Liver Disease In Childhood Research Articles

Alpha-1-Antitrypsin Deficiency Initially Presenting in an Adult Surgical Patient: A Case Report and Review of Current Understanding of Disease Process

Alpha-1-antitrypsin (AAT) is one of several serpin molecules which functions to balance the action of various endogenous proteolytic enzymes. A deficiency of functional levels of this enzyme is most commonly inherited in an autosomal recessive fashion. Greater than 95% of AAT-deficient persons are homozygous for the non-functional Z-variant of the enzyme. ZZhomozygosity is relatively common, affecting 1 in 2500 persons of northern European decent. Known complications of AATdeficiency include early-onset emphysema, childhood liver disease, cirrhosis, and increased incidence of hepatocellular carcinoma. Although AAT-deficiency is frequently diagnosed in early childhood, it is not uncommon for persons to go undiagnosed for many years until otherwise unexplained lung or liver disease become evident. We report a case of AATdeficiency in a 44-year-old female which became evident post-operatively after unexplained, uncontrollable ascites and respiratory failure.

Reloading Against Rare Liver Diseases

Reloading Against Rare Liver Diseases

Alpha-1-Antitrypsin Deficiency Initially Presenting in an Adult Surgical Patient: A Case Report and Review of Current Understanding of Disease Process

Alpha-1-antitrypsin (AAT) is one of several serpin molecules which functions to balance the action of various endogenous proteolytic enzymes. A deficiency of functional levels of this enzyme is most commonly inherited in an autosomal recessive fashion. Greater than 95% of AAT-deficient persons are homozygous for the non-functional Z-variant of the enzyme. ZZhomozygosity is relatively common, affecting 1 in 2500 persons of northern European decent. Known complications of AATdeficiency include early-onset emphysema, childhood liver disease, cirrhosis, and increased incidence of hepatocellular carcinoma. Although AAT-deficiency is frequently diagnosed in early childhood, it is not uncommon for persons to go undiagnosed for many years until otherwise unexplained lung or liver disease become evident. We report a case of AATdeficiency in a 44-year-old female which became evident post-operatively after unexplained, uncontrollable ascites and respiratory failure.

State of Research in Pediatric Gastroenterology, Hepatology, and Nutrition: 2010 and Beyond

State of Research in Pediatric Gastroenterology, Hepatology, and Nutrition: 2010 and Beyond

Childhood liver diseases in Ga-Rankuwa Hospital, South Africa.

To determine the pattern of liver diseases diagnosed in children at Ga-Rankuwa Hospital Histopathology Laboratory. A retrospective study. Ga-Rankuwa Histopathology Laboratory. Seventy two patients who underwent a liver biopsy during the study period. Laboratory records were reviewed and all liver biopsies were extracted. All slides were reviewed by the author to confirm the diagnoses. The findings were compared with similar studies elsewhere. Biliary atresia and neonatal hepatitis were the most common diseases. Metabolic liver diseases were rarely encountered. Neonatal hepatitis and biliary atresia are not uncommon amongst children who underwent liver biopsy at this hospital.

Progress in our understanding of severe drug-induced liver injury

Progress in our understanding of severe drug-induced liver injury

Biliary Atresia Screening: Why, When, and How?

Biliary atresia is one of the most important liver diseases in childhood. At an incidence of 1 in 13 000 live births in the United States, it is considered a rare disease; however, it is the indication for 40% to 50% of all liver transplants performed in children.1 It uniquely presents only during the first few months of life and seems to be a phenotype caused by at least several etiologies, including a proposed perinatal insult that initiates an immune-mediated obliteration of the extrahepatic bile duct lumen and a proposed embryonic or fetal defect in the normal morphogenesis of the biliary tree.2 Outcome is uniformly poor unless a hepatic portoenterostomy (HPE) (the Kasai operation) reestablishes bile drainage from the liver into the jejunum and leads to resolution of jaundice. If HPE is not successful or not performed, liver transplantation is the only life-saving alternative. Even with successful HPE, the majority of these children's conditions will progress to cirrhosis, leaving survival rates without liver transplantation at only 20% by 20 years … Address correspondence to Ronald J. Sokol, MD, Children's Hospital, Box B290, 13123 E 16th Ave, Aurora, CO 80045. E-mail: sokol.ronald{at}tchden.org

Caring for adults with pediatric liver disease

The etiology of liver disease in childhood varies significantly from its etiology in the adult population. More children with complex diseases are surviving into adulthood, providing challenges to the primary care provider. Adults with pediatric liver disease differ in management, treatment, complications, and extrahepatic considerations. To provide these patients with an optimal transition into the adult health care system, the provider needs a comprehensive knowledge of the common causes of childhood liver disease and their implications and must understand the differences in caring for these patients. This review addresses some of the most common childhood liver diseases, their causes, presentation, evaluation, management, complications, and additional concerns.

Effects of ursodeoxycholic acid therapy in children with alagille syndrome

Background. Alagille syndrome is a genetic disorder with autosomal dominant transmission but highly variable expression. It is clinically defined by the association of at least three of the major clinical features (chronic cholestasis, congenital heart disease, “butterfly-like” vertebrae, posterior embryotoxon and peculiar facies). Liver biopsy classically shows the presence of intrahepatic bile duct paucity. It is one of the most common genetic causes of chronic liver disease in childhood. Ursodeoxycholic acid (UDCA) might exert beneficial effects in cholestatic disease.

Cirrhosis Originally Diagnosed as Nonalcoholic Steatohepatitis

A 52-year-old white woman with a presumptive diagnosis of cirrhosis attributed to nonalcoholic steatohepatitis was referred for a liver transplant consultation. The patient reported increased abdominal discomfort, swelling, and lower extremity edema beginning 7 years earlier, as well as intermittent nausea, weakness, and confusion which had increased in frequency during the previous year. While undergoing a cholestectomy for gallstones 2 years previously, the patient was noted to have ascites and a cirrhotic-appearing liver. Results of routine laboratory tests and an abdominal ultrasound performed at that time were consistent with cirrhosis. The patient, a married housewife with 1 adult son, had a physical appearance that suggested chronic illness but was in no acute distress. She denied any history of drug or alcohol use and reported never having received a blood transfusion. She had no history of childhood liver disease and was unaware of any family history of gastrointestinal malignancy or liver disease. The patient did report, however, that 2 of her 7 siblings died from unknown causes as infants, her father died while in a coma of unknown etiology, her mother died from diabetic complications, and a third sibling died of a gynecologic cancer. The patient’s medical history was remarkable for obesity, gastroesophageal reflux disease, recurrent urinary tract infections, and arthritis. Physical examination was unremarkable, with the exception of mildly icteric sclera, spider nevi on the anterior chest wall, and bilateral lower extremity edema. Moderately decreased breath sounds in her lower left lung were also noted. Chest x-rays and spirometry were unremarkable. Laboratory data were consistent with end-stage liver disease and also revealed mild anemia as well as thrombocytopenia and chronic kidney disease. Although at the time of her referral to our institution the patient had a presumptive diagnosis of cirrhosis related to nonalcoholic steatohepatitis, we investigated other causes for her …

Partial external biliary diversion for the treatment of intractable pruritus in children with progressive familial intrahepatic cholestasis: Report of two cases

Progressive familial intrahepatic cholestasis (PFIC) is a cholestatic liver disease of childhood. Pruritus secondary to increased bile salts in the serum may not respond to medical treatment. Partial external biliary diversion (PEBD), which reduces the serum bile salt level in the enterohepatic cycle, is used in the treatment of this symptom. In this study, our experience in performing this technique and the early promising results of PEBD in two children with PFIC are reported along with a review of the current literature. Partial external biliary diversion was performed by interposing a 15-cm jejunum between the gallbladder and abdominal wall. Biliary drainage through a stoma began in the fi rst postoperative day and reached 120-200 ml/day. Pruritus improved and then stopped on the 15th postoperative day, while the serum bile acid concentration also decreased. Partial external biliary diversion by jejunal interposition provides an excellent control of pruritus in children with PFIC with no adverse effects. A cholecystectomy should therefore be avoided in patients with PFIC.

Hereditary alpha-1-antitrypsin deficiency and its clinical consequences.

Alpha-1-antitrypsin deficiency (AATD) is a genetic disorder that manifests as pulmonary emphysema, liver cirrhosis and, rarely, as the skin disease panniculitis, and is characterized by low serum levels of AAT, the main protease inhibitor (PI) in human serum. The prevalence in Western Europe and in the USA is estimated at approximately 1 in 2,500 and 1 : 5,000 newborns, and is highly dependent on the Scandinavian descent within the population. The most common deficiency alleles in North Europe are PI Z and PI S, and the majority of individuals with severe AATD are PI type ZZ. The clinical manifestations may widely vary between patients, ranging from asymptomatic in some to fatal liver or lung disease in others. Type ZZ and SZ AATD are risk factors for the development of respiratory symptoms (dyspnoea, coughing), early onset emphysema, and airflow obstruction early in adult life. Environmental factors such as cigarette smoking, and dust exposure are additional risk factors and have been linked to an accelerated progression of this condition. Type ZZ AATD may also lead to the development of acute or chronic liver disease in childhood or adulthood: prolonged jaundice after birth with conjugated hyperbilirubinemia and abnormal liver enzymes are characteristic clinical signs. Cirrhotic liver failure may occur around age 50. In very rare cases, necrotizing panniculitis and secondary vasculitis may occur. AATD is caused by mutations in the SERPINA1 gene encoding AAT, and is inherited as an autosomal recessive trait. The diagnosis can be established by detection of low serum levels of AAT and isoelectric focusing. Differential diagnoses should exclude bleeding disorders or jaundice, viral infection, hemochromatosis, Wilson's disease and autoimmune hepatitis. For treatment of lung disease, intravenous alpha-1-antitrypsin augmentation therapy, annual flu vaccination and a pneumococcal vaccine every 5 years are recommended. Relief of breathlessness may be obtained with long-acting bronchodilators and inhaled corticosteroids. The end-stage liver and lung disease can be treated by organ transplantation. In AATD patients with cirrhosis, prognosis is generally grave.

Gene Delivery to the Juvenile Mouse Liver Using AAV2/8 Vectors

Recombinant adeno-associated viral (rAAV) vectors have shown promise for use in liver-targeted gene delivery, but their effects have not been extensively investigated in the immature liver. Understanding the impact of liver growth on the efficacy of transduction is essential, because many monogenic liver diseases that are amenable to gene therapy will require treatment early in life. Here we show that rAAV2/8 transduces the neonatal mouse liver with high efficiency. With just one doubling in liver weight, however, there is a rapid reduction in vector genome numbers, irrespective of form, and the loss of episomal vector is almost complete by 2 weeks. Stable transgene expression is observed in a small percentage of hepatocytes, often in two- to eight-cell clusters, suggestive of genomic integration. Delivery at serially older ages was associated with progressively improved episome persistence and transgene expression. Vector re-administration was possible following initial neonatal administration, albeit at reduced efficacy because of an anticapsid humoral immune response. We also found that intraperitoneal (IP) delivery of rAAV2/8 was highly effective at all ages, and that promoter selection is the critical determinant of the intensity and pattern of transgene expression across the hepatic lobule. We conclude that successful use of rAAV to treat liver disease in early childhood will require optimally efficient vector constructs and probable re-administration.

A polymorphism of the alpha1-antitrypsin gene represents a risk factor for liver disease

Alpha(1)-antitrypsin deficiency (AATD) due to homozygosity of the protease inhibitor (Pi) Z variant predisposes to childhood liver disease and pulmonary emphysema. About 10% of all neonates with AATD develop liver disease, and about 3% overall progress to severe disease. AATD is a principal genetic indication for liver transplantation in children. The liver pathology is associated with accumulation of abnormally folded protein in hepatocytes, the principal producers of circulating alpha(1)-antitrypsin (AAT). It is currently unknown why only a small proportion of Pi ZZ individuals progress to clinically significant cirrhosis. The AAT gene shows significant variation, and we hypothesized that cryptic genetic variants within the AAT gene may contribute to susceptibility to liver disease. In a case-control study consisting of 42 patients with established moderate-to-severe liver disease and 335 homozygous Pi ZZ patients who mostly presented with chronic obstructive pulmonary disease (n = 322: 242 index cases and 80 unaffected sibs) or were asymptomatic (n = 13) with no evidence of liver disease, we identified a single nucleotide polymorphism (SNP) that conferred a significant risk for liver disease (P = 0.007). The frequency of the SNP was no different in 242 Pi ZZ cases with chronic obstructive pulmonary disease compared with 80 nonindex cases. The SNP therefore appears to confer susceptibility to liver disease, although reporter gene assays failed to show any functional differences between alleles. This is the first description of a genetic modifier of liver disease in homozygous ZZ children and has potential implications for screening and possible therapies that are currently being developed.

α1‐Antitrypsin deficiency is not an important cause of childhood liver diseases in a multi‐ethnic Southeast Asian population

We conducted a prospective study to determine the role of alpha1-antitrypsin (alpha1AT) deficiency in the pathogenesis of neonatal cholestasis and other childhood liver diseases in a multi-ethnic Southeast Asian population. Prospective patients with neonatal cholestasis (group 1), other liver diseases (group 2) and children with other medical conditions (group 3) referred to the Paediatric Unit, University of Malaya Medical Centre, Malaysia, from May 2002 to June 2005, were screened for alpha1AT level and phenotype. alpha1AT level below 80 mg/dL was considered as low. Of the 114 patients (group 1, n = 53; group 2, n = 42; group 3, n = 19) screened, seven patients (6% of total; group 1, n = 1; group 2, n = 4; group 3, n = 2) had a alpha1AT level below 80 mg/dL. All had marginally low level (range 57-79 mg/dL), but none had a clinical diagnosis of alpha1AT deficiency. One patient had PiZ- heterozygous phenotype (alpha1AT level 217 mg/dL) while another patient had PiMS heterozygous. alpha1AT deficiency is not an important cause of neonatal cholestasis and childhood liver diseases in Malaysian children. In Malaysian children with neonatal cholestasis or other liver diseases, routine assay for alpha1AT phenotype is not recommended if there is no family history of neonatal cholestasis of uncertain aetiology, or if alpha1AT level is above 80 mg/dL.

Pediatric Liver Disease: Translating Discoveries into Practice

The transformation of the practice of pediatric hepatology has begun. Characterization of molecular etiologies, pathogenesis, and clinical phenotypes of childhood liver diseases in recent years has legitimized the further development of this distinct discipline. As an illustration, delineation of the molecular underpinnings of the various clinical phenotypes of progressive familial intrahepatic cholestasis has led to a nosology that is of growing clinical utility and that begins to have implications far beyond the pediatric population. For example, MDR3 (ABCB4) deficiency is responsible for a chronic cholestatic disease, PFIC type 3, in childhood, but is now known to cause recurrent intrahepatic cholelithiasis and intrahepatic cholestasis of pregnancy in adults. Furthermore, basic and translational research evolving from clinical observations in children has brought forth an improved understanding of bile formation and identification of new targets for treatment of cholestasis. The remarkable success of liver transplantation as a lifesaving therapy in previously fatal pediatric liver disorders underscores the advances that have transformed the practice of pediatric hepatology. Applying the new biotechnologies of translational research to liver diseases in coming years holds the promise to build on these successes in both common and rare childhood liver diseases. Moreover, the publication of pediatric liver disease research agendas combined with the development of collaborative clinical research networks have put in place the infrastructure to prioritize and target resources toward answering important clinical and scientific questions. In this issue of Seminars in Liver Disease, we have highlighted recent translational research advances in 8 important childhood liver diseases, as described by recognized experts, which will illustrate this transformational process.

Obelix and the trouble of fatty liver disease in childhood

Obelix and the trouble of fatty liver disease in childhood

Late-Onset Wilson’s Disease

The clinical symptoms and age at onset of Wilson's disease (WD) are highly variable. This study investigated patients who became symptomatic at >40 years of age. Clinical features, laboratory data, and mutation analysis were evaluated in 46 (3.8%) of 1223 patients who were investigated in a multinational study on genotype-phenotype correlations (1053 index patients, 170 siblings) who were >40 years of age at onset of symptoms and, in 2 asymptomatic siblings, diagnosed at >40 years of age. Thirty-one patients presented with neurologic symptoms (mean age, 44.5 years; range, 40-52; male/female, 14/17), 15 presented with liver disease (mean age, 47.1 years; range, 40-58; male/female, 6/9), and 2 were asymptomatic siblings. Hepatic copper content was measured in 17 patients and was above 250 microg/g dry weight in 13. One patient with hepatic presentation had "fulminant" WD, the remaining 14 abnormal liver function tests and/or hepatomegaly. Liver biopsy specimens were available in 13 patients presenting with liver disease (cirrhosis, 10; chronic hepatitis, 2; steatosis, 1; no abnormalities, 1) and in 14 neurologic patients (cirrhosis, 9; advanced fibrosis, 1; chronic hepatitis, 2; no abnormalities, 2). Twenty-seven of the 46 index cases had mutations on both chromosomes (including 13 H1069Q/H1069Q), 13 on just 1 chromosome. Late-onset WD is a frequently overlooked condition. The diagnostic features and the frequency of late-onset WD gene mutations were not different than in patients with an earlier onset of disease. Factors other than ATP7B mutations may modify the phenotypic presentation of WD.

Growth evaluation in infants with neonatal cholestasis

[corrected] Chronic liver diseases in childhood often cause undernutrition and growth failure. To our knowledge, growth parameters in infants with neonatal cholestasis are not available To evaluate the nutritional status and growth pattern in infants with intrahepatic cholestasis and extrahepatic cholestasis. One hundred forty-four patients with neonatal cholestasis were followed up at the Pediatric Gastroenterology Service of the Teaching Hospital, State University of Campinas, Campinas, SP, Brazil, in a 23-year period, from 1980 to 2003. The records of these patients were reviewed and patients were classified into two groups, according to their anatomical diagnosis: patients with intrahepatic cholestasis - group 1, and patients with extrahepatic cholestasis - group 2. Records of weight and height measurements were collected at 4 age stages of growth, in the first year of life: 1) from the time of the first medical visit to the age of 4 months (T1); 2) from the 5th to the 7th month (T2); 3) from the 8th to the 10th month (T3); and 4) from the 11th to the 13th month (T4). The weight-by-age and height-by-age Z-scores were calculated for each patient at each stage. In order for the patient to be included in the study it was necessary to have the weight and/or height measurements at the 4 stages. Analyses of variance and Tukey's tests were used for statistical analysis. Repeated measurement analyses of variance of the weight-by-age Z-score were performed in a 60-patient sample, including 29 patients from group 1 and 31 patients from group 2. The height-by-age data of 33 patients were recorded, 15 from group 1 and 18 from group 2 The mean weight-by-age Z-scores of group 1 patients at the 4 age stages were: T1=-1.54; T2=-1.40; T3=-0.94; T4=-0.78. There was a significant difference between T2 X T3 and T1 X T4. The weight-by-age Z-scores for group 2 patients were :T1=-1.04; T2=-1.67; T3=-1.93 and T4=-1.77, with a significant difference between T1 X T2 and T1 X T4. The mean weight-by-age Z-scores also showed a significant difference between group 1 and group 2 at stages T3 and T4. The mean height-by-age Z-scores at the four stages in group 1 were: T1=-1.27; T2=-1.16; T3=-0.92 and T4=-0.22, with a significant difference between T3XT4 and T1XT4. The scores for group 2 patients were: T1=-0.93; T2=-1.89; T3=-2.26 and T4=-2.03, with a significant difference between T1XT2 and T1XT4. The mean height-by-age Z-scores also showed a significant difference between group 1 and group 2 at T3 and T4 The weight and height differences between the groups became significant from the 3rd measurement onward, with the most substantial deficit found in the extrahepatic group. In this group, there is evidence that the onset of weight and height deficit occurs between the first and second evaluation stages.

Children's Liver Disease Foundation

In this fifth article in the series profiling charities and organizations pertinent to gastrointestinal nursing, Catherine Arkley introduces the Children's Liver Disease Foundation, an organization dedicated to fighting childhood liver disease.