Evidence of psychosocial influences on acute rejection after liver transplantation

OUTCOMES

Evidence of Psychosocial Influences on Acute Rejection After Liver Transplantation M. Walter, M. Hildebrandt, J. Ru¨ter, A. Pascher, P. Neuhaus, G. Danzer, and B.F. Klapp

I

N ORTHOTOPIC LIVER transplantation (OLT), the occurrence of acute transplant rejection has decreased substantially as a result of novel immunosupressive regimens. The incidence of rejection within the first 3 weeks following OLT varies between 20% and 70% depending on the immunosuppressive regimen.1 Patients experiencing acute transplant rejection are not prone to an increased risk of chronic rejection2; the occurrence of an acute rejection episode, however, may be associated with insufficient immunosuppression.3 The impact of psychosocial stressors on the occurrence of complications following OLT has not been studied extensively. Higher values of anxiety, depression, and feelings of distress have been described mainly during the preoperative period.4 Following OLT, patients described an overall improvement in mood and quality of life.5 No evidence has been found for an association between post-surgical complications and quality of life.6 The present study describes the association between distinct preoperative psychosocial parameters and the incidence of acute transplant rejections following OLT. PATIENTS AND METHODS Patients The present study is embedded within a 10-year longitudinal analysis spanning 1990 to 2000 at the Charite´ University Hospital by the Department of Internal Medicine—Psychosomatics, in cooperation with the Department of Surgery. During the evaluation period for this special study (March 1998 to June 2000), OLTs were performed on 254 patients. Complete somatic and psychometric data were available for 62 patients before surgery, including 24 women (38.7%) and 38 men (61.3%) with an average age of 50 years. The youngest patient was aged 23 years, and the oldest was aged 69 years. The sample included 14 patients with acute rejection

episodes and 48 patients without acute rejection within the first 20 days after liver transplantation.

Acute Rejection The diagnosis of rejection was made by evaluation of clinical and laboratory findings together with histological findings. The rejection was divided into four histopathologic grades: 0, none; 1, mild periportal mononuclear infiltrates, minimal endothelitis, and minimal bile duct injury; 2, moderate periportal mononuclear infiltrates, marked endothelitis, marked bile duct injury, and single cell hepatocyte necrosis; and 3, similar but more aggressive alterations than in grade 2, and massive confluent hepatocyte necrosis.

Psychosocial Questionnaires Before surgery psychological well-being was analyzed using the Berlin Mood Questionnaire (Berliner Stimmungsfragebogen, BSF),7 covering the dimensions of elevated mood, anxious depression, anger, and tiredness. The physical complaints were examined with the Giessen Complaint Questionnaire (GCQ Gießener Beschwerdebogen, GBB).8 For the assessment of personality trait variables the Gießen-test (GT) was used in the self-assessment version.9 This instrument is widely used in German-speaking areas. Its advantage lies in the inclusion of social attitudes and reactions. Self-profiles were calculated on the basis of six GT-standard scales: social resonance, dominance, control, basic mood, emotional openness, From the Clinic for Internal Medicine—Psychosomatics and Clinic for Abdominal and General Surgery, Charite´, HumboldtUniversity Berlin, Berlin, Germany. Address reprint requests to Dr Marc Walter, Clinic for Internal Medicine—Psychosomatic, Charite´, Humboldt-University Berlin, Luisenstr. 13 a, D- 10117 Berlin, Germany. E-mail: [email protected]

0041-1345/02/$–see front matter PII S0041-1345(02)03623-0

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Transplantation Proceedings, 34, 3298 –3301 (2002)

PSYCHOSOCIAL INFLUENCES ON ACUTE REJECTION

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Table 1. Social Parameters and Primary Liver Disease Before OLT

Age (y) Sex Female Male Family situation Living with a partner Living without a partner Job situation Employed Retired Underlying disease Alcoholic cirrhosis Post-hepatitis cirrhosis Autoimmune cirrhosis Other diseases

Patients With Acute Rejection (n ⫽ 14)

Patients Without Acute Rejection (n ⫽ 48)

M ⫽ 50.0/SD ⫽ 2.6

M ⫽ 50.2/SD ⫽ 1.6

18 (37.5%) 30 (62.5%)

6 (42.9%) 8 (57.1%)

11 (78.6%) 3 (21.4%)

44 (91.7%) 4 (8.3%)

P

Z ⫽ 0.093, NS ␹2 ⫽ 2.31, NS

␹2 ⫽ 0.14, NS

␹2 ⫽ 3.14, NS 4 (21.4%) 10 (78.6%)

16 (33.3%) 32 (66.7%)

6 (42.9%) 3 (21.4%) 1 (28.6%) 4 (28.6%)

16 (33.3%) 13 (27.1%) 11 (22.9%) 8 (16.7%)

␹2 ⫽ 2.01, NS

and social competence. All of the above questionnaires have been validated as reliable in previous clinical studies. Statistical analyses were performed with SPSS/10.0 for Windows. We used the Mann-Whitney test (U test) for group comparisons and the chi-square test. The level of significance was set at P ⬍ .05.

RESULTS Social Parameters and Primary Liver Disease Before OLT

Fifty-five patients (88.7%) lived in stable partnerships. Twenty patients (32.3%) were employed and 42 subjects (67.7%) were retired because of chronic liver disease. The causes of primary liver disease were alcoholic cirrhosis (n ⫽ 21), post-hepatitis cirrhosis (n ⫽ 17), primary sclerotic cholangitis (n ⫽ 6), primary biliary cirrhosis (n ⫽ 6), hepatocellular carcinoma (n ⫽ 4), hematochromatosis (n ⫽ 2), Budd-Chiari syndrome (n ⫽ 2), Wilson’s disease (n ⫽ 2), polycystic liver disease (n ⫽ 1), and acute liver failure (n ⫽ 1). Social parameters and liver diseases for patients with versus without acute rejection episodes after OLT are noted in Table 1. Significant differences in distribution of social parameters and liver disease were not observed.

Acute Rejection After OLT

Overall 14 patients (22.6%) experienced an acute rejection episode within the first 20 days after transplantation. Seven rejections were graded as mild, five as moderate, and two as severe. The earliest rejection episode was observed at day 4 and the latest at day 20. Immunosuppression After OLT

Thirty-four patients (54.8%) were treated with cyclosporine and basiliximab, 19 (30.6%) with tacrolimus, and 9 (14.5%) with sirolimus. There were no significant differences in the incidence of acute rejection episodes among patients treated with the different regimens (␹2 ⫽ .22, NS). Physical Complaints Before OLT

The patients showed significantly higher complexes, “fatigue” and “upper-abdominal complaint” during preoperative assessment, (P ⬍ .001) than the average population (n ⫽ 1557).8 But there were no significant differences between patients with versus without acute rejection (Table 2). Patients with acute rejection episodes, however, reported a

Table 2. Symptoms and Mood Before OLT

Symptoms Fatigue Upper-abdominal symptoms Limb pain Cardiac symptoms Mood Tiredness Anxious depression Anger Elevated mood

Patients With Acute Rejection (n ⫽ 14)

Patients Without Acute Rejection (n ⫽ 48)

M (SD)

M (SD)

7.8 (5.0) 2.4 (2.7) 6.5 (4.5) 1.9 (2.3)

9.7 (6.4) 4.3 (4.4) 6.1 (5.1) 3.0 (3.9)

0.5 (0.6) 0.6 (0.7) 0.1 (0.1) 2.2 (1.2)

1.2 (1.1) 1.0 (0.7) 0.4 (0.5) 1.6 (1.0)

P

Z Z Z Z

⫽ ⫽ ⫽ ⫽

0.89, 1.61, 0.42, 0.83,

NS NS NS NS

Z ⫽ 2.10, P ⫽ .03 Z ⫽ 1.97, P ⫽ .04 Z ⫽ 2.32, P ⫽ .02 Z ⫽ 1.59, NS

WALTER, HILDEBRANDT, RU¨ TER ET AL

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Fig 1. Personality traits before OLT.

tendency toward less complaints with the exception of limb pain, suggesting more psychosomatic tension. Mood Before OLT

Prior to transplantation, the overall group of patients showed on average lower values (P ⬍ .001) of the mood dimensions of “tiredness” and “anger” than 229 healthy controls.7 Patients who experienced an acute transplant rejection episode showed significantly lower values for “tiredness,” “anxious depression,” and “anger” before transplantation than did patients free of early rejection. Both groups did not differ on the scale of “elevated mood” (Table 2). Personality Traits Before OLT

Figure 1 shows that the profiles of preoperative personality traits of patients with versus without acute rejection differed especially with regard to submissive behavior (Z ⫽ 2.04 P ⫽ .041). Patients with acute rejection viewed themselves as submissive, relatively controlled, of indifferent mood, relatively emotionally open, and socially competent. On the other hand, patients without acute rejection displayed less submissive, less controlled, and less emotionally open personalities. The basic mood and social competence of both groups, however, did not differ in their view of themselves. DISCUSSION

Accumulating evidence suggests that psychosocial factors may impinge on immune-related events such as modulation of T-cell responses10 or exacerbation of immune-related disorders.11 Distress as well as depressive moods have been shown to correlate with the modulation of distinct immune responses12 and therefore, may contribute to transplant rejections as well. With respect to OLT, possible interactions between psychosocial factors assessed prior to surgery and postoperative complications have been studied to only a small extent.13 In the present study, we report that, prior

to transplantation, patients who experienced acute rejection following OLT showed lower levels of negative moods and believed themselves to be more controlled and submissive than patients who did not develop acute rejection following OLT. In view of a potentially harmful procedure intended to provide cure from a life-threatening disease, these observations can be interpreted as a non-utterance or even denial of emotions experienced prior to OLT. This may be a sufficient coping strategy for an acute life-threatening situation,14 but it does not appear to be a sufficient measurement for subacute stress and distress resulting in higher risk for bodily disturbances like immunological imbalance. The observations presented here may contribute to a more thorough understanding of the implications of psychosocial factors on the outcome of disease, in this case OLT. Additional studies are needed to provide a link between changes in immune function during allograft rejection and psychosocial parameters, thus bridging the gap between existing animal models and observations in humans. Furthermore, psychosocial parameters could, if proven in other studies, contribute to an improved prediction of success or failure of OLT. REFERENCES 1. Neuberger J: Liver Transpl Surg 5:S30, 1999 2. Tippner C, Nashan B, Hoshino K, et al: Transplantation 72:1122, 2001 3. Neuberger J, Adams DH: J Hepatol 29M:143, 1998 4. Stilley CS, Miller DJ, Gayowski T, et al: Clin Transplant 12:416, 1998 5. Walter M, Moyzes D, Rose M, et al: Clin Transplant 16:301, 2002 6. Hunt CM, Camargo CA, Dominitz JA, et al: Clin Transplant 12:99, 1998 7. Ho ¨rhold M, Klapp BF: Med Psychol 2:27, 1993 8. Bra¨hler E, Scheer JW: Der Gießener Beschwerdebogen GBB. Bern; Huber; 1983 9. Beckmann D, Bra¨hler E, Richter HE: Der Gießen-Test (GT). Bern; Huber; 1991 10. Tournier JN, Mathieu J, Mailfert Y, et al: Immunology 102:87, 2001

PSYCHOSOCIAL INFLUENCES ON ACUTE REJECTION 11. Levenstein S, Prantera C, Varvo V, et al: Am J Gastroenterol 95:1213, 2000 12. Arck PC, Rose M, Hertwig E, et al: Hum Reprod 16:10505, 2001

3301 13. Braslavsky G, Rosas C, Ia Cava E, et al: Transplant Proc 31:3060, 1999 14. Klapp BF: Psychosoziale Intensivmedizin. Springer: Berlin; 1985