LIVER TRANSPLANTATION 20:1454–1461, 2014
ORIGINAL ARTICLE
Hepatic Encephalopathy Is Associated With Significantly Increased Mortality Among Patients Awaiting Liver Transplantation Robert J. Wong,1,2 Robert G. Gish,3,4 and Aijaz Ahmed1 Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford, CA; 2 Division of Gastroenterology and Hepatology, Veterans Affairs Palo Alto Health Care System, Palo Alto, CA; 3Robert G. Gish Consultants LLC, La Jolla, CA; and 4Hepatitis B Foundation, Doylestown, PA
1
The prioritization of liver transplantation (LT) for patients with end-stage liver disease uses the Model for End-Stage Liver Disease (MELD), which attempts to identify the sickest patients and thereby those who are in greatest need for LT. Hepatic encephalopathy (HE) is not included in MELD, and severity of liver disease and risk of wait-list removal or wait-list death may be underestimated by MELD in patients with HE. Using United Network for Organ Sharing registry data, we evaluated the impact of HE on 90-day wait-list survival among adult LT wait-list registrants in the United States from 2003 to 2012. Survival was stratified by HE severity (none, grade 1-2, grade 3-4) and MELD. There were 84,947 new LT wait-list registrants during the study period; 36.8% had no HE, 57.4% had grade 1-2 HE, and 5.9% had grade 3-4 HE. Ninety-day waitlist mortality was significantly higher among patients with grade 3-4 HE compared with patients with grade 1-2 HE or no HE (24.4% versus 6.8% versus 3.5%; P < 0.001). When stratified by MELD, patients with grade 3-4 HE had 90-day wait-list mortality similar to that of nonencephalopathic patients with MELD scores 6-7 points higher. With the multivariate Cox proportional hazards model, patients with grade 3-4 HE had 66% greater risk of 90-day mortality than patients without HE (hazard ratio 5 1.66, 95% CI 5 1.45-1.90; P < 0.001). The inclusion of HE severity in MELD improved the area under receiver operating curve for predicting 90-day wait-list survival from 0.6508 to 0.6863. In conclusion, grade 3-4 HE at time of wait-list registration significantly increases 90-day wait-list mortality independent of MELD score. Incorporating HE in the assessment of LT priority may improve prognostication of liver disease severity and prioritization for LT. Liver Transpl 20:1454C 2014 AASLD. 1461, 2014. V Received April 7, 2014; accepted August 10, 2014. Chronic liver disease is a leading cause of morbidity and mortality in the United States.1 Progressive hepatic fibrosis among patients with chronic liver disease leads to cirrhosis and its complications, including hepatocellular carcinoma (HCC) and end-stage liver disease.2-4 Liver transplantation (LT) is a curative option with 5-year post-LT survival greater than 80%.5 However, the growing number of patients
awaiting LT has far outpaced the availability of donor livers to be allocated for LT in the United States6,7 The implementation of the Model for End-Stage Liver Disease (MELD) score in 2002 was an attempt to institute an objective system by which to prioritize patients for LT.8,9 The MELD score incorporates objective measures of serum bilirubin, creatinine, and international normalized ratio (INR) to prioritize
Additional Supporting Information may be found in the online version of this article. Abbreviations: AUROC, area under the receiver operating curve; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; HE, hepatic encephalopathy; HR, hazard ratio; INR, international normalized ratio; ln, natural logarithm; LT, liver transplantation; MELD, Model for End-Stage Liver Disease; TIPS, transjugular intrahepatic portosystemic shunt; UNOS/OPTN, United Network for Organ Sharing/Organ Procurement and Transplantation Network. Potential conflict of interest: Nothing to report. Address reprint requests to Robert J. Wong, M.D., M.S., Division of Gastroenterology and Hepatology, Stanford University School of Medicine, 300 Pasteur Drive, Always Building, Suite M-211, Stanford, CA 94305. Telephone: 650-721-6190; FAX: 650-723-5488; E-mail: [email protected] DOI 10.1002/lt.23981 View this article online at wileyonlinelibrary.com. LIVER TRANSPLANTATION.DOI 10.1002/lt. Published on behalf of the American Association for the Study of Liver Diseases
C 2014 American Association for the Study of Liver Diseases. V
LIVER TRANSPLANTATION, Vol. 20, No. 12, 2014
patients awaiting LT. In addition to the MELD score, hyponatremia has also been shown to be an important predictor of mortality among patients with cirrhosis.10-13 With the concept of providing LT to patients who are the sickest first and thereby benefiting the sickest the most, LT is offered to patients with the highest MELD scores first. However, hepatic encephalopathy (HE), a marker of hepatic decompensation, is not included in the MELD scoring system, and several studies have raised concern that the MELD score underestimates the risk of mortality among patients with HE.14-19 In addition, HE may not correlate well with MELD across the range of MELD scores, and patients with HE may not receive needed LT in a timely manner under the current MELD scoring system.14,15 In an effort to assess the impact of HE on LT waitlist mortality, we performed a retrospective cohort study using 10 years of MELD-era data from a population-based registry of all adult LT wait-list registrants in the United States. We hypothesize that HE will be associated with significantly increased 90day wait-list mortality independent of MELD scores.
PATIENTS AND METHODS Study Population Adult men and women (age >18 years) who were registered on the wait-list for LT in the United States from January 1, 2003, to December 31, 2012, were evaluated with data from the United Network for Organ Sharing and Organ Procurement and Transplantation Network (UNOS/OPTN) registry. Our target population consisted of patients with chronic liver disease awaiting LT. Patients who were listed for LT secondary to acute liver failure were excluded. The prioritization of LT among patients with concurrent HCC in the United States incorporates an exception policy, such that patients with HCC within defined criteria are allocated additional points to their MELD score by regional transplant review boards, thereby increasing their priority and probability of receiving LT. The basis for this policy in part reflects the understanding that MELD score alone does not accurately predict 90-day mortality among patients with concurrent HCC. For this reason, patients with HCC were also excluded from our analyses. MELD scores at the time of wait-list registration and at the time of transplantation if LT was performed were calculated for each individual. MELD scores were calculated with standard formulae that incorporate the natural logarithms (ln) of INR, bilirubin, and creatinine: 11.2 3 ln(INR) 1 9.57 3 ln (creatinine, in milligrams per deciliter) 1 3.78 3 ln (bilirubin, in milligrams per deciliter) 1 6.43, with a lower limit of 1 for all variables and an upper limit of 4 for creatinine. Patients on hemodialysis are given a creatinine score of 4. The grading of HE severity was based on West Haven Criteria (grade 1 5 trivial lack of awareness, euphoria or anxiety, shortened attention span,
WONG, GISH, AND AHMED 1455
impaired performance of addition or subtraction; grade 2 5 lethargy or apathy, minimal disorientation for time or place, subtle personality change, inappropriate behavior; grade 3 5 somnolence to semistupor but responsive to verbal stimuli, confusion, gross disorientation; grade 4 5 coma (unresponsive to verbal or noxious stimuli).16 Severity of HE (no HE, grade 1-2 HE, grade 3-4 HE) at time of wait-list registration and at time of LT among transplant recipients were documented in the UNOS registry and relied on review of clinical medical records to determine the most recently documented grade of HE prior to wait-list registration. Treatment for HE was not captured in the UNOS registry data. The outcome for patients on the LT wait list (ie, death, receipt of liver transplant, or removal from wait list for other reasons) allowed the calculation of our primary outcome, 90-day mortality among wait-listed patients. This outcome is commonly used to evaluate LT wait-list mortality.
Statistical Analysis Descriptive statistics were stratified by severity of HE and presented as proportion (%) and frequency (N) for categorical variables, mean and standard deviation (SD) for normally distributed continuous variables, and median and range for nonnormally distributed variables. Comparisons between groups were performed with chi-square testing and analysis of variance methods. Kaplan-Meier methods were used to evaluate our primary outcome of 90-day wait-list mortality. Stratification by MELD score and degree of HE was applied in an attempt to determine whether the increased mortality associated with HE was dependent on MELD score at time of wait-list registration. In other words, for each MELD score (6-40), we calculated 90-day wait-list mortality for patients with no HE, grade 1-2 HE, and grade 3-4 HE. To determine whether there was a statistically significant nonlinear relationship between severity of HE and 90-day waitlist mortality, we used a second-order polynomial (quadratic) model to compare the graphic function represented by each category of HE. The resulting smooth curves depicted the relationship between severity of HE and 90-day wait-list mortality for individual MELD scores. Multivariate Cox proportional hazards models were used to evaluate the association between HE and 90-day wait-list mortality. Forward stepwise regression methods included variables that satisfied biological priori (eg, age, sex) and those that demonstrated significant associations in the univariate models (P < 0.10). The final multivariate model was adjusted for sex, age, race/ethnicity, etiology of liver disease [hepatitis C virus (HCV) versus nonHCV], MELD score, ascites, serum albumin, serum sodium, year of wait-list registration, and HE. Statistical significance was met with a two-tailed P value
ORIGINAL ARTICLE
Hepatic Encephalopathy Is Associated With Significantly Increased Mortality Among Patients Awaiting Liver Transplantation Robert J. Wong,1,2 Robert G. Gish,3,4 and Aijaz Ahmed1 Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford, CA; 2 Division of Gastroenterology and Hepatology, Veterans Affairs Palo Alto Health Care System, Palo Alto, CA; 3Robert G. Gish Consultants LLC, La Jolla, CA; and 4Hepatitis B Foundation, Doylestown, PA
1
The prioritization of liver transplantation (LT) for patients with end-stage liver disease uses the Model for End-Stage Liver Disease (MELD), which attempts to identify the sickest patients and thereby those who are in greatest need for LT. Hepatic encephalopathy (HE) is not included in MELD, and severity of liver disease and risk of wait-list removal or wait-list death may be underestimated by MELD in patients with HE. Using United Network for Organ Sharing registry data, we evaluated the impact of HE on 90-day wait-list survival among adult LT wait-list registrants in the United States from 2003 to 2012. Survival was stratified by HE severity (none, grade 1-2, grade 3-4) and MELD. There were 84,947 new LT wait-list registrants during the study period; 36.8% had no HE, 57.4% had grade 1-2 HE, and 5.9% had grade 3-4 HE. Ninety-day waitlist mortality was significantly higher among patients with grade 3-4 HE compared with patients with grade 1-2 HE or no HE (24.4% versus 6.8% versus 3.5%; P < 0.001). When stratified by MELD, patients with grade 3-4 HE had 90-day wait-list mortality similar to that of nonencephalopathic patients with MELD scores 6-7 points higher. With the multivariate Cox proportional hazards model, patients with grade 3-4 HE had 66% greater risk of 90-day mortality than patients without HE (hazard ratio 5 1.66, 95% CI 5 1.45-1.90; P < 0.001). The inclusion of HE severity in MELD improved the area under receiver operating curve for predicting 90-day wait-list survival from 0.6508 to 0.6863. In conclusion, grade 3-4 HE at time of wait-list registration significantly increases 90-day wait-list mortality independent of MELD score. Incorporating HE in the assessment of LT priority may improve prognostication of liver disease severity and prioritization for LT. Liver Transpl 20:1454C 2014 AASLD. 1461, 2014. V Received April 7, 2014; accepted August 10, 2014. Chronic liver disease is a leading cause of morbidity and mortality in the United States.1 Progressive hepatic fibrosis among patients with chronic liver disease leads to cirrhosis and its complications, including hepatocellular carcinoma (HCC) and end-stage liver disease.2-4 Liver transplantation (LT) is a curative option with 5-year post-LT survival greater than 80%.5 However, the growing number of patients
awaiting LT has far outpaced the availability of donor livers to be allocated for LT in the United States6,7 The implementation of the Model for End-Stage Liver Disease (MELD) score in 2002 was an attempt to institute an objective system by which to prioritize patients for LT.8,9 The MELD score incorporates objective measures of serum bilirubin, creatinine, and international normalized ratio (INR) to prioritize
Additional Supporting Information may be found in the online version of this article. Abbreviations: AUROC, area under the receiver operating curve; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; HE, hepatic encephalopathy; HR, hazard ratio; INR, international normalized ratio; ln, natural logarithm; LT, liver transplantation; MELD, Model for End-Stage Liver Disease; TIPS, transjugular intrahepatic portosystemic shunt; UNOS/OPTN, United Network for Organ Sharing/Organ Procurement and Transplantation Network. Potential conflict of interest: Nothing to report. Address reprint requests to Robert J. Wong, M.D., M.S., Division of Gastroenterology and Hepatology, Stanford University School of Medicine, 300 Pasteur Drive, Always Building, Suite M-211, Stanford, CA 94305. Telephone: 650-721-6190; FAX: 650-723-5488; E-mail: [email protected] DOI 10.1002/lt.23981 View this article online at wileyonlinelibrary.com. LIVER TRANSPLANTATION.DOI 10.1002/lt. Published on behalf of the American Association for the Study of Liver Diseases
C 2014 American Association for the Study of Liver Diseases. V
LIVER TRANSPLANTATION, Vol. 20, No. 12, 2014
patients awaiting LT. In addition to the MELD score, hyponatremia has also been shown to be an important predictor of mortality among patients with cirrhosis.10-13 With the concept of providing LT to patients who are the sickest first and thereby benefiting the sickest the most, LT is offered to patients with the highest MELD scores first. However, hepatic encephalopathy (HE), a marker of hepatic decompensation, is not included in the MELD scoring system, and several studies have raised concern that the MELD score underestimates the risk of mortality among patients with HE.14-19 In addition, HE may not correlate well with MELD across the range of MELD scores, and patients with HE may not receive needed LT in a timely manner under the current MELD scoring system.14,15 In an effort to assess the impact of HE on LT waitlist mortality, we performed a retrospective cohort study using 10 years of MELD-era data from a population-based registry of all adult LT wait-list registrants in the United States. We hypothesize that HE will be associated with significantly increased 90day wait-list mortality independent of MELD scores.
PATIENTS AND METHODS Study Population Adult men and women (age >18 years) who were registered on the wait-list for LT in the United States from January 1, 2003, to December 31, 2012, were evaluated with data from the United Network for Organ Sharing and Organ Procurement and Transplantation Network (UNOS/OPTN) registry. Our target population consisted of patients with chronic liver disease awaiting LT. Patients who were listed for LT secondary to acute liver failure were excluded. The prioritization of LT among patients with concurrent HCC in the United States incorporates an exception policy, such that patients with HCC within defined criteria are allocated additional points to their MELD score by regional transplant review boards, thereby increasing their priority and probability of receiving LT. The basis for this policy in part reflects the understanding that MELD score alone does not accurately predict 90-day mortality among patients with concurrent HCC. For this reason, patients with HCC were also excluded from our analyses. MELD scores at the time of wait-list registration and at the time of transplantation if LT was performed were calculated for each individual. MELD scores were calculated with standard formulae that incorporate the natural logarithms (ln) of INR, bilirubin, and creatinine: 11.2 3 ln(INR) 1 9.57 3 ln (creatinine, in milligrams per deciliter) 1 3.78 3 ln (bilirubin, in milligrams per deciliter) 1 6.43, with a lower limit of 1 for all variables and an upper limit of 4 for creatinine. Patients on hemodialysis are given a creatinine score of 4. The grading of HE severity was based on West Haven Criteria (grade 1 5 trivial lack of awareness, euphoria or anxiety, shortened attention span,
WONG, GISH, AND AHMED 1455
impaired performance of addition or subtraction; grade 2 5 lethargy or apathy, minimal disorientation for time or place, subtle personality change, inappropriate behavior; grade 3 5 somnolence to semistupor but responsive to verbal stimuli, confusion, gross disorientation; grade 4 5 coma (unresponsive to verbal or noxious stimuli).16 Severity of HE (no HE, grade 1-2 HE, grade 3-4 HE) at time of wait-list registration and at time of LT among transplant recipients were documented in the UNOS registry and relied on review of clinical medical records to determine the most recently documented grade of HE prior to wait-list registration. Treatment for HE was not captured in the UNOS registry data. The outcome for patients on the LT wait list (ie, death, receipt of liver transplant, or removal from wait list for other reasons) allowed the calculation of our primary outcome, 90-day mortality among wait-listed patients. This outcome is commonly used to evaluate LT wait-list mortality.
Statistical Analysis Descriptive statistics were stratified by severity of HE and presented as proportion (%) and frequency (N) for categorical variables, mean and standard deviation (SD) for normally distributed continuous variables, and median and range for nonnormally distributed variables. Comparisons between groups were performed with chi-square testing and analysis of variance methods. Kaplan-Meier methods were used to evaluate our primary outcome of 90-day wait-list mortality. Stratification by MELD score and degree of HE was applied in an attempt to determine whether the increased mortality associated with HE was dependent on MELD score at time of wait-list registration. In other words, for each MELD score (6-40), we calculated 90-day wait-list mortality for patients with no HE, grade 1-2 HE, and grade 3-4 HE. To determine whether there was a statistically significant nonlinear relationship between severity of HE and 90-day waitlist mortality, we used a second-order polynomial (quadratic) model to compare the graphic function represented by each category of HE. The resulting smooth curves depicted the relationship between severity of HE and 90-day wait-list mortality for individual MELD scores. Multivariate Cox proportional hazards models were used to evaluate the association between HE and 90-day wait-list mortality. Forward stepwise regression methods included variables that satisfied biological priori (eg, age, sex) and those that demonstrated significant associations in the univariate models (P < 0.10). The final multivariate model was adjusted for sex, age, race/ethnicity, etiology of liver disease [hepatitis C virus (HCV) versus nonHCV], MELD score, ascites, serum albumin, serum sodium, year of wait-list registration, and HE. Statistical significance was met with a two-tailed P value
