CIRRHOSIS

Dr akhondei

cirrhosis

Cirrhosis is a pathologically defined entity

that is associated with a spectrum of
characteristic clininical manifestation

1-Irreversible chronic injury of the

hepatic parenchyma
2-Extensive fibrosis
3-formation of regenerative
nodules

Normal liver

Cirrhosis of the liver is the third leading

cause of death in people between the
ages of 25 and 65 years, exceeded only
by cardiovascular disease and cancer.

The cost of cirrhosis in terms of human

suffering, financial burden, and loss of
productive life is devastating.

Patients with cirrhosis may present in

a variety of ways.

Variceal bleeding
New onset of ascites
Hepatomegaly and/or
splenomegaly

Patients with cirrhosis may present in

a variety of ways.

Incidental Discovery Of Abnormal

Laboratory Tests
Serum Aminotransferases,
Hypoalbuminemia,
Prolonged Prothrombin Time,
Hrombocytopenia)

Patients with cirrhosis may present

in a variety of ways.
Detection of the peripheral stigmata of
chronic liver disease such as
Jaundice,
Dupuytren's contracture,
Manifestations related to hyperestrogenemia
such as
o Spider angiomata,
o Palmar erythema,
o Gynecomastia, and testicular atrophy which may
also be related to low testosterone
concentrations

Patients with cirrhosis may present in

a variety of ways.

hepatic encephalopathy or one or

more complications or systemic
manifestations of hepatocellular
carcinoma
Some patients never come to
clinical attention. In older reviews,
cirrhosis was diagnosed at autopsy
in up to 30 to 40 percent of patients

Cirrhosis represents the terminal stage of a

number of chronic liver diseases including
those caused by
excessive ethanol consumption
Viral hepatitis
Drugs and toxins,
Vascular
Autoimmune
Metabolic disorders
Cryptogenic.
In some cases, no cause can be determined and the cirrhosis is

Early cirrhosis may be asymptomatic and

undetectable except by biopsy.
However, by the time cirrhosis becomes
clinically apparent, hepatic functional
reserve is markedly impaired.
If liver injury cannot be arrested, the
prognosis without intervention is poor

The onset of complications

(eg, ascites, encephalopathy, variceal
hemorrhage) indicates a more
advanced stage of disease and a poorer
prognosis, with median survival of
about 5 years or less.

CIRRHOSIS & PORTAL

HYPERTENSION

CIRRHOSIS

Term was 1st coined by Laennec in

1826
Many definitions but common theme is
injury, repair, regeneration and
scarring
NOT a localized process; involves
entire liver
Primary histologic features:
1.
2.
3.
4.

Marked fibrosis
Destruction of vascular & biliary elements
Regeneration
Nodule formation

Cirrhosis: Pathophysiology

Primary event is injury to hepatocellular

elements
Initiates inflammatory response with
cytokine release->toxic substances
Destruction of hepatocytes, bile duct cells,
vascular endothelial cells
Repair thru cellular proliferation and
regeneration
Formation of fibrous scar

Cirrhosis: Pathophysiology

Primary cell responsible for fibrosis is

stellate cell
Become activated in response to injury and
lead to ed expression of fibril-forming
collagen
Above process is influenced by Kupffer cells
which activate stellate cells by eliciting
production of cytokines
Sinusoidal fenestrations are obliterated
because of ed collagen and EC matrix
synthesis

Cirrhosis: Pathophysiology

Prevents normal flow of nutrients to

hepatocytes and increases vascular
resistance
Initially, fibrosis may be reversible if
inciting events are removed
With sustained injury, process of fibrosis
becomes irreversible and leads to
cirrhosis

Causes of Cirrhosis

Alcohol
Viral hepatitis
Biliary obstruction
Veno-occlusive disease
Hemochromatosis
Wilsons disease
Autommune
Drugs and toxins
Metabolic diseases
Idiopathic

Classification of Cirrhosis

WHO divided cirrhosis into 3 categories

based on morphological characteristics
of the hepatic nodules
1.
2.
3.

Micronodular
Macronodular
Mixed

Micronodular Cirrhosis

Nodules are <3 mm in diameter

Relatively uniform in size
Distributed throughout the liver
Rarely contain portal tracts or efferent
veins
Liver is of uniform size or mildly enlarged
Reflect relatively early disease

Macronodular & Mixed

Cirrhosis

Nodules are >3 mm in diameter and vary

considerably in size
Usually contain portal tracts and efferent
veins
Liver is usually normal or reduced in size
Mixed pattern if both type of nodules are
present in equal proportions

Cirrhosis - Alcohol

Also known as Laennecs cirrhosis

>50% of pts. with alcoholic cirrhosis die
within 4 yrs of diagnosis
Develops in only 10% to 30% of heavy
drinkers
Morphologically, micronodular pattern
Multifactorial - genetic, nutritional, drug
use and viral

Cirrhosis - Alcohol

Fatty liver, alcoholic hepatitis

Histology - megamitochondria, Mallory
bodies, inflammation, necrosis, fibrosis
Key mediator is acetaldehyde (ADH), the
product of alcohol metabolism by alcohol
dehydrogenase
ADH directly activates stellate cells,
inhibits DNA repair and damage
microtubules

NAFLD/NASH

Nonalcoholic Fatty Liver Disease and

Steatohepatitis
Becoming more common
Infiltration of the liver with fat
inflammation
Pathologically similar to alcoholic liver but
in absence of alcohol
Associated with obesity, hyperlipidemia,
NIDDM,

Viral Hepatitis

Most common cause of cirrhosis

worldwide (>50% of cases)
Incidence of cirrhosis in Hepatitis B pts.
is 1% and 10% in Hepatitis C pts.
Incidence increases to 70-80% in HBV
+ve pts. who are superinfected with HDV

DIAGNOSIS

Can be asymptomatic for decades

History
Physical findings: Hepatomegaly,
jaundice, ascites, spider angioma,
splenomegaly, palmar erythema, fetor
hepaticus, purpura etc.
Elevated LFTs, thrombocytopenia,

DIAGNOSIS

Definitive diagnosis is by biopsy or gross

inspection of liver
Noninvasive methods include US, CT
scan, MRI
Indirect evidence - esophageal varices
seen during endoscopy

Manifestations of Cirrhosis

Hepatorenal syndrome
Hepatic encephalopathy
Portal hypertension
Water retention
Hematologic
Hepatocellular carcinoma

Portal Hypertension (PH)

Portal vein pressure above the normal

range of 5 to 8 mm Hg
Portal vein - Hepatic vein pressure
gradient greater than 5 mm Hg (>12
clinically significant)
Represents an increase of the hydrostatic
pressure within the portal vein or its
tributaries

Pathophysiology of PH

Cirrhosis results in scarring (perisinusoidal

deposition of collagen)
Scarring narrows and compresses hepatic
sinusoids (fibrosis)
Progressive increase in resistance to portal
venous blood flow results in PH
Portal vein thrombosis, or hepatic venous
obstruction also cause PH by increasing
the resistance to portal blood flow

Pathophysiology of PH

As pressure increases, blood flow decreases

and the pressure in the portal system is
transmitted to its branches
Results in dilation of venous tributaries
Increased blood flow through collaterals and
subsequently increased venous return
cause an increase in cardiac output and
total blood volume and a decrease in
systemic vascular resistance
With progression of disease, blood pressure
usually falls

Portal Vein Collaterals

Coronary vein and short gastric veins ->

veins of the lesser curve of the stomach and
the esophagus, leading to the formation of
varices
Inferior mesenteric vein -> rectal branches
which, when distended, form hemorrhoids
Umbilical vein ->epigastric venous system
around the umbilicus (caput medusae)
Retroperitoneal collaterals ->gastrointestinal
veins through the bare areas of the liver

Etiology of PH

Causes of PH can be divided into

1.

Pre-hepatic

2.

Intra-hepatic

3.

Post-hepatic

Pre-hepatic PH

Caused by obstruction to blood flow at

the level of portal vein
Examples: congenital atresia, extrinsic
compression, schistosomiasis, portal,
superior mesenteric, or splenic vein
thrombosis

Post-hepatic

Caused by obstruction to blood flow at

the level of hepatic vein
Examples: Budd-Chiari syndrome,
chronic heart failure, constrictive
pericarditis, vena cava webs

Budd-Chiari Syndrome

Caused by hepatic venous obstruction

At the level of the inferior vena cava, the

hepatic veins, or the central veins within
the liver itself

result of congenital webs (in Africa and

Asia), acute or chronic thrombosis (in the
West), and malignancy

Budd-Chiari Syndrome

Acute symptoms include hepatomegaly, RUQ

abdominal pain, nausea, vomiting, ascites
Chronic form present with the sequelae of
cirrhosis and portal hypertension, including
variceal bleeding, ascites, spontaneous
bacterial peritonitis, fatigue, and
encephalopathy
Diagnosis is most often made by US
evaluation of the liver and its vasculature
Cross-sectional imaging using contrastenhanced CT or MRI

Budd-Chiari Syndrome

Gold standard for the diagnosis has been

angiography

Management has traditionally been surgical

intervention (surgical decompression with a
side-to-side portosystemic shunt)

Minimally invasive treatment using TIPS

may be first-line therapy now

Response rates to medical therapy are poor

Portal Vein Thrombosis

Most common cause in children (fewer

than 10% of adult pts.)
Normal liver function and not as
susceptible to the development of
complications, such as encephalopathy
Diagnosis by sonography, CT and MRI
Often, the initial manifestation of portal
vein thrombosis is variceal bleeding in a
noncirrhotic patient with normal liver
function

Portal Vein Thrombosis Causes

Umbilical vein infection (the most common

cause in children)
Coagulopathies (protein C and antithrombin
III deficiency),
Hepatic malignancy, myeloproliferative
disorders
Inflammatory bowel disease
pancreatitis
trauma
Most cases in adults are idiopathic

Portal Vein Thrombosis

Therapeutic options are esophageal

variceal ligation and sclerotherapy

Distal splenorenal shunt

Rex shunt in patients whose intrahepatic

portal vein is patent (most commonly
children)

Splenic Vein Thrombosis

Most often caused by disorders of the

pancreas (acute and chronic pancreatitis,
trauma, pancreatic malignancy, and
pseudocysts)
Related to the location of the splenic vein
Gastric varices are present in 80% of patients
Occurs in the setting of normal liver function
Readily cured with splenectomy (variceal
hemorrhage), although observation for
asymptomatic patients is acceptable.

Complications of PH

GI bleeding due to gastric and

esophageal varices
Ascites
Hepatic encephalopathy

Varices

Most life threatening complication is

bleeding from esophageal varices
Distal 5 cm of esophagus
Usually the portal vein-hepatic vein
pressure gradient >12 mm Hg
Bleeding occurs in 25-35% of pts. With
varices and risk is highest in 1st yr.

Prevention of Varices

Primary prophylaxis: prevent 1st episode

of bleeding
Secondary prophylaxis: prevent
recurrent episodes of bleeding
Include control of underlying cause of
cirrhosis and pharmacological, surgical
interventions to lower portal pressure

Prevention of Varices
Beta blockade: Beta blockade (Nadolol,
Propranolol)
Nitrates:Organic nitrates
Surgery: No longer performed *
Endoscopy: Sclerotherapy (no longer
used*) and variceal ligation
* Refers to primary prophylaxis

Treatment of Varices

Initial Management:
1.
2.
3.
4.
5.
6.

Airway control
Hemodynamic monitoring
Placement of large bore IV lines
Full lab investigation (Hct, Coags, LFTs,)
Administration of blood products
ICU monitoring

Pharmacologic Treatment of
Varices

Decreases the rate of bleeding

Enhances the endoscopic ability to
visualize the site of bleeding
Vasopressin - potent splanchnic
vasoconstrictor; decreases portal venous
blood flow and pressure
Somatostatin: decrease splanchnic blood
flow indirectly; fewer side effects
Octreotide: Initial drug of choice for acute
variceal bleeding

Endoscopic Therapy for

Varices

Endoscopic Sclerotherapy: complications

occur in 10-30% and include fever,
retrosternal chest pain, dysphagia,
perforation
Endoscopic variceal ligation: becoming
the initial intervention of choice; success
rates range from 80-100%

Balloon Tamponade

Sengstaken-Blakemore tube
Minnesota tube
Alternative therapy for pts. who fail
pharmacologic or endoscopic therapy
Complications: aspiration, perforation,
necrosis
Limited to 24 hrs; works in 70-80%

TIPS

Transjugular inrahepatic portasystemic

shunt
1st line treatment for bleeding esophageal
varices when earlier-mentioned methods
fail
Performed in IR
Success rates 90-100%
Significant complication is hepatic
encephalopathy

Surgical Intervention

Liver transplantation: only definitive

procedure for PH caused by cirrhosis
Shunts

Totally diverting (end-side portacaval)

Partially diverting (side-side portacaval)
Selective (distal splenorenal shunt)

Devascularization

Severe complications

such as spontaneous bacterial peritonitis

or ascites that is refractory to diuretic
therapy, occur in the most advanced
disease and are associated with a
median life expectancy of less than 1
year.

Cirrhosis, even if early and stable,

predisposes to development of primary
hepatocellular carcinoma in as many as
3% of patients per year.

Until recently, little could be done to

alter the prognosis of patients with
cirrhosis and most died of complications.
Today, the outlook has begun to change
because of advances in orthotopic liver
transplantation and development of
therapies to prevent and treat
complications.

Biologic Basis of hepatic fibrosis

Hepatic fibrosis is a wound-healing

response
The same cell type produce hepatic
fibrosis regardless of the underling
cause.
hepatic fibrosis follows chronic,but not
self-limited,injury.
Fibrosis occurs earliest in regions where
injury is most severe.

Antifibrotic therapies :
Rationale and specific
Agent
The
paradigm of satellite cell activation

provides an important framework to

define potential sites of antifibrotic
therapy follows
1.Cure the primary disease to prevent
injury.
2.Reduce inflammation or the host
response to avoid stimulating satellite
cells.
3.Directly down regulate stellate cell
activation

Antifibrotic therapies :Rationale and specific

Agent

4.Neutralize the
proliferative,fibrogenic,contractile,and
proinflammatory responses of stellate
cells.
5.Stimulate apoptosis of stellate cells.
6.Increase the degradation of scar
martix,either by stimulating cells that
produce matrix proteases,down-regulating
their inhibitors ,or directly administering
matrix proteases.

DIAGNOSTIC APPROACH

Unless the diagnosis is already

established, specific serologic tests and
often a liver biopsy are required to
establish the cause of the cirrhosis .

DIAGNOSTIC APPROACH

In addition, patients should undergo

laboratory testing to document the
severity of the disease and assessment
of whether ascites or hepatic
encephalopathy is present ..

DIAGNOSTIC APPROACH

Obtaining this information helps to

determine prognosis, the possibility of
specific therapy, and the possible
necessity for screening family members
for inherited diseases or chronic viral
hepatitis

specific therapy may be indicated

Antiviral therapy for chronic hepatitis

C and B,
Corticosteroids (with or without
immunosuppressive therapy) for
autoimmune hepatitis,
Phlebotomy for hereditary
hemochromatosis,
Penicillamine for Wilson's disease.

In some cases, even hepatic fibrosis can

be reversed; examples include
abstinence from alcohol in alcoholic liver
disease and immunosuppressive therapy
in autoimmune hepatitis

Progression of Hepatitis B Infection

Resolution

Short-term
Infection

Resolution

Long-term
Hepatitis

Long-term
Carrier

Silent
Cirrhosis

Cirrhosis

Cirrhosis

30 - 50 Years

Liver
Cancer

Death

Death

initial testing should consist of the following

Measurement of serum aminotransferases,

bilirubin, alkaline phosphatase, albumin,
creatinine, and sodium (otherwise
unexplained hyponatremia is a marker of
severe disease), the blood urea nitrogen,
platelet count, and prothrombin time
.

initial testing should consist of the following

Abdominal ultrasonography to assess

the portal circulation. In one study, the
severity of liver disease correlated with
portal vein blood velocity as determined
by ultrasound

Portal hypertension is the most common

and lethal complication of chronic liver
disease
Esophageal varices and hemorrhage
ascites renal dysfunction hypersplenism
portal-systemic encephalopathy
P H.. PPG>5mmHg

Hepatocellular
carcinoma

The issue of periodic surveillance of

such patients with serum alphafetoprotein (AFP) measurements
(values above 20 g/L being
abnormal) and ultrasound
examinations remains a contentious
issue from the viewpoint of costeffectiveness since an improvement
in survival has not yet been
demonstrate

All patients with cirrhosis should be

evaluated for the presence of varices
because of the beneficial effect of
prophylaxis with propranolol or nadolol

Patients with most forms of cirrhosis,

particularly due to hepatitis B and C,
hereditary hemochromatosis, and
alcoholic liver disease, are at high risk (1
to 6 percent per year) for the
development of hepatocellular
carcinoma

A.Cure the primary

disease
Clear chronic viral infection
Abstinence from alcohol,stop toxic drugs
Remove iron ,copper in overload disease
Eradicate schistosomiasis
Reverse biliary obstruction
Revers jejunoileal bypass

Nonalcoholic steatohepatitis NASH

NASH is a disorder diagnosed by liver

biopsy. The biopsy findings are
indistinguishable from those of alcoholic
hepatitis described above but the
patient lacks a history of significant
alcohol consumption. The liver disease is
stable in most patients but a minority
progress to cirrhosis

CIRRHOSIS & PORTAL HYPERTENSION

SURGICAL COMPLICATIONS

Turner Lisle

Resident Teaching Conference

May 2008

Cirrhosis
End result of anything that causes
hepatocellular
injury

Toxins, viruses, prolonged cholestasis,

autoimmunity, metabolic disorders

Pathologic response is uniform

Hepatocellular necrosis
Fibrosis
Nodular regeneration

Cirrhosis - why do we care

Hepatic failure
Portal hypertension - variceal bleeding

Ischemia & autoimmune factors thought

to play a role, although mechanism is not
clear

Anatomy

Dual blood supply

Total hepatic blood flow ~1500 mL/min or

25% of cardiac output
Portal vein

Hepatic arterial
Portal venous

2/3 of total hepatic blood flow

Hepatic artery

>1/2 of O2

Portal Hypertension

Usually due to increased portal venous

resistance
Classification based on site of increased
resistance

Prehepatic
Intrahepatic

Prehepatic Portal HTN

Portal vein thrombosis most common

Isolated splenic vein thrombosis

Usually caused by pancreatic inflammation

or neoplasm
Results in gastrosplenic HTN with ensuing
formation of gastric varices
Normal superior mesenteric & portal vein
pressure
Easily reversed by splenectomy alone

Intrahepatic Portal HTN

Often a combination of pre-, intra-, or post-sinusoidal

Presinusoidal

Schistosomiasis
Nonalcoholic cirrhosis

Sinusoidal

EtOH

Postsinusoidal - overall rare

EtOH
Budd-Chiari syndrome (hepatic vein thrombosis)
Constrictive pericarditis
Heart failure

Portal Hypertension

Portal pressure > 5 mmHg

Portal pressure > 8 mmHg needed for
collateralization

Collateralization

Evaluation of the Cirrhotic

1)
2)
3)
4)
5)

Dx of underlying liver disease

Estimation of fxn hepatic reserve
Definition of portal venous anatomy
Hepatic hemodynamic evaluation
If present, identification of site of UGI
bleeding

Evaluation of the Cirrhotic

Physical Exam

Jaundice
Ascites
Caput medusae
Asterixis
Spider angiomas
Palmer erythema
Testicular atrophy
Gynecomastia
+/- Palpable spleen
(portal HTN)

Lab tests

Anemia
Thrombocytopenia
Coagulopathy
Hypoalbuminemia
AST/ALT
Bili
Alk Phos
GGT
Hepatitis serologies
-fetoprotein

Liver biopsy

Cause of cirrhosis
Activity of liver disease
Approaches

Percutaneous (avoid with ascites or INR)

Transjugular venous
Laparoscopic
Open

Hepatic Functional Reserve

CHILD-PUGH

Encephalopathy grade
Amount of ascites
Bilirubin
Albumin
PT (INR)

Operative mortality

A (5%)
B (10-15%)
C (25%)

Subjective

MELD

Bilirubin
INR
Creatinine
Cr Max = 4.0 mg/dL
On dialysis calculate
with CR = 4.0 mg/dL

Calculators on the web

MELD 5-20
1% increase in mortality with each integer rise in
MELD score

MELD >20
Additional 2% increase in mortality with each integer
rise in MELD score

Diagnosis of bleeding

NGT decompression & lavage

Endoscopy - key procedure for UGIB
UGIB with portal HTN

90% due to varices

10% other causes (Mallory-Weiss tears, ulcers,
etc)

Majority are esophagogastric varices

Isolated gastric varices

Likely splenic vein thrombosis

Variceal Hemmorrhage

Single most life threatening complication of

portal HTN
Risk of death is related to the underlying hepatic
functional reserve
Pathogenesis of rupture incompletely understood

Multifactorial
Portal pressure >12mmHg

Treatment

Control the bleeding

Control the portal HTN

Treatment of acute variceal

bleeding
Emergency tx should be non-operative

Resuscitation first
Endoscopy

Pharmacotherapy

Successful in >85%
Vasopressin +/- NTG
Somatostatin/Octreotide (fewer complications)

Balloon tamponade (rare)

TIPS

Endoscopic treatment

Most common treatment modality for

acute bleeding as well as prevention
Sclerosis
Ligation
Equally efficacious (80-9
Complications

Esophageal ulceration
Perforation
Worsening hemorrhage
Aspiration

Failure after two unsuccessful attempts

Sengstaken-Blakemore tube

as pharmacotherapy and endo

Has been shown to be as effec
Potentially lethal complications
-esophageal perforation
-ischemic necrosis of esophagus

May be life saving

Deflation followed by
high re-bleeding rate

TIPS
Transjugular Intrahepatic Portosystemic Shunt

Portal decompression without surgery

(nonselective shunt)
Not recommended as initial therapy for
acute variceal bleeding
Preferred tx when pharmacotherapy and
endoscopic means have failed
Best when used as a bridge to transplant
Problems include shunt stenosis/occlusion,
encephalopathy (50% at 1-year)

Emergency surgery

Indications

Failure of acute endoscopic tx

Failure of TIPS placement
Hemorrhage from gastric varices

Esophageal transection rapid/simple

Portacaval shunt or splenorenal shunt
Operative mortality >25% in most series

Prevention of recurrent
hemorrhage
Likelihood of repeat episodes >70%

Goals

Prevention of recurrent bleeding

Maintenance of satisfactory hepatic function

Options

Pharmacotherapy (-blockers +/- nitrates)

Chronic endoscopy (successful in 2/3)
TIPS (less bleeding, more encephalopathy)
Operative shunts
Transplantation

Portosystemic shunts

Most effective means of preventing

recurrent bleeding in patients with portal
hypertension
Problems

Encephalopathy
Accelerated hepatic failure

Types

Nonselective - End-to-end/side portocaval

Selective - Distal splenorenal
Partial - Small diameter PTFE

Nonshunt procedures
Objectives

Ablation of varices
Extensive interruption of collateral vessels

Options

Transection and reanastamosis of the distal

esophagus
Extensive esophagogastric devascularization +
esophageal transection and splenectomy

Rebleeding rates similar to endoscopic

experience

Ascites

Usually an indicator of advanced cirrhosis

Initiated by altered hepatic and splanchnic
hemodynamics
Intravascular volume deficit resulting in
increased aldosterone..
Central goal is to achieve a NEGATIVE
sodium balance

Ascites treatment

Dietary restriction
Dietary restriction + Diuretics

5-10% are refractory

spironolactone +/- lasix

Intermittent paracentesis
TIPS
Peritoneovenous Denver shunt (rarely used)

SBP

PMN >250/mm3 or positive culture

Encephalopathy

Variety of manifestations
Pathogenesis - circulating cerebral toxins

Precipitated by multiple factors

Ammonia
Mercaptans
-aminobutyric acid
Shunts, hemorrhage, excessive diuresis, azotemia,
infection, increased dietary protein, sedatives

Management

Eliminate/treat precipitating factors

Lactulose, neomycin (decrease absorption of intestinal
ammonia)

Questions