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Milk-Alkali Syndrome

Milk Alkali Syndrome

Milk-alkali syndrome results due to an excessive intake of calcium and alkali. It presents with hypercalcemia, metabolic alkalosis, and renal injury. It is most commonly seen in postmenopausal women who are using prophylaxis for osteoporosis, and in patients with preexisting renal disease. The diagnosis is made by confirming alkalosis and high serum calcium levels, while treatment involves cessation of excessive calcium intake.


Presentation

Symptoms of milk-alkali syndrome can start within days, weeks, or months after consuming excessive calcium. As there are different forms of this syndrome - acute, subacute and chronic [9], the symptoms may vary depending on the duration of the illness. However, patients in all three subtypes of disease present with nausea, vomiting, headaches, dizziness, weight loss, anorexia, bulimia, and changes in mental status [10]. Patients with a prolonged course of disease may experience muscle aches, tremor, polyuria, polydipsia, and pruritus. Calcifications may develop at various sites, most prominently on the kidneys, resulting in nephrocalcinosis, but also on the conjunctiva and cornea, which can lead to keratopathy and vision problems. In patients with severe volume depletion, arrhythmia and tachycardia may be noted during physical examination.

Hypoventilation
  • The main trigger was a morphine overdose with volume contraction due to vomiting and a further aggravation of chronic compensatory elevation of bicarbonate due to hypoventilation leading to MAS; thus, suggesting hypoventilation as a risk factor for MAS[ncbi.nlm.nih.gov]
Constipation
  • When symptoms do occur, they can include: Back, middle of the body, and low back pain in the kidney area (related to kidney stones) Confusion, strange behavior Constipation Depression Excessive urination Fatigue Irregular heartbeat ( arrhythmia ) Nausea[nlm.nih.gov]
  • Clinical findings Although usually asymptomatic, milk-alkali syndrome can cause high urine output, fatigue, nausea, constipation, and pain in the abdomen, back or loin (due to kidney stones).[medical-dictionary.thefreedictionary.com]
  • Milk-alkali syndrome is usually asymptomatic but may also present with signs and symptoms related to hypercalcemia, such as fatigue, weakness, mental changes, constipation, excessive urination, and renal stones.[clinicaladvisor.com]
Polydipsia
  • Patients with a prolonged course of disease may experience muscle aches, tremor, polyuria, polydipsia, and pruritus.[symptoma.com]
  • The symptoms of chronic form of the Burnett's syndrome include myalgia, tremor, polyuria, polydipsia, soft tissue calcification, nephrocalcinosis and irreversible renal failure.[allnutriments.blogspot.com]
  • Patient 1 A 55-yr-old white man with a medical history that was significant for reflux esophagitis and dyspepsia presented to the outpatient clinic with complaints of polydipsia, polyuria, nausea, frequent emesis, and generalized fatigue for 2 wk.[cjasn.asnjournals.org]
  • Impairment of the renal concentrating mechanism leads to polyuria, nocturia, and polydipsia. Elevation of serum calcium 12 mg/dL ( 3.00 mmol/L) can cause emotional lability, confusion, delirium, psychosis, stupor, and coma.[merckmanuals.com]
Cardiomegaly
  • The chest x-ray showed cardiomegaly with mild pulmonary vascular congestion, and a computed tomography scan of the head was negative. A renal ultrasound showed normal-size kidneys without increased echogenicity.[cjasn.asnjournals.org]
Muscle Weakness
  • weakness, depression, anorexia, nausea, and constipation High level of calcium in the blood Higher than normal levels of calcium in the blood.[icd9data.com]
  • Abnormally high level of calcium in the blood; manifestations include fatigability, muscle weakness, depression, anorexia, nausea, and constipation. High level of calcium in the blood Higher than normal levels of calcium in the blood.[icd10data.com]
  • Hypercalcemia may cause neuromuscular symptoms, including skeletal muscle weakness. Hypercalciuria with nephrolithiasis is common.[merckmanuals.com]
Myalgia
  • The symptoms of chronic form of the Burnett's syndrome include myalgia, tremor, polyuria, polydipsia, soft tissue calcification, nephrocalcinosis and irreversible renal failure.[allnutriments.blogspot.com]
  • The acute form is characterized by fatigue, nausea, vomiting, myalgia and irritability.[ijem.in]
  • The available literatures indicate that influenza vaccine may cause fever and myalgias in the elderly, but no relation between H1N1-influenza vaccination and the MAS has been yet reported; a subject that needs further workup.[sjkdt.org]
Withdrawn
  • Milk alkali syndrome is a cause of hypercalcaemia, renal failure and alkalosis, and is potentially reversible if detected early and the calcium and alkali source withdrawn.[ncbi.nlm.nih.gov]
  • Foundation Trust, Stott Lane, Salford, M6 8HD, UK Ayesha.Irtiza‐Ali@lthtr.nhs.uk SUMMARY Milk alkali syndrome is a cause of hypercalcaemia, renal failure and alkalosis, and is potentially reversible if detected early and the calcium and alkali source withdrawn[doi.org]
Polyuria
  • Patients with a prolonged course of disease may experience muscle aches, tremor, polyuria, polydipsia, and pruritus.[symptoma.com]
  • The symptoms of chronic form of the Burnett's syndrome include myalgia, tremor, polyuria, polydipsia, soft tissue calcification, nephrocalcinosis and irreversible renal failure.[allnutriments.blogspot.com]
  • Hypercalcemia deteriorates renal functions through dehydration due to polyuria and renal vasoconstriction and resulted in decreased glomerular filtration rate. [6] Metabolic alkalosis secondary to hypercalcemia is caused by increased bicarbonate absorption[ijem.in]
  • Clinical features include polyuria, constipation, muscle weakness, confusion, and coma. Diagnosis is by measuring serum ionized calcium and parathyroid hormone concentrations.[merckmanuals.com]
  • Therapy with bisphosphonates can serve a palliative purpose for patients with hypercalcemia of malignancy, providing some improvement in polyuria and polydypsia, central nervous system symptoms, constipation, nausea, vomiting, anorexia and malaise, according[acphospitalist.org]
Flank Pain
  • We report a case of a 26-year-old woman in her second trimester of pregnancy who presented with 2 weeks of flank pain, nausea, vomiting, anorexia, headache, and lightheadedness.[ncbi.nlm.nih.gov]
Headache
  • We report a case of a 26-year-old woman in her second trimester of pregnancy who presented with 2 weeks of flank pain, nausea, vomiting, anorexia, headache, and lightheadedness.[ncbi.nlm.nih.gov]
  • Unlike most other body Hypothalamus Headaches Pituitary Headaches, visual defect 'systems' the very nature of the endocrine system Thyroid Pressure symptoms, dysphagia, ensures that the effects of disordered function in a goitre gland affect the body[books.google.com]
  • The most common symptoms are poor appetite, dizziness, headache, confusion, psychosis, and dry mouth; laboratory tests may show that a person with milk-alkali syndrome has high blood calcium, kidney failure, and metabolic alkalosis.[en.wikipedia.org]
  • However, patients in all three subtypes of disease present with nausea, vomiting, headaches, dizziness, weight loss, anorexia, bulimia, and changes in mental status.[symptoma.com]
  • This often takes a combination of: calcium supplements foods fortified with calcium foods naturally high in calcium (yogurt, milk) The most common symptoms are: poor-appetite dizziness headache confusion psychosis dry-mouth kidney failure metabolic disorders[reboundhealth.com]
Altered Mental Status
  • Today we discussed a case of altered mental status in a patient who was found to have hypercalcemia secondary to milk alkali syndrome .[imrespdx.com]
  • mental status -confusion, disorientation, stupor joint pain joint destruction needing hip replacement surgery A very famous medical text book Harrison's: The Princals of Internal Medicine 14th Edition has chapter 323 titled, Arthritis Due to Depostion[reboundhealth.com]
  • 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.[content.nejm.org]
  • The symptoms of Burnett's syndrome include: lack of appetite, nausea, vomiting, headache, constipation, abdominal pain, back pain, weakness, fatigue, drowsiness, depression, symptoms of altered mental status, malaise, symptom of confusion, dry oral mucosa[allnutriments.blogspot.com]
  • A young woman with altered mental status. J Emerg Med . 2002 May. 22(4):405-8. [Medline] . Robertson WC Jr. Calcium carbonate consumption during pregnancy: an unusual cause of neonatal hypocalcemia. J Child Neurol . 2002 Nov. 17(11):853-5.[emedicine.com]
Irritability
  • The acute form is characterized by fatigue, nausea, vomiting, myalgia and irritability.[ijem.in]
  • The symptoms include nausea, vomiting, headache, irritability, vertigo, depression, confusion, weakness, and ataxia. Radiological findings show multiple calcium deposits in soft tissues.[whonamedit.com]
Neglect
  • Non-malignant causes of hypercalcemia in cancer patients: a frequent and neglected occurrence. Support Care Cancer . 2013 May. 21(5):1415-9. [Medline] . LeGrand SB, Leskuski D, Zama I.[emedicine.com]
  • Kidney Int 65 : 1835 –1841, 2004 Hu M-S, Kayne LH, Willsey PA, Koteva AB, Jamgotchian N, Lee DB: Bile salts and ileal calcium transport in rats: A neglected factor in intestinal calcium absorption.[cjasn.asnjournals.org]

Workup

Patients in whom milk-alkali syndrome is suspected should be thoroughly investigated. The diagnostic workup comprises of various laboratory tests.

Prior to performing laboratory tests, however, a detailed patient history can be of great significance in determining the cause of symptoms. Recent use of calcium-containing drugs, changes in dietary habits, or history of preexisting disease may provide vital information.

Initial tests should evaluate levels of serum calcium, phosphorus, blood pH and bicarbonate levels, to assess the severity of hypocalcemia and metabolic alkalosis. Findings will reveal elevated serum calcium, low values of phosphorus, increased blood pH and bicarbonate levels.

In all patients, and especially in those with preexisting renal disease, renal function should be evaluated. Blood urea nitrogen (BUN), creatinine, estimation of GFR, and urinalysis must be obtained in all patients, to assess the functional capacity of the kidneys. Additionally, serum PTH and vitamin D should be measured as well, to rule out possible hyperparathyroidism or malignancy. PTH values are usually low, but in the case of renal failure, values may be paradoxically high [11].

Additional studies should include electrocardiography (EKG), to assess heart conduction and function, since hypercalcemia may have potentially fatal effects on the cardiac muscle [12], while abdominal ultrasound may be used for macroscopic evaluation of the renal system.

Nephrolithiasis
  • There is a family history of early vascular strokes, kidney failure, and nephrolithiasis.[pedsinreview.aappublications.org]
  • Although asymptomatic hypercalcemia is the most frequent presentation, nephrolithiasis is also common, particularly when hypercalciuria occurs due to long-standing hypercalcemia.[merckmanuals.com]
  • N Engl J Med 313 : 70 –73, 1985 Domrongkitchaiporn S, Sopassathit W, Stitchantrakul W, Prapaipanich S, Ingsathit A, Rajatanavin R: Schedule of taking calcium supplement and the risk of nephrolithiasis.[cjasn.asnjournals.org]
Calcium Increased
  • It is likely that bone, the primary repository for calcium, increases calcium uptake but becomes saturated during high calcium exposure.[cjasn.asnjournals.org]

Treatment

Once the diagnosis has been made, appropriate treatment can be initiated. In all patients, discontinuation of excessive calcium intake is the mainstay of treatment, and resolution of symptoms may be seen in a relatively short period of time. Calcifications that have developed usually resolve gradually, but patients with chronic disease may require additional forms of treatment:

  • Rehydration - since many patients report vomiting and polyuria, dehydration is a common finding. So intravenous fluid administration is one of the most important parts of therapy. By restoring normal blood volume, metabolic alkalosis may subside, and increased volume leads to improvement of GFR, resulting in improved kidney function.
  • Diuretics - Although the use of diuretics is a topic of debate, loop diuretics such as furosemide have been used in clinical practice to stimulate calcium excretion [13]. However, the use of diuretics is strongly contraindicated prior to rehydration, since they can further elevate serum calcium levels in that setting.
  • Bisphosphonates - Their use is questionable under these circumstances, but because they reduce serum calcium levels, they are sometimes used in therapy. Because of their potency, these drugs can sometimes cause hypocalcemia [14].
  • Dialysis - For patients with severe kidney injury, hemodialysis can be indicated, until normal serum calcium levels have been reached.

Prognosis

With a timely diagnosis, the prognosis is good in the vast majority of patients, as symptoms resolve within a short period of time after cessation of excessive calcium intake. Kidney injury is usually reversible, but patients in whom the disease is long standing (months), renal damage may persist, and lead to significant morbidity.

Etiology

As stated previously, this disease was initially identified in patients who consumed large quantities of milk rich in calcium for the treatment of peptic ulcer disease. Today, with the introduction of newer drugs against this disease, and because of the fact that virtually all cases occur in patients who ingest calcium from sources other than milk, the name of the disease is proposed to change to calcium-alkali syndrome [2]. The most common cause of this syndrome is consumption of calcium carbonate as prophylaxis for osteoporosis in postmenopausal women, while other causes include excessive dietary intake of calcium and heavy consumption of betel nuts [3].

Epidemiology

The exact prevalence of this syndrome is not known, but it has been established as one of the most common causes of hypercalcemia in hospitalized patients. Some studies report that in 9-12% of patients, hypercalcemia is caused by milk-alkali syndrome. It is the third most common cause of increased serum calcium levels, after hyperparathyroidism and malignancy [4].

Several patient groups have been identified to have an increased risk of developing this syndrome, including transplant recipients, bulimic patients, those using calcium-based antacids, and patients with preexisting kidney disease, including those who require hemodialysis [5]. This syndrome has also been described in pregnancy [6]. Gender predilection is slightly towards women, because the most significant predisposing factors are related to gender, while ethnic predilection has not been established. Age is also an important factor in the development of this syndrome, as the elderly are not able to maintain serum calcium levels within physiological limits due to the gradual decline in kidney function, but also because of reduced bone mineralization and subsequent release of calcium into the circulation.

Sex distribution
Age distribution

Pathophysiology

The homeostasis of serum calcium is controlled by a tightly regulated system comprising of numerous hormones and metabolically active substances [7]. Under physiological conditions, dietary calcium is absorbed through the intestine. Necessary amounts are utilized and deposited in the bone, while excessive amounts are excreted by the kidneys or through feces and minimal concentrations are lost through the skin. These processes are principally mediated by PTH, vitamin D, and phosphorus [8]. In the case of milk-alkali syndrome, excessive amounts of ingested and absorbed calcium cannot be excreted rapidly enough, resulting in increased serum levels of calcium. Hypercalcemia exerts several effects on the kidneys, such as reduction of the GFR, which impairs calcium excretion and thus contributes to further elevation of serum calcium. Simultaneously, metabolic alkalosis, which can occur as a result of vomiting and other causes of volume depletion, further contributes to hypercalcemia, as it increases the rate of renal calcium absorption. Metabolic alkalosis can occur due to hypercalcemia open link itself since calcium exerts natriuretic effects and promotes diuresis. Moreover, increased levels of calcium suppress PTH, which can cause increased bicarbonate retention by the kidneys. This illustrates that once hypercalcemia develops, a vicious cycle is set in motion with further elevation of calcium leading to various symptoms.

Prevention

Because this syndrome is caused by excessive intake of calcium, prevention can be achieved with regular monitoring of serum calcium levels. Patients who require supplementation, such as postmenopausal women, or elderly receiving vitamin D supplementation, should monitor their levels of calcium and adjust the dosages to prevent the development of milk-alkali syndrome. Dietary intake should be adequately reduced, depending on the age. In adults, restriction of calcium to < 1.5 grams per day is sufficient for preventing this syndrome.

Summary

Milk-alkali syndrome was initially described in the early 20th century in patients who were treated for peptic ulcer disease with milk and alkali, with the idea of increasing gastric pH [1]. Since the description of this syndrome, the epidemiology, and prevalence rates have substantially changed. Today, the most common cause of milk-alkali syndrome is the excessive intake of calcium and vitamin D supplements. It is primarily observed in postmenopausal women who take calcium supplements for the prevention of osteoporosis. The pathogenesis of this syndrome is due to the excess intake of calcium. This exceeds the excretory capacity of the kidneys resulting in hypercalcemia. From this point, a vicious cycle is triggered, as hypercalcemia reduces glomerular filtration rate (GFR) which in turn reduces the ability of the kidneys to excrete serum calcium. This is the reason why preexisting kidney disease is one of the greatest risk factors for the development of this syndrome. In addition, alkalosis following vomiting with volume depletion and excessive concentrations of bicarbonate, further decreases the capacity of the kidneys to excrete serum calcium. Age is also a significant factor in the development of this syndrome, as is the activity of parathyroid hormone (PTH), vitamin D, phosphorus, and other parts of the calcium homeostasis pathway. Clinical presentation of patients with milk-alkali syndrome can slightly vary. It depends on the duration of excessive ingestion of calcium. Common symptoms include nausea, vomiting, weakness, dizziness, and behavior disturbances. Patients with more severe hypercalcemia may present with polydipsia, polyuria, conjunctivitis, muscle aches and pruritus. The diagnosis can be made by lab tests like serum electrolytes and pH. Patient history is vital in determining the potential cause and amount of daily calcium intake. Milk-alkali syndrome is one of the most common causes of hypercalcemia in patients who are admitted to the hospital, which is why this syndrome should be suspected whenever elevated serum calcium levels are observed. Treatment comprises removal of dietary or pharmacologic sources of calcium together with supportive therapy, since chronic intoxication may lead to permanent and irreversible kidney injury. However, the symptoms of this syndrome are reversed quickly in the majority of cases, illustrating the fact that an early diagnosis can lead to complete recovery without any consequences for the patient.

Patient Information

Milk-alkali syndrome is a disease which occurs as a result of very high calcium levels in the body, most commonly due to very high supplementary or dietary intake of calcium. Together with increased calcium levels and blood pH, kidney injury is one of the main features in these patients. The most common cause of this syndrome is calcium supplementation for prophylaxis against osteoporosis in postmenopausal women. Risk factors include older age, the presence of renal disease and immunosuppressive therapy. Under normal circumstances, the body is able to maintain normal levels of calcium due to the action of several hormones and organs including the skeletal system, the kidneys, and the parathyroid glands. When calcium is absorbed from the bowels, it reaches the circulation and is either used, stored in the bones, or excreted through the kidneys. However, when excessive amounts of calcium are ingested, higher concentrations are present in the blood that are unable to be stored or excreted at the necessary rate. Consequently, increased calcium levels directly impair kidney function and suppress various regulatory hormones, and contribute to the development of increased pH. All of these changes lead to symptoms such as nausea, vomiting, anorexia, headaches, dizziness, and sometimes alterations in mental status. Frequent urination, arrhythmias, and fatigue are also commonly reported. The diagnosis of milk-alkali syndrome should include blood tests to confirm high levels of calcium, bicarbonate, and low levels of phosphorus, parathyroid hormone, as well as impaired kidney function. Patient history may reveal the use of calcium-based drugs, or changes in dietary habits that led to increased daily calcium intake. Treatment is based on removing the source of excessive calcium, and supportive measures to prevent kidney damage. Since a significant number of patients may develop permanent kidney injury, regular monitoring of serum calcium levels should be conducted, especially in patients who require calcium or vitamin D-based drugs.

References

Article

  1. Sippy BW. Gastric and duodenal ulcer: medical cure by an efficient removal of gastric juice corrosion. JAMA 1915;64:1625-1630.
  2. Patel AM, Goldfarb S. Got calcium? Welcome to the calcium-alkali syndrome. J Am Soc Nephrol. 2010;21(9):1440-3.
  3. Wu KD, Chuang RB, Wu FL,et al. The milk-alkali syndrome caused by betelnuts in oyster shell paste. J Toxicol Clin Toxicol. 1996;34(6):741-5.
  4. Kleinig TJ, Torpy DJ. Milk-Alkali syndrome: broadening the spectrum of causes to allow early recognition. Intern Med J. 2004;34(6):366-7.
  5. Patel AM, Adeseun GA, Goldfarb S. Calcium-alkali syndrome in the modern era. Nutrients. 2013;5(12):4880-93.
  6. Ennen CS, Magann EF. Milk-alkali syndrome presenting as acute renal insufficiency during pregnancy. Obstet Gynecol. 2006;108(3, pt 2):785-786.
  7. Felsenfeld AJ, Levine BS. Milk alkali syndrome and the dynamics of calcium homeostasis. Clin J Am Soc Nephrol. 2006;1(4):641-654.
  8. Dorsch TR. The milk-alkali syndrome, vitamin D, and parathyroid hormone. Ann Intern Med. 1986;105:800. 
  9. Punsar S, Somer T. The milk-alkali syndrome. A report of three illustrative cases and a review of the literature. Acta Med Scand. 1963;173:435-49.
  10. Medarov BI. Milk-alkali syndrome. Mayo Clin Proc. 2009;84(3):261-7. 
  11. Beall DP, Scofield RH. Milk-alkali syndrome associated with calcium carbonate consumption. Report of 7 patients with parathyroid hormone levels and an estimate of prevalence among patients hospitalized with hypercalcemia. Medicine (Baltimore) 1995;74:89. 
  12. Chhabra L, Spodick DH. Milk Alkali syndrome: an electrocardiographic masquerader for non-hypothermic Osborn phenomenon. Heart. 2013;99(17):1302-3.
  13.  LeGrand SB, Leskuski D, Zama I. Narrative review: furosemide for hypercalcemia: an unproven yet common practice. Ann Intern Med. 2008;149(4):259-63.
  14. Picolos MK, Lavis VR, Orlander PR. Milk-alkali syndrome is a major cause of hypercalcaemia among non-end-stage renal disease (non-ESRD) inpatients. Clin Endocrinol (Oxf). 2005;63(5):566-76.

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Last updated: 2019-07-11 21:07