Psychological effects of liver disease and transplantation.

UNLABELLED: Psychological adjustment in children with liver disease was investigated. Three groups of children 6-15 years old participated: ten had undergone a liver transplant (Gp1), 15 had ongoing chronic liver disease (Gp2) and 15 were healthy controls (Gp3). Children who had had a transplant appeared well adjusted and thought of themselves as healthy rather than ill, although areas of vulnerability were present, for example increased anxiety. No differences emerged in terms of coping with common or illness-related problems or understanding of the causes of illness and use of medication. Gps 1 and 2 showed higher levels of understanding of the functions of the liver but less understanding of illness prevention when compared to their healthy peers. Gp2 experienced less control over their health when compared to the other two groups. Gp1 rated themselves as more "healthy" than Gp2 but less so than Gp3. CONCLUSION: Children with chronic liver disease are able to communicate how they deal with the stresses of the condition. Though well adjusted in many ways, those who have had a transplant still show areas of psychological vulnerability which need to be addressed in clinical practice.

A 12-year-old girl with antimitochondrial antibody-positive autoimmune hepatitis.

Autoimmune hepatitis is rare and, in childhood, is typically associated with either the nuclear and/or smooth muscle antibody or with the liver kidney microsomal type 1 antibody. Antimitochondrial antibodies, which are considered diagnostic of primary biliary cirrhosis, have not been described in the paediatric age. We report for the first time a 12-year-old girl with antimitochondrial-antibody-positive autoimmune hepatitis. Antimitochondrial antibody positivity was determined by immunofluorescence and immunoblot. The patient's age, clinical, biochemical and histological features and response to immunosuppressive treatment support the diagnosis of autoimmune hepatitis.

Hepatic basolateral sodium-dependent-bile acid transporter expression in two unusual cases of hypercholanemia and in extrahepatic biliary atresia.

The recent cloning of a human sodium-dependent bile acid transporter (NTCP) permits analysis of its expression in human liver disease and investigation of potential primary defects in its expression. NTCP from normal human liver (NHL) was first characterized in detail. Northern blotting of RNA from NHL revealed a 1.8-kb NTCP transcript. Western blotting of crude NHL plasma membranes using a carboxyterminal antipeptide antibody showed that NTCP is a 39-kd polypeptide that is N-glycosylated to a final molecular weight of 56 kd. Indirect immunofluorescent analysis of NHL sections indicated that the NTCP protein is expressed on the basolateral surface of hepatocytes. We hypothesized that the clinical phenotype of a defect in NTCP might be hypercholanemia in the relative absence of liver disease. Accordingly, the coding region of the NTCP gene of two children with this phenotype was sequenced after reverse transcription/polymerase chain reaction (RT/PCR) amplification. No primary defects in the deduced NTCP amino acid sequence were found. Despite the extremely high serum bile salt levels (235 and 126 micromol/L) in these two patients, NTCP messenger RNA (mRNA) and protein expression were quantitatively normal, in contrast to the published observations in a rat model of cholestasis secondary to common bile duct ligation. Hepatic steady-state NTCP mRNA levels in a group of 23 pre- and postportoenterostomy biliary atresia patients were inversely related to total bilirubin, indicating that extrahepatic bile duct obstruction leads to down-regulation of NTCP mRNA levels, similar to that observed in rat common bile duct ligation. Therefore the lack of down-regulation in the two patients with hypercholanemia indicates that elevated serum bile salts are not sufficient to down-regulate NTCP expression, these two patients have abnormal responses to hypercholanemia, or these two patients have a defect in a gene other than NTCP that influences hepatic clearance of bile salts.

Molecular basis, clinical consequences and diagnosis of alpha-1 antitrypsin deficiency.

(1) Deficiency of alpha AT is one of the most common hereditary diseases affecting Caucasians in Europe. The alpha 1AT protein is extremely pleomorphic, and around 90 variants due to mutations have been recognized. The prime functions of alpha 1AT is to inhibit neutrophil elastase, and a proportion of individuals who are deficient in alpha 1AT develop emphysema. The most common deficiency variant (Z) is also associated with liver disease. The main site of alpha 1AT synthesis is in the liver. Not all deficient individuals are affected by lung or liver disease, however, so that other factors (genetic and environmental) are clearly important. (2) Investigation of alpha 1AT status is essential in any child or adult presenting with chronic liver disease. The genetic cause cannot be identified clinically or by any other laboratory investigation. The diagnosis carries important prognostic consequences and is important for other family members. Patients with emphysema should have their Pi type determined, especially if they are under the age of 50, have never smoked or there is a suggestive family history. Asymptomatic individuals who are homozygous type Z should be referred to a chest physician for a clinical and radiological assessment together with lung function tests. (3) Several laboratory tests are available to detect alpha 1AT deficiency, and the choice of test(s) will depend on circumstances. Quantitation of the serum protein is simple and cheap. Because alpha 1AT is an acute phase protein, however, quantitation used in isolation may give false negative results which are clearly unacceptable, particularly in association with paediatric liver disease. Phenotyping by isoelectric focusing requires some experience in distinguishing SZ and ZZ phenotypes, and phenotyping should ideally be used in conjunction with quantitation because heterozygous null phenotypes may appear identical to homozygous normal phenotypes. (4) Prenatal diagnosis is usually performed by DNA analysis of CVS samples obtained at 11-13 weeks. Because of the risk that CVS samples might be contaminated by maternal tissue, assays which are less likely to detect minor contaminants are preferable. At present, use of DNA tests is confined to prenatal diagnosis, but the availability of simple tests and the possibility of unequivocal identification of S and Z alleles means that these tests are likely to find greater use in the near future.

Autoimmune hepatitis in childhood: a 20-year experience.

To determine the clinical, biochemical, and histological features, and outcome of childhood autoimmune hepatitis (AIH), we reviewed the medical records of 52 children with AIH, 32 (median age: 10 [2-15] years) anti-nuclear and/or smooth muscle antibody (ANA/SMA) positive, 20 (7 [0.8-14] years) liver/kidney microsomal antibody (LKM-1) positive, with median follow-up of 5 years (range 0.3-19). At presentation: 56% had symptoms of prolonged acute hepatitis; LKM-1 positive were younger (P = .011), with higher bilirubin (P = .007), and AST (P = .047); ANA/SMA positive had lower albumin (P = .023); 69% ANA/SMA positive, and 38% LKM-1 positive were cirrhotic (P = .080). ANA/SMA positive had increased frequency of HLA haplotype A1/B8/DR3/DR52a compared with controls (53% vs. 14%, P < .001). Of six (5 LKM-1 positive) with fulminant hepatitis, four were transplanted, one died, and one ANA/SMA positive improved with immunosuppression. Of 47 treated with immunosuppression, 2 (1 LKM-1 positive) died with no remission and 4 (2 LKM-1 positive) were transplanted 8 to 14 years after diagnosis. Immunosuppression was stopped successfully in 19% of ANA/SMA positive after a median of 3 years of treatment, but in none of LKM-1 positive. Baseline bilirubin and international normalized prothrombin ratio (INR) were independent variables predictive of outcome. In conclusion, ANA/SMA positive and LKM-1 positive AIH in childhood have clinical, biochemical, and histological differences, but similar severity and long-term outcome.

Biliary atresia: the King's College Hospital experience (1974-1995)

UNLABELLED: The survival experience of 338 infants born with biliary atresia between January 1973 and December 1995 was analyzed. All the infants had their initial surgery at a single UK centre. These infants were divided into three groups based on year of birth; group 1 (1970s, n = 38); group 2 (1980s, n = 182), and group 3 (1990s, n = 118). The data from group 1 were incomplete and selected, and comparisons with the remaining groups were therefore restricted. However, all infants who had been treated since 1980 underwent portoenterostomy or hepaticojejunostomy and were included. RESULTS: In the whole cohort there were 89 deaths (26%), 79 children (23%) who underwent liver transplantation and 170 children (50%) who were alive at last follow-up. The 5- and 10-year actuarial survival for group 2 was 50% and 41%, respectively and the 5-year actuarial survival for group 3 was 60%. Overall, 57 children have survived to 10 years after surgery for biliary atresia. There has been a progressive fall in the age at surgery from a median of 77 days in group 1, through 69 days in group 2 to 56 days in group 3 (P < .0001). However, there was no significant difference in outcome to 5 years between the age cohorts (< 40 days, 41 to 60 days, 61 to 99 days, and > or = 100 days; P > .1) for the infants treated since 1980 (n = 200). CONCLUSIONS: Portoenterostomy is an effective long-term procedure for biliary atresia in about 40% to 50% of infants. The remaining 50% to 60% will require transplantation mostly within 2 years of age, although there is also a continuing need beyond 5 and 10 years. The age at surgery has limited usefulness as a predictor of survival after portoenterostomy and certainly should not be used to dictate primary treatment.

Orthotopic liver transplantation reverses the adverse nutritional changes of end-stage liver disease in children.

The changes in growth and body composition after orthotopic liver transplantation (OLT) were studied in 61 children [median age at OLT 3.49 y (range: 0.04-14.5 y), 26 boys and 35 girls] who had survived > or = 1 y post-OLT. Height, weight, midarm circumference (MAC), triceps skinfold thickness (TSF), and subscapular skinfold thickness (SSF) were measured at OLT, 3 and 6 mo later, then annually up to 5 y. SD scores (SDS) were derived from population standards. Results are reported as mean SDS +/- SEM. At OLT the children were short and malnourished (height: -0.98 +/- 0.22; weight -0.82 +/- 0.18; MAC: -1.77 +/- 0.21; TSF: -1.27 +/- 0.17; SSF: -1.49 +/- 0.17). By 3 mo post-OLT, there was a sustained improvement in MAC (-0.73 +/- 0.22), TSF (-0.48 +/- 0.18), and SSF (-0.50 +/- 0.18). Weight SDS (-0.48 +/- 0.20) improved by 6 mo without significant change in height SDS. The three children with Alagille syndrome were smaller (height, weight, and MAC) than children with other diagnoses but did show catch-up growth. Fulminant hepatic failure was not associated with growth failure before or after OLT. Infants (n = 14) were smaller and more malnourished at OLT (smaller skinfold thicknesses and lower weight SDS) than those who received transplants at an older age. By 1 y post-OLT, the only persisting difference was in TSF. Abnormal liver function at 1 y post-OLT (n = 8) and repeated episodes of steroid-treated rejection (n = 13) were associated with worsening height and weight SDS. The use of tacrolimus for graft salvage from rejection (n = 6) was not associated with growth failure. In conclusion, end-stage liver disease has a more adverse effect on MAC, TSF, and SSF than on height and weight, but a marked and rapid improvement occurred post-OLT. Children who were most severely malnourished and growth restricted at the time of OLT showed the greatest catch-up growth after OLT.

Ocular ultrasound in Alagille syndrome: a new sign.

BACKGROUND: Alagille syndrome (AS) is one of six forms of familial intrahepatic cholestasis, all of which present with neonatal jaundice and paucity of intrahepatic bile ducts. Differentiation of these individual syndromes is crucial as their treatments and prognoses vary. It is the ophthalmic features, posterior embryotoxon on particular, that distinguish AS. METHODS: The authors performed full ocular examination, including A- and B-scan ultrasound, refraction, and, where possible, fluorescein angiography in 20 unrelated children with AS and 8 with non-AS-related cholestasis. RESULTS: There was ultrasound evidence of optic disc drusen in at least one eye in 95% and bilateral disc drusen in 80% of patients with AS but in none of the patients who were non-AS at the time of examination. Independent review of hard-copy scans suggested drusen in at least one eye in 90% of the cases and bilateral drusen in 50%, although this latter figure rose to 65% on review of the angiograms. This is markedly higher than the incidence in the normal population (0.3%-2%). Axial lengths were shorter than expected for the older age group (older than 10 years of age), but this was not associated with gross ametropia. CONCLUSION: This strong association of AS and optic disc drusen has not been reported previously and represents not only the first significant association between a systemic condition and disc drusen but also a possibly useful tool in the diagnosis of AS, especially in young children.

Tacrolimus (FK506) malabsorption: management with fluconazole coadministration.

We report the use of fluconazole to control primary immunosuppressive management with tacrolimus in a 9-year-old liver transplant recipient. Progressive increases in the doses of both cyclosporin (up to 20 mg/kg/day) and, subsequently, tacrolimus (up to 60 mg/day) failed to maintain immunosuppressive levels of both agents. After excluding poor compliance, drug interactions and analytical problems and identifying poor bioavailability (< 2.6%) and rapid clearance (4.2 l/h), fluconazole (100 mg/day) was initiated to inhibit tacrolimus metabolism and consistent therapeutic blood levels of tacrolimus were achieved. However, graft function had deteriorated irrevocably and retransplantation was performed. Simultaneous use of tacrolimus (5 mg/day) and fluconazole (100 mg/day) maintained immunosuppression after transplantation. Three weeks later, obstruction of the Roux loop caused deteriorating liver function and tacrolimus blood levels fell. After correction at laparotomy, stabilisation was achieved and discharge was possible on 5 mg tacrolimus b.i.d. plus fluconazole (100 mg).

Current therapy for Crigler-Najjar syndrome type 1: report of a world registry.

This study represents a multicenter survey on the management of patients with Crigler-Najjar syndrome (CNS) type 1. The aim of the survey was to find guiding principles for physicians in the care of these patients. Fifty-seven patients were included. At the time of inclusion, 21 patients had received a liver transplant (37%). The average age at transplantation was 9.1 +/- 6.9 years (range, 1-23 years); the age of the patients who had not been transplanted at the time of inclusion was 6.9 +/- 6.0 years (range, 0-23 years). Brain damage had developed in 15 patients (26%). Five patients died, and 10 are alive with some degree of mental or physical handicap. In 2 patients, ages 22 and 23 years, early signs of bilirubin encephalopathy could be reversed, in 1 by prompt medical intervention followed by liver transplantation and in the other by prompt liver transplantation. Seven patients underwent transplantation with some degree of brain damage at the time of the surgery; 1 of these died after retransplantation, 2 improved neurologically, and 4 remained neurologically impaired. The age of 8 patients with and 13 without brain damage at or before transplantation was 14.3 +/- 5.9 and 5.9 +/- 5.4 years (P < .01), respectively. Therapy of CNS type 1 consists of phototherapy (12 h/d), followed by liver transplantation. Phototherapy, although initially very effective, is socially inconvenient and becomes less efficient in the older age group, thus also decreasing compliance. Currently, liver transplantation is the only effective therapy. This survey shows that, in a significant number of patients, liver transplantation is performed after some form of brain damage has already occurred. From this, one must conclude that liver transplantation should be performed at a young age, particularly in situations in which reliable administration of phototherapy cannot be guaranteed.

The changing clinical pattern of Reye's syndrome 1982-1990.

OBJECTIVE: To describe trends in the clinical pattern of Reye's syndrome in the British Isles between 1982 and 1990; and to determine the relation between any changes and the June 1986 warnings against the use of aspirin in children. DESIGN: Development, and application to reported cases, of a scoring system designed such that patients showing the typical clinical and pathological features of 'classical' Reye's syndrome scored highly. The relations between 'Reye scores' and a number of explanatory variables were explored using multivariable analysis. SETTING: British Isles. SUBJECTS: 445 cases fulfilling the Reye's syndrome case definition reported to the surveillance scheme between January 1982 and December 1990. MAIN OUTCOME MEASURE: Individual 'Reye score'. RESULTS: Cases with high scores were more likely to have occurred in the 4 1/2 year period before June 1986 compared with the subsequent period (p < 0.006). Numbers of cases in the low and intermediate score categories declined by about 50% after June 1986, whereas those in the high category fell by 79%. High scorers were more likely to have received aspirin (p < 0.0001) and were older than intermediate and low scorers (p < 0.008). No relation was identified between score and season of onset. CONCLUSIONS: The decline in Reye's syndrome after the aspirin warnings cannot be explained entirely, as has been proposed, by improved diagnosis of 'Reye-like' inherited metabolic and other disorders: this would not account for the greater decline of the high scoring subgroup which also contained those cases most likely to resemble 'classical' Reye's syndrome and to have received aspirin. This study provides further evidence for the role of aspirin in a subset of cases meeting the standard diagnostic criteria for Reye's syndrome and supports the need to consider this disorder as a heterogeneous group of conditions including Reye-like inherited metabolic disorders.

Hepatic artery thrombosis after liver transplantation in children under 5 years of age.

The incidence of hepatic artery thrombosis (HAT) following orthotopic liver transplantation in children varies from 4% to 26% and represents a significant cause of graft loss. The purpose of this study was to analyze the risk factors for HAT following liver transplantation in children less than 5 years old. Seventy-three transplants were performed in 62 children under 5 years of age, including 16 for acute hepatic failure, 46 for chronic liver disease, and 11 retransplants. Twenty-four whole liver grafts (WLG) and 49 reduced size grafts (3 right lobes, 16 left lobes, and 30 left lateral segments) were transplanted. The recipient common hepatic artery was used to provide arterial inflow in 22 transplants and an infrarenal iliac conduit in 51 transplants. The overall incidence of HAT was 8 out of 73 transplants (11%). The cold ischemia time (14.3 +/- 3.03 hr) in this group was significantly longer than the cold ischemia time for those without HAT (11.7 +/- 3.94 hr) (P = 0.049). The incidence of HAT for whole and reduced grafts was 25% (6/24) and 4% (2/49), respectively (P = 0.01). HAT occurred in 6 of 22 grafts (27.3%) revascularized from the recipient common hepatic artery, compared with 2 of 51 grafts (3.9%) using an infrarenal arterial conduit (P = 0.008). The combination of recipient hepatic arterial inflow to a WLG resulted in HAT in 50% (6/12), whereas there were no cases of HAT with an iliac conduit to a WLG (P = 0.01). Of the eight patients with HAT, five are alive (median follow-up, 20 months; range, 7-27 months). Five patients were retransplanted, three within the first 2 weeks and two at 4 and 5 months for abnormal liver function in association with clinical and histological features of chronic rejection. Prolonged cold ischemia time and use of a whole graft with recipient hepatic arterial inflow are risk factors for developing HAT. The use of reduced size grafts and infrarenal iliac arterial conduits are associated with a low incidence of HAT.

Choledochal cysts: lessons from a 20 year experience.

Cystic dilatation of the biliary tree is a rare congenital anomaly. To determine mode of presentation, diagnostic pitfalls, and long term outcome after surgery, 78 children (57 girls, 21 boys) with choledochal cyst treated between 1974 and 1994 were reviewed. Anatomical types were: Ic (n = 44), If (n = 28), IVa (n = 4), and V (n = 2); a common pancreaticobiliary channel was identified in 76% patients. Age at presentation ranged from 0-16 (median 2.2) years, six patients being diagnosed by prenatal ultrasonography. Of the 72 patients diagnosed postnatally, 50 (69%) presented with jaundice, associated with abdominal pain in 25 or a palpable mass in three, 13 (18%) presented with pain alone, and two (3%) with a palpable mass. The classic triad of jaundice, pain, and a right hypochondrial mass was present in only four (6%). Four children presented acutely after spontaneous perforation of a choledochal cyst, two presented with ascites and one cyst was discovered incidentally. Plasma and/or biliary amylase values were raised in 30 of 31 patients investigated for abdominal pain; seven had evidence of pancreatitis at operation. In 35 of 67 (52%) patients referred without previous surgery, symptoms had been present for more than one month, and in 14 of them for more than one year, before diagnosis. Delayed referral was due to misdiagnosis as hepatitis (n = 12), incomplete investigation of abdominal pain (n = 6), and failure to note the significance of ultrasonographic findings (n = 10). Two patients referred late died from liver failure. Of the 76 patients with type I or IV cysts, 59 underwent radical cyst excision and hepaticojejunostomy as a primary procedure and 10 as a secondary operation after previously unsuccessful surgery. Sixteen patients have been lost to follow up but most of the remainder are well after a mean period of 4.1 (0.1-13) years. Choledochal cysts are often misdiagnosed, but prognosis is excellent if radical excision is performed.

The major histocompatibility complex influences the development of chronic liver disease in male children and young adults with cystic fibrosis.

BACKGROUND/AIMS: Chronic liver disease is a well-recognised complication of cystic fibrosis. Recent reports suggest that its development is not determined by specific mutations within the cystic fibrosis gene; however, familial clustering of portal hypertension cases and inappropriate immune responses against liver membrane antigens demonstrated in children with cystic fibrosis and chronic liver disease suggest that other genetic loci may be relevant. As the major histocompatibility complex has an important immunoregulatory role, we have investigated for associations with this complex and chronic liver disease in cystic fibrosis. METHODS: We have determined human leucocyte antigen class I (A and B) and class II (DR) phenotypes by serological tissue typing and class II (DR and DQ) and class III (complement component C4 and 21-hydroxylase) gene polymorphisms in 274 children and young adults with cystic fibrosis, of whom 82 had evidence of chronic liver disease with portal hypertension in 49, and 146 healthy controls. RESULTS: A marked difference in human leucocyte antigen frequency was limited to DQ6, which was found in 66.7% of cystic fibrosis patients with liver disease compared to 32.9% of patients with no liver disease (Pc < 0.03) and 28.8% of controls (Pc < 0.006). An increased frequency of the two antigens in strong linkage disequilibrium with DQ6 was also observed within this patient group, namely DR15 and B7. When the patients were stratified for the presence of portal hypertension, these observations were confirmed, but the human leucocyte antigen associations were significant only for male patients and there was no association with the age of onset of liver disease. CONCLUSIONS: These data suggest that the haplotype B7-DR15-DQ6 may carry an increased risk of development of liver disease in male cystic fibrosis patients.

Copper-associated liver disease in childhood.

BACKGROUND/AIMS: Indian childhood cirrhosis is associated with high liver copper concentrations and progressive liver disease with a high mortality. Early treatment with penicillamine was found to reduce mortality and reverse liver damage. We aimed to define the clinical features of copper-associated liver disease outwith the Indian subcontinent and encourage the earlier consideration of the syndrome in cryptogenic liver disease. METHODS: Three European children presented between 10 and 29 months of age with abdominal distension, pyrexia and hepatosplenomegaly. Over 1-5 weeks their condition deteriorated rapidly due to liver failure. Two died within 2 months of onset and one received a successful liver transplant. In two cases consideration of the diagnosis occurred only on examination of the liver after orthotopic liver transplant or death. Light microscopy was used, with haematoxylin and eosin, reticulin and orcein stains. Tissue, plasma and water copper levels were measured by flame atomic absorption spectrometry. RESULTS: All had micronodular cirrhosis and severe hepatocellular necrosis with Mallory bodies and copious-orcein positive material. Liver copper concentrations ranged from 1100-1310 micrograms/g dry weight. For two patients domestic water with high copper content had been used for the preparation of feeds. No environmental source of excess copper could be identified in the third case. CONCLUSIONS: We suggest that the above condition, which is called Indian childhood cirrhosis in the Indian subcontinent and Copper Storage Disease elsewhere, would be better named 'Copper-Associated Liver Disease in Childhood', emphasising the need to consider this disorder in unexplained liver disease and to seek possible sources of excessive copper intake.

Liver transplantation for neonatal haemochromatosis.

Two cases of neonatal haemochromatosis, a rare and often fatal metabolic disorder, presenting with acute liver failure, are reported. Both presented in the first week of life with hypoglycaemia, jaundice, and coagulopathy, with rapid deterioration of liver function. Both received a transplantation using reduced liver grafts. One child was well 18 months later. Few survivors have been reported and despite the difficult perioperative management, liver transplantation is the best treatment for neonatal haemochromatosis.

Prognostic value of serum hyaluronic acid and type I and III procollagen propeptides in extrahepatic biliary atresia.

Although portoenterostomy has greatly improved the prognosis of extrahepatic biliary atresia (EHBA), 10-20% of patients still die before 5 y of age, and the only treatment option is liver transplantation (LT). To investigate whether these patients may be identified at an early stage, when the changes of successful LT are optimal, we have measured serum concentrations of hyaluronic acid (HA), the amino-terminal propeptide of type III procollagen (PIIINP) and the carboxy-terminal and amino-terminal propeptides of type I procollagen (PICP, PINP) in 24 selected patients with EHBA, both before portoenterostomy and then every 6 mo until death (n = 10, age at death = 7-20 mo), LT (n = 6, age at LT = 1.1-4.8 y) or 5 y of age (n = 8). Raised serum HA above 200 micrograms/L before portoenterostomy identified those patients who would die or require LT in the first 5 y of life with a positive predictive value of 88%; after portoenterostomy, longitudinal changes in HA reflected clinical status in each patient. None of the other three markers was of prognostic value, and only PIIINP showed any relationship with clinical status, and then only up to 1.5 y. Interestingly, PINP (but not PICP) tended to be low in all patients before portoenterostomy and may reflect impaired bone collagen metabolism during early skeletal changes in EHBA. This study therefore suggests that measurement of serum HA may be a useful complementary test in EHBA, particularly in identifying, at an early stage, those patients who should be considered for LT.