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Most patients with chronic liver disease have alterations in liver laboratory tests. This situation is common and could affect up to 8% of patients in primary care. These abnormalities are associated with long-term excess mortality, both general and related to liver complications. In the majority of cases, these causes are easily identified through questioning, clinical examination, and blood-biological tests. Patients without identified cause require additional work-up looking for rare liver diseases. However, the cause of liver disease remains undetermined in nearly 10% of cases. In absence of validated diagnostic -algorithm the management of patients is highly heterogeneous especially for the indication of liver biopsy. These liver abnormalities remain unexplained at the end of these explorations. A rationale and hierarchized approach combining precise analysis of medical history, utilisation of laboratory tests using reference technics, magnetic resonance imaging, liver biopsy and new generation sequencing are able to provide an etiologic diagnosis in the majority of patients. [ABSTRACT FROM AUTHOR]

Background: Public health measures for COVID-19 mitigation influenced the circulation of Respiratory Syncytial Virus (RSV) during the 2020–2021 winter season. In the following autumn, an unprecedented resurgence of RSV occurred. Our study monitored RSV pediatric infections one and two years after the relaxation of containment measures for the COVID-19 pandemic. Methods: We analyzed diagnostic molecular data for SARS-CoV-2, flu, and RSV infections and clinical data from children with respiratory symptoms referring to our hospital during the 2021–2022 and 2022–2023 seasons. Results: In the 2021–2022 season, the number of RSV-affected children was very high, especially for babies <1 year. The outbreak appeared in a shorter interval of time, with a high clinical severity. In the 2022–23 season, a reduced number of infected pediatric patients were detected, with a similar hospitalization rate (46% vs. 40%), and RSV accounted for 12% of the infections. Coinfections were observed in age <2 years. In RSV patients, symptoms were similar across the two seasons. Conclusions: The clinical presentation of RSV in the two post-COVID seasons suggests that the pathophysiology of the virus did not change across these two years. Further studies are needed to continuously monitor RSV to support an effective prevention strategy. [ABSTRACT FROM AUTHOR]

BACKGROUND: Drug poisoning in Pediatric Emergency Services is a rare event, especially in children under 3 years. Cocaine intoxication in childhood can occur passively or by intentionally. CLINICAL CASE: A 4-month-old infant presented with right eyelid edema, skin lesions, excessive sleepiness, and food refusal. The patient's general condition was fair, he complained, had pale skin and several ecchymoses and small hematomas were observed in different evolutionary stages, in addition to lesions compatible with scratches on the face, micropetechiae on the dorsum of the penis and anal fissures. Laboratory studies reported disorder in liver function/disorder of liver function. The urine toxicological examination tested positive for cocaine. He received intravenous fluid therapy in the first 12 hours of admission, with a negative response for cocaine in urine in the first 24 hours. Clinical evolution was favorable and transaminase, creatine phosphokinase and troponin values normalized 12 days after admission. A progressive decrease in hematomas was also observed. The diagnosis of hypertransaminasemia secondary to cocaine intoxication and suspicion of physical abuse where established. CONCLUSIONS: Patients with physical abuse (child abuse) have a higher risk of exposure to drugs, so this study supports the recommendation to to carry out drug screening in these cases. [ABSTRACT FROM AUTHOR]

Hypertransaminasemia is a common extra-intestinal manifestation of celiac disease. Aim. To analyze the frequency of hypertransaminasemia, clinical and anamnestic, serological and morphological picture in children in the active period of celiac disease. Materials and methods. The study included 272 children with celiac disease aged from 8 months to 17 years. The patients were divided into two groups: the first children with hypertransaminasemia, the second without hypertransaminasemia. Results. Hypertransaminasemia was detected in 55.9% of children with celiac disease. The age of manifestation of the disease in the first group was 1.0 [0.5; 2.0] years, in the second group 1.9 [0.5; 4.0] years (p=0.0004). Children of the first group were diagnosed at 2.5 [1.7; 4.9] years, the second group at 4.9 [3.0; 10.8] years (p0.001). The duration of the latency period in children of the first and second groups was 1.4 [0.6; 3.1] years and 2.4 [0.9; 4.3] years, respectively (p=0.002). The average values of IgA anti-tTG antibodies in children of the analyzed groups did not differ, and the indicators of IgG anti-tTG antibodies in the first group were 1.6 (p=0.04) times higher. The level of EMA in children with hypertransaminasemia was 2 times higher than in children without hypertransaminasemia. Conclusion. Hypertransaminasemia is more often detected in young children with early manifestation of the disease, increases with the deepening of atrophy in the mucous membrane of the small intestine. Higher titers of celiac-specific antibodies were detected in children with hypertransaminasemia.

Background: The antitumor efficacy of immune checkpoint inhibitors (ICIs) has increasingly emerged during the last few years. However, there is a need to identify the safety profile of these agents more comprehensively, including liver toxicity. Materials and methods: Herein, we performed a meta-analysis to assess the risk of all-grade and grade 3–4 hypertransaminasemia in cancer patients receiving ICIs—as monotherapy or in combination with other anticancer agents. All the relevant trials were retrieved through EMBASE, Cochrane Library, and PubMed/Medline databases; eligible studies were selected according to PRISMA statement. The pooled relative risk (RR) and 95% confidence interval (CI) were extracted. Results: Fifty-nine studies were included. The pooled RRs for all-grade AST and ALT increase were 1.45 (95% CI 1.26–1.67) (Supplementary Fig. 3) and 1.51 (95% CI 1.29–1.77) in patients receiving ICIs monotherapy and immune-based combinations compared to control treatment, respectively. The pooled RRs for grade 3–4 AST and ALT increase were 2.16 (95% CI 1.77–2.64) and 2.3 (95% CI 1.91–2.77). Conclusions: According to our results, ICIs monotherapy and immune-based combinations were associated with higher risk of all-grade and grade 3–4 hypertransaminasemia. Monitoring liver function should be recommended in cancer patients treated with ICIs monotherapy or immune-based combination, and in case of underlying liver disease, a careful risk–benefit assessment appears as a mandatory need. [ABSTRACT FROM AUTHOR]

IntroductionElevated transaminases and/or creatine phosphokinase can indicate underlying muscle disease. Therefore, this study aims to determine the frequency of Duchenne muscular dystrophy/Becker muscular dystrophy (DMD/BMD) in male children and Pompe disease (PD) in male and female children with isolated hypertransaminasemia.MethodsThis multi-center, prospective study enrolled patients aged 3–216 months with serum alanine transaminase (ALT) and/or aspartate transaminase (AST) levels >2× the upper limit of normal (ULN) for ≥3 months. Patients with a known history of liver or muscle disease or physical examination findings suggestive of liver disease were excluded. Patients were screened for creatinine phosphokinase (CPK) levels, and molecular genetic tests for DMD/BMD in male patients and enzyme analysis for PD in male and female patients with elevated CPK levels were performed. Genetic analyses confirmed PD. Demographic, clinical, and laboratory characteristics of the patients were analyzed.ResultsOverall, 589 patients [66.8% male, mean age of 63.4 months (standard deviation: 60.5)] were included. In total, 251 patients (188 male and 63 female) had CPK levels above the ULN. Of the patients assessed, 47% (85/182) of male patients were diagnosed with DMD/BMD and 1% (3/228) of male and female patients were diagnosed with PD. The median ALT, AST, and CPK levels were statistically significantly higher, and the questioned neurological symptoms and previously unnoticed examination findings were more common in DMD/BMD patients than those without DMD/BMD or PD (p

Children with elevated liver enzymes are occasionally discovered through laboratory work-up from different clinical scenarios. Although the majority will have transient and/or benign conditions, a subgroup will have underlying liver disorders. The differential diagnosis is broad and therefore, a systematic approach is of utmost importance. In this article, we reviewed the most recent and relevant literature to provide a comprehensive overview of the main disease processes that cause hypertransaminasemia in children. Ultimately, we propose a practical stepwise approach to guide primary care physicians in the evaluation of abnormal liver enzymes in asymptomatic children. The first step is to obtain a complete history along with a thorough physical examination to exclude red flags, which should dictate urgent consultation with a paediatric gastroenterologist or hepatologist. Conclusion: Hypertransaminasemia is a challenging scenario in the primary care setting. The aetiology can be broad, ranging from hepatic and extrahepatic to transient versus chronic liver disease. Timely referral to a specialised centre is of paramount importance for conducting targeted research and to not miss the chance of identifying a progressive, but still asymptomatic, treatable liver disease. What is Known: • Elevated liver enzyme is a challenging scenario in the primary care setting. • There are few studies guiding the evaluation of asymptomatic hypertransaminasemia in the paediatric population and a standardised approach is lacking. What is New: • We propose a practical stepwise approach to guide primary care physicians in the evaluation of abnormal liver enzymes. [ABSTRACT FROM AUTHOR]

Celiac disease (CD) has been associated with several genetic and autoimmune disorders, but its association with hereditary fructose intolerance (HFI) is very rare. The possibility of an association between CD and HFI should be considered, especially in patients with a lack of improvement after a gluten-free diet. Children with HFI often present with a wide range of symptoms, however, data about a strong aversion to fruits and sweets may be helpful to establish the diagnosis. The diagnosis of HFI should be confirmed in genetic testing. Both CD and HFI may present with liver steatosis with hypertransaminasemia. In patients with these two disorders, the dietary restrictions of gluten and fructose improve clinical symptoms and protect them from secondary complications. We report the case of a child with the concurrence of these two disorders.

Moyamoya angiopathy (MMA) is a rare cerebral vasculopathy in some cases occurring in children. Incidence is higher in East Asia, where the heterozygous p.Arg4810Lys variant in RNF213 (Mysterin) represents the major susceptibility factor. Rare variants in RNF213 have also been found in European MMA patients with incomplete penetrance and are today a recognized susceptibility factor for other cardiovascular disorders, from extracerebral artery stenosis to hypertension. By whole exome sequencing, we identified three rare and previously unreported missense variants of RNF213 in three children with early onset of bilateral MMA, and subsequently extended clinical and radiological investigations to their carrier relatives. Substitutions all involved highly conserved residues clustered in the C-terminal region of RNF213, mainly in the E3 ligase domain. Probands showed a de novo occurring variant, p.Phe4120Leu (family A), a maternally inherited heterozygous variant, p.Ser4118Cys (family B), and a novel heterozygous variant, p.Glu4867Lys, inherited from the mother, in whom it occurred de novo (family C). Patients from families A and C experienced transient hypertransaminasemia and stenosis of extracerebral arteries. Bilateral MMA was present in the proband's carrier grandfather from family B. The proband from family C and her carrier mother both exhibited annular figurate erythema. Our data confirm that rare heterozygous variants in RNF213 cause MMA in Europeans as well as in East Asian populations, suggesting that substitutions close to positions 4118–4122 and 4867 of RNF213 could lead to a syndromic form of MMA showing elevated aminotransferases and extracerebral vascular involvement, with the possible association of peculiar skin manifestations. [ABSTRACT FROM AUTHOR]

Resumen: La hipertransaminasemia es un hallazgo frecuente en pediatría, puede ser banal o reflejar enfermedad grave potencialmente tratable. El objetivo de este documento es establecer, mediante la revisión de la evidencia disponible, un consenso para un adecuado enfoque práctico desde la detección de la hipertransaminasemia hasta completar su estudio en la edad pediátrica. Para ello, se constituyó un grupo de trabajo con participación de miembros de la Sociedad de Gastroenterología, Hepatología y Nutrición Pediátrica (SEGHNP), Asociación Española de Pediatría de Atención Primaria (AEPap) y Sociedad Española de Pediatría de Atención Primaria (SEPEAP). Se establecieron 21 recomendaciones con el objetivo de que sirvan de utilidad en la práctica clínica habitual tanto en atención primaria como hospitalaria. Abstract: Hypertransaminasemia is a frequent finding in pediatrics, which could reflect potentially treatable serious disease. The aim of this document is to establish, by reviewing the available evidence, a consensus for an adequate management of hypertransaminasemia, from its detection until the study is complete. To this end, a working group was formed with the participation of members of the Society of Pediatric Gastroenterology, Hepatology and Nutrition (SEGHNP), the Spanish Association of Primary Care Pediatrics (AEPap) and the Spanish Society of Primary Care Pediatrics (SEPEAP). Twenty-one recommendations are established with a marked practical component that will be useful in hospital clinical practice and primary care.

Celiac disease clinical presentation is constantly changing. We set to determine the prevalence of elevated transaminases in newly diagnosed celiac patients and to evaluate this sub-group of patients for associated clinical and laboratory findings and assess their natural course of disease following therapeutic diet initiation. We conducted a prospective-observational study of all newly diagnosed pediatric celiac patients, between August 2016 and April 2018, in a pediatric gastroenterology clinic. Clinical data, anthropometrics, and blood test results were recorded at diagnosis and at 3, 6, and 12 months, respectively, of follow-up. We compared patients with normal and elevated transaminases at diagnosis. ALT threshold was set at 24 U/l. Of 125 newly diagnosed celiac patients, 31 (24.8%) had elevated ALT at diagnosis; two (1.6%) with over 3 × ULN. Patients with elevated ALT at diagnosis were significantly younger (mean age 5.5 (SD 3.4) vs. 7.3 (SD 3.7) years, p < 0.01) and more commonly presented with diarrhea (32.3% vs. 14.9%, p = 0.03). Eighty percent of patients with elevated ALT levels normalized their ALT within 3 months and all within 1 year. Following gluten-free diet initiation, patients with elevated ALT had similar clinical course, growth, serology normalization rate, and laboratory results, compared to patients with normal ALT over a 1-year follow-up. A single patient was simultaneously co-diagnosed with celiac disease and autoimmune hepatitis. Conclusion: Clinically significant ALT abnormalities are rare among newly diagnosed pediatric celiac patients. Significant elevations failing to normalize on a gluten-free diet should raise concern of a concomitant primary liver disease and warrant further investigations. What is Known: • Elevated liver enzymes may be an extra-intestinal manifestation of celiac disease. • Reported prevalences of ALT elevations among children with a new diagnosis of celiac disease ranges between 5 and 40%. What is New: • ALT elevations are present in 25% of children with a new diagnosis of celiac disease. • Significant elevations (>3 × ULN) are rare (1.6%). • Elevated liver enzymes are associated with earlier age at diagnosis. • The natural history of patients with elevated liver enzymes at diagnosis is comparable to those without. [ABSTRACT FROM AUTHOR]

Cyclin-dependent kinase inhibitors (CDKIs) and endocrine therapy (ET) are the corner-stone of systemic therapy for patients with hormone-positive (HR+) HER2-negative metastatic breast cancer (MBC). However, limited data exist regarding rechallenge treatment strategies with CDKIs after limiting toxicity. In this report, we provide evidence of the safety and efficacy of sequential treatment with palbociclib or abemaciclib in 6 HR+/HER- MBC patients who experienced grade ≥3 ribociclib-induced hypertransaminasemia. Until results from large observational or randomized studies are communicated, empirical evidence may help make individualized decisions on CDKI rechallenge beyond ribociclib-induced unacceptable liver toxicity.

Celiac disease is a chronic immune-mediated multisystem disorder that may affect several organs. Isolated hypertransaminasemia, with mild or nonspecific histologic changes in the liver biopsy, also known as "celiac hepatitis", is the most frequent presentation of liver injury in celiac disease. Both, histologic changes and liver enzymes reverse to normal after treatment with a gluten-free diet in most patients. Here we report the case of a young boy presenting with asymptomatic and persistent hypertransaminasemia whose etiologic investigation led to the diagnosis of celiac disease that resolved with dietary treatment alone. This case emphasizes the need to screen Celiac disease in patients with cryptogenic hypertransaminasemia, irrespective of the existence of gastrointestinal symptoms. It also exemplifies a particular situation in which a liver biopsy is useful to establish the diagnosis of celiac hepatitis. [ABSTRACT FROM AUTHOR]

Celiac disease (CD) has been associated with several genetic and autoimmune disorders, but its association with hereditary fructose intolerance (HFI) is very rare. The possibility of an association between CD and HFI should be considered, especially in patients with a lack of improvement after a gluten-free diet. Children with HFI often present with a wide range of symptoms, however, data about a strong aversion to fruits and sweets may be helpful to establish the diagnosis. The diagnosis of HFI should be confirmed in genetic testing. Both CD and HFI may present with liver steatosis with hypertransaminasemia. In patients with these two disorders, the dietary restrictions of gluten and fructose improve clinical symptoms and protect them from secondary complications. We report the case of a child with the concurrence of these two disorders. [ABSTRACT FROM AUTHOR]

Diagnosis of pediatric steatohepatitis is a challenging issue due to a vast number of established and novel causes. Here, we report a child with Multiple Acyl-CoA Dehydrogenase Deficiency (MADD) presenting with an underrated muscle weakness, exercise intolerance and an atypically severe steatotic liver involvement. A systematic literature review of liver involvement in MADD was performed as well. Our patient is a 11-year-old otherwise healthy, non-obese, male child admitted for some weakness/asthenia, vomiting and recurrent severe hypertransaminasemia (aspartate and alanine aminotransferases up to ×20 times upper limit of normal). Hepatic ultrasound showed a bright liver. MRI detected mild lipid storage of thighs muscles. A liver biopsy showed a micro-macrovacuolar steatohepatitis with minimal fibrosis. Main causes of hypertransaminasemia were ruled out. Serum aminoacids (increased proline), acylcarnitines (increased C4-C18) and a large excretion of urinary glutaric acid, ethylmalonic, butyric, isobutyric, 2-methyl-butyric and isovaleric acids suggested a diagnosis of MADD. Serum acylcarnitines and urinary organic acids fluctuated overtime paralleling serum transaminases during periods of illness/catabolic stress, confirming their recurrent nature. Genetic testing confirmed the diagnosis [homozygous c.1658A > G (p.Tyr553Cys) in exon 12 of the ETFDH gene]. Lipid-restricted diet and riboflavin treatment rapidly ameliorated symptoms, hepatic ultrasonography/enzymes, and metabolic profiles. Literature review (37 retrieved eligible studies, 283 patients) showed that liver is an extramuscular organ rarely involved in late-onset MADD (70 patients), and that amongst 45 patients who had fatty liver only nine had severe presentation.Conclusion: MADD is a disorder with a clinically heterogeneous phenotype. Our study suggests that MADD warrants consideration in the work-up of obesity-unrelated severe steatohepatitis.

Hepatitis-associated aplastic anemia is a well-recognized clinical syndrome in which marrow failure follows the development of hepatitis. Although aplastic anemia is intimately related to paroxysmal nocturnal hemoglobinuria, until now, no cases of PNH-associated hepatitis have been described. We report a case of recurrent acute hepatitis preceding the clinical onset of PNH. Treatment of PNH with the complement inhibitor eculizumab (Soliris®) prevented both recurrences of episodes of intravascular hemolysis and liver enzyme alteration. This is the first known published case of PNH-associated hepatitis. [ABSTRACT FROM AUTHOR]

Duchenne musculer dystrophy (DMD) is a X linked disorder caused by a deficient or abnormal synthesis of dystrophine protein. Children with DMD are rarely symptomatic at birth or in early infancy, and the diagnosis is extremely difficult and even depends on happenstances. In this article a 5.5-month-old infant in whom increases in liver function tests were detected in routine tests performed for general anesthesia and later diagnosed to have DMD is presented. DMD, as a rare disease should be considered in etiological investigations in infants with elevations in liver function tests of any origin and with normal physical examination findings, and the utility of simple biochemical markers such as creatinin kinase in establishing diagnosis before performing further detailed investigations should be remembered.

Introduction: The clinical spectrum of gluten-sensitive enteropathy is remarkably varied and the disease can affect many extraintestinal organs and systems, including the liver. Liver involvement, which is observed in patients with gluten-sensitive enteropathy, varies from an asymptomatic increase of hepatic enzymes or non-specific reactive hepatitis (cryptogenic hepatic disorders) to chronic liver disease. The histological changes and the dynamics of enzymes are notably different after a gluten-free diet (GFD) treatment. Patients and Methods: A clinical observation included 112 patients with gluten-sensitive enteropathy and 22 patients with gluten sensitivity, who passed through the Clinic of Gastroenterology, Hepatology and Nutrition at St. Marina University Hospital, Varna for the period from January, 2005 to June, 2015. Thirty-four men and 78 women between the ages of 18 and 76 were included. The control group consisted of 22 patients of whom 6 were men and 16 – women. Results and Discussion: Patients with proven hepatic diseases with autoimmune or viral genesis were excluded from the group participating in the current study. The observation and study were conducted on 8 patients – 3 men and 5 women put on a GFD for a period of 6 months. All 8 patients were with abnormal hepatic enzyme levels. The median levels (±SD) of ASAT and ALAT were 62.6 ±16.5 IU/mL with a range of 31-186 IU/mL, and 69.3 ± 9.3 IU/mL and a range of 63-432 IU/mL, respectively. The median concentrations of alkaline phosphatase were ± 280.3±118.7 mmol/L (range -160-428 mmol/L). Six months after GFD, the hepatic enzyme levels decreased to a level of 24.5±5.1 IU/mL in all patients. Hepatic abnormalities varying from mild changes of hepatic enzyme levels to liver failure at the time of diagnosis could be treated with GFD. Its effect on the severity of other hepatic diseases, for example autoimmune hepatitis, is not clear yet. Regardless of the effect on the concomitant hepatic diseases, GFD is needed for the improvement of the symptoms of gluten-sensitive enteropathy and all long-term consequences. The lack of sufficient amount of proof does not undermine the fact that clinicians should consider the diagnosis – gluten-sensitive enteropathy – when hypertransaminasemia is observed without the presence of other causes of liver dysfunction.

Cyclin-dependent kinase inhibitors (CDKIs) and endocrine therapy (ET) are the corner-stone of systemic therapy for patients with hormone-positive (HR+) HER2-negative metastatic breast cancer (MBC). However, limited data exist regarding rechallenge treatment strategies with CDKIs after limiting toxicity. In this report, we provide evidence of the safety and efficacy of sequential treatment with palbociclib or abemaciclib in 6 HR+/HER- MBC patients who experienced grade ≥3 ribociclib-induced hypertransaminasemia. Until results from large observational or randomized studies are communicated, empirical evidence may help make individualized decisions on CDKI rechallenge beyond ribociclib-induced unacceptable liver toxicity. [ABSTRACT FROM AUTHOR]

Objective: We aimed to determine the etiology of hypertransaminasemia in children, demonstrate the differences according to the age and evaluate course of transaminases. Method: We retrospectively analyzed the medical records of children who presented with elevated transaminase levels for at least 2 months, aged between 3 months and 18 years, for demographic features, laboratory, radiologic and histopathological findings. Results: Among total 292 children, 194 (66.4%) were male and 98 (33.6%) were female. The mean age was 6.5±5.4 years. The 45.9% of the children had no complaints at presentation. Majority of the patients had mildly elevated transaminases (81.6%). The most common etiology was nonalcoholic fatty liver disease (NAFLD) (25.7%). The NAFLD was more prevelant in patients older than 5 years-old (p<0.001). The second cause was infectious diseases (97.8% were viral infections) and more prevelant in patients younger than 2 years-old (p=0.043). In 34.1% of the children, no overt cause of hypertransaminasemia was identified. The patients with unidentified etiology were significantly younger, but had higher mean aspartate aminotransferase (AST) levels than the patients in whom the etiology was identified (p= <0.0001, p=0.008 respectively). The normalization of transaminases was seen in 40.4% of the patients at mean 5.4±4.4 months. The shortest normalization time was observed in drug related liver injury (DILI) among all other etiologies (p=0.015). Conclusions: The most common cause of hypertransaminasemia in childhood were NAFLD and viral infections, which varies by age. A stepwise approachment to hypertransaminasemia leads to early diagnosis. [ABSTRACT FROM AUTHOR]

Abstract Background Short stature (SS) is a relatively early sign of poor health. Only in 5% of cases we can explain it through the presence of endocrinological pathologies. Therefore, if SS is present since the first months of life, it is necessary to investigate all systemic disorders with secondary effects on growth. Case presentation We report the case of a 16-months-old male infant with severe SS apparently not associated with other clinical signs or symptoms. The patient arrived to our attention after he was hospitalized for an Echovirus enteritis, associated to moderate neutropenia (800/mm3) and hypertransaminasemia (AST 116 U/L, ALT 88 U/L) at the age of 13 months. SS was detected in that occasion. Since SS persisted even after the complete resolution of enteritis symptoms, he was taken care by our unit. Conclusions SS appeared in the first months of life and associated with moderate neutropenia and hypertransaminasemia led us to the diagnosis of Shwachmann-Diamond syndrome. We recommend paying further attention to this condition during the differential diagnosis of children with severe SS.

Abstract Background Crimean-Congo hemorrhagic fever is a tick-borne disease described in more than 30 countries in Europe, Asia, and Africa. Albania is located in the southwestern part of the Balkan Peninsula. In 1986, the first case of Crimean-Congo hemorrhagic fever was registered, and cases of patients with hemorrhagic fever are rising, and most of them present in a serious condition, when the mortality rate is very high. In districts like Mirdite, Lezhe, Gjirokaster, Skrapar, Erseke, and Kukes, there is delineated human-to-human transmission. Case presentation We report the case of a 32 year-old Albanian woman from a rural area of Albania. She was hospitalized at the Infectious Diseases Service, for a severe influenza-like illness of 4 days duration. Our patient had been bitten by a tick while working in her garden. She presented with nausea, vomiting, headache and muscle pain. A physical examination found a high fever of 40 °C, an enlarged liver, petechia, and vaginal bleeding; flapping tremor and fetor hepaticus were found as a sign for hepatic encephalopathy; and confusion and disorientation were observed in her neurological examination. Her platelet and white blood cell counts were very low, while her aspartate aminotransferase and alanine aminotransferase levels were very high. She was transferred to the intensive care unit because of her worsening condition. Serological and C-reactive protein test results for Crimean-Congo hemorrhagic fever were positive. She was treated with oral ribavirin and discharged with normal parameters. Conclusions People in high-risk professions in the endemic areas should be informed and trained on the risk of Crimean-Congo hemorrhagic fever as a matter of urgency. Vaginal bleeding is not always a gynecological problem. In Albania, these places are the mountainous areas, so people who have traveled to these areas and who have symptoms after a tick bite are advised to contact their doctors.

Alagille syndrome is an autosomal dominant multisystem disorder with variable phenotypic penetrance, caused by heterozygous mutations in JAG1 or NOTCH2, encoding for the components of the Notch signaling pathway. In this paper, we described a novel mutation not yet reported in literature. This 3-years old male child was referred to our Clinical Genetics Unit because of delayed psychomotor development, systolic murmur, dysmorphic facial features, and hypertransaminasemia. The novel JAG1 heterozygous c.2026delT variant in exon 16 was found. JAG1 mutations are classified as protein truncating and non-protein truncating, without any genotype-phenotype correlation. The detected mutation determines a stop codon (p.Cys676AlafsTer67) in the gene sequence, encoding a truncated protein. Our report broadens the spectrum of JAG1 gene mutations.

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Aim of the study: To evaluate the prevalence and the type of liver pathology in children at the time of diagnosis of celiac disease (CD). Material and methods: Data from newly diagnosed children with CD hospitalized in the university hospital were retrospectively reviewed. Liver pathology was defined as elevated alanine transaminase (ALT) and/or gamma-glutamyl transpeptidase (GGT) serum activity and/or pathological changes of the organ in ultrasound. Results: Liver pathology was detected in 17 of 149 children (11.4%). Ten patients (6.7%) had an elevated ALT serum activity, whereas no child had an elevated GGT activity. Pathological changes of liver in ultrasound (mainly enlargement or steatosis of the organ) were found in 12 patients (8.1%), of whom 5 children (3.4%) had simultaneously elevated ALT serum activity. Children with liver pathology had lower iron (Fe) (p = 0.02) and folic acid (p = 0.01) concentrations compared to the rest of the patients. There were no statistically significant differences between liver pathology existence and age, sex, serum immunoglobulin A anti-tissue transglutaminase type 2 antibodies (IgA anti-TG2), ferritin, vitamin B12, or vitamin D concentrations. Moreover, a positive correlation between IgA anti-TG2 concentration and ALT serum activity was found (p < 0.01, R = 0.29). Conclusions: Liver pathology is present at diagnosis in a significant proportion of children with CD in the form of hypertransaminasemia and pathological changes of the organ in ultrasound. There is a correlation between IgA anti-TG2 concentration and ALT serum activity. [ABSTRACT FROM AUTHOR]

The paper presents the case of a 12-year-old boy hospitalised due to persistent hypertransaminasemia of unknown origin, in whom rare metabolic disease - Pompe disease, was finally diagnosed. We discuss the possible symptoms and the diagnostic criteria for Pompe disease, as well as modern genetic methods of diagnosing. The importance of including this metabolic disease in differential diagnosis of hypertransaminasemia was underlined. The recombinant human a-glucosidase as the enzyme replacement therapy makes nowadays the early diagnosis of Pompe disease especially important. [ABSTRACT FROM AUTHOR]

Ming-Chang Ku,1,2 Victor C Kok,3,4 Ming-Yung Lee,5 Soa-Min Hsu,1 Pei-Yu Lee,1 Che-Wei Chang,1 Yeu-Sheng Tyan,6 Chi-Wen Juan7,8 1Department of Radiology, Kuang Tien General Hospital, Taichung, 2Department of Nursing, Jen-Teh Junior College of Medicine, Nursing and Management, Miaoli, 3Department of Internal Medicine, Division of Medical Oncology, Kuang Tien General Hospital, 4Department of Bioinformatics and Medical Engineering, Asia University, 5Department of Statistics and Informatics Science, Providence University, 6Department of Medical Imaging, Chung Shan Medical University Hospital, 7Department of Emergency Medicine, Kuang Tien General Hospital, 8Department of Nursing, HungKuang University, Taichung, Taiwan Objectives: Gallbladder opacification (GBO) on computed tomography (CT) imaging may obscure certain pathological or emergent conditions in the gallbladder, such as neoplasms, stones, and hemorrhagic cholecystitis. This study aimed to investigate the clinical contributing factors that could predict the presence of delayed GBO determined by CT.Methods: This study retrospectively evaluated 243 consecutive patients who received enhanced CT or intravenous pyelography imaging and then underwent abdominal CT imaging within 5 days. According to the interval between imaging, the patients were divided into group A (1 day), group B (2 or 3 days), and group C (4 or 5 days). Three radiologists evaluated CT images to determine GBO. Fisher’s exact test and multivariate backward stepwise elimination logistic regression were performed.Results: Positive GBO was significantly associated with the interval between imaging studies, contrast type, contrast volume, renal function, and hypertransaminasemia (P

Salmonella hepatitis is an infectious disease caused by liver involvement of salmonella enteritis and characterized by acute gastroenteritis and hypertransaminasemia. Levetiracetam is a new generation antiepileptic agent that activates the GABA-glycine system and may rarely cause hypertransaminasemia. An 11-year-old girl with epilepsy who had been taking levetiracetam for 15 months was consulted because of hypertransaminasemia with nausea-vomiting, fever and abdominal pain. The patient was diagnosed with salmonella enteritis. The clinical findings regressed with appropriate antibiotherapy but hypertransaminasemia lasted. The etiology of persistent hypertransaminasemia has been investigated. In addition to salmonella hepatitis, the use of levetiracetam was seen as causes but the drug was not discontinued. Normal liver enzyme levels were reached in the 12th weeks following Salmonella infection. Consequently, it is considered that before discontinuation of medication, salmonella hepatitis may be in differential diagnosis in patients who have acute gastroenteritis and hepatitis findings and also receiving levetiracetam. [ABSTRACT FROM AUTHOR]

Background: Short stature (SS) is a relatively early sign of poor health. Only in 5% of cases we can explain it through the presence of endocrinological pathologies. Therefore, if SS is present since the first months of life, it is necessary to investigate all systemic disorders with secondary effects on growth. Case presentation: We report the case of a 16-months-old male infant with severe SS apparently not associated with other clinical signs or symptoms. The patient arrived to our attention after he was hospitalized for an Echovirus enteritis, associated to moderate neutropenia (800/mm³) and hypertransaminasemia (AST 116 U/L, ALT 88 U/L) at the age of 13 months. SS was detected in that occasion. Since SS persisted even after the complete resolution of enteritis symptoms, he was taken care by our unit. Conclusions: SS appeared in the first months of life and associated with moderate neutropenia and hypertransaminasemia led us to the diagnosis of Shwachmann-Diamond syndrome. We recommend paying further attention to this condition during the differential diagnosis of children with severe SS. [ABSTRACT FROM AUTHOR]

The evaluation of serum liver enzyme levels is the most used surrogate marker of liver injury in clinical practice. The prevalence and association of abnormal enzyme values with hepatitis B virus (HBV) and hepatitis C virus (HCV) infections, and with other major causes of liver damage (obesity, diabetes, dyslipidemia, and alcohol abuse) were evaluated in individuals attending the surgeries of 14 general practitioners (GPs) working in Messina. Alanine-amino-transferase, aspartate-amino-transferase, and gamma-glutamyl-transpeptidase measurements were measured in 7816 individuals consecutively attending the GP surgeries between January 1, 2011 and June 30, 2012. Five-thousand-eight-hundred-six subjects (74.3 %) had the tests performed, and 1189 of them (20.5 %) showed increased liver enzyme levels. Sixty-nine of these 1189 individuals (5.8 %) were HCV positive and 12 HBV positive (1 %), 755 (63.5 %) were overweight or obese, 288 (24.2 %) had diabetes, and 351 (29.5 %) had dyslipidemia; 262 (22 %) drank >2 alcoholic units/day. Overall, 57 % of individuals with abnormal liver enzymes had multiple possible causes of liver disease, 28 % one cause, and 15 % no apparent cause. In conclusion, this study shows that 1/5 of individuals attending GP surgeries have altered liver biochemistry and that overweight and metabolic disorders have become the major causes of liver damage even in South Italy, where HBV and HCV were endemic in the past century. Notably, many HCV and HBV patients are still unaware of their infected status, and GPs are essential for their timely identification. [ABSTRACT FROM AUTHOR]

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Background: Celiac disease (CD) is an immune mediated condition that leads to small bowel atrophy and improve with a gluten free diet (GFD). Extra-intestinal manifestations of CD include hypertransaminasemia. In this study, the effects of a GFD on hypertransaminasemia in patients with newly diagnosed CD were studied. Methods: Ninety eight new diagnosed consecutive patients with CD 40 males and 58 females) with mean age of 32 ± 17.1 were studied. All patients with CD were treated with a GFD. Patients with hypertransaminasemia, at diagnosis, had a cirrhosis screen performed. Patients with a negative cirrhosis screen were reviewed, 6 months after the introduction of a GFD, and serum levels of liver transaminases were measured again. Results: Nine patients had hypertransaminasemia. One patient was Hepatitis B surface antigen positive and was excluded from this study. The 8 remaining patients had no obvious cause for the hypertransaminasemia. Mean (± SD) of baseline aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels were 42.6 ± 16.5 IU/L (range: 16-66 IU/L) and 69.3 ± 9.3 IU/L (range: 52-81 IU/L). Six months after treatment with a GFD, mean AST and ALT levels decreased to 24.5 ± 5.1 IU/L (range: 18-31 IU/L) (P: 0.04) and 24.6 ± 6 IU/L (range: 17-32 IU/L) (P: 0.01), respectively. In 7 patients the hypertransaminasemia, at diagnosis had resolved. Conclusions: This study provides further evidence that some patients with CD have a reversible hypertransaminasemia that resolves with a GFD.

Es frecuente que en pacientes con enfermedad inflamatoria intestinal se observen cambios analíticos o clínicos que indican la existencia de una enfermedad hepatobiliar. La frecuencia de estos hallazgos oscila entre 11-49 % en colitis ulcerosa y entre 15-30 % en enfermedad de Crohn. En algunos casos, estas alteraciones se observan desde el primer momento en que se estudia a los pacientes, otras surgen en el curso de la enfermedad. Se realizó un estudio descriptivo observacional retrospectivo donde se incluyó 180 pacientes con enfermedad inflamatoria intestinal, que se atienden en el Instituto de Gastroenterología, de ellos con manifestaciones hepatobiliares, 17 pacientes (9,4 %), 12 colitis ulcerosa y 5 Crohn. Las variables estudiadas fueron: sexo, edad, años de evolución según tipo de enfermedad inflamatoria, tipo de manifestación hepatobiliar, síntomas clínicos, estudio de enzimas hepáticas y hallazgos ultrasonográficos. Se concluyó que existe predominio de pacientes con colitis ulcerosa. Predominó el sexo femenino en la colitis ulcerosa; el Crohn no tuvo variaciones significativas. La edad estuvo comprendida entre 30 y 49 años. La manifestación hepatobiliar más frecuente en el Crohn fue la hepatopatía de etiología no filiada y en la colitis ulcerosa la colangitis esclerosante primaria. El síntoma clínico que predominó en ambos grupos fue la astenia, y en la colitis ulcerosa también predominó el prurito e íctero. Con respecto a las enzimas bioquímicas predominó la hipertransaminasemia, y por ultrasonido el aspecto granular y aumento de la ecogenicidad hepática.It is common for patients with inflammatory bowel disease to present analytical or clinical changes pointing to the presence of hepatobiliary disease. The frequency of such findings ranges between 11-49 % in ulcerous colitis and between 15-30 % in Crohn's disease. In some cases, the alterations are found when the patient is first examined, while in others they emerge during the course of the disease. An observational retrospective descriptive study was conducted of 180 patients with inflammatory bowel disease cared for at the Institute of Gastroenterology. Hepatobiliary manifestations were found in 17 patients (9.4 %): 12 with ulcerous colitis and 5 with Crohn's disease. The variables studied were sex, age, years of evolution by type of inflammatory disease, type of hepatobiliary manifestation, clinical symptoms, study of hepatic enzymes and ultrasonographic findings. There was a predominance of patients with ulcerous colitis. Female sex prevailed in ulcerous colitis. No significant differences were found in Crohn's disease. Age ranged between 30-49. The most common hepatobiliary manifestations were liver disease of unknown etiology in Crohn's disease and primary sclerosing cholangitis in ulcerous colitis. The prevailing clinical symptom in both groups was asthenia. Pruritus and jaundice were also predominant in ulcerous colitis. With respect to biochemical enzymes, there was a predominance of hypertransaminasemia. Ultrasonographically, a granular aspect and increased hepatic echogenicity were the prevailing features.

Background: Celiac disease (CD) has been found in up to 10% of the patients presenting with unexplained abnormal liver function tests (LFT). As there is no precise data from our country in this regard, we investigated the prevalence of CD in patients presenting with abnormal LFT. Methods: From 2003 to 2008, we measured IgA anti-tissue transglutaminase (t-TG) antibody (with ELISA technique) within the first-level screening steps for all patients presenting with abnormal LFT to three outpatient gastroenterology clinics in Isfahan, IRAN. All subjects with an IgA anti-tTG antibody value of >10 μ/ml (seropositive) were undergone upper gastrointestinal endoscopy and duodenal biopsy. Histopathological changes were assessed according to the Marsh classification. CD was defined as being seropositive with Marsh I or above in histopathology and having a good response to gluten free diet (GFD). Results: During the study, 224 patients were evaluated, out of which, 10 patients (4.4%) were seropositive for CD. Duodenal biopsies were performed in eight patients and revealed six (2.7%) cases of Marsh I or above (four Marsh IIIA, two Marsh I), all of them had good response to GFD. The overall prevalence of CD among patients with hypertransaminasemia, autoimmune hepatitis, and cryptogenic cirrhosis was determined as 10.7% (3/28), 3.4% (2/59), and 5.3% (1/19), respectively. Conclusion: Serological screening with IgA anti-tTG antibody test should be routinely performed in patients presenting with abnormal LFT and especially those with chronic liver diseases including hypertransaminasemia, autoimmune hepatitis, and cryptogenic cirrhosis.

Celiac disease is an autoimmune disorder primarily targeting the small bowel, although extraintestinal extensions have been reported. The autoimmune processes can affect the liver with manifestations such as primary biliary cirrhosis and autoimmune hepatitis. We describe a 61-year-old woman with celiac disease and an increased levels of aminotransferases. The persistence of increased levels of aminotransferases after 1 year of gluten-free diet and the positivity for an anti-nuclear and anti-double-strand DNA antibodies led to a misdiagnosis of systemic lupus erythematosus-related hepatitis. Based on these findings the patient was placed on steroids, which after a few months were stopped because of the onset of diabetes mellitus. Soon after steroid withdrawal, the patient had a marked increase in aminotransferases and γ-globulins, and a liver biopsy revealed chronic active hepatitis. A course of three months of steroids and azathioprine normalized both biochemical and clinical parameters. Currently the patient is symptom-free and doing well. In conclusion, a hypertransaminasemia persisting after a gluten-free diet should be interpreted as a sign of coexisting autoimmune liver disease. Any autoantibody positivity (in this case to ANA and anti-dsDNA) should be carefully considered in order to avoid misdiagnosis delaying appropriate clinical management.

Objectives: Gallbladder opacification (GBO) on computed tomography (CT) imaging may obscure certain pathological or emergent conditions in the gallbladder, such as neoplasms, stones, and hemorrhagic cholecystitis. This study aimed to investigate the clinical contributing factors that could predict the presence of delayed GBO determined by CT.Methods: This study retrospectively evaluated 243 consecutive patients who received enhanced CT or intravenous pyelography imaging and then underwent abdominal CT imaging within 5 days. According to the interval between imaging, the patients were divided into group A (1 day), group B (2 or 3 days), and group C (4 or 5 days). Three radiologists evaluated CT images to determine GBO. Fisher's exact test and multivariate backward stepwise elimination logistic regression were performed.Results: Positive GBO was significantly associated with the interval between imaging studies, contrast type, contrast volume, renal function, and hypertransaminasemia (P<0.05). Multivariate backward stepwise elimination logistic regression analysis of the three groups identified contrast type and hypertransaminasemia as independent predictors of GBO in group B patients (odds ratio [OR], 13.52, 95% confidence interval [CI], 1.72-106.38 and OR, 3.43, 95% CI, 1.31-8.98, respectively; P<0.05). Hypertransaminasemia was the only independent predictor of GBO in group C patients with an OR of 7.2 (95% CI, 1.62-31.73). Hypertransaminasemia was noted in three patients (100%) who initially underwent imaging 5 days prior to GBO.Conclusion: Delayed GBO on CT imaging may be associated with laboratory hypertransaminasemia, particularly in patients receiving contrast medium over a period of ≥4 days. A detailed clinical history, physical examination, and further workup are of paramount importance for investigating the underlying cause behind the hypertransaminasemia. [ABSTRACT FROM AUTHOR]

Introduction: Trichothiodystrophy type 4 and glutaric aciduria type 3 are rare autosomal recessive disorders caused by biallelic variants in the MPLKIP and SUGCT genes on chromosome 7p14, respectively. Trichothiodystrophy type 4 is characterized by neurologic and cutaneous abnormalities. Glutaric aciduria type 3 is a rare metabolic disorder with inconsistent phenotype and elevated urinary excretion of glutaric acid., Case Presentation: Here, we report on an infant presenting with hypotonia, failure to thrive, microcephaly, dysmorphic features, brittle hair, hypertransaminasemia, and recurrent lower respiratory tract infections. Microarray analysis revealed a homozygous microdeletion involving the MPLKIP and SUGCT genes, which are located close to each other., Conclusion: Copy number variations should be considered in patients with coexisting clinical expression of different genetic alterations. To the best of our knowledge, our patient is the second case with co-occurrence of trichothiodystrophy type 4 and glutaric aciduria type 3, resulting from a contiguous gene deletion., Competing Interests: The authors have no conflicts of interest to declare., (Copyright © 2022 by S. Karger AG, Basel.)

Aims: We performed a meta-analysis to assess the relative risk (RR) of all-grade and grade 3-4 hypertransaminasemia in studies comparing immune-based combinations with sunitinib in treatment-naive patients with advanced renal cell carcinoma. Materials & methods: Outcomes of interest included all-grade and grade 3-4 hypertransaminasemia measured as RRs and 95% confidence intervals (CIs). Results: RRs for all-grade hypertransaminasemia were 1.73 (95% CI: 1.25-2.4) and 1.63 (95% CI: 1.25-2.12) in patients receiving immunocombinations and sunitinib, respectively. The pooled RRs for grade 3-4 hypertransaminasemia were 3.24 and 3.04 in patients treated with immunocombinations or sunitinib. Conclusion: Immune-based combinations were associated with higher hypertransaminasemia risk. Physicians should pay attention to these common but overlooked events. Careful monitoring of tolerability remains a crucial need.