Benha University Faculty of medicine Surgery department
Undersupervision of:
Dr/ Sayed El-Kilany By: .2اسراء محمد عبد المىعم .1اسراء عاطف مرزوق .4أميرة جمال عبد .3أمل جمال عبد الرحمه العسيس
.6آيت طه عبدهللا عيد .5ايمان محمد طلبتالعسب .7تيسير عالءالديه ابراهيم .8جهاد السيد عفيفي .10راودا عطيتعبدالحميد .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. 34.5 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 Absorption (intestine) Reabsorption (kidney) Resorption (bone) Net result (blood)
calcitonin
Ca
P
Ca
Ca
P
Ca
Ca
P
Ca
P
Vitamen D Ca
P
P
Ca
P
Ca
P
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 o o o o
Primary parathyroid hyperplasia. Solitary parathyroid adenoma . Parathyroid carcinoma. Multiple endocrine neoplasia (MEN). Familial isolated hyperparathyroidism.
Tertiary
hyperparathyrodism:
with chronic defficiency.
renal
failure
or
Associated vitamen D
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 nonsmall 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 semipermeable 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 ii.
iii.
phosphate level. The parathyroid hormone level is abnormally high compared with an expected low level in response to the high calcium. A more powerful variant of comparing the balance between calcium and parathyroid
iv.
hormone is to perform a 3 hour calcium infusion. 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 MetaAnalysis". 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".