LIVER CIRRHOSIS

USMF “Nicolae Testemiţanu”,

CLINICA MEDICALA Nr 4,
DISCIPLINA GASTROENTEROLOGIE
 Epidemiology
 Cirrhosis of the liver is a disease
 found all over the world,
 affecting all races,
 all age groups and
 both sexes.

 However, there are geographical differences regarding

the most important causative factors:
 rate of alcohol consumption, and
 frequency of viral hepatitis.

 The incidence is about 240/million inhabitants/year.

 Epidemiology
 Cirrhosis is the ninth leading cause of death worldwide
and is responsible for 1.2% of all deaths

 Autopsy examinations suggest a prevalence of 4-10%.

 Many patients die from the disease in their fifth or sixth

decade of life
 Definition of Iiver cirrhosis
 Cirrhosis represents the final
common histologic pathway
for a wide variety of chronic
liver diseases, characterized
by
 distortionof the hepatic
architecture and the
 formation of regenerative
nodules.
Liver cirrhosis is characterized by the
following criteria:

 Pronounced, insufficiently repaired necrosis of the

parenchyma (with or without inflammatory
processes)
 Diffuse connective tissue proliferation
 Varying degrees of nodular parenchymal
regeneration
 Loss and transformation of the lobular structure
within the liver as a whole
 Impaired intrahepatic and intra-acinar vascular
supply
 Causes of cirrhosis

 l. Common causes of cirrhosis include:

 Alcoholic liver disease where considered to be the predominant
cause of cirrhosis in the US (21%)
 Hepatitis C has emerged as the nation's leading cause of both
chronic hepatitis and cirrhosis (up to 26% can develop cirrhosis).
 Hepatitis B infection (15%).
 Non-alcoholic fatty liver disease (NAFLD) and non-alcoholic
steatohepatitis (NASH) (up to 10% of patients with NASH can
develop cirrhosis).
Less common causes of liver cirrhosis (5%) include:
 Autoimmune hepatitis
 Primary biliary cirrhosis
 Secondary biliary cirrhosis - Associated with chronic extrahepatic
bile duct obstruction
 Primary sclerosing cholangitis
 Hemochromatosis
 Wilson disease
 Alpha-1 antitrypsin deficiency
 Granulomatous disease - Eg, sarcoidosis
 Type IV glycogen storage disease
 Drug-induced liver disease - Eg, methotrexate, alpha methyldopa,
amiodarone
 Venous outflow obstruction - Eg, Budd-Chiari syndrome, veno-
occlusive disease
 Chronic right-sided heart failure
 Tricuspid regurgitation
 Causes of cirrhosis
 Alcoholism  Cardiac cirrhosis
 Chronic viral hepatitis  Inherited metabolic
B, D and C liver disease
 Autoimmune hepatitis  Hemochromatosis

 Nonalcoholic  Wilson’s disease

steatohepatitis  1 Antitrypsin
deficiency
 Biliary cirrhosis
 glycogenosis
 Primary biliary cirrhosis
 Primary sclerosing
 Cystic fibrosis
cholangitis  Cryptogenic cirrhosis

Eric Goldberg, Sanjiv Chopra. Cirrhosis in adults: Etiologies, clinical

manifestations, and diagnosis. 2013
E. Kuntz, H.-D. Kuntz, Liver cirrhosis, 2008
Causes of cirrhosis
 Many cases of cryptogenic cirrhosis appear to have resulted from
nonalcoholic fatty liver disease( NAFLD) .

 Up to one third of Americans have NAFLD. About 2-3% of

Americans have nonalcoholic steatohepatitis (NASH)

 It is estimated that 10% of patients with NASH will ultimately

develop cirrhosis
Cirrhosis pathophysiology
 Pathogenesis of liver cirrhosis is complex:

 I HEPATOCYTES INJURY AND NECROSIS

 Liver cell are injured by a chronic hepatic process, which
then undergo inflammatory changes leading to cell death and
fibrosis.
 Localization of necro-inflammatory process determines the
latter appearance of fibrosis and the location of the following
forms:
 Focal, circular, central, porto-portal
 Central-lobular

 II. FIBROSIS
 III. CELL REGENERATION
 Fibrosis
 Fibrosis – reflects an alteration in the normally
balanced processes of extracellular matrix production
and degradation.
 The extracellular matrix, the normal scaffolding for
hepatocytes, is composed of collagens (especially
types l, lll, and V), glycoproteins and proteoglycans.
 Caused by necro-inflammatory processess of different
etiologies, that progresses as long as etiologic factor
persists
 However fibrosis may have a reverse development,
when this causative provocative factor is removed
 Fibrosis evolution

 Fibrosis progresses in stages:

 I stage – activation of Kupffer's cells and other cells
that participate in necro-inflammatory process.
 ll stage – activation of hepatic stellate cells (HSC)
 lll stage activation of overproduction of
myofibroblasts, with the subsequent secretion of
components of fibrosis in the absence of cytokine
 Stellate cells, located in the perisinusoidal space, are essential for
the production of extracellular matrix.
 Stellate cells, which were once known as Ito cells, lipocytes, or
perisinusoidal cells, may become activated into collagen-forming
cells by a variety of paracrine factors

 Fibrogenesis commences with the activation of Ito cells (Hepatic

stellate cells) by cytokines such as:
 TGFβ1(transforming growth factor),
 PDGF (platelet-derived growth factor),
 TNFα, EGF1 (epidermal growth factor).

 This induction of Ito cells leads to quantitatively increased (up to

ten times the norm) and qualitatively altered synthesis of the
extracellular matrix, which consists of collagens, glycoproteins,
proteoglycans and glucosaminoglycans.
 Degeneration of the matrix is reduced by:
 a decrease in matrix metalloproteinases (MMP) with a
simultaneous

 increase in the tissue inhibitors of metalloproteinases (TIMP).

 Both factors reduce further degradation of connective

tissue.
 The hepatocytes are now multilayered instead of
normal single-layered cell plates and lose their
microvilli.
 Fenestration of the sinusoids disappears, whereas the
sinusoidal extracellular matrix increases, leading to
capillarization of the sinusoids.
 Increased collagen deposition in the
space of Disse (the space between
hepatocytes and sinusoids) and the
diminution of the size of endothelial
fenestrae lead to the capillarization of
sinusoids.

 Activated stellate cells also have

contractile properties.
 Capillarization and constriction of
sinusoids by stellate cells contribute
to the development of portal
hypertension.
 In this way, the distance between the
hepatocytes and the blood becomes
Spatial relationship of sinusoid and hepatic cells:
greater, and the clearance of hepatocytes (H) in the form of boundary lamella (BL),
macromolecular substances is cell nucleus (CN), canaliculus (BC), Disse’s space (D),
endothelial cells (E), sieve plate (SP), Kupffer cell (K),
reduced. Ito cell (I).
Cirrhosis
pathophysiology
 Pathogenesis of
liver cirrhosis is
complex:

 HEPATOCYTES
INJURY AND
NECROSIS

 FIBROSIS

 CELL
REGENERATION

Friedman SL. Molecular regulation of hepatic fibrosis, an integrated cellular response to tissue injury. 2000.
Areeba Ahmad. Understanding the mechanism of hepatic fibrosis and potential therapeutic approaches. 2012
 Liver cirrhosis pathology
 Histologically liver cirrhosis is characterized by:
 Fibrosis with regeneration nodules,
 disruption of normal liver architectonics
 violation of microcirculation and
 presence of inflammation and necrosis of hepatocytes
 Normal liver Cirrhosis after fatty liver
Hepatic lobule
Hepatic cord
Centre vein

Cirrhosis after hepatitis

Fibrotic scar tissue

Regenerative nodules
Fatty granule
 Liver cirrhosis pathology
 Cirrhosis was historically classified morphologically
as micronodular, macronodular, or mixed.

 According the size of the nodules -
 Micronodular Liver Cirrhosis
 Regenerative nodules < 3 mm,
 the liver is atrophied present 1/3 of the normal size,
is more common in alcoholics (Laennec's type),
hemochromatosis, cholestatic causes of cirrhosis, and
hepatic venous outflow obstruction;
 Portal tracts are connected by thin fibrous septa.
 Liver cirrhosis pathology
 Macronodular Liver cirrhosis:

 Regenerative nodules > 3 mm up to 1 cm or more,

 the weight of the liver – 1,5 – 4 kg (hypertrophic

type Ganneau, - more frequent with viral hepatitis B,
C, D;

 Broad fibrous septa link portal tracts with each

other, or portal tract with central vein.
 Pathology
>3.0mm
Macronodular cirrhosis
Ongoing liver damage with liver cell
necrosis followed by fibrosis and
hepatocyte regeneration results in
cirrhosis. This produces a nodular,
firm liver. The nodules seen here are
larger than 3 mm and, hence, this is an
example of macronodular cirrhosis.
Mixed is including macro- and micronodular cirrhosis
<3.0mm
Micronodular cirrhosis
This is an example of a micronodular
cirrhosis. The regenerative nodules
are quite small, averaging less than 3
mm in size. The most common cause
for this is chronic alcoholism. The
process of cirrhosis develops over
many years.
 Liver cirrhosis pathology
 Mixed type of LC - there are small and large units of
regeneration;

 The normal anatomy of the spaces Disse is damaged,

normal portal tracts are absent,

 Appear necrosis of liver cells and other

manifestations, depending on the etiopathogenetic
factors
Liver cirrhosis forms
 Microscopically exist 2 forms:

 A. fibrous septum starting from the center of the lobule:

 Alcoholic liver cirrhosis
 Cardiac fibrosis
 Obstruction of the hepatic veins (Budd – Chiari syndrome,
hepatic venoocclusive disease;

 Liver showing a zone of centro-lobular necrosis - the necrotic

zone is between two portal tracts, where we would usually see
a central hepatic vein (dotted circle)
Liver cirrhosis forms
 B. Fibrous septum starting from the portal tracts

 Chronic hepatitis of viral etiology

 Primary biliary cirrhosis
 Obstruction of biliary ducts.

 The periportal fibrosis progresses to formation of porto-portal
bridges dissecting the hepatic parenchyma in nodules
(dissection nodules).

 Hepatocytes trapped in the connective tissue septa form

cholangioles.
 Clinical classification
 1. Latent cirrhosis
 2. Manifest cirrhosis
 active form
 inactive form

Manifest cirrhosis can present in two forms:

 Stage of compensation
 Stage of decompensation:
 portal decompensation
 metabolic decompensation

E. Kuntz, H.-D. Kuntz, Liver cirrhosis, 2008

Liver cirrhosis symptoms
 Symptoms depend on the etiology of liver cirrhosis,
activity of the liver process and evolutionary stage of
actual cirrhosis.

 People with latent cirrhosis may no have any

symptoms;

 Patients with compensated LC does not present any

complaints
 The diagnosis is usually set accidentally or due to
instrumental data
Liver cirrhosis symptoms
 Many people with cirrhosis have no symptoms during the early
phases of the disease.
 Symptoms are caused by either of 2 problems:
 Gradual failure of the liver to carry out its natural functions
 Distortion of the liver's usual shape and size because of
scarring

 The most common symptoms of cirrhosis are as follows:

 Tiredness (fatigue) or even exhaustion
 Weakness
 Nausea
 Loss of appetite leading to weight loss
 Loss of sex drive
Latent cirrhosis
 There are no subjective complaints or
clinical symptoms.
 This stage is identified by
 laboratory parameters,
 imaging procedures or

 histological examination of the liver.

 Frequency is between 10 and 20%.

 Manifest cirrhosis is characterized by
subjective complaints and clinical findings.

 Development of metabolic insufficiency (also known

as cellular decompensation) is due to:

 a significant loss of hepatocytes (e. g. mass

necroses) and/or a
 loss of function of the hepatocytes (e. g. insufficient
numbers of hepatocytes and accumulation of waste
products in cirrhotic transformation with the
development of shunts).
 Liver cirrhosis symptoms
 Decompensated liver cirrhosis  Decompensated liver cirrhosis
with portal hypertension, is with metabolic disorders, is
characterized by: characterized by:

 ascites,  Astheno-neurotic syndrome,

 “medusa head” on the anterior  encephalopathy,
abdominal wall,  weight loss,
 hidrothorax,  mucocutaneous syndrome,
 cardiovascular syndrom,
 edema, ascites,
 portal gastropathy,
 bleeding,
 splenomegaly,
 endocrine/articulare symptoms,
 Hypersplenism, muscle pain,
 flatulence  fiver, pain in the liver region,
 jaundice, itching, etc.
 Apart from histological activity (progressive) or inactivity
(stationary),
biochemical activity must also be defined.
Biochemical activity is determined by:
enzymatic activity,
mesenchymal activity, and
immunological activity.

 Enzymatic activity  Mesenchymal activity

 ALT , AST , GDH , γ-GT
 γ-globulins
 Immunological activity  immunoglobulins A, G, M
 hepatitis  copper
antigens/antibodies  procollagen-III-peptide
 immunoglobulins A, G, M
 autoantibodies
Liver cirrhosis symptoms
 Decompensated cirrhosis is marked by the
development of any of the follow-ing complications:
 jaundice,

 variceal hemorrhage,

 ascites,

 or encephalopathy.

 Jaundice results from hepatic insufficiency and,

other than liver transplantation, there is no specific
therapy for this complication.
 Extrahepatic manifestations of LC
 I. Digestive-tract
 GERD with reflux esophagitis
 Gastritis with HP +
 Gastric ulcer and duodenal ulcer
 Pancreatitis - acute and chronic
 Cholelithiasis

 II. The accumulation of fluid in the pleural cavity usually on the

right.

 III. Cardiac manifestations

 (tachycardia, hypotension, systolic murmur)
Extrahepatic manifestations of LC

 Endocrine disorders: hypogonadism, diabetes or

hypoglycemia, impaired thyroid function.

 Disorders of amino acids metabolism (↑ level of

aromathic amino acids), ↓ level of vitamins (C, B2,
B6, B12, A, D, K, E), elektrolytes (↓K, ↑ Na, ↓Ca)

 Changes in the bones and joints (joint pain,

synovitis, osteoporosis, osteoarthropathy)
 Endocrine disorders
 In women, chronic anovulation is common, which may manifest
as:
 amenorrhea,
 oligomenorrhea, or
 metrorrhagia (irregular episodes of light bleeding).
 Some of the abnormalities may be due to variations in
testosterone, estradiol, prolactin levels in patients with cirrhosis.

 Men with cirrhosis may develop hypogonadism.

 It is manifested by impotence, infertility, loss of sexual drive, and

testicular atrophy.

 It is a feature seen predominantly in patients with alcoholic

cirrhosis and hemochromatosis.
 Algorithm of Liver Cirrhosis diagnosis
 History
 History of previous liver or bile
duct diseases,
 blood/blood products
transfusion,
 eating disorders,
 alcoholism,
 Metabolic diseases,
 drug abuse,
 Exposure to toxic substances,
 travel,
 sexual perversion,
 genetic liver disease
 Clinical data
 Complaints:
 Asthenia, anorexia, weakness,
nausea, intolerance to fatty
foods, alcohol, smoking,
abdominal pain and bloating,
hemorrhagic syndrome (nasal,
gingival, gastrointestinal
bleeding), skin hemorrhagic
manifestations, itchy skin,
insomnia, apathy, irritability,
depression, impotence
 Algorithm of LC diagnosis
 Signs:
 Physical signs are variable and depend upon the extent of disease.
 Cutaneous features of cirrhosis include:
 Jaundice
 Scratch marks secondary to pruritus
 Spider angiomata/naevi (mainly found on the trunk and face)
 Skin telangiectasias (called paper money skin)
 Palmar erythema
 Bruising
 Petechiae or purpura.
 Hair loss.
 White nails (horizontal white bands or a proximal white nail plate; sign of
hypoalbuminemia).
 Finger clubbing.
 Dupuytren's contracture.
Smooth red tongue with Cutaneous haemorrhages (confluent
and streak-like) on the lower part and
angular cheilosis in liver wrist of the arm in a patient with
cirrhosis cirrhosis
 Spider angiomata (also referred to as spider telangiectasias) are
vascular lesions consisting of a central arteriole surrounded by
many smaller vessels.

 They are most frequently found on the trunk, face, and upper limbs.
 The body of the lesion (the central arteriole) can be seen pulsating
when compressed with a glass slide. Blood fills the central arteriole
first before traveling to the peripheral tips of each "leg" after
blanching.
 There are usually multiple radiating legs and surrounding erythema
that may encompass the entire lesion or only its central portion.

 The number and size of spider angiomata correlate with the

severity of liver disease.
 Patients with numerous, large spider angiomata may be at
increased risk for variceal hemorrhage.
Extremity findings — Findings on examination of the
extremities of a patient with cirrhosis may include palmar
erythema, nail changes, clubbing, hypertrophic
osteoarthropathy, and Dupuytren's contracture.

 Palmar erythema is an exaggeration of the normal

speckled mottling of the palm and is believed to be
caused by altered sex hormone metabolism.
 It is most frequently found on the thenar and
hypothenar eminences, while sparing the central
portions of the palm.
 Palmar erythema is not specific for liver disease and can be
seen in association with pregnancy, rheumatoid arthritis,
hyperthyroidism, and hematological malignancies.
 The pathogenesis of spider
angiomata is incompletely
understood, but they are believed to
result from alterations in sex
hormone metabolism, increased in
the estradiol to free testosterone
ratio.
Extremity findings — palmar erythema, nail changes,
clubbing, hypertrophic osteoarthropathy, and Dupuytren's
contracture.

 Nail changes include Muehrcke nails and Terry nails.

 Muehrcke nails are paired horizontal white bands separated by

normal color. The exact pathogenesis is unknown, but it is
believed to be caused by hypoalbuminemia.

 They are not specific for cirrhosis since they may also be seen
in other conditions associated with a low serum albumin, such
as the nephrotic syndrome.

 In patients with Terry nails, the proximal two-thirds of the nail

plate appears white, whereas the distal one-third is red. This
finding is also believed to be secondary to a low serum
albumin.
White nails and paper money skin in liver
cirrhosis
Dupuytren's contracture
 Dupuytren's contracture results from the thickening and
shortening of the palmar fascia, which causes flexion
deformities of the fingers.

 Pathologically, it is characterized by fibroblastic proliferation

and disorderly collagen deposition with fascial thickening.

 The pathogenesis is unknown but may be related to free radical

formation generated by the oxidative metabolism of
hypoxanthine.

 It is relatively common in patients with alcoholic cirrhosis, in

whom it may be found in as many as a third of patients
Dupuytren’s contracture in liver
cirrhosis
 Head and neck findings — Head and neck findings in
patients with cirrhosis may include parotid gland
enlargement and fetor hepaticus.

 Parotid gland enlargement is typically seen in patients

with alcoholic liver disease and is probably due to
alcohol, not cirrhosis per se. Enlargement is usually
secondary to fatty infiltration, fibrosis, and edema rather
than a hyperfunctioning gland.

 Fetor hepaticus refers to a sweet, pungent smell to the

breath of a patient with cirrhosis.
 It is caused by increased concentrations of dimethyl
sulfide, the presence of which suggests underlying
severe portal-systemic shunting
Algorithm of LC diagnosis
 Other signs include:

 Hepatomegaly and a nodular liver.

 Oedema.
 Gynaecomastia and loss of male hair pattern,
 Hypogonadism/testicular atrophy/amenorrhoea (due to the
direct toxic effect of alcohol in alcoholic cirrhosis or iron in
haemochromatosis).
 Kayser-Fleischer ring (a brown-green ring of copper deposit
around the cornea, pathognomonic for Wilson's disease).
 Chest findings — Gynecomastia is seen in up to two-
thirds of patients with cirrhosis.
 It is possibly caused by increased production of
androstenedione from the adrenals, and increased
conversion of estrone to estradiol.

 Men may also develop other features reflecting
feminization, such as loss of chest or axillary hair
and inversion of the normal male pubic hair pattern.
 Hepatomegaly
 The cirrhotic liver may be enlarged, normal sized, or small. While
the presence of a palpable liver may indicate liver disease, a non-
palpable liver does not exclude it.
 When palpable, the cirrhotic liver has a firm and nodular
consistency.
 Physical examination of the liver can be helpful for assessing its
shape, its consistency, and whether there is tenderness of the liver
edge.

 Splenomegaly — is common, especially in patients with

cirrhosis from nonalcoholic etiologies.
 It is believed to be caused primarily by congestion of the red
pulp resulting from portal hypertension.
 Caput medusae
 Caput medusae — The veins of the lower abdominal wall
normally drain inferiorly into the iliofemoral system, while the
veins of the upper abdominal wall drain superiorly into the
veins of the thoracic wall and axilla.

 When portal hypertension occurs as the result of cirrhosis, the

umbilical vein, normally obliterated in early life, may open.
 Blood from the portal venous system may be shunted through
the periumbilical veins into the umbilical vein and ultimately to
the abdominal wall veins, causing them to become prominent.
 This appearance has been said to resemble the head (caput) of
the mythical Gorgon Medusa.
Vein dilatation and tortuosity in the abdominal wall of
a cirrhotic patient suffering from ascites and jaundice

Seen here is "caput medusae"

which consists of dilated veins
seen on the abdomen of a patient
with cirrhosis of the liver.
Algorithm of LC diagnosis
 Signs of hepatic encephalopathy

 Asterixis ('flapping tremor') - suggests hepatic

encephalopathy

 To detect asterixis, take the patient's hand and

gently hyperextend the wrist and joints of the hand,
pushing gently on the tips of the four fingers.
 Ignore the thumb. Hold that position for several
seconds and you will feel a slow, clonic flexion-
relaxation movement against your hand if asterixis is
present.
lnvestigations
 Blood tests
 Liver Functional Tests: should include aspartate transaminase
(AST), alanine transaminase (ALT), alkaline phosphatase (ALP),
bilirubin, gamma-glutamyl transferase (gama-GT) ;
 AST and ALT are raised due to hepatocyte damage;
 gamma-GT is high in active alcoholics.
 Albumin: there is hypoalbuminaemia in advanced cirrhosis
 FBC: occult bleeding may produce anaemia;
 Hypersplenism may cause thrombocytopenia;
 Macrocytosis can suggest alcohol abuse.
 Renal function tests and electrolytes: hyponatraemia may be
present (due to increased activity of antidiuretic hormone). Poor
renal function may represent hepatorenal syndrome.
Mesenchymal activity
 Mesenchymal activity is accompanied by
an increase in γ-globulins and
immunoglobulins.
 Generally,
 IgA is elevated in alcoholic cirrhosis,
 IgG in autoimmune cirrhosis and
 IgM in primary biliary cholangitis
 Investigations
 Coagulation screen: abnormalities of coagulation are sensitive test
of liver function; prothrombin time is increased in advanced
cirrhosis
 Viral antibody screen: to look for evidence of hepatitis B or C
infection.
 Fasting glucose/insulin/triglycerides and uric acid levels: These
should be measured if non-alcoholic steatohepatitis (NASH) is
suspected.
 Autoantibody screen: anti-mitochondrial antibodies are a very
strong indicator of primary biliary cirrhosis.
 Alpha-1-antitrypsin level: to assess for alpha-1-antitrypsin
deficiency.
 Ceruloplasmin and urinary copper for Wilson's disease
 Fasting transferrin saturation, along with a raised ferritin, these
tests can screen for haemochromatosis
SCORING FIBROSIS
 Diagnosis of liver fibrosis may be laboratory and instrumental

 LABORATORY:
 Serum prothrombin time, platelets, ALT, AST, bilirubine, gama-GT,
alfa2 – macroglobulin, haptoglobin, apolipoproteine – alfa1;

 Direct serologic markers of fibrosis include those associated with

matrix deposition - eg, procollagen type lll, amino-terminal peptide
(P3NP), type I and lV collagens, laminin, hyaluronic acid, and
chondrex.

 Other direct markers of flbrosis are those associated with matrix

degradation, eg, matrix metalloproteinases 2 and 3 (MMP-2t MMP-3)
and tissue inhibitors of metalloproteinases 1 and 2 (TIMP-l' TIMP-2).

 Cytokines: PDGF, EGF, TGFB, lL 4, 5, 6, 10

 Scoring fibrosis – METAVIR
 F0 - A normal portal field without fibrosis
 Fl - Focal periportal and perineoductular fibrosis (incomplete
lamellae)
 F2 - Fully established periportal and perineoductular fibrosis building
complete lamellae, with or without sporadic portal-portal bridging
 F3 - Extension of the portal-portal bridging (three or more bridges per
10 portal fields;
 F4 - complete cirrhosis
 lndirect serologic markers of
fibrosis
 The AST:ALT ratio: The normal ratio of aspartate aminotransferase
(AST) to alanine aminotransferase (ALT) is approximately 0.8.
 A ratio greater than 1.0 povides evidence of cirrhosis. However,
findings have been inconsistent.

 PGA index - The combination of prothrombin, gamma glutamyl and

apolipoprotein A1 levels.

 APRI score - The AST:platelet ratio index(),

The AST:platelet ratio index( APRI
score)
 In a meta-analysis of 40 studies, investigators
concluded that an APRI cuttoff of 1.0 had a
sensitivity of 76% and specificity of 72% for
predicting cirrhosis.

 Similarly, an APRI cuttoff of 0.7 had a sensitivity

of 77% and specificity of 72% for predicting
significant hepatic fibrosis.
 lndirect serologic markers of
fibrosis
 Fibrolndex uses the platelet count, AST level and gamma globulin
level to detect significant fibrosis in chronic hepatitis C, but its
accuracy has yet to be validated.

 Fibrometer (based on the platelet count; the prothrombin index;

the levels of AST, alfa-2 macroglobulin, hyaluronate, and blood
urea nitrogen; and age) predicted fibrosis well in chronic viral
hepatitis

 FibroTest contains FibroTest and ActiTest: Assesays alpha2-

macroglobulin, haptoglobin, apolipoprotein A1, total bilirubin,
GGT, ALT, age, sex.

Garcia-Tsao G, Lim JK; Management and treatment of patients with cirrhosis and portal
hypertension: Am J Gastroenterol. 2009
 Imaging
Ultrasound , CT and MRI
are routinely used in the evaluation of cirrhosis,
where it may show a small and nodular liver in
advanced cirrhosis along with increased
echogenicity with irregular appearing areas.
Ultrasound may also screen for hepatocellular
carcinoma, portal hypertension and Budd-
Chiari syndrome (by assessing flow in the
hepatic vein).
 E. Kuntz, H.-D. Kuntz, Liver cirrhosis, 2008

lnstrumental methods in LC diagnosing

 Ultrasonography - in 85-90% liver is resized, surface echo-
structure is nodular, with increased ecogenicity,
inhomogenous with enlarged diameters of portal vien and
splenic vien, splenomegaly

Liver cirrhosis with ascites. Re-opened Macronodular liver cirrhosis due to

umbilical vein, hepatic bifurcation and chronic hepatitis C
hilum of the liver with ramification of the with nodular surface (arrows) and
portal vein inhomogeneous structure
 lnstrumental methods in LC
 Echo Doppler color - visualizes the size (diameter) v. porta, v.
lienalis, and/or the speed and volume of blood flowin in the
portal system (extra-and intrahepatic) and/or blood clots in the
v.porta, v.splenic.

Periumbilical venous
convolutes (V) in abdominal
wall (caput Medusae) and
subperitoneal area (P
peritoneum)

E. Kuntz, H.-D. Kuntz, Liver cirrhosis, 2008

 lnstrumental methods in LC
 Computer tomography (CT) and magnetic resonance
elastography:
 Provides information similar to that of ultrasonography, and it can
identify complications of cirrhosis including portal hypertension and
ascites.
 Help in differential diagnosis with proliferative processes of liver (tbc,
syphilise, Echinococcus, cysts,
abscesses, hemangiomas, (tumors)

Cirrhosis with regenerative node,

recanalized umbilical vein ( caput
Medusae) and ascites (•••) in CT
E. Kuntz, H.-D. Kuntz, Liver cirrhosis, 2008
MRI

Ascites

Hepatic cirrhosis
Enlarged spleen
 Tc99m sulfur colloid scan in case of cirrhosis of the
liver showing impaired colloid uptake in the liver and
increased uptake in the spleen with significant colloid
shift to bone marrow
 Instrumental methods in LC
 Esophago-gastroscopy :
 Reveals enlarged esophageal veins (varices), gastric
veins and presence of portal gastropathy
 A serious problem produced by portal hypertension results
when submucosal veins in the esophagus become dilated.
These are known as esophageal varices.

Varices are seen here in

the lower esophagus as
linear blue dilated veins.
Such varices are easily
eroded, leading to
massive gastrointestinal
hemorrhage
 Esophageal varices

Red spot
Image of portal
hypertensive gastropathy
seen on endoscopy of the
stomach.

The normally smooth

mucosa of the stomach has
developed a mosaic like
appearance, that
resembles snake-skin
 Instrumental methods in LC
 X-ray study of the esophagus with Barium sulphate
(less than esophago-gastroscopy) reveals the
presence of esophageal varices I-lV stages in the
lower esophagus and in cardia.

 Angiography, splenoportography: (including CT

scan) is used for the diagnosis of liver cirrhosis
complications – the portal system thrombosis after
liver resection, with portosystemic shunts, obscure
gastrointestinal bleeding.
 Laparoscope can observe hepatic regenerative
nodular, and get liver biopsy sample.

Spleen enlarges

Cirrhosis of Liver

 Laparoscopy – determines the liver size, surface firm

(visualizes micro/macro nodularity), lien, presence of
peritoneal collaterals, during the procedure could be
perform liver biopsy
Liver biopsy:
The gold standard for diagnosis of cirrhosis is a liver biopsy,
through a percutaneous, transjugular, laparoscopic, or fine-
needle approach.
However, a biopsy is not necessary if the clinical, laboratory, and
radiologic data suggests cirrhosis.
Furthermore, there is a small but significant risk to liver biopsy,
and cirrhosis itself predisposes for complications due to liver
biopsy.
Histologically determine the etiology of LC, the stage of disease,
the activity of hepatic process, the severity of fibrosis.

This method helps to differentiate between chronic hepatitis and

LC, as well as to detect cancer of the liver (primary or MT).
Instrumental methods in LC
 Ultrasound efastography

 The FibroScan device (EchoSens, Paris, France) uses a mild-

amplitude, low-frequency (50 Hz) vibration transmitted
through the liver. It induces an elastic shear wave that is
detected by pulse-echo ultrasonography as the wave
propagates through the organ.

 The velocity of the wave correlates with tissue stiffness: the

wave travels faster through denser, fibrotic tissue.

 Ultrasound elastography (also called transient elastography)

can sample a much larger area than liver biopsy can, providing
a better understanding of the entire hepatic parenchyma.
 Moreover, it can be repeated often without risk.
 Paracentesis
Paracentesis is a procedure in which a needle or catheteris inserted
into the peritoneal cavity to obtain ascitic fluid for diagnostic or
therapeutic purposes
 lnstrumental methods in LC
Paracentesis

 Diagnostic indications
 New onset ascites – Fluid evaluation helps to determine etiology,
to differentiate transudate versus exudate, to detect the presence
of cancerous cells, or to address other considerations
 Suspected spontaneous or secondary bacterial peritonitis

 Therapeutic indications
 Respiratory compromise secondary to ascites
 Abdominal pain or pressure secondary to ascites (including
abdominal compartment syndrome)
Complications of liver cirrhosis
 Refractory ascites
 Bleeding from the esophagus varices, stomach,
hemorrhoids
 Spontaneous Bacterial Peritonitis
 Hepatorenal syndrome
 Hepatopulmonary syndrome
 Coagulopathy
 Hepatic coma
 Hepatocellular carcinoma;
 Portal Hypertension
 Patients with cirrhosis demonstrate increased
splanchnic arterial flow and, accordingly, increased
splanchnic venous inflow into the liver.
 Increased splanchnic arterial flow is explained partly
by:
 decreased peripheral vascular resistance and
 increased cardiac output in the patient with cirrhosis.
 Nitric oxide appears to be the major driving force for
this phenomenon.
 Portal Hypertension
 Increased resistance across the sinusoidal vascular
bed of the liver is caused by fixed factors and dynamic
factors.
 1. Two thirds of intrahepatic vascular resistance can
be explained by fixed changes in the hepatic
architecture.
 Such changes include the formation of regenerating
nodules and, after the production of collagen by
activated stellate cells, deposition of the collagen
within the space of Disse.
 Portal Hypertension
 2. Dynamic factors account for one third of intrahepatic vascular
resistance. Stellate cells serve as contractile cells for adjacent
hepatic endothelial cells.
 The nitric oxide produced by the endothelial cells, in turn,
controls the relative degree of vasodilation or vasoconstriction
produced by the stellate cells.
 ln cirrhosis, decreased local production of nitric oxide by
endothelial cells permits stellate cell contraction, with resulting
vasoconstriction of the hepatic sinusoid.
 (This contrasts with the peripheral circulation, where there are
high circulating levels of nitric oxide in cirrhosis).
 Increased local levels of vasoconstricting chemicals, such as
endothelin, may also contribute to sinusoidal vasoconstriction.
Pathogenic mechanisms responsible for the activation of vasoactive
systems and hyperdynamic circulation in cirrhosis
 Portal Hypertension
Measurement
 During angiography, a catheter may be placed selectively via either the
transjugular or transfemoral route into the hepatic vein.

 The hepatic venous pressure gradient (HVPG) is

defined as the difference in pressure between the
portal vein and the inferior vena cava. Thus, the HVPG
is equal to the Wedged Hepatic Venous Pressure
WHVP value minus the free hepatic vein pressure
(FHVP) value (ie, HVPG = WHVP – FHVP).

 The normal HVPG is 3-5 mm Hg.

 Wedged Hepatic Venous Pressure
(WHVP)
 Wedged hepatic venous pressure (WHVP) is measured by
inflating a balloon at the catheter tip, thus occluding a hepatic
vein branch.

 Measurement of the WHVP provides a close approximation of

portal pressure.

 The WHVP actually is slightly lower than the portal pressure

because of some dissipation of pressure in the sinusoidal bed.

 The WHVP and portal pressure are elevated in patients with

sinusoidal portal hypertension, as is observed in cirrhosis.
 Portal Hypertension and
Variceal Bleeding
 Portal hypertension is defined as a sustained
elevation of portal pressure above normal.
 The normal HVPG is between 2 and 5 mmHg.
 Portal hypertension is present if HVPG is ≥6 mmHg.
 Portal hypertension typically becomes clinically significant
when the HVPG is >10 mmHg, at which point varices may
develop.
 Once the HVPG is >12 mmHg, patients are at risk for
variceal bleeding and the development of ascites.
 Approximately 50% of patients with cirrhosis develop
varices, most commonly in the distal 2 to 5 cm of the
esophagus.
 Portal Hypertension and Variceal
Bleeding
 Variceal hemorrhage is defined as bleeding from an
esophageal or gastric enlarged veins (varices) at the
time of endoscopy, or the presence of large
esophageal varices with blood in the stomach and no
other recognizable source of bleeding.

 The rate of variceal bleeding is approximately 10% to

30% per year.
 Complications of Portal Hypertension
 Portosystemic Collaterals
 Ascites
 Hepatic Encephalopathy

 Portosystemic Collaterals
 Collateral vessels can develop wherever there is a
communication between the portal and systemic circulations.

 Sites include the:

 umbilical vein (resulting in caput medusae),
 dilated abdominal wall veins,
 retroperitoneal veins and the
 clinically most important collateral, esophageal and gastric
varices.
 Ascites
 Ascites is defined as the pathologic accumulation of
fluid in the peritoneal cavity.
 Approximately 85% of patients with ascites have cirrhosis, and
the remaining 15% have a non hepatic causes of fluid retention.

 The formation of ascites in cirrhosis depends on the

presence of the hyperdynamic sate marked by low
peripheral vascular resistance induced by the
 presence of elevated level of vasodilators (such as
glucagon and nitric oxide) in the blood and a
 decreased vascular sensitivity to vasoconstrictive
agents.
 Ascites
 The body attempts to compensate for apparent
decrease in the circulating blood volume by
 increasing cardiac output and
 by activation of the rennin-angiotensin system
which results in increased renal sodium and free
fluid retention.
 Because of this, the intravascular space continues to
be inappropriately replenished and excessive hepatic
lymph production/ascites production continues.
Pathogenesis of ascitis
 Ascites
 Fluid and plasma proteins diffuse freely across the highly
permeable sinusoidal endothelium into the space of Disse.

 Fluid in the space of Disse, in turn, enters the lymphatic channels

that run within the portal and central venous areas of the liver.

 Because the trans sinusoidal oncotic gradient is approximately

zero, that develops in portal hypertension the increased sinusoidal
pressure and increases the amount of fluid entering the space of
Disse.

 When the increased hepatic lymph production observed in portal

hypertension exceeds the ability of the cisterna chyli and thoracic
duct to clear the lymph, fluid crosses into the liver interstitium.

 Fluid may then extravasate across the liver capsule into the
peritoneal cavity.
 Ascites Workup
 The presence of ascites does not always mean cirrhosis/portal
hypertension.

 Work-up of newly identified ascites should include:

 Serum-ascites albumin gradient: calculated by subtracting the ascitic

fluid albumin from the serum albumin.
 An albumin of greater than 1.1 mg/dl indicates portal hypertension as
the cause in almost all of the cases.
 Causes of a "low albumin gradient“ ascites include infection,
malignancy and pancreatitis among others.
 Cell count and ascitic fluid cultures. An ascitic polymorphonuclear cell
count of greater than 250/ml of ascitic fluid is diagnostic of bacterial
peritonitis.
 Ascitic fluid cytology to diagnose malignant ascites.
 Spontaneous bacterial peritonitis
 Ascites may be associated with spontaneous bacterial peritonitis.
 The most common infections in cirrhosis are the so-called
“spontaneous ” infections, namely SBP, spontaneous bacterial
empyema, and spontaneous bacteremia, which share pathogenic
mechanisms and management.
 They are called spontaneous because there is no obvious source of
bacteria that would explain their spread to ascites, pleural fluid or blood.

 lt is thought to be caused by the spread of bacteria across the gut wall

and/or haematogenous bacterial spread.

 Escherichia coli is among the most common organisms implicated.

 Patients of risk groups are those with high neutrophil counts in their
ascitic fluid (>250 neutrophils/mm3 (0,25 x109/L) )
 Early diagnosis is a key issue in the
management of SBP
 It is recommended that a diagnostic paracentesis
should be performed in any patient admitted to the
hospital with:
 cirrhosis and ascites;
 with cirrhosis and ascites who develops compatible
symptoms or signs (abdominal pain or tenderness on
palpation, fever, or chills);
 with cirrhosis and ascites and with worsening renal or
liver function
 Patients with SBP may have one of the
following:
 local symptoms and/or signs of peritonitis: abdominal pain,
abdominal tenderness, vomiting, diarrhea, ileus;
 signs of systemic inflammation: hyper or hypothermia, chills,
altered white blood cell count, tachycardia, and/or tachypnea;
 worsening of liver function;
 hepatic encephalopathy;
 shock;
 renal failure;
 gastrointestinal bleeding.

 However, it is important to point out that SBP may be asymptomatic,

particularly in outpatients
 Hepatorenal Syndrome
 Hepatorenal syndrome is defined as functional renal
failure in cirrhotic patients in the absence of intrinsic
renal disease.

 It is characterized by
 sodium and water retention in patients with renal
vasoconstriction,
 resulting in decreased renal blood flow, glomerular filtration rate,
and urinary output,
 which contribute to azotemia and oliguria (less than 500 ml of
urine/day)
 in association with a low urine sodium concentration (less than 10
meq/L) in a patient with advanced liver disease.
Hepatorenal Syndrome
 Criteria for the diagnosis of hepatorenal syndrome
(HRS):
 cirrhosis with ascites;
 serum creatinine greater than 1.5 mg/dL;
 no improvement of serum creatinine (decrease to a level of
1.5 mg/dL or less) after at least two days with diuretic
withdrawal and volume expansion with;
 absence of shock;
 no current or recent treatment with nephrotoxic drugs;
 absence of parenchymal kidney disease as indicated by
proteinuria >500 mg/day, microhematuria (>50 red blood
cells per high power field), and/or abnormal renal
ultrasonography.
 Hepatorenal Syndrome
 The syndrome may represent an imbalance between renal
vasoconstrictors and vasodilators.
 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 I 2 and atrial natriuretic factor.
 Hepatorenal syndrome progression may be slow (type ll) or rapid
(type l).
 Type I disease frequently is a acompanied by rapidly progressive
liver failure .
 In type Il hepato-renal syndrome, patients may have stable or
slowly progressive renal insufficiency. Many such patients develop
ascites that is resistant to management with diuretics.
Hepatorenal Syndrome
Hepatorenal syndrome: Pathogenesis

Baraldi O. Hepatorenal syndrome: Update on diagnosis and treatment. World J Nephrol 2015;
 Hepatorenal Syndrome
 Hepatorenal syndrome progression may be slow (type ll) or rapid
(type l).
 Type I is characterized by rapidly progressive reduction in renal
function as defined by a doubling of the initial serum creatinine
to a level greater that 2.5 mg/dL or a 50% reduction of the initial
24-hour creatinine clearance to a level lower that 20 mL per
minute in less than 2 weeks.
 At the time of diagnosis, some patients with type 1 hepatorenal
syndrome have a urine output less than 400 to 500 mL per day.

 In type Il hepato-renal syndrome, patients may have stable or

slowly progressive renal insufficiency. Many such patients
develop ascites that is resistant to management with diuretics.
Hepatorenal Syndrome
Diagnosis
 Hepatorenal syndrome is diagnosed when
 a creatinine clearance rate of less than 40 ml/min is
present or
 when a serum creatinine level of greater than 1.5
mg/dl,
a urine volume of less than 500 ml/day,
 and a urine sodium level of less than 10 mEq/L
are present
Hepatic Encephalopathy
 Hepatic (portosystemic) encephalopathy represents a
potentially reversible decrease in neuropsychiatric function
caused by acute and chronic liver disease, occurring
predominantly in patients with portal hypertension.

 The onset often is insidious and is characterized by subtle and

sometimes intermittent changes in memory, personality,
concentration, and reaction times.

 Hepatic encephalopathy is a diagnosis of exclusion; therefore,

all etiologies of altered mental status must be effectively
ruled out.
 Hepatic Encephalopathy
Pathogenesis
 A number of theories have been postulated do explain
the pathogenesis of hepatic encephalopathy in patients
with cirrhosis.
 Patients may have altered brain energy metabolism and
increased permeability of the blood-brain barrier. The
latter may facilitate the passage of neurotoxins into the
brain.
 Putative neurotoxins include:
 short-chain fatty acids,
 mercaptans,
 false neurotransmitters (eg, tyramine, octopamine, beta
phenylethanolamines),
 ammonia, and
 gamma-aminobutyric acid (GABA).
Ammonia Production
 Small intestine: degradation of glutamine produced NH3
 Large intestine: Breakdown of Urea and proteins by normal
flora
 Muscles: proportion to muscle work
 Kidney: increased production when hypokalemia and diuretic
therapy
 Liver: detoxified ammonia into urea
 Brain can also detoxified ammonia into glutamine
Ammonia hypothesis

 Normally, ammonia is detoxified in the liver by

conversion to urea and glutamine
 ln the liver disease or portosystemic shunting, portal
blood ammonia is not converted efficiently to urea.
 Increased levels of ammonia may enter the systemic
circulation because of portosystemic shunting
 Ammonia hypothesis
 Ammonia has multiple neurotoxic effects, including:
 alteration of the transit of amino acids, water, and electrolytes
across the neuronal membrane.
 also can inhibit the generation of excitatory and inhibitory
postsynaptic potentials.

 When ammonia levels rise acutely within the brain, astrocyte

and neuron function are affected.
 Astrocytes rapidly metabolize ammonia to glutamine, but the
subsequent rise in intracellular osmolarity causes astrocyte
swelling and loss.
 Gamma-aminobutyric acid
Hypothesis
 GABA is a neuroinhibitory substance produced in the Gl
tract.
 lt was postulated that GABA crosses the
extrapermeable blood-brain barriers of patients with
cirrhosis and then interacts with supersensitive
postsynaptic GABA receptors.

 This would lead to the generation of inhibitory

postsynaptic potentials.

 Clinically, this interaction was believed to produce the

symptoms of hepatic encephalopathy.
The severity of hepatic encephalopathy is
measured on a five-point scale
 Grade 0 — may appear normal, but tests show minimal changes in
memory, concentration, intellectual function, and 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 — Somnolence to semistup, 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, response to noxious stimuli preserved
 Grade 4—coma, no response to noxious stimuli
 Number connection test used in assessing
encephalopathy.
These 25 numbered circles can normally be joined together within 30
seconds.
 Hypersplenism
 Hypersplenism is a disorder that causes the spleen to rapidly and
prematurely destroy blood cells.

 Spleen major functions is to remove blood cells from the body's

bloodstream.

 ln hypersplenism, the spleen's normal function accelerates, and it

begins to remove cells that may still be normal in function.

 Sometimes, the spleen will temporarily hold onto up to 90% of the

body's platelets and 45 % of the red blood cells
Hypersplenism
 Symptoms of hypersplenism include:

 Easy bruising, easy contracting of bacterial diseases, fever,

weakness, heart palpitations, and ulcerations of the mouth,
legs and feet.
 Individuals may also bleed unexpectedly and heavily from the
nose or other mucous membranes, and from the gastro-
intestinal or urinary tracts.
 Most patients will develop an enlarged spleen, anemia,
leukopenia, or abnormally low white blood cell counts, or
thrombocytopenia, a deficiency of circulating platelets in the
blood
 Anaemia, thrombocytopenia
and coagulopathy
 Anaemia may result from folate deficiency, haemolysis, or
hypersplenism.

 Thrombocytopenia is usually secondary to hypersplenism and

decreased levels of thrombopoietin.

 Coagulopathy results from decreased hepatic production of

coagulation factors. lf present, cholestasis causes decreased
vitamin K absorption, leading to reduced hepatic production of
factors ll, Vll, lX, and X.

 Patients with cirrhosis also may develop fibrinolysis and

disseminated intravascular coagulation
Hepatocellular carcinoma
 Cirrhosis is a major risk factor for HCC.

 It is most often associated with cirrhosis caused by hepatitis C,

B infection, followed by cirrhosis caused by alcohol abuse,
hereditary haemochromatosis.
 Patients with cirrhosis should be screened for HCC.
 The AASLD and the European Association for the Study of the
Liver (EASL) guidelines recommend at least 1 screening per
year for HCC in patients with cirrhosis, using imaging with
ultrasonography, triphasic CT, or MRl .
 Screening using serum alpha-fetoprotein alone is no longer
recommended because of its poor sensitivity and specificity.
 Assessment of the Severity of Cirrhosis
Prognostic models are useful in estimating disease severity and
survival and are used to make decisions regarding specific medical
interventions.
 Two models are used commonly in the care of patients with chronic
liver disease:
 Child-Pugh score
 and the more recently described Model for End-stage Liver
Disease (MELD)

 MELD = 3.8[Ln serum bilirubin (mg/dL)] + 11.2[Ln INR] +

9.6[Ln serum creatinine (mg/dL)] + 6.4
 Lab values used in the MELD calculation:

 Bilirubin, which measures how effectively the liver excretes bile;

 INR (formally known as the prothrombin time), measures the liver’s ability to
make blood clotting factors;
 Creatinine, which measures kidney function. Impaired kidney function is
often associated with severe liver disease.
 Child-Turcotte-Pugh (CTP) classification of the
severity of cirrhosis
Points*

1 2 3
* 5-6 points= CTP class A; 7-9 points = CTP class B; 10-15 points = CTP class C.

Encephalopathy None Grade 1-2 Grade 3-4

(or precipitant-induced) (or chronic)
Ascites None Mild/Moderate Severe
(diuretic-responsive) (diuretic-refractory)

Bilirubin (mg/dL) <2 2-3 >3

Albumin (g/dL) >3.5 2.8-3.5 <2.8

PT (seconds <4 4-6 >6

prolonged) <1.7 1.7-2.3 >2.3
or INR
 Since 2002, liver transplant programs in the United States
have used the Model for End-Stage Liver Disease (MELD)
scoring system to assess the relative severity of patients'
liver disease.
 Patients may receive a MELD score of 6-40 points.

 The 3-month mortality statistics are associated with the

following MELD scores :
 MELD score of less than 9 - 2.9% mortality
 MELD score of 10-19 - 7.7% mortality
 MELD score of 20-29 - 23.5% mortality
 MELD score of 30-39 - 60% mortality
 MELD score of greater than 40 - 81% mortality
 MELD = 3.8[Ln serum bilirubin (mg/dL)] + 11.2[Ln
INR] + 9.6[Ln serum creatinine (mg/dL)] + 6.4
If the patient has been dialyzed twice within the last 7 days, then the value
for serum creatinine used should be 4.0

 MELD is a prospectively developed and validated chronic liver

disease severity scoring system that uses a patient's laboratory
values for serum bilirubin, serum creatinine, and the international
normalized ratio for prothrombin time (INR) to predict survival.
 The Model for End-Stage Liver Disease (MELD) system was
implemented February 27, 2002 to prioritize patients waiting for a
liver transplant. MELD is a numerical scale used for adult liver
transplant candidates. The range is from 6 (less ill) to 40 (gravely
ill). The individual score determines how urgently a patient needs
a liver transplant within the next three months. The number is
calculated using the most recent laboratory tests.
Lab values used in the MELD calculation:

 Bilirubin, which measures how effectively the

liver excretes bile;
 INR (formally known as the prothrombin time),
measures the liver’s ability to make blood
clotting factors;
 Creatinine, which measures kidney function.
Impaired kidney function is often associated with
severe liver disease.
MELD Score
 In interpreting the MELD Score in
hospitalized patients, the 3 month mortality
is:
 40 or more — 71.3% mortality
 30–39 — 52.6% mortality
 20–29 — 19.6% mortality
 10–19 — 6.0% mortality
 <9 — 1.9% mortality
 The four MELD levels are:
 greater than or equal to 25
 24-19
 18-11
 less than or equal to 10
 Child-Turcotte-Pugh (CTP) classification of the
severity of cirrhosis
Points*
1 2 3
PT=Prothrombin time; INR=international normalized ratio.
* 5-6 points= CTP class A; 7-9 points = CTP class B; 10-15 points = CTP class C.
Encephalopathy None Grade 1-2 Grade 3-4
(or precipitant-induced) (or chronic)
Ascites None Mild/Moderate Severe
(diuretic-responsive) (diuretic-refractory)

Bilirubin (mg/dL) <2 2-3 >3

Albumin (g/dL) >3.5 2.8-3.5 <2.8

PT (seconds <4 4-6 >6

prolonged) <1.7 1.7-2.3 >2.3
or INR
Clinical Variable 1 Point 2 Points 3 Points

Encephalopathy None Grade 1-2 Grade 3-4

Ascites Absent Slight Moderate or large
Bilirubin (mg/dL) <2 2-3 >3
Albumin (g/dL) >3.5 2.8-3.5 < 2.8
Prothrombin time(seconds < 4 s or INR < 4-6 s or INR 1.7-2.3 >6 s or INR >2.3
prolonged or INR) 1.7

Child Class A = 5-6 points,

Child Class B = 7-9 points,

Child Class C = 10-15 points

Tests for Liver Cancer
 Patients with cirrhosis must be screened
every 6 months to check for the
development of liver cancer
(hepatocellular carcinoma).
 To do this, a doctor will use both a blood
test to check for levels of alpha-fetoprotein
and an imaging test (ultrasound, MRI, or
CT scan).
 Stimulators such as HGF ( hepatocyte
growth factor),
 TGF- ( transforming growth factor), EGF ( epidermal
 growth factor), FGF-1 and 2 ( fibroblast growth
 factor), CT-1 ( cardiotrophin 1) and HSS ( hepatic
 stimulatory substance) affect DNA synthesis and the
 replication of hepatocytes. • The permissive substances,
 which are considered to be essential for the effectiveness
 of the growth factors, are glucagon, insulin, IGF-I and
 II, T3 and T4, calcitonin, ACTH, oestrogens, vasopressin
 and interleukins. • HGF is regarded as the most effective
 mitogen, whereby this effect is enhanced by noradrenaline.
 Cirrhosis pathophysiology
 Regeneration is rebundant, appear units and nodules of
regeneration that compress the parenchymal and
fibrotic tissue around
 These 2 processes – fibrosis and regeneration in the
form of nodules required for the diagnosis of the liver
cirrhosis
Cirrhosis pathophysiology conclusion
 Liver cirrhosis is caused by characteristics of the etiologic
factors and mechanisms of auto-progression

Inflammation

Regeneration
Restructuring of
Necrosis of liver
vascular system
parenchyma Active fibrosis

Parenchymal ischemia

 In autoimmune hepatitis and viral hepatitis – fibrogenesis

progresses from the portal ducts in the central lobular zone.
 ln alcoholic hepatitis – Fibrosis begins with a central lobular field
due to necrosis of hepatocytes in this area
 Metabolic decompensation
 Development of metabolic insufficiency (also known as
cellular decompensation) is due to:
 a significant loss of hepatocytes (e. g. mass necroses)
and/or a
 loss of function of the hepatocytes (e. g. insufficient
numbers of hepatocytes and accumulation of waste
products in cirrhotic transformation with the
development of shunts).
Instrumental methods in LC
 Fibroscan

 MR elastography

 Magnetic resonance elastography uses a vibrating device to

induce shear waves in internal organs, which are detected by a
modified magnetic resonance imaging machine. In this color-
coded image, areas toward the red end of the spectrum are
stiffer and therefore contain more fibrosis than areas toward
the violet end of the spectrum
Hepatocellular carcinoma
 Cirrhosis is a major risk factor for HCC.
 The risk varies according to the cause of cirrhosis.
 It is most often associated with cirrhosis caused by hepatitis C
infection, followed by cirrhosis caused by hereditary
haemochromatosis
 Worldwide, HCC as a result of cirrhosis secondary to hepatitis
B infection causes a large number of deaths.

 The risk of HCC is lower in those with alcoholic cirrhosis (8% 5

–year occurrence) or primary biliary cirrhosis (4% 5-year
occurrence)