|Year : 2022 | Volume
| Issue : 3 | Page : 157-162
A single-center cross-sectional study on the clinical profile of pancytopenia and a novel scoring system for megaloblastic anemia
Sanjaykumar Somsingbhai Rathwa, Darshankumar Manubhai Raval, Shashwat Mallik, Shahin Khan
Departments of Medicine, Baroda Medical College, SSGH, Vadodara, Gujarat, India
|Date of Submission||16-Apr-2022|
|Date of Decision||20-Jun-2022|
|Date of Acceptance||25-Jun-2022|
|Date of Web Publication||20-Jul-2022|
B-75, Matrusmruti Society, Diwalipura, Vadodara, Gujarat
Source of Support: None, Conflict of Interest: None
Background: Our study tries to identify the main culprits causing pancytopenia and its typical clinical presentation, along with the clinical and hematological profile of megaloblastic anemia (MGA)-induced pancytopenia, in a tertiary care hospital in western India. Methods: This observational cross-sectional study was carried out on 50 patients diagnosed with pancytopenia in our hospital over 1 year (January 2019–January 2020). A scoring system is also described to distinguish cobalamin deficiency from other etiologies of pancytopenia. Results: MGA due to cobalamin deficiency was the leading cause of pancytopenia. The most frequently seen sign was whiteness, while the most typical symptoms were lethargy, malaise, and generalized weakness. Patients between 20 and 50 years of age were most often affected, with a male predominance being noticed. While blood counts revealed life-threatening anemia in most patients, the leukopenia and thrombocytopenia were not as severe. Conclusion: It was concluded that MGA due to dietary deficiency of Vitamin B12 is the most common etiology for pancytopenia in western India. Our scoring system could be used as an alternative to serum cobalamin tests to diagnose cobalamin deficiency, subject to confirmation in larger populations.
Keywords: Novel scoring, pancytopenia, vegetarian diet, Vitamin B12 deficiency
|How to cite this article:|
Rathwa SS, Raval DM, Mallik S, Khan S. A single-center cross-sectional study on the clinical profile of pancytopenia and a novel scoring system for megaloblastic anemia. Apollo Med 2022;19:157-62
|How to cite this URL:|
Rathwa SS, Raval DM, Mallik S, Khan S. A single-center cross-sectional study on the clinical profile of pancytopenia and a novel scoring system for megaloblastic anemia. Apollo Med [serial online] 2022 [cited 2022 Sep 25];19:157-62. Available from: https://apollomedicine.org/text.asp?2022/19/3/157/351546
| Introduction|| |
Pancytopenia, a decrease in all three types of blood cells, is derived from the word cytopenia, which means a reduction in the count of a single category of blood cells., The disease peaks between 20 and 50 years of age., The incidence of pancytopenia is higher in Asian countries compared to the West, making a discussion on pancytopenia in an Asian setting very relevant so that early identification and prompt treatment of the underlying etiology can reduce its prevalence and its various complications.,
The etiology of pancytopenia varies in studies conducted in different geographical areas., In Asian countries, megaloblastic anemia (MGA), malaria, and hypersplenism are the predominant etiological contributors to pancytopenia. The clinical signs and symptoms of anemia, leukopenia, and thrombocytopenia should be followed up by laboratory tests for diagnosis. Blood examination with findings of hemoglobin (Hb) <9 g/dl, white blood cells (WBCs) <4000/cumm, and platelets <100000/cumm is defined as pancytopenia, and an absolute neutrophil count of <1500/cumm is also seen.,,
Bone marrow examination is the most reliable investigation in diagnosing pancytopenia, but it is only indicated when required. It is not routinely used as consent is difficult to obtain for such an invasive procedure, and the status of platelets and leukocytes cannot usually be known., Conditions such as aplastic anemia, some myelodysplasia syndromes, acute myelogenous leukemia, some acute lymphoblastic leukemia, and some bone marrow lymphomas have decreased bone marrow cellularity., Some primary disorders of the bone marrow such as paroxysmal nocturnal hemoglobinuria, myelofibrosis, some aleukemic leukemia, myelophthisis, bone marrow lymphomas, hairy cell leukemia and some infections such as malaria, dengue, and human immunodeficiency virus, and autoimmune diseases such as Systemic Lupus Erythematosus (SLE) have shown cellular marrow on histological examination.,,, Pancytopenia may also develop due to dysplastic marrow, as seen in cobalamin or folate deficiency and myelodysplastic syndromes.,
MGA is a group of diseases which is a part of megaloblastic, a more considerable generalized disorder. Countries with high malnutrition rates report a higher load of the disease, with an increased prevalence in older populations.,, It is one of the most common and reversible causes of pancytopenia.,, Cobalamin and folate deficiencies are the most common causes of MGA. Diet history is an important consideration. A purely vegetarian diet is commonly associated with Vitamin B12 deficiency as its external sources include meat, fish, and dairy products. Vitamin B12 is required for the formation and maturation of DNA. Its deficiency is characterized by a disproportion between nuclear and cytoplasmic development, which leads to macrocytic red blood cells (RBCs) with higher nuclear-to-cytoplasmic ratios, hypersegmented neutrophils, and abnormally large platelets.,
We have described a study of pancytopenia, its etiologies, and clinical and hematological profile, with a particular emphasis on Vitamin B12 deficiency. A scoring system to distinguish cobalamin deficiency from other causes of pancytopenia has also been described, as serum cobalamin tests are expensive and not always accurate in diagnosing Vitamin B12 deficiency.
| Methods|| |
The study was conducted in the Department of General Medicine, Baroda Medical College, S.S.G. Hospital, Vadodara. After taking due approval and clearance from the Institutional Ethical Committee (No. IECHR-PGR/122-19 dated December 2, 2019) and with due written and informed consent from all the subjects, the study was carried out in patients with pancytopenia admitted to the medical ward of S.S.G. Hospital, who fulfilled the inclusion and exclusion criteria.
A population-based, observational cross-sectional study was undertaken at S.S.G. Hospital, Vadodara, from 2019 to 2020 over 1 year. Patients aged >12 years with Hb level <9 g/dl, leukocyte count <4000/cumm, and platelet count <1 lakh/cumm, who directly presented to our hospital with symptoms and without prior treatment, were included in the study, while age <12 years was an exclusion criterion, as the Pediatric Department treats patients younger than 12 years. The total number of patients enrolled in the study was 50. Patients with pancytopenia aged >12 years and of both sexes were included in the study. A complete history, including presenting complaints, and history with specific reference to drug intake and radiation exposure, was taken. In diet history, a mixed diet was defined as regular consumption of eggs or meat, while in a purely vegetarian diet, this was absent. General examination was carried out with specific emphasis on pallor, icterus, petechiae, clubbing, skin changes, splenomegaly, and lymphadenopathy. All systems were examined in detail. Complete blood count with RBC indices, peripheral blood smear (PBS), and reticulocyte counts were done in all patients. If the above laboratory investigations were suggestive of findings of cobalamin deficiency such as macro-ovalocytes, hypersegmented neutrophils, anisopoikilocytosis, reticulocytopenia, or elevated mean corpuscular volume (MCV), then serum Vitamin B12 level was done in such patients. According to our laboratory, if serum cobalamin deficiency, defined as <187 pg/ml (severe deficiency is <83 pg/ml), was detected, it was considered pancytopenia due to Vitamin B12 deficiency. If it was found to be in the normal range, then alternative causes of pancytopenia were ruled out. Supporting laboratory investigations were done according to need.
Bone marrow biopsy and specific investigations such as serum iron, total iron-binding capacity, and ferritin were done whenever needed. Renal function test, liver function test, ultrasonography abdomen, stool examination for occult blood, and chest X-ray were also done as and when required.
Based on a pilot study of ten patients with pancytopenia (n = 7, MGA; n = 2, aplastic anemia; and n = 1, malaria), a scoring system was developed to diagnose Vitamin B12 deficiency without the use of serum cobalamin levels [Table 1]. A score of ≥15 indicated Vitamin B12 deficiency, while <15 pointed toward an alternative etiology for pancytopenia in the patient. Six out of seven cobalamin-deficient patients had a score ≥15, while the remaining three patients with pancytopenia had a score <15.
All statistical analyses were performed using the online software “socscistatistics,” and P < 0.05 was considered statistically significant.
| Results|| |
- Of the 50 patients, 33 (66%) were between 20 and 50 years of age, of which 25 (50%) were pure vegetarians. Thirty-five (70%) patients with pancytopenia consumed a vegetarian diet [Figure 1]. Pancytopenia was more common in males, with a male-to-female ratio of 1.27:1
- Hematological causes were found to be the most common etiology with 43 (86%) patients (MGA – 60%, aplastic anemia – 12%, hypersplenism – 10%, acute lymphoblastic leukemia – 2%, and myelofibrosis – 2%), followed by infectious (malaria – 6%, dengue – 2%, and HIV – 2%) and autoimmune causes (hemophagocytic lymphohistiocytosis and systemic lupus erythematosus – 2% each) [Figure 1]
- The most common presenting symptom was lethargy, malaise, and generalized weakness in 38 (76%) patients, followed by fever and dyspnea on exertion, which were seen in 24 (48%) and 20 (40%) patients, respectively. The most infrequently seen symptom was gum bleeding in 2 (4%) patients. Pallor was present in all 50 (100%) patients. Icterus in 24 (48%) was mainly seen in patients with acute viral hepatitis, cirrhosis of the liver, and Vitamin B12 deficiency. Knuckle and tongue hyperpigmentation were noted in 20 (40%), while splenomegaly in 17 (34%) patients. Patients rarely presented with lymphadenopathy (2%) or petechiae (8%) [Figure 1]
- Thirty-two (64%) patients had Hb <5 g/dl with equal distribution between two groups that is <3 and 3–4.99 g/dl, while only six (12%) had Hb >7 g/dl. Out of 16 with Hb <3 g/dl, 10 were females [Figure 2]
- Twenty-one (42%) patients had a total leukocyte count between 3000 and 4000/mm3, while only four (8%) had <1000/mm3, which included two patients with MGA [Figure 2]
- Sixteen out of 24 patients with platelet count <40000/mm3 were females. Out of 24 patients, 12 had MGA. The average Hb in 50 patients with pancytopenia is 4.3 g/dl, average WBCs is 2560/mm3, and average platelet is 46220/mm3 [Figure 2]
- On PBS examination, 64% of patients had macrocytic pictures, while 26% had microcytic pictures. Only 10% had no change in the PBS and contained normocytes. Twenty-one patients (42%) had MCV >99, 14 (28%) had MCV between 80 and 99, and an MCV <80 was seen in 15 (30%) patients. Bone marrow biopsy was done in 12 (24%) patients to evaluate pancytopenia. Seven (58.33%) patients had hypocellular and/or aplastic bone marrow picture, four (33.33%) had hypercellular and/or megaloblastic picture of bone marrow, and one (8.33%) had normocellular bone marrow
- Thirty patients had low serum Vitamin B12 levels (<187 pg/ml), and among them, twenty patients had severe Vitamin B12 deficiency (<83 pg/ml). The difference between males and females was by chance, and it was not statistically significant (P > 0.05)
- Of all the patients with low B12 levels (<187), 19 (63.33%) had lethargy, malaise, and generalized weakness, which was the most common symptom. Among the signs, whiteness is the most commonly seen in all 30 (100%) patients, followed by knuckle and tongue hyperpigmentation in 20 (66.66%) [Figure 3]
- Among the 21 patients with MCV > 99, 18 had low B12 serum levels (<187) (P < 0.05). However, 12 out of 30 cobalamin-deficient patients had an MCV <99. Furthermore, 13 out of 20 patients with severe B12 deficiency (<83) had an MCV >99 [Figure 4]. Patients' dietary habits revealed that 35 (70%) were pure vegetarian and 15 (30%) were taking a mixed diet. Of 35 pure vegetarian patients, 23 had a low B12 level (<187 pg/ml). Of 30 patients with low Vitamin B12 levels, 23 (65.71%) were vegetarian. Twelve (40%) patients also had a history of alcohol addiction
- Among the 30 patients diagnosed with Vitamin B12 deficiency-induced pancytopenia, 27 (90%) had macrocytosis, 16 (53.33%) showed macro-ovalocytes, and 10 (33.33%) showed hypersegmented neutrophils on PBS [Figure 4]
- According to our scoring system, 26 out of 30 patients with low serum cobalamin had a score ≥15 (cobalamin deficiency). Fifteen out of 20 patients with normal serum cobalamin had a score <15 (no cobalamin deficiency)
- The scoring system has 86.6% sensitivity, 75% specificity, 25% false-positive error rate, 13.3% false-negative error rate, 83.8% positive predictive value, and 78.9% negative predictive value.
|Figure 1: Age group-wise, diet-wise, etiology-wise, and sign- and symptom-wise distribution of cases|
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|Figure 2: Hemoglobin-wise, WBC count-wise, and platelet count-wise distribution of cases with gender subgrouping. WBC: White blood cell|
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|Figure 3: Serum B12-wise and sign- and symptom-wise distribution of Vitamin B12-deficient patients|
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|Figure 4: Correlation between low B12 (<187) and MCV level and distribution of various features in MGA. MCV: Mean corpuscular volume, MGA: Megaloblastic anemia|
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| Discussion|| |
An insight into the demographics of pancytopenia reveals that people aged 20–50 years are the most affected. At the same time, it is seen slightly more in males as compared to females, which is similar to studies by Jain and Naniwadekar and Gayathri and Rao.,
The present study demonstrated that Vitamin B12 deficiency MGA was the most common cause of pancytopenia in this geography, similar to Gayathri and Rao, but profoundly dissimilar to other studies in more developed countries that have recorded aplastic anemia or neoplastic diseases and radiation as their most common etiology.,,,, This points toward the nutritional inadequacy of our country. Aplastic anemia was the second most common cause of pancytopenia in our study, followed by hypersplenism, which was the most common etiology in Jain ad Naniwadekar's study. It was exclusively seen to affect chronic alcoholic males in our study.
Lethargy, malaise, and generalized weakness, probably due to decreased oxygen-carrying capacity of the blood, were the most common symptoms, followed by fever and dyspnea on exertion, which was consistent with the findings of Khattak et al., Pallor was present in all the patients in our study, and this was comparable to the survey by Gayathri and Rao. Icterus was the second most common sign in our study, and it was mainly seen in patients with acute viral hepatitis, liver cirrhosis, and Vitamin B12 deficiency. Hyperpigmentation of knuckles and tongue is also seen in cobalamin-deficient patients, supporting Thakkar et al.'s findings., Most patients with pancytopenia may present with life-threatening anemia, as evidenced by our study in which 64% of patients had Hb <5 g/dl, which was in contrast to the findings of Thakkar et al. in which only 34.3% of patients had Hb <5 g/dl. Severe leukopenia and critical thrombocytopenia were not detected in most patients, similar to Thakkar et al.'s study, indicating that the RBCs might be the first and most affected of all the blood cells.
Thirty out of 50 patients in our study had low Vitamin B12 levels, out of which 20 had severe cobalamin deficiency, which supports other studies having Vitamin B12 deficiency as the most common etiological factor for pancytopenia.,,,, It was noticed that potent Vitamin B12 deficiency (<83 pg/ml) was more likely in patients with a higher MCV value, but this correlation was not seen in mild deficiency (83–187 pg/ml). This explains the association of cobalamin-deficient patients with the finding of macrocytes (90%) or macro-ovalocytes (53.33%) in their PBS. The PBS examination findings were compared with the results of Premkumar et al., which had only 34.1% of patients with macrocytes or macro-ovalocytes in their PBS. Dietary insufficiency was the foremost reason for cobalamin deficiency as Vitamin B12 is absent in green leafy vegetables and other vegetarian foods, as seen in Thakkar et al.'s study.,, In our study, 65.71% of cobalamin-deficient patients with pancytopenia consumed strictly vegetarian diets. This finding could have been affected by a primarily vegetarian population of India.
Limitations of this study include a cross-sectional design, as this study only captures a snapshot of the study population (etiology, clinical features, and hematological parameters) without any follow-up. Furthermore, our study was limited to patients of a particular geographical area. Hence, the race and regional variability of the findings cannot be commented upon. Since the sample size was small, further large-scale population studies are required to validate our scoring system.
| Conclusion|| |
Pancytopenia is most frequently seen in pure vegetarian patients aged 20–50 years, and the most common etiology is hematological, while infectious and autoimmune causes are rarely seen. Among hematological causes, MGA was found to be the most common. Lethargy, malaise, generalized weakness, and pallor were the most common presenting symptoms and signs, respectively. Females were more prone to severe anemia (Hb <3 g/dl). Life-threatening anemia was much more commonly seen than severe leukopenia or thrombocytopenia. While a normal or low MCV does not exclude MGA, there was a strong association of B12 <83 pg/ml and increased MCV >99 fL. A purely vegetarian diet increases the incidence of Vitamin B12 deficiency. The scoring system described in this study showed a significant difference between cobalamin-deficient and noncobalamin-deficient patients based on the included parameters. Further studies are required to validate it.
Special thanks to DR for developing the novel scoring system and SM and SK for validating the same.
Ethics approval and consent to participate
The study was conducted in the Department of General Medicine, Baroda Medical College, S.S.G. Hospital, Vadodara, after taking due approval and clearance from the institutional ethical committee (No. IECHR-PGR/122-19 dated December 2, 2019), and with due written and informed consent from all the subjects.
Availability of data and materials
The datasets used and analyzed during the current study are available from the corresponding author on reasonable request.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
SR: Conception or design of the work, Data collection, Data analysis and interpretation, Drafting the article, Critical revision of the article, Final approval of the version to be published DR: Conception or design of the work, Data collection, Data analysis and interpretation, Drafting the article, Critical revision of the article, Final approval of the version to be published SM: Data collection, Drafting the article, Technical help SK: Data collection, Drafting the article, Technical help.
| References|| |
Vargas-Carretero CJ, Fernandez-Vargas OE, Ron-Magaña AL, Padilla-Ortega JA, Ron-Guerrero CS, Barrera-Chairez E. Etiology and clinico-hematological profile of pancytopenia: Experience of a Mexican Tertiary Care Center and review of the literature. Hematology 2019;24:399-404.
Chiravuri S, De Jesus O. Pancytopenia. In: StatPearls. Treasure Island (F.L.): StatPearls Publishing; 2021.
Jain A, Naniwadekar M. An etiological reappraisal of pancytopenia – Largest series reported to date from a single tertiary care teaching hospital. BMC Hematol 2013;13:10.
Chandra H, Gupta AK, Nath UK, Singh N, Kumar U, Kishore S. Clinico-hematological study of pancytopenia: A single-center experience from north Himalayan region of India. J Family Med Prim Care 2019;8:3944-8.
] [Full text]
Le Clef Q, Menter T, Tzankov A. Our approach to bone marrow biopsies in cytopenia. Pathol Res Pract 2019;215:152447.
Gayathri BN, Rao KS. Pancytopenia: A clinico hematological study. J Lab Physicians 2011;3:15-20.
] [Full text]
Kirk SE, Young E, Ray A, Dzurik Y, Elghetany T, Sasa G. Transient pancytopenia subsequently diagnosed with acute leukemia: A report of 4 cases of acute lymphoblastic leukemia and acute myeloid leukemia. J Pediatr Hematol Oncol 2021;43:e715-7.
Devitt KA, Lunde JH, Lewis MR. New onset pancytopenia in adults: A review of underlying pathologies and their associated clinical and laboratory findings. Leuk Lymphoma 2014;55:1099-105.
Shackleton L, Langabeer SE, O'Brien D, McCarron SL, Byrne B, Barry R, et al.
Hairy cell leukemia masquerading as pancytopenia in pregnancy. Case Rep Hematol 2019;2019:3238168.
Santra G, Das BK. A cross-sectional study of the clinical profile and aetiological spectrum of pancytopenia in a tertiary care centre. Singapore Med J 2010;51:806-12.
Stover PJ. Vitamin B12 and older adults. Curr Opin Clin Nutr Metab Care 2010;13:24-7.
Yokuş O, Gedik H. Etiological causes of pancytopenia: A report of 137 cases. Avicenna J Med 2016;6:109-12.
Khattak MB, Ismail M, Marwat ZI, Khan F. Frequency and characterisation of pancytopenia in megaloblastic anaemia. J Ayub Med Coll Abbottabad 2012;24:53-5.
Hariz A, Bhattacharya PT. Megaloblastic Anemia. In: StatPearls. Treasure Island (F.L.): StatPearls Publishing; 2021.
Khera S, Pramanik SK, Patnaik SK. Transcobalamin deficiency: Vitamin B12
deficiency with normal serum B12
levels. BMJ Case Rep 2019;12:e232319.
Simşek OP, Gönç N, Gümrük F, Cetin M. A child with vitamin B12 deficiency presenting with pancytopenia and hyperpigmentation. J Pediatr Hematol Oncol 2004;26:834-6.
Thakkar BB, Bhavsar UN, Trivedi NJ, Agnihotri AS. A study of pancytopenia in adult patients more than 12 years of age in the North West region of Saurashtra. Natl J Med Res 2013;3:48-52.
Kim M, Lee SE, Park J, Lim J, Cho BS, Kim YJ, et al.
Vitamin B (12)-responsive pancytopenia mimicking myelodysplastic syndrome. Acta Haematol 2011;125:198-201.
Premkumar M, Gupta N, Singh T, Velpandian T. Cobalamin and folic Acid status in relation to the etiopathogenesis of pancytopenia in adults at a tertiary care centre in north India. Anemia 2012;2012:707402.
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