Complications of Cirrhosis -- Clinical Insights and Implications for Practice

Introduction

New insights into the pathophysiology of liver disease, as highlighted at this year's postgraduate course, have provided advances in the understanding, diagnosis, and management of the various manifestations of cirrhosis and portal hypertension. The annual meeting of the American Association for the Study of Liver Diseases (AASLD) also offered new information regarding challenges in identification, prevention, and prognosis for these very ill patients. This clinical overview summarizes some of the more important new concepts and data related to these topics, as presented during AASLD 2007.

Varices/Bleeding

Because of the high prevalence and generally poor outcome of variceal hemorrhage, it is accepted that all patients with cirrhosis should be screened for the presence of esophageal varices so as to allow the administration of primary prophylaxis. Currently, the only reproducible method for such screening is gastrointestinal endoscopy. Previous research has promulgated the recommendation that cirrhotic patients with portal vein diameter of ≥ 13 mm and/or platelet count of less than 140,000/mm³ should be screened endoscopically.^[1] In an attempt to refine these recommendations, Giannini and colleagues^[2] from Genoa, Italy, and Lahore, Pakistan, reported on the performance of platelet count/spleen diameter ratio in screening for esophageal varices. Using a study cohort of 311 patients with cirrhosis undergoing endoscopy and a cut-off value ratio of 909, the investigators found a sensitivity of 100%, specificity of 97.6%, positive predictive value of 76.9%, and a negative predictive value of 100% for the diagnosis of esophageal varices. The ratio outperformed the AASLD rubric and would have avoided 75 unnecessary endoscopies. If confirmed, such easily obtained measurements would allow more efficient use of endoscopy as a mode to screen for esophageal varices.

Patients who undergo surveillance and are found to have large esophageal varices are currently treated with a nonselective beta-blocker with or without a nitrate to reduce the risk of first hemorrhage. Although effective in meta-analysis, beta-blockers require aggressive dosing to insure efficacy, a practice that leads to significant side effects. Tripathi and colleagues^[3] from Edinburgh, Glasgow, and Paisley, United Kingdom, hypothesized that carvedilol,* a nonselective vasodilating beta-blocker that lowers portal pressure more effectively than propranolol, might show efficacy as a primary prophylactic agent. In this study, 152 patients over a period of 6 years with nonbleeding esophageal varices, were randomized to carvedilol 12.5 mg/day or endoscopic variceal ligation biweekly, until eradication. During the Presidential Plenary Session, the investigators reported that patients who received carvedilol had a lower risk of first bleed, but no improvement in survival or bleeding-related mortality. This carefully conducted trial offers believable data that carvedilol therapy is superior to band ligation in the prevention of first bleed. It is possible that improvement in band ligation technique could obviate this difference, but pharmacologic therapy remains the primary prophylaxis method of choice. However, at present, the standard nonselective beta-blockers -- propranolol, nadolol, and timolol -- have been reproducibly shown to be the standard of care for the primary prophylaxis of esophageal varices.

Infused vasoactive therapy remains a mainstay of acute therapy for variceal hemorrhage. As physicians in the United States continue to await the availability of terlipressin* and other somatostatin analogues that have shown good results in international trials, octreotide* remains the standard of care for acute reduction of portal pressures. Spahr and colleagues^[4] from Geneva, Switzerland, noting that the most substantial hemodynamic effect of octreotide is during the initial bolus, provided data regarding the circulatory effects of repeat octreotide bolus in patients with cirrhosis and portal hypertension. In this pilot, noncontrolled study, the investigators measured azygous vein blood flow, cardiac output, and mean arterial pressure following 2 infusions given 60 minutes apart. The initial 50 mcg octreotide bolus provided a 34% reduction in azygous vein blood flow, a reduction that persisted for the 60 minutes of measurement. The second bolus resulted in a mean azygous blood flow reduction of 18%. The investigators concluded that octreotide exerts its beneficial hemodynamic effects by bolus infusion, although no data were provided on infused therapy for comparison.

When screening and subsequent primary prophylaxis fail to prevent variceal hemorrhage, and bleeding in controlled, secondary prophylaxis can be of benefit in reducing the risk of recurrent hemorrhage. Data for secondary prophylaxis have been less compelling than those for primary prophylaxis, but Jha and colleagues^[5] from New Delhi, India, reported on their investigation of a suggested regimen to the portal hypertension parallel session audience during AASLD 2007. A cohort of 171 patients with acute variceal hemorrhage were randomized to endoscopic variceal ligation alone vs endoscopic variceal ligation plus propranolol* and isosorbide mononitrate* (ISMN). Hepatic vein pressure gradient was measured at baseline, but propranolol was titrated to achieve target blood pressure and heart rate reductions. The study authors found no improvement in outcome for the group treated with band ligation plus pharmacotherapy. The jury is still out regarding the optimal management of such patients, but data currently support the use of serial band ligation to achieve varix obliteration.

Ascites/Spontaneous Bacterial Peritonitis/Hepatorenal Syndrome

Ascites

High-volume paracentesis is commonly used for the treatment of patients with refractory ascites. Circulatory disturbances induced by the rapid removal of ascitic fluid have been well described, and may be associated with irreversible renal dysfunction. Intravascular volume replacement, most often with human albumin, is frequently used to reverse these circulatory effects. Given the variations in the clinical applications of albumin, its high cost, and the potential utility of managing paracentesis-induced circulatory dysfunction with vasoconstrictors, Singh and colleagues^[6] from Chandigarh, India, reported their experience with midodrine,* an oral alpha-adrenergic agonist, in this clinical setting. Forty patients undergoing high-volume paracentesis for tense ascites were randomized to receive albumin or midodrine. Plasma renin activity, 24-hour urine volume, and urine sodium excretion were measured at baseline and 6 days after paracentesis. Although no data were given regarding volume of paracentesis, volume of albumin, or dose of midodrine, the investigators found similar parameters of circulatory disturbance in the 2 groups. Given the ease of administration, low cost, and apparent efficacy of midodrine in this setting, larger scale controlled trials are indicated.

Terlipressin,* a potent vasoconstrictor has shown promise in the acute control of variceal hemorrhage and in the reversal of hepatorenal syndrome. Krag and colleagues^[7] from Copenhagen, Denmark, sought to expand the indications for this compound in their study of patients with cirrhosis and ascites. In this prospective, controlled study, 15 patients with nonrefractory ascites were randomized to receive terlipressin or placebo, while a group of patients with refractory ascites all received terlipressin. Compared to placebo, terlipressin induced significant increases in glomerular filtration rate, sodium clearance, and urine sodium concentration. Similar, albeit blunted, changes were seen in the refractory ascites group (there was no control group). This small study suggests that early intervention in the circulatory disturbances of cirrhosis may provide significant clinical benefit.

Repeated high-volume paracentesis is an accepted therapy for refractory ascites, but patient acceptance of this regimen, especially if prolonged, can be poor. Although transjugular intrahepatic portosystemic shunt (TIPS) insertion has been shown to be effective for refractory ascites, concerns regarding the potential risk for encephalopathy, disease progression, and the associated costs may limit its widespread applicability. Hajjafar and colleagues^[8] from Case Western Reserve University in Cleveland, reported on the cost effectiveness of TIPS vs repeated high-volume paracentesis for the treatment of refractory ascites using a Markov model. Estimates of treatment outcomes were derived from 5 randomized controlled trials; costs were determined by Medicare reimbursement. Health state utilities were derived from the medical literature. The investigators found that TIPS was a cost-effective alternative to repeated large-volume paracentesis with albumin administration, if the frequency of paracentesis exceeded once monthly. Although this is only a mathematical model of the "real" situation, the analysis provides food for thought when facing this common management decision.

Spontaneous Bacterial Peritonitis

As is the case with many manifestations of advanced chronic liver disease, prophylaxis, early detection, and decisive treatment can significantly affect clinical outcome. A specific case in point is spontaneous bacterial peritonitis, which connotes an approximate 50% chance of 6-month mortality. Bajaj and colleagues^[9] from the Medical College of Wisconsin in Milwaukee, investigated the hypothesis that the use of proton-pump inhibitors (PPI) allows enteric bacterial overgrowth and thus may lead to a higher risk for bacterial translocation, with subsequent development of spontaneous bacterial peritonitis. Using a retrospective study design, this group reviewed the medical records of 985 patients with cirrhosis, 44 of whom had ascitic fluid analysis consistent with spontaneous bacterial peritonitis. Using a control cohort of 88 patients with cirrhosis matched for age and Child-Turcotte-Pugh score, both univariate and multivariate analysis showed correlation of spontaneous bacterial peritonitis with high Child-Turcotte-Pugh score and PPI use. This study, which should be replicated to confirm the findings, offers an important conclusion regarding the routine use of PPIs in patients with cirrhosis and ascites.

Early detection of spontaneous bacterial peritonitis significantly improves outcome. The current standard of care for early detection involves measurement of absolute neutrophil counts from aspirated ascites fluid. Zapater and colleagues^[10] from Alicante, Barcelona, Valencia, and Madrid, Spain, reported on the measurement of a novel marker, bacterial DNA, in ascites fluid as a predictor of survival in cirrhotic patients with noninfected ascites. They analyzed the ascites fluid from 156 patients with sterile ascites, 48 of whom had bacterial DNA detected by polymerase chain reaction (PCR) analysis. The presence of bacterial DNA (mostly Escherichia coli) was significantly associated with 12-month mortality (ie, was an indicator of poor prognosis), but surprisingly, the DNA-containing group did not have a higher incidence of spontaneous bacterial peritonitis. If these findings can be reproduced, this important prognostic indicator may give rise to new preventive strategies or may even help refine liver graft allocation.

Hepatorenal Syndrome

Hepatorenal syndrome is a dreaded complication of end-stage liver disease with ascites. Once considered uniformly fatal, deeper understanding of the pathophysiology of this syndrome has led to the hope for improved outcomes using vasodilator therapy. Sanyal and colleagues^[11] provided an analysis of a moderate-sized hepatorenal syndrome therapeutic trial, with data specifically focused on early detection and treatment of this complication. Using multivariate analysis, the investigators found that reversal of hepatorenal syndrome was more likely to occur in patients with lower serum creatinine, lower MELD (Model for End-Stage Liver Disease) scores, and randomization to terlipressin.* In fact, reversal of hepatorenal syndrome was only seen in subjects who had creatinine levels < 5.6 mg/dL at enrollment and more than 3 days of terlipressin treatment. This analysis underscores the importance of early detection and treatment of hepatorenal syndrome.

Hepatic Encephalopathy

Clinicians familiar with the treatment of patients with chronic liver disease are often quick to note the difficulty of diagnosing and managing portosystemic encephalopathy. Few manifestations of advanced cirrhosis are more disabling to patients or more disconcerting to family members. Investigators are increasingly recognizing and assessing data on subclinical hepatic encephalopathy, which can result in the insidious loss of cognitive function and have a negative impact on patient performance on neuropsychological tests. Alterations in sleep pattern, especially day/night reversal, is recognized as an early manifestation of hepatic encephalopathy. Montagnese and colleagues^[12] from the Royal Free Hospital and University of Surrey in the United Kingdom, tested the hypothesis that day/night reversal may be less associated with hepatic encephalopathy than generally thought. Using a study cohort including 93 patients with cirrhosis (two-thirds with Child-Turcotte-Pugh A score) and 26 healthy volunteers, they conducted structured interviews and administered a battery of sleep performance questionnaires. Findings confirmed that patients with cirrhosis slept less well than controls; these abnormalities in sleep-wake indices were not correlated with hepatic encephalopathy, as determined by clinical and psychometric criteria. This information should encourage the development and use of bedside clinical tools that reproducibly diagnose subclinical hepatic encephalopathy. Polysomnographic study of patients with cirrhosis may also yield interesting findings.

Portal Hypertension/Hepatic Venous Pressure Gradient

The benefits of hepatic venous pressure gradient (HVPG) measurement, particularly in providing prognostic information in patients with advanced chronic liver disease, have been established. Rincón and colleagues^[13] from Madrid, Spain, studied the capacity of HVPG to predict clinical decompensation in patients with compensated cirrhosis. Over a 9-year period, 798 patients underwent HVPG measurement at a single center in Madrid; 173 of these patients had compensated liver disease and became the study cohort, with a mean of 25 months of follow-up. Clinical decompensation was observed in 13%, 30%, and 52% at 1, 3, and 5 years. Multivariate analysis demonstrated an association between clinical decompensation and 2 variables: age older than 60 and HVPG > 13 mm Hg.

Despite the virtues of HVPG, it is clear that the measurement of this parameter, being specialized and invasive, is not in general clinical use. The technology of transient elastography has demonstrated efficacy in assessing liver stiffness and its correlate of liver fibrosis. Indeed, liver stiffness as measured by transient elastography has been shown to correlate with HVPG. Bureau and colleagues^[14] from Toulouse, France, assessed the prognostic value of liver stiffness and compared it with HVPG. The study involved 78 patients who underwent HVPG measurement and transient elastography on the same day, and then followed for 1 year or until reaching a study endpoint of bleeding, ascites, sepsis, encephalopathy, hepatocellular carcinoma, death, or liver transplantation. Transient elastography and HVPG had similar performance characteristics in predicting complications at 1 year in patients with chronic liver disease. It is a safe prediction that transient elastography will continue to add to our ability to diagnose and manage chronic liver disease.

Miscellaneous

Despite advances in prophylaxis and treatment of variceal hemorrhage, spontaneous bacterial peritonitis, hepatorenal syndrome, and hepatic encephalopathy, there is little evidence to support the notion that any of these modalities, short of liver transplantation, provide a significant survival advantage. In this setting, Lebrec and colleagues^[15] studied the effects of pentoxifylline,* an inhibitor of proinflammatory cytokine production, on short-term survival in patients with advanced cirrhosis. They reported data from 332 patients with Child-Turcotte-Pugh C cirrhosis who received either pentoxifylline or placebo for 6 months. Not only did pentoxifylline have no effect on 2- or 6-month survival in the overall group, but it also failed to provide significant benefit in the subgroup most predicted to improve (those with severe alcoholic hepatitis, with or without renal dysfunction). Although this was a "negative study," the results provide important information regarding this widely employed therapy.

Conclusion

The high level of basic investigations into the pathophysiology of portal hypertension and its manifestations have yielded promising clinical results, as demonstrated by the studies outlined above. Continued work on diagnostic tools, pharmacologic agents to counteract the circulatory disturbances of cirrhosis, and agents to lower portal pressures promises to continue these trends.

This activity is supported by an independent educational grant from Bristol-Myers Squibb

References