1.

1 CIRRHOSIS
Cirrhosis is the most advanced stage of most types of chronic liver disease. The term
cirrhosis is derived from the Greek kirrhos meaning orange-colored, and refers to the
yellow-orange hue of the liver seen by the pathologist. Histologically, it is defined as
a diffuse disorganization of normal hepatic architecture into structurally abnormal
nodules. Fibrosis is potentially reversible if the causative agent is removed. However,
advanced cirrhosis comprises major alterations in the hepatic vascular bed and is
usually irreversible. (Bataller R, Gines P.2005)

ETIOLOGY OF CIRRHOSIS
The main causes of cirrhosis are hepatitis C virus (HCV) infection and alcoholic liver
disease, which account for two thirds of all cirrhosis cases. Other major causes are
listed in Table 1.1a

(Bataller R, Gines P.2005)

Viral diseases Genetic diseases
• Hepatitis B • Wilson disease
• Hepatitis C • Hemochromatosis
• Hepatitis D • Type IV glycogen storage
disease
• Tyrosinemia
• α1-Antitrypsin deficiency
Autoimmune diseases Vascular diseases
• Autoimmune hepatitis • Chronic right-sided heart failure
• Primary biliary cirrhosis • Budd-Chiari syndrome
• Primary sclerosing cholangitis • Veno-occlusive disease
• Graft versus host disease • Inferior vena cava thrombosis
Hepatotoxic agents Acquired metabolic diseases
• Alcohol abuse • Non-alcoholic steatohepatitis
• Drugs (e.g.,methotrexate,α- Miscellaneous
methyldopa, amiodarone) • Secondary biliary cirrhosis
• Vitamin A intoxication • Cryptogenic

PATHOPHYSIOLOGY
Cirrhosis results in elevation of portal blood pressure because of fibrotic changes
within the hepatic sinusoids, changes in the levels of vasodilatory and vasoconstrictor
mediators, and an increase in blood flow to the Splanchinic
vasculature.Pathophysiology of liver cirrhosis can be best explained by the
elaborating the normal blood filtration process of liver that receive blood from the
portal vein and the hepatic artery. Blood enters the liver via the portal triad and drains
through the hepatic lobule, the smallest functional unit of this filtration system and
into the central vein. The hepatic lobule is hexagonal in shape at the angles of which
are the sites of the portal triads, which contain the smallest branches of the portal vein
and hepatic artery, as well as the bile and lymphatic ducts. Within the lobule,
individual hepatocytes are arranged in plates, radiating from the periphery to a central
vein. After passing through the hepatic lobules, blood collects in the central veins,
which ultimately coalesce into the hepatic veins, which then enter the inferior vena
cava.

4
In areas of hepatocellular injury, regardless of the nature of the inciting agent, stellate
cells, normally involved in the storage of retinoids like vitamin A, become activated,
lose their retinoid, and develop features of fibroblasts. They then become a major
source of the collagen and other matrix proteins that proliferate during fibrosis. The
progressive deposition of fibrous material within the sinusoids disrupts the normal
blood flow through the hepatic lobule. As fibrous tissue accumulates, resistance to
portal blood flow increases, resulting in persistent and progressive elevations in portal
blood pressures (portal hypertension (PHT)). Normal portal venous pressure is 5 to 10
mm Hg.Clinically significant PHT exists when the portal venous pressure increases to
a point where it is 10 mm Hg greater than the pressure within the inferior vena cava.
Figure 1.1a

There is also evidence that there are changes in the vasodilatory and vasoconstricting
mediators that regulate the hepatic sinusoidal blood flow. A decrease in the
production of nitric oxide, which acts as a vasodilator, and increase in the levels of the
vasoconstrictor endothelin combine to increase the resistance to blood flow.
Concurrently, there also appears to be an increase in the blood flow to the Splanchinic
vasculature through a nitric oxide–mediated effect on the Splanchinic arteriole. These
physiologic changes are the target of the pharmacologic approach to therapy. (Timm
EG, Stragand JJ. 2005)

CLINICAL PRESENTATION OF CIRRHOSIS

Physical examination can be normal in patients with early cirrhosis. The liver is
enlarged initially and is palpable. In advanced cirrhosis, liver size usually decreases.
(Timm EG, Stragand JJ. 2005)

5
 Table 1.1b: SIGNS AND SYMPTOMS (PERCENT OF PATIENTS)
 Fatigue (65%),  Splenomegaly (15%)  Encephalopa Hepatomegaly
 Pruritus  Palmer thy Gynecomastia
(55%) erythema,  Pleural Ascites oedema
 Hyperpigmentati  Spider angiomata effusion, (25%)
on (25%),  Malaise, Aspiratory difficulties
 Jaundice (10%)  Anorexia,
and Weight loss

LABORATORY TESTS
Liver function test results are commonly abnormal in patients with cirrhosis.

• Hypoalbuminemia
• Elevated prothrombin time
• Thrombocytopenia
• Elevated alkaline phosphates
• Elevated aspartate transaminase (AST), alanine transaminase (ALT), and γ
-glutamyl transpeptidase (GGT).

Table 1.1c IDENTIFICATION OF THE MAIN CAUSES OF CIRRHOSIS

(Bataller R,Gines P.2005)
CAUSE DIAGNOSTIC METHOD
Alcohol-related Medical history (also obtained from relatives),urinary alcohol levels,
histological findings
Hepatitis C virus (HCV Anti-HCV antibodies, HCV RNA assay
Hepatitis B virus (HBV) HBsAg, HBV DNA assay
Hepatitis D virus Anti-delta IgM or IgG
(HDV)
Autoimmune disease Antitissue antibodies(ANA,LKM,ASMA),hypergammaglobulinemia,
histologic findings
Primary biliary AMA, histologic findings
cirrhosis
Primary sclerosing Severe cholestasis; detection of biliary tract abnormalities by magnetic
cholangitis resonance
imaging/magnetic resonance cholangiopancreatography (MRI/MRCP)
or ERCP; ANCA; presence of inflammatory bowel disease; histologic
findings
Wilson disease Serum ceruloplasmin levels, Kayser-Fleischer rings, copper content in
the liver, genetic studies. Serum ferritin levels, total iron binding
capacity, iron content in the liver, genetic studies
Hemochromatosis Serum ceruloplasmin levels, Kayser-Fleischer rings, copper content in
the liver, genetic studies
Non-alcoholic Metabolic syndrome, histologic findings (may be absent in cirrhosis),
steatohepatitis absence of alcohol abuse

6
MANAGEMENT OF CIRRHOSIS
STANDARD TREATMENT GUIDELINES:
General approaches to therapy should include:
1. Identify and eliminate the causes of cirrhosis (e.g., alcohol
abuse).
2. Assess the risk for variceal bleeding and begin pharmacologic
prophylaxis when indicated, reserving Endoscopic therapy for
high-risk patients or acute bleeding episodes.
3. Evaluate the patient for clinical signs of ascites and manage
with pharmacologic therapy (e.g., diuretics and Paracentesis).
Careful monitoring for spontaneous bacterial peritonitis should
be employed in patients with ascites who undergo acute
deterioration.
4. Hepatic encephalopathy is a common complication of cirrhosis
and requires clinical vigilance and treatment with dietary
restriction.
5. Frequent monitoring for signs of hepatorenal syndrome,
pulmonary insufficiency, and endocrine dysfunction is
necessary.

PHARMACOTHERAPY OF CIRRHOSIS
DESIRED OUTCOMES
Desired therapeutic outcomes can be viewed in two categories:
resolution of acute complications, such as tamponade of
bleeding and resolution of hemodynamic instability for an episode of
acute variceal hemorrhage; and prevention of complications,
through lowering of portal pressure with medical therapy.

7
 Table 1.1d Cirrhosis Management Approach and Outcome Assessments
Complication Treatment Approach Monitoring Parameter Outcome
Assessment
Ascites Diet, diuretics, Daily assessment of Prevent or eliminate
paracentesis, TIPS weight ascites and its
secondary
complications
Spontaneous Antibiotic therapy, Evidence of clinical Prevent/treat infection
bacterial prophylaxis if deterioration(e.g., to decrease Mortality
peritonitis undergoing paracentesis abdominal pain, fever,
anorexia, malaise,
fatigue
Variceal bleeding Pharmacologic Child-Pugh score, Appropriate reduction
prophylaxis endoscopy, CBC in heart rate and portal
pressure
Endoscopy, Vasoactive
drug therapy CBC, evidence of over- Acute: control acute
(octreotide), bleeding bleed
sclerotherapy, volume Chronic: variceal
resuscitation obliteration, reduce
portal pressures
Coagulation Blood products (PPF, CBC, prothrombin Normalize PT time,
disorders platelets), vitamin K time, platelet count maintain/improve
haemostasis
Hepatic Ammonia reduction Grade of Maintain functional
encephalopathy (Lactulose, cathartics), encephalopathy, EEG, capacity, prevent
elimination of drugs psychological testing, hospitalization for
causing CNS depression, mental status changes, encephalopathy,
limit excess protein in concurrent drug therapy decrease ammonia
diet levels, provide
adequate nutrition
Hepatorenal Eliminate concurrent Serum and urine Prevent progressive
Syndrome nephrotoxins (NSAIDs), electrolytes, concurrent renal injury by
decrease or discontinue drug therapy preventing dehydration
diuretics, volume and avoiding other
resuscitation, nephrotoxins
liver transplantation
Hepatopulmonary Paracentesis, O2 therapy Dyspnoea, presence of Acute: relief of
syndrome ascites dyspnoea and hypoxia
Chronic: manage ascites
as above
CBC, complete blood cell count; CNS, central nervous system; EEG, electroencephalogram; PT, prothrombin time;
NSAID, nonsteroidal anti-inflammatory drug; PPF, plasma protein fraction; TIPS, transjugular intrahepatic
portosystemic shunt

1. COMPENSATED CIRRHOSIS

Specific medical therapies may be applied to different liver diseases to diminish

disease progression. However, these therapies may become progressively less effective
if chronic liver disease evolves into cirrhosis. In patients with compensated cirrhosis,
specific therapies prevent the development of clinical complications and therefore
delay the need for liver transplantation. Treatment with pegylated interferon plus
8
 ribavirin should be considered in patients with compensated cirrhosis from HCV
infection, although the rate of sustained response is lower than in noncirrhotic patients.
Moreover, antiviral treatment may worsen existing anaemia or thrombocytopenia, and
drug discontinuance is frequent. In patients with HBV-related cirrhosis, lamivudine
appears to be a safe and effective antiviral agent, which may improve or stabilize liver
disease in selected patients with advanced cirrhosis and active HBV replication.15
However; viral resistance can develop with prolonged treatment. Adefovir and
entecavir are newer antiviral agents that have activity against both wild-type and
lamivudine-resistant HBV. The most effective measure for patients with alcohol-
induced cirrhosis is to stop drinking. (Timm EG, Stragand JJ.2005)

DECOMPENSATED CIRRHOSIS

VARICEAL B LEEDING
Rupture of gastroesophageal varices because of portal hypertension is a severe and
frequent complication of cirrhosis. Portal hypertension is caused by increased
intrahepatic vascular resistance, as well as increased portal blood flow secondary to
splanchnic vasodilatation. Primary prophylaxis of variceal bleeding should be initiated
in patients with medium-size to large varices.

Table 1.1e: Management strategy after results of screening endoscopy in patients with
cirrhosis
No varices Repeat endoscopy in 3 years (sooner if decompensation occurs)
Small varices -Start propranolol (20 mg b.i.d.) or
In a CTP B / C Nonselective Beta-blockers -Nadolol (20 mg q.d.) Titrate to maximal
patient or varices (propranolol or nadolol) tolerable dose or a heart rate of 55 – 60
with red signs b.p.m. No need to repeat EGD
In a CTP A Nonselective Beta-blockers
patient, without optional Same as above
red signs If no beta blockers are given,
repeat endoscopy in 2 years (sooner
if decompensation occurs)
Medium / large
varices All Nonselective Beta-blockers Same as above
patients (propranolol, nadolol)
independent of or a Ligate every 1 – 2 weeks until variceal
CTP class Endoscopic variceal ligation obliteration First surveillance endoscopy 1 –
3 months after obliteration, then every 6 –
12 months indefinitely
b.i.d., twice a day; b.p.m., beats / min; CTP, Child – Turcotte – Pugh; EGD, esophagogastroduodenoscopy; q.d., once daily.
Choice depends on patient characteristics and preferences, local resources.

9
Table 1.1f : Diagnosis and management strategy of patient with acute variceal hemorrhage
Diagnosis • Any of the following findings on upper endoscopy performed within 12 h of
admission:
Active bleeding from a varix or Stigmata of variceal hemorrhage (white nipple
sign) or
Presence of gastroesophageal varices without another source of hemorrhage
General • Cautious transfusion of fluids and blood products, aiming to maintain a
managemen haemoglobin of ~ 8 g / dl
t • Antibiotic prophylaxis (3 – 7 days) with: Ciprofloxacin 500 mg b.i.d. (p.o.) or
400 mg b.i.d. (i.v.) or
• Ceftriaxone 1 g / day (i.v.) particularly in facilities with known quinolone
resistance and in patients with two or more of the following : malnutrition,
ascites, encephalopathy, serum bilirubin > 3 mg / dl
Specific • Pharmacological therapy initiated as soon as diagnosis is suspected Octreotide
initial 50 mcg i.v. bolus followed by continuous infusion 50 mcg / h (3 – 5 days)
managemen and
t • Endoscopic therapy (ligation preferable) performed at time of diagnostic
endoscopy (performed within 12 h of admission)
Rescue • Considered in patients with bleeding esophageal varices who have failed
managemen pharmacological + Endoscopic therapy or in patients with bleeding gastric
t fundal varices who have failed one Endoscopic therapy
• TIPS or Shunt therapy (CTP A patients where available)
b.i.d., twice a day, CTP, Child – Turcotte – Pugh; i.v., intravenous; p.o., orally; TIPS, transjugular intrahepatic portosystemic shunt.

SPONTANEOUS BACTERIAL PERITONITIS

SBP is severe infections found in 15% to 25% of cirrhotic patients

hospitalized with ascites. Predisposing factors include severe liver
insufficiency and low protein content in ascitic fluid (< 1 g/dl). SBP
should be treated empirically

1.1g: Diagnosis and management strategy in spontaneous bacterial peritonitis

(SBP)
Diagnosis • Consider SBP and perform diagnostic paracentesis if:
Symptoms / signs (abdominal pain, fever, chills),Patient is in
emergency room or admitted, Worsening renal function or
encephalopathy
• SBP present if ascites PMN count > 250 cells /µl (if fluid
bloody, subtract 1 PMN per 250 RBC /µl)
General • Avoid therapeutic paracentesis during active infection
management • Intravenous albumin (1 g / kg of body weight) if BUN > 30
mg / dl, creatinine > 1 mg / dl, bilirubin > 4 mg / dl; repeat at
day 3 if renal dysfunction persists Avoid aminoglycosides
Specific • Cefotaxime (2 g i.v. every 12 h) or
management • Ceftriaxone (2 g every 24 h) or
• Ampicillin / sulbactam (2g / 1 g i.v. every 6 h)
Follow-up • Continue therapy for 7 days
10
 •Repeat diagnostic paracentesis at day 2
•If ascites PMN count decreases by at least 25 % at day 2,
intravenous therapy can be switched to oral therapy
(quinolone such as ciprofloxacin or Levofloxacin 250 mg p.o.
b.i.d.) to complete 7 days of therapy
b.i.d., twice a day; BUN, blood urea nitrogen; i.v., intravenous; PMN,
polymorphonuclear (neutrophil) cell count; p.o., orally; RBC, red blood cell
count.
1.1h: Management strategy in the prevention of recurrent SBP
Recommended • Oral norfloxacin 400 mg p.o. q.d. (preferred) or
therapy • Oral ciprofloxacin 250 – 500 mg q.d. a or
• Oral Levofloxacin 250 mg q.d. a
Alternative • TMP-SMX 1 double-strength tablet p.o. q.d.
therapy • (Patients who develop quinolone resistant organisms may also
have resistance to TMP-SMX)
Duration • Prophylaxis should be continued until the disappearance of
ascites or until liver transplantation

ASCITES
Ascites is the most frequent complication of cirrhosis. It impairs quality of life and
increases the risk of bacterial infections It is caused primarily by Splanchinic
vasodilatation from increased synthesis of vasodilators (e.g., nitric oxide). Severe
Splanchinic vasodilatation decreases effective arterial blood volume, which activates
systemic vasoconstrictor and sodium-retaining factors. The initial management of
ascites includes reduction of sodium intake to 60 to 90 mEq/day. In patients with
dilutional hyponatremia (i.e., a serum sodium concentration of 130 mmol/L in the
presence of ascites or edema), fluid intake should be restrict to less than 1,000 ml/day,
although compliance is problematic. Practice guidelines recommend that diuretic
therapy be initiated with the combination of spironolactone and frusemide. If tense
ascites is present, paracentesis should be performed prior to institution of diuretic
therapy and salt restriction. For patients who respond to diuretic therapy, this
approach is preferred over the use of serial paracentesis .Current therapeutic strategies
for patients with refractory ascites include repeated large-volume paracentesis

HEPATORENAL SYNDROME
HRS is the most severe complication of patients with cirrhosis. It is a functional renal
failure resulting from extreme renal vasoconstriction. HRS may occur spontaneously
or after precipitating conditions such as SBP. There are two clinical types of HRS.
Type 1: characterized by progressive oliguria and a rapid rise of serum creatinine
concentration to more than 2.5 mg/dl.Survival of patients with type1.HRS is
extremely poor.
Type 2: characterized by a moderate and stable increase in the serum creatinine
concentration and is frequently associated with refractory ascites

11
 1.1i: Diagnosis and management strategy of hepatorenal syndrome
Diagnosis • Consider HRS in a patient with cirrhosis and ascites and a
creatinine level of > 1.5 mg / dl
• It is a diagnosis of exclusion; before making the diagnosis, the
following need to be ruled out and treated:
Sepsis (patient needs to be pancultured)
Volume depletion (hemorrhage, diarrhoea, overdiuresis)
Vasodilators
Organic renal failure (urine sediment, kidney ultrasound)
• Diuretics should be discontinued and intravascular volume
expanded with i.v. albumin
• If renal dysfunction persists despite above, diagnose HRS
Recommended • Liver transplant (priority dependent on MELD score)
therapy • If patient is on transplant list, MELD score should be updated
daily and communicated to transplant centre; if patient s not on
transplant list, packet should be prepared urgently
Alternative Vasoconstrictors Octreotide 100 – 200 mcg s.c. Goal to
(bridging PLUS t.i.d increase
therapy) Midodrine MAP by
Or 5 – 15 mg p.o. t.i.d. 15 mm Hg
Terlipressin 0.5 – 2.0 mg i.v.
And every 4 – 6 h
Intravenous albumin 50 – 100 g i.v. q.d.
(both for at least 7
days)
i.v., intravenous; HRS, hepatorenal syndrome; MAP, mean arterial pressure; MELD,
model for end-stage liver disease; t.i.d.; thrice a day; s.c., subcutaneously; p.o., orally a
Not available in the United States

HEPATIC ENCEPHLOPATHY

12
 1.1j Management strategy of episodic hepatic encephalopathy (HE )

General management -Identify and treat precipitating factor (GI hemorrhage, infection, pre-
renal azotemia, constipation, sedatives)
-Short-term ( < 72 h) protein restriction may be considered in severe HE

Specific therapy -Lactulose enemas (300 cm3 in 1L of water) in patients who are unable
to take it p.o.
or
-Lactulose 30 cm3 p.o. every 1 – 2 h until bowel evacuation, then adjust
to a dosage that will result in 2 – 3 formed bowel movements per day
(usually 15 – 30 cm3 p.o. b.i.d.)
-Lactulose can be discontinued once the precipitating factor has resolved

b.i.d., twice a day; GI, gastrointestinal; p.o., orally.

1.1k Management strategy of persistent hepatic encephalopathy (HE)

General -No long-term protein restriction

management -Protein from dairy or vegetable sources is preferable to animal protein
-Avoid sedatives and tranquilizers
-Avoid constipation

Specific therapy -Lactulose dosage that produces

2 – 3 soft, formed bowel movements per day, starting at 15 – 30 cm 3 p.o. b.i.d.

Alternative -Rifaximin 400 mg p.o. t.i.d. in patients who cannot tolerate Lactulose
therapy

b.i.d., twice a day; p.o., orally; t.i.d., thrice a day.

(Garcia-Tsao G, Lim Joseph. 2009)

13