Biomedical subjects
Arun J Sanyal
Publications and source records attributed to Arun J Sanyal.
MELD-XI: a rational approach to "sickest first" liver transplantation in cirrhotic patients requiring anticoagulant therapy.
Priority for "sickest first" liver transplantation (LT) in the United States is determined by the model for end-stage liver disease (MELD). MELD is a good predictor of short-term mortality in cirrhosis, but it can overestimate risk when international normalized ratio (INR) is artificially elevated by anticoagulation. An alternate prognostic index omitting INR is needed in this situation. We retrospectively analyzed survival data for 554 cirrhotic veterans referred for consideration of LT prior to December 1, 2003 (training group). Using logistic regression we derived a predictive formula for 90-day pretransplant mortality incorporating bilirubin and creatinine but omitting INR. We normalized this formula to the same scale as MELD using linear regression. This yielded MELD-XI (for MELD excluding INR) = 5.11 Ln(bilirubin) + 11.76 Ln(creatinine) + 9.44. Accuracy of MELD-XI was validated in a holdout group of 278 cirrhotic veterans referred after December 1, 2003, and in an independent validation dataset of 7,203 cirrhotic adults listed for LT in the United States between May 1, 2001, and October 31, 2001. MELD-XI and MELD correlated well in training, holdout, and independent validation cohorts (r = 0.930, 0.954, and 0.902, respectively). In the holdout cohort, c-statistics of MELD vs. MELD-XI for mortality were, respectively, 0.939 vs. 0.906 at 30 days;0.860 vs. 0.841 at 60 days; 0.842 vs. 0.829 at 90 days; and 0.795 vs. 0.797 at 180 days. In the independent validation dataset, c-statistics for MELD vs. MELD-XI as predictors of 90-day survival were, respectively, 0.857 vs. 0.843 in noncholestatic liver diseases and 0.905 vs. 0.894 in cholestatic liver diseases. Comparable MELD and MELD-XI scores were associated with comparable prognosis. In conclusion, MELD-XI, despite omission of INR, is nearly as accurate as MELD in predicting short-term survival in cirrhosis. In patients treated with oral anticoagulants, substitution of MELD-XI for MELD may permit more accurate assessment of risk and more rational assignment of "sickest first" priority for LT.
Similarities and differences in outcomes of cirrhosis due to nonalcoholic steatohepatitis and hepatitis C.
The objective of this study was to prospectively define outcomes of cirrhosis due to nonalcoholic steatohepatitis (NASH) and compare them with those associated with hepatitis C virus (HCV) infection. We compared 152 patients with cirrhosis due to NASH with 150 matched patients with cirrhosis due to HCV. Over 10 years, 29/152 patients with cirrhosis due to NASH died compared with 44/150 patients with HCV (P < .04). This was mainly due to the lower mortality rate in patients with Child class A cirrhosis due to NASH versus HCV (3/74 vs. 15/75; P < .004). There were no significant across-group differences in mortality in patients with Child class B or C cirrhosis. Sepsis was the most common cause of death in both groups; patients with NASH had a higher cardiac mortality (8/152 vs. 1/150; P < .03). Patients with Child class A cirrhosis due to NASH also had a significantly lower risk of decompensation, defined by a 2-point increase in Child-Turcotte-Pugh score (P < .007). Cirrhosis due to NASH was associated with a lower rate of development of ascites (14/101 vs. 40/97 patients at risk; P < .006). NASH also had a significantly lower risk of development of hepatocellular carcinoma (10/149 vs. 25/147 patients at risk; P < .01). In conclusion, compensated cirrhosis due to NASH is associated with a lower mortality rate compared with that due to HCV. It is also associated with a lower rate of development of ascites, hyperbilirubinemia, and hepatocellular carcinoma. However, cardiovascular mortality is greater in patients with NASH.
Coagulation disorders and hemostasis in liver disease: pathophysiology and critical assessment of current management.
Normal coagulation has classically been conceptualized as a Y-shaped pathway, with distinct "intrinsic" and "extrinsic" components initiated by factor XII or factor VIIa/tissue factor, respectively, and converging in a "common" pathway at the level of the FXa/FVa (prothrombinase) complex. Until recently, the lack of an established alternative concept of hemostasis has meant that most physicians view the "cascade" as a model of physiology. This view has been reinforced by the fact that screening coagulation tests (APTT, prothrombin time--INR) are often used as though they are generally predictive of clinical bleeding. The shortcomings of this older model of normal coagulation are nowhere more apparent than in its clinical application to the complex coagulation disorders of acute and chronic liver disease. In this condition, the clotting cascade is heavily influenced by numerous currents and counter-currents resulting in a mixture of pro- and anticoagulant forces that are themselves further subject to change with altered physiological stress such as super-imposed infection or renal failure. This report represents a summary of a recent multidisciplinary symposium held in Charlottesville, VA. We present an overview of the coagulation system in liver disease with emphasis on the limitations of the current clinical paradigm and the need for a critical re-evaluation of the current tenets governing clinical practice. With the realization that there is often limited or conflicting data, we have attempted to represent diverse opinion and experience from the perspectives of both hepatology and hematology beginning with a brief update on the physiology of normal coagulation.
Role of obesity, insulin resistance, and steatosis in hepatitis C virus infection.
Hepatitis C, nonalcoholic fatty liver characterized by hepatic steatosis, and obesity inflict significant health and economic burdens on the Western world. Insulin resistance is the key player in these disease processes. Complex interplay between these conditions results in the ultimate phenotype of liver disease. This article focuses on the current understanding of host and viral interactions as well as on consequent clinical implications.
The prevalence and risk factors associated with esophageal varices in subjects with hepatitis C and advanced fibrosis.
BACKGROUND: The factors predictive of the presence or the absence of esophageal varices in hepatitis C virus (HCV) and advanced fibrosis have not been defined. OBJECTIVES: To define the prevalence of esophageal varices and the factors that are positively and negatively with such varices in hepatitis C and advanced fibrosis. DESIGN: A prospective study of esophageal varices and associated risk factors in subjects with hepatitis C and advanced fibrosis. SETTING: Prerandomization data from the HALT-C (hepatitis C long-term antiviral treatment against cirrhosis) clinical trial. PATIENTS AND INTERVENTION: Subjects with bridging fibrosis or cirrhosis, who were virologic nonresponders to treatment with pegylated interferon alpha 2a and ribavirin, underwent endoscopy. RESULTS: Sixteen percent of subjects with bridging fibrosis (95/598) and 39% of subjects with cirrhosis (164/418) had varices (P < .0001); 2% of subjects with bridging fibrosis (13/598) and 11% of those with cirrhosis (48/418) had medium or large varices. Subjects with bridging fibrosis and varices had a significantly lower platelet count and higher bilirubin and international normalized ratio (INR) compared with those without varices, suggesting that the biopsy may have underestimated the severity of fibrosis. A platelet count >150,000/mm(3) was associated with a negative predictive value of 99% for esophageal varices. By logistic regression modeling, African American race and female sex were protective, whereas a lower platelet count and higher bilirubin and INR predicted varices (c statistic, 0.758). CONCLUSIONS: The risk of having varices increases with decreasing platelet counts, increasing bilirubin, and INR. The probability of having medium or large varices at platelet counts >150,000/mm(3) is negligible in this population.
Physiologic concentrations of leptin increase collagen production by non-immortalized human hepatic stellate cells.
The effects of leptin, in concentrations seen in obesity, on collagen production and turnover in non-immortalized human hepatic stellate cell (HSC), were unknown. The profibrogenic effects of leptin in these cells were studied. Hepatic stellate cells were obtained from resected livers. Collagen I/III gene expression and protein production were measured by quantitative real-time polymerase chain reaction and sodium dodecyl sulfate-polyacrylamide gel electrophoresis, respectively. The signal transduction pathways involved were evaluated by specific blockers of the phosphatidylinositol 3-kinase (PI3K), mitogen-activated protein kinase kinase (MEK), and Janus kinase 2 (JAK2). The effects on matrix metalloproteinase 1 (MMP-1) and tissue inhibitor of metalloproteinase 1 (TIMP-1) were assessed by their gene transcript levels, collagenolytic activity of cell culture supernatants, and MMP-1 protein levels. At concentrations seen in nonobese individuals ([leptin] < 10 ng/mL), leptin did not affect collagen production. At concentrations seen in obesity (30-50 ng/mL), leptin increased collagen I and III messenger RNA (mRNA) transcript levels by 286% +/- 55% (P < .001) and 167% +/- 62% (P < .007) and protein production by 45.8% +/- .02% and 84.39% +/- .01%, respectively. These effects were blocked by JAK2 inhibition as well as PI3K inhibition. Although MEK inhibition blocked leptin-induced procollagen I and III mRNA levels, there were no significant effects on collagen I and III protein levels. Leptin (10-50 ng/mL) had no significant effects on MMP-1 or TIMP-1 mRNA levels, collagenolytic activity, or MMP-1 protein levels. In conclusion, leptin, at levels seen in obese individuals, produces an increase in collagen production by HSC acting through the JAK and PI3K pathways. At these concentrations, leptin does not affect MMP-1 or TIMP-1 expression or collagenolytic activity of HSC.
Portal hypertensive gastropathy in chronic hepatitis C patients with bridging fibrosis and compensated cirrhosis: results from the HALT-C trial.
OBJECTIVES: The clinical significance of portal hypertensive gastropathy (PHG) in patients with compensated liver disease is not well established. The aim of this study was to determine the prevalence and correlates of PHG in a large cohort of patients with chronic hepatitis C virus (HCV) infection and bridging fibrosis/compensated cirrhosis entering the randomized phase of the Hepatitis C Antiviral Long-term Treatment against Cirrhosis trial (HALT-C). METHODS: The presence and severity of PHG in 1,016 HCV patients with no prior history of gastrointestinal bleeding was determined at surveillance endoscopy using the New Italian Endoscopy Club criteria. RESULTS: Overall, 37% of HALT-C patients had PHG with 34% having mild and 3% with severe changes. The mucosal mosaic pattern was identified in 33%, red marks in 15%, and gastric antral vascular ectasia (GAVE) features in only 3%. Independent correlates of PHG included biochemical markers of liver disease severity (lower serum albumin, higher bilirubin), portal hypertension (lower platelet count), insulin resistance (higher glucose), and non-African American race. Independent correlates of GAVE included a history of smoking, nonsteroidal anti-inflammatory drugs (NSAIDs) use within the past year, and higher serum bilirubin and glucose levels. There was a strong positive association between the presence of PHG and esophageal varices (p < 0.0001). CONCLUSIONS: PHG is associated with the histological and biochemical severity of liver disease in patients with HCV and advanced fibrosis but is mild in most patients. The clinical relevance of these findings will be further explored during the randomized phase of the HALT-C study.
Design and validation of a histological scoring system for nonalcoholic fatty liver disease.
Nonalcoholic fatty liver disease (NAFLD) is characterized by hepatic steatosis in the absence of a history of significant alcohol use or other known liver disease. Nonalcoholic steatohepatitis (NASH) is the progressive form of NAFLD. The Pathology Committee of the NASH Clinical Research Network designed and validated a histological feature scoring system that addresses the full spectrum of lesions of NAFLD and proposed a NAFLD activity score (NAS) for use in clinical trials. The scoring system comprised 14 histological features, 4 of which were evaluated semi-quantitatively: steatosis (0-3), lobular inflammation (0-2), hepatocellular ballooning (0-2), and fibrosis (0-4). Another nine features were recorded as present or absent. An anonymized study set of 50 cases (32 from adult hepatology services, 18 from pediatric hepatology services) was assembled, coded, and circulated. For the validation study, agreement on scoring and a diagnostic categorization ("NASH," "borderline," or "not NASH") were evaluated by using weighted kappa statistics. Inter-rater agreement on adult cases was: 0.84 for fibrosis, 0.79 for steatosis, 0.56 for injury, and 0.45 for lobular inflammation. Agreement on diagnostic category was 0.61. Using multiple logistic regression, five features were independently associated with the diagnosis of NASH in adult biopsies: steatosis (P = .009), hepatocellular ballooning (P = .0001), lobular inflammation (P = .0001), fibrosis (P = .0001), and the absence of lipogranulomas (P = .001). The proposed NAS is the unweighted sum of steatosis, lobular inflammation, and hepatocellular ballooning scores. In conclusion, we present a strong scoring system and NAS for NAFLD and NASH with reasonable inter-rater reproducibility that should be useful for studies of both adults and children with any degree of NAFLD. NAS of > or =5 correlated with a diagnosis of NASH, and biopsies with scores of less than 3 were diagnosed as "not NASH."
Quality of life in refractory ascites: transjugular intrahepatic portal-systemic shunting versus medical therapy.
Uncontrolled studies suggest that transjugular intrahepatic portal-systemic shunting (TIPS) may improve quality of life in patients with refractory ascites. We hypothesized that any improvement of quality of life in patients with TIPS would be matched in controls due to the competing effects of improved ascites and worsened hepatic encephalopathy. Thus, an analysis of quality of life was performed using original data from the North American Study for the Treatment of Refractory Ascites, a multicenter trial of 109 patients randomized to TIPS or repeated large volume paracentesis (LVP) for refractory ascites. Short form 36 (SF-36) surveys were completed at baseline and at 6- and 12-month follow-up. Variables analyzed were: randomization group, number of LVP performed, cumulative volume from LVP, shortness of breath, abdominal distention, abdominal pain, diuretic usage, confusion, hospitalizations, and emergency room visits. Outcomes were changes in physical component scale (PCS) and mental component scale (MCS) of SF-36 results. We constructed multivariable, mixed effects models, including randomization group and baseline MCS and PCS. Changes in PCS and MCS from baseline were similar between the two randomization groups. In multivariate analysis, PCS improvement was associated with lack of confusion, improved ascites, and lack of hospitalizations, but not directly with randomization group. Improvement in MCS was associated with randomization to TIPS and lack of confusion. In conclusion, patients with refractory ascites randomized to TIPS or repeated LVP had similar changes in quality of life. Competing effects of hepatic encephalopathy, requirement for repeated LVP, and need for hospitalizations explain similar changes in quality of life between the two groups.
Hepatorenal syndrome.
Hepatorenal syndrome (HRS) is defined as functional renal failure that develops in patients with advanced liver disease. HRS may be either slowly or rapidly progressive (type I and II HRS, respectively). Untreated HRS carries a high mortality. Liver transplantation is the best available treatment for HRS. However, all patients with HRS are not suitable candidates for transplantation. Moreover, an organ is often not available in a timely manner in those who are candidates for transplantation. Treatment with vasoconstrictors (terlipressin, octreotide, and midodrine) and plasma expansion with albumin is beneficial and serves as a bridge to transplantation in such cases. The vasopressin analog, terlipressin, produces a sustained reversal of HRS in about 57% to 78% of the patients. The benefits of terlipressin are seen mainly in those who are also receiving albumin simultaneously. In those who improve, recurrence of HRS is reported to be relatively uncommon in the short and intermediate term. In the United States, terlipressin is not available, and octreotide and midodrine are often used for the medical management of HRS. Unfortunately, there are only limited uncontrolled data to support the use of these drugs for HRS. In those who respond to octreotide and midodrine, the subsequent placement of a transjugular intrahepatic portasystemic shunt (TIPS) has been shown to produce a sustained improvement in renal function. TIPS alone also improves renal functions in selected patients with HRS. The exact role of TIPS in HRS needs further evaluation, as patients with HRS are particularly at risk for complications such as encephalopathy and liver failure. Molecular adsorbent recirculating system (MARS) is an albumin-based dialysis system that has a promising role in the treatment of HRS and liver failure. MARS is a very expensive form of treatment, and further clinical trials are needed to establish its utility. Development of HRS can be prevented by adding albumin to the antibiotic regimen to treat spontaneous bacterial peritonitis and through pentoxifylline administration to the patients with acute alcoholic hepatitis.
Management of ascites in cirrhosis.
Onset of ascites in cirrhosis of the liver is associated with worsened quality of life, increased risk of spontaneous bacterial peritonitis, and renal failure. Portal hypertension produces splanchnic vasodilation that triggers the cascade of events leading to release of Na retentive vasoconstrictor hormones. Management of ascites caused by cirrhosis is based on improving the Na excretion with diuretics and Na restriction in diet. Refractory ascites and hepatorenal syndrome are the complications of ascites that carry a very high mortality. Large volume paracentesis and transjugular intrahepatic porto-systemic shunts are useful in managing patients with refractory ascites. Liver transplant is the only way to improve survival in ascites caused by cirrhosis.
Mechanisms of Disease: pathogenesis of nonalcoholic fatty liver disease.
Nonalcoholic fatty liver disease (NAFLD) is associated with the metabolic syndrome. The metabolic syndrome is characterized by insulin resistance, which is produced by a complex interaction between genetic factors, macronutrient intake and lifestyle that alters the cytokine profile, cell biology and biochemical milieu of the liver, adipose tissue and striated muscle. The resultant disequilibrium in lipid homeostasis causes triglycerides to accumulate in the liver. An increase in oxidative stress, due to the generation of reactive oxygen species as a result of mitochondrial abnormalities and induction of the cytochrome P-450 system could be one mechanism by which the nonalcoholic fatty liver develops into nonalcoholic steatohepatitis. The pathogenesis of cytologic ballooning and Mallory body formation and their role in NAFLD remain to be defined. In addition, inflammation and fibrosis are likely to be secondary to hepatocyte injury and death.
The spectrum of chronic hepatitis C virus infection in the Virginia Correctional System: development of a strategy for the evaluation and treatment of inmates with HCV.
BACKGROUND AND OBJECTIVE: Chronic hepatitis C virus (HCV) is common in the inmate population of the United States. Long-standing HCV can progress to cirrhosis, which can contribute to significant morbidity and mortality. However, those inmates with histologically mild disease are unlikely to develop liver-related morbidity or mortality during their period of incarceration. Our objective was to develop an economic strategy for evaluation and treatment of inmates with chronic HCV. METHODS AND MEASURES: A retrospective cohort analysis of 302 inmates within the Virginia Department of Corrections (VDOC) who underwent liver biopsy for chronic HCV at the Virginia Commonwealth University Health System between 1998 and 2002 was performed. The data from this analysis was to utilized to develop a cost model for treatment of chronic HCV in this population based upon biochemical or histologic criteria. We used the perspective of the VDOC using actual costs paid to providers, hospitals, and pharmacies. The primary endpoint was cost-effectiveness of HCV treatment. RESULTS: Eighty percent of inmates with chronic HCV were genotype 1, 49% had a normal value for serum ALT at the time of evaluation, 30% had no fibrosis, and 24% had bridging fibrosis or cirrhosis. The cost to evaluate and treat 100 consecutive inmates with peginterferon and ribavirin regardless of serum ALT and liver histology was calculated to be $1,775,900 or $35,500 per sustained virologic response (SVR). Although the cost declined by 50% if only those patients with an elevated serum ALT were treated, 45% of those inmates with varying degrees of fibrosis, and 21% with cirrhosis would not have received therapy utilizing this scenario. In contrast, the cost of performing liver biopsy and treating only those patients with any degree of fibrosis was $1,367,043; a savings of slightly more than $400,000 per 100 patients evaluated. The overall cost of treatment was most influenced by the price of peginterferon and ribavirin, which declined as the histologic criteria utilized for treatment increased. CONCLUSIONS: A strategy in which inmates with chronic HCV are evaluated and a decision regarding treatment is based upon either biochemical or histologic criteria, which appears to balance both the health-care rights of the inmate and the impact of treating this disease on the financial and other resources of the correctional system.
Antibody-mediated pure red cell aplasia due to epoetin alfa during antiviral therapy of chronic hepatitis C.
Anemia frequently complicates the treatment of chronic hepatitis C with interferon and ribavirin (RVN), requiring dose reduction and jeopardizing sustained virologic response. Increasingly, epoetin alfa is used to prevent anemia in this setting. Below, we report the first case of pure red cell aplasia (PRCA) in a patient with chronic hepatitis C who received epoetin alfa (Procrit) to manage anti-viral treatment-induced anemia. Red blood cell transfusion-dependence developed 16 wk after the patient was started on peginterferon alfa-2b and RVN for chronic hepatitis C despite the simultaneous administration of epoetin alfa and subsequent discontinuation of the antiviral medications. Bone marrow biopsy was consistent with PRCA. High-titer erythropoietin antibodies, assayed by two methods, appeared shortly after epoetin alfa was administered, and were associated with a decline in serum erythropoietin to undetectable levels. Erythropoietin antibodies directed toward epoetin alfa were shown to cross react with darbepoetin alfa (Aranesp), and a neutralization assay confirmed that they inhibited cell growth in the presence of erythropoietin. Transfusion-dependence resolved approximately 16 wk after discontinuing epoetin alfa, and 6 wk after starting danazol. PRCA caused by the development of erythropoietin antibodies is a potentially life-threatening complication of administering epoetin alfa to prevent the anemia associated with antiviral therapy in patients with chronic hepatitis C.
Evaluation and management of non-alcoholic steatohepatitis.
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Persistent ascites and low serum sodium identify patients with cirrhosis and low MELD scores who are at high risk for early death.
Despite the adoption of "sickest first" liver transplantation, pretransplant death remains common, and many early deaths occur despite initially low Model for End-stage Liver Disease (MELD) scores. From 1997-2003, we studied 507 cirrhotic United States veterans referred for consideration of liver transplantation to identify additional predictors of early mortality. Most of the patients were male (98%) with cirrhosis caused by hepatitis C and/or alcohol (88%). Data for 296 patients referred prior to February 27, 2002 (training group), were analyzed; findings were validated in 211 patients referred subsequently (validation group). In the training group, 61 patients (21%) died within 180 days without transplantation; their median initial MELD score was 21. MELD score, persistent ascites, and low serum sodium (<135 meq/L) were independent predictors of early mortality. In patients with a MELD score of less than 21, only low serum sodium and persistent ascites were independent predictors of mortality; for MELD scores above 21, only MELD was independently predictive. Prognostic significance of persistent ascites and low serum sodium for low MELD score patients was confirmed in the validation group. Risk varied continuously with worsening hyponatremia. Modifying MELD, by including points for persistent ascites and low serum sodium, improved prediction of early pretransplant mortality in low MELD score patients. In conclusion, persistent ascites and low serum sodium identify patients with cirrhosis with high mortality risk despite low MELD scores. Ascites, hyponatremia, and other findings indicative of hemodynamic decompensation merit further prospective study as prognostic indicators in patients awaiting liver transplantation, and should be considered in setting minimal listing criteria.
Effects of interferon treatment on liver histology and allograft rejection in patients with recurrent hepatitis C following liver transplantation.
Recurrent hepatitis C after liver transplantation remains a significant cause of graft loss and retransplantation. Although treatment of recurrent hepatitis C with interferon-based regimens has become widely accepted as safe and can lead to sustained virologic clearance of hepatitis C virus (HCV) RNA, long-term histologic improvement and the risk of precipitating graft rejection remain controversial. The present study is a retrospective evaluation of the clinical and histological consequences of treating recurrent hepatitis C with interferon-based therapy in a selected group of liver transplant recipients. Twenty-three liver transplant recipients with recurrent hepatitis C and histologic evidence of progressive fibrosis completed at least 6 months of interferon, 83% of whom received pegylated-interferon alpha-2b; only 4 tolerated ribavirin. Overall, 11 patients (48%) had undetectable HCV RNA at the end of 6 months of treatment. Of these patients, 3 remained HCV RNA-negative on maintenance interferon monotherapy for 33 months, and the other 8 (35%) completed treatment and remained HCV RNA-undetectable 24 weeks after discontinuation of interferon. Overall necroinflammatory activity in liver biopsies obtained 2 years after HCV RNA became undetectable decreased significantly (7.73 +/- 2.37 vs. 5.64 +/- 2.94 units before and after treatment, respectively; P =.016). However, 5 of these 11 patients had no histologic improvement in follow-up liver histology. Liver biopsies in the 12 nonresponders demonstrated disease progression. Of the 23 patients treated with interferon, 8 (35%) had evidence of acute or chronic rejection on posttreatment liver biopsy, most of whom had no previous history of rejection (P <.01 for comparison of pretreatment and posttreatment prevalence of histologic rejection), and 2 experienced graft loss from chronic rejection, requiring retransplantation. In conclusion, interferon treatment of recurrent hepatitis C does not consistently improve histologic disease after virologic response, and it may increase the risk of allograft rejection.