Pathophysiology

Jaundice itself is not a disease, but rather a sign of one of many possible underlying pathological
processes that occur at some point along the normal physiological pathway of the metabolism of
bilirubin in blood.

When red blood cells have completed their life span of approximately 120 days, or when they are
damaged, their membranes become fragile and prone to rupture. As each red blood cell traverses
through the reticuloendothelial system, its cell membrane ruptures when its membrane is fragile
enough to allow this. Cellular contents, including hemoglobin, are subsequently released into the
blood. The hemoglobin is phagocytosed by macrophages, and split into its heme and globin
portions. The globin portion, a protein, is degraded into amino acids and plays no role in
jaundice. Two reactions then take place with the heme molecule. The first oxidation reaction is
catalyzed by the microsomal enzyme heme oxygenase and results in biliverdin (green color
pigment), iron and carbon monoxide. The next step is the reduction of biliverdin to a yellow
color tetrapyrol pigment called bilirubin by cytosolic enzyme biliverdin reductase. This bilirubin
is "unconjugated," "free" or "indirect" bilirubin. Approximately 4 mg of bilirubin per kg of blood
is produced each day.[29] The majority of this bilirubin comes from the breakdown of heme from
expired red blood cells in the process just described. Approximately twenty percent comes from
other heme sources, however, including ineffective erythropoiesis, and the breakdown of other
heme-containing proteins, such as muscle myoglobin and cytochromes.[29]

Hepatic events

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The unconjugated bilirubin then travels to the liver through the bloodstream. Because this
bilirubin is not soluble, however, it is transported through the blood bound to serum albumin.
Once it arrives at the liver, it is conjugated with glucuronic acid (to form bilirubin diglucuronide,
or just "conjugated bilirubin") to become more water-soluble. The reaction is catalyzed by the
enzyme UDP-glucuronyl transferase.

This conjugated bilirubin is excreted from the liver into the biliary and cystic ducts as part of
bile. Intestinal bacteria convert the bilirubin into urobilinogen. From here urobilinogen can take
two pathways. It can either be further converted into stercobilinogen, which is then oxidized to
stercobilin and passed out in the feces, or it can be reabsorbed by the intestinal cells, transported
in the blood to the kidneys, and passed out in the urine as the oxidised product urobilin.
Stercobilin and urobilin are the products responsible for the coloration of feces and urine,
respectively.

Category Definition

The pathology is occurring prior to the liver due to either:

Pre-hepatic/hemolytic
A. Intrinsic defects in RB cells B. Extrinsic causes external to RB cells
The pathology is located within the liver caused due to disease of
Hepatic/hepatocellular
parenchymal cells of liver.
Post- The pathology is located after the conjugation of bilirubin in the liver
hepatic/cholestatic caused due to obstruction of biliary passage.[14]

Pre-hepatic

Pre-hepaticular jaundice is caused by anything that causes an increased rate of hemolysis

(breakdown of red blood cells). Unconjugated bilirubin comes from the breakdown of the heme
pigment found in red blood cells' hemoglobin. The increased breakdown of red blood cells leads
to an increase in the amount of unconjugated bilirubin present in the blood and deposition of this
unconjugated bilirubin into various tissues can lead to a jaundiced appearance. In tropical
countries, severe malaria can cause jaundice in this manner. Certain genetic diseases, such as
sickle cell anemia, spherocytosis, thalassemia, pyruvate kinase deficiency, and glucose 6-
phosphate dehydrogenase deficiency can lead to increased red cell lysis and therefore hemolytic
jaundice. Commonly, diseases of the kidney, such as hemolytic uremic syndrome, can also lead
to coloration.

In jaundice secondary to hemolysis, the increased production of bilirubin leads to the increased
production of urine-urobilinogen. Bilirubin is not usually found in the urine because
unconjugated bilirubin is not water-soluble, so, the combination of increased urine-urobilinogen
with no bilirubin (since, unconjugated) in urine is suggestive of hemolytic jaundice.[citation needed]

Hepatocellular

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Hepatocellular (hepatic) jaundice can be caused by acute or chronic hepatitis, hepatotoxicity,
cirrhosis, drug-induced hepatitis and alcoholic liver disease. Cell necrosis reduces the liver's
ability to metabolize and excrete bilirubin leading to a buildup of unconjugated bilirubin in the
blood. Other causes include primary biliary cirrhosis leading to an increase in plasma conjugated
bilirubin because there is impairment of excretion of conjugated bilirubin into the bile. The blood
contains an abnormally raised amount of conjugated bilirubin and bile salts, which are excreted
in the urine. Jaundice seen in the newborn, known as neonatal jaundice, is common in
newborns[15] as hepatic machinery for the conjugation and excretion of bilirubin does not fully
mature until approximately two weeks of age. Rat fever (leptospirosis) can also cause hepatic
jaundice. In hepatic jaundice, there is invariably cholestasis. Defects in bilirubin metabolism also
leads to jaundice, as in Gilbert's syndrome (a genetic disorder of bilirubin metabolism that can
result in mild jaundice, which is found in about 5% of the population) .

Bilirubin transport across the hepatocyte may be impaired at any point between the uptake of
unconjugated bilirubin into the cell and transport of conjugated bilirubin into biliary canaliculi.
In addition, swelling of cells and oedema due to inflammation cause mechanical obstruction of
intrahepatic biliary tree. Hence in hepatocellular jaundice, concentration of both unconjugated
and conjugated bilirubin rises in the blood. In hepatocellular disease, there is usually interference
in all major steps of bilirubin metabolism—uptake, conjugation and excretion. Excretion is the
rate-limiting step, however, and usually impaired to the greatest extent. As a result, conjugated
hyperbilirubinaemia predominates.[16]

The unconjugated bilirubin still enters the liver cells and becomes conjugated in the usual way.
This conjugated bilirubin is then returned to the blood, probably by rupture of the congested bile
canaliculi and direct emptying of the bile into the lymph leaving the liver. Thus, most of the
bilirubin in the plasma becomes the conjugated type rather than the unconjugated type, and this
conjugated bilirubin, which did not go to intestine to become urobilinogen, gives the urine the
dark color.[17]

Post-hepatic

Post-hepatic jaundice, also called obstructive jaundice, is caused by an interruption to the

drainage of bile containing conjugated bilirubin in the biliary system. The most common causes
are gallstones in the common bile duct, and pancreatic cancer in the head of the pancreas. Also, a
group of parasites known as "liver flukes" can live in the common bile duct, causing obstructive
jaundice. Other causes include strictures of the common bile duct, biliary atresia,
cholangiocarcinoma, pancreatitis, cholestasis of pregnancy, and pancreatic pseudocysts.

In complete obstruction of the bile duct, no urobilinogen is found in the urine, since bilirubin has
no access to the intestine and it is in the intestine that bilirubin gets converted to urobilinogen by
microorganisms, with the urobilinogen later being partially reabsorbed from the intestine into the
general circulation, and then excreted into the urine. In this case, presence of bilirubin
(conjugated) in the urine without urine-urobilinogen suggests obstructive jaundice, either intra-
hepatic or post-hepatic.

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The presence of pale stools and dark urine suggests an obstructive or post-hepatic cause as
normal feces get their color from bile pigments. They can, however, occur in many intra-hepatic
illnesses and are therefore not a reliable clinical feature to distinguish obstruction from hepatic
causes of jaundice.[18]

Jaundice, also known as icterus, is a yellowish or greenish pigmentation of the skin and whites of the
eyes due to high bilirubin levels.[2][5] It is commonly associated with itchiness.[1] The feces may be pale
and the urine dark.

Clinical Features

yellow color on the skin and in the whites of the eyes

vomiting

high fever( If caued by hepatitis)

dark coloured urine (buildup of conjugated bilirubin leaks into the urine. Bilirubin is also pigmented! bili-
rubin (rubin for red, which is why you get dark urine).

loss of appetite

pale coloured stool

abdominal pain (especially in the liver region)

weakness

weight loss

swelling of the abdomen due to the accumulation of fluid

heme->biliverdin->bilirubin->to liver->conjugation to bile (aka conjugated bilirubin)->secreted into
duodenum->broken down in large intestine by bacteria->urobilinogen->stercobilinogen OR resorbed
into bloodstream and oxidized to urobilin which gives urine its color.

Now urobilin gives urine the yellow color. Sterobilin gives poop the brown color.
In obstructive jaundice, you don't have secretion of conjugated bilirubin (bile) into the GI tract, so the
bacteria in the large intestine does not have any bilirubin to breakdown into sterobilin which is why you
get pale stool!
So why do you still get dark urine? Note: you also don't get any urobilin either. BUT the buildup of
conjugated bilirubin leaks into the urine. Bilirubin is also pigmented! bili-rubin (rubin for red, which is
why you get dark urine)