Sarcoidosis and interferon therapy: report of five cases and review of the literature

European Journal of Internal Medicine 14 (2003) 237–243 www.elsevier.com / locate / ejim

Original article

Sarcoidosis and interferon therapy: report of five cases and review of the literature ´ Stephanie Leclerc a , Robert P. Myers b , Joseph Moussalli b , Serge Herson a , Thierry Poynard b , a, Olivier Benveniste * a

´ ´ ˆ ` , 47 – 83, boulevard de l’ Hopital ˆ , 75651 Paris Cedex 13, France Service de Medecine Interne, Groupe Hospitalier Pitie-Salpetriere ´ ´ ˆ ´ ˆ ` , 47 – 83, boulevard de l’ Hopital ˆ , Hopital Pitie-Salpetriere , 75651 Paris Cedex 13, France Service de Hepato-gastro-enterotologie

b

Received 10 October 2002; received in revised form 11 December 2002; accepted 16 January 2003

Abstract Background: Sarcoidosis is a multi-system disease of unknown etiology. Interferons (IFN) have been implicated in its pathogenesis. The objective of this study was to examine the causal relationship between sarcoidosis and IFN therapy. Methods: Patients admitted for sarcoidosis (n560) were reviewed for a history of IFN therapy. In addition, all cases of sarcoidosis in a cohort of hepatitis C-infected patients treated with IFN-a (n51159) were analyzed. Results: Five patients with prior IFN-a therapy and sarcoidosis were identified; an additional 23 have been reported in the literature. The median age of the 28 reported patients was 50 years, 16 (57%) were female, and 16 (57%) had isolated cutaneous disease. The median time to diagnosis was 4 months (range 1–16 months) following the introduction of IFN. A remission was observed in all patients with adequate follow-up (n527): 15 (53%) upon dosage reduction or IFN discontinuation, seven (25%) with systemic corticosteroids, three (11%) with topical treatment, and three (11%) despite ongoing IFN therapy. Relapse was observed in both of the patients rechallenged with IFN. Conclusions: There is a potential causal relationship between IFN therapy and sarcoidosis. In patients with sarcoidosis in the setting of IFN therapy, the majority respond to IFN withdrawal or dosage reduction; however, some require corticosteroid therapy.  2003 Elsevier B.V. All rights reserved. Keywords: Adverse effects; Cytokine; Hepatitis C; Interferon; Sarcoidosis

1. Introduction Sarcoidosis is a chronic multi-system disease of unknown etiology, characterized histologically by the formation of non-caseating granulomas [1,2]. The immunopathology of sarcoidosis has been best characterized in cases of pulmonary disease, in which early lesions consist of an alveolitis with a high proportion of activated CD 4 lymphocytes. These lymphocytes are primarily of the Th1 phenotype, that is, they secrete cytokines including inter*Corresponding author. Tel.: 133-1-4216-1090; fax: 133-1-42161065. E-mail address: [email protected] (O. Benveniste). 0953-6205 / 03 / $ – see front matter  2003 Elsevier B.V. All rights reserved. doi:10.1016 / S0953-6205(03)00078-5

leukin (IL)-2, IL-12, interferon (IFN)-g, and tumor necrosis factor (TNF)-a [3,4]. These cytokines appear to be involved in the regulation of granuloma formation, a fact that may explain the efficacy of anti-TNF-a therapy [5]. Another cytokine, IFN-a, may also play a role in this condition [6]. In experimental studies, IFN-a activates T lymphocytes and promotes the secretion of IFN-g and IL-2 [7]. Furthermore, in therapeutic doses, IFN-a is known to induce autoimmune disorders including thyroiditis, cytopenias, and symmetric polyarthropathies [8]. The prevalence of sarcoidosis ranges from 10 to 47 per 100 000 in North America and France; a higher prevalence is reported in African-Americans [9]. Chronic hepatitis C virus (HCV) infection is found in 1–2% of the American and French populations [10,11]. Since the approval of

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IFN-a for the treatment of this condition, approximately 50 000 French patients have received this therapy [12]. Thus far, 23 cases of sarcoidosis in patients who have received IFN therapy have been reported in the literature [13–31]. The question still under debate is whether or not this represents a true causal relationship or the random association of two relatively frequent events. Because of the high prevalence of chronic HCV infection and the fact that therapeutic regimens including IFN are the only approved treatment, this disease is ideal for the study of this potential association. The objective of the current study was to address the relationship between sarcoidosis and IFN therapy by analyzing a well-described cohort of patients with chronic hepatitis C. In addition, a sample of patients requiring hospital admission for severe sarcoidosis was reviewed for a history of prior IFN therapy. Finally, the cases reported previously in the literature were reviewed.

2. Methods We analyzed two populations of patients followed at the ˆ ˆ ` in Paris, France. First, all admis´ Hopital Pitie-Salpetriere sions to the Department of Internal Medicine for a diagnosis of sarcoidosis were collected between January 1997 and June 2001 (n560). The median age was 49 years (range 18–67 years) and 34 (57%) of the patients were female. Second, a previously described cohort of patients with chronic hepatitis C (DOSVIRC) [32], followed in the Department of Gastroenterology and Hepatology, was analyzed (n53560). This cohort was retrospectively constituted before 1993 and prospectively thereafter. All patients had chronic hepatitis C as defined by the presence of antibodies to HCV (with at least a second-generation, enzyme-linked immunosorbent assay) and HCV RNA in serum by polymerase chain reaction assay. Of these patients, 1159 (33%) had previously received IFN therapy. The median age and duration of infection at the time of treatment were 45 years (range 15–81 years) and 15 years (1–51 years), respectively. Forty-one percent (474 / 1159) were female. A diagnosis of sarcoidosis was made according to the criteria of the American Thoracic Society and European Respiratory Society [33]. To retrieve prior reports of sarcoidosis in the setting of IFN therapy, MEDLINE was searched using the terms ‘interferon’, ‘IFN’, and ‘sarcoidosis’. Relevant publications were also identified via a search of the reference lists of the retrieved articles.

3. Case reports A total of five patients with a diagnosis of sarcoidosis and prior IFN therapy, all for chronic hepatitis C, were identified. Two patients were selected from the cohort of

inpatient admissions, and the remaining three patients from the cohort of outpatients with chronic hepatitis C. No case of sarcoidosis was identified among untreated patients with chronic hepatitis C. An additional 23 cases were retrieved via our review of the literature (Table 1) [13–31].

3.1. Case 1 In 1995, a 55-year-old female Caucasian diagnosed with sporadic chronic hepatitis C (genotype 1b). The alanine aminotransferase (ALT) and aspartate aminotransferase (AST) concentrations were both 1.5 times the upper limit of normal. Percutaneous liver biopsies in 1996 and 2000 revealed A1, F1 histologic changes as assessed by the Metavir scoring system [34]. In February 2000, a diagnosis of Gougerot-Sjogren syndrome was made, based on a constellation of symptoms including sicca syndrome, Raynaud’s phenomenon, and arthralgias, and a grade 4 Shisolm score on a salivary gland biopsy. In April 2000, the patient started IFN-a 3 million international units (MU) three times weekly and ribavirin 1000 mg / day. In June 2000, 2 months after starting antiviral therapy, the patient complained of chronic fatigue. Four months later, she noticed toughening and pigmentation of scars related to a previous appendectomy and blepharoplasty. A chest radiograph, which was normal prior to the initiation of IFN, showed bilateral interstitial infiltrates. In December 2000, the patient complained of increasing fatigue, myalgia, and moderate dyspnea. In addition, the changes in her scars had worsened. A CT scan of the chest showed mediastinal lymphadenopathy, interstitial infiltrates, and micronodules. The serum angiotensin conversion enzyme (ACE) concentration was elevated to 147 IU / ml (normal, 100 IU / ml) and the patient was lymphopenic (265 / mm 3 , normal.1500 / mm 3 ). A biopsy of her appendectomy scar revealed non-caseating granulomas containing epithelioid and giant cells. A diagnosis of systemic sarcoidosis was made, prompting the discontinuation of IFN-a and ribavirin. Within 1 month, she noticed an improvement in the changes in her scars. Six months later, a repeat CT scan of the chest revealed an improvement in the previously noted lesions. Despite less than 8 months of antiviral therapy, serum HCV RNA became undetectable and remained so until the end of follow-up.

3.2. Case 2 A 50-year-old Caucasian, female nurse was diagnosed with chronic hepatitis C in 1998 during a pretransfusion evaluation. The AST and ALT concentrations were two times the upper limit of normal, and serum HCV RNA by polymerase chain reaction assay was positive. Liver histology revealed mild chronic hepatitis and no fibrosis (Metavir score A0, F0). Despite the absence of fibrosis, the patient’s concerns about occupational transmission promp-

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Table 1 Characteristics of 28 patients with sarcoidosis in the setting of IFN therapy Reference

Age / sex

IFN 6RBV

Indication for IFN

Dose (duration)

Time to sarcoidosis a

Treatment

Time to remission

[13] [14] [15]

62 / F 52 / F 60 / F

a a / RBV a2a

HCV HCV HCV

3 MU tiw (2 months) 3 MU tiw (12 months) 6 MU tiw (17 months)

2 months 1 week after D/ C 4 months

24 months 3 weeks N /A

[16] [17]

35 39 / F

a2b a / RBV

HBV HCV

4 months 4 weeks after D/ C

[18]

50 / F

a

CML

5 MU tiw (4 months) 3 MU tiw (12 months); RBV (6 months) 8 MU daily (12 months)

IFN D/ C; C / S IFN / RBV D/ C IFN reduction; topical C / S IFN continued C/S IFN D/ C

6 weeks

[19] [20]

31 / M 41 / M

a a

CML HCV

4 months (7 months after reintro) 16 months 12 weeks

IFN D/ C IFN D/ C

2 months 2 months

[20]

39 / M

a

HCV

20 weeks

IFN D/ C

5 months

[20]

54 / M

a / RBV

HCV

4 weeks

IFN D/ C

8 months

[21]

57 / F

b1b

MS

2 months

9 months

[22] [23]

67 / M 48 / F

a a

HCV CML

5 months 8 months

N /A 8 months

[24] [25] [26] [27]

50 / F 45 / F 62 / F 57 / F

b a2b a2a b

MM CML HCV RCC

5 8 8 9

C/S IFN D/ C C/S IFN D/ C

N /A 3 months N /A N /A

[28] [29] [29] [30]

40 / M 44 / F 30 / F 50 / F

HCV HCV HCV HCV

15 days 3 months 2 months 1 month

IFN D/ C IFN / RBV D/ C IFN / RBV D/ C C/S

6 weeks 6 months 2 months N /A

[30]

38 / M

5 months

64 / M 55 / F 55 / F

HBV HCV HCV

Case 3 Case 4 Case 5

44 / M 58 / M 60 / M

a a / RBV a / RBV

HCV HCV HCV

3 MU tiw (6 months) 3 MU tiw (14 months) 3 MU tiw (11 months)

IFN / RBV/AMT D/ C C / S None IFN / RBV D/ C IFN / RBV D/ C, topical C / S N /A IFN continued IFN / RBV D/ C

6 months

[31] Case 1 Case 2

a a / RBV a / RBV a / RBV/ AMT a / RBV/ AMT a2b a / RBV a / RBV

Total 60 MU (5 months) 6 MU daily (7 months); 9 MU daily (1 month); 5 MU daily (3 months) 3 MU tiw 8 MU daily (8 months) 6 MU tiw (8 months) 30 MU daily every 3 weeks (9 months) 3 MU tiw 3 MU tiw (6 months) 3 MU tiw 9 MU daily (1 months) 3 MU tiw (8 months) 9 MU daily (1 month) 3 MU tiw (4 months) 5 MU tiw (4 months) 3 MU tiw (9 months) 3 MU tiw (12 months)

IFN D/ C, PUVA, nivaquin IFN D/ C; C / S IFN reduction

HCV

6 6 3 6 3 6 3 3

MU MU MU MU MU MU MU MU

daily (16 months) daily (4 weeks); daily (8 weeks) daily (12 weeks); daily (8 weeks) daily (4 weeks); daily (8 weeks) tiw (2 months)

months months months months

24 months 2 months 8 months 48 months 4 months 11 months

3 months 8 weeks

12 months 1 month 1 month N /A 8 months 1 month

CML, chronic myelogenous leukemia; C / S, corticosteroids; CXR, chest radiograph; D/ C, discontinuation; F; female; HBV, hepatitis B virus; HCV, hepatitis C virus; MS, multiple sclerosis; IFN, interferon; M, male; MM, multiple myeloma; MU, million international units; N /A, not available; PUVA, psoralen and ultraviolet light therapy; RBV, ribavirin; AMT, amantadine; RCC, renal cell carcinoma; reintro, reintroduction; tiw, three times weekly. a Time to sarcoidosis onset or relapse reported following the introduction of IFN unless otherwise indicated.

ted the initiation of IFN-a 3 MU three times weekly and ribavirin 1000 mg / day in February 1999. The patient had previously been diagnosed with pulmonary sarcoidosis and had been treated with prednisolone for 2 years, beginning in 1978. She was considered cured, based on the resolution of symptoms and a normal posttreatment chest radiograph in 1993. Eight months following the institution of IFN-a and ribavirin, erythematous papules on the nose and neck were noted. Subsequent investigations included a biopsy of one of these lesions; histology revealed non-caseating granulomas with epithelioid cells. Blood samples showed lymphopenia (910 /

mm 3 ) and an elevated ACE concentration (64 IU / ml, normal,52 IU / ml). Bilateral interstitial infiltrates were also found on a chest radiograph. The patient was diagnosed with a relapse of systemic sarcoidosis, prompting discontinuation of IFN-a and ribavirin, now 12 months after commencing therapy. One month later, she received topical corticosteroids for her rash. These approaches led to a progressive and complete regression of the skin and pulmonary lesions. Her sarcoidosis remains in remission, and she has demonstrated a sustained, virologic response, as demonstrated by persistently negative serum HCV RNA.

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3.3. Case 3 A 44-year-old black male with chronic hepatitis C was treated with IFN-a therapy in 1995. After 6 months of treatment, the patient remained viremic and treatment was discontinued. In August 1999, the AST and ALT concentrations were 5.5 times the upper limit of normal and the serum remained positive for HCV RNA. A liver biopsy revealed cirrhosis with severe necroinflammatory activity (Metavir score A3, F4), and a routine chest radiograph showed mediastinal and hilar lymphadenopathy, as well as interstitial infiltrates (especially of the left lower lobe). A fiber-optic bronchoscopy revealed nodules which, on biopsy, contained non-caseating granulomas. The serum ACE concentration was 1.5 times the upper limit of normal. A diagnosis of systemic sarcoidosis was made. However, the patient was lost to follow-up.

3.4. Case 4 A 58-year-old male Caucasian with a previous diagnosis of systemic sarcoidosis in 1975 was diagnosed in 1995 with a transfusionally acquired HCV infection (genotype 2). In 1997, liver histology revealed cirrhosis with minimal necroinflammatory activity (Metavir score A0, F4). IFN-a therapy, 3 MU three times weekly, was started in October 1997 and ribavirin was added in July 1998. Seven months later, the patient complained of chest pain and dyspnea. A chest radiograph showed bilateral hilar lymphadenopathy and interstitial infiltrates that had a ground glass appearance on CT scan. Bronchoalveolar lavage fluid, obtained via a grossly normal fiber-optic bronchoscopic examination, revealed 40% lymphocytes, predominantly of the CD 4 type. Based on these findings, the patient was diagnosed with a relapse of systemic sarcoidosis. Despite continuation of IFN-a therapy, the patient had a spontaneous remission of his respiratory symptoms in May 1998. A CT scan of the chest at that time was normal. In December 1998, IFN was discontinued but was reintroduced as monotherapy from December 1999 to August 2000. Despite this, the serum HCV RNA remained positive. In January 2001, the patient noticed a nodule on his right elbow, histology of which revealed non-caseating granulomas with epithelioid and giant cells consistent with cutaneous sarcoidosis. After clinical examination, a chest radiograph, pulmonary function tests, and serum samples did not show any evidence to support a diagnosis of systemic sarcoidosis. Consequently, oral corticosteroids were not introduced.

3.5. Case 5 A 60-year-old male Caucasian was diagnosed with chronic hepatitis C (genotype 1b) in 1998. A liver biopsy revealed A2, F3 histologic changes. He was treated with IFN-a 3 MU three times weekly and ribavirin 1000 mg /

day beginning in March 2000. In December 2000, the patient complained of progressive fatigue, arthralgias in his hands, and dyspnea. Clinical examination revealed violaceous nodules on several digits, the right canthus, and the left elbow (sites of previous childhood trauma). A cutaneous biopsy confirmed granulomatous changes typical of sarcoidosis, and a chest radiograph showed an alveolo-interstitial pattern. The latter was confirmed on a CT scan that also demonstrated micronodules and moderate fibrosis. Pulmonary function tests revealed a restrictive ventilatory defect (vital capacity 76% of predicted; FEV1 / FVC ratio 86.4%; DL CO / VA 85% of predicted). Additional investigations revealed lymphopenia (520 / mm 3 ) and an elevated serum ACE concentration (175 IU / ml). Based on these findings, a diagnosis of systemic sarcoidosis was made. As a result, despite ongoing viremia, IFN-a and ribavirin were discontinued 11 months after their introduction. The patient noticed a gradual improvement in the cutaneous lesions and a marked reduction in his dyspnea. Because of ongoing pulmonary lesions and mild symptoms, however, corticosteroids (1 mg / kg per day) were initiated in April 2001. His symptoms subsequently abated and regression of the pulmonary lesions was observed on a follow-up CT scan.

4. Discussion The first case of sarcoidosis following IFN therapy was reported in 1987 [27]. Since then, an additional 23 cases have been described (Table 1) [13–26,28–31]. We report an additional five cases in patients receiving IFN-a therapy for chronic hepatitis C. Among the 28 patients thus far reported, 16 (57%) have been female with a median age of 50 years (range 30–67 years). Sixteen patients (57%) have had isolated cutaneous involvement, independent of IFN injection sites. These characteristics are in accordance with previous studies of sarcoidosis unrelated to IFN therapy [9]. Of the 28 cases thus far described, the majority (23 / 28; 82%) received the alpha (a) formulation of IFN in doses ranging from 3 MU three times weekly to 9 MU daily; the higher doses were reserved for the treatment of chronic myelogenous leukemia. Nineteen patients (68%) were treated for HCV infection; the majority (11 / 19, 58%) also received ribavirin, and others presented with chronic myelomatous leukemia, HBV infection, multiple myeloma, multiple sclerosis, and renal cell carcinoma. IFN is a commonly prescribed medication, particularly in the management of chronic viral hepatitis; sarcoidosis, too, is not rare. The dilemma, then, is to differentiate the coincidental occurrence of two ‘common’ events from a true causal relationship. To implicate a treatment in the pathogenesis of a secondary disease, one must satisfy several criteria, including an appropriate temporal relationship, relapse with rechallenge, biologic plausibility, and

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the lack of an alternative explanation. We will consider these in turn with respect to sarcoidosis and IFN therapy. The temporal relationship between IFN therapy and the appearance of sarcoidosis was variable. In the 24 patients with a new onset or relapse of sarcoidosis during treatment with IFN, the diagnosis was made within 4 weeks to 24 months (median 4 months) of its introduction. An additional patient noticed an exacerbation of pre-existing symptoms within 15 days of starting IFN, and three others were diagnosed following its discontinuation (at 1 and 4 weeks, and at 4 years in the third case of our series). The relationship between IFN and the onset of sarcoidosis is debatable in the latter patient. Nevertheless, a causal association is strengthened by the resolution of symptoms after IFN discontinuation or dosage reduction in the absence of additional interventions in 15 of the 28 cases (53%) with adequate follow-up. Admittedly, in the absence of a ‘control’ group continuing IFN therapy, differentiation of this apparent treatment response from the natural history of sarcoidosis is difficult, since spontaneous remissions have been reported in a similar proportion of patients [35]. In addition, in three cases (11%), a remission was observed despite ongoing IFN treatment. It is possible that IFN therapy triggered the events leading to granulomatous reactions in these patients, yet the effect was temporary due to adaptive host mechanisms. Indeed, immune responses are strikingly heterogenous and may vary markedly during the course of IFN therapy [36]. In the remaining patients, adjuvant therapy consisting of oral corticosteroids was required in seven cases (25%) with systemic symptoms, and an additional three patients (13%) received topical treatments (corticosteroids, ultraviolet light) for cutaneous disease. All experienced remission of their sarcoidosis-related symptoms. In both of the reported cases describing rechallenge with IFN (case 4 [28]), a recurrence of symptoms was observed. In one case, pulmonary sarcoidosis recurred 7 months after the reintroduction of IFN for chronic myelogenous leukemia, despite its previous resolution within 6 weeks of IFN discontinuation [28]. In case 4 of our series, the patient originally experienced respiratory symptoms following the introduction of IFN; these symptoms resolved spontaneously despite IFN continuation. Five months after the discontinuation of a second course of IFN therapy, the patient experienced a relapse of histologically confirmed cutaneous sarcoidosis. Although only observed in two patients, these relapses support a causal relationship between IFN therapy and sarcoidosis since the natural history of this disease after complete remission is generally one of long-term stability [35]. The potential role of IFN therapy in the pathogenesis of sarcoidosis is also supported by its biologic plausibility. Although the etiology of sarcoidosis is unknown, the immune system appears to play an important role [1,2]. Experimental studies have confirmed that IFN-a is involved in the activation of T lymphocytes and their

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production of other cytokines including IFN-g and IL-2 [7]. Both of these cytokines have been implicated in the formation of granulomas, the pathognomonic histologic feature of sarcoidosis [4]. In addition, IFN-g and IL-2 are found in high concentrations in the bronchoalveolar lavage fluid of patients with active pulmonary sarcoidosis [3,4]. Finally, IFN in therapeutic doses is known to precipitate a variety of autoimmune conditions [8]. The absence of a likely alternative explanation is additional proof implicating IFN therapy in the pathogenesis of sarcoidosis in these patients. However, since detailed information regarding environmental exposure to agents implicated in the development of sarcoidosis-like lesions (e.g. beryllium and talc) is not available, we cannot exclude these potential explanations. In addition, the skeptic may argue that the patients described herein suffered from a variety of chronic infections and malignancies, all of which have been reported in association with sarcoidosis in the absence of IFN therapy. However, the majority of the cases, including all of our own, were treated for chronic hepatitis C. Indeed, in support of the ‘skeptic’s argument’, HCV infection has been associated with autoimmune conditions, particularly essential mixed cryoglobulinemia [32]. Furthermore, chronic HCV infection promotes a Th1 lymphocyte response [37]; this profile appears to be important for the formation of the granulomas of sarcoidosis. However, the remission of sarcoidosis in several patients despite the presence of ongoing HCV viremia, and the failure to find an increased prevalence of anti-HCV antibodies in patients with sarcoidosis [35,38], argue strongly against anything but a coincidental association between these conditions. The sum of the available evidence suggests that sarcoidosis may be precipitated or exacerbated in patients receiving IFN therapy. Nevertheless, this phenomenon remains rare: of 1159 patients receiving IFN-a for chronic HCV infection, only one (case 5) was newly diagnosed with sarcoidosis (incidence, 0.09%). Based on our prospective series of 60 patients requiring hospital admission for sarcoidosis, two had a history of IFN-a therapy (prevalence of prior IFN therapy, 3.3%). The significance of these figures, however, is difficult to assess in light of the hundreds of thousands of patients who have been treated with IFN globally. Selection bias by our series and / or underreporting of cases by others may account for our apparent over-estimation. In summary, although rare, relapse of pre-existing sarcoidosis or precipitation of new cases may be an adverse effect of IFN therapy. In over half of the patients thus far reported, sarcoidosis-related symptoms responded to a reduction in dosage or discontinuation of IFN; however, some required adjuvant treatments including systemic corticosteroids. In a minority, symptoms resolved despite continuation of IFN therapy. The association between sarcoidosis and therapeutic doses of IFN supports experimental evidence that IFN may be implicated in the

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pathogenesis of this disease and represents a potential avenue for future research into this enigmatic problem.

5. Notation ACE, angiotensin converting enzyme; HCV, hepatitis C virus; IFN, interferon; IL, interleukin; MU, million international units; TNF, tumor necrosis factor

Acknowledgements Dr Myers is supported by the Dr V. Feinman Hepatology Fellowship from the Canadian Association for the Study of the Liver and Schering Canada, and the Detweiler Traveling Fellowship from the Royal College of Physicians and Surgeons of Canada.

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