Metabolic liver function and lipoprotein metabolism after orthotopic liver transplantation in patients on immunosuppressive therapy with FK 506 or cyclosporine.
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Biomedical subjects
Publications and source records attributed to B Ringe.
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Hepatitis B virus reinfection as well as recurrence of hepatocellular carcinoma are frequent complications in liver allograft recipients. This is the report of a patient who had two liver transplantations with a 6-year interval, both for the same indication-postnecrotic cirrhosis and liver cancer. Following first and second transplantation, hepatitis B reinfection occurred at 12 and 6 months, and allograft cirrhosis developed after 20 and 10 months, respectively. Intrahepatic recurrence of hepatocellular carcinoma was found after 69 months. Two years following retransplantation, the patient is tumor-free, and has normal graft function. In selected patients with hepatitis B-related liver disease, and hepatocellular carcinoma liver replacement is indicated when combined with effective immunoprophylaxis, and other adjuvant therapy. Late recurrence of both diseases is unusual, and retransplantation may come into question.
40 patients after orthotopic liver transplantation were prospectively analysed by serial quantitative duplex Doppler signal analysis (DDSA) to quantify the abnormalities of Doppler waveform of the hepatic artery (HA), the portal vein (PV) and the hepatic vein (HV) under various conditions of graft dysfunction. Quantitative analysis of the HA, PV and HV was obtained before, during and after allograft dysfunction by different Doppler angle independent parameters. The results obtained later on were correlated with clinical and laboratory data, cytological and histological findings of liver core biopsy and quantitative DDSA data of healthy transplanted volunteers. The increase of the resistive index of Pourcelot calculated for the hepatic artery (HA-RI) was found to be significant in early graft reperfusion reaction (p < 0.01). No correlation was found between the HA-RI and acute allograft rejection. Different patterns of damping quantified by the damping index (DI = minimum velocity shift/maximum velocity shift) for the portal vein (PV-DI) and the hepatic vein (HV-DI) Doppler signal were observed under various conditions of allograft dysfunction. Acute rejection was identified by premature decrease of PV-DI and increase of HV-DI (p < 0.01) with a sensitivity of 75%, a specificity of 91%, a positive predictive value (ppv) of 75% and a negative predictive value (npv) of 91%. Chronic allograft rejection was not associated with an increase of HV-DI but only with a significant decrease of PV-DI (p < 0.01), with a sensitivity of 80%, a specificity of 95%, ppv of 95%, npv of 98%.(ABSTRACT TRUNCATED AT 250 WORDS)
The optimal treatment of Budd-Chiari syndrome (BCS) remains an open question. It is still a matter of controversial discussion whether venous decompression or liver transplantation is superior. To elucidate the role and prognosis of both surgical options in our own experience, a consecutive series of 50 patients treated between 1981 and 1993 was retrospectively analyzed. Twelve patients had different types of portosystemic shunts or local decompressive procedures, and transplantation was performed in 43 cases, including five with previous conventional surgery. The overall mortality of 18 of 50 was conventional surgery. The overall mortality of 18 of 50 was concentrated within the early postoperative period, with no patient lost after 1 year. In the venous decompression group, the success rate was only 29%, and treatment failure was closely related to the finding of cirrhosis or technical problems like vascular thrombosis. After transplantation, early complications were rejection, primary nonfunction, or graft necrosis, and contributed significantly to the risk of sepsis. Thirty of 43 liver recipients are currently alive, including four rescued after failed decompressive surgery, with 1- and 10-year survival of 69%, and excellent recurrence-free rehabilitation. These results clearly indicate that patient selection plays a dominant prognostic role in the treatment of BCS. Venous decompression and liver transplantation should both be integrated in a common therapeutic concept, and the individual decision for the preferred approach must be based on the leading clinical symptom: portal hypertension or liver failure, together with the assessment of reversibility of hepatic damage, and the potential of cure of the underlying disease.
Kidney or liver transplantation (KTx, LTx) today is a standard therapeutic procedure if one of these organs fails. However, the need for transplantation of both organs may arise with deterioration of organ function. To evaluate the success of combined LTx/KTx we analyzed 20 patients (aged 14-64) who received a total of 21 LTx and 31 KTx. Simultaneous LTx/KTx was performed in 14 patients, of whom 5 required further replacement of one or the other of the grafted organs. Six patients had sequential transplantation: 3 had LTx prior to the KTx, and 3 KTx prior to LTx. In 12 patients the indication for LTx was end-stage liver cirrhosis, and of these 8 died after LTx, mostly of infections. In a group of 8 transplant recipients without liver cirrhosis (e.g. polycystic liver), only 1 patient died. Eleven of the 20 grafted patients are still alive now (follow-up after LTx 14-120 months). Episodes of liver and kidney rejection occurred in only 30% and 15% of transplanted patients respectively. Only 1 patient is back on hemodialysis, the others have normal liver and kidney function. Combined LTx/KTx may be successful in appropriate circumstances. However, patients with liver cirrhosis have a very poor prognosis due to their poor overall clinical state at the time of terminal renal failure. In contrast, patients without liver cirrhosis are better candidates, even for simultaneous LTx/KTx. In general, the indication for simultaneous organ transplantation should be considered earlier than for transplantation involving only one organ.
Regulatory roles of insulin and glucagon in hepatic metabolism and function are well described. However, little is known about implications of host pancreatic hormones in primary function of grafted liver. This study aimed to investigate it in relation to hepatic mitochondrial function. Insulin, c-peptide, and glucagon in peripheral blood were monitored for 2 days in clinical liver transplantation by a continuous sampling technique to avoid influences of hormonal oscillation. In grafts with immediate function (n = 10), smooth increase of arterial ketone body ratio reflecting hepatic intramitochondrial redox state was accompanied by increased c-peptide and decreased glucagon, resulting in the increase of c-peptide/glucagon ratio. In other functioning grafts (n = 20), where ketone body ratio was rather lower, increased glucagon level, observed also during anhepatic phase, resulted in the slower increase of c-peptide/glucagon ratio. There were accompanied by increased free fatty acid and ketone body levels. In primary nonfunction (n = 4), rapid increase of c-peptide accompanied by hyperglycemia resulted in the accelerated increase of c-peptide/glucagon ratio, but ketone body ratio did not show any increase. Insulin/c-peptide ratio also showed a rapid increase. These findings suggest that the increase of insulin/glucagon ratio in portal blood, potentially influenced by recipient condition, is associated with the recovery of mitochondrial energy metabolism in survived hepatic grafts. However, this relationship does not work in failed grafts, where irreversible impairment of energy metabolism is attributed to graft itself.
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Veno-occlusive disease (VOD) is a frequent complication early after bone marrow transplantation. In cases of severe liver failure treatment by allogeneic liver transplantation is possible. We report the clinical and immunological course of a patient after bone marrow transplantation for AML and subsequent allogeneic liver transplantation for severe hepatic VOD. After liver transplantation the patient recovered well clinically. Early after liver transplantation he had large numbers of liver donor T and NK lymphocytes in his circulation. He had no liver graft rejection, but he developed mild acute GVHD which was caused by liver graft-derived T lymphocytes. Two years after transplantation he had persistent microchimerism with donor liver cells detectable in his bone marrow. Now 36 months after transplantation, the patient has no evidence of recurrent leukemia, stable liver function, and no signs of graft-versus-host disease or bone marrow dysfunction.
Fine-needle aspiration biopsy (FNAB) is a routine diagnostic tool used for the monitoring of the graft during the first postoperative weeks after liver transplantation. The cellular pattern of acute liver rejection is typical in transplant aspiration cytology (TAC), documented and published by several authors. The lymphoid response associated with various viral infections may, however, provide differential diagnostic problems in the cytological monitoring. In this study, we have investigated in detail the cellular pattern of lymphoid response associated with hepatitis C virus (HCV) reactivation, and compared it with the pattern of cytomegalovirus (CMV) infection and with the typical diagnostic findings of acute cellular rejection. HCV reactivation was associated with rather mild total inflammation in the graft (4.5 +/- 1.5 CIU at the peak). The inflammatory infiltrate consisted mainly of small lymphocytes (3.1 +/- 0.2 CIU at the peak), with only occasional activated cells and without lymphoid blast response. No lymphoid activation was seen in the blood. CMV infection was associated with a mild immune response (3.9 +/- 0.4 CIU at the peak) recorded as a slight lymphoid activation and occasional blast cells both in blood and in the graft together with lymphocytosis in the graft (2.4 +/- 0.7 CIU at the peak). The typical findings of acute rejection were easily distinguished from the cellular pictures of both viral infections. The rejections were lymphoid blast (3.6 +/- 3.4 CIU at the peak) and activated lymphocyte (3.5 +/- 2.6 at the peak), dominated by a high peak of total inflammation (9.3 +/- 7.0 CIU). No blast cells and only a few activated cells were seen in the blood during rejection episodes. Thus, the cellular patterns of HCV reactivation and CMV infection differed slightly from each other, but significantly from that of acute liver allograft rejection monitored with the FNAB cytology.
New concepts for the treatment of hepatitis B in immunocompromised patients are urgently needed. We describe our first experience with the new antiviral agent famciclovir in combination with a short course of prostaglandin E in a patient with severe hepatitis B after liver transplantation. Initial treatment with prostaglandin E reduced the inflammatory activity, as measured by transaminase activities, but did not affect viral replication. Consecutive long-term treatment with famciclovir further normalized liver function and profoundly suppressed viral replication. HBeAg and HBV-DNA -PCR all became negative and only HBsAg persisted. Histology documented marked reduction of cellular infiltration. The patient completely recovered and is back to regular work as a teacher.
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This report documents two cases of Budd-Chiari syndrome (BCS) with essential thrombocytosis and antithrombin (AT) III deficiency as underlying etiological factors. Orthotopic liver transplantation was successfully performed in both patients but with different therapeutic intention. In the patient with essential thrombocytosis, hepatic transplantation only relieved the symptoms of the predisposing thrombogenic condition; it did not cure the underlying disorder. Prophylactic long-term anticoagulation, as well as adjuvant therapy for the causative disease, remained necessary. On the other hand, in the patient with AT III deficiency, liver transplantation was curative, resulting in complete reconstitution of serum AT III activity with resolution of the hypercoagulable state postoperatively. Thus, depending on the underlying etiology, liver transplantation for BCS can be considered as palliative, necessitating long-term adjuvant therapy, or as curative, with correction of a metabolic defect.
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FK 506 plasma levels were analyzed in 89 liver-grafted patients under FK 506-based immunosuppression. Plasma levels were found to be influenced by the patients' liver function: compared to patients without major liver dysfunction, those with cholestasis had higher plasma levels and these plasma levels were able to differentiate between rejection and toxicity. In patients with stable liver function, no clear difference was observed with regard to the plasma levels detectable during toxicity or rejection. We conclude that plasma levels can be used to determine the FK 506 dose but only in patients with cholestasis (i.e., during the early post-transplant course, or in patients with cholestatic rejection). In patients with stable liver function, plasma levels are only of limited clinical relevance.
Chronic hepatitis B surface antigen (HBsAg) carriers run a high risk of developing chronic liver disease after renal transplantation. To determine the impact of liver disease on long-term morbidity and mortality of HBsAg carriers following kidney transplantation we analyzed 1977 patients, including 76 HBsAg carriers, who underwent renal transplantation during the period 1968-1992. Although the HBsAg carriers had a better 5-year patient and graft survival rate (94% and 83%) than HBsAg-negative patients (87% and 61%), the prognosis was poor after the tenth year of transplantation. Transplant loss is more frequently caused by death of the HBsAg carriers, in contrast to the total population (34% vs 17% for HBsAg-negative patients). Death occurs in 73% of cases due to complications of hepatitis B. In the HBsAg-negative patients, the predominant cause of death is cardiovascular failure (51% vs 11% in HBsAg carriers), whereas only 2% died of liver disease. Kidney transplantation in HBsAg carriers with normal liver function appears to be justified because of rare graft loss due to acute rejection, low early morbidity and mortality, and late onset of fatal hepatic deterioration.