Internal medicine: lec# 40

Date: 24/12/2009

Investigation of liver
diseases

Dr. Niazy Abu Farsakh.

Done By: Samer Q.Kuleib

Today we will talk about investigation of liver disease, this include pathological, biochemical and
radiological investigations, so I need you to concentrate with me because this subject is very difficult
and very important in medicine.
Types of liver disease:
1. Hepatitis: we have acute and chronic hepatitis, what determine this mainly is the
DURATION of the disease, if the duration is less than 6 months then it is acute hepatitis,
if the duration is more than 6 months then it is chronic.
2. Cirrhosis: very related to hepatitis whereas most of factors that lead to hepatitis could lead to
cirrhosis (most factors not all).
3. Vascular diseases, abscesses, cysts.
4. Infiltrating diseases of the liver.
In any liver disease the pathological changes are caused by:
1. Hepatocellular injury
2. Cholestasis: any condition of inability to secret bile, condition when the bile ducts are blocked.
But before talking about these I am going to talk about liver anatomy and histology:

At the microscopic level, the liver consists of hexagonal shaped functional units called hepatic
lobules. These, in turn, are made up mostly of hepatocytes (the commonest type of liver cell)
arranged in thin layers that radiate from the central canal (central vein) to the periphery of the
lobule. Between the radiating rows of hepatocytes are small blood vessels called sinusoids. These
receive oxygen-rich blood from the hepatic artery and nutrients from the intestines via the portal
vein. The oxygen and nutrients diffuse through the capillary walls into the liver cells.
Within the sinusoids are specialized macrophages called Kupffer cells that figure prominently in the
recycling of old red blood cells.

At the corners of each lobule is a complex, called the portal area, composed of branches of the
hepatic portal vein, hepatic artery, bile duct, and nerve. Bile drains from the hepatocytes by the
many small bile ducts that unite to form the main bile duct of the liver, the hepatic duct. This joins
the cystic duct, which leads from the gallbladder, to form the common bile duct, which drains into
the duodenum.
The central canal is a blood vessel in the middle of each lobule which receives blood from the
hepatic portal vein and hepatic artery via the sinusoids and drains the blood into the hepatic vein.
Back again:
1. Hepatocellular injury: it occurs in hepatitis and cirrhosis but what is the difference?
Hepatitis induces necroinflammatory reaction.
Cirrhosis induces necroinflammatory reaction + fibrosis + regenerating nodules.

Regenerating nodules lack the specific organization and the

architecture of the liver, you will find hepatocytes over each other with
no vessels nor biliary system, so they will not function properly
although the cells are healthy, it is just like when you bring scientists
and put them in a room without any equipments and demand from
them to make a computer, off course they cant, the same thing with
hepatocytes although they are healthy but they cant function because
they lack the equipments (vessels and biliary system) to perform their
job.
2. Cholestasis: the function of biliary system is to secrete bile, the bile consists of bile salts
(responsible for digestion & absorption of fat) & bile pigment & waste products, we
mainly concentrate on bile salts and BILIRUBIN (is a yellow breakdown product of
normal heme catabolism. Its levels are elevated in certain diseases and it is responsible for the yellow color
of bruises and the brown color of feces.)

Recall: the biliary system or the bath of bile from the liver to the duodenum:
Hepatocyte
bile capillaries
small bile duct
RT & LT hepatic duct
Common hepatic duct
common bile duct (= cystic duct + common hepatic duct)
ampulla of vater

We have 2 types of cholestasis:

1. Interhepatic cholestasis: here the bile flow rate is slow there is no obstruction or there is
a mild obstruction in a small bile duct of lobules, it is like ridding your car in an
overcrowded street, there is no accident (obstruction in a main bile duct) but there are some
cars on the right side of the road or there are some people want to cross the road (mild
obstruction in a small bile duct) so you ride very slowly so the same thing is here, a small
bile duct obstructed, so the bile will search for another way to go out and these ways is
already full with bile so the flow rate is decreased.
2. Extrahepatic cholestasis: there is obstruction in a major bile duct (common hepatic or
common bile duct ), it likes you ride on a high way and there is a huge accident so you
cant go forward.
Now we will talk about the tests that we used in liver diseases, when we do these tests we can know
if the pt has liver disease and the degree of damage and the cause of the disease, so we want to evaluate
the total function of the liver, how much remaining of the liver, is it working properly or not and what
is the underlying cause, in conclusion these tests will give us an idea about the degree of liver damage.
These tests include:
1. Biochemical tests (transaminase, albumin, ammonia, glucose, ALP,.)
2. Special tests (viral marker, autoantibody, tumor marker
3. Hematological tests (CBC, PT)
4. Radiological test (ultrasound, CT, MRI, Angiogram)
5. Liver biopsy.
And we are going to talk in details about all these tests.

I.

BIOCHEMICAL TEST:

1) TRANSAMINASE:
They are mainly elevated in liver cell injury, and they are the most sensitive indicator of
liver cell injury.
We have 2 types of transaminase elevated in liver injury:
1. ALT (alanine aminotransferase): it is found mainly and mostly in the liver,
because of that it is more specific than AST.
2. AST (aspartate aminotransferase): it is found in many places, it is found in brain,
heart, kidney, muscles, RBCs, and liver, so it can increase in any injury of these
organs.

When we want to investigate liver disease, we do AST & ALT:

1. If the ALT only raised (AST normal), then we are dealing with liver
disease.
2. If AST only raised (ALT normal), we are not dealing with liver
disease.
3. If ALT & AST are raised, then we are almost always dealing with liver
disease.
4. If AST & ALT are normal, we can say there is no liver injury.
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They are markedly increased in hepatocellular injury like hepatitis and cirrhosis.

The normal level of these enzymes is around 40s AST (12-40 u/L), ALT (5-40 u/L)
(these values from kumar).

These enzymes mildly elevated (more than 10 times) in:

1. Fatty liver.
2. Nonalcoholic steatohepatitis.
3. Chronic viral hepatitis.
4. Liver cirrhosis.

They are markedly increased in:

1. Alcoholic liver disease.
2. Autoimmune hepatitis.
3. Acute viral hepatitis.
4. Toxic and drug-induced liver necrosis.
5. Shock or ischemia to liver.

2) ALKALINE PHOSPHATASE (ALP):

Indicates biliary system injury.

Found in
1. Liver.
2. bone (elevated ALP indicates that there could be active bone deposition
occurring as ALP is a byproduct of osteoblast activity such as the case in Paget's
disease of bone)
3. Intestine: released from the intestine when there is gangrene, it is an acute
emergency.
4. Placenta: in pregnancy we accept high level of ALP.

How we can differentiate ALP of liver origin?

We look for an enzyme called -GT (gamma glutaml transpeptidase), this
enzyme only found in the liver, if you blow on liver it will release -GT, or we
look for 5-NT (5-nucleotidase), so if you find ALP & -GT raised this mean
that there is a problem in the biliary system of the liver.
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So ALP increased in hepatobiliary condition & the normal value of ALP in KAUH
and other labs is around 150 u/L, so dont forget the values because sometimes we
bring you a case and we dont mention the normal values, so be careful.

In hepatocellular injury ALP is slightly increased, and in hepatobiliary injury ALT &
AST slightly increased it is like (bait l 3azah, lamma ymoot wa7ad, ahlo byz3lo kteer
3laih o jeerano byz3lo shwai 3laih) so ALP & AST & ALT are neighbors when ALP
is increased in hepatobiliary injury AST & ALT slightly increased to support their
neighbor and vice versa. But if we want to determine the main problem we look for the
markedly increased enzyme, for ex if we found that AST & ALT are markedly increased
and ALP is slightly increased so we think in hepatocellular injury and so on.

Serum bilirubin is very important in liver diseases, so we are going to talk in details
about it in the next lecture, but I want to talk about very important information, as you
know bilirubin is mainly excreted in the biliary system, so if a small bile duct was
obstructed or destructed by a space occupying lesion like tumor or granuloma, the
bilirubin will find another way (another small bile duct) to go out, so it will not
increased, but the obstructed bile duct will produce ALP.
Whenever you find a normal serum bilirubin level & increased ALP of liver origin
(associated with increased -GT), then it is almost always a space occupying lesion
in liver.

3) SERUM ALBUMIN:

Albumin EXCLUSIVELY synthesized in the liver and its half life about 3 weeks,
it decreases in chronic and sever liver disease, but if we have hypoalbuminemia is
that mean that we are exclusively dealing with liver disease?
Of course not, because the level of albumin in the blood determines by 3 processes
and if there is any abnormality in these processes you will see hypoalbuminemia:
1. Synthesis in the liver (liver disease).
2. Excretion by the kidney (nephrotic syndrome) or the intestine (protein losing
enteropathies).
3. Intake of proteins (malnutrition).

4) SERUM LIPIDS: (dr didnt talk about them)

Cholesterol level increased in liver diseases especially cholestatic diseases with

decreased esterified fraction.

Abnormal lipoprotein X in biliary cirrhosis.

Triglyceride level increased due to decreased mobilization from liver cells.

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5) BLOOD SUGER:

Pt with fulminant hepatitis or terminal liver cirrhosis could develop hypoglycemia,

so any pt who is admitted for severe hepatic failure, put him on I.V glucose to
prevent his death from hypoglycemia, because if he dies in the hospital from
hypoglycemia shame on you, because you can easily prevent that, we are not talking
about liver transplantation, so be careful.

So it is a rule: whenever you had a pt with hepatic

failure put him on I.V GLUCOSE to prevent
hypoglycemia

You could see impaired Glucose tolerance test in liver cirrhosis.

6) SERUM AMMONIA:

Ammonia released in the gut mainly in the last colon by the action of bacteria on
proteins, and then ammonia absorbed and goes to the liver.

The liver detoxifies ammonia to urea by Krebs cycle, then urea will be excreted by
the kidneys, this is the main way to excrete ammonia, but there is another way by
muscles which convert ammonia to glutamine.

In severe liver disease (when detoxification of ammonia decreased) or when there

is portal systemic shunting as in cirrhosis, serum ammonia will increase and as
you know ammonia can cross BBB (blood brain barrier) and cause brain damage or
brain dysfunction which will result in what we call hepatic encephalopathies.

May be there is no correlation between the amount of ammonia & the degree of
hepatic encephalopathies, but the main cause of hepatic encephalopathies is
elevation of ammonia.

Whenever you suspect a pt with hepatic encephalopathies always

check his serum ammonia, because main cause of hepatic
encephalopathies is high serum ammonia

II.

Special tests:
1. VIRAL MARKERS:

The most common etiology of liver disease in human is viral infection,
mainly hepatitis viruses. As you know we have many types of hepatitis virus:
a) HAV: the most common one, 80% of population got this virus
during childhood or adolescent, so in order to diagnose HAV you
should look for IgM anti-HAV, but if you find IgG anti-HAV this
mean that the pt is immunized or had a past infection.
b) HBV: we look for HBsAg which mean that the pt had or has
infection, so to determine the acute infection we look for HBV-DNA
(and IgM anti-HBcAg), if HBV-DNA (-ve) and HBsAg (+ve) (and
IgG anti-HBcAg (+ve)) this indicate chronic infection, (we also look
for Hbe Ag and Ab), in the past the assessment of the viral DNA was
a difficult process, but now we can do it easily but it is very
expensive around 100 JD, while HBsAg is very cheap around 4 JD,
so we dont order viral DNA assessment unless we really need that to
assess the level of the disease because above certain level the pt will
become more liable to develop HCC (hepatocellular carcinoma) and
liver cirrhosis, by the way all the hepatitis viruses are RNA viruses
except HBV which is DNA virus.
c) HCV: it cause chronic infection in around 80% of cases, the least
common cause of fulminant hepatitis among hepatitis virus, the
usual screening test for HCV is HCV-Ab, if it (+ve) we assess the
level of the virus and we do that by assessing HCV-RNA.
d) HDV: it never come alone it always come with HBV as:
1) Co infection: it comes with HBV
2) Superinfection: the pt already has HBV, and then HDV
comes.
Because of that vaccination against HBV protects against
HDV, nowadays HDV almost eradicated from the world.
e) HBE: it is fatal when a pregnant lady becomes infected with it, the
mortality rate could reach 20%.

Dr talks about 2 important questions that may come in the exam:

Q1: Which one of hepatitis viruses doesnt cause chronic infection?

A1: HAV & HEV they dont cause chronic infection, we may laugh on you and tell you
that 1 or 3 % of HAV or HEV could develop chronic hepatitis, dont take it, they
NEVER EVER cause chronic hepatitis, so be careful.
Q2: which of hepatitis virus is the least common cause of fulminant hepatitis?
A2: HCV, because in 80% it is cause chronic infection, the chance of developing
fulminant hepatitis is increased with the virus that cause acute infection like HAV &
HEV.

2. AUTOANTIBODIES:

As we said the most common cause of liver disease in our region is virus,
but autoimmune diseases could affect the liver and cause many diseases, but
we will concentrate on 2 diseases AIH (autoimmune hepatitis) & primary
liver cirrhosis.

In primary liver cirrhosis you will find very specific auto-Ab, AMA
(antimitochondrial antibody), only seen in this disease.

AIH: we have many types:
a) Type 1: the most common type and we see 2 auto-Ab:
1) ANA (antinuclear Ab): in 80-90% of cases, ANA also found
in SLE (not specific for hepatitis), because of that in the past
AIH was called lupoid hepatitis.
2) ASMA (anti smooth muscle Ab).
b) Type 2: around 10% of AIH, we found LKM-1 (liver kidney
microsome 1).
c) Type 3: we will find Antibodies to soluble liver antigen.

3. TUMOR MARKERS:

Liver is liable for a lot of tumors, these tumors may arise in hepatocyte
(HCC), or in the biliary tree (cholangiocarcinoma), as you know in order to
diagnose a malignancy we should do tissue diagnosis, but sometimes we ask
for tumor marker which is easier and mainly for screening purpose do u
know why?
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Because any pt with chronic liver disease is more liable to develop

malignancy especially with liver cirrhosis, so we should be sure that our
pt doesnt develop cancer, and we do that by tumor markers.

We mainly concentrate on 2 markers:
1) -Fetoprotein: increased in hepatocellular carcinoma.
2) CA 19-9: increased in tumors of biliary tree.

III.

HEMATOLOGICAL TESTS:
1. RBCs: Hb could be lost, this will cause anemia, this anemia could be
a) Macrocytic: due to folate deficiency which is mainly stored in the liver.
b) Microcytic: due to hemolysis.
c) Spur cell anemia: type of anemia cause by defects in cell membrane.
d) anemia could be associated with bleeding due to variceses and ulcers.
2. WBCs: you will find leucopenia in hypersplenism and leucocytosis in pyogenic
infections.
3. PLTs: may be low due to cirrhosis and hypersplenism.

4. ESR: elevated in autoimmune diseases

5. PT (prothrombin time): the most important hematological test

Prolonged in severe liver disease (normal PT 12-16 seconds & INR 1-1.3)

the best prognostic test for severity of liver disease, because
almost all the coagulation factors are synthesized in the liver except factor 8,
and these factors have very short half life (hours), and they are reflected or
measured by PT, so PT used to detect day to day changes, so we measure
PT everyday to follow up our pt, and we dont use albumin for this purpose
(although albumin and coagulation factors synthesized in the liver) because
albumin half life is 3 weeks, so when we check the albumin we check it
again in 2-3 weeks and thats not helpful.

IV.

RADIOLOGICAL STUDIES:

The sensitivity and the specificity of these test depends on the skills of the operator,
the type of liver disease, and on the cost of the test


Mainly we have:
1. ULTRASOUND: cheap, very quick (we can do it at any time the pt want),
has no radiation.
2. CT: moderate cost, we can do it to the pt in the same day, has radiation.
3. MRI: very expensive, need an appointment, has no radiation.
4. Radio-isotope scanning.
5. Visualizing biliary tract.
6. Angiography

These tests indicated in these diseases:
1. Cholestasis.
2. Hepatomegaly.
3. Infiltrating diseases and space occupying lesions.
4. Vascular lesions.
5. Cirrhosis.
6. Fatty liver.
7. Gallbladder diseases.
8. Trauma to the abdomen.
9. Directing percutaneous needle biopsy.

Radio-isotope scanning which are rarely used in practice (Dr just mentioned
them):
1. 99Tc scan for SOL larger than 2 cm, liver cirrhosis, and diffuse liver
disease.
2. 67Galium scan for tumors and abscesses.
3. 113-Indium scan for vascular lesions.
4. HIDA and PIPIDA scan for acute calcular cholecystitis.

Visualizing biliary tract: (here dr said that he will talk about this subject in details
in the next lec)
1. Ultrasound, CT, MRI, MRCP: less accurate.
2. Endoscopic retrograde cholangio- pancreaticography (ERCP).
3. Percutaneous transhepatic cholangiography (PTC).

Angiography:
 to have an idea about the vascularity of the liver and this could help us in:
1. Detect a tumor in the liver, mainly HCC which increase the liver
vascularity.
2. Treatment of HCC: in one type of the treatment of HCC we do
embolization to obstruct the feeding vessels to the tumor.
 To determine portal pressure and patency and direction of flow in portal.
and hepatic veins
 Sensitive for detecting small vascular lesions and hepatic tumors.
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 To differentiate hemangioma from solid tumors.

 To study vascular anatomy preoperatively if indicated.
 Similar anatomic information but not the intravascular pressures can be
obtained by MRI-based techniques.

V.

LIVER BIOPSY:

Sometimes after all these tests we still cant reach a diagnosis, so we order liver
biopsy, but why we dont do it from the beginning?
Because the biopsy tells you there is damage but cant tell you the cause of the
damage, for ex: in hepatitis if we take a biopsy, you will find necroinflammatory
changes in the hepatocytes, but you cant know the type of hepatitis.

Usually we do it percutaneous (most common) under sonographic guidance and
we take the biopsy which consist 1/50,000 of the liver tissue, or we can take it
transjugular or operative.

Liver biopsy indicated in:
1. Unexplained abnormal LFTs.
2. Unexplained jaundice.
3. Chronic liver disease.
4. Unexplained hepatomegaly.
5. Granulomatous liver disease.
6. Liver tumors.
7. PUO.
8. Metabolic liver diseases.

There is complication of liver biopsy:
1. Pain.
2. Bleeding.
3. Infection.
4. Biliary peritonitis.
5. Sampling error: as we said the biopsy is 1/50,000 of liver tissue so you
may take the biopsy from the non-infected section of the liver, so you
should determine the infected area that the biopsy should be taken from.

There is something called biochemical marker of fibrosis (Dr want us to that there
is something called like that).
1. Transient elastography: it measures the degree of liver stiffness, we have
grades 1-4, and grade 3 & 4 are more liable to develop cirrhosis.
2. Fibroscan.
3. These methods are very new, they are commonly used in France.

Done by: Samer Q.Kuleib

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