An interesting case of fever, pancytopenia and hyperpigmentation


Vitamin B 12 deficiency is a rare cause of fever of unknown origin. We describe here a case report of a 24-year-old pure vegetarian male who presented to us as pyrexia of unknown origin (PUO). After meticulous evaluation and exclusion of infective, inflammatory and endocrine causes, the cause of illness was attributed to Vitamin B 12 deficiency. There was swift and dramatic recovery with parenteral Vitamin B 12 supplementation. Vitamin B 12 deficiency should be borne in mind, whereas evaluating a febrile patient particularly with pancytopenia and hyper pigmentation as it is one of the rarer, but easily correctable and reversible causes of PUO.

Keywords: Hyper pigmentation, megaloblastic anemia, pancytopenia, pyrexia of unknown origin, Vitamin B 12 deficiency

How to cite this article:
Mangaraj S, Sethy G, Behera SK, Sahu NC. An interesting case of fever, pancytopenia and hyperpigmentation. Ann Trop Med Public Health 2013;6:586-8


How to cite this URL:
Mangaraj S, Sethy G, Behera SK, Sahu NC. An interesting case of fever, pancytopenia and hyperpigmentation. Ann Trop Med Public Health [serial online] 2013 [cited 2017 Nov 14];6:586-8. Available from:



Vitamin B 12 deficiency is one of the rarer causes of pyrexia of unknown origin (PUO).

Nutritional deficiency represents an important cause of megaloblastic anemia in vegetarians, patients with mal absorption syndrome and intestinal resection. Although it takes on average 2-4 years for the deficiency state to develop, it is not uncommon to have clinical manifestation earlier due to Vitamin B 12 deficiency. Our nation harbors a large vegan population and thus putting a significant population at risk for developing the disease. Therefore, while evaluating a patient of fever with pancytopenia and hyper pigmentation, Vitamin B 12 deficiency should be sought as a potential cause as is elucidated by our case.

Case Report

The present case is about a 24-year-old male patient who presented to our emergency department with fever generalized weakness and decreased appetite for last 1 month. He also had breathlessness on exertion for last 2 months. The fever was low grade continuous in nature. It was not associated with chills and rigor. There was no history of headache, altered sensorium, weight loss, vomiting, diarrhea, cough with expectoration, yellowish discoloration of sclera. There was no past history of tuberculosis. There was no history of any prolonged drug intake.

On examination, patient was conscious and febrile with 101°F. There was severe pallor. He had a pulse rate of 94/min regular and high volume. Respiratory rate was 24/min abdominothoracic type. Oxygen saturation was 99% on room air. There was no edema, icterus, cyanosis, clubbing, lymphadenopathy, rash. There was black pigmentation on hand, foot and oral mucosa [Figure 1]. The tongue was atrophic and glossy. Evaluation of cardiovascular examination revealed a flow ejection systolic murmur in pulmonary area, rest was normal. Respiratory examination revealed no abnormality. There was mild splenomegaly on examining the abdomen. Neurological evaluation was normal. A baseline hematological and biochemical evaluation was done as depicted in [Table 1]. The positive findings included severe anemia (with increased mean corpuscular volume) with a pancytopenic blood picture. Peripheral smear examination showed moderate anisopoiklocytosis, macro-ovalocytes, cabot ring and basophilic stippling [Figure 2] and [Figure 3]. Total bilirubin level was raised. Slide examination and quantitative buffy coat for malaria parasite was negative. Dengue serology was negative. Antibodies to human immunodeficiency virus, hepatitis B and hepatitis C were negative. Urine and stool routine examination was normal. Samples for urine and blood cultures were sent prior to antibiotic therapy initiation. Bone marrow evaluation revealed a hypercellular marrow with decreased nuclear maturation identified by the presence of megaloblasts without evidence of parasites or granuloma [Figure 4]. Iron kinetic studies were essentially normal.

Figure 1: Hyper piç entation over knuckles of hand

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Figure 2: Peripheral smear shows moderate anisopoiklocytosis, macroovalocytes and presence of cabot ring

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Figure 3: Peripheral smear moderate anisopoiklocytosis, macroovalocytes and basophilic stippling

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Figure 4: Bone marrow picture shows hypercellular marrow, presence of megaloblast and mitotic figure

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Table 1: Baseline hematological and biochemical parameters

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As the patient was a vegan with megaloblastic anemia estimation of Vitamin B 12 and folic acid were sought. Ultrasonography showed only splenomegaly. Thyroid hormone profile and serum adrenocorticotropic hormone was within normal limit. Anti-nuclear antibody was negative. Chest X-ray, computed tomography chest done and 2D echocardiography done for PUO evaluation were normal. Upper gastrointestinal endoscopy and barium meal follow through revealed no abnormality. Serum Vitamin B 12 was 176 pg/l (211-960 pg/l) which was severe deficiency. Serum folic acid levels were normal.


On reviewing the clinical presentation and lab evaluation, a provisional diagnosis of neutropenic PUO was put forward and patient was put on piperacillin and tazobactam, amikacin pending culture reports. Despite antibiotic therapy patient remained to be febrile. On receiving Vitamin B 12 estimation report on day 3, parenteral supplementation was commenced. All samples of blood and urine cultures reports came out to be negative on 5 th day post-admission. Parenteral antibiotics were stopped on reviewing the report.

He became afebrile on day 7 of hospitalization and was afebrile thereafter during the entire stay. Blood evaluation also showed improvement in parameters over baseline [Table 2]. Hemogram and Vitamin B 12 estimation were dramatic and near normal. He was absolutely normal and healthy on a 2 month post-admission follow-up.

Table 2: Serial follow up of hematological parameters with treatment

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Fever is a common presentation in megaloblastic anemia. [1],[2],[3],[4] The grade of fever correlates to the severity of megaloblastic picture with high grade fever more common among those having severe degree of hematological abnormality. [5],[6] Pigmentation is seen in patients and resolves smoothly with replenishment of Vitamin deficiency. [4],[7]

The cause of fever in megaloblastic anemia is a speculative subject with various postulations. One opinion put forth attributes this due a thermoregulatory defect of the brain due to poor oxygenation of thermoregulatory area of the brain. [6],[8] However the postulation fail to explain the conspicuous absence of fever in other forms of anemia. Megoblastic anemia is a result of an over productive but ineffective functioning marrow. [1] Therefore an overactive bone marrow may be related to systemic pyrexia. [1] Pyrexia primarily due to megaloblastic anemia resolves within 2-4 days after Vitamin supplementation when other cause of pyrexia are ruled out. However pyrexia of hematological disease due to folate deficiency may take longer time to drop to normal. [9],[10] Failure of fever to resolve beyond 2-3 days after Vitamin supplementation should suggest the possibility of alternate cause of fever. [1]


This case clearly elucidates in realizing the importance of seeking Vitamin B 12 deficiency as a cause of PUO in a patient with pancytopenia and abnormal hyper pigmentation. A meticulous evaluation for infective inflammatory, autoimmune cause should be done to exclude these common causes in pancytopenic febrile patients. Estimation of Vitamin B 12 and folic acid should be done in these cases. Confirmation will eradicate the need of putting these patients on needless broad spectrum antibiotics as in generally done for febrile neutropenic patients.



1. McKee LC Jr. Fever in megaloblastic anemia. South Med J 1979;72:1423-4, 1428.
2. Cabot RC. Pernicious and secondary anemia, chloro-sis and leukemia. In: Osler W, Mac CT, editors. Modern Medicine. Vol. IV. Philadelphia: Lea and Febiger; 1908.
3. Gatenby PB, Lillie EW. Clinical analysis of 100 cases of severe megaloblastic anaemia of pregnancy. Br Med J 1960;2:1111-4.
4. Hoffbrand AV. Megaloblastic anemia. In: Longo DL, Fauci AS, Kasper DL, Hauser SL, Jameson JL, Loscalzo J, editors. Harisson′s Principles of Internal Medicine. 18 th ed. New York, NY: McGraw-Hill; 2011:Vol. 1. Ch. 105. p. 865
5. Hoffbrand HV. Megaloblastic anemia and miscellaneous deficiency anemias. In: Worrell DA, Cox TM, Firth JD, Ben Jr, editors. Oxford Textbook of Clinical Medicine. 4 th ed., Vol. 3. Oxford: Oxford University Press; 2003. p. 659-75.
6. Jones RV, Payne RW. The occurrence of fever in anaemia. Practitioner 1960;184:618-20.
7. Srivastava N, Chand S, Bansal M, Srivastava K, Singh S. Reversible hyperpigmentation as the first manifestation of dietary Vitamin B12 deficiency. Indian J Dermatol Venereol Leprol 2006;72:389-90.
8. Davidson S. Clinical picture of pernicious anaemia prior to introduction of liver therapy in 1926 and in Edinburgh subsequent to 1944. Br Med J 1957;1:241-3.
9. Singanayagam A, Gange N, Singanayagam A, Jones H. Folate deficiency presenting as pyrexia: A case report. Cases J 2008;1:275.
10. Case records of the Massachusetts General Hospital. Weekly clinicopathological exercises. Case 40-2000. A 38-year-old woman with gastric adenocarcinoma. N Engl J Med 2000;343:1951-8.

Source of Support: None, Conflict of Interest: None


DOI: 10.4103/1755-6783.133754


[Figure 1], [Figure 2], [Figure 3], [Figure 4]


[Table 1], [Table 2]

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