A functional approach to Nausea & vomiting


Dr.Panchadcharam Harinath MD,
Academia Grandiosa Medicinae,
Gautam Nagar, South Delhi.

Dr.Karishma Harbada MD,
J J Hospital, Mumbai.



Abstract
Emesis is a well coordinated reflex closely controlled centrally & peripherally. The anatomic functional components are located in Rhomboencephalon, formatio reticularis spinalis & limbic brain. Dopamine, Serotonin, Acetylcholine, Histamine, endogenous opioids & substance-P are the main neurotransmitters involved in the neurons of emetic reflex. There are hundred of Aetiologies to cause nausea & vomiting. Diseases & past history of patients are of utmost importance to reveal the aetiology. Evaluation of emesis includes other diagnostic modalities when the aetiology can not be diagnosed at primary assessment of patient. Elimination of causative agent is the first step of management & other therapeutic modalities can be used when the first step of management is unsatisfactory.

Key words
Emesis, Nausea, reflex, Rhomboencephalon, formatio reticularis spinalis, limbic brain, Dopamine, Serotonin, Acetylcholine, Histamine, endogenous opioids, substance-P, aetiology, dehydration, electrolytes, Chemoreceptor trigger zone, Nucleus tractus solitarius, Nucleus vestibularis, Spinoreticular fibres, Vomiting centre, Circumventricular organs, blood brain barrier, Enkephalins, Meniere’s disease, Labyrinthitis, pyelonephritis, urolithiasis, dysmenorrheal, , hyperemesis gravidarum, Melena , haematemesis, pararexia, Vertigo, nystagmus, Metabolic alkalosis, Hypokalemia, Oesophagitis, bulimics, Boerhaave's syndrome, Mallory-Weiss syndrome, Aspiration pneumonitis, atelectasis, abscesses, anamnesis morbid, vitae

Introduction
Vomiting or Emesis in physiological aspects is not a motility disorder of Gaterointestinal tract but an adaptive reflex to evacuate gastric contents; however Emetic reflex plays a pivotal role in pathologic conditions Eg- in food poisoning vomiting will evacuate GIT contents to prevent absorption of toxins but such adaptive process leads to dehydration & electrolytes disturbances. Vomiting acts as a protective reflex even though Nausea & vomiting that is chronic in nature reminds an underlying pathologic process & affects patient’s quality of life. A complete explanation to Physiologic & pharmacologic implications of emetic reflex is not detailed in any text book. This article deals more or less completely with the Physiologic & pharmacologic aspects of the emetic reflex & also emphasizes on physiologic as well as clinical aspects of vomiting such as Aetiology, Differential diagnosis, Evaluation & management.


Physiological aspects of emetic reflex
Emetic reflex is closely monitored by neural & humoral factors. Vomiting can be triggered either centrally or peripherally however essential centre to coordinate the reflex is located in brain stem.
There are 6 anatomic functional components to operate emetic reflex as given below1,
1-Vomiting centre (VC)
Vomiting centre (VC) which is a part of lateral reticular formation of medulla oblongata contains M1 cholinergic receptor, Miu opioid receptor & nk-1 substance-P receptor.
It receives inputs from the following components given below.
2-Chemoreceptor trigger zone (CTZ)
Chemoreceptor trigger zone (CTZ) is situated in area postrema which is also a component of Circumventricular organs2. The relative permeable regions of blood brain barrier are collectively called Circumventricular organs. CTZ is very rich in receptors such as dopaminergic receptors (D2), serotoninergic receptor (5HT3), opioid receptor (delta), substance-P receptor (nk-1), and angiotensin receptor (AT-II). Functional significance of all the receptors in CTZ is not fully understood.
3-Nucleus tractus solitarius (NTS)
Nucleus tractus solitarius (NTS) is the visceral sensory nucleus receives afferents from Cranial nerves VII, IX & X. It’s the relay station of Gag reflex (IX). It contains histaminergic receptors (H1) & M1 cholinergic receptor. Nervus Vagus is the main visceral efferent posses serotoninergic receptor (5HT3) that is responsible for peripheral stimulation of emtic reflex.
4-Nucleus vestibularis
Nucleus vestibularis(VN) receives afferents from Labyrinthus vestibularis & sends afferents to cerebellum. It contains histaminergic receptors (H1) & M1 cholinergic receptor too.
5-Spinoreticular fibres
Spinoreticular fibres are one of factors leads to emesis associated with Pain or physical injury. Reticular formation at spinal cord level receives short afferents from tractus spinothalamicus that carries pain stimulus to barin. Other mechanisms probably operates pain associated emesis are action of anti-nociceptive agents as Enkephalins on opioid receptors on CTZ or VC & activation of limbic brain by alteration in psychological state.
6-Limbic cortex
Limbic cortex is responsible for emesis associated with olfaction. Cortical afferents connect Lymbic system presumably accounts for emesis associated with unpleasant sight or emotional disturbances & also involved in the conditioned emetic reflex.

The reason why cannabinoids suppress vomiting is Probably CB1-tetra-hydro cannabinol receptors are located either in VC or CTZ; which still awaits proof3,4,5. But presence of these receptors in vagal afferents & their function in hunger & satiety is in experimental level, even though connection to emetic reflex is not still documented.
In pregnancy plasma concentration of catecholamines increase which can stimulate D2 receptors in addition emerging levels of hCG & sex steroids may sensitize these receptors in CTZ to multiply the effects of catecholamines. Altered psyche may play a role through limbic brain in pregnancy induced vomiting. In the case of Hyperemesis Gravidarum the above mentioned mechanisms run in hand to hand with ketonemia.
In dysmenorrhea increased levels of prostaglandins act on thrombocytes to increase serotonin which acts on CTZ to cause vomiting. The very same prostaglandins are the culprits to induce cramps & diarrhea in dysmenorrhea that’s why symptoms of dysmenorrhea can be controlled by NSAIDs.



Fig-1.The main neurotransmitters & the proposed inter connections between the emetic reflex components. (Designed by Dr.P.Harinath MD & Dr.Karishma Harbada MD)
VC-Vomiting centre, CTZ-chemo-trigger receptor zone, NTS-Nucleus tractus solitaries, VN-Nucleus vestibularis, 5HT-5 hydroxy tryptamine, PGs-Prostoglandins, hCG-Human chorionic gonadotrophin, ECLC-Entero-chromophin like cells, I-olfactory nerve, IX-Glossopharyngeal nerve, X-Vagus nerve, N.PLV- Nucleus posterior ventralis posterolateralis thalami.


Act of emesis
Emesis a well coordinated Visceral & somatic muscular phenomena characterized by reverse peristalsis of intestine to evacuate materials into gaster, then thoracic, abdominal & diaphragmatic muscles contract to raise the intra-abdominal pressure against closed glottis which prevents aspiration. Reversal of the thoracic pressure gradient by the synchronous contraction of inspiratory and expiratory muscles along with raised intra-abdominal pressure expulse the gastric contents out6,7.
Vomiting usually is preceded by nausea a feeling of imminent emesis increases the salivary secretion probably has a biological significance by counteracting the effects of gastric acid to the oesophagus by salivary bicarbonates which may lead to hypertrophy of salivary glands in patients with chronic recurrent vomiting eg-bulimia


Aetiology of emesis8

A-Intra carnial, ear & psychiatric causes
Increased intracranial pressure (Neoplasm, encephalitis, hydrocephalus), closed trauma, cerebrovascular insults, Migraine, Meningitis
Meniere’s disease, Labyrinthitis, otitis media, Motion sickness
Bulimia & other Psychogenic vomiting

B-GIT & Hepatobilio-pancreatic causes
Organic disorders-Peptic ulcer, Gasteroenteritis, GERD, Appendicitis, Cholecystitis/cholangitis, Hepatitis, Inflammatory bowel disease, Pancreatitis, Peritonitis.
Functional disorders- Intestinal pseudo-obstruction, Gastroparesis, Irritable bowel syndrome & functional dyspepsia.
Obstruction-Adhesions, achalasia, intussusception, Malignancy & Pyloric stenosis

C-Cardio-pulmonary & URT causes
Pharyngitis, tonsillitis, Pneumonia, pulmonary abscess, pleurisies, inferior wall MI & severe heart failure with hepatic congestion.

D-Genitourinary causes
UTI/pyelonephritis, urolithiasis, dysmenorrhea, premenstrual syndrome, pelvic inflammatory disease & ovarian tumors.

E-Infectious, inflammatory & toxic causes
Bacterial & viral infections, food born toxins, heavy metal poisoning, pesticides poisoning & other chemicals poisoning.
F-Metabolic & endocrine causes Adrenal disorders, Diabetic ketoacidosis, Parathyroid disorders, Pregnancy, hyperemesis gravidarum, Thyroid disorders, Uremia

G-Iatrogenic & pharmacologic causes
Antiarrhythmics, Antibiotics, Chemotherapeutics, Digoxin, Ethanol overdose, Nonsteroidal anti-inflammatory drugs, Opiates, Radiation therapy, anesthesia, invasive procedures, post operative.


Anamnestic & physical clues for Differential diagnosis9,10







Instrumental & laboratory investigations for differential diagnosis9,10

1-GIT conditions-
Abdominal Röntgenography- PUD, Ileus or urolithiasis
Abdominal sonography & CT- malignancy, other obstructions & appendicitis
Endoscopy- PUD & GERD
Fecal occult blood test- PUD & malignancy (melena)

2-Hepatobiliopancreatic conditions-
Liver function test-AST, ALT, Phosphatase, Clotting profile & serum albumin, bilirubin or urea-hepatitis
Serum lipase-pancreatitis
Abdominal sonography & CT- pancreatitis & complications, liver abscess, cyst or malignancy & cholecystitis
CBC/CRP-inflammatory conditions eg- cholecystitis

3-Endocrine & metabolic conditions-
Hormone assays-T3, T4, TSH-thyroid disorders
Corticoids & metabolites-adrenal disorders
Testosterone, oestrogens & prolactin- Gyneco-endocrine conditions eg-PCOD or Hormone secreting tumors
PTH-parathyroid disorders
Electrolytes & others- Ca2+, K+, Na+, acid-base status, ketones- DM ketosis or hyperemesis gravidarum
Pregnancy test-hChNH

4-CNS disorders-
CT & MRI of head- Brain tumor or abscess.
5-miscellaneous-

Renal function test-RF
ECG-Inferior MI

Management of Vomiting1,3,4,11
Algorithm of vomiting management is shown in the diagram below.




1-When diagnosis is made the primary & effective management is elimination of causative factor if possible Eg-drugs & toxins

2-Decompression technique can be used in surgical conditions eg-ileus

3-Anti-emetics can be used when the steps above are not satisfactory or temporarily



Classes of antiemetics
a- Histamine (H1) antagonists
DOC for prevention of motion sickness contraindicated in night workers or drivers because of their sedatory side effect

b- Antimuscuranic drugs
DOC for prevention of motion sickness side effects include dry mouth, dry eyes, urinary retention & constipation

c- Dopamine antagonists
DOC for pregnancy induced emesi(metachlorpromide) & anti-Parkinson therapy induced emesis(Domperidone). These drugs are prokinetics that are used in GERD, diabetic gastro-paresis, hypokinetic dyskinesia of bowel

d- Serotonin antagonists DOC for cancer chemotherapy induced emesis, also used to control few symptoms of carcinoid syndrome

e- neurokinin-1 antagonist (Sub-P) - vofopitant
New drug successfully used in chemotherapy induced as well as post operative emesis

f- Cannabinoids –nabilone & dronabinol
g- Corticosteroids
Drugs which can be used in cases where emesis is resistant to other drugs, especially chemotherapy induced ones. These two drugs are also used as non specific appetite stimulants in patients with cachexia


Complications of vomiting

Complications due to loss of secretions
1-Dehydration
2- Metabolic alkalosis
3-Hypokalemia

Complications due to loss nutrients & loss of appetite
1-vitamin deficiencies
2-mlnutrition

Complications due to gastric acid
1-Dental caries & erosions
2-Corrosive Oesophagitis
3-corrosive strictures
4-acid burns of hands in bulimics
5-sialadenohypertrophy

Complications due to acid + pressure
1- Boerhaave's syndrome
2-Mallory-Weiss syndrome

Complications due to aspiration
1- Aspiration pneumonitis
2-atelectasis
3-abcsesses

Conclusion
Neurophysiology of emetic reflex is the basis for the initial differential diagnosis & management of nausea & vomiting. Chronic nausea & vomiting are alarming signals to underlying pathologic process. Evaluation of nausea & vomiting starts with the anamnesis morbi & vitae of patients to diagnose the etiology, further evaluation is needed when diagnosis is not possible with the first assessment. When vomiting is managed its dangerous complications such as dehydration, electrolytes –acid-base dysbalances, Boerhaave's syndrome, Aspiration pneumonitis should be born in mind to prevent the morbidity & mortality of patients.

References
1- Michael Neal, J; Medical Pharmacology at a glance, Blackwell Science, 4th edition. 2003. 67-67.
2- Werner Kahle; Nervous system & sensory organs, Thieme, 2003. 286-287.
3- Rang, H. P; Pharmacology, Churchill Livingston, 3rd edition, 1995.393-396.
4- Heinz Lullmann, Klaus Mohr; Color atlas of Pharmacology, Thieme, 2nd editon, 2000. 330-331.
5- James Kalat, W; Biological Psychology, Brooks/Cole, 5th edition. 1995, 352-357.
6- William Ganong, F; Review of medical physiology, Mc Graw Hill, 20th edition, 1999. 224-225.
7- Stefan Silbernagel, Florian Lang, Color atlas of Pathophysiology, Thieme,2nd edition, 2000. 140-141.
8- Walter Siegenthaler; Differential Diagnosis in Internal Medicine, Thieme, 1st edition, 2007. 42-42.
9- Douglas Collins, R; Differential Diagnosis in Primary Care, Lippincott Williams & Wilkins, 4th Edition. 2008. 322-325,450.
10- Adler Stephen, N; A POCKET MANUAL OF DIFFERENTIAL DIAGNOSIS, Lippincott Williams & Wilkins, 5th Edition. 2008. 116-119.
11- KEITH SCORZA, AARON WILLIAMS,DANIEL PHILLIPS,JOEL SHAW; Evaluation of Nausea and Vomiting. American Family Physician, 2007; 76:76-84.

Evolution of Atherosclerosis

By- Dr.Panchadcharam Harinath MD

Director, Academia Grandisa medicinae, New Delhi.

Dr.Karishma Harbada MD

J J Hospital, Mumbai.

Abstract

Vitamin deficiency theory of atherogenesis was postulated in early 20^th century but was overlooked all the time. Ascorbate is an essential vitamin which is necessary for maintaining homeostasis when organism is under stress. Ability to synthesize endogenous ascorbate was lost in the evolution before about 60million years ago. The deleterious effects caused by ascorbate deficiency were compensated by synthesis of Lipoprotein a [Lp(a)] which is accumulated in vascular wall in order to strengthen the fragile vessels. However when the extent of accumulation is too great then it produces atheroma, in the presence of other risks atherogenesis progresses faster & greater. Vitamin B₁₂, folate & even B₆ are necessary maintain the turnover & concentration of homocysteine which is an independent risk factor of atherosclerosis. Vitamin E & omega-3 fatty acids change the composition of eicosanoids towards the favorable ones & reduce triglycerides. This article gives an inside for the origin of atherosclerosis & the mechanisms operating the endothelial injury & atherogenesis.

Key words

Atherosclerosis, ascorbate, paleontology, pisces, amphibia, reptilia, L-gulonolactone oxidase, mammalia, scurvy, mutation, Prosimii, Anthropoidea, fossil, Cretaceous, Paleocene, meteor, Lipoprotein(a), Low-density lipoprotein (LDL), apoprotein B-100 , apoprotein(a), differentiation, organogenesis, extracellular matrix, fibrinolysis, thrombosis, inflammation, plasminogen, collagen, Atheroma, fetus, neonate, billiverdin, billirubin, jaundice, shear stress, Homocysteinemia, Vit B12, folate, microflora^, Pseudomonas, Klebsiella, Eicosanoids, Omega-3 fatty, peroxisome, cholesterol.

Introduction

Atherosclerosis is the main aetiology for the no-1 killer Ischemic heart disease in the world. There are several theories of atherogenesis even though “theory of inflammatory response to endothelial injury” gained popularity. There are multiple causes of injury to endothelia such as hyperlipidaemia, HTN & haemodynamic factors, smoking, homocysteine, infections & toxins. Animals that posses ability to synthesis endogenous ascorbate have sufficient amount of ascorbate to maintain the strength of vessels but species lack synthetic ability have fragility of vessels; in order to counteract such condition nature replaced ascorbate with Lp(a), which in excess amount causes atherosclerosis. This article emphasizes the importance of vitamin supplement in prophylaxis of atherosclerosis

Ascorbate synthesis & evolution

Ascorbic acid is one of the very essential vitamins necessary for persistence of lives. From physiologic, structural & even paleontologic point of view its worth to say survival is not possible in organisms without this compound. Except for few species that cannot synthesize ascorbate must rely on their foods, almost all animals synthesize their own ascorbate(Stone¹).

The enzymes synthesize ascorbate are located in kidneys in pisces, amphibia & reptilia. In evolution when animals became complex the inadequacy of kidneys to synthesize adequate amount of ascorabate is compensated by switching the synthesis to liver. Ascorbate maintains the homeostasis when the animal is stressed thus the amount of ascorbate synthesized in the organisms depends on the stress that is produced by complex reactions in the body.

The locus of the ascorbate synthesizing enzymes in evolution of the vertebrates from the pisces to the primates (Roy and Guha², Chaudhuri and Chatterjee.³)

The vitamin hypothesis was postulated by Funk in 1912, which stated that deficiency of water-soluble substance, called Vitamin –C causes scurvy.

In 1959 Burns showed that the absence of enzyme in livers of some mammalian species called, L-gulonolactone oxidase, which is rate limiting enzyme in ascorbic acid synthesis; leads to development of scurvy.

The Harvard in 1966 and Yerkes Primate Research Center in 1969 discovered an interesting finding after following the suggestion of Stone¹ to examine the whole order of primates for the presence of L-gulonolactone oxidase in their livers, to determine which species of order primata was mutated & lost the active L-gulonolactone oxidase.

The following diagram showing a chart of the fossil record of the primates as devised by Simons⁴ that is simplified by Dr.P.Harinath MD.

Results showed that active enzyme L-gulonolactone oxidase was present in species of the suborder Prosimii, but in species of the suborder Anthropoidea its absent. This data proves us the presence of not only anatomic but also physiochemical division between the Prosimii and the Anthropoidea.

When we analyze the fossil record from Simons⁴, the origin of the division between Prosimii and Anthropoidea lies at a point between the late Cretaceous and late Paleocene where a defect appears to have occurred which mutated the gene of enzyme that synthesize ascorbate. This mutation occurred in the vicinity of the appearance of primate ancestor on the earth, about 58 to 63 million years ago whose descendants evolved into the suborder Anthropoidea.( Stone¹)

In 1971, Russell and Tucker⁵ suggested that this mutation might have occurred due to the large fluxes of radiations produced by the impact of gigantic meteor on the earth in late Cretaceous period.

This mutation was compensated by ascorbate rich green & fruit supply to tree living species. However this value of compensation was lost when the decendants of these animals moved to land where the supply of ascorbate was not adequate all around the year.

Stone⁶ stated that humans consuming minidoses of ascorbate per day will not show the prominent & classic symptoms of frank clinical scurvy however might still suffer from severe subclinical biochemical scurvy; which I believe subclinical biochemical scurvy as a pathophysiologic component of atherosclerosis.

New approach for old problems?

Compensation fo nature for Vitamin-C deficiency

Nature compensated the vitamin C deficiency by its surrogate lipoprotein(a) to accelerate wound healing and other cell-repair mechanisms, to strengthen the extra-cellular matrix, & to scavenge the free radicals.

Lipoprotein(a) [Lp(a)] was discovered by Blumberg and Berg⁷. It’s a complex of low-density lipoprotein (LDL) with apoprotein B-100 and a unique glycoprotein, called apoprotein(a) which is linked to apo B by disulfide bonds. Lp(a) is detected only in the plasma of humans & other primates that have lost the active enzyme to synthesize ascorbate. This enzyme deficiency appeared to be compensated by acquiring the ability to synthesize apoprotein(a) to counteract stress.

Lipoprotein(a) [Lp(a)] is an adhesive protein which have positive roles in tissue differentiation & organogenesis, strengthening of extra-cellular matrix, repair process, wound healing & scavenging free radicals (by –SH group). Even though it’s pathologic roles are realized by blocking fibrinolysis to promote thrombosis & interacting with white cells to aggravate inflammation (Rath & Pauling^8,9).

However in conditions such as scurvy where capillary fragility is present & inhibition of fibrinolysis would be beneficial, Lp(a) competitively inhibits the binding of plasminogen to fibrin thus inhibits fibrinolysis; Because of homology of Apo(a) to plasminogen.

The detection Apo(a) in non-lesioned areas of arterial wall & plasma from neonates led us a clue that Lp(a) strengthens the arterial walls & participate in organogenesis directly or indirectly by counteracting the stress which is great during this period, but atherosclerosis would occur; if this accumulation is too great.

We can draw a conclusion that a possible mechanism for Lp(a) & its adhesive properties is a compensation for decreased rate in collagen synthesis, particularly due to ascorbate deficiency.

It’s worth mentioning type I&II fibrillar collagen which is a component of extra-cellular matrix formed by post transcriptional modification with the help of ascorbate; is deficient in suclinical scurvy too. Discussion about all details of fibrillar collagen is beyond the scope of this article but it’s important to emphasize that fibrillar collagen is not only participates in the static functions of matrix but also appears to inhibit the proliferation smooth muscles in atherosclerotic plaque.

Vitamin deficiency theory of atherosclerosis initiation

Severe subclinical biochemical scurvy initiates the degenerative process in atherosclerosis. As I mentioned earlier, accumulation of Lp(a) in extra-cellular matrix is to counteract fragility of vessels but when long standing accumulation beyond the limit would switch this compensatory mechanism into a pathologic one leading to development of Atheroma.

In fetal & neonatal period that are more stressful because of tissue remodeling & organogenesis producing a lot of reactive species; the ascorbate deficiency might be the reason of high level Lip(a)in plama & would be most probably the mechanism of primary fatty streak formation.

It’s noteworthy that conversions of billiverdin to billirubin & neonatal physiologic jaundice have biologic value of survival due to the anti-oxidant property of billirubin.

The compensatory mechanism to restore the integrity of the vascular wall in severe subclinical scurvy leads to insudation of Lip(a) & produces intimal thickening throughout the vascular system. When, however other risk factors such as haemodynamic stress & homocysteine group up with the underlying vascular lesion then atherogenesis will be greater.

This theory helps to explain the reason of development of atherosclerosis mainly at sites of high shear stress Eg-Bifurcatio Aortae, a.renails & a.coronaria.

Without any doubts “Gene therapy” is an outstanding option to this no-1 killer of the world by introducing the lost gene again in body however sponsors for these researches are limited because the pharmaceuticals prefer drugs than gene therapy.

Vitamin B12 & Folate

Homocysteinemia is an independent risk factor for atherosclerosis which is proved by many researchers now. At biochemical level Vit-B12, folate & B6 are necessary to control the turn over of Homocysteine in the body.

Body depends on external sources for Vit B12 & folate, however, the human small intestine also harbours microflora (at least two groups of organisms -Pseudomonas and Klebsiella sp ) that may synthesize significant amounts of the vitamin B12.( Albert, Mathan & Baker¹⁰ )

I believe that the food we consume may have sufficient amount of B12 & folate to run processes such as DNA synthesis but these amounts may not be sufficient enough to carry our minute processes such as regulation of homocysteine turnover. Compare to other species, Human’s foods became too artificial which is low in vitamins, also the intestinal normal flora may be less productive than other species in synthetic point of view (use of antibiotics destroys normal flora too).This minute deficiency may run a subclinical phase of Homocysteinemia which build up deleterious effects on atherosclerosis. Many animal studies shows B12 & B6 supplementation decreases atherosclerosis but this has to be determined in humans.

Vit E

They act as antioxidant decrease oxidation of LDL, decreases Eicosanoids synthesis, decrease adhesion molecules expression. Vitamin E was reported to inhibit serum-induced smooth muscle cell proliferation (Chan¹¹). As vitamins mentioned above minute deficiency subclinically affects atherosclerosis progression.

Omega-3 fatty acids

Omega-3 fatty acids increase 3 series eicosanoids which is hundred times less potent than the 2 series eicosanoids & decrease triglyceride synthesis in liver (HARRIS¹²).

Human liver cannot make double bonds beyond omega 3 position in fatty acids, because the peroxisomal enzyme which is responsible for this process is lost in evolution too where it’s still present in sum fishes.

This could be also a contributing factor in atherosclerosis in humans

Cholesterol excretion

Last but not least excretion of cholesterol is not as efficient as other species in humans which increases the availability of cholesterol to circulate can also be a contributing factor in atherosclerosis in humans.

Conclusion

Ascorbate deficiency is the main factor that makes the vessels susceptible to atheroma by raising the level of Lp(a); which is a protective action of turned out to de deleterious as all other chronic inflammatory diseases. Other vitamins such as Vit-B12, folate, B6, Vit-E are important controlling the turnover of injurious agents like Homocysteine & oxygen radicals; when deficiencies of such factors occur can lead to the accumulation of these injurious agents. When we substitute Arachidonate with Omega-3 fatty acids it obviously reduces the inflammatory process by synthesizing less potent mediators like PG3s.

Such deficiencies appeared to have occurred in our ancestors long time ago however as evolution progresses defects caused by mutations, behavior & environment accumulated through species & showing maximum impacts on humans.

This review emphasizes the necessity of the above mentioned vitamin supplements for prophylaxis of atherosclerosis, but “Gene therapy” is the only scope of permanent prophylaxis in future.

References

1-Stone, I.: Studies of a mammalian enzyme system for producing evolutionary evidence in Man. Amer. J. Phys. Anthrop. 1965; 3:83-85.

2-Roy, R. N. and Guha, B. C.: Species difference in regard to the biosynthesis of ascorbic acid. Nature, 1958; 182:319-320.

3- Chaudhuri, C. R. and Chatterjee, I. B.: Ascorbic acid synthesis in birds: Phylogenetic trend. Science, 1969; 164:435-436.

4-Simons, E. L.: The early relatives of man. Sc. Amer. 1964;1:55.

5- Russell, D. and Tucker, V. V.: Supernovae and the extinction of the dinosaurs. Nature.1971; 229:553-554.

6- Stone, I.: The genetic disease, Hypoascorbemia. A fresh approach to an ancient disease and some of its medical implications. Acta Genet. Med. et Gemel. 1967; 16:52-62.

7-Berg K: A new serum type system in man – The Lp system. Acta Pathologica

1963; 59: 369-382.

8-Rath M, Pauling L : Hypothesis: Lipoprotein(a) is a surrogate for

ascorbate. Proceedings of the National Academy of Sciences USA. 1990; 87: 6204-

6207.

9-Rath M. Apoprotein(a) Is an Adhesive Protein

Proceedings of the National Academy of Sciences, 1991; 87: 6204-6207.

10- Albert M. J. ,Mathan V. I. & Baker S. J.; Vitamin B₁₂ synthesis by human small intestinal bacteria, Nature, 1980; 283, 781 - 782 (21 February).

11-Alvin C. Chan ; Vitamin E and Atherosclerosis, The Journal of Nutrition, 1998;128,1593-1596.

12-Harris William S. & Bulchandani Diepti; Why do omega-3 fatty acids lower serum triqlycerides?, Current opinion in lipidology ,2006, 17, 387-393.