Correlation Between Hematological Parameters And Recurrent Aphthous Stomatitis

Correlation Between Hematological Parameters And Recurrent Aphthous Stomatitis
Nabiha Farasat Khan, Muhammad Saeed**, Ayaz Ali Khan*****

Incharge, Dept. Of Oral Pathology, Dental Section, Bolan Medical College. Quetta.
Incharge, Dept. Of Prosthodontics Dental Section, Bolan Medical College Quetta.
Professor and Head of Dental Department, Shaikh Zayed Federal Postgraduate Medical Institute Lahore.
Correspondence: “Dr. Nabiha Saeed”

How to CITE:

J Pak Dent Assoc 2010;19(2):124-128.


Recurrent Aphthous Stomatitis is a painful oral mucosal lesion affecting about 20% of the world’s population. On morphological basis RAS lesions can be divided into three main types including minor RAS (MiRAS), major RAS (MjRAS) and herpetiform RAS (HuRAS). Eighty five percent of all RAS lesions are Minor in nature. Classification based on severity of the lesion includes simple aphthosis and complex aphthosis. The etiology of the lesion is unknown. Many factors contribute in the Pathogenesis of RAS like inflammatory bowel disease, food allergy, stress, hormonal and immunological disturbances, Vitamin B12, Iron and Ferritin deficiencies. Deficiency of Hematological parameters especially Folate and Vit b12 causes Megaloblastic anemia which is more common in developing countries. Pakistan is a developing country and nutritional anemia is very common in the country. These nutritional deficiencies cause RAS. The aim of this review is therefore to determine the hematological parameters correlated with recurrent aphthous stomatitis. .


Recurrent aphthous stomatitis, etiology, Hematological parameters.


Ulcer means a damage of both epithelium and lamina propria. Oral ulceration is a common complaint of patients in Out Patient Department of any Hospital or Clinic. These patients become a challenge for general Practioners and dentist to diagnose and manage these ulcers. Patients suffering from oral ulceration some time referred to skin clinic, or to gastrointestional department. Of these two types of ulcerations are more frequently seen, these are recurrent herpetic stomatitis and recurrent aphthous stomatitis. 1

Recurrent Aphthous Stomatitis (RAS) is a very common oral mucosal disease.

It is a non-infectious, non-traumatic disorder. 2 The lesions of RAS are debilitating, self-limited, and recur at intervals on non-keratinized mucosa of tongue (lateral, dorsum) floor of mouth, buccal or labial mucosa.3 The lesions are superficial, rounded, and are yellow in color. It is surrounded by erythematous halo.2

Types of RAS:

RAS can be classified into 2 systems based on morphology, or clinical presentation. First classification is based on morphology and by using this classification RAS can be divided into three different variants according to their site, including Minor RAS (MiRAS), Major RAS (MjRAS), and Herpetiform RAS (HuRAS). About 80% of all RAS lesions are MiRAS. 4

Second classification of RAS is clinical, based on the severity of afflictions. Simple aphthosis represents the common presentation of a few lesions that heal in one to two weeks and recur.5Complex aphthosis represents a complicated clinical picture of severe disease. Complex aphthosis produces lesions continuously, with many ulcers at one time that continue throughout the year. This type of RAS develop later in life and is mostly associated with systemic diseases including Behcet’s disease, Cyclic Neutropenia, HIV AIDs, Inflammatory Bowel disease, and Hematinic deficiencies.5,6,7


The etiopathogenesis of RAS is not fully understood. Different etiologies and mechanisms have been postulated, resulting in identification of a variety of predisposing factors. Researchers are still trying to find the exact etiology of this painful condition. Local and systemic conditions that may cause these ulcers are all being intensely investigated, but to date; no principal cause/s has been discovered.6It has been suggested by the results of several studies that there is a significant role of hematological parameters (hemoglobin, ferritin, hematocrit, folate and B12) in the pathogenesis of RAS, but there is still some controversy remains.8, 9, 10, 11, 12 For better treatment planning it is important to recognize the lesions of aphthae secondary to systemic diseases like inflammatory bowl disease, Pemphigus vulgaris, Behcet’s disease, and hematinic deficiencies. 13 The treatment of this uncertain nature disease is not successfully completed as its pathogenesis reflects to the treatment planning. Although the effect of hematinic deficiencies on RAS and the results of their treatment is not clear but some recent studies reported reduce or eliminate recurrence of RAS lesions by treating these deficiencies in controlled and in preliminary studies.3, 14, 15, 16,

Hematinic deficiencies:

Hematinic deficiencies are found in 20% of patients with RAS. 6, 16 The recurrence rates of these ulcers is as high as 50%. 17, 18 It was observed that 60% patients with B-12 deficiency when received B-12 therapy were recovered completely 8, 9, 10 while 70% patients with RAS improved with hematinic replacement therapy.19, 20 Recurrent aphthous stomatitis have been still a public health problem of wide spread occurrence, however published studies on RAS in Pakistan are some what limited in number and most of published reports have been concerned with RAS and its correlation with intestinal parasitosis.21, 22 Since 1949 World Health Organization recognizing public health importance of nutritional anemia 23 which is a major health problem through out world especially in developing countries.24 Basic under standing of iron, folate and vitamin B-12 nutrition survey in a number of countries have high lighted the wide spread prevalence of nutritional anemia in developing countries.22 Infants, young children, menstruating and pregnant women are most frequently affected.24 Folate deficiency is the second most common cause of nutritional anemia in the world.24

It has been found that out of the total population of 159,196,336 of Pakistan 2 ½ people are anemic out of which 13% are suffering from pernicious anemia, a variant of megaloblastic anemia 25 which can cause oral ulceration, mucosal bleeding and glossitis.26, 27, 28

Malnutrition causes megaloblastic anemia 29 and also an contributing factor of RAS.

Deficiency of iron:

Iron deficiency causes iron deficiency anemia and iron deficiency anemia is common throughout world. Reports of a study showed about 50-60% of young children and pregnant women and 20-30% of non-pregnant women in the developing world are anemic.31

Idris M (2005) conducted a study to evaluate level of iron deficiency anemia and anemia based on ferritin level. One hundred anemic subjects were selected. Iron deficiency anemia was present in 68%, 39.71% (n=27), of these patients were males and 60.29% (n=41) were females. Iron deficiency anemia based on ferritin levels was seen in its moderate form in 53% and severe form in 47% of these anemic patients. 32 Although level of ferritin in Pakistani population was considered but no one of them considered any association between low level of ferritin or iron and RAS. Hematinic deficiency (Iron, Ferritin, Hematocrit, Folate and B12) have been reported to twice common in RAS patients as compared to controls. 13


Anemia is defined as clinical condition characterized by reduction in hemoglobin concentration of blood below normal for the age, sex, physiological condition and altitude above sea level of that person. 32 According to World Health Organization anemia is defined as hemoglobin less than 11g/dl for children (0-4 years) and pregnant women, Hb less than 12g/dl for 5-12 years of children and non-pregnant women, and hemoglobin less than 13g/dl for men.

Although anemia occurs world widely, about 1/3 out of 5.5 billion people of the world are anemic, 40% of children (0-12year) 35% women, 51% pregnant women and 18% of men are anemic. 33 Developing countries faces the most serious problems of anemia including blood loss, repeated pregnancies, most often iron deficiency anemia, hemoglobinopathies, folate deficiency, parasitic diseases (esp. malaria) and deficiency of essential elements for hemoglobin synthesis (iron, B-12) 33


Hamdani in 1987 conducted a study in Pakistan to rule out anemia in adult females. In his study the level of hemoglobin less than 11.5g/dl was considered as anemia and it was seen in 30% of females, but again correlation between hemoglobin and RAS was not considered. 34

Study conducted by Rogers 1986 revealed anemia in 6/102 RAS patients. 35 A recent study of Helay3 2004 revealed anemia in 10.5% RAS patients (6/57). However, study conducted by Burgan 2006 did not observed any statistical difference of hemoglobin between cases and controls, as out of 143 RAS patients 20 RAS patients (14%) were anemic compared to 15 out of 143 controls group (10.5%). Level of hemoglobin was seems to be normal in a study conducted by Thongprasom in 2002, and was also normal in study of Porter in 1988.


Anemia can be caused by deficiency in iron. Iron deficiency anemia based upon serum ferritin level was observed in a study conducted in Pakistan, where moderate serum ferritin anemia was seen in (53%) patients while severe serum ferritin anemia was present in (47%) of patients, 41 of them were females and 27 were males. 32 The low level of Ferritin is reported by previous studies with varying frequencies. Some had found low deficiency varying from 8.5% to 11.6%, 15, 36 while others reported a very high 96% ferritin deficiency in patients of RAS.3 In Bristol two studies were carried out for observation of the prevalence of iron deficiency in RAS patients. The level of serum ferritin was 11.6% in /69 patients suffering from RAS 37 and in other study out of 75 RAS patients 37% had deficiency of ferritin. 14


Hematocrit is the ratio of the volume of packed red blood cells to the total blood volume and is therefore also known as the packed cell volume, or PCV. 38 It measures the percentage of red blood cells in a given volume of whole blood and is used as a screening test for anemias. A low Hematocrit reflects a low number of circulating RBC’s. Level of Hematocrit is decreased in a variety of conditions including Chronic or acute blood loss, some cancers, malnutrition, vitamin B12 and Folic acid deficiencies and iron deficiency.38

Study conducted by Helay in 2004 observed low level of Hct in 18 RAS patients (18/57 RAS patients).3 Different studies conducted to evaluate relation of Hematological parameters with RAS did not mention level of Hct in their studies.

Deficiency of vitamin B12 and folate:

Deficiency of vitamin B12 and folate most commonly results in megaloblastic anemia (MA). In India and other developing countries, most cases of MA are caused by nutritional deficiency of folate, B12 or both. 30, 31Patient’s of MA from Pakistan revealed Vitamin B12 deficiency in over 50% of cases while only 8% cases were seen to be deficient in Folate. 2

Vitamin B12:

The role of Serum B12 in the pathogenesis is speculative. Due to the deficiency of B12 cell mediated immunity is suppressed causing changes in the tongue and buccal mucosa. 39 Serum B-12 and folic acid are essential for the synthesis of DNA. Deficiency of these units’ results in the development of megaloblastic anemia in developing countries including India 30, Turkey, 15 Israel, 17

Czech, 40 Thailand 16 Saudi-Arab 14 and Tunis.41 Study conducted by Volkov I (2006) 42 revealed that patients with RAS lesions were deficient in Serum B12. Intramuscular cobalamine injection prevents recurrence of the lesion over 18 months. Burgess et al in 2008, 43 Garcia BG et al in 2009 44 and Volkov I in 2009 reported that 74.1% patients with RAS when treated with cobalamine were free from aphthous ulcers at the end of treatment. 45As Serum B12 administration diminishes the occurrence of RAS lesions it has been suggested that possible Serum B12 deficiency should be considered in all subjects with RAS.16, 17, 46, 47

Wray et al found low level of Serum B12 in 5/23 (21.7%) RAS patients as compared to 8.5% (11) in controls 8 the results of Wray were supported by a recent study carried out by Burgan SZ 2006, 14 that showed 26.6% of RAS patients demonstrated B12 deficiency as compared to the control with B12 deficiency in 12.6%.8, 14

This study, coupled with numerous other references, suggested that Serum b12 had a role in the pathogenesis of RAS. 17, 18, 43, 44, 42, 48 The percentage of B12 deficiency was found 19-41% out of 228 individuals in Mexico, 42 while in Pakistan the deficiency of B12 was upto 50%. 29

Folic Acid:

Folic acid is essential for all body cells, especially to enhance the regeneration and healing of oral epithelium in response to damage. For diagnosis and management of this deficiency accurate hematologic assessment is important. 49 The level of deficiency of Folate in Pakistan is 8%.29 The study of Barnadas was carried out in Spain and found that folic acid deficiency was the commonest deficiency in 80 RAS patients.10 There were 11 out of 23 (47.83%) patients of RAS were reported to have low level of Folate in the study of Thongprasom in 2002, the study was carried out in Bangkok. 16 A recent report showed 46.9% of non-anemic adults having sub-normal levels of B12 only or combined Folate and B12 deficiency which was five times more common than Folate deficiency. 50

Deficiency of Folate in adult life produces “megaloblastic” anemia, while deficient Vitamin B12 not only produces a “megaloblastic” anemia but also causes irreversible damage to the central and peripheral nervous systems. 51 “Megaloblastic anemias” is known to be a predisposing factor of Aphthous stomatitis, sore tongue, gingivitis.26, 28 Published cases of different studies had pure deficiencies: iron (5%), vitamin B12 (5%), and folic acid (12%). 10 A study reported combined deficiency state in 3.6% (n=7) of RAS patients, while 1.0% (n=2) patients were vitamin B12 deficient, 96% (n=55) RAS patients had reduced Ferritin levels, and only 10.5% (6/57) were anemic.3


Recurrent Aphthous Stomatitis is a mulitfactorial disorder. Through previous published literature correlation seems to be present between hematinic deficiencies and recurrent aphthous stomatitis. There is low level of hematological parameters (including Hb, Hct, B12, Folate and Ferritin) in 20% of patients suffering from this painful and debilitating disease. Recurrent aphthous stomatitis is a common lesion that have been still a public health problem of wide spread occurrence. However, no work has been done to find any association between RAS and hematinic deficiencies. Published studies in Pakistan are some what limited in number and are concerned with RAS and its correlation with intestinal parasitosis. There is a need to evaluate the level of hematological parameters in patients suffering from this recurrent ulcerative disorder. Dentists and general Practioners should always consider RAS as secondary effect of hematinic deficiencies due to nutritional anemia and always carried out blood picture for diagnosing it.


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