Fujihiko Nishinomiya

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 schoolchildren (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/1, 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.

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.

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

A case of Downs 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 Downs 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 Downs 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 Downs syndrome.

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.

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.

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.

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.

Idiopathic neonatal hepatitis presenting as neonatal hepatic siderosis and steatosis.

Idiopathic neonatal hepatitis (INH) is aheterogenous disease of undetermined cause. We report aretrospective histologic reevaluation of INH. Sixtypatients with INH were reviewed along with 32 biliary atresia (BA) patients. Histologic findings,iron and fat deposits, giant cell transformation, portalfibrosis, and bile duct proliferation weresemiquantitatively graded from 0 to 4+. Significanthistologic findings were defined as ≥2+. Frequencies ofpatients with significant histologic findings in the INHgroup were compared with those of the BA group. Amongthe patients with significant histologic findings, those in the INH group had significantly lessiron deposits (P < 0.01), portal fibrosis (P <0.01), and bile duct proliferation (P < 0.01) thanthose of the BA group. A combination of significanthepatic macrovesicular steatosis and siderosis was observed in 10 INHpatients but not in any BA patient (10/60 vs 0/32, P< 0.05). Without extensive treatment, the 10 INHpatients all recovered, and hepatic abnormalitiesnormalized by the age of 12 months. In conclusion, thepresent study showed that the recognition of hepaticsiderosis is helpful to distinguish BA from INH and thatin a subset of INH patients hepatic macrovesicular steatosis and siderosis occurs.

Neonatal intrahepatic cholestasis with hepatic siderosis and steatosis

Abstract 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 supplement4–6 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.

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 (× 0.35 and × 0.22), whereas the numbers of female and breast‐milk feeding groups were close to the expected values (× 1.26 and × 1.08). When sex and feeding modality were combined, the formula‐milk fed male group showed the lowest value (× 0.10), and the breast‐milk fed female group showed the highest value (× 2.85). In conclusion, feeding type, especially in combination with gender, might be one causative factor in the occurrence of idiopathic neonatal hepatitis.