Prednisolone but Not Infliximab Aggravates the Upregulated Hepatic Nitrogen Elimination in Patients with Active Inflammatory Bowel Disease

Thomsen, Karen Louise; Grønbæk, Henning; Dahlerup, Jens Frederik; Aagaard, Niels Kristian; Christensen, Lisbet Ambrosius; Agnholt, Jørgen; Frystyk, Jan; Vilstrup, Hendrik

doi:10.1097/01.mib.0000437496.07181.4c

Cited by 8 publications

(10 citation statements)

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“…36,37 Ureagenesis is also upregulated by inflammatory mediators that are also increased in NASH (eg tumour necrosis factor α), independent of gene expression of urea cycle enzymes. [38][39][40][41] Since the same inverse relationship was present between GS and the functional capacity for urea synthesis, an alternative mechanism for the upregulated GS could be downstream regulation by metabolites accumulating due to the deficient urea cycle, for example, ammonia or carbamoyl phosphate. This possible coregulation indicated by our findings seems not to be able to completely counteract hyperammonaemia in NAFLD in all settings.…”

Section: Discussionmentioning

confidence: 99%

“…Apparently, the last is unrelated to NAGS gene expression and thus, glucagon‐induced CPS1 activation via N‐acetylglutamate could occur even with reduced NAGS expression . Ureagenesis is also upregulated by inflammatory mediators that are also increased in NASH (eg tumour necrosis factor α), independent of gene expression of urea cycle enzymes . Therefore, the inhibitory effect of hepatic fat on gene transcription of urea cycle and related enzymes and function may have been overruled by the upregulating effects of glucagon and/or inflammation in our NASH patients.…”

Section: Discussionmentioning

confidence: 99%

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Non‐alcoholic fatty liver disease alters expression of genes governing hepatic nitrogen conversion

Eriksen

Vilstrup

Rigbolt

et al. 2019

Liver International

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Background & Aims We recently showed that the functional capacity for ureagenesis is deficient in non‐alcoholic fatty liver disease (NAFLD) patients. The aim of this study was to assess expression of urea cycle‐related genes to elucidate a possible gene regulatory basis to the functional problem. Methods Liver mRNA expression analyses within the gene pathway governing hepatic nitrogen conversion were performed in 20 non‐diabetic, biopsy‐proven NAFLD patients (8 simple steatosis; 12 non‐alcoholic steatohepatitis [NASH]) and 12 obese and 14 lean healthy individuals. Sixteen NAFLD patients were included for gene expression validation. Relationship between gene expressions and functional capacity for ureagenesis was described. Results Gene expression of most urea cycle‐related enzymes were downregulated in NAFLD vs both control groups; markedly so for the urea cycle flux‐generating carbamoyl phosphate synthetase (CPS1) (~3.5‐fold, P < .0001). In NASH, CPS1 downregulation paralleled the deficit in ureagenesis (P = .03). Additionally, expression of several genes involved in amino acid uptake and degradation, and the glucagon receptor gene, were downregulated in NAFLD. Conversely, glutamine synthetase (GS) expression increased >1.5‐fold (P ≤ .03), inversely related to CPS1 expression (P = .004). Conclusions NAFLD downregulated the expression of urea cycle‐related genes. Downregulation of urea cycle flux‐generating CPS1 correlated with the loss of functional capacity for ureagenesis in NASH. On gene level, these changes coincided with an increase in the major ammonia scavenging enzyme GS. The effects seemed related to a fatty liver as such rather than NASH or obesity. The findings support gene regulatory mechanisms involved in the deficient ureagenesis of NAFLD, but it remains unexplained how hepatocyte fat accumulation exerts these effects.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Non‐alcoholic fatty liver disease alters expression of genes governing hepatic nitrogen conversion

Eriksen

Vilstrup

Rigbolt

et al. 2019

Liver International

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“…Details of the study participants and procedures have previously been described [27]. A total of 38 consecutive patients with active IBD were enrolled, of which 20 patients presented with ulcerative colitis and 18 with Crohn’s disease.…”

Section: Methodsmentioning

confidence: 99%

“…Baseline data have previously been described and analyzed [27]. The assumption of normality was checked using quantile plots, and non-normally distributed variables were transformed using the natural logarithm prior to statistical analyses.…”

Section: Methodsmentioning

confidence: 99%

The IGF system in patients with inflammatory bowel disease treated with prednisolone or infliximab: potential role of the stanniocalcin-2 / PAPP-A / IGFBP-4 axis

et al. 2019

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Background Patients with inflammatory bowel disease (IBD) present with reduced serum insulin-like growth factor I (IGF-I). Anti-inflammatory treatment with prednisolone or infliximab ameliorates symptoms and increases circulating IGF-I, but prednisolone induces catabolism, whereas infliximab may promote protein synthesis. Recently, stanniocalcin-2 (STC2) was discovered as a novel inhibitor of the enzyme pregnancy-associated plasma protein-A (PAPP-A), which modulates IGF-I activity. PAPP-A can cleave IGF binding protein-4 (IGFBP-4), upon which IGF-I is liberated. We hypothesized that prednisolone and infliximab exert different effects on levels of STC2, PAPP-A, and IGFBP-4, thereby explaining the distinct metabolic effects of prednisolone and infliximab. Methods Thirty-eight patients with active IBD treated with either prednisolone ( n = 17) or infliximab ( n = 21) were examined before and after 7 days of treatment. Circulating levels of IGF-I, IGF-II, IGFBP-3, PAPP-A, and STC2 were measured by immunoassays. Intact IGFBP-4 and two IGFBP-4 fragments were determined by a novel immunoassay. Bioactive IGF was assessed by cell-based IGF receptor activation assay. Concentrations of IGFBP-4, PAPP-A, and STC2 on day 0 and 7 were compared to healthy control subjects. Results Following seven days of prednisolone treatment, total and bioactive IGF-I were increased ( p < 0.001 and p < 0.05, respectively). Upon infliximab treatment, total IGF-I levels were augmented (p < 0.05), yet IGF bioactivity remained unaltered. Intact IGFBP-4 and the two IGFBP-4 fragments generated upon cleavage by PAPP-A were all decreased following treatment with either prednisolone or infliximab (all p < 0.05). PAPP-A levels were only increased by infliximab ( p = 0.005), whereas the inhibitor STC2 did not respond to any of the treatments. Conclusion IGF-I and IGFBP-4 concentrations were markedly altered in patients with IBD and near-normalized with disease remission following treatment with prednisolone or infliximab. Thus, IGFBP-4 may modulate IGF bioavailability in IBD. The effect of immunosuppression did not appear to extend beyond the regulation of IGF and IGFBP-4, as neither PAPP-A nor STC2 were discernibly affected. Trial registration ClinicalTrials.gov: NCT00955123 . Date of registration: August 7, 2009 (retrospectively registered).

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“…Conversely, the urea synthesis capacity is accelerated in stressful situations like pain, recent surgery, uncontrolled diabetes, and inflammation located outside of the liver (e.g. active inflammatory bowel disease) [ 5 – 9 ]. Moreover, experimentally induced inflammation has been shown to result in an increase in the urea synthesis capacity in rats [ 10 , 11 ].…”

Section: Introductionmentioning

confidence: 99%

Alcoholic Hepatitis Markedly Decreases the Capacity for Urea Synthesis

et al. 2016

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Background and AimData on quantitative metabolic liver functions in the life-threatening disease alcoholic hepatitis are scarce. Urea synthesis is an essential metabolic liver function that plays a key regulatory role in nitrogen homeostasis. The urea synthesis capacity decreases in patients with compromised liver function, whereas it increases in patients with inflammation. Alcoholic hepatitis involves both mechanisms, but how these opposite effects are balanced remains unclear. Our aim was to investigate how alcoholic hepatitis affects the capacity for urea synthesis. We related these findings to another measure of metabolic liver function, the galactose elimination capacity (GEC), as well as to clinical disease severity.MethodsWe included 20 patients with alcoholic hepatitis and 7 healthy controls. The urea synthesis capacity was quantified by the functional hepatic nitrogen clearance (FHNC), i.e., the slope of the linear relationship between the blood α-amino nitrogen concentration and urea nitrogen synthesis rate during alanine infusion. The GEC was determined using blood concentration decay curves after intravenous bolus injection of galactose. Clinical disease severity was assessed by the Glasgow Alcoholic Hepatitis Score and Model for End-Stage Liver Disease (MELD) score.ResultsThe FHNC was markedly decreased in the alcoholic hepatitis patients compared with the healthy controls (7.2±4.9 L/h vs. 37.4±6.8 L/h, P<0.01), and the largest decrease was observed in those with severe alcoholic hepatitis (4.9±3.6 L/h vs. 9.9±4.9 L/h, P<0.05). The GEC was less markedly reduced than the FHNC. A negative correlation was detected between the FHNC and MELD score (rho = -0.49, P<0.05).ConclusionsAlcoholic hepatitis markedly decreases the urea synthesis capacity. This decrease is associated with an increase in clinical disease severity. Thus, the metabolic failure in alcoholic hepatitis prevails such that the liver cannot adequately perform the metabolic up-regulation observed in other stressful states, including extrahepatic inflammation, which may contribute to the patients’ poor prognosis.

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Prednisolone but Not Infliximab Aggravates the Upregulated Hepatic Nitrogen Elimination in Patients with Active Inflammatory Bowel Disease

Cited by 8 publications

References 45 publications

Non‐alcoholic fatty liver disease alters expression of genes governing hepatic nitrogen conversion

Non‐alcoholic fatty liver disease alters expression of genes governing hepatic nitrogen conversion

The IGF system in patients with inflammatory bowel disease treated with prednisolone or infliximab: potential role of the stanniocalcin-2 / PAPP-A / IGFBP-4 axis

Alcoholic Hepatitis Markedly Decreases the Capacity for Urea Synthesis

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