The prevalence of obesity and related conditions like non-alcoholic fatty liver disease (NAFLD) is increasing worldwide and therapeutic options are limited. Alternative treatment options are therefore intensively sought after. An interesting candidate is the natural polyphenol resveratrol (RSV) that activates adenosinmonophosphate-activated protein kinase (AMPK) and silent information regulation-2 homolog 1 (SIRT1). In addition, RSV has known anti-oxidant and anti-inflammatory effects. Here, we review the current evidence for RSV-mediated effects on NAFLD and address the different aspects of NAFLD and non-alcoholic steatohepatitis (NASH) pathogenesis with respect to free fatty acid (FFA) flux from adipose tissue, hepatic de novo lipogenesis, inadequate FFA β-oxidation and additional intra- and extrahepatic inflammatory and oxidant hits. We review the in vivo evidence from animal studies and clinical trials. The abundance of animal studies reports a decrease in hepatic triglyceride accumulation, liver weight and a general improvement in histological fatty liver changes, along with a reduction in circulating insulin, glucose and lipid levels. Some studies document AMPK or SIRT1 activation, and modulation of relevant markers of hepatic lipogenesis, inflammation and oxidation status. However, AMPK/SIRT1-independent actions are also likely. Clinical trials are scarce and have primarily been performed with a focus on overweight/obese participants without a focus on NAFLD/NASH and histological liver changes. Future clinical studies with appropriate design are needed to clarify the true impact of RSV treatment in NAFLD/NASH patients.
Non-alcoholic fatty liver disease; Non-alcoholic steatohepatitis; Steatosis; Resveratrol; AMP-activated protein kinase; Silent information regulation-2 homolog 1; Anti-oxidants; Anti-inflammatory agents; Animal studies; Clinical trial
Inflammatory bowel disease (IBD), which comprises ulcerative colitis and Crohn’s disease, is characterized by inflammation of the gastrointestinal tract. The trefoil factors 1, 2, and 3 (TFF1-3) are a family of peptides that play important roles in the protection and repair of epithelial surfaces, including the gastrointestinal tract. TFFs may be involved in IBD pathogenesis and are a potential treatment option. In the present review, we describe the TFF family and their potential role in IBD by summarizing the current knowledge of their expression, possible function and pharmacological role in IBD.
Trefoil factors; Inflammatory bowel disease; Ulcerative colitis; Crohn’s disease; Inflammation
Background. Advanced HCC is a clinical challenge with limited treatment options. The multikinase inhibitor sorafenib is the first and only agent showing a survival benefit in these patients. In this study we evaluate the efficacy and tolerability of sorafenib in an unselected patient population. Furthermore we explore the role of alpha-fetoprotein (αFP) as a potential biomarker for treatment efficacy and correlation to survival. Methods. Seventy-six patients with advanced HCC, not eligible for locoregional therapy, treated with sorafenib between 2007 and 2009 were included. Followup was until 2011. Results. Patients in PS 0-1 had a median overall survival (mOS) of 6.2 months, compared to 1.8 months in patients with poorer PS (P = 0.005). Child-Pugh A patients had a mOS of 6.6 months versus 3.6 months among patients in Child-Pugh B or C (P = 0.0001). Serum αFP ≥ 200 at baseline was prognostic for a shorter survival. All patients with radiologically verified tumor response and baseline αFP ≥ 200 experienced a significant decline in αFP within the first four weeks of treatment. Conclusion. The survival of patients with advanced HCC treated with sorafenib is dependent on performance status and liver function. Treatment of patients with compromised liver function and poor performance status cannot be recommended. The correlation between αFP and objective tumor response warrants further investigation.
AIM: To evaluate long-term complications and survival in patients with Budd-Chiari syndrome (BCS) referred to a Danish transjugular intrahepatic portosystemic shunt (TIPS) centre.
METHODS: Twenty-one consecutive patients from 1997-2008 were retrospectively included [15 women and 6 men, median age 40 years (range 17-66 years)]. Eighteen Danish patients came from the 1.8 million catchment population of Aarhus University Hospital and three patients were referred from Scandinavian hospitals. Management consisted of tests for underlying haematological, endocrinological, or hypercoagulative disorders parallel to initiation of specific treatment of BCS.
RESULTS: BCS was mainly caused by thrombophilic (33%) or myeloproliferative (19%) disorders. Forty-three percents had symptoms for less than one week with ascites as the most prevalent finding. Fourteen (67%) were treated with TIPS and 7 (33%) were manageable with treatment of the underlying condition and diuretics. The median follow-up time for the TIPS-treated patients was 50 mo (range 15-117 mo), and none required subsequent liver transplantation. Ascites control was achieved in all TIPS patients with a marked reduction in the dose of diuretics. A total of 14 TIPS revisions were needed, mostly of uncovered stents. Two died during follow-up: One non-TIPS patient worsened after 6 mo and died in relation to transplantation, and one TIPS patient died 4 years after the TIPS-procedure, unrelated to BCS.
CONCLUSION: In our BCS cohort TIPS-treated patients have near-complete survival, reduced need for diuretics and compared to historical data a reduced need for liver transplantation.
Ascites; Budd-Chiari syndrome; Myeloproliferative disorder; Thrombophilia; Thrombosis; Transjugular intrahepatic portosystemic shunt
Alcoholic hepatitis (AH) has a severe prognosis due to hepatic inflammatory injury. The cytokine interleukin-22 (IL-22) is reported to exert anti-apoptotic and proliferative effects, but IL-22 has not been studied during the course of AH. IL-22 is mainly produced by CD4+ (helper) T cells, including Th17 cells. In addition, Th17 cells produce the proinflammatory cytokine IL-17A, which has been implicated in AH.
We aimed to study the levels of circulating IL-22- and IL-17A-producing T helper cells and plasma cytokines in patients with AH and to examine the observations in relation to the short-term disease course.
We collected blood samples from 21 consecutive patients with severe AH on days 0, 14 and 30 after diagnosis, and included 10 stable alcoholic cirrhosis patients and 10 healthy subjects as controls. Analyses were performed using flow cytometry and ELISA.
We found higher frequencies of IL-22-producing T helper cells in AH patients (median 1.7%) than in cirrhosis patients (1.0%, p = 0.03) and healthy controls (1.0%, p = 0.01), and a 1.5-fold increase in the plasma concentration of IL-17A in AH compared with healthy controls (p<0.01). Those patients who markedly improved their Glasgow Alcoholic Hepatitis Score demonstrated a 2-fold higher frequency of IL-22-producing T helper cells at baseline and during follow-up than patients whose condition deteriorated (p = 0.04).
The frequency of IL-22-producing T helper cells was increased in AH patients and most so in those whose condition seemed to improve. T cell differentiation toward an IL-22-producing phenotype may thus be favourable in AH.
Goblet cell carcinoid (GCC) tumors are a rare subgroup of neuroendocrine tumors almost exclusively originating in the appendix. The tumor most often presents in the fifth or sixth decade with a clinical picture of appendicitis or in advanced cases an abdominal mass associated with abdominal pain. Histologically tumors are most often positive for chromogranin A and synaptophysin, however, less homogenous than for classic appendix carcinoids. The malignant potential is higher than that for the classic appendix carcinoids due to local spread and distant metastases at diagnosis and the proliferation markers (Ki67 index) may determine prognosis. Octreotide receptor scintigraphy is usually negative while CT/MRI scans may be useful. Chromogranin A is usually negative and other biomarkers related to the mucinous component or the tumor (CEA, CA-19-9, and CA-125) may be used. Surgery is the main treatment with appendectomy and right hemicolectomy while patients with disseminated disease should be treated with chemotherapy. Overall 5-year survival is approximately 75%. The diagnosis and treatment of GCC tumorss should be restricted to high volume NET centers in order to accumulate knowledge and improve survival in GCC NET patients. The aim of this paper is to update on epidemiology, clinical presentation, and diagnostic markers including Ki67 index, treatment, and survival.
Gastrointestinal dysmotility may be involved in the development of bacterial translocation and infection in patients with liver cirrhosis. The aim of the present study was to describe gastric, small intestinal and colorectal motility and transit in patients with liver cirrhosis and portal hypertension using a magnet-based Motility Tracking System (MTS-1) and standard radiopaque markers.
We included 15 patients with liver cirrhosis (8 Child-Pugh A, 6 Child-Pugh B, and 1 Child-Pugh C) and portal hypertension (11 males, median age 54 years (range 38–73), median hepatic venous pressure gradient 18 mmHg (range 12–37)), and 18 healthy controls (8 males, median age 58 years (range 34–64)). The gastric emptying time and small intestinal motility were evaluated by MTS-1, and the total gastrointestinal transit time was assessed by radiopaque markers and abdominal radiographs.
The velocity through the proximal small intestine was significantly higher in cirrhotic patients (median 1.27 metres (m)/hour, range 0.82–2.68) than in the healthy controls (median 1.00 m/hour, range 0.46–1.88) (p = 0.03). Likewise, the magnet travelled significantly longer in both fast (p = 0.04) and slow movements (p = 0.05) in the patient group. There was no significant difference in either gastric emptying time—23 minutes (range 5–131) in patients and 29 minutes (range 10.5–182) in healthy controls (p = 0.43)—or total gastrointestinal transit time—1.6 days (range 0.5–2.9) in patients and 2.0 days (range 1.0–3.9) in healthy controls (p = 0.33). No correlation was observed between the hepatic venous pressure gradient and the velocity of the magnet through the small intestine.
Patients with liver cirrhosis and portal hypertension demonstrated faster-than-normal transit through the proximal small intestine. This may be due to an overactive bowel, as suggested by previous studies.
Liver cirrhosis; Portal hypertension; Gastrointestinal motility; Small intestinal transit time; Colonic transit time
Lanreotide Autogel® is supplied in prefilled syringes. Therefore, it is possible for patients with neuroendocrine tumors to use self-/partner-administered injections. The primary objective of this study was to assess the proportion of patients preferring self/partner injections over injections administered by health care professionals, and to describe the impact of self/partner administration on efficacy, safety, and costs.
Of 62 eligible patients, 26 (42%) patients with neuroendocrine tumors treated with a stable dose of lanreotide Autogel 90 mg or 120 mg every 4 weeks agreed to participate in this Phase IV, international, open-label, crossover study, conducted at hospitals in Sweden, Norway, and Denmark. Patients were randomized to two blocks, starting with administration of lanreotide Autogel by either self/partner or a health care professional. Preference for injections administered by self/partner or health care professionals was measured, as well as efficacy, safety, and health care resource utilization (both direct and indirect costs).
Of 25 evaluable patients, 22 (88%) preferred self/partner injections, mainly because they experienced increased independence. Based on all patients asked to participate (n = 62), 35% preferred self/partner injections on a regular basis. There was no difference in efficacy or safety between the two administration blocks.
Many patients with neuroendocrine tumors prefer self/partner injection of lanreotide Autogel, and are able to self/partner inject without any impact on efficacy or safety. This administration method seems to provide a good alternative for suitable patients to increase patient independence and reduce the number of clinic visits.
neuroendocrine tumors; carcinoid syndrome; self administration; somatostatin analogs; lanreotide
Ischemic pre- and postconditioning protects the liver against ischemia/reperfusion injuries. The aim of the present study was to examine how ischemic pre- and postconditioning affects gene expression of hypoxia inducible factor 1α (HIF-1α), vascular endothelial growth factor A (VEGF-A) and transforming growth factor β (TGF-β) in liver tissue.
28 rats were randomized into five groups: control; ischemia/reperfusion; ischemic preconditioning (IPC); ischemic postconditioning (IPO); combined IPC and IPO. IPC consisted of 10 min of ischemia and 10 min of reperfusion. IPO consisted of three cycles of 30 sec. reperfusion and 30 sec. of ischemia.
HIF-1α mRNA expression was significantly increased after liver ischemia compared to controls (p = 0.010). HIF-1α mRNA expression was significantly lower in groups subjected to IPC or combined IPC and IPO when compared to the ischemia/reperfusion group (p = 0.002). VEGF-A mRNA expression increased in the ischemia/reperfusion or combined IPC and IPO groups when compared to the control group (p < 0.05).
Ischemic conditioning seems to prevent HIF-1α mRNA induction in the rat liver after ischemia and reperfusion. This suggests that the protective effects of ischemic conditioning do not involve the HIF-1 system. On the other hand, the magnitude of the HIF-1α response might be a marker for the degree of I/R injuries after liver ischemia. Further studies are needed to clarify this issue.
Galactose elimination capacity (GEC) is used as a quantitative measure of liver metabolic function with prognostic value in adults with acute and chronic liver failure. Almost no data are available regarding GEC in children, however. This study thus aims to meet the previously unmet clinical need for age-related data on GEC in children.
Material and methods
We studied galactose elimination in 10 healthy children (median age 10.7 years; range 7 months to 16 years) and 30 children with chronic liver disease (median age 8.6 years; range 3 months to 16 years). GEC was estimated from the linear decrease in concentration of galactose in arterialized capillary blood from the ear following intravenous infusion of galactose.
In both groups of children, GEC (µmol/min/kg body weight) was highest in the youngest children and decreased with age, although at a significantly lower level in the children with liver disease (p = 0.05). GEC was significantly higher in healthy children than in healthy adults, diminishing to the adult level by the age of 16 years.
GEC was found to be higher in children than in adults until the age of 16 years. Moreover, GEC was significantly lower in children with chronic liver disease than in healthy children, underlining that GEC testing also has potential clinical usefulness as a quantitative measure of liver metabolic function in children.
Children; galactose; liver disease; liver failure; liver function test
AIM: To study complement activation in 46 patients with alcoholic cirrhosis and ascites but no spontaneous bacterial peritonitis (SBP) and 10 healthy controls.
METHODS: Complement activation was determined by the measurement of soluble membrane attack complex (sMAC) concentrations in ascites and plasma. In patients, metabolic liver function was determined by the galactose elimination capacity and the clinical status assessed by the Model of End-Stage Liver Disease and Child-Pugh scores.
RESULTS: Ascites sMAC levels were markedly higher than in the corresponding plasma sample (median (range): 596 (170 - 1519) vs 160 (77 - 848) μg/L; P < 0.01). Ascites sMAC levels correlated positively with liver status. There was no relationship between ascites sMAC and leukocyte count. No relationship between ascites sMAC and blood C-reactive protein, albumin or neutrophile count was found. Plasma sMAC concentrations were slightly higher in patients than in controls [130 μg/L (70 - 204); P = 0.04]. Neither sMAC in ascites nor plasma was related to mortality.
CONCLUSION: The increased sMAC concentration in ascites and plasma indicate an activation of the complement system in cirrhosis even in the absence of SBP. This was particularly evident in the peritoneal fluid and most marked in patients with preserved liver status. The high ascites sMAC levels may reflect transudation of membrane attack complexes from the liver. Whether this complement activation has any clinical implications remains to be clarified.
Ascites; Cirrhosis; Complement; sC5b-9; Soluble membrane attack complex
AIM: To investigate the effect of transjugular intrahepatic porto-systemic shunt (TIPS) on malnutrition in portal hypertensive cirrhotic patients.
METHODS: Twenty-one patients with liver cirrhosis and clinical indications for TIPS insertion were investigated before and 1, 4, 12, 52 wk after TIPS. For each patient we assayed body composition parameters [dry lean mass, fat mass, total body water (TBW)], routine liver and kidney function tests, and free fatty acids (FFA). Glucose and insulin were measured for the calculation of the homeostasis model assessment insulin resistance (HOMA-IR); liver function was measured by the galactose elimination capacity (GEC); the severity of liver disease was graded by model for end-stage liver disease (MELD).
RESULTS: Porto-systemic gradient decreased after TIPS (6.0 ± 2.1 mmHg vs 15.8 ± 4.8 mmHg, P < 0.001). Patients were divided in two groups according to initial body mass index. After TIPS, normal weight patients had an increase in dry lean mass (from 10.9 ± 5.9 kg to 12.7 ± 5.6 kg, P = 0.031) and TBW (from 34.5 ± 7.6 L to 40.2 ± 10.8 L, P = 0.007), as well as insulin (from 88.9 ± 49.2 pmol/L to 164.7 ± 107.0 pmol/L, P = 0.009) and HOMA-IR (from 3.36% ± 2.18% to 6.18% ± 4.82%, P = 0.023). In overweight patients only FFA increased significantly (from 0.59 ± 0.24 mmol/L to 0.93 ± 0.34 mmol/L, P = 0.023).
CONCLUSION: TIPS procedure is effective in lowering portal pressure in patients with portal hypertension and improves body composition without significant changes in metabolic parameters.
Insulin resistance; Liver cirrhosis; Malnutrition; Portal hypertension; Transjugular intrahepatic porto-systemic shunt
Soluble CD163 (sCD163) is a scavenger receptor shed in serum during inflammatory activation of macrophages. We investigated if sCD163 was increased and predicted outcome in acute liver failure (ALF).
Samples from 100 consecutive patients enrolled in the U.S. ALF Study Group for whom sera were available were collected on days 1 and 3, and clinical data were obtained prospectively. sCD163 levels were determined by ELISA.
The median level of sCD163 was significantly increased in ALF (21.1 mg/l (range 3.6 – 74.9)) as compared to healthy controls (2.3 mg/l (0.65 – 5.6), p < 0.0001) and patients with stable liver cirrhosis (9.8 mg/l (3.6 – 16.9), p=0.0002). sCD163 on day 1 correlated significantly with ALT, AST, bilirubin, and creatinine. sCD163 concentrations on day 3 were elevated in patients with fatal outcome of disease compared to spontaneous survivors, 29.0 mg/l ((7.2 – 54.0) vs. 14.6 mg/l (3.5 – 67.2), respectively (p = 0.0025). Patients that were transplanted had intermediate levels. Sensitivity and specificity at a cut off level of 26 mg/l was 62 % and 81 % respectively.
Activated macrophages are involved in ALF resulting in a 10-fold increase in sCD163. A high level (> 26 mg/l) of sCD163 was significantly correlated with fatal outcome and might be used with other parameters to determine prognosis.
acute liver failure; prognostic score; anti-inflammatory markers
Ischemia-reperfusion injury induced by the Pringle maneuver is a well-known problem after liver surgery. The aim of this study was to monitor metabolic changes in the pig liver during warm ischemia and the following reperfusion preceded by ischemic preconditioning (IPC).
Eight Landrace pigs underwent laparotomy. Two microdialysis catheters were inserted in the liver, one in the left lobe and another in the right lobe. A reference catheter was inserted in the right biceps femoris muscle. Microdialysis samples were collected every 30 min during the study. After 2 h of baseline measurement, IPC was performed by subjecting pigs to 10 min of ischemia, followed by 10 min of reperfusion. Total ischemia for 60 min was followed by 3 h of reperfusion. The samples were analyzed for glucose, lactate, pyruvate, and glycerol. Blood samples were drawn three times to determine standard liver parameters.
All parameters remained stable during baseline. Glycerol and glucose levels increased significantly during ischemia, followed by a decrease from the start of reperfusion. During the ischemic period, lactate levels increased significantly and decreased during reperfusion. The lactate–pyruvate ratio increased significantly during ischemia and decreased rapidly during reperfusion. Only minor changes were observed in standard liver parameters.
The present study demonstrated profound metabolic changes before, during, and after warm liver ischemia under the influence of IPC. Compared with a similar study without IPC, the metabolic changes seem to be unaffected by preconditioning.
Warm liver ischemia; Portal triad clamping; Preconditioning; Metabolic changes; Microdialysis
Liver diseases are suspected risk factors for intracerebral haemorrhage (ICH). We conducted a population-based case-control study to examine risk of ICH among hospitalised patients with liver cirrhosis and other liver diseases.
We used data from the hospital discharge registries (1991–2003) and the Civil Registration System in Denmark, to identify 3,522 cases of first-time hospitalisation for ICH and 35,173 sex- and age-matched population controls. Among cases and controls we identified patients with a discharge diagnosis of liver cirrhosis or other liver diseases before the date of ICH. We computed odds ratios for ICH by conditional logistic regressions, adjusting for a number of confounding factors.
There was an increased risk of ICH for patients with alcoholic liver cirrhosis (adjusted OR = 4.8, 95% CI: 2.7–8.3), non-alcoholic liver cirrhosis (adjusted OR = 7.7, 95% CI: 2.0–28.9) and non-cirrhotic alcoholic liver disease (adjusted OR = 5.4, 95%CI:3.1–9.5) but not for patients with non-cirrhotic non-alcoholic liver diseases (adjusted OR = 0.9, 95%CI:0.5–1.6). The highest risk was found among women with liver cirrhosis (OR = 8.9, 95%CI:2.9–26.7) and for patients younger than 70 years (OR = 6.1, 95%CI:3.4–10.9). There were no sex- or age-related differences in the association between other liver diseases (alcoholic or non-alcoholic) and hospitalisation with ICH.
Patients with liver cirrhosis and non-cirrhotic alcoholic liver disease have a clearly increased risk for ICH.
Sodium retention and ascites are serious clinical problems in cirrhosis. Urodilatin (URO) is a peptide with paracrine effects in decreasing sodium reabsorption in the distal nephron. Our aim was to investigate the renal potency of synthetic URO on urine sodium excretion in cirrhosis patients with sodium retention and ascites.
Seven cirrhosis patients with diuretics-resistant sodium retention received a short-term (90 min) infusion of URO in a single-blind, placebo-controlled cross-over study. In the basal state after rehydration the patients had urine sodium excretion < 50 mmol/24 h.
URO transiently increased urine sodium excretion from 22 ± 16 μmol/min (mean ± SD) to 78 ± 41 μmol/min (P < 0.05) and there was no effect of placebo (29 ± 14 to 44 ± 32). The increase of URO's second messenger after the receptor, cGMP, was normal. URO had no effect on urine flow or on blood pressure. Most of the patients had highly elevated plasma levels of renin, angiotensin II and aldosterone and URO did not change these.
The short-term low-dose URO infusion increased the sodium excretion of the patients. The increase was small but systematic and potentially clinically important for such patients. The small response contrasts the preserved responsiveness of the URO receptors. The markedly activated systemic pressor hormones in cirrhosis evidently antagonized the local tubular effects of URO.
Ulcerative colitis (UC) and Crohn's disease (CD) are characterized by intestinal inflammation mainly caused by a disturbance in the balance between cytokines and increased complement (C) activation. Our aim was to evaluate possible associations between C activation capacity and prednisolone treatment.
Plasma from patients with exacerbations of UC (n = 18) or CD (n = 18) were collected before and during high dose prednisolone treatment (1 mg/kg body weight) and tapering. Friedman's two way analysis of variance, Mann-Whitney U test and Wilcoxon signed-rank sum test were used
Before treatment, plasma from CD patients showed significant elevations in all C-mediated analyses compared to the values obtained from 38 healthy controls (p < 0.02), and in mannan binding lectin (MBL)-concentration and MBL-C4-activation capacity (AC) values compared to UC patients (p < 0.02). Before treatment, plasma from UC patients showed significant elevations only in the classical pathway-mediated C3-AC compared to values obtained from healthy controls (p < 0.01). After treatment was initiated, significant reductions, which persisted during follow-up, were observed in the classical pathway-mediated C3-AC and MBL-C4-AC in plasma from CD patients (p < 0.05).
Our findings indicate that C activation capacity is up-regulated significantly in plasma from CD patients. The decreases observed after prednisolone treatment reflect a general down-regulation in immune activation.
The objective of this study was to compare the effect
of an angiotensin-converting enzyme (ACE) inhibitor and
a calcium channel blocker on the development of renal
changes in diabetic rats. Diabetes was induced by an intravenous
injection of streptozotocin in normotensive Wistar
rats. Treatment was commenced immediately in 1 set of
rats with 4 treatment arms: nitrendipine (250 mg/kg fodder),
enalapril (35 mg/L drinking water), both treatments
in combination, or placebo. Treatment was continued for 9
weeks. Another set of rats was left with untreated diabetes
for 3 months followed by 7 weeks treatment as above. When
starting treatment right after induction of diabetes, nitrendipine
significantly reduced urinary albumin excretion
(UAE) to the nondiabetic level (P < .05) without reducing
blood pressure (BP), whereas enalapril failed to significantly reduce UAE despite a reduction in BP. Combining the
two treatments showed no further reduction in UAE compared
to monotherapy with nitrendipine, despite a lower
BP. When leaving diabetic rats untreated for 3 months, only
the coadministration of nitrendipine and enalapril showed
a significant reduction in UAE compared to monotherapy
and placebo treatment, but showed no significant effect