Dubin-johnson Syndrome (djs)

Dubin-Johnson Syndrome Author: Samir L Habashi, MD, Senior Gastroenterology Fellow, Department of Medicine, Division of Gastroenterology, University of Florida/Jacksonville-Florida Coauthor(s): Louis R Lambiase, MD, Associate Professor of Medicine, University of Florida College of Medicine; Chief, Division of Gastroenterology, Department of Internal Medicine, University of Florida Health Science Center/Jacksonville; Miriam K Anand, MD, Consulting Staff, Department of Allergy/Immunology, Allergy Associates and Lab, Ltd; Kenneth J Mishark, MD, Instructor, Department of Internal Medicine, Mayo Clinic Scottsdale, Mayo Medical School; Cuong Nguyen, MD, Instructor, Department of Internal Medicine, Section of Gastroenterology, Mayo Clinic Scottsdale Contributor Information and Disclosures Overview• Differential Diagnoses & Workup• Treatment & Medication• Follow-up• Multimedia• References• Keywords•

Introduction Background Dubin-Johnson syndrome (DJS) is a type of hereditary hyperbilirubinemia that was first described .independently in 1954 by Dubin and Johnson and by Sprinz and Nelson Hereditary hyperbilirubinemias can be divided into conjugated forms and unconjugated forms. While Gilbert syndrome and Crigler-Najjar syndrome are examples of the unconjugated hyperbilirubinemias, DJS and Rotor syndrome represent the 2 types of familial conjugated .hyperbilirubinemias Both types of conjugated hyperbilirubinemias have a relatively benign course, but establishing the diagnosis is important to spare patients from undergoing multiple unnecessary procedures and to .exclude other more serious causes of hyperbilirubinemia

Pathophysiology DJS 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. It is also called the multidrug resistance protein 2 (MRP2). This protein mediates ATP-dependent transport of certain organic anions across the canalicular membrane of the hepatocyte. The human MRP2 gene has been localized to band 10q23-10q24. A defect in the cMOAT (MRP2) protein results in the impaired hepatobiliary transport of non–bile salt organic anions and is thought to be responsible for .the conjugated hyperbilirubinemia and for the accumulation of hepatocellular pigment Several different mutations in the MRP2 gene have been identified in patients with DJS. Mutations in the ATP-binding region, which is critical for the functioning of the protein, form a significant proportion of the genetic lesions identified to date. One mutation causes impaired transcription and .mislocalization of the protein

Frequency United States .DJS is rare

International .DJS is rare, except in Iranian Jews, in whom the prevalence is about 1:1300

Mortality/Morbidity Life expectancy is normal. Reduced prothrombin activity, resulting from lower levels of clotting .factor VII, is found in 60% of patients with DJS

Race DJS has been described in all nationalities, ethnic backgrounds, and races. Prevalence reportedly is highest among Iranian Jews (1:1300). This group may have an associated deficiency in clotting .factor VII that is not observed in other populations

Sex .Both sexes are affected equally

Age .Patients with DJS tend to develop nonpruritic jaundice during their teenaged years

Clinical History .Patients with DJS tend to develop nonpruritic jaundice during their teenaged years• Although most patients are asymptomatic, some patients complain of nonspecific right• upper quadrant pain, which has been attributed to the anxiety associated with .prolonged diagnostic testing Subclinical cases can become evident during pregnancy or following the initiation of• .oral contraceptives A thorough family history can reveal a history of jaundice in an autosomal recessive• .pattern

Physical Aside from the presence of jaundice, physical examination findings are generally• .normal, with the exception of possible hepatosplenomegaly Hyperbilirubinemia and clinical icterus can be worsened by intercurrent illnesses, by• drugs that can decrease hepatic excretion of organic anions (eg, oral contraceptives), .and by pregnancy

Causes DJS is an autosomal recessive disorder that is caused by a mutation in the gene responsible for .the cMOAT protein

Differential Diagnoses Hyperbilirubinemia, Conjugated

Other Problems to Be Considered The differential diagnosis of DJS is that of conjugated hyperbilirubinemia. Disease categories to :consider include the following (Other inherited disorders (eg, Rotor syndrome• (Hepatocellular diseases (eg, viral hepatitis, drugs, alcohol, sepsis• (Infiltrative liver diseases (eg, metastatic cancer, pyogenic abscesses• Extrahepatic causes (eg, gallstone disease, cholangiocarcinoma, pancreatic head• (tumor

Workup Laboratory Studies The diagnosis of DJS can be confirmed by demonstrating an increase in the ratio of• .urinary coproporphyrin I to coproporphyrin III Coproporphyrins are byproducts of heme biosynthesis. Normally,○ coproporphyrin I is preferentially excreted in bile, whereas .coproporphyrin III is preferentially excreted in urine The total urinary coproporphyrin level is within the reference range in○ .patients with DJS Patients with DJS – 80% coproporphyrin I; 20% coproporphyrin III Patients without DJS – 25% coproporphyrin I; 75% coproporphyrin III Laboratory studies reveal conjugated hyperbilirubinemia, with total bilirubin levels in• .the 2- to 5-mg/dL range Results of other laboratory tests, including liver enzymes, serum○ albumin, and hematologic studies (eg, complete blood count, .reticulocyte count), tend to be within reference ranges Prothrombin time is usually normal, but it can be prolonged in○ .Iranian Jewish patients with associated factor VII deficiency

Imaging Studies .Oral cholecystography fails to visualize the gallbladder in patients with DJS• .These patients also tend to have unique findings on hepatobiliary scans• Specifically, the liver is visualized immediately following intravenous○ administration of the radiopharmaceutical dye and remains intensely .and homogenously visualized for up to 120 minutes While the gallbladder may be visualized up to 90 minutes after dye○ injection in some patients, it may not be observed at all in other patients. (Normally, images of the gallbladder should be observed (.within 30 minutes after dye injection This combination of intense and prolonged visualization of the liver○ .with delayed to no visualization of the gallbladder is unique to DJS These findings can be mistaken for evidence of gallbladder disease if the patient• .presents with abdominal pain and may result in an unnecessary cholecystectomy Computed tomographic findings of patients with DJS show a significantly higher• .attenuation as compared to that of control subjects

Procedures In general, procedures are not necessary to confirm the diagnosis of DJS. If a patient• is suspected of having DJS, diagnosis can be confirmed by the test for urinary .coproporphyrins described above A liver biopsy is not necessary for diagnosis. Patients may be noted to have a dark• liver during routine surgeries (eg, cholecystectomy), prompting biopsy. The histologic .findings are described below

Histologic Findings Deposition of melaninlike pigment occurs in the livers of patients with DJS but not with Rotor syndrome, which helps to differentiate the 2 diseases. Macroscopically, the pigment can cause the liver to appear dark or almost black. Microscopically, there is accumulation of coarsely granular pigment, most pronounced in the centrilobular zones. No associated scarring, hepatocellular necrosis, or distortion of zonal architecture is present. The amount of pigment can vary among patients and within an individual. Certain diseases (eg, viral hepatitis) can cause the pigment to disappear. The pigment reaccumulates slowly once the acute process is resolved. Electron spin resonance spectroscopy suggests that the pigment is composed of polymers of epinephrine .metabolites The changes in the hepatocytes coexist with marked stimulation and enhanced phagocytic activity of Kupffer cells. This manifests in the accumulation of pigment deposits within their cytoplasm that corresponds to those observed in hepatocytes. Hyperactive pericentral Kupffer cells, which are involved in the response to pigmentary material originating from disintegrated hepatocytes, may .play an essential role in the development of DJS

Treatment Medical Care DJS is a benign disorder and does not require any specific therapy. In the past, patients were treated with phenobarbital, which was primarily used to reduce serum bilirubin levels. This treatment is no longer recommended. Patients should be warned that pregnancy, oral .contraceptive use, and intercurrent illness can exacerbate the icterus

Follow-up Prognosis .DJS is a benign condition. The prognosis is excellent•

Patient Education Once the diagnosis is confirmed, patients should be informed of the disease process• .and its benign nature to prevent needless workup in the future

Miscellaneous Medicolegal Pitfalls The diagnosis of DJS is confirmed by the presence of hepatocellular pigmentation or• by demonstration of an altered pattern of urinary coproporphyrin excretion in a patient with conjugated hyperbilirubinemia. While the disease course is benign, and no specific treatment exists, establishing the correct diagnosis is important to prevent unnecessary tests and procedures. Once diagnosed, the 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