CHRONIC ACTIVE HEPATITIS ASSOCIATED WITH EOSINOPHILIA AND COOMBS'-POSITIVE HEMOLYTIC ANEMIA

GASTROENTEROLOGY 64: 1015-1019, 1973 Copyright 1973 by The Williams & Wilkins Co. Vol. 64, No.5 Printed in U.S.A. CASE REPORTS CHRONIC ACTIVE HEPATITIS ASSOCIATED WITH EOSINOPHILIA AND COOMBS'-POSITIVE HEMOLYTIC ANEMIA RICHARD S. PANUSH, M.D., LEE S. WILKINSON, M.D., AND RONALD R. FAGIN, M.D. Department of Internal Medicine, Silas B. Hays Hospital, Fort Ord, California Chronic active hepatitis, a disease of unknown etiology characterized by many serological abnormalities, may be "autoimmune" in nature. A patient with the unusual association of chronic active hepatitis, eosinophilia, and Coombs' -positive hemolytic anemia is reported. Since autoimmune hemolysis and eosinophilia are also thought to present abnormal immune responses, this clinical observation supports the possibility that chronic active hepatitis, at least in part, reflects abnormal immunological events. Chronic active hepatitis (CAH) is a clinicopathological syndrome characterized by continuous or episodic acute hepatic inflammation superimposed on changes of chronic liver disease. 1-7 Although the etiology is unknown, there has been considerable speculation as to the "autoimmune" nature of CAH.8-11 This concept has been based largely on its association with many immunological and serologic\il abnormalities. 10-12 This communication reports a patient with the unusual association of CAH, eosinophilia, and autoimmune hemolytic anemia. Since all three of these processes are thought to have an immune basis,13-16 this clinical example provides additional evidence that immunological mechanisms may be important in the pathogenesis and perpetuation of CAH. Case Report J. M. (01116265163), a 14-year-old boy, was in excellent health until October, 1971. He then Received August 8, 1972. Accepted January 16, 1973. Address requests for reprints to: Dr. Richard S. Panush, Department of Medicine, University of Florida College of Medicine, Gainesville, Florida 32601. 1015 developed insidious onset of malaise, intermittent fevers, and headaches. There were no rash, arthralgias, weight loss, jaundice, neurological symptoms, or other gastrointestinal or systemic complaints. Except for a trip to Mexico during the previous year, the patient had resided in California. He denied the use of oxyphenisatin or other medications. There was no known family history of hepatic disease. The initial physical examination disclosed an oral temperature of 100 F, pallor, minimal scleral icterus, and right upper quadrant tenderness with a smooth liver edge palpable at the right costal margin. Routine laboratory studies initially revealed hemoglobin 8.1 to 10.6 g per 100 ml, hematocrit 23 to 32%, reticulocyte count 1 to 11%, white blood cell count 15,200 to 20,100 cells per mm 3, with a differential count of 2 to 12% bands, 30 to 60% polys, 15 to 56% lymphocytes, and 9 to 37% eosinophils. Serum glutamic oxaloacetic transaminase ranged from 430 to 700 mu per ml, serum glutamic pyruvate transaminase 360 to 1,560 mu per ml, lactate dehydrogenase 280 to 363 m U per ml, alkaline phosphatase 180 to 300 mu per ml, total bilirubin 2.3 to 3.0 mg per 100 ml, cholesterol 140 to 185 mg per 100 ml, total serum protein 8.2 g per 100 ml, albumin 3.8 g per 100 ml, globulin 4.4 g per 100 ml, and 'Y-globulin 2.2 g per 100 ml. Serum calcium, phosphorus, fasting blood sugar, blood urea nitrogen, prothrombin time, partial thromboplastin time, erythrocyte sedimenta-

1016 CASE REPORTS Vol. 64, No.5 FIG. 1. A, percutaneous liver biopsy from patient J. M. demonstrating "aggressive" inflammatory portal infiltrate (hematoxylin and eosin, x 85). B, higher magnification of the same portal area showing lymphocytic infiltration, piecemeal necrosis, and destruction of the limiting plate (hematoxylin and eosin, x 275).

May 1973 CASE REPORTS 1017 tion rate, bleeding time, clotting time, electrolytes, stool guaiacs, urinalysis, electrocardiogram, chest X-ray, Australia antigen, monospot test, Venereal Disease Research Laboratories test, latex fixation test for rhematoid factors, lupus erythematosus cell test, numerous examinations of stool for ova and parasites, and hemagglutinating antibody test for amoebiasis were all normal or negative. Skin tests to mumps, intermediate strength purified protein derivative, coccidiodin, and histoplasmin antigens were all negative. Serum iron was 201 ~g per 100 ml and iron-binding capacity was 420 ~g per 100 ml. Cultures of the urine, throat, blood, and stool were negative. Additional studies included positive tests for antinuclear antibodies with a peripheral staining pattern and a serum B1C/B1A level of 160 mg per 100 ml (normal). Serum IgG was 2300 mg per 100 ml, IgA 66 mg per 100 ml, and IgM 205 mg per 100 ml. Smooth muscle antibodies were detected, but mitochondrial antibodies were absent from the serum. Serum ceruloplasmin was normal as was a careful opthalmological examination by slit lamp. Bone marrow examination showed nonspecific erythroid and myeloid hyperplasia with eosinophilia. Routine direct and indirect antiglobulin tests were strongly (3 to 4+) positive. Further characterization of these antibodies was kindly performed by Dr. Lawrence D. Petz. Direct antiglobulin test with antiserum to IgG was positive to a titer of 1 to 4094. No agglutination occurred, however, with antisera to C3 or C4 (third and fourth components of the complement system). Likewise, the indirect antiglobulin test was strongly positive. Antibody eluted from the patient's red blood cells and antibody in the patient's serum reacted similarly to all panel test cells without clear blood group specificity. Percutaneous liver biopsy revealed changes consistent with CAH (fig. 1, A and B). Immediately after liver biopsy the patient was started on 60 mg of prednisone daily with subsequent clinical and serological improvement. The white blood cell count and peripheral eosinophilia fell to normal values. The initial hemoglobin of 10.6 g per 100 ml fell to a nadir of 8.1 g per 100 ml with a concomitant 1600 1400 SGOT,11'1 U"ilt /ljll) TOTAL 81LIRUBIN 11119% 1 Ol"el,,.d',,el EOSINOPHILS,.., "" HEMATOCRIT I.., 20 PREON ISONE OR EOUIVALENT lillo/dot) 120 100 80 60 40 20 MAR FIG. 2. Graphic illustration of certain serial observations on patient J. M., indicating the initial presentation during November, 1971, with chronic active hepatitis, eosinophilia, and autoimmune hemolytic anemia. The patient had subsequent exacerbations of his liver disease during April and October, 1972.

1018 CASE REPORTS Vol. 64, No.5 reticulocytosis of 4%. After prednisone was begun the hemoglobin rose to 13 g per 100 ml with a peak reticulocyte response of 11.5%. Hemoglobin subsequently remained normal and reticulocyte counts fell to 1%, but red cell antibodies persisted. Similarly the liver function studies returned towards normal and 'Yglobulin level fell to 1.5 g per 100 ml (fig. 2). The remission lasted until April, 1972, with the patient requiring as little as 71/2 mg of prednisone daily. In both April and October, 1972, the disease exacerbated requiring hospitalization and reinstitution of large doses of corticosteroids (fig. 2). Interestingly, neither the overt hemolysis nor significant eosinophilia recurred, suggesting that these abnormalities were more readily and continuously suppressed by small amounts of steroids than was the smoldering hepatic inflammation. Discussion We report a patient with the unusual association of CAH, autoimmune hemolytic anemia, and eosinophilia, and suggest that the simultaneous occurrence of these processes reflects related abnormal immunological events. Our patient had biopsy-confirmed CAH. The clinical and laboratory features of his illness were entirely consistent with this diagnosis. He had a normal opthalmological exam and ceruloplasmin level, negative tests for Australia antigen, and no history of oxyphenisatin or other drug use or abuse. These data excluded Wilson's disease 17 and the chronic hepatitides associated with Australia antigen 18 or laxative ingestion. 19 No underlying cause for the patient's eosinophilia was evident. 20 The reactive bone marrow, lack of evidence for parasitic infection, and absence of other organ system involvement ruled out the possibilities of eosinophilic leukemia,21 diffuse eosinophilic collagen disease,22 or parasitic infestation. The combination of anemia, reticulocytosis, positive Coombs' tests, and response to steroids were interpreted as most compatible with mild to moderate autoimmune hemolysis. Many immunological abnormalities have been noted among patients with CAH. These have included hypergammaglobulinemia, positive lupus erythematosus cell tests, antinuclear antibodies, anti-i'-globulins, smooth muscle antibodies, and antibodies to thyroid constituents, gastric mucosal cells, epithelial cells, renal tubular cells, and hepatic parenchymal cells. I - 12 Also described have been autoimmune neutropenia, 23 changes of lupus nephritis, 2, 24, 25 positive Coombs' tests, and, rarely, eosinophilia. Series of patients with CAH have not consistently recorded Coombs' testing despite the frequency of anemia among these patients. Sporadically, individuals were reported to be Coombs' -positive by several authors, 4, 6, 8. 19 but the highest incidence noted, by Mackay et al.,8 was 12% of patients. It was not clear if any of these patients also had peripheral blood eosinophilia. Eosinophilia has been uncommon in most series of patients with CAH. In their series, Mackay and Wood 4 stated "eosinophilia was not a feature, the average count being 252 (range 50 to 910) per mm 3, and only 2 patients having counts over 500 per mm 3." Patients with CAH with 7%, 24 9%,25 and 15%26 eosinophils in the differential count and with bone marrow eosinophilia 2 have been observed. In a review of 33 patients (Willocx and Isselbacher3 noted 0 to 48% eosinophils in the peripheral blood of patients with CAH. They found that 17 out of 33 (51%) patients had greater than 4% eosinophils and 3 out of 33 (9%) had greater than 10% eosinophilia at some time in their course. None of these patients had positive Coombs' tests. Our patient is unusual in that he had CAH with autoimmune hemolytic anemia and eosinophilia. Upon original presentation the diganosis of CAH was initially obscured by the presence of the striking anemia and eosinophilia. This observation adds CAH to other conditions which have been associated with these hematological abnormalities. Further, both eosinophilia and autoimmune hemolysis are thought to represent immunological events. CAH, as noted, may also be an autoimmune disorder. The occurrence of these three processes together in the patient reported

May 1973 CASE REPORTS 1019 suggests that they may represent, in part, related abnormal host-immune responses. REFERENCES 1. Beam AG, Kunkel HG, Slater RJ: The problem of chronic liver disease in young women. Am J Med 21:3-15, 1956 2. Mackay IR, Taft LI, Cowling DC: Lupoid hepatitis. Lancet ii: 1323-1326, 1956 3. Willocx RG, Isselbacher KJ: Chronic liver disease in young people. Clinical features and course in thirty-three patients. Am J Med 30:185-195, 1961 4. Mackay IR, Wood IJ: Lupoid hepatitis: a comparison of 22 cases with other types of chronic liver disease. Q J Med 31:485-507, 1962 5. Reynolds TB, Edmondson HA, Peters RL, et al: Lupoid hepatitis. Ann Intern Med 61:650-666, 1964 6. Maclachlan MJ, Rodnan GP, Cooper WM, et al: Chronic active ("lupoid") hepatitis. Ann Intern Med 62:425-462, 1965 7. Mistilis SP, Blackburn CRB: Active chronic hepatitis. Am J Med 48:484-495, 1970 8. Mackay IR, Weiden S, Hasker J: Autoimmune hepatitis. Ann NY Acad Sci 124:767-780, 1965 9. Popper H, Paronetto F, Schaffner F: Immune processes in the pathogenesis of liver disease. Ann NY Acad Sci 124:781-799, 1965 10. Mackay IR: Lupoid hepatitis and primary biliary cirrhosis.: autoimmune disease of the liver? Bull Rheum Dis 18:487-494, 1968 11. Doniach D, Walker JG, Roitt 1M, et al: "Autoallergic" hepatitis. N Engl J Med 282:86-88, 1970 12. Sherlock S: The immunology ofliver disease. Am J Med 49:693-706, 1970 13. Basten A, Boyer MH, Beeson PB: Mechanism of eosinophilia. I. Factors affecting the eosinophil response of rats to Trichinella spiralis. J Exp Med 131:1271-1287, 1970 14. Basten A, Beeson PB: Mechanism of eosinophilia. II. Role of the lymphocyte. J Exp Med 131: 1288-1305, 1970 15. Cohen S, Ward PA: In vitro and in vivo activity of a lymphocyte and immune complex-dependent chemotactic factor for eosinophils. J Exp Med 133:133-146, 1971 16. Panush RS, Franco AE, Schur PH: Rheumatoid arthritis associated with eosinophilia. Ann Intern Med 75:199-205, 1971 17. Sternleib I, Scheinberg IH: Chronic hepatitis as a first manifestation of Wilson's disease. Ann Intern Med 76:59-64, 1972 18. Nielson JO, Dietrichson 0, Elling P, et al: Incidence and meaning of persistence of Australia antigen in patients with acute viral hepatitis: development of chronic hepatitis. N Engl J Med 285:1157-1160, 1970 19. Reynolds TB, Peters RL, Yamada S: Chronic active hepatitis caused by a laxative, oxyphenisatin. N Engl J Med 285:813-820, 1971 20. Wintrobe MM: Clinical Hematology. Sixth edition. Philadelphia, Lea and Febiger, 1968, p 273-276 21. Benvenisti DS, Ultmann JE: Eosinophilic leukemia. Report of five cases and review of the literature. Ann Intern Med 71:731-745, 1969 22. Hardy WR, Anderson RE: The hypereosinophilic syndromes. Ann Intern Med 68:1220-1229, 1968 23. Boxer LA, Yokoyama M, Wiebe RA: Autoimmune neutropenia associated with chronic active hepatitis. Am J Med 52:279-282, 1972 24. Benner EJ, Gourley RT, Cooper RA, et al: Chronic active hepatitis with lupus nephritis. Ann Intern Med 68:405-413, 1968 25. Bridi GS, Falcon PW, Brackett NC, et al: Glomerulonephritis and renal tubular acidosis in a case of chronic active hepatitis with hyperimmunoglobulinemia. Am J Med 52:267-278, 1972 26. Case Records of the Massachusetts General Hospital, Case 6-1968. N Engl J Med 278:323-329, 1968