Biomedical subjects
Publications and source records attributed to A L Gerbes.
Antidepressant-induced hepatotoxicity is generally considered of minimal clinical importance and is not well recognized. We report on a patient with recurrent major depression who was treated with nefazodone. Six weeks after initiation of therapy with nefazodone, he developed fatal liver failure. After cessation of the drug, the patient did not recover. He underwent liver transplantation but unfortunately died.
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HRS is a serious complication in patients with cirrhosis and ascites and associated with a poor prognosis unless liver transplantation can be performed. Two different types of HES are being differentiated according to the clinical presentation: while HRS type I is characterised by rapid deterioration of renal function indicated by a two-fold increase of serum creatinine to values above 2.5 mg/dl or a decrease of creatinine clearance to values below 20 ml/min, HRS type II shows moderately increased serum creatinine above 1.5 mg/dl remaining stable over a longer period. The most prominent circulatory alterations in patients with chronic liver disease comprise portal hypertension and peripheral (mainly splanchnic) arterial vasodilation. This leads to a decreased centrally effective blood volume in cirrhotic patients. As a consequence, activation of sodium- and volume-retaining neurohumoral systems such as the renin-angiotensin-aldosterone system and the sympathetic nervous system and a non-osmotic release of arginine-vasopressin can be observed. These neurohumoral alterations induce renal sodium and water retention which are responsible for accumulation of ascites and deterioration of renal function. Recent therapeutic strategies of the hepatorenal syndrome take into account these pathophysiologic considerations: whereas the transjugular intrahepatic portosystemic shunt lowers portal hypertension, infusion of vasoactive drugs increases systemic vascular resistance in cirrhotic patients. Several uncontrolled trials have reported a positive effect of these strategies on renal function. The present analysis of combined data from these reports shows that this positive effect on renal function also may improve survival of patients with HRS type I.
BACKGROUND: The aim of the present study was to compare the transjugular intrahepatic portosystemic shunt (TIPS) with variceal band ligation (VBL) in the prophylaxis of variceal rebleeding in patients with cirrhosis of the liver. METHODS: Fifty-four cirrhotic patients (21 Child-Pugh class A, 27 class B, 6 class C) were randomized to TIPS (n = 28) or VBL (n = 26) within 2 months after control of esophageal variceal hemorrhage. Statistical analysis was performed on the intention-to-treat principle. RESULTS: Mean follow-up was 2 years. Mortality risk at 1 and 2 years of follow-up was 7.8% +/- 5.3% and 19.9% +/- 8.8% in the TIPS group and 16.5% +/- 7.6% and 16.5% +/- 7.6% in the VBL group, respectively (n.s.); actuarial probability of remaining free from rebleeding was 83.7% +/- 77.4% and 71.4% +/- 10.4% in the TIPS group and 83.9% +/- 7.3% and 78.1% +/- 8.8% in the VBL group at 1 and 2 years, respectively (n.s.). Hepatic encephalopathy within 1 month after randomization was observed in 2 patients in the TIPS group and in 1 in the VBL group. CONCLUSION: TIPS is not superior to VBL in the prevention of variceal rebleeding. Furthermore, similar mortality rates in patients treated with TIPS or VBL negate TIPS as the preferred strategy for prevention of variceal rebleeding.
BACKGROUND AND AIMS: Diagnosis of moderately impaired renal function is of particular importance in patients with cirrhosis of the liver. Whereas patients with a markedly impaired glomerular filtration rate can be diagnosed easily by elevated serum creatinine concentrations, moderately reduced renal function may be missed by this conventional parameter. Recently, cystatin C has been suggested as a sensitive marker of renal function, independent of sex or muscle mass. Therefore, the aim of this study was to investigate the value of serum cystatin C concentration for the detection of moderately impaired renal function. METHODS: Ninety seven in-hospital patients with cirrhosis and a 24 hour creatinine clearance of at least 40 ml/min were investigated and divided into group 1 (creatinine clearance > or = 70 ml/min; n = 55) and group 2 (creatinine clearance 40-69 ml/min; n = 42). RESULTS: Serum cystatin C concentrations (mean (SD): 1.31 (0.51) v 1.04 (0.34) mg/l (p = 0.008)) and creatinine concentrations (1.03 (0.52) v 0.86 (0.22) mg/100 ml (p=0.03)) were higher in group 2 than in group 1; there was no significant difference in urea concentrations. Receiver-operator characteristics (ROC) revealed a differential diagnostic advantage of cystatin C over creatinine and urea. At cut off concentrations of 1.0 mg/l, 0.9 mg/100 ml, and 28 mg/100 ml, respectively, cystatin C, creatinine, and urea exhibited 69%, 45%, and 44% sensitivity (p<0.05). As patients with a small muscle mass or reduced physical activity could be particularly prone to overestimation of their renal function, separate analyses were performed for the subgroups of female and Child-Pugh class C patients, respectively. In both groups, discrimination between patients with moderately impaired and normal renal function was best with cystatin C. In female patients, sensitivity of cystatin C (77.8%) was superior (p<0.05) to that of creatinine (38.9%) and urea (41.2%). In Child-Pugh C patients, the ROC curve was significantly better for cystatin C than for creatinine. CONCLUSIONS: Serum cystatin C determination could be a valuable tool in patients with cirrhosis, particularly with Child-Pugh class C or in female patients, for early diagnosis of moderately impaired renal function.
BACKGROUND: Microcirculatory failure, activation of Kupffer cells (KC), and the formation of reactive oxygen species (ROS) are considered pivotal mechanisms of reperfusion injury after orthotopic liver transplantation. However, the sequence of these events and their impact on early graft function remain controversial. We therefore investigated whether KC induce microcirculatory disturbances through ROS release and whether microcirculatory failure contributes to early graft function after liver transplantation. METHODS: Donor livers of Lewis rats were pretreated either with saline or with gadolinium chloride (GdCl3), an inhibitor of KC function (n=8 each). Syngeneic OLT was performed after 24 hr of hypothermic preservation in University of Wisconsin solution. RESULTS: Intravital microscopy revealed significantly higher sinusoidal perfusion rates in GdCl3-treated allografts (92+/-1.1% vs. 75.7+/-0.8%; P<0.001) compared with untreated controls; permanent leukocyte sticking in sinusoids (23.5+/-2.1 vs. 62.6+/-3.3 cells/lobule, P<0.001) and in postsinusoidal venules (153.1+/-10.4 vs. 446.6+/-46.4 cells/mm(2), P<0.001) were markedly attenuated in GdCl3-treated allografts. Improvement of microcirculatory parameters in GdCl3-treated livers was correlated with a significant reduction of plasma glutathione disulfide formation by KC-derived ROS (0.96+/-0.1 microM vs. 1.79+/-0.5 microM; P<0.01). Despite these beneficial effects, GdCl3-pretreatment failed to improve postischemic alanine aminotransferase release and bile flow. CONCLUSIONS: Microcirculatory failure after liver transplantation is related to KC-derived oxidant stress but not involved in early graft dysfunction.
BACKGROUND/AIMS: Hyperlipoproteinemia is frequent following liver transplantation and may lead to atherosclerosis. Lipid-lowering agents may be useful, but could interfere with the function of the transplanted organ and with immunosuppression. We therefore evaluated in a prospective, randomized, open-labeled cross-over trial the effect of two frequently used 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (pravastatin 10 mg d(-1) and cerivastatin 0.1 mg d(-1)) in hyperlipoproteinemic patients after liver transplantation. METHODS: Sixteen patients (6.3 +/- 2.0 years post-transplantation, cyclosporine n = 11, tacrolimus n = 5) with hyperlipoproteinemia (cholesterol 246 +/- 42, triglycerides 191 +/- 87, low-density lipoprotein (LDL)-cholesterol 161 +/- 35, high-density lipoprotein (HDL)-cholesterol 44 +/- 11 mg d(-1)) were included. Treatment periods of 6 weeks were separated by a 4-week washout period. RESULTS: Both medications were tolerated well, no effects on serum concentrations of liver enzymes or immunosuppressive agents were observed. Cerivastatin and pravastatin decreased (P < 0.001) cholesterol by 21 +/- 10% and 15 +/- 10%, LDL-cholesterol by 27 +/- 14% and 17 +/- 15%, respectively, while triglyceride and HDL-cholesterol concentrations did not change significantly. LDL/HDL-cholesterol markedly improved (P < 0.001) by 29 +/- 16% (cerivastatin) and 16 +/- 16% (pravastatin). Cerivastatin was more potent than pravastatin in patients receiving cyclosporine A, while there was no significant difference in patients receiving tacrolimus. CONCLUSIONS: Low-dose cerivastatin and pravastatin significantly improve lipid profiles following liver transplantation without affecting liver function or immunosuppression.
BACKGROUND: In patients with cirrhosis and ascites, creation of a transjugular intrahepatic portosystemic shunt may reduce the ascites and improve renal function. However, the benefit of this procedure as compared with that of large-volume paracentesis is uncertain. METHODS: We randomly assigned 60 patients with cirrhosis and refractory or recurrent ascites (Child-Pugh class B in 42 patients and class C in 18 patients) to treatment with a transjugular shunt (29 patients) or large-volume paracentesis (31 patients). The mean (+/-SD) duration of follow-up was 45+/-16 months among those assigned to shunting and 44+/-18 months among those assigned to paracentesis. The primary outcome was survival without liver transplantation. RESULTS: Among the patients in the shunt group, 15 died and 1 underwent liver transplantation during the study period, as compared with 23 patients and 2 patients, respectively, in the paracentesis group. The probability of survival without liver transplantation was 69 percent at one year and 58 percent at two years in the shunt group, as compared with 52 percent and 32 percent in the paracentesis group (P=0.11 for the overall comparison, by the log-rank test). In a multivariate analysis, treatment with transjugular shunting was independently associated with survival without the need for transplantation (P=0.02). At three months, 61 percent of the patients in the shunt group and 18 percent of those in the paracentesis group had no ascites (P=0.006). The frequency of hepatic encephalopathy was similar in the two groups. Of the patients assigned to paracentesis in whom this procedure was unsuccessful, 10 received a transjugular shunt a mean of 5.5+/-4 months after randomization; 4 had a response to this rescue treatment. CONCLUSIONS: In comparison with large-volume paracentesis, the creation of a transjugular intrahepatic portosystemic shunt can improve the chance of survival without liver transplantation in patients with refractory or recurrent ascites.
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BACKGROUND/AIMS: The cardiovascular hormone Atrial Natriuretic Peptide (ANP) attenuates activation of the pro-inflammatory transcription factor NF-kappaB in macrophages. ANP was also shown to protect from ischemia-reperfusion injury of the rat liver. This study aimed to investigate the effects of this immunomodulatory hormone and its second messenger cGMP on the activation of the two redox-sensitive transcription factors AP-1 and NF-kappaB and the expression of corresponding pro-inflammatory target genes during ischemia and reperfusion of the liver. The identification of the mechanisms underlying the protection by ANP should reveal new aspects concerning the pathomechanisms of ischemia/reperfusion injury. METHODS: Rat livers were perfused with and without ANP or 8-Br-cGMP preceding 24 h of cold storage in University of Wisconsin solution. During reperfusion NF-kappaB and AP-1 DNA binding activities were determined in freeze-clamped liver samples by electrophoretic mobility shift assay. Protein levels of p50, p65, and of IkappaB were determined by Western blot. mRNA coding for inducible nitric oxide synthase, cyclooxygenase-2, and TNF-alpha was determined by RT-PCR and Northern blot. RESULTS: After 45 min of reperfusion DNA binding activities of NF-kappaB were increased, whereas in ANP pre-treated livers this effect was markedly reduced. AP-1, another important redox-sensitive transcription factor, was activated and in the course of reperfusion the subunit composition of AP-1 changed as assessed by supershift assays. ANP markedly reduced binding activities of both forms of AP-1. 8-Br-cGMP mimicked the effects of ANP on NF-kappaB and AP-1. Neither inducible nitric oxide synthase nor cyclooxygenase-2 mRNA could be detected. In contrast, a profound expression of transcripts coding for TNF-alpha was detected in the course of reperfusion and ANP markedly reduced TNF-alpha mRNA expression. CONCLUSION: ANP seems to mediate its protective effect during ischemia and reperfusion by reducing the activation of NF-kappaB and AP-1 via cGMP. The reduced binding activity of these redox-sensitive transcription factors was accompanied by a diminished mRNA expression of TNF-alpha, a cytokine known to be involved in cellular damage in ischemia reperfusion injury.
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Budd-Chiari syndrome is characterized by obstruction of the hepatic venous outflow tract. Therapeutic options for chronic Budd-Chiari syndrome are limited. We report the case of a 28-year-old woman who presented with recurrence of chronic Budd-Chiari syndrome with total obstruction of all major hepatic veins. Due to worsening liver function over the course of 1 year, she had to be listed for liver transplantation. Because of therapy-refractory ascites, declining renal function and severe esophageal varices, a transjugular intrahepatic portosystemic shunt (TIPS) was placed, planned as a bridge to transplantation. Following TIPS, a marked recovery of liver function could be observed, accompanied by disappearance of ascites, esophageal varices, and normalization of kidney function. Therefore, the patient could be removed from the waiting list for liver transplantation. This case demonstrates for the first time that the use of TIPS in chronic Budd-Chiari syndrome may result in marked recovery of liver function.
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UNLABELLED: High-frequency oscillatory ventilation (HFO) has been shown to reduce lung injury and pulmonary arterial pressure (PAP). We hypothesized that HFO leads to decreased endothelin 1 (ET-1) and endothelin 3 (ET-3) release when compared to conventional mechanical ventilation (CMV) in lung-lavaged rabbits. DESIGN: Prospective, randomized, controlled animal study. In 26 adult New Zealand White Rabbits ventilated by CMV or HFO under hypoxemic and normoxemic conditions after lung lavage (CMV-hypo: n = 5; CMV-normo: n = 8; HFO-hypo: n = 7; HFO-normo: n = 6) we recorded systemic and PAP, measured blood gases, ET-1 and ET-3 and calculated intrapulmonary venous admixture during a 4-h experiment. ET-1 was significantly increased after lavage (p < 0.05) with no further increase until the end of the experiment. Neither pulmonary arterial nor systemic arterial ET-1 differed between CMV and HFO or between hypoxemia and normoxemia. Systemic arterial ET-3, however, was significantly higher in HFO-hypo than in the other two groups ventilated under normoxemic conditions at the end of the experiment (HFO-hypo vs. CMV-normo, p < 0.05; HFO-hypo vs. HFO-normo, p < 0.05). PAP showed a continuous increase in all groups (p < 0.05). We did not find any correlation between PAP and ET-1 or ET-3. Intrapulmonary venous admixture increased in animals ventilated under hypoxemic conditions, whereas it decreased after lung lavage in those ventilated under normoxemic conditions until the end of the experiment (HFO-normo, p < 0.05). CONCLUSIONS: This study suggests that HFO does not decrease ET-1 and ET-3 release compared to CMV in lung-lavaged rabbits. Hypoxemia, however, may increase ET-3 release from the lungs, leading to an increased intrapulmonary shunt.
BACKGROUND: A transjugular intrahepatic portosystemic shunt (TIPS) is increasingly being used for treatment of patients with refractory ascites and functional renal failure. In contrast, organic renal disease is commonly considered a relative contraindication for TIPS placement. The aim of this pilot study was to investigate the effects of TIPS in patients with refractory ascites and organic or functional renal impairment. METHODS: A TIPS was placed for refractory or intractable ascites in 10 consecutive patients with liver cirrhosis and impaired renal function (serum creatinine > 1.5 mg/100 ml). Four of them had organic kidney disorders. Of these patients, three had moderate renal impairment, and one had end-stage renal disease and needed hemodialysis every other day. The other six patients had functional renal impairment due to the underlying liver disease. RESULTS: TIPS was effective in reducing ascites in 8 of 10 patients, including all patients with organic renal disease. Furthermore, after TIPS the renal function improved in all patients. Serum creatinine and serum urea levels decreased significantly from 1.8 +/- 0.1 to 1.5 +/- 0.1 mg/100 ml (P < 0.05) and from 107 +/- 13 to 78 +/- 14 mg/100 ml (P < 0.05), respectively. The renal function of the three patients with organic renal failure improved similarly, as observed in the six patients with functional renal failure. In the patient on hemodialysis, TIPS was effective in reducing the frequency of paracenteses. CONCLUSION: TIPS may be useful in patients with functional and in patients with organic renal disease, resulting in improvement of ascites and renal function.
BACKGROUND/AIMS: C-type natriuretic peptide (CNP), the third member of the natriuretic peptide family, is considered to be involved in the regulation of vascular tone. Furthermore, the recent demonstration of CNP in human kidney and urine may indicate a role for CNP in fluid and electrolyte homeostasis. Therefore, the aim of the present study was to investigate the possible role of CNP in renal function disturbances in patients with cirrhosis of the liver. METHODS: Peripheral venous and urinary concentrations of CNP were determined in samples from 11 healthy controls, 20 cirrhotic patients with normal renal function (creatinine clearance 117 (8) ml/min), and 20 cirrhotic patients with impaired renal function (creatinine clearance 35 (4) ml/min). In a second protocol, arterial and renal venous plasma concentrations of CNP were determined in 37 patients with cirrhosis of the liver to estimate renal extraction ratios of CNP. A sensitive and specific radioimmunoassay was applied after solid phase extraction of samples. RESULTS: Plasma CNP was lower in cirrhotic patients with normal and impaired renal function than in controls (3.0 (0.4) and 2.7 (0.2) v. 4.2 (0.4) pg/ml, respectively; p<0.05; mean (SEM)). In contrast, urinary CNP was higher in patients with impaired renal function compared with those with normal renal function and healthy controls (47.2 (7.4) v. 20.8 (1.9) and 17.0 (3.0) ng CNP/g creatinine, respectively; p<0.05). Urinary CNP was found to be inversely related to urinary sodium excretion in cirrhotic patients (r=-0.56; p<0.01). No differences were observed between arterial and renal venous concentrations of CNP in cirrhosis (2.4 (0.2) v. 2.4 (0.2) pg/ml). In cirrhotic patients with hepatorenal syndrome or refractory ascites (n=5), urinary CNP decreased from 132 (59) to 38 (7) ng/g creatinine (p<0.05) one week after either ornipressin infusion or insertion of a transjugular intrahepatic portosystemic shunt together with an increase in urinary sodium excretion from 27 (17) to 90 (34) mmol/24 hours. CONCLUSIONS: Increased urinary CNP in cirrhotic patients in the absence of renal arteriovenous concentration gradients suggests enhanced renal CNP production in cirrhosis. Furthermore, an inverse relation between urinary CNP and urinary sodium excretion suggests a role for this peptide in renal sodium handling in patients with cirrhosis.
BACKGROUND/AIMS: Liver transplantation (LTx) is the only established treatment in patients with end-stage primary biliary cirrhosis (PBC). Although short-term survival after LTx in this group of patients is usually good, few data exist on the long-term survival. The optimal timing of transplantation is difficult. Thus, the aims of this study were to assess the long-term survival of patients with PBC after LTx and to identify potential predictive factors for a positive outcome. METHODS: Survival of 28 patients with PBC who underwent LTx between 1985 and July 1999 in a single center was studied by Kaplan-Meier analysis and was compared to predicted survival without LTx using established prognostic models for PBC, the Mayo and European risk scores. Potential prognostic parameters obtained before LTx were tested for correlation to survival. Rates of bone fractures as markers of hepatic osteodystrophy were compared before and after LTx. RESULTS: Median follow-up after LTx was 90 months with a maximum of 140 months. Actuarial survival of patients with PBC was 89% after 1, 5, and 10 years and was significantly better than estimated survival without LTx after 1-7 years as calculated by the Mayo and European risk scores. Of several parameters tested, only serum bilirubin and the prognostic scores, but no other liver function tests obtained immediately prior to transplantation were significantly correlated with survival after LTx. The duration of intensive care after LTx was not associated with any parameters obtained before LTx. Bone fractures were diagnosed in 43% of patients of whom the vast majority were osteopenic before LTx as determined by osteodensitometry. CONCLUSION: Long-term survival of a well-defined group of patients with PBC was excellent after LTx and was inversely correlated with preoperative serum bilirubin levels as well as Mayo and European risk scores.
Liver failure represents a major therapeutic challenge, and yet basic pathophysiological questions about hepatic perfusion and oxygenation in this condition have been poorly investigated. In this study, hepatic blood flow (HBF) and splanchnic oxygen delivery (DO2, sp) and oxygen consumption (VO2,sp) were assessed in patients with liver failure defined as hepatic encephalopathy grade II or more. Measurements were repeated after high-volume plasmapheresis (HVP) with exchange of 8 to 10 L of plasma. HBF was estimated by use of constant infusion of D-sorbitol and calculated according to Fick's principle from peripheral artery and hepatic vein concentrations. In 14 patients with acute liver failure (ALF), HBF (1.78 +/- 0.78 L/min) and VO2,sp (3.9 +/- 0.9 mmol/min) were higher than in 11 patients without liver disease (1.07 +/- 0.19 L/min, P <.01) and (2.3 +/- 0.7 mmol/min, P <.001). In 9 patients with acute on chronic liver disease (AOCLD), HBF (1.96 +/- 1.19 L/min) and VO2,sp (3.9 +/- 2.3 mmol/min) were higher than in 18 patients with stable cirrhosis (1.00 +/- 0.36 L/min, P <.005; and 2.0 +/- 0.6 mmol/min, P <.005). During HVP, HBF increased from 1.67 +/- 0.72 to 2.07 +/- 1.11 L/min (n=11) in ALF, and from 1.89 +/- 1.32 to 2.34 +/- 1.54 L/min (n=7) in AOCLD, P <.05 in both cases. In patients with ALF, cardiac output (thermodilution) was unchanged (6.7 +/- 2.5 vs. 6.6 +/- 2.2 L/min, NS) during HVP. Blood flow was redirected to the liver as the systemic vascular resistance index increased (1,587 +/- 650 vs. 2, 020 +/- 806 Dyne. s. cm-5. m2, P <.01) whereas splanchnic vascular resistance was unchanged. In AOCLD, neither systemic nor splanchnic vascular resistance was affected by HVP, but as cardiac output increased from 9.1 +/- 2.8 to 10.1 +/- 2.9 L/min (P <.01) more blood was directed to the splanchnic region. In all liver failure patients treated with HVP (n=18), DO2,sp increased by 15% (P <.05) whereas VO2,sp was unchanged. Endothelin-1 (ET-1) and ET-3 were determined before and after HVP. Changes of ET-1 were positively correlated with changes in HBF (P <.005) and VO2,sp (P <.05), indicating a role for ET-1 in splanchnic circulation and oxygenation. ET-3 was negatively correlated with systemic vascular resistance index before HVP (P <.05) but changes during HVP did not correlate. Our data suggest that liver failure is associated with increased HBF and VO2, sp. HVP further increased HBF and DO2,sp but VO2,sp was unchanged, indicating that splanchnic hypoxia was not present.