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Issues in Cirrhosis
and Liver Transplantation
Tram T. Tran, MD

Introduction

Liver transplantation remains the only viable therapeutic option for acute and chronic liver failure. Excellent long-term outcomes have been achieved over the past 2 decades, with posttransplant survival rates approaching 90% at 1 year and 60% at 5 years.[1] Unfortunately, the continued limited availability of deceased donor organs as compared with the number of patients currently awaiting transplantation necessitates that gastroenterologists and hepatologists must try to effectively prevent and manage the common complications of cirrhosis in order to prolong survival until transplantation. The Model for End Stage Liver Disease (MELD) allocation system, now in place for 3 years, has proven to be an effective predictor of mortality in those patients with decompensated cirrhosis.[2]

Research presented on end-stage liver disease and transplantation during this year's Digestive Disease Week (DDW) meeting explored new developments in the management of complications of chronic liver disease, such as gastrointestinal bleeding, spontaneous bacterial peritonitis, hepatocellular carcinoma, MELD score utility, and posttransplant management.

Issues in Cirrhosis and Liver Transplantation

Decompensation of Cirrhosis

Because waiting times may approach months to years for some patients awaiting liver transplant, the management of common known complications of cirrhosis and portal hypertension is paramount to the survival of patients. D'Amico and colleagues[3] reported the outcome of 494 consecutive patients with newly diagnosed cirrhosis at their center who were followed for evidence of decompensation in the form of ascites, bleeding, encephalopathy, jaundice, or hepatocellular carcinoma. The majority of these patients had hepatitis C infection, and 117/494 (24%) had decompensation at the time of inclusion into the study. During the study period of 25 years, 63% of those patients who were compensated eventually developed decompensation. Ten-year actuarial survival for decompensated vs compensated cirrhosis was 7% vs 63%, respectively, and cumulative survival rates at 2, 5, and 10 years for decompensated cirrhotics were 50%, 31%, and 14%. Of patients who died, 43% died at the time of the first decompensation.

This study highlights that although a cirrhotic patient may remain stable for a long period of time, once an event occurs signaling decompensation of liver function, referral to a transplant center should be done in a timely fashion, because mortality dramatically increases thereafter.

Ascites

First-line management of ascites in the cirrhotic patient entails dietary sodium restriction and judicious use of diuretics as tolerated by renal function. Although still somewhat controversial, the use of transjugular intrahepatic portosystemic shunting (TIPS) has been used in refractory ascites that is not responsive to maximal diuretic dosages. Peritovenous shunting is rarely performed as risks of infection and malfunction are high. Large-volume paracentesis is a viable option for patients intolerant or refractory to diuretics, but should not be first line. The pathophysiology of TIPS seems to be a reduction in sinusoidal portal pressure resulting in a fall in the plasma renin activity and serum aldosterone levels, a rise in renal blood flow and glomerular filtration rate, and associated naturesis and diuresis.[4] Probability for 1-year survival without transplant in 1 cohort after TIPS was 69% compared with 52% in a non-TIPS large-volume paracentesis group.[5] However, risks include worsened hep atic encephalopathy, hepatic decompensation, and stent occlusion or malfunction.

Measurement of hepatic venous pressure gradient (HVPG) has been suggested as a means of monitoring degree of portal hypertension for risk of recurrent variceal bleeding secondary to esophageal varices. Campbell and colleagues[6] examined the measurement of HVPG after TIPS to determine the correlation with recurrent ascites. Fifty-two patients who had TIPS for refractory ascites were followed for recurrent ascites. Twenty-two of 52 patients (42%) developed recurrent ascites requiring large-volume paracentesis, and hepatic venous pressure measurements were obtained showing mean HVPG of 12 mmHg for patients with recurrent ascites compared with 10 mmHg in the non-recurrent group (P = .45). Sodium, MELD score, volume of paracentesis, and percent change in HVPG after TIPS did not predict recurrent ascites. Further detailed analysis of this patient population may yield other influencing factors in recurrent ascites, such as rapidity of diuretic withdrawal, patient dietary compliance after TIPS, and TIPS stenosis, but etiology may be multifactorial. Additional data are emerging on the use of TIPS for this indication, but at this time, only the carefully selected patient should be considered for TIPS.

Spontaneous Bacterial Peritonitis

Spontaneous bacterial peritonitis (SBP) occurs in cirrhotic patients with ascites and is usually due to infection with enteric gram-negative organisms. A high morbidity and mortality is associated with SBP, with one third of patients admitted for SBP dying from gastrointestinal bleeding, liver failure, or hepatorenal syndrome[7]; renal failure develops in 30% to 40% of these patients even with control of the infection. SBP can also occur more often after gastrointestinal bleeding.

During this year's DDW meeting, Planas and colleagues[8] reported the results of a randomized multicenter controlled trial comparing oral norfloxacin with intravenous ceftriaxone in decompensated cirrhotics for prophylaxis after gastrointestinal bleeding. They randomized patients to receive either norfloxacin 400 mg orally twice daily for 7 days (n = 55) or ceftriaxone 1 g intravenously for 7 days (n = 53). They found that the group receiving ceftriaxone had a lower probability of developing all bacterial infections than the oral norfloxacin group (11% vs 27%; P = .02). The types of bacterial infections included pneumonia, urinary tract infections, and SBP. It appeared that patients with more severe gastrointestinal bleeding, and those who already had been on norfloxacin prophylaxis, were at increased risk for acute bacterial infection. Patients admitted for gastrointestinal bleeding are clearly at increased risk for a host of complications, including infections. The role of antibiotic prophylaxis in these high-risk patients has been recommended, but the routine use of intravenous antibiotics needs further study as the development of more resistant bacterial strains needs to be considered.

Hepatic Encephalopathy

Portosystemic encephalopathy (PSE) is a common complication of cirrhosis, and can present mildly with only minimal symptoms such as memory loss, irritability, and an altered sleep-wake cycle, or more severely with deep somnolence or coma. It is important that when a patient presents with PSE underlying risk factors be ruled out, including infections, gastrointestinal bleeding, and medications that may precipitate encephalopathy, such as benzodiazepines. The mechanism underlying PSE is not clearly understood, but is believed to be partly due to hyperammonemia. PSE can often be controlled with the administration of lactulose, a nonabsorbable disaccharide that acts by several different mechanisms, including acidification of the gut lumen, leading to ammonia being converted into ammonium (NH4+), which is less membrane-permeable. Lactulose also acts as an osmotic agent, decreasing intestinal transit time. Other agents used in the management of PSE include nonabsorbable antibiotics such as neomycin, although its long-term use may be limited by nephrotoxicity because it has some systemic absorption and ototoxicity.

Administration of ornithine, which is a substrate for urea, has been explored as a treatment for PSE because it may increase the conversion of ammonia to urea. Mumtaz and colleagues[9] reported the results of a randomized study assessing the benefit of intravenous L-ornithine L-aspartate in patients with PSE. Patients admitted with PSE were randomized to receive either L-ornithine L-aspartate 20 g per day (n = 50) intravenously or placebo for 4 consecutive days. Measurement of PSE stage, the number connection test, serum ammonia level, length of hospital stay, and mortality were recorded. In this study, all of the reported measures of PSE were improved with L-ornithine L-aspartate compared with placebo, with no reported change in mortality or side effects related to the drug. Unfortunately, difficulty in defining and diagnosing PSE hampers the ability to really assess therapeutic benefits in this setting. Attempts to use quantifiable measures, such as serum ammonia levels, are not readily applicable, because serum ammonia is not well correlated to severity of encephalopathy. Additionally, this study compared L-ornithine L-aspartate with placebo, not lactulose, which would be considered the current standard of care; thus, further studies are needed at this time.

Gastrointestinal Bleeding

Upper gastrointestinal bleeding (UGIB) is often the first and most dramatic presentation in a patient with cirrhosis. Mortality can approach 50% with an upper gastrointestinal bleed from esophageal or gastric varices. Secondary prevention of UGIB with nonselective beta-blockers (such as propranolol) should be considered in patients with a history of upper gastrointestinal hemorrhage. The use of TIPS is reserved for patients with UGIB that is not controlled with endoscopic management, but it carries risk of worsened encephalopathy or hepatic decompensation. The especially difficult bleeding patient is one with gastric varices, which are difficult to manage with traditional variceal band ligation or injection sclerotherapy.

Seewald and colleagues[10] reported the use of tissue glue N-butyl-2-cyanoacrylate (CA)* in 131 patients with gastric fundal UGIB. They used a mixture of CA and lipiodol, and restricted the amount injected to 1.0 mL into a varix at one time to reduce risk of embolism; endoscopy was repeated at 4 days with repeat CA injection until obliteration of the varices. Rebleeding-free rates at 1 and 3 years were 94% and 89%, respectively. No embolism occurred in this study. This study is promising, and shows that in experienced hands, CA may be a "last ditch" lifesaving option; however, with the published risk of cerebral and pulmonary embolism, and lack of US FDA approval, cyanoacrylate will probably not be widely available to the clinician.

Hepatocellular Carcinoma

Hepatocellular carcinoma is an indication for liver transplantation, but only within set criteria that have yielded good survival and recurrence-free survival compared with nonhepatocellular carcinoma transplant indications. Mazzaferro and colleagues[11] published the current standard criteria for liver transplant in patients with hepatocellular carcinoma, the so-called "Milan criteria" also adopted by the United Network for Organ Sharing (UNOS), which are as follows: 1 lesion, not greater than 5 centimeters in diameter, or 3 lesions or fewer, none greater than 3 centimeters. With these criteria, overall 4-year survival was 75%.

Yao and colleagues[12] have recently published University of California, San Francisco (UCSF) guidelines proposing expansion of these criteria (single lesion not greater than 6.5 cm, or 2 or 3 lesions, none greater than 4.5 cm with total tumor diameter less than 8 cm) with good outcomes. With the risk of tumor growth and metastasis and the current long waiting times for transplant, treatment of lesions with bridging modalities such as percutaneous ethanol injection, radiofrequency ablation, and chemoembolization, have become fairly common at transplant centers. In their analysis of more than 3700 patients with hepatocellular carcinoma, Johnson and colleagues[13] found that more patients are now undergoing local ablative therapies and transplant than previously, and fewer patients are having hepatic resection.

During this year's DDW meeting, Yao and colleagues[14] reported on the impact of degree of tumor necrosis (as a marker of response to locoregional treatments) on tumor recurrence in 172 liver transplant recipients. Five-year recurrence-free probability was 93% for patients with > 60% necrosis of tumor on explant vs 83% for patients with < 60% necrosis (P = .027). Tumor necrosis > 60% was also associated with a significantly better 5-year recurrence-free probability in patients exceeding the Milan criteria (83% vs 63%; P = .46). The study authors concluded that pretransplant treatment of hepatocellular carcinoma that yields > 60% necrosis of the tumor may be associated with lower risk of recurrence. This study adds to the growing body of evidence that preoperative locoregional treatment of hepatocellular carcinoma, in carefully selected patients, is a viable option while awaiting transplantation, and may result in better short-term (getting the patient to transplant) and long-term (less recurrence) outcomes.

Acute Liver Failure

Acute liver failure is manifest by jaundice, coagulopathy, and encephalopathy within 26 weeks, and carries a high mortality (> 80%) without transplant. The US Acute Failure Study Group led by Lorenzo Rossaro published their study results investigating the prognostic value of the MELD score in 729 adult patients with acute liver failure.[15] Although they found that a MELD score of < 30 (negative predictive value 82%) may predict spontaneous survival, a high MELD score did not predict poor outcome well.

Taylor and colleagues[16] analyzed 29 patients with acute liver failure secondary to acute hepatitis A, and reported a 45% death or transplant rate. Factors associated with poor outcome were sex (male), low alanine amino transferase (ALT) and alkaline phosphatase levels, and higher serum creatinine. The study authors then developed a 4-variable index for predicting poor prognosis using any 2 out of 4 criteria upon admission to yield a positive predictive value of 86% and negative predictive value of 93%: creatinine > 2.0 mg/dL, ALT < 2600 IU/mL, use of pressors, or intubation. This group also reported the outcome in patients who had acute liver failure secondary to hepatic ischemia and as would be expected, cardiopulmonary disease and hypotension were identified risk factors.[17] Mortality rate in this group was 34%, and renal function again played a role in prognosis. Early prediction of which patients will require transplantation is still a difficult and elusive clinical task, and will require further study.

Viral Hepatitis in the Cirrhotic Patient

Treatment of hepatitis C with interferon has been relatively contraindicated in patients with a history of decompensated cirrhosis due to the risk of hepatic decompensation, poor tolerability, and low success rates. Everson and colleagues[18] published their experience treating 102 patients with decompensated cirrhosis (mean Child-Pugh score 7) with combination interferon and ribavirin therapy using the low but accelerating dose regimen (LADR). Sustained virologic response was achieved in 22% of patients; however, most important, those patients with sustained virologic response prior to transplantation did not have recurrent hepatitis C virus infection, which is normally universal in the posttransplant hepatitis C patient.

Kaiser and colleagues[19] investigated the role of consensus interferon* in Child-Pugh class A and B patients using a protocol starting at 9 micrograms (mcg) 3-times weekly for 6 weeks, followed by 9 mcg daily, then adding ribavirin at escalating dosages, increased as tolerated to weight-based dosing. Low platelet counts required dose reduction in 31% of the 58 patients treated, and growth factors were used for anemia and neutropenia. Sustained virologic response rates were 45% overall, and were highest in the early (Child-Pugh class A) cirrhotic patient compared with the patients with Child-Pugh class B disease.

Given the difficulties of posttransplant recurrent hepatitis C, more aggressive treatment is being attempted in the carefully selected cirrhotic patient -- but these patients should undergo therapy in clinical trials or at centers with extensive experience with treatment availability of liver transplantation.

Concluding Remarks

The continuing shortage of available donor organs for liver transplantation fuels the necessity for vigilance in the management of the patient with cirrhosis. Prevention of infection, control of ascites, effective endoscopic management of gastrointestinal bleeding, treatment of viral hepatitis, and surveillance and treatment of hepatocellular carcinoma are all important clinical goals.

*The US Food and Drug Administration has not approved this medication for this use.

References

2004 Annual Report of the U.S. Organ Procurement and Transplantation Network and the Scientific Registry of Transplant Recipients: Transplant Data 1999-2001. Rockville, Md: HHS/HRSA/SPB/DOT; UNOS; URREA.

Wiesner R, Edwards E, Freeman R, et al, and the United Network for Organ Sharing Liver Disease Severity Score Committee. The model for end-stage liver disease (MELD) and allocation of donor livers. Gastroenterology. 2003;124:91-96.

D'Amico G, Pasta L, D'Amico M, et al. Decompensation of cirrhosis: a 25-year inception cohort study. Gastroenterology. 2005;128(suppl 2):A-A686. [Abstract 187]

Wong F, Sniderman K, Liu P, Allidina Y, Sherman M, Blendis L. Transjugular intrahepatic portosystemic stent shunt: effects on hemodynamics and sodium homeostasis in cirrhosis and refractory ascites. Ann Intern Med. 1995;122:816-822.

Rossle M, Ochs A, Gulberg V, et al. A comparison of paracentesis and transjugular intrahepatic portosystemic shunting in patients with ascites. N Engl J Med. 2000;342:1701-1707.

Campbell MS, Clark TW, Sanyal AJ, et al. Hepatic venous pressure gradient does not correlate with recurrent ascites after transjugular intrahepatic portosystemic shunting. Gastroenterology. 2005;128(suppl 2):A-687. [Abstract 190]

Nasava M, Rodes J. Management of ascites in the patient with portal hypertension with emphasis on spontaneous bacterial peritonitis. Semin Gastrointest Dis, 1997;8:200-209.

Planas R, Fernandez J, Ruiz L, et al. Randomized, multicenter, controlled trial comparing oral norfloxacin vs intravenous ceftriaxone in the prevention of bacterial infections in cirrhotics with severe liver failure and gastrointestinal bleeding. Gastroenterology. 2005;128(suppl 2):A-687. [Abstract 191]

Mumtaz K, Abid S, Abbas Z, et al. Efficacy of infusion of L-ornithine L-aspartate in cirrhotic patients with portosystemic encephalopathy: a placebo controlled study. Gastroenterology. 2005;128(suppl 2):A-688. [Abstract 192]

Seewald S, Naga M, Omar S, et al. Standardized Injection technique and regimen minimizes complication and ensures safety of N-butyl-2-cyanoacrylate injection for the treatment of gastric fundal varices. Gastrointest Endoscp. 2005;61. [Abstract 372]

Mazzaferro JW, Regalia E, Doci R, et al. Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis. N Engl J Med. 1996; 34:693-699.

Yao FY, Ferrell L, Bass NM, et al. Liver transplantation for hepatocellular carcinoma: expansion of the tumor size does not adversely impact survival. Hepatology. 2001;33:1394-1403.

Johnson EW, Jensen CC, Yeung R, et al. Population trends in use and outcome of surgical treatments for primary liver cancer. Gastroenterology. 2005;128 suppl 2:A-690. [Abstract 232]

Yao FY, Ferrell LD, Bass NM, et al. Liver transplantation for hepatocellular carcinoma: the impact of the degree of tumor necrosis from pre-operative loco-regional therapy on recurrence. Gastroenterology. 2005;128(suppl 2):A-689. [Abstract 231]

Rossaro L, Chambers CC, Polson J, et al. Performance of MELD in predicting outcome in acute liver failure. Gastroenterology. 2005;128(suppl 2):[Poster S1492]

Taylor R, Fontana R, Bass NM, et al. A novel 4 variable index is superior to King's College Criteria in identifying non-survivors with acute liver failure due to hepatitis A. Gastroenterology. 2005;128(suppl 2):A-706. [Poster S1494]

Taylor R, Fontana R, Shakil A, et al. Acute liver failure due to ischemic hepatitis: Natural history and predictors of outcome in a prospective, multi-center U.S. study. Gastroenterology. 2005;128(suppl 2):A-706. [Poster S1495]

Everson GT, Trotter JF, Kugelmas M. Long-term outcome of patients with chronic hepatitis C and decompensated liver disease treated with the LADR protocol [low-accelerating-dose-regimen]. Hepatology. 2002;36:297A

Kaiser S, Hass H, Gregor M. Treatment of chronic hepatitis C patients with Child A and B cirrhosis with a low ascending daily dosing regimen with consensus interferon and ribavirin results in significant viral eradication rates. Gastroenterology. 2005;128(suppl 2):A-714. [Poster S1534]

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