Article Text
Abstract
Aim: The aim of this study was to determine the most common causes of hypophosphataemia (⩽0.5 mmol/l) in a hospital population in order to identify patient groups at risk of developing the condition.
Methods: The study was conducted at Tygerberg Hospital, a tertiary care centre in the Western Cape, South Africa. All patients identified with a phosphate level ⩽0.5 mmol/l during an 18-month period were included in the study. Medical records of these patients were reviewed.
Results: Of all the requests received for serum phosphate determination by the laboratory, 2% (861 out of 45 394 requests) were ⩽0.5 mmol/l. Thirty per cent (30%; n = 189) of the patients in the study population died during their hospital stay. Most (45%; n = 278) of the patients with low phosphate levels occurred in an intensive care setting, whereas 10% (n = 63) were most likely due to refeeding, and 6% (n = 35) had neoplastic disease. Sepsis was implicated as a contributing factor in 26% (n = 162).
Conclusion: Severe hypophosphataemia is associated with a very high mortality (30%, n = 189). Patients with a high risk of developing hypophosphataemia include those in an intensive care unit (ICU), patients suffering from neoplastic diseases, possible refeeding syndrome and septic patients. Regular phosphate determination is recommended in these patients to facilitate early diagnosis of hypophosphataemia.
Statistics from Altmetric.com
Hypophosphataemia is a commonly reported electrolyte disorder.1 Normal inorganic phosphate levels (referred to as phosphate from now on) vary with age. Hypophosphataemia is defined as a serum phosphate level below 0.80 mmol/l. Based on this, the typical prevalence of hypophosphataemia in hospitalised patients varies from 5 to 10%.1
Phosphate plays an important role in several aspects of cellular metabolism, including adenosine triphosphate (ATP) synthesis, which is the source of energy for many cellular reactions, and 2,3-diphosphoglycerate (2,3-DPG) concentrations, which regulate the dissociation of oxygen from haemoglobin. In addition, phosphate is an important component of phospholipids in cell membranes.2 It can also act as a physiological buffer, is involved in bone mineralisation and is an effector of certain enzymes, such as hexokinase and phosphofructokinase.3
Major determinants of serum phosphate concentration are dietary intake and gastrointestinal absorption, urinary excretion and shifts between the intracellular and extracellular spaces.2 Phosphate is predominantly an intracellular ion, with an intracellular-to-extracellular molar ratio of 80:3.3 Phosphate balance is maintained by means of regulation of renal excretion. Serum phosphate is freely filtered in the kidney where 90% is reabsorbed by the renal tubules by means of a sodium gradient-dependent process (Na-PO4 co-transporter) located on the apical brush border membrane.2
The term phosphate depletion refers to a reduction in total body phosphate and in most cases results from impaired intestinal absorption or from urinary wasting. Severe hypophosphataemia (<0.3 mmol/l) is associated with a significant morbidity and a fourfold increase in mortality.1 4
Hypophosphataemia can affect most organ systems. Typical symptoms for levels less than 0.5 mmol/l are insidious and include myalgia, muscle weakness and anorexia. At levels below 0.3 mmol/l, neurological symptoms (paraesthesia, tremor, confusion, decreased deep tendon reflexes, seizures and coma) may develop progressively.5–7 Rhabdomyolysis may occur due to structural and functional disturbances in skeletal muscle membranes, and hyperglycaemia may ensue due to insulin resistance.8 Haemolysis due to increased erythrocyte membrane rigidity, and reduced leucocyte and platelet function also may occur.4 5–7,9
Other serious clinical disorders resulting from hypophosphataemia include ventricular tachycardia, decreased tissue oxygenation (due to high haemoglobin affinity for oxygen resulting from reduced 2,3–DPG levels impairing O2 release), respiratory failure secondary to diaphragmatic weakness, hypotension and congestive heart failure due to reduced cardiac contractility.4 5 10 11 These disorders can be reversed with phosphate administration.6
AIM
There is a paucity of published information regarding the prevalence of severe hypophosphataemia in a hospitalised population, and no published data are available with reference to our local population. In this study, we aimed to determine the prevalence of severe hypophosphataemia in our hospital and elucidate the causes of hypophosphataemia, as well as the distribution and the mortality associated with hypophosphataemia.
METHODS
This study was a retrospective descriptive study based on the review and analysis of laboratory data (serum phosphate level) and selected clinical data (age, sex, diagnosis, treatment and outcome) of patients with documented moderate/severe hypophosphataemia (random serum phosphate levels of ⩽0.5 mmol/l) at Tygerberg Hospital. The study was approved by the Ethics Committee of the University of Stellenbosch.
Tygerberg Hospital is a tertiary academic hospital in the province of the Western Cape, South Africa. The population of the Western Cape is 4 524 336, of which 53.9% consists of the so-called coloured or mixed-race population.12
Reference values differ from laboratory to laboratory, but according to the literature, mild hypophosphataemia is defined as a level between 0.51 and 0.80 mmol/l,3 moderate hypophosphataemia as a level between 0.31 and 0.5 mmol/l and severe as a level <0.30 mmol/l. Levels of 0.5 mmol/l require appropriate therapy.3
All patients identified with serum phosphate levels ⩽0.5 mmol/l between January 2003 and June 2004 (18 months) were included in the study. A list of these patients was compiled using the laboratory information system of the National Health Laboratory Service (DISALAB system). Patient files were retrieved from Medical Records and specific laboratory data, and selected clinical data were documented. This included patient age, gender and diagnosis, treatment and outcome. Analyses were performed using Microsoft Excel and Statistica 7.
All phosphate measurements were performed on random serum samples on the BAYER® ADVIA 1650TM using a reagent from Bayer HealthCare (Boston, MA). The method used for the measurement of inorganic phosphate in our laboratory is based on the Daly and Ertinghausen procedure in which inorganic phosphate reacts with ammonium molybdate in the presence of sulfuric acid to form an unreduced phosphomolybdate complex, which is measured as an endpoint reaction at 340 nm.3 The between-batch coefficient of variation (CV) for this method is 3.0%.
RESULTS
A total of 45 394 serum samples were analysed for phosphate levels at the routine Clinical Chemistry laboratory at Tygerberg Hospital during the 18-month period from January 2003 to June 2004. Of these, 11% (n = 5208) had a low phosphate level (<0.8 mmol/l), which included 16.5% (n = 861) samples with a phosphate level of ⩽0.5 mmol/l.
Of the 861 moderately and severely low phosphate levels analysed, 240 were repeat requests. Table 1 lists the distribution of the number of requests.
Taking repeat requests into account, a total of 621 individual patients with moderately and severely low phosphate levels were identified. Ninety-nine per cent (n = 614) of our study population were inpatients, and 1% (n = 7) from various outpatient clinics. Overall, 30% (n = 189) of the inpatients (n = 614) died during their hospital stay.
There was no statistically significant difference in the incidence of hypophosphataemia in males (52%, n = 323) and females (48%, n = 298) with p = 0.336 (binomial test). Hypophosphataemia ⩽0.5 mmol/l was documented in patients from all age groups, with a range of 1 day to 89 years of age (25th percentile 13.0, 50th percentile 39 and 75th percentile 56 years). Ninety-two (14.8%) of the patients were children under the age of 1 year.
A significant number of patients had multiple possible causes and risk factors for the development of hypophosphataemia. Nearly half (45%; n = 278) of the patients with documented phosphate levels ⩽0.5 mmol/l occurred in an ICU setting. In our study group, 10% (n = 63) of patients had possible refeeding, and 6% (n = 35) had neoplastic disease as the main cause of the low serum phosphate levels.
Table 2 lists the causes/clinical status of the patients in this study identified with hypophosphataemia.
As mentioned before, 45% of patients with moderately and severely low phosphate levels were ICU patients. As expected, most of them had multiple possible causes and risk factors for the development of hypophosphataemia. Since patients in an ICU often receive insulin therapy for intensive glycaemic control and dextrose infusion as well as antacids (eg, Ulsanic) as adjunctive therapy (both of which may lead to low phosphate levels), these causes were excluded before evaluating possible causes of hypophosphataemia within our ICU population (table 3).
In 93% (n = 258) of ICU patients, mechanical ventilation was implicated as a contributing cause of the hypophosphataemia, whereas 36% (n = 100) of patients were found to be septic. One per cent (n = 2) of patients were recovering from surgery, while refeeding was identified as another contributing factor in 1% (n = 3) of cases within the ICU group.
Table 4 lists the causes within the refeeding group, where chronic diarrhoea (30%), kwashiorkor (16%) and marasmus (14%) were identified as the major contributors within the group.
DISCUSSION
Severe hypophosphataemia is associated with significant morbidity and a fourfold increase in mortality.1 It is for this reason that phosphate levels of less than 0.55 mmol/l (the cut-off value used at our Clinical Chemistry Laboratory) have been included in the list of critical values to be communicated directly to the requesting clinician when found during routine biochemical analysis in our laboratory. The use of 0.55 mmol/l as a critical phone-out value for phosphate at our institution is historical and has been the practice for over two decades. The Royal College of Pathology advises using a value of 0.3 mmol/l,13 but we use slightly higher cut-offs for our entire critical phone out values, as we prefer to be more conservative in our approach.
It is difficult to accurately assess the prevalence of hypophosphataemia seen at tertiary medical centres. Several factors contribute to this, including the use of chemistry panels that do not include the measurement of inorganic phosphate unless specifically ordered, difficulty in recognising high-risk groups of patients and the non-specificity of symptoms associated with severe hypophosphataemia.
The importance of identifying and treating hypophosphataemia cannot be overemphasised. A delay in the correct diagnosis, and therefore an additional delay in providing appropriate management, impacts negatively on optimal patient care. A high index of suspicion alone avoids the unnecessary withholding of treatment that can be life-saving.
We found, as reported in studies elsewhere,9 that most of the patients had multiple causes and potential risk factors for the development of hypophosphataemia. The primary precipitating factors identified in our study included admission to an ICU, malignant disease, refeeding syndrome, surgery, diabetes and the treatment of its metabolic complications (DKA), sepsis and alcohol abuse.
Severe hypophosphataemia (<0.3 mmol/l) has been associated with a high mortality of 30%.6 In our study, a high mortality was observed in patients with a phosphate of either ⩽0.3 mmol/l (31%) or ⩽0. 5 mmol/l (30%).
It is noteworthy that 45% of our hypophosphataemic patients originated from within an ICU setting. The effects of mechanical ventilation on the distribution of phosphate, in addition to glucose administration and antacid use (phosphate binders, eg, Ulsanic), must be considered as contributory factors to the development of hypophosphataemia. These figures correlate well with research done by Crook where the incidence was found to be 42%.3
A large percentage of patients with hypophosphataemia was septic. These included those patients where sepsis per se was the only cause found. In addition, sepsis was also identified as a contributory mechanism in groups where multiple causes were implicated. Thus, sepsis was implicated in the development of hypophosphataemia ⩽0.5 mmol/l in up to 26% of our study population, either per se or as part of a multitude of factors. In our severely hypophosphataemic patients (phosphate ⩽0.3 mmol/l, n = 15), sepsis was a contributing factor in 20% of cases. These findings differ from a similar study from the UK, where sepsis was implicated in 10% of patients with severe hypophosphataemia3 We postulate that this high incidence of sepsis as a cause of the hypophosphataemia in our population might be linked to the high incidence of sepsis per se, as well as the increased incidence of HIV and its associated complications in our local population.14
In our study, we also found that a large proportion of moderately and severely low phosphate levels were due to possible refeeding syndrome. This finding is expected, due to the high incidence of malnutrition, marasmus and kwashiorkor with their associated nutritional disturbances in our population. According to Migigima,15 it is estimated that 39% of the South African population is vulnerable to food insecurity. Interestingly, anorexia nervosa was implicated in 2% (n = 1) of patients within the refeeding group. This is in contrast to that observed in developed countries.16 We postulate that the high incidence of refeeding can be associated with the high prevalence of HIV in our population, since many patients in this group had pathological conditions associated with HIV, such as chronic diarrhoea, malnutrition, Candida oesophagitis, oral candidiasis and HIV-associated enteropathy.
With the high incidence of alcohol abuse in our local community, we anticipated alcohol to be a major contributory factor in our study. It was surprising to find that in only 3% (n = 20) of our patients, alcohol abuse was identified as the primary cause for the development of hypophosphataemia. In an additional 10 patients, alcohol abuse was implicated as being a contributory factor.
Take-home messages
Hypophosphataemia is a potentially life-threatening disorder.
The symptoms of hypophosphataemia are non-specific, and clinicians treating patients at high risk should have a high index of suspicion.
Phosphate levels need to be monitored in all seriously ill patients.
LIMITATIONS
There are several limitations to this study. First, this was a retrospective study where information was retrieved from patient records. These records are often incomplete, illegible and unreliable. Since patients were already discharged at the time of the study, patient histories could not be confirmed. Second, no additional tests could be requested. Third, our diagnosis of possible refeeding as a cause of hypophosphataemia was based on history and clinical information only and could not be confirmed. Fourth, the low incidence of alcohol abuse/withdrawal in this study is most likely an underestimation, since we have a very high incidence of alcohol abuse among our population. The use and abuse of alcohol is often not volunteered with patient history and was not apparent from the history and seldom documented in the clinical notes.
CONCLUSION
This study identified the major causes and patient groups susceptible to the development of severe hypophosphataemia within our local population. The authors feel that this will contribute to better identification of patients in which hypophosphataemia should be diagnosed without delay in an attempt to improve management of these patients and reduce morbidity and mortality associated with this important, but often overlooked, biochemical abnormality.
Acknowledgments
We gratefully acknowledge the expert assistance of M Kidd, from the Centre for Statistical Consultation, University of Stellenbosch, and Z Mohammed (University of the Western Cape). We also express our appreciation to the medical technologists in our laboratory for their technical assistance.
REFERENCES
Footnotes
Competing interests: None.
Ethics approval: Ethics approval was provided by the Ethics Committee of the University of Stellenbosch.