Cholecystitis is an inflammation of the gallbladder caused by many causes like stone that is cholesterol gallstone and sometimes the cause is due to bacterial infection also known as acalculous cholecystitis. The risk factors for this disease are female, 40, fatty, fair, aging, diabetes mellitus, pregnancy, oral contraceptive and the most common factor is the interaction between genetic and environmental factors. Genetic factors include human leukocyte antigens, ethnicity, race and single nucleotide polymorphism in genes involved in the synthesis of cholesterol, transport and excretion.
Cholecystitis is an inflammation of the gallbladder, originated from Greek word—
Cholecystitis is a gallbladder inflammation, which is most commonly caused by gallstones, tumor or scarring of the bile duct . The greatest risk factor for calculous cholecystitis is gallstones and the risk factors for gallstones include female sex, increasing age more than 60, pregnancy, oral contraceptives, obesity, diabetes mellitus, ethnicity like Native North American or Mexican American ethnicity, rapid weight loss and drugs like hormonal replacement therapy in women during menopause. Cholesterol gallstones, accountable for about 90% of gallstones, due to supersaturation of bile with cholesterol stand for a multifactorial disease with a significant genetic component (Figure 1) .
A genetic factor in the vulnerability to gallstones was recognized as early as 1937 . These stones were formed due to interactions of lithogenic alleles of gallstone susceptibility genes in DNA and many environmental factors . The genetic cause may be due to fibroblast growth factor receptor 4 (FGFR4) polymorphism, which is a genetic risk factor contributing to aggravation of gallstone disease by maintaining bile acid homeostasis by regulating the expression of cholesterol 7α-hydroxylase (CYP7A1). The Gly388Arg (G-388R) had a greater inhibitory activity against bile acid biosynthesis and polymorphism in it affects stabilization and activation of FGFR4 and overexpression of FGFR4, especially the G-388R mutant of FGFR4 that inhibits luciferase activity of CYP7A1 reporter . Acalculous cholecystitis is related to conditions associated with biliary stasis such as critical illness, major surgery or severe trauma/burns, sepsis, long-term total parenteral nutrition, prolonged fasting, myocardial infarction, sickle cell disease,
2.1. Genetic factor
Cholecystitis had been found in certain area of the world and had an epidemiological distribution raises an issue of genetic or chromosomal factors associated with it . The frequency of diseases of the gallbladder, gallstones (cholelithiasis), cancer of the gallbladder and other biliary tract system diseases is more common in western countries (North America, Europe and Africa) . This may be due to general response to some dietary or other environmental risk factor, suggesting a gene-environment interaction. The role of diet was attributed to the consumption of high-calorie, high-fat, low-fiber diets and insufficient exercise . There was an epidemic of gallbladder disease among Amerindians and peoples genetically related to them . The existence of this epidemic indicates a genetic basis of this disease. In addition to that, the prevalence of cholecystitis in geographically associated distribution may be related to genes of aboriginal Amerindian origin, the degree of Amerindian admixture. The person from New World genotype will do cholecystectomy by age 85 years and this constitutes about 40% in Mexican-American females and increased the risk of gallbladder cancer. Thus, genetic factor can be considered as Carcinogenic reason in New World peoples as any major environmental exposure . The genetic effect in gallbladder diseases starts from chromosomal changes in gallbladder cells that leads to gallbladder cancer either acquired or inherent genetic instability in normal cells of the gallbladder causing mutational events that result in neoplastic transformation of normal cells and provide such cells with a selective growth over normal cells that leads to carcinoma of the gallbladder .The cause was due to loss of heterozygosity in the 3p, 8p, 9q and 22q chromosomal regions of cancer patients . Other study demonstrated chromosomal aberrations were confined on chromosome 1’s long arm and translocation from the long arm of chromosome 4 to the long arm of chromosome 6. These aberrations constitutes about 16.6% and may be due to environmental effects, infections and inflammation . The frequency of gallbladder disease was increased in Eastern populations like China, this may be due to the diet of the Chinese in Taiwan is already Westernized and differences among genetic populations . The effect of genetic factor in the development of acute acalculous cholecystitis was manifested by infection with Epstein–Barr virus and development of disease . Other microorganism that causes acalculous cholecystitis is
The class II molecule of HLA is a heterodimer consisting of two chains, an alpha (DRA) and a beta chain (DRB), both anchored in the membrane of the cell wall. HLA DRB1 plays a central role in the immune system by presenting peptides derived from extracellular proteins and the class II molecules are expressed in cell wall of antigen presenting cells B lymphocytes, dendritic cell and macrophages. The beta chain is approximately 26–28 kDa and is encoded by six exons. Exon 1 encodes the leader peptide; exons 2 and 3 encode the two extracellular domains; exon 4 encodes the transmembrane domain and exon 5 encodes the cytoplasmic tail. Within the DR molecule the beta chain contains all the polymorphisms of HLA that specifying the peptide binding specificities. Allelic variants of DRB1 are linked with many diseases . Cholecystitis patients and control groups were typed for identifying the DRB1* alleles using DNA-based methodology (PCR-SSOP). Allele’s frequencies of HLA-DRB1 for cholecystitis patients and control group. There was an increased frequency of HLA-DRB1*03:01 in patients with cholecystitis compared with healthy controls (
Occurrence of genetic alterations is risk factors have been associated with gallbladder disease like cholecystitis, chronic inflammation of the gallbladder, congenital biliary abnormalities and polyps. Genetic predisposing factors associated with cancer of gallbladder like mutations in
2.2. Genetic cause of calculous cholecystitis disease
Gallstone disease is a very common biliary tract disease in the world. Gallstones are one of the most common and mainly costly digestive diseases in the developed countries. Geographic and ethnic differences in its occurrence imply that genetic factors influence risk of gallstone formation . Its prevalence in the western countries was 48% , whereas in Asian ones was 5.9–21.9% . It is a most common cause for cholecystitis, acute cholangitis and biliary pancreatitis. It is formed due to genetic-environmental factors interactions. Genetic factors that influence gallstone formation by its implication in different metabolic pathways, have been involved from linkage studies of twins, families study and ethnicities, it had been found that this disease is more common in siblings and other family members of affected persons than spouses or unrelated controls in a ratio 3:1 . Twin studies have provided a clue into the genetic effect on disease development; the rates of this disease in monozygotic twins of both sexes were higher than in dizygotic twins . This involves the genetic effects of multiple
Thus, in conclusion, there are a large number of genetic polymorphisms (SNPs) that causing calculus cholecystitis starting from cholesterol transporter , plasma transport , cholesteryl ester transfer protein  and cholesterol uptake , bile acid synthesis , transporter  and bilirubin excretion , mucin affect the formation of the gallstone genetically , gallbladder motility  and hormone receptor . Thus, genetic study provided an insight toward the pathogenesis of the calculus cholecystitis.
2.3. Immunologic causes
The role of immune system on development of calculus and cholecystitis is manifested by cell-mediated immunity (Th1 cell) exerting its effect on formation of cholesterol gallstone and local inflammation ). It was first be confirmed by Lee and coworkers . The proinflamatory cytokines had an effect on mucin production. Regarding immunoglobulins (particularly IgM and IgG), it had been found that they promote crystal nucleation . This immune mechanism in the biliary system was altered due to the presence of multiple microbial flora  and other bacteria like enterohepatic
Inflammation of the gallbladder whether calculus or acalculous is a complex process mediated by genetic and environmental factors. Cholecystitis required a strong involvement of a genetic factor whether in the immune response infection against pathogen, formation of a stone and defense mechanism against inflammation. Understanding the concept of genetic factor leads to a novel diagnostic tools, treatments and preventive measures.
Conflict of interest
The author confirms that there are no conflicts of interest.
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