CIRRHOSIS

Dr. Vishvas
Anatomy
 Cirrhosis

• Is a late sage of scarring (fibrosis) of the liver caused by many forms of

liver disease and condition such as hepatitis and chronic alcoholism

• Cirrhosis of the liver is one of the ten leading causes of death in

western world.
• It represent the irreversible end-stage several diffusion disease
causing hepatocellular injury
• Fallowing are
• It involve the entire liver

• The normal lobular architecture of hepatic parenchyma is disorganised

• There is formation of nodules separated from one another by irregular

bands of fibrosis

• It occurs following hepatocellular necrosis of varying etiology.

Additionally alternate area of necrosis and regeneration nodules.
However, regenerative nodules are not essential for diagnosis of cirrhosis
since biliary cirrhosis and haemochromatosis have little regeneration
 Pathogenesis

Irrespective of the etiology, cirrhosis in general is initiated by

hepatocellular necrosis.

Continued destruction of hepatocytes causes collapse of normal lobular

hepatic parenchyma followed by fibrosis around necrotic liver cells and
proliferated ductulus and there is formation of compensatory
regenerative nodules.
 FIBROGENESIS
• Liver lobules
• The mechanism of fibrosis is by increase synthesis of all type of
collagen and increase in the number of collagen producing cells.

In cirrhosis there is proliferation of fat storing cells underlying the

sinusoidal epithelium which become transformed into myofibroblast
and fibrocytes.

Beside collagen two glycoprotein, fibronectin and laminin are deposited

in excessive amount in area of liver cell damage
• The nature of factor acting as stimulants for fibrosis is not Clearly
known

Regenerative nodule : The cause of compensatory proliferation of

hepatocytes to form regenerative nodules is obscure. Possibly, growth
factors, chalones and hormonal imbalance, play a role in regeneration.
Cirrhosis can be classified on the basis of
morphology and etiology
A. MORPHOLOGIC CLASSIFICATION.

There are 3 morphologic types of cirrhosis—micronodular, macronodular and

mixed. Each of these forms may have an active and inactive form

An active form is characterized by continuing hepatocellular necrosis and

inflammatory reaction, a process that closely resembles chronic hepatitis.
An inactive form, on the other hand, has no evidence of continuing
hepatocellular necrosis and has sharply-defined nodules of surviving hepatic
parenchyma without any significant inflammation.
1. Micronodular cirrhosis.
In micronodular cirrhosis, the nodules are usually regular and small, less
than 3 mm in diameter.

There is diffuse involvement of all the hepatic lobules forming nodules by

thick fibrous septa which may be portal-portal, portal-central, or both.

The micronodular cirrhosis includes etiologic type of alcoholic cirrhosis

and represents impaired capacity for regrowth as seen in alcoholism,
malnutrition, severe anemia and old age.
• 2. Macronodular cirrhosis.
In this type, the nodules are of variable size and are generally larger
than 3 mm in diameter.
The pattern of involvement is more irregular than in micronodular
cirrhosis,
sparing some portal tracts and central veins, and more marked
evidence of regeneration.
Macronodular cirrhosis corresponds to post-necrotic (or post
hepatitis) cirrhosis of the etiologic classification.
Mixed Cirrhosis

• In mixed type, some parts of the liver show micronodular appearance while other
parts show macronodular pattern.
• All the portal tracts and central veins are not involved by fibrosis but instead
some of them are spared.
• Mixed pattern is a kind of incomplete expression of micronodular cirrhosis.
ETIOLOGIC CLASSIFICATION
Alcoholic Liver Disease and Cirrhosis
• Alcoholic liver disease is the term used to describe the spectrum of liver injury
associated with acute and chronic alcoholism.
• There are three sequential stages in alcoholic liver disease:
1) ALCHOLIC STEATOSIS (FATTY LIVER)
2) ALCOHOLIC HEPATITIES
3) ALCOHOLIC CIRRHOSIS
ETHANOL METABOLISM
• One gram of alcohol gives 7 calories. But alcohol cannot be stored in the body
and must undergo obligatory oxidation, chiefly in the liver.

• Thus, these empty calories make no contribution to nutrition other than to give
energy.

• Ethanol after ingestion and absorption from the small bowel circulates through
the liver where about 90% of it is oxidized to acetate by a two-step enzymatic
process involving two enzymes: alcohol dehydrogenase (ADH) present in the
cytosol, and acetaldehyde dehydrogenase (ALDH) in the mitochondria of
hepatocytes . The remaining 10% of ethanol is oxidized elsewhere in the body.
1st step
• Ethanol is catabolized to acetaldehyde in the liver by the following three
pathways, one major and two minor:
i) In the cytosol, by the major rate-limiting pathway of alcohol dehydrogenase
(ADH).
ii) ii) In the smooth endoplasmic reticulum, via microsomal P-450 oxidases (also
called microsomal ethanol oxidising system, MEOS), where only part of ethanol
is metabolised.
iii) iii) In the peroxisomes, minor pathway via catalase such as H2O2.
Acetaldehyde is toxic and may cause membrane damage and cell necrosis.
Simultaneously, the cofactor nicotinamide adenine dinucleotide (NAD) which is a
hydrogen acceptor, is reduced to NADH
2 step
nd

• The second step occurs in the mitochondria where acetaldehyde is converted to

acetate with ALDH acting as a co-enzyme.
• Most of the acetate on leaving the liver is finally oxidized to carbon dioxide and
water, or converted by the citric acid cycle to other compounds including fatty
acids
• the same cofactor, NAD, is reduced to NADH resulting in increased NADH: NAD
redox ratio which is the basic biochemical alteration occurring during ethanol
metabolism.
• A close estimate of NADH:NAD ratio is measured by the ratio of its oxidized and
reduced metabolites in the form of lactate-pyruvate ratio and β-hydroxy
butyrate-acetoacetate ratio
RISK FACTORS FOR ALCOHOLIC LIVER
DISEASE
1. Drinking patterns
2. Gender
3. Malnutrition
4. Infection
5. Genetic Factors
6. Hepatitis C infection
1 drinking pattern

• excessive consumption of alcohol invariably leads to fatty liver in >90% of chronic

alcoholics, progression to alcoholic hepatitis in 10-20% cases, and eventually to
alcoholic cirrhosis in more than 10 years.

• It is generally agreed that continued daily consumption of 60-80 gm of ethanol in

any type of alcoholic beverage for at least 10 years is likely to result in alcoholic
cirrhosis.

• Liver injury is related to the quantity of ethanol contained in alcoholic beverage

consumed and its duration
2. Gender.
• Women have increased susceptibility to develop advanced alcoholic
liver disease with much lesser alcohol intake (20-40 g/day). This
gender difference in disease progression is unclear but is probably
linked to effects of oestrogen.
3. Malnutrition
• Absolute or relative malnutrition of proteins and vitamins is regarded
as a contributory factor in the evolution of cirrhosis.

• The combination of chronic alcohol ingestion and impaired nutrition

leads to alcoholic liver disease and not malnutrition

• It appears that calories derived from alcohol displace other nutrients

leading to malnutrition and deficiency of vitamins in alcoholics.

• Additional factors contributing to malnutrition in alcoholics are

chronic gastritis and pancreatitis.
4. Infections
• Intercurrent bacterial infections are common in cirrhotic patients and
may accelerate the course of the disease.

• Lesions similar to alcoholic cirrhosis may develop in non-alcoholic

patients who have had viral infections in the past
5. Genetic factors
• The rate of ethanol metabolism is under genetic control. It is chiefly
related to altered rates of elimination of ethanol due to genetic
polymorphism for the two main enzyme systems, MEOS (microsomal
P-450 oxidases) and alcohol dehydrogenase (ADH).
6. Hepatitis C infection.
• Concurrent infection with HCV is an important risk factor for
progression of alcoholic liver disease.

• HCV infection in chronic alcoholic leads to development of alcoholic

liver disease with much less alcohol consumption (20-50 g/day),
disease progression at a younger age, having greater severity, and

• increased risk to develop cirrhosis and hepatocellular carcinoma, and

overall poorer survival.
 Pathogenesis

• Exact pathogenesis of alcoholic

liver injury is yet unclear as to why
only some chronic alcoholics
develop the complete sequence of
changes in the liver while others
don’t

• now it is known that ethanol and

its metabolites are responsible for
ill-effects on the liver in a
susceptible chronic alcoholic having
above-mentioned risk factors.
1. Direct hepatotoxicity by ethanol.

There is evidence to suggest that ethanol ingestion for a period of

8-10 days regularly may cause direct hepatotoxic effect on the liver and
produce fatty change.
Ethanol is directly toxic to microtubules, mitochondria and
membrane of hepatocytes
• 2. Hepatotoxicity by ethanol metabolites.
Hepatotoxic effects of ethanol are exerted by its metabolites, chiefly
acetaldehyde. Acetaldehyde levels in blood are elevated in chronic
alcoholics. Acetaldehyde produces hepatotoxicity by production of two
adducts:

i) Production of protein-aldehyde adducts which are extremely toxic

and can cause cytoskeletal and membrane damage and necrosis

ii) Formation of malon-di-aldehyde-acetaldehyde (MAA) adducts

which produce autoantibodies and initiate autoimmune response.
role in hepatic fibrogenesis due to peroxisome proliferator-activated
receptor (PPAR)-γ on hepatocytes.
3. Oxidative stress.
Oxidation of ethanol by the cytochrome450 oxidases (MEOS) leads
to generation of free radicals which causes oxidative damage to the
membranes and proteins.

4. Immunological mechanism.
Ethanol causes direct immunologic attack on hepatocytes. cessation
of alcohol consumption which is attributed to immunologic
mechanisms.
5. Inflammation.
Chronic ethanol ingestion is not only injurious to hepatocytes but
also damages the intestinal cells.
endotoxins which release proinflammatory cytokines, chiefly
tumour necrosis factor-α, IL-1, IL-6 and TGF-β.
These cytokines and endotoxinaemia produce apoptosis and
necrosis of hepatocytes and initiate inflammatory reaction in the
alcohol damaged liver.
6. Fibrogenesis.
Main event facilitating hepatic fibrogenesis is activation of stellate
cells by various stimuli:
i) by damaged hepatocytes,
ii) by malon-di-aldehyde-acetaldehyde adducts,
iii) by activated Kupffer cells, and
iv) direct stimulation by acetaldehyde.
All forms of collagen are increased and there is increased
transformation of fat-storing to cells into myofibroblasts and fibrocytes
7. Increased redox ratio.
Marked increase in the NADH:NAD redox ratio in the hepatocytes
results in increased redox ratio of lactate-pyruvate, leading to lactic
acidosis.
a number of metabolic consequences such as in fatty liver, collagen
formation,

8. Retention of liver cell water and proteins.

Alcohol is inhibitory to secretion of newly-synthesised proteins by
the liver leading to their retention in the hepatocytes.
Water is simultaneously retained in the cell in proportion to the
protein and results in swelling of hepatocytes resulting in
hepatomegaly in alcoholics.
9. Hypoxia.
Chronic ingestion of alcohol results in increased oxygen demand by
the liver resulting in a hypoxic state which causes hepatocellular
necrosis in centrilobular zone . Redox changes are also more marked in
zone 3.

10. Increased liver fat.

In chronic alcoholism, there is rise in the amount of fat available to
the liver which could be from exogenous (dietary) sources, excess
mobilization from adipose tissue or increased lipid synthesis by the liver
itself. This may account for lipid accumulation in the hepatocytes
Alcoholic cirrhosis
• most common form of lesion, constituting 60-70% of all cases of
cirrhosis. Several terms have been used for this type of cirrhosis such
as Laennec’s cirrhosis, portal cirrhosis, hobnail cirrhosis, nutritional
cirrhosis, diffuse cirrhosis and micronodular cirrhosis.

• Grossly, alcoholic cirrhosis classically begins as micronodular cirrhosis

(nodules less than 3 mm diameter), the liver being large, fatty and
weighing usually above 2 kg
Cont..
• Eventually over a span of years, the liver shrinks to less than 1 kg in
weight, becomes non-fatty, having macronodular cirrhosis (nodules
larger than 3 mm in diameter), resembling post-necrotic cirrhosis.
Laboratory diagnosis
1. Elevated transaminases: increase in SGOT (AST) is more than that of
SGPT (ALT).
2. Rise in serum γ-glutamyl transpeptidase (γ-GT).
3. Elevation in serum alkaline phosphatase.
4. Hyperbilirubinemia.
5. Hypoproteinaemia with reversal of albumin-globulin ratio.
6. Prolonged prothrombin time and partial thromboplastin time.
7. Anaemia.
8. Neutrophilic leucocytosis in alcoholic hepatitis and in secondary
infections.
CLINICAL MANIFESTATIONS AND
COMPLICATIONS OF CIRRHOSIS
portal hypertension
progressive hepatic failure
Hepatocellular carcinoma
chronic relapsing pancreatitis
steatorrhea
gallstone
infection
Portal hypertension
Increase in pressure in the portal system usually follows obstruction
to the portal blood flow anywhere along its course.
Portal veins have no valves and thus obstruction anywhere in the
portal system raises pressure in all the veins proximal to the
obstruction.
portal hypertension means obstruction to the portal blood flow by
cirrhosis of the liver. The normal portal venous pressure is quite low
(10-15 mm saline).
type: Intrahepatic , post hepatic , prehepatic,
• . Intrahepatic portal hypertension.

Cirrhosis is by far the commonest cause of portal hypertension.

Other less frequent intrahepatic causes are metastatic tumours,
non-cirrhotic nodular regenerative conditions, hepatic venous
obstruction (Budd-Chiari syndrome),
veno-occlusive disease, schistosomiasis, diffuse granulomatous
diseases and extensive fatty change.
In cirrhosis and other conditions, there is obstruction to the portal
venous flow by fibrosis, thrombosis and pressure by regenerative
nodules. About 30- 60% patients of cirrhosis develop significant portal
hypertension.
• 2. Post hepatic portal hypertension.

This is uncommon and results from obstruction to the blood flow

through hepatic vein into inferior vena cava.
The causes are neoplastic occlusion and thrombosis of the hepatic
vein or of the inferior vena cava (including Budd-Chiari syndrome).

Prolonged congestive heart failure and constrictive pericarditis may

also cause portal hypertension by transmitting the elevated pressure
through the hepatic vessels into the portal vein.
• 3. Prehepatic portal hypertension.

Blockage of portal flow before portal blood reaches the hepatic

sinusoids results in prehepatic portal hypertension.
Such conditions are thrombosis and neoplastic obstruction of the
portal vein before it ramifies in the liver, myelofibrosis, and congenital
absence of portal vein
MAJOR SEQUELAE OF PORTAL
HYPERTENSION.
1) Ascites:
ascites is associated with hemodilution, edema and decreased urinary
output. Ascitic fluid is generally transudate with specific gravity of 1.010,
protein content below 3 gm/dl and electrolyte concentrations like those of
other extracellular fluids
Pathogenesis
Systemic factor:
1) Decreased plasma colloid oncotic pressure :
hypoalbuminemia from impaired synthesis of plasma protein including
albumin in liver.
so loss albumin from plasma into the peritoneal cavity and reduce
plasma oncotic pressure and leads to loss of water in extracellular space.
2) Hyperaldosteronism: increase secretion of aldosterone
Probably due to reduce renal blood flow impaired hepatic metabolism
and excretion of aldosterone
3) Impaired renal excretion :
reduce renal blood flow and
excessive release of antidiuretic
hormone result in renal
retention Na and H2o and
impaired renal excretion.

Local factor : Increased Portal

pressure
Increase hepatic lymph
formation
• B. Local Factors:
i) Increased portal pressure.
Portal venous pressure is not directly related to ascites formation
but portal hypertension in combination with other factors contributes
to the formation and localization of the fluid retention in the peritoneal
cavity.
ii) Increased hepatic lymph formation. Obstruction of hepatic vein
such as in Budd-Chiari syndrome and increased intrasinusoidal pressure
found in cirrhotic patients stimulates hepatic lymph formation that
oozes through the surface of the liver.
 2. Varices (Collateral channels or Porto-systemic shunts).

As a result of rise in portal venous pressure and obstruction in

the portal circulation within or outside the liver, the blood tends to
bypass the liver and return to the heart by development of porto-
systemic collateral channels (or shunts or varices).

These varices develop at sites where the systemic and portal

circulations have common capillary beds. The principal sites are as
under
• i) Esophageal varices:

The development of esophagogastric varices which is frequently

manifested by massive
hematemesis is the most important consequence of portal
hypertension

i) Hemorrhoids:(anorectal dilation of collateral submucosal vessels

due to backflow in the vein of the rectum)

Development of collaterals between the superior, middle and

inferior hemorrhoidal veins resulting in hemorrhoids is another
common accompaniment. Bleeding from hemorrhoids is usually not as
serious a complication as hematemesis from esophageal varices.
• iii) Caput medusae:
Anastomoses between the portal and systemic veins may develop
between the hilum of the liver and the umbilicus along the
paraumbilical plexus of veins resulting in abdominal wall collaterals.
These appear as dilated subcutaneous veins radiating from the
umbilicus and are termed caput medusae (named after the snake-
haired Medusa).

iv) Retroperitoneal anastomoses:

In the retroperitoneum, portocaval anastomoses may be established
through the veins of Retzius and the veins of sappey
• 3. Splenomegaly.

The enlargement of the spleen in prolonged portal hypertension is

called congestive splenomegaly.
The spleen may weigh 500-1000 gm and is easily palpable. The
spleen is larger in young people and in macronodular cirrhosis than in
micronodular cirrhosis
4. Hepatic encephalopathy.

Porto-systemic venous shunting may result in a complex metabolic and

organic syndrome of the brain characterized by disturbed consciousness,

neurologic signs and flapping tremors. Hepatic encephalopathy is

particularly associated with advanced hepatocellular disease such as in
cirrhosis