Jody Balko

Screening for Wilson Disease in Acute Liver Failure: A Comparison of Currently Available Diagnostic Tests

Acute liver failure (ALF) due to Wilson disease (WD) is invariably fatal without emergency liver transplantation. Therefore, rapid diagnosis of WD should aid prompt transplant listing. To identify the best method for diagnosis of ALF due to WD (ALF‐WD), data and serum were collected from 140 ALF patients (16 with WD), 29 with other chronic liver diseases and 17 with treated chronic WD. Ceruloplasmin (Cp) was measured by both oxidase activity and nephelometry and serum copper levels by atomic absorption spectroscopy. In patients with ALF, a serum Cp <20 mg/dL by the oxidase method provided a diagnostic sensitivity of 21% and specificity of 84% while, by nephelometry, a sensitivity of 56% and specificity of 63%. Serum copper levels exceeded 200 μg/dL in all ALF‐WD patients measured (13/16), but were also elevated in non‐WD ALF. An alkaline phosphatase (AP) to total bilirubin (TB) ratio <4 yielded a sensitivity of 94%, specificity of 96%, and a likelihood ratio of 23 for diagnosing fulminant WD. In addition, an AST:ALT ratio >2.2 yielded a sensitivity of 94%, a specificity of 86%, and a likelihood ratio of 7 for diagnosing fulminant WD. Combining the tests provided a diagnostic sensitivity and specificity of 100%. Conclusion: Conventional WD testing utilizing serum ceruloplasmin and/or serum copper levels are less sensitive and specific in identifying patients with ALF‐WD than other available tests. More readily available laboratory tests including alkaline phosphatase, bilirubin and serum aminotransferases by contrast provides the most rapid and accurate method for diagnosis of ALF due to WD. (HEPATOLOGY 2008.)

Screening for Wilson disease in acute liver failure: A comparison of currently available diagnostic tests Potential conflict of interest: Nothing to report.

Acute liver failure (ALF) due to Wilson disease (WD) is invariably fatal without emergency liver transplantation. Therefore, rapid diagnosis of WD should aid prompt transplant listing. To identify the best method for diagnosis of ALF due to WD (ALF‐WD), data and serum were collected from 140 ALF patients (16 with WD), 29 with other chronic liver diseases and 17 with treated chronic WD. Ceruloplasmin (Cp) was measured by both oxidase activity and nephelometry and serum copper levels by atomic absorption spectroscopy. In patients with ALF, a serum Cp <20 mg/dL by the oxidase method provided a diagnostic sensitivity of 21% and specificity of 84% while, by nephelometry, a sensitivity of 56% and specificity of 63%. Serum copper levels exceeded 200 μg/dL in all ALF‐WD patients measured (13/16), but were also elevated in non‐WD ALF. An alkaline phosphatase (AP) to total bilirubin (TB) ratio <4 yielded a sensitivity of 94%, specificity of 96%, and a likelihood ratio of 23 for diagnosing fulminant WD. In addition, an AST:ALT ratio >2.2 yielded a sensitivity of 94%, a specificity of 86%, and a likelihood ratio of 7 for diagnosing fulminant WD. Combining the tests provided a diagnostic sensitivity and specificity of 100%. Conclusion: Conventional WD testing utilizing serum ceruloplasmin and/or serum copper levels are less sensitive and specific in identifying patients with ALF‐WD than other available tests. More readily available laboratory tests including alkaline phosphatase, bilirubin and serum aminotransferases by contrast provides the most rapid and accurate method for diagnosis of ALF due to WD. (HEPATOLOGY 2008.)

Association of cystatin C with left ventricular structure and function: The Dallas Heart Study

Background—Cystatin C, a novel marker of renal function, has been associated with heart failure and cardiovascular mortality in older individuals. We tested the hypothesis that cystatin C is associated with preclinical cardiac structural and functional abnormalities in a younger population-based sample. Methods and Results—The study included participants in the Dallas Heart Study (ages 30 to 65 years) who had measurements of cystatin C and cardiac MRI. The associations of cystatin C with left ventricular (LV) mass, LV end-systolic and -diastolic volumes, concentricity (LV mass/LV end-diastolic volume), LV wall thickness, and LV ejection fraction were evaluated. Cystatin C levels ranged from 0.46 to 6.55 mg/L. In univariable analyses, increasing levels of cystatin C correlated with higher LV mass, concentricity, and wall thickness (P<0.001), but not with LV end-systolic volume, LV end-diastolic volume, or LV ejection fraction. After adjustment with traditional covariates and estimated glomerular filtration rate by the modification of diet in renal disease formula, log-transformed cystatin C remained independently associated with LV mass (P<0.001), concentricity (P=0.027), and wall thickness (P<0.001). These associations persisted when creatinine or estimated glomerular filtration rate by the Cockcroft-Gault formula were included in the models. Conclusions—Higher levels of cystatin C were associated with increased LV mass and a concentric LV hypertrophy phenotype. These findings were independent of potential confounding variables including standard measurements of renal function, supporting the hypothesis that cystatin C may be useful to identify individuals with preclinical structural heart abnormalities.

Plasma concentration of Gc-globulin is associated with organ dysfunction and sepsis after injury.

ObjectiveClinical and experimental studies suggest that the proteins of the extracellular actin scavenger system have a role in the pathophysiological processes taking place in critically ill and injured patients. Circulating levels of Gc-globulin and gelsolin are reduced shortly after severe trauma, and admission levels of Gc-globulin are associated with survival. Herein, we sought to measure the association between admission levels of Gc-globulin and postinjury organ dysfunction and infection. We also wanted to describe the serial changes in Gc-globulin in these severely injured patients. DesignProspective cohort. SettingIntensive care unit at a county hospital that serves as a level one trauma center. PatientsNinety-eight consecutive trauma victims admitted to the intensive care unit for >24 hrs during a 4-month period. Measurements and Main ResultsCirculating levels of Gc-globulin were measured by using immunonephelometry. All patients were evaluated daily to obtain the necessary data for assessment of organ dysfunction and sepsis. The median Gc-globulin concentration at admission was 127 mg/L in patients who developed severe multiple organ dysfunction compared with 184 mg/L in patients who did not (p = .001). The admission level of Gc-globulin was comparable to known risk factors such as age and injury severity score, regarding development of organ dysfunction. Plasma concentrations of Gc-globulin remained significantly lower in patients who developed respiratory failure and sepsis, compared with patients who did not develop these complications (p = .02 and p = .015, respectively). ConclusionsAdmission plasma concentration of Gc-globulin is lower in patients who develop organ dysfunction and sepsis after traumatic injury. These data, combined with the work of others, support the hypothesis that actin release and depletion of the extracellular actin scavenger system proteins are associated with, and may contribute in part to, the complications of sepsis and organ dysfunction, particularly respiratory failure and thrombocytopenia.

Vitamin D binding protein is a key determinant of 25-hydroxyvitamin D levels in infants and toddlers.

Circulating 25‐hydroxyvitamin D (25‐OHD) levels vary among human populations. Only limited information regarding determinants of these measures is available for infants and children, particularly in minority groups at greatest risk for vitamin D deficiency. We identified demographic determinants of circulating 25‐OHD in a large cohort of minority children, and now extend our studies to examine potential roles of vitamin D binding protein (DBP) as a determinant of 25‐OHD levels. Serum DBP level and common single nucleotide polymorphisms (SNPs) at positions 432 and 436 in the GC gene, encoding DBP, were examined. We confirmed self‐reported ancestry using ancestry informative markers (AIMs), and included quantitative AIMs scores in the analysis. The multivariate model incorporated previously identified demographic and nutritional determinants of 25‐OHD in this cohort, as well as GC SNPs and circulating DBP. Genetic variants in GC differed by self‐reported ancestry. The 1f allele (D432/T436) was enriched in African Americans, occurring in 71%. Homozygosity for the 1f allele (DDTT) occurred in 53% of African Americans but only 6% of Caucasians and 13% of Hispanics. Circulating DBP was significantly correlated with 25‐OHD. GC SNPs were associated with both circulating DBP and 25‐OHD. It appears that progressive substitution of lysine for threonine at the 436 position results in lower circulating 25‐OHD. Multivariate analysis revealed that genetic variance in GC significantly contributes to circulating DBP as well as 25‐OHD. Moreover, the effect of GC SNPs on 25‐OHD are evident after adjusting for their effects on circulating DBP. Thus in young children genetic variance of the common GC T436K SNP affects circulating levels of the DBP protein, which in turn affects circulating 25‐OHD. However, the GC genotype also affects circulating 25‐OHD independently of its effect on circulating DBP. These findings provide data that may be important in the interpretation of vitamin D status in children of varying ancestral backgrounds.

Association of Cystatin C With Left Ventricular Structure and FunctionCLINICAL PERSPECTIVE

Background—Cystatin C, a novel marker of renal function, has been associated with heart failure and cardiovascular mortality in older individuals. We tested the hypothesis that cystatin C is associated with preclinical cardiac structural and functional abnormalities in a younger population-based sample. Methods and Results—The study included participants in the Dallas Heart Study (ages 30 to 65 years) who had measurements of cystatin C and cardiac MRI. The associations of cystatin C with left ventricular (LV) mass, LV end-systolic and -diastolic volumes, concentricity (LV mass/LV end-diastolic volume), LV wall thickness, and LV ejection fraction were evaluated. Cystatin C levels ranged from 0.46 to 6.55 mg/L. In univariable analyses, increasing levels of cystatin C correlated with higher LV mass, concentricity, and wall thickness (P<0.001), but not with LV end-systolic volume, LV end-diastolic volume, or LV ejection fraction. After adjustment with traditional covariates and estimated glomerular filtration rate by the modification of diet in renal disease formula, log-transformed cystatin C remained independently associated with LV mass (P<0.001), concentricity (P=0.027), and wall thickness (P<0.001). These associations persisted when creatinine or estimated glomerular filtration rate by the Cockcroft-Gault formula were included in the models. Conclusions—Higher levels of cystatin C were associated with increased LV mass and a concentric LV hypertrophy phenotype. These findings were independent of potential confounding variables including standard measurements of renal function, supporting the hypothesis that cystatin C may be useful to identify individuals with preclinical structural heart abnormalities.

Hepatitis B virus genotype G: Prevalence and impact in patients co‐infected with human immunodeficiency virus

Relatively little is known about the role of hepatitis B virus (HBV) genotype G (HBV/G) in patients co‐infected with human immunodeficiency virus (HIV) and HBV. This study examined the prevalence and association of HBV/G to liver fibrosis in co‐infected patients. HBV genotypes were determined by direct sequencing of the HBV surface gene or Trugene® HBV 1.0 assay in 133 patients infected with HIV/HBV. Quantitative testing of HBV‐DNA, HBeAg, and anti‐HBe were performed using the Versant® HBV 3.0 (for DNA) and the ADVIA®Centaur assay. The non‐invasive biomarkers Fib‐4 and APRI were used to assess fibrosis stage. Genotype A was present in 103/133 (77%) of the cohort, genotype G in 18/133 (14%) with genotypes D in 8/133, (6%), F 2/133 (1.5%), and H 2/133 (1.5%). Genotype G was associated with hepatitis B e antigen‐positivity and high HBV‐DNA levels. Additionally, HBV/G (OR 8.25, 95% CI 2.3–29.6, P = 0.0012) was associated with advanced fibrosis score using Fib‐4, whereas, being black was not (OR 0.19, 95% CI 0.05–0.07, P = 0.01). HBV/G in this population exhibited a different phenotype than expected for pure G genotypes raising the question of recombination or mixed infections. The frequent finding of HBV/G in co‐infected patients and its association with more advanced fibrosis, suggests that this genotype leads to more rapid liver disease progression. Further studies are needed to understand why this genotype occurs more frequently and what impact it has on liver disease progression in patients with HBV/HIV. J. Med. Virol. 83:1551–1558, 2011.

Intraoperative vs Central Laboratory PTH Testing During Parathyroidectomy Surgery

Intact parathyroid hormone (PTH) testing can be performed rapidly, directly in the operating room, using the QuiCK-Pak System (Nichols Institute Diagnostics, San Juan Capistrano, CA) or in a central laboratory using the IMMULITE Immunoassay System and Turbo PTH assay (Diagnostic Products, Los Angeles, CA). Correlation between parathyroid hormone values obtained on EDTA plasma samples using these systems was good (r = 0.84); at 20-minutes after excision of a suspected hyperfunctioning parathyroid gland, diagnostic agreement between the two systems was 100%. Based on 50 parathyroid gland surgeries for each of a 3-year contract period, the cost of intraoperative vs central laboratory PTH testing per surgery was

Two distinct subtypes of hepatitis B virus–related acute liver failure are separable by quantitative serum immunoglobulin M anti‐hepatitis B core antibody and hepatitis B virus DNA levels

760 and

Performance evaluation of the new ADVIA® Centaur system cyclosporine assay (single-step extraction)

360, respectively. Intraoperative parathyroid hormone testing using the QuiCK-Pak System provides faster, more reliable turnaround time for intraoperative PTH results and has other advantages over central laboratory PTH testing during parathyroid gland surgery.