CASE 1 - Hypercalcemia Flashcards
What hormone does the parathyroid gland produce, and what is its function?
Produces parathyroid hormone, which increases serum calcium levels
How does parathyroid hormone increase blood calcium levels? (3 mechanisms)
INCREASING ABSORPTION:
- Inc. absorption in the GIT
- Inc. bone resorption by osteoclasts
DECREASING EXCRETION:
- Dec. urinary excretion of calcium (by increasing kidney reabsorption)
The body likes to be electrically neutral. What does this mean for the number of cations and anions?
[CATIONS] = [ANIONS]
What is the anion gap?
The difference between primary measured cations (e.g. Na+) and primary measured anions (e.g. Cl- O3-)
The UNMEASURED anions are responsible for the anion gap
https://www.youtube.com/watch?v=2oN_bQaY9Oo
In normal individuals, the major unmeasured anion responsible for the existence of a serum anion gap is…
ALBUMIN
What is the pathophysiology behind a HIGH anion gap?
An increase in the unmeasured anions.
What is the difference between a NORMAL gap metabolic acidosis and a HIGH/ELEVATED gap metabolic acidosis?
NORMAL GAP: also known as hyperchloremic metabolic acidosis. There is decreased bicarbonate, but Cl- levels rise, thus there is no change in the [Na+] - [HCO3-] - [Cl-] equation used to calculate anion gap.
HIGH/ELEVATED GAP: increased production of a pathologic acid, causing more HCO3- to be used up as a buffer. No Cl- increase.
What is the only cause of a high/elevated gap acidosis which is NOT caused by excess production of a pathologic acid?
Severe renal failure - kidneys no longer able to normally excrete phosphate and sulphate, meaning that they accumulate in the unmeasured anions
Which 2 pathophysiological mechanisms are responsible for a NORMAL anion gap acidosis? Give examples for each.
- LOSS OF HCO3- (diarrhoea, type 2 RTA, acetazolamide)
2. DECREASED RENAL SECRETION OF H+ (renal failure, type 1 and 4 RTA)
What are the pathophysiological mechanisms responsible for a HIGH/ELEVATED anion gap acidosis?
There are many:
e. g. lactic acidosis, ketoacidosis
e. g. methanol ingestion, toluene inhalation, renal failure
dude just watch this video https://www.youtube.com/watch?v=qzU5UBxz4JA
What is creatinine?
A waste product derived from metabolism of skeletal muscle and meat intake
What is the difference between measuring creatinine levels and creatinine clearance?
CREATININE: measured from serum
CREATININE CLEARANCE: a measure of urinary excretion of creatinine
What are the complications of a high anion gap?
A high anion gap itself does not produce symptoms, but it may indicate an imbalance in blood acid levels, such as metabolic acidosis. Some symptoms of metabolic acidosis include:
- Nausea
- Vomiting
- Tachypnoea
- Fatigue
- Tachycardia
- Hypotension
- Confusion
What is the significance of having elevated calcium and ALP levels?
Increased ALP is a marker of increased bone turnover.
Elevated levels of serum calcium may indicate that more parathyroid hormone is being secreted, increasing osteoclast activity, hence increasing bone turnover and ALP.
How does the effect of parathyroid hormone (PTH) on kidneys result in increased calcium reabsorption?
PTH instructs the kidneys to:
- Increase calcium reabsorption
- Manufacture more calcitriol (active vitamin D), causing the GIT to increase calcium reabsorption
What is the difference between total calcium and ionised calcium?
TOTAL CALCIUM = all the calcium in your blood (including ionised calcium and calcium bound to proteins and anions)
IONISED CALCIUM = involved in cellular processes (e.g. action potentials, muscle contraction)
Describe the relationship between albumin and total calcium, and albumin and ionised calcium
Total serum calcium is directly related to albumin
Ionised calcium is inversely related to albumin
How does acidosis affect albumin and consequently ionised calcium levels?
ACIDOSIS results in a greater number of H+ ions. These H+ ions bind to albumin, making it more POSITIVELY-CHARGED.
Since calcium is also positively-charged, they repel each other and you end up with more ionised calcium in the blood.
Remember that ionised calcium is involved in cellular processes, so this causes symptoms of HYPERCALCEMIA (thirst, polyuria, abdominal pain, nausea, bone pain, muscle weakness, confusion, fatigue)
https://www.youtube.com/watch?v=630hhyQ-jE0
What are the 2 most common causes of hypercalcemia?
- Primary hyperparathyroidism
2. Malignancy
How do alkalosis and acidosis affect ionised calcium?
ALKALOSIS = more ionised calcium bound to albumin, possibly causing hypocalcemia.
ACIDOSIS = less ionised calcium bound to albumin (since H+ is binding to albumin and making it more positively-charged, repelling Ca2+), possibly causing hypercalcemia.
What is primary hyperparathyroidism? What is the underlying pathophysiological process that results in elevated PTH?
Primary hyperparathyroidism is usually caused by a tumour in the parathyroid gland, leading to excess secretion of PTH (and consequently symptoms of HYPERCALCEMIA).
What is secondary hyperparathyroidism? What is the underlying pathophysiological process that results in elevated PTH?
Secondary hyperparathyroidism can be caused by:
a. Renal failure
b. Decreased vitamin D
This results in less renal reabsorption and less GIT calcium reabsorption (decreasing serum calcium), thus upregulating PTH as a compensatory mechanism.
What is tertiary hyperparathyroidism? What is the underlying pathophysiological process that results in elevated PTH?
Tertiary hyperparathyroidism carries over from secondary hyperparathyroidism. There has been hyperplasia of the chief cells in the parathyroid gland, increasing the baseline level of PTH that they produce.
https://www.youtube.com/watch?v=j_LPQT5t_88
State the calcium levels that you would expect to find in primary, secondary, and tertiary hyperparathyroidism.
PRIMARY: elevated Ca2+
SECONDARY: normal or low Ca2+
TERTIARY: elevated Ca2+ (given that the underlying causing of secondary hyperparathyroidism has been treated)
https://www.youtube.com/watch?v=j_LPQT5t_88
What are the treatments for primary, secondary, and tertiary hyperparathyroidism?
PRIMARY: surgery (remove the adenoma)
SECONDARY: treat underlying cause (kidney transplant or increase vitamin D levels)
TERTIARY: surgery (remove parathyroid gland)
What causes pseudohypercalcemia / false Hypercalcemia?
HYPERALBUMINAEMIA causes false hypercalcemia.
This is because there is more calcium bound to albumin, whilst the concentration of free ionised calcium stays the same.
List 4 medications that can increase calcium levels
- Thiazides (dec. renal reabsorption of calcium)
- Lithium (inc. PTH)
- Vitamin D supplements
- Calcium supplements
What is the difference between ionised/free calcium and bound calcium?
Free/ionised is biologically active
Bound calcium is biologically INACTIVE and does not get excreted because it is bound to proteins (to large to clear the kidneys)
What is the main calcium reservoir in the body?
Bones
List 4 physiological processes that calcium is involved in
- Formation of bone and teeth
- Cardiac depolarisation
- Blood clotting
- Muscle contraction
TRUE OR FALSE? Small changes in ionised calcium cause large changes in PTH.
TRUE
Change can occur in seconds (e.g. following a meal)
What is calcitonin secreted by, and what is its effect?
Calcitonin is secreted by parafollicular cells of the thyroid gland. It acts to reduce serum calcium levels, opposing the effects of PTH.
Long-term effect unclear.
List 4 SYMPTOMS of hypercalcemia
General: fatigue
GIT: anorexia, nausea, vomiting, constipation, dyspepsia
RENAL: polyuria, polydipsia
PSYCHIATRIC: anxiety, depression, altered consciousness
‘Bones, stones, abdominal moans, and psychic groans’
How does hypercalcemia cause polyuria and polydipsia?
Hypercalcemia –> detected by Ca-Sensing Receptors (CaSR) in thick ascending LOH (TAL) –> decreased insertion of K+ channels –> decreased K+ in TAL lumen to drive Na-K-Cl co-transporter –> increased NaCl in tubule lumen –> osmotically draws water out –> POLYDIPSIA, POLYURIA
List 5 causes of hypercalcemia
- Artefact (e.g. dehydration)
- Primary hyperparathyroidism
- Malignancy
- Vitamin D-mediated (e.g. granulomatous disease)
- Familial
- Drugs
- Endocrine (thyroid disease, cortical insufficiency)
What is the usual demographic of people diagnosed with primary hyperparathyroidism?
Female, ~55 years of age
What are the indications for surgical treatment of primary hyperparathyroidism?
- HIGH CALCIUM LEVELS
- SKELETAL INDICATIONS (T score
Why must surgery for primary hyperparathyroidism be carefully considered before proceeding?
There are associated risks:
- Giving them hypoparathyroidism by removing the parathyroid gland
- Damage to vocal cords
- Injury to oesophagus or trachea
What is the treatment for hypercalcemia? (short and long-term)
- IMMEDIATE:
Rehydration (with isotonic saline) - Lower serum calcium by: IV bisphosphonates (if rehydration is unsuccessful) + calcitonin salmon (if acute and life-threatening)
- Treat any complications (e.g. arrhythmia, nephrolithiasis)
LONG-TERM: treat the underlying cause (e.g. adenoma, CKD)
When do signs of neuromuscular irritability appear in HYPOcalcemia? Give 2 examples of these.
In the acute period.
Trousseau’s sign and Chvostek’s sign
List 4 SIGNS of hypercalcemia
STONES: nephrolithiasis, nephrocalcinosis, prerenal failure (secondary to dehydration)
BONES: bone pain
ABDOMINAL MOANS: NV, abdo pain, dehydration
PSYCHIATRIC GROANS: anxiety, depression, cognitive dysfunction
‘Bones, stones, abdominal moans, and psychic groans’
CARDIAC: arrhythmia, HTN, calcification of valves and arteries (if longstanding hypercalcemia)
NEUROMUSCULAR: muscle weakness
EYE: band keratopathy (very rare)
List 3 causes of HYPOcalcemia
- Artefact (e.g. low albumin)
- Primary HYPOparathyroidism (e.g. previous surgical removal, thyroidectomy, autoimmune)
- Secondary HYPOparathyroidism (e.g. low vitamin d)
but there’s many more
Outline 4 investigations that can be undertaken to evaluate the CAUSE of hypercalcemia (other than serum calcium levels).
- Serum PTH: to differentiate PTH-mediated from non-PTH-mediated disease
- Urine calcium excretion: to detect FHH (urine excretion of Ca2+ will be lower)
- PTHrP: malignancy
- Calcitriol: granulomatosus disease or lymphoma
- Calcidiol: vitamin D intoxication
(good table on amboss under diagnostics: https://www.amboss.com/us/knowledge/Hypercalcemia/)
Where is most of the phosphate in our body found?
~85% locked up with calcium in bones (in the form of hydroxyapatite, which makes bones hard)
https://www.youtube.com/watch?v=o0KCbyf-rkU
What are 4 symptoms of hyperphosphotemia?
MILD CASES: no symptoms
SEVERE CASES: tetany, chvostek’s and trousseau’s signs, tingling around the mouth, seizures, bone pain, kidney stones
What effect does parathyroid hormone (PTH) have on phosphate?
When PTH is release (e.g. due to hypocalcemia), it stimulates bone reabsorption.
This causes calcium and phosphate to be released into the blood.
Whilst PTH stimulates renal reabsorption of calcium, it shuts down the reabsorption of phosphate, so more is lost in the urine.
What is the relationship between phosphate and calcium?
There is usually an inverse relationship
How can acute and chronic kidney disease cause secondary hyperparathyroidism?
- Poor renal reabsorption of calcium
- Low serum calcium levels causes PTH to be released
- Continual PTH release as no calcium is being reabsorbed
LOW calcium and LOW PTH indicates…?
LOW calcium and LOW PTH indicates
PRIMARY HYPOPARATHYROIDISM
LOW calcium and HIGH PTH indicates…?
LOW calcium and HIGH PTH indicates
SECONDARY HYPERPARATHYROIDISM
HIGH calcium and HIGH PTH indicates…?
HIGH calcium and HIGH PTH indicates
PRIMARY HYPERPARATHYROIDISM
HIGH calcium and LOW PTH indicates…?
HIGH calcium and LOW PTH indicates
Malignancy, granuloma, milk alkali disease
A finding of raised PTHrP (parathyroid-related protein) and hypercalcemia suggests which underlying pathology?
Give a few examples of pathologies which cause PTHrP release.
Malignancy.
PTHrP can be secreted by tumours such as breast and squamous-cell lung carcinoma
(note that PTHrP also has normal functions too)
Why does hypercalcemia occur in multiple myeloma?
Has multifactorial causes, but multiple myeloma is an osteolytic tumour
Phosphate is typically ___ in primary hyperparathyroidism.
Why is this?
Phosphate is typically LOW in primary hyperparathyroidism.
This is because PTH inhibits renal reabsorption of phosphate.
The presentation of hypercalcemia is similar to that of vitamin _ overdose.
The presentation of hypercalcemia is similar to that of vitamin D overdose.
What is the relevance of genetics and family history when it comes to hypercalcemia?
Assessment of familial hypocalciuric hypercalcemia (FHH)
These patients typically do not experience any symptoms of hypercalcemia. This is an important clinical clue when differentiating between FHH and primary hyperparathyroidism.
During a thyroidectomy, care should be taken to avoid injury of which nerves?
Superior laryngeal
Recurrent laryngeal (inferiorly)
What is the difference between true and factitious hypercalcemia?
TRUE hypercalcemia also demonstrates raised levels of IONISED calcium.
FACTITIOUS hypercalcemia is a raised TOTAL calcium with normal ionised calcium (therefore asymptomatic).
Paraneoplastic production of PTHrP occurs in which types of cancers? (Give 4 examples)
Squamous cell lung carcinoma
Breast cancer
Ovarian cancer
Leukaemia
Lymphoma
Why do granulomatous disorders cause hypercalcemia?
Activated monocytes produce calcitriol outside of the kidneys
Which cause of hypercalcemia (primary hyperparathyroidism or malignancy) results in more severe symptoms?
MALIGNANCY causes more severe/symptomatic hypercalcemia.
In primary hyperparathyroidism, serum calcium is typically lower and rises more slowly than in hypercalcemia of malignancy.
Patients are, therefore, less symptomatic.
Which 3 ECG findings may be present in someone with hypercalcemia?
- Arrhythmias
- Bradycardia
- QT interval shortening (and J wave in severe cases)
Explain the purpose of each of the following laboratory studies when evaluating hypercalcemia:
- Albumin
- Phosphate
- ALP
- ABG/VBG
- CBC
- Albumin: needed to calculate corrected calcium
- Phosphate: low in primary hyperparathyroidism and PTHrP-mediated hypercalcemia
- ALP: elevated in conditions with high bone turnover (e.g. hyperparathyroidism, thyrotoxicosis) and osteolytic lesions (e.g. multiple myeloma)
- ABG/VBG: metabolic alkalosis may suggest milk-alkali syndrome
- CBC: hemoconcentration may be seen in patients with polyuria and dehydration secondary to hypercalcemia.
link between hypercalcemia and metabolic acidosis?
.
4 multiple myeloma signs
CRAB
Increased calcium
Renal failure
Anaemia
Bony tenderness
(RAB = triad of multiple myeloma)
How is FHH diagnosed?
24-hour urinary calcium
How is the corrected calcium calculated?
Corrected calcium (mmol/L) = total calcium (mmol/L) + 0.02 (40 - albumin [g/L])
What are the ranges used in the classification of mild, moderate, and severe hypercalcemia?
MILD: total calcium 2.63 - 3mmol/L
MODERATE: total calcium 3 - 3.5mmol/L
SEVERE: total calcium >3.5mmol/L
(there are ranges for ionised calcium too but I cbf)
NORMAL phosphate levels with a HIGH/HIGHER END OF NORMAL PTH indicates…?
Malignancy
Serum Protein Electrophoresis reveals no monoclonal bands and no Bence-Johnson proteins. Which condition is made less likely by this?
Multiple myeloma
What is the pathophysiology behind multiple myeloma?
- Malignant plasma cells infiltrate the bone marrow
- Suppression of haematopoiesis
- Leukopenia, anaemia, thrombocytopenia
How does multiple myeloma cause hypercalcemia?
Proliferation of malignant plasma cells –> stimulates osteoclast activity –> osteolysis –> hypercalcemia
How is a T and Z-score interpreted?
T-score: comparison to a young, healthy adult (used to measure osteoporosis).
Z-score: comparison to others in your age group. Tells us that there is an abnormality because the patient is osteoporotic and osteopenic even in their age group.
Name the 5 criteria for surgical management of primary hyperparathyroidism (parathyroidectomy)
- Osteoporosis (T-score < -2.5)
- Age <50 years
- Calcium level 0.25 mol/L above reference range
- 24-hour urinary calcium excretion >400mg
- 30% or more reduction in creatinine clearance
If the patient has ONE of these criteria discussions about surgery can be considered along with their other
comorbidities.
What is the most common cause of primary hyperparathyroidism?
Single adenoma in 85% of cases
Adenoma = benign tumour of epithelial tissue with glandular origin
How does surgical treatment differ for primary vs. tertiary hyperparathyroidism?
How does this affect the potential complications after surgery?
PRIMARY: usually caused by a single adenoma, therefore requiring only ONE gland to be removed.
TERTIARY: hypertrophy and hyperplasia of the parathyroid glands has occurred, potentially requiring 3.5 glands to be removed.
Greater risk of hypoparathyroidism & hypocalcemia if more parathyroid glands have been resected.
Name 4 generic complications that should be explained to a patient before surgery
- Damage to local structures (e.g. nerves,
blood vessels) - Scarring
- Infection
- The operation could be unsuccessful and we will need to operate again.
Which nerves are at risk of being damaged in a parathyroidectomy?
Recurrent laryngeal
What are the consequences of recurrent laryngeal nerve injury?
- Hoarse voice
- Significant voice loss (since RLN controls most of the laryngeal muscles. Superior laryngeal nerve only controls a few of these muscles)
- Aspiration risk (vocal chords are important in preventing aspiration)
What does conservative (non-surgical) management of primary hyperparathyroidism involve?
‘Watch and wait’
- Symptom monitoring
- Calcium levels and kidney function every 6-12 months
- BMD every 2 years
- Dietary: avoid high calcium and vitamin D intake, stay hydrated
How do Calcimimetics work and when are they used?
Work by binding to parathyroid calcium sensing receptor, increase its sensitivity to ionized calcium. This decreases plasma PTH levels.
Used in the treatment of secondary hyperparathyroidism
Name 2 drugs that commonly cause hypercalcemia
Thiazide diuretics (mainly in patients with underlying primary hyperparathyroidism)
Lithium
What is the pathophysiology behind FHH?
- Mutation in CaSR gene
- Decreased sensitivity of parathyroid glands and nephrons to calcium
- More calcium needed to suppress PTH release and kidney reabsorption of calcium
- Hypercalcemia + hypocalciuria
Raised CALCIDIOL levels indicate which cause of hypercalcemia?
Vitamin D intoxication
Raised CALCITRIOL levels indicate which cause of hypercalcemia?
Lymphoma, granulomatous disease
Name 3 malignancy-related causes of hypercalcemia
- Paraneoplastic PTHrP production: SCC of the lung, breast cancer, ovarian cancer, lymphoma, leukaemia
- Osteolytic lesions: breast cancer, prostate cancer, MULTIPLE MYELOMA, lymphoma
- Paraneoplastic calcidiol (Vitamin D) production: lymhpoma
