#19 GASMEN, Cyrille F.

MED-1C

Biochemical - Genetic Case 14

Case:
A 30 years old office clerk is referred to the hepatology clinic for recurrent episodes of jaundice
and right upper quadrant abdominal pain. She said that the painful episodes usually resolve
spontaneously. According to her medical chart, liver function tests during these episodes are consistent
with conjugated hyperbilirubinemia and elevations in her aminotransferases. After an ultrasound does
not elucidate the cause of her symptoms, a liver biopsy was done. Pathology report is that the gross
specimen of liver is darkly pigmented. The hepatologist begins to suspect that this patient might suffer
from a rare autosomal recessive condition that is caused by defective transport of bilirubin out of the
liver.

Diagnosis:
Congenital hyperbilirubinemias

Laboratory:
Conjugated, unconjugated and total bilirubin

Discussion:
1. What are the possible differential diagnoses?
The patient may have Dubin-Johnson Syndrome or Rotor Syndrome.

2. For each of the differential diagnoses, describe the genetic defects, effect of each of the genetic
defects, clinical manifestations and treatments.

A. Dubin-Johnson Syndrome

GENETIC DEFECT: Dubin-Johnson syndrome is caused by changes in a gene known as ABCC2.

The ABCC2 gene provides instructions for making a protein that transports certain substances out of
cells so they can be released (excreted) from the body. For example, this protein transports a substance
called bilirubin out of liver cells and into bile (a digestive fluid produced by the liver). Bilirubin is
produced during the breakdown of old red blood cells and has an orange-yellow tint.

EFFECT: ABCC2 gene mutations result in the production of a protein with reduced or absent activity that
cannot effectively transport substances out of cells. These mutations particularly affect moving bilirubin
into bile. As a result, bilirubin accumulates in the body, causing a condition called hyperbilirubinemia.
The buildup of bilirubin in the body causes the yellowing of the skin and whites of the eyes in people
with Dubin-Johnson syndrome. The black liver in affected individuals is due to a buildup of different
substance normally transported out of the liver by the protein produced from the ABCC2 gene.
CLINICAL MANIFESTATIONS: Jaundice, which is caused by excess bilirubin (bile pigment), is usually the
only symptom of Dubin-Johnson Syndrome. Otherwise a physical examination is normal. The disorder
rarely appears before puberty. Occasionally the patient may have an enlarged and tender liver and
complain of weakness and a painful abdomen, but the liver will function normally. There may
sometimes be a mild recurrence of the jaundice. 
TREATMENT: Treatment of Dubin Johnson Syndrome is symptomatic and supportive. In many cases
patients may require no treatment even though they have recurrent mild jaundice. However,
metabolism of certain drugs may be affected in patients with Dubin-Johnson Syndrome since many
pharmaceutical products are metabolized in the liver. Therefore, medications should be carefully
supervised by a physician. Genetic counseling may be of benefit for patients and their families affected
by Dubin Johnson Syndrome.

B. Rotor Syndrome

GENETIC DEFECT: Rotor syndrome is caused by mutations in SLCO1B1 and SLCO1B3 genes.The SLCO1B1
and SLCO1B3 genes provide instructions for making similar proteins, called organic anion transporting
polypeptide 1B1 (OATP1B1) and organic anion transporting polypeptide 1B3 (OATP1B3), respectively.
Both proteins are found in liver cells; they transport bilirubin and other compounds from the blood into
the liver so that they can be cleared from the body. In the liver, bilirubin is dissolved in a digestive fluid
called bile and then excreted from the body.

EFFECT: The SLCO1B1 and SLCO1B3 gene mutations that cause Rotor syndrome lead to abnormally
short, nonfunctional OATP1B1 and OATP1B3 proteins or an absence of these proteins. Without the
function of either transport protein, bilirubin is less efficiently taken up by the liver and removed from
the body. The buildup of this substance leads to jaundice in people with Rotor syndrome.

CLINICAL MANIFESTATIONS: Jaundice, characterized by yellowing of the skin and/or whites of the
eyes (conjunctival icterus), is usually the only symptom of Rotor syndrome. Jaundice usually begins
shortly after birth or in childhood and may come and go.

TREATMENT: As ROTOR SYNDROME is a benign condition, no specific treatment is recommended or

generally required. Affected individuals are advised to avoid alcohol and hepatotoxic drugs.