Milk-alkali syndrome overview

# Overview
Milk-alkali syndrome (also known as calcium-alkali syndrome) is characterized by a history of excessive calcium intake and  hypercalcemia, metabolic alkalosis and varying degrees of renal insufficiency. In 1915, Bertram Sippy introduced a treatment for peptic ulcer disease which was an hourly mixture of milk and cream combined with alkaline powders. In 1923, the toxic effects of Sippys regimen were reported for the first time. With the introduction of histamine antagonists and decrease in antacid consumption since the 1970s, the incidence of milk-alkali syndrome has decreased significantly. However, since the 1990s, there has been an increase in milk-alkali syndrome due to an increase in calcium and vitamin D consumption in postmenopausal women for osteoporosis prevention. Treatment of milk-alkali syndrome is mostly supportive and mainly includes the withdrawal of the offending agent, hydration, and intravenous volume expansion. Prognosis of milk-alkali syndrome is generally good and early diagnosis and treatment, with the withdrawal of the offending agent and supportive therapy, usually resolve the symptoms and abnormalities in milk-alkali syndrome (hypercalcemia, alkalosis and renal insufficiency).

# Historical Perspective
In 1915, Bertram Sippy introduced a treatment for peptic ulcer disease which was an hourly mixture of milk and cream combined with alkaline powders. In 1923, the toxic effects of Sippys regimen was reported for the first time. With the introduction of histamine antagonists and decrease in antacid consumption since the 1970s, the incidence of milk-alkali syndrome has decreased significantly. However, since the 1990s, there has been an increase in milk-alkali syndrome due to increase in calcium and vitamin D consumption in postmenopausal women for osteoporosis prevention.

# Classification
Milk-alkali syndrome may be classified as the following: acute (toxemic form), subacute (Cope's syndrome) and chronic (Burnett's syndrome).

# Pathophysiology
The exact pathogenesis of milk-alkali syndrome is unknown. Hypercalcemia in milk-alkali syndrome involves several mechanisms including: intestinal absorption of calcium is increased, bone buffering of calcium becomes saturated, and renal excretion of calcium is decreased. Several factors that increase bicarbonate reabsorption and contribute to the alkalosis in milk-alkali syndrome include: volume depletion due to increased sodium and free water excretion caused by increased calcium intake, suppression of PTH, direct tubular effects of calcium and other factors that cause volume depletion or alkalosis such as vomiting or thiazide use.

# Causes
Currently, the main cause of milk-alkali syndrome is calcium carbonate consumption, mostly in postmenopausal women for osteoporosis prevention or treatment or in patients on glucocorticoid therapy (for example in organ transplantation), and chronic renal disease. With the introduction of histamine antagonists and decrease in antacid consumption since the 1970s, the incidence of milk-alkali syndrome has decreased significantly. However, since the 1990s, there has been an increase in milk-alkali syndrome mostly due to increase in calcium and vitamin D consumption in postmenopausal women for osteoporosis prevention.

# Differentiating Milk-alkali syndrome from other Diseases
Milk-alkali syndrome should be differentiated from other disorders that cause hypercalcemia such as hyperparathyroidism, malignancies, hyperthyroidism, immobilization, sarcoidosis and some drugs (thiazides, vitamin D, lithium and vitamin A toxicity)

# Risk Factors
Patients with the following conditions are more susceptible to milk-alkali syndrome: Older age, preexisting chronic renal disease, concurrent vomiting (bulimia nervosa  or hyperemesis gravidarum ) and use of certain drugs like thiazide, NSAIDs, and ACE inhibitors.

# Screening
There is insufficient evidence to recommend routine screening for milk-alkali syndrome.

# Natural History, Complications and Prognosis
Most patients with milk-alkali syndrome are asymptomatic and may be incidentally diagnosed. Complications of milk-alkali syndrome may include: confusion, psychosis, renal insufficiency, pancreatitis, abnormalities in cardiac conduction, and metastatic calcification. Prognosis of milk-alkali syndrome is generally good and early diagnosis and treatment, with withdrawal of the offending agent and supportive therapy, usually resolve the symptoms and abnormalities in milk-alkali syndrome (hypercalcemia, alkalosis and renal insufficiency).

# Epidemiology and Demographics
The exact incidence and prevalence of milk-alkali syndrome is not known.
With the introduction of histamine antagonists and decrease in antacid consumption since the 1970s, the incidence of milk-alkali syndrome has decreased significantly. However, since the 1990s, there has been an increase in milk-alkali syndrome due to increase in calcium and vitamin D consumption in postmenopausal women for osteoporosis prevention. Milk-alkali syndrome is the third most common cause of hypercalcemia in hospitalized patients after primary hyperparathyroidism and malignancies.

# Diagnosis

## Diagnostic Study of Choice
Milk-alkali syndrome is diagnosed by a history of excessive calcium consumption, hypercalcemia, metabolic alkalosis and variable degrees of renal insufficiency. 

## History and Symptoms
In patients with milk-alkali syndrome, there is a history of excessive calcium and absorbable alkali consumption. Symptoms of milk-alkali syndrome may inculde: dizziness, vertigo, confusion, apathy, nausea, vomiting, anorexia, distaste for milk, headache, anorexia, pruritus, polydipsia, polyuria, myalgia, tremor, psychosis, and abnormal calcifications (keratopathy, renal calcinosis).

## Physical Examination
The following should be considered in the physical examination of milk-alkali syndrome: vertigo, confusion, apathy, nausea, vomiting, pruritus, polydipsia, polyuria, myalgia, tremor, psychosis, and abnormal calcifications (keratopathy, renal calcinosis).

## Laboratory Findings
The following laboratory findings are usually seen in milk-alkali syndrome: hypercalcemia, metabolic alkalosis, variable degrees of renal insufficiency, low or normal phosphorus, low Vitamin D, and low PTH.

## Electrocardiogram
Milk-alkali syndrome causes hypercalcemia and hypercalcemia may cause the following findings on electrocardiogram (ECG): shortened QT interval (the most common finding), shortened ST segment, PR prolongation, increased amplitude of QRS complex, decreased amplitude of T wave, T wave notching, transient ST segment elevation, bradycardia, sinus arrest, and  ventricular arrhythmias.

## X-ray
X-ray is not useful in the diagnosis of milk-alkali syndrome. However, X-ray may be useful in excluding other causes of hypercalcemia. Renal calcium deposits are not seen on X-ray in milk-alkali syndrome.

## Echocardiography and Ultrasound
Echocardiography is not useful in the diagnosis of milk-alkali syndrome. Ultrasound is not useful in the diagnosis of milk-alkali syndrome. However, ultrasound may be helpful in excluding other causes of hypercalcemia.

## CT Scan
CT scan is not useful in the diagnosis of milk-alkali syndrome. However, CT scan may be helpful in excluding other causes of hypercalcemia.

## MRI
MRI is not useful in the diagnosis of milk-alkali syndrome. However, MRI may be helpful in excluding other causes of hypercalcemia.

## Other Imaging Findings
There are no other imaging findings associated with milk-alkali syndrome.

## Other Diagnostic studies
There are no other diagnostic studies associated with milk-alkali syndrome.

# Treatment

## Medical therapy
Treatment of milk-alkali syndrome is mostly supportive and mainly includes withdrawal of the offending agent, hydration and intravenous volume expansion. However, other treatments such as therapy with calcium supplements (in temporary hypocalcemia) and hemodialysis (in acute or chronic irreversible renal insufficiency) may be required.

## Surgery
Surgical intervention is not recommended for the routine management of milk-alkali syndrome.

## Primary Prevention
Effective measures for the primary prevention of milk-alkali syndrome includes public education about the potential adverse effects of calcium supplements. Calcium intake less than 2 g/daily is usually safe, however, 1.2 to 1.5 g/daily of calcium intake should be taken by individuals with risk factors for milk-alkali syndrome.

## Secondary Prevention
There are no established measures for the secondary prevention of milk-alkali syndrome.

## Cost-Effectiveness of Therapy
There is insufficient evidence about the cost-effectiveness of therapy in milk-alkali syndrome.

## Future or Investigational Therapies
No further or investigational therapies have been suggested in milk-alkali syndrome.