Articles on Medical Diseases and Conditions

Tag: Hypothyroidism

  • Summary of Laboratory Tests in Hypothyroidism

    From the preceding discussion, several conclusions seem warranted:

    1. Serum T4 is the most widely used screening test for hypothyroidism, but some physicians use FT4 or serum TSH assay instead. Values in the upper half of the T4 and FT4 reference range are strong evidence against hypothyroidism unless the TBG level is increased (congenital, pregnancy, or estrogen induced).
    2. The THBR test is useful to detect TBG-induced alterations in T4.
    3. The new FT4 methods circumvent the majority of TBG-induced problems and significantly reduce the number of pseudo hypothyroid cases due to severe non thyroidal illness. However, even the FT4 may give falsely decreased results in seriously ill patients.
    4. The TSH assay is the most useful single test to confirm primary hypothyroidism. In occasional patients a TRH test may be necessary.
    5. Certain conditions may produce decreased T4 levels, increased TSH levels, or both in occasional patients without primary hypothyroidism.

  • Thyroid Tests in Hypothyroidism

    Serum thyroxine. Thyroxine is frequently used as the major screening test for hypothyroidism, since the T4 level is low in most cases. There is some overlap between hypothyroid patients and normal persons in the lower part of the T4 reference range, since persons with mild, early, or subclinical disease may be inadvertently included in groups of clinically normal persons used to establish the reference range. There is some evidence that nearly all hypothyroid patients within euthyroid population reference limits have T4 values in the lower 50% of the reference range, so that T4 values in the upper half of the reference range are generally reliable in excluding hypothyroidism. Laboratory error, of course, must be considered if the laboratory result does not conform to the clinical picture. If the patient specimens are kept at room temperature for more than 48-72 hours, as might happen when they are sent by mail, increase in fatty acids during transit may falsely increase T4values when competitive binding (displacement) T4 methods rather than radioimmunoassay methods are used. Conditions that alter T4 results, such as TBG changes, non thyroidal illness, and certain medications must be remembered. Some endocrinologists are using TSH assay as a screening test instead of T4.

    Triiodothyronine-radioimmunoassay. T3-RIA has not proved very useful in the diagnosis of hypothyroidism. The majority of reports indicate that one fourth to one third of hypothyroid patients have T3-RIA values within normal range. In some cases, typically in Hashimoto’s thyroiditis or after treatment of hyperthyroidism with radioactive iodine, it is thought that normal-range T3-RIA values are due to preferential secretion of T3 in what has been called the “failing gland syndrome.” Test alterations due to non thyroidal illness, age-related decrease, and TBG alterations further complicate interpretation.

    Thyroid hormone-binding ratio. The THBR (T3U) test is another test that has not been very helpful in screening for myxedema because of substantial overlap with the euthyroid reference range. The major benefit from its use in possible hypothyroidism is for detection of TBG abnormality.

    Serum thyrotropin (TSH) assay. Serum TSH levels are increased in the great majority of patients with primary hypothyroidism, and serum TSH assay is currently the most useful first-line confirmatory test. Since secondary hypothyroidism (pituitary failure) is uncommon and dysfunction due to hypothalamic etiology is rare, TSH assay has also been advocated as a screening test. Until recently TSH assay had not found wider use in screening for thyroid disease in general because of considerable overlap in the low range between hyperthyroid and euthyroid persons. This occurred because in most TSH assay kits the lower limit of the euthyroid reference range is relatively close to zero. In addition, these kits had relatively poor sensitivity in the low range, so that it was difficult to separate hyperthyroid values, which typically are subnormal, from zero on one hand and lower limit of normal on the other. Some euthyroid lowerormal specimens demonstrated the same problem. Therefore, TSH assay was restricted mostly to diagnosis of hypothyroidism. As mentioned earlier, several ultra sensitive TSH kits have recently become available that have adequate sensitivity in the low range to reliably separate decreased TSH values from low normal values. The ultra sensitive TSH is now being advocated by some investigators as the best single screening test for thyroid disease in general. But as I mentioned earlier, in my experience, at present all ultra sensitive TSH kits are not equally reliable. The TSH levels may be increased, usually (but not always) to mild degree, in some clinically euthyroid patients with a variety of conditions (see the box). When the TSH level is elevated in conditions other than primary hypothyroidism, TSH values are usually less than twice the upper reference range limit. However, sometimes they may be as high as 3 times the upper limit and occasionally even higher.

    Primary hypothyroidism constitutes 95% or more of hypothyroid cases. The TSH assay in conjunction with the serum T4 assay is sufficient for diagnosis in the great majority of these patients (decreased T4 level with TSH level elevated more than twice and preferably more than 3 times the upper reference limit). In equivocal cases, a TRH test may be useful either to confirm primary hypothyroidism or to differentiate primary from secondary or tertiary etiology. As noted in the section on the TRH test, usefulness of the TRH test may be limited in severe non thyroidal illness. In those circumstances, a TSH stimulation test might be useful.

    It has been reported that there are several subgroups of patients with primary hypothyroidism, ranging from those with classic symptoms and markedly elevated TSH values to those with milder symptoms and only mildly elevated TSH values to those with equivocal or single symptoms and T4 and TSH values remaining within population reference range and only the TRH test result abnormal.

    About 5%-10% of patients referred to psychiatrists with symptoms of mood depression (“melancholia”) have been reported to have laboratory evidence of hypothyroidism. This evidence ranges from decreased T4and elevated TSH levels to an exaggerated TRH test response as the only abnormality.

    In secondary hypothyroidism, the thyroid is normal but malfunction occurs in either the hypothalamus or the pituitary. Typically, both T4 (or FT4) and TSH values are decreased. In a few cases, the TSH value is within normal range; the TSH however is structurally defective and cannot stimulate the thyroid normally.

    Thyrotropin-releasing hormone (TRH) test. A more complete discussion of the TRH test is located in the early part of this chapter. The TRH test has been mentioned as a confirmatory test for hypothyroidism. The TRH test has also been used to differentiate secondary from tertiary hypothyroidism. A significant increase in TSH after administration of TRH should theoretically suggest a hypothalamic rather than pituitary etiology for nonprimary hypothyroidism. Unfortunately, 40% of TSH hyposecretors of pituitary origin demonstrate adequate response to TRH stimulation. Therefore, only proof of pituitary hyposecretion by a poor response is considered sufficiently reliable for definite diagnosis. Even a poor response may not be reliable in the presence of severe non thyroidal illness.

  • Laboratory Test Patterns in Hypothyroidism

    The physiology of thyroid hormone production in hypothyroidism is similar to that described in hyperthyroidism. Hypothyroidism may be divided into three types, depending on functional defect. Each of these categories may have various etiologies: (1) primary (primary thyroid T4/T3 secretion defect), (2) secondary (pituitary TSH secretion defect), and (3) tertiary (hypothalamus TRH secretion defect).

    From the laboratory standpoint there are three basic laboratory test patterns:

    1. Decreased T4 value and markedly elevated TSH value (usually more than 3 times reference range upper limit). This pattern is diagnostic of primary hypothyroidism (with the possible exception of very severe iodine deficiency) and is found in the great majority of primary hypothyroid patients.
    2. Thyroxine level in the lower half of the reference range with markedly elevated TSH level. This pattern may be seen in patients with early or mild primary hypothyroidism.
    3. Decreased T4 level with decreased TSH values. This pattern suggests secondary or tertiary hypothyroidism.

  • Thyroid Function Tests: Thyrotropin-releasing hormone (TRH) test

    Synthetic TRH (Thypinone) is now available. Intravenous bolus administration of TRH normally results in a marked rise in serum TSH levels by 30 minutes after the dose. Serum prolactin levels also increase. There is some disagreement as to how much TRH to administer, with doses reported in the literature ranging from 100-500 µg. Early studies reported that at least 400 µg was needed to obtain full TRH effect. Interpretation depends on whether the patient has evidence of hyperthyroidism or hypothyroidism. One problem, however, is disagreement in the literature concerning how much TSH increase over baseline is considered “exaggerated.” The normal limit of increase over baseline varies in the literature from 20-40 µU/ml, so that 25 µU/ml seems to be a reasonable compromise. Reactions to the TRH injection are uncommon, but can occur, and the patients should be closely monitored during the procedure. In general, the smaller the dose, the lower the incidence of reactions. Therefore, many laboratories and investigators use a 200-µg dose; and a few, even a 100-µg dose. However, I have not seen any reports that compared sensitivity of these doses to the gold standard of the 400- or 500-µg dose. Even if such a report appears, it would take several studies including a very substantial number of patients with hypothyroidism and hyperthyroidism to verify satisfactory performance.

    Drawbacks. (1) There is conflicting evidence in the literature regarding the effects of severe non thyroid illness on TRH test results. At least one report indicates that a blunted response may occur in some apparently euthyroid patients with depressed T4 levels associated with severe non thyroid illness and also in some patients with hypothyroidism who also had severe non thyroid illness. This would complicate the diagnosis of hypothyroidism in some cases as well as the differential diagnosis of primary versus secondary etiology. (2) Several reports suggest that TSH response to TRH may be less in elderly persons. (3) In addition, certain conditions such as psychiatric unipolar depression, fasting more than 48 hours duration, and therapy with aspirin, levodopa, or adrenocorticosteroids depress TSH response to TRH. (4) Patients should discontinue desiccated thyroid or T4 therapy for 3-4 weeks (literature range, 2-5 weeks) before a TRH test. (5) Another (although not major) drawback is the $30-$40 cost for TRH and the need for two or three TSH assay specimens.

    Thyrotropin-releasing hormone results in hyperthyroidism. In hyperthyroidism, pituitary TSH production is suppressed by direct effect of excess circulating T4/T3 on the pituitary, and TSH assay after TRH fails to demonstrate a significant degree of TSH increase from pretest baseline values (positive test result). Unfortunately, about 5% false positive results (failure to elevate serum TSH levels after TRH) have been reported in persons without demonstrable hyperthyroidism. A flat or blunted TSH response to TRH has also been reported in patients with autonomous thyroid nodules but no clinical evidence of hyperthyroidism, in a considerable number of patients after adequate treatment of Graves’ disease, and in some patients with multinodular goiter. Certain other conditions (discussed later) may also affect results. A flat TRH test result is therefore considered very suggestive but not conclusive evidence of thyrotoxicosis. A normal result (normal degree of TSH elevation after TRH) is considered very reliable in excluding thyrotoxicosis. For this reason the TRH test is currently considered the most reliable confirmatory procedure for hyperthyroidism and is the standard against which all other tests are compared for accuracy.

    Thyrotropin-releasing hormone results in hypothyroidism. In primary hypothyroidism the TRH test usually demonstrates an exaggerated TSH response. This may render the test useful in the occasional patient with both equivocal symptoms and equivocal serum TSH values. Theoretically, the TRH test should be able to differentiate between hypothyroidism from inability of the pituitary to secrete TSH due to pituitary disease (secondary hypothyroidism) and inability of the hypothalamus to secrete TRH (tertiary hypothyroidism). In pituitary disease, the serum TSH level should not rise significantly after TRH administration, whereas in hypothalamic disease there characteristically is a TSH response that is normal in degree but that is delayed for approximately 30 minutes. Unfortunately, a substantial number of patients with pituitary lesions demonstrate relatively normal or delayed TRH test response. Therefore, absent or markedly blunted response is strongly suggestive of primary pituitary disease, but response to TRH is not diagnostic of hypothalamic disease.

    Thyrotropin-releasing hormone results in psychiatric patients. There have been reports that the TRH test is useful in differentiating unipolar (primary depression only) from bipolar (manic-depressive) psychiatric illness and from secondary types of depression. In unipolar depression, TRH-induced TSH response is said to be blunted in up to two thirds of patients, whereas most patients with other categories of depression have normal TSH response. Occasional patients with symptoms of depression may actually have thyrotoxicosis (“apathetic hyperthyroidism”) and some may have hypothyroidism.

  • Thyroid Function Tests

    The classic picture of hyperthyroidism or hypothyroidism is frequently not complete and may be totally absent. There may be only one noticeable symptom or sign, and even that may be vague or misleading or suggestive of some other disease. The physician must turn to the laboratory to confirm or exclude the diagnosis.

    There is a comparatively large group of laboratory procedures that measure one or more aspects of thyroid function (see the box). The multiplicity of these tests implies that none is infallible or invariably helpful. To get best results, one must have a thorough knowledge of each procedure, including what aspect of thyroid function is measured, sensitivity of the test in the detection of thyroid conditions, and the rate of false results caused by non thyroid conditions. In certain cases, a brief outline of the technique involved when the test is actually performed helps clarify some of these points.

  • Signs and Symptoms of Thyroid Disease

    Many persons have at least one sign or symptom that could suggest thyroid disease. Unfortunately, most of these signs and symptoms are not specific for thyroid dysfunction. Enumeration of the classic signs and symptoms of thyroid disease is the best way to emphasize these facts.

    Hyperthyroidism

    Thyrotoxicosis from excess secretion of thyroid hormone is usually caused by a diffusely hyperactive thyroid (Graves’ disease, about 75% of hyperthyroid cases) or by a hyperfunctioning thyroid nodule (Plummer’s disease, about 15% of hyperthyroid cases). A much less common cause is iodine-induced hyperthyroidism (Jod-Basedow disease), and rare causes include pituitary overproduction of TSH, ectopic production of thyroid hormone by the ovary (struma ovarii), high levels of chorionic gonadotropin (with some thyroid-stimulating activity) from trophoblastic tumors, and functioning metastic thyroid carcinoma. Thyroiditis (discussed later) may produce symptoms of thyrotoxicosis (comprising about 10% of hyperthyroid cases), but the symptoms are caused by leakage of thyroid hormones from damaged thyroid tissue rather than over secretion from intact tissue. Many hyperthyroid patients have eye signs such as exophthalmos, lid lag, or stare. Other symptoms include tachycardia; warm, moist skin; heat intolerance; nervous hyperactive appearance; loss of weight; and tremor of fingers. Less frequent symptoms are diarrhea, atrial fibrillation, and congestive heart failure. The hemoglobin level is usually normal; the white blood cell (WBC) count is normal or slightly decreased. There is sometimes an increase in the lymphocyte level. The serum alkaline phosphatase level is elevated in 42%-89% of patients. In elderly patients the clinical picture is said to be more frequently atypical, with a higher incidence of gastrointestinal symptoms, atrial fibrillation, and apathetic appearance.

    Hypothyroidism

    Myxedema develops from thyroid hormone deficiency. Most common signs and symptoms include nonpitting edema of eyelids, face, and extremities; loss of hair in the outer third of the eyebrows; large tongue; cold, dry skin; cold intolerance; mood depression; lethargic appearance; and slow mental activity. Cardiac shadow enlargement on chest x-ray film is common, with normal or slow heart rate. Anorexia and constipation are frequent. Laboratory tests show anemia in 50% or more of myxedema patients, with a macrocytic but non- megaloblastic type in approximately 25%. The WBC count is usually normal. The cerebrospinal fluid (CSF) usually has an elevated protein level with normal cell counts, for unknown reasons. Serum creatine kinase (CK) is elevated in about 80% (range, 20%-100%) of patients; aspartate aminotransferase (AST; formerly SGOT) is elevated in about 40%-50%; and serum cholesterol is frequently over 250 mg/dl in overt cases.

    Hypothyroidism in the infant is known as “cretinism.” Conditions that superficially resemble or simulate cretinism include mongolism and Hurler’s disease (because of mental defect, facial appearance, and short stature); various types of dwarfism, including achondroplasia (because of short stature and retarded bone age); and nephrosis (because of edema, high cholesterol levels, and low T4 levels). Myxedema in older children and adults may be simulated by the nephrotic syndrome, mental deficiency (because of mental slowness), simple obesity, and psychiatric depression.

  • Anemia Associated With Systemic Disease

    As noted in Chapter 3, anemia associated with various chronic diseases is usually normocytic and either normochromic or hypochromic. The serum iron and total iron-binding capacity (TIBC) are typically both decreased. In 100 consecutive patients in our hospital who had chronic disease and red cell or iron-related biochemical abnormalities, 68 had anemia with normal mean corpuscular volume (MCV), decreased serum iron, and decreased TIBC; 7 had no anemia; 9 had normal serum iron levels; 6 had normal TIBC; and 7 had decreased MCV (with normal serum ferritin levels). Others have reported that decreased MCV may occur in up to 25% of cases.

    Chronic renal disease

    Anemia of moderate degree is frequently found in association with uremia. Some investigators claim it is almost always present when the blood urea nitrogen (BUN) level is persistently more than twice normal, and it often appears before this level is reached. Patients with prolonged but potentially reversible azotemia (e.g., acute renal failure) often develop anemia until the kidneys recover. Transient types of azotemia usually do not produce anemia unless azotemia is prolonged or due to the underlying cause itself. The anemia of actual renal insufficiency develops regardless of the cause of the uremia.

    The peripheral blood RBCs are usually normocytic-normochromic; there is often mild to moderate anisocytosis. Varying numbers of burr cells (triangular shrunken RBCs with irregular pointed projections from the surface (Chapter 2) are found in some patients. In some cases there is mild hypochromia and, occasionally, some degree of microcytosis. On the other hand, mild macrocytosis may be present in a few patients.

    Bone marrow usually shows normal cellularity, although in some cases there is mild RBC hypoplasia. Marrow iron is adequate. The serum iron level is usually normal, but about 20%-30% of patients have low serum iron levels even though they do not have iron deficiency. Most of these patients also have a low or low-normal TIBC typical of chronic disease anemia (Chapter 3). Reticulocyte counts are usually normal; occasionally, they may be slightly elevated.

    The pathophysiology involved is not well understood. The primary known abnormality is a lack of incorporation of iron into RBCs within the bone marrow. There is depression both of hemoglobin synthesis and of formation and release of mature RBCs into the peripheral blood. In 10%-15% of patients there is also decreased RBC survival in the peripheral blood, although the hemolytic aspect is usually not severe. There is, however, a rare condition known as the hemolytic-uremic syndrome that features a severe microangiopathic (RBC fragmentation) hemolytic anemia. Patients in the late stages of uremia may have a bleeding tendency due to coagulation defects, most commonly thrombocytopenia. Platelet function may be abnormal even with normal numbers of platelets. The effect of hemorrhage, if it occurs, is separate and additional to the anemia of chronic renal disease.

    Anemia of neoplasia

    Anemia develops in 60%-90% of patients with moderate or far-advanced cancer. The anemia of neoplasia is usually normocytic with normal reticulocyte counts, unless there is hemorrhage or chronic blood loss. Cytotoxic chemotherapy is accompanied by a macrocytic MCV in 30%-40% (12%-82%) of patients. A hemolytic component is present in a considerable minority of patients, but hemolysis is generally mild and is not detectable except with radioisotope RBC survival procedures. Occasionally, hemolysis may be severe, especially in patients with chronic lymphocytic leukemia and malignant lymphomas. In one series, anemia was ascribed to a combination of decreased RBC survival and decreased marrow production in 56% of patients, to blood loss in 29%, and to marrow metastases by the tumor in 13%. Thrombocytopenia may be found in certain types of leukemia and in myelophthisic anemias. Fibrinolysins appear in occasional cases of widespread malignancy, most often prostate carcinoma.

    Anemia of infection

    Mild to moderate anemia is frequently associated with subacute or chronic infection. The mechanism of this anemia is not well understood, but there seems to be a decreased rate of erythropoiesis, coupled in some patients with slightly shortened RBC survival time and failure to use iron normally. The anemia of infection usually does not develop unless the infection lasts 1 month or more, although it may develop rapidly in patients with severe acute infection such as septicemia. Chronic infection producing anemia generally is of at least moderate severity. Infections in which anemia is likely to develop include bronchiectasis, salpingitis, abscess of visceral organs or body cavities, and severe pyelonephritis. Anemia is a common finding in subacute bacterial endocarditis and in the granulomatous diseases such as tuberculosis and sarcoidosis. The anemia is usually normocytic and normochromic, but sometimes it is hypochromic. Reticulocyte counts are usually normal, although occasionally they may be slightly increased. Bone marrow aspiration shows either normal marrow or hyperplasia of the granulocytes. The serum iron level is usually low or low-normal, and plasma TIBC is reduced (in iron deficiency anemia the TIBC is elevated).

    Aplastic anemia is a rare complication of type C (non-A, non-B) hepatitis virus infection.

    Rheumatoid-collagen disease group

    Rheumatoid-collagen diseases are frequently associated with mild to moderate normocytic anemia. In one study 40% of males and 63% of females with rheumatoid arthritis were anemic. Active disease is more likely to produce anemia. Incidence of coexistent iron deficiency ranges from 10%-30%. Reticulocytes are usually normal, and the bone marrow is unremarkable. In many patients there apparently is decreased erythropoiesis with a slightly shortened RBC survival time, but there is some disagreement regarding frequency of decreased RBC survival. About 5%-10% of patients with rheumatoid arthritis have splenomegaly, which may be associated with cytopenias.

    Chronic liver disease

    The type and frequency of anemia in liver disease vary with the type and severity of hepatic dysfunction, but anemia has been reported in up to 75% of patients. It is most frequently seen in far-advanced cirrhosis. Extensive metastatic carcinoma of the liver may produce the same effect, although it is difficult to say whether the liver involvement or the neoplasm itself is the real cause. About 30%-50% (8%-65%) of patients with anemia have macrocytosis; about one third are normocytic. Some have hypochromia due to GI blood loss. Target cells in varying numbers are a frequent finding on peripheral blood smear.

    Macrocytic anemia in liver disease is most often found in severe chronic liver damage; this type of anemia is not frequent in acute liver disease, even when severe, or in chronic disease of only slight or mild extent. A small but significant percentage of hepatic macrocytic anemias are megaloblastic, usually secondary to folic acid dietary deficiency, although most are not megaloblastic and are not corrected by folic acid treatment. A peripheral blood smear may be macrocytic even when there is a normal hemoglobin or hematocrit reading, and sometimes even with a normal MCV.

    GI bleeding occurs in a considerable number of cirrhotic patients; often it is very slight and intermittent. Esophageal varices are present in some. Other lesions may be demonstrated in other patients. In a considerable proportion of cases the source of bleeding cannot be located.

    Hypersplenism occurs in some patients with portal vein hypertension and its resulting splenic congestion. Thrombocytopenia, usually mild, is reported to occur in up to 50% of patients with cirrhosis, and other cytopenias may sometimes develop. In severe chronic (or massive acute) liver disease, coagulation problems may result from insufficient hepatic synthesis of several blood coagulation factors.

    Some liver-diseased patients have shortened RBC survival demonstrated only by using radioactive isotope studies and show no evidence of GI bleeding. There is no clinical or laboratory evidence of hemolysis otherwise. About 3%-5% develop Zieve’s syndrome, a combination of hyperlipemia, cirrhosis, and microangiopathic hemolytic anemia. This hemolytic anemia is associated with reticulocytosis and the other classic features of hemolysis.

    Unless blood loss is a factor, and excluding megaloblastic anemia, the bone marrow is unremarkable in liver disease and the reticulocyte count is usually close to normal. Not all cases of anemia associated with liver disease can be explained.

    Hypothyroidism

    Anemia is found in 30%-50% (21%-60%) of hypothyroid patients. About 15% (8%-20%) of the anemic patients have macrocytosis, most of the remainder having either normocytic-normochromic or normocytic-hypochromic indices. A small percentage have hypochromic-microcytic RBCs.

    The hypochromic anemia of hypothyroidism responds to a combination of iron and thyroid hormone preparation. The iron deficiency component is frequently produced by excessive menstrual bleeding. In patients without demonstrable blood loss it is speculated that decreased intestinal iron absorption may occur, since thyroid hormone is known to affect intestinal carbohydrate absorption. Most of the macrocytic cases respond only to thyroid hormone. In these patients the bone marrow is not megaloblastic and is sometimes slightly hypocellular. The reticulocyte count is usually normal. Isotope studies reportedly show normal RBC survival time in most cases. Lack of thyroid hormone seems to have a direct effect on erythropoiesis, since thyroid hormone therapy cures both the myxedema and the anemia (unless there is superimposed iron deficiency). A minority of patients with macrocytic anemia have folic acid or vitamin B12 deficiency, presumably secondary to decreased intestinal absorption. Thyroid hormone is required in addition to folic acid or vitamin B12. About 5% have actual pernicious anemia, with megaloblastic bone marrow.

    Comments on chronic disease anemia

    To conclude this discussion, it should be noted that the normocytic-normochromic anemia of systemic disease has often been called“simple chronic anemia,” although the pathophysiology is far from simple. The disease categories listed in this chapter are only the most common. In many cases, the diagnosis is one of exclusion; the patient has anemia for which no definite etiology can be found, so whatever systemic disease he or she has is blamed for the anemia. Some investigators restrict the diagnosis of chronic disease anemia to those who have decreased serum iron and TIBC. Regardless, it is important to rule out treatable serious diseases. This is especially true for hypochromic anemias (in which blood loss might be occurring) and macrocytic anemias (which may be due to vitamin B12 or folic acid deficiency). A normocytic-normochromic anemia may be due to an occult underlying disease, such as malignant lymphoma or multiple myeloma.