Search

Drug-induced liver injury (DILI) remains a challenging diagnosis due to an absence of specific biomarkers. DILI due to volatile anaesthetics (VA-DILI) is characterised by trifluoroacetyl and CYP2E1 antibodies, but may not be seen for weeks after injury. Interleukin-4 (IL-4) may be involved in the production of these antibodies and may serve as a clinically useful early biomarker of VA-DILI. To prospectively compare serum IL-4 levels between patients who develop VA-DILI and controls following exposure to the volatile anaesthetic. A nested case-control study of patients exposed to VA during surgery was conducted. Thirteen DILI cases were identified from the original cohort, and 26 controls were matched according to age, sex and VA agent. Serum samples were collected before and 48-96 h after VA exposure, and analysed for IL-4 using quantitative enzyme-linked immunosorbent assay techniques. There was a statistically significant difference in serum IL-4 in post-VA samples between DILI cases and controls (control: 0.030 pg/mL, IQR: 0.030 − 0.030 pg/mL vs DILI: 0.044 pg/mL, IQR: 0.030 − 0.061 pg/mL; p = 0.039). A greater proportion of DILI cases had post-VA IL-4 levels above the assay lower limit of detection compared to controls (control: 23% vs DILI: 69%; p = 0.013). IL-4 is a potential biomarker of DILI. Clinical diagnosis and understanding of DILI disease mechanisms may be improved by further investigation of novel biomarkers, and this IL-4 signal in serum is important as proof of concept for prospective study designs.

Systemic inflammation (SI) is involved in the pathogenesis of acute decompensation (AD) and acute-on-chronic liver failure (ACLF) in cirrhosis. In other diseases, SI activates tryptophan (Trp) degradation through the kynurenine pathway (KP), giving rise to metabolites that contribute to multiorgan/system damage and immunosuppression. In the current study, we aimed to characterize the KP in patients with cirrhosis, in whom this pathway is poorly known. The serum levels of Trp, key KP metabolites (kynurenine and kynurenic and quinolinic acids), and cytokines (SI markers) were measured at enrollment in 40 healthy subjects, 39 patients with compensated cirrhosis, 342 with AD (no ACLF) and 180 with ACLF, and repeated in 258 patients during the 28-day follow-up. Urine KP metabolites were measured in 50 patients with ACLF. Serum KP activity was normal in compensated cirrhosis, increased in AD and further increased in ACLF, in parallel with SI; it was remarkably higher in ACLF with kidney failure than in ACLF without kidney failure in the absence of differences in urine KP activity and fractional excretion of KP metabolites. The short-term course of AD and ACLF (worsening, improvement, stable) correlated closely with follow-up changes in serum KP activity. Among patients with AD at enrollment, those with the highest baseline KP activity developed ACLF during follow-up. Among patients who had ACLF at enrollment, those with immune suppression and the highest KP activity, both at baseline, developed nosocomial infections during follow-up. Finally, higher baseline KP activity independently predicted mortality in patients with AD and ACLF. Conclusion: Features of KP activation appear in patients with AD, culminate in patients with ACLF, and may be involved in the pathogenesis of ACLF, clinical course, and mortality., info:eu-repo/semantics/published

Patients admitted with acute variceal bleeding (AVB) and Child-Pugh C score (CP-C) or Child-Pugh B plus active bleeding at endoscopy (CP-B+AB) are at high risk for treatment failure, rebleeding, and mortality. A preemptive transjugular intrahepatic portosystemic shunt (p-TIPS) has been shown to improve survival in these patients, but its use in clinical practice has been challenged and not routinely incorporated. The present study aimed to further validate the role of preemptive TIPS in a large number of high-risk patients. This multicenter, international, observational study included 671 patients from 34 centers admitted for AVB and high risk of treatment failure. Patients were managed according to current guidelines, and use of drugs and endoscopic therapy (D+E) or p-TIPS was based on individual center policy. p-TIPS in the setting of AVB is associated with a lower mortality in CP-C patients compared with D+E (1 year mortality 22% vs. 47% in D+E group; P = 0.002). Mortality rate in CP-B+AB patients was low, and p-TIPS did not improve it. In CP-C and CP-B+AB patients, p-TIPS reduced treatment failure and rebleeding (1-year cumulative incidence function probability of remaining free of the composite endpoint: 92% vs. 74% in the D+E group; P = 0.017) and development of de novo or worsening of previous ascites without increasing rates of hepatic encephalopathy. Conclusion: p-TIPS must be the treatment of choice in CP-C patients with AVB. Because of the strong benefit in preventing further bleeding and ascites, p-TIPS could be a good treatment strategy for CP-B+AB patients. ispartof: HEPATOLOGY vol:69 issue:1 pages:282-293 ispartof: location:United States status: published

BACKGROUND: Insulin-like growth factors (IGFs) and their binding proteins (BPs) regulate cell differentiation, proliferation and apoptosis, and may have a role in the aetiology of various cancers. Information on their role in pancreatic cancer is limited and was examined here in a case-control study nested within the European Prospective Investigation into Cancer and Nutrition. METHODS: Serum concentrations of IGF-I and IGFBP-3 were measured using enzyme-linked immunosorbent assays in 422 cases and 422 controls matched on age, sex, study centre, recruitment date, and time since last meal. Conditional logistic regression was used to compute odds ratios (OR) and 95% confidence intervals (CI) adjusted for confounding variables. RESULTS: Neither circulating levels of IGF-I (OR = 1.21, 95% CI 0.75-1.93 for top vs bottom quartile, P-trend 0.301), IGFBP-3 (OR = 1.00, 95% CI 0.66-1.51, P-trend 0.79), nor the molar IGF-I/IGFBP-3 ratio, an indicator of free IGF-I level (OR = 1.22, 95% CI 0.75-1.97, P-trend 0.27), were statistically significantly associated with the risk of pancreatic cancer. In a cross-classification, however, a high concentration of IGF-I with concurrently low levels of IGFBP-3 was related to an increased risk of pancreatic cancer (OR = 1.72, 95% CI 1.05-2.83; P-interaction = 0.154). CONCLUSION: On the basis of these results, circulating levels of components of the IGF axis do not appear to be the risk factors for pancreatic cancer. However, on the basis of the results of a subanalysis, it cannot be excluded that a relatively large amount of IGF-1 together with very low levels of IGFBP-3 might still be associated with an increase in pancreatic cancer risk. British Journal of Cancer (2012) 106, 1004-1010. doi:10.1038/bjc.2012.19 www.bjcancer.com Published online 7 February 2012 (C) 2012 Cancer Research UK

If GH and IGF-I are involved in early and probably long-term renal changes following kidney ablation, and therefore theoretically also in the series of events after a kidney transplantation, the effect of somatostatin analogue should be investigated further. Pronounced effects have been observed in a small number of reports in unilateral nephrectomy and experimental diabetes models, but until now no trials have been published on kidney transplantation models. In contrast, studies have already been performed on somatostatin analogues' effects on vascular wall changes and SMCs during vascular regeneration and in graft vessel disease. The effect of somatostatin analogues, which are potent inhibitors of GH and IGF-I production, has been investigated in short-term (octreotide and lanreotide) and long-term (octreotide only) models of uninephrectomy and diabetes both comprising early renal and glomerular growth, and subsequently an effect has been demonstrated on urinary albumin/protein excretion, a marker of kidney disease. Only octreotide inhibited the early local IGF-I accumulation and renal growth following unilateral nephrectomy in rats while lanreotide (Gronbaek et al, unpublished results) and octreotide both inhibited the renal hypertrophy after diabetes induction. Long-term octreotide studies demonstrated significant reductions in renal and glomerular growth and urinary albumin excretion in octreotide-treated control and diabetic rats, while no effect was observed in a diabetic uninephrectomized model, although using a much lower octreotide dose. Further, Igarashi et al treated uninephrectomized diabetic rats with octreotide for 3 weeks after an untreated period of 15 weeks and observed diminished kidney hypertrophy and normalization of albuminuria. It can be concluded from these studies that somatostatin analogues have pronounced effects on pathophysiological renal growth and on the development of long-term renal changes in diabetes and following uninephrectomy. As for chronic graft vessel disease and vascular growth and regeneration lanreotide has been shown to inhibit myointimal thickening following aortic or coronary balloon injury in various animal models. This effect may be partly mediated through an inhibition of vascular IGF-I production as demonstrated by Howell et al. A few studies have used a vessel allograft model and lanreotide significantly inhibited myointimal proliferation and, in addition, Hayry et al observed a decrease in IGF-I, epidermal growth factor, and platelet-derived growth factor BB following lanreotide treatment. In a rat kidney transplant model, lanreotide inhibited arterial graft myointimal thickening, however, the authors did not measure IGF-I expression. From these experiments it is hypothesized that beneficial effects of treatment with somatostatin analogues may be achieved following kidney transplantation through reducing adverse effects of GH and IGF-I on long-term changes in the transplanted kidney.