Elizabeth C. Wright

Long-Term Mortality after Transfusion-Associated Non-A, Non-B Hepatitis

Abstract Background. Acute non-A, non-B hepatitis after blood transfusion often progresses to chronic hepatitis and sometimes culminates in cirrhosis or even hepatocellular carcinoma. However, the frequency of these sequelae and their effects on mortality are not known. Methods. We traced patients with transfusion-related non-A, non-B hepatitis who had been identified in five major prospective studies conducted in the United States between 1967 and 1980. We matched each patient with two control subjects (identified as the first and second controls) who received transfusions but who did not have hepatitis. The mortality rates in the three groups were determined with use of data from the National Death Index and Social Security Death Tapes. Cause-specific mortality was determined by reviewing death certificates. Results. Vital status was established for over 94 percent of the 568 patients who had had non-A, non-B hepatitis and the two control groups (526 first controls and 458 second controls). After an ave...

Airways Obstruction and the Risk for Lung Cancer

The presence of airways obstruction identify in middle-aged male smokers at increased risk for lung cancer. This hypothesis was tested in a sample of patients with moderate to severe obstruction from the Intermittent Positive Pressure Breathing Trial and a sample of patients with no obstruction to moderate obstruction from the Johns Hopkins Lung Project, all of whom were followed for the development of lung cancer. On follow-up, the risk of developing lung cancer was found to be associated with entry values for age, smoking, and ventilatory status by linear, proportional hazard, and log-linear adjustment techniques. Among cigarette smokers, the presence of airways obstruction was more of an indicator for the subsequent development of lung cancer than was age or the level of smoking. The risk for lung cancer also increased in proportion to the degree of airways obstruction. These data suggest that smokers with ventilatory obstruction are at greater risk for lung cancer than are smokers without obstruction.

Type B hepatitis: the infectivity of blood positive for e antigen and DNA polymerase after accidental needlestick exposure.

To determine the relation between the presence of donor DNA polymerase and e antigen, and recipient hepatitis, we tested, under code, serums from a controlled trial of hepatitis B immune globulin used to treat individuals accidentally inoculated with HBs Ag-positive blood. All recipients lacked antibody to HBs Ag. In 29 of 31 donors, both polymerase and e were in perfect agreement; both demonstrated a highly significant correlation with recipient hepatitis (P less than 0.001). DNA polymerase/e-negative blood did not cause hepatitis. Blood containing polymerase or e antigen did not cause hepatitis in six of 31 and four of 18 recipients, respectively. Hepatitis did not correlate with transaminase or duration of antigenemia in the donor. Polymerase and e appear to be indicators of the relative infectivity of HBs Ag-positive serum, particularly after small-volume exposure. They may be important determinants in assessing infectivity of chronic carriers of HBs Ag and in evaluating efficacy of hepatitis B immune globulin and hepatitis B vaccines.

Des-γ-Carboxy Prothrombin and α-Fetoprotein as Biomarkers for the Early Detection of Hepatocellular Carcinoma

BACKGROUND & AIMS The outcome of patients with hepatocellular carcinoma (HCC) remains poor because of late diagnosis. The aim of this study was to compare the accuracy of alpha-fetoprotein (AFP) and des-gamma-carboxy prothrombin (DCP) in the early diagnosis of HCC. METHODS Among 1031 patients randomized in the Hepatitis C Antiviral Long-term Treatment Against Cirrhosis (HALT-C) Trial, a nested case-control study of 39 HCC cases (24 early stage) and 77 matched controls was conducted to compare the performance of AFP and DCP. Testing was performed on sera from 12 months prior (month -12) to the time of HCC diagnosis (month 0). RESULTS The sensitivity and specificity of DCP at month 0 was 74% and 86%, respectively, at a cutoff of 40 mAU/mL and 43% and 100%, respectively, at a cutoff of 150 mAU/mL. The sensitivity and specificity of AFP at month 0 was 61% and 81% at a cutoff of 20 ng/mL and 22% and 100% at a cutoff of 200 ng/mL. At month -12, the sensitivity and specificity at the low cutoff was 43% and 94%, respectively, for DCP and 47% and 75%, respectively, for AFP. Combining both markers increased the sensitivity to 91% at month 0 and 73% at month 12, but the specificity decreased to 74% and 71%, respectively. Diagnosis of early HCC was triggered by surveillance ultrasound in 14, doubling of AFP in 5, and combination of tests in 5 patients. CONCLUSIONS Biomarkers are needed to complement ultrasound in the detection of early HCC, but neither DCP nor AFP is optimal.

Predicting cirrhosis in patients with hepatitis C based on standard laboratory tests: Results of the HALT-C cohort†

Knowledge of the presence of cirrhosis is important for the management of patients with chronic hepatitis C (CHC). Most models for predicting cirrhosis were derived from small numbers of patients and included subjective variables or laboratory tests that are not readily available. The aim of this study was to develop a predictive model of cirrhosis in patients with CHC based on standard laboratory tests. Data from 1,141 CHC patients including 429 with cirrhosis were analyzed. All biopsies were read by a panel of pathologists (blinded to clinical features), and fibrosis stage was determined by consensus. The cohort was divided into a training set (n = 783) and a validation set (n = 358). Variables that were significantly different between patients with and without cirrhosis in univariate analysis were entered into logistic regression models, and the performance of each model was compared. The area under the receiver‐operating characteristic curve of the final model comprising platelet count, AST/ALT ratio, and INR in the training and validation sets was 0.78 and 0.81, respectively. A cutoff of less than 0.2 to exclude cirrhosis would misclassify only 7.8% of patients with cirrhosis, while a cutoff of greater than 0.5 to confirm cirrhosis would misclassify 14.8% of patients without cirrhosis. The model performed equally well in fragmented and nonfragmented biopsies and in biopsies of varying lengths. Use of this model might obviate the requirement for a liver biopsy in 50% of patients with CHC. In conclusion, a model based on standard laboratory test results can be used to predict histological cirrhosis with a high degree of accuracy in 50% of patients with CHC. (HEPATOLOGY 2005.)

A Controlled Clinical Trial of Dichloroacetate for Treatment of Lactic Acidosis in Adults

Abstract Background. Mortality is very high in lactic acidosis, and there is no satisfactory treatment other than treatment of the underlying cause. Uncontrolled studies have suggested that dichloroacetate, which stimulates the oxidation of lactate to acetyl-coenzyme A and carbon dioxide, might reduce morbidity and improve survival among patients with this condition. Methods. We conducted a placebo-controlled, randomized trial of intravenous sodium dichloroacetate therapy in 252 patients with lactic acidosis; 126 were assigned to receive dichloroacetate and 126 to receive placebo. The entry criteria included an arterial-blood lactate concentration of ≥5.0 mmol per liter and either an arterial-blood pH of ≤7.35 or a base deficit of ≥6 mmol per liter. The mean (±SD) arterial-blood lactate concentrations before treatment were 11.6±7.0 mmol per liter in the dichloroacetate-treated patients and 10.4±5.5 mmol per liter in the placebo group, and the mean initial arterial-blood pH values were 7.24±0.12 and 7.24±0...

Protection from obesity and diabetes by blockade of TGF-β/Smad3 signaling

Imbalances in glucose and energy homeostasis are at the core of the worldwide epidemic of obesity and diabetes. Here, we illustrate an important role of the TGF-β/Smad3 signaling pathway in regulating glucose and energy homeostasis. Smad3-deficient mice are protected from diet-induced obesity and diabetes. Interestingly, the metabolic protection is accompanied by Smad3(-)(/-) white adipose tissue acquiring the bioenergetic and gene expression profile of brown fat/skeletal muscle. Smad3(-/-) adipocytes demonstrate a marked increase in mitochondrial biogenesis, with a corresponding increase in basal respiration, and Smad3 acts as a repressor of PGC-1α expression. We observe significant correlation between TGF-β1 levels and adiposity in rodents and humans. Further, systemic blockade of TGF-β signaling protects mice from obesity, diabetes, and hepatic steatosis. Together, these results demonstrate that TGF-β signaling regulates glucose tolerance and energy homeostasis and suggest that modulation of TGF-β activity might be an effective treatment strategy for obesity and diabetes.

Prospective RBC phenotype matching in a stroke-prevention trial in sickle cell anemia: a multicenter transfusion trial

BACKGROUND: Most sickle cell anemia patients undergo transfusion therapy to prevent complications. The Stroke Prevention Trial in Sickle Cell Anemia showed that transfusion therapy is effective in the primary prevention of stroke. Despite its efficacy, transfusion therapy is limited by alloimmunization. The purpose of this study was to determine if a multicenter trial could implement a transfusion program utilizing phenotypically matched blood to reduce alloimmunization.

Stroke Prevention Trial in Sickle Cell Anemia

Stroke occurs in 7-8% of children with Sickle Cell Disease (Hb SS) and is a major cause of morbidity. Rates of recurrence have been reduced from 46-90% to less than 10% through chronic blood transfusions. Prevention of first stroke, however, would be preferable because even one stroke can cause irreversible brain injury. Transcranial Doppler (TCD) ultrasound can detect arterial blood flow rates associated with subsequent stroke risk. By combining TCD screening and a potentially effective treatment, first stroke may be prevented. The Stroke Prevention Trial in Sickle Cell Anemia (STOP) is the first stroke prevention trial in Hb SS and the first randomized, controlled use of transfusion in Hb SS. This multi-center trial is designed to test whether reducing sickle hemoglobin to 30% or less with periodic blood transfusions will reduce first-time stroke by at least 70% compared to standard care. Primary endpoints will be clinically evident symptoms of cerebral infarction with consistent findings on Magnetic Resonance Imaging and Angiography (MRI/MRA) or symptomatic intracranial hemorrhage. Secondary endpoints will be asymptomatic brain lesions detected by MRI in brain areas not involved in primary endpoints. The design calls for a 6-month start-up interval, 18 months of TCD screening and randomization, and observation for stroke from entry through month 54. Key features of the trial are standardized TCD and MRI/MRA protocols interpreted blindly, and blinded adjudication of endpoints. The sample size (60 per treatment group) is based on prospective data relating TCD velocity to risk of stroke. A time-averaged mean velocity of > or = 200 cm/sec is associated with a 46% risk of cerebral infarction over 39 months. The sample size is sufficient to detect 70% reduction in the primary endpoint at 90% power. This trial will determine if transfusion is effective in the primary prevention of stroke. Secondary aims may further the understanding of the effects of transfusion on the brain and guide future research into cerebrovascular disease in Hb SS.

The Relationship of Acute Transfusion-Associated Hepatitis to the Development of Cirrhosis in the Presence of Alcohol Abuse

Seroprevalence data from the Third National Health and Nutrition Examination Survey (1984 to 1999) suggest that 3 million persons in the United States are infected with the hepatitis C virus (HCV) (1). Treatment fails to clear the virus in 80% to 85% of acutely infected persons. Not all persons who remain infected eventually develop progressive liver disease (2), but in those who do, clinical evidence of liver damage may not appear until decades later (3). It is widely believed that progression of liver disease in persons with chronic HCV infection is enhanced by concomitant heavy alcoholism (4-12). We sought to quantify the association of transfusion-associated HCV infection and history of alcohol abuse with development of cirrhosis among patients followed from the time of acute HCV infection. Methods The source of this investigation, described in detail elsewhere (13), is a long-term follow-up study of acute non-A, non-B hepatitis in patients included in earlier prospective studies of transfusion-related HCV infection. All patients provided informed consent, and the study was approved by the relevant institutional review boards. Briefly, non-A, non-B hepatitis was identified by otherwise unexplained elevations in serum alanine aminotransferase (ALT) levels developing 2 to 24 weeks after transfusion, in the absence of serologic evidence of hepatitis A or B (13). The ALT level had to be elevated on two consecutive measurements, and at least one of the values had to exceed twice the upper limit of normal. Stored sera from case-patients and controls from three of the prospective studiesthe second Veterans Administration Cooperative study (14), the Transfusion-Transmitted Viruses study (15), and the National Institutes of Health Blood Bank Study (16)were tested for anti-HCV by enzyme immunoassay (HCV EIA 2.0, Abbott Laboratories, North Chicago, Illinois). Transfusion-associated HCV infection was diagnosed if anti-HCV appeared and persisted, was temporally related to elevated ALT levels, and was confirmed by using the supplementary recombinant immunoblot assay (RIBA version 3.0, Ortho Diagnostics, Raritan, New Jersey). Because repository samples were not optimally stored for minimizing nucleic acid loss, HCV RNA testing was not performed. Controls consisted of transfused patients from the original three prospective studies who had not developed hepatitis (13). Controls were matched to case-patients by initial treatment center, sex, ethnicity, use of hepatitis immune globulin, presence or absence of a history of alcoholism, age, number of units of blood transfused, and date of transfusion. We excluded patients with anti-HCVpositive samples that predated the index transfusion and those with anti-HCV reactivity but no confirmatory test. Anti-HCVpositive/RIBA-negative and anti-HCVnegative patients were classified as having transfusion-associated non-A, non-B, non-C hepatitis. Controls with anti-HCV in repository samples were excluded. We used a multifaceted approach to gather information on each patients history of liver disease from participation in the prospective studies through initiation of the follow-up study (13). Vital status was ascertained through searches of death registries, and copies of death certificates were obtained. Patients or their designated proxies (if the patient was deceased or incompetent) were invited to participate in a personal interview that included questions about previous hospitalizations. Authorization for release of medical records was obtained, and information on all hospitalizations at each facility identified was requested. Medical records, death certificates, and biopsy and autopsy reports were reviewed by trained abstractors for the diagnosis of cirrhosis, which was based on the occurrence of features of portal hypertension and overt clinical manifestations of cirrhosis. Evaluation of a sample of records indicated a high level of agreement between abstractors and one of the investigators. Potential risk factors were derived primarily from personal interview. A composite variable aimed at identifying a history of heavy alcohol abuse was designed to minimize the possibility of misclassifying unexposed patients. The composite variable was based on one or more of the following criteria: loss of friends, family, or a job because of drinking; admitting to ever having a problem with alcoholism; evidence of heavy drinking abstracted from medical records; or quantification of usual intake of more than 80 g of alcohol per day during the years when the patient drank. Univariate methods (the Fisher exact, exact FisherFreemanHalton [17], and Wilcoxon rank-sum tests) were used to compare the distribution of characteristics between patients included in and those excluded from the analysis and to examine associations between potential risk factors and development of cirrhosis. The strength of the association between risk factors and cirrhosis was assessed by using the odds ratio obtained from multiple logistic regression. The likelihood of developing cirrhosis associated with a combination of risk factors was estimated from the logistic model (18). Results Of 1030 patients who were followed up from the original prospective studies that had collected repository samples, 836 (81.2%) were included in this analysis. We excluded 108 patients whose repository samples were exhausted, 79 with ALT levels or HCV assays that did not permit reliable classification of hepatitis status, 1 with cirrhosis that predated the index transfusion, and 6 with data inconsistencies that could not be resolved. As shown in Table 1, included and excluded patients differed only in median number of blood units originally transfused. The number of units received could affect the probability of developing acute transfusion-associated hepatitis or its severity but would probably not influence development of cirrhosis decades later. Table 1. Characteristics of Included and Excluded Patients Preliminary analyses indicated that development of cirrhosis was unrelated to tattooing, ear piercing, occupational exposures, extended travel to areas in which hepatitis is endemic, and use of injection or other illegal drugs. Information on prescription drug use was unavailable for analysis. Development of cirrhosis differed (P<0.05) according to transfusion-associated hepatitis status, study cohort, race/ethnicity, units of blood originally transfused, history of heavy alcohol abuse, and vital status at follow-up (Table 2). The absolute risk for developing cirrhosis was higher among patients with transfusion-associated HCV infection (17.0% [35 of 206 patients]) (P<0.001) than among those with transfusion-associated non-A, non-B, non-C hepatitis infection (3.2% [3 of 95 patients]) or controls (2.8% [15 of 535 patients]) but did not differ between the latter two groups (P>0.2). The median time from index transfusion to initiation of follow-up (15.6 years overall) did not differ by cirrhosis status, transfusion-associated hepatitis status, or race/ethnicity (P 0.10). Table 2. Association of Patient Characteristics with Development of Cirrhosis Logistic regression modeling indicated that patients with transfusion-associated HCV infection were 7.8 times (95% CI, 4.0 to 15.1 times) more likely to develop cirrhosis than controls, after adjustment for history of heavy alcohol abuse and study cohort. Patients with transfusion-associated non-A, non-B, non-C hepatitis were at increased risk for developing cirrhosis, but this finding was not significant (odds ratio, 1.4 [95% CI, 0.4 to 5.0]). Patients with transfusion-associated HCV were 5.6 times (CI, 1.6 to 19.3 times) more likely to develop cirrhosis than those with non-A, non-B, non-C hepatitis. A history of heavy alcohol abuse was associated with an increased risk for developing cirrhosis (odds ratio, 4.0 [CI, 2.1 to 7.7]). The HosmerLemeshow goodness-of-fit test indicated that the model fit the data well (P>0.2). From this model, it was estimated that patients with both transfusion-associated HCV infection and a history of heavy alcohol abuse were 31.1 times (CI, 11.4 to 84.5 times) more likely to develop cirrhosis than controls without a history of alcohol abuse. Patients with transfusion-associated non-A, non-B, non-C hepatitis and a history of heavy alcohol abuse were also more likely than controls without such a history to develop cirrhosis (odds ratio, 5.5 [CI, 1.3 to 24.3]). Although cirrhosis was less common among African-Americans (2.2%) than among persons of other ethnicities (7.2%), addition of race/ethnicity, follow-up duration, units of blood originally transfused, vital status, and receipt of additional transfusions to the model changed the risks associated with hepatitis status and history of heavy alcohol abuse only slightly. None of these factors made a significant independent contribution to the model (data not shown). Discussion Patients who contracted transfusion-associated HCV infection were at increased risk for developing cirrhosis (odds ratio, 7.8), and this risk increased substantially if the patient also had a history of heavy alcohol abuse (odds ratio, 31.1). Although numerous reports have identified a strong role of alcohol in promoting progression of liver disease among persons with chronic HCV infection (4-12), our findings provide a quantitative measure to assess the strength of this association. Some patients who were originally classified as having acute non-A, non-B hepatitis tested negative for HCV infection. These patients developed cirrhosis more frequently than controls, but not significantly so. This finding suggests that the elevated ALT levels observed during the original prospective studies were caused by intrinsic liver disease. It remains to be determined, however, whether these patients had been infected with a virus other than hepatitis A, B, or C virus or whether the elevated enzyme levels resulted from other causes (for example, nonviral infection