[Show abstract][Hide abstract] ABSTRACT: Background and aims:
EASL/AASLD hepatic encephalopathy (HE) guidelines proposed the alternative use of the term 'Covert HE' combining minimal HE (mHE) and Grade 1 HE into a single entity. However, longitudinal data to indicate that these are indeed a single entity are lacking. The aims of this study were to determine whether the occurrence of complications of cirrhosis requiring hospital admission and mortality were similar in these sub-groups of patients.
Clinically-stable cirrhotic patients (n = 106) with no previous history of 'Overt HE' were included over a 2-year period and classified as having no HE (n = 23), mHE (n = 39) or Grade 1 HE (n = 44). Standard biochemistry, venous ammonia, bacterial DNA and neutrophil function were measured at inclusion and the patients were followed for a mean of 230±95 days.
Patients with Grade 1 HE had significantly more complications requiring hospitalisation (infection 9/18/34%; HE 4/8/18%; other 13/10/11%; P = 0.02) and significantly greater mortality (4/5/20%; P = 0.04) compared to patients with no HE or mHE respectively. Patients with mHE and grade 1 HE had similar ammonia levels, but higher than the no HE group (P<0.001). MELD score was similar between groups but Grade 1 HE patients had increased frequency of bacterial translocation (P = 0.06) and neutrophil spontaneous respiratory burst (P = 0.02) compared to patients with mHE.
The results of this study show for the first time that 'Covert HE' is a heterogeneous entity with significantly greater hospitalisations and mortality in the Grade 1 HE patients compared with mHE. Further prospective longer-term studies are required before EASL/AASLD guidance is fully implemented.
[Show abstract][Hide abstract] ABSTRACT: Background and aims:
Non-selective beta-blockers (NSBBs) have been shown to have deleterious outcomes in patients with refractory ascites, alcoholic hepatitis and spontaneous bacterial peritonitis leading many physicians to stop the drug in these cases. Acute on chronic liver failure (ACLF) is characterized by systemic inflammation and high mortality. As NSBBs may have beneficial effects on gut motility and permeability and, systemic inflammation, the aims of this prospective, observational study were to determine whether on-going use of NSBBs reduced 28-day mortality in ACLF patients.
The study was performed in 349 patients with ACLF included in the CANONIC study, which is a prospective observational investigation in hospitalized cirrhotic patients with acute deterioration. The data about the use of NSBBs, its type and dosage was specifically recorded. Patient characteristics at enrollment significantly associated with treatment and mortality were taken into account as potential confounders to adjust for treatment effect. A logistic regression model was fitted.
164 (47%) ACLF patients received NSBBs whereas 185 patients did not. Although the CLIF-C ACLF scores were similar at presentation, more patients in the NSBB treated group had lower grades of ACLF (P=0.047) at presentation and significantly more patients improved. Forty patients (24.4%) died in NSBB treated group compared with 63 patients (34.1%) (P=0.048) [estimated risk-reduction 0.596 (95%CI: 0.361-0.985; p=0.0436)]. This improvement in survival was associated with a significantly lower white cell count (NSBB: 8.5 (5.8); no NSBB: 10.8 (6.6); P=0.002). No long-term improvement in survival was observed.
This study shows for the first time that ongoing treatment with NSBBs in cirrhosis is safe and reduces the mortality if they develop ACLF. Careful thought should be given before stopping NSBBs in cirrhotic patients.
No preview · Article · Oct 2015 · Journal of Hepatology
[Show abstract][Hide abstract] ABSTRACT: Objective:
The role of renal aquaporin-2 (AQP2) water channel turnover in patients with liver cirrhosis, portal hypertension and water retention remains unclear. Transjugular intrahepatic portosystemic shunt (TIPS) insertion reduces portal hypertension, improves water excretion and lowers plasma vasopressin. The aim of this study was to establish whether TIPS insertion decreases urinary AQP2 excretion (uAQP2) in parallel with improved water excretion.
Material and methods:
Fourteen cirrhosis patients with refractory ascites were studied before TIPS insertion and 4 and 12 weeks after insertion. A 24-h urine collection was followed by an oral water load (20 ml/kg body weight) with a 4-h blood and urine sampling.
TIPS reduced the portal pressure gradient from a median 18(4) (25-75% InterQuartile-range) to 7(2) mmHg, p < 0.05 and the need for diuretics (p < 0.05). TIPS increased plasma sodium from 136(6) mmol/l to 139(4), (p < 0.05) and diuresis from 1650(1043) ml/24 h to 2230(560) (p < 0.05), although the 24-h urinary sodium excretion did not change. There was no change in the baseline uAQP2 before 274(249) ng/(mmol creatinine/24 h) and 12 weeks after TIPS 242(201). There were no systematic changes in uAQP2, plasma vasopressin or other vasoactive substances during the water loads, before or after TIPS.
The effective amelioration of portal hypertension improved the patient's water excretion and plasma sodium, but there was no change in renal AQP2 trafficking or vasopressin. These findings do not support a primary role for renal AQP2 water channels in portal hypertensive water retention.
No preview · Article · Jan 2015 · Scandinavian Journal of Gastroenterology
[Show abstract][Hide abstract] ABSTRACT: 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 anti-tumour necrosis factor (TNF)-α antibody or prednisolone treatment. We also investigated the CD163 expression on circulating monocytes. 58 CD patients, 40 UC patients, 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 CD patients receiving anti-TNF-α antibody treatment. Baseline sCD163 levels were elevated in CD (1.99 [1.80-2.18] mg/l) and UC patients (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 CD and UC patients 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 normalised sCD163 levels in UC patients, whereas CD patients exhibited sustained increased sCD163 levels. In CD patients, 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.This article is protected by copyright. All rights reserved.
No preview · Article · Oct 2014 · Scandinavian Journal of Immunology
[Show abstract][Hide abstract] ABSTRACT: Background: Non-alcoholic steatohepatitis (NASH) is increasing in prevalence, yet the consequences for liver function are unknown. We studied ureagenesis, an essential metabolic liver function of importance for whole-body nitrogen homeostasis, in a rodent model of diet induced NASH. Methods: Rats were fed a high-fat, high-cholesterol diet for 4 and 16 weeks, resulting in early and advanced experimental NASH, respectively. We examined the urea cycle enzyme mRNAs in liver tissue, the hepatocyte urea cycle enzyme proteins and the in vivo Capacity of Urea-Nitrogen Synthesis (CUNS). Results: Early NASH decreased all the urea cycle mRNAs to an average of 60% and the ornithine transcarbamylase protein to 10% while the CUNS remained unchanged. Advanced NASH further decreased the carbamoyl phosphate synthetase protein to 63%, and in addition decreased the CUNS by 20% (from 5.65 ± 0.23 to 4.58 ± 0.30 μmol x (min x 100 g) -1; P = 0.01). Conclusion: Early NASH compromised the genes and enzyme proteins involved in ureagenesis, while advanced NASH resulted in a functional reduction in the capacity for ureagenesis. The pattern of urea cycle perturbations suggests a prevailing mitochondrial impairment by NASH. The decrease in CUNS has consequences for the ability of the body to adjust to changes in the requirements for nitrogen homeostasis e.g. at stressfull events. NASH, thus, in terms of metabolic consequences is not an innocuous lesion and the manifestations of the damage seem to be a continuum with increasing disease severity.
Full-text · Article · Jun 2014 · AJP Gastrointestinal and Liver Physiology
[Show abstract][Hide abstract] ABSTRACT: 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.
Full-text · Article · Apr 2014 · World Journal of Hepatology
[Show abstract][Hide abstract] ABSTRACT: Patients with non-alcoholic steatohepatitis (NASH) have increased mortality, including from infections. We, therefore, tested in a rodent model of steatohepatitis whether the hepatic acute phase response is intact.
Steatohepatitis was induced in rats by feeding a high-fat, high-cholesterol diet for 4 (early) and 16 weeks (advanced NASH). 2 hours after low-dose LPS (0.5 mg/kg i.p.) we measured the serum concentrations of tumour necrosis factor-α (TNF-α) and interleukin-6 (IL-6). We also measured liver mRNA's and the serum concentrations of acute phase proteins 24 hours after LPS.
NASH in itself increased the liver mRNA levels of TNF-α and IL-6 and also the liver mRNA and serum levels of the acute phase proteins. The exposure to LPS increased serum TNF-α in both early and advanced NASH and more so than in the control rats. However, the increases in acute phase protein genes in liver tissue and proteins in the blood were lower than in the control rats.
In rats with early or advanced experimental NASH, LPS despite an increased interleukin release resulted in a blunted acute phase protein response. This tachyphylaxis may be part of the mechanism for the increased infection susceptibility of patients with NASH. We speculate that the steatosis-related interleukin release desensitizes the signalling pathway leading to acute phase protein synthesis. This article is protected by copyright. All rights reserved.
No preview · Article · Mar 2014 · Liver international: official journal of the International Association for the Study of the Liver
[Show abstract][Hide abstract] ABSTRACT: Abstract Context: Inflammatory bowel disease (IBD) induces increased risk of thrombo-embolism. CD36 is involved in platelet activation, glucose metabolism and inflammation. Objective: The relationship between CD36 expression on platelets and monocytes, plasma sCD36, and CD36-positive platelet-derived microparticles (PDMPs) and inflammation in both active IBD and after one week of anti-tumour necrosis alpha antibody (anti-TNF) treatment was investigated. Material and methods: Patients with exacerbation of Crohn's disease (n = 8) or ulcerative colitis (n = 5) and 13 healthy controls were enrolled. Seven patients underwent anti-TNF treatment for one week. Platelet, monocyte, and PDMP-CD36 were measured by flow-cytometry. Results: Platelet CD36 expression was 34% higher in patients, and correlated with insulin resistance and fasting glucose. sCD36 was 37% lower and restored after anti-TNF treatment. Conclusion: Elevated platelet CD36 expression may contribute to increased risk of thrombo-embolism in active IBD. This may not entirely be attributed to inflammation and secondary insulin resistance may play a role.
Full-text · Article · Jul 2013 · Archives of Physiology and Biochemistry
[Show abstract][Hide abstract] ABSTRACT: Catabolism is a serious clinical problem in patients with active inflammation. Under such stressful conditions, the catabolism and loss of tissue nitrogen (N) result from proteolysis and are augmented by an up-regulation of the hepatic capacity to eliminate amino-N via urea-N. Our earlier studies suggest that this is part of the acute phase response to inflammation despite the increased need for amino-N for incorporation into acute phase proteins synthesised by the liver. It is, therefore, patho-physiologically and potentially therapeutically important to identify regulators of urea synthesis which, in this way, aggravate the inflammatory loss of body N; this study aimed at identifying such mediators, quantifying their effects, and unravelling their mode of action. The cytokines tumour necrosis factor alpha (TNF-α) and interleukin-6 (IL-6) play key roles in inflammation, and they both induce protein breakdown and catabolism. Therefore, they are both potential mediators of the up-regulation of urea synthesis. Our first experiments showed that TNF-α administration in rats acutely, i.e. after 3 h, up-regulated the in vivo capacity of urea-N synthesis (CUNS) by 30%, whereas IL-6 was observed not to acutely change CUNS. Furthermore, our experiments aimed at characterising the regulation of hepatic N elimination via urea during different phases of the TNF-α-induced acute phase response and to identify the steps between gene expression and physiological function that might be involved. We did so by using four different methods 1, 3, 24, and 72 h after TNF-α injection in rats: examination of urea cycle enzyme mRNA levels in liver tissue, the hepatocyte urea cycle enzyme proteins, CUNS, and known hormonal regulators of CUNS. The major serum acute phase proteins and their liver mRNA levels were also measured. Despite a progressive down-regulation of the urea cycle genes and a fully established acute phase response 24 h after TNF-α administration, no change in the in vivo capacity for the disposal of amino-N by urea synthesis was observed 1, 24, and 72 h after TNF-α injection. Moreover, TNF-α actually up-regulated urea synthesis 3 h after administration (cf. above). The dissociation of the effects of TNF-α on the urea genes and on physiological functions remains unexplained. The lack of down-regulation of whole body urea synthesis may promote the loss of N from the body and contribute towards inflammatory catabolism. This indicates the presence of an independent hepatic component of the inflammation response that is of primary importance for the stress-catabolic state.
No preview · Article · Apr 2013 · Danish Medical Journal
[Show abstract][Hide abstract] ABSTRACT: Background: The acute phase response is a catabolic event involving increased waste of amino-nitrogen (N) via hepatic urea synthesis, despite an increased need for amino-N incorporation into acute phase proteins. This study aimed to clarify the regulation of N elimination via urea during different phases of the tumour necrosis factor-α (TNF-α)-induced acute phase response in rats. Methods: We used four methods to study the regulation of urea synthesis: We examined urea cycle enzyme mRNA levels in liver tissue, the hepatocyte urea cycle enzyme proteins, the in vivo capacity of urea-N synthesis (CUNS), and known humoral regulators of CUNS at 1, 3, 24 and 72 h after TNF-α injection (25 μg⋅kg(-1) i.v. rrTNF-α) in rats. Serum acute phase proteins and their liver mRNA levels were also measured. Results: The urea cycle enzyme mRNA levels acutely decreased and then gradually normalised, whereas the urea cycle enzyme proteins remained essentially unchanged over time. The CUNS rose after 3 h and then normalised. The acute phase response was fully activated at 24 h with markedly increased serum levels of the acute phase proteins. Conclusion: TNF-α acutely up-regulated the CUNS. Later, despite the fully established 24-h acute phase response and the decreased activity of the urea cycle enzyme genes, there was no change in the urea cycle enzyme proteins or the CUNS. Thus, in no phase after the initiation of the acute phase response was in vivo urea synthesis orchestrated in combination with acute phase protein synthesis so as to limit N waste.
Full-text · Article · Feb 2013 · AJP Gastrointestinal and Liver Physiology
[Show abstract][Hide abstract] ABSTRACT: BACKGROUND & AIMS: Decompressing the portal hypertension by inserting a transjugular intrahepatic porto-systemic shunt (TIPS) in undernourished liver cirrhosis patients results in gains in body weight. It is important to understand whether this reflects an advantageous or unfavourable shift in nutrition status. This to some extent can be judged from the changes in the patients' adipokine patterns. We, therefore, examined the circulating levels of the most important adipokines before and after the TIPS procedure. METHODS: Twenty-five liver cirrhosis patients were examined before TIPS insertion and followed for six months after the procedure. Their body composition was determined by the bioimpedance technique. The serum concentrations of adiponectin, retinol binding protein 4 (RBP4), and leptin were measured. RESULTS: The TIPS procedure induced a 12% increase in body cell mass (P = 0.03) but did not change the body fat mass. At six months, serum adiponectin was increased by 60% (mean ± SD, 10.7 ± 6.1 vs. 16.9 ± 8.9 mg/L; P = 0.001), serum RBP4 was decreased by 45% (28.6 ± 20.0 vs. 16.3 ± 9.6 mg/L; P = 0.01), and the leptin levels remained unchanged. CONCLUSIONS: The TIPS-related tissue build up was accompanied by increased adiponectin and decreased RBP4. Such changes are associated with an anabolic condition where the adipose tissue possesses residual capacity for energy storage. TIPS, therefore, can be considered to be nutritionally beneficial to cirrhosis patients.
[Show abstract][Hide abstract] ABSTRACT: Alcoholic hepatitis is an acute life- and health-threatening disease that may be increasingly frequent. However, accurate and representative data on time trends in its incidence and prognosis are not available. This study aims to provide nationwide population-based estimates of alcoholic hepatitis incidence and mortality in Denmark, 1999-2008.
We identified, from the Danish National Registry of Patients, all patients with a first-time discharge diagnosis of alcoholic hepatitis from 1999 and through 2008. We also ascertained whether patients had cirrhosis. We computed the annual incidence rates as well as 28-, 84-day, 5-year, and 10-year mortality rates.
We found 1951 patients with alcoholic hepatitis, 63% men. During the study decade, the annual incidence rate in the Danish population rose from 37 to 46 per 10(6) for men and from 24 to 34 per 10(6) for women. The steepest increase was observed among middle-aged women. The 28-day mortality rate rose from 12% to 15%, and the 84-day mortality rate rose from 14% to 24%, similarly for men and women. The increase in short-term mortality was attributable to increasing patient age and prevalence of cirrhosis. The 5-year mortality was 56% overall, 47% without cirrhosis, and 69% with cirrhosis.
The incidence of alcoholic hepatitis in Denmark has increased during the recent decade. The patients are older at diagnosis and more have cirrhosis, resulting in worse short-term prognosis. The long-term prognosis is grave, especially for patients with cirrhosis. The increase in incidence mirrors changes in alcohol consumption in Denmark.
No preview · Article · Sep 2010 · Journal of Hepatology
[Show abstract][Hide abstract] ABSTRACT: Wilson's disease (WD) can present in a fulminant form with hepatocellular dysfunction, hemolysis and multiorgan failure (Wilson's crisis). We present a previously healthy young woman with severe WD whose WD severity score was 13. A score >11 indicates a poor chance of survival and liver transplantation will usually be recommended.
Penicillamine and acetylcysteine were initially administered, but the patient deteriorated further, and extracorporeal liver support with the Prometheus FPSA (fractionated plasma separation and adsorption) system was initiated. The patient was treated 6 h daily during 3 consecutive days.
Severe hemolysis was reduced to low-grade hemolysis, with no further need for transfusions. The mental state improved and after 4 months practically all biochemical markers were normalized.
This is the first report of FPSA albumin dialysis of a patient with Wilson's crisis and the first report in which a patient with a WD score >11 survived without transplantation.
No preview · Article · May 2009 · Blood Purification
[Show abstract][Hide abstract] ABSTRACT: Nonalcoholic fatty liver disease (NAFLD) is a common disease that is usually accompanied by insulin resistance (IR). Whether or how NAFLD and IR are temporally and mechanistically related is controversial. Recent studies focus on their epidemiology, the importance of dietary fat, the role of adipocytokines and the sterol regulatory element-binding protein-1c. NAFLD and IR may progress to severe diseases, such as cirrhosis, diabetes or both, and understanding the pathogenesis of the precursor conditions has preventive and therapeutic implications. This review focuses on the possible relationships between NAFLD and IR and the treatment options available.
Full-text · Article · Nov 2008 · Expert review of gastroenterology & hepatology
[Show abstract][Hide abstract] ABSTRACT: Patients with liver cirrhosis have disturbances in the insulin-like growth factor I (IGF-I) system that favour insulin resistance and catabolism. High morbidity and mortality of such patients from infections may be related to further aggravation of this problem but human data are controversial. Here, the effect of lipopolysaccharide (LPS) endotoxin on the IGF system was studied in rats with cirrhosis.
One month after induction of cirrhosis by bile duct ligation, LPS was administered (0.5 mg/kg) and the IGF system assessed 24 h later. Sham-operated animals acted as controls. Circulating and liver mRNA of IGF-I and its binding proteins (IGFBPs) were measured.
LPS reduced IGF-I and IGFBP-3 by 20% in the cirrhosis group. LPS induced insulin resistance (HOMA) in both groups.
Our results show that LPS administered to cirrhotic rats induced changes in the IGF system that facilitate catabolism. This may be of importance for the accelerated tissue loss during infection and the acute phase response in liver cirrhosis.
Full-text · Article · Nov 2008 · In vivo (Athens, Greece)