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 TransplantationDecompensation 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 hepatic 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, increasing 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
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Gastroenterology. 2005;128(suppl 2):A-714. [Poster S1534]






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