Hypercalcaemia certainly possesses some diagnostic challenges Cases are too different in ways of presentation and management do need a lot of things to be checked out. This is merely an approach for such patients.

1. Let’s See A Case Scenario

2. A Case History
A patient named M, 55 years old from Mymensingh
admitted in Medicine Unit VIII with the complaints of
drowsiness for 5 hours, generalised weakness, nausea,
loss of appetite and bodyache for about 1-2 years
which has gradually worsen in the last 1 month. She
has been complaining gradual weakness in walking
and for the last couple of weeks she is unable to walk.
In the past couple of months she complained
constipation for several episodes which was not

3. associated with any rectal bleeding or pain during
defecation. She has lost about 5 Kg weight in past 2
months. She gave no history of polyuria and
polydipsia. She is normotensive, non diabetic, non
asthmatic and gave no history of contact with
tuberculosis. On examination she anxious, a bit
dehydrated, pulse being 112 b/min,BP-120/80mmHg,
RR- 18 breaths/min, Temp- 99 degree F. There was
mass on the right side of neck 3 cm x 2 cm in size,
nodular, firm in consistency & non tender and there
was bowing of the tibia.

4. Investigations
• Her CBC showed Hb% 12.1 mg/dl, RBC- 3.94 x
10^12/L, WBC- Neutrophilic Leucocytosis,
Platelet- 385 x 10^9/L, ESR- 85 mm in 1st hour.
• Serum Creatinine- 1.72 mg/dl
• Serum FT3-1.81 pg/ml ,FT4- 0.93ng/dl, TSH-
2.18 microIU/ml
• SGPT- 15 U/L, ALP- 213 U/L
• Serum Calcium- 16.0 mg/dl
• Spot Urine Calcium- 21.9 mg/dl
• Serum Inorganic PO4- 3.8 mg/dl

5. • Serum PTH- 1450.8 pg/ml
• BMD- Marked osteoporosis of lumber spine (-5.8)
and left femoral neck (-5.5).
• USG of neck- Enlargement of the both lobes of
thyroid glands with few small nodules in the right
lobe and suspected large parathyroid mass.
• CT features consistent with multi-nodular goitre
involving right thyroid lobe causing compression
and leftward displacement of adjacent trachea.
• FNAC from Parathyroid mass- Suggestive of
Parathyroid adenoma.

6. Approach to a Patient with
Hypercalcaemia
Presented By:
Dr. Md. Asif Hossain
K-66 Batch
Dhaka Medical College Hospital

7. Regarding Calcium
• Calcium is one of the most abundant mineral in
the human body and it has many important
biological functions
• 1000-2000 g of Ca is present normally in human
body
• 99% - in the skeleton
• Remaining amount -distributed in the ECF and
other soft tissues
• Normal range 2.1–2.6 mmol/L (8.5-10.5 mg/dl)

8. • In Blood , total Ca conc. is normally 8.5-10.5
mg/dl, of which approximately 50% is ionized
• Remainder is bound ionically to negatively
charged proteins- Predominantly albumin (40%)
and immunoglobulins or lossely complexed with
PO4 , citrate ,SO4 and other anions

9. Calcium homeostasis
• Total body : 1 Kg
▫ 99%  bone
▫ 0.9%  intracellular
▫ 0.1%  ECF
• In blood
▫ 40-45%  mostly albumin
▫ 40-50%  free or ionized
▫ 10-15%  small anions : phosphate and citrate
Ionized Ca is Physiologically important.

10. • Dietary intake of Ca 400-1500 mg/day
• Daily intestinal absorption of Ca 200-400 mg/day
• Renal excretion regulated by conc of ionised Ca in blood
• Approx 8-10 g/day of Ca filtered by the glomeruli of which
only 2-3% appears in urine (200mg)
• 65% absorbed in PCT – passively – paracellular route that
is coupled to NaCl reabsorption
• AL of Henles loop- 20% paracellular mechanism
Requires a protein Paracellin-1 which is inhibited by
increased blood conc of Ca and Mg acting via CaSR
expressed on BL membrane
Metabolism

11. Serum Calcium can be influenced by pH.
• Metabolic acidosis = decrease protein binding =
increase ionized calcium.
• Metabolic alkalosis = increase protein binding =
=decrease ionized calcium.
• Fall in pH by o.1 increases serum calcium by 0.1
mmol/L

12. • Corrected calcium
• For every 1-g/dL drop in serum albumin below
4 g/dL, measured serum calcium decreases by
0.8 mg/dL.
• Corrected calcium =
Measured Ca + [0.8 x (4 - measured albumin)]
(Calcium in mg/dl; albumin in g/dl)

13. FUNCTIONS of Calcium
• Normal cellular function & intracellular signalling
• Neuromuscular / nerve conduction
• Cardiac contractility
• Bone formation
• Coagulation
• Hormone & Enzyme regulation
• Maintenance of plasma membrane stability.

14. Hormones in Calcium Homeostasis

18. 18
CALCIUM, PTH, AND VITAMIN D FEEDBACK
LOOPS
NORMAL BLOOD Ca
RISING BLOOD Ca
FALLING BLOOD Ca
SUPPRESS PTH
STIMULATE PTH
BONE RESORPTION
URINARY LOSS
1,25(OH)2 D PRODUCTION
BONE RESORPTION
URINARY LOSS
1,25(OH)2 D PRODUCTION

19. About Hypercalcaemia
• Hypercalcaemia is one of the most common
biochemical abnormalities and is often detected
during routine biochemical analysis in
asymptomatic patients.
• Mild asymptomatic hypercalcaemia occurs in
about 1 in 1000 of the population, with an
incidence of 25–30 per 100000 population. It
occurs mainly in elderly females, and is usually
due to primary hyperparathyroidism.

20. • Mild hypercalcaemia (up to 11–11.5 mg/dL or <3
mmol/L) is usually asymptomatic and recognized
only on routine calcium measurements)
• 3.0 to 3.5 mmol/l may be well tolerated if it has
risen slowly, but may be symptomatic and prompt
treatment is usually indicated.
• Severe hypercalcaemia is defined as total serum
calcium > 14 mg/dl (> 3.5 mmol/L). Risk of
severe neurological symptoms or cardiac
arrhythmias are present in such patient.

23. Evaluation
Evaluation of a patient with hypercalcemia
should include a careful history and physical
examination focusing on
• clinical manifestations of hypercalcemia,
• risk factors for malignancy,
• causative medications,
• and a family history of hypercalcemia-
associated conditions

24. General Symptoms Of Hypercalcaemia
Renal “stones”
• Severe loin pain radiating to groin mimicking a
typical renal colic
• Polyuria and polydipsia
• Dehydration
• Nephrocalcinosis
Skeleton “bones”
• Bone pain
• Arthritis
• Osteoporosis and fractures
• Osteitis fibrosa cystica in hyperparathyroidism
(sub-periosteal resorption, bone cysts)

25. Abdominal “groans”
• Nausea, vomiting
• Anorexia, weight loss
• Constipation
• Severe abdominal pain due to Pancreatitis or
Peptic ulcer disease
psychic “moans”
• Impaired concentration and memory
• Confusion, stupor, coma
• Lethargy and fatigue
• Muscle weakness

26. Cardiovascular
• Hypertension
• Cardiac arrhythmias
• Vascular calcification
Other
• Itching
• Redness of Eye and pain resembling Conjunctivitis
or Symptoms of Keratitis

27. Symptoms related to Underlying
Etiologies
• Commonest etiology in a patient with
hypercalcaemia being overactive parathyroid gland
(specifically single parathyroid adenoma 80-
90%). Initailly have milder or no symptoms. Later it’s
characterized by
-hypercalcemia
-PTH equal to or above the normal range
-hypercalciuria
-increased risk of fractures
-increased risk of kidney stones
-seldom causes extreme hypercalcemia unless
confounded by renal failure, dehydration, etc.

28. • On the background of CKD, hypercalcaemia
may favour tertiary hyperparathyroidism.
• A family history of such symptoms like renal
stones may point towards FHH.
• Symptoms of abdominal pain, diarrhoea
resembling Zollinger Ellison or features related
to insulinoma, pituitary tumor,
pheochromocytoma with family history point
towards rare MEN I or II.

29. • Hypercalcaemia in malignancy (due to PTHrP
over production in Solid Tumours, osteolytic metastasis
in Ca breast or Myeloma, extra renal vit D activation)-
Look for Squamous Cell Carcinoma lung, breast,
renal, thyroid or Haematological malignancies
(Leukaemia, lymphoma, Multiple myeloma).
Rapidity of the course is the striking features here.
• Thiazide diuretics, excess vitamin D analogues,
chronic lithium administration, vitamin A,
teriparatide, theophylline intake or excess TPN
must be searched as etiologies in patient with
hypercalcaemia.

30. • Hypercalcaemia in patient with low grade fever
evening rise, cough we must exclude
tuberculosis.
• Hypercalcaemia patient having chest complains
with fever, arthralgia, erythema nodosum or
chest problems think of sarcoidosis.
• Patient working on mining, glass manufacturing
factory with chest problem, hypercalcaemia
might think of silicosis.
• Also HIV and leprosy must be ruled out.

31. • Features of Thyrotoxicosis, Acromegaly,
Addison’s must be searched in continued mild
hypercalcaemic patient.
• Patient taking high doses of calcium antacids might
present hypercalcaemia in rare milk- alkali
syndrome. The chronic form of the disease, termed
Burnett’s syndrome which is associated with
irreversible renal damage.
• Hypercalcaemia may be present in immobilized
patient with high bone turnover (e.g., Paget’s
disease, bedridden child)

32. • Hypercalcaemia in infant multiple congenital
development defects, including supravalvular
aortic stenosis, mental retardation, and an elfin
facies may point towards Williams’
syndrome.

33. Signs
• Mostly non-specific, may be related to
underlying disorders
• Dehydration
• Hypertension
• Chondrocalcinosis may be due to ectopic
calcification
• Corneal calcifcation or band keropathy

34. Band Keratopathy

35. Investigations
• After ensuring baseline investigations CBC (anaemia
in myeloma, malignancy etc.), several fasting serum
calcium and phosphate samples should be
performed. Serum albumin must be measured to rule
out pseudo-hypercalcaemia.
• Serum PTH:
-The hallmark of primary hyperparathyroidism
is ↑ Ca and ↓ PO4 with detectable or elevated intact
PTH levels. Nothing is necessary if such patient
asymptomatic except for excluding any drug history
like lithium intake and FHH.

37. • 24-hour urinary calcium or single
calcium creatinine ratio (<0.01) effectively
excludes familial hypocalciuric hypercalcaemia.
• Hyperchloraemic acidosis – often mild.
• Renal function is usually normal except for
Tertiary hyperparathyroidism or multiple
myeloma.
• Elevated serum alkaline phosphatase is
found in severe parathyroid bone disease
otherwise it suggests an alternative cause.

38. • Activated Vitamin D level >100 mg/ml may suggest
vitamin D intake or granulomatous diseases
• PTH-related protein (PTHrP): High levels in a
hypercalcaemic patient with ↓ PTH may suggest solid
malignancies. So, if PTH levels are not elevated, then a
thorough workup must be undertaken for malignancy,
including Chest x-ray, CT of chest and abdomen
& bone scan.
• Protein electrophoresis/immunofixation: to
exclude myeloma
• Serum TSH: to exclude hyperthyroidism
• 09:00 hours cortisol and/or ACTH test: to
exclude Addison’s disease
• Serum ACE: helpful in the diagnosis of sarcoidosis

39. • Hydrocortisone suppression test:
hydrocortisone 40 mg three times daily for 10 days
leads to suppression of plasma calcium in
sarcoidosis, vitamin D-mediated hypercalcaemia.

40. ECG in Hypercalcaemia
Short QT interval, Broad T, Heart Block will present. Rarely
Osborn wave may be found.

41. Imaging: Chest X-ray
Pulmonary TuberculosisSarcoidosis
Also used to detect any malignacy, hyperparathyroidism, paget’s etc.

42. Skull X-ray
Very significant for
Multiple myeloma, Primary
hyperparathyroidism and
Paget’s disease, acromegaly
as a cause for patient with
hypercalcaemia etc.

44. Imaging(contd.)
• Abdominal X-rays may show renal calculi or
nephrocalcinosis. High-defnition hand X-rays
can show subperiosteal erosions in the middle or
terminal phalanges.
• DXA bone density scan: is useful to detect
bone effects in asymptomatic people with
hyperparathyroidism (HPT).

45. Parathyroid Imaging
The success of parathyroid imaging is frequently far
less accurate than exploration. Methods include:
• Ultrasound which is insensitive for small tumours
• High-resolution CT scan or MRI (more sensitive)
• Radioisotope scanning using 99mTc-sestamibi,
which is approximately 90% sensitive in detecting
adenomas.

47. DDX Ca PO4 PTH PTHrP 1,25(OH)D U Ca
Malignancy
↑ N/↑ ↓ ↑↑ ↓/N ↓/N
Primary PTH ↑ ↓ ↑ N ↑ ↑
Granulomatous
disease
↑ ↑ ↓ N ↑↑ ↑
Vit D excess ↑ ↑ ↓ N ↑↑ ↑
Thiazide ↑/N ↑ ↓/N N N ↓
Milk alkali syndrome ↑/N ↑ ↓/N N N ↓

49. Treatment
Aimed both at
• Lowering the serum calcium if possible,
• Treating the underlying disease.
Main Principle of treatment aimed at reducing
serum calcium by -
1. Inhibiting bone resorption
2. increasing urinary calcium excretion or
3. decreasing intestinal calcium absorption

50. • Patients with mild hypercalcaemia (<12 mg/dL)
do not require immediate treatment. They should
stop any medications, foods causing hypercalcaemia,
avoid volume depletion and physical inactivity and
maintain adequate hydration.
• Moderate Hypercalcaemia (12 to 14 mg/dL),
especially if acute and symptomatic, requires more
aggressive therapy.
• Severe hypercalcaemia (>14 mg/dL), even
without symptoms, should be treated intensively.
• Treatment of underlying conditions.
Goals of Treatment

51. Management of Severe Hypercalcaemia
Acute hypercalcaemia often presents with dehydration,
nausea, vomiting, polyuria, drowsiness and altered
consciousness. Urgent treatment is needed if the patient is
seriously ill or if the Ca2+ is above 3.5 mmol/L (14 mg/dl).
Four basic principles to be followed-
1. Rehydration: At least 4–6 L of 0.9% normal saline on
day 1 and 3–4 L for several days thereafter. Loop diuretics
only used if fluid overload develops (not for reducing
serum calcium). Need to consider hemodialysis with a
low- or no-calcium dialysate if comatose, in severe
renal failure, or cannot receive aggressive hydration.

52. 2. Intravenous bisphosphonates: are the
treatment of choice for hypercalcaemia as it
inhibits osteoclastic bone resorption in malignancy
or of undiagnosed cause.
-Zoledronic acid (e.g., 4 mg over ∼30 min),
-Pamidronate (e.g., 60–90 mg over 2–4 h),
-Etidronate (e.g., 7.5 mg/kg per day for 3–7
consecutive days).
Onset of action is within 1–3 days, with
normalization occurs in 60–90% of patients.
Repeated if relapse occurs.
• Side Effect: Esophagitis, Osteonecrosis Of Jaw

53. 3. Intravenous hydrocortisone (100–300 mg
daily) or oral prednisone (40–60 mg daily): is
effective in some instances (e.g. in myeloma,
sarcoidosis and vitamin D excess) but in most cases is
ineffective. Ketoconazole, chloroquine, and
hydroxychloroquine may serve same purpose.

54. 4. Calcitonin (200 units i.v. 6-hourly): Has a
short-lived action and is little used. Can only be
considered if poor response to bisphosphonates.
Efficacy of calcitonin is limited to the first 48 hours.

55. Others
• Calcimimetic agent (cinacalcet): Target
the calcium-sensing receptors (e.g. cinacalcet) used
in parathyroid carcinoma and in dialysis patient and
in primary hyperparathyroidism where surgical
intervention is contraindicated.
• IV Phosphates- Chelates calcium & level. But, this
therapy can be toxic because calcium-phosphate
complexes may deposit in tissues and cause
extensive organ damage.
• Gallium nitrate

57. Treatment of Underlying Conditions
1. Primary hyperparathyroidism
Patients who are treated conservatively without surgery
should have calcium biochemistry and renal function
checked annually and bone density monitored
periodically.
Medical management in milder cases
• No effective medical therapies
• A high fluid intake should be maintained
• A high calcium or vitamin D intake avoided and
exercise encouraged

58. Surgical management
• Asymptomatic patients with significant hypercalcaemia
(corrected serum calcium > 2.85 mmol/L (> 11.4 mg/dL)
• Individuals aged less than 50 years with symptoms or
complications (such as peptic ulceration, renal stones,
renal impairment or osteoporosis/Low bone mineral
density(T-score ≤2.5) at any site.
Side Effects:
• Postoperative hypocalcaemia
• Bleeding and recurrent laryngeal nerve palsies (<1%).
(Vocal cord function should be checked preoperatively)

59. 2. Familial hypocalciuric hypercalcemia
• Differentiation must be needed from Primary
PTH because surgery is not all necessary
here (except for rare consanguineous marriages
of a homozygous or compound heterozygote
state, resulting in severe impairment of calcium-
sensing receptor function neonatal severe
hypercalcemia, total parathyroidectomy is
mandatory.)

60. 3. Malignancy-Associated Hypercalcaemia :
• Control of tumor should be considered best
management as reduction of tumor mass usually
corrects hypercalcaemia.
• Intravenous bisphosphonates: For acute
management as well as maintenance.
4. Excessive Vit D Production related causes:
• Restriction of dietary calcium intake or Vit D intake
• Glucocorticoids: 100 mg/d of hydrocortisone.
• Treatment of specific disease (TB etc.)

61. 5. Withdrawal of offending drugs (lithium)
if present considering the risk- benefit
ratio.
6. Treatment of other disorders especially
endocrinopathies: Patients with thyrotoxicosis,
addison’s, acromegaly, pheochromocytoma should
be treated accordingly.

62. Conclusion
• The diagnostic approach to hypercalcaemia
often is made incidentally in asymptomatic
patients but that does not mean to take it lightly.
• Hypercalcaemia do serve as a harbinger of light
to severe underlying disease. Significant occult
malignancies may present with hypercalcaemia
for one just month.
• So, a proper clinical attitude must be served to
all the suspect patients accordingly. We must ‘hit
early’ & ‘hit good.’