Case No 1 – Severe Microcytic Anaemia

A 17-year-old woman from a farming community presented with the history of severe weakness, fatigue and dyspnoea on moderate exertion.

She was well till about 4 months before presentation when she complained of fatigue that gradually became worse. Though progressively symptomatic she was able to attend school till 3 days before presentation.

There was no history of fever, weight loss, abnormal bleeding or melena. There was no increase in the menstrual blood loss. The patient was living with her parents and two sisters both of whom were healthy.

Her appetite had been normal through most of the illness though off late it had diminished.

On examination the patient was comfortable but tachypnic  in bed. She had severe pallor of the skin, conjunctiva and mucous membranes.  There was platonychia and glossitis. The jugular venous pressure was elevated. There was no icterus, clubbing, lymphadenopathy. The pulse was 108/min and the blood pressure 110/60. The third heart sound was audible at the apex. She had bilateral fine crepitation in the bases of both lungs. The was no hepatomegaly. There was no splenomegaly. Examination of the neurological system revealed no abnormality.

A haemogram was performed and the results were as follows:

• Haemoglobin: 1.7g/dL
• RBC Count: 0.9 X 10¹²/L
• Haematocrit: 5.9%
• WBC Count: 4.1 X 10⁹/L
• Differential Count:
  • Neutrophils: 35%
  • Lymphocytes 49%
  • Monocytes 10%
  • Eosinophils: 6%
• Platelet Count: 505 X 10⁹/L
• RBC Indices
  • MCV: 66.1 fl
  • MCH: 19.4 pg
  • MCHC: 29.3 g/L
  • RDW: 44%
• Reticulocyte Count: 8%

What are the probable causes of anaemia in this patient?

Presence of platelet and/or leucocyte anomalies in a patients with anaemia suggests that the pathology lies in the bone marrow. Anaemia without leucocyte or platelet anomalies may be caused by increased erythrocyte loss or decreased erythrocyte production. Anaemias caused by decreased production of erythrocytes are further divided according to erythrocyte size into microcytic, normocytic and macrocytic  (see Evaluating anaemia).

This patient does not have platelet or leucocyte anomalies. The anaemia is either a result of a decreased production or increased loss of erythrocytes. Both erythrocyte loss and decreased production are difficult to quantify in clinical practice and are diagnosed by indirect methods. Increased eryrthrocyte production should increase haemoglobin unless there is an equal or greater loss. Increased erythrocyte production result in reticulocytosis. In patients with anemia the reticulocyte production index is a more accurate index of erythrocyte production. A patient with normal or low haemoglobin but an increased reticulocyte production index is presumed to be loosing erythrocytes  (see diagnosis of haemolytic anaemia).  Others are presumed to have decreased erythrocyte production.

Reticulocyte production index is calculated as follows:

RPI = [Reticulocyte count X HCT_Patient] / [HCT_Normal X CF]

where

RPI is the Reticulocyte Production Index. RPI values less than 2 indicate inadequate erythrocyte production

HCT_Patient is the patient’s haematocrit

HCT_Normal is the normal haematocrit

CF is the correction factor. The correction factor depends on the haematocrit. It’s values are as follows:

• Haematocrit 40-45%: 1
• Haematocrit 35-40%: 1.5
• Haematocrit 25-35%: 2
• Haematocrit 15-25%: 2.5

The reticulocyte production index in this patient is as follows

RPI = [8 X 5.9 ] / [45*2.5]  =  0.41

RPI of 2 indicates an adequate marrow response. This patient, despite having a high reticulocyte count, has decreased erythrocyte production.

Anaemias due to inadequate erythrocyte production are classified according to erythrocyte size as microcytic, normocytic and macrocytic (see red cell indices). This patient has microcytosis. The causes of microcytic anaemia include:

• Iron deficiency
• Thalassaemia
• Sideroblastic anaemia
• Anaemia of chronic disease

Chronic inflammation is associated with mild to moderate anaemia that is proportional to the degree of inflammation. Most of the patients have normochromic anaemia but about 30-50% of the patients may develop mild microcytosis with a normal RDW.  This patient has no evidence of chronic inflammatory process. She has severe anaemia, pronounced microcytosis and a high RDW. She is unlikely to have anaemia of chronic disease.

Iron deficiency and thalassaemia are the commonest causes of microcytic anaemia. β-Thalassaemia has three clinical forms, major, minor and intermedia. Thalassaemia minor does not cause symptoms. Symptomatic β-thalassaemia (thalassaemia major and intermedia) usually present early. The transfusion dependent patients present by 8.4±9.1months and non-transfusion dependent patients by 17± 11.8 months (Cao A Birth Defects 1988;23;219) . This patent has a late presentation making thalasaemia unlikely.

The haemogram of patients with iron deficiency shows anaemia, microcytosis, hypochromia and anisocytosis. Thrombocytois is not uncommon. The platelet counts in patients with iron deficiency are twice those without deficiency (Dan K Intern Med 2005; 10: 1025). The thrombocytosis associated with iron deficiency has an inverse relationship with serum iron but no relationship with TIBC and transferrin saturation. (Park MJ et al Platelets 2012 Jun 27. [Epub ahead of print]). This patients has anaemia, microcytosis, hypochromia and thrombocytosis. The high red cell distribution width (RDW) indicated the presence of anisocytosis. The most likely diagnosis in this patient is iron deficiency anaemia.

Is there a haemoglobin value that should trigger a blood transfusion?

It was common to use the 10/30 (haemoglobin 10g/dL or PCV 30%) trigger for transfusion. Transfusion is associated with morbidity and mortality (Marik et al. Crit Care Med 2008; 36:2667-74). Following the 10/30 rule results in overtransfusion. The case highlights poor relation between haemoglobin levels and symptoms. Anaemia is compensated by increasing cardiac output, redistributing blood from non-critical to critical circulations and increasing oxygen extraction (see Pathophysiology of anaemia). Older individuals may have one or more of these mechanisms compromised hampering their ability to withstand anaemia. Younger individuals can compensate efficiently and can withstand lower haemoglobin values. Compensation takes time and is more complete in anaemias that have a slow onset. Nutritional deficiencies develop slowly. Patients with nutritional anaemia compensate better and become symptomatic at lower haemoglobin values than anaemia with a more acute onset.

She was in cardiac failure and was transfused. But would she have been transfused if she was not in cardiac failure and had a haemoglobin of 7g/dL? The threshold for transfusion according to most current guidelines is 7-8 g/dL. Trials evaluating transfusion threshold have been performed in hospitalized, surgical or intensive care patients. Transfusion guidelines are most appropriate when used for indications the were developed. There are few trials addressing the issue of transfusion in patients with nutritional anaemia. Clinical experience shows that patients without respiratory or cardiovascular co-morbidities are able to tolerate severe nutritional anaemia. One needs to balance the risk of anaemia against risk of transfusion in patients with nutritional anaemias. The transfusion trigger for patients of nutritional is not established. Symptoms guide transfusion in patients with nutritional anaemia.

How should the patient be investigated?

As iron deficiency is the commonest cause of microcytic anaemia, patients should be evaluated for iron deficiency. The serum iron, total iron binding capacity and serum ferritin are estimated and the transferrin saturation calculated . The results of these investigation are diagnostic for iron deficiency and often allow the diagnosis of other causes of microcytic anaemia. The interpretation these tests are as follows:

	Serum Iron	Total Iron Binding Capacity	Transferrin Saturation	Serum Ferritin
Iron Deficiency Anaemia	Low	Normal/High	Low (<16%)	Low (<12ng/ml)
Thalassaemia	Normal	Normal	Normal	Normal/High
Sideroblastic Anaemia	High	Normal	High (>50%)	High
Chronic Disease	low/Normal	Low	Normal	Normal/High

This patients was diagnosed as iron deficiency anaemia because of a low serum iron, high total iron binding capacity and a low transferrin saturation. Does that complete the diagnosis?

The diagnosis of iron deficiency is incomplete without finding out its cause. The following populations are prone to iron deficiency.

1. Preterm infants: Most of the iron transfer to the foetus takes place in the third trimester. Premature infants have less time to absorb iron from the mother.
2. Infants and Toddles: Dietary iron is not able to keep up with the requirements of rapid growth.
3. Women in the childbearing age group: Losses due to menstruation and pregnancy cause iron deficiency.

Iron deficiency is due to inadequate iron intake or increased iron/blood loss. Blood/iron is lost because of diseases/conditions causing exacerbation of physiological blood/iron loss or diseases causing physiological loss. Multiple pregnancies cause exacerbation of physiological iron loss. The only physiological blood loss is menstrual blood loss.

This patient gave no history of increased menstrual blood loss. Hookworm (Ancyclostoma duodenale and Necator americanus) infestations infestations affect over 500 million individuals in the hot and humid areas of the world. Infestations are common in farming communities. The stool examination of this patients showed hookworm ova.

Finally, does the diagnosis of iron deficiency rule out other causes of microcytic anaemia? No. Iron deficiency is very common that it may co-exit with another cause of microcytic anaemia particularly anaemia of chronic disease and thalassaemia trait. Anaemia of chronic disease is characterized by a low iron, low total iron binding capacity and normal transferrin saturation. When such patients become iron deficient the transferrin saturation falls below 16%. Ferritin is increased in the presence of inflammation/infection. While a low ferritin is diagnostic of iron deficiency in the presence of infection/inflammation, a normal ferritin does not exclude iron deficiency. β-Thalassaemia is diagnosed by an elevated HbA₂. HbA₂ has been shown to fall with iron deficiency. This may not have any clinical significance (Madan N et al. Ann Hematol 1998; 77; 93-6, Passarello C et al 2012; 97:472). If the haemoglobin and/or microcytosis fail to correct after therapy the patients must be evaluated for thalassaemia.