Valproic Acid-associated Hypoalbuminemia in Medically Fragile Patients

Completed

• Conditions: Hypoalbuminemia
• Interventions: Procedure: Specimen collection

• Registration Number: NCT00723762
• Lead Sponsor: Akron Children's Hospital

Brief Summary

The purpose of this study is to investigate potential mechanisms of valproic acid-associated low serum albumin in medically fragile pediatric and young adult epileptic patients of a long-term care facility.

Detailed Description

Valproic acid (VPA) is a long-chain fatty acid frequently used as an antiepileptic agent in pediatric and adult seizure patients. Other adverse effects that have been associated with VPA use include hepatic steatosis, altered mitochondrial function and decreased concentrations of serum proteins. The exact mechanism or mechanisms by which VPA induces these associated adverse drug effects are not fully understood though multiple theories have been postulated including impaired vesicle transport within the hepatocyte, inhibition of hepatic synthetic metabolic pathways and renal protein loss. Decreased serum albumin concentrations with concomitant VPA use have been identified in multiple studies. Albumin synthesis is sensitive to tryptophan concentrations (other amino acids are also able to stimulate albumin synthesis), oncotic pressure near the synthetic site, and energy supply while albumin release from the hepatocyte is sensitive to intrahepatocellular potassium concentrations. Based on available literature, VPA appears to inhibit an enzyme(s) either directly or indirectly involved with albumin synthesis or albumin gene expression. VPA is known to inhibit the urea cycle, including patients with ornithine-transcarbamylase (OTC) deficiency, possibly by inhibiting mitochondrial carbamoyl-phosphate synthase. Oratz et al discussed the potential correlation between the urea cycle and albumin synthesis identified after the administration of various amino acids increased both albumin and urea synthesis. Ornithine is an intermediate amino acid within the urea cycle and it is also a precursor to polyamines which have been shown to increase the degree of aggregation of polysomes, responsible for protein synthesis, bound to the endoplasmic reticulum. Thus, VPA may indirectly inhibit protein synthesis by interfering with the urea cycle leading to decreased ornithine concentrations and subsequently a decrease in polyamine concentrations and a decrease in the number of bound polysomes resulting in alterations in albumin synthesis and release. The purpose of this study is to investigate potential mechanisms of VPA-associated hypoalbuminemia in medically fragile pediatric and young adult epileptic patients of a long-term care facility.

Study Timeline

• Study First Submitted: 2008-07-25
• Study First Submitted QC: 2008-07-28
• Study First Posted: 2008-07-29
• Study Start: 2009-02
• Primary Completion: 2009-12
• Study Completion: 2010-12
• Status Verified: 2011-03
• Last Update Submitted: 2011-03-08
• Last Update Posted: 2011-03-10

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 90

Inclusion Criteria

• Resident of Hattie Larlham long-term care facility receiving VPA for > 3 months at the start of the study
• Resident of Hattie Larlham long-term care facility matched to a resident receiving VPA for > 3 month based on concomitant AED, length of time on AED, age, and gender
• Resident of Hattie Larlham long-term care facility not receiving AED matched to a resident receiving VPA for > 3 month based on age and gender

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Exclusion Criteria

• Received albumin products within the past 1 month
• Receiving VPA for < 3 months or discontinuation of VPA therapy within the past four weeks
• Medical need for specific protein supplementation
• Diagnosed with protein-losing nephropathy or enteropathy

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Study & Design

• Study Type: OBSERVATIONAL
• Study Design: Not specified

Arm && Interventions

Group	Intervention	Description
1	Specimen collection	Resident of Hattie Larlham long-term care facility receiving VPA

Primary Outcome Measures

Name	Time	Method
The primary outcome will be serum albumin concentrations at baseline in the patients receiving VPA.	Baseline

Secondary Outcome Measures

Name	Time	Method
Secondary outcome variables will include serum amino acid concentrations, total protein, AST, ALT, alkaline phosphatase, ammonia, BUN, and sCr and urine albumin, protein, and urea.	Baseline

Trial Locations

Locations (1)

Hattie Larlham Center for Children with Disabilities; 🇺🇸 Mantua, Ohio, United States