Seung Hwan Cha

Histological subclassification of cirrhosis using the Laennec fibrosis scoring system correlates with clinical stage and grade of portal hypertension

BACKGROUND & AIMS Further histological subclassification of cirrhosis may be useful because of heterogeneity of severity within cirrhosis. We aimed to determine the relationship between histological subclassification and clinical stage of cirrhosis as well as grade of portal hypertension. METHODS One hundred-twenty-three biopsy-proven cirrhosis patients, whose clinical stage of cirrhosis and hepatic venous pressure gradient (HVPG) could be estimated, were included in this prospective study. Histology of cirrhosis was blindly subclassified using the Laennec fibrosis scoring system semi-quantitatively without knowledge of the clinical stage or the HVPG results. The Laennec system subclassifies cirrhosis as mild - thin septa, moderate - at least two broad septa, and severe - at least one very broad septum or many minute nodules. Clinical stages were determined by the presence or absence of varices, ascites, and variceal hemorrhage. Biological and laboratory data were also collected. RESULTS Alcohol intake was the most common cause of cirrhosis in this cohort (87, 70.7%). Histology of cirrhosis subclassified using the Laennec scoring system significantly correlated with both the clinical stage of cirrhosis (p < 0.001) and HVPG (mild: 8.1 ± 2.6 mm Hg, moderate: 12.4 ± 3.3mm Hg, severe: 16.3 ± 4.0 mm Hg, p < 0.001). With higher grades of histological subclassification of cirrhosis, increased frequency in both severe portal hypertension (HVPG ≥ 12 mm Hg) and episodes of variceal hemorrhage were observed (p < 0.001). CONCLUSIONS Histological subclassification of cirrhosis by the Laennec fibrosis scoring system is tightly correlated with both the clinical stage of cirrhosis and grade of portal hypertension. This suggests that cirrhosis should be subclassified into different stages according to its histological severity.

Hepatic vein arrival time as assessed by contrast-enhanced ultrasonography is useful for the assessment of portal hypertension in compensated cirrhosis.

The measurement of the hepatic venous pressure gradient (HVPG) for the estimation of portal hypertension (PH) in cirrhosis has some limitations, including its invasiveness. Hepatic vein arrival time (HVAT), as assessed by microbubble contrast‐enhanced ultrasonography (CEUS), is negatively correlated with the histological grade of liver fibrosis because of the associated hemodynamic abnormalities. Anatomical and pathophysiological changes in liver microcirculation are the initial events leading to PH. However, the direct relationship between HVAT and PH has not been evaluated. The present study measured both HVPG and HVAT in 71 consecutive patients with compensated cirrhosis and analyzed the relationship between the two parameters (i.e., the derivation set). Results were validated in 35 compensated patients with cirrhosis at another medical center (i.e., the validation set). The derivation set had HVPG and HVAT values of 11.4 ± 5.0 mmHg (mean ± standard deviation; range, 2‐23) and 14.1 ± 3.4 seconds (range, 8.4‐24.2), respectively; there was a statistically significant negative correlation between HVPG and HVAT (r2 = 0.545; P < 0.001). The area under the receiver operating characteristic curve (AUROC) was 0.973 for clinically significant PH (CSPH; HVPG, ≥10 mmHg), and the sensitivity, specificity, positive predictive value, negative predictive value, and positive and negative likelihood ratios for CSPH for an HVAT cut‐off value of 14 seconds were 92.7%, 86.7%, 90.5%, 89.7%, 6.95, and 0.08, respectively. In addition, a shorter HVAT was associated with worse Child‐Pugh score (P < 0.001) and esophageal varices (P = 0.018). In the validation set, there was also a significant negative correlation between HVAT and HVPG (r2 = 0.538; P < 0.001), and AUROC = 0.953 for CSPH. HVAT was significantly correlated with PH. These results indicate that measuring HVAT is useful for the noninvasive prediction of CSPH in patients with compensated cirrhosis. (HEPATOLOGY 2012;56:1053–1062)

Cetuximab in combination with 5-fluorouracil, leucovorin and irinotecan as a neoadjuvant chemotherapy in patients with initially unresectable colorectal liver metastases

Background: The efficacy and safety of a combination of cetuximab, irinotecan, and 5-fluorouracil/leucovorin (FOLFIRI) in downsizing unresectable colorectal liver metastases was investigated. Patients and Methods: Patients with unresectable colorectal liver metastases with or without resectable extrahepatic metastasis were enrolled. 23 patients initially received 400 mg/m2 of cetuximab, followed by a weekly infusion of 250 mg/m2 and a biweekly dose of irinotecan (180 mg/m2), with 5-fluorouracil both by bolus (400 mg/m2) and by a 46-h infusion (total of 2,400 mg/m2) with leucovorin (400 mg/m2). Results: The overall response rate was 39.1% (n = 9; 95% confidence interval (CI): 17.6-60.7%). The most common grade 3-4 toxicities were skin reactions (30.4%) and diarrhea (26.1%). The rate of conversion to resectable liver metastases was 30.4% (n = 7; 95% CI: 10.1-50.8%). The factors found to be significantly associated with R0 resection were lower serum carcinoembryonic antigen levels after chemotherapy (p = 0.039), being chemonaive (p = 0.002), and showing a higher incidence of grade 3-4 skin toxicity (p = 0.011). Conclusions: Cetuximab with FOLFIRI may be an effective and safe treatment option for downsizing unresectable colorectal liver metastases.

Beneficial effects of candesartan, an angiotensin‐blocking agent, on compensated alcoholic liver fibrosis ‐ A randomized open‐label controlled study

Recent studies have shown that the renin‐angiotensin system is implicated in hepatic fibrogenesis in vitro and in vivo. However, no study was done in humans with alcoholic liver disease.

Hepatic venous pressure gradient can predict the development of hepatocellular carcinoma and hyponatremia in decompensated alcoholic cirrhosis.

Objective Portal hypertension is closely associated with serious complications of cirrhosis, which contribute to bad prognosis. Hepatocellular carcinoma (HCC) and low serum sodium (SNa) are manifestations of end-stage liver disease and are associated with poor survival in decompensated cirrhosis patients. We aimed to determine the relationship between hepatic venous pressure gradient (HVPG) and the development of HCC or low SNa in decompensated alcoholic cirrhosis patients. Methods Child-Pugh scores, Model for End-Stage Liver Disease scores, and HVPG at baseline, and the development of HCC or low SNa (SNa <130 mEq/l) during follow-up were analyzed prospectively in 170 patients with decompensated alcoholic cirrhosis from December 1999 to January 2008 (mean follow-up period of 33.9±27.9 months). The predictive value of different risk factors for the development of HCC and low SNa and survival were investigated. Results Twenty-four patients developed HCC during the follow-up period. In the multivariate analysis, only baseline HVPG greater than 15 mmHg was an independent predictive factor for the development of HCC (relative risk=1.128, P<0.05) and which showed a significantly shorter time for the development of HCC on the Kaplan–Meier analysis. Twenty patients developed low SNa during follow-up. Initial HVPG was also an independent predictive factor for the new development of low SNa in the multivariate analysis (relative risk=1.169, P<0.05) and which also showed significantly shorter times for the development of low SNa on the Kaplan–Meier analysis. Conclusion In decompensated alcoholic cirrhosis, HVPG may be a useful predictive factor for the development of HCC and low SNa.

Measurement of hepatic venous pressure gradient in liver cirrhosis: relationship with the status of cirrhosis, varices, and ascites in Korea

BACKGROUND/AIMS The relationships between the hepatic venous pressure gradient (HVPG) and the status of cirrhosis, complications of portal hypertension and the severity of cirrhosis are not clear. The aim of this study was to determine the relationships between HVPG and the complications or status of cirrhosis. METHODS The HVPG, gastroesophageal varices, Child-Pugh score, Model for End-Stage Liver Disease (MELD) score, presence of ascites, recent bleeding history and the status of cirrhosis were assessed in a cohort of 172 patients (156 males, 16 females) with liver cirrhosis. RESULTS The HVPG was 15.6+/-5.1 (mean+/-SD) mmHg (4-33 mmHg) and was significantly higher in patients in the decompensated stage than in those in the compensated stage (16.6+/-4.3 vs. 10.8+/-6.1 mmHg, respectively; P<0.01). HVPG was higher in bleeders than in nonbleeders (16.9+/-4.5 vs. 12.8+/-5.3 mmHg, respectively; P<0.01), and in patients with ascites than in those without ascites (16.4+/-4.1 vs. 14.5+/-6.2 mmHg, respectively; P<0.05). HVPG was significantly lower in the presence of gastric varices than in their absence (14.0+/-3.4 vs. 16.0+/-5.3 mmHg, respectively; P<0.05); however, no significant correlation was detected between HVPG and the grade of esophageal varices (P>0.05). HVPG was significantly higher in Childs B cirrhosis (n=87, 15.6+/-4.7 mmHg) and Childs C cirrhosis (n=36, 18.4+/-4.7 mmHg) than in Childs A cirrhosis (n=49, 13.7+/-5.1 mmHg; P<0.01). HVPG also was strongly correlated with the MELD score (P<0.01). The time required to measure the HVPG was 11.2+/-6.4 min, and only three cases of minor complication occurred during the procedure. CONCLUSIONS HVPG was correlated with the severity of liver cirrhosis, presence of ascites, and risk of variceal bleeding in patients with liver cirrhosis.

Effects of candesartan and propranolol combination therapy versus propranolol monotherapy in reducing portal hypertension

Background/Aims Angiotensin receptor blockers (ARBs) inhibit activated hepatic stellate cell contraction and are thought to reduce the dynamic portion of intrahepatic resistance. This study compared the effects of combined treatment using the ARB candesartan and propranolol versus propranolol monotherapy on portal pressure in patients with cirrhosis in a prospective, randomized controlled trial. Methods Between January 2008 and July 2009, 53 cirrhotic patients with clinically significant portal hypertension were randomized to receive either candesartan and propranolol combination therapy (26 patients) or propranolol monotherapy (27 patients). Before and 3 months after the administration of the planned medication, the hepatic venous pressure gradient (HVPG) was assessed in both groups. The dose of propranolol was subsequently increased from 20 mg bid until the target heart rate was reached, and the candesartan dose was fixed at 8 mg qd. The primary endpoint was the HVPG response rate; patients with an HVPG reduction of >20% of the baseline value or to <12 mmHg were defined as responders. Results The mean portal pressure declined significantly in both groups, from 16 mmHg (range, 12-28 mmHg) to 13.5 mmHg (range, 6-20 mmHg) in the combination group (P<0.05), and from 17 mmHg (range, 12-27 mmHg) to 14 mmHg (range, 7-25 mmHg) in the propranolol monotherapy group (P<0.05). However, the medication-induced pressure reduction did not differ significantly between the two groups [3.5 mmHg (range, -3-11 mmHg) vs. 3 mmHg (range, -8-10 mmHg), P=0.674]. The response rate (55.6% vs. 61.5%, P=0.435) and the reductions in mean blood pressure or heart rate also did not differ significantly between the combination and monotherapy groups. Conclusions The addition of candesartan (an ARB) to propranolol confers no benefit relative to classical propranolol monotherapy for the treatment of portal hypertension, and is thus not recommended.

The need for histological subclassification of cirrhosis: a systematic review and meta‐analysis

The need for further histological subclassification of cirrhosis has been increasingly recognized because of the heterogeneity of severity within cirrhosis. We sought to identify evidence in the literature regarding the histological subclassification of cirrhosis using the Laennec stage.

The usefulness of contrast-enhanced ultrasonography in the early detection of hepatocellular carcinoma viability after transarterial chemoembolization: pilot study.

Background/Aims The therapeutic effect of transarterial chemoembolization (TACE) against hepatocellular carcinoma (HCC) is usually assessed using multidetector computed tomography (MDCT). However, dense lipiodol depositions can mask the enhancement of viable HCC tissue in MDCT. Contrast-enhanced ultrasonography (CEUS) could be effective in detecting small areas of viability and patency in vessels. We investigated whether arterial enhancement in CEUS after treatment with TACE can be used to detect HCC viability earlier than when using MDCT. Methods Twelve patients received CEUS, MDCT, and gadoxetic-acid-enhanced dynamic magnetic resonance imaging (MRI) at baseline and 4 and 12 weeks after TACE. The definition of viable HCC was defined as MRI positivity after 4 or 12 weeks. Results Eight of the 12 patients showed MRI positivity at 4 or 12 weeks. All patients with positive CEUS findings at 4 weeks (n=8) showed MRI positivity and residual viable HCC at 4 or 12 weeks. Five of the eight patients with positive CEUS findings at 4 weeks had negative results on the 4-week MDCT scan. Four (50%) of these eight patients did not have MRI positivity at 4 weeks and were ultimately confirmed as having residual HCC tissue at the 12-week MRI. Kappa statistics revealed near-perfect agreement between CEUS and MRI (κ=1.00) and substantial agreement between MDCT and MRI (κ=0.67). Conclusions In the assessment of the response to TACE, CEUS at 4 weeks showed excellent results for detecting residual viable HCC, which suggests that CEUS can be used as an early additive diagnosis tool when deciding early additional treatment with TACE.