Claudio Veropalumbo

Aminotransferases and muscular diseases: A disregarded lesson. Case reports and review of the literature

The aim of this study was to call the attention to the often disregarded message that hypertransaminasemia may be a marker of both liver and muscle diseases by presenting personal case reports and a systematic literature review. Three male children (mean age 5.7 years) were inappropriately addressed, during the last 12 months, to our paediatric liver unit for diagnostic work‐up of a chronic hypertransaminasemia of unknown origin. In one of them, a liver biopsy had already been performed. On admission, physical examination, evaluation of serum levels of creatine kinase, and dystrophin genetic testing finally led to a diagnosis of muscular dystrophy. One hundred fourteen similar cases, 21 with unnecessary liver biopsy, were found by Medline search. Expensive and invasive tests planned to investigate liver diseases should be postponed until alternative sources of increased serum aminotransferases, primarily myopathic injury, have been excluded.

Paediatric arterial ischemic stroke: acute management, recent advances and remaining issues

Stroke is a rare disease in childhood with an estimated incidence of 1-6/100.000. It has an increasingly recognised impact on child mortality along with its outcomes and effects on quality of life of patients and their families. Clinical presentation and risk factors of paediatric stroke are different to those of adults therefore it can be considered as an indipendent nosological entity. The relative rarity, the age-related peculiarities and the variety of manifested symptoms makes the diagnosis of paediatric stroke extremely difficult and often delayed. History and clinical examination should investigate underlying diseases or predisposing factors and should take into account the potential territoriality of neurological deficits and the spectrum of differential diagnosis of acute neurological accidents in childhood. Neuroimaging (in particular diffusion weighted magnetic resonance) is the keystone for diagnosis of paediatric stroke and other investigations might be considered according to the clinical condition. Despite substantial advances in paediatric stroke research and clinical care, many unanswered questions remain concerning both its acute treatment and its secondary prevention and rehabilitation so that treatment recommendations are mainly extrapolated from studies on adult population. We have tried to summarize the pathophysiological and clinical characteristics of arterial ischemic stroke in children and the most recent international guidelines and practical directions on how to recognise and manage it in paediatric emergency.

Pediatric parenteral nutrition-associated liver disease and cholestasis: Novel advances in pathomechanisms-based prevention and treatment

Parenteral nutrition constitutes a life-saving therapeutic tool in patients unable to ingest/absorb oral or enteral delivered nutrients. Liver function tests abnormalities are a common therapy-related complication, thus configuring the so-called Parenteral Nutrition Associated Liver Disease (PNALD) or cholestasis (PNAC). Although the damage is frequently mild, and resolves after discontinuation of parenteral nutrition, in some cases it progresses into cirrhotic changes, especially in neonates and infants. We present a literature review focusing on the pathogenetic mechanisms-driven prevention and therapies for the cases where parenteral nutrition cannot be discontinued. Ursodeoxycholic acid has been proposed in patients with cholestatic hepatopathy, but its efficacy needs to be better established. Little evidence is available on efficacy of anti-oxidants, antibiotics, probiotics and anti TNFα. Lipid emulsions based on fish oil with a high content of long-chain polyunsaturated fatty acids ω-3 appear effective both in decreasing intrahepatic inflammation and in improving biliary flow. Most recent promising variations such as soybean/MCT/olive/fish oil emulsion [third generation lipid emulsion (SMOFlipid)] are under investigation. In conclusion, we remark the emergence of a number of novel pathomechanisms underlying the severe liver impairment damage (PNALD and PNAC) in patients treated with parenteral nutrition. Only few traditional and innovative therapeutic strategies have hitherto been shown promising.

Treatment of children with chronic viral hepatitis: what is available and what is in store

BackgroundAt present, therapy of children with chronic hepatitis B and C is still based on few drugs, all burdened by a series of side-effects, unsatisfactory serum conversion rates, and/or drug-resistance. Moreover, selection of subjects to treat with conventional therapies is not univocal, especially during the pediatric age when the disease course is often mild with significant spontaneous seroconversion rate. Our review deals with pros and cons points when a physician decides to design a drug therapy for a child with chronic viral hepatitis, and different possible therapeutic opportunities.MethodsA literature search was performed through PubMed. The newest articles, reviews, systematic reviews, and guidelines were included in this review.ResultsThe management of children with viral hepatitis is still controversial over whom and when to treat and the use of drug(s). Novel therapeutic strategies have been evaluated only in clinical and preclinical trials involving, for instance, “therapeutic” vaccines. The data on safety and effectiveness of new drugs are also reviewed.ConclusionThe results of reported studies confirmed that at least some of the new drugs, with greater efficacy and/or minor side-effects, will be used clinically.

Citrin deficiency: learn more, and don't forget to add it to the list of neonatal cholestasis and the NASH trash bin.

itrin is the liver-type mitochondrial aspartate glutamate carrier. Its deficiency, also known as type II citrullinemia, C is an autosomal recessive genetic disorder causing metabolic derangements in aerobic glycolysis and gluconeogenesis. Urea cycle mechanisms, uridine diphosphate-galactose epimerase activity, acylcarnitine metabolism, and fatty acid synthesis and utilization are also affected mainly due to a defective aspartate export from the mitochondria to the cytosol and impairment of the malate-aspartate shuttle. Patients with this defect may harbor different mutations on gene SLC25A13 located on chromosome 7q21.3. Mutations have a carrier rate of 1:65 in Japan and China, whereas they are much less frequent in the Western world, and are responsible for 2 phenotypes of the disease. The first is a usually self-limiting neonatal (intrahepatic) cholestatic and steatotic condition (neonatal intrahepatic cholestasis caused by citrin deficiency [NICCD], OMIM #605814). The second is an adult-onset disease, mainly characterized by fatty liver and late recurrent hyperammonemic neurological disturbance (citrullinemia2, OMIM #603471) (1). Failure to thrive may be an additional presentation (2). In this issue of JPGN, Lee et al (3) present 2 cases that examine some basic aspects of this often still poorly recognized disorder. NICCD is associated with growth retardation/failure to thrive, severe intrahepatic cholestatic jaundice and fatty liver, hypoproteinemia, hypoglycemia, galactosemia, and multiple aminoacidemia including citrulline, methionine, threonine, and tyrosine and increased serum concentration of pancreatic secretory trypsin inhibitor (4). Possible misdiagnosis of galactosemia and tyrosinemia may arise. The occurrence of a chubby face, objectively measurable by the ‘‘Chubby index,’’ has recently been described in JPGN (5) as a useful clinical marker. Similar to the biochemical findings, this phenotypic feature tends to disappear mostly within the first year of life. Probably because most citrin deficiency cases have been reported in east Asian children, the current North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition recommendations for the evaluation of infants with cholestatic jaundice did not include NICCD testing (6). A more recent expert opinion (7) based on case reports from other ethnic groups (1) advises us to consider this condition when evaluating an infant with cholestasis, whichever her or his ethnicity. Although

Duchenne and Becker muscular dystrophy presenting as nonalcoholic fatty liver disease.

JPGN Volume 53, N N onalcoholic fatty liver disease (NAFLD) encompasses a wide spectrum of conditions ranging from simple steatosis to steatohepatitis and liver cirrhosis (1). It is the most common liver disorder in the pediatric age group, paralleling the epidemic of obesity (2,3). Duchenne and Becker muscular dystrophy (DBMD) is often characterized in the early stage by central obesity and increased muscular fat content (4). We report on the first case of biopsy-proven NAFLD in a patient with DBMD to emphasize the relation between these 2 conditions as well as the peculiar weightloss management. The patient, a 9-year-old Italian boy, was born at the 32nd week of gestation. His clinical history, including the achievements of motor milestones, was uneventful up to the age of 7 years, when he complained of mild and ill-defined general asthenia. Because of this, he underwent routine laboratory examinations. The only reported abnormal laboratory tests were the increased serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) (3 times upper normal values [unv] for both enzymes). He was then hospitalized because of the persistence of isolated hypertransaminasemia for approximately 1 year (levels ranging from 4 to 6 times unv for AST and from 3 to 5 times unv for ALT). Laboratory tests performed to exclude the most common viral and autoimmune causes of liver diseases were within normal limits. Ultrasonography of the liver showed a bright pattern compatible with steatosis, which was also confirmed at histology after needle liver biopsy (Fig. 1). Because of his obesity (both body mass index [BMI] and weight/height [W/H] ratio >95th percentile) and excessive caloric intake, a slimming diet was prescribed. Four months after starting the diet he lost some weight (4.2 kg, 8% of basal weight) and ultrasonographic liver brightness decreased. Hypertransaminasemia, however, remained unchanged (AST and ALT 5 and 4 times unv, respectively). The patient was therefore referred to our pediatric liver unit at the age of 8 years 10 months. His mother and father were obese and overweight, respectively. His mother presented with a pattern of insulin resistance (HOMA 2.9) without other components of the metabolic syndrome, and his father had borderline HOMA (2.4). Both parents had normal serum aminotransferase levels and a recently performed abdominal ultrasonography without liver brightness. At physical examination,

Muscular dystrophy revealed by incidentally discovered elevated aminotransferase levels.

To the Editor: We read with interest the report by Ciafaloni et al and the related editorial by Kaufmann on the persisting delay (approximately 2.5 years) between the onset of symptoms and time of definitive diagnosis of Duchenne/Becker Muscular Dystrophy (DBMD), because of the frequent misdiagnosis with motor or global developmental delay. We call the attention to another possible confounding factor not mentioned by the authors. During the last 12 months, 3 children (mean age, 5.7 years), who subsequently turned out to be affected by DBMD, were referred inappropriately to our pediatric liver unit for investigation of a chronic elevated aminotransferase level of unknown origin. All the children had already undergone an exhaustive search for the most common causes of liver disease, as has been the case in similar patients previously. In 1 obese patient, a liver biopsy had been performed, and the results showed only mild steatosis. After admission, physical examination, determination of serum levels of creatine kinase, and genetic testing for dystrophinopathies, a diagnosis of muscular dystrophy was made. Patients were referred to the pediatric neurology unit for a more detailed assessment and setting up appropriate rehabilitation. The delay in diagnosis of muscular disease, since elevated aminotransferase levels were first discovered, amounted to approximately 15 months. In apparently healthy children, aminotransferase levels are assessed more frequently than creatine kinase (CK) or aldolase levels. Economic restrictions may influence negatively the broadening of laboratory tests, leaving the only monitoring of transaminases before the signs of a muscular disease become clinically obvious in patients with incidental elevated aminotransferase levels. This persisting pitfall does not seem to be restricted to our center and to our country. The compelling need of considering elevated aminotransferase levels as a possible marker of unsuspected muscle disease has been underlined by at least a dozen of reports and warning articles in the international literature beginning from 1984 and until 2006. In some instances, useless and possibly dangerous liver biopsies had been performed before a definitive correct diagnosis of DBMD could be reached. It is worth a reminder that CK testing should be performed at the beginning of the diagnostic algorithm also in patients with cryptogenetic elevated aminotransferase levels, especially before invasive and expensive examinations such as liver biopsy. Moreover, general pediatricians should always carry out a complete physical examination of these patients, looking in particular to lower limbs for subtle signs of calf pseudohypertrophy and muscular weakness. Pietro Vajro, MD Ennio Del Giudice, MD Claudio Veropalumbo, MD Pediatric Liver and Neurology Units Department of Pediatrics University of Naples ‘‘Federico II’’ Naples, Italy 10.1016/j.jpeds.2009.11.047

Shwachman-Diamond syndrome with autoimmune-like liver disease and enteropathy mimicking celiac disease

Liver abnormalities that normalize during infancy as well an enteropathy are reported in Shwachman-Diamond syndrome (SDS). The pathogenesis of both conditions is unknown. We report two SDS cases with autoimmune-like (antismooth muscle and/or antinuclear antibody positivity) liver disease and antigliadin antibody positive inflammatory enteropathy. Hypertransaminasemia did not resolve after immunosuppressive therapy and/or a gluten-free diet. These transient autoimmune phenomena and gut-liver axis perturbations may have played a role in transient SDS hepatopathy and enteropathy. Our report may stimulate other studies to define the relationship between the SDS genetic defect and intestinal permeability as the pathogenic mechanism underlying SDS related liver and intestinal inflammation.

Point-of care lung ultrasound in the NICU: uses and limitations of a new tool

Pulmonary imaging in the neonatal intensive care unit (NICU) relies traditionally on the conventional chest radiogram. Translating evidences from adult emergency medicine, pediatricians and neonatologists have recently started to apply lung ultrasonography to the critical infant and child with respiratory problems [1]. Because of the high impedance of a normally aerated lung, an ultrasound scan does not render an anatomical image of the organ. However, ultrasounds clearly define the pleural surface with the normal sliding movement. Pleural effusions and lung consolidations can also be reliably diagnosed with ultrasonography. However, ultrasounds penetrating the lung will also generate artifacts (i.e. structures not naturally present in the living that appear as authentic images). These imagery anomalies come from the machine acquisition of the ultrasound beam path through means with markedly different acoustic impedance in close proximity. The horizontal reverberations of the pleural line (aka the A lines - see Figure ​Figure1A)1A) and the vertical hyperecoic image departing from the pleura (aka the B lines- see Figure ​Figure1B)1B) are commonly seen artifacts. Figure 1 1A: reverberations of the pleural image (aka A-lines) in the normally aerated lung. 1B: the prevalence of vertical B-lines (in between arrows) has been linked to the interstitial syndrome in the adult and to a progressive aeration of the neonatal lung ... Real and artefactual images have been combined in disease specific ultrasound profiles. Using these profiles, adult emergency physicians have shown that lung ultrasound outperforms conventional radiology in relevant diagnoses such as pleural effusion, pneumonia or pneumothorax. Pediatricians have started to use lung ultrasound with success to their patients affected by pneumonia but also by bronchiolitis [2]. In the NICU, lung ultrasound has found its specific applications, not without controversies [3]. Transient Tachypnea of the Newborn and Respiratory Distress Syndrome have been described with ultrasound profiles that are both highly sensitive and specific [4]. A relevant limitation of chest ultrasound is that surfactant administration gives a persistent white lung image rendering any follow-up essentially unfeasible. Ultrasounds can, however, accurately describe the fluid to air transition after birth and identify those neonates who will fail to adapt to extrauterine life needing respiratory support [5]. In a series of preterm neonates with moderate respiratory distress, recent work by our group shows that chest ultrasound is significantly more accurate than conventional radiograph in predicting the failure of non invasive ventilation [6]. Lung ultrasound is a very promising clinical tool in the NICU whose potential applications are well worth future multicenter trials.

Treating children with HBeAg-positive chronic hepatitis B: No small accomplishment

Despite the introduction of a highly effective hepatitis B virus(HBV) vaccine and hepatitis B immunoglobulin, mother-to-childtransmission unfortunately remains a leading cause of HBV infec-tion in children. Non-response to standard vaccines occurs inapproximately 5–10% of appropriately immunized cases, and isprobably due to very early (transplacental/intrauterine) infection.Emergence of escape mutants (mutations in the “s” gene of HBVcausing conformational changes in the “a” determinant) insteaddoes notappeartobeamajorthreat.Therecentrecommendationofprescribing Tenofovirdisoproxiltohighlyviremicpregnantwomenin the third trimester is another still missed goal to reduce therisk of perinatal transmission of HBV [1]. These situations appeareven more serious in developing countries where HBV infectionis endemic, and where a significant percentage of the populationsimply may not have access to the vaccine or cannot return for therequired booster doses [2].Children with chronic hepatitis B (CHB) when tested are mostlyin the so-called “immune-tolerant phase” (normal or mildly ele-vated aminotransferase levels, minimal histological activity, highserum HBVDNAlevels,HBeAgandHBsAgpositive).Datashowthatup to one seventh of infected children spontaneously lose theirHBeAg every year so that most become “inactive” carriers beforeadulthood [3].Because of its asymptomatic course, in general pediatric CHBis thought to require a conservative approach to therapy. Recentguidelines and expert opinions [1,4–6] agree that treatment indi-cations shouldbeverycarefullyevaluated.Childreninfectedwitharapidly replicating virus causing extensive liver damage when theimmune system attacks infected hepatocytes might represent anindication forimmediatemedicalintervention;however,anunfor-tunately small arsenal of drugs is currently available at this ageto halt HBV liver disease progression. Furthermore, with availabledrugs, treatmentfailureiscommonespeciallyinpatientswithveryhigh levels of HBV replication (>20,000IU/ml) and normal/near