Calcium and Phosphate Metabolism Flashcards
How much calcium is contained in the body and what is its distribution?
25,000 mmol (1kg)
99% contained in mineral phase of bones as hydroxyapatite
Extracellular, ionised 1.2mmol/L
Intracellular, cytosolic 10^-4-3 mmol/L
What are some biological roles of calcium?
Muscle contraction Nerve excitability intracellular messenger blood coagulation enzymes of intermediary metabolism
How is calcium transported?
47% Bound- largely by albumin, some to small anions like phosphate
47% is unbound/ionised
6% complexed
When measuring serum calcium, which forms are measured?
Can measure total or free calcium
More difficult to measure free
What is the reference range for calcium?
2.20 - 2.60 mmol/L
Where is most calcium absorbed?
Dietary intake of about 25mmol/day, 6mmol are absorbed daily by Duodenum and jejunum
How is calcium absorbed in the GI?
Cell-mediated active transport, influenced by calcitriol, on apical surface of duodenum and jejunum.
Passive diffusion which depends on luminal Ca concentration (unaffected by calcitriol). Occurs paracellularly through claudin tight junctions, along the length of the intestines
Within the kidney, how is calcium moved?
65% reabsorbed at proximal tubule (passive- coupled with Na and water)
20% reabsorbed at thick ascending loop
15% reabsorbed at distal tubule
About 6mmols net excretion /day
Where does PTH influence reabsorption of Ca within the kidneys?
Thick ascending loop and distal tubule
What regulates PTH secretion by parathyroid gland?
Free/ ionised calcium levels which are sensed by calcium sensing receptors (GCPR)
How are PTH levels related to calcium levels?
Inversely.
As calcium increases, PTH decreases.
How does PTH impact the body?
PTH stimulates renal tubular calcium reabsorption
Promotes bone resorption
Stimulates formation of calcitriol in kidney which enhances Ca absorption from gut
How is active vitamin D created?
Cholecalciferol undergoes hydroxylation in liver to 25 Hydroxy cholecalciferol (25 OHCCC)
25 OHCCC then undergoes hydroxylation in the proximal T of the kidneys by 1-alpha hydroxylase, creating 1,25 dihydroxycholecalciferol (calcitriol, aka 1,25 DHCCC) which is regulated by PTH
What factors influence the hydroxylation of 25 OH cholecalciferol by the kidneys?
PTH
Hypocalcaemia
Hypophosphatemia
What are some examples of causes of hypocalcaemia?
PTH problems- hypoparathyroidism due to neck surgery, idiopathic, magnesium deficiency
Vitamin D problems- deficiency (malabsorption, little sun exposure) or renal disease (kidneys fail to hydroxylate 25 OHCCC into active form)
What are some examples of causes of hypercalcaemia?
PTH problems - Hyperparathyroidism due to adenoma of parathyroid gland, or Grave’s disease (autoantibodies binding/activating parathyroid gland)
Vitamin D Problem- Inappropriate dosage
Malignancy- production of PTH related peptide (it isn’t measure in assays used to measure PTH) in some cases of breast, lung, multiple myeloma cancers
How is malignancy in terms of hypercalcaemia different from other causes?
Hypercalcaemia typically involves high PTH with high calcium.
In malignancy, there can be high calcium with low PTH- but high PTH-related peptide.
The PTH levels will be low as the PTHRP is not measured, but PTHRP is raised in malignancy and will act in the same fashion to raise calcium levels.
Why is phosphate important?
Skeletal development, bone mineralization, composition of cell membranes, nucleotide structure, and cell signalling
Where is phosphate found?
85% in mineralized matrix of bone
15% intracellular- bound to lipids and proteins, only 1% of it is in the EF fluid(30% inorganic, which is what is measured)
What hormones regulate phosphate levels and how?
Parathyroid Hormone -decreases proximal tubule reabsorption
Fibroblast Growth Factor 23 -decreases proximal tubule reabsorption
1,25 DHCC (calcitriol) -increases kidney reabsorption
How much phosphate is moved within the body daily?
32 mmol absorbed in gut
25 mmol loss via urinary excretion
7mmol in / out of bone
How is phosphate reabsorbed within the kidneys and what controls this?
PTH and FGF23 inhibit reabsorption
75% of filtered phosphate reabsorbed at proximal, 5-20% from distal
How would a high serum phosphate influence the body?
Sensed by parathyroid gland, would increase PTH
Osteocytes release FGF23.
Elevated FGF23 and PTH cause an inhibition of phosphate reabsorption by the kidney, allowing for increase Pi excretion
How can FGF23’s impact on the kidney be clinically important?
Plays role in reducing phosphate reabsorption
Can result in excessive urinary loss of phosphate and impaired bone mineralization
How do serum phosphate levels differ throughout the day?
High after midnight
Lowest before noon
difference in nadir amplitude is about 30%
Don’t know why, maybe altered balance in blood in tissue
How does insulin impact phosphate?
It causes phosphate levels to fall
Insulin moves glucose and phosphate into cells
How does phosphate change as a person develops?
It is higher for infants due to high growth velocity, and reducing with aging.
What regulates Vitamin D levels?
PTH stimulates production of active Vit D.
How does Vit D work within the gut?
Binds Vitamin D receptors and works as a transcription factor that modulates production of proteins (TRPV6, calbindin) which aid in calcium absorption.
What health problems are associated with hypocalcaemia?
Rickets
Osteomalacia
What is osteomalacia?
Impaired mineralization of bone leading to an accumulation of unmineralized bone matrix called osteoid. Typically due to lack of vitamin D
Occurs after the epiphyseal plate has fused (rickets is before fusion)
-Bone pain, difficulty rising from chair, bone tenderness
How is osteomalacia diagnosed?
Imaging (DXA and T-Score calculation, look for cortical thinning, pseudo fractures)
Isotope bone scan (lots of ‘hot spots’ due to high bone turnover)
Biochemistry
Bone biopsy
How would you make the differentiation between osteoporosis and osteomalacia when looking at blood serum levels of Calcium, Phosphate, Alkaline Phosphatase, 25OH Vit D, and PTH?
Calcium: Normal (Osteoporosis), vs Low/normal (Osteomalacia) Phosphate: Normal vs low or normal Alk Phos: Normal vs Normal or high 250H Vit D: Normal or Low vs Low PTH: Normal vs High
What are some primary and secondary causes of vitamin D deficiency?
Primary: Asian Immigrants (lack of sun, chapattis), Elderly housebound, Bizarre diet
Secondary: Partial gastrectomy, small bowel malabsorption, pancreatic disease, chronic renal failure, anticonvulsants
What are some suggested effects of Vit D?
Reduce inflammation Modulate cell growth Glucose metabolism Immune function Reduction in hip fractures in elderly
What differences are seen in Vit D levels based on a person’s weight?
Obese people tend to have less Vit D levels
What are some possible causes of rickets?
Vit D dependent Rickets
Hypophosphatemia Disorders
Fanconi Syndrome (disorder of kidney tubules)
Renal tubulopathies
Hypophosphatasia
Fat malabsorption (caeliac, bile acid synthesis)
What are the type 1 forms of of Vitamin D Dependent Rickets?
Vita D Hydroxylation-Deficient Rickets Type 1A- mutation in CYP27B1 Gene (hydroxylation at 1-alpha in kidneys to form active calciferol). Can treat easily with 1,25-DH Vit D, 1 alpha calciferol.
Vit D Hydroxylation-Deficient Rickets Type 1B- CYP2R1Loss of function. Pseudovitamin D3 deficiency Rickets due to 25-hydroxylase deficiency.
What are the type 2 forms of of Vit D-Dependent Rickets?
Type 2A- VDDR2A: with or without alopecia. Caused by defects in the Vit D receptor gene causing 1,25 DH Vit D resistance. Can be treated with large amounts of 1, 25 dihydroxyvitamin d
Type 2B- Normal Vit D receptor (VDDR2B). Due to abnormal expression of hormone response element-binding protein that interferes with normal functioning of vit d receptors
What are the two forms of vitamin D, and what reaction is needed to convert them to their active forms?
Ergocalciferol (D2) from ergosterol UV exposure (plants)
Cholecalciferol (D3) from animal tissue.
2 step hydroxylation at 25th and 1st carbon. First hydroxylation done by 25-hydroxylase in liver, second by 1a-hydroxylase in kidneys.
What factors impact FGF23 levels?
Phosphate Intestinal phosphate absorption PTH 1,25 Dihydroxy Vit D production Increased phosphate in Extracellular Fluid
What impact does FGF23 have in the body?
Helps to regulate phosphate levels
Suppresses phosphate reabsorption in the kidneys
What is FGF23 formed by?
Osteocytes
Under control by locally derived bone factors (DMP1 )
What are some disorders of phosphate?
- Tumoral calcinosis- Defective FGF 23 (needed for normal o-glycosylation of FGF23, results in increased phosphate and causes ectopic calcification)
- Autosomal Dom. Hypophosphatemic Rickets- Have high levels of FGF23.
3 forms;
FGF23 Resistant Proteolysis (dominant) - resistant to proteolysis, increasing 1/2 life
X-Linked Hypophosphataemic Rickets- reduced phosphate and 1,25 HCC. Most common, caused by mutation in PHEX Protein (involved in FGF23 breakdown, high FGF23 in serum).
AR Hypophosphataemic Rickets- DMP1 affected (it inhibits FGF23), high FGF23 levels and low phosphate
What are current treatments for phosphate disorders?
Additional Phosphate
adequate 1,25 diOH Vit D
Avoid calcinuria and elevated PTH
New therapies: Burosumad (antibody binds FGF23, given subcutaneously, it reduces FGF23 which prevents excess Pi excretion)
Where, in cells, is the calcitriol (1,25 DHCCF) receptor found?
Intracellularly- it is derived from cholesterol and can pass through the cell membrane
How does calcitonin regulate calcium levels?
Released by parafollicular C-cells in thymus in response to high Ca.
Binds to osteoclasts to inhibit activity, reducing bone resorption.
