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Congenital dyserythropoietic anemia and drug-induced liver injury present as bland cholestasis: A case report.

ABSTRACT: Anemias and drug-induced liver injury(DILI) are separate disorders, which are difficult to diagnose. The clinical effects of DILI vary among individuals. However, the outcome determinants remain to be fully established. To the best of our knowledge, the role of anemia in DILI has yet to be reported. The present study reported on the case of one Chinese patient (male; age, 21 years) who experienced obvious drug-induced cholestasis. Of note, the hepatocyte injury was minimal compared with that in previously reported cases treated with the same drug. In addition, the patient suffered from mild hemolytic anemia with no obvious cause. A genetic pedigree analysis revealed compound heterozygous mutations in the congenital anemia-associated gene codanin 1, including the novel rare p.R1067H mutation. Treatment with ursodeoxycholic acid alone sufficed and the outcome was good. Therefore, whilst chronic hemolysis predisposed the liver to cholestasis, it could have shielded the liver from further injuries, since bilirubin, a by-product of hemolysis, is a known antioxidant. The results of the present study indicated that genetic screening may be used for the diagnosis of liver injury concurring with undiagnosed anemia.

SUBMITTER: Han Y

PROVIDER: S-EPMC7967802 | biostudies-literature | 2021 May

REPOSITORIES: biostudies-literature

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Congenital dyserythropoietic anemia and drug-induced liver injury present as bland cholestasis: A case report.

Han Yue Y Zhuang Yan Y Tang Weiliang W Chen Lu L Chen Yejing Y Gong Qiming Q Zhang Xinxin X

Experimental and therapeutic medicine 20210302 5

Anemias and drug-induced liver injury(DILI) are separate disorders, which are difficult to diagnose. The clinical effects of DILI vary among individuals. However, the outcome determinants remain to be fully established. To the best of our knowledge, the role of anemia in DILI has yet to be reported. The present study reported on the case of one Chinese patient (male; age, 21 years) who experienced obvious drug-induced cholestasis. Of note, the hepatocyte injury was minimal compared with that in ...[more]

PMID: 33777192

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Project description:Congenital dyserythropoietic anemia type II (CDAII) is an autosomal recessive disease resulting from loss-of-function mutations in SEC23B, which encodes a component of coat complex protein II (COPII) vesicles. We have previously shown that the expression of SEC23A, a paralogous protein for SEC23B, is significantly lower than that of SEC23B in human erythroid cells and that increased SEC23A expression rescues CDAII. In this study, we generated a human erythroid cell line that expresses eGFP from the endogenous genomic locus of SEC23A and performed a small molecule screen to identify compounds that increase the SEC23A-eGFP level. The top compound passing all filters was an LSD1 inhibitor. We validated that LSD1 inhibition with RN1 i) results in increased SEC23A mRNA and protein levels in primary erythroid cells derived from CD34+ human hematopoietic stem and progenitor cells (HSPCs), at doses that do not impair erythroid cell growth or differentiation and ii) rescues the defect resulting from SEC23B deletion in primary human erythroid cells. We validated LSD1 as the target of RN1 by showing that genetic downregulation of LSD1 also led to a profound induction of SEC23A mRNA levels in HPSC-derived erythroid cells. Subsequently, we validated our findings in vivo, demonstrating that deletion of Lsd1 in mouse erythroid cells results in increased Sec23a expression and that RN1 treatment rescues the erythroid defect observed in CDAII mice. Finally, using CUT&RUN, we found that LSD1 occupies a sequence in the SEC23A promoter, which when deleted, results in increased SEC23A expression and rescue of CDAII. These finding suggest that LSD1 occupies the SEC23A promoter, repressing SEC23A transcription and that in the setting of LSD1 inhibition, SEC23A expression is de-repressed, resulting in CDAII rescue. Therefore, using an unbiased screen, we have identified and validated a novel promising therapeutic strategy for CDAII, using a compound that inhibit LSD1 or a genetic approach based on deleting the SEC23A promoter sequence that is occupied by LSD1.

Project description:BackgroundCongenital dyserythropoietic anemia type II (CDAII), the most common form of CDA, is an autosomal recessive condition. CDAII diagnosis is based on invasive, expensive, and time consuming tests that are available only in specialized laboratories. The recent identification of SEC23B mutations as the cause of CDAII opens new possibilities for the molecular diagnosis of the disease. The aim of this study was to characterize molecular genomic SEC23B defects in 16 unrelated patients affected by CDAII and correlate the identified genetic alterations with SEC23B transcript and protein levels in erythroid precursors.MethodsSEC23B was sequenced in 16 patients, their relatives and 100 control participants. SEC23B transcript level were studied by quantitative PCR (qPCR) in peripheral erythroid precursors and lymphocytes from the patients and healthy control participants. Sec23B protein content was analyzed by immunoblotting in samples of erythroblast cells from CDAII patients and healthy controls.ResultsAll of the investigated cases carried SEC23B mutations on both alleles, with the exception of two patients in which a single heterozygous mutation was found. We identified 15 different SEC23B mutations, of which four represent novel mutations: p.Gln214Stop, p.Thr485Ala, p.Val637Gly, and p.Ser727Phe. The CDAII patients exhibited a 40-60% decrease of SEC23B mRNA levels in erythroid precursors when compared with the corresponding cell type from healthy participants. The largest decrease was observed in compound heterozygote patients with missense/nonsense mutations. In three patients, Sec23B protein levels were evaluated in erythroid precursors and found to be strictly correlated with the reduction observed at the transcript level. We also demonstrate that Sec23B mRNA expression levels in lymphocytes and erythroblasts are similar.ConclusionsIn this study, we identified four novel SEC23B mutations associated with CDAII disease. We also demonstrate that the genetic alteration results in a significant decrease of SEC23B transcript in erythroid precursors. Similar down-regulation was observed in peripheral lymphocytes, suggesting that the use of these cells might be sufficient in the identification of Sec23B gene alterations. Finally, we demonstrate that decreased Sec23B protein levels in erythroid precursors correlate with down-regulation of the SEC23B mRNA transcript.

Dataset Information

Congenital dyserythropoietic anemia and drug-induced liver injury present as bland cholestasis: A case report.

Publications

Congenital dyserythropoietic anemia and drug-induced liver injury present as bland cholestasis: A case report.

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