Clinical Calcium Homeostasis COPY Flashcards
Name Dietary sources of calcium
- milk, cheese and other dairy foods
- green leafy vegetables – such as broccoli, cabbage and okra, but not spinach
- soya beans
- Tofu
- nuts
- bread and anything made with fortified flour
- fish where you eat the bones – such as sardines and pilchards
what are the functions of calcium?
- Bone formation
- Cell division & growth
- Muscle contraction
- Neurotransmitter release
What percentage of Ca2+ is found where?
What proportion of calcium is bound in plasma?
45% bound (mainly to albumin)
10% non-ionised or complexed to citrate, PO4 etc.
45% ionised - biologically important (Ionized calcium is calcium in your blood that is not attached to proteins. It is also called free calcium)
what is the normal range of plasma calcium?
Normal range 2.20-2.60 mmol/l
how do we calculate and adjust free calcium?
Increased albumin decreases free calcium
Decreased albumin increases free calcium
Adjust Ca2+ by 0.1mmol/l for each 5g/l reduction in albumin from 40g/l
Acidosis increases ionised calcium thus predisposing to hypercalcaemia
what are sources of vitamin D?
- Vitamin D is also found in a small number of foods. Good food sources are:
- oily fish – such as salmon, sardines and mackerel
- eggs
- fortified fat spreads
- fortified breakfast cereals
- some powdered milks
what cells make up the parathyroid gland?
chief cells and the oxyphil cells
what is the role of parathyroid hormone?
Chief cells respond directly to changes in calcium concentrations
Alterations in ECF Ca2+ levels are transmitted into the parathyroid cells via calcium-sensing receptor (CaSR)
PTH is secreted in response to a fall in calcium
Chief cells– The role of this cell type is to secrete parathyroid hormone
how does parathyroid hormone increase calcium?
PTH has direct effects that promote reabsorbtion of calcium from renal tubules & bone
What bone problem might lengthy exposure to inappropriate levels of PTH lead to? - osteoprosis
PTH mediates the conversion of vitamin D from its inactive to active form
PTH mediates the conversion of vitamin D from its inactive to active form
Where in the body does this conversion take place?
Why do some patients need activated vitamin D?
if their kidneys do not work
what levels of serum calcium are classed as hypocalcaemia?
Serum Calcium <2.20 (reference range 2.20-2.60mmol/L)
Symptoms of hypocalcaemia typically develop when adjusted serum calcium levels fall below 1.9mmol/L. However this threshold does vary and is dependent on the rate of fall
what are the clinical features of hypocalcaemia?
what tests can be done to see if someone is hypocalcaemic?
Trosseau’s sign - if low calcium then hand goes into spasm when taking blood pressure
Chovstek’s sign
62 years old woman
She presents to a GP practice complaining of muscle spasms
She was discharged from hospital a couple of days ago following a “neck operation”
What operation has she had?
What are the recognised complications of this operation?
What should we do?
Her adjusted calcium is 1.9mmol/L (2.2-2.6)
just think about questions form the last slide
whata re the causes of hypocalcaemia?
Disruption of parathyroid gland due to total thyroidectomy. May be temporary or permanent
Following selective parathyroidectomy (usually transient & mild)
Severe vitamin D deficiency
Mg2+ deficiency (which drug can cause this?) - PPI
Cytotoxic drug-induced hypocalcaemia
Pancreatitis, rhabdomyolysis and large volume blood tranfusions
Most common cause of low albumin is surgeons doing things to peoples necks
what are the causes of hypocalcaemia with low PTH (hypoparathyroidism)?
Low calcium and low PTH then something wrong with parathyroid gland as PTH should go up
Genetic disorders
Post-surgical (thyroidectomy, parathyroidectomy, radical neck dissection)
Autoimmune
Infiltration of the parathyroid gland (granulomatous, iron overload, metastases)
Radiation-induced destruction parathyroid glands
Hungry bone syndrome (post parathyroidectomy)
HIV infection
what are the causes of hypocalcaemia with high PTH (secondary hyperparathyroidism in response to hypocalcemia)
Vitamin D deficiency or resistance
Pseudohypoparathyroidism
Hypomagnesemia
Renal disease
Tumor lysis
Acute pancreatitis
Acute respiratory alkalosis
what drugs can cause hypocalcaemia?
Inhibitors of bone resorption (bisphosphonates, calcitonin, denosumab)
Cinacalcet
Calcium chelators (EDTA, citrate, phosphate)
Foscarnet (due to intravascular complexing with calcium)
Phenytoin (due to conversion of vitamin D to inactive metabolites)
Fluoride poisoning
what is the diagnostic approach of hypocalcaemai
• History:
- Symptoms
- Ca & Vit D intake
- Neck surgery
- Autoimmune disorders
- Medications
- Family history
- Examination - Neck scars
- Investigations:
- ECG - look for a prolonged QT
- Serum calcium
- Albumin
- Phosphate
- PTH
- U&Es
- Vitamin D
- Magnesium
pictures showing how investigations for hypocalcaemia work
how does low magnesium cause hypocalcaemia?
Magnesium is required for the production and release of parathyroid hormone, so when magnesium is too low, insufficient parathyroid hormone is produced and blood calcium levels are also reduced (hypocalcemia). The hypocalcemia is described as “secondary” because it occurs as a consequence of hypomagnesemia
hypoarathyroidism may result form what?
agenesis (e.g. DiGeorge syndrome)
destruction (neck surgery, autoimmune disease)
Infiltration (e.g. haemochromatosis or Wilson’s disease)
reduced secretion of PTH (neonatal hypocalcaemia, hypomagnesaemia)
Resistance to PTH (discussed on next slide)
What is Pseudohypoparathyroidism?
Pseudohypoparathyroidism (PHP) is a genetic disorder in which the body fails to respond to parathyroid hormone
Pseudohypoparathyroidism, which presents in childhood, refers to a group of heterogeneous disorders defined by target organ (kidney and bone) unresponsiveness to PTH. It is characterized by hypocalcemia, hyperphosphatemia and, in contrast to hypoparathyroidism, elevated rather than reduced PTH concentrations
Albright’s heriditary Osteodystrophy (AHO): Obesity, short stature, shortening of the metacarpal bones that can occur in some patients with Pseudohypoparathyroidism
AHO alone without abnormalities of calcium or parathyroid hormone (pseudo-pseudohypoparathyroidism)
what is the treatment of “Mild” hypocalcaemia
(Asymptomatic, >1.9mmol/L)?
Commence oral calcium tablets
If post thyroidectomy repeat calcium 24 hours later
If vit D deficient, start vitamin D
If low Mg2+, stop any precipitating drug and replace Mg2+
what is the treatment of “Severe” hypocalcaemia
(Symptomatic or <1.9mmol/L)?
This is a medical emergency
Administer IV calcium gluconate
Initial bolus (10-20ml 10% calcium gluconate in 50-100ml of 5% dextrose IV over 10 minutes with ECG monitoring)
Calcium gluconate infusion
Treat the underlying cause
Read this, case study 2:
Mrs Smith is 62 years old
She presents to a GP practice complaining of vague symptoms
GP does some blood tests
Her adjusted calcium is 1.95mmol/L
Her GP phones for advice
What should we do?
History? - She is on a bisphosphonate for osteoporosis, Dietary intake of calcium seems reasonable
Examination?
Investigations? - Low Ca, Low PO4, PTH awaited
Treatment - Vitamin D replacement
how is vitamin D replacement done in someone with hypocalcaemia?
Advice regarding dietary sources
Most tablets contain a combination of vitamin D and calcium
Maintenance dose ~400-1000 international units
Higher loading dose required (e.g. 3200 units daily for 12 weeks)
Vitamin D requires hydroxylation by the kidney to its active form, therefore the hydroxylated derivatives alfacalcidol or calcitriol should be prescribed if patients with severe renal impairment require vitamin D therapy
what levels of calcium is classed as hypercalcaemia?
dpeending on how quickly it happens and by how much by determines how symptomatic someone is
what are parathyroid mediated causes of hypercalcaemia?
High calcium and inappropriately normal PTH then we know problem is coming form the parathyroid gland
Primary hyperparathyroidism (sporadic)
Inherited variants:
- Multiple endocrine neoplasia (MEN) syndromes
- Familial isolated hyperparathyroidism
- Hyperparathyroidism-jaw tumor syndrome
Familial hypocalciuric hypercalcemia
Tertiary hyperparathyroidism (renal failure)
what are non-parathyroid mediated causes of hyperglycaemia?
High calcium should be a lowered PTH and if that’s what we find and the parathyroid glands are doing what they are meant to be doing then it is coming form somewhere else
Hypercalcaemia of malignancy:
- PTHrp
- Activation of extrarenal 1 alpha-hydroxylase (increased calcitriol)
- Osteolytic bone metastases and local cytokines
Vitamin D intoxication
Chronic granulomatous disorders:
- Sarcoid, TB, Berylliosis, Histioplasmosis, Wegener’s
what medications can cause hypcalcaemia?
Thiazide diuretics
Lithium
Teriparatide
Excessive vitamin A
Theophylline toxicity
What are miscellaneous causes of hypercalcaemia?
Hyperthyroidism
Acromegaly
Pheochromocytoma
Adrenal insufficiency
Immobilisation
Parenteral nutrition
Milk alkali syndrome
what are the renal clinical features of hypercalcaemia?
“Bones, stones, groans & psychic moans”
Polyuria
Polydipsia
Nephrolithiasis - renal calculi/kindey stones
Nephrocalcinosis
Distal renal tubular acidosis
Nephrogenic diabetes insipidus
Acute & chronic renal dysfunction
what are the Gastrointestinal clinical features of hypercalcaemia?
“Bones, stones, groans & psychic moans”
Anorexia
Nausea & vomiting
Bowel hypomotility & constipation
Pancreatitis
Peptic ulcer disease
what are the Musculoskeletal clinical features of hypercalcaemia?
“Bones, stones, groans & psychic moans”
Muscle weakness
Bone pain
Osteopenia/osetoporosis
what are the neurological clinical features of hypercalcaemia?
“Bones, stones, groans & psychic moans”
Decreased concentration
Confusion
Fatigue
Stupor, coma
what are the cardiovascular clinical features of hypercalcaemia?
“Bones, stones, groans & psychic moans”
Shortening of the QT interval
Bradycardia
Hypertension
read this, case study 3:
Mr Bloggs presented with changed bowel habit and weight loss
Blood tests showed calcium 2.76 (2.20-2.60)
Corrected calcium 2.86
Other tests? Hb, Glucose, TFTs? CXR?
Heavy smoker
Chronic cough on systemic enquiry
Repeat corr calcium was 2.81 (2.20-2.60) and PTH was <0.1 (1.7-9.2)
Most likely diagnosis? Hypercalcaemia of malignancy
what is the diagnostic approach of hypercalcaemia?
• History
- Symptoms of hypercalcaemia
- Systemic enquiry
- Medications
- Family history
• Examination
- Lymph nodes
- Concerns about malignancy (breast, lung etc.)
• Investigations
- U&Es
- Ca
- PO4
- Alk phos
- Myeloma screen
- Serum ACE
- PTH
• Consider ECG
read this, case 4
Mrs Jones - 54 years old
Routine blood test showed adjusted calcium of 3.05mmol/L
She is asymptomatic
Systemic enquiry is unremarkable
Serum calcium was 2.95mmol/L 2 years ago while an inpatient for a choleycystectomy - no malignancy as been going on a while
Diagnosis?
what is Primary hyperparathyroidism?
The parathyroid gland(s) becomes overactive and secretes excess amounts of parathyroid hormone (PTH). As a result, the blood calcium rises to a level that is higher than normal (called hypercalcemia)
who is primary hyperparathyroidism common in?
- Female: male = 3:1
- Incidence peaks 50-60 years
primary hyperparathyroidism - most patients are ___________ at diagnosis
asymptomatic
primary hyperparathyroidism - Most cases are ________ but has been associated with neck irradiation or prolonged lithium use
sporadic
what are the different causes of primary hyperparathyroidism?
- 85% parathyroid adenoma
- 15% four gland hyperplasia
- <1% MEN type 1 or 2A
- <1% parathyroid carcinoma
- Often present for years prior to diagnosis
what investigations can be done for primary hyperparathyroidism?
Ca, PTH
U&Es: check renal function
Abdominal imaging: renal calculi
DEXA (a means of measuring bone mineral density): osteoporosis - too much PTH = taking calcium form bone
24 hour urine collection for calcium: Excl. FHH
Vitamin D
(Para) thyroid ultrasound
SESTAMIBI: After 15mins there is uptake in the thyroid gland (& inferior parathyroid gland), after 2 hours uptake is only evident in the inferior parathyroid gland (shown in the pictures on the right)
one treatment of primary hyperparathyroidism is surgery
The presence of what features would be an indication for parathyroid surgery
eGFR - Estimated glomerular filtration rate is the best test to measure your level of kidney function and determine your stage of kidney disease
what is the medical management of primary hyperparathyroidism?
(treatment of choice is surgery if possible though)
Generous fluid intake
Cinacalcet (acts as a calcimetic, i.e. mimics the effect of calcium on the calcium sensing receptor on Chief cells, this leads to a fall in PTH and subsequently calcium levels)
is msot tumour associated hypercalcaemia major or not?
Most-tumour associated hypercalcaemia is mild
Unless an endocrine tumour, prognosis usually poor
what are the types of hypercalcaemia caused by malignancy?
High calcium and low PTH so look for malignancy
May be obvious as the person may be known for having a malignancy
May produce a PTH like protein or a direct effect of metastases on bone
What is Familial Hypocalciuric Hypercalcaemia?
Autosomal dominant disorder of the calcium sensing receptor
an inherited disorder that causes abnormally high levels of calcium in the blood (hypercalcemia) and low to moderate levels of calcium in urine (hypocalciuric). People with FHH usually do not have any symptoms and are often diagnosed by chance during routine bloodwork
Low levels of urinary calcium - High serum calcium then you should have high urinary calcium but in this one your urinary calcium is low
Benign, no therapy indicated
Positive family history, screen young family members for diagnosis
PTH may be normal or slightly elevated
No evidence of abnormal parathyroid tissue on ultrasound or isotope scan
What is Multiple Endocrine Neoplasia? and what types is there?
Multiple endocrine neoplasia is a group of disorders that affect the body’s network of hormone-producing glands called the endocrine system
MEN type 1
MEN type 2A
what is MEN type 1?
- Primary hyperparathyroidism
- Pancreatic
- Pituitary
- >95% of MEN 1 will have hyperparathyroidism
- MENIN mutation (Chr 11)
- 2-4% of cases of PHP may be MEN 1
- Usually presents in the 2nd to 4th decade of life
- Multi-gland involvement, High Recurrence Risk
what is MEN type 2A?
- Medullary thyroid cancer
- Phaeochromocytoma
- Primary hyperparathyroidism
- RET mutation
- 20-30 % of MEN2A have hyperparathyroidism
- Usually milder disease than in MEN 1
Is family history very important in patients with primary hyperparathyroidism?
yes
what is the management of hypercalcaemia?
• Rehydration
- 0.9% Saline 4-6 litres over 24 hours
- Monitor for fluid overload
- Consider dialysis if severe renal failure
• After rehydration, intravenous bisphosphonates (Bisphosphonates are a group of drugs that work by slowing bone loss)
- Zolendronic acid 4mg over 15 mins
- Give more slowly and consider dose reduction if renal impairment
- Calcium will reach nadir at 2-4 days
what is 2nd line management of hypercalcaemia?
read this, case study 5:
Mr Arthur - 74 years old
Wife took patient to GP complaining that he appear confused
Under treatment for multiple myeloma (a type of bone marrow cancer)
Adjusted calcium is 3.7mmol/L
What should you do?
- Admit
- History
- Examination
- Investigation
- Management
