Fraction of exhaled nitric oxide is higher in liver transplant recipients than in controls from the general population: a cohort study.

Background: Fraction of exhaled nitric oxide with an expiratory flow of 50 mL/s (FENO50) is a biomarker of eosinophilic airway inflammation. Liver transplant recipients have an increased risk of pulmonary infections, but little is known about the burden of chronic pulmonary diseases in this group. We aimed to assess the prevalence of elevated FENO50 in liver transplant recipients and compare it to controls from the general population. Methods: FENO50 was measured in 271 liver transplant recipients from The Danish Comorbidity in Liver Transplant Recipients (DACOLT) study and 1,018 age- and sex-matched controls from The Copenhagen General Population Study (CGPS). Elevated FENO50 was defined as ≥25 or ≥50 parts per billion (ppb). The analyses were adjusted for known and suspected confounders. Results: The median age of the liver transplant recipients was 55 years (interquartile range (IQR) 46-64), and 58% were men. The liver transplant recipients had a higher median FENO50 than the controls [16 ppb (IQR 10-26) vs. 13 ppb (IQR 8-18.), p < 0.001]. Furthermore, the liver transplant recipients had a higher prevalence of elevated FENO50 (for FENO50 ≥25 ppb 27% vs. 11%, p < 0.001 and ≥50 ppb 4% vs. 2%, p = 0.02). The results were similar after adjusting for age, sex, smoking status, use of airway medication, and blood eosinophil counts [the adjusted odds ratio (OR) for FENO50 ≥25 ppb was 3.58 (95% CI: 2.50-5.15, p < 0.0001) and the adjusted OR for FENO50 ≥50 ppb was 3.14 (95% CI: 1.37-7.20, p = 0.007)]. Conclusion: The liver transplant recipients had elevated FENO50, implying increased eosinophilic airway inflammation. The clinical impact of this finding needs further investigation.

Metformin Stimulates Intestinal Glycolysis and Lactate Release: A single-Dose Study of Metformin in Patients With Intrahepatic Portosystemic Stent.

The pharmacodynamic effects of metformin remain elusive, but several lines of evidence suggest a critical role of direct effects in the gastrointestinal (GI) tract. We investigated if metformin stimulates intestinal glucose metabolism and lactate release in the prehepatic circulation. We included eight patients with transjugular intrahepatic portosytemic stent in an open label study. Portal and arterialized peripheral blood was obtained before and 90 minutes after ingestion of 1,000 mg metformin. Metformin increased lactate concentrations by 23% (95% confidence interval (CI): 6-40) after 90 minutes in the portal vein. The plasma concentration of glucose, insulin, and C-peptide was higher in the portal vein compared with arterialized blood (P < 0.05, all) and was lowered at both sampling sites following metformin ingestion (P < 0.01, all). Plasma concentration of GLP-1 was 20% (95% CI: 2-38) higher in the portal vein at baseline and metformin increased the concentration with 11% (1.5 pM, P = 0.05). The median concentration of growth differentiation factor 15 was 10% (95% CI: 1-19) higher in the portal vein compared with arterialized blood. Ninety minutes after metformin administration, the median portal vein concentration increased to around 3,000 ng/mL with a mean portal/arterial ratio of 1.5 (95% CI: 1.2-1.8). Non-targeted metabolomics showed that metformin acutely affected benzoate-hippurate metabolism. A single-dose of metformin directly affects substrate metabolism in the upper GI tract in humans with direct stimulation of nonoxidative glucose metabolism. These data suggest glucose lowering effects of metformin can be intrinsically linked with the GI tract without hepatic uptake of the drug.

Equal efficacy of gastric and jejunal tube feeding in liver cirrhosis and/or alcoholic hepatitis: a randomised controlled study.

BACKGROUND AND AIM: Malnutrition and muscle mass loss are complications in liver cirrhosis and alcoholic hepatitis (AH). Hospitalised patients who do not meet nutritional requirements are recommended to be fed enterally or parenterally, but no guidelines recommend a specific type of tube. This study aimed to compare the efficacy of jejunal versus gastric feeding. METHOD: 40 inpatients with liver cirrhosis and/or AH, a nutritional risk score more than 2 and a reduced daily energy intake were included. Half were randomised to nasogastric (NG) and half to nasojejunal (NJ) tube feeding. All received Peptamen AF as a supplement to oral intake. Participants were followed up until discharge or death. FINDINGS: The study evaluated the data for 33 patients for 7 days after tube insertion. Mean daily energy intake for 7 days was 6509 kJ (NG) vs 6605kJ (NJ) (P=0.90). Tubes accidently removed by patients: once (n=16); twice (n=9); three times (n=6), with no differences between NG and NJ. CONCLUSION: There were no significant differences in total nutritional intake between early NG feeding and early NJ feeding 7 days after tube insertion. The number of tube replacements was similar in both groups. Choice of tubes for patients with severe liver disease will depend on individual patient characteristics and needs and local facilities.

ß-Blockers Improve Presinusoidal Portal Hypertension.

BACKGROUND: Presinusoidal portal hypertension is a clinically important cause of gastric and gastroesophageal varices. Whereas ß-blockers have an established prophylactic role against bleeding from esophageal and gastric varices in portal hypertension due to cirrhosis, the effect on presinusoidal portal hypertension is unknown. AIMS: To evaluate the hemodynamic effect of ß-blockers in non-cirrhotic patients with presinusoidal portal hypertension. METHODS: We measured the blood pressure gradient from spleen pulp to free hepatic vein in 12 patients with presinusoidal portal hypertension by combined hepatic vein catheterization and spleen pulp puncture while on and off ß-blocker treatment (random sequence). RESULTS: The ß-blockers reduced the gradient from a mean off-treatment value of 32 mm Hg to a on-treatment value of 26 mm Hg (P < 0.05) with a reduction of at least 20% in five patients (42%). CONCLUSIONS: ß-blocker treatment caused a clinically significant reduction in the pressure gradient from spleen pulp to the free hepatic vein. This finding supports the recommendation for prophylactic ß-blockage in patients with presinusoidal portal hypertension.

Prednisolone but not infliximab aggravates the upregulated hepatic nitrogen elimination in patients with active inflammatory bowel disease.

BACKGROUND: 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. METHODS: 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. RESULTS: 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). CONCLUSIONS: 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.

Renal effects of NO-inhibition in patients with cirrhosis vs. healthy controls: a randomized placebo-controlled crossover study.

BACKGROUND: Nitric oxide (NO) is an important regulator of renal hemodynamics and sodium excretion. Systemic and splanchnic NO-synthesis is increased in liver cirrhosis contributing to the characteristic hyperdynamic circulation. The significance of renal NO in human cirrhosis is not clear. AIMS: In order to clarify the role of NO in the regulation of renal hemodynamics and sodium excretion in human cirrhosis, we studied the effects of N(G)-monomethyl-L-arginine (L-NMMA) - a nonselective NO-inhibitor - on blood pressure (MAP), heart rate (HR), GFR, RPF, UNa × V, FENa, FELi and plasma levels of renin, angII, aldo, ANP, BNP and cGMP in 13 patients with cirrhosis (Child gr.A: 8; Child gr.B+C: 5) and 13 healthy controls. METHODS: The study was randomized and placebo-controlled. Renal hemodynamics were assessed by measuring renal clearance of (51) Cr-EDTA and (125) I-Hippuran for GFR and RPF, respectively. RESULTS: L-NMMA induced a similar, significant increase in MAP in both groups and a more pronounced relative decrease in HR in the CIR group (P = 0.0209, anova). L-NMMA did not change GFR in any group, but RPF decreased significantly in both groups, but most pronouncedly in CIR (P = 0.0478, anova). FENa decreased significantly in both groups after l-NMMA, but the response was again most pronounced in the CIR group (P = 0.0270, anova). All parameters remained stable after placebo. No significant differences were observed between the effects of L-NMMA in Child gr.A vs. Child gr. B+C patients. CONCLUSION: The data supports the hypothesis that renal NO is enhanced in human cirrhosis.

Oral branched-chain amino acids have a beneficial effect on manifestations of hepatic encephalopathy in a systematic review with meta-analyses of randomized controlled trials.

Supplements with branched-chain amino acid (BCAA) have cerebral, metabolic, and nutritional effects that may benefit patients with hepatic encephalopathy (HE). We therefore conducted a systematic review on the effects of oral BCAAs compared with control supplements or placebo for patients with cirrhosis and recurrent overt or minimal HE. The quantitative analyses included data from 8 trials (n = 382 patients). Individual patient data were retrieved from 4 trials to recalculate outcomes (n = 255 patients). The mean dose of the oral BCAA supplements was 0.25 g/(kg body weight · d). Random effects meta-analysis showed that improvements in HE manifestations were registered for 87 of 172 patients in the BCAA group compared with 56 of 210 controls [risk ratio = 1.71 (95% CI: 1.17, 2.51) number needed to treat = 5 patients]. The effect of BCAAs differed (P = 0.04) for patients with overt [risk ratio = 3.26 (95% CI: 1.47, 7.22)] and minimal HE [risk ratio = 1.32 (95% CI: 0.97, 1.79)]. Subgroup, sensitivity, regression, and sequential analyses found no other sources of heterogeneity or bias. BCAA supplements had no effect on mortality or markers of nutritional status and did not induce adverse events. In conclusion, oral BCAA supplements improve manifestations of HE but have no effect on survival.

Lower muscle endurance in patients with alcoholic liver disease.

Patients with alcoholic liver disease often complain of restricted physical capacity, which could be due to decreased muscle endurance. The aim of this study was to assess the muscular endurance in patients with alcoholic liver disease. In a cross sectional study, 24 patients with alcoholic liver disease and 22 controls were evaluated using isometric dynamometry. Endurance was determined during contractions for 3 min elicited by intermittent external electrical stimuli to the femoral quadriceps muscle. Second, endurance was evaluated during voluntary contractions by performance of a maximal isometric knee extension maintained for 1.5 min. Although no difference between patients and controls was found for voluntary contractions, the patients did have lower involuntary muscular endurance. Muscular endurance was not related to lean body mass. Maximal voluntary isometric muscle strength and total work of knee extensors were almost halved in the patients and lower also after correction for differences in lean body mass. In addition to low-muscle strength, patients with alcoholic liver disease have lower involuntary isometric muscular endurance unrelated to lean body mass.

Normalisation of insulin-like growth factor-I does not improve insulin action in cirrhosis.

BACKGROUND & AIMS: Cirrhosis of the liver is characterised by insulin resistance and low levels of insulin-like growth factor I (IGF-I). Lack of IGF-I may contribute to this insulin resistance, as IGF-I increases insulin sensitivity. This study aimed to determine the effects of normalisation of IGF-I on insulin action in cirrhosis. METHODS: This article is a randomised sequence-crossover placebo controlled study. Eight patients with cirrhosis and eight controls were studied following treatment with IGF-I (50 µg/kg twice daily) or saline. Insulin action, glucose utilisation and endogenous glucose production were measured during the euglycaemic hyperinsulinaemic clamp. RESULTS: The patients with cirrhosis had normal fasting glucose level, but increased levels of insulin (P < 0.05) and C-peptide (P < 0.05). Insulin resistance resulted from a defect in glycogen synthesis, whereas insulin-mediated suppression of glucose production was unaltered. In cirrhosis, IGF-I treatment normalised free (from 0.07 ± 0.01 to 0.26 ± 0.05 µg/L) and total IGF-I (from 73 ± 6 to 250 ± 39 µg/L), whereas in controls, the IGF-I level increased into the upper physiological range (free IGF-I from 0.23 ± 0.02 to 0.61 ± 0.06 µg/L; total IGF-I from 200 ± 19 to 500 ± 50 µg/L) (all P-values < 0.05). In cirrhosis, IGF-I treatment did not change fasting glucose, insulin or C-peptide levels (P > 0.05). In the controls, insulin and C-peptide levels decreased (P < 0.05). IGF-I treatment did not improve insulin sensitivity in cirrhosis. CONCLUSIONS: Because normalisation of IGF-I levels did not affect insulin sensitivity lack of IGF-I is unlikely to result in insulin resistance in cirrhosis. IGF-I supplementation is therefore unlikely to improve insulin action in patients with cirrhosis.

Resting myocardial dysfunction in cirrhosis quantified by tissue Doppler imaging.

BACKGROUND: Cirrhotic cardiomyopathy is described as latent cardiac failure. However, it remains to be investigated whether the myocardial dysfunction is present even at rest. AIMS: The aim of the present study was to quantify left ventricular function at rest by means of tissue Doppler imaging in patients with cirrhosis and relate the findings to liver status and cirrhosis aetiology. METHODS: Forty-four consecutive patients and 23 age-matched healthy controls were included. Conventional echocardiographic- and tissue Doppler-derived indices of systolic and diastolic function were obtained. Liver function was quantified by the galactose elimination capacity and clinical stage by the Child-Pugh and MELD scores. RESULTS: Both systolic and diastolic myocardial functions were compromised in the patients at rest. Left ventricular ejection fraction (56.4 ± 6.1 vs. 59.9 ± 3.9%, P<0.02), mean peak systolic tissue velocity (4.6 ± 0.9 vs. 5.6 ± 0.7 cm/s, P<0.001) and mean systolic strain rate (-1.23 ± 0.19 vs. -1.5 ± 0.14/s, P<0.001) were all reduced in cirrhosis patients. Thirty-four patients (54%) had diastolic dysfunction, 11 had impaired diastolic relaxation pattern (25%), 12 had the more severe pseudonormal filling pattern (27%) and one had restrictive filling or severe diastolic dysfunction (2%). None of the echocardiographic findings were related to the cirrhosis aetiology. CONCLUSION: Tissue Doppler imaging during rest detected substantial systolic and diastolic myocardial dysfunction in cirrhotic patients. This supports the existence of a distinct cirrhotic cardiomyopathy.

Unchanged capacity of urea synthesis during acute phase response in rats.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

IL-6 has no acute effect on the regulation of urea synthesis in vivo in rats.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Effects of insulin-like growth factor-I administration on in vivo regulation of urea synthesis in normal subjects and patients with cirrhosis.

BACKGROUND: 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. AIMS: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Tumor necrosis factor-alpha acutely up-regulates urea synthesis in vivo in rats--a hepatic component of inflammatory catabolism?

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.