Colitis-associated sclerosing cholangitis in children: a single centre experience.

OBJECTIVE: Sclerosing cholangitis (SC) is an important immune-mediated extra-intestinal manifestation of inflammatory bowel disease (IBD), primarily affecting patients with ulcerative colitis (UC). The reported prevalence of SC in adults and children with UC is low at between 2 and 7%. We present findings from a hepatological work-up in children with inflammatory colitis and elevated liver function tests (LFT) from a tertiary paediatric gastroenterology unit. DESIGN: This study is designed as a retrospective review of the medical records of 17 children and adolescents with inflammatory colitis and abnormal LFTs who presented to our IBD service between April 2004 and April 2012. RESULTS: Over the eight year period a total of 52 patients were diagnosed with inflammatory colitis (ulcerative colitis and unclassified colitis). Seventeen of the 52 patients had abnormal liver function tests and underwent liver biopsy and cholangiography. All 17 patients (32.6%) were diagnosed with hepato-biliary disease. CONCLUSION: This is one of the largest reported series of children with inflammatory colitis and associated hepato-biliary disease. The data from this patient group indicate that the prevalence of IBD-associated hepato-biliary disease in children with abnormal LFTs is much higher than previously reported. As the diagnosis of IBD-associated hepato-biliary disease affects patient management, we recommend liver biopsy and cholangiography in all children with inflammatory colitis and abnormal liver function tests.

Use of small bowel MRI enteroclysis in the management of paediatric IBD.

INTRODUCTION: Children with inflammatory bowel disease (IBD) frequently present with small bowel involvement at some stage of their disease. Hence, reliable assessment of the entire small bowel is required in order to adjust treatment accordingly. Recently, magnetic resonance imaging (MRI) of the small bowel in combination with luminal contrast agent delivered via a naso-jejunal tube (MR enteroclysis) is an emerging technique demonstrating good results in adult patients. However, data on its use and benefits in children is limited. AIMS: In this study we report our experience on performing small bowel MR enteroclysis (MRE) in children with IBD. Specifically, we reviewed indications, MR findings, advantages and disadvantages of the technique in a tertiary unit. METHODS: A total of 34 MRE studies (29 paediatric IBD patients) were retrospectively analysed. All patients underwent upper and lower endoscopy under general anaesthetic (GA) the day before MR imaging was performed. Nasojejunal (NJ)-tube was placed during endoscopy. RESULTS: Frequently detected findings included small and large bowel wall thickening, small bowel strictures and intestinal lymph node enlargement. Importantly, in all our clinical cases, MRE results were key to making a clinical decision in the given scenario regardless of whether MRE findings were positive or negative. CONCLUSIONS: Within our setup, MR enteroclysis is a well-tolerated, sensitive technique for small bowel imaging, providing detailed information at crucial clinical decision points. Moreover, accurate information then allows appropriate clinical decisions to be made.

Intestinal alpha-defensin expression in pediatric inflammatory bowel disease.

BACKGROUND: Reduced alpha-defensin expression has been reported in the terminal ileum (TI) of adult patients with ileal Crohn's disease (CD). However, little is known about alpha-defensin expression in children with chronic inflammatory bowel disease (IBD). METHODS: In all, 283 intestinal biopsies were obtained from children with CD, ulcerative colitis (UC), and healthy controls. Absolute mRNA copy numbers for HD5, HD6, IL-8, Villin 1, and Tcf-4 were analyzed by reverse-transcription polymerase chain reaction (RT-PCR). HD5 immunostaining was performed on biopsy sections and patients genotyped for NOD2 mutations. RESULTS: Equal expression levels of alpha-defensins (HD5 and HD6) were found in TI biopsies of children with ileal CD (L1+L3) compared to patients with colonic disease (L2) and healthy controls. In contrast, we found significantly higher levels of alpha-defensins in the TI of children with UC compared to CD and controls. Reduced expression of Tcf-4 was observed exclusively in the duodenum and TI of CD patients with L1+L3 phenotype. We demonstrate significantly increased expression of HD5 and HD6 in the inflamed colon of IBD children (UC and CD) attributable to the presence of metaplastic Paneth cells. CONCLUSIONS: In this study no difference in alpha-defensin expression was found in the TI of CD children and controls. However, significant reduction of Tcf-4 in L1+L3 phenotype suggests that a possibly impaired PC differentiation may lead to altered HD5 and HD6 expression at some stage of disease. Additionally, substantially increased expression of alpha-defensins in the inflamed colonic mucosa of children with IBD raises the question for their potential involvement in modulating inflammation in these patients.

Growth of long-term survivors of liver transplantation.

OBJECTIVE: To assess growth in survivors of liver transplantation. STUDY DESIGN: Growth was studied in 105 children up to seven years after liver transplantation. RESULTS: At transplantation, mean height standard deviation score (zH) was -1.22 but 19% of patients were severely growth retarded (height below 0.4th centile). Growth and pubertal retardation were seen in the first six months after liver transplantation. Significant catch up in growth and puberty continued for more than five years. At five years, mean zH was -0.95 and at seven years -0.84. The mean zH of patients at final height was -0.55. zH at six months was predicted by zH and bilirubin at the time of transplantation and prednisolone dose at six months. At four years, zH was predicted by zH at the time of transplantation and the cumulative prednisolone dose. There was no association between zH and age at transplantation, sex, or diagnosis, although those with biliary atresia and those undergoing transplantation under 2 years of age showed more initial growth delay and subsequent catch up. Average age at menarche was 14.2 years. CONCLUSIONS: The mean height of the group to have reached final height after liver transplantation was on the 27th centile. Those transplanted earlier in childhood are likely to achieve more normal final heights. High steroid dose, poor liver function, and retransplantation are associated with poorer height outcomes. Persisting severe short stature is largely confined to children with severely retarded growth at the time of transplantation. Transient delay in puberty and menarche occur early after transplantation, although appropriate pubertal progress is resumed after two to three years.

Successful use of size-mismatched liver allografts in children by delayed primary closure of the abdominal wall.

Children who are too ill to await a liver graft of suitable size may be transplanted with a relatively oversized graft by leaving the abdominal wound partially open, the defect reduced being bridged with polypropylene mesh and the mesh reduced in stages until it can be removed and the wound directly closed. This technique has been used in seven children who received nine grafts (five reduced and four full size). Their mean age was 7.3 (range 0.5-11) months and mean weight 5.8 (range 2.3-7.2) kg. Progressive reduction in the size of the transplanted liver made primary closure possible in survivors in up to four stages. Over a follow-up period of 3 to 58 months, five of the nine grafts and five of the seven patients survived. No significant complications attributable to the technique were encountered. The technique of delayed primary abdominal wall closure may be of benefit in children at risk of graft failure because of a size-mismatched graft.

Liver transplantation for hepatic cirrhosis in cystic fibrosis.

About 10% of children with CF develop hepatic cirrhosis and progressive portal hypertension. As the portal hypertension worsens these children are likely to develop serious variceal bleeding and other complications including malnutrition and a decline in respiratory function. Indices of lung function may fall as much as 50% in a year and chest infections may require frequent admissions to hospital. The respiratory symptoms are often attributed to CF related lung disease and affected children may therefore be considered unsuitable for liver transplantation. We propose a simple scoring system which can help to select patients who should be referred for assessment of liver transplantation. After careful assessment and preparation children with lung function indices as low as 30% predicted can have a successful outcome after liver transplantation. With good graft function portal hypertension is relieved and absorption, nutrition and respiratory function all improve. The improved quality of life of these children is remarkable.

Liver transplantation for homozygous familial hypercholesterolaemia.

Homozygous familial hypercholesterolaemia is a rare inherited condition with an incidence of approximately one in a million. It is associated with severe premature atherosclerosis and early death from cardiovascular complications. The results of liver transplantation reported to date have suggested only partially effective reduction of the hypercholesterolaemia. Three boys with familial hypercholesterolaemia, aged 10.0 to 15.1 years, received liver grafts at Addenbrooke's Hospital. Their untreated fasting lipid concentrations were grossly raised. All three had angiographic evidence of coronary atheroma and two had exertional angina. One child had such severe atheroma that coronary artery bypass surgery was considered necessary before liver transplantation. All three had straightforward operative and postoperative courses and their lipid concentrations returned rapidly to normal. One boy developed chronic rejection requiring retransplantation. Currently all three boys are well, on normal diets, and with normal liver function. It is concluded that (1) liver transplantation offers highly effective treatment for this lethal condition, (2) timing the operation is difficult but it should be undertaken before coronary artery disease has progressed too far (when combined liver and heart transplantation may be the only possibility), and (3) in well grown children with no previous abdominal surgery the immediate risks of liver transplantation are low but chronic rejection remains a danger.

Hypercalcaemia in primary oxalosis: role of increased bone resorption and effects of treatment with pamidronate.

Primary oxalosis is a rare congenital disorder characterised by widespread deposition of calcium oxalate crystals throughout the body. In this paper, we describe the development and treatment of hypercalcaemia associated with oxalosis in a child who had undergone renal transplantation, combined liver and kidney transplantation, and two liver retransplant procedures in the past 5 years. Hypercalcaemia occurred on three separate occasions in association with liver dysfunction due to graft rejection; renal function was not grossly impaired and serum intact parathyroid hormone levels were normal. Intravenous pamidronate therapy led to rapid normalisation of the serum calcium concentration on all three occasions. Iliac crest biopsy revealed large numbers of oxalate crystals in the bone marrow, many of which were associated with macrophages, identified using the antibody MAC 387. Bone histomorphometry demonstrated an increase in the percentage eroded surface but no increase in osteoid surface. These observations indicate that hypercalcaemia associated with oxalosis can occur in the absence of renal dysfunction and may result from excessive bone resorption, induced either directly or indirectly by macrophages surrounding oxalate crystals in the bone marrow. Pamidronate therapy was effective in restoring serum calcium to normal.

Twenty-seven years of liver transplantation at Addenbrooke's Hospital, Cambridge.

Twenty-seven years ago, liver transplantation at Addenbrooke's Hospital was a very experimental procedure. It is now recognized as an accepted mode of treatment for end-stage liver failure. In the coming year, over 600 liver transplants will take place in the United Kingdom. All western European countries now have an active liver transplantation program and more than 17,000 liver transplants have already been performed. As results improve and the procedure becomes more readily and widely accepted, the donor shortage is likely to get worse, and will be only partially met by the introduction of split livers and living-related donors.

Serum alpha-glutathione S-transferase--a sensitive marker of hepatocellular damage associated with acute liver allograft rejection.

The wide hepatic distribution, high cytosolic concentration, and short in vivo plasma half-life of serum alpha-glutathione s-transferase are properties which may make monitoring this enzyme more clinically useful than conventional biochemical liver function tests as a marker of hepatocellular damage associated with acute liver allograft rejection. In a prospective longitudinal study of 58 liver transplants in 45 patients, serum alpha-glutathione S-transferase concentrations rose significantly more consistently and more rapidly than conventional liver function tests in association with acute rejection. However, a rise in alpha-glutathione S-transferase was less specific for rejection than conventional liver function tests although none of the tests had a positive predictive value for rejection of greater than 32%. Compatible with the particularly short in vivo plasma half-life of this enzyme, alpha-glutathione S-transferase concentrations fell to or toward normal more rapidly than conventional liver function test measurements following uncomplicated transplantation as well as during high-dose steroid treatment of rejection. This may be valuable, both in improving the resolution of biochemical changes associated with early rejection episodes and in determining when treatment of rejection has been successful. Further studies are warranted, however, to assess whether the fall in GST during rejection treatment does genuinely reflect the histological resolution of rejection.

Liver transplantation for hepatic cirrhosis in cystic fibrosis.

Five children with cystic fibrosis complicated by hepatic cirrhosis received liver grafts. They all had portal hypertension with varices and three had variceal bleeding; respiratory function was only moderately impaired, but four were colonised with pseudomonas and one with aspergillus. Liver transplantation was well tolerated and there was no increase in respiratory or other early postoperative complications. Four of the children were fully well from 14 to 35 months after transplantation; the most recently transplanted had problems from a biliary stricture. In spite of the need for immunosuppression there was no increase in infection and respiratory function improved or remained stable. Once the children were stabilised after transplantation their nutrition and general health were greatly improved.

Intrapulmonary shunting in the biliary atresia/polysplenia syndrome: reversal after liver transplantation.

UNLABELLED: One hundred and seventy three children, including 93 with biliary atresia, received liver grafts at Addenbrooke's Hospital between 1983 and 1993. Of these, only seven developed cyanosis due to intrapulmonary shunting as a complication of their liver disease, and all seven of these had the biliary atresia/polysplenia syndrome. Intrapulmonary shunting was confirmed by a radioisotope scan in four children. Only one child with the syndrome did not have cyanosis when undergoing transplantation. Seven of the eight children are alive 6-54 months after transplantation, with normal pulmonary and hepatic function. Cyanosis recurred in one child who developed chronic rejection with liver failure. IN CONCLUSION: (a) there is a strong association between the biliary atresia/polysplenia syndrome and cyanosis due to intrapulmonary shunting; (b) intrapulmonary shunting is fully reversible after successful liver transplantation; and (c) cyanosis, once present, is progressive, and these children should be considered for liver transplantation as soon as it occurs.

Neurological crisis in hereditary tyrosinaemia and complete reversal after liver transplantation.

A 19 month old Indian girl with tyrosinaemia developed a severe generalised neuropathy involving both phrenic nerves. Treatment with haemarginate failed to improve her condition. After liver transplantation the raised concentrations of the neurotoxin delta amino-laevulinic acid returned to normal and gradual but complete neurological recovery occurred over a period of 13 months.

Continuous axillary nerve block for chronic pain.

Continuous axillary nerve block was used to relieve pain after a chemical burn to the arm in a child on mechanical ventilation after liver transplantation. The analgesia was sufficient to replace parenteral analgesia and allow extubation.

Glomerulonephritis with end-stage liver disease in childhood.

Renal biopsies were done perioperatively in 18 children receiving liver grafts. All specimens showed glomerulonephritis, which was mesangial-proliferative in 15 and mesangio-capillary in 3. Of the 16 children who were alive four or more months after transplantation, only 1 showed progressive deterioration of renal function; 1 other had a subnormal but static glomerular filtration rate. In all 6 children who had proteinuria before operation, the urine became normal.