Chelation therapy in liver diseases of childhood: Current status and response

Seetharaman, Jayendra; Sarma, Moinak Sen

doi:10.4254/wjh.v13.i11.1552

Cited by 7 publications

(8 citation statements)

References 98 publications

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“…TXGNN ranked Deferasirox as the most promising candidate for Wilson’s disease. Wilson’s disease and Deferasirox had a log-OR of 5.26 in the medical records, and literature indicates that Deferasirox may effectively eliminate hepatic iron 54 . In a separate analysis, we evaluated TXGNN on ten recent FDA approvals introduced after the knowledge cutoff date (Table S1).…”

Section: Resultsmentioning

confidence: 98%

“…This prediction is substantiated by the EHR records, where lomustine has a high off-label prescription rate for anaplastic astrocytoma with a Log-OR=10.64, further supported by evidence suggesting lomustine's efficacy towards anaplastic astrocytoma 33 . Similarly, TXGNN ranks deferasirox as the most promising therapy for Wilson's disease, a common cause of liver cirrhosis in children (Log-OR=5.26), suggesting that deferasirox's might have a similar efficacy as deferoxamine in removing hepatic iron 34 . These analyses demonstrate that TXGNN 's novel predictions are consistent with clinical decisions on off-label prescription.…”

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confidence: 97%

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A foundation model for clinician-centered drug repurposing

Huang

Chandak

Wang

et al. 2023

Preprint

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Of the several thousand diseases that affect humans, only about 500 have treatments approved by the U.S. Food and Drug Administration. Even for those with approved treatments, discovering new drugs can offer alternative options that cause fewer side effects and replace drugs that are ineffective for certain patient groups. However, identifying new therapeutic opportunities for diseases with limited treatment options remains a challenge, as existing algorithms often perform poorly. Here, we leverage recent advances in geometric deep learning and human-centered AI to introduce TxGNN, a model for identifying therapeutic opportunities for diseases with limited treatment options and minimal molecular understanding. TxGNN is a graph neural network pre-trained on a comprehensive knowledge graph of 17,080 clinically-recognized diseases and 7,957 therapeutic candidates. The model can process various therapeutic tasks, such as indication and contraindication prediction, in a unified formulation. Once trained, we show that TxGNN can perform zero-shot inference on new diseases without additional parameters or fine-tuning on ground truth labels. Evaluation of TxGNN shows significant improvements over existing methods, with up to 49.2% higher accuracy in indication tasks and 35.1% higher accuracy in contraindication tasks. TxGNN can also predict therapeutic use for new drugs developed since June 2021. To facilitate interpretation and analysis of the model's predictions by clinicians, we develop a human-AI explorer for TxGNN and evaluate its usability with medical experts. Finally, we demonstrate that TxGNN's novel predictions are consistent with off-label prescription decisions made by clinicians in a large healthcare system. These label-efficient and clinician-centered learning systems pave the way for improvements for many therapeutic tasks.

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Section: Resultsmentioning

confidence: 98%

mentioning

confidence: 97%

A foundation model for clinician-centered drug repurposing

Huang

Chandak

Wang

et al. 2023

Preprint

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“…For treating iron overload, iron chelators have been reported to reduce serum ferritin levels, reduce organ damage, and prolong life [ 9 – 11 ]. However, in this case, despite commencing administration of an iron-chelating agent, the increase in serum ferritin levels could not be fully suppressed, and liver damage progressed.…”

Section: Discussionmentioning

confidence: 99%

Neonatal hemochromatosis with εγδβ-thalassemia: a case report and analysis of serum iron regulators

Tsuge

Kodera²,

Sumitomo³

et al. 2022

BMC Pediatr

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Background Neonatal hemochromatosis causes acute liver failure during the neonatal period, mostly due to gestational alloimmune liver disease (GALD). Thalassemia causes hemolytic anemia and ineffective erythropoiesis due to mutations in the globin gene. Although neonatal hemochromatosis and thalassemia have completely different causes, the coexistence of these diseases can synergistically exacerbate iron overload. We report that a newborn with εγδβ-thalassemia developed neonatal hemochromatosis, which did not respond to iron chelators and rapidly worsened, requiring living-donor liver transplantation. Case presentation A 1-day-old Japanese boy with hemolytic anemia and targeted red blood cells was diagnosed with εγδβ-thalassemia by genetic testing, and required frequent red blood cell transfusions. At 2 months after birth, exacerbation of jaundice, grayish-white stool, and high serum ferritin levels were observed, and liver biopsy showed iron deposition in hepatocytes and Kupffer cells. Magnetic resonance imaging scans showed findings suggestive of iron deposits in the liver, spleen, pancreas, and bone marrow. The total amount of red blood cell transfusions administered did not meet the criteria for post-transfusion iron overload. Administration of an iron-chelating agent was initiated, but iron overload rapidly progressed to liver failure without improvement in jaundice and liver damage. He underwent living-donor liver transplantation from his mother, after which iron overload disappeared, and no recurrence of iron overload was observed. Immunohistochemical staining for C5b-9 in the liver was positive. Serum hepcidin levels were low and serum growth differentiation factor-15 levels were high prior to living-donor liver transplantation. Conclusions We reported that an infant with εγδβ-thalassemia developed NH due to GALD, and that coexistence of ineffective erythropoiesis in addition to erythrocyte transfusions may have exacerbated iron overload. Low serum hepcidin levels, in this case, might have been caused by decreased hepcidin production arising from fetal liver damage due to neonatal hemochromatosis and increased hepcidin-inhibiting hematopoietic mediators due to the ineffective hematopoiesis observed in thalassemia.

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“…It is poorly absorbed with a bioavailability of 8-30%. It reaches maximum plasma concentration in 1-3 h[ 100 , 101 ]. Plasma concentration of trientine is significantly reduced when given after food[ 95 ].…”

Section: Treatmentmentioning

confidence: 99%

Challenges and dilemmas in pediatric hepatic Wilson’s disease

Ghosh,

Sen Sarma,

Samanta

2023

World J Hepatol

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Patients with liver cirrhosis are advised to limit their sodium consumption to control excessive fluid accumulation. Salt is the most common form in which sodium is consumed daily. Consequently, various recommendations urge patients to limit salt intake. However, there is a lack of consistency regarding salt restriction across the guidelines. Moreover, there is conflicting evidence regarding the efficacy of salt restriction in the treatment of ascites. Numerous studies have shown that there is no difference in ascites control between patients with restriction of salt intake and those without restriction. Moreover, patients with cirrhosis may have several negative effects from consuming too little salt, although there are no recommendations on the lower limit of salt intake. Sodium is necessary to maintain the extracellular fluid volume; hence, excessive salt restriction can result in volume contraction, which could negatively impact kidney function in a cirrhotic patient. Salt restriction in cirrhotic patients can also compromise nutrient intake, which can have a negative impact on the overall outcome. There is insufficient evidence to recommend restricted salt intake for all patients with cirrhosis, including those with severe hyponatremia. The existing guidelines on salt restriction do not consider the salt sensitivity of patients; their nutritional state, volume status and sodium storage sites; and the risk of hypochloremia. This opinion article aims to critically analyze the existing literature with regard to salt recommendations for patients with liver cirrhosis and identify potential knowledge gaps that call for further research.

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Chelation therapy in liver diseases of childhood: Current status and response

Cited by 7 publications

References 98 publications

A foundation model for clinician-centered drug repurposing

A foundation model for clinician-centered drug repurposing

Neonatal hemochromatosis with εγδβ-thalassemia: a case report and analysis of serum iron regulators

Challenges and dilemmas in pediatric hepatic Wilson’s disease

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