RESUMEN
BACKGROUND: Acetaminophen toxicity is the most common form of acute liver failure in the U.S. After acetaminophen overdoses, quantitation of plasma acetaminophen can aid in predicting severity of injury. However, recent case reports have suggested that acetaminophen concentrations may be falsely increased in the presence of hyperbilirubinemia. METHODS: We tested sera obtained from 43 patients with acute liver failure, mostly unrelated to acetaminophen, utilizing 6 different acetaminophen quantitation systems to determine the significance of this effect. In 36 of the 43 samples with bilirubin concentrations ranging from 1.0-61.5 mg/dl no acetaminophen was detectable by gas chromatography-mass spectroscopy. These 36 samples were then utilized to test the performance characteristics of 2 immunoassay and 4 enzymatic-colorimetric methods. RESULTS: Three of four colorimetric methods demonstrated 'detectable' values for acetaminophen in from 4 to 27 of the 36 negative samples, low concentration positive values being observed when serum bilirubin concentrations exceeded 10 mg/dl. By contrast, the 2 immunoassay methods (EMIT, FPIA) were virtually unaffected. The false positive values obtained were, in general, proportional to the quantity of bilirubin in the sample. However, prepared samples of normal human serum with added bilirubin showed a dose-response curve for only one of the 4 colorimetric assays. CONCLUSIONS: False positive acetaminophen tests may result when enzymatic-colorimetric assays are used, most commonly with bilirubin concentrations >10 mg/dl, leading to potential clinical errors in this setting. Bilirubin (or possibly other substances in acute liver failure sera) appears to affect the reliable measurement of acetaminophen, particularly with enzymatic-colorimetric assays.
Asunto(s)
Acetaminofén/sangre , Acetaminofén/envenenamiento , Bilirrubina/sangre , Hiperbilirrubinemia/sangre , Fallo Hepático Agudo/sangre , Anciano , Sobredosis de Droga/diagnóstico , Reacciones Falso Positivas , Femenino , Humanos , Hiperbilirrubinemia/diagnóstico , Fallo Hepático Agudo/diagnóstico , Pruebas de Función Hepática , Masculino , Persona de Mediana EdadRESUMEN
Antimicrobial drugs are important causative agents in idiosyncratic drug-induced liver injury (DILI). As with idiosyncratic DILI in general, antibiotic-induced liver injury is rare but difficult to diagnose and almost impossible to predict. Diagnosis requires awareness of possible causal agents, vigilance in monitoring symptoms and sometimes biochemical tests, attention to careful history taking and establishing temporal association, and exclusion of competing etiologies. In most instances, patients with antibiotic-associated DILI recover if the offending agent is withdrawn in a timely fashion.
Asunto(s)
Antibacterianos/efectos adversos , Enfermedad Hepática Inducida por Sustancias y Drogas , Humanos , Factores de RiesgoRESUMEN
Determining prognosis in acute liver failure (ALF) is vital to consideration of transplantation for these critically ill patients. Transplanting a likely survivor may be as unfortunate as not transplanting someone whose outcome is very poor. Prognostic scoring systems have largely failed to accurately portray outcomes, partly because the use of transplantation does not allow the true transplant-free outcome to unfold. The King's College Hospital criteria have not proved accurate enough in predicting outcome for those with moderate illness; sensitivity is reasonable while specificity is poor. Use of APACHE II or MELD systems suffers from similar deficiencies. Use of specialized biomarkers such as Gc protein, alpha-fetoprotein, or troponin shows some promise but has not proven effective to date. Considering etiology and coma grade prior to development of scores based on routine or specialized biomarkers may be important. The rapid evolution of ALF as well as the different etiologies encountered may continue to frustrate our efforts to accurately predict outcomes in ALF.
Asunto(s)
Fallo Hepático Agudo/mortalidad , Biomarcadores/metabolismo , Humanos , Fallo Hepático Agudo/etiología , Fallo Hepático Agudo/metabolismo , Modelos Biológicos , PronósticoRESUMEN
BACKGROUND & AIMS: Acetaminophen toxicity is the most common cause of acute liver failure (ALF) in the United States and Great Britain, but may be underrecognized in certain settings. Acetaminophen-protein adducts are specific biomarkers of drug-related toxicity in animal models and can be measured in tissue or blood samples. Measurement of serum adducts might improve diagnostic accuracy in acute liver failure (ALF) patients. METHODS: We measured serum acetaminophen-protein adducts using high-pressure liquid chromatography with electrochemical detection in coded sera of 66 patients with ALF collected prospectively at 24 US tertiary referral centers. Samples were included from 20 patients with well-characterized acetaminophen-related acute liver failure, 10 patients with ALF owing to other well-defined causes, 36 patients with ALF of indeterminate etiology, and 15 additional patients without ALF but with known acetaminophen overdose and minimal or no biochemical liver injury. RESULTS: Acetaminophen-protein adducts were detected in serum in 100% of known acetaminophen ALF patients and in none of the ALF patients with other defined causes, yielding a sensitivity and specificity of 100%. In daily serial samples, serum adducts decreased in parallel with aminotransferase levels. Seven of 36 (19%) indeterminate cases demonstrated adducts in serum suggesting that acetaminophen toxicity caused or contributed to ALF in these patients. Low adduct levels were present in 2 of 15 patients with acetaminophen overdose without significant liver injury. CONCLUSIONS: Measurement of serum acetaminophen-protein adducts reliably identified acetaminophen toxicity, and may be a useful diagnostic test for cases lacking historical data or other clinical information.
Asunto(s)
Acetaminofén/envenenamiento , Proteínas Sanguíneas/metabolismo , Fallo Hepático Agudo/inducido químicamente , Acetaminofén/metabolismo , Acetilcisteína/uso terapéutico , Adolescente , Cromatografía Líquida de Alta Presión , Femenino , Humanos , Fallo Hepático Agudo/sangre , Fallo Hepático Agudo/diagnóstico , Masculino , Persona de Mediana Edad , Intoxicación/diagnósticoRESUMEN
The question of whether viruses persist after apparent clearance of infection remains unanswered. Here, we describe a patient with hypogammaglobulinemia whose acute hepatitis C virus (HCV) infection appeared to resolve after receipt of interferon therapy, relapse immediately, and then clear spontaneously--only to relapse after receipt of corticosteroid therapy, and clear again, 8.5 years later. Sequencing indicated that the viruses detected during each relapse were virtually identical, with the hypervariable region 1 of E2 appearing to be monoclonal, which is typical of patients with hypogammaglobulinemia. Nonstructural 5A sequences exhibited quasispecies diversity initially but, after 8.5 years, had become monoclonal. The prolonged period of negativity for HCV RNA followed by relapse suggests that HCV may persist in apparent sustained viral responders.
Asunto(s)
Agammaglobulinemia/complicaciones , Hepacivirus/aislamiento & purificación , Hepatitis C/virología , Corticoesteroides/uso terapéutico , Adulto , Agammaglobulinemia/virología , Alanina Transaminasa/sangre , Secuencia de Aminoácidos , Antivirales/farmacología , Antivirales/uso terapéutico , Femenino , Hepatitis C/complicaciones , Hepatitis C/tratamiento farmacológico , Humanos , Interferones/farmacología , Interferones/uso terapéutico , Mutación , Polimorfismo Genético , ARN Viral/genética , ARN Viral/aislamiento & purificación , Recurrencia , Análisis de Secuencia de ADN , Homología de Secuencia , Proteínas del Envoltorio Viral/genética , Proteínas no Estructurales Virales/genéticaRESUMEN
Severe acetaminophen hepatotoxicity frequently leads to acute liver failure (ALF). We determined the incidence, risk factors, and outcomes of acetaminophen-induced ALF at 22 tertiary care centers in the United States. Detailed prospective data were gathered on 662 consecutive patients over a 6-year period fulfilling standard criteria for ALF (coagulopathy and encephalopathy), from which 275 (42%) were determined to result from acetaminophen liver injury. The annual percentage of acetaminophen-related ALF rose during the study from 28% in 1998 to 51% in 2003. Median dose ingested was 24 g (equivalent to 48 extra-strength tablets). Unintentional overdoses accounted for 131 (48%) cases, intentional (suicide attempts) 122 (44%), and 22 (8%) were of unknown intent. In the unintentional group, 38% took two or more acetaminophen preparations simultaneously, and 63% used narcotic-containing compounds. Eighty-one percent of unintentional patients reported taking acetaminophen and/or other analgesics for acute or chronic pain syndromes. Overall, 178 subjects (65%) survived, 74 (27%) died without transplantation, and 23 subjects (8%) underwent liver transplantation; 71% were alive at 3 weeks. Transplant-free survival rate and rate of liver transplantation were similar between intentional and unintentional groups. In conclusion, acetaminophen hepatotoxicity far exceeds other causes of acute liver failure in the United States. Susceptible patients have concomitant depression, chronic pain, alcohol or narcotic use, and/or take several preparations simultaneously. Education of patients, physicians, and pharmacies to limit high-risk use settings is recommended.
Asunto(s)
Acetaminofén/envenenamiento , Fallo Hepático Agudo/inducido químicamente , APACHE , Adolescente , Adulto , Anciano , Alcoholismo/complicaciones , Sobredosis de Droga , Femenino , Humanos , Fallo Hepático Agudo/epidemiología , Fallo Hepático Agudo/prevención & control , Masculino , Persona de Mediana Edad , Estudios ProspectivosRESUMEN
BACKGROUND & AIMS: Progression of hepatic encephalopathy (HE) is a major determinant of outcome in acute liver failure (ALF). Our aim was to identify predictive factors of worsening HE, including the relation of encephalopathy with the systemic inflammatory response (SIRS) and infection. METHODS: We included 227 consecutive patients with stage I-II HE prospectively enrolled in the U.S. Acute Liver Failure Study. Univariate and multivariate analysis of 27 variables at admission were performed separately for acetaminophen (n = 96) and nonacetaminophen (n = 131) etiologies. RESULTS: On multivariate analysis, acquisition of infection during stage I-II HE (P < 0.01), increased leukocyte levels at admission (P < 0.01), and decreased platelet count (P < 0.05) were predictive factors of worsening HE in the acetaminophen group. By contrast, only increased pulse rate (P < 0.05) and AST levels (P < 0.05) at admission were predictors in nonacetaminophen patients. In patients who progressed to deep HE, the first confirmed infection preceded progression in 15 of 19 acetaminophen patients compared with 12 of 23 nonacetaminophen patients. In patients who did not demonstrate positive microbiologic cultures, a higher number of components of SIRS at admission was associated with more frequent worsening of HE (25% vs. 35% vs. 50% for 0, 1, and >or=2 components of SIRS, P < 0.05). CONCLUSIONA: This prospective evaluation points to infection and/or the resulting systemic inflammatory response as important factors contributing to worsening HE in ALF, mainly in patients with acetaminophen- induced ALF. The use of prophylactic antibiotics in these patients and the mechanisms by which infection triggers hepatic encephalopathy require further investigation.