Marco Sciveres

Autoimmune liver disease associated with celiac disease in childhood: a multicenter study

BACKGROUND & AIMS Celiac patients are at risk to develop an autoimmune liver disease. The aim of this study was to describe the clinical features of children and adolescents presenting with an autoimmune liver disease associated with celiac disease. METHODS A retrospective multicenter national survey was made for the period 1990-2005. RESULTS Among 140 pediatric patients with autoimmune liver disease in italy, we identified 23 with celiac disease: 19 with autoimmune hepatitis, 2 with autoimmune cholangitis, and 2 with overlap syndrome. Diagnosis of celiac disease preceded the diagnosis of liver disease in 18 of them, but elevation of aminotransferase activity was present in 16 when celiac disease was diagnosed. Acute hepatitis developed in 2 infants on gluten-free diet, and a hidden celiac disease was discovered in 5 other patients. Nineteen patients had liver-related non-organ-specific autoantibodies. Liver histology showed inflammatory lesions with features of autoimmune damage and different degrees of fibrosis in all of them and cirrhosis in 4. All patients, on gluten-free diet, achieved remission on immunosuppressive therapy, 14 relapsed because of discontinuation of therapy or during spontaneous gluten challenge, 20 are still on immunosuppressive treatment, and 3 could stop therapy. CONCLUSIONS Autoimmune liver diseases are frequently associated with celiac disease, but they might remain undiagnosed because of lack of symptoms, because of absence of liver-specific autoantibodies, or because of a misdiagnosis of celiac hepatitis. Acute hepatitis in celiac patients should induce one to suspect an autoimmune origin. Patients with autoimmune liver disease might have a hidden celiac disease, suggesting a rigorous check in any cryptogenic liver disease.

Relapsing features of bile salt export pump deficiency after liver transplantation in two patients with progressive familial intrahepatic cholestasis type 2.

BACKGROUND & AIMS PFIC2 is caused by mutations in ABCB11 encoding BSEP. In most cases affected children need liver transplantation that is thought to be curative. We report on two patients who developed recurrent normal GGT cholestasis mimicking primary BSEP disease, after liver transplantation. METHODS PFIC2 diagnosis was made in infancy in both patients on absence of canalicular BSEP immunodetection and on ABCB11 mutation identification. Liver transplantation was performed at age 9 (patient 1) and 2.8 (patient 2) years without major complications. Cholestasis with normal GGT developed 17 and 4.8years after liver transplantation, in patient 1 and patient 2, respectively, during an immunosuppression reduction period. RESULTS Liver biopsies showed canalicular cholestasis, giant hepatocytes, and slight lobular fibrosis, without evidence of rejection or biliary complications. An increase in immunosuppression resulted in cholestasis resolution in only one patient. Both patients developed atrial fibrillation, and one melanonychia. The newborn of patient 1 developed transient neonatal normal GGT cholestasis. Immunofluorescence staining of normal human liver sections with patients sera, collected at the time of cholestasis, and using an anti-human IgG antibody to detect serum antibodies, showed reactivity to a canalicular epitope, likely to be BSEP. Indeed, Western blot analysis showed that patient 2 serum recognized rat Bsep. CONCLUSIONS Allo-immune mediated BSEP dysfunction may occur after liver transplantation in PFIC2 patients leading to a PFIC2 like phenotype. Extrahepatic features and/or offspring transient neonatal cholestasis of possible immune mediated mechanisms, may be associated. Increasing the immunosuppressive regimen might be an effective therapy.

Giant Cell Hepatitis with Autoimmune Hemolytic Anemia in Early Childhood: Long-Term Outcome in 16 Children

OBJECTIVE To assess the outcome of giant cell hepatitis combined with autoimmune hemolytic anemia in early childhood. STUDY DESIGN We report on 16 children with this disease evaluated over a 28-year period. RESULTS Children (nine boys; median age, 6 months) presented with jaundice, hepatomegaly, elevated aminotransferases, a positive Coombs test, and diffuse giant-cell transformation of hepatocytes on histology. Treatment with prednisone and azathioprine, plus, in three children, cyclosporine, resulted in complete remission in eight, partial remission in six, and failure in two. Relapses of hepatitis and/or anemia occurred in 11 and 10 children, respectively, requiring prolonged high levels of immunosuppression, and splenectomy or Rituximab, respectively. Treatment was stopped after a mean duration of 6 years, with no relapse, in seven children, with a median follow-up of 14 years. One child is alive 9 years after liver transplantation. Four children died of sepsis or multiple organ failure. CONCLUSIONS Giant cell hepatitis combined with autoimmune hemolytic anemia requires rigorous treatment. Immunosuppressive therapy results in remission in most cases. A complete cure can be expected after several years of intensive treatment. Liver transplantation may be associated with prolonged survival.

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.

Global profiling of viral and cellular non-coding RNAs in Epstein-Barr virus-induced lymphoblastoid cell lines and released exosome cargos.

The human EBV-transformed lymphoblastoid cell line (LCL), obtained by infecting peripheral blood monocular cells with Epstein-Barr Virus, has been extensively used for human genetic, pharmacogenomic, and immunologic studies. Recently, the role of exosomes has also been indicated as crucial in the crosstalk between EBV and the host microenvironment. Because the role that the LCL and LCL exosomal cargo might play in maintaining persistent infection, and since little is known regarding the non-coding RNAs of LCL, the aim of our work was the comprehensive characterization of this class of RNA, cellular and viral miRNAs, and cellular lncRNAs, in LCL compared with PBMC derived from the same donors. In this study, we have demonstrated, for the first time, that all the viral miRNAs expressed by LCL are also packaged in the exosomes, and we found that two miRNAs, ebv-miR-BART3 and ebv-miR-BHRF1-1, are more abundant in the exosomes, suggesting a microvescicular viral microRNA transfer. In addition, lncRNA profiling revealed that LCLs were enriched in lncRNA H19 and H19 antisense, and released these through exosomes, suggesting a leading role in the regulation of the tumor microenvironment.

Diagnosis of sclerosing cholangitis in children: Blinded, comparative study of magnetic resonance versus endoscopic cholangiography

BACKGROUND Magnetic resonance cholangiography (MRC) has been validated as comparable to endoscopic retrograde cholangiography (ERC) for the diagnosis of sclerosing cholangitis (SC) in adult patients. In children, MRC is widely used based mainly on non-comparative studies. PATIENTS AND METHODS ERCs and MRCs of seven children (median age 9, range: 7-20 years) with SC and 17 controls (median age 6, range: 2 months-20 years) with other chronic liver diseases were reviewed in a blinded, random and independent way. All patients underwent both examinations within a 6-months slot. All ERCs and 17 MRCs were performed under general anesthesia. One radiologist evaluated both ERCs and MRCs and one interventional endoscopist independently reviewed only ERCs. Reviewers did not receive any clinical information. Diagnosis of SC, established on the basis of history, laboratory data, radiological examinations and clinical course, was used as gold standard to compare ERC and MRC diagnostic accuracy. RESULTS Overall image quality was graded as very good in 57% of MRC and in 71% of ERC cases; difference was not statistically significant (P=0.24) although the probability for MRC to be diagnostic increased with patients age. Depiction of first, second and fourth-order intrahepatic bile duct was better in ERC (P=0.004, 0.02 and 0.023, respectively); depiction of the extrahepatic bile duct was comparable (P=0.052). Diagnostic accuracy of MRC and ERC was very high, without statistically significant difference (P=0.61). CONCLUSION Despite an overall better depiction of the biliary tree by ERC, MRC is comparable for the diagnosis of SC in children. These data support MRC as the first imaging approach in children with suspected SC.

Hepatocarcinoma in a child with cholesterol ester storage disease

1 d Diagnosis of cholesterol ester storage disease (CESD) as suggested in a 5-year-old girl by a liver biopsy perormed because of a large hepatomegaly of fortuitous nding, and confirmed by the measurement of lysosomal cid lipase activity in cultured skin fibroblasts. The patient eveloped portal hypertension and a new liver biopsy, hen 11-year-old, showed micronodular cirrhosis with iffuse microvesicular steatosis. The child was listed for iver transplantation and received an extended right lobe raft (segments I + IV + VIII) obtained by in situ split liver rocurement from a 13-year-old donor. Histological examination of the native liver showed iffuse cirrhotic transformation, mild mixed inflammaory infiltrate, hydropic degeneration and microvesicular teatosis. A 1.4 cm non-encapsulated nodule of trabecuar hepatocellular carcinoma (HCC) (G1/G2) was identified n segment VII (Figs. 1 and 2). Patient underwent postransplant total body CT scan that excluded extra hepatic ocalizations. Post-operative -fetoprotein was normal. The atient did not received adjuvant chemotherapy and 30 onths after transplantation she is in good clinical condition, ithout evidence of HCC recurrence. CESD is a rare autosomal recessive disorder characterzed by accumulation of cholesterol esters and triglycerides n hepatocytes, adrenal cortical spongiocytes, and in histioytes. Patients with CESD may develop a progressive liver ailure necessitating liver transplantation. HCC has been described in a number of genetic and etabolic disorders in children including progressive familal intrahepatic cholestasis, Alagille syndrome, hereditary yrosinemia type I, glycogen storage diseases, alpha-1ntitrypsin deficiency, liver mitochondrial respiratory chain

Mutation analysis of the ATP7B gene in a new group of Wilson's disease patients: Contribution to diagnosis.

Wilsons disease (WD), an autosomal recessive disorder of copper transport with a broad range of genotypic and phenotypic characteristics, results from mutations in the ATP7B gene. Herein we report the results of mutation analysis of the ATP7B gene in a group of 118 Wilson disease families (236 chromosomes) prevalently of Italian origin. Using DNA sequencing we identified 83 disease-causing mutations. Eleven were novel, while twenty one already described mutations were identified in new populations in this study. In particular, mutation analysis of 13 families of Romanian origin showed a high prevalence of the p.H1069Q mutation (50%). Detection of new mutations in the ATP7B gene in new populations increases our capability of molecular analysis that is essential for early diagnosis and treatment of WD.

Out-of-reach obscure bleeding: single-balloon enteroscopy to diagnose and treat varices in hepaticojejunostomy after pediatric liver transplant.

Curcio G, Sciveres M, Mocciaro F, Riva S, Spada M, Tarantino I, Barresi L, Traina M. Out‐of‐reach obscure bleeding: Single‐balloon enteroscopy to diagnose and treat varices in hepaticojejunostomy after pediatric liver transplant.

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,