Abstract
High mortality rates have been reported in the first 90 days of antiretroviral therapy in Zambia and other low-income countries. We report a case of acute hypophosphataemia and hypokalaemia in the first week of antiretroviral therapy in a patient with extreme AIDS wasting. Given its occurrence in an extremely wasted patient, it may be physiologically similar to refeeding syndrome but other causes could be relevant as well. Acute hypophosphataemia may contribute to early antiretroviral therapy associated mortality in low-income countries.
BACKGROUND
This patient represents the first reported description of severe acute hypophosphataemia and hypokalaemia early in the course of antiretroviral therapy (ART) not related to treatment with tenofovir. Because of physiological similarities to refeeding syndrome, it is possible that it represents a variant of refeeding syndrome. Our observations were prompted by reports of high mortality rates in the first 90 days of ART in Zambia and other low-income countries.1–3 Although risk factors for early mortality have been identified (including body mass index (BMI) <16 kg/m2), its causes are not known. Our observations in this and other patients suggest that refeeding syndrome may be among them.
CASE PRESENTATION
A 35-year-old male with WHO clinical stage 3 HIV disease presented to a Zambian Ministry of Health clinic in Lusaka, Zambia, for initiation of ART 32 weeks after testing HIV positive. He had recently completed a 6-month course of treatment for pulmonary tuberculosis. He reported anorexia and diarrhoea and he was severely cachectic (height 165 cm and weight 40 kg (BMI 14.9 kg/m2)). His CD4+ count was 326 cells/μl; viral load measurements are not routinely available in this setting. He was started on ART (zidovudine, lamivudine and efavirenz), multivitamins, including thiamine, and cotrimoxazole for standard prophylaxis against Pneumocystis pneumonia.
In the first 4 weeks the patient experienced periodic diarrhoea associated with normal-anion gap metabolic acidosis, pre-renal azotemia and persistent hypokalaemia despite oral potassium supplementation. In the second week of ART, his condition markedly deteriorated. He reported shortness of breath, diarrhoea, and vomiting, and he appeared volume-depleted and extremely weak. There was no clinical evidence of an opportunistic infection. Results from the 1-week visit revealed severe hypophosphataemia (biochemical results are reported after 5–7 days, introducing delays in correcting abnormalities). He improved after 24 hours’ treatment with intravenous hydration and infusion of sodium phosphate, and was discharged on oral potassium phosphate powder. Although he reported full adherence to the prescribed supplements, at week 3 the serum phosphate had again decreased to a critical level. He declined readmission for intravenous intervention so further oral supplementation was provided. At week 4 he reported recurrence of diarrhoea and loss of appetite, and appeared volume-depleted; in this dehydrated state, his serum phosphate and potassium were normal. Intravenous fluids were administered in the clinic and oral rehydration solution was provided. At week 6, he reported swelling and shortness of breath but also extreme hunger and consumption of substantial quantities of food. He had gained 15 kg and exhibited anasarca, tachycardia and pulmonary oedema. Serum chemistries were acceptable. Low-dose oral furosemide was prescribed. At weeks 8 and 14, he reported hunger but was otherwise asymptomatic, and he gained further weight even as his oedema resolved. Serum chemistries remained acceptable except albumin, which later normalised.
INVESTIGATIONS
Because of resource constraints inherent to the setting, no additional investigations were possible.
DIFFERENTIAL DIAGNOSIS
In one retrospective report, hypophosphataemia has been associated with the use of non-nucleoside reverse transcriptase inhibitor drugs4 (such as efavirenz in our patient) and with use of tenofovir5 (which our patient did not receive). However, these associations are inconsistent, the mechanisms are unknown and the reports have not assessed nutritional status (for example, BMI), so some cases of hypophosphataemia may have been unrecognised refeeding syndrome. Our patient’s improvement in renal parameters after volume repletion makes cotrimoxazole an unlikely cause for renal failure. Other causes, such as alcohol abuse (an exclusion criterion for the study in which the patient was enrolled), effects of other drugs, paraneoplastic syndrome and renal tubular reabsorptive dysfunction, such as Fanconi’s syndrome, are also unlikely.
TREATMENT
Phosphorus and potassium supplements, intravenous fluids (when dehydrated) and furosemide (when oedematous) were given.
OUTCOME AND FOLLOW-UP
After 1 year on ART the patient was doing well clinically and had normal serum chemistry values, including albumin.
DISCUSSION
This patient represents the first reported case of severe hypophosphataemia and hypokalaemia not associated with tenofovir early in the course of ART. He exhibited the series of clinical and biochemical changes typical of refeeding syndrome as observed in patients with severe wasting of any cause (for example, repatriated prisoners of war and patients with anorexia nervosa) who experience sudden increases in nutrient intake due to improved food supply or therapeutic feeding.6 Although his hypophosphataemia did not occur after an increase in dietary intake, another pathophysiological scenario is possible. HIV enteropathy, which is common in patients with HIV, impairs gastrointestinal function and nutrient absorption.7 With rapid reductions in viral load after ART is started, improvements in HIV enteropathy occur even in the first week of ART.8 This is likely to increase nutrient absorption, giving peripheral organs a sudden increase in nutrient flux. This could trigger all the responses, both adaptive and maladaptive, that occur in classic refeeding syndrome.
Hypophosphataemia is a hallmark of refeeding syndrome,9 but a broad range of metabolic derangements involving potassium, magnesium, glucose and vitamins have also been described, along with weakness, muscle paralysis, cardiorespiratory failure with pulmonary and peripheral oedema, leukocyte dysfunction and osteomalacia.10–14 It is probable that some of the electrolyte deficiencies observed in our patient (for example, hyponatremia and acidosis) were caused by diarrhoea and volume depletion, but we believe his acute hypophosphataemia and hypokalaemia, which developed in his first week on ART and, after volume repletion, were followed by anasarca, represent an exaggerated metabolic response to refeeding and/or to improved intestinal macronutrient absorption. Between weeks 1 and 3, his serum phosphate was normal only when he was volume-depleted. His severe clinical presentation in spite of a relatively high CD4+ count at ART initiation suggests that malnutrition placed him at particular risk for refeeding syndrome.
Our observations were prompted by reports of high mortality rates in the first 90 days of ART in Zambia and other low-income countries.1–3 Although risk factors for early mortality have been identified (including BMI <16 kg/m2), its causes have not been clearly established. Our observations in this and other patients suggest that a variant of refeeding syndrome may be among them. In other settings, refeeding can be prevented by gradual nutritional restoration with intake of calories (especially from carbohydrate), salt and fluids increasing gradually over a period of days or weeks rather than rapidly.15,16 In the first few weeks of feeding and/or ART, it may be helpful to encourage at-risk patients (particularly those with wasting, for example, BMI <16) not to consume substantial quantities of carbohydrate-containing foods, but to emphasise foods high in protein and fat. Research is needed to determine whether using these or other measures such as phosphate supplementation will reduce morbidity and mortality in wasted HIV patients who start ART.
LEARNING POINTS
Acute hypophosphataemia and hypokalaemia may occur early (even in the first week) of antiretroviral therapy for HIV/AIDS.
Patients with extreme AIDS wasting may be particularly at risk.
This phenomenon is similar to, and may be a variant of, refeeding syndrome.
Acute hypophosphataemia and hypokalaemia may contribute to early antiretroviral therapy-associated mortality in low-income countries.
Acknowledgments
We gratefully acknowledge the support of the UAB Center for AIDS Research and the Fogarty International Clinical Research Scholars Program, US National Institutes of Health; and the Fulbright Scholars Program, US Department of State. The data for this case report were collected early in the course of our study, Nutritional Causes for Early ART Mortality in Zambia, funded by grants from the University of Alabama at Birmingham (UAB) Center for AIDS Research (CFAR), the US National Institutes of Health, and the Centre for Infectious Disease Research in Zambia, the Fogarty International Center of the US National Institutes of Health, and the Fulbright US Scholars Program, US Department of State. The UAB CFAR approved the study concept as described in a grant application, but had no further role in the conduct of the study; CIDRZ provided important assistance in designing and launching the study; the Fogarty International Center and the Fulbright Program supported the participation of Drs Nyirenda and Heimburger, respectively, but had no role in the design or conduct of the work presented. The investigators acted independently of all funding sources.
We appreciate the advice and helpful comments provided by staff of the Global AIDS Program at the Centers for Disease Control and Prevention.
Footnotes
Competing interests: none.
Patient consent: Patient/guardian consent was obtained for publication. The patient was one of the first participants enrolled in an observational study entitled: Nutritional Causes for Early ART Mortality in Zambia. Results of the full cohort are currently being analysed.
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