Autoimmune hemolytic anemia

Autoimmune hemolytic anemia (or autoimmune haemolytic anaemia; AIHA) occurs when antibodies directed against the person's own red blood cells (RBCs) cause the RBCs to burst (lyse), leading to insufficient plasma concentration. The lifetime of the RBCs is reduced from the normal 100–120 days to just a few days in serious cases. The intracellular components of the RBCs are released into the circulating blood and into tissues, leading to some of the characteristic symptoms of this condition. The antibodies are usually directed against high-incidence antigens, therefore they also commonly act on allogenic RBCs (RBCs originating from outside the person themselves, e.g. in the case of a blood transfusion) AIHA is a relatively rare condition affecting 1–3 people per 100,000 per year.

The terminology used in this disease is somewhat ambiguous. Although MeSH uses the term "autoimmune hemolytic anemia", some sources prefer the term "immunohemolytic anemia" so that drug reactions can be included in this category. . The National Cancer Institute considers "immunohemolytic anemia", "autoimmune hemolytic anemia", and "immune complex hemolytic anemia" to all be synonyms. .

Classification
AIHA is classified as either warm autoimmune hemolytic anemia or cold autoimmune hemolytic anemia which includes cold agglutinin disease, and paroxysmal cold hemoglobinuria. These classifications are based on the characteristics of the autoantibodies involved in the pathogenesis of the disease. Each of these has a different underlying cause, management and prognosis making classification important when handling a patient with AIHA.

Causes
The causes of AIHA are poorly understood. The disease may be primary or secondary to another underlying illness. The primary illness is idiopathic (the two terms being used synonymously). Idiopathic AIHA accounts for approximately 50% of cases. Secondary AIHA can result from many other illnesses. Warm and cold type AIHA each have their own more common secondary causes. The most common causes of secondary warm-type AIHA include lymphoproliferative disorders (e.g. chronic lymphocytic leukemia, lymphoma) and other autoimmune disorders (e.g. systemic lupus erythematosis, rheumatoid arthritis, scleroderma, ulcerative colitis). Less common causes of warm-type AIHA include neoplasms other than lymphoid and infection. Secondary cold type AIHA is also primarily caused by lymphoproliferative disorders but is also commonly caused by infection, especially by mycoplasma, viral pneumonia, infectious mononucleosis and other respiratory infections. Less commonly it can be caused by concomitant autoimmune disorders.

Drug induced AIHA is also a rare cause of the disease. It can be caused by a number of drugs including α-methyldopa and penicillin. This is a type II immune response in which the drug binds to macromolecules on the surface of the RBC and acts as an antigen. Antibodies are produced against the RBC and lead to complement activation. Complement fragments such as C3a, C4a and C5a activate granular leukocytes (e.g. neutrophils); while other components of the system (C6, C7, C8, C9) can either form the membrane attack complex (MAC) or can bind the antibody stimulating phagocytosis by macrophages (C3b). This is one type of "penicillin allergy".

Pathophysiology
AIHA can be caused by a number of different autoantibodies. IgG and IgM are the main classes of antibody which cause the disease. Depending on which is involved the pathology will differ. As IgG is poor at activating complement but effectively binds the Fc receptor (FcR) of phagocytic cells, AIHA involving IgG is generally characterized by phagocytosis of RBCs. IgM is a potent activator of the classical complement pathway, thus, AIHA involving IgM is characterized by complement mediated lysis of RBCs. IgM also leads to phagocytosis of RBCs however, because phagocytic cells have receptors for the bound complement (rather than FcRs as in IgG AIHA). IgG AIHA generally takes place in the spleen, while IgM AIHA takes place in Kupffer cells – phagocytic cells of the liver. Phagocytic AIHA is termed extravascular while complement mediated lysis of RBCs is termed intravascular AIHA. In order for intravascular AIHA to be recognizable it requires overwhelming complement activation, therefore most AIHA is extravascular – be it IgG or IgM mediated.

There is no single autoantibody which can be pinned down in AIHA. In order to determine the autoantibody or autoantibodies present in a patient, the Coombs test is performed – also known as the antiglobulin test. There are two types of Coombs test – direct and indirect – more commonly the direct test is used (direct antiglobulin test – DAT). Classification of the antibodies is based on their activity at different temperatures and their aetiology. Antibodies with high activity at physiological temperature (approximately 37°C) are termed warm autoantibodies. Cold autoantibodies act best at temperatures of 0–4°C. Patients with cold-type AIHA therefore have higher disease activity when body temperature falls into a hypothermic state. Usually the antibody becomes active when it reaches the limbs, at which point it opsonizes RBCs. When these RBCs return to central regions they are damaged by complement. Patients may present with one or both types of autoantibody, if both are present the disease is termed "mixed-type" AIHA.

When DAT is performed the typical presentations of AIHA are as follows. Warm-type AIHA shows a positive reaction with antisera to IgG antibodies with or without complement activation. Cases may also arise with complement alone or with IgA, IgM or a combination of these three antibody classes and complement. Cold type AIHA usually reacts with antisera to complement and occasionally to the above antibodies. This is the case in both cold agglutinin disease and cold paroxysmal hematuria. Mixed warm and cold AIHA generally shows a positive reaction to IgG and complement, sometimes IgG alone and sometimes complement alone. Mixed type can, like the others, present unusually with positive reactions to other antisera.

Diagnosis
Diagnosis is made by first ruling out other causes of hemolytic anemia such as G6PD, thalassemia, sickle-cell disease, etc. Clinical history is also important to elucidate any underlying illness or medications which may have led to the disease.

Following this, laboratory investigations are carried out to determine the etiology of the disease. A positive DAT test has poor specificity for AIHA (having many differential diagnoses), therefore supplemental serological testing is required to ascertain the cause of the positive reaction. Hemolysis must also be demonstrated in the lab. The typical tests used for this are a CBC with peripheral smear, bilirubin, LDH (in particular with isoenzyme 1), haptoglobin and urine hemoglobin.


 * Evidence for hemolysis
 * Increased red cell breakdown
 * Elevated serum bilirubin (unconjugated)
 * Excess urinary urobilinogen
 * Reduced plasma haptoglobin
 * Raised serum lactic dehydrogenase (LDH)
 * Hemosiderinuria
 * methemalbuminemia
 * Increased red cell production:
 * Reticulocytosis
 * Erythroid hyperplasia of the bone marrow
 * Specific investigations
 * Positive direct Coombs test

Treatment
Much literature exists regarding the treatment of AIHA. Efficacy of treatment depends on the correct diagnosis of either warm or cold-type AIHA.

Warm type AIHA is usually a more insidious disease, not treatable by simply removing the underlying cause. First line therapy for this is usually with corticosteroids such as prednisolone. Following this, other immunosuppressants are considered such as rituximab, danazol, cyclophosphamide, azathioprine or cyclosporine.

Cold agglutinin disease is treated by avoiding the cold or sometimes with rituximab. Removal of the underlying cause is also important

Paroxysmal cold hematuria is treated by removing the underlying cause such as infection.

History
"Blood induced icterus" produced by the release of massive amounts of a coloring material from blood cells followed by the formation of bile was recognized and described by Vanlair and Masius' in 1871. About 20 years later Hayem distinguished between congenital hemolytic anemia and an acquired type of infectious icterus associated with chronic splenomegaly. In 1904 Donath and Landsteiner suggested that a serum factor was responsible for hemolysis in paroxysmal cold hemoglobinuria. French investigators led by Chauffard stressed the importance of red-cell autoagglutination in patients with acquired hemolytic anemia. In 1930 Lederer and Brill described cases of acute hemolysis with rapid onset of anemia and rapid recovery after transfusion therapy. These hemolytic episodes were thought to be due to infectious agents. A clear distinction between congenital and acquired hemolytic anemia was not drawn, however, until Dameshek and Schwartz in 1938 and in 1940 demonstrated the presence of abnormal hemolysins in the sera of patients with acquired hemolytic anemia and postulated an immune mechanism.

During the past three decades, studies defining red-cell blood groups and serum antibodies have produced diagnostic methods that have laid the basis for immunologic concepts relevant to many of the acquired hemolytic states. Of these developments, the antiglobulin test described by Coombs, Mourant, and Race in 1945 has proved to be one of the more importantly useful tools now available for the detection of immune hemolytic states. This technique demonstrated that a rabbit antibody against human globulin would induce agglutination of human red cells "coated with an incomplete variety of rhesus antibody." C. Moreschlit had used the same method in 1908 in a goat antirabbit-red-cell system. The test was historically premature and was forgotten. In 1946 Boorman, Dodd, and Loutit applied the direct antiglobulin test to a variety of hemolytic anemias and laid the foundation for the clear distinction of autoimmune from congenital hemolytic anemia.

A hemolytic state exists whenever the red-cell survival time is shortened from the normal average of 120 days. Hemolytic anemia is the hemolytic state in which anemia is present, and bone-marrow function is inferentially unable to compensate for the shortened life-span of the red cell. Immune hemolytic states are those hemolytic states, both anemic and nonanemic, which involve immune mechanisms consisting of antigen-antibody reactions. These reactions may result from unrelated antigen-antibody complexes that fix to an innocent-bystander erythrocyte, or from related antigen-antibody combinations in which the host red cell or some part of its structure is or has become antigenic. The latter type of antigen-antibody reaction may be termed "autoimmune," and hemolytic anemias so produced are autoimmune hemolytic anemias.

In Children
AIHA in children generally has a good prognosis and is self-limiting. However, if it presents within the first two years of life or in the teenage years, the disease often follows a more chronic course, requiring long term immunosuppression with serious developmental consequences. The aim of therapy may sometimes be to lower the use of steroids in the control of the disease. In this case, splenectomy may be considered as well as other immunosuppressive drugs. Infection is a serious concern in patients on long-term immunosuppressant therapy, especially in the very young (<2 years).