Two types of lactic acidosis (LA) are described and seen in clinical practice: type A LA, which is caused by tissue hypoperfusion or acute severe hypoxemia, and type B LA, which is a result of common diseases, drugs, toxins, and hereditary and miscellaneous disorders6 (Table 1). Type B LA represents a rare and often lethal complication when present in the setting of hematologic malignancy. It is thought to develop from several mechanisms including overproduction of lactate from aberrant glycolytic processes and decreased clearance due to hepatic or renal dysfunction17,26. This complication occurs more commonly in adults, and it carries a poor prognosis. Any favorable responses to chemotherapy are generally transient. In the medical literature before 2001, we found reports of 53 cases of type B LA in patients with lymphoma or leukemia13,17,18,20,26. In the current study we report 7 cases from our institution. In addition, we performed a literature review to identify any cases of type B LA described since a review published in 200126.
PATIENTS AND METHODS
We performed a retrospective review of medical records to identify patients at our institution who developed type B LA as a complication of hematologic malignancy. The medical records department identified patients with a diagnostic code of "acidosis" and "leukemia" or "lymphoma" from 1990 to 2003. Patients with multiple myeloma were not included. Thirty patients were identified, and their charts were reviewed. To be included in the final analysis, patients had to have type B LA, as defined by the criteria of Luft and associates (pH ≤7.35 and serum lactate concentration ≥5 meq/L)16 and associated with leukemia or lymphoma. Any patients with hypotension (systolic blood pressure [BP] <90 mm Hg or mean arterial pressure <65 mm Hg), and thus type A LA, were excluded. Of the 30 patients reviewed, 7 were found to have type B LA associated with hematologic malignancy (Figure 1). Clinical and laboratory features of these 7 patients are summarized in Tables 2 and 3, respectively. The medical record review at both Rhode Island and Miriam Hospitals (Providence, RI) was approved by the Lifespan Institutional Review Board.
Patients outside of our institution were identified by performing a MEDLINE and PubMed (National Library of Medicine, Bethesda, MD) review of literature with the key words "type B lactic acidosis" and "leukemia" or "lymphoma" in the English language from the years 1990 to 2006. Each of the identified cases also met the criteria of Luft and associates for LA as above16. Sillos et al reported 53 cases of type B LA in patients with leukemia and lymphoma before 200126. From our recent review of the literature we identified 14 additional cases.
CLINICAL CASE REPORTS FROM MIRIAM AND RHODE ISLAND HOSPITALS
A 79-year-old man with a history of hypertension and acute lymphoblastic leukemia who was in remission for 1 year after treatment with CALGB protocol 19802 (chemotherapy agents included cyclophosphamide, daunorubicin, prednisone, vincristine, L-asparaginase, and granulocyte colony stimulating factor; maintenance with methotrexate) presented with 1 month of fevers, cough productive of green sputum, and generalized malaise. He was started on cefuroxime as an outpatient but was found to have an increasing white blood cell (WBC) count and was therefore sent to the emergency department for evaluation. On the day of admission, he had a temperature of 38.4 °C, pulse of 83 beats per minute, and BP of 114/54 mm Hg. On physical examination he had hepatosplenomegaly and a soft systolic murmur. His WBC count was 49.0 × 103/uL with 9% blasts, serum creatinine was 1.5 mg/dL, and serum uric acid was 10.6 mg/dL. The patient was started on cefepime and fluconazole. The WBC count increased to 78.0 × 103/uL and the hemoglobin dropped to 8.3 g/dL. Blood, urine, and sputum cultures showed no growth. He was started on hydroxyurea. On hospital day 2 the patient had a bone marrow biopsy that showed new acute myeloid leukemia. He subsequently became unresponsive. He was tachypneic but hemodynamically stable, and an arterial blood gas analysis showed pH of 7.05, pCO2 of 28 mm Hg, pO2 of 68 mm Hg, and arterial lactate of 19 mEq/L (normal, 0.2-2.2 mEq/L). Serum bicarbonate was 10 mEq/L, anion gap was 28, and creatinine was 4.3 mg/dL. He was endotracheally intubated and subsequently became hypotensive and required vasopressor support. He then had a seizure and became asystolic. Blood glucose was 9 mg/dL and bicarbonate was 8 mEq/L. The patient's family decided to withdraw support, and he expired.
A 75-year-old woman with a history of stage IV follicular lymphoma presented with increasing abdominal girth and progressive, severe dyspnea. On admission she was normotensive, her pulse was 104 beats per minute, respiratory rate was 25 per minute, and she was in mild respiratory distress. There were decreased breath sounds at her lung bases and her abdomen was tense and distended. Her WBC count was 4.0 × 103/uL with a normal differential count, creatinine was 1.6 mg/dL, phosphorus was <1.0 mg/dL, uric acid was 14.5 mg/dL, aspartate aminotransferase (AST) was 468 IU/L (normal, 10-42 IU/L), alanine aminotransferase (ALT) was 321 IU/L (normal, 5-60 IU/L), alkaline phosphatase was 488 IU/L (normal, 40-130 IU/L), and total bilirubin was 5.1 mg/dL (normal, 0.2-1.3 mg/dL). The international normalized ratio (INR) was 1.4, and partial thromboplastin time (PTT) was 20.4 seconds. An arterial blood gas analysis showed pH of 7.48, pCO2 of 29 mm Hg, and pO2 of 78 mm Hg. Venous lactate was 4.2 mEq/L (normal, 0.2-2.2 mEq/L). Computed tomography (CT) of the chest, abdomen, and pelvis showed bilateral pleural effusions, ascites with omental nodularity, and a thickened gallbladder. The patient was started on piperacillin/tazobactam, her phosphorus was repleted, and allopurinol was initiated. A right upper quadrant ultrasound showed no cholecystitis. The serum creatinine level rose to 2.9 mg/dL. Serum bicarbonate subsequently dropped to 17 mEq/L, and she was started on treatment with VP-16. The next day she was found confused with a serum bicarbonate of 11 mEq/L, serum arterial lactate of 5.4 mEq/L, and creatinine of 4 mg/dL. At the time she was hemodynamically stable. An arterial blood gas analysis showed pH of 7.20, pCO2 of 26 mm Hg, and pO2 of 91 mm Hg. She received a second dose of VP-16. The following morning she became apneic and pulseless. She had an advanced directive stating she did not want to be resuscitated, and she died.
A 54-year-old woman with chronic lymphocytic leukemia who had previously been treated with cyclophosphamide, vincristine, and prednisone (CVP) for several months was admitted to the hospital with weakness, low-grade fever, abdominal discomfort, and diaphoresis. Physical examination was notable only for a normal BP and profound splenomegaly. Both CT scan and abdominal ultrasonography revealed massive splenomegaly and gallstones without cholecystitis. Initial laboratory tests showed a WBC count of 2.7 × 103/uL with normal differential count, serum creatinine of 1.1 mg/dL, lactate dehydrogenase (LDH) of 744 IU/L (normal, 296-558 IU/L), AST of 179 IU/L, and ALT of 106 IU/L. Four days after admission, the patient's serum bicarbonate was 13 mEq/L and an arterial blood gas analysis showed pH of 7.30, pCO2 of 24 mm Hg, and pO2 of 106 mm Hg. Serum glucose was 71 mg/dL. At that time, she was afebrile with a pulse of 91 beats per minute and a BP of 138/73 mm Hg. Her serum lactate level was 12 mEq/L. CT of the abdomen again showed massive splenomegaly, this time with a small wedge-shaped infarct. A bone marrow biopsy was performed. The underlying lymphoma was felt to have transformed into a stage IV, high-grade, large B-cell, CD20 positive lymphoma. The patient received cyclophosphamide and doxorubicin and subsequently rituximab. Within 3 days, her serum bicarbonate rose to 20 mEq/L and remained between 21 and 29 mEq/L for 2 weeks, while her arterial blood gas improved to pH 7.49. Approximately 3 weeks after her initial inpatient chemotherapy, the patient's serum LDH began to rise above 900 IU/L and LA returned. She received salvage chemotherapy with methylprednisolone, cisplatin, and cytarabine. She developed multisystem organ failure, and she died 1 month after receiving the first cycle of inpatient chemotherapy.
A previously healthy 54-year-old man presented with a 3-week history of low-grade fevers, nausea/vomiting, anorexia, night sweats, and 20-lb weight loss. He was normotensive and tachycardic, with no remarkable findings on physical examination. Admission laboratory data showed a WBC count of 6.8 × 103/uL, serum LDH of 1022 IU/L, and AST of 70 IU/L. He developed high-grade fevers and mental status changes, and an extensive infectious disease workup was negative. Additional laboratory data showed an INR of 1.4, PTT of 34.2 seconds, fibrinogen of 252 mg/dL (normal, 150-480 mg/dL), normal haptoglobin, and negative direct/indirect Coombs tests. Arterial blood gas showed pH of 7.32, with lactate of 12 mEq/L. At this time the patient had a temperature of 38.8 °C, pulse of 92 beats per minute, and BP of 120/50. CT of the abdomen showed no evidence of lymphadenopathy or organomegaly. A presumptive diagnosis of thrombotic thrombocytopenic purpura was made, and daily plasma exchange was begun 5 days after admission. Despite this, the patient's mental status did not improve, the serum lactate remained elevated, and the serum bicarbonate dropped to 14 mEq/L. A bone marrow biopsy revealed the diagnosis of extranodal primary bone marrow T-cell lymphoma. Chemotherapy was initiated using cyclophosphamide, vincristine, doxorubicin, and prednisone. A repeat bone marrow examination showed hypoplasia with no recovery. Serum bicarbonate had recovered to 28 mEq/L. He remained disoriented and had a lumbar puncture which was unremarkable. Magnetic resonance imaging showed no central nervous system disease. He ultimately developed acute respiratory distress syndrome and septic shock. He died approximately 10 weeks after admission.
A 66-year-old woman with advanced chronic lymphocytic leukemia was admitted for altered mental status. She had been maintained on oral cyclophosphamide for many years. Several months before this admission, she received 4 cycles of fludarabine for bulky lymphadenopathy and a leukocyte count of 100 × 103/uL. She subsequently received 4 weekly consolidative treatments with rituximab. On admission she was obtunded, serum calcium was 13 mg/dL, serum uric acid was 14.9 mg/dL, WBC count was 6.1 × 103/uL with 71% lymphocytes, and serum creatinine was 1.5 mg/dL. She had bulky cervical, axillary, and inguinal lymphadenopathy and prominent hepatosplenomegaly. The patient received intravenous fluids and furosemide for hypercalcemia, and her mental status improved along with normalization of serum calcium and uric acid levels. On hospital day 5, however, her serum bicarbonate was 16 mEq/L and serum lactate was 5.3 mEq/L. At that time she was afebrile, her pulse was 81 beats per minute, and BP was 119/63 mm Hg. Arterial blood gas confirmed metabolic acidosis with pH of 7.35. She was diagnosed with type B LA and chemotherapy with cyclophosphamide, vincristine, doxorubicin, and prednisone (CHOP) was administered for primary treatment. On day 1 of chemotherapy, the serum bicarbonate level was 9 mEq/L. By day 8, it rose to 18 mEq/L, and by day 21 it improved to 26 mEq/L. Her serum lactate levels ranged from 5.3 to 7.5 mEq/L throughout her hospitalization. Glucose levels were normal. The patient was discharged to a rehabilitation facility with close outpatient follow-up. Despite further CHOP chemotherapy, she subsequently died.
A 61-year-old woman with a past history of hypertension presented with lightheadedness, fatigue, and a 30-lb weight gain over the prior few weeks. She had been at an outside cardiologist's office where she was lightheaded and had anasarca, and serum albumin was found to be 1.7 mg/dL. An echocardiogram showed normal left ventricular function, but she was admitted to the hospital for further workup. On admission she was afebrile with a pulse of 110 beats per minute and BP of 118/62 mm Hg. The physical examination was notable for anasarca and a mildly tender abdomen diffusely. The complete blood count was normal. Serum LDH was 711 IU/L. A CT of the abdomen showed marked splenomegaly with multiple areas of low attenuation but no other abnormalities. Subsequently a bone marrow biopsy revealed atypical clusters of B cells but was nondiagnostic. High-dose intravenous dexamethasone was initiated for presumed lymphoma. A repeat bone marrow examination showed intravascular lymphoma. She subsequently developed a fever to 40.4 °C and became extremely tachypneic but remained normotensive. An arterial blood gas analysis showed pH of 7.32 with arterial lactate of 11.6 mEq/L. She was transferred to the intensive care unit where she was endotracheally intubated. On hospital day 48 she was given rituximab, but she soon became bradycardic and died.
A 54-year-old man with a recent diagnosis of diffuse large B-cell lymphoma and recent initiation of hemodialysis for chronic renal insufficiency was admitted to the hospital with dysarthria. He had been complaining of recent weakness and sweats, and 2 weeks before admission had been treated with Cytoxan and prednisone. On admission his pulse was 118 beats per minute, respiratory rate was 21 per minute, and BP was 96/40 mm Hg, which was his usual long-standing BP. The physical examination was unremarkable. Laboratory data were notable for a WBC count of 35.1 × 103/uL with 30% neutrophils and 4% bands. His bicarbonate was 8 mEq/L, creatinine was 6.7 mg/dL, and glucose was 40 mg/dL. An arterial blood gas analysis showed pH of 7.21 and serum arterial lactate of 16.9 mEq/L. He was admitted to the medical intensive care unit and given cefepime and vancomycin and dialyzed for severe acidemia. He became progressively tachypneic with a respiratory rate of 43 per minute, but remained hemodynamically stable. A repeat arterial lactate was 18 mEq/L. He was subsequently endotracheally intubated for severe respiratory distress. Shortly after intubation his temperature rose to 41.4 °C and his WBC count rose to 59 × 103/uL. He became hypotensive and required vasopressor support. No source of infection was found. On hospital day 4 the patient's family requested withdrawal of support, and he subsequently died.
Summary of Cases From the Literature Review
We found 14 additional cases of type B LA associated with leukemia and lymphoma (Tables 4 and 5). Ten of the patients were male and 4 were female. There were 6 cases of leukemia, and the remaining 8 cases were non-Hodgkin lymphoma. Two of the non-Hodgkin lymphoma cases were Burkitt lymphoma. The majority of cases (11 patients) developed type B LA at the time of diagnosis, while the remaining 3 developed type B LA during relapse. Eight cases had presumed hepatic involvement. Three of the 6 patients with leukemia had thiamine deficiency associated with the development of type B LA, and all 3 of the patients' LA improved solely with the administration of thiamine. However, 1 patient died from graft rejection shortly after bone marrow transplantation. The remaining 3 patients with leukemia were treated with chemotherapy; 2 of the 3 improved and were reportedly doing well. All 8 of the patients with lymphoma were treated with chemotherapy, and the LA improved in only 1 patient after treatment. All 8 patients with lymphoma died despite initiation of chemotherapy.
The development of type B LA in the setting of hematologic malignancy is thought to be an uncommon complication, but it has devastating consequences. Despite its severity, little is known about type B LA in patients with leukemia and lymphoma; the pathophysiologic processes involved are poorly understood and there is little evidence supporting various treatments. The data in the current study build on a prior case series and newly published case reports26.
There are several proposed mechanisms for the development of type B LA in the setting of a hematologic malignancy, but the cause is likely to be multifactorial. Two mechanisms that probably contribute to the development of this complication are liver and kidney dysfunction. Lactate, which is the end product of anaerobic metabolism, is converted to pyruvate, and subsequently into glucose by both the liver and kidneys. The kidney clearance of lactate is approximately 10%, while 90% is by hepatic metabolism30. Therefore, severe dysfunction in the liver or kidneys, whether it is from tumor infiltration, ischemic damage, or other causes of impairment, may lead to accumulation of lactate. However, many patients with liver and kidney dysfunction do not develop this complication, and therefore there must be more complex processes occurring that contribute to type B LA.
Another possible mechanism involves tumor cell overexpression of certain glycolytic enzymes and mitochondrial dysfunction26,28. Some tumor cells overexpress insulin-like growth factor-I and hexokinase, which results in high rates of glycolysis and thus higher glucose levels, which allow the cells to proliferate rapidly26. Cancer cells often utilize anaerobic metabolism even in the presence of oxygen, and therefore a significant proportion of the glucose is converted to lactate. Additionally, dense compressing tumor mass or leukemic microemboli might impair tissue perfusion and cause ischemia with a resulting increase in anaerobic glycolysis3.
TNF-alpha may also play a role in the development of type B LA in these patients10,24. It has multiple paracrine actions on tumor cells, including effects on mitochondrial function. The presence of TNF-alpha causes a reduction in the activity of pyruvate dehydrogenase and also inhibits the cytochrome-dependent electron transport system, both of which result in increased levels of lactate. It also has systemic effects that alter hepatic glucose metabolism, which results in systemic LA.
Another mechanism in the development of type B LA that has been described is thiamine deficiency. Thiamine is an important cofactor in the pyruvate dehydrogenase complex (Figure 2). Without thiamine, this enzyme cannot convert pyruvate into acetyl coenzyme A, and instead anaerobic metabolism occurs by conversion into lactate21,27. This has been reported as a complication in patients, some with malignancy, receiving total parenteral nutrition without vitamin supplementation5,21,27. In this situation, the acidosis was reversed when thiamine was added to the alimentation solution.
The type of chemotherapy a patient has received may also play a role in the development of type B LA. Methotrexate competes with the thiamine transport systems, and therefore reduces the availability of thiamine and may cause type B LA by the same mechanisms described above in patients with thiamine deficiency27,31.
Additionally, type B LA has been found to be a complication of nucleoside reverse transcriptase inhibitors used to treat patients with human immunodeficiency virus (HIV)19,25. This effect is also likely due to mitochondrial dysfunction with aberrant glycolytic processes. There have been case reports of both riboflavin and thiamine successfully treating this complication1,7. Resolution of nucleoside analog-induced LA with high doses of riboflavin or thiamine also supports the hypothesis that vitamin deficiencies may be an important cofactor in the development of this condition in patients with HIV.
Tumor lysis syndrome has been described as a possible mechanism in the development of type B LA29. Apoptosis of tumor cells causes a loss in the mitochondrial membrane potential and thus a loss of mitochondrial function. This leads to compensatory glycolysis in these cells, which is the cause of the lactate accumulation and acidosis.
The 7 new patients we report here with type B LA and hematologic malignancies, and many of those previously reported, likely had multiple mechanisms contributing to the development of the disorder. Many had both hepatic and renal dysfunction, but it is not clear how much that may have played a role in the development or progression of type B LA.
When we compared our 7 patients with the 53 patients reported by Sillos26 and the 14 recently published cases that we reviewed, we noted some differences. In the cases previously reported, there were proportionately more leukemia patients than in the current study, but our sample size was small. Also, a significant number of the 53 patients previously reported and 8 of the 14 cases from our literature review had hepatic involvement, while only 3 of 7 patients from our case series had hepatic involvement. These numbers may be difficult to interpret, however, because there was little tissue documentation of this abnormality in the literature or in our 7 patients.
One important similarity to the cases reported in the literature is that all 7 of our patients had bulky disease or large tumor burden. This may be important in recognizing which patients are at highest risk of developing type B LA. Unfortunately, no CD markers are reported in most prior cases. We were unable to demonstrate a unique CD marker on the lymphoma cells from our patients, but of the patients we were able to evaluate, the most common marker was CD20, perhaps reflecting the prevalence of B-cell disorders. We hope that karyotypic, genetic microarray, or newer molecular studies will be done in the future to investigate whether such patients share unique genetic or molecular abnormalities.
The best treatment of patients with hematologic malignancies who develop type B LA is not clear. Initiating aggressive chemotherapy has been effective in a small number of patients26. In such patients it is believed that if neoplastic cells are producing excess lactate and inhibiting its clearance, their destruction should reduce the LA. This treatment would not be effective in patients whose tumor is unresponsive to chemotherapy. Renal replacement therapy with either intermittent hemodialysis or continuous venous-venous hemodialysis in patients with renal dysfunction may be useful in addition to chemotherapy, as it will help eliminate the excess lactate. In order to learn if there is thiamine deficiency, serum levels of this vitamin could be measured; however, this might not accurately reflect levels in malignant cells or other tissues. Most reported cases of type B LA do not include levels of thiamine or riboflavin, and in our 7 patients they were not measured. However, because there are few successful therapeutic interventions available for these patients, repletion of B vitamins might be an easy and safe way to help reverse type B LA.
Type B LA is thought to be a rare yet life-threatening complication in patients with hematologic malignancies, and it is likely underrecognized and therefore under diagnosed. If patients with leukemia or lymphoma develop an anion gap acidosis in the setting of a normal BP, or acute respiratory distress without an obvious pulmonary source, the possibility of type B LA should be entertained and the lactate level should be checked. It is important for physicians to be aware of this condition so a rapid diagnosis can be made and therapy can be initiated without delay.
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