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Saudi Journal of Kidney Diseases and Transplantation
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CASE REPORT Table of Contents   
Year : 2010  |  Volume : 21  |  Issue : 5  |  Page : 923-926
Metformin induced severe hypophosphatemia in a patient on hemodialysis


Renal Department, General Hospital of Komotini, N. Mosinoupoli, Komotini, Greece

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Date of Web Publication31-Aug-2010
 

   Abstract 

A 67-year-old diabetic and hypertensive woman presented to us with very low serum phosphate levels (PO4 - =1.1 mg/dL) about 40 days after initiation of hemodialysis (HD). The phosphate binders were discontinued, because they were thought to be the cause of hypo­phosphatemia. However, the serum phosphate levels continued to remain low during subsequent follow-up visits over one month (PO4 --- = 0.7 and 0.6 mg/dL respectively). The patient had been started on metformin hydrochloride (850 mg thrice a day) about 18 days after the beginning of HD. The drug was stopped immediately (approximately 50 days after it was started) and the serum phosphate levels increased progressively, reaching 4.3 mg/dL. During the period with hypophos­phatemia, the patient suffered from very intense fatigue and weakness (she was unable to walk), anorexia, diarrhea and tenesmus. There were no features suggestive of rhabdomyolysis, hemo­lysis, low blood pressure or hypoglycemia; she had low white blood cell and platelet counts. The patient was in good clinical condition 2-3 days after the discontinuation of metformin and she recovered totally 15 days later. This case is presented due to its rarity as well as the observation that despite the patient having severe hypophosphatemia, she showed only side effects of metformin. Hypophosphatemia caused only intense fatigue and no other symptoms.

How to cite this article:
Tsitsios T, Sotirakopoulos N, Armentzioiou K, Kalogiannidou I, Kolaggis A, Mavromatidis K. Metformin induced severe hypophosphatemia in a patient on hemodialysis. Saudi J Kidney Dis Transpl 2010;21:923-6

How to cite this URL:
Tsitsios T, Sotirakopoulos N, Armentzioiou K, Kalogiannidou I, Kolaggis A, Mavromatidis K. Metformin induced severe hypophosphatemia in a patient on hemodialysis. Saudi J Kidney Dis Transpl [serial online] 2010 [cited 2020 Oct 30];21:923-6. Available from: https://www.sjkdt.org/text.asp?2010/21/5/923/68893

   Introduction Top


Metformin is a euglycemic agent, which can augment the cellular uptake of glucose. Its use is contraindicated in patients with end-stage re­nal failure (ESRF). However, there are many reports in the literature where the drug has been used, and has caused serious side effects, espe­cially life-threatening lactic acidosis. Although hypophosphatemia is not referred to as a side effect in the drug's summary of product cha­racteristics (SPC) information leaflet, we ob­served it in an elderly woman with ESRF who took the drug due to a medical error.


   Case Report Top


A 67-year-old woman with ESRF was started, in February 2005, on bicarbonate-based hemo­dialysis (HD), administered three times per week, lasting four hours per session, using low­flux polysulfone dialyzer. She was diabetic since 1999 and hypertensive since 1983. Forty days after she started HD, during the second monthly lab check-up (April), severe hypo­phosphatemia (PO4 -- = 1.1 mg/dL) was noticed. Phosphate binders were immediately discon­tinued because they were thought to be res­ponsible; her dietary survey revealed that her intake of phosphate was adequate and no other cause could be found for the hypophospha­temia. Despite this, the hypophosphatemia per­sisted in two subsequent evaluations performed the same month (PO4 -- = 0.7 and 0.6 mg/dL res­pectively). Thus, an attempt was made to find the cause of hypophosphatemia. It was then found that the patient had been started on metformin (850 mg thrice a day), about 18 days after the commencement of HD, due to a presciption error. The drug was immediately discontinued. Following this, the serum phos­phate levels increased progressively, reaching 4.3 mg/dL three months later [Figure 1].
Figure 1 :Graphic representation of the relationship between serum phosphate levels at the initiation of
HD, teicoplanin and glucophage, as well as the discontinuation of glucophage and phosphate binders.


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During the period when the patient had hypo­phosphatemia, she suffered from severe weak­ness (unable to walk alone), anorexia, severe diarrhea and tenesmus. The arterial blood pre­ssure was satisfactorily controlled by ramipril (5 mg twice a day) and terazosin (2.5 mg twice a day). During this period, no episodes of hy­potension were recorded. Furthermore, the pa­tient never had hypoglycemia and the serum glucose levels ranged from 120 to 130 mg/dL.

The patient did not have any features of rhab­domyolysis or hemolysis, despite the very low levels of serum phosphate; the serum creatine phosphokinase (CPK) and serum glutamate oxaloacetate (SGOT) levels as well as serum bilirubin, reticulocyte count and hematocrit were normal. The serum iPTH levels were 68.6 pg/mL (normal range < 55 pg/mL), while the patient had very low white blood cell (WBC) (2040/μL) and platelet counts (90000/μL). During this period, the patient was thought to have an active infection, and was treated with teicoplanin (400 mg initially and continued with 200 mg for 7 days). The cultures of blood, urine and tip of catheter were negative. The clinical features of the patient started to im­prove three days after the discontinuation of metformin and she recovered totally 15 days later.


   Discussion Top


Metformin is a biguanide and is considered to be an euglycemic agent, and not hypoglycemic agent. It acts by:

  1. promoting anerobic glucolysis in the peri­pheral tissues (augmenting the uptake and usage of glucose from the cells),
  2. suppressing the hepatic gluconeogenesis:
  3. reducing glucose absorption from the gut and,
  4. promoting insulin binding to the peripheral tissue receptors. [1]


Metformin's bioavailability is 40-60% and the absorption from the gut is completed with­in six hours. Its volume of distribution follows the model of two compartments [2] and it is not conjugated with serum proteins. [3] It has no me­tabolites and is eliminated by the kidneys (elimination time of half life 4-8.7 hours), while it can be removed by HD. [4] It is possible that metformin and creatinine compete for the same secretory pathway. [5]

The usual side effects of metformin overdose include metallic taste in the mouth, muscle weakness, mild anorexia, nausea, vomiting, ma­laise and pain in the abdomen, augmentation of gas production and diarrhea. [1],[5],[6] Obviously, the symptoms in our patient can be attributed to the metformin overdose because, despite the very low levels of phosphorous, she did not have any signs of hypophosphatemia such as rhabdomyolysis, hemolysis and/or lactic aci­dosis. This was further confirmed by the im­provement of her health status 2-3 days after the discontinuation of metformin, despite the severe hypophosphatemia, which persisted for another 10 days. It is probable that hypophos­phatemia might have contributed to the muscle weakness, which is one of the earliest side effects of metformin and is due to suspension of phosphorylysis, because of the intracellular augmentation of inorganic phosphate. [7]

Metformin is contraindicated in patients suf­fering from renal, hepatic, heart or respiratory failure, because it induces dangerous lactic acidosis (especially in patients older than 65 years). [1],[6] In a review, 22% of the patients who had taken phenformin had a predisposing fac­tor for lactic acidosis, [8] which, although is very rare (9 cases per 100.000 human-years of treat­ment with the drug), is very severe. [9] This is confirmed by the fact that, despite her age, HD treatment and the very high dose of metformin (850 mg thrice a day), our patient did not have any signs of metabolic acidosis (blood pH = 7.47 and lactate = 2.9 mEq/L).

The best approach for the treatment of lactic acidosis caused by metformin is HD, [10],[11] be­cause it dialyzes metformin with very high clearance (170 mL/min) as well as lactate. It is most likely that this was the reason behind the mild clinical and laboratory signs seen in our patient. This has been observed by other au­thors as well who have found severe lactic acidosis in a HD patient who was taking phen­formin, only after the patient had missed two HD sessions. [12]

When glucose becomes intracellular, media­ted by the action of insulin, despite the meta­bolic pathway it will eventually follow, initia­lly it is phosphorylated. In other words, insulin helps the movement of phosphate intracellu­larly (metformin has the same action on the tissues, where it augments the use of glucose). Thereafter, phosphorylated glucose cannot exit the cell. In our patient, metformin overdose helped tissue glucose uptake and led to move­ment of phosphate intracellularly, resulting in hypophosphatemia due to redistribution. [12]

It is well known that hypophosphatemia cau­ses clinical manifestations when serum phos­phate is reduced to less than 1 mg/dL (this was not noted in our patient). This leads to low stores of intracellular adenosine triphosphate (ATP) and tissue hypoxia (due to the decrease of erythrocyte 2,3-DPG level, due to which the hemoglobin (Hb) affinity to O2 is increased and the release of O2 is decreased). Furthermore, in hypophosphatemia due to redistribution, the clinical manifestations are usually mild. There­fore, despite the severe hypophosphatemia, our patient did not have significant clinical mani­festations. However, general malaise is a com­mon manifestation of hypophosphatemia (as was noted in our patient), and it can affect any muscle-groups to varying degrees. Our patient had severe weakness (she was unable to walk alone), but this could have been caused by metformin overdose; she did not have any in­volvement of the respiratory muscles, smooth muscles of blood vessels (she did not have hypotension) and the myocardium (she did not have heart failure), obviously because phos­phorylysis is suspended in situations where there is accumulation of large quantities of phosphate intracellularly. [7]

Thus far, only two cases of lactic acidosis due to metformin have been reported in pa­tients with ESRF on HD, [4],[12] and three reports in patients on continuous ambulatory perito­neal dialysis (CAPD). [13],[14],[15] The use of HD was life-saving in four cases but the fifth patient died. Since the drug has a very large distri­bution volume, its removal by HD is slow and requires a few days to be completed. [5],[16] Peri­toneal dialysis is not considered to be a good method of treatment of lactic acidosis due to metformin, since lactate is present in most PD solutions and also, its effectiveness in hyper­catabolic cases is not satisfactory. [10]

Finally, it should be underlined that in our case as well as in the other reported cases, [13],[15] medical error was responsible for prescribing metformin in patients with ESRF.

In conclusion, despite the high dose resulting in severe hypophosphatemia, metformin did not cause serious side effects in HD patients, such as lactic acidosis. Probably, the removal of the drug and lactate during the HD sessions every two days and the severe diarrhea, reduced the serum levels of metformin and lactate.

 
   References Top

1.Bailey CJ, Turner RC. Metformin. N Engl J Med 1996;334:574-9.  Back to cited text no. 1  [PUBMED]  [FULLTEXT]  
2.Tacker GT, Casey C, Phillips PJ, Connor H, Ward JD, Woods HF. Metformin kinetics in healthy subjects and in patients with diabetes mellitus. Br J Clin Pharmacol 1981;12:235-46.  Back to cited text no. 2      
3.Pentikainen PJ, Neuvonen PJ, Penttila A. Phar­macokinetics of metformin after intravenous and oral administration to man. Eur J Clin Pharmacol 1979;16:195-202.  Back to cited text no. 3      
4.Chang CT, Chen YC, Fang JT, Huang CC. Metformin-associated lactic acidosis: Case reports and literature review. J Nephrol 2002; 15(4):398-402.  Back to cited text no. 4      
5.Sambol NC, Chiang J, Lin ET, et al. Kidney function and age are both predictors of phar­macokinetics of metformin. J Clin Pharmacol 1995;35:1094-102.  Back to cited text no. 5  [PUBMED]  [FULLTEXT]  
6.Scheen AJ. Clinical pharmacokinetics of met­formin. Clin Pharmacokinet 1996;30(5):359­71.  Back to cited text no. 6      
7.Cooke R, Franks G, Luciani GB, Pate E. The inhibition of rabbit skeletal muscle contraction by hydrogen ions and phosphate. J Physiol (Lond) 1988;395:77- 97.  Back to cited text no. 7      
8.Horlen C, Malone R, Bryant B, et al. Frequency of inappropriate metformin prescriptions. JAMA 2002;287:2504-5.  Back to cited text no. 8  [PUBMED]  [FULLTEXT]  
9.Stang MR, Wysowski DK, Bulter-Jones D. Incidence of lactic acidosis inmetformin users. Diabetes 1999;22:925-7.  Back to cited text no. 9      
10.Heaney D, Majid A, Junor B. Bicarbonate hae­modialysis as a treatment of metformin over­dose. Nephrol Dial Transplant 1997;12:1046-7.  Back to cited text no. 10  [PUBMED]  [FULLTEXT]  
11.Von Mach MA, Sauer O, Sacha Weilemann L. Experiences of a poison center with metfor­min-associated lactic acidosis. Exp Clin Endo­crinol Diabetes 2004;112(4):187-90.  Back to cited text no. 11      
12.Gan SC, Barr J, Arieff AI, Pearl RG. Biguanide­associated lactic acidosis. Case report and review of the literature. Arch Intern Med 1992; 152:2333 - 6.  Back to cited text no. 12  [PUBMED]  [FULLTEXT]  
13.Lim PS, Huang CC, Wei JS. Metformin­induced lactic acidosis: Report of a case. J Formos Med Assoc 1992;91:374-6.  Back to cited text no. 13  [PUBMED]    
14.Khan IH, Catto GRD, MacLeod AM. Severe lactic acidosis in patient receiving continuous ambulatory peritoneal dialysis. BMJ 1993;307: 1056-7.  Back to cited text no. 14      
15.Schmidt R, Horn E, Richards J, Stamatakis M. Survival after metformin-associated lactic aci­dosis in peritoneal dialysis-dependent renal failure. Am J Med 1997;102:486-8.  Back to cited text no. 15  [PUBMED]  [FULLTEXT]  
16.Lee AJ. Metformin in non-insulin-dependent diabetes mellitus. Pharmacotherapy 1996;15: 327-51.  Back to cited text no. 16      

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Correspondence Address:
Konstantinos Mavromatidis
Nephrologist, Director of Renal Department, General Hospital of Komotini, Ant. Rossidi 11, N. Mosinoupoli 69100, Komotini
Greece
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PMID: 20814133

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