eMedicine Specialties > Pediatrics: General Medicine > Gastroenterology

Cholestasis: Differential Diagnoses & Workup

Author: Karan M Emerick, MD, Consulting Staff, Department of Pediatrics, Division of Gastroenterology, Hepatology and Nutrition, Connecticut Children's Medical Center
Contributor Information and Disclosures

Updated: Jun 23, 2009

Differential Diagnoses

Other Problems to Be Considered

Jaundice not due to cholestasis
Nonconjugated hyperbilirubinemia
Dubin-Johnson syndrome
Rotor syndrome
Carotinemia
Dark urine not due to bilirubinuria
Hematuria
Drug ingestion
Dehydration
Pruritus not due to cholestasis
Atopic disease
Drug ingestion
Behavior disorder
Xanthomatosis not due to cholestasis
Familial hypercholesterolemia
Cerebrotendinous xanthomatosis
Malabsorption not due to cholestasis
Pancreatic insufficiency
Intestinal mucosal diseases
Small bowel bacterial overgrowth
Bile acid malabsorption
Ileal resection

Workup

Laboratory Studies

  • Serum bilirubin levels are elevated in virtually all patients with cholestasis.
  • Serum direct or conjugated bilirubin levels are elevated in virtually all cholestatic diseases and not in other diseases causing hyperbilirubinemia.
  • Total serum bile salt concentration levels are elevated in virtually all cholestatic diseases.
  • Qualitative serum and urine bile acids by mass spectroscopy are used to identify genetically determined errors in bile acid synthesis.
  • The total serum cholesterol level is elevated in virtually all obstructive cholestatic diseases, whereas the high-density lipoprotein (HDL) level is within the reference range or low. Total cholesterol is within the reference range in certain hepatocellular cholestatic diseases, whereas the HDL level is within the reference range or low.
  • Serum lipoprotein-X levels are elevated in virtually all obstructive cholestatic diseases.
  • Serum alkaline phosphatase levels are elevated in virtually all obstructive cholestatic diseases and most hepatocellular cholestatic diseases.
  • Serum 5'-nucleotidase levels are elevated in virtually all obstructive cholestatic diseases and most hepatocellular cholestatic diseases.
  • Serum gamma-glutamyl transferase (GGT) levels are elevated in virtually all obstructive cholestatic diseases and many hepatocellular cholestatic diseases. A small number of hepatocellular cholestatic diseases occur in which the GGT level is within the reference range or low (eg, progressive familial intrahepatic cholestasis, inborn errors of bile acid synthesis).
  • Fecal fat levels are elevated in virtually all cholestatic diseases.

Imaging Studies

  • Ultrasonography of liver and bile ducts is used to identify anatomic causes of obstructive cholestasis (eg, choledochal cyst, gallstones).
  • Abdominal CT scanning is used to identify anatomic causes of obstructive cholestasis (eg, choledochal cyst, gallstones).
  • Biliary nuclear medicine study (ie, hepatoiminodiacetic acid [HIDA] scanning) is used to identify anatomic causes of obstructive cholestasis (eg, choledochal cyst, gallstones) and to differentiate between obstructive and hepatocellular cholestasis (ie, biliary atresia versus neonatal hepatitis).
  • Endoscopic retrograde cholangiography is used to identify anatomic causes of obstructive cholestasis (eg, choledochal cyst, gallstones).
  • Percutaneous transhepatic cholangiography is used to identify anatomic causes of obstructive cholestasis (eg, choledochal cyst, gallstones).

Procedures

  • Liver biopsy is the single most useful test to determine the cause of cholestasis but requires a high degree of expertise in interpretation.
  • Exploratory surgery is a very useful tool for diagnosing neonatal cholestasis. Older literature suggested that exploratory surgery placed patients with neonatal hepatitis at risk, but this is not the case with modern anesthesia and surgical techniques.
    • If surgical disease is in question, initiate exploratory surgery to provide a definitive demonstration of bile duct anatomy.
    • In institutions with less experience and expertise, perform exploratory surgery more frequently, rather than less so.
  • Operative cholangiography is simple, straightforward, time-efficient, and definitive.

Histologic Findings

  • Many histologic findings are disease specific; therefore, refer to articles about disease states (see Causes). The typical histopathologic features of hepatocellular cholestasis include the presence of bile within hepatocytes and canalicular spaces, in association with generalized cholate injury. Typical of obstructive cholestasis is bile plugging of the interlobular bile ducts, portal expansion, and bile duct proliferation in association with centrilobular cholate injury.
  • Differentiating between idiopathic neonatal hepatitis and biliary atresia is a diagnostic challenge. With expert evaluation, nothing contributes as much to that differential diagnosis as the findings on percutaneous liver biopsy.
  • The landmark 1974 paper of Brough and Bernstein demonstrated the diagnostic usefulness of the percutaneous liver biopsy.6 In this study of 158 patients, the authors compared the original pathologic diagnosis to the ultimate diagnosis that included surgical findings and long-term follow-up. The original diagnosis was an error in 10 patients (6.3%), which makes biopsy an excellent diagnostic procedure. The type of error observed in these 10 patients was more important. In 9 of 10 misdiagnoses, the pathologic diagnosis was obstructive disease when the patient actually had neonatal hepatitis or alpha1-antitrypsin deficiency. This error led to exploratory surgery to confirm the diagnosis, which was of little harm to the patient. In only 1 patient with biliary atresia was the pathologic diagnosis that of hepatitis, which led to delay in the diagnosis of this surgical obstructive disease. Thus, in only 1 of 158 patients (0.6%) did a diagnostic error lead to meaningful clinical consequences.
  • Liver biopsy, therefore, has a very high sensitivity and specificity for the diagnosis of biliary atresia, with somewhat less specificity for the diagnosis of neonatal hepatitis.

More on Cholestasis

Overview: Cholestasis
Differential Diagnoses & Workup: Cholestasis
Treatment & Medication: Cholestasis
Follow-up: Cholestasis
Multimedia: Cholestasis
References
Further Reading
[ CLOSE WINDOW ]

References

  1. Poddar U, Thapa BR, Das A, Bhattacharya A, Rao KN, Singh K. Neonatal cholestasis: differentiation of biliary atresia from neonatal hepatitis in a developing country. Acta Paediatr. May 13 2009;[Medline].

  2. Strople J, Lovell G, Heubi J. Prevalence of Subclinical Vitamin K Deficiency in Cholestatic Liver Disease. J Pediatr Gastroenterol Nutr. Jun 3 2009;[Medline].

  3. Hutchin T, Preece MA, Hendriksz C, et al. Neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD) as a cause of liver disease in infants in the UK. J Inherit Metab Dis. Jun 11 2009;[Medline].

  4. Mathias A, Wax JR, Pinette MG, Cartin A, Blackstone J. Progressive familial intrahepatic cholestasis complicating pregnancy. J Matern Fetal Neonatal Med. Jun 1 2009;1-3. [Medline].

  5. Shneider BL. Liver transplantation for progressive familial intrahepatic cholestasis: the evolving role of genotyping. Liver Transpl. Jun 2009;15(6):565-6. [Medline].

  6. Brough AJ, Bernstein J. Conjugated hyperbilirubinemia in early infancy. A reassessment of liver biopsy. Hum Pathol. Sep 1974;5(5):507-16. [Medline].

  7. [Guideline] Moyer V, Freese DK, Whitington PF, et al. Guideline for the evaluation of cholestatic jaundice in infants: recommendations of the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition. J Pediatr Gastroenterol Nutr. Aug 2004;39(2):115-28. [Medline]. [Full Text].

  8. [Guideline] Murray KF, Carithers RL Jr. AASLD practice guidelines: Evaluation of the patient for liver transplantation. Hepatology. Jun 2005;41(6):1407-32. [Medline]. [Full Text].

  9. Balistreri WF. Neonatal cholestasis. J Pediatr. Feb 1985;106(2):171-84. [Medline].

  10. Elferink RP, Groen AK. The mechanism of biliary lipid secretion and its defects. Gastroenterol Clin North Am. Mar 1999;28(1):59-74, vi. [Medline].

  11. Jones EA, Bergasa NV. The pruritus of cholestasis and the opioid system. JAMA. Dec 16 1992;268(23):3359-62. [Medline].

  12. Kaufman SS, Murray ND, Wood RP. Nutritional support for the infant with extrahepatic biliary atresia. J Pediatr. May 1987;110(5):679-86. [Medline].

  13. Oude Elferink RP, Paulusma CC, Groen AK. Hepatocanalicular transport defects: pathophysiologic mechanisms of rare diseases. Gastroenterology. Mar 2006;130(3):908-25. [Medline].

  14. Sabesin SM. Cholestatic lipoproteins--their pathogenesis and significance. Gastroenterology. Sep 1982;83(3):704-9. [Medline].

  15. Suchy FJ. Approach to the infant with cholestasis. In: Liver Disease in Children. 1st ed. St. Louis, Mo:. Mosby;1994:349-355.

  16. Trauner M, Meier PJ, Boyer JL. Molecular pathogenesis of cholestasis. N Engl J Med. Oct 22 1998;339(17):1217-27. [Medline].

  17. Whitington PF. Chronic cholestasis of infancy. Pediatr Clin North Am. Feb 1996;43(1):1-26. [Medline].

  18. Whitington PF, Whitington GL. Partial external diversion of bile for the treatment of intractable pruritus associated with intrahepatic cholestasis. Gastroenterology. Jul 1988;95(1):130-6. [Medline].

[ CLOSE WINDOW ]

Keywords

cholestasis, reduced bile formation, reduced bile flow, bile duct obstruction, cholestatic disorders, Dubin-Johnson syndrome, Rotor syndrome, Alagille syndrome, hyperchloremia, gram-negative sepsis, heart failure, metabolic disease, pruritus, itching, scratching, hyperlipidemia, xanthomas, xanthoma, failure to thrive, cholestatic liver disease, vitamin E deficiency, vitamin D deficiency, osteomalacia, rickets, biliary atresia, steatorrhea, scleral icterus, cutaneous jaundice, choledochal cyst, choledochal cyst, cholelithiasis, primary sclerosing cholangitis, hepatitis A, hepatitis B, hepatitis C, progressive familial intrahepatic cholestasis, treatment, diagnosis

[ CLOSE WINDOW ]

Contributor Information and Disclosures

Author

Karan M Emerick, MD, Consulting Staff, Department of Pediatrics, Division of Gastroenterology, Hepatology and Nutrition, Connecticut Children's Medical Center
Karan M Emerick, MD is a member of the following medical societies: American Academy of Pediatrics, American Association for the Study of Liver Diseases, American Gastroenterological Association, and North American Society for Pediatric Gastroenterology and Nutrition
Disclosure: Nothing to disclose.

Medical Editor

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.

Pharmacy Editor

Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine
Disclosure: Pfizer Inc Stock Investment from financial planner; Avanir Pharma Stock Investment from financial planner ; WebMD Salary and stock Employment and investment from financial planner

CME Editor

Paul D Petry, DO, FACOP, FAAP, Consulting Staff, Freeman Pediatric Care, Freeman Health System
Paul D Petry, DO, FACOP, FAAP is a member of the following medical societies: American Academy of Osteopathy, American Academy of Pediatrics, American College of Osteopathic Pediatricians, and American Osteopathic Association
Disclosure: Nothing to disclose.

Chief Editor

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.

 
 
HONcode

We subscribe to the
HONcode principles of the
Health On the Net Foundation

All material on this website is protected by copyright, Copyright© 1994- by Medscape.
This website also contains material copyrighted by 3rd parties.

DISCLAIMER: The content of this Website is not influenced by sponsors. The site is designed primarily for use by qualified physicians and other medical professionals. The information contained herein should NOT be used as a substitute for the advice of an appropriately qualified and licensed physician or other health care provider. The information provided here is for educational and informational purposes only. In no way should it be considered as offering medical advice. Please check with a physician if you suspect you are ill.