Asunto(s)
Vitamina B 12 , Complejo Vitamínico B , Anciano , Ácido Fólico , Hematínicos , Humanos , Deficiencia de Vitamina B 12RESUMEN
BACKGROUND AND AIM: Treatment of neuropathic pain and chemotherapy-induced peripheral neuropathy (CIPN) in patients with malignancy is often unsuccessful. Functional vitamin B12 deficiency, defined by elevated levels of the B12-dependent metabolites, methylmalonic acid (MMA), and/or homocysteine, despite normal B12 values, may cause neuropathy and is associated with disorders linked to increased oxidative stress. Since both cancer and neurotoxic antineoplastic agents increase oxidative stress, a role for functional B12 deficiency in CIPN was considered. METHODS: A retrospective record review of 241 cancer subjects evaluated by the adult palliative care service for B12 deficiency in a university-based cancer center between October 2008 and September 2012 with measurement of B12, MMA, and/or homocysteine levels was performed. RESULTS: B12 values were elevated (>900 pg/ml) in 30 % and low (≤300 pg/ml) in 17 % of subjects tested. Elevated MMA (>250 nmol/l) and homocysteine (>12.1 µmol/l) levels occurred in 38 and 23 % of subjects respectively and at least one metabolite was increased in 54 % of evaluable subjects. Even when B12 values were ≥1500 pg/ml (n = 36), increased MMA and homocysteine values occurred in 31 and 23 % of subjects, respectively. B12 therapy decreased MMA values in all four subjects studied and improved neurologic findings in the three subjects tested. CONCLUSIONS: Functional vitamin B12 deficiency is common in subjects with advanced malignancy. Further studies are needed to determine if this disorder is a risk factor for CIPN and if B12 therapy has a role in the management and/or prevention of neuropathy and neuropathic pain in this population.
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Ácido Metilmalónico/uso terapéutico , Neoplasias/complicaciones , Neuralgia/inducido químicamente , Enfermedades del Sistema Nervioso Periférico/inducido químicamente , Deficiencia de Vitamina B 12/etiología , Vitamina B 12/uso terapéutico , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Neoplasias/tratamiento farmacológico , Neuralgia/tratamiento farmacológico , Enfermedades del Sistema Nervioso Periférico/tratamiento farmacológico , Estudios Retrospectivos , Factores de RiesgoRESUMEN
BACKGROUND: Cobalamin (B12) deficiency can lead to irreversible neurocognitive changes if unrecognized. Screening involves measurement of serum cobalamin levels, but the sensitive metabolic indicators of cobalamin deficiency, methylmalonic acid (MMA) and homocysteine (HCys), may be normal when cobalamin values are low and elevated when cobalamin values are normal. Because cobalamin is inactivated by oxidation, the relationship between these metabolites and comorbidities associated with increased oxidative stress (oxidant risks) in subjects with low and low-normal cobalamin levels was studied. METHODS: A retrospective record-review was conducted of community-dwelling adults evaluated for cobalamin deficiency during a 12-year period with serum cobalamin values in the low (≤ 200 pg/mL; n = 49) or low-normal (201-300 pg/mL; n = 187) range and concurrent measurement of MMA. RESULTS: When "No" oxidant risk was present, elevated MMA (>250 nmol/L) and HCys (>12.1 µmol/L) values occurred in 50% and 30% of subjects, respectively (P <.01). In contrast, when "Three or More" oxidant risks were present, mean MMA and HCys values were significantly higher, and elevated MMA and HCys values occurred in 84% and 78% of these subjects, respectively (P ≤.012). Pharmacologic doses of cyanocobalamin significantly decreased metabolite values in ≥ 94% of treated subjects. CONCLUSION: In subjects with low or low-normal cobalamin values, metabolic evidence of cobalamin deficiency is more frequent when 3 or more oxidant risks are present. Thus, defining a low serum cobalamin level to screen for cobalamin deficiency may be a "moving target" due to the variable presence and severity of often subtle, confounding clinical conditions in individual subjects.
Asunto(s)
Deficiencia de Vitamina B 12/diagnóstico , Vitamina B 12/sangre , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores/sangre , Comorbilidad , Femenino , Homocisteína/sangre , Humanos , Masculino , Ácido Metilmalónico/sangre , Persona de Mediana Edad , Estrés Oxidativo , Estudios Retrospectivos , Vitamina B 12/uso terapéutico , Deficiencia de Vitamina B 12/sangre , Deficiencia de Vitamina B 12/tratamiento farmacológico , Adulto JovenRESUMEN
OBJECTIVES: Neuropathies often accompany vitamin B12 deficiency. Since many neuropathies are linked to oxidative stress and since B12 has both antioxidant and neurotrophic properties, B12 may also be effective treatment in non-deficient subjects. Thus, the characteristics and predictors of B12-responsive neuropathies and their relationship to disorders associated with increased oxidative stress (oxidant risks) were examined. METHODS: Retrospective review of 78 subjects with neurological abnormalities treated with B12 and evaluated by the measurement of B12 and the B12-dependent metabolites, methylmalonic acid (MMA), and homocysteine. RESULTS: Sixty-five subjects had neurological improvement (83%), including 35 with other known causes of neuropathy. Only two responders had B12-responsive macrocytosis. Pretherapy B12, MMA, and homocysteine values were normal in 72, 33 and 54% of responders, with all three normal in 23%. Moreover, B12 therapy did not significantly decrease elevated MMA and homocysteine levels in 20 and 37%, respectively, of responders tested but did decrease both metabolites in 75% of evaluable non-responders. At least one oxidant risk was present in 41 of the 46 responders with normal B12 levels (89%). Oral therapy was effective, but parenteral B12 improved responses in four subjects. DISCUSSION: B12-responsive neuropathies are thus (1) common even when confounding disorders are present; (2) dissociated from the presence of hematological abnormalities; (3) dissociated from the presence of B12-responsive metabolical abnormalities; and (4) associated with the presence of oxidant risks when B12 levels are normal. Since no predictors of responses to B12 therapy were identified, empiric trials with parenteral B12 should be considered in appropriate subjects.
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Antioxidantes/uso terapéutico , Enfermedades del Sistema Nervioso/tratamiento farmacológico , Estrés Oxidativo/efectos de los fármacos , Deficiencia de Vitamina B 12/tratamiento farmacológico , Vitamina B 12/uso terapéutico , Administración Oral , Adulto , Anciano , Anciano de 80 o más Años , Antioxidantes/administración & dosificación , Antioxidantes/análisis , Antioxidantes/farmacocinética , Biotransformación , Femenino , Homocisteína/sangre , Humanos , Inyecciones Intramusculares , Masculino , Registros Médicos , Ácido Metilmalónico/sangre , Persona de Mediana Edad , Enfermedades del Sistema Nervioso/sangre , Enfermedades del Sistema Nervioso/etiología , Estado Nutricional , Estudios Retrospectivos , Factores de Riesgo , Vitamina B 12/administración & dosificación , Vitamina B 12/sangre , Vitamina B 12/farmacocinética , Deficiencia de Vitamina B 12/sangre , Deficiencia de Vitamina B 12/fisiopatologíaAsunto(s)
Anticuerpos Monoclonales/efectos adversos , Antineoplásicos/efectos adversos , Colchicina/efectos adversos , Supresores de la Gota/efectos adversos , Gota/tratamiento farmacológico , Trombocitopenia/inducido químicamente , Interacciones Farmacológicas , Humanos , Masculino , Melanoma/tratamiento farmacológico , Persona de Mediana Edad , NivolumabRESUMEN
OBJECTIVES: To determine whether high serum folate levels contribute to metabolite changes in elderly subjects with normal cobalamin levels. DESIGN: Case series. SETTING: Outpatient clinic at a university-based staff model health maintenance organization. PARTICIPANTS: Two hundred thirty-three ambulatory individuals without diabetes mellitus with normal renal function and normal cobalamin levels evaluated for cobalamin deficiency. MEASUREMENTS: Cobalamin, serum folate, methylmalonic acid (MMA), and homocysteine. RESULTS: Older individuals (≥60) with low-normal cobalamin levels (201-300 pg/mL) had higher MMA and lower homocysteine levels when serum folate levels were high (>20 ng/mL) than when serum folate levels were normal (P < .02), but serum folate levels within the normal range were not a determinant of either metabolite. In younger subjects with low-normal cobalamin levels, high serum folate levels were not associated with significant differences in either metabolite. At mid-normal cobalamin levels (301-600 pg/mL), high serum folate levels were associated with lower homocysteine levels in older adults (P < .001) but not with differences in MMA in either age group. Cobalamin therapy decreased or normalized MMA and homocysteine in 89% or more of participants even at pretherapy cobalamin levels greater than 600 pg/mL. CONCLUSION: High serum folate levels are associated with higher MMA levels when cobalamin levels are low-normal, and this effect is age dependent, not progressive within the normal serum folate range (suggesting a threshold effect), and reversed by cobalamin therapy. Because MMA may be neurotoxic, these findings suggest caution in the use of folic acid supplements in elderly adults.
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Ácido Fólico/sangre , Ácido Metilmalónico/sangre , Deficiencia de Vitamina B 12/sangre , Vitamina B 12/sangre , Anciano , Anciano de 80 o más Años , Causalidad , Trastornos del Conocimiento/epidemiología , Comorbilidad , Femenino , Evaluación Geriátrica , Homocisteína/sangre , Humanos , Masculino , Factores de Riesgo , Índice de Severidad de la Enfermedad , Deficiencia de Vitamina B 12/epidemiología , Deficiencia de Vitamina B 12/prevención & controlAsunto(s)
Anemia de Células Falciformes/complicaciones , Transfusión de Eritrocitos/efectos adversos , Sobrecarga de Hierro/tratamiento farmacológico , Anemia de Células Falciformes/terapia , Humanos , Quelantes del Hierro/uso terapéutico , Sobrecarga de Hierro/etiología , Cirrosis Hepática/etiologíaRESUMEN
OBJECTIVE: Functional cobalamin (Cbl) deficiency (i.e., high methylmalonic acid [MMA] values despite normal serum Cbl levels) is common in the elderly and associated with neuropathy and anemia. Because diabetes is also common in the elderly and diabetic neuropathy resembles that of Cbl deficiency, the role of diabetes in functional Cbl deficiency was explored. RESEARCH DESIGN AND METHODS: A retrospective review was performed of all ambulatory community-dwelling adults with normal renal function evaluated for Cbl deficiency over a 12-year period in a primary care setting. Functional Cbl deficiency was defined as MMA values >250 nmol/L with Cbl levels >400 pg/mL. RESULTS: In nondiabetic subjects, MMA values varied directly with age and inversely with serum Cbl. In diabetic subjects, MMA values also increased with age but did not fall as Cbl levels increased. Thus, when Cbl levels were >400 pg/mL, mean MMA values and the incidence of functional Cbl deficiency were both significantly greater in elderly diabetic subjects (at least 70 years old) than in elderly nondiabetic subjects. Moreover, neuropathy was present in 62% of diabetic subjects with high MMA values and in only 18% of diabetic subjects with normal MMA values. Finally, pharmacologic doses of Cbl improved MMA values and neuropathy in 88 and 86% of evaluable diabetic subjects, respectively. CONCLUSIONS: These observations suggest that functional Cbl deficiency is common in elderly diabetic individuals, is associated with neuropathy, and is responsive to Cbl therapy. A role for oxidative stress in the pathogenesis of functional Cbl deficiency is proposed.
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Diabetes Mellitus/sangre , Diabetes Mellitus/fisiopatología , Vitamina B 12/sangre , Anciano , Neuropatías Diabéticas/sangre , Neuropatías Diabéticas/fisiopatología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios RetrospectivosRESUMEN
Guidelines for pain management in adult sickle cell patients with vaso-occlusive crises suggest prompt, frequent administration of parenteral opioids. Neither the ability to implement these guidelines in a busy urban emergency department nor opioid dose requirements in uncomplicated vaso-occlusive crisis have been previously documented. Thus, a retrospective review of vaso-occlusive crisis treated in an urban medical center emergency department in 2005 was performed to define opioid requirements and barriers to guideline implementation. Fifty-seven visits by 19 patients were evaluable. Opioid treatment was not initiated for more than 2 hours during 30% of visits; the interval between the first and second opioid doses exceeded 1 hour in 26% of visits and increased with subsequent doses; and total treatment time was less than 1 hour during 21% of visits (median, 2.2 hours). Opioid doses (as intravenous morphine equivalents) ranged from 4 to 26.7 mg (0.05-0.50 mg/kg) and exceeded 10 mg during 40 visits (70%) and in 10 patients (53%). Hospitalization occurred on 25 occasions with 48% of patients admitted after 3 or fewer opioid doses and 50% of patients admitted after less than 3 hours of treatment. Moreover, return emergency department visits occurred within 3 days after 9 of 32 home discharges (28%) with treatment times uniformly less than 3 hours during the preceding visit. It is concluded that: (1) opioid dose requirements vary widely, often exceeding guideline recommendations; and (2) treatment time and timely opioid administration are often compromised, resulting in delayed pain control and premature decisions on disposition with early return visits and possibly avoidable hospital admissions.
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Analgésicos Opioides/uso terapéutico , Anemia de Células Falciformes/tratamiento farmacológico , Servicio de Urgencia en Hospital/organización & administración , Dolor/tratamiento farmacológico , Pautas de la Práctica en Medicina/estadística & datos numéricos , Adulto , Analgésicos Opioides/administración & dosificación , Anemia de Células Falciformes/complicaciones , Distribución de Chi-Cuadrado , Femenino , Humanos , Masculino , Persona de Mediana Edad , Dolor/etiología , Dimensión del Dolor , Admisión del Paciente/estadística & datos numéricos , Resultado del TratamientoRESUMEN
Pain due to vaso-occlusive crisis is the major cause of hospital use in sickle cell disease. Although available guidelines provide recommendations for opioid administration in this setting, only 4 (21%) of 19 medical textbooks present treatment regimens that are consistent with them. Moreover, only 7 texts (37%) note that addiction is infrequent in this population, while 11 (92%) of 12 texts provide such reassurance for cancer-related pain (P < .005). Finally, hydroxyurea use to decrease the frequency of vaso-occlusive crises is completely defined only in 2 textbooks. Thus, most medical texts provide neither adequate information for the treatment or prevention of pain due to vaso-occlusive crisis in sickle cell disease nor reassurance of the unlikelihood of addiction in this population. In contrast, treatment recommendations for less common hematologic disorders are consistent with current standards in 53% to 84% of appropriate texts (P < .05). Limited knowledge regarding the principles and appropriateness of opioid therapy; a lack of evidence-based research on pain control; and misconceptions and prejudices about drug abuse and addiction contribute to this educational void. Thus, research and training on pain control in sickle cell disease are needed to parallel studies of environmental and genetic factors contributing to the known clinical heterogeneity of this disorder.
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Anemia de Células Falciformes/complicaciones , Dolor/tratamiento farmacológico , Dolor/prevención & control , Guías de Práctica Clínica como Asunto , Enfermedad Aguda , Analgésicos Opioides/efectos adversos , Analgésicos Opioides/uso terapéutico , Anemia de Células Falciformes/tratamiento farmacológico , Competencia Clínica , Humanos , Hidroxiurea/sangre , Trastornos Relacionados con Opioides/complicaciones , Dolor/etiología , Médicos , Guías de Práctica Clínica como Asunto/normasRESUMEN
Although cobalamin (vitamin B12) was isolated almost 60 years ago, its biochemical, physiologic and neurologic effects remain incompletely defined. New observations suggest renal regulation of cobalamin metabolism; actions of cobalamin on nucleic acid and protein function; and a role for cobalamin in cytokine and growth factor regulation. Clinically, no gold standard has emerged for the diagnosis of cobalamin deficiency. Moreover, cobalamin resistance may occur in diabetes, renal insufficiency and advanced age, leading to functional cobalamin deficiency despite adequate cobalamin nutriture. Finally, high-dose cobalamin therapy may have salutary pharmacologic effects on neurologic function in a variety of disorders. Many studies lacked appropriate control groups. However, at this time, therapeutic trials with pharmacologic doses of cobalamin are suggested when findings consistent with cobalamin deficiency are present regardless of the results of diagnostic tests. While oral cobalamin immediate-release is adequate for many patients, its effectiveness in reversing neurologic abnormalities has yet to be established.
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Deficiencia de Vitamina B 12 , Vitamina B 12/uso terapéutico , Humanos , Enfermedades del Sistema Nervioso/tratamiento farmacológico , Vitamina B 12/metabolismo , Vitamina B 12/fisiología , Deficiencia de Vitamina B 12/diagnóstico , Deficiencia de Vitamina B 12/tratamiento farmacológico , Deficiencia de Vitamina B 12/etiología , Deficiencia de Vitamina B 12/fisiopatologíaRESUMEN
Early recognition of cobalamin (Cbl)-responsive disorders in the ambulatory care setting is essential to prevent irreversible neurologic deficits. However, diagnostic algorithms using Cbl, methylmalonic acid (MMA), and homocysteine (HCys) measurements reflect studies in academic centers, and their negative predictive values have not been established. Thus, records of 456 ambulatory patients evaluated for Cbl deficiency at a staff model HMO were reviewed. Pretherapy Cbl, MMA, and HCys values in individual patients varied by 23%, 23%, and 17%, respectively, over 2 to 6 weeks. Hematologic or neurologic responses to pharmacologic doses of Cbl occurred in 37 of the 95 evaluable patients. In these patients, pretherapy Cbl, MMA, and HCys values were normal in 54%, 23%, and 50%, respectively. If therapy had been restricted to symptomatic patients with both low or intermediate Cbl levels and increased metabolite values, 63% of responders would not have been treated. Twenty-five patients did not respond to treatment, including 5 of 11 patients (45%) with low Cbl, 22 of 49 patients (45%) with high MMA, and 13 of 30 patients (43%) with high HCys values. It is concluded that Cbl, MMA, and HCys levels fluctuate with time and neither predict nor preclude the presence of Cbl-responsive hematologic or neurologic disorders.