Evaluating Anaemia

Anaemia is not disease but a manifestation of an underlying disease. The list of diseases causing anaemia is exhaustive. The list includes disease as innocuous as a nutritional iron deficiency or as serious as a leukaemia or iron deficiency from a colonic cancer. Every patient of anaemia must have a complete evaluation. Failure to do so may may delay the diagnosis of serious diseases like cancer. Figure 1 gives the outline for evaluation of a patients with anaemia. The details of evaluation are given below.

 

Approach to anaemia: Given above is a flowchart for the approach to a patients with anaemia. The diagnosis depends on whether the anaemia occurs with changes in platelets and/or leucocytes and whether the bone marrow is responding normally to anaemia. Bone marrow response to anaemia manifest as reticulocytosis. Abbreviations used AA: Aplastic anaemia, BM: Bone Marrow, CML: Chronic Myeloid Leukaemia, MDS: Myelodysplastic syndrome, MDS/MPN: Myelodysplastic/myeloproliferative neoplasms, MPD: Myeloproliferative disease (click for a larger image)

Definition of Anaemia

Anaemia is defined and severity classified as per the WHO guidelines given in table 1. These definitions are for non-smokers individuals living at sea level (<1000 meters above seas level). Definitions for smokers and those living ≥1000 meters above sea level can be found at Haemoglobin concentrations for the diagnosis of anaemia and assessment of severity. World Health Organization (WHO/NMH/NHD/MNM/11.1)

Population	Normal haemoglobin	Mild Anaemia	Moderate Anaemia	Severe Anaemia
6-59 months	≥11 g/dL	10-10.9 g/dL	7-9.9 g/dL	7 g/dL
5-11 years	≥11.5 g/dL	11-11.4 g/dL	8-10.9 g/dL	<8 g/dL
12-14 years	≥12 g/dL	11-11.9 g/dL	8-10.9 g/dL	<8 g/dL
Pregnant Woman	≥12 g/dL	11-11.9 g/dL	8-10.9 g/dL	<8 g/dL
Non-Pregnant Woman	≥11 g/dL	10-10.9 g/dL	7-9.9 g/dL	<7 g/dL
Men (≥15 years)	≥13 g/dL	10-12.9 g/dL	8.8-10.9 g/dL	<8 g/dL

Initial Evaluation of a Patient of Anaemia

1. The diagnostic workup of a patient of anaemia should establish the
   1. type of anaemia,
   2. the cause of anaemia and
   3. complications caused by anaemia.
2. Red cell transfusions in anaemic patients are for relieving symptoms due to a low haemoglobin. Patients without symptoms should not be transfused. A pre-transfusion serum sample should be stored to perform tests likely to be affected by blood transfusion (e.g. serum ferritin, serum B12, serum folic acid and haemoglobin electrophoresis). Apart from risks associated with transfusion the relief of symptoms following transfusion reduces the patient’s and the doctor’s zeal to pursue a complete diagnosis.
3. The history, examination, haemogram and red cell indices are available in all anaemic patients. This information gives a reasonable idea about the cause of anaemia. A diagnosis can be made with a few additional investigations. No patient should be treated without a complete diagnosis.
4. Iron deficiency is the commonest cause of anaemia. It may be a result of an innocuous cause like nutritional iron deficiency or may be a manifestation of a serious underlying disease like a cancer of the gastrointestinal tract. Most patient of anaemia will respond to iron supplementation. Iron supplementation without complete investigation of anaemia is a common but dangerous practice as it may delay the diagnosis of dangerous underlying illnesses like colorectal carcinoma.

Clinical manifestations of anaemia result from manifestations of  impaired oxygen deliver, manifestations of the underlying disorder and manifestations due to compensation to anaemia.

Manifestations of of anaemia: The symptoms of anaemia depend on the

1. Degree of anaemia
2. Rate of fall of haemoglobin
3. Conditions of the vessels.

The body adapts to anaemia by increasing cardiac output, redistribution of blood from non-critical to the critical circulations and the and increased oxygen extraction (see Pathophysiology of anaemia). These adaptation occurs slowly. Patients with a gradual fall in haemoglobin can tolerate a more severe anaemia than a patient who become  anaemic rapidly because they get time to adapt to anaemia. Vascular disease results in the patient becoming symptomatic at a higher haemoglobin level. These patients manifest with ischaemic symptoms of the region supplied by the vessel. A patient with a gradually developing anaemia and without coronary heart disease becomes symptomatic at a lower haemoglobin than a patient who develops anaemia rapidly or one having a coronary artery disease or one having both.  Nutritional anaemias have a slow onset and thus present with a lower haemoglobin than anaemia or blood loss or acute haemolysis. If one sees a patients who is asymptomatic with severe anaemia one can be fairly certain that the patients suffers from nutritional deficiency. If the haemogram shows microcytosis the anaemia is likely to be due to iron deficiency. If there is macrocytosis the anaemia is likely to be due to B12 or folate deficiency.
Manifestations of anaemia are a result of impaired oxygen delivery. In patients without a significant coronary compromise the symptoms of anaemia include fatigue, lightheadedness and breathlessness. Frank cardiac failure sets in as the severity increases. Ischaemic symptoms, typically angina pectoris, may predominate in patients with significant coronary narrowing. Pallor, the most prominent sign of anaemia is of less diagnostic use than it is percieved to be. It has been reported to have a sensitivity of 19% to 70% and a specificity of 70% to 100%. There is inter-observer variation and clinical examination can not exclude mild anaemia. There have been suggestions that the tongue is the best site for diagnosing anaemia others have differed (PLoS ONE 5(1): e8545. doi:10.1371/journal.pone.0008545). Lack of pallor does not exclude mild anaemia and a haemoglobin assessment must be done is every patient with suspected anaemia.

Clinical features may give a clue to the nature of the disease causing anaemia:

The table below gives clinical features that may give a clue to the nature of the disease causing anaemia.

Clinical Finding	Significance
Painful Crisis	Sudden onset of pain is a feature of sickle cell disease. Painful crisis commonly affects bone, chest, abdominal and joints
Jaundice	Achloruric Januduce: Achloruric jaundice is a result of increased haemoglobin catabolism (see haemoglobin catabolism) It is seen in patients with haemolytic anaemia and megaloblastic anaemia. In haemolytic anaemia the source of haemoglobin is erythrocytes and in megaloblastic anaemia the it the haemoglobinized erythroid precursors that are destroyed as a part ineffective erythropoiesis. The presence of reticulocytosis in haemolytic anaemias (see diagnosis of haemolytic anaemia) as opposed to reticulocytopenia megaloblastic anaemia differentiates the two conditions. Every anaemia with achloruric jaundice may not be a haemolytic anaemia or megaloblastic anaemia. Gilbert’s syndrome is a common asymptomatic defect of bilirubin metabolism that may co-exist of anemia of another cause. Rarely achloruric jaundice with reticulocytosis may be seen in large occult haematomas. Haematomas of the retroperitoneal region may present in this manner. Chloruric Jaundice: Patinets with haemolytic anaemia may develop chloruric jaundice because of biliary obstruction from pigment stones.
Nail Changes	Platonychia (flat nails) and koilonychia (spoon shaped nails) are features of iron deficiency. These changes may be congenital and the duration of the changes must be enquired into.
Clubbing	Clubbing is seen in infectious endocarditis, chronic liver diseases, bronchiectasis, inflammatory bowel disease and lung cancer
Leg ulcers	Leg ulcers are a complication typically seen in patients with sickle cell anaemia. They are not specific to sickle cell disease. They may be seen in severe α and β thalassaemia, hereditary spherocytosis and pyruvate kinase deficiency. The incidence of leg ulcers increases with age. They are more common in the tropics where footwear is not worn. The are less common in Sβ0 and not seen in Sβ+ and SC disease. Co-inheritance of α thalassaemia with sickle cell disease decreases the incidence of ulcers. They are typically seen on the medial aspect of the tibia of behind the medial malleolus, are persistent and are a major cause of morbidity in sickle cell disease
Bleeding Manifestations	Bleeding due to thrombocytopenia is characterized by petichiae and purpura. Anaemia with thrombocytopenia may be seen in Bone marrow pathology: Aplastic anaemia, acute leukaemia, bone marrow infiltrations and myelodysplastic syndromes Increased periphreal distruction/sequestration of platelets: Thrombotic thrombocytopenic purpura/Haemolytic ureaemic syndrome, Evan’s syndrome and hypersplenism Anaemia caused by bleeding associated with thrombocytopenia
Mouth ulcers	Mouth ulcers are a feature of aplastic anaemia
Lymphadenopathy	Generalized lymphadenopathy is seen in patients with acute or chronic lymphoid leukaemia and sometimes in autoimmune diseases
Splenomegaly	Splenomegaly may be seen in patients with lymphoid neoplasia, chronic myeloid leukemia, idiopathic myelofibrosis, extra-hepatic portal hypertension and hairy cell leukemia
Neurological changes	Subacute Combined degeneration of the Spinal Cord: Subacute combined degeneration is a myelopathy caused by B12 deficiency. It presents with parasthesiae of the upper and lower limbs that progress to weakness and ataxia in untreated patients. Vibratory and joint position sense is lost early in disease and progresses to impaired pinprick, light touch and temperature sensations. Upper motor neuron involvement results in hyperreflexia of the knees but the ankle reflexes are depressed due to a co-existing peripheral neuropathy. Plantars reflexes give a extensor response. Rarely features of autonomic involvements may be seen including orthostatic hypotension and bladder and bowel incontinence. Neuropathy: Chronic lead poisoning is characterized by a peripheral neuropathy that manifests with motor disturbances with few sensory symptoms. Other Neurological Manifestations: B12 deficiency can rarely cause cognitive or psychiatric manifestations (3%) or bilateral optic neuropathy and blindness (0.5%). Exposure to lead can cause encephalopathy.

Manifestations due to compensatory changes:

1. Cardiovascular: Tachycardia, wide pulse pressure and decreased exercise tolerance result from cardiovascular compensation to anaemia.
2. Musculoskeletal: Chronic haemolytic anaemias result in marrow hyperplasia. Marrow hyperplasia causes typical facies and increased risk of fracture. Facial features include bossing of the skull hypertrophy of the maxilla resulting in exposure of upper teeth, prominent malar eminences with depression of the bridge of the nose, puffiness of the eyelids and a mongoloid slant of the eyes.

Initial Investigations in a Patient of Anaemia

The starting point in evaluation of an anaemic patient is a haemogram and a reticulocyte count. The aim of initial investigation is determine

1. If the pathology involves only the red cells or is there involvement of the white cells and /or platelets.
2. If the bone marrow responding to anaemia by producing erythrocytes

Alterations in more than one cell lines of blood cells occurs because blood cells share precursors, developmental microenvironment and antigens. Diseases involving more than one series of blood cell include.

1. Diseases of haemopoietic precursors: Aplastic anaemia, Acute leukaemia, myeloproliferative diseases, Myelodysplastic syndrome, Myelodysplastic syndrome/myeloproliferative neoplasm.
2. Pathology of bone marrow microenviorment: Bone marrow infiltration, myelofibrosis
3. Antibodies mediates diseases
   1. Antibody to antigen of precursors: Aplastic Anaemia
   2. Shared antigen Aplastic anaemia: Autoimmune pancytopenia, Evan’s syndrome
4. Complement Mediated Damage: Paroxysmal nocturnal haemoglobinuria
5. Other diseases: Thrombotic thrombocytopenia purpura/haemolytic uraemic syndrome (TTP/HUS)

All the above diseases other the TTP/HUS need a bone marrow examination for diagnosis. TTP/HUS is characterized by microangiopthic haemolytic anaemia in a patients with characteristic clinical presentation.

Anaemia induces erythropoietin production. Erythropoietin stimulated red cell production. Increased erythrocyte production manifests as reticulocytosis (see reticulocyte count). Reticulocytosis in an anaemic patient indicates that the anaemia is because of erythrocyte loss and the bone marrow is normally responding to anaemia. Patients with erythrocyte loss may fall into three catagories.

1. Acute blood loss: These patients give history of blood loss and present with anemia with reticulocytosis without evidence of haemolysis.
2. Chronic Blood loss: Blood loss is a alarming symptom that prompts patients to immediately seek medical advise. Patients with occult blood loss, those with altered blood loss or those with not capable of recognizing a blood loss may present with manifestations of chronic blood loss. Chronic blood loss causes iron deficiency. Unlike acute blood loss the manifestations of chronic blood loss are those of iron deficiency anaemia (microcytic anaemia with reticulocytopenia).
3. Haemolytic anaemia: Patinets who have anaemia with reticulocytosis but have no demonstrable blood loss should be considered to have a haemolytic anaemia.

Evaluation of Microcytic Anaemia

Evaluation of Microcytic Anaemia

As haemoglobin forms about 97% of the erythrocyte proteins. Disorders impairing haemoglobin synthesis cause microcytic anaemia. Haemoglobin synthesis needs an functional genetic code, normal heme synthesis, adequate supply of iron and proper incorporation of heme in haemoglobin. If any of these are defective a microcytic anaemia develops. The commonest cause of microcytic anaemia is iron deficiency. The first investigation in a patients of microcytic anaemia is assessment of serum iron, total iron binding capacity and serum ferritin. The results of iron studies microcytic anaemia are depicted in figure 3. Further evaluation of patients depends on the result of iron studies. If the irons studies are normal then an study for abnormal haemoglobin should be performed either by HPLC or cellulose acetate electrophoresis in alkaline pH. Patients with HbA₂ between 3.5-7% have heterozygous β-thalassaemia. Higher HbA₂ values should be considered to be due to an abnormal haemoglobin that separates with HbA₂ (e.g. HbE). Patients with homozygous and heterozygous HbE disease may be diagnosed in this manner. Those with a normal hemoglobin electrophoresis are likely to have α-thalassaemia trait. α-Thalassaemia needs estimation of globin chains synthesis. This investigation may not be readily available. If HbH disease is prevalent in the ethnic group the patients belongs to, it is essential to compete evaluation for α-thalassaemia to prevent Bart’s hydrops fetalis. Patients with transferrin saturation more than 50% need to have  bone marrow aspiration for diagnosis of sideroblastic anaemia.

 

 

Evaluation of Normocytic Anaemia

Evaluation of Normocytic Anaemia

Patinets with normocytic anaemia need to be evaluated for liver disease, renal failure or endocrine disease. The endocrine disease associated with anaemia include hypothyroidism, hyperthyroidism, adrenal insufficiency and hypopituitarism. If these disorders are not found the iron status should be assessed. Patinets may have iron deficiency (transferrin saturation <16%), anaemia of chronic disease (transferrin saturation ≥16% with a low total iron binding capacity). A bone marrow aspiration should be performed in whom diagnosis can not be made by the above investigations.

 

 

Evaluation of Microcytic Anaemia

Evaluation of Macrocytic Anaemias

Macrocytic anaemias may be megaloblastic or non-megaloblastic. Features of megaloblastic anaemia include hypersegmentation of neutrophils, macroovalocytosis, indirect hyperbilirubinaemia and markedly elevated lactate dehydrogenase levels. Macrocytosis is pronounced and almost all patients with an MCV > 110fl have nutritional megaloblastic anaemia, are of antiviral therapy or on chemotherapy. The converse is not true. Patients of megaloblastic anaemia may have a MCV <110fl in early disease or in the presence of co-existing iron deficiency. Serum iron levels are increase in nutritional megaloblastic anaemia. They  fall rapidly within 24-48 hours after therapy. Iron studies should be performed after a few days after administration of vitamins when the iron levels have stabilized. Nonmegaloblastic macrocytic anaemias are seen with alcoholism, hypothyroidism, liver disease and myelodysplastic syndromes.