Outcome following liver transplantation for primary sclerosing cholangitis in the Nordic countries

Background: Primary sclerosing cholangitis (PSC) is the most common indication for liver transplantation in the Nordic countries. Because these patients are difficult to evaluate with regard to timing of liver transplantation, it is important to establish predictors of post‐transplant survival. Methods: Data from two groups of patients receiving liver allografts during 1982–2001 were recorded: (a) PSC patients and (b) comparison patients. Outcome following transplantation has been recorded for all patients. Regression analyses have been performed for PSC patients to analyse predictors of patient and graft survival. Results: A total of 245 PSC and 618 comparison patients received a first liver allograft in the period 1982 until the end of the study. The overall 1‐, 3‐ and 5‐year patient survival rates were 82%, 77% and 75%, and 80%, 77% and 74% in the PSC group and comparison group, respectively. Survival following transplantation has increased with time in both the PSC and the comparison group. Recent year of transplantation, no previous hepatobiliary surgery and a lower MELD score were predictors of survival following transplantation for PSC patients. PSC patients had a higher rate of re‐transplantations (13% versus 8%, P?=?0.01). Predictors of re‐transplantation in PSC patients were an episode of early rejection and vascular thrombosis. Conclusion: In PSC patients, year of transplantation, previous hepatobiliary surgery and MELD score are predictors of survival following transplantation and these patients are more frequently in need of re‐transplantation compared to the comparison group.     

MRI findings and Axis I and II psychiatric disorders after traumatic brain injury: a 30-year retrospective follow-up study

We studied the association between psychiatric disorders and the presence and location of traumatic lesions on magnetic resonance imaging (MRI) in 58 patients, on average, 30 years after traumatic brain injury. Axis I psychiatric disorders that had begun after the injury were assessed with the Schedules for Clinical Assessment in Neuropsychiatry (version 2.1), and Axis II disorders with the Structured Clinical Interview for DSM-III-R Personality Disorders. A 1.5-Tesla MRI scanner was used. One-third of the subjects had traumatic lesions visible on MRI. Only three psychiatric disorders, that is, delusional disorder, dementia, and the disinhibited type of organic personality syndrome, were significantly more common in subjects with contusions. Concerning the location of contusions, organic personality syndrome and its disinhibited subtype were associated with frontal lesions, and major depression was, surprisingly, inversely associated with temporal lesions. These results, which should be interpreted with caution due to the limited size of the study group, suggest that the majority of psychiatric disorders after traumatic brain injury are not closely related to the specific location or even the presence of contusions detectable with post-acute MRI.     

Is It Possible to Gain Extra Waiting Time to Liver Transplantation in Acute Liver Failure Patients Using Albumin Dialysis?

Hepatic encephalopathy (HE)‐associated brain edema is a common cause of death in acute liver failure (ALF). Molecular Adsorbent Recirculating System (MARS) albumin dialysis detoxifies endogenous and exogenous toxins from blood and improves HE. In this study we assessed the effect of MARS on increasing the length of time available while waiting for liver graft. Thirty‐seven patients with ALF who received a high‐urgent liver transplant (LTx) were divided into three groups according to the amount of histological necrosis in the explanted liver: group I = 100% necrosis; group II = 80–99% necrosis; group III = less than 80% necrosis. MARS was used continuously until LTx. Median time (range) on MARS treatment prior to LTx in groups I–III was 7 days (2–26), 6 days (1–17), and 5 days (1–15), and the median time on the waiting list was 5 days (1–11), 3 days (0–13), and 1 day (0–12), respectively. The HE grade prior to and after MARS was similar in all groups. In two patients the HE grade decreased during MARS treatment, even though the explanted liver showed a complete lack of viable cells. Overall 30‐day and one‐year survival were 97% and 92%, respectively, without differences between the three groups. In ALF patients the liver cell damage progressed to total or near total necrosis of the liver when the waiting time was prolonged. Yet, with MARS treatment some patients with total hepatic necrosis showed an absence of encephalopathy. With MARS treatment some patients might be able to wait longer for a LTx with good results.     

Outcome of traumatic brain injury after three decades--relationship to ApoE genotype

Significant traumatic brain injury (TBI) is nearly always associated with cognitive deficits, but in a highly variable manner. Apolipoprotein E (ApoE) plays a pivotal role in CNS response to injury. To examine the association of ApoE genotype with long-term outcome in TBI patients, we determined the ApoE genotype from 61 TBI patients who had been injured over three decades earlier. All patients had been studied neuropsychologically after their injuries. The long-term outcome was evaluated with repeated neuropsychological testing and by applying various measures of everyday functioning and quality of life. After three decades, TBI patients with the ApoE epsilon4 allele showed significantly poorer general cognitive level than those without this allele. This decline was wholly accounted for by a subgroup of these patients who had developed incident or clinical dementia, while the majority of the ApoE epsilon4 positive patients showed no decline at all. The other outcome measures describing vocational, physical, or subjective symptom outcome did not show significant relationships to the ApoE genotype. A portion of the TBI patients with the ApoE epsilon4 allele seem to be at risk of long-term cognitive decline.     

Vascular adhesion protein-1 (VAP-1) mediates lymphocyte-endothelial interactions in chronic kidney rejection

The pathogenesis of chronic kidney rejection characterized by persistent low-level inflammation and intimal thickening of the arteries in the graft remains poorly understood. We studied whether two important endothelial adhesion molecules, vascular adhesion molecule-1 (VAP-1) and peripheral node addressin (PNAd), would contribute to the lymphocyte recruitment into the rejected organ. VAP-1 was found to be present both in the normal kidney and prominently also in the chronically rejected kidneys. In the kidney VAP-1 was a homodimeric sialoglycoprotein expressed in peritubular capillaries, but not on glomerular endothelium or on tubular cells. In contrast, PNAd was absent from all kidney samples, indicating that kidney inflammation differs from other sites of chronic inflammation. Blocking of VAP-1 with mAbs abolished > 50 % of lymphocyte binding to renal vessels in rejected kidney in in vitro adhesion assays. Levels of circulating soluble VAP-1 (sVAP-1) decreased back to normal levels in patients with well-functioning transplants. These results are the first evidence that VAP-1 is able to mediate leukocyte binding into a rejected organ. Thus, anti-adhesive therapies targeting VAP-1 may be useful in controlling chronic kidney graft rejection.     

Albumin dialysis has a favorable effect on amino acid profile in hepatic encephalopathy

According to one popular theory, hepatic encephalopathy (HE) is partly caused by an imbalance in plasma amino acid levels. The Fischer's ratio between branched chain amino acids (BCAAs) and aromatic amino acids (AAAs) correlates with the degree of HE; the lower Fischer's ratio, the higher the grade of HE. Extra-corporeal liver support systems, like MARS(R)-albumin dialysis (Molecular Adsorbents Recirculating System), can improve HE. The MARS(R) system uses a hyperosmolar albumin circuit to remove both water-soluble and albumin-bound substances. Plasma levels of neuroactive amino acids were analyzed in 82 consecutive patients with life-threatening liver failure admitted to our ICU. All patients fulfilled our indications for MARS treatment and most also fulfilled the criteria for liver transplantation (LTx). In patients with acute liver failure (ALF), as compared to those with acute decompensation of chronic liver failure (AcOChr), levels of leucine and isoleucine were significantly higher before MARS(R) treatment. In all patients, before MARS(R) treatment the higher the grade of HE grade the lower was the Fischer's ratio and higher were the levels of inhibitory neuroactive amino acids. During MARS(R) treatments the Fischer's ratio increased, and the grade of HE decreased. The increase in Fischer's ratio was mainly due to the decrease in AAAs. The plasma levels of neuroactive amino acids, methionine, glutamine, glutamate, histidine and taurine decreased during MARS(R)-treatment. In this study MARS(R)-albumin dialysis had a favorable effect on the plasma amino acid profile of patients with HE.     

Renal allograft immunosuppression

Serum lipid and lipoprotein profiles were performed in order to investigate lipid abnormalities 2 years post-transplantation in first cadaveric renal allograft recipients immunosuppressed with cyclosporin (CyA), azathioprine (Aza), and methylprednisolone (MP), or with any combination of two drugs. CyA was used in low doses. Total serum cholesterol, triglyceride, LDL cholesterol, HDL cholesterol, HDL2 cholesterol, HDL3 cholesterol, apolipoprotein A1, and apolipoprotein B were determined in 88 prospectively randomized patients with functioning grafts. When considering only the patients who remained on the original randomized treatment, there were no significant differences between the four groups in any of the measured variables. Mean total cholesterol was highest in the group receiving Aza and MP (6.8 mmol/l) and lowest in the group receiving triple therapy (5.8 mmol/l; NS). Mean triglyceride level was highest in the group receiving Aza and MP (2.3 mmol/l) versus 1.8–2.2 mmol/l in the groups receiving triple therapy, Aza+CyA, and CyA+MP. For all patients mean triglyceride level was highest in the group receiving Aza and MP (2.7 mmol/l) and lowest in the group receiving triple therapy (1.7 mmol/l; P<0.05). Mean HDL cholesterol ranged from 1.5 to 1.6 mmol/l in all groups. Neither CyA concentration nor CyA or MP dose correlated with cholesterol or triglyceride concentration. However, the average MP dose was twice as high in the group receiving Aza and MP as in the other two groups employing steroids. Serum cholesterol and triglyceride concentrations were related to body mass index (r=0.28, P=0.045 and r=0.30, P=0.029, respectively). Hyperlipidemia was most common in the group receiving Aza and MP. The frequency of hypercholesterolemia (serum cholesterol level >6.5 mmol/l) was 18%, 45%, 60%, and 35% for the patients continuing with the originally randomized treatment in the groups receiving triple therapy, Aza+CyA, Aza+MP, and CyA+MP, respectively. In a normal Finnish reference population, 35% of all males and 31% of all females have a serum cholesterollevel above 6.5 mmol/l. Thus, only patients receiving Aza and MP had a clearly higher frequency of hypercholesterolemia than that found in a normal population. Taken together, this study shows no lipid abnormalities associated with the use of low-dose CyA for 2 years after transplantation. Hyperlipidemia occurring after transplantation is probably multifactorial and more associated with other risk factors than with the immunosuppressive therapy.     

Renal allograft immunosuppression

The long-term effects of different immunosuppressive drugs and regimens on renal allograft histology are virtually unknown. Therefore, in order to investigate the long-term effects of triple drug treatment versus different combinations of two immunosuppressive drugs on allograft histology, a prospective, randomized trial was performed. One group received triple therapy consisting of low-dose cyclosporin (CyA), azathioprine (Aza), and methylprednisolone (MP), and three groups received combinations of two drugs, i.e., Aza plus CyA, Aza plus MP, and CyA plus MP. At 2 years, there were no significant differences with regard to graft (80%) or patient (87%) survival, or to graft function between the four groups. After 2 years, a protocol core biopsy was taken of all 102 patients having a functioning graft. Of these patients, 61 (60%) were still following the original, randomized treatment protocol; in the remaining cases, changes had occurred in the original protocol and so these cases were considered drop-outs in this study. Histological specimens were examined blindly by two independent observers. Most of the 34 histological variables examined showed no changes. Diffuse fibrosis was most frequent in the CyA plus MP group (70%) and significantly more severe than in the triple therapy group. Mesangial matrix increase in glomeruli was significantly less common in the triple therapy group (8%) than in any one of the double drug combination groups (47%). Two other changes in glomeruli--Bowman capsular thickening and global glomerular sclerosis--were also less frequent in the triple therapy group.(ABSTRACT TRUNCATED AT 250 WORDS)