Severe hepatic steatosis promotes increased liver stiffness in the early stages of metabolic dysfunction-associated steatotic liver disease.

BACKGROUND & AIMS: The predictors of progression from steatosis to more advanced stages of metabolic dysfunction-associated steatotic liver disease (MASLD) remain unclear. We evaluated the association between the quantity of hepatic steatosis and longitudinal changes in liver stiffness measurements (LSMs) using magnetic resonance elastography (MRE) in patients with MASLD. METHODS: We retrospectively analysed patients with MASLD who underwent at least two serial MRE and magnetic resonance imaging-based proton density fat fraction (MRI-PDFF) examinations at least 1 year apart. Fine-Gray competitive proportional hazard regression was used to identify LSM progression and regression factors. RESULTS: A total of 471 patients were enrolled. Factors linked to LSM progression were steatosis grade 3 (MRI-PDFF ≥17.1%, adjusted hazard ratio [aHR] 2.597; 95% confidence interval [CI] 1.483-4.547) and albumin-bilirubin grade 2 or 3 (aHR 2.790; 95% CI 1.284-6.091), while the only factor linked to LSM regression was % decrease rate of MRI-PDFF ≥5% (aHR 2.781; 95% CI 1.584-4.883). Steatosis grade 3 correlated with a higher incidence rate of LSM progression than steatosis grade 1 (MRI-PDFF <11.3%) in patients with LSM stage 0 (<2.5 kilopascal [kPa]), and a % annual decrease rate of MRI-PDFF ≥5% correlated with a higher incidence rate of LSM regression than that of MRI-PDFF >-5% and <5% in patients with LSM stage 1 or 2-4 (≥2.5 kPa). CONCLUSIONS: Severe hepatic steatosis was linked to significant LSM progression in patients with MASLD and low LSM (<2.5 kPa).

Multivariable Quantitative US Parameters for Assessing Hepatic Steatosis.

Background Because of the global increase in the incidence of nonalcoholic fatty liver disease, the development of noninvasive, widely available, and highly accurate methods for assessing hepatic steatosis is necessary. Purpose To evaluate the performance of models with different combinations of quantitative US parameters for their ability to predict at least 5% steatosis in patients with chronic liver disease (CLD) as defined using MRI proton density fat fraction (PDFF). Materials and Methods Patients with CLD were enrolled in this prospective multicenter study between February 2020 and April 2021. Integrated backscatter coefficient (IBSC), signal-to-noise ratio (SNR), and US-guided attenuation parameter (UGAP) were measured in all participants. Participant MRI PDFF value was used to define at least 5% steatosis. Four models based on different combinations of US parameters were created: model 1 (UGAP alone), model 2 (UGAP with IBSC), model 3 (UGAP with SNR), and model 4 (UGAP with IBSC and SNR). Diagnostic performance of all models was assessed using area under the receiver operating characteristic curve (AUC). The model was internally validated using 1000 bootstrap samples. Results A total of 582 participants were included in this study (median age, 64 years; IQR, 52-72 years; 274 female participants). There were 364 participants in the steatosis group and 218 in the nonsteatosis group. The AUC values for steatosis diagnosis in models 1-4 were 0.92, 0.93, 0.95, and 0.96, respectively. The C-indexes of models adjusted by the bootstrap method were 0.92, 0.93, 0.95, and 0.96, respectively. Compared with other models, models 3 and 4 demonstrated improved discrimination of at least 5% steatosis (P < .01). Conclusion A model built using the quantitative US parameters UGAP, IBSC, and SNR could accurately discriminate at least 5% steatosis in patients with CLD. © RSNA, 2023 Supplemental material is available for this article. See also the editorial by Han in this issue.

Diagnostic Accuracy of Two-Dimensional Shear Wave Elastography for Liver Fibrosis: A Multicenter Prospective Study.

Chronic liver disease (CLD) leads to the development of hepatocellular carcinoma, which is one of the leading causes of cancer-related deaths globally.1 Liver fibrosis is the most important prognostic factor for hepatocellular carcinoma development and prognosis in CLD, and accurate staging of liver fibrosis is pivotal in clinical practice.2 Although liver biopsy is the gold standard for evaluating liver fibrosis, liver biopsy has several limitations including invasiveness, sampling error, and intraobserver and interobserver reproducibility.3 To resolve these problems, several noninvasive methods for evaluating liver fibrosis have been developed using serum fibrosis markers, ultrasound-based modalities, and magnetic resonance imaging-based modalities.4.

Utility of Ultrasound-Guided Attenuation Parameter for Grading Steatosis With Reference to MRI-PDFF in a Large Cohort.

BACKGROUND & AIMS: Ultrasound-guided attenuation parameter (UGAP) is recently developed for noninvasive evaluation of steatosis. However, reports on its usefulness in clinical practice are limited. This prospective multicenter study analyzed the diagnostic accuracy of grading steatosis with reference to magnetic resonance imaging-based proton density fat fraction (MRI-PDFF), a noninvasive method with high accuracy, in a large cohort. METHODS: Altogether, 1010 patients with chronic liver disease who underwent MRI-PDFF and UGAP were recruited and prospectively enrolled from 6 Japanese liver centers. Linearity was evaluated using intraclass correlation coefficients between MRI-PDFF and UGAP values. Bias, defined as the mean difference between MRI-PDFF and UGAP values, was assessed by Bland-Altman analysis. UGAP cutoffs for pairwise MRI-PDFF-based steatosis grade were determined using area under the receiver-operating characteristic curve (AUROC) analyses. RESULTS: UGAP values were shown to be normally distributed. However, because PDFF values were not normally distributed, they were log-transformed (MRI-logPDFF). UGAP values significantly correlated with MRI-logPDFF (intraclass correlation coefficient = 0.768). Additionally, Bland-Altman analysis showed good agreement between MRI-logPDFF and UGAP with a mean bias of 0.0002% and a narrow range of agreement (95% confidence interval [CI], -0.015 to 0.015). The AUROCs for distinguishing steatosis grade ≥1 (MRI-PDFF ≥5.2%), ≥2 (MRI-PDFF ≥11.3%), and 3 (MRI-PDFF ≥17.1%) were 0.910 (95% CI, 0.891-0.928), 0.912 (95% CI, 0.894-0.929), and 0.894 (95% CI, 0.873-0.916), respectively. CONCLUSIONS: UGAP has excellent diagnostic accuracy for grading steatosis with reference to MRI-PDFF. Additionally, UGAP has good linearity and negligible bias, suggesting that UGAP has excellent technical performance characteristics that can be widely used in clinical trials and patient care. (UMIN Clinical Trials Registry, Number: UMIN000041196).

Augmented hepatic Toll-like receptors by fatty acids trigger the pro-inflammatory state of non-alcoholic fatty liver disease in mice.

AIM: There is considerable evidence that intestinal microbiota are involved in the development of metabolic syndromes and, consequently, with the development of non-alcoholic fatty liver disease (NAFLD). Toll-like receptors (TLRs) are essential for the recognition of microbiota. However, the induction mechanism of TLR signals through the gut-liver axis for triggering the development of non-alcoholic steatohepatitis (NASH) or NAFLD remains unclear. In this study, we investigated the role of palmitic acid (PA) in triggering the development of a pro-inflammatory state of NAFLD. METHODS: Non-alcoholic fatty liver disease was induced in mice fed a high fat diet (HFD). The mice were killed and the expression of TLRs, tumor necrosis factor (TNF), interleukin (IL)-1ß, and phospho-interleukin-1 receptor-associated kinase 1 in the liver and small intestine were assessed. In addition, primary hepatocytes and Kupffer cells were treated with PA, and the direct effects of PA on TLRs induction by these cells were evaluated. RESULTS: The expression of inflammatory cytokines such as TNF, IL-1ß, and TLR-2, -4, -5, and -9 was increased in the liver, but decreased in the small intestine of HFD-fed mice in vivo. In addition, the expression of TLRs in primary hepatocytes and Kupffer cells was increased by treatment with PA. CONCLUSION: In the development of the pro-inflammatory state of NAFLD, PA triggers the expression of TLRs, which contribute to the induction of inflammatory cytokines through TLR signals by intestinal microbiota.

Advanced fibrosis leads to overestimation of steatosis with quantitative ultrasound in individuals without hepatic steatosis.

PURPOSE: The effect of hepatic fibrosis stage on quantitative ultrasound based on the attenuation coefficient (AC) for liver lipid quantification is controversial. The objective of this study was to determine how the degree of fibrosis assessed by magnetic resonance (MR) elastography affects AC based on the ultrasound-guided attenuation parameter according to the grade of hepatic steatosis, using magnetic resonance imaging (MRI)-derived proton density fat fraction (MRIderived PDFF) as the reference standard. METHODS: Between February 2020 and April 2021, 982 patients with chronic liver disease who underwent AC and MRI-derived PDFF measurement as well as MR elastography were enrolled. Multiple regression was used to investigate whether AC was affected by the degree of liver stiffness. RESULTS: AC increased as liver stiffness progressed in 344 patients without hepatic steatosis (P=0.009). In multivariable analysis, AC was positively correlated with skin-capsule distance (P<0.001), MR elastography value (P=0.037), and MRI-derived PDFF (P<0.001) in patients without hepatic steatosis. In 52 of 982 patients (5%), the correlation between AC and MRIderived PDFF fell outside the 95% confidence interval for the regression line slope. Patients with MRI-derived PDFF lower than their AC (n=36) had higher fibrosis-4 scores, albumin-bilirubin scores, and MR elastography values than patients with MRI-derived PDFF greater than their AC (n=16; P=0.018, P=0.001, and P=0.011, respectively). CONCLUSION: AC is affected by liver fibrosis (MR elastography value ≥6.7 kPa) only in patients without hepatic steatosis (MRI-derived PDFF <5.2%). These values should be interpreted with caution in patients with advanced liver fibrosis.

Survey of non-B, non-C liver cirrhosis in Japan.

AIM: The aim of this survey was to reveal clinical features for each etiology of non-B, non-C liver cirrhosis (NBNC LC) in Japan. METHODS: In a nationwide survey of NBNC LC in Japan at the 15th General Meeting of the Japan Society of Hepatology, 6999 NBNC LC patients were registered at 48 medical institutions. Epidemiological and clinical factors were investigated. RESULTS: The percentage of NBNC LC among LC patients was 26%. NBNC LC patients were categorized into 11 types according to etiological agents: non-alcoholic steatohepatitis (NASH), 14.5%; alcoholic liver disease (ALD), 55.1%; fatty liver disease (FLD), except NASH, ALD, and other known etiology, 2.5%; primary biliary cirrhosis, 8.0%; other biliary cirrhosis, 0.8%; autoimmune hepatitis, 6.8%; metabolic disease, 0.6%; congestive disease, 0.8%; parasitic disease, 0.2%; other known etiology, 0.2%; and unknown etiology, 10.5%. Compared with previous surveys, the percentage of ALD remained unchanged, whereas that of NASH increased. The mean age and percentage of females were significantly higher in NASH patients than in ALD and FLD patients. Prevalence of diabetes mellitus was significantly higher in NASH and FLD patients than in ALD ones. Prevalence of hepatocellular carcinoma (HCC) in NBNC LC patients was 35.9%. Among NASH, ALD and FLD patients, 50.9%, 34.3% and 54.5% had HCC, respectively. Positivity of hepatitis B core antibody was significantly higher in HCC patients than in those without HCC (41.1% vs 24.8%). CONCLUSION: This survey determined the etiology of NBNC LC in Japan. These results should contribute new ideas toward understanding NBNC LC and NBNC HCC.

Validation of the FIB4 index in a Japanese nonalcoholic fatty liver disease population.

BACKGROUND: A reliable and inexpensive noninvasive marker of hepatic fibrosis is required in patients with nonalcoholic fatty liver disease (NAFLD). FIB4 index (based on age, aspartate aminotransferase [AST] and alanine aminotransferase [ALT] levels, and platelet counts) is expected to be useful for evaluating hepatic fibrosis. We validated the performance of FIB4 index in a Japanese cohort with NAFLD. METHODS: The areas under the receiver operating characteristic curves (AUROC) for FIB4 and six other markers were compared, based on data from 576 biopsy-proven NAFLD patients. Advanced fibrosis was defined as stage 3-4 fibrosis. FIB4 index was assessed as: age (yr) × AST (IU/L)/(platelet count (10(9)/L) × âˆšALT (IU/L)) RESULTS: Advanced fibrosis was found in 64 (11%) patients. The AUROC for FIB4 index was superior to those for the other scoring systems for differentiating between advanced and mild fibrosis. Only 6 of 308 patients with a FIB4 index below the proposed low cut-off point (< 1.45) were under-staged, giving a high negative predictive value of 98%. Twenty-eight of 59 patients with a FIB4 index above the high cut-off point (> 3.25) were over-staged, giving a low positive predictive value of 53%. Using these cutoffs, 91% of the 395 patients with FIB-4 values outside 1.45-3.25 would be correctly classified. Implementation of the FIB4 index in the Japanese population would avoid 58% of liver biopsies. CONCLUSION: The FIB4 index was superior to other tested noninvasive markers of fibrosis in Japanese patients with NAFLD, with a high negative predictive value for excluding advanced fibrosis. The small number of cases of advanced fibrosis in this cohort meant that this study had limited power for validating the high cut-off point.

Type IV Collagen 7S Is the Most Accurate Test For Identifying Advanced Fibrosis in NAFLD With Type 2 Diabetes.

This study aimed to examine whether the diagnostic accuracy of four noninvasive tests (NITs) for detecting advanced fibrosis in nonalcoholic fatty liver disease (NAFLD) is maintained or is inferior to with or without the presence of type 2 diabetes. Overall, 874 patients with biopsy-proven NAFLD were enrolled. After propensity-score matching by age, sex, and the prevalence of dyslipidemia, 311 patients were enrolled in each group of with or without diabetes. To evaluate the effect of diabetes, we compared the diagnostic accuracy of the fibrosis-4 (FIB-4) index, the NAFLD fibrosis score (NFS), the aspartate aminotransferase to platelet ratio index (APRI), and type IV collagen 7S (COL4-7S) in patients with NAFLD with and without diabetes. The areas under the receiver operating characteristic curve (AUROC) for identifying advanced fibrosis in patients without diabetes were 0.879 for the FIB-4 index, 0.851 for the NFS, 0.862 for the APRI, and 0.883 for COL4-7S. The AUROCs in patients with diabetes were 0.790 for the FIB-4 index, 0.784 for the NFS, 0.771 for the APRI, and 0.872 for COL4-7S. The AUROC of COL4-7S was significantly larger than that of the other NITs in patients with NAFLD with diabetes than in those without diabetes. The optimal high and low cutoff points of COL4-7S were 5.9 ng/mL and 4.8 ng/mL, respectively. At the low cutoff point, the accuracy of COL4-7S was better than that of the other NITs, especially in patients with diabetes. Conclusion: COL4-7S measurement might be the best NIT for identifying advanced fibrosis in NAFLD, especially in NAFLD with diabetes.

Hereditary hemorrhagic telangiectasia: how to efficiently detect hepatic abnormalities using ultrasonography.

INTRODUCTION: Hereditary hemorrhagic telangiectasia (HHT) is a multiorgan genetic angiodysplastic affection characterized by visceral vascular malformations. It affects mainly the brains, lungs, gastrointestinal tract, and nasal mucosa. Unlike those organs, hepatic involvement, although very frequently occurring, is insufficiently recognized, mainly because of the complex vascular structure of this organ. Thus, treating HHT patients requires a solid understanding of these hepatic anomalies. It is especially important for any general clinicians to be able to recognize clinical findings in HHT, which leads to a high suspicion of HHT and have an index of suspicion for liver abnormalities of HHT. For this purpose, keen awareness of clinical as well as hepatic sonographic (US) findings is paramount. AIM: The aim of this review is to summarize previously reported findings on the hepatic US through a thorough analysis of related articles, and to (a) determine the role of US in the diagnosis of hepatic involvement in HHT patients and (b) propose the most simple and easy way to detect HHT-related abnormalities during routine US examinations. CONCLUSION: Hepatic US serves to diagnose the detailed complex hepatic changes typical of HHT, and contributes to increased diagnostic confidence of hepatic changes in HHT patients, with the most simple way not to overlook HHT-related abnormalities being to find hepatic artery dilatation.

Dysregulation of systemic iron metabolism in alcoholic liver diseases.

Alcoholic liver diseases (ALD) are frequently associated with iron overload. Until recently, the effects of ethanol in hepatic iron uptake and intestinal iron absorption have not been clarified in detail. Two possible mechanisms for iron overload are the uptake of iron into hepatocytes in a specific manner through the increased expression of transferrin receptor (TfR) 1; and increased intestinal iron absorption by the lowering of hepcidin. It is worthwhile to examine whether a similar mechanism is present in the development of steatosis and non-alcoholic steatohepatitis (NASH). Hepatocytes have several iron uptake pathways. Ethanol increases transferrin (Tf)-mediated uptake via a receptor-dependent manner, but downregulates the non-Tf-bound iron uptake. According to immunohistochemical study, TfR1 was increased in hepatocytes in 80% of hepatic tissues of patients with ALD, but was not detected in normal hepatic tissues. In an experimental model, ethanol exposure to the primary cultured-hepatocytes in the presence of iron increased TfR1 expression and (59)Fe-labeled Tf uptake. In patients with ALD, intestinal iron absorption is increased by oral iron uptake assay. The regulatory hormone for iron homeostasis, hepcidin is downregulated in ethanol-loaded mice liver. As well as ALD, a similar mechanism was present in the mouse model fed with a high-fat diet, a model of the initial phenomenon of steatosis. The common mechanism for hepatic iron deposition and the triggering role of iron may be present in the development of ALD and non-alcoholic fatty liver disease/NASH.

The novel cutoff points for the FIB4 index categorized by age increase the diagnostic accuracy in NAFLD: a multi-center study.

BACKGROUND: The FIB4 index is clinically useful, but because its formula includes age, the appropriate cutoff point may differ by age group. Here, new FIB4 index cutoff points were validated using cohort data from 14 hepatology centers in Japan. METHODS: The FIB4 index was determined in biopsy-confirmed NAFLD patients (n = 1050) who were divided into four groups: ≤ 49, 50-59, 60-69, and ≥ 70 years. ROC analysis predicted advanced fibrosis in each age group; low and high cutoff points were defined by a sensitivity and specificity of 90%. The new and conventional cutoffs were compared for detecting advanced fibrosis. RESULTS: The modified low and high cutoff points were 1.05 and 1.21 in ≤ 49 years, 1.24 and 1.96 in 50-59 years, 1.88 and 3.24 in 60-69 years, and 1.95 and 4.56 in ≥ 70 years. In ≥ 60 years, the false-negative rate was increased using the modified high cutoff point, and the high cutoff point was better with the conventional cutoff point. The new proposed low and high cutoff points are 1.05 and 1.21 in ≤ 49 years, 1.24 and 1.96 in 50-59 years, 1.88 and 2.67 in 60-69 years, and 1.95 and 2.67 in ≥ 70 years; these cutoff points improved the accuracy of advanced fibrosis diagnosis. CONCLUSIONS: FIB4 index cutoff points for predicting advanced fibrosis in NAFLD increased with age. Cutoff points modified by age improved the diagnostic accuracy of estimations of advanced liver fibrosis using the FIB4 index.

Correction to: The novel cutoff points for the FIB4 index categorized by age increase the diagnostic accuracy in NAFLD: a multi-center study.

The coauthor Masashi Yoneda's affiliation has been incorrectly published in the original publication of the article. The correct affiliation is provided in this correction.

A Data Mining-based Prognostic Algorithm for NAFLD-related Hepatoma Patients: A Nationwide Study by the Japan Study Group of NAFLD.

The prognosis of patients with nonalcoholic fatty liver disease-related hepatocellular carcinoma (NAFLD-HCC) is intricately associated with various factors. We aimed to investigate the prognostic algorithm of NAFLD-HCC patients using a data-mining analysis. A total of 247 NAFLD-HCC patients diagnosed from 2000 to 2014 were registered from 17 medical institutions in Japan. Of these, 136 patients remained alive (Alive group) and 111 patients had died at the censor time point (Deceased group). The random forest analysis demonstrated that treatment for HCC and the serum albumin level were the first and second distinguishing factors between the Alive and Deceased groups. A decision-tree algorithm revealed that the best profile comprised treatment with hepatectomy or radiofrequency ablation and a serum albumin level ≥3.7 g/dL (Group 1). The second-best profile comprised treatment with hepatectomy or radiofrequency ablation and serum albumin levels <3.7 g/dL (Group 2). The 5-year overall survival rate was significantly higher in the Group 1 than in the Group 2. Thus, we demonstrated that curative treatment for HCC and serum albumin level >3.7 g/dL was the best prognostic profile for NAFLD-HCC patients. This novel prognostic algorithm for patients with NAFLD-HCC could be used for clinical management.

Hepcidin is down-regulated in alcohol loading.

BACKGROUND: It is common for alcoholic patients to have excess iron accumulation in the liver, which may contribute to the development of alcoholic liver disease (ALD). However, the mechanism of hepatic iron uptake in ALD is still obscure. Recently, a novel iron-regulatory hormone hepcidin was found that suppresses the absorption of iron from the small intestine and the release of iron from macrophages. To elucidate the contribution of hepcidin toward the hepatic excess iron accumulation in ALD, we examined whether alcohol loading affects hepcidin expression both in ALD patients and in an ethanol-fed mouse model. METHODS: Serum prohepcidin concentration was quantified by enzyme-linked immunosorbent assay. Hepatic hepcidin-1 and hepcidin-2 mRNA expressions in mouse liver were evaluated by quantitative real-time reverse-transcriptase polymerase chain reaction method. The protein expression of prohepcidin in mouse liver was examined immunohistochemically by rabbit antimouse prohepcidin antibody. RESULTS: Serum prohepcidin concentration in ALD was significantly lower than that in healthy subjects (p<0.001). Especially, serum prohepcidin concentrations were decreased in the patients whose serum ferritin value was high. In the ethanol-fed mouse model, hepatic hepcidin-1 mRNA expression was significantly lower than that in control (p=0.04). Prohepcidin was expressed in the cytoplasm of hepatocytes of mice liver tissue sections, and its expression was decreased after ethanol loading. CONCLUSION: Alcohol loading down-regulates hepatic hepcidin expression and leads to the increase of iron absorption from the intestine.

Hepatocellular carcinoma in Japanese patients with nonalcoholic fatty liver disease and alcoholic liver disease: multicenter survey.

BACKGROUND: In Japan, the prevalence of hepatocellular carcinoma (HCC) associated with nonviral liver disease, especially with nonalcoholic fatty liver disease (NAFLD-HCC) and alcoholic liver disease (ALD-HCC), has been increasing. Clarification of the clinical features of NAFLD-HCC and ALD-HCC is needed. We performed a large retrospective multicenter survey to clarify the clinical course of these two types of HCC. METHODS: Clinical characteristics, survival, and recurrence were examined in 532 patients with ALD-HCC and 209 patients with NAFLD-HCC who were diagnosed between January 2000 and December 2013. RESULTS: The ALD-HCC patients were predominantly male and were younger than the patients with NAFLD-HCC. Lifestyle-related diseases were significantly more common in the NAFLD-HCC group, but the prevalence of cirrhosis was significantly higher in the ALD-HCC group. The histological diagnosis of NAFLD-HCC showed a gender difference (F4; 72.7 % in the females vs. 37.6 % in the males). The characteristic features of HCC including histology, survival rate, and recurrence rate were quite similar in the NAFLD-HCC and ALD-HCC groups: 5-year survival rates 49.1 vs. 43.7 %; 5-year recurrence rates 69.6 vs. 65.4 %, respectively. However, the risk factors for recurrence differed between the two groups: des-gamma-carboxy prothrombin was a risk factor in NAFLD-HCC and α-fetoprotein was a risk factor in ALD-HCC. CONCLUSIONS: Although the characteristic features underlying these two diseases are different, the two HCC groups showed a similar clinical course. The recurrence rates of the two HCC groups were relatively high. We found that critical tumor markers for recurrence differed between the two diseases.

Usefulness of recombinant Em18-ELISA to evaluate efficacy of treatment in patients with alveolar echinococcosis.

Alveolar echinococcosis (AE) is a rare parasitic disease caused by Echinococcus multicularis and most commonly involves the liver. Early diagnosis is essential to improve the prognosis of patients with AE of the liver. Em18, an 18-kD diagnostic antigen from Echinococcus multilocularis, is highly specific and sensitive to detect AE. We previously reported that an enzyme-linked immunosorbent assay (ELISA) system using a recombinant Em18 antigen (RecEm18) was highly useful in the differential serodiagnosis of AE. In this report, we present seven AE patients who showed dynamic changes in RecEm18-ELISA values in the course of long-term follow up of albendazole (ABZ) chemotherapy, and/or resections of the liver or bone metastasis. All seven AE patients revealed positive values, over the cutoff level, of the RecEm18-ELISA before the treatments. The values in six patients fell below the cutoff level after the treatments, but the value in a patient with recurrence never fell below the cutoff level, and increased again. From these results, it seems that the RecEm18-ELISA is useful to evaluate the efficacy of treatment and predict recurrence in patients with AE. RecEm18-ELISA may be an important examination for: (a) the mass screening of AE in Japan, (b) the confirmative diagnosis of AE prior to surgical and/or chemotherapeutic treatments, (c) the follow up of AE patients after treatments, and (d) for deciding on the discontinuation of chemotherapy in patients with an appropriate response.

Up-regulation of transferrin receptor 1 in chronic hepatitis C: Implication in excess hepatic iron accumulation.

BACKGROUND/AIMS: : To clarify the mechanism of excess hepatic iron accumulation in chronic hepatitis C, we investigated the expressions of transferrin receptor 1 and divalent metal transporter 1 in hepatocytes, both of which are involved in cellular iron uptake, in relation to the degree of hepatic iron accumulation and hepatic fibrosis by immunohistochemistrical study. METHODS: : Forty-six hepatic tissues with chronic hepatitis C and five normal hepatic tissues were examined. Chemical detection of hepatic iron accumulation was performed by Perl's Prussian blue stain. The immunohistochemistrical study was performed by avidin-biotin complex method with alkaline phosphatase. RESULTS: : In chronic hepatitis C: (1) Hepatic iron accumulation was significantly increased in relation to the advance of the fibrosis. (2) Divalent metal transporter 1 decreased significantly in relation to the advance of hepatic fibrosis. (3) Transferrin receptor 1 expression was always detected, although not in normal hepatic tissues; there was no relation between expression levels and the degree of hepatic fibrosis. CONCLUSIONS: : These data demonstrated that the transferrin receptor 1 expression was up-regulated irrespective of the degree of hepatic iron accumulation, suggesting that the up-regulation of transferrin receptor 1 might act as one of the key mechanisms implicated in the accumulation of hepatic iron in chronic hepatitis C.

Clinical utility of sequential imaging of hepatocellular carcinoma by contrast-enhanced power Doppler ultrasonograpy.

The aim of this study was to investigate the clinical utility of sequential imaging of hepatocellular carcinoma (HCC) by contrast-enhanced power Doppler ultrasonograpy (CE-PDUS) to differentiate hepatocellular carcinoma from adenomatous hyperplasia (AH) and regenerated nodule (RN) and to predict the degree of differentiation of HCC. Fifty-one patients with 62 hepatic lesions including 33 moderately and poorly differentiated HCCs, 19 well-differentiated HCCs, seven AHs and three large RNs were examined by CE-PDUS. The imaging patterns during early arterial phase (tumor vessel image), late vascular phase (tumor perfusion image) and post-vascular phase (liver perfusion image) were classified as diffuse, basket, peripheral, central and no enhancement; as whole tumor, partial tumor and no enhancement; as whole tumor, partial tumor and no defect, respectively. The diffuse pattern in the tumor vessel image, the whole enhancement pattern in the tumor perfusion image and the whole defect pattern in the liver perfusion image were observed in moderately and poorly differentiated HCCs only. The basket pattern in the tumor vessel image and the partial defect pattern in the tumor perfusion image were observed in HCCs only. All AH/RNs showed no defect pattern in the liver perfusion image. The sequential imaging of HCC during early arterial, late vascular and post-vascular phases by CE-PDUS is clinically useful to differentiate HCC from AH/RN and to predict the degree of differentiation of HCC.