Presentation is variable and depends upon the speed with which anaemia develops, the capacity of the bone marrow to compensate and the effects of any associated disease. Most commonly, the onset is insidious, with the gradual awareness of symptoms of anaemia or the observation of pallor or icterus by friends or relatives. Occasionally, the onset is acute, with rapidly developing anaemia and, in older patients, the risk of heart failure. If there is an acute onset with intravascular haemolysis, haemoglobinuria may be noticed. Mild jaundice is present. More marked icterus (bilirubin > 90 ^mol/L) suggests coexisting liver disease or biliary tract obstruction due to pigment gallstones or biliary sludge. Splenomegaly is common, but rarely at more than 2-3 cm below the costal margin at presentation. Marked splenomegaly suggests the possibility of a lymphopro-liferative disease. The peripheral blood film is characterized
by spherocytosis and polychromasia (Figure 10.1), circulating nucleated red cells, and, in some cases, red cell agglutination. Rarely, there may be reticulocytopenia associated with a positive DAT. There is a moderate increase in bilirubin, which is unconjugated, so bilirubin does not appear in the urine, which contains excess urobilinogen. There is an increase in lactate dehydrogenase (LDH) due to lysis of red cells, but other liver function tests are normal unless there is associated liver or biliary tract disease. The DAT is positive except in very rare cases where the amount of antibody remaining on the red cell surface is insufficient to be detected by the conventional DAT.
In approximately 30% of patients with a DAT-positive haemolytic anaemia, no associated disorder is found. Idiopathic AIHA may occur at any age. There is a peak incidence during infancy and early childhood, a second rise during the third decade, with the majority of cases occurring after the fifth decade. There is a preponderance of female patients in both idiopathic and secondary AIHA. A careful drug history should always be taken to exclude drug-induced AIHA, and chemical exposure at work or in the domestic environment must be assessed. In girls, AIHA may precede clinical or immunological evidence of SLE, so that negative serology for SLE does not exclude that disease at a later date. As mentioned above, the presentation may vary from the gradual onset of anaemia to an acute haemolytic process. Systemic symptoms are rare other than those of anaemia. Pallor and jaundice are present. The spleen is nearly always enlarged, usually to between one and a half to five times its normal size. Enlargement to the umbilicus or below is not a feature of idiopathic AIHA and suggests a secondary AIHA.
A small subgroup of patients with idiopathic AIHA also have immune thrombocytopenia (ITP). The thrombocytopenia may coincide with the haemolysis or may arise as separate episodes. This is known as Evans's syndrome. The platelet and red cell antibodies are distinct and do not cross-react. The diagnosis is important because there appears to be a higher incidence of underlying illness such as immunodeficiency or autoimmune lymphoproliferative disease in children and SLE and T-cell lymphoma in adults. Management is as for warm AIHA or immune thrombocytopenic purpura (see Chapter 56) but patients with Evans's syndrome tend to be more resistant to initial therapy with prednisolone. Episodes of immune neutropenia or pancytopenia have also been described in association with a positive DAT.
Warm autoimmune haemolytic anaemia in infancy and childhood
AIHA of unknown cause occurs in infancy and in young children. In infancy, the onset is often acute and anaemia may be profound and difficult to control. The majority of cases in children are transient, although the onset may also be acute. It is interesting that in this group the sex difference is reversed, with more boys being affected. In childhood, the haemolytic episode is frequently precipitated by infection. IgG antibodies may be transferred from a mother with AIHA across the placenta to produce haemolysis in the newborn.
Warm autoimmune haemolytic anaemia associated with other autoimmune diseases
AIHA is often associated with SLE, especially in young women. Autoantibodies are usually IgG, and both IgG and C3d are found on the red cell surface. Occasionally, the DAT may be positive owing to immune complexes absorbed on to the red cell surface. The spleen is important for clearing such coated cells and splenectomy should be avoided if possible. Otherwise, treatment is as for idiopathic AIHA (see below). This condition is also described with other autoimmune, or presumed autoimmune, diseases notably rheumatoid arthritis, Sjogren's syndrome and ulcerative colitis; AIHA is also part of the spectrum of autoimmune diseases associated with agammaglobulinaemia.
Warm autoimmune haemolytic anaemia in lymphoproliferative diseases
The most common association is with B-cell chronic lymphocytic leukaemia (CLL), low-grade B-cell non-Hodgkin's lymphoma or Hodgkin's disease. The antibodies are polyclonal and have no distinct pattern of antibody type or specificity. The formation of antibodies in this group is thought to be due to immune dysregu-lation rather than direct production by the malignant clone. The AIHA may precede the diagnosis of lymphoma, sometimes by months or years. On other occasions, the presentations may be simultaneous or the AIHA may be delayed.
Warm AIHA has most frequently been associated with methyl-dopa. Mefenamic acid, L-dopa and procainamide have also been reported to provoke this condition. About 20% of patients receiving methyldopa develop a positive DAT, but only 1-2% develop haemolytic anaemia. IgG is always present on the red cell surface, and antibodies usually show rhesus specificity, most commonly anti-e or anti-c. The other drugs are more likely to produce clinically important haemolysis. The mechanism by which AIHA is produced by exposure to drugs is not known. Alteration to the red cell membrane or modulation of the immune response by the drug have both been suggested. Treatment of patients with CLL with fludarabine and other purine analogues may provoke a very severe and life-threatening acute autoimmune haemolytic anaemia and, less commonly, other autoimmune cytopenias. The mechanism may be related to a decrease in autoregulatory T cells caused by treatment with fludarabine.
AIHA has been recorded with a number of malignancies, but it is not clear that there is a true association. It may be associated with ovarian cysts, with the cyst fluid containing the agglutinin. It has been suggested that there is also an association with ovarian carcinoma.
Warm autoimmune haemolytic anaemia and viral infections
In children, but rarely in adults, AIHA may follow a viral infection. Haemolysis is usually brisk but self-limiting. It is possible that the virus alters the red cell membrane, which provokes 'auto' antibodies against the altered antigens or that antiviral antibodies cross-react with membrane antigens. A third possibility is that immune complexes form between the virus and specific antibodies are secondarily absorbed onto the red cell surface, leading to immune destruction.
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