Sunday, May 20, 2012

Complications of Cirrhosis

From Current Opinion in Gastroenterology

Complications of Cirrhosis

Robert S. Rahimi; Don C. Rockey
Posted: 05/18/2012; Curr Opin Gastroenterol. 2012;28(3):223-229. © 2012 Lippincott Williams & Wilkins

Abstract and Introduction
Purpose of review Chronic liver disease (CLD) causes significant morbidity and mortality, mainly due to complications [hepatic encephalopathy, ascites, hepatorenal syndrome (HRS), and esophageal variceal hemorrhage (EVH)]. Studies of the complications, management and outcomes in patients with CLD over the past 18 months are reviewed.

Recent findings Percutaneous liver biopsy can be safely performed in patients with advanced liver disease with minimal complications. Predictors of response to lactulose, probiotics and L-ornithine-L-aspartate therapy in minimal hepatic encephalopathy have been reported. Rifaximin was found to lead to better maintenance of remission and decreased re-admission rates in patients with cirrhosis and hepatic encephalopathy, and may improve driving performance in those with minimal hepatic encephalopathy. In a controversial study, patients with refractory ascites taking propranolol were found to have poorer outcomes, perhaps related to beta-blockade associated paracentesis-induced circulatory dysfunction. Terlipressin and albumin therapy currently appears to be the best medical therapy available in patients with type 1 HRS, although pentoxifylline may be effective to treat HRS in patients with cirrhosis and ascites. In patients with gastric varices, primary prophylaxis with cyanoacrylate may decrease the probability of gastric variceal hemorrhage compared to nonselective beta-blockers. In patients with esophageal varices without bleeding, prophylaxis with variceal ligation or beta-blockers was similar in terms of bleeding, mortality, and adverse events. Erythromycin given 30 min prior to endoscopic evaluation in suspected EVH was associated with an overall benefit in visibility, duration of the procedure and length of hospital stay.

Summary Refinement in clinical management strategies for patients with cirrhosis and its complications appears to continue to contribute to improved patient outcomes.

The prevalence of chronic liver disease (CLD) continues to rise, especially with the epidemic of viral hepatitis and obesity. CLD and cirrhosis were estimated by the Centers for Disease Control and Prevention (CDC) to be the 12th leading cause of mortality in the USA in 2007 accounting for 29 165 deaths which is 3.4% higher than 2006, resulting in the 2nd largest percentage increase of all-cause mortality.[1] However, data suggest that liverrelated mortality is in fact substantially higher than estimated; a study reported it to be 121% higher than CDC estimates, making CLD the 8th leading cause of death in the US.[2] This review will highlight recent data on the complications of cirrhosis.

Chronic Liver Disease Complications
Chronic injury to the liver, regardless of the cause, results in a wounding response that leads to fibrosis, and ultimately scarring and replacement of normal liver architecture by regenerative nodules. This process, along with the overproduction of endogenous vasoconstrictors like endothelins and underproduction of vasodilators like nitric oxide, results in an increase in intrahepatic resistance and portal hypertension. Clinically significant complications of CLD due to portal hypertension appear to be limited to situations in which the hepatic venous pressure gradient (HVPG) is elevated above 10mmHg.[3]

Liver Biopsy
A liver biopsy can provide useful information regarding diagnosis and management of CLD, including in patients with suspected cirrhosis; therefore, the overall safety and complication rates in patients with advanced liver disease were evaluated using the Hepatitis C Antiviral Long-Term Treatment against Cirrhosis (HALT-C) trial.[4•] Serial liver biopsies were obtained from each patient at baseline, 18 and 42 months later from 10 separate study sites in those with advanced liver disease (i.e. bridging fibrosis or cirrhosis) with compensated hepatitis C. A total of 2740 liver biopsies were performed (1187 at baseline, 852 at 18 months, and 701 at 42 months after randomization) using a single pass technique in 40% of the cases, whereas two or more passes were made in the remaining 60% in order to attempt to obtain at least 1.5cm of unfragmented liver tissue. All three biopsies were accomplished in 523 (38%) patients; 309 (22%) had two biopsies and 553 (40%) had only one biopsy performed. One of the reasons for missed biopsies that might have influenced the observed complication rate was withholding the procedure due to thrombocytopenia (range 26 000–73 000 mm3). The most common reasons for missed biopsies included outcomes reached and patient withdrawal. All participants discontinued aspirin 7–14 days prior to the procedure, and nonsteroidal anti-inflammatory drugs were stopped 1–10 days before the biopsy. The total complication rate for liver biopsies in this large cohort was 2.3% (63/2740), of which 54% (34/63) were classified as nonserious adverse events, whereas 46% (29/63) were categorized as serious adverse events (SAEs). Ninety-four percent of nonserious adverse events were due to transient pain at the biopsy site, with the remaining two patients experiencing a localized hematoma at the biopsy site or inflammation at the intravenous cannula site. The overall frequency of SAEs was 1.1% (29/2740), of which bleeding accounted for 55% (16/29), severe pain seen in 24% (7/29), a punctured gallbladder in 7% (2/29), and hypotension, pneumothorax, syncope and presumed dehydration occurred in one patient each or 3%. No deaths occurred overall as a result of the biopsy. Significant associations with bleeding and SAEs include: a lower albumin level (median level for all SAE patients, 3.7 vs. 3.9 g/l for non-SAE patients; P<0.02); platelet count 60 000mm3 or less (P<0.0001); International normalized ratio (INR) of at least 1.3 (P<0.01), and the presence of any esophageal varices seen on endoscopy restricted to the second and third biopsies (P<0.004). There was no correlation with bleeding SAEs observed regarding the person who performed the biopsy or the number of passes made. Overall, these data suggest that percutaneous liver biopsies can be safely performed in patients with advanced liver disease, with an acceptable complication rate. Care should be taken in patients with a platelet count 60 000 mm3 or less or INR of at least 1.3.

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[5••] 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.[6••] 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).[7•] 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.[8••] 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.

Portal hypertension leads to ascites, which usually can be managed by dietary sodium restriction and diuretics; however, 'refractory ascites' can be challenging to manage. In two notable studies, it was shown that outcomes in patients with refractory ascites taking nonselective beta-blockers (NSBBs) (i.e. propranolol) were found to be poor[9••] and may be associated with paracentesis-induced circulatory dysfunction (PICD) [10•]. In the first study, 151 patients (104 diuretic-intractable and 47 diuretic-resistant) were regularly treated with large- volume paracentesis (LVP) and intravenous albumin, 77 (51%) received propranolol for the prevention of gastrointestinal hemorrhage. The median follow-up was 8 months (1–47 months) with median survival of 5 months in the NSBB group (3.5–6.5 months) and 20 months in those not treated with NSBB (4.8–35.2 months; P = 0.0001). A total of 97 patients died from complications and progression of their underlying liver disease (63 receiving NSBB and 34 without). The 1 and 2-year survival (95% CI) was lower in patients who received NSBB [19%(9–29%) and 9% (0–19%)] vs. those who did not [64% (52–76%) and 45% (31–59%); P<0.0001]. Independent predictors of mortality [hazard ratio (95% CI)] were causes of refractory ascites which include: hyponatremia [7.07 (3.77– 13.25)] and renal failure [3.27 (1.73–6.17)], treatment with NSBB [2.61 (1.63–4.19)], hepatocellular carcinoma [1.94 (1.25–3.02)] and Child-Pugh class C [1.76 (1.09–2.8)].
The same group of investigators also studied 10 patients (4 diuretic-intractable and 6 diureticresistant) with refractory ascites on NSBB for prevention of gastrointestinal bleeding.[10•] The first assessment of heart rate (HR), arterial pressure, and plasma renin concentrations (PRCs) occurred pre and post LVP. Once varices were eradicated, NSBB therapy was then tapered over 1 week, in which secondary assessments were collected. PICD was later determined based on an increase in PRC of at least 50% above baseline 1 week after LVP, with comparative hemodynamic changes analyzed. Those on NSBB had an average of 2.7 ± 0.7 LVPs per month with 7.1 ± 0.9 l removed. Once NSBBs were discontinued, LVPs occurred 2.9 ± 0.6 times per month with 6.3 ± 1.6 l removed (these differences were found not to be significant). Although HR increased while systolic blood pressure and mean arterial pressure decreased overall within 1 h after LVP, these differences were not significant overall, as they returned to baseline 1 week later. After NSBB discontinuation, PICD was seen in 10% of those studied; however, when treated with NSBB, PICD developed in 80%. The exact mechanism of this difference occurring in this cross-over study is unknown; however, it might suggest that NSBB may contribute to PICD. Although both studies are intriguing, the results must be interpreted with caution given their design and sample size; further study in this area is clearly required.

Hepatorenal Syndrome
Hepatorenal syndrome (HRS) is an extremely problematic complication of CLD, and (type 1) HRS portends a poor prognosis. An interesting randomized, double-blind, placebo-controlled multicenter clinical trial evaluated the predictors of response to terlipressin and albumin in HRS type 1.[11••] HRS reversal was seen in 34% (19/56) vs. 13% (7/56) of patients treated with terlipressin or placebo, respectively (P = 0.002). When therapy was not considered, serum creatinine (SCr) became the only significant predictor of HRS reversal (P = 0.029). The likelihood of HRS reversal in either treatment arm was greatest in those with SCr below 3.0 mg/dl (50% response rate with terlipressin vs. 33% in placebo), less so in those with SCr of 3.0–5.0mg/dl (31% response rate with terlipressin vs. 9% in placebo), and least in those with SCr above 5.0mg/dl (11% response rate with terlipressin vs. 0% in placebo). On univariate analysis, predictors of overall survival were alcoholic hepatitis, SCr and MELD score. On multivariate analysis, baseline SCr was also predictive of survival (P<0.001), with a 50% increase in risk of mortality for every mg/dl increase in creatinine. Even though the only variable predictive of HRS reversal was baseline SCr, if SCr had not decreased by day 4, patients did not subsequently respond to therapy. Baseline SCr, Child-Pugh score, and presence of alcoholic hepatitis were predictive of survival at 180 days. Although patients responding to terlipressin will show a sustained improvement in mean arterial pressure (MAP) during therapy, the change in MAP immediately following the administration of terlipressin is not predictive of a response. One might consider the use of terlipressin with albumin in HRS type 1 if SCr is less than 5 mg/dl; however, once the SCr exceeds 7 mg/dl, or if the SCr does not decrease by day 4, the likelihood of response with terlipressin is negligible and the utility of using it can be questioned. Unfortunately, terlipressin continues to be unavailable in the US at this time.

Another RCT examined whether pentoxifylline might prevent HRS in cirrhotics with ascites; this study compared pentoxifylline 400mg p.o. t.i.d. (group A) to placebo (group B) for 6 months.[12•] Those in group A had an improvement in creatinine clearance at 1 (P = 0.001) and 3 months (P = 0.001) without any significant changes in SCr over a 1, 3, and 6-month period. Also, there was an improvement in sodium and MAP at 1, 3 and 6 months (P = 0.01). Those in group B had an increase in SCr at 1 month (P = 0.007), 3 months (P = 0.001), and 6 months (P = 0.001) with a decline in serumsodium at 1 month (P = 0.02) and 6 months (P = 0.002). Overall 21% of patients developed HRS [2 patients in group A (6%) and 10 patients in group B (32%); P = 0.01] with 75% of patients responding to terlipressin and albumin. There was no difference found between the cause of cirrhosis and occurrence of HRS; however, patients who developed HRS had higher TNF-a (P = 0.01), lower MAP (P = 0.01), and lower serum sodium levels (P = 0.003), according to baseline characteristics. Hence pentoxifylline can be considered in preventing HRS in patients with cirrhosis and ascites at risk for HRS if creatinine clearance is between 41 and 80 ml/min.

An interesting study characterized the types of renal dysfunction in 152 cirrhotics admitted with SCr of at least 1.5 mg/dl; 70% of patients had acute kidney injury (AKI), 17% had chronic kidney disease (CKD) with associated AKI, and 13% had CKD alone.[13] The cause of renal dysfunction was further characterized as prerenal azotemia, intrinsic renal disease, HRS type 1, HRS type 2, and postrenal disease; of which 56, 33, 9, 0, and 2% of the cohort were represented, respectively. The overall mortality for the cohort was 31%, the highest of which was found in type 1 HRS overall (11/14 or 79%), with 8/11 (73%) presenting with AKI only, and 3/3 (100%) presenting with AKI þ CKD. The mortality figure for type 1 HRS is typical and is consistent with a robust patient cohort. It was interesting that the authors were unable to identify any patients meeting diagnostic criteria for type 2 HRS as defined according to the International Ascites Club criteria,[14] suggesting that the diagnostic criteria for this form of HRS may need re-evaluation, or more interestingly, that HRS type 2 may not represent a unique functional kidney disorder.

Variceal Hemorrhage
Gastroesophageal varices (GOVs) are a result of portal hypertension which are usually present in about 50% of cirrhotics at the time of diagnosis, have a growth rate potential of 7% per year and a 1-year rate of first variceal hemorrhage ranging from 5 to 15% with approximately a 6-week mortality rate of 15–20% with each episode.[15] Because of the importance of GOV in patients with cirrhosis, multiple studies have examined hemorrhage in GOV.

A multicenter RCT comparing endoscopic variceal band ligation (EVBL) to propranolol in patients with large (diameter >5mm) esophageal varices without a history of gastrointestinal bleeding for primary prophylaxis was notable.[16•] Of the 73 patients, 40 were randomized to EVBL (received every 2 weeks until esophageal varices were eradicated), whereas 33 received propranolol at a starting dose of 20mg twice daily until beta-blockade was adequate (with dose adjustments of 20–40mg at weekly intervals to achieve a reduction in baseline heart rate of 25%, not to decrease below 55 beats/min). Patients in the EVBL arm received an average of 2.2 ± 1.2 endoscopic sessions with a mean of 11 ± 6 bands placed overall, with all patients exhibiting esophageal varices eradication. The mean daily dose required to achieve an adequate beta-blocker response was 66.7 ± 30.6mg over a mean time period of 26.3 ± 13.8 days. Although no serious side effects were seen in the NSBB group, 4 patients (12%) did not achieve adequate reduction in HR, whereas 14 patients (42%) reported one or more minor side effects. There were no significant differences seen in bleeding, mortality or adverse events overall in the 18-month follow-up period; however, the study was underpowered to capture any of these differences, hence determining between these two prophylactic treatments should be made on an individual basis.

Another RCT examined primary prophylaxis for gastric variceal hemorrhage comparing cyanoacrylate injection to NSBB or no treatment. Eighty-nine patients without any esophageal varices [GOV type 2 or isolated gastric varices (IGV) type 1] with no history of gastric variceal hemorrhage were randomized to cyanoacrylate injection (group I, n = 30), beta-blocker (group II, n = 29) or no treatment (group III, n = 30) [17••]. A decrease in the size of gastric varices was seen in group I, from 20 to 5mm (P<0.01) compared to an increase in size in groups II and III (20 to 25mm; 20 to 30mm; P<0.01). HVPG remained elevated (>12mmHg) in groups I and III, whereas it decreased in about half of group II patients. With a median follow-up of 26 months, patients in groups I, II and III had an actuarial probability of overall gastric variceal hemorrhage of 13, 28 and 45% (P = 0.003); however, overall survival was not significant between groups I and II and II and III. On multivariate analysis, size of gastric varices greater than 20mm (P = 0.038), MELD score at least 17 (P = 0.006) and presence of portal hypertensive gastropathy (PHG) (P = 0.008) were independent predictors of gastric variceal bleed.

Endoscopic visibility in cirrhotics with esophageal variceal hemorrhage (EVH) can be challenging in regards to endoscopic intervention, hence a double-blind, randomized, placebo-controlled trial compared patients receiving either 125mg of a motilin agonist (i.e. erythromycin) or placebo administered intravenously 30 min before endoscopy in order to compare endoscopic visibility, duration of the procedure, need for repeat endoscopy, complication rates, length of stay (LOS), and blood transfusion needed within 24 h.[18••] Of the 102 eligible patients, 90 patients were found to have EVH, in which 47 were randomized to receive erythromycin, whereas 43 received placebo. An empty stomach was seen in 48.9% compared to 23.3% of patients receiving erythromycin vs. placebo, respectively (P<0.01). Average endoscopic duration (19 vs. 26 min; P<0.005) and LOS (3.4 vs. 5.1 days; P<0.002) were both shorter in the erythromycin group compared to the placebo group. As endoscopic visibility was better in the erythromycin group, bleeding control by EVBL was achieved in higher numbers (70.2 vs. 48.8%; P<0.04) compared to the placebo arm. Repeat endoscopy and the mean number of blood transfusions did not differ between the two groups. Although not statistically significant, the risk of aspiration pneumonia was higher in the placebo group. As erythromycin is inexpensive with very few side effects, its use 30 min before endoscopy may benefit cirrhotic patients presenting with EVH.

Many recent studies have provided insight in the area of management of patients with cirrhosis and in improving outcomes. However, further research is still required, and in particular in assessing the most cost-effective strategies. The emergence of rifaximin for use in patients with hepatic encephalopathy will require further study to better understand its costeffectiveness. We will need further studies, including prospective trials, on the subject of the use of NSBB in patients with ascites. Terlipressin appears to be the most effective medical treatment for type 1 HRS, but we need to understand better which patients are likely to respond. Endoscopic variceal band ligation might be effective in primary prophylaxis in large varices; however, beta-blockers in addition to band ligation have been previously shown to be an overall better strategy.

  1. Xu JQ, Kochanek KD, Murphy SL, Tejada-Vera B. Deaths: final data for 2007. National vital statistics reports; Vol 58 no 19. Hyattsville, MD: National Center for Health Statistics; 2010.
  2. Asrani S, Kamath P, Pedersen R, et al. Liver related mortality in the US is underestimated. Hepatology 2010; 52:408; A169.
  3. Miñano C, Garcia-Tsao G. Clinical pharmacology of portal hypertension. Gastroenterol Clin North Am 2010; 39:681•ndash;695.
  4. Seeff LB, Everson GT, Morgan TR, et al. Complication rate of percutaneous liver biopsies among persons with advanced chronic liver disease in the HALT-C trial. Clin Gastroenterol Hepatol 2010; 8:877–883.
    • Out of 2740 liver biopsies in patients with advanced liver disease, overall complication rates were 2.3%, with bleeding accounting for 55% of SAEs. The highest association with bleeding occurred in over 5% of the cases when platelet count was less than 60 000 mm3 and in 4% of cases when INR was greater than 1.3.
  5. Bass NM, Mullen KD, Sanyal A, et al. Rifaximin treatment in hepatic encephalopathy. N Engl J Med 2010; 362:1071–1081.
    •• Over a 6-month treatment period, rifaximin compared to placebo has a hazard ratio of 0.42 (95% CI 0.28–0.64, P<0.001) for breakthrough hepatic encephalopathy episodes with a 58% relative reduction and a number needed to treat (NNT) of 4 patients to prevent 1 episode of overt hepatic encephalopathy. Hospitalization in the rifaximin group had a hazard ratio of 0.50 (95%CI 0.29–0.87, P = 0.01) with a 50% risk reduction with the NNT of 9 patients to prevent 1 hospitalization compared to placebo.
  6. Mittal VV, Sharma BC, Sharma P, Sarin SK. A randomized controlled trial comparing lactulose, probiotics, and L-ornithine L-aspartate in treatment of minimal hepatic encephalopathy. Eur J Gastroenterol Hepatol 2011; 23:725–732.
    ••This RCT compared lactulose, probiotics and LOLA to no therapy to evaluate HRQoL and progression to overt hepatic encephalopathy in those with MHE. Any of the three therapies showed a significant improvement in HRQoL and reversal of MHE compared to no therapy; however, there were no significant differences between the therapies used.
  7. Bajaj JS, Heuman DM, Wade JB, et al. Rifaximin improves driving simulator performance in a randomized trial of patients with minimal hepatic encephalopathy. Gastroenterology 2011; 140:478–487; e1.
    • Those receiving rifaximin for 8 weeks, showed improvement in driving simulations regarding total driving errors, speeding, and illegal turns; however, the number of collisions were not significantly different when compared to those receiving placebo. Cognitive function also showed improvement when receiving rifaximin vs. placebo.
  8. Riggio O, Ridola L, Angeloni S, et al. Clinical efficacy of transjugular intrahepatic portosystemic shunt created with covered stents with different diameters: results of a randomized controlled trial. J Hepatol 2010; 53:267–272.
    ••This RCT compared 8 vs. 10mm PTFE covered stents and found no difference in overt episodes of hepatic encephalopathy over 1 year between the groups; however, remaining free of portal hypertension complications were significantly lower in the 10mm group (83%) vs. the 8mm group (42%) at 1 year (P = 0.002).
  9. Serste T, Melot C, Francoz C, et al. Deleterious effects of beta-blockers on survival in patients with cirrhosis and refractory ascites. Hepatology 2010; 52:1017–1022.
    ••Overall survival is decreased when using nonselective beta-blockers in a cohort of refractory ascites patients that either have hyponatremia, renal failure, hepatocellular carcinoma or Child-Pugh C. Caution should be advised in using NSBB to prevent gastrointestinal hemorrhage in these patients.
  10. Serste T, Francoz C, Durand F, et al. Beta-blockers cause paracentesisinduced circulatory dysfunction in patients with cirrhosis and refractory ascites: a cross-over study. J Hepatol 2011; 55:794–799.
    • Performing LVPs on patients with refractory ascites and discontinuing NSBBs resulted in 10% developing PICD, whereas the same patients show PICD 80% of the time when treated with NSBBs, but the mechanism for this discrepancy is unknown at this time.
  11. Boyer TD, Sanyal AJ, Garcia-Tsao G, et al. Predictors of response to terlipressin plus albumin in hepatorenal syndrome (HRS) type 1: relationship of serum creatinine to hemodynamics. J Hepatol 2011; 55:315–321.
    .••The use of terlipressin and albumin in treating type 1 HRS is most likely to benefit patients with SCr of below 5 mg/dl, knowing that the only predictive variable for reversal of HRS was shown to be baseline SCr. Having alcoholic hepatitis and a higher CTP score also influenced survival.
  12. Tyagi P, Sharma P, Sharma BC, et al. Prevention of hepatorenal syndrome in patients with cirrhosis and ascites: a pilot randomized control trial between pentoxifylline and placebo. Eur J Gastroenterol Hepatol 2011; 23:210–217.
    • This study evaluated the efficacy of pentoxifylline in preventing HRS in patients with cirrhosis and ascites. Although 21% of patients developed HRS (10 patients receiving placebo vs. 2 receiving pentoxifylline; P = 0.01), those treated with pentoxifylline showed improvements in creatinine clearance, serum sodium and MAP over the 6-month period.
  13. Warner NS, Cuthbert JA, Bhore R, Rockey DC. Acute kidney injury and chronic kidney disease in hospitalized patients with cirrhosis. J Investig Med 2011; 59:1244–1251.
  14. Salerno F, Gerbes A, Gines P, et al. Diagnosis, prevention and treatment of hepatorenal syndrome in cirrhosis. Gut 2007; 56:1310–1318.
  15. Garcia-Tsao G, Bosch J. Management of varices and variceal hemorrhage in cirrhosis. N Engl J Med 2010; 362:823–832.
  16. Drastich P, Lata J, Petrtyl J, et al. Endoscopic variceal band ligation compared with propranolol for prophylaxis of first variceal bleeding. Ann Hepatol 2011; 10:142–149.
    • This multicenter RCT evaluated prophylactic EVBL vs. propranolol in those with large esophageal varices without previous variceal hemorrhage, and found no significant differences in bleeding, mortality or adverse events overall, however this study was underpowered.
  17. Mishra SR, Sharma BC, Kumar A, Sarin SK. Primary prophylaxis of gastric variceal bleeding comparing cyanoacrylate injection and beta-blockers: randomized controlled trial. J Hepatol 2011; 54:1161–1167.
    ••This RCT demonstrated that cyanoacrylate injection should be used as first-line therapy for high-risk gastric varices (high MELD, large gastric varices and presence of PHG) for primary prophylaxis compared to NSBB.
  18. Altraif I, Handoo FA, Aljumah A, et al. Effect of erythromycin before endoscopy in patients presenting with variceal bleeding: a prospective, randomized, double-blind, placebo-controlled trial. Gastrointest Endosc 2011; 73:245–250.
    ••Double-blind, randomized, placebo-controlled trial showed that erythromycin administered before endoscopy in cirrhotic patients with EVH improves endoscopic visualization (48.9 vs. 23.3%; P<0.01) and decreases procedure time (19 vs. 26 min; P<0.005) as well as LOS (3.4 vs. 5.1 days; P<0.002) compared to placebo.

    Papers of particular interest, published within the annual period of review, have been highlighted as:
    • of special interest
    •• of outstanding interest
    Additional references related to this topic can also be found in the Current World Literature section in this issue (pp. 292–293).

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