Modelling the variation in skin-test tuberculin reactions, post-mortem lesion counts and case pathology in tuberculosis-exposed cattle: Effects of animal characteristics, histories and co-infection.

Correctly identifying bovine tuberculosis (bTB) in cattle remains a significant problem in endemic countries. We hypothesized that animal characteristics (sex, age, breed), histories (herd effects, testing, movement) and potential exposure to other pathogens (co-infection; BVDV, liver fluke and Mycobacterium avium reactors) could significantly impact the immune responsiveness detected at skin testing and the variation in post-mortem pathology (confirmation) in bTB-exposed cattle. Three model suites were developed using a retrospective observational data set of 5,698 cattle culled during herd breakdowns in Northern Ireland. A linear regression model suggested that antemortem tuberculin reaction size (difference in purified protein derivative avium [PPDa] and bovine [PPDb] reactions) was significantly positively associated with post-mortem maximum lesion size and the number of lesions found. This indicated that reaction size could be considered a predictor of both the extent (number of lesions/tissues) and the pathological progression of infection (maximum lesion size). Tuberculin reaction size was related to age class, and younger animals (<2.85 years) displayed larger reaction sizes than older animals. Tuberculin reaction size was also associated with breed and animal movement and increased with the time between the penultimate and disclosing tests. A negative binomial random-effects model indicated a significant increase in lesion counts for animals with M. avium reactions (PPDb-PPDa < 0) relative to non-reactors (PPDb-PPDa = 0). Lesion counts were significantly increased in animals with previous positive severe interpretation skin-test results. Animals with increased movement histories, young animals and non-dairy breed animals also had significantly increased lesion counts. Animals from herds that had BVDV-positive cattle had significantly lower lesion counts than animals from herds without evidence of BVDV infection. Restricting the data set to only animals with a bTB visible lesion at slaughter (n = 2471), an ordinal regression model indicated that liver fluke-infected animals disclosed smaller lesions, relative to liver fluke-negative animals, and larger lesions were disclosed in animals with increased movement histories.

Expression of IGFBP-1 in normal and cirrhotic human livers.

Cirrhosis of the liver, a condition characterised by hepatocyte regeneration, is also associated with elevated insulin levels and insulin resistance. In animal models hepatic regeneration is associated with increased IGFBP-1 gene expression. Insulin is known to be an inhibitor of IGFBP-1 gene expression and circulating insulin levels in man demonstrate a negative correlation with IGFBP-1 levels. To further our understanding of the regulation of IGFBP-1 in cirrhosis we have studied steady state levels of IGFBP-1 mRNA in human liver from three groups of patients: Group 1, tissue obtained at the time of harvesting donor liver for orthotopic liver transplantation (n = 4); group 2, patients undergoing major liver resection with no histological evidence of chronic liver disease (n = 4); and group 3, patients undergoing orthotopic transplantation for chronic liver failure (n = 9). Simultaneous samples of serum were taken at the time of surgery in some patients and in these patients IGFBP-1 mRNA levels were related to circulating levels of IGFBP-1 and insulin. IGFBP-1 mRNA was detectable in all the human liver samples with the greatest levels seen from the normal livers of group 2 patients. Insulin levels were elevated in the cirrhotic group 3 patients compared to a normal range as were IGFBP-1 levels. There was no relationship between circulating levels of IGFBP-1 and IGFBP-1 gene expression. In conclusion, IGFBP-1 mRNA is present in human adult liver at the time of surgery and also in cirrhotic liver despite high levels of insulin suggesting that there are factors other than insulin regulating IGFBP-1 gene expression.

Portal hypertension and hypersplenism in a patient with a Bochdalek hernia: a case report.

BACKGROUND: A congenital diaphragmatic hernia (Bochdalek's hernia) rarely presents in adulthood. CASE PRESENTATION: We present the case of a 21-year-old woman with thrombocytopenia secondary to hypersplenism due to left-sided (sinistral) portal hypertension. This portal hypertension was caused by strangulation of the spleen within a Bochdalek's hernia. Subacute gastric volvulus compounded by portal hypertensive gastropathy resulted in her presentation with acute haematemesis. CONCLUSIONS: Congenital diaphragmatic hernias may present in the adult. Their presentation is variable, and they may produce life-threatening complications.

Insulin-like growth factor bioactivity and its modification in growth hormone resistant states.

Acquired growth hormone (GH) resistance is an increasingly recognized feature of catabolic states. Low circulating levels of the insulin-like growth factors (IGF-I and II) have been shown to be associated with changes in the IGF binding proteins (IGFBP-1 to -6) that may significantly impact on IGF bioactivity. IGFBP-3 binds IGF and a third glycoprotein, the acid labile subunit (ALS), to form a stable 150 kDa ternary complex that serves as an intravascular store for IGFs and prolongs IGF half-life. IGFBP-1 is present at much lower concentration in serum but levels fluctuate acutely, suggesting regulation of IGF bioactivity in response to short-term metabolic changes. The function of IGFBP-2 remains unclear, but studies suggest that this protein may act as an alternative carrier for IGF when IGFBP-3 levels are low. Multiple regulatory influences on circulating IGFBP levels have been identified but three appear prominent. Nutritional influences, in particular substrate availability, appear to be a central regulatory influence on IGFBP levels in catabolic states. Low substrate availability increases IGFBP-1 levels acutely and decreases IGFBP-3 and IGFBP-2 levels in the intermediate term, with each of these changes likely to further limit IGF bioactivity. End organ failure, particularly of liver and kidney significantly affects production and clearance rates of the circulating IGFBPs and may contribute to the catabolism frequently seen in these states. Severe protein catabolism often accompanies malignancy and chronic sepsis and it is likely that additional ill-defined factors influence IGF bioactivity in this setting. Recent studies have identified post-translational modifications to the IGFBPs such as proteolysis and phosphorylation, which appear to further impact on IGF bioactivity. The relative contributions of these changes to the overall impairment of IGF bioactivity in GH-resistant states remains to be fully elucidated.

The heterogeneity of bone disease in cirrhosis: a multivariate analysis.

This study aimed to assess the clinical, biochemical and hormonal factors contributing to low bone density in a large ambulatory group of patients with cirrhosis of diverse aetiology. Bone density of the lumbar spine, neck of femur, total hip, total body, as well as total body fat, was measured by dual X-ray (DEXA) absorptiometry in 81 men and 32 women (average age 50.3 years). Morning blood and urine samples were taken for hormonal and biochemical analysis. Viral hepatitis was the most common cause of cirrhosis (54%) and the severity of cirrhosis ranged from Child-Pugh A5-C14. Osteoporosis was most common in the lumbar spine but was present at any site in 31% of women and 22% of men, with osteopenia present in another 40% of both genders. Urinary deoxypyridinoline, a marker of bone resorption, was elevated in 56% of patients and was associated with increasing severity of cirrhosis and a higher prevalence of osteoporosis, particularly of the lumbar spine. Hip-bone density was primarily affected by low 25-hydroxyvitamin D levels and was associated with secondary hyperparathyroidism in one third of these patients. Additional important predictors for low bone density at all sites were age in women and testosterone in men. These findings indicate that, although the pathophysiology of osteoporosis in chronic liver disease is heterogeneous, high bone turnover may be the underlying pathophysiological mechanism in a significant subgroup of cirrhotic patients and may reflect metabolic effects of hypogonadism or secondary hyperparathyroidism on bone.

Growth hormone, insulinlike growth factor-1, and insulinlike growth factor binding proteins 1 and 3 in chronic liver disease.

The liver is the major source of circulating insulinlike growth factor-I (IGF-I) and has been suggested as a major source of at least two of the major binding proteins that modify its bioavailability. We aimed to assess the direct effects of liver dysfunction on serum levels of IGF-1 and its major binding proteins by measuring fasting levels of growth hormone, IGF-1, IGFBP-1, IGFBP-3, insulin, C peptide, and glucose in 35 patients with cirrhosis and during an oral glucose tolerance test in 16 of those patients. Serum levels of growth hormone (GH) were high in the patients: median, 12.0 mU/L (range, 1 to 87) compared with normals, 0.95 mU/L (0.1 to 20) (P < .0005) and serum IGF-1 levels were low: 81 ng/mL (38 to 153) versus 193 ng/mL (151 to 235) (P < .0001). Serum IGFBP-3 levels were low in the patients: 1.59 mg/L (0.46 to 4.43) compared with normals, 5.41 (4.34 to 6.11) (P < .0001), and there was a significant negative correlation between IGFBP-3 levels and Childs Pugh score (r = .63 P < .0001). Fasting IGFBP-1 levels were significantly higher in the patients 31 ng/mL (11 to 92) than normals, 14 (7 to 20) (P < .0001). There was no correlation between fasting insulin and IGFBP-1 levels despite high fasting insulin levels. A decrease in IGFBP-1 levels was seen during the glucose tolerance test (GTT) in all patients. In conclusion, there are significant changes in the levels of two of the major IGF-1 binding proteins that may further limit the bioavailability of already low circulating IGF-1 levels. Substrate availability appears to be a stronger influence on fasting IGFBP-1 levels than does insulin, and the close correlation of IGFBP-3 with liver function indicates a dominant regulatory role of the hepatocyte.

Antibodies to colonic epithelial cells from the serum and colonic mucosal washings in ulcerative colitis.

It has been suggested that antibodies to a colonocyte protein of 40 kD (an intestinal isoform of tropomyosin) are specifically found in the serum and mucosa of patients with ulcerative colitis, which has important pathogenic implications. This study isolated and purified tropomyosin from the colonic mucosa, but no specific binding to this protein has been detected in serum samples or immunoglobulins isolated from mucosal washings of 20 ulcerative colitis (UC) patients by enzyme linked immunosorbent assay (ELISA) compared with 21 controls or 17 Crohn's disease (CD) patients. Samples from a further 12 patients with UC and primary sclerosing cholangitis (it is proposed that cross reactivity against the intestinal tropomyosin isoform accounts for the extraintestinal disease) also did not show binding to tropomyosin, whereas monoclonal antitropomyosin antisera bound both ELISAs and western blots. This study also examined the proteins in the normal colonic biopsy specimens on western blots that are bound by both serum samples and mucosal immunoglobulin preparations from these patients groups; there was no specific IgG or IgA binding to patients with UC or UC/primary sclerosing cholangitis, whereas binding to mitochondrial proteins of 70,000 and 45,000 was seen in samples from 12 primary biliary cirrhosis positive controls. This work does not support the hypothesis that autoimmune activity against the intestinal isoform or tropomyosin is important in the pathogenesis of ulcerative colitis.

Serum tumor markers for the diagnosis of cholangiocarcinoma in primary sclerosing cholangitis.

BACKGROUND/AIMS: The diagnosis of cholangiocarcinoma in primary sclerosing cholangitis (PSC), even with the use of current imaging techniques and brush cytology, is difficult and particularly important in patients being assessed for liver transplantation. This study investigated the accuracy of serum levels of a combination of the tumor markers carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA19-9) in the diagnosis of cholangiocarcinoma in patients with PSC. METHODS: Seventy-four patients with PSC were studied. Fifteen patients had tumors (11 occult on imaging), 22 had severe PSC that necessitated transplantation (with explanted liver known to be free of tumor), and 37 patients had stable PSC. RESULTS: An index of the two serum tumor markers [using the formula CA19-9 + (CEA x 40)] gave an accuracy of 86% in diagnosis of cholangiocarcinoma, with 10 of the 15 cases of cholangiocarcinoma having an increased value compared with none in a group of 22 comparable cases with no tumor. In addition, 6 of the 11 patients with occult tumors had abnormal values. Ultrasonography, computerized tomographic scanning, and endoscopic retrograde cholangiopancreatography were poor predictors of the presence of tumor. CONCLUSIONS: A combination of serum tumor markers will identify most occult tumors and will improve selection of appropriate cases for orthotopic liver transplantation.

Safety and efficacy of target controlled infusion (Diprifusor) vs manually controlled infusion of propofol for anaesthesia.

In this multi-centre, randomized trial, we compared the safety and efficacy of Diprifusor TCI with manually controlled infusion (MCI) of propofol for anaesthesia. With approval, 123 adult male and female patients were studied. Firstly, each investigator anaesthetized five patients to familiarize themselves with Diprifusor TCI. In Stage 2, 98 patients were randomized to receive propofol-based anaesthesia via TCI or MCI. Adjuvant drugs, airway management and monitoring were managed at the discretion of the anaesthetist. Results are presented as mean (SD). Induction times were significantly longer [67 (32) vs 54 (17)s] and induction doses were significantly lower [14 (5) vs 16 (4) ml] in the TCI vs the MCI group. Recovery times and total doses were not significantly different. There were statistically but not clinically significant differences in mean arterial blood pressure and heart rate. Quality of anaesthesia and ease of control of anaesthesia were similar. We conclude that Diprifusor TCI and MCI are similar in terms of safety and efficacy.

Growth hormone therapy in patients with cirrhosis: a pilot study of efficacy and safety.

BACKGROUND & AIMS: The protein catabolic state of cirrhosis is associated with severe growth hormone (GH) resistance, with low levels of insulin-like growth factor (IGF)-I and its major binding protein (IGFBP)-3. The aim of this study was to conduct a randomized, double-blind, placebo-controlled pilot study of GH therapy in 20 cirrhotic patients to assess the reversibility of GH resistance and subsequent impact on protein economy and safety. METHODS: Patients were treated with GH (0.25 IU/kg body wt) or placebo for 7 days. Serum levels of GH, IGF-I, IGFBP-3, and insulin were measured by radioimmunoassay and 24-hour urinary nitrogen by the Kjeldahl technique. RESULTS: IGF-I levels increased only in the GH-treated group (mean, 69.2 +/- SE 7.0 to 170.6 +/- 48.8 ng/mL; P < 0.05) together with IGFBP-3 (1.65 +/- 0.3 to 2.94 +/- 0.6 mg/L; P < 0.005). Cumulative nitrogen balance similarly improved only in the GH group (2.87-24.16 g; P < 0.05). No significant side effects of GH were observed. CONCLUSIONS: GH therapy can overcome the GH resistance of cirrhosis. The resulting improvement in nitrogen economy and possible influences on clinical outcomes will need to be confirmed in controlled studies of longer duration.