• Aetiology of chronic liver disease
• Symptoms and signs of chronic liver disease
• Investigations in chronic liver disease
• Complications in chronic liver disease
Cirrhosis is derived from Greek word
kirros=orange or tawny and osis=condition
-WHO definition : it is defined as a diffuse
process characterized by liver necrosis and
fibrosis and conversion of normal liver
architechture into structurally abnormal
nodules that lack normal lobular
• Cirrhosis is a form of chronic liver injury that
represents an end stage of virtually any progressive
• cirrhosis may be superimposed on the primary liver disease
and obscure the nature of the original insult.
As cirrhosis advances, it results in distortion of liver
architecture and compression of hepatic vascular and biliary
structures. These critical architectural changes lead to irregular
delivery of nutrients, oxygen, and metabolites to various areas
of the liver and may perpetuate the cirrhotic process even after
the original insult has been brought under control or has
It can be classified on the basis of morphology and
• Micronodular cirrhosis : In micronodular cirrhosis
the nodules are regular and small nodules and It is
<3mm in diameter . There is diffuse involvement of
all the hepatic lobules separated by the thick diffuse
In its early stages extra hepatic Billiary atresia is
• Macronodular cirrhosis : in this type the
nodules are of various size and are generally
larger than 5mm in diameter and the nodules
are separated by irregular septa of varying
• Macronodular cirrhosis is a feature of advanced
Wilson’s disease, α-1 antitrypsin deficiency,
chronic active hepatitis
cirrhosis is characterized by bile stasis, general reduction of bile
ducts, and increased amounts of connective tissue within and
extending from portal tracts .
The lobular structure generally is preserved.
This pattern often is ultimately seen in children with biliary
atresia, cystic fibrosis, and progressive familial intrahepatic
Postnecrotic cirrhosis, also known as irregular
cirrhosis, is the result of chronic and recurrent liver
It is usually not a result of a single necrotic injury
and is characterized by piecemeal necrosis that
occurs at the interface between hepatocytes and
portal tracts or fibrous septa.
Bridging fibrosis, collapsed hepatic lobules, and
regenerative nodules of varying sizes develop,
usually producing micronodular cirrhosis .
In children, postnecrotic cirrhosis may occur as a
sequela of neonatal hepatitis.
It is associated with chronic active hepatitis, caused by
viral hepatitis B or C, or a result of autoimmune or
idiopathic inflammation .
Drugs such as methyldopa or isoniazid, which may
cause chronic active hepatitis, also can cause irregular
or postnecrotic cirrhosis .
Cardiac cirrhosis develops as a result of centrilobular
Increased right atrial pressure (resulting from
congestive heart failure, congenital heart disease, or
constrictive pericarditis) results in increased hepatic
vein pressure and congestion of blood flow in
Necrosis leads to formation of fibrous bridges between
Vaso occlusive disorders and the Budd–Chiari
syndrome, which results from the congential or
acquired obstruction of the hepatic veins, also result in
Glycogen storage disease, type III
Glycogen storage disease, type IV
Indian childhood cirrhosis
Chronic hepatitis B +/− delta
Chronic hepatitis C
Cell injury leads to cell death (necrosis), which is followed by scar
formation (fibrosis) and, in some cases, nodule formation
Cirrhosis is the result of these three processes :
Cell injury ( extracellular matrix)
The first step in the process that leads to cirrhosis is
direct injury to the hepatocyte.This injury may occur
as a result of almost any insult, including viral
invasion, ischemia, and toxin exposure.
After injury the parenchymal cells regenerate and
replace the necrotic cell . This is associated with
inflammation and deposition of additional extracellular
matrix (ECM), including collagen.
The cells responsible for intrahepatic fibrosis have
not all been identified. The hepatic stellate cell is of
high importance. Other cells like endothelial cell,
hepatic stellate cell, kupffer cells are responsible for
If stimulated by inflammatory cells or by various
cytokines, hepatocytes and their supportive cells secrete
an altered ECM. The ECM is vital to the survival and
proper function of each cell; the ECM provides a stable
environment within tissue compartments.
In cirrhosis, the ECM is altered qualitatively and
In the normal liver, connective tissue proteins are
seen along the basement membranes surrounding
lymphatic and blood vessels, and around bile ducts.
There is also scanty collagen in the perisinusoidal
space. The hepatocytes and greater part of the
portal triads are virtually free of connective tissue.
In cirrhosis, there are increased collagen types III
and IV in the perisinusoidal space. The sinusoids are
lined with a new basement membrane intimately
associated with laminin and collagen type 3
The altered proteins (mostly synthesized by
hepatocyte stellate cells) are laid down at the space of
Disse, and initially there is no effect on the function of
As the collagen network becomes thicker, it becomes a
barrier to the intimate interface between blood and
hepatocytes and interferes with exchange of
substances across the hepatocyte membranes.
Laminin deposition increases along sinusoids and is
related to the formation of a sinusoidal basement
membrane . This is so called capillarization of
The reduction in the amount of viable, well-
vascularized hepatic tissue leads to compensatory
growth, or nodule formation. As hepatic nodules form,
they increasingly impede blood flow to the lobules by
direct compression of the hepatic arterial and venous
Normal Hepatic SInusoid
Space of Disse
Activation of stellate cells
Collagen deposition in space of Disse
Constriction of sinusoids
Defenestration of sinusoids
Alterations in Microvasculature in Cirrhosis
Although initially considered to be permanent,
there is evidence suggesting that fibrosis is
reversible, at least in some cases .
Some reversal of liver fibrosis has been seen in
some liver diseases, such as chronic hepatitis C and
nonalcoholic steatohepatitis (NASH) .
Hepatic stellate cells (HSCs) are responsible for the excess
production of ECM components, thus activation of HSC appears
to be a key step toward the development of hepatic fibrosis.
Inhibition of HSC activation has been of interest in reversing or
preventing the development of hepatic fibrosis.
Such treatments include the inhibition of transforming growth
factor-β (TGF-β) , platelet-derived growth factor , and herbal
extracts such as silymarin.
Antioxidants such as vitamin E and silymarin protect hepatocytes
from necrotic injury, inhibit hepatocyte stellate cell activation,
and may result in decreased rates of fibrogenesis .
Attempts are being made to treat liver fibrosis. The removal of
the causative agent when possible is the first step in treating
liver fibrosis and in some cases, may result in some reversal of
the fibrotic process.
In general, most treatments have not been widely applied or
have not been tested in adults or children and thus are not used
in children with progressive liver disease.
Because inflammation is associated with the fibrotic process,
anti-inflammatory medications such as corticosteroids have
been used in patients with chronic liver disease.
These drugs are especially effective in treating patients with
autoimmune hepatitis .
In response to insult by viral invasion, cirrhosis, ischemia,
trauma, or partial hepatectomy, hepatocyte proliferation
increases to replace lost cells. Hepatic regeneration is a com-
plex process, highly regulated at the cellular level in an
autocrine or paracrine manner by cytokines, some of which
themselves are regulated by prostaglandins or by other
Many hormones are known to influence the process of hepatic
regeneration, including insulin, glucagon, growth hormone,
adrenocorticotropic hormone (ACTH), vasopressin, cortisol,
thyroxin, and estrogen.
All of these can promote hepatic proliferation, but none appears
to be the initiator of the process. The recent isolation and
identification of specific cytokine hepatic growth factors has
shed light on the initiation and control of hepatocyte
proliferation as well as fibrogenesis.
Salivary glands, Brunner’s
Initiator of hepatic
Stimulates hepatocyte DNA
Hepatocyte growth factor
Unknown Stimulates hepatocyte DNA
Fibroblast growth factor
Endothelial cells Stimulates hepatocyte
regeneration at low levels.
High levels regulate
epidermal growth factor
Cytokines Associated with Hepatic Regeneration
CYTOKINE SOURCE ACTION
Epidermal growth factor
cirrhosis of the
The clinical presentation of cirrhosis depends on the cause
of the primary liver disease as well as on the pace of
progression of hepatocellular failure and fibrosis. Many
children and adolescents present with findings
incidentally during routine physical examinations. In such
patients, the cirrhosis is referred to as latent or
In others, chronic liver disease may be sudden and
dramatic, such as with the onset of hematemesis,
encephalopathy, ascites, or infection. If the signs and
symptoms of cirrhosis are apparent and progressive, the
term decompensated or active cirrhosis applies
The common mode of presentation include :
Failure to thrive
Anorexia , nausea , vomiting
Prolonged or recurrent jaundice
Pain abdomen ( Colicky type)
Features of portal hypertension (
hementemesis , malena, epitaxis.)
Fever is generally presented in
decompensated liver disease.
Other points in history
• Fever, prodrome (anorexia ,vomiting ,nausea)
–which disappears with onset of jaundice –
acute viral hepatitis
• Young individual with extrapyramidal
symptoms, neuropsychiatric manifestation,
• Colicky abdomen pain, jaundice, fever - gall
• Drug history ( acetoaminophen toxicity)
• fatigue, malaise
• anorexia, nausea
• Biliary colic
• Deep jaundice
• +++ pruritus
• +++ abdominal pain and pancreatitis
• +++ gray or clay-colored stools
General Poor growth, malnutrition, fever, muscle
Skin and extremities Jaundice, flushing or pallor, palmar
erythema, spider angiomata, digital
Abdomen Distention, caput medusa, ascites,
larger tender liver or shrunken liver,
large spleen, rectal varices
Central nervous system Asterixis, positive Babinski’s reflex,
prolonged relaxation phase of deep
tendon refluxes, mental status changes
Gastrointestinal tract :
cirrhosis is associated with esophageal and
gastric varices, which form as a consequence of
Hematemesis secondary to variceal bleeding .
Bleeding from hemorrhoids, which arise from
portosystemic shunting through the inferior
mesenteric venous collateral system, is much less
Chronic gastritis and peptic ulcer disease
Excess gastric acid may be secreted in response to
direct gastric stimulation by histidine, the
decarboxylated form of histamine. In healthy people,
histidine is cleared from the circulation by the liver;
with hepatic disease, serum histidine levels are
Gastroesophageal reflux is seen in cirrhosis and is
caused by increased intra-abdominal pressure
secondary to ascites and hepatosplenomegaly.
Diarrhea is a common manifestation of liver disease
and may be a result of malabsorption, bile acid
deficiency, or malnutrition.
pulmonary manifestation :
Development of arteriovenous shunts, which lead to
cyanosis and dyspnea. Hypoxemia is seen in up to
30% of children with cirrhosis and can be severe
enough to cause cyanosis .
Digital clubbing often accompanies longstanding
These shunts may result from increased vasodilation
caused by vasoactive substances such as ferritin released
from the diseased liver
Hematologic changes :
cirrhosis include anemia and coagulopathy.
The cause of the anemia of cirrhosis may be multifactorial
and may include blood loss due to GI bleed, hemolysis
secondary to hypersplenism, iron and folic acid deficiency
secondary to malabsorption , anorexia, and dilution of red
blood cell volume as a result of sodium and water retention .
The coagulopathy of cirrhosis also is multifactorial . A
decrease in the synthesis of liver derived clotting proteins,
including prothrombin and factors VII and IX, and increased
consumption of clotting factors through increased fibrinolysis
and disseminated intravascular coagulation (DIC) occur
commonly in late, decompensated cirrhosis.
cirrhosis include a high cardiac output state related to
changes in systemic vascular resistance, pulmonary
vascular resistance, and hepatic blood flow (portal
The sustained increase in cardiac output results in the
flushed appearance of patients with cirrhosis. Systemic
hypertension is not common in cirrhosis
Skin manifestations :
Spider angiomata and palmar erythema.
Spider angiomata are easily recognizable as small, raised,
dark lesions with radially distributed convoluted vascular
branches. They arise because of vasoactive substances such
as estradiol in the circulation of patients with cirrhosis.
The presence of more than five in the body region drained by
the superior vena cava is abnormal and is suggestive of
Palmar erythema, a well-recognized sign of cirrhosis, is not
specific to cirrhosis but is seen in other conditions associated
with increased cardiac output or altered sex hormone
Caput medusae may also be present. This refers to prominent
abdominal wall veins seen in patients with portal venous
Nail changes characterized by horizontal white bands
(Muehrcke’s nails) may be seen in cirrhosis or in other
conditions resulting in hypoalbuminemia.
Endocrine manifestations :
Failure of the liver to conjugate or metabolize hormones
include diabetes mellitus, which may present as subtle
hyperinsulinemia without overt signs; syndrome of
inappropriate secretion of antidiuretic hormone, presenting
Gynecomastia may be caused by increased production of
androstenedione and the increased conversion of estrone to
In the mature adolescent, decreased libido, delayed puberty
decreased facial hair, and impotence are caused by
reduced testosterone synthesis in the liver .
Changes in consciousness include hypersomnia, reversal
of sleep pattern, apathy, slowed speech, decreased
spontaneous movement, and eventually coma.
Personality changes commonly seen in chronic liver
disease include irritability, inability to cooperate,, and their
true cause may not be understood until frank
encephalopathy is present.
Intellectual deterioration with slight or gross confusion may
be present. Tests of constructional apraxia such as writing
difficulty or the Reitan trail-making test may be difficult to
administer if the child is at too early a developmental stage.
cirrhosis result in increased susceptibility to bacterial and
mycobacterial infections, resulting in an increased rate of
pneumonia and spontaneous bacterial peritonitis (SBP).
Evaluation of a patient with liver dysfunction and
suspected cirrhosis should focus on determining
both the cause and the stage of liver disease.
Serologic testing for infectious diseases should include
screens for hepatitis B and C.
In appropriate clinical situations (fever in the setting of
previous biliary tree surgery), bacterial cultures of
blood and possibly liver tissue should be obtained.
Tests for metabolic liver disease should include
quantitation of the serum α1-antitrypsin level with
determination of levels of protease inhibitor (“π-
type”), fasting blood sugar (glycogen storage
disease), urinary reducing substances
(galactosemia), serum amino acids with urinary
organic acids (tyrosinemia), serum iron, and iron
binding capacity and ferritin (hemochromatosis), as
well as the sweat chloride test (for cystic fibrosis).
The initial evaluation for Wilson’s disease should
include serum copper, serum ceruloplasmin, a 24-
hour urine collection for copper, and a slit-lamp
An abdominal ultrasound examination aids in the evaluation
of gallstones, choledochal cyst, and Caroli’s disease (cystic
dilation of the intrahepatic biliary tree).
The anatomy and blood flow of the hepatic arterial and
venous system also should be evaluated.
In infants, in whom the consideration of extrahepatic biliary
atresia is paramount, a biliary scintiscan should be done.
In patients with suspected extrahepatic biliary tree obstruction,
ERCP may be considered. The timing of liver biopsy in the
investigtion of suspected cirrhosis in children remains a matter of
A biopsy may be critical to confirm the presence of cirrhosis
suspected on clinical grounds, or if the investigations outlined here
fail to reveal the caus of the chronic liver disease
Biochemical tests in
LIVER FUNCTION TEST : AST , ALT , ALP
TOTAL BILIRUBIN / DIRECT BILIRUBIN
PT /APTT/ INR
COMPLETE BLOOD COUNT / PLATELETS
ANA – ASMA-AMA
• AST/ALT >> ALP
• Unconjugated bil >>
• USG – BILE DUCTS NORMAL
• Conjugated bil>>
• ↑GGT, 5’nucleotidase
• USG- Intrahepatic biliary
Non hepatic cause of elevated
• Muscle disease
• Thyroid diseases
• Bone disease - ALP
Diagnostic Tests in Chronic Liver Disease and Cirrhosis
Disorder Diagnostic Test
HBV HBsAg, E antigen/antibody, HBV
HCV HCV antibody, HCV RNA
CMV CMV serology, urine for CMV antigen
EBV EBV serology, heterophile
Bacterial cholangitis Blood and liver tissue culture
Autoimmune chronic active hepatitis Sedimentation rate, ANA, anti–smooth
muscle antibody, antimitochondrial
α1-antitrypsin deficiency Serum α1-antitrypsin level, Pi type
Glycogen storage disease Lactic acid, fasting blood sugar, uric
acid, liver and muscle tissue enzyme
Galactosemia Urinary non–glucose reducing sugar,
red blood cell galactose-1-phosphate
uridyl transferase level
Tyrosinemia Serum amino acid levels, urine organic
Hemochromatosis Serum iron TIBC, ferritin
Liver Function Tests: Normal Values & Changes
Tests Normal Values Hepatocellular
Urine bilirubin None Increased Increased
Alb, 3.5-5.5 g/dL
Tot, 6.5-8.4 g/dL
Alk phos 30-115 IU/L Increased (+) Increased (++++)
Prothrombin time INR of 1.0-1.4; 10%
inc. after vit K in 24
No response to
parenteral vit. K;
parenteral vit. K
ALT, AST ALT: 5-35 IU/L
AST: 5-40 IU/L
Inc. in hepato-
Differential Diagnosis of Hereditary Jaundice with Normal Liver
Chemistries & No Signs or Symptoms of Liver Disease
Gilbert’s Type I Type II
usual total (mg/dL)
Age at onset of
<7% of pop’n Very rare Uncommon
AD AR AR
<3; <6 >20 <20
Mostly B1; inc. All indirect All indirect
Hepatic UDP-glucuronyl transferase activity
Decreased Absent Marked dec.
Adolescence early neonatal childhood
Differential Diagnosis of Hereditary Jaundice with Normal
Liver Chemistries & No Signs or Symptoms of Liver Disease
Gilbert’s Type I Type II
Appear in early Jaundice, Asymptomatic
adulthood; kernicterus in jaundice,
often 1st re- infants, kernicterus
cognized w/ 1st 3day of life rare
Normal Normal Normal
Not needed Liver transplant Phenobarbital
Differential Diagnosis of Hereditary Jaundice with Normal Liver
Chemistries & No Signs or Symptoms of Liver Disease
Dubin-Johnson Rotor’s Syndrome
Serum bilirubin usual
Urine total coproporphyrin
Age at onset of jaundice
Usual clinical features
2-7; < 25
Direct ~ 60%
jaundice in young
GB not visualized
2-7; < 20
Direct ~ 60%
• Wilson ́s disease (WD) is an autosomic recessive
genetic disorder affecting gene ATP7B in
chromosome 13q . It codes for trans membrane
copper transporter in hepatocytes and for
excretion into the bile canaliculus as well as for
joining copper to ceruloplasmin.
• As a result, there is an abnormal accumulation of
copper in liver, brain, kidney, and other organs,
mitochondrial damage, and low levels of bile
copper and coeruloplasmin.
Prevalence in Europe is 1/30,000, with 1/100
heterozygous. It may present as asymptomatic
hypertransaminasaemia or as chronic hepatitis, cirrhosis,
or acute liver failure in childhood.
In older children and adults, extrapyramidal neurological
symptoms (dysarthria, dystonia, ataxia, tremor,
dysphagia), psychiatric manifestations, Kayser–Fleischer
ring (due to copper deposits in the Descemet corneal
membrane, very specific but not pathognomonic of WD),
and renal tubulopathies (with aminoaciduria and
phosphaturia) are more frequent.
t is typical to find low plasma ceruloplasmin,
although in 5–10% of patients it may be normal
(>20 mg/dl), and decreased serum copper levels.
A raised urine copper after penicillamine (higher
than 100 μg/day) and an elevated liver copper
concentration (higher than 250 μg/g of dry liver
tissue) are helpful in diagnosis. Liver biopsy
shows the stage of the disease. Genetic tests
(>150 mutations) may help.
In this autosomal recessive disease there is a
chromosome 14 mutation that leads to the production of
abnormal and hepatotoxic α1-AT that is retained in the
endoplasmic reticulum . Frequency is 1:2000 newborns.
α1-AT glycoprotein may present as 100 variants, with
codominant inheritance, which are classified according to
the protease inhibitor (Pi) phenotype system based on
their electrophoretic moiety: Pi MM variant (with normal
serum concentration and normal activity), Pi null-null
variant (absence of α1-AT associated with lung disease),
defective variants (such as Pi Z and Pi S, with low serum
concentration and lung and liver disease).
MM phenotype is found in healthy individuals; ZZ
phenotype causes the most severe deficiency and
it represents 95% of patients. SZ phenotype may
cause liver disease (neonatal cholestasis, mild
dysfunction, chronic hepatitis, liver failure,
cirrhosis, hepatocellular carcinoma), while
MS/MZ phenotypes do not produce liver disease
in children but do in adults.
Diagnosis is based on a decrease in the α1 band
(electrophoretic gel) , a decrease in α1-AT in
blood and Pi phenotype. On the liver biopsy, an
abnormal accumulation of α1-AT in liver is
Nonalcoholic fatty liver disease
• Nonalcoholic fatty liver disease (NAFLD)
includes simple fatty liver (steatosis),
nonalcoholic steatohepatitis (NASH) and
cirrhosis . Most patients with NAFLD present
with obesity, mainly central adiposity, as part
of the metabolic syndrome21
The pathology of the NAFLD in children
Type 1, characterized by steatosis, hepatocyte
balloonization, and perisinusoidal fibrosis
(similar to NAFLD in adults and more frequent in
white children in both sexes), and
Type 2 (infantile), characterized by steatosis,
portal inflammation, and portal fibrosis (more
common in male and children of Asian, Native
American, and Hispanic ethnicity).
• Clinical experience in children with NAFLD is
limited. NAFLD in childhood and adolescence
used to occur in the male obese patient, with
AST>ALT , hypertriglyceridaemia , acanthosis
• Although most patients remain asymptomatic,
other individuals may present with a variety of
symptoms: hypertension, dyslipidaemia, insulin
resistance, type 2 diabetes, and central obesity.
The gold standard test to distinguish between
simple steatosis and NASH is liver biopsy.
It confirms diagnosis, assesses steatosis
severity, and serves as a prognostic marker.
Patients with simple esteatosis have a benign
course without histological progression, but
patients with NAFLD may progress to cirrhosis
or hepatocarcinoma .
Weighting Factor Variable
+15 If cholesterol <100 mg/dL
+15 If positive history of ascites
If indirect bilirubin >6 mg/dL
If indirect bilirubin is 3–6 mg/dL
+10 If PTT is prolonged >29 seconds
Total score of 0–28 places patient in low-risk
group (<25% risk of death within 6 months);
score of 28–39 is associated with moderate- risk
(25–75% risk of death within 6 months);
score greater than 39 is associated with high
risk (>75% of death within 6 months).