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Annals of Cardiac Anaesthesia Jan 2024
Topics: Humans; Tricuspid Valve; Perioperative Care; Heart Valve Prosthesis Implantation; Gilbert Disease; Male; Tricuspid Valve Insufficiency
PubMed: 38722133
DOI: 10.4103/aca.aca_58_23 -
Viruses Mar 2024Primary Epstein-Barr virus (EBV) infection manifests with diverse clinical symptoms, occasionally resulting in severe complications. This scoping review investigates the... (Review)
Review
Primary Epstein-Barr virus (EBV) infection manifests with diverse clinical symptoms, occasionally resulting in severe complications. This scoping review investigates the rare occurrence of acute acalculous cholecystitis (AAC) in the context of primary EBV infection, with a focus on understanding its prevalence, clinical features, and underlying mechanisms. The study also explores EBV infection association with Gilbert syndrome, a condition that potentially exacerbates the clinical picture. Additionally, a case report of an 18-year-old female presenting with AAC and ascites secondary to EBV infection enhances the review. A comprehensive literature review was conducted, analyzing reported cases of AAC secondary to EBV infection. This involved examining patient demographics, clinical presentations, laboratory findings, and outcomes. The search yielded 44 cases, predominantly affecting young females. Common clinical features included fever, cervical lymphadenopathy, tonsillitis/pharyngitis, and splenomegaly. Laboratory findings highlighted significant hepatic involvement. The review also noted a potential link between AAC in EBV infection and Gilbert syndrome, particularly in cases with abnormal bilirubin levels. AAC is a rare but significant complication of primary EBV infection, primarily observed in young females, and may be associated with Gilbert syndrome. This comprehensive review underscores the need for heightened clinical awareness and timely diagnosis to manage this complication effectively.
Topics: Female; Humans; Adolescent; Epstein-Barr Virus Infections; Acalculous Cholecystitis; Herpesvirus 4, Human; Gilbert Disease; Ascites
PubMed: 38543828
DOI: 10.3390/v16030463 -
The American Journal of Case Reports Mar 2024BACKGROUND In the absence of liver transplantation, the natural history of acetaminophen-induced liver failure is characterized by a progressive increase of liver...
BACKGROUND In the absence of liver transplantation, the natural history of acetaminophen-induced liver failure is characterized by a progressive increase of liver function tests, including bilirubin mainly as its conjugated form. The presence of high levels of unconjugated bilirubin is more unusual; its etiology is unclear and its prognostic factor has been poorly investigated. CASE REPORT A 52-year-old man with a history of chronic analgesics, alcohol, and illicit drug abuse developed acute liver failure in relationship with the ingestion of largely supra-therapeutic doses of acetaminophen over the days preceding admission. The patient received the classical N-acetylcysteine treatment regimen for acetaminophen overdose. Clinical course was characterized by a progressive worsening of the neurological condition, evolving to grade IV encephalopathy. Coagulation disorders persisted, with factor V level <10%. He fulfilled the criteria for liver transplantation, but this option was rejected after a careful psychiatric evaluation. Laboratory investigations revealed a progressive increase in serum unconjugated bilirubin until his death. As evidence for hemolysis was lacking, acquired deficit in bilirubin glucuronidation appeared likely and diagnosis of Gilbert's syndrome was excluded. CONCLUSIONS After the exclusion of other causes of high unconjugated bilirubin levels, the progressive increase in unconjugated bilirubin can reflect a persistent defect in bilirubin conjugation in relationship with liver centrilobular injury, but the relationship with acetaminophen-glucuronidation is not known and there are insufficient data to affirm that the ratio unconjugated/conjugated bilirubin could be used as a prognostic factor.
Topics: Male; Humans; Middle Aged; Acetaminophen; Hyperbilirubinemia; Gilbert Disease; Liver; Bilirubin; Liver Failure, Acute
PubMed: 38514990
DOI: 10.12659/AJCR.942703 -
Orphanet Journal of Rare Diseases Mar 2024Recently, the safety and efficacy of gene therapy were evaluated in patients with Crigler-Najjar syndrome (CNS). Although it is a promising curative option for CNS, many...
Recently, the safety and efficacy of gene therapy were evaluated in patients with Crigler-Najjar syndrome (CNS). Although it is a promising curative option for CNS, many doubts still persist about its long-term efficacy and safety. Furthermore, there is a risk of overlooking several unresolved problems still present in current clinical practice. This letter is a call for action on crucial open issues that remain nowadays an unmet need in the management of CNS patients.
Topics: Humans; Crigler-Najjar Syndrome; Emotions; Genetic Therapy
PubMed: 38448957
DOI: 10.1186/s13023-024-03108-x -
Journal of Human Lactation : Official... May 2024Neonatal jaundice and prematurity pose significant barriers to breastfeeding in the first days of life. There is limited literature exploring the relationship between...
INTRODUCTION
Neonatal jaundice and prematurity pose significant barriers to breastfeeding in the first days of life. There is limited literature exploring the relationship between prolonged jaundice in breastfed infants and Gilbert's (Meulengraght) syndrome. This case study describes the diagnostic and therapeutic challenges associated with Gilbert's syndrome in a late preterm breastfed infant born in Germany.
MAIN ISSUE
In this case report, an infant born to a primipara woman presented at 3 weeks postpartum to an International Board Certified Lactation Consultant. The initial assessment revealed a late preterm infant with inadequate weight gain and jaundice. The dyad received breastfeeding support and eventually achieved adequate weight gain; however, the infant's jaundice persisted.
MANAGEMENT
The consulting midwife suggested that the persistent jaundice was "breastmilk jaundice" and recommended temporarily interrupting breastfeeding. Due to a suspected family history of Gilbert's Syndrome, the dyad was referred, instead, to a pediatric gastroenterologist. Pathologic liver disease was excluded, and genetic testing confirmed Gilbert's Syndrome. At 6 months of age, the dyad was successfully breastfeeding and beginning complementary feeding.
CONCLUSION
Genetic testing for Gilbert's Syndrome should be considered for infants with prolonged jaundice and positive family history. Interruption or cessation of breastfeeding are not evidence-based recommendations, and current guidelines do not support these practices. Lactation professionals play a critical role in the management of breastfeeding for preterm infants with prolonged jaundice and should refer to specialists to rule out pathologic etiologies.
Topics: Female; Humans; Infant, Newborn; Breast Feeding; Gilbert Disease; Infant, Premature; Jaundice; Weight Gain
PubMed: 38334089
DOI: 10.1177/08903344241227226 -
Journal of the American Heart... Feb 2024Transthyretin cardiac amyloidosis (ATTR-CA) is a progressive and ultimately fatal cardiomyopathy. Biomarkers reflecting multiorgan dysfunction are of increasing...
BACKGROUND
Transthyretin cardiac amyloidosis (ATTR-CA) is a progressive and ultimately fatal cardiomyopathy. Biomarkers reflecting multiorgan dysfunction are of increasing importance in patients with heart failure; however, their significance in ATTR-CA remains largely unknown. The aims of this study were to characterize the multifaceted nature of ATTR-CA using blood biomarkers and assess the association between blood biomarkers and prognosis.
METHODS AND RESULTS
This is a retrospective cohort study of 2566 consecutive patients diagnosed with ATTR-CA between 2007 and 2023. Anemia (39%), high urea (52%), hyperbilirubinemia (18%), increased alkaline phosphatase (16%), increased CRP (C-reactive protein; 27%), and increased troponin (98.2%) were common findings in the overall population, whereas hyponatremia (6%) and hypoalbuminemia (2%) were less common. These abnormalities were most common in patients with p.(V142I) hereditary ATTR-CA, and became more prevalent as the severity of cardiac disease increased. Multivariable Cox regression analysis demonstrated that anemia (hazard ratio [HR], 1.19 [95% CI, 1.04-1.37]; =0.01), high urea (HR, 1.23 [95% CI, 1.04-1.45]; =0.01), hyperbilirubinemia (HR, 1.32 [95% CI, 1.13-1.57; =0.001), increased alkaline phosphatase (HR, 1.20 [95% CI, 1.01-1.42; =0.04), hyponatremia (HR, 1.65 [95% CI, 1.28-2.11]; <0.001), and troponin-T >56 ng/L (HR, 1.72 [95% CI, 1.46-2.03]; <0.001) were all independently associated with mortality in the overall population. The association between biomarkers and mortality varied across the spectrum of genotypes and left ventricular ejection fraction, with anemia remining independently associated with mortality in p.(V142I) hereditary ATTR-CA (HR, 1.58 [95% CI, 1.17-2.12]; =0.003) and in a subgroup of the overall population with a left ventricular ejection fraction ≤40% (HR, 1.39 [95% CI, 1.08-1.81]; =0.01).
CONCLUSIONS
Cardiac and noncardiac biomarker abnormalities were common and reflect the complex and multifaceted nature of ATTR-CA, with a wide range of biomarkers remaining independently associated with mortality. Clinical trials are needed to investigate whether biomarker abnormalities represent modifiable risk factors that if specifically targeted could improve outcomes.
Topics: Humans; Prealbumin; Cardiomyopathies; Amyloid Neuropathies, Familial; Stroke Volume; Retrospective Studies; Alkaline Phosphatase; Hyponatremia; Ventricular Function, Left; Prognosis; Biomarkers; Anemia; Hyperbilirubinemia; Urea
PubMed: 38314569
DOI: 10.1161/JAHA.123.033094 -
Medicine Jan 2024Dubin-Johnson syndrome (DJS) is a rare autosomal recessive liver disorder, characterized by conjugated hyperbilirubinemia. This case report investigates the clinical...
BACKGROUND
Dubin-Johnson syndrome (DJS) is a rare autosomal recessive liver disorder, characterized by conjugated hyperbilirubinemia. This case report investigates the clinical characteristics and longitudinal outcomes of a neonate diagnosed with DJS.
METHODS
A newborn presented with elevated bilirubin levels and abnormal liver enzyme readings. Comprehensive genetic evaluation was conducted, which included peripheral blood sample collection from the infant and both parents after obtaining informed consent and high-throughput trio exome sequencing was performed. The genetic analysis revealed 2 significant mutations in the ABCC2 gene on chromosome 10: the insertion mutation c.4237(exon30)_c.4238(exon30)ins CT, inherited from the father, and the missense mutation c.517(exon5)G > A, inherited from the mother. Both mutations were classified as pathogenic according to the ACMG 2015 guidelines, indicating a compound heterozygous inheritance pattern. The patient's treatment regimen included phototherapy, which was initiated to address her jaundice upon admission. To support liver function and regulate gut activity, oral ursodeoxycholic acid (20 mg/kg/dose, twice a day) and probiotics were administered. Additionally, a postdischarge medication plan involving a low-dose regimen of phenobarbital (3.5 mg/kg/dose, twice a day) was implemented for 2 weeks.
RESULTS
During a 2-year follow-up after discharge, the infant's bilirubin levels significantly decreased, and liver enzymes, including GGT, progressively normalized.
CONCLUSION
This case report enhances the understanding of DJS in neonates by emphasizing the clinical ramifications of compound heterozygous mutations within the ABCC2 gene and documenting the evolution of the disease. The gradual normalization of liver function tests suggests potential compensatory mechanisms in response to the genetic abnormalities in neonates with DJS. The correlation between the patient's genetic profile of compound heterozygosity and her milder clinical phenotype warrants attention, suggesting that this specific genetic configuration may be associated with less severe manifestations of the disease. The necessity for long-term follow-up is highlighted, recognizing that intercurrent stress conditions could influence the hepatic profile and potentially exacerbate symptoms. Such sustained observation is crucial to further delineate the genomic and clinical landscape of DJS, offering opportunities to refine prognostic and therapeutic approaches.
Topics: Female; Humans; Infant, Newborn; Aftercare; Bilirubin; Follow-Up Studies; Jaundice, Chronic Idiopathic; Multidrug Resistance-Associated Protein 2; Multidrug Resistance-Associated Proteins; Patient Discharge
PubMed: 38277553
DOI: 10.1097/MD.0000000000036991 -
Stem Cell Reports Nov 2023UGT1A1 (UDP glucuronosyltransferase family 1 member A1) is the primary enzyme required for bilirubin conjugation, which is essential for preventing hyperbilirubinemia....
UGT1A1 (UDP glucuronosyltransferase family 1 member A1) is the primary enzyme required for bilirubin conjugation, which is essential for preventing hyperbilirubinemia. Animal models lack key human organic anion transporting polypeptides with distinct epigenetic control over bilirubin metabolism, necessitating a human model to interrogate the regulatory mechanism behind UGT1A1 function. Here, we use induced pluripotent stem cells to develop human liver organoids that can emulate conjugation failure phenotype. Bilirubin conjugation assays, chromatin immunoprecipitation, and transcriptome analysis elucidated the role of glucocorticoid antagonism in UGT1A1 activation. This antagonism prevents the binding of transcriptional repressor MECP2 at the expense of NRF2 with associated off-target effects. Therefore, we introduced functional GULO (L-gulonolactone oxidase) in human organoids to augment intracellular ascorbate for NRF2 reactivation. This engineered organoid conjugated more bilirubin and protected against hyperbilirubinemia when transplanted in immunosuppressed Crigler-Najjar syndrome rat model. Collectively, we demonstrate that our organoid system serves as a manipulatable model for interrogating hyperbilirubinemia and potential therapeutic development.
Topics: Humans; Animals; Rats; Bilirubin; NF-E2-Related Factor 2; Liver; Crigler-Najjar Syndrome; Hyperbilirubinemia; Glucuronosyltransferase; Pluripotent Stem Cells
PubMed: 37832542
DOI: 10.1016/j.stemcr.2023.09.006 -
Cells Sep 2023Bilirubin-induced neurological damage (BIND), which might progress to kernicterus, occurs as a consequence of defects in the bilirubin conjugation machinery, thus...
Bilirubin-induced neurological damage (BIND), which might progress to kernicterus, occurs as a consequence of defects in the bilirubin conjugation machinery, thus enabling albumin-unbound free bilirubin (BF) to cross the blood-brain barrier and accumulate within. A defect in the UGT1A1 enzyme-encoding gene, which is directly responsible for bilirubin conjugation, can cause Crigler-Najjar syndrome (CNS) and Gilbert's syndrome. We used human-induced pluripotent stem cell (hiPSC)-derived 3D brain organoids to model BIND in vitro and unveil the molecular basis of the detrimental effects of BF in the developing human brain. Healthy and patient-derived iPSCs were differentiated into day-20 brain organoids, and then stimulated with 200 nM BF. Analyses at 24 and 72 h post-treatment point to BF-induced neuro-inflammation in both cell lines. Transcriptome, associated KEGG, and Gene Ontology analyses unveiled the activation of distinct inflammatory pathways, such as cytokine-cytokine receptor interaction, MAPK signaling, and NFκB activation. Furthermore, the mRNA expression and secretome analysis confirmed an upregulation of pro-inflammatory cytokines such as IL-6 and IL-8 upon BF stimulation. This novel study has provided insights into how a human iPSC-derived 3D brain organoid model can serve as a prospective platform for studying the etiology of BIND kernicterus.
Topics: Humans; Crigler-Najjar Syndrome; Induced Pluripotent Stem Cells; Kernicterus; Brain; Cytokines; Bilirubin
PubMed: 37759499
DOI: 10.3390/cells12182277 -
Hepatology Communications Oct 2023Gilbert syndrome (GS) is genotypically predetermined by UGT1A1*28 homozygosity in Europeans and is phenotypically defined by hyperbilirubinemia using total bilirubin...
BACKGROUND AND AIMS
Gilbert syndrome (GS) is genotypically predetermined by UGT1A1*28 homozygosity in Europeans and is phenotypically defined by hyperbilirubinemia using total bilirubin (TB) cutoff ≥1mg/dL (17 μmol/L). The prevalence of illnesses associated with GS and hypobilirubinemia has never been studied prospectively. As TB varies with UGT1A1*28 genotyping, sex, and age, we propose stratified definitions of TB reference intervals and report the prevalence of illnesses and adjusted 15 years survival.
METHODS
UK Biobank with apparently healthy liver participants (middle-aged, n=138,125) were analyzed after the exclusion of of nonhealthy individuals. The stratified TB was classified as GS when TB >90th centile; <10th centile indicated hypobilirubinemia, and between the 10th and 90th centile was normobilirubinemia. We compared the prevalence and survival rates of 54 illnesses using odds ratio (OR), logistic regression, and Cox models adjusted for confounders, and causality by Mendelian randomizations.
RESULTS
In women, we identified 10% (7,741/76,809) of GS versus 3.7% (2,819/76,809) using the historical cutoff of ≥1 mg/dL (P<0.0001). When GS and hypobilirubinemia participants were compared with normobilirubinemia, after adjustment and Mendelian randomizations, only cholelithiasis prevalence was significantly higher (OR=1.50; 95% CI [1.3-1.7], P=0.001) in men with GS compared with normobilirubinemia and in causal association with bilirubin (P=0.04). No adjusted survival was significantly associated with GS or hypobilirubinemia.
CONCLUSIONS
In middle-aged Europeans, the stratified TB demonstrates a careless GS underestimation in women when using the standard unisex 1 mg/dL cutoff. The prevalence of illnesses is different in GS and hypobilirubinemia as well as survivals before adjusting for confounding factors. With the exception of cholelithiasis in men, these differences were no more significant after adjustment and Mendelian randomization.
Topics: Male; Middle Aged; Female; Humans; Adolescent; Gilbert Disease; Bilirubin; Hyperbilirubinemia; Liver; Healthy Volunteers
PubMed: 37738404
DOI: 10.1097/HC9.0000000000000245