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1.  Advances in understanding and treating liver diseases during pregnancy: A review 
Liver disease in pregnancy is rare but pregnancy-related liver diseases may cause threat to fetal and maternal survival. It includes pre-eclampsia; eclampsia; haemolysis, elevated liver enzymes, and low platelets syndrome; acute fatty liver of pregnancy; hyperemesis gravidarum; and intrahepatic cholestasis of pregnancy. Recent basic researches have shown the various etiologies involved in this disease entity. With these advances, rapid diagnosis is essential for severe cases since the decision of immediate delivery is important for maternal and fetal survival. The other therapeutic options have also been shown in recent reports based on the clinical trials and cooperation and information sharing between hepatologist and gynecologist is important for timely therapeutic intervention. Therefore, correct understandings of diseases and differential diagnosis from the pre-existing and co-incidental liver diseases during the pregnancy will help to achieve better prognosis. Therefore, here we review and summarized recent advances in understanding the etiologies, clinical courses and management of liver disease in pregnancy. This information will contribute to physicians for diagnosis of disease and optimum management of patients.
PMCID: PMC4419059  PMID: 25954092
Pregnancy; Liver injury; Low platelets; Haemolysis elevated liver enzymes; Acute fatty liver of pregnancy; Hyperemesis gravidarum; Intrahepatic cholestasis of pregnancy
2.  Factors predicting aggressiveness of non-hypervascular hepatic nodules detected on hepatobiliary phase of gadolinium ethoxybenzyl diethylene-triamine-pentaacetic-acid magnetic resonance imaging 
AIM: To establish a prognostic formula that distinguishes non-hypervascular hepatic nodules (NHNs) with higher aggressiveness from less hazardous one.
METHODS: Seventy-three NHNs were detected in gadolinium ethoxybenzyl diethylene-triamine-pentaacetic-acid magnetic resonance imaging (Gd-EOB-DTPA-MRI) study and confirmed to change 2 mm or more in size and/or to gain hypervascularity. All images were interpreted independently by an experienced, board-certified abdominal radiologist and hepatologist; both knew that the patients were at risk for hepatocellular carcinoma development but were blinded to the clinical information. A formula predicting NHN destiny was developed using a generalized estimating equation model with thirteen explanatory variables: age, gender, background liver diseases, Child-Pugh class, NHN diameter, T1-weighted imaging/T2-weighted imaging detectability, fat deposition, lower signal intensity in arterial phase, lower signal intensity in equilibrium phase, α-fetoprotein, des-γ-carboxy prothrombin, α-fetoprotein-L3, and coexistence of classical hepatocellular carcinoma. The accuracy of the formula was validated in bootstrap samples that were created by resampling of 1000 iterations.
RESULTS: During a median follow-up period of 504 d, 73 NHNs with a median diameter of 9 mm (interquartile range: 8-12 mm) grew or shrank by 68.5% (fifty nodules) or 20.5% (fifteen nodules), respectively, whereas hypervascularity developed in 38.4% (twenty eight nodules). In the fifteen shrank nodules, twelve nodules disappeared, while 11.0% (eight nodules) were stable in size but acquired vascularity. A generalized estimating equation analysis selected five explanatories from the thirteen variables as significant factors to predict NHN progression. The estimated regression coefficients were 0.36 for age, 6.51 for lower signal intensity in arterial phase, 8.70 or 6.03 for positivity of hepatitis B virus or hepatitis C virus, 9.37 for des-γ-carboxy prothrombin, and -4.05 for fat deposition. A formula incorporating the five coefficients revealed sensitivity, specificity, and accuracy of 88.0%, 86.7%, and 87.7% in the formulating cohort, whereas these of 87.2% ± 5.7%, 83.8% ± 13.6%, and 87.3% ± 4.5% in the bootstrap samples.
CONCLUSION: These data suggest that the formula helps Gd-EOB-DTPA-MRI detect a trend toward hepatocyte transformation by predicting NHN destiny.
PMCID: PMC4402305  PMID: 25914467
Hepatocellular carcinoma; Magnetic resonance imaging; Ethoxybenzyl moiety; Non-hypervascular hepatic nodule; Fate prediction
3.  Active treatments are a rational approach for hepatocellular carcinoma in elderly patients 
AIM: To determine whether an active intervention is beneficial for the survival of elderly patients with hepatocellular carcinoma (HCC).
METHODS: The survival of 740 patients who received various treatments for HCC between 1983 and 2011 was compared among different age groups using Cox regression analysis. Therapeutic options were principally selected according to the clinical practice guidelines for HCC from the Japanese Society of Hepatology. The treatment most likely to achieve regional control capability was chosen, as far as possible, in the following order: resection, radiofrequency ablation, percutaneous ethanol injection, transcatheter arterial chemoembolization, transarterial oily chemoembolization, hepatic arterial infusion chemotherapy, systemic chemotherapy including molecular targeting, or best supportive care. Each treatment was used alone, or in combination, with a clinical goal of striking the best balance between functional hepatic reserve and the volume of the targeted area, irrespective of their age. The percent survival to life expectancy was calculated based on a Japanese national population survey.
RESULTS: The median ages of the subjects during each 5-year period from 1986 were 61, 64, 67, 68 and 71 years and increased significantly with time (P < 0.0001). The Child-Pugh score was comparable among younger (59 years of age or younger), middle-aged (60-79 years of age), and older (80 years of age or older) groups (P = 0.34), whereas the tumor-node-metastasis stage tended to be more advanced in the younger group (P = 0.060). Advanced disease was significantly more frequent in the younger group compared with the middle-aged group (P = 0.010), whereas there was no difference between the middle-aged and elderly groups (P = 0.75). The median survival times were 2593, 2011, 1643, 1278 and 1195 d for 49 years of age or younger, 50-59 years of age, 60-69 years of age, 70-79 years of age, or 80 years of age or older age groups, respectively, whereas the median percent survival to life expectancy were 13.9%, 21.9%, 24.7%, 25.7% and 37.6% for each group, respectively. The impact of age on actual survival time was significant (P = 0.020) with a hazard ratio of 1.021, suggesting that a 10-year-older patient has a 1.23-fold higher risk for death, and the overall survival was the worst in the oldest group. On the other hand, when the survival benefit was evaluated on the basis of percent survival to life expectancy, age was again found to be a significant explanatory factor (P = 0.022); however, the oldest group showed the best survival among the five different age groups. The youngest group revealed the worst outcomes in this analysis, and the hazard ratio of the oldest against the youngest was 0.35 for death. The survival trends did not differ substantially between the survival time and percent survival to life expectancy, when survival was compared overall or among various therapeutic interventions.
CONCLUSION: These results suggest that a therapeutic approach for HCC should not be restricted due to patient age.
PMCID: PMC3699049  PMID: 23840122
Hepatocellular carcinoma; Population aging; Survival; Life expectancy; Active intervention
4.  A safe and effective dose of cisplatin in hepatic arterial infusion chemotherapy for hepatocellular carcinoma 
Cancer Medicine  2013;2(1):86-98.
Cisplatin (CDDP) is an anticancer agent that is commonly used in hepatic arterial infusion (HAI) chemotherapy for hepatocellular carcinoma (HCC). This study aimed to clarify the safe and effective dose of CDDP in HAI for HCC. The hypervascular area was measured in 42 HCCs before and after HAI with CDDP. Serum platinum concentration was quantified in the peripheral and/or middle hepatic veins by atomic absorption spectrometry. The relation between the HCC response and CDDP dose was statistically analyzed. The multiple HCC nodules in an individual case generally demonstrated the same response to CDDP. The free-platinum concentration stayed relatively constant in the hepatic vein during HAI followed by a rapid decline, while total-platinum gradually increased then slowly disappeared over several days. After CDDP-HAI, 15 HCCs shrunk and 27 HCCs grew. The reduction rate in the shrunken nodules was tended to be correlated with CDDP dose after standardization with the target liver volume. On the other hand, the growth rate of the enlarged HCCs was significantly correlated with CDDP dose after normalization with creatinine clearance. These data support a recommendation of CDDP-HAI infusion where the amount of CDDP (mg) administered is less than patient creatinine clearance (mL/min/1.73 m2) upon an assumption of HCC doubling time of 90 days, and the targeted liver is smaller than 200 times the CDDP dose (mg). A further analysis is required to define appropriate injection speeds.
PMCID: PMC3797567  PMID: 24133631
Cisplatin; dose recommendation; hepatic arterial infusion chemotherapy; hepatocellular carcinoma
5.  Phase I study of miriplatin combined with transarterial chemotherapy using CDDP powder in patients with hepatocellular carcinoma 
BMC Gastroenterology  2012;12:127.
There is no standard therapeutic procedure for the hepatocellular carcinoma (HCC) in patients with poor hepatic reserve function. With the approval of newly developed chemotherapeutic agent of miriplatin, we have firstly conducted the phase I study of CDDP powder (DDP-H) and miriplatin combination therapy and reported its safety and efficacy for treating unresectable HCC in such cases. To determine the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) for the combination of transarterial oily chemoembolization (TOCE) and transarterial chemotherapy (TAC) using miriplatin and DDP-H for treating unresectable hepatocellular carcinoma (HCC).
Transarterial chemotherapy using DDP-H was performed through the proper hepatic artery targeting the HCC nodules by increasing the dose of DDP-H (35–65 mg/m2) followed by targeting the HCC nodules by transarterial oily chemoembolization with miriplatin.
A total of nine patients were enrolled in this study and no DLT was observed with any dose of DDP-H in all cases in whom 80 mg (median, 18–120) miriplatin was administered. An anti-tumour efficacy rating for partial response was obtained in one patient, while a total of four patients (among eight evaluated) showed stable disease response, leading to 62.5% of disease control rate. The pharmacokinetic results showed no further increase in plasma platinum concentration following miriplatin administration.
Our results suggest that a combination of DDP-H and miriplatin can be safely administered up to their respective MTD for treating HCC.
Trial registration
This study was registered with the University Hospital Medical Information Network Clinical Trials Registry (UMIN-CTR000003541).
PMCID: PMC3482551  PMID: 22994941
Miriplatin; Hepatocellular carcinoma; Cisplatin powder; Phase I clinical trial
6.  Identification of cellular genes showing differential expression associated with hepatitis B virus infection 
World Journal of Hepatology  2012;4(4):139-148.
AIM: To investigate the impact of hepatitis B virus (HBV) infection on cellular gene expression, by conducting both in vitro and in vivo studies.
METHODS: Knockdown of HBV was targeted by stable expression of short hairpin RNA (shRNA) in huH-1 cells. Cellular gene expression was compared using a human 30K cDNA microarray in the cells and quantified by real-time reverse transcription-polymerase chain reaction (RT-PCR) (qRT-PCR) in the cells, hepatocellular carcinoma (HCC) and surrounding non-cancerous liver tissues (SL).
RESULTS: The expressions of HBsAg and HBx protein were markedly suppressed in the cells and in HBx transgenic mouse liver, respectively, after introduction of shRNA. Of the 30K genes studied, 135 and 103 genes were identified as being down- and up-regulated, respectively, by at least twofold in the knockdown cells. Functional annotation revealed that 85 and 62 genes were classified into four up-regulated and five down-regulated functional categories, respectively. When gene expression levels were compared between HCC and SL, eight candidate genes that were confirmed to be up- or down-regulated in the knockdown cells by both microarray and qRT-PCR analyses were not expressed as expected from HBV reduction in HCC, but had similar expression patterns in HBV- and hepatitis C virus-associated cases. In contrast, among the eight genes, only APM2 was constantly repressed in HBV non-associated tissues irrespective of HCC or SL.
CONCLUSION: The signature of cellular gene expression should provide new information regarding the pathophysiological mechanisms of persistent hepatitis and hepatocarcinogenesis that are associated with HBV infection.
PMCID: PMC3345538  PMID: 22567186
Hepatitis B virus; Differential gene expression; Hepatocellular carcinoma; Gene expression signature; Adipose most abundant 2
7.  Multicentric occurrence of hepatocellular carcinoma with nonalcoholic steatohepatitis 
World Journal of Hepatology  2011;3(1):15-23.
AIM: To reveal the manner of hepatocellular carcinoma (HCC) development in patients with nonalcoholic steatohepatitis (NASH) focusing on multicentric occurrence (MO) of HCC.
METHODS: We compared clinicopathological characteristics between patients with and without MO of HCC arising from NASH background. The clinical features were implicated with reference to the literature available.
RESULTS: MO of HCC was identified with histological proof in 4 out of 12 patients with NASH-related HCC (2 males and 2 females). One patient had synchronous MO; an advanced HCC, two well-differentiated HCCs and a dysplastic nodule, followed by the development of metachronous MO of HCC. The other three patients had multiple advanced HCCs accompanied by a well-differentiated HCC or a dysplastic nodule. Of these three patients, one had synchronous MO, one had metachronous MO and the other had both synchronous and metachronous MO. There were no obvious differences between the patients with or without MO in terms of liver function tests, tumor markers and anatomical extent of HCC. On the other hand, all four patients with MO of HCC were older than 70 years old and had the comorbidities of obesity, type 2 diabetes mellitus (T2DM), hypertension and cirrhosis. Although these conditions were not limited to MO of HCC, all the conditions were met in only one of eight patients without MO of HCC. Thus, concurrence of these conditions may be a predisposing situation to synchronous MO of HCC. In particular, old age, T2DM and cirrhosis were suggested to be prerequisite for MO because these factors were depicted in common among two other cases with MO of HCC under NASH in the literature.
CONCLUSION: The putative predisposing factors and necessary preconditions for synchronous MO of HCC in NASH were suggested in this study. Further investigations are required to clarify the accurate prevalence and predictors of MO to establish better strategies for treatment and prevention leading to the prognostic improvement in NASH.
PMCID: PMC3035698  PMID: 21307983
Nonalcoholic steatohepatitis; Hepatocellular carcinoma; Multicentric occurrence
8.  Shear wave velocity is a useful marker for managing nonalcoholic steatohepatitis 
AIM: To investigate whether a noninvasive measurement of tissue strain has a potential usefulness for management of nonalcoholic steatohepatitis (NASH).
METHODS: In total 26 patients, 23 NASHs and 3 normal controls were enrolled in this study. NASH was staged based on Brunt criterion. At a region of interest (ROI), a shear wave was evoked by implementing an acoustic radiation force impulse (ARFI), and the propagation velocity was quantified.
RESULTS: Shear wave velocity (SWV) could be reproducibly quantified at all ROIs in all subjects except for 4 NASH cases, in which a reliable SWV value was not calculated at several ROIs. An average SWV of 1.34 ± 0.26 m/s in fibrous stage 0-1 was significantly slower than 2.20 ± 0.74 m/s and 2.90 ± 1.01 m/s in stages 3 and 4, respectively, but was not significantly different from 1.79 ± 0.78 m/s in stage 2. When a cutoff value was set at 1.47 m/s, receiver operating characteristic analysis showed significance to dissociate stages 3 and 4 from stage 0-1 (P = 0.0092) with sensitivity, specificity and area under curve of 100%, 75% and 94.2%, respectively. In addition, the correlation between SWV and hyaluronic acid was significant (P < 0.0001), while a tendency toward negative correlation was observed with serum albumin (P = 0.053).
CONCLUSION: The clinical implementation of ARFI provides noninvasive repeated evaluations of liver stiffness at an arbitrary position, which has the potential to shed new light on NASH management.
PMCID: PMC2887589  PMID: 20556839
Nonalcoholic steatohepatitis; Ultrasound; Liver stiffness measurement; Shear wave velocity; Acoustic radiation force impulse
9.  Features of hepatocellular carcinoma in cases with autoimmune hepatitis and primary biliary cirrhosis 
AIM: To characterize the clinical features of hepatocellular carcinoma (HCC) associated with autoimmune liver disease, we critically evaluated the literature on HCC associated with autoimmune hepatitis (AIH) and primary biliary cirrhosis (PBC).
METHODS: A systematic review of the literature was conducted using the Japana Centra Revuo Medicina database which produced 38 cases of HCC with AIH (AIH-series) and 50 cases of HCC with PBC (PBC-series). We compared the clinical features of these two sets of patients with the general Japanese HCC population.
RESULTS: On average, HCC was more common in men than in women with AIH or PBC. While many patients underwent chemolipiodolization (CL) or transcatheter arterial embolization (TAE) (AIH-series: P = 0.048 (vs operation), P = 0.018 (vs RFA, PEIT); PBC-series: P = 0.027 (vs RFA, PEIT), others refused therapeutic interventions [AIH-series: P = 0.038 (vs RFA, PEIT); PBC-series: P = 0.003 (vs RFA, PEIT)]. Liver failure was the primary cause of death among patients in this study, followed by tumor rupture. The survival interval between diagnosis and death was fairly short, averaging 14 ± 12 mo in AIH patients and 8.4 ± 14 mo in PBC patients.
CONCLUSION: We demonstrated common clinical features among Japanese cases of HCC arising from AIH and PBC.
PMCID: PMC2653317  PMID: 19132775
Autoimmune hepatitis; Autoimmune liver disease; Hepatocellular carcinoma; Literature review; Primary biliary cirrhosis
10.  Long-term outcomes of hepatectomy vs percutaneous ablation for treatment of hepatocellular carcinoma ≤ 4 cm 
AIM: To determine which treatment modality - hepatectomy or percutaneous ablation - is more beneficial for patients with small hepatocellular carcinoma (HCC) (≤ 4 cm) in terms of long-term outcomes.
METHODS: A retrospective analysis of 149 patients with HCC ≤ 4 cm was conducted. Eighty-five patients underwent partial hepatectomy (anatomic in 47 and non-anatomic in 38) and 64 underwent percutaneous ablation (percutaneous ethanol injection in 37, radiofrequency ablation in 21, and microwave coagulation in 6). The median follow-up period was 69 mo.
RESULTS: Hepatectomy was associated with larger tumor size (P < 0.001), whereas percutaneous ablation was significantly associated with impaired hepatic functional reserve. Local recurrence was less frequent following hepatectomy (P < 0.0001). Survival was better following hepatectomy (median survival time: 122 mo) than following percutaneous ablation (median survival time: 66 mo; P = 0.0123). When tumor size was divided into ≤ 2 cm vs > 2 cm, the favorable effects of hepatectomy on long-term survival was seen only in patients with tumors >2 cm (P = 0.0001). The Cox proportional hazards regression model revealed that hepatectomy (P = 0.006) and tumors ≤ 2 cm (P = 0.017) were independently associated with better survival.
CONCLUSION: Hepatectomy provides both better local control and better long-term survival for patients with HCC ≤ 4 cm compared with percutaneous ablation. Of the patients with HCC ≤ 4 cm, those with tumors > 2 cm are good candidates for hepatectomy, provided that the hepatic functional reserve of the patient permits resection.
PMCID: PMC4066085  PMID: 16489666
Liver neoplasms; Hepatocellular carcinoma; Hepatectomy; Percutaneous ablation; Prognosis; Multivariate analysis

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