Real-world management of juvenile autoimmune liver disease.

BACKGROUND AND AIMS: Juvenile autoimmune liver disease (JAILD) includes paediatric forms of autoimmune hepatitis (AIH) and autoimmune sclerosing cholangitis (ASC). Since evidence is scarce, there are currently no evidence-based management guidelines for juvenile AIH. This survey was carried out amongst the paediatric members of the International AIH Group (IAIHG) to describe their practices in the management of JAILD. METHODS: An online survey questionnaire was distributed to members of the IAIHG with active practice (https://www.surveymonkey.de/r/Juvenile_AILD). The questionnaire consisted of four clinical scenarios on different presentations of AIH. RESULTS: Fifty-eight surveys were sent to the IAIHG members, out of which 43 (74%, 22 countries, four continents) were returned. None reported budesonide as a first-line induction agent for the acute presentation of AIH. Sixteen (37%) routinely perform liver biopsy at three years of biochemical remission. Thirty-five respondents (81%) perform magnetic resonance cholangiography (MRC) at presentation. Ciclosporin is the most widely used second-line agent (number of patients treated = ∼360, 21 centres). Mycophenolate mofetil (n = ∼225, 31 centres), tacrolimus (n = ∼130, 21 centres) and sirolimus (n = ∼5, 3 centres) are less often reported. Rescue therapy with infliximab and rituximab has been tried in eight centres (n = ∼19) and nine centres (n = ∼16), respectively. CONCLUSIONS: Prednisolone remains the preferred first-line induction agent in JAILD. MRC at presentation is performed by the large majority of participants. Participants reported a wide variation in performing liver biopsy for therapy evaluation during follow-up. Within the paediatric members of the IAIHG there is considerable experience with second-line therapeutic agents.

Immunosuppressive drugs affect interferon (IFN)-γ and programmed cell death 1 (PD-1) kinetics in patients with newly diagnosed autoimmune hepatitis.

Autoimmune hepatitis (AIH) is characterized by overwhelming effector immune responses associated with defective regulatory T cells (Tregs ). Several lines of evidence indicate CD4 as the main effectors involved in autoimmune liver damage. Herein we investigate the in-vitro effects of prednisolone, 6-mercaptopurine, cyclosporin, tacrolimus, mycophenolic acid (MPA) and rapamycin, immunosuppressive drugs (ISDs) used in AIH treatment, on the expression of proinflammatory cytokines, co-inhibitory molecules and ability to proliferate of CD4+ CD25- cells, isolated from the peripheral blood of treatment-naive patients with AIH. We note that in healthy subjects (HS) following polyclonal stimulation and in the absence of ISDs, the expression of interferon (IFN)-γ, interleukin (IL)-17 and tumour necrosis factor (TNF)-α by CD4 effectors peaks at 48 h and decreases at 96 h to reach baseline levels. In contrast, in AIH the expression of all these proinflammatory cytokines continue rising between 48 and 96 h. Levels of programmed cell death-1 (PD-1), T cell immunoglobulin and mucin domain-containing molecule-3 (TIM-3) and cytotoxic T lymphocyte antigen-4 (CTLA-4) increase over 96-h culture both in HS and AIH, although with faster kinetics in the latter. Exposure to ISDs contains IFN-γ and PD-1 expression in AIH, where control over CD4+ CD25- cell proliferation is also noted upon exposure to MPA. Treatment with tacrolimus and cyclosporin render CD4+ CD25- cells more susceptible to Treg control. Collectively, our data indicate that in treatment-naive patients with AIH, all ISDs restrain T helper type 1 (Th1) cells and modulate PD-1 expression. Furthermore, they suggest that tacrolimus and cyclosporin may ameliorate effector cell responsiveness to Tregs .

Bilirubin, a physiological antioxidant, can improve cryopreservation of human hepatocytes.

The availability of cryopreserved hepatocytes is required for a more widespread use of hepatocyte transplantation, but human hepatocytes are easily damaged during freezing-thawing. Here, preincubation with unconjugated bilirubin, a physiological antioxidant, resulted in increased viability and function of hepatocytes (as determined by trypan blue exclusion, mitochondrial succinate dehydrogenases activity, urea synthesis, and cytochrome P450 1A/2) compared with cells incubated without the pigment. These findings suggest that unconjugated bilirubin may be used as cryoprotectant in clinical hepatocyte transplantation.

HCV infection: pathogenesis, clinical manifestations and therapy.

Chronic hepatitis C virus (HCV) infection is a worldwide public health problem with a global prevalence of 2-3%. It is believed that about 170 million people are currently infected (about 3% of the world's population), and a further 3-4 million are infected each year. HCV is the main reason for liver transplantation in the developed world, and the main cause of liver-related morbidity and mortality in a number of countries, including Italy. It is not only a frequent cause of chronic liver diseases such as hepatitis, cirrhosis and hepatocellular carcinoma, but is also involved in the pathogenesis of various autoimmune and rheumatic disorders (arthritis, vasculitis, sicca syndrome, porphyria cutanea tarda, lichen planus, nephropathies, thyroid diseases, and lung fibrosis), as well as in the development of B-cell lymphoproliferative diseases. Furthermore, patients suffering from C hepatitis tend to produce rheumatoid factor, cryoglobulins and a large series of autoantibodies (ANA, anti-SSA/SSB, SAM, ATG, aCL). The use of glucocorticoids or immuno-suppressant agents in HCV infected individuals, which are needed to treat autoimmune and rheumatic disorders, leads to a risk of worsening the clinical outcome of HCV. Under these conditions, the viral infection often needs to be treated with antiviral agents, mainly pegylated interferon combined with ribavirin. However, cyclosporine A seems to be safe and effective in patients with autoimmune disease (AD) and concomitant chronic HCV infection as is documented by the reduction in viremia and transaminases, particularly in patients with high baseline levels. Finally, HCV is the main trigger of mixed cryoglobulinemia. An attempt at viral eradication is therefore indicated in most patients, and is particularly effective in the case of mild or moderate manifestations. In severe cases, rituximab is an apparently safe and effective alternative to conventional immunosuppression and, specifically, it controls B-cell proliferation.

Living related liver transplantation in children.

BACKGROUND: Living related liver transplantation (LRLT) has become established for treating children with end-stage liver disease. The aim of this study was to review a single-centre experience of left lateral segment liver transplants from living donors in children. METHODS: Fifty left lateral segment LRLT procedures have been performed since 1993. There were 17 girls and 33 boys, of median age 1.5 years (range 0.5 to 13 years), with a median weight of 10 (range 0.7-44) kg. Donors included 23 mothers, 26 fathers and one uncle, with a median age of 33 (range 19-46) years. RESULTS: At a median follow-up of 86 months, there was no donor mortality and low morbidity. Patient and graft survival rates were 98, 96 and 96 per cent, and 98, 96 and 93 per cent at 1, 3 and 5 years respectively. Three children had a second transplant at a median of 9 years after the first. The incidence of hepatic artery thrombosis, portal vein thrombosis and biliary complications was 6, 4 and 14 per cent respectively. CONCLUSION: Living related liver transplantation has good long-term results in children.

A novel treatment of congenital hepatoportal arteriovenous fistula.

Congenital hepatoportal arteriovenous fistula is a rare cause of portal hypertension in young children. Unlike the acquired form, which is usually isolated and can be cured by hepatic artery (HA) embolization, recurrence of portal hypertension often occurs with congenital hepatoportal arteriovenous fistula after embolization and/or HA ligation because of early, rapid collateralization and the presence of multiple arterioportal fistula. Although long-term outcome after embolization is not known, liver transplantation has been proposed as the only option for this condition. However, portal vein and hepatic arterial anastomoses are made difficult because of the presence of portal vein arterialization and previous HA ligation, with a significantly increased risk of vascular complications. We report a case where resolution of portal hypertension has been achieved by an end-to-side portocaval shunt, to preserve the portal vein and HA for future liver transplantation, should it be required.

Segmental liver transplantation from non-heart beating donors--an early experience with implications for the future.

We report our experience of pediatric liver transplantation with partial grafts from non-heart beating donors (NHBD). Controlled donors less than 40 years of age with a warm ischemia time (WI) of less than 30 min were considered for pediatric recipients. Death was declared 5 min after asystole. A super-rapid recovery technique with aortic and portal perfusion was utilized. Mean donor age was 29 years and WI 14.6 min (range 11-18). Seven children, mean age 4.9 years (0.7-11), median weight 20 kg (8.4-53) received NHBD segmental liver grafts. Diagnoses included seronegative hepatitis, neonatal sclerosing cholangitis, familial intrahepatic cholestasis, hepatoblastoma, primary hyperoxaluria and factor VII deficiency (n=2). The grafts included four reduced and one split left lateral segments, one left lobe and one right auxiliary graft. Mean cold ischemia was 7.3 h (6.2-8.8). Complications included one pleural effusion and one biliary collection drained percutaneously. At 20 months (10-36) follow-up all children are alive and well with functioning grafts. Donation after cardiac death is a significant source of liver grafts for adults and children with careful donor selection and short cold ischemic times.

Liver abscesses in children: a single center experience in the developed world.

OBJECTIVES: The aim of this study was to investigate the clinical and radiologic features, predisposing risk factors, and complications of children with pyogenic liver abscess (PLA) referred to a tertiary pediatric hepatology center. METHODS: We analyzed our database of all children referred to our unit over a 10 year period and performed a case note review of all patients with a radiologically proven PLA. RESULTS: PLA was diagnosed in 15 children (7 boys), 0.5% of all referrals. They presented at a median age of 10 years (range 2 months-15 years). In three children (2 boys), PLA was the first manifestation of chronic granulomatous disease. Among the others, five had radiologic evidence of other intra-abdominal pathology (1 with subsequently proven appendicitis), and four developed portal vein thrombosis with portal hypertension. The commonest isolated pathogen was Staphylococcus aureus. Combined treatment with guided aspiration and prolonged intravenous antibiotics was successful in all patients. CONCLUSION: PLA is a rare diagnosis in children in the developed world. It may be caused by primary neutrophil disorders even in the absence of a previous history of infection. Co-existent appendicitis, intra-abdominal sepsis, and ascending pylephlebitis must be sought because these children are at risk of developing portal vein obstruction and portal hypertension. Prolonged intravenous antibiotic treatment guided by microbiologic sensitivities is highly effective.

The outcome of the older (> or =100 days) infant with biliary atresia.

BACKGROUND: There is a detrimental effect of increasing age on the results of the Kasai portoenterostomy for biliary atresia (BA), and some centers routinely advocate primary liver transplantation for the older infant, irrespective of other criteria. This perception that such infants are indeed irretrievable was tested by retrospective analysis. METHODS: All infants who had undergone surgery for BA during the period 1980 through 2000 aged > or =100 days were reviewed. Actuarial survival was calculated using 2 end-points (death and transplantation). A retrospective review of their ultrasonography (n = 12) and preoperative liver histology (n = 22) was also undertaken to ascertain possible predictive criteria. RESULTS: A total of 422 infants had BA diagnosed during this period, of which 35 (8.2%) were > or =100 days at surgery (median [interquartile range], 133 [range, 108 to 180] days). Surgery included portoenterostomy (n = 26), hepaticojejunostomy (n = 7), and a resection and end-to-end anastomosis (n = 1). A laparotomy only was performed in 1. Five- and 10-year actuarial survival rate with native liver was 45% and 40%, respectively. Currently, 12 (35%) patients are alive with their native liver (8 are anicteric), 9 (28%) have undergone transplantation, and 13 have died. Although there were some survival advantages for types 1 or 2 BA and "noncirrhosis" at time of surgery, neither reached statistical significance. Individual histologic features (eg, degrees of fibrosis, giant cell transformation, bile duct destruction) in the retrospective review of available material were not discriminatory. The finding of a "heterogeneous" parenchyma on ultrasonography was predictive of poor outcome but lacked sensitivity. CONCLUSIONS: The potential for reasonable medium-term survival is present in about one third of infants 100 days or older coming to primary corrective surgery. In the absence of accurate discrimination, the authors continue to favor this option rather than subject all to transplant simply on the basis of age.

Multiple viral/self immunological cross-reactivity in liver kidney microsomal antibody positive hepatitis C virus infected patients is associated with the possession of HLA B51.

Liver Kidney Microsomal autoantibody type 1(LKM1) directed to cytochrome P4502D6 (CYP2D6) characterises autoimmune hepatitis type-2 (AIH-2), but is also found in a proportion of chronic hepatitis C virus (HCV) infected patients, CYP2D6252-271 being a major B- cell autoepitope. Molecular mimicry and immunological cross-reactivity between CYP2D6252-271, HCV polyprotein and the infected cell protein 4 (ICP4) of herpes simplex virus type 1 (HSV-1) have been suggested as triggers for the induction of LKM1, but reactivity and cross-reactivity to the relevant sequences have not been investigated experimentally. CYP2D6252-271 and its viral homologues were constructed and tested by ELISA in the sera of 46 chronically infected HCV patients, 23 of whom were LKM1 positive. Reactivity to the E1 HCV and ICP4 HSV1 mimics was frequently found in HCV infected patients irrespectively of their LKM1 status; viral/self cross-reactivity (as indicated by inhibition studies), however, was present in the only 2 of the 23 LKM1 seropositive HCV patients, who possessed the HLA allotype B51. Our results indicate that in HCV infected patients virus/self cross-reactivity is dependent on a specific immunogenetic background, a finding awaiting confirmation by studies in larger series of patients.

Autoimmune hepatitis.

Autoimmune hepatitis (AIH) is characterised histologically by interface hepatitis, and serologically by the presence of non-organ and liver specific autoantibodies and increased levels of immunoglobulin G. Its onset is often ill-defined, frequently mimicing acute hepatitis. AIH usually responds to immunosuppressive treatment, which should be instituted as soon as diagnosis is made. Two types of AIH are recognized according to seropositivity for smooth muscle and/or antinuclear antibody (SMA/ANA, type 1 AIH) or liver kidney microsomal type 1 antibody (LKM1, type 2 AIH). There is a female predominance in both. LKM1 positive patients tend to present more acutely, at a younger age and commonly have immunoglobulin A deficiency, while duration of symptoms before diagnosis, clinical signs, family history of autoimmunity, presence of associated autoimmune disorders, response to treatment and long-term prognosis are similar in the 2 groups. Susceptibility to AIH type 1 is conferred by possession of HLA DR3 and DR4, while to AIH type 2 by possession of HLA DR7. Liver damage is likely to derive from an immune reaction to liver cell antigens, possibly triggered by a mechanism of molecular mimicry, where immune responses to external pathogens, e.g. viruses, become directed towards structurally similar self-components. In AIH this process would be perpetuated by impairment in immune regulation.

The spectrum of surgical jaundice in infancy.

BACKGROUND: Conjugated jaundice arising during infancy may be caused by a number of different surgical conditions. The aim of this study was to compare clinical features, management, and outcome of all types of surgical jaundice presenting in the first year of life. METHODS: A retrospective review was conducted of all infants born in the United Kingdom with jaundice caused by a surgical cause referred to the authors' institution from January 1992 to December 1999. RESULTS: There were 171 infants who could be separated into 3 specific groups: biliary atresia (BA, n = 137), inspissated bile syndrome (IBS; n = 14), and choledochal malformation (CM; n = 12) together with a group containing various miscellaneous conditions (n = 8). Infants with BA had higher bilirubin (P <.01) and aspartate aminotransferase levels (P <.001) and came to surgery earlier (P <.01) than infants with either IBS or CM. Infants with IBS and CM were more likely to be premature and have other malformations, respectively. Ultrasound scan was the principal investigation in the differentiation of BA from other causes of jaundice. Accurate prelaparotomy diagnosis was made by percutaneous liver biopsy in 87% of cases later shown to be BA. Currently, 88 (64%) of children with BA are alive with their native liver postportoenterostomy, 4 have died, and 45 have undergone liver transplantation (with 1 death postoperatively). A policy of primary portoenterostomy for BA followed by transplantation, if necessary, resulted in a survival rate of over 95%. All children in the other diagnostic groups are alive and anicteric after appropriate surgical intervention. CONCLUSIONS: Approximately 80% of infants presenting with surgical jaundice have biliary atresia, whereas those with inspissated bile syndrome and choledochal malformations make up most of the remainder. Mortality in this age-group is confined to infants with BA, but even on these infants an overall survival rate of greater than 95% is currently expected.

Mimicry between the hepatitis C virus polyprotein and antigenic targets of nuclear and smooth muscle antibodies in chronic hepatitis C virus infection.

Autoantibodies to smooth muscle (SMA) and nuclear components (ANA) arise in the natural course of chronic infection with hepatitis C virus. In view of the growing evidence for 'molecular mimicry' as a mechanism of autoimmunity we investigated whether cross-reactive immune reactions between host smooth muscle/nuclear components and HCV antigens may contribute to the formation of SMA and ANA in chronic HCV infection. Computer-assisted protein database search methods were used to identify three smooth muscle (smoothelin698-717, myosin1035-1054, vimentin69-88) and three nuclear (matrin722-741, histone H2A11-30, replication protein A133-152) host antigens with the highest local sequence similarity to the HCV polyprotein and 20-mer peptides corresponding to these regions were constructed. Sera from 51 children with chronic HCV infection [median age: 8 (2-16); 27 boys], 26 SMA positive and five ANA positive, were tested for reactivity to the synthesized HCV peptides and their human homologues by enzyme linked immunosorbent assay (ELISA). Sera from patients with HBV infection and chronic liver disease of different aetiologies were used as controls. 'Double reactivity' to HCV peptides and smooth muscle/nuclear homologues was associated strongly with HCV infection (P < 0.001 for both). Humoral cross-reactivity was established as the basis for double recognition by competition ELISA. Double-reactivity to smooth muscle and HCV peptide antigens correlated with SMA positivity by indirect immunofluouresence (P = 0.05). Of 15 patients double-reactive to myosin1035-1054 and its HCV homologue, 13 recognized whole myosin by immunoblot. These results suggest that ANA and SMA in chronic HCV infection may arise, at least in part, as a consequence of cross-reactive immune responses to HCV and host smooth muscle/nuclear antigens.

Basiliximab (Simulect) for the treatment of steroid-resistant rejection in pediatric liver transpland recipients: a preliminary experience.

BACKGROUND: The role of interleukin-2 receptor antibodies as rescue therapy in steroid-resistant rejection (SRR) has not been studied. We evaluated the safety and efficacy of an interleukin-2 receptor antibody, basiliximab (Simulect, Novartis, East Hanover, NJ), in treating SRR in pediatric liver transplant recipients. METHODS: This was a prospective study of seven pediatric liver transplant recipients with biopsy-proven SRR who would have otherwise received OKT3 or antithymocyte globulin. The primary immunosuppression consisted of cyclosporine (Neoral, Novartis), azathioprine, and prednisolone in four patients and tacrolimus and prednisolone in three patients who had undergone retransplantation for chronic rejection (n=2) and hyperacute rejection (n=1). Four patients had received two cycles of high-dose steroids, and three patients had received a single cycle; all had been converted to tacrolimus, followed by the addition of mycophenolate mofetil. RESULTS: The median time from transplant to SRR was 30 days (range, 8 days-23 months). Five children received two doses of basiliximab (10 mg, 3-7 days apart), and two children received a single dose. Aspartate aminotransferase levels normalized in three children 12, 21, and 30 days after basiliximab treatment. Aspartate aminotransferase levels decreased without normalizing in two children, but there was no further evidence of cellular rejection on repeat biopsies. All five children are rejection-free with a median follow-up of 22 months (range, 5-32 months). Biochemical abnormalities persisted in the remaining two children, and both developed chronic rejection. There were no immediate side effects associated with basiliximab. Two patients were treated empirically for possible cytomegalovirus infection 21 and 57 days after basiliximab treatment, with no evidence of cytomegalovirus disease. CONCLUSION: Five of seven pediatric liver transplant recipients with SRR experienced successful outcomes with basiliximab treatment without major side effects, indicating that it is a safe alternative to OKT3 and other antilymphocyte antibodies.

Serum hyaluronic acid concentrations are increased in cystic fibrosis patients with liver disease.

AIM: To determine whether serum hyaluronic acid (HA) concentrations are abnormal in patients with cystic fibrosis (CF) liver disease, and if so, whether the abnormality is associated with disease severity. METHODS: A total of 74 patients with CF were assessed for evidence of liver involvement as indicated by clinical, ultrasound, and biochemical findings. Serum hyaluronic acid concentrations were measured and compared with concentrations in 293 normal controls. Lung function in the CF patients was also recorded. RESULTS: Thirty four CF patients had no evidence of liver disease; in these, serum HA concentrations were similar to those in healthy controls (median (range): 16.1 (9.4-75.1) v 15 (1-77) microg/l). Nineteen CF patients had established liver disease detected by clinical and ultrasound examination, with significantly increased HA concentrations (56.1 (26-355) microg/l). Serum HA concentrations were also significantly increased, although to a lesser extent, in 21 CF patients with an abnormal liver ultrasound scan alone (22.4 (9.5-43.4) microg/l). There was no correlation between serum HA concentration and lung function. CONCLUSION: Serum HA concentrations were significantly increased in children with clinical or ultrasound evidence of liver disease, being higher in those with more advanced hepatic damage. Despite the inflammation and fibrosis present in CF lungs there was no correlation between HA concentration and lung function, suggesting that high concentrations were a failure of hepatic clearance rather than overproduction in the lung. Longitudinal measurement of HA concentrations may prove a useful marker for the development of significant liver damage in CF patients.

Mutations in the sterol 27-hydroxylase gene (CYP27A) cause hepatitis of infancy as well as cerebrotendinous xanthomatosis.

Follow-up investigations were undertaken on a previously reported patient who had severe familial giant cell hepatitis in infancy associated with substantially increased urinary excretion of bile alcohol glucuronides. By the age of 11 years, he had developed a profile of cholanoids in plasma and urine that closely resembled the pattern seen in cerebrotendinous xanthomatosis (CTX). Sequencing of the sterol 27-hydroxylase gene (CYP27A) showed that he was homozygous for a deletion (525/526delG) that causes a frameshift and a premature stop codon. This genotype has previously been described in an adult female with classical symptoms of CTX (tendon xanthomata, cataracts and deteriorating cognitive function). A review of past medical histories of a group of patients with CTX revealed that prolonged neonatal cholestatic jaundice was common. The family histories also revealed fetal and neonatal deaths among siblings of patients with CTX. We conclude that defective activity of cholesterol 27-hydroxylase can lead to neonatal cholestatic jaundice ('hepatitis of infancy'), which may be self-limiting. After a latent period, however, progressive accumulation of cholesterol and cholestanol can lead to the xanthomata, neurodegeneration, cataracts and atherosclerosis that are typical of CTX.

Autoantibodies to human cytosol: a marker of sporadic porphyria cutanea tarda.

The enzymes potentially involved in the pathogenesis of sporadic porphyria cutanea tarda (PCT) reside in liver cytosoles and microsomes. PCT is frequently associated with hepatitis C virus (HCV) infection, which is in turn associated with autoimmune manifestations. To investigate whether autoimmune reactions, possibly triggered by HCV, are involved in the pathogenesis of PCT, we measured by immunoblot autoantibodies to human cytosolic and microsomal liver fractions in 82 patients with PCT (77% with HCV infection), 105 with other liver disorders and 40 healthy subjects. Anti-liver cytosolic antibodies were more frequent in PCT patients (38/82, 46%) than in pathological controls (P < 0.05-P < 0.001) or in healthy subjects (3/40, 8%, P < 0.001). Among PCT patients, anticytosolic antibodies were more frequent in HCV positive (36/63, 57%) than in HCV negative (2/19, 11%, P < 0.05) cases. Reactivity to a 40-kDa cytosolic polypeptide was present in 20 PCT patients (19 HCV positive), being more frequent than in all pathological controls (P < 0.01-P < 0.0001). Histological activity index (P = 0.04) and antibodies to HCV (P = 0.027) - but not HCV RNA - were associated independently with anticytosolic antibodies as assessed by multivariate analysis. In contrast, frequency of antiliver microsomal antibodies was similar in PCT patients (24/82, 29%) and pathological controls (8-26%), being higher in the autoimmune hepatitis control group (23/23, 100%, P < 0.0001). In conclusion, anticytosolic antibodies, particularly to a 40-kDa polypeptide, are frequent in PCT and associated with HCV infection and severity of liver damage.

Hemodynamic response to continuous infusion of dobutamine in Alagille's syndrome.

BACKGROUND: Alagille's syndrome is a rare condition that is characterized by paucity of interlobular bile ducts and peripheral pulmonary artery stenosis. Liver transplantation in the setting of peripheral pulmonary stenosis and right ventricular hypertension seems to be associated with a higher mortality, which raises the concern that these patients are unable to increase their cardiac output in the immediate posttransplantation period to meet the demands of reperfusion and early graft dysfunction and cope with further increases in pulmonary vascular resistance. METHOD: Cardiac catheterization was performed in 15 children with Alagille's syndrome and peripheral pulmonary artery stenosis to measure the cardiac output response to dobutamine infusion. The cardiac output was measured before and during each increment of infusion of dobutamine at 10 microg/kg/min and 20 microg/kg/min by using a thermodilution catheter placed in the pulmonary artery. RESULTS: There was a significant change in the baseline cardiac index (P<0.001) with an infusion of 20 microg/kg/min of dobutamine with an increase from 4.4(1.0) L/min/m2 to 6.4(1.5) L/min/m2. There was, however, a wide variation between individuals in the increase in cardiac index, ranging from 7.3-95%. There was no correlation between the baseline systolic right ventricular/aortic pressure ratios and the increase in cardiac index (r=0.1086). CONCLUSION: The increase in cardiac index, in response to dobutamine in patients with Alagille's syndrome, is independent of the more conventional measurement of the right ventricular pressure. This method of producing a hemodynamic response is closer to the response that results after liver transplantation, and thus, it may be a better way of predicting the outcome of liver transplantation in these patients.

Classification and genetic features of neonatal haemochromatosis: a study of 27 affected pedigrees and molecular analysis of genes implicated in iron metabolism.

Neonatal haemochromatosis (NH) is a severe and newly recognised syndrome of uncertain aetiology, characterised by congenital cirrhosis or fulminant hepatitis and widespread tissue iron deposition. NH occurs in the context of maternal disease including viral infection, as a complication of metabolic disease in the fetus, and sporadically or recurrently, without overt cause, in sibs. Although an underlying genetic basis for NH has been suspected, no test is available for predictive analysis in at risk pregnancies. As a first step towards an understanding of the putative genetic basis for neonatal haemochromatosis, we have conducted a systematic study of the mode of transmission of this disorder in a total of 40 infants born to 27 families. We have moreover carried out a molecular analysis of candidate genes (beta(2)-microglobulin, HFE, and haem oxygenases 1 and 2) implicated in iron metabolism. No pathogenic mutations in these genes were identified that segregate consistently with the disease phenotype in multiplex pedigrees. However, excluding four pedigrees with clear evidence of maternal infection associated with NH, a pedigree showing transmission of maternal antinuclear factor and ribonucleoprotein antibodies to the affected infants, and two families with possible matrilineal inheritance of disease in maternal half sibs, a large subgroup of the affected pedigrees point to the inheritance of an autosomal recessive trait. This included 14 pedigrees with affected and unaffected infants and a single pedigree where all four affected infants were the sole offspring of consanguineous but otherwise healthy parents. We thus report three distinct patterns of disease transmission in neonatal haemochromatosis. In the differentiation of a large subgroup showing transmission of disease in a manner suggesting autosomal recessive inheritance, we also provide the basis for further genome wide studies to define chromosomal determinants of iron storage disease in the newborn.

Sclerosing cholangitis in the paediatric patient.

Sclerosing cholangitis in childhood is a heterogeneous condition, which has different aetiologies. Sclerosing cholangitis may be inherited and diagnosed in the neonatal period (neonatal sclerosing cholangitis); it may present later with features of autoimmunity (autoimmune sclerosing cholangitis); or it may be associated with a variety of disorders, including Langerhans cell histiocytosis, immunodeficiency, psoriasis, cystic fibrosis, reticulum cell sarcoma and sickle cell anaemia. In contrast to the experience in adult patients, sclerosing cholangitis occurring as an individual disease (primary sclerosing cholangitis) is rare. The initiating events and possible pathogenic mechanisms differ in the various forms of sclerosing cholangitis and are still obscure. Treatment and prognosis depend on the type of sclerosing cholangitis present.