1 Department of Intensive Care, 2 Department of Radiology, 3 Department of Nephrology-Hypertension, Stuivenberg General Hospital, Antwerp, Belgium, 4 Department of Anatomopathology, University Hospital of Antwerp, University of Antwerp, Antwerp, Belgium and 5 Department of Intensive Care, Royal Darwin Hospital, Darwin, Australia
Keywords: chemotherapy; lactic acidosis; neoplasia; T-cell acute lymphoblastic leukaemia
Introduction
Lactic acidosis is a common cause of metabolic acidosis in intensive care patients. Two different types of lactic acidosis exist. Type A lactic acidosis is due to widespread tissue hypoperfusion or hypoxaemia. Type B lactic acidosis can occur in haematological malignancies, such as leukaemia or lymphoma. We describe a patient, previously successfully treated for a T-cell acute lymphoblastic leukaemia (T-ALL), presenting with a symptomatic type B lactic acidosis due to a relapse with isolated renal localization.
Case
A 29-year-old Caucasian male was admitted to the hospital because of a painful cutaneous lesion on the skull with, on physical examination, hepatomegaly and splenomegaly. Blood examination revealed moderate leucocytosis (24 000/mm3) with 50% blast cells and severe thrombocytopaenia (10 000/mm3). Liver function tests were abnormal: aspartate aminotransferase 90 U/l (normal values 1759 U/l), alanine aminotransferase 158 U/l (2172 U/l) and lactate dehydrogenase 5573 U/l (316618 U/l). A T-ALL, with involvement of skin, bone marrow, spleen, liver and mediastinal lymph nodes was diagnosed. After treatment with chemotherapy according to the HOVON-37 protocol (vincristine, daunorubicine, methotrexate, asparaginase, cytarabine, mitoxantrone and mercaptopurine), a complete remission was observed.
In November 2000, he developed a peripheral facialis paralysis, without evidence of leukaemic relapse. Imaging of the brain, consisting of computed tomography (CT) and magnetic resonance imaging, was normal. A viral infection was thought to be the cause of the paralysis. Treatment with aciclovir and corticosteroids was successful.
Three weeks later, he complained of nausea and vomiting, resulting in a weight loss of 3 kg. Clinical examination was normal. Laboratory studies showed a haemoglobin level of 11.7 g/dl, a platelet count of 127 000/mm3 and white blood cell count of 5300/mm3 (with 62.6% polymorphonuclear cells, 1.4% monocytes, 0.2% basophils, 21.3% lymphocytes and 14.5% monocytes). Biochemistry revealed a normal blood urea nitrogen, an elevated serum creatinine of 1.73 mg/dl (normal values 0.51.2 mg/dl) with a creatinine clearance of 60.6 ml/min, and an elevated uric acid of 9.99 mg/dl (3.58.5 mg/dl). Serum electrolytes were: sodium 139 meq/l; potassium 3.1 meq/l; chloride 107 meq/l; bicarbonate of 13.7 meq/l (2231 meq/l). Blood glucose and CRP levels were normal. Lactate dehydrogenase was increased to 943 U/l, the other liver function tests remained within normal limits. A gastroscopy showed a gastro-oesophageal reflux disease, grade I. Despite treatment with proton pump inhibitors and antiemetics, nausea and vomiting persisted. There were no signs of papilloedema on eye ground examination. Because imaging of the brain was recently performed and was found to be normal, it was not repeated. Cerebrospinal fluid examination showed minimal invasion of atypical lymphocytes, without the presence of the previously detected T lymphoblasts. An additional bone marrow examination was normal. Meanwhile, serum bicarbonate levels further dropped, with an increased anion gap of 26.8 meq/l (1018 meq/l). Arterial blood gas determination revealed a pH of 7.29, a PO2 of 118.2 mmHg, a PCO2 of 23.4 mmHg, a HCO3- of 10.9 mmol/l and a normal saturation. Because of this metabolic acidosis with increased anion gap, a serum lactate level was obtained, which was 11 mmol/l (0.72.1 mmol/l) (Table 1). None of the classical aetiologies for lactic acidosis was present and thiamine levels (98 nmol/l) were within normal limits. Treatment with bicarbonate (total of 800 meq/l) and vitamin B1 (100 mg/day) was not successful. An ultrasound examination of the abdomen revealed two diffusely enlarged kidneys (diameter 15 cm), which was confirmed by CT scanning (Figure 1
). A kidney biopsy showed a diffusely infiltrated interstitium by CD3-positive neoplastic T cells, suggestive for a renal relapse of the T-ALL.
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Discussion
Lactic acidosis was first described by Huckabee in 1961 [1]. A few years later Cohen and Woods [2] proposed a new classification for this clinical picture, making a distinction between lactic acidosis type A and type B. Normally, the metabolic production and consumption of lactate are in balance. The liver, and to a lesser degree, the kidney, utilize lactate produced by tissues such as skin, erythrocytes, brain, muscles and intestines. If oxygen delivery is inadequate, any tissue will generate lactic acid, being the end-product of the anaerobic metabolism of glucose. In type A lactic acidosis there is clinical evidence of poor tissue perfusion or oxygenation (shock, sepsis, hypoxia), while type B occurs without clinical evidence of tissue hypoperfusion. Already in 1966, type B lactic acidosis was described by Field et al. [3] in patients with acute leukaemia. Since then, various haematological malignant neoplasms have been reported to cause lactic acidosis [48]. We observed in our patient with a history of T-ALL, a metabolic acidosis with a high anion gap and a lactate of 7.8 mmol/l. In the absence of clinically apparent tissue hypoxia, shock or overwhelming sepsis, we assumed that this lactic acidosis was due to a relapse of his leukaemia. Surprisingly enough, bone marrow and cerebrospinal fluid examination were normal as well as his liver function tests and CT scan of the liver. The isolated renal localization is a rather unique presentation of a relapse of leukaemia. The mechanisms for the development of lactic acidosis in neoplasm are still unclear. Tumour cells in general have an intrinsically higher rate of anaerobic glycolysis then normal cells. One of the possible factors contributing to this higher rate of glycolysis is the overexpression or aberrant expression of glycolytic enzymes, such as hexokinase, by insulin growth factors and their receptors. These insulin growth factors and their receptors are overexpressed in some cancer cells. So the production of lactate by these tumour cells might be explained by an imbalance of the glycolysis over the gluconeogenesis [4]. In vitro experiments have demonstrated that under hypoxic conditions, leukaemic cells are able to produce sufficient amounts of lactate to explain lactic acidosis in vivo [5]. Another mechanism of lactate formation could be tissue ischaemia due to leukaemia microemboli or a tightly packed neoplastic tissue bed. Aggregates of tumour cells get overcrowded in various organs so that they become poorly oxygenated resulting in the production of lactate by their dependence on anaerobic glycolysis. Also, a decreased lactate clearance by the liver and the kidneys due to massive leukaemic infiltration could be a contributing factor to this clinical picture [4]. In an analysis by Sculier et al. [6] they found neoplastic involvement of the liver in 20 out of 25 patients. A similar case was published in 1994 in a 12-year-old boy by Ali et al. [7] where the bone marrow examination revealed an ALL with enlarged kidneys due to parenchymal infiltration by leukaemia cells. Probably the combination of a higher lactate production by tumour cells, tissue ischaemia and a decreased lactate clearance by liver and kidney is responsible for the lactic acidosis in patients with leukaemia. Nevertheless, it is still unclear why some of these patients develop lactic acidosis and others not.
The most striking aspect of this patient's illness was the profound and prolonged metabolic acidosis not correctable despite aggressive fluid resuscitation, sodium bicarbonate and the immediate resolution after the initiation of antineoplastic therapy. In our patient, bicarbonate should not have been started as sodium bicarbonate seems to increase lactate production in cancer patients. However, if the acidosis is very severe (blood pH <7.2), haemodynamic instability and reduced responsiveness to catecholamines can occur and sodium bicarbonate should be started.
In conclusion, this case illustrates that a relapse of a T-ALL with isolated renal localization can cause profound lactic acidosis. Treatment with chemotherapy resulted in a prompt resolution of the lactic acidosis and normalization of its renal size. We recommend that patients presenting with lactic acidosis without clinical evidence of tissue hypoperfusion, should have prompt consideration of underlying malignancy, haematological disorders or a relapse when no other obvious causes of type B lactic acidosis are present.
Conflict of interest statement. None declared.
Notes
Correspondence and offprint requests to: Dr Bart De Keulenaer, Royal Darwin Hospital, Intensive Care, Rocklands, Rocklands Drive, Tiwi 0810, Australia. Email: bdekeul{at}hotmail.com
References