deficiency autosomal recessive inheritance Ca N or, Phos n or, PTH 25 vit D N, 1,25 vit D. VITAMIN D resistant rickets RARE, VDDR type 2 due to abnormal vitamin D receptor In hormone binding domain or DNA binding domain Ca N or, Phos N or, PTH 25 vit D N, 1,25 vit D.

10 MAJOR DIFFERENTIAL DIAGNOSES OF HYPOCALCAEMIA (2) Related to parathyroid hormone: Hypoparathyroidism Ca P due to low PTH or PTH action Isolated congenital hypoparathyroidism Di George Syndrome 22q11.2 CATCH 22 + deafness X linked Kenny Caffey -with medullary tubular stenosis surgical (with total thyroidectomy/parathyroidectomy) 2 to Mg

11 2 to destruction Autoimmune + other autoimmune hormone deficiencies Abnormal calcium sensing or regulation of PTH gene Abnormal PTH gene -abnormal molecule Altered receptor (resistance) Pseudohypoparathyroidism AHO on 20q13.2

12 Imaging long-bone X-rays / skeletal survey Investigation of hypocalcaemia Biochemistry ionised Ca U&E s/crt, (LFTs) Mg,P ALP total Ca/ albumin Urinary Ca/Cr ratio 1,25 di OH vit D, 25 OH vit D Other Tests As clinically indicated: maternal vit D studies FBE/blood film/iron studies Parathyroid autoantibodies Fat soluble Vitmans (other than Vit D) Blood sample Ca and PO4- Fasting, free flowing PTH- Plastic syringe, ice fast processing Correct total Ca for ph & alb CORR Ca = Ca TOTAL + (40- Alb) x 0.02 ALP, PO4 levels high in childhood

13 Hypomagnesaemia Congenital Intestinal absorption defect Magnesium losing kidney Acquired Malabsorption Renal tubular damage eg Cisplatin Impairment of PTH secretion & action Primary familial hypomagnesaemia Autosomal recessive Tetany/convulsions in infancy, refractory to Ca Rx but respond to Mg Rx 15 cases: 13 N devt with prompt & Rx, 2 neurological impairment after delay in Selective defect of Mg absorption in small intestine Mutations in TRPM6 on 9q22- ion channel expressed in kidney & colon likely role in epithelial Mg absorption

14 Hypocalcaemia with normal PTH Familial Hypocalcaemia ( autosomal dominant) Hypercalciuria ( Urine Ca/Cr ratio > 0.3 mmol/mmol) Vitamin D Rx Nephrocalcinosis Heterozygous gain of function mutations in calcium sensing receptor Lowered setpoint for PTH secretion renal calcium excretion No treatment indicated if asymptomatic Polyuria/Polydipsia at normal plasma calcium

15 Pseudohypoparathyroidism Type Ia and Pseudopseudohypoparathyroidism Autosomal dominant Same kindreds Reduction in Gs activity Mutations in GNAS 1 gene Chromosome 20q13.2 Gs activity Maternal transmission PHP Type Ia Paternal transmission Pseudo PHP Type Ib Usually sporadic Normal Gs activity Also maps to 20q13 -?promoter of GNAS1

16 Vitamin D deficient rickets Biochemistry will vary according to duration of deficiency Ca normal or, Phos normal or PTH, alkaline phosphatase 25 OH vit D (vit D stores), 1,25 diohvit D normal or. Risk factors: Latitude/seasonal, pigmentation, skin covering, breastfeeding, malabsorption, liver disease, anticonvulsants NB rickets is a disease of growing bone. Bony changes may NOT be seen in a child who is not growing eg. before or just after liver transplant.

17 Vit D def treatment Intermittent dosing (megadose/stoss) vs regular Calcium co-treatment (early hungry bones effect) Monitoring Treating families encouraging appropriate supplementation esp breastfeeding

18 Rickets Hypophosphatemic FGF 23 related (XLH, Klotho, ADHR, ARHR, tumour induced osteomalacia) Primary defect in Na/PO4 co-transporter (HHRH have hypercalcemia as 1 α hydroxylation not inhibited) Need to assess renal handling of phosphate (serum levels variable) inappropriate losses/phosphaturia lowered renal threshold Often associated with short stature, significant bowing/lower limb deformities Treatment supplement phosphate and avoid secondary hyperparathyroidism

19 Actions of Vitamin D Estimate: 1 billion people worldwide have vitamin D deficiency or insufficiency Actions: Bone Cardiac Immune Cancer Risk 1,25-dihydroxyvitamin D controls >200 genes, for regulation of cellular proliferation, differentiation, apoptosis + angiogenesis It cellular proliferation of both normal cells & cancer cells & induces their terminal differentiation. N Engl J Med Jul 19;357(3):266-81

20 Vitamin D and sunlight: strategies for cancer prevention and other health benefits. Holick M Clin J Am Soc Nephrol Sep;3(5): % risk for developing colorectal, breast & prostate cancer by vit D intake to 1000 IU/d vit D or sun exposure to raise blood levels of 25(OH)D >60 nmol/l? local production of 1,25(OH)(2)D responsible for anticancer benefit of vitamin D vit D deficient women have 253% risk for developing colorectal cancer women who ingested 1500 mg/d calcium and 1100 IU/d vitamin D(3) for 4 yr risk for developing cancer by >60%

21 What can we learn? Calcium and vitamin D rickets (consider phosphate) awareness of risks for: Increased pigmentation apartment living mothers & sibs of affected children epileptic Rx How should issues be addressed? Public forum / education awareness of risks of indoor life government level intervention school milk programmes child health nurses information / regulation obstetric advice / education for hospitals

22 Treatment of hypocalcaemia CaCl 10% infusion if symptomatic only with ECG monitor for QT interval Need central access ideally (extravasation/iv burns) oral calcium carbonate or Ca gluconate 1,25 DiOH vitamin D g/kg/day Cholealciferol 5000 IU/ day for rickets initially (>12 months) Maintenance IU/day of 25OH D Adequate calcium intake for age Calcium carbonate- 1-2 mmol/kg/day Target calcium Ca R defect mmol/l (hypercalciuria) HP mmol/l (nephrocalcinosis) OR stoss Rx ,000IU/dose once every 6wks-6 months

23 Hypercalcaemia

24 Neonatal hypercalcaemia Fat necrosis (1,25 Vit D excess) William s syndrome familial hypocalciuric hypercalcaemia (FHH) hypophosphatasia renal failure

25 Hypercalcaemia Calcium sensing receptor related vitamin D related William s syndrome vitamin D toxicity bone turnover Vitamin A toxicity immobilization hyperparathyroidism adenoma MEN Malignancy haematological -lymphoma / leukaemia solid with metastases humoral hypercalcaemia (PTHrP)

26 More commonly seen problems Primary hyperparathyroidism 1,25 vit D excess granulomatous disease subcutaneous fat necrosis vitamin D intoxication Acute/chronic renal insufficiency Immobilisation (eg Burns) Lytic bone metastases Humoral hypercalcaemia of malignancy, especially in unusual childhood renal tumours e.g. congenital mesoblastic nephroma / malignant rhabdoid PTHrP (parathyroid hormone-related protein)

27 Primary hyperparathyroidism neonatal hyperparathyroidism 3q13 DNA encoding extracellular Ca sensing receptor 3 receptor gene mutations described hetero and homozygotes of FHH can have Neonatal HPT receptor present in parathyroid cells, C cells of thyroid and kidney interaction with Ca to PTH release & alter absorption of Ca

28 Primary hyperparathyroidism autosomal dominant - part of MEN 1 MENIN gene mutation (Chr 11q13) Pituitary (prolactin, GH) Pancreas (insulinoma, gastrinoma, VIPoma) Parathyroids (90% of MEN 1) Also carcinoid syndrome, adrenocortical hyperplasia Lesions tend to be benign, functioning adenomas (vs more malignant lesions in MEN2) 15-20% MEN2 also have parathyroid hyperplasia

29 Schlingmann et al N Engl J Med 2011; 365: Vitamin D toxicity Rare with normal physiology described with bolus therapy at high doses Recently published series of loss of function mutations in CYP24A1 (24 hydroxylase, first step in deactivating 1,25 DiOH Vitamin D) 6 infants (4 families) with idiopathic infantile hypercalcaemia (presumed AR), others with hypercalcaemia post bolus therapy (4 patients)

30 Less commonly seen problems Milk-alkali Syndrome Hypophosphatasia (alk phos + rickets-like Δ on XR) Jansen s Metaphyseal Dysplasia (1,25 vit D +rickets-like XR/increased bone resorption) Other Endocrine Disorders (usually mild hypercalcaemia): Phaeochromocytoma adrenal insufficiency/addison s thyrotoxicosis

31 Clinical featuresof hypercalcaemia GIT: nausea/vomiting RENAL: polyuria/polydipsia failure to thrive nephrocalcinosis constipation acute pancreatitis CNS: confusion/apathy CVS: hypertension drowsiness shortened QT interval impaired conscious state/coma `

32 Investigation of hypercalcaemia Biochemistry U&E s/ creatinine, phosphate, alkaline phosphatase total calcium/albumin, ionized calcium parathyroid hormone 1,25 di OH vitamin D, 25 OH vitamin D parathyroid hormone related protein 24 hour urine calcium OR calcium/creatinine ratio (spot urine) Other tests as indicated clinically: eg TFT s, 8am cortisol, urinary catecholamines Imaging Skeletal Survey Renal ultrasound for evidence of nephrocalcinosis Other tests as indicated clinically: bone scan etc.

33 Treatment of hypercalcaemia Immediate management REHYDRATION with normal saline/5% dextrose (there is renal co-excretion of Na & Ca). In infants <2 years, use N/2 saline /5% dextrose. MONITOR fluid status 4hrly to prevent fluid overload. B.D. weight, 2-4hrly TPR/BP

34 LOW CALCIUM DIET (Locosol) Longer term measures STEROIDS particularly for conditions related to vitamin D excess eg. subcutaneous fat necrosis, leukaemia associated hypercalcaemia, granulomatous disease. (Prednisolone 2mg/kg/day and taper according to response.) BISPHOSPHONATES particularly for conditions associated with increased bone resorption e.g. immobilisation, PTHrP associated malignancies. Onset of effect is in hours,peak effect within a week. Pamidronate mg/kg infuse I.V. in 2-500ml N saline 2/24 Zoledronic acid mg/kg infuse I.V. in 2-500ml saline over 15 mins. Onset of action more rapid normalisation of calcium usually byday 4 TREATMENT OF UNDERLYING CONDITION IF POSSIBLE

35 Bone health issues Requirements to achieve normal bone health outcomes: Activity/muscle pull Calcium Vitamin D Puberty/gonadal function Adequate nutrition Minimizing falls/impact of falls Avoidance/minimizing of agents that impair bone mass accrual (prednisolone,??aeds)

36 Bone density assessment DXA scanning Measures bone mineral content and bone area Estimates bone mineral density (areal) Advantages Well validated, proven link to fracture risk Good reference data Assess multiple sites (lumbar spine, hip, total body less head, forearm) Body composition Low radiation

37 DXA limitations Stature affects areal measurement Maturational delay/advancement validity of age matched Z scores

38 Other methods of assessment Peripheral quantitative computerized tomography (pqct) Advantages True volumetric density Trabecular vs cortical bone Skeletal geometry, including bending strength Muscle cross sectional area/muscle bone subunit Limitations Peripheral (appendicular) skeleton only Presence of growth plate/reproducibility