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CHAPTER 25: LIVER FUNCTION

LIVER
 Very large and complex organ responsible for performing
vital tasks that impact all body systems.
 Functions include:
o Metabolism of carbohydrates, lipids, proteins and
bilirubin.
o Detoxification of harmful substances.
o Storage of essential compounds.
o Excretion of substances to prevent harm.
 A relatively resilient organ that can regenerate cell that EXCRETORY SYSTEM OF THE LIVER
have been destroyed by some short-term injury or disease Bile Canaliculi  Intrahepatic ducts  Right and Left
or have been removed. Hepatic Duct  Common Hepatic Duct + Cystic Duct 
 If damaged repeatedly over a long period of time  Common Bile Duct  secretions are expelled into the
undergo irreversible changes that permanently interfere Duodenum
with its essential functions.  Bile canaliculi – this is where the excretory system of the
 If completely nonfunctional  death within 24 hours due to liver begins; small spaces between the hepatocytes that
hypoglycemia. form intrahepatic ducts, where excretory products of the cell
can drain.
ANATOMY
MICROSCOPIC ANATOMY
GROSS ANATOMY
 Divide into microscopic units called lobules.
 Large and complex organ
o Lobules – functional units of the liver; responsible
 Weighs 1.2 to 1.5 kg in a healthy adult.
for all metabolic and excretory functions; roughly
 Located beneath and attached to the diaphragm.
a six-sided structure with a central vein with portal
 Protected by the lower rib cage.
triads at each of the corners.
 Held in place by ligamentous attachments.
 Portal triad:
 Simple in structure.
o Hepatic Artery
 Falciform ligament – divides the liver into two unequal
o Portal Vein
lobes; lobes are insignificant; however, communication
o Bile Duct
flows freely between all areas of the liver.
 Two major cell types:
o Right Lobe – approximately 6 times larger than the
o Hepatocytes – approximately 80% of the volume
left lobe.
of the organ; large cells that radiate outward from
o Left Lobe
the central vein in plates to the periphery of the
 Extremely vascular organ that receives its blood supply
lobule; performs the major functions associated
from two sources
with the liver; responsible for the regenerative
o Hepatic Artery – a branch of the aorta; supplies
properties of the liver.
oxygen-rich blood from the heart to the liver;
o Kupffer Cells – macrophages that line the
responsible for providing approximately 25% of
sinusoids of the liver; act as active phagocytes
the total blood supply to the liver.
capable of engulfing bacteria, debris, toxins, and
o Portal Vein – supplies nutrient-rich blood
other substances flowing through the sinusoids.
(collected as food is digested) from the digestive
tract; responsible for providing approximately 75% BIOCHEMICAL FUNCTIONS
of the total blood supply to the liver.
 Hepatic sinusoid is lined with hepatocytes capable of EXCRETORY AND SECRETORY
removing potentially toxic substance from the blood.
 Most important function:
 ~1500mL/min of blood passes through the liver.
o Processing and excretion of endo- and exogenous
substances into the bile or urine (ex: Bilirubin –
major heme waste product).
 Bile is made up of:
o Bile acids or salts
o Bile pigments
o Cholesterol
BLOOD SUPPLY TO THE LIVER o Other substances extracted from the blood.
Hepatic Artery + Portal Vein  Hepatic Sinusoid  Central  Body produces 3L/day of bile and excretes 1L/day.
Canal (aka Central Vein)  blood leaves the Liver

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 Bilirubin – principal pigment in bile; derived from the
breakdown of RBCs.
 Reticuloendothelial tissue  RBCs  (After 126 days)
Phagocytized  Hemoglobin is released.
 Hemoglobin is degraded into:
o Heme – converted into bilirubin in 2-3hrs.
o Globin – degraded to its constituent amino acids,
which are reused by the body.
o Iron – bound by transferrin; returned to iron stores
in the liver of bone marrow for reuse.
 Unconjugated Bilirubin – insoluble in water; cannot be
removed from the body until it has been conjugated in the
liver.
 Ligandin – carrier protein; located in the hepatocyte;
responsible for transporting unconjugated bilirubin to the
ER, where it may be rapidly conjugated.
 Uridyldiphosphate Glucuronyl Transferase (UDPGT) –
transfers a gluconic acid molecule to each of the two
propionic acid side chains of bilirubin to form bilirubin
diglucuronide.
 Conjugated Bilirubin – bilirubin diglucoronide; able to be
secreted from the hepatocyte into the bile canaliculi.
 Urobilinogen – colorless product; 80% is oxidized to
urobilin.
 Urobilin – aka stercobilin; orange colored product; excreted
in feces; gives stool its brown color (50-250mg/day).
BILIRUBIN METABOLISM
RBC Destruction  Heme  Bilirubin  +Albumin =
Unconjugated Bilirubin (UB)  Liver
In the LIVER
Sinusoidal spaces  UB – Albumin (released) 
+Ligandin  +UDPGT = Conjugated Bilirubi (CB)  Bile
canaliculi  CB (in hepatic duct)+ Gall Bladder secretions
(thru cystic duct)  Common Bile duct  Intestines
In the INTESTINES
+Intestinal bacteria  Mesobilirubin  Mesobilirubinogen
 Urobilinogen  80% oxidized to Urobilin  Excreted in
Feces
 Remaining 20% of Urobilinogen
o Majority: reabsorbed by extrahepatic circulation to
be recycled through the liver and reexcreted.
o Small quantity: enter the systemic circulation and
will subsequently be filtered by the kidney and
excreted in the urine (1-4mg/day)
 Total Bilirubin in healthy adults:
o 0.2 – 1.0 mg/dL in serum
o Majority is in unconjugated form.
METABOLISM
 Responsible for metabolizing many biological compounds
including carbohydrates, lipids, and proteins.
 Metabolism of carbohydrates – one of the most important
functions.
 When carbohydrates are ingested and absorbed, the liver:
o Use the glucose for its own cellular energy
requirements.
o Circulate the glucose for use at the peripheral
tissue.
o Store glucose as glycogen within the liver itself or
within the tissue.
 Major player in maintain stable glucose concentrations due
to:
o Glycogenesis – store glucose as glycogen.
o Glycogenolysis – degrade/break down stored
glycogen.
o Gluconeogenesis – create glucose from non-
sugar substrates (e.g. pyruvate, lactate, and
amino acids).
 Responsible for metabolizing both lipids and the
lipoproteins and is responsible for gathering free fatty acids
from the diet, and those produced by the liver itself, and
breaking them down to produce Acetyl-CoA,
 Greatest source of cholesterol in the body comes from what
is produced by the liver.
o Daily production: 70% or roughly 1.5g to 2.0g.
 All proteins, except immunoglobulin and adult hemoglobin,
are synthesized in the liver.
 Plays an essential role in the development of hemoglobin
in infants.
 Albumin – most important protein synthesized in the liver.
 Responsible for synthesizing the positive and negative
acute-phase reactants and coagulation proteins.
 Serves to store a pool of amino acids through protein
degredation.
 Most critical aspect of protein metabolism:
o Transamination – via transaminase; exchange of
an amino group on one acid with a ketone group
on another acid.
o Deamination – degrades them to produce
ammonium ions that are consumed in the
synthesis of urea and urea is excreted by the
kidneys.
DETOXIFICATION AND DRUG METABOLISM
 Gatekeeper between substances absorbed by the GI tract
and those released into systemic circulation.
 First pass – important function; it can allow important
substances to reach the systemic circulation; barrier to
prevent toxic or harmful substances from reaching systemic
circulation.
 Two mechanisms for detoxification of foreign materials and
metabolic products:
o Bind the material reversibly so as to inactivate the
compound.
o Chemically modify the compound so it can be
excreted.
 Drug-metabolizing system – most important mechanism;
responsible for the detoxification of many drugs through
oxidation, reduction, hydrolysis, hydroxylation,
carboxylation, and demethylation
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o Takes place in the liver microsomes via
cytochrome P-450 isoenzymes.
LIVER FUNCTION ALTERATIONS DURING DISEASE
JAUNDICE
 One of the oldest known pathologic conditions reported,
having been described by Hippocratic physicians.
 Jaundice – aka icterus; yellow discoloration of skin, eyes
and mucous membranes resulting from the retention of
bilirubin.
 Overt jaundice – jaundice that is not noticeable to the naked
eye until bilirubin levels reach 3.0 – 5.0 mg/dL.
 Icterus – most commonly used in the clinical laboratory to
refer to a serum or plasma sample with a yellow
discoloration due to an elevated bilirubin level.
 Classified based on the site of the disorder:
o Pre-hepatic
o Hepatic
o Post-hepatic
 Pre-hepatic (Unconjugated hyperbilirubinemia)
o Problem causing the jaundice occurs prior to liver
metabolism.
o Increased amount of bilirubin being presented to
the liver such as that seen in acute and chronic
hemolytic anemia.
 Hemolytic anemia – increased amount of
RBC destruction; subsequent release of
increased amounts of bilirubin presented
to the liver for processing.
 Hemolytic Disease of the Newborn
 Hemolytic Transfusion Reaction
 Malaria
o Rarely have bilirubin levels that exceed 5.0 mg/dL
because the liver is capable of handling the
overload.
o Liver responds by functioning at maximum
capacity.
o People with the disease rarely have bilirubin levels
that exceed 5.0 mg/dL because the liber is
capable of handling the overload.
 Hepatic
o Occurs when the primary problem causing the
jaundice resides in the liver.
o Intrinsic Liver Defect – disorders of bilirubin
metabolism and transport defects.
 Crigler-Najjar syndrome, Gilbert’s
disease, Neonatal physiologic jaundice
of the newborn – elevations in B1.
 Dubin-Johnson syndrome, Rotor
syndrome – elevations in B2.
o Gilbert’s Syndrome
 Benign autosomal recessive hereditary
disorder.
 Genetic mutation in the gene UGT1A1
that produces UDPGT.
 Most common cause of jaundice.
 No morbidity or mortality.
 No clinical consequence.
 Intermittent unconjugated
hyperbilirubinemia, underlying liver
disease due to a defective conjugation
system in the absence of hemolysis.
 Manifests during adolescence or early
adulthood.
 Total serum bilirubin:
 1.5-3.0 mg/dL
 Rarely exceeds 4.5 mg/dL
o Crigler-Najjar Syndrome
 Crigler and Najjar in 1952
 More sever and dangerous form of
hyperbilirubinemia.
 Chronic nonhemolytic unconjugated
hyperbilirubinemia.
 Inherited disorder of bilirubin
metabolism.
 Molecular defect within the gene involved
with bilirubin conjugation.
 Two types:
 Type I – complete absence of
enzymatic bilirubin conjugation.
 Type II – mutation causing a
sever deficiency of UDPGT.
 Rare and more serious disorder that may
result to death.
o Dubin-Johnson Syndrome
 Conjugated hyperbilirubinemia.
 Rare autosomal recessive inherited
disorder caused by a deficiency of the
canalicular multidrug
resistance/multispecific organic anionic
transporter protein (MDR2/cMOAT).
 Liver’s ability to uptake and conjugate
bilirubin is functional; removal of
conjugated bilirubin from the liver cell
and the excretion into the bile are
defective.
 Accumulation of B2 leading to
hyperbilirubinemia and bilirubinuria.
 Obstructive in nature; much of the B2
circulates bound to albumin.
 Delta bilirubin – B2 bound to albumin;
reacts as B2 in laboratory methods
measuring total bilirubin and B2.
 Distinguishing feature: dark-stained
granules on a liver biopsy sample.
 Total bilirubin concentration:
 2-5mg/dL; more than 50% due
to the conjugated fraction.
 No treatment is necessary.
o Rotor Syndrome
 Similar to Dubin-Johnson.
 Cause not known.
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 Hypothesized to be due to a reduction in Autoimmune hepatitis Infections

the concentration or activity of ligandin. Inherited disorders
 No dark pigmented granules in liver
biopsy. TUMORS
 Less common.
 Benign condition with excellent  Cancers of the liver are classified as:
prognosis. o Primary Liver Cancer – begins in the liver cells.
 Treatment is not warranted. o Metastatic Liver Cancer – when tumors from other
 Requires an accurate diagnosis. parts of the body spread (metastasize) to the liver;
o Physiologic Jaundice of the Newborn much more common; spreads from colon, lung
 Deficiency in the enzyme glucuronyl and breast cancer.
transferase.  Tumors may be classified as:
 One of the last liver functions to o Benign Tumors:
be activated in prenatal life  Hepatocellular adenoma – occurs almost
since bilirubin processing is exclusively in females of child-bearing
handled by the mother of the age.
fetus.  Hemangiomas – masses of blood
 Rapid buildup of B1; life threatening. vessels with no known etiology.
 Kernictus - B1 deposited in the nuclei of o Malignant Tumors:
the brain and degenerate nerve cells;  Hepatocellular carcinoma – aka
results in cell damage and death in hepatocarcinoma or hepatoma; most
newborn. common.
 Usually treated with UV radiation.  Bile duct carcinoma
 Level of B1 in blood:  Hepatoblastoma – uncommon; occurs in
 ~20mg/dL children.
 Posthepatic REYE’S SYNDROME
o Results from biliary obstructive disease
(cholestasis).  Group of disorders caused by infectious, metabolic, toxic or
o Physical obstructions that prevent flow of B2 into drug-induced disease found almost exclusively in children.
the bile canaliculi:  Often preceded by a viral syndrome.
 Gall stones  Aspirin-associated disease.
 Tumors  Avoid Salicylate use in children with viral syndrome (CDC).
o Stool loses its source of normal pigmentation and  Non-inflammatory encephalopathy and fatty degeneration
becomes clay colored. of the liver.
 Profuse vomiting accompanied with varying degrees of
TYPE TOTAL B1 B2 neurologic impairment such as:
Prehepatic ↑ ↑ ↔ o Fluctuating personality changes.
Gilbert’s ↑ ↑ ↔ o Deterioration in consciousness.
Crigler-Najjar ↑ ↑ ↓
Dubin-Johnson ↑ ↔ ↑ DRUG- AND ALCOHOL-RELATED DISORDERS
Rotor ↑ ↔ ↑  Most common mechanism of toxicity is via an immune-
Jaundice of Newborn ↑ ↑ ↔ mediated injury to the hepatocytes.
Posthepatic ↑ ↑ ↑ o Drug induces an adverse immune response
directed against the liver itself and results in
CIRRHOSIS hepatic and/or cholestatic disease.
 Ethanol – most important drug associated with hepatic
 Scar tissue replaces liver tissue resulting to blockage of
toxicity; causes very mild, transient and unnoticed injury to
blood flow.
the liver; can lead to alcoholic cirrhosis if prolonged and
 Treatment depends on the cause of Cirrhosis and any
heavier consumption.
coexisting complications.
o Interferon for viral hepatitis. 90% alcohol  stomach and small intestines  liver
o Corticosteroids for autoimmune hepatitis. In the Liver:
 Most common cause: Alcohol alcohol dehydrogenase + acetaldehyde
Chronic alcoholism Nonalcoholic steatohepatitis dehydrogenase  acetate  oxidized  H2O + CO2 
HBV Blocked bile ducts Citric Acid Cycle
HCV Drugs
HDV Toxins

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 Alcohol dehydrogenase + Acetaldehyde dehydrogenase – o Conjugated bilirubin bound to albumin.

required to convert alcohol to acetaldehyde and
subsequently to acetate. METHOD OF ANALYSIS
 Long term excessive alcohol consumption can result to:  Measured using Diazotized Sulfanilic Acid.
o Steatohepatitis – alcoholic fattry liver with  B1 = TOTAL BILIRUBIN – B2
inflammation.  Types of reaction:
o Hepatic fibrosis – scar tissue formation. o Direct Van den Bergh
o Hepatic cirrhosis – destruction of normal liver  B2 + Diazo reagent  Azobilirubin
structure.  Conjugated Bilirubin
 Three stages: o Indirect Van den Bergh
o Alcoholic Fatty Liver – mildest category; very few  B1 + Diazo reagent  No reaction
changes in liver are measurable; affect young to  B1 + Accelerator + Diazo reagent 
middle-aged people with a history of moderate Azobilirubin
alcohol consumption.  Total Bilirubin
 Elevated AST, ALT, GGT
 Fatty infiltrates in the vacuoles of the liver Malloy-Evelyn Jendrassik-Grof
in biopsy Accelerator 50% Methanol Caffeine-Benzoate-Acetate
o Alcoholic Hepatitis – presents with common signs Stopper None Ascorbic Acid
and symptoms including fever, ascites, and pH 1.2 (Acidic) Basic (Alkaline Tartrate)
proximal muscle loss. End Product Azobilirubin
End Color Purple @ 560nm Blue @600nm
 Elevated AST, ALT, GGT and ALP
 Total bilirubin is >5mg/dL
 De Ritis Ratio (AST/ALT) greater than 2 SPECIMEN COLLECTION AND STORAGE
 Elevated INR  Serum or Plasma
 INR – International Normalized o Serum for Malloy-Evelyn
Ratio; ratio of coagulation time  Fasting sample
compared with a normal o Lipemia  Falsely high
coagulation time.  Avoid hemolysis
 Decreased albumin o Hemolysis  False low
o Alcoholic Cirrhosis – risk increases proportionally  Protect from light
with the consumption of more than 30g of alcohol o Will decrease by 30-50% per hour
per day, with the highest degree seen with the
consumption of >120g per day; most severe; most ENZYME TEST IN LIVER DISEASE
common in males; nonspecific symptoms. AMINOTRANSFERASES
 Elevated AST, ALT, GGT, ALP, Total
Bilirubin  Responsible for catalyzing the conversion of aspartate and
 Decreased Albumin alanine to oxaloacetate and pyruvate, respectively.
 Prolonged PTT  Most useful in the detection of hepatocellular damage to the
 Acetaminophen – most common drug associated with liver.
serious hepatic injury; in massive doses, can cause fatal  Rises rapidly in almost all diseases of the liver and may
hepatic necrosis. remain elevated for up to 2-6 weeks.
 Highest levels are found in:
ASSESSMENT OF LIVER FUNCTION/LIVER FUNCTION o Viral hepatitis
TESTS
o Drug- and toxin-induced liver necrosis
BILIRUBIN o Hepatic ischemia
 Elevations of these enzymes may be a result of other organ
ANALYSIS OF BILIRUBIN: A BRIEF REVIEW dysfunction or failure.
 Aspartate Aminotransferase
 Unconjugated Bilirubin (Indirect Bilirubin or B1)
o Serum Glutamic Oxaloacetic Transaminase
o Non-polar and water insoluble.
o Found mainly in the liver; lesser amounts in
o Found in plasma bound to albumin.
skeletal muscle and kidney.
o Reacts with Diazo reagent with accelerator.
o Liver specific marker.
 Conjugated Bilirubin (Direct Bilirubin or B2)
o Increases activity greater than that of AST.
o Polar and Water soluble.
 Alanine Aminotransferase
o Found in plasma in a free.
o Serum Glutamic Pyruvic Transminase
o Reacts with Diazo reagent directly.
 Delta Bilirubin

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o Equally distributed in the heart, skeletal muscle, o Sensitive test for cholestasis caused by chronic
and liver. alcohol or drug ingestion.
o Useful if jaundice is absent for the confirmation of
PHOSPHATASES hepatic neoplasms.
 Alkaline phosphatase  Lactate Dehydrogenase
o Zinc metalloenzymes that are widely distributed in o Released into circulation when cells of the body
all tissues. are damaged or destroyed.
o Highest activity is seen in: o General, nonspecific marker of cellular injury.
Liver Kidney o Slight elevations are caused by:
Bone Placenta  Biliary tract disease
Intestine o Moderate elevations are caused by:
o Differentiate hepatobiliary disease from  Acute viral hepatitis
osteogenic bone disease.  Cirrhosis
o In the liver, it is localized to the microvilli of the bile o High elevations may be found in:
canaliculi.  Metastatic carcinoma of the liver
 Marker for extrahepatic biliary  No additional clinical information.
obstruction.  Fractionation of LD isoenzymes may give useful
o High concentrations in cases of extrahepatic information about the site of origin of the LD elevation.
obstruction. TEST MEASURING HEPATIC SYNTHETIC ABILITY
o Slight to moderate increase seen in those with
hepatocellular disorders such as hepatitis and  Measurement of proteins assess the synthetic ability of the
cirrhosis. liver; not sensitive to minimal liver damage; useful in
o May be elevated in bone-related disorders (e.g. quantitating severity of hepatic dysfunction.
Paget’s disease), bone metastases, increase in  Albumin
osteoblastic activity and rapid bone growth. o Decrease in chronic liver diseases.
o Found elevated in pregnancy due to its release  α1-globulins
from the placenta. o Decrease in Alpha1-antitrypsin deficiency in
o Interpretation can be difficult; can increase in the chronic liver diseases.
absence of liver damage.  γ-globulin
 5’-Nucleotidase o Increased in acute and chronic liver diseases.
o Responsible for catalyzing the hydrolysis of  IgG and IgM – chronic active hepatitis
nucleoside-5’-phosphate esters.  IgM – primary biliary cirrhosis
o Significantly elevated in hepatobiliary disease.  IgA – alcoholic cirrhosis
o In liver disease:  Prothrombin Time
 5NT + ALP  elevated o Increase in liver disease
o In bone disease  Inadequate production of clotting factors
 ALP  elevated (I, II, V, VII, IX and X)
 5NT  normal or only slightly elevated  Inadequate absorption of Vitamin K from
o Much more sensitive to metastatic liver disease. the intestine.
o Not elevated by other conditions. o Not routinely used in the diagnosis of liver
o Increase in enzyme activity may be noted after disease.
abdominal surgery. o Useful in following the progression of disease and
 γ-Glutamyltransferase the assessment of the risk of bleeding.
o Membrane-localized enzyme found in high o Prolonged PTT  sever diffuse liver disease and
concentrations in the: a poor prognosis.
Kidney Intestine
Liver Prostate
Pancreas
o Similar to 5NT, plays a role in differentiating ALP
elevations.
 Highest levels are seen in biliary
obstruction.
o A hepatic microsomal enzyme.
 Ingestion of alcohol or certain drugs 
elevated.

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