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Bilirubin metabolism

Authors Section Editors Deputy Editor

Namita Roy-Chowdhury, PhD Sanjiv Chopra, MD, MACP Anne C Travis, MD, MSc, FACG,
Jayanta Roy-Chowdhury, MD, Elizabeth B Rand, MD AGAF
MRCP

All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Aug 2016. | This topic last updated: Jul 17, 2014.

INTRODUCTION — Bilirubin is the potentially toxic catabolic product of heme metabolism. Fortunately,
there are elaborate physiologic mechanisms for its detoxification and disposition. Understanding these
mechanisms is necessary for interpretation of the clinical significance of high serum bilirubin
concentrations. Furthermore, because bilirubin shares its metabolic pathway with various other sparingly
water soluble substances that are excreted in bile, understanding bilirubin metabolism also provides
insight into the mechanisms of transport, detoxification, and elimination of many other organic anions [1].

An overview of the major aspects of bilirubin formation and disposition will be reviewed here. The
settings in which bilirubin disposition is impaired will also be discussed briefly. Clinical aspects of serum
bilirubin determination, the evaluation of patients with hyperbilirubinemia, and the classification of
causes of jaundice are presented separately. (See "Clinical aspects of serum bilirubin determination"
and "Diagnostic approach to the adult with jaundice or asymptomatic hyperbilirubinemia" and
"Classification and causes of jaundice or asymptomatic hyperbilirubinemia".)

FORMATION OF BILIRUBIN — Bilirubin is formed by breakdown of heme present in hemoglobin,

myoglobin, cytochromes, catalase, peroxidase and tryptophan pyrrolase. Eighty percent of the daily
bilirubin production (250 to 400 mg in adults) is derived from hemoglobin [2]; the remaining 20 percent
being contributed by other hemoproteins and a rapidly turning-over small pool of free heme. Enhanced
bilirubin formation is found in all conditions associated with increased red cell turnover such as
intramedullary or intravascular hemolysis (eg, hemolytic, dyserythropoietic, and megaloblastic anemias).

Heme consists of a ring of four pyrroles joined by carbon bridges and a central iron atom
(ferroprotoporphyrin IX). Bilirubin is generated by sequential catalytic degradation of heme mediated by
two groups of enzymes:

● Heme oxygenase
● Biliverdin reductase

Heme oxygenase initiates the opening of the porphyrin ring of heme by catalyzing the oxidation of the
alpha-carbon bridge (figure 1). This leads to formation of the green pigment, biliverdin, which is then
reduced by the biliverdin reductase to the orange-yellow pigment bilirubin IX-alpha. Iron is released in
this process, and the oxidized alpha-bridge carbon is eliminated as carbon monoxide (CO).
Measurement of intrinsic CO production has been used to quantify bilirubin production [3].

Heme oxygenase is present in the high concentrations in reticuloendothelial cells of the spleen, the
principal site of red cell breakdown, and in the Kupffer cells in the liver [4]. It is also induced by heme
(eg, in hemolytic states).

Heme oxygenase is thought to be rate-limiting in bilirubin production [5]. As an example, pharmacologic

inhibition of heme oxygenase by tin-protoporphyrin or tin-mesoporphyrin reduces bilirubin production [6].

Conjugation — Bilirubin is very poorly soluble in water at physiologic pH because of internal hydrogen
bonding that engages all polar groups and gives the molecule a contorted "ridge-tile" structure [7]. The
fully hydrogen-bonded structure of bilirubin is designated bilirubin IX-alpha-ZZ. Water-insoluble

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unconjugated bilirubin is associated with all known toxic effects of bilirubin. Thus, the internal hydrogen
bonding is critical in producing bilirubin toxicity and also preventing its elimination.

Conversion of bilirubin IX-alpha to a water-soluble form, by disruption of the hydrogen bonds, is

essential for the elimination by the liver and kidney. This is achieved by glucuronic acid conjugation of
the propionic acid side chains of bilirubin. Bilirubin glucuronides are water-soluble and are readily
excreted in bile. Bilirubin is primarily excreted in normal human bile as the diglucuronide; unconjugated
bilirubin accounts for only 1 to 4 percent of pigments in normal bile.

During phototherapy, which is used to reduce serum bilirubin concentrations in babies with severe
neonatal hyperbilirubinemia, configurational and structural photoisomers of bilirubin are produced [8].
These isomers lack hydrogen bonding and are excreted into bile without further metabolism. In the bile,
the configurational isomers may revert back to the hydrogen-bonded bilirubin-IXa-ZZ.

Measurement of serum bilirubin — Reaction of bilirubin with diazo reagents causes breakdown of the
tetrapyrrole to two azodipyrroles (the van den Bergh reaction) [9] which can be readily measured
spectrophotometrically. Diazo assays are most commonly used for quantification of bile pigments for
clinical purposes via the following sequence.

● Because the central carbon bridge of bilirubin is buried within the molecule by hydrogen bonds,
unconjugated bilirubin reacts slowly with the diazo reagent. In comparison, conjugated bilirubin,
which lacks hydrogen bonds, reacts rapidly even in the absence of accelerators ("direct" van den
Bergh reaction).

● On disruption of hydrogen bonds by addition of "accelerators" such as methanol or caffeine, the

reaction is completed rapidly (total bilirubin).

● Unconjugated bilirubin ("indirect" bilirubin) concentration is calculated by subtracting the direct-

reacting fraction from total bilirubin.

Direct reacting bilirubin slightly overestimates the conjugated bilirubin concentration because a fraction
of unconjugated bilirubin (about 10 to 15 percent) also gives a direct van den Bergh reaction. There are
several other potential sources of error. As an example, endogenous substances, such as plasma lipids,
and drugs, such as propranolol, interfere with the diazo assay. This can produce unreliable results, but
only when the bilirubin concentration is normal or slightly elevated. Albumin-bilirubin complexes (delta-
bilirubin) also may give a direct reaction. More accurate and sensitive quantification of bilirubin requires
chromatographic analysis such as high performance liquid chromatography and reflectance fluorimetry
[10-12].

METABOLISM OF BILIRUBIN — A number of steps are involved in the metabolism of bilirubin (figure
2).

Albumin binding of bilirubin in plasma — Binding to albumin and, to a much lesser degree, high
density lipoprotein, keeps bilirubin in solution in plasma; only a small fraction of bilirubin circulates in the
unbound state. Binding to high density lipoprotein may become significant in states of severe
hypoalbuminemia.

Albumin binding keeps bilirubin in the vascular space, thereby preventing its deposition into extrahepatic
tissues, including sensitive tissues such as the brain, and minimizing glomerular filtration. It also
transports bilirubin to the sinusoidal surface of the hepatocyte, where the pigment dissociates from
albumin and enters the hepatocyte (see 'Uptake and storage of bilirubin by hepatocytes' below).

Free bilirubin can cause cerebral toxicity when the molar concentration of bilirubin exceeds that of
albumin (see 'Bilirubin toxicity' below). On the other hand, the plasma bilirubin content increases after
albumin infusion because of transfer of the pigment from tissue stores to the intravascular space.

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Several other ligands bind to albumin at the same site as bilirubin, including sulfonamides, warfarin,
antiinflammatory drugs, and cholecystographic contrast media. These agents can displace bilirubin from
albumin, thereby precipitating bilirubin encephalopathy in newborns without an alteration in the total
serum bilirubin concentration [13]. Many other compounds such as fatty acids bind at a different albumin
site but may, in some cases, reduce the binding constant of albumin for bilirubin [14].

Albumin binding of bilirubin is usually reversible. However, irreversible binding can occur in the presence
of prolonged conjugated hyperbilirubinemia (eg, during biliary obstruction). The bilirubin fraction
irreversibly bound to albumin (delta-bilirubin) is not cleared by the liver or the kidney and, because of the
long half-life of albumin, lingers in the plasma [15]. This may result in prolonged hyperbilirubinemia after
endoscopic or surgical relief of biliary obstruction. Because delta-bilirubin gives a "direct" diazo reaction,
this may give a false impression of a persistent blockage of the bile ducts [16]. The presence of delta-
bilirubin can be inferred by the absence of bilirubin excretion in the urine despite the apparent presence
of direct hyperbilirubinemia and can be identified by high performance liquid chromatography of serum
(figure 3).

Uptake and storage of bilirubin by hepatocytes — In the liver sinusoids, the albumin-bilirubin
complex dissociates, and the bilirubin is taken up efficiently by the hepatocyte while the albumin remains
in the circulation. Bilirubin is taken up by hepatocytes by a process of facilitated diffusion, which is not
energy-consuming; as a result, transport cannot occur against a concentration gradient, and is
bidirectional. Defects in the specific transporters that mediate each of the steps in bilirubin transport can
lead to hyperbilirubinemia. (See "Inherited disorders associated with conjugated hyperbilirubinemia" and
"Gilbert syndrome and unconjugated hyperbilirubinemia due to bilirubin overproduction".)

Sinusoidal bilirubin uptake requires inorganic anions, such as chloride, and is thought to be mediated by
carrier proteins which have not been fully characterized [17,18]. Passage of bilirubin across the
hepatocyte sinusoidal surface membrane is bidirectional. Normally, canalicular excretion, rather than
sinusoidal uptake or glucuronidation in the endoplasmic reticulum, is rate limiting for bilirubin throughput.
Bilirubin entering the hepatic sinusoids is efficiently extracted by hepatocytes close to its point of entry
(ie, periportal region). A fraction of the unconjugated and conjugated bilirubin within the hepatocytes is
transported back into the sinusoidal blood. This fraction undergoes re-uptake by hepatocytes
downstream to the sinusoidal blood flow. The re-uptake is mediated by two proteins, organic anion
transporter protein 1B1 and 1B3 (OATP1B1 and OATP1B3), encoded by the genes SLCO1B1 and
SLCO1B3. This results in the recruitment of additional hepatocytes in this process, thereby increasing
the net bilirubin excretory capacity of the liver [19]. Within the hepatocyte, bilirubin and other organic
anions bind to glutathione S-transferases (GSTs). GST-binding reduces the efflux of the internalized
bilirubin, thereby increasing net uptake (figure 2).

This process of bilirubin uptake is impaired in certain disease states:

● Bilirubin uptake is reduced in some, but not all, patients with Gilbert syndrome (see "Gilbert
syndrome and unconjugated hyperbilirubinemia due to bilirubin overproduction"), and is inhibited
by certain drugs (eg, rifampin, flavaspidic acid, and cholecystographic dyes).

● The re-uptake of conjugated and unconjugated bilirubin is disrupted Rotor syndrome, which is
caused by mutations or deletion of both SLCO1B1 and SLCO1B3, resulting in loss of function of
both OATP1B1 and OATP1B3. (See "Inherited disorders associated with conjugated
hyperbilirubinemia".)

● In patients with cirrhosis, a portion of the bilirubin produced in the spleen may bypass the liver via
portosystemic collaterals. Furthermore, the sinusoidal endothelium, which is normally fenestrated,
may lose the fenestrae (capillarization), thereby creating a barrier between the plasma and the
hepatocytes. As a result, serum unconjugated bilirubin concentrations often increase in this
condition.

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Conjugation of bilirubin — Glucuronidation of bilirubin, a large variety of endogenous compounds (eg,

steroid hormones, thyroid hormones, catecholamines), and a wide array of exogenous substrates (eg,
drugs, toxins, carcinogens and laboratory xenobiotics) is mediated by a family of enzymes, termed
uridine-diphosphoglucuronate glucuronosyltransferase (UGT) (figure 2) [20]. As noted above,
glucuronides are more water soluble, and are readily excreted in bile and urine.

Enzyme-catalyzed glucuronidation is one of the most important detoxification mechanisms of the body.
Of the various isoforms of the UGT family of enzymes, only one isoform, UGT1A1 is physiologically
important in bilirubin glucuronidation (figure 3) [21]. UGT1A1 is an intrinsic protein of the endoplasmic
reticulum (ER) and its catalytic site is located within the ER lumen. Therefore, the sugar donor substrate
uridine diphosphate glucuronic acid (UDPGA) must enter the ER lumenal space for conjugation. UDP-N-
acetylglucosamine is the natural stimulator of the transport of the polar substrate, UDPGA into the ER
lumen. It has been suggested that four nucleotide sugar transporter proteins mediate UDP-N-
acetylglucosamine stimulation of [22].

Bilirubin diglucuronide is the predominant pigment in normal adult human bile, representing over 80
percent of the pigment. However, in subjects with reduced bilirubin-UGT activity, the proportion of
bilirubin diglucuronide decreases, and bilirubin monoglucuronide may constitute more than 30 percent of
the conjugates excreted in bile. Reduction of conjugating enzyme activity to approximately 30 percent of
normal results in a mild but discernible increase in serum bilirubin concentrations. (See "Gilbert
syndrome and unconjugated hyperbilirubinemia due to bilirubin overproduction".)

Inhibitory factor(s) for hepatic UGT1A1 is secreted in the milk of some mothers (breast milk jaundice). In
other cases, an inhibitory factor present in maternal plasma may be transplacentally transferred to the
fetus (the Lucey Driscoll syndrome). UGT1A1 deficiency also may be seen in neonates, chronic
hepatitis, and in certain inherited disorders (Gilbert syndrome and Crigler-Najjar syndrome I and II).

Excretion of conjugated bilirubin — Conjugated bilirubin and other substances destined to be

excreted in bile are secreted across the bile canalicular membrane of the hepatocyte against a
concentration gradient that may reach 1:1000, indicating the presence of active transport [23]. Among
the four types of canalicular transporters, the multispecific organic anion transporter, also termed
multidrug resistance protein 2 or ATP-binding cassette (ABC) C2 (cMOAT/MRP2/ABCC2), appears to
be the most important for the canalicular secretion of bilirubin and many other organic anions, with the
exception of bile acids (figure 2) [24]. Interestingly, a portion of the conjugated bilirubin is secreted back
into the sinusoidal blood via the ATP hydrolysis-coupled pump ABCC3. Reuptake of the conjugated
bilirubin by hepatocytes downstream to the sinusoidal blood flow is mediated by the sinusoidal surface
organic anion transporters OATP1B1 and OATP1B3. The recruitment of additional hepatocytes
increases the hepatic excretory capacity for conjugated bilirubin, which is rate limiting in bilirubin
throughput [19].

Enhanced bile flow (eg, by infusion of bile salts) or phenobarbital treatment increases the maximal
bilirubin excretory capacity. On the other hand, the excretion of conjugated bilirubin is impaired in a
number of acquired conditions (eg, alcoholic or viral hepatitis, cholestasis of pregnancy) and inherited
disorders (eg, Dubin-Johnson syndrome, Rotor syndrome, benign recurrent intrahepatic cholestasis). It
can also be caused by a variety of drugs (eg, alkylated steroids, chlorpromazine). (See "Classification
and causes of jaundice or asymptomatic hyperbilirubinemia" and "Gilbert syndrome and unconjugated
hyperbilirubinemia due to bilirubin overproduction" and "Inherited disorders associated with conjugated
hyperbilirubinemia".)

Degradation of bilirubin in the digestive tract — Bile pigment appearing in bile is mostly (more than
98 percent) conjugated. Conjugated bilirubin is water soluble and is not absorbed across the lipid
membrane of the small intestinal epithelium; in comparison, the unconjugated bilirubin fraction is
partially reabsorbed and undergoes enterohepatic circulation (figure 4) [25]. This fraction increases
during phototherapy because of the excretion of photoisomers of bilirubin. Oral administration of
charcoal, agar, or cholestyramine may interfere with the absorption of unconjugated bilirubin, thereby

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increasing the efficacy of phototherapy. In contrast, excessive amounts of bilirubin are available for
reabsorption in neonates with obstruction of the upper intestinal tract, delayed passage of meconium, or
fasting; this may increase the intensity and duration of neonatal jaundice.

Bilirubin is reduced by bacterial enzymes in the colon to a series of molecules, termed urobilinogens
[26]. The two major urobilinoids found in stool, urobilinogen and stercobilinogen, are colorless and turn
orange-yellow only after oxidation to urobilins. In complete biliary obstruction or severe intrahepatic
cholestasis (eg, in the early phase of acute viral hepatitis), feces may take the appearance of china clay.
Thus, the absence of urobilinogen in stool and urine in a jaundiced patient indicates complete biliary
obstruction. Urobilinogens and their derivatives are partly absorbed from the bowel, undergo
enterohepatic recycling, and are eventually excreted in urine and feces (see 'Urobilinogen' below) (figure
4).

The intestinal microflora influence serum levels of bilirubin. In a study in Gunn rats (which have a
congenital deficiency of bilirubin UDP-glucuronosyltransferase), treatment with oral clindamycin and
neomycin resulted in the disappearance of fecal urobilinoids while serum bilirubin increased dramatically
(from 10.8 mg/dL [186 micromol/L] to 17 mg/dL [289 micromol/L]) [27]. Intestinal colonization with
Clostridium perfringens led to reappearance of fecal urobilinoid production accompanied by a partial
decrease in serum bilirubin levels. The authors speculated that prolonged use of certain antibiotics may
lead to an increase in serum bilirubin levels in humans. Patients with abnormal bilirubin conjugation may
be at particular risk.

Alternative pathways of bilirubin elimination — Alternative pathways of bilirubin elimination may be

important in certain clinical settings. One such pathway is oxidation of bilirubin by mixed function
oxidases in liver and other organs. In addition, induction of cytochrome P-450c by chlorpromazine
reduced the serum bilirubin concentration in one patient with Crigler-Najjar syndrome type I (enzyme
catalyzed oxidation) [28].

In conditions associated with elevated conjugated plasma bilirubin concentrations (eg, intrahepatic or
extrahepatic cholestasis), the kidney is responsible for 50 to 90 percent of conjugated bilirubin excretion
[29,30]. However, bile remains the main excretion route for unconjugated hyperbilirubinemia.

Urobilinogen — Urobilinogen is produced by bacterial breakdown of bilirubin excreted in bile into the
bowel. It is partly absorbed in the bowel and undergoes hepatobiliary recirculation. The fraction that is
not cleared by the liver enters the general circulation and is partly excreted in urine. As a result, urinary
urobilinogen excretion may be increased in the following situations:

● Excessive bilirubin production (eg, in cases of hemolysis or absorption of hematoma)

● Inefficient hepatic clearance of the reabsorbed urobilinogen (eg, in patients with cirrhosis or at
some stages of hepatitis)
● Excessive exposure of bilirubin to intestinal bacteria (eg, constipation or bacterial overgrowth).

By contrast, urinary urobilinogen excretion can be reduced or abolished in near-complete biliary

obstruction (eg, carcinoma of the pancreas) or severe cholestasis (eg, in early stages of viral hepatitis).

Standard clinical tests for urobilinogen do not distinguish between normal and low urinary urobilinogen
levels. Furthermore, urobilinogen excretion can be reduced, normal, or elevated in patients with hepatitis
as noted above. Tubular reabsorption and instability of the pigment in acid urine can also influence
results. Because of these complexities, tests for urinary urobilinogen are usually not useful in the
differential diagnosis of liver diseases.

BILIRUBIN IN DISEASE STATES — In normal plasma, about 4 percent of bilirubin is conjugated. This
relationship may vary in disease states:

● In inherited disorders of bilirubin conjugation, the proportion of conjugated bilirubin is reduced.

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In Rotor syndrome (defect in re-uptake of conjugated and unconjugated bilirubin) and in Dubin-
Johnson syndrome (defect in canalicular excretion of bilirubin), both conjugated and unconjugated
bilirubin accumulate in plasma [19].

● In biliary obstruction or hepatocellular diseases, both conjugated and unconjugated bilirubin

accumulate in plasma [15].

● In hemolytic jaundice, total plasma bilirubin increases, but the proportion of the unconjugated and
conjugated fractions remains unchanged.

Bilirubin binds to the elastic tissue of skin and sclera, and is also found in all tissue fluids with a high
albumin content. The usual tight but reversible binding to albumin precludes glomerular filtration of
unconjugated bilirubin; similar principles apply to irreversible covalently bound bilirubin (delta-bilirubin).
In contrast, conjugated bilirubin is less strongly bound to albumin and can be excreted in the urine.
Thus, the finding of bilirubin in the urine, in the absence of albuminuria, indicates the presence of an
increased amount of conjugated bilirubin in the plasma.

Potential beneficial effects of bilirubin — Although clinicians are generally concerned with serum
bilirubin levels as a marker of liver disease and the direct toxicity of bilirubin (see 'Bilirubin toxicity'
below), within a near-physiological range of serum bilirubin concentrations, the antioxidative action of
bilirubin may provide beneficial effects. An inverse relationship between serum bilirubin levels and risk of
ischemic coronary artery disease has been reported in middle-aged British men [31]. A population study
in Belgium showed an inverse relationship between serum bilirubin levels and cancer mortality [32].
More recently, the study of a very large number of subjects in the United States revealed that the odds
ratio for the history of colorectal cancer is reduced to 0.295 in men and 0.186 in women per 1 mg/dL
increment in serum bilirubin levels [33]. However, such statistical associations do not conclusively prove
a causative role of bilirubin. In addition to biliverdin (and bilirubin), the other products of
hemeoxygenase-mediated heme breakdown (namely iron and CO) may also have physiological roles in
the liver. As an example, one study found that induction or overexpression of heme oxygenase
attenuated the replication of hepatitis C virus [34].

Bilirubin toxicity — Unconjugated bilirubin is toxic to many cells and organelles. Physiologic
mechanisms that protect against bilirubin toxicity include, as described above, binding to plasma
albumin, and rapid uptake, conjugation, and clearance by the liver. Because of these efficient protective
mechanisms, the harmful effects of unconjugated bilirubin is limited to neonates with a high degree of
unconjugated hyperbilirubinemia and subjects with inherited disorders of bilirubin conjugation.

Markedly elevated serum unconjugated bilirubin concentrations (usually over 20 mg/dL) in the newborn
may result in clinical evidence of brain damage, ranging from subtle neurologic abnormalities to severe
encephalopathy or permanent neurologic damage (kernicterus) to death [35]. The serum concentration
at which clinical signs of neurotoxicity occur is variable and is influenced by many factors such as
protein-binding of bilirubin, putative bilirubin transporters in the brain, and enzymes in the central
nervous system that oxidize bilirubin [36]. (See "Clinical manifestations of unconjugated
hyperbilirubinemia in term and late preterm infants", section on 'Kernicterus'.)

SUMMARY AND RECOMMENDATIONS

● Bilirubin is formed by the breakdown of heme present in hemoglobin, myoglobin, cytochromes,

catalase, peroxidase, and tryptophan pyrrolase. Eighty percent of the daily bilirubin production (250
to 400 mg in adults) is derived from hemoglobin. (See 'Formation of bilirubin' above.)

● Bilirubin is very poorly soluble in water at physiologic pH because of internal hydrogen bonding that
engages all polar groups and gives the molecule a contorted "ridge-tile" structure. The conversion
of bilirubin IX-alpha to a water-soluble form by disruption of the hydrogen bonds is essential for the
elimination by the liver and kidney. (See 'Conjugation' above.)

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A number of steps are involved in the metabolism of bilirubin (figure 2). (See 'Metabolism of
bilirubin' above.)

● In normal plasma, about 4 percent of bilirubin is conjugated. This relationship may vary in disease
states. (See 'Bilirubin in disease states' above.)

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33:387.
36. Watchko JF, Tiribelli C. Bilirubin-induced neurologic damage--mechanisms and management
approaches. N Engl J Med 2013; 369:2021.

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GRAPHICS

Bilirubin synthesis

Conversion of heme to biliverdin and then bilirubin. Heme ring-opening

at the alpha-carbon bridge of heme is catalyzed by heme oxygenase,
resulting in the formation of biliverdin. This is followed by reduction of
biliverdin to bilirubin in a reaction catalyzed by biliverdin reductase.

NADH: reduced nicotinamide adenine dinucleotide; NADPH: reduced

nicotinamide adenine dinucleotide phosphate.

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Bilirubin throughput in hepatocytes

Schematic representation of the steps involved in bilirubin (B) throughput

in hepatocytes: transport to the liver (primarily as albumin-bound
bilirubin), uptake at the sinusoidal membrane, intracellular binding,
conjugation (glucuronidation), and canalicular excretion. Sinusoidal
bilirubin uptake requires inorganic anions such as chloride, and is thought
to be mediated by carrier proteins. Within the hepatocyte, bilirubin binds
to glutathione S-transferases (GSTs). GST-binding reduces the efflux of
the internalized bilirubin, thereby increasing the net uptake. GSTs also
bind bilirubin glucuronides (BG) prior to excretion. Bilirubin also enters
hepatocytes by passive diffusion. Glucuronidation of bilirubin is mediated
by a family of enzymes, termed uridine diphosphoglucuronosyltransferase
(UGT), the most important of which is bilirubin-UGT-1 (UGT1A1).
Conjugated bilirubin is secreted actively across the bile canalicular
membrane of the hepatocyte against a concentration gradient that may
reach 1:1000. The canalicular multi-drug resistance protein 2 (MRP2)
appears to be the most important for the canalicular secretion of bilirubin.
A portion of the conjugated bilirubin is transported into the sinusoidal
blood via the ATP hydrolysis-couple pump, ABCC3, to undergo reuptake
via OATP1B1 and OATP1B3 by hepatocytes downstream to the sinusoidal
blood flow.

UDP: uridine diphosphate; UDPGA: uridine 5'-diphosphoglucuronic acid;

ABCC3: ATP-binding cassette subfamily C number 3; OATP1B1: organic anion-

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transporting polypeptide 1B1; OATP1B3: organic anion-transporting

polypeptide 1B3.

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UDP-glucuronosyltransferases (UGT)

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Enterohepatic and systemic circulation of bilirubin

and its metabolites in adults

Graphic 78388 Version 1.0

Contributor Disclosures
Namita Roy-Chowdhury, PhD Nothing to disclose. Jayanta Roy-Chowdhury, MD, MRCP Nothing to
disclose. Sanjiv Chopra, MD, MACP Nothing to disclose. Elizabeth B Rand, MD Nothing to disclose.
Anne C Travis, MD, MSc, FACG, AGAF Equity Ownership/Stock Options: Proctor & Gamble [Peptic
ulcer disease/GI bleeding (omeprazole)].

Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these
are addressed by vetting through a multi-level review process, and through requirements for references
to be provided to support the content. Appropriately referenced content is required of all authors and
must conform to UpToDate standards of evidence.

Conflict of interest policy

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