Paediatric porto-sinusoidal vascular disease: Two different clinical phenotypes with subtle histological differences.

BACKGROUND AND AIMS: In paediatrics, porto-sinusoidal vascular disease (PSVD) is relatively unknown and probably underdiagnosed. We aimed to describe clinical phenotypes, histology and outcome of children diagnosed with PSVD. METHODS: Retrospective multicentre study of children diagnosed with PSVD. Diagnosis of PSVD was based on histopathology reports; liver specimens were re-evaluated by two expert liver pathologists. RESULTS: Sixty two children diagnosed with PSVD (M/F = 36/26, median age 6.6 years, range 3.3-10.6), from 7 centres, were included. Thirty-six presented with non-cirrhotic portal hypertension, PH, (PH-PSVD Group = 58%) while 26 had a liver biopsy because of chronic elevation of transaminases without PH (noPH-PSVD Group = 42%). On histology review, the two groups differed for the prevalence of obliterative portal venopathy (more prevalent in PH-PSVD, p = 0.005), and hypervascularised portal tracts (more common in noPH-PSVD, p = 0.039), the other histological changes were equally distributed. At multivariate analysis, platelet count ≤185 000/mm3 was the only independent determinant of PH (p < 0.001). After a median follow-up of 7 years (range 3.0-11.2), in PH-PSVD group 3/36 (8%) required TIPS placement, 5/36 (14%) developed pulmonary vascular complications of PH, and 7/36 (19%) required liver transplantation. In noPH-PSVD none progressed to PH nor had complications. CONCLUSIONS: Paediatric patients with PSVD present with two different clinical phenotypes, one characterised by PH and one by chronic elevation of transaminases without PH. PSVD should be included among the conditions causing isolated hypertransaminasaemia. On histology, the differences between the two groups are subtle. Medium-term outcome is favourable in patients without PH; progression of the disease is observed in those with PH.

Safety and Effectiveness of Compounded Galenic Cholic Acid for Bile Acid Synthesis Disorder: A Case Report.

BACKGROUND: Bile acid synthesis disorders are rare congenital diseases that can lead to cirrhosis and end-stage liver disease if left untreated. Cholic acid administration is the only treatment that can prevent patients from fatal outcomes. Since 2013 in Europe, there has been just one formulation of cholic acid: Orphacol®. It is difficult to administer to infant patients because of its formulation (capsules) and the need for dose titration depending on the patient's weight. CASE PRESENTATION: Two sisters affected by 3-ß-hydroxy-Δ-5-C27-steroid dehydrogenase deficiency showed soon after birth failure to thrive, cholestasis, and fat-soluble vitamin deficiency. Both biochemical findings and liver biopsies confirmed cholestasis and initial liver damage. Patients were treated for eight years with a liquid formulation of a cholic acid galenic compound, and then they started to be treated with capsules of the registered drug. Clinical conditions and biochemical findings were checked periodically during both therapies. CONCLUSION: Clinical and laboratory data showed no differences between the cholic acid galenic compound and the registered drug in terms of efficacy and safety. Furthermore, the galenic compound showed benefits of more manageable dose titration, easier intake due to its liquid formulation, and lower costs than commercial cholic acid capsules.

MYO5B Gene Mutations: A Not Negligible Cause of Intrahepatic Cholestasis of Infancy With Normal Gamma-Glutamyl Transferase Phenotype.

OBJECTIVES: Progressive familial intrahepatic cholestasis is an expanding group of autosomal recessive intrahepatic cholestatic disorders. Recently, next-generation sequencing allowed identifying new genes responsible for new specific disorders. Two biochemical phenotypes have been identified according to gamma-glutamyltransferase (GGT) activity. Mutations of the myosin 5B gene (MYO5B) are known to cause microvillus inclusion disease. Recently, different mutations in MYO5B gene have been reported in patients with low-GGT cholestasis. METHODS: A multicenter retrospective and prospective study was conducted in 32 children with cryptogenic intrahepatic cholestasis. Clinical, biochemical, histological, and treatment data were analyzed in these patients. DNA from peripheral blood was extracted, and all patients were studied by whole exome sequencing followed by Sanger sequencing. RESULTS: Six patients out of 32 had mutations in the MYO5B gene. Of these six patients, the median age at disease onset was 0.8 years, and the median length of follow-up was 4.2 years. The most common signs were pruritus, poor growth, hepatomegaly, jaundice, and hypocholic stools. Two patients also showed intestinal involvement. Transaminases and conjugated bilirubin were moderately increased, serum bile acids elevated, and GGT persistently normal. At anti-Myo5B immunostaining, performed in liver biopsy of two patients, coarse granules were evident within the cytoplasm of hepatocytes while bile salt export pump was normally expressed at the canalicular membrane. Six variants in homozygosity or compound heterozygosity in the MYO5B gene were identified, and three of them have never been described before. All nucleotide alterations were located on the myosin motor domain except one missense variant found in the isoleucine-glutamine calmodulin-binding motif. CONCLUSIONS: We identified causative mutations in MYO5B in 18.7% of a selected cohort of patients with intrahepatic cholestasis confirming a relevant role for the MYO5B gene in low-GGT cholestasis.

Diagnostic approach to neonatal and infantile cholestasis: A position paper by the SIGENP liver disease working group.

Neonatal and infantile cholestasis (NIC) can represent the onset of a surgically correctable disease and of a genetic or metabolic disorder worthy of medical treatment. Timely recognition of NIC and identification of the underlying etiology are paramount to improve outcomes. Upon invitation by the Italian National Institute of Health (ISS), an expert working grouped was formed to formulate evidence-based positions on current knowledge about the diagnosis of NIC. A systematic literature search was conducted to collect evidence about epidemiology, etiology, clinical aspects and accuracy of available diagnostic tests in NIC. Evidence was scored using the GRADE system. All recommendations were approved by a panel of experts upon agreement of at least 75% of the members. The final document was approved by all the panel components. This position document summarizes the collected statements and defines the best-evidence diagnostic approach to cholestasis in the first year of life.

Pregnancy outcome in women with childhood onset autoimmune hepatitis and autoimmune sclerosing cholangitis on long-term immunosuppressive treatment.

INTRODUCTION: Autoimmune hepatitis and autoimmune sclerosing cholangitis may lead to maternal and fetal complications in pregnant women diagnosed during childhood and treated long-term with immunosuppressive drugs. Immunosuppressive treatment with azathioprine is usually employed during pregnancy to maintain remission but his safety is still controversial. The aim of our study is to investigate pregnancy outcomes after maternal long-term immunosuppressive treatment for autoimmune hepatitis/sclerosing cholangitis. METHODS: We conducted a retrospective cohort study including all pregnant women who received a diagnosis of autoimmune hepatitis or autoimmune sclerosing cholangitis during childhood and followed-up from 1989 to 2021. RESULTS: Fifteen pregnancies in 12 women were observed. The median follow-up from disease onset was 26.7 years. All patients had been treated with prednisone and azathioprine (AZA) as first line therapy. At the beginning of the pregnancy, 11/12 (91.6%) patients were in spontaneous or pharmacologically induced clinical and biochemical remission and one had received a liver transplant. During pregnancy, 8 patients continued azathioprine. No relapse during pregnancy occurred in any patient. One woman presented a flare five months after delivery and a second one, one year after delivery when AZA was discontinued. The 15 pregnancies resulted in 13 livebirths (86.6%) with 9 (69.2%) full-term healthy neonates. Two miscarriages (13.3%) were recorded and cesarean section was performed in 3 women (23%). No congenital malformations were observed. CONCLUSIONS: Pregnancy in women diagnosed during pediatric age with autoimmune hepatitis or autoimmune sclerosing cholangitis and treated long-term with immunosuppressants is possible with good maternal and neonatal outcomes. Azathioprine allows, in most cases, to maintain remission with a good safety profile. Careful monitoring of these patients during pregnancy is, however, mandatory.

Giant cell hepatitis associated with autoimmune hemolytic anemia: an update.

Giant cell hepatitis associated with autoimmune hemolytic anemia (GCH-AHA) is a rare and severe disease characterized by autoimmune hemolysis associated with acute liver injury, histologically defined by widespread giant cell transformation. It occurs after the neonatal period, most commonly in the first year of life and uniquely affects pediatric patients. It is still poorly understood and likely underdiagnosed, although in recent years there have been advances in the understanding of its pathogenesis and the liver injury is now hypothesized to be secondary to a humoral immune mechanism. Although no laboratory test specific for the diagnosis currently exists, given its severity, it is fundamental to rule out GCH-AHA when evaluating a patient in the first year of life presenting with AHA and/or with acute liver disease of unknown etiology. While GCH-AHA is progressive in nature as other autoimmune liver disorders, it differs significantly from juvenile autoimmune hepatitis (JAIH) in that a cure can be achieved after several years of intensive treatment in a portion of patients. Conventional first line therapy consist of prednisone/prednisolone combined with azathioprine, however, several immunosuppressive drugs, commonly used in the treatment of JAIH have been tried as second line therapy, including cyclosporine, cyclophosphamide, mycophenolate mofetil, 6-mercaptopurine, calcineurin inhibitors, and sirolimus. Intravenous immunoglobulins have also been used in cases of severe liver dysfunction and/or severe anemia allowing for transitory remission. More recently treatment with B-cell depletion has been attempted in some patients and encouraging results have been reported in refractory cases. Although what constitutes optimal treatment has yet to be determined, the recent progress in the understanding of the pathogenetic mechanisms of GCH-AHA have made positive strides, cautiously pointing toward a hopeful prognosis for some of these patients.

Successful fenofibrate therapy for severe and persistent hypertriglyceridemia in a boy with cirrhosis and glycerol-3-phosphate dehydrogenase 1 deficiency.

Glycerol-3-phosphate dehydrogenase 1 deficiency is a rare autosomal recessive disorder caused by mutations in the GPD1 gene (GPD1; OMIM*138420). Very few cases are reported in literature. It usually manifests in early infancy with transient hypertriglyceridemia, hepatomegaly, steatosis, and fibrosis. We report the case of a 16-year-old boy followed since the age of 1 year for hepatomegaly, elevated liver enzymes, and persistent hypertriglyceridemia. Abdominal ultrasound showed diffuse liver echogenicity and liver biopsy disclosed cirrhosis with micro and macrovesicular steatosis. Next-generation sequencing for metabolic and genetic liver diseases was conducted with the identification of the homozygous mutation c.895G>A in GPD1 gene resulting in the aminocidic substitution p.G299R. Considering the persistent and progressive increase of plasma triglycerides, fenofibrate treatment was started at 15 years of age allowing triglyceride level reduction in the following 1-year follow-up.

B-cell depletion induces prolonged remission in patients with giant cell hepatitis and autoimmune hemolytic anemia.

BACKGROUND: Giant cell hepatitis with autoimmune hemolytic anemia (GCH-AHA) is a rare and severe immune-mediated disorder. Despite aggressive immunosuppressive treatments, the mortality is high. Prednisone has been effectively employed to achieve remission, but with a risk of relapse, if discontinued, and with severe side effects. A possible causative role of humoral immune response has paved the way to anti CD-20 monoclonal antibody (rituximab; RTX). Nevertheless, data about timing of remission and long-term side effects are sparse. METHODS AND MATHERIALS: We have retrospectively evaluated 3 refractory GCH-AHA patients in whom a prolonged remission has been achieved with RTX. In all patients, response to first and second line therapy was incomplete or transitory and severe steroid side effects occurred. RESULTS: A stable and sustained remission was achieved after multiple doses of RTX allowing withdrawing all the other treatments. No life-threatening infections have been recorded, however two patients developed persistent, paucisymptomatic hypogammaglobulinaemia. The only patient who did not develop hypogammaglobulinemia received IgG replacement during RTX. CONCLUSION: RTX induced complete and long-lasting remission allowing discontinuing all the other immunosuppressive drugs. A persistent, paucisymptomatic hypogammaglobulinaemia has been the unique side effect. Although further studies need to replicate our data, RTX can be considered as an effective and safe therapy for sustained remission in patients with severe refractory GCH-AHA.

Long-term follow-up of children and young adults with autoimmune hepatitis treated with cyclosporine.

BACKGROUND: Cyclosporine (CSA) is an alternative treatment for autoimmune hepatitis (AIH), however, its unknown long-term safety and efficacy have limited its use. AIMS: Examine the long-term outcome of children and young adults with AIH treated with CSA for at least 4 years. METHODS: Twenty patients were included in this retrospective study: 15 with classical AIH and 5 with autoimmune hepatitis/autoimmune sclerosing cholangitis overlap syndrome (ASC). CSA was administered as first (12 patients) or second-line (8 patients) treatment, alone or in combination with azathioprine or mycophenolate mofetil and/or prednisone. RESULTS: CSA determined initial clinical and biochemical remission in all patients. At the end of follow-up (median 8.6; range 4-20.4 years), all patients are alive with their native liver; 15 in complete remission (75%), 2 with incomplete response to treatment and 3 listed for liver transplant. Side effects were mild and transitory after dose tapering or, in 1 case, after CSA withdrawal. Hypertrichosis and moderate gingival hyperplasia were the most frequent. Two patients presented mild transient glomerular filtration rate (GFR) reduction. Median GFR at the beginning and end of treatment was not statistically different for all patients. CONCLUSIONS: CSA was effective and safe in the long-term treatment of our cohort of patients with AIH, tailoring the treatment remains key-points during CSA administration.

Cholic acid for primary bile acid synthesis defects: a life-saving therapy allowing a favorable outcome in adulthood.

BACKGROUND: Oral cholic acid (CA) replacement has been shown to be an effective therapy in children with primary bile acid synthesis defects, which are rare and severe genetic liver diseases. To date there has been no report of the effects of this therapy in children reaching adulthood. The aim of the study was to evaluate the long-term effectiveness and safety of CA therapy. METHODS: Fifteen patients with either 3ß-hydroxy-Δ5-C27-steroid oxidoreductase (3ß-HSD) (n = 13) or Δ4-3-oxosteroid 5ß-reductase (Δ4-3-oxo-R) (n = 2) deficiency confirmed by mass spectrometry and gene sequencing received oral CA and were followed prospectively. RESULTS: The median age at last follow-up and the median time of follow-up with treatment were 24.3 years (range: 15.3-37.2) and 21.4 years (range: 14.6-24.1), respectively. At last evaluation, physical examination findings and blood laboratory test results were normal in all patients. Liver sonograms were normal in most patients. Mean daily CA dose was 6.9 mg/kg of body weight. Mass spectrometry analysis of urine showed that excretion of the atypical metabolites remained low or traces in amount with CA therapy. Liver fibrosis scored in liver biopsies or assessed by elastography in 14 patients, after 10 to 24 years with CA therapy, showed a marked improvement with disappearance of cirrhosis (median score < F1; range: F0-F2). CA was well tolerated in all patients, including five women having 10 uneventful pregnancies during treatment. CONCLUSIONS: Oral CA therapy is a safe and effective long-term treatment of 3ß-HSD and Δ4-3-oxo-R deficiencies and allows affected children to reach adulthood in good health condition without the need for a liver transplantation.

Vanishing Bile Ducts in the Long Term after Pediatric Hematopoietic Stem Cell Transplantation.

There are no structured studies on liver histology after hematopoietic stem cell transplantation (HSCT). We aimed to prospectively describe the clinicopathologic features of liver disease in the long term after HSCT in an observational, longitudinal study of liver histology in a consecutive cohort of children undergoing allogeneic HSCT. First liver biopsy was performed in presence of abnormal liver function tests and repeated per protocol thereafter. A previously reported semiquantitative score evaluating inflammation, cholestasis, and ductopenia (bile ducts-to-portal tracts ratio ≤ .5) was adopted. Graft-versus-host disease (GVHD) was diagnosed according to standard criteria. We evaluated 131 biopsies taken in 50 HSCTs performed in 47 children (mean age, 9.7 ± 5.2 years). Pre-HSCT chemotherapy was administered in 36 of 50 (72%). GVHD was diagnosed in 17 of 50 (34%). Over time the overall score decreased from a mean of 6 ± 2.7 to 3.25 ± .96 (P < .01), inflammation from 1.22 ± 1.19 to 1 ± 0 (not significant), and cholestasis from 3.9 ± 2.08 to 1.5 ± .58 (P < .01). Ductopenia, found in 113 of 131 biopsies (93%), worsened from .63 ± .35 to .16 ± .14 (P < .01). On multivariate analysis severe ductopenia (ratio ≤ .2) was associated with previous chemotherapy (P = .04), in particular with thiotepa, but not with history of GVHD. Vanishing bile duct syndrome after HSCT may be due to drug-induced liver disease. Longer follow-up will reveal whether these patients are prone to late liver-related morbidity and mortality.

Old and New Treatments for Pediatric Autoimmune Hepatitis.

BACKGROUND: Autoimmune hepatitis is a rare inflammatory disease of the liver that most frequently affects children and young adults. It is a multifactorial disease of unknown etiology, characteristically progressive in nature, and if left untreated, may lead to cirrhosis and terminal liver failure. It has been known for several decades now that immunosuppressive treatment convincingly alters the outcome of most patients with autoimmune hepatitis and as such it should be started as soon as diagnosis is made. Primary goals of treatment are: normalization of hepatocellular function, extinction of the hepatic necroinflammatory process, and maintenance of a stable remission, thus preventing progression to cirrhosis and its complications. This article aims to review old and new treatments for this rare chronic disorder, from the oldest and most frequently used treatment consisting of the association of prednisone and azathioprine, to alternative medical treatments, liver transplant and promising medical strategies currently under investigation. RESULT AND CONCLUSION: The review will focus on the efficacy and safety profile of each drug, as well as on the published clinical experience with them in pediatric patients with autoimmune hepatitis.

Relapse and metastasis of atypical teratoid/rhabdoid tumor in a boy with neurofibromatosis type 1 treated with recombinant human growth hormone.

Even though no increased recurrence rate seems to be reported in patients with brain tumors receiving recombinant human growth hormone (rhGH) replacement, in some patients multiple risk factors could put at higher risk for recurrence. In such cases, the decision to start rhGH therapy should be very cautious. A boy with neurofibromatosis type 1 developed an atypical teratoid/rhabdoid tumor (AT/RT) of right cerebellum, treated with surgery, radiotherapy, and chemotherapy. After 3 years of remission, he started rhGH for growth hormone deficiency, having a negative magnetic resonance imaging (MRI) scan. Ten weeks after starting therapy, the boy became symptomatic and MRI showed relapse of AT/RT in the right cerebellum and a new lesion in the brainstem. The boy died of progressive disease. In this case, the connection between AT/RT recurrence and the beginning of rhGH therapy, with a negative pretreatment MRI, cannot be excluded. Additional caution should be used for rhGH in patients with multiple risk factors.

Antiepileptic drugs and breastfeeding.

INTRODUCTION: This review provides a synopsis for clinicians on the use of antiepileptic drugs (AEDs) in the breastfeeding mother. METHODS: For each AED, we collected all retrievable data from Hale's "Medications and Mother Milk" (2012), from the LactMed database (2013) of the National Library of Medicine, and from a MedLine Search of relevant studies in the past 10 years. RESULTS: Older AEDs, such as carbamazepine, valproic acid, phenytoin, phenobarbital, primidone are considered to have a good level of safety during lactation, due to the long term clinical experience and the consequent amount of available data from the scientific literature. On the contrary, fewer data are available on the use of new AEDs. Therefore, gabapentin, lamotrigine, oxcarbazepine, vigabatrin, tiagabine, pregabalin, leviracetam and topiramate are compatible with breastfeeding with a less documented safety profile. Ethosuximide, zonisamide and the continue use of clonazepam and diazepam are contraindicated during breastfeeding. CONCLUSIONS: Although the current available advice on the use of AEDs during breastfeeding, given by different accredited sources, present some contradictions, most AEDs can be considered safe according to our review.

The dietary paradox in food allergy: yesterday's mistakes, today's evidence and lessons for tomorrow.

During the last decades the prevalence of food allergy has significantly increased among children and antigen avoidance still remains the standard care for the management of this condition. Most reactions are IgE-mediated with a high risk of anaphylaxis requiring emergency medications in case of inadvertent ingestion. Recent studies showed that continuous administration of the offending food, rather than an elimination diet, could promote the development and maintenance of oral tolerance. Indeed, intestinal transit of food proteins and their interaction with gut-associated lymphoid tissue (GALT) is the essential prerequisite for oral tolerance. On the contrary, low-dose cutaneous exposure to environmental foods in children with atopic dermatitis and altered skin barrier facilitates allergic sensitization. The timing and the amount of cutaneous and oral exposure determine whether a child will have allergy or tolerance. Furthermore, previous preventive strategies such as the elimination diet during pregnancy and breastfeeding, prolonged exclusive breastfeeding and delayed weaning to solid foods did not succeed in preventing the development of food allergy. On the other hand, there could be an early narrow window of immunological opportunity to expose children to allergenic foods and induce natural tolerance. Finally, the gradual exposure to the offending food through special protocols of specific oral tolerance induction (SOTI) may be a promising approach to a proactive treatment of food allergy.