Tetsuro Sohda

Frequencies in the Japanese population of HFE gene mutations.

We studied the frequencies of C282Y and H63Dmutations in the HFE gene, thought to be responsible forhereditary hemochromatosis (HH), in 504 chromosomesobtained from 252 unrelated Japanese. Allele-specific PCR and PCRrestriction fragment lengthpolymorphism methods revealed that the C282Y mutationwas not found and the H63D mutation was low in frequency(at only 0.99%) compared with data from European people. Since most HH is thought to be associated withthe HFE gene mutation, the low incidence of thesemutations is a likely reason for the rarity of thisdisease in the Japanese population.

In situ detection of insulin-like growth factor II (IGF2) and H19 gene expression in hepatocellular carcinoma

AbstractTo assess the relationship between insulin-like growth factor II (IGF2) and H19 gene expression at the cellular level, we have examined the distribution of IGF2 and H19 mRNA by means of in situ hybridization in hepatic malignancies consisting of hepatocellular carcinoma (HCC), cholangiocellular carcinoma (CCC), and metastatic liver cancer (MLC). In HCC, 15 of 27 tumors (56%) and 11 of 27 tumors (41%) demonstrated increased IGF2 and H19 gene expression, respectively. Of 16 HCCs with increased expression of either IGF2 or H19, 10 tumors coexpressed both transcripts at comparable levels. Moreover, the spatiotemporal distribution and the cellular localization of the two gene transcripts were almost identical, suggesting the presence of a reciprocal relation between IGF2 and H19. In addition, 5 HCCs showed increased IGF2 expression without concomitant H19 expression, whereas 1 HCC showed increased H19 expression without IGF2 transcripts. However, 11 HCCs showed no IGF2 or H19 expression. On the other hand, neither IGF2 transcripts nor H19 transcripts were detected in 2 CCCs or 10 MLCs studied. The data suggest that IGF2 and/or H19 gene expression may be characteristic of some HCCs.

Levels of the Oxidative Stress Marker γ-Glutamyltranspeptidase at Different Stages of Nonalcoholic Fatty Liver Disease

OBJECTIVES: This study investigated oxidative stress in the liver, by determining hepatic expression and serum levels of γ-glutamyltranspeptidase (GGT) and 8-hydroxy-2′-deoxyguanosine (8-OHdG) in different stages of nonalcoholic fatty liver disease (NAFLD), and assessed whether GGT can differentiate between the various stages of NAFLD. METHODS: Expression of GGT and 8-OHdG was examined in biopsy specimens by immunohistochemistry, and serum GGT and 8-OHdG levels were measured by enzyme-linked immunosorbent assays in patients with simple fatty liver (n = 10), nonalcoholic steatohepatitis (NASH; n = 10) and, as a control, in alcoholic liver disease (ALD; n = 10). RESULTS: Hepatic tissue expression of GGT and 8-OHdG was seen in ALD, NASH and fatty liver patients. The percentage of hepatocytes positive for 8-OHdG expression and serum 8-OHdG levels was significantly higher in patients with NASH than simple fatty liver. Serum GGT levels were increased in all cases with ALD, NASH and fatty liver, and correlated significantly with serum levels of 8-OHdG in ALD and NASH, but not in simple fatty liver. CONCLUSIONS: Levels of GGT in fatty liver patients may compensate for mild oxidative stress by repressing 8-OHdG levels and preventing progression to NASH; however further oxidative stress leads to increased levels of 8-OHdG and the development of NASH.

Cholangiocellular carcinoma that produced both granulocyte-colony- stimulating factor and parathyroid hormone-related protein

A 56-year-old man was admitted to our hospital because of consciousness disturbance. Abdominal computed tomography revealed a large low-density tumor in the left lobe of the liver. He presented with marked leukocytosis and hypercalcemia with high levels of serum granulocyte-colony-stimulating factor (G-CSF) and parathyroid hormone-related protein (PTH-rP). A diagnosis of cholangiocellular carcinoma (CCC) of the liver was confirmed by histological examination of an autopsy specimen. The tumor cells showed positivity for both G-CSF and PTH-rP with immunohistochemical staining. These results suggest that the tumor was producing both G-CSF and PTH-rP. This paraneoplastic G-CSF and PTH-rP production caused by CCC is very rare. Such cases must be followed up carefully, since tumors associated with paraneoplastic syndrome progress rapidly, resulting in a poor prognosis.

Promoter-specific insulin-like growth factor 2 gene imprinting in human fetal liver and hepatoblastoma.

Insulin‐like growth factor 2 (IGF2) gene imprinting has been demonstrated to be promoter‐specific, in that expression from the P1 promoter is biallelic whereas that from the P2–P4 promoters is monoallelic. In the present study, in order to investigate IGF2 gene imprinting status at the cellular level, allelic analysis was performed of IGF2 gene expression transcribed from the P1 and P3 promoters, using reverse transcription polymerase chain reaction (RT‐PCR) on human fetal liver and hepatoblastoma. In situ hybridization was also undertaken, to obtain information about the cellular localization of transcripts expressed from the P1 and P3 promoters. The results indicated that transcripts expressed from the P1 and P3 promoters co‐localized in the same fetal or neoplastic hepatocytes. These data should provide information regarding the molecular basis of genomic imprinting, suggesting that an imprint recognized for the differential expression may be strictly local and localized downstream of the IGF2 P1 promoter.

Late‐evening snack with branched‐chain amino acids improves liver function after radiofrequency ablation for hepatocellular carcinoma

Aim:  This prospective study was designed to examine whether consumption of a branched‐chain amino acid (BCAA)‐enriched nutrient mixture as a late‐evening snack (LES) helps maintain and/or improve liver functioning in liver cirrhosis (LC) patients who have undergone radiofrequency ablation (RFA) for hepatocellular carcinoma (HCC).

Hemochromatosis with HFE gene mutation in a Japanese patient

A case of hemochromatosis associated with HFE gene mutation has never been previously reported in a Japanese patient. A 65-yr-old Japanese woman presenting with primary hemochromatosis underwent HFE mutation analyses, which demonstrated a C282Y mutation, this being the definitive gene mutation of Caucasian hemochromatosis.

CASE REPORT: Insulin ‐ like growth factor II expression in hepatocellular carcinoma with alcoholic liver fibrosis accompanied by hypoglycaemia

This case of hepatocellular carcinoma (HCC) with alcoholic liver fibrosis, which was not associated with hepatitis viruses, was accompanied by hypoglycaemia. The immunoreactive insulin level was low and other hormonal examinations were almost normal. Immunohistochemical studies showed a high level of insulin‐like growth factor II (IGF2) peptide in the HCC section and the size heterogeneity of serum IGF2 investigated by western blot revealed a large form at approximately 15 kDa. These results suggest that the HCC with alcoholic liver fibrosis produced IGF2 and that the hypoglycaemia was caused by tumour‐associated IGF2.

Sustained upregulation of sodium taurocholate cotransporting polypeptide and bile salt export pump and downregulation of cholesterol 7α-hydroxylase in the liver of patients with end-stage primary biliary cirrhosis

To examine the mRNA expression of hepatobiliary transporters in primary biliary cirrhosis (PBC) patients and to compare bile acid absorption, synthesis, and efflux in patients with non-end-stage and end-stage PBC, we obtained liver samples from PBC patients by percutaneous needle biopsy. End-stage PBC was defined as follows: histological stage IV; cirrhosis; serum total bilirubin, ≥4.0 mg/dl; and Child-Pugh Class C. The mRNA expression levels of sodium taurocholate cotransporting polypeptide (NTCP), bile salt export pump (BSEP), and hepatic cholesterol 7α-hydroxylase (CYP7A1) were significantly higher in the PBC patients than in the controls (P < 0.01). The mRNA levels of NTCP and BSEP were significantly higher in the end-stage PBC patients than in the controls (P < 0.01). However, hepatic CYP7A1 mRNA expression decreased significantly (by 70%) in the patients with end-stage PBC as compared to the controls and the patients with non-end-stage PBC (P < 0.01). The hepatic expression of transporters mediating bile acid influx and efflux showed sustained elevation, whereas that of the rate-limiting enzyme for bile acid biosynthesis was attenuated in the end-stage PBC patients. Thus, mechanisms may be present preventing the accumulation of toxic bile acids in the hepatocytes of end-stage PBC patients.

Nonalcoholic steatohepatitis associated with psoriasis vulgaris.

A 24-year-old man was admitted to our hospital because of liver dysfunction. He had been diagnosed as having psoriasis vulgaris at 18 years of age. Physical examination demonstrated obesity, general erythema, and hepatomegaly. Laboratory data revealed elevated serum levels of aspartate aminotransferase, alanine aminotransferase, lactate dehydrogenase, and glucose. A histological examination of the liver revealed macrovesicular fatty change and infiltration of inflammatory cells, including lymphocytes and polymorphonuclear cells, within the liver lobules. Pericentral fibrosis and pericellular fibrosis were also recognized. He was diagnosed as having nonalcoholic steatohepatitis (NASH), based on the fact that he had no habit of drinking alcohol, as well as psoriasis vulgaris and diabetes mellitus. We herein report a very rare case of NASH associated with psoriasis vulgaris.