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BACKGROUND: Pancreatic enzyme replacement therapy frequently fails to correct intestinal fat malabsorption completely in cystic fibrosis (CF) patients. The reason for this failure is unknown. OBJECTIVE: We investigated whether fat malabsorption in CF patients treated with pancreatic enzymes is caused by insufficient lipolysis of triacylglycerols or by defective intestinal uptake of long-chain fatty acids. DESIGN: Lipolysis was determined on the basis of breath 13CO2 recovery in 10 CF patients receiving pancreatic enzyme replacement therapy after they ingested 1.3-distearoyl,2[1-13C]octanoyl glycerol ([13C]MTG). Intestinal uptake of long-chain fatty acids was determined by analyzing plasma [13C]linoleic acid ([13C]LA) concentrations after patients ingested [13C]LA. For 3 d, dietary intakes were recorded and feces were collected. RESULTS: Fecal fat excretion ranged from 5.1 to 27.8 g/d (mean+/-SD: 11.1+/-7.0 g/d) and fat absorption ranged from 79% to 93% (89+/-5%). There was no relation between breath 13CO2 recovery and dietary fat absorption (r = 0.04) after ingestion of [13C]MTG. In contrast, there was a strong relation between 8-h plasma [13C]LA concentrations and dietary fat absorption (r = 0.88, P < 0.001). CONCLUSION: Our results suggest that continuing fat malabsorption in CF patients receiving enzyme replacement therapy is not likely due to insufficient lipolytic enzyme activity, but rather to incomplete intraluminal solubilization of long-chain fatty acids, reduced mucosal uptake of long-chain fatty acids, or both. Copyright (c) 1999 American Society for Clinical Nutrition [ABSTRACT FROM AUTHOR]

Background: Data on the frequency of resolution of anaphylaxis to foods are not available, but such resolution is generally assumed to be rare., Objective: To determine whether the frequency of negative challenge tests in children with a history of anaphylaxis to foods is frequent enough to warrant challenge testing to re-evaluate the diagnosis of anaphylaxis, and to document the safety of this procedure., Methods: All children (n=441) who underwent a double-blind, placebo-controlled food challenge (DBPCFC) between January 2003 and March 2007 were screened for symptoms of anaphylaxis to food by history. Anaphylaxis was defined as symptoms and signs of cardiovascular instability, occurring within 2 h after ingestion of the suspected food., Results: Twenty-one children were enrolled (median age 6.1 years, range 0.8-14.4). The median time interval between the most recent anaphylactic reaction and the DBPCFC was 4.25 years, range 0.3-12.8. Twenty-one DBPCFCs were performed in 21 children. Eighteen of 21 children were sensitized to the food in question. Six DBPCFCs were negative (29%): three for cows milk, one for egg, one for peanut, and one for wheat. In the positive DBPCFCs, no severe reactions occurred, and epinephrine administration was not required., Conclusions: This is the first study using DBPCFCs in a consecutive series of children with a history of anaphylaxis to foods, and no indications in dietary history that the food allergy had been resolved. Our study shows that in such children having specific IgE levels below established cut-off levels reported in other studies predicting positive challenge outcomes, re-evaluation of clinical reactivity to food by DBPCFC should be considered, even when there are no indications in history that anaphylaxis has resolved. DBPCFCs can be performed safely in these children, although there is a potential risk for severe reactions.

Background: The vast majority of children will undergo their first exposure to common allergenic foods at home. However, the first exposure may lead to clinical reactions. It has been proposed to introduce allergenic foods gradually into the diets of children at risk for food allergy, but no practical dietary advice has been devised., Objective: The aim of this study was to devise safe introduction schedules for common allergenic foods for use at home, based on the challenge doses as administered in double-blind, placebo-controlled food challenge (DBPCFCs) in children who were never exposed previously to these foods., Methods: Seventy-two DBPCFCs were performed in 63 children as a first known exposure. The incrementing challenge doses were converted into equivalent portions of these foods in their usual household form and incorporated in introduction schedules. The feasibility of the introduction scales was tested in parents of the children attending our clinic., Results: Based on the results of the positive challenges (37) in which severe reactions did not occur, detailed introduction schedules and a reference photograph of the required increasing amounts of food were devised for use at home. Feasibility testing showed that, when using these introduction schedules, parents portioned the initial doses significantly lower than without detailed instructions., Conclusions: The introduction schedules and reference photograph provide information for parents to introduce the required amounts of allergenic foods in initial low doses at home. This is expected to improve the safety of this procedure.

Between November 1982 and March 2006, 67 children with body weight < or =10 kg had a primary liver transplantation from deceased donors in our unit. The aim of this study was to analyze the outcome in terms of patient and graft survival and to search for factors affecting this outcome. Overall, one-, three-, five-, and 10-yr primary patient and graft survival rates were 73%, 71%, 66%, 63% and 59%, 56%, 53%, 48%, respectively. Twenty-four of 67 (36%) children died and in the remaining 22 (33%), the first grafts failed and they were retransplanted. Cox regression analysis revealed that a need for retransplantation and urgent transplantation were important predictors for patient survival (p = 0.04 and p = 0.001, respectively). To assess whether the need for retransplantation can be influenced, all study variables were compared between surviving grafts and failed grafts. Cox regression analysis showed that only donor/recipient (D/R) weight ratio proved to be independent predictor for graft survival (p = 0.004). After comparison of graft survival with the long rank test according to different D/R weight ratios (3.0-7.0), the cut-off point for significantly different graft survival approached 4.0. The one-, three-, five-, and 10-yr graft survival for technical variant grafts with a D/R weight ratio <4.0 was 85%, 68%, 68%, and 68% compared with a D/R weight ratio >4.0 was 44%, 38%, 38%, and 30%, respectively (p = 0.02). In summary, patient survival in children with body weight < or =10 kg is determined by urgent transplantation and the need for retransplantation. Graft loss and retransplantation in small children can be prevented by adequate size matching of donor and recipient whereby a D/R weight ratio <4.0 seems to offer the favorable outcome.

Background: Growth assessment can be used to monitor health at individual and population level. For asylum seekers' children with different geographic backgrounds, growth reference values are frequently not available. We assessed nutritional condition and growth of asylum seekers' children upon arrival and follow-up in The Netherlands, using national growth charts, and related these parameters to geographic origin., Methods: Height and weight of 135 children originating from Africa (n=47), Central Asia (n=41), and Eastern Europe (n=47), were assessed longitudinally (median follow-up 3 years, range 1-8 years). Body-mass-index (BMI) was calculated, and overweight and obesity were defined according the international BMI cut-off values for age and gender., Results: Upon arrival at a median age of 4.5 years (range 0-11.5 years), 13% of the children were small for age (below -2 SD of the Dutch height for age reference), which decreased to 5% during follow-up (P<0.05). During follow-up, 90% of the height measurements in boys and 85% in girls were within the normal range (+/-2 SD) of the Dutch references. The proportion of children with overweight including obesity increased from 15% at arrival to 21% during follow-up (P<0.05). Irrespective of age, children originating from Africa were taller than children from Central Asia or Eastern Europe at follow up (P<0.05). Overweight and obesity was most prominent among children of Eastern Europe., Conclusion: Dutch national reference values allow monitoring growth and the development of overweight or obesity in asylum seekers' children in The Netherlands. Prevention strategies to reduce the development of overweight and obesity among these children seem warranted.

Objectives: To investigate, in asylum seekers' children in the Netherlands, biochemical iron status and the prevalence of iron deficiency (ID) and anemia in relation to age, region of origin, length of stay in the Netherlands, body mass index (BMI), and dietary iron intake., Patients and Methods: Hemoglobin (Hb) and plasma ferritin concentrations were determined in 122 asylum seekers' children (median age, 7.1 years; range, 2-12 y). ID was defined by plasma ferritin levels <15 microg/L. Anemia was defined by Hb levels <6.8 mmol/L (11 g/dL) for children <6 years of age and Hb levels <7.1 mmol/L (11.5 g/dL) for children between 6 and 12 years of age. Nutritional status of the children was assessed by BMI and dietary intake of iron was estimated by 24-hour recall., Results: Twenty percent of the children had compromised iron status (16% with ID, 4% with ID anemia [IDA]). Another 6% of the children had anemia caused by thalassemia. ID was significantly more prevalent in children <6 years of age and in children of African origin. The iron status was not significantly correlated with the length of stay in the Netherlands (r = 0.6; P = 0.48). Higher BMI z scores were positively correlated with iron status. Adequate or marginal dietary iron intake was not significantly related to the presence of ID (r = 0.02; P = 0.9) or anemia (IDA and thalassemia; r = 0.15; P = 0.9)., Conclusions: Iron deficiency is highly prevalent among the children of asylum seekers in the Netherlands. Our data indicate that systematic biochemical screening for ID is warranted in asylum seekers' children.

Background: A cardinal feature of the double-blind, placebo-controlled food challenge (DBPCFC) is that placebo administration is included as a control. To date, the occurrence and diagnostic significance of placebo events have not extensively been documented., Objective: To analyse the occurrence and features of placebo events in DBPCFCs and to assess their contribution to the diagnostic accuracy of the DBPCFC in children., Methods: The study population consisted of 132 challenges in 105 sensitized children (age range 0.7-16.6 years, median 5.3 years), who underwent DBPCFCs with cow's milk, egg, peanut, hazelnut and soy. Placebo and active food challenges were performed on different days., Results: A total number of 17 (12.9%) positive placebo events occurred, which could be classified as immediate (9/17), late-onset (8/17), objective (11/17) or subjective (6/17). Four of 74 (5.4%) positive active food challenges were revealed to be false positive by administration of a placebo challenge. This is 3% (4/132) of all challenges. When computed by a statistical model, the false positive rate was 0.129 (12.9% of all challenges)., Conclusion: Placebo events with diverse clinical characteristics occur in DBPCFCs in a significant number of children. The diagnostic significance of the administration of a placebo challenge is first, to identify false positive diagnoses in DBPCFCs by refuting false positive tests in individual patients. Secondly, to allow for blinding of the active food challenge. Thirdly, applying a statistical model demonstrates that some positive challenges may be false positive and that the test may need to be repeated in selected cases.

Low dietary intake and limited sun exposure during Dutch winters, in particular when combined with highly pigmented skin, could compromise the vitamin D status of asylum seekers' children in The Netherlands. We determined the vitamin D status of children living in The Netherlands, but originating from Africa, Central Asia, or Eastern Europe. In a subgroup, we reassessed the vitamin D status after the summer, during which the children had been assigned at random to remain unsupplemented or to receive vitamin D supplementation. In total 112 children (median age 7.1 yr, range 2-12 yr) were assessed for serum concentrations of 25-Hydroxyvitamin D [25(OH)D], intact parathyroid hormone (I-PTH) and plasma alkaline phosphatase (ALP). Vitamin D deficiency (VDD) and hypovitaminosis D were defined as 25(OH)D below 30 or 50 nmol/L, respectively. Dietary intake of vitamin D and calcium was estimated using a 24 h recall interview. In mid-spring, 13% of the children had VDD, and 42% had hypovitaminosis D. I-PTH and ALP levels were significantly higher in children with VDD. The dietary intake of vitamin D was below 80% of the recommended daily allowances (RDA) in 94% of the children, but the dietary calcium intake was not significantly related to the s-25(OH)D levels found. After the summer, median s-25(OH)D increased with +35 nmol/L (+85%) and +19 nmol/L (+42%) in children with or without supplementation, respectively. The effect of supplementation was most prominent among African children. VDD and hypovitaminosis D are highly prevalent in mid-spring among asylum seekers' children in The Netherlands. Although 25(OH)D levels increase in African children during Dutch summer months, this does not completely correct the compromised vitamin D status. Our data indicate that children from African origin would benefit from vitamin D supplementation.

Objective: To monitor the dietary intake of energy, macro- and micronutrients in asylum seeker children., Design and Setting: Cross-sectional study in three asylum seeker centres in The Netherlands., Subjects: Hundred and sixteen children 2-12 years old (86% of the study cohort) provided a dietary history., Method: The dietary intake was estimated by 24 h recall, and the origin of the children was classified in three geographic regions: African (n=45), Central Asia (n=34) or Eastern Europe (n=37)., Results: The total energy intake from fat was in 24% of the children above 40En%. Seventy per cent of the children above 4 year of age had a saturated fat intake above 10En%. The children from Eastern Europe had a higher intake of fat and disaccharides than the children from the other regions. Among the children, an intake less than 80% of the recommended daily allowances of micronutrients was found for calcium (42%), iron (49%), vitamin A (45%) and vitamin D (80%). An inadequate dietary intake of iron and vitamin D was significantly more seen among the youngest children, whereas an inadequate intake of calcium and vitamin A was found more among the elder children., Conclusions: The dietary intake of a prominent proportion of these children contains too much fat and insufficient amounts of calcium, iron, vitamin A and vitamin D. The low micronutrient intake of the asylum seeker children can be considered as a nutritional risk. Nutritional education and strategies to improve the macro- and micronutrient intake of asylum seeker children is indicated.

Objective: The purpose of this investigation was to verify if avoidance of allergenic foods in children adhering to a food allergen avoidance diet from birth was complete and feasible, and whether dietary assessment can be used as a tool in predicting the outcome of double-blind, placebo-controlled food challenges (DBPCFCs)., Design: Children adhering to an allergen avoidance diet from birth underwent DBPCFCs. The investigator-dietician verified whether the elimination was complete, using food frequency questionnaires for common allergenic foods., Setting: University Medical Centre Groningen, the Netherlands., Subjects: Thiry-eight children aged 1-13 years, who were consecutively referred to the University Medical Centre Groningen for DBPCFC between January 2002 and February 2004., Results: Among the 38 children undergoing DBPCFCs, there were 15 challenges with egg, 15 with peanut, five with hazelnut and three with soy. Fifteen food challenges (39%) were positive. Small quantities of allergenic foods were inadvertently present in the diets of 13 patients (34%), were possibly present in the diets of 14 patients (37%) and could not be identified in the diets of 11 patients (29%). Seven patients (54%) who had inadvertently ingested small quantities of allergenic foods without sequelae had a positive DBPCFC., Conclusion: Dietary avoidance was incomplete and not feasible in most cases. Tolerance of small amounts of allergenic foods does not preclude positive challenge reactions. Dietary assessment does not seem a useful tool in predicting the outcome of DBPCFC in children adhering to an elimination diet., Sponsorship: The Stichting Astma Bestrijding (Foundation for the Prevention of Asthma), The Netherlands.

Background: Tyrosinemia type I is associated with an increased risk of liver cancer development. The formation of the pathogenic fumarylacetoacetate is prevented by 2-(2-nitro-4-3 trifluoro-methylbenzoyl)-1,3-cyclohexanedione (NTBC). Still, some patients with NTBC treatment develop liver cancer. A rise of alpha-fetoprotein (AFP) is an indicator of liver cancer., Aim: To study the predictive value of AFP in tyrosinemia type I patients for the discrimination between patients at high and low risk of liver cancer development., Methods: We examined the course of AFP values of 11 Dutch patients with tyrosinemia type I treated by NTBC, of whom four were diagnosed with liver cancer., Results: The four patients with liver cancer had a course of AFP different from the other patients in either velocity of the decrease of AFP, achieving normal AFP and/or having a rise of AFP concentrations., Conclusion: Apart from a rise of AFP, a slow AFP decrease, and never normalizing levels of AFP are important predictors of liver cancer development in further life.

It is unclear whether cyclosporine A (CsA) can be withdrawn safely during follow-up after pediatric liver transplantation. In our transplant program we have been using a strict protocol to withdraw CsA. The aim of this study was to retrospectively assess the effects of CsA withdrawal after pediatric liver transplantation on the incidence of rejection and renal function. Between 1986 and 2001, 91 children received CsA for at least 2 yr after liver transplantation. Specific criteria for eligibility to withdraw CsA were set. In 53 of the 91 children CsA was withdrawn. In 35 patients (66%) withdrawal of CsA did not cause rejection. In these patients the renal function improved compared with baseline values (glomerular filtration rate (GFR) at 1 yr, +16 mL/minute/1.73 m3, P < 0.001; at 2 yr, +10 mL/minute/1.73 m3, P < 0.05). After CsA withdrawal, 18 patients developed rejection (34%), which could be effectively treated by methylprednisolone and restarting CsA. Failure to withdraw CsA was not associated with increased incidence of graft loss. A body weight below 10 kg at the time of transplantation correlated significantly with successful withdrawal of CsA (<10 kg, 85% vs. > 10 kg, 60%; P < 0.05). In conclusion CsA can successfully be withdrawn in a major proportion of selected pediatric liver transplantation patients during follow-up. The success rate is the highest in children with a body weight below 10 kg at the time of transplantation. Successful withdrawal improves renal function, whereas failure to withdraw is not associated with graft loss or persisting morbidity., (Copyright 2006 AASLD)

Intestinal transplantation for intestinal failure is no longer an experimental procedure, but an accepted treatment for patients who fail total parenteral nutrition (TPN) therapy. Early referral for evaluation for small bowel transplantation has to be considered in patients with permanent intestinal failure who have occlusion of more than two major veins, frequent line-related septic episodes, impairment of liver function or an unacceptable quality of life. With the increased experience in post-transplant patient care and newer forms of induction (thymoglobulin, IL-2 receptor antagonists) and maintenance (tacrolimus) therapies the 1-year graft survival has increased to 65% for isolated and to 59% for liver/small bowel transplantation, and is further improving. Rejection, bacterial, fungal and viral (CMV, EBV) infection, post-transplant lymphoproliferative disease (PTLD) and graft versus host disease (GvHD) are the most common complications after intestinal transplantation. Although most of the long-term survivors are TPN-independent and have a good quality of life, the risk of the procedure and long-term adverse effects of immunosuppressive medication limits small bowel, or liver/small bowel transplantation only to patients with severe complications of TPN therapy.

Esophageal cancer development after previous atresia repair is extremely rare in young patients. We present the clinical course of a patient who developed an adenocarcinoma of the esophagus at the age of 22 years, after repair of a tracheoesophageal fistula with esophageal atresia in the neonatal period. She developed a stricture of the esophageal anastomosis requiring frequent dilatations. Six years after an antireflux procedure because of a difficult treatable severe gastroesophageal reflux, an advanced adenocarcinoma was detected at the site of the end-to-end anastomosis of the previous atresia.

The aim of this study was to analyze the effect of human leukocyte antigen (HLA) class I and HLA-DR mismatching, sharing cross-reactive antigen groups (CREGs), and sharing HLA-DR antigens on the outcome after pediatric liver transplantation. Outcome parameters were graft survival, acute rejection, and portal fibrosis. A distinction was made between full-size (FSLTx) and technical-variant liver transplantation (TVLTx). A total of 136 primary transplants were analyzed. The effect of HLA on the outcome parameters was analyzed by adjusted multivariate logistic and Cox regression analysis. HLA mismatches, shared CREGs, and shared HLA-DR antigens affected neither overall graft survival nor survival after FSLTx. Survival after TVLTx was superior in case of 2 mismatches at the HLA-DR locus compared to 0 or 1 mismatch (P = 0.01) and in case of no shared HLA-DR antigen compared to 1 shared HLA-DR antigen (P = 0.004). The incidence of acute rejection was not influenced by HLA. The incidence of portal fibrosis could be analyzed in 62 1-yr biopsies and was higher after TVLTx than FSLTx (P = 0.04). The incidence of portal fibrosis after TVLTx with 0 or 1 mismatch at the HLA-DR locus was 100% compared to 43% with 2 mismatches (P = 0.004). After multivariate analysis, matching for HLA-DR and matching for TVLTx were independent risk factors for portal fibrosis. In conclusion, an overall beneficial effect of HLA matching, sharing CREGs, or sharing HLA-DR antigens was not observed. A negative effect was present for HLA-DR matching and sharing HLA-DR antigens on survival after TVLTx. HLA-DR matching might be associated with portal fibrosis in these grafts.

Small bowel transplantation for intestinal failure is no longer an experimental procedure, but an accepted treatment for patients where total parenteral nutrition (TPN) therapy for intestinal failure is unsuccessful. Early referral for screening for small bowel transplantation should be considered in patients with permanent intestinal failure who have occlusion of more than 2 major veins, frequent line-related septic episodes, impairment of liver function or an unacceptable quality of life. With the increased experience in post-transplant patient care and newer forms of induction (thymoglobulin, IL-2 receptor antagonists) and maintenance (tacrolimus) therapies, the 1-year graft survival has increased to 65% for isolated and to 59% for liver/small bowel transplantation and is further improving. Rejection, bacterial, fungal and viral (Cytomegalovirus, Epstein-Barr-virus) infections, post-transplant lymphoproliferative disease and graft versus host disease are the most common complications after intestinal transplantation. Although most of the long-term survivors are TPN-independent and have a good quality of life, the risk of the procedure and long-term adverse effects ofimmunosuppressive medication limits small bowel, or liver/small bowel transplantation only to patients with severe complications of TPN therapy.

Three children, 2 boys aged 5 and 4 years, and 1 girl aged 2 years, who suffered from intestinal failure as a result of a short bowel syndrome and who were dependent on total parenteral nutrition (TPN), were screened for small bowel transplantation. The girl also had progressive liver failure. Each child had a clear indication for either isolated small bowel or combined small bowel/liver transplantation. All three children were enrolled in an intestinal rehabilitation program because they were referred early. The intestinal rehabilitation consisted of a systematic analysis of the absorptive capacity of the residual intestine, optimizing enteral and parenteral feeding, prevention of catheter sepsis and further deterioration of liver function. The rehabilitation was performed in an in-patient setting. All three children were partially weaned from TPN, while their growth improved. None of the children were consequently listed for small bowel transplantation. When a child is initially referred for small bowel transplantation, intestinal rehabilitation should be considered as part of an intestinal transplantation program.

Hereditary tyrosinaemia type I is an autosomal recessive inborn error of tyrosine catabolism caused by a deficiency of the enzyme fumarylacetoacetase that results in liver failure, hepatocellular carcinoma, renal tubular dysfunction and acute intermittent porphyria. When treated with liver transplantation, tyrosinaemia type I was considered to be cured. Some years after the first liver transplantations in these patients, some reports focused on the renal function after transplantation. These reports showed that urinary succinylacetone excretion remained but that tubular function normalized. In this report we discuss the long-term renal follow-up (mean follow-up time 11 years, range 7-14 years) after liver transplantation in 9 patients with tyrosinaemia type I treated by liver transplantation in our centre. An evaluation was made of renal function and succinylacetone excretion in urine. In all patients we found a persistent excretion of succinylacetone in the urine. With respect to the glomerular function, we can conclude that there is no clear change in GFR. At the same time, tubulopathy persisted in some patients. We consider that excretion of metabolites such as succinylacetone will be an important contributing factor to tubular dysfunction after liver transplantation in patients with tyrosinaemia type I. Therefore, notwithstanding the major effect of liver transplantation on tyrosine metabolism, renal tubular dysfunction remains at risk and needs careful monitoring. Progressive tubular dysfunction can cause glomerular damage. The use of low-dose NTBC might be considered after liver transplantation in case of tubulopathy to prevent progression of tubular and glomerular dysfunction.

A few months after birth two sisters aged 5 and 9 years had developed cholestasis and abnormal liver functions with symptoms including itching and jaundice. The younger sister also developed rickets and clotting disorders. On clinical, biochemical and immunohistopathological grounds the diagnosis of 'progressive familial intrahepatic cholestasis (PFIC) type 2' was made. Medical treatment was not succesfull in reducing symptoms. An ileocolonic bypass in the younger child was not effective. Subsequently, both patients underwent partial external biliary diversion (PEBD). Except for a period of intermittent itching in the younger child, both patients remained free of symptoms 2 years after PEBD. In cases where an early diagnosis is made, PEBD could delay or even prevent the necessity of liver transplantation.

Multidrug resistance associated proteins (MRPs) and P-glycoprotein (P-gp) are involved in hepatobiliary transport of various compounds. Our aim was (1) to define transporter specificity of the cholescintigraphic agents 99mTc-HIDA and 99mTc-MIBI, which are used clinically for myocardial perfusion measurements; and (2) to deduce MRP and P-gp functions in vivo from hepatic 99mTc kinetics. Accumulation of radioactivity was measured in the human tumor cell lines GLC4, GLC4/ADR150x (MRP1-overexpressing/P-gp-negative) and GLC4/P-gp (P-gp-overexpressing). Bile secretion was quantified in untreated and in glutathione-depleted control and MRP2-deficient (GY/TR-) rats. Hepatobiliary transport was measured using a gamma camera in both types of rats. 99mTc-HIDA accumulated 5.8-fold less in GLC4/ADR150x calls than in GLC4 or GLC4/P-gp cells. In GLC4/ADR150x, the cellular 99mTc-HIDA content was increased 3.4-fold by the MRP1,2 inhibitor MK571 (50 microM), while MK571 had no measurable effect in GLC4 and GLC4/P-gp cells. 99mTc-MIBI accumulated less in GLC4/P-gp and GLC4/ADR150x cells than in GLC4 cells. Bile secretion of 99mTc-HIDA was impaired in GY/TR- compared to control rats and not affected by glutathione depletion in GY/TR- rats. Hepatic secretion of 99mTc-HIDA was slower in GY/TR- (t1/2 40 min) than in control rats (t1/2 7 min). Bile secretion of 99mTc-MIBI was similar in both rat strains and impaired by glutathione depletion in control rats only, indicating compensatory activity of additional transporter(s) in GY/TR- rats. 99mTc-HIDA is transported only by MRP1,2 only, while 99mTc-MIBI is transported by P-gp and MRP1,2. The results indicate that hepatic P-gp and MRP1,2 function can be assessed in vivo by sequential use of both radiopharmaceuticals.

Hyperlipidemia is a common side effect of cyclosporine A (CsA) after solid organ transplantation. CsA also markedly reduces the synthesis rate of bile salts in rats and can inhibit biliary bile salt secretion. It is not known, however, whether CsA inhibits the synthesis of bile salts in humans, and whether the hyperlipidemic effects of CsA are related to bile salt metabolism. Our objective was to assess the effects of CsA on the synthesis rate of bile salts and on plasma triglycerides and cholesterol levels in pediatric liver transplant patients. Before and after discontinuation of CsA treatment after liver transplantation, synthesis rate and pool size of the primary bile salts cholate and chenodeoxycholate were determined using a stable isotope dilution technique and related to plasma lipids. In 6 children (age: 3-16 years) CsA treatment was discontinued at 2 years (median 2.3 years) after liver transplantation. Discontinuation of CsA increased synthesis rate of chenodeoxycholate (+38%, P <.001) and cholate (+21%, P <.05) and the pool size of chenodeoxycholate (+54%, P <.001). Discontinuation of CsA decreased plasma levels of cholesterol (-18%, P <.05) and triglycerides (-23%, P <.05). Bile salt synthesis rate appeared to be inversely correlated with plasma cholesterol (Spearman rank correlation coefficient [r(s)] = -0.82, P <.01) and plasma triglyceride levels (r(s) = -0.62, P <.05). In conclusion, CsA inhibits bile salt synthesis and increases plasma concentration of cholesterol and triglycerides in pediatric liver transplant patients. Suppression of bile salt synthesis by long-term CsA treatment may contribute to hyperlipidemia and thus to increased risk for cardiovascular disease.

Unlabelled: Post-transplant lymphoproliferative disease (PTLD) is one of the major causes of morbidity and mortality in transplantation patients. A primary Epstein-Barr virus (EBV) infection is a major risk factor for developing PTLD. The aim of this study was to determine circulating EBV DNA after liver transplantation in pediatric patients in relation to primary EBV infection and development of PTLD. EBV serology was performed before transplantation. Every 4 weeks after transplantation a competitive quantitative polymerase chain reaction (PCR) assay for EBV nuclear antigen-1 was performed in 13 patients. Patients were followed for development of a PTLD. Before transplantation four patients were EBV seropositive and nine patients were EBV seronegative. In one of the four patients who were EBV seropositive before transplantation, EBV DNA became detectable after transplantation, with a peak load of 3600 copies/mL. None of these four patients developed a PTLD. Eight of the nine patients who were EBV seronegative before transplantation developed positive EBV DNA samples. EBV DNA was first detected at a mean of 64 days after transplantation (range 38-89). The mean peak EBV DNA load was 79,700 copies/mL (3600-446,000). Two of these patients developed PTLD, but they could not be identified based on prior or concomitant EBV PCR results., Conclusions: In pediatric liver transplantation EBV DNA load is higher in patients with a primary infection than in patients who were EBV seropositive before transplantation. The EBV PCR cannot be used to identify individual patients who develop PTLD. However, elevated EBV DNA load can be used to detect a group of patients at increased risk for PTLD.

Background: The use of double-blind, placebo-controlled food challenges (DBPCFCs) is considered the gold standard for the diagnosis of food allergy. Despite this, materials and methods used in DBPCFCs have not been standardized., Objective: The purpose of this study was to develop and validate recipes for use in DBPCFCs in children by using allergenic foods, preferably in their usual edible form., Methods: Recipes containing milk, soy, cooked egg, raw whole egg, peanut, hazelnut, and wheat were developed. For each food, placebo and active test food recipes were developed that met the requirements of acceptable taste, allowance of a challenge dose high enough to elicit reactions in an acceptable volume, optimal matrix ingredients, and good matching of sensory properties of placebo and active test food recipes. Validation was conducted on the basis of sensory tests for difference by using the triangle test and the paired comparison test. Recipes were first tested by volunteers from the hospital staff and subsequently by a professional panel of food tasters in a food laboratory designed for sensory testing. Recipes were considered to be validated if no statistically significant differences were found., Results: Twenty-seven recipes were developed and found to be valid by the volunteer panel. Of these 27 recipes, 17 could be validated by the professional panel., Conclusion: Sensory testing with appropriate statistical analysis allows for objective validation of challenge materials. We recommend the use of professional tasters in the setting of a food laboratory for best results.

The two most common inherited forms of colorectal cancer are familial adenomatous polyposis and hereditary non-polyposis colorectal cancer. Simultaneous inheritance of both an APC gene mutation and a mismatch repair gene (for example, MLH1) mutation has never been described. In the present case report, we report rapidly progressive adenomatous polyposis in a 10 year old boy with a germline frame shift mutation in the APC gene and a germline splice site mutation in the MLH1 gene. Immunohistochemical investigations showed abnormal expression of beta-catenin in early adenomas with low grade dysplasia, attributed to the APC gene mutation. Subsequent loss of function of the MLH1 gene, as shown by absent immunostaining of its protein in adenomas with high grade dysplasia, may well have caused the rapid progression to high grade dysplasia in many of the adenomas.

A boy suffered from severe recurrent intestinal infections from the age of 8 months onwards; investigation into an immune disorder ultimately resulted in the diagnosis of 'hyper-IgM syndrome'. He was treated successfully with bone marrow transplantation, using an HLA-matched donor. Another boy had severe recurrent respiratory tract infections from the age of 3 months onwards. At the age of 6.5 years, 'hyper-IgM syndrome' was diagnosed. No suitable donor was available. In addition, he developed sclerosing cholangitis and end-stage liver disease, making a combined bone marrow and liver transplantation too risky. He died at 10.5 years of age. X-linked hyper-IgM syndrome is a rare congenital immunodeficiency disorder, characterised by a defect in both humoral and cellular immune responses. Deficiency in the membrane glycoprotein CD40 ligand (expressed on activated T-cells) compromises T-cell interactions with antigen-presenting cells. In a child with severe recurrent infections, and with dysgammaglobulinaemia with a normal or increased IgM level, the diagnosis of 'X-linked hyper-IgM syndrome' should be considered.

Objectives: To evaluate Near-Infrared Analysis (NIRA) method for determining fecal fat, water and nitrogen., Design and Methods: The results of fecal fat, water and nitrogen by NIRA were compared with results of van de Kamer and Acid Steatocrit (AS), Dumas and vacuum drying methods for fat, nitrogen and water respectively. Results of fat determining methods were also compared with total fecal energy as obtained by bomb calorimeter., Results: NIRA results correlated significantly (p < 0.001) with standard methods for nitrogen (r = 0.79), fat (r = 0.84 and r = 0.88 for van de Kamer and AS respectively) and water (r = 0.91). The limits of agreement for nitrogen and fat results were too wide for the methods to be used interchangeably. The fecal fat results correlated significantly (p < 0.001) with fecal energy results., Conclusion: NIRA may be valuable for monitoring malabsorption but the diagnostic value remains to be determined.

The familial cholestatic diseases Benign Recurrent Intrahepatic Cholestasis (BRIC) and Progessive Familial Intrahepatic Cholestasis type 1 (PFIC1) are characterized by intermittent or permanently elevated plasma bile salt levels, therapy-resistant extreme pruritus and peculiar biochemical abnormalities including low apolipoprotein apo A-I. Previously, symptomatic improvement has been demonstrated in BRIC patients after extracorporal albumin dialysis (MARS). We hypothesized that MARS improves cholestasis, induces changes in the bile salt profile and normalizes apo A-I serum levels in BRIC. A 17-year-old-female patient with BRIC experienced an episode of cholestasis lasting for more than 6 months with extreme pruritus and diarrhoea not responding to standard therapy. During a period of five days the patient was treated 3 x 8 h with MARS. The procedures were well tolerated and resulted in reduction of plasma bile salts by 58%. The plasma bile salt profile changed into a more hydrophilic composition after MARS. Diarrhoea discontinued and the pruritus improved significantly from 9 to 4 on a subjective scale. These effects lasted 4 months until a relapse occurred. Low plasma apo A-I levels (0.52 g/l) normalized after MARS (0.98 g/l). The procedures were well tolerated. Fatigue was noted as the only transient side-effect. In conclusion, MARS may induce a long-term symptomatic improvement and decrease of cholestatic markers in BRIC. Further studies evaluating efficacy and mechanism of MARS in patients with BRIC are needed.

Objective: To describe the epidemiology and causes of graft loss after pediatric liver transplantation and to identify risk factors., Summary Background Data: Graft failure after transplantation remains an important problem. It results in patient death or retransplantation, resulting in lower survival rates., Methods: A series of 157 transplantations in 120 children was analyzed. Graft loss was categorized as early (within 1 month) and late (after 1 month). Risk factors were identified by analyzing recipient, donor, and transplantation variables., Results: Kaplan-Meier 1-month and 1-, 3-, and 5-year patient survival rates were 85%, 82%, 77%, and 71%, respectively. Graft survival rates were 71%, 64%, 59%, and 53%, respectively. Seventy-one of 157 grafts (45%) were lost: 18 (25%) by death of patients with functioning grafts and 53 (75%) by graft-related complications. Forty-five grafts (63%) were lost early after transplantation. Main causes of early loss were vascular complications, primary nonfunction, and patient death. Main cause of late graft loss was fibrosis/cirrhosis, mainly as a result of biliary complications or unknown causes. Child-Pugh score, anhepatic phase, and urgent transplantation were risk factors for early loss. Donor age, donor/recipient weight ratio, blood loss, and technical-variant liver grafts were risk factors for late loss., Conclusions: To prevent graft loss after pediatric liver transplantation, potential recipients should be referred early so they can be transplanted in an earlier phase of their disease. Technical-variant liver grafts are risk factors for graft survival. The logistics of the operation need to be optimized to minimize the length of the anhepatic phase.

Unlabelled: Metabolic diseases (MD) are the second largest indication group for orthotopic liver transplantation (OLTx) in children after biliary atresia (BA). A better outcome after transplantation can be expected because of a better pretransplant condition and the absence of previous abdominal surgery. To prove this statement, patient survival, graft survival, and morbidity were compared between a group of 24 for MD and 52 for BA consecutively transplanted children. The actuarial one- and five-year patient survival rates for MD were 96% and 84%, and for BA 84% and 70%, respectively (p logrank test = 0.17). Three MD children (13%) and 15 BA children (29%) died. The actuarial one- and five-year graft survival rates for MD were 75% and 58%, and for BA 75% and 64%, respectively (p logrank test = 0.76). Seven MD children (29%) and 11 BA children (21%) were retransplanted. Postoperative bleeding and gastrointestinal complications occurred less frequent (4% vs. 18% and 4% vs. 14%, respectively), whereas biliary complications, viral infections, and acute rejection occurred more frequently (38% vs. 21%, 29% vs. 15%, and 50% vs. 37%, respectively) in MD children. The difference in the incidence of the various postoperative complications between both groups was not statistically significant. The mean ICU and ventilator stay was 7.5 and four days, respectively, in MD children and 16 and 10 days, respectively, in BA children (p = ns). The mean infection, complication, intervention, and retransplantation rate was equal in both groups., Conclusion: Mortality and morbidity after pediatric liver transplantation for MD and BA are not different despite the better starting point for children with MD.

Background: Because of the poor outcome of hepatic retransplantation, it is still debated whether this procedure should be performed in an era of donor organ scarcity. The aim of this study was to analyze outcome of hepatic retransplantation in children, to identify risk factors influencing this outcome, and to assess morbidity and causes of death., Methods: A series of 97 children after a single transplantation and 34 children with one retransplantation was analyzed., Results: The 1-, 3-, and 5-year survival of children with a retransplantation was 70, 63, and 52%, respectively, compared with 85, 82, and 78%, respectively, for children after a single transplantation (P=0.009). Survival of children with a retransplantation within 1 month after primary transplantation was worse (P=0.007) and survival of children with a late retransplantation was comparable (P=0.66) with single transplantation. In early retransplantations, the Child-Pugh score was higher, donors were older and weighed more, and more technical variant liver grafts were used compared with single transplantations. Biliary atresia and a high Child-Pugh score were associated with decreased patient survival after retransplantation. Sepsis was the most important complication and cause of death after retransplantation., Conclusions: Retransplantation is a significant event after pediatric liver transplantation. Outcome after hepatic retransplantation in children is inferior compared with single transplantation. This difference is explained by low survival after early retransplantation and can be explained by the poor clinical condition of the children at time of retransplantation, especially in children with biliary atresia, and by the predominant use of technical variant liver grafts in retransplantations.

Background: Recent histopathological studies showed an unexpected high incidence of pathological changes in asymptomatic survivors after pediatric liver transplantation. The aim of this study was to analyze the occurrence of histological abnormalities, to assess the clinical significance, and to identify predictive factors for these pathological changes., Methods: The first annual protocol graft biopsies of 84 consecutive liver transplants were analyzed and correlated with concomitant liver function tests. Identification of predictive factors for the histological abnormalities in the biopsies was performed by a multivariate logistic regression analysis., Results: The incidence of portal fibrosis (PF) was 31%. Liver function tests showed except for the albumin level, an increase in the PF group compared with the group without PF. Mean values of alkaline phosphatase and direct bilirubin were 264 U/liter and 3 micromol/liter, respectively, in the normal group, and 435 U/liter and 23 micromol/liter, respectively, in the PF group (P=0.043 and 0.037). Eight of 19 univariantly tested variables were entered into a logistic regression model: cold ischemia time, preservation solution, type of allograft, cytomegalovirus recipient status, type of biliary reconstruction, biliary complications, graft complications, and rejection. A significant positive correlation with PF was found for cold ischemia time, biliary complications, and cytomegalovirus status. Acute rejection showed a negative correlation., Conclusions: The incidence of PF within 1 year post liver transplantation was 31%. This finding was accompanied by cholestatic liver function test abnormalities. Factors predisposing to PF were a prolonged cold ischemia time, biliary complications, and a positive cytomegalovirus recipient status. Acute rejection seemed to prevent for PF.

Background: Orthotopic liver transplantation has become the treatment of choice for children with end-stage liver disease. Although results have improved the last decades, still a considerable number of children die after transplantation. The aim of this study was to analyze long-term actual survival and to identify prognostic factors for such survival rates., Methods: A consecutive series of 66 children receiving transplants who had or could have had a follow-up of at least 5 years was retrospectively analyzed. Actual survival and prognostic factors in relation to patient, donor, and operation related variables were assessed after multivariate analysis., Results: Actual 1-, 3-, and 5-year patient survival was 86%, 79%, and 73%, respectively. A high Child-Pugh (C-P) score or C-P class C, high donor age, high blood loss index, and retransplantation were predictive factors for actual patient survival. A high blood loss index was correlated with biliary atresia, low recipient age and weight, and with previous upper abdominal operations. The duration of stay of the donor at the intensive care unit (ICU) was a predictive factor for retransplantation., Conclusions: Children with diseases eligible for liver transplantation should be seen early in the course of their disease in a transplantation center. All possible measures should be taken during the transplantation procedure to keep the blood loss at a minimum. Children with biliary atresia deserve special attention in this respect. The choice of donors has implications for survival.

Rationale and Objectives: To describe the findings of routinely performed angiographic examinations in patients at discharge 2 months after orthotopic liver transplantation (OLT) and at follow-up 1 year later., Methods: The findings of 315 angiographic examinations performed in 190 patients 2 months and 1 year after OLT were reviewed, and the changes at the anastomotic site of the hepatic artery and portal vein were analyzed., Results: Routine angiography 2 months and 1 year after OLT demonstrated a normal anastomosis or low-grade stenosis in 82% and 84% of the patients (hepatic artery) and in 88% and 84% (portal vein), respectively. High-grade stenosis occurred in 9% and 5% of the patients (hepatic artery) and in 3% and 5% (portal vein). Hepatic artery occlusion and portal vein occlusion were observed in two and seven patients and in one and three patients, respectively. In 76% of patients, the anastomotic site of the hepatic artery did not change significantly. In eight patients, a normal anastomosis or a low- or medium-grade stenosis developed into high-grade stenosis or occlusion. Conversely, in nine patients, medium- or high-grade stenosis developed into a normal anastomosis or a low-grade stenosis. In all eight patients who initially had a high-grade stenosis, the hepatic artery proved to be patent at 1 year. In 98% of patients, the anastomotic site of the portal vein did not change significantly. In one patient who initially had a normal anastomosis, occlusion was found at I year., Conclusions: In most patients, routine angiography 2 months and 1 year after OLT demonstrated normal findings or a low-grade stenotic anastomosis of the hepatic artery and portal vein. Significant changes occurred mainly at the anastomotic site of the hepatic artery and could not be predicted by previous angiograms.

Unlabelled: The prerequisite for liver transplantation as a therapeutic option for inherited metabolic diseases should be that the enzyme defect, being responsible for the major clinical (hepatic and/or extra-hepatic) abnormalities, is localised in the liver. Furthermore, no adequate dietary or pharmacological treatment should be available or such treatment should have an unacceptable influence on the quality of life. We report an infant, who developed end-stage liver disease with persistent lactic acidaemia in his first months of life. Analysis of the mitochondrial respiratory chain in liver tissue revealed a combined partial complex I and IV deficiency. No extra-hepatic involvement could be demonstrated by careful screening for multiple organ involvement, including analysis of the mitochondrial respiratory chain in muscle tissue and cultured skin fibroblasts. The boy received a reduced size liver graft at the age of 8 months. He recovered successfully. Almost 5 years after transplantation he is in good clinical condition. No clinical or biochemical signs of any organ dysfunction have been demonstrated. The considerations on which basis it was decided that there was no contra-indication to perform liver transplantation in this patient are discussed., Conclusion: The possibility of a mitochondrial respiratory chain deficiency should be considered in liver disease of unknown origin prior to liver transplantation. Liver transplantation is a therapeutic option in mitochondrial respiratory chain deficiency-based end-stage liver disease provided that extra-hepatic involvement is carefully excluded.

Vascular complications have a detrimental effect on the outcome after liver transplantation. Most studies focus exclusively on hepatic artery thrombosis (HAT). The current study analyzed the incidence, consequences, and risk factors for HAT, portal vein thrombosis (PVT), and venous outflow tract obstruction (VOTO) in a consecutive series of 157 pediatric liver transplantations. The overall incidence of vascular complications was 21%. The incidences of HAT, PVT, and VOTO were 10%, 4%, and 6%, respectively. Patient survival after PVT and VOTO and graft survival after HAT and PVT were less compared with survival of grafts without vascular complications. To identify risk factors for vascular complications, factors related to recipient, donor, and surgical techniques were analyzed. A low donor-recipient (D/R) age ratio, long surgical time, and use of the proper hepatic artery of the recipient for arterial reconstruction were risk factors for HAT. Young age, low weight, segmental grafts, and piggyback technique were risk factors for PVT. Fulminant hepatic failure, high D/R age and weight ratios, and use of segmental grafts were related to VOTO. Vascular complications, which occurred in 21% of the pediatric liver transplantations, had a significant impact on patient and graft survival. Size disparity between donor and recipient was an important risk factor for vascular complications, especially in the case of transplantation of segmental grafts. Patient and graft survival might improve by avoiding the identified risk factors.

Taste perception in 45 3- to 6-year-old children was tested using procedures specifically designed for this age group. Detection thresholds for sucrose and urea were measured by a staircase method and aversion to urea was assessed hedonically, using drawings of facial expressions. All children understood the task and could perform the necessary actions. A subgroup of 20 children participated in a second measurement after a mean interval of 9.5 days: there was a satisfactory degree of stability between the sessions. However, a third measurement, on a subgroup of 13 children after a somewhat longer interval, showed a marked drop in the stability of the urea thresholds. This drop was thought to arise from a decrease in the children's motivation, leading to increased distractibility. Mean threshold estimates were 31 mmol/l for sucrose detection, 59 mmol/l for urea detection and 134 mmol/l for urea aversion, but some children were extremely sensitive to the taste of urea. The findings show that it is possible to study taste perception in very young children if their age is taken into consideration in developing the test procedure. Valid data can be obtained if the procedures are short, easy to understand and intrinsically motivating., (Copyright 2000 Academic Press.)

Background & Aims: Progressive familial intrahepatic cholestasis (PFIC), an inherited liver disease of childhood, is characterized by cholestasis and either normal or increased serum gamma-glutamyltransferase activity. Patients with normal gamma-glutamyltransferase activity have mutations of the FIC1 locus on chromosome 18q21 or mutations of the BSEP gene on chromosome 2q24. Also, patients with bile acid synthesis defects have low gamma-glutamyltransferase activity. We investigated expression of the bile salt export pump (BSEP) in liver samples from patients with a PFIC phenotype and correlated this with BSEP gene mutations., Methods: BSEP and multidrug resistance protein 2 (MRP2) expressions were studied by immunohistochemistry in liver specimens of 28 patients and BSEP gene mutation analysis in 19 patients. Bile salt kinetics were studied in 1 patient., Results: Sixteen of 28 liver samples showed no canalicular BSEP staining. Staining for MRP2 showed a normal canalicular pattern in all but 1 of these samples. Ten of 19 patients showed BSEP gene mutations; BSEP protein expression was lacking in all 10 patients. No mutations were found in 9 of 19 patients, and in all except 1, BSEP protein expression was normal. Bile salt concentration in bile of BSEP-negative/MRP2-positive PFIC patients was 0.2 +/- 0.2 mmol/L (n = 9; <1% of normal) and in BSEP-positive PFIC patients 18.1 +/- 9.9 mmol/L (n = 3; 40% of normal). The kinetic study confirmed the dramatic decrease of bile salt secretion in BSEP-negative patients., Conclusions: The findings show a close correlation between BSEP gene mutations and canalicular BSEP expression. Biliary secretion of bile salts is greatly reduced in BSEP-negative patients.

Background: To alleviate the shortage of size-matched whole-donor organs, too-large-for-size cadaveric donor grafts are modified by liver resection techniques. These modifications result in technical-variant liver transplantation (TVLTx). Patient and graft survival rates after TVLTx are considered comparable to those after full-size liver transplantation (FSLTx). However, morbidity after TVLTx is often underexposed. The aim of this study was to analyze the results of FSLTx and TVLTx in terms of patient and graft survival rates and morbidity., Methods: A consecutive series of 97 primary and elective pediatric liver transplantations performed in a single center was retrospectively analyzed. Forty-seven children had a FSLTx and 50 a TVLTx (38 reduced-size liver grafts and 12 split-liver grafts). The overall median follow-up period was 3.5 years., Results: There were no differences in patient and graft survival rates between FSLTx and TVLTx. However, after TVLTx there was a significantly higher complication rate (1.42 vs. 0.81 after FSLTx). TVLTx is more hampered by biliary complications (30% vs. 17%), expressed by a higher incidence of cholangitis and leakage of bile. These complications led to a significantly higher incidence of sepsis (44% vs. 19%) and a significantly higher intervention rate (0.40 vs. 1.28) after TVLTx. There was no difference in the incidence of retransplantations between FSLTx and TVLTx., Conclusions: Both FSLTx and TVLTx offer the same prognosis in terms of patient and graft survival rates for children after a primary and elective liver transplantation. However, TVLTx has a higher morbidity.

Background: Cirrhosis and portal hypertension affect the flow profile of the liver vasculature. In these conditions Doppler ultrasound can provide important information on the hemodynamics of the portal venous system, the hepatic artery and the hepatic veins., Methods: The value of Doppler ultrasound in the assessment of the patient with cirrhosis and portal hypertension was determined by reviewing the literature., Results: Portal venous blood flow becomes reversed with advanced portal hypertension. Reversed flow is also demonstrated in patients with veno-occlusive disease and portosystemic shunts. Despite general agreement that portal flow velocity is decreased in cirrhotic patients, the absolute values of portal flow velocity in both healthy subjects and cirrhotic patients vary considerably. Errors in Doppler measurements, observer variability and collateral pathways contribute to these variations. Furthermore, portal blood flow is influenced by numerous factors such as changes in the body position, phase of respiration, timing of meals, exercise and cardiac output. Finally, portal flow may be unaltered due to a combination of high inflow from the splanchnic organs and increased resistance within the liver. High resistive index of the hepatic artery is seen in patients with end-stage liver disease, particularly in children with severe cirrhosis secondary to biliary atresia. However, hepatic artery flow remains normal in most patients. Abnormal hepatic vein flow profiles are seen in patients with cirrhosis, but dampening or flattening of the flow profile has a multifactorial origin (Budd-Chiari, metastases, ascites) and can be observed in healthy subjects., Conclusions: Although many factors may affect the accuracy of volume flow and velocity measurements and the flow profile of the liver vasculature may change in different situations, Doppler ultrasound is useful in the assessment of the patient with cirrhosis and portal hypertension.

Background: The aim of the study was to diagnose hypolactasia with a higher accuracy than with the traditional H2 breath test., Methods: We used a combined 13C-lactose 13CO2/H2 breath test, which was performed in 33 patients in whom lactase activity was measured., Results: Lactase activity was reduced in 13 cases. The sensitivity and specificity of the H2 test were 54% and 90%; those of the 13CO2 test 69% and 70%. False-negative results did not always occur in the same patients. In five of six patients with both test results abnormal, lactase activity was low. In 13 of 15 patients with both test results normal, lactase activity was normal. In 6 of 12 cases with only 1 test abnormal, lactase activity was low., Conclusion: The combined H2/13CO2 breath test (sensitivity, 85%; specificity, 65%) is more adequate for diagnosis of hypolactasia than the H2 breath test alone.

To assess the role of routine Doppler ultrasound in the detection of clinically unsuspected vascular complications in the early postoperative phase after orthotopic liver transplantation (OLT), the findings of 858 routinely performed Doppler ultrasound examinations were analyzed in 268 transplants. At various time intervals after OLT, we encountered 46 abnormal Doppler findings: hepatic artery (thrombosis), portal vein [anastomotic stenosis, (non)occlusive thrombosis or reversed flow], inferior vena cava [anastomotic stenosis with reversed flow, no flow, or (non)occlusive thrombosis], and hepatic veins (to-and-fro flow or stenosis with reversed flow) in 14, 20, 9, and 2 transplants, respectively. Most of these abnormal Doppler findings were confirmed by angiography, cavography, or surgery. The positive predictive value for hepatic artery thrombosis (HAT) was 12 out of 14, or 86%. In the first 2 weeks after OLT, routine Doppler ultrasound revealed 20 of the 46 abnormal findings (43%). Clinically unsuspected complications of the hepatic artery, portal vein, inferior vena cava, and hepatic veins were found in 9 of the 14 (64%), 6 of the 20 (30%), 3 of the 9 (33%), and 2 of the 2 (100%) transplants, respectively. The highest incidence--nine vascular complications--was found on the 1st day. On each of the remaining days (except for the 2nd and 9th days), one or two vascular complications were detected. HAT was found mainly in the 1st week. Vascular complications developed independently or concomitantly. We conclude that routine Doppler ultrasound is very important for the detection of clinically unsuspected vascular complications, particularly HAT, in the first 2 weeks after OLT. We recommend routine Doppler ultrasound of all hepatic vessels every 3 days in the early postoperative phase after OLT. Special attention should be paid to the 1st day.

Benign recurrent intrahepatic cholestasis (BRIC) is an autosomal recessive liver disease characterized by multiple episodes of cholestasis without progression to chronic liver disease. The gene was previously assigned to chromosome 18q21, using a shared segment analysis in three families from the Netherlands. In the present study we report the linkage analysis of an expanded sample of 14 BRIC families, using 15 microsatellite markers from the 18q21 region. Obligate recombinants in two families place the gene in a 7-cM interval, between markers D18S69 and D18S64. All intervening markers had significant LOD scores in two-point linkage analysis. Moreover, we identified one family in which the BRIC gene seems to be unlinked to the 18q21 region, or that represents incomplete penetrance of the BRIC genotype.

Three children suffering from cystic fibrosis, two girls aged 15 and 7 and one boy aged 18 years, presented growth retardation resulting from increased energy requirements and relative undernourishment. Since oral hyperalimentation was insufficiently efficacious, extra nutrition was administered by tube (at night): a naso-gastric tube, a percutaneous endoscopial gastrostomy catheter or an intragastric tube with a stopper in the skin. All three patients achieved a higher percentile line in the weight/height growth diagram, with stable or improved pulmonary function.

Background: Ursodeoxycholic acid (UDCA) is beneficial in cholestasis related to cystic fibrosis (CF). High-dose treatment has been recommended to compensate for bile salt malabsorption. We compared the results of low-dose (10 mg/kg/day) and high-dose (20 mg/kg/day) UDCA treatment on liver biochemistry after 3 and 12 months' treatment., Methods: Thirty CF patients (age > 5 years) with biochemical cholestasis and compensated liver disease were randomized for low-dose (n = 17) or high-dose (n = 13) UDCA. Baseline clinical variables were comparable., Results: After 1 year one patient had died of liver failure (low dose), and three had dropped out because of pruritus (one in each group) or personal choice (low dose). In the high-dose group improvement in gamma-glutamyl transferase values was more pronounced after 3 months and 1 year (P < 0.004), and improvement of alanine aminotransferase was better after 1 yer (P < 0.02). Improvement of alkaline phosphatase and aspartate aminotransferase was comparable. Complete normalization of liver enzymes and bilirubin occurred more often in the high-dose group., Conclusion: High-dose UDCA induces a better response of liver biochemistry values than low-dose UDCA in CF patients with cholestatic liver disease.

Background: The treatment of giant symptomatic haemangioma of the liver is still controversial. This retrospective study reviewed the results of surgical treatment., Methods: Twenty-eight patients with symptomatic giant haemangioma of the liver were treated by liver resection (n = 24) or liver transplantation (n = 4). The median diameter of the haemangiomas was 11 (range 5-20) cm., Results: Complications occurred in five of the 24 patients treated by partial liver resection, although all survived and remain alive and well more than 2 years after surgery. In six patients there was residual haemangioma in the liver remnant which did not enlarge during the 2-year follow-up. In four patients the haemangioma was considered irresectable and liver transplantation was performed. One died after a 'two-stage' liver transplantation; the remaining three patients are alive and well, 1, 4 and 9 years after transplantation., Conclusion: Liver resection is the treatment of choice for giant haemangioma of the liver where possible. In selected cases liver transplantation is indicated.

Digestion and absorption of lipids is a highly efficient process. From Western diets about 95% will be absorbed. This implies that together with lipids from endogenous sources 6-8 g of lipids will enter the colon daily. This input significantly increases during various lipid malabsorption syndromes. It has long been assumed that the biological fate of unabsorbed lipids is physiologically not relevant. However, significant microbial lipid metabolism occurs. Circumstantial evidence is arising which supports a role of unabsorbed lipid metabolites in the development of colonic diseases. Lipid metabolites may act as detergents in the colon, leading to mucosal injury and reactive hyperproliferation, which in its turn could promote tumour development. Lipid metabolites could also be transformed in biological active metabolites, which have a tumour promoting potency. More mechanistic information is needed on the colonic metabolic fate of lipids in order to develop strategies for manipulating colonic flora in the prevention of lipid related colonic diseases.

Rationale and Objectives: To analyze changes in Doppler ultrasound variables of the portal vein in relation to liver biopsy findings, the authors performed a prospective study of 316 Doppler ultrasound examinations in the first 2 weeks after orthotopic liver transplantation on 23 patients., Methods: Recordings were obtained daily from the portal vein (diameter, maximum velocity, and flow). Correlations were explored between the Doppler ultrasound findings and histologic data. The chi-square test was used to analyze differences in Doppler ultrasound variables in patients with and without acute rejection., Results: In our series of 23 patients, acute rejection was diagnosed by liver biopsy in nine of them (39%). Changes in portal vein diameter, maximum velocity, and flow did not correlate consistently with liver biopsy findings, due to a multifactorial origin. Changes in portal hemodynamics were observed in patients with hepatic artery thrombosis, portal vein stenosis, acute rejection, and sepsis., Conclusions: Although routine screening using Doppler ultrasound proved to be useful for the determination of rapid changes in portal hemodynamics within a short time, serial Doppler ultrasound examinations were not helpful in predicting acute rejection.

Background: Selective angiography involves increased risk for children and may cause vascular complications. The aim of this study was to determine whether selective angiography is still necessary for viewing the portal vein and hepatic artery., Methods: Doppler ultrasound, abdominal aortography, and selective angiography were performed and interpreted independently in 62 children (median age = 1 year 3 months), with end-stage liver disease, who were candidates for orthotopic liver transplantation., Results: Selective angiography agreed with the Doppler ultrasound findings of patency, flow direction, and diameter of the extrahepatic portal vein in 84%, 73%, and 79% of the children, respectively. Important additional information was obtained from selective angiography in only five of the 62 children (8%). Selective angiography showed an anomaly of the hepatic artery in 21 of the 62 children (33%). In 18 out of these 21 children (85%), an anomaly of the hepatic artery was already visible on the abdominal aortogram., Conclusion: Selective angiography did not play any significant role in the detection of an anomaly of the hepatic artery and should only be done if the Doppler ultrasound findings of the portal vein are inconclusive or if abdominal aortography cannot provide reliable information about the hepatic artery. For the evaluation of the portal vein and hepatic artery, we recommend Doppler ultrasound and abdominal aortography, a less invasive angiographic procedure.

Rationale and Objectives: To analyze changes in Doppler ultrasound variables in relation to liver biopsy findings for the diagnosis of acute rejection after orthotopic liver transplantation (OLT), the authors performed in a prospective study 316 Doppler ultrasound examinations in the first 2 weeks after OLT on 23 patients., Methods: Recordings were obtained daily from the hepatic artery (resistive index [RI]) and hepatic vein (damping index [DI]). Correlations were explored between the Doppler ultrasound findings and histologic data. The chi-square test was used to analyze differences in Doppler ultrasound variables in patients with and without acute rejection., Results: Serial Doppler ultrasound examinations showed a significant increase in the RI in 11 of 22 patients (50%); the 23rd patient was excluded because of hepatic artery thrombosis. Despite an agreement in 15 of 22 patients (68%) no statistically significant correlation could be found (positive predictive value 6/11 = 55%; negative predictive value 9/11 = 82%; chi-square = 3.14; P > 0.05). A significant increase in the DI was observed in 14 of 23 patients (61%). However, no statistically significant correlation could be found as well with this parameter (positive predictive value 6/14 = 43%; negative predictive value 6/9 = 67%; chi-square = 0.00; P > 0.05)., Conclusion: Serial Doppler ultrasound examinations were not helpful in predicting acute rejection.