Case #1. Azathioprine에 의한 심한 골수부전 환자를 소개 하였습니다. 실제로 소개드린 첫번째 문헌(GUT)에 의하면 골수 억제의 부작용은 초기 치료 기간에 집중되어 있지만 전 치료 기간에 발생될 수 있는 것으로 되어 있습니다. 문헌들에 의하면 TPMT 활성이 저하된 환자에게 많이 발생하고 투여 전 TPMT 활성을 검사 한 후 치료를 시작 하여야 한다는 내용들이 많습니다. 그러나 TPMT 검사는 고가에 오랜 검사기간이 걸리는 검사입니다(비보험 225,750원, 20일). 또한 슬라이드에 소개드린 두번째 문헌(DDS)에는 스크리닝 검사의 효용성에 대하여 회의적인 결과를 보고 하였습니다. 면역 억제제 투여시 첫 약물로써 가장 간단하게 투여할 수 있는 이뮤란(Azathioprine)이라는 이름의 약물 역시도 주의하며 투여 해야 할 약물 이라 생각 됩니다. 심각한 혈액학적 합병증의 발생률은 약 6% 정도로 보고되고 있으며, 류마티스질환 치료 하시는 분들 역시도 오랜 치료기간 한두번의 경험을 할 수 있는 정도라고 합니다. 사용을 안할 수 없는 약물인 만큼 투여 전 환자와 보호자에게 발생 가능한 부작용에 대한 충분한 설명이 필요 하다고 생각 합니다. Case #2. Hepatic enz. elevation 주소로 오신 분이고, non-A, non-B hepatitis로써 ANA 검사상 high titer 소견을 보였습니다. 그런데 ANA 보고시 간과할 수 있는 ANA pattern이 'Discrete speckled' 로 보고되고 Anti Centromere Ab. 양성소견 이었습니다. 다시 병력 청취 하였더니 Raynaud disease가 의심 되었던 case 입니다. ANA 검사 결과를 볼때 titer 뿐 아니라 pattern도 챙겨 보아야 한다는 교훈을 얻었던 case 입니다.

1. Autoimmune hepatitis
천안 충무병원 소화기내과 류기현

2. 206XXX
이O희
48/F
• C.C.: OT/PT elevation
• P.I.: 외부병원 급성 간염 소견으로 추가 검
사 위해 의뢰 됨.

3. Initial Blood Examination
•
•
•
•
CBC: 4300-11.3-35.2-163K
PT/PTT: 11.7/27.2
OT/PT: 586/822, TB/DB: 1.3/1.0, GGT:676
HBsAg/Anti-HBsAb (-/+), Anti-HCV(-)

4. Blood Examination
•
•
•
•
ANA(+,1:1280), ASMA(+), Anti LKM Ab(-)
AMA(-)
IGG: 3415mg/dl(700~1600)
SPEP: polyclonal gammopathy
Biopsy
• Bridging necrosis with early cirrhotic changes

5. Impression
• Autoimmune hepatitis

6. Progress
• 2013-7-2
– Pd(15)+Azt(50) combination therapy start
• 2013-7-9
– Hair loss, sore throat
– ANC: 71.4

7. Progress

8. Progress
• G-CSF 약 2주간의 투여 후 백혈구 수치의
호전.
• 혈색소 수치는 약 2개월 후 회복.

9. Autoimmune hepatitis
• 자가면역질환
– 면역 이상으로 특정 자가세포를 외부세포로 인지
하고 공격하여 파괴하는 질환
• Autoimmune hepatitis.
– Unresolving, predominantly periportal hepatitis of
unknown etiology.
– Usually with hypergammaglobulinemia and tissue
autoantibodies.
– Which is responsive to immunosuppressive
therapy.

10. Dignostic Scoring System

11. Indications for Treatment
Absolute
Relative
None
Serum AST≥10 fold ULN
Symptoms (fatigue, arthralgia,
jaundice)
Asymptomatic with normal or
near normal serum AST and γ
globulin levels
Serum AST≥5 fold ULN and γ
globulin level≥2 fold ULN
Serum AST and/or c globulin
less than absolute criteria
Inactive cirrhosis or mild portal
inflammation
(portal hepatitis)
Bridging necrosis or multiacinar
necrosis on histological
examination
Interface hepatitis
Severe cytopenia (white blood
cell counts <2.5X109/L or
platelet counts <50X109/L)
or known complete deficiency of
TPMT activity precludes
treatment with azathioprine
Incapacitating symptoms
Osteopenia, emotional instability,
hypertension, diabetes, or
cytopenia (white blood cell
counts 2.5 109/L
or platelet counts 50 109/L)
Vertebral compression,
psychosis, brittle diabetes,
uncontrolled hypertension,
known intolerances to
prednisone or azathioprine

12. Immunosuppressive Treatment

13. Azathioprine-Related Side Effects
Thiopurine
methyltransferase
6-mercaptopurine
6-methyl mercaptopurine
hypoxanthine guanine
phosphoribosyl transferase
6-thioguanines
Interfere with purine nucleotide synthesis within the cell cycle and
impair proliferation of rapidly dividing T and B lymphocytes

14. Myelosuppression is an important and potentially lethal complication of azathioprine treatment. The
blood count has been reviewed in all patients treated with azathioprine for inflammatory bowel disease
over 27 years in one hospital. Altogether 739 patients (422 with Crohn's disease, 284 with ulcerative
colitis, and 33 with indeterminate colitis) were treated with 2 mg/kg/day azathioprine for a median of
12.5 months (range 0.5-132) between 1964 and 1991. Full blood counts were performed monthly for
the duration of treatment. In 37 patients (5%) who developed bone marrow toxicity, the drug was
withdrawn or the dose reduced. Thirty two of these patients were asymptomatic and five developed
symptoms. Leucopenia (white blood count less than 3.0 x 10g/l) occurred in 28 (3.8%) patients, in nine
of whom it was severe (white blood count < 2.0 x 10(9)/l). Of these nine patients, three were
pancytopenic: two died from sepsis and the other had pneumonia but recovered. A further two patients
with severe leucopenia developed a mild upper respiratory infection only. Thrombocytopenia (platelet
count < 100,000 x 10(6)/l) in 15 patients was associated with leucopenia in six and developed in
isolation in a further nine (total 2%). Isolated thrombocytopenia was never clinically severe.
Myelotoxicity from azathioprine developed at any time during drug treatment (range 2 weeks-11 years
after starting the drug) and occurred either suddenly or over several months. Bone marrow
suppression as a result of azathioprine treatment is uncommon when a moderate dose is used, but is
potentially severe. Leucopenia is the commonest and most important haematological complication.
Regular monitoring of the full blood count is recommended during treatment.

15. Result

17. Result

19. Others
• Cyclosporine, tacrolimus, budesonide, met
hotrexate, infliximab, and mycophenolate
mofetil have also been used in small
numbers of patients who fail or cannot
tolerate conventional therapy.
1.Mieli-Vergani G, Heller S, Jara P, et al. Autoimmune hepatitis. J Pediatr Gastroenterol Nutr 2009; 49:158.
2.Fernandes NF, Redeker AG, Vierling JM, et al. Cyclosporine therapy in patients with steroid resistant autoimmune hepatitis. Am J Gastroenterol 1999; 94:241.
3.Baven-Pronk AM, Coenraad MJ, van Buuren HR, et al. The role of mycophenolate mofetil in the management of autoimmune hepatitis and overlap syndromes. Aliment Pharmacol Ther 2011; 34:335.
4.Burak KW, Urbanski SJ, Swain MG. Successful treatment of refractory type 1 autoimmune hepatitis with methotrexate. J Hepatol 1998; 29:990.
5.Sciveres M, Caprai S, Palla G, et al. Effectiveness and safety of ciclosporin as therapy for autoimmune diseases of the liver in children and adolescents. Aliment Pharmacol Ther 2004; 19:209.
6.Aqel BA, Machicao V, Rosser B, et al. Efficacy of tacrolimus in the treatment of steroid refractory autoimmune hepatitis. J Clin Gastroenterol 2004; 38:805.
7.Larsen FS, Vainer B, Eefsen M, et al. Low-dose tacrolimus ameliorates liver inflammation and fibrosis in steroid refractory autoimmune hepatitis. World J Gastroenterol 2007; 13:3232.
8.Richardson PD, James PD, Ryder SD. Mycophenolate mofetil for maintenance of remission in autoimmune hepatitis in patients resistant to or intolerant of azathioprine. J Hepatol 2000; 33:371.
9.Inductivo-Yu I, Adams A, Gish RG, et al. Mycophenolate mofetil in autoimmune hepatitis patients not responsive or intolerant to standard immunosuppressive therapy. Clin Gastroenterol Hepatol 2007; 5:799.
10.Hlivko JT, Shiffman ML, Stravitz RT, et al. A single center review of the use of mycophenolate mofetil in the treatment of autoimmune hepatitis. Clin Gastroenterol Hepatol 2008; 6:1036.
11.Hennes EM, Oo YH, Schramm C, et al. Mycophenolate mofetil as second line therapy in autoimmune hepatitis? Am J Gastroenterol 2008; 103:3063.
12.Zachou K, Gatselis N, Papadamou G, et al. Mycophenolate for the treatment of autoimmune hepatitis: prospective assessment of its efficacy and safety for induction and maintenance of remission in a large cohort of
treatment-naïve patients. J Hepatol 2011; 55:636.
13.Weiler-Normann C, Schramm C, Quaas A, et al. Infliximab as a rescue treatment in difficult-to-treat autoimmune hepatitis. J Hepatol 2013; 58:529.

20. 269XXX
박O경
47/F
• C.C.: OT/PT elevation
• P.I.: 마라톤 및 근육운동 많이 하는 분으로
외부병원 검진상 OT/PT 105/67 소견으로
의뢰됨.

21. Initial Blood Examination
•
•
•
•
CBC: 5900-12.8-38.2-224K
OT/PT: 27/24, TB: 0.5, GGT:17
CPK: 149
HBsAg/Anti-HBsAb (-/+), Anti-HCV(-)
• Normal
Liver US

22. Blood Examination
• ASMA(-), Anti LKM Ab(-), AMA(-)
• ANA(+,1:1280)
– ANA Pattern : Discrete speckled
• Anti Centromere Ab. (+,178.8)

23. Repeat history taking
• 차가운 환경에 손의 색조가 하얗게 변하는
양상이 있고, 손이 뻣뻣해지는 느낌이 있었
다. 이러한 신체 변화가 신체 운동을 많이
하게 된 계기라고 함.

24. Impression
• Raynaud disease.
• r/o systemic sclerosis.

25. 감사합니다.