1. Calcium disorders
Roderick Warren
Registrar teaching
Buckfastleigh, July 2014

2. Calcium homeostasis
Please see the handout (assuming I remembered it)

3. Vitamin D from
skin and diet 25-hydroxylase
25(OH)-D – inactive (?)
1-OHase
PTH effects on the kidney
1.Stimulates activation of vit D.
2.Promotes phosphate excretion.
3.Reduces calcium resorption.
1,25(OH)2-D effects on kidney
Increases Ca resorption
1α-hydroxylation
Stimulated by Inhibited by
PTH 1,25(OH)2-D
Low PO4 High PO4
PTH effect on bone
Calcium export
PTH production
Main stimulus is low Ca2+.
Inhibited by 1,25(OH)2-D.
Mg required.
Calcitonin production
Main 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 gut
Increases Ca2+ and PO4
absorption
Vit D direct
effect on bone?
Unclear
Parathyroid
hormone
Calcitonin
1,25-OH2-D

4. Hypercalcaemia

5. Question
Sue has this:
• Calcium 3.4 mmol/L
• PTH 0.6 pmol/l (1.6-6.9)
What are the differential diagnoses?

6. 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

7. Causes of hypercalcaemia
Malignancy 90% of
Primary hyperparathyroidism all cases
Other causes
Familial
Drugs: lithium, thiazides, activated vitamin D
Granulomatous diseases: sarcoid etc
Milk alkali syndrome
Hyperthyroidism
Prolonged immobilisation

8. 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

9. 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

10. 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

11. Question
Bob has this:
• Calcium 2.9 mmol/L
• Phosphate 2.4 mmol/L
• PTH 42 pmol/l (1.6-6.9)
What are the differential diagnoses?

12. 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

13. Hyperparathyroidism
Primary Secondary
Parathyroid adenoma Renal failure
Impaired PO4 excretion
High PTH Impaired Vit D activation
High calcium High PTH
Low phosphate Normal or high phosphate
Normal or low calcium

14. Hyperparathyroidism
Primary Secondary
Parathyroid adenoma Renal failure
Impaired PO4 excretion
High PTH Impaired Vit D activation
High calcium High PTH
Low phosphate Normal or high phosphate
Normal or low calcium

15. Vitamin D from
skin and diet 25-hydroxylase
25(OH)-D – inactive (?)
1-OHase
PTH effects on the kidney
1.Stimulates activation of vit D.
2.Promotes phosphate excretion.
3.Reduces calcium resorption.
1,25(OH)2-D effects on kidney
Increases Ca resorption
1α-hydroxylation
Stimulated by Inhibited by
PTH 1,25(OH)2-D
Low PO4 High PO4
PTH effect on bone
Calcium export
PTH production
Main stimulus is low Ca2+.
Inhibited by 1,25(OH)2-D.
Mg required.
Calcitonin production
Main 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 gut
Increases Ca2+ and PO4
absorption
Vit D direct
effect on bone?
Unclear
Parathyroid
hormone
Calcitonin
1,25-OH2-D

16. 1y hyperparathyroidism - epidemiology
Age
Increases with age
90% aged over 50
Gender
Female preponderance 70-80%

17. 1y hyperparathyroidism - epidemiology
Prevalence
Increasing
Tayside
6 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).
California
About 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.

18. 1y hyperparathyroidism - epidemiology
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?

19. 1y hyperparathyroidism - diagnosis
Elevated calcium
Elevated or non-low PTH
Not secondary to renal failure
High phosphate
eGFR<60

20. Question
Mary has this:
• Calcium 2.75 mmol/L
• PTH 18.2 pmol/L
What are the differential diagnoses?

21. 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

22. 1y hyperparathyroidism - diagnosis
Elevated calcium
Elevated or non-low PTH
Not secondary to renal failure
High phosphate
eGFR<60
Not due to drugs
Thiazides
Lithium
Not due to vitamin D deficiency

23. 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

24. Vitamin D from
skin and diet 25-hydroxylase
25(OH)-D – inactive (?)
1-OHase
PTH effects on the kidney
1.Stimulates activation of vit D.
2.Promotes phosphate excretion.
3.Reduces calcium resorption.
1,25(OH)2-D effects on kidney
Increases Ca resorption
1α-hydroxylation
Stimulated by Inhibited by
PTH 1,25(OH)2-D
Low PO4 High PO4
PTH effect on bone
Calcium export
PTH production
Main stimulus is low Ca2+.
Inhibited by 1,25(OH)2-D.
Mg required.
Calcitonin production
Main 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 gut
Increases Ca2+ and PO4
absorption
Vit D direct
effect on bone?
Unclear
Parathyroid
hormone
Calcitonin
1,25-OH2-D

25. 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

26. Is vitamin D replacement safe in
primary 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 baseline
Unchanged
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.

27. 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

28. Parathyroid bone disease
Left – sub-periosteal erosions
Above – bands of osteosclerosis
“rugby jersey” appearance
Right – above, metaphyseal erosion in
adolescence, and below, after vit D
treatment
Cundy, Ulst Med J 1985, 54, S34-43

29. Brown tumours
Osteitis fibrosa cystica
Wikipedia

30. Primary hyperparathyroidism
Investigations
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.

31. 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?

32. 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

33. Primary hyperparathyroidism
Guidelines - 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.

34. Primary hyperparathyroidism
Reasons to operate
Symptoms
Nausea. Thirst. Fatigue. Aches. Constipation.
Progressive hypercalcaemia
Risk of future symptoms or hospital admission.
Osteoporosis
Renal stones
Cardiovascular disease??

35. Primary hyperparathyroidism
Reasons 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.

36. Primary hyperparathyroidism
Non-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

37. 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.

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

39. 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.

40. 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

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

42. Outcomes
Solid line – surgery Dashed line - observation

43. 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

44. Natural history of untreated PHPT
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>6.9
Definition of progression
• Serum calcium 2.90
• Serum calcium rise of 0.2 mmol/L
Yu et al, Q J Med 2011, 104, 513-521.

45. Natural history of untreated PHPT
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.

46. 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

47. 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?

48. 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?

51. Primary hyperparathyroidism
Reasons 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?

52. Primary hyperparathyroidism
Investigations
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.

53. 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

54. 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

55. Primary hyperparathyroidism
Localisation studies
What is the aim?
• Exclude retrosternal/ectopic adenoma
• Identify solitary parathyroid adenoma
vs multiple adenomata
vs hyperplasia
• Least possible surgery

56. Primary hyperparathyroidism
Localisation studies
Conventional (Kochers) incision
• Originally 8-10cm
• Eventually reduced to 4-6cm
Minimal access
• Arbitrary definition
• E.g. below 2.5cm

57. Primary hyperparathyroidism
MIBI 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

58. Parathyroid surgery
Exeter
Parathyroid SestaMIBI
Lateralising
With no pointers to secondary hyperpara Not lateralising
(appropriate PTH, PO4, eGFR) Or possibility of secondary
hyperpara
Unilateral neck exploration
Examination of both parathyroids Bilateral exploration
One abnormal Both abnormal
Remove and close

59. Primary hyperparathyroidism
Other 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

60. Post-op hypocalcaemia
Frequency
• About 10-30% of cases
• More likely with… severe hypercalcaemia
vitamin D deficiency
very high PTH
multi-gland surgery
Prevention
• Vitamin D repletion
• Cinacalcet?
• Bisphosphonates?

61. Post-op hypocalcaemia
Post-operative monitoring
Check corrected calcium 1st post-op day
Ca >2.2 Ca 2.0 – 2.19
and/or more than 0.2
mmol/l lower than
pre-op
Ca 1.7 – 1.99 * Ca <1.7 *or
markedly
symptomatic
Low risk group
Repeat Ca day 7
High risk group
Repeat day 3-4
and day 7
Start or
Continue pre-op
Adcal D3
Repeat in 2 days
Start 1alpha
calcidol
1mcg od
and Sandocal
1000 bd
Give iv calcium gluconate
10ml. 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
days
If Ca >2.0
repeat day 7
Review 6 weeks by Endocrinology service
Ca 1.7 – 1.99
Increase 1 alpha
to 2mcg od.
Repeat daily until Ca >2.0
Ca >2.2
Rob Dyer – draft, 2012.

62. 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

63. 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

64. 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

65. Primary vs secondary vs tertiary
hyperparathyroidism
Divide calcium by 4 to get mmol/L
DividePTHbyabout10togetpmol/L

66. Primary Secondary
Parathyroid adenoma Renal failure
Impaired PO4 excretion
High PTH Impaired Vit D activation
High calcium High PTH
Low phosphate Normal or high phosphate
Normal or low calcium
Secondary hyperparathyroidism

67. Secondary hyperparathyroidism
High or normal phosphate
Low or normal calcium
High PTH
eGFR below 60
Levin–AmJKidDis1991,34,125-134.

68. 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 hyperparathyroidism
management

69. 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

70. Surgical options – no agreement which is best
• Total parathyroidectomy (unpopular)
• Total parathyroidectomy with auto-transplantation into forearm
Theoretically – if recurrent, no need for re-exploration
of 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

71. 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

72. Causes of hypercalcaemia
Malignancy 90% of
Primary hyperparathyroidism all cases
Other causes
Familial
Drugs: lithium, thiazides, activated vitamin D
Granulomatous diseases: sarcoid etc
Milk alkali syndrome
Hyperthyroidism
Prolonged immobilisation

73. 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

74. Familial (benign) (hypocalciuric)
hypercalcaemia
PHPT FBHH
PTH pmol/L 50% above 8-9 50% below 3
95% below 8.5
99% below 9.1
24-hr urine calcium
mmol
70% above 6.5 50% below 2.3
95% below 6.5
99% below 9.0
Calcium:creatinine
clearance ratio
98% below 0.02 65% above 0.02
95% 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).

75. Familial benign (hypocalciuric)
hypercalcaemia
Severe cases are reported
• Homozygous mutations
• Severe symptomatic hypercalcaemia
• Osteoporosis
• Very high PTH

76. 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.

77. 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.

78. 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.

79. Lithium – management of
hyperparathyroidism
Surgery
Adenoma vs hyperplasia
Withdrawal of lithium
Mainly ineffective (short-term studies only)
But worth a try

80. 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.

81. 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”

82. No cause found. What next?
Hypercalcaemia
Low or non-elevated PTH
No evidence of malignancy
No lithium
No thiazides
No calcium/vit D supplements
Normal thyroid function

83. Rarer stuff
Granulomatous diseases: sarcoid etc
CT chest. s-ACE??
Milk alkali syndrome
Prolonged immobilisation
Cirrhosis
I don’t know the mechanism
Adrenal insufficiency
I don’t know the mechanism
Primary or secondary

84. 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

85. Acute management of hypercalcaemia
1. Hydration
• 4-6 litres 0.9% saline over 24 hours
• Loop diuretics for fluid overload – not effective at lowering
calcium
2. IV bisphosphonate
• Zoledronate 4mg
• Pamidronate 30-90mg
3. Alternatives
• Prednisolone 40mg (inhibits 1,25-D production – useful in
granuloma, lymphoma, 25-D intoxication)
• Cinacalcet
• Calcitonin
Society for Endocrinology 2013 guideline

89. Hypocalcaemia

90. Causes of hypocalcaemia
EDTA contamination
Low magnesium
Respiratory alkalosis
PPI
Vit D deficiency
Hypoparathyroidism
- primary
- post-surgical
- pseudo

91. EDTA contamination
EDTA leakage into biochem tube causes...
High potassium
Low calcium, magnesium, alk phos
Fill biochem tubes before haematology tubes

92. 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

93. 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.

94. 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

95. 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

96. 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

97. 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

98. 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

99. Question
Bill has this:
• Calcium 1.4 mmol/L
• PTH 76 pmol/l (1.6-6.9)
What is the diagnosis?

100. 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

101. Hypoparathyroidism
Causes
• Usually post-surgical
• Rarely, primary or pseudo
Features
• Low calcium
• High phosphate
• High PTH
• Vitamin D replete
• Normal renal function

102. Vitamin D from
skin and diet 25-hydroxylase
25(OH)-D – inactive (?)
1-OHase
PTH effects on the kidney
1.Stimulates activation of vit D.
2.Promotes phosphate excretion.
3.Reduces calcium resorption.
1,25(OH)2-D effects on kidney
Increases Ca resorption
1α-hydroxylation
Stimulated by Inhibited by
PTH 1,25(OH)2-D
Low PO4 High PO4
PTH effect on bone
Calcium export
PTH production
Main stimulus is low Ca2+.
Inhibited by 1,25(OH)2-D.
Mg required.
Calcitonin production
Main 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 gut
Increases Ca2+ and PO4
absorption
Vit D direct
effect on bone?
Unclear
Parathyroid
hormone
Calcitonin
1,25-OH2-D

103. 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)

104. 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..

105. 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
Maybe
Treatment Activated vitamin D Activated vitamin D
Parathyroidectomy

106. 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

107. 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