Long-term phlebotomy successfully alleviated hepatic iron accumulation in a ferroportin disease patient with a mutation in SLC40A1: a case report.

BACKGROUND: Hereditary hemochromatosis is a heterogenous group of inherited iron-overload conditions that is characterized by increased intestinal absorption and deposition in vital organs. Hepcidin is a soluble regulator that acts to attenuate both intestinal iron absorption and iron release from reticuloendothelial macrophages through internalization of ferroportin-1, an iron exporter. Ferroportin disease is hereditary hemochromatosis which is affected by SLC40A1, a gene coding ferroportin-1, and phenotypically classified into two forms (classical and nonclassical). In nonclassical form, ferroportin mutations are responsible for a gain of function with full iron export capability but insensitivity to downregulation by hepcidin. Here, we report a case of nonclassical ferroportin disease. CASE PRESENTATION: A 46-year-old Japanese man showed elevated serum iron (284 µg/dl), ferritin (1722 ng/ml), transferrin saturation ratio (91.3%), and hepcidin-25 level (139.6 ng/ml). Magnetic resonance imaging (MRI) demonstrated a marked reduction in the signal intensity of the liver in T1- and T2-weighted images. The liver histology exhibited a large amount of iron that had accumulated predominantly in hepatocytes. We identified a heterozygous 1520A > G (p.H507R) mutation in the SLC40A1 gene. Phlebotomy (400 ml at a time) was monthly performed for 3 years in this patient. Importantly, the serum hepcidin level (1.0 ng/ml) was normal when the serum ferritin level was normal and hepatic iron accumulation was remarkably reduced after 3 years of phlebotomy. CONCLUSIONS: The present case demonstrated for the first time that there was a correlation between hepatic iron levels as measured by MRI and serum hepcidin levels through long-term phlebotomy in a patient with ferroportin disease with the p.H507R mutation of in SLC40A1.

Gastric Hyperplastic Polyps after Argon Plasma Coagulation for Gastric Antral Vascular Ectasia in Patients with Liver Cirrhosis: A Case Suggesting the "Gastrin Link Theory".

We herein report a case of gastric hyperplastic polyps after argon plasma coagulation (APC) for gastric antral vascular ectasia (GAVE) in the antrum of a 65-year-old man with liver cirrhosis and hypergastrinemia induced by long-term proton pump inhibitor (PPI) use. Two years after APC therapy, endoscopy demonstrated multiple gastric polyps in the antrum and angle. A gastric polyp biopsy indicated foveolar epithelium hyperplasia, which was diagnosed as gastric hyperplastic polyps. One year after switching to an H2 blocker antagonist, endoscopy revealed that the polyps and GAVE had disappeared, with normal gastrin levels suggesting that PPI-induced hypergastrinemia had caused gastric hyperplastic polyps after APC therapy, and the polyps had disappeared after discontinuing PPIs.

Branched-chain amino acids reduce hepatic iron accumulation and oxidative stress in hepatitis C virus polyprotein-expressing mice.

BACKGROUND & AIMS: Branched-chain amino acids (BCAA) reduce the incidence of hepatocellular carcinoma (HCC) in patients with cirrhosis. However, the mechanisms that underlie these effects remain unknown. Previously, we reported that oxidative stress in male transgenic mice that expressed hepatitis C virus polyprotein (HCVTgM) caused hepatic iron accumulation by reducing hepcidin transcription, thereby leading to HCC development. This study investigated whether long-term treatment with BCAA reduced hepatic iron accumulation and oxidative stress in iron-overloaded HCVTgM and in patients with HCV-related advanced fibrosis. METHODS: Male HCVTgM were fed an excess-iron diet that comprised either casein or 3.0% BCAA, or a control diet, for 6 months. RESULTS: For HCVTgM, BCAA supplementation increased the serum hepcidin-25 levels and antioxidant status [ratio of biological antioxidant potential (BAP) relative to derivatives of reactive oxygen metabolites (dROM)], decreased the hepatic iron contents, attenuated reactive oxygen species generation, and restored mitochondrial superoxide dismutase expression and mitochondrial complex I activity in the liver compared with mice fed the control diet. After 48 weeks of BCAA supplementation in patients with HCV-related advanced fibrosis, BAP/dROM and serum hepcidin-25 increased and serum ferritin decreased compared with the pretreatment levels. CONCLUSIONS: BCAA supplementation reduced oxidative stress by restoring mitochondrial function and improved iron metabolism by increasing hepcidin-25 in both iron-overloaded HCVTgM and patients with HCV-related advanced fibrosis. These activities of BCAA may partially account for their inhibitory effects on HCC development in cirrhosis patients.

Risk factors for survival and the development of hepatocellular carcinoma in patients with primary biliary cirrhosis.

OBJECTIVE: Early diagnosis of hepatocellular carcinoma (HCC) is critical in the management of patients with primary biliary cirrhosis (PBC), since the prognosis of PBC has improved. The aim of this study was to investigate whether HCC development affects the prognosis of PBC and to identify the risk factors for HCC in Japanese patients with PBC. METHODS: We compared the survival rates between patients with HCC and those without and analyzed the risk factors for HCC development in 210 patients with PBC who were followed up for a median period of 8.5 years. RESULTS: HCC developed during follow-up in 11 patients (5.2%) and was diagnosed simultaneously at the time of diagnosis of PBC in five patients (2.4%) who were excluded from the analysis. A Kaplan-Meier analysis showed a significant difference in overall survival between the patients who did and did not develop HCC (p<0.001). A multivariate analysis revealed age (OR: 1.08, 95% confidence interval [CI]: 1.03-1.13, p=0.001), the albumin level (OR: 0.24, 95% CI: 0.10-0.56, p=0.001), the total bilirubin level (OR: 1.60, 95% CI: 1.09-2.36, p=0.017) and HCC development (OR: 2.97, 95% CI: 1.24-7.15, p=0.015) to be significant prognostic factors and identified only an advanced histological stage (Scheuer's classification III or IV, OR: 6.27, 95% CI: 1.80-21.83, p=0.004) to be a risk factor associated with HCC. CONCLUSION: HCC development significantly affects the survival of patients with PBC, and an advanced histological stage is the only risk factor associated with HCC development. These results highlight the important role of liver fibrosis in hepatocarcinogenesis in patients with PBC.

Clinical usefulness of non-protein respiratory quotient measurement in non-alcoholic fatty liver disease.

AIM: Little is known about the effects of non-alcoholic fatty liver disease (NAFLD) on energy metabolism, although this disease is associated with metabolic syndrome. We measured non-protein respiratory quotient (npRQ) using indirect calorimetry, which reflects glucose oxidation, and compared this value with histological disease severity in NAFLD patients. METHODS: Subjects were 32 patients who were diagnosed with NAFLD histopathologically. Subjects underwent body composition analysis and indirect calorimetry, and npRQ was calculated. An oral glucose tolerance test was performed, and plasma glucose area under the curve (AUC glucose) was calculated. RESULTS: There were no differences in body mass index, body fat percentage or visceral fat area among fibrosis stage groups. As fibrosis progressed, npRQ significantly decreased (stage 0, 0.895 ± 0.068; stage 1, 0.869 ± 0.067; stage 2, 0.808 ± 0.046; stage 3, 0.798 ± 0.026; P < 0.005). Glucose intolerance worsened and insulin resistance increased with fibrosis stage. npRQ was negatively correlated with AUC glucose (R = -0.6308, P < 0.001), Homeostasis Model of Assessment - Insulin Resistance (R = -0.5045, P < 0.005), fasting glucose (R = -0.4585, P < 0.01) and insulin levels (R = -0.4431, P < 0.05), suggesting that decreased npRQ may reflect impaired glucose tolerance due to insulin resistance, which was associated with fibrosis progression. Estimation of fibrosis stage using npRQ was as accurate as several previously established scoring systems using receiver-operator curve analysis. CONCLUSION: npRQ was significantly decreased in patients with advanced NAFLD. Our data suggest that measurement of npRQ is useful for the estimation of disease severity in NAFLD patients.

Focal nodular hyperplasia-like nodule with reduced expression of organic anion transporter 1B3 in alcoholic liver cirrhosis.

We report a patient with alcoholic liver cirrhosis who had a 15 mm focal nodular hyperplasia (FNH)-like nodule in the liver. This FNH-like nodule was diagnosed as hepatocellular carcinoma (HCC) mainly based on hypervascularity during the hepatic arterial phase, washout pattern during the equilibrium phase and low signal intensity during the hepatobiliary phase in gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid (Gd-EOB-DTPA)-enhanced MRI; it was surgically resected. Its histology exhibited hepatocyte hyperplasia, fibrous septa containing unpaired small arteries accompanied by reactive bile ductules, remarkable iron deposits and sinusoidal capillarization, and was compatible with the diagnosis of an FNH-like nodule. When we analyzed the images of the present nodule retrospectively, low signal intensity on in-phase and isosignal intensity on opposed-phase T1-weighted MRI may have reflected iron deposits in the FNH-like nodule. In addition, a low signal intensity on T2-weighted MRI and no detection in diffusion-weighted MRI may help in distinguishing FNH-like nodules from HCC, since these image findings are inconsistent with typical HCC. Immunohistochemical analysis revealed a markedly reduced expression of organic anion transporter (OATP) 1B3 in this nodule, which implied decreased Gd-EOB-DTPA uptake by hepatocytes and accounted for the low signal intensity during the hepatobiliary phase on Gd-EOB-DTPA-enhanced MRI. To the best of our knowledge this is the first report in which an FNH-like nodule was assessed for OATP1B3 expression.

Type 1 interferon receptor in peripheral blood mononuclear cells may predict response to intra-arterial 5-fluorouracil + interferon therapy for advanced hepatocellular carcinoma.

BACKGROUND: Type 1 interferon alpha receptor 2 (IFNAR2) in the liver has been reported to be a predictive factor for the response to intra-arterial 5-fluorouracil (5-FU) + systemic interferon (IFN)-alpha combination therapy in patients with advanced hepatocellular carcinoma. We tested whether IFNAR2 expression in peripheral blood mononuclear cells could predict the response to 5-FU + IFN. METHODS: Predictive factors for survival and response to therapy were determined in 30 patients with advanced hepatocellular carcinoma who underwent treatment with 5-FU + IFN. IFNAR2 expression in peripheral blood mononuclear cells was measured in 11 of the 30 patients. RESULTS: With a mean number of 4.2 courses of combination therapy, one patient (3%) showed a complete response, eight (27%) showed partial responses, 13 (43%) had stable disease, and eight (27%) showed progressive disease. The median survival time of responders (complete response/partial response) was 12.7 months and that of nonresponders (stable disease/progressive disease) was 7.5 months. The one-year and two-year cumulative survival rates of responders and nonresponders were 87/69% and 40/11%, respectively (P = 0.019). Multivariate analysis identified response to therapy (P = 0.037) as the sole independent determinant of survival. The expression level of IFNAR2 in peripheral blood mononuclear cells was significantly (P = 0.012) higher in responders (6.5 ± 2.4) than in nonresponders (2.4 ± 0.6), even though no clinical factors were identified as being associated with the response to the combination therapy. CONCLUSION: IFNAR2 expression in peripheral blood mononuclear cells may predict the response to 5-FU + IFN therapy in patients with advanced hepatocellular carcinoma, although these data are preliminary.

Comparison of therapeutic effects between radiofrequency ablation and percutaneous microwave coagulation therapy for small hepatocellular carcinomas.

BACKGROUND: Although thermal ablation therapies have gained fairly wide acceptance as an effective treatment for small hepatocellular carcinoma (HCC), there have been only a few clinical studies comparing the response to radiofrequency ablation (RFA) and percutaneous microwave coagulation therapy (PMCT). We evaluated the therapeutic efficacy and safety of these two procedures for the treatment of small HCC measuring < or = 2 cm in diameter. METHODS: Thirty-four patients who had 37 nodules were treated by RFA and were compared with 49 patients (56 nodules) who underwent PMCT. Treatment was repeated until complete tumor necrosis was confirmed by contrast computed tomography (CT) scanning. The therapeutic efficacy and complications were retrospectively compared between the two procedures. RESULTS: (i) There were significantly fewer treatment sessions (P < 0.001) in the RFA group than in the PMCT group, but the necrotic area was significantly larger (P < 0.001) in the former group. (ii) The local recurrence rate was significantly lower (P = 0.031) after RFA than after PMCT, although the ectopic recurrence rate showed no significant difference. (iii) The cumulative survival rate was significantly higher (P = 0.018) after RFA than after PMCT. (iv) The incidence of pain and fever after treatment was significantly higher in the PMCT group. Bile duct injury, pleural effusion, and ascites were also significantly more common in the PMCT group. CONCLUSIONS: RFA is more useful than PMCT for the treatment of small HCC because it is minimally invasive and achieves a low local recurrence rate, high survival rate, and extensive necrosis after only a few treatment sessions.

[Pyogenic liver abscess complicated by gastric fistula and bacterial meningitis].

A 77-year-old woman was admitted suffering from fever and headache. On laboratory examination, bacterial meningitis and sepsis due to Klebsiella pneumoniae were diagnosed. In addition, a hepatic cystic lesion measuring 13 cm in diameter in the left lobe was indicated on diagnostic imaging. After treatment with antibiotics, her signs of infection improved and the hepatic lesion decreased in size. After discharge, however, the cystic liver mass increased and a gastric fistula developed. Hepatic and gastric resections were performed because of the possibility of biliary cystadenocarcinoma and gastric invasion. Pathologically, a pyogenic liver abscess complicated by gastric fistula was diagnosed.

Radiofrequency ablation versus percutaneous microwave coagulation therapy for small hepatocellular carcinomas: a retrospective comparative study.

BACKGROUND/AIMS: Although local ablation procedures are useful in eradication treatment for small hepatocellular carcinoma (HCC), there have only been a few clinical studies comparing the response to radiofrequency ablation (RFA) and percutaneous microwave coagulation therapy (PMCT). We evaluated the clinical effect and safety of these two procedures for the treatment of small HCCs measuring 2cm or less in diameter. METHODOLOGY: Twenty-four patients with HCC who were treated by RFA and were compared with 39 patients with HCC who underwent PMCT. These procedures were repeated until complete tumor necrosis was achieved. The therapeutic and adverse effects were retrospectively compared between the two procedures. RESULTS: (1) There were significantly fewer treatment sessions (P < 0.001) in the RFA group than the PMCT group, and the necrotic area was significantly larger (P < 0.001) in the former group. (2) The local recurrence rate was significantly lower (P = 0.012) after RFA than after PMCT, even though the ectopic recurrence rate showed no significant difference. 3) The cumulative survival rate was significantly higher (P = 0.028) in the RFA group. (4) The incidence of pain and fever after treatment was significantly higher after PMCT than after RFA. Bile duct injury and pleural effusion were also more frequent in the PMCT group. CONCLUSIONS: RFA is more useful than PMCT in the treatment of small HCCs because it is minimally invasive and achieves a low local recurrence rate, high survival rate, and extensive necrosis after only a few treatment sessions.

[Hepatocellular carcinoma occurring after 11 year-long sustained viral response to interferon therapy for chronic hepatitis C].

The patient was a 61-year-old man with chronic hepatitis C who achieved a sustained virological response to interferon therapy in 1993. As a result, the status of his liver improved pathologically from F2A2 to F1A1. Eleven years later, however, a tumor measuring 15 mm in diameter in segment 6 of the liver was indicated by CT. A well-differentiated hepatocellular carcinoma was detected by a fine needle biopsy. The lesion was treated by transcatheter arterial chemoembolization combined with radiofrequency ablation. Even if patients with chronic hepatitis C have achieved a sustained virological response to interferon therapy, patients with risk factors for the development of hepatocellular carcinoma, such as being a male of advanced age and with progressive fibrosis of the liver, should receive careful long-term follow-up.

CO2-enhanced sonographically guided radiofrequency ablation and transcatheter arterial chemoembolization for small hepatocellular carcinoma poorly defined on conventional sonography.

We report a case of hepatocellular carcinoma located just below the right hemidiaphragm that was diagnosed as having hepatitis C virus-related cirrhosis 12 years ago. Although the lesion was not clear on conventional sonography, it was clearly defined on CO(2)-enhanced sonography, allowing safe and accurate radiofrequency ablation. By combining radiofrequency ablation with transcatheter arterial chemoembolization, extensive cauterization and complete tumor necrosis were obtained with only 1 session of treatment. The patient had no serious adverse effects and has shown no recurrence during 35 months of follow-up.

Thermal ablation therapy for hepatocellular carcinoma: comparison between radiofrequency ablation and percutaneous microwave coagulation therapy.

BACKGROUND/AIMS: To evaluate the initial therapeutic effect and safety of radiofrequency ablation (RFA) and percutaneous microwave coagulation therapy (PMCT) for the treatment of small hepatocellular carcinomas (HCCs). METHODOLOGY: Forty-eight patients with HCC were treated by RFA and 70 patients with HCC were treated by PMCT. These procedures were repeated until complete tumor necrosis was confirmed by contrast CT scanning. The therapeutic and adverse effects were compared between the two procedures. RESULTS: 1) The number of treatment sessions was significantly lower in RFA patients, and the necrotic area was significantly larger. 2) The local recurrence rate was significantly lower after RFA than after PMCT, while the ectopic recurrence rate showed no significant difference between the two procedures. 3) The survival rate was significantly higher after RFA compared with PMCT. 4) The incidence of pain and fever after treatment was significantly higher in PMCT patients. Occurrence of bile duct injury, pleural effusion and ascites were also significantly more common in PMCT patients. CONCLUSIONS: RFA is more useful for the treatment of small HCCs compared with PMCT because it is minimally invasive and achieves a low local recurrence rate, a high survival rate, and extensive necrosis after only a few treatment sessions.

Use of intra-arterial carbon-dioxide-enhanced ultrasonography for guidance of radiofrequency ablation and transcatheter arterial chemoembolization in hepatocellular carcinoma.

A 73-year-old man with hepatitis-C-related cirrhosis and an elevated alpha-fetoprotein level and tumor in segment 3 of his liver was referred for interventional radiologic treatment. He was not a candidate for surgical resection due to impaired liver function and his personal preferences. On conventional ultrasonography no lesion could be detected, but the tumor was clearly depicted by intra-arterial carbon-dioxide-enhanced ultrasonography. Radiofrequency ablation was performed safely and accurately under the guidance of carbon-dioxide-enhanced ultrasonography. By concomitant performance of transcatheter arterial chemoembolization with radiofrequency ablation, extensive necrosis was obtained and adequate tumor volume reduction achieved with only one treatment session.

Carbon dioxide-enhanced sonographically guided radiofrequency ablation plus transcatheter arterial chemoembolization for hepatocellular carcinoma.

A 78-year-old man had a history of blood transfusion and hepatitis C virus-related liver cirrhosis. He was admitted to the authors' hospital with a hepatocellular carcinoma just below the right hemidiaphragm. Although the lesion was not well visualized with standard sonography, it was clearly defined by performance of sonography with intraarterial injection of carbon dioxide, allowing safe and accurate radiofrequency ablation. To increase the extent of tumor ablation, transcatheter arterial chemoembolization was performed immediately before radiofrequency ablation. By concomitant application of these two techniques, complete tumor necrosis was achieved without the need to perform additional ablation.

Improved prognosis of cirrhosis patients with esophageal varices and thrombocytopenia treated by endoscopic variceal ligation plus partial splenic embolization.

The aim of this study was to assess the efficacy of the combination of endoscopic variceal ligation (EVL) and partial splenic embolization (PSE) compared with EVL alone in cirrhosis patients with thrombocytopenia. In a prospective study, 84 cirrhosis patients with esophageal varices and thrombocytopenia (platelet count < 50,000/mm(3)) underwent EVL plus PSE (N = 42) or EVL alone (N = 42). Primary end points assessed during the follow-up period included the recurrence of varices, progression to variceal bleeding, and death. Comparison between combined treatment and variceal ligation alone by multivariate analysis showed a hazard ratio of 0.44 for the recurrence of varices (P = 0.02), 0.19 for progression to variceal bleeding (P = 0.01), and 0.31 for death (P = 0.04). These results suggest that the combination of EVL plus PSE can prevent the recurrence of varices, progression to variceal bleeding, and death in cirrhosis patients with esophageal varices and thrombocytopenia.

Carbon dioxide-enhanced sonographically guided radiofrequency ablation combined with transcatheter arterial chemoembolization for sonographically undetectable hepatocellular carcinoma.

A 73-year-old man was diagnosed as having hepatitis C virus-related liver cirrhosis 11 years ago. Two years ago, he developed hepatocellular carcinoma in segment 6 of the right lobe and received radiofrequency ablation. This time, he was admitted to our hospital with a local recurrence in segment 6 of the liver. Standard sonography could not visualize the lesion clearly. However, carbon dioxide-enhanced sonogram clearly showed the whole lesion, so a needle electrode could be inserted precisely, allowing safe and accurate radiofrequency ablation. By combining radiofrequency ablation with transcatheter arterial chemoembolization, complete tumor necrosis was achieved without the need to perform additional ablation. In conclusion, carbon dioxide-enhanced sonographically guided radiofrequency ablation combined with transcatheter arterial chemoembolization is useful for complete cure of localized tumors, such as recurrent hepatocellular carcinoma, which cannot be detected clearly by conventional sonography.