Lactic acidosis expediting a diagnosis of acute lymphoblastic leukaemia

Abstract

We report the finding of a low venous bicarbonate and lactic acidosis in a patient with mild pancytopenia which raised the suspicion of haematological malignancy and expedited the diagnosis of acute lymphoblastic leukaemia. This report highlights the value of testing for lactic acidosis when haematological malignancies are considered and reviews the metabolism of lactic acidosis.

BACKGROUND

Lactic acidosis can be defined as a serum lactate concentration >4 mmol/l, although several thresholds exist.¹ It is felt to be a rare feature of haematological malignancies but there may be a degree of under-diagnosis as it is not routinely sought and its incidence has never been formally investigated.² Venous bicarbonate is a commonly available test that might prompt arterial blood gas analysis for lactic acid estimation. We report the chance finding of a low venous bicarbonate and lactic acidosis in a patient with mild pancytopenia which raised the suspicion of haematological malignancy and expedited the diagnosis of acute lymphoblastic leukaemia. We were not aware of the incidence of lactic acidosis in haematological malignancies and a search through the literature found case reports and small case series only. We wanted to highlight the value of a simple blood test and also identify a topic that warrants further study.

CASE PRESENTATION

A 78-year-old woman presented with a 4 week history of lethargy, epistaxis, leg cramps and palpitations. She had a past history of hypertension and a transient ischaemic attack. Routine examination was unremarkable and overall she appeared fit and well.

INVESTIGATIONS

Routine blood results were unremarkable except for pancytopenia (haemoglobin 103 g/l, white blood cell count 1.6×10⁹/l, platelets 81×10⁹/l).

DIFFERENTIAL DIAGNOSIS

• Myelodysplasia

OUTCOME AND FOLLOW-UP

She was referred to the haematology team and the most likely diagnosis at the initial assessment was felt to be myelodysplasia. A bone marrow aspirate and trephine were arranged and samples were sent on a routine basis with further review planned in outpatients.

However, on the same day, a renal profile revealed a low bicarbonate at 16 mmol/l (normal 24–30 mmol/l). Subsequent arterial blood gas sampling found a profound compensated lactic acidosis with a lactate of 12.5 mmol/l (normal <2 mmol/l). The causes of a compensated lactic acidosis were considered systematically and haematological malignancy was suspected. Her discharge was postponed while the bone marrow samples were urgently examined.

Blood film examination found moderate pancytopenia but bone marrow aspiration showed a predominance of small to medium sized blast cells with high nuclear to cytoplasmic ratio (fig 1). Residual myeloid and erythroid progenitors were morphologically normal. Flow cytometry confirmed common acute lymphoblastic leukaemia (ALL) while cytogenetic analysis revealed a hypodiploid karyotype (32XX) which is associated with a poorer prognosis. Palliative chemotherapy was initiated before discharge.

Figure 1.

Bone marrow aspirate showing an abundance of neoplastic blast cells (marked with horizontal arrows). Residual myeloid and erythroid progenitors were normal (a neutrophil is marked with a vertical arrow).

DISCUSSION

Lactic acid is a glycolytic byproduct derived from the anaerobic metabolism of pyruvic acid. Lactic acid is rapidly buffered by bicarbonate to produce lactate. Lactic acid is converted back to pyruvate which is either metabolised through to carbon dioxide and water via the Kreb’s cycle or is converted back to glucose via the glycolytic pathway. Over 50% of lactate is cleared hepatically with the remainder being metabolised by the kidneys and skeletal muscle.

Lactic acidosis is a consequence of either increased production, decreased clearance, or a combination of both. The underlying causes are differentiated into type a or type b dependent on whether there is evidence of tissue hypoxia and hypoperfusion.

Type A lactic acidosis occurs in the setting of poor tissue oxygenation or perfusion and thus includes diagnoses such as epileptic seizures, cardiac failure, septicaemia, and cardiac arrest. Although the main biochemical disturbance is anaerobic production of lactate, there may be diminished clearance as well if renal impairment or hepatic dysfunction occur.

In contrast, type B is characterised by toxin induced impairment of cellular metabolism and can be categorised into three subtypes based on the underlying aetiology.

• B1—systemic disease: renal and hepatic failure, diabetes, malignancy, HIV.

• B2—drug therapy and toxins: biguanides, alcohol, salicylates, iron.

• B3—inborn errors of metabolism.

Figure 2 illustrates the biochemistry of lactic acidosis with examples of pathology that may affect the homeostasis.

Figure 2.

Schematic diagram illustrating the biochemistry of lactic acidosis with examples of pathology that may affect its homeostasis.

The exact mechanism of lactic acidosis in haematological malignancy is not well recognised. Suggestions include anaerobic metabolism in dense neoplastic clusters, the maintenance of a high rate of glycolysis despite adequate tissue oxygenation, changes in mitochondrial metabolism,³ over expression of enzymes in the glycolysis pathway,⁴ paracrine effects of tumour necrosis factor α (TNF-α), deficiencies of riboflavin or thiamine that act as enzymatic cofactors,⁵ and hepatic infiltration resulting in impaired lactic acid clearance.² Although most reported cases of lactic acidosis and haematological malignancy involve hepatic infiltration, it can occur in those with limited tumour burden.²

Lactic acidosis in haematological malignancies is reported to be rare but no studies have systematically examined the true incidence. More specifically in ALL, our literature search only found case reports of lactic acidosis in paediatric patients.² It may be that lactic acidosis is being missed as it is not part of routine blood testing in most units. In addition, as this finding was evident before diagnosis, lactic acidosis may not just be a feature of late disease as previously suggested.⁶ Venous bicarbonate may prove useful at initial assessment. The finding of a low venous bicarbonate and lactic acidosis in this case increased our suspicion of malignant disease and led to earlier treatment.

In conclusion, compensated lactic acidosis occurs in haematological malignancies including acute lymphoblastic leukaemia, and may be found at the time of diagnosis. Venous bicarbonate should be considered if haematological malignancy is in the differential diagnosis, and a result below the reference range should prompt lactate measurement. Confirmation of lactic acidosis should be regarded as a positive predictor of haematological malignancy in the absence of other explanations.

LEARNING POINTS

• Venous bicarbonate may be a useful investigation when haematological malignancies form part of the differential diagnosis.

• Causes of lactic acidosis can be differentiated into type A and type B, depending on the presence of hypoperfusion.

• Lymphoma and leukaemia are rare causes of type B compensated lactic acidosis, although the exact incidence remains uncertain.