David D. Koch

Glucose-Independent, Black–White Differences in Hemoglobin A1c Levels: A Cross-sectional Analysis of 2 Studies

BACKGROUND A previous study of participants with prediabetes found that hemoglobin A(1c) (HbA(1c)) levels differed between black and white participants with no differences in glucose concentration. OBJECTIVE To determine whether black-white differences in HbA(1c) level are present in other populations and across the full spectrum of glycemia. DESIGN Cross-sectional, retrospective. SETTING Outpatient. PARTICIPANTS 1581 non-Hispanic black and white participants between 18 and 87 years of age without known diabetes in the SIGT (Screening for Impaired Glucose Tolerance) study and 1967 non-Hispanic black and white participants older than 40 years without known diabetes in the NHANES III (Third National Health and Nutrition Examination Survey). MEASUREMENTS HbA(1c) levels, anthropometry, and plasma glucose levels during oral glucose tolerance testing. RESULTS Hemoglobin A(1c) levels were higher in black than in white participants with normal glucose tolerance (0.13 percentage point [P < 0.001] in the SIGT sample and 0.21 percentage point [P < 0.001] in the NHANES III sample), prediabetes (0.26 percentage point [P < 0.001] and 0.30 percentage point [P < 0.001], respectively), or diabetes (0.47 percentage point [P < 0.020] and 0.47 percentage point [P < 0.013], respectively) after adjustment for plasma glucose levels and other characteristics known to correlate with HbA(1c) levels. LIMITATION The mechanism for the differences is unknown. CONCLUSION Black persons have higher HbA(1c) levels than white persons across the full spectrum of glycemia, and the differences increase as glucose intolerance worsens. These findings could limit the use of HbA(1c) to screen for glucose intolerance, indicate the risk for complications, measure quality of care, and evaluate disparities in health.

Misleading Hyponatremia Due to Hyperlipemia: A Method-Dependent Error

Excerpt Serum from patients with hyperlipemia has been clearly shown to have low sodium values when analyzed by flame photometry (1-10). This artifactually low sodium value is due to a decrease in ...

Effect of sample preparation and liquid chromatography column choice on selectivity and precision of plasma catecholamine determination

Research into the role of the catecholamines has often depended on the reliable determination of plasma catecholamine concentrations, which present a challenge since they are normally in the low pg/ml range. Most methods employ liquid chromatography, with variations in sample preparation, the separation mechanism, and detection. We tested a new approach to sample clean-up using boric acid gel instead of alumina. No advantage was found. We also compared cation-exchange separation with ion-pair chromatography. Several improvements are possible with the former, most notably greater precision, better specificity, and increased throughput.

Epidemiological evidence for the disruption of ionized calcium homeostasis in the elderly.

Ionized calcium (Ca2+), phosphate, albumin, total calcium, and pH measurements taken from participants in a large population-based epidemiological study were examined to determine the change in physiological variation with age for persons over 43 years old. Only Ca2+ showed a statistically significant increase in SD with age (p < 0.0001). The Ca2+ coefficients of variation (CV) increased from 2.92% in the youngest age group (43-54 years) to 3.69% in the oldest age group (75-86 years of age). In females, the increase in Ca2+ variability was nearly complete by age 55. Males also showed a significant (p = 0.006) increase in SD between the 43-54 age group and the 55-64 age group, however, Ca2+ variability did not plateau after age 55 in men as it did in women. In the 43-54 (p = 0.04) and 55-64 (p = 0.03) age group men showed significantly better physiological control of Ca2+ than women. Phosphate showed a slight decrease in CV with age. These data suggest that Ca2+ homeostasis is disrupted in the same age groups that are most vulnerable to osteoporosis.

Determination of urinary 3-methoxy-4-hydroxyphenyl-glycol by liquid chromatography with electrochemical detection

The increasing popularity of urinary 3-methoxy-4-hydroxyphenylglycol (MHPG) determinations has placed a demand on clinical laboratories to provide these data. Previous methods for MHPG either exhibit unacceptable performance, are too slow, or utilize instrumentation not commonly employed in these laboratories. The liquid chromatography electrochemical detection method described here has several positive features. MHPG is isolated by extraction, separated by liquid chromatography, and quantitated at an amperometric electrode. The precision, simplicity, and relatively low cost makes this new method an ideal choice for the clinical laboratory.

Concepts in the validation of neurochemical methods: the proper generation and use of statistics.

Nearly every advance made in the study of neurotransmission has resulted from the development of new analytical methods or from the application of such methods to neurochemical problems in new ways. Each investigator places extremely high dependence on the laboratory method from which the data are gathered. It is therefore vital that these methods be proven valid when first selected and when used throughout the experiments being conducted. The process of method validation has flourished and been refined in the field of laboratory medicine. Methods are primarily validated by their accuracy and reproducibility in determining the analyte of interest in the tissue(s) to be studied. It is important that standards of performance be established that will allow objective decisions to be made when methods are tested for these characteristics. Performance standards for several neurotransmitters are suggested. Studies performed to collect method performance data are presented. From these data, statistics can be generated that help to estimate analytical errors. Guidelines for the proper generation and use of these statistics are discussed. Use of these validation approaches should be expanded in the whole of neurochemistry, which should enrich the data gathered within a laboratory and improve the harmonization between laboratories.

Outcomes in Adults With Acute Liver Failure Between 1998 and 2013An Observational Cohort StudyOutcomes in Adults With Acute Liver Failure Between 1998 and 2013

Context Whether changes have occurred in the causes of acute liver failure (ALF), its management, or the survival of patients with the condition (with or without liver transplantation) is not known. Contribution This large cohort study found that despite similar causes and severity of ALF among patients referred to specialty centers from 1998 to 2013, the proportion of patients listed for liver transplantation decreased and survival improved among those who did not receive a transplant as well as those who did. Implication More study is warranted to better understand the specific changes in care that may have led to improved survival of patients with ALF. Acute liver failure (ALF) is defined as severe liver injury with rapid onset that results in hepatic encephalopathy (HE) and coagulopathy in persons without preexisting liver disease. The principal causes of ALF include acetaminophen (N-acetyl-p-aminophenol [APAP]) overdose, ischemic and pregnancy-associated liver injury, acute infection with hepatitis A or B virus, drug-induced liver injury, autoimmune hepatitis, BuddChiari syndrome, and Wilson disease (1, 2). For some causes, such as APAP toxicity, outcomes are favorable and transplant-free survival (TFS) approaches 70%, whereas other causes have unfavorable outcomes, including a much lower likelihood (<30%) of recovery without liver transplantation (2). One-year survival after emergency liver transplantation in patients with ALF in the United States and Europe is reportedly good but is lower than among patients with cirrhosis who receive a transplant (3). Patients with ALF often deteriorate rapidly and therefore receive the most urgent ranking (status 1) in the United Network for Organ Sharing transplantation system. Treatment of ALF in the intensive care unit is largely supportive and includes ventilator and vasopressor support for respiratory and/or circulatory failure, renal replacement therapy, plasma and blood transfusions, antibiotics, and measures to decrease intracranial pressure (46). N-acetylcysteine is used to treat APAP overdose and has shown efficacy in patients with ALF not due to APAP toxicity, particularly those referred early and having only mild HE (7). However, few disease-specific or general treatments are available that yield improved outcomes. In this study, our aim was to update the U.S. experience with ALF at specialized liver disease and transplant centers since the last published overview by the Acute Liver Failure Study Group (ALFSG) in 2002 (2). This group initiated its registry in January 1998 to better characterize the causes, clinical features, and outcomes of this super-orphan condition and aimed to enroll cases prospectively from participating liver transplant centers across North America. Accordingly, we analyzed data on all patients with ALF enrolled between 1998 and 2013, focusing on whether clinical features or outcomes of the ALF syndrome have changed over time. In addition, we sought to determine the relationship between ALF causes and rates of TFS and whether utilization of liver transplantation changed in the 16-year observation period. Methods Study Population From 1 January 1998 through 31 December 2013, adult patients were consecutively enrolled in the ALFSG registry (2) from 31 U.S. academic liver centers (of which only 5 legacy sites participated continuously throughout the 16-year period). All enrolled patients had both coagulopathy (international normalized ratio [INR] 1.5) and any grade of HE (as clinically defined by the classic West Haven criteria [8]) within 26 weeks of the first symptoms and had no evidence of significant chronic liver disease, especially cirrhosis. Patients for whom prior liver transplantation failed (due to primary graft nonfunction or other causes) were excluded. During the 16-year period, the number of sites participating, their geographic locations, and the number of cases contributed per site varied depending on each sites ability to continually identify and enroll patients over time (Appendix Figure 1). Appendix Figure 1. Site enrollment over time. Patients were usually admitted to intensive care units; 82.4% were hospitalized before transfer to the referral tertiary care study site, and the remainder were admitted directly to the study site. All were screened for inclusion according to the ALF criteria defined earlier. Written informed consent was obtained from the legal next of kin. A log of screen failures and consent refusal was maintained. All centers complied with local institutional review board requirements. Data Management and Integrity At enrollment into the study, we prospectively collected patient demographic characteristics (age, sex, race, and ethnicity); a complete medical history, including the timing of the first symptom of ill health, onset of jaundice and HE, and the number of days between the first symptom, hospital admission, transfer to the study site (where relevant), and enrollment in the study; and clinical features, including blood pressure and need for vasopressor support, mechanical ventilation, and renal replacement therapy, which allowed calculation of the systemic inflammatory response syndrome (SIRS) score (9). We also collected standard liver and metabolic test results and clinical data daily for up to 7 days, as well as serologic and other tests to determine the cause. All data were managed and housed on a central server at the Medical University of South Carolina. A data query system and periodic monitoring are in place to manage data integrity. In addition, ALFSG leadership conducted annual visits to clinical sites to verify data and ensure compliance with study procedures. Statistical Analysis Statistical analyses were performed using SAS, version 9.4 (SAS Institute). Missing values were not replaced or estimated. Patients with missing data were excluded from the respective analyses for those variables, and patients who were lost to follow-up before 21 days were excluded from the study. Descriptive statistics were used to characterize the demographic and other clinical variables. Categorical variables were compared using the chi-square test or the Fisher exact test (the latter when expected cell counts were <5). Medians were reported with interquartile ranges (IQRs) and were compared with the Wilcoxon rank-sum test. Survival and transplant outcomes at 21 days after study enrollment were classified as TFS (survival without liver transplantation), liver transplantation, or death (2). Outcomes were also determined at 1 and 2 years after study enrollment, but these data were less complete than the 21-day outcome data. Survival rates over time were assessed descriptively at the individual-site level to verify that changes in TFS were not affected by varying accrual of patients from different sites. Treatment utilization and survival and transplant outcomes were analyzed over time annually for trends and were also stratified into two 8-year periods: early (1998 to 2005) and later (2006 to 2013). Trends over time were analyzed using the CochranArmitage test. A significance level of less than 0.05 was used for all comparisons. Role of the Funding Source This study was funded by the National Institutes of Health. The funding source had no direct role in the design, conduct, or reporting of the study. Results Demographic Characteristics and Comorbidities During the 16-year study, 2070 patients (median age, 39.0 years [IQR, 29.0 to 52.0 years]) were enrolled in the ALFSG registry. Over the same interval, there were 660 confirmed ALF screen failures (286 due to failure to meet inclusion criteria, 212 for whom consent could not be obtained, and 162 for other reasons). Among enrolled patients, 69.3% were women and 76.4% were white (Table 1). Patients did not differ in sex, race, or ethnicity between the two 8-year periods but were significantly older and heavier in the later period. Prevalence of hypertension, heart disease, diabetes, psychiatric illness, and substance dependency all increased significantly between the early and later periods, whereas prevalence of renal disease did not. Table 1. Demographic Characteristics, Comorbidities, Clinical Severity, and Causes at Admission Causes and Clinical Severity of ALF The percentage of enrollment as a reflection of the most common causes of ALF did not change during the two 8-year periods. Hepatotoxicity due to APAP accounted for almost half the cases of ALF for the entire 16-year period (Table 1), with the highest annual prevalence (53.0%) occurring in 2013. Unintentional APAP overdoses (those in which patients took excessive medication over several days for such ailments as pain, malaise, or fever [10, 11]) were more common than intentional (suicidal) overdoses. Hepatitis A virus infection was significantly less evident during the later period (9 cases [0.8%]) than the early period (28 cases [2.8%]) (P< 0.001). Hepatic ischemia and autoimmune hepatitis increased modestly, whereas hepatitis B virus infection, drug-induced liver injury, Wilson disease, and BuddChiari syndrome were less frequently noted. Patients entered either the primary or the referral (study) site more rapidly after initial symptom onset in the later period (2.0 days [IQR, 0.0 to 8.0 days]) than the early period (3.0 days [IQR, 1.0 to 14.0 days]) (P< 0.001) (Table 1). However, the corresponding interval between symptom onset and HE onset was 4.0 days in both the early (IQR, 1.0 to 15.0 days) and later (IQR, 1.0 to 12.0 days) periods, and time from onset of jaundice to enrollment also was unchanged (3.0 days in each period [IQRs, 1.0 to 12.0 and 1.0 to 10.0 days, respectively]). Most patients with ALF were severely ill at study enrollment, with nearly 50% having grade 3 or 4 (that is, deep) HE throughout. Biochemical liver test results varied widely but indicated severe illness in most patients (Appendix Table 1). Appendix Table 1. Laboratory Values at Study Enrollment Laboratory Tests fo