The heart transplantation team and gastroenterology section at Temple University Hospital had informally noted the occurrence of pancreaticobiliary disease in several patients after orthotopic heart transplantation. Because our institution is one of the most active cardiac transplantation centers in the United States, we studied this problem in detail.

Methods

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We did a retrospective case–control analysis of 255 transplant recipients who were evaluated before transplantation, received transplants, and were followed after transplantation exclusively at Temple University Hospital from August 1985 to July 1994. Patients who did not have their complete follow-up at Temple were excluded from the analysis (n = 132).

We searched for cases using two methods. First, a computer search of the hospital's Medical Information System was done. Cases with discharge diagnosis International Classification of Diseases 9th revision codes for both orthotopic heart transplantation and pancreatic or biliary disease were identified. Appropriateness was determined by review of the chart. Second, cases were identified by interviews with the heart transplantation staff. Because this was a retrospective study, there were no uniform criteria for establishing a clinical diagnosis of pancreaticobiliary tract disease. Diagnostic testing and the need for surgery were determined by the physician or physicians caring for the patient.

Two controls were selected for each case-patient from the available 235 patients. Each control had received a transplant at about the same time as a case-patient and had survived for the same interval. The controls were not matched for age or sex. Both outpatient and inpatient records were reviewed by a single physician reviewer. Information was gathered using a structured data abstraction protocol created before the start of data collection. Risk factors assessed before transplantation were cause of heart disease, history of diabetes, reproductive history, and sex. Risk factors assessed at the time of presentation with pancreaticobiliary disease were weight change after transplantation, alcohol use, use of medications, recent total parenteral nutrition, age at symptom onset, rejection episode in the past month, cyclosporine level, complete blood count, time between orthotopic heart transplantation and symptom onset, body mass index, calcium level, liver function test results before and after symptom onset, and lipid profile. Controls were assessed at an interval after transplantation similar to that of the case-patients.

Outcomes after treatment of pancreaticobiliary disease were assessed by telephone interview or office visit at both 2 and 6 months with the following grading scale: excellent (no further symptoms after the initial episode), good ( two episodes of discomfort not requiring rehospitalization), fair (more than two episodes not requiring rehospitalization), poor (rehospitalization for symptoms), and very poor (reoperation or death). An indeterminate result was reserved for patients who did not survive to the assessment interval because of death due to causes other than pancreaticobiliary disease or for patients who were lost to follow-up.

Statistical analysis was done with Systat for Windows, version 5.0 (SPS, Inc., Chicago, Illinois). The Student t-test was used for parametric comparisons, the chi-square test was used for categorical data, and multiple regression analysis was used for the determination of risk factors. Results were considered statistically significant if the P value was less than 0.05.

Results

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Twenty cases of pancreaticobiliary disease were identified in the transplantation population at risk (mean age, 51.1 ± 11.7 years), and 40 controls were identified (mean age, 52.6 ± 12.2 years). Demographic data are shown in Table 1. Case-patients consisted of 17 men and 3 women, and the control group comprised 30 men and 10 women. No statistically significant differences were seen in age, sex, recent rejection, body mass index, weight change, or cyclosporine or triglyceride levels between case-patients at the time of presentation for pancreaticobiliary disease and controls. A significantly decreased calcium level relative to that of controls was noted in the case-patients (2.19 ± 0.17 mmol/L for case-patients compared with 2.31 ± 0.14 mmol/L for controls; P = 0.005). However, both levels remained within the laboratory's normal range (2.12 mmol/L to 2.62 mmol/L).

Ischemia was the most frequent cause of endstage heart disease in both case-patients and controls (Table 2). Idiopathic conditions (not otherwise identified) were the second most frequent cause in both groups. Other diagnoses were hypertensive, viral, valvular, and miscellaneous causes, including postpartum cardiomyopathy.

The 20 case-patients with pancreaticobiliary disease represented 7.8% of 255 eligible transplant recipients. Median time from transplantation to symptom onset was 319 days (range, 17 to 2891 days). Ten of 20 cases (3.9% of eligible recipients) occurred within the first year after transplantation, and 15 occurred within the first 2 years. Surgical intervention was necessary in 15 of the 20 case-patients: Fourteen had cholecystectomies and 1 had cholecystostomy. Surgical or radiologic evidence of cholelithiasis was found in 14 case-patients, gallbladder sludge was found in 5 case-patients, and a combination of the two was found in 1 case-patient.

Mean length of hospital stay was 17.1 ± 16.1 days (median, 11 days) for orthotopic heart transplant recipients compared with 7.2 ± 10.2 days (median, 4 days) for 104 patients with pancreaticobiliary disease who did not have heart transplantation and were treated at Temple University Hospital during a similar period (P < 0.001).

Acute cholecystitis was the most common manifestation of pancreaticobiliary disease (40%). Symptomatic cholelithiasis accounted for 30% of cases of pancreaticobiliary disease, chronic cholecystitis accounted for 25%, and gallstone pancreatitis accounted for 5%.

The incidence of pancreaticobiliary disease in patients receiving orthotopic heart transplants increased substantially during the first 2 years of our study and then paralleled the incidence expected in the general U.S. population (Figure 1). The difference between the two groups was significant (P < 0.01).

View larger version (15K): [in this window] [in a new window]   Figure 1. Cumulative incidence of pancreaticobiliary disease in recipients of orthotopic heart transplantation. Shown are data for patients in this study and for age-corrected adults in the general U.S. population [10]. The incidence increases dramatically over the first 2 years and then parallels that of the comparison group. Solid line indicates incidence in transplant recipients; dashed line indicates expected incidence in the general U.S. population.

Assessment at both 2 and 6 months showed that most patients had an excellent outcome. At both assessments, 75% of patients had either good or excellent outcomes; no patients had fair, poor, or very poor results. At 2 months, 70% of patients had excellent outcomes, 5% had good outcomes, and 25% had indeterminate outcomes. At 6 months, 55% of patients had excellent outcomes, but 20% had good outcomes. Outcomes in the rest of the patients were indeterminate.

Discussion

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The results of our study support the hypothesis that the incidence of pancreaticobiliary disease increases after orthotopic heart transplantation. The incidence of pancreaticobiliary disease in orthotopic heart transplant recipients in our study (7.8%) was higher than that found in all but one of the previously reported studies [7]. One year after orthotopic heart transplantation, the incidence was 17.4 times (95% CI, 9.2 to 32.7 times) higher in the patients receiving orthotopic heart transplants than that expected in the age-corrected general U.S. population [10].

Possible causes for the increased incidence of pancreaticobiliary disease after orthotopic heart transplantation include gallbladder dysmotility due to surgical vagotomy at transplantation, intraoperative or postoperative ischemia, idiosyncratic responses to cyclosporine, preexisting gallstone disease with symptoms developing after transplantation, and other factors that have not yet been determined.

Hypercalcemia has been associated with pancreaticobiliary disease (pancreatitis) in rare cases [11]. We found that calcium levels were substantially decreased in case-patients compared with those of controls. Both values, however, were within the normal range for our institution. The pathophysiologic significance of this finding is unclear. Pancreatitis occurred only in one case-patient.

Gallbladder emptying is controlled by both neural and humoral factors. During transplantation, the vagus nerve is transected, a physiologic insult that has been associated with an increased incidence of gallstones [12, 13]. Dysmotility may then lead to stasis, which is a risk factor for cholelithiasis [14]. Prolonged stasis of bile within the gallbladder results in increased water reabsorption and increased lithogenicity of bile. Nucleation could then occur, and stone formation could result.

The Framingham group [15] has reported that ischemic heart disease, the most frequent reason for heart transplantation in this series, is associated with cholesterol cholelithiasis. In this study, the association was found in men but not in women. After transplantation, patients depend on cholecystokinin to stimulate gallbladder contraction because of vagotomy at surgery. Ischemia of the gallbladder may occur during transplantation, rejection episodes, or reoperation.

Cyclosporine may also have a role in the formation of gallstones after transplantation. Investigators [16, 17] have found that cyclosporine decreases bile flow in rats through both bile salt-dependent and bile salt-independent mechanisms. Cyclosporine metabolites have also been found in human bile, but the effect of cyclosporine on bile lithogenicity has not been studied in humans [18]. Cyclosporine causes cholestasis in renal and heart transplantation recipients and causes cholelithiasis in renal transplant recipients [19, 20]. Because no statistically significant difference was seen in cyclosporine levels between case-patients and controls, the cyclosporine level itself may not be the causal connection. However, individual patients may be hypersensitive to the biliary effects of the cyclosporine level, which result in sludge or stone formation.

Preexisting gallstone disease in patients who have not yet received transplants is an important consideration but has not been adequately evaluated. Determination of the prevalence of cholelithiasis before transplantation would permit the evaluation of 1) the development of pancreaticobiliary disease in patients with cholelithiasis or sludge formation before transplantation and 2) the occurrence of pancreaticobiliary disease after transplantation in patients whose cholelithiasis or sludge developed after transplantation.

Potential limitations of our study include ascertainment bias and the loss of 132 patients to follow-up. Because these patients were in a heart transplantation program, they were followed more closely than persons in the general population would have been. This may have led to a higher rate of diagnosis (ascertainment bias), especially in the groups with chronic cholecystitis and symptomatic cholecystitis. It is unlikely that the patients with acute pancreatitis or acute cholecystitis (about half of all case-patients) would have been affected by ascertainment bias. The incidence of pancreaticobiliary disease in the 132 patients not followed is unknown. However, even if no cases of pancreaticobiliary disease developed in the excluded patients, the incidence rate would decrease to only 5.7%, which is still much higher than the expected 0.2%.

In summary, our data suggest that pancreaticobiliary disease occurs more frequently in patients receiving orthotopic heart transplants than in a similar U.S. population, particularly in the first 2 years after transplantation. Although hospitalization for pancreaticobiliary disease lasted longer than expected in patients receiving orthotopic heart transplantations, the outcomes of these patients were generally excellent. We conclude that pancreaticobiliary disease is a little recognized yet common complication of heart transplantation. Because there is no evidence that the transplantation itself is the cause of pancreaticobiliary disease, further study is needed to determine why heart transplant recipients are at increased risk for the disease and how their risk can be reduced.

Dr. Pina: Cardiology Section, Temple University Hospital, 3401 North Broad Street, Philadelphia, PA 19140.

Dr. Krevsky: Gastroenterology Section, Temple University Hospital, 3401 North Broad Street, Philadelphia, PA 19140.