An Explanation of the relationship between Gilbert syndrome and autoimmune diseases Asst.Prof. Meroj A. Jasem Ph.D. Student Immunological diseases course Gilbert Syndrome (GS) • The condition was first described in 1901 by Augustin Nicolas Gilbert • Gilbert syndrome (GS) is a common genetic variant in which plasma unconjugated bilirubin levels are elevated throughout life, in the absence of hepatic pathology. • Liver does not properly process bilirubin • Gilbert's syndrome is due to a mutation in the UGT1A1 gene which results in decreased activity of the bilirubin uridine diphosphate glucuronosyltransferase enzyme. • It is typically inherited in an autosomal recessive pattern and occasionally in an autosomal dominant pattern depending on the type of mutation. Structure of Bilirubin Inheritance Patterns • Gilbert syndrome can have different inheritance patterns. When the condition is caused by the UGT1A1 change in the promoter region of the UGT1A1 gene, it is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have the mutation. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition. • When the condition is caused by a missense mutation in the UGT1A1 gene, it is inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder. A more severe condition known as Crigler-Najjar syndrome occurs when both copies of the UGT1A1 gene have mutations. Mechanism of bilirubin metabolism • Bilirubin is the normal by-product of the breakdown of hemoglobin. • Bilirubin circulates in the blood bound to albumin and is taken up by hepatocytes in the liver. • Within hepatocytes, bilirubin is conjugated with glucuronic acid, a process catalysed by uridine diphosphoglucuronateglucuronyltransferase (UDP-GT). • The conjugated bilirubin then exits the liver through the biliary ducts into the bile where it is eliminated through the digestive system. • This process is normally highly efficient so plasma unconjugated (indirect) bilirubin concentrations remain low. • Hyperbilirubinemia can be caused by conditions leading to predominantly unconjugated hyperbilirubinemia and those characterized by predominantly conjugated hyperbilirubinemia . • (Gilbert syndrome) :A disease that reduce the rate of bilirubin conjugation result in increased levels of indirect bilirubin . GS is asymptomatic ! • Episodes of jaundice (mild yellowing of the eyes) may be triggered by stress such as exercises, menstruation, starvation, dehydration. • People with Gilbert syndrome are otherwise entirely normal with no other signs or symptoms. • Gilbert syndrome is most commonly diagnosed after puberty, when alterations in sex hormone levels cause the blood bilirubin levels to rise, or it is diagnosed in the course of routine blood screening. • There is no need for treatment, and the prognosis is excellent. • Diagnosis is based on higher levels of unconjugated bilirubin in the blood without either signs of other liver problems or red blood cell breakdown. All liver serum chemistries are normal Rheumatoid arthritis (RA) • Rheumatoid arthritis (RA) is the most common inflammatory arthropathy worldwide. • Rheumatoid arthritis is a long-term, progressive, and disabling autoimmune disease. It causes inflammation, swelling, and pain in and around the joints and other body organs. • It is characterized by the presence of long-standing inflammation of the joints resulting in symmetric polyarthritis and synovial membrane hypertrophy with progressive joint damage, bone and cartilage destruction as well as deformity. • The autoimmune compromise is systemic, leading to extra-articular manifestations (EAM) . • Therefore, disability impaired quality of life and premature mortality, which is two times that of the general population characterize the disease. • The prediction of RA risk is one of the major challenges of personalized medicine and uses gene-environment interactions, cytokine measurements, and detection of autoantibodies. The Keys ! • Oxidative stress* and immune imbalance play an important role in the pathogenesis of rheumatoid arthritis (RA). • Bilirubin is a powerful antioxidant and also regarded as immunomodulator. • Physiological intracellular levels of unconjugated bilirubin inhibit certain common isoforms of NADPH oxidase. • Increased evidence shows that bilirubin should be a protective factor for autoimmune disease. However, the relationship between bilirubin and RA remain unclear. * reflects an imbalance between the systemic manifestation of reactive oxygen species(ROS) and a biological system's ability to readily detoxify the reactive intermediates or to repair the resulting damage. Antioxidants • Antioxidants are compounds that inhibit oxidation. Oxidation is a chemical reaction that can produce free radicals, thereby leading to chain reactions that may damage the cells of organisms. Antioxidants such as thiols or ascorbic acid (vitamin C) terminate these chain reactions. To balance the oxidative state, plants and animals maintain complex systems of overlapping antioxidants, such as glutathione and enzymes (e.g., catalase and superoxide dismutase), produced internally, or the dietary antioxidants vitamin C, and vitamin E. How come!!?? HOW!!! The exact nature of this protective effect is not clear. • The inflammation inherent to RA results from immunological reactions involving the activation of granulocytes, macrophages and lymphocytes .These inflammatory cells, in the synovial fluid, are in an activated state, releasing oxygen-derived free radicals that are lethal to the joint tissue .One possibility for the protective effect of TBili with regard to RA risk suggests that Bilirubin clears peroxyl radicals, decreases oxidative stress and by binding to serum albumin can prevent in-vitro oxidation of albumin-bound fatty acids . • Furthermore, unconjugated Bilirubin and Biliverdin have been shown to exhibit immune protective effects on murine liver and cardiac grafts. In the case of Biliverdin, this effect has been shown to be mediated by suppression of IL-2 production, via inhibition of nuclear factor. Recent research has shown that intracellular redox cycling of bilirubin to biliverdin, a metabolite of bilirubin, may be important for cytoprotection . Orientations… Mimicking GS as a clinical antioxidant strategy How to increase plasma and tissue bilirubin levels?? • Scavenging antioxidants vs. source antioxidants • Oral administration of bilirubin… • Drugs or nutraceuticals that inhibit UGT1A1… ‘iatrogenic Gilbert syndrome’ THANK YOU
