Effect Of Orthotopic Liver Transplantation Research Articles

Liver Transplantation Improves Survival of Rats Bearing Hepatoma-3924A

There was interest in developing a rat model of hepatocellular carcinoma with tumor dissemination that would respond to liver transplantation. Thus, a model of intrahepatic hepatoma implantation with micrometastases was developed by modifying a previously reported technique in the ACI rat. The pattern of tumor growth permits surgical resection with liver transplantation if done early in the course of disease. In addition, this model results in a reproducible rate of pulmonary metastatic disease. The pulmonary metastatic rate (number of rats developing pulmonary metastases) was 45.5% (n= 11) 2 weeks following intrahepatic tumor implantation and rose to 100% at the fifth week (n= 7). To examine the long-term outcome of animals with tumor, 46 animals were followed until death or 100 days after tumor implantation. Of these animals, 67.4% died from tumor within 100 days, all with pulmonary metastases. Several of the animals that were followed long term had advanced liver tumor as well, with intraperitoneal spread and ascites. To evaluate the effect of orthotopic liver transplantation (OLTX) in this model, syngeneic OLTX was performed 16 days after intrahepatic tumor implantation (n= 11). OLTX improved the 100-day survival of the recipients from 32.6% (control group) to 80.0% (P< 0.05). None of the long-term survivors had evidence of tumor on postmortem examination. The mechanisms responsible for decreased metastases following syngeneic liver transplantation are being investigated. The influence of immunosuppression, more advanced stage of tumor at the time of OLTX, and chemotherapeutic agents on this survival benefit could be be investigated with this model.

Effect of orthotopic liver transplantation on employment and health status.

Employment, functional status, health status, and prevalence of anxiety and depression were assessed in patients who had undergone orthotopic liver transplantation at Duke University from 1984 to 1993 to identify social and economic factors that might influence return to work after liver transplantation. Patients were asked to complete mailed questionnaires. A transplant nurse coordinator assigned patients a Karnofsky score, unaware of the questionnaire responses. The response rate was 71% (52 of 72 patients). The median age of the post-liver transplantation patients was 49 years. Median years of education were 13. Sixty-five percent of patients were male. Sixty percent of patients were employed posttransplantation. Employed and unemployed posttransplantation patients showed no significant difference in age, education, gender, marital status, race, family coping skills, or cause of liver disease. Return to work after transplantation did not correlate with socioeconomic status or spouse's employment. Posttransplantation return to work was highly correlated with pretransplant employment (P < .0005). The prevalence of anxiety and depression, assessed by the Hospital Anxiety and Depression Scale (HAD), was 9% and was no different in the employed or unemployed patients. Health status, as measured by Karnofsky score, was excellent; all patients received Karnofsky scores > or = 80%. Health perceptions were compared in employed versus unemployed posttransplantation patients with the SF-36, a 36-item short form survey developed by the investigators of the Medical Outcome Study. This revealed significantly different values in the subscale, physical functioning, with a mean score of 70.6 in the employed and a mean score of 48.4 in the unemployed posttransplantation patients (P = .004) and role-physical with a mean score of 61.8 in the employed and a mean score of 27.6 in the unemployed posttransplantation patients (P = .005). Eighty percent of patients not returning to work cited "problems with their health" as their major obstacle to employment. Although objective health status was good to excellent in all patients after transplantation, patients perceived that their health status was poor, with the lowest scores observed in unemployed posttransplantation patients.

Effect of orthotopic liver transplantation on employment and health status: [formula omitted], M.D. 1, J.S. Tart, R.N., M.S.N. 2, E. Dowdy, A.C.S.W. 3, B.P. Bute, Ph.D. 1, and D.M. Williams, M.D. 1 Departments of Medicine 1, Surgery 2, and Social Work 3, Duke University Medical Center, Durham NC 27710

Effect of orthotopic liver transplantation on employment and health status: [formula omitted], M.D. 1, J.S. Tart, R.N., M.S.N. 2, E. Dowdy, A.C.S.W. 3, B.P. Bute, Ph.D. 1, and D.M. Williams, M.D. 1 Departments of Medicine 1, Surgery 2, and Social Work 3, Duke University Medical Center, Durham NC 27710

Liver transplantation induces cytochrome P450 1A1 dependent monooxygenase activity in rat lung and kidney.

Although liver transplantation has been the subject of intensive investigation, comparatively little is known regarding the effects of this procedure on the metabolism of xenobiotics. The objective of the present study was to examine the effect of orthotopic liver transplantation on rat hepatic, pulmonary, and renal microsomal cytochrome P450 (P450) monooxygenase activity through the use of isozyme-selective substrates. Pulmonary microsomal P450 1A1 dependent 7-ethoxyresorufin O-deethylation (ERFD) activity increased over time in recipient rats, with maximal induction (750% of donor) observed after 21 days. Similarly, ERFD activity in renal microsomes was increased (200% of donor) after 21 days. Both pulmonary and renal microsomal P450 2B dependent 7-pentoxyresorufin O-depentylation (PRFD) activity was decreased (50 and 75% of donor) 1 day after transplantation but was essentially unchanged 3, 7, and 21 days after transplantation. Pulmonary and renal microsomal heme oxygenase activities were not significantly affected by liver transplantation. In contrast, total hepatic microsomal P450 concentrations were decreased maximally (to 45% of donor concentration) 7 days after transplantation and remained low (55% of donor) up to 21 days. Similarly, hepatic P450 1A dependent ERFD and P450 2B dependent PRFD activities were maximally depressed (20 and 25% of donor activities) after 7 days and remained low (75 and 30% of donor) up to 21 days after transplantation. The decreases in rates of hepatic P450 monooxygenation were accompanied by significant increases in microsomal heme oxygenase activity. The data presented in this study suggest the existence of generalized stress responses to inflammation that result in tissue- and isozyme-selective modulation of P450 monooxygenase activity.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of Orthotopic Liver Transplantation on Bone Mineral Content and Serum Vitamin D Metabolites in Infants and Children With Chronic Cholestasis

Almost all infants and children with chronic cholestasis have osteopenia. We evaluated the effect of orthotopic liver transplantation on bone mineral content and serum 25(OH)-vitamin D-[25(OH)D]-of nine infants and children (five girls; age, 6 to 21 mo at the time of orthotopic liver transplantation) with end-stage liver disease resulting from chronic cholestasis. We hypothesized that after orthotopic liver transplantation, decreased bone mineral content will recover and the serum 25(OH)D level will either normalize or remain normal in those who were previously vitamin D deficient or sufficient, respectively. All had subnormal bone mineral content before transplant. On long-term follow-up (> 4 mo) of seven patients, bone mineral content normalized in all between 6.5 and 19 mo after transplant, with a mean of 11.2 +/- 4.5 mo. In six patients with normal serum 25(OH)D levels before orthotopic liver transplantation, the serum 25(OH)D levels had declined markedly 1 to 2 mo after transplant, followed by return to normal by 3 to 6 mo. Low serum 25(OH)D levels (< 15 ng/ml) in three patients before orthotopic liver transplantation normalized after transplant. Although there was no correlation between bone mineral content and serum 25(OH)D level before transplant, sustained normal serum 25(OH)D and 1,25(OH)2D levels preceded or accompanied normalization of bone mineral content in the seven patients available for long-term follow-up. We conclude that (a) in infants and children younger than 2 yr with chronic cholestasis, bone mineral content normalizes approximately 11 mo after orthotopic liver transplantation. This normalization is preceded by a sustained period of normal serum 25(OH)D levels.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of orthotopic liver transplantation on bone mineral content and serum vitamin D metabolites in infants and children with chronic cholestasis

Almost all infants and children with chronic cholestasis have osteopenia. We evaluated the effect of orthotopic liver transplantation on bone mineral content and serum 25(OH)-vitamin D–[25(OH)D]–of nine infants and children (five girls; age, 6 to 21 mo at the time of orthotopic liver transplantation) with end-stage liver disease resulting from chronic cholestasis. We hypothesized that after orthotopic liver transplantation, decreased bone mineral content will recover and the serum 25(OH)D level will either normalize or remain normal in those who were previously vitamin D deficient or sufficient, respectively. All had subnormal bone mineral content before transplant. On long-term follow-up (>4 mo) of seven patients, bone mineral content normalized in all between 6.5 and 19 mo after transplant, with a mean of 11.2 + 4.5 mo. In six patients with normal serum 25(OH)D levels before orthotopic liver transplantation, the serum 25(OH)D levels had declined markedly 1 to 2 mo after transplant, followed by return to normal by 3 to 6 mo. Low serum 25(OH)D levels (<15 ng/ml) in three patients before orthotopic liver transplantation normalized after transplant. Although there was no correlation between bone mineral content and serum 25(OH)D level before transplant, sustained normal serum 25(OH)D and 1,25(OH)2D levels preceded or accompanied normalization of bone mineral content in the seven patients available for long-term follow-up. We conclude that (a) in infants and children younger than 2 yr with chronic cholestasis, bone mineral content normalizes approximately 11 mo after orthotopic liver transplantation. This normalization is preceded by a sustained period of normal serum 25(OH)D levels. (b) Normal baseline serum 25(OH)D levels decrease 1 to 2 mo after orthotopic liver transplantation, with subsequent normalization, whereas initially low serum 25(OH)D levels gradually normalize within 2 to 4 mo. We speculate that maintenance of normal serum 25(OH)D levels with oral vitamin D supplementation may enhance recovery of bone disease after orthotopic liver transplantation. (HEPATOLOGY 1994;20:598–603).

The effect of orthotopic liver transplantation (OLT) on the osteopenic bone disease of patients with chronic liver disease Hay JE, Porayko MK, Dickson ER, Gores GJ, Steers JL, KROM RAF, Wiesner RH, Mayo Clinic, Rochester, MN 55905

The effect of orthotopic liver transplantation (OLT) on the osteopenic bone disease of patients with chronic liver disease Hay JE, Porayko MK, Dickson ER, Gores GJ, Steers JL, KROM RAF, Wiesner RH, Mayo Clinic, Rochester, MN 55905

Effect of orthotopic liver transplantation and chemical denervation of the liver on the activities of hepatic monoamine oxidase and catechol-O-methyltransferase.

The denervation of some tissue is associated with a fall in the activities of monoamine oxidase (MAO) and catechol-O-methyltransferase (COMT). Here we report on the effect of orthotopic liver transplantation and chemical denervation of the liver on the enzymes. Liver transplantation was performed on Lewis rats (n = 7). Denervation (n = 8) was by intraportal injection of 6-hydroxydopamine (75 mg/kg). A control group (n = 8) was also included. The norepinephrine content of the transplanted and denervated livers was reduced by greater than 99% (P < 0.001) and 95% (P < 0.001), respectively. The activity of hepatic COMT (substrate: catechol [5 mM] was not affected by transplantation or denervation. The activity of MAO with 0.1 mM 5-hydroxytryptamine (5-HT) (substrate for MAO-A) and with 0.01 mM 2-phenylethylamine (substrate for MAO-B) were not affected by denervation. In the transplanted liver, the activity of MAO with 5-HT and 2-phenylethylamine was increased by 26% (P < 0.05) and by 53% (P < 0.001), respectively. The ratios of the activities of the A to B forms of MAO (approximately 70% A to 30% B) was not affected by either procedure. Enzyme sensitivity for MAO inhibitors clorgyline and deprenyl were not significantly altered by transplantation. The concentration of plasma norepinephrine in the transplantation group was significantly lower than either the control (P < 0.001) or denervation groups (P < 0.05). We conclude from our results that the metabolism of circulating catecholamines by the liver is unlikely to be impaired after liver transplantation.

ELEVATION OF PLASMA ENDOTHELIN ASSOCIATED WITH SYSTEMIC HYPERTENSION IN HUMANS FOLLOWING ORTHOTOPIC LIVER TRANSPLANTATION

Endothelin (ET) is a 21-amino-acid peptide of endothelial origin, is a potent systemic and renal vasoconstrictor associated with sodium retention and modulation of the renin-angiotensin-aldosterone system. The present study was designed to determine if plasma ET is elevated in humans with cirrhosis (n = 12), a state characterized by sodium retention and increased plasma renin activity (PRA) and plasma aldosterone (PA), and to determine the effect of orthotopic liver transplantation (OLT) upon plasma ET, PRA, and PA at 1, 3, and 7 days after transplantation. Plasma ET before OLT was 1.62 +/- 0.23 pg/ml, which was not different as compared with normal controls. Plasma ET significantly increased to 4.18 +/- 0.66, 3.87 +/- 0.58, and 4.07 +/- 0.61 pg/ml, respectively following OLT. PRA remained elevated throughout the postoperative course, in contrast to PA that decreased following OLT. Mean arterial pressure increased significantly from 82 +/- 4 pre-OLT to 98 +/- 4 and 103 +/- 2 mmHG on days 3 and 7 respectively.

Reversal of hypersplenism following orthotopic liver transplantation.

The purpose of this study was to clarify the effect of orthotopic liver transplantation on hypersplenism. In a 1-year period from July 1, 1986 to June 30, 1987, 196 adult patients underwent 233 orthotopic liver transplantations. Of the 58 patients with hypersplenism who were analyzed in this study, hypersplenism was more commonly associated with postnecrotic cirrhosis than other kinds of liver disease (55.3% (47/85) vs. 14.5% (11/76); p less than 0.001). Postoperative platelet counts were statistically higher than preoperative values (p less than 0.05). The latest platelet counts were more than 100,000/mm3 in 53 patients (91.4%). Of the eight patients whose preoperative and postoperative spleen volumes could be compared, all showed the reduction in the spleen size (p less than 0.02). We conclude that orthotopic liver transplantation, which is a radical surgical procedure for portal hypertension, reverses hypersplenism.