Dubin–Johnson syndrome is a rare,

autosomal recessive In genetics, dominance is the phenomenon of one variant (allele) of a gene on a chromosome masking or overriding the effect of a different variant of the same gene on the other copy of the chromosome. The first variant is termed dominant and t ...

, benign disorder that causes an isolated increase of conjugated

bilirubin Bilirubin (BR) (Latin for "red bile") is a red-orange compound that occurs in the normal catabolic pathway that breaks down heme in vertebrates. This catabolism is a necessary process in the body's clearance of waste products that arise from the ...

in the serum. Classically, the condition causes a black liver due to the deposition of a pigment similar to melanin. This condition is associated with a defect in the ability of hepatocytes to secrete conjugated bilirubin into the bile, and is similar to

Rotor syndrome Rotor syndrome (also known as Rotor type hyperbilirubinemia) is a rare cause of mixed direct (conjugated) and indirect (unconjugated) hyperbilirubinemia, relatively benign, autosomal recessive bilirubin disorder characterized by non-hemolytic jau ...

. It is usually asymptomatic, but may be diagnosed in early infancy based on laboratory tests. No treatment is usually needed.

Signs and symptoms

Around 80 to 99% of people with Dubin–Johnson syndrome have jaundice, abnormal urinary color, biliary tract abnormality, and conjugated bilirubinemia. Around 30 to 79% of people with the disorder have abnormality of the gastric mucosa. Other rare symptoms include fever and fatigue.

Pathophysiology

The conjugated hyperbilirubinemia is a result of defective endogenous and exogenous transfer of anionic conjugates from hepatocytes into bile.Suzanne M Carter, MS Impaired biliary excretion of bilirubin glucuronides is due to a mutation in the canalicular multiple drug-resistance protein 2 (MRP2). A darkly pigmented liver is due to polymerized epinephrine metabolites, not bilirubin. Dubin–Johnson syndrome is due to a defect in the

multiple drug resistance Multiple drug resistance (MDR), multidrug resistance or multiresistance is antimicrobial resistance shown by a species of microorganism to at least one antimicrobial drug in three or more antimicrobial categories. Antimicrobial categories are c ...

protein 2 gene (

ABCC2 Multidrug resistance-associated protein 2 (MRP2) also called canalicular multispecific organic anion transporter 1 (cMOAT) or ATP-binding cassette sub-family C member 2 (ABCC2) is a protein that in humans is encoded by the ''ABCC2'' gene. Functi ...

), located on

chromosome 10 Chromosome 10 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 10 spans about 133 million base pairs (the building material of DNA) and represents between 4 and 4.5 percent of the tot ...

. It is an autosomal recessive disease and is likely due to a loss of function mutation, since the mutation affects the cytoplasmic/binding domain.

Diagnosis

A hallmark of Dubin–Johnson syndrome is the unusual ratio between the byproducts of heme biosynthesis: * Unaffected subjects have a coproporphyrin III to coproporphyrin I ratio around 3–4:1. * In patients with Dubin–Johnson syndrome, this ratio is inverted, with coproporphyrin I being 3–4 times higher than coproporphyrin III. Analysis of urine

porphyrin Porphyrins ( ) are a group of heterocyclic macrocycle organic compounds, composed of four modified pyrrole subunits interconnected at their α carbon atoms via methine bridges (=CH−). The parent of porphyrin is porphine, a rare chemical com ...

s shows a normal level of coproporphyrin, but the I isomer accounts for 80% of the total (normally 25%). For the first two days of life, healthy neonates have ratios of urinary coproporphyrin similar to those seen in patients with Dubin–Johnson syndrome; by 10 days of life, however, these levels convert to the normal adult ratio. In ''post mortem ''

autopsy An autopsy (post-mortem examination, obduction, necropsy, or autopsia cadaverum) is a surgical procedure that consists of a thorough examination of a corpse by dissection to determine the cause, mode, and manner of death or to evaluate any di ...

, the liver will have a dark pink or black appearance due to

pigment A pigment is a colored material that is completely or nearly insoluble in water. In contrast, dyes are typically soluble, at least at some stage in their use. Generally dyes are often organic compounds whereas pigments are often inorganic compo ...

accumulation. Plentiful canalicular multiple drug-resistant protein causes bilirubin transfer to

bile canaliculi Bile canaliculus (plural:bile canaliculi; also called bile capillaries) is a thin tube that collects bile secreted by hepatocytes. The bile canaliculi empty into a series of progressively larger bile ductules and ducts, which eventually become comm ...

. An isoform of this protein is localized to the apical hepatocyte membrane, allowing transport of

glucuronide A glucuronide, also known as glucuronoside, is any substance produced by linking glucuronic acid to another substance via a glycosidic bond. The glucuronides belong to the glycosides. Glucuronidation, the conversion of chemical compounds to glucur ...

and

glutathione Glutathione (GSH, ) is an antioxidant in plants, animals, fungi, and some bacteria and archaea. Glutathione is capable of preventing damage to important cellular components caused by sources such as reactive oxygen species, free radicals, pero ...

conjugates back into the blood. High levels of

gamma-glutamyl transferase Gamma-glutamyltransferase (also γ-glutamyltransferase, GGT, gamma-GT, gamma-glutamyl transpeptidase; ) is a transferase (a type of enzyme) that catalyzes the transfer of gamma-glutamyl functional groups from molecules such as glutathione to ...

(GGT) help in diagnosing pathologies involving biliary obstruction.

Differentiation from Rotor syndrome

Dubin–Johnson syndrome is similar to

, but can be differentiated by: A test of MRP2 activity can also be done to differentiate between Dubin–Johnson syndrome and Rotor syndrome. The clearance of bromsulphthalein is used to determine this, the test for which is called bromsulphthalein clearance test. 100 units of BSP is injected intravenously and then the clearance. In case of Dubin–Johnson syndrome, clearance of bromsulphthalein will be within 90 minutes, while in case of Rotor syndrome, the clearance is slow, i.e., it takes more than 90 minutes for clearance.

Treatment

Dubin–Johnson syndrome is a benign condition and no treatment is required. However, it is important to recognize the condition so as not to confuse it with other hepatobiliary disorders associated with conjugated hyperbilirubinemia that require treatment or have a different prognosis.Up-to-date: "Inherited disorders associated with conjugated hyperbilirubinemia"

Prognosis

Prognosis is good, and treatment of this syndrome is usually unnecessary. Most patients are asymptomatic and have normal lifespans. Some neonates present with cholestasis.

Hormonal contraceptive Hormonal contraception refers to birth control methods that act on the endocrine system. Almost all methods are composed of steroid hormones, although in India one selective estrogen receptor modulator is marketed as a contraceptive. The origin ...

s and

pregnancy Pregnancy is the time during which one or more offspring develops ( gestates) inside a woman's uterus (womb). A multiple pregnancy involves more than one offspring, such as with twins. Pregnancy usually occurs by sexual intercourse, but ca ...

may lead to overt

jaundice Jaundice, also known as icterus, is a yellowish or greenish pigmentation of the skin and sclera due to high bilirubin levels. Jaundice in adults is typically a sign indicating the presence of underlying diseases involving abnormal heme meta ...

and icterus (yellowing of the eyes and skin).

History

Dubin–Johnson syndrome was first described in 1954 by two men—Dr. Frank Johnson, a military physician and researcher at the Veterans Administration and Armed Forces Institute of Pathology in Washington, DC, and Dr. Isadore Dubin, a Canadian pathologist then working alongside him. Johnson had studied medicine at

Howard University College of Medicine The Howard University College of Medicine (HUCM) is an academic division of Howard University that grants the Doctor of Medicine (M.D.), Ph.D., M.S., and the M.PH. HUCM is located at the Howard University Health Sciences Center in Washington, D ...

and faced substantial discrimination in his medical career, on account of being an African-American, and was even turned away from active duty during the

Battle of the Bulge The Battle of the Bulge, also known as the Ardennes Offensive, was the last major German offensive (military), offensive military campaign, campaign on the Western Front (World War II), Western Front during World War II. The battle lasted fr ...

, despite being a

first lieutenant First lieutenant is a commissioned officer military rank in many armed forces; in some forces, it is an appointment. The rank of lieutenant has different meanings in different military formations, but in most forces it is sub-divided into a s ...

and trained physician.Kennedy, Charles Stuart (1992)
Dr. Frank B. Johnson Oral History Interview
''Armed Forces Institute of Pathology Oral History Program''. Archived by the

Internet Archive The Internet Archive is an American digital library with the stated mission of "universal access to all knowledge". It provides free public access to collections of digitized materials, including websites, software applications/games, music, ...

, retrieved March 24, 2016. Later, during his internship, he was required to sleep in a tuberculosis sanitarium, as the hospital did not allow African-American physicians to live in the same residencies as white physicians, and he was prevented from rotating on several services, including general surgery. These experiences, coupled with his inherent interest in chemistry, compelled him to pursue pathology, where he ultimately met Dubin and described this syndrome for the first time.

References

External links

Dubin-Johnson syndrome
at MedlinePlus.gov

at Medline Plus encyclopedia * {{DEFAULTSORT:Dubin-Johnson syndrome Accessory digestive gland disorders Hepatology Syndromes affecting the hepatobiliary system Membrane transport protein disorders Autosomal recessive disorders Heme metabolism disorders Rare syndromes