RESUMEN
3-methylcrotonyl-CoA carboxylase (3-MCC) deficiency is an autosomal recessive disorder of leucine metabolism. Since 3-MCC deficiency is thought to be a benign condition, a few newborn screening programs discontinued to screen this condition. We report a case of a 24-year-old previously healthy male patient who developed generalized rhabdomyolysis, weakness, respiratory and renal failure, acute pancreatitis, hyperammonemia, and altered consciousness after strenuous exercise. Diagnosis of 3-MCC was made based on increased plasma C5OH carnitine, urine 3-methylcrotonylglycine, and 3-hydroxyisovalerate, and later whole genome sequencing study confirmed the diagnosis. Low plasma carnitine and high creatine kinase (CK) levels were again noted after two months of poor compliance with carnitine therapy. Since 3-MCC deficiency is often incidentally diagnosed in asymptomatic mothers through positive newborn screening in the newborns and most positive newborn screening cases have benign clinical outcomes, 3-MCC deficiency has been considered a benign condition. Observation of a life-threatening episode triggered by strenuous exercise and recurrent occurrence of low carnitine and high CK without carnitine supplementation may support 3-MCC deficiency to be the condition covered by the newborn screen since carnitine supplementation likely prevents an episode that can be life-threatening. Asymptomatic adults with 3-MCC deficiency may benefit from periodic evaluation of plasma carnitine levels.
RESUMEN
BACKGROUND: Drug-induced hypocarnitinemia has been noted as a cause of hypoglycemia in children. However, adult cases are extremely rare and pre-existing conditions (including endocrine disorders and frailty) have been suggested to be involved. Hypoglycemia due to drug-induced hypocarnitinemia is quite rare, and there were few reports of pivoxil-containing cephalosporin (PCC)-induced hypocarnitinemia in adults. CASE PRESENTATION: We present a case of an 87-year-old man with malnutrition, and frailty. He developed severe hypoglycemia with unconsciousness after taking cefcapene pivoxil hydrochloride, one of PCC, and hypocarnitinemia was diagnosed. Despite levocarnitine administration, asymptomatic mild hypoglycemia had persisted. Subsequent investigation revealed subclinical ACTH deficiency due to empty sella, which played a key role to maintain mild hypoglycemia as underlying disorder, and PCC-induced hypocarnitinemia triggered severe hypoglycemia. The patient responded to hydrocortisone therapy. CONCLUSIONS: We need to be aware of the facts that PCC can induce severe hypocarnitinemic hypoglycemia in elderly adults associated with frailty, malnutrition, and subclinical ACTH syndrome.
Asunto(s)
Fragilidad , Hipoglucemia , Desnutrición , Adulto , Niño , Anciano , Masculino , Humanos , Anciano de 80 o más Años , Cefalosporinas , Monobactamas , Hormona AdrenocorticotrópicaRESUMEN
Carnitine is a water-soluble amino acid derivative required for ß-oxidation of long-chain fatty acids. In carnitine cycle abnormalities and low carnitine states, fatty acid ß-oxidation is inhibited during fasting, resulting in hypoglycemia. Pivalic acid is a substance used in prodrugs to increase absorption of parent drugs, and antibiotics containing pivalic acid are frequently used as wide spectrum antibiotics for pediatric patients in Japan. Pivalic acid released after absorption is conjugated with free carnitine to form pivaloylcarnitine, which is then excreted in urine. As a consequence, long-term administration of pivalic acid containing antibiotics has been associated with depletion of free carnitine, inhibition of energy production and subsequent hypoglycemia. Here we report a case of a 23-month-old boy treated with an antibiotic containing pivalic acid for 3 days for upper respiratory tract infection. Laboratory data at referral indicated hypoglycemia, decreased free carnitine and elevated five-carbon acylcarnitine. Isomer separation confirmed the major component of increased five-carbon acylcarnitine to be pivaloylcarnitine, thereby excluding the possibility of a genetic metabolic disorder detected with similar acylcarnitine profile. The level of carnitine was normal when the antibiotic was not administered. Our case shows that the use of antibiotics containing pivalic acid in young children requires consideration of hypocarnitinemia, even with short-term administration.
Asunto(s)
Antibacterianos/efectos adversos , Carnitina/sangre , Carnitina/orina , Enfermedades Metabólicas/inducido químicamente , Enfermedades Metabólicas/diagnóstico , Ácidos Pentanoicos/efectos adversos , Carbono/química , Carnitina/análogos & derivados , Humanos , Hipoglucemia/diagnóstico , Lactante , Masculino , Oxígeno/química , Espectrometría de Masas en TándemRESUMEN
OBJECTIVE: To explore the risk factors for the development of sodium valproate (VPA)-induced renal tubular dysfunction for early diagnosis and treatment. STUDY DESIGN: The subjects were selected from patients who were diagnosed with epilepsy and administered VPA. Blood and spot urine samples were collected and measured the concentration of VPA, the level of serum phosphorus, serum uric acid, serum free carnitine, serum cystatin-c, and urine ß2-microglobulin (BMG). Patients with urine BMG/creatinine levels above 219.2 were treated as renal proximal tubular dysfunction (RTD), with all others treated as non-RTD. RESULTS: Eighty-seven patients, 4-48 years, 53 men and 34 women, were studied. RTD group is 17 patients and non-RTD group is 70 patients. Univariate analyses revealed that the RTD patients were more likely to be bedridden, receiving enteral tube feeding, taking more anticonvulsants, and demonstrating significantly lower serum levels of free carnitine, uric acid, and phosphorus. Among them, bedridden, free serum carnitine, and phosphorus levels were associated with the development of RTD by multivariate analysis. CONCLUSIONS: Bedridden patients receiving VPA are susceptible to hypocarnitinemia, which can cause RTD and may lead to FS. Therefore, urinary BMG should be measured regularly in all patients receiving VPA to assess renal tubular function. An additional measurement of serum free carnitine level should be considered in patients who developed RTD. Supplementation of carnitine for those patients to prevent such complication deserves for further study.
Asunto(s)
Anticonvulsivantes/efectos adversos , Epilepsia/tratamiento farmacológico , Enfermedades Renales/inducido químicamente , Túbulos Renales Proximales/efectos de los fármacos , Ácido Valproico/efectos adversos , Adolescente , Adulto , Anticonvulsivantes/sangre , Anticonvulsivantes/orina , Biomarcadores/sangre , Biomarcadores/orina , Carnitina/sangre , Distribución de Chi-Cuadrado , Niño , Preescolar , Creatinina/orina , Monitoreo de Drogas , Femenino , Humanos , Enfermedades Renales/diagnóstico , Enfermedades Renales/fisiopatología , Túbulos Renales Proximales/fisiopatología , Masculino , Persona de Mediana Edad , Análisis Multivariante , Factores de Riesgo , Resultado del Tratamiento , Ácido Valproico/sangre , Ácido Valproico/orina , Adulto Joven , Microglobulina beta-2/orinaRESUMEN
Administration of pivalate-containing antibiotics decreases serum carnitine and increases urinary pivaloylcarnitine, resulting in hypocarnitinemia. Carnitine and acylcarnitines are important biomarkers in the diagnosis of carnitine deficiency, but the relationship between acylcarnitines and drug-induced hypocarnitinemia remains unclear. Quantification of acylcarnitines enables discovery of new biomarkers for prediction and diagnosis of drug-induced hypocarnitinemia. Here we describe a liquid chromatography/tandem mass-spectrometric method for simultaneously quantifying carnitine, 15 acylcarnitines, and cefditoren (the pivoxilated product of an antibiotic prodrug) in human urine. The matrix effect is corrected in 87.8-103% using deuterium-labeled internal standards (2H9-carnitine, 2H3-hexanoylcarnitine, and 2H3-stearoylcarnitine). The surrogate matrix method had an error of <13% in comparison with a standard addition method. Dynamic ranges were 0.1-100µmol/l for acylcarnitines and 0.3-300µg/ml for cefditoren. Both accuracy and precision were <19.7% at the lower limit of quantification and <14.8% for other quality controls. In an example application of this method, urine samples from eight healthy volunteers (five adults and three children) were analyzed, and individual differences were clearly observed.
Asunto(s)
Carnitina/análogos & derivados , Cromatografía Liquida/métodos , Espectrometría de Masas en Tándem/métodos , Urinálisis/métodos , Adulto , Calibración , Carnitina/orina , Niño , Humanos , Reproducibilidad de los ResultadosRESUMEN
Infants often develop hypocarnitinemia and resultant hypoglycemia during long-term treatment with antibiotics that contain pivalic acid, but it is unknown whether maternal treatment with such agents during pregnancy induces hypocarnitinemia in fetuses or neonates. A woman at week 28 of pregnancy was prescribed cefcapene pivoxil for 84 consecutive days for treatment and prophylaxis of pyelonephritis. Using tandem mass spectrometry, both the mother and newborn were found to have hypocarnitinemia soon after delivery. It was concluded that the baby suffered from secondary hypocarnitinemia due to long-term prenatal treatment with antibiotics containing pivalic acid. Long-term treatment with antibiotics containing pivalic acid in pregnant women can induce hypocarnitinemia in both the mother and neonate; reported herein is the first case observed in humans.