Indian Journal of Medical Sciences, Vol. 58, No. 9, September, 2004, pp. 400-404
BSES MG Hospital and Holy Family Hospital, 6/32, Hari-Kripa,
S. V. Road, Santacruz (W), Mumbai - 400 054
Code Number: ms04069
Hemolytic anemia results from an increase in the rate of red cell destruction. The normal red cell life span is about 120 days; in hemolytic anemia it is shortened by varying degrees, in very severe cases it may be only a few days.
NORMAL RED CELL DESTRUCTIONThe normal red cell life is 120 days. As the cell ages, its enzyme activity declines and ultimately its metabolic system fails resulting in changes in the cell and its surface membrane which make it susceptible to phagocytosis by the reticuloendothelial system of the spleen, liver and the bone marrow.
When the senile red cells undergo phagocytosis, hemoglobin is released and is then broken down to haem and globin. Globin returns to body′s protein pool and is reutilized. Haem is further broken down to form bilirubin and iron is released back to marrow for re utilization. Bilirubin released into the plasma is the unconjugated bilirubin bound to albumin and is taken up by the hepatocytes where it is conjugated and excreted into the bile ducts and then into the intestines. Bacterial flora of the intestine reduces bilirubin to urobilinogen. A major part of urobilinogen is excreted in feces, but about 10 - 20 % enters enterohepatic circulation and small quantity enters systemic circulation and is excreted by the kidneys.
Thus whenever there is excessive destruction of red cells there is increase in bilirubin formation and if this increased bilirubin production exceeds the capacity of the hepatocytes to conjugate it; the unconjugated bilirubin fraction rises and is clinically evident as jaundice.
CAUSES OF HEMOLYTIC ANEMIA1. Defect in the red cell: The basic defect is either in the red cell membrane, hemoglobin molecule, or in the enzymes concerned with red cell metabolism. Majority of these defects are congenital. Common disorders among these are as follows:
a) Red Cell Membrane defects:
b) Hemoglobin defects:
Sickle cell anemia
Other abnormal hemoglobins like Hb-C, Hb-H,Hb-D etc.
c) Enzyme defects:
2. Defect outside the red cell i.e. in the plasma or circulatory system. Majority of these defects are acquired.
a) Immune mechanism:
b) Non immune mechanism:
CLINICAL FEATURESAnemia and recurrent jaundice are commonly present. A history of more than two episodes of jaundice in the past in any patient should raise the suspicion of a hemolytic process and the patient should be investigated to rule out hemolytic anemia. Also, if a patient has jaundice for a long time i.e. few months to few years, he should be investigated for hemolytic anemia.
Age at onset of anemia or jaundice is very important pointer towards diagnosis. Congenital hemolytic anemias like thalassemia major present early in childhood with symptoms of anemia, jaundice and need for regular blood transfusions for survival.
In the neonatal period, severe hemolysis and hyperbilirubinemia can leave permanent neurological sequelae. Unconjugated bilirubin can get deposited in the brain - a condition called ′Kernicterus.′ The patient becomes drowsy, can have convulsions, coma and may even die. If the patient survives, he may have mental retardation.
The course of chronic hemolytic anemia is interspersed with acute crises during which anemia becomes more severe. This is commonly seen in patients with sickle cell anemia but can be seen with many other hemolytic anemias as well. Acute crises may be precipitated by infections, increased red cell destruction when jaundice is also increased, or by marrow depression (aplastic crisis) when jaundice may disappear. Crises are characterized by fever with rigors, abdominal pain, bone pains and joint pains. The condition may mimic acute abdominal catastrophe like acute appendicitis or peritonitis. Many a patients have been wheeled into the operation theatre during these episodes! Presence of jaundice and history of similar episodes in the past should raise a suspicion of hemolysis and the patient should be investigated for it.
Family history is also very important in case of hemolytic anemias. Patients suffering from congenital hemolytic anemias like thalassemia, sickle cell anemia, hereditary spherocytosis, G-6-PD deficiency usually have other family members who are also suffering from the disease and even if they are clinically not symptomatic their investigations would suggest the presence of hemolytic anemia. This becomes very important if the patient′s diagnosis is in doubt or if the patient has already received transfusion prior to establishing the diagnosis, in which case his investigations may not be conclusive due to presence of normal transfused red cells.
Conditions like G-6-PD deficiency and infections like malaria can give rise to intravascular hemolysis and hence hemoglobinuria. The patient presents with acute onset jaundice, anemia, severe weakness and even shock and renal shut down. Mismatched blood transfusion can also cause similar clinical picture.
Complications of chronic hemolysis
2) Hemolytic facies: increased erythropoietic activity to compensate for hemolysis leads to expansion of the marrow space. During childhood red marrow occupies almost the whole of the skeleton and there is hardly any space for expansion without encroaching on the cortex of the bones. This results in thinning of the inner and outer tables of the skull and increased space between them. The head appears large with frontal and parietal prominences. The eyes are widely spaced and nose bridge is flattened. The malar bones are prominent and increase markedly in size exceeding the growth in the soft tissues thereby exposing the upper teeth. Due to overgrowth of the upper jaw there is malocclusion of the teeth. All these features together give rise to characteristic hemolytic facies which are an evidence of hemolysis since early childhood.
3) Hypersplenism and Hyposplenism or Asplenia: Certain hemolytic anemias like thalassemia have progressive enlargement of spleen and this manifests as increased transfusion requirements and require splenectomy to reduce transfusion requirement.
As against this, in conditions like sickle cell anemia, there is hyposplenia or asplenia i.e. reduced splenic function. This is due to repeated splenic infarcts leading to splenic atrophy. These patients are prone to infections (like splenectomised patients) with capsulated organisms like pneumococci.
4) Iron overload and iron deficiency:Iron derived from hemolysed red cells is retained in the body and re-utilized for hemoglobin synthesis. Anemia and increased erythropoietic activity increase iron absorption. Over the years this iron accumulates and gets deposited in organs like liver, pancreas, heart, testis etc. leading to their dysfunction. Thus patients may have cirrhosis, diabetes, cardiac failure and sterility. The common practice of giving iron to any anemic patient without any investigations could thus be hazardous and should be avoided at all costs.
In patients suffering from thalassemia this problem of iron overload is more marked because of multiple transfusions and requires chelation therapy to reduce the body iron stores.
As against this patients with chronic hemoglobinuria (e.g. those with severe valvular heart disease and mechanical heart valves) have iron deficiency because with every gram of hemoglobin lost in urine the patient loses 3.4 mg of iron. These patients require iron supplements.
5) Chronic non healing ulcers on the leg: this is commonly seen in sickle cell disease and hereditary spherocytosis. Maintaining normal hemoglobin with transfusions along with local therapy promotes healing in majority of cases.
6) Transfusion transmitted diseases: patients who are multi transfused face the hazards of diseases transmitted via blood like hepatitis C, HIV etc. Meticulous screening of donors and blood would minimize this hazard.
IVESTIGATIONS TO DEMONSTRATE EVIDENCE OF HEMOLYSIS1) Hyperbilirubinemia and jaundice: A raised bilirubin is usually present in hemolytic anemia but absence of jaundice does not rule out hemolytic anemia, as it depends on the hepatic reserve which enables to excrete the increased bilirubin load. Bilirubin is unconjugated i.e. indirect hyperbilirubinemia.
2) Hemoglobinemia and hemoglobinuria: In cases with intravascular hemolysis, plasma hemoglobin levels rise and when it exceeds renal threshold, there is hemoglobinuria. The patient complains of passing "cola coloured urine." Spectroscopic examination of urine will show bands of oxyhemoglobin.
3) Hemosiderinuria: Iron resulting from breakdown of hemoglobin in the renal tubular cells is passed in urine as hemosiderin. This can be demonstrated by centrifuging urine and staining the sediment with Prussian blue which demonstrates bluish intracellular as well as extracellular granules. Hemosiderinuria is seen in chronic intravascular hemolysis.
4) Examination of blood smear: Careful examination of peripheral blood smear by an experienced person provides valuable information in the diagnosis of hemolytic anemia. Macrocytosis, polychromasia, punctuates basophilia and nucleated red cells are usually seen in hemolytic anemia and indicate increased erythropoietic activity. Presence of spherocytes points towards hereditary spherocytosis or autoimmune hemolysis. Presence of marked anisopoikilocytosis, hypochromia and target cells should prompt the clinician to investigate for thalassemia syndromes. Malarial parasites should always be looked for in all patients with suspected intravascular hemolysis. Fragmented red cells and schistocytes suggest microangiopathic hemolytic anemia, cardiac hemolytic anemia or chronic intravascular hemolysis. Irreversibly sickled cells may be seen in sickle cell disease.
5) Reticulocytosis: The reticulocyte count is elevated in majority of cases of hemolytic anemia and this can be demonstrated by supravital staining of the red cells.
6) Skeletal radiological abnormalities: In congenital chronic hemolytic anemias, marked marrow hypertrophy leads to bony changes which are evident radiologically. Lateral skull x rays show "hiar on end" appearance common in thalassemia. In tubular bones of the extremities, marrow hyperplasia causes thinning of the cortex, decreased density of medulla and coarse trabecular pattern. These changes can be best demonstrated in the metacarpal bones and the ribs.
If the initial investigations point towards the diagnosis of hemolytic anemia it needs to be confirmed by tests specific for that particular disease so that it can be treated accordingly.
Copyright 2004 - Indian Journal of Medical Sciences