Serum interleukin-4 is elevated in clinical drug-induced liver injury.

BACKGROUND: 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. AIM: To prospectively compare serum IL-4 levels between patients who develop VA-DILI and controls following exposure to the volatile anaesthetic. METHODS: 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. RESULTS: 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). CONCLUSION: 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.

Clinical efficacy of first and second series of peptide receptor radionuclide therapy in patients with neuroendocrine neoplasm: a cohort study.

OBJECTIVES: Peptide receptor radionuclide therapy (PRRT) is an established treatment for metastatic neuroendocrine neoplasms (NEN). However, only limited data exists for the effect of multiple series of PRRT. The aim of this study was to investigate PFS and OS inNEN patients treated with multiple series of PRRT conforming to the ENETS treatment protocol. METHODS: We included all patients with gastrointestinal (GI), pancreatic and bronchopulmonary (BP) NEN treated with PRRT from 2008 to 2018. We used Kaplan-Meier estimation to evaluate PFS and OS with subgroup analysis of primary tumor, Ki67-index, type of radioisotope and number of PRRT series. RESULTS: 133 patients (female/male 61/72) were included, median age 70 (interquartile range 64-76) years. GI-NEN comprised 62%, pancreatic 23% and BP 11%. Median Ki67-index was 5%. After first PRRTG1- and G2-tumors had PFS of 25 and 22 months, compared to 11 months in G3-NENs (p < .05) and PFS was longer in G1/G2 GI-NENs than BP-NEN (30vs. 12 months, p < .05). After retreatment with a second series of PRRT, the overall PFS (G1-G3) was 19 months, with G1- and G2-tumors having the highest PFS of 19 and 22 months, respectively. Overall, the GI and BP tumors had an OS of 54 and 51 months. CONCLUSIONS: PRRT is an effective therapy with long-term PFS and OS, especially in G1 and G2 NENs, and with better prognosis in GI-NEN compared with BP-NENs. OS and PFS was shorter after the second series of PRRT compared with the first, however results were still encouraging.

Circulating sCD36 levels in patients with non-alcoholic fatty liver disease and controls.

BACKGROUND AND OBJECTIVE: CD36 is implicated in fatty-acid uptake in multiple tissues, including hepatocytes and adipocytes. Circulating CD36 (sCD36) is increased in non-alcoholic fatty liver disease (NAFLD). We explored this association further by investigating correlations between sCD36 levels, intrahepatic lipid content and markers of obesity in NAFLD patients and controls. METHODS: In total, 111 NAFLD patients and 33 normal/overweight controls were included. Intrahepatic lipid content was measured by magnetic resonance spectroscopy; and subgroups of participants had a dual-energy X-ray absorptiometry (n=99), magnetic resonance imaging (n=94, subcutaneous and visceral adipose tissue) and liver biopsy (n=28 NAFLD patients) performed. Plasma sCD36 was assessed by enzyme-linked immunosorbent assay. RESULTS: NAFLD patients had elevated sCD36 levels compared with controls (0.68 (0.12-2.27) versus 0.43 (0.10-1.18), P<0.01). sCD36 correlated with intrahepatic lipid (rs=0.30), alanine transaminase (ALT) (r=0.31), homeostasis model assessment index-insulin resistance (r=0.24), high-density lipoprotein (r=-0.32) and triglyceride (r=0.44, all P<0.01). Intrahepatic lipid and plasma triglyceride were independent predictors of sCD36 levels in a multiple regression analysis. Further, sCD36 and body mass index were weakly correlated (r=0.17, P=0.04); yet, we found no correlations between sCD36 and other measures of fat distribution except an inverse relation to visceral adipose tissue (rs=-0.21, P<0.05). We observed a trend for correlation between sCD36 and hepatic CD36 mRNA expression (r=0.37, P=0.07). CONCLUSIONS: sCD36 levels increased with the level of intrahepatic lipid, insulin resistance and dyslipidemia. The weak association with markers of obesity and the association with hepatic CD36 mRNA expression suggest that excess sCD36 in NAFLD patients is derived from the hepatocytes, which may support that CD36 is involved in NAFLD development. An unhealthy and unbalanced CD36 expression in adipose and hepatic tissue may shift the fatty-acid load to the liver.

Soluble CD163, a specific macrophage activation marker, is decreased by anti-TNF-α antibody treatment in active inflammatory bowel disease.

Activated macrophages shed the haemoglobin-haptoglobin scavenger receptor CD163 into the circulation as soluble(s)-CD163. We measured sCD163 as an in vivo macrophage activation marker in patients with Crohn's disease (CD) or ulcerative colitis (UC) receiving antitumour necrosis factor (TNF)-α antibody or prednisolone treatment. We also investigated the CD163 expression on circulating monocytes. 58 patients with CD, 40 patients with UC and 90 healthy controls (HC) were included. All patients had active disease at inclusion and were followed for 6 weeks of anti-TNF-α antibody or prednisolone treatment. We measured plasma sCD163 levels at baseline, 1 day, 1 week and 6 weeks after initiating treatment. CD163 expression on circulating CD14(+) monocytes was measured in 21 patients with CD receiving anti-TNF-α antibody treatment. Baseline sCD163 levels were elevated in patients with CD [1.99 (1.80-2.18) mg/l] and in patients with UC [2.07 (1.82-2.32) mg/l] compared with HC [1.51 (1.38-1.63) mg/l] (P < 0.001). Anti-TNF-α antibody treatment induced a rapid decrease in sCD163 levels in patients with CD and in patients with UC 1 day after treatment initiation (P < 0.05). One week of prednisolone treatment did not induce a reduction in sCD163 levels. Anti-TNF-α treatment normalized sCD163 levels in patients with UC, whereas patients with CD exhibited sustained increased sCD163 levels. In patients with CD, CD163 expression on CD14(+) monocytes was increased compared with HC. This study highlights that active CD and UC are associated with increased macrophage activation, as indicated by elevated sCD163 levels and monocytic CD163 expression. Anti-TNF-α antibody treatment induced a rapid decrease in sCD163 levels, suggesting a specific effect on macrophage activation in inflammatory bowel diseases.

Predictive and prognostic factors for treatment and survival in 305 patients with advanced gastrointestinal neuroendocrine carcinoma (WHO G3): the NORDIC NEC study.

BACKGROUND: As studies on gastrointestinal neuroendocrine carcinoma (WHO G3) (GI-NEC) are limited, we reviewed clinical data to identify predictive and prognostic markers for advanced GI-NEC patients. PATIENTS AND METHODS: Data from advanced GI-NEC patients diagnosed 2000-2009 were retrospectively registered at 12 Nordic hospitals. RESULTS: The median survival was 11 months in 252 patients given palliative chemotherapy and 1 month in 53 patients receiving best supportive care (BSC) only. The response rate to first-line chemotherapy was 31% and 33% had stable disease. Ki-67<55% was by receiver operating characteristic analysis the best cut-off value concerning correlation to the response rate. Patients with Ki-67<55% had a lower response rate (15% versus 42%, P<0.001), but better survival than patients with Ki-67≥55% (14 versus 10 months, P<0.001). Platinum schedule did not affect the response rate or survival. The most important negative prognostic factors for survival were poor performance status (PS), primary colorectal tumors and elevated platelets or lactate dehydrogenase (LDH) levels. CONCLUSIONS: Advanced GI-NEC patients should be considered for chemotherapy treatment without delay.PS, colorectal primary and elevated platelets and LDH levels were prognostic factors for survival. Patients with Ki-67<55% were less responsive to platinum-based chemotherapy, but had a longer survival. Our data indicate that it may not be correct to consider all GI-NEC as one single disease entity.

Concentrations of IGF-I and IGFBP-3 and pancreatic cancer risk in the European Prospective Investigation into Cancer and Nutrition.

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.

Partial liver ischemia is followed by metabolic changes in the normally perfused part of the liver during reperfusion.

BACKGROUND: Temporary vascular in- and outflow occlusion is an effective technique for bleeding control during liver resection. However, occlusion can result in ischemia/reperfusion (I/R) injury to the liver. The aim of this study in a porcine model was to investigate the effect of in- and outflow occlusion of part of the liver on the metabolism of the normally perfused parenchyma of the same liver measured by microdialysis. METHODS: Eight pigs underwent laparotomy. A microdialysis catheter was inserted into in the left and right part of the liver, respectively. Microdialysis samples were collected every 30 min. Occlusion of the left part of the liver was achieved for 60 min, followed by 5 h of reperfusion. Samples were analyzed for glucose, lactate, pyruvate and glycerol. Blood samples were drawn to determine standard liver and biochemical parameters. RESULTS: Comparing the ischemic part of the liver with the normally perfused part, significant differences in the levels of lactate, pyruvate and glycerol were found. During reperfusion, similar and continuous decreases below baseline levels were observed for lactate and pyruvate in both the ischemic and normally perfused part of the liver. No significant changes in liver parameters or blood glucose levels were seen. CONCLUSIONS: Partial ischemia of the liver is without effects on metabolism in the normally perfused part. Metabolic changes in the ischemic part of the liver were reversible. However, partial liver ischemia was followed by similar continuous decreases in lactate and pyruvate levels in the whole liver, even though the ischemic insult was not detectable in transaminase levels.

Family involvement in the treatment of childhood obesity: the Copenhagen approach.

INTRODUCTION: The objective of this study was to assess the impacts of a family-based childhood obesity treatment on anthropometry and predictors of dropout and successful weight loss. MATERIALS AND METHODS: The 18-month treatment consisted of a intensive period (IP) including physical exercise, nutritional guidance, family psychotherapy, child group sessions and a 1-year follow-up (FU). RESULTS: One hundred children (10-12 years old, >140% of median weight-for-height) participated. The 81 children completing the IP decreased significantly from 2.9 to 2.6 body mass index (BMI) standard deviation score (SDS) units (p < 0.001). Furthermore, mean body fat percentage decreased significantly from 33.7 to 31.9 during IP. The 49 children completing the FU had a further decrease of 0.2 BMI SDS units (p = 0.003). Weight loss was less in children from immigrant families. Drop-out was higher if the mother had limited education and in immigrant families. CONCLUSIONS: This treatment with a psychological approach is feasible and results in significant weight loss during the programme. Future research should focus on how to improve the results of families with limited education and immigrants with non-European origin.

Cytokine changes during warm ischemia and reperfusion of the pig liver with or without preconditioning.

BACKGROUND: Hepatic inflow occlusion results in ischemia-reperfusion injury. The aim of the present porcine study was to investigate whether the pro- and anti-inflammatory cytokine response is involved in mediating the protective effect of ischemic preconditioning (IPC) during, and after warm liver ischemia. METHODS: Fifteen randomized pigs--7 non-IPC and 8 (IPC)--underwent laparotomy followed by 60 min of total ischemia with or without IPC continued by 3 h of reperfusion. Plasma cytokines (IL-6, IL-8, IL-10, and TNF-alpha) were measured during the study period as well as liver parameters (alanine-aminotransferase, alkaline phosphatase, bilirubin, and prothrombin time). RESULTS: In the IPC group, IL-6 increased significantly during reperfusion compared to baseline and the non-IPC group. TNF-alpha increased nonsignificantly in the non-IPC group, while the levels remained stable in the IPC group. IL-8 and IL-10 increased in both groups after reperfusion. Only minor differences were observed in liver parameters. CONCLUSIONS: Warm liver ischemia with or without IPC activates inflammatory cytokines. IL-6 increased significantly in the IPC group compared to the non-IPC group, while the opposite was observed for TNF-alpha. These cytokine changes may be involved in the hepatoprotective mechanism induced by IPC.

Soluble CD163 and soluble mannose receptor predict survival and decompensation in patients with liver cirrhosis, and correlate with gut permeability and bacterial translocation.

BACKGROUND: Activated hepatic macrophages play a key role in inflammation and fibrosis progression in chronic liver disease. AIM: To assess the prognostic value of soluble (s)CD163 and mannose receptor (sMR) in cirrhotic patients and explore associations with markers of intestinal permeability (lactulose-mannitol ratio, diamine oxidase), bacterial translocation (endotoxin, lipopolysaccharide-binding protein) and markers of systemic immune activation (interleukin-6, interleukin-8, sCD14). METHODS: We prospectively investigated 101 cirrhotic patients (Child-Pugh class A: n = 72, Child-Pugh classes B and C: n = 29) and 31 healthy controls. Patients were observed for a median follow-up of 37 months. RESULTS: Median plasma levels of sCD163 and soluble mannose receptor were significantly elevated in cirrhotic patients (P < .001) and increased with disease severity (sCD163 in healthy controls = 1.3, Child-Pugh class A = 4.2, Child-Pugh classes B and C = 8.4 mg/L; sMR in healthy controls = 15.8, Child-Pugh class A = 36.5, Child-Pugh classes B and C = 66.3 µg/dL). A total of 21 patients died during the observation period. Patients with sCD163 levels above 5.9 mg/L showed significantly reduced survival (survival rate after 36 months: 71% versus 98%, P < .001). Patients with soluble mannose receptor levels above 45.5 µg/dL developed significantly more complications of cirrhosis within 12 months (73% versus 9%, P < .001). Furthermore, both variables correlated with the lactulose-mannitol ratio, diamine oxidase, lipopolysaccharide and interleukin-8. CONCLUSION: Our data demonstrate the prognostic value of sCD163 in predicting long-term survival in patients with liver cirrhosis and identify soluble mannose receptor as a prognostic marker for occurrence of cirrhosis-associated complications. The correlation between gut barrier dysfunction and activation of macrophages points towards a link between them.

Diet, serum insulin-like growth factor-I and IGF-binding protein-3 in European women.

OBJECTIVE: The aim of this study was to examine the relationship of diet with serum insulin-like growth factor-I (IGF-I) and IGF-binding protein-3 in women. DESIGN: Cross-sectional study. SETTING AND SUBJECTS: The population are 2109 women who were control subjects in a case-control study of breast cancer nested in the European Prospective Investigation into Cancer and Nutrition. Control subjects were randomly chosen among risk sets consisting of female cohort members alive and free of cancer (except non-melanoma skin cancer) at the time of diagnosis of the index case. Matching criteria were age at enrolment, follow-up time, time of the day of blood collection and study centre. Diet was measured through validated questionnaires. Serum hormone concentrations were measured by enzyme-linked immunosorbent assays. The relationship between serum IGF-I, IGFBP-3, and intake of nutrients and foods was explored by linear regression in models adjusted for energy intake, age, body mass index, smoking, physical activity, centre and laboratory batch. RESULTS: Serum IGF-I levels were positively related to protein intake (P(trend)<0.001), but not related to energy, fat or carbohydrate intake. Positive relationships were observed with the intake of milk (P(trend)=0.007), calcium (P(trend)<0.001), magnesium (P(trend)=0.003), phosphorus (P(trend)<0.001), potassium (P(trend)=0.002), vitamin B6 (P(trend)=0.03), vitamin B2 (P(trend)=0.001) and inverse relationships with vegetables (P(trend)=0.02) and beta-carotene (P(trend)=0.02). IGFBP-3 was not related with most of the nutrients and foods in this study. CONCLUSIONS: In this population, circulating IGF-I is modestly related with the intake of protein and minerals, and with milk and cheese, while IGFBP-3 does not appear to be related with diet.

Results after surgical treatment of liver metastases in patients with high-grade gastroenteropancreatic neuroendocrine carcinomas.

BACKGROUND: Gastroenteropancreatic neuroendocrine carcinomas (GEP-NEC) are generally characterized by synchronous metastases, high aggressiveness and a dismal prognosis. Current international guidelines do not recommend surgical treatment of liver metastases, however the existing data are scarce. The aim of this study was to evaluate the results of curatively intended resection/radiofrequency ablation (RFA) of liver metastases in patients with metastatic GEP-NEC. METHODS: 32 patients with a diagnosis of high-grade gastroenteropancreatic neuroendocrine neoplasm (Ki-67 > 20%) and with intended curative resection/RFA of liver metastases, were identified among 840 patients from two Nordic GEP-NEC registries. Tumor morphology (well vs poor differentiation) was reassessed. Overall survival (OS) and progression-free survival (PFS) was assessed by Kaplan-Meier analyses for the entire cohort and for subgroups. RESULTS: Median OS after resection/RFA of liver metastases was 35.9 months (95%-CI: 20.6-51.3) with a five-year OS of 43%. The median PFS was 8.4 months (95%-CI: 3.9-13). Four patients (13%) were disease-free after 5 years. Two patients had well-differentiated morphology (NET G3) and 20 patients (63%) had Ki-67 ≥ 55%. A Ki-67 < 55% and receiving adjuvant chemotherapy were statistically significant factors of improved OS after liver resection/RFA. CONCLUSION: This study shows a long median and long term survival after liver surgery/RFA for these selected metastatic GEP-NEC patients, particularly for the group with a Ki-67 in the relatively lower G3 range. Our findings indicate a possible role for surgical treatment of liver metastases in the management of this patient population.

Reduced sCD36 following weight loss corresponds to improved insulin sensitivity, dyslipidemia and liver fat in obese children.

BACKGROUND/OBJECTIVES: Childhood obesity is a major health problem with serious long-term metabolic consequences. CD36 is important for the development of obesity-related complications among adults. We aimed to investigate circulating sCD36 during weight loss in childhood obesity and its associations with insulin resistance, dyslipidemia, hepatic fat accumulation and low-grade inflammation. SUBJECTS/METHODS: The impact of a 10-week weight loss camp for obese children (N=113) on plasma sCD36 and further after a 12-month follow-up (N=68) was investigated. Clinical and biochemical data were collected, and sCD36 was measured by an in-house assay. Liver fat was estimated by ultrasonography and insulin resistance by the homeostasis model assessment (HOMA-IR). RESULTS: Along with marked weight loss, sCD36 was reduced by 21% (P=0.0013) following lifestyle intervention, and individual sCD36 reductions were significantly associated with the corresponding decreases in HOMA-IR, triglycerides and total cholesterol. The largest sCD36 decrease occurred among children who reduced HOMA-IR and liver fat. After 12 months of follow-up, sCD36 was increased (P=0.014) and the metabolic improvements were largely lost. CONCLUSIONS: Weight-loss-induced sCD36 reduction, coincident with improved insulin resistance, circulating lipids and hepatic fat accumulation, proposes that sCD36 may be an early marker of long-term health risk associated with obesity-related complications.

The macrophage activation marker sCD163 combined with markers of the Enhanced Liver Fibrosis (ELF) score predicts clinically significant portal hypertension in patients with cirrhosis.

BACKGROUND: Noninvasive identification of significant portal hypertension in patients with cirrhosis is needed in hepatology practice. AIM: To investigate whether the combination of sCD163 as a hepatic inflammation marker and the fibrosis markers of the Enhanced Liver Fibrosis score (ELF) can predict portal hypertension in patients with cirrhosis. METHODS: We measured sCD163 and the ELF components (hyaluronic acid, tissue inhibitor of metalloproteinase-1 and procollagen-III aminopeptide) in two separate cohorts of cirrhosis patients that underwent hepatic vein catheterisation. To test the predictive accuracy we developed a CD163-fibrosis portal hypertension score in an estimation cohort (n = 80) and validated the score in an independent cohort (n = 80). A HVPG ≥10 mmHg was considered clinically significant. RESULTS: Both sCD163 and the ELF components increased in a stepwise manner with the patients' Child-Pugh score (P < 0.001, all), and also with increasing HVPG (P < 0.001). receiver operator characteristics (ROC) analyses showed that each one of the individual components predicted a HVPG >10 mmHg with AUROC's of approximately 0.80. The combined score optimised by logistic regression analyses improved the AUROC to 0.91 in the estimation cohort and 0.90 in the validation cohort. Furthermore, a high value of the combined score was associated with a high short-term mortality. CONCLUSIONS: The combination of the macrophage activation marker sCD163 and the fibrosis markers predicted significant portal hypertension in patients with cirrhosis. This score may prove useful for screening purposes and highlights the importance of both the inflammatory and the fibrotic components of cirrhotic portal hypertension.

Single-centre experience of the macrophage activation marker soluble (s)CD163 - associations with disease activity and treatment response in patients with autoimmune hepatitis.

BACKGROUND: Autoimmune hepatitis (AIH) is characterised by liver inflammation with reversibility upon anti-inflammatory treatment. Soluble (s)CD163, a specific macrophage activation marker, is associated with inflammation in other liver diseases, but never investigated in AIH. AIM: To investigate sCD163 in patients with acute AIH and in complete and incomplete responders to standard anti-inflammatory pharmacotherapy, and during follow-up in treatment naive patients. METHODS: In a cross-sectional design, we studied 121 AIH patients (female/male 89/32, median age 49 years); of these, we prospectively studied 10 treatment naïve AIH patients during prednisolone treatment and tapering. Twenty patients had variant syndromes of AIH and primary biliary cholangitis or primary sclerosing cholangitis. sCD163 was compared with markers of disease activity, severity and treatment response. RESULTS: In the patients with acute AIH (n = 21), sCD163 was sixfold increased compared with the normalised levels in patients (n = 32) with complete response to standard treatment [9.5 (3.3-28.8) vs. 1.6 (0.8-3.2) mg/L, P < 0.01)], while the patients (n = 27) with incomplete response had higher sCD163 [2.2 (1.3-7.9), P < 0.05] than the complete responders. sCD163 was positively associated with ALAT, IgG and bilirubin (rho: 0.45-0.59, P < 0.001, all), and negatively to external coagulation factors (rho:-0.34, P < 0.001). In the treatment naïve patients, sCD163 fell during high-dose prednisolone treatment and tapering. Immunohistochemical staining confirmed increased CD163 expression in liver biopsies from patients with acute AIH. CONCLUSIONS: sCD163 was markedly elevated in AIH in the acute phase, normalised by successful treatment in complete responders, but remained higher in the incompletely responding cases. Our results demonstrate macrophage activation in AIH paralleling disease activity, severity and treatment response, suggesting a role for macrophage activation in AIH.

Fibrosis is not just fibrosis - basement membrane modelling and collagen metabolism differs between hepatitis B- and C-induced injury.

BACKGROUND: While morphological patterns differ, the molecular phenotype of liver fibrosis is considered a stereotypical response to chronic liver injury. However, with different cellular triggers and networks regulating fibrosis, the molecular responses of the injured liver may not be identical. AIM: To investigate whether differences in extracellular matrix (ECM) composition of the liver during fibrogenesis in two seemingly similar types of viral hepatitis could be reflected by differences in ECM turnover. METHODS: Utilising a cross-sectional design, we measured specific ECM protein fragments in plasma from 197 chronic hepatitis B (CHB) patients and 403 chronic hepatitis C (CHC) patients matched for inflammation grade and fibrosis stage. Markers of matrix metalloprotease degraded type I, III, IV and VI collagen (C1M, C3M, C4M, C6M) and type III and IV collagen formation (Pro-C3, P4NP7S). RESULTS: P4NP7S, C3M, C4M and C6M were significantly elevated in CHB compared to CHC. In contrast, Pro-C3 was significantly elevated in CHC compared to CHB. Pro-C3, C3M and C4M were increased in parallel with inflammation and fibrosis in both cohorts. C6M and P4NP7S were associated with inflammation and fibrosis only in CHC. Basement membrane collagen fragments P4NP7S and C4M were significantly higher in matched activity and fibrosis cohorts within CHB vs CHC. CONCLUSION: The main parameters to determine extracellular matrix biomarker levels are inflammation, fibrosis, and type of viral insult. Compared to CHC, CHB appears to induce a higher basement membrane turnover. This suggests that there are aetiology-dependent molecular signatures in liver fibrosis that could have pathogenic and diagnostic implications.

Octreotide prevents the early increase in renal insulin-like growth factor binding protein 1 in streptozotocin diabetic rats.

The early renal growth in streptozotocin (STZ)-induced diabetic rats is preceded by a transient rise in renal tissue insulin-like growth factor (IGF)-I concentration. Administration of the long-acting somatostatin analog octreotide to STZ diabetic rats inhibits the early increase in kidney IGF-I and the increase in kidney size without affecting metabolic control. We studied the effects of octreotide treatment on the intrarenal IGF axis at 2 and at 7 days after the induction of STZ diabetes. Two days after induction of diabetes, kidney IGF-I was increased from 850 +/- 43 ng/g tissue in controls to 1,648 +/- 165 ng/g tissue (P < 0.001) in diabetic animals. The diabetes-associated increase in renal IGF-I 48 h after STZ injection was totally prevented by octreotide (IGF = 780 +/- 57 ng/g tissue). However, 7 days after the induction of diabetes, kidney IGF-I was similar to that of control and was not affected by octreotide. No difference in serum IGF-I was observed between controls and diabetic rats after 2 days of diabetes; however, octreotide treatment resulted in a significant decrease of serum IGF-I after 2 days when compared with control rats (P < 0.05). Renal IGF-I mRNA was significantly decreased to the same extent in both diabetic groups 2 and 7 days after the induction of diabetes, while renal IGF-I receptor (IGF-IR) mRNA was unchanged in rats from either group. Two days after induction of diabetes, renal insulin-like growth factor binding protein (IGFBP)-1 mRNA and 30-kDa IGFBPs (containing IGFBP-1) increased by 186 and 192%, respectively, in untreated diabetic animals compared with controls. Octreotide treatment prevented the diabetes-associated rise in renal IGFBP-1 mRNA and protein. However, 7 days after the induction of diabetes, renal IGFBP-1 mRNA and protein were similarly increased in both octreotide-treated or untreated diabetic rats. Renal IGFBP-3 gene expression and protein and IGFPB-5 mRNA remained unchanged after 2 and 7 days of diabetes when treated or untreated with octreotide. We conclude that the well-known inhibitory effect of octreotide on the early increase in renal IGF-I concentration and renal size in diabetes may be mediated through a direct effect on renal IGFBP-1 levels.

Omega-3 fatty acids inhibit an increase of proinflammatory cytokines in patients with active Crohn's disease compared with omega-6 fatty acids.

BACKGROUND: Crohn's disease is a chronic inflammatory condition affecting the gastrointestinal tract. Polyunsaturated omega-3 fatty acids given orally may reduce the secretion of proinflammatory cytokines and hereby downregulate the inflammatory process. AIM: To assess the effects of enteral fatty acids, in the form of Impact Powder (Novartis, Switzerland), as adjuvant therapy to corticosteroid treatment on the proinflammatory and anti-inflammatory cytokine profiles in patients with active Crohn's disease. METHODS: The proinflammatory and anti-inflammatory cytokines were measured in plasma from 31 patients with active Crohn's disease. Patients were randomized for oral intake of omega-3 fatty acid (3-Impact Powder) or omega-6 fatty acids (6-Impact Powder). Clinical and biochemical markers of inflammation were studied at baseline and after 5 and 9 weeks. RESULTS: Within the 3-Impact Powder group, no significant changes in concentrations of interleukin-6, interferon-gamma, monocyte chemoattractant protein-1, interleukin-2, interleukin-5 and interleukin-10, whereas a significant differences in concentration of interleukin-1beta and interleukin-4 were observed during therapy. Within the 6-Impact Powder group a significant changes in concentrations of interleukin-1beta, interleukin-6, interferon-gamma, monocyte chemoattractant protein-1, interleukin-2, interleukin-4, interleukin-5 and interleukin-10 were observed. CONCLUSIONS: The 3-Impact Powder showed immunomodulatory properties and might inhibit an increase of proinflammatory cytokines in contrast to the 6-Impact Powder.

Effects of pure ethanol and alcopops on glucose, insulin, and the insulin-like growth factor system in healthy subjects.

INTRODUCTION: Alcohol induces disturbances in insulin-like growth factor-I (IGF-I) and IGF binding protein-1 (IGFBP-1) levels. The aim of the present study was to compare pure ethanol and alcopop effects on total and free IGF-I, IGFBP-1, IGF-I:IGFBP-1 complex, insulin and plasma glucose levels in healthy subjects. METHODS: Five males and seven females (21-51 years) consumed pure ethanol and alcopops with identical alcohol content in a cross-over design after 6h fasting. Blood samples were obtained for determination of serum ethanol and plasma glucose at 0, 30, 60, 90, 120 and 180 min. Serum total and free IGF-I, IGFBP-1, IGF-I:IGFBP-1 complex, and insulin were measured at 0, 60 and 180 min. RESULTS: Area under the curve for serum ethanol concentration was significantly less following alcopop compared to pure ethanol (1124+/-201 vs. 1691+/-359 mmol/Lh, P<0.01). Serum insulin and glucose levels were unchanged by ethanol while alcopop intake was followed by a transient increase in glucose and insulin levels (P<0.05). Pure ethanol and alcopop reduced free IGF-I levels by the end of the study period (P=0.05). IGFBP-1 and the IGF-I:IGFBP-1 complex increased following ethanol intake (P<0.05) while only a small transient IGFBP-1 increase was observed following alcopop intake. No change in total IGF-I was observed. CONCLUSION: Both drinks resulted in reduced free IGF-I levels, however, only pure ethanol increased IGFBP-1 and the IGF-I:IGFBP-1 complex. Alcopop intake was associated with a transient increase in IGFBP-1 and unchanged IGF-I:IGFBP-1 complex levels probably due to marked changes in insulin and glucose levels.

The macrophage activation marker sCD163 is associated with changes in NAFLD and metabolic profile during lifestyle intervention in obese children.

BACKGROUND: Obesity is associated with metabolic derangement and non-alcoholic fatty liver disease (NAFLD). Macrophages are involved in liver inflammation and fibrosis, and soluble (s)CD163 is a macrophage activation marker. OBJECTIVES: To associate sCD163 with parameters of paediatric obesity and NAFLD, as well as changes in these parameters during lifestyle intervention. METHODS: We studied 117 obese children during a 10-week lifestyle intervention; 71 completed the 12-month follow-up. We recorded clinical and biochemical data, and performed liver ultrasonography. RESULTS: Baseline sCD163 was higher in children with elevated alanine transaminase (ALT) (2.3 ± 0.7 vs. 2.0 ± 0.6 mg L(-1), P = 0.03), steatosis (2.3 ± 0.7 vs. 2.0 ± 0.6 mg L(-1), P = 0.01) and high paediatric NAFLD fibrosis index (2.3 ± 0.7 vs. 1.9 ± 0.6 mg L(-1) , P = 0.03). Baseline sCD163 was independently associated with ALT, cholesterol and high-sensitivity C-reactive protein (hs-CRP). The change in sCD163 during lifestyle intervention was associated with changes in ALT, homeostatic model assessment of insulin resistance (HOMA-IR), hs-CRP and cholesterol, and inversely associated with the change in high-density lipoprotein cholesterol. CONCLUSION: sCD163 was associated with markers of liver injury and metabolic parameters in obese children, and changes in these parameters during lifestyle intervention. This may suggest that activated macrophages play a role in NAFLD and sCD163 may serve as a marker of liver disease severity and treatment effect.