Hypercalcemia

Olivia Faye Listanco

Renal rotator- July 2016

Objectives

To present a case of a patient with

PTB in hypercalcemic crisis
To discuss the differential diagnosis
and present the algorithm for the
management of hypercalcemia

General Data

CA
86 year old
Female
Widow
Housewife

CC: Generalized body

weakness

Episodes of black tarry stool at 2-3x days at -1/2

cup per bout. No meds taken or consult done.
No abdominal pains, light-headedness, dizziness or
wks vomiting.
Noted to have decreased in appetite and only
preferred to have ensure milk.

Interi
m

3
days

Melena persisted.

Noted to be generally weak. Mostly confined to the

bed and needed assistance going to the bathroom
Melenic bouts persisted .

Review of system

General: (-) fever (+) weight loss, unquantified

HEENT: (-) diplopia, (-) dysphagia
Respiratory: (+) intermittent cough, (-)
hemoptysis, (-) dyspnea
Cardiac: (-) chest pain
GI: (-) diarrhea, (-) constipation
Genitourinary: (-) dysuria, (-) hematuria, (-)
discharge, (-) decrease in UO
Neuro: (-) seizure, (-) dizziness, (-) loss of
consciousness

Past Medical History

DM type 2, non insulin requiring
Denies HPN, allergy or asthma
Previous PTB infection, unrecalled
status of treatment
No reports of kidney disorder, claimed
to have normal creatinine levels
Able to ambulate with assistance but
has been bedbound the past 2 weeks

Family and Social History

No heredo-familial diseases
Non smoker, non alcoholic beverage
drinker
No illicit drug use
No use of OCPs/injectables

Physical Examination
General: Weak-looking, conscious, coherent
Vital Signs: BP 150/70 HR 75 RR 20 Temp
37C
O2sat 98% at room air
HEENT: Anicteric sclerae, pale palpebral
conjunctivae, (-) neck vein engorgement or
cervical lymphadenopathy, (-) palpable
mass, dry tongue
Respiratory and Chest: Symmetric chest
expansion, (+) bibasal crackles

Cardiac: Adynamic precordium, normal

rate, regular rhythm, distinct S1/S2, PMI at
6th ICS, left anterior axillary line; no murmurs
GI: Soft, nontender, flabby abdomen, (-)
palpable masses
DRE: no externals lesion, palpated mass
at1cm
non tender at 12 oclock position
Extremities: (-) bipedal edema, cyanosis
Neuro: Awake and oriented, Pupils 2mm
equally reactive to light, full EOMS, tongue
midline, no facial asymmetry, no motor nor
sensory deficits

Admitting impression
Upper GI Bleed probably sec to
1. Bleeding peptic ulcer disease,
2. 2. R/O Colon cancer
Community acquired pneumonia,
moderate risk;
PTB III (?);
DM type 2

Day 1 of admission
Subjective

Objective

86F
Diabetic, unknown hx
of PTB infection
CC: Melena x 2 wks
Assoc with
generalized body
weakness and poor
appetite
ROS: coughing x 2
wks, unquantified wt
loss weakness of
bilateral
extremities ,no fever

Weak-looking, 150/70
75 RR 20 afebrile
O2sat 98% at room
air
(-) palpable neck
mass, dry tongue
Symmetric chest
expansion, (+)
bibasal crackles
Regular rhythm

No recurrence of
melena at floors

***Labs done

Assessment / Plan
Gen:
Calculated diet,
hydration with PNSS
1Lx 12hrs,
P: UGIB pro sec to
1. BPUD, 2. R/O Colon
cancer
Started with
Omeprazole 40mg
BID, NAC 600mg.tab
Q12,
P: CAP-MR; R/O PTB,
active infection
Sputum GSCS, AFB
Started with
Ceftriaxone 1mg Q12
P: DM
CBG TID HS, Resumed
gliclazide and


7/5
CBC

Hgb
115
Hct
0.35
WBC
13.10
Neu
0.71
Lymp
0.18
Plt
521
MCV
86.3
MCH
28.2
MCHC
32.7
ABO
B+
Creatinine
61
(N 46-92)
BUN
5.4
(N 2.5-6.10)
Na+
138
(N 137-145)
K+
3.4
(N 3.5-5.1)
PT
102.8/ 0.97
PTT
27.5/24.3

Laboratory results
(7/5/16)

Ches (7/5) Lung are

t hyperaerated. Bilateral PTB
Xray with cavitary and bullous or
bronchiectasis changes,
Left pleural reaction
(thickening vs effusion).
Elevated right hemi
diaphragm.

Discussion

Calcium
Element number 20
Makes up 3% of the Earths crust

Calcium ion: Ca2+

Divalent cation

 5th most abundant element in the human

body
Most is present in this fixed form: bones
and teeth
A little is in the cytoplasm of all the cells
A tiny amount circulates bound to albumin
Miniscule portion is circulating as Ca++ ion
Only physiologically active form is the
Ca++ ion
Endocrine Physiology, 3rd ed. P.E.

Distribution of calcium in the

human body

Hydroxyapatit
e

98.9
%
= 31 mol
= 1250g
1% of which is

1% of total body calcium is present in the

cells
0.1% of total body calcium is in the
extracellular fluid:
Ionised Calcium:
Present as free, active
Ca++
cation
Diffuses easily across
50%
capillary membranes

1.2 mmol/L

Protein-bound
Calcium:

41%

Bound mainly to albumin

Cannot diffuse across
capillary membranes

1.2 mmol/L

Anion-bound calcium:

Bound to small anionic

9 %, 0.2 mmol/L molecules, eg. phosphate
and citrate
diffuses easily across
capillary membranes

& Hall Textbook of Medical physiology, 11th ed.; J.E.Hall; Chapter 79

What are we measuring,

exactly

CMP calcium from venous blood

Total calcium: ionized calcium +

protein bound + anion bound; should be
2.2 to 2.6 mmol/L
Corrected calcium:
when the albumin is low, protein-bound calcium will also be low;
however the levels of ionized calcium remain unchanged

Corrected calcium is what the total calcium

WOULD BE if the patient had a normal albumin
corrected
[Ca] in mmol/L = measured
level.

total [Ca] (mmol/L) + 0.02 x (40

serum albumin in g/L)

& Hall Textbook of Medical physiology, 11th ed.; J.E.Hall; Chapter 79

What are we measuring,

exactly

ABG calcium:

Just the ionized fraction

This is the fraction that is under homeostatic control
Measured precisely with ion-selective glass electrode

The most accurate impression of

whether somebody is hypo or
hypercalcemic
Especially in patients on TPN, acidotic patients,
ICU patients with low albumin, patients on
dialysis, cases of hyperparathyroidism, and
patients receiving citrated blood (because
citrate binds ionized calcium)

McLean et al, Clinical Estimation and Significance of Calcium-Ion Concentrations in the Blood ; Am J Med Sci may 1935 vol.
189:5 pp21-612
Calvi et.al, When Is It Appropriate to Order an Ionized Calcium? 2008 J Am Soc Nephrol 19: 1257-1260, 2008

What is the point of calcium

Muscle contraction

caused by Ca++ efflux from

sarcoplasmic reticulum

Neurotransmitter release
into presynaptic terminal

caused by Ca++ influx

Uses Ca++ instead of Na+
to depolarise

Conduction systemCa++
of influx
theis responsible
heartfor the
plateau phase of the action
potential
Myocardial contraction
Ca++ is a cofactor required at most factor activation
steps, thats why blood bank purple top tubes contain a
calcium chelator (EDTA)
Clotting cascade
Bone integrity

& Hall Textbook of Medical physiology, 11th ed.; J.E.Hall; Chapter 79

Daily dietary calcium

requirements
40 mg = 1
mmol

Health and Medical Research Council. (2006) Executive Summary of Nutrient Reference Values for
a and New Zealand Including Recommended Dietary Intakes.
nwealth Department of Health and Aging, Australia, Ministry of Health, New Zealand.

Daily calcium requirements in the

ICU
0.1 mmol/Kg /day - INTRAVENOUSLY
Thus, a 100kg ICU pt on TPN needs
10mmol every day

Ohs Intensive Care Manual, 6th ed. R.Leonard; Chapter 87 Enteral

Usual Sources of Calcium

Dairy:
200ml yoghurt = 10mmol
1 litre of milk = 25 mmol

Spinach
Baked beans
Oranges
Nuts
Small canned fish with intact bones:
canned sardines = 10mmol per 100g

Unusual Sources of Calcium

Jevity 1cal contains ~23 mmol of
calcium per litre (910 mg)
One Caltrate tablet = 15 mmol
(600mg)
Calcium resonium: exchanges
calcium for potassium in the gut.
Calcium content is 1.6 to 2.4 mmol/g, so each
30g dose = potentially 48 to 72 mmol

Calcium gluconate: 2.2 mmol per 10ml vial

Calcium chloride: 6.6 mmol per 10ml vial

Calcium absorption
NORMALLY, 30-35% of ingested calcium is absorbed
Thus, to get your 10mmol, you need to ingest ~ 25-30mmol;
Thus, ~ 1 litre of milk or 1.2 litres of Jevity

Absorption occurs in the duodenum

Active transport out of the gut
Rate of absorption closely linked to calcium demand
Controlling hormone is mainly Vitamin D

(activated vitamin D greatly increases calcium absorption)

~ 7 mmol is lost in the intestine as sloughed cells/juices

NET: 30mmol go in, 27 mmol come out. 3 mmol remain.
Thus, you only end up keeping 10% of the calcium you ingest

& Hall Textbook of Medical physiology, 11th ed.; J.E.Hall; Chapter 65

Calcium transport in the

blood
50% as ionized, 41% bound to protein
(mainly albumin, some globulins) and 9%
bound to anions in soluble complexes
Ionized fraction depends on pH:
protein binding decreases as pH decreases

Alkalosis: increased calcium binding to

protein;
decreased ionized fraction

pH 7.
45
Acidosis:
pH 7.35
protein;

Each 0.1 decrease in pH

increases ionized calcium by
0.05 mmol/L

decreased calcium binding to

increased ionized fraction

& Hall Textbook of Medical physiology, 11th ed.; J.E.Hall; Chapter 79

Calcium storage
98.9% stored in bone

1% stored in cytoplasm and 0.1% is present in the

extracellular fluid

Stored as HYDROXYAPATITE mineral

Balance of storage is influenced by balance of
osteclast vs osteoblast activity: building vs
destruction of the bony matrix
This is influenced by parathyroid hormone and to
a lesser degree calcitonin

& Hall Textbook of Medical physiology, 11th ed.; J.E.Hall; Chapter 79

Intestinal calcium excretion

INTESTINAL LOSSES
7 mmol (~ 250mg) lost in sloughed cells and
intestinal secretions
More if there is a vitamin D deficiency
More if there is hypercalcemia

& Hall Textbook of Medical physiology, 11th ed.; J.E.Hall; Chapter 79

Renal calcium excretion

2.5mmol (100mg) is excreted through the kidneys
daily
The ionized calcium is the only excretable variety
because protein-bound calcium does not make it
past the glomerulus
90% of the filtered calcium is reabsorbed in the
proximal tubule
The reabsorption of the remaining 10% is
controlled by PTH and depends on ionic calcium
concentration
This remaining 10% is reabsorbed in the early
collecting ducts

& Hall Textbook of Medical physiology, 11th ed.; J.E.Hall; Chapter 65

Ca metabolism
Dietary intake of Ca 400-1500 mg/day
Daily intestinal absorption of Ca 200-400 mg/d
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
cTAL 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

Calcium Homeostasis

HYPERCALCEMIA
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).

Renal stones
Nephrolithiasis
Nephrogenic
diabetes insipidus
Dehydration
Nephrocalcinosis

Clinical Manifestations of
NeuromuscularHypercalcemia
Gastrointestinal

Skeleton bones
Bone pain
Arthritis
Osteoporosis
Osteitis fibrosa
cystica in
hyperparathyroidism

psychic groans
Impaired
concentration and
memory
Confusion, stupor,
coma
Lethargy and fatigue
Muscle weakness
Corneal calcification
(band
keratopathy)

abdominal
moans
Nausea, vomiting
Anorexia, weight
loss
Constipation
Abdominal pain
Pancreatitis
Peptic ulcer
disease

Cardiovascular
Hypertension
Shortened QT
interval on ECG
Cardiac arrhythmias
Vascular calcification

Other
Itching
Keratitis,
conjunctivitis

 Among all causes of hypercalcemia, primary

hyperparathyroidism and malignancy are
the most common, accounting for greater than
90 percent of cases.
Therefore, the diagnostic approach to
hypercalcemia typically involves distinguishing
between the two.
Patients with hypercalcemia of malignancy
usually have higher Ca concentrations and are
more symptomatic from hypercalcemia than
individuals with primary hyperparathyroidism.
Serum Ca must be corrected for serum albumin
before labelling it as a case of Hypercalcemia.

HYPERPARATHYROIDISM
Measurement of intact PTH levels
Normal or High i-PTH Diagnosis of
Primary or Tertiary HyperPTH
80% due to single parathyroid
adenoma
Hyperparathyroidism also can result
from hyperplasia of the parathyroid
glands or, rarely, parathyroid
carcinoma

 80 % cases: asymptomatic, diagnosed on

routine lab finding of increased serum
calcium
20-25% cases: chronic course with mild or
intermittent hypercalcemia, recurrent renal
stones, complication of nephrolithiasis
5-10% have severe and symptomatic
hypercalcemia and overt osteitis fibrosa
cystica; in these patients the
parathyroid tumor is usually large (greater
than 5.0 g).

 The diagnosis of PHPT is established by laboratory

testing showing
*hypercalcemia,
* normal or elevated PTH,
* hypercalciuria,
* hypophosphatemia,
*-phosphaturia, and
*increased urinary excretion of cyclic adenosine
monophosphate.

Chronic renal failure generally causes hypocalcemia.

If untreated, prolonged high phosphate and low
vitamin D levels can lead to increased PTH secretion
and subsequent hypercalcemia ie Tertiary
hyperparathyroidism.

VITAMIN D-MEDIATED CAUSES

Oral Vit D supplements consists of 25 OH Vit D2
Ealvated levels of 25 OH Vit D levels are usually due
to OTC medications (value >150 ng/mL (374 nmol/L
On the other hand, increased levels of
1,25-dihydroxyvitamin D may be induced by
direct intake of this metabolite,
extrarenal production in granulomatous diseases or
lymphoma, or
increased renal production that can be induced by
primary hyperparathyroidism but not by PTHrp

 In patients with elevated 1,25dihydroxyvitamin D, chest radiograph

(looking for malignancy or sarcoidosis) may
be helpful
Hypercalcemia mediated by excessive
vitamin D responds to a short course of
glucocorticoids if the underlying disease is
treated.

HYPERCALCEMIA OF
MALIGNANCY
Humoral hypercalcemia of malignancy is one of
the most common causes of non-PTH-mediated
hypercalcemia.
It should be particularly suspected if there is
clinical evidence of malignancy, usually a solid
tumor, and the hypercalcemia is of relatively
recent onset.
Have an elevated serum concentration of PTHrelated protein (PTHrp) which mimics the bone
and renal effects of PTH
Low Levels of PTH and 1,25-dihydroxyvitamin D

 Multiple myeloma and metastatic breast cancer

can present as Hypercalcemia due to extensive
bone lysis
Elavated ALP in these cases

Hodgkins lymphoma causes hypercalcemia

through increased production of calcitriol

FAMILIAL HYPOCALCIURIC
HYPERCALCEMIA
Familial hypocalciuric hypercalcemia16 (FHH) is
an autosomal-dominant condition
caused by a mutation in the calcium sensing
receptor gene (CaSR)
Moderate hypercalcemia from an early age but
relatively low urinary calcium excretion.
PTH levels can be normal or only mildly elevated
despite the hypercalcemia
24 hr urinary calcium is low in Pts with FHH
compared to Primary HPTH
(or Low urinary calcium/creatinine of <0.01)

Other Causes of Hypercalcemia

Thiazide diuretics:

Enhance ca reabsorption in the distal

tubule urinary ca excretion.

Rarely causes Ca in N persons, but lead to Ca

in pts 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 inv : high Ca, PTH, low urinary 24(h)
calcium

Milk Alkali Syndrome

Consumption of large amounts of
calcium carbonate via calciumcontaining antacids can lead to
hypercalcemia, alkalosis, and renal
insufficiency
Thyroid disorders
Phaeochromocytoma
Pagets disease

Diagnostic Approach to Hypercalcaemia - Summary

DDX

Ca

PO4

PTH

PTHrP 1,25(OH) U Ca
D

N/

/N

/N

Primary PTH

Granulomatous
disease

Vit D excess

Thiazide

/N

/N

Milk alkali
syndrome

/N

/N

Malignancy

TREATMENT OF HYPERCALCEMIA
Aimed both at
Lowering the serum calcium and, 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

 Patients with mild hypercalcemia (<12

mg/dL) do not require immediate treatment.
They should stop any medications implicated
in causing hypercalcemia, avoid volume
depletion and physical inactivity, and
maintain adequate hydration.
Moderate Hypercalcemia (12 to 14 mg/dL),
especially if acute and symptomatic, requires
more aggressive therapy.
Patients with severe hypercalcemia (>14
mg/dL), even without symptoms, should be
treated intensively.

SALINE HYDRATION
Correction of the ECF volume is the first and the
most important step in the treatment of severe
hypercalcemia from any cause.
Volume repletion can lower calcium concentration
by approximately 1 to 3 mg/dL by increasing GFR
and decreasing sodium and calcium reabsorption
in proximal and distal tubules.
. A reasonable regimen, in the absence of edema,
is the administration of isotonic saline at an initial
rate of 200 to 300 mL/hour that is then adjusted to
maintain the urine output at 100 to 150 mL/hour

FUROSEMIDE 10- 20 mg iv as necessary

after achieving adequate hydration
Promotes calciuresis and prevents edema
Lasix infusion not advisable due to
complications

CALCITONIN
Is Beneficial in symptomatic patients with serum
calcium >14 mg/L (3.5 mmol/L),
along with hydration and bisphosphonates.
It works rapidly, lowering the serum calcium
concentration by a maximum of 1 to 2 mg/dL
(0.3 to 0.5 mmol/L) beginning within four to six
hours
It Acts by increasing Renal calcium excretion
and,
by decreasing bone resorption via interference
with osteoclast function

 DOSING:
Salmon calcitonin 4 IU/kg im or s/c every
12 hours; doses can be increased up to 6 to
8 international units/kg every six hours
efficacy of calcitonin is limited to the first
48 hours, even with repeated doses, due
development of tachyphylaxis, perhaps due
to receptor downregulation

BISPHOSPHONATES
Are nonhydrolyzable analogs of inorganic
pyrophosphate that adsorb to the surface of bone
hydroxyapatite and inhibit calcium release by
interfering with osteoclast-mediated bone resorption
They are effective in treating hypercalcemia
resulting from excessive bone resorption of any
cause
Maximum effect occurs in 2-4 days,
so usually given in conjunction with saline and/or
calcitonin, which reduce calcium concentration more
rapidly.

 IV Zoledronic acid (ZA) or Pamidronate are

bisphosphonates of choice

Other Bisphosphonates that are in use are ,

ibandronate , clodronate , and etidronate

 Common complications of Bisphosphonate use

are hypocalcemia, hypophosphatemia,
impaired renal function, nephrotic syndrome,
osteonecrosis of the jaw(Repetitive iv)

GLUCOCORTICOIDS
Increased calcitriol production occurs in
patients with chronic granulomatous
diseases (eg, sarcoidosis) and in
occasional patients with lymphoma.
eg, prednisone in a dose of 20 to 40
mg/day- reduces serum Ca concentrations
within 2-5 days by decreasing calcitriol
production by the activated mononuclear
cells in the lung and lymph nodes.

GALLIUM NITRATE
It Inhibits osteoclastic bone resorption,
in part via inhibition of an ATPase
dependent proton pump on the
osteoclast ruffled membrane, without
being directly cytotoxic to bone cells .
It also inhibits PTH secretion from
parathyroid cells in vitro
Complications- Nephrotoxic and Bone
Marrow suppresion

DIALYSIS
In severely hypercalcemic patients who are
comatose, have ECG changes, in severe
renal failure, or cannot receive aggressive
hydration, hemodialysis with a low- or nocalcium dialysate is an effective treatment.
Continuous renal replacement therapy can
also be used to treat severe hypercalcemia.
The effect of dialysis is transitory, and it
must be followed by other measures.

 Calcimimetic agent (cinacalcet )

reduces the serum Ca concentration in
patients with severe hypercalcemia due to
parathyroid carcinoma and in hemodialysis
patients with an elevated calciumphosphorous product and secondary
hyperparathyroidism
Parathyroidectomy curative in
Hypercalcemic crisis resulting from Primary
Hyperparathyroidism

Thank you