Vitamin A Deficiency Clinical Trial
Official title:
Niveles de Retinol Hepatico y óseo en cadáveres de Adolescentes y Adultos Guatemaltecos (Liver and Bone Retinol Levels in Guatemalan Adolescents and Adults)
Guatemala has enforced mandatory fortification of sugar with vitamin A (VA) since June 1974 and has led to a highly successful reduction in VA deficiency and associated disease. However, Ribaya-Mercado et al. 2014, estimated the biological impact of sugar fortified with retinyl palmitate that there may be a risk of chronic excess intake of preformed VA associated with programs of mass fortification. A recent food consumption survey in two departments in Guatemala found the average daily sugar intake in children under the age of two who aren´t being breastfed is 30.3 g, which translates into a daily intake of 272 μg of retinol (almost the full estimated average requirement (EAR) for that age group). Since data from the second National Survey on Micronutrients suggest a risk of VA toxicity, it is important to determine the levels of hepatic VA directly in corpses of individuals, of all ages, who have died of non-metabolic causes. Due to this, the investigators propose to assess liver and bone VA levels in combination with gene expression, histopathology and biochemical analyses, to elicit indications of hypervitaminosis A in Guatemala.
Objectives:
1. To determine the post mortem concentration of hepatic and bone VA in corpses of
adolescent, young and elderly adults as an indicator of exposure to dietary VA
2. To assess the effect of high VA exposure on key enzymes in liver and bone tissue and to
assess the risk of hypervitaminosis A in people exposed to compulsory mass vitamin A
fortification program in Guatemala.
Methodology:
Setting and sampling The corpses for this study will be obtained from the National Institute
of Forensic Sciences' (INACIF) departmental morgues in 2 hospitals in Guatemala City. The
study population will be 150 cadavers sampled for VA tissue concentration; gene expression
analysis combined with histopathology.
Sample collection process and duration All samples will be collected during necropsies
carried out at the INACIF forensic morgue. During necropsy, the liver will be weighed and the
information recorded. A range of up to 10 x 3 g samples of the liver's right lobe will be
obtained. Each sample will be properly labelled with previously prepared codes. Liver samples
for histopathological analysis will be stored in 10% buffered formalin for 24 hours prior to
transfer to ethanol before embedding, sectioning and staining. All samples collected for
retinoid analysis will be frozen on dry ice in the morgue, transported as such to the
laboratory and subsequently stored at -80˚C. Liver samples for gene expression analysis will
be collected in RNAlater solution to protect RNA stability and subsequently stored at -80˚C
until shipment to Newcastle University. The hepatic VA analysis will be done in Newcastle
University using established High Perfromance Liquid Chromatography (HPLC) methods. Samples
for analysis of gene expression will be sent on dry ice to Newcastle for RNA extraction and
quantification. Since it is possible to obtain good quality RNA suitable for Quantitative
Polymerase Chain Reaction (q-PCR) based analyses from post mortem tissue up to 72 hours after
death, tissue samples stored in RNAlater within 24 hours of death will be adequate for gene
expression analysis. Furthermore, experience from the investigators human biobank in
Newcastle shows that tissue RNA can be extracted successfully after the demise of a patient
up to 72 hours after death as long as the tissue has a pH of over 6. Gene expression of key
regulatory proteins, such as LRAT and CYP26A1 will be performed in Newcastle. Choice of genes
was based on the fact that LRAT may become saturated at very high levels of VA, leading to
increasing levels of free circulating VA that can be metabolized to retinoic acid and other
metabolites via CYP26A. Histopathological analysis will be carried out by pathologists in
Guatemala with digitised slides being sent to the pathologist within Newcastle University -
these slides will be analysed by both pathologists independently.
Bone samples will also be obtained during the necropsy carried out at the INACIF forensic
morgue. The iliac crest bone will be exposed by making an incision and removing the overlying
soft tissue (skin, adipose tissue, connective tissue and muscle). The periosteum and cortical
bone shall be removed via osteotomy exposing the spongy bone. Biopsy needles will be used to
take samples from the spongy bone for analysis of tissue VA concentrations and gene
expression, as previously described, at Newcastle University.
All samples will be shipped to Newcastle University on dry ice.
Study duration According to the information provided by INACIF 18 autopsies were performed
between March and May 2013 on children less than one year of age, 24 on children from 1 to 4
years old, 11 on children 5 to 9 years old, 51 on individuals from 10 to 14 years old, 281 on
adolescents 15 to 19 years old, and 401 on young adults 20 to 24 years old. According to
INACIF`s forensic doctor, ~60% of the total number of autopsies carried out in Guatemala are
performed in the capital city. The main causes of death in children under the age of 9 were
head injuries and other types of trauma. Individuals from 10 to 24 years of age died mainly
due to violence: firearms, stabbings, choking and different types of trauma.
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