Milk-alkali syndrome pathophysiology: Difference between revisions
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* There is limited evidence on the renal [[Histopathology|histopathological]] findings of milk-alkali syndrome.<ref name="pmid19252114" /> | * 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: ( | * 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]] | ** [[Nephrocalcinosis]] | ||
** [[Glomerulus]] hyalinization (partial to complete) | ** [[Glomerulus]] hyalinization (partial to complete) | ||
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** Diffuse [[Lymphocyte|lymphocytic]] infiltration | ** Diffuse [[Lymphocyte|lymphocytic]] infiltration | ||
* The following findings on [[Biopsy|biopsies]] have been reported:10/ | * 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> | ||
** Focal [[calcification]] in the [[Nephron|renal tubules]] | ** Focal [[calcification]] in the [[Nephron|renal tubules]] | ||
** [[Degeneration]] of the [[Nephron|tubular]] [[epithelium]] | ** [[Degeneration]] of the [[Nephron|tubular]] [[epithelium]] | ||
| Line 77: | Line 77: | ||
** Thickened basement membrane | ** Thickened basement membrane | ||
* 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]]. | * 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> | ||
==References== | ==References== | ||
Revision as of 12:25, 16 July 2020
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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 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.Ingesting over two grams of elemental calcium per day produces this disorder in susceptible individuals. Gastrointestinal absorption of such a large amount of calcium leads to hypercalcemia.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 tubules of the kidney. Elevated bicarbonate levels in the blood raises the pH, producing an alkalemia.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.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.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.The understanding of this mechanism led to the development of a simple yet elegant treatment for hypercalcemia. The first and most important step is intravenous infusion of 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.[1]
Pathophysiology
- The exact pathogenesis of milk-alkali syndrome is unknown.
- Consumption of excessive amounts of calcium and absorbable alkali causes milk-alkali syndrome.[2]
Pathogenesis
The pathogenesis of milk-alkali syndrome involves the kidneys, bones, and intestines.[3]
Hypercalcemia
- Hypercalcemia involves the following:[4]
- 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.
- Hypercalcemia causes vasoconstriction in the kidneys, which decreases glomerular filtration rate (GFR) and calcium excretion in the kidneys.[4]
- Hypercalcemia activates calcium-sensing receptors (CaSRs) in different areas and the following effects happen:[5]
- Renal tubules
- 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.
- Distal convoluted tubules (luminal membrane) :
- Calcium reabsorption through transient receptor potential vanilloid member 5 (TRPV5) channels is increased.
- Collecting duct (luminal membranes):
- Expression of aquaporin 2 water channels is decreased, and that decreases water reabsorption and dilutes the urine.
- Thick ascending loop of Henle:
- Renal tubules
- 25-hydroxylation of vitamin D in the kidneys is reduced by excessive calcium consumption, which decreases calcium absorption in the intestine.[2]
- 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.[4]
- Hypercalcemia causes nausea and vomiting, which in turn deteriorate volume depletion and metabolic alkalosis.[4]
Metabolic Alkalosis
- Increases the affinity of the CaSRs to calcium, which increases natriuresis.
- Stimulates TRPV5 which increases calcium reabsorption and worsens hypercalcemia.[1][5]
- Several factors that increase bicarbonate reabsorption and contribute to the alkalosis in milk-alkali syndrome include:[6]
Histopathology
- There is limited evidence on the renal histopathological findings of milk-alkali syndrome.[2]
- The following findings on autopsies have been reported:[7][8][9][10]
- Nephrocalcinosis
- Glomerulus hyalinization (partial to complete)
- Thickened Bowman's capsule
- Atrophy of the tubules
- Vascular changes
- Diffuse lymphocytic infiltration
- The following findings on biopsies have been reported:[11][12][13]
- Focal calcification in the renal tubules
- Degeneration of the tubular epithelium
- Granular material (presumably calcium laden) in and around the collecting tubules
- Hyalinization of some glomeruli
- Thickened basement membrane
- It has been suggested that the prognosis of milk-alkali syndrome is associated with the severity of the histologic changes on the biopsies and that renal calcium deposition are usually not detectable on x-ray.[13]
References
- ↑ 1.0 1.1 Picolos MK, Lavis VR, Orlander PR (November 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.
- ↑ 2.0 2.1 2.2 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.
- ↑ 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.
- ↑ 4.0 4.1 4.2 4.3 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.
- ↑ 5.0 5.1 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 13.0 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.