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Complications of Cirrhosis

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					Complications of Cirrhosis: Clinical Perspectives and Implications CME

Disclosures

Helena Cortez-Pinto, MD, PhD

Introduction

The final stage of liver disease is punctuated by several major complications: ascites,
hepatorenal syndrome (HRS), spontaneous bacterial peritonitis (SBP; a potentially lethal
infection of the ascitic fluid that occurs in the absence of a local source of infection),
variceal hemorrhage, and hepatic encephalopathy. Although liver transplantation is
indicated whenever these complications are present, there are still many patients who
have to be managed through them, either while waiting for a liver or because they have
contraindications to liver transplantation. The appropriate management of these patients
is crucial, not only because these complications can be life-threatening, but also because
it is now clear that influencing the pretransplant status of patients results in better
transplant outcomes.

During this year's meeting of the European Association for the Study of the Liver
(EASL), this broad topic was not primarily addressed in formal lectures, but rather most
of the new data were presented in poster sessions. This clinical overview addresses some
of the more important new data related to complications of cirrhosis -- ascites/ SBP,
varices, and hepatic encephalopathy, as presented during these meeting proceedings.

Ascites/SBP/HRS

Background

Ascites is one of the more frequent complications of liver cirrhosis and will develop in
approximately 50% of patients with compensated cirrhosis who are followed for 10
years. Development of this complication is an ominous sign in that approximately 50% of
patients with ascites die within 2 years if not transplanted. It is usually associated with a
marked deterioration in nutritional status and in quality of life.

The management of this clinical problem is challenging for the patient and physician
alike because it requires very careful monitoring of the pharmacologic treatment, with
special attention given to fluid and weight balance. Treatment of ascites has been based
on a sodium-restriction diet and the progressive administration of diuretics, starting with
spironolactone (100 mg/day) and furosemide (40 mg/day), and increasing progressively
every 3-5 days, if weight loss is inadequate, until a maximum dosage of 400 mg/day of
spironolactone and 160 mg/day of furosemide is reached. Fluid restriction is not
necessary in treating most patients with cirrhosis and ascites. The chronic hyponatremia
usually seen in patients with cirrhotic ascites is seldom morbid. In this setting, attempts to
rapidly correct hyponatremia with hypertonic saline can lead to more complications than
the hyponatremia itself.[1] Preliminary data suggest that aquaretic drugs may have some
promise in correcting hyponatremia, and may also be useful in treating HRS. Therapeutic
paracentesis may be used in patients with refractory ascites; its use in patients with
diuretic-sensitive ascites is more controversial. Administration of albumin at a dose of 5-
10 g/L of ascitic fluid removed has been strongly advised to prevent paracentesis-induced
circulatory dysfunction in large-volume paracentesis (> 5 L).[1]

Treatment and Complications

Ascites. Alessandria and colleagues,[2] from San Giovanni Battista Hospital in Turin,
Italy, compared low-dosage infusion of albumin (4g/L of ascitic fluid removed) with the
standard dose of 8g/L of ascitic fluid removed in 25 patients undergoing large-volume
paracentesis. In both groups, the amount of ascitic fluid removed was similar, as was
plasma renin activity. The study authors found a similar incidence of paracentesis-
induced circulatory dysfunction, suggesting that low doses of albumin are as effective as
standard doses in the prevention of this complication -- a finding that may support a
significant cost reduction in the management of patients with cirrhotic ascites.

Renal failure. Another significant complication of ascites in patients with cirrhosis is the
development of renal failure. Ballesté and colleagues,[3] from Badalona and Barcelona,
Spain, assessed the incidence and prognosis of different types of nonorganic renal failure
(ie, functional, reversible renal failure) in 263 consecutive cirrhotic patients followed for
41 ± 3 months after their first ascites. They considered 3 types of such renal failure:
prerenal failure when associated with a depletion of intravascular volume; renal failure
associated with infection not leading to HRS; and HRS as defined by preestablished
criteria. It is interesting to note that these investigators found that 49% of cirrhotic
patients with ascites developed some type of nonorganic renal failure, prerenal failure
being the most frequent (27.4% of all patients) during follow-up. This complication was
associated with a significantly worse prognosis, suggesting that efforts to prevent
prerenal failure should be implemented.

HRS, a common and serious problem in patients with advanced liver disease, is a
functional form of renal failure that can occur in end-stage liver disease. Its pathogenesis
involves vasodilation of the splanchnic vessels. The vasoconstrictor terlipressin* may be
useful in patients with HRS. Gluud and colleagues[4] from the Cochrane Hepato-Biliary
group in Copenhagen, Denmark, presented a systematic review of randomized controlled
trials assessing the effect of terlipressin in the treatment of HRS. They found 3 published
and 2 ongoing trials eligible for inclusion. All patients had cirrhosis and HRS type 1 or
type 2. The most commonly evaluated dose of terlipressin was 1 mg given every 12 hours
for 5-15 days. Survival rates were 62% for patients randomized to terlipressin and 20%
for those in the control group, with terlipressin demonstrating a significant beneficial
effect on creatinine clearance. The study authors concluded that terlipressin may be
considered for patients with HRS in spite of its potential adverse effects, namely ischemia
of myocardium, gut, or digits, although evidence is still needed for definitive treatment
recommendations, especially regarding dose and duration of therapy.
SBP. Nousbaum and colleagues,[5] from France, presented data regarding the rapid
diagnosis and prevalence of SBP in cirrhotic ascites. The diagnosis of SBP in patients
with cirrhosis requires an ascitic fluid polymorphonuclear cell count > 250/mm3. Using
leukocyte esterase reagent strips (the type used for urinalysis), these investigators
collected data on a total of 2123 ascites samples in 1069 patients in this multicenter
prospective study. The samples were tested with commercially available reagent strips,
with each strip read twice by different members of the team to avoid investigator bias.
One hundred and seventeen SBP episodes (5.5% prevalence) were identified among the
samples. Among these, 56 were associated with a positive ascitic fluid culture. Using the
threshold of 2+ for positivity of the reagent strip (ie, a positive reagent strip result of 2 or
more), sensitivity was 43.6% and specificity was 99.2% for the diagnosis of SBP, with a
positive predictive value of 76.1% and negative predictive value of 96.8%. With regard to
the sensitivity of the test, these results are not as good as those previously reported by
other groups -- although specificity was excellent. Thus, the study authors concluded that
a negative result on reagent strip cannot exclude the diagnosis of SBP.

Varices

Background

The management of portal hypertension encompasses therapy to prevent hemorrhage in
patients who have never bled (primary prophylaxis), treatment for those who are actively
bleeding, and therapy for those who have previously bled (secondary prophylaxis). In
primary prophylaxis, after a screening endoscopy, if medium- or large-sized varices are
present, nonselective beta-blockers (ie, propranolol or nadolol) remain the treatment of
choice. The drug dose is increased until heart rate decreases by 25%, with a frequency
between 50 and 60 beats/minute. Specific hemostatic treatments for variceal bleeding
include vasoactive drugs that decrease portal pressure, such as terlipressin* or
somatostatin, endoscopic band ligation, and surgical portosystemic shunts or TIPS
(transjugular intrahepatic portosystemic shunt). As secondary prophylaxis, both beta-
blockade and endoscopic band ligation can be used. When possible, hepatic venous
pressure gradient (HVPG) should be monitored, with the goal of reduction to < 12
mmHg; otherwise, the goal of reducing heart rate by 25% is acceptable. HVPG provides
valuable prognostic information in the pharmacologic management of portal hypertension
in helping to predict the risk of variceal hemorrhage.[6]

Primary Prophylaxis

With regard to prophylaxis of the first variceal bleed, Drastich and colleagues,[7] from the
Czech Republic, conducted a prospective, multicenter, randomized trial to compare the
efficacy and safety of propranolol therapy vs endoscopic variceal ligation in the
prophylaxis of the first variceal bleed. Of 73 cirrhotic patients with high-risk varices (> 5
mm in diameter), 33 received propranolol (at a dose sufficient to decrease baseline heart
rate by 25%) and 40 underwent endoscopic variceal ligation until eradication. They found
no significant difference in the actuarial risk for first variceal bleed between the 2 groups
(9% for endoscopic variceal ligation and 20% for the propranolol group). As to
associated complications, there was 1 bleed related immediately to endoscopic variceal
ligation and no complications in the propranolol group. The study authors concluded that
both propranolol and endoscopic variceal ligation seem to be safe and effective in this
setting. In fact, previous randomized controlled trials have shown that variceal banding is
as effective as beta-blockers for preventing a first variceal bleed. However, it is still
recommended to initiate management with beta-blockers if there are no contraindications
because these agents are inexpensive, easy to use, and relatively safe, considering
prophylactic band ligation of varices in those patients who cannot tolerate the appropriate
doses of beta-blockers.[8]

Another interesting study concerning portal hypertension-related bleeding was presented
by Beauchant and colleagues[9] from France. This study aimed to examine French
management practices in this setting. This cross-sectional survey examined 127 bleeding
events and involved 103 men and 23 women; mean age was 58.5 years. Cirrhosis was
linked to alcohol in 85% of patients. The bleeding event was the first episode in 79 (62%)
patients, 40 (51%) of whom had known cirrhosis and 25 had prior endoscopy (with stage
II esophageal varices found in 18 of 25, and prophylaxis with beta-blockers given in 14
of 18 cases). The main causes of bleeding were esophageal varices in 73% of cases, other
varices in 10% of cases, and portal hypertensive gastritis in 5%. Vasoactive treatment
was given in 89% of cases, endoscopic ligature in 42%, sclerosis in 21%, and/or
tamponade in 6% of cases. The study authors concluded that although management was
usually in line with general consensus, one third of known cirrhotics did not have
endoscopy or prophylaxis before the first bleeding event.

Secondary Prophylaxis

As mentioned previously, HVPG provides valuable prognostic information in the
pharmacologic management of portal hypertension. After a variceal bleed, a spontaneous
decrease in HVPG has been observed in some patients treated with endoscopic
procedures, but the impact of a spontaneous hemodynamic response on clinical outcome
in these patients has not been extensively investigated. In this setting, Aracil and
colleagues[10] conducted a study to assess the influence of such a spontaneous response in
the prevention of variceal rebleeding. This study included 99 patients treated with an
endoscopic procedure (ligation or sclerotherapy) to prevent rebleeding after an acute
bleeding episode. HVPG measurements were performed at baseline (once the acute
bleeding was controlled) and again 1-3 months later (once varices had been eradicated).
A spontaneous decrease in HVPG by > 10% was observed in 22% of patients
(responders). Variceal eradication occurred more frequently in responders than in
nonresponders (94% vs 58%; P < .001), and variceal rebleeding was less frequent in
responders (20% vs 42% in nonresponders at 2 years; P = .04). On the basis of these
findings, the study authors suggested that efficacy of endoscopic therapy may be related
to spontaneous hemodynamic response.

TIPS have long been used to lower portal pressures in the setting of variceal hemorrhage
and refractory ascites, their major associated complications being the development of
hepatic encephalopathy and shunt stenosis, which is seen in up to 50% of patients within
6 months. The polytetrafluorothethylene (PTFE)-covered stents* appear to have the
potential to improve TIPS patency. During this year's EASL meeting, Angeloni and
colleagues[11] prospectively compared TIPS safety and 1-year patency in 56 patients
using PTFE-covered stents vs in 87 patients treated with conventional stents. The 1-year
probability of remaining free of shunt dysfunction was significantly higher in the covered
stent group compared with the conventional stent group: 82% vs 57.5%; P = .003. The
probability of rebleeding was significantly lower among those patients in the covered
stent group. Although the number of hepatic encephalopathy episodes was similar
between the 2 groups in the first 12 months after TIPS, 6 of the 56 patients treated with
covered stents had intractable episodes of hepatic encephalopathy, and none of the
patients in the conventional stent group suffered from recurrent intractable hepatic
encephalopathy. The study authors concluded that although PTFE-covered stent-grafts
have a higher patency and a lower rebleeding rate, a higher incidence of intractable
hepatic encephalopathy may occur.

Kalambokis and colleagues,[12] from Greece, compared the hemodynamic effects of
terlipressin, somatostatin, and terlipressin plus somatostatin in cirrhotic patients with
portal hypertension; they also examined the effect of each treatment on sodium renal
excretion. Terlipressin monotherapy significantly reduced portal vein velocity and portal
flow volume, and increased mean arterial pressure (MAP) and systemic vascular
resistance along with a decrease in cardiac output. In patients without ascites, it
significantly increased fractional excretion of sodium, although it did not change in
patients with ascites. Somatostatin monotherapy did not alter portal hemodynamics,
whereas it significantly reduced MAP, heart rate, and -- in patients with ascites --
fractional excretion of sodium. The addition of terlipressin to the regimen induced similar
changes in hemodynamic parameters and sodium excretion to those observed after
receiving terlipressin alone, although the increase in MAP was significantly lower than in
those patients receiving terlipressin alone. The study authors concluded that the use of
terlipressin as monotherapy appears to be advantageous, whereas a combination of
somatostatin and terlipressin does not seem to exert an additive portal hypotensive effect
in cirrhotic patients.

Prevention of Infection

Another important issue concerning the management of cirrhotic patients with upper
gastrointestinal bleeding is the risk of infection. During General Session 1: Clinical
Hepatology, Fernandez and colleagues[13] from Barcelona, Spain, presented the results of
a randomized, multicenter, controlled trial, comparing oral norfloxacin (400 mg twice
daily for 7 days; n = 55) vs intravenous ceftriaxone (1 g/day for 7 days; n = 53) in the
prevention of bacterial infections in 108 cirrhotics with severe liver failure and
gastrointestinal bleeding within 10 days after inclusion. They found that the probability
of developing bacterial infections during the study period was significantly lower in
patients receiving ceftriaxone than in those treated with norfloxacin (11% vs 27%; P =
.02), with all types of infections except pneumonia occurring less frequently in the
ceftriaxone group (urinary tract infection, 5.7% vs 14.5%; spontaneous bacteremia, 0%
vs 1.8%; pneumonia, 3.8% vs 1.8%). The study authors concluded that intravenous
ceftriaxone was more effective than oral norfloxacin in the prevention of bacterial
infections in cirrhotic patients with severe liver failure and upper gastrointestinal
bleeding.

Hepatic Encephalopathy

Background

Hepatic encephalopathy is a complex neuropsychiatric syndrome due to hepatic failure.
In most cases, the diagnosis is clinical, and relies on the exclusion of other causes of
disordered mental status. In difficult cases, the use of brain imaging (computed
tomography or magnetic resonance) may be useful. Unfortunately, there have been no
major advances in this area during the last decade. Therapy is primarily based on
supportive care and the treatment of common precipitating factors, such as
gastrointestinal bleeding, infections, renal and electrolyte disturbances, psychoactive
medications, volume depletion, constipation, excessive dietary protein intake, and the
presence of shunts (surgical or TIPS). Oral lactulose is still the first-line pharmacologic
treatment for hepatic encephalopathy, the recommended dose being 15-45 mL given
orally every 6-8 hours, adjusted to achieve 3 bowel movements. Several oral antibiotics
can be used in this setting, such as neomycin (dose = 3-6 g/day), metronidazole (dose =
250 mg/day), and rifamixin (dose = 1200 mg/day). More controversial therapies include
L-ornithine L-aspartate, flumazenil,* and bromocriptine, whose efficacy have not been
demonstrated.[6]

Risk Factors and Treatment

Sánchez-Muñoz and colleagues,[14] from Seville, Spain, presented the results of a study
comparing the impact of hepatic encephalopathy on survival in 1037 patients with
hepatitis C virus (HCV)-related cirrhosis and 180 patients with HCV-related cirrhosis
who were coinfected with HIV. Hepatic encephalopathy was more often seen in
coinfected patients (14% vs 7.3%; P < .001), and was also the cause of death in 46% of
HCV/HIV-coinfected vs 22% of HCV-infected patients. The 1- and 3-year estimated
survival rates after development of hepatic encephalopathy were 38% and 23% in
coinfected patients, and 52% and 31% in those with HCV-related cirrhosis; P < .05. The
study authors concluded that hepatic encephalopathy was more frequent and shows a
more severe course in HCV/HIV-coinfected patients, which may in part be explained by
the enhanced systemic inflammatory response seen in these coinfected patients.

Hyponatremia may occur in patients with cirrhosis and is associated with considerable
changes in brain cells. Torre and colleagues,[15] from several centers in Spain,
hypothesized that hyponatremia-induced changes in the brain may predispose to the
development of hepatic encephalopathy. They analyzed the incidence and predictive
factors of hepatic encephalopathy in 70 patients with cirrhosis and refractory ascites who
had no hepatic encephalopathy at entry. During a median follow-up of 10 months, 71% of
patients developed at least 1 episode of hepatic encephalopathy. In multivariate analysis
of several variables, including demographic and clinical data as well as liver and renal
function obtained at randomization and in the absence of treatment for 5 days, only age
and severe hyponatremia (medium sodium < 125 mEq/L) were associated with an
independent predictive value for development of hepatic encephalopathy. Severe
hyponatremia increased the risk of hepatic encephalopathy 3.2 times. This finding is
interesting in that it suggests new possibilities for investigating intracerebral factors
leading to the development of hepatic encephalopathy in patients with cirrhosis and
refractory ascites.

Abid and colleagues,[16] from Pakistan, conducted a randomized study to examine the
efficacy of intravenous infusion of L-ornithine L-aspartate* in patients with hepatic
encephalopathy due to liver cirrhosis. They randomized 120 patients to receive L-
ornithine L-aspartate 20 g/day (n = 60) or placebo (n = 60) in 100 mL 5% dextrose
infusion over 4 hours for 4 consecutive days. The 2 groups were comparable at baseline.
Hepatic encephalopathy improved by at least 1 stage on day 4 in 53 patients given L-
ornithine L-aspartate vs in 44 patients on placebo (P = .016). Duration of hospital stay
was shorter in the L-ornithine L-aspartate group (3.9 vs 5.6 days; P = .04). Mortality was
similar in the 2 groups and there were no side effects associated with L-ornithine L-
aspartate. Thus, the study authors concluded that infusions of L-ornithine L-aspartate
appear to be safe and effective in the treatment of hepatic encephalopathy, resulting in
improvement in hepatic encephalopathy and reduction in hospital length of stay.

Concluding Remarks

On the basis of data reported during this year's EASL meeting, it seems that in cirrhotic
patients with diuretic-resistant ascites, large-volume paracentesis can be safely performed
using lower doses of albumin, thereby reducing the associated costs. In cirrhotic ascites,
attention must be paid to the prevention of volume depletion because the associated
deterioration in renal function can worsen the prognosis. Additionally, the use of reagent
strips for a rapid diagnosis of SBP was not confirmed to be reliable, as reported in
previous studies. Additionally, as addressed in this overview, the utility of terlipressin is
increasingly being recognized in the management of HRS as well as in the management
of variceal bleeding, showing more favorable hemodynamic effects than somatostatin. As
addressed further during these meeting proceedings, the prevention of infection during
esophageal bleeding with intravenous ceftriaxone was shown to be more effective than
oral norfloxacin. Also, although TIPS using PTFE-covered stent-grafts show a higher
patency and lower rebleeding rate, the fact that this approach is associated with a higher
incidence of intractable hepatic encephalopathy warrants consideration. As a final point
of commentary, the primary prophylaxis of variceal bleeding is mandatory, and beta-
blockers remain the first option in management. It is evident that the management of
cirrhosis and its related complications conitnue to pose a significant challenge to the
practicing gastroenterologist-hepatologist, and will remain a major focus of many
research efforts in the field.

Supported by an independent educational grant from Gilead.

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