This lecture explains the basics of calcium and phosphate metabolism, types, mechanisms involved, etiology, symptoms, diagnosis, management and other related aspects.
Outline of Lecture
Disorders Of Calcium Metabolism
Parathyroid hormone (PTH)
Calcitriol (active form of vitamin D3)
Role of PTH
Stimulates renal reabsorption of calcium
Inhibits renal reabsorption of phosphate
Stimulates bone resorption
Inhibits bone formation and mineralization
Stimulates synthesis of calcitriol
Regulation of PTH
Low serum [Ca+2] à Increased PTH secretion
High serum [Ca+2] Decreased PTH secretion
Role of Calcitriol
Stimulates GI absorption of both calcium and phosphate
Stimulates renal reabsorption of both calcium and phosphate
Stimulates bone resorption
Regulation of Calcitriol
Overview of Calcium-Phosphate Regulation
Different Forms of Calcium
At any one time, most of the calcium in the body exists as the mineral hydroxyapatite, Ca10(PO4)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)
To estimate the physiologic levels of ionized calcium in states of hypoalbuminemia:
[Ca+2]Corrected = [Ca+2]Measured + [ 0.8 (4 – Albumin) ]
Etiologies of Hypercalcemia
Increased GI Absorption
Milk-alkali syndrome
Elevated calcitriol
Vitamin D excess
Excessive dietary intake
Granuomatous diseases
Elevated PTH
Hypophosphatemia
Increased Loss From Bone
Increased net bone resorption
Elevated PTH
Hyperparathyroidism
Malignancy
Osteolytic metastases
PTHrP secreting tumor
Increased bone turnover
Paget’s disease of bone
Hyperthyroidism
Etiologies of Hypocalcemia
Decreased GI Absorption
Poor dietary intake of calcium
Impaired absorption of calcium
Vitamin D deficiency
Poor dietary intake of vitamin D
Malabsorption syndromes
Decreased conversion of vit. D to calcitriol
Liver failure
Renal failure
Low PTH
Hyperphosphatemia
Decreased Bone Resorption/Increased Mineralization
Low PTH (aka hypoparathyroidism)
PTH resistance (aka pseudohypoparathyroidism)
Vitamin D deficiency / low calcitriol
Hungry bones syndrome
Osteoblastic metastases
Overview of Phosphate Balance
Etiologies of Hyperphosphatemia
Increased GI Intake
Fleet’s Phospho-Soda
Decreased Urinary Excretion
Renal Failure
Low PTH (hypoparathyroidism)
s/p thyroidectomy
s/p I131 treatment for Graves disease of thyroid cancer
Autoimmune hypoparathyroidism
Cell Lysis
Rhabdomyolysis
Tumor lysis syndrome
Etiologies of Hypophosphatemia
Decreased GI Absorption
Decreased dietary intake (rare in isolation)
Diarrhea / Malabsorption
Phosphate binders (calcium acetate, Al & Mg containing antacids)
Decreased Bone Resorption / Increased Bone Mineralization
Vitamin D deficiency / low calcitriol
Hungry bones syndrome
Osteoblastic metastases
Increased Urinary Excretion
Elevated PTH (as in primary hyperparathyroidism)
Vitamin D deficiency / low calcitriol
Fanconi syndrome
Internal Redistribution (due to acute stimulation of glycolysis)
Refeeding syndrome (seen in starvation, anorexia, and alcholism)
During treatment for DKA
Case 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. Labs are as follows:
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
Case 2
A 40 year old man with a history of alcoholism. He had not seen a doctor for 15 years before police brought him to the ER after finding him confused and disheveled behind a local convenience store. In the ER, he was thought to be confused simply due to intoxication, but was admitted for mild alcoholic hepatitis and marked malnutrition. His mental status cleared up about 8 hours after admission. During morning rounds on hospital day #2, he complained of feeling fatigued and weak. Later that day, the nurses find him seizing. The seizures stop with low dose IV diazepam. Stat labs are sent:
Sodium – 136 meq/L
Potassium – 3.2 meq/L
Calcium (total) – 6.8 mg/dL (normal ~ 8.5-10.2 mg/dL)
Phosphate – 0.7 mg/dL (normal ~ 2.0-4.3 mg/dL)
Albumin – 1.8 g/dL (normal ~ 3.5-5.0 g/dL)
Creatinine – 1.3 mg/dL
CK – 3500 U/L
Case 3
A 74 year old man with a past history significant for hypertension and COPD from smoking 2 packs per day for the last 40 years. He presented to an urgent pulmonary clinic appointment with 2 months of increased cough and 5 days of “mild” hemoptysis. Upon further obtaining further history, he reports feeling fatigued, nauseous, and chronically thirsty for several weeks. His exam is significant for bilateral rhonchi (no change from baseline lung exam) and absent reflexes. Stat labs are ordered from clinic:
Sodium – 138 meq/L CBC, PT/PTT – WNL
Potassium – 3.7 meq/L PTH – Pending
Magnesium – 1.8 mg/dL Albumin – 2.2 g/dL
Calcium (total) – 13.1 mg/dL
Phosphate – 1.3 mg/dL
Creatinine – 2.8 mg/dL (baseline creatinine = 1.1)
Case 4
A 16 year old woman with no significant past medical history, who is brought to the ER by her mother after she noted her to be acting bizarrely for the past several weeks. Thought to be actively psychotic, a psychiatry consult is asked to see the patient, who recommends checking routine labs:
Sodium – 142 meq/L Urine tox. screen – Negative
Potassium – 4.1 meq/L Urine pregnancy – Negative
Magnesium – 2.3 mg/dL
Calcium (total) – 6.9 mg/dL
Phosphate – 4.4 mg/dL
Albumin – 4.2 g/dL
Creatinine – 0.8 mg/dL
Metabolic Bone Disease
Hypercalcaemia
Hyperparathyroid bone disease
Hypocalcaemia
Osteomalacia
Pagets Disease
Actions of PTH
Increase [Ca2+], decrease [PO42-]
In bone
osteoclastic reabsorption releases Ca2+ and PO42-
In kidney
increased PO42- excretion
increased Ca2+ reabsorption
increased hydroxylation of vitamin D
Actions of vitamin D
Kidney
decreased Ca2+ excretion
Bone
increased bone mineralisation
Small bowel
increased Ca2+ and PO42- absorption
Case 1
63 year old woman
abdo pains, nocturia, kidney stones
generally unwell
Hb 12.9 (11.5-16.5) Calcium 3.05 (2.2-2.6)
WCC 4.7 (4.9-11.0) Phosphate 0.82 (0.85-1.45)
Plt 253 (150-400) Albumin 39 (35-50)
ESR 12 Alk Phos 96 (25-96)
Clotting Normal Total protein 72 (60-80)
Urea 10.2 (3.0-6.5) LFTs normal
Creat 142 (35-120)
results
Bone scan: Normal
PTH: 5.6 pmol/L (1.1—6.5)
Xrays, other scans….
Metabolic Bone Disease
Hypocalcaemia
Hyper parathyroid bone disease
Hypocalcaemia
Osteomalacia
Pagets Disease
Hyperparathyroidism
[Ca2+] high [PO42-] lowPTH high
Prevalence 1 in 1000 (ish)
Primary hyperparathyroidism:
Often an incidental finding
May be part of MEN I, MEN II
Secondary hyperparathyroidism
Compensates for chronic low Ca eg. Renal failure or malabsorption
[Ca2+] and [PO42-] normal PTH highTertiary hyperparathyroidism
Hyperplasia in longstanding secondary disease
Primary hyperparathyroidism
PTH raised inappropriately relative to [Ca2+]
may be within normal range
Pathology:
Single adenoma 85%
hyperplasia 14%
due to carcinoma <1%
Xrays can be helpful if chronic
bone scan negative unless severe
Management:
moderate [Ca2+] (<2.9mmol/l) watch
high [Ca2+], renal failure, symptomatic parathyroidectomy by experienced surgeon
Sestamibi scan can be used to localise
Case 2
investigations
Immunoglobulins:
IgA 0.3g/l (0.5-4.0)
IgG 16.9g/l (5.0-15)
IgM 0.4g/l (0.6-2.8)
Monoclonal band on electophoresis
bence jones protein positive: Kappa chains
Xray appearance
holes in bone without sclerotic reaction
no reaction of the host bone to the lesions
Bone scan may be negative
Myeloma
Management
Immediate care:
treat hypercalcaemia
renal input
haematology input
Metabolic Bone Disease
Hypercalcaemia
Hyperparathyroid bone disease
Hypocalcaemia
Osteomalacia
Pagets Disease
Hypercalcaemia
Hyperparathyroidism
Malignancy
Myeloma
Increased Calcium or vitamin D intake
Others
sarcoid
adrenal failure
Hypercalcaemia
Malaise
Muscle weakness
Confusion
Lethargy
Kidney stones
Constipation
Re-hydrate
consider i.v. bisphosphonate
Treat cause
?steroids
Case 3
Case 3
65 male with Ca prostate, ? Metastatic
Hb 13.9 (13.0-18.0) Calcium 2.3 (2.2-2.6)
WCC 9.7 (4.9-11.0) Phosphate 0.89 (0.85-1.45)
Plt 222 (150-400) Albumin 39 (35-50)
ESR 1 Alk Phos 985 (25-96)
Clotting Normal Total protein 71 (60-80)
Urea 4.5 (3.0-6.5) LFTs normal
Creat 112 (35-120)
Pagets Disease
Disease of bone remodelling
osteoclast mediated bone resorption followed by new bone formation
Disorganised mosaic pattern bone with increased vascularity and fibrosis
Cause unknown ?virus
paramyxovirus, canine distemper
More common in caucasian
M:F ratio 3:2 10% in over 70’s
Pagets Disease: clinical manifestations
Bone pain
Joint pain
Deformity
Spontaneous fractures
Alk Phos high
[Ca2+] normal unless immobilised
Pagets Disease: complications
Fractures
Deafness
Nerve entrapment
Spinal stenosis
Cardiac failure
Osteogenic sarcoma
Hypercalcaemia
Pagets Disease: investigations
Raised serum alk phos
Urinary hydroxyproline, pyridinoline cross-links
Radiology
cortical thickening
osteolytic, osteosclerotic and mixed lesions
osteoporosis circumscripta
bone scan
Pagets Disease: treatment
Bisphosphonates
Disodium etidronate
risedronate
Pamidronate (iv)
Calcitonin
Pagets: Indications for Therapy:
bone pain
osteolytic lesion in wt bearing bone
neurological complications
mal-union of fractures
immobilisation hypercalcaemia
pre- or post-surgery
Case 4
Case 4
63 woman post-op parathyroidectomy
acutely unwell, paresthesiae
muscular irritability
Hb 12.9 (11.5-16.5) Calcium 2.2 (2.2-2.6)
WCC 4.7 (4.9-11.0) Phosphate 0.84 (0.85-1.45)
Plt 253 (150-400) Albumin 39 (35-50)
ESR 12 Alk Phos 96 (25-96)
Clotting Normal Total protein 72 (60-80)
Urea 6.5 (3.0-6.5) LFTs normal
Creat 132 (35-120)
Signs of hypocalcaemia
Chvostek’s sign:
tap facial nerve twitching of facial muscles
Trousseau’s sign:
Inflate arm cuff > diastolic BP 3 minutes carpopedal spasm
Flexion at Wrist
Flexion at MCP joints
Flexion of thumb against palm
Extension of PIP joints and DIP joints
Adduction of fingers (forms a cone)
Hypocalcaemia: causes
Post-surgical!
Hypoparathyroidism
Hypovitaminosis D (osteomalacia)
Renal failure
Others eg. Rhabdomyolysis, sepsis
Hypocalcaemia: clinical features
Neuromuscular excitability
Tetani
Seizures
Muscle weakness
Confusion
Paresthesiae
Prolonged Q-T syndrome
Treatment
In this case:
Restore calcium levels with immediate infusion of calcium gluconate in saline
