Biermer Disease : Initial Presentation and Follow-Up of 66 Patients in Internal Medicine Department in Senegal

Pernicious anemia in black people, is little known. Through this study we assess its diagnostic and evolutive aspects, and compare vitamin therapy B12 intramuscular and oral. Sixty six Biermer disease patients followed (January 2000-June 2014) at Internal Medicine Department of Aristide Le Dantec University Teaching Hospital (Senegal) are included. They were 26 men and 46 women (gender ratio: 0.65), who had a mean age of 47.84 years ± 15.25 years. Patients consulted for anemia (65 cases), acquired melanodermia (36 cases), gastrointestinal symptoms (30 cases), peripheral neuropathy (27 cases), venous thrombosis (2 cases), acute depression (1 case). Macrocytosis was observed in 52 cases. The mean hemoglobin in the vitamin B12 intramuscular group (52 patients) or oral group (14 patients) was the inclusion: 6.55 g/dl ± 3.12 g/dl vs 6.52 g/dl ± 2.18 g/dl (p = 0.04); and at day 8 treatment: 8.69 g/dl ± 2.49 g/dl vs 8.85 g/dl ± 1.9 g/dl (p = 0.43). Neurological and vascular presentations are unusual in contrast to macrocytic anemia. Oral administration of vitamin B12, simple and effective should be recommended in country with limited resources.


Introduction
Biermer disease or pernicious anemia is a chronic auto-immune disease responsible for a chronic gastritis and a vitamin B12 deficiency, reversible under vitamin B12 therapy which oral administration is validated [1].It is considered rare in black people and re-lated literature in sub-Saharan Africa is limited to few case reports [2]- [5].To our knowledge no publications about practice of oral vitamin therapy B12, is available in sub-Saharan Africa.With this series we propose to describe diagnostic and progression aspects, and to compare outcome on vitamin therapy B12, intramuscular and oral.

Patients and Methods
It is a retrospective, descriptive study with analytical outlook conducted upon comprehensive enrollment of medical files of Biermer disease patients followed from 1 st January 2000 to 30 th June 2014.The study held at Internal Medicine Department of superior referral hospital of Aristide Le Dantec University Teaching Hospital (Senegal) which has consultation, hospitalization and research activities.Our study included 66 files of Biermer disease, onto an annual average of 685 inpatients and 14,871 outpatients at Internal Medicine Department.
The diagnosis of Biermer disease was made in the presence of positive anti-intrinsic factor or anti-parietal cells antibodies, associated or not with vitamin B12 deficiency and atrophic gastritis [1].Epidemiological, clinical and paraclinical data were analyzed.Bone marrow aspiration and analysis provided precision on the existence of megaloblastosis.Vitamin B12 deficiency was defined by measurements below normal values between 187 and 883 pg/ml.
Positive anti-intrinsic factor and anti-parietal cells antibodies were defined by measurements higher than 1.53 and 40 AU/ml respectively.Upper gastro-intestinal-tract (GIT) endoscopy with systematic antrum and fundusbiopsies and histology revealed gastric atrophy, metaplasia and helicobacter pylori (HP).
Cyanocobalamine is administered intramuscularly (1000 µg once a day for the 1st week, then once a week for a month and once a month for life) or orally (2000 µg per day for 10 days, followed by the same dose once a week for 4 weeks and then once a month for life).Indications for oral administration were: Ongoing anticoagulation, thrombocytopenia below 50,000/mm 3 and difficult access to intramuscular injections.The median follow-up of patients treated with vitamin B12 (oral or intramuscular) was 1135.72,days [8 -4886 days].
Statistic tests (medium, standard deviation, Student test) were done using Statistical Package for Social Sciences 20 software.

Results
The files of 40 women and 26 men (gender ratio: 0.65), with mean age of 47.84 years ± 15.25 were included.
Overall evolution after intramuscular (52 cases) or oral (14 cases) vitamin therapy B12 is favorable.On day eighth, is observed a mean reticulocytosis crisis of 119.63 G/L ± 97.94 G/L [36 to 466.46 G/L].Hemoglobin levels is rising during vitamin B12 administration (Figure 1).Hemoglobin levels increased after 6 months in 83.9% of patients Figure 1.Evolution of the average rate of hemoglobin.and after 1 year the improvement was at 91.7% of patients.
In analytical study the mean hemoglobin level on vitamin B12 supplements in the intramuscular group versus oral, was on day eight 8.69 ± 2.5 g/dl Vs 8.85 ± 1.9 g/dl (p = 0.43) and after 1 month it was 10.83 ± 2.2 g/dl Vs 11.81 ± 1.1 g/dl (p = 0.16) (Table 2).
In oral group the reticulocyte count which was at 49.29 G/L initially rose to 297 G/ Lafter 6 months (Table 2).

Discussion
The available literature on Biermer disease in sub-Saharan Africa is made of limited series.
In 2003, Segbenaet al [2] reported 4 observations and in 2013, Diopet al [3] collected 28 cases over 6 years.To our knowledge, our study is the largest series carried out in Senegal (66 cases) and is the 1 st describing oral vitamin B12 therapy.
In our study as well as in other african publications [2]- [5], Biermer disease is common in women in their fifties.Predominant signs on presentation in our study were anemia signs, which also were almost present in de Segbenaet al [2] and Ndiaye et al. [4] with respective prevalences of 100% and 80%.
In our study, anemia signs are predominantly made of anemic syndromefar ahead of hemolytic anemia and anemic heart disease.Heart failure as described in our patients is a chronic complication of cardiovascular manifestations common to all vitamin B12 deficiencies as described in almost 50% of cases by Nafil et al. [6].
Acquired melanodermia, second presenting sign in our study is also frequently reported in African publications [3] [4].It is a diffuse homogenous melanodermia with buccal and palmo-plantar predominance secondary to disturbed tyrosine synthesis, this being a melanin precursor [7].
The third diagnostic condition in our study was GIT signs with atypical epigastric pain, followed by Hunter glossitis.This one is more specific of Biermer disease and was noted in 78.57% of patients in Diop et al. series [3].
The least observed manifestation in our patients was deep venous thrombosis.As a comparison Zulfiquar et al. [8] and Diop et al. [3] respectively reported 10 and 2 observations.
Beside thrombosis, acute depression and combined sclerosis of the bone marrow are rare in our study (1 case) like in the literature [4] [8] [9].
Main BC abnormalities were macrocytic anemia followed by thrombocytopenia and neutropenia both in our patients and in Song and al series [10] who reported 65% of thrombocytopenia and 45.5% of leucopenia.However some authors [11] didn't note any difference in the prevalence of leukocytopenia and thrombocytopenia.These cytopenias are more combined into pancytopenia orbicytopenia [3] [4] [8].Early diagnosis at the macrocytosis stage before cytopenia is rare [5], we only hadone observation.Beside the frequent macrocytosis, normocytosis and hypochromia are not exceptional [3] [8].They are due to additional factors like iron deficiency in bleeding of our patients for example or other comorbidities like association with beta thalassemia and Plummer Vinson [3].
Positive anti-intrinsic factor antibody which is more specific of the disease [3] [9], was almost constantly present in our study.
Prevalence of atrophic gastritis was high unlike HP surinfection which was rare.Similar findings in this regard were also obtained by Wun Chun et al. [9] who published cases of HPsurinfection par HP in 109 Biermer disease patients who underwend upper GIT endoscopy with biopsies.
On therapeutic aspect, hematologic abnormalities are reversible with vitamin B12 treatment, more frequently administered intramuscularly in our study and in the literature [1] [4].Song et al. [10] noted that 94.3% of anemia regressed after 3 months treatment with vitamin B12.
Oral route of administration is effective and is indicated in case of severe thrombocytopenia or anticoagulation treatment [1].In addition therapeutic compliance is better obtained with oral administration in patients with difficult access to health care.In analytical study we noted that oral vitamin B12 allowed cytopenia regression by day eight and reticulocytosis was statistically significant after 6 months.The absence of statistical significance of some of our tests was a bias due to the limited number our series enrolled.

Table 1 .
Clinical and paraclinical characteristics of the patients of our study.

Table 2 .
Blood Count and reticulocyte count: At the beginning of the study and progression according to the administration route of vitamin B12.