Abstract
This case highlights the complex presentation of common medical problems in HIV-infected individuals on antiretroviral therapy.
Introduction
Lactic acidosis refers to the presence of an elevated plasma concentration of lactate anions causing an elevated anion gap metabolic acidosis with pH <7.35 and lactate concentration >5 mmol/L. 1 Lactic acidosis is associated with tissue ischaemia and anaerobic respiration, underlying disease processes, pharmacological or toxic causes, and metabolic disorders. 1 The medical literature has recognized a link between antiretroviral therapy (ART) and lactic acidosis, 2 thus complicating the diagnosis further in HIV-positive patients. The following case report highlights the multiple aetiologies of lactic acidosis in such patients. It also discusses the role of antiretroviral therapy (ART) and hyperosmolar non-ketotic coma (HONK) in the patient's presentation.
Case
A 46-year-old black African heterosexual man was admitted to hospital with a two-day history of leg weakness, dizziness, urinary incontinence and fever. He walked into the A&E department, but while awaiting medical attention he collapsed with reduced consciousness.
He was known to have HIV and, since diagnosis in 2005, had been taking ART in the form of zidovudine/lamivudine and nevirapine. He had previously been treated for tuberculosis. Past medical history was otherwise unremarkable. He was on holiday in the UK at the time of admission. He consumed 10 units of alcohol per week and was a non-smoker.
On examination his Glasgow Coma Score (GCS) was fluctuating between 9 and 11, he was moderately distressed and tachypnoeic despite oxygen supplementation. He was haemodynamically unstable, with blood pressure 70/40 mmHg and pulse rate of 140 bpm. Temperature was 41.1°C. Speech was incomprehensible, however, the patient was obeying commands. There were no signs of meningism, and the remainder of the neurological examination was unremarkable. Oral candidiasis was evident. Chest was clear on auscultation and abdominal examination was normal.
Arterial blood gas sampling on oxygen revealed pH 7.26, bicarbonate 14.4 mmol/L (22–30 mmol/L), base excess 13.4 mmol/L (−2.3– +2.3 mmol/L), PaO2 19.7kPa (10–13.33 kPa), PaCO2 3.55 kPa (4.67–6.0 kPa), sodium 158 mmol/L (134–146 mmol/L), potassium 2.8 mmol/L (3.4–5.2 mmol/L), glucose unrecordably elevated and lactate 6.73 mmol/L (0.5–2.0 mmol/L). A venous blood sample revealed urea 25.4 mmol/L (3.4–7.6 mmol/L), creatinine 331 umol/L (60–126 mmol/L), phosphate 0.22 mmol/L (0.80–1.40 mmol/L), glucose 62 mmol/L, creatine kinase 24040 U/L (24–195 U/L), amylase 2224 U/L (<100 U/L), albumin 35 g/L (34–51 g/L), AST 86 U/L (5–43 U/L), ALP 269 U/L (70–330 U/L), haemoglobin 13 g/dl (13.5–18 g/dl), white cells 5.9 × 109/L (4–11 × 109/L), platelets 102 × 109/L (150–450 × 109/L), INR 1.2. Serum osmolality was elevated at 410 mOsm/L. There were no ketones in his urine.
Differential diagnoses at this stage included central nervous system and/or urinary tract sepsis. Initial management comprised fluid and electrolyte replacement alongside an insulin infusion. He was commenced on intravenous anti-microbial therapy, with ceftriaxone and tazobactam-piperacillin, and intravenous aciclovir to cover herpes encephalitis. Anti-retroviral medications were discontinued.
Results of remainder of investigations
Haemofiltration was required for 10 days. Throughout this time, he improved neurologically, and was fully conscious by day 4 post-admission. Renal function normalized over the patient's 38-day stay in hospital and he was discharged independent of renal support. ART was recommenced in the form of abacavir/lamivudine and lopinavir/ritonavir. In addition, he was commenced on subcutaneous Detemir insulin.
Discussion
Lactic acidosis may have been a feature of HONK, from new onset diabetes mellitus, dehydration or sepsis, or more rarely nucleoside reverse transcriptase inhibitor (NRTI) use. Despite features of a systemic inflammatory response, no organisms were isolated and C-reactive protein and total white cell count remained normal. Interestingly, the lactate did not normalize with fluid resuscitation. Pancreatitis is a recognized presenting feature of HONK and also of NRTI use; however, despite an elevated amylase level, USS and CT imaging in this case did not support this.
Lactate is produced as a result of anaerobic metabolism and/or in the setting of impaired mitochondrial oxidative phosphorylation. The mode of action of NRTIs is by inhibition of reverse transcriptase, with the desired effect being HIV viral suppression. However, it appears that mitochondrial DNA polymerase gamma is also inhibited. 3, 4 Mitochondrial DNA polymerase gamma is essential for mitochondrial DNA synthesis and replication. Inhibition, therefore, leads to production of impaired mitochondria with reduced ability for oxidative phosphorylation with resulting hyperlactataemia. 4, 5
Given the persistent hyperlactataemia and poor clinical condition prior to haemofiltration, a decision was made to stop ART despite the risks of resistance. However, given this man's complex presentation we cannot be sure of the cause of his lactic acidosis. Our final diagnosis was that of HONK associated with acute renal failure on a background of HIV and long-term NRTI use.
Prior to discharge, a resistance assay confirmed a fully sensitive virus, and the patient was HLA B5701 negative. Enzyme assay and cell culture studies have revealed a hierarchy of mitochondrial DNA polymerase gamma inhibition. Therefore, ART regimes containing newer NRTIs, such as tenofovir and abacavir, have less potential to cause hyperlactataemia. 4, 5 Consideration was given to all the above factors, and to the availability of ART in the patient's home country, before re-starting therapy.
With the increased global burden of HIV, however, and the continued use of ‘older’ NRTI drugs in resource-poor settings, we must remain aware of the risk of NRTI associated hyperlactataemia.
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Acknowledgements
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