Síndrome de Gilbert: Revisão de literatura direcionada aos métodos diagnósticos
DOI:
https://doi.org/10.33448/rsd-v12i4.40829Palavras-chave:
Síndrome de Gilbert; Hiperbilirrubinemia; UGT1A1.Resumo
A síndrome de Gilbert é uma condição de herança autossômica dominante com penetrância incompleta caracterizada por hiperbilirrubinemia não conjugada, pouco aumentada, crônica e não associada a doenças hepáticas ou hemólise. Os portadores da síndrome possuem transtorno da glicuronidação da bilirrubina e consequente hiperbilirrubinemia indireta, decorrentes de uma mutação no gene UGT1A1. Geralmente se manifesta entre o período pós-puberdade até os 20 anos de idade. Os sintomas normalmente aparecem após exercícios físicos, períodos de jejum e em quadros infecciosos. A maioria dos pacientes são assintomáticos, e em alguns o único sinal é a icterícia. O diagnóstico é dado pela concentração aumentada de bilirrubina sérica, raramente ultrapassando 3 mg/dL, além de anamnese e exame físico direcionado. No exame físico é imprescindível investigar a presença de telangiectasia (aranha vascular), contratura de Dupuytren (mão em garra), ginecomastia e ascite na intenção de descartar cirrose hepática. Também é necessário certificar-se da ausência de massa palpável em quadrante superior direito, pois poderia sugerir patologia biliar justificando a icterícia por obstrução. A síndrome de Gilbert possui caráter benigno com prognóstico e evolução favoráveis, sendo o diagnóstico clínico o mais importante.
Referências
Abnet, C., Fagundes, R., Strickland, P., Kamangar, F., Roth, M. & Taylor, P. et al. (2007). The influence of genetic polymorphisms in Ahr, CYP1A1, CYP1A2, CYP1B1, GST M1, GST T1 and UGT1A1 on urine 1-hydroxypyrene glucuronide concentrations in healthy subjects from Rio Grande do Sul, Brazil. Carcinogenesis. 28(1):112-117.
Bailey, A., Robinson, D. & Dawson, A. M. (1976). Does Gilbert’s disease exist? The Lancet. 1977;310(8033):363.
Ben, M. D., Gazzin, S. & Tiribelli, C. (2014). Neonatal hyperbilirubinemia. Ben et al. Italian Journal of Pediatrics. 40(Suppl 2):A10.
Borlak et al. (2000). Molecular Diagnosis of a Familial Nonhemolytic Hyperbilirubinemia (Gilbert’s Syndrome) in Healthy Subjects. Hepatology. (4):792-795.
Bulmer, A. C., Verkade, H. J. & Wagner, K. H. (2013). Bilirubin and beyond: A review of lipid status in Gilbert’s syndrome and its relevance to cardiovascular disease protection. Prog Lipid Res. 52(2):193-205.
Canu, G., Minucci, A., Zuppi, C. & Capoluongo, E. (2013). Gilbert and Crigler Najjar syndromes: an update of the UDP-glucuronosyltransferase 1A1 (UGT1A1) gene mutation database. Blood Cells Mol Dis. 50(4):273-80.
Claridge, L., Armstrong, M., Booth, C. & Gill, P. (2011). Gilbert's syndrome. BMJ. 2293-d2293.
Dabke, P., Colah, R., Ghosh, K. & Nadkarni, A. (2013). Role of co-inherited Gilbert syndrome on hyperbilirubinemia in Indian beta thalassemia patients. Hematology. 19(7):388-392.
Ehmer, U., Kalthoff, S., Fakundiny, B., Pabst, B., Freiberg, N. & Naumann, R. et al. (2012). Gilbert syndrome redefined: A complex genetic haplotype influences the regulation of glucuronidation. Hepatology. 55(6):1912-1921.
Esteitie, R. (2015). Fundamentos de pesquisa clínica. Porto Alegre, Brasil: AMGH Editora LTDA.
Felsher et al. (1970). The reciprocal relation between calorie intake and the degree of hyperbilirubinemia in Gilbert’s syndrome. The New England Journal of
Medicine. 283 (4): 170-172.
Fevery, J. (2008). Bilirubin in clinical practice: a review. Liver International. 28(5):592-605.
Flores, E. V., Rodriguez, C. M., Arredondo, G. S., Bosques, F. P., Zertuche, T. M. & Torre L. F. (2016) Unusual presentation of Gilbert disease with high levels of unconjugated bilirubin: report of two cases. Rev. esp. enferm. dig. 108(4): 228-230.
Foulk, W. T., Butt, H. R., Owen, C. A., Withcomb, F. F. & Mason, H. L. (1959). Constitutional hepatic dysfunction (Gilbert disease): its natural history and related syndromes. Medicine (Baltimore). 38(1):25-46.
Fretzayas, A., Moustaki, M., Liapi, O. & Karpathios, T. (2012). Gilbert syndrome. Eur J Pediatr. 171(1): 11-5.
Gazzin, S., Masutti, F., Vitek, L. & Tiribelli, C. (2017). The molecular basis of jaundice: An old symptom revisited. Liver International. 37(8):1094-1102.
Gollan J, Bateman C, Billing B. Effect of dietary composition on the unconjugated hyperbilirubinaemia of Gilbert's syndrome. Gut. 17(5):335-340.
Hauser, S. C. & Holland, J. (1992). Bilirubin metabolism and hyperbilirrubinaemic disorders. In: Millward-Sadler GH, Wright R, Arthur MJ, eds. Wright's liver and biliary disease. London: W.B. Saunders. 318-351.
Hinds, T., Hosick, P., Chen, S., Tukey, R., Hankins, M. & Nestor-Kalinoski, A. et al. (2017). Mice with hyperbilirubinemia due to Gilbert’s syndrome polymorphism are resistant to hepatic steatosis by decreased serine 73 phosphorylation of PPARα. American Journal of Physiology-Endocrinology and Metabolism. 312(4):E244-E252.
Horsfall, L., Nazareth, I., Pereira, S. & Petersen, I. (2013). Gilbert's syndrome and the risk of death: a population-based cohort study. Journal of Gastroenterology and Hepatology. n/a-n/a.
Horsfall, L., Zeitlyn, D., Tarekegn, A., Bekele, E., Thomas, M. & Bradman, N. et al. (2011). Prevalence of Clinically Relevant UGT1A Alleles and Haplotypes in African Populations. Annals of Human Genetics. 75(2):236-246.
Jamwal, M., Aggarwal, A., Kumar, V., Sharma, P., Sachdeva, M. & Bansal, D. et al. (2016). Disease-modifying influences of coexistent G6PD-deficiency, Gilbert syndrome and deletional alpha thalassemia in hereditary spherocytosis: A report of three cases. Clinica Chimica Acta. 458:51-54.
Jenko-Pražnikar, Z., Petelin, A., Jurdana, M. & Žiberna, L. (2013). Serum bilirubin levels are lower in overweight asymptomatic middle-aged adults: An early indicator of metabolic syndrome? Metabolism. 62(7):976-985.
Kadakol, A., Ghosh, S., Sappal, B., Sharma, G., Chowdhury, J. & Chowdhury, N. (2000). Genetic lesions of bilirubin uridine-diphosphoglucuronate glucuronosyltransferase (UGT1A1) causing Crigler-Najjar and Gilbert syndromes: Correlation of genotype to phenotype. Human Mutation. 16(4):297-306.
Kamal, S., Salam, A. A., Shahid, K. & Huda, H. (2015). Patterns and Genetic Polymorphisms in Unconjugated Hyperbilirubinemia (Gilbert Syndrome). Pediatrics. 135:2014–3330.
Kaplan, M., Wong, R. & Stevenson, D. (2017). Heme oxygenase-1 promoter polymorphisms: do they modulate neonatal hyperbilirubinemia? Journal of Perinatology. 37(8):901-905.
Kathemann, S., Lainka, E., Baba, H., Hoyer, P. & Gerner, P. (2012). Gilbert’s syndrome - a frequent cause of unconjugated hyperbilirubinemia in children after orthotopic liver transplantation. Pediatric Transplantation. 16(2):201-204.
Kawase, A., Yamamoto, T., Egashira, S. & Iwaki, M. (2016). Stereoselective Inhibition of Methotrexate Excretion by Glucuronides of Nonsteroidal Anti-inflammatory Drugs via Multidrug Resistance Proteins 2 and 4. J Pharmacol Exp Ther. 356(2):366-74.
Kundur, A., Singh, I. & Bulmer, A. (2015). Bilirubin, platelet activation and heart disease: A missing link to cardiovascular protection in Gilbert's syndrome? Atherosclerosis. 239(1):73-84.
Kutsuno, Y., Itoh, T., Tukey, R.H. & Fujiwara, R. (2014). Glucuronidation of drugs and drug-induced toxicity in humanized UDP-glucuronosyltransferase 1 mice. Drug Metab Dispos. 42(7):1146-52.
Liaury, K., Miyaoka, T., Tsumori, T., Furuya, M., Hashioka, S. & Wake, R. et al. (2014). Minocycline improves recognition memory and attenuates microglial activation in Gunn rat: A possible hyperbilirubinemia-induced animal model of schizophrenia. Progress in Neuro-Psychopharmacology and Biological Psychiatry. 50:184-190.
Marques, S. C. & Ikediobi, O. N. (2010). The clinical application of UGT1A1 pharmacogenetic testing: gene-environment interactions. Hum Genomics. 4(4):238-49.
Marschall, H., Krawczyk, M., Grünhage, F,, Katsika, D., Einarsson, C. & Lammert, F. (2013). Gallstone disease in Swedish twins is associated with the Gilbert variant of UGT1A1. Liver International. 33(6):904-908.
Martelli, A. (2010). Síntese e metabolismo da bilirrubina e fisiopatologia da hiperbilirrubinemia associados à Síndrome de Gilbert: revisão de literatura. Rev Med Minas Gerais 22(2): 216-220. <http://www.hermespardini.com.br/scripts/mgwms32.dll?MGWLPN=HPHOSTBS&App=HELPE&EXAME=S%7C%7CBIL>. Acesso em: 14/11/2017.
Maruhashi, T., Soga, J., Fujimura, N., Idei, N., Mikami, S., Iwamoto, Y., Kajikawa, M., Matsumoto, T., Kihara, Y., Chayama, K., Noma, K., Nakashima, A., Tomiyama, H., Takase, B., Yamashina, A. & Higashi, Y. (2012) Hyperbilirubinemia, augmentation of endothelial function, and decrease in oxidative stress in Gilbert syndrome. Circulation. 126(5):598-603.
Maruo, Y., Nakahara, S., Yanagi, T., Nomura, A., Mimura, Y., Matsui, K., Sato, H. & Takeuchi, Y. (2016). Genotype of UGT1A1 and phenotype correlation between Crigler-Najjar syndrome type II and Gilbert syndrome. J Gastroenterol Hepatol. 31(2):403-8.
Mölzer, C., Wallner, M., Kern, C., Tosevska, A., Schwarz, U. & Zadnikar, R. et al. (2016). Features of an altered AMPK metabolic pathway in Gilbert’s Syndrome, and its role in metabolic health. Scientific Reports. 6(1).
Muraca, M., Fevery, J. & Blanckaert, N. (1987). Relationships between serum bilirubins and production and conjugation of bilirubin. Gastroenterology. 92(2):309-317.
Murthy et al. (2001). Rifampin. in Diagnosing Gilbert’s Syndrome. Am. Coll. of Gastroenterology. 96 (4): 1150–1154.
Owens, D. & Evans, J. (1975). Population studies on Gilbert's syndrome. Journal of Medical Genetics. 12:152.
Owens, D. & Sherlock, S. (1973). Diagnosis of Gilbert's Syndrome: Role of Reduced Caloric Intake Test. British Medical Journal. 3, 559-563.
Owens, D. & Sherlock, S. (1973). Reduced Caloric Intake and Nicotinic Acid Provocation Tests in the Diagnosis of Gilbert's Syndrome. British Medical Journal; 3:559.
Powell, L., Hemingway, E., Billing, B. & Sherlock, S. (1967). Idiopathic Unconjugated Hyperbilirubinemia (Gilbert's Syndrome). New England Journal of Medicine. 277(21):1108-1112.
Radoi, V. E., Ursu, R. I., Poenaru, E., Arsene, C., Bohiltea, C. L. & Bohiltea, R. (2017). Frequency of the UGT1A1*28 polymorphism in a Romanian cohort of Gilbert syndrome individuals. Journal of Gastrointestinal and Liver Diseases. 26(1).
Rollinghoff, W., Paumgartener, G. & Preisg, R. (1981). Nicotinic acid test in the diagnosis of Gilbert's syndrome: correlation with bilirubin clearance. Gut. 22:663-668.
Rowland, R., O’Hara, G. A., Hamill, M., Poulton, I. D., Donaldson, H., Dinsmore, L. & McShane, H. (2015). Determining the validity of hospital laboratory reference intervals for healthy young adults participating in early clinical trials of candidate vaccines. Human Vaccines & Immunotherapeutics. 1741–1751.
Shiu, T., Huang, H., Lin, H., Shih, Y., Chu, H. & Chang, W. et al. (2015). Restriction fragment length polymorphism effectively identifies exon 1 mutation of UGT1A1 gene in patients with Gilbert's Syndrome. Liver International. 35(8):2050-2056.
Sieg, A., Stiehl, A., Raedsch, R., Ullrich, D., Messmer, B. & Kommerell, B. (1986). Gilbert’s syndrome: diagnosis by typical serum bilirubin pattern. Clinica Chimica Acta. 154:41-48.
Smith, P., Middleton, J. & Williams, R. (1967). Studies on the familial incidence and clinical history of patients with chronic unconjugated hyperbilirubinaemia. Gut. 8(5):449-453.
Stender, S., Frikke-Schmidt, R., Nordestgaard, B., Grande, P. & Tybjaerg-Hansen, A. (2012). Genetically elevated bilirubin and risk of ischaemic heart disease: three Mendelian randomization studies and a meta-analysis. Journal of Internal Medicine. 273(1):59-68.
Strassburg C. Hyperbilirubinemia syndromes (Gilbert-Meulengracht, Crigler-Najjar, Dubin-Johnson, and Rotor syndrome). Best Practice & Research Clinical Gastroenterology. 2010;24(5):555-571.
Sullivan, J. I. & Rockey, D. C. (2017). Diagnosis and evaluation of hyperbilirubinemia. Curr Opin Gastroenterol. 33(3):164-170.
Tapan, S., Karadurmus, N., Dogru, T., Ercin, C., Tasci, I. & Bilgi, C. et al. (2011). Decreased small dense LDL levels in Gilbert's syndrome. Clinical Biochemistry. 44(4):300-303.
Te, H. S., Schiano, T. D. & Das, T. et al. (2000). Donor liver uridine diphosphate (UDP) -glucuronosyltransferase -1A1 deficiency causing Gilbert’s syndrome in liver transplant recipients. Transplantation. 69:882-6.
Thomsen, H. F., Hardt, F. & Juhl, E. (1981). Diagnosis of Gilbert’s syndrome. Reliability of the caloric restriction and phenobarbital stimulation tests. Scand. J. Gastroenr. 16, 699-703.
Tosevska, A., Moelzer, C., Wallner, M., Janosec, M., Schwarz, U. & Kern, C. et al. (2016). Longer telomeres in chronic, moderate, unconjugated hyperbilirubinaemia: insights from a human study on Gilbert’s Syndrome. Scientific Reports. 6(1).
Wallner, M., Marculescu, R., Doberer, D., Wolzt, M., Wagner, O. & Vitek, L. et al. (2013). Protection from age-related increase in lipid biomarkers and inflammation contributes to cardiovascular protection in Gilbert's syndrome. Clinical Science. 125(5):257-264.
Wallner, M., Bulmer, A. C., Mölzer, C., Müllner, E., Marculescu, R., Doberer, D., Wolzt, M., Wagner, O. F. & Wagner, K. H. (2013). Haem catabolism: a novel modulator of inflammation in Gilbert's syndrome. Eur J Clin Invest. 43(9):912-9.
Watson, K. J. R. & Gollan, J. L. (1976). Gilbert's syndrome. Bailliere's Clinical Gastroenterology. 3(2): 337-355.
Wong, R. J., Bhutani, V. K. & Abrams, S. A. (2015). Pathogenesis and etiology of unconjugated hyperbilirubinemia in the newborn. Up to Date.
Žaja, O., Tiljak, M. K., Štefanović, M., Tumbri, J. & Jurčić, Z. (2014). Correlation of UGT1A1 TATA-box polymorphism and jaundice in breastfed newborns-early presentation of Gilbert's syndrome. J Matern Fetal Neonatal Med. 27(8):844-50.
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