The liver

CH.9.Liver Disorder 1
 The liver
- The liver is the largest organ in the human body; it weighs approximately 1.2 to 1.5 kg in the adult.
- The liver has a dual blood supply;
1.the portal vein, which carries nutrient-rich blood
from the capillary bed of the alimentary tract,
2. the hepatic artery, which carries well-oxygenated blood to the liver.
Venous drainage from the liver occurs via the right and left hepatic veins.
- The liver is of vital importance in
- Intermediary metabolism
- Detoxification
- Elimination of toxic substances.
Major functions of the liver …METABOLISM
Carbohydrate metabolism: gluconeogenesis, glycogen synthesis & glycogenolysis
Fat metabolism: fatty acid synthesis, cholesterol synthesis & excretion, lipoprotein synthesis,
ketogenesis and bile & synthesis 25-hydroxylation of vitamin D
Protein metabolism: synthesis of plasma proteins (including some coagulation factors but not
immunoglobulins, urea synthesis
Hormone metabolism: metabolism and excretion of steroid hormones, metabolism of polypeptide
hormones
Drugs and foreign compounds metabolism and excretion
Storage: glycogen vitamin A vitamin B12 iron 2
Metabolism and excretion of bilirubin
Excretion and detoxification function of the liver:

1. Bilirubin
2. Amino acids, which are deaminated in the liver. Amino groups, and the ammonia produced
by intestinal bacterial action and absorbed into the portal vein are converted to urea.
3. Cholesterol, which is excreted in the bile either unchanged or after conversion to bile acids.
4. Steroidal hormones, which are metabolised and inactivated by conjugation with
glucuronate or sulphate and excreted in the urine in these water-soluble forms.
5. Many drugs.
6. Toxins, the reticuloendothelial Kupffer cells in the hepatic
sinusoids are well placed to extract toxic substances which
have been absorbed from the GIT.

Efficient excretion of the end-products of metabolism and

of bilirubin depends on:
1. Normally functioning liver cells.
2. Normal blood flow through the liver.
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3. Normal biliary ducts.
Damage to the organ may not obviously affect its activity since the liver has considerable
functional reserve.
- So simple tests of liver function (e.g., plasma bilirubin and albumin concentrations) are
insensitive indicators of liver disease,
-a fall in plasma albumin concentration could be attributed to advanced liver disease.

- Tests reflecting liver damage (measurements of the activities of

hepatic enzymes in plasma) are used.
The most common disease processes affecting the liver are:
• Hepatitis, with damage to liver cells.
• Cirrhosis, in which increased fibrous tissue formation
leads to shrinkage of the liver, decreased hepatocellular function
and obstruction of bile flow.
• Tumours, most frequently secondary; for example, metastases
from cancers of the large bowel, stomach and bronchus.
-Patients with liver disease often present with characteristic symptoms and signs, but the clinical
features may be non-specific and in some patients, liver disease is discovered incidentally.
- Extrahepatic biliary disease may present with clinical features suggestive of liver disease ➔
may have secondary effects on the liver; for instance, obstruction to the common bile duct may
cause jaundice and, if prolonged, a form of cirrhosis.
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Hepatitis

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Tumour CH.9.Liver Disorder
 Bilirubin metabolism CH.9.Liver Disorder

-Bilirubin is derived from the haem moiety of the haemoglobin, myglobin and
cytochrome molecules
Haem & Pophyrins
-Porphyrins: are cyclic compounds that bind metal ions usually Fe +2,Fe+3.
-Heme: one ferrous ion coordinated in the center of porphyrins.
-Heme is highly turned over: 6–7 gm is synthesized and destroyed daily

Structure of porphorins
-Ring structure of 4 pyrrole rings linked with methylenyl bridge.
-Side chains: different porphyrins vary of the side chain that are attached to pyrrole
rings.

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CH.9.Liver Disorder
Bilirubin metabolism

- Iron is reutilized
-RBC are taken up by liver and spleen and macrophages, and
degraded by reticulo-endothelial system (RE)

Formation of billirubin
-Degradation is catalyzed by microsomal heme oxygenase enzyme
of the ER cells.
-The enzyme add the –OH to the methylen bridge oxidation➔ CO
and Fe +3 is released and the product is Billiverdin then it is
reduced into Billirubin.
Uptake of Billirubin by liver
- Billirubin is slightly soluble in water ➔transported in the blood
through complexion to albumin, then taken by hepatocytes.
Formation of Billirubin diglucuronide
- In hepatocytes, the solubility of Billirubin is increased by addition
of two molecules of Glucuronic acid catalyzed by “Billirubin
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glucuronyl transferase” using UDP-glucuronic acid.
 CH.9.Liver Disorder
Heme Degradation

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A small fraction of unconjugated bilirubin circulates unbound, and
this free portion is able to cross lipid-containing membranes,
including the blood-brain barrier, leading to neurotoxicity 9
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 Excretion of Billirubin into bile

-Conjugated bilirubin is water-soluble and is secreted actively into the biliary

canaliculi, eventually reaching the small intestine via the ducts of the biliary system.

- Secretion into the biliary canaliculi is the rate limiting step in bilirubin
metabolism
-Billirubin diglucuronide is hydrolyzed and reduced by bacteria in the gut to yield
urobillinogen.

Reabsorbed, go to kidneys and converted excreted

Urobillinogen as urobillinogen & urobillin (yellow color)
Most are oxidized by bacteria to stercobillin
(brown color)

CH.9.Liver Disorder 11
 CH.9.Liver Disorder
Jaundice
❖ Jaundice: The yellow discoloration of
tissues skin and sclera due to bilirubin deposition,
is a frequent feature of liver disease.

❖ High level Bilirubin is toxic to CNS

❖The bilirubin normally present in plasma is mainly (approximately 95%) unconjugated;
since it is protein bound, it is not filtered by the renal glomeruli and, in health, bilirubin is not
detectable in the urine.

❖ Bilirubinuria: appearance of bilirubin in urine ➔ reflects an increase in the plasma

concentration of conjugated bilirubin, and is always pathological.
❖Clinical jaundice may not be seen unless the plasma bilirubin concentration is more than two
and half times the upper limit of normal.

❖ Hyperbilirubinaemia can be caused by increased production of bilirubin,➔

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impaired metabolism, decreased excretion or even combination.
 CH.9.Liver Disorder

Jaundice can be classified to:

1. • An increased rate of bilirubin production exceeds
normal excretory capacity of the liver (prehepatic
jaundice)(Hemolytic jaundice: sickle cell anemia, or
malaria).
2. • The normal load of bilirubin cannot be conjugated
and/or excreted by damaged liver cells (hepatic
jaundice). Hepatocellular Jaundice: liver damage,
cirrhosis, hepatitis.
3. • The biliary flow is obstructed, so that conjugated
bilirubin cannot be excreted into the intestine and is
returned into the systemic circulation (posthepatic
jaundice) Obstructive jaundice: bile duct obstruction.

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 Biochemical assessment of liver function CH.9.Liver Disorder

1-Bilirubin
A. Unconjugated hyperbilirubinaemia occurs if there is:
1-A marked increase in the bilirubin load ➔ as a result of haemolysis, or of the breakdown
of large amounts of blood after haemorrhage into the GIT.
In haemolysis, hyperbilirubinaemia is due to increased production of bilirubin, which
exceeds the capacity of the liver to remove and conjugate the pigment.
2-Impaired binding of bilirubin to ligand or impaired conjugation with glucuronate in the
liver. Like in some liver disease.
3- Or it could be due to an inherited abnormality of bilirubin metabolism (defect in the
conjugating enzyme) ’Gilbert’s syndrome’,

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-Unconjugated hyperbilirubinaemia can also be associated to high urobilinogen.
Haemolytic disease ➔ to more bilirubin is excreted in the bile ➔ the amount of
urobilinogen entering the hepatic circulation➔
increased and urinary urobilinogen is increased.

- As a result of haemolytic disease ➔

the plasma concentration of unconjugated bilirubin
may be as high as 500 mol/L (30 mg/dl) and
exceeds the plasma protein-binding capacity.
-Unconjugated bilirubin is normally totally
bound to albumin.
-It is not water soluble and therefore cannot be excreted in the urine.
- Patients with unconjugated hyperbilirubinaemia do not have bilirubinuria.

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 Jaundice in newborns
- It is physiological jaundice is defined as: mild jaundice not present at birth, which
develops during the first few days and continues during the first week of life, and
for which there is no obvious pathological reason.

- The transient ‘physiological’ jaundice of the new-borns reflects decrease in the

activity of Billirubin glucuronyl transferase
-The activity increases rapidly.
-Jaundice during the first 24 hours of life is more likely to be pathological than
physiological.
- Proportionally more unconjugated bilirubin reaches the liver in the newborn
infant than in the adult because:
1. The red cell half-life is shorter; the blood haemoglobin concentration falls rapidly
during the first week of life, even in normal infants.
2. Delayed clamping of the umbilical cord may significantly increase red cell mass.
3. Damages may occur during birth ➔ haemoglobin breakdown increases the
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plasma bilirubin concentration.
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- Newborns pathological Jaundice that diagnosed in during the first 24 hours of life
could occur due:
1. With excessive haemolysis, as in Rhesus incompatibility,
2. A lack of enzyme activity, as occurs in prematurity and in Crigler-Najjar
syndrome, there may be massive rise in plasma concentration of unconjugated
bilirubin.
In Crigler-Najjar patients the enzyme is either :
inactive (type I) or severely reduced (type II).

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3. The high plasma level of unconjugated bilirubin leads to jaundice and
kernicterus (bilirubin encephalopathy)
If bilirubin levels exceed approximately 340 mol/L; its uptake into the brain
may cause sever brain damage (kernicterus).
Bilirubin is destroyed by ultraviolet light and lesser degrees of unconjugated
hyperbilirubinaemia can be treated by phototherapy.
Water loss from the skin may be high and fluid balance must be carefully
monitored.

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CH.9.Liver Disorder
A. Unconjugated hyperbilirubinaemia

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 B-Conjugated hyperbilirubinaemia
-Due to leakage of bilirubin from either hepatocytes or the biliary system into the
bloodstream when its normal route of excretion is blocked.

- The water-soluble conjugated bilirubin entering the systemic circulation is excreted in

the urine, giving it a deep orange-brown colour.
- In complete biliary obstruction, ➔no bilirubin reaches the gut, ➔no urobilin is
formed and the stools are pale in colour.
- Hyperbilirubinaemia can be due:
to an excess of both conjugated
and unconjugated bilirubin.
- Bilirubinuria is always pathological.
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 CH.9.Liver Disorder
Methods for the determination of bilirubin
-The most widely used routine methods for bilirubin measurements are
photometric methods based on diazo reaction.

- The diazo reagent reacts with bilirubin to produce➔ colorimetric dye.

- The fraction of bilirubin that reacted with the diazo reagent in the absence of
alcohol is called the direct bilirubin fraction (conjugated).

-The indirect bilirubin (for Un-Conjugated) is used for the difference

between total bilirubin (found after the addition of alcohol to the reaction
mixture) and the direct bilirubin fraction.

- Bilirubin levels in an adult in serum 0.3-1.2 mg/dl (5-21 mol/L), urine

negative
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- Conjugated bilirubin (direct) in serum 0-0.2 mg/dl (0-3.4 mol/L)
Diseases of the Liver

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 CH.9.Liver Disorder
Diseases of the Liver
1.Cholestasis: is any condition in which bile excretion from the liver
is blocked, which can occur either in the liver or in the bile ducts.

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; autoimmune disease (primary biliary cirrhosis); cystic fibrosis.
*extrahepatic: due to obstruction to the flow of preformed 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.

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Alkaline phosphatase activity is the most sensitive test for cholestasis.
Increased synthesis of ALP in the affected ducts increases the activity of this enzyme in plasma.
* Patients with prolonged cholestasis may present with :
➢ severe jaundice
➢ itching due to deposition of retained bile salts in the skin;
➢ More rarely there is bleeding due to malabsorption of vitamin K,
➢ with consequent prothrombin deficiency.
-Cholesterol retention may cause hypercholesterolaemia.
-Dark urine and pale stools suggest biliary retention of conjugated bilirubin

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2. Hepatitis: CH.9.Liver Disorder

Hepatitis is the Latin word for liver inflammation. It is characterized by the ➔

• destruction of a number of liver cells
• the presence of inflammatory cells in the liver tissue.

a. Acute Hepatitis:
Acute hepatitis is most frequently caused by infectious agents, particularly viruses, and toxins.
-Many toxins and drugs can also cause acute hepatitis, including alcohol, paracetamol and
carbon tetrachloride.
-The viruses primarily associated with hepatitis are hepatitis A, B and ‘non-A,
non-B’ (principally hepatitis C virus)
-Most cases of viral hepatitis resolve completely.
-In severe cases➔, hepatic failure may develop, but most patients who survive the acute illness
eventually recover completely, transaminase activities ➔falling to normal in ten to twelve
weeks. Infection with hepatitis A never leads to chronic disease.
- Patients may present with jaundice but this is often not apparent early in the course of
the disease.
- The biochemical findings in acute hepatitis are associated with those of cell membrane
damage with an increase in plasma ALT activity greater than that of AST. 28
Hepatitis A (infectious hepatitis), an RNA enterovirus,
spread by contact with faecal matter, ➔most often through ingestion of contaminated food.
- Rarely fatal, it cannot be treated except by bed rest for 1–4 weeks,
during which time no alcohol should be consumed.
- It may recur after 3 months.

Hepatitis B (serum hepatitis): Hepatitis B ranks as the ninth leading killer in the world
- is shed through blood, semen, vaginal secretions, and saliva
approximately 4–6 weeks after symptoms develop.
- the virus may take up to 6 months to incubate,
and people may also become asymptomatic carriers.
- Hepatitis B may heal slowly, and is a leading cause of chronic liver disease and cirrhosis.
- Effective vaccines exist,

Hepatitis C: remains in the blood for years and accounts for a

large percentage of cirrhosis, liver failure, and liver cancer cases.
Its main mode of transmission is through blood transfusion, and possibly sexual intercourse
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b. Chronic hepatitis

CH.9.Liver Disorder 30
b. Chronic hepatitis : hepatic inflammation persisting without improvement for six months.
Causes include:
1. autoimmune liver damage,
2. chronic infection with hepatitis B or C,
3. alcohol
4. drugs.
*Chronic active hepatitis (is caused by →active hepatocellular destruction with episodes of
relapses and remissions, hepatitis usually progresses to cirrhosis.

*Chronic persistent hepatitis (a form of chronic hepatitis that is usually benign, not
progressing to cirrhosis, and usually asymptomatic without physical findings but with
continuing abnormalities of tests of liver status).

Chronic persistent hepatitis has good prognosis;

chronic active hepatitis may respond to treatment with immunosuppresive or antiviral
agents, according to its etiology, but the natural history is of progression to cirrhosis,
which may be present at the time of diagnosis.
-Plasma transaminase activities are elevated in all types, → reflecting the continuing
hepatocellular damage.
-ALP activity is usually normal.
-Indices of synthetic function (albumin, prothrombin time) are often➔ abnormal in chronic
active hepatitis but not in chronic persistent hepatitis. 31
3. Cirrhosis
- Progressive disease of the liver characterised by➔
1.diffuse damage to hepatic parenchymal cells,
2.with nodular regeneration,
3.fibrosis,
4.disturbance of normal architecture;
-associated with:
1. failure in the function of hepatic cells and interference with blood flow in the liver,
2.frequently resulting in jaundice, portal hypertension, ascites,
and ultimately hepatic failure.
- Cirrhosis is the end result of many inflammatory and metabolic diseases involving
the liver, including prolonged toxic damage due to alcohol.
- Causes of cirrhosis include:
1.chronic excessive alcohol intake,
2.autoimmune disease,
3.persistence of hepatitis B or C virus
4.various inherited metabolic diseases, such as Wilson’s disease, haemochromatosis
and  -antitrypsin deficiency. 32
CH.9.Liver Disorder 33
•Cirrhosis can be the cause of biochemical abnormalities ➔ that reflect specific
alterations in metabolism i.e.,:
•decreased albumin synthesis,
•increased prothrombin time,
•decreased cholesterol synthesis
•insulin resistance.
* Most of clotting factors are synthesized in the liver (Factor VII is an important one)
clotting factors are plasma proteins include, so if there is any liver problem ➔ clotting
time will be increased ➔ Acute diseases
Factor VII is vit K dependent so in certain cases, the high prothrombine time is not
due to liver diseases but due to vit K deficiency

•Due to the great functional capacity of the liver,➔ metabolic and clinical
abnormalities may not become apparent until late in the course of the disease; until
this time, the cirrhosis is said to be ‘compensated’.
•There are no reliable, simple biochemical tests ➔ to diagnose subclinical
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disease.
 CH.9.Liver Disorder

3. Tumors
-The liver is a common site for tumor metastasis.

- Primary liver tumors are

-rare
-associated with cirrhosis,
-persistence of serological markers for hepatitis B and C, and various
carcinogens, including aflatoxins.

Plasma -fetoprotein is
-elevated at diagnosis in approximately 70-80% of patients with primary
hepatocellular carcinomas
➔ a valuable marker for this tumor although it can be increased, usually to a
lesser extent, in acute and chronic hepatitis and in cirrhosis. 35
 CH.9.Liver Disorder
Liver Function Tests and Diseases
Liver function Tests
1) Testing of Bilirubin which indicates the excretory capacity of the liver:
prehepatic, hepatic, posthepatic jaundice

2) Testing of enzymes (ALT, AST, ALP and GGT)

ALT is more specific for liver,
ALP can indicate the Cholestasis,
GGT is sensitive to liver diseases but non-specific

3) Testing of plasma proteins, which indicates the synthetic capacity of the liver
✓ Measurement of albumin conc➔ chronic diseases
✓ Prothrombin time, clotting time ➔ acute diseases
✓ Polyclonal response in the Ig mainly IgG.➔ When there is liver cirrhosis of
autoimmune origin ➔ high level of IgG 36
 Typical Liver Function Test
:
Result Unit Reference
AP (Alk Phos)...............................................................
30 to 120 U/L

GGT (Gamma GT)........................................................ 5 to 35 U/L

LD Lactate Dehydrogenase......................................... 100 to 225 U/L

AST (Aspartate aminotransferase)............................... 5 to 45 U/L

ALT (Alanine aminotransferase).................................. 5 to 45 U/L

Albumin....................................................................... 38-55 g/L

Total Bilirubin-Normal range is 3 - 18 umol/L.............. 0.174 - 1.04mg/dL
Clotting Studies (Prothrombin Time)........................... 1 to 13.5 Seconds

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