Abstract Background Helsmoortel–Van der Aa syndrome is a neurodevelopmental disorder in which patients present with autism, intellectual disability, and frequent extra-neurological features such as feeding and gastrointestinal problems, visual impairments, and cardiac abnormalities. All patients exhibit heterozygous de novo nonsense or frameshift stop mutations in the Activity-Dependent Neuroprotective Protein (ADNP) gene, accounting for a prevalence of 0.2% of all autism cases worldwide. ADNP fulfills an essential chromatin remodeling function during brain development. In this study, we investigated the cerebellum of a died 6-year-old male patient with the c.1676dupA/p.His559Glnfs*3 ADNP mutation. Results The clinical presentation of the patient was representative of the Helsmoortel–Van der Aa syndrome. During his lifespan, he underwent two liver transplantations after which the child died because of multiple organ failure. An autopsy was performed, and various tissue samples were taken for further analysis. We performed a molecular characterization of the cerebellum, a brain region involved in motor coordination, known for its highest ADNP expression and compared it to an age-matched control subject. Importantly, epigenome-wide analysis of the ADNP cerebellum identified CpG methylation differences and expression of multiple pathways causing neurodevelopmental delay. Interestingly, transcription factor motif enrichment analysis of differentially methylated genes showed that the ADNP binding motif was the most significantly enriched. RNA sequencing of the autopsy brain further identified downregulation of the WNT signaling pathway and autophagy defects as possible causes of neurodevelopmental delay. Ultimately, label-free quantification mass spectrometry identified differentially expressed proteins involved in mitochondrial stress and sirtuin signaling pathways amongst others. Protein–protein interaction analysis further revealed a network including chromatin remodelers (ADNP, SMARCC2, HDAC2 and YY1), autophagy-related proteins (LAMP1, BECN1 and LC3) as well as a key histone deacetylating enzyme SIRT1, involved in mitochondrial energy metabolism. The protein interaction of ADNP with SIRT1 was further biochemically validated through the microtubule-end binding proteins EB1/EB3 by direct co-immunoprecipitation in mouse cerebellum, suggesting important mito-epigenetic crosstalk between chromatin remodeling and mitochondrial energy metabolism linked to autophagy stress responses. This is further supported by mitochondrial activity assays and stainings in patient-derived fibroblasts which suggest mitochondrial dysfunctions in the ADNP deficient human brain. Conclusion This study forms the baseline clinical and molecular characterization of an ADNP autopsy cerebellum, providing novel insights in the disease mechanisms of the Helsmoortel–Van der Aa syndrome. By combining multi-omic and biochemical approaches, we identified a novel SIRT1-EB1/EB3-ADNP protein complex which may contribute to autophagic flux alterations and impaired mitochondrial metabolism in the Helsmoortel–Van der Aa syndrome and holds promise as a new therapeutic target. Graphical abstract

Autoimmune pancreatitis type 2 is a relatively novel entity with some still controversial issues. The current diagnostic algorithm relies on imaging studies and histology. Therapy includes corticosteroids with consequently low risk of relapse in the following year. However, the pathogenesis remains unclear, and data are insufficient for long-term prognosis. We have treated a 17-year-old boy whose autoimmune pancreatitis type 2 was revealed during surgery for a pre-existing biliary tract anomaly with concurrent protozoal infection. We discuss the co-occurrence of these conditions in terms of eventual pathogenesis correlation and combined effect on long-term prognosis.

Biliary atresia (BA) is a rare disease of unknown etiology which leads to cirrhosis and death if left untreated. The standard of care is an early hepatoportoenterostomy (HPE). Long-term follow-up is mandatory, during which most patients will require a liver transplant. Activin A belongs to the transforming growth factor-β (TGF-β) superfamily. TGF-β is a central regulator in chronic liver disease. We have studied the expression of activin A in liver tissue collected intraoperatively during the HPE. We included patients who underwent HPE in a single medical center. Clinical, ultrasonographic, and pathohistological data were collected. Activin A immunostaining was performed. Expression in the bile duct epithelium and hepatocytes was scored as either weakly positive, moderately positive, or strongly positive. Patients were then divided into three groups accordingly. We observed the outcome after the HPE at 3 months, 2 years, and at the end of follow-up. The study encompassed 37 patients. At 3 months after HPE, 92.3% of those with a weakly positive activin A reaction (group A) achieved good jaundice clearance, whereas only 44.4% of those with a moderately (group B) and 40% of those with a strongly positive reaction (group C) achieved good jaundice clearance (p = 0.008). Furthermore, 2 years after the HPE, 92.3% of those in group A survived with native liver (SNL), but only 33.3% of those in group B and 46.7% of those in group C had SNL (p = 0.007). At the end of follow-up, 83.3% of those in group A survived with native liver, as did 33.3% in group B and 40% in group C. Activin A is a valuable pathohistological predictor of the outcome of BA after an HPE.

Kolestaza je poremećaj stvaranja i/ili protoka žuči koji dovodi do zadržavanja žuči u jetri. Javlja se kod 1 : 2500 terminske dojenčadi, najčešće u prva tri mjeseca života. Konjugirana hiperbilirubinemija je biokemijska manifestacija kolestaze o kojoj govorimo kada je konjugirani bilirubin veći od 17 umol/L i/ili na njega otpada više od 20% ukupnog bilirubina. Kolestaza je uvijek patološka i zahtijeva opsežnu obradu. Najčešći pojedinačni uzroci su atrezija žučnih vodova, infekcija, kolestaza uzrokovana parenteralnom prehranom i manjak alfa-1 antitripsina, dok u četvrtine bolesnika etiologija ostaje nerazjašnjena pa govorimo o idiopatskom neonatalnom hepatitisu. Kliničke su manifestacije kolestaze žutica, pruritus i pojava svijetlih (hipokoličnih ili akoličnih) stolica i tamnijeg urina. Otežana apsorpcija masti i vitamina topivih u masti, pothranjenost i pruritus izazovni su klinički problemi koje susrećemo u ovih bolesnika. Zaključak: Kolestaza u dojenačkoj dobi rijetko je stanje koje je često uzrokovano teškim bolestima, te je stoga temeljna zadaća svakog pedijatra pravovremeno prepoznati ove bolesnike i uputiti ih na daljnju obradu.

Crigler-Najjar syndrome (CNS) is an exceedingly rare autosomal recessive disease with an estimated incidence of 1 in a million live births. CNS type 1 (CNS1) is the most severe form, characterized by severe unconjugated hyperbilirubinemia since birth due to the absence of hepatic uridine 5'-diphosphate glucuronyltransferase (UGT1A1) activity. Daily phototherapy (PT) and liver transplant (LT) are the mainstays of therapy. Here, we present a higher-than-expected incidence of CNS1 in Croatia (6,1 in a million). In the last 31 years, we treated eight CNS1 patients from five families with no reported consanguinity. Four patients are descendants of an isolated enclave in Kosovo with a small gene pool and a high potential for inbreeding. Severe unconjugated hyperbilirubinemia was verified in a neonatal period and PT was initiated. Four patients underwent LT from living-related donors. One of them had unsuccessful hepatocyte transplantation earlier. LT was successful in three patients, and one patient died due to primary graft dysfunction. Four patients are currently treated with 9-12 h daily PT with inconsistent disease control, and gradually increasing bilirubin. One patient developed kernicterus before LT, while others have normal psychomotor development and no neurologic impairment. Genetic testing of the UGT1A1 gene in six patients from three families revealed three different homozygous mutations (c.722_723 delAG, c.717_718 delAG, and c.1021 C >T), all previously described in other populations. There is a possibility of the founder effect as an explanation for the higher incidence of CNS1 in at least a subgroup of Croatians.

Background: Acute hepatitis-associated aplastic anemia (AHAAA) is a rare clinical syndrome characterized by the development of aplastic anemia 2-3 months following an episode of acute hepatitis. Several immunosuppressive agents, but not mycophenolate mofetil (MMF), and bone marrow transplantation are the standard treatment options for AHAAA. Case Report: In this report, we present a case of a young boy with AHAAA manifesting as acute liver failure. The etiology was type 1 autoimmune hepatitis responsive to the second-line therapeutic combination of steroids and MMF. The liver has fully recovered, but bone marrow failure ensued. After 4 months, Clinical and laboratory improvement occurred without the need for bone marrow transplantation. An important aspect of this case is the full recovery of aplastic anemia without calcineurin inhibitors, anti-thymocyte globulin utilization, or bone marrow transplantation. Conclusion: Our case history supports MMF as a potentially crucial adjunctive therapy for patients with AHAAA who poorly respond to standard procedures.

SAŽETAK.Kolestaza je poremećaj stvaranja i/ili protoka žuči koji dovodi do zadržavanja žuči

ABSTRACT Many neurodevelopmental disorders, including autism, are caused by de novo mutations, that might arise as early as in the parental germline, during embryonic, fetal development, or as late as post-natal aging. Intra-tissue mutation-load variations could impact clinical presentation. One of the most common causes of autism is de novo mutations in ADNP . We developed an ultra-sensitive, highly-quantitative droplet digital PCR assay to determine ADNP mutation levels in patient tissues, including blood, teeth, hair, and 24 different tissues from a post-mortem de novo ADNP -mutated child (∼6-years old), including a transplanted liver from a non-mutant donor (retained for 22 months). Striking variations of ADNP mosaicism arose between tissues of the same individual. Mutation load differences were evident between post-mortem tissues, but not in the transplanted liver — supporting a cell autonomous genetic vulnerability to de novo mutations, arguing against a transferable environmentally-sensitive DNA damage/mutation predisposition. Variations between tissues suggest a developmental timing of the mutations. Most individuals showed at least one tissue with less than heterozygous mutations, where the presence of the homozygous non-mutant cells indicates that de novo ADNP mutations arose post-zygotically. Highly variable ADNP mosaicism between tissues, that within an individual can be less than heterozygous or approach homozygosity, indicate rapid ongoing post-zygotic, and possibly post-natal, somatic mutations, contributing to clinical variability.

We report the case of a full term male child with multiple organ dysfunctions caused by mutations of the TTN gene. Our patient had cardiac abnormalities verified by fetal echocardiography at 26 weeks of gestational age, when fetal hydrops due to cardiac decompensation was shown. Due to specific appearance seen at birth – generalized oedema, light facial and sexual dimorphism with hypogenitalism and chryptorchidism, axial hypotonia in addition to the proven congenital heart defects, a genetic disorder or syndrome with muscle involvement was suspected. Multiple comorbidities were present since birth, mainly cardiac and neurologic, some of which have been described in patients with core myopathies (atrial and ventricular septal defects, supraventricular tachycardia, hypotonia, developmental delay, myopathy). Due to the complexity of the heart defect at the age of 2 months a partial pulmonary trunk banding and ligation of the ductus Botalli (PDA) was initially carried out, and at 9 months a complete correction of heart defect was performed. Our patient also had failure to thrive as well as recurrent vomiting, wich was later on asociated with extraluminal compression of the proximal duodenum, intestinal malrotation and malfixation. Although a surgical approach somewhat increased tolerance of peroral food intake, chronic diarrhoea and failure to thrive persisted. In addition, our patient had several metabolic and endocrine disorders including hypocalcemia, hypomagnesemia, hyponatremia, repeatedly elevated levels of PTH, hypothyroidism etc. Our patient had recurrent, mainly respiratory infections with multiresistant microorganisms, and recuired intubation and long-lasting mechanical ventilation. The above mentioned multiple disorders of various organ systems, with complications caused by multiple sepses, ultimately resulted in multiorgan failure, and despite all the applied treatment at the ICU, resulted in a lethal outcome. Coresponding findings described in other patients with core myopathies included neonatal hypotonia, poor suckling, severe motor skill delay, complex heart defects and cardiomyopathy.

This is a one-year follow-up study looking into the nutritional status and the rate of re-hospitalizations in children at the UHC Zagreb, Dept. of Paediatrics who were first evaluated during the nutritionDay (nDay) in November 2018. The aim is to evaluate the accuracy of STRONGkids questionnaires, subjective assessment within nDay survey and anthropometry in detecting malnutrition and possible relation to number of hospital admissions and disease outcomes (for oncology patients) within a year. The study included 50 patients (mean age 13.48 years ±3.79, 22 males) whose nutritional status was estimated in November 2018. Additional data were collected after the period of 12 months. Mann-Whitney U, Kruskal Wallis and Wilcoxon signed-ranks tests were applied. A significantly different BMI was found among subgroups categorized through the nDay survey (without risk, at risk, malnourished patients) and among subgroups assessed by STRONGkids (low, medium and high risk for malnutrition) (p1=0.002, p2=0.003, resp.). Post hoc tests showed that statistical significance could be contributed to differences between groups malnourished patients vs. those not at risk within nDay (p3=0.009) and between groups low vs. high and medium vs. high risk defined through STRONGkids questionnaires (p4=0.020, p5=0.004, resp.). In the one-year follow-up period, 28/50 children were re-hospitalized once or several times. The number of re-hospitalizations was significantly higher for children classified by STRONGkids to have high risk for malnutrition (p6=0.002), as well as for those categorized as malnourished through the nDay survey (p7=0.024). No significant difference in z-score BMI values was found between years 2018 and 2019 (Wilcoxon signed-rank test: p8=0.086). Re-hospitalized oncology patients (11) were additionally analysed in respect of their disease status: favourable outcome (disease regression; 8/11) vs. unfavourable outcome (progression or unchanged state; 3/11). No difference was observed in the initial BMI between these groups (Mann-Whitney U test: p9=0.921), and no significant change in their BMI during this period was observed in either group (Wilcoxon signed-rank test: p10=0.161, p11=0.593). Patients categorized as malnourished both with STRONGkids and nDay survey had significantly lower BMI than the rest of subjects. Our data support the hypothesis that malnourished patients have a higher rate of re-hospitalizations. Within the observational period, re-hospitalized patients neither improved nor worsened their nutritional status according to the BMI z-scores. We were not able to connect the nutritional status of oncology patients with their disease outcome after one year, perhaps due to a rather small sample or short time of follow-up.

Objective To describe the characteristics of patients with cystic fibrosis-associated liver disease (CFLD), a complication of cystic fibrosis (CF) that is often asymptomatic until an advanced stage. Methods Retrospective analysis included patients aged 0-20 years followed in 2018. at the Cystic Fibrosis Centre of the University Hospital Centre Zagreb. CFLD1 was diagnosed if ≥2 of the following were present: hepatomegaly and/or splenomegaly, elevated transaminases or gamma-glutamyl transferase (GGT) 3 times during 12 months, ultrasound signs of liver involvement or portal hypertension (PTH), suggestive pathohistological findings. Severe CFLD was defined as a disease with signs of PTH. Results 61 patients with a mean age of 10.9 years (9 months-19 years, male: female = 34:27) were included. 9/61 (14.8%) of them had CFLD, 6 girls and 3 boys, aged 2-19 years (average age 10.7 years). They all had at least one F508del mutation, and 7/9 were homozygous. Regarding the severity of the disease, 4 patients (3 boys and 1 girl, 6-19 years) had a severe form of CFLD with PTH and presumed cirrhosis, which was confirmed by liver biopsy in one patient. Two patients also had impaired synthetic liver function, two had hypersplenism with platelet count <80x109/L, and one had esophageal varices without bleeding. The remaining 5/9 patients had mild CFLD with ultrasound changes (hyperechoic or nodular liver parenchyma, periportal fibrosis) and/or elevated liver enzymes. We observed a trend of poor nutritional status in patients with severe CFLD (mean BMI z-value -0.66, range -0.26 to 0.62) compared to those with mild form of CFLD (mean BMI z-value -0.41, range – 2.76 to 1.49), but the difference wasn’t significant, and the most severely malnourished patient had mild CFLD. We also assessed some noninvasive biomarkers of fibrosis: the APRI index was elevated (≥0.5) in all patients with severe CFLD and in one with mild CFLD, and Fibrosis-4 score was pathological in only one patient with PTH. Elastography was performed in 5 patients: it was normal in one patient with mild CFLD, whereas in four increased liver stiffness was found (significantly increased in two patients with severe CFLD, and mildly in two patients with mild CFLD). 4/9 patients with CFLD had meconium ileus, which is approximately twice the frequency compared to all included CF patients. Conclusion The diversity of clinical expression and findings in our patients is consistent with the literature data on the spectrum of CFLD manifestations. We confirmed a higher incidence of meconium ileus and severe mutations, and male dominance in CFLD with PTH. In all CF patients, liver disease should be actively sought from an early age (clinical examination once a year + abdominal ultrasound + AST, ALT, GGT).

Goal The aim of this study was to evaluate children with functional gastrointestinal disorders (FGIDs) seen by the paediatric gastroenterologist (PG) and their outcome during a three-year period. Method The study included children with FGIDs who visited the PG at the UHC Zagreb from January 1st 2017 to December 31st 2017 (N=328). This retrospective cohort was followed until December 31st 2019, data was extracted retrospectively from clinical records and their outcomes were assessed. Descriptive statistics and McNemar’s test were used, statistical significance was determined as p < 0.05. Results About 2/3 of outpatients (222/328) dropped out during the year 2017. The leading diagnosis was functional constipation (90/222 or 40.5%) and more than half of these patients were younger than 11 years (106/222). Most drop-outs visited the PG only once in 2017 (134/222), but for 33 patients this was a control visit, meaning that 101/222 (45.5%) needed no further subspecialist’s follow-ups after the index visit. During the year 2018 the number of patients who dropped out was 63/106 (59.4%) or 1/5 of the initial group. Finally, 43/328 or 13.1% of children from the initial cohort were still supervised by PG during the year 2019. About half of them had functional constipation (20/43), followed by irritable bowel syndrome (IBS) (12/43) and other functional abdominal pain disorders. Majority of patients were in the adolescent group (28/43). Further, we assessed the severity of symptoms at their last appointment in a subgroup of 227 patients who had one or more check-ups in the three-year period. About half of the patients claimed some improvement (115/227 patients), while 1/5 stated they were symptom-free (49/227). About 1/4 of children reported no change in the severity of symptoms (58/227). The vast majority of patients were correctly diagnosed with FGID, although the type of FGID changed in 13/328 subjects. In one patient, however, the diagnosis of IBS was reversed to ulcerative colitis. A significant number of children was included in a child psychologist/psychiatrist treatment (74/328 or 22.5%). Conclusion This survey reveals that almost half of children referred to the PG because of FGID needs only one subspecialist consultation. Less than 15% of children with FGID have persistent complaints lasting three years and requiring prolonged PG follow-ups. Adolescents tend to have more pronounced symptoms difficult to treat, as they were more prevalent in the subgroup followed to 2019 than in the initial 2017 cohort (28/43 vs. 143/328, p <0.001).

Acute esophageal necrosis (black esophagus, Gurvits syndrome) is a rare clinical entity which leads to upper gastrointestinal bleeding. First description dates to 1990, with around115 cases described in the literature. The condition has pathognomonic endoscopic appearance characterized by circumferential black mucosa in the distal esophagus, and discontinuing abruptly at the gastroesophageal junction. The pathogenesis is unclear, apparently multifactorial mucosal ischemia due to low flow vascular state or microvascular thrombosis is predisposing to topical damage by gastric content reflux. It’s commonly seen in elderly men, with risk factors like diabetes, malignancy, alcohol consumption, shock, major surgery. Diagnosis is made endoscopically. Management requires hemodynamic stabilization, acid suppressive medication with avoidance of nasogastric tube placement. The condition has very poor prognosis, with mortality rate up to 35%, and various complications including strictures and stenosis, perforation with mediastinitis and abscess formation. Our patient, a 15 year old boy underwent surgery for scoliosis. During the immediate post surgical period he had hematemesis with consequent hemorrhagic shock. He was stabilized (IV fluids, packed red blood cells), nasogastric tube was inserted with evacuation of around 160 mL of blood and he was referred to our ICU. He required mechanical respiratory support and inotropic medications. Continuous parenteral PPI therapy was commenced. Black, charcoal-like content was draining from the nasogastric tube, with further deterioration in hemoglobin levels. Esophagogastroduodenoscopy showed black mucosa of lower esophagus, partly circumferential, partly linear, with cutoff at gastroesophageal junction. There were no radiological signs of esophageal perforation, bilateral lung consolidates were surrounded by ground-glass interstitial changes. Patient was kept NPO, on parenteral nutrition, with PPI and antibiotic treatment. He was weaned mechanical ventilation after three days, followed by brief stint of non-invasive respiratory support. Unfortunately, significant stenosis with stricture formed in the area overlying initial necrosis. After several attempts of endoscopic ballon dilatation, refractory strictures reemerged. Surgical gastrostomy was performed to enable sufficient enteral caloric intake, and bring the patient to ideal physical condition for further treatment. Planned colonic interposition surgery was not performed because of inadequate length of colon, hence thoracic surgeons performed retrosternal esophagogastroplasty Our patient had no further postoperative complications and was able to establish adequate oral feeding. Acute esophageal necrosis should be considered as one of the causes of upper gastrointestinal bleeding, especially because its high mortality and complications rate requires immediate and aggressive early management.

Objective Reevaluation of our experiences in adherence to the established local guidelines in our population of pediatric patients diagnosed with foreign body ingestion. Methods A retrospective study of patients aged 0-18 years who were admitted to pediatric emergency department of the University Hospital Centre Zagreb between 1.1.2015. and 31.12.2019. due to suspected foreign body ingestion. We grouped them according to their age and localization of the foreign body along the digestive tract. We analyzed how many patients and with what success underwent endoscopy in relation to the applicable guidelines in our Institution. Results Of the 410 patients with suspected foreign body ingestion, a foreign body was found in 175 patients (x = 4 years ± 9 months), more common in male children (100/175). Most of them (78/175, 45%) were in the age group 3-7 years, followed by 1-3 year group (51/175, 29%). Foreign body was localized radiologically in 165 (94%), by endoscopy in 8 (5%) patients, while in the two patients localization hasn’t been determined, and there was also one spontaneous foreign body expulsion. Most common foreign bodies were coins in 61 children (35%), followed by another metal object in 51 (29%), button battery in 35 (20%) and plastic object in 7 (4%) patients. In 11 children (6%) it was food bolus impaction, and 10 of them swallowed other objects. Most foreign bodies were localized in the stomach (95 patients, 54%), followed by the small intestine (38 patients, 22%), the esophagus (27 patients, 15%) and the colon (9 patients, 5%). Two toothpicks were found in piriform sinus and tonsils. Endoscopy was performed in a third of patients (59/175; 34%), and it was successful (resulting in foreign body extraction) in 48 of them (81%). In 25/27 of patients with foreign body localized in the esophagus endoscopy was performed, while the two asymptomatic patients were observed. 7/8 patients with food bolus impaction were previously diagnosed with esophageal stenosis. According to guidelines, 41 endoscopies (70%) were warranted and 18 (30%) were not. We compared our results from this period (III) with the two previous ones: before the adoption of guidelines (I) and the early period following the introduction of guidelines (II). The following was shown: endoscopy in 67% of patients with foreign body ingestion with 77% success rate (I), endoscopy in 20% of patients with 90% success rate, and in 34% of patients with 81% success rate (III). Conclusion Global experiences suggest that endoscopic extraction is indicated in 10-20% of cases of all foreign body ingestions in children. In the study period, in one third of 34% of patients in which the endoscopy was performed, it was not indicated according to current guidelines. Despite the existence of guidelines, tenacity and the vigilance of adherence to them decreases over time. Their existence by itself is not sufficient in reducing children’s exposure to unnecessary and potentially harmful interventions.

Objective Comparing the referral diagnosis as an indication for EGD with final histological diagnosis, and to assess whether it was justified to perform these endoscopies in our patients. Methods Retrospective analysis of patients who underwent gastroscopy with biopsy in the period from 1.1.2016. to 29.02.2020 at the Clinical Hospital Center Zagreb. The study did not include foreign body removal procedures, follow up endoscopies and endoscopies for the purpose of placing medical orthopedic aids. We have described the symptoms leading to referral for endoscopy, as well as their average duration prior to endoscopy. We analyzed the correlation between referral and final histological diagnosis. Results In a cohort of a total of 100 patients, the most common indication for gastroscopy in 24/100 (24%) was abdominal pain, and in approximately half of them (13/24, 54.2%) the histological cause of the discomfort was found (gastritis in 12 and celiac disease in 1). Of the 20 gastroscopies performed on suspicion of gastritis, in 12/20 (60%) pathological substrate was found (9 gastritis, 2 eosinophilic esophagitis, 1 celiac disease). Due to celiac disease suspicion, we endoscopied 18 patients, of whom in 10 (55.6%) celiac disease was histologically confirmed. In 6/11 (54.5%) patients with dyspeptic symptoms diagnosis of gastritis was made after the endoscopy. In almost half of the patients, the pathohistological finding was normal. From 52 pathological findings; 31/52 (59.6%) corresponds to gastritis, 12/52 (23.1%) to celiac disease, 5/52 (9.6%) to eosinophilic esophagitis, and in 2 patients (3.8%) esophageal varices and stomach polyps were found. The average duration of discomfort was 10 months and 26 days, while the largest number of patients; 17 of them had symptoms for a year, 16 had problems for 6 months, 9 had symptoms for 2 years, and 8 had symptoms for 1 and 3 months, respectively before the endoscopy. It should be noted that 10 were asymptomatic and were referred for endoscopy on the basis of pathological laboratory findings (complete blood count, iron, antibodies to tissue transglutaminase) or specific anamnesis (body weight loss, failure to thrive). Endoscopy completion rate by entering into the distal end of duodenum was 100%. We did not record any complications. Conclusion Considering the nonspecific symptoms of the disease that greatly correlate with functional difficulties the number of negative findings is not surprising. But since gastroscopy is the most sensitive method of confirmation/exclusion of the disease itself it is clear that a high number of negative findings point to the necessity of developing clearer guidelines to avoid unnecessary endoscopies. Furthermore, comparing our results with the results of similar foreign studies we can say that we are within the world average and that this indeed is a global problem that requires team effort especially at a time when the number of endoscopic procedures grows rapidly every day due to increased endoscopic possibilities.

Introduction Acute hepatitis associated aplastic anemia (AHAAA) is a rare condition in which acute hepatitis is complicated by development of aplastic anemia. It is more common in young males, and presents with pancytopenia 2-3 months after an episode of acute hepatitis. The etiology of hepatitis mostly remains unknown and it is thought that aplastic anemia is caused by immune dysregulation provoked by perhaps infection triggered cytokine production that injures hematopoetic stem cells. Options for treating severe AHAAA are bone marrow transplantation or immunosuppressive therapy (corticosteroids, cyclosporin A, antithymocyte globulin, antilymphocite globulin). Case Report We present a case of a previously healthy 10-year old boy, admitted due to sudden onset of jaundice and nausea. Laboratory results showed highly elevated aminotransferase (AST 2089 U/L, ALT 3228 U/L), conjugated hyperbilirubinemia (total bilirubin 391 umol/L, conjugated 302 umol/L) and initially preserved synthetic liver function. Extensive workup excluded infectious, toxic and metabolic causes. Hypergammaglobulinemia was not present, but anti smooth muscle antibodies were positive in two consecutive testing (1:20). Liver biopsy showed unspecific mixed type acute inflammation. In the next few days he developed liver failure (INR 2.6) so immunosuppressive therapy for autoimmune hepatitis (AIH) was initiated (corticosteroids and azathioprine), together with symptomatic therapy (fresh frozen plasma).Due to potential adverse toxic effect (decreased activity of the enzyme thiopurinmethyltransferase) azathioprin was changed to mycophenolate mofetil. In the following weeks patient’s synthetic liver function completely recovered and aminotransferase and bilirubin levels improved. Six weeks after initial onset of his symptoms patient developed severe thrombocytopenia and leukopenia followed by mild anemia. Bone biopsy showed hypoplastic to aplastic bone marrow. Screening for opportunistic pathogens revealed positive Pneumocystis carinii, and also CMV and VZV reactivation so treatment with trimethoprim-sulfametoxazole and valganciclovir was started together with antifungal therapy for oral candidiasis. He also required repeated platelet transfusions. After two months his bone marrow started showing signs of recovery and he was discharged from hospital. At last follow up, his leukocyte counts was 4.3 x 109/L, hemoglobin 142 g/L and platelet count 57 x 109/L. Discussion Our patient followed the typical presentation of AHAAA described in the scarce literature. The notable aspect of our case is potentially spontaneous recovery of bone marrow aplasia without the need for bone marrow transplantation. Mycophenolate mofetil might be viable therapeutic step in treatment for this type of disease.