| 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|| |
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|| |
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.
Click here to view
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|| |
Metformin is a biguanide and is considered to be an euglycemic agent, and not hypoglycemic agent. It acts by:
- promoting anerobic glucolysis in the peripheral tissues (augmenting the uptake and usage of glucose from the cells),
- suppressing the hepatic gluconeogenesis:
- reducing glucose absorption from the gut and,
- promoting insulin binding to the peripheral tissue receptors. 
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  and it is not conjugated with serum proteins.  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.  It is possible that metformin and creatinine compete for the same secretory pathway. 
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. ,, 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. 
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). , In a review, 22% of the patients who had taken phenformin had a predisposing factor for lactic acidosis,  which, although is very rare (9 cases per 100.000 human-years of treatment with the drug), is very severe.  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, , 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. 
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. 
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. 
Thus far, only two cases of lactic acidosis due to metformin have been reported in patients with ESRF on HD, , and three reports in patients on continuous ambulatory peritoneal dialysis (CAPD). ,, 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. , 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. 
Finally, it should be underlined that in our case as well as in the other reported cases, , 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|| |
|1.||Bailey CJ, Turner RC. Metformin. N Engl J Med 1996;334:574-9. [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. |
|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. |
|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. |
|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. [PUBMED] [FULLTEXT] |
|6.||Scheen AJ. Clinical pharmacokinetics of metformin. Clin Pharmacokinet 1996;30(5):35971. |
|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. |
|8.||Horlen C, Malone R, Bryant B, et al. Frequency of inappropriate metformin prescriptions. JAMA 2002;287:2504-5. [PUBMED] [FULLTEXT] |
|9.||Stang MR, Wysowski DK, Bulter-Jones D. Incidence of lactic acidosis inmetformin users. Diabetes 1999;22:925-7. |
|10.||Heaney D, Majid A, Junor B. Bicarbonate haemodialysis as a treatment of metformin overdose. Nephrol Dial Transplant 1997;12:1046-7. [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. |
|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. [PUBMED] [FULLTEXT] |
|13.||Lim PS, Huang CC, Wei JS. Metformininduced lactic acidosis: Report of a case. J Formos Med Assoc 1992;91:374-6. [PUBMED] |
|14.||Khan IH, Catto GRD, MacLeod AM. Severe lactic acidosis in patient receiving continuous ambulatory peritoneal dialysis. BMJ 1993;307: 1056-7. |
|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. [PUBMED] [FULLTEXT] |
|16.||Lee AJ. Metformin in non-insulin-dependent diabetes mellitus. Pharmacotherapy 1996;15: 327-51. |
Nephrologist, Director of Renal Department, General Hospital of Komotini, Ant. Rossidi 11, N. Mosinoupoli 69100, Komotini