Cirrhosis and its Complications

Definition
Histopathologically defined chronic liver disease
o Consists of the development of fibrosis to the
point that there is architectural distortion with
the formation of regenerative nodules
o Results in a net decrease in hepatocellular
mass, and thus function, and an alteration of
blood flow
o Previously thought to be irreversible; however,
it has become apparent that when the
underlying insult that has caused the cirrhosis
has been removed, there can be reversal of
fibrosis.
o The pathologic process of cirrhosis should be
viewed as a final common pathway of many
types of chronic liver injury.
Types of cirrhosis include:
o Alcoholic cirrhosis
End-stage liver disease due to the excessive
and chronic ingestion of alcohol
Regenerative nodules are usually < 3 mm in
diameter and referred to
asmicronodular; however, with cessation of
alcohol use, larger nodules may form,
resulting in a mixed micronodular and
macronodular cirrhosis.
o Posthepatitic cirrhosis
Causes include chronic viral hepatitis B or C
infection, autoimmune hepatitis,
nonalcoholic fatty liver disease, and
inherited metabolic liver disease.
The liver is small and shrunken with
characteristic features of a mixed micro-
and macronodular cirrhosis seen on liver
biopsy.
In addition to increased fibrosis, an
inflammatory infiltrate is found in portal
areas with interface hepatitis and
occasionally some lobular hepatocellular
injury and inflammation.
o Biliary cirrhosis
Results from injury to or prolonged
obstruction of either the intrahepatic or
extrahepatic biliary system
Cholestatic liver disease may result from
necroinflammatory lesions, congenital or
metabolic processes, or external bile duct
compression.
o Cardiac cirrhosis
Patients with long-standing right-sided
congestive heart failure may develop
chronic liver injury and cardiac cirrhosis.
Increasingly uncommon given the advances
made in the care of patients with heart
failure
o Cryptogenic cirrhosis
Reserved for those cases in which the
etiology of cirrhosis is unknown


Epidemiology
*Alcohol and post-hepatitis are common in the
Philippines

Risk Factors
Alcoholic cirrhosis
o Heavy alcohol consumption
o Cirrhosis is significantly accelerated if
concomitant hepatitis C virus infection is
present.
Risk factors for hepatitis B virus
o Persons who engage in unprotected sex with
multiple partners
Especially men who have sex with men
o Injection drug users
Risk factors for hepatitis C virus
o Injection drug users
o Health care workers
o Hemodialysis
o Organ transplantation
o Persons who engage in unprotected sex with
multiple partners
Etiology
Pathogenesis
o Final common pathway of many types of
chronic liver injury
o Chronic injury of the hepatic parenchyma leads
to extensive fibrosis in association with the
formation of regenerative nodules.
o Activation of the hepatic stellate cell is the
central event leading to hepatic fibrosis.
o The fibrosis may be reversed once the
underlying insult has been removed.
Following successful treatment of chronic
hepatitis C or hemochromatosis
In patients with alcoholic liver disease who
have discontinued alcohol use
Causes of cirrhosis

o Alcoholism
o Chronic viral hepatitis
Hepatitis B
Hepatitis C
o Autoimmune hepatitis
o Nonalcoholic steatohepatitis
o Inherited metabolic liver disease
Hemochromatosis
Wilson disease

1
Antitrypsin deficiency
Cystic fibrosis
o Biliary cirrhosis
Primary biliary cirrhosis (PBC)
Primary sclerosing cholangitis (PSC)
Autoimmune cholangiopathy
Idiopathic adulthood ductopenia
o Cardiac cirrhosis
o Cryptogenic cirrhosis

Symptoms & Signs
General
o May be asymptomatic
o Anorexia
o Weight loss
o Fatigue/weakness
o Reduction in skeletal muscle mass/muscle
wasting
Skin and hair
o Progressive jaundice
o Spider angiomas
o Palmar erythema
o Pruritus
o Xanthelasmas
o Xanthomas
o Decreased body hair
o Melanosis (primary biliary cirrhosis)
Abdomen
o Firm, nodular liver
o Splenomegaly
o Ascites
Increasing abdominal girth
Shortness of breath (elevation of
diaphragm)
Shifting dullness
Fluid wave
Bulging flanks
Endocrine
o Gynecomastia
o Testicular atrophy
o Menstrual irregularities
o Signs of virilization in women
Hematologic/vascular
o Caput medusa
o Easy bruising and bleeding
o Hematemesis/bleeding from gastroesophageal
varices
o Melena
Other
o Encephalopathy
o Parotid and lacrimal gland enlargement
o Digital clubbing
o Melanosis: gradual darkening of the exposed
areas of the skin
o Steatorrhea
o Edema

Diagnostic Approach
Alcoholic cirrhosis
Diagnosis is based on clinical features, physical
examination findings, and laboratory studies.
o Requires accurate knowledge that the patient
is continuing to use and abuse alcohol
Other causes of chronic liver disease must be
considered and ruled out.
o Only 1015% of individuals with excessive
alcohol intake develop cirrhosis.
o If other forms of chronic liver disease are
present, an estimate of relative causality along
with the alcohol use should be determined.
Liver biopsy
o Can be helpful to confirm a diagnosis
o Generally withheld until abstinence has been
maintained for at least 6 months in order to
determine residual, nonreversible disease
Posthepatitic and cryptogenic cirrhosis
Should be suspected in patients with signs and
symptoms of cirrhosis or portal hypertension
Needle or operative liver biopsies confirm the
diagnosis.
PBC
PBC should be considered in middle-aged women
with unexplained pruritus or elevated serum
alkaline phosphatase with other clinical or
laboratory features of protracted impairment of
biliary excretion.
Positive serum antimitochondrial antibody
determination provides important diagnostic
evidence.
Liver biopsy should be performed to confirm
diagnosis.
Secondary biliary cirrhosis
Should be considered in any patient with clinical
and laboratory evidence of prolonged obstruction
to bile flow, especially when there is a history of:
o Previous biliary tract surgery or gallstones
o Bouts of ascending cholangitis
o Right upper quadrant pain
Cholangiography (either percutaneous or
endoscopic) usually demonstrates underlying
pathologic process.
Liver biopsy, although not always necessary from a
clinical standpoint, can document the
development of cirrhosis.
Cardiac cirrhosis
Signs and symptoms of heart failure usually
overshadow liver disease.
Presence of firm, enlarged liver with signs of
chronic liver disease in patients with valvular heart
disease, constrictive pericarditis, or cor pulmonale
of long duration (> 10 years) should suggest
cardiac cirrhosis.
Liver biopsy can confirm the diagnosis but is often
contraindicated because of coagulopathy or
ascites.
Metabolic, hereditary, drug-related, and other types of
cirrhosis
May be suggested by individual features obtained
by history, examination, or laboratory
Usually requires additional disease-specific testing
and liver biopsy to confirm the diagnosis
Laboratory Tests
General
o Anemia
Microcytic due to blood loss
Macrocytic due to folate deficiency
o Pancytopenia due to hypersplenism
o Prolonged prothrombin time (PT), rarely overt
disseminated intravascular coagulation
o Hyponatremia can be seen with ascites.
o Hypokalemic alkalosis
o Glucose disturbances
o Hypoalbuminemia
Hepatitis serologies
o HBsAg
o Anti-HBc
o Anti-HBs
o HBeAg
o Anti-Hbe
o HBV DNA levels
o Anti-HCV
o HCV RNA levels
o HCV genotype
o Anti-HDV
Hemochromatosis
o Iron
o Total iron-binding capacity
o Ferritin
Autoimmune hepatitis
o Antinuclear antibody
o Anti-smooth-muscle antibody
Alcoholic cirrhosis
o Anemia
Folic acid and B
12
deficiency
Hypersplenism
Direct suppressive effect of alcohol on the
bone marrow
Zieves syndrome is a unique form of
hemolytic anemia (with spur cells and
acanthocytes) that can occur in patients
with severe alcoholic hepatitis.
o Hyperbilirubinemia
o Elevated aminotransferases with aspartate
aminotransferase (AST)/alanine
aminotransferase (ALT) ratio 2:1
o Elevated ammonia levels
PBC
o Antimitochondrial antibody (AMA)
Present in ~ 90% of patients with PBC
Present in < 5% of patients with other liver
diseases
o Cholestatic liver enzyme abnormalities
Elevation in -glutamyl transpeptidase and
alkaline phosphatase (ALP)
Mild elevations in aminotransferases (ALT
and AST).
Immunoglobulins, particularly IgM, are
typically increased.
Hyperbilirubinemia is usually seen once
cirrhosis has developed.
PSC
o Most patients have at least a 2-fold increase in
ALP and may have elevated aminotransferases
as well.
o Perinuclear antineutrophil cytoplasmic
antibody (P-ANCA) is positive in about 65% of
patients with PSC.
Cardiac cirrhosis
o ALP levels are characteristically elevated.
o Aminotransferases may be normal or slightly
increased with AST usually higher than ALT.
Miscellaneous
o Ceruloplasmin
o
1
antitrypsin (and pi typing)
Imaging
Abdominal ultrasound with doppler, CT, or MRI
may show:
o Cirrhotic liver
o Splenomegaly
o Development of collateral vessels
o Venous thrombosis, if present
MRI with magnetic resonance
cholangiopancreatography (MRCP)
o Imaging technique of choice for initial
evaluation of PSC
o Typical cholangiographic findings in PSC are
multifocal stricturing and beading involving
both the intrahepatic and extrahepatic biliary
tree.
Diagnostic Procedures
Liver biopsy (percutaneous, transjugular, or open)
o Required for definitive diagnosis of cirrhosis
Classification
Child Pugh Turcotte (CPT) classification[1]
o Widely used
o Based on clinical and laboratory values
o Class predicts survival, development of
complications, response to surgical procedures
Model for End Stage Liver Disease (MELD)[1]

o Predicts 3-month mortality
o Used to prioritize liver transplant applicants on
waiting list in U.S.
o Based on creatinine, bilirubin, and
international normalized ratio
Treatment Approach
General
o Specific treatment is often directed at
complications.
o Liver transplantation is an option for selected
patients.
Alcoholic cirrhosis
o Abstinence is the cornerstone of therapy.
o Patients also require good nutrition and long-
term medical supervision in order to manage
underlying complications that may develop.
Posthepatitic
o Antiviral therapy can be beneficial in patients
with chronic hepatitis B or C.
o Immunosuppressive therapy may help some
patients with autoimmune hepatitis.
PBC
o No specific therapy
o Ursodiol has been shown to improve
biochemical and histologic features.
o Cholestyramine may reduce pruritus and
hypercholesterolemia.
Cardiac cirrhosis
o Focuses on treatment of underlying cardiac
disorder
Treatment of complications
Variceal bleeding
Acute hemorrhage
o Intensive care unit monitoring
o Intravenous fluids and blood product
replacement
o Vasoconstrictors (somatostatin or octreotide)
Direct splanchnic vasoconstrictors
o Somatostatin 250 g bolus followed by
250 g/h
o Octreotide 50100 g/h
Vasopressin is no longer commonly used.
o Balloon tamponade (esophageal and gastric)
can be used in patients who cannot get
endoscopic therapy immediately or who need
stabilization prior to endoscopic therapy.
o Endoscopic intervention
First-line treatment
Variceal band ligation is used to control
acute bleeding in over 90% of cases and
should be repeated until obliteration of all
varices is accomplished.
Some endoscopists will use variceal
injection therapy (sclerotherapy) as initial
therapy, particularly when bleeding is
vigorous.
o Transjugular intrahepatic portosystemic shunt
(TIPS)
Should be reserved for those individuals
who fail endoscopic or medical
management or who are poor surgical risks
Sometimes used as a bridge to
transplantation
Encephalopathy can occur in as many as
20% of patients after TIPS.
o Surgical esophageal transsection is a procedure
that is rarely used and generally is associated
with a poor outcome.
Prevention of recurrent bleeding
o Usually requires repeated variceal band
ligation until varices are obliterated
o Beta blockade may be of adjunctive benefit.
o Portosystemic shunt surgery
Less commonly performed with the advent
of TIPS
Should be considered for patients with
good hepatic synthetic function who could
benefit by having portal decompressive
surgery
o TIPS
o Liver transplantation
Splenomegaly
Usually requires no specific treatment
Splenectomy
o Can be successfully performed under very
special circumstances
o Should be avoided in patients eligible for liver
transplantation
See Splenomegaly.
Ascites
Patients with small amounts of ascites can usually
be managed with dietary sodium restriction alone.
o < 2 g of sodium per day
o Patients are frequently surprised to realize how
much sodium is in the standard U.S. diet, and
thus it is important to make educational
pamphlets available to the patient.
When a moderate amount of ascites is present,
diuretic therapy is usually necessary.
o Spironolactone 100200 mg/d; maximum: 400
mg/d
o Furosemide 40 mg/d; maximum: 160 mg/d
may be added
Refractory ascites
o Ascites still present despite maximal dosages of
diuretics in patients who are compliant with a
low-sodium diet
o Treatment options
Repeated large-volume paracentesis
TIPS
See Ascites.
Spontaneous bacterial peritonitis
Empirical therapy should cover gram-negative
aerobic bacilli and gram-positive cocci; empirical
coverage for anaerobes is not necessary.
o Third-generation cephalosporins
Cefotaxime (2g q8h IV) for moderately ill
patients
o Broad-spectrum antibiotics (another option)
Piperacillin/tazobactam (3.375 g q6h IV)
Ceftriaxone (2 g q24h IV)
After organism is identified, treatment should
target specific pathogen.
Duration of therapy
o Can be administered for 5 days if rapid
improvement occurs, blood cultures are
negative
o Administer for up to 2 weeks if improvement is
slow; blood cultures are positive
o In patients who have had an episode of
spontaneous bacterial peritonitis (SBP) and
recovered, once-weekly administration of
antibiotics is used as prophylaxis for recurrent
SBP.
Hepatorenal syndrome
Treatment has been difficult and unsuccessful.
Currently patients are treated
with midodrine with octreotide and
intravenousalbumin.
The best therapy is liver transplantation.
Hepatic encephalopathy
Hydration and correction of electrolyte imbalance
are sometimes adequate therapy.
Lactulose 30120 mL, 14 times daily to promote
23 stools a day
Poorly absorbed antibiotics are often used as
adjunctive therapies for patients who have had a
difficult time with lactulose.
o The alternating administration
of neomycin and metronidazole has commonly
been employed to reduce the individual side
effects of each.
Neomycin 5001000 mg qid
Metronidazole 250 mg tid
o More recently, rifaximin has been very
effective in treating encephalopathy without
the known side effects of neomycin or
metronidazole.
Zinc supplementation is sometimes helpful in
patients with encephalopathy and is relatively
harmless.
Coagulopathy
If asymptomatic, no specific treatment
Vitamin K: intravenous or intramuscular
o Can correct coagulopathy from cholestatic
disease due to diminished absorption of
vitamin K
o More commonly, the synthesis of vitamin K
dependent clotting factors is diminished
because of a decrease in hepatic mass and
administration of parenteral vitamin K will not
improve the clotting factors or the
prothrombin time.
If bleeding
o Platelet transfusion if thrombocytopenic
o Fresh-frozen plasma if prolonged PT
o Preliminary studies: Selective replacement of
factor VII can correct PT.
Hepatopulmonary syndrome
No specific treatment
Embolization of large arteriovenous shunts
Liver transplantation if advanced pulmonary
hypertension is not present
o Select patients

Prognosis
In the U.S., chronic liver disease is the 10th most
common cause of death in adults.
Alcoholic cirrhosis
o Accounts for ~40% of deaths due to cirrhosis
o Patients who have had a major complication of
cirrhosis and who continue to drink have a 5-
year survival of < 50%.
o Patients who remain abstinent have a
substantially better prognosis.
Liver transplantation is a viable option.
Posthepatitic and cryptogenic cirrhosis
o Approximately 75% of patients have
progressive disease despite supportive
therapy.
o Typically, patients die within 15 years of
complications.
Variceal hemorrhage
Hepatic encephalopathy
Superimposed hepatocellular carcinoma
Complications
o Esophageal varices
Approximately one-third of patients with
histologically confirmed cirrhosis have
varices.
Roughly one-third of patients with varices
will develop bleeding.
2030% mortality associated with each
episode of bleeding.
o Ascites
Poor prognosis
Some studies have shown that < 50% of
patients survive 2 years after the onset of
ascites.
o SBP
Can occur in up to 30% of patients with
cirrhosis and ascites severe enough for
hospitalization
In-hospital mortality rate is 25%.
Prevention
Alcoholic liver disease can be prevented by limiting
alcohol intake.
o Men should drink less than 40 g/d.
o Women should drink less than 20 g/d.
Prevention of first variceal hemorrhage in patients
with large varices
o Nonselective -adrenergic antagonists
Propranolol or nadolol
Decreases the incidence of bleeding by 40
50%
Decrease in mortality but only from variceal
bleeding, not overall mortality
o Endoscopic variceal ligation
Prevention of recurrent bleeding variceal
hemorrhage
o Usually requires repeated variceal band
ligation until varices are obliterated
o Beta blockade may be of adjunctive benefit.
o Portosystemic shunt surgery
Less commonly performed with the advent
of TIPS
Should be considered for patients with
good hepatic synthetic function who could
benefit by having portal decompressive
surgery
o TIPS
o Liver transplantation
SBP
o In 1 study, norfloxacin was shown to
significantly reduce the incidence of SBP at 1
year and increase survival in patients with
advanced cirrhosis.[4]