6-thioguanine associated nodular regenerative hyperplasia in patients with inflammatory bowel disease may induce portal hypertension

BACKGROUND: Recent studies suggest an association between 6-thioguanine (6-TG) therapy and hepatic nodular regenerative hyperplasia (NRH) in patients with inflammatory bowel disease (IBD). An influence of 6-TG on portal pressure remains to be determined. The aim of the study was to examine the functional relevance of long-term 6-TG treatment on hepatic hemodynamics in IBD patients and its association with NRH. METHODS: Patients treated with 6-TG for IBD underwent measurement of the hepatic venous pressure gradient (HVPG) and liver biopsy. 6-TG therapy was stopped when NRH was diagnosed. If elevated, HVPG measurement was repeated after 1 yr. RESULTS: Twenty-six patients (15 women, 11 men; median age 41 yr, range 23-76) treated with 6-TG for 38 months (median; range 12-45) were included. Among 24 patients with sufficient liver biopsy, 6 patients (25%) were diagnosed with NRH. In these 6 patients, the HVPG was higher (median HVPG 7 mmHg, range 3-14) than in the 18 patients without NRH (median 3 mmHg, range 2-5; P < 0.001). In the patients with NRH, two had clinically significant portal hypertension (CSPH) (13 and 14 mmHg, respectively); in one patient the HVPG was slightly elevated (7 mmHg). No overt clinical signs of portal hypertension were observed. One year after stopping 6-TG therapy, HVPG decreased in all 3 patients with initially elevated HVPG levels. CONCLUSIONS: We demonstrate that IBD patients under long-term 6-TG therapy are at a substantial risk for developing NRH. NRH results in elevation of HVPG and may cause CSPH. Discontinuation of 6-TG therapy extenuates portal hypertension and may thus reduce the risk of complications.     

Hepatic venous pressure gradient measurement: Time to learn!

Portal hypertension is a clinical syndrome defined by a pathological increase in portal pressure. The development of cirrhosis of the liver is characterized by clinical manifestations related to portal hypertension like esophageal varices, ascites, bleeding, and encephalopathy. Direct measurement of portal pressure is invasive, inconvenient, and clinically impractical. Currently, the most commonly used parameter is the Hepatic Venous Pressure Gradient (HVPG), i.e., the difference between the wedged (WHVP) and the free hepatic venous pressures. HVPG represents the gradient between pressures in the portal vein and the intra-abdominal portion of inferior vena cava. When blood flow in a hepatic vein is stopped by a wedged catheter, the proximal static column of blood transmits the pressure from the preceding communicated vascular territory (hepatic sinusoids) to the catheter. Thus, WHVP reflects hepatic sinusoidal pressure and not the portal pressure itself. In the normal liver, due to pressure equilibration through interconnected sinusoids, wedged pressure is slightly lower than portal pressure, though this difference is clinically insignificant. In liver cirrhosis, the static column created by balloon inflation cannot be decompressed at the sinusoidal level due to disruption of the normal intersinusoidal communications; therefore, WHVP gives an accurate estimation of portal pressure in cirrhosis. The normal HVPG value is between 1 to 5 mmHg. Pressure higher than this defines the presence of portal hypertension, regardless of clinical evidence. HVPG >/= 10 mmHg (termed clinically significant portal hypertension) is predictive of the development of complications of cirrhosis, including death. HVPG above 12 mmHg is the threshold pressure for variceal rupture. The main advantages of HVPG are its simplicity, reproducibility, and safety. This review summarizes the technique of the HVPG measurement.     

Urotensin II: a novel vasoactive mediator linked to chronic liver disease and portal hypertension.

BACKGROUND/AIMS: Urotensin II (UII) is recognised as the most potent human vasoconstrictor; however, its role in chronic liver disease (CLD) is unknown. AIM: We sought to determine serum UII levels in CLD and explore its relationship with clinical features and outcomes of patients with CLD and portal hypertension. METHODS: UII was analysed by radio-immunoassay on cirrhotic patients undergoing hepatic venous pressure gradient (HVPG) determination and age- and sex-matched controls. Follow-up data were prospectively recorded. RESULTS: From 1997 to 2004, 80 patients (male/female: 74/6) underwent a total of 94 HVPG assessments. UII was higher in cirrhotic patients compared with controls (2.05+/-0.06 and 1.55+/-0.09 pmol/L, P<0.001) and was correlated with HVPG (r=+0.35, P=0.001) and severity of CLD (r=+0.6, P<0.001). UII was higher in patients who developed refractory ascites (2.45+/-0.13 vs. 1.7+/-0.12 pmol/L, P<0.001) and in those who died during the follow-up period (2.27+/-0.15 pmol/L vs. 1.95+/-0.08 pmol/L, P<0.05). CONCLUSION: Serum UII is elevated in patients with CLD, and is associated with the severity of the underlying liver disease and the degree of portal hypertension. Baseline levels can predict future complications such as refractory ascites and patient survival.     

Effect of poorly absorbable antibiotics on hepatic venous pressure gradient in cirrhosis: A systematic review and meta-analysis

BackgroundThe effects of poorly/non-absorbable antibiotics on hepatic venous pressure gradient (HVPG) are debated.AimTo analyze the effects of rifaximin or norfloxacin on HVPG and on markers of bacterial translocation and proinflammatory cytokines.MethodsWe performed a systematic search of randomized clinical trials (RCTs) involving patients with cirrhosis and portal hypertension, assessing the effect of rifaximin or norfloxacin vs control on HVPG. Pooled analyses were based on random-effects models, heterogeneity was assessed by Cochran's Q, I² statistic and subgroup analyses.ResultsFive studies (215 patients) were included. Risk of bias was high in three. We found no significant differences using antibiotics versus control. The summary mean difference in HVPG was of -0.55 mmHg (95%CI:-1.52, 0.42; P = 0.27), with moderate heterogeneity (P = 0.15; I² = 40%). RCTs with longer therapy (60–90 days) used non-selective-beta-blockers (NSBB) in both antibiotics and control arms. Subgroup analysis showed a significantly greater reduction in HVPG in the combination arm over controls (mean difference -1.46 mmHg [95%CI: −2.63, −0.28; P = 0.01]) with no heterogeneity (P = 0.46; I² = 0%). Serum lipopolysaccharide-binding protein (LBP) significantly decreased with antibiotics, but with high heterogeneity (P < 0.001; I² = 92%).ConclusionsRifaximin or norfloxacin did not significantly reduce HVPG in patients with cirrhosis and portal hypertension. Studies using antibiotic for longer periods on top of NSBB showed a significant decrease in HVPG.     

Antiviral therapy decreases hepatic venous pressure gradient in patients with chronic hepatitis C and advanced fibrosis

BACKGROUNDS: Antiviral therapy (AVT) may improve liver histology in patients with advanced viral hepatitis but its effect on portal pressure remains unknown. AIM: This study was aimed to evaluate the influence of antiviral therapy (AVT) on hepatic venous pressure gradient (HVPG) in hepatitis C virus infected patients with portal hypertension. METHODS: Twenty compensated patients with chronic hepatitis C, fibrosis stage 3 or 4 and HVPG > 5 mmHg received PEG-IFN alpha2b plus ribavirin. Every patient underwent liver biopsy and portal pressure measurements before and immediately after AT. Biopsies were evaluated according to METAVIR score. RESULTS: HVPG significantly dropped in all but one treated patient, with a mean (SD) reduction of 28.2 (12)%[13.8 (5.6) Vs. 10.2 (3.8) mmHg, p = 0.005]. The percentage of HVPG decrease was significantly greater in patients who achieved a virological end of treatment response [26.2 (12.5)% Vs. 12.7 (8.5)%, p = 0.05] and in those with a decrease of at least 2 points in the grade of inflammation [35.7 (4.5)% Vs. 22.1 (9.5)%, p = 0.015]. Nine out of 11 patients with baseline HVPG > or = 12 mmHg showed a decrease greater than 20% (3/11) or under the 12 mmHg threshold (6/11). CONCLUSIONS: AVT reduces HVPG in compensated patients with advanced hepatitis C (fibrosis stage 3 or 4) and portal hypertension.     

Intrahepatic Heterogeneity of Hepatic Venous Pressure Gradient in Human Cirrhosis

Background: The hepatic venous pressure gradient (HVPG) is used to evaluate portal hypertension. Methods: We measured HVPG in two separate liver veins in 169 liver vein catheterizations in 102 cirrhosis patients and in 27 patients with no liver disease (controls). Results: In the controls, the two measurements differed by 0.0 ± 1.8 mmHg (mean ± s , n = 27), upper 95% confidence limit 3.6 mmHg (mean + 2 s ). HVPG ranged from-0.1 to 8.3 mmHg, upper 95% confidence limit 6.7 mmHg. In cirrhosis, the two measurements agreed within ± 3.6 mmHg in 39%. In 61%, the measurements differed by 4-34 mmHg. In 35%, fluoroscopy demonstrated hepatic vein-to-hepatic-vein shunting in veins with low HVPG values. In some patients with HVPG measurements above 30 mmHg, Doppler ultrasound examination showed arterialization of the hepatic vasculature. Discussion: Our results demonstrate a hitherto unrecognized notable heterogeneity of the intrahepatic vasculature and HVPG measurements in cirrhosis. The presumption of interposition of non-flowing blood between the catheter tip and the portal system for the measurement of HVPG may thus be violated in about one-third of the cirrhosis cases because of abnormal outlet into hepatic venous shunts and in a minor fraction because of abnormal arterial inlet. In 26%, one measurement was below 12 mmHg, the other measurement above. If the HVPG had been measured in only one liver vein, 13% of the cases would have been classified in a lower risk group than appropriate according to the 12 mmHg concept of risk of bleeding from oesophageal varices.     

Hepatic Venous Pressure Gradient: Worth Another Look?

Portal hypertension is one of the most important complications of chronic liver disease and accounts for significant morbidity and mortality. Measurement of the hepatic venous pressure gradient (HVPG) is a simple, invasive, and reproducible method of assessing portal venous pressure. Measurement of HVPG provides the clinician an estimate of the degree of intrahepatic portal flow resistance, guides therapy for variceal bleeding (primary and secondary prophylaxis), assesses feasibility of resection in patients with hepatocellular cancer, and predicts response to therapy of patients with chronic hepatitis C. Achieving hemodynamic targets of reducing the HVPG to <10 mmHg or a 20% reduction from baseline virtually eliminates complications related to portal hypertension from chronic liver disease. This review explores the role of HVPG measurement in the contemporary treatment of patients with cirrhosis and portal hypertension.     

Liver collagen proportionate area predicts decompensation in patients with recurrent hepatitis C virus cirrhosis after liver transplantation

Background and Aims: Current histological scoring systems do not subclassify cirrhosis. Computer‐assisted digital image analysis (DIA) of Sirius Red‐stained sections measures fibrosis morphologically producing a fibrosis ratio (collagen proportionate area [CPA]). CPA could have prognostic value within a disease stage, such as cirrhosis. The aim of the present study was to evaluate CPA in patients with recurrent hepatitis C virus (HCV) allograft cirrhosis and assess its relationship with hepatic venous pressure gradient (HVPG). Methods: In 121 consecutively‐transplanted HCV patients with HVPG, measured contemporaneously with transjugular liver biopsies, 65 had Ishak stage 5 or 6 disease (43 with HVPG measurement). Biopsies were stained with Sirius Red for DIA, and the collagen content was expressed as a CPA. In three cases, a tissue for Sirius Red staining was not obtained, and the patients were excluded. Results: Sixty‐two patients were analyzed. The median HVPG was 8 mmHg (interquartile range [IQR]: 5–10). Portal hypertension (HVPG ≥ 6 < 10 mmHg) was present in 30 (69.8%), and HVPG ≥ 10 mmHg in 13 (30.2%). The median CPA was 16% (IQR 10.75–23.25). Median Child–Pugh score and HVPG were not significantly different between Ishak fibrosis stage 5 or 6, whereas CPA was statistically different: 13% in stage 5 (IQR 8.3–12.4) versus 23% in stage 6 (IQR 17–33.7, P < 0.001). In the multivariate analysis, CPA was the only variable significantly associated with clinically‐significant portal hypertension (HVPG ≥ 10 mmHg, odds ratio: 1.085, confidence interval: 1.004–1.172, P = 0.040). A CPA of 14% was the best cut‐off value for clinically‐significant portal hypertension (CSPH) and liver decompensation, which occurred in 24 patients. Event‐free survival was significantly shorter in patients with CSPH or with a CPA value ≥ 14%, or with a combination of both. Conclusion: In Ishak stages 5 and 6, CPA correlated with HVPG, but had a wider range of values, suggesting a greater sensitivity for distinguishing “early” from “late” severe fibrosis/cirrhosis. CPA was a unique, independent predictor of HVPG ≥ 10 mmHg. CPA can be used to subclassify cirrhosis and for prognostic stratification.     

Hepatic and systemic haemodynamic changes after MARS in patients with acute on chronic liver failure

Abstract Hyperdynamic circulation and portal hypertension characterize acute on chronic liver failure (AoCLF), partially because of circulating mediators. Molecular Absorbents Recirculating System (MARS) may remove some of these substances. The objective of this study was to evaluate the effect of MARS on portal pressure, systemic haemodynamic and endogenous vasoactive systems. MARS treatment was performed in four patients with AoCLF (mean age 36.2 ± 3.1 years; Child–Pugh C 11 ± 1.8 points; three AAH and one NASH). Systemic and splanchnic haemodynamic measurements were performed before and after each session. Plasmatic renin activity (PRA) and NE were measured at baseline, at the end of the sessions and 10 days after MARS. All patients had severe portal hypertension (HVPG = 23 ± 7 mmHg) and pronounced hyperdynamic circulation (MAP 77.8 ± 11.7 mmHg; CO 11.2 ± 1.6 L/min; SVRI 478.5 ± 105 dyne s/cm⁵). HVPG decreased at the end of the first session in all patients (23 ± 7 mmHg vs 17.3 ± 9.9 mmHg; P = 0.05; mean decrease 32 ± 24%) because of a decrease in WHVP (40.7 ± 5.6 mmHg vs 34 ± 9.6 mmHg; P = 0.025; mean decrease 18 ± 19%). MARS significantly attenuated hyperdynamic circulation as shown by a decrease in CO (11.2 ± 1.6 L/min vs 9.4 ± 2.1 L/min; mean decrease 12.3%), with an increase in MAP (77.8 ± 11.7 mmHg vs 84.2 ± 8 mmHg; mean increase 9.2%) and in SVRI (478.5 ± 105 dyne s/cm⁵ vs 622 ± 198 dyne s/cm⁵; mean increase 41%). PRA and NE decreased significantly (14.2 ± 17.2 ng/mL/h vs 3.7 ± 3.4 ng/mL/h; 1319 ± 1002 pg/mL vs 617 ± 260 pg/mL, respectively). The NE decrease was correlated to HVPG decrease (r = 1, P = 0.01). MARS decreases portal hypertension and ameliorates hyperdynamic circulation in patients with AoCLF, probably mediated by clearance of vasoactive substances. Further studies are necessary to confirm these results.     

Use of transient elastography (FibroScan®) for the noninvasive assessment of portal hypertension in HIV/HCV-coinfected patients

The hepatic venous pressure gradient (HVPG) is the gold standard for assessing portal pressure and correlates with the occurrence of portal hypertension (PH)-related complications. Transient elastography (TE) is a new, highly accurate noninvasive technique, which enables us to evaluate hepatic fibrosis to detect advanced fibrosis and cirrhosis. We performed a hepatic haemodynamic study and TE in 38 HIV/HCV-coinfected patients. The association between HVPG and liver stiffness was assessed by linear regression. The diagnostic value of TE was assessed by receiver operating characteristic (ROC) curves. We considered clinically significant PH as an HVPG ≥ 10 mmHg and severe PH as an HVPG ≥ 12 mmHg. A total of 38 HIV/HCV-coinfected patients were included. Twenty-eight patients (73.7%) had clinically significant PH (HVPG ≥ 10 mmHg), and 23 (60.5%) of these had severe PH (HVPG ≥ 12 mmHg). We found a statistically significant association between liver stiffness (kPa) and HVPG (r(2) = 0.46, P < 0.001, straight line equation HVPG=7.4 + 0.204*TE). The areas under the ROC curves were 0.80 [95% confidence interval (CI), 0.64-0.97] and 0.80 (95% CI, 0.66-0.94) for the prediction of HVPG ≥ 10 and ≥ 12 mmHg, respectively. Our data suggest that TE can predict the presence of clinically significant and severe PH in HIV/HCV-coinfected patients.     

Hemodynamic Studies in Acute-on-Chronic Liver Failure

Background Patients with decompensated cirrhosis and acute liver failure have circulatory dysfunctions leading to high portal pressure and cardiac output (CO) and low systemic vascular resistance (SVR). Circulatory changes in acute-on-chronic liver failure (ACLF) patients have not been studied. We studied the portal, systemic, and pulmonary hemodynamics in patients with ACLF and compared them with compensated and decompensated cirrhotics. Patients and Methods Clinical features and hemodynamic profile were studied in patients with ACLF and compared with age- and sex-matched compensated and decompensated cirrhotics with portal hypertension. Results The study cohort comprised 144 patients categorized into one of three groups (ACLF, compensated cirrhosis, and decompensated cirrhosis), with 48 (33%) patients in each group. All values are given as the mean ± standard deviation, except for frequencies (%). The mean arterial pressure (MAP) and SVR were lower in the ACLF than the compensated group and were similar to those of the decompensated group (MAP 90 ± 16 vs. 99 ± 15 vs. 96 ± 16 mmHg; SVR 912 ± 435 vs. 1350 ± 449 vs. 891 ± 333 dyn s/cm⁵). The mean CO of the ACLF patients was higher than that of the compensated group and similar to that of the decompensated group (CO 8.9 ± 3.5 vs. 6.1 ± 1.7 vs. 9.0 ± 3.0 l/min). The pulmonary vascular resistance (PVR) and pulmonary capillary wedge pressures (PCWP) were similar in all the three groups (PVR 78 ± 48 vs. 109 ± 70 vs. 61 ± 47 dyn s/cm⁵; PCWP 8 ± 4 vs. 8 ± 4 vs. 10 ± 5 mmHg). The mean hepatic venous pressure gradient (HVPG) in the ACLF group was 15.1 ± 6.3 mmHg, which was significantly higher than that of the compensated group (11.7 ± 6.3 mmHg), but lower than that of the decompensated cirrhosis group (20.2 ± 6.0 mmHg). When patients of ACLF were categorized on the basis of their variceal size, the mean HVPG in ACLF patients with small varices was similar to that of compensated cirrhotics (13.7 ± 5.7 vs. 11.7 ± 6.3 mmHg; P = 0.146), while in the ACLF patients with large varices, the HVPG was comparable to that of the decompensated cirrhotics (18.7 ± 6.6 vs. 20.2 ± 6.0 mmHg; P = 0.442). Conclusions The systemic hemodynamics in patients with ACLF is similar to that in decompensated cirrhotics. The portal pressure in these patients is higher than that in the compensated cirrhotics, and in the subgroup with large varices, it becomes similar to that of decompensated cirrhotics.     

Low-dose midazolam sedation: an option for patients undergoing serial hepatic venous pressure measurements

The hepatic venous pressure gradient (HVPG) is becoming increasingly used clinically. It is useful in the differential diagnosis of portal hypertension and provides a prognostic index in cirrhotic patients. Performance of serial measurements has been shown to be useful in guiding pharmacological therapy of portal hypertension and variceal hemorrhage. The technique is safe to perform; however, many patients are anxious and reluctant to undergo serial measurements. The effects of sedatives on portal pressure measurements have not yet been defined. The objective of this study was to evaluate the effects of midazolam on the HVPG. Twenty patients with compensated cirrhosis were included in this prospective, double-blind study. The HVPG was determined by subtracting the free hepatic venous pressure (FHVP) from the wedged hepatic venous pressure (WHVP). Patients were randomized to receive either placebo, 0.02 mg/kg midazolam, or 0.03 mg/kg midazolam, administered intravenously over 3 minutes. Immediately after drug administration and every 3 minutes thereafter, for a total of 30 or 40 minutes, measurements were repeated. Three hours later, patients were asked to state whether the sedative affected their state of comfort/relaxation. The effects of both doses of midazolam on HVPG did not differ significantly from those of placebo. Furthermore, neither dose of midazolam induced significant changes in HVPG as compared with baseline values. However, higher-dose midazolam (0.03 mg/kg) was associated with significant reductions in FHVP from baseline and a tendency for a reduction in WHVP. Both doses significantly increased patient comfort and relaxation during the test. Midazolam, used at a dose of 0.02 mg/kg, is effective in increasing patient comfort and relaxation during hepatic venous pressure measurements, without significantly affecting pressures (HVPG, WHVP, or FHVP). It is therefore an acceptable option for patients undergoing serial hepatic venous pressure measurements.     

Non-selective β-blockers improve the correlation of liver stiffness and portal pressure in advanced cirrhosis

Background

Liver stiffness (LS) correlates with portal pressure (hepatic venous pressure gradient, HVPG). However, the dynamic components of portal hypertension (PHT) in advanced cirrhosis may not be adequately assessed by TE. The influence of treatment with non-selective β-blockers (NSBB) on the correlation of HVPG and LS has not been investigated.

Methods

One hundred and twenty-two patients with esophageal varices were included. LS, hemodynamic parameters, and HVPG were recorded at baseline (BL) and after 6?weeks of treatment with NSBB (FU). The correlation of LS and HVPG was compared to control patients with HVPG?≤?12?mmHg.

Results

Patients with higher Child-Pugh stages (A:88/B:25/C:9) had higher levels of liver stiffness (47.4?±?16.5 vs. 70.3?±?7.9 vs. 73.7 ± 2.1 kPa) and HVPG (21?±?5 vs. 26?±?5 vs. 26?±?4?mmHg). The correlation of LS and HVPG was stronger in controls with HVPG?≤?12?mmHg (R?=?0.951; P??12?mmHg (R?=?0.538; P?=?0.0004). The association of HVPG with LS became stronger under treatment with NSBB, which finally restored the linear correlation of HVPG and LS (R?=?0.930; P?R?=?0.864), but not in nonresponders (R?=?0.535), whereas changes in LS, heart rate, and MAP were similar in responders and nonresponders.

Conclusions

Targeting the hyperdynamic circulation and the increased splanchnic blood inflow by treatment with NSBB unmasks the linear (mechanical) correlation of HVPG and LS in patients with HVPG?>?12?mmHg. Measurement of LS by TE is not a feasible method to assess the dynamic components of PHT.     

Hepatic venous pressure gradient as a predictor of fibrosis in chronic liver disease because of hepatitis B virus

Background: Liver biopsy has been considered to be a gold standard for assessing hepatic fibrosis. Sample variability, interobserver variability and step‐wise evaluation limit its use. Hepatic venous pressure gradient (HVPG) correlates with hepatic fibrosis in chronic liver disease (CLD) because of hepatitis C. Aim: To evaluate the utility of HVPG for assessing hepatic fibrosis in patients with hepatitis B virus (HBV)‐related CLD. Patients and Methods: Sixty‐one patients with HBV‐related CLD who underwent both liver biopsy and hepatic haemodynamic studies were studied. Results: Forty‐nine (80.3%) patients had clinically significant portal hypertension (PHT) (HVPG≥10 mmHg), 39 (63.9%) severe PHT (i.e. HVPG≥12 mmHg), six (9.8%) HVPG≤5 mmHg and another six (9.8%) had preclinical PHT (i.e. HVPG>5 but <10 mmHg). A positive correlation between HVPG and fibrosis score was found (r=0.436, P<0.001). In patients with HVPG<10 or <12 mmHg there was a significant correlation with fibrosis score (r=0.603, P=0.029 and r=0.887, P<0.001 respectively). A positive correlation also existed in patients with HVPG≥10 mmHg and in patients with HVPG≥12 mmHg (r=0.512, P≤0.001 and r=0.543, P<0.001 respectively). Receiver operating characteristic curve of HVPG for the prediction of advanced fibrosis (stage≥3) had an area under curve of 0.906. HVPG value above 13.0 mmHg had a sensitivity of 79% and a specificity of 89% for predicting advanced fibrosis on histology. Conclusions: HVPG correlates well with the degree of histological fibrosis in patients with HBV‐related CLD.     

Systemic and pulmonary hemodynamics in patients with non-cirrhotic portal fibrosis (NCPF) is similar to compensated cirrhosis

Background Non-cirrhotic portal fibrosis (NCPF) is an important cause of portal hypertension (PHT) and variceal bleeding, especially in the developing countries. While the hepatic parenchyma and liver functions are normal, the patho-anatomic defect in these patients is pre- and peri-sinusoidal in nature. Aim To study the systemic and pulmonary hemodynamic alterations in patients with NCPF and compare them with compensated cirrhotic patients. Patients and Methods Patients with NCPF (n = 20, mean age 29.3 ± 9.8 year) and matched Child’s A cirrhotic patients (n = 17, age 34.1 ± 9.8 year) who had bled in the past, underwent hemodynamic measurements using a balloon tipped catheter. Results In NCPF patients, the hepatic venous pressure gradient (HVPG) was significantly lower than in the cirrhotic patients (4.9 ± 1.5 mmHg vs. 15.7 ± 4.5 mmHg; P < 0.01). NCPF patients had hyperdynamic circulation and peripheral vasodilatation comparable to cirrhotic patients; cardiac output (8.0 ± 1.2 l/min vs. 8.4 ± 1.9 l/min; P = 0.4), cardiac index (5.4 ± 0.8 l/min/m² vs. 5.5 ± 1.9 l/min/m²; P = 0.86), mean arterial pressure (88.2 ± 14.1 mmHg vs. 89.9 ± 17.3 mmHg; P = 0.73), systemic vascular resistance (852.8 ± 204.3 dynes · s/cm⁵ vs. 854.1 ± 189.9 dynes · s/cm⁵; P = 0.98) and pulmonary vascular resistance (41.6 ± 18.1 dynes · s/cm⁵ vs. 41.3 ± 17.9 dynes · s/cm⁵; P = 0.95) were comparable in the two groups. Conclusions NCPF associated portal hypertension leads to a hyperdynamic state with high cardiac index and low systemic and pulmonary vascular resistance comparable to compensated cirrhosis. These novel observations suggest a primary role of portal hypertension in the development of hyperdynamic state.     

Histological-hemodynamic correlation in cirrhosis-a histological classification of the severity of cirrhosis

BACKGROUND/AIMS: While the definitive diagnosis of cirrhosis is histological, it is the degree of portal hypertension, as determined by the hepatic venous pressure gradient (HVPG), that is an important determinant of the severity of cirrhosis. An HVPG > or =10 mmHg (termed clinically significant portal hypertension or CSPH) is predictive of the development of complications of cirrhosis, including death. This study aimed to determine the relationship between specific histological parameters and HVPG in cirrhosis. METHODS: Forty-three patients with biopsy-proven cirrhosis and HVPG measurements within 6 months of the biopsy were included in the study. The following parameters were scored semiquantitatively and without knowledge of HVPG results: sinusoidal fibrosis, septal thickness, loss of portal tracts and central veins, nodule size, inflammation, steatosis, and iron. RESULTS: Septal thickness (p=0.03), small nodularity (p=0.003), loss of portal tracts (p=0.01), inflammation (p=0.04) and alcoholic etiology (p=0.01) correlated with the presence of CSPH. However, small nodularity and septal thickness were the only parameters independently predictive of CSPH (r=0.658, p<0.05). CONCLUSIONS: We describe a subclassification of histological cirrhosis based on the severity of portal hypertension that consists of a combination of nodule size and septal thickness, with small nodularity and thick septa being independent predictors of the presence of CSPH.     

Use of portal pressure studies in the management of variceal haemorrhage

Portal hypertension occurs as a complication of liver cirrhosis and complications such as variceal bleeding lead to significant demands on resources. Endoscopy is the gold standard method for screening cirrhotic patients however universal endoscopic screening may mean a lot of unnecessary procedures as the presence of oesophageal varices is variable hence a large time and cost burden on endoscopy units to carry out both screening and subsequent follow up of variceal bleeds. A less invasive method to identify those at high risk of bleeding would allow earlier prophylactic measures to be applied. Hepatic venous pressure gradient (HVPG) is an acceptable indirect measurement of portal hypertension and predictor of the complications of portal hypertension in adult cirrhotics. Varices develop at a HVPG of 10-12 mmHg with the appearance of other complications with HPVG > 12 mmHg. Variceal bleeding does not occur in pressures under 12 mmHg. HPVG > 20 mmHg measured early after admission is a significant prognostic indicator of failure to control bleeding varices, indeed early transjugular intrahepatic portosystemic shunt (TIPS) in such circumstances reduces mortality significantly. HVPG can be used to identify responders to medical therapy. Patients who do not achieve the suggested reduction targets in HVPG have a high risk of rebleeding despite endoscopic ligation and may not derive significant overall mortality benefit from endoscopic intervention alone, ultimately requiring TIPS or liver transplantation. Early HVPG measurements following a variceal bleed can help to identify those at risk of treatment failure who may benefit from early intervention with TIPS. Therefore, we suggest using HVPG measurement as the investigation of choice in those with confirmed cirrhosis in place of endoscopy for intitial variceal screening and, where indicated, a trial of B-blockade, either intravenously during the initial pressure study with assessment of response or oral therapy with repeat HVPG six weeks later. In those with elevated pressures, primary medical prophylaxis could be commenced with subsequent close monitoring of HVPG thus negating the need for endoscopy at this point. All patients presenting with variceal haemorrhage should undergo HVPG measurement and those with a gradient greater than 20 mmHg should be considered for early TIPS. By introducing portal pressure studies into a management algorithm for variceal bleeding, the number of endoscopies required for further intervention and follow up can be reduced leading to significant savings in terms of cost and demand on resources.     

Hepatic venous pressure gradient determination in patients with hepatitis C virus-related and alcoholic cirrhosis

OBJECTIVES: Few data exist regarding the degree of portal hypertension in hepatitis C virus (HCV)-related cirrhosis, as the majority of studies have included mainly patients with alcoholic cirrhosis. This study was aimed at comparing the severity of portal hypertension in patients with HCV-related or alcoholic cirrhosis. METHODS: In total, 59 cirrhotic patients with portal hypertension (HCV-related in 34 cases and alcoholic in 25) underwent main right hepatic vein catheterization, with determination of the wedged and free hepatic venous pressures, and of hepatic venous pressure gradient (HVPG). RESULTS: HVPG values did not differ between the two groups of patients (19.4 +/- 6.0 mmHg vs 18.5 +/- 3.5 mmHg; P = 0.51). The prevalence and degree of oesophageal and gastric varices and portal hypertensive gastropathy did not correlate with the aetiology. Patients with viral cirrhosis had a lower prevalence of previous bleeding than those with alcoholic cirrhosis, despite a similar proportion of large varices in the two groups and similar HVPG levels. In both groups of patients, HVPG did not differ between patients with previous bleeds and those without. CONCLUSIONS: The degree of portal hypertension in cirrhotic patients does not correlate with the cause of the disease. Thus, current statements on the management of portal hypertension, although based upon studies including mainly patients with alcoholic cirrhosis, can be applied also to patients with viral-related cirrhosis.     

Osteopontin: A non-invasive parameter of portal hypertension and prognostic marker of cirrhosis

AIM: To investigate the relationship between osteopontin plasma concentrations and the severity of portal hypertension and to assess osteopontin prognostic value.METHODS: A cohort of 154 patients with confirmed liver cirrhosis(112 ethylic, 108 men, age 34-72 years)were enrolled in the study. Hepatic venous pressure gradient(HVPG) measurement and laboratory and ultrasound examinations were carried out for all patients. HVPG was measured using a standard catheterization method with the balloon wedge technique. Osteopontin was measured using the enzyme-linked immunosorbent assay(ELISA) method in plasma. Patients were followed up with a specific focus on mortality. The control group consisted of 137 healthy age- and sex- matched individuals.RESULTS: The mean value of HVPG was 16.18 ± 5.6 mm Hg. Compared to controls, the plasma levels of osteopontin in cirrhotic patients were significantly higher(P 0.001). The plasma levels of osteopontin were positively related to HVPG(P = 0.0022, r = 0.25) and differed among the individual Child-Pugh groups of patients. The cut-off value of 80 ng/m L osteopontin distinguished patients with significant portal hypertension(HVPG above 10 mm Hg) at 75% sensitivity and 63% specificity. The mean follow-up of patients was 3.7 ± 2.6 years. The probability of cumulative survival was 39% for patients with HVPG 10 mm Hg and 65% for those with HVPG ≤ 10 mm Hg(P = 0.0086, odds ratio(OR), 2.92, 95% confidence interval(CI): 1.09-7.76). Osteopontin showed a similar prognostic value to HVPG. Patients with osteopontin values above 80 ng/m L had significantly lower cumulative survival compared to those with osteopontin ≤ 80 ng/m L(37% vs 56%, P = 0.00035; OR = 2.23, 95%CI: 1.06-4.68).CONCLUSION: Osteopontin is a non-invasive parameter of portal hypertension that distinguishes patients with clinically significant portal hypertension. It is a strong prognostic factor for survival.     

Prolonged Q-T(c) interval in mild portal hypertensive cirrhosis

BACKGROUND/AIMS: The Q-T(c) interval is prolonged in a substantial fraction of patients with cirrhosis, thus indicating delayed repolarisation. However, no information is available in mild portal hypertensive patients. We therefore determined the Q-T(c) interval in cirrhotic patients with hepatic venous pressure gradient (HVPG) < 12 mmHg. METHODS: Forty-four patients with cirrhosis and HVPG < 12 mmHg underwent a haemodynamic study. They were compared with 36 cirrhotic patients with clinically significant portal hypertension (HVPG> or = 12 mmHg) and controls without liver disease. RESULTS: The fraction with prolonged Q-T(c) interval (> 0.440 s(1/2)) was similar in the two cirrhotic groups (49 vs 50%, ns) and significantly above that of the controls (5%, P < 0.005). Q-T(c) was normal in patients with normal HVPG. Likewise, mean Q-T(c) was 0.449 and 0.447 s(1/2) in the two cirrhotic groups (ns), values which are significantly above that of the controls (0.410 s(1/2), P < 0.01). In the mild portal hypertensive group, the Q-T(c) interval was inversely related to indicators of liver function, such as indocyanine green clearance (r = -0.34, P < 0.02). CONCLUSIONS: Delayed repolarisation of the myocardium already occurs in a substantial fraction of patients with cirrhosis with only a mild increase in portal pressure. The prolonged Q-T(c) interval may be related to liver dysfunction and to the presence of portal hypertension.