RESUMEN

BACKGROUND: Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes and nemaline myopathy are two rare genetic conditions. We report the first case reported in world literature with coexistence of both these rare disorders. CASE PRESENTATION: A 11-year-old previously healthy Sri Lankan male child, product of a nonconsanguineous marriage with normal development presented with acute onset short lasting recurring episodes of right-sided eye deviation with impaired consciousness. In between episodes he regained consciousness. Family history revealed a similar presentation in the mother at 36 years of age. Examination was significant for short stature and proximal upper and lower limb weakness. His plasma and cerebrospinal fluid lactate were elevated. Magnetic resonance imaging brain had evidence of an acute infarction in the right occipital territory. Sanger sequencing for common mitochondrial variants of mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes confirmed this diagnosis. Whole exome sequencing revealed pathogenic compound heterozygous variants in NEB gene implicating in coexisting nemaline myopathy. Acute presentation was managed with supportive care, antiepileptics, and mitochondrial supplementation. Currently he is stable on daily supplementation of arginine and limb-strengthening physiotherapy. He is being monitored closely clinically and with serum lactate level. CONCLUSION: Genetic diseases are rare. Coexistence of two genetic conditions is even rarer. Genetic confirmation of diagnosis is imperative for prediction of complications, accurate management, and genetic counseling.

Asunto(s)

Miopatías Nemalínicas , Humanos , Masculino , Miopatías Nemalínicas/genética , Miopatías Nemalínicas/complicaciones , Niño , Encefalomiopatías Mitocondriales/genética , Encefalomiopatías Mitocondriales/complicaciones , Encefalomiopatías Mitocondriales/diagnóstico , Imagen por Resonancia Magnética , Accidente Cerebrovascular , Sri Lanka , Acidosis Láctica/genética , Secuenciación del Exoma

RESUMEN

Metformin-associated lactic acidosis (MALA) is a rare and potentially life-threatening complication of metformin use. It typically occurs in patients who are diabetic and also have other risk factors for lactic acidosis, including kidney and liver conditions, malignancy, or use of certain medications. We report a case of MALA in a man in his 70s with diabetes who presented with gradually worsening gastrointestinal symptoms, including severe abdominal pain and nausea. He reported these symptoms in the setting of metformin use with an acute kidney injury (AKI), likely brought on by poor oral intake and excessive antibiotic use for a urinary tract infection. He was promptly started on intravenous fluids with a bicarbonate drip to concurrently treat his prerenal AKI and lactic acidosis, which resulted in rapid resolution of his symptoms. Renal function normalised within 12 days of admission. Since diabetic patients commonly use metformin and are also at higher risk of renal dysfunction, this case highlights the vulnerability of this group of patients and the need for increased knowledge and awareness of MALA.

Asunto(s)

Acidosis Láctica , Lesión Renal Aguda , Hipoglucemiantes , Metformina , Humanos , Metformina/efectos adversos , Acidosis Láctica/inducido químicamente , Masculino , Hipoglucemiantes/efectos adversos , Anciano , Lesión Renal Aguda/inducido químicamente , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/complicaciones , Dolor Abdominal/inducido químicamente

RESUMEN

INTRODUCTION: Holocarboxylase synthetase deficiency (HLCS deficiency, OMIM #253270) is an exceedingly rare metabolic disorder resulting in multiple carboxylase deficiencies owing to impaired biotin cycle. Clinical manifestations include severe metabolic acidosis, hyperammonemia, tachypnea, skin rash, alopecia, feeding problems, hypotonia, developmental delay, seizures, and, in severe cases, death. METHODS AND RESULTS: An 8-day-old female neonate presented with severe lactic acidosis, necessitating sedation and mechanical ventilation. Despite receiving supportive care, no evident clinical improvement was observed, accompanied by the onset of generalized ichthyosis. Genetic analysis of actionable metabolic disorders revealed compound heterozygous variants of HLCS (NM_000411.8), specifically c.[710T>C (p.Leu237Pro)]; [1544G>A (p.Ser515Asn)], prompting the initiation of biotin mega-dose therapy (10 mg/day). Remarkably, dramatic clinical improvement in lactic acidosis was observed the day after initiating biotin administration, leading to the discontinuation of mechanical ventilation within 6 days. The patient remained in stable condition during follow-up, exhibiting normal growth and development along with consistently stable laboratory findings up to 18 months of age. CONCLUSION: Our case highlights the significance of early genetic testing in neonates with unexplained metabolic disorders to enable timely diagnosis and therapy initiation. Biotin therapy has demonstrated remarkable efficacy in improving the clinical condition of patients with HLCS deficiency, leading to favorable outcomes.

Asunto(s)

Biotina , Deficiencia de Holocarboxilasa Sintetasa , Humanos , Femenino , Recién Nacido , Biotina/uso terapéutico , Biotina/administración & dosificación , Deficiencia de Holocarboxilasa Sintetasa/genética , Deficiencia de Holocarboxilasa Sintetasa/tratamiento farmacológico , Acidosis Láctica/genética , Acidosis Láctica/tratamiento farmacológico , Complejo Vitamínico B/uso terapéutico , Complejo Vitamínico B/administración & dosificación

Asunto(s)

Acidosis Láctica , Síndrome Coronario Agudo , Diabetes Mellitus Tipo 2 , Insuficiencia Cardíaca , Hipoglucemiantes , Insulina , Metformina , Humanos , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/mortalidad , Insuficiencia Cardíaca/mortalidad , Insuficiencia Cardíaca/inducido químicamente , Insuficiencia Cardíaca/tratamiento farmacológico , Metformina/efectos adversos , Síndrome Coronario Agudo/mortalidad , Acidosis Láctica/inducido químicamente , Acidosis Láctica/mortalidad , Acidosis Láctica/sangre , Femenino , Masculino , Hipoglucemiantes/efectos adversos , Hipoglucemiantes/uso terapéutico , Insulina/efectos adversos , Anciano , Hospitalización , Persona de Mediana Edad

RESUMEN

A LOx-based electrochemical biosensor for high-level lactate determination was developed. For the construction of the biosensor, chitosan and Nafion layers were integrated by using a spin coating procedure, leading to less porous surfaces in comparison with those recorded after a drop casting procedure. The analytical performance of the resulting biosensor for lactate determination was evaluated in batch and flow regime, displaying satisfactory results in both modes ranging from 0.5 to 20 mM concentration range for assessing the lactic acidosis. Finally, the lactate levels in raw serum samples were estimated using the biosensor developed and verified with a blood gas analyzer. Based on these results, the biosensor developed is promising for its use in healthcare environment, after its proper miniaturization. A pH probe based on common polyaniline-based electrochemical sensor was also developed to assist the biosensor for the lactic acidosis monitoring, leading to excellent results in stock solutions ranging from 6.0 to 8.0 mM and raw plasma samples. The results were confirmed by using two different approaches, blood gas analyzer and pH-meter. Consequently, the lactic acidosis monitoring could be achieved in continuous flow regime using both (bio)sensors.

Asunto(s)

Técnicas Biosensibles , Técnicas Electroquímicas , Ácido Láctico , Técnicas Biosensibles/métodos , Técnicas Biosensibles/instrumentación , Concentración de Iones de Hidrógeno , Ácido Láctico/sangre , Técnicas Electroquímicas/métodos , Técnicas Electroquímicas/instrumentación , Humanos , Acidosis Láctica/sangre , Acidosis Láctica/diagnóstico , Quitosano/química , Polímeros de Fluorocarbono/química , Compuestos de Anilina/química , Enzimas Inmovilizadas/química , Oxigenasas de Función Mixta

RESUMEN

ß-Adrenergic agonist medications such as albuterol are the mainstay for treatment of patients with acute asthma exacerbations. Patients who present to the emergency department with severe symptoms are often treated with multiple albuterol doses in sequence to maximize the impact of the medications, relax bronchoconstriction, and relieve their breathlessness. Patients who present with acute dyspnea have numerous potential causes of hyperlactatemia and acidosis including an uncommonly recognized outcome of albuterol administration. This clinical case report outlines a scenario where a patient who was treated for an acute asthma exacerbation had rising lactate levels despite improving clinically. Causes of elevated lactate levels are discussed, particularly related to ß-adrenergic agonist use, and considerations for monitoring and withdrawal of albuterol administration are outlined.

Asunto(s)

Acidosis Láctica , Agonistas Adrenérgicos beta , Albuterol , Humanos , Acidosis Láctica/inducido químicamente , Agonistas Adrenérgicos beta/efectos adversos , Albuterol/efectos adversos , Albuterol/uso terapéutico , Albuterol/administración & dosificación , Asma/tratamiento farmacológico , Masculino , Femenino , Persona de Mediana Edad , Adulto

RESUMEN

PURPOSE: The standard of care for burned patients experiencing hyperglycemia associated with the hypermetabolic response is insulin therapy. Insulin treatment predisposes burn patients to hypoglycemia, which increases morbidity and mortality. Metformin has been suggested as an alternative to insulin therapy for glycemic control in burn patients given its safety profile, but further research is warranted. This study investigated whether metformin use in burn patients is associated with improved glycemic control and morbidity/mortality outcomes compared to insulin use alone. MATERIALS AND METHODS: Using the TriNetX database, we conducted a retrospective study of burned patients who were administered insulin, metformin, or both within one week of injury. Demographic, comorbidity, and burn severity information were collected. Patients were categorized by treatment type, propensity score-matched, and compared for the following outcomes within 3 months: hyperglycemia, hypoglycemia, sepsis, lactic acidosis, and death. Statistical significance was set a priori at p ≤ 0.05. RESULTS: The insulin cohort was at increased risk for all outcomes (all p < 0.0001) compared to the metformin cohort, and an increased risk for sepsis, lactic acidosis, and death (all p ≤ 0.0002) compared to the insulin/metformin combination cohort. When compared to the metformin cohort, the combination cohort was at increased risk for all outcomes (all p ≤ 0.0107) except death. CONCLUSIONS: Treatment with metformin after burn is associated with a reduced risk of morbidity and mortality compared to insulin. The combination of insulin and metformin is no more effective in reducing the risk of hyperglycemia and hypoglycemia than insulin alone but is less effective than metformin alone.

Asunto(s)

Quemaduras , Hiperglucemia , Hipoglucemiantes , Insulina , Metformina , Sepsis , Humanos , Metformina/uso terapéutico , Quemaduras/mortalidad , Quemaduras/tratamiento farmacológico , Quemaduras/complicaciones , Masculino , Femenino , Hipoglucemiantes/uso terapéutico , Insulina/uso terapéutico , Estudios Retrospectivos , Persona de Mediana Edad , Adulto , Hiperglucemia/tratamiento farmacológico , Sepsis/tratamiento farmacológico , Sepsis/mortalidad , Anciano , Hipoglucemia/inducido químicamente , Hipoglucemia/epidemiología , Acidosis Láctica/inducido químicamente , Acidosis Láctica/epidemiología , Puntaje de Propensión , Quimioterapia Combinada , Control Glucémico/métodos

RESUMEN

Metformin is the first-line medication for type 2 diabetes. It is effective and safe, provided some caution is taken in specific populations. In patients with chronic kidney disease, metformin may provide long-term benefits, and it is a first-line therapy for diabetes, but the estimated glomerular filtration rate (eGFR) must be assessed regularly, to minimize the risk for metformin accumulation. When eGFR is 30-60 mL/min/1.73m2, the dose should be reconsidered, and sick-days education provided. Metformin should be discontinued when eGFR falls below 30 mL/min/1.73m2. Metformin accumulation may increase the risk for lactic acidosis if concomitant risk factors for hyperlactataemia (liver or respiratory insufficiency, sepsis, acute heart failure) are present; in these conditions, metformin is contraindicated, even although the available evidence is reassuring. Patients on metformin often complain of gastrointestinal side effects (mainly diarrhoea and nausea) during therapy initiation, but they may sometimes occur after years of stable therapy. These usually resolve if the dose is carefully titrated, or by switching to the extended-release formulation. Patients with obesity may benefit from the significant, although modest, metformin-associated weight loss and appetite reduction. During pregnancy, metformin is associated with a reduction of pregnancy complications, especially in obese women, but some concern remains, because metformin crosses the placenta, and it is associated with a significantly lower mean birth weight than insulin. In the elderly, gastrointestinal tolerability and renal function must be reassessed more often. Vitamin B-12 should be screened regularly in long-time metformin users because metformin may induce clinical vitamin B-12 deficiency.

Asunto(s)

Diabetes Mellitus Tipo 2 , Hipoglucemiantes , Metformina , Metformina/uso terapéutico , Metformina/efectos adversos , Humanos , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/complicaciones , Hipoglucemiantes/uso terapéutico , Hipoglucemiantes/efectos adversos , Femenino , Embarazo , Tasa de Filtración Glomerular/efectos de los fármacos , Obesidad/complicaciones , Resultado del Tratamiento , Insuficiencia Renal Crónica/complicaciones , Masculino , Acidosis Láctica/inducido químicamente

RESUMEN

OBJECTIVE: The objective of this study was to investigate the correlation between metformin exposure and the incidence of lactic acidosis in critically ill patients. METHODS: The patients with type 2 diabetes mellitus (T2DM) were included from Medical Information Mart for Intensive Care IV database (MIMIC-IV). The primary outcome was the incidence of lactic acidosis. The secondary outcomes were lactate level and in-hospital mortality. Propensity score matching (PSM) method was adopted to reduce bias of the confounders. The multivariate logistic regression was used to explore the correlation between metformin exposure and the incidence of lactic acidosis. Subgroup analysis and sensitivity analysis were used to test the stability of the conclusion. RESULTS: We included 4939 patients. There were 2070 patients in the metformin group, and 2869 patients in the nonmetformin group. The frequency of lactic acidosis was 5.7% (118/2070) in the metformin group and it was 4.3% (122/2869) in the nonmetformin group. There was a statistically significant difference between the two groups (P < 0.05). The lactate level in the metformin group was higher than in the nonmetformin group (2.78 ± 2.23 vs. 2.45 ± 2.24, P < 0.001). After PSM, the frequency of lactic acidosis (6.3% vs. 3.7%, P < 0.001) and lactate level (2.85 ± 2.38 vs. 2.40 ± 2.14, P < 0.001) were significantly higher in the metformin group compared with the nonmetformin group. In multivariate logistic models, the frequency of lactic acidosis was obviously increased in metformin group, and the adjusted odds ratio (OR) of metformin exposure was 1.852 (95% confidence interval (CI) = 1.298-2.643, P < 0.001). The results were consistent with subgroup analysis except for respiratory failure subgroup. Metformin exposure increased lactate level but did not affect the frequency of lactic acidosis in patients of respiratory failure with hypercapnia. However, the in-hospital mortality between metformin and nonmetformin group had no obvious difference (P = 0.215). In sensitivity analysis, metformin exposure showed similar effect as the original cohort. CONCLUSIONS: In critically ill patients with T2DM, metformin exposure elevated the incidence of lactic acidosis except for patients of respiratory failure with hypercapnia, but did not affect the in-hospital mortality.

Asunto(s)

Acidosis Láctica , Enfermedad Crítica , Diabetes Mellitus Tipo 2 , Metformina , Humanos , Metformina/efectos adversos , Metformina/uso terapéutico , Acidosis Láctica/inducido químicamente , Acidosis Láctica/epidemiología , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/epidemiología , Enfermedad Crítica/epidemiología , Masculino , Femenino , Estudios Retrospectivos , Incidencia , Persona de Mediana Edad , Anciano , Hipoglucemiantes/efectos adversos , Hipoglucemiantes/uso terapéutico , Mortalidad Hospitalaria , Ácido Láctico/sangre , Ácido Láctico/metabolismo

RESUMEN

Pyruvate dehydrogenase complex (PDHC) deficiency is a common genetic disorder leading to lactic acidosis, which can also result from several nongenetic conditions, such as septic shock. The present study reports a case of PDHC deficiency masked by septic shock-induced lactic acidosis. This case involved a 16-year-old adolescent with poor exercise tolerance compared with his peers, and no underlying diseases. The disease onset was characterized by cough, fever, and dyspnea, with hypotension and elevated lactate levels, which indicated septic shock. However, severe hypoglycemia and lactic acidosis persisted despite resolution of a pulmonary infection and correction of septic shock, requiring continuous intravenous infusion of 50% glucose. Although the patient did not experience acute kidney injury and had normal urine output, continuous renal replacement therapy was used to regulate the internal environment owing to the severity of the acidosis. The diagnosis of PDHC deficiency was considered on the basis of the persistent hypoglycemia and hyperlactatemia, before genetic mutation testing was completed. The clinical thinking process required a rich accumulation of pathophysiological knowledge. This article reports a case of PDHC deficiency masked by septic shock-induced lactic acidosis to raise awareness of the disease and avoid misdiagnosis and missed diagnosis.

Asunto(s)

Acidosis Láctica , Enfermedad por Deficiencia del Complejo Piruvato Deshidrogenasa , Choque Séptico , Humanos , Choque Séptico/diagnóstico , Choque Séptico/etiología , Masculino , Acidosis Láctica/diagnóstico , Acidosis Láctica/etiología , Adolescente , Enfermedad por Deficiencia del Complejo Piruvato Deshidrogenasa/diagnóstico , Hipoglucemia/diagnóstico , Hipoglucemia/etiología , Diagnóstico Diferencial

RESUMEN

Pathogenic ACAD9 variants cause complex I deficiency. Patients presenting in infancy unresponsive to riboflavin have high mortality. A six-month-old infant presented with riboflavin unresponsive lactic acidosis and life-threatening cardiomyopathy. Treatment with high dose bezafibrate and nicotinamide riboside resulted in marked clinical improvement including reduced lactate and NT-pro-brain type natriuretic peptide levels, with stabilized echocardiographic measures. After a long stable period, the child succumbed from cardiac failure with infection at 10.5 months. Therapy was well tolerated. Peak bezafibrate levels exceeded its EC50. The clinical improvement with this treatment illustrates its potential, but weak PPAR agonist activity of bezafibrate limited its efficacy.

Asunto(s)

Acidosis Láctica , Bezafibrato , Cardiomiopatías , Niacinamida , Compuestos de Piridinio , Humanos , Niacinamida/análogos & derivados , Niacinamida/uso terapéutico , Cardiomiopatías/tratamiento farmacológico , Bezafibrato/uso terapéutico , Acidosis Láctica/tratamiento farmacológico , Lactante , Compuestos de Piridinio/uso terapéutico , Masculino , Resultado del Tratamiento , Acil-CoA Deshidrogenasa/deficiencia , Resultado Fatal

RESUMEN

Metformin is a hypoglycemic agent used as the first line for the treatment of non-insulin dependent Diabetes Mellitus. While it is a generally safe drug, it has an infrequent adverse reaction called lactic acidosis. We report a 49 year-old patient with non-insulin-requiring type 2diabetes who developed an acute kidney failure injury along with severe metabolic acidosis secondary to pneumonia during treatment.

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La metformina es un agente hipoglucemiante que se ocupa de primera línea para el tratamiento de la Diabetes Mellitus no insulino dependiente. Si bien es un medicamento bien tolerado, tiene una reacción adversa bastante infrecuente que es la acidosis láctica. Reportamos el caso de una paciente de 49 años insulino no dependiente que desarrolló una injuria renal aguda junto con acidosis metabólica severa secundaria a una neumonía en tratamiento.

Asunto(s)

Humanos , Masculino , Persona de Mediana Edad , Acidosis Láctica/inducido químicamente , Acidosis Láctica/terapia , Lesión Renal Aguda/inducido químicamente , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Hipoglucemiantes/efectos adversos , Metformina/efectos adversos

RESUMEN

The mitochondrial phosphate carrier is critical for adenosine triphosphate synthesis by serving as the primary means for mitochondrial phosphate import across the inner membrane. Variants in the SLC25A3 gene coding mitochondrial phosphate carrier lead to failure in inorganic phosphate transport across mitochondria. The critical dependence on mitochondria as an energy source is especially evident in tissues with high-energy demands such as the heart, muscle; defects in the mitochondrial energy production machinery underlie a wide range of primary mitochondrial disorders that present with cardiac and muscle diseases. The characteristic clinical picture of a prominent early-onset hypertrophic cardiomyopathy and lactic acidosis may be an indication for analysis of the SLC25A3 gene. Here, described a patient with suspicion of infantile Pompe disease due to involvement of heart and muscle and high-level of plasma creatinine kinase but finally diagnosed mitochondrial phosphate-carrier deficiency.

Asunto(s)

Enfermedad del Almacenamiento de Glucógeno Tipo II , Mitocondrias , Proteínas de Transporte de Fosfato , Humanos , Enfermedad del Almacenamiento de Glucógeno Tipo II/genética , Enfermedad del Almacenamiento de Glucógeno Tipo II/diagnóstico , Enfermedad del Almacenamiento de Glucógeno Tipo II/patología , Proteínas de Transporte de Fosfato/genética , Mitocondrias/genética , Mitocondrias/metabolismo , Mitocondrias/patología , Lactante , Enfermedades Mitocondriales/genética , Enfermedades Mitocondriales/diagnóstico , Enfermedades Mitocondriales/patología , Mutación/genética , Diagnóstico Diferencial , Masculino , Femenino , Fosfatos/sangre , Fosfatos/metabolismo , Acidosis Láctica/genética , Acidosis Láctica/diagnóstico

RESUMEN

OBJECTIVES: The mitochondrial elongation factor Tu (EF-Tu), encoded by the TUFM gene, is a GTPase, which is part of the mitochondrial protein translation mechanism. If it is activated, it delivers the aminoacyl-tRNAs to the mitochondrial ribosome. Here, a patient was described with a homozygous missense variant in the TUFM [c.1016G>A (p.Arg339Gln)] gene. To date, only six patients have been reported with bi-allelic pathogenic variants in TUFM, leading to combined oxidative phosphorylation deficiency 4 (COXPD4) characterized by severe early-onset lactic acidosis, encephalopathy, and cardiomyopathy. CASE PRESENTATION: The patient presented here had the phenotypic features of TUFM-related disease, lactic acidosis, hypotonia, liver dysfunction, optic atrophy, and mild encephalopathy. CONCLUSIONS: We aimed to expand the clinical spectrum of pathogenic variants of TUFM.

Asunto(s)

Factor Tu de Elongación Peptídica , Humanos , Acidosis Láctica/genética , Mitocondrias/genética , Mitocondrias/patología , Enfermedades Mitocondriales/genética , Enfermedades Mitocondriales/patología , Proteínas Mitocondriales , Mutación , Mutación Missense , Factor Tu de Elongación Peptídica/genética , Pronóstico

RESUMEN

BACKGROUND: Patients with status asthmaticus (SA) frequently present with lactic acidosis (LA). Our goal is to identify the nature of this LA using the Stewart physicochemical model and to identify the independent factors associated with LA in children with SA. METHODS: Analytical study of a retrospective cohort using a nested case-control design. Twenty-eight episodes of SA in 24 children were included. Patients admitted to a paediatric intensive care unit (PICU) for SA over a 9-year period were recruited consecutively. Data were analysed using the Stewart model and the Strong Ion Calculator. Data were analysed using descriptive statistics and regression models were fitted within the general linear model. RESULTS: Hyperlacticaemia (Lact[mM/L] = 3.905 [95% CI = 3.018-4.792]) and acidosis (pH = 7.294 [95% CI = 7.241-7.339]) were observed in 18 episodes (15 patients; 62.5%). According to the Stewart model, acidosis was caused by a decrease in strong ion difference. Initially, pCO2 was high (pCO2[mmHg] = 45.806 [95% CI = 37.314-54.298]) but the net unmeasured ion (NUI) component was normal (NUI = -4,461 [95% CI = -3.51 to -5.412]), and neither changed significantly over the clinical course. There was no need to determine pyruvate, as the NUI was normal and the LA was type B (non-hypoxic, lactate/pyruvate < 25). We observed a correlation (P = .023) between LA and intramuscular epinephrine administered on arrival at hospital, but not between LA and the cumulative dose of nebulized salbutamol. CONCLUSIONS: Most patients with SA presented LA. The Stewart model confirmed that LA is not hypoxic, probably due to sympathomimetic-related glycolysis.

Asunto(s)

Acidosis Láctica , Hiperlactatemia , Estado Asmático , Humanos , Estudios Retrospectivos , Hiperlactatemia/etiología , Masculino , Femenino , Estudios de Casos y Controles , Niño , Estado Asmático/complicaciones , Acidosis Láctica/etiología , Acidosis Láctica/sangre , Preescolar , Lactante , Epinefrina/administración & dosificación , Unidades de Cuidado Intensivo Pediátrico/estadística & datos numéricos , Ácido Láctico/sangre , Albuterol/administración & dosificación , Albuterol/uso terapéutico

RESUMEN

MELAS syndrome, characterized by mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes, represents a devastating mitochondrial disease, with the stroke-like episodes being its primary manifestation. Arginine supplementation has been used and recommended as a treatment for these acute attacks; however, insufficient evidence exists to support this treatment for MELAS. The mechanisms underlying the effect of arginine on MELAS pathophysiology remain unclear, although it is hypothesized that arginine could increase nitric oxide availability and, consequently, enhance blood supply to the brain. A more comprehensive understanding of these mechanisms is necessary to improve treatment strategies, such as dose and regimen adjustments; identify which patients could benefit the most; and establish potential markers for follow-up. This review aims to analyze the existing evidence concerning the mechanisms through which arginine supplementation impacts MELAS pathophysiology and provide the current scenario and perspectives for future investigations.

Asunto(s)

Acidosis Láctica , Síndrome MELAS , Accidente Cerebrovascular , Humanos , Síndrome MELAS/tratamiento farmacológico , Arginina/uso terapéutico , Suplementos Dietéticos

Asunto(s)

Acidosis Láctica , Cardiomiopatía Hipertrófica , Homocigoto , Humanos , Cardiomiopatía Hipertrófica/genética , Acidosis Láctica/genética , Lactante , Mutación , Masculino , Anemia/genética , Femenino , Pueblo Asiatico/genética , China , Pueblos del Este de Asia

RESUMEN

Introduction: The link between gut microbiota and host immunity motivated numerous studies of the gut microbiome in tuberculosis (TB) patients. However, these studies did not explore the metabolic capacity of the gut community, which is a key axis of impact on the host's immunity. Methods: We used deep sequencing of fecal samples from 23 treatment-naive TB patients and 48 healthy donors to reconstruct the gut microbiome's metabolic capacity and strain/species-level content. Results: We show that the systematic depletion of the commensal flora of the large intestine, Bacteroidetes, and an increase in Actinobacteria, Firmicutes, and Proteobacteria such as Streptococcaceae, Erysipelotrichaceae, Lachnospiraceae, and Enterobacteriaceae explains the strong taxonomic divergence of the gut community in TB patients. The cumulative expansion of diverse disease-associated pathobionts in patients reached 1/4 of the total gut microbiota, suggesting a heavy toll on host immunity along with MTB infection. Reconstruction of metabolic pathways showed that the microbial community in patients shifted toward rapid growth using glycolysis and excess fermentation to produce acetate and lactate. Higher glucose availability in the intestine likely drives fermentation to lactate and growth, causing acidosis and endotoxemia. Discussion: Excessive fermentation and lactic acidosis likely characterize TB patients' disturbed gut microbiomes. Since lactic acidosis strongly suppresses the normal gut flora, directly interferes with macrophage function, and is linked to mortality in TB patients, our findings highlight gut lactate acidosis as a novel research focus. If confirmed, gut acidosis may be a novel potential host-directed treatment target to augment traditional TB treatment.

Asunto(s)

Acidosis Láctica , Microbioma Gastrointestinal , Humanos , Fermentación , Ácido Láctico , Glucólisis , Firmicutes

RESUMEN

Metformin (N,N-dimethylbiguanide), an inhibitor of gluconeogenesis and insulin sensitizer, is widely used for the treatment of type 2 diabetes. In some patients with renal insufficiency, metformin can accumulate and cause lactic acidosis, known as metformin-associated lactic acidosis (MALA, defined as lactate ≥ 5 mM, pH < 7.35, and metformin concentration > 38.7 µM). Here, we report on the post-translational modification (PTM) of proline (Pro) to 4-hydroxyproline (OH-Pro) in metformin-associated lactic acidosis and in metformin-treated patients with Becker muscular dystrophy (BMD). Pro and OH-Pro were measured simultaneously by gas chromatography-mass spectrometry before, during, and after renal replacement therapy in a patient admitted to the intensive care unit (ICU) because of MALA. At admission to the ICU, plasma metformin concentration was 175 µM, with a corresponding lactate concentration of 20 mM and a blood pH of 7.1. Throughout ICU admission, the Pro concentration was lower compared to healthy controls. Renal excretion of OH-Pro was initially high and decreased over time. Moreover, during the first 12 h of ICU admission, OH-Pro seems to be renally secreted while thereafter, it was reabsorbed. Our results suggest that MALA is associated with hyper-hydroxyprolinuria due to elevated PTM of Pro to OH-Pro by prolyl-hydroxylase and/or inhibition of OH-Pro metabolism in the kidneys. In BMD patients, metformin, at the therapeutic dose of 3 × 500 mg per day for 6 weeks, increased the urinary excretion of OH-Pro suggesting elevation of Pro hydroxylation to OH-Pro. Our study suggests that metformin induces specifically the expression/activity of prolyl-hydroxylase in metformin intoxication and BMD.

Asunto(s)

Acidosis Láctica , Diabetes Mellitus Tipo 2 , Metformina , Distrofia Muscular de Duchenne , Humanos , Metformina/efectos adversos , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Acidosis Láctica/inducido químicamente , Acidosis Láctica/terapia , Hidroxiprolina , Cromatografía de Gases y Espectrometría de Masas , Prolina , Hidroxilación , Distrofia Muscular de Duchenne/tratamiento farmacológico , Ácido Láctico , Oxigenasas de Función Mixta/uso terapéutico , Hipoglucemiantes/efectos adversos

RESUMEN

Linezolid is a commonly prescribed antibiotic in clinical practice. Although thrombocytopenia and peripheral neuropathy are frequently encountered following prolonged administration of linezolid, lactic acidosis is a rare adverse drug reaction. We present the case of a patient on linezolid for disseminated multidrug-resistant tuberculosis who presented with vomiting, dyspnoea, hypotension and high anion gap metabolic acidosis. The initial presentation mimicked sepsis syndrome. Ketoacidosis and renal dysfunction were ruled out. There was no history of ingestion of toxins/toxic alcohols. Sepsis was unlikely because extensive radiological and microbiological testing could not identify an infection. Given the possibility of linezolid-induced lactic acidosis (LILA), linezolid was discontinued on admission. The patient's lactic acidosis resolved, and his overall condition improved. A retrospective diagnosis of LILA was thus established. LILA should be considered when patients on linezolid present with lactic acidosis and other causes for the lactic acidosis have been ruled out.

Asunto(s)

Acidosis Láctica , Acidosis , Humanos , Linezolid/efectos adversos , Acidosis Láctica/diagnóstico , Estudios Retrospectivos , Antibacterianos/efectos adversos , Acidosis/inducido químicamente