Calcium

What is hyperparathyroidism?

3 types: Primary - excess PTH in absence of hypocalcemia Typically caused by: parathyroid adenoma, carcinoma and hyperplasia - normally an adenoma Results in hypercalcaemia -leads to: polyuria, polydipsia kidney stones osteoporosis mood disorder (anxiety, concentration etc.) Secondary - basically a result of compensation for hypocalcaemia (due to other mechanisms) Tertiary - where we get autonomous PTH production following chronic secondary hyperthryoidism - no longer needs any triggers or responds to inhibition

Describe the storage of Ca in bone

99% of Ca (and 85% of phosphate) in body = stored in bone. Ca and phosphate are kept together as hydroxyappetite Serum concentrations of Ca and phosphate are close to the levels which would lead to precipitation of Ca and phosphate crystals - THUS must be closely regulated

Give a brief overview of bone physiology

Bone resorption and remodelling = controlled by osteoblasts and osteoclasts (blasts synthesise, clasts breakdown) Bone = actually made up of collagen and hydroxyappetite Mineralisation of bone involves phosphate, calcium and alkaline phosphatase

Explain the mechanism of Ca absorption in the gut and how vitamin D effects it

Calcium absorption across enterocytes occurs via the transcellular, paracellular and vesicular routes - all 3 are upregulated by vitamin D. Vitamin D up regulates synthesis of TRPV5/6 (apical channels), calbindin (transport protein), PMCA1b (basal Ca2+ ATPase), NCX1 (basal Ca2+/3x Na+ antiporter)

What are the other effects of PTH in the kidney (aside from upregulating Ca channels, Ca ATPase and Na/Ca exchanger)?

Downregulates NaPi (inorganic phosphate) transporters - thus reduced phosphate reabsorption Activates vitamin D - stimulates calcidiol to calcitriol production via promoting the activation 1-alpha hydroxylase Promotes proximal tubule gluconeogenesis - thus hyperparathyroidism can lead to diabetes

Describe the calcium sensing receptor

GPCR found primarily on kidneys and parthyroid glands When Ca binds: 1. It will reduce PTH secretion 2. Increase breakdown of stored PTH 3. Suppresses transcription of PTH gene Also acts to inhibit calcium absorption in the kidney via action on the loop of Henle Na+/K+/Cl- cotransporter (symporter) Inactivating mutations can lead to FHH (Familial hypocalciuric hypercalcemia - serum calcium high, low in urine)

How do we diagnose primary hyperthyroidism?

1. Serum Ca + PTH (low phosphate and high Ca in serum) 2. 24 hour urine calcium - to see if Ca levels are too high - kidney unable to clear it 3. Urine calcium creatinine excretion index (to rule out FHH) 4. Renal ultrasound (kidney stones) 5. Dexa scan (bone density) Consider SUUD -Serum, urine, ultrasound and DEXA We then have to find out where the adenoma (normally an adenoma which causes primary) is: 1. Neck ultrasound 2. MIBI scan 3. CT scan 4. Parathyroid venous sampling Normally 2 scans as sometimes the 1st scan may show simply non-specific abnormalities TREAT: Cinacalcet (drug) activates CaSR and reduces calcium levels via inhibition of PTH secretion (can be used to treat hyperparathyroidism).

What is the main control of serum Ca? Describe the parathyroid gland What is the function of PTH?

Ca under control of PTH - fall in serum Ca leads to increase in PTH - acts to increase Ca concentration Basic negative feedback Made up of chief cells + oxyphil cells Chief cells = more numerous with round nucleus + small cytoplasm. Chief cells produce PTH. The oxyphil cells are seen in scattered groups among the chief cells Parathyroid hormone (PTH) act to upregulate calcium levels via: 1. Improved gut absorption 2. Increased kidney reabsorption 3. Increased bone resorption

What happens when calcium levels fall (feedback)? What is FGF23?

Calcium falls, and PTH is secreted PTH triggers kidney reabsorption of calcium (and loss of phosphate), bone resorption and calcitriol formation via 1-alpha-hydroxylase upregulation. Vitamin D further enhances effects, assisting in renal absorption and bone resorption Vitamin D also has the effect of stimulating gut uptake of calcium and phosphate Due to bone breakdown and gut absorption, phosphate levels are high High phosphate triggers FGF23 release from osteoblasts, causing a fall in phosphate levels FGF23 increases urine phosphate loss and inhibits vit D activation (to decrease its effects on phosphate reabsorption in the gut) by inhibiting the 1-alpha hydroxylation in the kidney. It is a phosphaturic agent. Mutations in the FGF23 gene can lead to hypophosphatemic rickets

What is FHH?

Familial Hypocalciuric Hypercalcemia Inactivating mutation of CaSR - thus unable to sense if we have high calcium This stimulates PTH release which upregulates Ca absorption from the urine. The CaSR usually inhibits urine Ca reabsorption when high (this no longer happens thus we have increased Ca reabsorpion from kidney, hence less in urine. This causes high serum calcium, yet low urine calcium (and highs serum Mg). The PTH-calcium curve shifts to the right. These patients don't symptoms of hypercalcaemia. Hyperparathyroidism patients have high urine calcium and symptoms.

Describe the vitamin D receptor

Hormone receptors are either on cell surface, cytoplasm or on nucleus Most vitamin D receptors = nuclear receptors - thus affects gene transcription - SLOW [GENOMIC] - thus main effect of vitamin D = on gene transcription Can get vitamin D receptor on cell membrane - this allows for rapid effects [NON-GENOMIC] Vitamin D inhibits production of vitamin D receptor Macrophage: activation of vitamin D receptor activates cathelicidin - a mechanism by which macrophages destroy pathogens In macrophage we get a positive feedback loop where the vitamin D binding to the vitamin D receptor doesn't have any negative feedback effect on receptor production - this positive feedback is important to destroy pathogens e.g. Tb

What are the actions of PTH on kidney, bone and intestine?

Kidney: DECREASES Ca excretion and INCREASES phosphate excretion (basically because many mechanisms which reabsorb Ca also reabsorb phosphate - we don't really want to increase serum phosphate thus need to excrete it at kidney) Bone: Increases Ca and phosphate reabsorption [remember that Ca and phosphate are stuck together in bone as calcium hydroxyappetite - hence to reabsorb one you have to also reabsorb the other] Intestine: Increases absorption of Ca and phosphate - mainly works indirectly via calcitriol - stimulates its production in the kidney (stimulates 1-alpha hydroxylase). Has a small direct effect In hyperparathyroidism, (e.g. tumour making too much PTH) this will increase phosphate excretion and increase serum Ca - leads to reduction in serum phosphate - seeing this indicates hyperparathyroidism

What are the effects of hypo and hyper-calcaemia on cells?

Low calcium increases excitability of muscle and nerve cells due to the fact that it changes (lowers) the threshold potential for AP generation by affecting the ability of Na to get into a cell - thus can cause heart arrhythmias etc. Hypercalcaemia = good - stabalising effect on membranes - thus Ca infusion = treatment to stabalise membrane e.g. of cardiac myocytes when there is another underlying reason for the arhythmias (not low Ca) e.g. low K Symptoms of hypocalcaemia: "CATS go numb"- Convulsions, Arrhythmias, Tetany (spasms) and numbness/parasthesias in hands, feet, around mouth and lips

What is the cause and what are the consequences of hypoparathyroidism?

Most commonly iatrogenic (related to surgical issues) Many genetic causes Leads to hypocalcaemia - convulsions, arrhythmias, tetany, parasthesia due to the effects of low Ca on cell membrane Chronic kidney disease (less Ca reabsorption) and vitamin D deficiency = other causes of hypocalcaemia TREAT: Give calcium Can give PTH (not as a tablet - as it is a peptide hormone - degraded in stomach) but as subcutaneous infusion Can give alfacalcidol tablets - increase intestinal calcium (Ca) absorption but increases urinary Ca excretion (BAD long term as this can lead to kidney stones). Increases serum Ca levels, and suppresses parathyroid hormone (PTH) secretion

How is Ca carried in the blood? Describe the difference between extra and intra cellular concentrations of calcium and phosphate

Mostly bound to albumin Albumin also naturally has a certain amount of H+ bound to it - this changes dependent on if body is acidotic/alkalinic Respiratory alkalosis - less H+ in blood, thus less H+ bound to albumin - more space for Ca to bind - hence less serum ionised Ca2+ - leads to hypocalcaemia e.g. tingling sensation peripherally (lips + fingers) as it increases excitability of nerve + muscle cells Intracellular Ca = v. low - huge difference between intra + extra cellular Ca stores Within cell, involved in cell signalling Phosphate has similar intra and extra cellular concentrations Almost all serum phosphate = ionised

What is the difference between Rickets and osteomalacia?

NONE - rickets = in younger individuals and osteomalacia = in older. Both due to vitamin D deficiency Defects in mineralisation - thus bones soft and malleable Cannot tell the difference between osteoporosis and osteomalacia in a bone density scan (DEXA). Osteoporosis = more severe Osteoporosis makes bones more brittle - fractures are thus very common Typically caused by oestrogen loss post-menopause, another common cause is Cushing's syndrome

What effects do PTH, calcitriol, glucocorticoids and oestrogen have on bone?

PTH + calcitriol stimulate production of RANKL on osteoblasts - this activates osteoclasts - thus increased breakdown of bone and reabsorption of Ca PTH and calcitriol downregulate OPG (normally secreted from the osteoblast - works as a decoy receptor - competitively binds to RANKL, inbititing it - prevents osteoclast binding and thus orevents BONE REABSORPTION). Note that denusomab is a monoclonal antibody which essentially mimics this action. PTH also increases IGF1 + IL1 - this is a stimulus for bone formation PTH basically promotes both formation and resorption of bone, but more resorption vs formation Main effect of calcitriol = to increase gut reabsorption of Ca (and phosphate) Glucocorticoids increase breakdown (downregulate osteoblasts, increase RANKL) Oestrogen leads to epiphyseal closure, reduced cytokine sensitivity and inhibits bone remodelling

What are the other effects of vitamin D (other than Ca reabsorption in gut)?

Parathyroid: Reduced PTH transcription Bone: Increases breakdown and decreases type 1 collagen production Gut: Increases phosphate absorption in the gut. Also increases amino acid uptake (vitamin D deficiency leads to myopathy) Increased renal absorption of calcium in PCT

Describe parathyroid hormone - production and stimulus to production What are the 3 responses of the parathyroid gland to low Ca?

Peptide hormone - formed from longer precursors - preproPTH - then cleaved to proPTH and then to PTH Secreted in response to low serum Ca2+ -> causes release of stored PTH + increased production of PTH + causes hyperplasia of chief cells Equivalent mechanism else where e.g. from adrenal gland in response to ACTH Calcitriol suppresses PTH production, phosphate stimulates it PTH IS NEVER full suppressed regardless of how high Ca levels are Normal Ca = 2.2.-2.6 mmol/L. If someone has a serum Ca of 2.6 and it falls to 2.2, this will provoke PTH production - thus rapid falls in calcium, even if still in the normal range, will trigger PTH release

How does the kidney handle Ca?

Proximal tubule: 65% of renal Ca reabsorption occurs here - paracellular + PTH independent - instead driven by voltage gradient Loop of Henle: 20% of renal Ca reabsorption here - para and trans-cellular Again voltage dependent, PTH-independent Ca reabsorption inhibited here by loop diuretics (blocks actions of NaK2Cl transporter and hence affect the voltage gradient and thus inhibit Ca reabsorption) CASR (Ca sensing receptor) also down-regulates the NaK2Cl symporter here [basically negative feedback] Distal tubule: 15% of Ca reabsorption - PTH DEPENDENT PTH upregulates PTH upregulates the (luminal) calcium channel, Ca ATPase (basolateral) and calcium/sodium exchanger (basolateral) in the DCT Thiazide diuretics will increase blood Ca - the Na/Cl symporter which thiazides target (distal tubule) is key to set up the gradient for Ca reabsorption - inhibited by the thiazide - thus less Na inside the cell (less able to enter from lumen via this transporter). HOWEVER, this sets up the gradient for the basolateral Na/Ca channel which causes 3Na in and 1 Ca out. Thus low intracellular Na = increased activity of Na/Ca exchanger (antiporter) - thus Na comes into the cell from blood and Ca enters blood (from the cell) - thus less intracellular Ca - promotes Ca enters from the tubule lumen via the luminal Ca transporter Bartter syndrome = mutation in Na/K/Cl channel - thus this is basically the equivalent as loop diuretic action Consider that it 'bars Ca entry' Gitelman syndrome = mutation in Na/Cl channel - equivalent to thiazide diuretics Consider that it 'gits' Ca in

Describe the 3 main types of hormones

Steroid hormones (corticosteroids: glucocorticoids + mineralocorticoids and sex steroids) Amine hormones (T3/4, dopamine, noradrenaline and adrenaline) Peptide hormones (prolactin, TSH, ACTH, GH, ADH, Oxytoxin, ANP, Glucagon, Insulin, Somatostatin, CCK and Leptin)