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Unconjugated Hyperbilirubinemia Workup

  • Author: Hisham Nazer, MB, BCh, FRCP, , DTM&H; Chief Editor: BS Anand, MD  more...
 
Updated: May 02, 2016
 

Approach Considerations

All patients with impaired bilirubin conjugation have an elevated total serum bilirubin level that is due primarily to the unconjugated form; however, the level of elevation varies according to the underlying disease process.

Transient elevation of plasma bilirubin may be seen in healthy neonates. The plasma bilirubin usually returns to normal within 10 days. For infants in whom the plasma bilirubin level remains elevated, search for the inherited disorders of bilirubin metabolism.

In neonates, transcutaneous devices that use multiwavelength spectral reflectance can be used to estimate total serum bilirubin levels and avoid blood sampling. At higher total serum bilirubin levels, the transcutaneous measurements may underestimate the total serum bilirubin concentration; therefore, serum measurements should be obtained. Also, the transcutaneous measurements are not reliable in infants undergoing phototherapy.

In a study, Cakmak et al suggested that by measuring haptoglobin levels from cord blood, neonatologists and pediatricians could stratify neonates into high- versus low-risk groups for developing jaundice, leading to earlier intervention. Because haptoglobin levels decrease during hemolysis, which in turn plays a significant role in raising bilirubin levels in neonates, the investigators examined the relationship between decreasing haptoglobin levels and the risk of jaundice in 84 term babies.[58]

The average gestational age of the mothers was 39.5 ± 1.5 weeks. The authors noted a negative correlation between haptoglobin levels drawn from umbilical cord blood and bilirubin values on the fifth postpartum day.

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Crigler-Najjar Syndrome

Although no simple, widely available clinical test is available to confirm the diagnosis of Crigler-Najjar syndrome, unconjugated hyperbilirubinemia in the presence of normal liver function test findings is characteristic of the disease.

Direct bilirubin is less than 15% of the total serum bilirubin in Crigler-Najjar syndrome. High-performance liquid chromatography analysis of duodenal bile reveals that, in Crigler-Najjar syndrome type 1, negligible bilirubin diglucuronides or monoglucuronides are present; in the type 2 syndrome, these conjugates are present but in low concentrations. DNA analysis can be very helpful in establishing the correct diagnosis.

Persistent unconjugated hyperbilirubinemia levels of more than 20 mg/dL after the first week of life in the absence of liver disease or hemolysis strongly suggests UGT deficiency.

Findings on abdominal imaging studies, such as plain radiography, computed tomography (CT) scanning, and ultrasonography, are normal in Crigler-Najjar syndrome.

Definitive diagnosis of Crigler-Najjar syndrome requires high-performance liquid chromatography of bile or a tissue enzyme assay of a liver biopsy sample.

Crigler-Najjar syndrome type 1

Except for the presence of high serum unconjugated bilirubin levels, the results of liver tests in Crigler-Najjar syndrome type 1 are normal. Serum bilirubin levels range from 20-50 mg/dL. Conjugated bilirubin is absent from serum, and bilirubin is not present in urine.

Bile collected through duodenal aspiration is light yellow because of small amounts of unconjugated bilirubin. Bilirubin conjugates are nearly absent from the bile.

Crigler-Najjar syndrome type 2

Crigler-Najjar syndrome type 2 results in lower bilirubin concentrations than does type I, with levels ranging from 7-20 mg/dL. Higher bilirubin levels may be seen if coexisting hemolysis or intercurrent illness is present.

This disorder may be distinguished definitively from type 1 by chromatographic analysis of pigments excreted in bile. In type 2, bile contains significant amounts of conjugated bilirubin, although the proportion of bilirubin monoglucuronide in bile is increased.

Transferase activity measurements and the response to phenobarbital treatment can also distinguish Crigler-Najjar syndrome type 1 from type 2. Phenobarbital has no effect in type 1 but causes an approximately 25% reduction in plasma bilirubin level in most patients with type 2.

Liver function testing

Liver enzyme levels are usually within the reference range. Occasionally, however, these levels may be somewhat elevated, as a result of intrahepatic cholestasis.

Percutaneous liver biopsy

Liver biopsy reveals normal histology other than the occasional bile plugs in the bile canaliculi. Bile is sometimes observed in the portal triad, in dilated bile canaliculi, in hepatocytes, and in Kupffer cells.

Enzymatic assay of liver tissue reveals absent UGT activity in Crigler-Najjar syndrome type 1 and diminished activity in Crigler-Najjar syndrome type 2.

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Gilbert Syndrome

As a rule, Gilbert syndrome can be diagnosed by a thorough history and physical examination and confirmed by standard blood tests. Repeated investigations and invasive procedures are not usually justified for establishing a diagnosis.

Hyperbilirubinemia is the only biochemical serum abnormality in Gilbert syndrome. Serum bilirubin concentrations range from 1-5 mg/dL. Two provocative tests, energy deprivation and nicotinic acid administration, have been used to diagnose the condition. However, a significant number of false-positive and false-negative results limit the value of these tests in patients with marginal elevation of serum bilirubin concentration.

A polymerase chain reaction (PCR) assay has also been introduced to identify TA repeats and may be used as a screening test.

A complete blood count (CBC), including a reticulocyte count and a blood smear, is a useful screening test for excluding hemolysis. Rarely, red blood cell abnormalities resembling variegate porphyria, possibly resulting from the increased hepatocellular bilirubin concentration, have been described in persons with Gilbert syndrome,.

Serum lactate dehydrogenase (LDH) levels are elevated in persons with hemolysis but are normal in those with Gilbert syndrome.

A familial increase in serum alkaline phosphatase (ALP) levels has been reported in persons with Gilbert syndrome.

Additional diagnostic tests are rarely required, because a diagnosis of Gilbert syndrome can generally be made on the basis of the following findings:

  • Unconjugated hyperbilirubinemia noted on several occasions
  • Normal results from the CBC, reticulocyte count, and blood smear
  • Normal liver function test (LFT) results
  • An absence of other disease processes

Nevertheless, certain specialized tests (including some that are of historical interest, as well as the newer molecular genetic techniques) are occasionally performed to confirm a diagnosis of Gilbert syndrome. These tests are described below to introduce the clinician to the broad diagnostic armamentarium available for diagnosing Gilbert syndrome. Recourse to these specialized tests should be rare and is usually difficult to justify in clinical practice, given that the diagnosis of Gilbert syndrome is generally straightforward.

Fasting test

Within 48 hours of the start of a fast, there is usually a 2- to 3-fold rise in the plasma unconjugated bilirubin level, which returns to normal levels within 24 hours after resumption of a normal diet. Although unconjugated bilirubin levels also rise with fasting in patients with hemolysis or liver disease, the magnitude of the rise is less than that observed with Gilbert syndrome. A similar rise in plasma bilirubin is also observed with normocaloric diets deficient in lipids and reverses promptly with lipid replacement.

Nicotinic acid test

Intravenous (IV) administration of 50 mg of nicotinic acid results in a 2- to 3-fold rise in plasma unconjugated hyperbilirubinemia within 3 hours. The mechanisms are multifactorial and probably related to the following:

  • Elevated osmotic fragility of red blood cells
  • Increase in splenic production of bilirubin
  • Transient inhibition of hepatic bilirubin-UGT activity
  • Increased splenic heme oxygenase activity

Because a similar, if less impressive, increase is observed in healthy individuals and those with hemolysis or liver disease, the nicotinic test, like the fasting test, does not clearly distinguish patients with Gilbert syndrome from those who are healthy or who have other disease processes.

Phenobarbital test

Phenobarbital and other enzyme inducers of the bilirubin-UGT system will normalize plasma bilirubin levels in patients with Gilbert syndrome. This effect is predominantly due to accelerated bilirubin clearance from enzyme induction, but it is also due to reduced bilirubin turnover. Steroids can also reduce plasma bilirubin levels in Gilbert syndrome, by increasing hepatic uptake and storage of bilirubin.

Radiolabeled chromium test

The radiolabeled chromium test is used to measure red blood cell survival. As many as 60% of patients with Gilbert syndrome have a mild and fully compensated state of hemolysis together with increased hepatic heme production. This means that hyperbilirubinemia may develop due to reduced clearance, as well as increased production, of bilirubin, with higher production resulting from increased erythroid or hepatic heme turnover.

Thin-layer chromatography

Thin-layer chromatography is diagnostic of Gilbert syndrome when it shows a significantly higher proportion of unconjugated bilirubin than is seen in individuals with chronic hemolysis or liver disease or is found in healthy individuals. If confirmation of the diagnosis is truly essential, chromatographic determination is of potential use. In Gilbert syndrome, this shows an increased ratio of bilirubin monoglucuronide to diglucuronide, reflecting reduced bilirubin-UGT activity.

Drug clearance test

In approximately 30% of patients with unconjugated hyperbilirubinemia, there is impaired clearance of bromosulfophthalein, indocyanine green, and free fatty acid, suggesting an abnormality in hepatic uptake, transport, or both. Metabolic clearance of tolbutamide is also reduced in persons with Gilbert syndrome, but because the drug does not undergo glucuronidation, hepatic uptake appears to be defective.

Plasma clearance of most drugs that undergo glucuronidation (eg, benzodiazepines) is unaffected. With regard to acetaminophen, however, patients with Gilbert syndrome are a heterogeneous group, with some demonstrating normal metabolism and others exhibiting marked reduction in glucuronidation and an increase in oxidation.[59, 60] These changes suggest that people in this subgroup may be more susceptible to liver injury after an acetaminophen overdose, though no such adverse events have been reported.

Polymerase chain reaction assay

PCR assay is a novel and rapid method of identifying genetic polymorphisms in the TATA box of the UGT1A1 gene by using fluorescence resonance energy transfer. It is well recognized that genetic testing can confirm the diagnosis of Gilbert Syndrome in settings where there is diagnostic confusion.

Imaging studies

Japanese researchers have reported that patients with schizophrenia associated with Gilbert syndrome have specific changes in the signal intensities on fluid-attenuated inversion-recovery magnetic resonance imaging (FLAIR MRI) scans. This suggests that schizophrenia with associated Gilbert syndrome may produce changes in the frontotemporal cortex, limbic system, and basal ganglia.

Percutaneous liver biopsy

Liver biopsies are not performed routinely in Gilbert syndrome and are rarely necessary. Histologically, the liver is normal in persons with this disorder, except for occasional accumulation of a lipofuscinlike pigment around the terminal hepatic venules.

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Neonatal Jaundice and Ineffective Erythropoiesis

Physiologic jaundice

In physiologic jaundice, the peak total serum bilirubin level is 5-6 mg/dL (86-103 µmol/L), occurs at age 48-120 hours, and does not exceed 17-18 mg/dL (291-308 µmol/L).

Breast milk jaundice

In breast milk jaundice, the bilirubin can increase to levels as high as 20 mg/dL, necessitating the need for phototherapy and the discontinuation of breastfeeding.

Increased production of bilirubin

Ineffective erythropoiesis (ELB production) is characterized by a marked increase in fecal urobilinogen excretion and a normal or near-normal red blood cell lifespan.

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Contributor Information and Disclosures
Author

Hisham Nazer, MB, BCh, FRCP, , DTM&H Professor of Pediatrics, Consultant in Pediatric Gastroenterology, Hepatology and Clinical Nutrition, University of Jordan Faculty of Medicine, Jordan

Hisham Nazer, MB, BCh, FRCP, , DTM&H is a member of the following medical societies: American Association for Physician Leadership, Royal College of Paediatrics and Child Health, Royal College of Surgeons in Ireland, Royal Society of Tropical Medicine and Hygiene, Royal College of Physicians and Surgeons of the United Kingdom

Disclosure: Nothing to disclose.

Coauthor(s)

Praveen K Roy, MD, AGAF Chief of Gastroenterology, Presbyterian Hospital; Medical Director of Endoscopy, Presbyterian Medical Group; Adjunct Associate Research Scientist, Lovelace Respiratory Research Institute

Praveen K Roy, MD, AGAF is a member of the following medical societies: American Gastroenterological Association, American Society for Gastrointestinal Endoscopy

Disclosure: Nothing to disclose.

Specialty Editor Board

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

Disclosure: Received salary from Medscape for employment. for: Medscape.

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.

Additional Contributors

Ann Ouyang, MBBS Professor, Department of Internal Medicine, Pennsylvania State University College of Medicine; Attending Physician, Division of Gastroenterology and Hepatology, Milton S Hershey Medical Center

Disclosure: Nothing to disclose.

Julian Katz, MD Clinical Professor of Medicine, Drexel University College of Medicine

Julian Katz, MD is a member of the following medical societies: American College of Gastroenterology, American College of Physicians, American Gastroenterological Association, American Geriatrics Society, American Medical Association, American Society for Gastrointestinal Endoscopy, American Society of Law, Medicine & Ethics, American Trauma Society, Association of American Medical Colleges, Physicians for Social Responsibility

Disclosure: Nothing to disclose.

Acknowledgements

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, and American Society for Gastrointestinal Endoscopy

Disclosure: Nothing to disclose.

Showkat Bashir, MD Assistant Professor, Department of Medicine, Division of Gastroenterology, George Washington University, Washington, DC

Showkat Bashir, MD is a member of the following medical societies: American College of Gastroenterology, American College of Physicians, American Gastroenterological Association, and American Medical Association

Disclosure: Nothing to disclose.

David Eric Bernstein, MD Director of Hepatology, North Shore University Hospital; Professor of Clinical Medicine, Albert Einstein College of Medicine

David Eric Bernstein, MD is a member of the following medical societies: American Association for the Study of Liver Diseases, American College of Gastroenterology, American College of Physicians, American Gastroenterological Association, and American Society for Gastrointestinal Endoscopy

Disclosure: Nothing to disclose.

Manoop S Bhutani, MD Professor, Co-Director, Center for Endoscopic Research, Training and Innovation (CERTAIN), Director, Center for Endoscopic Ultrasound, Department of Medicine, Division of Gastroenterology, University of Texas Medical Branch; Director, Endoscopic Research and Development, The University of Texas MD Anderson Cancer Center

Manoop S Bhutani, MD is a member of the following medical societies: American Association for the Advancement of Science, American College of Gastroenterology, American College of Physicians, American Gastroenterological Association, American Institute of Ultrasound in Medicine, and American Society for Gastrointestinal Endoscopy

Disclosure: Nothing to disclose.

Jack Bragg, DO Associate Professor, Department of Clinical Medicine, University of Missouri School of Medicine

Jack Bragg, DO is a member of the following medical societies: American College of Osteopathic Internists and American Osteopathic Association

Disclosure: Nothing to disclose.

Annie T Chemmanur, MD Attending Physician, Metrowest Medical Center and University of Massachusetts Memorial Hospital, Marlborough Campus

Annie T Chemmanur, MD is a member of the following medical societies: American College of Physicians-American Society of Internal Medicine, American Gastroenterological Association, American Medical Association, and Massachusetts Medical Society

Disclosure: Nothing to disclose.

Carmen Cuffari, MD Associate Professor, Department of Pediatrics, Division of Gastroenterology/Nutrition, Johns Hopkins University School of Medicine

Carmen Cuffari, MD is a member of the following medical societies: American College of Gastroenterology, American Gastroenterological Association, North American Society for Pediatric Gastroenterology, Hepatology and Nutrition, and Royal College of Physicians and Surgeons of Canada

Disclosure: Nothing to disclose.

Gautam Dehadrai, MD Department Chair, Section Chief, Department of Interventional Radiology, Norman Regional Hospital

Gautam Dehadrai, MD is a member of the following medical societies: American College of Radiology, Medical Council of India, and Radiological Society of North America

Disclosure: Nothing to disclose.

Jayant Deodhar, MD Associate Professor in Pediatrics, BJ Medical College, India; Honorary Consultant, Departments of Pediatrics and Neonatology, King Edward Memorial Hospital, India

Disclosure: Nothing to disclose.

Shirley Donelson, MD Program Director, Assistant Professor, Department of Internal Medicine, Division of Digestive Diseases, University of Mississippi Medical School

Shirley Donelson, MD is a member of the following medical societies: American College of Gastroenterology, American College of Physicians, American Gastroenterological Association, American Medical Association, and Mississippi State Medical Association

Disclosure: Nothing to disclose.

Sandeep Mukherjee, MB, BCh, MPH, FRCPC Associate Professor, Department of Internal Medicine, Section of Gastroenterology and Hepatology, University of Nebraska Medical Center; Consulting Staff, Section of Gastroenterology and Hepatology, Veteran Affairs Medical Center

Disclosure: Merck Honoraria Speaking and teaching; Ikaria Pharmaceuticals Honoraria Board membership

Dena Nazer, MD Medical Director, Child Protection Center, Children's Hospital of Michigan; Assistant Professor, Wayne State University

Dena Nazer, MD is a member of the following medical societies: Ambulatory Pediatric Association, American Academy of Pediatrics, American Professional Society on the Abuse of Children, and Helfer Society

Disclosure: Nothing to disclose.

Mohamed Othman, MD Resident Physician, Department of Internal Medicine, University of New Mexico School of Medicine

Disclosure: Nothing to disclose.

Nuri Ozden, MD Assistant Professor, Department of Internal Medicine, Meharry Medical College

Nuri Ozden, MD is a member of the following medical societies: American College of Gastroenterology, American College of Physicians, American Gastroenterological Association, and American Society for Gastrointestinal Endoscopy

Disclosure: Nothing to disclose.

Tushar Patel, MB, ChB Professor of Medicine, Ohio State University Medical Center

Tushar Patel, MB, ChB is a member of the following medical societies: American Association for the Study of Liver Diseases and American Gastroenterological Association

Disclosure: Nothing to disclose.

David A Piccoli, MD Chief of Pediatric Gastroenterology, Hepatology and Nutrition, The Children's Hospital of Philadelphia; Professor, University of Pennsylvania School of Medicine

David A Piccoli, MD is a member of the following medical societies: American Association for the Study of Liver Diseases, American Gastroenterological Association, and North American Society for Pediatric Gastroenterology and Nutrition

Disclosure: Nothing to disclose.

Alessio Pigazzi, MD PhD, Head, Minimally Invasive Surgery Program, Division of Surgery, Department of General Oncologic Surgery, City of Hope National Medical Center

Disclosure: Nothing to disclose.

Praveen K Roy, MD, AGAF Gastroenterologist, Ochsner Clinic Foundation; Adjunct Associate Research Scientist, Lovelace Respiratory Research Institute; Editor-in-Chief, The Internet Journal of Gasteroenterology; Editorial Board, Signal Transduction Insights; Editorial Board, The Internet Journal of Epidemiology; Editorial Board, Gastrointestinal Endoscopy Review Letter

Praveen K Roy, MD, AGAF is a member of the following medical societies: American College of Gastroenterology, American Gastroenterological Association, and American Society of Gastrointestinal Endoscopy

Disclosure: Nothing to disclose.

Jeanette G Smith, MD Fellow, Department of Gastroenterology-Hepatology, University of Connecticut School of Medicine

Jeanette G Smith, MD is a member of the following medical societies: American College of Physicians, American Gastroenterological Association, and American Public Health 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

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

George Y Wu, MD, PhD Professor, Department of Medicine, Director, Hepatology Section, Herman Lopata Chair in Hepatitis Research, University of Connecticut School of Medicine

George Y Wu, MD, PhD is a member of the following medical societies: American Association for the Study of Liver Diseases, American Gastroenterological Association, American Medical Association, American Society for Clinical Investigation, and Association of American Physicians

Disclosure: Springer Consulting fee Consulting; Gilead Consulting fee Review panel membership; Vertex Honoraria Speaking and teaching; Bristol-Myers Squibb Honoraria Speaking and teaching; Springer Royalty Review panel membership; Merck Honoraria Speaking and teaching

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Production of bilirubin.
Enterohepatic circulation of bilirubin.
Conjugation of bilirubin.
 
 
 
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