Özlem Durmaz

Diagnosis of nonalcoholic fatty liver disease in children and adolescents: position paper of the ESPGHAN Hepatology Committee.

ABSTRACT Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in children and adolescents in the United States, and most probably also in the rest of the industrialized world. As the prevalence of NAFLD in childhood increases with the worldwide obesity epidemic, there is an urgent need for diagnostic standards that can be commonly used by pediatricians and hepatologists. To this end, we performed a PubMed search of the adult and pediatric literature on NAFLD diagnosis through May 2011 using Topics and/or relevant Authors as search words. According to the present literature, NAFLD is suspected based on the association of fatty liver combined with risk factors (mainly obesity), after the exclusion of other causes of liver disease. The reference but imperfect standard for confirming NAFLD is liver histology. The following surrogate markers are presently used to estimate degree of steatosis and liver fibrosis and risk of progression to end-stage liver disease: imaging by ultrasonography or magnetic resonance imaging, liver function tests, and serum markers of liver fibrosis. NAFLD should be suspected in all of the overweight or obese children and adolescents older than 3 years with increased waist circumference especially if there is a NAFLD history in relatives. The typical presentation, however, is in children ages 10 years and older. The first diagnostic step in these children should be abdominal ultrasound and liver function tests, followed by exclusion of other liver diseases. Overweight/obese children with normal ultrasonographic imaging and normal liver function tests should still be monitored due to the poor sensitivity of these tests at a single assessment. Indications for liver biopsy include the following: to rule out other treatable diseases, in cases of clinically suspected advanced liver disease, before pharmacological/surgical treatment, and as part of a structured intervention protocol or clinical research trial.

Liver biopsy in children: position paper of the ESPGHAN Hepatology Committee.

Liver biopsy (LB) is still the criterion standard procedure for obtaining liver tissue for histopathological examination and a valuable tool in the diagnosis, prognosis, and management of many parenchymal liver diseases. The aim of this position paper is to summarise the present practice of paediatric LB and make recommendations about its performance. Although histological evaluation of the liver is important in assessing prognosis and exploring treatment, noninvasive techniques (ie, imaging, laboratory markers) may replace use of liver histology. The indications for LB are changing as present knowledge of aetiologies, pathomechanism, and therapeutic options in paediatric liver disease is evolving. Adult and paediatric literature was reviewed to assess the existing clinical practice of LB with focus on the technique, indications, risk of complications, and contraindications in paediatrics. This position paper presents types of LB, indications, complications, contraindications, and an essential checklist for paediatric LB.

A novel bile acid biosynthesis defect due to a deficiency of peroxisomal ABCD3

ABCD3 is one of three ATP-binding cassette (ABC) transporters present in the peroxisomal membrane catalyzing ATP-dependent transport of substrates for metabolic pathways localized in peroxisomes. So far, the precise function of ABCD3 is not known. Here, we report the identification of the first patient with a defect of ABCD3. The patient presented with hepatosplenomegaly and severe liver disease and showed a striking accumulation of peroxisomal C27-bile acid intermediates in plasma. Investigation of peroxisomal parameters in skin fibroblasts revealed a reduced number of enlarged import-competent peroxisomes. Peroxisomal beta-oxidation of C26:0 was normal, but beta-oxidation of pristanic acid was reduced. Genetic analysis revealed a homozygous deletion at the DNA level of 1758bp, predicted to result in a truncated ABCD3 protein lacking the C-terminal 24 amino acids (p.Y635NfsX1). Liver disease progressed and the patient required liver transplantation at 4 years of age but expired shortly after transplantation. To corroborate our findings in the patient, we studied a previously generated Abcd3 knockout mouse model. Abcd3-/- mice accumulated the branched chain fatty acid phytanic acid after phytol loading. In addition, analysis of bile acids revealed a reduction of C24 bile acids, whereas C27-bile acid intermediates were significantly increased in liver, bile and intestine of Abcd3-/- mice. Thus, both in the patient and in Abcd3-/- mice, there was evidence of a bile acid biosynthesis defect. In conclusion, our studies show that ABCD3 is involved in transport of branched-chain fatty acids and C27 bile acids into the peroxisome and that this is a crucial step in bile acid biosynthesis.

An outstanding non-transplant surgical intervention in progressive familial intrahepatic cholestasis: partial internal biliary diversion.

AimProgressive familial intrahepatic cholestasis (PFIC) is a hereditary disease with severe cholestasis progressing to cirrhosis and chronic renal failure usually during the first decade. An alternative approach is partial diversion of bile. The aim of this study is to describe four patients with PFIC who underwent partial internal biliary diversion (PIBD).MethodsReview of three patients, their clinical, laboratory and histologic workups to evaluate the short-term effects of PFIC, a 1-year follow-up. For PIBD, a conduit is performed between the terminolateral side of the gall bladder and distal colon using a segment of jejunum, to divert the biliary flow from the enterohepatic cycle without any external stoma.ResultsAll four patients were presented with jaundice, pruritus, hepatomegaly, sleep disturbance. They fulfilled the criteria for PFIC. The surgery was uneventful. At follow-up, biochemical parameters improved significantly, growth was regained, relief in pruritus, sleeping pattern was normalized.ConclusionsPartial internal biliary diversion had a dramatic effect on cholestasis, growth, sleeping and biochemical parameters. It also avoids the disadvantages of a permanent stoma. We believe that it is one of the best surgical procedures ever described for PFIC. Since long-term results of partial external biliary diversion on liver histopathology are successful, we hope that our long-term results will also be similar.

Valproic Acid-Associated Vanishing Bile Duct Syndrome:

Hepatotoxicity as a result of valproic acid therapy is well documented. Elevation in aminotransferase activities is rarely associated with symptoms. It sometimes manifests as acute liver failure. Here, we report a 8-year-old girl who was referred for unresolving jaundice and itching for 3 months. Past history revealed afebrile convulsion 5 months previously and beginning of valproic acid treatment. Valproic acid was discontinued after the development of jaundice. Physical examination revealed ichterus, xanthomas on extensor surfaces of extremities, and hepatomegaly without any sign of chronic liver disease. Total and direct bilirubin levels were 20.2 and 12.9 mg/dL, respectively. Enzyme activities indicating cholestasis were increased together with blood cholesterol. Tests for infectious and autoimmune, metabolic, and genetic disorders were not informative. Liver biopsy revealed portal inflammation, severe bile duct loss, and cholestasis. The patient was considered to have valproic acid—associated vanishing bile duct syndrome, which has not been reported previously.

Interobserver agreement on endoscopic classification of oesophageal varices in children

Objectives: Data regarding agreement on endoscopic features of oesophageal varices in children with portal hypertension (PH) are scant. The aim of this study was to evaluate endoscopic visualisation and classification of oesophageal varices in children by several European clinicians, to build a rational basis for future multicentre trials. Methods: Endoscopic pictures of the distal oesophagus of 100 children with a clinical diagnosis of PH were distributed to 10 endoscopists. Observers were requested to classify variceal size according to a 3-degree scale (small, medium, and large, class A), a 2-degree scale (small and large, class B), and to recognise red wales (presence or absence, class Red). Overall agreement was considered fair if Fleiss and Cohen &kgr; test was ≥0.30, good if ≥0.40, excellent if ≥0.60, and perfect if ≥0.80. Results: Agreement between observers was fair with class A (&kgr; = 0.34) and class B (&kgr; = 0.38), and good with class Red (&kgr; = 0.49). The agreement was good on presence versus absence of varices (class A = 0.53, class B = 0.48). The agreement among the observers was good in class A when endoscopic features of severe PH (medium and large sizes, red marks) were grouped and compared with mild features (absent and small varices) (&kgr; = 0.58). Conclusions: Experts working in different centres show a fairly good agreement on endoscopic features of PH in children, although a better training of paediatric endoscopists may improve the agreement in grading severity of varices in this setting.

Investigation of cardiomyopathy in children with cirrhotic and noncirrhotic portal hypertension.

Background: Cirrhotic cardiomyopathy (CCMP) is a functional disorder characterized by electrophysiological disturbances, and diastolic and/or systolic dysfunction in patients with liver disease. This disorder is a well-defined entity in adults, but pediatric data are limited. The aim of the study was to determine the incidence, features, and risk factors of CCMP in children with portal hypertension (PHT). Methods: This study included 50 children with cirrhotic PHT (40/50) and noncirrhotic PHT (10/50). Fifty healthy children were also selected for the control group. Electrocardiography and echocardiography were used to evaluate cardiac functions. Corrected QT (QTc) ≥ 0.45 was accepted as prolonged on electrocardiography. The study group was divided into 3 groups: cirrhotic, noncirrhotic, and control. Then, the CCMP group was created according to the diagnostic criteria. Latent CCMP was diagnosed in the presence of prolonged-QTc along with a minor criterion (tachycardia). Manifest CCMP was diagnosed in the presence of at least 2 major criteria (prolonged-QTc along with abnormal echocardiographic findings). Moreover, in this study, the risk factors for CCMP were investigated. Results: The CCMP group included 10 cases (20%). Nine of these cases had latent CCMP (18%), and the remaining one (2%) had manifest CCMP. All of the cases with CCMP had cirrhosis and ascites. None of the patients with CCMP had severe cardiac symptoms, but they were already using some cardioprotective drugs such as propanolol and spironolactone. As risk factors for CCMP, pediatric end-stage liver disease scores, Child-Pugh scores, and ascites grades were found to be significant for the determination of CCMP. The most important risk factor was ascites severity (P = 0.001, odds ratio 9.4). Conclusions: Approximately 20% of children with PHT have CCMP. A detailed cardiac examination should be carried out periodically in children with cirrhotic PHT, especially in the presence of ascites and high Child-Pugh score.

The role of the non-invasive serum marker FibroTest-ActiTest in the prediction of histological stage of fibrosis and activity in children with naïve chronic hepatitis B infection.

Abstract The aim of this study was to investigate whether the non-invasive serum marker FibroTest–ActiTest (FT–AT) reliably predicts the histological stage of fibrosis and/or activity, and decreases the need for a liver biopsy. Twenty-five children with naïve chronic hepatitis B were analyzed for haptoglobin, α2-macroglobulin, apolipoprotein A1, bilirubin, γ-glutamyl transferase, and alanine aminotransferase activity, and the FT–AT scores were computed. FT–AT scores were compared with histological data. FT predicted insignificant fibrosis in 14/23 (61%) patients at a cut-off level of 0.31. Nine patients (36%) had significant histological fibrosis, but none were predicted by FT. There was no correlation between FT scores and histological stage of fibrosis (r: −0.221, p = 0.228). All 4 patients with significant histological activity had corresponding significant activity in AT (100%). Fifteen out of the 19 patients (78.9%) with significant activity in AT had insignificant histological activity. At the cut-off level of 0.36, AT predicted insignificant activity in all 6 patients (100%). There was no correlation between AT scores and histological activity (r: 0.245, p = 0.237). According to histological data, 12 patients were candidates for treatment, but FT–AT did not predict 3 of them (25%). FT–AT does not appear ready for use in detecting either the stage of fibrosis or activity in children with chronic hepatitis B.

Human herpes virus type 8-associated Kaposi sarcoma in a pediatric liver transplant recipient

Çeltik C, Ünüvar A, Aydoğan A, Gökçe S, Öztürk G, Güllüoğlu M, Yılmaz G, Türkoğlu S, Anak S, Sökücü S, Durmaz Ö. Human herpes virus type 8‐associated Kaposi sarcoma in a pediatric liver transplant recipient.
Pediatr Transplantation 2011: 15: E100–E104.

Portal gastropathy and duodenopathy in children with extrahepatic and intrahepatic portal hypertension: endoscopic diagnosis and histologic scoring.

Objectives:The aim of the study was to determine the frequency of portal gastropathy (PG) and duodenopathy (PD) in children, to document the correlation of various clinical and laboratory parameters associated with portal hypertensive gastroduodenal lesions, to compare the endoscopic portal hypertensive lesions with different histologic findings, and to evaluate the use of a possible histologic scoring system. Methods:All children undergoing endoscopic investigation for portal hypertension (PH) between January 2006 and November 2007 were analysed retrospectively. Clinical and demographical data and endoscopic and histologic findings were recorded. Histologic findings suggestive of PG and PD (capillary dilation, increased numbers of capillaries, histologic bleeding, and edema) were scored. Results:Of 51 consecutive children (29 boys, mean age 10.1± 3.6 years [range 2.5–15.8 years]), 28 were cirrhotic. PG was diagnosed in 58.8% endoscopically. Children with cirrhotic PH had the highest rate of PG (64.3%), whereas those with extrahepatic or intrahepatic noncirrhotic PH were alike (50% and 54.5%, respectively). Baveno PG scores were higher in children with cirrhosis with higher Child-Pugh scores. Capillary dilation was the only histologic finding showing significant association with the endoscopic diagnosis. Only 9% had PD on endoscopy. None of the histologic findings correlated with endoscopic diagnosis of PD. Conclusions:PG and PD are seen in children with extrahepatic and intrahepatic PH at rates similar to those reported in adult studies. Baveno PG scores increased in parallel with Child-Pugh class in children with cirrhosis. Capillary dilation was the only histologic finding showing significant association with the endoscopic diagnosis of PG in this study.