HypercalcemiaAhmed ElshebinyAhmed Elshebiny

University of MenoufyiaUniversity of Menoufyia

Case : History A 41-year-old woman was brought by her

husband to the emergency department with a history of 72 hours of epigastric pain, nausea, repeated vomiting, and altered mental status. Her blood calcium was found to be 18.9 mg per deciliter (4.7 mmol per liter).

Alcoholic, peptic ulcer, analgesics for back pain

Examination On physical examination, the blood pressure was 160/90 mm Hg, the heart rate 100 beats per minute, and the temperature 37.4°C. The patient was disoriented and intermittently writhing in pain. Her skin turgor was poor, and her oral mucosa was dry. The cardiac examination was significant only for tachycardia, and the pulmonary examination was normal. There was epigastric tenderness on palpation but no rebound

tenderness. The patient was responsive to simple commands and was not

tremulous. There were no other significant neurologic findings.

Investigations

Specific investigations Intact parathyroid= undetectable 25 hydroxy vitamin D = normal PTH related protein= normal Calcium fall with hydration only

Computed tomography (CT) of the neck revealed no parathyroid masses. CT of the chest was normal. Abdominal CT showed an edematous pancreas with surrounding infiltration of the mesenteric fat, a finding consistent with acute pancreatitis. No bone lesions were noted on the chest or abdominal CT scans.

Diagnosis In response to further questioning, the patient

reported that during the days before admission she had consumed the contents of entire containers of Tums and a preparation containing sodium bicarbonate (Alka-Seltzer, Bayer) because of the severe abdominal pain. She did not consume any other medications or supplements.

This history, together with the laboratory-test results, establishes the "milk alkali syndrome" as the primary diagnosis

Milk Alkali Syndrome The pathogenesis of the milk alkali syndrome involves a reduction in the

ability of the kidney to excrete excess calcium. This reduction is secondary to a decrease in the glomerular filtration rate

(due to renal vasoconstriction and hypovolemia) and to a significant increase in tubular reabsorption of calcium (secondary to metabolic alkalosis).

The plasma PTH level decreases with the rise in the serum calcium level. Thus, the constellation of excess oral intake of calcium and milk, plus

impaired renal function, may result in PTH suppression, hypercalcemia, and hyperphosphatemia.

In cases of chronic ingestion of excessive alkaline calcium preparations and milk, metastatic calcifications and occasionally nephrocalcinosis may occur,7 whereas such complications are not expected with acute milk alkali syndrome, as in the present case.

Calcium Plays a role inside (intracellular) and outside (extarcellular) cells Functions of calcium

Muscle contraction Nerve conduction Coagulation Enzyme and electrolyte regulation Hormone release and exocytosis Cell division

Calcium enters extra-cellular fluid from intestine and bone Calcium is excreted through kidneys Calcium is tightly controlled by hormones (PTH, Calcitriol, calcitonin) Human body contains 1100 g calcium

Hypercalcemia For hypercalcemia to develop, the normal calcium regulation

system must be overwhelmed by an excess of PTH, Calcitriol, some other serum factor that can mimic these hormones, or a huge calcium load.

Between 20 and 40% of patients with cancer develop hypercalcemia at some point in their disease

the most common serious electrolyte presenting in adults with malignancies

primary hyperparathyroidism is considerably higher in women.

Hyperparathyroidism and malignancy increases with age Breast cancer is one of the most common malignancies

responsible for hypercalcemia.

PTH dependent hypercalcemia Primary hyperpara( adenoma commonly) Tertiary hyperparathyroidism FHH MEN syndromes Lithium therapy

PTH independent hypercalcemia Malignancy related Vitamin D related( Granulomas, infections,

toxcicity, williams syndrome) Other endocrine( hyperthyroidism,

pheochromocytoma, adrenal insufficiency, islet cell tumor)

Miscellaneous( immobilization, milk alkali, other medications)

Hypercalcemia of Hyperparathyroid Primary: Usually adenoma Secondary tertiary Hypophosphatemia and elevated urine

calcium Surgery Complications of surgery

PTH and calcium measurment PTH assay PTH related protein Total calcium Ionized calcium

FHH Autosomal dominant, usually mild elevation Shift of the set point Urine calcim is low Previous history of normal calcium rules out

FHH

Hypercalcemia of Malignancy Secretion of PTH related peptide Osteoclastic activation Secretion of vitamin D Unknown mechanisms Common with( Breast cancer with bone

metastasis, lung cancer, multiple myeloma, Hodgikins, pancreatic islet tumors, cholangiocarcinoma and adenocarcinomas)

Symptoms Depends on the underlying disease and rate of

increase in serum calcium Mild elevations in calcium levels usually have few

or no symptoms Manifestations include

Nausea, vomiting, abd pain, stones, constipation, pancreatitis, ulcer Polyuria, polydepsia, nocturia Weakness and vague muscle and Joint aches Altered mental state, lethargy, depression, Headache , confusion Coma

Hypercalcemia of malignancy Hypercalcemia of Hyperparathroid

Examination Mental state Pulse and blood pressure Abdomen Reflexes and muscle power Hydration Malignancy Other specific disease Band keratopathy

ECG Short Q-T Prolonged P-R At high levels …. Wide QRS Flat or inverted T Variable degrees of Heart block N.B. Digoxin effects are amplified

Phosphate and Chloride Serum phosphate levels tend to be low or normal

in primary hyperparathyroidism and hypercalcemia of malignancy.

Phospate levels are elevated in hypercalcemia secondary to vitamin D–related disorders or thyrotoxicosis.

Serum chloride levels usually are higher than 102 mEq/L in hyperparathyroidism and less than this value in other forms of hypercalcemia.

Investigations and DD

Vitamin D metabolism

Treatment1. Hydration

2. Loop diuretics (avoid thiazide)

3. Biphosphonates and other medications

4. Dialysis

5. Surgery

6. Chemo or radiotherapy for malignancy

Medications used to treat Hypercalcemia

Medications used to treat Hypercalcemia

Bisphosphonates Calcitonin Gallium nitrate(Ganite) Plicamycin Glucocorticoids Phosphate Cinacalcite

Pamidronate Zolidronic acid Etidronate

Acute management Rehdrate + or - lasix Bisphosphonate Other Medicate Calcitonin May be phosphate

Chronic management Indications of surgery in hyperparathyroidism Biphosphonates Cortisone in myeloma Cortisone in granulomas and /or hydroxy

chloroquine or ketokonazole Cinacalcet

Take home points Majority of hypercalcemias are caused by

hyperparathyroid or malignancy but others other sought when the diagnosis is not clear

Symptoms are usually subtle Severer hypercalcemia(stones , bones, moans and

groans) History + PTH levels are the essentials for diagnosis Acute management focuses on hydration the other

medications Chroni management focuses on the underlying

aetiology

References Washington subspecialty consult:

Endocrinology 2009 Kumar and Klark’s Medicine 2009 E-medicine online text book – emergency

medicine/ and Nephrology Nejm CASES, 2008