Autoimmune Hemolytic Anemia Associated with Primary Biliary Cirrhosis

Case report

Fumio Omata, MD, MPH1), Shinkichi Sato, MD, PhD2), Yasuharu Tokuda, MD, MPH1), Osamu Takahashi, MD, MPH1), Tsuguya Fukui, MD, MPH1)

1) St Lukeʼs International Hospital 2) Department of Pathology, Tokai University School of Medicine

ABSTRACT：Both primary biliary cirrhosis（PBC）and autoimmune hemolytic anemia（AIHA）are uncommon diseases. Immunological dysregulation is suggested as a causative factor for both diseases. We report a 77-year-old woman who suffered from warm type AIHA complicated by PBC. Her direct antiglobulin test was positive for IgG, and negative for C3. Both anti-mitochondrial antibody and its M2 component were detected. Both alkaline phosphatase （Alp）and IgM were elevated in the serum. She was initially treated with steroids for 8 months. Her steroids were discontinued when she underwent a laparoscopic splenectomy. Ursodeoxycholic acid was discontinued due to an allergic skin reaction. Her Alp improved with bezafibrate.

KEY WORDS：Primary biliary cirrhosis, Autoimmune hemolytic anemia, Splenectomy, Bezafibrate

Gen Med：2008；9：65-70

However, the list of diseases associated with AIHA does not INTRODUCTION include PBC2. Due to the complexities and toxicities of rimary biliary cirrhosis（PBC）is a chronic treatment for each disease, it is challenging to treat a patient cholestatic liver disease involving the interlobular with both diseases. P and septal bile ducts. The cause of PBC is unknown, but considerable evidence points to an autoim- CASE REPORT mune basis for this disease. The disease is uncommon, with a reported prevalence between 19and 402 cases per million. A77-year-old woman developed exertional dyspnea a The vast majority（90%）of patients affected are women, month prior to visiting our hospital. Her past medical history with the usual time of diagnosis between 30 and 60 years. was noncontributory. Physical examination suggested ane- The list of associated diseases does not include autoimmune mia. Laboratory examination revealed the following：a white hemolytic anemia（AIHA)1. AIHA is also a rare disease with blood cell count of 6. 4×109／／／l, hemoglobin 4. 1 mmol／l, incidences reported in the range of 1 per 75,000 to 2 per platelet 16.9×109／l, and reticulocyte 2.94. Albumin was 39 100,000. Primary or idiopathic warm AIHA accounts for less g／dl, aspartate aminotransferase（AST）0.68 mkat／l, alanine than half of the cases and most patients will be found to have aminotransferase（ALT）0.33 mkat／l, alkaline phosphatase underlying associated conditions including tumors, autoim- （Alp）12.3 mkat／l, g-glutamyltranspeptidase（gGTP）4.65 mune diseases, or an acquired immunodeficiency syndrome. mkat／／／l, gglobulin 28%, IgM 4.55 g／l, and Haptoglobin＜0.1

Author for Corresponding：Fumio Omata, MD 9-1 Akashicho Chuo-city, Tokyo 104-8560 Japan, Phone：＋81-3-3541-5151, Fax：＋81-3- 5550-2426, E-mail：[email protected] Received for publication 11 April 2008 and accepted in revised form 21 August 2008 66 General Medicine, Vol. 9, No. 2, 2008

Table 1. Laboratory Values at presentation CBC Albumin 39.1 g／l Hb 4.0 mmol／l T. Bilirubin 27.3 mmol／l Reticulocyte 2.94 D. Bilirubin 11.9 mmol／l WBC 6.4×109／l Alkalinephosphatase 11.5 mkal／l Platelet 169×109／l LDH 24.1 mkat／l Direct Coombs（Anti-IgG) 4＋ AST 0.71 mkat／l Indirect Coombs 3＋ ALT 0.26 mkat／l AMA ×160 Cr 53 mmol／l AM2A（IgG) 171×103 U／l BUN 4.2 mmol／l ANA ×160 Uric acid 226 mmol／l Homogeneous ×160 Na 137 mmol／l Speckled ×160 K 4.0 mmol／l IgG 18.6 g／l Cl 102 mmol／l IgM 4.55 g／l IgA 6.08 g／l Haptoglobin ＜0.1 g／l AMA, anti-mitochondrial antibody, AM2A, anti-M2 antibody, ANA, anti-nuclear antibody Note；AMA and AM2A（IgG）were measured by fluorescence assay and enzyme immunoassay, recpectively. Reference values are the followings, Hb, 7.50-9.36 mmol／l；reticulocyte, 0.005-0.015； WBC, 3.8-9.8×109／／／l；platelet, 140-440×109／l；AMA, ＜×20；AM2A（IgG), C20×103 U／l； ANA, ＜×40；IgG, 7.00-14.50 g／／／／／l；IgM, 0.30-2.10 g／l；IgA, 0.70-3.70 g／l；albumin, 36-50 g／ l；total bilirbin, 5.13-18.80 mmol／／／l；direct bilirubin, 0-5.1 mmol／l；alkaline phosphatase, 0.13-2.10 mkal／／／／／／l；LDH, 1.67-4.17 mkal／l；AST, 0.18-0.78 mkal／l；ALT, 0.12-0.88 mkal／l；Cr, 53-133 mkal／ l；BUN, 2.9-8.9mmol ／／／／l；uric acid, 179-476 mmol／l；haptoglobin, 0.3-2.2 g／l

Figure 1. No relapse of anemia was observed after laparoscopic splenectomy without steroids. The alkaline phosphatase improved by the administration of bezafibrate. PSL, prednisolone；AST, aspartate aminotransferase；ALT, alanine aminotransferase

g／l. Direct and indirect Coombs tests were positive. Both splenomegaly on exam or seen by abdominal ultrasonogra- anti-mitochondrial antibody（AMA）and M2 antibody phy. The diagnosis of PBC and AIHA were made and （AM2A）（IgG）were positive（Table 1). There was no prednisolone（PSL）40 mg／day was started 9days after Omata F. Autoimune hemolytic anemia associated with primary billiary cirrhosis 67

a b Figure 2. The tissue obtained by needle biopsy was fixed in 10% buffered formalin, embedded in paraffin and cut at 4 micrometer. Sections were stained with haematoxylin-eosin（H&E). Sections of the liver, stained byH&E,show rather well preserved lobular architecture. Portal areas reveal occasional degenerative（a), destructive（b, c）and granulomatous（c）changes of interlobular portal areas with mild lymphoplasmacytic infiltration. No active foci of necro-inflammatory reaction in the hepatic parenchyma are identified. These features are consistent with primary biliary cirrhosis（Scheuer stage Ⅰ).（Original magnification a：×50, b：×50, c：×100)

c initial presentation. At the two-month mark, the patientʼs In addition to steroid treatment, two months after initial hemoglobin level improved enough to taper the dosage of diagnosis administration of ursodeoxycholic acid（UDCA） PSL：the 40 mg of PSL was gradually reduced to 5 mg／day 300 mg／day was started for the patientʼs PBC. She suffered by decreasing 5 mg every 2 weeks over the subsequent 3 from generalized erythematous maculopapular skin lesions months.（approximately 5 months later steroid treatment was within a few days of starting the medicine, and the initiated). However, it was difficult to withdraw PSL administration of UDCA was discontinued. We started completely even with the addition of azathioprine 50 mg／ bezafibrate（200 mg／day）for her PBC at 20 months. Alp day. In consideration of the side effects of long-term steroid quickly improved at 21 months（Figure 1) use and the patientʼs preference, a laparoscopic splenectomy was performed, followed by tapered and complete withdraw DISCUSSION of PSL eight months after initial presentation（Figure 1). Needle biopsy of the liver during laparoscopic splenectomy PBC has been reported in association with a variety of showed rather well preserved lobular architecture. Portal autoimmune diseases, such as sicca syndrome, autoimmune areas revealed occasional degenerative（Figure 2a), de- thyroiditis, rheumatoid arthritis, CREST syndrome and IgA structive（Figure 2b), and granulomatous（Figure 2c） deficiency, type 1 diabetes mellitus, scleroderma, pernicious changes of the interlobular biliary ducts with lymphoplasma- anemia and renal tubular acidosis4. However, the report of a cytic infiltration. No active foci of necro-inflammatory case of both PBC and AIHA is very rare, and treatment of reaction in the hepatic parenchyma were identified. These AIHA may need careful tailoring, adjustment, and monitor- features were consistent with a diagnosis of PBC, Scheuerʼs ing that is different from standard therapy if the patient also stage Ⅰ3. has PBC. Likewise, treatment of PBC may need to be 68 General Medicine, Vol. 9, No. 2, 2008

Table 2. Thirteen patients with both PBC and AIHA reported in past literatures Anti Findings Type of Year Author Age Gender Race AMA M2 of Liver Other diseases Rx of AIHA Rx of PBC AIHA Ab Biopsy 1970 Hume 50 F NR Warm ×512 NR NR NR NR NR et al 1980 Orlin 57 F Cocasian Cold ×640 NR CWPBC NR PPE, Azathio- D-penicilla- et al prine mine 1984 Shicihri 32 F Japanese Warm ×80 NR CWPBC Thrombocytop- Steroids NR et al enia, Reticuloc- ytopenia 1996 Yoshida 66 NR Indian Warm ×80 NR stage Ⅰ NR Steroids UDCA et al 1997 Chen 49 F NR Cold & positive NR Bile duct Sicca syndromeSteroids, BTF UDCA et al Warm destruction 1997 Kobayashi 50 F NR Warm ×20 ×40 Bile duct NR Steroids UDCA et al destruction 2000 Brackstone 49 F NR Cold positive NR state Ⅳ Hypothyroidi- Steroids UDCA, Cho- et al sm, Osteodystr- lestyramine ophy 66 F NR Warm positve NR stage Ⅳ NR Steroids, Aza- UDCA, Cho- thioprine lestyramine 2000 Nakasone 68 F NR Warm negative negative stage Ⅲ Hashimoto Steroids UDCA et al disease, ILD 2003 Fuller 62 F NR Warm ×2540 NR NR NR No steroids UDCA et al 2006 Azad 83 F NR Warm positive NR Not Evans syndrome Steroids, Aza- UDCA et al performed thioprine 2007 Kaibori 52 F Japanese Cold NR ×135 stage Ⅲ NR Splenectomy Living donor et al liver transplantation 2008 Kornfliht 67 F NR Warm postive NR NR PMF, FGN, Steorids, BTF NR et al AML Rx, treatment；PBC, primary biliary cirrhosis；AIHA, autoimmune hemolytic anemia；AMA, anti-mitochondria antibody；F, female； NR, not reported；CWPBC, consistent with PBC；CNSDC, chronic non-suppurative destructive cholangitis；PPE, partial plasma exchange；UDCA, ursodeoxycholic acid；ILD, interstitial lung disease；PMF, primary myelofibrosis；FGN, fibrillary glomeruloneph- rititis；AML, acute myelogenous leukemia；BTF, blood transfusion Note；Stage in findings of liver biopsy is by Scheuer PJ. customized from conventional therapy if the patient has a reviewing the 18 English articles, there were only 13 patients drug allergy to UDCA and also has AIHA. with both PBC and AIHA in 12 citations5-16.（Table 2) Hume et al reported coincidence of PBC and AIHA for the In these cases, there was one patient whose PBC was first time in 1970. They measured red blood cell（RBC） diagnosed based on the pathological findings of liver biopsy, survival time in eight patients of PBC and reported that four though both her AMA and AM2A were negative12. Nine of eight patients had shortened RBC survival time. One of the cases had warm type autoantibody, three had cold type, and eight patients was diagnosed with AIHA in addition to PBC5. one mixed type. Five of 13 cases were complicated with An autoimmune process is assumed to cause PBC, and a additional autoimmune diseases（two cases of common epitope may be the cause of immunodysregulation, hypothyroidism11,12, two cases of idiopathic such as generation of autoantibody, for both diseases. thrombocytopenia7,14, and one of sicca syndrome9). All cases Searching PubMed from 1949 to June 2008 with two key were women except one case without a description of words（PBC, AIHA）retrieved 22 citations（18 English).In gender8. Omata F. Autoimune hemolytic anemia associated with primary billiary cirrhosis 69

Steroids were effective for AIHA in all 9cases that 2．Thomas AT. Autoimmune hemolytic anemias. In：Lee GR, received steroids. There was one patient who received partial Foerster J, Lukens J, et al., editors. Wintrobeʼs Clinical plasma exchange and azathioprine for AIHA. This patient Hematology. 10 ed. Baltimore：Williams & Wilkins；1999. recovered from anemia but her liver disease progressed and p. 1246. she died suddenly of gastrointestinal hemorrhage6. AIHA 3．Scheuer P. Primary biliary cirrhosis. Proc R Soc Med 1967； 60：1257-60. resolved without steroids or a splenectomy in one patient 4．Chung RT, Podolsky DK. Cirrhosis and its complication. whose PBC was treated with UDCA for one year13. AIHA In：Braunwald E, Fauci AS, Kasper DL, et al., editors. with cold-type antibody was initially treated with a Harrisonʼs Principles of Internal Medicine, 15th Ed, New splenectomy in one patient who underwent a living-donor York San Francisco：McGraw-Hill；2001. p. 1756-7. 15 liver transplantation for advanced PBC . PBC was treated 5．Hume R, Williamson JM, Whitelaw JW. Red cell survival in with UDCA in most of these cases except for one patient who biliary cirrhosis. J Clin Pathol 1970；23：397-401. received D-penicillamine6 and one case who underwent a 6．Orlin JB, Berkman EM, Matloff DS, et al. Primary biliary living-donor liver transplantation15. cirrhosis and cold autoimmune hemolytic anemia：effect of To our knowledge, our patient is the first case reported in partial plasma exchange. Gastroenterology 1980；78：576- the English literature that underwent laparoscopic splenecto- 8. my for AIHA associated with PBC. She has been off 7．Shichiri M, Koyama W, Tozuka S, et al. Primary biliary medication for AIHA since her splenectomy. cirrhosis. A patient with adverse reactions to tiopronin and autoimmune hemolytic anemia with reticulocytopenia. Arch Steroid use should be avoided in patients with PBC Intern Med 1984；144：89-91. because a substantial proportion of PBC patients have 8．Yoshida EM, Nantel SH, Owen DA, et al. Case Report：a 17 osteoporosis, which can be worsened by steroids . patient with primary biliary cirrhosis and autoimmune Therefore, we decided to perform a splenectomy rather than hemolytic anemia. J Gastroenterol Hepatol 1996；11：439- continuing small amounts of PSL. In addition, we think that 42. the less invasive laparoscopic splenectomy was better than 9．Chen CY, Lu CL, Chiu CF, et al. 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