hypercalcalcemia

Benha University

Faculty of medicine

Surgery department

Undersupervision of:

Dr/ Sayed El-Kilany

By:

اسراء محمد عبد المىعم.2اسراء عاطف مرزوق .1 أميرة جمال عبد .4أمل جمال عبد الرحمه .3

العسيسآيت طه عبدهللا عيد.6ايمان محمد طلبتالعسب .5

جهاد السيد عفيفي.8تيسير عالءالديه ابراهيم .7

راودا عطيتعبدالحميد.10 جهاد سمير السيد .

Contents

Ca metabolism.

Definition.

Signs and symptoms.

Causes.

Diagnosis.

Treatment.

"Primary hyperparathyroidism":

Mechanism.

Causes.

Clinical picture.

Diagnosis.

Treatment.

References.

Ca metabolism

Ca is present in the body in 2 forms:

a. Ionized (active): 50%

b. Non-ionized (reserve): 50%:

i. 40% bound to albumin.

ii. 10% to any other bond (ca carbonate,

phosphate,……..).

Regulation of ca:

o Ca levelis closely affected & related to P (normal. 3-

4.5 mg%).

o Ca × P = constant (40).

o Serum ca & P level are controlled by certain

hormones:

1. Parathrmone.

2. Calcitonin.

3. Active vitamin D.

o Regulation involve 3 sites: bone, intestine, kidney.

Parathormone calcitonin Vitamen D

Absorption

(intestine) Ca P Ca Ca P

Reabsorption (kidney)

Ca P Ca P Ca P

Resorption

(bone) Ca P Ca P Ca P

Net result

(blood) Ca P Ca P Ca P

Definition

Hypercalcemia is an elevated calcium level in the blood.

(Normal range: 9–10.5 mg/dL or 2.2–

2.6 mmol/L). Because an elevated calcium level is

often indicative of other diseases, a workup should be

undertaken if it persists. It can be due to excessive skeletal

calcium release, increased intestinal calcium absorption,

or decreased renal calcium excretion.

Pathophysiology

o Usually, hypercalcemia is reported as elevation of total plasma calcium levels rather than ionized calcium levels.

o Approximately 50% of total calcium is protein bound, and

the total calcium level will vary with protein-binding capacity. This phenomenon may rarely result in

pseudohypercalcemia—for example, in patients with

hyperalbuminemia secondary to dehydration and in some patients with multiple myeloma. More commonly, lowering

of total calcium levels is observed in patients with low

levels of binding proteins (hypoalbuminemia). This physiology requires that the total plasma calcium level be

corrected for the albumin level.

o Normal calcium levels may range from 9 to 10.5 mg/day, assuming an albumin level of 4.5 g/dL. The calcium

concentration [Ca] usually changes by 0.8 mg/dL for

every 1.0-g/dL change in plasma albumin concentration. Thus, this formula estimates the actual total plasma

calcium level:

Corrected [Ca] = Total [Ca] + (0.8 × [4.5 −

albumin level])

o Acidosis decreases the amount of calcium bound to

albumin, whereas alkalosis increases the bound fraction of calcium.

o A small amount of calcium (about 6%) is complexed to

anions such as citrate and sulfate. The remainder is ionized calcium that is biologically active.

Signs and symptoms

1. ( These symptoms are more common at

high calcium blood values (12.0 mg/dL or

3 mmol/l)) There is a general mnemonic for remembering the

effects of hypercalcaemia: "Stones, Bones, Groans,

Thrones and Psychiatric Overtones":

Stones (renal or biliary) , lead to renal failure .

Bones (bone pain).

Groans (abdominal pain, nausea and vomiting).

Thrones (sit on throne - polyuria).

Psychiatric overtones (Depression 30-40%,

anxiety, cognitive dysfunction, insomnia, coma) Other symptoms can include fatigue, anorexia, and

pancreatitis.

ECG findings of a short QT interval and a

widened T wave suggest hypercalcaemia.

Hypercalcaemia can increase gastrin production,

leading to increased acidity so peptic ulcers may also occur.

2. Severe hypercalcaemia (above 15–16 mg/dL or

3.75–4 mmol/l) "Hypercalcaemic crisis": It is considered a medical emergency: at these levels,

coma and cardiac arrest can result. This can be

explained as following: the high levels of calcium ions decrease neuronal excitability, which leads to

hypotonicity of smooth and striated muscle. This

explains the fatigue, muscle weakness, low tone and

sluggish reflexes in muscle groups. In the gut this causes constipation. The sluggish nerves also explain

drowsiness, confusion, hallucinations, stupor and / or

coma. The main symptoms of a hypercalcaemic crisis are

oliguria or anuria, as well as somnolence or coma.

After recognition, primary hyperparathyroidism should be proved or excluded.

In extreme cases of primary hyperparathyroidism,

removal of the parathyroid gland after surgical neck exploration is the only way to avoid death

. The

diagnostic program should be performed within hours,

in parallel with measures to lower serum calcium.

Causes

1) Physiologic:

Young, growing dogs, especially large breeds, often have Ca slightly higher than the reference range for

adult dogs.

2) Abnormal parathyroid gland function

Primary hyperparathyroidism :

o Primary parathyroid hyperplasia. o Solitary parathyroid adenoma . o Parathyroid carcinoma. o Multiple endocrine neoplasia (MEN). o Familial isolated hyperparathyroidism.

Tertiary hyperparathyrodism: Associated

with chronic renal failure or vitamen D defficiency.

Lithium use. Familial hypocalciuric hypercalcaemia/familial benign

hypercalcaemia .

3) Malignancy:

Solid tumour with metastasis (e.g. breast cancer or

classically squamous cell carcinoma, which can be

PTHrP-mediated) . Solid tumour with humoral mediation of

hypercalcaemia (e.g. lung cancer, most commonly non-

small cell lung cancer or kidney cancer, phaeochromocytoma) . Haematologic malignancy (multiple myeloma,

lymphoma, leukaemia) . Ovarian small cell carcinoma of the hypercalcemic

type.

N.B. Primary hyperparathyrodism and

malignency accounts for about 90%

of cases of hypercalcaemia.

4)Vitamin-D metabolic disorders:

Hypervitaminosis D (vitamin D intoxication) . Elevated 1,25(OH)2D levels (e.g. sarcoidosis,

tuberculosis, lymphoma and other granulomatous

diseases) . Idiopathic hypercalcaemia of infancy. Rebound hypercalcaemia after rhabdomyolysis.

5)Disorders related to high bone-turnover rates:

*Hyperthyroidism . *Prolonged immobilization.

*Thiazide use. *Vitamin A intoxication.

*Paget's disease of the bone

6)Renal failure:

Severe secondary hyperparathyroidism.

Aluminium intoxication.

Milk-alkali syndrome (from calcium antacids) .

7)Others:

Acromegally.

Diagnosis

High levels of calcium in the blood are a good indication of

hypercalcemia, but these levels may fluctuate. Calcium levels

are influenced by other compounds in the blood that may

combine with calcium.

The blood levels of protein (serum albumin) and parathyroid

hormone (PTH) are also measured in the diagnosis of

hypercalcemia.

Levels of calcium and phosphate in the urine should also be

measured.

Conditions iPTH ICa 25-Hydroxy D

primary hyperPTH N or High High -

renal hyperPTH High Low -

Hypercalcemia

of malignancy Low High Normal

Vit D intoxication Low High High

Treatment

The treatment of hypercalcemia depends on how high the

calcium level is and what is causing the elevation.

Hypercalcemia can be life-threatening and rapid reduction

may be necessary.

If the patient has normal kidney function, fluids can be

given by vein (intravenously) to clear the excess calcium.

The amount of fluid taken in and eliminated must be

carefully monitored.

If the patient's kidneys are not working well, acute

hemodyalysis is probably the safest and most effective

method to reduce dangerous calcium levels. In this

procedure, blood is circulated through tubes made of semi-

permeable membranes against a special solution that

filters out unwanted substances before returning the blood

to the body.

Drugs:

Furosemide\"loop diuretics" can be given after

adequate fluid intake is established. These drugs

inhibit calcium reabsorption in the kidneys and

promote urine production.

Drugs that inhibit bone loss, such as calcitonin,

biphosphates, and plicamycin, are helpful in

achieving long-term control.

Phosphate pills help lower high calcium levels

caused by a deficiency in phosphate.

Anti-inflammatory agents such as steroids are

helpful with some cancers and toxic levels of vitamin

D.

Treatment of the underlying cause of the

hypercalcemia will also correct the imbalance.The

hypercalcemia caused by cancer is difficult to treat

without controlling the cancer.

Prognosis

Surgery to remove the parathyroid glands and any

misplaced tissue that is producing excessive amounts of

hormone succeeds in about 90% of all cases. Outcome is

also influenced by whether any damage to the kidneys

can be reversed. Mild hypercalcemia can be controlled through good fluid

intake and the use of effective drugs. Hypercalcemia generally develops as a late complication

of cancer and the expected outlook is grim without

effective anticancer therapy.

N.B. Since the primary hyperparathyroidism is the most common cause of hypercalcaemia,

we find that we must talk briefly about it.

"Primary hyperparathyroidism"

Mechanism:

It causes hypercalcemia (elevated blood calcium

levels) through the excessive secretion of parathyroid

hormone (PTH), usually by an adenoma (benign tumors) of the parathyroid glands

Causes:

1. The most common cause of primary

hyperparathyroidism is a sporadic, single

parathyroid adenoma , parathyroid carcinoma (malignant tumor), and adenomas in more than one

gland .

2. Primary hyperparathyroidism is also a feature of several familial endocrine disorders: Multiple

endocrine neoplasia type 1 and type 2A (MEN type 1

and MEN type 2A), and familial hyperparathyroidism.

3. Primary hyperparathyroidism can also result from

pregnancy. It is apparently very rare.

Clinical picture: As hypercalcaemia:

Nephrocalcinosis, diabetes insipidus& renal failure.

The classic bone disease in hyperparathyroidism is osteitis fibrosa cystica.

Osteoporosis, osteomalacia, and arthritis.

Constipation, indigestion, nausea and vomiting

Peptic ulcers and acute pancreatitis

Lethargy, fatigue, depression, memory loss,

psychosis, ataxia, delirium, and coma.

Left ventricular hypertrophy.

Diagnosis:

In the setting of elevated serum calcium levels and elevated PTH levels, the diagnosis of primary

hyperparathyroidism is certain. However,

radiographic findings of subperiosteal resorption are most specific for the disease and should prompt

consideration of the primary hyperparathyroidism:

Hyperparathyrodism is a disease of increased bone resorption and bone formation.

Subsequently, plain radiographic findings may

include resorption and sclerosis of numerous sites in the skeletal system.

Historically, osteitis fibrosa cystica was used to describe the advanced skeletal disease in

primary hyperparathyroidism. Bone findings

were characterized by the osteoclastic resorption of bone, osteoblastic bone

formation, and fibrous replacement of marrow,

with radiographic findings of subperiosteal resorption, brown tumors, bone cysts, and

sclerosis.

These days, the most common radiologic finding in primary hyperparathyroidism is

osteopenia, which may be generalized or asymmetric.

The diagnosis of primary hyperparathyroidism is made by blood tests:

i. Serum calcium levels are elevated with low

phosphate level. ii. The parathyroid hormone level is

abnormally high compared with an expected

low level in response to the high calcium.

iii. A more powerful variant of comparing the balance between calcium and parathyroid

hormone is to perform a 3 hour calcium

infusion. iv. The serum chloride/phosphate ratio is 33 or

more in most patients with primary

hyperparathyroidism. However, usage of thiazide medications have been reported to

causes ratios above 33.

Urinary cAMP is occasionally measured; this is generally elevated.

Treatment:

Treatment is usually surgical removal of the gland(s) containing adenomas.

1) Medications:

Medications include estrogen replacement therapy in postmenopausal women and bisphosphonates.

Newer medications termed "calcimimetics" used in

secondary hyperparathyroidism are now being used in Primary hyperparathyroidism. Calcimimetics

reduce the amount of parathyroid hormone released

by the parathyroid glands. They are recommended in patients in whom surgery is inappropriate.

2) Surgery:

The symptoms of the disease, listed above, are indications for surgery. Surgery reduces all cause

mortality as well as resolving symptoms. However,

cardiovascular mortality is not significantly reduced.

A consensus statement in 2002 recommended the

following indications for surgery in asymptomatic

hyperparathyroidism:

Serum calcium: 1.0 mg/dl above upper

limit of normal .

24-h urinary calcium >400 mg.

Creatinine clearance reduced by 30%

compared with age-matched subjects.

Bone mineral density t-score <−2.5 at any

site .

Age <50

More recently, three randomized controlled trials

have studied the role of surgery in patients with

asymptomatic hyperparathyroidism. The largest study reported that surgery showed increase in bone

mass, but no improvement in quality of life after one

to two years among patients with:

Untreated, asymptomatic primary

hyperparathyroidism .

Serum calcium between 2.60–2.85 mmol/liter

(10.4–11.4 mg/dl) .

Age between 50 and 80 yr .

No medications interfering with Ca

metabolism

No hyperparathyroid bone disease .

No previous operation in the neck .

Creatinine level < 130 µmol/liter

(<1.47 mg/dl)

3) Future therapies:

Future developments such as calcimimetic agents

(e.g. cinacalcet) which activate the parathyroid calcium-sensing receptor may offer a good

alternative to surgery.

References

1. Dorland's Medical Dictionary . 2. Wesson, L.; Suresh, V.; Parry, R. (2009). "Severe

hypercalcaemia mimicking acute myocardial infarction". Clinical medicine (London, England) .

3. Serafi S, Vliek C, Taremi M (2011) "Osborn waves in a hypothermic patient" The Journal of Community Hospital Internal Medicine Perspectives .

4. Mitchell, Richard Sheppard; Kumar, Vinay; Abbas, Abul K.; Fausto, Nelson. Robbins Basic Pathology.

5. Tierney, Lawrence M.; McPhee, Stephen J.; Papadakis, Maxine A. (2006). Current Medical Diagnosis and Treatment 2007 (Current Medical Diagnosis and Treatment).

6. Online 'Mendelian Inheritance in Man' (OMIM) . 7. Online 'Mendelian Inheritance in Man' (OMIM) . 8. Online 'Mendelian Inheritance in Man' (OMIM) . 9. Deshmukh, R. G.; Alsagoff, S. A. L.; Krishnan, S.; Dhillon, K.

S.; Khir, A. S. M. (1998). "Primary hyperparathyroidism presenting with pathological fracture".

10. Bilezikian, John P.; Silverberg, Shonni J. (2002). "Primary hyperparathyroidism: Epidemiology and clinical consequences". Clinical Reviews in Bone and Mineral Metabolism.

11. Bolland, M. J.; Grey, A. B.; Gamble, G. D.; Reid, I. R. (2004). "Association between Primary Hyperparathyroidism and Increased Body Weight: A Meta-Analysis". Journal of Clinical Endocrinology & Metabolism .

12. Barreras, R. F.; Donaldson, R. M. (1967). "Role of Calcium in Gastric Hypersecretion, Parathyroid Adenoma and Peptic Ulcer". New England Journal of Medicine .

13. Stefenelli T, Abela C, Frank H, et al. (1997). "Cardiac abnormalities in patients with primary hyperparathyroidism: implications for follow-up".