Karen Louise Thomsen

Aarhus University Hospital, Aarhus, Central Jutland, Denmark

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Publications (19)39.05 Total impact

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    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.
    American journal of physiology. Gastrointestinal and liver physiology. 06/2014;
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    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.
    World journal of hepatology. 04/2014; 6(4):188-198.
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    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.
    Liver international: official journal of the International Association for the Study of the Liver 03/2014; · 3.87 Impact Factor
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    ABSTRACT: Catabolism and weight loss are serious problems in patients with active inflammatory bowel disease (IBD). The body nitrogen (N) depletion is partly related to increased hepatic capacity for the elimination of N through urea synthesis. This is probably caused by the inflammation per se, and the treatment with prednisolone may aggravate the problem, whereas the effect of biological therapy is unknown. Therefore, we examined the effects of prednisolone or infliximab on the regulation of urea synthesis in patients with active IBD. Urea synthesis was quantified by the functional hepatic nitrogen clearance (FHNC), i.e., the slope of the linear relationship between the urea nitrogen synthesis rate and the blood α-amino nitrogen concentration during alanine infusion. Thirty-seven patients with active IBD treated with either prednisolone or infliximab were examined before and after 7 days of treatment. At baseline, the FHNC was similar in the 2 treatment groups (36 L/h). After 7 days, prednisolone increased the FHNC by 40% (55 L/h) (P = 0.03), whereas infliximab tended to reduce the FHNC by 15% (30 L/h) (P = 0.09). The changes in the FHNC differed significantly between the 2 treatment groups (P < 0.01). Prednisolone treatment further upregulated urea synthesis, which increases the hepatic loss of nitrogen and promotes body catabolism. In contrast, infliximab treatment caused no such aggravation and likely reduced the N loss. These results may argue in favor of infliximab therapy for IBD and add to the pathophysiological understanding of the interplay between inflammation, catabolism, and anti-inflammatory treatment.
    Inflammatory Bowel Diseases 11/2013; · 5.12 Impact Factor
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    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.
    Archives of Physiology and Biochemistry 07/2013;
  • Karen Louise Thomsen
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    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.
    Danish medical journal. 04/2013; 60(4):B4617.
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    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.
    AJP Gastrointestinal and Liver Physiology 02/2013; · 3.65 Impact Factor
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    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.
    Clinical nutrition (Edinburgh, Scotland) 04/2012; · 3.27 Impact Factor
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    ABSTRACT: The acute phase response presents a catabolic event related to increased waste of amino-N via hepatic urea synthesis despite an increased need for amino-N incorporation into acute phase proteins. In our previous studies, tumour necrosis factor-α (TNF-α) acutely up-regulated the in vivo capacity of urea-nitrogen synthesis (CUNS) in rats before the hepatic acute phase response was established. To extend these observations, this study aimed to clarify the regulation of N elimination via urea during the later stages of the acute phase response. Twenty-four hours after i.v. injection of 25 μg kg(-1) TNF-α or placebo, we determined the in vivo CUNS, hepatocyte urea cycle enzyme protein levels and mRNA levels of the urea cycle enzyme genes in pair-fed rats. In addition, serum acute phase proteins and their liver mRNA levels were measured. After TNF-α, CUNS and hepatocyte urea cycle enzyme protein expressions were unchanged while urea cycle enzyme mRNA levels decreased. Liver mRNA levels of α2MG, haptoglobin and α1AGP rose and their serum levels increased equally. Despite a fully established 24-h acute phase response, there was no change in the in vivo capacity for disposal of amino-N by urea synthesis or in the urea cycle enzyme proteins, although the expression of the urea cycle enzyme genes was decreased. Thus, in vivo urea synthesis was not orchestrated together with acute phase protein synthesis so as to limit N waste despite genetic regulation to this effect. This may contribute towards catabolism of inflammation.
    European Journal of Clinical Investigation 01/2011; 41(1):16-22. · 3.37 Impact Factor
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    ABSTRACT: Clinical or experimentally induced, active inflammation up-regulates the in vivo capacity of urea synthesis (CUNS), which promotes nitrogen removal from the body and metabolic catabolism. We have shown that tumor necrosis factor α (TNF-α) up-regulates CUNS and increases interleukin 6 expression (IL-6) within hours of administration. The described effect of TNF-α on nitrogen homeostasis may, therefore, depend on IL-6. Three hours after the i.v. injection of 125 μg.kg⁻¹ of IL-6 or placebo, we evaluated the CUNS, hepatocyte urea cycle enzyme protein levels and the mRNA levels of the urea cycle enzyme genes in rats. The prevailing rat serum acute phase proteins and their liver mRNA levels were also measured. IL-6 did not change CUNS or hepatocyte urea cycle enzyme protein levels, whereas urea cycle enzyme mRNA levels, except for ornithine transcarbamylase (OTC), decreased by approximately 20%. The liver mRNA levels of α2MG, haptoglobin and α1AGP all increased by 1.5- to 2-fold (p < 0.001). In serum, only the α2MG concentration slightly increased (p < 0.001), whereas the levels of the other circulating acute phase proteins remained unchanged. IL-6 is not the mediator of the in vivo CUNS up-regulation observed 3 h after TNF-α administration, but it may be involved in the down-regulation of urea cycle genes. IL-6 may also mediate TNF-α effects on acute phase protein gene expression. Thus, IL-6 did not contribute to the in vivo hepatic component of inflammation-associated catabolism.
    Scandinavian journal of clinical and laboratory investigation 12/2010; 71(2):150-6. · 1.38 Impact Factor
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    ABSTRACT: The anabolic effects of insulin-like growth factor-I (IGF-I) may involve a decrease of hepatic nitrogen (N) clearance, but this has never been studied in humans. Patients with cirrhosis have low levels of IGF-I and might benefit from IGF-I therapy. Conversely, a possible decrease in hepatic N clearance by IGF-I could increase the risk of hepatic encephalopathy. To examine the effects of 1-week IGF-I administration on the functional hepatic N clearance (FHNC), viz. the linear slope of the relationship between blood-α-amino-N concentration and urea-N synthesis rate as controlled by an infusion of alanine. A randomized sequence-crossover placebo-controlled study. Eight healthy volunteers and eight patients with alcoholic cirrhosis received injections of saline or IGF-I twice daily (50 μg/kg) for 7 days. IGF-I levels at baseline were lower in the patients than those in the controls. The IGF-I treatment normalized patient levels and caused an increase in the controls to supra-physiological levels. FHNC was lower in patients compared with healthy subjects (23.0 vs 36.5 L/h, P=0.03). IGF-I treatment reduced FHNC by 30% in healthy subjects (from 36.5 to 25.7 L/h, P = 0.02), whereas no effect was found in the patients. IGF-I downregulates urea synthesis in normal subjects. This may be part of the explanation behind the anabolic effects of IGF-I. The normalization of IGF-I in cirrhosis patients without an effect on urea synthesis implies that the patients were resistant to IGF-I with regard to reduction of hepatic amino-N elimination. IGF-I treatment of cirrhosis patients evidently carries no risk of N accumulation.
    Liver international: official journal of the International Association for the Study of the Liver 10/2010; 31(1):132-7. · 3.87 Impact Factor
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    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.
    Journal of Hepatology 09/2010; 54(4):760-4. · 9.86 Impact Factor
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    ABSTRACT: Catabolism is a serious problem in patients with active inflammation. The tissue nitrogen (N) depletion is related to increased hepatic capacity for elimination of N via conversion of amino-N into urea-N. This is caused by the inflammatory process, but the mediators responsible are unknown. Tumor necrosis factor-alpha (TNF-alpha) plays a key role in inflammation, and we hypothesized that TNF-alpha up-regulates urea synthesis. We examined the in vivo capacity of urea-N synthesis (CUNS) and mRNA levels of urea cycle enzyme genes 3 h after TNF-alpha injection in rats. Circulating concentrations of glucagon, corticosterone, insulin, glucose, cytokines and acute phase proteins and their liver tissue gene expressions were measured. TNF-alpha increased CUNS by 40% (p=0.03) despite decreased urea-cycle enzyme gene expression. TNF-alpha increased interleukin 6 (IL-6) (p < 0.001); circulating acute phase proteins were unchanged. TNF-alpha in rats caused an acute up-regulation of the in vivo capacity of urea synthesis which may promote loss of nitrogen from the body and catabolism. The results indicate that TNF-alpha has a post-transcriptional effect on regulation of urea synthesis that is independent of the acute phase protein synthesis. Effects of IL-6 may be involved.
    Scandinavian journal of clinical and laboratory investigation 02/2010; 70(3):151-7. · 1.38 Impact Factor
  • Journal of Hepatology - J HEPATOL. 01/2010; 52.
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    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.
    Blood Purification 05/2009; 28(2):102-7. · 2.06 Impact Factor
  • Journal of Hepatology - J HEPATOL. 01/2009; 50.
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    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.
    Expert review of gastroenterology & hepatology 11/2008; 2(5):705-11.
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    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.
    In vivo (Athens, Greece) 01/2008; 22(6):655-61. · 1.22 Impact Factor
  • Henning Grønbaek, Karen Louise Thomsen, Peter Ott, Hendrik Vilstrup
    Ugeskrift for laeger 09/2007; 169(34):2761-3.

Publication Stats

49 Citations
39.05 Total Impact Points

Institutions

  • 2008–2014
    • Aarhus University Hospital
      • Department of Hepatology and Gastroenterology
      Aarhus, Central Jutland, Denmark
  • 2013
    • Aarhus University
      Aarhus, Central Jutland, Denmark