Lect.

4 Liver Function Tests

 The liver is the largest internal organ of the body, approximately 1.2 to 1.5 kg in weight. It can
regenerate cells that have been destroyed by some short-term injury or disease. However, if the
liver is damaged repeatedly over a long period of time, it may undergo irreversible changes that
permanently interfere with its essential functions.
 The liver is an extremely vascular organ that receives its blood supply from two sources: the
hepatic artery and the portal vein. The main blood supply to the liver is via the portal vein. The
liver is made up of hexagonal lobules of cells. Rows of hepatocytes radiate from the central
hepatic vein and are separated by sinusoidal spaces, along the walls of which are interspersed
hepatic macrophages, the Kupffer cells. These phagocytic cells are part of the reticuloendothelial
system and have an important detoxifying function. At the corners of each lobule are the portal
tracts that contain branches of the hepatic artery, the portal vein, and bile ducts. Blood flows from
the portal tracts towards the central hepatic vein.


Functions of the liver
1. Carbohydrate and fat metabolism
2. Storage of glycogen, vitamins and Iron
3. Hormone metabolism (steroid hormones, 25-hydroxylation of vitamin D)
4. synthesis of all plasma proteins, except -globulins, most coagulation factors, bile acids,
lipoproteins, urea.
5. excretion of bilirubin, Cholesterol, urea
6. detoxification of Many drugs and toxins

 Formation and excretion of bilirubin:

 At the end of RBCs lifespan, they are broken down by the reticuloendothelial system, mainly in the
spleen. The released hemoglobin is split into globin and haem, which is converted to bilirubin after
the removal of iron. About 80 % of bilirubin is derived from RBCs and the remainder comes from the
breakdown of immature red cells in the bone marrow and myoglobin and the cytochromes. Less than
300 µmol of bilirubin is produced daily from the breakdown of erythrocytes, while the normal liver
can conjugate up to about 1 mmol/day. Therefore, hyperbilirubinemia is an insensitive index of
parenchymal hepatic disease.
 Bilirubin (unconjugated bilirubin) is insoluble in water and is carried in plasma bound to albumin.
On reaching the liver, the bilirubin is taken into the hepatocyte, where it is conjugated with
glucuronate by a process catalyzed by uridine diphosphate (UDP) glucuronyl transferase to produce
bilirubin glucuronides, which are water-soluble and readily transported into bile and then excreted
into the bile canaliculi. In the intestine, bilirubin is reduced to urobilinogen by bacterial action. These
compounds oxidize to brown compounds known as urobilins and stercobilins and are excreted in the
feces.
 A small percentage of urobilinogen is
absorbed and carried to the liver in the portal
blood supply, that is, it undergoes an
enterohepatic circulation. In normal urine,
only urobilinogen is present, and in normal
stool, stercobilinogen is present.

 Measurements of serum bilirubin:

 Normal serum bilirubin level varies from 0.2
to 0.8 mg/dl. The unconjugated bilirubin
varies from 0.2–0.7 mg/dl, and conjugated
bilirubin from 0.1–0.4 mg/dl.
 The bilirubin is estimated by the van den
Bergh reaction, where diazotized sulfanilic
acid reacts with bilirubin to form a purple-
colored complex, azobilirubin. Normal serum
does not give a positive van den Bergh
reaction.
 When bilirubin is conjugated, the purple color
is produced immediately on mixing with the
reagent; the response is said to be van den
Bergh direct positive.
 When the bilirubin is unconjugated, the color is obtained only when alcohol is added, and this
response is known as indirect positive.
 If both conjugated and unconjugated bilirubin are present in increased amounts, a purple color is
produced immediately and the color is intensified upon adding alcohol. Then the reaction is called
biphasic.
 Urinary Bilirubin
 In all cases of jaundice, urine should be examined for the presence of bile pigments (bilirubin), bile
salts, and urobilinogen.
 Only conjugated bilirubin is soluble in water and is excreted in urine. Hence, in prehepatic
jaundice, when the unconjugated bilirubin is increased in blood, it does not appear in urine; thus,
it is called acholuric jaundice.
 But in obstructive jaundice, conjugation of bilirubin is taking place, which cannot be excreted
through the normal passage, and so it is regurgitated back into the bloodstream; this is then
excreted through urine. So, in obstructive jaundice, urine contains bilirubin; hence in old
literature, it is called choluric jaundice.
 Urinary Urobilinogen
 In cases of obstruction, bile does not reach the intestine, so that urobilinogen may be decreased
or absent in urine.
 In hepatocellular jaundice, urobilinogen is initially elevated, then decreases or disappears when
the obstructive stage sets in and reappears when an obstruction is cleared.
 Urobilinogen is absent in urine when there is an obstruction to bile flow. The first indication of the
recovery is the reappearance of urobilinogen in urine.
 In hemolytic anemias, urobilinogen is increased.
 Bilirubin is detected by Fouchet's test, and urobilinogen by Ehrlich's test.
 Urine Bile Salts
 Normally, bile salts (sodium salts of taurocholic acid and glycocholic acid) are present in the bile,
but are not seen in urine. Bile salts in urine are detected by Hay’s test.
 Positive Hay’s test indicates the obstruction in the biliary passages causing regurgitation of bile
salts into the systemic circulation leading to its excretion in urine.
 Obstruction can occur in obstructive jaundice and also in hepatic jaundice due to obstruction of
microbiliary channels caused by inflammation.
 BIOCHEMICAL TESTS FOR LIVER DISEASE
Several biochemical tests constitute liver function tests. Different tests can give different information
about hepatic dysfunction.
1. Hepatocyte damage
Changes in plasma enzyme activity generally indicate liver cell membrane damage rather than hepatic
function capacity.
 Aminotransferases (alanine and aspartate)
 A rise in plasma aminotransferase activities is a sensitive indicator of damage to cytoplasmic and/
or mitochondrial membranes. Liver cells contain more aspartate aminotransferase (AST) than
alanine aminotransferase (ALT),
 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.
 The relative plasma activities of ALT and AST may help to indicate the type of cell damage. A
plasma AST: ALT ratio of > 2 is suggestive but not diagnostic of alcoholic liver disease, and a ratio <
1 suggests chronic viral hepatitis or hepatic steatosis.
 In chronic hepatocellular disease (e.g., cirrhosis), serum AST tends to be increased to a greater
extent than ALT.
2. Cholestasis:
 Alkaline phosphatases and γ-glutamyl transferase:
 ALP and GGT are usually attached, or ‘anchored’, to the biliary canalicular and sinusoidal
membranes of the hepatocyte. They are released in much greater amounts when there is
cholestasis, since their synthesis is induced. Serum GGT has the advantage of being more liver-
specific, as serum ALP may also be elevated due to bone release in bone disease.
 However, alcohol and many drugs, such as anti-convulsant, may induce the expression of GGT
without causing cholestasis.
 In acute liver disease without cholestasis, levels of ALT and AST are significantly elevated and ALP
is raised, but usually less than three times the upper limit of the normal value. Therefore, ALT and
AST levels exceeding 500 U/L are a common finding in acute liver disease.
 Very high levels of ALP (10–12 times the upper limit) may be noticed in extrahepatic obstruction
(obstructive jaundice) caused by gallstones or by pressure on the bile duct by carcinoma of the
head of the pancreas. Intrahepatic cholestasis may be due to a virus (infective hepatitis) or to
drugs (chlorpromazine)
 Drastically high levels of ALP (10–25 times of upper limit) are seen in bone diseases where
osteoblastic activity is enhanced. For example, Paget's disease (osteitis deformans), rickets,
osteomalacia, osteoblastoma, metastatic carcinoma of bone, and hyperparathyroidism.
 In children showing only elevated ALP, it is most likely related to osteoblastic activity in their
growing bones.
 A normal liver function test, except for elevated GGT, is a characteristic of excessive alcohol
intake.
3. Hepatic synthetic function:
 Plasma albumin and prothrombin time measurements may be used to assess function. The hepatic
synthetic and secretory capacities are large; only severe and usually prolonged liver disease, for
example, cirrhosis, demonstrably impairs albumin and prothrombin synthesis.
 Albumin
 In chronic hepatocellular damage, there is impaired albumin synthesis with an accompanying fall
in serum albumin. Albumin measurements serve as a guide to the severity of the liver disease.
 In acute liver disease, however, there may be little or no reduction in serum albumin, as the
biological half-life of albumin is about 20 days and the fractional clearance rate is therefore low.
 Factors other than impaired hepatic synthesis may lead to a decreased serum albumin, including
loss of albumin into the extravascular compartment, ascites, increased degradation, and poor
nutritional status.
 Albumin has a fairly long half-life of 20 days; in all chronic diseases of the liver, the albumin level is
decreased.
 A reversal in the A/G ratio is often the rule in cirrhosis, due to hypoalbuminemia and associated
hypergammaglobulinemia.
 Normal albumin level in blood is 3.5 to 5 g/dl; and globulin level is 2.5 to 3.5 g/dl.
 Prothrombin time:
 PT is the best test to assess the extent of liver dysfunction. In liver disease, the synthesis of
prothrombin and other clotting factors is diminished, leading to an increased PT. This may be one
of the earliest abnormalities seen in patients with hepatocellular damage since prothrombin has a
short half-life (<6 h). The PT is often expressed as a ratio to a control value (the INR).
 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. The abnormality is then
corrected by parenteral administration of the vitamin. A prolonged prothrombin time may also
result from severe impairment of synthetic ability if the liver cell mass is greatly reduced; in such
cases, it is not corrected by parenteral administration of vitamin K.
 Serum globulins
 Their measurements are of little value in liver disease because the changes are of low specificity.
 They constitute immunoglobulins produced by B lymphocytes as well as alpha and beta globulins
synthesized mainly by hepatocytes.
4. Serological tests
 Anti-mitochondrial antibodies are present in over 95% of patients with primary biliary cirrhosis.
 Anti-smooth muscle and anti-nuclear factor antibodies are found in about 50% of patients with
chronic active hepatitis.
 Viral antigens and antibody measurements are also important in detecting infectious causes of
liver disease.
5. Special Tests
 In special circumstances, special tests may be done to confirm the diagnosis. Some examples are:
 Glutathione S-transferase activity is a highly sensitive indicator of liver function.
 Alpha fetoprotein (AFP):
 It is a normal component of fetal blood. It disappears after birth within a few weeks. It is a
tumor marker. Mild elevation is suggestive of chronic hepatitis or cirrhosis; drastic increase is
seen in hepatocellular carcinoma, germ cell tumors, and teratoma of the ovary. Elevated AFP in
the maternal serum is seen in cases of fetal open neural tube defects and also in cases with
multiple fetuses or fetal death. Low AFP is seen in maternal serum in cases of fetal Down
syndrome
 Common features of significant liver dysfunction include:
_ Prolonged PT, low serum glucose, and urea.
_ Severe hypoalbuminemia, a common feature of chronic liver disease

 Clinical Manifestations of Liver Dysfunction

A number of conditions are indicative of liver disease, including (1) jaundice, (2) portal hypertension,
(3) disordered hemostasis, and (4) the release of enzymes into various body fluids.
Pattern of Abnormal Liver Function Tests in Various Liver Diseases
Liver Disease Abnormal Liver Function Tests

Pre-hepatic jaundice Total and unconjugated bilirubin are high. Liver enzymes (ALT, AST, ALP,
(hemolytic anemia) and GGT) are normal. PT and proteins are normal.

Hepatocellular Total bilirubin is high. Liver enzymes are elevated. ALT and AST may be
jaundice very high (in thousands); ALP is less than three times normal. Total
protein and albumin may be normal. PT may be prolonged if liver damage
is significant.

Cholestatic jaundice Total bilirubin and conjugated bilirubin are high. Liver enzymes are
elevated (typically mildly). ALP is more than three times normal. PT may
be prolonged due to reduced absorption of fat-soluble vitamin K.

Acute liver disease PT is the best marker for assessment of the extent of acute liver disease.
Total protein and albumin are typically normal.

Chronic liver disease The albumin level is decreased. Total protein could be elevated if
hypergammaglobulinemia is present; liver enzymes may or may not be
elevated.

Liver metastasis Only ALP and GGT may be elevated.

Bone disease or .Only ALP may be elevated
Metastasis

Alcoholic liver disease Only GGT is elevated.

Jaundice (icterus)
is a yellow discoloration of the skin, eyes, and mucous membranes most often resulting from the
deposition of bilirubin. It is the most specific clinical manifestation of hepatic dysfunction. It is,
however, not present in many individuals with liver disease (especially chronic liver disease) and may
also occur with bilirubin overproduction (hemolysis) or congenital disorders of bilirubin metabolism.
Jaundice is usually apparent clinically when the plasma bilirubin concentration reaches 2 to 3 mg/dL.
 Symptoms:
- Yellow discoloration of the skin, sclerae, and mucous membranes
- Itching (pruritus) due to deposits of bile salts on the skin
- Stool becomes light in color
- Urine becomes deep orange and foamy
 Classification of jaundice:
 Jaundice is most commonly classified based on the site of the disorder: prehepatic, hepatic, and
post-hepatic jaundice.
 Prehepatic and post-hepatic jaundice are caused by abnormalities outside of the liver. In these
conditions, liver function is normal or may function at maximum capacity to compensate for
abnormalities elsewhere. With hepatic jaundice, the jaundice is due to a problem with the liver
itself.
 Prehepatic jaundice:
 It is most commonly caused by increased bilirubin production, as seen in acute and chronic
hemolytic anemias. Hemolytic anemia causes an increased amount of red blood cell destruction
and subsequently increased amounts of bilirubin produced. The liver responds by functioning at
maximum capacity; therefore, people with prehepatic jaundice rarely have bilirubin levels
exceeding 5 mg/dL because the liver is capable of handling the overload. This type of jaundice may
also be referred to as unconjugated hyperbilirubinemia because the fraction of bilirubin increased
is the unconjugated fraction.
 Hepatic jaundice:
 Occurs when the primary problem causing the jaundice resides in the liver ( liver defect or
disease). This liver defect or disease can be due to disorders of bilirubin metabolism and transport
defects (Crigler-Najjar syndrome, Dubin-Johnson syndrome, Gilbert disease, and neonatal
physiologic jaundice of the newborn) or due to diseases resulting in hepatocellular injury or
destruction.
 Gilbert disease, Crigler-Najjar syndrome, and physiologic jaundice of the newborn are hepatic
causes of jaundice that result in elevations in unconjugated bilirubin. Conditions such as Dubin-
Johnson and Rotor syndrome are hepatic causes of jaundice that result in elevations in conjugated
bilirubin.
 Gilbert syndrome (also called familial non-hemolytic non-obstructive jaundice) is a benign
hereditary disorder. It is characterized by mild unconjugated Hyperbilirubinemia. It affects 3% –
5% of the population. The concentration of bilirubin in serum fluctuates between 1.5 and 3 mg/dl.
 In this condition, the activity of hepatic glucuronyltransferase is low as a result of a mutation in the
bilirubin-UDP-glucuronyltransferase gene (UGT1A1).
 Crigler-Najjar syndrome I is a rare genetic disorder caused by the complete absence of UDP-
glucuronyltransferase and manifested by very high levels of unconjugated bilirubin. Most patients
 die of severe brain damage caused by kernicterus within the first year of life. Early liver
transplantation is the only effective therapy.
 Crigler-Najjar Syndrome (Type II): is a rare autosomal dominant disorder. It is characterized by a
partial deficiency of UDP-glucuronyl transferase. Unconjugated bilirubin is usually 5 – 20 mg/dl.
Unlike Crigler-Najjar Type I, Type II responds dramatically to Phenobarbital & a normal life can be
expected.
 Dubin-Johnson syndrome is a rare inherited disorder caused by a defect in the removal of
conjugated bilirubin from the liver cell and the excretion into the bile. This results in accumulation
of conjugated and, leading to hyperbilirubinemia and bilirubinuria. A distinguishing feature of
Dubin-Johnson syndrome is the appearance of dark-stained granules on a liver biopsy sample.
Usually, the total bilirubin concentration remains between 2–5 mg/dL. This syndrome is relatively
mild in nature, and people with Dubin-Johnson have a normal life expectancy, so no treatment is
necessary.
 Rotor syndrome is clinically similar to Dubin-Johnson syndrome but the defect causing Rotor
syndrome is not known. Unlike in Dubin-Johnson syndrome, a liver biopsy does not show dark
pigmented granules. It is a relatively benign condition and carries an excellent prognosis, and
therefore, treatment is not warranted.
 Posthepatic jaundice:
 results from biliary obstructive disease, usually from physical obstructions (gallstones or tumors),
that prevent the flow of conjugated bilirubin into the bile canaliculi. Since the liver cell itself is
functioning, bilirubin is effectively conjugated; however, it is unable to be properly excreted from
the liver. Since bile is not being brought to the intestines, stool loses its source of normal
pigmentation and becomes clay-colored.
Pre-hepatic Jaundice Hepatic Jaundice Post hepatic Jaundice

Cause Excessive break down of Liver defects or diseases Bile Duct Obstruction
RBC’s

Serum Bilirubin Unconjugated Both conj + unconj. Conjugated

Urine bilirubin Absent Bilirubinemia + ++

Deep yellow urine
Urine Increases Decreases Absent
urobilinogen

Fecal Markedly increased Reduced Absent

urobilinogen Dark brown stool Pale colored stool clay colored stool
20-50mg/day
 Liver functions Normal Impaired AST/ALT Normal
Alkaline phosphatases ++

Van den burg Indirect + Biphasic Direct+

test

 Physiologic jaundice of the newborn (Neonatal hyperbilirubinemia)

 Common, particularly in premature infants.
 Jaundice develops on days 3-5 (never on day 1).
 Transient (resolves in the first 10 days).
 It is caused by a deficiency in the enzyme glucuronyl transferase.
 deficiency of this enzyme in premature infants, results in the rapid buildup of unconjugated
bilirubin.
- High levels of unconjugated bilirubin are toxic to the newborn – due to its hydrophobicity it
can cross the blood-brain barrier and deposited in the nuclei of the brain and nerve cells
causing a type of mental retardation known as kernicterus. Kernicterus or brain
encephalopathy often results in cell damage and death in the newborn. This condition
develops in newborns with prolonged jaundice due to: Polycythemia and Rh incompatibility
between the mother & fetus.

Treatment:
• Phenobarbital is oftentimes administered to Mom before an induced labor of a premature infant;
crosses the placenta and induces the synthesis of UDP glucuronyl transferase.
• Phototherapy; is usually not needed unless the bilirubin levels rise very quickly or go above 16-20
mg/dl in healthy, full-term babies. ultraviolet radiation destroys the bilirubin and converts it to a
water-soluble, non-toxic form that can be eliminated from the body.
• In extreme cases, some infants require an exchange blood transfusion.

Liver diseases
 Acute liver disease
 Acute liver damage occurs due to poisoning, infection, or inadequate perfusion. It can progress in
three ways:
 It may resolve, as indeed it does in the majority of cases.
 It may progress to acute hepatic failure.
 It may lead to chronic hepatic damage.
1. Poisoning and drugs
 Many drugs are capable of inducing acute hepatitis similar to that seen in viral hepatitis. In its
severest form, hepatitis can lead to acute hepatic failure. The most commonly implicated agents in
 liver dysfunction include paracetamol, nonsteroidal anti-inflammatory agents (NSAIDs), statins,
and antimicrobials.
 Some agents primarily exert acute hepatitis (e.g., paracetamol, NSAIDs), whereas others may
predominantly cause cholestasis (e.g., chlorpromazine and tricyclic antidepressants). The chronic
use of some agents may cause chronic hepatitis (e.g., methyldopa, diclofenac) or long ‐term risk of
fibrosis and cirrhosis (e.g., methotrexate). The toxicity demonstrated will depend on both the
individual patient and the dose and duration of therapy. Some agents (e.g., phenytoin, ethanol)
can induce GGT synthesis without necessarily causing liver damage.
2. Liver infection:
 Both bacteria and viruses can cause infectious hepatitis. It is usually caused by viruses (hepatitis A,
B, C, D, and E).
 pre‐icteric phase  increases in ALT, AST activities, and urobilinogen in urine.
 icteric phase  clinical jaundice appears, serum ALT and AST activities > 6 times (sometimes > 100
times) the upper reference value. The stools may be very pale, due to impaired biliary excretion of
bilirubin, and urobilinogen disappears partially or completely from the urine. ALP activity is usually
slightly increased (2 times URV).
 Acute viral hepatitis due to the hepatitis A virus usually resolves quickly, and biochemical indices
of abnormality return to normal within a few weeks. The virus is spread through the fecal-oral
route.
 Hepatitis B and C are transmitted through blood products or other infected body fluids. Hepatitis B
can cause acute hepatitis, but this is less common with hepatitis C. 50 - 80% of individuals infected
with hepatitis C become chronically infected and develop chronic liver disease. In hepatitis B,
fewer than 5% of infected individuals develop a chronic infection.
Acute liver failure (ALF):
- It is a life-threatening condition occurring most commonly in adults without pre-existing liver
disease. ALF typically presents with rapid evolution of disturbed liver function to coagulopathy
(inability to clot blood, defined by an INR ≥ 1.5) and encephalopathy (altered mental status). It is
usually caused by paracetamol poisoning or a viral infection causing severe hepatitis.
- It is accompanied by major metabolic disturbances, including hyperammonemia, hyponatremia,
hypocalcemia, hypoglycemia, and lactic acidosis, often masked by respiratory alkalosis.
Aminotransferase levels do not correlate well with disease severity. In severe cases, the prognosis is
poor unless treated by transplantation (Survival rates = 60% at 1 year following transplantation).

 Chronic liver diseases (CLD):

- If the clinical and biochemical manifestations of liver disease persist for more than 6 months, the
condition is called chronic liver disease. The most common causes of CLD are chronic hepatitis (viral
hepatitis, alcohol abuse, autoimmune in origin), and nonalcoholic fatty liver disease.

Non-alcoholic fatty liver disease:

 It is the most common cause of chronic hepatitis. Obesity, Diabetes mellitus T2, and metabolic
syndrome have caused an increase in the incidence of non-alcoholic fatty liver disease (NAFLD).
 NAFLD is considered today as a hepatic manifestation of metabolic syndrome.
 A key factor in its pathogenesis is insulin resistance, which leads to dyslipidemia and fat
accumulation in the form of TAG in the liver. In addition to oxidative stress and inflammation.
 All individuals with persistently abnormal liver enzymes should be screened for NAFLD, because
NAFLD is the main reason for unexpectedly elevated liver enzymes.
 In high-risk individuals diagnosed with NAFLD (age >50 years, T2DM, metabolic syndrome), it is
recommended to evaluate the presence and extent of fibrosis using noninvasive laboratory
markers (such as; FIB-4 index) or transient elastography (ultrasound).

Cirrhosis of the liver:

 Is a disease characterized by extensive liver fibrosis. Fibrosis is the formation of scar tissue,
resulting in the disorganization of liver architecture and its shrinkage. It is the terminal stage of
chronic liver damage and leads eventually to hepatic insufficiency (hepatic failure).
 Clinical features
 Cirrhosis may remain "compensated" for many years before hepatic failure is precipitated by some
event, often a GIT bleed from esophageal varices.
 In mild cirrhosis, marked abnormalities in liver function tests are rarely preset.
 In severe cirrhosis, the following clinical features may occur, either alone or in combination:
Jaundice, Hepatic encephalopathy (Hyperammonemia, Hypoglycemia), Ascites, Anemia, and
Endocrine changes (gynecomastia, loss of body hair, and testicular atrophy).
 The AST: ALT ratio has long been established as a marker of hepatic fibrosis; in cirrhotic patients,
the concentration of AST predominates such that an AST: ALT ratio >1 is predictive of cirrhosis.
False positives are known to occur in patients with alcoholic hepatitis.

Metabolic liver diseases

 They are congenital metabolic diseases that attack the liver.
A. α1-antitrypsin deficiency (AAT):
 AAT is an important inhibitor of proteases in the blood, and it prevents elastin degradation. A gene
defect leads to the abnormal formation of AAT which prevents its release into the circulation and
results in its accumulation in hepatocytes with consequent damage and apoptosis.
B. Wilson’s disease:
 is an autosomal recessive disorder of copper metabolism. It involves a mutation in the copper-
transporting ATPase (ATP7B), which moves copper into bile for excretion. It is characterized by
decreased biliary excretion of copper and decreased incorporation of copper into ceruloplasmin
(low serum ceruloplasmin) excess copper deposits in the liver, cornea of the eye, and brain.
 Bile excretion is the main mechanism to maintain balance; in cholestasis, copper is retained in the
liver cells.
 The treatment of Wilson’s disease consists of using d-Penicillamine, a copper-chelating agent that
increases urinary excretion of copper.