hypercalcemia atee
TRANSCRIPT
Discuss the differential diagnosis and laboratory investigations of a 50-year old woman who
presents with a serum calcium concentration of 3.8 mmol/L
Dr Nur Karyatee bt KassimMpath 4th yr
DefinitionPathophysiologySigns and symptoms Causes
Hypercalcaemia
Common condition ◦ Prevalence of <2 % in the general population◦ 4% in the hospital population
Malignancy commonest cause in hospital patients Primary hyperparathyroidism commonest in general
population
Pathophysiology
Occurs when calcium influx into the ECF from the intestine and/or bone exceeds renal calcium excretory capacity.
Hypercalcemia…..
Defination Hypercalcemia is defined as total serum
calcium > 10.2 mg/dl(>2.5 mmol/L ) or ionized serum calcium > 5.6 mg/dl ( >1.4 m mol/L )
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).
Definition
• Concentration in ECF maintained within narrow limit (2.2 – 2.6 mmol/L) by a control of hormones:
a)Parathyroid hormone (PTH)b)Calcitriol (1,25-dihydroxycholecalciferol)c)Calcitonin- minor role
Principle organ systems : a)Gutb)Bonec)Kidneys
Homeostasis
Ca Homeostasis
Bone◦ Inhibits osteoblasts◦ Accelerates osteoclastic bone resorption
Kidneys◦ Increases renal tubular reabsorption of Ca◦ Increases PO4 excretion◦ Increases calcitriol activity (1-hydroxylation) indirectly
raises [Ca] Gut
◦ Does not directly affect GIT absorption of Ca◦ Effects are mediated indirectly through regulation of
synthesis of calcitriol
PTH - Actions
Vitamin DGut (Principal target)
Increases absorption of Ca and PO4
BoneEnhances bone resorption
32- amino acid hormone Produced Parafollicular C cells of thyroid Weak inhibitor of osteoclasts Opposes PTH effects of kidneys
◦ Promotes Ca and PO4 excretion Its exact physiological role in human is
uncertain◦ Has few long term effects on serum Ca
Calcitonin
Summary
COMMON• Hyperparathyroidism
• Primary • Tertiary
• Malignant disease• Solid organ tumour• Haematological
LESS COMMON Thyrotoxicosis Vit D intoxication Thiazide diuretics F. hypercalciuric hypercalcaemia Sarcoidosis
Causes of Hypercalcaemia
UNCOMMON Milk-alkali syndrome Immobilization Lithium Tuberculosis Acute adrenal failure Diuretic phase of ARF Idiopathic hypercalcaemia of
infancy
Most likely Dx – 50 y.o woman with Se Ca of 3.8 mmol/L (severe)
Most common Hypercalcaemia of
malignancy◦ Solid tumours◦ Haematological
malignancies
Primary Hyperparathyroidism (PHPT)
Less common Adrenal insufficiency Vitamin D intoxication Drug treatment Chronic Renal Failure Endocrine
◦ Thyrotoxicosis Sarcoidosis Immobilisation
30% of pts with Ca will develop hyperCa
Pathophysiology1. Local osteolytic hyperCa due to direct effects of
bone mets2. Humoral hyperCa of malignancy (HHM)
Secretion of PTHrp by malignant tumours3. 1,25(OH)2 Vit D – secreting lymphomas4. Ectopic secretion of PTH (very rare)
HyperCa of malignancy
LOH accounts for 20% of cases of hypercalcemia of malignancy.
Extensive bone lysis due to tumor metastases
Characterized by ↑Ca, N/↑ se PO4,↓PTH, ↑ALP, ↑24(h) urinary calcium excretion, increase marker of bone resorption.
1) HyperCa of malignancy -Local osteolytic hypercalcemia”(LOH)
Result from the production of PTHrP Most often have squamous ca ( lung, esophagous,
head, neck, cervic,ovary) Has N-terminal amino acid sequence similar to
PTH Permit binding of identical receptors and
stimulation of second messanger, (cAMP). Thus, able to induce actions of PTH• Increase bone resorption↑Ca, ↓PTH• Inhibit proximal tubule phosphate transport ↓PO4
HyperCa of malignancy – HHM
Multiple myeloma◦ Release of osteoclast activating factors by the
tumour cells◦ IL-1B, lymphotoxin, TNF, IL-6, macrophage CSF,
hepatocyte GF◦ Actions: stimulates osteoclastic activity
In Hodgkin lymphoma, ◦ induced by production of 1,25(OH)2D ◦ Malignant lymphocyte & macrophage converting
the 25(OH)D to 1,25(OH)D bone resorption and intestinal Ca2+ absorption
HyperCa of malignancy-Haematology
1 HPTH is the leading cause of hyperCa. Often, pts are women in their 50s who have
parathyroid adenoma Incidence ; 1 in 500 to 1 in 1000 Occur sporadically or assoc with MEN Type
1or 2
2.PRIMARY HYPERPARATHYROIDISM (HPTH)
In primary HPTH due to adenomas,◦ PTH secretion is independent of the negative
feedback mechanism◦ :. Secretion continues despite elevated Ca2+
level.
Pathophysiology◦ Excess PTH leads to
Direct increase in renal Ca absorption Increase in serum Calcitriol Increasing GIT Ca
absorption Increase bone turnover, resorption > formation
Primary HPTH
Signs and symptoms
Diagnosis = Hypercalcaemia + raised [iPTH] Additional lab findings
- ↓ serum phosphate- urinary excretion of Ca2+ ( PTH amount of filtered Ca2+ > normal resorptive capacity of the kidney xs Ca2+ secreted in urine)
-↑ Se ALP (when bone disease present) -↑ se Cl and ↓ se Bicarb - ↑1,25 (OH)2D -bone markers(↑bone specific ALP,osteocalcin)
Other Ix◦ Sestamibi scan of the Parathyroid
PRIMARY HPTH
Rare, life threathening cx of primary hyperparathyroidism
Sx: acutely ill wt profound dehydration,GIT sx, urinary symptom,altered mental status& cardiac arythmia.
Lab ix;significantly ↑se Ca,↑PTH,↑ ALP.
Acute parathyroid crisis/storm
In ESRF, prolonged hypocalcaemia will cause autonomous PTH secretion by parathyroid.
This in turn will cause hypercalcaemia (Tertiary hyperparathyroidism)
Hypercalcaemia may manifest for the first time in patient post renal transplant when there is normalization of calcitriol production
Increases the PTH effect on bone Directly enhances intestinal Ca absorption
Tertiary HPTH
◦ Pt with sarcoidosis have increased sensitivity to vitamin D.
◦ High Ca may develop in normocalcaemic pt after minimal intake of vit D and sunlight exposure
◦ Caused by increase production of 1,25(OH)2D from non-renal sites.
◦ Macrophage from sarcoid granuloma may cause 1-hydroxylation of 25-(OH)D to produce calcitriol Ca 2+
◦ High/inappropriately elevated se 1,25(OH)D despite PTH level is suppressed and se PO4 is relatively elevated.
Granulomatous diseaseSarcoidosis
Thiazide diuretics: ◦ Enhance ca reabsorption in the distal tubule
↓urinary ca excretion. • Rarely cause Ca in N persons, but lead to Ca
in pt with underlying bone resorption (eg in hyperparathyroidism)
• Mild hypercalcaemia,↓/N PTH
Lithium therapy: ◦ Increased PTH secretion Increasing set point
of PTH, hence higher [Ca] to switch off PTH◦ Lab ix: high Ca, PTH, low urinary 24(h) calcium
Drugs
The most commonly available vit D supplement 25-(OH)Vit D◦ Excess of VIT D 25000-50000 IU/week◦ Resulting primarily from a combination of increase
bone resorption of calcium and increase bone reabsortion
◦ Lab ix: ↑Ca, ↑Po4,↓/N PTH, ↑25(OH)D, N/slightly 25(OH)D
Vit D mediated causes
In immobilization, Decreased stimulus to bone formation and
continued resorption rapid efflux of ca fr bone suppresed PTH 1,25(OH) D results in hypercalciuria
Hypercalcemia seen if there is pre-existing increased bone turnover
Paget’s disease Hyperparathyroid Malignancy associated hypercalcemia
Immobilisation
Prev – milk alkali syndrome◦ Milk-alkali syndrome: ingestion of
milk/antacids(alkaline) for treatment of dyspepsia . Alkali increases renal reabsorption of filtered calcium. Precise mechanism unknown
Calcium-alkali syndrome◦ Due to Rx of osteoporosis ◦ Triad of hypercalcemia,systemic alkalosis and renal
insufficiency.◦ Lab Ix: ↑ca,↓/ N PTH,↑/N PO4, ↓urinary 24 (h) Ca
Calcium – alkali syndrome
Hypercalcaemia seen in pt treated with◦ Calcium carbonate or calcium acetate to bind
dietary phosphate◦ Calcitriol ( to reverse hypocalcaemia and
secondary hyperparathyroidism)
Endocrine◦ Thyrotoxicosis-mild hypercalcemia ◦ Thyroid hormoneIncreased bone resorption
ratereleases ca into circulation suppress PTH low 1,25(OH)D
Chronic Kidney Disease
How to approach? Medical History Physical Examination
What Investigations? -Lab -Others
Clinical approach
Approach Acute or Unknown duration
◦ PTH high; Acute paratyroid crisis◦ PTH low ; CA, PTHrp
Chronic duration(month)◦ PTH low ; granulomatous dz, Milk alkali,
Li,thiazide, Immobilization, Vit D,Thyrotoxicosis◦ PTH high ; 1,3 ry hyper PTH, MEN
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WORK-UP OF HYPERCALCEMIA
Re-review History
1. Acute or Chronic ??????
Classic presentation very rare– Stones– Bones– Abdominal groans– Psychic moans
Subtle manifestations more common– Fatigue– Weakness– Arthralgias– Depression– Impairment of intellectual performance
Associated conditions– Pseudogout– Nephrolithiasis– Evidence of MEN
WORK-UP (cont.) Review medications
– Thiazides– Lithium– Antacids– Food additives
Pursue symptoms of underlying malignancy– Breast– Lung– Hematological
Past History of head and neck irradiation during childhood
Family history Risk factor of Ca
Lab WORK-UP (cont.) Step 1
– Confirm hypercalcemia– Ionized calcium– Serum albumin levels– Correction for the measured calcium (low
albumin)
Step 2– Once obvious causes ruled out, obtain serum intact
PTH
WORK-UP (cont.) Step 3: Measurement of the serum PTH concentration.
Ca, iPTH ; 1ry HyperPTH, Familial (MENI and MENII),Ectopic PTH secretion by
tumors (rare)
– Ca, N /iPTH; – Malignancy associated
• Osteolytic• Humoral
• Vitamin D mediated• Intoxication• Granulomatous disorders
• Thyrotoxicosis• Prolonged immobilization• Acute /chronic renal failure• Milk alkali syndrome• Drug:Thiazide,Lithium
Lab WORK-UP (cont.) Step 4: Measurement of the serum
phosphate concentration.
◦ Ca, PO4 ; 1ry HyperPTH, PTHrP(SCC)
◦ Ca, N /PO4 ; 3ry HyperPTH, Granulomatous dz, lymphoma, Vit D
overdose , Immobilization, Metastatic bone dis. Milk Alkali Syndrome
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Lab WORK-UP (cont.) Measurement urinary calcium excretion
◦ Urinary calcium excretion is usually raised or high-normal:
◦ hyperparathyroidism,hypercalcemia of malignancy,granulomtous disease,Vit D excess
3 disorders in which an increase in renal calcium reabsorption leads to relative hypocalciuria (<2.2 mmol/day):◦ The milk-alkali syndrome◦ Thiazide diuretics◦ Familial hypocalciuric hypercalcemia (children)
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Lab WORK-UP (cont.)
Next step… Analyze vitamin d metabolite levels
◦Elevated 25(OH)D Vit D intoxication◦High 1,25 (OH)D Primary HPTH
sarcoidoisis & granulomatous dz
Analyze serum PTH-related protein level (PTHrp)◦May help in diagnosis of occult cancer –
associated hypercalcemia.
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Approach
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PTH PTHrP 1,25D Ca
1ry HyperPTH -
2nd HyperPTH - -
3ry HyperPTH - -
CA High -
Granuloma High
LOOK FOR OTHER CAUSES OF HYPERCALCEMIA
◦ Se Immunoglobulin/ Serum/urine electrophoresis Multiple myeloma
◦ Thyroid function test Thyrotoxicosis◦ Renal function test to assses renal function◦ Liver function testraised ALP level suggest
bone involvement◦ raised serum bicarb suggest Milk-alkali
syndrome◦ Chest xray reveal sign of sarcoidoisis & lung ca◦ Mamogrambreast ca
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DDX Ca PO4 PTH PTHrP 1,25(OH)D
U Ca
Malignancy1)Solid tumor2)Humoral
↑↑
N/↑↓
↓↓
N↑↑
↓↓/N
↑↓/N
Pry PTH ↑ ↓ ↑ N ↑ ↑
Granulomatous disease
↑ ↑ ↓ N ↑↑ ↑
Vit D excess ↑ ↑ ↓ N ↑↑ ↑
Thiazide ↑/N ↑ ↓/N N N ↓
Milk alkali syndrome
↑/N ↑ ↓/N N N ↓
Summary…
Approach to Hypercalcaemia – Assadi F, IJKD 2009
Medical Mx: Acute
1st step in Mx – Stabilising the pt! Correct hypovolemia wt isotonic saline infusion
and to promote renal excretion of calcium
◦ Replenish body fluids 2-4 L of IV normal saline per day
Medical Mx 2nd Step
◦ Diuresis with furosemide
3rd Step◦ Administration of bisphosphonates◦ Zoledronate or Pamidronate
Block osteoclast activity and bone resorption Reduce malignant bone pain Delay onset of progressive bone disease in various
Ca
Surgical MxAACE/AAES Position Statement, Endocr Pract 2005
Acute parathyroid crisis urgent parathyroidectomy
For symptomatic PHPT◦ Those <50 years◦ Who cannot participate in appropriate follow up◦ Ca level > 0.25 mmol/l above upper limit◦ Complications of PHPT
Osteoporosis Nephrocalcinosis Severe psychoneurologic disorder
Management
Review / remove any known agents that cause / aggravate hypercalcaemia◦ Medications
Thiazide Lithium Over the counter supplements
CONCLUSION
Hypercalcaemia has a wide differential diagnosis and several investigations may be required to determine the underlying cause.
Clues pointing to the Dx of underlying disease can be obtained from careful history taking and physical examination.
Lab tests should be requested based on clinical suspicion.
Long term control of hypercalcaemia is best achieved by identifying and treating the underlying disease.