The changing pattern of diagnosis of infantile cholestasis.

OBJECTIVE: Cholestatic liver disease in infancy is caused by a wide range of conditions. This study reviews the pattern of diagnosis of infants with cholestasis presenting to a tertiary referral paediatric hospital in Sydney, Australia, during a 12-year period (1985-96). METHODOLOGY: Infants aged less than 6 months with cholestasis were identified retrospectively from hospital records and data retrieved from the medical records. RESULTS: There were 205 infants identified as having cholestatic liver disease. The aetiology of the cholestasis was idiopathic in 25%, metabolic/genetic in 23%, and due to obstruction in 20%, parenteral nutrition in 20%, infection in 9% and bile duct hypoplasia in 3%. CONCLUSIONS: This study highlights the changing patterns of diagnosis of cholestatic liver disease in infants at a tertiary paediatric facility, demonstrating that up to 50% of cases are now due to genetic/metabolic diseases or parenteral nutrition, and a high proportion are due to idiopathic disease.

Accidental paracetamol overdosing and fulminant hepatic failure in children.

OBJECTIVE: To delineate clinical characteristics useful for identifying children with liver failure due to accidental paracetamol overdose. DESIGN: Retrospective review of medical records of all patients admitted from 1985 to 1998 with fulminant hepatic failure. SETTING: Royal Alexandra Hospital for Children, a tertiary referral centre for paediatric liver transplantation. MAIN OUTCOME MEASURES: Contribution of paracetamol to liver failure; other risk factors for liver failure; comparison of clinical features of paracetamol group and others. RESULTS: 18 patients were identified. Eight were considered to have accidental paracetamol hepatotoxicity. In a further three, other risk factors were present but paracetamol was considered a major contributor to liver failure. The seven remaining patients had other risk factors for liver failure. Patients with paracetamol-induced liver failure usually had an acute prodromal illness with prolonged fasting and, at presentation, had encephalopathy, coagulopathy, very high transaminase levels, but disproportionately low total bilirubin levels. Five patients had hypoglycaemia. End-stage liver failure occurred in 4/11 of the paracetamol group compared with 7/7 of the others. CONCLUSION: Accidental paracetamol overdose is associated with fulminant hepatic failure in infants and children. Patients present with high transaminase levels and liver synthetic failure out of proportion to the level of serum bilirubin. Prompt identification of such patients is important as many recover with supportive therapy.

ABO blood group incompatibility in liver transplantation: a single-centre experience.

BACKGROUND: For most organ transplantation (Tx), ABO blood group incompatibility (ABOI) is an absolute contraindication because of the high incidence of hyperacute rejection (HAR). While HAR occurs in ABOI liver Tx (LTx), it is known that some liver grafts can be accepted. METHODS: ABO-incompatible (ABOI) liver allografts were used in seven of 355 orthotopic LTx operations performed at our institution over a 10-year period. All seven recipients were in fulminant hepatic failure (FHF) prior to Tx. RESULTS: Following Tx, all grafts functioned immediately. One patient died without recovering consciousness. Six patients recovered consciousness following Tx but three patients subsequently required re-transplantation (with ABO-compatible grafts (ABOC)) because of severe acute rejection (2) and chronic rejection (1). Hyper-acute rejection did not occur. All six patients are now well, with a mean survival of 61.5 months. When compared to 36 other FHF patients who received ABOC grafts, graft survivals were 3/7 (43%) for ABOI versus 23/36 (64%) for ABOC (P = not significant (NS)). Patient survivals were 6/7 (85.7%) for ABOI patients and 23/36 (64%) for ABOC (P = NS). The re-transplantation rate was significantly higher in the ABOI group (P = 0.001). CONCLUSIONS: The results confirm that ABOI liver grafts should be used in urgent circumstances when compatible grafts are not available. Some grafts function indefinitely, while those that fail may function for sufficient time to allow successful retransplantation with ABOC grafts.

Hepatobiliary disease in cystic fibrosis patients with pancreatic sufficiency.

Focal and multilobular biliary cirrhosis are considered pathognomonic of cystic fibrosis (CF) and almost invariably have been reported in patients with steatorrhea. In contrast, patients with pancreatic sufficiency and normal absorption are considered less likely to develop liver or biliary tract problems. The authors report three patients with CF and pancreatic sufficiency, presenting with recurrent abdominal pain (unrelated to pancreatitis). All had common bile duct disease, one with multilobular cirrhosis and portal hypertension. Pancreatic sufficiency was proven by quantitative pancreatic stimulation tests, 3-day fecal fat analyses, and serum pancreatic isoamylases. All three patients had mild lung disease. Two were homozygous for the common delta F508 mutation, and the other, a delta F508 compound heterozygote. Hepatobiliary structure and function were determined by serial hepatobiliary scintigraphy, percutaneous transhepatic cholecystography, and biochemical liver function tests. Patients 1 and 3 had mild hepatomegaly, normal liver biochemistry, and distal common bile duct strictures. Patient 2 had a firm nodular liver with splenomegaly, abnormal liver biochemistry, and a cholangiographic appearance of sclerosing cholangitis. All have undergone operative treatment for persistent abdominal pain. These cases confirm the occurrence of common bile duct pathology and liver disease in patients with CF and pancreatic sufficiency. They demonstrate that liver and biliary tract disease can occur independently of the underlying disease severity and the presence of steatorrhea. Further, they suggest that obstruction of the biliary tract may be an additional factor in the evolution of liver disease in CF.

Renal proximal tubular dysgenesis associated with severe neonatal hemosiderotic liver disease.

We report the necropsy findings for three infants with the unusual combination of proximal renal tubular dysgenesis and severe congenital liver disease with excessive iron in several organs resembling neonatal hemochromatosis. Two of the infants were caucasian siblings and one was an Australian aborigine. One died in utero at 35 weeks of gestation and two died at 7 days. The liveborn infants presented with anuria and liver failure. The livers all showed marked loss of hepatocytes and replacement by pseudotubules in the collapsed lobules. The liveborn infants also showed giant cell transformation of hepatocytes, small regenerative nodules, cholestasis, and normal bile ducts. Absence of proximal renal convolutions was confirmed by epithelial membrane antigen positivity in nearly all tubules. In each family there was another sibling with congenital liver disease, fatal in one case, but no renal tubular dysgenesis. No infection or metabolic disease was uncovered in any of our patients, and the cause of the hepatocyte destruction was not determined. The combination in three infants of two rare congenital diseases could be genetic or acquired in utero from the same etiological agent. Alternatively, the absence of proximal convolutions could be secondary to hypoperfusion, perhaps because of shock due to extensive necrosis of hepatocytes.

Sclerosing cholangitis in children with inflammatory bowel disease.

BACKGROUND: Primary sclerosing cholangitis (PSC) with inflammatory bowel disease (IBD) has been rarely reported in children. AIM: To describe the clinical presentation, sequential liver function test abnormalities, radiological bile duct anomalies and liver histology in four children with PSC and IBD. METHODS: Over a period of 18 years, four of 130 patients with IBD developed abnormal liver function tests. Three of the four patients had ulcerative colitis and the other Crohn's disease. All four patients had baseline and follow-up liver function tests, percutaneous transhepatic cholangiography and a needle biopsy of the liver. RESULTS: The four patients at presentation had minimal symptoms or signs of liver disease. All had elevation of serum transaminases, gamma glutamyl transferase and/or alkaline phosphatase. Three had the typical onion skin fibrosis of bile ducts. Percutaneous transhepatic cholangiography demonstrated irregularity and beading of the hepatic and common bile ducts in three patients. The other with normal cholangiography had fibrosing cholangitis on liver biopsy and was considered to have small duct disease. CONCLUSIONS: We conclude that yearly biochemical assessment of liver function should be performed on all children with IBD, and if abnormal should raise the suspicion of PSC. The latter diagnosis can be confirmed by liver biopsy and cholangiography.

Temporary wound closure with expanded polytetrafluoroethylene in pediatric liver transplantation.

A shortage of donor organs of appropriate size causes lengthy delays for many children awaiting liver transplantation, and results in the death of some children on the active waiting list. A major contribution to overcoming this problem has been the use of reduced livers from adult donors. However, reduced adult livers are frequently too large to be used for small pediatric recipients ( less than 8 kg) because of the serious problems which occur when too tight an abdominal closure is attempted. We report a technique which we have used successfully in 2 children, involving the insertion of a temporary patch graft of expanded polytetrafluoroethylene. This allowed comfortable abdominal wound closure, which would not otherwise have been possible. Delayed primary closure of the abdomen 4-5 days later was achieved without difficulty in each case, the liver grafts having decreased markedly in size by this time. The technique allows greater flexibility in the use of donor livers for pediatric recipients, and thus has the potential to reduce waiting times and deaths on the waiting list for small children requiring liver transplantation.

The first five years' clinical experience of the Australian National Liver Transplantation Unit.

OBJECTIVE: To report the first five years' clinical experience of the Australian National Liver Transplant Unit. PATIENTS: Three hundred and seventy patients were referred--292 adults (79%) and 78 children (21%). The major causes of liver failure in the adults were chronic active hepatitis (25%), primary biliary cirrhosis (12%), primary sclerosing cholangitis (12%), alcoholic cirrhosis (9%) and malignancy (9%). Ten per cent of patients were referred in fulminant hepatic failure. In children, the major causes were biliary atresia (40%) and inborn errors in metabolism (27%). RESULTS: Two hundred and sixty-three patients (71%) were accepted for transplantation. Of 158 (43%) accepted for early transplantation, 22 (14%) died before a donor became available. Four hundred and forty-three suitable organ donors were referred. One hundred and twenty-six patients, including 32 children (25%), received 137 grafts. Three patients with renal failure due to hyperoxaluria type 1 received concurrent renal grafts. Ninety-two patients survived (73%). For all recipients, one-year survival was 75%. Two, three and four-year survivals were 69%. One to four-year survivals for adults with benign conditions were 77%, contrasting with results for those with hepatic malignancy (40% one-year survival). Children weighing more than 8 kg had good outcomes whether they received whole grafts or reduced-size grafts (83% one to five-year survival in both cases). Infants weighing less than 8 kg who received reduced adult grafts did significantly worse (37% one to-five year survival, P less than 0.05). Thirteen (87%) of 15 patients with fulminant hepatic failure who received grafts survived. Five of these patients were given ABO-incompatible grafts and two subsequently required retransplantation. All three patients with concurrent renal and hepatic grafts survived. Rehabilitation of survivors was excellent with 95% of adults and 100% of children pursuing normal activities. Only three grafts (2%) failed with primary non-function, all in infants because of graft infarction. Graft survival was significantly worse (P less than 0.01) in patients with a positive result to a direct cross match test against the donor. CONCLUSIONS: The need for liver transplantation in Australia is approximately eight per million of population per year. More donor offers are required to prevent deaths of patients on the waiting list. Reduced-size livers are successful for children and have alleviated considerably the critical shortage of paediatric donor livers. Successful treatment by liver transplantation can now be achieved in more than 80% of patients with non-malignant liver disorders including those with fulminant hepatic failure not responding to conservative therapy.

Acute and subacute fulminant hepatic failure: the role of liver transplantation.

OBJECTIVES: To report the experience of the Australian National Liver Transplant Unit with patients with fulminant hepatic failure and to describe the role of liver transplantation. PATIENTS: Twenty-seven patients presented with acute or subacute fulminant hepatic failure during the period from January, 1986, to March, 1990. Twenty-two had acute and five had subacute fulminant hepatic failure. The causes were hepatitis B in 10 patients, presumed non-A, non-B (NANB) hepatitis in eight patients, drug-induced hepatic damage in five patients, and Wilson's disease in four patients. There were 13 males and 14 females. Ages were 2-43 years (mean, 23). Twenty patients (74%) were in grade IV encephalopathy on presentation. RESULTS: Six patients (22%) began to improve soon after admission and went on to full recovery. Spontaneous recovery was more frequent in patients with drug-induced hepatic damage (four patients [80%]) and was less frequent in those with hepatitis B (one patient [10%]) and NANB hepatitis (one patient [12%]). The other 21 patients (78%) were considered for orthotopic liver transplantation. Eight (30%) were judged to be unsuitable and went on to early death. Thirteen (48%) were suitable for transplantation. Of these five (19%) died before a liver donor became available and eight (30%) received liver grafts and went on to full recovery. Overall, 14 patients (52%) survived and 13 (48%) died. Patients with Wilson's disease (four [100%]) were most suitable for orthotopic liver transplantation whereas eight (44%) of those with hepatitis B or NANB hepatitis were unsuitable. Of the eight patients receiving liver grafts one had hepatitis B, three had NANB hepatitis and four had Wilson's disease. Five were in grade IV encephalopathy at the time of operation. The mean waiting time for transplantation was 6.4 days. Five patients received ABO blood group compatible grafts and three received ABO incompatible grafts. Of the latter group, two subsequently required secondary orthotopic liver transplantation with ABO compatible grafts. All eight patients who received transplants are alive and well 3-24 months after the operation. No patient has any neurological sequelae. CONCLUSIONS: Orthotopic liver transplantation is a preferred option for patients with fulminant hepatic failure whose condition is not responding to conservative management. ABO incompatible livers transplanted in emergency circumstances may prove life-saving either by functioning successfully or by providing time during which ABO compatible grafts become available.(ABSTRACT TRUNCATED AT 400 WORDS)

Failure of liver transplantation in Wilson's disease with pulmonary arteriovenous shunting.

A 12-year-old boy with Wilson's disease developed exertional dyspnea, cyanosis, and finger clubbing 10 months after diagnosis. The hypoxemia was caused by arteriovenous shunting, demonstrated by radionuclide scanning and pulmonary arteriography. Orthotopic liver transplantation was performed after the development of severe hypoxemia. There was no apparent reversal of the intrapulmonary arteriovenous shunting and he died 10 days posttransplantation of multiple organ failure secondary to hypoxemia. Monitoring arterial oxygen saturation in children with cirrhosis is warranted since the presence of significant arteriovenous shunting may influence prognosis and decisions regarding liver transplantation.

Pancreatic function in infants identified as having cystic fibrosis in a neonatal screening program.

The use of the dried-blood immunoreactive-trypsin assay for the detection of cystic fibrosis in newborns has been questioned on the grounds that it may fail to identify patients with enough pancreatic function to have normal fat absorption. To investigate this possibility, we assessed pancreatic function in 78 patients identified in a neonatal screening program as having cystic fibrosis. The diagnosis of cystic fibrosis was confirmed by abnormal results on a sweat chloride test. The results of measurements of fecal fat excretion, pancreatic-stimulation tests, and estimations of the serum level of pancreatic isoamylase indicated that 29 of the 78 children (37 percent) had substantial preservation of pancreatic function. These children (median age, four years) had growth that was close to normal and comparable to growth in children with severe pancreatic insufficiency who received oral enzyme therapy. Pancreatic insufficiency subsequently developed in 6 of the 29 patients, at 3 to 36 months of age. We conclude that the serum immunoreactive-trypsin assay used in neonatal screening programs identifies patients with cystic fibrosis who have sufficient pancreatic function to have normal fat absorption and that a substantial proportion of infants identified as having cystic fibrosis are in this category.

VIP secreting tumours in infancy. A review of radiological appearances.

Vasoactive intestinal polypeptide (VIP) secreting neural crest tumours are an uncommon but important treatable cause of intractable childhood diarrhoea. The radiological appearances of two cases are presented with a review of radiological findings in childhood VIP secreting neural crest tumours. Twenty eight cases of childhood VIP secreting neural crest tumours were reviewed. Nineteen (68%) were ganglioneuroblastomas and nine (32%) were ganglioneuromas. The majority of tumours (66%) were in a paravertebral location in the abdomen indicating that a search for such a tumour should be initiated at this site. Eighteen of the twenty-eight cases reviewed discussed relevant radiological investigations. Calcification was detected in 50% of abdominal radiographs. Gut dilatation was often a prominent feature. A mass was detected in 5 of 5 cases where ultrasound findings were reported, and seven of seven cases with CT findings reported. Prior to the availability of CT and ultrasound the most useful investigation was IVU which demonstrated evidence of a mass in 5 of 9 cases. The presence of paravertebral calcification and gut dilatation on the plain radiograph of a child with intractable diarrhoea suggests the presence of a VIP secreting neural crest tumour. If an abdominal tumour is not found in the appropriate clinical setting and VIP levels are elevated, a widespread search of the paravertebral region is indicated.

Liver transplantation: an Australian experience.

During a 4 and a half-year experience, 283 patients were referred to the Australian National Liver Transplant Unit. Sixty (21%) were children. The major causes of liver failure in the adults were chronic active hepatitis (27%), primary biliary cirrhosis (13%), primary sclerosing cholangitis (12%), fulminant hepatic failure (9%), alcoholic cirrhosis (9%), and malignancy (9%). In the children they were biliary atresia (43%) and inborn errors of metabolism (18%). One hundred and ninety-seven (69%) were accepted for liver transplantation. Of 111 (39%) accepted for early transplantation, 18 (16%) died before a donor became available. There were 319 possible organ donors. Ninety patients (24 of them children) received 100 grafts. Sixty-three (70%) patients survived. For all recipients, 1-year survival was 73%. Two-, 3- and 4-year survivals were 67%. One- to 4-year survivals for adults with benign conditions were 76%, contrasting with results for those with hepatic malignancy (20% 1-year survival). Children weighing greater than 8 kg did well whether they received whole grafts (80% 1- to 4-year survival) or reduced grafts (75% 1- to 4-year survival). Infants weighing less than 8 kg who received reduced adult grafts did significantly worse (20% 1- to 4-year survival). All 8 (100%) patients with fulminant hepatic failure who received grafts survived, including 3 who received ABO-incompatible grafts, though 2 of these subsequently required retransplantation. Rehabilitation of survivors was excellent with 91% of adults and 94% of children pursuing normal activities. Only 2 (2%) grafts failed with primary nonfunction, both in infants because of infarction. Graft survival was significantly worse (p less than 0.01) in patients with a positive direct crossmatch test against the donor. We calculate that the need for liver transplantation in Australia is approximately 7 per million of population per year. Increased donor offers are required to avoid deaths of patients on the waiting list. Reduced-size adult livers are successful for children and have alleviated considerably the critical shortage of pediatric donor livers. Liver transplantation is a highly satisfactory treatment for patients with benign liver disorders but not for those with malignant conditions. Patients with fulminant hepatic failure not responding to conservative therapy should be treated by liver transplantation. In this and other urgent circumstances, an ABO-incompatible liver may be lifesaving though retransplantation with an ABO-compatible liver may subsequently be required. The results of liver transplantation for nonmalignant conditions have improved steadily with clinical experience, with 1- and 2-year patient survivals during the past 28 months of 85%.

Outcome of surgery for biliary atresia.

Forty-seven infants (26 male, 21 female) with biliary atresia under- went hepatic portoenterostomy during the 16-year period 1971-87. Twenty-six patients (55%) are alive 1-17 years after surgery, with 21 (45%) being jaundice-free. For children who became jaundice-free, the mean age at surgery was 78 days (range: 34-125 days), compared with 97 days (range: 48-224 days) for those who did not. Of 39 patients operated on at less than 120 days of age, 24 (60%) are alive. All four patients operated on after 125 days of life died. Of 31 patients operated on more than 5 years ago, 12 (39%) have survived, the oldest being 17 years. Ten (32%) have normal serum bilirubin concentrations, have non-active cirrhosis on liver biopsy, have had normal growth and development, and lead normal lives. The oldest two patients suffered variceal haemorrhage in their teenage years. In our recent experience, 11 of 16 patients (69%) have had complete clearing of jaundice, lead normal lives and do not currently require assessment for liver transplantation. It is believed that early referral of children with biliary atresia to experienced surgical units for portoenterostomy will lead to long-term survival, without the need for liver transplantation in a majority of cases. Liver transplantation should be offered in infancy only after failed portoenterostomy, except for patients presenting after 120 days in whom transplantation may be considered primary therapy.

Familial Mediterranean fever in six Australian children.

Six Australian children fulfilled the diagnostic criteria for familial Mediterranean fever. None had a family history of the disease, but five children came from ethnic groups that typically were associated with the disease. The symptoms commenced before five years of age in all the children, and three children underwent unnecessary operations because of the symptoms of recurrent fever and abdominal pain. All six children benefited from colchicine prophylaxis by mouth. More cases can be expected to be recognized in Australia because of the large number of Australian children with a Mediterranean heritage.