Information on the following diseases can be found in the Related Disorders section of this report:

• Dubin-Johnson Syndrome
• Rotor Syndrome
• Crigler-Najjar Syndrome
• Hyperbilirubinemia, Arias Type

Although Gilbert syndrome may become apparent shortly after birth, it may not be recognized for many years. Episodes of mild jaundice may appear in young adults and is more common in males than females. Frequently, episodes of jaundice are overlooked. Gilbert syndrome is associated with fluctuating levels of bilirubin in the blood (hyperbilirubinemia). Bilirubin levels may increase with stress, strain, dehydration, fasting, infection or exposure to cold. In many individuals, jaundice is only evident when one of these triggers raises the bilirubin levels.

Some affected individuals have reported vague, unspecific symptoms including fatigue, weakness and gastrointestinal symptoms such as nausea, abdominal discomfort, and diarrhea. Researchers do not believe that these symptoms are related to excess bilirubin in the blood and may occur coincidentally or due to other reasons such as anxiety over the diagnosis.

Gilbert syndrome is inherited as an autosomal recessive trait. Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother.

Recessive genetic disorders occur when an individual inherits abnormal gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females.

Researchers have determined that Gilbert syndrome is caused by mutations to the UGT1A1 gene located on the long arm (q) of chromosome 2 (2q37). Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated "p" and a long arm designated "q". Chromosomes are further sub-divided into many bands that are numbered. For example, "chromosome 2q37" refers to band 37 on the long arm of chromosome 2. The numbered bands specify the location of the thousands of genes that are present on each chromosome.

The UGT1A1 gene contains instructions for creating (encoding) a liver enzyme known as uridine disphosphate-glucuronosyltransferase (UGT1A1). This enzyme is required for the conversion (conjugation) and subsequent excretion of bilirubin from the body.

Mild jaundice associated with Gilbert syndrome occurs due to reduced amounts of this enzyme, which results in the accumulation of unconjugated bilirubin in the body. Bilirubin is an orange-yellow bile pigment that is mainly a byproduct of the natural breakdown (degeneration) of red blood cells (hemolysis). Bilirubin circulates in the liquid portion of the blood (plasma) bound to a protein called albumin; this is called unconjugated bilirubin, whichdoes not dissolve in water (water-insoluble). Normally, this unconjugated bilirubin is taken up by the liver cells and, with the help of the UGT1A1 enzyme, is converted to form water-soluble bilirubin diglucuronide (conjugated bilirubin), which is then excreted in the bile. The bile is stored in the gall bladder and, when called upon, passes into the common bile duct and then into the upper portion of the small intestine (duodenum) and aids in digestion. Most bilirubin is eliminated from the body in the feces.

Individuals with Gilbert syndrome retain approximately one third of the normal UGT1A1 enzyme activity and are able to conjugate enough bilirubin to prevent symptoms from developing. However, in some cases, especially when an affected individual is fasting, dehydrated or not feeling well, mild jaundice may develop.

Gilbert syndrome is diagnosed more often in males than females. The disorder affects approximately 3-7 percent of individuals in the general population. Gilbert syndrome affects individuals of all races. It is present at birth, but may remain undiagnosed until the late teen or early twenties. Gilbert syndrome was first described in the medical literature in 1901.

Symptoms of the following disorders can be similar to those of Gilbert syndrome. Comparisons may be useful for a differential diagnosis.

Crigler-Najjar syndrome is a rare genetic disorder characterized by elevated levels of bilirubin in the blood (hyperbilirubinemia). Bilirubin is a yellow waste product that is formed when old or worn out red blood cells are broken down (hemolysis). Individuals with Crigler-Najjar syndrome develop hyperbilirubinemia in the absence of excessive hemolysis. The elevated bilirubin levels occur because affected individuals lack a specific liver enzyme required to break down (metabolize) bilirubin. The hallmark finding of Crigler-Najjar syndrome is persistent yellowing of the skin, mucous membranes and whites of the eyes (jaundice). There are two forms of this disorder: Crigler-Najjar syndrome type I, characterized by a nearly complete lack of enzyme activity and severe symptoms; and Crigler-Najjar syndrome type II, characterized by partial enzyme activity and milder symptoms. Most cases of Crigler-Najjar syndrome are inherited as autosomal recessive traits. (For more information on this disorder, choose "Crigler-Najjar" as your search term in the Rare Disease Database.)

Rotor syndrome is an extremely rare inherited metabolic disorder characterized by the presence of excessive bilirubin in the blood (hyperbilirubinemia). The hyperbilirubinemia is caused by impaired storage of bilirubin in the liver. In most cases, affected individuals exhibit no symptoms of this disorder (asymptomatic). In some cases, persistent yellowing of the skin, mucous membranes, and whites of the eyes (jaundice) is present. Unlike Crigler-Najjar syndrome, affected individuals have high levels of conjugated bilirubin. Rotor syndrome is thought to be inherited as an autosomal recessive trait.

Dubin-Johnson syndrome is a rare genetic liver disorder characterized by elevated levels of bilirubin in blood (hyperbilirubinemia). Persistent yellowing of the skin, mucous membranes, and whites of the eyes (jaundice) is usually the only symptom, in most cases. Dubin-Johnson syndrome is usually diagnosed after puberty. In rare cases, enlargement of the liver or spleen may occur (hepatomegally). Like Rotor syndrome, and unlike Crigler-Najjar syndrome, high levels of conjugated bilirubin characterizes this disorder. Dubin-Johnson syndrome is inherited as an autosomal recessive disorder. (For more information, choose "Dubin Johnson" as your search term in the Rare Disease Database.)

Diagnosis
A diagnosis of Gilbert syndrome is often made when blood was drawn for another illness, such as an infection, detects mildly elevated bilirubin levels. Because the levels of bilirubin fluctuate, blood tests may not always show elevated bilirubin. Individuals are determined to have Gilbert syndrome by the presence of hyperbilirubinemia in the absence of hemolysis (premature breakdown of red blood cells) or structural liver damage.

Treatment
In most cases, Gilbert syndrome does not cause symptoms and no treatment is necessary. Mild jaundice may occur, but does not cause any problems. Gilbert syndrome is considered a mild, harmless (benign) condition. and is associated with normal life expectancy.

Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.

For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:

Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: prpl@cc.nih.gov

For information about clinical trials sponsored by private sources, contact:
www.centerwatch.com

TEXTBOOKS
Rimoin D, Connor JM, Pyeritz RP, Korf BR. Eds. Emory and Rimoin's Principles and Practice of Medical Genetics. 4th ed. Churchill Livingstone. New York, NY; 2002:1803-1817.

Scriver CR, Beaudet AL, Sly WS, et al. Eds. The Metabolic Molecular Basis of Inherited Disease. 8th ed. McGraw-Hill Companies. New York, NY; 2001:3083-3085.

Bennett JC, Plum F., eds. Cecil Textbook of Medicine. 20th ed. Philadelphia, PA: W.B. Saunders Co; 1996:756-757.

JOURNAL ARTICLES
Rossi F, Francese M, Iodice RM, et al. Inherited disorders of bilirubin metabolism. Minerva Pediatr. 2005;57:53-63.

Monaghan G, McLellan A, McGeehan A, et al. Gilbert's syndrome is a contributory factor in prolonged unconjugated hyperbilirubinemia of the newborn. J Pediatr. 1999;134:441-446.

Bosma PJ, Chowdhury JR, Bakker C, et al. The genetic basis of the reduced expression of bilirubin UDP- glucuronosyltransferase 1 in Gilbert's syndrome. N Engl J Med. 1995;3331171-1175.

Aono S, Adachi Y, Uyama E, et al. Analysis of genes for bilirubin UDP-glucuronosyltransferase in Gilbert's syndrome. Lancet. 1995;345:958-959.

Koiwai O, Nishizawa M, Hasada K, et al. Gilbert's syndrome is caused by a heterozygous missense mutation in the gene for bilirubin UDP-glucuronosyltransferase. Hum Mole Genet. 1995;4:1183-1186.

FROM THE INTERNET
Mukherjee S. Gilbert Syndrome. Emedicine Journal, November 8 2006. Available at: http://www.emedicine.com/med/topic870.htm Accessed on: November 6, 2007.

McKusick VA., ed. Online Mendelian Inheritance in Man (OMIM). Baltimore. MD: The Johns Hopkins University; Entry No:143500; Last Update:03/08/2004. Available at: http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=143500 Accessed on: November 6, 2007.

Mayo Clinic for Medical Education and Research. Gilbert's Syndrome. April 18, 2006. Available at: http://www.mayoclinic.com/health/gilberts-syndrome/DS00743 Accessed On: November 6, 2007.