JOURNAL OF CANCER RESEARCH AND ONCOBIOLOGY (ISSN:2517-7370)

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A Rare Case of Lactic Acidosis Associated with Small Lymphocytic Lymphoma

Sushil K. Mehandru1*, Supreet Kaur1, Jaraad Dattadeen1, Brian Erler1, Arif Asif1, Tushar J Vachharajani2

1Department of Medicine,  Division of Nephrology & Hypertension, Department of Pathology, Jersey Shore University Medical Center, Hackensack Meridian School of Medicine, Neptune, New Jersey, United States
2Department of Nephrology and Hypertension, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Glickman Urological & Kidney Institute Cleveland Clinic, Cleveland, Ohio, United States

CitationCitation COPIED

Mehandru S, Kaur S, Dattadeen J, Erler B, Asif A, et al. A Rare Case of Lactic Acidosis Associated with Small Lymphocytic Lymphoma. J Cancer Res Oncobiol. 2020 Dec;3(3):131.

Copyright: © 2020 Mehandru S, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 international License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

Type B lactic acidosis is a rare occurrence in patients with lymphomas, leukemias, and solid neoplasms. Several types of lymphomas have been associated with type B lactic acidosis, however, small lymphocytic lymphoma (SLL) has not been associated with lactic acidosis; to the best of our knowledge. We report a case with biopsy proven small lymphocytic lymphoma admitted for chemotherapy. Lactic acidosis was present on admission, progressing within 48 hours to lactic acid levels of over 10 mmol/L, a substantial increase from 2.8 mmol/L on admission. Presence of lactic acidosis in a patient with small lymphocytic lymphoma is a poor prognostic factor. Chemotherapy is indicated in patients with SLL and concomitant lactic acidosis. In some cases of B-cell lymphoma, thiamine deficiency has been reported to cause Type B lactic acidosis. This type of lactic acidosis may be corrected with thiamine administration. Chemotherapy and thiamine both have been studied by some authors; however, overall prognosis remains poor. Although, our patient received thiamine during this admission, lactic acidosis continued to worsen. We report an 86 year old male with history of small lymphocytic lymphoma who developed severe lactic acidosis, most likely secondary to SLL. We recommend early administration of chemotherapy and thiamine, if levels are low, this may slow the rise of lactic acid in patients with lymphomas, leukemias, particularly small lymphocytic lymphoma.

Keywords

Lactic acidosis; Small lymphocytic lymphoma; Renal Replacement Therapy, Sodium Bicarbonate, Thiamine

Introduction

Lactic acidosis (LA) is a life threatening event encountered in solid neoplasms as well as leukemias and lymphomas. We are reporting a case with small lymphocytic lymphoma, never been reported before to the best of our knowledge, developing severe progressive lactic acidosis. Pathogenesis of malignancy induced lactic acidosis is not well understood; however associated factors include glycolysis, increased lactate production by cancer cells, and decreased hepatic clearance of lactate. When it occurs, lactic acidosis is a poor prognostic sign in these patients [1]. Lactic acidosis is infrequently encountered in malignancies; yet when present portends an extremely poor prognosis [2]. Moreover, the strikingly high mortality rate associated with lactic acidosis has prompted some oncologists to consider this as an emergency as reported [3] in several dozen patients with leukemias and high grade lymphomas, mostly with poor prognosis. No case has been reported with SLL resulting in lactic acidosis to the best of our knowledge. Several types of lactic acidosis have been reported, type A refers to lack of sufficient oxygenation and poor tissue perfusion resulting in lactic acid build up, whereas type B lactic acidosis occurs in normal tissue perfusion, and type D has also been described, which may be observed in patients with short bowel syndrome or ingestion of propylene glycol [4]. However, the usual laboratory analysis does not detect D-lactate. Causes of Type B LA range from liver disease, errors in metabolism, toxins or drugs and in rare cases, malignancy. The exact mechanism is unclear and as such there are limited treatment options, aside from addressing the underlying cause. Diffuse Large B cell lymphoma [5], Follicular lymphoma [5], T cell lymphoma [5], Anaplastic large B-cell lymphoma [6], Burkitt’s lymphoma [7], Mucosa Associated Lymphoid Tissue (MALT) lymphoma [8], Mantle cell lymphoma [6] and Hodgkin’s lymphoma [9] have previously been associated with lactic acidosis. We present a case of small lymphocytic lymphoma, previously not reported, that is associated with severe type B lactic acidosis.

Lactic acidosis (LA) has been reported to be associated with high grade lymphomas as a terminal event. While the mechanism of type B lactic acidosis is not entirely understood, there are several theories, which include intrinsic lactate production by tumor cells, impaired clearance of lactate in the kidneys or liver dysfunction, riboflavin and thiamine deficiency. Tumor cells have been found to have increased lactate production, as they primarily utilize aerobic glycolysis, which is also known as Warburg effect [10]. Thiamine acts as a co-factor for various enzymes involved in aerobic metabolism, such as pyruvate dehydrogenase; therefore, its deficiency promotes anaerobic metabolism, which results in the production of lactate (10). Only a few reported cases illustrate this phenomenon in patients with lymphomas [11,12]. The cases have generally been reported in pediatric patients receiving parenteral nutrition without vitamin supplementation [13]. Small lymphocytic lymphoma (SLL) is a malignancy of the immune system effecting B-cells. SLL is a type of non-Hodgkin’s lymphoma along with chronic lymphocytic leukemia, these two malignancies are alike and treated similarly. In SLL, malignant cells are mainly in the lymph nodes and spleen. In CLL, however, most of the malignant cells are in the blood and bone marrow. Treatment of SLL and CLL is chemotherapy and combination of monoclonal antibodies and radiation. SLL and CLL are the most common types of leukemias in adults in the United States [14]. Type B lactic acidosis has been reported in cases with CLL [15]. To the best of our knowledge, our case is the first report of Type B lactic acidosis in a patient with SLL. Outcome of Type B lactic acidosis is poor regardless of the type of malignancy. Type B lactic acidosis has been found in malignancies, thiamine deficiency, alcoholism, liver failure, and seizures. Treatment of underlying malignancy along with possible thiamine administration appears to be common management strategy. However, in the absence of well-defined treatment protocols, more research is necessary to understand and manage malignancy related Type B lactic acidosis.

Case Presentation

86 year old male presented for progressive generalized weakness, loss of appetite, and chills one week prior to admission. He was recently diagnosed, with biopsy proven small lymphocytic lymphoma. Patient was scheduled to start chemotherapy. Vital signs at the time of presentation were temperature 97.60 Fahrenheit, pulse of 80 beats/min, respiratory rate of 18 resp/ min, oxygen saturation of 95% on room air and blood pressure of 120/60 mmHg. Physical examination revealed anterior cervical lymphadenopathy, the rest of the examination was unremarkable. Notable lab values on admission include White blood cell 14.8 103 /μL, Hemoglobin 10.7 g/dL, Hematocrit 33.8 %, Platelets 176 103 /μL, AST 56 U/L, ALT 28 U/L, Total bilirubin 2.3 mg/dL, Blood Urea Nitrogen 24 mg/dL, Creatinine 1.09 mg/dL, Lactic acid 2.8 mmol/L. Computer Tomography (CT) scan of abdomen and pelvis with contrast showed moderate splenomegaly with multiple intrasplenic lesions, most likely secondary to lymphoma, mild hepatomegaly with diffuse intrahepatic lesions most likely secondary to lymphoma and extensive adenopathy in retroperitoneum and iliac chains. There was no known history of medications that could cause elevated lactic acid levels, such as metformin. Other causes of metabolic acidosis were not noted in this patient. Despite interventions as per hospital protocol, his lactic acid levels continued to rise. At that time, patient was started on sodium bicarbonate. His lactic acid continued to increase regardless of the current therapy. Patient received Thiamine intravenously for three days. Due to patient’s overall poor condition, chemotherapy was not initiated. On day #3 of hospitalization, patient’s clinical appearance and respiratory status worsened. He became tachypneic. Arterial blood gas reports showed worsening metabolic acidosis due to rising lactic acid levels. Patient was intubated for respiratory support. He was given 2 liters of IV normal saline and bicarbonate infusion rate was increased. On hospital day #4, patient’s lactate levels remained elevated and because of worsening renal functions, decision to initiate renal replacement therapy (RRT) was made. Discussion was held with patient’s family, and due to his poor prognosis and widespread malignancy, care was withdrawn and subsequently patient passed away the same day (Figure 1,2,3). 

Figure 1: (A) Lactic acid trend. (B) Bicarbonate Trend

Figure 2: CT Abdomen/Pelvis showing hypodense lesions in the spleen (Red arrow - 4x3 cm lesion)

Figure 3: Cervical lymph node biopsy showing small lymphocytic lymphoma 

Discussion

Most of the information about type B lactic acidosis associated with malignancy is derived from case reports without any randomized controlled trials to compare different therapeutic modalities. Type B lactic acidosis is most, please re-arrange spacing. Although, formal prospective trials are underway, type B lactic acidosis in malignancy seems to be a marker of poor prognosis regardless of the treatment offered and may eventually be fatal. Overall, the prognosis appears poor with 77% mortality rate in few days to weeks [16]. Thiamine IV administration has corrected lactic acidosis in a case reported by Masood et al [13]. Early administration of chemotherapy has shown lowering of lactic acidosis levels in some cases of colorectal cancer. Lactic acidosis is known to occur in patients with leukemia and lymphoma as a terminal event. It occurs in rapidly proliferating tissue (17). Severe lactic acidosis in malignancies is rare but fatal complication [18]. Ribavirin exhibits inhibitory effects on the epigenetic enzyme enhancer of zeste homolog 2 (EZH2), which participates in lymphomagenesis. Additionally, preclinical and clinical studies have demonstrated the anti-lymphoma activity of this drug (Gomez, Ribavirin). Anti-retroviral drugs used in human immunodeficiency virus (HIV) infected patients along with ribavirin have been reported to cause mitochondrial toxicity that can account for type B lactic acidosis. Nucleoside reverse transcriptase inhibitors (NRTIs) inhibit mitochondrial DNA replication, resulting in liver damage and impaired gluconeogenesis [4,10,13,20]. It was hypothesized that the recent treatment in the patient in above study with ribavirin and peginterferon possibly contributed further to the mitochondrial dysfunction and worsening of lactic acidosis. As yet, there was no reported case of lactic acidosis in non-HIV patients treated with ribavirin or interferon [18]. Severe lactic acidosis has been reported in Hodgkin’s lymphoma as well [21]. Remission of Hodgkin’s Lymphoma with chemotherapy has been reported to have been rapidly resolved lactic acidosis [21]. Hyperlacticaemia is defined as serum lactate levels greater than 2 mmol/L and is considered severe when the levels are greater than 5 mmol/L. Better outcomes have been reported by Hiroshi Mase et al. [22], hyperlactatemia and impaired consciousness were dramatically improved in their patient by critical care management and chemotherapy. Only chemotherapy has so far been effective in correcting acute lactic acidosis in a few patients; however it has not necessarily improved ultimate outcome [2].

Lactic acidosis is an accumulation of hydrogen ions and lactate from the dissociation of lactic acid. This compound is a metabolic intermediate product produced in anaerobic conditions or when metabolic needs cannot be met, as in malignancy [10]. This gives rise to the two types of LA. Type A occurs in states of poor perfusion such as in ischemia, hypoxia, shock, sepsis and is the more common of the two. Type B, on the other hand, occurs in tissues that are well-perfused but are unable to meet the metabolic demands of the cells [13]. As in our patient, causes of type A lactic acid, were ruled out as he was not septic, hypoxic or in any state of shock. He was not on any home medications nor did he have a history of alcohol abuse. Nevertheless, he received broad spectrum antibiotics, but lack of improvement and newly diagnosed malignancy, pointed us more towards type B lactic acidosis. Cervical lymph node biopsy revealed Small lymphocytic lymphoma (SLL). Largely most of the information about LA and malignancy had come from case reports, and as far as our research had gone, there were no documented instances of association between LA and SLL. SLL is morphologically similar to chronic lymphocytic leukemia (CLL) and sometimes referred to as the solid form of it which can then later progress to CLL [23]. Tumor cells produce energy required for their growth by either respiration or fermentation. It is described by the Warburg effect that tumor cells prefer metabolism via glycolysis over oxidative phosphorylation, regardless of oxygen supply, which is in contrast to that of normal human cells [24]. Pyruvate is formed as the end product of glycolysis and then converted to lactate which leads to lactic acidosis. Additionally, when there is hypoxia present in tumors, there is thought to be an increase of hypoxia inducible factor-1α in the cells. This then progresses to an increase in glucose uptake and upsurge in lactic acid production via overexpression of glycolytic enzymes, glucose transporter and decreased metabolism via the mitochondria [25]. It has been found that those patients that develop Type B LA secondary to malignancy are at greater risk for deterioration and invariably death [20]. There is a greater than 80% mortality rate associated with this [26] (Figure 4).

Curative therapy for this condition has not been fully established. Correcting the underlying etiology would be the ultimate goal. Initiation of chemotherapy has shown promising results in some patients. Previous studies have mentioned good outcomes with renal replacement therapy (RRT) and sodium bicarbonate infusion but mainly as bridging therapies until chemotherapy can be initiated. The idea behind use of bicarbonate therapy is to prevent any hemodynamic instability and respiratory failure that may arise with severe metabolic acidosis. However, this is not without its caveats as bicarbonate therapy has been known to have side effects of its own. Most notably are hypervolemia and hypernatremia but can also increase lactic acid production [27,28]. In combination with RRT, this can effectively be used to remove lactate, correct pH as well as correct the hypervolemia and hypernatremia associated with continuous sodium bicarbonate therapy [1,22]. Additional benefits with RRT can also be seen in tumor lysis syndrome which inevitably happens after chemotherapy has been started. Depletion of thiamine has been also noted since this is an important co-factor for pyruvate to enter the Krebs cycle. Without this, further shunting of glucose substrates to lactate can occur. Masood et al. describes a case where a patient with lactic acidosis and diffuse large B-Cell lymphoma was given intravenous thiamine, 500 milligrams every 8 hours, coupled with chemotherapy who was then noted to have significant improvement in overall prognosis and lactic acid levels [13]. In the case of our patient, significant and rapid deterioration of the patient was seen despite initiation of sodium bicarbonate infusion and subsequent continuous RRT. In hindsight, although no treatment option has been proven to be effective in every case of LA and malignancy, initiation of chemotherapy rather than delay could have had a positive outcome on our patient. Thiamine administration has been reported to decrease lactic acid levels [13]. In adequate conditions of oxygenation and nutrient supply, a normal cell obtains its energy requirements from the glycolytic production of pyruvate, followed by the conversion of pyruvate to acetyl CoA by the enzyme pyruvate dehydrogenase, which uses thiamine as a cofactor (Figure 5). Acetyl CoA then enters the tricarbonic acid cycle (TAC) that takes place in the mitochondria. This process results in the production of 36 molecules of ATP from a single molecule of glucose. In the absence of oxygen, the TAC in the mitochondria cannot occur and therefore the cell has to depend on the glycolytic pathway to derive energy. The glycolytic pathway only supplies four molecules of ATP by virtue of the conversion of accumulated pyruvate to lactic acid [20].

However, in our patient thiamine administration had no effect on lowering of lactic levels. Early initiation of chemotherapy in patients with small cell lymphocytic lymphoma with lactic acidosis is although recommended, it has not proven beneficial.

Figure 4: Model of lactate shuttles in cancer

Solid tumors typically comprise oxygenated tumor cells close to blood vessels and hypoxic cells at distance from blood vessels. Hypoxic cells produce energy from glucose using glycolysis uncoupled from oxidative phosphorylation of the tricarboxylic acid (TCA) cycle, which requires high-rate glucose import by glucose transporters (GLUT) to produce 2 ATP per molecule of glucose. Pyruvate, produced either from glycolysis or generated by the malic enzyme (ME) from cataplerotic malate, is reduced to lactate by lactate dehydrogenase-5 (LDH-5). NADH is oxidized to NAD+ , which is as a substrate of glyceraldehyde-3-P (P = phosphate) dehydrogenase (GAPDH) and therefore maintains glycolysis at high rate. Lactate is exported together with a H+ by monocarboxylate transporters (MCT), primarily MCT4. Once exported from glycolytic tumor cells or, as recently described, from stromal cells, lactic acid readily dissociates to lactate and H+ (lactic acidosis). Oxidative tumor cells have a preference for lactate compared to glucose to fuel their oxidative metabolism. Lactate together with a H+ is taken up by MCT1, oxidized to pyruvate by LDH-1, and pyruvate is incorporated into the TCA cycle to yield up to 18 ATP per molecule of lactate. CO2 is produced and exported to the extracellular space where it generates bicarbonate and additional H+ (carbonic acidosis). According to the model, tumors are metabolic symbionts in which lactate as a preferential oxidative fuel increases glucose bioavailability for glycolytic activities. Disrupting the symbiosis therapeutically is achievable with MCT inhibitors, especially drugs targeting MCT1 in cells close to blood vessels.

Image credit: Dhup et al. [10], Multiple Biological Activities of Lactic Acid in Cancer: Influences on Tumor Growth, Angiogenesis and Metastasis.

Figure 5: Lactic acid synthesis and role of thiamine as a cofactor in the process (Image Credit – Ruiz et al.: Type B lactic acidosis secondary to malignancy [20].

Conclusion

Type B lactic acidosis in the setting of malignancy holds an extremely poor prognosis. Several kinds of lymphomas and leukemias have been reported with severe type B lactic acidosis. The outcomes is mostly poor across the spectrum, regardless of chemotherapy, ICU management or thiamine administration. Case presented herein to the best of our knowledge is the first of its kind showing a patient with severe progressive lactic acidosis in the presence of Small Lymphocytic Lymphoma. Being a rare complication and not completely understood, more studies involving lactic acidosis in SLL need to be done.

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