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A 13-year and 4-month-old girl was brought to the emergency department due to fever, dizziness,vomiting, and blurred vision. Laboratory data revealed hyperglycemia with an HbA1C of 7.3 percent, ketonuria, and lactic acidosis. The initial impression was diabetic ketoacidosis. During admission, recurrent focal impaired awareness seizures were noted, and magnetic resonance imaging of the brain revealed multiple brain infarctions in the bilateral cerebrum. Mitochondrial gene report showed A3243 G with 64 percent heteroplasmy, and mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes was diagnosed. At 16 years and 7 months old, recurrence of vomiting and onset of right hemianopia and mild right limb weakness were observed and follow-up T2 images showed massive edema in her left parieto-occipital region. At 16 years and 10 months old, she developed clonus in her left hand associated with an unsteady gait and blurred vision. MRI of the brain revealed recurrent brain infarction, and T2 images showed massive edema of the right parieto-occipital region. MELAS is a rare disease entity and occasionally comorbid with mitochondrial diabetes in childhood. Characteristic radiological features of MELAS include infarction-like lesions over the parieto-occipital or parieto-temporal areas, which help distinguish MELAS from childhood ischemic stroke.

Rationale: Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome is a subset of rare mitochondrial diseases characterized by diverse clinical manifestations, which often complicates its diagnosis., Patient Concerns: This report chronicles the experiences of a 14-year-old female patient who underwent multiple misdiagnoses before the eventual identification of MELAS syndrome. Her journey began with symptoms that included growth retardation, hypertrophic cardiomyopathy, and epilepsy., Diagnosis: The definitive diagnosis of MELAS syndrome was established through genetic confirmation, revealing a mutation in the MT-TL1 gene (m.3242A > G)., Interventions: Upon diagnosis, the patient received targeted symptomatic treatment, which led to pronounced improvements in her symptoms., Outcomes: The patient's condition stabilized with the administered treatments, and she exhibited significant symptom relief, emphasizing the importance of accurate diagnosis and timely intervention., Lessons: This case underscores the imperative for heightened clinical vigilance and thorough differential diagnosis in the face of complex clinical presentations, such as those seen in MELAS syndrome, to ensure timely and appropriate interventions., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2023 the Author(s). Published by Wolters Kluwer Health, Inc.)

Thiamine is present in many foods and is well recognised as an essential nutrient critical for energy metabolism. While thiamine deficiency is commonly recognised in alcoholism, it can present in many other settings where it is often not considered and goes unrecognised. One challenging aspect to diagnosis is that it may have varied metabolic, neurological and cardiac presentations. Here we present an overview of the disorder, focusing on the multiple causes and clinical presentations. Interestingly, thiamine deficiency is likely increasing in frequency, especially among wildlife, where it is linked with changing environments and climate change. Thiamine deficiency should be considered whenever neurological or cardiological disease of unknown aetiology presents, especially in any patient presenting with lactic acidosis., (© The Author(s) 2022. Published by Oxford University Press on behalf of Postgraduate Medical Journal. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Fructose-1,6-bisphosphatase (FBPase) deficiency, caused by an FBP1 mutation, is an autosomal recessive disorder characterized by hypoglycemic lactic acidosis. Due to the rarity of FBPase deficiency, the mechanism by which the mutations cause enzyme activity loss still remains unclear. Here we identify compound heterozygous missense mutations of FBP1, c.491G>A (p.G164D) and c.581T>C (p.F194S), in an adult patient with hypoglycemic lactic acidosis. The G164D and F194S FBP1 mutants exhibit decreased FBP1 protein expression and a loss of FBPase enzyme activity. The biochemical phenotypes of all previously reported FBP1 missense mutations in addition to G164D and F194S are classified into three functional categories. Type 1 mutations are located at pivotal residues in enzyme activity motifs and have no effects on protein expression. Type 2 mutations structurally cluster around the substrate binding pocket and are associated with decreased protein expression due to protein misfolding. Type 3 mutations are likely nonpathogenic. These findings demonstrate a key role of protein misfolding in mediating the pathogenesis of FBPase deficiency, particularly for Type 2 mutations. This study provides important insights that certain patients with Type 2 mutations may respond to chaperone molecules., (© 2023. The Author(s).)

Background: During corona virus pandemic, various neurological complications of COVID-19 have been reported. Recent studies demonstrated different pathophysiology for neurological manifestations of COVID-19 such as mitochondrial dysfunction and damage to cerebral vasculature. In addition, mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome is a mitochondrial disorder with a variety of neurological symptoms. In this study, we aim to assess a potential predisposition in mitochondrial dysfunction of COVID-19, leading to MELAS presentation., Methods: We studied three previously healthy patients with the first presentation of acute stroke-like symptoms, following COVID-19 infection. We analyzed the patients' clinical data and brain magnetic resonance imaging (MRI) lesions that presented to the neurological center of a university-affiliated hospital in Tehran, Iran, from September 2020 to August 2021., Results: All cases are characterized by a temporoparietal abnormality in imaging studies and electroencephalogram (EEG). Based on electrodiagnostic tests, three patients were diagnosed with myopathy. In two brothers with relatively the same symptoms, one performed muscle biopsy finding myopathic process, and genetic testing confirmed a 3243A>G point mutation in a heteroplasmic state in one of our patients., Conclusion: Although MELAS is not a prevalent condition, the recent increase in the number of these patients in our center might indicate the potential role of COVID-19 in triggering the silent pre- existing mitochondrial dysfunction in these patients.

Rationale: Mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) is the most common subtype of mitochondrial encephalopathy. In the past, it was believed that most hereditary white matter lesions were lysosome storage disorders or peroxisome diseases. However, in recent years, white matter lesions have been increasingly regarded as a common feature of patients with mitochondrial diseases. In addition to stroke-like lesions, about half of the patients with MELAS reported white matter lesions in the brain., Patient Concerns: Herein, we provide a case of A 48-year-old female who presented with episodic loss of consciousness with twitching of extremities. Previous medical history revealed 10 years of history of epilepsy, 10 years of history of diabetes, a history of hearing loss, and unknown etiology. Ancillary findings included brain magnetic fluid-attenuated inversion recovery showed symmetrical lesions in the bilateral parietal lobe with high signal intensity at the edge, and high signal intensity in the bilateral occipital lobe, paraventricular white matter, corona radiata, and the center of semiovale., Diagnoses: Mitochondrial deoxyribonucleic acid gene sequencing returned A3243G point mutation and it supports the diagnosis of intracranial hypertension., Interventions: Considered the diagnosis of symptomatic epilepsy, the patient was treated with mechanical ventilation, midazolam, and levetiracetam, and the limb twitching symptoms were controlled. The patient was comatose, chronically bedridden, with gastrointestinal dysfunction, and was treated prophylactically with antibiotics against infection, parenteral nutrition, and other supportive measures. B vitamins, vitamin C, vitamin E, coenzyme Q10, and idebenone were given, and mechanical ventilation and midazolam were stopped after 8 days. He was discharged from the hospital on 30 days and continued symptomatic treatment with B-vitamins, vitamin C, vitamin E, coenzyme Q10, and idebenone, and antiepileptic treatment with levetiracetam, with outpatient follow-up., Outcomes: No further seizures were recorded and the patient recovered well., Lessons: MELAS syndrome without stroke-like episodes of diffuse posterior cerebral white matter lesions is rare in clinical practice, and the possibility of MELAS syndrome should be considered in symmetric posterior cerebral white matter lesions., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2023 the Author(s). Published by Wolters Kluwer Health, Inc.)

Objective: Metformin, commonly prescribed in diabetic patients, can cause lactic acidosis. Although generally rare, this side effect remains a source of concern in procedures requiring contrast media, due to the risk of contrast-induced nephropathy. Temporarily withdrawing metformin during the peri-procedural period is often practiced, but clinical decisions are difficult in emergency situations, such as acute coronary syndromes. In this systematic review with meta-analysis, we aimed to further investigate the safety of percutaneous coronary interventions in patients on concurrent metformin therapy. Design, Setting and Participants: We analyzed studies in patients undergoing (elective or emergency) percutaneous coronary interventions with or without concurrent metformin administration, reporting on the incidence of metformin-associated lactic acidosis and peri-procedural renal function. Methods: PubMed, ClinicalTrials.gov, Cochrane Library, and Scopus were systematically searched without language restrictions throughout August 2022. Randomized clinical trials and observational studies were assessed with the Revised Cochrane Collaboration Risk of Bias tool and the Newcastle-Ottawa quality scale, respectively. Data synthesis addressed the mean drop in estimated glomerular filtration rate (eGFR) and the incidence of contrast-induced nephropathy, in addition to lactic acidosis. Results: Nine studies were included, totaling 2235 patients (1076 continuing metformin during the peri-procedural period), mostly with eGFR above 30 mL/min/1.73m 2 No cases of lactic acidosis were reported. The mean post-procedural drop in eGFR was 6.81mL/min/1.73m 2 (95% confidence interval [CI]: 3.41 to 10.21) in the presence of metformin and 5.34 mL/min/1.73m 2 (95% CI: 2.98 to 7.70) in its absence. The incidence of contrast-induced nephropathy was not affected by concurrent metformin, as shown by a (between-groups) standardized mean difference of 0.0007 (95% CI: -0.1007 to 0.1022). Conclusion: Concurrent metformin during percutaneous coronary interventions in patients with relatively preserved renal function is safe, without added risk of lactic acidosis or contrast-induced nephropathy. Thus, emergency revascularization in the context of acute coronary syndromes should not be deferred. More data from clinical trials in patients with severe renal disease are needed., Competing Interests: Disclosure: The authors have not reported financial support or personal conflicts of interest related to this work., (Copyright © 2023 Marshfield Clinic Health System.)

A 15-year-old boy was admitted to the hospital due to ataxia, drowsiness and bradypsychia. He was known to have a short bowel syndrome Initial venous blood gases revealed a metabolic acidosis with a high anion gap of 24 mmol/L and normal L-lactate. He improved with fasting and fluids and was discharged with oral metronidazole. 2 weeks later he was admitted again with similar symptoms. A specific study of D-Lactic acidosis was carried out, confirming the diagnosis. D-lactic acidosis is an uncommon complication of short bowel syndrome. It occurs as a consequence of the metabolism of unabsorbed carbohydrates. The symptoms are mainly neurological. Limiting the dietary carbohydrates is useful to avoid recurrences. Poorly absorbable antibiotics are used but with varying results. Surgery may be an option if medical treatment fails. Probiotics might be useful to avoid symthoms recurrence.

Objective: The pathophysiology of stroke-like episode (SLE) in mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS) was uncertain, though mitochondrial metabolic crisis of cortical neurons and mitochondrial proliferation in small vessels of brain have been considered. However, the involvement of major cerebral vessels was debated. We aimed to investigate whether major cerebral vessels participate in SLE., Methods: We retrospectively collected the clinical and neuroimaging data of MELAS patients diagnosed in our center. Through follow-up, the cases harboring reversible cerebral artery constriction on brain magnetic resonance angiography (MRA) examination were included in this study., Results: There were 20 patients with intact brain MRA data at acute and non-acute phases. Only 3 cases with m.3243A > G mutation were enrolled. They suffered once or twice SLEs manifesting headache, blurred vision, seizures or mental and behavior disorder. New lesions were present in temporo-parietal and/or temporo-occipital regions. Segmental stenosis at middle cerebral artery and/or posterior cerebral artery, proximal portions in particular, was ipsilateral to the lesions at acute phase in all the 3 patients, which was resolved during the subacute or chronic stages. Moreover, the SLEs lesions were located within the stenotic arteries territory. In addition, dilation at distal portions of the stenotic arteries was observed at acute phase as well in 2 patients., Conclusion: Reversible constriction of cerebral arteries may contribute to SLE of MELAS. MELAS should be a differential diagnosis when stenosis of major cerebral vessels is present at acute phase of SLE., Competing Interests: Declaration of Competing Interest Y. Zhao, X. Yu, K. Ji, Y. Lin, X. Xu, W. Wang and C. Yan declare that they have no competing interests., (Copyright © 2022. Published by Elsevier B.V.)

A mitochondrial stroke-like event is an evolving subacute neurological syndrome linked to seizure activity and focal metabolic brain derangement in a genetically determined mitochondrial disorder. The acronym "MELAS" (mitochondrial encephalopathy associated with lactic acidosis and stroke-like lesions) identifies subjects with molecular, biochemical and/or histological evidence of mitochondrial disorder who experience stroke-like lesions. MELAS is a rare inherited mitochondrial disease linked to severe multiorgan involvement and stress-induced episodes of metabolic decompensation and lactic acidosis. Unfortunately, there are no etiopathogenetic therapies for stroke-like episodes to date, and the treatment is mainly based on anti-epileptic drugs and supportive therapies. This perspective opinion article discusses the current care standards for MELAS patients and revises current and innovative emerging therapies for mitochondrial stroke-like episodes., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background Lactic acidosis is associated with mortality in patients with cardiogenic shock (CS). Elevated lactate levels and systemic acidemia (low blood pH) have both been proposed as drivers of death. We, therefore, analyzed the association of both high lactate concentrations and low blood pH with 30-day mortality in patients with CS. Methods and Results This was a 2-center historical cohort study of unselected patients with CS with available data for admission lactate level or blood pH. CS severity was graded using the Society for Cardiovascular Angiography and Intervention (SCAI) shock classification. All-cause survival at 30 days was analyzed using Kaplan-Meier curves and Cox proportional-hazards analysis. There were 1814 patients with CS (mean age, 67.3 years; 68.5% men); 51.8% had myocardial infarction and 53.0% had cardiac arrest. The distribution of SCAI shock stages was B, 10.8%; C, 30.7%; D, 38.1%; and E, 18.7%. In both cohorts, higher lactate or lower pH predicted a higher risk of adjusted 30-day mortality. Patients with a lactate ≥5 mmol/L or pH <7.2 were at increased risk of adjusted 30-day mortality; patients with both lactate ≥5 mmol/L and pH <7.2 had the highest risk of adjusted 30-day mortality. Patients in SCAI shock stages C, D, and E had higher 30-day mortality in each SCAI shock stage if they had lactate ≥5 mmol/L or pH <7.2, particularly if they met both criteria. Conclusions Higher lactate and lower pH predict mortality in patients with cardiogenic shock beyond standard measures of shock severity. Severe lactic acidosis may serve as a risk modifier for the SCAI shock classification. Definitions of refractory or hemometabolic shock should include high lactate levels and low blood pH.

Purpose: To propose that transient postictal hyperglycemia as a diagnostic clue of mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS)., Case Report: We reported two non-diabetic patients presenting with generalized seizure and transient postictal hyperglycemia. At the acute stage, both patients had hyperglycemia with serum glucose levels more than 400 mg/dl, normal glycated hemoglobin (HbA1C) levels, normal ketone body levels, and absence of infection signs. Within three days of the seizure event, both patients were euglycemic and did not require any diabetes treatment. Brain MRI examination revealed gyriform restricted diffusion at bilateral superior temporal gyrus in one patient, and diffuse cerebral and cerebellar atrophy without restricted diffusion lesions in another patient. Polymerase chain reaction and restriction fragment length polymorphism (RFLP) analysis confirmed that both patients harbored the m.3243A more than G mutation., Conclusion: Seizure-induced stress hyperglycemia is uncommon in normal individuals, but such kind of energy crisis may be pronounced in patients with mitochondrial dysfunction. Early diagnosis of mitochondrial diseases-related epilepsy and hyperglycemia is crucial since certain antiepileptic drugs (ex. Valproic acid) and antihyperglycemic agents (ex. Metformin) are contraindicated in patients with mitochondrial diseases. Our findings support that transient postictal hyperglycemia may be a red flag to consider the diagnosis of MELAS.

Type B lactic acidosis is a rare complication of non-tissue perfusion abnormalities caused by solid tumors or hematologic malignancies. Herein, we present the case of a 42-year-old man with type B lactic acidosis and hypoglycemia who was found to have a diffuse large B-cell lymphoma. The cause of lactic acidosis and/or hypoglycemia is thought to be the Warburg effect, which is when the metabolic rate of a rapidly growing malignant tumor is very high and dominated by glycolysis. Systemic damage from type B lactic acidosis can occur when the increased rate of glycolysis exceeds the normal muscle and liver lactic acid clearance rate. The Warburg effect is a rare but serious condition that needs to be recognized, not only in diffuse large B-cell lymphoma, but also in other malignancies. The prognosis of lactic acidosis in patients with malignant tumors is very poor. Currently, effective chemotherapy seems to be the only hope for survival.

In patients undergoing open myocardial revascularization under cardiopulmonary bypass (CB), one of the complications is cognitive dysfunction. The aim of the work is to study the effect of intraoperative lactic acidosis, anemia and the duration of myocardial anoxia on the change in cognitive status with the help of FAB after coronary artery bypass grafting (CABG) with CB. The negative impact of lactic acidosis on cognitive status in patients after CABG has been proven. The relationship between the decrease in hemoglobin concentration during surgery and the negative dynamics of cognitive changes in the postoperative period (R=0,41; p=0,021) was determined. A negative effect of prolonged myocardial anoxia during surgery on the dynamics of cognitive functions of patients was revealed. Thus, the above indicators may be markers of the formation of postoperative cognitive dysfunction in patients undergoing CABG with CB.

D-lactic acidosis represents a rare form of metabolic acidosis that occurs most commonly in patients with short bowel syndrome. This is a serious, sometimes life-threatening complication. The cause is the accumulation of D-lactate in the body, which is formed in excessive amounts by fermentation of unabsorbed carbohydrates by the intestinal microbiota. The nervous system is predominantly affected, which also results in clinical manifestations. The clinical picture is dominated by a wide range of non-specific neurological symptoms. The disease can sometimes manifest as somnolence to coma. From the aspect of laboratory diagnostics, the disease is characterized by severe metabolic acidosis with an increased anion gap. In this case report, we present a unique case of a 54-year-old woman with Crohns disease and short bowel syndrome who in a short time was repeatedly hospitalized for recurrence of severe metabolic acidosis with severe impaired consciousness. Based on the evaluation of anamnestic data, clinical picture and laboratory tests, the patient was diagnosed with D-lactic acidosis. In the discussion we discuss the individual steps that led to this diagnosis and compare our experience with data in the world literature.

Objective: To report a Chinese family with combined m.14459G>A mutation and m.6064A>T mutation of which the female proband presenting unique Leber hereditary optic neuropathy and dystonia (LDYT) overlapping mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS) phenotype., Methods: Clinical information of the pedigree was collected. We performed muscle biopsy and whole-length mitochondrial DNA (mtDNA) sequencing on the proband. The activity of respiratory chain complexes in immortalized lymphoblasts was determined., Results: The current 23-year-old proband suffered from vision decline at age 15 and developed seizures and dystonia with bilateral lesions in precentral gyri at age 18. When she was 21, the lesions in bilateral putamen were found with elevated cerebrospinal fluid lactate. Her mother had optic atrophy; one of her brother died at age 4 with respiratory distress; and the other 8-year-old brother was asymptomatic. Muscle biopsy of the proband was unremarkable. The mtDNA sequencing revealed a heteroplasmic m.14459G>A mutation and a previously unreported m.6064A>T mutation. The respiratory chain complex I activity in the proband's immortalized lymphoblasts was 50% less than the normal control; while there was no statistical difference between the proband and the normal control in the activity of complex IV., Conclusions: We presented the first case exhibiting LDYT and MELAS phenotype with m.14459G>A mutation, and the decreased complex I activity contributed to the pathogenicity. Our study expanded the clinical spectrum of m.14459G>A mutation., (© 2021. Fondazione Società Italiana di Neurologia.)

Abnormal glucose metabolism in cancer cells causes generation and secretion of excess lactate, which results in acidification of the extracellular microenvironment. This altered metabolism aids not only in survival and proliferation but also in suppressing immune-mediated destruction of cancer cells. However, how it influences the response of cancer cells to chemotherapeutic drugs is not clearly understood. We employed appropriate in vitro approaches to explore the role of mono-carboxylate transporter 4 (MCT4) mediated altered intra and extracellular pH on the outcome of the therapeutic efficacy of chemotherapeutic drugs in breast and lung cancer models. We demonstrate by in vitro experiments that inhibition of complex I enhances glycolysis and increases expression as well as membrane translocation of MCT4. It causes a decrease in extracellular pH (pH e ) and impairs doxorubicin and paclitaxel's therapeutic efficacy. Acidic pH e inhibits doxorubicin's uptake, while acidic intracellular pH (pH i ) impairs the efficacy of paclitaxel. Under in vivo experimental settings, the modulation of pH e with phloretin or alkalizer (NaHCO 3 ) enhances cytotoxicity of drugs and inhibits the growth of MCF-7 xenografts in mice. In a nutshell, this study indicates that MCT4 mediated extracellular acidosis is involved in impairing chemotherapeutic drugs' efficacy on cancer cells. Therefore, the use of pH neutralizing agents or MCT inhibitors may be beneficial towards circumventing impairment in the efficacy of certain drugs that are sensitive to pH changes., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: Our objective was to identify possible associations between clinical and laboratory variables and the risk of developing acute kidney injury (AKI) in severely injured patients admitted to the intensive care unit (ICU) for whom creatine kinase (CK) levels were available., Methods: For this retrospective observational study, we analyzed adult trauma patients admitted to the ICU from 2011 to 2015 at Fundación Valle del Lili (FVL) University Hospital. Our primary outcome was the incidence of AKI. Multivariate regression analysis was used to assess risk factors for this outcome., Results: A total of 315 patients were included. The trauma mechanisms were blunt (n = 130), penetrating (n = 66) and blast (n = 44) trauma. The median (interquartile range, IQR) of injury severity score (ISS) was 21 (16-29). AKI developed in 75 patients (23.8%). Multivariate regression analysis revealed that the thoracic abbreviated injury scale (AIS) value (median (IQR) in the AKI group: 3 (0-4)), Acute Physiology and Chronic Health Evaluation (APACHE II) score (median (IQR) in the AKI group: 18 (10-27)), CK greater than 5000 U/L, lactic acid concentration at admission, and dobutamine administration were independently associated with AKI., Conclusion: We found that age, APACHE II score, thoracic trauma, lactic acidosis, and dobutamine administration were independently associated with AKI. Trauma surgeons need to be aware of the increased odds of AKI if one of these factors is identified during the evaluation and treatment of injured patients.

Introduction: FOLFOX therapy is the main chemotherapy regimen for colorectal cancer. Peripheral neuropathy, hematotoxicity, and digestive symptoms are known to be the most frequent adverse events. Hyperammonemia and lactic acidosis rarely occur simultaneously during treatment with FOLFOX therapy; the number of case reports is limited worldwide. We report a case of disturbance of consciousness, considered to be caused by hyperammonemia and lactic acidosis that occurred during treatment with mFOLFOX6 therapy that was administered as postoperative adjuvant treatment for rectal cancer., Patient Concerns: This case was of a 71-year-old man who had been receiving oral treatment for chronic kidney disease and diabetes mellitus. Laparoscopic low anterior resection and artificial anal construction surgery were performed for stage III rectal cancer. As adjuvant postoperative therapy, mFOLFOX6 therapy was started but was followed by a disturbance of consciousness., Diagnoses: Results of the blood tests revealed notable hyperammonemia (ammonia level, 1,163 μg/dl) and lactic acidosis (pH 7.207; lactate, 17.56 mmol/L); however, imaging diagnosis did not reveal intracranial lesions that could cause disturbance of consciousness., Interventions: For hyperammonemia, branched-chain amino acid agents and Ringers solution supplementation were administered. For acidosis, 7% sodium hydrogen carbonate was administered as treatment., Outcomes: The disturbance of consciousness improved within 12 hours of initiating the treatment, and the patient was discharged with no sequelae on 7th day after hospitalization., Conclusion: In patients with chronic kidney disease, FOLFOX regimen may confer risks of hyperammonemia and lactic acidosis.

Rationale: Mitochondrial encephalomyopathy with lactic acidosis and stroke- like episodes (MELAS) syndrome is caused by mitochondrial respiratory chain dysfunction and oxidative phosphorylation disorder. It is a rare clinical metabolic disease involved with multiple systems., Patient Concerns: A 22-year-old patient presented with limb convulsion accompanied by loss of consciousness, headache, partial blindness, blurred vision, and so on., Diagnoses: Brain magnetic resonance imaging showed a high-intensity area in bilateral occipital cortex, left parietal lobe and cerebellum on diffusion-weighted imaging. These focus did not distribute as vascular territory. The pathological examination of skeletal muscle revealed several succinate dehydrogenase reactive vessels with overreaction and increased content of lipid droplets in some muscle fibers. Genetic testing showed that the patient carried m.10158T>C mutation., Interventions: She was provided with traditional arginine hydrochloride therapy and orally medication of coenzyme Q (10 mg)., Outcomes: Mitochondrial DNA of blood and hair follicle of patient carried m.10158T>C mutation LESSONS:: For the suspected patients of MELAS syndrome, if the hot-spot mutation test is negative, more detection sites should be selected.

A 47-year-old female patient presented nausea and vomiting for half a year and elevated serum creatinine for 3 days. Proximal renal tubular acidosis (RTA) complicated with anemiawas confirmed after admission. Secondary factors, such as autoimmune disease, drugs, poison, monoclonal gammopathy, were excluded. Renal biopsy revealed acute interstitial nephritis. The patient was administrated with daily prednisone 50 mg, sodium bicarbonate 4 g, 3 times per day, erythropoietin 3 000 U, 2 times per week, combined with potassium, calcium, and calcitriol tablets. Serum creatinine reduced to 90 μmol/L. However nausea and vomiting deteriorated with lactic acidosis. Bone marrow biopsy indicated the diagnosis of non-Hodgkin lymphoma, therefore the patient was treated with chemotherapy. Although metabolic acidosis improved gradually after chemotherapy, severe pneumocystis carinii pneumonia developed two weeks later. The patient refused further treatment and was discharged.

A 59-year-old woman unaware of having diabetes was transferred due to coma. Upon discovery at home, her consciousness on the Glasgow Coma Scale was E1V2M4, BP 95/84 mmHg, body temperature 34.7°C. On arrival at ER, height was 1.63 m, weight 97 kg, plasma glucose (PG) 1,897 mg/dL, HbA 1c 13.6%, osmolality 421 mosm/kg, arterial pH 7.185, lactate 6.34 mmol/L, β-hydroxybutyrate 7.93 mmol/L. With saline and regular insulin infusion, PG was lowered to 1,440 mg/dL at 2 hours and then to 250 mg/dL by Day 3, and consciousness normalized by Day 5. On admission, serum immunoreactive insulin (IRI) was undetectable (<0.03 U/mL), C-peptide immunoreactivity (CPR) undetectable (<0.003 ng/mL), and anti-glutamic acid decarboxylase antibody negative. Following the above-described treatment, fasting PG was 186 mg/dL and CPR 1.94 ng/mL, respectively, on Day 14; 2-h post-breakfast PG 239 mg/dL and CPR 6.28 ng/mL, respectively, on Day 18. The patient discharged on Day 18 with 1,800 kcal diet, 32 U insulin glargine and 40 mg gliclazide. Fifteen months later at outpatient clinic, her HbA 1c was 6.9% and 2-h post-breakfast PG 123 mg/dL and CPR 5.30 ng/dL with 750 mg metformin, 10 mg gliclazide and 18 U insulin glargine. Transient, but total cessation of insulin secretion was documented in a patient with type 2 diabetes under severe metabolic decompensation. Swift, sustained recovery of insulin release indicated that lack of insulin at the time of emergency was due to secretory failure, i.e., unresponsive exocytotic machinery or depletion of releasable insulin, rather than loss of beta cells.

Critically ill patients are known to have a variety of electrolyte abnormalities. Lactic acidosis can frequently be seen secondary to shock states and is usually treated with aggressive volume resuscitation. Interestingly, hypophosphatemia is a potential cause of resistant lactic acidosis, which may not be as commonly identified or considered. We present a case of a 42-year-old man admitted twice over a span of 6 months with an elevated lactate level that did not resolve with volume resuscitation. It was ultimately determined that his lactic acidosis was due to hypophosphatemia after ruling out other potential causes. Phosphate replacement therapy resulted in the normalization of his lactate. In the literature, multiple theories have indicated the association of hypophosphatemia with lactic acidosis though no prior cases exist supporting a direct relationship. In this case, we set forth to evaluate the complicated relationship between all of these factors and to highlight the importance of early detection and treatment of hypophosphatemia, which may be beneficial in treating lactic acidosis.

Background: Metformin is commonly used for the treatment of type 2 diabetes mellitus. Renal insufficiency is one of the contraindications for its use. Inadvertent prescription in patients with renal insufficiency may lead to metformin-associated lactic acidosis (MALA), which is associated with a high risk of mortality. Consequently, the early recognition and management of MALA is essential., Case Report: We present the case of a 68-year-old man who had reversible blindness resulting from severe lactic acidosis. On presentation, he was alert, oriented, and had no complaints except mild abdominal discomfort and blindness. He denied any history of trauma or drug abuse. The results of the laboratory studies showed severe metabolic acidosis with a high anion gap and increased levels of serum creatinine. There were no predisposing ocular or neurologic lesions that could have induced the blindness. Although the blood levels of methanol, ethanol, and metformin were not estimated, correction of acidosis and hemodialysis led to a complete recovery. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Rarely, transient blindness may occur in patients with fatal severe metabolic acidosis. Evaluation for the presence of metabolic acidosis and a detailed medical history are essential in the management of acute blindness in such patients., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Heat shock protein 70 (HSP70), a chaperone protein associated with tumorigenesis and chemoresistance, has attracted significant attention as a potential therapeutic target for the development of anticancer drugs. Here, the effects of pifithrin-μ, an effective dual inhibitor of HSP70 and p53, on anticancer activities and epithelial-mesenchymal transition (EMT) were investigated in malignant mesothelioma (MM) cells. MSTO-211HAcT cells, pre-incubated in a medium containing lactic acid, showed more potent resistance to cisplatin and gemcitabine, compared with their acid-sensitive parental MSTO-211H cells. Pifithrin-μ treatment induced both apoptosis and necroptosis, which were accompanied by an EMT-like phenomenon, as evidenced by an elongated cell morphology, decreased levels of epithelial cell markers including E-cadherin, claudin-1, and β-catenin, increased levels of mesenchymal markers including Snail, Slug, and vimentin, and increased cell migratory property. Moreover, pifithrin-μ increased intracellular ROS levels, which is associated with mitochondrial dysfunction and decreased cellular ATP content. A series of changes caused by pifithrin-μ treatment were effectively restored by lowering the ROS level through pretreatment with N-acetylcysteine. Collectively, our results suggest that pifithrin-μ may promote the metastatic behavior of surviving cells by triggering the EMT, despite its effective cell-killing action against MM cells, possibly linked to oxidative mitochondrial dysfunction and ATP depletion.

Introduction: Metabolic acidosis is a dangerous and potentially life-threatening condition encountered in the inpatient and emergency department setting. Metabolic acidoses due to renal failure, bicarbonate losses, or lactic acidosis are common conditions, and the appropriate medical management of each is relevant to any inpatient medical provider. Therefore, we created a learning activity that utilizes blackboard-style videos followed by an interactive case-based learning session to help the medical student recognize, diagnose, and manage common causes of metabolic acidosis., Methods: We organized this learning activity by assigning digital videos, followed by application in an interactive team-based format. We created electronic blackboard-style videos and a quiz to assess medical knowledge related to concepts discussed in the videos. Next, we created case resources that facilitate an interactive case-based teaching session so the learners could apply their knowledge and simulate the management of metabolic acidosis., Results: We implemented this activity for 34 medical students. All students viewed the videos prior to the in-class session. In a pre/post assessment of medical knowledge, we observed a significant improvement in quiz scores. Next, we successfully facilitated the case-based active learning session, allowing the assessment of higher-order cognitive skills related to management of patients with metabolic acidosis. Our medical students felt highly satisfied and competent at the completion of our course., Discussion: Our medical students rated this as an excellent learning activity. Others may find this activity useful within the context of any course or rotation related to patients with metabolic acidosis., Competing Interests: None to report., (Copyright © 2019 Berkoben and Roberts.)

Methylmalonic aciduria (MMA) is an inherited metabolic disease caused by methylmalonyl-CoA mutase deficiency. Early-onset disease usually presents with a neonatal acute metabolic acidosis, rapidly causing lethargy, coma, and death if untreated. Late-onset patients have a better prognosis but develop common long-term complications, including neurological deterioration, chronic kidney disease, pancreatitis, optic neuropathy, and chronic liver disease. Of note, oncogenesis has been reported anecdotally in organic acidurias. Here, we present three novel and two previously published cases of MMA patients who developed malignant liver neoplasms. All five patients were affected by a severe, early-onset form of isolated MMA (4 mut 0 , 1 cblB subtype). Different types of liver neoplasms, that is, hepatoblastoma and hepatocellular carcinoma, were diagnosed at ages ranging from infancy to adulthood. We discuss pathophysiological hypotheses involved in MMA-related oncogenesis such as mitochondrial dysfunction, impairment of tricarboxylic acid cycle, oxidative stress, and effects of oncometabolites. Based on the intriguing occurrence of liver abnormalities, including neoplasms, we recommend close biochemical and imaging monitoring of liver disease in routine follow-up of MMA patients., (© 2019 SSIEM.)

We present here a case of hypoglycemia and lactic acidosis in an elderly diabetic lady with underlying leukemia∖lymphoma. Possible mechanisms responsible for both hypoglycemia as well as lactic acidosis are discussed. The case emphasizes the need for thorough chasing of all clinical leads obtained from history taking, physical examination, as well as laboratory evaluation in order to avoid getting misled by apparently obvious diagnosis. To the best of the author's knowledge, this is the first time such a case is reported in Indian literature., (Copyright © 2018. Published by Elsevier Ltd.)

Rationale: Mitochondrial encephalopathy, lactic acidosis and stroke-like episodes (MELAS) are thought to be rarely accompanied by macroangiopathy. We reported a case of MELAS that presented right distal internal carotid arterial (ICA) stenosis and reviewed 12 similar previously reported cases involving intracranial large blood vessels., Patient Concerns: A 38-year-old man suffered from recurrent stroke-like episodes (SE) such as alternating hemiparesis (right lesion 3 years ago and current left lesion), cortical blindness and seizure for 3 years, and was previously misdiagnosed as cerebral infarction. Magnetic Resonance Angiography (MRA) and Digital Subtraction Angiography (DSA) revealed right distal ICA stenosis and sparse cortex blood vessels, which were related to the previous SE., Diagnoses: He was diagnosed by genetic screening (a mitochondrial DNA A3243G point mutation) and presence of high lactic acidosis (4.03 mmol/L), which rose to 7.8 mmol/L after exercise., Intervention: The patient received Coenzyme Q10, vitamin C, L-arginine for 2 weeks and valproic acid sodium (400 mg bid) to prevent seizures till now., Outcomes: He is currently less active and intelligent than his peers, with occasional seizures, and needs family care., Lessons: Till date, there are 12 reported cases of MELAS combined with major cerebral arteries abnormalities including stenosis, dissection, occlusion, reversible vasoconstriction, aneurysms, and atherosclerosis. Hence, macroangiopathy in MELAS is not very rare. There is correlation between the affected vessels and the lesions in some cases, but not in others, which may increase the misdiagnosis rate. Hence, mitochondrial diseases cannot be excluded due to concurrent macroangiopathic lesions.

We report the results of serial F-FDG PET/CT investigations in a 49-year-old woman presenting with an advanced cecal high-grade neuroendocrine carcinoma harboring a somatic BRAF mutation. Patient was refractory to standard chemotherapy regimen showing life-threatening hyperlactatemia. Early after the beginning of BRAF-MEK therapy (dabrafenib and trametinib), impressive improvement in PET/CT imaging was achieved. The pathological F-FDG uptake in cecal primary tumor as well as in nodal, hepatic, and bone metastases drastically decreased. Moreover, the reduction of total lesion glycolysis on PET/CT images was strictly related to extraordinary patient clinical response and lactic acid level normalization.

Metformin is an antidiabetic drug; used to treat type II diabetes mellitus, metformin associated lactic acidosis has an incidence of 2-9 cases / 100,000 patients / year with high mortality (30%). We have had the case of a 75-year-old woman with metabolic acidosis as a result of metformin assumption, treated by renal replacement therapy (CRRT) with continuous veno-venous hemodiafiltration (CVVHDF)., Results: after a short treatment period there was a reduction in Lactates (from 16.8 mmol/L to 12.6 mmol/L) and a progressive improvement of acidosis. In 72 hours the recovery of diuresis and subsequent suspension of CRRT was achieved., Conclusion: CRRT, in addition to ensuring support for renal failure and volume correction, allowed a rapid recovery from metformin-associated lactic acidosis., (Copyright by Società Italiana di Nefrologia SIN, Rome, Italy.)

Seven subunits of the mitochondrial contact site and cristae junction (CJ) organizing system (MICOS) in humans have been recently described in function and structure. QIL1 (also named MIC13) is a small complex that is crucial for the maintenance and assembling of MICOS. A novel mutation of an essential splice site in the C19orf70 gene encoding QIL1 induces severe mitochondrial encephalopathy, hepatopathy and lactate acidosis consistent with psychomotor retardation. In addition, bilateral kidney stones were observed. Disassembly of MICOS complex subunits displays lack of MIC10-MIC26-MIC27-QIL1 subcomplex, resulting in aberrant cristae structure and a loss of cristae junctions and contact sites. In liver and muscle tissue, the activity of the respiratory chain complexes (OXPHOS) was severely impaired. Defects in MICOS complex do not only affect mitochondrial architecture, but also mitochondrial fusion, metabolic signalling, lipid trafficking and cellular electric homeostasis.

Metformin remains a widely-used, first-line pharmacotherapy agent for patients with type 2 diabetes mellitus because of its efficacy, mild side effects, and affordability.However, use of this medication has traditionally been shunned by clinicians in patient populations that are considered at risk of lactic acidosis, such as those with heart failure. The underutilization of metformin can largely be attributed to the historical stigma of its biguanide predecessor, phenformin, and its association with lactic acidosis. Despite various studies finding low rates of lactic acidosis and the United States Federal Drug Administration's subsequent removal of heart failure from metformin's contraindication labeling in 2006, this oral hypoglycemic remains underutilized in this patient population. In addition to reports of the safe use of metformin in the heart failure population, a multitude of studies have also additionally suggested a modest reduction in mortality and morbidity. Metformin's role should be strongly reconsidered in the armamentarium of diabetes management in heart failure patients.

The mitochondrial cytopathies are a heterogeneous group of diseases characterized by heteroplasmic maternal transmission and selective dysfunction of tissues and organs highly dependent on aerobic respiration (eg, skeletal muscle, cardiac muscle, and brain). Mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS) is a specific subtype of mitochondrial cytopathy that is commonly associated with mood disturbances in individuals who survive until adulthood. Because of the altered cellular metabolism inherent in MELAS, it is often difficult to determine drug dosing, drug choice, and treatment response in patients with this rare disease. Historically, management of these patients focused on symptomatic relief and supplementation of compounds thought to optimize aerobic respiration (specifically, enzyme Co-Q10). We report a case in which an adult patient with MELAS and comorbid major depressive disorder demonstrated excellent response to the selective serotonin-norepinephrine reuptake inhibitor medication duloxetine.

Mutations in mitochondrial ATP synthase 6 (MT-ATP6) are a frequent cause of NARP (neurogenic muscle weakness, ataxia, and retinitis pigmentosa) or Leigh syndromes, especially a point mutation at nucleotide position 8993. M.8969G>A is a rare MT-ATP6 mutation, previously reported only in three individuals, causing multisystem disorders with mitochondrial myopathy, lactic acidosis, and sideroblastic anemia or IgA nephropathy. We present two siblings with the m.8969G>A mutation and a novel, substantially milder phenotype with lactic acidosis, poor growth, and intellectual disability. Our findings expand the phenotypic spectrum and show that mtDNA mutations should be taken account also with milder, stable phenotypes.