Obtaining a full history is usually the first port of call regarding clinical evaluation for individuals with Dubin-Johnson syndrome or other suspected causes of conjugated hyperbilirubinemia [7].

Wild mushrooms, environmental chemicals (e.g solvents) and drugs (potential toxins) have to be excluded carefully. Failing to appropriately diagnose toxic hepatitis often leads to hepatic failure and death.

It is equally important to elicit some of the possible risk factors for viral hepatitis. Some of these possible risk factors are: Exposure to an infected individual, multiple sexual partners, intravenous drug use and transfusion [8].

• Presence of abdominal pain or fever suggests gallstone disease.
• If there is history of anesthesia with use of halothane, halothane hepatitis may be present.
• If the history shows presence of intense pruritus, cholestatic disease resulting from biliary obstruction or intrahepatic cholestasis may be present.
• Inborn errors of bilirubin metabolism is denoted by a family history of jaundice.
• Cholestasis may be present if the patient is on parenteral nutrition. This often improves with the addition of lipid infusions.
• If there is tricuspid insufficiency with hepatomegaly or severe right heart failure hepatic congestion may be present.
• Sepsis, hepatitis ischemia and opportunistic infections should be considered for patients with severe intercurrent illnesses.

• Splenomegaly

  Discrete hepatomegaly is one of the symptoms of the syndrome, and there are no reports of associated splenomegaly. [scielo.iec.gov.br]

  […] syndrome are likely to be full-term, well-looking neonates in whom cholestasis manifests in the first weeks of life, which then usually resolves within age 3–6 months, followed by a benign course. [27] Features such as failure to thrive, hepatomegaly, or splenomegaly [emedicine.medscape.com]

• Abdominal Pain

  Main findings of the disease are hepatomegaly associated with abdominal pain and jaundice. [accessanesthesiology.mhmedical.com]

  Major clinical manifestations were recurrent or persistent jaundice, abdominal pain and fever. Duration of illness ranged from 9 months to 58 years (median 10 years). [ncbi.nlm.nih.gov]

  […] over time You also have abdominal pain or other symptoms (which may be a sign that another disorder is causing the jaundice) Prevention If you have a family history of DJS, genetic counseling may be helpful if you plan to have children. [mountsinai.org]

  pain or other symptoms (which may be a sign that another disorder is causing the jaundice) Prevention Genetic counseling may be helpful for people who wish to have children and have a family history of Dubin-Johnson syndrome. [web.archive.org]

  Patient may be asymptomatic or present with weakness, abdominal pain, dark urine, jaundice, and icterus. Liver may be somewhat enlarged. [visualdx.com]

• Right Upper Quadrant Pain

  •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. [medicalgeek.com]

  Some patients complain of nonspecific right upper quadrant pain, which has been attributed to the anxiety associated with prolonged diagnostic testing. [emedicine.medscape.com]

• Failure to Thrive

  […] to thrive, hepatomegaly, or splenomegaly are usually absent, and this disease generally does not affect the growth and development of children. [21, 31] Affected neonates have increased serum total and direct bilirubin concentrations, along with normal [emedicine.medscape.com]

• Jaundice

  Clinical History •Patients with DJS tend to develop nonpruritic jaundice during their teenaged years. [medicalgeek.com]

  Jaundice may transiently increase postoperatively. Consequently, it seems prudent to avoid halothane to prevent its implication in the development of postoperative jaundice. [accessanesthesiology.mhmedical.com]

  The time at which jaundice is first noticed also is significant. [medical-dictionary.thefreedictionary.com]

  Possible Complications Complications are unusual, but may include the following: Reduced liver function Severe jaundice When to Contact a Medical Professional Call your health care provider if any of the following occurs: Jaundice is severe Jaundice gets [web.archive.org]

• Hepatomegaly

  Main findings of the disease are hepatomegaly associated with abdominal pain and jaundice. [accessanesthesiology.mhmedical.com]

  1][2] History and exam Key diagnostic factors intermittent jaundice lack of pruritus More key diagnostic factors Other diagnostic factors illness, infection, or stress pregnancy-triggered jaundice medication-triggered jaundice abdominal pain fatigue hepatomegaly [bestpractice.bmj.com]

  Discrete hepatomegaly is one of the symptoms of the syndrome, and there are no reports of associated splenomegaly. [scielo.iec.gov.br]

  Affected infants typically also have enlarged livers (hepatomegaly) and a severely reduced ability to produce and release a digestive fluid called bile (cholestasis). [ghr.nlm.nih.gov]

  It is characterized by mild recurrent jaundice with hepatomegaly. Pathophysiology This is a rare genetic autosomal recessive disorder. [labpedia.net]

• Suggestibility

  Inheritance Three sibs from a first-cousin marriage were affected in the family reported by Pereira Lima et al. (1966), suggesting recessive inheritance. [omim.org]

  We suggest ursodeoxycholic acid in treatment for Dubin-Johnson Syndrome with severe direct hyperbilirubinemia presenting in the neonatal age. [ncbi.nlm.nih.gov]

Accurate laboratory testing for DJS and other cases of conjugated hyperbilirubinemia is dependent on the physical examination findings and clinical history of the patient [9]. However, all patients of this condition should be tested for:

• Alpha-1 antitrypsin fractionation and other relevant studies if considering hereditary liver diseases.
• Copper studies if Wilson disease is suspected.
• Iron and genetic studies if hemochromatosis is suspected.
• Antinuclear antibodies (ANAs), smooth-muscle antibodies, and other types of serologic studies if autoimmune hepatitis is suspected.
• Antimitochondrial antibody if primary biliary cirrhosis is suspected.
• Alkaline phosphatase (ALP): If an obstruction is suspected or if it is elevated, it is important to obtain images of the bile ducts.
• Blood alcohol or acetaminophen levels. This often proves useful later on.
• Fractionated bilirubin.
• Serologic screen for hepatitis. This should include hepatitis C virus (HCV) antibody and hepatitis B surface antigen (HBsAg) or antihepatitis B core antibody (anti-HBcAb).
• Serum aminotransferases (aspartate aminotransferase [AST], alanine aminotransferase [ALT]).
• Complete blood cell (CBC) count to confirm hemolysis when present.

• Liver Biopsy

  Liver biopsies revealed presence of coarse granular brown pigment in the cytoplasm of hepatocytes more concentrated in the pericanalicular region and more prominent in centrilobular hepatocytes. [ncbi.nlm.nih.gov]

Dubin-Johnson syndrome is a benign disorder which usually does not require any specific treatment.

The outlook is very positive for Dubin-Johnson syndrome and other conditions that lead to conjugated hyperbilirubinemia and generally the condition does not shorten the lifespan of the individual.

The condition develops as a result of reduced secretion of conjugated bilirubin into the bile and is often present in patients with hepatitis.

It can equally be seen with patients with biliary obstruction, where there is an impaired flow of bile into the intestine [5]. The formation of bile is very sensitive and thus can be affected by various conditions like high levels of inflammatory cytokines, etc.

In the United States, conjugated hyperbilirubinemia is commonly seen among patients with other biliary or notable liver diseases. It is equally common seen in patients with sepsis, cardiogenic shock and other systemic illnesses. Dubin-Johnson syndrome however, is very rare [3].

Internationally, ascariasis, clonorchiasis, and other parasistic diseases commonly lead to biliary obstruction especially in lesser-developed countries. Malaria and other haemolytic differences can equally make patients susceptible to biliary obstruction due to the formation of gallstone pigments. Dubin- Johnson syndrome equally occurs rarely.

Regarding racial differences, conjugated hyperbilirubinemia will only reflect the differences noted for the underlying disease condition. No difference is recorded for Dubin Johnson syndrome. The situation is the same for sex related differences in occurrence. [4]

The age at which conjugated hyperbilirubinemia is reflected is also dependent on the disease state. Biliary artesia leads to conjuhated bilirubinemia within the first month of life, the occurrence is more frequent within midlife for patients with primary biliary cirrhosis or viral hepatitis to senescence as is the case with malignancies and biliary stones.

Dubin-Johnson syndrome or high levels of conjugated bilirubin often secondarily increase the level of unconjugated bilirubin.

The mechanism behind this is not clearly defined but one possible cause is the reduced hepatic clearance of unconjugated bilirubin. This is due to competition with conjugated bilirubin for excretion or uptake [6].

There are no guidelines for prevention of Dubin-Johnson syndrome.

Dubin-Johnson syndrome is a disorder that brings about an increase in levels of conjugated bilirubin found in the serum [1]. When the increase occurs, there is no elevation of ALT, AST and other liver enzymes.

The syndrome is an autosomal recessive disorder. Dubin-Johnson syndrome has similarities with the Rotor syndrome as it is a defect in the ability of hepatocytes to disseminate bilirubin into the bile.

The condition is generally asymptomatic but it can be diagnosed early in infants with the aid of laboratory tests.

Before being eliminated from the body, bilirubin must be converted into a soluble conjugate since it is not soluble in water. Uridine diphosphate (UDP)-glucuronyl transferase is the compound which converts bilirubin to a mixture of monoglucuronides and diglucuronides (conjugate bilirubin) in the liver. An ATP-dependent transporter disseminates the conjugate bilirubin into the bile. Under normal conditions, this process is very efficient leading to low concentration levels of plasma unconjugated bilirubin [2].

Apart from the Dubin-Johnson syndrome, there are many conditions that lead to the accumulation of bilirubin in the plasma. Conditions like hemolysis which bring about an increase in the bilirubin formation or conditions like Gilbert syndrome which reduce the rate of bilirubin conjugation bring about unconjugated hyperbilirunemia.

If the disease reduces the flow of bile into the intestine or the secretion of conjugated bilirubin into the bile conjugated hyperbilirunemia sets in. This is because of the reflux of conjugates into the plasma. Hepatobiliary diseases lead to elevated conjugated bilirubin levels.

The patients need to be reassured that no treatment is required if only Dubin-Johnson syndrome is diagnosed. Again, there is typically no reduction in life expectancy [10].

1. Westwood A. The analysis of bilirubin in serum. Ann Clin Biochem. Mar 1991;28 ( Pt 2):119-30.
2. Iyanagi T, Emi Y, Ikushiro S. Biochemical and molecular aspects of genetic disorders of bilirubin metabolism. Biochim Biophys Acta. Sep 30 1998;1407(3):173-84.
3. Klein CJ, Revenis M, Kusenda C, Scavo L. Parenteral nutrition-associated conjugated hyperbilirubinemia in hospitalized infants. J Am Diet Assoc. Nov 2010;110(11):1684-95.
4. Johnston DE. Special considerations in interpreting liver function tests. Am Fam Physician. Apr 15 1999;59(8):2223-30.
5. Shani M, Seligsohn U, Gilon E, et al. Dubin-Johnson syndrome in Israel. I. Clinical, laboratory, and genetic aspects of 101 cases. Q J Med 1970; 39:549.
6. Dittrich H, Seifert E. On the behavior of pigment and biligraffin excretion in a patient with Dubin-Johnson syndrome. Acta Hepatosplenol 1962; 9:45.
7. Morita M, Kihara T. Intravenous cholecystography and metabolism of meglumine iodipamide (Biligrafin) in Dubin-Johnson syndrome. Radiology 1971; 99:57.
8. Essner E, Novikoff AB. Human hepatocellular pigments and lysosomes. J Ultrastruct Res 1960; 3:374.
9. Swartz HM, Sarna T, Varma RR. On the natural and excretion of the hepatic pigment in the Dubin-Johnson syndrome. Gastroenterology 1979; 76:958.
10. Nisa AU, Ahmad Z; Dubin-Johnson syndrome. J Coll Physicians Surg Pak. 2008 Mar;18(3):188-9.