清野 宗一郎

AIMS: We evaluated the long-term prognosis of patients with obscure gastrointestinal bleeding (OGIB) who underwent capsule endoscopy (CE). METHODS: In our hospital, 429 patients underwent CE between November 2007 and March 2012. Among them, 259 patients underwent CE as the first examination for OGIB and were then followed at 77 clinics and hospitals. The clinical characteristics were investigated, including age, gender, overt/occult bleeding, the use of antithrombotic drugs and NSAIDs, complications (liver cirrhosis and hemodialysis), and CE. We asked the medical institutions for their survival data as of August 2017 (> 5 years after CE). RESULTS: The prognoses of 240 patients (92.6%) were analyzed. The average follow-up period was 55.7 (1-115) months. During the follow-up period, 57 patients (23.8%) died and the survival rates were 90.5% at 1 year, 81.7% at 3 years, and 74.7% at 5 years. Age 65 years or older and liver cirrhosis were predictive factors for a poor prognosis. Rebleeding occurred in 42 patients (17.9%) and small bowel cancer and gastrointestinal stromal tumor were found at 12 and 21 months after CE, respectively. CONCLUSIONS: Patients with OGIB showed a poor prognosis, especially those who were elderly or who had liver cirrhosis.

Background: To examine the incidence of cirrhosis patients with high-risk esophageal varices (EV) who show hepatic venous pressure gradient (HVPG) < 10 mmHg and to identify their hemodynamic features. Methods: This prospective study consisted of 110 cirrhosis patients with EV, all with the candidate for primary or secondary prophylaxis. Sixty-one patients had red sign, and 49 patients were bleeders. All patients underwent both Doppler ultrasound and HVPG measurement. Results: There were 18 patients (16.4%) with HVPG < 10 mmHg. The presence of venous-venous communication (VVC) was more frequent in patients with HVPG < 10 mmHg (10/18) than in those with HVPG ≥ 10 mmHg (19/92; p = 0.0021). The flow volume in the left gastric vein (LGV) and the incidence of red sign were higher in the former (251.9 ± 150.6 mL/min; 16/18) than in the latter (181 ± 100.5 mL/min, p = 0.02; 45/92; p = 0.0018). The patients with red sign had lower HVPG (13.3 ± 4.5) but advanced LGV hemodynamics (velocity 13.2 ± 3.8 cm/s; flow volume 217.5 ± 126.6 mL/min), whereas those without red sign had higher HVPG (16.2 ± 4.6, p = 0.001) but poorer LGV hemodynamics (10.9 ± 2.3, p = 0.002; 160.1 ± 83.1, p = 0.02). Conclusion: Patients with high-risk EV with HVPG < 10 mmHg showed 16.4% incidence. Although low HVPG may be underestimated by the presence of VVC, the increased LGV hemodynamics compensates for the severity of portal hypertension, which may contribute to the development of red sign.

OBJECTIVE: To examine the effect of hemodynamic assessment of the left gastric vein (LGV) as a noninvasive test to diagnose esophageal varices (EV) in cirrhosis patients. METHODS: This cross-sectional study consisted of 229 cirrhosis patients (62.7 ± 11.8 years; Child-Pugh score 5-14). One hundred fifty-four patients had EV (67.2%; small, 53; medium, 71; large, 30). All patients underwent a blood test and Doppler ultrasound followed by upper gastrointestinal endoscopy on the same day. The diagnostic ability for EV was compared between LGV-related findings and the platelet count/spleen diameter ratio (Plt/Spl). RESULTS: The detectability of the LGV was higher in patients with EV (129/144, 89.6%) than in those without (35/75, 46.7%; p < 0.0001), and was higher in those with large EV (30/30, 100%) than in those without (134/199, 67.3%; p = 0.0002). The positive detection of the LGV showed 100% sensitivity and negative predictive value (NPV) to identify large EV in the whole cohort and compensated group (n = 127). The best cutoff value in the LGV diameter was 5.35 mm to identify large EV, showing 0.753 area under the receiver operating characteristic curve (AUROC) with 90% sensitivity and 96.5% NPV. The Plt/Spl showed 62.1% sensitivity and 87.1% NPV, and the best cutoff value was 442.9 to identify large EV with 0.658 AUROC, which was comparable to LGV-based assessment (p = 0.162). CONCLUSIONS: This same-day comparison study demonstrated the value of LGV-based noninvasive test to identify large EV with high sensitivity and NPV in cirrhosis patients at a lower cost.

BACKGROUND: To propose an ultrasound-based parameter for the diagnosis of muscle mass loss (MML) in cirrhosis. METHODS: This is an IRB-approved cross-sectional study (October 2013 to January 2017) with written informed consent including 357 subjects-234 cirrhosis and 123 controls. MML was diagnosed using the skeletal muscle index at the L3 level (L3-SMI) on computed tomography (CT). Transcutaneous ultrasound was used to demonstrate a cross section of the right iliopsoas muscle, and the iliopsoas muscle index (IP index) was defined by the iliopsoas muscle area/height2 (mm2/m2). Receiver operating characteristic (ROC) curve analysis was performed to assess the diagnostic ability of IP index for MML. RESULTS: The iliopsoas muscle was detected in all subjects. The IP index was lower in cirrhosis than in controls: males (211.2 ± 73.8 vs. 295.5 ± 139.4, P < 0.0001) and females (200.2 ± 72.5 vs. 284.4 ± 112.4, P < 0.0001). L3-SMI and IP index showed correlations in males (r = 0.699, P < 0.0001) and in females (r = 0.707, P < 0.0001). Independent factors for MML by multivariate analysis were body mass index and IP index in both males and females. Sensitivity, specificity, and area under the ROC curve by IP index to detect MML were 79.5%, 73.1%, and 0.835, respectively, with the best cut-off value of 189.2 for males, and 84.6%, 78.8%, and 0.874, respectively, with the best cut-off value of 180.6 for females. CONCLUSIONS: Using transcutaneous ultrasound, the IP index may be a valuable diagnostic parameter for MML in cirrhosis.

Background Regorafenib has been investigated for its efficacy and safety as a second-line treatment in patients with advanced hepatocellular carcinoma (HCC). We assessed the characteristics of patients with HCC treated with sorafenib who might be eligible for second-line treatment in general and regorafenib in particular. Methods Patients with HCC treated with sorafenib were retrospectively analyzed. We defined second-line candidate patients as maintaining Child-Pugh A and ECOG-PS ≤1 at the time of sorafenib failure. We also defined regorafenib candidate patients as follows: 1) continuing sorafenib at the time of radiological progression, 2) maintaining Child-Pugh A and ECOG-PS ≤ 1 at the time of sorafenib failure, and 3) continuing sorafenib 400 mg or more without intolerable adverse events at least 20 days of the last 28 days of treatment. Results Of 185 patients, 130 (70%) and 69 (37%) were candidates for second-line treatment and regorafenib. Child-Pugh score 6 and ECOG-PS 1 at the time of starting sorafenib were significantly lower in both second-line treatment and regorafenib candidate patients. Moreover, hand-foot skin reaction and liver failure during sorafenib treatment were associated with significantly low and high probabilities, respectively, of both Child-Pugh score > 6 and ECOG-PS > 1 at the time of sorafenib failure. Conclusion Regorafenib candidate patients after sorafenib failure are limited, and generally fewer than those who are candidates for second-line treatment. A lower Child-Pugh score and a better ECOG-PS were predictors of eligibility for second-line therapy and regorafenib treatment in sorafenib-treated patients with advanced HCC patients.

BACKGROUND: Sustained virologic response (SVR) by interferon and interferon-free treatment can results in the reduction of advanced liver fibrosis and the occurrence of hepatocellular carcinoma in patients infected with hepatitis C virus (HCV). Recent interferon-free treatment for HCV shortens the duration of treatment and leads to higher SVR rates, without any serious adverse events. However, it is important to retreat patients who have had treatment-failure with HCV non-structural protein 5A (NS5A) inhibitor-including regimens. Combination of sofosbuvir and ledipasvir only leads to approximately 100% SVR rates in HCV genotype (GT1b), NS5A inhibitor-naïve patients in Japan. This combination is not an indication for severe renal disease or heart disease, and these patients should be treated or retreated with a different regimen. CASE SUMMARY: Retreatment with HCV non-structural protein 3/4A inhibitor, grazoprevir, and HCV NS5A inhibitor, elbasvir, successfully eradicated HCV RNA in three patients with HCV genotype 1b infection who discontinued prior interferon-free treatments including HCV NS5A inhibitors due to adverse events within 2 weeks. CONCLUSION: Retreatment with the 12-week combination regimen of grazoprevir and elbasvir is effective for HCV GT1b patients who discontinue the HCV NS5A inhibitor-including regimens within 2 weeks. The treatment response may be related to the short duration of initial treatment, which did not produce treatment-emergent RASs.

BACKGROUND: Interferon-free treatment can achieve higher sustained virological response (SVR) rates, even in patients in whom hepatitis C virus (HCV) could not be eradicated in the interferon treatment era. Immune restoration in the liver is occasionally associated with HCV infection. We examined the safety and effects of interferon-free regimens on HCV patients with autoimmune liver diseases. RESULTS: All 7 HCV patients with autoimmune hepatitis (AIH) completed treatment and achieved SVR. Three patients took prednisolone (PSL) at baseline, and 3 did not take PSL during interferon-free treatment. In one HCV patient with AIH and cirrhosis, PSL were not administered at baseline, but she needed to take 40 mg/day PSL at week 8 for liver dysfunction. She also complained back pain and was diagnosed with vasospastic angina by coronary angiography at week 11. However, she completed interferon-free treatment. All 5 HCV patients with primary biliary cholangitis (PBC) completed treatment and achieved SVR. Three of these HCV patients with PBC were treated with UDCA during interferon-free treatment. CONCLUSIONS: Interferon-free regimens could result in higher SVR rates in HCV patients with autoimmune liver diseases. As interferon-free treatment for HCV may have an effect on hepatic immunity and activity of the autoimmune liver diseases, careful attention should be paid to unexpected adverse events in their treatments. METHODS: Total 12 patients with HCV and autoimmune liver diseases [7 AIH and PBC], who were treated with interferon-free regimens, were retrospectively analyzed.

This retrospective study aimed to assess the diagnostic performance of contrast-enhanced ultrasound with Sonazoid (S-CEUS) for liver metastasis. We enrolled in this study 98 patients with 148 histologically proven liver lesions, with 121 metastases and 27 non-metastases. The S-CEUS technique showed sensitivity in 95.0% (115 of 121), specificity in 44.4% (12 of 27) and accuracy in 85.8% (127 of 148) for the diagnosis of metastasis. Higher body mass index had a negative influence on the positive predictive value and accuracy, and a greater depth of the lesion had a negative influence on the accuracy. The management was changed in 8 patients (8.2%) because of S-CEUS findings. In conclusion, the addition of S-CEUS may offer a great benefit by improvement of the quality of diagnosis and management for patients with cancer who have a tentative diagnosis of liver metastasis by contrast-enhanced computed tomography.

We report a case of asymptomatic non-cirrhotic primary biliary cholangitis (PBC) showing splenorenal shunt with neither anti-mitochondrial antibody nor M2 antibody. A 67-year-old female with Sjögren’s syndrome was admitted to our hospital to undergo liver biopsy and hepatic venous catheterization for detailed evaluation of liver disease because of the elevation of serum ammonia level and to-and-fro appearance in the splenic vein. There were no clinical signs of encephalopathy and itching. Abdominal computed tomography showed no findings for chronic liver disease, no evidence of splenomegaly or ascites. Hepatic venography showed no abnormal findings in the hepatic vein and intrahepatic portal vein, and hepatic venous pressure gradient was 4.8 mmHg. Final diagnosis was made by liver biopsy showing chronic non-suppurative destructive cholangitis, indicating PBC (Scheuer’s classification, stage 2 Nakanuma’s classification, stage 3).

A 25-year-old male was admitted to our hospital to undergo detailed evaluation of liver disease and abdominal hemodynamics because of suspicious abnormality of inferior vena cava (IVC) on computed tomography. Doppler ultrasonography showed tortuous-shaped vessel at the hepatic tract of IVC with continuous blood flow. Furthermore, he was accompanied with splenorenal shunt showing bidirectional flow or hepatopetal direction and cystic dilatation at the left renal vein. These findings were confirmed by angiogram, which also revealed continuation of IVC with azygos vein. There were no abnormal findings on liver biopsy sample and hepatic venous pressure gradient (0.74 mmHg), however he was accompanied with splenomegaly probably due to the increased inflow to portal system. Although congenital anomalies of the IVC are increasingly recognized even in asymptomatic condition with frequent use of radiological imaging, this is a very rare case of infrahepatic incomplete interruption of IVC with both azygos and portal continuation.

Background: There are only limited data regarding the effect of impaired portal circulation on the glucose metabolism. The study prospectively examined the interrelationship between insulin resistance (IR) and portal haemodynamic abnormality in cirrhosis. Methods: There were 53 cirrhosis patients (61.6 ± 13.0 years) all presenting gastroesophageal varices. Portal haemodynamics by both hepatic venous catheterisation and Doppler ultrasound were examined with respect to the homeostasis model assessment (HOMA)-IR and HOMA2-IR. The IR was defined by HOMA-IR > 3.0 or HOMA2-IR > 2.0. Results: Forty-two patients (79.2%) had collateral vessels, 38 with left gastric vein, 12 with short/posterior gastric vein, 9 with splenorenal shunt, and 3 with inferior mesenteric vein. Multivariate analysis provided significant factors; wedged hepatic venous pressure (HR1.183, 95% CI 1.012-1.383, p=0.035) for HOMA-IR > 3.0, body mass index for HOMA2-IR > 2.0 (HR1.490, 95% CI 1.176-1.888, p=0.001), and collateral flow volume for both HOMA-IR > 3.0 (HR1.007, 95% CI 1.001-1.014, p=0.015) and HOMA2-IR > 2.0 (HR 1.007, 95% CI 1.002-1.013, p=0.009). The best cut-off value of collateral flow volume was 165 ml/min for detecting the HOMA-IR > 3.0 showing area under the receiver operating characteristic curve (AUROC) 0.688 (Odds ratio, 5.33) with sensitivity 70% and specificity 69.6%, and was 165 ml/min for detecting median value of HOMA2-IR > 2.0 showing AUROC 0.698 (odds ratio, 5.7) with sensitivity 75% and specificity 65.5%. Conclusion: There is a close linkage between the IR and impaired portal haemodynamics presented by the collateral development, suggesting the underlying pathogenesis of portal hypertension in cirrhosis patients.

Background: To examine the influence of the severity of portal hemodynamic abnormality on the prognosis of cirrhosis with respect to the muscle mass loss (MML). Methods: The study involved a subgroup analysis in 98 cirrhosis patients (63.5 ± 11.8 years) who prospectively underwent both Doppler ultrasound and hepatic venous catheterization. The prognostic influence of MML diagnosed by computed tomography using the L3 skeletal muscle index was evaluated (median observation period, 32.7 months). Results: The cumulative survival rate showed difference between patients with MML (n = 34; 82.2%/1year, 41.2%/3years and 36.1%/5years) and those without (n = 64; 92.1%/1year, 74.9%/3years and 69.4%/5years; P = 0.005). When divided with respect to the portal velocity, the survival rate showed differences between patients with and without MML in the cohort < 12.8 cm/s (n=52, p=0.009) and ≥ 12.8 cm/s (n=44, p=0.041). The survival rate also showed differences between patients with MML (n = 24; 78.8%/1year, 40.6%/3years and 34.8%/5years) and those without (n = 45; 91.1%/1year, 71.3%/3years and 63.1%/5years; P = 0.008) in the cohort with hepatic venous pressure gradient (HVPG) > 12 mmHg. However, in the cohort with HVPG ≤ 12 mmHg, survival rate showed no difference between patients with MML (n=10; 100%/1year, 61.9%/3years and 61.9%/5years) and those without (n=19; 93.8%/1year, 71.2%/3years and 59.4%/5years; p = 0.493) Conclusion: Lower HVPG has a compensating effect on the MML-induced poor prognosis of cirrhosis. Care should be taken in the evaluation of the influence of MML in consideration of the severity of portal hypertension.

AIM: To determine the prognostic effect of portal hemodynamic responses after balloon-occluded retrograde transvenous obliteration (B-RTO) for gastric varices (GV) in cirrhosis patients. METHODS: This retrospective study consisted of 37 cirrhosis patients (aged 62.5 ± 9.7 years) with medium- or large-grade GV treated with B-RTO. Portal hemodynamic response was assessed by the changes in flow volume in the portal trunk (PFV, mL/min) before and after the treatment. Group I showed increased PFV and group II showed no increase in PFV. The median observation period was 49.8 months (range, 4.7-150.3 months). RESULTS: All patients showed complete embolization of GV without any recurrence. There were 30 patients in group I and 7 patients in group II (decreased PFV in 6 and unchanged PFV in 1). The PFV at baseline was significantly lower in the former (583.5 ± 232.0 mL/min) than in the latter (880.7 ± 345.9 mL/min; P = 0.009). The survival rate was significantly lower in group II (83.3% at 1 year and 66.7% at 3 years) than in group I (96.7% at 1 year, 81.5% at 3 years, and 61.8% at 5 years; P = 0.012). The incidence of deterioration of the esophageal varices was 18/30 (60%) in group I and 5/7 (71.4%; P = 0.687) in group II. Multivariate analysis identified only no increase in portal response (hazard ratio, 8.086; P = 0.005) as an independent factor for poor prognosis. CONCLUSION: Balloon-occluded retrograde transvenous obliteration for GV may result in a poor prognosis when portal hemodynamics shows no increase in portal response.

BACKGROUND: To examine the hemodynamic effect of the left gastric artery (LGA) on the esophageal varices (EV) in cirrhosis. METHODS: This was a prospective study performed in 48 cirrhosis patients (35 men, 13 women; median age 61.6 ± 11.3 years, range 38-83 years) with EV (medium 35, large 13), who underwent selective LGA angiography, hepatic venous catheterization, endoscopic ultrasonography (EUS) and Doppler ultrasonography before endoscopic treatment for EV. Angiographic findings including diameter of the main trunk, detection time of EV, and mild/severe degree of peripheral staining were assessed. The median period of post-treatment observation was 17.1 months. RESULTS: LGA angiograms were successfully obtained in 45/48 patients. EV were demonstrated in 45/45 patients, with a mean detection time of 6.9 s (2-21), which was longer in patients with variceal recurrence (7.0 s) than in those without (5.6 s, P = 0.480). The staining was mild in 25 patients (55.6 %) and severe in 20 patients (44.4 %), and portal hypertensive gastropathy was more frequent in the latter (13/20, 65.0 %) than in the former (7/25, 28.0 %, P = 0.013). Multivariate analysis showed that pre-treatment detection time (P = 0.04) and post-treatment submucosal vascular area at the cardia wall by EUS (P = 0.036) were significant factors for variceal recurrence. No other factors, including hepatic venous pressure gradient and Doppler parameters, showed significant relationships with the variceal recurrence. CONCLUSIONS: The hemodynamics in the LGA may act as an initiator of variceal formation, showing close linkage with variceal recurrence, and independent of portal pressure.

BACKGROUND: The aim of the present study was to examine the diagnostic ability of two-dimensional shear wave elastography (2D-SWE) with propagation-based reliability for grading of hepatic fibrosis and portal hypertension. METHODS: This prospective study (UMIN000022838) consisted of 135 subjects. Phase I (n = 40) examined the effect of standard deviation (SD)/median as the reliability criterion of 2D-SWE, and phase II (n = 95) compared the diagnostic ability of 2D-SWE under the best SD/median value and transient elastography (TE). RESULTS: Phase I reported 0.49 as a best cut-off SD/median value. In phase II, the elasticity showed a correlation between the 2D-SWE and TE (r = 0.88, P < 0.001). The area under the receiver operating characteristic curve (AUROC) was comparable between the 2D-SWE and TE (0.936 and 0.948 for chronic hepatitis, P = 0.34; 0.939 and 0.956 for cirrhosis, P = 0.25). The hepatic venous pressure gradient showed a positive correlation with the 2D-SWE (r = 0.435, P = 0.043) and TE (r = 0.378, P = 0.083) in 22 patients. The AUROC was comparable between the 2D-SWE (0.844 for ≥10 mmHg, 0.838 for ≥12 mmHg) and TE (0.781 for ≥10 mmHg, P = 0.484; 0.800 for ≥12 mmHg, P = 0.589). CONCLUSIONS: 2D-SWE is promising for the assessment of the grade of hepatic fibrosis and portal hypertension, with the SD/median value as a reliability criterion.

The aim of the study described here was to elucidate the efficacy of contrast-enhanced ultrasound (CEUS) prospectively as a tool in the diagnosis of portal hypertensive gastropathy (PHG). The peak enhancement time at the upper stomach wall (PT) and intensity ratio at the upper stomach/the spleen (IR) between pre- and peak enhancement were evaluated by CEUS with perflubutane microbubble agent in 56 patients, 42 with cirrhosis (16 with PHG) and 14 controls. The IR was higher in patients with PHG (1.21 ± 0.11) than in those without (0.91 ± 0.15, p < 0.05) and the controls (0.78 ± 0.11, p < 0.01), although PT did not differ between these groups. The area under the receiver operating characteristic curve for IR was 0.8199 in the presence of PHG, with the best cutoff value of 0.94, sensitivity 65.9%, specificity 72.6%, positive predictive value 62.2%, negative predictive value 73.1% and accuracy 70.4%. CEUS may have potential as a less invasive tool for diagnosis of PHG in patients with cirrhosis.

AIM: To evaluate the clinical features and prognoses in adult patients with extrahepatic portal vein obstruction (EHO) from the aspect of portal hypertension during the last 20 years in Japan. METHODS: There were 40 EHO patients (aged 21-77 years; mean ± standard deviation [SD], 54.6 ± 15.0). Clinical findings and prognoses were examined retrospectively during the median observation period of 71.6 months. RESULTS: Twenty-two patients (55%) showed positive signs of portal hypertension; 18 with esophageal varices (F0, one; F1, eight; F2, nine), two with gastric varices (F1, one; F2, one) and seven with mild ascites. Multivariate analysis showed that platelet count and spleen size were significant factors for the presence of gastroesophageal varices, with odds ratios of 0.989 (95% confidence interval [CI], 0.980-0.997; P = 0.011) for platelet count and 1.003 (95% CI, 1.001-1.005; P = 0.003) for spleen size. Ten of 20 patients with gastroesophageal varices received primary prophylaxis and only one patient (10%) showed variceal recurrence. The cumulative overall survival rate was 100% at 1 year, 94.2% at 3-7 years and 68.7% at 10 years. The cumulative survival rates did not differ between the patients with and without gastroesophageal varices, with and without ascites, and patterns of portal cavernoma at baseline. CONCLUSION: Forty-five percent of adult EHO patients in Japan were free from signs of portal hypertension, and platelet count and spleen size are predictive for identifying patients with gastroesophageal varices. EHO patients with gastroesophageal varices show favorable prognoses comparable to those without, if primary/secondary prophylaxis was performed appropriately.

BACKGROUND AND AIM: To demonstrate the effect of endoscopic injection sclerotherapy (EIS) with argon plasma coagulation (APC) as a primary/secondary prophylaxis for esophageal varies (EV) on portal hemodynamics and long-term outcomes in cirrhosis. METHODS: This prospective study included 48 cirrhotic patients (64.5 ± 11.4 years; 26 bleeders, 22 non-bleeders). Post-treatment outcomes (EIS and APC; median observation period, 12.8 months for recurrence and 21.1 months for prognosis) were evaluated with respect to the findings of hepatic venous catheterization, Doppler ultrasound, and endoscopic ultrasonography (EUS). RESULTS: All patients showed EV eradication after endoscopic treatment, and a decreased frequency of a patent left gastric vein (pre: 83.3%, post: 27.1%, P < 0.001). However, hepatic venous pressure gradient (HVPG, mmHg) remained unchanged after the treatment, pre: 16.1 ± 3.6, post: 15.6 ± 3.8 (P = 0.269). Cumulative variceal recurrence/rebleeding rates were 25.5%/5.6% and 62.4%/23.1% at 1 and 3 years, respectively. Post-treatment EUS finding, area of submucosal vessels in the cardia ≥12 mm2 was the only significant factor for variceal recurrence (hazard ratio 9.769, 95% confidence interval 3.046-31.337; P < 0.001). Cumulative recurrence rate was significantly higher in patients with area of submucosal vessels in the cardia ≥12 mm2 (58.3% at 1 year and 100% at 3 years) than in those without (11.4% at 1 year and 40.9% at 3 years, P < 0.001). Cumulative overall survival rates were 95.2% and 71.9% at 1 and 3 years, respectively, showing no significant relationship with HVPG. CONCLUSION: EIS with APC for EV is unlikely to have a significant influence on portal pressure.

The aim was to examine the effect of free fatty acids on the regulation of PPARγ-PGC1α pathway, and the effect of PPARγ/PGC1α in NAFLD. The mRNA and protein expression of PGC1α and phospho/total PPARγ were examined in Huh7 cells after the palmitate/oleate treatment with/without the transfection with siRNA against PGC1a. The palmitate content, mRNA and protein expression of PGC1α and PPARγ in the liver were examined in the control and NAFLD mice. Palmitate (500 μM), but not oleate, increased protein expression of PGC1α and phospho PPARγ (PGC1α, 1.42-fold, P=0.038; phospho PPARγ, 1.56-fold, P=0.022). The palmitate-induced PPARγ mRNA expression was reduced after the transfection (0.46‑fold), and the protein expressions of PGC1α (0.52-fold, P=0.019) and phospho PPARγ (0.43-fold, P=0.011) were suppressed in siRNA-transfected cells. The palmitate (12325.8 ± 1758.9 μg/g vs. 6245.6 ± 1182.7 μg/g, p=0.002), and mRNA expression of PGC1α (11.0 vs. 5.5, p=0.03) and PPARγ (4.3 vs. 2.2, p=0.0001) in the liver were higher in high-triglyceride liver mice (>15.2 mg/g) than in low-triglyceride liver mice (<15.2 mg/g). The protein expressions of both PGC1α and PPARγ were higher in the NAFLD group than in the controls (PGC1α, 1.41-fold, P=0.035; PPARγ, 1.39-fold, P=0.042), and were higher in the high-triglyceride liver group (PGC1α, 1.52-fold, p=0.03; PPARγ, 1.22-fold, p=0.05) than in the low-triglyceride liver group. In conclusion, palmitate appear to up-regulate PPARγ via PGC1α in Huh7 cells, and both PGC1α and PPARγ are up-regulated in the NAFLD mice liver, suggesting an effect on lipid metabolism leading to intrahepatic triglyceride accumulation.

This prospective study aimed to elucidate the effect of phase-related quantitative parameters of contrast-enhanced ultrasound (CEUS) with perflubutane microbubble agent to assess the cellular differentiation of hepatocellular carcinoma (HCC). Intensity was analyzed in 94 lesions (19.4 ± 4.9 mm, 86 patients), 47 well-differentiated HCCs (wHCCs) and 47 moderately-differentiated HCCs (mHCCs): I(e) (early phase) = I(te) (tumor) - I(le) (liver), I(p) (post-vascular phase) = I(tp) (tumor) - I(lp) (liver), I(ep) = I(e) - I(p). The area under the receiver operating characteristic curve with the best cutoff value (I(e), 13.2, I(p), -4.5, I(ep), 21.3) for discriminating between wHCC and mHCC was 0.6922 for Ie, 0.7680 for Ip and 0.7925 for Iep, which indicated a significantly greater ability to differentiate between wHCC and mHCC compared with visual/qualitative assessment (early phase, 0.6170, p = 0.04; post-vascular phase, 0.6702, p = 0.01; both phases, 0.7021, p = 0.04). In conclusion, I(ep) was found to have the highest diagnostic ability, suggesting it is a promising parameter for the cellular differentiation of HCCs with CEUS.

BACKGROUND AND AIM: To examine the relationship between hyponatremia and portal hemodynamics and their effect on the prognosis of cirrhosis. METHODS: Portal hemodynamic parameters measured by Doppler ultrasound and serum sodium concentrations were examined in 153 cirrhosis patients (mean age 62.2 ± 12.0 years; median observation period, 34.1 m). RESULTS: Study participants included 16 patients with hyponatremia (Na < 135 mEq/L), who showed a significantly greater frequency of possessing a splenorenal shunt (SRS; P = 0.0068), and 137 patients without hyponatremia. Serum sodium concentrations were significantly lower in patients with SRS than in those without (P = 0.0193). An increased prothrombin time-international normalized ratio was a significant predictive factor for developing hyponatremia a year later (8/96; Hazard ratio 14.415; P = 0.028). The cumulative survival rate was significantly lower in patients with hyponatremia (46.7% at 1 and 3 years) than in those without (91.8% at 1 year, 76.8% at 3 years; P < 0.001). The cumulative survival rate was significantly lower in patients who had developed hyponatremia after 1 year (100% at 1 year, 62.5% at 3 years) than those who had not (100% at 1 year, 89.0% at 3 years; P < 0.001). The cumulative survival rate was significantly worse in patients with both hyponatremia and SRS (20% at 1 year). CONCLUSIONS: There was a close linkage between the serum sodium concentration and portal hemodynamic abnormality, presence of SRS, and their interaction may negatively influence the prognoses in cirrhosis.

BACKGROUND: To identify prognostic factors prospectively in cirrhosis after the eradication of esophageal varices (EV). METHODS: There were 52 cirrhosis patients (Child-Pugh A 24, B 28) who showed the eradication of EV after the endoscopic sclerotherapy (median observation period, 25.5 months). RESULTS: Eighteen patients showed a recurrence of EV. The cumulative overall survival rate was 92.2% at 1 year, 70.9% at 3 years, and 47.2% at 5 years. Univariate analysis showed that serum sodium concentration (hazard ratio [HR] 0.724, P = 0.0006), serum aspartate transaminase (HR 1.019, P = 0.0075), serum alanine transaminase (HR 1.025, P = 0.0239), and serum creatinine (HR 11.311, P = 0.044) levels before treatment were significant factors for a poor prognosis. Multivariate analysis revealed that serum sodium concentration (HR 0.711, P = 0.0022) was the only significant factor. The cumulative survival rate was lower in patients with hyponatremia (<135 mEq/l, a best cut-off value; 83.3% at 1 year, and 33.3% at 3 years), than in those without (93.3% at 1 year, 77.3% at 3 years and 47.2% at 5 years). CONCLUSIONS: Pre-treatment hyponatremia is a significant prognostic factor in cirrhosis with Child A/B after the eradication of EV by the endoscopic sclerotherapy.

The aim of this prospective study was to assess the relationship between liver stiffness and hepatic vein waveform patterns in 42 patients with chronic hepatitis and 55 with cirrhosis. Liver stiffness measurement (LSM) values (FibroScan, Echosens, Paris, France) were significantly lower in the triphasic pattern group (11.3 ± 8.4 kPa) than in the monophasic pattern (32.5 ± 23.5 kPa, p = 0.001) and biphasic pattern (25.6 ± 18.1 kPa, p = 0.001) groups, indicating no significant relationship with portal pressure. The ability to diagnose cirrhosis represented by the highest area under the receiver operating characteristic curve was 0.921 (83.6% sensitivity, 90.5% specificity, best cutoff value: 16.9 kPa) by LSM and 1.000 (best cutoff value: 19.4 kPa) by LSM combined with the monophasic pattern. This study revealed a close linkage between liver stiffness and hepatic vein waveform findings, resulting in a better understanding of hepatic vein hemodynamics and wider application of its analysis.

BACKGROUND AND AIM: Impaired splanchnic hemodynamics are well-documented phenomena in cirrhosis. However, comprehensive hemodynamic features from the superior mesenteric artery (SMA) to the superior mesenteric vein (SMV) via intestinal capillaries have not been studied. The aim was to examine splanchnic hemodynamics and their relationship with clinical presentations. METHODS: Contrast-enhanced ultrasound was performed for both the SMA and SMV under fasting conditions and postprandially following ingestion of a liquid diet. The microbubble traveling time (MTT) was determined as the difference between the contrast onset in the SMA and SMV, indicating the time required for microbubble transit through the splanchnic circulation. RESULTS: There were 192 subjects for fasting conditions (81 cirrhosis, 72 chronic hepatitis, 39 healthy controls), and 74/192 for postprandial conditions (44 cirrhosis, 11 chronic hepatitis, 19 healthy controls). The MTT (fasting; postprandial) was significantly longer in cirrhosis (7.7 ± 2.9 s; 7.0 ± 0.3 s) than in controls (5.4 ± 2.3 s, P < 0.001; 3.9 ± 0.9 s, P<0.001) and chronic hepatitis (6.3 ± 2.5 s, P=0.007; 5.1 ± 1.4 s, P=0.013). The MTT ratio (postprandial/fasting) showed disease-related changes: 0.75 ± 0.20 in controls, 0.78 ± 0.15 in chronic hepatitis, and 1.00 ± 0.28 in cirrhosis (P=0.003, vs controls; P=0.036, vs chronic hepatitis). CONCLUSIONS: The real-time observation of traveling microbubble on the sonogram revealed a prolonged transit with a weak postprandial response in the intestinal circulation, suggesting better understanding of underlying pathophysiology of splanchnic hemodynamics in chronic liver disease.

OBJECTIVE: To examine the clinical effect of splenorenal shunt (SRS) on the long-term outcomes in patients with cirrhosis. METHODS: The study consisted of 162 cirrhosis patients (male 85, female 77; 62.6 ± 11.7 years). The clinical findings and prognosis were examined with respect to portal hemodynamics including collateral vessel patterns, with or without the presence of SRS or short gastric vein (SGV). Median observation period was 30 months. RESULTS: The incidence was 18.5% for SRS and 10.5% for SGV. Decompensated cirrhosis was significantly more frequent in patients with SRS (22/30) than those with SGV (5/17, p = 0.0034), and in patients with SRS >5.5 mm (14/15) or >95 ml/min (14/15) (both, median values) than those with SRS <5.5 mm (8/15, p = 0.013) or <95 ml/min (8/15, p = 0.013). Cumulative overall survival rate was 87.4% at 1 year, 73.4% at 3 years, and 59.1% at 5 years. There was no significant difference in the cumulative survival rate according to the development of SRS: 80% at 1 year, 66.6% at 3 years, and 58.3% at 5 years in patients with SRS; 94.1% at 1 year, 87.4% at 3 years, and 72.8% at 5 years in patients with SGV; 88.3% at 1 year, 73.1% at 3 years, and 58% at 5 years in patients without SGV/SRS; 94.1% at 1 year, 87.4% at 3 years, and 72.8% at 5 years in patients with SGV (overall, p = 0.2). CONCLUSION: In spite of no significant effect on the prognosis in cirrhosis, careful management may be necessary for the patients with SRS because of potential poor liver function demonstrated by the close linkage between the presence of SRS and decompensation.

BACKGROUND AND AIM: Little is known about the clinical features of cardia varices (CV). The aim was to examine the background, bleeding risk, and post-treatment outcomes of CV in patients with portal hypertension. METHODS: The subjects of this retrospective study were 277 patients (179 males, 98 females, 62.9 ± 11.5 years) with esophageal varices (EV). In patients with CV, there were 65 bleeders, and 95 patients received endoscopic treatment for primary or secondary prophylaxis. RESULTS: There were 147 patients with CV (53.1%). The higher grade of EV (P < 0.01) and the lower grade of gastric fundal varices (FV) (P = 0.046) were significant factors for the presence of CV. Significant risk factors for bleeding were: the higher grade of EV (P < 0.01), red sign on EV (P < 0.01), lower albumin (P = 0.01), and Child-Pugh B/C (P < 0.01) for EV and red sign on CV (P < 0.01) and use of non-steroidal anti-inflammatory drugs (NSAIDs)/aspirin (P < 0.01) for CV. All CV disappeared by sclerotherapy combined with argon plasma coagulation or band ligation, and 20 patients (21.1%) in EV and 18 patients (18.9%) in CV had recurrences during the median observation period of 19.4 months. There was no significant difference in the cumulative survival rate between non-bleeders, bleeders from EV, and those from CV. CONCLUSIONS: The CV were closely associated with advanced grade of EV and less-advanced grade of FV. Further, usage of NSAIDs/aspirin and red sign were significantly related to the bleeding from CV, suggesting the need for careful management.

The aim of the study described here was to evaluate the significance of the hepatic filling rate of a perflubutane microbubble agent in predicting long-term outcomes and prognoses in 32 patients with cirrhosis (37-76 y, 20 females, Child-Pugh A16, B16). The time from delivery of the contrast agent to the hepatic artery to maximum enhancement of the liver parenchyma on the sonogram was defined as the hepatic filling rate (mean = 18.6 s). Hepatic filling rate did not correlate significantly with the Child-Pugh score or the model for end-stage liver disease score. However, the survival rate was lower (93.3% at 1 y, 60.2% at 3 y) and the rate of occurrence of hepatocellular carcinoma (HCC) was higher (13.3% at 1 y, 33.3% at 3 y) in the group with the slow filling rate (≥18 s) than in the group with the rapid filling rate (<18 s) (93.3% at 1 and 3 y for survival, 6.3% at 1 and 3 y for HCC occurrence). Hepatic filling rate may constitute a non-invasive marker for the occurrence of HCC and prognosis of cirrhosis.

OBJECTIVE: To examine the efficacy of saline-enhanced ultrasound (US) in predicting the X-ray appearance of hepatic venography. MATERIALS AND METHODS: This prospective study consisted of 50 cirrhosis patients (31 males and 19 females; mean age, 64.2±11.1 years). US patterns in the liver, after injection of agitated saline via balloon-occluded catheter, were evaluated with respect to the findings of CO2-enhanced hepatic venogram. RESULTS: US demonstrated two patterns: type I showing positive parenchymal enhancement (40 patients) and type II showing negative parenchymal enhancement with detection of hepatic vein (10 patients). There were also two patterns shown by hepatic venography: type A showing retrograde detection of intrahepatic portal vein (41 patients) and type B showing hepatic venous enhancement via intrahepatic venous-venous communications with no detection of intrahepatic portal vein (9 patients). All patients with type I showed retrograde detection of intrahepatic portal vein via hepatic sinusoid on X-ray venograms (type A). Of the 10 patients with type II, nine showed type B and one showed type A. Sensitivity and specificity of type I US pattern to predict the detection of intrahepatic portal vein on the venogram were 100% and 90%, respectively. There was no significant difference in hepatic venous pressure gradient or wedged hepatic venous pressure between patients with type I and type II. CONCLUSIONS: Saline-enhanced US is effective in predicting the findings of hepatic venogram. As type II strongly suggests the shunt-modified venogram, image taking in these cases would be superfluous with the added advantage of avoiding unnecessary radiation exposure.