Disorders of Calcium and

Phosphate Metabolism
ANISH JOSHI

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 Major Mediators of Calcium and
Phosphate Balance

 Parathyroid hormone (PTH)

 Calcitriol (active form of vitamin D3)

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 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

Net effect of PTH  ↑ serum calcium

↓ serum phosphate
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 Regulation of PTH

Low serum [Ca+2]  Increased PTH secretion

High serum [Ca+2]  Decreased PTH secretion

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 Role of Calcitriol
 Stimulates GI absorption of both calcium
and phosphate
 Stimulates renal reabsorption of both
calcium and phosphate
 Stimulates bone resorption

Net effect of calcitriol  ↑ serum calcium

↑ serum phosphate

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Regulation of Calcitriol

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Overview of Calcium-Phosphate Regulation

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 Ca++
 Most abundant cation
 1.2 to 1.4 kg of calcium
 99 % in bone, 1% in cells of soft tissue,
0.15 % in ECF

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 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) ] 9

 Values
 Normal serum calcium levels are 8 to 10
mg/dL (2.0 to 2.5 mmol/L)
 Normal ionized calcium levels are 4 to 5.6
mg /dL (1 to 1.4 mmol per L)
 Hypercalcemia is defined as total serum
calcium > 10.5 mg/dl(>2.5 m mol/L ) or
ionized serum calcium > 5.6 mg/dl ( >1.4 m
mol/L )

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 Values..
 Severe hypercalemia is defined as total serum
calcium > 14 mg/dl (> 3.5 mmol/L)
 Hypercalcemic crises is present when severe
neurological symptoms or cardiac
arrhythmias are present in a patient with a
serum calcium > 14 mg/dl (> 3.5 mmol/L) or
when the serum calcium is > 16 mg/dl (> 4
mmol/L)

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Overview of Calcium Balance

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 Etiologies of Hypercalcemia

Increased GI Absorption Decreased Bone Mineralization

Milk-alkali syndrome
Elevated calcitriol Elevated PTH
Vitamin D excess Aluminum toxicity
Excessive dietary intake
Granuomatous diseases
Elevated PTH Decreased Urinary Excretion
Hypophosphatemia
Thiazide diuretics
Increased Loss From Bone Elevated calcitriol
Increased net bone resorption
Elevated PTH Elevated PTH
Hyperparathyroidism( 1O 2O) Familial Hypocalciuric
Malignancy hypercalcemia
Osteolytic metastases
PTHrP secreting tumor Acure Adrenal
Increased bone turnover insufficiency
Paget’s disease of bone Li, Vitamin A
Hyperthyroidism
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 Differential Diagnosis
 Hyperparathyroidism : most common
 Malignancy : second most common ,
(severe hypercalcemia and hypercalcemic
crises)
squamous carcinoma of the lung 、 breast
cancer 、 renal cell cancer ,head and neck
squamous cancer 、 multiple myeloma
,hematogenous and lymphomatous
malignancies
 Together they account for > 90% of cases

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 Differential Diagnosis
 Primary hyperparathyroidism is usually
secondary to a parathyroid adenoma (85%),
parathyroid hyperplasia (15%) and rarely due
to a parathyroid carcinoma (< 1%)
 Primary hyperparathyroidism rarely
produces severe hypercalcemia and/or a
hypercalcemic crises, unless renal insufficiency
+/- dehydration is superimposed on the
underlying hyperparathyroidism

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 Differential Diagnosis
 Malignancy accounts for the majority of
cases of severe hypercalcemia and
hypercalcemic crises
 Malignancy increases osteoclastic activity by
two mechanisms - production of a PTH-like
substance called PTH-related protein = PTHrP
(humoral hypercalcemia of malignancy -
HHM - 80% of cases) and due to local
osteoclastic activity secondary to bone
metastasis (local osteolytic hypercalcemia
of malignancy - 20% of cases)
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 Differential Diagnosis
 Granulomatous disease :
sarcoidosis 、 tuberculosis 、 leprosy 、 berylliosis
histoplasmosis/coccidiomycosis
disseminated candidiasis/cryptococcosis
 Non-parathyroid endocrine disorders :
Hyperthyroidism 、 adrenal insufficiency
pheochromocytoma

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 Clinical Manifestations
 Hypercalcemia leads to hyperpolarization of
cell membranes
 Patients with levels of calcium between 10.5
and 12 mg /dl can be asymptomatic.
 When the serum calcium level rises above this
stage, multisystem manifestations become
apparent

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 Clinical Manifestations
 CVS : Shortened QT interval on electrocardiogram,
bradyarrhythmias and heart block and cardiac arrest
 Renal : polyuria , nephrolithiasis, impaired concentrating
ability, dehydration.
 GI : anorexia , nausea , vomiting , constipation ,
Pancreatitis , PUD
 CNS : weakness , fatigue , confusion , stupor , altered
behavior, including lethargy, depression, decreased
alertness, obtundation, and coma
 Cornea : band keratopathy
 Skeletal: Increased bone resorption, fracture risk

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 Treatment
 Increase renal calcium excretion
 Saline/fluid hydration :

4 to 6 L IV 0.9 % NS daily for 1 to 3 days

 Diuretics: Frusemide. Avoid thiazides
 Inhibition of bone resorption
 Biphosphonates :

Pamidronate (Aredia), 60 to 90 mg IV over 4 hours.

Maximal effect at 2-3 days. Lasts for several weeks

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 Treatment
 Inhibition of bone resorption and increased renal
excretion
 Calcitonin :

4 to 8 IU per kg IM or SQ every 6 hours for 24 hours

 Plicamycin (Mitharmycin) :
25 mcg per kg per day IV over 6 hours for 3 to 8 doses
Not used due to toxicity, avoided in renal, hepatic &
marrow disorders

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 Treatment
Gallium nitrate :
100 to 200 mg per m2 IV over 24 hours for 5 days
Not used due to nephrotoxicity
 Inhibits absorption & vitamin D conversion to
calcitriol
 Glucocorticoids :

Hydrocortisone, 200 mg IV daily for 3 days

 Ketoconazole & Hydroxyl chloroquine
 Oral phosphates
 Hemodialysis :
used in patients with renal failure
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 Treatment
 Clinical indications for surgery in patients
with primary hyperparathyroidism :
1. Significant symptoms of life threatening hypercalcemia
2. Nephrolithiasis
3. Decreased bone mass (> 2 standard deviations below
mean for age)
4. Serum calcium > 12mg/dl
5. Age < 50 years
6. Infeasibility of long-term follow-up
7. Reduced creatinine clearance (<70% of that for age-
matched healthy people)
8. Raised 24 h urinary calcium excretion (> 400 mg)
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 Treatment
 Medical management of primary
hyperparathyroidism :
---medical therapy with drugs have not been shown to
affect the eventual outcome
---Oestrogens (premarin 1.25mg/day) preserve bone mass
in post-menopausal females
---Well-hydrated by drinking 2 - 3 litres of fluid, and 8 - 10
g of salt daily
-- Dietary restriction of calcium is not necessary , thiazide
diuretics must not be used
---Oral phosphate should only be used if symptomatic
hypercalcemia cannot be corrected surgically
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 Treatment
 Medical management of
hypercalcemia in cancer patients :
--- 2 - 3 litres per day + 8 - 10g of salt/day
--- Pamridonate can be used every few weeks to
keep the serum calcium in the normal range
--- Prednisone (20 - 50 mg bid) is only useful in
certain malignancies eg. multiple myeloma and
certain lymphomas

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 Treatment
 Medical management of other
disorders :
--prednisone and low-calcium diet ( < 400 mg/day )

 Medical management of
hypercalcemia in sarcoidosis :
--a low dose of prednisone (10 - 20 mg/day) is
usually adequate

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Hypocalcemia

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 Etiologies of Hypocalcemia
Increased Urinary Excretion
Low PTH
Thyroidectomy
Decreased GI Absorption
Poor dietary intake of calcium I131 treatment
Impaired absorption of calcium
Autoimmune hypoparathyroidism
Vitamin D deficiency
Poor dietary intake of vitamin D PTH resistance
Vit D dependent rickets
Malabsorption syndromes Vitamin D deficiency / low calcitriol
Decreased conversion of vit. D to calcitriol
Liver failure
Hypoalbuminemia
Renal failure Misc Fat embolism, Cardiopul. bypass
Low PTH
Hyperphosphatemia Met or resp. alkalosis

Decreased Bone Resorption/Increased Mineralization

Sepsis, Toxic shock syndrome
Low PTH (hypoparathyroidism) Ac. Pancreatitis, Burns
PTH resistance (pseudohypoparathyroidism)
Vitamin D deficiency / low calcitriol Massive citrated BT
Hungry bones syndrome
Osteoblastic metastases Severe Acute hyperphosphatemia
Hypomagnesemia
Tumorlysis synd
ARF 30

Rhabdomyolysis
HYPOCALCEMIA: SIGNS AND
SYMPTOMS
 NEUROMUSCULAR: INVOLUNTARY MUSCLE CONTRACTION
(TETANY), 7TH CRANIAL NERVE EXCITABILITY (CHVOSTEK’S SIGN),
NUMBNESS AND TINGLING IN FACE, HANDS, AND FEET,
TROUSSEAU’S SIGN, LARYNGOSPASM.
 CNS: IRRITABILITY, SEIZURES, PERSONALITY CHANGE,
IMPAIRED COGNITION, CALCIFICATION OF BASAL GANGLIA.
 CARDIOVASCULAR: QT PROLONGATION ON ECG, IN THE
EXTREME, ELECTROMECHANICAL DISSOCIATION MAY OCCUR,
REVERSIBLE HEART FAILURE, HYPOTENSION, VASODILATATION.

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Mild hypocalcaemia
• No treatment (investigate – PTH, PO4, 25-OHD,
Mg, ttg, ALP)
• Treat underlying causes
• Oral Calcium 500 mg – 2 to 6 tabs daily
• Oral Calcium and Vitamin D3(Calcitriol) – 1000
mg and 800 iu daily
•Fastest onset,shortest duration of action
•Disadvantage- higher cost
• Vitamin D(ergocalciferol)
• Low cost, long half life and storage in fat
• Disadvantage- vitamin D intoxication
several weeks to achieve full 32

effect
 Severe hypocalcaemia

 Calcium gluconate 10% (90 mg/10 ml)- 10 ml slow i.v.

bolus
 Calcium gluconate 10% - 60 ml infusion in 500 ml of
D5 over 24 hours
 If iv Ca does not relieve tetany rule out and correct
hypomagnesemia.
 Start oral alfacalcidol 1- 2 mcg daily
 Monitor calcium at least daily and adjust / await Ix

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 PHOSPHATE HOMEOSTASIS

 Essential element.
 Pi containing compounds have imp. roles in,
1. Cell structure (cell membrane and nucleic
acids),
2. Cellular metabolism (generation of ATP),
3. Regulation of subcellular processes
(phosphorylation of key enzymes),
4. Maintenance of acid–base homeostasis
(urinary buffering).
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 Normal Values
 In the average adult, total body phosphorus
content is 700 g,
 Distribution:
1. Bone and teeth – 85% , 14%
2. Soft tissues – 14%,
3. ECF - 1%.
 Daily Intake - 800–1,400 mg/day.
 Normal- 2.5–4.5 mg/dl

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 Overview of Phosphate Balance

High risk groups

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 The serum assay measures inorganic
orthophosphates, of which 10% are bound to
protein, 5% are complexed with Ca & Mg, & 85%
are H2PO4– and HPO4 2–.
 In theory, there are potentially four species of
free orthophosphate that can be measured
(H2PO4– , HPO4 2–, H3PO4and PO4 3–),
 At physiologic pH, H3PO4 and PO4 3–
concentrations are negligible.

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 Circadian rhythm

1. Rapidly decreasing in the early morning, reaching a

nadir of 3.3 ± 0.3 mg/dl at 11a.m.,
2. Increasing to a plateau at 4 p.m., and
3. Peaking at 4.6 ± 0.2 mg/dl between 1a.m.& 3 a.m.
 So measured in fasting state

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 In urine, Pi is an effective buffer, a function of its
relatively high tubular conc.& pKa of 6.8, which
is close to the pH of urine under normal
conditions.
 Maintaining normal phosphorus concentrations
is essential for optimal cellular function.

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 The kidney & the small int. are the main organs
that maintain Pi homeostasis.
 Intestinal phosphorus absorption occurs through
both cellular and paracellular pathways.
 Transepithelial phosphate transport across intact
int. epithelium is driven by an active Na
dependent process.
 In proximal tubule cells and enterocytes, type II
sodium–phosphate cotransporters (NaPi-II) are
expressed in the apical membrane;
 Their activity limits transepithelial phosphate
transport.
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 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 / Nutritional recovery 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 alcoholism)
During treatment for DKA
Respiratory alkalosis 44
Dextrose infusions
 Clinical features
 Acute
 Muscular: Rhabdomyolysis, Proximal muscle weakness,
Impaired diaphramgatic function, Respiratory failure,
difficulty in weaning from ventilator
 CVS: CHF, Cardiomyopathy
 CNS: Paresthesias, Dysarthria, Confusion, Seizures &
coma
 Haemat: Lt. shift of O2 dissociation curve, haemolysis &
tissue hypoxia, Impaired phagocytosis & opsonization
leading to increased chance of bacterial & fungal infections
 Chronic
 Rickets (Children) & Osteomalacia (Adults)

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 Mod.(1.0–2.5 mg/dl) & severe (<1.0
mg/dl) hypophosphatemia.

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 Oral phosphorus is available from milk &
milk products. Milk contains 1 gram of
inorganic phosphate/L.
 Solutions like Na3PO4 & K3PO4 & neutral
sodium phosphate. Upto 3 gms in divided
doses in 24 hours.
 Correct hypokalemia & hypomagnesemia

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 Etiologies of Hyperphosphatemia
Increased GI Intake
Fleet’s Phospho-Soda
Vit D intoxication

Decreased Urinary Excretion

Renal Failure (ARF, CRF)
Low PTH (hypoparathyroidism)
Thyroidectomy
I131 treatment for Graves disease / thyroid cancer
Autoimmune hypoparathyroidism
Acromegaly
Thyrotoxicosis

Cell Lysis
Rhabdomyolysis
Tumor lysis syndrome
Haemolysis
Misc
Met or resp. acidosis

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 Clinical features
 Due to hypocalcemia & ectopic
calcification of soft tissue including blood
vessels, cornea, skin & kidney
 Chronic: Renal osteodystrophy

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 Restricting dietary PO4 to 600-900 mg/d.
 Avoid phosphorus rich products like milk & dairy products
& carbonated beverages containing phosphoric acid
 Phosphate binding agents: Ca acetate, carbonate or
AlOH3
 Administered with meals. AlOH3 if used on long term basis in
renal failure may cause aluminium toxicity causing adynamic
bone disease, proximal myopathy & anaemia.
 If hyperphosphatemia & hypocalcemia coexist correct
hyperphosphatemia first before correcting hypocalcemia.
Keep Ca Pi product below 60, so as to minimize ectopic
calcification
 Saline diuresis
 Direct removal: Dialysis

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Thank you !! 52