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Milk-Alkali Syndrome

  • Boris I. Medarov
    Correspondence
    Individual reprints of this article are not available. Address correspondence to Boris I. Medarov, MD, Division of Pulmonary and Critical Care Medicine, Keck School of Medicine, University of Southern California, 1200 N State St, GNH-11900, Los Angeles, CA 90033
    Affiliations
    Division of Pulmonary and Critical Care Medicine, Keck School of Medicine, University of Southern California, Los Angeles
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      Milk-alkali syndrome (MAS) consists of hypercalcemia, various degrees of renal failure, and metabolic alkalosis due to ingestion of large amounts of calcium and absorbable alkali. This syndrome was first identified after medical treatment of peptic ulcer disease with milk and alkali was widely adopted at the beginning of the 20th century. With the introduction of histamine2 blockers and proton pump inhibitors, the occurrence of MAS became rare; however, a resurgence of MAS has been witnessed because of the wide availability and increasing use of calcium carbonate, mostly for osteoporosis prevention. The aim of this review was to determine the incidence, pathogenesis, histologic findings, diagnosis, and clinical course of MAS. A MEDLINE search was performed with the keyword milk-alkali syndrome using the PubMed search engine. All relevant English language articles were reviewed. The exact pathomechanism of MAS remains uncertain, but a unique interplay between hypercalcemia and alkalosis in the kidneys seems to lead to a self-reinforcing cycle, resulting in the clinical picture of MAS. Treatment is supportive and involves hydration and withdrawal of the offending agents. Physicians and the public need to be aware of the potential adverse effects of ingesting excessive amounts of calcium carbonate.
      GFR (glomerular filtration rate), MAS (milk-alkali syndrome), 1,25-OH vitamin D (1,25-dihydroxyvitamin D), PTH (parathyroid hormone)
      Milk-alkali syndrome (MAS) consists of hypercalcemia, various degrees of renal failure, and metabolic alkalosis as a result of ingestion of large amounts of calcium and absorbable alkali. This syndrome was discovered in the 1930s after treatment of peptic ulcer disease with milk and sodium bicarbonate had become common.
      • Cope CL
      Base changes in the alkalosis produced by the treatment of gastric ulcer with alkalies.
      Initially considered a rare condition, MAS is now believed to be the third most common cause of in-hospital hypercalcemia, after hyperparathyroidism and malignant neoplasms.
      • 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.
      As newer treatments of peptic ulcer disease were introduced, calcium carbonate became the predominant source of calcium and alkali.
      • Beall DP
      • Henslee HB
      • Webb HR
      • Scofield RH
      Milk-alkali syndrome: a historical review and description of the modern version of the syndrome.
      Hypercalcemia can be severe. Renal failure is generally reversible, but impairment in renal function may persist in some cases.
      The aim of this review was to determine the incidence, pathogenesis, histologic findings, diagnosis, and clinical course of MAS. A MEDLINE search was performed with the keyword milk-alkali syndrome using the PubMed search engine. All relevant English language articles were reviewed.

      REPORT OF A CASE

      A 47-year-old woman was referred to the emergency department because of abnormal laboratory results. The patient had undergone routine laboratory work performed before elective neck surgery for cervical stenosis. The following abnormalities were found (reference ranges shown parenthetically): creatinine, 7.2 mg/dL (0.6-1.0 mg/dL); serum urea nitrogen, 50 mg/dL (7-18 mg/dL); total calcium, 21.1 mg/dL (7.7-10.3 mg/dL); bicarbonate, 43 mEq/L (21-32 mEq/L); phosphate, 2.6 mg/dL (2.5-4.9 mg/dL); ionized calcium, 10.04 mg/dL (4.80-5.60 mg/dL); sodium, 133 mEq/L (136-145 mEq/L); and venous serum pH, 7.52 (7.35-7.38). The patient reported recent memory impairment and profound fatigue. She was taking calcium carbonate (1000 mg) plus vitamin D (400 U) twice daily. The patient had no medical or family history of renal failure. She had a history of bulimia but claimed to be in remission. The patient was admitted to the intensive care unit, and aggressive hydration was initiated. On the basis of the laboratory findings and clinical picture, MAS was diagnosed.
      On further questioning, the patient admitted to perhaps taking more calcium than she should have. The patient was self-medicating with additional antacids (calcium carbonate [Tums, GlaxoSmithKline, Research Triangle Park, NC]) besides her twice daily calcium supplements with vitamin D because of occasional heartburn and because she believed more calcium was good for her bones.

      HISTORY

      Milk-alkali treatment of peptic ulcer disease was developed in early 1910 by Sippy,
      • Sippy BW
      Gastric and duodenal ulcer: medical cure by an efficient removal of gastric juice corrosion.
      who subsequently published his landmark article. Sippy proposed that gastric acidity was the fueling force behind chronic ulcer disease. His therapy was designed to protect the ulcer from gastric juice corrosion until the ulcer was healed. Bedrest was required for approximately 4 weeks. Every hour throughout the day, 90 mL of a mixture of milk and cream was administered orally. Halfway between feedings and every half hour after the last meal, substantial amounts of alkali (0.65-2.00 g of heavy calcined magnesia [magnesium oxide], sodium bicarbonate, and bismuth subcarbonate) were administered. Occasionally, doses of up to 6.5 g of sodium bicarbonate were given every hour. Sippy reported an excellent response to this regimen, even in cases of ulcer disease recurrent for years with resulting high-grade pyloric obstruction. Milk-alkali therapy shortly became the standard for ulcer treatment.
      In 1923, Hardt and Rivers
      • Hardt LL
      • Rivers AB
      Toxic manifestations following the alkaline treatment of peptic ulcer.
      at Mayo Clinic described the toxic adverse effects of Sippy's regimen, particularly in patients who required higher doses of alkali to control stomach acidity. Those patients would develop distaste for milk and experience headaches, irritability, dizziness, and occasionally nausea or vomiting. Three years earlier, MacCallum et al
      • MacCallum WG
      • Lintz J
      • Vermilye HN
      • Leggett TH
      • Boas E
      The effect of pyloric obstruction in relation to gastric tetany.
      induced severe alkalosis and “gastric tetany” in dogs, leading to convulsions and death by mechanical pyloric obstruction. Administering sodium chloride prolonged the animals' lives. Hardt and Rivers found that patients who showed signs of toxemia were azotemic and had high serum bicarbonate levels. Although serum pH was not measured, the authors speculated that individuals had severe alkalemia, similar to that induced in animals by MacCallum et al. Preexistent renal failure and male sex seemed to be risk factors. The symptoms almost invariably disappeared within 24 to 48 hours after discontinuation of oral alkali. Serum calcium levels were not measured.
      In 1936, Cope
      • Cope CL
      Base changes in the alkalosis produced by the treatment of gastric ulcer with alkalies.
      described several adverse effects of calcium carbonate-containing alkali therapy. He commonly found hypercalcemia, hyperphosphatemia, hypermagnesemia, azotemia, and increased bicarbonate levels in patients who had toxic symptoms. The symptoms and electrolyte abnormalities resolved with discontinuation of the antacid therapy. Renal function impairment persisted for weeks in some cases. The author expressed a strong belief that excessive calcium ingestion cannot be the sole cause of hypercalcemia: “It seems probable, therefore, that the renal impairment first occurs and that this renders the kidney unable to excrete sufficiently rapidly all the calcium, which continues to be absorbed from the gut.”
      In 1949, Burnett et al
      • Burnett CH
      • Commons RR
      • Albright F
      • Howare JE
      Hypercalcemia without hypercalciuria or hyperphosphatemia, calcinosis and renal insufficiency: syndrome following the prolonged intake of milk and alkali.
      described a “milk and alkali syndrome” in a report of 6 male patients treated with milk and absorbable alkali (usually sodium bicarbonate) for peptic ulcer disease. The common findings were hypercalcemia without hypercalciuria or hypophosphatemia, normal alkaline phosphatase level, alkalosis, renal insufficiency, corneal calcium deposits (band keratopathy), or other calcinosis (subcutaneous tissue, lung, falx cerebri, and lymph nodes). Except for renal failure, the majority of symptoms resolved shortly after discontinuation of the antacid therapy. Most of the patients developed chronic renal failure, and 4 died. The poor prognosis was strikingly different from the overall good outcome of the patients described by Cope.
      • Cope CL
      Base changes in the alkalosis produced by the treatment of gastric ulcer with alkalies.
      The authors concurred with Cope's theory that kidney damage resulted from excessive intake of calcium and alkali, which subsequently led to inability to excrete calcium and hypercalcemia.
      In 1957, Wenger et al
      • Wenger J
      • Kirsner JB
      • Palmer WL
      The milk-alkali syndrome: hypercalcemia, alkalosis and azotemia following calcium carbonate and milk therapy of peptic ulcer.
      reviewed a series of 35 patients who had evidence of MAS among 3300 hospitalized patients with ulcers during a 10-year period. Similar to the Cope report, the patients had a good prognosis and fully recovered. No patient had persistent renal failure. The authors concluded that MAS is uncommon and generally reversible.
      In 1963, Punsar and Somer
      • Punsar S
      • Somer T
      The milk alkali syndrome: a report of three illustrative cases and a review of the literature.
      reexamined all previously reported cases of MAS and, based on the chronicity of symptoms and prognosis, differentiated 2 forms: Burnett syndrome (chronic) and Cope syndrome (acute). Burnett syndrome is a chronic irreversible condition in which band keratopathy or other metastatic calcification was commonly seen. The most common symptoms in both forms were anorexia, dizziness, headache, confusion, psychosis, and dry mouth. Pruritus and pyuria were common in Burnett syndrome. Preexisting renal disease was observed in up to one-third of cases of Burnett syndrome. Hypercalcemia was present in all cases. Hyposthenuria was common. Urinary calcium excretion was generally normal. Among patients with Burnett syndrome, band keratopathy was seen in approximately 85% and nephrocalcinosis in more than 60%. The hallmark of Cope syndrome was an overall good prognosis, whereas mortality due to chronic renal failure was common in patients with Burnett syndrome. Before the widespread availability of parathyroid hormone (PTH) assays, differentiating between hyperparathyroidism and MAS was difficult and often was based on the clinical response to a diet low in calcium and absorbable alkali
      • Scholz DA
      • Keating Jr, FR
      Milk-alkali syndrome: review of 8 cases.
      • Texter Jr, EC
      • Laureta HC
      The milk-alkali syndrome.
      or on evidence of osteosclerosis.
      • Punsar S
      • Somer T
      The milk alkali syndrome: a report of three illustrative cases and a review of the literature.

      INCIDENCE

      In the first decades after the discovery of MAS, reports on the incidence in patients treated by the Sippy program varied widely, from 2% to 18%.
      • Rafsky HA
      • Schwartz L
      • Kruger AW
      The relation of alkalosis to peptic ulcer.
      • Cooke AM
      Alkalosis occurring in the alkaline treatment of peptic ulcers.
      • Kirsner JB
      • Palmer WL
      Alkalosis complicating the Sippy treatment of peptic ulcer: an analysis of one hundred and thirty-five episodes.
      • Gatewood WE
      • Gaebler OH
      • Muntwyler E
      • Myers VC
      Alkalosis in patients with peptic ulcer.
      Individual variations in the amount of ingested alkali may provide an explanation for this phenomenon.
      • Jephers H
      • Lerner HH
      The syndrome of alkalosis complicating the treatment of peptic ulcer: report of cases with review of the pathogenesis, clinical aspects and treatment.
      The mortality rate in the early days of MAS was reported to be 4.4%.
      • Cooke AM
      Alkalosis occurring in the alkaline treatment of peptic ulcers.
      In their original study, Wenger et al
      • Wenger J
      • Kirsner JB
      • Palmer WL
      The milk-alkali syndrome: hypercalcemia, alkalosis and azotemia following calcium carbonate and milk therapy of peptic ulcer.
      found that the incidence of MAS among hospitalized patients with peptic ulcer disease was approximately 1%. After the clinical introduction of nonabsorbable alkali and histamine2 blockers, the incidence of MAS decreased substantially.
      • Schuman CA
      • Jones III, HW
      The ‘milk-alkali’ syndrome: two case reports with discussion of pathogenesis.
      In the 1970s and 1980s, MAS was considered responsible for less than 1% to 2% of hypercalcemia.
      • 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.
      • Jamieson MJ
      Hypercalcaemia.
      In 2006, Beall et al
      • Beall DP
      • Henslee HB
      • Webb HR
      • Scofield RH
      Milk-alkali syndrome: a historical review and description of the modern version of the syndrome.
      described the “modern version” of MAS. During the past 20 years, a reemergence of MAS has been noted with different demographics and clinical backgrounds. Calcium carbonate is the primary source of calcium and alkali. The increased use of calcium carbonate in postmenopausal women, patients receiving long-term corticosteroid therapy, and patients with renal failure, as well as the wide availability of nonabsorbable alkali, histamine2 blockers, and proton pump inhibitors, has changed the profile of the typical patient with MAS. The male prevalence observed in the original MAS is no longer seen. Hyperphosphatemia is rare, reflecting the less prevalent consumption of large quantities of milk and dairy products and the phosphate-binding properties of calcium carbonate. Because of its resurgence, MAS is now considered the third most common cause of hypercalcemia, after hyperparathyroidism and malignant neoplasms, with a prevalence of 9% to 12% among hospitalized patients with hypercalcemia.
      • 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.
      • Picolos MK
      • Lavis VR
      • Orlander PR
      Milk-alkali syndrome is a major cause of hypercalcaemia among non-end-stage renal disease (non-ESRD) inpatients.
      Among the subset of patients with severe hypercalcemia (total calcium level >14 mg/dL), MAS is more prevalent than malignant neoplasms.
      • Picolos MK
      • Lavis VR
      • Orlander PR
      Milk-alkali syndrome is a major cause of hypercalcaemia among non-end-stage renal disease (non-ESRD) inpatients.
      Increased availability of over-the-counter calcium carbonate supplements and greater awareness of osteoporosis among medical professionals and consumers likely contribute to this trend.
      • Beall DP
      • Henslee HB
      • Webb HR
      • Scofield RH
      Milk-alkali syndrome: a historical review and description of the modern version of the syndrome.
      In a study by Kapsner et al,
      • Kapsner P
      • Langsdorf L
      • Marcus R
      • Kraemer FB
      • Hoffman AR
      Milk-alkali syndrome in patients treated with calcium carbonate after cardiac transplantation.
      more than 20% of heart transplant recipients taking calcium carbonate (8-12 g) daily for corticosteroid-induced osteoporosis prevention developed hypercalcemia. Half of the patients with hypercalcemia had alkalosis.
      An unusual form of MAS has been described in the Far East in betel nut chewers.
      • Lin SH
      • Lin YF
      • Cheema-Dhadli S
      • Davids MR
      • Halperin ML
      Hypercalcaemia and metabolic alkalosis with betel nut chewing: emphasis on its integrative pathophysiology.
      • Wu KD
      • Chuang RB
      • Wu FL
      • Hsu WA
      • Jan IS
      • Tsai KS
      The milk-alkali syndrome caused by betelnuts in oyster shell paste.
      • Norton SA
      Betel: consumption and consequences.
      The lime paste (calcium oxide and calcium hydroxide) ingested during betel nut chewing serves as a source of calcium and alkali. The incidence of MAS among betel nut chewers is unknown.
      Several cases of MAS have also been described in pregnant women.
      • Picolos MK
      • Sims CR
      • Mastrobattista JM
      • Carroll MA
      • Lavis VR
      Milk-alkali syndrome in pregnancy.
      • Ennen CS
      • Magann EF
      Milk-alkali syndrome presenting as acute renal insufficiency during pregnancy.

      PATHOGENESIS

      Despite extensive clinical experience, scant data are available on the pathogenesis of MAS. Throughout the years, several contributing factors have been proposed, including loss of gastric juice, preexisting renal disease, insufficient chloride intake, hemorrhage, anemia, impaired liver function, and warm weather.
      • Jephers H
      • Lerner HH
      The syndrome of alkalosis complicating the treatment of peptic ulcer: report of cases with review of the pathogenesis, clinical aspects and treatment.
      • Eisele CW
      Changes in acid-base balance during alkali treatment for peptic ulcer.
      • Wilkinson SA
      • Jordan SM
      Significance of alkalosis in treatment of peptic ulcer.
      • Frouin A
      L'action des chlorures de l'alimentation sur la sécrétion gastrique.
      • Bockus HL
      • Bank J
      Alkalosis and duodenal ulcer.
      • Hubble D
      Correspondence.
      • Sippe C
      Dangers of indiscriminate alkali therapy.
      Ingestion of excessive quantities of calcium and absorbable alkali is a prerequisite for establishing the diagnosis. What constitutes “excessive” is unclear but generally indicates at least 4 to 5 g of calcium carbonate daily.
      • Orwoll ES
      The milk-alkali syndrome: current concepts.
      • Newmark K
      • Nugent P
      Milk-alkali syndrome: a consequence of chronic antacid abuse.
      However, ingesting large amounts of alkali and calcium alone does not result in alkalosis and hypercalcemia, respectively. McGee et al
      • McGee LC
      • Martin Jr, JE
      • Levy F
      • Purdum RB
      The influence of alkalis on renal function.
      administered 1.3 to 2.0 g of a mixture of calcium carbonate and magnesium oxide hourly from 7 am to 9 pm for 8 days to 17 individuals with healthy kidneys. No significant changes in serum bicarbonate levels were observed. The authors speculated that hypochloremia and dehydration were key factors in the development of alkalosis.
      • Kirsner JB
      • Palmer WL
      The role of chlorides in alkalosis: following the administration of calcium carbonate.
      In the first reports of toxicity due to the Sippy program, Hardt and Rivers
      • Hardt LL
      • Rivers AB
      Toxic manifestations following the alkaline treatment of peptic ulcer.
      noted a definite correlation between the incidence of alkalosis and the presence of kidney disease. Subsequent reports confirmed that preexisting renal disease seemed to be a predisposing factor.
      • Kapsner P
      • Langsdorf L
      • Marcus R
      • Kraemer FB
      • Hoffman AR
      Milk-alkali syndrome in patients treated with calcium carbonate after cardiac transplantation.
      • Eisele CW
      Changes in acid-base balance during alkali treatment for peptic ulcer.
      • Wilkinson SA
      • Jordan SM
      Significance of alkalosis in treatment of peptic ulcer.
      • French JK
      • Holdaway IM
      • Williams LC
      Milk alkali syndrome following over-the-counter antacid self-medication.
      However, it is widely recognized that MAS can develop without renal impairment.
      • Wildman HA
      Chloride metabolism and alkalosis in the alkali treatment of peptic ulcer.
      Furthermore, even in patients with impaired renal function, large amounts of absorbable alkali do not lead to alkalosis in most individuals.
      • Kirsner JB
      • Palmer WL
      Alkalosis complicating the Sippy treatment of peptic ulcer: an analysis of one hundred and thirty-five episodes.
      • Jordan SM
      Calcium, chloride and carbon dioxide content of venous blood in cases of gastroduodenal ulcer treated with alkalis.
      • Oakley WM
      Alkalosis arising in the treatment of peptic ulcer.
      Some authors found no preexisting kidney disease in most of their patients with MAS.
      • Cope CL
      Base changes in the alkalosis produced by the treatment of gastric ulcer with alkalies.
      • Gatewood WE
      • Gaebler OH
      • Muntwyler E
      • Myers VC
      Alkalosis in patients with peptic ulcer.
      Underlying renal disease does not seem to be a prerequisite but rather a contributing factor in the pathogenesis of MAS.
      For hypercalcemia to develop, calcium intake must be excessive, but inability to excrete the excess calcium is also an essential part of the process. Because the skeletal system does not have unlimited calcium buffer capacity, tight regulation of calcium absorption from the small intestine and excretion by the kidneys are paramount to maintain serum calcium levels. Individual variations in the buffering capacity of bone may also have a role in the susceptibility to development of hypercalcemia.
      • Felsenfeld AJ
      • Levine BS
      Milk alkali syndrome and the dynamics of calcium homeostasis.
      The role of vitamin D and PTH in MAS is unclear. Limited data suggest that 1,25-dihydroxyvitamin D (1,25-OH vitamin D; also known as calcitriol) and PTH levels are suppressed in MAS.
      • Picolos MK
      • Lavis VR
      • Orlander PR
      Milk-alkali syndrome is a major cause of hypercalcaemia among non-end-stage renal disease (non-ESRD) inpatients.
      • Dorsch TR
      The milk-alkali syndrome, vitamin D, and parathyroid hormone [letter].
      • Spital A
      • Freedman Z
      Severe hypercalcemia in a woman with renal failure.
      • Abreo K
      • Adlakha A
      • Kilpatrick S
      • Flanagan R
      • Webb R
      • Shakamuri S
      The milk-alkali syndrome: a reversible form of acute renal failure.
      However, the extent of suppression varies, and calcitriol levels may remain well within the reference range.
      • Adams ND
      • Gray RW
      • Lemann Jr, J
      The effects of oral CaCO3 loading and dietary calcium deprivation on plasma 1,25-dihydroxyvitamin D concentrations in healthy adults.
      Increased intake of calcium results in decreased 25-hydroxylation of vitamin D by the kidneys, which leads to a marked decrease of fractional calcium absorption in the small intestine. Besides this active regulated mechanism, nonsaturable passive diffusion occurs. Individual variability of calcium absorption varies widely. In certain individuals, high urinary calcium excretion indicative of high intestinal absorption persists despite continuous calcium ingestion and suppressed 1,25-OH vitamin D levels.
      • Adams ND
      • Gray RW
      • Lemann Jr, J
      The effects of oral CaCO3 loading and dietary calcium deprivation on plasma 1,25-dihydroxyvitamin D concentrations in healthy adults.
      • Vincent PC
      • Radcliff FJ
      The effect of large doses of calcium carbonate on serum and urinary calcium.
      Under normal conditions, renal calcium excretion is a close reflection of calcium absorption.
      • Schuman CA
      • Jones III, HW
      The ‘milk-alkali’ syndrome: two case reports with discussion of pathogenesis.
      • Sutton RAL
      • Diks JH
      Renal handling of calcium, phosphate, and magnesium.
      These “hyperabsorbers” readily excrete the excess calcium as long as their excretory capability is unaffected. However, if large quantities of calcium are continuously ingested and the renal excretory capacity is blocked, hypercalcemia may be a predictable result.
      • Orwoll ES
      The milk-alkali syndrome: current concepts.
      Failure to fully suppress calcitriol levels may contribute to development of MAS in a subset of individuals with high oral calcium intake.
      • Felsenfeld AJ
      • Levine BS
      Milk alkali syndrome and the dynamics of calcium homeostasis.
      The inability of some individuals to properly suppress 1,25-OH vitamin D levels, despite high calcium intake and absorption from the gut, has been well documented.
      • Broadus AE
      • Insogna KL
      • Lang R
      • Ellison AF
      • Dreyer BE
      Evidence for disordered control of 1,25-dihydroxyvitamin D production in absorptive hypercalciuria.
      Although controversial (as previously discussed), preexistent renal insufficiency has been implicated in the pathogenesis of MAS. Medications that interfere with calcium excretion have also been considered risk factors. Thiazides decrease calcium excretion by inhibiting the thiazide-sensitive sodium chloride cotransporter and promote intravascular depletion and alkalemia.
      • Nijenhuis T
      • Vallon V
      • van der Kemp AW
      • Loffing J
      • Hoedenerop JG
      • Bindels RJ
      Enhanced passive Ca2+ reabsorption and reduced Mg2+ channel abundance explains thiazide-induced hypocalciuria and hypomagnesemia.
      • Greger R
      New insights into the molecular mechanism of the action of diuretics [editorial].
      • Sebastian A
      Thiazides and bone [editorial].
      It is well recognized that alkalosis decreases calcium excretion by increasing its tubular reabsorption.
      • Sutton RA
      • Wong NL
      • Dirks JH
      Effects of metabolic acidosis and alkalosis on sodium and calcium transport in the dog kidney.
      • Peraino RA
      • Suki WN
      Urine HCO3 augments renal Ca2+ absorption independent of systemic acid-base changes.
      The mechanism seems to be PTH independent.
      • Sutton RA
      • Wong NL
      • Dirks JH
      Effects of metabolic acidosis and alkalosis on sodium and calcium transport in the dog kidney.
      However, hypercalcemia impairs the kidneys' ability to excrete excess bicarbonate, possibly closing a vicious cycle that in susceptible individuals may lead to severe hypercalcemia and renal failure. The increased serum calcium level causes afferent arteriole constriction and reduction in the glomerular filtration rate (GFR).
      • Benabe JE
      • Martinez-Maldonado M
      Hypercalcemic nephropathy.
      • Humes HD
      • Ichikawa I
      • Troy JL
      • Brenner BM
      Evidence for a parathyroid hormone-dependent influence of calcium on the glomerular ultrafiltration coefficient.
      Also, hypercalcemia has a well-known natriuretic and diuretic effect, presumably by activating the calcium-sensing receptor, and leads to intravascular depletion.
      • Brown EM
      Physiology and pathophysiology of the extracellular calcium sensing receptor.
      • Beck N
      • Singh H
      • Reed SW
      • Murdaugh HV
      • Davis BB
      Pathogenic role of cyclic AMP in the impairment of urinary concentrating ability in acute hypercalcemia.
      Aspiration of gastric content to control acidity in the original Sippy regimen can further exacerbate intravascular depletion, as does hypercalcemia-induced renal hyposthenuria.
      • Beck N
      • Singh H
      • Reed SW
      • Murdaugh HV
      • Davis BB
      Pathogenic role of cyclic AMP in the impairment of urinary concentrating ability in acute hypercalcemia.
      • Zeffren JL
      • Heineman HO
      Reversible defect in renal concentrating mechanism in patients with hypercalcemia.
      The resulting GFR reduction further limits excretion of bicarbonate and calcium. The increasing serum calcium level propagates the toxic effects of calcium on the kidneys. Long-term exposure to high calcium levels can result in nephrocalcinosis, tubular necrosis, and other structural changes.
      • Ganote CE
      • Philipsborn DS
      • Chen E
      • Carone FA
      Acute calcium nephrotoxicity: an electron microscopical and semiquantitative light microscopical study.
      An alkalotic environment is known to facilitate calcium precipitation.
      • Punsar S
      • Somer T
      The milk alkali syndrome: a report of three illustrative cases and a review of the literature.
      • Parfitt AM
      Soft-tissue calcification in uremia.
      Aging results in a decreased capacity to handle excess calcium, probably because of decreased renal function and down-regulation of the calcium-sensing receptor in chronic renal disease, and may predispose patients to developing hypercalcemia.
      • Felsenfeld AJ
      • Levine BS
      Milk alkali syndrome and the dynamics of calcium homeostasis.
      • Mathias RS
      • Nguyen HT
      • Zhang MY
      • Portale AA
      Reduced expression of the renal calcium-sensing receptor in rats with experimental chronic renal insufficiency.
      Hypokalemia due to gastric suctioning and vomiting may have an additional renal deleterious effect. The combination of calcium and absorbable alkali seems to be necessary for the development of MAS. Absorbable alkali alone does not produce alkalosis. Even large administered amounts of sodium bicarbonate are readily excreted by the kidneys without persistent alkalemia. This has been well documented in humans and animals.
      • van Goidsenhoven GM
      • Gray OV
      • Price AV
      • Sanderson PH
      The effect of prolonged administration of large doses of sodium bicarbonate in man.
      • Sanderson PH
      Renal response to massive alkali loading in the human subject.
      • Seldin DW
      • Rector Jr, FC
      The generation and maintenance of metabolic alkalosis.
      The PTH level should be depressed by the high serum calcium level in patients with MAS. However, data are limited. Occasional reports showed inappropriately elevated PTH levels.
      • Newmark K
      • Nugent P
      Milk-alkali syndrome: a consequence of chronic antacid abuse.
      • Carroll PR
      • Clark OH
      Milk alkali syndrome: does it exist and can it be differentiated from primary hyperparathyroidism?.
      In at least some of those cases, use of C-terminal assays to measure PTH levels in the setting of renal failure could explain the high levels. Decreasing serum calcium levels have been contemplated as the cause of high PTH levels even if the patient is still hypercalcemic.
      • Carroll PR
      • Clark OH
      Milk alkali syndrome: does it exist and can it be differentiated from primary hyperparathyroidism?.
      Data to support this theory are lacking, but a similar phenomenon has been observed in hypercalcemia seen in the polyuric phase of rhabdomyolysis.
      • Llach F
      • Felsenfeld AJ
      • Haussler MR
      The pathophysiology of altered calcium metabolism in rhabdomyolysis-induced acute renal failure: interactions of parathyroid hormone, 25-hydroxycholecaciferol, and 1,25-dihydroxycholecalciferol.
      Intact PTH measurements generally reveal appropriately suppressed hormone levels,
      • 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.
      but available data are scant. The low serum PTH level further contributes to alkalemia by increasing urinary resorption of bicarbonate.
      • Muldowney FP
      • Carroll DV
      • Donohoe JF
      • Freaney R
      Correction of renal bicarbonate wastage by parathyroidectomy: implications in acid-base homeostasis.
      • Nordin BE
      The effect of intravenous parathyroid extract on urinary pH, bicarbonate and electrolyte excretion.
      Temporary hypocalcemia is not unusual after treatment of MAS and likely reflects a suppressed PTH level.
      • 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.

      HISTOLOGIC FINDINGS

      The available data on pathologic changes in the kidneys determined by biopsy and autopsy are limited. Burnett et al
      • Burnett CH
      • Commons RR
      • Albright F
      • Howare JE
      Hypercalcemia without hypercalciuria or hyperphosphatemia, calcinosis and renal insufficiency: syndrome following the prolonged intake of milk and alkali.
      described nephrocalcinosis during the single autopsy performed in their series. Other autopsy reports described partial to complete glomerulus hyalinization, thickening of the Bowman capsule, tubular atrophy, vascular changes, and diffuse lymphocytic infiltration.
      • Wermer P
      • Kuschner M
      • Riley EA
      Reversible metastatic calcification associated with excessive milk and alkali intake.
      • Holten C
      • Lundbaek K
      Renal insufficiency and severe calcinosis due to excessive alkali intake.
      • Dufault Jr, FX
      • Tobias GJ
      Potentially reversible renal failure following excessive calcium and alkali intake in peptic ulcer therapy.
      Extensive calcification of convoluted renal tubular cells and the tubular lamina was described as a striking feature.
      • Wermer P
      • Kuschner M
      • Riley EA
      Reversible metastatic calcification associated with excessive milk and alkali intake.
      Scholz and Keating
      • Scholz DA
      • Keating Jr, FR
      Milk-alkali syndrome: review of 8 cases.
      reported a case of focal calcification in the renal tubules that was apparent on a kidney biopsy specimen from a patient with MAS. Randall et al
      • Randall Jr, RE
      • Strauss MB
      • McNeely WF
      The milk-alkali syndrome.
      reported findings on kidney biopsy specimens from 2 patients. Tubular epithelium degeneration and granular (presumably calcium laden) material in and around the collecting tubules, as well as hyalinization of several glomeruli and thickening of the basement membrane, were described. In 1976, Junor and Catto
      • Junor BJ
      • Catto GR
      Renal biopsy in the milk-alkali syndrome.
      reported a series of 3 cases in which kidney biopsy specimens showed focal calcium deposition within and adjacent to the renal tubules (Figure 1). Some correlation was found between the amount of calcium deposition and renal outcome. The 2 patients with persistent renal impairment had more prominent calcium deposition, as well as interstitial fibrosis, areas of inflammatory changes, and periglomerular fibrosis. The authors concluded that prognosis depends on the severity of the histologic changes apparent on the biopsy specimens and noted that calcium deposition in the kidneys is not usually seen radiographically.
      Figure thumbnail gr1
      FIGUREKidney biopsy specimen from patient with milk-alkali syndrome (Von Kassa stain, original magnification ×150). Calcium deposits are stained black by silver nitrate. Adapted from J Clin Pathol,
      • Junor BJ
      • Catto GR
      Renal biopsy in the milk-alkali syndrome.
      with permission from BMJ Publishing Group Ltd.

      DIAGNOSIS AND CLINICAL COURSE

      The diagnosis of MAS requires a history of excessive calcium and absorbable alkali ingestion and findings of hypercalcemia, metabolic alkalosis, and variable degrees of renal impairment. The symptoms may develop within several days to several weeks and months after the start of therapy with absorbable alkali and calcium. Three forms of MAS have been described: acute, subacute (Cope syndrome), and chronic (Burnett syndrome).
      • Punsar S
      • Somer T
      The milk alkali syndrome: a report of three illustrative cases and a review of the literature.
      Because overlap among the 3 forms is substantial, they should be considered a continuum. The first symptoms may occur within a few days. Nausea, vomiting, anorexia, distaste for milk, headache, dizziness, vertigo, apathy, and confusion are early signs of toxemia.
      • Orwoll ES
      The milk-alkali syndrome: current concepts.
      Muscle aches, psychosis, tremor, polyuria, polydipsia, pruritus, and abnormal calcifications are typical of the chronic phase.
      • Burnett CH
      • Commons RR
      • Albright F
      • Howare JE
      Hypercalcemia without hypercalciuria or hyperphosphatemia, calcinosis and renal insufficiency: syndrome following the prolonged intake of milk and alkali.
      • Texter Jr, EC
      • Laureta HC
      The milk-alkali syndrome.
      Ocular calcification is a classic physical sign that consists of keratopathy and calcium deposits in the conjunctiva. Keratopathy can be mistaken for arcus senilis.
      • Punsar S
      • Somer T
      The milk alkali syndrome: a report of three illustrative cases and a review of the literature.
      On closer inspection, individual minute corneal calcifications can generally be distinguished.
      • Dufault Jr, FX
      • Tobias GJ
      Potentially reversible renal failure following excessive calcium and alkali intake in peptic ulcer therapy.
      The nasal and temporal areas of the circle contain the greatest concentration of calcium.
      • Dufault Jr, FX
      • Tobias GJ
      Potentially reversible renal failure following excessive calcium and alkali intake in peptic ulcer therapy.
      Renal calcinosis is not uncommon (see “Histologic Findings” section). Other less common sites of metastatic calcification have been described, including periarticular tissue,
      • Randall Jr, RE
      • Strauss MB
      • McNeely WF
      The milk-alkali syndrome.
      subcutaneous tissue,
      • Snapper I
      • Bradley WG
      • Wilson VE
      Metastatic calcification and nephrocalcinosis from medical treatment of peptic ulcer.
      central nervous system,
      • Dufault Jr, FX
      • Tobias GJ
      Potentially reversible renal failure following excessive calcium and alkali intake in peptic ulcer therapy.
      liver,
      • Kyle LH
      Differentiation of hyperparathyroidism and the milk-alkali (Burnett) syndrome.
      adrenal,
      • Kyle LH
      Differentiation of hyperparathyroidism and the milk-alkali (Burnett) syndrome.
      bone,
      • Punsar S
      • Somer T
      The milk alkali syndrome: a report of three illustrative cases and a review of the literature.
      and lungs.
      • Dufault Jr, FX
      • Tobias GJ
      Potentially reversible renal failure following excessive calcium and alkali intake in peptic ulcer therapy.
      A case was described in 1993 in which discovery of bilateral breast calcifications in a patient led to the diagnosis of MAS.
      • Abreo K
      • Adlakha A
      • Kilpatrick S
      • Flanagan R
      • Webb R
      • Shakamuri S
      The milk-alkali syndrome: a reversible form of acute renal failure.
      Withdrawal of the offending agents generally leads to quick resolution of the symptoms, except for renal failure, which invariably improves but does not always resolve completely.
      • Burnett CH
      • Commons RR
      • Albright F
      • Howare JE
      Hypercalcemia without hypercalciuria or hyperphosphatemia, calcinosis and renal insufficiency: syndrome following the prolonged intake of milk and alkali.
      Keratopathy and conjunctival calcium deposits can be reversible.
      • Punsar S
      • Somer T
      The milk alkali syndrome: a report of three illustrative cases and a review of the literature.
      • Wenger J
      • Kirsner JB
      • Palmer WL
      The milk-alkali syndrome: hypercalcemia, alkalosis and temporary renal insufficiency during milk-antacid therapy for peptic ulcer.
      Hypercalcemia is always present and may be severe. The combination of an elevated serum bicarbonate level and alkalotic pH in the setting of renal failure always places MAS high on the differential diagnosis. A low to normal phosphate level is usually seen in the modern form of MAS as opposed to hyperphosphatemia, which was the norm in the classic syndrome. Levels of 1,25-OH vitamin D and intact PTH are generally suppressed. In less typical cases of MAS, the PTH level may need to be measured to exclude primary hyperparathyroidism. Conversely, misdiagnosing MAS as primary hyperparathyroidism was common in the past and likely still happens today. In a study by Beall and Scofield,
      • 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.
      approximately 10% of patients with MAS underwent unnecessary parathyroid exploration. Obtaining accurate medication and diet histories is paramount to establishing the correct diagnosis. Unusual sources of calcium, such as cheese, have been reported occasionally, especially in patients with pica or bulimia.
      • Kallner G
      • Karlsson H
      Recurrent factitious hypercalcemia.
      Evidence of resorptive bone disease and renal stones, as well as failure to respond to withdrawal of calcium and alkali, strongly suggests hyperparathyroidism or some other etiology.
      • Orwoll ES
      The milk-alkali syndrome: current concepts.
      However, hypercalcemia in advanced cases of MAS may be slow to resolve. As previously mentioned, PTH levels have been occasionally elevated in patients with MAS, and coexistence of hyperparathyroidism and MAS may need to be considered.
      Supportive therapy and hydration after withdrawal of the offending agent are generally sufficient treatment in most cases. Recovery from the acute form usually occurs within 1 or 2 days. With the chronic form, symptomatic improvement is a slower process. In refractory cases, hemodialysis may occasionally be necessary. Furosemide may be used to enhance calciuresis. Administering bisphosphonates to patients with MAS has been reported,
      • Picolos MK
      • Lavis VR
      • Orlander PR
      Milk-alkali syndrome is a major cause of hypercalcaemia among non-end-stage renal disease (non-ESRD) inpatients.
      but no data are available to support the theory that bisphosphonates alter outcome. Hypercalcemia generally resolves within several days, although some evidence suggests that serum calcium levels can be elevated up to 6 months.
      • Carroll PR
      • Clark OH
      Milk alkali syndrome: does it exist and can it be differentiated from primary hyperparathyroidism?.
      Temporary hypocalcemia, which can be severe and symptomatic, is not unusual and may require replacement therapy.
      • 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.
      Slow recovery of the serum PTH level is likely responsible for this phenomenon. In some cases, the PTH level has been noted to increase by more than 1 order of magnitude as the serum calcium level decreases below physiologic levels.

      CONCLUSION

      The resurgence of MAS in the current era is a result of increased osteoporosis awareness and routine use of calcium supplements for prevention. The public needs to be educated about calcium supplementation and the potential adverse effects if the recommended dosage is exceeded. Daily elemental calcium intake of no more than 2 g is considered safe.
      • 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.
      • Whiting SJ
      • Wood R
      • Kim K
      Calcium supplementation.
      However, even doses lower than 2 g daily may result in MAS if additional predisposing factors are present. Muldowney and Mazbar
      • Muldowney WP
      • Mazbar SA
      Rolaids-yogurt syndrome: a 1990s version of milk-alkali syndrome.
      described a patient with bulimia who developed MAS by taking about 1.7 g of calcium daily. Reducing daily calcium intake or close monitoring may be prudent in patients taking thiazides,
      • Gora ML
      • Seth SK
      • Bay WK
      • Visconti JA
      Milk-alkali syndrome associated with use of chlorothiazide and calcium carbonate.
      • Jenkins JK
      • Best TR
      • Nicks SA
      • Murphy FY
      • Bussell KL
      • Vesely DL
      Milk-alkali syndrome with a serum calcium level of 22 mg/dL and J waves on the ECG.
      patients who have preexisting renal failure, or those who experience concurrent vomiting (bulimia or hyperemesis of pregnancy).
      • Kallner G
      • Karlsson H
      Recurrent factitious hypercalcemia.
      • Muldowney WP
      • Mazbar SA
      Rolaids-yogurt syndrome: a 1990s version of milk-alkali syndrome.
      • Ullian ME
      • Linas SL
      The milk-alkali syndrome in pregnancy: case report.
      • Gordon MV
      • McMahon LP
      • Hamblin PS
      Life-threatening milk-alkali syndrome resulting from antacid ingestion during pregnancy.
      Patients with bulimia seem to be particularly vulnerable because of the frequent combination of vomiting, diuretic use, and deviant eating habits.
      • Kallner G
      • Karlsson H
      Recurrent factitious hypercalcemia.
      • Muldowney WP
      • Mazbar SA
      Rolaids-yogurt syndrome: a 1990s version of milk-alkali syndrome.
      In these susceptible patient groups, supplementing calcium in a form that contains no absorbable alkali is probably a safer choice.
      • 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.
      The exact pathomechanism of MAS remains uncertain, but a unique interplay between hypercalcemia and alkalosis in the kidneys seems to lead to a self-reinforcing cycle, resulting in the clinical picture of MAS. Treatment is supportive and involves hydration and withdrawal of the offending agents. Physicians and the public need to be aware of the potential adverse effects of ingesting excessive amounts of calcium carbonate.

      CASE OUTCOME

      Our patient's hypercalcemia resolved within 72 hours. Transiently, she had mild hypocalcemia, with a total calcium level of 6.9 mg/dL. As expected, her intact PTH level was suppressed at 10 pg/mL (reference range, 10-65 pg/mL). Her 25-OH cholecalciferol level was normal at 44 ng/mL (reference range, 20-100 ng/mL), and her 25-OH ergocalciferol level was undetectable, ruling out vitamin D toxic effects. After 1 week, the patient's creatinine level stabilized at 1.4 mg/dL and remained in that range at follow-up a few weeks later. The estimated GFR was 47 mL/min, consistent with persistent mild renal insufficiency. The patient was counseled on the nature of her condition, and she was advised to avoid taking excessive amounts of calcium. In the following months her serum creatinine normalized, and she remained asymptomatic.

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