Classification and Causes of Jaundice or Asymptomatic Hyperbilirubinemia - UpToDate

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Classification and causes of jaundice or asymptomatic

hyperbilirubinemia
AUTHORS: Namita Roy-Chowdhury, PhD, FAASLD, Jayanta Roy-Chowdhury, MD, MRCP, AGAF, FAASLD
SECTION EDITORS: Sanjiv Chopra, MD, MACP, Elizabeth B Rand, MD
DEPUTY EDITOR: Shilpa Grover, MD, MPH, AGAF
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Jan 2024.

This topic last updated: Sep 05, 2023.
INTRODUCTION
The normal serum bilirubin concentration in children and adults is less than 1 mg/dL (17
micromol/liter), less than 5 percent of which is present in conjugated form. The measurement is
usually made using diazo reagents and spectrophotometry. Conjugated bilirubin reacts rapidly
("directly") with the reagents. The measurement of unconjugated bilirubin requires the addition
of an accelerator compound and is often referred to as indirect bilirubin.
Jaundice is often used interchangeably with hyperbilirubinemia. However, a careful clinical

examination cannot detect jaundice until the serum bilirubin is greater than 2 mg/dL (34
micromol/liter), twice the normal upper limit. The yellow discoloration is best seen in the
periphery of the ocular conjunctivae and in the oral mucous membranes (under the tongue,
hard palate). Icterus may be the first or only sign of liver disease; thus, its evaluation is of critical
importance.
This topic will review the causes of asymptomatic hyperbilirubinemia. The diagnostic approach
to the patient with jaundice and the causes of hyperbilirubinemia presenting in the neonatal
period are discussed separately. (See "Diagnostic approach to the adult with jaundice or
asymptomatic hyperbilirubinemia" and "Unconjugated hyperbilirubinemia in neonates: Etiology
https://www.uptodate.com/contents/classification-and-causes-of-jaundice-or-asymptomatic-hyperbilirubinemia/print?search=sindrome colestasico&source=search_r… 1/22

and pathogenesis" and "Causes of cholestasis in neonates and young infants" and "Bilirubin
metabolism".)
CLASSIFICATION
For clinical purposes, the predominant type of bile pigments in the plasma can be used to
classify hyperbilirubinemia into two major categories ( table 1).
● Unconjugated hyperbilirubinemia – Unconjugated hyperbilirubinemia is characterized

by plasma elevation of predominantly unconjugated bilirubin due to the overproduction of
bilirubin, impaired bilirubin uptake by the liver, or abnormalities of bilirubin conjugation.
● Conjugated hyperbilirubinemia – In patients with conjugated

hyperbilirubinemia, both unconjugated and conjugated bilirubin levels increase.
Conjugated hyperbilirubinemia may be due to hepatocellular diseases, impaired
canalicular excretion, defective reuptake of conjugated bilirubin, or biliary obstruction.
DISORDERS ASSOCIATED WITH UNCONJUGATED HYPERBILIRUBINEMIA
Three basic pathophysiologic mechanisms, overproduction of bilirubin, reduced bilirubin

uptake, and impaired bilirubin conjugation, are mainly responsible for unconjugated
hyperbilirubinemia.
Overproduction of bilirubin — Bilirubin overproduction may result from excessive breakdown

of heme derived from hemoglobin. Extravascular or intravascular hemolysis, extravasation of
blood in tissues, or dyserythropoiesis are causes of enhanced heme catabolism.
● Conditions associated with bilirubin overproduction
• Hemolysis – The reticuloendothelial cells of the spleen, bone marrow, and liver are
responsible for the increased extravascular destruction of erythrocytes, which occurs in
most hemolytic disorders. These phagocytic mononuclear cells are rich in heme
oxygenase and biliverdin reductase activities and rapidly degrade heme to bilirubin
( figure 1). (See "Bilirubin metabolism".)
With intravascular hemolysis, bilirubin is predominantly formed in the liver and the
kidneys. Hemoglobin released in the circulation is bound to haptoglobin; this complex
is internalized and degraded by hepatocytes. However, circulating haptoglobin may be
depleted with massive hemolysis. In these cases, unbound hemoglobin is converted to
methemoglobin, from which heme is transferred to hemopexin or to albumin, forming

methemalbumin. Heme-hemopexin and methemalbumin are internalized by
hepatocytes, where heme is degraded to bilirubin. A significant fraction of free
methemoglobin is filtered by renal glomeruli after dissociation of the tetrameric globin
to two dimers. Only the free (unbound) dimer is small enough to be filtered across the
glomeruli. The heme moiety of filtered methemoglobin is largely degraded by tubular
epithelial cells to bilirubin.
• Dyserythropoiesis – In a variety of diseases including megaloblastic and sideroblastic

anemias, severe iron deficiency anemia, erythropoietic porphyria, erythroleukemia,
lead poisoning, and a rare disorder of unknown pathogenesis termed primary shunt
hyperbilirubinemia, the incorporation of hemoglobin into erythrocytes is defective
[1,2]. This leads to the degradation of a large fraction of unincorporated hemoglobin
heme.
• Extravasation – When blood is extravasated into tissues, or pleural or peritoneal

cavities, erythrocytes are phagocytosed by tissue macrophages that degrade heme to
biliverdin, resulting in the sequential green and yellow discoloration of the skin
overlying a hematoma. The biliverdin is immediately reduced to unconjugated bilirubin
by the enzyme biliverdin reductase and is released into the plasma.
● Pattern of bilirubin elevation based on the presence of underlying liver disease
• Patients without liver disease – In hemolysis, unconjugated bilirubin production can

increase up to 10-fold. The canalicular excretion of bilirubin is the rate-limiting step in
bilirubin elimination since hepatic conjugating capacity normally exceeds maximum
bilirubin production. These relationships account for two findings at a steady state of
maximum bilirubin production in patients with normal hepatic function. First, the
serum bilirubin concentration will not exceed 4 mg/dL (68 micromol/liter) in patients
with normal liver function [3] and second, the proportion of conjugated bilirubin in
plasma (approximately 3 to 5 percent of the total) remains normal [4]. However,
hemolysis can lead to severe mixed conjugated and unconjugated hyperbilirubinemia
in patients who have even mild hepatic disease.
• Patients with coexisting liver disease – Most liver diseases affect canalicular
excretion, resulting in the accumulation of both conjugated and unconjugated bilirubin
in hepatocytes. In cholestatic states, the canalicular ATP-dependent organic anion
pump, MRP2 (also termed ABCC2), is down-regulated. This may lead to upregulation of
other forms of MRP, such as MRP3 (also termed ABCC3), in the contiguous membranes

of the hepatocyte, resulting in active transport of unconjugated and conjugated

bilirubin into the plasma [5,6]. Thus, plasma bilirubin accumulating in conditions
resulting from a combination of bilirubin overload and liver disease is usually a mixture
of unconjugated and conjugated bilirubin. In cases where there is an inherited
deficiency of conjugation (eg, Gilbert syndrome), hemolysis causes almost pure
unconjugated hyperbilirubinemia. The rate-limiting step in these patients is bilirubin
glucuronidation, rather than canalicular excretion. (See "Gilbert syndrome".)
Impaired hepatic bilirubin uptake — Impaired delivery of bilirubin to the liver and disorders
of internalization of bilirubin by the hepatocyte result in reduced hepatic bilirubin uptake
( figure 2).
● Medications (eg, rifamycin antibiotics, probenecid, flavaspidic acid, and bunamiodyl, a

cholecystographic agent) can cause abnormal bilirubin uptake. The drug-induced defect
usually resolves within 48 hours after discontinuation of the drug [7].
● Impaired bilirubin uptake at the sinusoidal surface of hepatocytes has been reported in
some cases of Gilbert syndrome. (See "Gilbert syndrome".).
● Congestive heart failure or portosystemic shunts (spontaneously occurring collaterals in

cirrhosis or surgical shunts) reduce hepatic blood flow and the delivery of bilirubin to
hepatocytes, resulting in predominantly unconjugated hyperbilirubinemia. In some
patients with cirrhosis, the direct contact of plasma with the hepatocytes may be
compromised due to capillarization of the sinusoidal endothelial cells (loss of fenestrae),
resulting in a further reduction in bilirubin uptake [8].
Impaired bilirubin conjugation — Reduced bilirubin conjugation as a result of a decreased or

absent UDP-glucuronosyltransferase activity is found both in several acquired conditions and
inherited diseases, such as Crigler-Najjar syndrome type I and II and Gilbert syndrome. (See
"Gilbert syndrome" and "Crigler-Najjar syndrome".)
UGT activity toward bilirubin is modulated by various hormones. Hyperthyroidism and ethinyl
estradiol, but not other oral contraceptives, inhibit bilirubin glucuronidation [9]. In comparison,
the combination of progestational and estrogenic steroids results in increased enzyme activity.
Bilirubin glucuronidation can also be inhibited by certain antibiotics (eg, novobiocin or
gentamicin at serum concentrations exceeding therapeutic levels) and antiretroviral drugs (eg,
atazanavir) [10]. Reduced bilirubin glucuronidation by liver tissue has been reported in chronic
persistent hepatitis, advanced cirrhosis, and Wilson's disease.

DISORDERS ASSOCIATED WITH CONJUGATED HYPERBILIRUBINEMIA
Disorders with conjugated hyperbilirubinemia can be categorized according to their

pathophysiology into those that are due to biliary obstruction (extrahepatic cholestasis),
intrahepatic cholestasis, and hepatocellular injury ( table 2 and table 3).
Cholestatic disorders — In disorders associated with cholestasis, both conjugated and

unconjugated bilirubin accumulate in serum and patients have elevations in alkaline
phosphatase. There is a disproportionate elevation in the alkaline phosphatase compared with
the serum aminotransferases. Tests of synthetic function (eg, albumin, prothrombin time) may
be abnormal. (See "Approach to the patient with abnormal liver biochemical and function tests",
section on 'Patterns of liver test abnormalities'.)
Extrahepatic cholestasis/biliary obstruction — In biliary obstruction, both conjugated and

unconjugated bilirubin accumulate in serum. Bilirubin may be transported back to the plasma
via an MRP group of ATP-consuming pumps [6,11]. The serum concentrations of conjugated
bilirubin and alkaline phosphatase can be used as markers for hepatobiliary obstruction.
Obstruction of biliary flow causes retention of conjugated bilirubin within the hepatocytes,
where reversal of glucuronidation may take place. The unconjugated bilirubin formed by this
process may diffuse or be transported back into the plasma. (See "Bilirubin metabolism",
section on 'Excretion of conjugated bilirubin'.)
Differential diagnosis of conjugated hyperbilirubinemia due to biliary obstruction varies with

age ( table 2). In adults, it includes cholelithiasis, intrinsic and extrinsic tumors, primary
sclerosing cholangitis (PSC), parasitic infections, lymphoma, AIDS cholangiopathy, acute and
chronic pancreatitis, and strictures after invasive procedures [12].
Intrahepatic cholestasis — A number of intrahepatic disorders can lead to jaundice and an

elevated serum alkaline phosphatase (in relation to serum aminotransferases) ( table 3). This
presentation mimics that of biliary obstruction but the bile ducts are patent.
Inherited diseases — Elevated levels of conjugated bilirubin may occur in inherited

diseases such as Dubin-Johnson syndrome, Rotor syndrome, progressive familial intrahepatic
cholestasis (PFIC), benign recurrent intrahepatic cholestasis (BRIC), and low phospholipid-
associated cholelithiasis (LPAC). BRIC is seen in adolescents and adults, while LPAC presents
mainly in young adults. (See "Inherited disorders associated with conjugated
hyperbilirubinemia in adults".)

Disorders of fatty acid oxidation are characterized by episodes of metabolic decompensation,

with hypoglycemia, liver dysfunction, and/or cardiomyopathy, triggered by fasting or
intercurrent illness. These disorders may present at any age, from birth through adulthood. (See
"Metabolic myopathies caused by disorders of lipid and purine metabolism", section on 'Defects
of beta-oxidation enzymes'.)
Inherited diseases that cause conjugated hyperbilirubinemia that present during the neonatal
period include Alagille syndrome, cystic fibrosis, and disorders of carbohydrate, lipid, or bile
acid metabolism. These diseases are discussed in detail separately. (See "Causes of cholestasis
in neonates and young infants".)
Hepatitis
● Viral hepatitis – Viral hepatitis can present as a predominantly cholestatic syndrome with
marked pruritus. Serologic evaluation is needed to distinguish this clinically from other
causes of cholestasis.
● Alcoholic hepatitis – Cholestasis with fever and leukocytosis is often the distinctive sign of
alcoholic hepatitis [13]. The diagnosis should be strongly considered in the jaundiced
patient with ethanol dependency, especially if the ratio of serum aspartate
aminotransferase (AST) to alanine aminotransferase (ALT) exceeds 2.0 with the values
being below 500 international units/L. (See "Clinical manifestations and diagnosis of
alcohol-associated fatty liver disease and cirrhosis".)
● Metabolic dysfunction-associated steatotic liver disease (MASLD) or MASLD-associated

steatohepatitis (MASH) – Most patients with MASLD are asymptomatic, although some
patients with MASH may complain of fatigue, malaise, and vague right upper abdominal
discomfort [14]. A variety of conditions such as diabetes mellitus, morbid obesity, certain
stomach and small bowel operations, and drugs can cause this disorder. (See
"Epidemiology, clinical features, and diagnosis of nonalcoholic fatty liver disease in
adults".)
Primary biliary cholangitis — Primary biliary cholangitis typically presents with a

cholestatic picture, though evidence of hepatocellular injury also exists. (See "Clinical
manifestations, diagnosis, and prognosis of primary biliary cholangitis".)
Drugs and toxins — Drug-induced cholestasis can occur in a dose-related fashion (eg,
alkylated steroids such as methyltestosterone and ethinyl estradiol) or as an idiosyncratic or
allergic reaction in a minority of subjects (eg, chlorpromazine). Drugs and toxins causing
hepatocellular injury may eventually present as a predominantly cholestatic syndrome [15].

Certain plants used in "natural" medicines (eg, Jamaican bush tea) contain pyrrolizidine
alkaloids, which may cause veno-occlusive disease of the liver [16,17] (see "Hepatotoxicity due
to herbal medications and dietary supplements").
Arsenic can cause cholestasis. It has recently gained increased attention because of its
contamination of ground water in various parts of the world [18]. In addition to the well-known
skin lesions, arsenic-contaminated drinking water has been associated with hepatic fibrosis and
portal hypertension, usually without the formation of cirrhotic nodules.
Parenteral nutrition — Steatosis, lipidosis, and cholestasis are frequently encountered in

patients receiving parenteral nutrition. This complication usually requires at least two to three
weeks of therapy for the development of cholestasis [19]. The underlying illness, preexisting
liver disease, hepatotoxic drugs, and the parenteral nutrition itself all may contribute to the
cholestasis.
Parenteral nutrition promotes bacterial overgrowth in the small intestine, which in turn favors
conditions well known to induce cholestasis such as translocation of intestinal endotoxins into
the portal system [20], bacterial sepsis [21], and the formation of secondary bile acids (eg,
lithocholic acid). Other contributing factors to cholestasis include biliary sludge, which occurs in
all patients after six weeks of total parenteral nutrition (TPN), and hepatotoxic factors such as
tryptophan degradation products and aluminum contaminants.
Sepsis and low perfusion states — Bacterial sepsis is very often accompanied by
cholestasis. Multiple factors including hypotension, drugs, and bacterial endotoxins are
responsible for the jaundice in these patients [22-24]. On the other hand, hyperbilirubinemia
can promote bacterial sepsis by increasing intestinal wall permeability and altering mucosal
immunity [25]. Signs of cholestasis can also be found in other low perfusion states of the liver
(heart failure, hypotension) and hypoxemia that is not profound enough to produce hepatic
necrosis.
Infiltrative disorders — Infiltrative processes of the liver (eg, amyloidosis, lymphoma,

sarcoidosis, tuberculosis) can precipitate intrahepatic cholestasis. Paraneoplastic syndromes
associated with malignancy can induce a reversible form of cholestasis (Stauffer syndrome) [26].
It has most commonly been described in association with renal cell carcinoma, though it has
also been reported in patients with malignant lymphoproliferative diseases, gynecologic
malignancies, and prostate cancer [27,28].
Intrahepatic cholestasis of pregnancy — Pruritus, usually occurring in the third

trimester of pregnancy but sometimes earlier, typically heralds cholestasis, which may evolve
into frank jaundice [29] and may be associated with an increased frequency of stillbirths and
prematurity [30]. All the pathologic changes disappear following delivery (see "Intrahepatic
cholestasis of pregnancy"). It is of crucial importance to distinguish this entity from other
potentially lethal liver disorders in pregnancy such as acute fatty liver and the HELLP
(Hemolysis, Elevated Liver enzymes and Low Platelets) syndrome. (See "Acute fatty liver of
pregnancy".)
Other conditions associated with cholestasis
● Postoperative jaundice – Jaundice occurs commonly in postoperative patients and is

usually multifactorial in origin. Serum unconjugated bilirubin levels may increase because
of blood transfusions, hematoma resorption, and hemolysis after heart surgery. Other
contributing factors include sepsis, TPN, the administration of hepatotoxic drugs during
surgery (such as halothane) [31], postoperative hypoxia, hypotension, or a newly acquired
viral hepatitis [32]. Concomitant renal failure will exaggerate the hyperbilirubinemia.
Surgery also can exacerbate a preexisting hemolytic disease or unmask an underlying
genetic disorder (eg, Gilbert syndrome or glucose-6-phosphate dehydrogenase deficiency).
(See "Approach to the patient with postoperative jaundice".)
● Organ transplantation – Intrahepatic cholestasis is common in transplant recipients

(especially bone marrow and liver). These patients often require TPN and receive multiple
potentially hepatotoxic drugs including immunosuppressive agents, which increase the
susceptibility to infection. In addition to the skin and intestinal epithelium, other target
sites of graft-versus-host disease in bone marrow transplants include the small
interlobular bile ducts. The resulting inflammation and destruction lead to cholestasis.
Intensive pretransplantation radiation and chemotherapy predisposes to the development
of veno-occlusive disease of the liver, with cholestasis and liver failure.
Signs of cholestasis after orthotopic liver transplantation may reflect preservation injury of
the donor organ, an operative complication (bile leak, stricture) [33], and chronic allograft
rejection ("vanishing bile duct syndrome"). In addition, cholestasis is occasionally the sole
indicator of acute transplant rejection.
● End-stage liver disease – With chronic hepatocellular injury, the biochemical profile
changes over time as the liver injury progresses to cirrhosis and liver failure. The elevation
of liver enzymes, a marker of active liver injury, becomes less prominent or even
disappears. The primary manifestations at this time result from impaired hepatic protein
synthesis (eg, hypoalbuminemia and a prolonged prothrombin time) and impaired
excretory function, leading to jaundice. The hallmarks of end-stage liver disease and
cirrhosis, regardless of its etiology, include jaundice with an elevation of both conjugated

and unconjugated bilirubin as well as portal hypertension and decreased hepatic synthetic
function.
Hepatocellular injury — Hepatocellular injury is typically characterized by the release of

intracellular proteins and small molecules into the plasma. Thus, in contrast to cholestatic
syndromes, the elevations in serum conjugated and unconjugated bilirubin and bile salts are
accompanied by elevations in the serum concentrations of hepatocellular enzymes, such as AST
and ALT. Disorders frequently associated with hepatocellular jaundice are listed in the table
( table 4). However, many of these conditions can also present with cholestatic syndromes.
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Here are the patient education articles that are relevant to this topic. We encourage you to print
or email these topics to your patients. (You can also locate patient education articles on a variety
of subjects by searching on "patient info" and the keyword(s) of interest.)
● Basics topic (see "Patient education: Jaundice in adults (The Basics)" and "Patient
education: Gilbert syndrome (The Basics)")
SUMMARY AND RECOMMENDATIONS
● Classification of hyperbilirubinemia – Based on the predominant type of bile pigments

in the plasma, hyperbilirubinemia is classified into two major categories: conjugated and
unconjugated ( table 1). Unconjugated hyperbilirubinemia is characterized by plasma
elevation of predominantly unconjugated bilirubin due to the overproduction of bilirubin,
impaired bilirubin uptake by the liver, or abnormalities of bilirubin conjugation. In patients
with conjugated hyperbilirubinemia, both unconjugated and conjugated bilirubin levels
increase. (See "Diagnostic approach to the adult with jaundice or asymptomatic
hyperbilirubinemia".)
● Mechanisms for unconjugated hyperbilirubinemia – Three basic pathophysiologic

mechanisms, overproduction of bilirubin, reduced bilirubin uptake, and impaired bilirubin
conjugation, are mainly responsible for unconjugated hyperbilirubinemia. Bilirubin
overproduction may result from excessive breakdown of heme derived from hemoglobin.
Extravascular or intravascular hemolysis, extravasation of blood in tissues, or
dyserythropoiesis are causes of enhanced heme catabolism. (See 'Disorders associated
with unconjugated hyperbilirubinemia' above.)
● Causes of conjugated hyperbilirubinemia – Disorders with conjugated

hyperbilirubinemia can be categorized according to their pathophysiology as those due to
biliary obstruction (extrahepatic cholestasis), intrahepatic cholestasis, or hepatocellular
injury.
In cholestatic disorders, both conjugated and unconjugated bilirubin accumulate in serum

and patients have elevations in alkaline phosphatase. In patients with hepatocellular
causes of hyperbilirubinemia, elevations in serum conjugated and unconjugated bilirubin
and bile salts are accompanied by elevations in the serum concentrations of hepatocellular
enzymes, such as aspartate aminotransferase (AST) and alanine aminotransferase (ALT).
The differential diagnosis of extrahepatic and intrahepatic hyperbilirubinemia is

summarized in the tables ( table 2 and table 3). (See 'Disorders associated with
conjugated hyperbilirubinemia' above.)
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REFERENCES
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Topic 3615 Version 32.0

GRAPHICS
Classification of jaundice according to type of bile pigment and mechanism
Unconjugated hyperbilirubinemia Conjugated hyperbilirubinemia

Increased bilirubin production*
(continued)
Extravascular hemolysis Extrahepatic cholestasis (biliary obstruction)
Extravasation of blood into tissues Choledocholithiasis
Intravascular hemolysis Intrinsic and extrinsic tumors (eg,

cholangiocarcinoma, pancreatic cancer)
Dyserythropoiesis
Primary sclerosing cholangitis
Wilson disease
AIDS cholangiopathy
Impaired hepatic bilirubin uptake
Acute and chronic pancreatitis
Heart failure
Strictures after invasive procedures
Portosystemic shunts
Certain parasitic infections (eg, Ascaris
Some patients with Gilbert syndrome lumbricoides, liver flukes)
Certain drugs ¶ – Rifampin, probenecid, Intrahepatic cholestasis
flavaspadic acid, bunamiodyl
Viral hepatitis
Impaired bilirubin conjugation
Alcohol-associated hepatitis
Crigler-Najjar syndrome types I and II
Non-alcohol-associated steatohepatitis
Gilbert syndrome
Chronic hepatitis
Neonates
Primary biliary cholangitis
Hyperthyroidism
Drugs and toxins (eg, alkylated steroids,
Ethinyl estradiol chlorpromazine, herbal medications [eg,
Liver diseases – Chronic hepatitis, advanced Jamaican bush tea], arsenic)
cirrhosis Sepsis and hypoperfusion states
Conjugated hyperbilirubinemia Infiltrative diseases (eg, amyloidosis,
lymphoma, sarcoidosis, tuberculosis)
Defect of canalicular organic anion transport
Total parenteral nutrition
Dubin-Johnson syndrome
Postoperative cholestasis
Defect of sinusoidal reuptake of conjugated
bilirubin Following organ transplantation
Rotor syndrome Hepatic crisis in sickle cell disease
Pregnancy
End-stage liver disease

AIDS: acquired immunodeficiency syndrome.
* Serum bilirubin concentration is usually less than 4 mg/dL (68 mmol/L) in the absence of underlying
liver disease.
¶ The hyperbilirubinemia induced by drugs usually resolves within 48 hours after the drug is
discontinued.
Graphic 55607 Version 13.0

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.

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 multidrug
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-transporting polypeptide 1B1; OATP1B3: organic anion-
transporting polypeptide 1B3.


Differential diagnosis of cholestatic jaundice: Extrahepatic
Cholangiopathies and other disorders involving bile ducts Extrinsic causes
Cholelithiasis Pancreatitis (acute and chronic)
Biliary strictures after invasive procedure Pancreatic carcinoma
Cholangiocellular carcinoma Portal adenopathy
Primary sclerosing cholangitis Metastases
AIDS cholangiopathy Tuberculosis
CMV Periampullary carcinoma
Cryptosporidium sp Periampullary diverticulum
HIV Mirizzi's syndrome
Choledochal cyst
Sphincter of Oddi dysfunction
Parasitic infections
Ascaris lumricoides
Histiocytosis X
CMV: cytomegalovirus; HIV: human immunodeficiency virus.

Differential diagnosis of cholestatic jaundice: Intrahepatic
Acute hepatocellular Miscellaneous
Viral hepatitis Hypotension/hypoxemia/HF
Alcohol-associated fatty liver and/or hepatitis Budd-Chiari syndrome
Non-alcoholic steatohepatitis Parasitic infection (Clonorchis sinensis; Fasciola

hepatica)
Drugs
Idiopathic adulthood ductopenia
Chronic hepatocellular
Other cholangiopathies (IgG4 cholangiopathy;
ischemic cholangiopathy; COVID-19)
Inherited/endocrine
Drugs
Benign recurrent intrahepatic cholestasis (BRIC)
Hepatitis (viral, alcohol, autoimmune)
Progressive familial intrahepatic cholestasis
Cirrhosis of any cause (PFIC)
Multifactorial Low phospholipid-associated cholestasis (LPAC)
Total parental nutrition Thyrotoxicosis
Systemic infection Alagille syndrome
Postoperative Disorders of carbohydrate, lipid, or bile acid

metabolism
Sickle cell disease/crisis
Caroli's disease
Organ transplantation (rejection; graft-versus-
host disease; venoocclusive disease) Pregnancy
Protoporphyria
Infiltrative/granulomatous
Amyloidosis
Lymphoma*
Sarcoidosis
Tuberculosis
* Rarely patients with lymphoma may have hyperbilirubinemia (direct) in the absence of tumor
involvement of the liver or extrahepatic obstruction.

Differential diagnosis of hepatocellular jaundice
Neoplasms Infections
Hepatocellular carcinoma Viral

Cholangio carcinoma Hepatitis viruses
Metastases (bronchogenic, GI tract, Herpes viruses
breast, GU tract)
"Hemorrhagic" viruses: yellow fever, Ebola, Marburg, Lassa
Lymphoma
Adenoviruses, enteroviruses, etc
Hemangioendothelioma
Bacterial
Hepatoblastoma
Tuberculosis, leptospirosis, syphilis, pyogenic abscess,
Metabolic/hereditary Brucella, Rickettsia, Tropheryma whippeli, Rochalimea
Wilson disease Parasitic

Alpha-1 antitrypsin deficiency Helminths: Ascaris, Fasciola, Clonorchis, schistosomiasis,
Hemochromatosis echinococcosis
Porphyrias Protozoa: amebiasis, plasmodia, babesiosis, toxoplasmosis,

leishmaniasis
Congenital hepatic fibrosis
Fungal
Fibropolycystic disease
Candida, Blastomyces, Coccidioides, Histoplasma, Cryptococcus
Systemic
Toxic/immunologic
Acute ischemia
Medications (allergic, idiosyncratic)
Severe heart failure
Alcohol
Tricuspid insufficiency
Chlorinated hydrocarbons (carbon tetrachloride, chloroform)
Constrictive pericarditis
Amanita phalloides toxin
Budd-Chiari syndrome
Aflatoxin B1
Venoocclusive disease
Vitamin A
Telangiectasias
Pyrrolizidine alkaloids
Sarcoidosis
Arsenic
Amyloidosis
Phosphorous
Miscellaneous
Autoimmune hepatitis
Secondary biliary cirrhosis
Cryptogenic cirrhosis
Overlap syndrome

Autoimmune cholangiopathy
Nonalcoholic steatohepatitis
GI: gastrointestinal; GU: genitourinary.

Contributor Disclosures
Namita Roy-Chowdhury, PhD, FAASLD No relevant financial relationship(s) with ineligible companies to
disclose. Jayanta Roy-Chowdhury, MD, MRCP, AGAF, FAASLD No relevant financial relationship(s) with
ineligible companies to disclose. Sanjiv Chopra, MD, MACP No relevant financial relationship(s) with
ineligible companies to disclose. Elizabeth B Rand, MD No relevant financial relationship(s) with ineligible
companies to disclose. Shilpa Grover, MD, MPH, AGAF No relevant financial relationship(s) with ineligible
companies to disclose.
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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22/2/24, 07:31 Classification and causes of jaundice or asymptomatic hyperbilirubinemia - UpToDate

Official reprint from UpToDate®

Classification and causes of jaundice or asymptomatic

Literature review current through: Jan 2024.

Jaundice is often used interchangeably with hyperbilirubinemia. However, a careful clinical

https://www.uptodate.com/contents/classification-and-causes-of-jaundice-or-asymptomatic-hyperbilirubinemia/print?search=sindrome colestasico&source=search_r… 1/22

● Unconjugated hyperbilirubinemia – Unconjugated hyperbilirubinemia is characterized

● Conjugated hyperbilirubinemia – In patients with conjugated

DISORDERS ASSOCIATED WITH UNCONJUGATED HYPERBILIRUBINEMIA

Three basic pathophysiologic mechanisms, overproduction of bilirubin, reduced bilirubin

Overproduction of bilirubin — Bilirubin overproduction may result from excessive breakdown

● Conditions associated with bilirubin overproduction

methemoglobin, from which heme is transferred to hemopexin or to albumin, forming

• Dyserythropoiesis – In a variety of diseases including megaloblastic and sideroblastic

• Extravasation – When blood is extravasated into tissues, or pleural or peritoneal

● Pattern of bilirubin elevation based on the presence of underlying liver disease

• Patients without liver disease – In hemolysis, unconjugated bilirubin production can

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of the hepatocyte, resulting in active transport of unconjugated and conjugated

● Medications (eg, rifamycin antibiotics, probenecid, flavaspidic acid, and bunamiodyl, a

● Congestive heart failure or portosystemic shunts (spontaneously occurring collaterals in

Impaired bilirubin conjugation — Reduced bilirubin conjugation as a result of a decreased or

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DISORDERS ASSOCIATED WITH CONJUGATED HYPERBILIRUBINEMIA

Disorders with conjugated hyperbilirubinemia can be categorized according to their

Cholestatic disorders — In disorders associated with cholestasis, both conjugated and

Extrahepatic cholestasis/biliary obstruction — In biliary obstruction, both conjugated and

Differential diagnosis of conjugated hyperbilirubinemia due to biliary obstruction varies with

Intrahepatic cholestasis — A number of intrahepatic disorders can lead to jaundice and an

Inherited diseases — Elevated levels of conjugated bilirubin may occur in inherited

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Disorders of fatty acid oxidation are characterized by episodes of metabolic decompensation,

● Metabolic dysfunction-associated steatotic liver disease (MASLD) or MASLD-associated

Primary biliary cholangitis — Primary biliary cholangitis typically presents with a

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Parenteral nutrition — Steatosis, lipidosis, and cholestasis are frequently encountered in

Infiltrative disorders — Infiltrative processes of the liver (eg, amyloidosis, lymphoma,

Intrahepatic cholestasis of pregnancy — Pruritus, usually occurring in the third

Other conditions associated with cholestasis

● Postoperative jaundice – Jaundice occurs commonly in postoperative patients and is

● Organ transplantation – Intrahepatic cholestasis is common in transplant recipients

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Hepatocellular injury — Hepatocellular injury is typically characterized by the release of

INFORMATION FOR PATIENTS

SUMMARY AND RECOMMENDATIONS

● Classification of hyperbilirubinemia – Based on the predominant type of bile pigments

● Mechanisms for unconjugated hyperbilirubinemia – Three basic pathophysiologic

● Causes of conjugated hyperbilirubinemia – Disorders with conjugated

In cholestatic disorders, both conjugated and unconjugated bilirubin accumulate in serum

The differential diagnosis of extrahepatic and intrahepatic hyperbilirubinemia is

Use of UpToDate is subject to the Terms of Use.

1. ROBINSON S, VANIER T, DESFORGES JF, SCHMID R. Jaundice in thalassemia minor: a

5. Donner MG, Keppler D. Up-regulation of basolateral multidrug resistance protein 3 (Mrp3)

https://www.uptodate.com/contents/classification-and-causes-of-jaundice-or-asymptomatic-hyperbilirubinemia/print?search=sindrome colestasico&source=search_… 10/22

9. Chowdhury JR, Chowdhury NR, Moscioni AD, et al. Differential regulation by

15. Stricker BHCH. Drug-induced Hepatic Injury, Elsevier, Amsterdam 1993.

https://www.uptodate.com/contents/classification-and-causes-of-jaundice-or-asymptomatic-hyperbilirubinemia/print?search=sindrome colestasico&source=search_… 11/22

26. Dourakis SP, Sinani C, Deutsch M, et al. Cholestatic jaundice as a paraneoplastic

https://www.uptodate.com/contents/classification-and-causes-of-jaundice-or-asymptomatic-hyperbilirubinemia/print?search=sindrome colestasico&source=search_… 12/22