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CASE REPORT
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Autoimmune Hepatitis in a Patient with Pulmonary Arterial Hypertension Treated with Endothelin Receptor Antagonists Akira Naito 1, Jiro Terada 1, Nobuhiro Tanabe 1, Toshihiko Sugiura 1, Seiichiro Sakao 1, Tatsuo Kanda 2, Osamu Yokosuka 2 and Koichiro Tatsumi 1
Abstract A 48-year-old woman was diagnosed with idiopathic pulmonary arterial hypertension (PAH) and administered PAH-specific therapies, including bosentan. Four years after the initiation of treatment with bosentan, liver dysfunction appeared, and ambrisentan was substituted for bosentan. One-and-a half years later, a second episode of liver dysfunction occurred. The pathological findings of a liver biopsy specimen were not definitive, although drug-induced hepatotoxicity caused by ambrisentan was considered. However, the patient’s liver dysfunction did not improve even after the discontinuation of ambrisentan. Finally, we diagnosed her with autoimmune hepatitis (AIH). Providing careful observation with a suspicion of AIH is important when treating PAH patients with autoantibodies. Key words: pulmonary arterial hypertension, endothelin receptor antagonist, autoimmune hepatitis, druginduced hepatotoxicity (Intern Med 53: 771-775, 2014) (DOI: 10.2169/internalmedicine.53.1362)
Introduction Idiopathic pulmonary arterial hypertension (IPAH) is diagnosed when a high pulmonary arterial pressure is observed on right heart catheterization after excluding other possible associated conditions, such as collagen vascular disease (CVD) and chronic thromboembolism (1). Prostacyclin agonists, endothelin receptor antagonists (ERAs) and phosphodiesterase-5 inhibitors are potent treatment options in patients with PAH, although hepatotoxicity is a wellknown adverse event in patients treated with ERAs, particularly sulfonamide-based ERAs, such as bosentan and sitaxsentan (2, 3). These drugs are reported to inhibit bile salt export pumps, which causes bile salt accumulation in hepatocytes (4). On the other hand, autoimmune hepatitis (AIH) induces liver injury via an immune-mediated mechanism and has been reported to coexist with many other autoimmune diseases. However, it is unclear whether AIH can present as
a PAH-related complication, and the association between AIH and ERA treatment remains unknown. We herein report a case of PAH associated with AIH that developed during ERA treatment.
Case Report A 48-year-old woman with a one-year history of exertional dyspnea was referred to our hospital in March 2006. She was diagnosed with PAH based on normal perfusion scan findings and the presence of precapillary pulmonary hypertension (mean pulmonary arterial pressure [mPAP], 48 mmHg; pulmonary capillary wedge pressure, 5 mmHg; cardiac index [CI], 3.38 L/min/m2; pulmonary vascular resistance [PVR], 684 dyn.s.cm-5) on right heart catheterization. An arterial blood gas analysis indicated a partial pressure of arterial oxygen (PaO2) value of 98.3 torr and a partial pressure of arterial carbon dioxide (PaCO2) value of 29.3 torr on room air. Although tests for anti-nuclear (×1,280) and anti-
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Department of Respirology, Graduate School of Medicine, Chiba University, Japan and ２Department of Medicine and Clinical Oncology, Graduate School of Medicine, Chiba University, Japan Received for publication July 13, 2013; Accepted for publication October 14, 2013 Correspondence to Dr. Akira Naito,
[email protected]
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Intern Med 53: 771-775, 2014
DOI: 10.2169/internalmedicine.53.1362
600
*2
Transaminase IU/L
500 400 300
*1 referral to our hospital
*3
200 100 0 1
11
21
31
41 Months
51
61
71
81
PSL Beraprost
Epoprostenol Bosentan
Ambrisentan Sildenafil
Tadalafil
Figure 1. Time course of the liver function in relation to the pulmonary arterial hypertension(PAH)specific therapies. The levels of aspartate transaminase (AST) () and alanine transaminase (ALT) () are shown. No precise data were obtained from December 2006 to August 2008 because the patient was followed up at a clinic close to her home. The first liver dysfunction episode occurred in 2010 (*1). The second liver dysfunction episode occurred one-and-a-half years after the initiation of ambrisentan as an alternative therapy to bosentan (*2). At that time, laboratory tests (results shown in Table 1) and a liver biopsy were performed. The third liver dysfunction episode occurred approximately one year after the second episode (*3). PSL: prednisolone
centromere antibodies yielded positive results, the patient had neither symptoms associated with CVD nor portal hypertension on abdominal Doppler ultrasonography. There were no chest computed tomography (CT) findings suggestive of the presence of interstitial pneumonia. Therefore, we diagnosed her with idiopathic PAH after excluding the presence of associated PAH. First episode of liver dysfunction Despite the sequential administration of beraprost, bosentan and sildenafil, the patient’s symptoms worsened with the occurrence of syncope. Intravenous epoprostenol treatment was initiated in October 2008. The dose of epoprostenol was gradually increased to 53 ng/kg/min without any adverse events. During the treatment period, however, bosentan was discontinued due to elevation of the transaminase levels (aspartate aminotransaminase (AST), 204 IU/L; alanine aminotransaminase (ALT), 421 IU/L) in December 2010 (Fig. 1). We consulted a hepatologist at that time; however, there were no remarkable signs of hepatic cirrhosis, portal hypertension or congestion of the liver on abdominal Doppler ultrasonography. The elevated transaminase levels rapidly returned to the normal ranges following the discontinuation of bosentan. Another right heart catheterization procedure performed in January 2011 showed the mPAP, CI and PVR to be 49 mmHg, 3.39 L/min/m2 and 626 dyn.s.cm-5, respectively, and ambrisentan was subsequently introduced as an alternative to bosentan.
Second episode of liver dysfunction Although no elevation in the transaminase levels was initially observed following the introduction of ambrisentan, repeat exacerbation of the AST and ALT levels with severe thrombocytopenia occurred in June 2012, and the patient was admitted to our hospital. Elevated liver enzyme levels, thrombocytopenia and a high level of soluble interleukin-2 (sIL-2) receptor were observed (Table 1). There were no signs of portal hypertension or congestion in the liver on abdominal Doppler ultrasonography, as noted during the first liver dysfunction episode. Because we believed that the bosentan had caused the previous episode of liver dysfunction, we suspected that the new findings were related to drug-induced hepatotoxicity and decided to discontinue ambrisentan. However, the transaminase levels did not improve, and the platelet count continued to decrease. A fever of 38-39℃ developed and hepatosplenomegaly, bile duct wall thickening and epigastric lymphadenopathy were observed on abdominal CT. Blood tests did not indicate any evidence of infection by viruses, including hepatitis A, B, C and E or human herpes viruses. The autoantibody test results were the same as those observed on the patient’s referral. A bone marrow biopsy sample showed an increase in the megakaryocyte count (26/mm3), and reactive enlargement of the inguinal lymph node was detected. Based on these findings, we suspected the presence of acquired thrombocytopenia mediated by an immune response due to druginduced hepatotoxicity. The administration of prednisolone
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Intern Med 53: 771-775, 2014
DOI: 10.2169/internalmedicine.53.1362
Table 1. Laboratory Data Following the Second Liver Dysfunction Episode (shown as *2 in Fig. 1). A Low Platelet Count and High Transaminase and SIL-2 Receptor Levels were Noted. The Serum Immunoglobulin G (IgG) and Brain Natriuretic Peptide (BNP) Levels were Slightly Elevated. Tests for Antinuclear Antibodies (×1,280) and Anti-centromere Antibodies Yielded Positive Results. Hematology
Blood Chemistry
Serology
6,400 /ȝ/
TP
6.5 g/d/
CRP
Neu
81.5 %
Alb
3.4 g/d/
V,/-2 R
/ym
8.5 %
AST
318 U//
BNP
31.2 pg/m/
Eos
1.5 %
A/T
521 U//
Bas
0.5 %
$/3
742 U//
IgG
1,786 mg/G/
Mon
7.5 %
/'+
237 U//
IgA
121 mg/d/
Ȗ-GTP
203 U//
IgM
33 mg/d/
T-Bil
0.9 U//
IgE(RIST)
72 U/m/
BUN
13 mg/d/
