TREATMENTOF

LIVER CIRRHOSIS

BERLIBA ELINA

TREATMENTof liver
cirrhosis

TREATMENTThe major goals of

treating patients with cirrhosis include:

Slowing or reversing the progression of

liver disease
Preventing superimposed insults to the
liver
Preventing and treating the complications
Determining the appropriateness and
optimal timing for liver transplantation

Slowing or reversing the

progression of liver disease

Although cirrhosis is generally considered to be

irreversible in its advanced stages, the exact point at
which it becomes irreversible is unclear.

Some chronic liver diseases respond to treatment even

when the liver disease has progressed to cirrhosis.

Thus, specific therapies directed against the underlying

cause of the cirrhosis should be instituted. As examples:

Abstinence from alcohol substantially improves survival

in alcoholic cirrhosis.

Slowing or reversing the

progression of liver disease

The 10-year survival rate in patients with cirrhosis from autoimmune

hepatitis who are treated with steroids or immunosuppressive is
similar to survival rates of treated patients with autoimmune hepatitis
who do not have cirrhosis.

Successful treatment of chronic viral hepatitis can improve long-term

outcomes and may affect fibrosis.

Patients with chronic hepatitis C and significant fibrosis based upon

liver elastography, patients who achieved a sustained virologic
response had a significant decrease in liver stiffness 24 weeks after
the end of treatment

Preventing superimposed
insults

Preventing superimposed insultsPatients with

cirrhosis should avoid any agent that has the
potential to cause additional liver injury.

This includes abused substances such as alcohol,

over-the-counter medications (such as high doses
of acetaminophen), prescribed drugs with
hepatotoxic side effects, and certain herbal
remedies.

Although the exact amount of acetaminophen that

is safe in cirrhosis is uncertain, we recommend that
patients not use more than a total of 2 g per day
(in divided doses).

Preventing superimposed
insults

VaccinationVaccination against hepatitis A

and B can help prevent a superimposed
insult to a liver that may have little
functional reserve.

Treatment of patients with

cirrhosis caused by HBV
infection
Treatment
of patients with cirrhosis should not be based on ALT
levels, as these may be normal in advanced disease.

PEG-IFN may increase the risk of bacteraemic infection and

hepatic decompensation in patients with advanced cirrhosis.

However, PEG-IFN in regimens similar to those used in CHB can

be used for the treatment of well compensated cirrhosis.

Among Nucleoside/nucleotide analogues (Nas), monotherapies

with tenofovir or entecavir are preferred because of their potency
and minimal risk of resistance.

Treatment of patients with

cirrhosis caused by HBV
infectionshould not be used in such
Lamivudine
patients.

Close monitoring of HBV DNA levels every 3

months at least during the first year of
therapy and until HBV DNA undetectability is
important, as exacerbations of hepatitis B
may occur in patients with cirrhosis requiring
urgent management.

Thus, patients with cirrhosis require longterm therapy, with careful monitoring for
resistance and flares.

Treatment of patients with

cirrhosis caused by HBV infection

NA therapy should usually be continued indefinitely

in cirrhotic patients.

After at least 12 months of consolidation therapy,

treatment might be stopped in HBeAg-positive
patients if they achieve confirmed anti-HBe
seroconversion or ideally HBsAg loss and anti-HBs
seroconversion and in HBeAg-negative patients if
they achieve confirmed HBsAg loss and anti-HBs
seroconversion.

Treatment of patients with

decompensate cirrhosis caused by
HBV infection

Patients with decompensate cirrhosis should be

treated in specialized liver units, as the
application of antiviral therapy is complex, and
these patients may be candidates for liver
transplantation.
Antiviral treatment is indicated irrespective of
HBV DNA level in order to prevent reactivation.

(PEG-)IFN is contraindicated in this

setting.
Entecavir or tenofovir should be used

Treatment of patients with

decompensate cirrhosis caused by
HBV infection

The licensed entecavir dose for patients with

decompensated cirrhosis is 1 mg (instead of 0.5 mg for
patients with compensated liver disease) once daily.

Recent studies have shown that both drugs are not

only effective but generally safe in these patients, at
least in the first years of therapy.

Lactic acidosis has been reported to develop in some

NA, particularly entecavir, treated patients with
advanced decompensated cirrhosis (MELD score >20).
Therefore, clinical and laboratory parameters should be
closely monitored in this setting.

Treatment of patients with

compensated cirrhosis due to HCV

Patients with compensated cirrhosis must be treated with

pegylated IFN-a and ribavirin in the absence of contraindications, in order to prevent the complications of
chronic HCV infection that occur exclusively in this group
in the short- to mild-term.

However, the sustained virologic response (SVR) rates

with pegylated IFN-a and ribavirin are lower in patients
with advanced fibrosis or cirrhosis than in patients with
mild to moderate fibrosis.

Thus, it may also be justified to wait for the approval of

triple therapies with protease inhibitors (genotype 1) if
their local availability is anticipated within a few months.

Treatment of patients with

compensated cirrhosis due to HCV

Assiduous monitoring and management of side-effects

is required in this group of patients, who are generally
older and have a lower tolerance than patients with
less advanced liver disease.

Due to portal hypertension and hypersplenism,

leukocyte and platelet counts at baseline may be low
in cirrhotic patients.

Hematological side effects are more frequent in

cirrhotic than in non-cirrhotic patients, and may
contraindicate therapy.

Treatment of patients with

compensated cirrhosis due to HCV

Recommendations

Patients with compensated cirrhosis should be

treated, in the absence of contraindications, in order
to prevent short to mid-term complications.

Assiduous monitoring and management of sideeffects, especially those linked to portal

hypertension and hypersplenism, is required.

Growth factors are particularly useful in this group.

Treatment of patients with

decompensated cirrhosis due to HCV

Liver transplantation is the treatment of choice for

patients with end-stage liver disease.

However, hepatitis C recurrence due to graft infection

is universal after transplantation.

Antiviral therapy in patients awaiting transplantation

prevents graft infection if an SVR is achieved.

More than half of the patients have contraindications

for the use of pegylated IFN-a and ribavirin, and the
results of therapy are generally poor in this group of
individuals with advanced or decompensated liver
disease.

Treatment of patients with

decompensated cirrhosis due to HCV

Antiviral therapy is indicated in patients with

conserved liver function (ChildPugh A) in whom the
indication for transplantation is HCC.

In patients with ChildPugh B cirrhosis, antiviral

therapy may be offered on an individual basis in
experienced centers, preferentially in patients with
predictors of good response, such as patients infected
with HCV genotypes 2 or 3, or patients with a low
baseline HCV RNA level.

Patients with ChildPugh C cirrhosis should not be

treated with the SoC, due to a high risk of lifethreatening complications.

Liver cirrhosis due to

Autoimmune Hepatitis

Autoimmune hepatitis is treated

with the corticosteroid prednisone
and also sometimes
immunosuppressants, such as
azathioprine (Imuran).

Bile Duct Disorders

Ursodeoxycholic acid, also known as ursodiol or

UDCA, is used for treating primary biliary cirrhosis
but does not slow the progression.
Itching is usually controlled with cholesterol drugs
such as cholestyramine (Questran, generic) and
colestipol (Colestid).
Antibiotics for infections in the bile ducts.
Drugs that quiet the immune system (prednisone,
azathioprine, cyclosporine, methotrexate) may
also be used.
Several surgical procedures may also be tried to
open up the bile ducts.

Nonalcoholic Fatty Liver Disease

(NAFLD) and Nonalcoholic
Steatohepatitis (NASH).

Weight reduction through diet and

exercise, and diabetes and
cholesterol management are the
primary approaches to treating
these diseases.

Hemochromatosis

Hemachromatosis is treated with

phlebotomy, a procedure that involves
removing about a pint of blood once or
twice a week until iron levels are normal.

The two goals in the management of

compensated cirrhosis are:
treatment of the underlying liver disease (e.g.,
hepatitis C or B, alcohol, non-alcoholic
steatohepatitis),
prevention/early diagnosis of the complications
of cirrhosis.
The treatment of the underlying liver disease is
beyond the scope of these recommendations.
The main recommendations specific to patients
with newly diagnosed cirrhosis are screening
for varices and HCC

Screening for gastroesophageal

varices and primary prophylaxis of
variceal hemorrhage
An esophagogastroduodenoscopy (EGD)
should be performed once the diagnosis
of cirrhosis is established.

The objective of EGD is to detect the

presence/size of varices for determining
whether the patient should receive
therapy for prevention of first variceal
hemorrhage (primary prophylaxis).

Treatment of portal
hypertension

Two therapies are currently accepted in the prevention

of the first episode of variceal hemorrhage, namely
nonselective beta-blockers (NSBBs) and
endoscopic variceal ligation (EVL).
NSBBs (i.e., propranolol, nadolol) reduce portal
pressure by reducing the cardiac output (beta-1blockade effect) and, more importantly, by reducing
portal blood inflow through splanchnic vasoconstriction
(beta-2-blockade effect).
Therefore, selective beta-1-blockers (e.g., atenolol,
metoprolol) are less effective and are not recommended
for the primary prophylaxis of variceal hemorrhage .

Treatment schedule

Given the lack of correlation between

decreases in heart rate and decreases in
portal pressure, the dose of NSBB is
adjusted to the maximal tolerated doses
to heart rates of 55-60 beats/min

Propranolol is administered twice a day

(BID) and is usually started at a dose of
20 mg BID. Nadolol is administered QD
(once a day) and is started at a dose of
20-40 mg QD.

Contraindications/side
effects.

Approximately 15% of patients have

contraindications to the use of NSBB, such as
asthma, insulin-dependent diabetes (with
episodes of hypoglycemia), and peripheral
vascular disease.

The most common side effects related to

NSBB in cirrhosis are lightheadedness,
fatigue, and shortness of breath.

Some of these side effects disappear with

time or after a reduction in the dose of NSBB.

Management strategy after results of

screening endoscopy in patients with
cirrhosis
Small
varices

In a CTP B/C patient

or varices with red
signs

Nonselectiveblockers
(propranolol or
nadolol)

Start propranolol (20 mg

b.i.d.) or nadolol (20 mg
q.d.)
Titrate to maximal
tolerable dose or
a heart rate of 55 60
b.p.m.
No need to repeat EGD

In a CTP A patient,
without red signs

Nonselective blockers optional

If no -blockers
are given, repeat
endoscopy in 2
years (sooner if
decompensation
occurs)

Same as above

Management strategy after results of

screening endoscopy in patients with
cirrhosis
Medium/
large
varices

All patients
independent of CTP
class

Nonselective blockers
(propranolol,
nadolol)
ora

Same as above

Endoscopic
variceal ligation

Ligate every 1-2 weeks

until variceal
obliteration
First surveillance
endoscopy 1-3 months
after obliteration, then
every 6-12 months
indefinitely

Management of Decompensated
Cirrhosis

Treatment of acute variceal hemorrhage

General measures.
Volume should be expanded to maintain a systolic
blood pressure of 90-100 mm Hg and a heart rate of
below 100 bpm.
Colloids are more effective than crystalloids and
packed red blood cells in reaching optimal
hemodynamic and oxygen transport goals.
Transfusion goals are required to maintain a
hemoglobin of ~8 g/dl as, in experimental studies,
total blood restitution is associated with increases in
portal pressure, and higher rates of rebleeding and
mortality.

Management of Decompensated
Cirrhosis

One of the main complications associated with variceal

hemorrhage is bacterial infection.

Short-term antibiotic prophylaxis not only decreases

the rate of bacterial infections but also decreases
variceal rebleeding and increases survival.

Oral norfloxacin at a dose of 400 mg BID for 7 days was

recommended by consensus,

but intravenous (IV) ceftriaxone (1 g/day) is more

effective in patients with two or more of the following:
malnutrition, ascites, encephalopathy, or serum
bilirubin >3 mg/dl.

Management of Decompensated
Cirrhosis

The transfusion of fresh frozen

plasma and platelets can be
considered in patients with
significant coagulopathy and/or
thrombocytopenia.

Specific measures to control acute

hemorrhage and prevent early
recurrence
Accepted therapies.

The most rational approach in the

control of acute variceal
hemorrhage consists of the
combination of pharmacological and
endoscopic therapy

Specific measures to control acute

hemorrhage and prevent early
recurrence

Pharmacological therapy has the advantages of being

generally applicable and drugs with a low rate of adverse
events, such as somatostatin or analogs (octreotide,
vapreotide), can be initiated as soon as a diagnosis of
variceal hemorrhage is suspected, before diagnostic EGD.

Drugs used in this setting act by producing splanchnic

vasoconstriction and, there by decreasing portal blood inflow.

Randomized controlled trial (RCTs) comparing different

pharmacological agents (vasopressin, somatostatin,
terlipressin, octreotide, vapreotide), show no differences
among them regarding control of hemorrhage and early
rebleeding, although vasopressin is associated with more
adverse events.

Specific measures to control acute

hemorrhage and prevent early
recurrence

Treatment schedule.

Octreotide is recommended at an initial bolus dose of 50 g

IV followed by a continuous IV infusion of 50 g/h.

Although the optimal duration of pharmacological therapy

has not been well established in RCTs, considering that
~50% of early recurrent hemorrhage occurs within the first
5 days, continuing vasoactive drugs for 5 days seems
rational.

However, as shorter lengths of treatment have also been

successful, shorter duration is acceptable, particularly in
patients with a low risk of rebleeding (e.g., CTP class A).

Specific measures to control acute

hemorrhage and prevent early
recurrence

Regarding endoscopic therapy, EVL is more

effective than endoscopic variceal
sclerotherapy with greater control of
hemorrhage, less rebleeding, lower rates of
adverse events, but without differences in
mortality.

EVL should be performed at the time of

diagnostic EGD if and when a variceal source
of hemorrhage is confirmed.

Sclerotherapy is reserved for cases in which

EVL cannot be performed.

Specific measures to control acute

hemorrhage and prevent early
recurrence

EVL should be performed during diagnostic

endoscopy when the possible variceal source of
bleeding is confirmed.

The process should be started at the

gastroesophageal junction by placing ~6 bands
particularly on the vessel with stigmata of
bleeding.

Repeat EVL can be attempted if hemorrhage is

not controlled or if the patient has an early
recurrence of variceal hemorrhage.

Specific measures to control acute

hemorrhage and prevent early
recurrence
Other therapies.
Despite an urgent endoscopic and/or
pharmacological therapy, variceal bleeding
cannot be controlled or recurs early in
approximately 10-20% of patients, and other
therapies should be implemented.
An increased portal pressure, as measured
by the hepatic venous pressure gradient
(HVPG) within 24 h of presentation, predicts
treatment failure

Specific measures to control acute

hemorrhage and prevent early
recurrence

Shunt therapy, either shunt surgery (in CTP

class A patients) or TIPS, has proven clinical
efficacy as salvage therapy for patients who
fail to respond to endoscopic or
pharmacological therapy.

This approach has not been validated by

other groups and is not widely practiced.

Specific measures to control acute

hemorrhage and prevent early
recurrence

Balloon tamponade is very effective in controlling bleeding

temporarily with immediate control of hemorrhage in >80% of
patients.

However, rebleeding after the balloons are deflated is high and its
use is associated with potentially lethal complications, such as
aspiration, migration, and necrosis/perforation of the esophagus
with mortality rates as high as 20%.

Although the Sengstaken-Blakemore tube (with both an esophageal

and a gastric balloon) is recommended for esophageal varices,

the Linton tube, with a larger gastric balloon (and no esophageal

balloon) is preferred for uncontrolled bleeding from fundal gastric
varices.

Diagnosis and management

strategy of patient with acute
variceal
hemorrhage

DIAGNOSIS

Any of the following findings on upper

endoscopy performed within 12h of
admission:
Active bleeding from a varixor
Stigmata of variceal hemorrhage (white nipple
sign)or
Presence of gastroesophageal varices without
another source of hemorrhage

Diagnosis and management

strategy of patient with acute
variceal hemorrhage

GENERAL MANAGEMENT

Cautious transfusion of fluids and blood products,

aiming to maintain a hemoglobin of ~8g/dl

Antibiotic prophylaxis (3-7 days) with:

Ciprofloxacin 500mg BID (PO) or 400mg BID (IV)or

Ceftriaxone 1g/day (IV) particularly in facilities with

known quinolone resistance and in patients with
two or more of the following: malnutrition, ascites,
encephalopathy, serum bilirubin >3mg/dl

Diagnosis and management

strategy of patient with acute
variceal hemorrhage

SPECIFIC INITIAL MANAGEMENT

Pharmacological therapy initiated as soon as

diagnosis is suspected

Octreotide 50mcg IV bolus followed by

continuous infusion 50mcg/h (3-5 days)and

Endoscopic therapy (ligation preferable)

performed at time of diagnostic endoscopy
(performed within 12 h of admission)

Diagnosis and management

strategy of patient with acute
variceal hemorrhage

RESCUE MANAGEMENT

Considered in patients with bleeding

esophageal varices who have failed
pharmacological+endoscopic therapy or in
patients with bleeding gastric fundal varices
who have failed one endoscopic therapy:

TIPSor

Shunt therapy (CTP A patients where

available)

Prevention of recurrent variceal

hemorrhage

The following interventions arerecommendedbased

on randomized clinical trials and meta-analyses:

Nonselective -blockers (propranolol,

nadolol)plusendoscopic variceal ligation

Nonselective -blockersplusnitrates (e.g. isosorbide

mononitrate)

Rescue therapies: TIPS or shunt surgery

Treatment of ascites

Management of Sodium Balance

Because sodium retention is a major factor in the

development of ascites, a key goal of therapy is the
attainment of a negative sodium balance.

To achieve this, sodium output must exceed sodium

input.
Accordingly, appropriate sodium restriction is very
important in the treatment of ascites and in
maintenance of cirrhotic patients who are ascites free.

Treatment of ascites

Management of Sodium Balance

Most authorities now believe that restriction of salt to 4

g/day is reasonable. This translates into a sodium
intake of 2000 mg/day (or 20 mEq/day).

Patients need detailed dietary instructions as to hidden

sources of sodium in their diet.

Treatment of ascites

Bed rest often facilitates diuresis because

upright posture activates sodium-retaining
systems and impairs renal profusion and
sodium excretion.

It is usually not necessary to restrict water

intake unless the serum sodium is less than
125 mEq/dL.

Water restriction should not be prescribed if

fever, sepsis, bleeding, or azotemia are
present.

Treatment of ascites

Diuretics are usually required in patients with ascites, especially

those with moderate to severe ascites who retain sodium avidly and
for whom sodium restriction will not be sufficient to retain negative
sodium balance.

In such cases, it is reasonable to begin with a potassium-sparing

diuretic such as spironolactone initially, given as a dosage of 100
200 mg/day.

This can be increased cautiously to 400 mg/day, but one needs to

watch for hyperkalemia and metabolic acidosis.

Treatment of ascites

The spironolactone dose need not be split and can be given once
daily.

An effect of spironolactone can be noted as early as 3 days after

initiation of treatment.

Effective therapy with spironolactone usually results in a reversal of

the potassium-sodium abnormalities in the urine, with an increase
of sodium excretion to more than 10 mEq/day and a decrease in
potassium secretion.

Treatment of ascites

Patients with the first episode of grade 2 (moderate) ascites should

receive an aldosterone antagonist such as spironolactone alone,
starting at 100 mg/day and increasing stepwise every 7 days (in 100
mg steps) to a maximum of 400 mg/day if there is no response.

In patients who do not respond to aldosterone antagonists, as

defined by a reduction of body weight of less than 2 kg/week, or in
patients who develop hyperkalemia,

furosemide should be added at an increasing stepwise dose from 40

mg/day to a maximum of 160 mg/day (in 40 mg steps).

Treatment of ascites

Patients should undergo frequent clinical and

biochemical monitoring particularly during the first month
of treatment.

Patients with recurrent ascites should be treated with a

combination of an aldosterone antagonist plus
furosemide, the dose of which should be increased
sequentially according to response, as explained above

The maximum recommended weight loss during diuretic

therapy should be 0.5 kg/day in patients without edema
and 1 kg/day in patients with edema.

Complications of diuretic therapy

The use of diuretics may be associated with several complications

such as:
renal failure,

hepatic encephalopathy,

electrolyte disorders,

gynaecomastia, and

muscle cramps.

Diuretic-induced renal failure is most frequently due to

intravascular volume depletion that usually occurs as a result of an
excessive diuretic therapy.

Complications of diuretic therapy

Diuretic therapy has been classically considered a

precipitating factor of hepatic encephalopathy, yet the
mechanism is unknown.

Hypokalemia may occur if patients are treated with loop

diuretics alone.

Hyperkalemia may develop as a result of treatment

with aldosterone antagonists or other potassiumsparing diuretics, particularly in patients with renal
impairment.

Complications of diuretic therapy

Hyponatremia is another frequent complication of diuretic therapy.

The level of hyponatremia at which diuretics should be stopped is
contentious.

However, most experts agree that diuretics should be stopped

temporarily in patients whose serum sodium decreases to less
than 120125 mmol/L.

Gynaecomastia is common with the use of aldosterone

antagonists, but it does not usually require discontinuation of
treatment.

Finally, diuretics may cause muscle cramps. If cramps are severe,

diuretic dose should be decreased or stopped and albumin
infusion may relieve symptoms.

Complications of diuretic therapy

All diuretics should be discontinued if there is

severe hyponatremia (serum sodium concentration
<120 mmol/L),
Progressive renal failure,
worsening hepatic encephalopathy, or
incapacitating muscle cramps.
Furosemide should be stopped if there is severe
hypokalemia (<3 mmol/L).
Aldosterone antagonists should be stopped if
patients develop severe hyperkalemia (serum
potassium >6 mmol/L).

Large-volume
paracentesis

Large-volume paracentesis (LVP) is the treatment of choice

for the management of patients with grade 3 ascites. The
main findings of studies comparing LVP with diuretics in
patients with grade 3 ascites are summarized as follows:

LVP combined with infusion of albumin is more effective than

diuretics and significantly shortens the duration of hospital
stay.

LVP plus albumin is safer than diuretics, the frequency of

hyponatremia, renal impairment, and hepatic
encephalopathy being lower in patients treated with LVP
than in those with diuretics, in the majority of studies.

LVP is a safe procedure and the risk of local complications,

such as hemorrhage or bowel perforation is extremely low.

Large-volume
paracentesis

The removal of large volumes of ascitic fluid is associated

with circulatory dysfunction characterized by a reduction of
effective blood volume, a condition known as postparacentesis circulatory dysfunction (PPCD) .

Several lines of evidence indicate that this circulatory

dysfunction and/or the mechanisms activated to maintain
circulatory homeostasis have detrimental effects in cirrhotic
patients.

First, circulatory dysfunction is associated with rapid reaccumulation of ascites.

Large-volume
paracentesis

Secondly, approximately 20% of these patients develop

HRS and/or water retention leading to dilutional
hyponatremia.

Thirdly, portal pressure increases in patients developing

circulatory dysfunction after LVP, probably owing to an
increased intrahepatic resistance due to the action of
vasoconstrictor systems on the hepatic vascular bed.

Finally, the development of circulatory dysfunction is

associated with shortened survival.

Large-volume
paracentesis

The most effective method to prevent circulatory

dysfunction after LVP is the administration of
albumin.

Albumin is more effective than other plasma

expanders (dextran-70, polygeline) for the
prevention of PPCD.

When less than 5 L of ascites are removed,

dextran-70 (8 g/L of ascites removed) or
polygeline (150 ml/L of ascites removed) show
efficacy similar to that of albumin.

Large-volume
paracentesis

However, albumin is more effective than these other

plasma expanders when more than 5 L of ascites are
removed.

Contraindications to large-volume paracentesis

include:

sepsis,

spontaneous bacterial peritonitis (SBP),

recent gastrointestinal bleeding,

azotemia,

marked wasting, and

low blood pressure.

Transjugular intrahepatic
portosystemic shunting (TIPS)

Recommendations

Repeated large-volume paracentesis plus albumin (8 g/L of ascites

removed) is the first line of treatment for refractory ascites.

Diuretics should be discontinued in patients with refractory

ascites who do not excrete >30 mmol/day of sodium under diuretic
treatment.

TIPS is effective in the management of refractory ascites but is

associated with a high risk of hepatic encephalopathy and studies
have not been shown to convincingly improve survival compared
to repeated large-volume paracentesis .

Transjugular intrahepatic
portosystemic shunting (TIPS)

TIPS should be considered in patients with very

frequent requirement of large-volume paracentesis, or
in those in whom paracentesis is ineffective (e.g. due
to the presence of loculated ascites).

Resolution of ascites after TIPS is slow and most

patients require continued administration of diuretics
and salt restriction.

Transjugular intrahepatic
portosystemic shunting (TIPS)

TIPS cannot be recommended in patients with:

severe liver failure (serum bilirubin >5 mg/dl, INR >2 or ChildPugh score >11,

current hepatic encephalopathy grade 2 or chronic hepatic

encephalopathy),

concomitant active infection,

progressive renal failure, or

severe cardiopulmonary diseases.

In selected patients TIPS may be helpful for recurrent

symptomatic hepatic hydrothorax

Management of spontaneous
bacterial peritonitis

Empirical antibiotics should be started immediately

following the diagnosis of SBP.

Since the most common causative organisms of SBP are

Gram-negative aerobic bacteria, such as E. coli, the first line
antibiotic treatment are third-generation cephalosporins .

Alternative options include amoxycillin/clavulanic acid and

quinolones such as ciprofloxacin or ofloxacin.

However, the use of quinolones should not be considered in

patients who are taking these drugs for prophylaxis against
SBP, in areas where there is a high prevalence of
quinoloneresistant bacteria or in nosocomial SBP.

Management of spontaneous
bacterial peritonitis

Current guidelines call for the use of a thirdgeneration cephalosporin such as cefotaxime or
ceftazidime, given at a dosage of 2 g/8 h.
Other third-generation cephalosporins, such as
ceftizoxime or ceftriaxone, are also suitable
antibiotics.
The cephalosporins have been shown to be as
effective as, if not more effective than, combinations
of ampicillin and an aminoglycoside.
Antibiotic therapy usually can be discontinued after 5
days.

Management of spontaneous
bacterial peritonitis

The use of intravenous albumin in the treatment of

SBP is supported by randomized controlled trials that
have shown that antibiotics and intravenous albumin
given at a dosage of 1.5 g/kg at the time of diagnosis
and then 1.0 g/kg at day 3 reduces the incidence of
renal impairment and improves hospital survival
compared with antibiotics given alone.

Management of spontaneous
bacterial peritonitis

Patients who recover from an episode of SBP have a high

risk of developing recurrent SBP.

In these patients, the administration of prophylactic

antibiotics reduces the risk of recurrent SBP.

Norfloxacin (400 mg/day, orally) is the treatment of choice.

Alternative antibiotics include ciprofloxacin (750 mg once

weekly, orally) or co-trimoxazole (800 mg sulfamethoxazole
and 160 mg trimethoprim daily, orally), but evidence is not
as strong as that with norfloxacin.

Patients who recover from SBP have a poor long-term

survival and should be considered for liver transplantation

Management of hepatorenal
syndrome

Monitoring: Patients with type 1 HRS should be monitored

carefully. Parameters to be monitored include urine output,
fluid balance, and arterial pressure, as well as standard vital
signs.

Screening for sepsis: Bacterial infection should be identified

early, by blood, urine and ascitic fluid cultures, and treated
with antibiotics.

Patients who do not have signs of infection should continue

taking prophylactic antibiotics, if previously prescribed.

There are no data on the use of antibiotics as empirical

treatment for unproven infection in patients presenting with
type 1 HRS.

Management of hepatorenal
syndrome

Use of beta-blockers: There are no data on

whether it is better to stop or continue with
beta-blockers in patients with type 1 HRS who
are taking these drugs for prophylaxis against
variceal bleeding.

Use of paracentesis: if patients have tense

ascites, large-volume paracentesis with
albumin is useful in relieving patients
discomfort.

Management of hepatorenal
syndrome

Use of diuretics: All diuretics should be

stopped in patients at the initial evaluation
and diagnosis of HRS. There are no data to
support the use of furosemide in patients with
ongoing type 1 HRS.

Nevertheless furosemide may be useful to

maintain urine output and treat central
volume overload if present.
Spironolactone is contraindicated because of
high risk of life-threatening hyperkalemia .

Management of type 1
hepatorenal syndrome

Drug therapy of type 1 hepatorenal syndrome Terlipressin (1 mg/46 h

intravenous bolus) in combination with albumin should be considered the
first line therapeutic agent for type 1 HRS.

The aim of therapy is to improve renal function sufficiently to decrease

serum creatinine to less than 133 lmol/L (1.5 mg/dl) (complete response).

Contraindications to terlipressin therapy include ischemic cardiovascular

diseases.

Patients on terlipressin should be carefully monitored for development of

cardiac arrhythmias or signs of splanchnic or digital ischemia, and fluid
overload, and treatment modified or stopped accordingly.

Terlipressin administration significantly increases mean

arterial pressure and systemic vascular resistance;
while the heart rate, cardiac output, HVPG and portal
venous blood flow decrease significantly.
This decrease correlates well with the decrease in
plasma renin activity.
Thus the vasoconstrictor effect of Terlipressin reverses
the basic pathology of HRS by reducing the plasma
renin activity.
The improvement in hemodynamics with Terlipressin is
associated with an increase in glomerular filtration rate
and deactivation of the vasoconstrictor and sodiumconserving hormones with reduced activity of the
RAAS resulting in increased natriuresis.

Management of type 1
hepatorenal syndrome

Potential alternative therapies to terlipressin include

norepinephrine ormidodrine plus octreotide, both in
association with albumin, but there is very limited
information with respect to the use of these drugs in
patients with type 1 HRS.

Management of type 1
hepatorenal syndrome

Non-pharmacological therapy of type 1 hepatorenal syndrome:

Although the insertion of TIPS may improve renal function in

some patients, there are insufficient data to support the use of
TIPS as a treatment of patients with type 1 HRS.

Renal replacement therapy may be useful in patients who do not

respond to vasoconstrictor therapy, and who fulfill criteria for
renal support.

Management of type 2
hepatorenal syndrome

Terlipressin plus albumin is effective in 6070% of

patients with type 2 HRS.

Liver transplantation

Liver transplantation is the best treatment for both type 1

and type 2 HRS.
HRS should be treated before liver transplantation, since
this may improve post-liver transplant outcome .

Management of type 2
hepatorenal syndrome

Prevention of hepatorenal syndrome

Patients who present with SBP should be treated with intravenous

albumin since this has been shown to decrease the incidence of HRS
and improve survival .

There are some data to suggest that treatment with pentoxifylline

decreases the incidence of HRS in patients with severe alcoholic
hepatitis and advanced cirrhosis and treatment with norfloxacin
decreases the incidence of HRS in advanced cirrhosis, respectively.

Further studies are needed .

Management of chronic portal

systemic encephalopathy.
Therapy

Considerations

Initial treatment
Precipitating
Factors
Nutrition

Identify and treat if present

Protein restriction (4060 g) not

appropriate to
restrict protein intake to < 0.75 g/kg
long
term (6080 g/day)
Patients need > 2535 kcal/kg and 200
g
carbohydrate to spare protein catabolism
Vegetable-based diet increases
elimination
Initial treatment includes identifying
and of
treating any precipitating factors.
nitrogen
products
in stool
Attention to nutrition is also
important.
Rigid protein
restriction is not
Branched-chain
amino
acidsthan
are200
costly
appropriate. Patients need at least 2535 kcal/kg and more
g of
and
data
carbohydrate to spare protein metabolism.
on efficacy are controversial

Management of chronic portal

systemic encephalopathy.
Therapy

Considerations

Initial treatment
Precipitating
Factors

Identify and treat if present

Nonabsorbable
disaccharides

Lactulose (galactose fructose), 1530 mL 4

times daily
Decreases fecal pH by inhibiting
production of
NH3 by fecal flora
Increases fecal N2 excretion
Lactose is effective in lactase-deficient
patients

Medical treatment for PSE is based largely on efforts to control the

generation of putative neuroactive toxins, most notably ammonia.
Lactulose, a synthetic disaccharide consisting of galactose and fructose, is
not metabolized by intestinal disaccharidases and therefore reaches the
colon, where it is broken down by the fecal flora. The breakdown of
lactulose to short-chain fatty acids results in a decreased fecal pH that
inhibits ammonia production by urea splitting microorganisms, and traps

Management of chronic portal

systemic encephalopathy.
Therapy

Considerations

Initial treatment
Precipitating
Factors

Identify and treat if present

Antibiotics
Neomycin

Potential for nephrotoxicity; taper dose (12

g/day) for prolonged use
No evidence of potentiation of response to
lactulose

Metronidazole

250 mg twice daily

Antibiotics
such as neomycin and
metronidazole,
which
can alter the
fecalmg
flora,
not
Rifaximin
Poorly
absorbed
antibiotic
(200
3 are
times
recommended for routine use in patients with PSE. Controlled studies have shown that
daily)
neomycin in doses as high as 6 g/day is not significantly better
than placebo in reducing ammonia levels. Rifaximin, a poorly absorbed antibiotic, has
been shown to be equivalent to neomycin or paromomycin in the treatment of PSE and
appears to be better tolerated. The usual dosage is 200 mg three times daily.
Other treatments have included zinc, sodium benzoate, and vancomycin, but no large
randomized controlled trials have been performed that would permit further assessment
of these treatment modalities.

Management of chronic portal

systemic encephalopathy.
Therapy

Considerations

Initial treatment
Precipitating
Factors

Identify and treat if present

Nonabsorbable
disaccharides

Lactulose (galactose fructose), 1530 mL

4 times
daily
Decreases fecal pH by inhibiting
production of
NH3 by fecal flora
Increases fecal N2 excretion
Lactose is effective in lactase-deficient
patients

Management of chronic portal

systemic encephalopathy.

Additional administration of ornithine

aspartate (13 x 6 g/day).
This may be indicated by the detection
of latent HE (stages 0, 0I).
Usually, the administration of zinc (1530
mg/day) is also indicated in this context.

Fat-soluble vitamins

Oral intake of vitamins A, D and E is

usually sufficient as is the dosage
contained in multivitamin preparations
when taken daily. Biochemical evidence
of deficiency or the occurrence of
diseases due to deficiency usually
require vitamins A, D, E and K to be
supplied parenterally as a compound
preparation.

Silymarin

At present, there is no unequivocal

confirmation of the positive effects of
silymarin as a cytoprotective agent
against various noxae; in particular,
the scavenger effects attributed to
this substance and its alleged
regenerative properties have not
been confirmed in cirrhosis

Phosphatidylcholine

As is the case with silymarin, there is a

vast amount of information in the
literature about this substance.
Animal experiments have shown that the
development of septal fibroses and the
occurrence of cirrhosis could be prevented
despite chronic alcohol consumption.
The studies available to date on cirrhotic
patients provide insufficient information.

Colchicine

Inhibition of progressive fibrosis in cirrhotic

patients with a markedly improved survival
time was reported (dosage: 1 mg/day, 5
days/week).

However, this was not confirmed in a later

study. We have no information about
potential side effects, particularly during
long-term treatment (which is usually
desirable in cirrhosis therapy).