PubMed Health⌕ Search

Biomedical subjects

Patrick J McKiernan

Publications and source records attributed to Patrick J McKiernan.

18 recordsLinked to original sources
PubMed2007

Paediatric Hepatology Dependency score (PHD score): an audit tool.

BACKGROUND: The aim was to develop a tool that measures patient dependency and disease severity in children with mild to severe liver disease. METHODS: The initial pilot score was based on known markers of disease severity in acute and chronic liver disease. Between 1997 and 2001, the score was modified 4 times and reduced to comprise 10 key parameters: aspartate transaminase, prothrombin time, albumin, bilirubin, ascites, nutritional support, organ dysfunction, blood product support, sepsis and intravenous access. The score's face validity, internal consistency, interobserver agreement and construct validity were evaluated statistically and by the use of endpoints such as survival and transplant after 6 months. RESULTS: The final 10 variable score was tested on 71 children admitted over two 3-month periods. The Cronbach's alpha score (a test for internal consistency) for the total score was 0.72. Serial data paralleled clinical deterioration and response to interventions. A Paediatric Hepatology Dependency score >15 had an odds ratio of 7 (P = 0.0125) for death or transplant at 6 months. The score was also found to agree with the paediatric end-stage liver disease score for the 12 patients being listed for liver transplantation (r = 0.660, P < 0.05). CONCLUSION: The Paediatric Hepatology Dependency score is valid and internally consistent and is a convenient measure of dependency and disease severity in a heterogeneous group of patients with liver disease. It also allows admissions to be audited for comparison between eras and for monitoring the progress of patients while on the ward.

Acute Disease↗
PubMed2006

Clinical and molecular genetic features of ARC syndrome.

Arthrogryposis, renal dysfunction and cholestasis (ARC) syndrome (MIM 208085) is an autosomal recessive multisystem disorder that may be associated with germline VPS33B mutations. VPS33B is involved in regulation of vesicular membrane fusion by interacting with SNARE proteins, and evidence of abnormal polarised membrane protein trafficking has been reported in ARC patients. We characterised clinical and molecular features of ARC syndrome in order to identify potential genotype-phenotype correlations. The clinical phenotype of 62 ARC syndrome patients was analysed. In addition to classical features described previously, all patients had severe failure to thrive, which was not adequately explained by the degree of liver disease and 10% had structural cardiac defects. Almost half of the patients who underwent diagnostic organ biopsy (7/16) developed life-threatening haemorrhage. We found that most patients (9/11) who suffered severe haemorrhage (7 post biopsy and 4 spontaneous) had normal platelet count and morphology. Germline VPS33B mutations were detected in 28/35 families (48/62 individuals) with ARC syndrome. Several mutations were restricted to specific ethnic groups. Thus p.Arg438X mutation was common in the UK Pakistani families and haplotyping was consistent with a founder mutation with the most recent common ancestor 900-1,000 years ago. Heterozygosity was found in the VPS33B locus in some cases of ARC providing the first evidence of a possible second ARC syndrome gene. In conclusion we state that molecular diagnosis is possible for most children in whom ARC syndrome is suspected and VPS33B mutation analysis should replace organ biopsy as a first line diagnostic test for ARC syndrome.

Abnormalities, Multiple↗
PubMed2006

Improved outcome of referrals for intestinal transplantation in the UK.

AIM: To describe the outcome of children with intestinal failure referred to Birmingham Children's Hospital (BCH) for consideration of intestinal transplantation (ITx), to determine factors for an adverse outcome and to analyse the impact of post-1998 strategies on survival. SUBJECTS AND METHODS: A retrospective analysis was performed of children referred for ITx assessment from January 1989 to December 2003. Children were assessed by a multidisciplinary team and categorised into: (a) stable on parenteral nutrition; (b) unsuitable for transplantation (Tx); and (c) recommended for Tx. To analyse the impact of the post-1998 strategies on survival, a comparison was made between the two eras (pre-1998 and post-1998). RESULTS: 152 children with chronic intestinal failure were identified (63M:89F, median age 10 months (range 1-170)). After assessment, 69 children were considered stable on parenteral nutrition (5-year survival 95%); 28 children were unsuitable for Tx (5-year survival 4%); and 55 children were recommended for Tx (5-year survival 35%, which includes 14 children who died waiting for size-matched organs). Twenty three ITx and nine isolated liver transplants (iLTx) were performed. In a multivariate analysis, the following factors in combination had an adverse effect on survival: the presence of a primary mucosal disorder (p = 0.007, OR ratio 3.16, 95% CI 1.37 to 7.31); absence of involvement of a nutritional care team at the referring hospital (p = 0.001, OR ratio 2.55, 95% CI 1.44 to 4.52); and a serum bilirubin>100 micromol/l (p = 0.001, OR ratio 3.70, 95% CI 1.84 to 7.47). Earlier referral (median serum bilirubin 78 micromol/l in the post-1998 era compared with 237 micromol/l in the pre-1998 era, p = 0.001) may be a contributory factor to improved survival. The strategies of combined en bloc reduced liver/small bowel transplantation and iLTx resulted in fewer deaths on the waiting list in the post-1998 era (2 deaths in post-1998 era v 12 deaths in pre-1998 era). The overall 3-year survival in the post-1998 era (69%) has improved compared with the pre-1998 era (31%; p<0.001) CONCLUSION: The changing characteristics at the time of referral, including earlier referral and innovative surgical strategies have resulted in improved long-term survival of children referred for ITx.

Adolescent↗
PubMed2006

Progressive histological damage in liver allografts following pediatric liver transplantation.

The long-term histological outcome after pediatric liver transplantation (OLT) is not yet fully understood. De novo autoimmune hepatitis, consisting of histological chronic hepatitis associated with autoantibody formation and allograft dysfunction, is increasingly recognized as an important complication of liver transplantation, particularly in the pediatric population. In this study, 158 asymptomatic children with 5-year graft survival underwent protocol liver biopsies (113, 135, and 64 at 1, 5, and 10 years after OLT, respectively). Histological changes we re correlated with dinical,biochemical, and serological findings. All patients received cydosporine A as primary immunosuppression with withdrawal of corticosteroids at 3 months post OLT. Normal or near-normal histology was reported in 77 of 113 (68%), 61 of 135 (45%), and 20 of 64 (31%) at 1, 5, and 10 years, respectively. The commonest histological abnormality was chronic hepatitis (CH), the incidence of which increased with time [25/113 (22%), 58/135 (43%), and 41/64 (64%) at 1, 5, and 10 years, respectively) (P < .0001)]. The incidence of fibrosis associatedwith CH increasedwith time [13/25 (52%), 47/58 (81%), and 37/41 (91%) at 1, 5, and 10 years, respectively) (P < .0001)]. The severity of fibrosis associated with CH also increased with time, such that by 10 years 15% had progressed to cirrhosis. Aspartate aminotransfemse (AST) levels were slightly elevated in children with CH (median levels 52 IU/L, 63 IU/L, and 48 IU/L at 1, 5, and 10 years, respectively), but this did not reach statistical significance compared with those with normal histology. On multivariate analysis, the only factor predictive of chronic hepatitis was autoantibody positivity (present in 13% and 10% of children with normal biopsies at 5 and 10 years, respectively, and 72% and 80% of those with CH at 5 and 10 years, respectively) (P < .0001). Four children with CH and autoantibodies, who also had raised immunoglobulin G (IgG) levels and AST greater than 1.5 x normal fulfilled the diagnostic criteria for de novo autoimmune hepatitis (AIH). Another two were found to be hepatitis C positive. No definite cause for CH could be identified in the other cases. In condusion, chronic hepatitis is a common finding in children after liver transplantation and is associated with a high risk of developing progressive fibrosis, leading to cirrhosis. Standard liver biochemical tests cannot be relied on either in the diagnosis or in the monitoring of progress of chronic allograft hepatitis. In contrast, the presence ofautoantibodies is strongly associated with the presence of CH. The cause of chronic hepatitis in transplanted allografts is uncertain but may be immune mediated, representing a hepatitic form of chronic rejection.

Adolescent↗
PubMed2006

6-Thioguanine-related chronic hepatotoxicity and variceal haemorrhage in children treated for acute lymphoblastic leukaemia--a dual-centre experience.

BACKGROUND: 6-Thioguanine treatment in childhood acute lymphoblastic leukaemia (ALL) has been shown to cause hepatic veno-occlusive disease, but this usually resolved with drug withdrawal. Recent reports suggested that treatment of ALL with 6-thioguanine can lead to chronic hepatotoxicity and portal hypertension. We describe our experience from 2 UK centres of chronic hepatotoxicity in children receiving maintenance 6-thioguanine for ALL in the national leukaemia protocol ALL 97/99. METHODS: Retrospective review of children who were referred with liver disease secondary to 6-thioguanine treatment of ALL was performed. A paediatric pathologist blinded to the clinical features reviewed liver histology slides. RESULTS: Ten of 75 children (13%) treated with 6-thioguanine in both centres were referred at a median of 6 months (range, 2-29) after discontinuation of chemotherapy. In 8 cases, referral was due to persistent thrombocytopenia and splenomegaly. Two children presented with acute variceal bleeding. All had thrombocytopenia at referral, and ultrasonography showed coarse hepatic echo texture and splenomegaly in all. Endoscopy showed oesophageal varices in 7 and gastric varices in 1. Nine underwent liver biopsy that showed features compatible with nodular regenerative hyperplasia in 5 cases. After a median follow-up of 36 months, a further child has had a variceal haemorrhage and all but 2 children remain thrombocytopenic. CONCLUSIONS: 6-Thioguanine-induced chronic hepatotoxicity is a significant complication in children treated with this agent for ALL. Children may present several months to years after discontinuation of 6-thioguanine. All children given maintenance treatment of ALL with this agent should be screened, and affected children require long-term surveillance.

Adolescent↗
PubMed2006

Lectin-reactive alpha-fetoprotein in patients with tyrosinemia type I and hepatocellular carcinoma.

Despite the introduction of 2-(2-nitro-4-trifluormethyl-benzoyl)-1,3-cyclohexandion into the treatment of hereditary tyrosinemia type I (HT1), patients remain at risk of developing hepatocellular carcinoma (HCC). Serial total alpha-fetoprotein (AFP) levels are used to monitor the individual patient. Lectin-reactive alpha-fetoprotein (L3-AFP) is an AFP isoform that is expressed by malignant liver tumors. We investigated whether the analysis of L3-AFP could lead to earlier detection of HCC in HT1 compared with judgement based on total AFP alone. AFP electrophoresis using lectin-containing agarose gel identifies L3-AFP by the affinity of its specific carbohydrate chain to lectin. We report the retrospective analysis of sequential serum samples of 12 patients with HT1 and histologically proven HCC. AFP isoforms could be identified in all 12 patients. In 6 patients, the L3-AFP increased before the total AFP. In 3 patients, the rise in L3-AFP was parallel to the rise of total AFP; and in 3 patients, the L3-AFP was raised after the total AFP or did not increase at all. We were able to identify 6 of 12 patients with an early increase in the new tumor marker. Lectin-affinity electrophoresis may have a role in discriminating benign liver disease from HCC in HT1. We suggest the further evaluation of L3-AFP in HT1.

Adolescent↗
PubMed2006

Immunosuppression in infants with short bowel syndrome undergoing isolated liver transplantation.

BACKGROUND: Little data exist on immunosuppressive drug absorption in children with short bowel syndrome and intestinal failure associated liver disease (SBS-IFALD). AIM: To evaluate the absorption of immunosuppressive medications in children with SBS-IFALD undergoing isolated liver transplantation (iLTx). METHODS: A retrospective review was performed in children with SBS-IFALD undergoing LTx and comparison made with weight, age-matched children undergoing iLTX (extra-hepatic biliary atresia (EHBA) and normal intestinal length and function). RESULTS: Seven children with SBS-IFALD undergoing iLTx (median residual bowel length, 60 cm, range 40-80) were compared with 15 children undergoing LTx for EHBA. SBS-IFALD children had significantly lower trough tacrolimus levels at three months (5.8 vs. 7.9 ng/mL, p<0.05) and six months (5.0 vs. 8.0 ng/mL, p<0.05), but equivalent levels at 12 months after iLTx. The median calculated dose-normalized concentrations indicated that systemic availability of tacrolimus was comparable in two groups at 3, 6, 12 months (33.1 vs. 23.3; 42.4 vs. 36; 51 vs. 52.9) despite the differences in enteral function. The incidence of acute rejection was 1/7 (SBS-IFALD) and 10/15 (EHBA) group (p = 0.06). CONCLUSION: Children with SBS-IFALD demonstrated adequate absorption of oral tacrolimus without significant acute rejection rate after iLTx suggesting that modification of immunosuppression is not necessary.

Female↗
PubMed2006

Nitisinone in the treatment of hereditary tyrosinaemia type 1.

Hereditary tyrosinaemia type 1 (HT-1) is a rare genetic disease caused by mutations in the gene for the enzyme fumarylacetoacetase. It usually presents with liver failure but can be manifest as chronic liver disease. Rarely, it may present with nonhepatic manifestations such as renal dysfunction, porphyria-like illness or cardiomyopathy. There is a high lifetime risk of developing hepatocellular carcinoma (HCC). Prior to the development of liver transplantation, most patients died in childhood.The clinical manifestations stem from the cytotoxicity of tyrosine metabolites accumulating proximal to the metabolic defect. Nitisinone acts on tyrosine metabolism upstream of the defect to prevent the production of these metabolites. Nitisinone is used in combination with a tyrosine- and phenylalanine-restricted diet. Nitisinone has transformed the natural history of tyrosinaemia. Liver failure is controlled in 90% of patients, those with chronic liver disease improve and nonhepatic manifestations are abolished. Nitisinone is well tolerated and has few adverse effects other than a predictable rise in plasma tyrosine levels. Nitisinone provides protection against HCC if it is started in infancy, but if commenced after the age of 2 years, a significant risk of HCC remains. Furthermore, where nitisinone is used pre-emptively, liver disease appears to be prevented, suggesting the importance of neonatal screening for tyrosinaemia where possible. Nitisinone is indicated for all children with HT-1, and liver transplantation is only indicated where nitisinone fails, or where the development of HCC is likely or suspected.

Carcinoma, Hepatocellular↗
PubMed2005

Requirement of VPS33B, a member of the Sec1/Munc18 protein family, in megakaryocyte and platelet alpha-granule biogenesis.

Bleeding problems are associated with defects in platelet alpha-granules, yet little is known about how these granules are formed and released. Mutations affecting VPS33B, a novel Sec1/Munc18 protein, have recently been linked to arthrogryposis, renal dysfunction, and cholestasis (ARC) syndrome. We have characterized platelets from patients with ARC syndrome and observed reduced aggregation with arachidonate and adenosine diphosphate (ADP). Structural abnormalities seen in ARC platelets included increased platelet size, a pale appearance in blood films, elevated numbers of delta-granules, and completely absent alpha-granules. Soluble and membrane-bound alpha-granule proteins were significantly decreased or undetectable in ARC platelets, suggesting that both the releasable protein pools and membrane components of alpha-granules were absent. The role of VPS33B in platelet granule biogenesis was evaluated by immunofluorescence microscopy in normal human megakaryocytes. VPS33B colocalized appreciably with markers of alpha-granules, moderately with late endosomes/lysosomes, minimally with delta-granules/lysosomes, and not with cis-Golgi complexes. VPS33B protein expression determined by immunoblotting confirmed the presence of VPS33B in control fibroblasts but not in ARC fibroblasts, and in normal megakaryocytes but not in platelets. We conclude that like other Sec1/Munc18 proteins, VPS33B is involved in intracellular vesicle trafficking, being essential for the development of platelet alpha-granules but not for granule secretion.

Arthrogryposis↗
PubMed2005

Mycophenolate mofetil for renal dysfunction after pediatric liver transplantation.

BACKGROUND: Cyclosporine A (CsA) and tacrolimus (Tac) provide effective immunosuppression after orthotopic liver transplantation (OLT) but can cause renal dysfunction that may progress to end-stage renal failure (ESRF). Mycophenolate mofetil (MMF) is a newer immunosuppressant that does not affect renal function. Its long-term use in children with renal dysfunction after OLT has not yet been fully evaluated. METHODS: A retrospective analysis was performed of all children begun on MMF for renal dysfunction and followed up for at least 1 year. Renal dysfunction was defined as calculated glomerular filtration rate (cGFR) of less than 65 mL/min/1.73 m2. cGFR and liver function were measured before and after transfer. Data were analyzed using the Wilcoxon signed rank test. RESULTS: Forty-eight children (23 males) began MMF at a median age of 11.1 (0.9-18.1) years and at a median of 4.0 (0.3-12.4) years postOLT. Median baseline cGFR was 54 (range 29-65) mL/min/1.73 m2. Immunosuppression after transfer was MMF monotherapy in 36, MMF with steroids, in 4 and MMF with low-dose CsA or Tac in 8. In 44 (92%) patients, there was a statistically significant increase to a median cGFR of 69 (28-114) mL/min/1.73 m2 by 1 month and a further increase to a median cGFR of 77 (24-105) mL/min/1.73 m2 by 2 months of MMF treatment, after which time cGFR was maintained. Children aged less than 3 years at OLT or who were less than 5 years postOLT when MMF was begun demonstrated greater increases in cGFR. Four children with a median baseline cGFR of 34 (range 31-49) mL/min/1.73 m2 did not respond and progressed to ESRF. Mild side effects occurred in seven (15%) and gastrointestinal bleeding requiring discontinuation of MMF in one (2%). Liver function abnormalities occurred in seven (15%): transient transaminitis in three, acute rejection in two, and chronic rejection in two, of whom one required retransplantation. CONCLUSIONS: In 92% children with renal dysfunction after OLT, MMF treatment provided safe and effective immunosuppression and allowed CsA or Tac to be discontinued or reduced, leading to improvement of renal function. The improvement was greatest in younger children and those who began MMF early postOLT. Side effects were uncommon. Additional steroid cover during the transfer to MMF should be considered to prevent liver-allograft rejection.

Adolescent↗
PubMed2004

Mutations in VPS33B, encoding a regulator of SNARE-dependent membrane fusion, cause arthrogryposis-renal dysfunction-cholestasis (ARC) syndrome.

ARC syndrome (OMIM 208085) is an autosomal recessive multisystem disorder characterized by neurogenic arthrogryposis multiplex congenita, renal tubular dysfunction and neonatal cholestasis with bile duct hypoplasia and low gamma glutamyl transpeptidase (gGT) activity. Platelet dysfunction is common. Affected infants do not thrive and usually die in the first year of life. To elucidate the molecular basis of ARC, we mapped the disease to a 7-cM interval on 15q26.1 and then identified germline mutations in the gene VPS33B in 14 kindreds with ARC. VPS33B encodes a homolog of the class C yeast vacuolar protein sorting gene, Vps33, that contains a Sec1-like domain important in the regulation of vesicle-to-target SNARE complex formation and subsequent membrane fusion.

Arthrogryposis↗
PubMed2004

Histiocytic sarcoma with interdigitating dendritic cell differentiation.

The authors describe a rare tumor with overlapping features of true histiocytic sarcoma and interdigitating dendritic cell sarcoma occurring in infancy. A 3-month-old boy presented with hepatosplenomegaly and abdominal distention. He presented a diagnostic challenge at initial presentation despite extensive investigations. On follow-up at age 16 months he had progressive splenomegaly, thrombocytopenia, and worsening coagulopathy. A diagnosis of histiocytic sarcoma with interdigitating dendritic cell differentiation was established after an open biopsy of liver and spleen. A repeat liver biopsy coupled with splenic biopsy is recommended in young children with unexplained hepatosplenomegaly and thrombocytopenia.

Biopsy↗
PubMed2002

A prospective study of endoscopic esophageal variceal ligation using a multiband ligator.

BACKGROUND: Endoscopic variceal band ligation (EVL) is the preferred method of treating variceal hemorrhage in adults. The need to reinsert the endoscope after reloading for each varix ligation has been a drawback. The Saeed multiband ligator allows ligation of multiple varices during a single insertion. The multibander has not been used previously in children. METHODS: Twenty-eight consecutive children were referred to a pediatric liver unit because of esophageal variceal bleeding from 1998 to 2000. Endoscopic variceal band ligation was performed at initial endoscopy and repeated monthly until varices were obliterated or were too small to ligate. RESULTS: Results are expressed as median (range). Age at EVL was 11 years (3 months to 16 years) and weight 30 kg (5.4-63 kg). Portal hypertension was caused by cirrhosis in 15 children. Endoscopic variceal band ligation was performed on 66 occasions with 4 bands applied per session. Ten children had active bleeding at initial endoscopy and all responded to EVL. Interval bleeding developed in 2 children before variceal ablation. Varices were obliterated in 26 of 28 patients after 2 sessions. During the 21-month follow-up (2 months to 3 years), six children have undergone elective liver transplantation and three have had mesoportal bypass procedures. Rebleeding developed in 2 of 26; 1 from recurrent esophageal varices that responded to repeat EVL and 1 from gastric varices. Following variceal ablation, 2-year actuarial variceal recurrence risk was 40%. CONCLUSIONS: Endoscopic variceal ligation is highly effective in obliterating esophageal varices in children. The use of a multibander device for endoscopic variceal ligation is technically feasible and safe even in small children, and its use results in more rapid ablation of esophageal varices.

Adolescent↗