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Anemia in Diseases of the Intestinal Tract
ANEMIA IN DISEASES OF THE INTESTINAL TRACT RUSSELL L. HADEN, M.D., F.A.C.P. AND DONALD W. BORTZ, M.D. EVERY patient with disease of the intestinal tract deserves a careful blood study.! Anemia is often a significant feature in such conditions. The reduction in red cells and hemoglobin may be due (1) to abnormal blood loss or excessive hemolysis of erythrocytes or (2) to decreased blood formation resulting from a toxic depression of the bone marrow by a wide variety of substances or from a lack of iron and the specific maturing factor, supplied by liver and liver substitutes, necessary for normal bone marrow activity. An exact laboratory study of the blood often gives a clue to the cause of the anemia. If it is due to hemorrhage which is primarily iron loss or to some other iron deficiency, the cells first become deficient in hemoglobin, as indicated by a lowered color index. As the iron deficiency becomes more chronic and more severe the red cells become smaller, as indicated by a low volume index. Thus a mild iron deficiency causes a low col or index while a severe one shows both a low volume and a low color index. With a loss of the specific erythrocyte factor normally found in the stomach and stored in the liver, the formation of stroma is impaired and the remaining cells are larger than normal (increased volume index). With excessive hemolysis or a simple depression of marrow the number of cells and the hemoglobin are decreased, but there is little variation from normal in the volume and hemoglobin content of the red cells (normal volume index 1.0, normal color index 1.0). A significant loss of blood due to ulceration from infection or malignant disease in the small intestine necessarily produces a hypochromic and later a microcytic anemia. This is detected in a study of the blood and tests for blood in the stool. Extensive regional enteritis may produce such a picture. Ulcers in the duodenum, polyps in the small intestine, and bleeding from Meckel's diverticulum are other possible causes for abnormal blood loss. There is little toxic depression of bone marrow in such cases, so there is a pure iron deficiency anemia. Disease of the small intestine may cause severe anemia without blood loss. Pernicious anemia was long considered to result from the toxic action on red cells of some toxic substance absorbed from the intestinal tract. This view is no longer held, since it has been proved that pernicious anemia is a deficiency disease due to defective formation of a specific erythrocyte-maturing factor (E.M.F.) in the stomach. This substance is normally present in the upper intestinal tract From the Department of Medicine, Cleveland Clinic, Cleveland, Ohio.
382
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and is used by the bone marrow for building the stroma of red cells, or it is stored in the liver. If the specific maturing factor is lacking, the resulting anemia is always macrocytic unless the red cells are made smaller by a coincident iron deficiency. ANEMIA DUE TO IMPAIRED ABSORPTION FROM THE SMALL INTESTINE
Macrocytic anemia may result from defective absorption of the specific factor in the small intestine. This seems to explain the macrocytic anemia seen so frequently in sprue. Both the anemia and the diarrhea of sprue are relieved by the use of a potent liver extract or of folic acid, which may be the active hematopoietic principle (E.M.F.). In other conditions involving the small intestine, macrocytic anemia may also develop. With a benign obstruction of the lower small intestine a severe chronic macrocytic anemia indistinguishable from pernicious anemia may result. Regional ileitis with consequent scarring over a wide area may cause a similar anemia. This is especially likely to develop if some short-circuiting operation has been carried out. The fundamental defect so far as the anemia is concerned seems to be impaired absorption. The specific principle (E.M.F.) is formed, since free hydrochloric acid is present in the stomach. In pernicious anemia, where the specific principle is not formed, free hydrochloric acid is always absent. The following two cases illustrate the development of macrocytic anemia due to impaired absorption of the specific principle from the small intestine. CASE I. Macrocytic AneD1ia Due to Obstruction of the JejunuD1.-A housewife, aged 51, had had a hysterectomy, a laparotomy for a suspected ovarian tumor, and another operation for an acute intestinal obstruction. Nine years later she developed a resistant macrocytic anemia. Numbness and tingling of the hands and feet appeared, associated with generalized weakness. Physical examination revealed only impaired vibratory sense. Tests of liver function were normal. The red cell count was 2,910,000, hemoglobin 68 per cent (10.5 gm.), hematocrit reading 34 cc. per 100 cc. of blood (76 per cent of normal), volume index 1.3, color index 1.17, and the white cell count 5700. Repeated test meals demonstrated adequate free hydrochloric acid (free 47, total 48). Sternal puncture revealed a megaloblastic marrow. X-ray examination of the gastrointestinal tract disclosed an obstruction in the small bowel, with a lumen of about 0.5 cm., evidently due to adhesions. Adequate parenteral liver therapy has maintained the blood count at normal leveJs. The neurologic lesion, though greatly benefited, has never completely cleared after treatment for several years.
Comment.-Impaired absorption of the erythrocyte-maturing factor (KM.F.) produced a macrocytic anemia and neurologic changes, which have responded satisfactorily to liver extract therapy. The finding of free hydrochloric acid excluded pernicious anemia.
384
RUSSELL L. HADEN, DONALD BORTZ
CASE 11. Macrocytic Anemia Due to Impaired Absorption.-A man, aged 51, had had several extensive resections of the terminal ileum with anastomoses because of regional ileitis. Subsequently, abdominal distress had reappeared, associated with numbness and tingling of the hands. Vibratory sense remained intact. The general physical examination remained negative. X-ray examination showed a large area of obstruction secondary to the scarring of regional ileitis. The red cell count was 3,830,000, hematocrit reading 42 cc. per 100 cc. (93 per cent of normal, 13.5 gm.), volume index 1.21, color index 1.13, hemoglobin 87 per cent, and white cell count 11,600. The mean cell diameter was 8.4 microns. An abundance of free hydrochloric acid was present (free 21, total 39). Parenteral liver therapy was started with a subsidence of symptoms and return of the volume index to 0.96. On discontinuing liver extract injections a macrocytosis again developed. With folic acid alone numbness and tingling again appeared. The patient has remained symptom-free on continuous liver therapy.
Comment.-Lack of erythrocyte-maturing factor due to prolonged diarrhea and decreased absorption precipitated macrocytic anemia and early neurologic lesions, both of which have remained controlled with adequate liver therapy for several years. ANEMIA IN CHRONIC ULCERATIVE COLITIS
Anemia is an almost constant accompaniment of chronic nonspecific ulcerative colitis, and the reduction in red cells and hemoglobin may be extreme. Relief of the anemia is a most important part of the treatment. A large part of the colon may be involved after the disease is well established. As the stools contain blood in varying amounts, the iron loss is considerable. With the chronic hemorrhage and consequent iron loss the hemoglobin is lowered out of proportion to the decrease in red cells. The anemia is hypochromic, and as the disease progresses the cells become small as well as deficient in hemoglobin, as shown by the low volume index. The characteristic blood picture, then, in chronic nonspecific ulcerative colitis is a hypochromic anemia which may also be microcytic. The rapid passage of food materials through the intestinal tract in colitis interferes with absorption of all building materials, including the specific erythrocyte-maturing factor. A deficiency of this factor alone leads to a macrocytic anemia. If both iron and the specific principle are lacking the macrocytosis of iron deficiency is balanced by the macrocytosis of an erythrocyte-maturing factor-deficiency, so the cells are normal in size, even with a marked deficiency. CASE Ill. Hypochromic and Microcytic Anemia Due to Chronic Ulcerative Colitis.-A woman, a pottery worker, had had severe diarrhea for eighteen months. She had passed some noticeable blood and had lost 87 pounds in weight. The only positive findings on the general physical examination were the evident anemia and impaired nutrition. The test meal showed a normal acidity. Roentgenograms of the colon and proctoscopic examination showed the typical findings of chronic ulcerative colitis. The blood study revealed red blood cells 4,980,000, hematocrit reading 33 cc. per 100 cc. of blood (73 per cent), hemoglobin 8.9 gm. per 100 cc. (58 per cent), volume index 0.73, and color index 0.58. The white cells were normal.
ANEMIA IN DISEASES OF THE INTESTINAL TRACT
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The ulcerative colitis responded well to treatment, and as the condition improved the blood returned to normal. Ferrous sulfate was given in addition to treatment for the inflammatory process. The last blood count showed 4,670,000 red cells and 12.9 gm. (84 per cent) hemoglobin.
Comment.- This patient had a typical anemia of the iron deficiency type, as indicated by the low volume and color indices. The diarrhea, the infection, and the blood loss all played a part in the development of the anemia. It is possible that a deficiency of vitamins, especially of Band C, may play a part in the anemia. The toxemia incident to the severe infection causing the colitis may also depress the normal development and delivery of red cells from the marrow. It is apparent that any type of anemia, hypochromic and microcytic, may be found in chronic ulcerative colitis, but by far the most common type is the hypochromic and microcytic anemia due to chronic blood loss and a consequent deficiency of iron. TREATMENT OF ANEMIA DUE TO DISEASE OF THE SMALL INTESTINE
Before treating an anemia due to disease of the small intestine it is most important to determine the type present by complete laboratory study. If the anemia is hypochromic and microcytic, iron is indicated; if macrocytic, liver or liver substitutes are needed. If the anemia is due to toxic depression of marrow, transfusion is needed. Iron should be given in the ferrous form. I have long used a pill containing ferrous sulfate and sodium bicarbonate, which is much like the original mixture of Blaud. When absorption of iron is interfered with by an active inflammation or from some other reason, iron may be given intravenously. Iron cacodylate, 0.65 gm. (1 grain), is well tolerated. Iron may also be given in liquid form in the following prescription (Witts 2 ): Ferrous chloride ............................ 6 gm. (90 grains) Simple syrup ................................... 30 cc. ( 1 oz.) Water ..........................•...... q.s. ad 120 cc. (4 oz. )
This is taken in teaspoonful doses containing 0.2 gm. (3 grains) of ferrous chloride after meals. The syrup is added to prevent oxidation of the ferrous iron. If absorption is adequate, anemia due to iron loss may be quickly compensated by administration of iron in adequate dos~s.
If the anemia is macrocytic, as illustrated in Cases I and II, liver or a liver substitute is indicated. Folic acid seems to be of benefit in sprue. Here there is seldom if ever any neurologic involvement, therefore the folic acid is a satisfactory substitute for liver. In pernicious anemia folic acid does not protect against a nerve lesion so should never be depended upon for treatment.
386
RUSSELL L. HADEN, DONALD BORTZ
ANEMIA IN MALIGNANT DISEASE OF THE COLON
Cancer of the colon nearly always causes ulceration, which may result in sufficient mechanical loss of blood to produce anemia. Such an anemia is hypochromic and microcytic if the hemorrhage is prolonged or significant. A loss of blood, however, is not the principal cause for the anemia. It is unusual to have a marked anemia in cancer of the transverse or descending colon or rectum. On the other hand, cancer of the cecum and ascending colon almost always causes severe hypochromic and microcytic anemia all out of proportion to the blood loss. With an equal amount of blood in the stools and a carcinoma equally large, the lesion in the cecum will cause an extreme anemia, while the one in the rectum will cause only a minimal degree. In each instance the anemia is typical of an iron deficiency. It is evident that some factor in cancer of the cecum must prevent the utilization of iron by the bone marrow since the severe anemia may oceur with little or no demonstrable loss of iron by hemorrhage. The hypochromic and microcytic anemia is thus due to impaired utilization of iron rather than to loss of supply to the marrow, where the iron is incorporated into the hemoglobin molecule and into the red cell. The contents of the bowel in the cecum and ascending colon are liquid, hence a tumor in this area may beeome quite large before symptoms are produced. This allows a large surface area to develop for the oozing of blood and for toxic absorption. Alvarez, Judd, MacCarty and Zimmerman;{ came to the conclusion that this significant surface area is the most important factor in determining the frequency and severity of anemia in cancer of the cecum and ascending colon. There is evidently, however, some undetermined element operative in this location which is not dependent on the size of the tumor. Other diseases of the cecum, such as amebic colitis, tuberculous and regional enteritis, with changes in the mucosa affording large areas of active absorption, seldom give rise to a significant anomia. While the anemia of cancer located in the cecum and ascending colon is typically hypochromic and microcytic it may occasionally be macrocytic. Butt and Watkins 4 have reported such a case; we have recently observed another. The following case reports illustrate the anemia of cancer of the colon. CASE IV. Hypochromic and Microcytic Anemia Due to Carcinoma of the Cecum.-A man, aged 67, had ex],:erienced progressive dyspnea and fatigue for the past two months. For one month he had noticed some generalized abdominal distress which had not been serious. His appetite was good, and there was no nausea, vomiting, constipation, or blood in the stools. The only significant finding in the physical examination was the evident anemia. No mass could be palpated. A roentgenogram of the colon showed a deformity in the cecum which was interpreted as being due to a malignancy. The blood count on admission showed 3,520,000 red cells and 5.5 gm. (36 per cent) hemoglobin. A complete blood study after the first three transfusions showed
ANEMIA IN DISEASES OF THE INTESTINAL TRACT
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red blood ceIls 4,340,000, hematocrit reading 32 cc. per 100 cc. of blood (71 per cent of normal), hemoglobin 7.8 gm. per 100 cc. (51 per cent of normal), volume index 0.82, and color index 0.59. The white ceIl count was 7750 with a normal differential. The striking finding was the marked reduction in hemoglobin without a parallel decrease in red cells. The anemia was microcytic and hypochromic, as indicated by the low volume index (0.82) and low color index (0.59). At operation a large tumor mass was found in the terminal portion of the cecum without metastasis to adjacent lymph glands or elsewhere. The pathologic sections showed a mucinous adenocarcinoma. Numerous transfusions were given. Convalescence was complicated by localized abscess formation and prostatic obstruction. Recovery was complete. Two years later, signs of metastasis have not developed.
Comment.-The only significant symptoms complained of by the patient were due to the severe microcytic and hypochromic anemia. This finding should always suggest the possibility of cancer in the cecum or ascending colon. Although this anemia is of an iron deficiency type, it does not respond to iron therapy, indicating that it is due to lack of utilization and not to a deficient supply of iron. Transfusion helps temporarily, but the anemia is relieved only by removing the tumor, which, by some poorly understood mechanism, evidently prevents the utilizaton of iron. CASE V. Macrocytic Anemia Due to Cancer of the Cecum.-A woman, aged 58, developed pallor, weakness, and shortness of breath over several months and seemed to feel improved after receiving liver extract. Physical examination, with the exception of pallor and some enlargement of the liver, was negative. Change in bowel habit had not occurred. The red cell count was 2,900,000, hematocrit reading 29 cc. per 100 cc. of cells (64 per cent of normal), hemoglobin 47 per cent (7.3 gm.), volume index 1.10, and color index 0.91. The white ceIl count was 16,800. Sternal puncture showed erythroid hypoplasia. Gastroscopic examination revealed no abnormalities. A gastrointestinal x-ray examination revealed a deformed and contracted cecum. Stool specimens were repeatedly positive for occult blood. The patient failed to respond to parenteral liver therapy, and a laparotomy revealed an inoperable carcinoma of the cecum. The macrocytosis continued to persist in spite of large doses of liver extract.
It is most probable that the macrocytosis in this case is due to impaired utilization of the specific maturing principle in the bone marrow. SUMMARY
Anemia is a common accompaniment of diseases of the intestinal tract. Proper treatment depends on a careful laboratory study. The anemia of sprue and impaired absorption from the small intestine due to chronic obstruction or the end results of extensive regional enteritis is often macrocytic and responds to liver therapy. If the anemia in disease of the small intestine is due to bJood loss it is hypochromic and microcytic and should respond to adequate iron administration.
388
RUSSELL L. HADEN, DONALD BORTZ
An anemia due to bone marrow depression by toxemia of infection or other factors is usually normocytic and responds only to removal of the cause and transfusion. In true colitis, especially of the nonspecific type, the anemia is due to blood loss, depression of marrow function, and deficient absorption of materials needed for erythrocyte formation. Anemia is uncommon in cancer of the transverse and descending colon and rectum. A severe anemia of the hypochromic and microcytic type is almost constant in cancer of the ascending colon andcecum. While the anemia is of the iron deficiency type, it is not improved by administration of iron. The anemia of cancer in this area is probably due to interference with the utilization of iron rather than to a loss of supply to the marrOw. It disappears with removal of the tumor, although transfusions are a necessary preparation for operation. REFERENCES 1. Haden, R. L.: Technic of Blood Examination. J, Lab. & Clin. Med. 17:843-859 (June) 1932. 2. Witts, J. L.: Therapeutic Action of Iron. Lancet 1:1-5 (Jan. 4) 1936. 3. Alvarez, W. C., Judd, E. S., MacCarty, W. C. and Zimmerman, A. R.: Varying Degrees of Anemia Produced by Carcinoma in Different Parts of Colon. Arch. Surg. 15:402-417 (Sept.) 1927. 4. Butt, H. R. and Watkins, C. H.: Occurrence of Macrocytic Anemia in Association with Lesions of the Bowel. Ann. Int. Med. 10:222-233 (Aug.) 1936.
382
ANEMIA IN DISEASES OF THE INTESTINAL TRAGr
383
and is used by the bone marrow for building the stroma of red cells, or it is stored in the liver. If the specific maturing factor is lacking, the resulting anemia is always macrocytic unless the red cells are made smaller by a coincident iron deficiency. ANEMIA DUE TO IMPAIRED ABSORPTION FROM THE SMALL INTESTINE
Macrocytic anemia may result from defective absorption of the specific factor in the small intestine. This seems to explain the macrocytic anemia seen so frequently in sprue. Both the anemia and the diarrhea of sprue are relieved by the use of a potent liver extract or of folic acid, which may be the active hematopoietic principle (E.M.F.). In other conditions involving the small intestine, macrocytic anemia may also develop. With a benign obstruction of the lower small intestine a severe chronic macrocytic anemia indistinguishable from pernicious anemia may result. Regional ileitis with consequent scarring over a wide area may cause a similar anemia. This is especially likely to develop if some short-circuiting operation has been carried out. The fundamental defect so far as the anemia is concerned seems to be impaired absorption. The specific principle (E.M.F.) is formed, since free hydrochloric acid is present in the stomach. In pernicious anemia, where the specific principle is not formed, free hydrochloric acid is always absent. The following two cases illustrate the development of macrocytic anemia due to impaired absorption of the specific principle from the small intestine. CASE I. Macrocytic AneD1ia Due to Obstruction of the JejunuD1.-A housewife, aged 51, had had a hysterectomy, a laparotomy for a suspected ovarian tumor, and another operation for an acute intestinal obstruction. Nine years later she developed a resistant macrocytic anemia. Numbness and tingling of the hands and feet appeared, associated with generalized weakness. Physical examination revealed only impaired vibratory sense. Tests of liver function were normal. The red cell count was 2,910,000, hemoglobin 68 per cent (10.5 gm.), hematocrit reading 34 cc. per 100 cc. of blood (76 per cent of normal), volume index 1.3, color index 1.17, and the white cell count 5700. Repeated test meals demonstrated adequate free hydrochloric acid (free 47, total 48). Sternal puncture revealed a megaloblastic marrow. X-ray examination of the gastrointestinal tract disclosed an obstruction in the small bowel, with a lumen of about 0.5 cm., evidently due to adhesions. Adequate parenteral liver therapy has maintained the blood count at normal leveJs. The neurologic lesion, though greatly benefited, has never completely cleared after treatment for several years.
Comment.-Impaired absorption of the erythrocyte-maturing factor (KM.F.) produced a macrocytic anemia and neurologic changes, which have responded satisfactorily to liver extract therapy. The finding of free hydrochloric acid excluded pernicious anemia.
384
RUSSELL L. HADEN, DONALD BORTZ
CASE 11. Macrocytic Anemia Due to Impaired Absorption.-A man, aged 51, had had several extensive resections of the terminal ileum with anastomoses because of regional ileitis. Subsequently, abdominal distress had reappeared, associated with numbness and tingling of the hands. Vibratory sense remained intact. The general physical examination remained negative. X-ray examination showed a large area of obstruction secondary to the scarring of regional ileitis. The red cell count was 3,830,000, hematocrit reading 42 cc. per 100 cc. (93 per cent of normal, 13.5 gm.), volume index 1.21, color index 1.13, hemoglobin 87 per cent, and white cell count 11,600. The mean cell diameter was 8.4 microns. An abundance of free hydrochloric acid was present (free 21, total 39). Parenteral liver therapy was started with a subsidence of symptoms and return of the volume index to 0.96. On discontinuing liver extract injections a macrocytosis again developed. With folic acid alone numbness and tingling again appeared. The patient has remained symptom-free on continuous liver therapy.
Comment.-Lack of erythrocyte-maturing factor due to prolonged diarrhea and decreased absorption precipitated macrocytic anemia and early neurologic lesions, both of which have remained controlled with adequate liver therapy for several years. ANEMIA IN CHRONIC ULCERATIVE COLITIS
Anemia is an almost constant accompaniment of chronic nonspecific ulcerative colitis, and the reduction in red cells and hemoglobin may be extreme. Relief of the anemia is a most important part of the treatment. A large part of the colon may be involved after the disease is well established. As the stools contain blood in varying amounts, the iron loss is considerable. With the chronic hemorrhage and consequent iron loss the hemoglobin is lowered out of proportion to the decrease in red cells. The anemia is hypochromic, and as the disease progresses the cells become small as well as deficient in hemoglobin, as shown by the low volume index. The characteristic blood picture, then, in chronic nonspecific ulcerative colitis is a hypochromic anemia which may also be microcytic. The rapid passage of food materials through the intestinal tract in colitis interferes with absorption of all building materials, including the specific erythrocyte-maturing factor. A deficiency of this factor alone leads to a macrocytic anemia. If both iron and the specific principle are lacking the macrocytosis of iron deficiency is balanced by the macrocytosis of an erythrocyte-maturing factor-deficiency, so the cells are normal in size, even with a marked deficiency. CASE Ill. Hypochromic and Microcytic Anemia Due to Chronic Ulcerative Colitis.-A woman, a pottery worker, had had severe diarrhea for eighteen months. She had passed some noticeable blood and had lost 87 pounds in weight. The only positive findings on the general physical examination were the evident anemia and impaired nutrition. The test meal showed a normal acidity. Roentgenograms of the colon and proctoscopic examination showed the typical findings of chronic ulcerative colitis. The blood study revealed red blood cells 4,980,000, hematocrit reading 33 cc. per 100 cc. of blood (73 per cent), hemoglobin 8.9 gm. per 100 cc. (58 per cent), volume index 0.73, and color index 0.58. The white cells were normal.
ANEMIA IN DISEASES OF THE INTESTINAL TRACT
385
The ulcerative colitis responded well to treatment, and as the condition improved the blood returned to normal. Ferrous sulfate was given in addition to treatment for the inflammatory process. The last blood count showed 4,670,000 red cells and 12.9 gm. (84 per cent) hemoglobin.
Comment.- This patient had a typical anemia of the iron deficiency type, as indicated by the low volume and color indices. The diarrhea, the infection, and the blood loss all played a part in the development of the anemia. It is possible that a deficiency of vitamins, especially of Band C, may play a part in the anemia. The toxemia incident to the severe infection causing the colitis may also depress the normal development and delivery of red cells from the marrow. It is apparent that any type of anemia, hypochromic and microcytic, may be found in chronic ulcerative colitis, but by far the most common type is the hypochromic and microcytic anemia due to chronic blood loss and a consequent deficiency of iron. TREATMENT OF ANEMIA DUE TO DISEASE OF THE SMALL INTESTINE
Before treating an anemia due to disease of the small intestine it is most important to determine the type present by complete laboratory study. If the anemia is hypochromic and microcytic, iron is indicated; if macrocytic, liver or liver substitutes are needed. If the anemia is due to toxic depression of marrow, transfusion is needed. Iron should be given in the ferrous form. I have long used a pill containing ferrous sulfate and sodium bicarbonate, which is much like the original mixture of Blaud. When absorption of iron is interfered with by an active inflammation or from some other reason, iron may be given intravenously. Iron cacodylate, 0.65 gm. (1 grain), is well tolerated. Iron may also be given in liquid form in the following prescription (Witts 2 ): Ferrous chloride ............................ 6 gm. (90 grains) Simple syrup ................................... 30 cc. ( 1 oz.) Water ..........................•...... q.s. ad 120 cc. (4 oz. )
This is taken in teaspoonful doses containing 0.2 gm. (3 grains) of ferrous chloride after meals. The syrup is added to prevent oxidation of the ferrous iron. If absorption is adequate, anemia due to iron loss may be quickly compensated by administration of iron in adequate dos~s.
If the anemia is macrocytic, as illustrated in Cases I and II, liver or a liver substitute is indicated. Folic acid seems to be of benefit in sprue. Here there is seldom if ever any neurologic involvement, therefore the folic acid is a satisfactory substitute for liver. In pernicious anemia folic acid does not protect against a nerve lesion so should never be depended upon for treatment.
386
RUSSELL L. HADEN, DONALD BORTZ
ANEMIA IN MALIGNANT DISEASE OF THE COLON
Cancer of the colon nearly always causes ulceration, which may result in sufficient mechanical loss of blood to produce anemia. Such an anemia is hypochromic and microcytic if the hemorrhage is prolonged or significant. A loss of blood, however, is not the principal cause for the anemia. It is unusual to have a marked anemia in cancer of the transverse or descending colon or rectum. On the other hand, cancer of the cecum and ascending colon almost always causes severe hypochromic and microcytic anemia all out of proportion to the blood loss. With an equal amount of blood in the stools and a carcinoma equally large, the lesion in the cecum will cause an extreme anemia, while the one in the rectum will cause only a minimal degree. In each instance the anemia is typical of an iron deficiency. It is evident that some factor in cancer of the cecum must prevent the utilization of iron by the bone marrow since the severe anemia may oceur with little or no demonstrable loss of iron by hemorrhage. The hypochromic and microcytic anemia is thus due to impaired utilization of iron rather than to loss of supply to the marrow, where the iron is incorporated into the hemoglobin molecule and into the red cell. The contents of the bowel in the cecum and ascending colon are liquid, hence a tumor in this area may beeome quite large before symptoms are produced. This allows a large surface area to develop for the oozing of blood and for toxic absorption. Alvarez, Judd, MacCarty and Zimmerman;{ came to the conclusion that this significant surface area is the most important factor in determining the frequency and severity of anemia in cancer of the cecum and ascending colon. There is evidently, however, some undetermined element operative in this location which is not dependent on the size of the tumor. Other diseases of the cecum, such as amebic colitis, tuberculous and regional enteritis, with changes in the mucosa affording large areas of active absorption, seldom give rise to a significant anomia. While the anemia of cancer located in the cecum and ascending colon is typically hypochromic and microcytic it may occasionally be macrocytic. Butt and Watkins 4 have reported such a case; we have recently observed another. The following case reports illustrate the anemia of cancer of the colon. CASE IV. Hypochromic and Microcytic Anemia Due to Carcinoma of the Cecum.-A man, aged 67, had ex],:erienced progressive dyspnea and fatigue for the past two months. For one month he had noticed some generalized abdominal distress which had not been serious. His appetite was good, and there was no nausea, vomiting, constipation, or blood in the stools. The only significant finding in the physical examination was the evident anemia. No mass could be palpated. A roentgenogram of the colon showed a deformity in the cecum which was interpreted as being due to a malignancy. The blood count on admission showed 3,520,000 red cells and 5.5 gm. (36 per cent) hemoglobin. A complete blood study after the first three transfusions showed
ANEMIA IN DISEASES OF THE INTESTINAL TRACT
387
red blood ceIls 4,340,000, hematocrit reading 32 cc. per 100 cc. of blood (71 per cent of normal), hemoglobin 7.8 gm. per 100 cc. (51 per cent of normal), volume index 0.82, and color index 0.59. The white ceIl count was 7750 with a normal differential. The striking finding was the marked reduction in hemoglobin without a parallel decrease in red cells. The anemia was microcytic and hypochromic, as indicated by the low volume index (0.82) and low color index (0.59). At operation a large tumor mass was found in the terminal portion of the cecum without metastasis to adjacent lymph glands or elsewhere. The pathologic sections showed a mucinous adenocarcinoma. Numerous transfusions were given. Convalescence was complicated by localized abscess formation and prostatic obstruction. Recovery was complete. Two years later, signs of metastasis have not developed.
Comment.-The only significant symptoms complained of by the patient were due to the severe microcytic and hypochromic anemia. This finding should always suggest the possibility of cancer in the cecum or ascending colon. Although this anemia is of an iron deficiency type, it does not respond to iron therapy, indicating that it is due to lack of utilization and not to a deficient supply of iron. Transfusion helps temporarily, but the anemia is relieved only by removing the tumor, which, by some poorly understood mechanism, evidently prevents the utilizaton of iron. CASE V. Macrocytic Anemia Due to Cancer of the Cecum.-A woman, aged 58, developed pallor, weakness, and shortness of breath over several months and seemed to feel improved after receiving liver extract. Physical examination, with the exception of pallor and some enlargement of the liver, was negative. Change in bowel habit had not occurred. The red cell count was 2,900,000, hematocrit reading 29 cc. per 100 cc. of cells (64 per cent of normal), hemoglobin 47 per cent (7.3 gm.), volume index 1.10, and color index 0.91. The white ceIl count was 16,800. Sternal puncture showed erythroid hypoplasia. Gastroscopic examination revealed no abnormalities. A gastrointestinal x-ray examination revealed a deformed and contracted cecum. Stool specimens were repeatedly positive for occult blood. The patient failed to respond to parenteral liver therapy, and a laparotomy revealed an inoperable carcinoma of the cecum. The macrocytosis continued to persist in spite of large doses of liver extract.
It is most probable that the macrocytosis in this case is due to impaired utilization of the specific maturing principle in the bone marrow. SUMMARY
Anemia is a common accompaniment of diseases of the intestinal tract. Proper treatment depends on a careful laboratory study. The anemia of sprue and impaired absorption from the small intestine due to chronic obstruction or the end results of extensive regional enteritis is often macrocytic and responds to liver therapy. If the anemia in disease of the small intestine is due to bJood loss it is hypochromic and microcytic and should respond to adequate iron administration.
388
RUSSELL L. HADEN, DONALD BORTZ
An anemia due to bone marrow depression by toxemia of infection or other factors is usually normocytic and responds only to removal of the cause and transfusion. In true colitis, especially of the nonspecific type, the anemia is due to blood loss, depression of marrow function, and deficient absorption of materials needed for erythrocyte formation. Anemia is uncommon in cancer of the transverse and descending colon and rectum. A severe anemia of the hypochromic and microcytic type is almost constant in cancer of the ascending colon andcecum. While the anemia is of the iron deficiency type, it is not improved by administration of iron. The anemia of cancer in this area is probably due to interference with the utilization of iron rather than to a loss of supply to the marrOw. It disappears with removal of the tumor, although transfusions are a necessary preparation for operation. REFERENCES 1. Haden, R. L.: Technic of Blood Examination. J, Lab. & Clin. Med. 17:843-859 (June) 1932. 2. Witts, J. L.: Therapeutic Action of Iron. Lancet 1:1-5 (Jan. 4) 1936. 3. Alvarez, W. C., Judd, E. S., MacCarty, W. C. and Zimmerman, A. R.: Varying Degrees of Anemia Produced by Carcinoma in Different Parts of Colon. Arch. Surg. 15:402-417 (Sept.) 1927. 4. Butt, H. R. and Watkins, C. H.: Occurrence of Macrocytic Anemia in Association with Lesions of the Bowel. Ann. Int. Med. 10:222-233 (Aug.) 1936.