CHAPTER 25 LIVER FUNCTION

INTRODUCTION

Liver

Functions
Metabolism of carbohydrates, lipids,
proteins, and bilirubin
Detoxification of harmful substances
Storage of essential compounds
Excretion of substances to prevent
harm
Can regenerate cells that have been
destroyed by some short-term injury or
disease or have been removed
If the liver becomes nonfunctional, death will
occur within approximately 24 hours due to
hypoglycemia

Branch of the aorta

Supplies oxygen-rich blood from the heart to
the liver
About 25% of total blood supply

Portal Vein

Supplies nutrient-rich blood from

digestive tract
About 75% of total blood supply

the

*Note

The two blood supplies eventually merge

into the hepatic sinusoid, which is lined with
hepatocytes capable of removing potentially
toxic substances from the blood
The liver is drained by a collecting system of
veins that empties into the hepatic veins
and ultimately into the inferior vena cava

ANATOMY
Gross Anatomy

Reddish brown in color

Largest organ inside the body
Divided into two lobes
Right side is usually 6 times larger
Divided by falciform ligament
Weights approximately 1.2 to 1.5 kg
Held in place by ligamentous attachments
Around 1500 mL of blood circulates in the
liver per minute
Highly vascularized
Has two blood supplies

Hepatic Artery

Excretory system

Excretory system of the liver begins at the

bile canaliculi
Small spaces between hepatocytes
Forms the intrahepatic ducts where
excretory products of the cell can
drain
Intrahepatic ducts
Join to form right and left hepatic
ducts which drains the secretion
from the liver
Common hepatic duct
Formed by the right and left hepatic
ducts

Eventually joined with the cystic duct

of the gallbladder to form the
common bile duct
Combined digestive secretions are then
expelled into the duodenum

Microscopic Anatomy
Lobules

Macromolecular synthesis

Biliary System

Excretory
Metabolism of bilirubin and bile salts

Reticuloendothelial System

Functional units of the liver

Responsible for all the metabolic and
excretory functions
Roughly six-sided structure with a centrally
located vein (central vein) with portal triads
at each of the corners
Each portal triad contains a hepatic artery,
a portal vein, and a bile duct surrounded by
connective tissue

Immune system and production of heme

and globin metabolites

Two major cell types

Hepatocytes

Making up approximately 80% of the

volume of the organ
Radiate outward from the central vein in
plates to the periphery of the lobule
Perform major functions associated with the
liver and are responsible for the
regenerative properties of the liver

BIOCHEMICAL FUNCTIONS
Excretory and Secretory

Kupffer cells

Macrophages that line the sinusoids of the

liver
Act as active phagocytes capable of
engulfing bacteria, debris, toxins, and other
substances

3 Systems of the Liver

Bile

Hepatocyte System

Involves metabolic reactions

Aerobic and anaerobic glucose
metabolism
Glycogenesis
Glycogenolysis
Gluconeogenesis
Lipoprotein synthesis
Hormone production
Xenobiotic metabolism (drug)

One of the most important functions of the

liver is processing and excretion of
endogenous and exogenous substances
into the bile or urine such as the major
heme waste product, bilirubin
Only organ that can rid the body of heme
waste products

Made up of bile acids or salts, bile

pigments, cholesterol, and other substances
extracted from the blood
Body produces approximately 3 L of bile per
day and excretes 1 L

*NOTES:

Primary bile acids cholic acid,

chenodeoxycholic acid
Excretion is done via carrier mediated active
transport

Bilirubin

NOTES:

Principal pigment in bile

Derived from breakdown of RBCs

Porphyrin is reduced by heme oxygenase

Biliverdin is reduced by biliverdin reductase
B1
Prehepatic
Hemobilirubin
Indirect
Prebilirubin
B2
Direct
Hepatic
Bilirubindiglucoronide
Conjugated cholebilirubin

Step by step process

After 126 days, RBCs are phagocytized and

hemoglobin is released
Hemoglobin is degraded into heme, globin,
and iron
Iron is bound to transferrin and is
stored in the liver or bone marrow for
reuse
Globin is degraded into its
constituent amino acids which are
reused
Heme is converted to bilirubin in 2 to
3 hours
Bilirubin is bound by albumin and
transported to the liver
This form is called unconjugated or
indirect bilirubin
Insoluble in water and cannot be
removed from the body until it is
conjugated by the liver

Unconjugated bilirubin flows into the

sinusoidal spaces and is released from
albumin so it can be picked up by a carrier
protein called ligandin
Ligandin
Located in hepatocyte
Responsible
for
transporting
unconjugated
bilirubin
to
the
endoplasmic reticulum (where it may
be rapidly conjugated)
Conjugation (esterification) of bilirubin
occurs in the presence of the enzyme
uridyldiphosphate glucuronyl transferase
(UDPGT), which transfers a glucuronic acid
molecule to each of the two propionic acid
side chains of bilirubin to form bilirubin
diglucuronide (conjugated bilirubin)
This form of bilirubin is water soluble
Able to be secreted from the
hepatocyte into the bile canaliculi
Once in the hepatic duct, it combines with
secretions from the gallbladder through the
cystic duct and is expelled through the
common bile duct to the intestines
Intestinal bacteria work on conjugated
bilirubin to produce mesobilirubin, which is
reduced to form mesobilirubinogen and then
urobilinogen (colorless)
Most of the urobilinogen formed (about
80%) is oxidized to an orange-colored
product called urobilin (stercobilin) and is
excreted in the feces
Urobilin gives the stool its brown
color
The majority of the remaining 20%
will be absorbed by extrahepatic
circulation to be recycled
The other part will enter systemic
circulation and be excreted in the
urine
Approximately 200 to 300 mg of bilirubin is
produced per day, and it takes a normally
functioning liver to process the bilirubin and
eliminate it from the body
The healthy adult has very low levels of total
bilirubin (0.2 to 1.0 mg/dL)

Metabolism
Carbohydrates

Metabolism of carbohydrates is one of the

most important functions of the liver
Liver can do three things to carbohydrates
Use the glucose for its own cellular
energy requirements
Circulate the glucose for use at the
peripheral tissues
Store glucose as glycogen

Lipids

Metabolized in the liver under normal

circumstances when nutrition is adequate
and the demand for glucose is being met
Approximately 70% of the daily production
of cholesterol (roughly 1.5 to 2.0 g)

Proteins

Almost all proteins are synthesized by the

liver except for the immunoglobulins and
adult hemoglobin
One of the most important proteins
synthesized in the liver is albumin
Synthesis of positive and negative acutephase reactants and coagulation proteins

Vitamins

Fat soluble
A, D, E, K
Water soluble
B12

Detoxification and Drug Metabolism

Every substance that is absorbed in the

gastrointestinal tract must first pass through
the liver (referred to as first pass)
The liver can serve as a barrier to prevent
toxic or harmful substances from reaching
systemic circulation
It may either bind the material reversibly so
as to inactivate the compound or it may
chemically modify the compound so it can
be excreted
The drug-metabolizing system of the liver is
responsible for the detoxification of many
drugs
through
oxidation,
reduction,
hydrolysis, hydroxylation, carboxylation, and
demethylation

Storage

Glycogen
Lipids
Amino acids and proteins

LIVER FUNCTION
DISEASE

ALTERATIONS

DURING

Drug and Alcohol-Related Disorders

Drugs

Alcohol

Ethanol
In very small amounts, causes very
mild, transient, and unnoticed injury
to the liver
Can lead to alcoholic cirrhosis
Alcohol-induced liver injury may be
categorized into three stages
Alcoholic fatty liver
Alcoholic hepatitis
Alcoholic cirrhosis

*Alcoholic fatty liver

*Alcoholic hepatitis

Liver is a primary target organ for adverse

drug reactions because it plays a central
role in drug metabolism
Drugs can cause liver damage by a variety
of mechanisms, but the most common is via
an immune-mediated injury to the
hepatocytes
Drug induces an adverse immune
response directed against the liver
itself and results in hepatic and/or
cholestatic disease
Other drugs
Some antibiotics
Antineoplastic agents
Tranquilizers
Lipid-lowering medication
Anti-inflammatory drugs

Represents the mildest category where very

few changes in liver function are
measurable
Characterized by slight elevations in
aspartate aminotransferase (AST), alanine

aminotransferase (ALT), and Gamma

glutamyltransferase (GGT)
Tends to affect young to middle-aged
people with history of moderate alcohol
consumption

Fever, ascites, proximal muscle loss

Moderately elevated AST, ALT, GGT, and
alkaline phosphatase (ALP)
Bilirubin greater than 5 mg/dL

*Alcoholic cirrhosis

Dependent on the nature and severity of

associated
conditions
such
as
a
gastrointestinal bleeding or ascites
Increased liver function tests, decreased
albumin, and prolonged prothrombin time
Liver biopsy is the only method by which a
definitive diagnosis may be made
The risk of development of cirrhosis
increases
proportionally
with
the
consumption of more than 30 g of alcohol
per day
Amount of alcohol and effects
>1000 mg/L under influence
3000 mg/L CNS impairment/coma
4000 mg/L death

Reye Syndrome

Group of disorders caused by infectious,

metabolic, toxic, or drug-induced disease
found almost exclusively in children
Idiopathic
Often preceded by a viral syndrome such as
varicella, gastroenteritis, or an upper
respiratory tract infection
Strong epidemiologic association between
ingestion of aspirin during a viral syndrome
and subsequent development of the disease
Acute illness characterized by noninflammatory encephalopathy and fatty
degeneration of the liver, profuse vomiting,
and varying degrees of neurological
impairment
Degeneration of the liver is characterized by
a mild hyperbilirubinemia and threefold

increases
in
aminotransferases

ammonia

and

Tumors

Primary liver cancer

Begins in liver cells
Metastatic cancer
When tumors from other parts of the
body spread to the liver
Much more common
Colon, lung, and breast cancer
commonly spread to the liver
Previous infection with hepatitis
Tumors of the liver may also be classified
as benign or malignant

Benign

Hepatocellular adenoma
A
condition
occurring
almost
exclusively in females of childbearing age
Hemangiomas
Masses of blood vessels with no
known etiology

Malignant

Hepatocellular carcinoma
Also known as hepatocarcinoma and
hepatoma
Most common
Bile duct carcinoma
Hepatoblastoma
Uncommon hepatic malignancy of
children

Viral infections account for the majority of

hepatitis cases
Infections with these viruses can
lead to the onset of acute disease
with symptoms, including jaundice,
dark
urine,
fatigue,
nausea,
vomiting, and abdominal pain

Types

RNA virus (picorna virus)

Fecal-oral route

Hepadna virus (DNA)

Flavivirus

Delta agent
Needs coinfection
surface antigen

Hepevirus
Fecal-oral route

Toga virus

B
C
D
with

heap

F
G
G-B virus
Transfusion-transmitted virus
SEN virus
Alcoholic Hepatitis
Drug
Ketoconazole
Methyl dopa
Nitrofurantoine
Isoniazid

Hepatitis

Injury to the liver characterized by the

presence of inflammation in the liver tissue
Infectious causes
Bacterial
Viral
Parasitic infections
Non-infectious causes
Radiation
Drugs
Chemicals
Autoimmune diseases
Toxins

Cirrhosis

Comes from the Greek word for yellow

Irreversible scarring of liver
2 cardinal features
Fibrosis prevents regeneration
Nodules

macronodules
micronodules

or

Scar tissue replaces normal, healthy liver

tissue
Blocks the flow of blood through the organ
Signs and symptoms
Fatigue
Nausea
Unintended weight loss
Jaundice
Bleeding from the gastrointestinal
tract
Intense itching
Swelling in legs and abdomen
May lead to portal hypertension portal
vein is blocked
Splenomegaly
Esophageal varices
Fatal hemorrhage
Synthetic function is affected
Hypoalbuminemia
Low clotting factors
Ascitic fluid accumulates in abdomen
Autoantibodies that lead to cirrhosis
Anti-P62
Anti-centromere

Classifications of Jaundice

Pre-hepatic
Hemolytic hyperbilirubinemia
Hepatic
Hepatocellular hyperbilirubinemia
Post-hepatic
Obstructive hyperbilirubinemia

Pre-hepatic

Occurs when the problem causing jaundice

occurs prior to liver metabolism
Most commonly caused by an increased
amount of bilirubin being presented to the
liver
RBC destruction
Excessive amount of bilirubin is presented
to the liver for metabolism
Characterized
by
unconjugated
hyperbilirubinemia
Malaria and hemolytic anemia
Unconjugated bilirubin is not seen in urine
because it is not water soluble and bound to
albumin

Hepatic

Jaundice or Icterus

French
Jaune which means yellow
Yellowish discoloration of the skin and
sclera
Hyperbilirubinemia
>1 mg/dL up to 2-3 mg/dL
Associated with kernicterus

Occurs when the primary problem resides in

the liver
Can be due to disorders of bilirubin
metabolism and transport defects or
due to diseases resulting in
hepatocellular injury or destruction
Due to impaired cellular uptake, defective
conjugation or abnormal secretion of
bilirubin by the liver cell
Increased B1 and B2
Viral hepatitis, liver cirrhosis, Fasciola
hepatica

*Gilbert Syndrome

Gilbert-Muelengracht syndrome
Benign autosomal recessive hereditary
disorder
Results from a genetic mutation in the gene
UGT1A1
Impaired cellular uptake of bilirubin
Asymptomatic; only mild icterus
Increased B1

Characterized by intermittent unconjugated

hyperbilirubinemia

*Crigler-Najjar Syndrome

Syndrome
of
chronic
non-hemolytic
unconjugated hyperbilirubinemia
Deficiency of the enzyme UDPGT
Type I
Complete absence of enzymatic
bilirubin conjugation
No B2 is formed
Bile is colorless
Type II
Mutation
causing
a
severe
deficiency
of
the
enzyme
responsible for bilirubin conjugation

Impaired excretion of bilirubin caused by

mechanical obstruction of the flow of bile
into the intestines
Increased B1 and B2
Stool loses its source of normal
pigmentation clay colored
Gallstones (cholecystolithiasis), stones in
the common bile duct (choledocholithiasis),
constriction
of
bile
ducts/strictures,
parasitism
Results from biliary obstructive disease

*Lucey Driscoll

Increased B1 (defect in UDPGT, congenital,

maternal steroids)

*Dubin-Johnson Syndrome

LABORATORY TESTS

Deficiency of the canalicular multidrug

resistance/multispecific organic anionic
transporter protein (MDR2/cMOAT)
Livers ability to uptake and conjugate
bilirubin is functional; however the removal
of conjugated bilirubin from the liver cell and
the excretion into the bile are defective
Obstructive in nature
Delta bilirubin conjugated bilirubin bound
to albumin

Direct Measurement of Natural Color

Icterus Index

*Rotor Syndrome

Defect causing RS is not known

Idiopathic
Conjugated hyperbilirubinemia
defective excretion

Used in the development of the Icterus

Index

Muelengracht Method
Dilute serum with NSS and compare
with 0/01% potassium dichromate
Newberger Method
Sodium citrate is used

Number of times the serum is diluted

due

to

Carotene, xanthophyll II, hemoglobin affects

the result

Diazo-Colorimetric Procedure

Evelyn and Malloy (1937)

Post-hepatic

*Reagents

Diazotized sulphalinic acid (DSA)

Sulphanilic acid
Sodium nitrite
50% methanol
Sodium acetate
Ascorbic acid
Urine Urobilinogen Ehrlichs Method
*Reagents

Jendrassik and Grof (1938)

*Reagents

Diazotized sulphalinic acid (DSA)

Sulphanilic acid
Sodium nitrite
Caffeine sodium benzoate
Sodium acetate ascorbic acid

*Advantages of JG over EM

Insensitive to sample pH changes

Insensitive to a 50-fold variation in protein
concentration
Adequate optical sensitivity even for low
bilirubin concentration
Minimal turbidity and with constant serum
blank
Not affected by hemoglobin up to 750
mg/dL

Fecal
Urobilinogen
aldehyde/Watsons Reaction)

*Note

Avoid hemolyzed sample when measuring

bilirubin

Specimen
considerations
Measurement

p-dimethyl aminobenzaldehyde (Ehrlichs

reagent)
Ascorbic acid
Reducing
agent
to
maintain
urobilinogen in reduced state
Sodium acetate
Stops the reaction and minimizes
the
combination
of
other
chromogens
Product red colored compound
Ehrlichs unit of measurement is used
1 Ehrlich unit = 1 mg urobilinogen
Reference range
0.1-1.0 Ehrlich units/2 hours
0.5-4.0 Ehrlich units/day (0.868
mmol/day)

for

Bilirubin

Specimen: fasting, non-hemolyzed, nonlipemic

Source of errors: lipochrome, hemolysis,
lipemia, exposure to light

(Ehrlichs

Aqueous extract of fresh feces + Fe(OH) 2 +

Ehrlichs reagent red colored compound
Fe(OH)2
reduces
urobilin
to
urobilinogen
Reference values
75-275 Ehrlichs unit/100g or 75-400
Ehrlich units/24 hours

*Clinical Significance of Urobilinogen

Increased
Hemolytic disease
Defective
liver
(hepatitis)
Absence
Biliary obstruction

cell

function

Hepatocellular disease

Test for Bile Salts

Urine Bilirubin

Hay Test

Sprinkle sulphur powder to 5 mL of urine

Interpretation
Sulphur powder floats at the top
bile salts absent
Sulphur powder sinks to the bottom
bile salts present (obstructive
jaundice)
Unreliable

Measure the products of liver

Total protein
Albumin
-globulin
Prothrombin time
Prolonged

inadequate
clotting factors
Albumin-Globulin ratio is also measured

Test for Excretory Function

Excretion of Foreign Dyes

Measure
%
retention
sample)
Dyes are injected IV
Bromsulphalein Test
Rose Bengal Test

Bromsulphalein Test

Foam Test

Yellow foam indicates positive result

Urine color inspection

Brown to amber indicates positive result

Fouchets Test or Harrison Spot Test

Test for Synthetic Function

Uses tagged I131

Radioactivity of the dye

Urine + BaCl2 filter

Barium chloride acts as precipitant
Precipitate + FeCl3 in TCA green colored
precipitate

Diazotization Test

Tablet test/Ictotest
Strip test

Detoxification Function Test

(serum

Quicks Test or Hippuric Acid Test

Patient is given a sodium benzoate
meal
40% is excreted within 60 minutes

Sodium benzoate Benzoic Acid Conjuagted

with glycine Hippuric acid in urine Titrate with
standard alkali
Enzymes

AST aspartate aminotransferase

ALT alanine aminotransferase
ALP alkaline phosphatase
GGT gamma glutamyl transferase
5-nucleotidase
LD lactate dehydrogenase

%retention-%excretion

BSP is toxic

Rose Bengal Test

[Flying Cockroach]