Metabolic Medicine Flashcards
(42 cards)
Vitamin D is relatively inactive. List the Vitamin D activation steps
Vitamin D is made in the skin following UV exposure to sunlight.
1,25(OH)2 vitamin D is made from vitamin D (D2 or D3 forms).
Both vitamin D2 and D3 undergo 25-hydroxylation in the liver and α-hydroxylation in the kidney to produce the activated form ,25(OH)2 vitamin D.
The rate-limiting step is the α-hydroxylation.
Calcium - sites of reabsorption
Kidney - calcium is reabsorbed in the distal convoluting tubule
Gut - calcium is reabsorbed in duodenum and upper jejunum
Calcium, PTH, Vitamin D Axes - what happens if there is a drop in calcium serum level
Low blood Ca
Release of PTH by parathyroid gland
Increased vitamin D hydroxylation
Increased bone resorption
Increased Ca reabsorption in kidneys
Decrease in PO4 levels (increased excretion)
Effects of PTH at high levels
High levels of PTH + poor control of serum phosphate and calcium-phosphate product in CKD causes increased cardiovascular disease risk and vascular calcification.
Calcific uraemic arteriolopathy (calciphylaxis), a painful ulcerating skin condition carrying a high mortality, is also a risk factor in patients with chronic kidney disease.
Effects of Vitamin D
- Gut: multiple actions on different proteins serve to increase absorption of calcium and phosphate.
- Kidney: inhibits its own synthesis by reduced 1α-hydroxylase activity.
- Parathyroid glands: inhibits PTH synthesis.
- Bone: at high concentrations, activated vitamin D increases osteoclastic activity, promoting bone
resorption.
Hypercalcaemia - what are calcium levels adjusted and why are they necessary?
Calcium is protein-bound
Adjusted calcium concentration = Measured calcium + [(0.02 × (42-albumin level in g/L)].
A low adjusted calcium may be found in patients with severe hypoalbuminaemia, while true ionised calcium levels are normal.
At what level will hypercalcemia be symptomatic? List the symptoms of hypercalcemia.
- Adjusted calcium concentration >3.8 mmol/L carries risk of arrhythmias.
Adjusted calcium concentration >3.0 mmol/L, usually causes symptoms.
BONES
STONES
ABDOMINAL GROANS
PSYCHIC MOANS - malaise, polyuria, polydipsia, nocturia, renal calculi, bone pain (due to osteitis fibrosa cystica), abdominal pain, nausea, constipation, dehydration, low mood and confusion.
- Adjusted calcium concentration >3.8 mmol/L carries risk of arrhythmias.
Causes of hypercalcemia [8]
Primary and tertiary hyperparathyroidism
Malignancy (cytokine release & production of PTH related peptide or calcitriol)
Thyrotoxicosis
Hypoadrenalism
Thiazide diuretics, excess Vit D, Milk-alkali syndrome
Immobility
Sarcoidosis
Familial hypocalciuric hypercalcemia
Primary, secondary & tertiary hyperparathyroidism
Why does secondary hyperPTH not cause hypercalcemia?
- Primary hyperparathyroidism:
◆ Increased PTH due to parathyroid adenoma(s) or hyperplasia.
◆ 80% due to a benign solitary adenoma.
◆ MEN types 1 and 2A (2%)
◆ Characterised by high corrected serum and urine calcium, and low serum phosphate. - Tertiary hyperparathyroidism: autonomous secretion with high PTH despite hypercalcaemia.
(Secondary hyperparathyroidism does not cause hypercalcaemia but is characterised by increased
PTH in response to hypocalcaemia with low active vitamin D levels because of renal disease or dietary deficiency.
Hypercalcemia Ix [10]
- History: exclude iatrogenic causes and immobility; ask about symptoms of malignancy.
- Examination: look for signs of malignancy and investigate as appropriate.
- Blood tests for urea and electrolytes (to exclude renal impairment), calcium, PTH, vitamin D,
phosphate and magnesium. - Urine test for calcium (ideally a 24-hour collection) and calcium:creatinine ratio to exclude familial
hypocalciuric hypercalcaemia. - X-rays: look for characteristic sub-periosteal resorption of distal phalanges, tapering of distal
clavicles, ‘salt and pepper pot’ skull lucencies and brown tumours of long bones. - If PTH levels are appropriately suppressed in the face of a normal PTH axis, check thyroid
stimulating hormone (TSH), protein electrophoresis, urinary Bence–Jones protein and consider a Synacthen® (tetracosactide) test. - Parathyroid technetium (99mTc) sestamibi scan to identify parathyroid adenomas in primary
hyperparathyroidism. - If all aforementioned tests are negative, investigate further for malignancy.
- Dual energy X-ray absorptiometry (DEXA) scan for evidence of resulting osteoporosis.
Hypercalcemia Treatment
Mild - monitor for renal stones
Moderate - fluid resuscitation, loop diuretic (furosemide)
Primary hyperparathyroidism - surgical resection
Cinacalcet
Glucocorticoids for cancer, sarcoidosis, vitamin D toxicity
Bisphosphonates
Calcinet for hypercalcemia
Mechanism of action? Indications?
Cinacalcet is a calcium sensing receptor agonist- acts on the parathyroid cells, mimics effect of hypercalcaemia, suppressing PTH synthesis and secretion.
Indications: tertiary hyperparathyroidism due to chronic kidney disease, primary hyperparathyroidism unsuitable for surgery and hypercalcaemia from malignancy not responding to treatment.
The combined use of vitamin D and calcimimetics has reduced the need for parathyroidectomy in the management of renal bone disease.
Bisphosphonates for hypercalcemia
Mechanism of action? What is used in emergency? Chronic severe?
- Bisphosphonates inhibit osteoclastic activity
- prevent calcium release from bone.
- Intravenous pamidronate - emergency situations.
- Chronic severe hypercalcaemia may benefit from a bisphosphonate with a longer half-life (e.g. risedronate or zoledronic acid).
Hypocalaemia - severity classification into mild, moderate, severe
- Adjusted calcium concentration 2.0–2.5 mmol/L is often asymptomatic.
- Adjusted calcium concentration <2.0 mmol/L may cause symptoms
- Adjusted calcium concentration <.8 mmol/L may result in arrhythmias or seizures, especially with a rapid fall in serum calcium.
Symptoms of hypocalcemia
Give 3 points
- Neuromuscular excitability, tetany and paraesthesiae of the extremities and perioral area, along with cramps and tetany.
- Trousseau and Chvostek signs may be demonstrated
- ECG may show a prolonged QTc interval.
Causes of hypocalcemia Part 1
Causes of hypocalcaemia
Give 8 points
- Lysis syndromes- rhabdomyolysis, tumour lysis syndrome, widespread release of phosphate from damaged cells binding to calcium, lowering serum levels.
- Osteoblastic metastases with calcium uptake
- Rx
- DiGeorge syndrome (Ch22)
- Acute pancreatitis (marker of severity)
- Diet
- CKD
- Underactivity of PTH and vitamin D axes
- Magnesium deficiency impairs PTH secretion and promotes resistance to the actions of PTH.
Causes of hypocalcemia: Part 2
Which cancers are associated?
How does infusion of citrate blood products cause hypocalcaemia?
How does CKD cause hypocalcaemia?
Prostate, breast or bladder cancers cause osteoblastic mets with calcium uptake.
Infusion of citrate-containing blood products that can cause pronounced hypocalcaemia due
to citrate complexing with calcium.
CKD causes underactivity of axes:
Reduced hydroxylation of vit D > lack of active Vit D > unable to feedback to PTH to increase levels. Reduced phosphate excretion inhibits Vit D.
What other causes can result in inactivity of PTH and vitamin D axes?
- Hypoparathyroidism: associated with parathyroid damage, surgical removal (e.g. during
thyroidectomy), autoimmune polyglandular endocrine syndromes and various mutations affect-
ing the calcium sensing receptor. - Pseudohypoparathyroidism (Albright’s hereditary osteodystrophy): hypocalcaemia with
measureable PTH, caused by end-organ resistance to the effects of PTH due to mutations.
Hypocalcaemia: Investigation
History: ?chronic kidney disease, longstanding hypertension, diabetes mellitus, malabsorption and family history. Review medication.
Examination: ?malignancy, features of
chronic kidney disease or Albright’s hereditary osteodystrophy
- Blood tests: bone profile, Mg, vitamin D, urea & Cr, LFTs, CK.
- Urinary calcium and PO4 excretion.
- Imaging: growth plate abnormalities in children, pseudofractures (Looser’s zones), reduced bone mineral density (BMD) on DEXA.
Management of hypocalcaemia
CKD? Hypophosphatemic rickets? Oncogenic osteomalacia
- CKD - 1-alpha hydroxylated vitamin D and alfacalcidiol corrects hypocalcaemia and suppresses PTH synthesis & secrertion.
- Oncogenic osteomalacia requires tumour resection.
Osteomalacia - bone profile?
low vitamin D levels
low calcium, phosphate (in around 30%)
raised alkaline phosphatase (in 95-100% of patients)
Osteomalacia
Definition
Cause
Features
Osteomalacia
* Osteomalacia describes softening of the bones because of low vitamin D levels
* If this occurs in growing children it is referred to as rickets, with the term osteomalacia preferred for adults.
* vitamin D deficiency
* Features: bone pain, bone muscle tenderness, femoral neck fracture, proximal myopathy > waddling gait
Osteomalacia
Radiological signs
translucent bands (Looser’s zones or pseudofractures)
Treatment includes loading dose vit D with ca supplementation
Inherited metabolic disorders
Phenylketonuria
an inability to convert phenylalanine into tyrosine due to lack of phenylalanine hydroxylase. This results in hyperphenylalaninaemia and increased excretion of its metabolite, phenylpyruvic acid (‘phenylketone’) in the urine.
