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.