CIRRHOSIS LIVER
Dr. M. A. SOFI MD; FRCP (London);
FRCPEdin; FRCSEdin
Definition
Cirrhosis represents a late stage of progressive
hepatic fibrosis characterized by distortion of the
hepatic architecture and the formation of
regenerative nodules.
The progression of liver injury to cirrhosis may
occur over weeks to years.
Epidemiology
Chronic liver disease and cirrhosis result in
about 35,000 deaths each year in the United
States.
• Cirrhosis is the ninth leading cause of death
in the United States and is responsible for
1.2% of all US deaths.
• Many patients die from the disease in their
fifth or sixth decade of life.
Etiology and pathogenesis
• Viral hepatitis
• Alcoholic Liver Disease
• Nonalcoholic Fatty Liver
Disease
• Primary Biliary Cirrhosis
• Primary Sclerosing
Cholingitis
• Autoimmune Hepatitis
• Alph 1Antitrypsin
Deficiency
• Hepatic-Venous outflow
obstruction
• Hereditary
Hemochromatosis
• Wilson’s Disease
• Heptotoxic Drugs
• Glycogen Storage
Disease
• Cryptogenic cirrhosis
Viral hepatitis
• Chronic hepatitis C. Infection
with the hepatitis C virus causes
inflammation of the liver and a
variable grade of damage to the
organ.
• Among patients with chronic
hepatitis C 20-30% will develop
cirrhosis.
• Can be diagnosed with serologic
assays that detect hepatitis C
antibody or viral RNA.
• Cirrhosis caused by hepatitis C
and alcoholic liver disease are the
most common reasons for liver
transplant.
• Chronic hepatitis B. The hepatitis
B virus causes liver inflammation
and injury that over several
decades can lead to cirrhosis.
• Hepatitis D is dependent on the
presence of hepatitis B and
accelerates cirrhosis in coinfection.
• Chronic hepatitis B can be
diagnosed with detection of
HBsAG > 6 months after initial
infection.
• HBeAG and HBV DNA are
determined to assess whether
patient needs antiviral therapy
Alcoholic liver disease
• Of all chronic heavy drinkers,
only 15–20% develop hepatitis
or cirrhosis, which can occur
concomitantly or in succession
• Chronic consumption of alcohol
results in the secretion of proinflammatory cytokines (TNFalpa, IL6 andIL8], oxidative
stress, peroxidation, and
acetaldehyde toxicity. These
factors cause inflammation,
apoptosis and eventually
fibrosis of liver cells.
• Patients may also have
concurrent alcoholic hepatitis
with fever, hepatomegaly,
jaundice, and anorexia.
• AST and ALT are both elevated
but less than 300 IU/L with an
AST:ALT ratio > 2.0, a value
rarely seen in other liver
diseases
• In the United States, 2/5 of
cirrhosis related deaths are due
to alcohol
Biliary cirrhosis
Primary Biliary Cirrhosis:
• Damage of the bile ducts leading to secondary liver damage.
• May be asymptomatic or complain of fatigue, pruritus, and
non-jaundice skin hyperpigmentation with hepatomegaly.
• There is prominent alkaline phosphatase elevation as well as
elevations in cholesterol and bilirubin.
• Gold standard diagnosis is antimitochondrial antibodies
(positive in 90% of PBC patients).
• Liver biopsy if done shows bile duct lesions.
• It is more common in women
Biliary cirrhosis
Primary Sclerosing Cholangitis.
• PSC is a progressive cholestatic disorder presenting
with pruritus, steatorrhea, fat soluble vitamin
deficiencies, and metabolic bone disease.
• There is a strong association with inflammatory bowel
disease (IBD), especially ulcerative colitis.
• Diagnosis is best with contrast cholangiography showing diffuse,
multifocal strictures and focal dilation of bile ducts, leading to a
beaded appearance. Non-specific serum immunoglobulins may
also be elevated
Hereditary, Metabolic and other causes of cirrhosis
Hereditory Hemachromatosisis:
• Usually presents with family history of
cirrhosis, skin hyperpigmentation,
diabetes mellitus, pseudogout,
cardiomyopathy,
• Labs show fasting transferrin saturation
of > 60% and ferritin > 300 ng/ml.
Wilson's disease. Autosomal recessive
disorder characterized by low serum
ceruloplasmin and increased hepatic
copper content on liver biopsy, and
elevated 24-hour urine copper.
• May also have Kayser-Fleischer ring
Indian Childhood Cirrhosis
• Is a form of neonatal cholestasis
characterised by deposition of
copper in the liver.
• Alpha 1-antitrypsin deficiency
(A1AD). Autosomal recessive
disorder of decreased levels of
the enzyme alpha 1--antitrypsin.
Patients may also have COPD,
especially if they have a history
of tobacco smoking.
• Cardiac cirrhosis. Due to
chronic right sided heart failure
which leads to liver congestion.
• Galactosemia
Other conditions that may cause cirrhosis
Hepatic-Venous
outflow obstruction
• Hepatic Venoocclusive disease
• Budd-chiari syndrome
• Constrictive
pericarditis
• Chronic congestive
heart failure
• Glycogen storage
disease type IV
• Cystic fibrosis
• Hepatotoxic drugs or
toxins – Carbon
Tetrachloride
• Cryptogenic
cirrhosis
Clinical Features
• Insidious development
• Often produces no clinical manifestations
• Common symptoms
–Anorexia, nausea, abdominal discomfort,
weakness, weight loss, and malaise
11
Clinical Features
Direct consequence of
liver cells not
functioning
• Enlargement of the
liver and spleen due
to PHTN
• Ascites
• Peripheral edema
• Jaundice
• Spider angiomas
• GI bleeding
• Palmer erythema
• Gynecomastia
• Hypogonadism
• Fetor hepaticus
Clinical Features
• There are some changes seen in
cirrhosis whose causes are not
clearly known. They may also be a
sign of other non-liver related
causes
• Nail changes.
– Muehrcke's lines - paired
horizontal bands separated by
normal color resulting from
hypoalbuminemia. It is not
specific for cirrhosis.]
– Terry's nails - proximal twothirds of the nail plate appears
white with distal one-third red,
also due to hypoalbuminemia
– Clubbing
• Hypertrophic osteoarthropathy.
Chronic proliferative periostitis of
the long bones that can cause
considerable pain. It is not specific
for cirrhosis.
• Dupuytren's contracture.
Thickening and shortening of
palmar fascia that leads to flexion
deformities of the fingers. It is
relatively common (33% of
patients).
• Other.
–
–
–
–
Weakness
Fatigue
Anorexia
Weight loss
Muehrcke's lines
Clubbing
Terry's nails
Dupuytren's contracture
Lab Findings
• Thrombocytopenia - typically
multifactorial. However, this rarely
results in platelet count < 50 000/mL
• Aminotransferases - AST and ALT
are moderately elevated, with AST >
ALT. However, normal
aminotransferases do not preclude
cirrhosis
• Gamma-glutamyl transferase–
correlates with AP levels.
• Bilirubin- Levels normal when
compensated but may elevate as
cirrhosis progresses.
• Albumin - levels fall as the
synthetic function of the liver
declines
• Prothrombin time - increases
since the liver synthesizes clotting
factors.
• Globulins- increased due to
shunting of bacterial antigens
away from the liver to lymphoid
tissue.
• Hyponatremia due to inability to
excrete free water resulting from
high levels of ADH and
aldosterone
• Leukopenia and neutropenia due to splenomegaly
Portal Hypertension
Liver cirrhosis increases resistance to blood flow and higher pressure in
the portal venous system, resulting in portal hypertension. Effects of
portal hypertension include:
• Splenomegaly is found in 35% to 50% of patients.[7]
• Esophageal varices result from a process called Portacaval
anastomosis). When these blood vessels become enlarged, they are
called varices and are more likely to burst.
• Caput medusa are dilated periumbilical collateral veins due to portal
hypertension.
• Cruveilhier-Baumgarten murmur is a venous hum heard in the
epigastric region due to collateral connections forming between portal
system and the periumbilical veins
Portal Hypertension
Complications of portal hypertension include:
• Ascites
• Hepatic encephalopathy
• Variceal hemorrhage
• Spontaneous bacterial peritonitis
• Hepatorenal syndrome
• Portal hypertensive gastropathy
• Hepatic hydrothorax
• Hepatopulmonary syndrome
• Portopulmonary hypertension
• Cirrhotic cardiomyopathy
Ascites
• Ascites is the accumulation
of fluid within the
peritoneal cavity.
• It is the most common
complication of cirrhosis.
• The first step leading to
fluid retention and
ultimately ascites is the
development of portal
hypertension
• Patients without portal
hypertension do not
develop ascites or edema.
• Those with ascites have
several circulatory,
vascular, functional, and
biochemical abnormalities
that contribute to the
pathogenesis of fluid
retention
Non-peritoneal causes of ascites
Causes of Nonperitoneal Ascites
Examples
Intrahepatic portal hypertension
Cirrhosis
Fulminant hepatic failure
Veno-occlusive disease
Extrahepatic portal hypertension
Hepatic vein obstruction (i.e., Budd-Chiari syndrome)
Congestive heart failure
Malignant ascites
Primary peritoneal mesothelioma
Secondary peritoneal carcinomatosis
Granulomatous peritonitis
Tuberculous peritonitis
Fungal and parasitic infections (e.g., Candida,
Histoplasma, Cryptococcus, Schistosoma mansoni,
Strongyloides, Entamoeba histolytica)
Sarcoidosis
Miscellaneous disorders
Myxedema
Ovarian tumors
Pancreatic ascites
Biliary ascites
Hypoalbuminemia
Nephrotic syndrome
Protein-losing enteropathy Malnutrition
General Management
The major goals of managing patients with cirrhosis
include:
• Slowing or reversing the progression of liver disease
• Preventing superimposed insults to the liver
• Identifying medications that require dose
adjustments or should be avoided entirely
• Managing symptoms and laboratory abnormalities
• Preventing, identifying, and treating the
complications of cirrhosis
• Determining the appropriateness and optimal timing
for liver transplantation
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Management of ascites
• Sodium restriction
• Fluid restriction
• Diuresis
• Paracentesis
• Side-to-side portacaval shunt
• Peritoneovenous shunt
• Transjugular intrahepatic portosystemic shunts
(TIPS)
Management of ascites
• Sodium restriction (20-30 mEq/d) and diuretic therapy constitute the
standard medical management for ascites and are effective in
approximately 95% of patients.
• Water restriction is used only if persistent hyponatremia is present
• Therapeutic paracentesis may be performed in patients who require
rapid symptomatic relief for refractory or tense ascites.
• The removal of 5 L of fluid or more is considered large-volume
paracentesis.
• Total paracentesis, that is, removal of all ascites (even >20 L), can
usually be performed safely.
Paracentesis
Major complications
• Shock
• Oliguria
• Hepatorenal syndrome
• Hemorrhage
• Perforation of abdominal vicera
• Infection, bacterial peritonitis
• Protein depletion
Upper gastrointestinal bleeding
• Major complication
• Incredible high mortality
• Source of bleeding:
esophageal varices
60%~80%
gastric varices
7%
congestive gastropathy
5%~20%
(peptic ulcer, acute erosive gastritis etc)
Upper GI Bleed ? Varices
• Resuscitation, multiple organ support,
• correction coagulopathy /thrombocytopenia
• Endotracheal intubation
• Septic screen& empirical antibiotics
• Medical therapy to reduce PHT
Emergency endoscopy
Esophageal Varices ELB/ES
Gastric Varices/ Cyanoacrylate Glue
Uncontrolled: Salvage therapy
Baloon temponade
Shunt - Surgical TIPS
Controlled : Secondary prophylaxis
EBI eradication program
+/- Beta blockade
Referral transplantation
Controlled : Secondary prophylaxis
Beta blockade
Consider transplantation
Consider TIPS/Surgery
CTP score may predict life expectancy in patients with advanced cirrhosis. A
CTP score of 10 or greater is associated with a 50% chance of death in 1 year
Child-Turcotte-Pugh Scoring System for Cirrhosis
Clinical Variable
1 Point
2 Points
3 Points
Grade 3-4
Encephalopathy
None
Grade 1-2
Moderate or large
Ascites
Absent
Slight
>3
Bilirubin (mg/dL)
<2
2-3
10
Bilirubin in PBC* or PSC**
<4
4-10
(mg/dL)
< 2.8
Albumin (g/dL)
>3.5
2.8-3.5
Prothrombin time(seconds
< 4 s or INR < 1.7 4-6 s or INR 1.7- >6 s or INR >2.3
prolonged or INR)
2.3
PBC = Primary biliary cirrhosis
**PSC = Primary sclerosing cholangitis
Child Class A = 5-6 points, Child Class B = 7-9 points, Child Class C = 10-15 points
Hepatic Encephalopathy:
Hepatic encephalopathy, a syndrome is marked by personality changes, intellectual
impairment, and a depressed level of consciousness. The symptoms of hepatic may be
observed in as many as 70% of patients with cirrhosis. Symptoms are graded on the
following scale:
• Grade 0 - Subclinical; normal mental
status but minimal changes in memory,
concentration, intellectual function,
coordination
• Grade 1 - Mild confusion, euphoria or
depression, decreased attention, slowing
of ability to perform mental tasks,
irritability, disorder of sleep pattern (ie,
inverted sleep cycle)
• Grade 2 - Drowsiness, lethargy, gross
deficits in ability to perform mental tasks,
obvious personality changes,
inappropriate behavior, intermittent
disorientation (usually with regard to time
• Grade 3 - Somnolent, but
arousable, state; inability to
perform mental tasks;
disorientation with regard to time
and place; marked confusion;
amnesia; occasional fits of rage;
speech is present but
incomprehensible
• Grade 4 - Coma, with or without
response to painful stimuli
Hepatorenal syndrome
• This syndrome represents a
continuum of renal dysfunction
that may be observed in patients
with a combination of cirrhosis
and ascites.
• Hepatorenal syndrome is
caused by the vasoconstriction
of large and small renal arteries
and the impaired renal perfusion
that results
• The syndrome is an imbalance
between renal vasodilators
vasoconstrictors
• Plasma levels of a number of
vasoconstricting substances—
including angiotensin,
antidiuretic hormone, and
norepinephrine—are elevated in
patients with cirrhosis.
• Renal perfusion appears to be
protected by vasodilators,
including prostaglandins E2 and
I2 and atrial natriuretic factor.
Slowing or reversing the progression of liver disease
• Patients with hepatitis C and
advanced fibrosis or cirrhosis
who achieve a sustained
virologic response (SVR) with
antiviral treatment
• Abstinence from alcohol
substantially improves survival
in alcoholic cirrhosis
• Successful treatment of
chronic viral hepatitis can
improve long-term outcomes
and may affect fibrosis
Preventing superimposed insults
to the liver
• Vaccinations — Vaccination
against hepatitis A and B for
those who are not already
immune can help prevent
superimposed insults to the
liver. Other vaccinations, such
a yearly influenza vaccination,
are also recommended
• Avoidance of hepatotoxins
• Medication adjustments
Liver transplantation
Latest advance in management of
cirrhosis includes liver transplantation.
Indications for liver transplantation need
to be carefully considered when medical
and surgical treatment options have failed.
Summary
• Cirrhosis is a condition in which the liver
slowly deteriorates and malfunctions due
to chronic injury, preventing the liver from
working as it should.
• Heavy alcohol consumption and chronic
hepatitis C have been the most common
causes of cirrhosis. Many people with
cirrhosis have more than one cause of liver
damage.
• Other causes of cirrhosis include hepatitis
B, hepatitis D, and autoimmune hepatitis;
diseases that damage or destroy bile ducts,
inherited diseases, and nonalcoholic fatty
liver disease; and drugs, toxins, and
infections.
• Many people with cirrhosis have no
symptoms in the early stages of the
disease. As the disease progresses,
symptoms may include weakness, fatigue,
loss of appetite, nausea, vomiting, weight
loss, abdominal pain and bloating, itching,
and spiderlike blood vessels on the skin.
• As liver function deteriorates, one or more
complications may develop. In some
people, complications may be the first
signs of the disease.
• The goals of treatment are to stop the
progression of scar tissue in the liver and
prevent or treat complications.
• Treatment for cirrhosis includes avoidance
of alcohol and other drugs, nutrition
therapy, and other therapies that treat
specific complications or causes of the
disease.
• Hospitalization may be necessary for
cirrhosis with complications.
• A liver transplant is considered when
complications of cirrhosis cannot be
controlled by treatment.