Successful use of ursodeoxycholic acid in nodular regenerative hyperplasia of the liver.

OBJECTIVE: To report, to our knowledge, the first case of a patient with nodular regenerative hyperplasia of the liver (NRHL) associated with portal hypertension in whom ursodeoxycholic acid (UDCA) therapy had a therapeutic effect on liver enzymes and was associated with nonprogression of portal hypertension. CASE SUMMARY: A symptom-free 13-year-old boy was hospitalized for splenomegaly and thrombocytopenia identified during a routine check-up. Infectious, autoimmune, and neoplastic causes were ruled out. Two years later, laboratory findings revealed high levels of aminotransferases and γ-glutamyltransferase (GGT), thrombocytopenia, and neutropenia. Ultrasound scanning of the abdomen confirmed portal hypertension. Results of liver pathology studies showed diagnostic features of NRHL. Given the biochemical evidence of cholestasis, UDCA was administered, with an initial dosage of 10 mg/kg/day that was progressively increased to 20 mg/kg/day (1800 mg/day). After 5 months of treatment, GGT and then aminotransferase levels normalized and remained within normal limits in the following months. With arbitrary withdrawal of UDCA after 30 months of therapy, a rapid increase in transaminase levels was observed. Prompt reinstitution of UDCA was followed by sustained normalization of liver enzymes. Laboratory and sonographic signs of portal hypertension remained stable and tended to improve during UDCA therapy, as demonstrated by regularization of the mean portal vein flow velocity, reduction of the congestion index, progressive increase of the platelet count, and improvement of the esophagogastroscopy pattern. DISCUSSION: NRHL is a rare disease that is characterized by multiple regenerative nodules in the hepatic parenchyma that may lead to noncirrhotic portal hypertension. No specific treatment is available, and management of patients with a primary form of NRHL consists mainly of treating the complications of portal hypertension. In our patient, UDCA therapy was followed by a prompt reduction and sustained normalization of liver enzyme levels and no progression of portal hypertension throughout the follow-up period. CONCLUSIONS: Since in this patient with primary NRHL, ongoing UDCA administration resulted in improved biochemical and portal hypertension markers, this therapy can be considered in cases of NRHL associated with abnormalities of liver enzymes.

Helicobacter pylori chronic gastritis in children: to eradicate or not to eradicate?

OBJECTIVE: To evaluate the efficacy of triple eradication therapy versus symptomatic therapy in children with Helicobacter pylori-associated chronic active gastritis (H pylori-ACAG). STUDY DESIGN: Symptomatic patients with H pylori-ACAG (n=31) were randomly assigned into two groups: (1) patients infected with H pylori who were treated with triple eradication therapy (n = 16); and (2) patients infected with H pylori who were treated with symptomatic therapy (n=15). RESULTS: After 1 year of follow-up, macroscopic appearance was significantly different in group B (P=.023), and chronic inflammation, H Pylori density, and activity were significantly higher in group B than in group A (P=.022, .007, and .002, respectively); however, we did not find a significant difference in the symptoms comparing both groups (P=.287). After 1 year of follow-up, we observed the persistence of the H pylori infection in all children who had not received eradication treatment. CONCLUSIONS: There is no correlation between eradication of H pylori infection and improvement of dyspeptic symptoms. Self-eradication does not occur within 1 year of follow-up. A trend toward a higher rate of chronic inflammation in noneradicated children at 1 year limited the time of our study.

Hepatic steatosis is uncommon in children with chronic hepatitis B.

BACKGROUND: Differently from chronic hepatitis C, factors associated with hepatic steatosis in children with chronic hepatitis B are not clearly elucidated. OBJECTIVE: Aim of this study was to investigate prevalence of steatosis at liver biopsy in HBV-infected children. STUDY DESIGN: A retrospective study including 56 children with chronic hepatitis B undergoing liver biopsy at median age of 8.1 years. In all patients demographic, anthropometric, clinical and laboratory data were evaluated at the time of liver biopsy. RESULTS: Steatosis was present in 2 (4%) children. BMI was significantly higher in 2 patients with steatosis compared with those without steatosis. Demographic, biochemical and virological parameters did not differ between children with and those without steatosis. CONCLUSIONS: Liver steatosis in HBV-infected children seems to be related to obesity and metabolic factors rather than to viral factors. Detection of steatosis in non-obese children with HBV infection requires a careful investigation to rule out other causes of fatty liver.

Clinical phenotype of lathosterolosis.

Lathosterolosis (LS) is a defect of cholesterol biosynthesis due to the deficiency of the enzyme sterol-C5-desaturase. Only two patients have been described to date, both presenting with multiple malformations, mental retardation, and liver involvement. In addition in one of them pathological examination revealed mucolipidosis-like inclusions on optic microscopy analysis, and peculiar lysosomal lamellar bodies on electron microscopy analysis. This study is focused on a better characterization of the clinical phenotype of LS. We describe a further case in a fetus, sibling of the first patient reported, presenting with neural tube defect, craniofacial and limb anomalies, and prenatal liver involvement. The fetal phenotype suggests the possible occurrence of significant intrafamilial variability in LS, and expands the phenotypic spectrum of the disease. Histological examination of autopsy samples from the fetus and skin fibroblasts from the living sibling suggested that the mucolipidosis-like picture previously reported is not a constant feature of LS, being possibly associated with the most severe biochemical defects, but confirmed the ultrastructural finding of lamellar inclusions. The LS phenotype appears to be characterized by the distinctive association of a recognizable pattern of congenital anomalies, involving axial and appendicular skeleton, liver, central nervous and urogenital systems, and lysosomal storage. This condition partially overlaps with other defects of sterol metabolism, suggesting intriguing pathogenic links among these conditions.

Diagnostic value of HSP70, glypican 3, and glutamine synthetase in hepatocellular nodules in cirrhosis.

UNLABELLED: Hepatocellular nodules in cirrhosis include regenerative (large regenerative, LRN) and dysplastic (low and high grade, LGDN and HGDN) nodules, early and grade 1 HCC (eHCC-G1), and overt HCC. The differential diagnosis may be particularly difficult when lesions such as HGDN and eHCC-G1 are involved. We investigated the diagnostic yield of a panel of 3 putative markers of hepatocellular malignancy such as HSP70, glypican 3 (GPC3), and glutamine synthetase (GS). We selected 52 surgically removed nonmalignant nodules (15 LRNs, 15 LGDNs, 22 HGDNs) and 53 HCCs (10 early, 22 grade 1, and 21 grade 2-3) and immunostained them for HSP70, GPC3, and GS. The sensitivity and specificity of the individual markers for the detection of eHCC-G1 were 59% and 86% for GS, 69% and 91% for GPC3, and 78% and 95% for HSP70. We identified 2 main phenotypes: (1) all negative, seen in 100% LRN and LGDN, 73% HGDN and 3% eHCC-G1; (2) all positive, a feature detected in less than half the eHCC-G1. Using a 3-marker panel, when at least 2 of them, regardless which, were positive, the sensitivity and specificity for the detection of eHCC-G1 were respectively 72% and 100%; the most sensitive combination was HSP70+/GPC3+ (59%) when a 2-marker panel was used. CONCLUSION: The adopted panel of 3 markers is very helpful in distinguishing eHCC-G1 from dysplastic nodules arising in cirrhosis.

Expression of p53/HGF/c-met/STAT3 signal in fetuses with neural tube defects.

Neural tube defects (NTD) are morphogenetic alterations due to a defective closure of neural tube. Hepatocyte growth factor (HGF)/c-met system plays a role in morphogenesis of nervous system, lung, and kidney. HGF/c-met morphogenetic effects are mediated by signal transducers and activators of transcription (STAT)3 and both HGF and c-met genes are regulated from p53. The aim of our study was to analyze mRNA and protein expressions of p53, HGF, c-met, and STAT3 in fetuses with NTD. By reverse transcriptase-polymerase chain reaction and immunohistochemistry, we analyzed neural tissues from four NTD fetuses and the corresponding non-malformed lungs, kidneys and placentas. We found a reduced mRNA expression of HGF/c-met/STAT3 pathway, in the malformed nervous systems and placentas. The reduced expression of this pathway correlated with the absence of p53 in all these samples. On the contrary, detectable expression levels of p53, HGF, c-met, and STAT3 were observed in non-malformed lungs and kidneys obtained from the same fetuses. Comparable results were obtained by immunohistochemistry, with the exception of p53, which was undetected in all fetal tissues. In conclusion, in NTD fetuses, both the defective neural tube tissue and the placenta have a reduction in all components of the p53/HGF/c-met/STAT3 cascade. This raises the possibility of using the suppression of these genes for early diagnosis of NTD especially on chorionic villus sampling.

Is HCV infection associated with liver steatosis also in children?

BACKGROUND/AIMS: Prevalence and significance of steatosis in children with chronic hepatitis C are not well defined. We analysed the prevalence of steatosis in children with chronic hepatitis C and its relationship with clinical, laboratory features and response to interferon. METHODS: Sixty-four consecutive children with CHC undergoing liver biopsy were retrospectively evaluated. RESULTS: Twenty-five percent of children showed mild to moderate steatosis. Only one child was infected by genotype 3. Body mass index did not significantly differ between children with and without steatosis. Although no significant difference in necroinflammatory and fibrosis scores between children with and without steatosis was found, 3 (18.7%) of 16 patients with steatosis and only one (2.1%) of 48 patients without steatosis had a fibrosis score >2 (P<0.05). Forty-seven children (13 with steatosis) received interferon after liver biopsy. A sustained response was observed in 3 (23%) children with steatosis and in 18 (53%) without steatosis. CONCLUSIONS: Histological evidence of steatosis is detectable in a quarter of children with CHC. Differently from adults, genotypes other than 3 may be associated with steatosis independently from classical metabolic risk factors. Children with steatosis seem to have more severe fibrosis and lower rates of sustained response to interferon therapy compared to children without steatosis.

Cryptogenic liver disease in four children: a novel congenital disorder of glycosylation.

We investigated the metabolic defect(s) of four children who presented with isolated cryptogenic chronic liver disease, coagulopathy, and abnormalities of several unrelated serum glycoproteins. Analysis of the patients' serum glycoproteins and fibroblasts suggest they have a novel congenital disorder of glycosylation (CDG). All had abnormal transferrin (Tf) isoelectric focusing (IEF) profiles. More detailed analysis of Tf by electrospray ionization mass spectrometry (ESI-MS) showed a plethora of abnormal glycosylations that included loss of 1-2 sialic acids and 1-2 galactose units, typical of Group II defects. Tf from two patients also lacked 1-2 entire oligosaccharide chains, typical of Group One disorders. Total serum N-glycans were analyzed by HPLC and matrix-assisted laser desorption/ionization mass spectrometry and also showed increased proportion of neutral glycan chains lacking sialic acids and galactose units. Analysis of patient fibroblasts eliminated CDG-Ia, through CDG-Ih, -IL and CDG-IId. Our results suggest that a subset of children with clinically asymptomatic, cryptogenic hypertransaminasemia and/or liver steato-fibrosis may represent a novel type of CDG-X with an unknown defect(s). Clinicians are encouraged to test such patients for abnormal Tf glycosylation by ESI-MS.

Chronic hepatitis C in childhood: an 18-year experience.

BACKGROUND: The long-term outcome of chronic hepatitis C (CHC) has not been well studied, both for untreated and interferon-treated children. The aim of this study was to evaluate the long-term outcome of disease in a large series of children with CHC. METHODS: Clinical, biochemical, virological, and histological features were evaluated in all children (age, 2-18 years) with CHC who did not have concomitant disease and who attended at our hospital's liver unit during the period of 1986-2004. RESULTS: One hundred twenty-five children with CHC were studied. All patients remained free of symptoms throughout the period of observation. On the basis of transaminase levels during the first year of positivity for antibodies to hepatitis C virus (HCV), children were divided into 2 groups: patients with hypertransaminasemia (100 patients, all of whom had detectable HCV RNA), and those with normal transaminases (25 patients; 16 had viremia and 9 did not have viremia). Sustained clearance of viremia was achieved in 38% of the patients treated with interferon, compared with 12% of untreated children (P<.05). A sustained response to therapy was obtained in 64.7% of children infected with an HCV genotype other than genotype 1 and in 24.2% of those infected with HCV genotype 1 (P<.05). Histological lesions were mild in all 64 patients who underwent liver biopsy. No linear correlation was found between duration of disease and progression of fibrosis. Examination of a follow-up liver biopsy specimen revealed cirrhosis only in 1 (4.7%) of 21 children. CONCLUSIONS: Children with CHC were symptom free and had a morphologically mild liver disease. Interferon therapy may be effective for patients infected with HCV genotypes other than genotype 1, whereas lower response rates are expected for HCV genotype 1-infected children. The real impact of therapy on long-term outcome remains to be established.

Characterization of liver involvement in defects of cholesterol biosynthesis: long-term follow-up and review.

Inborn defects of cholesterol biosynthesis are a group of metabolic disorders presenting with mental retardation and multiple congenital anomalies (MCA/MR syndromes). Functional and structural liver involvement has been reported as a rare (2.5-6%) complication of the Smith-Lemli-Opitz syndrome (SLOS) and it has not been fully characterized. Here, we report on a long-term follow-up study of four patients with SLOS, and one case with lathosterolosis who presented with liver disease and underwent an extensive diagnostic work-up. Reports of liver involvement in cholesterol biosynthesis defects are reviewed. Two main different patterns of liver involvement emerged: progressive cholestasis, and stable isolated hypertransaminasemia. In our series, the first pattern was found in two patients with SLOS and one with lathosterolosis, and the second in two SLOS cases. Cholestasis was associated with early lethality and normal serum gamma-glutamyl-transferase (GGT) levels in SLOS, while possible prolonged survival and high GGT levels were seen in lathosterolosis. Hepatic fibrosis was present in both conditions. Liver biopsy performed in one of our SLOS patients with isolated hypertransaminasemia, showed only mild hydropic degeneration of the hepatocytes. The presence of liver involvement in 16% of the SLOS patients diagnosed at our Center suggests that this complication might have been underestimated in previously reported cases, possibly overshadowed by the severity of multiple malformations. Fetal hepatopathy, cholestasis, and isolated hypertransaminasemia can occur also in other disorders of cholesterol biosynthesis, such as mevalonic aciduria, desmosterolosis, Conradi-Hunermann syndrome, Greenberg dysplasia, and Pelger-Huet homozygosity syndrome. This group of inherited disorders should be considered in the differential diagnosis of patients presenting with liver disease associated with developmental delay and/or multiple malformations. Periodic liver function evaluations are recommended in these patients.

Silent non-alcoholic fatty liver disease-a clinical-histological study.

BACKGROUND/AIMS: We studied the prevalence of non-alcoholic fatty liver disease and non-alcoholic-steatohepatitis in patients with metabolic-syndrome but normal liver enzymes. The histological findings of patients with normal liver enzymes and non-alcoholic-steatohepatitis were compared with those of a control-group with persistently abnormal liver enzymes. METHODS: Patients presenting with normal liver enzymes were enrolled in the study and underwent liver biopsy. Prevalence of non-alcoholic-steatohepatitis and risk factors for fibrosis and cirrhosis were evaluated. Data from a control-group with non-alcoholic-steatohepatitis and abnormal liver enzymes were used to compare the histological findings. RESULTS: Fifty-eight of the 80 patients enrolled had varying degrees of non-alcoholic steatohepatitis, of these 26 had fibrosis and 8 silent cirrhosis. The association of metabolic-syndrome, female-sex, a long-history of obesity and body mass index>45 were considered to be independent risk-factors for fibrosis. Comparing the histological findings of cases and controls we found a similar severity of steatosis and fibrosis, with a greater prevalence of ballooning degeneration and glycogenated-nuclei rather than lobular-inflammation. CONCLUSIONS: In the subjects selected according to our criteria, liver enzyme levels could not be used as surrogate markers of non-alcoholic-steatohepatitis. Histological hallmarks of patients with metabolic-syndrome, normal liver enzymes and non-alcoholic-steatohepatitis consist to a lesser degree of lobular-inflammation and a more severe ballooning and glycogenated-nuclei.

Comparative genomic hybridization analysis of hepatoblastoma reveals high frequency of X-chromosome gains and similarities between epithelial and stromal components.

Hepatoblastoma (HB) is the most common liver tumor in childhood and differs in its environmental risk factors and genetic background from hepatocellular carcinoma. HB is associated with inherited conditions such as familial adenomatous polyposis and Beckwith-Wiedemann syndrome, suggesting the importance of genetic abnormalities in the pathogenesis and progression of this disease. It has a very polymorphous morphology. A diverse range of cytogenetic alterations has been reported to date, the most frequent being trisomy 2 and trisomy 20. Thirty-five HB specimens from 31 patients (22 purely epithelial, 4 purely mesenchymal, 9 mixed) were examined by comparative genomic hybridization (CGH), a technique that enables us to screen the entire tumor genome for genetic losses and gains. Our aims were as follows: (1) to characterize chromosome abnormalities that appear in this tumor and (2) to identify possible differences between different histologic subtypes of HB. We found significant gains of genetic material, with very little difference in the number and type of alterations between the different histologic components of HB. The most frequent alterations were gains of Xp (15 cases, 43%) and Xq (21 cases, 60%). This finding was also confirmed by fluorescent in situ hybridization performed on nuclei extracted from 6 specimens. Other common alterations were 1p-, 2q+, 2q-, 4q-, and 4q+. We found no difference between different histologic subtypes, a finding that may be in agreement with the hypothesis of a common clonal origin for the different components. An hitherto-unreported high frequency of X chromosome gains may support the assumption that X-linked genes are involved in the development of this neoplasm.