Achmad Rudijanto

Endocrine and Metabolic Division of Internal Medicine Department

Faculty of Medicine Brawijaya University – Saiful Anwar Hospital
Malang
Disclosure
 Calcium

• Calcium is a mineral involved in a large number of vital functions

• The role of calcium has been primarily focused on bone health
• Calcium regulates many cellular processes and has important structural roles
in living organisms. Skeletal muscle structure and function
• Calcium involved in regulation of conduction of impulses in the nervous
system.
• Calcium as an important intracellular second messenger activates some
intracellular proteins. Involved in muscle cell contraction and cytoplasmic
calcium (Ca2+) concentration modulates various cellular functions, such as
gene expression, metabolism, proliferation, secretion, neural excitation and
fertilization
Some Role of Intracellular Calcium ion
Distribution of calcium and phosphate in normal human adults

Calcium Phosphorous
(Ca) (P)
Total body content (70 Kg Human) 10.000-1500 mg 7000-10.000 mg
Skeleton 98% 85%
Skeletal Muscle 0.3% 6%
Skin 0.08% 1%
Liver 0.02% 1%
Central Nervous System 0.01% 1%
Extracellular Fluid 1% 1%
Other Tissues 0.6% 5%

Widdowson EM & Dickerson JW. T. Chemical Composition of the Body, in Mineral

Metabolism, eds. C. L. Comar, F. Bronner, Vol. 2A. London, Academic Press (1964).
 Calcium

• Parathyroid hormone, calcitonin and 1, 25 dihydroxyvitamin D, and some

systemic (thyroid, sex steroid, glucocorticoid) hormones or humoral factors
(cytokines, growth factors) are involved in the regulation of the Ca2+ level in
blood and in bone metabolism
• The total body calcium weight is around 10.000-15.000 mg
• The total serum calcium concentration consist of 3 fraction:
• 15% bound to multiple organic and inorganic anions, such as: sulphate,
phosphate, lactate and citrate
• 40% bound to albumin
• 45% circulates as physiologically active ionized ca

Carmeliet G, et al. Best Pract Res Clin Endocrinol Metab Dec 17: 529-46, 2003.
Calcium Balance
Pathways in
Calcium
Homeostasis:

The body regulates calcium

homeostasis with two
pathways; one is signalled to
turn on when blood calcium
levels drop below normal and
one is the pathway that is
signalled to turn on when
blood calcium levels are
elevated
The major movements of calcium (mg/day) through the
principal organs (intestine, kidney, and bone) involved In
calcium homoeostasis in a normal adult man.

1000 mg
Vit D (+) Vit D (+)

400 mg Plasma 200 mg

Ca+ 400-500 mg BONE: 990 g
200 mg (10mg/dL) 200 mg

9.800 mg (ICF+ECF) PTH (+)

PTH (+) CT (-)
10.000 mg(ICF+ECF) Vit D (-)
800 mg (fecal)

200 mg
Modified: Tinawi et al. Cureus 13(1): e12420, 2021. DOI 10.7759/cureus.12420
 Intestinal calcium absorption.

Calcium is absorbed by
paracellular or transcellular
pathway:
• If dietary calcium intake is high,
the paracellular pathways
predominates. It is a passive
non-saturable diffusion process
which occurs along the entire
intestine (claudins)
• If dietary calcium intake is
normal or low the intracellular
saturable pathway, controlled
by 1.25(OH)2D, transports
calcium mainly in the
duodenum and jejunum
Boullion et al, Endoc Res, 2008
Sascha Kopic, J. Geibel, 2013
Regulation of
Serum Calcium
and Phosphorus
Calcium metabolism disorders
Hypocalcemia
• Hypoparathyroidism
• Idiopathic, post surgery, hypo-magsenemia
• Low PTH
• PTH resistance
• N/Low PTH, hypocalcemia, hyperphosphatemia
• Non-parathyroid
• Vitamin-D deficiency
• Malabsorption
• Liver diseases
• Renal diseases
Michels T, et al. Am Fam Physician. 2013;88(4):249-257.
Michels T, et al. Am Fam Physician. 2013;88(4):249-257.
 Symptoms* Laboratory evaluation
Evaluating done for other reasons

patients with
hypocalcaemia.
Hypocalcemia

Serum magnesium, albumin,

Ca2+, corrected calcium level⍭

Correct hypo or hypermagnesemia Verified hypocalcemia

Immediate treatment if Serum phosphorous, creatinine, Patient and family history,

symptomatic☨ PTH, 25-hydroxyvit-D levels ⍬ physical examination⍑

Suspect underlying cause ℔

Elevated creatinine level Elevated PTH level Normal or low PTH level

Calcium/creatinine ratio with

(PTH = parathyroid hormone; Chronic kidney disease –
24-hours urine collection
mineral & bone disorders** Phosphorous level low or
PTHrp: parathyroid hormone– Phosphorous level high or
lower normal limit upper normal limit
related peptide.) Low vitamin-D level High Low
Pseudo-
Vitamin-D deficiency hypoparathyroidism CaSR abnormality Hypoparathyroidism
Chronic hypocalcaemia be management

• Parathyroid hormone supplementation

• → used in special condition
• Calcium supplementation
• The mainstay of calcium supplementation is Ca-carbonate.
• Active and parental vitamin D
• Dose used generally it is between 0.25 and 2 ug daily. Due to impairs the renal
conversion of 25-hydroyvitamim D to its activated form
• Thiazide diuretics
• Thiazide diuretics promote renal tubular calcium retention
• Phosphate binders
• Used when hyperphosphatemia is above normal level (eg, >6.5 mg/dL)
Chronic hypocalcaemia be management

• Indication of parathyroid hormone supplementation:

• Inadequate control of the serum calcium concentration due to intercurrent
illness, poor compliance with calcium and active vitamin D therapy, GI-
malabsorption
• When doses of used of oral calcium/vit-D medications required to control
the serum calcium or symptoms are too high (>2.5 g of calcium or >1.5 ug
of active vit-D or >3.0 ug of the 1-alpha vit-D analogue
• Hypercalciuria, renal stones, nephrocalcinosis, stone risk, or reduced
creatinine clearance or eGFR (<60 mL/min)
• Hyperphosphatemia and/or calcium-phosphate product that exceeds 55
mg2/dL2 (4.4 mmol2/L2)
Acute hypocalcaemia be management
• Acute hypocalcaemia may require management in hospital with intravenous
calcium.
• Calcium gluconate is the preferred salt to be administered i.v as it is less
irritating to the veins than calcium chloride.
• 1–2g of 10% calcium gluconate bolus (corresponding to 90–180mg of elemental
calcium) in 50mL of 5% dextrose be administered over 20min followed by a
continuous infusion of intravenous calcium with 1–3mg/kg/h of elemental
calcium administered as calcium gluconate.
• During the calcium bolus and infusion continuous cardiac monitoring is
advised.
• Oral calcium supplements and active vitamin D are also initiated in
accompanied with infusion therapy
• Hypomagnesemia should be corrected and vitamin D levels should be
normalized Al-Azem H & Khan AA.. Best Practice and Research: Clinical Endocrinology and Metabolism, 2012
Bilezikian JP. Journal of Clinical Endocrinology and Metabolism, 101:2313–2324, 2016
Calcium metabolism disorders

Cause of Parathyroid hormone-independent

• Renal failure, acute or chronic*
Hypercalcemia • Neoplasms
• Parathyroid hormone-related protein
dependent
• Osteolytic metastases and multiple myeloma
• Other hormonal syndrome
• Excess vit-D
• Ingested or topical vit-D analogues
Parathyroid hormone-dependent • Granulomatous disease
• Primary hyperparathyroidism • William syndrome
• Familial hypocalciuric hypercalcemia • Other endocrine diseases: thyrotoxicosis, adrenal
• Lithium-associated insufficiency
• Tertiary hyperparathyroidism • Drugs: vit-A intoxication, milk-alkali syndrome,
• Genetic disorders (eg, MEN type-1 or 2A, thiazide diuretics, theophylline
familial hyperparathyroidism • Other immobilization, Jansen disease

Michels T, et al. Am Fam Physician.

 Symptoms Associated with Hypercalcemia
Organ system Most common symptoms and possible diagnosis
Cardiovascular Angina, dyspnea, palpitations, syncope
Possible diagnosis: diastolic dysfunction, dysrhythmias, hypertension, LVH,
vascular calcification
Gastrointestinal Anorexia, constipation, epigastric pain, nausea, vomiting
Possible diagnosis: pancreatitis, peptic ulcer disease
Neuromuscular Anxiety, confusion, depression, fatigue, forgetfulness, impaired vision,
insomnia, lethargy, weakness
Possible diagnosis: corneal calcification, delirium, mild cognitive
impairment
Renal Polydipsia, polyuria, renal colic
Possible diagnosis: nephrocalcinosis, nephrolithiasis, nephrogenic diabetes
insipidus
Skeletal Arthralgia, bone pain, fracture
Possible diagnosis: bone disease, insufficiency fracture, osteomalacia,
osteoporosis
Michels T, et al. Am Fam Physician. 2013;88(4):249-257.
 Symptoms* Incidental laboratory finding

Algorithm for
evaluating
Hypercalcemia

patients with Serum albumin, ionized calcium,

corrected calcium levels ⇞
Elevated PTHrp level
hypercalcemia. Verified hypercalcemia → Immediate treatment
If severe
Obtain history and perform
physical examination if not done.
Perform common laboratory
History and physical examination⍬ testing (eg, complete blood
Measure vit-D, magnesium, count, liver testing); serum/urine
creatinine, PTH levels electrophoresis; chest
radiography; bone scan;
abdominal and chest
Specific cause PTH level normal or high (PTH PTH level low(<20 pg/ml); tomography
identified, such dependent hypercalcemia PTH-independent
as CKD – mineral hypercalcemia Elevated 1.25 dihydroxyvit-D
and bone Calcium creatinine ratio with level
disorder ♇, 24-hour urine collection Chest radiography (eg,
medications** Measure PTHrp, lymphoma, sarcoid)
25-hydroxyvit-D,
1.25 dihydroxy- Elevated 25 hydroxyvit-D level
Elevated ratio Low ratio vit-D level Check medications, including
(>0.01) (<0.01)
vitamin and herbal
(eg, vitamin-D toxicity
Primary hyperparathyroidism Familial
Risk factors for MEN, hypocalciuric
Normal PTHrp and vitamin-
carcinoma? ⇞⇞ hypercalcemia
Dlevel
(PTH = parathyroid hormone; Perform other tests, such as
Yes No serum and urine protein
PTHrp: parathyroid hormone– electrophoresis, measurement
Gene analysis, other
related peptide.) hormone evaluation TSH, vit-A, or cortisol levels.
Possible causes include
immobilization, vit-A toxicity,
Localization studies, BMD milk-alkali syndrome
measurement, renal USG〒〒
Hypercalcemic crisis management:
• Rehydration: 4- 6 litres of fluid are often required to restore normal fluid
volumes in the first 24 h. This increases calcium excretion by 25-75 mEq day"
but rarely normalizes serum calcium if used alone;
• Forced saline diuresis: loop diuretics depress the proximal tubular
reabsorption of calcium and can increase urinary calcium excretion by 200-250
mEq day-I. Furosemide (40 mg i.v. every 4 h) should not be initiated until
volume repletion has been achieved. The risks of forced diuresis include
cardiac decompensation (central venous pressure monitoring is needed for
some patients), hypophosphataemia, hypokalaemia and hypomagnesaemia;
• Antiresorptive agents: bisphophonates (pamidronate, etidronate, clodronate)
are now first-line treatment because of their rapid and longer-lasting effect;
• Calcitonin: salmon, porcine and human calcitonin rapidly decrease the skeletal
release of calcium and phosphorus but the effects are temporary and not
usually significant.
• Dialysis is reserved for patients with renal failure. Peritoneal dialysis can
remove 100-500 mEq of calcium in 24 h, and haemodialysis approximately 70
mEq h- I
Miahi R & Farndon JR. Br J Anaesth 2000; 85: 29-43
C-cells
Parathyroid Hormone (PTH):
Chemistry, Biosynthesis and Biochemical Actions
Feedback Mechanisms
 Calcium
CaSR signalling in
the parathyroid
gland.
Increased serum
calcium levels lead to Inhibition of cell
Kinase phosporylation

an inhibition of PTH
growth IP3

secretion 1.25(OH)2-D
Sascha Kopic, J. Geibel, 2013

Increases VDR expression

Inhibits PTH
secretion
Reduces PTH
synthesis
Parathyroid gland
The Role of Parathyroid Hormone on Bone

Fan Y, et al. Cell Metabolism 25:661-672, 2017

The Role of Parathyroid Hormone on Intestine
Effects of (1-84)PTH and (7-84)PTH on kidney
Chen H, et al. BioMed Research International. Volume 2018, Article ID 9619253, 14 pages
https://doi.org/10.1155/2018/9619253
Michels T, et al. Am Fam Physician. 2013;88(4):249-257.
Evaluation of
Hypoparathyroidism

Brandi et al.
J Clin Endocrinol Metab, 2016, 101(6):2273–2283
Management of Chronic Hypoparathyroidism

Brandi et al. J Clin Endocrinol Metab, 2016, 101(6):2273–2283

Monitoring conventional management with calcium
and vitamin D

Brandi et al. J Clin Endocrinol Metab, June 2016, 101(6):2273–2283

Indications for Considering the Use of rhPTH (1-84) in
Hypoparathyroidism

Brandi et al. J Clin Endocrinol Metab, 2016, 101(6):2273–2283

The causes of primary hyperparathyroidism

• Primary hyperparathyroidism is a common endocrine disorder.

• Most patients have a single parathyroid adenoma (80%); multiple gland
hyperplasia in 10-20% of patients and parathyroid carcinoma in1%.
• Monoclonality occurs in parathyroid adenomas and can be found in sporadic
multiglandular hyperplasia and familial multiple endocrine neoplasia (MEN)
type 1.
• Findings in patients with primary hyperparathyroidism include persistent
hypercalcemia and elevated serum parathyroid hormone (PTH) levels

Friedman E, et al. New EnglJMed. 321: 213-218, 1989.

Friedman E, et al. J Clin Endocrinol Metab. 71: 293-7, 1990.
Guidelines for Monitoring Patients with Asymptomatic
PHPT Who Do Not Undergo Parathyroid Surgery

Bilezikian JP, et al. J Clin Endocrinol Metab 99: 0000–0000, 2014. doi: 10.1210/jc.2014-1413
Management of primary hyperparathyroidism

• To avoid dehydration drink at least six 8-oz glasses of water per day
• Patients should maintain a moderate daily elemental calcium intake of 800 to
1000 mg
• Maintain a vitamin D intake appropriate for their age and sex (400 IU/d for
women >50 years, 600 IU/d for women >75 years, and 400 IU/d for men >65
years
• Calcimimetic (cinacalcet) lowers PTH secretion by enhancing calcium-receptor
sensitivity
• Antiresorptive drugs—oestrogen (including selective oestrogen receptor
modulator) , bisphosphonates, and raloxifene

Agus ZS. In: Rose BD, ed. UpToDate. Waltham, Ma; 2005.
Shoback DM, et al. J Clin Endocrinol Metab. 88:5644-5649, 2003.
Pallan S, et al. BMJ 2012;344:e1013 doi: 10.1136/bmj.e1013
Surgical therapy is recommended for primary
hyperparathyroidism:

• Serum Ca2+ >2.85 mmol/L

• Hypercalciuria, urine Ca2+ >10.0 mmol/day
• Creatine clearence ≤70% of age matched normal
• Osteoporosis (bone density T score < -2.5)
• Less than 50 years of age
• Patients for whom medical surveillance is not possible or desirable

Bilezikian JP, et al. J Clin Endocrinol and Metab, 101:2313–2324, 2016.

The causes of secondary hyperparathyroidism:
• Chronic Renal Failure
• Rickets (vit-D deficiency; vit-D resistance syndromes; Renal tubular
phosphate-wasting disorders)
• Osteomalacia
• Malabsorption
• Pseudohypoparathyroidism
• Drug induce hypercalcemia (high dose phosphate therapy in patient with X-
linked
• Familial Hyperparathyroidism Syndrome:
• Hypocalciuric Hypercalcemia (FHH)
• Familial Hyperparathyroidism
• Hyperparathyroidism jaw tumour syndrome
• Multiple endocrine neoplasia (MEN) type I,
• MEN type IIA Mihai R and Farndon JR. Br J Anaesth 2000; 85: 29-43
Blackburn M. Australian Family Physician, 36:1029-1033, 2007
Genetic characteristics, presentation of HPTH, and associated
features with Familial hyperparathyroidism disorders

Udelsman R. J Clin Endocrinol Metab 96: 2950–2958, 2011

 Biochemical differences of Primary, secondary and
tertiary hyperparathyroidism
Primary Secondary Tertiary
hyperparathyroidism hyperparathyroidism hyperparathyroidism
PTH
Ca2+ * /N
PO4+ /N
Vit-D N/ /N
Comments In 85% a solitary Causes include: Caused by:
parathyroid adenoma is • Chronic renal failure • End stage renal failure
present • Vit-D deficiency
Important differential
diagnosis is FHH
• Differential diagnosis of hypercalcemia induces drug induced (eg. Lithium, thiazide) and hypercalcemia
of malignancy

Blackburn M. Australian Family Physician, 36:1029-1033, 2007

Medical treatment of secondary hyperparathyroidism

• Dietary phosphate restriction <1000 mg 24 h-can be coupled with phosphate-

binding agents
• Daily calcium intake +/-1500 mg
• Long-term treatment with calcium a-ketoglutarate (approximately 4.5 g day-I),
correcting the calcium/phosphate ratio in serum and may without vitamin D
treatment
• Routine vitamin D supplementation is started before a patient becomes
dependent on dialysis
• Bisphosphonates
• Calcimimetic (cinacalcet)
Garrett JE, et al. J Bone Min Res. 10: S387-M539, 1995.
Summary

• Calcium is a mineral involved in a large number of vital functions, primarily

focused on bone health, and also regulates many cellular processes and has
important structural roles in living organisms.
• PTH, CT and 1, 25 dihydroxyvit-D, and some systemic (thyroid, sex steroid,
glucocorticoid) hormones or humoral factors (cytokines, growth factors) are
involved in the regulation of the Ca2+ level in blood and in bone metabolism
• PTH plays a central role in the rapid control of calcium homeostasis. Its co-
ordinated actions on bone, kidney and intestine increase the flow of calcium
into the extracellular fluid and increase the concentration of calcium in blood.
• Two major manifestations of calcium metabolism and PTH disorders are hypo
or hypercalcemia, and the management of both condition depend on clinical
manifestation (acute or chronic) and the causes.
Ploceus manyar

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