Milk-alkali syndrome pathophysiology: Difference between revisions

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__NOTOC__
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{{Milk-alkali syndrome}}
{{Milk-alkali syndrome}}
{{CMG}}
{{CMG}} {{AE}} {{SHA}}
==Overview==
==Overview==
==Pathophysiology==
The exact [[pathogenesis]] of milk-alkali syndrome is unknown. Hypercalcemia in milk-alkali syndrome involves several mechanisms including: [[Intestine|intestinal]] absorption of [[calcium]] is increased, [[bone]] buffering of [[calcium]] becomes saturated, and [[Kidney|renal]] excretion of [[calcium]] is decreased. Several factors that increase [[bicarbonate]] [[reabsorption]] and contribute to the [[alkalosis]] in milk-alkali syndrome include: [[Hypovolemia|volume depletion]] due to increased [[sodium]] and free water [[excretion]] caused by increased [[calcium]] intake, suppression of [[Parathyroid hormone|PTH]], direct [[Nephron|tubular]] effects of [[calcium]] and other factors that cause [[Hypovolemia|volume depletion]] or [[alkalosis]] such as [[Nausea and vomiting|vomiting]] or [[thiazide]] use.
*<s>The name "milk-alkali syndrome" derives from when patients would take in excessive amounts of milk and antacids to control their dyspepsia, leading to over ingestion of two key ingredients that lead to the disorder, excess calcium and excess base.</s>
*<s>Ingesting over two grams of elemental [[calcium]] per day produces this disorder in susceptible individuals. [[Gastrointestinal tract|Gastrointestinal]] absorption of such a large amount of calcium leads to [[hypercalcemia]].</s>
* This inhibits [[parathyroid hormone]] secretion by the [[parathyroid gland]] and may also lead to [[diabetes insipidus]].
* The body's attempt to rid itself of the excess base in the urine may cause bicarbonaturia and subsequent hypovolemia due to transport of sodium ions to accompany the bicarbonate.
* Hypovolemia may increase the reabsorption of calcium and [[bicarbonate]] in the [[proximal convoluted tubule]]s of the kidney. Elevated bicarbonate levels in the blood raises the [[pH]], producing an alkalemia.
*<s>In this state, excess bicarbonate eventually begins to reach the [[distal convoluted tubule]], leading to sodium retention in the lumen, an effect similar to the action of [[thiazide]] diuretics, hence increasing lumen positivity and driving calcium through the passive calcium channels to bind intracellular [[calbindin]].</s>
* Finally, because of the decreased intracellular sodium, there is an increased driving force for the basolateral Na+/Ca++ antiporter, thus facilitating calcium reabsorption.  Basically, hypovolemia is the culprit that prevents correction of the hypercalcemia.
*<s>Hypercalcemia causes the following effects in the kidney : Vasoconstriction which decreases the glomerular filtration rate ,Activation of calcium–sensing receptor in the medullary thick ascending limb which inhibits the Na-K-2Cl cotransporter causing natriuresis.</s>
*<s>The understanding of this mechanism led to the development of a simple yet elegant treatment for hypercalcemia. The first and most important step is [[Route of administration#Parenteral by injection or infusion|intravenous infusion]] of [[Saline (medicine)|normal saline]] to restore the intravascular volume, which reverses the calcium and bicarbonate retention in the PCT. Then a [[loop diuretic]] is used, but only after the volume replacement is complete, otherwise volume contraction would result, which would further exacerbate the hypercalcemia. The loop diuretics inhibit the [[Na-K-2Cl symporter]] and hence eliminate passive diffusion of potassium into the lumen via the [[ROMK]] channel. This effectively removes the net positive charge from the lumen, one of the main driving forces for calcium reabsorption via the paracellular pathway. In addition, loop diuretics increase the flow of luminal contents, which helps flush the calcium to the distal nephron.<ref name="pmid16268810">{{cite journal |vauthors=Picolos MK, Lavis VR, Orlander PR |title=Milk-alkali syndrome is a major cause of hypercalcaemia among non-end-stage renal disease (non-ESRD) inpatients |journal=Clin. Endocrinol. (Oxf) |volume=63 |issue=5 |pages=566–76 |date=November 2005 |pmid=16268810 |doi=10.1111/j.1365-2265.2005.02383.x |url=}}</ref></s>
 
 
== Overview ==


== Pathophysiology ==
== Pathophysiology ==


* The exact pathogenesis of milk-alkali syndrome is unknown.
* The exact [[pathogenesis]] of milk-alkali syndrome is unknown.
* Consumption of excessive amounts of calcium and absorbable alkali causes milk-alkali syndrome.<ref name="pmid19252114">{{cite journal| author=Medarov BI| title=Milk-alkali syndrome. | journal=Mayo Clin Proc | year= 2009 | volume= 84 | issue= 3 | pages= 261-7 | pmid=19252114 | doi=10.1016/S0025-6196(11)61144-0 | pmc=2664604 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19252114  }} </ref>
* Consumption of excessive amounts of [[calcium]] and absorbable alkali causes milk-alkali syndrome.<ref name="pmid19252114">{{cite journal| author=Medarov BI| title=Milk-alkali syndrome. | journal=Mayo Clin Proc | year= 2009 | volume= 84 | issue= 3 | pages= 261-7 | pmid=19252114 | doi=10.1016/S0025-6196(11)61144-0 | pmc=2664604 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19252114  }} </ref>


=== Pathogenesis ===
=== Pathogenesis ===
The pathogenesis of milk-alkali syndrome involves the kidneys, bones, and intestines.<ref name="pmid23543983">{{cite journal| author=Arroyo M, Fenves AZ, Emmett M| title=The calcium-alkali syndrome. | journal=Proc (Bayl Univ Med Cent) | year= 2013 | volume= 26 | issue= 2 | pages= 179-81 | pmid=23543983 | doi=10.1080/08998280.2013.11928954 | pmc=3603742 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23543983  }} </ref>
The [[pathogenesis]] of milk-alkali syndrome involves the [[Kidney|kidneys]], [[Bone|bones]], and [[Intestine|intestines]].<ref name="pmid23543983">{{cite journal| author=Arroyo M, Fenves AZ, Emmett M| title=The calcium-alkali syndrome. | journal=Proc (Bayl Univ Med Cent) | year= 2013 | volume= 26 | issue= 2 | pages= 179-81 | pmid=23543983 | doi=10.1080/08998280.2013.11928954 | pmc=3603742 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23543983  }} </ref>


===== '''Hypercalcemia''' =====
===== '''Hypercalcemia''' =====


* Hypercalcemia involves the following:<ref name="pmid17699269">{{cite journal| author=Felsenfeld AJ, Levine BS| title=Milk alkali syndrome and the dynamics of calcium homeostasis. | journal=Clin J Am Soc Nephrol | year= 2006 | volume= 1 | issue= 4 | pages= 641-54 | pmid=17699269 | doi=10.2215/CJN.01451005 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17699269  }} </ref>
* Hypercalcemia involves the following:<ref name="pmid17699269">{{cite journal| author=Felsenfeld AJ, Levine BS| title=Milk alkali syndrome and the dynamics of calcium homeostasis. | journal=Clin J Am Soc Nephrol | year= 2006 | volume= 1 | issue= 4 | pages= 641-54 | pmid=17699269 | doi=10.2215/CJN.01451005 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17699269  }} </ref>
** Intestinal absorption of calcium is increased.
**[[Intestine|Intestinal]] absorption of [[calcium]] is increased.
** Bone buffering of calcium becomes saturated.
**[[Bone]] buffering of [[calcium]] becomes saturated.
** Renal excretion of calcium is decreased.  
**[[Kidney|Renal]] excretion of [[calcium]] is decreased.


* Intestines absorb the high quantities of consumed calcium and cause hypercalcemia.
*[[Intestine|Intestines]] absorb the high quantities of consumed [[calcium]] and cause [[hypercalcemia]].
* Bones have a limited capacity of calcium buffering and the variations in this capacity may contribute to hypercalcemia.
*[[Bone (disambiguation)|Bones]] have a limited capacity of [[calcium]] buffering and the variations in this capacity may contribute to hypercalcemia.
* Hypercalcemia causes vasoconstriction in the kidneys, which decreases glomerular filtration rate (GFR) and calcium excretion in the kidneys.<ref name="pmid17699269">{{cite journal| author=Felsenfeld AJ, Levine BS| title=Milk alkali syndrome and the dynamics of calcium homeostasis. | journal=Clin J Am Soc Nephrol | year= 2006 | volume= 1 | issue= 4 | pages= 641-54 | pmid=17699269 | doi=10.2215/CJN.01451005 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17699269  }} </ref>
*[[Hypercalcemia]] causes [[vasoconstriction]] in the [[Kidney|kidneys]], which decreases [[Glomerular filtration rate|glomerular filtration rate (GFR)]] and [[calcium]] excretion in the [[Kidney|kidneys]].<ref name="pmid17699269">{{cite journal| author=Felsenfeld AJ, Levine BS| title=Milk alkali syndrome and the dynamics of calcium homeostasis. | journal=Clin J Am Soc Nephrol | year= 2006 | volume= 1 | issue= 4 | pages= 641-54 | pmid=17699269 | doi=10.2215/CJN.01451005 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17699269  }} </ref>
* Hypercalcemia activates calcium-sensing receptors (CaSRs) in different areas and the following effects happen:<ref name="pmid19923405">{{cite journal| author=Riccardi D, Brown EM| title=Physiology and pathophysiology of the calcium-sensing receptor in the kidney. | journal=Am J Physiol Renal Physiol | year= 2010 | volume= 298 | issue= 3 | pages= F485-99 | pmid=19923405 | doi=10.1152/ajprenal.00608.2009 | pmc=2838589 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19923405  }} </ref>
*[[Hypercalcemia]] activates [[calcium]]-sensing receptors (CaSRs) in different areas and the following effects happen:<ref name="pmid19923405">{{cite journal| author=Riccardi D, Brown EM| title=Physiology and pathophysiology of the calcium-sensing receptor in the kidney. | journal=Am J Physiol Renal Physiol | year= 2010 | volume= 298 | issue= 3 | pages= F485-99 | pmid=19923405 | doi=10.1152/ajprenal.00608.2009 | pmc=2838589 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19923405  }} </ref>
** Renal tubules  
**[[Nephron|Renal tubules]]
*** Thick ascending loop of Henle:  
*** Thick ascending [[loop of Henle]]:  
**** Reabsorption of sodium chloride is blocked, which leads to diuresis and an increase in calcium excretion in the kidneys. These, in turn, result in volume depletion and metabolic alkalosis.
****[[Reabsorption]] of [[sodium chloride]] is blocked, which leads to [[diuresis]] and an increase in [[calcium]] excretion in the [[Kidney|kidneys]]. These, in turn, result in [[Hypovolemia|volume depletion]] and [[metabolic alkalosis]].
***[[Distal convoluted tubule|Distal convoluted tubules]] (luminal membrane) :
****[[Calcium]] [[reabsorption]] through [[TRPV5|transient receptor potential vanilloid member 5 (TRPV5)]] channels is increased.
***[[Collecting duct system|Collecting duct]] (luminal membranes):
**** Expression of [[Aquaporin 2|aquaporin 2 water channels]] is decreased, and that decreases water [[reabsorption]] and dilutes the [[urine]].
* 25-hydroxylation of [[vitamin D]] in the [[Kidney|kidneys]] is reduced by excessive [[calcium]] consumption, which decreases [[calcium]] absorption in the [[intestine]].<ref name="pmid19252114">{{cite journal| author=Medarov BI| title=Milk-alkali syndrome. | journal=Mayo Clin Proc | year= 2009 | volume= 84 | issue= 3 | pages= 261-7 | pmid=19252114 | doi=10.1016/S0025-6196(11)61144-0 | pmc=2664604 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19252114  }} </ref>
*[[Hypercalcemia]] inhibits [[Parathyroid hormone|parathyroid hormone (PTH)]] which decreases [[bone turnover]] and the capacity of the [[bone]] for [[calcium]] buffering and increases the [[excretion]] of [[calcium]] in the [[Kidney|kidneys]].<ref name="pmid17699269">{{cite journal| author=Felsenfeld AJ, Levine BS| title=Milk alkali syndrome and the dynamics of calcium homeostasis. | journal=Clin J Am Soc Nephrol | year= 2006 | volume= 1 | issue= 4 | pages= 641-54 | pmid=17699269 | doi=10.2215/CJN.01451005 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17699269  }} </ref>
*[[Hypercalcemia]] causes [[nausea and vomiting]], which in turn deteriorate [[Hypovolemia|volume depletion]] and [[metabolic alkalosis]].<ref name="pmid17699269">{{cite journal| author=Felsenfeld AJ, Levine BS| title=Milk alkali syndrome and the dynamics of calcium homeostasis. | journal=Clin J Am Soc Nephrol | year= 2006 | volume= 1 | issue= 4 | pages= 641-54 | pmid=17699269 | doi=10.2215/CJN.01451005 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17699269  }} </ref>


*** Distal convoluted tubules (luminal membrane) :
===== '''Metabolic Alkalosis''' =====
**** Calcium reabsorption through transient receptor potential vanilloid member 5 (TRPV5) channels is increased.


*** Collecting duct (luminal membranes):
* Increases the affinity of the CaSRs to [[calcium]], which increases natriuresis.  
**** Expression of aquaporin 2 water channels is decreased, and that decreases water reabsorption and dilutes the urine.
* Stimulates [[TRPV5]] which increases [[calcium]] [[reabsorption]] and worsens [[hypercalcemia]].<ref name="pmid16268810">{{cite journal| author=Picolos MK, Lavis VR, Orlander PR| title=Milk-alkali syndrome is a major cause of hypercalcaemia among non-end-stage renal disease (non-ESRD) inpatients. | journal=Clin Endocrinol (Oxf) | year= 2005 | volume= 63 | issue= 5 | pages= 566-76 | pmid=16268810 | doi=10.1111/j.1365-2265.2005.02383.x | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16268810  }} </ref><ref name="pmid19923405">{{cite journal| author=Riccardi D, Brown EM| title=Physiology and pathophysiology of the calcium-sensing receptor in the kidney. | journal=Am J Physiol Renal Physiol | year= 2010 | volume= 298 | issue= 3 | pages= F485-99 | pmid=19923405 | doi=10.1152/ajprenal.00608.2009 | pmc=2838589 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19923405  }} </ref>
* Several factors that increase [[bicarbonate]] [[reabsorption]] and contribute to the [[alkalosis]] in milk-alkali syndrome include:<ref name="pmid9436295">{{cite journal| author=Fiorino AS| title=Hypercalcemia and alkalosis due to the milk-alkali syndrome: a case report and review. | journal=Yale J Biol Med | year= 1996 | volume= 69 | issue= 6 | pages= 517-23 | pmid=9436295 | doi= | pmc=2589043 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9436295  }} </ref>
**[[Hypovolemia|Volume depletion]] due to increased [[sodium]] and free water [[excretion]] caused by increased [[calcium]] intake
** Suppression of [[Parathyroid hormone|PTH]] 
** Direct [[Nephron|tubular]] effects of [[calcium]]  
** Other factors that cause [[Hypovolemia|volume depletion]] or [[alkalosis]] such as [[Nausea and vomiting|vomiting]] or [[thiazide]] use


* 25-hydroxylation of vitamin D in the kidneys is reduced by excessive calcium consumption, which decreases calcium absorption in the intestine.<ref name="pmid19252114">{{cite journal| author=Medarov BI| title=Milk-alkali syndrome. | journal=Mayo Clin Proc | year= 2009 | volume= 84 | issue= 3 | pages= 261-7 | pmid=19252114 | doi=10.1016/S0025-6196(11)61144-0 | pmc=2664604 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19252114  }} </ref>
== Histopathology ==
* Hypercalcemia inhibits parathyroid hormone (PTH) which decreases bone turnover and the capacity of the bone for calcium buffering and increases the excretion of calcium in the kidneys.<ref name="pmid17699269">{{cite journal| author=Felsenfeld AJ, Levine BS| title=Milk alkali syndrome and the dynamics of calcium homeostasis. | journal=Clin J Am Soc Nephrol | year= 2006 | volume= 1 | issue= 4 | pages= 641-54 | pmid=17699269 | doi=10.2215/CJN.01451005 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17699269  }} </ref>
* Hypercalcemia causes nausea and vomiting, which in turn deteriorate volume depletion and metabolic alkalosis.<ref name="pmid17699269">{{cite journal| author=Felsenfeld AJ, Levine BS| title=Milk alkali syndrome and the dynamics of calcium homeostasis. | journal=Clin J Am Soc Nephrol | year= 2006 | volume= 1 | issue= 4 | pages= 641-54 | pmid=17699269 | doi=10.2215/CJN.01451005 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17699269  }} </ref>


===== '''Metabolic Alkalosis''' =====
* There is limited evidence on the renal [[Histopathology|histopathological]] findings of milk-alkali syndrome.<ref name="pmid19252114" />
* The following findings on [[Autopsy|autopsies]] have been reported:<ref name="pmid18126919">{{cite journal| author=BURNETT CH, COMMONS RR| title=Hypercalcemia without hypercalcuria or hypophosphatemia, calcinosis and renal insufficiency; a syndrome following prolonged intake of milk and alkali. | journal=N Engl J Med | year= 1949 | volume= 240 | issue= 20 | pages= 787-94 | pmid=18126919 | doi=10.1056/NEJM194905192402001 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18126919  }} </ref><ref name="pmid13016590">{{cite journal| author=WERMER P, KUSCHNER M, RILEY EA| title=Case reports; reversible metastatic calcification associated with excessive milk and alkali intake. | journal=Am J Med | year= 1953 | volume= 14 | issue= 1 | pages= 108-15 | pmid=13016590 | doi=10.1016/0002-9343(53)90362-3 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=13016590  }} </ref><ref name="pmid14375805">{{cite journal| author=HOLTEN C, LUNDBAEK K| title=Renal insufficiency and severe calcinosis due to excessive alkali-intake. | journal=Acta Med Scand | year= 1955 | volume= 151 | issue= 3 | pages= 177-83 | pmid=14375805 | doi=10.1111/j.0954-6820.1955.tb10281.x | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=14375805  }} </ref><ref name="pmid13124355">{{cite journal| author=DUFAULT FX, TOBIAS GJ| title=Potentially reversible renal failure following excessive calcium and alkali intake in peptic ulcer therapy. | journal=Am J Med | year= 1954 | volume= 16 | issue= 2 | pages= 231-6 | pmid=13124355 | doi=10.1016/0002-9343(54)90339-3 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=13124355  }} </ref>
** [[Nephrocalcinosis]]
** [[Glomerulus]] hyalinization (partial to complete)
** Thickened [[Bowman's capsule]]
** [[Atrophy]] of the [[Tubule|tubules]]
** [[Vascular]] changes
** Diffuse [[Lymphocyte|lymphocytic]] infiltration


* Increases the affinity of the CaSRs to calcium, which increases natriuresis.  
* The following findings on [[Biopsy|biopsies]] have been reported:<ref name="pmid14349424">{{cite journal| author=SCHOLZ DA, KEATING FR| title=Milk-alkali syndrome; review of eight cases. | journal=AMA Arch Intern Med | year= 1955 | volume= 95 | issue= 3 | pages= 460-8 | pmid=14349424 | doi=10.1001/archinte.1955.00250090098012 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=14349424 }} </ref><ref name="pmid13739449">{{cite journal| author=RANDALL RE, STRAUSS MB, McNEELY WF| title=The milk-alkali synfcmme. | journal=Arch Intern Med | year= 1961 | volume= 107 | issue= | pages= 163-81 | pmid=13739449 | doi=10.1001/archinte.1961.03620020013003 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=13739449 }} </ref><ref name="pmid1010876">{{cite journal| author=Junor BJ, Catto GR| title=Renal biopsy in the milk-alkali syndrome. | journal=J Clin Pathol | year= 1976 | volume= 29 | issue= 12 | pages= 1074-6 | pmid=1010876 | doi=10.1136/jcp.29.12.1074 | pmc=476303 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=1010876 }} </ref>
* Stimulates TRPV5 which increases calcium reabsorption and worsens hypercalcemia.<ref name="pmid16268810">{{cite journal| author=Picolos MK, Lavis VR, Orlander PR| title=Milk-alkali syndrome is a major cause of hypercalcaemia among non-end-stage renal disease (non-ESRD) inpatients. | journal=Clin Endocrinol (Oxf) | year= 2005 | volume= 63 | issue= 5 | pages= 566-76 | pmid=16268810 | doi=10.1111/j.1365-2265.2005.02383.x | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16268810 }} </ref><ref name="pmid19923405">{{cite journal| author=Riccardi D, Brown EM| title=Physiology and pathophysiology of the calcium-sensing receptor in the kidney. | journal=Am J Physiol Renal Physiol | year= 2010 | volume= 298 | issue= 3 | pages= F485-99 | pmid=19923405 | doi=10.1152/ajprenal.00608.2009 | pmc=2838589 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19923405 }} </ref>
** Focal [[calcification]] in the [[Nephron|renal tubules]]
* Several factors that increase bicarbonate reabsorption and contribute to the alkalosis in milk-alkali syndrome include:<ref name="pmid9436295">{{cite journal| author=Fiorino AS| title=Hypercalcemia and alkalosis due to the milk-alkali syndrome: a case report and review. | journal=Yale J Biol Med | year= 1996 | volume= 69 | issue= 6 | pages= 517-23 | pmid=9436295 | doi= | pmc=2589043 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9436295 }} </ref>
** [[Degeneration]] of the [[Nephron|tubular]] [[epithelium]]
** Volume depletion due to increased sodium and free water excretion caused by increased calcium intake
** Granular material (presumably [[calcium]] laden) in and around the [[Connecting tubule|collecting tubules]]
** Suppression of PTH 
** Hyalinization of some [[Glomerulus|glomeruli]]
** Direct tubular effects of calcium  
** Thickened basement membrane
** Other factors that cause volume depletion and alkalosis such as vomiting or thiazide use


== Histopathology ==
* It has been suggested that the [[prognosis]] of milk-alkali syndrome is associated with the severity of the [[Histology|histologic]] changes on the [[Biopsy|biopsies]] and that renal [[calcium]] deposition are usually not detectable on [[X-rays|x-ray]].<ref name="pmid1010876">{{cite journal| author=Junor BJ, Catto GR| title=Renal biopsy in the milk-alkali syndrome. | journal=J Clin Pathol | year= 1976 | volume= 29 | issue= 12 | pages= 1074-6 | pmid=1010876 | doi=10.1136/jcp.29.12.1074 | pmc=476303 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=1010876  }} </ref>


==Referen==
==References==
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{{reflist|2}}
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Shakiba Hassanzadeh, MD[2]

Overview

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.

Pathophysiology

  • The exact pathogenesis of milk-alkali syndrome is unknown.
  • Consumption of excessive amounts of calcium and absorbable alkali causes milk-alkali syndrome.[1]

Pathogenesis

The pathogenesis of milk-alkali syndrome involves the kidneys, bones, and intestines.[2]

Hypercalcemia
Metabolic Alkalosis

Histopathology

References

  1. ↑ 1.0 1.1 1.2 Medarov BI (2009). "Milk-alkali syndrome". Mayo Clin Proc. 84 (3): 261–7. doi:10.1016/S0025-6196(11)61144-0. PMC 2664604. PMID 19252114.
  2. ↑ Arroyo M, Fenves AZ, Emmett M (2013). "The calcium-alkali syndrome". Proc (Bayl Univ Med Cent). 26 (2): 179–81. doi:10.1080/08998280.2013.11928954. PMC 3603742. PMID 23543983.
  3. ↑ 3.0 3.1 3.2 3.3 Felsenfeld AJ, Levine BS (2006). "Milk alkali syndrome and the dynamics of calcium homeostasis". Clin J Am Soc Nephrol. 1 (4): 641–54. doi:10.2215/CJN.01451005. PMID 17699269.
  4. ↑ 4.0 4.1 Riccardi D, Brown EM (2010). "Physiology and pathophysiology of the calcium-sensing receptor in the kidney". Am J Physiol Renal Physiol. 298 (3): F485–99. doi:10.1152/ajprenal.00608.2009. PMC 2838589. PMID 19923405.
  5. ↑ Picolos MK, Lavis VR, Orlander PR (2005). "Milk-alkali syndrome is a major cause of hypercalcaemia among non-end-stage renal disease (non-ESRD) inpatients". Clin Endocrinol (Oxf). 63 (5): 566–76. doi:10.1111/j.1365-2265.2005.02383.x. PMID 16268810.
  6. ↑ Fiorino AS (1996). "Hypercalcemia and alkalosis due to the milk-alkali syndrome: a case report and review". Yale J Biol Med. 69 (6): 517–23. PMC 2589043. PMID 9436295.
  7. ↑ BURNETT CH, COMMONS RR (1949). "Hypercalcemia without hypercalcuria or hypophosphatemia, calcinosis and renal insufficiency; a syndrome following prolonged intake of milk and alkali". N Engl J Med. 240 (20): 787–94. doi:10.1056/NEJM194905192402001. PMID 18126919.
  8. ↑ WERMER P, KUSCHNER M, RILEY EA (1953). "Case reports; reversible metastatic calcification associated with excessive milk and alkali intake". Am J Med. 14 (1): 108–15. doi:10.1016/0002-9343(53)90362-3. PMID 13016590.
  9. ↑ HOLTEN C, LUNDBAEK K (1955). "Renal insufficiency and severe calcinosis due to excessive alkali-intake". Acta Med Scand. 151 (3): 177–83. doi:10.1111/j.0954-6820.1955.tb10281.x. PMID 14375805.
  10. ↑ DUFAULT FX, TOBIAS GJ (1954). "Potentially reversible renal failure following excessive calcium and alkali intake in peptic ulcer therapy". Am J Med. 16 (2): 231–6. doi:10.1016/0002-9343(54)90339-3. PMID 13124355.
  11. ↑ SCHOLZ DA, KEATING FR (1955). "Milk-alkali syndrome; review of eight cases". AMA Arch Intern Med. 95 (3): 460–8. doi:10.1001/archinte.1955.00250090098012. PMID 14349424.
  12. ↑ RANDALL RE, STRAUSS MB, McNEELY WF (1961). "The milk-alkali synfcmme". Arch Intern Med. 107: 163–81. doi:10.1001/archinte.1961.03620020013003. PMID 13739449.
  13. ↑ 13.0 13.1 Junor BJ, Catto GR (1976). "Renal biopsy in the milk-alkali syndrome". J Clin Pathol. 29 (12): 1074–6. doi:10.1136/jcp.29.12.1074. PMC 476303. PMID 1010876.
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