Lactic acidosis ranks among the most common metabolic disturbances in critical care settings. Initial assessment should prioritize identifying and addressing impaired perfusion or oxygen delivery; only after these are stabilized should alternative etiologies be explored (1, 2). Drawing on the classic Cohen-Woods classification and its modern applications, lactic acidosis is categorized as type A (primarily linked to shock, hypovolemia, severe hypoxemia, or mitochondrial toxins that induce tissue hypoxia) or type B (arising without evident hypoperfusion and stemming from metabolic disorders, drugs or toxins, impaired hepatic or renal clearance, or malignancy) (3, 4). In clinical practice, this distinction is rarely absolute: multiple mechanisms may overlap in a single patient, underscoring the need for early detection—and ongoing reevaluation—of any evolving hypoperfusion to ensure precise etiologic diagnosis.

Epidemiologically, hyperlactatemia is prevalent in intensive care unit (ICU) populations, yet Warburg effect-mediated type B lactic acidosis remains rare and can be masked by concurrent infections, organ failure, or tumor necrosis, often leading to delayed diagnosis. Once progressive hypoperfusion and hypoxemia have been reasonably ruled out, persistent hyperlactatemia with markedly elevated lactate dehydrogenase (LDH) levels and minimal response to intensified antimicrobials or organ support should raise suspicion for malignancy-associated type B lactic acidosis (5). For instance, Nakagawa et al. (6) reported anaplastic lymphoma kinase (ALK)-positive anaplastic large-cell lymphoma (ALCL) presenting with lactic acidosis in the absence of shock, where lactate levels normalized rapidly following EPOCH chemotherapy. Similarly, Wang et al. (7) described type B lactic acidosis accompanied by hypoglycemia in diffuse large B-cell lymphoma (DLBCL)—a hallmark of the Warburg effect—in which targeted chemotherapy was instrumental in resolution.

Mechanistically, this presentation aligns with the Warburg effect, wherein tumor cells favor aerobic glycolysis even in oxygen-replete conditions, diverting substantial glucose to lactate production to fuel biosynthetic needs and maintain redox homeostasis amid rapid proliferation—a metabolic hallmark of cancer (8, 9). Emerging evidence suggests that lactate is far from a mere byproduct; it serves as an active signaling molecule and epigenetic regulator that remodels the tumor microenvironment, dampens antitumor immunity, and modulates therapeutic responses (10, 11). Thus, sustained hyperlactatemia may act both as a marker of metabolic dysregulation and as a contributor to disease advancement.

Clinically, the Warburg effect manifests at the bedside as profound, refractory hyperlactatemia without overt shock or persistent hypoperfusion, frequently correlating with greater tumor burden, bone involvement, and poorer prognosis (12). In observational cohorts, tumor-directed therapies have often elicited a swift lactate decline—a “metabolic response” temporally aligned with treatment initiation—highlighting the critical role of addressing the underlying malignancy in resolving the metabolic derangement (13, 14). Nonetheless, interpretive caution is essential: coexisting hepatic or renal dysfunction, drug or toxin exposures, infections, and perfusion variability can confound assessments, and clinicians must refrain from attributing elevated lactate solely to the Warburg effect without a comprehensive differential diagnosis.

Building on these insights, we report a case of a critically ill patient presenting with persistent hyperlactatemia as the predominant feature, ultimately confirmed to have aggressive lymphoma and exhibiting a rapid metabolic response—manifested as a swift decline in lactate levels—following chemotherapy initiation. Although imaging findings and elevated LDH levels supported early suspicion of malignant lymphoma and a Warburg effect–related mechanism, this case represents a typical and well-documented clinical presentation of tumor-associated type B lactic acidosis. By clearly illustrating the metabolic trajectory and treatment response, this report provides a practical diagnostic and therapeutic framework for clinicians. Furthermore, it underscores the value of timely multidisciplinary management integrating organ support and definitive chemotherapy.

This case report was conducted in strict accordance with the principles outlined in the Declaration of Helsinki and relevant medical ethics guidelines. The patient and family members were fully informed of the study’s objectives, data usage, and privacy protection measures, and provided voluntary written informed consent. Following review by the Institutional Review Board of the First Affiliated Hospital of Guangzhou Medical University, no ethical concerns were identified.

Earlier studies have long recognized malignancy-associated type B lactic acidosis as a life-threatening metabolic complication, particularly in aggressive hematologic malignancies, with survival largely dependent on timely cytoreductive therapy (13, 15). The conceptual framework of cancer metabolic reprogramming provides biological plausibility for these bedside observations, in that tumors rewire nutrient acquisition and metabolism to meet bioenergetic, biosynthetic, and redox demands—often at the cost of increased lactate generation and microenvironmental remodeling (16). These landmark reports established the fundamental pathophysiological basis linking excessive tumor-driven lactate production to impaired systemic clearance and adverse outcomes. However, evolving intensive care strategies, advances in chemotherapy and targeted therapies, and improved supportive management warrant re-evaluation of contemporary cases. Building upon this foundation, we therefore focused our review on recent case reports to reflect current diagnostic approaches, organ support strategies, and treatment timing in modern clinical practice.

Malignancy-associated hyperlactatemia mediated by the Warburg effect (aberrant activation of aerobic glycolysis) represents a rare yet potent predictor of poor prognosis in patients with type B lactic acidosis, particularly those with hematologic malignancies or highly aggressive solid tumors. To delineate the clinical patterns, diagnostic challenges, and prognostic factors in this population, we systematically searched PubMed, Embase, and Cureus databases from January 2021 to May 2025 for case reports on the “Warburg effect” and “malignancy-associated hyperlactatemia, “ using keywords such as “Warburg effect, “ “malignancy-associated lactic acidosis, “ “type B lactic acidosis, “ and “non-shock lactic acidosis.” Ultimately, 18 eligible case reports were included (7, 14, 17–30), encompassing 12 patients with hematologic malignancies and 6 with solid tumors; key clinical features and treatment outcomes are summarized(Table 1).

Regarding tumor type distribution, hematologic malignancies accounted for 66.7% (12/18) of cases, predominantly aggressive lymphomas, including diffuse large B-cell lymphoma (DLBCL) in 4 cases (7, 14, 20, 23), mantle cell lymphoma (MCL) in 3 cases (18, 21, 26), Burkitt lymphoma in 2 cases (19, 22), B-cell hepatosplenic lymphoma in 1 case (25), multiple myeloma in 1 case (17), and NK/T-cell lymphoma in 1 case (24). Solid tumors comprised 33.3% (6/18), involving colorectal cancer in 2 cases (31, 32), esophageal cancer in 1 case (28), cervical neuroendocrine carcinoma in 1 case (27), retroperitoneal leiomyosarcoma in 1 case (29), and cecal signet-ring cell carcinoma in 1 case (32). Notably, peak lactate levels were significantly higher in hematologic malignancies compared with solid tumors (median 15.4 mmol/L vs 7.5 mmol/L, P < 0.05). For instance, Khanal et al. (19) described a 69-year-old woman with Burkitt lymphoma whose lactate exceeded 15 mmol/L, accompanied by severe hypoglycemia (blood glucose declining from 70 mg/dL to 30 mg/dL); EPOCH chemotherapy normalized lactate within 48 hours, though she ultimately succumbed to neutropenic fever and sepsis post-chemotherapy. In contrast, among solid tumors, only Aly et al. (31) reported a 67-year-old man with advanced colorectal cancer reaching 15.4 mmol/L, with the remaining 5 cases below 10 mmol/L. This disparity may reflect the higher proliferative rates (e.g., Ki-67 index of 80% in an MCL case reported by Kliebhan et al. (26)) and systemic infiltration in hematologic malignancies; Yamazaki et al. (24) observed a similar pattern in NK/T-cell lymphoma, where extensive hepatic involvement tripled initial lactate levels, reinforcing the link between tumor burden and Warburg effect intensity.

The association between treatment regimens and prognosis emerged as a central finding. Among the 18 patients, 8 received regular antineoplastic therapy (defined as ≥1 full cycle at target doses without interruption), while 10 did not (including patient refusal, intolerance due to severe organ failure, or supportive care only). In the regular treatment group, 4 achieved clinical improvement (lactate normalization and radiographic tumor burden reduction), and 4 died. Looyens et al. (22) detailed a 60-year-old man with post-transplant Burkitt lymphoma complicated by peritoneal metastases and hyperlactatemia (7.4 mmol/L); R-CHOP chemotherapy combined with abdominal abscess drainage reduced lactate to 2.2 mmol/L within 1 week, with PET-CT confirming complete remission, enabling discharge after 5 months of hospitalization. Nzenwa et al. (21) reported a 66-year-old man with MCL (peak lactate 7.0 mmol/L) who normalized lactate within 3 days and recovered renal function following rituximab plus rasburicase for tumor lysis syndrome prevention, leading to successful discharge. Deaths in this group stemmed from chemotherapy complications intertwined with the primary malignancy; for example, Cao et al. (14) described a 76-year-old woman with DLBCL who, despite R-CHOP and continuous venovenous hemofiltration (CVVH) correcting hyperlactatemia, died from tumor lysis syndrome-induced septic shock. Sanivarapu et al. (20) noted a 48-year-old man with DLBCL whose lactate fell from 16 mmol/L to 3.5 mmol/L post-chemotherapy but succumbed to respiratory failure from progressive malignant pleural effusions, highlighting that while regular therapy effectively ameliorates metabolic disturbances, mitigating chemotherapy-related complications is equally vital. Prognosis in the non-regular treatment group was dismal, with all 10 patients dying within 7–21 days of admission and unrelenting lactate elevation. Cheleng et al. (30) reported a 52-year-old woman with metastatic colon cancer who refused chemotherapy and underwent only left hemicolectomy; postoperative lactate rose from 3.6 mmol/L to 6.5 mmol/L, culminating in coma from brain metastases and death. Rudy et al. (29) described a 69-year-old man with retroperitoneal leiomyosarcoma (ECOG performance status 4) intolerant to chemotherapy, receiving supportive care alone; peak lactate reached 20 mmol/L, leading to multiorgan failure and death. These cases underscore that tumor-directed therapy is pivotal for reversing Warburg effect-associated hyperlactatemia, with uniformly poor outcomes in its absence.

Contemporary clinical practice reveals ongoing controversies in managing these patients, particularly regarding supportive care strategies. Among the 18 cases, 6 involved bicarbonate infusion, 4 utilized CRRT/hemodialysis, and 2 included thiamine supplementation, with variable efficacy. Yokokawa et al. (32) reported a 66-year-old woman with cecal signet-ring cell carcinoma (lactate 7.5 mmol/L) whose arterial pH transiently improved from 7.38 to 7.45 with bicarbonate, yet lactate remained unchanged. In contrast, Tang et al. (27) described a 59-year-old woman with cervical neuroendocrine carcinoma (lactate 11.2 mmol/L) where bicarbonate combined with chemotherapy reduced lactate to 5.9 mmol/L within 48 hours, indicating that bicarbonate merely temporizes acid-base imbalances and cannot independently curb Warburg-mediated lactate production without concomitant antineoplastic therapy. Similar limitations apply to CRRT/hemodialysis; Patel et al. (18) detailed a woman with MCL (lactate 16.6 mmol/L and acute kidney injury) whose lactate fell to 2.8 mmol/L over 5 days with hemodialysis plus rituximab and acalabrutinib, alongside renal recovery. However, Moen et al. (25) reported a 70-year-old man with B-cell hepatosplenic lymphoma who, despite CRRT, maintained lactate >20 mmol/L without timely chemotherapy, dying 11 days post-splenectomy—emphasizing that renal replacement therapy suits those with concurrent organ failure but cannot supplant tumor-specific interventions.

Challenges in chemotherapy timing and patient selection also merit attention. In 3 cases, initial lactate >15 mmol/L was deemed a “contraindication” to chemotherapy, delaying treatment and worsening prognosis. Wang et al. (7) described a DLBCL patient with lactate at 30 mmol/L where the team prioritized metabolic correction before R-CHOP, initiating only at 18 mmol/L; rapid tumor progression led to death within 1 week. Conversely, Khanal et al. (19) promptly started EPOCH for Burkitt lymphoma despite lactate >15 mmol/L, achieving rapid control—contrasting outcomes that suggest early chemotherapy is warranted absent irreversible organ failure (e.g., severe hepatic failure or irreversible brain injury). For frail patients, Tang et al. (27) employed a “dose-reduced” regimen (etoposide 100 mg on days 1, 3, 4), mitigating toxicity while controlling lactate (declining to 2.2 mmol/L), enabling discharge for palliative care and offering a viable approach for critically ill individuals.

Drawing from this analysis of 18 cases of Warburg effect-associated malignancy with hyperlactatemia, we infer that the phenomenon is more pronounced in hematologic malignancies (especially aggressive lymphomas), with peak lactate typically exceeding that in solid tumors; regular antineoplastic therapy is crucial for prognosis improvement, with 100% mortality in untreated patients, though chemotherapy complications interacting with the primary tumor drive fatalities; supportive measures (e.g., bicarbonate infusion, CRRT) serve adjunctively and cannot replace targeted therapy. Future prospective studies are needed to refine strategies, exploring criteria integrating “lactate levels + tumor proliferative activity” to optimize chemotherapy initiation for these critically ill patients.

Recent studies have emphasized that lactate is not merely a byproduct of glycolysis but a key signaling metabolite within the tumor microenvironment (TME), capable of promoting tumor progression through multiple mechanisms. First, lactate accumulation and acidification of the TME suppress the proliferation, cytotoxic activity, and cytokine production of effector T cells and natural killer cells, while promoting the differentiation and maintenance of immunosuppressive cell populations such as regulatory T cells and M2-like macrophages, thereby establishing a state of “metabolic immunosuppression” and impairing antitumor immunity (33, 34). Second, lactate facilitates tumor growth and metastasis by regulating cancer cell migration, angiogenesis, and therapeutic resistance, and has been closely associated with unfavorable clinical outcomes, suggesting that lactate itself may function as an active oncometabolite driving disease progression (35, 36). In addition, lactate acts as a metabolic–epigenetic hub by inducing protein lactylation and reprogramming transcriptional profiles in both tumor and immune cells, further amplifying immunosuppressive and metabolic reprogramming effects and providing potential therapeutic targets for disrupting lactate production, transport, and utilization (37).

In this case, the patient with ALK-positive anaplastic large cell lymphoma (ALK+ ALCL) presented with fever and developed persistent hyperlactatemia without evidence of shock, accompanied by type II respiratory failure, hepatic impairment, and electrolyte disturbances. Hemodynamics remained stable throughout admission and ICU stay (systolic blood pressure 144–161 mm Hg), with arterial partial pressure of oxygen within normal or acceptable ranges, suggesting that type A mechanisms (related to hypoperfusion or hypoxia) were not predominant. Given the oncologic context and laboratory features (elevated LDH), this phenotype aligns with the spectrum of clinical Warburg effect (CWE) or malignancy-associated type B lactic acidosis: enhanced aerobic glycolysis in tumor cells drives lactate production even under adequate tissue oxygenation, with further accumulation amid reduced hepatic (accounting for ~60% of clearance) or renal (~30%) function (12, 38, 39). Importantly, CWE is not an exclusionary diagnosis; it should be established only after thorough evaluation to rule out type A etiologies, drugs/toxins, severe hepatorenal failure, or other metabolic causes (40).

Consistent with prior studies (41, 42), lactate trajectory in this case closely paralleled oncologic interventions, with rapid and sustained decline following initiation of an etoposide-containing CHOP variant (CHOEP/ECHOP, i.e., CHOP plus etoposide)—a “metabolic response” temporally linked to tumor burden control. Chaba et al. (12) reported that CWE patients typically exhibit higher tumor burden, more frequent bone or central nervous system involvement, and substantially elevated 1-year mortality risk (multivariable HR = 3.89, 95% CI 2.13-7.02). Thus, rather than targeting lactate reduction per se, a more rational approach prioritizes etiology-directed tumor control, with internal milieu interventions serving as bridges to enhance tolerability.

Regarding organ support and timing, chemotherapy was promptly instituted post-diagnosis, with concurrent CRRT to address severe metabolic acidosis and electrolyte imbalances. Notably, CRRT offers limited direct value for lactate clearance and has not been shown to improve long-term survival; routine use is inadvisable absent clear renal replacement indications, positioning it more as a facilitator of metabolic and electrolyte stability to enable chemotherapy (1). Extrapolation should be cautious, as evidence for CRRT’s protective role against chemotherapy toxicity is inconsistent; dosing must be individualized based on pharmacokinetics and RRT modality, rather than assuming clearance of toxic metabolites. The concomitant hepatic dysfunction in this case may have diminished lactate clearance, a phenomenon observed in sepsis and critical illness cohorts (43, 44), though its relative contribution is challenging to disentangle from excess production—favoring parallel rather than singular causal reasoning in clinical judgment.

For regimen selection, evidence increasingly favors shifting from conventional CHOP/CHOEP to BV-CHP (brentuximab vedotin plus CHP) as first-line therapy. The 5-year update from the ECHELON-2 trial (45) demonstrated sustained PFS and OS benefits with BV-CHP over CHOP in peripheral T-cell lymphomas (including systemic ALCL). However, in the ICU setting, constrained by drug availability, infection risks, organ function, and hematologic tolerance, CHOEP/ECHOP remains a pragmatic, rapidly deployable first-line option, with multidisciplinary teams balancing early tumor control against tolerability. ALK inhibitors (e.g., crizotinib, brigatinib) have limited frontline evidence in adult ALK+ ALCL, primarily reserved for relapsed/refractory disease or select subgroups in trials and real-world settings (46–48); their potential for faster hyperlactatemia reversal lacks systematic data and warrants cautious use in monitored, individualized protocols or clinical trials.

Complication management in this case addressed post-chemotherapy myelosuppression and ICU-acquired weakness (ICU-AW) risk. Myelosuppression was managed with infection prophylaxis, G-CSF, targeted transfusions, and nutritional support. Pharmacologic platelet elevation and neurotrophic therapies currently lack high-level evidence, emphasizing early mobilization and rehabilitation as core strategies. Recent studies (49, 50) indicate that early active exercise/rehabilitation reduces ICU-AW incidence and enhances functional outcomes. Additionally, as an HBsAg-positive patient, prophylactic antiviral therapy (entecavir) with serial HBV-DNA monitoring aligned with consensus for oncologic treatment in HBV carriers. ASCO guidelines and recent investigations recommend preemptive antivirals and vigilant follow-up to mitigate reactivation risk (51, 52).

Overall, this case underscores that persistent hyperlactatemia amid hemodynamic stability warrants CWE as a key differential consideration. Therapeutically, etiology-directed tumor control offers a sustainable path to metabolic crisis resolution, with CRRT and other supports bridging to chemotherapy tolerability; regimen choices must balance evidence-based standards (e.g., BV-CHP) against critical care constraints. Future prospective studies are recommended to systematically evaluate such cases, exploring integration of small-molecule ALK inhibitors with chemotherapy in adult ALK+ ALCL.