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Predictors of psychiatric disorders in liver transplantation candidates: Logistic regression models
Predictors of Psychiatric Disorders in Liver Transplantation Candidates: Logistic Regression Models Paola Rocca,* Elena Cocuzza,* Roberta Rasetti,* Giuseppe Rocca,† Enrico Zanalda,‡ and Filippo Bogetto* This study has two goals. The first goal is to assess the prevalence of psychiatric disorders in orthotopic liver transplantation (OLT) candidates by means of standardized procedures because there has been little research concerning psychiatric problems of potential OLT candidates using standardized instruments. The second goal focuses on identifying predictors of these psychiatric disorders. One hundred sixty-five elective OLT candidates were assessed by our unit. Psychiatric diagnoses were based on the Structured Clinical Interview for the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition. Patients also were assessed using the Hamilton Depression Rating Scale (HDRS) and the Spielberger Anxiety Index, State and Trait forms (STAI-X1 and STAI-X2). Severity of cirrhosis was assessed by applying Child-Pugh score criteria. Chi-squared and general linear model analysis of variance were used to test the univariate association between patient characteristics and both clinical psychiatric diagnoses and severity of psychiatric diseases. Variables with P less than .10 in univariate analyses were included in multiple regression models. Forty-three percent of patients presented at least one psychiatric diagnosis. Child-Pugh score and previous psychiatric diagnoses were independent significant predictors of depressive disorders. Severity of psychiatric symptoms measured by psychometric scales (HDRS, STAI-X1, and STAI-X2) was associated with Child-Pugh score in the multiple regression model. Our data suggest a high rate of psychiatric disorders, particularly adjustment disorders, in our sample of OLT candidates. Severity of liver disease emerges as the most important variable in predicting severity of psychiatric disorders in these patients. (Liver Transpl 2003; 9:721-726.)
O
rthotopic liver transplantation (OLT) is an accepted standard of care for end-stage liver disease. The pre-OLT period is marked by declining physical function, adjustment-related anxiety and depression, and development of organic brain deficits.1-4 Although several psychiatric follow-up studies are available for recipients and donors after OLT,5-7 there are few studies concerning the psychiatric status of potential OLT candidates before OLT. There is heterogeneity in the results of these studies, and the findings need to be interpreted with caution because psychiatric diagnoses were determined by means of psychometric scales and only in few cases by a comprehensive clinical interview.7,8-12 Reported prevalence rates of psychiatric disorders among OLT candidates vary from 15% to 50%.8-12 Another recent study describing psychological
characteristics of a large sample of OLT candidates reports that more than half the patients presented at least mild levels of depression, and more than one third were affected by clinically elevated levels of anxiety, suggesting a greater incidence of depression and anxiety than previously reported.13 A number of studies have attempted to correlate cause of hepatopathy with psychiatric disorders in patients with end-stage liver disease. Results are contradictory. In early studies, the morbidity of mood and anxiety disorders was increased in patients with alcoholic cirrhosis compared with cirrhoses of other causes, using the Schedule for Affective Disorders and Schizophrenia and Research Diagnostic Criteria.14,15 EwusiMensah et al14 found that two thirds of in-patients with alcoholic liver disease had diagnosable psychiatric disorders compared with one third of a control group of patients with nonalcoholic liver disease. Another study found that three quarters of patients with alcoholic liver disease were affected by psychiatric disorders compared with only a quarter of nonalcoholic patients with liver disease.15 Recent data reported that patients with endstage liver disease caused by hepatitis C virus (HCV) are more likely to have psychiatric disorders, with depression being the most frequent and clinically important.10,16 A recent review of available studies regarding neuropsychiatric symptoms in patients with chronic HCV infection indicated that the depression rate ranges between 2% and 30%.17 Aims of this prospective study are to: (1) identify and quantify the prevalence of psychiatric disorders present in elective OLT candidates at the time of their evaluation for hepatic transplantation by using stanFrom the *Department of Neuroscience, Psychiatric Section, University of Turin; †Statistical Unit, Molinette Hospital, Turin; and ‡Centro di Salute Mentale, Venaria (Torino), Department of Mental Health, Azienda Sanitaria Locale 6, Italy. Address reprint requests to Paola Rocca, MD, Department of Neuroscience, Psychiatric Section, University of Turin, Via Cherasco 11, 10126 Torino, Italy. Telephone: 39-011-663-4848; FAX: 39-011-673-473; E-mail: [email protected] Copyright © 2003 by the American Association for the Study of Liver Diseases 1527-6465/03/0907-0011$30.00/0 doi:10.1053/jlts.2003.50133
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dardized procedures, including a semistructured psychiatric interview and Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) diagnostic criteria; and (2) identify predictors of psychiatric disorders in these patients.
Methods Subjects All consecutive elective candidates for OLT presented to the Liver Transplant Unit, University of Turin, at the San Giovanni Battista Hospital of Turin, Italy, from 1990 to 1999 were referred to our Psychiatric Unit, Department of Neuroscience, University of Turin. Patients were considered for OLT if liver function suggested a poor prognosis, correlated with Child-Pugh score B or C. Child-Pugh classification is a prognostic index that has been used extensively to risk stratify patients with cirrhosis and evaluate the efficacy of therapeutic procedures, e.g., sclerotherapy, band ligation, transjugular intrahepatic portosystemic shunt placement, and surgical procedures.18-22 Child-Pugh grading of liver cirrhosis (grades A, B, and C) includes clinical (degree of ascites and hepatic encephalopathy [HE]) and laboratory parameters (values for albumin, prothrombin time, and bilirubin).23 We excluded patients transferred from intensive care units and those affected by acute complicated liver disorders. No patient included in the study had a previous or current history of delirium. For patients with alcohol-related liver disease, at least 1 year of abstinence and an ongoing treatment program were requested. All subjects, after a complete description of the study, provided their informed consent.
Psychiatric Assessment Each subject was assessed by two psychiatrists (E.Z. and P.R.). The psychiatric evaluation included a semistructured interview to collect demographic information and psychiatric history. Psychiatric diagnoses were made on the basis of the Structured Clinical Interview for DSM-IV (SCID). The interviewers had graduate degrees and clinical experience in the mental health field and had been trained in the use of SCID and assessment battery. In addition, severity of symptoms of affective functioning was assessed using the 21-item Hamilton Depression Rating Scale (HDRS) and the 40-item StateTrait Anxiety Inventory (STAI), a self-report measure of both current (STAI-X1) and dispositional anxiety symptoms (STAI-X2). Medical diagnosis and Child-Pugh score were assessed by experienced gastroenterologists of the unit. Medical diagnoses of chronic liver disease were based on extensive medical evaluation, including clinical and biochemical assessment of hepatic function and injury, imaging studies, serological testing, and histopathologic examination of a percutaneous liver biopsy (when indicated).
Statistical Analysis According to the current psychiatric diagnoses, the sample was divided into five groups as follows: dysthymic disorder (n ⫽ 4), major depression (n ⫽ 12), adjustment disorder with anxious mood (n ⫽ 17), adjustment disorder with depressed mood (n ⫽ 13), and adjustment disorder with mixed emotional features (n ⫽ 25). Differences between these groups were analyzed as follows: categorical data (underlying liver disease, sex, past psychiatric history, and previous alcohol abuse) were compared using Chi-squared, and continuous variables (age, Child-Pugh score, HDRS, STAI-X1, and STAI-X2) were compared using analysis of variance (ANOVA). Some patients were affected by alcohol cirrhosis. When patients with other cirrhoses had a positive history of alcohol abuse, effects of alcohol were assessed both independently and in association with other liver diseases. Distribution of all quantitative variables was checked for normality, and normal logarithmic transformation was performed for HDRS given its nonnormal distribution. A nonparametric statistical analysis was performed for those tests, but because statistical results closely paralleled the counfounding linear models, only results of linear analysis are reported here. Variables with P less than .10 in univariate analyses were included in multiple regression models. We estimated two separate logistic models. One model was the depressed patients model: major depression (n ⫽ 12), dysthymic disorder (n ⫽ 4), adjustment disorders with depressed mood (n ⫽ 13), and adjustment disorders with mixed emotional features (n ⫽ 25; total n ⫽ 54). The other model used for multiple regression analysis was the adjustment disorder group model: adjustment disorders with anxious mood (n ⫽ 17), adjustment disorders with depressed mood (n ⫽ 13), and adjustment disorders with mixed emotional features (n ⫽ 25; total n ⫽ 55). Analyses for psychological scales (HDRS, STAI-X1, and STAI-X2) were performed using ANOVA. Variables with P less than .10 in univariate analyses were included in multiple regression models. We used the two separate logistic models described (depressed patients model, n ⫽ 54; adjustment disorder group model, n ⫽ 55). The median value for each quantitative scale was used to obtain numerically balanced groups for the specific logistic model. Different logistic models (all not reported here) were used to test specific etiologic hypotheses.
Results One hundred sixty-five OLT candidates were assessed by our unit. Baseline sociodemographic and clinical characteristics of study patients are listed in Table 1. Sixty-six percent were men. Median age was 46 years (range, 16 to 62 years). One hundred seven patients (65%) had Child’s class C, and 58 patients (35%), class B. The most common liver diseases requiring OLT were HCV infection in 26%, hepatitis B virus (HBV) infection in 23%, and alcoholic liver disease in 41%.
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Predictors of Psychiatric Disorders in OLT Candidates
Table 1. Demographic and Clinical Variables in Pre-OLT Patients Variable
Value
No. of patients Age (yr) Gender (men/women) Underlying liver disease Alcoholic cirrhosis Viral hepatitis HCV HBV Other diagnoses Cryptogenic cirrhosis Primary biliary cirrhosis Familial amyloidosis Wilson’s disease Child-Pugh score Past psychiatric history Major depression Dysthymic disorder Generalized anxiety disorder Alcohol abuse/dependence Substance abuse/dependence HDRS STAI-X1 STAI-X2
165 46 ⫾ 9.11 109/56 68 81 43 38 16 8 4 3 1 10.1 ⫾ 2.14 10 (6) 5 (3) 6 (4) 83 (50) 25 (15) 9.95 ⫾ 6.74 42.7 ⫾ 11.9 41.7 ⫾ 11.5
NOTE. Values expressed as mean ⫾ SD or number (percent). Abbreviations: OLT, orthotopic liver transplantation; HCV, hepatitis C virus; HBV, hepatitis B virus; HDRS, Hamilton Depression Rating Scale; STAI, State-Trait Anxiety Inventory.
Based on an HDRS cutoff score greater than 8, 49% of patients (81 of 165 patients) had scores indicative of depressive symptoms. STAI scores can range from 20 to
80 for each of the two subscales; higher scores indicate more anxiety. Fifty-five percent of our sample (91 of 165 patients) reported state anxiety scores in the clinical range, and 53% (88 of 165 patients) had clinically elevated trait anxiety scores. In our sample, 71 subjects had a current psychiatric diagnosis: 77% (55 of 71 patients) had an adjustment disorder, and 23% (16 of 71 patients) had a mood disorder. Table 2 lists the distribution of psychiatric disorders according to underlying liver disease. To identify factors independently associated with psychiatric disorders, we analyzed the univariate association between both clinical psychiatric diagnoses and patient characteristics (variables: age, sex, cause of liver disease, Child-Pugh score, past psychiatric history, and alcohol abuse) using Chi-squared for categorical data and ANOVA for continuous variables. In univariate analysis, sex, cause of liver disease, previous psychiatric history, and Child-Pugh score were significant predictors of current psychiatric disorders (Table 3). Psychiatric disorders were not associated with previous alcohol abuse and age. Variables with P less than .10 in univariate analyses were included in multiple regression models. Multiple logistic regression analysis detected ChildPugh score and previous psychiatric history, but not cause of liver disease and sex, as independent predictors of psychiatric disorders for depressed patients (previous psychiatric history,  ⫽ 0.15; odds ratio [OR] ⫽ 1.16; 95% confidence limit [CL] relative risk [RR], 1.04 to 1.28; P ⫽ .006; Child-Pugh score,  ⫽ 3.34; OR ⫽ 28.22; 95% CL RR, 26.92 to 29.52; P ⫽ 0.0001) and only Child-Pugh score for the adjustment disorders group ( ⫽ 0.66; OR ⫽ 1.93; 95% CL RR, 1.65 to 2.21; P ⫽ .0001).
Table 2. Current DSM-IV Psychiatric Diagnoses of the Sample According to Liver Disease
No psychiatric diagnosis Adjustment disorders With anxious mood With depressed mood With mixed emotional features Total Depressive disorders Major depression Dysthymic disorder Total
Total (n ⫽ 165)
ALD (n ⫽ 68)
HCV (n ⫽ 43)
HBV (n ⫽ 38)
Other (n ⫽ 16)
94 (57)
42 (62)
20 (47)
26 (68)
6 (38)
17 (10) 13 (8) 25 (15) 55 (33)
7 (10) 3 (5) 8 (12) 18 (26)
3 (7) 6 (14) 10 (23) 19 (44)
4 (10) 1 (3) 6 (16) 11 (29)
3 (19) 3 (19) 1 (6) 7 (44)
12 (7) 4 (2) 16 (10)
5 (8) 3 (4) 8 (12)
3 (7) 1 (2) 4 (9)
1 (3) 0 (0) 1 (3)
3 (19) 0 (0) 3 (19)
NOTE. Values expressed as number (percent). Abbreviations: ALD, alcoholic liver disease; HCV, hepatitis C virus; HBV, hepatitis B virus.
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Table 3. Statistical Comparison using ANOVA and Chi-squared for Psychiatric Disorders and Psychological Scales Variable Gender Previous psychiatric history Underlying liver disease Alcohol abuse Age Child-Pugh score HDRS STAI-X1 STAI-X2
Psychiatric Disorders
HDRS
STAI-X1
STAI-X2
.048* .001* .068* .81 (NS)* .34 (NS)† .0001† .0001† .0001† .0001†
.12 (NS)† .0018† .16 (NS)† .53 (NS)† .48 (NS)† .0001†
.04† .0016† .11 (NS)† .38 (NS)† .17 (NS)† .0001†
.02† .0001† .16 (NS)† .68 (NS)† .16 (NS)† .0001†
NOTE. According to current psychiatric diagnoses, the sample (n ⫽ 126) was divided into five groups (see Methods section). Differences between these groups were analyzed as follows: categorical data (underlying liver disease, sex, past psychiatric history, previous alcohol abuse) were compared using Chi-squared, and continuous variables (age, Child-Pugh score, HDRS, STAI-X1, STAI-X2), using ANOVA. Analyses for psychological scales (HDRS, STAI-X1, STAI-X2) were by ANOVA. Abbreviation: HDRS, Hamilton Depression Rating Scale; STAI, State-Trait Anxiety Inventory; NS, not significant. *Chi-squared. †ANOVA.
Severity of psychiatric symptoms measured by psychometric scales (HDRS, STAI-X1, and STAI-X2) was associated with both previous and current psychiatric diagnoses, Child-Pugh score, and cause of liver disease in univariate analysis (Table 3), but with only ChildPugh score in the multiple regression model (dependent variable, HDRS; independent predictor, Child-Pugh score:  ⫽ 1.24; OR ⫽ 3.47; 95% CL RR, 3.03 to 3.91; P ⫽ .0001; dependent variable, STAI-X1; independent predictor, Child-Pugh score:  ⫽ 0.63; OR ⫽ 1.89; 95% CL RR, 1.67 to 2.11; P ⫽ .0001; dependent variable, STAI-X2; independent predictor, Child-Pugh score:  ⫽ 0.59; OR ⫽ 1.79; 95% CL RR, 1.59 to 1.99; P ⫽ .0001).
Discussion This study has two goals. The first goal is to assess the prevalence of psychiatric disorders in OLT candidates by means of standardized procedures because there has been little research concerning psychiatric problems of potential OLT candidates using standardized instruments. The second goal focuses on identifying predictors of these psychiatric disorders because results of other studies are contradictory. The prevalence of psychiatric diagnoses using the SCID has been assessed in a liver transplant population in few studies.8,9,12 Much of the relevant literature focuses on quality of life and psychiatric disorders throughout the transplantation process.5-7,24,25 A number of studies have assessed the prevalence of psychiatric disorders using psychometric scales, but findings need
to be interpreted with caution because the diagnosis of depression or anxiety needs a comprehensive clinical interview.11,13,26 We found a psychiatric morbidity prevalence of 43% (71 of 165 patients) in patients undergoing OLT. Our results show that nearly half the subjects studied had at least one psychiatric disorder. Thirty-three percent of patients (55 of 165 patients) had an adjustment disorder, usually with either depressed or anxious features. Our results partially agree with the previous studies of Trzepacz et al.8,9 First, nearly half the patients were not affected by specific psychiatric diagnoses, although they were in terminal stages of a severe medical illness and stressed by the uncertainty of whether they would be accepted for possible OLT. Second, adjustment disorders were the most common diagnoses, whereas major depression was infrequent. This finding is understandable given that most OLT candidates are under a high degree of stress. The transplantation process is characterized by uncertainty. Patients and families have no control over the availability of organs, timing of transplantation, events surrounding transplantation, transplant team decisions, or the development of problems after transplantation. The second aim of the study focuses on identifying predictors for psychiatric disorders in OLT candidates. Previous studies found an association between cause of liver disease (HCV infection, HBV infection, or alcoholic cirrhosis) and psychiatric disorders. Previous studies of the association between psychiatric disorders and cause of liver disease indicated that the morbidity of
Predictors of Psychiatric Disorders in OLT Candidates
mood and anxiety disorders was increased among patients with alcoholic cirrhosis compared with cirrhosis of other causes.14,15,27 Other studies supported an association between HCV infection and depression. These studies found that patients with HCV infection were more likely to have psychiatric disorders; depression was the most frequent and clinically important diagnosis.10,16,17,24,28-31 The described association by some investigators between a specific cause of liver failure and psychiatric diagnoses can be interpreted as a confounding finding emerging from a sample of patients taken at different times during the natural history of the progressive liver disease. To explain this apparent discordance, we found that previous psychiatric history and, above all, severity of liver disease (ChildPugh score) were factors independently associated with current psychiatric disorders and their severity. Our data are similar to those reported by other researchers.13,32,33 Severity of liver disease remains the most important independent predictor of severity of psychiatric disorders. One suggested explanation is that end-stage liver disease may produce changes in immune function that may lead to depressive symptoms.34 Another possible explanation is that psychiatric disorders could be related to HE or subclinical HE (SHE). Detection of overt HE is made clinically and does not provide a major diagnostic challenge. In our sample, no patient had symptoms suggesting a cognitive impairment; therefore, we did not proceed with specific tests of cognitive function. In our sample, the absence of HE could be caused by the selection criteria because our psychiatric unit did not evaluate all OLT candidates referred to the Gastroenterologic Unit, but only patients considered vulnerable to psychiatric disorders. Certainly, these selection criteria of patients, with no HE diagnosis and with elective patients, vulnerable to psychiatric disorders are an important limitation of our study; thus, our results could overestimate the presence of psychiatric disorders, particularly of adjustment disorders. Another important limitation is the undetected diagnosis of SHE. Additional studies are necessary to investigate the correlation between SHE and psychiatric disorders to identify a specific link between these two diagnoses. OLT before an advanced stage of disease progression could prevent the onset of psychiatric disorders. Moreover, many patients with psychiatric disorders may appropriately benefit from OLT, reducing the progression of severity of their psychiatric disorder. Future studies are indicated to determine whether early OLT could improve prognoses of psychiatric disorders.
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However, a relative scarcity of donor organs makes it necessary to distribute organs, and results in patient morbidity are greatest by the time of surgery. New horizons for OLT are posed by clinical accounts of living related liver transplantation. Living related liver transplantation is an established treatment for children with end-stage liver disease and recently has been performed successfully in adult patients. Another important aspect is the management of distressing emotional conditions in patients awaiting surgery and preoperative teaching. Patient information manuals, visits from successful liver transplant recipients, and conferences for the patient, family, and surgical team are additional steps to enhance the alliance between the patient and transplant team. Symptoms of psychological distress and depression should be specifically sought in these patients so that appropriate psychological interventions can be implemented early.
Acknowledgment The authors thank the Liver Transplantation Unit, Molinette Hospital, for help in patient recruitment.
References 1. Surman OS, Dienstag JL, Cosimi AB, Chauncey S, Russell PS. Psychosomatic aspects of liver transplantation. Psychother Psychosom 1987;48:26-31. 2. Surman OS. Psychiatric aspects of organ transplantation. Am J Psychiatry 1989;146:972-982. 3. Collis I, Lloyd G. Psychiatric aspects of liver disease. Br J Psychiatry 1992;161:12-22. 4. Wiltfang J, Nolte W, Weienborn K, Kornhuber J, Ru¨ ther E. Psychiatric aspects of portal-systemic encephalopathy. Metab Brain Dis 1998;13:379-389. 5. Wolcott DL. Organ transplant psychiatry: Psychiatry’s role in the second gift of life. Psychosomatics 1990;31:91-97. 6. Levenson JL, Olbrisch ME. Psychosocial evaluation of organ transplant candidates. A comparative survey of process, criteria, and outcomes in heart, liver, and kidney transplantation. Psychosomatics 1993;34:314-323. 7. Kita Y, Fukunishi I, Harihara M, Hirata M, Kubota K, Takayama T, et al. Psychiatric disorders in living-related liver transplantation. Transplant Proc 2001;33:1350-1351. 8. Trzepacz PT, Maue FR, Coffman G, Van Thiel DH. Neuropsychiatric assessment of liver transplantation candidates: Delirium and other psychiatric disorders. Int J Psychiatry Med 1986;16: 101-111. 9. Trzepacz PT, Brenner R, Van Thiel DH. A psychiatric study of 247 liver transplantation candidates. Psychosomatics 1989;30: 147-153. 10. Singh N, Gayowski T, Wagener MM, Marino IR. Vulnerability to psychologic distress and depression in patients with end-stage liver disease due to hepatitis C virus. Clin Transplant 1997;11: 406-411. 11. Caccamo L, Azara V, Doglia M, Sessini M, Rossi G, Gala C,
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Fassati LR. Longitudinal prospective measurement of the quality of life before and after liver transplantation among adults. Transplant Proc 2001;33:1880-1881. Fukunishi I, Sugawara Y, Takayama T, Makuuchi M, Kawarasaki H, Surman OS. Psychiatric disorders before and after living-related transplantation. Psychosomatics 2001;42: 337-343. Streisand RM, Rodrigue JR, Sears SF Jr, Perri MG, Davis GL, Banko CG. A psychometric normative database for pre-liver transplantation evaluations. The Florida Cohort 1991-1996. Psychosomatics 1999;40:479-485. Ewusi-Mensah I, Saunders JB, Wodak AD, Murray RM, Williams R. Psychiatric morbidity in patients with alcoholic liver disease. Br Med J 1983;287:1417-1419. Sarin SK, Sachdev G, Jiloha RC, Siloah RC, Bhatt A, Munjal GC. Pattern of psychiatric morbidity and alcohol dependence in patients with alcoholic liver disease. Dig Dis Sci 1988;33:443448. Singh N, Gayowski T, Wagener MM, Marino IR. Quality of life, functional status, and depression in male liver transplant recipients with recurrent viral hepatitis C. Transplantation 1999;67: 69-72. Dieperink E, Willenbring M, Ho SB. Neuropsychiatric symptoms associated with hepatitis C and interferon alpha: A review. Am J Psychiatry 2000;157:867-876. Conn Ho. A peek at the Child-Turcotte classification. Hepatology 1981;1:673-676. Garrison RN, Cryer HM, Howard DA, Polk HC Jr. Clarification of risk factors for abdominal operations in patients with hepatic cirrhosis. Ann Surg 1984;199:648-655. Infante-Rivard C, Esnaola S, Villeneuve JP. Clinical and statistical validity of conventional prognostic factors in predicting short-term survival among cirrhotics. Hepatology 1987;7:660664. Grossman MD, McGreevy JM. Effect of delayed operation for bleeding esophageal varices on Child’s class and indices of liver function. Am J Surg 1988;156:502-505. Hartmann AH, Bircher J, Cretzfeldt W. Superiority of the Child-Pugh classification to quantitative liver function tests for assessing prognosis of liver cirrhosis. Scand J Gastroenterol 1989; 24:269-276.
23. Child CG, Turcotte JC. Surgery and portal hypertension. Major Probl Clin Surg 1964;1:1-85. 24. De Bona M, Ponton P, Ermani M, Iemmolo RM, Feltrin A, Boccagni P, et al. The impact of liver disease and medical complications on quality of life and psychological distress before and after liver transplantation. J Hepatol 2000;33:609-615. 25. Shih FJ, Hu RH, Ho MC, Lin HY, Lin MH, Lee PH. Changes in health-related quality of life and working competence before and after liver transplantation. Transplant Proc 2000;32:21442148. 26. Singh N, Gayowski T, Wagener MM, Marino IR. Depression in patients with cirrhosis. Impact on outcome. Dig Dis Sci 1997; 42:1421-1427. 27. Romano DR, Jimenez C, Rodrı`guez F, Loinaz C, Colina F, Uren˜ a MA, et al. Orthotopic liver transplantation in alcoholic liver cirrhosis. Transplant Proc 1999;31:2491-2493. 28. Johnson ME, Fisher DG, Fenaughty A, Theno SA. Hepatitis C virus and depression in drug users. Am J Gastroenterol 1998;93: 785-789. 29. Yates WR, Gleason O. Hepatitis C and depression. Depress Anxiety 1998;7:188-193. 30. Dwight MM, Kowdley KV, Russo JE, Ciechanowski PS, Larson AM, Katon WJ. Depression, fatigue, and functional disability in patients with chronic hepatitis C. J Psychosom Res 2000;49: 311-317. 31. Zdilar D, Franco-Bronson K, Buchler N, Locala JA, Younossi ZM. Hepatitis C, interferon-alfa, and depression. Hepatology 2000;31:1207-1211. 32. Edwin D, Flynn L, Klein A, Thuluvath PJ. Cognitive impairment in alcoholic and nonalcoholic cirrhotic patients. Hepatology 1999;30:1363-1367. 33. Marchesini G, Bianchi G, Amodio P, Salerno F, Merli M, Panella C, et al, and The Italian Study Group for Quality of Life in Cirrhosis. Factor associated with poor health-related quality of life of patients with cirrhosis. Gastroenterology 2001;120:170178. 34. Connor TJ, Leonard BE. Depression, stress and immunological activation: The role cytokines in depressive disorders. Life Sci 1998;62:583-606.
O
rthotopic liver transplantation (OLT) is an accepted standard of care for end-stage liver disease. The pre-OLT period is marked by declining physical function, adjustment-related anxiety and depression, and development of organic brain deficits.1-4 Although several psychiatric follow-up studies are available for recipients and donors after OLT,5-7 there are few studies concerning the psychiatric status of potential OLT candidates before OLT. There is heterogeneity in the results of these studies, and the findings need to be interpreted with caution because psychiatric diagnoses were determined by means of psychometric scales and only in few cases by a comprehensive clinical interview.7,8-12 Reported prevalence rates of psychiatric disorders among OLT candidates vary from 15% to 50%.8-12 Another recent study describing psychological
characteristics of a large sample of OLT candidates reports that more than half the patients presented at least mild levels of depression, and more than one third were affected by clinically elevated levels of anxiety, suggesting a greater incidence of depression and anxiety than previously reported.13 A number of studies have attempted to correlate cause of hepatopathy with psychiatric disorders in patients with end-stage liver disease. Results are contradictory. In early studies, the morbidity of mood and anxiety disorders was increased in patients with alcoholic cirrhosis compared with cirrhoses of other causes, using the Schedule for Affective Disorders and Schizophrenia and Research Diagnostic Criteria.14,15 EwusiMensah et al14 found that two thirds of in-patients with alcoholic liver disease had diagnosable psychiatric disorders compared with one third of a control group of patients with nonalcoholic liver disease. Another study found that three quarters of patients with alcoholic liver disease were affected by psychiatric disorders compared with only a quarter of nonalcoholic patients with liver disease.15 Recent data reported that patients with endstage liver disease caused by hepatitis C virus (HCV) are more likely to have psychiatric disorders, with depression being the most frequent and clinically important.10,16 A recent review of available studies regarding neuropsychiatric symptoms in patients with chronic HCV infection indicated that the depression rate ranges between 2% and 30%.17 Aims of this prospective study are to: (1) identify and quantify the prevalence of psychiatric disorders present in elective OLT candidates at the time of their evaluation for hepatic transplantation by using stanFrom the *Department of Neuroscience, Psychiatric Section, University of Turin; †Statistical Unit, Molinette Hospital, Turin; and ‡Centro di Salute Mentale, Venaria (Torino), Department of Mental Health, Azienda Sanitaria Locale 6, Italy. Address reprint requests to Paola Rocca, MD, Department of Neuroscience, Psychiatric Section, University of Turin, Via Cherasco 11, 10126 Torino, Italy. Telephone: 39-011-663-4848; FAX: 39-011-673-473; E-mail: [email protected] Copyright © 2003 by the American Association for the Study of Liver Diseases 1527-6465/03/0907-0011$30.00/0 doi:10.1053/jlts.2003.50133
Liver Transplantation, Vol 9, No 7 ( July), 2003: pp 721-726
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dardized procedures, including a semistructured psychiatric interview and Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) diagnostic criteria; and (2) identify predictors of psychiatric disorders in these patients.
Methods Subjects All consecutive elective candidates for OLT presented to the Liver Transplant Unit, University of Turin, at the San Giovanni Battista Hospital of Turin, Italy, from 1990 to 1999 were referred to our Psychiatric Unit, Department of Neuroscience, University of Turin. Patients were considered for OLT if liver function suggested a poor prognosis, correlated with Child-Pugh score B or C. Child-Pugh classification is a prognostic index that has been used extensively to risk stratify patients with cirrhosis and evaluate the efficacy of therapeutic procedures, e.g., sclerotherapy, band ligation, transjugular intrahepatic portosystemic shunt placement, and surgical procedures.18-22 Child-Pugh grading of liver cirrhosis (grades A, B, and C) includes clinical (degree of ascites and hepatic encephalopathy [HE]) and laboratory parameters (values for albumin, prothrombin time, and bilirubin).23 We excluded patients transferred from intensive care units and those affected by acute complicated liver disorders. No patient included in the study had a previous or current history of delirium. For patients with alcohol-related liver disease, at least 1 year of abstinence and an ongoing treatment program were requested. All subjects, after a complete description of the study, provided their informed consent.
Psychiatric Assessment Each subject was assessed by two psychiatrists (E.Z. and P.R.). The psychiatric evaluation included a semistructured interview to collect demographic information and psychiatric history. Psychiatric diagnoses were made on the basis of the Structured Clinical Interview for DSM-IV (SCID). The interviewers had graduate degrees and clinical experience in the mental health field and had been trained in the use of SCID and assessment battery. In addition, severity of symptoms of affective functioning was assessed using the 21-item Hamilton Depression Rating Scale (HDRS) and the 40-item StateTrait Anxiety Inventory (STAI), a self-report measure of both current (STAI-X1) and dispositional anxiety symptoms (STAI-X2). Medical diagnosis and Child-Pugh score were assessed by experienced gastroenterologists of the unit. Medical diagnoses of chronic liver disease were based on extensive medical evaluation, including clinical and biochemical assessment of hepatic function and injury, imaging studies, serological testing, and histopathologic examination of a percutaneous liver biopsy (when indicated).
Statistical Analysis According to the current psychiatric diagnoses, the sample was divided into five groups as follows: dysthymic disorder (n ⫽ 4), major depression (n ⫽ 12), adjustment disorder with anxious mood (n ⫽ 17), adjustment disorder with depressed mood (n ⫽ 13), and adjustment disorder with mixed emotional features (n ⫽ 25). Differences between these groups were analyzed as follows: categorical data (underlying liver disease, sex, past psychiatric history, and previous alcohol abuse) were compared using Chi-squared, and continuous variables (age, Child-Pugh score, HDRS, STAI-X1, and STAI-X2) were compared using analysis of variance (ANOVA). Some patients were affected by alcohol cirrhosis. When patients with other cirrhoses had a positive history of alcohol abuse, effects of alcohol were assessed both independently and in association with other liver diseases. Distribution of all quantitative variables was checked for normality, and normal logarithmic transformation was performed for HDRS given its nonnormal distribution. A nonparametric statistical analysis was performed for those tests, but because statistical results closely paralleled the counfounding linear models, only results of linear analysis are reported here. Variables with P less than .10 in univariate analyses were included in multiple regression models. We estimated two separate logistic models. One model was the depressed patients model: major depression (n ⫽ 12), dysthymic disorder (n ⫽ 4), adjustment disorders with depressed mood (n ⫽ 13), and adjustment disorders with mixed emotional features (n ⫽ 25; total n ⫽ 54). The other model used for multiple regression analysis was the adjustment disorder group model: adjustment disorders with anxious mood (n ⫽ 17), adjustment disorders with depressed mood (n ⫽ 13), and adjustment disorders with mixed emotional features (n ⫽ 25; total n ⫽ 55). Analyses for psychological scales (HDRS, STAI-X1, and STAI-X2) were performed using ANOVA. Variables with P less than .10 in univariate analyses were included in multiple regression models. We used the two separate logistic models described (depressed patients model, n ⫽ 54; adjustment disorder group model, n ⫽ 55). The median value for each quantitative scale was used to obtain numerically balanced groups for the specific logistic model. Different logistic models (all not reported here) were used to test specific etiologic hypotheses.
Results One hundred sixty-five OLT candidates were assessed by our unit. Baseline sociodemographic and clinical characteristics of study patients are listed in Table 1. Sixty-six percent were men. Median age was 46 years (range, 16 to 62 years). One hundred seven patients (65%) had Child’s class C, and 58 patients (35%), class B. The most common liver diseases requiring OLT were HCV infection in 26%, hepatitis B virus (HBV) infection in 23%, and alcoholic liver disease in 41%.
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Predictors of Psychiatric Disorders in OLT Candidates
Table 1. Demographic and Clinical Variables in Pre-OLT Patients Variable
Value
No. of patients Age (yr) Gender (men/women) Underlying liver disease Alcoholic cirrhosis Viral hepatitis HCV HBV Other diagnoses Cryptogenic cirrhosis Primary biliary cirrhosis Familial amyloidosis Wilson’s disease Child-Pugh score Past psychiatric history Major depression Dysthymic disorder Generalized anxiety disorder Alcohol abuse/dependence Substance abuse/dependence HDRS STAI-X1 STAI-X2
165 46 ⫾ 9.11 109/56 68 81 43 38 16 8 4 3 1 10.1 ⫾ 2.14 10 (6) 5 (3) 6 (4) 83 (50) 25 (15) 9.95 ⫾ 6.74 42.7 ⫾ 11.9 41.7 ⫾ 11.5
NOTE. Values expressed as mean ⫾ SD or number (percent). Abbreviations: OLT, orthotopic liver transplantation; HCV, hepatitis C virus; HBV, hepatitis B virus; HDRS, Hamilton Depression Rating Scale; STAI, State-Trait Anxiety Inventory.
Based on an HDRS cutoff score greater than 8, 49% of patients (81 of 165 patients) had scores indicative of depressive symptoms. STAI scores can range from 20 to
80 for each of the two subscales; higher scores indicate more anxiety. Fifty-five percent of our sample (91 of 165 patients) reported state anxiety scores in the clinical range, and 53% (88 of 165 patients) had clinically elevated trait anxiety scores. In our sample, 71 subjects had a current psychiatric diagnosis: 77% (55 of 71 patients) had an adjustment disorder, and 23% (16 of 71 patients) had a mood disorder. Table 2 lists the distribution of psychiatric disorders according to underlying liver disease. To identify factors independently associated with psychiatric disorders, we analyzed the univariate association between both clinical psychiatric diagnoses and patient characteristics (variables: age, sex, cause of liver disease, Child-Pugh score, past psychiatric history, and alcohol abuse) using Chi-squared for categorical data and ANOVA for continuous variables. In univariate analysis, sex, cause of liver disease, previous psychiatric history, and Child-Pugh score were significant predictors of current psychiatric disorders (Table 3). Psychiatric disorders were not associated with previous alcohol abuse and age. Variables with P less than .10 in univariate analyses were included in multiple regression models. Multiple logistic regression analysis detected ChildPugh score and previous psychiatric history, but not cause of liver disease and sex, as independent predictors of psychiatric disorders for depressed patients (previous psychiatric history,  ⫽ 0.15; odds ratio [OR] ⫽ 1.16; 95% confidence limit [CL] relative risk [RR], 1.04 to 1.28; P ⫽ .006; Child-Pugh score,  ⫽ 3.34; OR ⫽ 28.22; 95% CL RR, 26.92 to 29.52; P ⫽ 0.0001) and only Child-Pugh score for the adjustment disorders group ( ⫽ 0.66; OR ⫽ 1.93; 95% CL RR, 1.65 to 2.21; P ⫽ .0001).
Table 2. Current DSM-IV Psychiatric Diagnoses of the Sample According to Liver Disease
No psychiatric diagnosis Adjustment disorders With anxious mood With depressed mood With mixed emotional features Total Depressive disorders Major depression Dysthymic disorder Total
Total (n ⫽ 165)
ALD (n ⫽ 68)
HCV (n ⫽ 43)
HBV (n ⫽ 38)
Other (n ⫽ 16)
94 (57)
42 (62)
20 (47)
26 (68)
6 (38)
17 (10) 13 (8) 25 (15) 55 (33)
7 (10) 3 (5) 8 (12) 18 (26)
3 (7) 6 (14) 10 (23) 19 (44)
4 (10) 1 (3) 6 (16) 11 (29)
3 (19) 3 (19) 1 (6) 7 (44)
12 (7) 4 (2) 16 (10)
5 (8) 3 (4) 8 (12)
3 (7) 1 (2) 4 (9)
1 (3) 0 (0) 1 (3)
3 (19) 0 (0) 3 (19)
NOTE. Values expressed as number (percent). Abbreviations: ALD, alcoholic liver disease; HCV, hepatitis C virus; HBV, hepatitis B virus.
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Table 3. Statistical Comparison using ANOVA and Chi-squared for Psychiatric Disorders and Psychological Scales Variable Gender Previous psychiatric history Underlying liver disease Alcohol abuse Age Child-Pugh score HDRS STAI-X1 STAI-X2
Psychiatric Disorders
HDRS
STAI-X1
STAI-X2
.048* .001* .068* .81 (NS)* .34 (NS)† .0001† .0001† .0001† .0001†
.12 (NS)† .0018† .16 (NS)† .53 (NS)† .48 (NS)† .0001†
.04† .0016† .11 (NS)† .38 (NS)† .17 (NS)† .0001†
.02† .0001† .16 (NS)† .68 (NS)† .16 (NS)† .0001†
NOTE. According to current psychiatric diagnoses, the sample (n ⫽ 126) was divided into five groups (see Methods section). Differences between these groups were analyzed as follows: categorical data (underlying liver disease, sex, past psychiatric history, previous alcohol abuse) were compared using Chi-squared, and continuous variables (age, Child-Pugh score, HDRS, STAI-X1, STAI-X2), using ANOVA. Analyses for psychological scales (HDRS, STAI-X1, STAI-X2) were by ANOVA. Abbreviation: HDRS, Hamilton Depression Rating Scale; STAI, State-Trait Anxiety Inventory; NS, not significant. *Chi-squared. †ANOVA.
Severity of psychiatric symptoms measured by psychometric scales (HDRS, STAI-X1, and STAI-X2) was associated with both previous and current psychiatric diagnoses, Child-Pugh score, and cause of liver disease in univariate analysis (Table 3), but with only ChildPugh score in the multiple regression model (dependent variable, HDRS; independent predictor, Child-Pugh score:  ⫽ 1.24; OR ⫽ 3.47; 95% CL RR, 3.03 to 3.91; P ⫽ .0001; dependent variable, STAI-X1; independent predictor, Child-Pugh score:  ⫽ 0.63; OR ⫽ 1.89; 95% CL RR, 1.67 to 2.11; P ⫽ .0001; dependent variable, STAI-X2; independent predictor, Child-Pugh score:  ⫽ 0.59; OR ⫽ 1.79; 95% CL RR, 1.59 to 1.99; P ⫽ .0001).
Discussion This study has two goals. The first goal is to assess the prevalence of psychiatric disorders in OLT candidates by means of standardized procedures because there has been little research concerning psychiatric problems of potential OLT candidates using standardized instruments. The second goal focuses on identifying predictors of these psychiatric disorders because results of other studies are contradictory. The prevalence of psychiatric diagnoses using the SCID has been assessed in a liver transplant population in few studies.8,9,12 Much of the relevant literature focuses on quality of life and psychiatric disorders throughout the transplantation process.5-7,24,25 A number of studies have assessed the prevalence of psychiatric disorders using psychometric scales, but findings need
to be interpreted with caution because the diagnosis of depression or anxiety needs a comprehensive clinical interview.11,13,26 We found a psychiatric morbidity prevalence of 43% (71 of 165 patients) in patients undergoing OLT. Our results show that nearly half the subjects studied had at least one psychiatric disorder. Thirty-three percent of patients (55 of 165 patients) had an adjustment disorder, usually with either depressed or anxious features. Our results partially agree with the previous studies of Trzepacz et al.8,9 First, nearly half the patients were not affected by specific psychiatric diagnoses, although they were in terminal stages of a severe medical illness and stressed by the uncertainty of whether they would be accepted for possible OLT. Second, adjustment disorders were the most common diagnoses, whereas major depression was infrequent. This finding is understandable given that most OLT candidates are under a high degree of stress. The transplantation process is characterized by uncertainty. Patients and families have no control over the availability of organs, timing of transplantation, events surrounding transplantation, transplant team decisions, or the development of problems after transplantation. The second aim of the study focuses on identifying predictors for psychiatric disorders in OLT candidates. Previous studies found an association between cause of liver disease (HCV infection, HBV infection, or alcoholic cirrhosis) and psychiatric disorders. Previous studies of the association between psychiatric disorders and cause of liver disease indicated that the morbidity of
Predictors of Psychiatric Disorders in OLT Candidates
mood and anxiety disorders was increased among patients with alcoholic cirrhosis compared with cirrhosis of other causes.14,15,27 Other studies supported an association between HCV infection and depression. These studies found that patients with HCV infection were more likely to have psychiatric disorders; depression was the most frequent and clinically important diagnosis.10,16,17,24,28-31 The described association by some investigators between a specific cause of liver failure and psychiatric diagnoses can be interpreted as a confounding finding emerging from a sample of patients taken at different times during the natural history of the progressive liver disease. To explain this apparent discordance, we found that previous psychiatric history and, above all, severity of liver disease (ChildPugh score) were factors independently associated with current psychiatric disorders and their severity. Our data are similar to those reported by other researchers.13,32,33 Severity of liver disease remains the most important independent predictor of severity of psychiatric disorders. One suggested explanation is that end-stage liver disease may produce changes in immune function that may lead to depressive symptoms.34 Another possible explanation is that psychiatric disorders could be related to HE or subclinical HE (SHE). Detection of overt HE is made clinically and does not provide a major diagnostic challenge. In our sample, no patient had symptoms suggesting a cognitive impairment; therefore, we did not proceed with specific tests of cognitive function. In our sample, the absence of HE could be caused by the selection criteria because our psychiatric unit did not evaluate all OLT candidates referred to the Gastroenterologic Unit, but only patients considered vulnerable to psychiatric disorders. Certainly, these selection criteria of patients, with no HE diagnosis and with elective patients, vulnerable to psychiatric disorders are an important limitation of our study; thus, our results could overestimate the presence of psychiatric disorders, particularly of adjustment disorders. Another important limitation is the undetected diagnosis of SHE. Additional studies are necessary to investigate the correlation between SHE and psychiatric disorders to identify a specific link between these two diagnoses. OLT before an advanced stage of disease progression could prevent the onset of psychiatric disorders. Moreover, many patients with psychiatric disorders may appropriately benefit from OLT, reducing the progression of severity of their psychiatric disorder. Future studies are indicated to determine whether early OLT could improve prognoses of psychiatric disorders.
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However, a relative scarcity of donor organs makes it necessary to distribute organs, and results in patient morbidity are greatest by the time of surgery. New horizons for OLT are posed by clinical accounts of living related liver transplantation. Living related liver transplantation is an established treatment for children with end-stage liver disease and recently has been performed successfully in adult patients. Another important aspect is the management of distressing emotional conditions in patients awaiting surgery and preoperative teaching. Patient information manuals, visits from successful liver transplant recipients, and conferences for the patient, family, and surgical team are additional steps to enhance the alliance between the patient and transplant team. Symptoms of psychological distress and depression should be specifically sought in these patients so that appropriate psychological interventions can be implemented early.
Acknowledgment The authors thank the Liver Transplantation Unit, Molinette Hospital, for help in patient recruitment.
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