Conjugated Hyperbilirubinemia

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Background

Bilirubin is a tetrapyrrole produced by the normal breakdown of heme. Most bilirubin is produced during the breakdown of hemoglobin and other hemoproteins. Accumulation of bilirubin or its conjugates in body tissues produces jaundice (ie, icterus), which is characterized by high plasma bilirubin levels and deposition of yellow bilirubin pigments in the skin, sclerae, mucous membranes, and other less visible tissues.[1, 2, 3, 4]

Because bilirubin is highly insoluble in water, it must be converted into a soluble conjugate before elimination from the body. In the liver, uridine diphosphate (UDP)-glucuronyl transferase converts bilirubin to a mixture of monoglucuronides and diglucuronides, referred to as conjugated bilirubin, which is then secreted into the bile by an ATP-dependent transporter. This process is highly efficient under normal conditions, so plasma unconjugated bilirubin concentrations remain low.

A large number of disease states lead to bilirubin accumulation in plasma. Diseases that increase the rate of bilirubin formation, such as hemolysis, or diseases that reduce the rate of bilirubin conjugation, such as Gilbert syndrome, produce unconjugated hyperbilirubinemia.

Diseases that reduce the rate of secretion of conjugated bilirubin into the bile or the flow of bile into the intestine produce a mixed or predominantly conjugated hyperbilirubinemia due to the reflux of conjugates back into the plasma. Elevated conjugated bilirubin levels usually indicate hepatobiliary disease.

Laboratory assays for bilirubin typically involve its cleavage in the presence of diazotized sulfanilic acid to generate a colored azodipyrrole that can be assayed spectrophotometrically. Because of its limited aqueous solubility, unconjugated bilirubin reacts slowly in the absence of an accelerator, such as ethanol, whereas conjugated bilirubin reacts rapidly. Total bilirubin is measured in the presence of an accelerator, whereas directly reacting bilirubin is measured without an accelerator. Indirectly reacting bilirubin is calculated by subtracting the directly reacting bilirubin score from the total bilirubin score.

Although the directly reacting bilirubin concentration approximates the conjugated bilirubin concentration in most cases, the 2 terms do not mean the same thing. Similarly, indirect bilirubin is not the same as unconjugated bilirubin.

The kidneys do not filter unconjugated bilirubin because of its avid binding to albumin. For this reason, the presence of bilirubin in the urine indicates the presence of conjugated hyperbilirubinemia.

Normal serum values of total bilirubin typically are 0.2-1 mg/dL (3.4-17.1 µmol/L), of which no more than 0.2 mg/dL (3.4 µmol/L) are directly reacting.

For patient education resources, see Digestive Disorders Center and Infections Center, as well as Cirrhosis, Gallstones, and Newborn Jaundice.

Pathophysiology

Conjugated hyperbilirubinemia results from reduced secretion of conjugated bilirubin into the bile, such as occurs in patients with hepatitis, or from impaired flow of bile into the intestine, as in patients with biliary obstruction. Bile formation is sensitive to various hepatic insults, including high levels of inflammatory cytokines, as may occur in patients with septic shock.

High levels of conjugated bilirubin may secondarily elevate the level of unconjugated bilirubin. Although the mechanism of this effect is not fully defined, one likely cause is reduced hepatic clearance of unconjugated bilirubin that results from competition with conjugated bilirubin for uptake or excretion.

Etiology

In a review of the literature, in which Gottesman et al selected 17 studies comprising 1692 infants as meeting their selection criteria for the evaluation of the etiologies of conjugated hyperbilirubinemia, idiopathic neonatal hepatitis was the most common cause in infancy (26.0%), and extrahepatic biliary atresia (25.89%) and infection (11.4%) were the most commonly specified etiologies.[5] Selection criteria were noted as the following[5] :

A categoric listing of the most common diseases that produce conjugated hyperbilirubinemia is presented in the table below.

Table. Differential Diagnosis of Conjugated Hyperbilirubinemia



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See Table

 

Epidemiology

United States data

Conjugated hyperbilirubinemia is a common abnormality among patients with notable liver or biliary disease. It may also be observed in patients with systemic illnesses, such as sepsis and cardiogenic shock. The frequencies of the liver and biliary diseases that cause conjugated hyperbilirubinemia are described for each specific disease.

International data

In certain lesser-developed countries, parasitic diseases, such as clonorchiasis and ascariasis, commonly produce biliary obstruction. Hemolytic diseases, such as malaria, may predispose patients to biliary obstruction through the formation of pigment gallstones.

Race-, sex-, and age-related differences in incidence

Racial and sexual differences reflect those for the specific disease states causing conjugated hyperbilirubinemia.

The age distribution of those with conjugated hyperbilirubinemia reflects the age distribution of the underlying disease states and ranges from the first month of life, as in cases of biliary atresia; through midlife, as in cases of viral hepatitis or primary biliary cirrhosis; and to senescence, as in cases of biliary stones and malignancies.

Prognosis

Mortality/morbidity

Unlike unconjugated bilirubin, conjugated bilirubin does not bind significantly to neural tissue and does not lead to kernicterus or other forms of toxicity.

Green, discolored teeth have been reported as a late complication (later infancy) of prolonged conjugated hyperbilirubinemia in extremely low birth weight infants.[6] [7]

The morbidity and mortality associated with conjugated hyperbilirubinemia result from the underlying disease process.

In certain disease states, such as alcoholic hepatitis or primary biliary cirrhosis, bilirubin levels correlate strongly with, but do not contribute to, short-term mortality.

History

Clinical evaluation of those with suspected conjugated hyperbilirubinemia always starts with obtaining a full history.

Potential toxins (eg, drugs), environmental chemicals (eg, solvents), or wild mushrooms must be carefully excluded. Failure to promptly diagnose toxic hepatitis may result in hepatic failure and death.

Risk factors for viral hepatitis should be elicited. Possible risk factors include the following:

Also note the following:

Physical Examination

The first manifestation in cases of conjugated hyperbilirubinemia is commonly a brownish discoloration of the urine. Although scleral icterus may also be present, this typically reflects the unconjugated fraction of bilirubin that binds tissues much more avidly.

If sufficient unconjugated bilirubin is present, the skin, sclerae, and mucous membranes take on a yellow color, although this may be difficult to detect if the tissues are pigmented naturally.

Depending on the underlying illness, stigmata of chronic liver disease may or may not be present.

Palpation of the abdomen may reveal the following:

In cases of biliary obstruction or stasis, stool may be acholic and light gray.

Unexplained darkening of the skin, diabetes, or heart failure suggests hemochromatosis.

Kaiser-Fleisher rings (accompanied with a low serum ceruloplasmin concentration) suggests Wilson disease.

Cutaneous or neurologic findings of chronic alcoholism may be helpful diagnostic findings.

Approach Considerations

Appropriate initial laboratory testing in cases of conjugated hyperbilirubinemia depends on the clinical history and physical examination findings.[2, 3, 10, 11, 12, 13] Misdiagnosis of cholestatic jaundice potentially delays the identification of severe liver disease; investigate all cases of prolonged neonatal jaundice (>2 weeks after birth).[14, 15]

Obtain the following laboratory studies for all patients with suspected conjugated hyperbilirubinemia:

Obtain fractionated bilirubin levels.[13]  Devgun et al indicate a direct bilirubin concentration of 10 μmol/L or higher should be used to consider the presence of conjugated hyperbilirubinemia, provided that total bilirubin concentration is also above the reference interval.[16] The North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition and the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition consider a direct/conjugated bilirubin level above 1.0 mg/dL (17 μmol/L) as abnormal in the presence of an elevated total bilirubin.[13] In newborns, rule out infection for levels of conjugated bilirubin of 0.5 mg/dL and above, up to 2 mg/dL, and monitor the infant; for those with conjugated bilirubin levels of 2 mg/dL and higher, a more thorough evaluation of the hepatobiliary system is warranted.[17]

For formula-fed infants who are jaundiced after age 2 weeks or otherwise-well breast-fed infants who are icteric at age 3 weeks, obtain serum total and conjugated bilirubin levels.[13]

Liver biopsy is indicated in cases with causes in which irreversible liver damage may occur,[18] such as biliary atresia, the most common cause of neonatal cholestasis.[14] Talachian et al reported a significant delay between pediatric patients presenting with infantile cholestasis and subsequently undergoing liver biopsy in the setting of potential irreversible liver damage.[18]

The gold standard for diagnosing biliary atresia is intraoperative cholangiography and histologic evaluation of the duct remnant.[13]

Imaging Studies

Ultrasonography

Abdominal ultrasonography should be performed to exclude biliary obstruction and to evaluate the liver parenchyma for possible cirrhosis, tumor, steatosis, or congestion.[13]

Ultrasonography is safe, noninvasive, and portable. This image modality provides good visualization of the gallbladder, bile ducts, and cystic lesions and can detect parenchymal liver disease, such as cirrhosis or infiltration, and signs of portal hypertension.

However, ultrasonography also has a limited resolution, and it may not detect common bile duct stones because of the presence of bowel gas.

Computed tomography (CT) scanning

Abdominal CT scans provide additional information about patients with abnormal ultrasonography scans. CT scanning may be the initial imaging modality in some cases.

Advantages

CT scanning offers the following advantages:

Disadvantages

Disadvantages of CT scanning include the following:

Magnetic resonance imaging (MRI)

Abdominal magnetic resonance imaging (MRI) produces images comparable in quality to CT scans without patient exposure to ionizing radiation. Following administration of suitable contrast agents, detailed imaging of the biliary tract is possible. Magnetic resonance cholangiopancreatography (MRCP) may be particularly useful when evaluating cholestasis of pregnancy or patients who are too debilitated to tolerate traditional cholangiography.

Advantages

MRI offers the following advantages:

Disadvantages

Disadvantages of MRI include the following:

Endoscopic retrograde cholangiopancreatography (ERCP)

ERCP is useful in cases where biliary obstruction is strongly suspected. It is the investigation of choice to detect and treat common bile duct stones and is also useful for making a diagnosis of pancreatic cancer. Other conditions in which ERCP may be useful include primary sclerosing cholangitis and the presence of choledochal cysts.

Advantages

ERCP offers the following advantages:

Disadvantages

Disadvantages of ERCP include the following:

Percutaneous transhepatic cholangiography (PTC or PTHC)

PTC or PTHC offers most of the diagnostic and therapeutic possibilities of ERCP and may be more readily available in some settings. It can be useful in cases in which ERCP has been unsuccessful or is not available.

Advantages

PTC or PTHC offers the following advantages:

Disadvantages

Disadvantages of PTC or PTHC include the following advantages:

Approach Considerations

Treatment of conjugated hyperbilirubinemia is dependent on the cause; it may include supportive or curative measures.[8]

Failure to diagnose liver toxicity due to ongoing drug or toxin exposure may lead to liver failure and death. For this reason, it is best to stop all potentially hepatotoxic drugs until the cause of the conjugated hyperbilirubinemia can be determined.

Consultations

In most patients, the cause of conjugated hyperbilirubinemia is apparent, such as those with viral hepatitis or sepsis. When this is not the case or when multiple causes are possible, consultation with a gastroenterologist or a hepatologist may be helpful.

What causes conjugated hyperbilirubinemia?Which diseases cause conjugated hyperbilirubinemia?How is conjugated hyperbilirubinemia diagnosed?What is the difference between direct and indirect bilirubin?What is the role of the kidneys in the etiology of conjugated hyperbilirubinemia?What are normal bilirubin levels?What is the pathophysiology of conjugated hyperbilirubinemia?What are the most common etiologies of conjugated hyperbilirubinemia?What are the most common diseases that cause conjugated hyperbilirubinemia?What is the prevalence of conjugated hyperbilirubinemia in the US?What is the global prevalence of conjugated hyperbilirubinemia?How does the prevalence of conjugated hyperbilirubinemia vary by sex and race?How does the prevalence of conjugated hyperbilirubinemia vary by age?What is the morbidity and the mortality associated with conjugated hyperbilirubinemia?What is the focus of clinical history in suspected conjugated hyperbilirubinemia?What are risk factors for viral hepatitis-related conjugated hyperbilirubinemia?What are the signs and symptoms of conjugated hyperbilirubinemia?What are physical manifestations of conjugated hyperbilirubinemia?Which findings of abdominal palpation suggest conjugated hyperbilirubinemia?Which findings of biliary obstructions suggest conjugated hyperbilirubinemia?Which physical findings suggest hemochromatosis?What is the significance of a finding of Kaiser-Fleisher rings in the evaluation of conjugated hyperbilirubinemia?Which findings may suggest a chronic alcoholism etiology for conjugated hyperbilirubinemia?What is essential when diagnosing conjugated hyperbilirubinemia?Which conditions should be considered in the differential diagnosis of suspected conjugated hyperbilirubinemia?What are the differential diagnoses for Conjugated Hyperbilirubinemia?What is the role of clinical history in the selection of initial lab tests for diagnosis of conjugated hyperbilirubinemia?Which lab studies are necessary for the diagnosis of conjugated hyperbilirubinemia?What is the role of fractionated bilirubin levels in the diagnosis of conjugated hyperbilirubinemia?When are serum total and conjugated bilirubin levels indicated for the diagnosis of conjugated hyperbilirubinemia?When is a liver biopsy indicated for the diagnosis of conjugated hyperbilirubinemia?How is biliary atresia diagnosed in patients with conjugated hyperbilirubinemia?What is the role of ultrasonography in the diagnosis of conjugated hyperbilirubinemia?What is the role of CT scanning in the diagnosis of conjugated hyperbilirubinemia?What are the advantages of CT scanning for the diagnosis of conjugated hyperbilirubinemia?What are the disadvantages of CT scanning for the diagnosis of conjugated hyperbilirubinemia?What is the role of MRI in the diagnosis of conjugated hyperbilirubinemia?What are the advantages of MRI for the diagnosis of conjugated hyperbilirubinemia?What are the disadvantages of MRI for the diagnosis of conjugated hyperbilirubinemia?What is the role of endoscopic retrograde cholangiopancreatography (ERCP) in the diagnosis of conjugated hyperbilirubinemia?What are the advantages of ERCP for the diagnosis of conjugated hyperbilirubinemia?What are the disadvantages of ERCP for the diagnosis of conjugated hyperbilirubinemia?What is the role of percutaneous transhepatic cholangiography (PTC or PTHC) in the diagnosis of conjugated hyperbilirubinemia?What are the advantages of percutaneous transhepatic cholangiography (PTC or PTHC) for the diagnosis of conjugated hyperbilirubinemia?What are the disadvantages of percutaneous transhepatic cholangiography (PTC or PTHC) for the diagnosis of conjugated hyperbilirubinemia?What are the treatment options for conjugated hyperbilirubinemia?Which specialist consultations are needed for the management of conjugated hyperbilirubinemia?

Author

Richard A Weisiger, MD, PhD, Emeritus Professor, Department of Internal Medicine, University of California, San Francisco, School of Medicine

Disclosure: Nothing to disclose.

Chief Editor

BS Anand, MD, Professor, Department of Internal Medicine, Division of Gastroenterology, Baylor College of Medicine

Disclosure: Nothing to disclose.

Acknowledgements

Vivek V Gumaste, MD Associate Professor of Medicine, Mount Sinai School of Medicine of New York University; Adjunct Clinical Assistant, Mount Sinai Hospital; Director, Division of Gastroenterology, City Hospital Center at Elmhurst; Program Director of GI Fellowship (Independent Program); Regional Director of Gastroenterology, Queens Health Network

Vivek V Gumaste, MD is a member of the following medical societies: American College of Gastroenterology and American Gastroenterological Association

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

References

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  2. Muraca M, Fevery J, Blanckaert N. Analytic aspects and clinical interpretation of serum bilirubins. Semin Liver Dis. 1988 May. 8 (2):137-47. [View Abstract]
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Gross liver specimen from a patient with Dubin-Johnson syndrome showing multiple areas of dark pigmentation. Image courtesy of Cirilo Sotelo-Avila, MD.

Microscopic histology of the liver in Dubin-Johnson syndrome showing multiple areas of granulated pigment. Fontana Mason stain. Image courtesy of Cirilo Sotelo-Avila, MD.

Liver biopsy specimen showing ground-glass appearance of hepatocytes in a patient with hepatitis B.

Plain abdominal radiograph in a patient with a clinical diagnosis of acute cholecystitis. The diagnosis was confirmed by means of abdominal ultrasonography. The radiograph shows faint opacities in the region of the gallbladder fossa (red circle) and dilated loops of small bowel in the epigastrium and midabdomen secondary to localized ileus.

A 26-year-old man known to be human immunodeficiency virus (HIV) positive presented with pain in the right upper quadrant and mild jaundice. Axial sonogram through the gallbladder (GB) and pancreas (P) shows sludge within the gallbladder and the lower common bile duct (arrow). A diagnosis of acalculous cholecystitis was confirmed. A = aorta; IVC = inferior vena cava; S = splenic vein.

I. Acute or Chronic Hepatocellular Dysfunction II. Diseases That Prevent Flow of Bile into the Intestine
A. Infection A. Damage to Intrahepatic Bile Ducts or Portal Tracts
Viral hepatitis A-E



Cytomegalovirus (CMV) hepatitis



Epstein-Barr virus hepatitis



Sepsis



Primary biliary cirrhosis



Graft versus host disease



Veno-occlusive disease



Sclerosing cholangitis



B. Inflammation Without Infection B. Damage to or Obstruction of Larger Bile Ducts
Toxic liver injury



Drug toxicity (eg, acetaminophen)



Halothane hepatitis



Alcoholic hepatitis



Iron overload (hemochromatosis)



Copper overload (Wilson disease)



Autoimmune hepatitis



Choledocholithiasis



Sclerosing cholangitis



AIDS cholangiopathy



Hepatic arterial chemotherapy



Postsurgical strictures



Bile duct cancers



Developmental disorders of the bile ducts (eg, Caroli disease)



Extrinsic compression of the bile duct



Tumors



Acute pancreatitis



C. Metabolic Dysfunction C. Diffuse Infiltrative Diseases
Ischemia ("shock liver")



Acute fatty liver of pregnancy



Alpha-1 antitrypsin deficiency



Preeclampsia



Reye syndrome



Total parenteral nutrition



Granulomatous diseases



Sarcoidosis



Disseminated mycobacterial infections



Lymphoma



Wegener granulomatosis



Amyloidosis



Diffuse malignancy



D. Inborn Errors of Metabolism D. Diseases That Interfere with Biliary Secretion of Bilirubin
Dubin-Johnson syndrome



Rotor syndrome



Benign recurrent cholestasis



Drug-induced cholestasis, as with the following:



- Chlorpromazine



- Erythromycin



- Estrogens



- Anabolic steroids



- Many others