THE ANEMIA OF CHRONIC DISEASE

A mild to moderate anemia, termed the Anemia of Chronic Disease (ACD), is a common finding in many chronic infectious, inflammatory and malignant disorders. Suppurative infections are regularly accompanied by anemia, the degree of which is proportional to the severity of constitutional symptoms. Anemia is also characteristic of chronic inflammatory disorders, including rheumatoid arthritis and other connective tissue disorders, and inflammatory bowel disease. Patients with a wide variety of neoplastic disorders, including carcinomas, sarcomas and lymphomas are frequently anemic. The anemia can occur in those with localized disease as well as those with metastases.

The anemia of these inflammatory and neoplastic disorders shares common features: it is mild to moderate and is characterized by ineffective iron metabolism, decreased erythropoietin (EPO) production, inhibition of red cell production and slightly shortened red cell survival.

Laboratory findings

The hemoglobin is usually in the range of 70 to 110 g/L. The red cells may be microcytic or normocytic (MCV < 80 fL). White blood cell and platelet production are not impaired and the counts may be normal or increased in response to the primary disease. The differential diagnosis includes other causes of a microcytic or normocytic anemia, including blood loss with or without iron deficiency, renal failure, hemolysis, marrow infiltration and marrow suppression by toxic agents. Often the diagnosis is one of exclusion.

Serum iron is characteristically decreased in ACD and, in contrast to iron deficiency anemia, is accompanied by a low iron binding capacity. The percentage saturation is also decreased, although is not as low as in iron deficiency. Ferritin levels are normal to increased in ACD. However, co-existing iron deficiency may be masked as ferritin is an acute phase reactant that increases in inflammatory disorders and malignancy.

Thus, the determination of iron status can be difficult in patients with these disorders and a bone marrow examination for the assessment of stainable iron may be indicated. It is valuable to identify coexisting iron deficiency as correction can alleviate the anemia to some degree. Serum ferritin levels in the low normal range (e.g. < 60 µg/L) suggest coexisting iron deficiency. Recently, the measurement of serum transferrin receptor (sTfR) and sTfR-log ferritin index has been suggested as providing a more accurate assessment of iron status. STfR is increased in iron deficiency and decreased in iron-replete ACD. However, sTfR measurement is not routinely available and not all studies show it to be a clear discriminator.

Table: Iron Studies in the Anemia of Chronic Disease and Iron Deficiency Anemia

Pathogenesis

Decreased reutilization of iron, while characteristic of ACD, is not the only factor contributing to anemia. Red cell production is impaired and the red cells have a mildly shortened survival time as a result of extramedullary destruction. While the pathogenesis is not completely understood, current studies indicate that release of cytokines is responsible for these manifestations. Levels of Tumor Necrosis Factor a (TNFa) and Interleukin 1 (IL-1) are increased in patients with inflammatory processes and malignancies. TNFa, secreted by macrophages, has been shown experimentally to decrease serum iron and to inhibit red cell production. IL-1 inhibits EPO production in rats exposed to hypoxemia and also impairs production of red blood cells. The effects of TNFa and IL-1 may both be mediated by interferon.

Treatment principles

The anemia is often asymptomatic and no treatment is needed. As stated above, patients who are also iron deficient do respond to correction of the deficiency. Hemoglobin levels rise with treatment of the underlying condition, where this is possible. For those patients requiring treatment, erythropoietin has been shown to be effective and a safe alternative to transfusion.

SAIGE SERUM ALLERGY TESTING

MDS Metro is now offering Specific Allergen IgE testing using the Pharmacia SAIGE system. This diagnostic tool identifies the presence of circulating IgE molecules that react with specific allergens and is therefore a diagnostic aid in the identification of IgE mediated hypersensitivity reactions.

Skin vs. Serum Testing

Traditional teaching is that skin tests are more sensitive and more closely correlate with clinical symptoms than serum testing. However, in recent years the isolation of allergens for SAIGE testing has improved significantly over the earlier RAST procedures and is considered by some to be equal to skin testing. (Poon AW, Goodman CS, Rubi RJ Am J Manag Care 1998; 7: 969-85.) Indeed, the detection of moulds and food allergies may be better with in vitro methods.

SAIGE testing is particularly recommended in the following situations:

1. testing of patients with severe dermatographism, ichthyosis, or generalized eczema,
2. pre-desensitization,
3. testing of patients who have been receiving long-acting antihistamines, tricyclic antidepressants, or medications that may put the patient at undue risk if they are discontinued,
4. testing of uncooperative patients with mental or physical impairments,
5. the evaluation of cross-reactivity between insect venoms,
   determining food allergy,
6. postmortem examination for IgE antibodies to identify allergens responsible for lethal anaphylaxis,
7. as adjunct laboratory tests for evaluating the activity of allergic bronchopulmonary aspergillosis and certain parasitic diseases, and
8. when the clinical history suggests a high risk of anaphylaxis from skin testing.

From: Practice Parameters for Allergy Diagnostic Testing. Ann Allergy, Asthma & Immunol. 75: December 1995 (updated March 15, 1996).

The MSP will pay for SAIGE testing under limited conditions. To quote from the fee schedule, these are: "1. Debilitating symptoms unresponsive to usual management. 2. A history of life-threatening severe reactions where greater effort is needed to identify the specific allergen. 3. Generalized skin diseases of patients for whom skin tests cannot be done." A special MDS Metro allergen request form provides a check-off box to confirm these conditions, if they exist. All other patients are not covered by the MSP but we are able to provide the test for $35 for the first allergen and $20 for each allergen thereafter. Results will generally be available in less than one week. The Allergen Request form can be obtained in the same way you obtain other collection material from the lab, or you can phone 604-412-4481 or 250-881-3111(124).

Selection of Tests

In spite of modern testing, Medical School lessons still apply and a careful clinical history is the basis of all allergy investigations. If SAIGE testing is to be used, the history can be used to guide the selection of tests from the special MDS Metro allergen request form. This form presents approximately 70 common allergens. For special cases we have an additional 400 allergens available.

A number of mixed allergen tests are available and may help to reduce the overall cost of testing if used strategically. These are: Children’s food (egg white, milk, wheat, peanut, soybean); Mite mix (house dust, D. pternoyssinus, cockroach, D. farinae); Nut mix (peanut, hazelnut, almond, coconut, brazilnut); Seafood mix (cod, tuna, shrimp, mussel, salmon). A negative result on a mix indicates the absence or undetectable levels of specific IgE toward all the allergens in the mix. A positive test indicates IgE to one or more members of the mixture. Further testing with single allergens is then recommended. Food mixtures have a very high negative predictive value but positive tests must be considered as a starting point for specific IgE testing and food elimination trials.

Interpretation

As with skin testing, there are potentially misleading positive and negative results. We prefer not to call them "false" positive or negative because the test is virtually always identifies the specific IgE if it is present. However, the clinical correlation between positive and negative tests and allergies is mitigated by a number of factors.

Positive Test but No Allergy: This can be caused by a specific IgE that does not activate mast cells. It may also be due to the presence of high titres of IgG that are specific to the allergen and "mop" it up before it has time to bind with IgE. (This, of course, is the mechanism of desensitization.) Occasionally, generalized atopy may cause so many IgEs to be present they cross react non-specifically. It should be noted that the level of the results in positive sera may not correlate with the severity of symptoms.

Negative Test with an Allergy: The most common reason for this is that the allergen protein used in the test is not the allergen to which the patient is allergic. Almost every food, plant, insect, spore, and pollen contains several allergens. The SAIGE test uses the proteins that are the usual offenders, but occasionally a person will be allergic to some minor and unusual component of the allergy causing material. Another reason is an IgE level that is lower than the cut-off value because exposure has not occurred in a prolonged period of time. This is important in the case of drug allergies where exposure is minimal and even a few weeks after a clinical event the IgE level may revert to normal.

More than 170 foods have been reported to cause allergies. SAIGE testing is particularly good for immediate type food allergies but the interpretation of the results must be made with caution. The SAIGE test is now recognised to have a predictive value (+ and -) of over 90%. However, many patients will be convinced that they have an allergy to a particular food and when they are tested will not show a positive test. There are several reasons for this. First of all, they may be suffering from a non-IgE mediated food "intolerance" rather than an allergy. Food intolerances include reactions to spices, lactose intolerance (due to lactase deficiency), tyramine in cheese (a pharmacologic effect), gluten intolerance (not IgE mediated – order Tissue Transglutaminase), reaction to baked beans, and numerous other legitimate problems that are not immediate-type hypersensitivity allergic reactions. Another reason why food tests may turn out negative is that the patient may not be allergic to the food, but may be allergic to a sauce that is served with it, a preservative that is used in its preparation, or a substance that is altered during industrial processing or cooking.

Of particular interest to health care workers is the latex allergy test that has a very high predicitve value for both positive and negative results. Note that non-immunologic irritant dermatitis is the most common latex caused skin reaction and it will show a negative IgE test.

The important message is that SAIGE testing is available, correlates with IgE mediated hypersensitivity, but should never be considered definitive. If you have any questions concerning SAIGE, please contact Dr. Michael McNeely by phone 250-881-3109 or email.

FALSE POSITIVE HCG ASSAYS

Recently, Abbott Diagnostics Division issued a product warning regarding false positive Chorionic Gonadotropin (hCG) assays. This warning comes on the heels of a class action lawsuit against Abbott on behalf of a number of women who allege that false positive hCG assays resulted in their being treated for malignant disease when, in fact, none was present.

The reason for these false positives is either a heterophile antibody or a HAMA (human anti-mouse antibody). This phenomenon may occur with any immunologically based assay and about 1:1000 persons carries the antibodies that cause this problem.

Thus, when an hCG assay does not correlate with clinical findings and your differential diagnosis begins to expand, it is important to consider this antibody cause. Such patients, in spite of a positive serum hCG will have a negative urine test. Alternatively, you may contact the lab and we will arrange to re-assay the sample using an alternative method.

Finally, it should be remembered that the most common reason for a positive hCG in a woman who does not develop a pregnancy, is a missed, early abortion. In such cases, of course, the hCG will revert to negative over several days depending upon its peak value.

Rotmensch S. and Cole L. "False diagnosis and needless therapy of presumed malignant disease in women with false-positive human chorionic gonadotropin concentrations." The Lancet 2000; 355: 712-15.

HOW USEFUL IS SERUM FOLATE?

Folate studies are very commonly requested and yet over the past year we can identify only four patients who have demonstrated a low serum folate level. At the same time, at least 20% of the tests have been requested on people who are taking folate supplements. Our data show that 5% of doctors order about 40% of the folates and these doctors order at least one folate per week. It is also notable that only 12% of patients undergoing folate studies have macrocytosis.

FACTOR V LEIDEN AND PROTHROMBIN G20210A GENE MUTATIONS.

Effective April 1, 2001 MDS Metro will begin offering molecular testing for the Factor V Leiden (FVL) and Prothrombin G20210A gene mutations. We recently introduced a polymerase chain reaction (PCR) method for identifying these two mutations. FVL is the most common genetic defect associated with venous thromboembolism, followed by the prothrombin mutation.

Factor V Leiden (FVL), which results from a single point mutation in the factor V gene, is resistant to degradation by activated protein C. Activated protein C resistance predisposes to venous thrombosis. FVL is inherited in an autosomal dominant manner. Heterozygotes for the defect are reported to have a 3–7 fold increased risk of venous thrombosis compared with non-carriers, while homozygotes have a 50 to 100-fold increased risk. FVL is commonly seen in Caucasians, especially those of European descent, with a prevalence rate of 2% - 7%; it is rarely found in Asians and Africans.

The G20210A mutation in the prothrombin gene causes increased prothrombin levels which in turn increase the risk of venous thrombosis. However, this risk is reported to be slightly less than that observed with FVL. In Caucasians, the prevalence of the prothrombin mutation is reported to be 1 % - 6%. It is rare or absent in Asians and Africans.

Carriers of FVL and/or prothrombin G20210A, have a significantly higher risk of thrombosis when they are exposed to other risk factors such as surgery, prolonged immobilization, oral contraceptives or pregnancy.

Factor V Leiden and Prothrombin G20210A are frequently co-inherited; as a result, testing at MDS Metro will routinely screen for both mutations. Some studies suggest that carriers of both mutations often develop thrombosis at an earlier age.

References:

1. Martinelli Ida, Bucciarelli Paolo et al., (2000) The risk of venous thromboembolism in family members with mutations in the genes of factor V or prothrombin or both. British J. Haematology, 111, 1223-1229.
   
2. Chan Daniel K.Y., Gang Hu et al., (2000) A comparison of polymorphism in the 3 ¢ – untranslated region of the prothrombin gene between Chinese and Caucasians in Australia. British J. Haematology 111, 1253 – 1255.
   
3. Friedline John A, Ahmad Ejaz, et al.,(2001) Combined Factor V Leiden and Prothrombin Genotyping in patients presenting with thromboembolic episodes. Arch Pathol Lab med, Vol 125, January 2001.