Metabolic investigations prevent liver transplantation in two young children with citrullinemia type I

Acute liver failure may be caused by a variety of disorders including inborn errors of metabolism. In those cases, rapid metabolic investigations and adequate treatment may avoid the need for liver transplantation. We report two patients who presented with acute liver failure and were referred to our center for liver transplantation work-up. Urgent metabolic investigations revealed citrullinemia type I. Treatment for citrullinemia type I avoided the need for liver transplantation. Acute liver failure as a presentation of citrullinemia type I has not previously been reported in young children. Although acute liver failure has occasionally been described in other urea cycle disorders, these disorders may be underestimated as a cause. Timely diagnosis and treatment of these disorders may avoid liver transplantation and improve clinical outcome. Therefore, urea cycle disorders should be included in the differential diagnosis in young children presenting with acute liver failure

Reduced absorption of long-chain fatty acids during methotrexate-induced gastrointestinal mucositis in the rat

<p>Background & aims: Patients with chemotherapy-induced gastrointestinal mucositis suffer from weight loss and possibly malabsorption. Since long-chain fatty acids serve important functions in the body, we aimed to determine the intestinal capacity of fat absorption in rats with and without methotrexate-induced mucositis.</p><p>Methods: Four days after intravenous injection with methotrexate (60 mg/kg) or saline, rats received saturated ([U-C-13]palmitic acid) and unsaturated ([U-C-13]linoleic acid) fatty acids dissolved in oil, either as a single bolus by oral gavage or by continuous intraduodenal infusion. We determined plasma and liver label concentrations at specific time points.</p><p>Results: We confirmed methotrexate-induced mucositis by villus atrophy using microscopy. Methotrexate treatment severely reduced the appearance of [U-C-13]palmitic- and [U-C-13]linoleic acid in plasma and liver, compared to controls, either when administered as a bolus or continuously (all at least -63%, P <0.05). Liver [U-C-13]palmitic acid appearance was higher than [U-C-13]linoleic acid appearance, either when administered as a bolus (2.8-fold, P <0.01) or continuously (5.7-fold, P <0.01).</p><p>Conclusions: The intestinal capacity to absorb long-chain fatty acids is severely reduced in rats with methotrexate-induced mucositis. Continuous administration does not overcome this impairment. The liver takes up and/or retains mainly saturated fatty acids during mucositis. (C) 2012 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.</p>

Intestinal capacity to digest and absorb carbohydrates is maintained in a rat model of cholestasis

Cholestasis is associated with systemic accumulation of bile salts and with deficiency of bile in the intestinal lumen. During the past years bile salts have been identified as signaling molecules that regulate lipid, glucose, and energy metabolism. Bile salts have also been shown to activate signaling routes leading to proliferation, apoptosis, or differentiation. It is unclear, however, whether cholestasis affects the constitution and absorptive capacity of the intestinal epithelium in vivo. We studied small intestinal morphology, proliferation, apoptosis, expression of intestinespecific genes, and carbohydrate absorption in cholestatic ( 1 wk bile duct ligation), bile- deficient ( 1 wk bile diversion), and control ( sham) rats. Absorptive capacity was assessed by determination of plasma [ H-2]- and [ C-13] glucose concentrations after intraduodenal administration of [ 2H] glucose and naturally enriched [ 13C] sucrose, respectively. Small intestinal morphology, proliferation, apoptosis, and gene expression of intestinal transcription factors ( mRNA levels of Cdx- 2, Gata- 4, and Hnf- 1 alpha, and Cdx- 2 protein levels) were similar in cholestatic, bile- deficient, and control rats. The ( unlabeled) blood glucose response after intraduodenal administration was delayed in cholestatic animals, but the absorption over 180 min was quantitatively similar between the groups. Plasma concentrations of [ 2H] glucose and [ 13C] glucose peaked to similar extents in all groups within 7.5 and 30 min, respectively. Absorption of [ 2H] glucose and [ 13C] glucose in plasma was similar in all groups. The present data indicate that neither accumulation of bile salts in the body, nor their intestinal deficiency, two characteristic features of cholestasis, affect rat small intestinal proliferation, differentiation, apoptosis, or its capacity to digest and absorb carbohydrates

Laxative treatment with polyethylene glycol decreases microbial primary bile salt dehydroxylation and lipid metabolism in the intestine of rats

<p>Polyethylene glycol (PEG) is a frequently used osmotic laxative that accelerates gastrointestinal transit. It has remained unclear, however, whether PEG affects intestinal functions. We aimed to determine the effect of PEG treatment on intestinal sterol metabolism. Rats were treated with PEG in drinking water (7%) for 2 wk or left untreated (controls). We studied the enterohepatic circulation of the major bile salt (BS) cholate with a plasma stable isotope dilution technique and determined BS profiles and concentrations in bile, intestinal lumen contents, and feces. We determined the fecal excretion of cholesterol plus its intestinally formed metabolites. Finally, we determined the cytolytic activity of fecal water (a surrogate marker of colorectal cancer risk) and the amount and composition of fecal microbiota. Compared with control rats, PEG treatment increased the pool size (+51%; P <0.01) and decreased the fractional turnover of cholate (-32%; P <0.01). PEG did not affect the cholate synthesis rate, corresponding with an unaffected fecal primary BS excretion. PEG reduced fecal excretion of secondary BS and of cholesterol metabolites (each P <0.01). PEG decreased the cytolytic activity of fecal water [54 (46-62) vs. 87 (85-92)% erythrocyte potassium release in PEG-treated and control rats, respectively; P <0.01]. PEG treatment increased the contribution of Verrucomicrobia (P <0.01) and decreased that of Firmicutes (P <0.01) in fecal flora. We concluded that PEG treatment changes the intestinal bacterial composition, decreases the bacterial dehydroxylation of primary BS and the metabolism of cholesterol, and increases the pool size of the primary BS cholate in rats.</p>

Delayed immune recovery following sequential orthotopic liver transplantation and haploidentical stem cell transplantation in erythropoietic protoporphyria

A nine-yr-old boy with EPP suffered from severe skin burns and liver failure caused by progressive cholestasis and fibrosis. OLT was performed without major complications. Four months following liver transplantation he underwent parental haploidentical HSCT. The myeloablative conditioning regimen was relatively well tolerated and hematological engraftment was rapid (on day 10). Protoporphyrin concentrations returned to normal following HSCT. However, immune recovery was significantly delayed. Varicella zoster virus reactivation resulted in impaired vision, prolonged hospitalization and eventually in multiorgan failure and death. Sequential liver and haploidentical HSCT proved feasible though a high risk procedure in this EPP patient. The management of post-IST after these combined transplantations remains a challenge and needs to be further established