Hyperlactatemia following pesticide exposure

Pesticides have been associated with mitochondrial toxicity in humans through various mechanisms, including oxidative stress, reduced adenosine triphosphate (ATP) production, and alterations in mitochondrial DNA copy number, with potential links to chronic diseases and mitochondrial dysfunction.^[1] These effects, often mediated by respiratory chain inhibition or increased reactive oxygen species, may trigger metabolic decompensation or unmask latent mitochondrial disorders in susceptible individuals.^[1]

Mitochondrial encephalomyopathy (ME) represents a heterogeneous group of disorders caused by impaired oxidative phosphorylation, predominantly affecting organs with high energy demands such as the brain and heart. ME with lactic acidosis and stroke-like episodes (MELAS) is the most common subtype, accounting for up to 80% of cases.^[2] Agents such as metformin,^[3] valproic acid, high-dose propofol, and certain statins^[4] can precipitate lactic acidosis or exacerbate neurological dysfunction in patients with underlying mitochondrial disease. Such pharmacologic or environmental stressors may lead to mitochondrial dysfunction or aggravate preexisting pathology.^[4]

Given this background, pesticides that impair the respiratory chain warrant consideration as potential triggers of metabolic decompensation. Here, we report a patient who exposed to a mixture of pesticides, including cyetpyrafen, a succinate dehydrogenase inhibitor (SDHI), and developed acute hyperlactatemia and neurological deterioration.

A 22-year-old woman with a 4-day history of abdominal pain and 3 d of recurrent convulsions was admitted to the emergency department. Symptoms developed shortly after she sprayed agricultural pesticides containing cyetpyrafen, thiamethoxam, difenoconazole, abamectin, and mancozeb for approximately 30 min without protective measures. She initially presented at a local hospital, where abdominal ultrasound and computed tomography (CT) scans revealed no acute abnormalities; she received symptomatic treatment, including fluid resuscitation, acidosis correction, and analgesia. Despite supportive treatment, her condition deteriorated with progressive convulsions, tachypnea, and delirium over the next 3 d. Arterial blood gas analysis revealed severe lactic acidosis (lactate 10.6 mmol/L; pH 6.90). She was intubated, mechanically ventilated, and transferred to the Emergency Intensive Care Unit (EICU) of West China Hospital.

Physical examination on admission revealed a thin body, with height 148 cm, weight 30 kg, and BMI 13.7 kg/m². Laboratory findings showed pH 7.24 (reference range: 7.35-7.45), plasma lactate 14.1 mmol/L (reference range: 0.5-2.2 mmol/L), lactate dehydrogenase 352 U/L (reference range: 0-248 U/L), and creatine kinase 2,124 U/L (reference range: 0-171 U/L). Renal function was normal, with a glomerular filtration rate of 154.9 mL/(min·1.73 m²). Cranial CT demonstrated high-density signals in the bilateral basal ganglia (Figure 1). Serum cholinesterase activity and toxicology screening for valproic acid, midazolam, diazepam, and common pesticides such as organophosphates and propargite were negative. Given the exposure history, cyetpyrafen was considered based on its SDHI mechanism, and experts from the Research Laboratory of the Emergency Department of West China Hospital were consulted for detection methods.

Figure 1. Axial non-contrast CT showing bilateral symmetric high-density in thalami and bilateral basal ganglia areas. CT: computed tomography.

After admission, blood lactate levels were persistently elevated, accompanied by new-onset thrombocytopenia, impaired consciousness, and recurrent seizures. A peripheral blood smear revealed 2.5% schistocytes, with markedly reduced haptoglobin concentration (<0.058 g/L). Disintegrin-like and metalloproteinase with thrombospondin type 1 motifs 13 (ADAMTS-13) expression was mildly decreased (68.9%), excluding thrombotic thrombocytopenic purpura (TTP). Brain magnetic resonance imaging (MRI) revealed symmetrical hyperintensities in the basal ganglia and periventricular regions (Figure 2). Because of her low body weight, seizures, hyperlactatemia, and neuroimaging findings, MELAS was suspected. Whole-exome sequencing confirmed the diagnosis, identifying a mitochondrial DNA mutation (m.3243A>G) in the MT-TL1 gene at chrM:3243, with a heteroplasmy level of 45.4% (540/1189 reads) (supplementary Figure 1).

Figure 2. Brain MRI findings. A (T1-weighted image): cortical hypointensity in the left parieto-occipital region and bilateral basal ganglia hyperintensity; B (T2/FLAIR image): hyperintensities of periventricular white matter, stroke-like lesions in a non-vascular distribution; C (DWI images): restricted diffusion in the same regions. MRI: magnetic resonance imaging.

The patient received multiple sessions of continuous veno-venous hemodiafiltration (CVVHDF) and one plasma exchange session (supplementary Table 1). She was also treated with disodium adenosine triphosphate to support cellular metabolism. Supportive management, including anti-infective therapy and renal replacement therapy, resulted in a decrease in the levels of lactate (supplementary Figure 2) and other metabolic markers (supplementary Figure 3). By day 23 of hospitalization, she was successfully extubated and transferred out of the EICU.

The patient presented with hyperlactatemia and seizures, with elevated lactate levels as the primary diagnostic indicator. According to the Cohen-Woods classification,^[5] type A hyperlactatemia arises from tissue hypoxia or hypoperfusion, whereas type B hyperlactatemia occurs without overt hypoxia and includes systemic diseases (B1), drug-induced or toxin-induced causes (B2), and inborn metabolic errors (B3). In this case, type A was ruled out because of stable hemodynamics and oxygenation. Therefore, the differential focused on type B etiologies, particularly toxic exposure (B2) and mitochondrial inborn errors (B3).

Persistent lactic acidosis can be explained by two mechanisms. First, lactate production increases when pyruvate cannot enter mitochondrial oxidative pathways—such as under hypoxia, respiratory chain inhibition, or intrinsic mitochondrial dysfunction—and is instead reduced in the cytoplasm. Second, lactate clearance is impaired when metabolic routes are disrupted. Under normal physiological conditions, lactate is reconverted to pyruvate and metabolized via the pyruvate dehydrogenase complex to acetyl-CoA, via pyruvate carboxylase to oxaloacetate, or through gluconeogenesis in the Cori cycle. Defects in these pathways, whether due to genetic enzyme deficiencies or acquired mitochondrial toxins, impair clearance and drive accumulation.^[6] In this case, the m.3243A>G mitochondrial mutation likely played a crucial role, with pesticide exposure potentially contributing to the impairment of oxidative phosphorylation.

Cyetpyrafen (SYP-9625) is a novel SDHI acaricide. By inhibiting complex II (succinate-ubiquinone oxidoreductase) in the mitochondrial respiratory chain, it disrupts oxidative phosphorylation and predisposes cells to lactate accumulation.^[7] Similar mechanisms are seen in cyanide poisoning, rotenone poisoning, aluminum phosphide poisoning, and pyridaben poisoning. Although the seizures were controlled, the persistence of hyperlactatemia suggests another primary mechanism.

MELAS is a multisystem disorder most commonly caused by the m.3243A>G mutation in the MT-TL1 gene,^[8] accounting for approximately 80% of cases. It usually presents in childhood or early adulthood and manifests as stroke-like episodes, seizures, recurrent headaches, short stature, hearing loss, and muscle weakness.^[9] Our patient’s genetic testing confirmed the m.3243A>G mutation, which is consistent with her clinical presentation.

Currently, there are no specific medications for MELAS, and treatment remains supportive. L-arginine supplementation may reduce stroke-like episodes, with better outcomes reported when plasma arginine concentrations are maintained above 168 μmol/L.^[10] Although cyetpyrafen was not detected in the serum, the temporal relationship between exposure and symptom onset suggests a potential triggering role. Several factors may explain the negative toxicology results: delayed blood sampling, lack of standardized assays, and limited knowledge on pharmacokinetics.

In conclusion, this case highlights the diagnostic challenges posed by unexplained hyperlactatemia and illustrates how environmental toxins may unmask latent mitochondrial disease.

Funding: None

Ethical approval: Any studies involving human participants are reviewed and approved by the Biomedical Ethics Committee of the West China Hospital. Informed consent was obtained from the patient for publication of this report and any accompanying images.

Conflicts of interest: The authors declare no conflicts of interest.

Contributors: AAN and ZJ contributed equally to this study. AAN and ZJ contributed to the analysis, manuscript preparation and writing. ZYJ, AHP and SJZ contributed to manuscript preparation and data collection. ZJ and YXZ contributed to the conception of the study and management of the patient. YC was responsible for the final revision of the study. All authors contributed to the article and approved the submitted version.

All the supplementary files in this paper are available at http://wjem.com.cn.