Close
New

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

 

Dubin-Johnson Syndrome

  • Author: Simon S Rabinowitz, MD, PhD, FAAP; Chief Editor: BS Anand, MD  more...
 
Updated: Jun 24, 2015
 

Practice Essentials

Dubin-Johnson syndrome is an inherited, relapsing, benign disorder of bilirubin metabolism. This rare autosomal recessive condition is characterized by conjugated hyperbilirubinemia with normal liver transaminases, a unique pattern of urinary excretion of heme metabolites (coproporphyrins), and the deposition of a pigment that gives the liver a characteristic black color (see the image below).

Gross liver specimen from a patient with Dubin-Joh Gross liver specimen from a patient with Dubin-Johnson syndrome showing multiple areas of dark pigmentation. Image courtesy of Cirilo Sotelo-Avila, MD.

Signs and symptoms

Patients with Dubin-Johnson syndrome tend to develop nonpruritic jaundice during their teenaged years.

Some patients complain of nonspecific right upper quadrant pain, which has been attributed to the anxiety associated with prolonged diagnostic testing. Hepatosplenomegaly also occurs in some patients, but in most cases, Dubin-Johnson syndrome is asymptomatic.

See Clinical Presentation for more detail.

Diagnosis

Laboratory studies reveal conjugated hyperbilirubinemia, with total bilirubin serum levels usually in the 2- to 5-mg/dL range (but potentially as high as 25 mg/dL).

In patients with elevated conjugated bilirubin levels but otherwise normal liver function findings, the diagnosis of Dubin-Johnson syndrome can be confirmed by demonstrating an increase in the ratio of urinary coproporphyrin I to coproporphyrin III; type I makes up 80%, rather than the usual 25%, of the urinary coproporphyrin content in these patients.

Patients with Dubin-Johnson syndrome tend to have unique findings on hepatobiliary scintigraphy scans, demonstrating a combination of intense and prolonged visualization of the liver and delayed or failed visualization of the gallbladder.

See Workup for more detail.

Management

Dubin-Johnson syndrome is a benign disorder that requires no specific therapy, although patients should be warned that pregnancy, oral contraceptive use, and intercurrent illness can exacerbate the associated jaundice.

In the past, patients were treated with phenobarbital, which was used primarily to reduce serum bilirubin levels. This treatment is no longer recommended.

Rifampicin and ursodeoxycholic acid (UDCA) therapy have beneficial effects in chronic cholestatic diseases. These may result, in part, from the induction of MRP2 expression in the liver and kidney.

However, neither an indication nor a general role for these 2 agents has been defined in Dubin-Johnson syndrome. Rifampicin and UDCA should, in fact, be used with caution in patients with the disease, since they may actually increase conjugated bilirubinemia and bile acid levels in such cases.[1]

See Treatment and Medication for more detail.

Next

Background

First described in 1954,[2] Dubin-Johnson syndrome is an inherited, relapsing, benign disorder of bilirubin metabolism. This rare autosomal recessive condition is characterized by conjugated hyperbilirubinemia with normal liver transaminases, a unique pattern of urinary excretion of heme metabolites (coproporphyrins), and the deposition of a pigment that gives the liver a characteristic black color (see the image below). (See Clinical Presentation and Workup.)

Gross liver specimen from a patient with Dubin-Joh Gross liver specimen from a patient with Dubin-Johnson syndrome showing multiple areas of dark pigmentation. Image courtesy of Cirilo Sotelo-Avila, MD.

The primary defect in Dubin-Johnson syndrome is a mutation in an apical canalicular membrane protein responsible for the excretion of bilirubin and other nonbile salt organic anions. The protein was originally termed the canalicular multiple organic anion transporter (cMOAT) but is also known as multidrug resistance protein 2 (MRP2); it is a member of the ABC transporter superfamily. (See Pathophysiology and Etiology.)[3, 4, 5]

Clinical onset of Dubin-Johnson syndrome is most often seen in early adulthood; however, a neonatal onset has also been rarely described. Because of possible recurrence and second attacks of jaundice in later life, the neonatal form requires closer long-term follow-up. (See Epidemiology.)[6]

Hereditary hyperbilirubinemias can be divided into conjugated and unconjugated forms. Examples are as follows[7] :

The conjugated and unconjugated hyperbilirubinemias are also classified as being, respectively, directly reacting and indirectly reacting. Directly reacting bilirubin reacts quickly with diazotized sulfanilic acid, forming a colored azodipyrrole, while indirectly reacting bilirubin reacts very slowly with the acid unless an accelerator, such as ethanol, is present.

Both inherited conjugated hyperbilirubinemias have a relatively benign course. However, diagnosing these conditions allows the physician to exclude more serious causes of hyperbilirubinemia and, thus, avoid unnecessary investigations and procedures. (See Clinical Presentation, Workup, Treatment, and Medication.)

Patient education

Once diagnosed with Dubin-Johnson syndrome, patients should be informed of the disease process and its benign nature, and they should understand that no further investigative workup is required in the future.

For patient education information, see the Digestive Disorders Center and the Children's Health Center, as well as Jaundice and Newborn Jaundice.

Previous
Next

Pathophysiology and Etiology

Dubin-Johnson syndrome is an autosomal recessive disorder that is caused by a mutation in the gene responsible for the human canalicular multispecific organic anion transporter (cMOAT) protein, also called the multidrug resistance protein 2 (MRP2) or ABCC2.[3, 4, 8, 9] This protein mediates adenosine triphosphate (ATP)-dependent transport of certain organic anions across the canalicular membrane of the hepatocyte.

The cMOAT/MRP2/ABCC2 protein is encoded by a single-copy gene, MRP2/cMOAT/ABCC2, on chromosome 10q24.[10]

The conjugated hyperbilirubinemia observed in Dubin-Johnson syndrome results from defective transport of bilirubin glucuronide across the membrane that separates the hepatocyte from the bile canaliculi. Pigment that is not secreted from the hepatocyte is stored in the lysosome and causes the black liver color.

A hallmark of Dubin-Johnson syndrome, the mechanism of which is not fully understood, is a reversal of the usual ratio between the byproducts of heme biosynthesis: urinary coproporphyrin I levels are higher than coproporphyrin III levels. In unaffected individuals, the ratio of coproporphyrin III to coproporphyrin I is approximately 3-4:1.[11]

MRP2

MRP2 plays an important role in the detoxification of many drugs by transporting a wide range of compounds, especially conjugates of glutathione, glucuronate, and sulfate, which are collectively known as phase II products of biotransformation. Unlike other members of the MRP/ABCC family, MRP2 is expressed only on the apical membrane domain of polarized cells. Besides hepatocytes, MRP2 is located in renal proximal tubular cells, enterocytes, and syncytiotrophoblasts of the placenta.[12]

Energy derived from ATP is critical for the secretory function of MRP2. Mutations in the ATP-binding region of MRP2 represent a significant proportion of the recognized genetic defects in Dubin-Johnson syndrome.[13, 14]

Mutations

A common missense mutation, Delta (R,M), leads to the loss of 2 amino acids from the second ATP-binding domain of MRP2. Delta (R,M) is associated with the absence of the MRP2 glycoprotein from the apical membrane of the hepatocytes. In this mutation, only core glycosylation of the protein occurs, which interferes with transport from the endoplasmic reticulum to the canalicular membrane of the hepatocyte. The mutated protein is sensitive to endoglycosidase H digestion in the endoplasmic reticulum. Proteasomes are also involved in the degradation of the mutated protein.[15, 16]

A report from China described mutations in 2 patients with neonatal-onset Dubin-Johnson syndrome who also had no immunohistochemical staining for MRP2. These children, along with 2 patients with adolescent-onset Dubin-Johnson syndrome, had a total of 6 novel mutations, including deletions and missense and nonsense mutations, all of which involved 1 of the 2 ATP-binding cassettes (ABC) of the MRP2 protein.[17]

Previous
Next

Epidemiology

Occurrence in the United States

The overall prevalence of Dubin-Johnson syndrome is extremely low. However, although no accurate prevalence figures are available, it is known to be far more common than Rotor syndrome.

Race-related demographics

Dubin-Johnson syndrome has been described in all nationalities, ethnic backgrounds, and races. The highest recognized prevalence of the disease (1 case per 1300 population) is in Iranian Jews and is clustered in the same families.[18] This group may have an associated deficiency in clotting factor VII that is not observed in other populations.[19] The prevalence in Moroccan Jews is nearly as high, a reflection of the fact that these populations diverged about 2000-2500 years ago.[19]

Sex- and age-related demographics

Dubin-Johnson syndrome occurs in both sexes, but some authors have reported increased incidence and earlier onset in males.[18]

Dubin-Johnson syndrome is rarely detected before puberty, although neonatal cases have been reported. It is most often diagnosed in the late teens and early adulthood.

Previous
Next

Prognosis

Dubin-Johnson syndrome is a benign condition, and life expectancy among patients is normal. An interesting case report describes an infant who received a living related liver transplant donor graft from his mother, who had Dubin-Johnson syndrome. One year after transplantation there were no unexpected issues with the donor or the child who had "inherited" Dubin-Johnson syndrome from his mother.[20]

Previous
Next

Complications

Complications of Dubin-Johnson syndrome include jaundice (the most consistent finding) and hepatomegaly. Oral contraceptives, pregnancy, and intercurrent illness may exacerbate jaundice. Reduced prothrombin activity, resulting from lower levels of clotting factor VII, is found in 60% of patients.

Some neonates present with cholestasis, which may be severe. Increased fetal wastage was reported in one study. In a case report, cholecystolithiasis and choledocholithiasis developed in the presence of Dubin-Johnson syndrome.[21]

Previous
 
 
Contributor Information and Disclosures
Author

Simon S Rabinowitz, MD, PhD, FAAP Professor of Clinical Pediatrics, Vice Chairman, Clinical Practice Development, Pediatric Gastroenterology, Hepatology, and Nutrition, State University of New York Downstate College of Medicine, The Children's Hospital at Downstate

Simon S Rabinowitz, MD, PhD, FAAP is a member of the following medical societies: American Gastroenterological Association, American Academy of Pediatrics, Phi Beta Kappa, American Association for the Advancement of Science, American College of Gastroenterology, American Medical Association, New York Academy of Sciences, North American Society for Pediatric Gastroenterology, Hepatology and Nutrition, Sigma Xi

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

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.

Miriam K Anand, MD, FAAAAI, FACAAI Consulting Staff, Department of Allergy/Immunology, Allergy Associates and Lab, Ltd; Clinical Assistant Professor, Midwestern School of Osteopathic Medicine

Miriam K Anand, MD, FAAAAI, FACAAI is a member of the following medical societies: American Academy of Allergy Asthma and Immunology, American College of Allergy, Asthma and Immunology, American College of Physicians-American Society of Internal Medicine, and American Medical Association

Disclosure: TEVA pharmaceuticals Honoraria Speaking and teaching

Suzanne M Carter, MS Senior Genetic Counselor, Associate, Department of Obstetrics and Gynecology, Division of Reproductive Genetics, Montefiore Medical Center, Albert Einstein College of Medicine

Suzanne M Carter, MS is a member of the following medical societies: American Bar Association

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: Prometheus Laboratories Honoraria Speaking and teaching; Abbott Nutritionals Honoraria Speaking and teaching

Hamza Elkhidir, MBBS Resident Physician, Department of Pediatrics, Richmond University Medical Center

Disclosure: Nothing to disclose.

Susan J Gross, MD, FRCS(C), FACOG, FACMG Codirector, Division of Reproduction Genetics, Associate Professor, Department of Obstetrics and Gynecology, Albert Einstein College of Medicine

Susan J Gross, MD, FRCS(C), FACOG, FACMG is a member of the following medical societies: American College of Medical Genetics, American College of Obstetricians and Gynecologists, American Institute of Ultrasound in Medicine, American Medical Association, American Society of Human Genetics, and Royal College of Physicians and Surgeons of Canada

Disclosure: Nothing to disclose.

Samir L Habashi, MD Assistant Professor of Medicine, Department of Medicine, Division of Gastroenterology, University of Florida at Jacksonville

Samir L Habashi, MD is a member of the following medical societies: American College of Gastroenterology, American College of Physicians-American Society of Internal Medicine, American Gastroenterological Association, and American Society for Gastrointestinal Endoscopy

Disclosure: Nothing to disclose.

Louis R Lambiase, MD, MHA Professor of Medicine, University of Tennessee College of Medicine Chattanooga; Chief, Division of Gastroenterology, University of Tennessee Chattanooga Unit; Assistant Dean for Clinical Affairs, University of Tennessee College of Medicine Chattanooga

Louis R Lambiase, MD, MHA is a member of the following medical societies: American Gastroenterological Association, American Pancreatic Association, and American Society for Gastrointestinal Endoscopy

Disclosure: Nothing to disclose.

Kenneth J Mishark, MD Consultant, Division of Hospital Internal Medicine, Department of Internal Medicine, Mayo Clinic, Assistant Professor of Medicine, College of Medicine, Mayo Clinic

Kenneth J Mishark, MD is a member of the following medical societies: American College of Physicians

Disclosure: Nothing to disclose.

Hisham Nazer, MB, BCH, FRCP, FRCPCH, DCH, DTM&H Professor of Pediatrics, Consultant in Pediatric Gastroenterology, Hepatology and Clinical Nutrition, Bushnaq Medical Centre, Amman, Jordan

Hisham Nazer, MB, BCH, FRCP, FRCPCH, DCH, DTM&H is a member of the following medical societies: American College of Physician Executives, Royal College of Paediatrics and Child Health, Royal College of Physicians and Surgeons of the United Kingdom, Royal College of Surgeons of Ireland, and Royal Society of Tropical Medicine and Hygiene

Disclosure: Nothing to disclose.

Cuong Nguyen, MD Instructor, Department of Internal Medicine, Section of Gastroenterology, Mayo Clinic Scottsdale

Disclosure: Nothing to disclose.

Kanika Puri, MD Resident Physician, Department of Pediatrics, State University of New York Downstate Medical Center, Brooklyn

Disclosure: Nothing to disclose.

Waqar A Qureshi, MD Associate Professor of Medicine, Chief of Endoscopy, Department of Internal Medicine, Division of Gastroenterology, Baylor College of Medicine and Veterans Affairs Medical Center

Waqar A Qureshi, 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.

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.

References
  1. Regev RH, Stolar O, Raz A, Dolfin T. Treatment of severe cholestasis in neonatal Dubin-Johnson syndrome with ursodeoxycholic acid. J Perinat Med. 2002. 30(2):185-7. [Medline].

  2. Dubin IN, Johnson FB. Chronic idiopathic jaundice with unidentified pigment in liver cells; a new clinicopathologic entity with a report of 12 cases. Medicine (Baltimore). 1954 Sep. 33(3):155-97. [Medline].

  3. Paulusma CC, Kool M, Bosma PJ, et al. A mutation in the human canalicular multispecific organic anion transporter gene causes the Dubin-Johnson syndrome. Hepatology. 1997 Jun. 25(6):1539-42. [Medline].

  4. Toh S, Wada M, Uchiumi T, et al. Genomic structure of the canalicular multispecific organic anion-transporter gene (MRP2/cMOAT) and mutations in the ATP-binding-cassette region in Dubin-Johnson syndrome. Am J Hum Genet. 1999 Mar. 64(3):739-46. [Medline]. [Full Text].

  5. Kruh GD, Zeng H, Rea PA, et al. MRP subfamily transporters and resistance to anticancer agents. J Bioenerg Biomembr. 2001 Dec. 33(6):493-501. [Medline].

  6. Kimura A, Ushijima K, Kage M, et al. Neonatal Dubin-Johnson syndrome with severe cholestasis: effective phenobarbital therapy. Acta Paediatr Scand. 1991 Mar. 80(3):381-5. [Medline].

  7. Strassburg CP. Hyperbilirubinemia syndromes (Gilbert-Meulengracht, Crigler-Najjar, Dubin-Johnson, and Rotor syndrome). Best Pract Res Clin Gastroenterol. 2010 Oct. 24(5):555-71. [Medline].

  8. Benz-de Bretagne I, Respaud R, Vourc'h P, et al. Urinary elimination of coproporphyrins is dependent on ABCC2 polymorphisms and represents a potential biomarker of MRP2 activity in humans. J Biomed Biotechnol. 2011. 2011:498757. [Medline]. [Full Text].

  9. Nisa AU, Ahmad Z. Dubin-Johnson syndrome. J Coll Physicians Surg Pak. 2008 Mar. 18(3):188-9. [Medline].

  10. van Kuijck MA, Kool M, Merkx GF, et al. Assignment of the canalicular multispecific organic anion transporter gene (CMOAT) to human chromosome 10q24 and mouse chromosome 19D2 by fluorescent in situ hybridization. Cytogenet Cell Genet. 1997. 77(3-4):285-7. [Medline].

  11. Frank M, Doss M, de Carvalho DG. Diagnostic and pathogenetic implications of urinary coproporphyrin excretion in the Dubin-Johnson syndrome. Hepatogastroenterology. 1990 Feb. 37(1):147-51. [Medline].

  12. Jedlitschky G, Hoffmann U, Kroemer HK. Structure and function of the MRP2 (ABCC2) protein and its role in drug disposition. Expert Opin Drug Metab Toxicol. 2006 Jun. 2(3):351-66. [Medline].

  13. Hashimoto K, Uchiumi T, Konno T, et al. Trafficking and functional defects by mutations of the ATP-binding domains in MRP2 in patients with Dubin-Johnson syndrome. Hepatology. 2002 Nov. 36(5):1236-45. [Medline].

  14. Tate G, Li M, Suzuki T, Mitsuya T. A new mutation of the ATP-binding cassette, sub-family C, member 2 (ABCC2) gene in a Japanese patient with Dubin-Johnson syndrome. Genes Genet Syst. 2002 Apr. 77(2):117-21. [Medline].

  15. Keitel V, Kartenbeck J, Nies AT, Spring H, Brom M, Keppler D. Impaired protein maturation of the conjugate export pump multidrug resistance protein 2 as a consequence of a deletion mutation in Dubin-Johnson syndrome. Hepatology. 2000 Dec. 32(6):1317-28. [Medline].

  16. Uchiumi T, Tanamachi H, Kuchiwaki K, et al. Mutation and functional analysis of ABCC2/multidrug resistance protein 2 in a Japanese patient with Dubin-Johnson syndrome. Hepatol Res. 2013 May. 43(5):569-75. [Medline].

  17. Lee JH, Chen HL, Chen HL, Ni YH, Hsu HY, Chang MH. Neonatal Dubin-Johnson syndrome: long-term follow-up and MRP2 mutations study. Pediatr Res. 2006 Apr. 59(4 Pt 1):584-9. [Medline].

  18. Zlotogora J. Hereditary disorders among Iranian Jews. Am J Med Genet. 1995 Jul 31. 58(1):32-7. [Medline].

  19. Mor-Cohen R, Zivelin A, Fromovich-Amit Y, Kovalski V, Rosenberg N, Seligsohn U. Age estimates of ancestral mutations causing factor VII deficiency and Dubin-Johnson syndrome in Iranian and Moroccan Jews are consistent with ancient Jewish migrations. Blood Coagul Fibrinolysis. 2007 Mar. 18(2):139-44. [Medline].

  20. Liu C, Niu DM, Hsia CY, et al. Living donor liver transplantation using a graft from a donor with Dubin-Johnson syndrome. Pediatr Transplant. 2012 Feb. 16(1):E25-9. [Medline].

  21. Zhou L, Liu C, Bai J, Dong S, Wei J. Dubin-Johnson syndrome with cholecystolithiasis and choledocholithiasis. Int J Surg Case Rep. 2013. 4(7):587-8. [Medline]. [Full Text].

  22. Korkmaz U, Duman AE, Ogutmen Koc D, et al. Severe jaundice due to coexistence of Dubin-Johnson syndrome and hereditary spherocytosis: a case report. Turk J Gastroenterol. 2011 Aug. 22(4):422-5. [Medline].

  23. Fretzayas A, Kitsiou S, Papadopoulou A, Nicolaidou P. Clinical expression of co-inherited Dubin-Johnson and thalassaemic heterozygous states. Dig Liver Dis. 2007 Apr. 39(4):369-74. [Medline].

  24. Mayatepek E, Lehmann WD. Defective hepatobiliary leukotriene elimination in patients with the Dubin-Johnson syndrome. Clin Chim Acta. 1996 May 30. 249(1-2):37-46. [Medline].

  25. Respaud R, Benz-de Bretagne I, Blasco H, Hulot JS, Lechat P, Le Guellec C. Quantification of coproporphyrin isomers I and III in urine by HPLC and determination of their ratio for investigations of multidrug resistance protein 2 (MRP2) function in humans. J Chromatogr B Analyt Technol Biomed Life Sci. 2009 Nov 15. 877(30):3893-8. [Medline].

  26. Rocchi E, Balli F, Gibertini P, et al. Coproporphyrin excretion in healthy newborn babies. J Pediatr Gastroenterol Nutr. 1984 Jun. 3(3):402-7. [Medline].

  27. Shimizu T, Tawa T, Maruyama T, Oguchi S, Yamashiro Y, Yabuta K. A case of infantile Dubin-Johnson syndrome with high CT attenuation in the liver. Pediatr Radiol. 1997 Apr. 27(4):345-7. [Medline].

  28. Sobaniec-Lotowska ME, Lebensztejn DM. Ultrastructure of Kupffer cells and hepatocytes in the Dubin-Johnson syndrome: a case report. World J Gastroenterol. 2006 Feb 14. 12(6):987-9. [Medline].

  29. Corpechot C, Ping C, Wendum D, Matsuda F, Barbu V, Poupon R. Identification of a novel 974C-->G nonsense mutation of the MRP2/ABCC2 gene in a patient with Dubin-Johnson syndrome and analysis of the effects of rifampicin and ursodeoxycholic acid on serum bilirubin and bile acids. Am J Gastroenterol. 2006 Oct. 101(10):2427-32. [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.
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 (CBD) (arrow). A diagnosis of acalculous cholecystitis was confirmed. A = aorta; IVC = inferior vena cava; S = splenic vein.
 
 
 
All material on this website is protected by copyright, Copyright © 1994-2016 by WebMD LLC. This website also contains material copyrighted by 3rd parties.