Pediatr Transplantation 2014: 18: E240–E245
© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Pediatric Transplantation DOI: 10.1111/petr.12343
Fulminant hepatitis linked to dapsone hypersensitivity syndrome requiring urgent living donor liver transplantation: A case report Garcia A, Yi N-J, Lee KB, Lee J-M, Choi YR, Suh S-W, You T, Lee K-W, Park JD, Kang HJ, Kim JG, Kang EK, Hong G, Suh K-S. (2014) Fulminant hepatitis linked to dapsone hypersensitivity syndrome requiring urgent living donor liver transplantation: A case report. Pediatr Transplant, 18: E240–E245. DOI: 10.1111/petr.12343. Abstract: Dapsone is a sulfone-type drug used widely for different infectious, immune, and hypersensitivity disorders as an antibacterial treatment alone or in combination for leprosy and sometimes for infected skin lesions. DHS is a severe idiosyncratic adverse reaction with multi-organ involvement. However, acute necrotic hepatitis requiring an emergent LT is rare. Herein, we report a case of 12-yr-old girl who suffered from fulminant hepatitis and multi-organ failure due to DHS for PPD. She was saved by emergent LDLT. A high index of suspicion and rapid diagnosis are necessary not to miss this potentially lethal but rare disease.
Angelica Garcia1,*, Nam-Joon Yi1, Kyoung Bun Lee2, Jeong-Moo Lee1, Young Rok Choi1, Suk-Won Suh1, Tae You1, Kwang-Woong Lee1, June Dong Park3, Hyoung Jin Kang3,4, Joon Gon Kim3, Eun Kyeong Kang5, Geun Hong1 and Kyung-Suk Suh1 1
Department of Surgery, Seoul National University College of Medicine, Seoul, Korea, 2Department of Pathology, Seoul National University College of Medicine, Seoul, Korea, 3Department of Pediatrics, Seoul National University College of Medicine, Seoul, Korea, 4Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea, 5Department of Pediatrics, Dongguk University Ilsan Hospital, Goyang, Korea Key words: fulminant hepatitis – dapsone hypersensitivity syndrome – liver transplant – pigmented purpuric dermatosis Nam-Joon Yi, MD, PhD, Associate Professor, Division of HBP Surgery, Department of Surgery, Seoul National University College of Medicine, 101 Daehak-ro, Jongro-gu, 110-744 Seoul, Korea Tel: +82 2 2072 2990 Fax: +82 2 766 3975 E-mail: [email protected] *Present address: Seoul National University Hospital, Seoul, South Korea Accepted for publication 23 July 2014
Dapsone is a sulfone-type bacteriostatic antibiotic used widely for different infectious, immune, and hypersensitivity disorders (1–5). DHS is rare (0.5–3%) but sometimes a serious cause of death (6, 7). The main characteristic of DHS is the Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; DHS, dapsone hypersensitivity syndrome; FANA, fluorescent antinuclear antibody; HD, hospital day; LDLT, living donor liver transplantation; LT, liver transplantation; MELD, model of end-stage liver disease; POD, postoperative day; PPD, pigmented purpuric dermatosis.
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triad of fever, skin eruption, and internal organ involvement (lung, liver, neurological, and other systems). Therefore, laboratory monitoring should be frequently performed during treatment, including complete blood counts and liver function tests. Skin rash must be attended by medical staff. Skin lesions may be a severe idiosyncratic adverse reaction with multi-organ involvement (3). Usual treatment includes discontinuing dapsone and anti-inflammatory steroid pulse therapy. However, fulminant hepatic failure requiring a LT is rare. Herein, we report fulminant hepatitis requiring an emergent living donor liver
Dapsone hypersensitivity induces fulminant liver failure
transplant (LDLT) due to DHS in a 12-yr-old girl with PPD.
(a)
Ethics statement
This study was reviewed and approved by the institutional review board of Seoul National University Hospital (H-1310-020-523). Informed consent was waived by the board. Case report Patient presentation
A 12-yr-old girl was prescribed dapsone as treatment for PPD (Fig. 1). She had no unusual health history and was previously healthy. Twenty days later she developed a high fever (up to 40 °C). Two days after the fever, a skin rash appeared over her body but particularly on the hands, feet, trunk, and face (Fig. 2). The next day, she required hospitalization. The dapsone was discontinued on HD 1. Her laboratory findings were total bilirubin, 1.8 mg/dL (normal reference, total bilirubin 0.2–1.2 mg/dL); ALT, 141 IU/L (normal reference, 0–40 IU/L); AST, 158 IU/L (normal reference, 0–40 IU/L); and creatinine, 0.71 mg/dL (normal reference, 0.70– 1.40 mg/dL). Steroid therapy was started on HD 5. On HD 8, septic shock was suspected because of fever, diminished consciousness level, and hypotension. Thus, she was transferred to the intensive care unit. The laboratory findings revealed that creatinine had increased to 1.37 mg/dL and liver function had worsened. She showed hemolytic anemia, pleural effusion, ascites, and deterioration of liver function on HD 12: white blood cells, 39.46 9 103/lL (normal reference, 4.0–10.0 9 103/lL); hemoglobin,
Fig. 1. PPD of a 12-yr-old girl.
(b)
Fig. 2. Skin lesions after dapsone treatment. (a) Facial skin lesions and edema. (b) Rash on arms and hands.
9.2 g/dL (normal reference, 13–17 g/dL); platelets, 117 9 103/lL (normal reference, 130– 400 9 103/lL); total bilirubin, 11.6 mg/dL; AST, 737 IU/L; ALT, 372 IU/L; albumin, 2.4 mg/dL (normal reference, 3.3–5.2 g/dL); prothrombin time, 15.0 s, 1.4 INR (normal reference, 9.8–12.2 s); D-dimer, 12.24 (normal reference, 0–0.4 lg/mL); lactic acid, 17 mmol/L (normal reference, 0.7–2.5 mmol/L); ammonia, 90 lg/dL (normal reference, 15–51 ㎍/dL); creatinine 0.75 mg/dL (normal reference, 0.70– 1.40 mg/dL), and C-reactive protein, 8.38 mg/ dL (normal reference, 0–0.5 mg/dL). A peripheral blood smear showed normocytic anemia and fragmented red blood cells. A direct Coombs test was positive, C3/C4 was 51 (normal reference, 70–150 mg/dL)/7 mg/dL (normal reference, 10–35 mg/dL), CH50 was 21 (normal reference, 23–46 mg/dL), and unidentified cold autoantibody was positive. She was referred to the Transplant Unit Service of our institution for management of multiorgan failure including fulminant hepatic failure without evidence of infection on HD 14. Her laboratory findings showed altered liver function plus coagulopathy (Fig. 3); total bilirubin, 19.6 mg/dL; AST, 1146 IU/L; ALT, 199 IU/L; and prothrombin, time, 26.8 s, 2.58 INR. On HD 15, she developed hepatic encephalopathy (grade 3) and hepatorenal syndrome requiring mechanical ventilation and renal replacement therapy; ammonia, 124 lg/dL; and creatinine, 2.13 mg/dL. Without evidence of bleeding, her E241
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hemoglobin decreased to 6.3 g/dL and hemolytic anemia was diagnosed. Ceruloplasmin was normal (19.3 mg/dL, normal reference, 15–40 mg/ dL). The direct Coombs test was positive, and C3 (normal reference, 70–150 mg/dL)/C4 (normal reference, 10–35 mg/dL) was low (15 and 3 mg/dL). But FANA test was negative. Serum
IgG and IgM levels were elevated (2272 mg/dL; normal reference, 800–1750 mg/dL and 624 mg/ dL; normal reference, 50–320 mg/dL), but IgA was within normal range (207 mg/dL, normal reference, 69–382 mg/dL). Plasma hemoglobin was negative. Anti-cardiolipin antibodies IgG and IgM, as well as anti-dsDNA, were negative.
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Rituximab and plasma pheresis were applied, and she was registered as UNOS status 1. LT and recovery
She underwent an emergent LDLT on HD 17 because her general condition had deteriorated. At the time of transplantation, the Child–Pugh score was 11, and the MELD score was 38. The donor was her cousin, a 21-yr-old male, and the right graft was used. The operation time for the recipient was 395 min, and ischemic time was 85 min. The explanted liver (Fig. 4) revealed diffuse parenchymal necrosis, stromal hemorrhage in
(a)
the perivenular area with infiltration of lymphocytes in portal tracts. Hemosiderin laden histiocytes were frequently identified around hemorrhage, but eosinophils and neutrophils were rare. Vasculitis or thrombosis was not identified. The histologic findings were summarized as submassive hepatic necrosis compatible with the patient’s clinical situation of fulminant hepatic failure. After the surgery, her recovery was uneventful without neurological sequels. Her mentality was comatose for 48 h, but she became alert on POD 6. She was extubated on POD 7, and renal replacement therapy was discontinued on POD 11. She was transferred to the general ward on POD 29 and discharged on POD 41. During six months after LT, her immunosuppressants were triple therapy composed of low-dose tacrolimus, steroid, and mycophenolate mofetil. She is now on POD 247 and her maintenance immunosuppression is tacrolimus monotherapy. Her laboratory findings, including anemia, liver function, and renal function as well as the skin lesions have completely resolved. Discussion
(b)
Fig. 4. Pathology of the explant liver. In gross examination, totally resected liver was hyperemic and soft without nodular lesion. Microscopy revealed diffuse parenchymal necrosis and stromal hemorrhage in perivenular area with infiltration of lymphocytes in portal tracts. Vasculitis or thrombosis was not identified. Histologic findings are summarized as submassive hepatic necrosis and compatible with the patient’s clinical situation of fulminant hepatic failure. (a) (H&E, 912.5) (b) (H&E, 912.5).
DHS is a rare syndrome first described by Allday, Lowe, and Barnes (6) as a hypersensitivity vasculitis syndrome. DHS is a potentially fatal adverse drug reaction with unknown prevalence and risk factors. Symptoms appear as early as 2–6 h or as late as six months after initial administration of the drug. This variability in latency is related to dose and treatment modality. The main characteristics of DHS are fever, skin eruption, and internal organ involvement. Other side effects uncommonly associated are severe hemolysis, peripheral neuropathy, acute psychosis, nephrotic syndrome, hypersensitivity reactions, and lupus-like syndrome (3). The cutaneous lesions can be erythematous papules, plaques, pustules, or eczematous lesions. The severity of the cutaneous changes does not correlate with the severity of the internal organ involvement. Usually, these skin lesions resolve within two wk after stopping therapy. This disease can also be related to severe entities such as Steven–Johnson syndrome or toxic epidermal necrolysis. Factors that may complicate the illness are severe cases of malnutrition, protein loss, or secondary infection. Pulmonary manifestations are related with eosinophilic pneumonia, hypersensitivity pneumonia, and pleural effusion. Rapid clinical deterioration can lead to respiratory failure and can be the main E243
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cause of severe organ dysfunction and/or death if not treated or be unrecognized. A systematic review (6) reported on 114 articles (17 epidemiological and 97 case reports) including 336 patients with DHS. The total prevalence rate of DHS was 1.4%. Mucosal involvement, hepatitis, higher age, and disease occurrence in non-affluent countries were associated with a higher risk for a fatal outcome, with an overall fatality of 9.9%. Rechallenge with dapsone should not be undertaken in these patients and they must be told that they are allergic to sulfa drugs. Patients with DHS and the medical staff must know that they can develop an allergy to any kind of sulfa drug and must be aware of what medications they cannot take for the rest of their life. The symptoms of this patient fit all associated side effects of dapsone. Thus, it was diagnosed as DHS, which induced fulminant hepatic failure. Most cases of hepatotoxicity resolve rapidly within 2–4 wk after stopping dapsone unless the cholestasis is severe. Dapsone hepatotoxicity is a dose-dependent effect, and hepatic injury can also be sustained due to other sulfone drugs. The best approach to DHS is immediate discontinuation of the drug and prompt administration of oral or intravenous glucocorticoids. However, steroid therapy has variable success. In this particular patient, the use of steroid therapy had no effect, and her clinical course deteriorated, requiring LT. One of our main concerns in this case was that the first diagnosis of PPD may have triggered the final evolution of severe DHS. PPD is a spectrum of idiopathic disorders, also considered as a group of vascular disorders (8), and unknown etiology, although aberrant cell-mediated immunity has been proposed (9). Cell-mediated immunity might play a role in Schamberg’s disease (8), and lichen aureus could be associated with trauma and hepatitis (10). Moreover, PPD can also be related with underlying diseases (11). However, we did not recognize the underlying liver disease because the explanted liver was totally necrotic, and other findings were similar to lupus-like syndrome overlapping with DHS. On the other hand, in this case, an emergent LDLT for fulminant hepatic failure was conducted within 48 h. In 2002, the New York State Committee on Quality Improvement in Living Liver Donation recommended that adult-toadult LDLT should be prohibited in recipients with MELD scores 25 (12). However, recent data from a few large-center studies show that LDLT is a safe and effective treatment modality, even in adult recipients in poor condition (13–15). The E244
urgent use of a living donor organ for acute liver failure has not been prohibited in Korea, if the full evaluation is complete and the institutional ethical committee and national organ sharing network committee permits the procedure in a live donor within the third degree of consanguinity (16). LDLT may potentially lead to better outcomes and the rapid course of acute liver failure provides only a very narrow window for LT. The donor outcome of this report was uneventful. In conclusion, DHS is a rare entity. This is the first case report of LDLT for fulminant hepatic failure due to DHS. Therefore, we must be alert because it could be potentially fatal. Monitoring laboratory studies must be performed during the administration of the drug. The patient must be educated that in case of any rash or systemic symptoms to go immediately to the emergency room. Due to the wide indications for dapsone use, all medical specialties may be familiar to DHS. A high index of suspicion and rapid diagnosis are necessary not to miss this potentially lethal but rare disease. Authors’ contribution Angelica Garcia and Nam-Joon Yi: Concept/design; Angelica Garcia, Nam-Joon Yi, Jeong-Moo Lee, Eun Kyeong Kang, June Dong Park and Geun Hong: Data collection; Kyoung Bun Lee, Young Rok Choi, Suk-Won Suh, Tae You: Data interpretation; Angelica Garcia and Nam-Joon Yi: Drafting the article; Kwang-Woong Lee, June Dong Park, Hyoung Jin Kang, and Joon Gon Kim: Critical revision of the article; Nam-Joon Yi and Kyung-Suk Suh: Approval of the article.
References 1. KOSSEIFI SG, GUHA B, NASSOUR DN, CHI DS, KRISHNASWAMY G. The dapsone hypersensitivity syndrome revisited: A potentially fatal multisystem disorder with prominent hepatopulmonary manifestations. J Occup Med Toxicol 2006: 1: 9. 2. MEHREGAN D. Pigmented purpuric dermatitis. WebMD, LLC. www.rxlist.com 2013. 3. Food and Drug Administration (FDA). Product labeling at DailyMed, National Library of Medicine, NIH 2013. 4. STRINGER JR, BEARD CB, MILLER RF, WAKEFIELD AE. A new name (Pneumocystis jiroveci) for pneumocystis from humans. Emerg Infect Dis 2002: 8: 891–896. 5. ITHA S, KUMAR A, DHINGRA S, CHOUDHURI G. Dapsone induced cholangitis as a part of dapsone syndrome: A case report. BMC Gastroenterol 2003: 3: 21. 6. LORENZ M, WOZEL G, SCHMITT J. Hypersensitivity reactions to dapsone: A systematic review. Acta Derm Venereol 2012: 92: 194–199. 7. CHALASANI P, BAFFOE-BONNIE H, JURADO RL. Dapsone therapy causing sulfone syndrome and lethal hepatic failure in an HIVinfected patient. South Med J 1994: 87: 1145–1146. 8. SHARMA L, GUPTA S. Clinicoepidemiological study of pigmented purpuric dermatoses. Indian Dermatol Online J 2012: 3: 17–20.
Dapsone hypersensitivity induces fulminant liver failure 9. TRISTANI-FIROUZI P, MEADOWS KP, VANDERHOOFT S. Pigmented purpuric eruptions of childhood: A series of cases and review of literature. Pediatr Dermatol 2001: 18: 299–304. 10. TORRELO A, REQUENA C, MEDIERO IG, ZAMBRANO A. Schamberg’s purpura in children: A review of 13 cases. J Am Acad Dermatol 2003: 48: 31–33. 11. SARDANA K, SARKAR R, SEHGAL VN. Pigmented purpuric dermatoses: An overview. Int J Dermatol 2004: 43: 482–488. 12. SELZNER M, KASHFI A, CATTRAL MS, et al. Live donor liver transplantation in high MELD score recipients. Ann Surg 2010: 251: 153–157. 13. YI NJ, SUH KS, LEE HW, et al. Improved outcome of adult recipients with a high model for end-stage liver disease score and a small-for-size graft. Liver Transpl 2009: 15: 496–503.
14. PARK SJ, LIM YS, HWANG S, et al. Emergency adult-to-adult living-donor liver transplantation for acute liver failure in a hepatitis B virus endemic area. Hepatology 2010: 51: 903–911. 15. YAMASHIKI N, SUGAWARA Y, TAMURA S, et al. Outcomes after living donor liver transplantation for acute liver failure in Japan: Results of a nationwide survey. Liver Transpl 2012: 18: 1069–1077. 16. YI NJ, SUH KS, CHO JY, et al. Three-quarters of right liver donors experienced postoperative complications. Liver Transpl 2007: 13: 797–806.
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© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Pediatric Transplantation DOI: 10.1111/petr.12343
Fulminant hepatitis linked to dapsone hypersensitivity syndrome requiring urgent living donor liver transplantation: A case report Garcia A, Yi N-J, Lee KB, Lee J-M, Choi YR, Suh S-W, You T, Lee K-W, Park JD, Kang HJ, Kim JG, Kang EK, Hong G, Suh K-S. (2014) Fulminant hepatitis linked to dapsone hypersensitivity syndrome requiring urgent living donor liver transplantation: A case report. Pediatr Transplant, 18: E240–E245. DOI: 10.1111/petr.12343. Abstract: Dapsone is a sulfone-type drug used widely for different infectious, immune, and hypersensitivity disorders as an antibacterial treatment alone or in combination for leprosy and sometimes for infected skin lesions. DHS is a severe idiosyncratic adverse reaction with multi-organ involvement. However, acute necrotic hepatitis requiring an emergent LT is rare. Herein, we report a case of 12-yr-old girl who suffered from fulminant hepatitis and multi-organ failure due to DHS for PPD. She was saved by emergent LDLT. A high index of suspicion and rapid diagnosis are necessary not to miss this potentially lethal but rare disease.
Angelica Garcia1,*, Nam-Joon Yi1, Kyoung Bun Lee2, Jeong-Moo Lee1, Young Rok Choi1, Suk-Won Suh1, Tae You1, Kwang-Woong Lee1, June Dong Park3, Hyoung Jin Kang3,4, Joon Gon Kim3, Eun Kyeong Kang5, Geun Hong1 and Kyung-Suk Suh1 1
Department of Surgery, Seoul National University College of Medicine, Seoul, Korea, 2Department of Pathology, Seoul National University College of Medicine, Seoul, Korea, 3Department of Pediatrics, Seoul National University College of Medicine, Seoul, Korea, 4Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea, 5Department of Pediatrics, Dongguk University Ilsan Hospital, Goyang, Korea Key words: fulminant hepatitis – dapsone hypersensitivity syndrome – liver transplant – pigmented purpuric dermatosis Nam-Joon Yi, MD, PhD, Associate Professor, Division of HBP Surgery, Department of Surgery, Seoul National University College of Medicine, 101 Daehak-ro, Jongro-gu, 110-744 Seoul, Korea Tel: +82 2 2072 2990 Fax: +82 2 766 3975 E-mail: [email protected] *Present address: Seoul National University Hospital, Seoul, South Korea Accepted for publication 23 July 2014
Dapsone is a sulfone-type bacteriostatic antibiotic used widely for different infectious, immune, and hypersensitivity disorders (1–5). DHS is rare (0.5–3%) but sometimes a serious cause of death (6, 7). The main characteristic of DHS is the Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; DHS, dapsone hypersensitivity syndrome; FANA, fluorescent antinuclear antibody; HD, hospital day; LDLT, living donor liver transplantation; LT, liver transplantation; MELD, model of end-stage liver disease; POD, postoperative day; PPD, pigmented purpuric dermatosis.
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triad of fever, skin eruption, and internal organ involvement (lung, liver, neurological, and other systems). Therefore, laboratory monitoring should be frequently performed during treatment, including complete blood counts and liver function tests. Skin rash must be attended by medical staff. Skin lesions may be a severe idiosyncratic adverse reaction with multi-organ involvement (3). Usual treatment includes discontinuing dapsone and anti-inflammatory steroid pulse therapy. However, fulminant hepatic failure requiring a LT is rare. Herein, we report fulminant hepatitis requiring an emergent living donor liver
Dapsone hypersensitivity induces fulminant liver failure
transplant (LDLT) due to DHS in a 12-yr-old girl with PPD.
(a)
Ethics statement
This study was reviewed and approved by the institutional review board of Seoul National University Hospital (H-1310-020-523). Informed consent was waived by the board. Case report Patient presentation
A 12-yr-old girl was prescribed dapsone as treatment for PPD (Fig. 1). She had no unusual health history and was previously healthy. Twenty days later she developed a high fever (up to 40 °C). Two days after the fever, a skin rash appeared over her body but particularly on the hands, feet, trunk, and face (Fig. 2). The next day, she required hospitalization. The dapsone was discontinued on HD 1. Her laboratory findings were total bilirubin, 1.8 mg/dL (normal reference, total bilirubin 0.2–1.2 mg/dL); ALT, 141 IU/L (normal reference, 0–40 IU/L); AST, 158 IU/L (normal reference, 0–40 IU/L); and creatinine, 0.71 mg/dL (normal reference, 0.70– 1.40 mg/dL). Steroid therapy was started on HD 5. On HD 8, septic shock was suspected because of fever, diminished consciousness level, and hypotension. Thus, she was transferred to the intensive care unit. The laboratory findings revealed that creatinine had increased to 1.37 mg/dL and liver function had worsened. She showed hemolytic anemia, pleural effusion, ascites, and deterioration of liver function on HD 12: white blood cells, 39.46 9 103/lL (normal reference, 4.0–10.0 9 103/lL); hemoglobin,
Fig. 1. PPD of a 12-yr-old girl.
(b)
Fig. 2. Skin lesions after dapsone treatment. (a) Facial skin lesions and edema. (b) Rash on arms and hands.
9.2 g/dL (normal reference, 13–17 g/dL); platelets, 117 9 103/lL (normal reference, 130– 400 9 103/lL); total bilirubin, 11.6 mg/dL; AST, 737 IU/L; ALT, 372 IU/L; albumin, 2.4 mg/dL (normal reference, 3.3–5.2 g/dL); prothrombin time, 15.0 s, 1.4 INR (normal reference, 9.8–12.2 s); D-dimer, 12.24 (normal reference, 0–0.4 lg/mL); lactic acid, 17 mmol/L (normal reference, 0.7–2.5 mmol/L); ammonia, 90 lg/dL (normal reference, 15–51 ㎍/dL); creatinine 0.75 mg/dL (normal reference, 0.70– 1.40 mg/dL), and C-reactive protein, 8.38 mg/ dL (normal reference, 0–0.5 mg/dL). A peripheral blood smear showed normocytic anemia and fragmented red blood cells. A direct Coombs test was positive, C3/C4 was 51 (normal reference, 70–150 mg/dL)/7 mg/dL (normal reference, 10–35 mg/dL), CH50 was 21 (normal reference, 23–46 mg/dL), and unidentified cold autoantibody was positive. She was referred to the Transplant Unit Service of our institution for management of multiorgan failure including fulminant hepatic failure without evidence of infection on HD 14. Her laboratory findings showed altered liver function plus coagulopathy (Fig. 3); total bilirubin, 19.6 mg/dL; AST, 1146 IU/L; ALT, 199 IU/L; and prothrombin, time, 26.8 s, 2.58 INR. On HD 15, she developed hepatic encephalopathy (grade 3) and hepatorenal syndrome requiring mechanical ventilation and renal replacement therapy; ammonia, 124 lg/dL; and creatinine, 2.13 mg/dL. Without evidence of bleeding, her E241
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hemoglobin decreased to 6.3 g/dL and hemolytic anemia was diagnosed. Ceruloplasmin was normal (19.3 mg/dL, normal reference, 15–40 mg/ dL). The direct Coombs test was positive, and C3 (normal reference, 70–150 mg/dL)/C4 (normal reference, 10–35 mg/dL) was low (15 and 3 mg/dL). But FANA test was negative. Serum
IgG and IgM levels were elevated (2272 mg/dL; normal reference, 800–1750 mg/dL and 624 mg/ dL; normal reference, 50–320 mg/dL), but IgA was within normal range (207 mg/dL, normal reference, 69–382 mg/dL). Plasma hemoglobin was negative. Anti-cardiolipin antibodies IgG and IgM, as well as anti-dsDNA, were negative.
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Rituximab and plasma pheresis were applied, and she was registered as UNOS status 1. LT and recovery
She underwent an emergent LDLT on HD 17 because her general condition had deteriorated. At the time of transplantation, the Child–Pugh score was 11, and the MELD score was 38. The donor was her cousin, a 21-yr-old male, and the right graft was used. The operation time for the recipient was 395 min, and ischemic time was 85 min. The explanted liver (Fig. 4) revealed diffuse parenchymal necrosis, stromal hemorrhage in
(a)
the perivenular area with infiltration of lymphocytes in portal tracts. Hemosiderin laden histiocytes were frequently identified around hemorrhage, but eosinophils and neutrophils were rare. Vasculitis or thrombosis was not identified. The histologic findings were summarized as submassive hepatic necrosis compatible with the patient’s clinical situation of fulminant hepatic failure. After the surgery, her recovery was uneventful without neurological sequels. Her mentality was comatose for 48 h, but she became alert on POD 6. She was extubated on POD 7, and renal replacement therapy was discontinued on POD 11. She was transferred to the general ward on POD 29 and discharged on POD 41. During six months after LT, her immunosuppressants were triple therapy composed of low-dose tacrolimus, steroid, and mycophenolate mofetil. She is now on POD 247 and her maintenance immunosuppression is tacrolimus monotherapy. Her laboratory findings, including anemia, liver function, and renal function as well as the skin lesions have completely resolved. Discussion
(b)
Fig. 4. Pathology of the explant liver. In gross examination, totally resected liver was hyperemic and soft without nodular lesion. Microscopy revealed diffuse parenchymal necrosis and stromal hemorrhage in perivenular area with infiltration of lymphocytes in portal tracts. Vasculitis or thrombosis was not identified. Histologic findings are summarized as submassive hepatic necrosis and compatible with the patient’s clinical situation of fulminant hepatic failure. (a) (H&E, 912.5) (b) (H&E, 912.5).
DHS is a rare syndrome first described by Allday, Lowe, and Barnes (6) as a hypersensitivity vasculitis syndrome. DHS is a potentially fatal adverse drug reaction with unknown prevalence and risk factors. Symptoms appear as early as 2–6 h or as late as six months after initial administration of the drug. This variability in latency is related to dose and treatment modality. The main characteristics of DHS are fever, skin eruption, and internal organ involvement. Other side effects uncommonly associated are severe hemolysis, peripheral neuropathy, acute psychosis, nephrotic syndrome, hypersensitivity reactions, and lupus-like syndrome (3). The cutaneous lesions can be erythematous papules, plaques, pustules, or eczematous lesions. The severity of the cutaneous changes does not correlate with the severity of the internal organ involvement. Usually, these skin lesions resolve within two wk after stopping therapy. This disease can also be related to severe entities such as Steven–Johnson syndrome or toxic epidermal necrolysis. Factors that may complicate the illness are severe cases of malnutrition, protein loss, or secondary infection. Pulmonary manifestations are related with eosinophilic pneumonia, hypersensitivity pneumonia, and pleural effusion. Rapid clinical deterioration can lead to respiratory failure and can be the main E243
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cause of severe organ dysfunction and/or death if not treated or be unrecognized. A systematic review (6) reported on 114 articles (17 epidemiological and 97 case reports) including 336 patients with DHS. The total prevalence rate of DHS was 1.4%. Mucosal involvement, hepatitis, higher age, and disease occurrence in non-affluent countries were associated with a higher risk for a fatal outcome, with an overall fatality of 9.9%. Rechallenge with dapsone should not be undertaken in these patients and they must be told that they are allergic to sulfa drugs. Patients with DHS and the medical staff must know that they can develop an allergy to any kind of sulfa drug and must be aware of what medications they cannot take for the rest of their life. The symptoms of this patient fit all associated side effects of dapsone. Thus, it was diagnosed as DHS, which induced fulminant hepatic failure. Most cases of hepatotoxicity resolve rapidly within 2–4 wk after stopping dapsone unless the cholestasis is severe. Dapsone hepatotoxicity is a dose-dependent effect, and hepatic injury can also be sustained due to other sulfone drugs. The best approach to DHS is immediate discontinuation of the drug and prompt administration of oral or intravenous glucocorticoids. However, steroid therapy has variable success. In this particular patient, the use of steroid therapy had no effect, and her clinical course deteriorated, requiring LT. One of our main concerns in this case was that the first diagnosis of PPD may have triggered the final evolution of severe DHS. PPD is a spectrum of idiopathic disorders, also considered as a group of vascular disorders (8), and unknown etiology, although aberrant cell-mediated immunity has been proposed (9). Cell-mediated immunity might play a role in Schamberg’s disease (8), and lichen aureus could be associated with trauma and hepatitis (10). Moreover, PPD can also be related with underlying diseases (11). However, we did not recognize the underlying liver disease because the explanted liver was totally necrotic, and other findings were similar to lupus-like syndrome overlapping with DHS. On the other hand, in this case, an emergent LDLT for fulminant hepatic failure was conducted within 48 h. In 2002, the New York State Committee on Quality Improvement in Living Liver Donation recommended that adult-toadult LDLT should be prohibited in recipients with MELD scores 25 (12). However, recent data from a few large-center studies show that LDLT is a safe and effective treatment modality, even in adult recipients in poor condition (13–15). The E244
urgent use of a living donor organ for acute liver failure has not been prohibited in Korea, if the full evaluation is complete and the institutional ethical committee and national organ sharing network committee permits the procedure in a live donor within the third degree of consanguinity (16). LDLT may potentially lead to better outcomes and the rapid course of acute liver failure provides only a very narrow window for LT. The donor outcome of this report was uneventful. In conclusion, DHS is a rare entity. This is the first case report of LDLT for fulminant hepatic failure due to DHS. Therefore, we must be alert because it could be potentially fatal. Monitoring laboratory studies must be performed during the administration of the drug. The patient must be educated that in case of any rash or systemic symptoms to go immediately to the emergency room. Due to the wide indications for dapsone use, all medical specialties may be familiar to DHS. A high index of suspicion and rapid diagnosis are necessary not to miss this potentially lethal but rare disease. Authors’ contribution Angelica Garcia and Nam-Joon Yi: Concept/design; Angelica Garcia, Nam-Joon Yi, Jeong-Moo Lee, Eun Kyeong Kang, June Dong Park and Geun Hong: Data collection; Kyoung Bun Lee, Young Rok Choi, Suk-Won Suh, Tae You: Data interpretation; Angelica Garcia and Nam-Joon Yi: Drafting the article; Kwang-Woong Lee, June Dong Park, Hyoung Jin Kang, and Joon Gon Kim: Critical revision of the article; Nam-Joon Yi and Kyung-Suk Suh: Approval of the article.
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14. PARK SJ, LIM YS, HWANG S, et al. Emergency adult-to-adult living-donor liver transplantation for acute liver failure in a hepatitis B virus endemic area. Hepatology 2010: 51: 903–911. 15. YAMASHIKI N, SUGAWARA Y, TAMURA S, et al. Outcomes after living donor liver transplantation for acute liver failure in Japan: Results of a nationwide survey. Liver Transpl 2012: 18: 1069–1077. 16. YI NJ, SUH KS, CHO JY, et al. Three-quarters of right liver donors experienced postoperative complications. Liver Transpl 2007: 13: 797–806.
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