Silvia Nastasio

Celiac disease-associated autoimmune hepatitis in childhood: long-term response to treatment.

Objectives: Celiac disease (CD) is common in patients with autoimmune liver disease (AILD); however, the long-term response to treatment of patients with AILDs coexistent with CD has not been explored in detail. The aim of the present study was to analyze the features and the long-term response to immunosuppressive treatment in children with autoimmune hepatitis (AIH) associated with CD. Methods: Retrospective and prospective evaluation of patients followed at a single center. Results: Among 79 patients with AIH, 15 (19%) had CD (9 type 1, 3 type 2, 3 seronegative). In the group of patients with AIH and CD, female sex was significantly more represented than in the group of patients with AIH alone; also, in the former group, diagnosis was made significantly earlier (P < 0.05). All of the 15 patients on a gluten-free diet achieved sustained remission when treated with prednisone and azathioprine or cyclosporine. The mean period of follow-up was 73 months; discontinuation of therapy was attempted in 9 patients while in remission: 4 patients relapsed, 5 (33%) could definitively stop immunosuppressive treatment with a mean period of treatment-free sustained remission of 89 months (range 26–174). In the same period, treatment discontinuation, attempted in 24 of 64 patients with AIH without CD, was successful in 5 patients (8%; P < 0.05). Conclusions: Patients with AIH coexisting with CD achieve treatment-free sustained remission in a significantly higher proportion, when compared with patients with AIH without CD, suggesting a possible long-term adjuvant effect of a gluten-free diet.

Long-term outcome of liver disease-related fibrinogen aguadilla storage disease in a child.

T o the Editor: Sogo et al (1) reported in this journal a case of aguadilla hepatic fibrinogen storage disease (HFSD) with considerable liver disease. Severe liver disease with early liver fibrosis was also present at diagnosis in a child with HFSD presenting with persisting abnormalities of liver enzymes, described by us in 2006 (2). HFSD, in fact, results in a wide range of liver injuries, from mild liver damage to severe hepatic fibrosis in children (3) and leads to decompensated cirrhosis in adults (4). No follow-up data on natural history for these patients or suggestions for any possible treatment of this disorder are available. HFSD belongs to the endoplasmic reticulum storage diseases, a group of inborn errors of metabolism affecting secretory proteins and resulting in hepatocytic storage and plasma deficiency of the corresponding protein (5). Hepatocellular storage is the result of a genetically determined molecular abnormality hindering the translocation of the abnormal protein from the rough to the smooth endoplasmic reticulum. The storage of the mutant protein predisposes to the development of chronic liver damage. Endoplasmic reticulum storage diseases include a1-antitrypsin (AAT) deficiency, one of the most common genetic disorders causing liver disease in childhood. As in HFSD, the Z deficiency allele (PI Z) of SERPINA1, which encodes the serine protease inhibitor AAP, results in storage of the mutant protein in endoplasmic reticulum and leads to a wide range of liver injuries, from minimal damage to cirrhosis and to end-stage liver disease. The genetic and environmental factors that predispose some individuals with AAT deficiency to liver disease while sparing others are unknown. Similarly, the susceptibility of each patient with HFSD to progression of liver damage may be determined by several factors. Even though a specific therapy is not available for children with AAT deficiency and liver damage, ursodeoxycholic acid has been shown to significantly improve clinical status and liver test results in some children with moderate liver disease (6). Moreover, oxidative free radicals have been suggested to play a role in promoting liver damage in AAT deficiency (7). We thus decided to treat our patient with aguadilla HFSD with ursodeoxycholic acid 20 mg kg 1 day , and a-tocopherol 14 mg kg 1 day . When we started this treatment, he was 3 years 11 months old, in good general condition, although with a liver palpable below the costal edge that presented an increased consistency; aspartate aminotransferase (AST) was 3 times the upper limit of normal (N) and alanine aminotransferase (ALT) 4 N. Treatment was well tolerated without adverse effects. He was reviewed after 12 months: clinical examination was normal, liver was not palpable, and there were no clinical signs of chronic liver disease. Biochemical evaluation showed reduction of aspartate aminotransferase to 1.2 N and of ALT to 1.6 N. Treatment was continued and the patient was reviewed after a total of 24 months of treatment. Again, the clinical examination was normal; aspartate aminotransferase and ALT activity and total serum bile acids were normal. After 6 months of treatment, the child underwent yearly follow-up for a total of 89 months, showing normal clinical examination and liver enzymes. At the last clinical examination, at age 11 years 4 months,

Seronegative autoimmune hepatitis in children: Spectrum of disorders

BACKGROUND A few children with acute or chronic liver disease display histological features compatible with autoimmune hepatitis, but lack specific serological markers. AIM To describe features, management and outcome of childhood seronegative autoimmune hepatitis. METHODS From 1988 to 2010, 38 children were included under the following criteria: negative virological studies, no serum autoantibodies, exclusion of other causes of liver diseases, and liver histology compatible with autoimmune hepatitis. RESULTS Four groups were identified: (1) 12 with increased serum gamma globulin concentrations; (2) 10 with normal or low serum gamma globulins and no combined blood disease; (3) 10 with combined aplastic anemia; and (4) 6 with peripheral thrombocytopenia with/without neutropenia. Immunosuppressive treatment was associated with aminotransferases normalization in all but one child who required liver transplantation. Relapses occurred in 10 children. Lymphocytopenia was found at the time of the diagnosis of hepatitis in 13 children, 12 in groups 3 or 4. All 38 children are alive after 4-17 years, 18 still under immunosuppression. CONCLUSIONS Childhood seronegative autoimmune hepatitis includes a spectrum of disorders. Early liver histology is recommended and, if compatible with autoimmune hepatitis, immunosuppressive treatment should be started. Initial lymphocytopenia may indicate future hematological complication.

Juvenile autoimmune hepatitis: Spectrum of the disease.

Juvenile autoimmune hepatitis (JAIH) is a progressive inflammatory liver disease, affecting mainly young girls, from infancy to late adolescence, characterized by active liver damage, as shown by high serum activity of aminotransferases, by elevated immunoglobulin G levels, high titers of serum non organ-specific and organ-specific autoantibodies, and by interface hepatitis on liver biopsy. It is a multifactorial disease of unknown etiology in which environmental factors act as a trigger in genetically predisposed individuals. Two types of JAIH are identified according to the autoantibody panel detected at diagnosis: AIH-1, characterized by the presence of anti-smooth muscle antibody and/or antinuclear antibody and AIH-2, by anti-liver-kidney microsomal antibody type 1 and/or by the presence of anti-liver cytosol type 1 antibody. Epidemiological distribution, genetic markers, clinical presentation and pattern of serum cytokines differentiate the two types of AIH suggesting possible pathogenetic mechanisms. The most effective therapy for AIH is pharmacological suppression of the immune response. Treatment should be started as soon as the diagnosis is made to avoid severe liver damage and progression of fibrosis. The aim of this review is to outline the most significant and peculiar features of JAIH, based largely on our own personal database and on a review of current literature.

Efficacy of intravenous immunoglobulin therapy in giant cell hepatitis with autoimmune hemolytic anemia: A multicenter study.

BACKGROUND AND OBJECTIVE Giant cell hepatitis with autoimmune hemolytic anemia (GCH-AHA) is a rare disease of infancy, of possible autoimmune mechanism with poor prognosis due to its scarce response to immunosuppressive drugs. The aim of this retrospective multicenter study was to evaluate the efficacy and safety of intravenous immunoglobulin (IVIg) treatment in inducing and maintaining remission of the liver disease, in patients with GCH-AHA. METHODS Seven children with GCH-AHA, four newly diagnosed, and three in relapse, being treated with different therapies, received one to three IVIg infusions (0.5 to 2g/kg) in association with other immunosuppressive drugs. Subsequently five of them received monthly sequential IVIg infusions (mean 13.4, range 7-24). RESULTS IVIg infusions as first-line therapy associated with prednisone and other immunosuppressive drugs significantly (P=0.04) reduced the aminotransferase activity in all patients and normalized prothrombin activity in the only patient with severe liver dysfunction. Sequential monthly IVIg infusions determined a steroid-sparing effect and allowed a complete or partial remission in all patients, although with temporary efficacy, since relapse of the hemolytic anemia and/or of liver disease occurred in all patients. IVIg infusions were associated with mild side effects in two patients. CONCLUSIONS IVIg infusion can be safely and effectively administered in patients with severe GCH-AHA at diagnosis, or in case of relapse, in association with other immunosuppressive drugs. Repeated IVIg infusions may help maintain remission, however, due to their temporary efficacy, they should not be routinely employed.

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.

Spontaneous Extra-hepatic Portosystemic Shunt in Congenital Hepatic Fibrosis.

Physical examination of a 14-year-old asymptomatic girl revealed splenomegaly. Ultrasound examination revealed a large vessel between a patent umbilical vein and the left branch of the portal vein. CT-angiography imaging revealed that this large vessel was a spontaneous extra-hepatic porto-caval shunt draining portal flow to the iliac veins through the inferior epigastric veins. An upper gastrointestinal endoscopy showed portal hypertensive gastropathy without esophageal and/or gastric varices. Liver biopsy confirmed the diagnosis of congenital hepatic fibrosis. Extrahepatic portosystemic shunts of the omphalo-ilio-caval type are very uncommonly observed. In this patient

Cholestasis in preterm infants: when is a yellow alert?

Besides the transient bilirubin transport immaturity, preterm infants are particularly at risk for different forms and degrees of bile formation impairment because of metabolic demands that are not matched by functional maturation in the first weeks of life. Cholestasis, affecting approximately 1 of 2 500 infants, is more commonly reported in preterm infants with an incidence varying between 10 and 20%, and it is mainly due to a combination of factors including delayed enteral nutrition, low birth weight, prolonged parenteral nutrition, hypoxia, infection, liver ischemia, immaturity of bile acid metabolism, surgical procedures and multiple drug treatments [1]. This reality of the setting is defined as transient or multifactorial cholestasis [2], which is the most frequent form of cholestasis in neonatal intensive care unit, usually transient and followed by a gradual full recovery [3]. Cholestasis in preterm infants may however also be indicative of a severe liver disease such as biliary atresia (BA) or other biliary tract disorders. The development of a persistent cholestatic jaundice, even in presence of colored stools, incentives to conduct a thorough investigation [4]. Abdominal ultrasonography may support the diagnosis of BA showing: absence of gallbladder, the “triangular cord” sign or a cyst located at porta hepatis. Transient multifactorial cholestasis is a diagnosis of exclusion and a definitive diagnosis can be made only after the complete resolution of the clinical picture. Moreover, diagnosis of biliary atresia in preterm jaundiced neonates is difficult since discoloration of stools can occur several weeks after birth [4]. Besides specific cholestatic disorders for which specific medical and surgical treatment are available, there is no unequivocal evidence that any medical treatment alters the natural history of multifactorial cholestasis. Treatment with ursodeoxycholic acid may indeed be useful, although there is no evidence of effectiveness. Every effort must be made to remove all risk factors for liver injury. Consequences of cholestasis also need to be managed by administering fat -soluble vitamins, especially vitamin K and nutritional formulas containing medium-chain fatty acids. Although multifactorial transient cholestasis is the most common cause of prolonged jaundice in preterm infants, neonatologists need to be aware that premature infants can also present with signs of severe liver disease. To avoid any diagnostic delay it is mandatory to promptly identify all the conditions suitable for an early and specific treatment with a structured approach to the investigation of cholestasis tailored to the preterm infant [5].