Catherine Lenaerts

Meconium ileus and its equivalent as a risk factor for the development of cirrhosis: an autopsy study in cystic fibrosis

Although dehydrated obstructing mucus is thought to account for the obstructive pathology involving the lungs, the pancreas, the reproductive system, and the intestinal tract, its relationship with CF-associated liver disease remains largely hypothetical and little is known about possible risk factors. Complete clinical and autopsy records were available in 38 of 73 deaths occurring over a 10-year period. The liver was normal in only five cases, and they were all infants. Steatosis was the only lesion present in 9, hypoxic liver disease was documented in 8, and biliary cirrhosis in 16 (focal in 10 and multilobular in 6). There was no relationship between the presence of cirrhosis, gallbladder abnormalities, age at death, and clinical status recorded during the year precoding their demise. Mucus plugs characterized by amorphous eosinophilic material within proliferated bile ductules were present in 75% of children with focal or multilobular biliary cirrhosis as opposed to 14% in those without (p = 0.015). A history of meconium ileus or its equivalent was recorded more frequently (p = 0.038) in those with cirrhosis. Finally, biliary cirrhosis was invariably present when there was a history of meconium ileus or its equivalent and when mucus plugs were noted. These findings suggest that patients with intestinal obstruction are at greater risk for the development of cirrhosis and that strategies should be developed to increase the detergent capacity of bile and its flow in order to decrease the viscosity of mucus in the biliary tree.

Ursodeoxycholic acid improves the hepatic metabolism of essential fatty acids and retinol in children with cystic fibrosis

OBJECTIVE Several clinical trials of ursodeoxycholic acid (UDCA) have shown improvement of liver-function test results in cystic fibrosis (CF) with liver disease; however, there is no evidence that the long-term course will be affected. In view of the observations that UDCA can change the lipid profile and that patients with CF and liver disease are more likely to have essential fatty acid (EFA) deficiency, we elected to examine changes in the lipid profile and in the status of fat-soluble vitamins in response to UDCA. METHODS Nineteen children with CF and liver dysfunction were recruited for a double-blind, crossover study of 1 years duration, followed by treatment of the entire group. UDCA was administered at a dosage of 15 mg/kg per day, which, in the absence of a 50% decrease of alanine transaminase or aspartate transaminase or both within 2 months, was increased to 30 mg/kg per day. RESULTS At entry, all patients had biochemical evidence of EFA deficiency. The lipid profiles during an average period of 25 months of follow-up showed a significant decrease in triglycerides (p <0.002), cholesterol (p <0.02), and total fatty acids (p <0.006). In addition, UDCA therapy led to an improvement in EFA status, as indicated by an increase (p <0.05) in the n-6 fatty acid concentration and a reduction (p <0.04) in the 20:3n-9/20:4n-6 fatty acid ratio. Although no change in vitamin E levels was observed, retinol metabolism was altered. There was an increase (p <0.02) in the unesterified retinol/retinol binding protein molar ratio in the absence of a difference in retinol binding protein concentration. Furthermore, retinyl esters, which normally account for less than 3% of circulating retinol, decreased (p <0.05) from 13.7% +/- 3.6% to 8.1% +/- 1.7%. CONCLUSIONS This study confirms that UDCA alters lipoprotein metabolism and shows that it improves the EFA and retinol status of patients with CF and liver disease.

Surveillance for cystic fibrosis-associated hepatobiliary disease: early ultrasound changes and predisposing factors

OBJECTIVE To investigate routine ultrasonography (US) as an early marker and to identify risk factors for the development of cirrhosis and portal hypertension (PHT) in cystic fibrosis (CF). STUDY DESIGN A cohort of 106 children with CF aged 5.9+/-2.3 years were followed for 10.4+/-0.2 years in a CF clinic. RESULTS At enrollment, the US was normal, but biochemical and/or clinical disease was present in 10%. By the end of the study, 19 had developed US changes, eight with evidence of PHT. At the time of the initial US change, only 36.4% of those had, at the end of the study, either a heterogeneous or a nodular parenchyma, and only 50% of those with PHT had biochemical and/or clinical disease. Of the 30 patients treated with ursodeoxycholic acid for biochemical and/or clinical disease with (n=15) and without (n=15) associated US changes, PHT developed in six of the former and two of the latter. Univariate analysis and logistic regression showed that children with more severe disease in terms of forced expiratory volume in one second were at somewhat greater risk (P<.06) of PHT developing. CONCLUSION US was an early marker of liver disease and more severe CF disease, a predictor of progressive liver disease. A controlled trial should be done to assess isolated US-detected disease as an indication for UDCA.

AIRE gene analysis in children with autoimmune hepatitis type I or II.

The present report describes AIRE gene analysis in 25 children with autoimmune hepatitis type I or II. The heterozygous transversion c.961C > G (p.Ser278Arg) located in exon 7 was identified in 4 patients with autoimmune hepatitis type I, and mostly in those presenting with a positive family history for autoimmune diseases. In this subgroup of patients, the allelic frequency of this polymorphic variant was at least 3-fold higher than in healthy controls. These results suggest that heterozygous AIRE gene mutation may represent a genetic predisposition to childhood autoimmune hepatitis type I.

Evaluation of guidelines for management of familial adenomatous polyposis in a multicenter pediatric cohort.

Objective: To retrospectively assess, in a pediatric multicenter cohort, guidelines for the management of familial adenomatous polyposis (FAP). Methods: Ten centers from the French-speaking Pediatric Gastroenterology Hepatology and Nutrition Group provided follow-up data on patients up to 18 years of age. Clinical records, genetic test results, endoscopy with histopathology examination, and therapeutic modalities were reviewed. Results: A total of 70 children from 47 families were included. When initial consultation resulted from a surveillance program because of an affected family member, 12 of 59 children were already symptomatic. Among 11 patients whose initial consultation was based only on symptoms, families were unaware at the time of a familial FAP history for 7 children, whereas only 4 cases were sporadic. A panel of 27 different pathogenic adenomatous polyposis coli (APC) germ-line mutations and large genomic deletions were identified in 43 families. Extracolonic manifestations were found in half of the patients. As part of the standard practice for initial screening, the entire cohort underwent colonoscopy, which revealed adenoma above an intact rectosigmoid in 8 cases. Prophylactic colectomy was performed in 42 cases; high-grade dysplastic adenoma and 1 invasive carcinoma were detected in 6 children. For timing of surgery, indications were in accordance with recent international guidelines. Conclusions: Defining optimal screening and therapeutic modalities in pediatric FAP cohorts is a challenge. Specific advice for genetic screening, endoscopy surveillance, and type of surgery based on recent guidelines is recommended.

EVALUATION OF TYROSINEMIC CHILDREN FOR LIVER TRANSPLANTATION

We evaluated 19 patients (8/12-16 8/12 years) with Tyrosinemia for possible liver transplantation. Ten children had repeated neurological crises (severe paresthesias, automutilation, paralysis), and 12 had evidence of renal disease as assessed by a GFR < 60 (4), Fanconi-like syndrome (5), nephromegaly with or without nephrocalcinosis (10). The following liver tests were abnormal; AST/ALT (12), Alk. Phos. (8), bilirubin (5), γ GT (13), PT (11), PTT (7), albumin (6). Portal hypertension was present in 8 patients. Nodules were present on liver imaging in 10 children, with α fetoprotein (AFP) levels ranging from normal to 33000 ng/ml. Of the 8 whole livers available for histological examination, 2 contained foci of hepatocarcinoma. No relationship between AFP, hepatocarc inoma, or the presence of nodules could be found. Five children had a liver transplant, and 2 a combined liver-kidney transplant (one of the two died from primary non-function of the liver graft). The 6 remaining transplanted patients are alive and thriving with normal liver tests, and none have had recurrence of neurological crises. Two patients died while on the waiting list and 3 during severe neurological crises. Liver transplantation cures the hepatic metabolic disease, protects from the development of hepatocarcinoma, and prevents further neurological crises. Combined liver-kidney transplantation should be considered in children with low CFRs in light of the long-term effects of CSA.

81. UPPER GI TRACT INVOLVEMENT IN CHILDREN WITH CROHN'S DISEASE

Crohns disease may affect any part of the GI tract but involvement proximal to the jejunum (UGI) is considered uncommon. Among 228 Crohns disease patients diagnosed over the past 15 years, 73(32%) had UGI disease. Duodenal lesions were most commonly noted followed by gastric and esophageal. Although in 70% of cases, there was concordance between Xray and endoscopic findings, UGI Crohns disease was endoscopically documented in 9/32 with normal Xrays. Epithelioid, multinucleated cells or granulomas were found in 30% of biopsies while chronic inflammatory changes were present in the others. A peptic disease type of pain or postprandial nausea or vomiting was present in 2/3 of cases. There was no increase in the incidence of extra-intestinal manifestations in those with UGI disease except for aphtous lesions of the mouth (50%). In only 5 patients was the disease limited to the UGI tract. Of 31 cases with terminal ileitis, less than 20% had UGI compared to an incidence of 30% in the 151 with ileocolitis and than 40% in colitis. Of interest was the fact that radiological and endoscopic findings pointed erroneously to a diagnosis of ulcerative colitis in 12.3% of the patients with UGI. This study demonstrates a high incidence of Crohns disease proximal to the jejunum in children and suggests that an upper endoscopy should be carried out whenever chronic IBD is suspected.