RESUMO
BACKGROUND: Hepatocarcinogenesis has a variety of risk factors. In Mexico City, autopsies found 14% of hepatocellular carcinomas (HCCs) without cirrhosis. OBJECTIVE: The objective of the study was to explore if HCCs carry the TP53 R249S mutation that has linked them to aflatoxin exposure and describe the associated risk factors. METHODS: A retrospective review of consecutive cases of HCC was performed. Exposure to hepatotropic viruses, alcoholism, metabolic diseases, diabetes mellitus, and hypertension, as well as episodes of ascites, portal hypertension, and body mass index were retrieved. Slides were re-reviewed, macrodissected and DNA was extracted. TP53 exon 7 was amplified, purified, and used as a template for sequencing. RESULTS: In 14 years, 74 HCCs were identified in 1863 (4%) consecutive liver biopsies. No data were available in five excluded patients; the rest was submitted to exon 7 screening. Patients had a median age of 62 years, and 46 (67%) were male. Stage 4 fibrosis was observed in 46 patients (67%) and their associated risk factors were hepatitis C virus (39%, 18/46), alcoholism (20%, 9/46), hepatitis B virus (2%, 1/46), and 18 were cryptogenic. Fibrosis stage 3 or lower was observed in 23 (33%) patients without demonstrated liver disease; 8/23 had diabetes and 6/23, systemic hypertension. Steatohepatitic variants of HCC were observed in 4 and in 5, the remnant liver had steatohepatitis. A 238-bp fragment was obtained in each tumor without the expected TP53 R249S mutation. CONCLUSIONS: There was no evidence of aflatoxin exposure in HCCs, with and without the known "classical" risk factors. One-third of non-cirrhotic HCCs had steatohepatitis or conditions associated to metabolic syndrome.
RESUMO
VEXAS (Vacuoles, E1 enzyme, X-linked, Autoinflammatory, Somatic) syndrome is an adult-onset autoinflammatory syndrome characterized by somatic mutations in the UBA1 gene and is considered the prototype of hematoinflammatory diseases. Patients with VEXAS syndrome exhibit inflammatory and hematological manifestations that can lead to clinical diagnoses such as relapsing polychondritis, polyarteritis nodosa, Sweet syndrome, and myelodysplastic syndrome. Diagnosis requires bone marrow evaluation to identify cytoplasmic vacuoles in myeloid and erythroid precursors. However, genetic confirmation of mutations in UBA1 is necessary. Treatment is challenging and often involves glucocorticoids and immunosuppressants with variable responses. Hypomethylating agents and allogenic haemopoietic stem cell transplant are considered promising therapies. Prognosis is influenced by genetic and clinical factors. The aim of this review is to provide an overview of the pathogenesis, clinical presentation, treatment, and prognosis of VEXAS syndrome for the Latin American medical community.
Assuntos
Síndromes Mielodisplásicas , Dermatopatias Genéticas , Adulto , Humanos , Glucocorticoides , Imunossupressores , MutaçãoAssuntos
Proteínas de Transporte/metabolismo , Distrofias Neuroaxonais/complicações , Transtornos Parkinsonianos/complicações , Conformação Proteica em Folha beta , Adolescente , Adulto , Proteínas de Transporte/química , Proteínas de Transporte/genética , Feminino , Humanos , Deficiência Intelectual , Masculino , Transtornos Parkinsonianos/diagnóstico por imagem , Adulto JovemRESUMO
Chronic inflammation causes target organ damage in patients with systemic autoimmune diseases. The factors that allow this protracted response are poorly understood. We analyzed the transcriptional regulation of PPP2R2B (B55ß), a molecule necessary for the termination of the immune response, in patients with autoimmune diseases. Altered expression of B55ß conditioned resistance to cytokine withdrawal-induced death (CWID) in patients with autoimmune diseases. The impaired upregulation of B55ß was caused by inflammation-driven hypermethylation of specific cytosines located within a regulatory element of PPP2R2B preventing CTCF binding. This phenotype could be induced in healthy T cells by exposure to TNF-α. Our results reveal a gene whose expression is affected by an acquired defect, through an epigenetic mechanism, in the setting of systemic autoimmunity. Because failure to remove activated T cells through CWID could contribute to autoimmune pathology, this mechanism illustrates a vicious cycle through which autoimmune inflammation contributes to its own perpetuation.
Assuntos
Apoptose/efeitos dos fármacos , Doenças Autoimunes/metabolismo , Metilação de DNA , Proteínas do Tecido Nervoso/metabolismo , Proteína Fosfatase 2/metabolismo , Doenças Autoimunes/imunologia , Doenças Autoimunes/patologia , Fator de Ligação a CCCTC/metabolismo , Citocinas/metabolismo , Citosina/metabolismo , Metilação de DNA/efeitos dos fármacos , Regulação da Expressão Gênica , Humanos , Inflamação , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/farmacologia , Proteína Fosfatase 2/genética , Proteína Fosfatase 2/farmacologia , Linfócitos T , Regulação para CimaRESUMO
Methylenetetrahydrofolate reductase (MTHFR) is a key enzyme in folate metabolism. Folate deficiency has been related to several conditions, including neural tube defects (NTDs) and cardiovascular diseases. Hence, MTHFR genetic variants have been studied worldwide, particularly the C677T and A1298C. We genotyped the C677T and A1298C MTHFR polymorphisms in Mexican Amerindians (MAs), from the largest sample included in a genetic study (n = 2026, from 62 ethnic groups), and in a geographically-matched Mexican Mestizo population (MEZ, n = 638). The 677T allele was most frequent in Mexican individuals, particularly in MAs. The frequency of this allele in both MAs and MEZs was clearly enriched in the South region of the country, followed by the Central East and South East regions. In contrast, the frequency of the 1298C risk allele in Mexicans was one of the lowest in the world. Both in MAs and MEZs the variants 677T and 1298C displayed opposite allele frequency gradients from southern to northern Mexico. Our findings suggest that in Mestizos the 677T allele was derived from Amerindians while the 1298C allele was a European contribution. Some subgroups showed an allele frequency distribution that highlighted their genetic diversity. Notably, the distribution of the frequency of the 677T allele was consistent with that of the high incidence of NTDs reported in MEZ.
Assuntos
Predisposição Genética para Doença , Indígenas Norte-Americanos/genética , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Defeitos do Tubo Neural/genética , Polimorfismo Genético , Alelos , Etnicidade , Frequência do Gene , Genótipo , Humanos , Masculino , MéxicoRESUMO
Abstract Background: Hepatocarcinogenesis has a variety of risk factors. In Mexico City, autopsies found 14% of hepatocellular carcinomas (HCCs) without cirrhosis. Objective: The objective of the study was to explore if HCCs carry the TP53 R249S mutation that has linked them to aflatoxin exposure and describe the associated risk factors. Methods: A retrospective review of consecutive cases of HCC was performed. Exposure to hepatotropic viruses, alcoholism, metabolic diseases, diabetes mellitus, and hypertension, as well as episodes of ascites, portal hypertension, and body mass index were retrieved. Slides were re-reviewed, macrodissected and DNA was extracted. TP53 exon 7 was amplified, purified, and used as a template for sequencing. Results: In 14 years, 74 HCCs were identified in 1863 (4%) consecutive liver biopsies. No data were available in five excluded patients; the rest was submitted to exon 7 screening. Patients had a median age of 62 years, and 46 (67%) were male. Stage 4 fibrosis was observed in 46 patients (67%) and their associated risk factors were hepatitis C virus (39%, 18/46), alcoholism (20%, 9/46), hepatitis B virus (2%, 1/46), and 18 were cryptogenic. Fibrosis stage 3 or lower was observed in 23 (33%) patients without demonstrated liver disease; 8/23 had diabetes and 6/23, systemic hypertension. Steatohepatitic variants of HCC were observed in 4 and in 5, the remnant liver had steatohepatitis. A 238-bp fragment was obtained in each tumor without the expected TP53 R249S mutation. Conclusions: There was no evidence of aflatoxin exposure in HCCs, with and without the known classical risk factors. One-third of non-cirrhotic HCCs had steatohepatitis or conditions associated to metabolic syndrome. (REV INVEST CLIN. 2020;72(5):316-22)
RESUMO
El síndrome de VEXAS (Vacuolas, enzima E1, ligado al X, Autoinflamatorio, Somático) es un síndrome autoinflamatorio de inicio en la edad adulta que se caracteriza por mutaciones somáticas en el gen UBA1 y se considera el prototipo de enfermedad hematoinflamatoria. Los pacientes con síndrome de VEXAS exhiben manifestaciones inflamatorias y hematológicas que pueden conducir a diagnósticos clínicos como policondritis recidivante, poliarteritis nodosa, síndrome de Sweet y síndrome mielodisplásico. El diagnóstico requiere la evaluación de la médula ósea en búsqueda de vacuolas citoplásmicas en precursores mieloides y eritroides. Sin embargo, la confirmación genética de las mutaciones en UBA1 es necesaria. El tratamiento es un desafío y a menudo incluye glucocorticoides e inmunosupresores, con respuestas variables. Las terapias hipometilantes y el trasplante alogénico de células progenitoras hematopoyéticas se consideran terapias prometedoras. El pronóstico es influido por factores genéticos y clínicos. El objetivo de esta revisión es proporcionar una visión general sobre la patogénesis, la presentación clínica, el tratamiento y el pronóstico del síndrome de VEXAS para la comunidad médica latinoamericana.(AU)
VEXAS (Vacuoles, E1 enzyme, X-linked, Autoinflammatory, Somatic) syndrome is an adult-onset autoinflammatory syndrome characterized by somatic mutations in the UBA1 gene and is considered the prototype of hematoinflammatory diseases. Patients with VEXAS syndrome exhibit inflammatory and hematological manifestations that can lead to clinical diagnoses such as relapsing polychondritis, polyarteritis nodosa, Sweet syndrome, and myelodysplastic syndrome. Diagnosis requires bone marrow evaluation to identify cytoplasmic vacuoles in myeloid and erythroid precursors. However, genetic confirmation of mutations in UBA1 is necessary. Treatment is challenging and often involves glucocorticoids and immunosuppressants with variable responses. Hypomethylating agents and allogenic haemopoietic stem cell transplant are considered promising therapies. Prognosis is influenced by genetic and clinical factors. The aim of this review is to provide an overview of the pathogenesis, clinical presentation, treatment, and prognosis of VEXAS syndrome for the Latin American medical community.(AU)