Florence Lacaille

Irreversible intestinal failure.

Intestinal failure (IF) can be defined as the reduction of functional gut mass below the minimal amount necessary for digestion and absorption adequate to satisfy the nutrient and fluid requirements for maintenance in adults or growth in children. In developed countries, IF mainly includes individuals with the congenital or early onset of conditions requiring protracted or indefinite parenteral nutrition (PN). Short bowel syndrome was the first commonly recognized cause of protracted IF. The normal physiologic process of intestinal adaptation after extensive resection usually allows for recovery of sufficient intestinal function within weeks to months. During this time, patients can be sustained on parenteral nutrition. Only a few children have permanent intestinal insufficiency and life-long dependency on PN. Non-transplant surgery including small bowel tapering and lengthening may allow weaning from PN in some cases. Hormonal therapy with recombinant human growth hormone has produced poor results while therapy with glucagon-like peptide-2 holds promise. Congenital diseases of enterocyte development such as microvillus inclusion disease or intestinal epithelial dysplasia cause permanent IF for which no curative medical treatment is currently available. Severe and extensive motility disorders such as total or subtotal intestinal aganglionosis (long segment Hirschsprung disease) or chronic intestinal pseudo-obstruction syndrome may also cause permanent IF. PN and home-PN remain are the mainstays of therapy regardless of the cause of IF. Some patients develop complications while receiving long-term PN for IF especially catheter related complications (thrombosis, sepsis) and liver disease. These patients may be candidates for intestinal transplantation. This review discusses the causes of irreversible IF and emphasizes the specific medico-surgical strategies for prevention and treatment of these conditions at several stages of IF.

Role of lipid emulsions in cholestasis associated with long-term parenteral nutrition in children.

BACKGROUNDnIn children who depend on long-term parenteral nutrition (PN), liver disease is a major complication that may lead to end-stage liver failure requiring liver transplantation.nnnMETHODSnThis retrospective study investigated the influence of lipid emulsions on cholestasis onset in children receiving long-term total parenteral nutrition (TPN) with lipids. Ten children who presented with a total of 23 episodes of cholestasis, associated in 13 cases with thrombocytopenia, were studied.nnnRESULTSnChanges in the lipid delivery preceded these complications in more than half the cases. The temporary decrease in lipid administration led to normalization of bilirubin in 17 episodes.nnnCONCLUSIONSnThese data suggest that lipid supply is one of the risk factors for PN-associated cholestasis. The link between cholestasis and the reticuloendothelial system overload needs to be better understood. Prevention of cholestasis might include the decrease in the lipid load. When cholestasis occurs, lipid supply should be temporarily stopped, especially in the case of associated thrombocytopenia.

Genetic Modifiers of Liver Disease in Cystic Fibrosis

CONTEXTnA subset (approximately 3%-5%) of patients with cystic fibrosis (CF) develops severe liver disease with portal hypertension.nnnOBJECTIVEnTo assess whether any of 9 polymorphisms in 5 candidate genes (alpha(1)-antitrypsin or alpha(1)-antiprotease [SERPINA1], angiotensin-converting enzyme [ACE], glutathione S-transferase [GSTP1], mannose-binding lectin 2 [MBL2], and transforming growth factor beta1 [TGFB1]) are associated with severe liver disease in patients with CF.nnnDESIGN, SETTING, AND PARTICIPANTSnTwo-stage case-control study enrolling patients with CF and severe liver disease with portal hypertension (CFLD) from 63 CF centers in the United States as well as 32 in Canada and 18 outside of North America, with the University of North Carolina at Chapel Hill as the coordinating site. In the initial study, 124 patients with CFLD (enrolled January 1999-December 2004) and 843 control patients without CFLD were studied by genotyping 9 polymorphisms in 5 genes previously studied as modifiers of liver disease in CF. In the second stage, the SERPINA1 Z allele and TGFB1 codon 10 genotype were tested in an additional 136 patients with CFLD (enrolled January 2005-February 2007) and 1088 with no CFLD.nnnMAIN OUTCOME MEASURESnDifferences in distribution of genotypes in patients with CFLD vs patients without CFLD.nnnRESULTSnThe initial study showed CFLD to be associated with the SERPINA1 Z allele (odds ratio [OR], 4.72; 95% confidence interval [CI], 2.31-9.61; P = 3.3 x 10(-6)) and with TGFB1 codon 10 CC genotype (OR, 1.53; 95% CI, 1.16-2.03; P = 2.8 x 10(-3)). In the replication study, CFLD was associated with the SERPINA1 Z allele (OR, 3.42; 95% CI, 1.54-7.59; P = 1.4 x 10(-3)) but not with TGFB1 codon 10. A combined analysis of the initial and replication studies by logistic regression showed CFLD to be associated with SERPINA1 Z allele (OR, 5.04; 95% CI, 2.88-8.83; P = 1.5 x 10(-8)).nnnCONCLUSIONSnThe SERPINA1 Z allele is a risk factor for liver disease in CF. Patients who carry the Z allele are at greater risk (OR, approximately 5) of developing severe liver disease with portal hypertension.

Real-time blood plasma polymerase chain reaction for management of disseminated adenovirus infection.

We evaluated the usefulness of quantifying blood plasma adenovirus DNA loads for the management of adenovirus infection. Quantification of adenovirus A, B, and C DNA loads was done with real-time polymerase chain reaction (PCR) assays. Blood plasma specimens obtained from 44 immunocompromised patients were screened prospectively with this method. PCR findings for 36 patients were negative, and none of the patients developed disseminated adenoviral disease. PCR findings for 8 patients were positive; all 8 had invasive adenoviral disease and were treated with cidofovir. Sequential measurements of adenovirus DNA loads were performed to monitor the effect of cidofovir therapy. Decrease in the blood plasma DNA load was significantly higher in patients with a good response to cidofovir than in patients with a poor response and was therefore correlated with survival. Detection of adenovirus DNA in blood plasma appears to be useful for identifying patients at risk for invasive disease. Moreover, quantification of adenovirus DNA loads in plasma is helpful for monitoring the efficacy of antiviral therapy.

Early central catheter infections may contribute to hepatic fibrosis in children receiving long-term parenteral nutrition

Background: Bacterial infections in infants constitute a risk factor for parenteral nutrition (PN)–related cholestasis. The possible role of infections in the development of liver fibrosis, the most severe long-term complication, has yet to be documented. This study retrospectively compares the incidence of sepsis in children with and without severe liver fibrosis. Patients and Methods: Medical reports of 30 children in prolonged PN programs between March 1985 and March 2000 were reviewed. Starting at birth, the mean PN duration was 65 months (range, 8–150 months). According to the results of liver biopsy (LB), patients were split into 2 groups: group A (n = 16) with severe liver fibrosis (ie, septal fibrosis involving >50% of portal fields or cirrhosis) and group B (n = 14) with normal hepatic architecture or mild fibrosis (<50% of portal fields). Results: Duration of PN at the time of LB was shorter in group A (30.5 months; range, 8–96 months) than in group B (105 months; range, 37–150 months; P < 0.001). In group A the incidence of sepsis was significantly higher than in group B (3.2 ± 0.3/year vs 1.5 ± 0.2/year) and the first infection occurred earlier (group A, 1 month [range, 1–2 months]; group B, 4 months [range, 1–19 months]). By contrast, both groups were similar in terms of pregnancy duration, birth weight, age of PN onset, underlying diseases, mode of PN delivery, and number of cholestasis episodes. Conclusions: Incidence and early onset of infections may contribute to the development of liver fibrosis in cases of long-term PN. New strategies are required in prevention and treatment of infections in children receiving PN.

New perspectives for children with microvillous inclusion disease: early small bowel transplantation.

Background. Microvillous inclusion disease (MVID) is a congenital intestinal epithelial cell disorder leading to lifelong intestinal failure. Despite long-term total parenteral nutrition, life expectancy is extremely reduced because of metabolic or septic complications or liver failure. Methods. Twelve patients with early-onset MVID were evaluated between 1995 and 2002 for the possibility of small bowel transplantation (SbTx). Three patients died before they could be placed on the waiting list for SbTx, and one patient is still awaiting SbTx. SbTx was contraindicated in one patient. Results. Seven of 12 patients (six boys and one girl) underwent transplantation (three SbTxs and four combined liver-SbTxs). Actuarial survival rates were 100% and 75% in the SbTx and combined liver-SbTx groups, respectively, with a mean follow-up of 3 years (1.1–8.5 years). In contrast, the survival rate was only 40% in the subgroup of five patients who did not undergo transplantation. After transplantation, all patients were weaned from parenteral nutrition: the five patients with an additional colon graft were weaned within 36 days as opposed to the others without colonic transplant who obtained full intestinal autonomy several months after transplantation. The only two surviving patients who did not undergo SbTx remain highly dependent on total parenteral nutrition, which is complicated by repeated episodes of metabolic decompensation. Conclusions. SbTx alone or in combination with the liver is highly successful in children with MVID, offering them a long-term perspective for the first time. Associated colon grafting markedly improves the outcome and quality of life after SbTx in patients with MVID.

Liver biopsy in children: position paper of the ESPGHAN Hepatology Committee.

Liver biopsy (LB) is still the criterion standard procedure for obtaining liver tissue for histopathological examination and a valuable tool in the diagnosis, prognosis, and management of many parenchymal liver diseases. The aim of this position paper is to summarise the present practice of paediatric LB and make recommendations about its performance. Although histological evaluation of the liver is important in assessing prognosis and exploring treatment, noninvasive techniques (ie, imaging, laboratory markers) may replace use of liver histology. The indications for LB are changing as present knowledge of aetiologies, pathomechanism, and therapeutic options in paediatric liver disease is evolving. Adult and paediatric literature was reviewed to assess the existing clinical practice of LB with focus on the technique, indications, risk of complications, and contraindications in paediatrics. This position paper presents types of LB, indications, complications, contraindications, and an essential checklist for paediatric LB.

Microvillous Inclusion Disease: How to Improve the Prognosis of a Severe Congenital Enterocyte Disorder

Background and Objective: Microvillous inclusion disease (MVID) is a rare congenital enterocyte disorder causing severe diarrhea and intestinal failure. The objective of this study was to analyze clinical evolution and the most frequent complications of MVID in children receiving parenteral nutrition (PN) and after small-bowel transplantation (SBTx) with the aim to improve treatment strategies and prognosis. Patients and Methods: From 1995 to 2009, 24 patients (16 boys, median follow-up 4.7 years, range: from birth to 23.5 years) with MVID were admitted to our unit. The recorded parameters included growth, neurological development, liver and renal functions, bone disease, and outcome. Results: Almost half of the children were from consanguineous families from the Mediterranean area. All of the patients completely depended on PN. Four children died of PN complications before 4 years of age. Before or without SBTx, growth failure was common (mean height −2.5 standard deviations [SD]), as was developmental delay (12/24), liver (20/22 with fibrosis) or kidney disease (3/23 with moderate renal insufficiency), and osteoporosis (6/24). Thirteen children underwent SBTx (9 isolated, 4 combined with liver Tx) at a median age of 3.5 years. Follow-up after SBTx was 0.4 to 14 years. Patient survival rates were 63% without SBTx and 77% with SBTx. After SBTx, 4 children experienced catch-up growth. Conclusions: PN in MVID is difficult to manage and requires expertise. Despite improved results in expert centers, the risk of death or irreversible sequelae is higher with PN than after Tx. SBTx, despite being complicated, remains the only hope to improve the quality of life and long-term prognosis of these children.

Intestinal transplantation in children: preliminary experience in Paris.

From November 1994 to November 1998, 20 children (2.5 to 14 years) received a jejunoileal graft alone (SBTx; n = 10) or in combination with the liver (SBLTx; n = 10 and/or the right colon (5 SBTx). Indications were intractable diarrhea of infancy (n = 8), short bowel syndrome (n = 6), extensive Hirschsprung disease (n = 4), and chronic intestinal pseudoobstruction (n = 2). Immunosuppression included tacrolimus, methylprednisolone, and azathioprine. Current follow-up ranges from 6 to 54 months. Five patients died (3 SBTx) within the first 2 months. Acute liver rejection occurred in 5 patients during the first 2 months. Sixteen episodes of intestinal rejection during the first 3 months in 11 patients (8 in 4 SBTx) were successfully treated in all but 3 by increasing tacrolimus dose and/or a 3-day methyprednisolone bolus or required antilymphoglobulins in 3 cases. Surgical complications occurred 8 times after SBLTx and 3 after SBTx. Infectious complications were more frequent in SBLTx recipients. Reversible Epstein-Barr virus-related posttransplant lymphoproliferative disease occurred in 3 recipients. Five presented cytomegalovirus infection. The SB graft was removed in 5 recipients (3 chronic rejection). All patients were started with oral and/or enteral feeding from the 7th postoperative day by using either normal food or protein hydrolysate diet. Currently, 10 of 11 children (8 SBLTx) achieved digestive autonomy after 5 to 30 weeks. All recipients gained weight; however, growth velocity remained reduced during the first 6 months because of the steroid therapy. Overall graft and patient survival is higher after SBLTx. Intestinal transplantation is indicated for patients with permanent intestinal failure. However, because parenteral nutrition is generally well tolerated, even for long periods, each indication for transplantation must be weighed carefully in terms of risk and quality of life.

Intestinal transplantation: indications, results and strategy.

The term ‘intestinal failure’ is now often used to describe gastrointestinal function insufficient to satisfy body nutrient and fluid requirements. The first recognized condition of intestinal failure was short bowel syndrome. Severe motility disorders such as chronic intestinal pseudo-obstruction syndrome in children as well as congenital intractable intestinal mucosa disorders are also forms of intestinal failure, because no curative treatment for these diseases is yet available. Parenteral nutrition and home parenteral nutrition remain the mainstay of therapy for intestinal failure, whether it is partial or total, provisional or permanent. However, some patients develop complications while receiving standard therapy for intestinal failure and are considered for intestinal transplantation. Indeed, recent advances in immunosuppressive treatment and the better monitoring and control of acute rejection have brought intestinal transplantation into the realm of standard treatment for intestinal failure. Although it has been used in humans for the past two decades, this procedure has had a slow learning curve. According to the current results, this challenging procedure may be performed in children or adults, only under certain conditions.