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Disorders of Calcium and Phosphate Metabolism

This lecture explains the basics of calcium and phosphate metabolism, types, mechanisms involved, etiology, symptoms, diagnosis, management and other related aspects.

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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-] low

PTH 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 high

Tertiary 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

 

 

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