Marie-Astrid Piquet

Glucocorticoids plus N-Acetylcysteine in Severe Alcoholic Hepatitis

BACKGROUND Mortality among patients with severe acute alcoholic hepatitis is high, even among those treated with glucocorticoids. We investigated whether combination therapy with glucocorticoids plus N-acetylcysteine would improve survival. METHODS We randomly assigned 174 patients to receive prednisolone plus N-acetylcysteine (85 patients) or only prednisolone (89 patients). All patients received 4 weeks of prednisolone. The prednisolone-N-acetylcysteine group received intravenous N-acetylcysteine on day 1 (at a dose of 150, 50, and 100 mg per kilogram of body weight in 250, 500, and 1000 ml of 5% glucose solution over a period of 30 minutes, 4 hours, and 16 hours, respectively) and on days 2 through 5 (100 mg per kilogram per day in 1000 ml of 5% glucose solution). The prednisolone-only group received an infusion in 1000 ml of 5% glucose solution per day on days 1 through 5. The primary outcome was 6-month survival. Secondary outcomes included survival at 1 and 3 months, hepatitis complications, adverse events related to N-acetylcysteine use, and changes in bilirubin levels on days 7 and 14. RESULTS Mortality was not significantly lower in the prednisolone-N-acetylcysteine group than in the prednisolone-only group at 6 months (27% vs. 38%, P = 0.07). Mortality was significantly lower at 1 month (8% vs. 24%, P = 0.006) but not at 3 months (22% vs. 34%, P = 0.06). Death due to the hepatorenal syndrome was less frequent in the prednisolone-N-acetylcysteine group than in the prednisolone-only group at 6 months (9% vs. 22%, P = 0.02). In a multivariate analysis, factors associated with 6-month survival were a younger age (P<0.001), a shorter prothrombin time (P<0.001), a lower level of bilirubin at baseline (P<0.001), and a decrease in bilirubin on day 14 (P<0.001). Infections were less frequent in the prednisolone-N-acetylcysteine group than in the prednisolone-only group (P = 0.001); other side effects were similar in the two groups. CONCLUSIONS Although combination therapy with prednisolone plus N-acetylcysteine increased 1-month survival among patients with severe acute alcoholic hepatitis, 6-month survival, the primary outcome, was not improved. (Funded by Programme Hospitalier de Recherche Clinique; AAH-NAC ClinicalTrials.gov number, NCT00863785 .).

Semi-elemental formula or polymeric formula: is there a better choice for enteral nutrition in acute pancreatitis? Randomized comparative study.

BACKGROUND Jejunal nutrition is recommended during acute pancreatitis. The use of semi-elemental formulas presents several theoretical advantages over polymeric formulas, but their clinical value has been poorly documented. Our aim was to evaluate in patients with acute pancreatitis the effect of enteral nutrition by a semi-elemental formula compared with a polymeric formula. METHODS A randomized prospective pilot study, stratified according to severity, was performed in 30 consecutive patients with acute pancreatitis requiring jejunal nutrition. The semi-elemental group received 35 kcal/kg/d of Peptamen (n = 15), and the polymeric group received the same quantity of Sondalis-Iso (n = 15). Tolerance was evaluated after 7 days of enteral nutrition (D7) on visual analog scale (VAS), stool frequency, and 24-hour steatorrhea/creatorrhea. Outcome was evaluated by weight loss, length of hospital stay, and infection rate. RESULTS Results were calculated as mean +/- SEM, t-test, or chi2. Patients of the 2 groups were comparable in terms of age, gender, and severity. Tolerance was good in both groups (semi-elemental vs polymeric: VAS, 7.4 +/- 0.6 vs 7.1 +/- 0.6, not significant (NS); number of stools per 24 hours, 1.7 +/- 0.4 vs 1.8 +/- 0.4, NS). Steatorrhea and creatorrhea were lower than normal in both groups. In semi-elemental group, the length of hospital stay was shorter (23 +/- 2 vs 27 +/- 1, p = .006) and weight loss was less marked (1 +/- 1 vs 2 +/- 0, p = .01). One patient in semi-elemental group and 3 patients in polymeric group developed an infection (NS). CONCLUSIONS Semi-elemental and polymeric nutrition are very well tolerated in patients with acute pancreatitis. Nutrition with a semi-elemental formula supports the hypothesis of a more favorable clinical course than nutrition with a polymeric formula, but this conclusion needs to be established in larger adequately powered clinical trials.

Cardiac sources of embolism should be routinely screened in ischemic colitis

OBJECTIVES:Potential cardiac sources of embolism may promote ischemic colitis. The aim of this study was to evaluate their role in segmental, nongangrenous ischemic colitis and to determine the usefulness of routine cardiac evaluation in patients with this disease.METHODS:Sixty case and 60 control patients matched for age and gender were included and questioned regarding treatment and prior cardiovascular history or risk factors. Potential cardiac sources of embolism, classified as “proven” or “still debated,” were screened using an electrocardiogram, rhythmic Holter monitoring over 24 h, and transthoracic echocardiography.RESULTS:Sex ratio (male:female) was 1:2, and mean age was 70 ± 14 yr. Case and control patients had similar drug use, prior cardiovascular history, and risk factors. A potential cardiac source of embolism was found in 26/60 case (43%), compared with 14/60 control patients (23%) (p = 0.02; OR = 2.5, 95% CI = 1.2–5.5). Excluding the “still debated,” 21/60 case (35%), compared with 8/60 control patients (13%), had a “proven” cardiac source of embolism (p < 0.01; OR = 3.5, 95% CI = 1.4–8.4). Electrocardiogram alone misdiagnosed 72% of the “proven” cardiac sources of embolism, whereas the combination electrocardiogram plus Holter monitoring detected 71%, and electrocardiogram plus echocardiography 62%. Twelve of 21 case patients with at least one proven cardiac source of embolism, were previously unknown. Anticoagulant therapy was required in 32% of case patients and antiarrhythmic therapy in 25% of cases.CONCLUSIONS:Potential cardiac sources of embolism were more common in patients with segmental, nongangrenous ischemic colitis than in control patients. Therefore, these patients should undergo a routine electrocardiogram, rhythmic Holter monitoring, and transthoracic echocardiography. Anticoagulant therapy should also be considered for this patient population.

Mitochondrial Adaptation to in vivo Polyunsaturated Fatty Acid Deficiency: Increase in Phosphorylation Efficiency

Polyunsaturated fatty acid (PUFA) deficiency affects respiratory rate both in isolated mitochondria and in hepatocytes, an effect that is normally ascribed to major changes in membrane composition causing, in turn, protonophoriclike effects. In this study, we have compared the properties of hepatocytes isolated from PUFA-deficient rats with those from control animals treated with concentrations of the protonophoric uncoupler 2,4-dinitrophenol (DNP). Despite identical respiratory rate and in situ mitochondrial membrane potential (ΔΨ), mitochondrial and cytosolic ATP/ADP–Pi ratios were significantly higher in PUFA-deficient cells than in control cells treated with DNP. We show that PUFA-deficient cells display an increase of phosphorylation efficiency, a higher mitochondrial ATP/ADP–Pi ratio being maintained despite the lower ΔΨ. This is achieved by (1) decreasing mitochondrial Pi accumulation, (2) increasing ATP synthase activity, and (3) by increasing the flux control coefficient of adenine nucleotide translocation. As a consequence, oxidative phosphorylation efficiency was only slightly affected in PUFA-deficient animals as compared to protonophoric uncoupling (DNP). Thus, the energy waste induced by PUFA deficiency on the processes that generate the proton motive force (pmf) is compensated in vivo by powerful adaptive mechanisms that act on the processes that use the pmf to synthesize ATP.

Oxidative phosphorylation in intact hepatocytes: Quantitative characterization of the mechanisms of change in efficiency and cellular consequences

Two mechanisms may affect the yield of the oxidative phosphorylation pathway in isolated mitochondria: (i) a decrease in the intrinsic coupling of the proton pumps (H+/2ea or H+/ATP), and (ii) an increase in the inner membrane conductance (proton or cation leak). Hence three kinds of modifications can occur and each of them have been characterized in isolated rat liver mitochondria (see preceding chapter by Rigoulet et al.). In intact isolated hepatocytes, these modifications are linked to specific patterns of bioenergetic parameters, i.e. respiratory flux, mitochondrial redox potential, DY, and phosphate potential.

Enteral nutrition in adult Crohn's disease : Present status and perspectives

Enteral nutrition has long been a therapeutic alternative often used in adult Crohns disease patients to obtain remission or clinical response, especially in those not responding to conventional therapy such as corticosteroids. However, the increasing use of immunosuppressors (6-mercaptopurine and azathioprine, methotrexate, etc.), and the advent of biotherapies (especially anti-tumor necrosis factor-alpha (TNF-alpha) antibodies), decreased its use in adult Crohns disease. Nevertheless, enteral nutrition remains of interest in patients presenting concomitant malnutrition (in particular in nonobstructed patients needing surgery), or in those intolerant or who failed to other therapeutics. In addition, recent studies provide data indicating its potential interest in maintenance therapy in selected patients groups. Finally, future research (in particular in the field of immuno- or pharmaconutrition) could lead to enteral formulas improvement, with better tolerance and acceptability, as well as increased efficacy.

Feasibility of Self-Propelling Nasojejunal Feeding Tube in Patients With Acute Pancreatitis

BACKGROUND & AIMS To assess the success rate of a self-propelling nasojejunal feeding tube in patients with acute pancreatitis. METHODS All patients admitted for acute pancreatitis were included. A self-propelling nasojejunal feeding tube was introduced into the stomach, and gastrointestinal motility was stimulated using metoclopramide. If the tube failed to advance to the ligament of Treitz, a nasojejunal tube was placed endoscopically. RESULTS A total of 108 patients, 94 with necrotizing pancreatitis (Balthazar D/E) and 14 with nonnecrotizing pancreatitis (Balthazar B/C), were referred for artificial nutrition. In 11 cases, ileus persisted and parenteral nutrition was initiated. Among the remaining 97 patients, 5 refused tube placement. The self-propelling feeding tube was inserted in 92 patients with successful migration to the ligament of Treitz in 61% (n = 56) and failure in 39% (n = 36). Of the 36 patients with an initial failed placement, endoscopic placement of a nasojejunal tube was successful 80% of the time (29 patients). The success rate of a nasojejunal self-propelling feeding tube placement correlated directly with the severity of the acute pancreatitis (92% in B/C vs 61% in D vs 48% in E; P < .05). CONCLUSIONS Use of a self-propelling nasojejunal tube is a simple technique that can be successfully performed in the majority of patients with acute pancreatitis. The utility of this procedure in the most severe cases of acute pancreatitis continues to pose a challenge.

Flux-force relationships in intact cells: a helpful tool for understanding the mechanism of oxidative phosphorylation alterations?

On isolated mitochondria, numerous studies of the relationships between fluxes and their associated forces have led to the description of some properties of the oxidative phosphorylation pathway. However whether such an approach can be applied to understanding the actual situation in intact living cells needs further consideration. In this study on isolated hepatocytes, we describe the dependence of the respiratory rate on the three thermodynamic forces linked to oxidative phosphorylation (i.e. the redox span over the respiratory chain, the electrical potential difference across the inner mitochondrial membrane and the free energy of ATP synthesis reaction). Even if this description is phenomenological and some objections may be raised regarding the relevance of such a bulk-phase force estimation, we present some results showing that the study of flux-force relationships in intact cells may be a helpful approach for understanding the mechanisms by which oxidative phosphorylation activity is changed.

Traitements nutritionnels au cours des MICI :où en est-on ?

Resume Une denutrition proteino-energetique et des carences specifiques sont frequentes au cours des maladies inflammatoires chroniques intestinales (MICI), plus particulierement en cas de maladie de Crohn. Chez l’adulte, l’utilisation de la nutrition artificielle est indiquee en cas de denutrition, de syndrome du grele court, ou de MICI refractaire a tous traitements. Chez l’enfant, la nutrition enterale a une place en premiere intention afin d’eviter les effets secondaires de la corticotherapie sur la croissance. L’utilisation comme outil therapeutique de nutriments specifiques (acides gras n-3, glutamine, vitamines et mineraux anti-oxydants, TGF-β, aliments riches en probiotiques, …) semble interessante sur le plan physiopathologique. Neanmoins, ces nutriments sont encore en cours d’evaluation et les etudes disponibles ne permettent pas de les recommander en routine clinique. Une voie tres prometteuse est l’utilisation des probiotiques pour le traitement des pochites refractaires.

Increased oro-cecal transit time in grade I or II hepatic encephalopathy.

UNLABELLED The pathogenic mechanisms of hepatic encephalopathy remain to be elucidated. It has been suggested that a digestive motor disorder could promote the absorption of toxins produced within the lumen and thus enhance hepatic encephalopathy. AIM To evaluate oro-cecal transit time in cirrhotic patients with and without hepatic encephalopathy. METHODS Hospitalized patients with alcoholic cirrhosis without encephalopathy and with spontaneous grade I and II encephalopathy were included. Severity of hepatic encephalopathy was assessed clinically and the Child-Pugh score was used to describe cirrhosis severity. Nine healthy volunteers constituted a control group. Oro-cecal transit time was measured with the sulfasalazine test. RESULTS Twenty-eight patients (mean age 62.5 +/- 8.5 years) were included. Ten had hepatic encephalopathy of unknown cause and 18 were free of hepatic encephalopathy. Oro-cecal transit time was significantly longer in patients with hepatic encephalopathy (641 +/- 350 min) compared to patients without hepatic encephalopathy (298 +/- 96; P<0.05) and to controls (354 +/- 90; P<0.05). Oro-cecal transit time was comparable for each Child-Pugh score and was not different between the two grades of hepatic encephalopathy. CONCLUSION Oro-cecal transit time is longer in alcoholic cirrhosis patients with hepatic encephalopathy. This digestive motor disorder provides a partial explanation of hepatic encephalopathy of unknown etiology.