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Saudi Journal of Kidney Diseases and Transplantation
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CASE REPORT  
Year : 2017  |  Volume : 28  |  Issue : 4  |  Page : 912-915
Milk-Alkali syndrome induced by H1N1 influenza vaccine


Department of Internal Medicine, Division of Nephrology, King Fahd Hospital of the University, Al-Khobar, Saudi Arabia

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Date of Web Publication21-Jul-2017
 

   Abstract 


Milk-Alkali syndrome (MAS) consists of a triad of hypercalcemia, metabolic alkalosis, and acute renal failure. We hereby report a 75-year-old Indian gentleman who presented to our emergency department with a history of generalized weakness and easy fatigability. Investigations were consistent with MAS secondary to calcium carbonate and calcitriol treatment to prevent osteoporosis, aggravated by H1N1 influenza vaccine. The patient was treated with hemodialysis and zoledronate. To our knowledge, this is the first reported case of such association in the literature.

How to cite this article:
Al-Hwiesh AK, Abdul-Rahman IS, Al-Oudah N, Al-Solami S, Al-Muhanna FA. Milk-Alkali syndrome induced by H1N1 influenza vaccine. Saudi J Kidney Dis Transpl 2017;28:912-5

How to cite this URL:
Al-Hwiesh AK, Abdul-Rahman IS, Al-Oudah N, Al-Solami S, Al-Muhanna FA. Milk-Alkali syndrome induced by H1N1 influenza vaccine. Saudi J Kidney Dis Transpl [serial online] 2017 [cited 2021 Aug 1];28:912-5. Available from: https://www.sjkdt.org/text.asp?2017/28/4/912/211354



   Introduction Top


Despite extensive clinical experience, few data are available on the pathogenesis of milk- alkali syndrome (MAS). Throughout the years, several factors have been proposed to induce MAS, including loss of gastric juice, preexisting renal disease, insufficient chloride intake, hemorrhage, anemia, impaired liver function, and warm weather.[1],[2],[3],[4],[5] 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 4–5 g of calcium carbonate daily.[6],[7]

MAS induced by influenza vaccine has not been reported previously. We hereby report an elderly male, who presented with MAS one week after H1N1 influenza vaccination and was treated with hemodialysis and zoledronate. To our knowledge, this is the first reported case of such association in the literature.


   Case Report Top


A 75-year-old Indian gentleman presented to our hospital with a 10-day history of generalized weakness and lethargy. On the day of admission, he developed an acute change in his mental status. He became disoriented and confused. The patient is known to have hypertension and diabetes mellitus for more than 10 years and was maintained on valsartan hydrochlorothiazide 80/12.5 mg, metformin 1000 mg, aspirin 81 mg, pantoprazole 40 mg, in addition to calcium carbonate 1000 mg and Vitamin D3 400 units daily for osteoporosis prevention. He received H1N1 influenza vaccine 0.5 mL (A/Brisbane/59/2007) one week before admission.

On arrival to the hospital, the patient looked ill, dehydrated, and disoriented to time, place, and persons. His blood pressure was 120/70 mm Hg, heart rate 110/min, and temperature was 37°C. Other system examinations were unremarkable.

Initial blood tests showed blood urea nitrogen (BUN): 60 mg/dL, serum creatinine: 6.9 mg/dL, serum sodium: 131 mEq/L, potassium: 3.5 mEq/L, chloride: 97 mEq/L, CO2: 32 mEq/ L, and anion gap: 3 mEq/L. Liver function tests were within normal. Serum calcium was 14.5 mg/dL on arrival then 16.5 mg/dL 2 h later, phosphorus: 3.2 mg/dL, magnesium: 1.8 mg/dL, uric acid: 10 mg/dL, and serum glucose: 95 mg/dL. Urine analysis showed multiple granular casts. Serum and urine protein electrophoresis, cardiac enzymes and isoenzymes, HIV antibodies, hepatitis profile, prothrombin and partial thromboplastin times, lipid profile, serum amylase, and lipase as well as parathyroid hormone were all normal. Chest X-ray, skeletal surveys, and abdominal ultrasound showed normal findings. Two weeks before admission, his serum creatinine was 1.4 mg/dL, BUN 20 mg/dL, and serum calcium 9.1 mg/dL.

The patient was admitted to the critical care unit, under the impression of MAS. Aggressive saline hydration was given, but his serum calcium was found to have risen to 16.3 mg/dL and he became more confused. Urgent hemodialysis was carried out followed by a drop of his serum calcium to 11.1 mg/dL. Zoledronate 4 mg intravenously was infused with 0.9% normal saline. His condition improved, and he was discharged from the hospital one week later. The latest renal functions showed BUN 24 mg/dl, glomerular filtration rate (GFR) of 60 mL/min, and serum creatinine of 1.2 mg/dL with serum calcium of 8.5 mg/dL [Table 1].
Table 1: Laboratory results throughout the course of the disease.

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   Discussion Top


MAS consists of a triad of hypercalcemia, metabolic alkalosis and renal insufficiency caused by the ingestion, of large amounts of calcium and absorbable alkali as described by Sippy in 1915.[8] The syndrome virtually disappeared with the advent of new therapies of peptic ulcer disease.[9],[10] In the first decades after the discovery of MAS, reports on its incidence in patients treated by the Sippy program varied widely from 2% to 18%.[11],[12] Individual variations in the amount of ingested alkali may provide an explanation for this phenomenon.[1] The mortality rate in the early days of MAS was reported to be 4.4%.[13]

In 1963, Punsar and Somer[10] re-examined all previously reported cases of MAS, and based on the chronicity of symptoms and prognosis, they differentiated them into two forms: Burnett syndrome (chronic) and Cope syndrome (acute). Burnett syndrome is a chronic irreversible condition, in which band keratopathy or other metastatic calcifications were commonly seen. The most common symptoms in both forms were anorexia, dizziness, headache, confusion, psychosis, and feeling of dry mouth. Hypercalcemia was present in all cases of Burnett syndrome, while preexisting renal disease was observed in one-third of cases, band keratopathy 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. Although both MAS and hyperparathyroidism present with hypercalcemia, the differentiation between them is often based on the parathyroid hormone assays.[14] In the 1970s and 1980s, MAS was considered the cause of <2% of cases of hypercalcemia.[15] However, there has been a resurgence of this disorder, as it now accounts for up to 12% of cases, making it the third leading cause of hypercalcemia behind hyperparathyroidism and malignancy.[16] Recently, Beall et al[16] described the “modern version” of MAS with different demographic and clinical backgrounds. 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, histamine-2 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 in addition to the phosphate-binding properties of calcium carbonate. After its resurgence, MAS is now considered as the third most common cause of hypercalcemia, after hyperparathyroidism and malignant neoplasms, with a prevalence of 9%–12% among hospitalized patients with hypercalcemia.[17],[18],[19] Increased availability of over-the-counter calcium carbonate supplements and greater awareness of osteoporosis among medical professionals and consumers likely has contributed to this trend.[20]

Medications that interfere with calcium excretion have also been considered risk factors. Thiazides, for example, decrease calcium excretion by inhibiting the thiazide-sensitive sodium chloride cotransporter and promoting intravascular depletion and alkalemia.[21],[22] It is well known that alkalosis decreases calcium excretion by increasing its tubular reabsorption.[23],[24] The increased serum calcium level causes afferent arteriolar constriction and reduction in the GFR.[25] The resulting GFR reduction further limits excretion of bicarbonate and calcium. The increasing serum calcium level magnifies the toxic effect of calcium on the kidneys.[26] Aging results in a decreased capacity to handle excess calcium, probably because of decreased GFR and downregulation of the calcium-sensing receptors, which facilitate hypercalcemia.[27]

Our patient presented with severe hypercalcemia, acute kidney injury, and metabolic alkalosis; the classical triad of MAS, which is possibly induced by small doses of calcium carbonate, calcitriol, and thiazide diuretic in preexistent renal insufficiency. The fact that the patient was maintained on this medication for a long time without developing MAS, but the occurrence of the later after H1N1-influenza vaccination raise important question about the possibility of the vaccine-induced MAS either through interferences with calcium excretion (like thiazide diuretic effect) or by decreasing calcium excretion through enhancing tubular reabsorption or both. 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.


   Acknowledgment Top


The authors are pleased to express their great thanks and appreciation to the staff nurse in the ICU and Male Medical Ward for their valuable support during the patient’s hospitalization.

Conflict of interest: None declared.



 
   References Top

1.
Jephers H, Lerner HH. The syndrome of alkalosis complicating treatment of peptic ulcer: Report of cases with reviews of the pathogenesis, clinical aspect and treatment. NEJM 1936;214:1236-44.  Back to cited text no. 1
    
2.
Eisele CW. Changes in acid-base balance during alkali treatment for peptic ulcer. Arch Intern Med 1939;63:1048-67.  Back to cited text no. 2
    
3.
Wilkinson SA, Jordan SM. Significance of alkalosis in treatment of peptic ulcer. Am J Dig Dis Nutr 1934;1:509-12.  Back to cited text no. 3
    
4.
Bockus HL, Bank J. Alkalosis and duodenal ulcer. Med Clin North Am 1932;16:143.  Back to cited text no. 4
    
5.
Hubble D. Correspondence. Lancet 1935;2:634.  Back to cited text no. 5
    
6.
Sippe C. Dangers of indiscriminate alkali therapy. M J Aust 1935;1:48s.  Back to cited text no. 6
    
7.
Orwoll ES. The milk-alkali syndrome: Current concepts. Ann Intern Med 1982;97:242-8.  Back to cited text no. 7
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8.
Sippy BW. Gastric and duodenal ulcer: Medical care by an efficient removal of gastric juice corrosion. JAMA 1915;64:1625.  Back to cited text no. 8
    
9.
Texter EC Jr., Laureta HC. The milk-alkali syndrome. Am J Dig Dis 1966;11:413-8.  Back to cited text no. 9
    
10.
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.  Back to cited text no. 10
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11.
Rafsky HA, Schwartz L, Kruger AW. The alkalosis in peptic ulcer disease. JAMA 1932;99:1582.  Back to cited text no. 11
    
12.
Gatewood WE, Gaebler OH, Muntwyler E, Myers VC. Alkalosis in patient with peptic ulcer. Arch Inter Med 1928;42:79-105.  Back to cited text no. 12
    
13.
Cook AM. Alkalosis occurring in the alkaline treatment of peptic ulcer. Q J Med 1932;1:527-41.  Back to cited text no. 13
    
14.
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 hypercal-cemia. Medicine (Baltimore) 1995;74:89-96.  Back to cited text no. 14
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15.
Jamieson MJ. Hypercalcaemia. Br Med J (Clin Res Ed) 1985;290:378-82.  Back to cited text no. 15
[PUBMED]    
16.
Beall DP, Henslee HB, Webb HR, Scofield RH. Milk-alkali syndrome: A historical review and description of the modern version of the syndrome. Am J Med Sci 2006;331:233-42.  Back to cited text no. 16
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17.
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;63:566-76.  Back to cited text no. 17
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18.
Kapsner P, Langsdorf L, Marcus R, Kraemer FB, Hoffman AR. Milk-alkali syndrome in patients treated with calcium carbonate after cardiac transplantation. Arch Intern Med 1986; 146:1965-8.  Back to cited text no. 18
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19.
Lin SH, Lin YF, Cheema-Dhadli S, Davids MR, Halperin ML. Hypercalcaemia and metabolic alkalosis with betel nut chewing: Emphasis on its integrative pathophysiology. Nephrol Dial Transplant 2002;17:708-14.  Back to cited text no. 19
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20.
Norton SA. Betel: Consumption and consequences. J Am Acad Dermatol 1998;38:81-8.  Back to cited text no. 20
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21.
Sebastian A. Thiazides and bone. Am J Med 2000;109:429-30.  Back to cited text no. 21
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22.
Kleinig TJ, Torpy DJ. Milk-Alkali syndrome: Broadening the spectrum of causes to allow early recognition. Intern Med J 2004;34:366-7.  Back to cited text no. 22
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23.
Greger R. New insights into the molecular mechanism of the action of diuretics. Nephrol Dial Transplant 1999;14:536-40.  Back to cited text no. 23
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24.
Nijenhuis T, Vallon V, van der Kemp AW, Loffing J, Hoenderop JG, Bindels RJ. Enhanced passive calcium reabsorption and reduced magnesium channel abundance explains thiazide-induced hypocalciuria and hypomagnesemia. J Clin Invest 2005;115:1651-8.  Back to cited text no. 24
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25.
Humes HD, Ichikawa I, Troy JL, Brenner BM. Evidence for a parathyroid hormone-dependent influence of calcium on the glomerular ultra-filtration coefficient. J Clin Invest 1978;61:32-40.  Back to cited text no. 25
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26.
Ganote CE, Philipsborn DS, Chen E, Carone FA. Acute calcium nephrotoxicity. An electron microscopical and semiquantitative light microscopical study. Arch Pathol 1975;99:650-7.  Back to cited text no. 26
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27.
Mathias RS, Nguyen HT, Zhang MY, Portale AA. Reduced expression of the renal calcium-sensing receptor in rats with experimental chronic renal insufficiency. J Am Soc Nephrol 1998;9:2067-74.  Back to cited text no. 27
[PUBMED]    

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Correspondence Address:
Abdullah K Al-Hwiesh
Department of Internal Medicine, Division of Nephrology, King Fahd Hospital of the University, Al-Khobar 31952
Saudi Arabia
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PMID: 28748897

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