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A 66-Year-Old Woman With Sudden Onset of Disseminated Intravascular Coagulation, Lactic Acidosis, and Hypoglycemia FREE TO VIEW

Benjamin Henkle, MD, MPH; Patrick Arndt, MD
Author and Funding Information

aDepartment of Medicine, University of Minnesota, Minneapolis, MN

bDivision of Pulmonary, Allergy, Critical Care and Sleep Medicine, Department of Medicine, University of Minnesota, Minneapolis, MN

CORRESPONDENCE TO: Benjamin Henkle, MD, MPH, Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, Department of Medicine, University of Minnesota, 420 Delaware St SE, MMC 276, Minneapolis, MN 55455


Copyright 2016, American College of Chest Physicians. All Rights Reserved.


Chest. 2017;151(2):e41-e44. doi:10.1016/j.chest.2016.08.1441
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A 66-year-old woman presented to an urgent care clinic for 2 to 3 weeks of general malaise, nausea/vomiting, night sweats, and dyspnea. On examination, she was tachycardic, and her laboratory evaluation was normal except for a lactate level of 4.4 mmol/L and platelet count of 118 × 109/L. CT imaging was performed. Two days later in the follow-up clinic, the patient’s international normalized ratio (INR) was elevated, and she was hospitalized with initial findings of disseminated intravascular coagulation (DIC) (ie, INR > 10, platelets 97 × 109/L, fibrinogen < 60 mg/dL, positive D-dimer result). Bone marrow aspirate and peripheral blood smears were unrevealing. On day 4 of her hospitalization, the patient developed severe lactic acidosis (24 mmol/L) and hypoglycemia (11 mg/dL), and she was transferred to our institution. The patient had a history of a benign ovarian tumor, was a nonsmoker, did not drink alcohol, and was not taking any medications prior to admission. No ingestions or environmental exposures were noted.

Figures in this Article

The patient was tachypneic with a respiratory rate of 31 breaths/min and oxygen saturation of 100% on 5 L nasal cannula. She was afebrile and had a heart rate of 108 beats/min and BP of 113/60 mm Hg. She was alert and oriented but was in moderate distress secondary to tachypnea. Her oropharynx was clear and without petechiae, and her heart, lungs, and abdomen were unremarkable. Her left and right upper extremities had large purple ecchymosis extending from bicep to wrist and hand; pulses were intact, and there was 1+ bilateral lower extremity pitting edema. No peripheral adenopathy was detected. The remainder of the physical examination was normal.

The following diagnostic study results were reported: hemoglobin level, 9.1 g/dL; WBC count, 8,700/μL; and platelet count, 36,000 × 109/L. The patient’s sodium level was 132 mmol/L, potassium level was 3.4 mmol/L, bicarbonate level was 10 mmol/L, BUN level was 38 mg/dL, creatinine level was 1.16 mg/dL, and glucose was 66 mg/dL. The alanine aminotransferase level was 29 U/L, the aspartate aminotransferase level was 113 U/L, and total bilirubin was 7.9 U/L. Lactic acid measurement was 27 mmol/L. INR was 4.79, fibrinogen was 149 mg/dL, and D-dimer finding at the previous institution was 1.2 μg/mL. Arterial blood gas analysis showed a pH of 7.23, Po2 of 127 mm Hg, and Pco2 of 21 mm Hg. Results of blood cultures from the previous institution showed no growth to date and previous CT imaging was reviewed (Fig 1).

Figure 1
Figure Jump LinkFigure 1 Representative images from CT imaging of the chest.Grahic Jump Location

What is the diagnosis?

Diagnosis: Lymphoma complicated by the Warburg effect and DIC. The next diagnostic step is an emergent endoscopic ultrasound-guided biopsy of enlarged mediastinal lymph nodes found in the paraesophageal and subcarinal regions on chest CT imaging.

Lactic acidosis with DIC is a constellation of laboratory findings often found in patients in the ICU and frequently attributed to septic shock or tissue hypoperfusion. In these cases, it is critical to maintain a broad differential and consider both types of lactic acidosis seen in clinical practice: type A and type B. Type A lactic acidosis is secondary to tissue hypoperfusion and anaerobic glycolysis converting glucose into lactate. It is most commonly seen in states of shock (septic, cardiogenic, obstructive, or hypovolemic), severe hypoxemia, or severe anemia. Type B lactic acidosis occurs when clinical evidence of tissue hypoxia is absent and can have numerous causes, including drugs or toxins, certain underlying diseases such as malignancy, and hereditary disorders. In the setting of some hematologic malignancies, type B lactic acidosis can develop with hypoglycemia and, rarely, DIC.

Normal differentiated cells generate energy for cellular functions by mitochondrial oxidative phosphorylation. In contrast, most cancer cells use nonmitochondrial cytosolic aerobic glycolysis with the production of fewer adenosine triphosphate units per glucose molecule in a phenomenon called the Warburg effect (initially described in 1924 by Otto Warburg). This mechanism to maintain cellular processes in tumor cells occurs in the presence of adequate oxygen to support mitochondrial oxidative phosphorylation and necessitates increased levels of glucose uptake with high rates of lactic acid production. Clinically, this process presents as hypoglycemia and type B lactic acidosis (Fig 2). There has been speculation that this metabolic mechanism favors cancer cells by providing substrates such as amino acids, nucleotides, and lipids, which allow improved cancer cell growth, proliferation, and angiogenesis. Others have hypothesized that the glycolytic phenotype is an adaptation to local hypoxia or that glycolysis provides an acidic environment that favors tumor cell growth over growth of normal cells. Aerobic glycolysis may also produce fewer reactive oxygen species (eg, superoxide, singlet oxygen, hydroxyl radical) than oxidative phosphorylation. This scenario would then provide the tumor genome protection from oxidative injury via decreased exposure to damaging reactive oxygen species.

Figure 2
Figure Jump LinkFigure 2 Diagram of the differences between oxidative phosphorylation, anaerobic glycolysis, and aerobic glycolysis. PDH = pyruvate dehydrogenase.Grahic Jump Location

Malignancy-induced type B lactic acidosis has been well described, but its presentation with concomitant hypoglycemia is less frequently seen. This uncommon presentation is most often reported in hematologic malignancies such as lymphoma and leukemia but can also occur in solid organ malignancies, including lung, breast, colorectal, prostate, and bladder cancers. Malignancy-induced DIC is generally less severe in presentation than DIC associated with sepsis or trauma but still indicates severe illness of the host. Among hematologic malignancies, the incidence of DIC is difficult to quantify but has been diagnosed in approximately 15% of acute leukemia cases, and it is considered an important cause of morbidity and mortality in other malignancies (eg, lymphoma).

Initiation of treatment is the optimal management of both Warburg physiology and malignancy-induced DIC. Therefore, prompt identification and recognition of the underlying malignancy causing the Warburg effect and DIC are critical for the expeditious initiation of tumor-directed chemotherapy. Hemodialysis and IV bicarbonate may be used in the management of lactic acidosis but should be regarded as a temporizing measure, and the utility of this approach has been debated. Thiamine, a critical cofactor of pyruvate dehydrogenase, has also been proposed as an additional therapy to treat the Warburg effect by converting pyruvate to acetyl-coenzyme A and not lactic acid (Fig 2). Utilization of the ICU and advanced diagnostic modalities can aid in patient stabilization and provide an opportunity for both diagnosis and then treatment.

Case reports suggest that the clinical syndrome of lactic acidosis and hypoglycemia portends a very poor prognosis and, when occurring in combination with DIC, the prognosis may worsen. Patients are often relatively stable just prior to admission but then develop a rapid onset of symptoms. Urgent treatment of the underlying malignancy seems to be the only effective therapeutic option. However, despite critical care intervention and early initiation of therapy, patients often die of their underlying illness. Mortality in malignant type B lactic acidosis is reportedly in excess of 80% and, when the Warburg effect is present, it is further increased to > 90%. Lactic acidosis in the presence of hypoglycemia and DIC should raise suspicion for a hematologic malignancy and be regarded as a hematologic and metabolic/oncologic emergency. With rapid recognition, attempts at diagnosis and therapeutic intervention are possible in this critically ill patient group and are often the patient’s only chance at survival.

Clinical Course

The patient’s history of night sweats and laboratory findings of DIC, lactic acidosis, and hypoglycemia in the setting of mediastinal lymphadenopathy on CT imaging were suggestive of malignancy. The patient was intubated due to work of breathing and supported with high minute volume-assisted ventilation and IV bicarbonate. Hypoglycemia was stabilized with concentrated glucose products, and DIC was treated with transfusion of blood components. Upon stabilization, an endoscopic ultrasound-guided lymph node biopsy sample was obtained. With biopsy results pending, the lactic acidosis worsened (arterial pH < 7.20), and empiric methylprednisolone and thiamine were started to treat the suspected lymphoma. Biopsy results suggested extranodal NK/T-cell lymphoma, and a modified rituximab, chemotherapy regimen of cyclophosphamide, doxorubicin, vincristine, and prednisone was initiated. Shortly after initiation of therapy, the patient’s glucose level stabilized, and DIC required only infrequent transfusions. The lactic acid level trended down and reached a nadir on day 13 (1.3 mmol/L). On day 14, lactate acid levels again increased, hypoglycemia worsened, and DIC became more active, all indications of treatment failure. The patient continued to deteriorate and died on hospital day 19.

  • 1.

    Many cancers cells use aerobic glycolysis for energy production and cell proliferation, and this scenario may result in severe type B lactic acidosis and hypoglycemia.

  • 2.

    Presentation with DIC is a rare addition to the findings of severe hypoglycemia and lactic acidosis, causing the Warburg effect in patients with malignancies.

  • 3.

    Sudden development of severe lactic acidosis and hypoglycemia should raise suspicion for a hematologic malignancy and be regarded as a hematologic and metabolic/oncologic emergency.

  • 4.

    The clinical syndrome of DIC, lactic acidosis, and hypoglycemia portends a very poor prognosis.

Financial/nonfinancial disclosures: None declared.

Other contributions:CHEST worked with the authors to ensure that the Journal policies on patient consent to report information were met.


Figures

Figure Jump LinkFigure 1 Representative images from CT imaging of the chest.Grahic Jump Location
Figure Jump LinkFigure 2 Diagram of the differences between oxidative phosphorylation, anaerobic glycolysis, and aerobic glycolysis. PDH = pyruvate dehydrogenase.Grahic Jump Location

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