AASLD 2006 - Complications of Cirrhosis and Portal Hypertension-Variceal Bleedin

[Guest guest]

AASLD 2006 - Complications of Cirrhosis and Portal Hypertension-

Variceal Bleeding: Clinical Insights and Implications for Practice

Disclosures

K. Herrine, MD

Introduction

The 2006 meeting of the American Association for the Study of Liver

Diseases (AASLD) was rich in content and new data. Exciting

developments in viral hepatitis, including much awaited information

on new therapies, were matched by some very exciting developments in

the field of portal hypertension and complications of chronic liver

disease. Additionally, insights offered into the chemical mediators

of portal hypertension may have therapeutic implications. Evidence of

improvement in the natural history of patients with variceal

hemorrhage was also presented, along with information on noninvasive

tools to stratify bleeding risk. The ongoing controversy concerning

the appropriateness of prophylactic band ligation for high-risk

varices continues, as evidenced by ongoing focus during this year's

meeting. Finally, diagnostic and prognostic abilities of the hepatic

venous pressure gradient have now been correlated with a new tool,

elastography, for which other uses were also described. This clinical

overview summarizes some of the more important new concepts and data

pertaining to these topics, as presented during these meeting

proceedings.

Pathogenesis

It is accepted that portal hypertension results in peripheral

arterial vasodilatation, which in turn results in the hemodynamic

dysregulation that characterizes advanced liver disease. During the

Portal Hypertension II parallel session at this year's AASLD meeting,

Wiest and colleagues[1] from Regensburg, Germany, presented their

data regarding the vasoconstrictor neuropeptide Y and its ability to

ameliorate arterial vasoconstriction in a rat model of cirrhosis. The

investigators were able to demonstrate improvement in mesenteric

vascular contractility in cirrhotic rats with perfusion of

neuropeptide Y. The study authors suggested a potential therapeutic

role for this compound.

During this same session, Geerts and colleagues[2] from Ghent,

Belgium, reviewed their previously published findings that described

angiogenesis in the mesenteric microvasculature of rats with portal

hypertension. Noting that placental growth factor (PIGF) has been

otherwise implicated in pathologic angiogenesis (ie, there are no

data in the field of portal hypertension), the investigators

described their experiments in a partial portal vein ligation model

of portal hypertension. Increased expression of both vascular

endothelial growth factor and PIGF was seen. Additionally, mice

deficient in PIGF had less angiogenesis, smaller spleens, and lower

portal pressures than did sham wild-type mice. These findings

confirmed the importance of angiogenesis in the pathophysiology of

portal hypertension and may eventually have therapeutic implications.

Further insights into the pathophysiology of portal hypertension were

offered during the Portal Hypertension I parallel session. Kemp and

colleagues[3] from Melbourne, Australia, provided information and

data on the potent vasoconstrictor urotensin II (UII). The

investigators measured peripheral and hepatic venous UII in cirrhotic

patients undergoing hepatic venous pressure gradient (HVPG)

determination. Additionally, they measured the vasoactive effects of

microinfusion of UII into the forearms of a subset of patients with

cirrhosis and noncirrhotic controls. UII was significantly higher in

cirrhotic patients compared with controls, with levels positively

correlated with the degree of portal hypertension (as measured by

HVPG). The in-vivo portion of the study showed dose-dependent

vasoconstriction of the cutaneous microcirculation only in those

persons with cirrhosis.

Trebicka and colleagues[4] from Bonn, Germany, have also published

findings on the potent vasodilator UII, noting, as reported above,

increased levels in patients with cirrhosis. This group investigated

the effects of palosuran*, a specific agonist of the UII receptor.

Monitoring portal and arterial pressure in bile duct ligated rats,

the investigators observed significant reductions in portal pressure,

without an effect on mean arterial pressure. The reduced portal

pressure was due to reduction in splanchnic blood flow. The study

authors surmised that palosuran may have important therapeutic

applications.

In summary, it appears that deeper understanding of the mediators

underlying the altered hemodynamics of portal hypertension will allow

for the development of targeted therapies.

Variceal Bleeding

Variceal bleeding remains the most common and most morbid major

complication of end-stage liver disease. New information related to

this important topic was presented at this year's AASLD meeting and

focused on noninvasive methods to identify high-risk varices, the

role of endoscopic band ligation for primary prophylaxis against

bleeding, and issues regarding invasive portosystemic shunting

procedures, both surgical and radiologic.

A variety of biochemical models for the prediction of cirrhosis have

been described over the years. These testing batteries, which can

involve many values combined by regression methods, are relatively

accurate in determining fibrosis in hepatitis C, but have not been

extensively validated in predicting the natural history of advanced

liver disease. Qamar and colleagues[5] from the multinational Portal

Hypertension Collaborative Group described a simple strategy using

platelet count to predict the presence of varices and the need for

nonselective beta-blockade for primary prophylaxis. Although

platelets were found to correlate with HVPG, change in platelet count

was an unacceptable surrogate for measuring change in HVPG.

Furthermore, this inexpensive approach did not provide adequate

stratification of risk to allow for reduction in the need for

endoscopy.

Using a more high-tech approach, Frenette and colleagues[6] from

Scipps Clinic in La Jolla, California, described their experience

with esophageal capsule endoscopy for grading of esophageal varices.

Comparing direct endoscopic visualization with capsule studies in 30

patients with cirrhosis, the authors found a grading accuracy of 40%,

sensitivity of 45%, and specificity of 30% for capsule endoscopy.

Regarding treatment decision, capsule endoscopy had an accuracy of

80%, sensitivity of 64%, and specificity of 89%. Although only 2

patients had gastric varices, the capsule study missed 1 of these

cases. This small study does little to encourage the replacement of

standard esophagogastroduodenoscopy with less invasive alternatives

at this time.

The evolving issue of primary prophylaxis of esophageal varices was

addressed by a number of investigators at this year's meeting.

Dell'Era and colleagues[7] from Milan, Italy, described their rather

robust prophylaxis strategy and its outcome. Patients without

contraindications to beta-blockade were offered measurement of HVPG

followed by nonselected beta-blockade. These patients underwent

repeat HVPG measurement to insure adequate lowering of the

portosystemic gradient. Those who were intolerant to beta-blockade or

who had inadequate lowering of portosystemic gradient underwent

endoscopic band ligation (EBL). Patients with contraindications to

beta-blockers underwent EBL. Patients who refused the catheterization

received beta-blockers without HVPG measurements. Bleeding rates were

22% in the group given beta-blockers without HVPG measurement, 11.5%

in the group treated with EBL, and 10.5% in those adequately (as

determined by HVPG) treated with beta-blockers. The investigators

concluded that HVPG-directed beta-blockade and EBL are more effective

methods of primary prophylaxis than the traditional beta-blocker

regimen.

The above findings received further validity from data reported in

another study by Tripathi and colleagues[8] from Edinburgh, United

Kingdom. This meta-analysis included data from 734 patients (356 who

received EBL, 378 who received beta-blockers) from 9 peer-reviewed

randomized trials. The investigators found a relative risk of 0.61

(95% confidence interval [CI] = 0.44-0.84) favoring band ligation for

first variceal bleed, with a number-needed-to-treat of 11. A trend

toward reduced rebleeding deaths was seen in the EBL group, but

overall mortality was not different.

The very important issue of patient preference in medical decision-

making was addressed in a study presented during this same session by

Longacre and colleagues[9] from Yale University, New Haven,

Connecticut. In this study, 49 subjects with varices and no

contraindications to EBL or beta-blockers were educated about the

choices for primary prophylaxis and then surveyed; their preferences

were evaluated using a computerized questionnaire and Adaptive

Conjoint Analysis (a validated method describing preferences when

there are competing options available). Sixty-three percent of

patients (predominantly male, white, and educated) preferred EBL;

concerns of dyspnea, hypotension, fatigue and procedure-induced

bleeding were most important. The choice of EBL was correlated with

college education and higher annual income. The investigators

concluded that given the effectiveness of both therapies, proper

education and consent is of vital importance.

These studies reflect the growing trend toward considering

prophylactic band ligation in cirrhotic patients with high-risk

varices. As will be discussed below, noninvasive techniques to

approximate HVPG may change our current paradigms.

Despite advances in primary prophylaxis, variceal hemorrhage remains

a common clinical problem, with rebleeding being a major cause of

morbidity and mortality. A group from Barcelona, Spain, described

results of a trial conducted in 159 patients with variceal hemorrhage

who were randomized to drug therapy (nadolol* and isosorbide*) vs EBL

+ the same drug regimen.[10] Variceal rebleeding was decreased in the

EBL + drug group, but overall rebleeding and survival were similar

between the groups. The rebleeding rate (26% to 33%) was in the range

as that reported previously, and underscores the amount of work that

remains to be done in this population.

For those patients who fail to respond to endoscopic and

pharmacologic therapy to prevent rebleeding, portovenous shunting is

the most frequently employed next step in management. Although

transjugular intrahepatic portosystemic shunt (TIPS) has largely

supplanted surgical shunting, there are data to support the use of

distal splenorenal shunt (DSRS) in the prevention of rebleeding as

well. Two posters,[11,12] presented by a group led by Dr. Boyer from

the University of Arizona, addressed the long-term outcome of a

multicenter trial comparing TIPS with DSRS. The first study found

that although TIPS is more costly than DSRS, there is no difference

in cost-effectiveness. The need for TIPS revisions led to higher

costs (even when adjusted for coated stents), but the slight edge in

survival brought the cost-effectiveness of the 2 interventions back

in line.[11] The second study showed that in multivariate analysis,

the number of prior bleeds and the prothrombin time were correlated

with risk for death in patients undergoing either TIPS or DSRS for

refractory bleeding; therefore, refractory variceal bleeding could be

effectively treated with either TIPS or DSRS.[12]

With the increasing use of TIPS in patients with refractory bleeding,

the issue of shunt patency has become the focus of investigation.

and colleagues[13] from the Cleveland Clinic Foundation,

Cleveland, Ohio, and the University of Arizona, Tucson, were able to

maintain low (11% over 4 years) rebleeding rates in their DIVERT

(Decompression Intervention of Variceal Rebleeding Trial) trial by

frequent direct measurements of shunt pressures. Their findings

indicated that although Doppler ultrasound is most accurate in

predicting shunt patency using portal vein end measurements, it is an

overall poor tool for this purpose, with a sensitivity of 0.63 and

specificity of 0.77. Doppler interrogation at mid-TIPS and hepatic

vein end performed even more poorly. The study authors recommended

regular direct measurements to ensure TIPS patency. Whether the use

of coated stents will decrease this need has yet to be investigated.

Hepatic Venous Pressure Gradient

The direct measurement of HVPG has great utility in the management of

portal hypertension and its complications. The multinational Portal

Hypertension Collaborative Group presented their long-term data on

the use of HVPG in the prediction of clinical decompensation during

the Portal Hypertension I parallel session.[14] A cohort of 213

patients underwent HVPG measurement and were followed for a mean of

51.1 months. Patients with entry HVPG measurements < 10 mm Hg had

significantly less chance of clinical decompensation than did

patients with higher pressure gradients. During the same parallel

session, Albillos and colleagues[15] from Madrid, Spain, presented

their meta-analysis of 10 studies (N = 595) assessing the role of

HVPG guidance in the pharmacologic management of portal hypertension.

Patients who achieved an HVPG < 12 mm Hg or a reduction of 20% had a

significantly lower risk for variceal bleeding (relative risk = 0.27;

95% CI = 0.14-0.52). A shorter interval between HVPG measurements

improved the accuracy of prediction.

Despite the validity of HVPG measurement in the management of portal

hypertension, the technique is costly and invasive. Park and

colleagues[16] from Wonju, South Korea, and Calgary, Alberta, Canada,

described the correlation between the extent of abnormalities in

ultrasonographic hepatic vein waveforms measured by damping index and

HVPG to assess its utility for the noninvasive evaluation of the

severity of portal hypertension. A damping index of 0.7 was more

likely to be associated with severe portal hypertension, and

construction of a ROC (receiver operating characteristic) curve at

this damping index value of 0.7 showed a sensitivity of 72% and

specificity of 79% for the presence of severe portal hypertension

(HVPG > 15 mm Hg). Despite this acceptable performance, this approach

may become supplanted or supplemented by transient elastography, a

technique that is enjoying increasing popularity with investigators

and clinicians.

Elastography

The relatively new parameter of liver stiffness measurement (LSM)

using transient elastography for the evaluation of liver fibrosis has

been the focus of quite a number of investigations. During the Portal

Hypertension I parallel session at this year's AASLD meeting, Lemoine

and colleagues[17] from Paris, France, described their work in

assessing the correlation between LSM and HVPG in patients with

cirrhosis. Excluding patients with active variceal bleeding,

hepatorenal syndrome, hepatocellular carcinoma, portal vein

thrombosis, serious infection, antiviral or beta-blocker therapy,

HIV, hepatitis B, or heart failure, they found a significant positive

correlation between LSM and HVPG. The 17-kPa (kilopascals)

sensitivity of LSM was 90% for the detection of HVPG ¡Ý 12 mm Hg.

These results will undoubtedly be retested and expanded upon.

Other studies also demonstrated the reproducibility and utility of

this technique. Fraquelli and colleagues[18] from Milan, Italy,

correlated the results of transient elastography with the degree of

liver fibrosis on biopsy. These authors noted that with a mean scan

time of just over 3 minutes, transient elastography demonstrated high

intraobserver correlation, a rapid learning curve, and excellent

correlation with the degree of fibrosis in their cohort of 200

consecutive patients with liver disease of various etiologies.

Kim and colleagues[19] from Seoul, South Korea, reported on the use

of elastography in screening for esophageal varices in patients with

hepatitis B virus-related cirrhosis. In their cohort of 56 patients

with biopsy-proven Child-Pugh class A cirrhosis, a cutoff

elastography score of 9.7 kPa yielded a sensitivity of 83%,

specificity of 60%, positive predictive value of 78%, and a negative

predictive value of 67% for the presence of esophageal varices of any

kind. There was poor correlation with varix size or bleeding.

The availability of such a noninvasive tool for guiding risk

stratification and management decisions in patients with portal

hypertension is of immense potential importance.

Ascites/Hepatorenal Syndrome and Spontaneous Bacterial Peritonitis

The management of the hyperdynamic, sodium avid state of cirrhosis is

a common scenario for clinicians who provide clinical care for

patients with advanced liver disease. Although sodium restriction and

diuretics will remain the standard of care for years to come, the

development of aquaretic therapy may alter clinical care in the

future. Wong and colleagues[20] from Toronto, Barcelona, Zagreb,

Padova, and Brussels reported their experience with the selective

vasopressin V2 receptor antagonist satavaptan* in the management of

cirrhotic ascites during the Presidential Plenary III session. In

their cohort of 151 patients requiring frequent large-volume

paracentesis, subjects were randomized to treatment with satavaptan

in 1 of 3 doses vs placebo, in addition to their 100-mg daily dose of

spironolactone. Urine output was increased in a dose-dependent manner

in all patients receiving satavaptan. Additionally, the frequency of

paracentesis was decreased in all satavaptan treatment groups. Larger

trials are planned for this promising agent.

During the same Presidential Plenary session, Terg and colleagues[21]

from Buenos Aires, Argentina, presented their data on primary

prophylaxis to prevent spontaneous bacterial peritonitis in patients

with low-protein ascites. Low protein concentration in ascitic fluid

has been suggested as a risk factor for the development of

spontaneous bacterial peritonitis in patients with cirrhosis. In a

prospective, randomized, double-blind study design, cirrhotic

patients with low-protein ascites (without previous spontaneous

bacterial peritonitis) received ciprofloxacin* 500 mg daily (n = 50)

or placebo (n = 50). Although the rate of occurrence of spontaneous

bacterial peritonitis did not statistically differ between groups,

patients in the active treatment arm had better survival (86% vs 66%;

P < .04) and fewer bacterial infections (20% vs 45%; P < .05).

Mortality was most commonly due to spontaneous bacterial peritonitis

or sepsis. Side-effect profiles/complications were similar, and 2

patients in the treatment arm developed ciprofloxacin-resistant

infections. The publication of these results has the potential to

alter clinical practice.

Conclusion

The progress in portal hypertensive hepatology as reported at this

year's AASLD meeting can be characterized by advances in our

understanding of the pathophysiology of the disease, with the intent

to provide more directed and less toxic therapies. A parallel

development is evident in the clear move toward the use of

noninvasive surrogates as tools for the diagnosis, risk

stratification, and management of patients with advanced liver

disease.