This Project Contains Intro about hypervitaminosis A , Function, Source of Toxicity, M.O.A , Sign and symptoms, Lab Diagnosis, Treatment and prevention This Project by Group student in faculty of pharmacy and approved.

1. TOXICOLOGY
“HEALTH HAZARDS OF
HYPERVITAMINOSIS (VIT.A)”
UNDER SUPERVISOR: DR. HANAN & DR. YOUSRA
T.A: DR. AHMED BADR
Spring 2019

2. POINTS OF PRESENTATION
• Introduction
• Function
• Source of Toxicity
• Mechanism of Action
• Sign and Symptoms
• Lab Diagnosis
• Treatment
• Prevention

3. INTRODUCTION
• Retinoids (vitamin A and its natural and synthetic congeners) are fat-soluble
signaling molecules that are mainly derived from the diet as preformed vitamin A (or
retinyl esters), which is found in animal foods (milk, fish oil) and drug supplements.
Dietary vitamin A is also obtained from provitamin A carotenoids from plant sources,
principally carrots.
• Vitamin A can be found in two principal forms in foods:
•Retinol, the form of vitamin A absorbed when eating animal food sources, is a
yellow, fat-soluble substance.
After absorption, retinol is transported via chylomicrons to the liver.
•Carotenoids (alpha-carotene, beta-carotene and gamma-carotene); The enzyme
15-15'-dioxygenase converts carotenoids to retinal.

4. In the organism vitamin A is available in three forms:
• Retinol (ROL) The retinol form functions as a storage form of the
vitamin.
• Retinaldehyde, or retinal. Converted from retinol by retinol
dehydrogenase.
• Retinoic Acid (RA). Converted from retinal by retinaldehyde
dehydrogenase. This oxidation is an irreversible step.
In circulation it is bound to retinol-binding protein (RBP).
About 80% of the body stores of vitamin A are contained in the liver, in
quantities sufficient to last the average adult about two years without the
need for additional intake.

6. FUNCTIONS
Vitamin A plays a role in a variety of functions throughout the body, such as:
• Vision: specifically related to the retinal form. Within the eye, 11-cis-retinal is bound to protein "opsin" to
form rhodopsin in rods and iodopsin (cones). It's important for the mechanism of transduction.
• Gene transcription: Retinoic acid exerts its effects by binding to and activating two types of nuclear
protein receptors: the RARs and RXRs (rexinoids, RXRs), both of which exist as three distinct gene
products (alpha, beta, and gamma). These receptors control the expression of numerous target genes by
binding to specific DNA sequences termed RA response elements (RAREs).
• Immune function: vitamin A stimulates functioning of the immune system in the body and increases its
resistance to infections.
• Embryonic development and reproduction: It accelerates the synthesis of collagen and elastin fibres by
fibroblasts, as well as the processes of cell division, thanks to which it stimulates growth of fetus and
young organisms.

7. • Bone metabolism: Vitamin A positively influences the development of skeleton by
regulating activities of osteoblasts and osteoclasts. It participates in hormonal
regulation of the body by decreasing secretion of thyroxin (one of thyroid hormones)
by means of suppressing production of thyrotropin by the pituitary gland.
• Hematopoiesis
• Skin health: It ensures proper proliferation and differentiation of epithelial cells,
contributing also to their regeneration
• Cellular health
• Antioxidant activity: A vital property of vitamin A is also its antioxidative action,
including both prevention against reactive oxygen species (ROS) and termination of
reactions taking place with their participation.

8. SOURCE OF TOXICITY
• Diet – Liver is high in vitamin A. The liver of certain animals,
including the polar bear, bearded seal, walrus, and moose, are
particularly toxic.
• Supplements – Dietary supplements can be toxic when taken
above recommended dosages. Cod liver oil is particularly high in
vitamin A.
• Medications – Many drugs are used on a long-term basis in
numerous preventive and therapeutic medical applications, which
may lead to hypervitaminosis A.

9. Absorption and storage in the liver of preformed vitamin A occur very efficiently until a
pathologic condition develops
Delivery to tissues
• Absorption
When ingested, 70–90% of preformed vitamin A is absorbed and used.
• Storage
80–90% of the total body reserves of vitamin A are in the liver (with 80–90% of this amount being stored
in hepatic stellate cells and the remaining 10–20% being stored in hepatocytes). Fat is another
significant storage site, while the lungs and kidneys may also be capable of storage.
MECHANISM OF ACTION

10. Transport
Until recently, it was thought that the sole important retinoid delivery pathway to tissues involved retinol
bound to retinol-binding protein (RBP4). More recent findings, however, indicate that retinoids can be
delivered to tissues through multiple overlapping delivery pathways, involving chylomicrons, very low
density lipoprotein (VLDL) and low density lipoprotein (LDL), retinoic acid bound to albumin, water
soluble β-glucuronides of retinol and retinoic acid, and provitamin A carotenoids.
The range of serum retinol concentrations under normal conditions is 1–3 μmol/l. Elevated amounts of
retinyl ester (i.e., >10% of total circulating vitamin A) in the fasting state have been used as markers for
chronic hypervitaminosis A in humans. Candidate mechanisms for this increase include decreased
hepatic uptake of vitamin A and the leaking of esters into the bloodstream from saturated hepatic
stellate cells

11. Effects
Effects include increased bone turnover and altered metabolism of fat-soluble vitamins. More research is
needed to fully elucidate the effects.
Increased bone turnover
• Retinoic acid suppresses osteoblast activity and stimulates osteoclast formation in vitro, resulting in
increased bone resorption and decreased bone formation. It is likely to exert this effect by binding to
specific nuclear receptors (members of the retinoic acid receptor or retinoid X receptor nuclear
transcription family) which are found in every cell (including osteoblasts and osteoclasts).
• This change in bone turnover is likely to be the reason for numerous effects seen in hypervitaminosis
A, such as hypercalcemia and numerous bone changes such as bone loss that potentially leads to
osteoporosis, spontaneous bone fractures, altered skeletal development in children, skeletal pain,
radiographic changes, and bone lesions.

12. Altered fat-soluble vitamin metabolism
• Vitamin A is fat-soluble and high levels have been reported to affect metabolism of the other fat-
soluble vitamins D,E, and K.
• The toxic effects of vitamin A might be related to altered vitamin D metabolism, concurrent ingestion
of substantial amounts of vitamin D, or binding of vitamin A to receptor heterodimers. Antagonistic
and synergistic interactions between these two vitamins have been reported, as they relate to
skeletal health.
• Stimulation of bone resorption by vitamin A has been reported to be independent of its effects on
vitamin D.
Mitochondrial toxicity
• Vitamin A exerts several toxic effects regarding redox environment and
mitochondrial function

13. SIGN AND SYMPTOMS
Symptoms vary based on whether toxicity is acute or
chronic. Headaches and rash are common in both forms of the illness.
Symptoms of acute vitamin A toxicity include:
• drowsiness
• irritability
• abdominal pain
• nausea
• vomiting
• increased pressure on the brain

14. CHRONIC VITAMIN A TOXICITY
• blurry vision or other vision
changes
• swelling of the bones
• bone pain
• poor appetite
• dizziness
• nausea and vomiting
• sensitivity to sunlight
• Dry, rough skin
• itchy or peeling skin
• cracked fingernails
• skin cracks at the corners of your
mouth
• mouth ulcers
• yellowed skin (jaundice)
• hair loss
• respiratory infection
• confusion

15. In infants and children, symptoms may also include:
softening of the skull bone
bulging of the soft spot on the top of an infant’s skull (fontanel)
double vision
bulging eyeballs
inability to gain weight
coma

16. In a pregnant or soon-to-become pregnant woman, defects in their baby can result
with too much vitamin A.
If you’re pregnant, don’t take more than one prenatal vitamin each day. There is
enough vitamin A in prenatal vitamins. If you need more iron, for example, add an iron
supplement to your daily prenatal vitamin. Don’t take two or more prenatal vitamins, as
the risk of deformities in your baby increases.
If you’re pregnant, don’t use retinol skin creams, which are very high in vitamin A.
The correct amount of vitamin A is crucial for the development of a fetus. However,
excess vitamin A consumption during pregnancy is known to cause birth defects that
may affect a baby’s eyes, skull, lungs, and heart.

17. LABORATORY DIAGNOSIS
Tests may include:
•bone x-rays
•blood calcium test
•cholesterol test
•liver function test
•blood test for Vitamin A (Retinol esters as markers).

18. TREATMENT
• Stopping high Vitamin A intake is the standard treatment. Most people fully recover.
• Phosphatidylcholine (in the form of PPC or DLPC), the substrate for Lecithin retinol
acyltransferase, which converts retinol into Retinyl esters (the storage forms of
vitamin A).
• Vitamin E may alleviate hypervitaminosis A. Liver transplantation may be a valid
option if no improvement occurs. If liver damage has progressed into fibrosis,
synthesizing capacity is compromised and supplementation can replenish PC.
However, recovery is dependent on removing the causative agent: halting high
Vitamin A intake.

19. PREVENTION
Hypervitaminosis A can be prevented by not ingesting more than the Tolerable Upper
Level of intake for Vitamin A. This level is for synthetic and natural retinol ester forms
of vitamin A.
Carotene forms from dietary sources are nontoxic. The dose over and above
the RDA is among the narrowest of the vitamins and minerals. Possible pregnancy,
liver disease, high alcohol consumption, and smoking are indications for close
monitoring and limitation of vitamin A administration.
Vitamin E - may alleviate hypervitaminosis A.

20. Life stage group category Upper Level (μg/day)
Infants
0–6 months
7–12 months
600
600
Children
1–3 years
4–8 years
600
900
Males
9–13 years
14–18 years
19 – >70 years
1700
2800
3000
Females
9–13 years
14–18 years
19 – >70 years
1700
2800
3000
Pregnancy
<19 years
19 – >50 years
2800
3000
Lactation
<19 years
19 – >50 years
2800
3000

22. REFERENCES
• http://flipper.diff.org/app/items/info/6430
• https://academic.oup.com/ajcn/article/83/2/191/4
649798
• https://www.medicalnewstoday.com/articles/3222
38.php
• https://www.healthline.com/health/hypervitamino
sis-a

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