Close
New

Medscape is available in 5 Language Editions – Choose your Edition here.

 

Conjugated Hyperbilirubinemia

  • Author: Richard A Weisiger, MD, PhD; Chief Editor: BS Anand, MD  more...
 
Updated: Jan 05, 2016
 

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 CirrhosisGallstones, and Newborn Jaundice.

Next

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.

Previous
Next

Etiology

In a review of the literature, in which Gottesman et al selected 17 studies comprising 1692 infants as meeting their selection criteria for 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] :

  • Prospective/retrospective case series or cohort study with at least 10 patients
  • Consecutive infants who presented with conjugated hyperbilirubinemia
  • Patients who received appropriate diagnostic work-up for conjugated hyperbilirubinemia
  • No specific diagnoses were excluded in the studied cohort

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

Table. Differential Diagnosis of Conjugated Hyperbilirubinemia (Open Table in a new window)

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)



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



 

Previous
Next

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.

Previous
Next

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.

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.

Previous
 
 
Contributor Information and Disclosures
Author

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

Richard A Weisiger, MD, PhD is a member of the following medical societies: American Association for the Study of Liver Diseases, American Society for Clinical Investigation

Disclosure: Nothing to disclose.

Chief Editor

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

BS Anand, MD is a member of the following medical societies: American Association for the Study of Liver Diseases, American College of Gastroenterology, American Gastroenterological Association, American Society for Gastrointestinal Endoscopy

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
  1. Lathe GH. The degradation of haem by mammals and its excretion as conjugated bilirubin. Essays Biochem. 1972. 8:107-48. [Medline].

  2. Muraca M, Fevery J, Blanckaert N. Analytic aspects and clinical interpretation of serum bilirubins. Semin Liver Dis. 1988 May. 8(2):137-47. [Medline].

  3. Westwood A. The analysis of bilirubin in serum. Ann Clin Biochem. 1991 Mar. 28 ( Pt 2):119-30. [Medline].

  4. Iyanagi T, Emi Y, Ikushiro S. Biochemical and molecular aspects of genetic disorders of bilirubin metabolism. Biochim Biophys Acta. 1998 Sep 30. 1407(3):173-84. [Medline].

  5. Gottesman LE, Del Vecchio MT, Aronoff SC. Etiologies of conjugated hyperbilirubinemia in infancy: a systematic review of 1692 subjects. BMC Pediatr. 2015 Nov 20. 15 (1):192. [Medline].

  6. Klein CJ, Revenis M, Kusenda C, Scavo L. Parenteral nutrition-associated conjugated hyperbilirubinemia in hospitalized infants. J Am Diet Assoc. 2010 Nov. 110(11):1684-95. [Medline].

  7. Johnston DE. Special considerations in interpreting liver function tests. Am Fam Physician. 1999 Apr 15. 59(8):2223-30. [Medline].

  8. Segal I, Rassekh SR, Bond MC, Senger C, Schreiber RA. Abnormal liver transaminases and conjugated hyperbilirubinemia at presentation of acute lymphoblastic leukemia. Pediatr Blood Cancer. 2010 Sep. 55(3):434-9. [Medline].

  9. Gotze T, Blessing H, Grillhosl C, Gerner P, Hoerning A. Neonatal cholestasis - differential diagnoses, current diagnostic procedures, and treatment. Front Pediatr. 2015. 3:43. [Medline].

  10. Dani C, Pratesi S, Raimondi F, Romagnoli C, for the Task Force for Hyperbilirubinemia of the Italian Society of Neonatology. Italian guidelines for the management and treatment of neonatal cholestasis. Ital J Pediatr. 2015 Oct 1. 41:69. [Medline].

  11. Devgun MS, Chan MK, El-Nujumi AM, Abara R, Armbruster D, Adeli K. Clinical decision limits for interpretation of direct bilirubin--a CALIPER study of healthy multiethnic children and case report reviews. Clin Biochem. 2015 Jan. 48 (1-2):93-6. [Medline].

  12. Talachian E, Bidari A, Mehrazma M, Nick-khah N. Biopsy-driven diagnosis in infants with cholestatic jaundice in Iran. World J Gastroenterol. 2014 Jan 28. 20 (4):1048-53. [Medline].

  13. Memon N, Weinberger BI, Hegyi T, Aleksunes LM. Inherited disorders of bilirubin clearance. Pediatr Res. 2015 Nov 23. [Medline].

  14. van Dijk R, Beuers U, Bosma PJ. Gene replacement therapy for genetic hepatocellular jaundice. Clin Rev Allergy Immunol. 2015 Jun. 48 (2-3):243-53. [Medline].

 
Previous
Next
 
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 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.
Table. Differential Diagnosis of Conjugated Hyperbilirubinemia
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)



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



Previous
Next
 
 
 
 
 
All material on this website is protected by copyright, Copyright © 1994-2016 by WebMD LLC. This website also contains material copyrighted by 3rd parties.