NSAID‐induced symptomatic hypophosphataemia

Tables of Links

TARGETS
Transporters
NaPi‐IIa (Sodium phosphate 1 / SLC34A1)
NaPi‐IIc (Sodium phosphate 1 / SLC34A3)
PiT2 (Sodium‐dependent phosphate transporter 2 / SLC20A2)

LIGANDS
Aspirin	Indomethacin
Diclofenac	Insulin
Ibuprofen

These Tables list key protein targets and ligands in this article which are hyperlinked to corresponding entries in http://www.guidetopharmacology.org, the common portal for data from the IUPHAR/BPS Guide to PHARMACOLOGY 1 and are permanently archived in the Concise Guide to PHARMACOLOGY 2015/16 2.

Hypophosphataemia is defined in Denmark as a plasma phospate concentration lower than 0.71 mmol l⁻¹. The condition is underdiagnosed and may lead to death and increased morbidity and prolonged hospitalization increases the risk of hypophosphataemia. The most frequent symptoms of hypophosphataemia are musculoskeletal pain and muscle weakness and if acute and severe it may induce respiratory and cardiac failure, confusion, haemolysis and rhabdomyolysis 3. In approximately 80% of the cases of hypophosphataemia it is observed to be drug‐associated 4 and the following patient history describes NSAID‐induced symptomatic hypophosphataemia.

Case report

A 53‐year‐old healthy man was investigated for muscle pain by his general practitioner since the year of 2006. His symptoms consisted of universal muscle tenderness, tiredness and fatigue of the eye muscles, which made it difficult for him to concentrate and focus. At first, the patient was referred to a rheumatologist, who did not find any connective tissue diseases, myasthenia gravis or gout. The patient was then examined by an ophthalmologist, still without any abnormal findings. Due to a single measured plasma phosphate of 0.50 mmol l⁻¹ (0.71–1.23) in early 2013 the patient was referred to an endocrinologist, who concluded that the growth curve through the patient's childhood was normal. Besides, no inherited diseases in the patient's family were suspected. The patient declared to take different kinds of vitamins including 25 μg vitamin D on a daily basis. He had been smoking about 40 cigarettes per day until 2006 and he drank 2 l of wine each weekend.

At the endocrinology outpatient clinic, the blood work of most relevance was initially (all measured in plasma) phosphate 0.99 mmol l⁻¹, ionized free calcium (pH = 7,4) 1.25 mmol 1^−l (1.18–1.32), 25‐OH‐vitamin D(D3 + D2) 100 nmol l⁻¹ (>50), PTH 3.7 pmol l⁻¹ (1.6–6.9); BUN 7.7 mmol l⁻¹ (3.5–8.1), creatinine 99 μmol l⁻¹ (60–105), potassium 3.6 mmol l⁻¹ (3.5–4.6), magnesium 0.94 mmol l⁻¹ (0.71–0.94) and sodium 140 mmol l^–1 (137–144). The remaining blood work was completely normal. A bone scintigraphy showed increased radioactive uptake located at an old fracture of the left ankle. A dual‐energy X ray absorptiometry (DXA) was negative for osteoporosis and osteomalacia.

By the first consultation, at which the phosphate concentration was normal, earlier malabsorption or vitamin D deficiency was suspected and the endocrinologist prescribed the patient with calcium, zinc and magnesium supplements. By the second consultation the hypophosphataemia had returned with a plasma phosphate of 0.57 mmol l⁻¹, while the rest of the blood work was still normal. At this point the patient admitted regular use of non‐steroidal anti‐inflammatory drugs (NSAIDs), ibuprofen 400 mg and diclofenac 200 mg for pain in his right knee. However, no other drugs or herbal medicine were taken when asked specifically for. The endocrinologist recommended avoidance of NSAIDs until next appointment. After a period of 3 months the phosphate concentration was normal at 0.74 mmol l⁻¹. To verify a suspected causal relationship between the use of NSAIDs and hypophosphataemia, the doctor asked the patient to re‐start the NSAID use. The patient had again developed hypophosphataemia 1.5 months later. A new trial of NSAID exposure and avoidance was done with the same result (Table 1). During exposure to NSAIDs and hypophosphataemia the patient's muscle symptoms were present but they disappeared in periods without NSAID treatment.

Table 1.

Blood work and 24 h urine specimen concentrations with or without NSAID treatment over time

	NSAID treatment 29.11.2013	No NSAID 17.01.2014	NSAID treatment 26.02.2014	No NSAID 03.11.2014
Blood work
Plasma phosphate (0.71–1.23 mmol l−1)	0,57	0,74	0,57	0,75
Plasma Ca2+ (1.18–1.32 mmol l−1)	1,31	1,26	1,28	1,26
Plasma PTH (1.6–6.9 pmol l−1)	1,5	1,8	3,9
Plasma 25‐OH‐vitamin D (D3 + D2) (>50 nmol l−1)	100	125	104	113
24 h urine specimen
Pt(U) – calcium (2.5–8.1 mmol day−1)		6,4	5,1
U – calcium (mmol/l)		4,3	3,7
Pt(U) – phosphate (11–63 mmol day−1)		31	37
U – phosphate (mmol l−1)		21	26
Pt(U) – volume (ml)		1487	1400

Blood samples were directly brought to centrifugation and analysis after venipuncture.

Urine specimen were kept refrigerated when received and analyzed the same day at 14.00 h.

The case report strongly suggests that in the present patient, there was a strong causal relationship between the use of NSAIDs and the development of hypophosphataemia and muscular symptoms. To our knowledge this has not been reported before in man. In a study with rats, orally administered NSAIDs induced hypophosphataemia after 24 h. However, after 7 days of drug administration phosphate concentrations in plasma and urine had normalized 5. Another study in mice with a mutation of the X chromosome, which in humans normally induces hypophosphataemia, NSAID injections with indomethacin actually led to a reduction of phosphate in urine and an increase in plasma 6.

Hypophosphataemia may develop through four mechanisms: 1) redistribution of phosphate from the extracellular space into the cells. This is most typically seen during intravenously infusion of glucose solution and insulin and in poorly nourished patients, a phenomenon called refeeding syndrome 7; 2) reduced intestinal absorption of phosphate. About 80% of the phosphate from foods is absorbed in the small intestine, which is far more than what the body actually requires. Reduced absorption may be caused by simultaneous treatment with antacids and chronic diarrhoea or steatorrhoea; 3) increased renal phosphate secretion. Normally the filtrated phosphate from the glomerulus is reabsorbed by sodium–phosphate co‐transporters, which are up‐regulated during hypophosphataemia 8. Primary and secondary hyperparathyroidism and vitamin D deficiency cause an increased renal loss of phosphate 9 and the same is observed in Fanconi syndrome (dysfunction of the proximal tubules) and 4) dialysis‐induced hypophosphataemia 10.

In the present case, NSAID‐induced increase in renal phosphate secretion seems to be the most probable reason for the hypophosphataemia. It is well known that NSAIDs can cause renal damage either by renal papillary necrosis, acute interstitial nephritis, by inducing hyperpotassaemia with sodium and water retention or chronic kidney damage. However, the patient's creatinine was stationary through the whole period and these conditions rarely induce hypophosphataemia, which speaks against those being the reason for the hypophosphataemia. Phosphate reabsorption happens mainly in the proximal tubules, so Fanconi syndrome could induce hypophosphataemia. However, this syndrome is accompanied by metabolic acidosis, hypopotassaemia and hyperchloraemia and the patient was normopotassaemic at all times. There is only one described case of NSAID‐induced proximal tubular dysfunction, where a 17 year old girl developed proximal tubular dysfunction temporarily after an overdose of aspirin (12,5 g). The condition was fully reversed after 2 days. 11. Another possibility is that people with genetic disposition develop hypopotassaemia if exposed to NSAIDs. There are mainly three transport proteins involved in reabsorption of phosphate in the nephron and mutations have been observed in humans for all three transporters and all induces congenital hypophosphataemia. These proteins are NAPi‐IIa, NAPi‐IIc and PIT‐2 expressed by the genes SLC34A1, SLC34A3 og SLC20A2, respectively. The latter seems to have less influence on the phosphate secretion than the two former, which both are co‐transporters for sodium and phosphate 12. The patient did not have congenital hypophosphataemia, but it is likely that an undiscovered polymorphism in a gene coding for one of the transport proteins may be involved in the present case.

This case report stresses the need to consider drugs as a driver for development of symptoms which cannot otherwise be diagnosed as part of a disease. Exposure, withdrawal and re‐exposure of a drug can be a powerful tool to uncover if symptoms are related to drugs or not.

Competing Interests

All authors have completed the Unified Competing Interest form at www.icmje.org/coi_disclosure.pdf and declare no support from any organization for the submitted work, no financial relationships with any organizations that might have an interest in the submitted work in the previous 3 years and no other relationships or activities that could appear to have influenced the submitted work.

Skeid, M. S. , Pedersen‐Bjergaard, U. , Kristensen, P. L. , and Brandi, L. (2016) NSAID‐induced symptomatic hypophosphataemia. Br J Clin Pharmacol, 82: 1399–1401. doi: 10.1111/bcp.13061.