Lactic Acidosis Research Articles

Effects of Hyperthermia and Acidosis on Mitochondrial Oxidative Phosphorylation.

The intracellular environment of skeletal muscle can develop pronounced hyperthermia and acidosis during strenuous exercise, and these alterations in the typical intracellular conditions have been shown to alter mitochondrial respiration. However, the impact of these conditions on ATP synthesis is poorly understood. We used Thoroughbred racehorses to test the hypothesis that both hyperthermia and acidosis decrease the rate of ATP synthesis, but that athletic conditioning mitigates this loss of phosphorylation capacity. Isolated mitochondria were harvested from skeletal muscle before and after a 9-week racetrack conditioning program that increased whole-body aerobic capacity by 19%, and oxidative phosphorylation capacity was tested ex vivo under normothermic and hyperthermic conditions, as well as normal pH and acidic pH created by the addition of lactic acid. In unfit horses, hyperthermia caused a 30-55% decrease in the rate of ATP synthesis and loss of phosphorylation efficiency (P/O ratio decreased from 4.2 to 1.7 during maximal oxidative phosphorylation). Aerobic conditioning resulted in increased phosphorylation efficiency under hyperthermic conditions. Lactic acidosis had a small negative effect on ATP synthesis in unfit horses, but aerobic conditioning increased the sensitivity of isolated mitochondria to the deleterious effects of lactic acidosis. These data support a prominent role of hyperthermia in skeletal muscle fatigue during exercise, particularly in unfit subjects. However, acidosis may be a more important cause of failure of ATP synthesis in fit subjects.

Pathogenic PDE12 variants impair mitochondrial RNA processing causing neonatal mitochondrial disease.

Pathogenic variants in either the mitochondrial or nuclear genomes are associated with a diverse group of human disorders characterized by impaired mitochondrial function. Within this group, an increasing number of families have been identified, where Mendelian genetic disorders implicate defective mitochondrial RNA biology. The PDE12 gene encodes the poly(A)-specific exoribonuclease, involved in the quality control of mitochondrial non-coding RNAs. Here, we report that disease-causing PDE12 variants in three unrelated families are associated with mitochondrial respiratory chain deficiencies and wide-ranging clinical presentations in utero and within the neonatal period, with muscle and brain involvement leading to marked cytochrome c oxidase (COX) deficiency in muscle and severe lactic acidosis. Whole exome sequencing of affected probands revealed novel, segregating bi-allelic missense PDE12 variants affecting conserved residues. Patient-derived primary fibroblasts demonstrate diminished steady-state levels of PDE12 protein, whilst mitochondrial poly(A)-tail RNA sequencing (MPAT-Seq) revealed an accumulation of spuriously polyadenylated mitochondrial RNA, consistent with perturbed function of PDE12 protein. Our data suggest that PDE12 regulates mitochondrial RNA processing and its loss results in neurological and muscular phenotypes.

LNC-ing Genetics in Mitochondrial Disease.

Primary mitochondrial disease (MD) is a group of rare genetic diseases reported to have a prevalence of 1:5000 and is currently without a cure. This group of diseases includes mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS), maternally inherited diabetes and deafness (MIDD), Leber's hereditary optic neuropathy (LHON), Leigh syndrome (LS), Kearns-Sayre syndrome (KSS), and myoclonic epilepsy and ragged-red fiber disease (MERRF). Additionally, secondary mitochondrial dysfunction has been implicated in the most common current causes of mortality and morbidity, including cardiovascular disease (CVD) and cancer. Identifying key genetic contributors to both MD and secondary mitochondrial dysfunction may guide clinicians to assess the most effective treatment course and prognosis, as well as informing family members of any hereditary risk of disease transmission. Identifying underlying genetic causes of primary and secondary MD involves either genome sequencing (GS) or small targeted panel analysis of known disease-causing nuclear- or mitochondrial genes coding for mitochondria-related proteins. Due to advances in GS, the importance of long non-coding RNA (lncRNA) as functional contributors to the pathophysiology of MD is being unveiled. A limited number of studies have thus far reported the importance of lncRNAs in relation to MD causation and progression, and we are entering a new area of attention for clinical geneticists in specific rare malignancies. This commentary provides an overview of what is known about the role of lncRNAs as genetic and molecular contributors to disease pathophysiology and highlights an unmet need for a deeper understanding of mitochondrial dysfunction in serious human disease burdens.

A cross-sectional study of point-of-care lactate testing in integrated community care management (ICCM) for children with acute respiratory illness in rural uganda.

Integrated community case management (iCCM) programs leverage lay village health workers (VHWs) to carry out the initial evaluation of children with common conditions including malaria, pneumonia and diarrhea. Therefore, it is imperative that VHWs are able to identify children who are critically ill and require referral to a health facility. Elevated venous lactate levels have been associated with severe illness and adverse health outcomes, including death. However, lactic acidosis may not be recognized in rural settings because it is not routinely measured outside of hospitals and research studies. Point-of-care lactate tests may help identify patients in need of a higher level of care and improve VHWs' ability to make timely and appropriate referrals. The study was a cross-sectional evaluation of children aged <5 y presenting to VHWs in rural southwestern Uganda with complaints of fever and cough. Demographics, clinical presentation, evaluation, management and disposition were recorded. VHWs were trained and instructed to perform lactate testing using a point-of-care assay in eligible participants. During the study period, 238 children were enrolled and completed an initial assessment. Of the 204 participants included in the analysis, 113 (55.4%) were female, and the median (IQR) age was 23 (9-36) months. Most participants, 139/200 (69.5%), had negative results on the malaria rapid diagnostic test. The median lactate level was 2.1mmol/L; 12% (24/204) had a lactate ≥3.5 mmol/L and only nine participants (4.4%) had a lactate ≥5mmol/L. Having a lactate level above either cut-off was not associated with the presence of danger signs at presentation. Few children presenting with fever and cough to VHWs in western Uganda had elevated lactate levels. However, most of the children with elevated lactate levels did not otherwise satisfy established iCCM criteria based on physical examination findings for referral to a health facility. Therefore, while elevated lactate was not associated with danger signs in this small study, it is possible that there is under-recognition of severe illness using current iCCM guidelines.

An Unusual Case of Alarming Lactic Acidosis: Brain Metabolic Cross-Talk

AbstractA 39-year-old male with a BMI of 30.8 kg/m2 and a normal medical history underwent excision of a left orbito-cavernal hemangioma (4 × 2 × 2 cm) under general anesthesia. Balanced anesthesia and fluid management guided by pulse pressure variation (kept below 12%) were employed. Despite stable hemodynamics and normal blood sugar levels, arterial blood gas (ABG) analysis revealed a progressive rise in lactate levels, reaching 10.6 mmol/L, accompanied by acidemia. Systemic hypoperfusion was ruled out by maintaining mean arterial pressure between 70-80 mm Hg, ensuring a capillary refill time of less than 3 seconds, and confirming a central venous oxygen saturation of 72%. With a total blood loss of 800 mL, one unit of packed red blood cells was transfused due to concerns about decreased microcirculation and tissue hypoxia. After 10 hours of surgery, sodium bicarbonate (NaHCO3) was administered to mitigate metabolic acidosis and its potential impact on intracranial pressure. Postoperatively, lactate levels remained elevated (8-9 mmol/L), but with continued NaHCO3 infusion, lactate reduced to 6.4 mmol/L, allowing extubation. The patient's lactate normalized by the evening, and recovery was uneventful. This case highlights the significant metabolic disturbances, particularly lactic acidosis, that can arise during brain tumor surgery due to prolonged operative times, large tumor size, higher BMI, and stress-induced metabolic derangements. Awareness and prompt management of these disturbances are crucial for successful patient outcomes.

A case of lactic acidosis and stress hyperglycemia in a non-diabetic patient with vasospastic angina

A case of lactic acidosis and stress hyperglycemia in a non-diabetic patient with vasospastic angina

Neuronal Intranuclear Inclusion Disease Presenting with Acute-Onset Dementia and Cortical Edema: A Case Report.

Neuronal Intranuclear Inclusion Disease (NIID) is a neurodegenerative disorder characterized by the formation of eosinophilic inclusions in the neurons, visceral and skin cells. The cause is associated with the GGC nucleotide repeat expansion in the NOTCH2NLC gene. The imaging hallmark of NIID is hyperintensities on diffusion-weighted imaging (DWI) at the corticomedullary junction. Clinical manifestations of NIID are highly heterogeneous. Here, we report a case of NIID presenting with acute-onset dementia and cortical edema. We describe an elderly male patient who presented with sudden dementia within a day. Considering the abrupt onset and the stroke history, we initially diagnosed vascular disease. However, further imaging revealed cortical edema in the temporo-parieto-occipital lobes. Blood and cerebrospinal fluid tests ruled out immunological, metabolic, infectious, or neoplastic etiologies. Genetic testing ultimately confirmed the diagnosis of NIID. Intravenous immunoglobulin (IVIG) therapy did not improve the patient's symptoms; However, about 1 month after treatment, spontaneous improvement was observed. It is noteworthy that 22 months before the onset of cognitive impairment, the patient's MRI for headaches already exhibited the typical imaging lesions of this disease in the cerebellum paravermal region. Patients with encephalopathy syndrome exhibiting imaging features resembling mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome or Creutzfeldt-Jakob disease should consider the NIID as differential diagnosis. Chronic headaches and symmetric lesions in the cerebellar paravermal region on MRI may be noteworthy indicators of NIID during non-episodic phases.

Advancing cardiac 3D organoid-on-chip: integrating iPSC-derived MELAS syndrome models to study electromechanical synchronicity and cardiac memory using contactless technology

Abstract Background Mitochondrial DNA mutations affect 1:5000 newborns, posing life-threatening risks, especially to high-energy organs such as the brain, heart, and muscles. Mortality rates can reach 71% when cardiomyopathy is present. MELAS syndrome (Mitochondrial Encephalopathy with Lactic Acidosis and Stroke-like Episodes), primarily affecting protein synthesis (MTTL1 gene, tRNALeu(UUR)), disrupts the electron transport chain complex I and is associated with cardiac conduction defects and hypertrophy. Manifesting symptoms typically appear between ages 3 and adulthood, presenting a complex clinical scenario. Human induced pluripotent stem cells (hiPSCs) offer a unique platform for studying cardiac manifestations of this disease when differentiated into cardiomyocytes. Purpose We adopted a highly adaptable in-vitro model, organized in 3D cardioids, to explore potential impairments in electromechanical coupling of cells. Methods We utilized hiPSCs carrying the MELAS mutation and their respective isogenic controls differentiated into cardiomyocytes, cultured in 3D cardioids. Electromechanical coupling was assessed using laser-poration technology combined with video kinematics evaluation under various stimulation patterns. Results Morphological analysis revealed a statistically significant reduction in the diameter of MELAS cardioids compared to the isogenic 3D structures (368±17.15 μm vs. 527±36.76 μm). In a spontaneous regimen, MELAS samples exhibited higher beating frequency (0.88±0.28 Hz vs. 0.17±0.05 Hz) and contractile speed (99.35±39.11 μm/s vs. 33.46±5.57 μm/s). Additionally, the response to different electric field stimulation protocols varied significantly, with the isogenic cell line showing better adaptation to sinusoidal stimuli than the pathological one, characterized by rectangular monophasic stimuli. Laser-poration technology, combined with MEA chips and video kinematic evaluation, revealed modulation of electromechanical coupling, affecting action potential upstroke and duration, reducing contraction velocity, and altering electromechanical delay. Furthermore, MELAS hiPSCs and primary cardiomyocytes exhibited reduced protein levels of various OXPHOS subunits (SDHB, ATPB, and COX IV) compared to isogenic controls. The mutated cell line also showed increased ROS production in non-stimulated samples compared to stimulated ones (1.3-fold vs. 1.2-fold), with this difference magnifying after 24 hours from stimulation (1.8-fold vs. 1.3-fold). Conclusions This study characterizes MELAS hiPSCs differentiated into cardiac organoids, offering insight into the cardiac aspect of this complex syndrome. Our findings deepen understanding of the syndrome's cardiac impact and response to extracellular stimuli, potentially benefiting affected tissues. This research defines critical physiological and kinematic parameters for MELAS, paving the way for future investigations.

Mechanism of lactic acidemia-promoted pulmonary endothelial cells death in sepsis: role for CIRP-ZBP1-PANoptosis pathway

BackgroundSepsis is often accompanied by lactic acidemia and acute lung injury (ALI). Clinical studies have established that high serum lactate levels are associated with increased mortality rates in septic patients. We further observed a significant correlation between the levels of cold-inducible RNA-binding protein (CIRP) in plasma and bronchoalveolar lavage fluid (BALF), as well as lactate levels, and the severity of post-sepsis ALI. The underlying mechanism, however, remains elusive.MethodsC57BL/6 wild type (WT), Casp8−/−, Ripk3−/−, and Zbp1−/− mice were subjected to the cecal ligation and puncture (CLP) sepsis model. In this model, we measured intra-macrophage CIRP lactylation and the subsequent release of CIRP. We also tracked the internalization of extracellular CIRP (eCIRP) in pulmonary vascular endothelial cells (PVECs) and its interaction with Z-DNA binding protein 1 (ZBP1). Furthermore, we monitored changes in ZBP1 levels in PVECs and the consequent activation of cell death pathways.ResultsIn the current study, we demonstrate that lactate, accumulating during sepsis, promotes the lactylation of CIRP in macrophages, leading to the release of CIRP. Once eCIRP is internalized by PVEC through a Toll-like receptor 4 (TLR4)-mediated endocytosis pathway, it competitively binds to ZBP1 and effectively blocks the interaction between ZBP1 and tripartite motif containing 32 (TRIM32), an E3 ubiquitin ligase targeting ZBP1 for proteasomal degradation. This interference mechanism stabilizes ZBP1, thereby enhancing ZBP1-receptor-interacting protein kinase 3 (RIPK3)-dependent PVEC PANoptosis, a form of cell death involving the simultaneous activation of multiple cell death pathways, thereby exacerbating ALI.ConclusionsThese findings unveil a novel pathway by which lactic acidemia promotes macrophage-derived eCIRP release, which, in turn, mediates ZBP1-dependent PVEC PANoptosis in sepsis-induced ALI. This finding offers new insights into the molecular mechanisms driving sepsis-related pulmonary complications and provides potential new therapeutic strategies.

Case report: Dichloroacetate-induced methaemoglobinaemia in a G6PD-deficient neonate.

A 3-week-old neonate with glucose-6-phosphate dehydrogenase (G6PD) deficiency and primary lactic acidosis developed haemolytic jaundice and methaemoglobinaemia following treatment with dichloroacetate (DCA), a standard treatment for primary lactic acidosis. While this mechanism has been reported in the sheep model, it has not been described in humans. Our case reinforces the uncommon observation that a G6PD-deficient individual experiencing oxidative stress may develop concurrent methaemoglobinaemia. In this case, methylene blue, the standard treatment for methaemoglobinaemia, may result in further oxidative stress. The judicious use of blood transfusion to correct the oxygen-carrying capacity of our patient led to reversal of the methaemoglobinaemia.

MELAS Presenting as Bilateral Symmetric Occipital and Temporal Cortices Lesions: A Case Report and Literature Review.

Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episode (MELAS) is one of the most common maternally inherited mitochondrial diseases. The stroke-like episode affecting the cortical cortex is the hallmark of MELAS; however, it rarely presents as simultaneously bilateral symmetric cortices lesions. We reported a case of MELAS in a 46-year-old female patient with bilateral symmetric occipital and internal temporal cortices involvements on brain magnetic resonance imaging (MRI). A literature review of MELAS patients and a retrospective analysis were performed. She had a family history of diabetes. Although she denied a history of diabetes, elevated blood glucose was noted after admission, and diabetes was diagnosed. Laboratory examination revealed elevated lactate acid and creatine kinase levels in blood. Cranial computed tomography (CT) image demonstrated basal ganglia calcification, as well as subtle decreased attenuation in bilateral symmetric occipital and internal temporal cortices. Brain magnetic resonance imaging (MRI) demonstrated symmetric gyriform hyperintensity in bilateral occipital lobes and internal temporal lobes in both grey and white matter on fluid-attenuated inversion recovery (FLAIR) images with restricted diffusion on diffusion weighted images (DWI). A genetic test revealed a point mutation in the mtDNA(3243A > G) by blood examination. Literature review showed that there were 231 eligible patients with MELAS identified from 212 published papers. Symmetric cortical involvements were seen in 15 (6.5%) patients on brain MRI. MELAS should be considered as a potential diagnosis in the patients with bilateral symmetric stroke-like cortices lesions.

Mitochondrial disorders are associated with morphological neuromuscular junction defects

We aimed to evaluate whether inherited mitochondrial dysfunction is associated with neuromuscular junction remodeling in patients with mitochondrial disorders.Muscle biopsies from 15 patients with mitochondrial disorders and 10 control patients were analyzed through immunostaining for various neuromuscular junction components. The patient group, with a mean age of 49.9 years, exhibited various mitochondrial disorders including chronic progressive external ophthalmoplegia, Kearns-Sayre syndrome, and mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes. Patients with mitochondrial disorders had a high percentage of remodeled (p= 0.0001), neoformed (p= 0.0049) and dilated (p= 0.016) endplates. There was a trend toward an increased proportion of neuromuscular junctions with terminal Schwann cell extension in these patients (p= 0.052). No significant difference was found in myofiber diameter between the groups. The observed neuromuscular junction defects varied widely across different mitochondrial disorder phenotypes and were present even without accompanying muscle weakness or neuropathy.This suggest that mitochondrial disorders are associated with a primary NMJ remodeling independent of muscle structural damage. Pathomechanisms underpinning this remodeling of the neuromuscular junction, as well as clinical factors predictive of this remodeling, remain to be fully characterized.

Postanesthetic rhabdomyolysis in 7 warmblood horses.

To describe the clinical findings, outcomes, and muscle histopathology in warmblood horses that developed severe rhabdomyolysis in the perianesthetic period despite remaining stable while under general anesthesia. 7 warmblood horses, 6 geldings and 1 mare, with a median age of 9 years (range, 4 to 18 years) and median weight of 615 kg (range, 550 to 703 kg). Records from the Valberg Neuromuscular Diagnostic Laboratory and Michigan State University were reviewed (2016 to 2023) to identify warmbloods with postanesthetic myopathy (PAM). Warmblood horses with no history of myopathy developed PAM after remaining stable while under general anesthesia. Five of 7 horses were in regular work prior to anesthesia, and activity level was unknown in 2 horses. Time to standing in recovery was prolonged, 3 horses were euthanized due to persistent recumbency, and rhabdomyolysis recurred in 4 horses 5 to 11 days after anesthesia, with 1 surviving. Horses had muscle stiffness, pain, and sweating and struggled to remain standing. As PAM developed, serum creatine kinase activity and lactate concentrations (12 ± 7 mmol/L; n = 5) were markedly increased. At necropsy, histopathology revealed complete glycogen depletion (5 of 7), acute myodegeneration (6 of 7), and chronic active myodegeneration of representative skeletal muscle samples. A semimembranosus biopsy obtained 14 days after anesthesia from the survivor had rare glycogen-depleted fibers. Warmblood horses are susceptible to fatal PAM characterized by acute myodegeneration, lactic acidosis, and muscle glycogen depletion that occurs up to 11 days after anesthesia. In horses with delayed recovery after anesthesia, monitoring for 2 weeks after anesthesia, including assessment of serum creatine kinase activity and blood lactate, could potentially improve outcomes.

Targeted nanopore sequencing using the Flongle device to identify mitochondrial DNA variants

Variants in mitochondrial genomes (mtDNA) can cause various neurological and mitochondrial diseases such as mitochondrial myopathy, encephalopathy, lactic acidosis, stroke-like episodes (MELAS). Given the 16 kb length of mtDNA, continuous sequencing is feasible using long-read sequencing (LRS). Herein, we aimed to show a simple and accessible method for comprehensive mtDNA sequencing with potential diagnostic applications for mitochondrial diseases using the compact and affordable LRS flow cell “Flongle.” Whole mtDNA amplification (WMA) was performed using genomic DNA samples derived from four patients with mitochondrial diseases, followed by LRS using Flongle. We compared these results to those obtained using Cas9 enrichment. Additionally, the accuracy of heteroplasmy rates was assessed by incorporating mtDNA variants at equimolar levels. Finally, mtDNA from 19 patients with Parkinson’s disease (PD) was sequenced using Flongle to identify disease risk-associated variants. mtDNA variants were detected in all four patients with mitochondrial diseases, with results comparable to those obtained from Cas9 enrichment. Heteroplasmy levels were accurately detected (r2 > 0.99) via WMA using Flongle. A reported variant was identified in three patients with PD. In conclusion, Flongle can simplify the traditionally cumbersome and expensive mtDNA sequencing process, offering a streamlined and accessible approach to diagnosing mitochondrial diseases.

MELAS syndrome and risk of infection

Abstract This perspective explores the relationship between mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome and an increased risk of infections. Mitochondrial dysfunction impairs immune cell function, impacting the body’s defense against pathogens. Additional effects on the immune system may manifest through altered B-cell function and disruptions in the gut microbiota balance. The complex connection between infections, MELAS symptoms, and treatment complicates patient management. We propose greater focus on genetic abnormalities and their immunologic impacts, indicating a possible path for targeted pharmaceutical therapies to improve overall illness management.

Metabolic management of a successful pregnancy and postpartum complications in fructose-1,6-bisphosphatase deficiency.

Fructose-1,6-bisphosphatase (FBPase) deficiency is a rare, inborn error of metabolism, that causes hypoglycemia and lactic acidosis in response to inadequate glucose intake and/or high intakes of fructose, sucrose, or sorbitol. Pregnancy in women with FBPase deficiency puts them at high risk for metabolic decompensation due to increased glucose demands from the growing fetus. Here we report a 31-year-old primipara who was treated starting at 14 weeks gestation with a diet high in complex carbohydrates and low in fructose, sucrose, and sorbitol and close monitoring of glucose levels throughout her pregnancy. She delivered a healthy 2860 g baby at 37 weeks via vaginal delivery with no complications or hypoglycemia. At 5 months postpartum and 5 months of life, the patient and baby are doing well, although the patient experienced an episode of hypoglycemia and lactic acidosis at 4 months postpartum due to the increased metabolic demands of breastfeeding. This report adds to the limited case reports that discuss outcomes and proposed interventions during pregnancy in individuals with FBPase deficiency.

Post-transcriptional methylation of mitochondrial-tRNA differentially contributes to mitochondrial pathology

Human mitochondrial tRNAs (mt-tRNAs), critical for mitochondrial biogenesis, are frequently associated with pathogenic mutations. These mt-tRNAs have unusual sequence motifs and require post-transcriptional modifications to stabilize their fragile structures. However, whether a modification that stabilizes a wild-type (WT) mt-tRNA would also stabilize its pathogenic variants is unknown. Here we show that the N1-methylation of guanosine at position 9 (m1G9) of mt-Leu(UAA), while stabilizing the WT tRNA, has a destabilizing effect on variants associated with MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes). This differential effect is further demonstrated, as removal of the m1G9 methylation, while damaging to the WT tRNA, is beneficial to the major pathogenic variant, improving the structure and activity of the variant. These results have therapeutic implications, suggesting that the N1-methylation of mt-tRNAs at position 9 is a determinant of pathogenicity and that controlling the methylation level is an important modulator of mt-tRNA-associated diseases.

A rare and underestimated cause of anion gap metabolic acidosis in a pediatric patient

Abstract Recognized causes of anion gap metabolic acidosis include methanol, uremia, diabetic ketoacidosis, propylene glycol, isoniazid, iron, lactic acidosis, ethylene glycol, and salicylates, which is taught as the mnemonic, MUDPILES. While this mnemonic can be a useful learning tool, it is important to consider other, atypical causes. Here, we present the case of a 9-year-old male patient with a complex medical history, including trisomy 21 and Lennox-Gastaut syndrome who presented to the emergency department (ED) in hypotensive shock. Upon admission, he was noted to have a distended abdomen, evidence of acute pancreatitis and possible sepsis. Of note, his initial labs revealed an anion gap of 30.1 mmol/L, a whole blood lactate of 4.4 mmol/L, a pH of 7.2, and a normal pCO2, indicting an anion gap metabolic acidosis. Importantly, methanol, ethylene glycol, ketones, and salicylates were not detected, and renal function was normal. However, he did have an extensive medication history, including several antiepileptic drugs (AEDs). Over the coming weeks, he recovered from the acute pancreatitis, but developed fluid overload, electrolyte derangements (hypernatremia and hypokalemia), a worsening metabolic acidosis with an anion gap up to 54.6 mmol/L, and hyperammonemia (plasma NH3 of 232 μmol/L). At this point, the metabolism team was contacted for concerns regarding the rising ammonia levels, which subsequently responded to a combination of lactulose and Rifaximin. An inborn error of metabolism (IEM) was considered, and plasma amino acid analysis was performed (Waters Acquity MassTrak AAA solution) but was not diagnostic. Notably, the patient developed a significantly elevated gamma glutamyl transpeptidase (GGT) up to 4088 U/L, suggesting glutathione depletion, however, transaminases and alkaline phosphatase were normal. The laboratory was contacted by the metabolism providers for other possible causes of metabolic acidosis and it was suggested that the patient undergo urine organic acid testing. Urine specimens were analyzed using gas chromatography/mass spectrometry (GC/MS) (Aligent system). The results were notable for marked excretion of pyroglutamic acid (5-oxoproline), which is typically associated with acetaminophen, however, the patient’s acetaminophen levels were less than 5 μg/mL, indicating another, atypical cause of increased pyroglutamic acid. In this case, vigabatrin, an anticonvulsant known to cause glutathione depletion and secondary pyroglutamic aciduria was suspected, and subsequently withdrawn. The patient was also started on a trial of N-acetylcysteine (NAC) to replenish glutathione, which resolved the pyroglutamic aciduria and anion gap, and corrected the metabolic acidosis. This case highlights the importance of recognizing pyroglutamic acid as a rare cause of anion gap metabolic acidosis, even in the setting of normal acetaminophen levels, and the importance of organic acid testing in the work-up of such patients. Wider use of the mnemonic GOLD MARK, where the “O” stands for oxoproline, may help in the differential diagnosis of anion gap metabolic acidosis.

Neonatal Hemochromatosis Secondary to an Inborn Error of Metabolism (Mitochondrial Disorder): Post- mortem Diagnosis in the Fetus of a Young Primipara

Abstract Introduction/Objective Neonatal hemochromatosis (NH), an extremely rare congenital phenotype of acute hepatic failure with hepatic and extrahepatic siderosis, is primarily (98%) caused by gestational alloimmune liver disease (GALD) and, rarely (2%), by infection, metabolic disorders, bile acid defects, and mitochondrial hepatopathy. This report presents an extremely rare case of NH caused by an inborn error of metabolism (suspected mitochondrial dysfunction). This low-birth-weight female was born with acute liver failure, metabolic acidosis, multisystem failure, and progressive lactate acidosis, and expired on day 7. On autopsy, liver was less than 50% of normal size and without nodularity. Microscopic architecture was preserved with erythropoiesis, canalicular bile plugs, microvesicular steatosis (oil red O stain) and abundant coarsely granular siderosis (iron stain). GALD was unlikely because of the absence of the typical hepatocytic injury, fibrosis or biliary destruction, and the negative immunohistochemistry for MAC (C5b-C9). Extrahepatic siderosis was demonstrated in thyroid follicles, thymic Hassall corpuscles, myocardium, and adenohypophysis. Sanger sequencing and deletion testing of mitochondrial genome on a maternal buccal biopsy identified a homoplasmic variant (m.15482 T&amp;gt;C p.(S246P) in maternal MT-CYB gene but without molecular diagnosis of a mitochondrial DNA disorder. Infant plasma had increased C6DC, C5, C12-OH acylcarnitine, alanine, and proline. Urine contained elevated organic acids (lactate/pyruvate, 2-ketoacids, 3-methylglutarate, 3-methylglutaconate), concerning acute mitochondrial respiratory chain dysfunction. Methods/Case Report: Case Study Results (if a Case Study enter NA) NA Conclusion Diagnosis of NH warrants exclusion of the most common etiology, GALD. Mitochondrial genetic mutations are the most difficult to diagnosis because of heterogeneity and typically undiagnosed maternal defects. This is the first report of NH with a homoplasmic maternal variant of uncertain significance. Neonatal lactic acidosis is the strongest clinical clue for mitochondrial dysfunction and should trigger phenotyping, maternal mitochondrial genetic variants (mtDNA, nuDNA), functional, biochemical, and genetic studies.

Urgent-Start Peritoneal Dialysis in Metformin-Associated Lactic Acidosis: A Critical Alternative When Immediate Hemodialysis is Unavailable.

Introduction Intermittent hemodialysis (IHD) is a preferable renal replacement therapy (RRT) option in metformin-associated lactic acidosis (MALA) due to rapid correct metabolic acidosis. However, IHD might not be started immediately. Immediate urgent-start peritoneal dialysis (iUSPD) is used as a life-saving dialysis option and then followed by IHD. The outcomes of iUSPD were compared with other extracorporeal dialysis in MALA. Methods In two tertiary hospitals in Thailand, the outcomes of patients with MALA who had received three different RRT modalities (iUSPD followed by IHD, IHD, and continuous renal replacement therapy [CRRT]) from January 2015 to December 2019 were compared. The primary outcome was 30-day mortality. The secondary outcomes were door-to-dialysis time and 90-day RRT dependence. Results 180 MALA cases that required dialysis were included (20 iUSPD, 120 IHD, and 40 CRRT). Their mean age was 64 years. Most of the patients had severe metabolic acidosis (mean pH 6.91, HCO3 6 mmol/L, and anion gap 40 mmol/L) and were critically ill. The 30-day mortality was 30% in iUSPD, 9.2% in IHD, and 32.5% in CRRT, p = 0.001). The mortality risk in the iUSPD group was not significantly different from those of the IHD and CRRT groups (adjusted HR 2.5, 95% CI 0.65-9.6 and adjusted HR 0.75, 95% CI 0.2-2.78, respectively). All dialysis modalities had comparable 90-day dialysis dependence. iUSPD exhibited the shortest door-to-dialysis time. Conclusion In MALA, iUSPD followed by IHD might be a viable RRT option to save patient lives if no other dialysis option are available.