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A Short Presentation on Hypercalcaemia
- 1. Laura Wills
- 2. Case Study 49 ♂ PC- presented to GP about rash on face & snoring Investigations revealed hypercalcaemia – 3.2mmol/L Came to A&E at HRI
- 3. Clerking in AAU 3-4 month history of abdominal discomfort Elbow pain 2-3 month history of ↑ fatigue Polydipsia & ↑ fluid intake
- 4. Negative findings No change in mood No excessive dietary calcium No unintentional weight loss No change in appetite No fever No night sweats No loin-groin colicky pain No PR bleeding, haematuria, haemoptysis No chest pain or palpitations No SOB No vomiting & nausea No urinary symptoms No bowel symptoms
- 5. PMH – nil Drugs – nil Allergies – nil SH – non smoker alcohol – 5 units a week lives with wife & two children very active (runner), good diet PHD in engineering – works at Kimberley Clarke FH – dad died of multiple myeloma age 62
- 6. Examination General – comfortable at rest alert & orientated observations stable no signs of dehydration no signs of anaemia • Chest - NAD • HS – I + II + 0 • Abdomen – NAD • Neurological – NAD • Elbows – no bony tenderness not red, hot, swollen FROM pain on wrist extension
- 7. Differentials 1. Primary hyperthyroidism 2. Myeloma 3. Bone metastases 4. Dehydration 5. Inflammatory disease 6. Thyrotoxicosis 7. Famillial hypocalciuric hypercalcaemia
- 8. Investigations FBC Hb – 15.3 WCC – 6.4 Plts – 216 RCC – 4.67 Hct – 0.445 MCV – 95.3 MCH – 32.8 RDW – 12.4 Neu – 3.09 Lym – 2.69 Mon – 0.49 Eos – 0.15 Bas – 0.02 PV – 1.64
- 9. BCP Na – 140 K – 4.6 Cl – 107 Bicarb – 27 Urea – 6.5 Creatinine – 96 Ca – 3.31 ↑ Adj Ca – 3.26 ↑ Ph – 0.64 ↓ Bil – 27 ↑ AP – 139 ALT – 60 ↑ TP – 73 Al – 46 TSH - normal Amylase – normal PSA – normal Coeliac screen – negative PTH – 403 ↑
- 10. ECG – NAD CXR – NAD Abdominal USS – NAD Management Fluids Bisphosphonates Treat cause
- 11. The role of calcium Formation & maintenance of bones & teeth Role in blood clotting Hormone release Muscle contraction Nerve & brain function Enzymatic reactions
- 13. The importance of vitamin D Essential for calcium absorption in the small intestine Cholesterol Cholecalciferol Calcidiol Calcitrol Skin Liver Kidney & peripherally Dietary calcium
- 14. Calcium levels 2.2-2.6 mmol/L Adjusted Calcium levels (40-albumin) x 0.02 + albumin
- 15. Hypercalcaemia “The presence in the blood of an abnormally high concentration of calcium” Oxford concise medical dictionary 2007 Mild hypercalcaemia = 2.6 – 2.9 mmol/L Moderate hypercalcaemia = 3.0 – 3.4 mmol/L Severe hypercalcaemia = greater than 3.4 mmol/L
- 16. Symptoms Bone pain Renal stones Abdominal pain Mood changes Vomiting Constipation Muscle twitching & weakness Polyuria & polydipsia Anorexia & weight loss Lethargy & fatigue Confusion Pyrexia ECG changes “Bones, stones, groans & moans”
- 17. ECG changes in hypercalcaemia – short QT intervals - J waves - widening T waves
- 18. Aetiology 1. Primary hyperparathyroidism 2. Malignancy •Adrenal gland failure •Milk/alkali syndrome •Dehydration •Iatrogenic •Thyrotoxicosis •Granulomatous disease •Chronic renal failure •Vitamin D excess •Famillial benign hypocalciuric hypercalcaemia •Paget’s disease •Immobilisation •Phaeochromocytoma •Cuffed specimen
- 19. ↑ PTH release – primary parathyroidism, paraneoplastic syndrome, chronic renal failure ↑ bone breakdown – Paget’s, Malignancy, Thyrotoxicosis, Immobilization ↑ Ca2+ ingestion – milk-alkali syndrome Iatrogenic – vitamin D, lithium, thiazide diuretics, cuffed sample Increased absorption – adrenal gland failure Ectopic production of calcitrol – granulomatous disease ↓ blood volume - dehydration
- 20. Hypercalcaemia Albumin raised Albumin normal or low Urea raised Urea normal Phosphate low or normal Phosphate raised or normal Dehydration Cuffed specimen Urea normal Primary or tertiary hyperparathyroidism Alk Phos normalAlk Phos raised Bone mets Sarcoidosis Thyrotoxicosis Myeloma Vitamin D excess Sarcoidosis Milk alkali syndrome
- 21. Complications Renal –Nephrocalcinosis Renal failure Renal stones GI - Peptic ulcer disease Pancreatitis Neuro - Corneal calcification Confusion, dementia & coma Cardiac – Arrhythmia Cardiac failure MSK - Osteoporosis & fractures
- 22. Management Urgent treatment if calcium > 3.5mmol/L ↓ consciousness or confusion Hypotension Severe dehydration causing pre-renal failure IV fluids Diuretics IV bisphosphonates Treat the cause
- 23. Primary hyperparathyroidism Epidemiology 3rd most common endocrine disorder ♂:♀ = 1:3 Incidence – 25-30/ 100,000 Prevalence – 3/1000 ↑ post menopausal women
- 24. Symptoms 70-80% asymptomatic As per hypercalcaemia Aetiology Sporadic single parathyroid adenoma – 75-85% Parathyroid hyperplasia Multiple adenomas Parathyroid carcinoma MEN type 1 & 2A Familial isolated hyperparathyroidism
- 25. Diagnosis PTH ↑ Ca 2+ ↑ Ph ↓ 3hr Ca2+ infusion Parathyroid imaging – nuclear medicine Biopsy DEXA scan Renal USS/XR
- 26. Treatment Mild asymptomatic – monitor creat & Ca2+ every 6 months DEXA scan annually avoid dehydration avoid thiazides moderate Ca2+ intake Surgical – parathyroidectomy Medical – HRT & raloxifene bisphosphonates cinacalcet
- 27. Thank you for listening Any Questions?
Editor's Notes
- 3-4 month history of abdominal discomfort. Mainly bloating across the whole of the abdomen, radiating round the left side. Possible link to white bread – improved when cut out of diet. Not very severe, more discomfort than pain. Worse in the morning. No nausea & vomiting. No diarrhoea or constipation. No steatorrhea. No RUQ pain. 1 month history of elbow pain. Worse on movement, not present at rest. No worse at night. Possible tennis elbow. Worse on wrist flexion. No long bone pain Increased fatigue for which no known cause. Not noted any pallor, SOB. No decrease in appetite or weight loss. Has noticed he has been thirstier and drinking more recently
- First diagnosis because few other symptoms which would suggest other causes. For example, GI discomfort with coeliac, weight loss & anaemia with malignancy, signs of thyrotoxicosis, sarcoidosis & pancreatitis. Also the most common cause in someone his age. Possible due to there being an increased risk with primary relatives, however unlikely as no obvious anaemia, weight loss, appetite change. Unlikely as no systemic symptoms & low risk factors however you would want to rule out Possible although does not fit with polydipsia Granulomatous disease. Sarcoidosis, TB, inflammatory lung disease. Possible however usually does not have calcium levels that high. Diagnosis of exclusion.
- Normal Hb makes malignancy less likely. Normal WCC count makes inflammatory disease less likely
- Electrolytes & urea are normal which doesn’t suggest dehydration. Calcium & phosphate exist in a delicate balance. Phosphorus is also stored in bones & teeth. Phosphate is excreted by PTH
- Main component Co-factor in the coagulation cascade. Activates protein kinase C. Also rewuired for prothrombinase function Ca2+ Channels Co-factor in many enzymatic reactions
- This system is mainly controlled by PTH, released from the parathyroid gland. When calcium levels are low in the blood, PTH is released which triggers more Ca2+ to be reabsorbed in the kidneys and bone breakdown to release Ca2= into the blood. This stimulates the kidneys to produce more vitamin D which increases calcium absorption from the gut. Also important to mention that the kidneys have their own homeostatic mechanism with calcium receptors that monitor levels & adapt renal reabsorption/excretion accordingly. When the calcium is mildly elevated the thyroid stops releasing PTH & this is generally enough to stop levels rising. However when levels are especially high the thyroid gland releases calcitonin which stimulates osteoblasts to absorb Ca2+ back into bone and increases excretion in the kidneys.
- This is a simplified lifecycle for vitamin D. Vitamin D is essential for the absorption of calcium from the gut. It basically binds to vitamin D receptors in the gut which stimulates absorption. The body can synthesise vitamin D itself from cholesterol using UV B waves from sunlight. This then creates cholecalciferol. This is also the form in which most of our dietary vitamin D is. In the liver Cholecalciferol is converted in calcidiol (also known as calcifediol (INN), 25-hydroxycholecalciferol, or 25-hydroxyvitamin D—abbreviated 25(OH)D; and which is the specific vitamin D metabolite that is measured in serum to determine a person's vitamin D status) The majority of this is then converted to calcitrol (active vitamin D hormone) in the kidneys. A small amount of cacidiol circulates in the blood & is converted to active vitamin D in the peripheries where it is needed. It performs functions such as proliferation, differentiation & apoptosis of cells, especially in areas of inflammation. The role of vitamin D includes the regulation of Ca2+ by increasing absorption from the gut, and promoting resorption from bone by increasing the number of osteoclasts.
- Almost 50% of calcium in the blood is bound to proteins. Corrected calcium takes into account the changes in calcium there may be if the amount of albumin is abnormal. Eg, if less albumin more may be free giving the impression of hypercalcaemia
- Often asymptomatic in the early stages. Has to be quite severe to cause symptoms.
- J waves or Osborn waves – positive deflection at the J point
- Primary hyperparathyroidism -Going to discuss in more detail Malignancy - Cause of hypercalcaemia is bone breakdown. Metastases – most commonly breast, kidney, lung, thyroid, prostate, ovary, colon. Paraneoplastic symdrome – non small cell lung cancer, ovarian cancer, phaeochromocytoma. Also cancer without mets can produce hypercalcaemia The mechanism for hypercalcaemia in almost all people with cancer is secretion (by cancer cells) of parathyroid hormone-related peptide (PTHrP) and other circulating factors. These patients have about 2-3 months. Adrenal gland failure – enhanced absorption of calcium in the gastrointestinal tract, hemoconcentration, decreased GFR from volume contraction and increased complexing and protein binding of calcium. A component of decreased renal excretion may contribute. Loss of the antagonistic effects of glucocorticoids on calcium absorption and bone mobilization, together with dehydration. Calcium excess in diet. Sources of calcium – dairy products, leafy greens, eggs, legumes, nuts & whole grains. This also includes milk alkali syndrome – too much milk in diet or medical products like calcium carbonate, gaviscon. Dehydration - Due to less fluid in the blood so relatively higher ca2+ concentration Iatrogenic – Thiazide diuretics can cause hypercalcaemia by increasing the renal tubular reabsorption of calcium, but other mechanisms are postulated. Hypercalcaemia is usually mild. Often, the underlying cause is found to be primary hyperparathyroidism, with hypercalcaemia only worsened by the thiazide. Lithium causes hypercalcaemia by altering the parathyroid feedback threshold, stimulating parathyroid hypertrophy (with long-term use), and reducing renal calcium clearance. Most people taking lithium have a slight increase in serum calcium concentration within 4 weeks of starting treatment, but the level is usually within the normal range and returns to baseline when treatment is discontinued. Thyrotoxicosis – usually mild hypercalcaemia. T3 is essential for normal bone growth & bone metabolism. It stimulates bone formation directly through T3 receptors in osteoblasts. Also stimulates bone resorption by osteoclasts probably secondary through osteoblasts. In thyrotoxicosis accelerated bone resorption results in hypercalcaemia in the blood Inflammation - Eg. sarcoidosis, TB, leprosy, histoplasmosis, & types of granuloma. Tissue injury causes an ectopic production of 1,25-dihydroxyvitamin D3 (calcitriol), which causes vitamin D toxicity. Renal failure- Due to tertiary hyperparathyroidism. In chronic renal failure you get hypocalcaemia because the kidney is important in producing vit D, this creates secondary hyperparathyroidism as PTH release increases to try to increase calcium. The parathyroid hypertrophies. After a while the hypertrophied parathyroid starts to release excess parathyroid hormone autonomously which becomes unregulated & you get hypercalcaemia. Vitamin D excess – increased vitamin D causes increased calcium ingestion from the gut. FBHH – loss of function mutation in the CASR gene which encodes a calcium sensing receptor in the parathyroid & kidney. Percieved lack of calcium leads to high levels of parathyroid hormone and decreased excretion by the kidneys. Rare autosomal dominant disorder. Characterised by asymptomatic hypercalcaemia & a normal PTH. Pagets = increased bone turnover Immobilization- Immobilization can lead to hypercalcaemia in people with accelerated bone turnover, due to enhanced osteoclast activity and diminished osteoblast activity ('uncoupling' of bone cell activity). People with Paget's disease, cancer, or primary or secondary hyperparathyroidism are at risk.
- Primary hyperparathyroidism -Going to discuss in more detail Malignancy - Cause of hypercalcaemia is bone breakdown. Metastases – most commonly breast, kidney, lung, thyroid, prostate, ovary, colon. Paraneoplastic symdrome – non small cell lung cancer, ovarian cancer, phaeochromocytoma. Also cancer without mets can produce hypercalcaemia The mechanism for hypercalcaemia in almost all people with cancer is secretion (by cancer cells) of parathyroid hormone-related peptide (PTHrP) and other circulating factors. These patients have about 2-3 months. Adrenal gland failure – enhanced absorption of calcium in the gastrointestinal tract, hemoconcentration, decreased GFR from volume contraction and increased complexing and protein binding of calcium. A component of decreased renal excretion may contribute. Loss of the antagonistic effects of glucocorticoids on calcium absorption and bone mobilization, together with dehydration. Calcium excess in diet. Sources of calcium – dairy products, leafy greens, eggs, legumes, nuts & whole grains. This also includes milk alkali syndrome – too much milk in diet or medical products like calcium carbonate, gaviscon. Dehydration - Due to less fluid in the blood so relatively higher ca2+ concentration Iatrogenic – Thiazide diuretics can cause hypercalcaemia by increasing the renal tubular reabsorption of calcium, but other mechanisms are postulated. Hypercalcaemia is usually mild. Often, the underlying cause is found to be primary hyperparathyroidism, with hypercalcaemia only worsened by the thiazide. Lithium causes hypercalcaemia by altering the parathyroid feedback threshold, stimulating parathyroid hypertrophy (with long-term use), and reducing renal calcium clearance. Most people taking lithium have a slight increase in serum calcium concentration within 4 weeks of starting treatment, but the level is usually within the normal range and returns to baseline when treatment is discontinued. Thyrotoxicosis – usually mild hypercalcaemia. T3 is essential for normal bone growth & bone metabolism. It stimulates bone formation directly through T3 receptors in osteoblasts. Also stimulates bone resorption by osteoclasts probably secondary through osteoblasts. In thyrotoxicosis accelerated bone resorption results in hypercalcaemia in the blood Coeliac disease - Calcium & vitamin D malabsorption leading to secondary hyperparathyroidism, may cause osteopenia & bone breakdown hence increased blood calcium. Inflammation - Eg. sarcoidosis, TB, leprosy, histoplasmosis, & types of granuloma. Tissue injury causes an ectopic production of 1,25-dihydroxyvitamin D3 (calcitriol), which causes vitamin D toxicity. Renal failure- Due to tertiary hyperparathyroidism. In chronic renal failure you get hypocalcaemia because the kidney is important in producing vit D, this creates secondary hyperparathyroidism as PTH release increases to try to increase calcium. The parathyroid hypertrophies. After a while the hypertrophied parathyroid starts to release excess parathyroid hormone autonomously which becomes unregulated & you get hypercalcaemia. Vitamin D excess – increased vitamin D causes increased calcium ingestion from the gut. FBHH – loss of function mutation in the CASR gene which encodes a calcium sensing receptor in the parathyroid & kidney. Percieved lack of calcium leads to high levels of parathyroid hormone and decreased excretion by the kidneys. Rare autosomal dominant disorder. Characterised by asymptomatic hypercalcaemia & a normal PTH. Pagets = increased bone turnover Immobilization- Immobilization can lead to hypercalcaemia in people with accelerated bone turnover, due to enhanced osteoclast activity and diminished osteoblast activity ('uncoupling' of bone cell activity). People with Paget's disease, cancer, or primary or secondary hyperparathyroidism are at risk.
- Cuffed blood sample – leaving the tourniquet on too long can cause hyperkalaemia, hypercalcaemia & lactic acidosis
- These long term complications of hypercalcaemia are uncommon today. Nephrocalcinosis = calcium deposits in the kidney
- IV fluids – Normal saline 0.9%> Aim for 3-6L/24hrs depending on fluid status, urine output & cardiac function. Diuretics – once patient is rehydrated continue saline infusion & add frusemide 40mg every 2-4hrs. Monitor carefully. Be aware k+ & Mg2+ which may fall rapidly with rehydration & fursemide. If this fails:- Bisphosphonates- pamidronate at 30-60mg IV over 4-6hrs. Works by inhibiting osteoclasts. Ca2+ levels begin to fall after 48hrs & remain suppressed for 14 days. Then treat the cause & it will resolve
- Up to 21/1000 post menopausal women
- Multiple endocrine neoplasia Famillial – average age of presentation of 22yrs. Autosomal dominant inheritance. Asymptomatic. In all cases the disease is idiopathic however there has been shown to be increased risk with radiation exposure. See after the chenoble disaster. Excess PTH causes hypercalcaemia by increasing renal calcium reabsorption and mobilizing calcium from bone. It also indirectly increases intestinal calcium absorption, by increasing synthesis of serum 1,25-dihydroxyvitamin D3 (calcitriol, the active form of vitamin D3
- Bloods - sensitivity of 60%-80% and a specificity of approximately 90% for primary hyperparathyroidism.[ Infusion - sensitivity of 100% and a specificity of 93% in detecting primary hyperparathyroidism, with a confidence interval of 80% to 100%
- If it is one gland then it is easy. If it is all 4 3.5 glands are taken out. Post surgical complications include hypocalcaemia as the majority of the Ca2+ and phosphate is reabsorbed back into the bone. The parathyroid gland takes time to become resensitised so also hypoparathyroidism which is often transient but can become long term requiring supplements. Guidelines for whom surgery should be offered were produced by a National Institutes of Health (NIH) Workshop on Asymptomatic Primary Hyperparathyroidism in 2002:[7] Serum albumin-adjusted calcium greater than 0.25 mmol/L above the upper limit of local laboratory reference range. 24 hour total urinary calcium excretion greater than 10 mmol (400mg). Creatinine clearance reduced by 30% or more. Bone mineral density T score less than -2.5 (at any site). Age younger than 50 years. Patient request; adequate follow-up unlikely. HRT & raloxifene may be used in post-menopausal women. They have been shown to reduce calcium levels as well as improve bone density.[1] However, because of the risks associated with oestrogen replacement, it should not be used purely to treat primary hyperparathyroidism.[2] Bisphosphonates (particularly alendronate) may be a useful treatment.[1] Cinacalcet reduces both serum calcium and PTH levels and raises serum phosphorus. Cinacalcet does not, however, reduce bone turnover or improve bone mineral density.[9]