hypercalcemia - esim 2012 · bp 186/92, p 96/min, bmi 31; struma nodosa ii; 3/6 systolic murmur, no...
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Hypercalcemia
Christoph Henzen
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1. Calcium homeostasis: physiology and
pathophysiology
2. Signs and symptoms of hypercalcemia
3. Primary hyperparathyreoidism
3.1 Epidemiology – symptomatic vs
"asymptomatic" HPT?
3.2 Diagnosis and treatment
3.3 Cinacalcet – alternative to surgery?
4. Differential diagnosis of hypercalcemia
5. Summary
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Parathyroidea
Schilddrüse
Calcium
1,25(OH)2D3
phosphate HCO3-
Relationship
vitamin D and PTH
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PTH
1.4 1.8 2.2 2.4 2.6 3.0
plasma calcium (mmol/l)
Calcium concentration and
parathyroid hormone (PTH) secretion
secre
tion o
f para
thyro
id
ho
rmo
ne
feedback
mechanism
vitamin D-deficiency
osteomalacia
PTH hypersecretion
(pHPT)
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extracellular
calcium
900 mg 45% protein-bound
1g/d
800mg/d
200mg/d
200mg/d
(10 g/d)
1000g
Calcium flux in the adult
500 mg
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Causes of hypercalcemia
extracellular
calcium
PTH-rP
vitamin A
thyrotoxicosis
immobilisation
M.Paget
vitamin D
granulomas
milk-alkali
Thiazid diuretics
estrogens
pHPT (MEN)
Lithium
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1833-1910
"Stein-, Bein- und Magenpein"
"Stones, bones, abdominal
groans and psychiatric moans"
Signs and symptoms
of hypercalcemia
Friedrich von Recklinghausen
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Signs and symptoms of hypercalcemia
Metabolic CNS dysfunction
Depression, anxiety, fatigue, adynamia, cognitive
impairment, arterial hypertension
Neuromuscular
Muscular weakness, constipation, short QT syndrome
Renal
Polyuria, reduced GFR, ECV deficit, metab. acidosis
Gastrointestinal
nausea, anorexia, pancreatitis, ulcer (?)
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Ostitis fibrosa cystica
in about 2%
"Rugger jersey spine"
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Nephrolithiasis 15%
Osteoporosis of the
cortical bone
(femur or 1/3 radius)
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acute pankreatitis 5%
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Mrs M. S., 74y
Fatigue, diffuse arthralgias
Ca2+ 2.23 (N 2.1 - 2.6)
Phosph 1.2 (N 0.9 - 1.5)
PTH 84 (N 13 - 65)
Mr B. M., 38y
Fatigue, diffuse arthralgias
Ca2+ 2.79 (N 2.1 - 2.6)
Phosph 0.7 (N 0.9 - 1.5)
PTH 59 (N 13 - 65)
Vitamin D deficiency
(osteomalacia)
Primary
hyperparathyreoidism
Primary
Hyperparathyroidism
(pHPT)?
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Primary hyperparathyroidism Prevalence: 1:500 F/1:2000 M; >60y 0.4-2.6%
Incidence: 22/100.000 ( Christensson, Acta Med Scan 1976, Heath, NEJM 1980, Marcocci, NEJM 2011)
Etiology: 85% solitary parathyroid adenoma
Localization: imaging vs. surgeon
Treatment: symptomatic pHPT
parathyreoidectomy (alternative: calcimimetics)
(„asymptomatic“ pHPT?)
Curative Tx in 90 – 98%, morbidity < 2%
CAVE experienced surgeon! (Sosa, JCEM 1998; Strewler, Clin Endo 2000)
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Mr K.A., 1927
Hypercalcemia
Osteoporosis (vertebral fractures),
Reflux oesophagitis/gastritis 8/05,
Urolithiasis 2/01 and 7/08.
Adynamia, intestinal discomfort, constipation,
polyuria, weight loss –3kg Ca++ 3.2
BP 186/92, P 96/min, BMI 31; Struma nodosa II;
3/6 systolic murmur, no focal neurological deficits.
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Mr K.A., 1927
Ca++ : 3.2 mmol/l (N 2.1 -2.6)
Phosph: 0.7 mmol/l (N 0.9-1.4)
Albumin: 40 g/l
Creatinine: 154 mmol/l (N 48-100)
TSH : 2.8 mU/l (N 0.27-4.2)
PTH : 143 pg/ml (N 13-65)
Primary hyperparathyreoidism
PTH : 12 pg/ml ?
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Localization imaging
sensitivity
Ultrasound 36 – 70%
CT 42 – 68%
MRI 57 – 90%
Scintigraphy 70 – 91%
Surgeon 95 – 98% Marcocci 2011, Eigelberger 2000, Shen 1996, Numerow 1995, Rodriquez 1994
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Mr K.A., 1927 Ultrasound
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Herr K.A., 1927 Tc 99m-Sestamibi scan SPECT-CT
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„asymptomatic“ hyperparathyoridism
Lundgren et al, BMJ 1998;317; 848-
5202 women 55-75y 109 (2.1%) pHPT
calcium: 2.6 mmol/l (N 2.2-2.6)
PTH : 69 ng/l (N 12-55)
0
20
40
60
80
100
120
140
160
180
Infect. Psychiatr. Cardiovas. Respirat. Gastroint. Rheumatol.
p=0.01
Lo
ss o
f w
ork
ing
days
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Surgery for asymptomatic pHPT?
121 patients over 10 y
Serum-Ca++ 2.65, PTH 121
Surgery: 61 patients No surgery: 60 patients
Serum-Ca++ 2.35 Serum-Ca++ 2.6
PTH 49 PTH 106
BMD +12% LS
BMD +14% Femur
0/12 Nephrolithiasis
BMD + 0%
6/8 Nephrolithiasis
Bilezikian JP et al, NEJM 1999;341;1249-
Bollerslev et al, JCEM 2007;92:1687-
...progression of disease in about ¼ of
asymptomatic patients...
Surveillance Calcium 6 mts
BMD 2 y
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Guidelines for parathyreoidectomy
serum-calcium >3 mmol/l (>0.25 UNL)
hypercalcaemic crisis
Creatinine (-clearence) -30% or <60 ml/min
hypercalciuria >10 mmol/24h
T-Score <-2.5 SD at any site or fragility fx
age <50y
NIH Consensus 2002,
Intern Workshop, JCEM 2009;94:335-
NEJM 2011;365:2389-
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Pharmacological treatment of pHPT
Estrogens (progestogens)
Drinking > 1.5 L
Cinacalcet (Mimpara®)
Correction of vitamin D-deficiency
CAVE: Thiazids, lithium, vitamin A
Acute hypercalcemia:
NaCl 0.9% + loop diuretics
Bisphosphonates
Calcitonin
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Cinacalcet (Mimpara®) in patients with pHPT Peacock et al, JCEM 2004;90;135-
Cinacalcet
Placebo
2
2,2
2,4
2,6
2,8
3
Cinacalcet
0 4 12 24 36 44 52
weeks
Ca
lciu
m m
mo
l/l
78 patients (57 F/21 M, 27 – 83y) with pHPT RCT Cinacalcet 2x30 –
50mg/d vs Placebo normocalcemia
p<0.001 PTH 127
p<0.01
PTH 95
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59y man with necrotizing pancreatitis with
cyst/fistula and intraabdominal bleeding
Primary hyperparathyroidism adenoma excision
Persistent hypercalcemia MRI and scintigraphy
negative
Recurrent pancreatitis Treatment with cincalcet
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2
2,4
2,8
3,2
3,6
4
Aredia® i.v.
Cinacalcet
2x30mg 2x60mg
weeks
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Extrazellular
Intrazellular
PTH „Loss of function“-Mutation
DD: Hypercalcemia
PTH
Familial hypocalciuric hypercalcemia (FHH)
Ca++/Kreatinin-Cl < 0.01
(24h-urinary calcium < 2.5 mmol/l)
Ca2+
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Strewler GJ, NEJM 2002
DD: Tumor-induced hypercalcemia
80% humoral hypercalcemia
20% local osteolysis
(exzessive secretion 1,25(OH)2D or PTH)
Lung cancer
breast cancer
esophagus ca
renal cell carcinoma
lymphoma
hepatoma
melanoma…
Parathyroid
hormone-related
peptide
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Multiple endokrine Neoplasie 2
hyperparathyreoidism 10-20%
pheochromocytoma 50%
Medullary thyroid carcinoma
100%
Multiple endokrine Neoplasie 1
hyperpara 95%
Pituitary
adenoma 25%
endocrine
pancreatic
tumors ~ 80%
Multiple endocrine Neoplasia (MEN) DD:
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68y man, flu-like infection
immobilization fatigue
shoulder pain at left, radiating
in the arm
Prostatic hyperplasia; 34 PY;
Hypertension (amlodipine 5 mg)
Laboratory findings:
Ca++ 2.6 (n 2.1-2.5),
PTH 17 ng/ml (n 10-65),
alk phosph: 567 (n 30-120)
PSA: 6.8 (n< 4.0),
BSR 34,
CRP 11.
DD:
Paget‘s
disease
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Summary I
1. Hypercalcemia and pHPT are common,
particularly in >60y (prevalence ~2%)
2. Signs and symptoms may be subtle:
parathyroidectomy for symptomatic pHPT,
guidelines for „asymptomatic“ pHPT (trial with
cinacalcet?)
3. However, pHPT may be the cause of kidney
stones, cortical osteoporosis, or pancreatitis
4. Beware of secondary elevated PTH levels in
patients with vitamin D-deficit
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Summary II
5. pHPT may be part of MEN 1, particularly in
patients <40y, with familial history or other
endocrine tumours
6. Hypercalcemia in sarcoidosis is caused by
overproduction of calcitriol
7. Calcimimetics (Mimpara®) are a pharmacological
alternative to surgery
8. In acute hypercalcemia treatment consists of
fluid administration with NaCl 0.9% and loop
diuretics, and bisphosphonates (e.g.
zolendronate i.v.)