Functions of the liver :

• general metabolic functions : synthesis of glycogen

postprondialy
and storage of excess glucose , during fasting the
systemic plasma
glucose concentration is maintained by breakdown of
stored
glycogen or by synthesis of glucose from such
substrate as glycerol
, lactate and amino acids by gluconeogensis ,
metabolism of
vitamins and minerals.
• Synthetic functions : the hepatocyte synthesize :
1- plasma protein except immunoglobulin and
complement.
2- most coagulation factors including fibrinogen and
factorII
(prothrombin), factors V,VII, IX, X, XI, XII, and
XIII.
3- lipoproteins: such as VLDL and HDL .
4- primary bile acids

Excretion and detoxification function :

Excretion of bilirubin is very important, other
substances which are
inactivated and excreted by liver include :
1. amino acid : which are deaminated in the liver , the
amino groups
and any ammonia produced by intestinal bacterial
action and
absorped into the portal vein are converted to urea .
2. cholesterol : which is excreted in the bile either
unchanged or after
conversion to bile acid.
3. Steroid hormones : which are metabolized and
inactivated by
conjugation with glucuronate and sulphate and are
excreted in the
urine in these water-soluble forms.
4. Many drugs : which are metabolized and
inactivated by enzymes of
endoplasmic reticulum and some are excreted in the
bile .
5. Toxins : the reticuloendothelial Kupffer cells in the
hepatic
sinusoids are well placed to extract toxic substances
that have
been absorbed from the gastrointestinal tract.

Bilirubin metabolism and jaundice :

At the end of their lifespan of RBC which is 120
days are
broken down by reticuloendothelial system , mainly
in
spleen . the released Hb is split into globin and
haem .
globin will reabsorped in the blood to be used for
building
of different tissue. Haem will converted to bilirubin
after
removal of iron. The iron reabsorbed and reutilized
for
B.M. to be used for synthesis of new RBC or to the
liver
to be stored as ferritin . about 80 % of bilirubin is
derived
from the breakdown of haem within the RES , other
sources include breakdown of immature red cells in
the
bone marrow and compounds chemically related to
haemoglobin such as myoglobin and the cytochromes

The released bilirubin in the blood will combined with

albumin to form
protein bound bilirubin or unconjucated (indirect )
which is not water
soluble and doesn’t pass in the urine , (unconjucated
bilirubin
produced 250-300 ϻmol daily ) from catabolism of
haem after
removal of iron , while the liver normally able to
conjugate up to 1
mmol/ day most of unconjucated bilirubin go to the
liver and it
released from albumin to hepatocyte, then bound to
ligandin
(y protein) , it is actively transported to smooth ERC
and conjugated
with glucuronate by process catalyzed by uridyl
diphosphate (UDP)
glucuronyl transferase , to form conjugated or direct
bilirubin (water
soluble bilirubin) ,
most of conjugated bilirubin enter the gut in bile , it
is broken down
by bacteria in the distal ileum and colon into groups
of product
known collectively as stercobilinogen (or faecal
urobilinogen), some
is absorbed into portal circulation and most of it is
reexcreated in bile
(enterohepatic circulation) , small fraction enters the
systemic
circulation and excreted in the urine as urobilinogen
which can be
oxidized to the coloured pigment (urobilin) .
urinary urobilinogen is increased by (exaggurated of
normal
phenomena ) of urobilinogen formation :

1. haemolysis is sever : large amount of bilirubin

enter
the bowel lumen and are converted to stercobilinogen
an increased amount of urobilinogen is formed .
2. liver damage : impair reuptake of normal amount
of
urobilinogen into the bile.
Unabsorped stercobilinogen is oxidized to
stercobilin ,
apigment which contribute to the brown colour of
faeces. Pale stool may , therefore suggest biliary
obstruction.
Urobilinogen and stercobilinogen are colourless .
Bilirubin , urobilin and stercobilin are coloured (Bile
pigment).
Jaundice (icterus):
It is refer to yellowish discoloration of the skin ,
sclerae and
mucous membrane resulting from increased
bilirubin concentration
in the body fluid , it is usually detectable clinically
when the plasma
bilirubin exceed ( 3mg/dl) 50 Mmol/L .
Clinical classification of jaundice :
1. prehepatic jaundice : due to increase
haemolysis of RBC such as
SCA , thalassaemia , hereditary spherocytosis,
drugs……etc , in
this type mainly increased the indirect bilirubin ,
increase LDH1 and
LDH2 , reticulocytosis and low plama
haptoglobin but all the liver
function tests are normal . there is common
condition which is
similar to this type of jaundice by normal LFT
with indirect.
hyperbilirubinemia this condition is called Gilbert
disease , but it
differentiated from haemolytic jaundice by
normal reticulocyte count.
2. Hepatocellular jaundice : result from an
inability of the liver to
transport bilirubin into the bile due to
paranchymal liver disease ,
bilirubin transport across the hepatocyte may be
impaired at any
point between uptake of unconjugated bilirubin
into the cells and
transport of conjugated bilirubin into canaliculi .
In hepatocellular jaundice , both conjucated and
unconjugated bilirubin
increase because disturbance of bilirubin
transport across
hepatocyte are variable at any point as mention
above
Liver enzymes (SGOT and SGPT) which are
enzyme from hepatocyte
markedly increase in this type of jaundice ,
Alkaline phosphatase also moderately increase
due to disturbance of
cancliculi ,
The other important investigation which should
be measured here is
prothrombin time (PT) which is prolonged due to
coagulation defect
i.e. liver responsible for synthesis of most of
coagulation factors , so
when it impaired , this will lead to prolong (PT) ,
so this test is
important for diagnosis and prognosis .
When hepatocellular damage prolong more than
one month we found
that serum albumin concentration also decrease
but not in few days
due to half life of albumin more than three
weeks , so this test
important to diagnosis the chronicity of the
disease .
3 - cholestatic jaundice :
This type result from obstruction at any site of
biliary pathway i.e. from
small canaliculi to larger one , hepatic duct ,
common hepatic duct
until common bile duct .
increased bilirubin in this type of jaundice is
mainly conjugated type
because conjugation occurred in hepatocyte
which is normal here.

increased alkaline phosphatase( ≥ 3 fold) in
obstructive jaundice
because the enzyme synthesize in the biliary cells ,
not like SGOT
and SGPT in the hepatocytes which are increased
here mildly
due to biliary back pressure .
Patients with prolonged and more widespread
cholestasis may present
with pruritus due to the deposition of retained
bile salts in the skin.
Prothrombine time in this type also prolong with
bleeding (but lately)
not due to coagulation factors defect, but because
of vitamin K
deficiency due to malabsorption of vitamin K .
Cholesterol retention may cause
hypercholesterolaemia.
Dark urine and pale stools suggest biliary
retention of conjugated
bilirubin.
Cholestasis may be either :
● Intrahepatic: in which bile secretion from the
hepatocytes into the canaliculi is
impaired, due to:
– viral hepatitis,
– drugs such as chlorpromazine or toxins such as
alcohol,
– inflammation of the biliary tract (cholangitis),
– autoimmune disease (primary biliary
cirrhosis),
– cystic fibrosis .
● Extrahepatic : due to obstruction to the flow
of bile through the biliary tract
by:
– biliary stones,
– inflammation of the biliary tract,
– pressure on the tract from outside by
malignant tissue, usually of the head of
the pancreas,

Bile acids and bile salts :

Four bile acids are produced in human , two of
these cholic acid
and chenodeoxycholic acid are synthesized in the
liver from cholesterol and
are called primary bile acids . they are secreted in
the bile as sodium salts
, conjugated with amino acids glycine or taurine
to form primary bile salts.
These are converted by bacterial action within
the intestinal lumen to
secondary bile salts (deoxycholate and
lithocholate) respectively.
Secondary bile salts are actively absorped from
terminal ileum and are
reexcreted with bile by the liver (enterohepatic
circulation of bile salts).
Bile therefore contain mixture of primary and
secondary bile salts .
During absorption of meal , the conjugated bile
salts must be present in small
intestine in sufficient concentration for formation
of micelles. The
monoglyceride and free fatty acid aggregate with
bile salts to form water miscible micelles, the
micelles also contain free cholesterol (liberated
from
hydrolysis of cholesterol ester in the lumen) and
phospholipids, as well as
the fat soluble vitamin. The diameter of the
negative charge micelles is
small that allow it to pass through the
microvillous spaces.
Deficiency of conjugated bile salts in the
intestinal lumen lead to impaired
micelle formation and malabsorption of fat , and
can occur in the following
circumstances
1. insufficient synthesis of bile salts in the liver
(e.g. liver cirrhosis).
2. Obstruction to the outflow of bile (e.g. gall
stone).
3. Interruption of enterohepatic circulation :
failure of bile salt absorption from intestine (e.g.
ileal disease or
resection).
4. abnormal bacterial colonization of the upper
small intestine , some
colonizing bacteria split the bile salts conjugates
reducing their effective
concentration at the site of fat absorption
Formation of the bile :
About one to two liters of bile are produced by
the liver daily. Their hepatic bile
contain bilirubin , bile salt , phospholipids and
cholesterol as well as electrolytes
in concentration similar to those in plasma . small
amount of protein are also
present in the gall bladder there is active
reabsorption of sodium , chloride and
bicarbonate , together with an isosmotic amount
of water . The end result is
gall-bladder bile which is ten time more
concentrated than hepatic bile and in
which sodium is the major cation and bile salts
the major anions .
The concentration of the other non absorbable
molecules , conjugated
bilirubin, cholesterol and phospholipids also
increase .
Liver function tests :
1. bilirubin.
2. Aminotransferase ALT and AST .
3. Alkaline phosphatase.
4. ∂-glutamyl transferase GGT.
[Link] (total protein and albumin)
6. Coagulation tests.
1. Bilirubin :
two type conjugated and unconjugated , the
conjugated increase
more than unconjugated in hepatocellular
jaundice and obstructive
jaundice while in prehepatic type (haemolysis or
Gilbert diseases)
there is increase in uncojugated type while the
conjugated bilirubin
is normal.

2- Aminotransferase:
These are alanine aminotransaminase ALT
(GPT) and aspartate
aminotransferase AST (GOT)
Both ALT and AST are located in cytoplasm of
the hepatocyte , an alternative
form of AST is also located in the hepatocyte
mitochondria , although both
transaminase enzyme are widely distributed in
the other tissue of the body.
The activities of ALT out side the liver are low
(skeletal muscles, kidney and
heart) and therefore this enzyme is consider more
specific for hepatocellular
damage.
Liver cells contain more AST than ALT , but
ALT is confined to cytoplasm in
which its concentration is higher than of AST.
Raised plasma transaminase are indicative for
hepatocellular damage ,
In inflammatory or infective conditions, such as
viral hepatitis, the cytoplasmic
membrane sustains the main damage , leakage of
cytoplasmic contents causes
a relatively greater increase in plasma ALT than
AST activities.
In infiltrative disorders in which there is damage
to both mitochondrial and
cytoplasmic membranes, there is a proportionally
greater increase in plasma
AST than ALT activity.

3. alkaline phosphatase :
The alkaline phosphatase are group of enzymes
which hydrolyse
phosphate at high PH , it is widely distributed in
the body , with significant
activities in the liver , GIT , bone and placenta.
In the liver they are localized in the sinusoidal and
biliary canalicular
membrane.
It is most sensitive test for intra or extrahepatic
cholestasis ,
A raised ALP concentration in the presence of a
raised g-glutamyl transferase
(GGT) concentration implies that the ALP is of
hepatic origin.
4. ∂- glutamyl transferase (GGT) :
originated from ERC of the cells of hepatobiliary
tract .
As this reticulum proliferates, for example in
response to the prolonged intake
of alcohol and of drugs such as phenobarbital and
phenytoin, synthesis of the
enzyme is induced and plasma GGT activity
increases.
plasma GGT higher in men than women , raised
plasma activities do not
necessarily indicate hepatocellular damage, but
may reflect enzyme induction
or cholestasis. en. It is mainly increased in
alcoholic liver disease or enzyme
inducer drugs like (phenytoin and rifampicin) .

5. Protein (serum albumin):

liver produce (8-14) gm/day of albumin but the
reduction in serum albumin
observed with liver diseases involve changes in the
volume of distribution of
albumin in addition to reduction in the synthesis.
Reduction in serum albumin in
case of liver disease Indicate chronicity due to the
long half life of albumin
(28 days).
6. Coagulation test :
the liver synthesize most coagulation factors and
required vitamin K to activate
factor X, IX, VII and II . sever liver damage and
prolong biliary obstruction (the
later reduce vitamin K absorption) are associated
with reduce plasma
fibrinogen concentration and prolong PT. the half
life of vitamin K depedant
coagulation factor are short (5-72) hrs ,
therefore change in the PT occur
quickly following liver damage and provide
prognostic information in patient
with acute and chronic liver failure.
The prothrombin time may be prolonged by
cholestasis: fat-soluble vitamin K
cannot be absorbed normally if fat absorption is
impaired due to intestinal bile
salt deficiency

Primary biliary cirrhosis

This is a rare autoimmune disorder that occurs
most commonly in middle aged women.
Destruction and proliferation of the bile ducts
produce a predominantly
cholestatic picture, with pruritus and a plasma
ALP activity that may be very
high.
Jaundice develops late in most patients.
Antimitochondrial antibodies are detectable in the
plasma of more than 90 per
cent of cases; the plasma immmunoglobulin M
(IgM) concentration is usually
raised.
Patients may also manifest
hypercholesterolaemia, xanthelasma other
autoimmune disorders and osteoporosis

Jaundice in the newborn infant :

Red cell destruction, together with immature
hepatic processing of bilirubin,
may cause a high plasma level of unconjugated
bilirubin in the newborn infant;
so called physiological jaundice is common.
Normal fullterm babies may show jaundice
between days 2 and 8 of life.
Physiological jaundice rarely exceeds 100 µmol/
L. Jaundice on the first day of
life is invariably pathological, as are levels of
bilirubin exceeding 100 mmol/L or
if the hyperbilirubinaemia is conjugated.
As a result of haemolytic disease, the plasma
concentration of unconjugated
bilirubin may be as high as 500 µmol/L and may
exceed the plasma protein binding capacity; free
unconjugated bilirubin may be deposited in the
brain,
causing kernicterus. Proportionally more
unconjugated bilirubin reaches the
liver in the newborn infant than in the adult due
to The RBC half-life is shorter;
the blood haemoglobin concentration falls rapidly
during the first week of life,
even in normal infants , and also delayed
clamping of the umbilical cord may
significantly increase red cell mass

Physiological jaundice (unconjugated

hyperbilirubinaemia) is defined as mild
jaundice which is not present at birth but which
develops during the first few
days and continues during the first 10 days of
life, and for which there is no
obvious pathological reason. Such jaundice is very
common in normal newborn
infants (about 50 per cent of normal babies
develop this after 48 h) , The
plasma total bilirubin rarely exceeds 200 µmol/L,
with the conjugated bilirubin
unlikely to be greater than 40 µmol/L ,
Physiological jaundice can be
aggravated by prematurity, infections,
dehydration, hypoxia and poor nutrition .
Kernicterus is a serious complication which may
result in permanent brain
damage or death. The risk of kernicterus is
increased :
● the more premature the infant,
● if theplasma indirect bilirubin concentration is
rising rapidly(sever haemolysis)
● if the bilirubin-binding capacity is low, due
to :
– hypoalbuminaemia,
– displacement of bilirubin from albumin by some
drugs,
– displacement of bilirubin from albumin by
hydrogen ions in acidosis due to
hypoxia or other serious illness.

Jaundice during the first 24 h of life is more likely

to be pathological than
physiological. It may have the following causes :
● ABO blood group incompatibility .
● Inherited erythrocyte abnormalities associated
with haemolysis, such as
glucose-6-phosphate dehydrogenase deficiency,
pyruvate kinase deficiency or
hereditary spherocytosis.
● Intrauterine infections that affect the liver,
such as syphilis, rubella or
toxoplasmosis.

Unconjugated hyperbilirubinaemia
Gilbert’s syndrome :
This is a relatively common (3–7 per cent of the
population) familial
condition, which may be present at any age but
usually develops after the
second decade. Plasma unconjugated bilirubin
concentrations are usually
between 20 µmol/L and 40 µmol/L and rarely
exceed 80 µmol/L. They fluctuate,
and may rise during intercurrent illness,
dehydration, menstruation and fasting.
The condition is probably harmless but must be
differentiated from haemolysis
and liver disease.
Mutations in the hepatic uridine diphosphate
glucuronyl transferase (UGT)
gene are present with decreased activity to
approximately 30 per cent of
normal
It should be remembered that sometimes
thyrotoxicosis can cause raised
unconjugated bilirubin due to reduced UGT
activity , and so can reabsorption
of a large haematoma due to haemoglobin
breakdown .

Crigler–Najjar syndrome :
This is due to a rare deficiency of hepatic UGT,
and is a more serious
condition. It usually presents at birth.
The plasma unconjugated bilirubin may increase
to concentrations that exceed
the binding capacity of albumin and so cause
kernicterus.
The defect may be
complete (type I), and inherited as an autosomal
recessive condition,
or partial (type II), and inherited as an autosomal
dominant condition.
 Acute hepatitis :
1-Viral hepatitis
● Hepatitis A (‘infectious hepatitis’)
● Hepatitis B (‘serum hepatitis’)
● Hepatitis C (non-A, non-B hepatitis)
In all types there may be a 3- to 4-day history of
anorexia, nausea and
tenderness or discomfort over the liver before the
onset of jaundice. Some
patients remain anicteric. Plasma
aminotransferase activities are very high from
the onset of symptoms; they peak about 4 days
later, when jaundice becomes
detectable, but may remain elevated for several
months. Once jaundice
appears, some of the initial symptoms improve.
Plasma bilirubin concentrations is elevated , and
the plasma ALP moderately
raised, or even normal. If hepatocellular damage
is severe and extensive, the
prothrombin time may be increased .

patitis

Alcoholic hepatitis occurs in heavy drinkers,
often after a period of increased
alcohol intake. Although the clinical features may
mimic acute viral hepatitis,
the plasma aminotransferase activities and
bilirubin concentration are not
usually as markedly elevated, although GGT may
be.
A raised (MCV), hypertriglyceridaemia ,
hyperuricaemia and elevated
plasma GGT
3-Drugs and other toxins
Various drugs and other toxins are hepatotoxic,
sometimes directly and
sometimes due to a hypersensitivity reaction .
The clinical picture may
resemble that of acute viral hepatitis or
cholestasis.
A drug history is an essential part of the
assessment of a patient presenting
with liver disease such as paracetol, cytotoxic
drugs , aspirin , phenytoin …etc

Chronic hepatitis :
The finding of persistent, (usually only slightly)
raised plasma aminotransferase
activities, It may be the only abnormal
biochemical finding.
1- Chronic persistent hepatitis :
This is a term used to describe the finding of
raised plasma aminotransferase
activities without clinical signs or symptoms and
without a significant change in
activity over many years. The activities rarely
exceed three times the upper
reference limits. Jaundice is unusual.
2- Chronic active hepatitis :
This is caused by active hepatocellular destruction
with episodes of relapses
and remissions. It may progress to cirrhosis. It
occurs at any age, but is most
common in women. It may:
● be associated with, or a consequence of, viral
infections such as HBV or
HCV, or may be drug induced,
● be part of an autoimmune process that
sometimes involves more than one
organ,

The earliest findings that differentiate it from

chronic persistent hepatitis are an
increasing plasma IgG concentration, perhaps
detected by a rising plasma ɤ-
globulin concentration .
Presence of antismooth muscle antibody
( ASMA ) and antinuclear antibodies
( ANA) .
As the disease progresses, more cells are
destroyed and the plasma AST
activity may rise to or exceed that of ALT; slight
jaundice may develop .
If there is significant hepatocellular destruction,
the plasma albumin
concentration falls
Liver Cirrhosis
Cirrhosis is the end result of many inflammatory
and metabolic diseases
involving the liver, including prolonged toxic
damage, usually due to alcohol.
The fibrous scar tissue distorts the hepatic
architecture, and regenerating
nodules of hepatocytes disrupt the blood supply,
sometimes increasing the
pressure in the portal vein, causing portal
hypertension.
Blood may be shunted from the portal into the
hepatic vein, bypassing the liver.
In the early stages there may be no abnormal
biochemical findings.
During phases of active cellular destruction, the
plasma AST, and sometimes
ALT, activities rise. In advanced cases, the
biochemical findings are mostly
associated with a reduced functioning cell mass.
increased synthesis of IgG and IgA, producing
the typical serum protein
electrophoretic pattern of β–ɤ fusion .
Portal hypertension and impaired lymphatic
drainage lead to the accumulation
of fluid in the peritoneal cavity (ascites). This
may be aggravated by
hypoalbuminaemia, which may also cause
peripheral oedema.
In advanced cirrhosis, the findings of
hepatocellular failure develop.
INVESTIGATION OF SUSPECTED LIVER
DISEASE
The commonly available biochemical laboratory
tests for the diagnosis of liver
disease involve the measurement of plasma levels
of :
● bilirubin – excretory function,
● aminotransferases (ALT and/or AST) –
hepatocellular damage,
● alkaline phosphatase – cholestasis,
● albumin and/or prothrombin time – synthetic
function,
● ɤ-glutamyl transferase – enzyme induction,
cholestasis or hepatocellular
damage.
● Measure plasma bilirubin and unconjugated/
conjugated bilirubin fractions:
Predominantly unconjugated hyperbilirubinaemia
with plasma conjugated
bilirubin levels less than about 10 per cent of the
total, and with little or no
bilirubinuria, may suggest haemolysis as a
cause.
Haemolysis is supported by a raised reticulocyte
count and diagnostic blood
film, reduced plasma haptoglobin and raised
plasma lactate dehydrogenase
concentrations.
If haemolysis is excluded, consider Gilbert’s
syndrome provided other liver
tests are normal and other hepatic disorders have
been excluded.
● A fresh urine sample should be examined. This
test may show the presence
of bilirubin if conjugated hyperbilirubinaemia is
present. Dark-yellow or brown
urine suggests biliary obstruction ,
An absence of urinary urobilinogen is seen in
biliary obstruction.
Reagent strips are available for testing for
bilirubin and urobilinogen in urine.
● Pale stools suggest biliary obstruction as a
cause of jaundice.
plasma aminotransferase, ALP and GGT
assays:
– In hepatitis, there is a predominant increase in
the concentrations of plasma
aminotransferases; usually the plasma ALT
activity is higher than the AST
activity.
– In cholestasis, there is predominant elevation of
the plasma ALP and GGT
activities. Bile duct dilatation should be sought
using ultrasound or other
radiological tests:
if the plasma ALP activity is high but dilated
ducts are not demonstrated, there
is probably intrahepatic cholestasis.
● If acute alcoholic hepatitis is suspected, there
may be the finding of high
plasma GGT activity compared with those of the
aminotransferases. There may
also be macrocytosis, hypertriglyceridaemia and
hyperuricaemia.
● In obstructive jaundice (biliary obstruction),
the plasma ALP is usually more
than four to five times and GGT more than 10
times normal .
● Check hepatitis serology, for example A, B and
C.
● Detectable plasma antimitochondrial or
antismooth-muscle antibodies are
suggestive of primary biliary cirrhosis or chronic
active hepatitis, respectively.
● A raised plasma ferritin concentration with
high iron saturation may reveal
haemochromatosis .
● Plasma protein electrophoresis and
immunoglobulin assay may help in the
diagnosis of:
– cirrhosis – high plasma IgG and IgA
concentrations causing β–ɤ fusion on the
electrophoretic strip,
– alcoholic cirrhosis – may present with raised
IgA concentration,
– chronic active hepatitis – a high plasma IgG
concentration and normal IgA,
– primary biliary cirrhosis – a high plasma IgM
concentration