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Polycythemia Vera: Causes and Treatment

From the ancient times to the modern era of today where everything is said to be changed irrespective the good or bad, not only mankind had undergone an evolution but so as the diseases which is why new medical innovations are highly needed to counteract such dilemma. Diseases do not only invade a person externally but also can spread internally as well such as blood diseases. Blood diseases are diseases that involve the mechanisms, functions, site of production, and most importantly the components of blood. According to Hezy (2010), one of the major blood disease is polycythemia Vera, also known as erythremia, primary polycythemia, and polycythemia rubra Vera. Polycythemia Vera is a myeloproliferative rare blood disease in which the bone marrow produces excessive amount of erythrocytes and may also result in the overproduction of leukocytes or platelets causing the blood to be thicker and travels slower than normal. This is a very serious problem as sooner or later the person would suffer from heart attack or stroke as the possibility of having a stroke or heart failure increase by 80% if a person suffers from polycythemia Vera due to blockage of blood vessels. Although polycythemia Vera is considered a very rare disease, it still happens among us despite its low possibility. Therefore, treatments are highly recommended as it could be fatal or lead to another sort of diseases as well because a subset of patients with polcythemia Vera may progress to acute myelogenous leukemia or myelofibribrosis stated by ClinicalKey (2012).
From the research of Ann Intern Med (2013), the statistics shown that polycythemia Vera can occur in any individual irrespective age or gender but it has been proven that is it more common among people with the age group of 50 to 70 years. In overall, polycythemia Vera is more prevalent in men than in women.

According to Vanasse G., et al (2008), the data claimed from major commercial insurance payers in Connecticut and the Center for Medicare and Medicaid Services estimated that the number of patients with polycythemia Vera is 22 per 100,000 respectively for the age-standardized prevalence and it is also estimated that there is a total of approximately 65,200 patients with polycythemia Vera applying the age-specific prevalence to the entire US population in 2003 which is the first assessed prevalence of polycythemia Vera in the large US population. Moreover, Brian J.S., et al (2004) stated that a comprehensive review reported the incidence of polycythemia Vera to be 2.3 per 100,000 each year worldwide. After a thorough diagnosis, the seriousness of polycythemia Vera is underscored by the fact that the median survival for untreated symptomatic patients is about six months to one and a half year but for treating patients, the median survival can be surprisingly prolonged to about seven to fifteen years.
Based on DoctorTipster (2011), there are a few factors that may increase the risk of developing polycythemia Vera. Firstly, aging is one of the unavoidable factors as the chances of developing polycythemia Vera grow with age. Normally people around the age of 60 years are more prone to this disease and it is hardly found in people who are under 20 years of age. Secondly, it is a fact that polycythemia Vera effects with predilection men and lesser in women by comparison. Thirdly, families with medical history is also one of the risk factors that can lead to polycythemia Vera. Most cases of polycythemia Vera are not inherited, it is associated with genetic changes that are somatic, means that they acquire during a person’s lifetime and are only present in certain cells and not transmitted or passed down generally from parents to children. However, in rare instances family history of polycythemia Vera especially relatives are said to be the cause for the increase of risk for developing the disease. In these families, the risk of developing polycythemia appears to have an autosomal dominant pattern of inheritance. Autosomal dominant inheritance means that one copy of an altered gene in each cell is sufficient to increase the risk of developing polycythemia Vera, although in these cases no causative genes have been identified but these people seem to inherit an increased risk of polycythemia Vera, not the disease itself. Last but not least, the environmental conditions or lifestyles also count as a risk factor as well as polycythemia Vera can occur due to different lifestyles or even different exposures to environmental conditions such as radiation. Exposure to intense radiation may actually increase the risk for the condition or even trigger the disease because the main reason for the development of disease is genetic mutation. Lack of exercise or unhealthy diet will only aggravate the body conditions as most of the people nowadays are already in bad shape because of neglecting health care for work and stress.
Pr Jean B. (2010), stated that the main source of determining an individual either with or without polycythemia Vera is based on whether the mutation occurred in the body’s genes which is the major cause of polycythemia Vera. Polycythemia Vera happens because of the presence of abnormal clonal stem cell expansion that suppresses the growth and maturation of normal stem cell which is a somatic mutation known as JAK2-V617F commonly in exon 14 of the JAK2 gene or in exon 12 which is less common. However, exactly what causes the mutation is still a matter of debate. The presence of a V617F or a mutation of the JAK2 gene can be diagnosed because the gene actually functions to make a protein that aids the body in producing blood cells and so there will be an elevation in the amount of white blood cells, platelets, hematocrit, hemoglobin, and most of all the red blood cell mass which is about 125% greater compared with the normal. As a result, the blood will become thicker and harder to pump which is very dangerous as it can relate to heart attack, stroke, and other health diseases.
Almost all of the health problems associated with polycythemia Vera are caused by the blood of the individual being unusually thick due to overproduction of red blood cells in the body. The disease is more common in the elderly and can be either symptomatic or asymptomatic. TheFreeDictionary (2013), stated that normally there will be common signs and symptoms such as itching and severe burning pain in the hands or feet accompanied by a reddish and bluish colouration of the skin most likely on the face. Unfortunately, patients with polycythemia Vera are also likely to develop gouty arthritis. As the development of polycythemia Vera is rather slow, signs and symptoms might not show for years. Therefore, the disease is often found out when a blood test is done for other purposes. However, when the signs and symptoms are present due to the thickness of the blood slowing down the flow of oxygenated blood to all parts of the body and this will lead to many parts of the body unable to function properly with insufficient oxygen. As a result, one may experience headaches, dizziness, blurred or double vision, shortness of breath, numbness, itchiness especially after bathing with hot water, fatigue, and more. Besides that, there are actually levels or phases where symptoms or effects are shown at various stages. The symptoms of the early polycythemia Vera may be minimal so it is not unusual for the disease to be discovered easily. Patients often experience symptoms like headaches, confusion or impaired memories, breathing difficulty, giddiness, vomiting, hypertension and much more which people would treat them like a minor or a common issue. In some patients’ early symptoms include unusual heavy bleeding from minor cuts, nosebleeds, pain in the bone, or stomach ulcers but there are a few cases the first symptoms is the development of blood clots in an unusual part of the circulatory system such as the liver. As the disease develops, the patients may have episodes of thrombosis or hemorrhage where the fact that thrombosis is the most frequent cause of death from polycythemia Vera. Other complications include a high concentration of uric acid in the blood which increases the risk of getting other diseases. About 10% of the patients eventually develop gout and the other 10% develop peptic ulcers. Based on MayoClinic (2012), one of the effects of polycyhemia Vera is causing the spleen to be greatly enlarged also known as splenomegaly as the spleen aids the body against infections and filter unwanted materials such as old or damaged blood cells. With the increased number of blood cells caused by polycythemia Vera, the spleen intends to work harder than normal which leads to spleen enlargement and the patient’s spleen may even be able to fill the entire left side of the abdomen as time goes on. Therefore, the patients might have the feeling of fullness or bloated in the upper left part of the abdomen.
Where there is a problem, there will always be solutions to overcome it. According to the BodyandHealth.canada.com (1997), polycythemia Vera is treated with procedures, medicines, and some other treatments. A person with polycythemia Vera may need one or more treatments to manage this disease. The actual goals of treating this blood disease are to control the symptoms and reduce the risk of complications especially heart failure and stroke so in order to achieve the target, the treatments for polycythemia Vera reduce the number of erythrocytes and the level of hemoglobin in the blood which will make the thickness of the blood to be much closer to normal, thus reducing the chances of blood clots in the blood vessels. For this disease, the most recommended treatment is phlebotomy. Phlebotomy is a procedure that removes some blood from the body by inserting a needle into one of the veins and channels the blood into a sterile container via an airtight tube which is quite similar to the process of blood donation. Through this treatment, the red blood cell count is reduced and this brings the thickness of the blood closer to normal. Typically, 1 unit of blood which is around 350ml is removed per week until the hematocrit level which is the measure of how much space red blood cells occupied in the blood falls back to normal and this process is normally carried out every few months. The next treatment involves medications, the doctors may prescribe certain medicines for example hydroxyurea and interferon-alpha that prevents the bone marrow from making way too many red blood cells. Hydroxyurea is a medicine generally used in treating cancer, it has the ability to reduce the number of red blood cells and platelets in the blood whereas interferon-alpha is a substance that our bodies usually produces to prompt our immune system to fight against overactive bone marrow cells. Moreover, radiation treatment is also available as it can help to suppress overactive bone marrow cells which prevent them from making red blood cells uncontrollably but this treatment is less recommended by doctors as the radiation treatment can increase the risk of leukaemia or other blood diseases. Another treatment is by taking aspirin as aspirin can relieve bone pain and the burning sensation in the hands and feet due to polycythemia Vera. In addition, aspirin also has the function to dilute blood so besides relieving pains it also thins the blood causing the blood to flow better in the blood vessels. However, taking aspirin can have side effects without the controlling the amount or dosage. For those who cannot resist the itching caused by polycythemia Vera, the doctor may also prescribe ultraviolet light treatment to relieve the itching.
As preventions are better than cure, it is always a better choice not to rely too much on medications or drugs when solving problems related to health but try using other methods instead if possible. According to the NasionalHeartLung

Regulation of Gastric Acid Secretion

The stomach is a J-shaped enlargement of the gastrointestinal tract just lies below the diaphragm; the digestive tube dilates into an elongated pouchlike structure, the size of which varies according to several factors, notably the amount of distention. For sometime after a meal, the stomach is enlarged because of distention of its walls, but, as food leaves, the walls partially collapse, leaving the organ about the size of a large sausage. In adults the stomach usually holds a volume upto 1.0 to 1.5L.
ANATOMY OF STOMACH 1.1.1 Divisions of the stomach:
The fundus, body and the pylorus are the three divisions of the stomach. The fundus is the enlargement portion of the left and above opening of the oesophagus into the stomach. The body is the central part of the stomach, and the pylorus is its lower portion.
1.1.2 Curves of the stomach:
The curve formed by the upper right surface of the stomach is known as the lesser curvature; the curve formed by the lower left surface is known as the greater curvature.
1.1.3 Sphincter muscles:
Sphincter muscles guard both stomach openings. A sphincter muscle consists of circular fibres so arranged that there is an opening in the centre of them (like the hole in a doughnut) when they are relaxed and no opening when they are contracted.
The cardiac sphincter controls the opening of the oesophagus into the stomach, and the pyloric sphincter controls the opening from the pyloric portion of the stomach into the first part of the small intestine.
1.1.4 Stomach wall:
Gastric mucosa
The epithelial lining of the stomach is thrown into folds, called rugae, and marked by depressions called gastric pits. Numerous coiled tubular- type glands, gastric glands, are found below the level of the pits, particularly in the fundus and body of the stomach. The glands secrete most of the gastric juice, a mucous fluid containing digestive enzymes and hydrochloric acid.
1.1.5 Functions of the stomach:
The stomach carries on the following the functions:
It serves as a reservoir, storing food until it can be partially digested and moved further along the gastrointestinal tract.
It secretes gastric juice, containing acid and enzymes, to aid in the digestion of food.
It carries on the limited amount of absorption – of some water, alcohol, and certain drugs.
It produces the hormone gastrin, which helps regulation of digestive functions.
It helps to protect the body by destroying pathogenic bacteria swallowed with food or with mucous from the respiratory tract.
1.2 Regulation of gastric acid secretion:
The mechanisms operating at the gastric parietal cells as summarized in the above figure. The terminal enzyme H K ATPase (proton pump) which secretes H ions in the apical canaliculi of parietal cells can be activated by histamine, Ach and gastrin acting via their own receptors located on the basolateral membrane of these cells.Out of the three physiological secretagogues, histamine, acting through H2 receptors, plays the dominant role, because the other two, gastrin and Ach act partly directly by releasing histamine from paracrine enterochromaffin like cells called “histaminocytes” located in the oxyntic glands. While H2 receptors activate H K ATPase by generating cAMP, muscarinic and gastrin receptors appear to function through the phospholipaseC -IP3-DAG pathway that mobilizes intracellular Ca . The cAMP mediated proton pump activation also involves Ca . The secretomotor response to gastrin and cholinergic agonists is expressed fully only in the presence of cAMP generated by H2 activation. As such, histamine participates in the acid response to gastrin and Ach at more than one levels, and H2 antagonists suppress not only histamine but also Ach, pentagastrin and in fact any gastric acid secretory stimulus.
Gastrin is secreted from the antrum in response to rise in antral pH, food constituents and vagally mediated reflexes. The dominant muscarinic receptor mediating vagal responses is of M1 subtype. Its location on the ganglion cells of the intramural plexuses has been confirmed. The parietal cell muscarinic receptor is of the M2 subtype but the subtype of muscarinic receptor on histaminocytes has not been defined. Vagus releases Ach in dose proximity to histaminocytes and gastrin secreting cells, but apparently at a distance from the parietal cells.
Prostaglandins have been ascribed a “cytoprotective” role in the gastric mucosa by augmenting mucus and bicarbonate secretion, as well as other actions. PGE2, produced by gastric mucosa, inhibits acid secretion by opposing cAMP generation and gastrin release.
CONTROL OF GASTRIC ACID IN STOMACH: 1.3 Peptic Ulcer
Peptic ulcers disease refers to a group of disorders characterized by circumscribed lesions of the mucosa of the upper gastrointestinal tract (especially of the stomach and duodenum). The lesions occur in regions exposed to gastric juices. When the stomach’s natural protections from acid stop working ulcers will occur. Duodenal ulcers almost always develop in the duodenal bulb (the first few centimetres of the duodenum). A few, however, arise between the bulb and the ampulla. Gastric ulcers form most commonly in the antrum or at the antral-fundal junction. Nearly 80 % of peptic ulcers are duodenal the others are gastric ulcers. Most duodenal ulcers appear in people between ages 20 and 50 years, while gastric ulcer usually occurs between ages 45 and 55 years. Duodenal ulcer is twice as common in men as in women and gastric ulcers affect men and women equally. Approximately 10 to 20 % of gastric ulcer patients also have a concurrent duodenal ulcer.
Gastric ulcer is often a chronic disease and may persist for 10 to 20 years characterized by repeated episodes of healing and re-exacerbation. Peptic ulcers occur when there is an imbalance between offensive factors and defensive mucosal factors (Goel and Bhattacharya, 1991). Ulceration in the mucosa can be because of either breakdown of mucosa with the development of surface defects or failure of restitution of mucosal integrity resulting in retardation or failure of healing of the ulcers. No apparent causal factor is sufficiently uniquely associated with peptic ulcers to warrant unequivocal implication in pathogenesis of the ulceration. The mechanism of defensive action consists of humoral, functional and neuronal factors. All these factors are responsible for the mucosal protection.
The precise biochemical changes during ulcer generation are not clear yet, although various hypotheses have been proposed from time to time. Increased gastric motility, vagal over activity, mast cell degranulation decreased gastric mucosal blood flow and decreased prostaglandin level during stress condition is thought to be involved in ulcer generation. Similarly role of oxygen derived free radicals have been shown to play a role in experimental gastric damage induced by ischemia and reperfusion, hemorrhagic shock and ethanol administration. Helicobacter pylori a pathogen is now known to be the most common and important causes of gastric ulcer in humans (Davies et al., 1994), exhibits active inflammation with epithelial damage accompanied by neutrophil migration.
Although the currently used drugs for ulceration are broadly classified into two, those that decrease or counter increase in acid-pepsin secretion and those that afford cytoprotection by virtue of their effects on mucosal defensive factors. Ulcer treatment can be carried out by reducing the action of aggravating factors. Since gastric acid is one of the major aggressive factor contributing to peptic ulcer disease, the reduction of gastric acid either by surgical or pharmacological intervention has been used to promote ulcer healing. However, not all patients, with gastric or duodenal ulcer have high acid secretion. In fact, only 30%-40% of cases with duodenal ulcer have hypersecretion of gastric acid and, in patients with gastric ulcer, acid secretion is either normal or low (Gupta et al., 1980). In these cases, decreased mucosal resistance might be the dominant factor.
The neutralization of gastric acid can be done by antacid administration, but their effectiveness is only for a brief period. Muscarinic antagonists such as pirenzepine or telenzepine are effective inhibitors of acid production. The histamine H2-receptor antagonists (H2RA) like cimetidine, ranitidine, famotidine etc. act as potent inhibitors of acid secretion. Complete inhibition of parietal cells acid secretion by receptor antagonist is difficult because of complexity of known receptors on parietal cells and a variety of second messenger signaling system coupled to these receptors, which involve adenylate cyclase coupled with histamine receptor and intracellular Ca 2 with acetylcholine receptors. Thus, the most successful and desirable therapy is to inhibit the enzyme responsible for acid secretion. Moreover, H2RA have been reported to have some adverse reactions ranging from gastric carcinoid to tolerance and rebound acid secretion. Inhibition of gastric H /K -ATPase of the parietal cell by drugs such as by proton pump inhibitors (PPIs) like omeprazole, lansoprazole, timoprazole, etc. has been shown to be effective in the treatment of peptic ulcer disease. However, such agents irreversibly inactivate the ATPase and the return of acid secretion following such inhibition requires de novo synthesis of new pump.
Although these drugs have brought about remarkable changes in ulcer therapy, the efficiency of these drugs is still debatable. Reports on clinical evaluation of these drugs shows that there are incidences of relapses and adverse effects and danger of drug interactions during ulcer therapy. Further, in the developing countries, like India, most of the population is living in rural areas and depending on their indigenous system of drugs because of expensive modern treatment. Hence, the search for an ideal anti-ulcer drug continues and has also been extended to herbal drugs in search for new and novel molecules, which afford better protection, decrease the incidence of relapse and decrease the cost of the treatment.
Of late the search for new safe alternative drugs have rekindled the interest in cytoprotective drugs, which protects the mucosal layer from inducing agents. Cytoprotection has been defined as the ability of pharmacological agents-originally prostaglandins to prevent or reduce gastric, duodenal, or intestinal mucosal injury by mechanisms other than inhibition of gastric acid secretion. Although few drugs like sucralfate and prostaglandin analogs are recognized as cytoprotective agents (Vergin and Kori-Lindner, 1990), many natural drugs have been reported to posses this activity viz. plantain banana (Musa sapientum var Paradisiaca), Tectona grandis, Azadirachta indica and rasayana drugs like Centella asiatica, Asparagus racemosus, Convolvulus pluricaulis, Emblica officinalis, Bacopa monniera and Withania somnifera, etc. (Goel and Sairam , 2002).
India is one of the country rich in medicinal plants which were used by our ancestors. Traditionally, plants were used as medicine in a traditional way such as Ayurveda, Naturopathy, Siddha and Unani. After knowing the used of plants in medicine, synthetic drugs were now started replacing by herbal products.
Humans have used plant materials since prehistoric times and in some countries such as China documentary evidence shows that herbal medicines have been used for at least 7000 years. In Europe there is a rich history in the use of herbal medicines and these have been well documented in medieval herbals such as Culpeper’s and Gerard’s materia medica. Nowadays many countries are having interest in using Indian medicinal plants as it can cure many diseases and other purposes.
Herbal medicines differ from synthetic drugs in several attributes. Though, herbal medicines are mixed chemical compounds, all have not been isolated, characterized and quantified. When an extract of a plant or a compound isolated from the plant has to be clinically evaluated for a therapeutic effect not originally described in the texts of traditional systems or, the method of preparation is different, it has to be treated as a new substances or new chemical entity. The same type of acute, subacute and chronic toxicity data has to be generated.
Majority of medicinal herbs contain dozens of different compounds, often of great complexity, flavonoids, saponins, glycosides, alkaloids, mucilage, tannins, polysaccharides, etc., that buffer, modulates and modify the effect of any “active principles”. Study after study has shown that administering of isolated purified constituents of the whole or part of the plant cannot mimic effects produced by extracts of same part of the plant.
1.3.1 Pathophysiology of Peptic Ulcer
Peptic ulcer generally occurs when aggravating factors are higher than defensive mucosal factors(Goel

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