Quality of life before and after liver transplantation for cholestatic liver disease

Liver transplantation (LT) is an established therapy for patients with end-stage primary biliary cirrhosis (PBC) or primary sclerosing cholangitis (PSC). In this report, we describe the health status and quality of life (QOL) in patients with these cholestatic liver diseases before and after LT. A QOL questionnaire was completed by 157 adult patients with PBC or PSC before and 1 year after liver transplantation at the Mayo Clinic or Baylor University Medical Center. This questionnaire measured four aspects of QOL, including symptoms; physical, social, and emotional functioning; health perceptions; and overall QOL. Changes in these QOL parameters before and after LT were described, and regression analysis was used to assess the relationships between clinical and QOL factors. There were no differences in QOL parameters between patients with PBC and PSC. QOL following transplantation was substantially better than before transplantation. This was observed in all four aspects of QOL. The degree of improvement as measured by effect size (difference in mean scores divided by the pretransplantation standard deviation) was 0.53 for symptoms (P <.01), 1.16 for function (P <.01), 2.37 for health satisfaction (P <.01), and 1.16 for overall QOL (P <.01). Patients' overall QOL before transplantation was significantly related to subjective and objective health status indicators and clinical factors such as ascites and renal dysfunction. QOL at 1-year follow-up, however, could not be adequately predicted by the pretransplantation subjective health status and clinical factors. Patients with end-stage cholestatic disease undergoing LT experience substantial improvement in all aspects of QOL addressed in this study. The patients' QOL 1 year after LT could not be predicted by pretransplantation variables used in this study.     

Cerebral oedema and increased intracranial pressure in chronic liver disease

BACKGROUND: Cerebral oedema is a cause of morbidity and mortality in fulminant hepatic failure but has not been well documented as a complication of chronic liver diseases. We report here the development of cerebral oedema and increased intracranial pressure in 12 patients with chronic liver disease. METHODS: Between July 1, 1987, and Dec 31, 1993, we studied 12 patients aged 29-67 years with end-stage chronic liver disease. All the patients had cirrhosis, portal hypertension, hypoprothrombinaemia, hepatic encephalopathy, and decreased serum concentrations of albumin (<25 g/L). During the study, the patients developed signs of increased intracranial pressure and had documented intracranial hypertension, cerebral oedema, or both. Intracranial hypertension was suspected on physical examination and confirmed by epidural catheters. We detected cerebral oedema by computed axial tomography of the head and necropsy of the brain when possible. FINDINGS: All the patients had intracranial hypertension and cerebral oedema. Two patients had successful treatment of cerebral hypertension with improvement of intracranial pressure such that orthotopic liver transplantation was undertaken. Both patients became neurologically normal after transplantation. Eight patients had only a transient response to treatment and died of cerebral oedema before a transplant could be done. INTERPRETATION: Cerebral oedema and increased intracranial pressure can occur in chronic liver disease and presents as neurological deterioration. Treatment guided by monitoring of intracranial pressure can lead to the reversal of intracranial hypertension, but in most patients cerebral oedema contributes to death or places them at too high a risk for liver transplantation.     

Whole blood platelet aggregation and coagulation factors in patients with systemic sclerosis

It is unclear whether the changes in platelet function which are observed in systemic sclerosis are a primary characteristic of this disease or whether they occur secondary to vascular changes. Whole blood platelet aggregation was studied in 26 patients with systemic sclerosis, normal subjects matched for age, sex and secondary characteristics, 19 patients with Raynaud's disease and 19 patients with systemic lupus erythematosus. Plasma levels of fibrinogen, von Willebrand factor antigen and factor VIII:C were also measured. Systemic sclerosis was associated with a significant (P > 0.001) enhancement of the sensitivity of platelets to collagen. In contrast, significant enhancement of the response to either ADP or adrenaline was not observed. Enhanced sensitivity to collagen was not associated with the presence of either Raynaud's disease or systemic lupus erythematosus. Systemic sclerosis was associated with significantly raised levels of von Willebrand factor antigen and fibrinogen. On an individual patient basis, von Willebrand factor antigen was related to the severity of the disease whereas platelet sensitivity to collagen was not. In conclusion, this study suggests that the enhanced sensitivity to collagen which occurs in systemic sclerosis is due to a primary change in the platelet and that this change can combine with elevated levels of adhesive proteins.     

Regulation of cholesterol levels in plasma and liver of adult rats

The dynamics of cholesterol-system in the plasma is characterized by a parameter which is a linear function of the internal secretion of cholesterol. So, the level of plasma cholesterol from synthesis is a low as its flow is high. Moreover, the level of plasma cholesterol from diet is simultaneously proportional to the flow of cholesterol intestinal absorption and dependent on the dynamics controlled by the internal secretion. The laws of the cholesterolemia cumulate these partial laws. Similar relations concern the esterified cholesterol in the liver.     

Changes in plasma proteins and drug distribution in kidney and liver diseases

Kidney and liver diseases induce alterations in drug binding to plasma proteins. These alterations are caused by qualitative and quantitative changes of plasma proteins and the presence of endogenous substances which act as competitive inhibitors of drug binding to plasma proteins. These changes are the most prominent in nephrotic syndrome and uremia among kidney diseases and in cirrhosis among liver diseases. The more important drugs in which the free fraction is changed in these entities are listed in the tables. The changes in drug distribution caused by plasma protein alterations may induce significant changes in entire drug pharmacokinetics. Discussed are theoretically expected and experimentally proven changes in plasma proteins in kidney and liver diseases and their influence to drug action and dosing regimen.     

Instability of rat liver chromatin and other nuclear non-histone proteins in alkaline solution

Non-histone proteins from rat liver nuclei and chromatin were shown to be hydrolysed in 0.1M or-1M-NaOH solutions both at 4 degrees and 18 degrees C; 24h in 1M-NaOH at 18 degrees C is sufficient to break down approx. 77% of these proteins to low-molecular-weight peptides. Loss of protein material banding in the region of pH5.5-8.0 has been demonstrated by isoelectric focusing in polyacrylamide gels, and fine high-molecular-weight bands are no longer visible on sodium dodecyl sulphate/polyacrylamide-gel electrophoresis. The results indicate that care must be taken when analysing non-histone-protein fractions to avoid exposure to alkaline pH conditions.     

Leukocyte adhesion molecules in the liver and plasma cytokine levels in endotoxin-induced rat liver injury

BACKGROUND: The interactions between polymorphonuclear neutrophils (PMNs) and sinusoidal endothelial cells (SECs) have been known to be involved in the pathogenesis of acute liver injury. It has been also reported that tumor necrosis factor-alpha (TNF-alpha) up-regulates ICAM-1 expression on SECs and that interleukin-8 (IL-8) provokes rapid activation of CD11/CD18 on PMNs. These findings expand into the relationship between the expression of leukocyte adhesion molecules (ICAM-1, CD11a/CD18 and CD11b/CD18) in liver tissues and plasma TNF and IL-8 levels after lipopolysaccharide (LPS)-induced liver injury in rats. METHODS: Male Wistar rats weighing 200-250 g were treated with 2 mg LPS/kg intravenously in a 0.2- to 0.25-ml volume. Liver and blood samples were obtained at 1, 3, 8, and 12 h after LPS exposure. Plasma TNF and IL-8 levels were measured using bioassay and specific enzyme-linked immunosorbent assay, respectively. Liver samples were fixed and studied by immunohistochemistry using specific monoclonal antibodies against ICAM-1, CD11a, and CD11b. RESULTS: The TNF level showed a peak at 1 h (23.3 +/- 11.4 IU/ml), and the IL-8 level showed a peak at 3 h (343.1 +/- 110.5 ng/ml) after LPS exposure. An increase in the number of PMNs in the liver was observed as early as 1 h and continued until 12 h after LPS exposure. PMNs adhered to degenerated SECs and hepatocytes. ICAM-1 on SECs was diffusely and strongly expressed at 8 h, and PMNs adhered to SECs expressed both CD11a and CD11b. ICAM-1 was also observed on hepatocytes. CONCLUSION: These data suggest that PMN-SEC and PMN-hepatocyte interactions via leukocyte adhesion molecules, related to inflammatory cytokines such as TNF and IL-8, exist and play an important role in the pathogenesis of acute liver injury.     

Plasma cytokine levels and coagulation and complement activation during use of the extracorporeal liver assist device in acute liver failure

Multiple organ failure frequently occurs in patients with acute liver failure, and this has been associated with increased cytokine production. Treatment by hemoperfusion with an extracorporeal liver assist device (ELAD) containing human liver-derived cells was performed in 12 patients with acute liver failure. Over the first 6 h, there were significant increases in plasma tumor necrosis factor alpha (TNFalpha; from 114+/-54 pg/ml [mean+/-SEM] to 236+/-161 pg/ml, p < 0.05) and interleukin (IL)-6 (260+/-121 pg/ml to 445+/-149 pg/ml, p < 0.05) but not in interferon gamma (IFNgamma). A similar pattern with a small peak increase was observed for complement C5b-9 complex. Plasma C-reactive protein (CRP) and thrombin antithrombin (TAT) III complex showed small peaks after 24 h of ELAD hemoperfusion. No such changes were seen in 12 control patients with acute liver failure who were treated with intensive care alone. These transitory effects, without changes in blood pressure, are likely to be due to the contact of the blood with the dialyzer membrane. There was no evidence of the clearance of cytokines by the ELAD.     

Developmental variations in factors related to initial and increased levels of adolescent drug involvement

Effects of two 9-month sports programmes (four or two sessions per week) on level of daily physical activity (PA), fat mass (FM), and physical fitness were assessed in children with spastic cerebral palsy (CP; n = 20, 9.2 +/- 1.4 yr), randomly assigned to an experimental and control group after matching. Four sessions per week tended to increase PA ratio (24-h energy expenditure/sleeping (resting) energy expenditure) after 9 months from 1.34 +/- 0.25 to 1.55 +/- 0.18 (P = 0.07; not different versus controls). FM increased continuously in the control group (after 9 months + 1.1 +/- 1.6 kg, P < 0.05), whereas the experimental groups showed no changes. Training (respectively four and two sessions) increased peak aerobic power 35% (P < 0.01; P < 0.05 versus controls) and 21% (P < 0.01; P = 0.17 versus controls). Results also suggest that training has a favourable effect on isokinetic muscle strength. No training-related effects were found on anaerobic power. It was concluded that although aerobic training has a limited effect on PA in children with CP, it may prevent deterioration in body composition and muscle strength. Furthermore, training has a favourable effect on peak aerobic power.     

Observations on the relationship of parathyroid hormone and calcitonin to plasma and liver phosphate

1. The action of two active forms of bovine trypsin (alpha and beta-trypsin) on a series of specific methyl ester substrates of general formula: N-acetyl-(glycyl)n-L-lysine methyl ester (n = 0, 1, 2) and N2-benzoyl-L-arginine ethyl ester have been investigated. With the L-lysine methyl esters the catalytic rate constant for hydrolysis (kcat) was found to be significantly lower for alpha-trypsin than for beta-trypsin, whereas with N2-benzoyl-L-arginine ethyl ester there was no significant difference for the two enzymes. 2. By measurement of the kinetic constants (kcat and Km) in the presence of a nucleophile, which competes with water in the deacylation process, it has been shown that, in common with the specific ester substrates of trypsin, the rate-determining step for the extended L-lysine methyl esters is decaylation of the enzyme. 3. It has been found that by extending the aminoacyl group of N-acetyl-L-lysine methyl ester by one glycine residue (n = 1), a greatly enhanced deacylation rate constant is observed for both alpha and beta-trypsin. The higher rate constants were maintained at the higher levels by the addition of a further glycine residue (n = 2). These results have been interpreted in terms of the 'induced fit' hypothesis the substrates binding to an enzyme subsite adjacent to the active site. 4. The beta-trypsin-catalysed hydrolysis of the L-lysine substrates was investigated over a range of temperature (15--35 degrees C). The Arrhenius law was obeyed, within experimental error, by all three substrates allowing the estimation of the thermodynamic function of activation (delta S not equal to and deltaH note equal to) for the deacylation reactions. The significantly higher values of deltaS not equal to and deltaH not equal to obtained for the two extended substrates are interpreted in terms of additional hydrogen bonding between the longer aminoacyl chains and the enzyme molecule. The results are compared with those for non-extended specific substrates, which have a possible hydrophobic interaction with the enzyme surface.     

Distribution of vitronectin in plasma and liver tissue: relationship to chronic liver disease

To clarify the clinical significance of vitronectin, we compared the concentration of plasma vitronectin with serum fibrous markers and liver function test values in patients with chronic liver diseases. We also evaluated the vitronectin content in the liver by means of enzyme-linked immunosorbent assay and the localization of vitronectin in liver tissue with enzyme immunohistochemistry. In chronic liver disease, the concentration of plasma vitronectin was significantly lower than that in healthy controls, being related to the severity of liver disease. The plasma levels of vitronectin showed no correlation to fibrous markers but a significant correlation with those of serum albumin and prothrombin time. On the other hand, the content of vitronectin in liver tissue was significantly increased in chronic liver disease compared with that in normal controls. In the normal liver, vitronectin was observed in the portal area by light microscopy. In chronic hepatitis and cirrhosis, vitronectin was found in the connective tissue around the portal and central veins and in the areas of piecemeal and focal necrosis. These findings suggested that vitronectin is deposited in injured tissue through the process of repair and fibrosis and plays an important role as an adhesive protein. Moreover, the lower levels of plasma vitronectin in chronic liver disease may be due to its decreased synthesis, deposition or both in injured tissue.     

Alteration of plasma antithrombin III levels in ischemic heart disease

The amount of antithrombin III in plasma was determined quantitatively in 218 males between 45-60 years of age. The mean antithrombin III value was found to be low in the group with low risk for ischemic heart disease, intermediate in the group with high risk for ischemic heart disease and highest in the group with acute myocardial infarction. Concomitant study of kaolin-activated partial thromboplastin time revealed a sharp decrease in its mean value in the group with acute myocardial infarction. The high correlation between antithrombin III and kaolin-activated partial thromboplastin time for the entire population suggests that the development of ischemic heart disease is a gradual process and that failure of the damping mechanism results as an acute event. These findings may be useful in the determination of the coagulation state of these patients.     

Total cholesterol and high-density lipoprotein levels as risk factors for increased intraocular pressure

PURPOSE: To determine whether high-density lipoprotein and total cholesterol levels were risk factors for increased intraocular pressure in patients with chronic open-angle glaucoma or ocular hypertension. METHODS: We measured total cholesterol, high-density lipoprotein, and total cholesterol/high-density lipoprotein ratio in 25 patients with open-angle glaucoma or ocular hypertension who had taken no glaucoma medications for four weeks. We individually matched these patients to 25 control subjects who had no history of open-angle glaucoma or ocular hypertension, on the basis of age, race, gender, and history of vascular disease or diabetes mellitus. RESULTS: We found no statistical difference in the high-density lipoprotein (P = .702) or total cholesterol (P = .177) levels or total cholesterol/high-density lipoprotein ratio between groups (P = .178, paired t test). CONCLUSION: This study indicates that increased high-density lipoprotein and total cholesterol levels are not risk factors for increased intraocular pressure.     

Lung mechanics in congenital heart disease with increased and decreased pulmonary blood flow

Respiratory rate, tidal volume, dynamic lung compliance, functional residual capacity, and pulmonary resistance were measured withim 24 hours of cardiac catheterization in 25 infants, 12 of whom had increased pulmonary blood flow and 13 of whom had decreased PBF. There were no differences in the two groups of patients with respect to VT and FRC. Respiratory rate and pulmonary resistance were higher in infants with increased PBF. Lung compliance was significantly lower in infants with increased PBF (4.9 ml/cm H2O) than in those with decreased PBF (8.9 ml/cm H2O) (P less than 0.01). The decrease in CL in infants with increased PBF significantly correlated with mean pulmonary artery pressure (r = 0.798). No correaltion was found between CL and left atrial pressure or magnitude of the left-to-right shunt. Compliance was normal in patients with increased PBF and normal PAP, suggesting that PAP and not PBF is the primary factor that affects CL in patients with intracardiac left-to-right shunts.