American Journal of Hematology 3: 199-208 (1977)
I Autoimmune Hemolytic Anemia Associated With Ulcerative Colitis George G. Shashaty, Charles E. Rath, and E. James Britt Division of Hematology, Department of Medicine, Georgetown University School of Medicine, Washington, D.C.
Three patients are reported in whom autoimmune hemolytic anemia developed during the course of ulcerative colitis. A review of the literature yielded 11 additional cases, and the clinical, immunologic, and therapeutic characteristics are summarized. The results of steroid therapy and splenectomy are similar to those for idiopathic autoimmune hemolytic anemia. The cause and effect relationship between these two diseases is not clear, but colectomy appears to produce remission in hemolysis when the latter is refractory to both steroids and splenectomy. Key words: hemolytic anemia, ulcerative colitis, positive Coombs test, autoimmune hemolysis
INTRODUCTION
The association of a positive direct Coombs test with ulcerative colitis was first noted by Lorber et al in 1955 [1]. In that report, and in several others describing a similar relationship, anemia was either not present or was due to gastrointestinal blood loss or other factors related to ulcerative colitis, so that convincing evidence for autoimmune hemolytic anemia (AIHA) in ulcerative colitis (UC) has been presented only rarely. The purpose of this report is to describe three patients who had Significant hemolysis in association with a positive direct Coombs test during the course of ulcerative colitis. The literature has been reviewed to evaluate the clinical characteristics and appropriate management of such patients. CASE REPORTS
Case 1 (Figure 1) A 34-year-old white married male was in good health until he began to experience episodic diarrhea. At age 36 a rectal biopsy was performed and was consistent with the diagnosis of ulcerative colitis. At age 39, sigmoidoscopy revealed ulcerative proctitis, but Received for publication April 19, 1977; accepted October 17, 1977 Dr. Britt is now at the Division of Lung Diseases, National Heart and Lung Institute, National Institutes of Health, Bethesda, Maryland. Address reprint requests to George G. Shashaty, M.D., Georgetown University Hospital, 3800 Reservoir Road, N.W., Washington, D.C. 20007.
199
© 1977 Alan R. Liss, Inc., 150 Fifth Avenue, New York, NY 10011
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Shashaty, Rath, and Britt
a barium enema was normal. The hematocrit was 43 vol %. The diarrhea was treated with Lomotil®. Repeat hematocrits during the next year showed a progressive fall to 33 vol %, although the patient had no evidence of rectal bleeding. He was admitted to Georgetown University Hospital in December 1970 at age 41 because of weakness of three weeks' duration. The physical examination was normal except for the presence of slight icterus. Laboratory evaluation showed a hematocrit of 21 vol %, a reticulocyte count of 44%, a white blood cell count of 13,200 with a slight left shift, and 3 nucleated red cells per 100 white blood cells. The bilirubin was 0.3 mg direct, 2.2 mg indirect. The direct Coombs test was 4+. The antibody was an immunoglobulin G and no complement was present on the red cells. His red cells were 0 Rho (D) positive and the probable genotype was R'r(CDe/cde). The indirect Coombs test, as well as studies of the red cell eluate, showed a negative reaction with Rhuull cells and 0 negative e negative cells, and panel testing suggested a specificity against CD and e. Sigmoidoscopy revealed a diffusely granular mucosa and a rectal biopsy showed changes consistent with ulcerative colitis, including crypt abscesses and chronic inflammatory cells in the lamina propria. A bone marrow examination showed erythroid hyperplasia with adequate iron stores. The diagnoses were autoimmune hemolytic anemia and ulcerative colitis. Prednisone, 60 mg orally per day was administered, but because of an inadequate response this dosage was increased to 150 mg/day. The hematocrit gradually rose to 40% and the reticulocyte count fell to 3%. The Coombs test remained strongly positive. Six months later, the patient experienced recurrent fatigability associated with a fall in hematocrit and a rise in reticulocyte count. Despite an increase in prednisone dosage to 120 mg daily and the addition of 6-mercaptopurine, 100 mg daily, the hematocrit continued to fall and a splenectomy was performed. The spleen weight was 240 gm. Pathologic examination revealed increased endothelial cells in the sinusoids, packing of the Dillroth cords with red cells, and hemosiderosis, all consistent with a hemolytic process. A liver biopsy was not performed. The hematocrit rose to normal. Four years after splenectomy the hematocrit was 42 vol % and the reticulocyte count 2%. The Coombs test remained strongly positive. The activity of the patient's ulcerative colitis was manifested by occasional episodes of diarrhea, which were well controlled with salicylazosu1fapyridine (Azulfidine®). Case 2 (Figure 2)
This 12-year-old white male was well until May 1961, when he was admitted to Georgetown University Hospital complaining of paleness and fatigue of three weeks' duration. A history of one brief episode of rectal bleeding in the month before admission was obtained. Physical examination revealed icterus and hepatosplenomegaly. The hematocrit was 26 vol % and the reticulocyte count 7.8%. The white blood cell count was 7,700 with a normal differential except for 2 nucleated red blood cells per 100 white blood cells. The bone marrow showed erythroid hyperplasia with adequate iron stores. Multiple stool guaiacs were negative. The direct Coombs test was 4+ and the antibody eluted from the red blood cells reacted with all panel cells. No testing with Rh null cells was performed. The bilirubin was 1.7 mg direct, 1.1 mg indirect. A liver biopsy revealed mild, chronic hepatitis. Sigmoidoscopy, rectal biopsy, upper gastrointestinal (GI) series and barium enema were normal. A diagnosis of autoimmune hemolytic anemia and hepatitis was made. The patient was treated with prednisone 30 mg/day orally, with a rise in hematocrit to 39 vol %, but reticulocytosis of 8-9% persisted. Seven months after he was first seen, he experJenced the onset of bloody diarrhea. Sigmoidoscopy and rectal biopsy were con-
A I HA and Ulcerative Colitis
201
1601
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50
•
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Hematocrit. Ret,culoc)tes t!
I Autoimmune Hemolytic Anemia Associated With Ulcerative Colitis George G. Shashaty, Charles E. Rath, and E. James Britt Division of Hematology, Department of Medicine, Georgetown University School of Medicine, Washington, D.C.
Three patients are reported in whom autoimmune hemolytic anemia developed during the course of ulcerative colitis. A review of the literature yielded 11 additional cases, and the clinical, immunologic, and therapeutic characteristics are summarized. The results of steroid therapy and splenectomy are similar to those for idiopathic autoimmune hemolytic anemia. The cause and effect relationship between these two diseases is not clear, but colectomy appears to produce remission in hemolysis when the latter is refractory to both steroids and splenectomy. Key words: hemolytic anemia, ulcerative colitis, positive Coombs test, autoimmune hemolysis
INTRODUCTION
The association of a positive direct Coombs test with ulcerative colitis was first noted by Lorber et al in 1955 [1]. In that report, and in several others describing a similar relationship, anemia was either not present or was due to gastrointestinal blood loss or other factors related to ulcerative colitis, so that convincing evidence for autoimmune hemolytic anemia (AIHA) in ulcerative colitis (UC) has been presented only rarely. The purpose of this report is to describe three patients who had Significant hemolysis in association with a positive direct Coombs test during the course of ulcerative colitis. The literature has been reviewed to evaluate the clinical characteristics and appropriate management of such patients. CASE REPORTS
Case 1 (Figure 1) A 34-year-old white married male was in good health until he began to experience episodic diarrhea. At age 36 a rectal biopsy was performed and was consistent with the diagnosis of ulcerative colitis. At age 39, sigmoidoscopy revealed ulcerative proctitis, but Received for publication April 19, 1977; accepted October 17, 1977 Dr. Britt is now at the Division of Lung Diseases, National Heart and Lung Institute, National Institutes of Health, Bethesda, Maryland. Address reprint requests to George G. Shashaty, M.D., Georgetown University Hospital, 3800 Reservoir Road, N.W., Washington, D.C. 20007.
199
© 1977 Alan R. Liss, Inc., 150 Fifth Avenue, New York, NY 10011
200
Shashaty, Rath, and Britt
a barium enema was normal. The hematocrit was 43 vol %. The diarrhea was treated with Lomotil®. Repeat hematocrits during the next year showed a progressive fall to 33 vol %, although the patient had no evidence of rectal bleeding. He was admitted to Georgetown University Hospital in December 1970 at age 41 because of weakness of three weeks' duration. The physical examination was normal except for the presence of slight icterus. Laboratory evaluation showed a hematocrit of 21 vol %, a reticulocyte count of 44%, a white blood cell count of 13,200 with a slight left shift, and 3 nucleated red cells per 100 white blood cells. The bilirubin was 0.3 mg direct, 2.2 mg indirect. The direct Coombs test was 4+. The antibody was an immunoglobulin G and no complement was present on the red cells. His red cells were 0 Rho (D) positive and the probable genotype was R'r(CDe/cde). The indirect Coombs test, as well as studies of the red cell eluate, showed a negative reaction with Rhuull cells and 0 negative e negative cells, and panel testing suggested a specificity against CD and e. Sigmoidoscopy revealed a diffusely granular mucosa and a rectal biopsy showed changes consistent with ulcerative colitis, including crypt abscesses and chronic inflammatory cells in the lamina propria. A bone marrow examination showed erythroid hyperplasia with adequate iron stores. The diagnoses were autoimmune hemolytic anemia and ulcerative colitis. Prednisone, 60 mg orally per day was administered, but because of an inadequate response this dosage was increased to 150 mg/day. The hematocrit gradually rose to 40% and the reticulocyte count fell to 3%. The Coombs test remained strongly positive. Six months later, the patient experienced recurrent fatigability associated with a fall in hematocrit and a rise in reticulocyte count. Despite an increase in prednisone dosage to 120 mg daily and the addition of 6-mercaptopurine, 100 mg daily, the hematocrit continued to fall and a splenectomy was performed. The spleen weight was 240 gm. Pathologic examination revealed increased endothelial cells in the sinusoids, packing of the Dillroth cords with red cells, and hemosiderosis, all consistent with a hemolytic process. A liver biopsy was not performed. The hematocrit rose to normal. Four years after splenectomy the hematocrit was 42 vol % and the reticulocyte count 2%. The Coombs test remained strongly positive. The activity of the patient's ulcerative colitis was manifested by occasional episodes of diarrhea, which were well controlled with salicylazosu1fapyridine (Azulfidine®). Case 2 (Figure 2)
This 12-year-old white male was well until May 1961, when he was admitted to Georgetown University Hospital complaining of paleness and fatigue of three weeks' duration. A history of one brief episode of rectal bleeding in the month before admission was obtained. Physical examination revealed icterus and hepatosplenomegaly. The hematocrit was 26 vol % and the reticulocyte count 7.8%. The white blood cell count was 7,700 with a normal differential except for 2 nucleated red blood cells per 100 white blood cells. The bone marrow showed erythroid hyperplasia with adequate iron stores. Multiple stool guaiacs were negative. The direct Coombs test was 4+ and the antibody eluted from the red blood cells reacted with all panel cells. No testing with Rh null cells was performed. The bilirubin was 1.7 mg direct, 1.1 mg indirect. A liver biopsy revealed mild, chronic hepatitis. Sigmoidoscopy, rectal biopsy, upper gastrointestinal (GI) series and barium enema were normal. A diagnosis of autoimmune hemolytic anemia and hepatitis was made. The patient was treated with prednisone 30 mg/day orally, with a rise in hematocrit to 39 vol %, but reticulocytosis of 8-9% persisted. Seven months after he was first seen, he experJenced the onset of bloody diarrhea. Sigmoidoscopy and rectal biopsy were con-
A I HA and Ulcerative Colitis
201
1601
tJ \
50
•
lPV
)0.
Hematocrit. Ret,culoc)tes t!
