College of American Pathologists
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  Clinical Abstracts





December 2008

Michael Bissell, MD, PhD, MPH

Predictive value of serum sodium in cirrhosis patients awaiting liver transplant
Classification of CHF in end-stage renal disease
Different modes of thrombin inhibition for unfraction­ated heparin and bivalirudin
Association between C-reactive protein, fatty liver disease, and cardiac risk
Expansion of adipose tissue relative to insulin resistance

Predictive value of serum sodium in cirrhosis patients awaiting liver transplant Predictive value of serum sodium in cirrhosis patients awaiting liver transplant

The model for end-stage liver disease (MELD) score is the most widely used method for allocating organs in liver transplantation. The model, which includes variables related to liver and renal function, was implemented in the United States in 2002 and is being used in many countries to classify cirrhosis patients awaiting transplantation based on the severity of their liver disease. Nevertheless, several studies, as well as clinical observation, indicate that some subsets of patients with cirrhosis may have high mortality despite low MELD scores. Therefore, it is necessary to improve the MELD score. To this end, several studies have shown that serum sodium concentration is a good marker of prognosis for patients awaiting transplantation. Based on the results of these studies, serum sodium has been recommended for assessing the severity of cirrhosis. However, several issues surround the use of serum sodium as a predictor of prognosis. They are whether the value of serum sodium is equally effective in assessing short-term prognosis (three months) compared with mid-term prognosis (12 months); whether serum sodium is equally accurate in predicting prognosis in different subpopulations of patients with cirrhosis; and whether serum sodium improves the accuracy of the MELD score. The authors conducted a study to investigate these issues. The study included 308 consecutive patients with cirrhosis listed for transplantation during a five-year period. The end-point was survival at three and 12 months before transplantation. Variables obtained when being listed for transplantation were analyzed for prognostic value using multivariable analysis. Accuracy of prognostic variables was analyzed by receiver operating characteristic (ROC) curves. The authors found that the MELD score and serum sodium concentration were the only independent predictors of survival at three and 12 months after being listed. Low serum sodium was associated with an increased risk of death in all subpopulations of patients with cirrhosis categorized according to the major complication that developed before being listed. The area under the ROC curves for serum sodium and MELD score was not significantly different at three months (0.83 versus 0.79, respectively) and 12 months (0.70 versus 0.77, respectively). Adding serum sodium did not significantly improve the accuracy of the MELD score in predicting survival at three and 12 months. The authors concluded that in patients with cirrhosis awaiting liver transplantation, serum sodium and MELD were found to be independent predictors of survival. Larger studies are needed to determine whether adding serum sodium to MELD can improve its prognostic accuracy.

Londono M-C, Cardenas A, Guevara M, et al. MELD score and serum sodium in the prediction of survival of patients with cirrhosis awaiting liver transplantation. Gut. 2007;56:1283–1290.

Correspondence: Dr. Pere Gines at
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Classification of CHF in end-stage renal disease Classification of CHF in end-stage renal disease

Heart failure contributes substantially to adverse outcomes in the dialysis population. Clinically defined heart failure is remarkably similar across studies in end-stage renal disease (ESRD) patients. It was 31 percent in the dialysis cohort studied by Foley and Parfrey in Newfoundland and 36 percent in the Wave 2 study of the U.S. Renal Data System Dialysis Morbidity and Mortality Study by Stack. The New York Heart Association (NYHA) classification is the instrument most used to grade the severity of heart failure in the general population and represents an accepted standard worldwide. But while the classification is popular in cardiology, it rarely has been used to grade the severity of heart failure in dialysis patients. To the authors’ knowledge, there is no pro­spective study testing the predictive value of this instrument in ESRD. Relevance is the issue because the fre­quency of heart failure in ESRD patients is about one order of mag­nitude higher than in the general population. In a 2002 exploratory analysis based on a prevalent cohort of dialysis patients, the authors demonstrated that a slightly modified NYHA classification is an independent predictor of death. In the study, they tested the predictive value of the NYHA classification in patients with ESRD and compared it with that of two established indexes of disease severity—that is, the Khan index and the renal disease severity score (RDSS). The study cohort was composed of 1,322 incident patients in a dialysis registry (772 male and 550 female, ages 61±16 years). During the follow-up period (41±27 months), 551 patients died. A multivariate Cox model including the NYHA classification explained 39 percent of the variation in mortality, a figure almost identical to that of a model based on the RDSS (37 percent) and superior (P<.001) to that provided by the Khan index-based model (32 percent). The area under the receiver operating characteristic curve of NYHA classification, as related to all-cause mortality, was 0.74 (95 percent confidence interval [CI], 0.71–0.77; P<.001). Again, RDSS had a predictive value for mortality (0.74; 95 percent CI, 0.72–0.77) identical to that of the NYHA classification and higher than that of the Khan index (0.70; 95 percent CI, 0.67–0.72). The authors concluded that the NYHA classification is a powerful predictor of mortality in ESRD and provides prognostic information equal to or superior to that given by other established indexes of disease severity. Given the pervasive nature of cardiovascular disease in ESRD, this classification may be recommended to stratify risk in this population.

Postorino M, Marino C, Tripepi G, et al. Prognostic value of the New York Heart Association classification in end-stage renal disease. Nephrol Dial Transplant. 2007;22:1377–1382.

Correspondence: Carmine Zoccali at
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Different modes of thrombin inhibition for unfraction­ated heparin and bivalirudin Different modes of thrombin inhibition for unfraction­ated heparin and bivalirudin

Anticoagulation is often required perioperatively for cardiovascular procedures or to prevent thrombotic complications. Anticoagulation has been achieved conventionally with unfractionated heparin because of its ease of use and reversibility. Bivalirudin (Angiomax, formerly Hirulog-1) is a polypeptide direct thrombin inhibitor with a half-life of approximately 25 minutes. It’s used for patients with heparin-induced thrombocytopenia and for percutaneous coronary artery interventions. In contrast to heparin, which promotes antithrombin catalyzed inhibition of thrombin and factor Xa, bivalirudin directly inhibits thrombin but not factor Xa. Activated partial thromboplastin time (APTT) and activated clotting time (ACT) assays are commonly used to monitor anticoagulation. Both tests are terminated when fibrin gel formation occurs as a result of the production of trace amounts of thrombin (2 to 5 nM; less than five percent of total thrombin generated). Therefore, the results of APTT and ACT may not reflect the extent of thrombin inhibition by anticoagulants because the majority (approximately 95 percent) of thrombin generation—that is, propagation phase—takes place on the formed thrombus surface after the testing has stopped. The authors hypothesized that differences in the kinetics of thrombin generation and thrombus formation in the presence of either drug could only be detected by tests that were performed after the initial fibrin gel formation. Therefore, they conducted a study to determine if similar increases in APTT or ACT due to heparin or bivalirudin would reflect the same degree of inhibition of thrombin formation. The authors evaluated thrombin formation in platelet-poor plasma activated in the presence of heparin (0 to 5 U/mL) or bivalirudin (0 to 30 µg/mL) using a thrombin-generation assay (Thrombinoscope). Prothrombin activation was measured by prothrombin fragment 1.2 (F1.2) formation. Thrombus formation was further evaluated in kaolin-activated whole blood samples containing heparin (1.5 or 2.5 U/mL) or bivalirudin (12.5 or 2.5 µg/mL) using Sonoclot and thromboelastography. The authors found, based on the Thrombinoscope results, that increasing concentrations of bivalirudin and heparin progressively delayed the onset of thrombin formation, but only heparin dose-dependently decreased the amount of thrombin generated. Heparin and bivalirudin delayed the onset of F1.2 formation, but there was no difference in peak F1.2 levels between bivalirudin and non-anticoagulated samples (206±28.2 versus 182±23.9 nmol/L; P=.09). In heparinized samples, F1.2 levels were significantly lower (75.7±29.8 nmol/L; P<.05) than in controls. Heparin and bivalirudin prolonged the onset of clotting on viscoelastic monitors, but only heparin decreased the rate of thrombus formation. The authors concluded that thrombus formation kinetics differ between heparin and bivalirudin, despite clotting test values being prolonged for a similar length of time.

Tanaka K, Szlam F, Sun HY, et al. Thrombin generation assay and viscoelastic coagulation monitors demonstrate differences in the mode of thrombin inhibition between unfractionated heparin and bivalirudin. Anesth Analg. 2007;105:933–939.

Correspondence: Dr. Kenichi A. Tanaka at
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Association between C-reactive protein, fatty liver disease, and cardiac risk Association between C-reactive protein, fatty liver disease, and cardiac risk

Nonalcoholic fatty liver disease is an increasingly recognized condition that may progress to end-stage liver disease. The pathology resembles that of alcohol-induced liver injury, but it can occur in patients who do not abuse alcohol. Nonalcoholic fatty liver disease (NAFLD) refers to a wide spectrum of liver damage, ranging from simple steatosis to steatohepa­titis, advanced fibrosis, and cirrhosis. NAFLD can be found in 10 percent to 24 percent of the general population, and it is increased 4.6-fold in obese people. Other risk factors associated with NAFLD are waist circumference (greater than 102 cm in males and greater than 88 cm in females), hyperinsulinemia, hypertriglyceridemia, and impaired glucose tolerance or type 2 diabetes. NAFLD is clinically significant because of its general prevalence in the population and its potential to progress to fibrosis, cirrhosis, and liver failure. Several studies have demonstrated that the constellation of metabolic disturbances observed in people with NAFLD increases the risk of cardiovascular disease considerably. Ultrasensitive C-reactive protein (uCRP), a marker of coronary heart disease and other chronic diseases, has not been investigated in NAFLD. The authors tested the relationship between uCRP and NAFLD in middle-aged asymptomatic subjects independently of other metabolic disturbances associated with metabolic syndrome and cardiovascular risk. They compared 310 subjects with steatosis visible on ultrasound (cases) with 630 without (controls). Body mass index, blood pressure, and serum levels of uCRP, glucose, lipids, and lipoproteins were measured in all subjects. Differences between groups and the impact of serum uCRP levels were tested by univariate and multivariate logistic regression analysis. Cases differed statistically from controls relative to frequency of metabolic syndrome (66.4 percent versus 26.7 percent; P<.001). Cases were significantly older (P<.001) and had significantly higher values for body mass index, glucose, total cholesterol and triglycerides (P<.001), and mean uCRP concentrations (4.5 versus 2.79 mg/L; P<.001). By univariate analysis, variables significantly associated with cases were glucose (odds ratio, 4.09; 95 percent confidence interval [CI], 2.98–5.61), body mass index (odds ratio, 5.54; 95 percent CI, 4.09–7.49), and uCRP (odds ratio, 7.06; 95 percent CI, 4.51–11.02). By multivariate analysis, uCRP levels were associated with hepatic steatosis (odds ratio, 5.83; 95 percent CI, 3.07–11.06). Cardiovascular risk was also higher in subjects with NAFLD (4.7 versus 2.8). Subjects with hepatic steatosis showed an increased concentration of uCRP independently of other metabolic disturbances. This suggests an increased risk of cardiovascular diseases and could be used as a marker of chronic inflammation.

Lizardi-Cervera J, Chavez-Tapia NC, Perez-Bautista O, et al. Association among C-reactive protein, fatty liver disease, and cardiovascular risk. Dig Dis Sci. 2007;52:2375–2379.

Correspondence: J. Lizardi-Cervera at
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Expansion of adipose tissue relative to insulin resistance Expansion of adipose tissue relative to insulin resistance

Adipose tissue plays a central role in managing systemic energy stores as well as in many other processes. This is due, in part, to its capacity to store triglycerides but is also a function of its ability to secrete many proteins that influence energy homeostasis. A dysregulation of both processes leads to profound changes in insulin sensitivity at the level of the whole organism. Mice lacking specific adipocyte-derived secretory proteins, such as leptin, adiponectin, and resistin, have metabolic phenotypes. On the other hand, mice lacking adipocytes altogether also display profound changes. Studies of several lipoatrophic models have been published. Excess caloric intake can lead to insulin resistance. The underlying reasons are complex but likely are related to ectopic lipid deposition in nonadipose tissue. The authors hypothesized that the inability to appropriately expand subcutaneous adipose tissue may be an underlying reason for insulin resistance and β cell failure. Mice lacking leptin while overexpressing adiponectin showed normalized glucose and insulin levels and dramatically improved glucose as well as improved serum triglyceride levels. Therefore, modestly increasing the levels of circulating full-length adiponectin rescued the diabetic phenotype in ob/ob mice. The mice displayed increased expression of PPARy target genes and reduced macrophage infiltration in adipose tissue and systemic inflammation. As a result, the transgenic mice were morbidly obese, with significantly higher levels of adipose tissue than their ob/ob littermates, leading to a dichotomy of increased fat mass associated with improved insulin sensitivity. Based on these data, the authors proposed that adiponectin acts as a peripheral “starvation” signal, promoting the storage of triglycerides preferentially in adipose tissue. As a consequence, reduced triglyceride levels in the liver and muscle convey improved systemic insulin sensitivity. The authors concluded that these mice represent a novel model of morbid obesity associated with an improved metabolic profile.

Kim J-Y, Van de Wall E, Laplante M, et al. Obesity-associated improvements in metabolic profile through expansion of adipose tissue. J Clin Invest. 2007;117:2621–2637.

Correspondence: Philipp E. Scherer at
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Dr. Bissell is Professor and Director of Clinical Services and Vice Chair, Department of Pathology, Ohio State University Medical Center, Columbus.