Elevated bilirubin levels (>2.5-3 mg/dL) cause jaundice and can be classified into different anatomical sites of pathology: prehepatic (increased bilirubin production), hepatic (liver dysfunction), or posthepatic (duct obstruction).
Another way of approaching hyperbilirubinemia is to divide it into two general categories: unconjugated hyperbilirubinemia and conjugated hyperbilirubinemia. The prevalence of hyperbilirubinemia varies depending on the cause.
Conjugated hyperbilirubinemia is common in individuals with hepatocellular injuries and biliary obstruction and is also common in persons with sepsis. Some of the inherited diseases associated with conjugated hyperbilirubinemia are estimated to affect 4%-13% of the US population, while Dubin-Johnson syndrome (DJS) is rare except in Iranian Jews, in whom the prevalence is about 1 in 1300. [3]
Unconjugated hyperbilirubinemia is common in newborns and is likely related to a higher hematocrit (50%-60%) with increased cell turnover (the average lifespan of a red cell is about 85 days in the neonate) combined with decreased uridine diphosphoglucuronate glucuronosyltransferase (UGT) activity. One study found that up to 6.1% of neonates had unconjugated bilirubin levels higher than 12.9 mg/dL. Breastfeeding was more common in neonates with higher levels of unconjugated hyperbilirubin. [4, 5]
Causes of unconjugated and conjugated hyperbilirubinemia are discussed below.
Unconjugated hyperbilirubinemia
Increased bilirubin production via hemolysis and dyserythropoiesis
Increased destruction of red blood cells (hemolysis) can increase the production of unconjugated bilirubin.
Ineffective erythropoiesis is another cause of increased unconjugated bilirubin production that involves rapid hemoglobin turnover and destruction of a fraction of developing erythroid cells within the bone marrow. The percentage of bilirubin production from this mechanism can reach 70% in dyserythropoiesis disorders such as thalassemia major, megaloblastic anemia, congenital erythropoietic porphyria, and lead poisoning.
If the production of unconjugated bilirubin is prolonged, it can precipitate bilirubin salts, leading to the formation of gallstones.
Treatment is aimed at managing the underlying disease process.
Decreased hepatic clearance
Decreased hepatic clearance may be caused by congestive heart failure, cirrhosis/portosystemic shunts, and/or certain drugs.
Impaired delivery of bilirubin to the liver in conditions such as congestive heart failure or in patients with portosystemic shunts can decrease the hepatic bilirubin uptake by the liver. Occasionally, cirrhosis can cause unconjugated hyperbilirubinemia, as hepatic fibrosis leads to capillarization of the sinusoids, causing decreased bilirubin uptake by hepatocytes. Treatment includes treating the underlying condition.
Drugs such as rifamycin, rifampin, probenecid, flavaspidic acid, and bunamiodyl inhibit bilirubin uptake, which can be reversed upon cessation of these drugs. [6]
Defective bilirubin conjugation
Inherited disorders associated with defective bilirubin conjugation include Crigler-Najjar syndrome types I and II and Gilbert syndrome. Ethinyl estradiol and hyperthyroidism are also associated with defective bilirubin conjugation. Crigler-Najjar syndrome is a very rare autosomal-recessive disorder caused by an alteration of the coding region of the gene responsible for producing bilirubin-UGT, which normally conjugates bilirubin. This results in the production of an abnormal protein, which can cause a complete or near loss of function (type I) or a very low level of function (type II).
Individuals with type I Crigler-Najjar syndrome usually present with very high levels of unconjugated hyperbilirubin at birth, resulting in kernicterus. Treatment involves emergent plasma exchange to treat kernicterus followed by regular phototherapy. If left untreated, type I is fatal by about age two years. Patients with type II may not require any therapy or may be treated with phenobarbital, which can induce the expression of UGT. Patients with type I do not respond to phenobarbital, as the mutation is a loss-of-function mutation.
Gilbert syndrome has also decreased UGT activity (typically 10%-33% of normal), but results from a mutation in the promoter region and therefore decreased levels of a normal protein are produced. Gilbert syndrome is completely benign and has no effect on life expectancy. Therefore, management is centered on reassurance, and no medical therapy is indicated.
Multifactorial etiologies
Chronic hepatitis is also associated with unconjugated hyperbilirubinemia.
Conjugated hyperbilirubinemia
Hepatitis
Hepatitis (viral, alcoholic, autoimmune) is associated with conjugated hyperbilirubinemia
Liver infiltration
The following diseases may lead to liver infiltration, potentially resulting in conjugated hyperbilirubinemia:
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Amyloidosis
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Lymphoma
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Sarcoidosis
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Tuberculosis
Biliary obstruction
Biliary obstruction may be caused by the following:
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Malignancies (cholangiocarcinoma, pancreatic cancer)
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Chronic pancreatitis (pseudocysts, stricture)
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Acute pancreatitis
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Primary sclerosing cholangitis (PSC; discussed further below)
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Choledocholithiasis
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Postsurgical biliary strictures
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Choledochal cysts (discussed further below)
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Biliary atresia
PSC is characterized by progressive inflammation and scarring of the bile ducts. It is thought to be autoimmune in nature and is often associated with inflammatory bowel disease (IBD; ulcerative colitis or Crohn colitis). The disease course is independent of that of IBD. Treatment is mainly supportive. PSC is associated with an increased risk for cholangiocarcinoma. [7] Liver transplant is the treatment used when PSC results in end-stage liver disease.
Congenital cystic dilations of the bile duct are typically associated with intermittent abdominal pain, jaundice, and right upper quadrant mass. These are important to recognize owing to the risk of malignancy. Treatment is mostly surgical depending on the type of choledochal cysts.
Infections
Infections associated with conjugated hyperbilirubinemia include the following:
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CMV
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Parasitic infections
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Cholangitis
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Cholecystitis
Inherited disorders
DJS is an autosomal-recessive disease characterized by a mutation in the gene responsible for the human canalicular multispecific organic anion transporter (cMOAT) protein, also known as the multidrug resistance protein 2 (MRP2). This mutation results in the impaired transport of nonbile salt organic anions across the canalicular membrane of the hepatocyte, resulting in conjugated hyperbilirubinemia
Rotor syndrome is very similar to DJS. It is also autosomal recessive, although the exact genetic defect has yet to be determined. Like DJS, Rotor syndrome is benign and requires no specific therapy.
DJS can be differentiated from Rotor syndrome in that DJS is characterized by normal urinary levels of coproporphyrin, as opposed to Rotor syndrome, which is characterized by high levels. Additionally, DJS is associated with black pigmentation of the liver, whereas Rotor syndrome is not. [8, 9]
Primary biliary cirrhosis
Primary biliary cirrhosis is an autoimmune disease of the liver involving progressive destruction of small intrahepatic ducts. It is much more common in females and usually presents with pruritus, fatigue, and jaundice. It results in end-stage liver disease. Treatment with ursodiol slows the disease progression. Like PSC, liver transplantation is the treatment of choice whenever cirrhosis sets in.
Benign recurrent intrahepatic cholestasis
Benign recurrent intrahepatic cholestasis (BRIC) is a rare autosomal-recessive or sporadic disorder with recurrent episodes of intense pruritus and jaundice that resolves spontaneously without significant liver damage. [10]
AIDS cholangiopathy
AIDS cholangiopathy is a syndrome of biliary obstruction thought to result from infection-induced strictures of the biliary tract. The most common organism associated with AIDS cholangiopathy is Cryptosporidium parvum, although other organisms have also been implicated. Total parenteral nutrition
The etiology of total parenteral nutrition (TPN)–induced cholestasis is not completely understood and is likely multifactorial, involving excessive calories with deficiencies in micronutrients and possibly bacterial translocation from the gut.
Wilson disease
Wilson disease is an autosomal-recessive disease involving copper deposition in multiple tissues, including the brain and liver. Symptoms usually present by about age20 years, although cases in older people have been described. The ceruloplasmin levels are usually reduced. Cupper chelation is used for treatment.
Drugs
Many drugs can cause liver injury that results in hyperbilirubinemia associated with elevated liver enzymes. Isolated elevated bilirubin levels caused by drugs is much less common, but some drugs are known to do this, as follows:
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Isoniazid
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Chlorpromazine
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Erythromycin
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Anabolic steroids
Other
Other causes of conjugated hyperbilirubinemia include the following:
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Sepsis
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Shock
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Hemochromatosis
