Pathogenesis and Pathophysiology of the common, recurrent Illnesses and Diseases present in Kevadiya Colony and the Surrounding Tribal Villages
Malnutritional Disorder: Vitamin A Deficiency, Xerophthalmia, and Night Blindness (Nyctalopia)
General Overview—Vitamins are organic
compounds that are essential for the human body. They are referred to as
micronutrients because they are required in small amounts and are involved in
vital bodily functions including growth, metabolism, and maintenance of health.
It is important to realize that human bodies cannot biosynthesize vitamins; therefore,
they must be consumed as a part of a diet or as supplements. There are two
classes of vitamins, water-soluble vitamins (that involve the B-complex
Vitamins and Vitamin C) and fat-soluble vitamins (that include Vitamins A, D,
E, and K).
Vitamin A cannot be produce by de novo
biosynthesis by animals and humans. Thus, this essential micronutrient must be
obtained via dietary intake; it must be obtained from plants in the form of
pro-vitamin A carotenoids. The pro-vitamin A carotenoids include: α-, β- and
γ-carotenes as well as β-cryptozanthin (Zile, 2011)
and (Paranjpe, Newton, Pyott & Kirkness, 2010). (NOTE: A
pro-vitamin is an organic precursor that can be converted to its respective vitamin
within the body).
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Figure
5—The various forms of Vitamin A
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Vitamin
A is referred traditionally to all-trans-retinol—which
is the alcohol form of Vitamin A, Figure 5. Vitamin A is typically
stored within the hepatocytes of the liver as retinyl palmitate. Retinal—the
aldehyde form of Vitamin A—functions in the
physiological
process of vision. Lastly, retinoic acid is the most important Vitamin A
metabolite biologically because it functions at the level of gene expression
where it serves a role as a ligand for specific nuclear transcription factors
involved in the regulation of numerous genes responsible for the central
physiologic activities of the cell (Zile, 2011)
and (Paranjpe, Newton, Pyott & Kirkness, 2010).
The body obtains
Vitamin A either as preformed Vitamin A esters or a pro-Vitamin A carotenoids,
(Figure 6—below). As mentioned before, Vitamin A and its respective pro-vitamin
are classified as fat-soluble vitamins and thus their absorption is dependent
upon the presence of lipids and protein contained in a meal. Pro-Vitamin A that
is consumed and absorbed are converted to Vitamin A molecules within the small
intestine by dioxygenase—a carotene cleavage enzyme. (NOTE: β-carotene provides
two times the amount of Vitamin A compared to the other pro-Vitamin A
molecules). Vitamin A under goes further processing within the enterocyte
(cells of the intestine) where Vitamin A undergoes esterification to produce
retinyl palmitate. The retinyl palmitate is then taken up into chylomicrons—which
are small fate globules composed of protein and fat that serve to transport
absorbed fat from the enterocytes to the liver and adipose (fat) tissue. Via
lymph circulation, the retinyl palmitate within the chylomicrons is transported
to the liver for storage and or to the other peripheral tissues where Vitamin A
is needed. Vitamin A stores in the liver are low during birth; however, during
the first six months of life the amount increases by a factor of 60 provided
that the growing child is provided with a well-balanced diet rich in Vitamin A
or pro-Vitamin A (Zile, 2011).
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| Figure 6—Metabolism of Vitamin A and pro-Vitamin A |
When Vitamin A is
needed in peripheral tissues, retinyl palmitate that is stored in the liver is
released into the vascular circulation as retinol. The liberated retinol is
bound to retinol-binding protein (RBP)—a specific transport protein—which is
further bound to the thyroid hormone transport protein called transthyretin.
This protein complex transports retinol as well as thyroid hormone to the
peripheral tissues. Normal plasma level of retinol in an infant is 20-50 μg/dL
and 30-225 μg/dL in older children and adults (Zile, 2011)
and (Paranjpe, Newton, Pyott & Kirkness, 2010).
Epidemiology—Vitamin A deficiency and the
resulting conditions of xerophthalmia are vastly prevalent throughout much of
the developing countries and has been shown to be positively associated with
malnourishment and further complicated by illness. Xerophthalmia is a major
problem among the most destitute and most disadvantaged members of society who
often possess very limited access to healthcare (Zile, 2011).
Presently, it has been approximated that 7.2 million pregnant women are Vitamin
A deficient, while another 13.5 million pregnant women have reduced Vitamin A
levels. Every year, more than six million pregnant women develop night
blindness most frequently during the third trimester of pregnancy when both
maternal and fetal demands for Vitamin A are the greatest. More than 60% of all
maternal night blindness cases are found in Southeast and South Asia, with
India accounting for 75% of those cases (Paranjpe,
Newton, Pyott & Kirkness, 2010). Because a mother cannot
provide adequate amounts of Vitamin A to her newborn via breast milk, even the
newborns are Vitamin A deficient (Zile, 2011).
It has been estimated that about 140
million children globally are Vitamin A deficient allowing Vitamin A deficiency
to be classified as the second most prevalent nutritional disorder after
protein energy malnutrition (PEM). Of the 140 million cases, 4.4 million children
are xerophthalmic. Annually, approximately 250,000 to 500,000 xerophthalmic
children become permanently blind and about one half of these children will die
within twelve months of losing their vision (Frank &
Ashwal, 2006).
Both sexes are at equal
risk of developing Vitamin A deficiency; however in males, the metabolism of
Vitamin A is less efficient than in females. Thus, night blindness and Bitot’s
spots are more frequently witnessed in males (Frank &
Ashwal, 2006). With the improvement of Vitamin A levels in children
with this deficiency, approximately one to three million cases of childhood
mortality can be prevented. (NOTE: The cost of providing two days’ equivalent
of Vitamin A supplements is about ten US cents per child) (Paranjpe, Newton, Pyott & Kirkness, 2010).
(Patho-)physiology—Vitamin A is an
essential micronutrient that is needed at all stages of human life starting
with embryogenesis. Except in the role of vision, Vitamin A exerts pleiotropic
effects on many systemic functions. These pleiotropic actions are mediated at
the gene level by the all-trans-retinoic
acid which functions as a ligand for specific nuclear transcription factors
known as the retinoid factors: RARs and RXRs. In the presence of all-trans-retinoic acid, the retinoid
receptor RAR is activated and it heterodimerizes with RXR. The resulting
heterodimer complex binds to specific recognition sites of target genes (Figure 7).
Therefore, Vitamin A—in the all-trans-retinoic
acid form—regulates numerous target genes involved in central physiological
processes of the cell including cell division, differentiation, and death
(Zile, 2011).
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Figure
7—The role of Vitamin A, (all-trans-retinoic acid), on gene transcription via the RAR and RXR
nuclear transcription factors
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Retinoic
acid is one of the most important signaling molecules involved in vertebrate
ontogenesis. Retinoic acid participates in numerous biologic processes such as:
(1) growth, (2) reproduction, (3) embryonic and fetal development, as well as
(4) GI, (5) hematopoietic, (6) respiratory, and (7) immune functions (Figure 8,
below). The physiological role of retinoic acid in immune function and host
defense is especially important in developing nations, where Vitamin A
supplements and therapy has been shown to reduce both the morbidity and
mortality rates of numerous diseases and illnesses—i.e. measles (Zile, 2011)
and (Paranjpe, Newton, Pyott & Kirkness, 2010).
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| Figure 8—Vitamin A deficiency and its interaction with other biologic factors and
processes |
Vitamin A is exceptionally important in
the role of vision. The human retina contains two different photoreceptor
cells—the rods that contain rhodopsin which can perceive low-intensity light
and the cones that contain iodopsin which can perceive different colors of
light. Retinal, the aldehyde form of Vitamin A, is the prosthetic group on both
rhodopsin and iodopsin. The function of Vitamin A in the process of vision (Figure 9, below) is
based on the ability of retinal to photoisomerize—change structural
conformation when exposed to light. Hence, in the dark, low-intensity light
isomerizes the protein rhodopsin’s prosthetic group—11-cis retinal—to all-trans
retinal. This conformational change generates an excitatory electrical
potential that is transmitted through the optic nerve to the brain which
ultimately results in visual sensation (Zile, 2011). (NOTE: The same process
occurs in the protein iodopsin, except retinal is photoisomerized with colored
light).
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| Figure 9—The role of Vitamin A, (all-trans-retinol), on the physiological process of vision |
Vitamin A is crucial for the maintenance
of epithelial functions. Within the GI tract, especially the intestines, an
effective physical barrier against pathogenic attacks is a healthy
mucus-secreting epithelium. A similar sort of epithelium is needed in the
respiratory tract in order to eliminate inhaled pathogens and toxicants. An
unhealthy epithelium as a result from the deficiency in Vitamin A can lead to
diarrhea in the GI tract and bronchial obstruction in the respiratory tract.
Distinctive changes as a result of Vitamin A deficiency within the epithelia
include hyperkeratosis—which is a proliferation of the basal cells of the epithelium—as
well as the formation of stratified cornified squamous epithelium. As a result
of squamous metaplasia (Figure 10, below), there is an increased susceptibility for infections
within the epithelial linings of the
renal pelvis, ureters, vagina, as well as both the salivary and pancreatic
ducts. Within the urinary bladder, a lack of Vitamin A can lead to the loss of
the integrity of the epithelial lining resulting in pyuria and hematuria. Even
the epithelium of the skin is affected; dry, scaly, hyperkeratotic patches on
the shoulders and arms as well as buttocks and legs become evident with a
deficiency in Vitamin A. Hence, with the combination of a: (1) loss of
integrity of epithelial linings, (2) low immune response, and (3) a weakened
response to inflammatory stress—all a result of Vitamin A deficiency—stunted
growth and serious health complications and problems can occur (Zile, 2011) and
(Paranjpe, Newton, Pyott & Kirkness, 2010).
 |
| Figure 10—Vitamin A deficiency produces characteristic signs and
symptoms in the eyes and specialized epithelial surfaces. In this figure, the
pathophysiological states of night blindness and immune deficiency have not been
depicted. |
Clinical Manifestations—Many of the signs and
symptoms of Vitamin A deficiency manifest internally and therefore are hard to
observe during a physical exam. However, there are characteristic signs that
manifest in the eye—in the form of eye lesions—that are distinctive to Vitamin
A deficiency. One of the earliest symptoms of Vitamin A deficiency is a delayed
adaptation to the dark which can progress to night blindness (nyctalopia) if
retinal is not supplemented. As a result of night blindness, photophobia is a
common symptom. If Vitamin A is still not supplemented into the diet, the epithelial
lining—corneal lining—of the eye can loss integrity and vision can become
compromised (Zile, 2011).
The cornea is the first
tissue layer of the eye and hence protects the eye from the outside
environment. The cornea is also important for the refraction of light. Within
the early stages of Vitamin A deficiency, the condition of xerophthalmia may
ensue where the cornea becomes opaque as a result of keratinization and forms
dry, scaly layers of corneal cells. As a result, the eye is more prone to
infections. In more advanced stages of Vitamin A deficiency, infection of the
eye occurs and lymphocytes enter the eye. The cornea becomes wrinkled and
degenerates permanently leading to blindness. This condition is known as
keratomalacia (Figure 10, above). Bitot spots can also develop where the conjunctiva of the eye
keratinizes and plaques form (Figure 10, above). In an even later stage of Vitamin A deficiency,
the pigmented epithelium of the retina, (which is the structural element of the
retina that supports the rods and cones), keratinizes. As the pigmented
epithelium (Figure 11) loses integrity and disintegrates, the rods and cones have no
structural support and thus lose structural integrity and breakdown as well.
This process leads to blindness. These characteristic eye lesions are frequently
more prevalent in developing countries (Zile, 2011) and (Paranjpe, Newton, Pyott & Kirkness, 2010).
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| Figure 11—The pigmented epithelium offers structural support to both the rods and cones |
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There are other
clinical signs that can help diagnose for Vitamin A deficiency. These signs
include: stunted overall growth and development, increased susceptibility to infectious
diseases and illnesses, diarrhea, anemia, apathy, increased intracranial
pressure (with wide separation of cranial suture joints) and headaches, and
mental retardation (Zile, 2011).
Diagnosis—To determine early stage Vitamin A
deficiency, dark adaption tests may be utilized. To diagnose a later stage
Vitamin A deficiency, the characteristic eye lesion of xerophthalmia may be
utilized. However, caution must be taken to differentially diagnose the presenting
eye lesion as being associated with a Vitamin A deficiency rather than similar
eye abnormalities. To detect borderline Vitamin A deficiency status, there are
three clinical indicators that can be used: (1) conjunctival impression
cytology, (2) relative dose response, and (3) modified relative dose response. (NOTE:
Pregnant and lactating women tend to have a marginal Vitamin A deficiency). The
plasma retinol level should not be used as a diagnostic measure for Vitamin A
status as it is not an accurate indicator until there is an extreme Vitamin A
deficiency where the retinyl palmitate stores in the liver have been exhausted.
Plasma concentration of Vitamin A between 20 to 60 μg/dL is within a normal
range; however, a concentration that is less than 20 μg/dL indicates Vitamin A
deficiency (Zile, 2011).
Treatment—Both the efficacy and safety of
Vitamin A supplement therapy is dependent upon the patient’s overall state of
health and other treatments that they are on at the time. For treating an
underlying Vitamin A deficiency, a day-to-day Vitamin A supplement of 1,500 μg
is adequate. In treating xerophthalmia, 1,500 μg/kg body weight of Vitamin A is
given for five days orally followed by an intramuscular injection of 7,500 μg
of Vitamin A immersed in oil until the eye lesion is cured and plasma Vitamin A
levels is between 20 to 60 μg/dL. (NOTE: In young patients with an explicit
Vitamin A deficiency, routine administration of 1,5000 to 3,000 μg of Vitamin A
supplement can lower both the morbidity and mortality rates associated with
viral infections; however plasma Vitamin A levels should be monitored closely
to avoid Hypervitaminosis A) (Zile, 2011).
Prognosis—The prognosis is contingent upon
on how progressed the Vitamin A deficiency and the overall systemic health of
the patient. If the deficiency is mild and the cornea of the eye has not
permanently degenerated as a result of lymphocyte entry—keratomalacia—or the
pigmented layer of the retina has not degenerated, then with Vitamin A
supplementation therapy the related signs, symptoms, and complications may be
reversed. In more serious cases where a patient’s have been permanently damaged
due to Vitamin A deficiency, Vitamin A therapy will reverse the bodily and
systemic complications related to the deficiency however, the patient’s vision
will not be restored. Thus, Vitamin A deficiency and its resulting implications
can be reversed relatively swiftly; however the long-term prognosis is
contingent upon the patients and their ability to either modify their diets to
include rich, diverse, and nutritious foods that have Vitamin A or take
multivitamin supplements.
References
