Complications of Cirrhosis
Complications of Cirrhosis
Hepatic encephalopathy is a spectrum of reversible neuropsychiatric abnormalities seen in patients with cirrhosis after exclusion of neurologic and/or metabolic abnormalities. Hepatic encephalopathy ranges in a continuum that spans a range from normal cognitive function (grade 0) to minimal hepatic encephalopathy (within grade 0) to overt hepatic encephalopathy (grade 1–4). There is considerable controversy about treatment of patients with hepatic encephalopathy. A previous multicenter trial found that treatment with rifaximin compared to placebo decreased the risk of first hepatic encephalopathy breakthrough in 31/140 patients (22.1%) vs. 73/159 patients (45.9%) with a hazard ratio for breakthrough hepatic encephalopathy using rifaximin compared to placebo of 0.42 (0.28–0.64, P<0.001). There was also a decrease in hospitalization rate when using rifaximin [19/140 patients (13.6%)] compared to placebo [36/159 patients (22.6%)] with a hazard ratio of 0.50 (0.29–0.87, P = 0.01). Hence, the data suggest that the use of rifaximin over a 6-month period resulted in a decrease in hospital readmission rate and overt hepatic encephalopathy events compared to placebo. However, it should be emphasized that rifaximin is costly, and whether it is cost-effective for treatment of hepatic encephalopathy is largely unknown.
An area that has received considerable attention is minimal hepatic encephalopathy (MHE), and its treatment, as the prevalence of MHE ranges from 30 to 80%. A study comparing no therapy (group A), lactulose 30–60 ml b.i.d. (group B), probiotics of 110 billion colony-forming units b.i.d. (group C) or L-ornithine-L-aspartate 6 g t.i.d. (LOLA; group D) for 3 months examined overall health-related quality of life (HRQoL) improvement, and outcomes including progression to overt hepatic encephalopathy. Of the 322 eligible cirrhotic patients, 160 (49.7%) with MHE were enrolled, including 40 patients in each of the four groups. Using neuropsychological assessment, recovery of MHE (i.e. normal mental status) was seen in 10, 48, 35 and 35% of patients in groups A, B, C and D, respectively (P = 0.006). There was no significant difference in recovery from MHE or changes in ammonia levels when comparing lactulose to either probiotics or LOLA. Although no significant difference in overt hepatic encephalopathy progression was seen over 3 months, a total of nine patients (6% overall) developed overt hepatic encephalopathy. When comparing the sickness impact profile (SIP), which assesses the influence of disease and treatment on daily functioning (i.e. HRQoL), a statistically significant decrease in total SIP score was seen in the treatment groups compared to no treatment (P<0.001); however, no differences in SIP scores were seen when comparing within the treatment groups. The decrease in SIP scores correlated with an improvement in MHE on multivariate analysis; however, there was no correlation with the type of therapy offered. Overall, lactulose, probiotics and LOLA significantly improved MHE and HRQoL in cirrhotic patients compared with no therapy, hence one might consider using any of these three treatments in those proven to have MHE based on neuropsychological testing.
Another study evaluated driving simulator performances in patients with MHE at baseline and after randomization to receive either 8 weeks of rifaximin (n = 21) or placebo (n = 21). Those receiving rifaximin showed improvement in avoiding total driving errors (76 vs. 31%; P = 0.013), speeding (81 vs. 33%; P = 0.005), and illegal turns (62 vs. 19%; P = 0.01) compared to those given placebo; however, the number of collisions were not significantly different between groups. Of patients given rifaximin, cognitive performance improved (91 vs. 61%; P = 0.01) compared to those receiving placebo. Although this randomized, double-blind, placebo-controlled trial has interesting results, this study was partly funded by Salix pharmaceuticals, the makers of rifaximin, hence caution should be taken when interpreting the data.
It is known that transjugular intrahepatic portosystemic shunt (TIPS) is performed on selected patients who exhibit complications from portal hypertension; however, complications with hepatic encephalopathy can arise. An interesting RCT evaluated outcomes, namely overt hepatic encephalopathy findings after using polytetrafluoroethylene (PTFE) covered stents (8 vs. 10mm) after TIPS placement. A total of 45 cirrhotic patients whose past or present history did not include hepatic encephalopathy but had variceal bleeding or refractory ascites, were randomized to receive 8mm (n = 22) or 10mm (n = 23) PTFE covered stents. After successful TIPS placement, the HVPG decreased in both groups (from 21.3 ± 4.9 to 8.9 ± 2.7 mmHg) in the 8mm stent group and from 22.1 ± 7.1 to 6.5 ± 2.7 (P = 0.007) in the 10mm stent group. Nearly 55% had recurrence and/or persistence of complications of portal hypertension in the 8mm stent group vs. only 13% in the 10mm stent group; however, at 1 year, 42% [95% confidence interval (CI) 19– 64.7%] in the 8mm stent group vs. 83% (95% CI 64.9–100%) in the 10mm stent group (P = 0.002) remained free from portal hypertension complications, especially when considering the persistence of ascites and need for repeat paracentesis (6 out of 10 in the 8mm vs. 1 out of 14 in the 10mm stent group; P = 0.008). There was no difference in hepatic encephalopathy events as 11 of 22 patients with the 8mmstents vs. 11 of the 23 patients with the 10mm stent had hepatic encephalopathy episodes post TIPS, with the probability of remaining free of hepatic encephalopathy being similar among both groups; 43% (95% CI 19.5–65.7%) in the 8mmstent group vs. 47% (95% CI 23.7–69.6%) in the 10mm stent group; (P = 0.48) at 1 year. Although venous ammonia showed significant increase post TIPS in the 10mm stent group (P<0.01), there were no significant differences in psychometric testing regarding hepatic encephalopathy. The cumulative survival (80%) was similar in both groups. Although there was no difference in hepatic encephalopathy episodes post TIPS, one might consider using a 10mm PTFE covered stent during a TIPS procedure as this group had significantly fewer portal hypertension-related complications at 1 year.
Hepatic Encephalopathy
Hepatic encephalopathy is a spectrum of reversible neuropsychiatric abnormalities seen in patients with cirrhosis after exclusion of neurologic and/or metabolic abnormalities. Hepatic encephalopathy ranges in a continuum that spans a range from normal cognitive function (grade 0) to minimal hepatic encephalopathy (within grade 0) to overt hepatic encephalopathy (grade 1–4). There is considerable controversy about treatment of patients with hepatic encephalopathy. A previous multicenter trial found that treatment with rifaximin compared to placebo decreased the risk of first hepatic encephalopathy breakthrough in 31/140 patients (22.1%) vs. 73/159 patients (45.9%) with a hazard ratio for breakthrough hepatic encephalopathy using rifaximin compared to placebo of 0.42 (0.28–0.64, P<0.001). There was also a decrease in hospitalization rate when using rifaximin [19/140 patients (13.6%)] compared to placebo [36/159 patients (22.6%)] with a hazard ratio of 0.50 (0.29–0.87, P = 0.01). Hence, the data suggest that the use of rifaximin over a 6-month period resulted in a decrease in hospital readmission rate and overt hepatic encephalopathy events compared to placebo. However, it should be emphasized that rifaximin is costly, and whether it is cost-effective for treatment of hepatic encephalopathy is largely unknown.
An area that has received considerable attention is minimal hepatic encephalopathy (MHE), and its treatment, as the prevalence of MHE ranges from 30 to 80%. A study comparing no therapy (group A), lactulose 30–60 ml b.i.d. (group B), probiotics of 110 billion colony-forming units b.i.d. (group C) or L-ornithine-L-aspartate 6 g t.i.d. (LOLA; group D) for 3 months examined overall health-related quality of life (HRQoL) improvement, and outcomes including progression to overt hepatic encephalopathy. Of the 322 eligible cirrhotic patients, 160 (49.7%) with MHE were enrolled, including 40 patients in each of the four groups. Using neuropsychological assessment, recovery of MHE (i.e. normal mental status) was seen in 10, 48, 35 and 35% of patients in groups A, B, C and D, respectively (P = 0.006). There was no significant difference in recovery from MHE or changes in ammonia levels when comparing lactulose to either probiotics or LOLA. Although no significant difference in overt hepatic encephalopathy progression was seen over 3 months, a total of nine patients (6% overall) developed overt hepatic encephalopathy. When comparing the sickness impact profile (SIP), which assesses the influence of disease and treatment on daily functioning (i.e. HRQoL), a statistically significant decrease in total SIP score was seen in the treatment groups compared to no treatment (P<0.001); however, no differences in SIP scores were seen when comparing within the treatment groups. The decrease in SIP scores correlated with an improvement in MHE on multivariate analysis; however, there was no correlation with the type of therapy offered. Overall, lactulose, probiotics and LOLA significantly improved MHE and HRQoL in cirrhotic patients compared with no therapy, hence one might consider using any of these three treatments in those proven to have MHE based on neuropsychological testing.
Another study evaluated driving simulator performances in patients with MHE at baseline and after randomization to receive either 8 weeks of rifaximin (n = 21) or placebo (n = 21). Those receiving rifaximin showed improvement in avoiding total driving errors (76 vs. 31%; P = 0.013), speeding (81 vs. 33%; P = 0.005), and illegal turns (62 vs. 19%; P = 0.01) compared to those given placebo; however, the number of collisions were not significantly different between groups. Of patients given rifaximin, cognitive performance improved (91 vs. 61%; P = 0.01) compared to those receiving placebo. Although this randomized, double-blind, placebo-controlled trial has interesting results, this study was partly funded by Salix pharmaceuticals, the makers of rifaximin, hence caution should be taken when interpreting the data.
It is known that transjugular intrahepatic portosystemic shunt (TIPS) is performed on selected patients who exhibit complications from portal hypertension; however, complications with hepatic encephalopathy can arise. An interesting RCT evaluated outcomes, namely overt hepatic encephalopathy findings after using polytetrafluoroethylene (PTFE) covered stents (8 vs. 10mm) after TIPS placement. A total of 45 cirrhotic patients whose past or present history did not include hepatic encephalopathy but had variceal bleeding or refractory ascites, were randomized to receive 8mm (n = 22) or 10mm (n = 23) PTFE covered stents. After successful TIPS placement, the HVPG decreased in both groups (from 21.3 ± 4.9 to 8.9 ± 2.7 mmHg) in the 8mm stent group and from 22.1 ± 7.1 to 6.5 ± 2.7 (P = 0.007) in the 10mm stent group. Nearly 55% had recurrence and/or persistence of complications of portal hypertension in the 8mm stent group vs. only 13% in the 10mm stent group; however, at 1 year, 42% [95% confidence interval (CI) 19– 64.7%] in the 8mm stent group vs. 83% (95% CI 64.9–100%) in the 10mm stent group (P = 0.002) remained free from portal hypertension complications, especially when considering the persistence of ascites and need for repeat paracentesis (6 out of 10 in the 8mm vs. 1 out of 14 in the 10mm stent group; P = 0.008). There was no difference in hepatic encephalopathy events as 11 of 22 patients with the 8mmstents vs. 11 of the 23 patients with the 10mm stent had hepatic encephalopathy episodes post TIPS, with the probability of remaining free of hepatic encephalopathy being similar among both groups; 43% (95% CI 19.5–65.7%) in the 8mmstent group vs. 47% (95% CI 23.7–69.6%) in the 10mm stent group; (P = 0.48) at 1 year. Although venous ammonia showed significant increase post TIPS in the 10mm stent group (P<0.01), there were no significant differences in psychometric testing regarding hepatic encephalopathy. The cumulative survival (80%) was similar in both groups. Although there was no difference in hepatic encephalopathy episodes post TIPS, one might consider using a 10mm PTFE covered stent during a TIPS procedure as this group had significantly fewer portal hypertension-related complications at 1 year.
