Case of parvovirus B19 infection and immunodeficiency in the patient with Gilbert syndrome

A case of long-term persistence of parvovirus B19 is described for the first time in a patient with Gilbert's syndrome against the background of immunodeficiency with predominance of infectious symptoms (chronic herpesvirus infection). Previously, the patient (male, 48 years old) was diagnosed with Gilbert's syndrome, chronic rhinosinusopharyngitis, and chronic herpesvirus infection. In July 2017, parvovirus B19 DNA was detected in blood. No clinical manifestations of infectious erythema were noted. The patient was admitted to the medical center of St. Petersburg Pasteur Institute. His blood samples obtained under informed consent were examined at the medical center in Central Clinical and Diagnostic Laboratory of St. Petersburg Pasteur Institute in January and June 2018 and in November 2019. ELISA test systems “Anti-Parvovirus B19 ELISA (IgM)” and “Anti-Parvovirus B19 ELISA (IgG)” (Euroimmune, Germany), as well PCR reagent kit “AmpliSens Parvovirus B19-FL” (FSB Central Research Institute of Epidemiology of Rospotrebnadzor, Russia) were used for specific diagnostics. Interferon status was determined by the induced production of IFN types I, II and circulating (serum) interferons. Moreover, we considered the laboratory data obtained earlier at different medical facilities of St. Petersburg. IgM class antibodies to the parvovirus B19 were not detected in the blood samples obtained in 2018. IgG antibody titer was 96 IU/ml and 264 IU /ml, respectively. Parvovirus B19 DNA was isolated from blood plasma, but the viral load was less than 720 IU of PVB19 DNA/ml (1.5 x 102 and 1.9 x 102 copies of DNA/ml, respectively). Clinical blood analysis, showed only minor (no more than 7%) deviations from the reference values, increased hemoglobin saturation of red blood cells (RBC), a decreased width of RBC distribution curve, and relative lymphocytosis. A deficiency of various interferon types was revealed: IFNγ level was 80 IU/ml in both samples, IFNα, IFNβ amounts varied from 80 to 160 IU/ml, respectively. The period of parvovirus B19 DNA persistence in blood was 11 months in presence of immunodeficiency. The patient was administered drugs of the interferon group. Parvovirus B19 DNA was not detected in clinical samples of November 2019; IFNα, IFNβ and IFNγ values were 160 IU/ml. We have detected recovery of lymphoid cell ratio, increase in their number, and improved indexes of interferon status.

SÍNDROME DE GILBERT E SUA RELAÇÃO COM DOENÇAS CARDIOVASCULARES

RESUMO Introdução: A Síndrome de Gilbert (SG), caracterizada pelo aumento moderado de bilirrubina não conjugada (BNC), pode coexistir com outras condições mais clinicamente significativas e interferir em seus parâmetros clínicos e diagnósticos. Objetivo: Identificar na literatura a relação da Síndrome de Gilbert com doenças cardiovasculares (DCV), além de trazer uma visão geral sobre a associação da bilirrubina ao metabolismo lipídico alterado e a outros parâmetros hematológicos. Método: Trata-se de uma revisão integrativa, utilizando como fontes de pesquisa a SciELO, LILACS, PubMed e periódicos da CAPES. Artigos de revisão, relatos de casos, teses, dissertações e monografias foram excluídos. Os descritores “Doença de Gilbert”, “doenças cardiovasculares”, “hiperbilirrubinemia” e “testes hematológicos” foram utilizados no idioma inglês e seus correspondentes em português, empregando o operador booleano “AND”. Resultados: A busca nas bases de dados resultou na seleção de 11 artigos, publicados entre 2011 e 2017, que permitiram especular evidências sobre a relação existente entre a hiperbilirrubinemia leve na SG com as DCV. Níveis de estresse oxidativo reduzido, atenuação de ativação plaquetária e de processos pró-inflamatórios, hipocolesterolemia e outros achados foram associados à concentração de BNC. Conclusão: Os estudos evidenciaram possíveis mecanismos que podem contribuir para a redução do risco de DCV em indivíduos com SG, principalmente na incidência de arritmias cardíacas, doença arterial coronariana e cardiopatias ateroscleróticas. Palavras-chave: Doença de Gilbert; UDP-glucuronosiltransferase; Hiperbilirrubinemia; Doenças Cardiovasculares; Testes Hematológicos. ABSTRACT Introduction: Gilbert's Syndrome (GS), characterized by a moderate increase in unconjugated bilirubin (UCB), can coexist with other more clinically significant conditions and interfere with its clinical and diagnostic parameters. Objective: To identify in the literature the relationship between Gilbert's Syndrome and cardiovascular diseases (CVD), in addition to providing an overview of the association of bilirubin with altered lipid metabolism and other hematological parameters. Method: This is an integrative review, using SciELO, LILACS, PubMed and CAPES journals as research sources. Review articles, case reports, theses, dissertations and monographs were excluded. The descriptors "Gilbert Disease", "cardiovascular diseases", "hyperbilirubinemia" and "hematologic tests" were used in english and their correspondents in portuguese, using the boolean operator "AND". Results: The search in the databases resulted in the selection of 11 articles, published between 2011 and 2017, which allowed speculating evidence on the relationship between mild hyperbilirubinemia in GS and CVD. Levels of reduced oxidative stress, attenuation of platelet activation and pro-inflammatory processes, hypocholesterolemia and other findings were associated with UCB concentration. Conclusion: The studies showed possible mechanisms that can contribute to the reduction of CVD risk in individuals with GS, mainly in the incidence of cardiac arrhythmias, coronary artery disease and atherosclerotic heart diseases. Keywords: Gilbert Disease; UDP-glucuronosyltransferase; Hyperbilirubinemia; Cardiovascular Diseases; Hematologic Tests

Oral Manifestations of a Patient Suffering from a Rare Gilbert’s Syndrome: A Case Report

Gilbert's syndrome is a rare genetic disorder characterized by abnormal glucuronidation of bilirubin in the liver, presenting as unconjugated hyperbilirubinemia in the absence of hepatocellular injury or hemolysis. Diagnosis of this pathology is primarily made during routine examination described as the presence of a yellowish tinge in the eyes and skin in general. Normally, the oral manifestations of Gilbert's syndrome are present but mostly go unnoticed as the teeth are minimally affected which are visible to the patient and surrounding mucosa in the oral cavity, where yellow discoloration can be appreciated. Dental treatments are smoothly carried out for such patients like extractions, root canal treatment, cleaning prophylaxis. The patient in this case safely underwent the root canal treatment after being diagnosed with irreversible pulpitis without any unusual discomfort. Local anesthesia can also be safely administered to such patients such as infiltration and inferior alveolar block anesthesia.

Gilbert’s Syndrome and the Gut Microbiota – Insights From the Case-Control BILIHEALTH Study

The heme catabolite bilirubin has anti-inflammatory, anti-oxidative and anti-mutagenic effects and its relation to colorectal cancer (CRC) risk is currently under evaluation. Although the main metabolic steps of bilirubin metabolism, including the formation of stercobilin and urobilin, take place in the human gastrointestinal tract, potential interactions with the human gut microbiota are unexplored. This study investigated, whether gut microbiota composition is altered in Gilbert’s Syndrome (GS), a mild form of chronically elevated serum unconjugated bilirubin (UCB) compared to matched controls. Potential differences in the incidence of CRC-associated bacterial species in GS were also assessed. To this end, a secondary investigation of the BILIHEALTH study was performed, assessing 45 adults with elevated UCB levels (GS) against 45 age- and sex-matched controls (C). Fecal microbiota analysis was performed using 16S rRNA gene sequencing. No association between mildly increased UCB and the composition of the gut microbiota in this healthy cohort was found. The alpha and beta diversity did not differ between C and GS and both groups showed a typical representation of the known dominant phyla. Furthermore, no difference in abundance of Firmicutes and Proteobacteria, which have been associated with the mucosa of CRC patients were observed between the groups. A sequence related to the Christensenella minuta strain YIT 12065 was identified with a weak association value of 0.521 as an indicator species in the GS group. This strain has been previously associated with a lower body mass index, which is typical for the GS phenotype. Overall, sex was the only driver for an identifiable difference in the study groups, as demonstrated by a greater bacterial diversity in women. After adjusting for confounding factors and multiple testing, we can conclude that the GS phenotype does not affect the composition of the human gut microbiota in this generally healthy study group.

Oxidative Stress and Related Biomarkers in Gilbert’s Syndrome: A Secondary Analysis of Two Case-Control Studies

Bilirubin is an important antioxidant and a modulator of biological functions. However, most of the protection against oxidative stress was shown in vitro or ex vivo. The aim of this case-control study was to investigate whether subjects with Gilbert’s syndrome (GS) experience different levels of lipid and protein oxidation (as well as differences in oxidative stress related markers) compared to healthy controls. GS subjects (n = 119) demonstrated higher serum levels of unconjugated bilirubin (p < 0.001), a lower BMI (p < 0.001), 37% higher antioxidant potential assessed as ferric reducing ability potential (p < 0.001), higher advanced oxidation protein products (p < 0.01) andlower apolipoprotein B (p < 0.05), hs-C-reactive protein (p < 0.05), interleukin 6 (p < 0.001) and interleukin 1 beta (p < 0.05) values compared to healthy controls (n = 119). Furthermore, the resting heart rate was significantly lower in the GS group (p < 0.05). Stronger protective effects for GS subjects were demonstrated in the older subgroup (n = 104, average age 50 years) compared to those of the younger group (n = 134, average age 27 years). Although not all markers related to oxidative stress were different between the groups (e.g., malondialdehyde, homocysteine, oxLDL, and myeloperoxidase; p > 0.05), the observed differences contribute to the explanation of why GS serves as an important protector in the pathogenesis of metabolic, oxidative stress related diseases.

How dangerous Gilbert's syndrome is

Gilbert's syndrome is a benign (functional) hyperbilirubinemia, which is based on a hereditary disorder of bilirubin metabolism, as a result of which the concentration of unbound bilirubin can increase several times. Bilirubin, being a breakdown product of hemoglobin, circulates through the bloodstream, combining with albumin molecules. Such bilirubin is called indirect. In the endoplasmic reticulum, it is conjugated; the enzyme glucuronyltransferase is responsible for this process. In Gilbert's syndrome, as a result of insufficient production of this enzyme, the conjugation process is disrupted, and, as a result, the concentration of unconjugated bilirubin increases. According to statistics, this pathological condition is observed in about 5 % of Russians. This syndrome was first described in 1901 by the French physician Augustin Nicolas Gilbert, and was subsequently named after him. The literature also contains references to this syndrome, described as «constitutional hepatic dysfunction», «familial non-hemolytic hyperbilirubinemia», «idiopathic non-conjugated hyperbilirubinemia». Gilbert's syndrome is inherited in an autosomal recessive manner; men get ill 3–4 times more often than women. A number of scientists associate this with a possible inhibitory effect of testosterone on the enzyme UDP-GT1, which breaks down bilirubin. Clinically, Gilbert's syndrome is manifested by episodes of jaundice caused by an increase in the level of unconjugated bilirubin in the blood serum. Against the background of icterus of the sclera and skin, there is increased fatigue, the appearance of a feeling of bitterness in the mouth, loss of appetite, nausea, and sometimes vomiting. The association of Gilbert's syndrome with functional disorders of the biliary tract, in particular, with gallbladder dyskinesia, is often noted.

Prolonged Hyperbilirubinemia after Contrast Use in a 16-Year-Old Boy with Gilbert's Syndrome: A Case Report and Literature Review

This paper reports a child with Gilbert's syndrome who underwent cholecystectomy and endoscopic retrograde cholangiopancreatography, magnetic resonance cholangiopancreaticography to removal of the gallstones, then experienced increase in bilirubin of unknown cause.