TREATMENT OF

LIVER CIRRHOSIS

BERLIBA ELINA, MD
TREATMENT of liver
cirrhosis
 TREATMENT — The 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
 Preventing superimposed insults

 Patients 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),
 drugs with hepatotoxic side effects,

 certain herbal remedies.

 Vaccination — Vaccination against hepatitis

A and B can help prevent a superimposed
insult to a liver that may have little
functional reserve.
 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 (ethiologic) therapies directed against the

underlying cause of the cirrhosis should be instituted.
 Treatment of patients with cirrhosis
caused by HBV infection
 Who to treat
 • As a priority, all adults, adolescents and children with CHB and
clinical evidence of compensated or decompensated cirrhosis (or
cirrhosis based on APRI score >2 in adults) should be treated,
regardless of ALT levels, HBeAg status or HBV DNA levels.
 Patients with decompensated cirrhosis and detectable
HBV DNA require urgent antiviral treatment with
Nucleotide Analoges .

 Entecavir and tenofovir are potent HBV inhibitors

with a high barrier to resistance.
 Thus, they can be confidently used as first-line
monotherapies.
 Lamivudine should not be used in such patients
GUIDELINES FOR THE PREVENTION, CARE AND TREATMENT OF PERSONS WITH CHRONIC HEPATITIS B INFECTION MARCH 2015
NA therapy should usually be continued indefinitely in cirrhotic
GUIDELINESEASL Clinical Practice Guidelines: Management of chronic hepatitis B virus infection. European Association for the Study of the Liver. Journal of
 Treatment of patients with cirrhosis
caused by HBV infection
 In patients with decompensated cirrhosis, 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.
 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.

 Patients with cirrhosis require long-term therapy, with careful

monitoring for resistance and flares.

EASL Clinical Practice Guidelines: Management of chronic hepatitis B virus infection.

European Association for the Study of the Liver. Journal of Hepatology 2012 vol. 57.
 Treatment of HCV liver cirrhosis
Indications for treatment: who should be
treated?

 All treatment-naive and treatment-experienced patients with compensated

or decompensated chronic liver disease due to HCV must be considered
for therapy.

 Treatment should be considered without delay in patients with

significant fibrosis or cirrhosis (METAVIR score F2, F3 or F4),
including decompensated (Child-Pugh B or C) cirrhosis.

EASL Recommendations on Treatment of Hepatitis C 2016. J Hepatol (2016)

 Treatment of HCV liver cirrhosis


In 2016 and onwards, IFN-free regimens are
the best options in treatment-naïve and
treatment-experienced, direct-acting antivirals
(DAAs) -naïve patients with compensated and
decompensated liver disease, because of their
virological efficacy, ease of use and tolerability.

 Indications depend on the HCV

genotype/subtype, the severity of liver disease,
and/or the results of prior therapy.

EASL Recommendations on Treatment of Hepatitis C 2016. J Hepatol (2016)

 Treatment of HCV liver cirrhosis

Patients Treatment- Sofosbuvir/ Sofosbuvir/ Ombitasvir/ Ombitasvir/ Grazoprevir/ Sofosbuvir Sofosbuvir

naive or ledipasvir velpatasvir paritaprevir/ paritaprevir/ elbasvir and and
-experienced ritonavir Ritonavir daclatasvir simeprevir
and
dasabuvir
Genotype Treatment- 12 wk, no 12 wk, no 24 wk, with No 12 wk, no 12 wk, no No
1a naive ribavirin ribavirin ribavirin ribavirin if ribavirin
HCV RNA
Treatment- 12 wk with ≤800,000 12 wk with
experienced ribavirina (5.9 ribavirina
or log) IU/ml or
24 wk, no or 24 wk, no
ribavirin 16 wk with ribavirin
ribavirin if
HCV RNA
>800,000
(5.9
log) IU/mlb
Genotype Treatment- 12 wk, no 12 wk, no 12 wk, no No 12 wk, no 12 wk, no No
1b naïve ribavirin ribavirin ribavirin ribavirin ribavirin
Treatment-
experienced

Genotype Treatment- No 12 wk, no No No No 12 wk, no No

2 naïve ribavirin ribavirin
Treatment-
experienced
 Treatment of compensated HCV cirrhosis
Patients Treatment- Sofosbuvir/ Sofosbuvir/ Ombitasvir/ Ombitasvir/ Grazoprevir/ Sofosbuvir Sofosbuvir
naive or ledipasvir velpatasvir paritaprevir/ paritaprevir/ elbasvir and and
-experienced ritonavir Ritonavir daclatasvir simeprevir
and
dasabuvir

Genotype Treatment- No 12 wk with No No No 24 wk with No

3 naïve ribavirin ribavirin
Treatment- or
experienced 24 wk, no
ribavirin

Genotype Treatment- 12 wk, no 12 wk, no No 12 wk, no 12 wk, no 12 wk, no 12 wk, no

4 naive ribavirin ribavirin ribavirin ribavirin ribavirin ribavirin

Treatment- 12 wk with 12 wk, no 12 wk with 12 wk with

experienced ribavirina ribavirin if ribavirin ribavirin
or HCV RNA or or
24 wk, no ≤800,000 24 wk, no 24 wk, no
ribavirin (5.9 ribavirin ribavirin
log) IU/ml
or
16 wk with
ribavirin if
HCV RNA
>800,000
(5.9
log) IU/mlb

Genotype Treatment- 12 wk, no 12 wk, no No No No 12 wk, no No

5 or 6 naive ribavirin ribavirin ribavirin

Treatment- 12 wk with 12 wk with

experienced ribavirina ribavirin
or or
24 wk, no 24 wk, no
ribavirin ribavirin
 Interferon-free treatment
 Patients infected with HCV genotype 1 can be
treated with an interferon-free combination of
daily sofosbuvir (400 mg) and daily simeprevir
(150 mg) for 12 weeks

 Preliminary results do not indicate a major

advantage of adding ribavirin to this regimen.
However, adding daily weight-based ribavirin
(1000 or 1200 mg in patients <75 kg or ≥75 kg,
respectively) should be considered in patients
with predictors of poor response to anti-HCV
therapy, especially prior non-responders and/or
patients with cirrhosis
 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

side-effects, especially those linked to portal
hypertension and hypersplenism, is required.


 Treatment of decompensated HCV cirrhosis
Patients with Child-Pugh C cirrhosis should not be treated with IFN-a-based
regimens, due to a high risk of life-threatening complications.

 Liver transplantation is the treatment of choice

for patients with end-stage liver disease.
 In patients awaiting liver transplantation, antiviral therapy is
indicated, because it prevents graft infection.
 Treatment can be started at low doses of pegylated IFN-a and
ribavirin, following a low accelerated dose regimen, or at full
doses.

 It is possible that patients with decompensated cirrhosis

who are not on a transplant list could benefit from an IFN-
free treatment regimen.

 However the safety and efficacy of an IFN-free regimen in

patients with decompensated cirrhosis not on a transplant
waiting list is unknown,EASL
and the
Clinical impact
Practice on mortality
Guidelines: Management in infection.
of hepatitis C virus this
European Association for the Study of the Liver. Journal of Hepatology 2014
 Treatment of patients with HCV cirrhosis and with an
indication for liver transplantation

Patients with conserved liver function (Child-Pugh A) in

whom the indication for transplantation is HCC should be
treated with
Ribavirin, daily a combination of patients awaiting
weekly pegylated liver transplantation
weight-based
IFN-α, with genotype 1 to
(1000 or 1200 mg daily weight-based 4 infection can be
in patients <75 kg ribavirin (1000 or treated with daily
or ≥75 kg, 1200 mg in patients weight-based
<75 kg or ≥75 kg, ribavirin (1000 or
respectively), and
respectively), and 1200 mg in patients
Sofosbuvir/daily <75 kg or ≥75 kg,
sofosbuvir /daily (400 mg) 12 weeks. respectively), daily
(400 mg) until sofosbuvir (400
liver mg), and
daily daclatasvir (60
transplantation. mg) 12 weeks prior
toTreatment
Jean-Michel Pawlotsky EASL Recommendations on transplantation
of Hepatitis C. Guidelines
for the screening, care and treatment of persons with hepatitis C infection. London, 2014.
 Liver cirrhosis due to Autoimmune
Hepatitis
 Autoimmune cirrhosis is treated with the corticosteroid prednisone
monotherapy or in combination with immunosuppressants, such as
azathioprine (Imuran) - .
 Dosage of prednisone: Initial dose of approximately 1 mg/kg
BW/day of prednisone for about one week (until an obvious
reduction in transaminase values has been achieved).
 A further reduction should be made in steps of 2.5-5.0 mg at
intervals of five to ten days until the desired maintenance dose
of 4-8 mg is reached.
 An initial dose of azathioprine of 1 mg/kg BW/day is
recommended. A maintenance dose of 50 mg/day is sufficient.

 A mean duration of treatment of two to three years is generally

recommended.

 A combination of calcium and sodium fluorophosphates

 Bile Duct Disorders
Ursodeoxycholic acid (15 - 20 mgBW/day), also known as ursodiol or UDCA, is
used for treating primary biliary cirrhosis and pimary sclerosing cholangitis

 Itching is usually controlled with:

 cholesterol drugs such as cholestyramine (4-24 g/day) and colestipol (15-30 g/day),
 naloxone (0.2 μg/kg BW/min i.v. infusion or 0.4-0.8 mg i.m.), naltrexone (50 mg/day),
 rifampicin (10 mg/kg BW/day) or ultraviolet therapy (9-12 min/day)
 Antibiotics - for infections in the bile ducts.

 Immunosuppressants (prednisone, azathioprine, cyclosporine, methotrexate) may also

be used.
 Prevention or improvement in osteopathy: sodium fluoride (50 mg/day), calcium (1,500
mg/day), alendronate (10 mg/day orally), and vitamin D (500-5000 units/day orally)
 The deficiency of fat-soluble vitamins (A, D, E, K), accompanied by malabsorption of
fatty acids, is treated by i.m. administration of these vitamins as combined medication
(1-2 times a month).
 Zinc deficiency requires substitution of this trace element.
 The desired continuous detoxification of the intestine can be achieved using lactulose.
 Several surgical procedures may also be tried to open up the bile ducts.
Cirrhosis due to Nonalcoholic Fatty Liver Disease
(NAFLD)
Weight reduction through diet and exercise,
diabetes and cholesterol management are the primary approaches to treating
these diseases.

 Glitazones - pioglitazone in non-diabetic biopsy

proven NASH, in diabetic NAFLD
 Metformin - in diabetic NAFLD
 Vitamin E - in non-diabetic biopsy-proven NASH
 Omega-3 FA – in hypertriglyceridemic NAFLD
 Statins - not contraindicated in dyslipidemic NAFLD
 Bariatric surgery - in obese patients refractory to
medical measures
 Ursodeoxycholic acid – in NAFLD

Fabio Nascimbeni. From NAFLD in clinical practice to answers from guidelines, 2013
Mariana V. Machado, Helena Cortez-Pinto. Non-invasive diagnosis of non-alcoholic fatty liver disease. 2013
 Hemochromatosis
A low iron diet must be observed. Although a lacto-vegetarian diet is
desirable, attention should be paid to the high iron content of pulses, green
vegetables and dried fruit.
Black tea (2-3 cups per day) should be drunk regularly.

 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.
 Adequate hydration before and after treatment, and avoidance of
vigorous physical activity for 24 h after phlebotomy is
recommended.

 Deferoxamine (a daily dose of 25-50 mg/kg BW) - this specific iron-chelating

agent is obtained from actinomyces cultures.
 In a dose of 1.5 g, it is capable of mobilizing about 25 mg iron, i. e. the same
amount as during a 500 ml venesection.
 An indication may be given, even if only temporarily, when blood-letting cannot
be carried out (e. g. anaemia, cardiac insufficiency).
 Oral administration is ineffective. For this reason, subcutaneous injection is
required as a slow infusion EASL
of 12Clinical
hours (using a portable infusion pump).
Practice Guidelines for HFE Hemochromatosis. J Hepatol (2010).
Wilson’s disease Nutrition should be low in copper. Patients must avoid offal, nuts,
cocoa products, mushrooms, potato crisps, rye flour, oat flakes, beans, dried figs, certain types of
cheese, meat and fish, pineapple, mineral water.
Vegetarian food, from which copper cannot be easily mobilized, is therefore recommended.
Alcohol is strictly forbidden.

 D-penicillamine - the initial dose is adapted to the individual and

ranges from 900-1,200 mg/day, given in three to four single doses
per day, which have to be taken half an hour before meals.
Therapeutic success is expected after six months at the earliest.

 Zinc inhibits intestinal copper resorption and stimulates the

synthesis of metallothionein in the liver and intestinal mucosa.
 The recommended dosage is 3x50 mg/day, one hour before meals.
The duration of administration and the dose are adjusted in line
with therapeutic success.
 The intestinal absorption of copper can be reduced further by
potassium sulphide (3 x 20 mg).

 The copper-chelating agent triethylene tetramine (trientine) can

be considered as an alternative therapy to penicillamine. The
initial dose is 3x600 mg/day; the recommended maintenance dose
is 2x600 mg/day. EASL Clinical Practice Guidelines: Wilson’s disease. Journal of Hepatology 2012
  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-1-blockade 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 dizziness, fatigue, and
shortness of breath.
 Some of these side effects disappear with time
 Management strategy after results of
screening endoscopy in patients with
cirrhosis

Small In a CTP B/C patient Nonselective- Start propranolol (20 mg

varices or varices with red blockers b.i.d.) or nadolol (20 mg
signs (propranolol or q.d.)
nadolol) 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, Nonselective ß- Same as above
without red signs blockers optional 
If no ß-blockers
are given, repeat
endoscopy in 2
years (sooner if
decompensation
occurs)
 Management strategy after results of
screening endoscopy in patients with
cirrhosis

Medium/ All patients Nonselective ß- Same as above

large independent of CTP blockers
varices class (propranolol,
nadolol) 
ora
Endoscopic Ligate every 1-2 weeks
variceal ligation 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, 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,
 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 with drugs such as
somatostatin or analogs (octreotide, vapreotide), can
be initiated as soon as a diagnosis of variceal
hemorrhage is suspected, before diagnostic EGS.

 This drugs act by producing splanchnic vaso-

constriction and, thereby decreasing portal blood
inflow.

 There are no differences among different

pharmacological agents (vasopressin, somatostatin,
terlipressin, octreotide, vapreotide), 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
 Regarding endoscopic therapy, Endoscopic
variceal ligaturation 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 during of diagnostic
EGD if 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
 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
 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:
 TIPS or
 Shunt therapy (CTP A patients where
available)
 surgery
bypass

splenorenal
shunt
 Prevention of recurrent variceal
hemorrhage
 The following interventions
are recommended :

 Nonselective ß-blockers (propranolol,

nadolol) plus endoscopic variceal ligation
 Nonselective ß-blockers plus nitrates (e.g.
isosorbide mononitrate)
 Rescue therapies: TIPS or shunt surgery
 Medical treatment of
ascites
 Therapy for ascites should be tailored to the patient's
needs.

 Some patients with mild ascites respond to sodium

restriction or diuretics taken once or twice per week.

 Other patients require aggressive diuretic therapy,

careful monitoring of electrolytes, and occasional
hospitalization to facilitate even more intensive
diuresis.
 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


In general, patients begin with a diet

containing less than 2000 mg of sodium
daily.
 Some patients with refractory ascites
require a diet containing less than 500
mg of sodium daily.


 Patients need detailed dietary instructions as to hidden

sources of sodium in their diet.
 Treatment of ascites
 Bed rest often facilitates diuresis because
upright position 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
 Treatment of ascites
Diuretics
 Diuretics should be considered the second line of therapy.
 Diuretics are usually required in patients with ascites, especially
those with moderate to severe ascites who retain sodium.
 Spironolactone (Aldactone) blocks the aldosterone receptor at the
distal tubule. It is dosed at 50-300 mg once daily.
 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).

 Furosemide (Lasix) may be used as a solo agent or in combination with

spironolactone. The drug blocks sodium reuptake in the loop of Henle.
 Treatment of ascites
 Patients should undergo frequent clinical and
biochemical monitoring particularly during the first month
of treatment.

 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 potassium-
sparing 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 120–125 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.
 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.
 LVP is a safe procedure and the risk of local
complications, such as hemorrhage or bowel
perforation is extremely low.
Paracentesis
 The ALFApump® System

 The ALFApump® System is a

surgically implantable device for
the continuous removal of fluid
that may accumulate in the
abdomen due to liver cirrhosis
(ascites).
 The device draws fluid from the
abdominal cavity into the
bladder, where it is eliminated
through normal urination. This
may provide an alternative to
the current method of draining
the fluid with a needle through
the skin of the abdominal wall. If
shown to be safe and effective,
it may reduce the number of
repeat hospital visits and
drainage procedures carried out
for this patient group.
 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 post-paracentesis circulatory
dysfunction (PPCD) .

 Circulatory dysfunction is associated with rapid re-accumulation of

ascites.
 Aapproximately 20% of these patients develop HRS and/or water
retention leading to dilutional hyponatremia.
 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.

 Treatment of ascites

 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.
 Transjugular intrahepatic portosystemic shunting (TIPS) is
effective in the management of refractory ascites but is
associated with a high risk of hepatic encephalopathy.
 Transjugular intrahepatic
portosystemic shunting (TIPS)

 A TIPS is an effective tool in managing massive ascites in some

patients.

 Ideally, TIPS placement produces a decrease in sinusoidal

pressure and in plasma renin and aldosterone levels, with
subsequent improved urinary sodium excretion.

 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 Child-Pugh 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
 Patients with massive ascites have 1-year survival rate of
less than 50%. Liver transplantation should be considered as
a potential means of salvaging the patient prior to the onset
of intractable liver failure or hepatorenal syndrome.
 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 third-generation
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.

 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

 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.

 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/4–6 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.
 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,
 deactivation of the vasoconstrictor and sodium-conserving 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 60–70% 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
 treatment with norfloxacin decreases the incidence of HRS in
advanced cirrhosis, respectively.
 Further studies are needed .
 Management of chronic portal
systemic encephalopathy.
Therapy Considerations
Precipitating Initial treatment includes identifying and
Factors treating any precipitating factors.

Nutrition Attention to nutrition is also important.

Rigid protein restriction (< 0.75 g/kg) is not
appropriate.
Protein restriction (40–60 g) - not appropriate
long term (60–80 g/day)
Patients need at least 25–35 kcal/kg and more
than 200 g of carbohydrate to spare protein
metabolism
Vegetable-based diet increases elimination of
. nitrogen products in stool
Branched-chain amino acids are costly and
data
on efficacy are controversial
 Management of chronic portal
systemic encephalopathy.
Therapy Considerations
Initial treatment
Nonabsorbable Lactulose (galactose fructose), 15–30 mL 4
disaccharides times daily
• Decreases fecal pH by inhibiting production
of
NH3 by fecal flora
• Increases fecal N2 excretion
Lactose is effective in lactase-deficient
patients

Lactulose, a synthetic nonabsorbable disaccharide, 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 fecal ammonia, acidifying it to ammonium chloride and
resulting in an increase in fecal nitrogen excretion.

The lactulose dose needs to be titrated so the patient is

Laxative
.
 Management of chronic portal
systemic encephalopathy.
Therapy Considerations
Antibiotics Potential for nephrotoxicity; taper dose (1–2
Neomycin g/day) for prolonged use
No evidence of potentiation of response to
lactulose
Metronidazole 250 mg twice daily
Rifaximin Poorly absorbed antibiotic (200 mg 3 times
daily)
They work by decreasing the colonic concentration of ammoniagenic
bacteria with resulting improvement in the symptoms of hepatic
encephalopathy.

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.

 Additional administration of
ornithine aspartate (3 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.
 Treatment for hepatic
fibrosis
 Eliminate the cause(s) of injury and their
mediators.
 Reduce inflammation and the immune response –
caspase inhibition, TNFα/fibrosis, anti-oxidant,
hepatoprotection, anti-IL13, anti-PDE-4.
 Target specific signaling: receptor–ligand
interaction, intracellular signaling – cannabinoids
and 5HT-2B receptor antagonism, angiotensin receptor
blocker (Losartan), PPARγ.
 Reduce fibrogenesis, inhibit matrix synthesis .
 Resolve fibrosis by:
 ○ increasing scar matrix degradation – anti-lysyl
oxidase2 (simtuzamab);
Mechanisms of liver fibrosis progression and regression and targeted therapeutic approaches. Hepatic stellate cell (HSC)-myofibroblasts
(MFBs) and the factors that regulate HSC activation, proliferation, function, and survival represent important therapeutic targets; likewise,
therapies that directly degrade scar and/or promote liver regeneration. BEC, biliary epithelial cell; T/B LC, T/B lymphocyte; SAM, scar-
associated macrophage; LPS, lipopolysaccharide; PDGF, platelet-derived growth factor; FGF, fibroblast growth factor; VEGF, vascular
endothelial growth factor; MCP-1, macrophage chemotactic protein-1; TGF-1, transforming growth factor-; CTGF, connective tissue growth
factor; TIMP, tissue inhibitor of metalloproteinases; MMP, matrix metalloproteinase; TLR-4, Toll-like receptor; NO, nitric oxide; ET-1,
endothelin-1; BM, bone marrow; EMT, epithelial mesenchymal transition; NF-B, nuclear factor-B; FAS, apoptosis stimulating factor; NGF,
nerve growth factor; TRAIL, tumor necrosis factor-related apoptosis-inducing ligand; ECM, extracellular matrix.
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).
 Liver Transplantation
LT has emerged as an important strategy in the management of
patients with decompensated cirrhosis. Patients should be
referred for consideration of LT after the first signs of hepatic
decompensation.
Indications for Liver Transplant
Acute Liver Failure Liver-based metabolic conditions with
Complications of cirrhosis: systemic manifestations:
Ascites a1-Antitrypsin deficiency
Chronic gastrointestinal blood loss Familial amyloidosis
due to portal hypertensive Glycogen storage disease
gastropathy Hemochromatosis
Encephalopathy Primary oxaluria
Liver cancer Wilson disease
Refractory variceal hemorrhage
Synthetic dysfunction
Systemic complications of chronic liver disease:
Hepatopulmonary syndrome; Portopulmonary hypertension
Contraindications to Liver Transplant
MELD Score<15 Intrahepatic Cholangiocarcinoma
Severe cardiac or pulmonary disease Extrahepatic malignancy
AIDS Fulminant hepatic failure with
Ongoing alcohol or illicit substance sustained ICP >50 mm Hg or CPP <40
abuse mm Hg*
Hepatocellular carcinoma with Hemangiosarcoma
metastatic spread Persistent noncompliance
Living donor livet transplant