Carmen Camarena

Short-term cyclosporine induces a remission of autoimmune hepatitis in children

BACKGROUND/AIMSnThe current immunosuppressive treatment of patients with autoimmune hepatitis consists of prednisone and azathioprine. High doses of prednisone used to obtain the remission of the disease are associated with serious adverse effects. To avoid harmful consequences of prednisone therapy, we proposed to treat patients with oral cyclosporine to obtain the remission of the inflammatory process.nnnMETHODSnThis is a pilot, multinational, multicenter, clinical trial involving children with autoimmune hepatitis. Thirty-two children were recruited, who according to international criteria were considered as having definite autoimmune hepatitis. Cyclosporine alone was administered for 6 months, followed by combined low doses of prednisone and azathioprine for 1 month, after which cyclosporine was discontinued. Biochemical remission of the disease was established by the follow-up of serum transaminase activity levels. Growth parameters and adverse effects of the treatment were recorded.nnnRESULTSnTwo patients were withdrawn from the study: one for non-compliance and the other for liver failure which did not improve with cyclosporine. Of the 30 remaining patients, 25 normalized alanine aminotransferase activity levels by 6 months and all the patients by 1 year of treatment. Z-scores for height showed a trend towards improvement during treatment. Adverse effects of cyclosporine were mild and disappeared during weaning off the medication.nnnCONCLUSIONSnCyclosporine induced the biochemical remission of the hepatic inflammatory/necrotic process in children with autoimmune hepatitis, with few and well-tolerated adverse effects.

Outcome of chronic hepatitis B in Caucasian children during a 20-year observation period

BACKGROUND/AIMSnChronic hepatitis B virus infection can lead to cirrhosis and hepatocellular carcinoma, particularly in men over 40 years of age and in areas where childhood-onset infection is common. The sequence of events from paediatric infection to severe disease in adults is only partially known. The aim of this study was to evaluate the evolution of chronic hepatitis B acquired in childhood during 20 years of follow-up.nnnPATIENTSnOne hundred and eighty-five consecutive, otherwise healthy, Caucasian children were enrolled in Padua (Italy) and in Madrid (Spain) between 1975 and 1985, and followed for an average period of 13 years; 168 were hepatitis B e antigen (HBeAg) positive and five had cirrhosis.nnnRESULTSnThirty patients received steroids or levamisole and 21 interferon, but treatment did not significantly influence HBeAg clearance. Overall, two (1.1%) children, with initial cirrhosis, developed hepatocellular carcinoma and the other three (1.6%) cirrhotic patients became asymptomatic carriers of infection after anti-HBe seroconversion and biochemical remission; 14 (7.5%) children maintained HBeAg positive hepatitis; 155 (83.8%) became asymptomatic carriers of infection after anti-HBe seroconversion and biochemical remission; six (3.2%) experienced reactivation of liver disease and viral replication after remission and five (2.7%) maintained biochemical features of liver damage after HBeAg clearance. Only 6% cleared hepatitis B surface antigen.nnnCONCLUSIONSnEven considering the bias of treatment, the large majority of Caucasian children with chronic hepatitis B became asymptomatic carriers of infection with normal alanine amino-transferase during the first 20 years of observation. Cirrhosis is an early, rare complication, and a risk factor for hepatocellular carcinoma. A subgroup of patients who experienced reactivation or maintained liver damage after HBeAg clearance seems to be at greater risk for disease progression during adult life.

Efficacy and Safety of Peginterferon-α2b and Ribavirin Combination Therapy in Children With Chronic Hepatitis C Infection

Background: Interferon (IFN)-&agr;2b plus ribavirin is approved for treatment of hepatitis C in children; however, little is known about efficacy and tolerability of pegylated IFN (PEG-IFN)-&agr;2b in this population. The objective of this study was to test the efficacy and safety of PEG-IFN-&agr;2b plus ribavirin in children with chronic hepatitis C. Methods: Thirty children 3–16 years of age who had detectable hepatitis C virus (HCV) RNA for ≥3 years after exposure and elevated alanine aminotransferase values received PEG-IFN-&agr;2b 1.0 &mgr;g/kg/wk plus ribavirin 15 mg/kg/d for 24 weeks (genotype 2/3) or 48 weeks (genotype 1/4). The primary endpoint was sustained virologic response (SVR), defined as undetectable HCV RNA (<50 IU/mL) at week 24 of follow-up. Results: SVR was achieved in 50% of patients (3/3 genotype 3; 12/27 genotype 1/4). At week 12, 52% of patients were HCV RNA negative and 72% had a >2 log10 decrease in viral load, compared with baseline; 87% and 71% of these patients, respectively, attained an SVR. Therapy was discontinued in 3 patients as a result of adverse events. No patient required ribavirin dose reduction; PEG-IFN-&agr;2b dose was reduced in 23% of patients to manage neutropenia. Conclusions: Combination therapy with PEG-IFN-&agr;2b and ribavirin treatment was effective in children with chronic hepatitis C. Virologic status at week 12 identified future responders and nonresponders. PEG-IFN-&agr;2b and ribavirin were reasonably well tolerated, with no unexpected or permanent adverse effects. Further studies are needed to identify the optimum treatment regimen for this patient population.

Recurrence of Bile Salt Export Pump Deficiency after Liver Transplantation

Severe bile salt export pump (BSEP) deficiency is a hereditary cholestatic condition that starts in infancy and leads to end-stage liver disease. Three children who underwent orthotopic liver transplantation for severe BSEP deficiency had post-transplantation episodes of cholestatic dysfunction that mimicked the original disease. Remission of all episodes was achieved by intensifying the immunosuppressive regimen. The phenotypic recurrence of the disease correlated with the presence of circulating high-titer antibodies against BSEP that inhibit transport by BSEP in vitro. When administered to rats, these antibodies targeted the bile canaliculi and impaired bile acid secretion.

A High Index of Suspicion: The Key to an Early Diagnosis of Wilson's Disease in Childhood

BACKGROUNDnTo study the clinical features of Wilsons disease in childhood.nnnMETHODSnRetrospective review of the clinical, laboratory, and histologic features and prognosis of Wilsons disease in 26 Spanish children.nnnRESULTSnThe first medical visit, at age 9.8+/-3.4 years (range, 4-16 years), was prompted by liver dysfunction detected accidentally (61%), symptoms of liver disease (27%), family screening (8%), and extrapyramidal symptoms and personality changes (4%). There were laboratory data of hepatic failure in 27%. All copper metabolism test results (total serum copper, 24-hour urine excretion, serum ceruloplasmin) were abnormal in 62%, two in 27%, and one in 11%. All patients in whom extrahepatic involvement was found at diagnosis had severe liver disease. Histologic findings were portal fibrosis with steatosis (29%), cirrhosis (21%), portal fibrosis (17%), chronic active hepatitis (17%), and minimal changes or normality (17%). Penicillamine was administered to all but one patient. Four children underwent liver transplantation, three of them having received penicillamine for 12, 45, and 70 days. Three other patients recovered from liver failure after 1 year of treatment with penicillamine. After a follow-up of 4.5+/-3.3 years, all the children survived. Penicillamine caused severe toxicity in one patient.nnnCONCLUSIONSnWilsons disease in childhood is generally detected by maintaining a high suspicion of liver disease in patients who have no or nonspecific hepatic symptoms. Kayser-Fleischer ring is rare in childhood. Drug therapy is effective and well tolerated, even in some cases of hepatic insufficiency.

Autoimmune hepatitis type 2 and hepatitis C virus infection: study of HLA antigens

BACKGROUND/AIMSnMarkers for hepatitis C virus are often detectable in patients suffering chronic hepatitis with liver-kidney microsomal type 1 antibodies. Several authors have suggested that two subsets of those patients can be defined: a) hepatitis C virus negative and b) hepatitis C virus positive. The aim of this work was to further analyze the possible genetic association, HLA class I and II, in these two groups of patients.nnnMETHODSnHLA was analyzed in 49 patients. Class I was studied using a standard lymphocytotoxicity test and in class II a reverse hybridization-based test for DRB1 typing and PCR-SSO for DQB1 typing were used. Sixty healthy Spanish subjects and 39 chronic hepatitis C subjects without anti-LKM1 antibodies were used as control groups for the a and b subsets, respectively.nnnRESULTSnNo significant association was found with class I specificities in either group. DQB1 typing showed a very significant increase of DQ2 in the a group (93.3% vs. 48%; RR = 15; Pc = 0.0025), and DRB1 typing from the b group revealed a high association with DR7 (82.3% vs. 43.6%; RR = 6; Pc = 0.0086).nnnCONCLUSIONSnOur studies revealed a strong association with DQ2 for the a group and for the first time an extremely high association with DR7 antigen for the b subset. Hence it is possible to establish a different genetic profile in these two patient groups.

Efficacy and safety of valganciclovir in liver‐transplanted children infected with Epstein‐Barr virus

Epstein‐Barr virus (EBV) infection after liver transplantation (LT) is associated with increased risk of posttransplant lymphoproliferative disorder (PTLD). Lowering immunosuppression is the current method to prevent PTLD in LT children with a high viral load. The aim of this study was to assess the efficacy and safety of valganciclovir (VGCV) in children with EBV infection after LT. Forty‐seven children showing detectable EBV‐DNA (72% asymptomatic) were treated with VGCV (520 mg/sqm twice daily) with no immunosuppression decrease (except in 4 cases). VGCV treatment started 17 months (median) after the onset of EBV infection. A 30‐day treatment applied to 26 patients led to undetectable EBV‐DNA in 11/32 courses (34.3%), with 82% relapsing. A long VGCV treatment (median: 8 months) achieved undetectable EBV‐DNA in 20/42 (47.6%), 60% of whom maintained response off therapy. There were no new PTLD cases. Symptoms worsened in 1 (2.1%) in whom PTLD was suspected but not confirmed in liver and jejunum biopsies. Factors associated with achievement of undetectable EBV‐DNA were a longer time from LT and a lower rate of intervening infections in comparison with nonresponders. The safety profile for VGCV was excellent. Graft rejection occurred in 6%. In conclusion, in 47 LT children with a sustained increased EBV load treated with VGCV and unchanged immunosuppression, PTLD was suspected in 1 child (2.1%). A viral load decrease could be achieved as EBV‐DNA was undetectable in 47% of patients under prolonged treatment. Liver Transpl 14:1185–1193, 2008.

Monitoring of tacrolimus as rescue therapy in pediatric liver transplantation

The introduction of tacrolimus as rescue therapy represents a significant advance in the prevention of late graft failure and second liver transplantation. The authors report the blood level monitoring of tacrolimus as a rescue therapy in 21 children who underwent liver transplantation, and they report the dose-concentration relationship in the presence or absence of hepatitis C virus (HCV) in these patients. This was a retrospective study conducted from May 1993 to January 1997. Indication for the conversion from cyclosporine (CsA) to tacrolimus were acute rejection (62%), chronic rejection (33%), and CsA toxicity (5%). Mean daily dose in the first month was 0.32 mg/kg, whereas at the end of the follow-up period it was 0.14 mg/kg. Tacrolimus mean whole blood concentration levels were between 7.1 ng/ml and 9.4 ng/ml, without significant differences over time. Mean daily doses in HCV+ and HCV- patients were 0.08 and 0.24 mg/kg, respectively (p < 0.01), and mean concentrations were 8.3 and 8.4 ng/ml (NS). HCV+ children required a mean dose three times lower than the dose used in HCV- children to obtain the same tacrolimus trough blood level. Therefore, doses in HCV+ children must be decreased to achieve levels within the therapeutic range.

Hepatitis C serotypes in chronic hepatitis C of children

An enzyme linked immunosorbent assay has been recently developed which detects and distinguishes between infections with the three major hepatitis C virus (HCV) genotypes prevalent in Europe. Using this assay we have investigated the sera of 30 Italian and 37 Spanish children with chronic hepatitis C. Infection with HCV type 1 was found in 43% of Italian and 46% of Spanish children. Of the Italian children 7% were infected with HCV of type 2 and 7% had a mixed type 1/type 2 serotype. Infection with HCV type 3 was found in 7% of Italian and 8% of Spanish children while 36% of Italian and 46% of Spanish children had non-reactive sera. Serotype 3 was significantly more frequent in children with anti-HCV positive mothers (often drug abusers) than in those with percutaneous exposure (25% vs. 2%, p < 0.05). Mean alanine aminotransferase values were significantly higher in children with HCV type 1 than in those with non-reactive sera (P < 0.05). These results indicate a similar distribution of HCV serotypes in Italian and Spanish children. Serotype 1 is prevalent and associated with a more severe liver damage. The relevant proportion of non-reactive sera could be related to the existence of genetic variants different from those explored by the test and with low pathogenicity, or to a poor antibody response to viral antigens of the NS4 region in a consistent subgroup of children.

A new variant in PHKA2 is associated with glycogen storage disease type IXa

Glucogenosis type IX is caused by pathogenic variants of the PHKA2 gene. Herein, we report a patient with clinical symptoms compatible with Glycogen Storage Disease type IXa. PYGL, PHKA1, PHKA2, PHKB and PHKG2 genes were analyzed by Next Generation Sequencing (NGS). We identified the previously undescribed hemizygous missense variant NM_000292.2(PHKA2):c.1963G > A, p.(Glu655Lys) in PHKA2 exon 18. In silico analyses showed two possible pathogenic consequences: it affects a highly conserved amino acid and disrupts the exon 18 canonical splice donor site. The variant was found as a “de novo” event.