Infantile cholestatic jaundice associated with adult-onset type II citrullinemia.

Adult-onset type II citrullinemia, characterized by a liver-specific argininosuccinate synthetase deficiency, is caused by a deficiency of citrin that is encoded by the SLC25A13 gene. Three patients with infantile cholestatic jaundice were found to have mutations of the SLC25A13 gene. Adult-onset type II citrullinemia may be associated with infantile cholestatic disease.

Immunohistochemical study on transforming growth factor-beta1 expression in liver fibrosis of Down's syndrome with transient abnormal myelopoiesis.

A case of Down's syndrome associated with liver fibrosis is reported. The fibrosis was diffusely distributed along sinusoids, and an excess of megakaryocytes was also found in the liver. To determine the mechanism of liver fibrosis in Down's syndrome, we immunohistochemically stained the liver with markers of myofibroblast-like cells, antialpha smooth muscle actin antibodies and antidesmin antibodies. The myofibroblast-like cells were found along sinusoids, suggesting that liver fibrosis in Down's syndrome is caused by the myofibroblast-like cells derived from Ito cells/lipocytes. The expression of transforming growth factor (TGF)-betal, which is an important mediator of the activation of lipocytes, was immunohistochemically examined. The accumulation of TGF-betal was observed in cells in the sinusoidal spaces, which involve the intracellular expression of megakaryocytes. Together, these findings suggest that megakaryocyte-derived TGF-betal is one of the likely candidates in the lipocyte activation of liver fibrogenesis in Down's syndrome.

Neonatal intrahepatic cholestasis with hepatic siderosis and steatosis.

Neonatal intrahepatic cholestasis is a heterogeneous disease of undetermined cause. There is an unreported subset of idiopathic neonatal intrahepatic cholestasis with an unusual histological combination of hepatic siderosis and macrovesicular steatosis. The patients were a 34-day-old female and a 39-day-old male with normal birth weights. Their mothers had received oral iron supplement 4-6 weeks before delivery. The patients had obstructive jaundice noticed at the well-baby clinic at 1 month of life. They had high levels of serum galactose and tyrosine, hyperferritinemia. Urinary organic acid and bile acid analyses were negative, and galactose-1-phosphate uridyltransferase activity in red cells was normal. Liver biopsies showed diffuse iron deposits and macrovesicular fat. By substituting formula milk with lactose-free milk, the patients responded, and had normal biochemical tests within 5 months of life. Follow-up biopsies, at the age of 12 months, showed mild residual fibrosis without iron or fat deposits. They are both well at 3 and 6 years of age, respectively, without biochemical liver dysfunction and neurologic impairment. Prenatal iron-overload might contribute to the pathogenesis of the disease, but further studies are needed to confirm the assumption.

Idiopathic neonatal hepatitis presenting as neonatal hepatic siderosis and steatosis.

Idiopathic neonatal hepatitis (INH) is a heterogeneous disease of undetermined cause. We report a retrospective histologic reevaluation of INH. Sixty patients with INH were reviewed along with 32 biliary atresia (BA) patients. Histologic findings, iron and fat deposits, giant cell transformation, portal fibrosis, and bile duct proliferation were semiquantitatively graded from 0 to 4+. Significant histologic findings were defined as > or =2+. Frequencies of patients with significant histologic findings in the INH group were compared with those of the BA group. Among the patients with significant histologic findings, those in the INH group had significantly less iron deposits (P < 0.01), portal fibrosis (P < 0.01), and bile duct proliferation (P < 0.01) than those of the BA group. A combination of significant hepatic macrovesicular steatosis and siderosis was observed in 10 INH patients but not in any BA patient (10/60 vs 0/32, P < 0.05). Without extensive treatment, the 10 INH patients all recovered, and hepatic abnormalities normalized by the age of 12 months. In conclusion, the present study showed that the recognition of hepatic siderosis is helpful to distinguish BA from INH and that in a subset of INH patients hepatic macrovesicular steatosis and siderosis occurs.

Effect of weight changes on serum transaminase activities in obese children.

To examine the effect of weight changes on serum transaminase activities, glutamic oxaloacetic and pyruvic transaminases (GOT/GPT), a 3-month observation of 110 obese outpatients treated by a mild regimen for obesity was carried out. Patients were divided into two major groups, group I (n = 73) and group II (n = 37), with or without persistent elevation of serum GOT/GPT (> 30 IU/L), and retrospectively classified into four subgroups according to weight changes: group A, weight loss > 5%; group B, weight loss of < 5%; group C, an increase of < 5%; group D, an increase > 5%. In group IA, the incidence of cases with normalization of serum GOT/GPT was 70% and was significantly greater than those of the other three subgroups, respectively (P < 0.01). The incidences of decreased serum GOT/GPT activities were observed corresponding to the degree of weight changes not only in group I (100-27%) but also in group II (100-33%). These facts indicate that a mild regimen for obese outpatients for 3 months, significantly improves serum transaminase activities in patients not only with weight reduction but also weight gain, and that fatty liver may be present even in obese children with normal serum transaminase levels. The normalization of serum GPT activity in patients with weight gain suggests the presence of another factor contributing hypertransaminasemia in pediatric obese patients.

Heterogeneity of liver disorder in type B Niemann-Pick disease.

Patients with type B Niemann-Pick disease (NPD) are known to be complicated with varying degrees of prognosis-determining liver dysfunction. To see heterogeneity of the dysfunction histologically, we performed liver biopsies on three NPD patients from three different families, who were diagnosed by enzyme assay of acid sphingomyelinase (ASM) and analysis of the ASM gene. In a severe case, of a female patient in her childhood, the liver showed definite fibrosis despite her age. In contrast, in a very mild case, of an adult male patient, the liver showed little fibrosis, though the ballooning of hepatocytes and infiltration of foamy histiocytes were observed in the tissue. Three homo-allelic mutations (S436R, A599T, and S231P) were identified in the patients. Thus, various hepatic phenotypes in type B NPD were shown to be caused by the heterogeneity of liver lesions originating from different ASM gene mutations.

Serum alanine aminotransferase activity in obese children.

To confirm the significance of the serum alanine aminotransferase (ALT) test for the diagnosis of fatty liver and to clarify the relationship between serum ALT activity and the duration of obesity, we analysed 310 obese young school children (195M, 115F), who were classified into three duration groups (1-3 y, 4-6 y, 7 + y), three age groups (6-7 y, 8-9 y, 10-11 y), and four obesity groups (weight excess: mild, 20-29%; moderate, 30-39%; severe, 40-49%; very severe, 50%). Seventy-seven patients with abnormal ALT test, > 30 IU/l, and 27 patients with normal ALT test were examined by ultrasound study to identify the fatty-fibrotic pattern of the liver. Abnormal results of the serum ALT test were found in 24% of all patients. The fatty-fibrotic pattern was identified in 64/77 (83%) patients with abnormal ALT test and in 5/27 (18%) patients with normal ALT test. The serum ALT test has a sensitivity of 0.92 for detecting the fatty-fibrotic pattern proven by ultrasound study. Frequencies of cases with abnormal serum ALT levels increased with the duration of obesity. In the shortest duration group, however, the frequencies of abnormal results in serum ALT test did not increase with advanced ages or the grades of obesity. In conclusion, the present study confirmed the usefulness of the serum ALT test for screening fatty liver, and showed that a longer duration of obesity is generally associated with the occurrence of fatty liver in a paediatric obese population. In young patients with mild obesity or a short duration of obesity, however, fatty liver or fatty fibrosis may develop. Early intervention should be made in the case of obese children.

Relationship of feeding modality to clinical features in Japanese infants with idiopathic neonatal hepatitis of the non-familial form.

To clarify the relationship between idiopathic neonatal hepatitis and feeding type, that is, formula-milk feeding and breast-milk feeding, the medical records of 100 patients (68 male and 32 female babies) with idiopathic neonatal hepatitis of non-familial form referred to the medical centers of Akita University and Tohoku University during the past 18 years were reviewed. The patients were divided into two 9 year periods (1975-83 and 1984-92), and their clinical features were analyzed in terms of feeding type and sex. The number of patients enrolled decreased from 69 in the first half to 31 in the second half. The number of male patients dropped from 53 to 15, although the number of female patients (n = 16) remained the same in both 9 year periods. The frequency of formula-milk feeding significantly decreased in the second half (42/69 to 6/31, P < 0.01). Compared with the expected numbers of patients in the second half, calculated on the changes in the live birth population and feeding modality between the two halves, the actually enrolled numbers of patients in the second half were less in both the male and the formula-milk fed groups (x0.35 and x0.22), whereas the numbers of female and breast-milk feeding groups were close to the expected values (x1.26 and x1.08). When sex and feeding modality were combined, the formula-milk fed male group showed the lowest value (x0.10), and the breast-milk fed female group showed the highest value (x2.85). In conclusion, feeding type, especially in combination with gender, might be one causative factor in the occurrence of idiopathic neonatal hepatitis.

Relationships between clinical and histological profiles of non-familial idiopathic neonatal hepatitis.

Idiopathic neonatal hepatitis (INH) is a syndrome characterized clinically and histologically but there is little information concerning the relationship between the clinical features and histological findings. In the present study, sixty-two patients clinically diagnosed as non-familial INH were histologically classified into four groups according to a provisional definition based on predominant lesions and examination of their clinical features. Patients of cholestasis (n = 23) and giant cell hepatitis (GCH, n = 21) were most frequent (37% and 33%, respectively), and patients of fatty liver (n = 10) and hepatitis (n = 8) were less common (16% and 13%). The GCH group showed a dominance of male, low birthweight, older and breast-fed babies. The cholestasis group demonstrated a dominance of male, low birthweight, younger and bottle-fed babies. The hepatitis group had the highest frequencies of high-grade hepatomegaly and splenomegaly. Fifty six cases completely recovered. Two died of hepatic failure in early infancy and four had chronic liver diseases at the age of 12 months. The fatty liver group had the worst outcome. Histological features in non-familial INH were variable and typical giant cell hepatitis was seen in only one-third of patients. Characteristic clinical features in each histologically classified group may suggest heterogenous etiologies underlying non-familial INH.

The relationship between serum transaminase activities and fatty liver in children with simple obesity.

To determine hepatic diseases in obese children, biochemically and histologically, 11 obese patients with abnormal serum transaminase activities were subjected to this study. Fat accumulation in the liver was semiquantitatively graded, and histologically the 11 patients were classified into four groups; fatty liver, fatty hepatitis, fatty fibrosis and fatty cirrhosis. All patients had fat deposition in liver specimens, the grade of which did not significantly correlate with the degree of obesity. The grade of fat deposition in the liver specimens also did not significantly correlate with either serum transaminase activities or GOT/GPT ratio. Five patients were grouped into the fatty liver group, three into the fatty hepatitis group, and the remaining three patients into the fatty fibrosis group. However, no significant differences were found among the three histologically classified groups in terms of serum transaminase activities or GOT/GPT ratio. The usefulness of serum transaminase activities and GOT/GPT ratio was limited in predicting the severity of fat deposition or histological abnormality in pediatric obese patients.

Detection of neoplastic clone in the hypoplastic and recovery phases preceding acute lymphoblastic leukemia by in vitro amplification of rearranged T-cell receptor delta chain gene.

This study assessed the clonality of hypoplastic and subsequent recovery phases before the development of overt leukemia by molecular genetic analysis. We describe a boy who had transient granulocytopenia and anemia before the development of acute lymphoblastic leukemia (ALL). Initially, his bone marrow was hypocellular with 23.6% of lymphoblastic cells, whereas subsequent marrow after the administration of granulocyte colony-stimulating factor (G-CSF) appeared almost normal without any lymphoblasts. At diagnosis, we found the rearrangement of T cell receptor (TCR) delta gene in the leukemic cell DNA by Southern blot hybridization. The junctional sequence of the V delta 2-D delta 3 recombination of leukemic cells obtained by polymerase chain reaction (PCR) was used for a clonospecific probe. Using the probe, the presence of leukemic clone in the materials before and after diagnosis was examined. We found that the clonospecific probe could detect one leukemic cell in 10,000 normal cells, and we demonstrated the presence of the leukemic clone at the initial hypoplastic and the subsequent recovery phase. The PCR method is very useful to confirm the presence of leukemic clone even in a retrospective analysis using low-quality materials and may be helpful to understand the pathogenesis of a smoldering preleukemic phase.

A case of glycogen storage disease type III (glycogen debranching enzyme deficiency) with liver cirrhosis and hypertrophic cardiomyopathy.

We present a 26-year-old woman with glycogen storage disease type III (debranching enzyme deficiency) complicated with liver cirrhosis and hypertrophic cardiomyopathy. Glycogen debranching enzyme has two catalytic sites, oligo-1,4,-1,4- glucantransferase (EC 2.4.1.25) and amylo-1,6-glucosidase (EC 3.2.1.33). Variability in the clinical phenotype could be a function of the involvement of one or other catalytic site, or differences in tissue expression of the defective enzyme, or both. We hypothesize that some subtypes of glycogen storage disease (GSD) type III may cause liver cirrhosis as seen in GSD type IV due to the accumulation of glycogen of abnormal structure.

A case of fatal infectious mononucleosis presenting with fulminant hepatic failure associated with an extensive CD8-positive lymphocyte infiltration in the liver.

We describe a fatal case of infectious mononucleosis presenting with fulminant hepatic failure associated with extensive CD8-positive lymphocyte infiltration and diffuse karyorrhexis in the liver. Immunohistochemical analysis of mononuclear cells showed that Leu-2a (CD8)-positive lymphocytes were heavily distributed in the portal areas and the sinusoidal spaces, but Leu-3a (CD4)-, Leu-14 (CD22)-, or My 4 (CD14)-positive cells were undetectable in sections of the liver. Southern blot hybridization studies disclosed the presence of Epstein-Barr virus DNA fragments in the liver tissue. The unusual pathologic and immunologic responses observed in this case could not simply be explained by severe Epstein-Barr virus infection. Some superimposed factors should be considered.

Hepatocellular carcinoma in children with hepatitis B surface antigen.

This study discusses four children of hepatocellular carcinoma (HCC) who were asymptomatic HBsAg carriers or had HBsAg-positive chronic hepatitis for 3 to 11 years before the occurrence of the carcinoma. Three of these four patients were positive for anti-HBe at 3 to 5 years before the diagnosis of hepatocellular carcinoma. Autopsy findings disclosed liver cirrhosis in all the four patients. To the best of our knowledge few reports have documented children in HBsAg carrier status or with HBsAg-positive hepatitis prior to the development of hepatocellular carcinoma. It is emphasized that HBsAg-positive children, with or without detectable hepatic lesions in routine examinations, have a possibility of developing HCC, and should be carefully monitored for long periods.