Patrick G. Northup

Systematic review of risk factors for fibrosis progression in non-alcoholic steatohepatitis.

BACKGROUND/AIMS Non-alcoholic steatohepatitis (NASH) is a growing public health problem. Evaluation of risk factors for fibrosis in NASH will help to target resources to reduce development of cirrhosis. This study had two aims; the first to compile longitudinal histological data to characterize the natural history of fibrosis progression in NASH, and second, to identify predictive factors for progression to advanced fibrosis (stage 3 or greater) in NASH. METHODS Subjects had to have a histological diagnosis compatible with NASH on their initial biopsy, received no intervention of proven histological benefit, and undergone two liver biopsies with at least an interval of one year between them. RESULTS Ten studies were selected comprising 221 patients. 37.6% had progressive fibrosis over a mean follow-up interval of 5.3 years (SD, 4.2 years, median, 3.7 years, range 1.0-21.3 years). Proportional hazards regression analysis demonstrated that age (HR=0.98, p=0.009) and inflammation on initial biopsy (any inflammation, HR=2.5, p=0.001; grade 1, HR=2.5, p=0.001; grade 2, HR=2.4, p=0.003) are independent predictors of progression to advanced fibrosis. Other traditional parameters (e.g. obesity, diabetes, hypertension) were not statistically significant predictors. CONCLUSIONS Presence of inflammation on the initial biopsy and age are independent predictors of progression to advanced fibrosis 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. (HEPATOLOGY 2006;44:1039–1046.)

Coagulopathy does not fully protect hospitalized cirrhosis patients from peripheral venous thromboembolism

OBJECTIVE:Despite the endogenous coagulopathy of cirrhosis, some patients with cirrhosis experience thrombophilic states. This study aims to determine the incidence and predictors of venous thromboembolism (VTE), such as deep vein thrombosis (DVT) and pulmonary embolism, in hospitalized patients with cirrhosis.METHODS:A retrospective case-control study was performed in a tertiary-care teaching hospital over an 8-yr period. A total of 113 hospitalized patients with cirrhosis with a documented new VTE were compared to controls. Risk factors for VTE were determined using univariate and multivariate statistical analyses.RESULTS:Approximately 0.5% of all hospitalized patients with cirrhosis had a VTE. Traditional markers of coagulation such as INR and platelet count were not predictive of VTE. In the univariate analysis, serum albumin level was significantly lower in cases than controls (2.85 vs. 3.10 g/dL, respectively, p = 0.01). In the multivariate analysis, serum albumin remained independently predictive of VTE, with an odds ratio of 0.25 (95% CI 0.10–0.56).CONCLUSIONS:Approximately 0.5% of admissions involving cirrhosis patients resulted in a new thromboembolic event. Low serum albumin was strongly predictive of increased risk for developing VTE, independent of international normalized ratio or platelet count. Serum albumin deficiency may indicate low levels of endogenous anticoagulants.

Model for End-Stage Liver Disease (MELD) Predicts Nontransplant Surgical Mortality in Patients With Cirrhosis

Objective:We sought to determine the ability of the Model for End-Stage Liver Disease (MELD) score to predict 30-day postoperative mortality for patients with cirrhosis undergoing nontransplant surgical procedures. Summary Background Data:The Child-Pugh class historically has been used by clinicians to assist in management decisions involving patients with cirrhosis. However, this classification scheme has a number of limitations. Recently, MELD was introduced. It has been shown to be highly predictive of mortality in a variety of clinical scenarios. Methods:Adult patients with a diagnosis of cirrhosis undergoing nontransplant surgical procedures between January 1, 1996, and January 1, 2002, at a single center were analyzed. The preoperative MELD score was calculated for all patients, and the MELDs performance in predicting 30-day mortality was determined using multivariate regression techniques. Results:A total of 140 surgical procedures were identified and analyzed. The 30-day mortality rate was 16.4%. The mean admission MELD score for the patients who died (23.3, 95% confidence interval 19.6–27.0) was significantly different from those patients surviving beyond 30 days (16.9, 15.6–18.2), P = 0.0003. The c-statistic for MELD score predicting 30-day mortality was 0.72. Further subgroup analysis of 67 intra-abdominal surgeries showed an in-hospital mortality of 23.9%. The mean MELD score for patients dying (24.8, 20.4–29.3) was significantly different from survivors (16.2, 14.2–18.2), P = 0.0001. The c-statistic for this subgroup was 0.80. Conclusions:The MELD score, as an objective scale of disease severity in patients with cirrhosis, shows promise as being a useful preoperative predictor of surgical mortality risk.

Hemostasis and thrombosis in patients with liver disease: The ups and downs

Patients with chronic or acute liver failure frequently show profound abnormalities in their hemostatic system. Whereas routine laboratory tests of hemostasis suggest these hemostatic alterations result in a bleeding diathesis, accumulating evidence from both clinical and laboratory studies suggest that the situation is more complex. The average patient with liver failure may be in hemostatic balance despite prolonged routine coagulation tests, since both pro- and antihemostatic factors are affected, the latter of which are not well reflected in routine coagulation testing. However, this balance may easily tip towards a hypo- or hypercoagulable situation. Indeed, patients with liver disease may encounter both hemostasis-related bleeding episodes as well as thrombotic events. During the 3rd International Symposium on Coagulopathy and Liver disease, held in Groningen, The Netherlands (18-19 September 2009), a multidisciplinary panel of experts critically reviewed the current data concerning pathophysiology and clinical consequences of hemostatic disorders in patients with liver disease. Highlights of this symposium are summarized in this review.

Hypercoagulation and thrombophilia in liver disease

Summary.  A complex balance exists between endogenous procoagulants and the anticoagulant system in liver disease patients. Hypercoagulable events occur in cirrhosis patients despite the well‐known bleeding diathesis of liver disease. These events may be clinically evident, such as in portal vein thrombosis or pulmonary embolism, but these conditions may also be a silent contributor to certain disease states, such as portopulmonary hypertension or parenchymal extinction with liver atrophy as well as thrombosis of extracorporeal circuits in dialysis or liver assist devices. Moreover, liver disease‐related hypercoagulability may contribute to vascular disease in the increasingly common condition of non‐alcoholic fatty liver disease. Despite the incidence of these problems, there are few widely accessible and practical laboratory tests to evaluate the risk of a hypercoagulable event in cirrhosis patients. Furthermore, there is little research on the use of commonly accepted anticoagulants in patients with liver disease. This article is a result of an international symposium on coagulation disorders in liver disease and addresses several areas of specific interest in hypercoagulation in liver disease. Critical areas lacking clinical information are highlighted and future areas of research interest are defined with an aim to foster clinical research in this field.

Unresectable Cholangiocarcinoma: Comparison of Survival in Biliary Stenting Alone Versus Stenting With Photodynamic Therapy

BACKGROUND & AIMS Photodynamic therapy (PDT) for unresectable cholangiocarcinoma is associated with improvement in cholestasis, quality of life, and potentially survival. We compared survival in patients with unresectable cholangiocarcinoma undergoing endoscopic retrograde cholangiopancreatography (ERCP) with PDT and stent placement with a group undergoing ERCP with stent placement alone. METHODS Forty-eight patients were palliated for unresectable cholangiocarcinoma during a 5-year period. Nineteen were treated with PDT and stents; 29 patients treated with biliary stents alone served as a control group. Multivariate analysis was performed by using Model for End-Stage Liver Disease score, age, treatment by chemotherapy or radiation, and number of ERCP procedures and PDT sessions to detect predictors of survival. RESULTS Kaplan-Meier analysis demonstrated improved survival in the PDT group compared with the stent only group (16.2 vs 7.4 months, P<.004). Mortality in the PDT group at 3, 6, and 12 months was 0%, 16%, and 56%, respectively. The corresponding mortality in the stent group was 28%, 52%, and 82%, respectively. The difference between the 2 groups was significant at 3 months and 6 months but not at 12 months. Only the number of ERCP procedures and number of PDT sessions were significant on multivariate analysis. Adverse events specific to PDT included 3 patients with skin phototoxicity requiring topical therapy only. CONCLUSIONS ERCP with PDT seems to increase survival in patients with unresectable cholangiocarcinoma when compared with ERCP alone. It remains to be proved whether this effect is attributable to PDT or the number of ERCP sessions. A prospective randomized multicenter study is required to confirm these data.

Endoscopic cyanoacrylate versus transjugular intrahepatic portosystemic shunt for gastric variceal bleeding: a single-center U.S. analysis

BACKGROUND AND OBJECTIVES Gastric variceal hemorrhage treatment remains a difficult issue for clinicians. There is controversy regarding whether first-line treatment should be endoscopic therapy with cyanoacrylate glue or placement of a transjugular intrahepatic portosystemic shunt (TIPS). We compared these methods on the basis of rebleeding, survival, and complications. DESIGN, SETTING, PATIENTS, AND INTERVENTIONS: This was a retrospective cohort analysis of cirrhotic patients with gastric variceal hemorrhage treated with endoscopic cyanoacrylate therapy or TIPS placement at a single U.S. center from 1997 to 2007. The groups were compared for rebleeding at 72 hours, 3 months, and 1 year; survival rates at 3 months and 1 year; and acute and extended complications and morbidity. MAIN OUTCOME MEASUREMENTS AND RESULTS A total of 105 patients were included. There were no significant pretreatment differences between the 2 groups in age, sex, MELD (Model for End-Stage Liver Disease) score at the time of admission, or cause of liver disease. There were no significant differences in rebleeding at 72 hours, 3 months, and 1 year; survival at 3 months and 1 year; and aggregate long-term survival or acute complications. However, the TIPS group had a higher rate of long-term morbidity requiring hospitalization (41% with a TIPS and 1.6% in the cyanoacrylate arm, P < .0001). LIMITATIONS Retrospective and uncontrolled samples. CONCLUSION In patients with similar characteristics, cyanoacrylate therapy performed as well as a TIPS in controlling and preventing gastric variceal hemorrhage with no significant differences in survival. Patients receiving cyanoacrylate therapy experienced significantly less long-term morbidity related to therapy than patients who received a TIPS. Cyanoacrylate therapy appears to be safe and effective and compares favorably with TIPS therapy.

Partially covered self-expandable metallic stents for benign biliary strictures due to chronic pancreatitis

BACKGROUND AND STUDY AIMS Benign biliary strictures (BBS) may occur in patients with chronic pancreatitis and may lead to secondary biliary cirrhosis or recurrent cholangitis. Although surgical diversion may provide definitive therapy, it can be associated with significant morbidity. Endoscopic therapy with plastic stents has been used as an alternative to surgery but has resulted in unsatisfactory long-term outcomes. We evaluated the temporary placement of partially covered self-expandable metallic stents (PCMS) in patients with BBS due to chronic pancreatitis. PATIENTS AND METHODS A total of 20 patients with BBS due to chronic pancreatitis underwent temporary placement of PCMS over a 6-year period. The primary outcome of interest was the proportion of patients with stricture resolution persisting 6 months after stent removal. Secondary outcomes included the stent failure rate, number of endoscopic sessions required to achieve biliary drainage, total duration of stenting, and complication rate. RESULTS Adequate biliary drainage was achieved in 19 patients with PCMS (95%). Eighteen of the 20 patients (90%) had persistent stricture resolution 6 months after PCMS removal. In two of the 20 patients (10%), PCMS stenting failed and these patients underwent alternative therapies. Complications occurred in four patients (20%). Median duration of PCMS placement was 5 months, requiring a median of two endoscopic procedures. CONCLUSION In this series of patients with BBS due to chronic pancreatitis, temporary PCMS placement achieved persistent stricture resolution in the majority of patients with acceptable complication rates. Comparative trials evaluating temporary PCMS placement and plastic stenting in patients with BBS due to chronic pancreatitis are needed.

Excess mortality on the liver transplant waiting list: Unintended policy consequences and model for End‐Stage Liver Disease (MELD) inflation

The Model for End‐Stage Liver Disease (MELD) allocation system for liver transplantation provides “exceptions” for diseases such as hepatocellular carcinoma (HCC). It was the aim of this study to assess equipoise between exception candidates and nonexception candidates on the waiting list and to assess if the exception system contributes to steadily increasing regional MELD at transplant. In all, 78,595 adult liver transplant candidates between January 2005 and December 2012 were analyzed. Yearly trends in waiting list characteristics and transplantation rates were analyzed for statistical association with MELD exceptions. Regional variations in these associations and the effect of exceptions on regional MELD scores at transplant were also analyzed. 27.29% of the waiting list was occupied by candidates with exceptions. Candidates with exceptions fared much better on the waiting list compared to those without exceptions in mean days waiting (HCC 237 versus non‐HCC 426), transplantation rates (HCC 79.05% versus non‐HCC 40.60%), and waiting list death rates (HCC 4.49% versus non‐HCC 24.63%). Strong regional variation in exception use occurred but exceptions were highly correlated with waiting list death rates, transplantation rates, and MELD score at removal in all regions. In a multivariate model predicting MELD score at transplant within regions, the percentage of HCC MELD exceptions was the strongest independent predictor of regional MELD score at transplant. Conclusion: Liver transplant candidates with MELD exceptions have superior outcomes compared to nonexception candidates and the current MELD exception system is largely responsible for steadily increasing MELD scores at transplant independent of geography. (Hepatology 2015;61:285–291)