Case Series: Hyperbilirubinemia under elexacaftor/tezacaftor/ivacaftor in the presence of Gilbert's syndrome.

Liver-related side effects are a known complication of treatment with elexacaftor/tezacaftor/ivacaftor (ETI) for cystic fibrosis (CF). Gilbert's syndrome is caused by a genetic mutation that reduces activity of the enzyme UDP glucuronosyltransferase 1 polypeptide A1 (UGT1A1), causing elevated levels of unconjugated bilirubin in the blood and duodenal bile. The presence of Gilbert's syndrome and CF might represent additive risk factors for liver-related adverse events during ETI treatment. This case series describes six people with CF (pwCF) in whom previously unknown Gilbert's syndrome was unmasked after initiation of treatment with ETI. Although all patients had some level of hepatic dysfunction and/or elevated levels of bilirubin after initiation of ETI, the clinical course varied. Only one patient had to stop ETI therapy altogether, while the others were able to continue treatment (some at a reduced dosage and others at the full recommended daily dosage). All patients, even those using a lower dosage, experienced clinical benefit during ETI therapy. Gilbert's syndrome is not a contraindication for ETI therapy but may be mistaken for a risk factor for liver-related adverse events in pwCF. This is something that physicians need to be aware of in pwCF who show liver adverse events during ETI therapy.

Unconjugated Hyperbilirubinemia in Acetaminophen-Related Acute Liver Failure.

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.

Association Between Intrapartum Nitrous Oxide for Labor Analgesia and Short-Term Neonatal Outcomes.

OBJECTIVE: To evaluate the association between intrapartum nitrous oxide use and adverse short-term neonatal outcomes. METHODS: This was a retrospective cohort study of individuals with singleton gestations at 35 or more weeks who attempted labor and delivered at an academic hospital between June 1, 2015, and February 28, 2020. Data were extracted from the electronic medical record using billing and diagnostic codes. Patients were classified based on whether they received no intrapartum analgesia or received nitrous oxide only. Those who received other analgesia types were excluded. The primary outcome was neonatal intensive care unit (NICU) admission. Secondary outcomes included Apgar score less than 7 at 1 minute and 5 minutes, respiratory composite outcome (including meconium aspiration syndrome, neonatal bronchopulmonary disorders, neonatal transient tachypnea, and other neonatal respiratory distress that required NICU admission), hypoglycemia, and hyperbilirubinemia. Univariable and multivariable analyses were used to estimate the association between nitrous oxide exposure intrapartum and the selected outcomes. RESULTS: Of 6,047 included, 4,153 (68.7%) received no analgesia, and 1,894 (31.3%) received nitrous oxide only. In comparison with individuals who received no analgesia, those who received nitrous oxide were more likely to be nulliparous, be of Black racial identity, have noncommercial insurance, and be less likely to deliver by intrapartum cesarean. The reception of nitrous oxide, compared with the reception of no analgesia, was associated with a lower likelihood of NICU admission (6.4% vs 8.1%; adjusted odds ratio [aOR] 0.77, 95% CI, 0.62-0.96) and an increased likelihood of neonatal hyperbilirubinemia (aOR 1.23, 95% CI, 1.08-1.41). Inhaled nitrous oxide exposure, in comparison with the reception of no analgesia, was not associated with the other secondary outcomes, including Apgar score less than 7 at 1 minute (odds ratio [OR] 0.74, 95% CI, 0.50-1.10) or 5 minutes (OR 0.91, 95% CI, 0.32-2.60), respiratory composite outcome (OR 0.91, 95% CI, 0.70-1.17), and hypoglycemia (OR 0.82, 95% CI, 0.64-1.05). CONCLUSION: In this single-center retrospective cohort of low-risk patients, intrapartum inhaled nitrous oxide, compared with the reception of no analgesia, was associated with a decreased risk for NICU admission but with an increased risk for hyperbilirubinemia; other outcomes did not differ. These findings may be used to counsel patients when considering nitrous oxide for labor analgesia.

Three or four doses of intravenous immunoglobulin G treatment for isoimmune hemolytic disease: A case series and literature review.

BACKGROUND: Neonates affected by isoimmune hemolytic disease (HDN) are at risk of developing severe hyperbilirubinemia. Studies show that increasing levels of bilirubin impact neonatal neurodevelopment. To avoid complications associated with exchange transfusion, intravenous immunoglobulin G (IVIG) is used to treat hyperbilirubinemia. We included all infants who received more than two doses of IVIG treatment for isoimmune hemolytic disease. We analyzed the incidence of side effects associated with IVIG treatment and the rate of exchange transfusion. METHODS: A retrospective chart review performed between October 2011-October 2022 at East Carolina University Health identified neonates who received more than two doses IVIG for HDN. Neonates of postmenstrual age greater than 28 days old, receiving less than three doses of IVIG or received IVIG for other indications were excluded. The occurrences of adverse events, demographics and use of other medical therapies were reviewed. RESULTS: Eleven neonates were included in the case series. Most common cause of severe hyperbilirubinemia was attributed to ABO incompatibility. Six patients (54%) received three doses of IVIG, and five patients (45%) received four doses of IVIG with bilirubin levels decreasing below exchange transfusion. No treatment exceeding four doses of IVIG was reported, nor adverse events during treatment. CONCLUSIONS: In this cohort of neonates with HDN, bilirubin levels decreased after treatment with multiple doses of IVIG. Future research on recommendations of optimal total number doses of IVIG to reduce the risk for exchange transfusion.

Coloración amarillenta inducida por quinacrina en una paciente con lupus eritematoso cutáneo / Yellow Skin Discoloration Induced by Quinacrine in a Patient with Cutaneous Lupus Erythematosus

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Colestasis intrahepática grave asociada a la ingesta decetiricina / Severe intrahepatic cholestasis associated with cetirizine

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Farmacogenómica de los antirretrovirales / Pharmacogenomics of antiretrovirals

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Efectos adversos de atazanavir / Adverse effects of atazanavir

Atazanavir es un fármaco que inhibe la proteasa del virus de la inmunodeficiencia humana (VIH) con muchas de las características de otros inhibidores de la proteasa y algunas ventajas sobre éstos, como la posología sólo una vez al día, la baja carga de comprimidos, la menor alteración gastrointestinal y un perfil metabólico más favorable, incluida la alteración del metabolismo de los hidratos de carbono. La hiperbilirrubinemia y la ictericia secundaria son su principal efecto adverso, aunque en raras ocasiones lleva a la suspensión del fármaco. Otros efectos adversos, como la nefrolitiasis o las alteraciones electrocardiográficas, son francamente raras

Atazanavir is a drug that inhibits HIV protease. It has many of the characteristics of other protease inhibitors and also some advantages over these, such as the single dose of once per day, low capsule load, less gastrointestinal problems and a very friendly metabolic profile, including carbohydrate metabolism. Secondary high plasma bilirubin and jaundice are its main adverse effect which only on rare occasions requires stopping the drug. Other adverse effects, such as nephrolithiasis or ECG changes are extremely rare

Atazanavir en la coinfección por VIH y virus de la hepatitis B y/o C / Safety of atazanavir in patients with HIV and hepatitis B and/or C virus coinfection

Atazanavir es un inhibidor de la proteasa indicado, en combinación con otros antirretrovirales, como tratamiento inicial de la infección por el virus de la inmunodeficiencia humana (VIH) o en pacientes pretratados. El tratamiento antirretroviral basado en atazanavir se ha relacionado con una baja frecuencia de hepatotoxicidad, tanto en ensayos clínicos como en estudio de cohortes. Sin embargo, el hallazgo de hiperbilirrubinemia ha resultado común en estos estudios, aunque usualmente no es una causa para la retirada del tratamiento. En pacientes coinfectados por virus de la hepatitis B (VHB) o C (VHC), el grado de respuesta virológica a atazanavir no se encuentra afectada y la incidencia de efectos adversos, salvo en la mayor incidencia de hepatotoxicidad, no es superior a la de los sujetos no coinfectados. La incidencia de hepatotoxicidad grave (grado 3-4) en pacientes coinfectados por el VIH y el VHC que reciben combinaciones de fármacos que incluyen atazanavir es de un 6%. Atazanavir tiene un favorable perfil de tolerabilidad y seguridad en pacientes coinfectados por virus de la hepatitis, incluso en presencia de fibrosis significativa. La menor relación de atazanavir con el desarrollo de resistencia a la insulina, hecho que se ha relacionado con una mayor velocidad de progresión de la fibrosis hepática y una menor tasa de respuesta al tratamiento, supondría un beneficio añadido del uso de atazanavir en pacientes coinfectados y podría servir de argumento adicional para su empleo en estos pacientes

Atazanavir is a protease inhibitor indicated, in combination with other antiretrovirals, as an initial treatment of HIV infection or in previously treated patients. Antiretroviral treatment based on atazanavir has been associated with a low incidence of hepatotoxicity, both in Clinical Trials as well as in cohort studies. However, the finding of hyperbilirubinaemia has been common in these studies, although it usually does not involve withdrawing the treatment. In patients co-infected with hepatitis B or C, the level of virological response to does not appear to be affected and the incidence of adverse effects, except the higher incidence of hepatotoxicity, is no higher than in non-coinfected subjects. The incidence of severe hepatotoxicity (grade 3-4) in patients coinfected by HIV and HVC who receive drug combinations that contain atazanavir is 6%. Atazanavir has a favourable tolerance and safety profile in patients coinfected with hepatitis virus even in the presence of significant fibrosis. The lower association of atazanavir with the development of insulin resistance, a fact that has been associated with increasing the progression to hepatic fibrosis and lower treatment response rates, could be an added benefit of the use atazanavir in coinfected patients and could serve as an additional argument for its use in these patients

Toxicogenética del tratamiento antirretroviral (y II): neurotoxicidad, hepatotoxicidad, acidosis láctica, daño renal y otros efectos adversos del tratamiento antirretroviral / Toxicogenetics of antiretroviral treatment (II): Neurotoxicity, hepatotoxicity, lactic acidosis, kidney damage, and other adverse effects of antiretroviral drugs

Diversos estudios farmacogenéticos han analizado la influencia de determinados polimorfismos genéticos en la toxicidad del tratamiento antirretroviral. En esta revisión se describen algunos de los efectos adversos de los fármacos antirretrovirales en los que se ha documentado que puede existir una predisposición genética: la toxicidad neurológica en pacientes en tratamiento con efavirenz, por lo general asociada al polimorfismo 516G>T de la isoenzima hepática 2B6 del sistema del citocromo P450 (CYP2B6); las reacciones de hipersensibilidad a nevirapina asociadas con alelos específicos del complejo mayor de histocompatibilidad (HLA), principalmente el alelo HLADRB1* 0101 que, en combinación con un recuento elevado de linfocitos CD4, se ha asociado a reacciones sistémicas y hepatitis en pacientes de raza caucásica, y el alelo HLACw8 asociado con las reacciones de hipersensibilidad en personas de la isla italiana de Cerdeña y de Japón; la hepatotoxidad con nevirapina (NVP) asociada al polimorfismo C>T en la posición 3435T del gen ABCB1 (MDR-1) que codifica la glucoproteína P (gp- P) (protector); la hiperbilirrubinemia en pacientes expuestos a atazanavir o indinavir portadores del polimorfismo UGT1A1*28; la neuropatía periférica con análogos de nucleósidos asociada al haplogrupo T del genoma mitocondrial (mayor riesgo) y al genotipo HFE C282Y del gen de la hemocromatosis (protector); la mutación en el codón 964 (R964C) del gen POLG que codifica la ADN polimerasa mitocondrial gamma descrita en un paciente tailandés con acidosis láctica; los haplotipos ABCC2 asociados con la tubulopatía proximal inducida por tenofovir, y el riesgo de pancreatitis en las personas con mutaciones en los genes CFTR y SPINK-1(AU)

Several pharmacogenetics studies have analyzed the influence of specific genetic polymorphisms on the toxicity of antiretroviral treatment. The present review describes some of the adverse effects of antiretroviral drugs in which a genetic predisposition may be involved: efavirenz-induced neurological toxicity, generally associated with the 516G>T polymorphism of liver enzyme cytochrome P450 2B6 (CYP2B6); hypersensitivity reactions to nevirapine, associated with specific alleles of major histocompatibility complex, mainly the HLADRB1* 0101 allele, which, in combination with a high CD4 lymphocyte count, has been associated with systemic reactions and hepatitis in Caucasians, and the HLA-Cw8 allele, which is associated with hypersensitivity reactions in persons from the Italian island of Sardinia and from Japan; nevirapine-induced hepatotoxicity associated with the C>T polymorphism in position 3435T of the ABCB1 (MDR-1) gene codifying for glycoprotein P (lower risk); hyperbilirubinemia in patients exposed to atazanavir or indinavir carrying the UGT1A1*28 polymorphism; peripheral neuropathy with nucleoside analogues associated with haplogroup T of the mitochondrial genome (higher risk) and with the HFE C282Y genotype of the hemochromatosis gene (lower risk); the mutation in codon 964 (R964C) of the POLG gene that codifies the mitochondrial polymerase DNA gamma described in a Thai patient with lactic acidosis; the ABCC2 gene haplotypes associated with tenofovir-induced proximal tubulopathy, and the risk of pancreatitis in persons with mutations in the CFTR and SPINK-1 genes(AU)