Way Seah Lee

Etiology, outcome and prognostic indicators of childhood fulminant hepatic failure in the United Kingdom

Objective: To study the etiology, outcome and prognostic indicators in children with fulminant hepatic failure in the United Kingdom. Design: Retrospective review of all patients <17 years with fulminant hepatic failure from 1991 to 2000. Fulminant hepatic failure was defined as presence of coagulopathy (prothrombin time >24 seconds or International Normalized Ratio >2.0) with or without hepatic encephalopathy within 8 weeks of the onset of symptoms. Setting: Liver Unit, Birmingham Childrens Hospital, United Kingdom. Results: Ninety-seven children (48 male, 49 female; median age, 27 months; range, 1 day-192.0 months) were identified with fulminant hepatic failure. The etiologies were: 22 metabolic, 53 infectious, 19 drug-induced, and 3 autoimmune hepatitis. The overall survival rate was 61%. 33% (32/97) recovered spontaneously with supportive management. Fifty-five children were assessed for liver transplantation. Four were unstable and were not listed for liver transplantation; 11 died while awaiting liver transplantation. Liver transplantation was contraindicated in 10 children. Of the 40 children who underwent liver transplantation, 27 survived. Children with autoimmune hepatitis, paracetamol overdose or hepatitis A were more likely to survive without liver transplantation. Children who had a delay between the first symptom of liver disease and the onset of hepatic encephalopathy (median, 10.5 days versus 3.5 days), higher plasma bilirubin (299 μmol/L versus 80 μmol/L), higher prothrombin time (62 seconds versus 40 seconds) or lower alanine aminotransferase (1288 IU/L versus 2929 IU/L) levels on admission were more likely to die of fulminant hepatic failure or require liver transplantation (P < 0.05). On multivariate analysis, the significant independent predictors for the eventual failure of conservative therapy were time to onset of hepatic encephalopathy >7 days, prothrombin time >55 seconds and alanine aminotransferase ≤2384 IU/L on admission. Conclusions: Children with fulminant hepatic failure with severe coagulopathy, lower alanine aminotransferase on admission and prolonged duration of illness before the onset of hepatic encephalopathy are more likely to require liver transplantation. Early referral to a specialized center for consideration of liver transplantation is vital.

Identification of NOD2/CARD15 mutations in Malaysian patients with Crohn's disease

OBJECTIVE:  The NOD2/CARD15 gene has been identified as an important susceptibility gene for Crohns disease (CD) but the three common disease predisposing mutations (DPM) found in developed countries have not been identified in Asian populations. The aim of our study was to look for the DPM in our multiracial population and to discover whether there were any differences in the three major ethnic groups; Malay, Chinese and Indian.

Childhood Autoimmune Liver Disease: Indications and Outcome of Liver Transplantation

Background: Graft rejection and disease recurrence are well-recognized complications of liver transplantation (LT) for autoimmune hepatitis (AIH) and autoimmune sclerosing cholangitis (AISC). We describe indications and outcome of LT for childhood AIH and AISC. Patients and Methods: Twenty-year retrospective review of a cohort of children (n = 101) with AIH, AISC, or AIH/sclerosing cholangitis overlap syndrome from a single center. Results: AIH type 1 (AIH1, n = 67) was more common than AIH type 2 (AIH2, n = 18), AISC (n = 8), or overlap syndrome (n = 8). Overall, 18 patients (18%) required LT, the indications being failure of medical therapy (n = 16) and fulminant liver failure (n = 2). Patients with AIH who required LT had a more prolonged prothrombin time at presentation compared with those who did not undergo transplantation (P = 0.01). Patients with AIH1 who received LT had a lower aspartate transaminase (P = 0.009) and alanine transaminase (P = 0.02) levels at initial diagnosis compared with those with AIH1 who did not undergo transplantation. Post-LT, 11 patients (61%) had 18 episodes of rejection, most were steroid sensitive. Disease recurrence was observed in 7 patients (39%, median duration post-LT 33 months), more common in AIH2 (80% recurrence rate), and those taking cyclosporine (71%, 5/7 patients) compared with those taking tacrolimus (18%, 2/11 patients; P < 0.05) and in 3 of 3 children who did not have maintenance steroids post-LT. The overall 5- and 7-year post-LT survival rate was 94% and 88%, respectively. Conclusions: LT is a good therapeutic option for progressive AIH and AISC, although recurrence of the primary autoimmune process limits the outcome.

Non‐typhoid Salmonella gastroenteritis

To study the clinical features of non‐typhoid Salmonella gastroenteritis and the incidence, risk factors and outcome of invasive complications in urban Malaysian children. To describe the serotypes of Salmonella species isolated and the pattern of antibiotic susceptibility.

Extra-intestinal non-typhoidal Salmonella infections in children

Summary Extra-intestinal non-typhoidal Salmonella (NTS) infections are uncommon in developed countries but common in developing ones. The risk factors, clinical features and outcome of children admitted to the Department of Paediatrics, University of Malaya Medical Center, Kuala Lumpur from 1978 to 1998 with extra-intestinal NTS infections were reviewed. All positive cultures of NTS, blood, cerebrospinal fluid, urine, synovial, pericardial and other body secretions (except stools), were included. Of the 98 cases reviewed, 56 were boys and 42 girls. The mean age was 2.1 years (range: newborn to 14 years). Twenty-seven children were severely immunocompromised and 21 had underlying chronic medical disorders. Bacteraemia was the most commonly detected type of infection and meningitis the commonest focal infection. The overall mortality rate was 15%. An immunocompromised state or underlying chronic medical disorder was associated with increased mortality. The three serotypes most commonly isolated were S. enteritidis, S. paratyphi B and S. typhimurium. Most isolates were sensitive to antibiotics commonly used in salmonellosis.

Neonatal liver transplantation for fulminant hepatitis caused by herpes simplex virus type 2

Neonatal herpes simplex virus (HSV) infection can cause skin disease or disseminated infection, resulting in hepatitis, pneumonitis, intravascular coagulopathy, or encephalitis (1). It is usually acquired perinatally, with a high mortality rate in disseminated disease (1–3). We describe a 12-day-old girl with fulminant hepatitis and fulminant hepatic failure (FHF) secondary to HSV type 2 infection who underwent a successful liver transplantation (LT).

Seroprevalence of Helicobacter pylori infection in Malaysian children: Evidence for ethnic differences in childhood

Objectives: To determine the prevalence of Helicobacter pylor (H. pylori) in healthy Malaysian children and to discover whether differences exist among children of different races.

Intestinal Microbiota, Lipids, and the Pathogenesis of Intestinal Failure–Associated Liver Disease

Intestinal failure (IF) is considered the end result of gastrointestinal disorders in which functional intestinal mass is inadequate to promote adequate growth, hydration, and electrolye balance.1 Today, a substantial number of infants and children with IF, caused by short bowel syndrome (SBS), necrotizing enterocolitis (NEC), gastroschisis, intestinal atresias, motlity disorders and genetic enterocyte transport defects, depend upon long term parenteral nutrition (PN) for survival and the promotion of normal growth and development. PN-associated cholestasis (PNAC), referring to the development of conjugated hyperbilirubinemia and impaired bile flow, implies that PN itself is the predominant factor responsible for liver injury.2 However, recent understanding of the various factors causing liver injury in patients receiving PN has led to the broader descriptive term of IF–associated liver disease (IFALD),3 replacing the previous term PN-associated liver disease (PNALD). IFALD is defined as cholestasis and progressive biliary cirrhosis in the setting of PN in a patient with underlying intestinal disease, resection or dysfunction, if other specific causes of liver injury have been excluded.4 It is in these patients that the most severe, progressive, and sometimes fatal phenotypes of PNAC develop, hence IFALD has become the leading indication for intestinal and multi-visceral transplantation in children. In addition to progressive biliary cirrhosis and portal hypertension, hepatocellular carcinoma has been reported as a rare complication in children with liver cirrhosis secondary to long-term PN.5 Advanced IFALD is one of the most significant risk factors associated with mortality in infants on long-term PN.6, 7 There are several recent reviews on the pathogenic mechanisms predisosing to IFALD and various strategies to prevent or reverse established IFALD.2, 4, 8-10 Prematurity and small-for-gestational age, length of bowel remnant in those who had bowel resection, lack of enteral feeding, duration of PN, recurrent sepsis, protein under nutrition and excess of intravenous carbohydrate load have been considered as important factors for the development IFALD.3 Mechanisms receiving the most recent attention include the role of omega(ω)-6 polyunsaturated fatty acids (PUFA) and plant sterols found in the intravenous lipid emulsions (ILEs),8 bacterial overgrowth and microbiome dysbiosis of the small intestine,11 the role of bacteremia and fungemia related to microbial translocation across the intestinal barrier and central line associated blood stream infections (CLABSI), and increased intestinal permeability leading to absorption of bacterial products from injured intestine inducing innate immune responses in the liver.12, 13 The purpose of the present review is to discuss the latest understanding of the role of various ILEs and intestinal microbial dysbiosis.14, 15

Pre-admission consultation and late referral in infants with neonatal cholestasis.

Aims:  To study factors leading to delayed referral in neonatal cholestasis at a tertiary centre in Malaysia.

Mitochondrial hepatopathies: advances in genetics, therapeutic approaches, and outcomes.

Cellular mitochondria play important roles in the production of energy required by human cells, thermogenesis, calcium and iron homeostasis, innate immune responses, production of reactive oxygen species, and programmed cell death (apoptosis).1 Approximately 1000 nuclear genes encoding mitochondrial proteins have been identified to date. A mutation in any of these genes has the potential to give rise to monogenic or primary mitochondrial disorders.2 Mitochondrial dysfunction is also associated with many common human conditions, including cardiac disease,3 diabetes,4 cancer,5 epilepsy,6 obesity,7 and degenerative diseases such as Parkinson and Alzheimers diseases.8,9 A unique feature of mitochondria in mammalian cells is the presence of a separate genome, mitochondrial DNA (mtDNA), which is distinct from nuclear genes.1 The respiratory chain peptide components are encoded by both nuclear and mtDNA genes.1 Thirteen essential polypeptides are synthesized from the small (16.5-kb), circular, double-stranded mtDNA, and nuclear genes encode more than 70 respiratory chain subunits and an array of enzymes and cofactors required to maintain mtDNA.1 Mitochondrial hepatopathies, disorders in which dysfunction of hepatocyte mitochondria plays a key role in the pathogenesis of liver injury or failure,10-12 are divided into primary and secondary disorders.10,11 Mitochondrial hepatopathies as a whole have been characterized only relatively recently,10 and the identification of more types is anticipated. Primary mitochondrial hepatopathies occur when a mitochondrial protein, transfer RNA, or ribosomal RNA is miscoded by a mutation in either a nuclear gene or an mtDNA gene. Secondary mitochondrial hepatopathies are conditions in which mitochondria are the targets of endogenous or exogenous toxins. Examples include Reye syndrome, copper and iron overload conditions, drugs (eg, salicylates, reverse-transcriptase inhibitors, antimycin A) and toxins (eg, ethanol, cyanide), cholestasis, nonalcoholic steatohepatitis, and α-1 antitrypsin deficiency. 10,11 In primary mitochondrial hepatopahies, liver involvement is often part of multiorgan manifestations (Table I).1,10,12 Much of our current knowledge about mitochondria has come from studying patients with respiratory chain disorders, which compose a growing number of individually rare syndromes, each presenting in a unique and often devastating way.12 Table I Phenotypic classification of primary mitochondrial hepatopathies