GEP (Life Structure) Week 1 Flashcards

Question

What is corrected calcium

Answer 1

corrected" calcium is an estimate of the total calcium concentration, had serum protein (albumin) concentration been normal ## Footnote Acid levels in the blood can influence corrected calcium levels

Answer 2

The proximal tubule is responsible for the reabsorption of phosphate filtered at the glomerulus and is the primary regulator of phosphate balance in the body. Transportation in the proximal tubule is driven primarily by sodium–potassium ATPase, which is located in the baso-lateral membrane of the cell (8-11). Under normal conditions, about 85% of the filtered phosphate is reabsorbed via the sodium–phosphate co-transporter (NaPi2a and NaPi2c) in the proximal tubule

Answer 3

2 Pairs (4 Glands ) 3-5 mm 30-50mg Closely related to thyroid May be ectopic Chief cells and oxyphill cells Supplied by blood from the inferior thyroid arteries (thyroid surgery)

Answer 4

Circulating calcium levels sensed by Ca2+ receptor When calcium levels are high: 2) Gαi inhibits constitutive activity of AC cyclase: cAMP and PKA production reduced. 3) Gαq increases IP3 pathway. Intracellular concentrations of Ca2+ rise, PKA falls and PTH secretion is inhibited. Low levels of calcium decrease IP3, increase PKA and increase PTH secretion

Answer 5

Stimulate osteoblasts to produce M-CSF and RANK ligand-> increased bone resorption Increase Ca2+ reabsorption in the distal convoluted tubule Increase phosphate excretion Increases 1-α hydroxylase in the proximal tubule

Answer 6

Increases Ca2+ absorption in the gut Requires CaBP’s - synthesis stimulated by Vitamin D Synergises with PTH on bone Inhibits PTH synthesis Inhibits 1a-hydroxylase

Answer 7

## Footnote They have type 2 nuclear receptor (1 alpha-hydroxylase) plays an important role in calcium homeostasis by catalyzing synthesis of the active form of vitamin D, 1,25-dihydroxyvitamin D(3), in the kidney

Answer 8

Paracellular transport – diffusion through tight junctions dependent on concentration gradient; does not require energy Transcellular – at apical region calcium enters cell through a selective calcium transporter (TRPV), binds to calbindin, transported across cell and extruded at the basolateral membrane by a sodium-calcium exchanger and a Ca2+/ ATPase transporter.

Answer 9

Fibroblast growth factor 23 is a protein and member of the fibroblast growth factor family which participates in the regulation of phosphate in plasma and vitamin D metabolism. In humans it is encoded by the FGF23 gene. FGF23 decreases reabsorption of phosphate in the kidney. Regulation Increased FGF 23 high Phosphate High 1,25(OH)2 Vitamin D Action increases phosphate excretion inhibits 1-hydroxylase (CYP27B1) Inhibits PTH Secretion

Answer 10

The four main types of cells: Osteocytes → mature cells that maintain the bone tissue Osteogenic/osteoprogenitor cells → stem cells that differentiate into osteoblasts Osteoclasts → multinucleated cells that secrete acids and enzymes to resorb bone Osteoblasts → cells that form bone

Answer 11

Vitamin D and PTH stimulate osteoblasts to secrete factors (e.g. M-CSF) → osteoclast precursors proliferate and differentiate. With further stimulation by RANK ligand (RANKL) → mononuclear osteoclasts fuse to become multinucleated osteoclasts -OPG blocks the action of RANKL → negative feedback Osteoclasts resorb bone in discrete areas in contact with the “ruffled border” Osteoclast secrete acid and proteases into a confined resorption space (the lacuna) → dissolve bone mineral and hydrolyse matrix proteins Osteoblasts replace the osteoclast and build new bone matrix → promote mineralization ## Footnote MCS-F stands for macrophage colony stimulating factor

Answer 12

The final step in bone remodelling is bone mineralisation → need Ca2+ and PO43- for that Regulatory hormones of calcium metabolism: PTH (parathyroid hormone) → works on the bone and kidney, complex actions Vitamin D → ↑Ca2+ levels FGF23 → ↓PO43- levels Calcitonin → its role is not fully understood, potentially ↓Ca2+ levels

Answer 13

PTH is secreted by the chief cells of the parathyroid glands Circulating Ca2+ levels are sensed by the calcium sensing receptor (CaSR) CaSR binds Ca2+ → if there is too much Ca2+ in the blood → CaSR blocks the secretion of PTH (Gi-coupled GPCR) Low levels of Ca2+ → CaSR is not signalling → PTH is secreted Some cancers can also secrete a PTH-homologue (PTHrP) Small cell lung cancer, certain lymphomas etc.

Answer 14

Bone: Stimulation of osteoblasts →→ bone resorption → ↑Ca2+ and ↑phosphate Kidney: Increased Ca2+ reabsorption in the DCT → ↑Ca2+ Reduced phosphate reabsorption in the PCT → ↓phosphate Increased activity of 1ɑ-hydroxylase → ↑vitamin D conversion This will have a negative feedback on PTH secretion (i.e. vitamin D blocks PTH secretion)

Answer 15

Multi-step synthesis: UV light in the skin converts 7-dehydrocholesterol → cholecalciferol (D3) Diet (animal products) provides with vitamin D3 Vitamin D2 comes from plant sources 25-hydroxylase in the liver converts it to 25-hydroxyvitamin D3 (i.e. calcidiol) 1α-hydroxylase in the kidney converts calcidiol → calcitriol D3 (1,25-dihydroxyvitamin D3)

Answer 16

Increased Ca2+ and phosphate reabsorption in the gut (duodenum, jejunum) → ↑Ca2+ and ↑phosphate Increased bone resorption → ↑Ca2+ and ↑phosphate Inhibition of PTH synthesis Inhibition of 1α-hydroxylase function → negative feedback

Answer 17

Liver/kidney disease (synthesis) Resistance to hormone (receptor) Mal-absorption Dietary insufficiency Poor exposure to sunlight Sun block Obesity Latitude Skin pigmentation (melanocytes)

Answer 18

Calcium and vitamin D tablets 800-1000IU daily Vitamin D injection 300 000U im every 6 months Alpha calcidol (1alpha hydroxy vitamin D) 0.25-1mg daily

Answer 19

FGF23 is a hormone released by bones in response to high phosphate levels Acts on the the FGF23 receptor and its obligate co-receptor Klotho Actions of FGF23: Inhibition of phosphate reabsorption in the PCT (at the same site are PTH) Inhibition of 1α-hydroxylase function → ↓vitamin D Inhibition of PTH secretion ## Footnote Osteocytes produce fibroblast growth factor 23 (FGF23) FGF23 acts on the kidney to decrease synthesis of active vitamin D and to increase excretion of inorganic phosphate (Pi)

Answer 20

Primary= increase in Ca2+ Secondary= Equal or lower Ca2+ Tertiary= increase in Ca2+

Answer 21

Commonest cause of elevated PTH and calcium levels 0.5-5 per 1000 older than 40 years female-to-male ratio of 3:1 85% of cases are single adenoma 15% caused by diffuse hyperplasia < 1% by parathyroid carcinoma May be related to multiple endocrine neoplasia (MEN)

Answer 22

Secondary HPT compensatory hyperfunctioning of the parathyroid glands caused by hypocalcaemia or peripheral resistance to PTH. chronic renal insufficiency, calcium malabsorption, vitamin D deficiency, deranged vitamin D metabolism.

Answer 23

Tertiary HPT occurs following previous secondary HPT in which the glandular hyperfunction continue despite correction of the underlying abnormality, renal transplantation.

Answer 24

Surgery Medical - Observation - Bisphosponates Calcimimetics Cinacalcet

Answer 25

Symptoms: Bones → bone pain Stones → renal stones Abdominal groans → abdo pain, N/V, constipation etc. Psychic moans → depression, confusion Causes: Malignancy Hyperparathyroidism Primary → adenomas Secondary → ↓vitamin D (mostly present in hypocalcaemia) Tertiary → ESRD ## Footnote ESRD - end-stage renal disease You get tertiary hyperparathyroidism in ESRD because the patient was in secondary hyperparathyroidism for a long time beforehand (due to lack of activated vitamin D and thus low levels of blood calcium in chronic kidney disease). So when they get a kidney transplant, even if their new kidney can activate vitamin D now, their parathyroid gland has become hyperplastic and secretes PTH even in the presence of calcium.

Answer 26

Saline Rehydration 3-6L Frusemide Pamidronate Infusion 15-90mg Calcitonin 400iU im qds Prednisolone 40mg Dialysis

Answer 27

Clinical signs: Trousseau’s sign Chvostek’s sign Causes: Vitamin D deficiency → malnutrition, malabsorption (coeliac), liver disease, renal disease (CKD) Hypoparathyroidism → primary or secondary (after thyroid surgery) Chelation of calcium (massive blood transfusion, pancreatitis, rhabdomyolysis, ethylene glycol etc.)

Answer 28

Treat underlying cause Discontinue offending drugs Correct other electrolyte disorders Oral (enteral): Up to 2g per day Vitamin D supplementation **Severe Hypocalcamia:** Iv 10ml 10% Calcium gluconate diluted in 200ml N saline over 10 minutes Carpopedal spasm Fitting Arrhythmia Calcium < 1.7mmol/l

Answer 29

**Bone Softening** - due to faulty process of bone mineralisation -Deficient or impaired metabolsim of Vitamin D Phosphate and calcium This can lead to rickets in kids and the adult version is Osteomalacia

Answer 30

**Risk factors: ** Deficient diet → malnutrition Malabsorption conditions → Crohn's, coeliac disease Lack of exposure to sunlight Temperate regions → keep large parts of the skin covered Dark skin Regions of little sunlight (closer to poles) Liver disease → reduced fat absorption, vitamin D synthesis pathway affected Renal disease → vitamin D synthesis pathway affected **Clinical signs and symptoms: ** **Osteomalacia: ** Muscle weakness → due to proximal myopathy (not enough PO43- for energy) Waddling gait Difficulty climbing stairs and getting out of chair Widespread bone pain → hydration of the demineralised matrix → periosteal distension Dull, worse on weight-bearing and walking Can be reproduced by pressure on the sternum or tibia Insufficiency fractures → femoral neck **Rickets: ** Craniotabes → thin, deformed skull Widened epiphyses at the wrists and ankles Lower limb deformities → bow-legged, knock-kneed Myopathy, hypotonia

Answer 31

**Investigations: ** Bloods Ca2+ → low Phosphate → low PTH → high (no block from vitamin D) Serum vitamin D → low ALP → high (present in bone) **Radiographs** Decreased bone mineralisation → loss of cortical bone Looser's pseudo-fractures (mostly in scapula, inferior femoral neck and medial femoral shaft) → narrow radiolucent lines with sclerotic borders perpendicular to the cortex Cupped, ragged metaphyseal surfaces (Rickets) **Management: ** Vitamin D replacement Calcium supplementation

Answer 32

Osteoarthritis is a degenerative joint disease, in which the tissues in the joint break down over time. It is the most common type of arthritis and is more common in older people. People with osteoarthritis usually have joint pain and, after rest or inactivity, stiffness for a short period of time. Risk factors - Age, Female, Obesity, Trauma, Joint malalignment, Occupational Clinical features- Pain, Function impairment, Bony deformity, Reduced ROM, Malalignment, Crepitus

Answer 33

**Clinical Hx:** Risk factors and CFs **1st line test:** Xray, CRP, ESR **2nd line:** RF Anti CCP ## Footnote Most test will be -ve to rule out other forms of arthritis which you’ll cover later in the module

Answer 34

Management: No cure for OA it is about managing pain control and symptoms for patients

Answer 35

## Footnote Pain for >6 months - exists beyond physiological healing time

Answer 36

Calcium levels are closely controlled. Parathyroid hormone and Vitamin D are the main regulators of plasma Calcium levels Hypercalcaemia is Caused by Hyperparathyroidism Malignancy Hypocalcaemia is Caused by Vitamin D deficiency Parathyroid destruction