Examination of a patient

with liver disease

Dr. Alajos
j Pr

First Department of Medicine

University of Pcs
Examination of a patient
with liver disease

1. History

2 Ph
2. Physical
i l examination
i ti

3 Laboratory studies
3.

4. Liver biopsy
 Examination of a patient with liver disease
1. History
y
Present complaints:
(Liver diseases: Often symptomfree - with no complaint
only weekness, tiredness, or itching =pruritus!)
Sometimes: fever, loss of weight, pain
jaundice oedema,
jaundice, oedema ascites,
ascites hematemesis
changes in color of urine, stool
changes in behaviour (hetero
(hetero--anamnesis)
Family history:
history: genetic factors (autoimmunity, gallstone,
Wilson, hemochromatosis)
environmentall viral hepatitis in the family
environmenta
Occupation:: health care workers (HCV)
Occupation
chemical exposition (vinylchloride,
(vinylchloride PVC)
Habits: alcohol
alcohol,, smoking
Drugs paracetamol, INH, halothan (1100!)
Previous diseases:
diseases: viral hepatitis, blood transfusion, surgery
gallstone, tumor (lung, colon, stomach)
2. Physical examination
Inspection
sclera (subicterus)
skin (icterus, spider nevi, xantelasmas, suffusiones
palmar et plantar erythema,
gynecomastia,
gy , testis atrophy
p y
dilated abdominal wall veins (Caput medusae)
ascites,,
flapping tremor, ataxia
Auscultation?
Palpation:: abdominal masses, hepatomegaly
Palpation
(size,
( , surface,, edge, y, tenderness)
g , consistency,
spleen (potal hypertension+
gallbladder,, hyrops,
g y p , Courvoisier sign, g ,
Percussion:: liver size, disapperance of liver dullness
Percussion
 Cirrhosis: physical signs

spider nevi
varices

hepatomegaly splenomegaly
ascites
caput medusae

erythema

atrophia suffusiones
ff i
testis
oedema
d
3. Laboratory studies

a) biochemical liver test

( i
(urine, stool,
t l serum, plasma)
l )
b) virological studies

c) immunological
u o og ca tests

d) imaging techniques

e)) endoscopy
d

f) biopsy
a) Biochemical tests
Urine: bilirubin, urobilinogen
stool: acholic,
acholic
Serum
bilirubin (conjugated = direct,
direct
unconjugated = indirect)
enzymes
necrosis ALT /GPT (cytoplasmic,-
(cytoplasmic,- acute, viral, biliary)
AST/GOT ( mitochondrial,, - chr,, alcoholic))
excretion: ALP, GGT (obstruction, tu, pbc, alcoholic)
synthesis:: pseudocholinesterase
synthesis
(prothrombin)
proteins albumin, globulins (elfo)
tumor markers (AFP,
( C
CEA))
Plasma ammonia
b)) Virological
g tests

HAV: anti-
anti-HAV (IgM
(IgM, IgG) - only acute
HBV: HBsAg, HBe Ag, HBV-
HBV-DNA
anti--HBs, anti-
anti anti-HBc (IgM) anti
anti--HBe
HCV: HCV-
HCV-RNA,
RNA HCVcore ag,
ag
anti--HCV
anti
HDV: HDV-
HDV-RNA
HEV: anti
anti--HEV, HEV-
HEV-RNA - only acute
CMV,
EBV
Hepatitis B virus
Chronic hepatitis B virus
ir s infection
H
Hepatitis
titi DDelta
lt virus
i
Hepatitis Delta
Hepatitis C virus

HCV core
The course of HCV infection
Etiological diagnosis of viral hepatitis

HBV HCV HDV

Infection HBsAg anti-

anti-HCV anti-
anti-HDV

Vral replication HBV

HBV--DNA HCV
HCV--RNA HDV
HDV--RNA

Liver disease anti--HBc-

anti HBc-IgM anti
anti--HCV-
HCV-IgM anti
anti--HDV
HDV--IgM
c)) IImmunological
l i l tests
t t
Serum gammaglobulin, electrophoresis
Immunoglobulins
IgA - alcohol
IgG - autoimmune hepatitis
IgM - PBC

Autoantibodies (ab)
antinuclear (ANA),
(ANA), smooth muscle (SMA) LE
= autoimmune
t i hepatitis
h titi
antimitochondrial ab (AMA) = primary biliary cirrhosis
perinuclear anti
anti--neutrophil ab (pANCA)
= primary sclerosing cholangitis
d) Imaging techniques
Ultrasound:: non
Ultrasound non--invasive,
invasive cheap
cheap,
easily repeteable, no X-
X-ray
(but problem: the obesity)
CT, MRI tumors
cholegraphy (oral, or i.v.)
ERCP (endoscopic retrograd cholangio-
cholangio-
pancreatography)
bile ducts, panceatic head
PTC (percutaneous trashepaticus
cholangiograpgy)
angiography tumors,
scintigraphy
e) Endoscopy (oesophageal varices)
f) Biopsy

(Invasive, with risk and sample error,

not easily accepted by the patients)

Indication:: suspition of chronic liver disease

Indication
((AIH,, PBC,, HCV,, HBV,, TBC,, Wilson,, haemochromatosis))
suspition of liver tumor
fever of undetermined (tbc, tu, immune
assessment of treatment
Contraindication: protrombin < 60%
thrombocyte (platelet) < 80.000
hemophilia
empyema thoracis
thoracis,
terminal stage
 Liver biopsy
Directt way off visualizing
Di i li i
of liver disease

Reflects
- activity of necro-inflammation (grade)
- extent of fibrosis (stage)
- concomittant processes (e.g.virus
( i + ethanol)
th l)
- clinical diagnosis and differential diagnosis
- i di ti
indication and
d assessmentt off treatment
t t t

Semi-quantiative score systems

(Knodell, Ishak,, METAVIR)
Computer morphology
(useful for quantitation of fibrosis)
fibrosis)
 Advantages
g of liver biopsy
p y

- May play a role in etiological diagnosis

- HBV,
HBV HCV infection
- alcohol
- NASH
- autoimmune (AIH, PBC, PSC) diseases
- Wilson-disease
- drug
drug-induced
induced liver disease

- Immunhistology
useful for tumor differential-diagnosis
 Problems of biopsy
y
Invasive procedure:
- not without risk (0.3% morbidity , 0.03% mortality)
- aversion of patients from the repeated biopsies

Limitations:
- sampling error
- a sample of 20 mm long, 1.4 mm , wih 11 portal tracts needs
- captures
t only
l 1:1 50.000
50 000 off the th liver
li
- heterogenous distribution of fibrosis
(for cirrhosis biopsy may be false negative in 10
10- 20%)

- the provided information is static

(concerning the fibrogenesis and progression)
Instead of liver biopsy?
biopsy?
th
there i a need
is d for
f non
non--invasive
i i methods
th d
which can reflect the dynamics of fibrosis
the progression and the regression
regression,,
(Extracellular matrix formation and degradation),
degradation),

which can be useful

- in the initial pre-
pre-treatment studies
studies,,
- in
i the
th monitoring
it i off therapy
th and
d
reliable for evaluating of its efficacy
efficacy,,

which are sensitive and liver specific

specific,,
reproducible,
reproducible
p , fast and safe methods,
methods,
and could be performed repeatedly
repeatedly..

Two groups:
groups: - imaging techniques
- serum markers
Question:
could imaging
g g techniques
q eliminate
the problems of sampling error?

Ultrasound, Doppler, CT, MRI

MRI::
show morphological changes of the cirrhotic liver:
- reduction of the size of the righ lobe and concomittant
enlargement of the left lobe
- nodularity of liver surface
- pattern of hepatic venous blood flow,
- progressive
i arterialization
t i li ti off hepatic
h ti parenchyma
h
- microcirculatory changes of sinusoidal capillarization

Fibroscan
a new device based on transient elastography for
the measurement of liver stiffness - and fibrosis.
f
 FibroScan
Measures liver stiffness by
elastometry:
l t t

A vibrating device creates

elastic waves in the liver
and their propagation is
tracked by ultrasound.
Th speed
The d off propagation
ti off
waves is related to the stiffness
of the liver tissue measured.

Liver stiffness is directly correlated

to the degree of fibrosis.
 FibroScan
Non-invasive,
Non- invasive reliable
reliable,
direct examination of
the liver
liver,

without any risk and

side effects,

results obtained at the

moment of measurement
(duration of examination
about 5 minutes),

repeatable, useful for

regular monitoring of
Price: 70.000 Euro anti--fibrotic
anti therapy.
Elastography in chronic hepatitis C patients

Beaugrand, M, EASL Conference, Torino, 2004

Indirect fibrosis parameters
Biochemical - hematological tests

aminotransferases
i f (AST/GOT,
(AST/GOT ALT/GPT)
-glutamyl transpeptidase (GGT)
prothrombin
cholesterol
2macroglobulin
g
globulin
apolipoprotein A1,
haptoglobin
platelet
GOT / GPT ratio
Indexes GOT / platelet ratio
Forns index
FIBROTEST SCORE
Direct fibrosis markers
A) Markers of ECM deposition:
-procollagen-III-peptide (P-III-P)
-tenascin
-TIMP (metalloproteinase inhibitor)
-TGF (transforming growth factor)

B) Markers of matrix degradation:

procollagen
ll IV C peptide
tid
collagen IV
undulin
MMP (matrix metalloproteinase)

C) other: hyaluronic acid, laminine

 Direct fibrosis markers
R fl t both
Reflect b th matrix-
matrix
t i -deposition
d iti and
d -degradation
d d ti
even in the early (F1-
(F1-2) fibrosis stages and
may correlate with the progression

Fib
Fibrogenesis
i

matrix turnover: laminin, tenascin, hyaluronan

Conclusion on diagnosis of fibrosis
Liver biopsy remains the gold standard
for etiological diagnosis, grading and staging
and assessment of treatment - but has limits.

Imaging techniques and

serological markers
- non
non-invasive
invasive, repeteable,
repeteable reproducible
reproducible,
- provide information of the entire liver,
- differentiate between minimal and advanced
fibrosis - though still can not replace biopsy,
- may be useful in monitoring of patients
t
treated
t d for
f chronic
h i liver
li di
diseases

They represent a promising new chapter in

hepatology, combination panels of these methods
can lead to further developments.
Classification of liver diseases
accordingg to the aetiologygy

- alcoholic
- viral ((HAV, HBV, HCV, HDV, EBV, CMV, HS))
- autoimmune (AIH, PBC, PSC)
- metabolic (Wilson,
(Wilson haemochromatosis)
- drugs
- biliary
- circulatory
y g hearth failure)
((right
- malignancies
Manifestations of liver diseases

1. Jaundice
2 Hepatomegaly
2.
3. Hepatitis syndrome
4. Cirrhosis
5. Tumors
1. Jaundice

IIndirect
di t - unconjugated-prehepatic
j t d h ti
- hemolysis (reticulocyte,LDH, RBC lifespan)
- Gilberts disease (functional, fasting probe)
Direct - conjugated
j g
- hepatic (hepatitis) (medical)
- post-hepatic (surgical
( surgical - obstruction)

Note: long-lasting
long lasting jaundice = bad prognosis!
2. Hepatomegaly

Palpable liver - without true enlargement

(emphysema,visceroptosis)

Enlargement of the liver due to

- venous congestionti (right
( i ht heart
h t failure)
f il )
- hepatic infitrations (fatty liver, tbc, leukemia)
- inflammation (hepatitis virus, alcohol, AIH)
- bile duct stones, tumors (obstruction)
- tumors, cysts

Hepatomegaly itself does not mean bad prognosis!

3 Hepatitis syndrome
3.

Acute or chronic (6 months)

with or without jaundice,
j ,
but with transaminase (GOT,GPT) elevation

Aetiology: virus, alcohol, autoimmune, drug,

Wil
Wilson, bili
biliary i f ti
infection
Diagnosis: sebi, enzymes, viral markers,
immune tests
p y
Biopsy
4. Cirrhosis

Polyetiological inflammatory liver disease

chronic, liver cell necrosis
regeneration
fib
fibrosis
i
distorsion of hepatic architecture
alteration
l i off hepatic
h i blood
bl d flow
fl
portal hypertension (ascites, varices, bleeding)

Consequences: hepatic failure, jaundice

(d
(decompensation)
ti )
encephalopathy
5. Tumors
Benign: adenomas,
adenomas
hemangiomas,
cysts
t
Malignant:
Primary (HCC, cholangiocc)
Secondary
Seco da y ((metastases)
etastases)
(pancreas, breast, lung, colon, stomach)

Diagnosis: pain, loss of weight, fever, jaundice

tumor mass
ALP, US, GGT, ALP, LDH, DGP
CT,, MRI, aangiography,
C g og ap y, sc
scintigrapy
t g apy
US-guided targeted biopsy