Introduction
Pancytopenia is a hematological disorder involving in a decrease in the three blood cell lineages like erythrocytes, leucocytes and thrombocytes.1 It can manifest as a laboratory finding of many diseases. The etiology of pancytopenia has a wide age, sex and geographical variation which includes megaloblastic anemia, anemia of nutritional origin, aplastic anemia, blood cancer, myelodysplastic syndromes(MDS), multiple myeloma, lymphoma, sepsis, alcoholic diseases, viral diseases like HIV and hepatitis, autoimmune diseases, endocrinological disorders and infiltrating diseases of the bone marrow (Gaucher's disease).2 The usual attributable clinical features are unexplained weakness, lethargic, getting easily fatigued, difficulty in breathing, fever and other bleeding manifestations occurring as a result of decreased hemoglobin concentration, decreased white blood cells and a decrease in platelet concentration. Initial presentation of leucopenia is uncommon but can be serious life threatening.1 Physical findings and peripheral blood picture provide valuable information in the work up of pancytopenic patients and help in planning investigations on bone marrow samples.3 During the diagnostic process, patients undergo laboratory tests, radiological imaging and invasive procedures in case they are needed. Bone marrow evaluation is an invaluable diagnostic procedure in practice of medicine which may confirm the diagnosis of suspected cytopenia, from the clinical features and peripheral blood examination or occasionally give a previously unsuspected diagnosis. 4
Studies done elsewhere in the world show aplastic anemia and hypoplastic anemia as the most common cause of pancytopenia which is contrast with the studies done in India.5 Previous studies done in India stress the importance of megaloblastic anaemia as being the major cause of pancytopenia.3, 6 Although it is a common clinical pattern with an extensive differential diagnosis, there is a relatively little discussion of this abnormality in major textbooks of internal medicine and haematology. It has been observed in the Indian scenario that megaloblastic anemia (vitamin B12 and/or folate deficiency) is the commonest cause of pancytopenia. 7
The aim of the present study was to evaluate the cases of pancytopenia by peripheral smear and/or bone marrow aspiration and/or bone marrow biopsy and to find out the etiology of pancytopenia along with clinical, hematological, and histomorphologic features. This data would help in planning the diagnostic and therapeutic approach in patients with pancytopenia and treat treatable cause like megaloblastic anemia.
Materials and Methods
This was an observational study done in the Medicine and Clinical Hematology Department of our institute in Cuttack, Odisha during period from June 2019 to May 2020 involving 100 numbers of patients. Informed written consent was taken from individual participants in local odia language in the study.
Patient of the age group 18-75 years admitted to the General Medicine ward and Clinical Hematology ward with laboratory report showing pancytopenia as defined by haemoglobin percentage (Hb%) below 13.5gm/dl for male and below 11.5gm/dl for female, total leukocyte count(TLC) below 4 x 109/L and total platelet count(TPC) below 150x109/L were included.8 Patients with age <18 years, on radiotherapy and chemotherapy, and those who had undergone treatment for pancytopenia were excluded from the study.
From all the patients a written informed consent for considering themselves as a participant in the study was obtained after having fully understanding the tests and protocols of the study as well as risk to the patients. In all patients, a complete relevant medical history including age, sex, history of smoking, alcoholism, history of any drug ingestion, ingestion of or exposure to potentially harmful toxic chemical agents, irradiation, history of complaints of pain in bones, rise in temperature, night sweats, malaise, loss of weight and itching was taken. A detailed meticulous physical examination of every patient was done for pallor, jaundice, hepatosplenomegaly, lymphadenopathy, sternal tenderness and gum hypertrophy. An extensive correlation as regards to the clinico-pathological point of view was undertaken in all cases before arriving at a definite diagnosis.
Patients were subjected to hematological tests like complete blood count profile (CBC), peripheral smear (PS) comment, reticulocyte count and bone marrow (BM) aspiration study. In case of failed aspiration due to dry or bloody tap, a bone marrow trephine biopsy was done from the usual site of the posterior superior iliac spine wherever indicated. Additionally, serum vitamin B12, blood culture, ELISA for HIV, Hepatitis B and C viruses, chest X ray, bone radiographs, abdominal ultrasonography, erythrocyte sedimentation rate (ESR), urinary Bence Jones proteins, serum electrophoresis was done wherever indicated.
Other investigations like ESR, urine and stool examination, liver and renal function tests, other serological investigations were also done when required. The investigations were carried out with a focus on the suspected pathology and the provisional diagnosis. Investigative work up was done as directed by provisional diagnosis.
Results
In our study the commonest finding was megaloblastic anemia constituting (64%) of all causes of pancytopenia. Aplastic anemia (12%) was second most common cause followed by acute leukemia (6%), liver cirrhosis (4%), myelodysplastic syndrome (MDS) (4%), multiple myeloma (MM) (3%), systemic lupus (2%), malaria (2%). One case each of HIV, tuberculosis and dengue presented with pancytopenia [Figure 1].
The age of the patients ranged from 18 to 75years, majority (24%) in the range of 18 to 30. There was male predominance with male constituting (59%) and female (41%). Easy fatigability (95%), fever (28%) and breathing difficulty (20%) were the common symptoms of presentation. Bleeding manifestation was the presenting complaint in only 9%. Most common physical finding identified in our study group was pallor (96%), splenomegaly (21%), hepatomegaly (11%), lymphadenopathy and purpura (7%) each, pedal oedema(4%) and icterus(3%). Hb among the patients in the present study varied from 1.8-9.9 gm/dl. 53% of patients had Hb in the range 6-9gm/dl and 39% of patients in the range of 3-6gm/dl. The lowest value of 1.9 gm/dl was seen in a case of aplastic anemia. TLC ranged from 500-4000 cells/cmm. Most of patients had TLC in range of 3000-4000cells/cmm (56%). Lowest count of 500cells/cmm was seen in a case of aplastic anemia. TPC ranged from 0.04-1.5 lakh/cmm. Most of patients had 0.5-1.0lakh/cmm (37%) followed by 35% in the range of 0-0.5lakh/cmm. Lowest TPC was 4000/cmm in a case of aplastic anemia. Peripheral blood picture was mostly macrocytic (68%), normocytic normochromic (24%), dimorphic (6%) and microcytic hypochromic (2%).
The commonest BM aspiration finding in pancytopenia patients in our study was hypercellular marrow (70%), followed by normocellular marrow (18%) and hypocellular marrow (12%). There was male predominance in the age-sex distribution of megaloblastic anemia in all the cases of pancytopenia in the present study except for the 31-40 age group. [Figure 2]
Table 1
Various causes of pancytopenia compared to other studies.
|
Causes |
Khunger JM et al 7 (2002) |
Kumar R et al 9 (2001) |
Khodke et al 10 (2001) |
Tilak V et al 3 (1999) |
Present Study |
|
Aplastic anemia |
28(14%) |
49(29.5%) |
7(14%) |
6(7.8%) |
12(12%) |
|
Megaloblastic anemia |
144(72%) |
37(22.3%) |
22(44%) |
53(64.9) |
64(64%) |
|
Subleukemic leukemia |
10(5%) |
20(12.1%) |
1(2%) |
1(1.3%) |
6(6%) |
|
Lymphoma |
2(1%) |
10(6.2%) |
- |
2(2.6%) |
- |
|
Myelodysplastic syndrome |
4(2%) |
6(3.6%) |
1(2%) |
- |
4(4%) |
|
Marrow metastasis |
- |
2(1.2%) |
- |
- |
- |
|
Myelofibrosis |
2(1%) |
2(1.2%) |
- |
1(2%) |
- |
|
Malaria |
2(1%) |
5(3%) |
- |
3(3.9%) |
2(2%) |
|
Enteric fever |
- |
2(1.2%) |
- |
- |
- |
|
Malignant histiocytosis |
- |
1(0.6%) |
- |
- |
- |
|
Disseminated Tuberculosis |
1(0.5%) |
1(0.6%) |
1(2%) |
1(2%) |
1(1%) |
|
Multiple myeloma |
2(1%) |
- |
2(4%) |
1(2%) |
3(3%) |
|
Waldenstrom’s macroglobulinemia |
1(0.5%) |
- |
- |
1(2%) |
- |
|
Acquired immuno-deficiency syndrome(AIDS) |
- |
- |
1(2%) |
- |
1(1%) |
|
Dengue |
- |
- |
- |
- |
1(1%) |
|
Cirrhosis of liver |
- |
- |
- |
- |
4(4%) |
|
Total |
200 |
166 |
50 |
77 |
100 |
Table 2
Frequency of most common causes of pancytopenia in different studies in India
|
Study |
Country |
Year |
No. of Cases |
Most Common Cause |
Second Most Common Cause |
|
Tilak et al 3 |
India |
1998 |
77 |
Megaloblastic Anemia (68%) |
Aplastic Anemia (7.7%) |
|
Khodke et al 10 |
India |
2000 |
166 |
Aplastic Anemia (29.5%) |
Megaloblastic; Anemia (22.3%) |
|
Khunger et al 7 |
India |
2002 |
200 |
Megaloblastic Anemia (72%) |
Aplastic Anemia (28%) |
|
Gayathriand Rao et al 11 |
India |
2011 |
104 |
Megaloblastic Anemia (74%) |
Aplastic Anemia (18.3%) |
|
Jain and Naniwadekar et al 12 |
India |
2013 |
250 |
Hypersplenism (29.2%) |
Infection (25.6%) |
|
Sweta et al 13 |
India |
2014 |
100 |
Megaloblastic Anemia (66%) |
Aplastic Anemia (18%) |
|
Present study |
India |
2019 |
100 |
Megaloblastic Anemia (64%) |
Aplastic Anemia (12%) |
Table 3
Frequency of most common causes of pancytopenia in different studies outside India
|
Author |
Location |
Year of study |
No of cases |
Megaloblastic Anemia |
Aplastic Anemia |
|
Imbert et al 14 |
France |
1989 |
213 |
7.5% |
10% |
|
Savage et al 15 |
Zimbabwe |
1999 |
134 |
40% |
22% |
|
Jha A et al 16 |
Nepal |
2008 |
148 |
21.6% |
29% |
|
Elizabeth et al 17 |
USA |
2012 |
250 |
2% |
22% |
|
Present study |
India |
2019 |
100 |
64% |
12% |
Discussion
In clinical practice pancytopenia is commonly encountered and should be suspected on clinical grounds with presentation of unexplained anemia, prolonged fever and bleeding tendency in a patient. The physical findings and peripheral blood picture provides sufficient clue to the diagnosis of pancytopenic patients. BM aspiration is an important diagnostic tool in hematology which helps to evaluate various cases of cytopenias. It provides accurate, reproducible, rapidly available information at an economical cost and with minimal discomfort to the patient and to make a provisional diagnosis in cases of nutritional anemias and initial diagnosis of leukemia.
Pancytopenia is a striking feature of many serious and life-threatening illnesses and is caused by various different disorders.9 A total 100 cases of pancytopenia were studied. Age, gender wise incidence, presenting complaints, physical findings, peripheral blood picture, BM study and various causes of pancytopenia were studied in all cases and the observation were compared with studies published in the literature.
In our study, the commonest cause of pancytopenia was noted to be megaloblastic anemia [Table-1]. Similar kind of observation was noted in various studies conducted in India. [Table 2]. However the findings of the various reported studies outside India showed the commonest cause of pancytopenia, to be aplastic anemia [Table-3].
Various studies showed the overall incidence of megaloblastic anaemia varying from 22.3 to 72% in all pancytopenic patients. Our study found the incidence of megaloblastic anaemia to be 64%. Khunger JM et al7 reported the incidence of 72%, Tilak V et al3 of 64.9% and Khodke K et al10 found it to be 44%. [Table 1]
Incidence of aplastic anaemia varied from 7.8 to 29.5% among pancytopenic patients as reported in several studies conducted so far. The incidence of aplastic anemia was 12% in our study, which is comparable with the studies done by Khodke K et al10 and Khunger JM et al7 as the reported incidence in these studies for the same was 14%. Most of the cases of aplastic anemia were idiopathic. Western studies have shown much higher incidence of aplastic anaemia than that observed by us. This may be correlated to environmental factors such as increased exposure to toxic chemicals. Malaria presenting with pancytopenia was observed in 2% cases compared to Khunger JM et al7 who has reported an incidence of 1%, Tilak V et al3 reported 3.9% and Kumar R et al10 reported 3%. We encountered 4% cases of MDS with pancytopenia in our observation as compared to Khunger JM et al7 who have reported an incidence of 2% and Kumar R et al9 reported 3.6%. In contrast to other studies, our study encountered cirrhosis of liver in 4% cases which may be correlated with lower socioeconomic status and history of alcoholism in our region. From our study, we observed that the most common presenting complaint of patients was easy fatigability (95%) cases followed by fever in (28%) cases, breathing difficulty in (20%) cases. This is in comparison to a study by Thakkar BB et al,18 where the most common symptom was generalized weakness in (97%) cases, followed by fever in (70%) cases and dyspnoea in (32%) cases. Kumar R et al10 in their study showed generalized weakness being the most common symptom in (70.8%) cases, followed by fever in (6.25%) cases.
The high prevalence of nutritional anemia in our region is attributed to megaloblastic anaemia being the commonest cause. The other common causes were aplastic anemia and cirrhosis of liver. Bone marrow aspiration following a detailed hematological workup in pancytopenic patients is necessary for assessing the disease process. It is also helpful in diagnosis and segregating other etiological cause of pancytopenia, further supporting the investigative evaluation and accurate management of cytopenic patients.
Deficiency of vitamin B12/folate leading to megaloblastic anaemia seems to reflect the higher prevalence of pancytopenia in Indian subjects, with the second position being occupied by aplastic anemia, which is the leading cause for pancytopenia in the Western countries.
Conclusion
With appropriate treatment megaloblastic anemia can be a reversible cause of pancytopenia. In the context of Indian settings, megaloblastic anemia should be sorted during the investigative work up and depending upon the cause and severity, an early and prompt therapeutic intervention can result in a better prognosis.
