FUNCTIONS OF

LIVER &
DETOXIFICATION

Dr.Uzma Nasib
LEARNING OBJECTIVES
• By the end of this lecture, the student should be able to
describe:
• Biochemical functions of liver
• Common liver disorders
• Clinical manifestations of liver disorders
 STRUCTURE OF LIVER
Location:
• In humans, it is located
in the upper right quadrant of the
abdomen,below the diaphragm
• Largest organ in the body

• Contributing about 1/50 of the total

body weight (about 1.5 kg in adults)

 The Liver
• 2 main lobes, made up of thousands of lobules connected
to small ducts that connect with larger ducts to form the
common hepatic duct.
• transports the bile produced by the liver cells to the
gallbladder and duodenum .
 TYPES OF CELLS
1, Hepatic Cells 70% (Protein synthesis)
2. Stellate Cells 8%
• Stores fat soluble vitamins
a. particularly vitamin A
b. produce NO (nitrogen oxide)
c. On damage these cells causes fibrosis of liver due
to increased synthesis of collagen and causes portal
hypertension,(steatosis or cirrhosis vascular resistance
blood flow ↓)
3. kupffer cells:lining the walls of the sinusoids. They form part of
the mononuclear phagocyte system. macrophages (phagocytosis) first
innate immune cells and protect the liver from bacterial infections
 Dual Blood Supply of Liver

Oxygenated blood
flows in from the
hepatic artery.
 FUNCTIONS OF LIVER
• The liver has more than 200 functions,
including:

• Bile Secretion
• Breakdown of erythrocytes
• Detoxication
• Storage of Nutrients
• Synthesis of plasma Proteins
• Synthesis of cholesterol
• Metabolism of macromolecules
FUNCTIONS OF THE LIVER
• Formation and secretion of bile

• Bile is produce & secreted by the

liver cells (hepatocytes) stored in the
gallbladder and discharge through
the common bile duct into the
duodenum .
• 600 ml to 1 liter of bile produced in
a day
: COMPOSITION
TWO IMPORTANT FUNCTIONS OF BILE
• Bile acids Assists with diges on and
absorp on of fat and fat soluble vitamin
in the intes ne.

• Excrete waste products from the blood

(bilirubin from hemoglobin break down),
carries excess cholesterol out of the
body
 BILE ACIDS ARE DERIVATIVES OF CHOLESTEROL
SYNTHESIZED IN HEPATOCYTES

• Cholesterol, ingested as part of the diet or

derived from hepa c synthesis is converted into
the bile acids .
➢ Cholic and Chenodeoxycholic acids
• which are then conjugated to an amino acid
(glycine or taurine) to yield the conjugated form
that is ac vely secreted into canaliculi
EMULSIFICATION FUNCTIONS OF BILE SALTS
• Emulsifica on of lipids to facilitate the
diges on and absorp on.

• lipids are hydrophobic molecules and

have to be hydrolyzed and emulsified to
very small droplets (micelles) before they
can be absorbed
BILE SALTS PERMITS EMULSIFICATION OF THE
PRODUCTS OF LIPID DIGESTION

• Bile salts permits emulsifica on of the products of

lipid diges on into micelles together with
phospholipids and cholesterol from the bile.
 Metabolism of bile salts (exlusively in the liver)

4. a 5. Intestinal bacteria in the colon

produce enzymes that can attack and alter
1. The biosynthesis of bile acids from cholesterol the bile salts
2. The conjugation with the amino acids 6. Most of the bile acids are reabsorbed
from the intestine and, following transport to
3. The concentration in the gallbladder by removal the liver, returned once again into the bile
of water (enterohepatic circulation)
 Breakdown of Erythrocytes
• RBC’s have a life span of 120 days.
• RBC’s weaken and rupture, releasing hemoglobin into
the blood plasma.
• Hemoglobin is split into
• Heme groups
• Iron is removed from heme leaving a substance
called bilirubin (bile pigment).
• Iron is carried to bone marrow where it is used to
new hemoglobin for RBC’s
• Bilirubin becomes a component of bile

• Globins
• Hydrolysed to amino acids and returned to the
blood
 BILIRUBIN PRODUCTION
(RETICULOENDOTHELIAL CELLS OF SPLEEN, LIVER & BONE MARROW)

Heme proteins Hemoglobin Erythroid cells

myoglobin, cytochromes (70 to 80%)
(20 to 25%)
Heme
ferritin apoferritin (250 to 400 mg/day)
3 [O]
Heme oxygenase
Fe3+ + CO

Biliverdin
NADPH + H+
Biliverdin reductase
NADP+ indirect
albumin
Bilirubin unconjugated
Insoluble in H2O & toxic pre-hepatic
(serum)
 BILIRUBIN PROCESSING
Unconjugated, indirect ,prehepatic is transported form the surface of hepatocyte to ER through ligandin binding protein.

albumin-Bilirubin albumin

ligandin hepatocyte
ligandin-Bilirubin
2 UDP-glucuronate UDP-Glucuronyl Glucoronic acid added

ER transferase
deficiency
Mild Gilbert’s
2 UDP Severe Crigler-Najar
direct
Bilirubin diglucuronide conjugated
post-hepatic

bile (gall bladder)

 BILIRUBIN EXCRETION

Bilirubin diglucuronide
liver
2 glucuronate Bacterial enzyme
Intrahepatic
Bilirubin urobilinogen cycle

8H Bacterial enzyme
kidneys
intestines
Urobilinogen Urobilin urine
kidneys
Bacterial enzymes

Stercobilinogen Stercobilin feces

 Rela on to blood forma on
• Storage of vitamin B12
• Metabolism of iron and its storage as ferri n
(hepa c cell contains apoferri n and when
excess of iron in the blood it forms ferri n) =
blood iron buffer
• par cipa on on produc on of erythropoie n
 DETOXICATION OF VARIOUS SUBSTANCES

• Metabolic products of intestine microbes

• Exogenous toxins (medicaments, alcohol,
poisons)
• Hormones (thyroxine, estrogen, cortisol,
aldosterone)
 DETOXIFICATION OF TOXIC
SUBSTANCES IN LIVER
Phase I and phase II.

Phase I:
➢ oxidation.
➢ reduction,
➢ hydrolysis

These reactions introduce functional group (—OH, —

NH2, —SH, or —COOH) and usually result in a little
increase of hydrophilic properties
Phase II includes (conjugation reaction)
➢ glucurona on,
➢Glutathione
➢ glutamin
➢glycin
➢sulfa on,
➢ acetyla on,
➢ methyla on,
Phase II results in the marked increase of
hydrophilic properties of xenobiotic.
BIOTRANSFORMATIONS (THE DETOXIFICATION AND ELIMINATION; PREDOMINANTLY IN THE
LIVER)

Foreign substances: Self-substances

Xenobiotics (natural origin) Steroid hormones
Pharmaceuticals Bile pigments
Synthetics

Transformation reactions
Poorly soluble, biologically ➢ Either incorporate new functional
active, some toxic groups into apolar compounds,
Phas or alter groups that are already
eI present in the molecule
➢ The result is an increase in the
polarity and a decrease in the
biological activity or toxicity of the
substance
The most important reactions:
1. Oxidative reactions:
hydroxylation, epoxide formation,
Transformation dealkylation, deamination
products 2. Reductive reactions
3. Methylation
4. Desulfuration
BIOTRANSFORMATIONS

Transformation
products
Conjugate formation:
➢These reactions couple
substrates to highly polar,
Phase
II often negatively charged
molecules
➢The enzymes involved are
transferases

1. Glucuronidation
2. Esterification with sulfate
Conjugate
3. Amidation with glycine and
glutamate

Bile Urine
 SYNTHESIS OF PLASMA PROTEINS

Produced by RER of Hepatocytes

• Acute-phase proteins
• Albumin
• globulin
• fibrinogen
 COAGULATION
• (synthesis of most of the coagulating factors).
• Vitamin K is required for the formation of:
• Factors II (prothrombin),
• VII (proconvertin),
• IX (Christmas factor),
• X (Stuart factor)
. Immunity
• (Kupffer cells = macrophages)

. Storage
• metabolism and storage of vitamins A, D,E and
B12
• Iron as ferretin
 CARBOHYDRATE METABOLISM
• Glycogenesis (Storage of glycogen 1-4 %)
• Glycogenolysis
• Gluconeogenesis
• Conversion of galactose and fructose to glucose
• HMP shunt is source of the NADPH (required for
cholesterol and fatty acids synthesis)
• Formation of many chemical compounds from
intermediate products of carbohydrate metabolism
 CARBOHYDRATE METABOLISM DISORDER IN
HEPATIC DISEASES

• Hypoglycemia in alcohol abusers

• Alcohol suppresses citrate cycle and

thereby impairs gluconeogenesis from
amino acids
• A er deple on of glycogen storages
comes hypoglycemia that threatens the
pa ent’s life.
• Hyperglycemia in pa ents with cirrhosis a er
carbohydrate rich meal (50% has glucose
tolerance, 10% has hepa c diabetes mellitus)

•Combina on of pathological glucose tolerance

test, hyperinsulinemia, and increased insulin
tolerance.

• liver insufficiency decrease of glucose

u liza on hyperglycemia hyperinsulinemia
down-regula on of insulin receptors insulin
resistence.
FAT METABOLISM
• Fa y acids synthesis
• Triglycerides synthesis

• Oxida on of fa y acids to supply energy for

other body func on
• Cholesterol Synthesis

• Ketone bodies synethsis

• VLDL & HDL synthesis

• Synthesis of fat from proteins and

carbohydrates
 PROTEIN METABOLISM
• Transamina on of amino acids
• Deamina on of amino acids
• Forma on of urea for removal of ammonia from
the body fluids
• Forma on of plasma proteins (90% of all plasma
proteins, up to 50 g of plasma proteins daily) –
(cirrhosis = very low albumins = ascites and
edema)
 PROTEIN METABOLISM
• Protein metabolism disorder in hepa c diseases
• Ammonia detoxication disorder and failure of urea
formation
• ammonia comes from bacterial degradation of nitrogen
substances in intestines,
• from intestine mucosa during glutamin degradation,
• from degradation of amino acids in kidneys and
muscles
HYPERAMONEMIA
• ↑ ammonia in blood concentra on (>50
μmol/l)
• Hepatic encephalopathy
• toxic effect of ammonia in the brain ( Binding
of ammonia to glutamate = glutamine)
• Mental changes (capriciousness,
disorienta on, sleeping disorders, personality
changes)
• Motoric changes (increased in muscle
reac vity, hyper reflexion, tremor)
 Biochemical assessment of liver
function

➢Basic tests: albumin, ALT, AST, GGT, ALP,

bilirubin, U-urobilinogen, U-bilirubin
➢Special tests: serum protein electrophoresis,
prealbumin, glutamate dehydrogenase,
cholinesterase, lactate dehydrogenase, oral
glucose tolerance test (oGTT), P-Fe
➢Very special tests: ceruloplasmin, S-Cu, α1-
antitrypsin, ammonia, P-bile acids, serological
tests in hepatitis B, assessment of clotting
factors
➢ ALT (alanine aminotransferase):
▪ increased when cells of the liver are inflamed or undergo cell
death
▪ rises dramatically in acute liver damage, such as viral hepatitis
➢ AST (aspartate aminotransferase):
▪ less specific for liver disease
▪ raises in acute liver damage
➢ GGT (gamma-glutamyltransferase):
▪ produced by the bile duct (sensitive marker for cholestatic
damage)
▪ raises in alcohol toxicity
➢ ALP (alkaline phosphatase):
▪ associated with the biliary tract
▪ raises in biliary tract damage and inflammation
➢ Bilirubin
-total and direct (=conjugated)
➢ Urine urobilinogen:
-insufficient function of the liver
➢ Urine bilirubin:
-when plasma direct bilirubin is elevated
(obstructive and hepatocellular icterus)