Type B lactic acidosis: a rare oncological emergency

Abstract

Type B lactic acidosis is a rare metabolic complication of malignancy, more commonly in haematological malignancies. Due to the lack of formal prospective trials, treatment of lactic acidosis associated with malignancy is based on case reports. Given the poor prognosis, early recognition of type B lactic acidosis and prompt treatment are crucial. We report the first case of type B lactic acidosis in metastatic melanoma, followed by a brief literature review on the proposed pathophysiology and treatment.

Background

Lactic acidosis is a common metabolic acidosis characterised by increased serum lactate (>5.0 mmol/L) leading to decreased blood pH.¹ It is classified according to the underlying pathophysiological process.² Type A lactic acidosis is due to hypoxia in the setting of sepsis and poor tissue perfusion. Type B lactic acidosis, however, happens in the absence of hypoxemia. Known causes include underlying liver disease (leading to decreased lactate clearance), thiamine deficiency, toxins (drugs) and malignancy. Type D lactic acidosis is due to excessive production of D lactic acid from intestinal bacterial proliferation, commonly seen in patients with short bowel syndrome or other forms of gastrointestinal malabsorption.

The association between lactic acidosis and malignancy was first proposed by Otto Warburg, who hypothesised that under aerobic conditions, tumour tissues metabolise more than tenfold more glucose to lactate than the normal tissues.³ This phenomenon is commonly seen in haematological malignancies but is rarely reported with solid tumours.⁴ Here, we present a patient with metastatic melanoma who was found to have profound lactic acidosis in the absence of tissue hypoperfusion or hypoxaemia.

Case presentation

The patient is a woman in her 60s with metastatic melanoma (BRAF-negative, on nivolumab) who presented to the emergency department with chest pain and shortness of breath. Her only medical comorbidity was hypothyroidism. She was afebrile, with a heart rate at 97 beats per minute, blood pressure of 126/61 mm Hg, and respiratory rate of 26 per minute with oxygen saturation of 93% on room air. Physical examination revealed a cachectic woman with bilateral trace lower extremity edema.

Investigations

Complete blood count showed white cell count of 8.900×10⁹/L, platelet count of 2.24 ×10⁹/L and a stable haemoglobin of 92 g/L. Her laboratory studies were remarkable for lactic acid of 18.1 mmol/L, CO₂ of 8 mmol/L and an anion gap of 25. All the electrolytes were within normal limit and renal function was normal. PET (positron emission tomography) done 1 week prior showed metastatic disease including multilevel lymphadenopathy above and below the diaphragm, and metastatic lesions in the liver, bone and spleen. The patient had an elevated aspartate aminotransferase (AST) of 67 units/L and alkaline phosphatase of 529 units/L. These abnormalities were chronic and were thought to be due to liver metastasis. An arterial blood gas showed a pH of 7.31 and a bicarbonate level of 9 mmol/L. CT angiogram (CTA) showed no pulmonary emboli. Urinalysis did not show any signs of infection, and blood cultures were negative. Electrocardiogram showed sinus tachycardia. The patient was admitted to the medical oncology service.

Differential diagnosis

Differential diagnoses at presentation included lactic acidosis due to sepsis, type B lactic acidosis from tumour progression and nivolumab-induced lactic acidosis. The patient had no signs of infection (CTA was negative for pneumonia, blood culture was negative at 48 hours, and urinalysis was normal) or evidence of tissue hypoperfusion. Metabolic acidosis is not a well-known side effect of immune checkpoint inhibitors such as nivolumab. There have been two case reports of acidosis after initiation of nivolumab. One case reported lactic acidosis after first dose of nivolumab in a patient with metastatic renal cell carcinoma.² Another case was a patient with metastatic non-small cell lung cancer who developed renal tubular acidosis (RTA) after four doses of nivolumab. The RTA resolved on discontinuation of nivolumab and initiation of steroid therapy. Since we cannot exclude nivolumab as the cause of lactic acidosis, a trial of methylprednisolone was started.⁵ Type B lactic acidosis is a rare metabolic complication of malignancy and remains a diagnosis of exclusion. When observed, it is more common in the setting of lymphomas and leukaemia and less so in solid malignancies. Based on our review of the current literature, there are no reported cases of melanoma causing lactic acidosis.

Treatment

Given the severity of the patient’s lactic acidosis, she was started on thiamine 500 mg daily, intravenous sodium bicarbonate at 50 mL/hour and methylprednisolone (1 mg/kg daily). Her lactic acid level remained elevated despite being haemodynamically stable (mean arterial pressure above 65 mm Hg, systolic blood pressure above 90 mm Hg) and no clinical signs of poor tissue perfusion. Nephrology was consulted for consideration of haemodialysis. Since the patient was making >50 mL/hour of urine with normal creatinine, haemodialysis was deemed unnecessary.

Overnight, the patient’s acidosis worsened, with bicarbonate level downtrending to 7 mmol/L. Intravenous sodium bicarbonate was increased to 75 mL/hour. On day 2 of admission, the patient had a transient improvement in metabolic acidosis (bicarbonate of 10 mmol/L) and slight improvement in lactate to 12 mmol/L. Oral sodium bicarbonate was started due to fluid overload with worsening peripheral oedema. During hospital days 3–4, the metabolic acidosis continued to deteriorate, with lactic acid peaking at 19 mmol/L. The lack of improvement in acidosis despite receiving methylprednisolone suggests against nivolumab-induced lactic acidosis.

Outcome and follow-up

Given the patient’s poor performance status, she was deemed not a candidate for further chemotherapy. The lactic acid continued to uptrend despite oral sodium bicarbonate. She responded clinically to methylprednisolone with increased oral intake and energy level. The patient and her family elected to transition to comfort care. On hospital day 5, she was discharged home with hospice. She passed away 2 months after the lactic acidosis was identified.

Discussion

Lactic acidosis due to solid malignancies is rare and is associated with high mortality due to the advanced disease process and high tumour burden.⁶ A thorough literature search in PubMed yielded less than 50 cases reported in solid tumours, 14 cases since 2010 (table 1). Based on our review of published cases, this is the first case of an otherwise unexplained severe lactic acidosis in metastatic melanoma. Although the exact pathogenesis of lactic acidosis in malignancy is unclear, a few theories have been proposed. One theory is that dense clusters of tumour cells with very high turnover rate could induce anaerobic metabolism and enhance pyruvate production.³ A second theory is that rapidly proliferating tumour cells could induce thiamine deficiency, ultimately leading to lactic acidosis.⁷ Another contributing factor seems to be the rapid rate of glycolysis in tumour cells. Tumour cells overexpress type II hexokinase,⁸ the enzyme responsible for catalysing the first step of glycolysis. This overexpression may allow continued glycolysis, increasing lactic acid production. Lastly, metastasis to the liver can lead to impaired pyruvate metabolism.⁹ This is supported by the fact that majority of the reported cases were associated with significant metastasis to the liver.

Table 1.

Reported cases of type B lactic acidosis in solid tumour since 2010

Case	Age/gender	Diagnosis	Liver metastasis	Treatment	Outcome
16	71/male	Metastatic prostate cancer	Yes	Intravenous sodium bicarbonate	Fatal (days)
212	62/female	Pheochromocytoma	No	Phenoxybenzamine and nifedipine followed by surgical excision of adrenal tumour	Lactic acidosis resolved
39	86/female	High-grade infiltrating ductal adenocarcinoma of the breast	Yes	Intravenous thiamine, sodium bicarbonate	Fatal (weeks)
413	77/male	Small cell carcinoma of the liver	Yes	Pain control	Fatal (days)
514	71/female	CD30-positive gastric cancer	Presumed liver metastasis	Intravenous sodium bicarbonate	Fatal (days)
63	76/male	Adenocarcinoma of unknown primary origin	Yes	Continuous renal replacement therapy	Fatal (days)
715	81/male	Gastric adenocarcinoma	Yes	Comfort care	Fatal (days)
816	44/female	Colon cancer	Yes	Sodium bicarbonate infusion, chemotherapy	Death at 15 months after diagnosis
91	74/male	Small cell carcinoma of the lung	No	Thiamine, chemotherapy	Lactic acidosis resolved
1017	71/male	Neuroendocrine carcinoma	No	Intravenous sodium bicarbonate, haemodialysis, chemotherapy	Fatal in days
1118	73/female	Small cell carcinoma of the lung	Possible metastasis	Comfort care	Fatal in days
1210	56/male	Poorly differentiated neuroendocrine metastatic carcinoma and renal cell carcinoma	Yes	Antibiotics, intubation→ comfort care	Fatal in days
1319	37/female	Glioblastoma multiforme	No	Comfort care	Fatal in days
1420	Unknown age/female	Cervical squamous cell carcinoma	Possible metastasis	Thiamine, dexamethasone	Fatal in days

Treatment options for solid tumour lactic acidosis have not been fully established. Thiamine supplementation is often used. The rationale is that it would drive pyruvate to induce synthesis of acetyl coenzyme A (CoA) instead of being shunted towards the fermentation to lactic acid.^{10 11} However, there are also reports that suggest excess thiamine could increase tumour growth.⁸ In general, chemotherapy appears to be the most effective treatment as it reduces tumour burden and malignant liver involvement. The challenge, however, is that most patients have aggressive cancer with very short survival times and are unable to tolerate antineoplastic interventions. Intravenous bicarbonate and continuous renal replacement therapy are used as temporary measure with little success, because they do not target the mechanism that causes overproduction of lactic acid. Our patient received bicarbonate infusion and thiamine supplementation. Despite these interventions, her lactic acidosis continued to worsen.

Our patient was discharged home with hospice. Review of previous publications indicated that the majority had very poor outcomes with life expectancy of days to weeks. Those who survived more than several weeks had surgical or systemic therapy for their malignancies. Lactic acidosis in solid malignancy seems to be a marker of poor prognosis regardless of the treatment offered. Better understanding of the tumour metabolism pathway may not only hold promise for future approaches against cancer, but also allow for better control of lactic acidosis in patients such as ours by targeting responsible pathways rather than mitigate the downstream effects.

Learning points.

• Lactic acidosis associated with solid tumour is rare but often fatal.

• Prompt diagnosis of type B lactic acidosis and early initiation of chemotherapy may improve survival.

• Understanding the pathogenesis of lactic acidosis in malignancy may lead to novel treatments for cancer but may also improve survival in patients such as the one presented here.