Liver transplantation has evolved from its origin as an experimental procedure in 1963 to its acceptance as effective treatment for patients with variable causes of irreversible acute and chronic liver disease.1 Improvements in surgical technique, perioperative care, and immunosuppressive therapy that began in the early 1980s have led to sharp increases in patient survival after orthotopic liver transplantation.1 Access to liver transplantation in the United States involves three levels: referral of patients for evaluation for liver transplantation, placement of referred patients on a waiting list for liver transplantation, and allocation of donated livers to wait-listed patients. Multiple studies have characterized access to liver transplantation at the last two levels.2–7 However, to our knowledge no study has formally evaluated access to liver transplantation in the United States at the referral level. Although many patients who are referred for possible liver transplantation may not undergo the procedure due to various contraindications or organ availability, it is nevertheless important for health care providers to identify patients who might benefit from this potentially life-saving procedure and appropriately refer them for evaluation. Therefore, we sought to estimate the magnitude and determinants of consideration of liver transplantation in patients with liver disease in a single, large Veterans Affairs (VA) medical center. We defined appropriate consideration of patients for evaluation for liver transplantation according to the guidelines published by the American Association for the Study of Liver Diseases (AASLD).8
Access of patients to liver transplantation involves three levels: referral for evaluation for transplantation, placement on a waiting list for transplantation, and receipt of a liver transplant. No study has formally evaluated access to liver transplantation at the referral level. Therefore, we sought to estimate the magnitude and determinants of consideration of liver transplantation in patients at a single, large Veterans Affairs medical center. Patients with liver disease were identified between October 2002 and September 2003, and their entire medical records were examined for encounters involving potential indications for liver transplantation according to American Association for the Study of Liver Diseases (AASLD) guidelines, mention of liver transplantation, and potential contraindications. Liver transplantation was mentioned in only 59 (20%) of 300 encounters, constituting 41 (21%) of 199 patients satisfying AASLD guidelines for referral. The significant negative independent determinants of mention of liver transplantation were older age (adjusted odds ratio [OR]: 0.31; 95% confidence interval [CI]: 0.13-0.77, P = 0.01), alcoholic liver disease (adjusted OR: 0.10; 95% CI: 0.02-0.57, P = 0.01), and black race (OR: 0.15; 95% CI: 0.02-0.96, P = 0.045). Most patients had potential contraindications that were inferred (but not documented) as reasons for not being evaluated for transplantation; however, a small but significant proportion (7%) had no recorded evidence of contraindications. In conclusion, we found a low rate of mention of liver transplantation in patients who satisfied AASLD guidelines for referral, particularly among patients with alcoholic liver disease and blacks. Deficiencies at the referral level may lead to disparities at further levels of access to liver transplantation. (Liver Transpl 2005.)
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Materials and Methods
Study Sample and Data Collection
We used the electronic medical records of the Michael E. DeBakey VA Medical Center to conduct this retrospective cross-sectional study. The institutional review board at Baylor College of Medicine approved the study. This VA center is one of the largest in the United States; however, it does not have a local liver transplantation service. We generated a list of patients seen in outpatient or inpatient departments during fiscal year 2003 (October 1, 2002–September 30, 2003) with liver disease identified by diagnostic codes from the International Classification of Diseases-Ninth Revision (ICD-9). These codes included the following diagnoses: acute liver failure (ICD-9 570), acute alcoholic hepatitis (571.1), alcoholic cirrhosis (571.2), unspecified alcoholic liver damage (571.3), nonalcoholic cirrhosis (571.5), esophageal varices (456.0, 456.1, and 456.2), hepatic coma (572.2), hepatorenal syndrome (572.4), ascites (789.5), and hepatocellular carcinoma (155.0). We included all patients who had one or more of the following indications for referral, based on AASLD guidelines8: variceal bleeding, ascites, spontaneous bacterial peritonitis, porto-systemic encephalopathy, hepatocellular carcinoma, hepatorenal syndrome, fulminant hepatic failure, or a Child-Turcotte-Pugh score9, 10 of 7 or greater exclusive of another indication.
We then abstracted information from the detailed electronic medical record of each encounter at which one or more unique indications for referral were identified. We used standardized comprehensive data collection forms designed for the purpose of this study. A given patient could therefore be identified as having several encounters for separate indications, but only one encounter for indications occurring contemporaneously. We used the earliest date at which the indication for referral was documented as the date of the encounter. For each encounter we recorded the following demographic features: age, sex, race, and presence of insurance other than VA insurance. We also recorded the etiology of underlying liver disease: hepatitis C virus (HCV), hepatitis B virus (HBV), alcoholic liver disease, nonalcoholic steatohepatitis, primary biliary cirrhosis, secondary biliary cirrhosis, primary sclerosing cholangitis, hemochromatosis, autoimmune hepatitis, an “other” etiology, or “idiopathic” cirrhosis. HBV infection was identified as the presence of HBV surface antigen. “Other” categories included medication-induced hepatitis, congestive hepatopathy, and cirrhosis suggested by computed tomography imaging. Patients could have had more than one etiology. “Idiopathic” cirrhosis denoted the absence of any of the above etiologies. From available clinical and laboratory information we recorded the severity of liver disease as defined by the Child-Turcotte-Pugh score at the time of each encounter. We also calculated the Model for End-Stage Liver Disease (MELD) score11 for each encounter.
We then identified and recorded potential contraindications to liver transplantation at each encounter: active alcohol use, active recreational drug use, coronary artery disease, congestive heart failure, chronic obstructive or restrictive lung disease, morbid obesity, uncontrolled systemic infection, human immunodeficiency virus (HIV) infection or acquired immune deficiency syndrome (AIDS), extrahepatic malignancy within 5 years of the encounter, disseminated hepatocellular carcinoma, an uncontrolled psychiatric or neurological disorder, or thrombosis of the mesenteric and portal venous system. Active alcohol or drug use was defined as the use of any amount of alcohol or drugs, respectively, within 6 months of the encounter. Disseminated hepatocellular carcinoma referred to one mass greater than 5 cm in diameter, the largest of three masses greater than 3 cm, extrahepatic spread, or macrovascular invasion.
Finally, we attempted to determine adherence to guidelines for referral for possible liver transplantation by searching for the following outcomes: (1) any mention of liver transplantation in the medical record within 1 year of an encounter, (2) documented intention of referral for possible liver transplantation, and (3) documented consultation initiated by a referral. For encounters that did not result in either mention of or referral for possible transplantation, we ascertained reasons for the lack of mention/referral. These reasons could be either documented (written in the record as reasons for not referring), or inferred (recorded in any other context but as reasons for unsuitability of liver transplantation).
We defined the primary outcome of interest as mention of liver transplantation in the medical record. We compared the distribution of the following variables between patient encounters with mention of liver transplantation and those without mention: demographic characteristics, etiologies of underlying liver disease, potential indications for liver transplantation, severity of liver disease, and potential contraindications to liver transplantation. When comparing individual patients, we used t tests and chi-square tests to compare continuous and categorical variables, respectively. When comparing encounters, we used a nonlinear mixed modeling technique for univariable and multivariable analyses to account for the potential clustering of multiple encounters within unique patients. This technique generally results in more conservative estimates of associations. Variables found to have a P value of 0.25 or less in univariable analyses were included in the full multivariable model to derive adjusted odds ratios and 95% confidence intervals with respect to mention of liver transplantation. We constructed a final, most parsimonious model by removing variables with the highest Wald P values one at a time and running a new model; we repeated this process until all the variables left in the model had P values less than 0.05. We performed all analyses with SAS (Cary, NC) statistical software.
Characteristics of the Patients
We identified a total of 352 inpatient or outpatient encounters involving 251 patients with ICD-9 codes for liver disease between October 1, 2002, and September 30, 2003 (Fig. 1). We excluded 52 patients because we could not confirm liver disease (n = 6) or potential indications for liver transplantation referral (n = 46). There were 300 encounters involving 199 patients for which guidelines for referral for possible liver transplantation were satisfied. As expected at our institution, these 199 patients were mostly men (n = 195, 98%), with a mean age of 57.2 ± 9.8 years (Table 1). Most were white (n = 132, 66%) and had no insurance other than VA insurance (n = 163, 82%). Most had alcoholic liver disease (n = 153, 77%), half had HCV (n = 99, 50%), and a minority had HBV (n = 7, 4%). Both HCV and alcoholic liver disease were present in about a third of patients (n = 68, 34%), and only a few had both HCV and HBV (n = 3, 2%). Ascites was the most common indication for possible liver transplantation referral (n = 159 patients, 80%), followed by portosystemic encephalopathy (n = 87, 44%), variceal bleeding (n = 39, 20%), spontaneous bacterial peritonitis (25, 13%), a Child-Turcotte-Pugh score of 7 or greater as the only indication (n = 22, 11%), hepatocellular carcinoma (n = 16, 8%), hepatorenal syndrome (n = 10, 5%), and fulminant hepatic failure (n = 1, 1%). One quarter of patients had more than one indication for referral (n = 50, 25%).
|Mean ± SD||57.2 ± 9.8|
|Sex, n (%)|
|Race, n (%)|
|Private Medical Insurance, n (%)|
|Etiology of Underlying Liver Disease*, n (%)|
|HCV + HBV||3 (2)|
|HCV + alcoholic liver disease||68 (34)|
|Indication for Possible Liver Transplantation§|
|Variceal bleeding||39 (20)|
|Spontaneous bacterial peritonitis||25 (13)|
|Portosystemic encephalopathy||87 (44)|
|Hepatorenal syndrome||10 (5)|
|Fulminant hepatic failure||1 (1)|
|CTP score ≥ 7 as only indication||22 (11)|
|>1 of above||50 (25)|
The mention of liver transplantation anywhere in the medical record was identified in only 59 (20%) of 300 encounters, constituting 41 (21%) of the 199 patients. Among these 41 patients, an intention of referral for possible liver transplantation was documented in 20 (10%), and in those a consultation initiated by the referral took place in 15 patients (8%). Of the 41 patients with mention of liver transplantation, 21 (11%) were not referred for further evaluation, the most frequent reason (documented rather than inferred in all cases) being active alcohol use (16 encounters in 12 patients). However, across the categories of patients in whom liver transplantation was mentioned, there were three patients (2%) without documented or inferred contraindications in whom a consultation did not take a place.
There was no mention of liver transplantation in the medical records of 241 (80%) of the 300 encounters, constituting 158 (79%) of the 199 patients. Reasons for the lack of mention could be inferred in 209 encounters encompassing 147 patients. Active alcohol use was the most frequently inferred reason (112 encounters in 76 patients), followed by disseminated hepatocellular carcinoma (14 encounters in 11 patients) and both active alcohol and drug use (10 encounters in 5 patients). Importantly, among patients in whom liver transplantation was never mentioned, no reasons could be inferred in 32 encounters (11%) encompassing 11 patients (6%). Of these 241 encounters with no mention of liver transplantation, 142 (59%) generated a consultation by a gastroenterologist/hepatologist as well.
Determinants of the Mention of Liver Transplantation
Encounters with and without mention of liver transplantation were compared with respect to various demographic and clinical characteristics (Table 2). In univariable analyses, the statistically significant negative determinants of mentioning liver transplantation were older age, with an odds decrease of 56% per 10 years (P = 0.04), and active alcohol use, with an 82% decrease (P = 0.02). On the other hand, encounters with mention of liver transplantation were eight times more likely to involve spontaneous bacterial peritonitis (P = 0.01).
|Variable||Transplant mentioned (n = 59 encounters)||Transplant not mentioned (n = 241 encounters)||Unadjusted odds Ratio||95% confidence interval||P value|
|Age* (mean ± SD)||54.8 ± 7.1||57.4 ± 9.7||0.44||0.20–0.95||0.04|
|Male sex (%)†||58 (98)||238 (99)||1.50||0.17–13.25||0.72|
|White||49 (83)||148 (61)||Reference|
|Black||7 (12)||56 (23)||0.30||0.06–1.52||0.15|
|Hispanic||3 (5)||37 (15)||0.16||0.02–1.43||0.10|
|Private medical insurance (%)||7 (12)||41 (17)||0.63||0.12–3.24||0.57|
|Etiology of underlying liver disease|
|HCV (%)||37 (63)||125 (52)||3.58||0.88–14.57||0.07|
|HBV (%)||6 (10)||5 (2)||15.99||0.91–281.44||0.06|
|Alcohol (%)||38 (64)||196 (81)||0.26||0.06–1.04||0.06|
|Idiopathic (%)||4 (7)||9 (4)||1.83||0.10–33.06||0.68|
|Indication for possible transplantation|
|Variceal bleeding (%)||9 (15)||34 (14)||1.22||0.32–4.63||0.77|
|Ascites (%)||43 (73)||168 (70)||1.23||0.41–3.67||0.71|
|SBP (%)||10 (17)||15 (6)||8.15||1.64–40.51||0.01|
|Encephalopathy (%)||23 (39)||68 (28)||2.69||0.94–7.70||0.07|
|HCC (%)||2 (3)||15 (6)||0.39||0.03–5.10||0.47|
|Hepatorenal syndrome (%)||4 (7)||6 (2)||3.55||0.37–34.21||0.27|
|Fulminant hepatic failure (%)||0 (0)||1 (0)||N/A‡||N/A||N/A|
|Severity of liver disease|
|A (%)||1 (2)||14 (7)||Reference|
|B (%)||17 (33)||77 (38)||8.15||0.32–206.93||0.20|
|C (%)||33 (65)||112 (55)||16.43||0.66–410.96||0.09|
|MELD score** (mean ± SD)||17.2 ± 5.2||16.2 ± 6.9||1.05||0.96–1.14||0.28|
|Active alcohol use†† (%)||28 (48)||165 (71)||0.18||0.04–0.72||0.02|
|Active drug use‡‡ (%)||8 (14)||45 (20)||0.86||0.17–4.44||0.85|
|CAD (%)||7 (12)||31 (13)||0.64||0.09–4.50||0.65|
|CHF (%)||1 (2)||23 (10)||0.07||0.003–1.27||0.07|
|Chronic lung disease (%)||5 (8)||20 (8)||1.27||0.15–10.78||0.83|
|Morbid obesity (%)||2 (3)||7 (3)||3.05||0.11–81.79||0.50|
|Systemic infection (%)||5 (8)||25 (10)||0.86||0.13–5.74||0.87|
|HIV/AIDS (%)||3 (5)||5 (2)||2.44||0.07–89.30||0.63|
|Extra-hepatic malignancy (%)||4 (7)||17 (7)||1.13||0.11–11.95||0.92|
|Disseminated HCC (%)||1 (2)||4 (2)||1.28||0.02–82.78||0.91|
|Psych./neurological disorder (%)||4 (7)||23 (10)||0.31||0.03–3.60||0.35|
|Mesen./portal vein thrombosis (%)||1 (2)||5 (2)||1.19||0.02–69.69||0.93|
For the multivariable analysis, we considered all variables with P values of 0.25 or less in the unadjusted analyses, i.e., age, race, HCV, HBV, alcoholic liver disease, spontaneous bacterial peritonitis, encephalopathy, Child-Turcotte-Pugh B or C class, active alcohol use, and congestive heart failure. Active alcohol use was not included in the same model as alcoholic liver disease to avoid colinearity; results with inclusion of active alcohol use were similar to those with inclusion of alcoholic liver disease (data not shown). The final model is shown in Table 3. Older age persisted as a significant negative determinant of mention of liver transplantation, with an odds decrease of 69% per 10 years (P = 0.01). Alcoholic liver disease was also a significant, independent negative determinant, with an odds decrease of 90%. (P = 0.01). In addition, black race emerged as a significant, independent negative predictor; there was an 85% decrease in the odds of mentioning liver transplantation as compared with whites (P = 0.045). To further explain this finding, we examined potential differences between blacks and whites. There were no significant differences between blacks and whites in age (mean 56.1 for blacks vs. 56.7 years for whites, P = 0.81) or insurance other than VA insurance (14% of blacks vs. 20% of whites, P = 0.32). However, blacks had statistically significant differences from whites in the prevalence of alcoholic liver disease (61% of blacks vs. 81% of whites, P = 0.01) and HCV (64% of blacks vs. 42% of whites, P = 0.02). Finally, the significant, independent positive determinants of mention of liver transplantation were spontaneous bacterial peritonitis, with a 10-fold odds increase (P = 0.01), and also encephalopathy, with a 3.6-fold odds increase (P = 0.03).
|Variable||Adjusted odds ratio||95% confidence interval||P value|
|Alcoholic liver disease||0.10||0.02–0.57||0.01|
|Spontaneous bacterial peritonitis||10.38||1.77–60.96||0.01|
To our knowledge, this is the first study to attempt to characterize patterns of referral for evaluation for liver transplantation in the United States, and the second to evaluate referral patterns at all, along with a similar study from England.12 We found that only 21% (41 of 199) of patients who had an identifiable potential indication for liver transplantation had any mention of liver transplantation in the medical record, 10% (20 of 199) of patients were intended to be referred, and only 8% (15 of 199) actually had a consultation for possible liver transplantation. Although a majority of patients had active contraindications that could be inferred or (less likely) were documented, 22 patients satisfied AASLD referral guidelines and had no apparent contraindications; however, almost two thirds of those (14 of 22 patients) were never fully evaluated, either due to lack of mention, intention of referral, or consultation for possible liver transplantation. Alcoholic liver disease and black race were independent predictors of an even lower likelihood of mentioning liver transplantation. Given that all military veterans enrolled in the VA health care system are eligible for transplant services, including liver transplantation, our results are somewhat surprising.
A limitation of the study was its dependence on the accuracy of documentation of discussions pertaining to liver transplantation. Undocumented attitudes of patients and patient providers toward liver transplantation might have influenced mention of liver transplantation in the medical record, though the relatively closed nature of the electronic record system in our VA center is an advantage to our study. Also, we did not identify whether socioeconomic factors such as level of education, income, home stability, and psychosocial support influenced the lack of mention of liver transplantation, though we found no instances in which these factors were documented as reasons for lack of referral. Another limitation was the restriction of the study population to a single, non-transplant VA center without comparison to populations in transplant VA centers or non-VA centers. Finally, comparisons among the subgroups involved small numbers of encounters, though the large total number of encounters strengthened the study.
The lack of documented mention of liver transplantation is concerning given that active alcohol use, which was the most commonly documented or inferred contraindication identified in our study, is a potentially modifiable risk factor. The negative influence of alcoholic liver disease has also been suggested to occur at the further levels of access to liver transplantation, i.e., waiting list registration and receipt of a liver transplant.3, 4, 13 A number of factors may influence the decision to refer a patient with alcoholic liver disease or active alcohol use for possible liver transplantation, including public and professional attitudes toward alcoholism, the presence of comorbid psychosocial conditions, and notions of the effect of pretransplantation alcohol use on posttransplantation survival. For example, surveys have found that the general public and physicians alike are less likely to advocate liver transplantation for alcoholics,14, 15 perhaps because we tend to hold people accountable for socially undesirable behavior. Comorbidities such as poor living arrangements, depression, anxiety disorders, and associated drug addiction can increase the rate of alcohol relapse before and after transplantation.16, 17 It remains questionable to what extent the length of pretransplantation abstinence predicts posttransplantation sobriety18–21 or survival,22 or whether posttransplantation sobriety even influences survival.18 Nevertheless, most liver transplant programs in the United States, including the VA transplant system, require abstinence from alcohol for at least 6 months before listing a patient for liver transplantation.23 Regardless, it is valid to ask whether a discussion of liver transplantation as a potentially life-saving procedure in a patient with alcoholic liver disease might actually motivate the patient to modify a potentially reversible behavior. Of 91 patients in our study who had active alcohol use (referral mentioned and implemented in 3, mentioned but not referred in 12, and not mentioned in 76), 25 were enrolled in an outpatient alcohol rehabilitation program and in various stages of completion, 5 of whom had mention of liver transplantation in the medical record (20%). However, 28 patients were referred to a rehabilitation program and either refused the referral (8 patients), had no evidence of enrollment (6 patients), or failed the program once enrolled (14 patients); only two of these patients had mention of liver transplantation (7%).
The ability to transfer our findings to other VA and non-VA facilities with or without locally affiliated liver transplant programs is unknown but deserves further study. Apart from expected differences in gender distribution, there is a higher prevalence of alcoholic liver disease and HCV in VA patients.24, 25 One VA transplant center also found higher Child-Turcotte-Pugh scores in VA compared with non-VA patients at the time of initial evaluation for transplantation,24 while another did not.25 Whether VA patients are being referred later in the course of their liver disease is therefore also unknown.
One reason this might be occurring is inadequate awareness of the indications for referral of patients for possible liver transplantation on the part of health care providers in our institution. Spontaneous bacterial peritonitis and hepatic encephalopathy were more likely to be associated with a mention of liver transplantation in our study; however, variceal bleeding, ascites with no peritonitis, and hepatocellular carcinoma were not. Most of the patient encounters in the study did involve generalists, whether clinic providers in the outpatient setting or house staff in the inpatient setting, who may not have been as knowledgeable of referral guidelines as gastroenterology/hepatology specialists. However, of the 241 encounters in which there was no mention of liver transplantation, 142 (59%) generated a consultation by a gastroenterologist/hepatologist as well. Therefore, the lack of documented discussion of liver transplantation may be more systemic in extent and origin. In the current system, providers in VA institutions must send to a centralized, national transplant program office a comprehensive referral packet for all patients under consideration for transplantation, complete with documentation of various clinical and laboratory data, social and psychological evaluations, and successful completion of a formal rehabilitation treatment program in those with active alcohol or drug use. Furthermore, only four VA centers across the United States are currently performing liver transplantations, which limits the proximity of patients to a VA transplant center. In other organ transplantations, partnerships between VA and university hospitals have increased access of veterans to transplantation.26
Another concerning finding of our study was that after adjustment for age and several clinical variables including alcoholic liver disease and HCV, patients who had mention of liver transplantation were significantly less likely to be black than white. The reasons for this finding are not clear from the study. Studies on the effect of race on access to liver transplantation have suggested that there is a disparity between blacks and whites in access to liver transplantation at the referral level. For example, blacks are underrepresented on the United States liver transplantation waiting list and among liver transplant recipients based on their representation in the general population.13 Blacks have also been found to be sicker at the time of listing.2, 13, 27 Once blacks advance to the waiting list level, there seem to be no racial disparities in transplant and mortality rates.2 However, blacks have lower patient and graft survival after liver transplantation,2, 28, 29 even after adjustment for socioeconomic factors such as neighborhood income, education, and insurance.30
Renal transplantation provides a model for analyzing access to transplantation at the referral level. This is because all patients with end-stage renal disease require dialysis or transplantation, Medicare covers services for almost all such patients in the United States, and therefore almost all potential candidates for transplantation can be identified.31 Blacks have been found to be less likely than whites to be referred for evaluation for renal transplantation.31, 32 After adjustment for potential confounders such as socioeconomic status, patient preferences and expectations, and health status, the data are mixed, with some analyses showing continued black-white disparities in referral31 and others not.32 Studies formally evaluating how race influences patient and professional attitudes toward liver transplantation, as have been performed in renal transplantation,31–34 would be illuminating.
In summary, we attempted to characterize the magnitude and determinants of consideration of liver transplantation in patients with liver disease in a single, large VA medical center. We found a low rate of referral or even mention of liver transplantation in patients who satisfied AASLD guidelines for referral. Documentation of discussion of liver transplantation has not historically been emphasized in the liver transplantation referral process, although perhaps such an emphasis would enhance access of appropriate patients to liver transplantation. Indeed, this is all the more important if it is possible that mere discussion of this potentially life-saving option could effect a change in behaviors such as alcohol use. Mention of liver transplantation in our study was significantly less likely among patients with active alcohol use or alcoholic liver disease, and of further concern, less likely in blacks than whites, independent of differences in alcohol use or other clinical factors. Unstudied factors such as the knowledge and attitudes of patients and health-care providers toward liver transplantation, socioeconomic status, as well as system-related factors may explain our findings. Regardless, deficiencies at the referral level, which serves as the “gateway” level of access to liver transplantation, may be leading to disparities at further levels of access. Studies evaluating patterns of referral for liver transplantation at other VA centers, both non-transplant centers such as ours as well as transplant centers, would help direct how access of veterans to liver transplantation can be improved.