Aldo-keto reductase family 1 member B10 is associated with hepatitis B virus-related hepatocellular carcinoma risk.

AIM: Recent reports have indicated that aldo-keto reductase family 1 member B10 (AKR1B10), a cancer-related oxidoreductase, was upregulated in some chronic liver diseases. However, few studies have reported AKR1B10 expression in chronic hepatitis B virus (HBV)-infected patients. The aim of the present study was to analyze AKR1B10 expression and its relevance on hepatocellular carcinoma (HCC) development in patients with chronic HBV infection. METHODS: Expression of AKR1B10 in the liver of 119 chronic HBV-infected patients was assessed and quantified immunohistochemically. A multivariate Cox model was used to estimate the hazard ratios of AKR1B10 expression for HCC development. The cumulative incidences of HCC were evaluated using Kaplan-Meier analysis. RESULTS: Expression of AKR1B10 in the study cohort ranged from 0% to 84%. During the median follow-up time (6.2 years), 13 patients developed HCC. Multivariate analysis revealed that high AKR1B10 expression (≥15%) was an independent risk factor for HCC (hazard ratio, 10.8; 95% confidence interval, 3.0-38.6; P < 0.001). The 5-year cumulative incidences of HCC were 20.6% and 2.6% in patients with high and low AKR1B10 expression, respectively (P < 0.001). Patients with high AKR1B10 expression had significantly higher alanine aminotransferase levels during follow-up than those with low expression, even though antiviral treatment decreased HBV-DNA levels in both groups. CONCLUSION: Chronic HBV-infected patients with high hepatic AKR1B10 expression had an increased risk of HCC development. This suggests that AKR1B10 upregulation might play a role in the early stages of HBV-related hepatocarcinogenesis.

Impact of aldo-keto reductase family 1 member B10 on the risk of hepatitis C virus-related hepatocellular carcinoma.

BACKGROUND AND AIM: Aldo-keto reductase family 1 member B10 (AKR1B10), a cancer-related oxidoreductase, was recently reported to be upregulated in some chronic liver diseases. However, its relevance in hepatocellular carcinoma (HCC) development is not fully assessed, especially in patients with chronic hepatitis C virus (HCV) infection. METHODS: Aldo-keto reductase family 1 member B10 expression in the liver of 550 patients with chronic HCV infection was immunohistochemically assessed and quantified. A multivariate Cox model was used to estimate the hazard ratios (HRs) of AKR1B10 expression for HCC development, and the cumulative incidence of HCC was evaluated using the Kaplan-Meier method. RESULTS: Aldo-keto reductase family 1 member B10 expression in the patients ranged from 0% to 80%. During the median follow-up of 3.2 years, 43 of 550 patients developed HCC. Multivariate analysis demonstrated that high AKR1B10 expression (≥6%) was an independent risk factor for HCC (HR, 6.43; 95% confidence interval, 2.90-14.25; P < 0.001). The 5-year cumulative incidences of HCC were 22.8% and 2.2% in patients with high and low AKR1B10 expression, respectively (P < 0.001). In subgroup analyses, the effects of high AKR1B10 expression on HCC development risk were significant over strata. In particular, HRs attributed to high AKR1B10 expression were significant in the subgroups that had been considered at a lower risk of HCC, such as in patients with younger age and mild hepatic fibrosis or those who achieved sustained virological response after interferon therapy. CONCLUSION: Various degrees of AKR1B10 upregulation in the liver were observed in patients with chronic HCV infection, and high AKR1B10 expression could be a novel predictor of HCC.

Prediction of Hepatocellular Carcinoma Development after Hepatitis C Virus Eradication Using Serum Wisteria floribunda Agglutinin-Positive Mac-2-Binding Protein.

We aimed to clarify the association between a novel serum fibrosis marker, Wisteria floribunda agglutinin-positive Mac-2-binding protein (WFA⁺-M2BP), and hepatocellular carcinoma (HCC) development in 355 patients with chronic hepatitis C who achieved sustained virologic response (SVR) through interferon-based antiviral therapy. Pretreatment serum WFA⁺-M2BP levels were quantified and the hazard ratios (HRs) for HCC development were retrospectively analyzed by Cox proportional hazard analysis. During the median follow-up time of 2.9 years, 12 patients developed HCC. Multivariate analysis demonstrated that high serum WFA⁺-M2BP (≥2.80 cut off index (COI), HR = 15.20, p = 0.013) and high fibrosis-4 (FIB-4) index (≥3.7, HR = 5.62, p = 0.034) were independent risk factors for HCC development. The three- and five-year cumulative incidence of HCC in patients with low WFA⁺-M2BP were 0.4% and 0.4%, respectively, whereas those of patients with high WFA⁺-M2BP were 7.7% and 17.6%, respectively (p < 0.001). In addition, combination of serum WFA⁺-M2BP and FIB-4 indices successfully stratified the risk of HCC: the five-year cumulative incidences of HCC were 26.9%, 6.8%, and 0.0% in patients with both, either, and none of these risk factors, respectively (p < 0.001). In conclusion, pretreatment serum WFA⁺-M2BP level is a useful predictor for HCC development after achieving SVR.

Prediction of liver stiffness hepatocellular carcinoma in chronic hepatitis C patients on interferon-based anti-viral therapy.

BACKGROUND AND AIM: The purpose of this study was to evaluate the usefulness of liver stiffness measurement (LSM) for assessing the risk of hepatocellular carcinoma (HCC) in chronic hepatitis C (CHC) patients receiving interferon (IFN) therapy. METHODS: One hundred fifty-one CHC patients who underwent LSM and received IFN therapy were included in the estimation cohort, and 56 were included in the validation study. The cumulative HCC incidences were evaluated using Kaplan-Meier plot analysis and the log-rank test. Multivariate Cox proportional hazard analyses were used to estimate the hazard ratios (HRs) of variables for HCC. RESULTS: In the estimation cohort, 9 of 151 patients developed HCC during the median follow-up time of 722 days. Multivariate analysis identified three independent risk factors for HCC: LSM (≥ 14.0 kPa, HR 5.58, P = 0.020), platelet count (< 14.1 × 10(4) /µL, HR 5.59, P = 0.034), and non-sustained virological response (HR 8.28, P = 0.049). The cumulative incidence of HCC development at 3 years was 59.6%, 8.2%, and 0.0% in patients with all three risk factors, one to two risk factors, and none of these risk factors, respectively. The incidence of HCC was significantly different between these groups (P < 0.001). In the validation cohort, HCC incidence was also significantly different with respect to these risk factors (P = 0.037). CONCLUSION: LSM, platelet count, and IFN-therapeutic effect could be used to successfully stratify the risk of HCC in patients receiving IFN therapy and demonstrate the usefulness of LSM before IFN therapy for the management of CHC patients.

Expression of aldo-keto reductase family 1 member b10 in the early stages of human hepatocarcinogenesis.

Aldo-keto reductase family 1, member B10 (AKR1B10), a cancer-related oxidoreductase, is expressed in well-differentiated hepatocellular carcinomas (HCCs). However, AKR1B10 levels are minimal in normal liver tissues (NLs), similar to the 70-kilodalton heat shock protein (HSP70) and glypican-3. Moreover, the role of AKR1B10 in chronic hepatitis or cirrhosis, which are considered preneoplastic conditions for HCC, has not been fully elucidated. The aim of this study was to evaluate the expression of AKR1B10, HSP70, and glypican-3 in 61 HCC tissue samples compared to corresponding non-tumorous liver tissues (NTs), comprising 42 chronic hepatitis and 19 cirrhosis cases to clarify the significance of molecular changes at the preneoplastic stages of HCC. Immunohistochemical analysis demonstrated that the median expression levels of AKR1B10 were higher in HCCs than in NTs (p<0.001) and higher in NTs than NLs (p<0.001) with 54.8%, 2.1%, and 0.3% expression in HCCs, NTs, and NLs, respectively. HSP70 and glypican-3 were expressed in HCCs, but minimally in NTs and NLs with no significant difference between expression in NTs and NLs. Furthermore, a multivariate analysis identified an association between hepatic steatosis and AKR1B10 expression in NTs (p=0.020). Of the three protein expressed in well-differentiated HCCs, only AKR1B10 was upregulated in preneoplastic conditions, and a steatosis-related factor might influence its expression.

Up-regulated aldo-keto reductase family 1 member B10 in chronic hepatitis C: association with serum alpha-fetoprotein and hepatocellular carcinoma.

BACKGROUND: Elevated serum alpha-fetoprotein (AFP) is not only a diagnostic marker for hepatocellular carcinoma (HCC), but is also a risk factor for HCC in chronic hepatitis C patients who do not have HCC. AIM: The aim was to analyse the hepatic gene expression signature in chronic hepatitis C patients with elevated AFP, who were at high risk for HCC. METHODS: Liver tissue samples from 48 chronic hepatitis C patients were stratified by their serum AFP levels and analysed for gene expression profiles. The association between aldo-keto reductase family 1 member B10 (AKR1B10) expression and serum AFP was confirmed by quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR) and immunohistochemical analyses. A matched case-control study was performed to evaluate the risk of AKR1B10 expression for HCC development. RESULTS: Distinct hepatic gene expression patterns were demonstrated in patients with elevated AFP (≥10 ng/mL) and normal AFP (<10 ng/mL). Of the 627 differently expressed genes, the most abundantly expressed gene in patients with elevated AFP was AKR1B10 (fold change, 26.2; P < 0.001), which was originally isolated as an overexpressed gene in human HCC. The qRT-PCR and immunohistochemical studies confirmed a proportional correlation between AKR1B10 expression and serum AFP. A matched case-control study identified that AKR1B10 up-regulation (>6%) was an independent risk factor for HCC development (hazard ratio, 21.4; P = 0.001). CONCLUSION: AKR1B10 was up-regulated in association with serum AFP, and was an independent risk factor for HCC in chronic hepatitis C patients, suggesting its possible involvement at a very early stage of hepatocarcinogenesis.

[A case of hepatocellular carcinoma rapidly progressing after percutaneous radiofrequency ablation successfully treated with low-dose 5-FU and CDDP].

A 65-year-old Japanese man was admitted to our hospital for treatment of hepatocellular carcinoma (HCC) with alcoholic liver cirrhosis. He had been treated by transarterial chemoembolization (TACE) in another hospital before this admission. In our hospital, percutaneous radiofrequency ablation (PRFA) to HCC (2.5 cm diameter) in hepatic S8 was done, and the tumor was ablated completely with the treated margin. After 8 months of the PRFA procedure, abdominal CT revealed diffused-type HCC located in contact with the post RFA area and was diagnosed as a local recurrence of HCC. He was then treated with hepatic arterial infused chemotherapy, low-dose 5-FU and CDDP (FP); one course consisted of (5-FU 250 mg/day + CDDP 10 mg/day) x 5 days/w x 4 wks using a port-infusion system. He was treated with 3 courses of low-dose FP, and the diffuse-type HCC was completely diminished. No recurrence was seen 22 months after chemotherapy. Although rapidly progressing recurrent HCC after PRFA is potentially fatal and useful treatments have only rarely been reported, hepatic arterial infusion chemotherapy including low-dose FP should be considered a possible treatment.

Portal Vein Thrombosis in a Patient with Hereditary Antithrombin Deficiency.

Portal vein thrombosis (PVT) has been reported in many patients with and without liver cirrhosis. The portal vein is a rare site of thrombosis, and various conditions can predispose an individual to PVT. Among those conditions, hereditary thrombophilia has been increasingly reported recently. We herein report the case of a non-cirrhotic 30-year-old man who developed acute PVT with hereditary antithrombin deficiency. Antithrombin (AT) replacement therapy was required along with heparin. Given our experience with this case, we believe that a screening test for prothrombotic disorders, such as AT deficiency, should be considered in cases of PVT.

Pretreatment AKR1B10 expression predicts the risk of hepatocellular carcinoma development after hepatitis C virus eradication.

AIM: To clarify the association between aldo-keto reductase family 1 member B10 (AKR1B10) expression and hepatocarcinogenesis after hepatitis C virus eradication. METHODS: In this study, we enrolled 303 chronic hepatitis C patients who had achieved sustained virological response (SVR) through interferon-based antiviral therapy. Pretreatment AKR1B10 expression in the liver was immunohistochemically assessed and quantified as a percentage of positive staining area by using image-analysis software. A multivariate Cox analysis was used to estimate the hazard ratios (HRs) of AKR1B10 expression for hepatocellular carcinoma (HCC) development after achieving SVR. The cumulative incidences of HCC development were evaluated using Kaplan-Meier analysis and the log-rank test. RESULTS: Of the 303 chronic hepatitis C patients, 153 (50.5%) showed scarce hepatic AKR1B10 expression, quantified as 0%, which was similar to the expression in control normal liver tissues. However, the remaining 150 patients (49.5%) exhibited various degrees of AKR1B10 expression in the liver, with a maximal AKR1B10 expression of 73%. During the median follow-up time of 3.6 years (range 1.0-10.0 years), 8/303 patients developed HCC. Multivariate analysis revealed that only high AKR1B10 expression (≥ 8%) was an independent risk factor for HCC development (HR = 15.4, 95%CI: 1.8-132.5, P = 0.012). The 5-year cumulative incidences of HCC development were 13.7% and 0.5% in patients with high and low AKR1B10 expression, respectively (P < 0.001). During the follow-up period after viral eradication, patients expressing high levels of AKR1B10 expressed markedly higher levels of alanine aminotransferase and α-fetoprotein than did patients exhibiting low AKR1B10 expression. CONCLUSION: Chronic hepatitis C patients expressing high levels of hepatic AKR1B10 had an increased risk of HCC development even after SVR.

Functional analysis of transactivation by mutants of hepatitis B virus X gene in human hepatocellular carcinoma.

The X protein of the hepatitis B virus transactivates various cellular and viral promoters and enhancers. In this study, wild-type and mutants of the X gene, including the point mutations at codons 130 (AAG-->ATG, lysin-->methionine) and 131 (GTC-->ATC, valine-->isoleucine), commonly found in patients with human hepatocellular carcinoma (HCC), or deletions encompassing the same region, were cloned and inserted into expression vectors. Functional analysis of the mutants of the X gene was performed on the long terminal repeat of the Rous sarcoma virus in a transient transfection assay. A transactivating function was observed in the vector containing point mutations at codons 130 and 131 at the same level as that of wild-type X gene. Two constructs, each containing a different type of 8-nucleotide deletion mutant (codons 128-130 or 130-132,) dramatically lost their transactivating function. These findings suggest that the transactivating function is not necessarily associated with the development of HCC, and that not only transactivation by the X gene but also the mutation-enhanced oncogenic potential of the gene products could contribute to hepatocarcinogenesis.

Differences in the factors associated with serum viral load between genotypes 1 and 2 in patients with chronic hepatitis C.

PURPOSE: The serum hepatitis C virus (HCV) load is persistently stable in patients with untreated chronic hepatitis C, but its differences between individuals vary widely (above 4 logU/mL). Because serum viral load is an important factor for predicting clinical outcome of interferon-based antiviral therapy, this study was performed to clarify the factors associated with serum viral load in chronic hepatitis C patients. METHODS: We retrospectively analyzed data from 669 chronic hepatitis C patients with HCV genotype 1 or 2 infection. Stepwise regression analysis was used to estimate the relationship between demographic, viral, or biochemical variables and serum viral load. RESULTS: In univariate analysis, serum lipid profiles, such as total cholesterol, low-density lipoprotein (LDL) and triglyceride levels, and hemoglobin A1c (HbA1c) were correlated with the serum HCV viral load. In multivariate analysis, HCV genotype 1 infection and higher total cholesterol levels were associated with higher viral load. After stratification by HCV genotype, the serum viral load was associated with triglyceride and HbA1c in genotype 1 and with platelet counts and LDL in genotype 2. Histological data (413 patients) showed correlation between severe liver fibrosis and decreased serum viral load in patients with HCV genotype 2 but not genotype 1 infection. CONCLUSIONS: These results suggest that viral kinetics is affected by different host factors for genotypes 1 and 2.

Association of visceral obesity with high viral load and histological findings in elderly patients with genotype 1 chronic hepatitis C.

OBJECTIVE: Genotype 1 chronic hepatitis C (G1CHC) is generally accompanied by metabolic disturbances related to visceral obesity, such as insulin resistance, steatosis, or dyslipidemia. Because these abnormalities negatively influence the clinical course of G1CHC, we sought to clarify the effect of visceral obesity on the pathophysiology of G1CHC. METHODS: We evaluated 180G1CHC patients for the presence of visceral obesity on the basis of computed tomography findings. Multivariate analysis was performed to estimate the relationship between visceral obesity and demographic, viral, and biochemical characteristics of patients. The associations of visceral obesity with histological findings and serum adipokine levels were also analyzed. RESULTS: Multiple logistic regression analysis revealed that visceral obesity was independently associated with metabolic syndrome, platelet count, high-density lipoprotein level, and serum viral load in elderly patients (≥65 years). Multiple linear regression analysis confirmed the association between visceral obesity and high viral load. However, visceral obesity was not correlated with viral load in non-elderly patients (<65 years). Histological data (160 patients) demonstrated the significant association between visceral obesity and steatosis. Furthermore, patients with visceral obesity showed increase in the severity of fibrosis with advancing age. However, age-associated fibrosis progression was not evident in patients without visceral obesity. The serum adiponectin level was significantly low in patients with visceral obesity, whereas those of leptin, tumor necrosis factor-α, and interleukin-6 were not affected significantly. CONCLUSION: Visceral obesity was associated with high viral load and histological damage in elderly patients with reduced adiponectin levels.

A study of the effects of saliva stimulation by nizatidine on dry mouth symptoms of primary biliary cirrhosis.

AIM: To elucidate the effect of saliva stimulation by nizatidine on oral symptoms of primary biliary cirrhosis (PBC) by administering it to PBC cases. METHODS: From among 73 cases that had been definitively diagnosed as PBC at our hospital by February 2010, we selected 27 cases of PBC, 4 males and 23 females, as subjects. We obtained subjects' consent after giving them a full explanation of the administration of nizatidine. Nizatidine 150 mg was administered internally twice daily, after morning and evening meals. To observe changes in the quantity of saliva secreted, chewing gum tests were carried out four times: before the initial dose, and after 6 mo, 12 mo and 24 mo of administration. For subjective dry mouth symptoms, a visual analog scale (VAS) method was used to assess their feelings of oral dryness and eating difficulty, five times: before the initial dose, and after 1, 6, 12 and 24 mo of administration in 8 cases. The nutritional condition and the hepatic functional reserve were compared between before and after the nizatidine treatment. RESULTS: The result of a chewing gum test on the subjects before the administration of nizatidine showed that 50% produced less than 10 mL of saliva, i.e., the standard under which cases are considered to have hyposalivation. The results of these tests showed that the quantity of saliva secreted was 10.5 ± 6.8 mL before administration of nizatidine, 10.9 ± 6.0 mL after 6 mo, 10.6 ± 4.9 mL after 12 mo, and 11.8 ± 6.8 mL after 24 mo administration. Thus, there was a slowly increasing trend in the quantity of saliva in the whole group. The percentage of subjects with saliva production above 10 mL was 45.8% after 6 mo administration of nizatidine, that is, only a slight change from before its administration, but it was 64.3% after 12 mo, that is, a significant increase. The saliva secretion by subject patients was examined before the beginning of administration of nizatidine, 12 mo later, and 24 mo later, and Fisher's combined probability test was used to examine the results for increases in saliva secretion. The analysis yielded P values of 0.51 and 0.53 for 12 mo later and 24 mo later, respectively. Thus, although there was no statistically significant increase, it was confirmed that saliva secretion tended to increase. A VAS method was employed to study the intensities of subjective symptoms of oral dryness and eating difficulty. Almost every case indicated some improvement of subjective oral dryness on the VAS early in the administration, i.e., one month after. We also studied the effects of the administration of nizatidine on nutritional condition, hepatic functional reserve, and long-term prognosis of PBC. No significant improvements in cholinesterase (ChE) level, albumin (Alb) level, or Child-Pugh score were found during the period of observation from the beginning to the end of administration of nizatidine, nor in comparison with the non-administration group. A comparative analysis between before administration and 24 mo later yielded P values of 0.41 for Alb, 0.56 for ChE, and 0.59 for the Child-Pugh scores. CONCLUSION: It was confirmed that administering nizatidine to cases of PBC with dry mouth increased the secretion of saliva and improved the symptoms.

Clinical characteristics of patients who developed hepatocellular carcinoma after hepatitis C virus eradication with interferon therapy: current status in Japan.

OBJECTIVE: We attempted to elucidate the clinical features of chronic hepatitis C patients who develop hepatocellular carcinoma (HCC) after achieving a sustained viral response (SVR) to interferon (IFN) therapy. METHODS: The clinical features of 130 patients at 19 hospitals who developed HCC after obtaining an SVR were retrospectively reviewed. RESULTS: Overall, 107 (82%) of the 130 patients were men, with 92 (71%) being ≥60 years of age and 76, 38 and 16 developing HCC within 5, 5-10 and 10-16.9 years after IFN therapy, respectively. Before receiving IFN therapy, 92 (71%) patients had cirrhosis and/or a low platelet count (<15×10(4) cells/µL). Lower albumin (<3.9 g/dL) and higher alpha fetoprotein (AFP) (≥10 ng/mL) levels were identified in a multivariate analysis to be independent variables of the development of HCC within five years after IFN therapy. Among 4,542 SVR patients, HCC occurred in 109 (2.4%) during a 5.5-year follow-up period, thus resulting in an occurrence rate of 4.6% for men and 0.6% for women. CONCLUSION: SVR patients with lower albumin or higher AFP levels require careful assessments to prevent early HCC development after IFN therapy. HCC occurrence within >10 years of IFN therapy is not uncommon, and the risk factors remain uncertain, thus suggesting that all SVR patients should undergo long-term follow-up examinations for HCC development.

Recommendation of lamivudine-to-entecavir switching treatment in chronic hepatitis B responders: Randomized controlled trial.

AIM: In the 2007-2008 guidelines of the study group (Ministry of Health, Labor and Welfare of Japan), lamivudine (LAM)-continuous treatment was recommended in patients treated with LAM for more than 3 years who maintained hepatitis B virus (HBV) DNA less than 2.6 log copies/mL, because in these patients LAM resistance might exist and switching treatment to entecavir (ETV) might cause ETV resistance. However, there was no evidence on whether switching treatment to ETV- or LAM-continuous treatment was better in those patients. In the present study, we performed a randomized controlled trial of LAM-to-ETV switching treatment. METHODS: Twenty-seven patients treated with LAM for more than 3 years whose HBV DNA levels were less than 2.6 log copies/mL were enrolled and randomly divided into two groups, LAM-continued group or switching to ETV group. Then, we examined incidence of virological breakthrough (VBT) and breakthrough hepatitis (BTH) in each group. RESULTS: There was no BTH in any of the patients. VBT was observed in six patients of the LAM group (6/15, 40%), and no patient of the ETV group (0/11, 0%) (P = 0.02). The differences of the proportion of cumulated VBT using a log-rank test with Kaplan-Meier analysis were significant between the LAM and ETV groups (P = 0.025). CONCLUSION: In patients treated with LAM for more than 3 years maintaining HBV DNA less than 2.6 log copies/mL, switching treatment to ETV is recommended at least during the 2 years' follow-up period.

Docetaxel inhibits progression of human hepatoma cell line in vitro and is effective in advanced hepatocellular carcinoma.

BACKGROUND: Current chemotherapy for advanced hepatocellular carcinoma (HCC) is insufficient; only sorafenib has been proven to provide a modest survival benefit. A future direction of chemotherapy is to tailor treatment based on the chemosensitivity of each individual tumor. By doing so, only patients who stand to benefit from therapy will be exposed to potential side-effects and morbidity. Although the use of docetaxel (DTX) for the treatment of lung, breast and gastric cancer has been reported, there are few reports about its use in the setting of HCC. METHODS: To examine the efficacy of DTX for HCC, we established a human hepatoma cell line (TK cell) from the patient's malignant ascites from peritoneal carcinomatosis and treated it with DTX in vitro. RESULTS: After we confirmed the efficacy of DTX in vitro, we treated our patient with DTX with positive results. CONCLUSION: In this study, we present a therapeutic approach by using DTX that supports the potential usefulness of personalized medicine in vitro and demonstrates it clinically.

Development of osteomalacia in a post-liver transplant patient receiving adefovir dipivoxil.

We report the case of a patient treated with living donor-related liver transplantation who suffered from osteomalacia during adefovir dipivoxil (ADV)-containing antiviral therapy for lamivudine-resistant hepatitis B virus infection. The patient had generalized bone pain, with severe hypophosphatemia after 20 mo of ADV therapy. Radiographic studies demonstrated the presence of osteomalacia. The peak plasma ADV level was 38 ng/mL after administration of ADV at 10 mg/d. It was also found that ADV affected the metabolism of tacrolimus, a calcineurin-inhibitor, and caused an increase in the plasma levels of tacrolimus. The disability was reversed with the withdrawal of ADV and with mineral supplementation. ADV can cause an elevation of plasma tacrolimus levels, which may be associated with renal dysfunction. High levels of ADV and tacrolimus can cause nephrotoxicity and osteomalacia. This case highlights the importance of considering a diagnosis of osteomalacia in liver transplantation recipients treated with both ADV and tacrolimus.

Dietary supplement implicated in fulminant hepatic failure in a well-controlled Wilson disease patient.

We encountered a patient with previously well-controlled Wilson disease who experienced fulminant hepatic failure with hemolytic anemia, possibly caused by the dietary supplement Health Proportion(®) (Jubilant Co., Ltd., Ehime, Japan). A 21-year-old woman was admitted to our hospital with marked liver dysfunction and severe hemolytic anemia. Free serum copper level was elevated at 101 µg/dl, and urinary copper excretion was extremely increased (25,600 µg/day). Plasma exchange and continuous hemodiafiltration were performed to remove serum copper and to treat the hemolytic anemia. However, liver function did not improve, and she underwent liver transplantation on 28th day after admission. Copper and iron contents in the resected liver were high at 851.9 µg and 551.7 µg/dry liver weight (g), respectively, despite the patient having regularly taken D-penicillamine since diagnosis and having a well-controlled copper level 1 year before her admission. Two months before admission, the patient had taken a dietary supplement made from soybeans for 1 month. This supplement was labeled as containing large amounts of copper and iron, and we assume that this caused fulminant hepatic failure with hemolytic crisis in this patient. It is important to be mindful of the micronutrient content of dietary supplements, especially for metabolic disorder patients.

CTLA-4Ig suppresses liver injury by inhibiting acquired immune responses in a mouse model of fulminant hepatitis.

Expression of costimulatory molecules is significantly upregulated in various organs in an animal model of severe hepatitis induced by injection of Propionibacterium acnes (P. acnes) and lipopolysaccharide (LPS). In the present study, we examined whether blockade of costimulatory signals by CTLA-4Ig can suppress the liver injury in this model. We injected an adenovirus encoding CTLA-4Ig (AdCTLA-4Ig) into mice 7 days before, on the same day, or 3 days after P. acnes priming. The virus was found to infect the liver preferentially, and CTLA-4Ig was detected in the serum as early as 2 days after viral injection. After injection of LPS, liver injury and survival rates were examined. Most of the mice not injected with AdCTLA-4Ig died within 12 hours after injection of LPS. In contrast, all the AdCTLA-4Ig-injected mice survived when the virus was injected 7 days before or on the same day as P. acnes priming. Importantly, hemorrhagic liver injury and serum alanine aminotransferase levels were significantly reduced after LPS injection even when AdCTLA-4Ig was injected 3 days after P. acnes priming. Immunological analyses showed that CTLA-4Ig inhibited the activation and expansion of P. acnes-specific CD4+ T cells in the hepatic lymph nodes, leading to a reduction in the recruitment of the cells to the liver. The total amounts of interferon-gamma, interleukin-12, and various chemokines in the liver were then decreased, resulting in inhibition of the secondary recruitment of not only T cells but also macrophages. In conclusion, CTLA-4Ig could be useful for treatment of severe liver injury.