Hypercalcemia Flashcards
defintion of hypercalcemia
> 2.6mmol/l
normal range of calcium is 2.1-2.6mmol/l
over 3 mmol/l is when you start seeing symptoms
MILD (2.6 - 3 mmol/L): usually no/few symptoms, may be identified on
routine blood tests
MODERATE (3 - 3.4 mmol/L): symptoms present, usually requires hospital
admission for treatment
SEVERE (>3.5 mmol/L): associated with malignancy
what happens when there is high levels of calcium in the blood?
increased levels of the hormone calcitonin which is produced by the thyroid gland to try and reduce levels of calcium. PTH will be reduced and calcitonin increased
what is milk alkali syndrome
a very rare cause of hypercalcaemia. excess ingestion of milk or calcium containing compounds (e.g. calcium carbonate).
where is calcium stored in body and main functions??
majority of calcium is found in the mineral component of bone. remaining percentage is found in plasma and is in 3 different forms:
- free ionised- this is ca2+ the biologically active form that takes part in cellular reactions, neuronal transmission etc.
- bound to proteins mainly albumin
- complexed with ions e.g. citrate and phosphate
functions: muscle contraction, blood coagulation, neuronal transmission, intracellular signalling cascade
how is calcium regulated in the body?
what happens when there are low levels of calcium?
when calcium is low it is detected by:
- parathyroid glands
in parathyroid glands we have calcium sensing receptors, they detect when calcium levels are high or low
when they detect low calcium levels, it stimulates chief cells present within the parathyroid glands
- these chief cells release more PTH in response to low calcium
- functions of PTH to help INCREASE calcium:
travels to bone and increases bone resorption (increases osteoclast activity) = increase in calcium and phosphate ((as both calcium and phosphate are found in the mineral bone)) - also affects kidneys: increases calcium re uptake and phosphate exertion. therefore an increase in calcium and low phosphate
- it also affects the kidneys in another way: increases levels of alpha 1 hydroxylase
what does alpha 1 hydroxylase do?
(vit d pathway)- HOW DOES THIS HELP INCREASE CALCIUM?
to understand this we must know about the vit d pathway:
- when sunlight hits the skin, there is something called 7 dehydrocholestrol in the skin.
- the uv rays react with this and formed cholecalciferol (we can also make cholecalciferol from our diet)
- cholecalciferol then travels to the liver where it is acted on by an enzyme called 25 hydroxylase
- it then becomes 25 hydroxycholecalciferol/calcidiol
- this travels to the kidneys and acted on by alpha 1 hydroxylase
- forms 1,25 dihydroxycholecalciferol aka CALICTRIOL (ACTIVE FORM OF VIT D)
first part of vit d metabolism happens in liver and 2nd part happens in kidneys
THIS PATHWAY IS IMPORTANT BECAUSE IT HELPS WITH CALCIUM HOMEOSTASIS because calcitriol is involved in absorbing calcium and phosphate from the gut
DUE TO THE ACTION OF CALCITRIOL YOU GET AN INCREASE IN CALCIUM
Difference in PTH and calcitriol
PTH: increases calcium reabsorption and phosphate excretion in the kidneys and increases calcium and phosphate levels in bone resorption
however the NET effect is: increased calcium and decreased phosphate
CALCITRIOL: increases calcium and phosphate levels through GI absorption, increases calcium and phosphate reabsorption in kidneys and also on a smaller level increases calcium and phosphate levels in bone resorption
however the NET effect is : increased calcium and increased phosphate
what happens when there are high calcium levels in the body?
high levels detected by parathyroid glands by the calcium sensing receptors
this will inhibit the chief cells of the parathyroid glands
= reduced PTH produced
high calcium will also affect the THYROID GLAND
causes C cells of the thyroid glands to release CALCITONIN
- this REDUCES calcium levels by:
1. going to bone and inhibiting bone resorption
2. travels to kidneys and decreases calcium reabsorption and phosphate will decrease too
summary of hormones affected in calcium levels regulation
PTH: increases calcium and decreases phosphate
VIT D: increases calcium and increases phosphate
CALCITONIN: decreases calcium and decreases phosphate
causes of hypercalcaemia
its divided according to PTH levels
- High/inappropriately levels of PTH: meaning there is something wrong with the parathyroid gland because in a normal person, if they had high calcium, their PTH should be low because. High or normal PTH in this scenario signals something wrong with PTH gland
- low PTH levels: here the relationship between calcium and PTH is working as it should but there is some other pathology causing elevated calcium levels
what main 3 diseases/causes have high/inappropriate levels of PTH which in result of the PTH pathology cause hypercalcaemia?
Primary hyperparathyroidism
Familial benign hypocalciuric
hypercalcaemia
Tertiary hyperparathyroidism
what main diseases can cause hypercalcaemia with low PTH?
Malignancy Excess vitamin D Drugs Excessive dietary intake of calcium
more than 90% of hypercalcaemia cases are due to…?
> 90% of cases are due to Malignancy & Primary Hyperparathyroidism!
A 32-year-old man has been feeling
increasingly constipated over the past
couple of weeks, despite trying to maintain
adequate fluid intake. His father has also
experienced similar symptoms in his
thirties.
His kidney function is normal. Blood tests
reveal elevated calcium levels and normal
PTH.
Which of the following investigations need
to be carried out to aid the diagnosis?
A) ECG B) 24-hour urinary calcium C) USS of parathyroid gland D) Chest x-ray E) Serum ACE levels
B he has signs of hypercalcaemia some family history kidney function is normal his normal PTH suggests hypercalcemia with inappropriate PTH so something wrong with PTH gland
1 of the 3 main causes
- given his kidney function is normal it is unlikely to be tertiary hyperparathyroidism
- its therefore going to be either
Primary hyperparathyroidism
OR
Familial benign hypocalciuric
hypercalcaemia
and we can’t say for sure so we can do a 24 hour urinary calcium to figure out which one
- if it is primary hyperparathyroidism, you will see INCREASED urinary calcium
- if it is Familial benign hypocalciuric
hypercalcaemia you will see LOW urinary calcium
what is PRIMARY HYPERPARATHYROIDISM (one of the 3 main causes behind hypercalcaemia with inappropriate/high PTH level
When an increased production of PTH from the PTH gland either due to an adenoma or diffuse hyperplasia of the glands or a cancer of the PTH gland
This means that there is a tumour secreting lots of PTH, cos the cells are hyperactive secreting lots of PTH
- leads to elevated calcium levels
what is
Familial benign hypocalciuric
hypercalcaemia
(one of the 3 main causes behind hypercalcaemia with inappropriate/high PTH level
rare condition
autosomal dominant
usually would see a family history of mild hypercalcemia
usually dont see symptoms but may present with symptoms of hypercalcmia
the problem lies with the calcium sensing receptors
which are not responding to high levels of calcium, meaning PTH remains normal/elevated instead of being reduced as it should be according to negative feedback in hypercalcaemia.
What is Tertiary hyperparathyroidism ( (one of the 3 main causes behind hypercalcaemia with inappropriate/high PTH level)
develops in people with long lasting secondary hyperparathyroidism
what is secondary hyperparathyroidism
- seen in people with chronic kidney disease and these individuals have low calcium levels because the kidneys are not working properly and can’t reabsorb the calcium
- because of these low calcium levels in the body, the PTH will therefore be ELEVATED
- over time the increase in PTH leads to hyperplasia of PTH glands = excessive PTH levels causing lots of bone resorption and hypercalcemia.
initially started off as low calcium causing high PTH and progresses to SEVERLY HIGH PTH causing high calcium
how do we differentiate between
Familial benign hypocalciuric hypercalcaemia
and
primary hyperparathyroidism?
24 hour urinary calcium test
Urinary calcium levels elevated in primary hyperparathyroidism!
if it is Familial benign hypocalciuric
hypercalcaemia you will see LOW urinary calcium
What is . one of the main causes of hypercalcaemia with low PTH
MALIGNANCY
there are different mechanisms by which malignancy can cause hypercalcaemia:
- release of PTH related peptides: can be released by certain primary tumours like squamous cell lung cancer, bladder cancer, breast cancer.
these peptides act like PTH, but because it is not PTH it won’t be detected in blood
- Through bone metastases. The cancers which are more likely to metastasise to the bone are : Breast, Lung, Thyroid, Kidneys, Prostate (BLT with Kosher Pickle)
- Myeloma- activates RANK receptors on the osteoclasts via expression of RANK LIGANDS leading to bone resorption = increased Calcium
What are the rarer causes of hypercalcaemia with low PTH
1.EXCESS VIT D: because vit d acts on the gut to increase GI reabsorption of calcium and phosphate
excess vit d can occcur as a result of :
- Exogenous vitamin D – vitamin tablet overdose,
excess cod liver oil
- Endogenous production of calcitriol –
granulomatous disorders such as sarcoidosis, HIV, TB
-Lymphoma – production of calcitriol
- MILK ALKALI SYNDROME: (v. rare)
- Ingestion of large amounts of milk / calciumcontaining substances e.g. calcium carbonate in
antacids
symptoms: Triad of hypercalcaemia, metabolic alkalosis, AKI
- DRUGS:
these drugs can cause hypercalcaemia:
- Thiazide diuretics – decreased excretion of calcium
- Lithium – increased point at which calcium inhibits
PTH release
How does sarcoidosis result in hypercalcaemia?
Ectopic production of 1-
alpha-hydroxylase by noncaseating granulomas in
sarcoidosis
therefore:
Increased calcitriol, leading
to HYPERCALCAEM
signs and symptoms of hypercalcaemia?
signs: what you see • Dehydration • Hypertension • Arrhythmias • Bony tenderness • Confusion • Signs of underlying diagnosis e.g. cachexia & weight loss, cough
symptoms : what patient complains of-
“Bones, Stones, Groans, Thrones, Muscle Tones
and Psychiatric Moans”
- BONES: Bone pain, fractures
- STONES: Kidney Stones
- GROANS: Abdominal pain, nausea, vomiting (less
commonly peptic ulcers & pancreatitis) - THRONES: Constipation, increased thirst and urinary
frequency
MUSCLE TONES: Weakness, HYPOreflexia, lethargy
PSYCHIATRIC MOANS : Depression, anxiety, cognitive dysfunction, confusion
Investigations in hypercalcaemia?
BEDSIDE, BLOODS, IMAGING, SPECIAL TESTS
BEDSIDE • ECG – changes in moderate-severe hypercalcaemia • 24 hour urinary calcium – differentiate between PHPT and FHH
BLOODS
• Routine bloods – FBC, U+Es
• TFTs – hypercalcaemia may be seen in
thyrotoxicosis
• Bone profile – raised calcium, raised ALP if
high bone turnover
• PTH – high or low depending on cause
• Myeloma screen in suspected myeloma –
raised serum free light chains, paraprotein
spike in protein electrophoresis, BenceJones proteins in urine
IMAGING
• CXR – look for lung tumours,
granulomatous disorders
• CTAP – if malignancy suspected
SPECIAL TESTS
• USS of parathyroid gland – done in
those with confirmed PHPT and are
considering surgery
Investigations can be added/removed based
on clinical suspicion of underlying diagnosis
e.g. ACE levels in suspected sarcoidosis.
ECG changes in hypercalcaemia
- Signs of severe hypercalcaemia: Osborn waves /
J waves. (J waves are also seen in hypothermia!)
Extreme hypercalcaemia can lead to ventricular
irritability and VF arrest – RARE! - Shortened QT interval
Near absence of ST segment
(CHECK IMAGES, OR APARNA BIJUS NOTES GOOGLE DRIVE)
Treatment of hypercalcemia
for mild and moderate hypercalcaemia
MILD
• Increase oral fluid intake
• Avoid triggers / precipitants e.g. dehydration, thiazide diuretics, lithium, calcium containing compounds, reduce calcium and vitamin D intake
MODERATE
• May not require immediate therapy, use measures as described above
• Acute rise in calcium usually requires admission to hospital for IV fluids
treatment of acute severe hypercalcaemia
FIRST LINE:
Urgent aggressive fluid resuscitation – IV 0.9% saline 4-6 litres in 24 hours - FIRST LINE IS FLUID RESUSITATION
- Assess for fluid overload, especially in those with renal impairment / elderly
- Only use loop diuretics if fluid overload develops
- Consider dialysis if severe renal failure
- IV bisphosphonates – zoledronic acid 4mg over 15 minutes. Used in refractory hypercalcaemia (MEANS if hypercalcemia is not responsive to the fluid resuscitation.
- Calcitonin – if poor response to bisphosphonates, or if bisphosphonates are contraindicated
• Denosumab – if bisphosphonates are contraindicated
MONITER fluid balance, calcium, magnesium, urea & electrolytes
Treat underlying cause
Treatment of primary hyperparathyroidism (once of the most common causes of hypercalcaemia)
Parathyroidectomy or surgical excision of adenoma / hyperplastic glands
• Pre-operative USS to localise hyper-active glands
Calcimimetics e.g. cinacalcet
• Increases sensitivity of parathyroid glands to calcium, by increasing negative
feedback
