Calcium metabolism handout

transcript

Calcium disorders

Roderick WarrenRegistrar teaching

Buckfastleigh, July 2014

Calcium homeostasis

Please see the handout (assuming I remembered it)

Vitamin D from skin and diet 25-hydroxylase

25(OH)-D – inactive (?)

1-OHase

PTH effects on the kidney1.Stimulates activation of vit D.2.Promotes phosphate excretion.3.Reduces calcium resorption.

1,25(OH)2-D effects on kidneyIncreases Ca resorption

1α-hydroxylationStimulated by Inhibited by PTH 1,25(OH)2-D Low PO4 High PO4

PTH effect on boneCalcium export

PTH productionMain stimulus is low Ca2+.Inhibited by 1,25(OH)2-D.Mg required.

Calcitonin productionMain stimulus high Ca2+ (ionized>1.15) – also glucagon, gastrin, ß-adrenergic agonists (?reason for low Ca in acute illness)

Calcitonin effects on bone• inhibits osteoclast

resorption• thereby lowers Ca and PO4

• no effect on Mg

1,25(OH)2-D effects on gutIncreases Ca2+ and PO4

absorption

Vit D direct effect on bone?Unclear

Parathyroid hormone

Calcitonin

1,25-OH2-D

Hypercalcaemia

Question

Sue has this:• Calcium 3.4 mmol/L• PTH 0.6 pmol/l (1.6-6.9)

What are the differential diagnoses?

Answer

Sue has this:• Calcium 3.4 mmol/L• PTH 0.6 pmol/l (1.6-6.9)

Diagnosis could include:• Cancer• Vit D poisoning• Granulomatous disease etc

Causes of hypercalcaemia

Malignancy 90% ofPrimary hyperparathyroidism all cases

Other causesFamilialDrugs: lithium, thiazides, activated vitamin DGranulomatous diseases: sarcoid etcMilk alkali syndromeHyperthyroidismProlonged immobilisation

Malignancy causing hypercalcaemia

Cancer site Mechanism Lung PTH-rp (80%) Breast Bony mets (20%) Haematological e.g. myeloma Head and neck Renal Prostate Unknown GI

PTH-related peptide

Fetal equivalent of PTH Maintains fetal sCa slightly higher than maternal

Activates PTH receptor Typical pattern is - high calcium - low phosphate

High phosphate suggests non PTH/PTHrp cause

Is this hypercalcaemia due to cancer?

Low PTH - Cancer until proven otherwise: - Serum electrophoresis, Bence Jones - Tumour markers (PSA etc) - CT TAP - Bone scan - Endoscopy

Normal or high PTH - Almost certainly not cancer - rarely tumours co-secrete PTH and PTH-rp - parathyroid carcinoma

Question

Bob has this:• Calcium 2.9 mmol/L• Phosphate 2.4 mmol/L• PTH 42 pmol/l (1.6-6.9)

Answer

Bob has this:• Calcium 2.9 mmol/L• Phosphate 2.4 mmol/L• PTH 42 pmol/l (1.6-6.9)

Diagnosis could include:• CKD with tertiary hyperparathyroidism

Hyperparathyroidism

Primary SecondaryParathyroid adenoma Renal failure

Impaired PO4 excretionHigh PTH Impaired Vit D activation

High calcium High PTHLow phosphate Normal or high phosphate

Normal or low calcium

Hyperparathyroidism

1-OHase

• no effect on Mg

absorption

Parathyroid hormone

Calcitonin

1,25-OH2-D

1y hyperparathyroidism - epidemiology

AgeIncreases with age90% aged over 50

GenderFemale preponderance 70-80%

PrevalenceIncreasing

Tayside6 per 1000 population.About 20 per 1000 in women age >50. (Defined as Ca>2.55).

Mirrors increased calcium testing. (Calcium testing increased from 5% to 15% of population each year).

CaliforniaAbout 4 per 1000 in older women (Defined as Ca>2.6.)

Yu et al, Clin Endo 2009, 71, 485-493. Yeh et al, JCEM 2013, 98, 1122-1129.

How common is it really? In older women – 0.5 to 2% prevalence Based on 15% of population having blood tests

What would it be if 100% of population were tested?

1y hyperparathyroidism - diagnosis

Elevated calciumElevated or non-low PTHNot secondary to renal failure High phosphate eGFR<60

Question

Mary has this:• Calcium 2.75 mmol/L• PTH 18.2 pmol/L

Answer

Mary has this:• Calcium 2.75 mmol/L• PTH 8.2 pmol/L• Vitamin D 15 nmol/L

Diagnosis could include:• Primary hyperparathyroidism with vit D deficiency• Familial hypercalcaemia with vit D deficiency

1y hyperparathyroidism - diagnosis

Elevated calciumElevated or non-low PTHNot secondary to renal failure High phosphate eGFR<60Not due to drugs Thiazides LithiumNot due to vitamin D deficiency

Effect of vitamin D on PTH

Vitamin D insufficiency causes secondary hyperparathyroidism

PTH on Y-axis is approx 2-11 pmol/L

Vit D on X-axis is approx 0 to >75 nmol/L

1-OHase

• no effect on Mg

absorption

Parathyroid hormone

Calcitonin

1,25-OH2-D

How could vitamin D deficiency be relevant in a hypercalcaemic patient?

Theoretically (and, very occasionally, for real):

• PTH is too high for FHH• Vit D replacement lowers PTH• PTH now plausible for FHH

Is vitamin D replacement safe inprimary hyperparathyroidism?

Wagner Das Tucci Grey

N 35 16 56 21

Vit D baseline 36 29 36.4 28

Vit D final 105 71.8 88.6 77

Calcium baseline 2.69 2.75 2.74 2.70

Calcium final 2.60 2.65 2.73 2.69

PTH baselineUnchanged

18.6 15.3 12.4

PTH final 18.0 14.1 9.2

Problem patients None None None None

Wagner Endocr Pract 2013, 19(3), 420-5. Das, Endocr Abstr 2014, 34, P6. Tucci EJE 2009, 161, 189. Grey, JCEM 2005 90(4) 2122.

Local anecdotal reports of hypercalcaemia. Could this be due to natural variation? CV around 4% i.e. not unusual to see +/- 0.2 mmol/L.

Parathyroid bone disease

Osteoporosis• Decreased BMD in PHPT patients• Rate of bone less similar to normal population

Fracture• 1.5-fold increase in all fractures PHPT• 3-fold vertebra• 2-fold forearm• 1.5-fold hip

Parathyroid bone disease

Left – sub-periosteal erosionsAbove – bands of osteosclerosis “rugby jersey” appearanceRight – above, metaphyseal erosion in adolescence, and below, after vit D treatment

Cundy, Ulst Med J 1985, 54, S34-43

Brown tumoursOsteitis fibrosa cystica

Wikipedia

Primary hyperparathyroidismInvestigations

Bloods Calcium (high). Phosphate (low or low-normal). PTH (high or normal). Liver (alk phos often high but not diagnostic). Vitamin D (usually low and very occasionally confounds diagnosis).

Urine 24-hour urine calcium indices (see later).

Renal USS Only in patients with history suggestive of stones.

DEXA May influence surgery, or prompt bisphosphonate treatment.

Question

Jemima has this:• Age 79• No symptoms• Calcium 2.71 mmol/L• PTH 7.2 pmol/L• Vit D 50 nmol/L• 24-hr urine Ca 6.8 mmol• eGFR 51• DEXA T -2.7 Z -0.2 at spine

What treatment?

Answer

Jemima has this: What treatment?• Age 79 Looks like PHPT• No symptoms Osteoporosis• Calcium 2.71 mmol/L• PTH 7.2 pmol/L• Vit D 50 nmol/L Really not keen on surgery• 24-hr urine Ca 6.8 mmol “Why do I need an op doc?”• eGFR 51• DEXA T -2.7 Z -0.2 at spine

Primary hyperparathyroidismGuidelines - when to operate

Serum calcium > 2.80 mmol/L (Actually >0.25 mmol/L above reference range).

Osteoporosis BMD T-score <-2.5 at any site, or previous fragility fracture.

Renal stones

Age <50

Bilzekian et al, J Clin Endo Metab 2009, 94, 335-339.

Primary hyperparathyroidismReasons to operate

Symptoms Nausea. Thirst. Fatigue. Aches. Constipation.

Progressive hypercalcaemia Risk of future symptoms or hospital admission.

Osteoporosis

Renal stones

Cardiovascular disease??

Primary hyperparathyroidismReasons not to operate

Symptoms Vague. Conflicting evidence of benefit.

Progressive hypercalcaemia Rare in prospective studies - less than 5%.

Osteoporosis Often criteria met solely due to age. No proof of fracture reduction. Similar BMD benefit to bisphosphonates. Estimated absolute benefit is low - around 1:100 or less

Too much medicine? Prevalence tripled in 10 years as a result of more blood tests.

Primary hyperparathyroidismNon-surgical treatments

Vitamin D Not evidenced, sounds plausible.

Bisphosphonates Good evidence for # prevention though not tested in PHPT. Can lower sCa slightly – would not use for this purpose.

Cinacalcet Now licensed for PHPT where parathyroidectomy is inappropriate Cost £125-350 per month Lowers sCa by 0.25-0.3 mmol/L (perhaps more in more severe cases) No benefit on BMD demonstrated

Surgery for “asymptomatic” hyperparathyroidism - 1

Location Sweden, Norway, Denmark.

Subjects 191 patients with PHPT No parathyroid bone disease Calcium 2.6-2.85 No previous neck surgery Age 50-80 No renal impairment (creat>130) No interfering meds (thiazides etc) No kidney stones No MEN/familial hypercalcaemia No psych disorders

Intervention Surgery or observation

Follow-up 2 years

Bollerslev et al, J Clin Endo Metab 2007, 92, 1687-1692.

Outcomes

Surgery Observation

N 96 95

Age 64 64

Female/male 83/13 82/13

Baseline calcium 2.70 2.69

Calcium change -0.30 -0.02

Baseline creatinine 82 81

Final creatinine 0 0

BMD lumbar 1.09 1.06

BMD change +0.04 -0.04

Fractures Not reported

Outcomes

Physical component of SF36 – fell in both groups, no difference between groups.

Mental component of SF36 – fell in both groups, no difference between groups.

Surgery for “asymptomatic” hyperparathyroidism - 2

Ambrogini et al, J Clin Endo Metab 2007, 92, 1687-1692.

Location Italy.

Subjects 50 patients with PHPT No parathyroid bone disease Calcium 2.55-2.8 No kidney stones 24-hr urine calcium<10mmol No osteoporosis Age 50-75 No neck surgery No recent menopause No MEN/familial hypercalcaemia No major renal impairment

Intervention Follow-up Surgery or observation 1 year

Outcomes

Surgery Observation

N 24 26

Age 64 65

Female/male 22/2 24/2

Baseline calcium 2.55 2.55

Calcium change “Normalised” +0.05

Baseline creatinine clearance 93 93

Final creatinine clearance “Stable” 98

BMD lumbar 0.85 0.83

BMD change +4% -1%

Fractures Not reported

Outcomes

Solid line – surgery Dashed line - observation

Natural history of untreated PHPT

No really good long-term studies.

Surgery vs observation trials (as before) Bollerslev (Swedish study)

- tiny drop -0.02 over 2 years Ambrogini (Italian study)

- small rise +0.05 over 1 year

PEARS study – parathyroid epidemiology and audit research study, Dundee

Records linkage – lab data to hospital records

Definition of PHPT• Serum calcium >2.55 x 2 with PTH>3 (ref 1-6.9)• Serum calcium >2.55 x 1 with PTH>6.9Definition of progression• Serum calcium 2.90• Serum calcium rise of 0.2 mmol/L

Yu et al, Q J Med 2011, 104, 513-521.

Mean calcium clearly fell

Individual progression• 13% of total showed any.• 1% of total showed

sustained progression.

Possible problems• Was it really hyperpara?• Does it apply to more

severe hyperpara?

Yu et al, Q J Med 2011, 104, 513-521.

Osteoporosis

http://www.iofbonehealth.org/epidemiology. http://www.cdc.gov/nchs/data/nhanes/databriefs/osteoporosis.pdf . Both accessed 27th June 2014.

Prevalence increases with age• 30% of post-menopausal

women in Europe have osteoporosis.

• 87% of US women aged over 80 have osteopenia or osteoporosis

Fracture reduction

No RCT evidence for fracture reduction

Retrospective studies• Fewer fractures in surgically- versus medically-treated• But obvious confounders

Non-surgically treated were older and frailer

What about BMD?• RCT evidence shows 5-8% benefit after surgery• What does that mean?

Fracture risk estimation

No RCT evidence for fracture reduction

Retrospective studies• Fewer fractures in surgically- versus medically-treated• But obvious confounders

Non-surgically treated were older and frailer

What about BMD?• RCT evidence shows 5-8% benefit after surgery• What does that mean?

Primary hyperparathyroidismReasons not to treat

Symptoms Vague. Conflicting evidence of benefit.

Progressive hypercalcaemia Rare.

Osteoporosis Criteria met solely due to age. No proof of fracture reduction. Similar BMD benefit to bisphosphonates. Estimated benefit is low - around 1% absolute risk reduction.

Too much medicine? Prevalence tripled in 10 years as a result of more blood tests.

What treatment?

Primary hyperparathyroidismInvestigations

Bloods Calcium (high). Phosphate (low or low-normal). PTH (high or normal). Liver (alk phos often high but not diagnostic). Vitamin D (usually low and very occasionally confounds diagnosis).

Urine 24-hour urine calcium indices (see later).

Renal USS Only in patients with history suggestive of stones.

DEXA May influence surgery, or prompt bisphosphonate treatment.

Question

Roberta has this: Treatment:• Age 69 Keen to have surgery• Polyuria, fatigue, aches No contra-indications• Calcium 2.81 mmol/L• PTH 7.2 pmol/L SestaMIBI scan:• Vit D 50 nmol/L No apparent adenoma• 24-hr urine Ca 6.8 mmol• eGFR 51 What next?• DEXA T -2.7 Z -0.2 at spine

Answer

Roberta has this: Treatment:• Age 69 Keen to have surgery• Polyuria, fatigue, aches No contra-indications• Calcium 2.81 mmol/L• PTH 7.2 pmol/L SestaMIBI scan:• Vit D 50 nmol/L No apparent adenoma• 24-hr urine Ca 6.8 mmol• eGFR 51 What next?• DEXA T -2.7 Z -0.2 at spine Operate

Or further localisation studies

Primary hyperparathyroidismLocalisation studies

What is the aim?

• Exclude retrosternal/ectopic adenoma

• Identify solitary parathyroid adenoma vs multiple adenomata vs hyperplasia

• Least possible surgery

Primary hyperparathyroidismLocalisation studies

Conventional (Kochers) incision• Originally 8-10cm• Eventually reduced to 4-6cm

Minimal access• Arbitrary definition• E.g. below 2.5cm

Primary hyperparathyroidismMIBI scan

Theoretically:• 90% sensitivity, 98% specificity• 87% are solitary adenomas• 9% hyperplasia• 3% multiple adenomas• <1% cancer• Therefore, 78% of patients (90% of

87%) are candidates for unilateral neck exploration

Reality:• Often do not localise• Equipment dependent• Affected by MNG

Parathyroid surgeryExeter

Parathyroid SestaMIBI

LateralisingWith no pointers to secondary hyperpara Not lateralising (appropriate PTH, PO4, eGFR) Or possibility of secondary

hyperparaUnilateral neck exploration Examination of both parathyroids Bilateral exploration

One abnormal Both abnormal Remove and close

Primary hyperparathyroidismOther localisation studies

Ultrasound

Sesta-MIBI - SPECT/CT

Parathyroid venous sampling

Minimally-invasive radioguided parathyroidectomy (MIRP) (MIBI injection, Geiger counter to find active parathyroids)

Intra-operative PTH

Post-op hypocalcaemia

Frequency• About 10-30% of cases• More likely with… severe hypercalcaemia

vitamin D deficiencyvery high PTHmulti-gland surgery

Prevention• Vitamin D repletion• Cinacalcet?• Bisphosphonates?

Post-op hypocalcaemiaPost-operative monitoring

Check corrected calcium 1st post-op day

Ca >2.2 Ca 2.0 – 2.19and/or more than 0.2 mmol/l lower than pre-op

Ca 1.7 – 1.99 * Ca <1.7 *or markedly symptomatic

Low risk groupRepeat Ca day 7

High risk groupRepeat day 3-4 and day 7

Start or Continue pre-op Adcal D3 Repeat in 2 days

Start 1alpha calcidol1mcg odand Sandocal1000 bd

Give iv calcium gluconate10ml. Repeat serum calcium after 6 hours.Commence 1 alpha calcidol 2 mcg od and Sandocal 1000 bd

Ca 2.0 – 2.19 Repeat after 3 daysIf Ca >2.0repeat day 7

Review 6 weeks by Endocrinology service

Ca 1.7 – 1.99Increase 1 alpha to 2mcg od.

Repeat daily until Ca >2.0

Ca >2.2

Rob Dyer – draft, 2012.

Question

Jake has this: What investigations?• Age 39• Polyuria, fatigue, aches• Calcium 2.85 mmol/L• PTH 78.2 pmol/L• Vit D 52 nmol/L• 24-hr urine Ca 6.8 mmol• eGFR >90• DEXA T -0.4• Surgery shows four-gland hyperplasia

Answer

Jake has this: What investigations?• Age 39• Polyuria, fatigue, aches MEN guidelines 2012• Calcium 2.85 mmol/L 2+ MEN-associated tumours• PTH 78.2 pmol/L 1st deg rel of known MEN1• Vit D 52 nmol/L Parathyroid adenomas <30• 24-hr urine Ca 6.8 mmol Multigland parathyroid disease• eGFR >90 Gastinoma• DEXA T -0.4 Pancreatic NET• Surgery shows four-

gland hyperplasia

Prevalence of MEN in hyperparathyroidism

High penetrance (95%+) of PHPT in known MEN by age 50• Often said no need to consider MEN if diagnosed over 50

But would PHPT be diagnosed before 50 if MEN not known?• E.g. develops age 45, diagnosed age 55?

Prevalence of MEN in PHPT• Uchino et al – 25% menin mutations• Yip et al – 4% prevalence but 26% if hyperplasia• De Laat et al – 7% prevalence

Always ask about FH of hypercalcaemia, renal stones, brain tumours, neck surgery, ulcers, pancreatic tumours

Primary vs secondary vs tertiary hyperparathyroidism

Divide calcium by 4 to get mmol/L

Secondary hyperparathyroidism

High or normal phosphateLow or normal calciumHigh PTHeGFR below 60

NICE 2008 guidelines• Monitor in CKD 4/5 (e.g. in diabetes clinics)• Measure Ca, PO4, PTH• Decide frequency of monitoring by results and clinical

circumstances. Seek specialist opinion. (Just do it annually?).

• Cholecalciferol or ergocalciferol for CKD 1-3b• Alfacalcidol or calcitriol for CKD 4-5

Secondary hyperparathyroidismmanagement

AKA refractory secondary hyperparathyroidism• Development of autonomous nodular parathyroid hyperplasia• Hypercalcaemia

Indications for surgery• Severe hypercalcaemia/hyperphosphataemia• Parathyroid bone disease• Extraskeletal calcification• Unexplained symptomatic myopathy• WITH PTH>800 pg/mL (88 pmol/L) (all of the above can

develop in dialysis patients for other reasons, so must confirm presence of hyperparathyroidism)

“Tertiary” hyperparathyroidism

Surgical options – no agreement which is best

• Total parathyroidectomy (unpopular)

• Total parathyroidectomy with auto-transplantation into forearmTheoretically – if recurrent, no need for re-explorationof neck. But persistent hypercalcaemia after removal of arm graft is quite common, i.e. it was in the neck all along.

• Subtotal parathyroidectomy (leaving 40-60mg of the least hyperplastic gland)

“Tertiary” hyperparathyroidism

Persistent hyperparathyroidism• Nodular hyperplasia from prolonged secondary hyperpara

Normal renal function• Eliminates resistance to PTH due to uraemia• Restores normal 1-hydroxylation of vit D

Hypercalcaemia after renal transplant

Causes of hypercalcaemia

Malignancy 90% ofPrimary hyperparathyroidism all cases

Other causesFamilialDrugs: lithium, thiazides, activated vitamin DGranulomatous diseases: sarcoid etcMilk alkali syndromeHyperthyroidismProlonged immobilisation

Familial benign (hypocalciuric) hypercalcaemia

CaSR mutation• Body “sees” a high calcium level as normal• Present from birth• One explanation for failed parathyroid surgery

Misnamed• Normocalciuric (just lower than expected)

In most cases:• PTH not very high• Urine calcium not elevated• Calcium:creatinine clearance ratio <0.02• No osteoporosis• Asymptomatic

Familial (benign) (hypocalciuric) hypercalcaemia

PHPT FBHH

PTH pmol/L 50% above 8-9 50% below 395% below 8.599% below 9.1

24-hr urine calcium mmol

70% above 6.5 50% below 2.395% below 6.599% below 9.0

Calcium:creatinine clearance ratio

98% below 0.02 65% above 0.0295% above 0.06

Gunn et al Ann Clin Biochem 2004, 41, 441-458 Christensen et al Clin Endo 2008, 69, 713-720.

CCCR>0.02 excludes FHH.Consider genetic testing if <0.02 (NB only 70% of familial cases are positive on genetic tests).

Familial benign (hypocalciuric) hypercalcaemia

Severe cases are reported• Homozygous mutations• Severe symptomatic hypercalcaemia• Osteoporosis• Very high PTH

Parathyroid jaw tumour syndrome

• Rare• Autosomal dominant• Parathyroid tumours ~15% carcinomas• Fibro-osseous tumours of jaw bones• Plus loads of other tumours – Wilm’s, renal cysts, renal hamartomas,

renal cortical adenomas, papillary renal cell carcinomas, pancreatic adenocarcinomas, testicular seminomas, uterine.

Lithium

Causes hyperparathyroidism Expect PTH to be elevated. If low PTH - look for cancer.

Also causes diabetes insipidus Severe hypercalcaemia causes dehydration. DI causes dehydration. Dehydration worsens hypercalcaemia.

Nightmare combo Mania with severe hypercalcaemia and renal impairment.

Lithium – prevalence of hypercalcaemia

Lally et al 5% of 33 patients

Twigt et al 15.6% of 314 patients Duration of Li therapy was main predictor No hypercalcaemia in control group of non-Li psych patients

Bendz et al 6% incidence in 142 patients over 19 years 13 consented to trial of Li withdrawal – all ineffective

Ir Med J 2013 106 15-17. Int J Bipolar Dis 2013 1 18. J Int Med 1996 240 357-365.

Lithium – management of hyperparathyroidism

Surgery Adenoma vs hyperplasia

Withdrawal of lithium Mainly ineffective (short-term studies only) But worth a try

Thiazides

Effects● Small increase (1-2%) in serum total calcium● Small increase (10-20%) in PTH● Little or no effect on ionized calcium● Reduction in urinary calcium excretion

Does it matter?● Probably not● Most cases of hypercalcaemia with thiazides turn out

to be coincidental primary hyperparathyroidism

Rejnmark et al. Euro J Clin Invest 2003, 33, 41-50. Wermers et al, Am J Med 2007, 120, 911.

Thiazides and hypercalcaemia –practical points

Stop the thiazide● Recheck calcium and PTH● Is there malignancy?● Is there primary hyperparathyroidism?

Could restart it if all OK● E.g. if mild primary hyperpara for “watch and wait”

No cause found. What next?

HypercalcaemiaLow or non-elevated PTHNo evidence of malignancyNo lithiumNo thiazidesNo calcium/vit D supplementsNormal thyroid function

Rarer stuff

Granulomatous diseases: sarcoid etc CT chest. s-ACE??

Milk alkali syndromeProlonged immobilisationCirrhosis I don’t know the mechanism

Adrenal insufficiency I don’t know the mechanism Primary or secondary

Acute management of hypercalcaemia

When is admission required?• Definitely if sCa>3.5 mmol/L• 3-3.5 mmol/L – depends on trend, age, frailty, renal

function etc

Acute management of hypercalcaemia

1. Hydration• 4-6 litres 0.9% saline over 24 hours• Loop diuretics for fluid overload – not effective at lowering

calcium2. IV bisphosphonate• Zoledronate 4mg• Pamidronate 30-90mg3. Alternatives• Prednisolone 40mg (inhibits 1,25-D production – useful in

granuloma, lymphoma, 25-D intoxication)• Cinacalcet• Calcitonin

Society for Endocrinology 2013 guideline

Hypocalcaemia

Causes of hypocalcaemia

EDTA contaminationLow magnesiumRespiratory alkalosisPPIVit D deficiencyHypoparathyroidism - primary - post-surgical - pseudo

EDTA contamination

EDTA leakage into biochem tube causes... High potassium Low calcium, magnesium, alk phos

Fill biochem tubes before haematology tubes

Hypocalcaemia due to hypomagnesaemia

Low magnesium is common in…● elderly● diarrhoea● diuretics● patients taking PPIs

Treatment● stop diuretics● stop PPIs● oral magnesium supplements (limited efficicacy)

○ Maalox or Mucogel - 35 mL/day in divided doses○ magnesium glycerophosphate - 4 tabs per day

● IV replacement

What level of hypomagnesaemia requires treatment?

When you write a guideline, it always ends up more cautious than your real practice● Many guidelines say Mg<0.5 mmol/L requires urgent IV treatment

My comments● Hypomagnesaemia seems common in general medical patients● It definitely is common in frail elderly● In 169 long-term geriatric care patients, 53% had sMg<0.45 mmol/L,

18% had sMg<0.35 mmol/L● I would treat principally if symptomatic or hypocalcaemic or

hypokalaemic

Alinzon et al, Arch Geront Ger 2010, 51, 36-40.

Hypocalcaemia due to alkalosis

Normal● albumen carries negative charge● some albumen is bound to positive H+

● some Ca2+ is bound to remaining albumen● free/ionized Ca2+ is biologically active

Hyperventilation● respiratory alkalosis due to blowing off CO2

● lower H+ concentration● more negative charged albumen free to bind Ca2+

● free/ionized Ca2+ falls● total sCa does not change

When should we measure ionized calcium?

Ideally – always

In the real world● if you have a calcium abnormality but struggling to make a diagnosis● if symptoms suggest hypocalcaemia but normal total sCa

Hypocalcaemia due to vitamin D deficiency

Seen in…● malnutrition● elderly● institutionalised● coeliac / malabsorption / short bowel

Treatment● see formulary● Adcal D3 or Calcichew D3 (400 units per tab)● Fultium D3 (800 units per tab)● OTC - at least 2000 units per day, 8p per day from H&B

Oral: Hypocalcaemia is rare, well under 0.5% Usually occurs after a few weeks Transient

IV high dose: Hypocalcaemia more common but still rare

Most cases have other risk factors: + coeliac disease + hypoparathyroidism

Hypocalcaemia due to bisphosphonates

Gain of function CaSR mutation• Consider if diagnosed young, and never had normal calcium• Family history helpful. (NB affected relatives likely undiagnosed).

No simple characterisation• Earliest reported cases had marked hypocalcaemia, low PTH and

clearly elevated CCCR. (Perhaps that’s why they were identified).• Confirmed familial cases with no symptoms and normal CCCR.• Treat if symptomatic e.g. seizures• Many case reports of calcification of skull, brain, kidney, cataract• Treatment will increase calcium throughput

Familial (hypercalciuric) hypocalcaemia

Question

Bill has this:• Calcium 1.4 mmol/L• PTH 76 pmol/l (1.6-6.9)

What is the diagnosis?

Answer

Bill has this:• Calcium 1.4 mmol/L• PTH 76 pmol/l (1.6-6.9)

Diagnosis could include:• Vitamin D deficiency• Renal failure• Rhabdomyolysis• Pseudohypoparathyroidism• etc

Hypoparathyroidism

Causes• Usually post-surgical• Rarely, primary or pseudo

Features• Low calcium• High phosphate• High PTH• Vitamin D replete• Normal renal function

1-OHase

• no effect on Mg

absorption

Parathyroid hormone

Calcitonin

1,25-OH2-D

Hypoparathyroidism

Lack of PTH • Kidneys don’t retain calcium• Kidneys don’t excrete phosphate

Activated vitamin D treatment• Increase calcium absorption from gut• Increase phosphate absorption from gut

Overall effect• Forced intestinal calcium absorption• Increased renal calcium throughput• High calcium x phosphate product• Nephrocalcinosis (and other calcifcation)

Hypoparathyroidism

Treatment targets• sCa around lower limit of normal• “Non elevated” urine calcium• NB this may not be achievable – average 24-hr urine calcium in

appropriately-treated patients is around 8-8.5 mmol.

rPTH(1-84) therapy• Once daily injection• Achieved reduction in use of calcium and active vit D• Similar sCa and uCa levels - questionable benefit• High cost (Preotact licensed for osteoporosis, £4000 per year)

Mannstadt et al, Lancet 2013, 1, 275-283..

Pseudohypoparathyroidism

PTH inaction – defect downstream of PTH receptor

Type 1a Type 1b Pseudopseudo

Transmission Maternal. GNAS1 mutation. Loss of function in G-protein.

Methylation. Mostly sporadic, or maternal.

Paternal. GNAS1 mutation.

Kidney PTH resistance

Yes, hypocalcaemia Yes, hypocalcaemia No, normal

Bone PTH resistance

Yes, AHO No, hyperparathyroid bone disease

Yes, AHO

Other hormones

Can see resistance to TSH, ADH, FSH/LH, ACTH, GHRH

Treatment Activated vitamin D Activated vitamin DParathyroidectomy

Pseudohypoparathyroidism 1b

RN, diagnosed age 27• Presents with knee pain• X-ray shows cystic changes in bones• (Diagnosis not considered by ortho)• Later…• sCa 1.37• sPO4 1.67• PTH 76• Vit D normal

Pseudohypoparathyroidism 1b

RN - Treatment• Alfacalcidol to normalise PTH• PTH came down to 2• Calcium up to 2.3-2.9• Creatinine later up 60 to 114• USS - nephrocalcinosis

• Alfacalcidol reduced• Creatinine down to 70• Calcium 2.0-2.3• PTH 25-30• Urine calcium 2.4 mmol/24h• X-ray stable

• Observe• Consider parathyroidectomy

Calcium metabolism handout

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