MEDSCAPE

Issues in Cirrhosis

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 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.

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