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Biomedical subjects

K H Böker

Publications and source records attributed to K H Böker.

At least 19 recordsLinked to original sources
PubMed2001

Clinical and subclinical acute rejection early after liver transplantation: contributing factors and relevance for the long-term course.

Routine transplant aspiration cytology (TAC) after liver transplantation gives detailed information that concerns immunologic events in the graft. TAC can be helpful for diagnosis of acute rejection, but it also detects morphological signs of rejection without clinical correlate ("subclinical rejection"). The aim of this study was to systematically evaluate factors that influence the development of early clinical and subclinical rejection and to analyze the relevance of these early immunologic processes for the long-term course. The study includes the course of 340 patients after liver transplantation between 1988 and 1995 in whom TAC was performed routinely and who were followed for a minimum of 3 years. TAC findings were correlated with the following various clinical parameters: (1) Overall early clinical rejection occurred in 17.4%, subclinical rejection in 59.1%, and no immune activation was seen in 23.5% of patients. (2) Incidence of early clinical and subclinical rejection was markedly influenced by type of immunosuppression. (3) Basic disease and extent of preservation injury had only a minor influence; there was a trend towards lower early rejection associated with more severe preservation damage, increased patient age, and early retransplantation. (4) Presence of early clinical or subclinical rejection was not associated with a higher incidence of chronic dysfunction. (5) Falsely indicated antirejection treatment was associated with inferior graft survival. Subclinical rejection is very frequent early after liver transplantation, requires no treatment, and has no long-term adverse effect. Incidence of early clinical rejection is mainly determined by initial immunosuppression; its occurrence has no negative long-term effects and may even be associated with a lower risk for later immunological complications. Thus, the incidence of early acute rejection is no adequate parameter for evaluating the quality of an immunosuppressive treatment protocol.

Acute Disease↗
PubMed2001

Replacement of calcineurin inhibitors with mycophenolate mofetil in liver-transplant patients with renal dysfunction: a randomised controlled study.

BACKGROUND: Renal dysfunction is a major complication of long-term immunosuppressive therapy with calcineurin inhibitors (CNI) in liver-transplant recipients. We undertook a randomised study to assess the safety and efficacy of CNI withdrawal and replacement by mycophenolate mofetil. METHODS: 28 people who had had renal dysfunction attributable to suspected CNI toxicity after liver transplantation participated in the study. We replaced CNI with mycophenolate mofetil in a stepwise pattern in half the group (study patients); the other half (controls) stayed on CNI immunosuppression. Renal function, blood pressure, uric acid, and blood lipids were measured before and 6 months after study entry. Side-effects of medication and graft function were recorded throughout the study. FINDINGS: At the end of the study, mean (SD) serum creatinine had fallen by 44.4 (48.7) micromol/L in study patients compared with 3.1 (14.3) micromol/L in controls; a mean difference of 41.3 micromol/L (95% CI 12.4-70.2). Moreover, systolic and diastolic blood pressure, and serum uric acid decreased significantly in the study group but not in the control group (mean [95% CI] between group differences 10.8 mm Hg [3.0-18.6], 5.0 mm Hg [0.9-9.2], and 83.1 micromol/L [12.7-153.6], respectively). There were no changes in cholesterol or triglyceride concentrations in either group. Side-effects were reported by eight of the study patients. Three reversible episodes of acute graft rejection occurred in study patients during mycophenolate mofetil monotherapy, whereas none occurred in the control group. INTERPRETATION: Substitution of CNI by mycophenolate mofetil can improve renal function, blood pressure, and uric acid concentration of liver-transplant patients, but there is an increased rejection risk with mycophenolate mofetil monotherapy.

Blood Pressure↗
PubMed2001

Decreased splanchnic oxygen uptake and increased systemic oxygen uptake in cirrhosis are normalized after liver transplantation.

The aim of this study is to (1) characterize the impact of orthotopic liver transplantation (OLT) on splanchnic and systemic oxygen uptake (VO(2)) in patients with liver cirrhosis, and (2) investigate possible influencing factors, as well as metabolic consequences, of reduced splanchnic VO(2) in patients with cirrhosis. Therefore, we measured systemic VO(2) (indirect calorimetry), portal pressure (hepatic venous pressure gradient), hepatic blood flow (HBF; primed continuous infusion of indocyanine green), and hepatic turnover (arteriohepatic venous concentration differences multiplied by HBF) of oxygen, glucose, free fatty acids (FFAs), and aromatic amino acids (AAAs) in 52 patients with advanced cirrhosis and 16 patients with a clinically stable long-term course after OLT. Systemic VO(2) was significantly increased in patients with cirrhosis (261 +/- 7 mL/min) and normalized after OLT (216 +/- 8 mL/min; P < .001). Arterial and hepatic venous oxygen saturation and splanchnic oxygen extraction (in percent) were not different between patients with cirrhosis and after OLT. Splanchnic VO(2) was decreased in patients with cirrhosis (41 +/- 3 mL/min, representing 16% +/- 1% of systemic VO(2)) and normalized after OLT (69 +/- 6 mL/min; P < .001, representing 32% +/- 3% of systemic VO(2); P < .001). In patients with cirrhosis, a decrease in HBF was associated with decreased splanchnic VO(2) (r = 0.74; P < .001). Conversely, decreased splanchnic VO(2) reflected a decrease in hepatic glucose production (r = 0.34; P = .01) and hepatic extraction of FFAs (r = 0.40; P < .01) and AAAs (r = 0.30; P < .05). These results show that (1) splanchnic and systemic VO(2) normalize after OLT, indicating correction of hepatic and extrahepatic metabolic derangements; (2) in cirrhosis, HBF becomes limiting for hepatic oxygen supply; and (3) impaired splanchnic VO(2) reflects a decrease in metabolic liver function.

Adult↗
PubMed2000

Improvement of acute and chronic renal dysfunction in liver transplant patients after substitution of calcineurin inhibitors by mycophenolate mofetil.

BACKGROUND: Renal dysfunction caused by treatment with the calcineurin inhibitors (CNI) is a major problem in the long-term course after liver transplantation. PATIENTS: In 22 liver graft recipients with renal dysfunction and stable graft function between 3 weeks and 12 years after transplantation, CNI were substituted by MMF at a final dose of 1.5-3 g/day between October 1996 and October 1998. METHODS: In a prospective non-randomized study, the development of renal function, the side effects of MMF medication, and the stability of liver function were analyzed for a mean follow-up of 15 months. Results. (1) MMF was withdrawn in four patients for major side effects between 1 and 7 months after study entry; eight patients had minor side effects. (2) Six months after study entry, renal function had improved in 17 of the 22 study patients; mean serum creatinine +/-SD (micromol/L) was 201+/-77 at entry and 153+/-65 after 3 months (P<0.001). (3) Improvement occurred in 11 of 15 patients with creatinine elevation > or =12 months and in 6 of 6 patients with creatinine elevation < or =6 months. (4) One patient developed transient liver dysfunction and a second required retransplantation for progressive cholestasis but without signs of rejection. CONCLUSIONS: In patients who undergo liver transplantation, substitution of CNI by MMF leads to improvement of acute as well as chronic renal dysfunction in most cases. Side effects of MMF may be limiting in some patients, and the immunological consequences remain to be studied.

Adult↗
PubMed2000

Elevated bound leptin correlates with energy expenditure in cirrhotics.

BACKGROUND & AIMS: Leptin, found to be elevated in patients with liver cirrhosis, may contribute to the inadequate energy expenditure and malnutrition associated with a negative prognosis for these patients. Our aim was to characterize leptin components and their relationships to body composition, resting energy expenditure (REE), and substrate use in patients with posthepatic liver cirrhosis. METHODS: Using specific radioimmunoassays, we measured free leptin and bound leptin in 27 cirrhotics and 27 matched control subjects. In the cirrhotic group, body composition and REE were determined. RESULTS: Free leptin was not different in cirrhotics and control subjects and was related to body mass index (controls: r = 0.34, P < 0.05; cirrhotics: r = 0.55, P < 0.005) and to fat mass (cirrhotics: r = 0.76, P < 0.0001). Bound leptin was significantly higher in cirrhotic subjects than in controls (P < 0.001) and was related to REE x fat-free mass(-1) (r = 0.57, P < 0.005) or to the difference between measured and estimated REE (r = 0.55, P < 0.005). CONCLUSIONS: Free leptin reflects fat mass in controls and cirrhotics. Increased serum leptin in cirrhotics is a result of increased bound leptin serum concentrations, which are positively related to energy expenditure. Moreover, bound leptin may be a useful marker for inadequate energy expenditure in patients with liver cirrhosis.

Adipose Tissue↗
PubMed2000

Bone density and metabolism in patients with viral hepatitis and cholestatic liver diseases before and after liver transplantation.

OBJECTIVE: Osteoporosis is frequently found in patients with cholestatic liver disease (primary biliary cirrhosis/primary sclerosing cholangitis) and chronic viral hepatitis. There is limited information about the long-term effect of liver transplantation (OLT) on bone metabolism. The aim of this study was to investigate the effect of liver transplantation on bone metabolism in patients with cholestatic and viral liver diseases. METHODS: We randomly recruited 193 patients with chronic viral hepatitis or cholestatic liver diseases. Bone density (Z-score) and markers of bone metabolism (intact parathyroid hormone [iPTH], PTH 70-84, osteocalcin, procollagen, telopeptide, and vitamin D) were determined before and at time points (< and > 24 months) post-OLT. RESULTS: Before OLT, bone density (Z-score) was decreased in patients with cholestatic (-1) and viral (-0.4) liver diseases. In both groups bone density continued to decrease in the periods up to and more than 24 months after OLT. In the cholestatic group, bone density decreased significantly compared to pre-OLT (p < 0.05) and to the viral hepatitis group (p < 0,001). Markers of bone metabolism showed that after OLT, bone metabolism was enhanced and shifted versus bone resorption. Immunosuppressive drug therapy (glucocorticoids, cyclosporin, FK 506) directly correlated with increased bone metabolism post-OLT. CONCLUSIONS: Bone loss is a long-term problem after OLT, particularly in patients with cholestatic liver diseases. Drug therapy is a main factor of bone loss. Pre- and post-OLT therapy to reduce bone loss is recommended.

Adult↗
PubMed1999

Famciclovir treatment of chronic hepatitis B in heart transplant recipients: a prospective trial.

UNLABELLED: Hepatitis B may take a rapid and aggressive course in patients under immunosuppression. Nucleoside analogues have been shown to suppress viral replication effectively. To investigate the effect of famciclovir in immunosuppressed patients, 21 heart transplant recipients with chronic hepatitis B infection were included in a prospective study. PATIENTS AND METHODS: Patients have been treated with Famciclovir for a median of 14 months. Hepatitis B virus replication and biochemical parameters were regularly tested and liver biopsies were taken before treatment and after a median time of 7 months. HBV-polymerase was sequenced in all patients before therapy and in those patients who experienced virological breakthrough. RESULTS: Nineteen patients were treated for at least 6 months. Hepatitis B virus-DNA levels declined in all patients and became negative in 8 patients. Mean hepatitis B virus-DNA levels decreased from 199+/-269 to 34+/-53 pg/ml after 24 weeks (P=0.003). During treatment HBeAg became negative in five patients. Mean alanine aminotransferase decreased from 42+/-26 to 24+/-10 U/L (P=0.006). Histological analysis revealed improved inflammatory activity according to the Ishak-score in 11/16 (69%) patients. Total inflammatory activity scores decreased from 8 to 6 (median, NS), but interface hepatitis score (P=0.02) and lobular inflammation score (P=0.006) improved significantly. Median fibrosis scores fell from 5 to 3 (P=0.002). Three patients developed virological breakthrough on famciclovir after 7, 8, and 26 months of treatment showing HBV-polymerase amino acid changes L528 M, S567A, and I581K, respectively. CONCLUSIONS: Famciclovir improves not only biochemical and virological features but also hepatic inflammation and liver fibrosis in patients with chronic hepatitis B under heavy immunosuppression. Virological breakthrough may develop and requires close monitoring.

2-Aminopurine↗
PubMed1999

Mutational pattern of hepatitis B virus on sequential therapy with famciclovir and lamivudine in patients with hepatitis B virus reinfection occurring under HBIg immunoglobulin after liver transplantation.

Famciclovir (FCV) and lamivudine (LAM) reduce viral replication in patients with recurrent hepatitis B virus (HBV) infection after orthotopic liver transplantation (OLT). Eighteen of 20 patients with insufficient response to FCV were treated with 100 mg LAM daily after OLT. These patients had shown nonresponse (n = 5), partial response (n = 7), or breakthrough (n = 6) during FCV therapy. Despite passive immunoprophylaxis with hepatitis B immunoglobulin after liver transplantation, HBV reinfection had occurred in 14 of 15 transplanted patients. HBV-DNA levels and the regions A to E of the HBV-DNA polymerase gene were analyzed before and after treatment failure to either therapy. Within 4 weeks on LAM, all but 1 patient showed a 95% average reduction of the HBV-DNA level. As with FCV, we did not observe any severe side-effects attributable to LAM. However, 7 patients developed a breakthrough within 12, 29 (n = 2), 32, 37, 54, and 145 weeks under treatment with LAM associated with the methionine-to-valine signature mutation (M552V) in the YMDD motif in all. With FCV, no unique, but a dominant, resistance pattern with the L528M mutation was identified for patients with breakthrough under FCV. In contrast, nonresponders or patients with partial response to FCV did not exhibit such mutations. Our results indicate that the L528M mutation is a risk factor for LAM breakthrough, because breakthrough during LAM occurred earlier in patients with this mutation (50 +/- 10 weeks vs. 120 +/- 21 weeks). Because breakthrough on either treatment is frequent for this specific group of patients, the use of combination therapy should be explored.

2-Aminopurine↗
PubMed1999

Hypermetabolism in clinically stable patients with liver cirrhosis.

BACKGROUND: Hypermetabolism has a negative effect on prognosis in patients with liver cirrhosis. Its exact prevalence and associations with clinical data, the nutritional state, and beta-adrenergic activity are unclear. OBJECTIVE: We investigated resting energy expenditure (REE) in 473 patients with biopsy-proven liver cirrhosis. DESIGN: This was a cross-sectional study with a controlled intervention (beta-blockade) in a subgroup of patients. RESULTS: Mean REE was 7.12 +/- 1.34 MJ/d and correlated closely with predicted values (r = 0.70, P < 0.0001). Hypermetabolism was seen in 160 patients with cirrhosis (33.8% of the study population). REE was > 30% above the predicted value in 41% of the hypermetabolic patients with cirrhosis. Hypermetabolism had no association with clinical or biochemical data on liver function. REE correlated with total body potassium content (TBP; r = 0.49, P < 0.0001). Hypermetabolic patients had lower than normal body weight and TBP (P < 0.05). About 47% of the variance in REE could be explained by body composition whereas clinical state could maximally explain 3%. Plasma epinephrine and norepinephrine concentrations were elevated in hypermetabolic cirrhotic patients (by 56% and 41%, respectively; P < 0.001 and 0.01). Differences in REE from predicted values were positively correlated with epinephrine concentration (r = 0.462, P < 0.001). Propranolol infusion resulted in a decrease in energy expenditure (by 5 +/- 3%; P < 0.05), heart rate (by 13 +/- 4%; P < 0.01), and plasma lactate concentrations (by 32 +/- 12%; P < 0.01); these effects were more pronounced in hypermetabolic patients (by 50%, 33%, and 68%, respectively; each P < 0.05). CONCLUSIONS: Hypermetabolism has no association with clinical data and thus is an extrahepatic manifestation of liver disease. Increased beta-adrenergic activity may explain approximately 25% of hypermetabolism.

Adult↗
PubMed1999

Regulation of cytosolic free calcium concentration by extracellular nucleotides in human hepatocytes.

The effects of extracellular ATP and other nucleotides on the cytosolic free Ca2+ concentration ([Ca2+]i) have been studied in single primary human hepatocytes and in human Hep G2 and HuH-7 hepatoma cells. ATP, adenosine 5'-O-(3-thiotriphosphate) (ATPgammaS), and UTP caused a concentration-dependent biphasic increase in [Ca2+]i with an initial peak followed by a small sustained plateau in most cells. In some cells, however, repetitive Ca2+ transients were observed. The rank order of potency was ATP >/= UTP > ATPgammaS, and complete cross-desensitization of the Ca2+ responses occurred between ATP and UTP. The initial transient peak in [Ca2+]i was resistant to extracellular Ca2+ depletion, which demonstrates mobilization of internal Ca2+ by inositol 1,4,5-trisphosphate whose formation was enhanced by ATP and UTP. In contrast, the sustained plateau phase required influx of external Ca2+. Ca2+ influx occurs most likely through a capacitative Ca2+ entry mechanism, which was shown to exist in these cells by experiments performed with thapsigargin. On the molecular level, specific mRNA coding for the human P2Y1, P2Y2, P2Y4, and P2Y6 receptors could be detected by RT-PCR in Hep G2 and HuH-7 cells. However, ADP and UDP, which are agonists for P2Y1 and P2Y6 receptors, respectively, caused no changes in [Ca2+]i, demonstrating that these receptors are not expressed at a functional level. Likewise, alpha,beta-methylene-ATP, beta,gamma-methylene-ATP, AMP, and adenosine were inactive in elevating [Ca2+]i, suggesting that the ATP-induced increase in [Ca2+]i was not caused by activation of P2X or P1 receptors. Thus, on the basis of the pharmacological profile of the nucleotide-induced Ca2+-responses, extracellular ATP and UTP increase [Ca2+]i by activating P2Y2 and possibly P2Y4 receptors coupled to the Ca2+-phosphatidylinositol signaling cascade in human hepatocytes. This suggests that extracellular nucleotides from various sources may contribute to the regulation of human liver cell functions.

Adenosine Triphosphate↗
PubMed1998

Comparison of matrix metalloproteinase expression in normal and cirrhotic human liver.

To study the extend of ongoing tissue remodelling in end-stage cirrhosis, the expression of different matrix metalloproteinases [interstitial collagenase (MMP-1), Mr 72000 gelatinase (MMP-2), stromelysin-1 (MMP-3) and stromelysin-3 (MMP-11)] and of TIMP-1 was studied in 13 cirrhotic livers explanted at transplantation. The results were compared with those obtained in normal liver. Western blot, northern blot, ELISA, RT-PCR and zymogram analysis were used. Proenzymes of stromelysin-1 and -3, interstitial collagenase and Mr 72000 gelatinase were positive in normal liver, while activated enzymes were not detectable in western blot analysis. In cirrhosis proenzyme levels of the studied MMPs were reduced to a mean of 60-70%, but mRNA expression and gelatin-degrading activity increased. TIMP-1 expression was detectable on mRNA level and by ELISA in normal liver and also increased in cirrhosis. Our results show that mRNA expression of certain matrix metalloproteinases is increased in end-stage liver cirrhosis, while the amount of proenzyme is decreased, indicating enhanced MMP proenzyme turnover. These data suggest that besides increased TIMP-1 activity, altered MMP expression may also play a part in fibroproliferation in liver disease.

Adult↗
PubMed1998

Hepatoma with severe non-islet cell tumor hypoglycemia.

We report a 22-yr-old male patient with chronic hepatitis B and a large, well differentiated hepatoma who developed episodes of symptomatic fasting hypoglycemia, which were caused by paraneoplastic secretion of unprocessed "big" insulin-like growth factor-II. Initially, the patient presented with normal liver function, which deteriorated during the clinical course. Therapeutic attempts to reduce tumor mass failed and the patient subsequently died because of metastases of the hepatoma. The pathophysiology of non-islet cell tumor hypoglycemia, differential diagnosis, and therapeutic options are discussed.

Adult↗