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CONTENTS 2014 2(2):65–141
Original Article
Patient Characteristics, Safety, and Tolerability With Telaprevir Treatment for HCV in the Clinic: a Retrospective, Multicenter Study Steven L. Flamm, Paul J. Pockros, Leif Bengtsson and Mark Friedman ...... 65
Review Articles
An Update on Treatment of Drug-Induced Liver Injury Christin Giordano, John Rivas and Xaralambos Zervos ...... 74 Traditional Chinese Medicine Induced Liver Injury Rolf Teschke ...... 80 Hepatotoxicity Secondary to Chemotherapy Alla Grigorian and Christopher B. O’Brien ...... 95 Pathology of Alcoholic Liver Disease Romulo Celli and Xuchen Zhang ...... 103 Clinical Application of Transient Elastography in the Diagnosis of Liver Fibrosis: an Expert Panel Review and Opinion Expert Panel on Liver Stiffness Measurement ...... 110 Maternal-Fetal Hepatitis E Transmission: Is It Underestimated? Maysaa El Sayed Zaki, Mohammed Magdy Abd El Razek and Hassan Magdy Abd El Razek ...... 117 Management of Hepatitis C Before and After Liver Transplantation in the Era of Rapidly Evolving Therapeutic Advances Chalermrat Bunchorntavakul and K. Rajender Reddy ...... 124 Interaction Between the Neglected Tropical Disease Human Schistosomiasis and HCV Infection in Egypt: a Puzzling Relationship Mahmoud M. Bahgat ...... 134 Original Article
Patient Characteristics, Safety, and Tolerability With Telaprevir Treatment for HCV in the Clinic: a Retrospective, Multicenter Study
Steven L. Flamm1, Paul J. Pockros2, Leif Bengtsson3 and Mark Friedman3
1Northwestern University, Feinberg School of Medicine, Chicago, Illinois, USA; 2Scripps Clinic and Scripps Translational Science Institute, La Jolla, California, USA; 3Vertex Pharmaceuticals Incorporated, Boston, Massachusetts, USA
Abstract Introduction
Background and Aims: There is a paucity of information Randomized, controlled clinical studies are considered the regarding similarities and differences between patients from gold standard for the evaluation of efficacy, safety, and the phase 3 studies of telaprevir and those receiving tolerability of pharmaceutical drugs.1,2 Such studies allow telaprevir in clinical practice. Methods: This retrospective for rigorous assessment of these parameters in controlled chart review evaluated baseline characteristics and follow-up settings that prevent potential confounds when observing a safety and tolerability data for patients with hepatitis C virus drug’s effect(s).3 These studies, however, have important (HCV) infection treated with telaprevir and peginterferon alfa characteristics that may limit the generalizability of results, and ribavirin (PR) in clinical practice. Results: In total, 338 including evaluation of efficacy, safety, and/or tolerability in charts from patients at four academic and three community select patient populations with well-defined and often limited US treatment centers who received telaprevir and PR and had medical comorbidities. These include underrepresentation of at least 12 weeks of follow-updata were included; 62% were the elderly and women, patient selection bias, restrictions from academic centers and 38% were from community regarding concomitant medications, and intensive medical centers. Of the 338 patients, 269 completed 12 weeks of follow-upthat is generally not possiblein routine clinical telaprevir and PR; 32 discontinued due to adverse events. care.1,2,4 Such limitations have prompted the use of alter- Mean age was 55 years; patients were predominantly white native complementary approaches to assess drug treatment (79.3%) males (58.9%) with genotype 1a HCV infection outcomes in a clinical practice setting,4 including the assess- (61.8%); 35.5% were reported to have cirrhosis at baseline; ment of medical claims data, establishment of patient and 55.3% previously received PR. Hypertension and depres- registries, patient surveys, and retrospective review of sion were the most common comorbidities. Patient charac- patient charts from a clinical practice setting. Each of these teristics outside the per-protocol minimum criteria used in methods has been employed to evaluate the benefits and the phase 3 studies of telaprevir were, e.g., hemoglobin, risks associated with specific treatments for patients with 9.2%; albumin, 5.3%; platelets, 11.5%; and neutrophil chronic hepatitis C virus (HCV) infection,5–11 thereby provid- count, 5.6%. Adverse events occurred in 329/338 (97.3%) ing valuable information on factors influencing treatment patients, with anemia, fatigue, nausea, and rash being the adherence, underrepresentation of patients in clinical stu- most common. Of 38 hospitalizations, 26 were deemed dies, economic burden of treatment, management of patients related to telaprevir and PR. Three patients died due to with HCV infection, and treatment outcomes. pneumonia, septic shock, and hepatorenal syndrome (n51 The efficacy, safety, and tolerability of telaprevir, an NS3/ each). Conclusions: These findings complement those 4A protease inhibitor, in combination with peginterferon alfa reported from rigorous, randomized controlled studies with and ribavirin (PR) have been evaluated in three randomized, telaprevir-based treatment and provide a general assess- well-controlled, phase 3 clinical studies in patients with ment of similarities and/or differences between patients from genotype 1 chronic HCV infection. The ADVANCE12 and the phase 3 studies of telaprevir and those treated with ILLUMINATE13 studies enrolled treatment-naı¨ve patients, telaprevir in clinical practice. and the REALIZE study14 enrolled patients who had not 2014 The Second Affiliated Hospital of Chongqing Medical E achieved sustained virologic response (SVR) with prior University. Published by XIA & HE Publishing Ltd. All rights combination therapy with PR. Telaprevir administered in reserved. combination with PR for 12 weeks, followed by 12 or 36 weeks of PR alone, was associated with significantly improved Keywords: Hepatitis C virus; Combination drug therapy; Protease inhibitors; SVR rates versus PR alone in treatment-naı¨ve (74%–79% Liver diseases. versus 46%) and previously treated (32%–86% versus 5%– Abbreviations: AE, adverse event; HCV, hepatitis C virus; IL28B, interleukin 15 28B; IRB, institutional review board; PR, peginterferon alfa and ribavirin; SAE, 22%) patients. Adverse events (AEs) that occurred more serious adverse event; SVR, sustained virologic response. often (o5% higher frequency) with telaprevir and PR Received: 11 February 2014; Revised: 16 April 2014; Accepted: 18 April 2014 compared with PR alone included rash (56% vs 34%, q DOI of original article: 10.14218/JCTH.2014.00007. respectively), fatigue (56% vs 50%), pruritus (47% vs Correspondence to: Steven L. Flamm, Northwestern University, Feinberg School of Medicine, 676 N. Saint Clair, Arkes 19-041, Chicago, IL 60611, USA. Tel: +1- 28%), nausea (39% vs 28%), anemia (36% vs 17%), 312-695-1681, Fax: +1-312-695-5998, Email: [email protected] diarrhea (26% vs 17%), vomiting (13% vs 8%), hemorrhoids
Journal of Clinical and Translational Hepatology 2014 vol. 2 | 65–73 Flamm S.L. et al.: Telaprevir Treatment for HCV in Clinical Practice
(12% vs 3%), anorectal discomfort (11% vs 3%), dysgeusia of all participating centers waived the need for written (10% vs 3%), and anal pruritus (6% vs 1%).12,14,15 Serious informed consent from the patients. skin reactions, including drug reaction with eosinophilia and systemic symptoms and Stevens-Johnson Syndrome, were Inclusion criteria reported in ,1% of patients who received telaprevir and PR.15 All three phase 3 studies of telaprevir were controlled, Charts for the first 50 patients with genotype 1 chronic HCV with randomized, double-blind study designs, well-defined infection who received telaprevir and PR at one of seven US inclusion and exclusion criteria, and careful patient follow-up, treatment centers shortly after marketing approval of tela- and each study provided important data on treatment previr was granted were used (all patients began therapy response with telaprevir and PR for patients with HCV between May and September 2011). Some sites were infection. However, as with all randomized, controlled clinical permitted to provide more charts (no more than 70 con- studies, the study designs inherently limit the generalizability secutive charts) to compensate for sites that provided fewer of the results to real-world clinical practice settings. In than 50 charts. Patient charts were required to include particular, the rigorous entry criteria defined for these studies records for at least one dose of telaprevir with PR followed excluded adolescents and patients older than 70 years, those by at least 12 weeks of follow-up. Charts from patients who with human immunodeficiency virus or hepatitis B virus co- received treatment with telaprevir during participation in a infection, and those with blood chemistry and hematology randomized clinical study were not included. values that were outside normal limits. To date, there is little information available regarding the Data collection similarities and differences between patients enrolled in the phase 3 studies of telaprevir and those receiving telaprevir in Case report forms were provided to participating sites, and all a clinical practice setting. This post-marketing, retrospective appropriate patient data were recorded on these forms. To study reviewed patient charts obtained from academic and protect patient confidentiality, data collection was conducted community treatment centers and was conducted to evaluate by study site personnel, as designated by the study sponsor, prespecified baseline characteristics and medical follow-up who were trained by the developers of the case report form data during the telaprevir treatment phase for patients in the on the collection of data. If any data required in the case US treated with telaprevir and PR. While not designed to report form were not available for a given patient, this was make direct statistical comparisons, this study aimed to indicated on the case report form, and those charts were not assess general similarities and/or differences between the excluded because of missing data. patient populations in the phase 3 studies of telaprevir and Baseline information collected from the patient charts, those patients treated with telaprevir in real-world clinical when available, included sex, age, body mass index, race, practice settings since marketing approval was granted. ethnicity, medical history, HCV infection history (time since diagnosis, HCV genotype and viral load, interleukin 28B [IL28B] genotype, stage of liver fibrosis, and response to Methods prior HCV treatment), as well as hematology and clinical chemistry values and AEs at baseline and/or on treatment. In Study design some instances, baseline blood work was obtained as many as three months prior to initiation of therapy. This retrospective study was conducted at four academic and Key on-treatment data extracted from the patient charts, three community treatment centers in the US that were when available, included telaprevir dosing, including any selected based on physicians’ clinical experience and involve- modifications for anemia, rash, pruritus, or anorectal adverse ment with research activities in chronic HCV infection, events; PR dosing, including modifications based on the geographic diversity, and the number of patient charts above-listed events; transfusions or administration of ery- available for review. Patient charts from academic centers thropoietin-stimulating agents; concomitant medications; were provided by multiple physicians per site, whereas charts and AEs and serious AEs (SAEs). Modifications to telaprevir from community centers were provided by a sole physician. and/or PR dosing were made at the discretion of the Originally, the study protocol planned for 50 consecutive treatment center. Data regarding hospitalizations, clinical patient charts to be reviewed at each site. However, some chemistry, hematology, and HCV RNA levels were also sites provided fewer charts than planned and others were collected, when available. permitted to provide more charts to compensate. No site was Available information for AEs, as interpreted by study site allowed to provide more than 70 consecutive charts. personnel, included classification as serious or not serious, The study was conducted in accordance with the current dates of onset and resolution, severity, causal relation to Good Clinical Practice Guidelines of the International study drug(s), action taken, concomitant medications or Conference on Harmonization, the principles of the other treatments given, and outcomes as typically reported Declaration of Helsinki, and local applicable laws and regula- during the conduct of clinical studies. tions. The institutional review board (IRB) or independent ethics committee of each participating center (Baylor Pooled results from the phase 3 clinical studies of Research Institute IRB, Northwestern University Biomedical telaprevir IRB, Scripps Office for the Protection of Research Subjects IRB, Temple University Office for Human Subjects Protections Results from 1,797 treatment-naı¨ve and -experienced IRB, and Western IRB) reviewed and approved the protocol patients who were assigned to 8 weeks (n5364; not an and its revisions. Because no procedures were performed on approved treatment regimen) or 12 weeks (n51433; patients and their personal information was de-identified, the approved treatment regimen) of treatment with telaprevir institutional review boards or independent ethics committees and PR followed by 12 or 36 weeks of PR alone (total
66 Journal of Clinical and Translational Hepatology 2014 vol. 2 | 65–73 Flamm S.L. et al.: Telaprevir Treatment for HCV in Clinical Practice treatment duration of 24 or 48 weeks) were pooled, when been diagnosed with HCV infection for a mean of nine years; possible, from the three phase 3 studies of telaprevir. In these 35.5% of patients had cirrhosis at baseline. Assessment of phase 3 studies, telaprevir was administered at 750 mg every HCV RNA genotype showed that genotype 1a was predomi- 8 hours; the peginterferon alfa-2a dose was 180 micrograms nant (61.8%). Only 30.2% of patients in the clinical practice per week, and the ribavirin dose was 1,000 mg per day grouphad data available for IL28B genotype (8.0% CC, (patients weighing , 75 kg) or 1,200 mg per day (patients 14.5% CT, and 7.7% TT). Medical comorbidities were weighing o 75 kg). The post hoc review of data for these common, with hypertension (36.4%) and depression patients aimed to match information collected in the chart (30.2%) being the two most frequently observed comorbid review and included baseline demographic characteristics conditions in this patient population (Table 3). (sex, age, body mass index, race, and ethnicity), medical Of the 338 patients in the clinical practice group, 187 history, HCV infection history (time since diagnosis, HCV (55.3%) had been previously treated with PR therapy; of genotype and baseline viral load, IL28B genotype, stage of those, 80 (23.7%) had a null response to prior treatment. liver fibrosis at baseline, and response to prior HCV therapy), Most patient charts included information regarding the as well as hematology and clinical chemistry values and AEs frequency of telaprevir dosing; 257 (76.0%) and 73 at baseline and/or on treatment. (21.6%) patients received telaprevir three times daily and twice daily, respectively. Data analysis Selected baseline hematology and clinical chemistry vari- ables, including mean hemoglobin, albumin, total bilirubin Whenever possible, general comparisons were made with levels, platelet, and absolute neutrophil counts, are shown in pooled data from the phase 3 studies of telaprevir, but no Table 4 for patients in the clinical practice group and in the statistical analyses were performed. phase 3 studies of telaprevir. In the clinical practice group, 31 (9.2%) patients had baseline hemoglobin levels below the lower limits required per protocol (130 g/L for males; 120 g/L Results for females) for enrollment in the phase 3 studies of telaprevir. The mean reductions in hemoglobin levels for In total, 338 patient charts containing records for patients patients in the clinical practice group and in the phase 3 receiving telaprevir and PR with at least 12 weeks of follow-up studies of telaprevir over the first 12 weeks of treatment are were included in the study. Of these, 210 (62%) charts were shown in Fig. 1. Overall, mean reductions during the first four from patients treated at academic treatment centers, and weeks and the entire 12 weeks of treatment were similar. In 128 (38%) were from patients treated at community treat- the clinical practice group, patients who began treatment with ment centers. Of these 338 patients, 269 (79.6%) had telaprevir and PR with other baseline hematology and clinical completed the recommended 12 weeks of treatment with chemistry values below the per-protocol minimum criteria set telaprevir and PR. The most common reason for treatment for the phase 3 studies of telaprevir were as follows: 18 discontinuation, which occurred in 69 (20.4%) patients, was (5.3%) patients with albumin levels ,33 g/L, 9 (2.7%) AEs (Table 1). Almost half of the discontinuations in the patients with total bilirubin levels .38 mmol/L, 39 (11.5%) clinical practice group (n532) were attributable to AEs. patients with platelet counts ,90 6 109/L, 19 (5.6%) Baseline and demographic characteristics of the patients patients with absolute neutrophil counts ,1.5 6 109/L, and from clinical practice and patients from the phase 3 studies of three (0.9%) patients with thyroid-stimulating hormone telaprevir are shown in Table 2. Patients included in the levels .5.6 mIU/L (Table 4). Among patients who had plate- clinical practice group had a mean age of 55 years, were let counts ,90 6 109/L, 11 (28.2%) had platelet counts ,60 predominantly male (58.9%) and white (79.3%), and had 6 109/L. AEs experienced by at least 20% of patients are summar- Table 1. Reasons for discontinuation of telaprevir-based treatment for ized in Table 5. Overall, AEs were reported by 329 of the 338 patients in the clinical practice group (97.3%) patients in the clinical practice group. Four patients Total Patients in the clinical practice group experienced life-threatening AEs (n5338) (defined as a patient being at immediate risk of death from the event as it occurred) that included hepatorenal syn- Patients who completed 12 269 (79.6) drome, rectal cancer, and pneumonia in three patients (n51 weeks of T/ PR, n (%) each) and mental status change, respiratory distress, and Patients who discontinued 69 (20.4) septic shock in one patient. Three (0.9%) of these four treatment, n (%) patients died, with their deaths attributed separately to Reason for treatment discontinuation, n (%) pneumonia, septic shock, and hepatorenal syndrome. Thirty-nine patients (11.5%) reported AEs rated as severe Adverse event 32 (9.5) in intensity, and the most common (occurring in o2 patients) Physician decision 18 (5.3) were anemia (n515, 4.4%), rash (n56, 1.8%), thrombocy- Other 9 (2.7) topenia (n54, 1.2%), neutropenia (n52, 0.6%), pruritus Patient refused further dosing 4 (1.2) (n52, 0.6%), anxiety (n52, 0.6%), and syncope (n52, 0.6%). AEs experienced by 20% of patients that occurred Lost to follow-up3 (0.9) o at a rate of at least 5% higher in the clinical practice group Death 1 (0.3) than the Phase 3 pooled data were anemia and dyspepsia. Noncompliance with study drug 1 (0.3) Those that occurred at least 5% higher in the Phase 3 pooled Other noncompliance 1 (0.3) data than the clinical practice group were pruritus, headache, pyrexia, and influenza-like illness. A total of 70 SAEs occurred PR, peginterferon and ribavirin. in 40 (11.8%) patients in the clinical practice group; 48 of
Journal of Clinical and Translational Hepatology 2014 vol. 2 | 65–73 67 Flamm S.L. et al.: Telaprevir Treatment for HCV in Clinical Practice
Table 2. Patient baseline and demographic characteristics
a Clinical practice group Phase 3 pooled data Characteristic (n5338) (n51797) Prior therapy with PR, n (%) Treatment naı¨ve 148 (43.8) 1267 (70.5) Treatment experienced 187 (55.3) 530 (29.5) Prior relapser 61 (18.0) 286 (15.9) Partial responder 19 (5.6) 97 (5.4) Null responder 80 (23.7) 147 (8.2) Unknown response to PR 27 (8.0) 0 Unknown treatment experience 3 (0.9) 0 Mean age, years (SD) 55 (9.1) 49 (9.8) Male, n (%) 199 (58.9) 1122 (62.4) Mean BMI, kg/m2 (SD) 29 (5.9) 27 (5.3) Race, n (%) White 268 (79.3) 1565 (87.1) Black 35 (10.4) 158 (8.8) Other 27 (8.0) 61 (3.4) Not collected per local regulations 7 (2.1) 13 (0.7)b Unknown 1 (0.3) 0 Ethnicity, n (%) Hispanic or Latino 17 (5.0) 185 (10.3) Not Hispanic or Latino 273 (80.8) 1599 (89.0) b Not collected per local regulations 43 (12.7) 13 (0.7) Unknown 5 (1.5) 0 HCV genotype subtype, n (%) 1a 209 (61.8) 1103 (61.4) 1b 64 (18.9) 676 (37.6) Unknown/other 65 (19.2) 18 (1.0) IL28B genotype, n (%) CC 27 (8.0) Only CT 49 (14.5) partially TT 26 (7.7) assessed Unknown 236 (69.8)
Mean HCV RNA log10, IU/mL (SD) 6.2 (0.9) 6.4 (0.7) Mean time since HCV diagnosis, years (SD) 9 (8.2) 7 (6.6) Stage of fibrosis/cirrhosis, n (%) No or minimal fibrosis 61 (18.0) 528 (29.4) Portal fibrosis 59 (17.5) 705 (39.2) Bridging fibrosis 56 (16.6) 317 (17.6) Cirrhosis 120 (35.5) 247 (13.7) Unknown 42 (12.4) 0 aIncludes patients who were assigned to 8 or 12 weeks of treatment with telaprevir in combination with peginterferon alfa and ribavirin. bFrom the ILLUMINATE study.13 BMI, body mass index; HCV, hepatitis C virus; IL28B, interleukin 28B; N/A, not applicable; PR, peginterferon alfa and ribavirin; RNA, ribonucleic acid; SD, standard deviation. these SAEs were considered to be related to treatment in 31 (n522) of the patients who experienced SAEs had documen- (9.2%) patients. The most commonly reported SAEs were ted baseline cirrhosis. SAEs were reported in 18% of patients anemia and rash, occurring in seven (2.1%) and six (1.8%) with documented cirrhosis at baseline. Hospitalizations dur- patients, respectively (Table 6). There was also one (0.3%) ing the treatment period occurred in 38 (11.2%) patients; of patient with an SAE of drug reaction with eosinophilia and these hospitalizations, 26 were determined to be related to systemic symptoms; no SAEs of Stevens-Johnson syndrome telaprevir and PR treatment, with 11 due to the need for blood or toxic epidermal necrolysis were reported. Fifty-five percent transfusions.
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Table 3. Comorbid medical conditions reported in o5% of patients in and tolerability outcomes of the population of treated patients either the retrospective study or in the phase 3 studies that may not be represented within the controlled setting of a randomized study. The composite baseline patient profiles in Clinical Phase 3 this current study may be considered more difficult to treat practice group pooled dataa,b than those in the phase 3 studies, as many patients were Condition, n (%) (n5338) (n51267) older (mean age, 55 vs 49 years), a greater proportion had Hypertension 123 (36.4) 288 (22.7) cirrhosis (36% vs 14%), and more patients were treatment Depression 102 (30.2) 217 (17.1) experienced (55% vs 29%). In addition, a substantial percentage of patients treated with telaprevir and PR in the Gastroesophageal reflux 50 (14.8) 142 (11.2) clinical practice group would not have met the per-protocol disease minimum baseline clinical chemistry and hematology criteria Anxiety 49 (14.5) 113 (8.9) for inclusion in the phase 3 studies. Although this would Insomnia 34 (10.1) 180 (14.2) suggest that such patients may have been excluded from the Hepatic cirrhosis 34 (10.1) 5 (0.4) phase 3 studies, it is important to note that there were Hypothyroidism 31 (9.2) 53 (4.2) occasional protocol deviations in the phase 3 studies regard- ing clinical chemistry and hematology inclusion criteria. In the Asthma 24 (7.1) 53 (4.2) clinical practice group, the treatment of patients with Thrombocytopenia 24 (7.1) 10 (0.8) relatively low levels of hemoglobin, platelets, and albumin Diabetes mellitus 23 (6.8) 46 (3.6) suggests that physicians in clinical practice may feel an Obesity 23 (6.8) 33 (2.6) urgency to treat these patients. Additionally, patients included in the current study had comorbid conditions, Arthritis 20 (5.9) 48 (3.8) including depression, hypothyroidism, asthma, thrombocy- Esophageal varices 18 (5.3) 8 (0.6) topenia, and esophageal varices, which potentially could have Back pain 17 (5.0) 120 (9.5) excluded them from participation in the phase 3 studies of Fatigue 10 (3.0) 104 (8.2) telaprevir. Many of these observed differences in patient characteristics likely contributed to some of the differences Hemorrhoids 10 (3.0) 67 (5.3) observed in rates of AEs, particularly anemia. Seasonal allergy 8 (2.4) 94 (7.4) Since the approval of telaprevir in 2011, telaprevir-based Hysterectomy 8 (2.4) 66 (5.2) therapy has been purported to be less well tolerated than was Arthralgia 6 (1.8) 102 (8.1) expected given the data from the phase 3 studies. In the Headache 4 (1.2) 94 (7.4) current study, almost 80% of patients completed the recommended 12-week period of telaprevir and PR treat- Drug hypersensitivity 3 (0.9) 83 (6.6) ment, with 10% of patients discontinuing treatment because Drug abuse 10 (3.0) 94 (7.4) of an AE. This suggests that AEs experienced by patients in a clinical practice setting were generally manageable, and most a Includes patients who were assigned to 8 or 12 weeks of treatment with of the reported AEs were characterized as mild or moderate. telaprevir and peginterferon alfa and ribavirin. bIncludes data for treatment-naı¨ve patients enrolled in the ADVANCE and Anemia, rash, and pruritus were among the most common ILLUMINATE studies only. Data for treatment-experienced patients enrolled in AEs associated with the use of telaprevir, which is consistent the REALIZE study were excluded because the source data collection and with data from the phase 3 studies.12–14 The incidence of dictionary encoding methods for comorbid medical conditions were different for pruritus, headache, pyrexia, and influenza-like illness was the REALIZE study, resulting in different classifications for the medical conditions and preventing pooling of the data. higher in patients in the phase 3 studies, while the incidence of anemia and dyspnea was higher in patients in the clinical practice group. While 60% of clinical practice patients Telaprevir treatment was interrupted in 17 (5%) patients in experienced anemia as an AE, 33% of patients did so in the the clinical practice group due to AEs. Telaprevir doses were phase 3 studies. However, the proportion of patients who modified because of anemia in five (1.5%) patients, rash in 10 reported anemia as an SAE was similar between both groups (3.0%) patients, pruritus in five (1.5%) patients, anorectal (2.1% in the clinical practice group vs 1.8% in the phase 3 disorder in zero patients, and other reasons in 20 (5.9%) studies). In addition, while the pattern of reduction in patients. Peginterferon doses were modified because of hemoglobin levels during telaprevir treatment was similar anemia in 21 (6.2%) patients, rash in seven (2.1%) patients, between both groups, the mean levels were lower in patients pruritus in 2 (0.6%) patients, anorectal disorder in one (0.3%) in the clinical practice group. patient, and other reasons in 57 (16.9%) patients. Ribavirin It appears that incident anemia was managed successfully doses were modified due to anemia in 153 (45.3%) patients, in most cases with ribavirin dose reductions and erythropoie- rash in 21 (6.2%) patients, pruritus in seven (2.1%) patients, tin supplementation; blood transfusions were thought to be anorectal disorder in three (0.9%) patients, and other reasons necessary occasionally. Relatively few SAEs (n515) were in 39 (11.5%) patients. During treatment with telaprevir and associated with anemia, pruritus, or rash. PR, 114 (33.7%) and 23 (6.8%) patients received erythro- In the clinical practice group, 35.5% of patients had poietin and blood transfusions, respectively. cirrhosis at baseline. Of the 40 patients who reported SAEs, more than half had existing cirrhosis. The increased rate of Discussion SAEs observed in patients with cirrhosis is consistent with preliminary findings from the French Compassionate Use of This retrospective study of real-life clinical patients who Protease Inhibitors in Cirrhosis (CUPIC) study, an indepen- received telaprevir and PR for chronic HCV infection provides dent patient registry established in Europe to observe valuable insight into the baseline characteristics and safety patients undergoing HCV treatment in the clinical setting.10,16
Journal of Clinical and Translational Hepatology 2014 vol. 2 | 65–73 69 Flamm S.L. et al.: Telaprevir Treatment for HCV in Clinical Practice
Table 4. Selected mean baseline hematology and clinical chemistry variables
Clinical practice group Phase 3 pooled dataa Variable (n5338) (n51797) Hemoglobin, g/L n 299 1795 Mean (SD) 144 (16.2) 150 (13.0) Minimum, maximum 49, 184 105, 228 Patients with levels , per-protocol requirement for phase 3 study entry,b 31 (9.2) N/A n (%) Albumin, g/L n 287 1797 Mean (SD) 40 (4.7) 44 (3.1) Minimum, maximum 12, 50 32, 52 Patients with levels , per-protocol requirement for phase 3 study entry,c 18 (5.3) N/A n (%) Total bilirubin, mmol/L n 285 1797 Mean (SD) 14 (10.3) 10 (5.0) Minimum, maximum 3, 128 2, 50 Patients with levels . per-protocol requirement for phase 3 study entry,d 9 (2.7) N/A n (%) Platelet count, 109/L n 296 1790 Mean (SD) 174 (72.5) 238 (73.0) Minimum, maximum 39, 500 82, 655 Patients with levels , per-protocol requirement for phase 3 study entry,e 39 (11.5) N/A n (%) Absolute neutrophil count, 109/L n 257 1794 Mean (SD) 3 (1.3) 4 (1.4) Minimum, maximum 1, 8 1, 17 Patients with levels , per-protocol requirement for phase 3 study entry,f 19 (5.6) N/A n (%) Thyroid stimulating hormone, mIU/L n 166 1797 Mean (SD) 2 (7.3) 2 (1.0) Minimum, maximum 0, 95 0, 13 Patients with levels . per-protocol requirement for phase 3 study entry,g 3 (0.9) N/A n (%) aIncludes patients who were assigned to 8 or 12 weeks of treatment with telaprevir in combination with peginterferon alfa and ribavirin. bPer-protocol requirement for phase 3 study entry: o130 g/L (males); o120 g/L (females) cPer-protocol requirement for phase 3 study entry: o33 g/L dPer-protocol requirement for phase 3 study entry: f38 mmol/L ePer-protocol requirement for phase 3 study entry: o906109/L fPer-protocol requirement for phase 3 study entry: o1.56109/L gPer-protocol requirement for phase 3 study entry: f5.6 mIU/L N/A, not applicable; SD, standard deviation.
In the HCV-TARGET study, a similar registry established in the time points or had an incomplete history for treatment US, patients with cirrhosis were at increased risk for outcomes, which prevented analysis and interpretation of discontinuing treatment early because of AEs.6,17 These data the data. However, the CUPIC study in Europe10 and the HCV- highlight the need for careful and routine monitoring of TARGET study in the US6,17,18 have been designed to collect patients with cirrhosis in the clinical setting. data regarding on-treatment efficacy outcomes in the clinical Although an attempt was made to collect available data setting. with respect to on-treatment efficacy outcomes, an insuffi- Retrospective reviews of patient charts provide informa- cient number of patients had been assessed at the relevant tion from readily accessible, existing data, are relatively
70 Journal of Clinical and Translational Hepatology 2014 vol. 2 | 65–73 Flamm S.L. et al.: Telaprevir Treatment for HCV in Clinical Practice
Fig. 1. Mean reductions in hemoglobin levels during telaprevir-based treatment. Data for patients in the clinical practice group and in the phase 3 studies of telaprevir are plotted together for illustrative purposes; however, no statistical analyses were performed for comparison. aIncludes patients who were assigned to 8 or 12 weeks of treatment with telaprevir in combination with peginterferon alfa and ribavirin. BL, baseline. inexpensive to conduct, may be important in hypothesis number of patient charts available for review, may not fully generation for prospective studies, and may allow the study represent all treatment centers in which patients with chronic of rare occurrences or conditions where there is a long latency HCV infection are treated. Additionally, patients included in period between exposure and disease. However, limitations the clinical practice group were not randomly selected. Data inherent to retrospective studies include incomplete docu- were collected by site personnel who were trained by the mentation, problems in interpreting and verifying information developers of the case record form to record all appropriate (e.g., differences in terminology used by clinicians), variance patient data. However, uniform approaches of data entry may in the quality of information as recorded by clinicians, and not have occurred at all sites, and charts did not always difficulty in determining cause and effect between treatment contain complete patient information, resulting in some exposure and outcomes.19,20 The current study was per- missing data. For example, while obesity was reported as a formed at only seven sites that, despite the diversity in comorbidity in 6.8% of patients in the clinical practice group, physicians’ clinical experience and involvement with research the mean body mass index was 29 kg/m2, highlighting the activities in chronic HCV infection, the geography, and the lack of uniformity in approaches to data entry. In some instances, baseline blood work was obtained as many as three months prior to the initiation of therapy. Furthermore, Table 5. Adverse events experienced by o20% of patients in either the while most sites were associated with academic hospitals, retrospective study or phase 3 studies during telaprevir-based treatment
Clinical Phase 3 a Table 6. Serious adverse events during telaprevir-based treatment practice group pooled data experienced by o0.5% of patients in either the retrospective study or Event, n (%) (n5338) (n51797) in the phase 3 studies
Any AE 329 (97.3) 1773 (98.7) Clinical Phase 3 a Anemia 204 (60.4) 590 (32.8) practice group pooled data Fatigue 181 (53.6) 998 (55.5) Event, n (%) (n5338) (n51797) Nausea 147 (43.5) 704 (39.2) Patients with any SAEs 40 (11.8) 99 (5.5) Rash 122 (36.1) 597 (33.2) Anemia 7 (2.1) 33 (1.8) Pruritus 98 (29.0) 840 (46.7) Rash 6 (1.8) 6 (0.3) Dyspnea 76 (22.5) 242 (13.5) Syncope 3 (0.9) 2 (0.1) Diarrhea 75 (22.2) 458 (25.5) Anxiety 2 (0.6) 0 Insomnia 74 (21.9) 458 (25.5) Dehydration 2 (0.6) 2 (0.1) Headache 54 (16.0) 657 (36.6) Fatigue 2 (0.6) 0 Pyrexia 40 (11.8) 392 (21.8) Hypokalemia 2 (0.6) 0 Influenza-like illness 14 (4.1) 516 (28.7) Pruritus 2 (0.6) 2 (0.1) aIncludes patients who were assigned to 8 or 12 weeks of treatment with aIncludes patients who were assigned to 8 or 12 weeks of treatment with telaprevir in combination with peginterferon alfa and ribavirin. telaprevir in combination with peginterferon alfa and ribavirin. AE, adverse event. SAE, serious adverse event.
Journal of Clinical and Translational Hepatology 2014 vol. 2 | 65–73 71 Flamm S.L. et al.: Telaprevir Treatment for HCV in Clinical Practice which are more likely to test for IL28B genotype and HCV or stock options in that company. M. Friedman was an subtype, only a few charts included test results for IL28B employee of Vertex Pharmaceuticals Incorporated at the time genotype (30.2%), and the HCV 1 subtype was unknown in of this research and may own or may have owned stock or approximately 18% of patients. The limitations of obtaining stock options in that company. these data highlight the variance in the types and quality of information recorded by clinicians, as well as the lack of a Author contributions standardized approach in collecting such information. Lastly, while general comparisons were made between chart review Study designing (SLF, PJP, LB, MF), collection and assembly of data from the clinical practice group and the pooled data from data(LB, MF), data analysis and interpretation (SLF, PJP, LB, the phase 3 studies of telaprevir, no statistical analyses were MF), manuscript preparation (SLF, PJP, MF), critical review of performed, as direct comparisons cannot be made between manuscript (SLF, PJP, LB, MF), final approval of manuscript studies that were conducted at different times, with different (SLF, PJP, LB, MF) levels of rigor, and not designed in advance with the intent to demonstrate differences. Writing assistance Conclusions Medical writing and coordination support were provided by This retrospective study of real-life patients with chronic HCV Erika D. Reynoso, PhD, who was an employee of Vertex infection treated with telaprevir provides insight into baseline Pharmaceuticals Incorporated and may own stock or stock patient demographics and clinical characteristics, as well as options in that company. Medical writing, editorial, and dosing and safety and tolerability profiles for telaprevir-based graphic design support was provided by Bina J. Patel, treatment in clinical practice settings. Compared to the phase PharmD, of Peloton Advantage and was funded by Vertex 3 studies, in clinical practice, the composite baseline patient Pharmaceuticals Incorporated. profiles were considered more difficult to treat and anemia was reported twice as often. AEs led to discontinuation of Acknowledgments treatment in 10% of patients, suggesting that AEs experi- enced by patients in a clinical setting are generally manage- The authors thank Bryan Still, Mary Helen Broussard, Andrea able. Findings from this study complement those reported Scherschel, NP, and Jill Chang from the Scripps Clinic for their from rigorous, randomized controlled studies with telaprevir- assistance to Dr. Pockros during the study, and Vikas Gulati, based treatment and provide a general assessment of the of Vertex Pharmaceuticals Incorporated, for clinical data similarities and/or differences between patients from the management. Medical writing and coordination support were phase 3 studies of telaprevir and those treated with telaprevir provided by Erika D. Reynoso, PhD, formerly of Vertex in real-world clinical practice. Treatment with telaprevir- Pharmaceuticals Incorporated. Vikas Gulati is an employee based regimens should be individualized based on both of Vertex Pharmaceuticals, and Erika D. Reynoso was an clinical practice observations and data from randomized employee of Vertex Pharmaceuticals Incorporated. Both may controlled studies. own stock or stock options in that company. Medical writing, editorial, and graphic design support was provided by Bina J. Conflict of interest Patel, PharmD, of Peloton Advantage and was funded by Vertex Pharmaceuticals Incorporated. ThisstudywassponsoredbyVertexPharmaceuticals The following investigators also participated in this study: Incorporated. The sponsors were involved in study design, Michael Galambos (Digestive Healthcare of Georgia, Atlanta, data collection and analysis, decision to publish, and pre- GA); Stevan Gonzalez (Baylor All Saints Medical Center, Fort paration of the manuscript. Worth, TX); Mark Jonas (Consultants for Clinical Research, S.L. Flamm has served as a remunerated consultant/ Cincinnati, OH); Vishal Patel (Temple University, Philadelphia, lecturer for Bristol-Myers Squibb, AbbVie, Gilead Sciences, PA); and Vinod Rustgi (Metropolitan Research, Fairfax, VA). Merck & Co., and Vertex Pharmaceuticals Incorporated, and has received grants/research support from AbbVie, Achillion, References Anadys Pharmaceuticals, Bristol-Myers Squibb, Boehringer
Ingelheim, Gilead Sciences, Janssen Pharmaceuticals, Merck [1] Glasser SP, Salas M, Delzell E. Importance and challenges of studying & Co., Pfizer, and Vertex Pharmaceuticals Incorporated. He marketed drugs: what is a phase IV study? Common clinical research has also served as an advisor or review committee member designs, registries, and self-reporting systems. J Clin Pharmacol 2007;47: for Gilead Sciences, Merck & Co., and Vertex Pharmaceuticals 1074–1086, doi: 10.1177/0091270007304776. [2] Garrison LP, Jr., Neumann PJ, Erickson P, Marshall D, Mullins CD. Using real- Incorporated. PJ Pockros has served as a remunerated world data for coverage and payment decisions: the ISPOR Real-World Data consultant for Boehringer Ingelheim, Bristol-Myers Squibb, Task Force report. Value Health 2007;10:326–335, doi: 10.1111/j.1524- Genentech, Gilead Sciences, Janssen Pharmaceuticals, Merck 4733.2007.00186.x. & Co., Novartis, and Vertex Pharmaceuticals Incorporated, [3] Olsson J, Terris D, Elg M, Lundberg J, Lindblad S. The one-person randomized controlled trial. Qual Manag Health Care 2005;14:206–216, doi: 10.1097/ and has received research grants from Abbott, Bristol-Myers 00019514-200510000-00002. Squibb, Boehringer Ingelheim, Genentech, Gilead Sciences, [4] Healey M, Deverka P. Panel 1: methodological issues in pharmacoeconomic Janssen Pharmaceuticals, Merck & Co., and Vertex evaluations–clinical studies. Value Health 1999;2:73–77, doi: 10.1046/ Pharmaceuticals Incorporated. He has also received fees for j.1524-4733.1999.02202.x. non-CME services from Genentech, Merck & Co., and Vertex [5] Fusfeld L, Aggarwal J, Dougher C, Vera-Llonch M, Bubb S, Donepudi M, et al. Assessment of motivating factors associated with the initiation and comple- Pharmaceuticals Incorporated. L. Bengtsson is an employee tion of treatment for chronic hepatitis C virus (HCV) infection. BMC Infect Dis of Vertex Pharmaceuticals Incorporated and may own stock 2013;13:234, doi: 10.1186/1471-2334-13-234.
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[6] Fried MW, Reddy KR, Di Bisceglie AM, Jensen DM, Jacobson IM, Sulkowski [13] Sherman KE, Flamm SL, Afdhal NH, Nelson DR, Sulkowski MS, Everson GT, MS, et al. HCV-TARGET: a longitudinal, observational study of North et al. Response-guided telaprevir combination treatment for hepatitis C virus American patients with chronic hepatitis C (HCV) treated with boceprevir infection. N Engl J Med 2011;365:1014–1024. or telaprevir. J Hepatol 2013;58 (suppl 1):S335. [14] Zeuzem S, Andreone P, Pol S, Lawitz E, Diago M, Roberts S, et al. Telaprevir [7] Solomon M, Bonafede M, Pan K, Wilson K, Beam C, Chakravarti P, et al. Direct for retreatment of HCV infection. N Engl J Med 2011;364:2417–2428. medical care costs among pegylated interferon plus ribavirin-treated and [15] Incivek [package insert]. Cambridge, MA: Vertex Pharmaceuticals untreated chronic hepatitis C patients. Dig Dis Sci 2011;56:3024–3031, doi: Incorporated, 2013. 10.1007/s10620-011-1802-z. [16] He´zode C, Fontaine H, Dorival C, Larrey D, Zoulim F, Canva V, et al. Triple [8] Chew KW, Allen SA, Taylor LE, Rich JD, Feller E. Treatment outcomes with therapy in treatment-experienced patients with HCV-cirrhosis in a multi- pegylated interferon and ribavirin for male prisoners with chronic hepatitis C. centre cohort of the French Early Access Programme (ANRS CO20-CUPIC) - J Clin Gastroenterol 2009;43:686–691. NCT01514890. J Hepatol 2013;59:434–441, doi: 10.1016/ [9] Lo Re V, III, Teal V, Localio AR, Amorosa VK, Kaplan DE, Gross R. Relationship j.jhep.2013.04.035. between adherence to hepatitis C virus therapy and virologic outcomes: a [17] Afdhal N, Reau N, Everson GT, Morelli G, Lok AS, Sherman KE, et al. Safety cohort study. Ann Intern Med 2011;155:353–360, doi: 10.7326/0003-4819- and efficacy of telaprevir (TVR) or boceprevir (BOC) in patients with 155-6-201109200-00003. cirrhosis: interim results of a longitudinal, observational study. Hepatology [10] Fontaine H, Hezode C, Dorival C, Larrey D, Zoulim F, de Ledinghen V, et al. 2013;58 (suppl 4):1103a–1104a. SVR12 rates and safety of triple therapy including telaprevir or boceprevir in [18] Di Bisceglie AM, Kuo A, Rustgi VK, Sulkowski MS, Sterling RK, Stewart T, et al. 221 cirrhotic non responders treated in the French Early Access Program Virologic outcomes and adherence to treatment algorithms in a longitudinal (ANRS CO20-CUPIC). J Hepatol 2013;58 (suppl 1):S27. study of patients with chronic hepatitis C treated with boceprevir (BOC) or [11] Vera-Llonch M, Martin M, Aggarwal J, Donepudi M, Bayliss M, Goss T, et al. telaprevir (TVR) in the United States (HCV-TARGET). Hepatology 2013;58 Health-related quality of life in genotype 1 treatment-naive chronic hepatitis (suppl 4):227a–228a. C patients receiving telaprevir combination treatment in the ADVANCE study. [19] Hess DR. Retrospective studies and chart reviews. Respir Care 2004;49: Aliment Pharmacol Ther 2013;38:124–133, doi: 10.1111/apt.12354. 1171–1174. [12] Jacobson IM, McHutchison JG, Dusheiko G, Di Bisceglie AM, Reddy KR, [20] Gearing RE, Mian IA, Barber J, Ickowicz A. A methodology for conducting Bzowej NH, et al. Telaprevir for previously untreated chronic hepatitis C virus retrospective chart review research in child and adolescent psychiatry. J Can infection. N Engl J Med 2011;364:2405–2416. Acad Child Adolesc Psychiatry 2006;15:126–134.
Journal of Clinical and Translational Hepatology 2014 vol. 2 | 65–73 73 Review Article
An Update on Treatment of Drug-Induced Liver Injury
Christin Giordano1, John Rivas2 and Xaralambos Zervos2
1Department of Faculty and Academic Affairs, University of Central Florida, College of Medicine, Orlando, FL, USA; 2Digestive Disease Institute, Cleveland Clinic Florida, Weston, FL, USA
Abstract cause of DILI, now accounting for up to 9% of all cases.10 In fact, one study based in China, which spanned eight years, Drug-induced liver injury (DILI) has been linked to more than found that nearly half of all cases were secondary to 1,000 medications and remains the most common cause of medicinal herbs.11 While DILI is most commonly due to only acute liver failure in the United States. Here, we review the one drug, a prospective study demonstrated that nearly 10% most current literature regarding treatment and make of cases were attributable to more than one medication.9 recommendations for the management of this relatively DILI has several clinical manifestations ranging from common disease. Since treatment of DILI remains largely asymptomatic elevations in liver enzymes to fulminant liver elusive, recent studies have attempted to define new failure. Hepatic, or cytochrome P450, metabolism of a drug management strategies for these difficult patients. Early has been strongly linked to DILI, and one study demonstrated diagnosis and withdrawal of the suspected medication is the that those medications that rely on more than 50% hepatic mainstay of treatment of DILI. For acetaminophen and metabolism have a greater risk for alanine transferase (ALT) Amanita mushroom poisoning, there are specific therapies elevation, liver failure, and mortality.12 Other proposed in use. Finally, there are other possible management mod- mechanisms for DILI include autoimmunity and hypersensi- alities for DILI, including corticosteroids and ursodeoxycholic tivity.2,13 Despite the possible mechanisms, treatment acid. options all follow the same principles. The most important, E 2014 The Second Affiliated Hospital of Chongqing Medical and first, step is early diagnosis followed by discontinuation of University. Published by XIA & HE Publishing Ltd. All rights the offending agent.2 reserved. Diagnosis Introduction The most common presenting symptom in most cases of DILI is jaundice, although many cases are asymptomatic or have Drug-induced liver injury (DILI) is defined as a liver injury elevated enzymes incidentally detected.11 However, DILI can due to xenobiotics, herbs, or medications that leads to either present as cholestatic, hepatocellular, and mixed; and proper liver dysfunction or abnormal liver serology, in the setting of diagnosis will direct the treatment of a particular case. no other identifiable cause. Unlike idiosyncratic drug induced Cholestatic liver injury is defined by predominant elevations liver injury (IDILI), DILI seems to be dose-dependent, of alkaline phosphatase (ALP), whereas hepatocellular liver predictable, and reproducible. DILI has been associated with injury is defined as predominant elevations of aspartate more than 1,000 medications and is the most common cause transferase (AST) and ALT, and mixed has elevations in both of acute liver failure in the United States, accounting for ALP and transaminases.14 It is important to note that ALT is approximately 50% of fulminant cases.1–5,6 While retro- liver-specific, whereas elevations in AST may be associated spective studies have shown acetaminophen to be the most with damage to skeletal or cardiac muscle or in conditions common cause of DILI, studies in liver transplant patients such as myocardial infarction and rhabdomyolysis. have demonstrated antibiotics and immunosuppressive Hepatocellular injury remains the most common presentation agents, such as tacrolimus and azathioprine, as the top and is correlated with a worse outcome.15,16 Table 1 provides causes.7,8 Bjornsson et al. performed a prospective study and specific definitions for both cholestatic and hepatocellular found that amoxicillin-clavulanate was the most commonly injury, which may aid in the identification of the patient’s implicated antibiotic. The incidence was approximately 19 clinical diagnosis. cases per 100,000.9 In addition to the typical suspects stated Once liver injury has been established, the next step is to above, herbal and dietary supplements have been a rising determine the underlying cause. Risk factors for DILI have been difficult to determine with many studies because of Keywords: Drug-induced liver injury; Hepatotoxicity; Acetaminophen toxicity. conflicting results in regard to sex and age-related occur- Abbreviations: ALP, alkaline phosphatase; ALT, alanine transferase; AST, rences. However, a recent study found that older age and aspartate transferase; CDS, clinical diagnostic scale; DDW-J, digestive disease female sex was associated with a cholestatic type injury, week-Japan; DILI, drug-induced liver injury; IDILI, idiosyncratic drug induced liver injury; INR, international normalized ratio; IV, intravenous; NAC, N- while younger age and male sex was associated with acetylcysteine; PT, prothrombin; M&V, Maria and Victorino; PT, prothrombin time; hepatocellular type injury. Genetic polymorphisms have been RUCAM, Roussel Uclaf Causality Assessment Method; ULN, upper limit of normal. consistently found to be a risk factor for DILI but are not Received: 28 January 2014; Revised: 18 March 2014; Accepted: 24 March 2014 q typically tested for in patients prior to receiving a medica- DOIof original article: 10.14218/JCTH.2014.00005. 17,18 Correspondence to: Christin Giordano, 6850 Lake Nona Blvd, Orlando, FL 32827, tion. Finally, liver transplant patients where the reason USA. Tel: 203-216-5426, Fax: 407-266-1489, Email: [email protected] for transplant was primary sclerosing cholangitis are at
74 Journal of Clinical and Translational Hepatology 2014 vol. 2 | 74–79 Giordano C. et al.: Treatment of drug-induced liver injury
Table 1. Definitions of DILI20,23,24
Cholestatic Liver Injury Elevations of ALP o 2X the upper limit of normal (ULN) OR ALT/ALP ratio of , 2 with both ALT and ALP . ULN
Hepatocellular Liver Injury ALT o 5X ULN AND Total bilirubin o 2X ULN greater risk for developing DILI.8 Chronic liver disease is a therapy, both in combination with ursodeoxycholic acid, in the risk factor but only for certain medications, including metho- treatment of drug-induced liver injury, including patients with trexate, isoniazid, and HIV antiretroviral therapy.2 When hepatocellular and/or cholestatic injury. Both therapies demon- diagnosing DILI, several established criteria can be used, strated a decrease in time to normalization of bilirubin, AST, none of which is considered to be a gold standard. Hy’s law is and ALT values.26 However, since this was an uncontrolled specific but not sensitive, whereas the Roussel Uclaf Causality study, it is uncertain if the observed improvement in their Assessment Method (RUCAM) is more sensitive but more patient population actually reflected the natural history of DILI. difficult to administer in its truest form as it is complicated and requires rechallenging patients once they have recov- Specific treatment ered.19–21 One modification is the Digestive Disease Week- Japan (DDW-J) scale, which includes lymphocyte stimulation Treatment for acetaminophen toxicity largely consists of NAC 22 testing, although this test has not been validated. Yet therapy. Studies have conflicted between whether oral or another modification is the Clinical Diagnostic Scale (CDS) or intravenous (IV) therapy should be given. Yarema et al. Maria and Victorino (M&V) scale, which is more simple to compared IV to oral administration and found that hepatoxi- administer but less predictive in patients who have had a city occurred less often in patients who received IV therapy prolonged period of time between drug use and development within 12 hours of ingestion.27 However, a recent study of symptoms or in those patients who have developed chronic performed using a simulation system demonstrated that for 23–24 liver injury. When examining these scales, common those patients presenting within 24 hours of acetaminophen features, which make them specific and sensitive tests, ingestion, the oral protocol is superior to the 21-hour include temporal relationship, exclusion of other causes, intravenous protocol in persevering hepatocytes. These and prior reports of hepatoxicity of the suspected medication. authors argued that Yarema’s study contained two differing While specific criteria may be used, at a minimum the above treatment groups.28 Regardless, NAC therapy should be three commonalities should be investigated. For reference, started if there is an elevation in AST, a detectable acetami- Wang et al found in China that the majority of cases occurred nophen level, or if the level is above the treatment line on the 11 between 5 and 90 days of the initiation of the drug. As an Rumack-Matthew nomogram.29 A computer simulation sug- aid for the clinician, Table 2 provides medications and their gested that International Normalized Ratio (INR) did not typical liver injury presentation. undertreat patients but did lead to overtreatment, whereas Once a specific drug has been identified as the cause of treating until ALT peaked did not undertreat and rarely DILI, it must be discontinued.2 Following withdrawal of the overtreated patients.28 Current recommendations are to suspected agent, therapy is largely supportive with a few treat according to the protocol and to recheck AST and the notable exceptions for acetaminophen and Amanita mush- acetaminophen level. At this point, AST should be less than room poisoning. All patients’ laboratory values, including AST, 100 IU/L and acetaminophen level should be less than ALT, ALP, bilirubin, and international normalized ratio (INR) 10 mcg/mL. If not, therapy should be continued using the and mental statuses should be monitored for changes. It is normalization of INR as a marker of resolution.30 important to note that measuring only AST and ALT is Amanita mushroom ingestion can lead to liver injury via insufficient when monitoring liver function in DILI. Damage the amatoxin, which inhibits RNA polymerase II and leads to to hepatocytes causes elevation of AST and ALT levels, and hepatocyte necrosis. Presentation consists of a gastrointest- once sufficient damage has occurred, there are less hepato- inal phase followed by a hepatic phase. The gastrointestinal cytes and AST and ALT levels begin to decrease.14 Therefore, phase is characterized by nausea, vomiting, and abdominal bilirubin and INR must also be monitored. With discontinua- pain. This is followed by symptomatic improvement but an tion of the drug, most cases resolve without further sequelae, elevation in AST and ALT followed by the development of with one prospective study reporting a median duration from jaundice. Since the hepatic phase is preceded by a gastro- diagnosis to normalization of laboratory values of 64 days.9 intestinal phase where dehydration and metabolic derange- Lee et al. performed an eight year prospective, double- ments may have developed, it is important to treat any blind, placebo control trial of N-acetylcysteine (NAC) for dehydration and electrolyte abnormalities.31 While it has no patients with acute liver failure not secondary to acetamino- proven efficacy for long-term survival, repeated activated phen overdose. While overall survival was similar in the charcoal administration is often recommended, which will populations (70% vs. 66%), transplant-free survival was prevent reabsorption of the amatoxin. While amatoxin may significantly better for those who received NAC (40% vs. cause metabolic acidosis on its own, activated charcoal, 27%).25 At this time, NAC therapy can and should be which contains propylene glycol, can also cause a high anion considered for patients who are presenting with acute liver gap metabolic acidosis. While clinicians should be aware of failure. this potential complication, it should not preclude treatment In addition, a small uncontrolled study performed by Wree with activated charcoal.32 Silibinin is universally accepted as et al. compared steroid pulse therapy with steroid step down a treatment modality for amatoxin poisoning because it
Journal of Clinical and Translational Hepatology 2014 vol. 2 | 74–79 75 Giordano C. et al.: Treatment of drug-induced liver injury
Table 2. Common biochemical presentation in DILI and associated medications / environmental exposure
Biochemical presentation Associated medications / exposure
Cholestatic Antimicrobials: (ALP . 2 6 ULNor ALP/ALT ,2) N Amoxicillin-clavulanate acid, Erythromycin, Trimethoprim-sulfamethoxazole with both ALP and ALT . 1 6 ULN Cardiovascular: N Clopidogrel, ACE inhibitors Endocrine: N Anabolic steroids Immunosuppressive: N Azathioprine Gynecology: N Oral contraceptives Neuropsychiatric: N Carbamazepine, Chlorpromazine, Tricyclic antidepressants Anti-inflammatory: N Sulindac
Hepatocellular Anti-inflammatory: (ALT .5 6 ULNand Bilirubin N Acetaminophen, Bromfenac, Diclofenac, Ibuprofen, Naproxen .2 6 ULN) Antimicrobials: N Ciprofloxacin, Isoniazid, Ketoconazole, Nitrofurantoin, Protease inhibitors, Pyrazinamide, Rifampin, Tetracycline, Trimethoprim-sulfamethoxazole Cardiovascular: N Amiodarone, Lisinopril, Quinidine, Statins Endocrine: N Acarbose, Troglitazone Gastrointestinal: N Cimetidine, Omeprazole Immunosuppressive: N Allopurinol Neuropsychiatric: N Bupropion fluoxetine, Methyldopa, Nefazodone, Paroxetine, Risperidone, Sertraline, Trazodone, Valproic acid Environmental exposures: N Amatoxin Other: N Halothane
Mixed Antimicrobials: (ALT .5 6 ULNor Bilirubin N Clindamycin, Protease inhibitors, Reverse transcriptase inhibitors, Sulfonamides .2 6 ULN) and (ALP .2 6 ULN Cardiovascular: or ALP/ALT ,2 with both ALP and N ACE inhibitors, Statins ALT .1 6 ULN) Immunosuppressive: N Azathioprine Neuropsychiatric: N Amitriptyline, Phenytoin,
Steatohepatitis Antineoplastic: N Tamoxifen Cardiovascular: N Amioderone
Veno-occlusive Antineoplastic: N Busulfan, Cyclophosphamide Environmental exposures: N Arsenic, Thorium dioxide, Vinyl chloride, Other: N Vitamin A inhibits the transfer of amanitin into hepatocytes. It should be also known to displace amatoxin and promote its excretion. administered within 48 hours of mushroom ingestion. The The recommended dose is 1,000,000 IU/kg for first day and current recommended dose is 20 to 50 mg/kg/day IV, which 500,000 IU/kg for next two days via continuous IV adminis- should be continued for 48–96 hours. High dose penicillin G is tration. Some studies suggest co-administration with NAC as
76 Journal of Clinical and Translational Hepatology 2014 vol. 2 | 74–79 Giordano C. et al.: Treatment of drug-induced liver injury
Fig. 1. Proposed treatment algorithm well. Finally, if started early, the Molecular Adsorbent hepatocytes. Demetriou et al. conducted the first prospective Recirculating System may be considered as it does improve randomized trial using the HepatAssist Liver Support System. liver function, although no specific studies have been done The system, composed of a hollow-fiber cartridge lined with with Amanita mushroom poisoning.31 porcine hepatocytes, was used in a multi-center trial showing Patients who present with fever, rash, and eosinophilia survival benefit to those treated.35 Advances in bioartificial should be considered for a diagnosis of drug-induced auto- livers continue with current trials being conducted by Vital immune hepatitis. If the DILI is severe, corticosteroid therapy Therapies and Hepa Wash GmbH (clinicaltrials.gov). These should be considered as studies have demonstrated normal- devices provide the potential for significant benefit to patients ization of biochemical tests within six months.33 with DILI, subacute fulminate failure, and fulminate failure; Finally, patients who present with a cholestatic picture and we are encouraged for the use of this technology in the may complain of intense pruritus. Treatment options for these future treatment of these patients. patients include emollients, hydroxyzine, diphenhydramine, 34 bile acid resins, and rifampicin. Liver transplant referral considerations
Potential role for liver assist devices The King’s College criteria have been developed for both paracetamol and non-paracetamol causes in order to deter- Extracorporeal systems have progressed through advances in mine when a patient should be initially referred for trans- genetically produced cell lines, stem cell-derived functional plantation. The criteria include a prothrombin time (PT) over hepatocytes, immortalized human hepatocytes as well as 100 seconds or at least three of the following: PT over improved techniques and methods for preserving the 50 seconds, bilirubin. 300 micromol/Liter, age below 10 or
Journal of Clinical and Translational Hepatology 2014 vol. 2 | 74–79 77 Giordano C. et al.: Treatment of drug-induced liver injury over 40, an interval between jaundice and encephalopathy [9] Bjornsson ES, Bergmann OM, Bjornsson HK, Kvaran RB, and Olafsson S. greater than seven days, or drug toxicity.37 Other criteria that Incidence, presentation, and outcomes in patients with drug-induced liver injury in the general population of Iceland. Gastroenterology 2013;144: may be used include Clinchy’s criteria and Escudie’s criteria. 1419–1425. doi: 10.1053/j.gastro.2013.02.006. Patients with fulminant liver failure, defined as the [10] Chalasani N, Fontana RJ, Bonkovsky HL, Watkins PB, Davern T, Serrano J, presentation of hepatic encephalopathy within eight weeks et al. Causes, clinical features, and outcomes from a prospective study of of the development of symptoms related to liver disease, drug-induced liver injury in the United States. Gastroenterology 2008;135: 1924–1934. doi: 10.1053/j.gastro.2008.09.011. should be referred for transplant. In the United States, [11] Wang YP, Shi B, Chen, YX, Xu J, Jiang CF, and Xie WF. Drug-induced liver according to United Network for Organ Sharing (UNOS), a disease: an 8-year study of patients from one gastroenterological depart- status 1A listing may be obtained if the patient has a life ment. J Dig Dis 2009;10:195–200. expectancy of seven days or less, does not have a pre- [12] Lammert C, Bjornsson E, Niklasson A, Chalasani N. Oral medications with significant hepatic metabolism at higher risk for hepatic adverse events. existing liver disease, and is in the intensive care unit Hepatology 2010;51:615–620. doi: 10.1002/hep.23317. requiring either ventilator assistance or dialysis or with an [13] Farrell GC. Liver disease caused by drugs, anesthetics, and toxins. In: INR greater than two.38 However, it is important to keep in Feldman M, Friedman LS, Sleisenger MH, editors. Gastrointenstinal and liver mind the contraindications for transplant, which include disease. 7th edition. Philadelphia: WB Saunders; 2002. p. 1403–1447. [14] Aragon G, Younossi ZM. When and how to evaluate mildly elevated liver significant comorbidities and active malignancy. Each patient enzymes in apparently healthy patients. Cleve Clin J Med 2010;77:195–204. should be considered on a case-by-case basis, and the doi: 10.3949/ccjm.77a.09064. guidelines should be consulted when considering a patient [15] De Valle MB, Klinteberg V, Alem N, Olsson R, Bjo¨rnsson E. Drug-induced liver for transplant. injury in a Swedish university hospital out-patient hepatology clinic. Aliment Pharmacol Ther 2006;24:1187–1195. doi: 10.1111/j.1365-2036.2006.03117.x. [16] Andrade RJ, Lucena MI, Fernandez MC, Pelaez G, Pachkoria K, Garcı´a-Ruiz E, Conclusions et al. Drug-induced liver injury: an analysis of 461 incidences submitted to the Spanish registry over a 10-year period. Gastroenterology 2005;129: 512–521. doi: 10.1016/j.gastro.2005.05.006. DILI remains an important cause of liver disease. Although it [17] Bell LN, Chalasani N. Epidemiology of idiosyncratic drug-induced liver injury. has a varied presentation and multiple possible drug causes, Semin Liver Dis 2009;29:337–347. doi: 10.1055/s-0029-1240002. treatment for all cases requires discontinuation of the [18] Lucena MI, Andrade RJ, Kaplowitz N, Garcı´a-Cortes M, Ferna´ndez MC, offending agent. If a patient has ingested acetaminophen or Romero-Gomez M, et al. Phenotypic characterization of idiosyncratic drug- induced liver injury: the influence of age and gender. Hepatology 2009;49: Amanita mushrooms, appropriate therapy should be admi- 2001–2009. doi: 10.1002/hep.22895. nistered. All patients can now be considered for NAC therapy [19] Schomaker S, Warner R, Bock J, Johnson K, Potter D, Van Winkle J, et al. and should be monitored for normalization of biochemical Assessment of emerging biomarkers of liver injury in human subjects. tests. Finally, early referral for liver transplant may be life Toxicol Sci 2013;132:276–283. doi: 10.1093/toxsci/kft009. [20] http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/ saving for some patients. Guidances/ UCM174090.pdf. Accessed December 20, 2013. [21] Rochon J, Protiva P, Seef LB, Fontana RJ, Liangpunsakul S, Watkins PB, et al. Reliability of the Roussel Uclaf Causality Assessment Method for assessing Conflict of interest causality in drug-induced liver injury. Hepatology 2008;48:1175–1183. doi: 10.1002/hep.22442. None [22] Takikawa H, Takamori Y, Kumagi T, Onji M, Watanabe M, Shibuya A, et al. Assessment of 287 Japanese cases of drug induced liver injury by the diagnostic scale of the International Consensus Meeting. Hepatol Res 2003; Author contributions 27:192–195. doi: 10.1016/S1386-6346(03)00232-8. [23] Lucena MI, Camargo R, Andrade RJ, Perez-Sanchez CJ, Sanchez De La Cuesta F. Comparison of two clinical scales for causality assessment in hepatoxicity. Writing the manuscript and creating figures and tables (CG), Hepatology 2001;33:123–130. doi: 10.1053/jhep.2001.20645. performing literature searches (CG, XZ), and editing and [24] Maria VA, Victorino RM. Development and validation of a clinical scale for the revising the manuscript (XZ). diagnosis of drug-induced hepatitis. Hepatology 1997;26:664–669. doi: 10.1002/hep.510260319. [25] Lee WM, Hynan LS, Rossaro L, Fontana RJ, Stravitz RT, Larson AM, et al. References Intravenous N-acetylcysteine improves transplant-free survival in early stage non-acetaminophen acute liver failure. Gastroenterology 2009;137: 856–864. doi: 10.1053/j.gastro.2009.06.006. [1] Zimmerman H. Hepatotoxicity: the adverse effects of drugs and other [26] Wree A, Dechene A, Herzer K, Hilgard, Syn WK, Gerken G, et al. Steroid and chemicals on the liver. 2nd edition. Philadelphia: Lippincott, Williams ursodesoxycholic acid combination therapy in severe drug-induced liver &Wilkins; 1999. injury. Digestion 2011;84:54–59. doi: 10.1159/000322298. [2] Dienstag J L, Isselbacher K J. Toxic and drug-induced hepatitis. Harrison’s [27] Yarema MC, Johnson DW, Berlin RJ, Sivilotti ML, Nettel-Aguirre A, Brant RF, Principles of Internal Medicine 2001;2:1737–1741. et al. Comparison of the 20-hour intravenous and 72-hour oral acetylcys- [3] Lee W, Senior J. Recognizing drug-induced liver injury: current problems, teine protocols for the treatment of acute acetaminophen poisoning. Ann possible solutions. Toxicol Pathol 2005;33:155–164. doi: 10.1080/ Emerg Med 2009;54:606–614. doi: 10.1016/j.annemergmed.2009.05.010. 01926230590522356. [28] Woodhead JL, Howell BA, Yang Y, Harrill A, Clewell HJ, Andersen ME, et al.An [4] Kaplowitz N. Drug-induced liver disorders: implications for drug develop- analysis of N-acetylcysteine treatment for acetaminophen overdose usinga ment and regulation. Drug Saf 2001;24:483–490. doi: 10.2165/00002018- systems model of drug-induced liver injury. J Pharmacol Exp Ther 2012;342: 200124070-00001. 529–540. doi: 10.1124/jpet.112.192930. [5] Chang CY, Schiano TD. Review article: drug hepatoxicity. Aliment Pharmacol [29] Wolf SJ, Heard K, Sloan EP, Jagoda AS. Clinical policy: critical issues in the Ther 2007;25:1135–1151. doi: 10.1111/j.1365-2036.2007.03307.x. management of patients presenting to the emergency department with [6] Ostapowicz G, Fontana RJ, Schiodt FV, Larson A, Davern TJ, Han SH, et al. acetaminophen overdose. Ann Emerg Med 2007;50:292–313. doi: 10.1016/ Results of a prospective study of acute liver failure at 17 tertiary care centers j.annemergmed.2007.06.014. in the United States. Ann Intern Med 2002;137:947–954. doi: 10.7326/ [30] http://www.acep.org/content.aspx?id526830, Accessed on December 28, 0003-4819-137-12-200212170-00007. 2013. [7] Vuppalanchi R, Liangpunsakul S, Chalasani N. Etiology of new-onset [31] Santi L, Maggioli C, Mastroroberto M, Tufoni M, Napoli L, Caraceni P. Acute liver jaundice: how often is it caused by idiosyncratic drug-induced liver injury failure cuased by Amanita phalloides poisoning. Int J Hepatol 2012;2012:487480 in the United States? Am J Gastroenterol 2007;102:558–562. [32] Gatselis NK1, Liamis G, Makaritsis KP, Dalekos GN. Metabolic acidosis during [8] Sembera S, Lammert C, Talwalkar J, Sanderson SO, Poterucha JJ, Hay JE, treatment of mushroom poisoning: a diagnostic pitfall. Intern Med 2012;51: et al. Frequency, clinical presentation and outcomes of drug-induced liver 1077–1080. injury after liver transplantation. Liver Transpl 2012;18:803–810. doi: [33] Czaja A. Drug-induced autoimmune-like hepatitis. Dig Dis Sci 2011;56:958– 10.1002/lt.23424. 976. doi: 10.1007/s10620-011-1611-4.
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[34] Patel T, Yosipovitch G. Therapy of pruritus. Expert Opin Pharmacother 2010; [36] http://clinicaltrials.gov/show/NCT01079091. Accessed on December 30, 11:1673–1682. doi: 10.1517/14656566.2010.484420. 2013. [35] Demetrious AA, Brown RS, Busuttil RW, Fair J, McGuire BM, Rosenthal P, et al. [37] O’Grady JG1, Alexander GJ, Hayllar KM, Williams R. Early indicators of Prospective, randomized, multicenter, controlled trial of a bioartificial liver in prognosis in fulminant hepatic failure. Gastroenterology 1989;97:439–445. treating acute liver failure. Ann Surgery 2004;239:660–670. doi: 10.1097/ [38] http://optn.transplant.hrsa.gov/PoliciesandBylaws2/policies/pdfs/policy_8. 01.sla.0000124298.74199.e5. pdf, Accessed on December 29, 2013.
Journal of Clinical and Translational Hepatology 2014 vol. 2 | 74–79 79 Review Article
Traditional Chinese Medicine Induced Liver Injury
Rolf Teschke
Department of Internal Medicine II, Division of Gastroenterology and Hepatology, Klinikum Hanau, Academic Teaching Hospital of the Medical Faculty of the Goethe University Frankfurt/Main, Germany
Abstract severe,with risks for acute liver failure,liver transplantation requirement,and lethality. In conclusion,the use of few Traditional Chinese Medicine (TCM) is popular around the herbal TCM products may rarely be associated with hepato- world and encompasses many different practices with parti- toxicity in some susceptible individuals,necessitating a cular emphasis on herbal TCM. Using the PubMed database,a stringent pretreatment evaluation of the risk/benefit ratio, literature search was undertaken to assess the extent herbal based on results of multicenter,randomized,double-blind, TCM products exert rare hepatotoxicity. Analysis of reported placebo-controlled clinical trials. cases revealed numerous specified herbal TCM products with E 2014 The Second Affiliated Hospital of Chongqing Medical potential hepatotoxicity. Among these were An Shu Ling,Bai University. Published by XIA & HE Publishing Ltd. All rights Fang,Bai Xian Pi,Ban Tu Wan,Bo He,Bo Ye Qing Niu Dan, reserved. Bofu Tsu Sho San,Boh Gol Zhee,Cang Er Zi,Chai Hu,Chaso, Chi R Yun,Chuan Lian Zi,Ci Wu Jia,Da Chai Hu Tang,Da Introduction Huang,Du Huo,Gan Cao,Ge Gen,Ho Shou Wu,Hu Bohe You, Hu Zhang,Huang Qin,Huang Yao Zi,Hwang Geun Cho,Ji Gu Traditional Chinese Medicine (TCM) is one of the oldest Cao,Ji Ji,Ji Xue Cao,Jiguja,Jin Bu Huan,Jue Ming Zi, healing systems worldwide,originating in the ancient Kamishoyosan,Kudzu,Lei Gong Teng,Long Dan Xie Gan Chinese philosophy and dating back to more than 2,500 1,2 Tang,Lu Cha,Ma Huang,Mao Guo Tian Jie Cai,Onshido, years. In other Asian countries,TCM became popular and is Polygonum multiflorum,Qian Li Guang,Ren Shen,Sairei To, called Traditional Asian Medicine (TAM) or Traditional Oriental Shan Chi,Shen Min,Shi Can,Shi Liu Pi,Shou Wu Pian,Tian Medicine (TOM),and Kampo Medicine in Japan. Since these Hua Fen,White flood,Wu Bei Zi,Xi Shu,Xiao Chai Hu Tang, practices have been adopted in other parts of the world, Yin Chen Hao,Zexie,Zhen Chu Cao,and various unclassified technically the topic should be considered to be Traditional Chinese herbal mixtures. Causality was firmly established for Chinese and other Asian Medicine. However,in Western a number of herbal TCM products by a positive reexposure countries,the use of the popular name TCM has remained test result,the liver specific scale of CIOMS (Council for virtually unchanged without naming each individual country International Organizations of Medical Sciences),or both. engaged in Traditional Medicine originating from ancient Otherwise,the quality of case data was mixed,especially China. The basic principles of TCM are identical or vary only regarding analysis of the herb ingredients because of little between the numerous countries. Therefore,the use of adulteration with synthetic drugs,contamination with heavy TCM as the overall term is warranted and facilitates the discussions around major TCM related issues. metals,and misidentification. In addition,non-herbal TCM TCM is not a single entity but encompasses many different elements derived from Agaricus blazei,Agkistrodon, practices,including herbal medicine,acupuncture,moxibus- Antelope,Bombyx,Carp,Fish gallbladder,Phellinus, tion,massage,dietary therapy,and physical exercise such as Scolopendra,Scorpio,and Zaocys are also known or potential shadow boxing.1,2 TCM is a fully institutionalized part of hepatotoxins. For some patients,the clinical course was China’s health care system and is widely used within Western medicine.2 In 2006,the TCM sector included over 200 million Keywords: Traditional Chinese medicine; Traditional Chinese herbal medicine; outpatients and around seven million inpatients,accounting Herbal hepatotoxicity; Herb induced liver injury; Herbs. for 10–20% of health care in China.2 Although the exact Abbreviations: ALP,alkaline phosphatase; ALPb,alkaline phosphatase baseline; ALPr,alkaline phosphatase reexposure; ALT,alanine aminotransferase; ALTb, number of people who use TCM in the United States is alanine aminotransferase baseline; ALTr,alanine aminotransferase ree xposure; unknown,it was estimated in 1997 that some 10,000 AST,aspartate aminotransferase; CIOMS,Council for International Orga nization practitioners served more than one million patients each of Medical Sciences; CMV,cytomegalovirus; EBV,Epstein Barr virus; HAV, year.1 Despite its popularity,there has been concern about hepatitis A virus; HBV,hepatitis B virus; HCV,hepatitis C virus; HEV,hep atitis E 1–4 virus; HILI,herb induced liver injury; HSV,herpes simplex virus; LTX,li ver the efficacy and safety of TCM, and other issues related to transplantation; N,upper limit of normal; PA,pyrrolizidine alkaloid; R ,ratio; scattered and inappropriate randomized controlled clinical RUCAM,Roussel Uclaf Causality Assessment Methods; TAM,Traditional Asi an trials of TCM.2,4,5 Adverse reactions by TCM have been Medicine; TCM,Traditional Chinese Medicine; TOM,Traditional Oriental Medicine; reported,leading to systemic and organ specific health HSOS,hepatic sinusoidal obstruction syndrome; HVOD,hepatic veno-occl usive 2,6 7,8 disease; VZV,varicella zoster virus. risks including the liver. These reactions create concern Received: 17 January 2014; Revised: 27 February 2014; Accepted: 2 March 2014 and represent a particular clinical challenge because TCM q DOI of original article: 10.14218/JCTH.2014.00003. products are commonly perceived as natural and thereby Correspondence to: Rolf Teschke,Department of Internal Medicine II,Klinikum erroneously as safe. Hanau,Academic Teaching Hospital of the Goethe University of Frankfurt/ Main, Leimenstrasse 20,Hanau D-63450,Germany. Tel.: +49-6181/21859,E-mail: rolf. Hepatotoxicity by TCM is limited to natural products, [email protected] mainly herbs,from the more than 7,000Chinese herbal
80 Journal of Clinical and Translational Hepatology 2014 vol. 2 | 80–94 Teschke R.: Traditional Chinese medicine induced liver injury medications in use.8 Herb induced liver injury (HILI) is not toxicology database found the synonym Jin Bu Huan listed for restricted to Chinese herbs but may be commonly observed in An Shu Ling, virtually all countries where herbs are consumed.9 At present, L-tetrahydropalmitine was identified in chemical analysis. HILI has been documented with published case reports or The analogous hepatotoxic constituent to Jin Bu Huan also case series by at least 60 different herbs and herbal mixtures, contains Stephania sinica and various herbs. The two other including Chinese ones. In this review,a literature search was herbal medicines contained no suspected hepatotoxins. The performed for cases of herbal TCM with special reference to product lot of An Shu Ling was confiscated and a public health hepatotoxic side effects and addressed the question of how to warning was issued. No additional cases associated with the improve collection and evaluation of case data in the future in use of this particular product were reported. Although Jin Bu order to facilitate causality assessment. Huan itself was banned from importation into the United States18 due to the known hepatotoxic risks,7,9 a shipment of Literature search and identification of reports An Shu Ling reportedly cleared US customs because the respective shipping invoice contained only the Chinese For a selective literature search from 1990 to 2013,PubMed botanical name.18 See also Jin Bu Huan. was searched using the terms Traditional Chinese Medicine, Traditional Asian Medicine,Traditional Oriental Medicine, Traditional Chinese Medicine liver injury,Traditional Asian Ba Jiao Lian Medicine liver injury,Traditional Oriental Medicine liver injury, Chinese herbal hepatotoxicity,Chinese herbal liver injury, After drinking infusions made with the TCM Ba Jiao Lian herbal hepatotoxicity,and herb induced liver injury. From (Dysosma pleianthum) and consuming the recommended each search,the first 25 publications underwent analysis for dose,five patients in Taiwan manifested abnormal liver subject matter,data quality,and overall suitability. Citations function tests associated with nausea,vomiting,diarrhea, in retrieved publications were searched for other yet uni- abdominal pain,thrombocytopenia,leucopenia,sensory dentified case reports. The search was limited primarily to ataxia,altered consciousness,and persistent peripheral 19 English-language case reports,case series,and clinical tingling or numbness. In a recent report from Taiwan,17 20 reviews. Full lengths publications in Chinese,Japanese,or cases with poisoning by Ba Jiao Lian were published. other Asian languages were not considered,but their Podophyllotoxin is one of the main ingredients of the Ba Jiao 19–21 abstracts were used occasionally if provided in English. Lian root and is considered the toxic agent. However,the increase in the aminotransferases was small,with preference Individual cases for the aspartate aminotransferase (AST) over the alanine aminotransferase (ALT).19,21 The increase of AST19 could The selected publications represented reports of cases with reflect either isolated damage of mitochondria around the 21 herbal TCM induced liver injury and originated from China hepatic central vein or some muscular damage because of 19 including Hong Kong,Taiwan,Japan,Korea,Singapore, the associated increase of creatine phosphokinase. These Thailand,Australia,Italy,Spain,France,the Netherlands, uncertainties do not allow for the classification of Ba Jiao Lian the United Kingdom,Iceland,Canada,the United States,and as a potentially hepatotoxic herb,and it is therefore not Argentina. Outside of China,only around 500 TCM herbs are further considered within this review. commonly used,which is a small fraction of the medicinal herbs available. In China,this number is estimated to be Bai Fang more than 7,0008 or around 14,000 items.10 The present analysis includes data from a relatively low number of A 54-year old male patient in the United States developed potentially hepatotoxic TCM products,only a few dozen subtotal liver necrosis and survived following liver trans- herbal products and single herbs. However,non-English plantation (LTX).22 He used Bai Fang as a herbal TCM for an language publications were excluded from this review,and unknown time and had acute hepatitis B virus (HBV) as a the information here is not an exhaustive summary of all cofactor. Ingredients of Bai Fang include Angelica sinensis, information collected to date. Cyperus rotundus,Ginseng, Ligusticum wallichii, Paeonia In general,evaluation of cases with suspected herbal TCM alba,and Rehmannia glutinosa. The possible hepatotoxic induced liver injury is challenging because numerous aspects herb and its suspected ingredient remain unknown,and the need to be considered for a valid assessment (Table 1).11–15 causality for Bai Fang is questionable because of the This includes a liver specific causality assessment,preferen- concomitant acute hepatitis B. No other cases were tially with the scale of the Council for International reported. Organizations of Medical Sciences (CIOMS),also called the Roussel Uclaf Causality Assessment Method (RUCAM).13–15 Although rarely available,most valuable for the causality Bai Xian Pi evaluation is the assessment of unintentional reexposures, which requires the application of strict criteria (Table 2).16,17 In four Korean patients,the use of the herb TCM Bai Xian Pi (Dictamnus dasycarpus) was hepatotoxic,when applied as a An Shu Ling single herb.23 Similarly,it was hepatotoxic in three patients from the United Kingdom when it was coadministered with A 42-year old woman from the United States took three other herbs.24–26 Overall,fourteen patients from Korea different herbal medicines for insomnia.18 The products were developed acute toxic hepatitis due to Dictamnus dasycar- An Shu Ling (syn. Jin Bu Huan) as TCM,‘‘Ignatia Amara’’,and pus,27 and two other Korean patients required a liver ‘‘Relaxed Wanderer’’. Following a ten week treatment course, transplant due to acute liver failure.28 See also Chinese she experienced jaundice and developed acute hepatitis. A herbal mixtures.
Journal of Clinical and Translational Hepatology 2014 vol. 2 | 80–94 81 Teschke R.: Traditional Chinese medicine induced liver injury
Table 1. Required quality standards for assessing cases of suspected herbal Traditional Chinese Medicine (TCM) induced liver injury
Items with required quality specifications Quality specification of herbal TCM products N Good Agricultural Practices (GAPs) N Good Manufacturing Practices (GMPs) N Definition of plant family,subfamily,species,subspecies,and variety N Definition of plant part N Definition of solvents and solubilizers N Lack of impurities,adulterants,and misidentifications N Minimum batch to batch variability N Minimum product to product variability N Lack of variety to variety variability TCM herbs and their use N Brand name with details of ingredients,plant parts,batch number,and expiration date N Identification as herbal TCM,herbal drug,or herbal supplement N Herb as an ingredient of a polyherbal product or an undetermined herbal product N Manufacturer with address N Indication of herbal TCM use with dates of symptoms leading to herbal treatment N Daily dose with details of the application form N Exact date of herbal TCM start and herbal TCM end Details and clinical course ofpatients N Gender,age,body weight,height,and BMI N Ethnicity and profession N Past medical history regarding general diseases,specifically liver diseases N Definition of risk factors such as age and alcohol N Alcohol and drug use N Statement regarding actual treatment including steroids or ursodesoxycholic acid N Time frames of challenge,latency period,and dechallenge N Accurate dates of emerging new symptoms after herbal TCM start in chronological order N Accurate date of initially increased liver values N ALT value initially including normal range N ALT values during dechallenge at least on days 8,30,and later N ALT values during dechallenge to exclude a second peak N ALT normalization with exact date and actual value N ALP value initially including normal range N ALP values during dechallenge at least on days 8,30,and later N ALP values during dechallenge to exclude a second peak N ALP normalization with exact date and actual value N AST value initially including normal range N Laboratory criteria for definition of hepatotoxicity and its pattern N Verification or exclusion of a temporal association N Qualified data acquisition and documentation of complete data N Transparent presentation of all data,not just superficial data N Initial assessment of a temporal association,then causal relationship Liver specific assessment of causality N Liver specific causality assessment method N Assessment method validated for hepatotoxicity N Structured and quantitative method N Use of the CIOMS scale N Assessment by skilled hepatologist with clinical experience Continued
82 Journal of Clinical and Translational Hepatology 2014 vol. 2 | 80–94 Teschke R.: Traditional Chinese medicine induced liver injury
Table 1. Continued
Items with required quality specifications N Regulatory assessment with assistance of external experts N High graded transparency of causality assessment results N Presentation of the results item by item with individual scores Exclusion ofalternative diagnoses N Assessment of preexisting and coexisting liver unrelated diseases N Assessment of preexisting and coexisting liver diseases N Consideration of the several hundred other possible liver diseases N Providing details to exclude alternative diagnoses N Assessment and exclusion of HAV,HBV,HCV,HEV,CMV,EBV,HSV,VZV N Liver and biliary tract imaging,including color Doppler sonography of liver vessels N Specific evaluation of alcoholic,cardiac,autoimmune,and genetic liver diseases N Individual quantitative score of each alternative diagnosis N Comedicated synthetic drugs,herbal drugs,herbal,and dietary suppleme nts N Individual quantitative score of each individual comedication Reexposure tests and known hepatotoxicity ofthe herbal TCM N Definition of and search for accidental,unintended reexposure N Assessing and individual scoring of unintended reexposure N Search for evidence of prior known hepatotoxicity of the suspected herbal TCM N Assessing and individual scoring of known hepatotoxicity caused by the herbal TCM
Compiled for herbal hepatotoxicity by TCM and modified from previous reports.11,12,14 Abbreviations: ALP,alkaline phosphatase; ALT,alanine aminotransfera se; AST, aspartate aminotransferase; CMV,cytomegalovirus; EBV,Epstein Barr virus; HAV,hepatitis A virus; HBV,hepatitis B virus; HCV,hepatitis C virus; HEV,hepatitis E virus; HSV, herpes simplex virus; VZV,varicella zoster virus.
Ban Tu Wan Bo He
A middle-aged Asian female patient living in the United States Two men,45-years and 46-years,from Hong Kong with a acquired fulminant hepatic failure secondary to the use of the chronic HBV infection took the TCM Bo He (Mentha haploca- TCM Ban Tu Wan.29 Its ingredients were Angelica sinensis, lyx) in formulas that contained 11 elements with Bo He, Chaenomeles, Codonopsis pilosula, Notopterygium, shown to be hepatotoxic in the Chinese literature.30 Polygonum multiflorum, Rehmannia,and Schisandra. The patient was evaluated for a liver transplant but did not meet Bofu Tsu Sho San transplantation requirements because of septicemia,leading to a lethal outcome.29 Other hepatotoxicity cases caused by A 37-year old Japanese woman used the herbal TCM Bofu Tsu Ban Tu Wan have not been published. See also Ho Shou Wu, Sho San,a Japanese kampo medicine also called Bofu Tsu Polygonum multiflorum,Shen Min,and Shou Wu Pian. Sho San,and a diagnosis of herb induced liver injury was
Table 2. Prerequisites for positive reexposure tests in cases of suspected herbal Traditional Chinese Medicine (TCM) induced liver injury
Hepatocellular type of injury Cholestatic (± hepatocellular) type of injury Reexposure test result ALTb ALTr ALPb ALPr
Positive , 5N o 2ALTb , 2N o 2ALPb Negative , 5N , 2ALTb , 2N , 2ALPb Negative o 5N o 2ALTb o 2N o 2ALPb Negative o 5N , 2ALTb o 2N , 2ALPb Negative o 5N n.a. o 2N n.a. Uninterpretable , 5N n.a. , 2N n.a. Uninterpretable n.a. n.a. n.a. n.a.
Modified and derived from previous reports.16,17 Required data for the hepatocellular type of liver injury are the ALT levels commonly just before reexposure,designed as baseline ALT or ALTb,and the ALT levels during reexposure,designed as ALT r and correlated to 2ALTb. Response to reexposure is positive,if both crit eria are met: first,ALTb , 5N with N as the upper limit of normal,and second ALTr o 2ALTb. Other variations lead to negative or uninterpretable test results. For the cholestatic (± hepatocellular) type of liver injury,corresponding values of ALP are to be used rather than of ALT,but ALPb values focus on 2N rather than on 5N as for ALTb. Definitions of the hepatocellular and the cholestatic (± hepatocellular) type of liver injury are provided previously.13–16 Abbreviations: ALP,Alkaline phosphatase; ALT,Alanine aminotransferase; n.a.,not available.
Journal of Clinical and Translational Hepatology 2014 vol. 2 | 80–94 83 Teschke R.: Traditional Chinese medicine induced liver injury made.31 Bofu Tsu Sho San contains 16 herbs, Angelica, TCM herbal product Onshido,41 were reported. An additional Atractylis, Cnidium, Gardenia, Ephedra, Forsythia, 21 cases of Chaso-induced hepatotoxicity were reported to Glycyrrhhiza, Gypsum fibrosum, Ledebouriella, Mentha, health officials in Japan and not further analyzed.41 A Paeonia, Platycodon, Rheum, Schizonepeta, Scutellaria,and cautionary statement by the authors recommended further Zingiber,as well as Kadinum (talcum powder) and sodium toxicological analyses to determine possible hepatotoxicity sulfuricum.32 Several herbs are candidates for liver injury, by N-nitroso-fenfluramine,which was not established tox- including Ephedra that contains the hepatotoxic stimulant icologically or clinically until 2003.41 Toxicological evidence of ephedrine.9,33 For Ephedra see also Ma Huang. its hepatotoxic property was not provided since 2003,and clinical evidence cannot be expected because it was removed Boh Gol Zhee from the market in 1997. The popular and widely used slimming aid fenfluramine was withdrawn from clinical use Acute hepatitis was described after use of the TCM Boh Gol because of cardiac rather than hepatic complications,which Zhee (syn. Bol Gol Zhee,Bu Gu Zhi,Bu Ku Zi,Sheng Bu Gu remain unknown.41 Consequently,there is little toxicological Zhi,Sheng Po Gu Zhi) in two patients from Korea 34,35 and in and clinical evidence available regarding the hepatotoxicity of three patients from Hong Kong.36 Boh Gol Zhee represents fenfluramine or N-nitroso-fenfluramine. For more details and not a herbal mixture but seeds of Psoralea corylifolia,and discussions see Lu Cha (Camellia sinensis) and Onshido. when used at high amounts psoralens are potentially hepatotoxic.34–36 Psoralens were hepatotoxic candidates in Chi R Yun another patient who experienced severe hepatotoxicity with Indian Ayurvedic herbal products.37 These included Bakuchi Taiwanese patients who used the TCM Chi R Yun (Breynia tablets that contain extracts from Psoralea corylifolia leaves officinalis) experienced hepatotoxicity.45–47 There was inten- with psoralens for treatment of vitiligo. tional and unintentional Chi R Yun overdose in two patients45 and acute poisonings in 19 patients.46,47 Because of their Bupleurum similarities, Breynia officinalis was mistaken for another plant,the TCM Yi Yi Qui ( Securinega suffruticosa).46,47 See Chai Hu. Chinese herbal mixtures Camellia sinensis Patients of this section used an unnamed,unclassified herbal See Lu Cha. mixture of TCM. Additionally,in some of these cases,only individual herbs had been declared by name. Since the herbal Chai Hu mixtures have all herbs presented as ingredients,these mixtures could not be added to an existing named herbal The risk of liver injury was increased in overall 61 Taiwanese product group. patients with HBV infections treated with some products of Herbal hepatotoxicity was published for a heterogeneous TCM containing Chai Hu (Bupleurum falcatum).38 In particu- group of herbal mixtures of TCM,24–26,48–51 primarily from the lar,two products were involved,Xiao Chai Hu Tang with 19 United Kingdom.24–26,48–50 In three cases,hepatotoxicity patients and Long Dan Xie Gan Tang with 14 patients. In other was described following herbal TCM use,but firm details individuals without HBV infections,various herbal TCM concerning the applied herbs were missing.48–50 More products containing Bupleurum may be hepatotoxic,see for information was provided by other reports.24–26 One treat- instance Da Chai Hu Tang,39 Kamishoyosan,40 and a report ment consisted of Dictamnus dasycarpus (syn. Bai Xian Pi), referring to a herbal TCM mixture.25 See also Long Dan Xie Gentiana scabra, Hedyotis diffusa, Paeonia suffructicosa, Gan Tang and Xiao Chai Hu Tang. Paris polyphylla, Rehmannia glutinosa, Smilax glabra,and Sophora subprostrata.25 Another patient used Angelica Chaso sinensis, Bupleurum chinese, Dictamnus dasycarpus, Paeonia suffructiosa, Philodendron chinese, Saposhnikovia Six Japanese patients developed hepatic injury after using divaricata, Shisandra chinesis, Shizonepeta tenuifolia,and Chaso,a herbal TCM that promotes weight loss. 41 This Tribulus terrestris.25 A third patient with a fatal clinical course product contained Camellia sinensis (Green tea,syn. Lu Cha used a mixture consisting of Cocculus trilobus, Dictamnus as TCM),the hepatotoxic Cassia tora (Senna), Crataegus, dasycarpus, Eurysolen gracilis, Glycyrrhiza, Lophatherum, Chrysanthenum morifolium Ramat., Lotus,and Lycium bar- Paeonia, Potentilla,and Rehmannia glutinosa.24 Considering barum. As an ingredient of the Chaso formula, Camellia these three cases from two reports,24,25 it is possible that sinensis extract is known to facilitate weight loss. Since the either Dictamnus dasycarpus or Paeonia species could be the toxic property of Camellia sinensis extract was unknown in toxic herb.25 Four Korean patients with toxic liver injury used 2003 when Chaso hepatotoxicity was first described,it was Dictamnus dasycarpus as a single herb.23 In addition, not considered to be the hepatotoxic agent.41 Outcome was analysis of a herbal remedy taken by another patient with favorable in all patients,with only one patient requiring LTX. fulminant liver failure and unsuccessful LTX confirmed the Chemical product analysis showed lack of fenfluramine and presence of Dictamnus dasycarpus. These cases support an heavy metals,such as copper,lead,bismuth,cadmium, etiological role of this herb in TCM hepatoxicity.26 stibium,stanum,mercury,and chromium,but N-nitroso- The herbal mixture of TCM used by a patient in Canada led fenfluramine was found. N-nitroso-fenfluramine was consid- to acute liver failure and successful LTX in the United ered a possible but not yet proven culprit,41 since similar States.51 This mixture consisted of twelve herbs,including cases of hepatotoxicity by various other slimming aids in the Alisma plantago aquatica, Artemisia capillaris, Bupleurum, United Kingdom,42 Hong Kong43 and Japan44 including the Chrysanthemum morifolium, Circuma, Gardenia jasminoidis,
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Gentiana scabra, Glycyrrhiza, Magnolia, Paeonia, Plantago Ge Gen asiatica,and Saussurea lappa. The toxic culprit remains unknown. The two 57- and 58-years old women from Korea ingested juice of the herbal TCM Ge Gen (Pueraria lobata, syn. Arrowroot) and developed symptomatic toxic hepatitis.53 Chinese skullcap Clinical symptoms and laboratory findings rapidly improved following cessation of Ge Gen and supportive care. See Huang Qin.
Glycyrrhiza uralensis Chuan Lian Zi See Gan Cao. A 45-year old male patient with chronic HBV infection from Hong Kong was treated with the TCM Chuan Lian Zi (Melia Ho Shou Wu toosendan) and experienced herbal hepatotoxicity.30 A 54-year old Korean woman consumed Polygonum multi- Ci Wu Jia florum as the TCM Ho Shou Wu (syn. He Shou Wu,Shou Wu Wan,Fo Ti) and experienced toxic hepatitis. 54 Hepatotoxicity Two Korean patients consumed the herbal TCM Ci Wu Jia in a 33-year old woman from Hong Kong with a chronic HBV (Acanthopanax senticosus),developed acute toxic hepatitis infection was assumed to be due to Ho Shou Wu as well. with acute liver failure,and required LTX. 25 However,other medications also included the hepatotoxic Jue Ming Zi (Cassia obtusifolia tora,Senna) and 10 additional, unidentified herbal items.30 Da Chai Hu Tang
In a Japanese patient,autoimmune hepatitis was triggered by Huang Qin the use of the TCM Da Chai Hu Tang (syn. Dai Saiko To,TJ-8), a mixture of aqueous extracts from seven plants, Bupleurum Nineteen Japanese patients developed liver injury after the falcatum, Ginseng, Glycyrrhiza glabra, Pinellia, Scutellaria, use of the herbal TCM Huang Qin (Scutellaria baicalensis,syn. Zingiber officinale,and Zizyphus jujuba.39 The specific culprit Chinese skullcap),which is a herbal mixture called Ogon in 55 remained unknown. Da Chai Hu Tang contains the same Kampo medicine of Japan. Hepatotoxicity was described in components as the potentially hepatotoxic TCM Xiao Chai Hu four patients from the United States who used Huang Qin in a Tang (syn. Sho Saiko To Syo Saiko To,Syo Xiao Hu Tang,TJ- dietary supplement which also contained black catechu 9) but in different proportions.39,52 See also Bupleurum and (Acacia catechu),glucosamine,chondroitin,and hyaluronic 56–58 Xiao Chai Hu Tang. acid. Acacia catechu was used as one of several Indian Ayurvedic herbs in a patient with severe hepatotoxicity and is thereby a possible culprit.37 However,the herbal extract of Da Huang Chinese skullcap is the more likely cause of the reported hepatotoxicity.56–58 There are some hundred species of A 45-year old man from Hong Kong with chronic HBV infection skullcap (Scutellaria),including Scutellaria lateriflora,that used the herbal TCM Da Huang (Rhubarb, Rheum palmatum) have potential hepatotoxic risks,but often information and died from acute liver and organ failure due to herbal regarding respective species was missing.9 hepatotoxicity.30 Hwang Geun Cho Dai Saiko To A 37-year old Korean male patient consumed the herbal TCM See Dai Chai Hu Tang. Hwang Geun Cho (Corydalis speciosa) and was diagnosed with acute herbal hepatotoxicity.59 Symptoms disappeared and laboratory values gradually returned to near normal Dan Zhi Xiao Yao San values following cessation and supportive management. See Kamishoyosan. Ji Gu Cao
Dictamnus dasycarpus A 38-year old man from Hong Kong with chronic hepatitis B took the herbal TCM Ji Guo Cao (syn. Abrus cantoniensis,Ji See Bai Xian Pi. Gu Cao Wan) and was diagnosed with herb induced liver injury,possibly caused by contaminated hepatotoxic seeds. 30 Gan Cao Ji Xue Cao A 46-year old man from Hong Kong with a chronic HBV infection took the TCM Gan Cao (syn. Glycyrrhiza uralensis, Three women aged 61,52,and 49 years from Argentina Liquorice,Gan Cao Zhi,Shen Nong Ben Cao Jing,Zhi Gan ingested the herbal TCM Ji Xue Cao (Centella asiatica, Cao) in formulas. These contained 11 elements,and Gan Cao syn.Gotu Kola) and developed herbal hepatotoxicity by was the likely toxic agent for the observed hepatotoxicity.30 Centella asiatica.60 Outcomes were favorable after disconti- Recovery was complete after discontinuation of Gan Cao. nuation of the medication and ursodeoxycholic acid therapy.
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Jia Wei Xiao Yao San evidence for the hepatotoxic potential of Jing Tian San Qi. Therefore,the herbal TCM Sedum aizoon will not be further See Kamishoyosan. considered for hepatotoxicity.
Jiguja Jue Ming Zi
A 3.5 year old boy from Korea consumed tea prepared from A 33-year old woman from Hong Kong with a chronic HBV the herbal TCM Jiguja (Hovenia dulcis),resulting in the infection was treated with the herbal TCM Jue Ming Zi (syn. development of toxic hepatitis.61 Because acute liver failure Cassia obtusifolia, Senna obtusifolia,Cao Jue Ming) and emerged,the boy was transferred to another hospital for experienced liver injury.30 further evaluation and eventually LTX. In addition,two other adults from Korea developed toxic hepatitis after ingesting Kamishoyosan Hovenia dulcis,27,28,61 and one of these patients required LTX.28 In one single Japanese woman,liver injury was reported following the use Kamishoyosan,a traditional Japanese Jin Bu Huan herbal drug (Kampo medicine) and synonym to the TCM Jia Wei Xiao Yao San,Dan Zhi Xiao Yao San,or TJ-24. 40 Hepatotoxicity associated with the herbal TCM Jin Bu Huan, Kamishoyosan is a herbal mixture and contains several syn. An Shu Ling,18 was reported from Hong Kong,62 in eleven components,including Angelica sinensis, Atractylodes racea, patients from the United States,18,63–65 one patient from Bupleurum falcatum, Gardenia, Glycyrrhiza glabra, Mentha Canada,63 and one patient from Italy.66 L-tetrahydropalmi- haplocalyx, Moutan, Paeonia alba, Sclerotium Poriae Cocos, tate is the active ingredient of Jin Bu Huan and the presumed and Zingiber officinale,as described in the case report 40 or as causative agent for hepatotoxicity. The herbal medication assessed by an internet search for a refined botanical usually contains only Lycopodium serratum,or rarely several description of the herbal components. Detecting the causa- unrelated herbal species,including Corydalis species, Panax tive agents was difficult,but Scutellaria was definitively ginseng,Pseudo ginseng,or two species of Stephania.18,63–67 excluded.54,79 There is some uncertainty regarding the Mentha species,declared as Mentha herb in the case report40 79 Jing Tian San Qi and as mentha (pennyroyal) subsequently. An additional internet search to further determine the Mentha species Prior to 2008,there were 41 reported cases from China of commonly used in Kamishoyosan found Mentha haplocalyx hepatic sinusoidal obstruction syndrome (HSOS),formerly Briq or Mentha arvensis var. piperascens Malinvaud called hepatic veno-occlusive disease (HVOD),attributed to (Japanese field mint) as the most probable component. the herbal TCM Jing Tian San Qi (Sedum aizoon,syn. Stonecrop).68 However,causal attribution to Sedum aizoon Kudzu was in retrospect incorrect. Sedum aizoon lacks pyrrolizidine alkaloids (PAs),and when administered to experimental Six patients from Korea consumed the herbal TCM Kudzu animals,HSOS did not emerge. 69 This suggested that a herb (Pueraria thunbergiana) and were diagnozed with acute toxic containing PAs was likely responsible for the reported hepatitis.27 cases.68 Consistent with this,in another hepatotoxicity case from Hong Kong,HSOS was initially ascribed to Sedum aizoon Liquorice but was later determined to be caused by the herbal TCM Shan Chi (Gynura segetum).69 The appearance of Sedum See Gan Cao. aizoon is similar to Gynura segetum but can be differentiated by an expert eye.69 Comparative studies with both herbs Long Dan Xie Gan Tang provided clear supportive evidence for Gynura segetum as the culprit for additional cases of HSOS over Sedum aizoon. Overall,fourteen Taiwanese patients with HBV infection were Respective studies showed in mice that the PAs containing found to be at higher risk for hepatotoxicity when treated with Gynura segetum but not the PAs lacking Sedum aizoon the TCM Long Dan Xie Gan Tang (syn. Long Dan Xie Gan produced experimental HSOS as assessed by liver histol- Wan).38 This herbal mixture contains Acebia, Alisma, ogy.69 In an earlier experimental study,a model of the Angelica sinensis, Bupleurum, Gardenia, Gentiana, hepatic veno-occlusive disease was established by PAs Glycyrrhiza, Plantago, Rehmannia,and Scutellaria. A similar derived from a herb described erronously as Sedum aizoon,70 increase in risk was observed in another patient group treated which again does not contain PAs.69,71,72 This suggested that with the TCM Xiao Chai Hu Tang,which also contains the described experimental model70 was due to the action of Bupleurum among other herbs. See also Bupleurum and a herb containing PAs,most likely Gynura segetum,69,71–73 Xiao Chai Hu Tang. rather than to PAs lacking Sedum aizoon.71 Other authentica- tion problems of Gynura segetum had to be resolved in Long Dan Xie Gan Wan relation to the TCM Mao Guo Tian Jie Cai (Heliotropium lasiocarpum),another herb that also contains PAs. 74–76 HSOS See Long Dan Xie Gan Tang. cases had been initially attributed to Gynura segetum,74,75 but this causal attribution was in retrospect incorrect since Lu Cha Heliotropium lasiocarpum was determined as culprit.76 Overall,careful analyses finally led to a clear picture of Lu Cha (Camellia sinensis,green tea) is a TCM plant and one HSOS by Gynura segetum.77,78 Taken together,there is little of several herbal ingredients in the two herbal mixtures Chaso
86 Journal of Clinical and Translational Hepatology 2014 vol. 2 | 80–94 Teschke R.: Traditional Chinese medicine induced liver injury and Onshido. These mixtures were marketed as weight loss one with a lethal clinical course. Chemical product analysis of aids by Chinese pharmaceutical companies and found to be Onshido showed lack of fenfluramine and heavy metals such hepatotoxic,as described in 2003. 41 N-nitroso-fenfluramine as copper,lead,bismuth,cadmium,stibium,stanum,mer- but not green tea was discussed as the possible but cury,and chromium but the presence of N-nitroso-fenflur- unproven hepatotoxic ingredient for these herbal mixtures. amine as a possible but ultimately unproven hepatotoxic However,this case series did not prove that N-nitroso- agent. N-nitroso-fenfluramine was also considered the pos- fenfluramine was the toxic agent.41 Whether Camellia sible culprit in additional cases of hepatotoxicity by various sinesis may have contributed to the observed hepatotoxicity other slimming aids in the United Kingdom,42 Hong Kong,43 is unclear,because information on the amounts of green tea including the TCM product Chaso in Japan.41 Additional 135 in these two products was not provided. At least as an Onshido-induced cases of hepatotoxicity were reported to extract, Camellia sinensis is a potent weight loss aid with health officials in Japan but not further analyzed.41 The potentially hepatotoxic effects,as thoroughly discussed first hepatotoxic properties of Camellia sinensis extracts were in 200480–82 and in subsequent years.9,83–88 Therefore, discovered in 2004,9 and its role in Camellia sinensis induced hepatotoxicity of green tea as extracts was not yet clearly hepatotoxicity was not evaluated in 2003.41 For additional established in 2003 when the respective case reports were details and discussions see also Chaso and Lu Cha (Camellia 41 published. sinensis). Green tea is one of the most popular beverages,as are black tea and coffee. There is no question that the conven- Phyllanthus urinaria tional use of these beverages including green tea does not harm the liver. In the past,however,weight loss aids were See Zhen Chu Cao. supplemented by green tea concentrated as extracts,and these carried the risk of liver injury.9,80–88 According to the manufacturers,the weight loss aids Chaso and Onshido Polygonum multiflorum contained green tea and other herbs.41 Presumably,green tea was included as extracts to enhance weight loss,although Polygonum multiflorum is a member of the family the extract form was not specifically mentioned by the Polygonaceae,genus Fallopia. Either alone or in combination manufacturers. The producers did not mention that the with other herbs and vitamins,it is a constituent of various synthetic adulterant N-nitroso-fenfluramine was also an potentially hepatotoxic herbal TCM products.28–30,54,94–98 ingredient in the two products. This adulterant was later Among these are Ban Tu Wan,29 Ho Wu Shou,30,54 Shen identified by chemical analyses,but evidence of hepatotoxi- Min,95 and Shou Wu Pian.96–103 Occasionally, Polygonum city was not presented and evaluation by further studies was multiflorum containing herbal TCM products such as Ho Shou recommended.41 The most likely candidate for the liver injury Wu,Shen Min,Shou Wu Pian,and Zhi Shou Wu are was green tea,if it was supplied in the extract form. For considered interchangeable terms.94 However,ingredients details see also Chaso and Onshido. may vary from product to product,requiring specific and qualifying product names. The mechanism of hepatotoxicity Ma Huang of Polygonum multiflorum is not known and disputed,94–96,99– 101 although the injury is usually attributed to the anthraqui- Six patients originating from the United States experienced nones such as chrysophanol,emodin,and rhein,which are acute hepatitis associated with the use of the herbal TCM Ma major constituents in Polygonum multiflorum.94 In a single Huang and its ingredients of Ephedra species.9,22,33,89–91 Out report,however,the major compound identified in the of these six cases,one patient also coadministered kava,one recovered tablets was a stilbene glycoside,tetrahydroxystil- also had disulfiram,and one had a chronic HBV infection. 22 bene-glucopyranoside.94,96 LTX was necessary in three Two patients developed acute liver failure,22,90 and one of patients from Korea after using Polygonum multiflorum.28 them required LTX.22 In another patient from the United For details see Ban Tu Wan,Chinese herbal mixtures,Ho Wu Kingdom,acute liver failure emerged and LTX was neces- Shou,Shen Min and Shou Wu Pian. sary.92 Ma Huang is also one of the ingredients of Pro- Lean1,9 a potential hepatotoxic herbal mixture.93 For Rhen Shen Ephedra,see also Bofu Tsu Sho San. Six patients originating from Korea used the herbal TCM Rhen Mao Guo Tian Jie Cai Shen (Panax ginseng,Ren Seng) and developed acute toxic hepatitis.27 In four patients from Hong Kong,HSOS developed following the use of the PAs containing herbal TCM Mao Guo Tian Jie Cai (Heliotropium lasiocarpum).76 It was initially mistaken as the Sairei To PAs containing herbal TCM Gynura segetum.73–75 Outcome was deleterious for one of the four patients.76 Two Japanese men consumed the kampo medicine Sarei To (syn. Chai Ling Tang),which is a blend of two TCMs,Xiao Chai Onshido Hu Tang and Wu Ling San Wan,and experienced herbal hepatotoxicity.104,105 Among the Sairei To ingredients are Six Japanese patients experienced hepatic injury due to the Alisma, Atractylis, Bupleurum, Cinnamomum, Ginseng, use of the weight loss aid Onshido,a TCM herbal mixture. 41 Glycyrrhiza, Pinellia, Polyporus, Poria, Scutellaria, Zingiber, This herbal product contained Aloe, Camellia sinensis, and Zizyphus. Several possible culprits are under considera- Crataegus, Gynostemma pentaphyllum makino,and tion,including Pinellia ternate,104 and other components of Raphanus. Outcome was favorable in all patients except for Sairei To.105
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Shan Chi Shou Wu Pian
In two Chinese women,51 and 39 years old,HSOS emerged, As described in 1996,a 31-year old pregnant Chinese woman which was induced by PAs of the herbal TCM Shan Chi Gynura from Hong Kong developed acute hepatitis after consumption segetum (syn. Ju San Qi,Ju Shan Qi,Ju Ye San Qi,San Qi of the TCM Shou Wu Pian,with Polygonum multiflorum as the Cao).73 One of these two patients required a LTX. Other cases main component.99 Subsequently,similar case reports of HSOS by Gynura segetum were reported from related to Shou Wu Pian followed from Australia,100 China,59,60,77,78 with a lethal outcome in one patient.59 In a Italy,98,101 the Netherlands (a 5-year old girl),96 the United 54-year old woman with HSOS from Hong Kong,PAs derived States,102 Japan,103 and Korea.97 Shou Wu Pian is a herbal from Gynura segetum rather than the herbal TCM Jing Tian mixture with a wide variability of its ingredients,and details 94,97,103 San Qi (Sedum aizoon) devoid of PAs were the likely are rarely mentioned. For example,according to the hepatotoxic agents.69 information via the internet,one of the numerous possible Additional six cases were earlier suspected,74,75 but in at formula compositions could be: Achyranthes bidentata, least four cases the culprit was the PAs containing herb Cuscuta chinensis, Eclipta prostrata, Ligustrum lucidum, Heliotropium lasiocarpum rather than Gynura segetum.76 An Lonicera japonica, Morus alba, Polygonum multiflorum, additional four patients experienced HSOS by Gynura sege- Psoralea corylifolia, Rehmannia glutinosa, Rosa laevigata, tum,one with a lethal course. 71 Correspondingly,at least 52 Sesemum indicum, and Siegesbeckia orientalis. This compo- 95 HSOS cases have been attributed to Gynura segetum until sition varies substantially from the one of Shen Min, which 2011,69 and 116 cases until 2012.71 also contains Polygonum multiflorum and is discussed above. The clinical features have now been clearly described, See also Ho Shou Wu, Polygonum multiflorum,and Shen Min. establishing Gynura segetum but not Jing Tian San Qi (Sedum aizoon) as the cause of HSOS.69,71,72 The diagnosis Syo Saiko To was ascertained in a 54-year old female patient with HSOS by thorough investigations of the patient herself and by See Xiao Chai Hu Tang. animal studies.69 Her clinical diagnosis of HSOS was firmly established by meeting the modified Seattle criteria,char- TJ-8 acterized by hyperbilirubinemia,hepatomegaly,and weight gain due to fluid accumulation. Liver histology confirmed the See Da Chai Hu Tang. diagnosis of HSOS. Pyrrole-protein adducts as biomarkers and pyrrole-GSH conjugates detected in her blood using the TJ-9 new method ultra performance liquid chromatography-mass spectrometry See Xiao Chai Hu Tang. (UPLC-MS) analysis. Since the ingested herb was unknown,the cultivated herb from the patient’s home was TJ-24 collected and authenticated as the TCM herb Gynura sege- tum. Together with the authenticated TCM herb Sedum See Kamishoyosan. aizoon cultivated and collected from another Chinese area, various comparative studies in animals were made. All of White flood these studies confirmed that the observed HSOS arose from the consumption of PAs containing Gynura segetum,an A 23-year old man from the United States experienced erroneous substitute of the non PAs containing Sedum hepatotoxicity following use of the commercial product aizoon.69 The blood test of pyrrole-protein adducts using White flood,which contained the herbal TCM Wu Zhu Yu (Evodia rutaecarpa,club moss) and the herbal TCM Qian UPLC-MS analysis was employed as a biological biomarker in Ceng Ta (Huperzia serrata).106 Other ingredients included subsequent patients.71 acesulfame potassium,beet root,caffein,calcium silicate, carnitine tartrate,Carno-Syn 1 beta-alanine,citrulline,cocoa Shen Min bean,cryptoxanthin,folic acid,gamma-aminobutyric acid (GABA),glucuronolactone,selenium,L-norvaline,L-tyrosine, A 28-year old woman from the United States developed lutein,malic acid,ornithine,potassium gluconate,sucralose, acute hepatitis following the use of the herbal TCM Shen sugar cane,vinpocetine (from Vinca plant),watermelon Min.95 The product label for this Shen Min product had a list flavor,and zeaxanthin. After discontinuing use of the product, of components that included plants and vitamins. the outcome was favorable. Polygonum multiflorum is one of the main components of Shen Min,and the respective content was described as Xiao Chai Hu Tang Shen Min 12: 1 standardized extract (Polygonum multi- florum) 450 mg per serving and as He Shou Wu powder The treatment with the herbal TCM Xiao Chai Hu Tang (syn. 870 mg per serving. Polygonum multiflorum,however,was Sho Saiko To,Syo Saiko To,Syo Xiao Hu Tang,TJ-9) resulted not specified here. Other declared contents of the used in liver injury in four Japanese patients with increased liver 107 Shen Min product were vitamin A,vitamin B 6,biotin,niacin, values prior to treatment. For 19 Taiwan patients with HBV pantothenic acid,soy isoflavones,black cohosh,horse infection,treatment with Xiao Chai Hu Tang was associated chestnut,hydrolyzed collagen,silica from plant sources, with an increased risk for liver injury.38 One additional patient ginkgo biloba, uva ursi,Burdock,Cayenne pepper,and Piper from Taiwan had the same response to Xiao Chai Hu Tang nigrum. See also Ho Shou Wu, Polygonum multiflorum,and following cholecystectomy.108 Xiao Chai Hu Tang is a mixture Shou Wu Pian. of several herbs,including Bupleurum falcatum, Ginseng,
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Glycyrrhiza glabra, Pinellia tuber, Scutellaria baicalensis, including 14 cases due to herbal TCM,17 applying established Zingiber officinale, and Zizyphus jujuba.Therefore,its criteria for a positive reexposure test (Table 2). Among the composition is the same as the TCM Da Chai Hu Tang (syn. now assessed 25 patients of suspected herbal hepatotoxicity Dai Saiko To,TJ-8),but in different proportions. 39,52 See also of TCM with reported positive reexposure test results,criteria Bupleurum,Da Chai Hu Tang,and Long Dan Xie Gan Tang. based evaluation confirmed a positive reexposure test result in 14 cases,whereas the results were negative in four cases Yin Chen Hao or uninterpretable in seven cases (Table 3). Accordingly, positive reexposure test results were obtained for Chinese In seven patients from Korea,the use of the herbal TCM Yin herbal mixtures (cases 2 and 3),Hwang Geun Cho (case 6),Ji Chen Hao (Artemisia capillaris) resulted in the development Xue Cao (case 7),Jin Bu Huan (cases 9 and 10),Lu Cha of acute toxic hepatitis.27 One additional Korean patient did (cases 13–15), Polygonum multiflorum (case 20),Shou Wu require LTX.28 Pian (case 21),and Xiao Chai Hu Tang (cases 23–25) (Table 3),confirming the hepatotoxic risk of these pro- Zexie ducts.17 The liver specific CIOMS scale for causality assessment is A 59-year old man from Hong Kong with chronic hepatitis B applicable to all cases of suspected herbal TCM hepatotoxi- and associated HBeAg-positive liver cirrhosis was treated for city.14,15,27,28,30,53,69,71,97,109,110 This scale was rarely used cramps with a herbal TCM formula consisting of eleven in the cases of the present evaluation,18–108 although CIOMS different herbal elements,including the hepatotoxic Zexie data were provided for all 7,25,and 27 TCM cases in three (Alisma orientalis).30 He died from complications due to a studies.30,97,110 In the course of causality assessment,highly severe course of herbal hepatotoxicity. probable or probable causality levels were obtained for various types of TCM formulas,30 Bai Xian Pi,27,28 Chinese Zhen Chu Cao herbal mixtures,17 Ci Wu Jia,28 Gan Coa,30 Ge Gen,53 Ho Shou Wu,54 Juguja,28 Ji Xue Cao,60 Jin Bu Huan,17 Kudzu,27 Ling A 37-year old man from Hong Kong with a chronic hepatitis B Yang Qing Fei Keli,30 Lu Cha,82,83 Polygonum multi- had been taking the TCM Zhen Chu Cao (syn. Phyllanthus florum,17,30 Rhen Shen,27 Shan Chi,69,71 Shen Min,95 Syo urinaria) and experienced herbal hepatotoxicity due to Zhen Saiko To,17 Yin Chen Hao,27,28 and Zexie.30 Clinical assess- Chu Cao.30 After cessation of the toxic herbal product,there ment was partly difficult because data were often incomplete was a full recovery. in many cases regarding indication for treatment,daily dose, quantitative composition of herbal mixtures,duration of Zhi Gan Cao treatment,exclusion of alternative causes,and clinical course.18–108 These shortcomings are also common to cases See Gan Cao. of herb induced liver injury,which are unrelated to TCM7,12,14–17,111 and to drug induced liver injury.112 Clinical and regulatory considerations Some common TCM herbs and herbal products with potential hepatotoxicity were not discussed or specifically The present study is a very limited analysis of herbal TCM referenced above as additional cases since they were listed hepatotoxicity based on some hundred cases published in 91 without further details.62 Among these are Cang Er Zi reports. Most patients made a full recovery upon cessation of (Xanthium sibiricum),Chuan Lian Zi ( Melia toosendan),Hu the herbal TCM product,18–108 but some developed acute liver Bohe You (Mentha pulegium,Pennyroyal oil),Hu Zhang failure.24,28,29,30,41,51 In these publications,individual herbs (Polygonum cuspidatum),Huang Yao Zi ( Dioscorea bulbi- and herbal mixtures suggested to be hepatotoxic included An fera),Ji Ji ( Chloranthus serratus),Jin Bu Huan ( Lycopodium Shu Ling,Bai Fang,Bai Xian Pi,Ban Tu Wan,Bo He,Bofu Tsu serratum and other herbs),Lei Gong Teng ( Tripterygium Sho San,Boh Gol Zhee,Chai Hu,Chaso,Chi R Yun,Chuan wilfordii Hook),Ma Huang ( Ephedra sinica),Qian Li Guang Lian Zi,Ci Wu Jia,Da Chai Hu Tang,Da Huang,Gan Cao,Ge (Senecio scandens),Shi Can (Teucrium chamaedrys, Gen,Ho Shou Wu,Huang Qin,Hwang Geun Cho,Ji Gu Cao,Ji Germander),Shi Liu Pi ( Pericarpium granati),Tian Hua Fen Xue Cao,Jiguja,Jin Bu Huan,Jue Ming Zi,Kamishoyosan, (Trichosanthes kirilowii),Wu Bei Zi ( Galla chinensis),Xi Shu Kudzu,Long Dan Xie Gan Tang,Lu Cha,Ma Huang,Mao Guo (Camptotheca acuminata),and Xiao Chai Hu Tang Tian Jie Cai,Onshido, Polygonum multiflorum,Ren Shen, (Bupleurum falcatum, Scutellaria baicalensis,and other Sairei To,Shan Chi,Shen Min,Shou Wu Pian,White flood, herbs).62 Additional lists refer to 24 cases of liver damage Xiao Chai Hu Tang,Yin Chen Hao,Zexie,Zhen Chu Cao,and by Polygonum multiflorum,113 two cases of markedly ele- various unclassified Chinese herbal mixtures. The reporting vated liver enzymes with the herbal TCM Bo Ye Qing Niu Dan physicians likely assumed for each case a clear causal (Tinospora crispa),114 and to a single case of liver injury with association between the use of the herbal TCM product and verified causality by the CIOMS scale attributed to the herbal hepatotoxicity. However,this assumption is often based TCM Du Huo (Angelica archangelica).115 merely on a temporal association and requires further Problematic for human use is the possible lack of quality rigorous evaluation. control and authentication of herbal products (Table 1)12 as A good approach with some limitations for the establish- well as adulteration and contamination with dust,pollens, ment of causality for a given herb or herbal mixture in insects,rodents,parasites,microbes,fungi,mold,toxins,and hepatotoxicity is to assess reported positive reexposure test pesticides.6 For herbal TCM products,specific problems have results. They are obtained through unintentional readminis- been linked to mislabeling on the package insert3,63 including tration,although this is commonly observed in only a few the wrong herbs,46,47 insufficient sample amounts,116 adul- selected cases.16,17 In the past,this assessment has been teration with undeclared synthetic drugs,3,6,10,62 contamina- done for 34 cases of suspected herbal hepatotoxicity, tion by hepatotoxic seeds30 and heavy metals such as
Journal of Clinical and Translational Hepatology 2014 vol. 2 | 80–94 89 Teschke R.: Traditional Chinese medicine induced liver injury
Table 3. Analysis ofreported positive reexposure test results in cases of suspected herbal Traditional Chinese Medicine (TCM) induced liver injury
Case Reexposure tests in cases of suspected herbal TCM induced liver injury
Chinese herbal mixtures 1. N 28-year old UK woman:24 Chinese herbal mixture with 8 different herbs for 3–5 months. Jaundice. ALT value not available. Reexposure: episode of hepatitis reported without liver values,acute liver failure,died despite emergency LTX. Both ALTb and ALTr not available R uninterpretable reexposure. 2. N 39-year old UK woman:25 Chinese herbal mixture with 8 different herbs for 2 months. Short history of anorexia, nausea,fatigue,dark urine,yellow sclerae,jaundice. ALT 2440 U/L (normal 0–30) with R 68.3,ALT returned to normal after cessation. Reexposure after 6 weeks: ALT 1314 U/L. ALTb , 5N and ALTr o 2ALTbR positive reexposure. 3. N 9-year old UK girl:48 Unclassified Chinese herbal medicine for 6 months. Nausea,anorexia,central abdominal pain, jaundice,pale stool for the past 4–21 days. ALT 1950 U/L (normal , 45) with R 13.1,ALT returned to 50 U/L after cessation. Intentional reexposure: ALT 315 U/L. ALTb , 5N and ALTr o 2ALTb R positive reexposure. Ho Shou Wu 4. N 54-year old Korean woman:54 Unknown dose of Ho Shou Wu containing Polygonum multiflorum for 1 month. Diagnosis of toxic hepatitis. Cessation of Ho Shou Wu improved her condition. Reexposure started immediately after discharge with aggravation of liver values. English abstract and Korean article R uninterpretable reexposure. Huan Qin 5. N 78-year old US woman:57 Move Free Advanced1 2 tablets/d containing Huan Qin (Scutellaria baicalensis,Chinese skullcap),black catechu,glucosamine,and chondroitin for 3 weeks. Jaundice. ALT 1626 U/L (normal , 60) with R 10.2,ALT 678 U/L two weeks after cessation. Reexposure: ALT 1206 U/L. ALTb o 5N and ALTr , 2ALTb R negative reexposure. Hwang Geun Cho 6. N 37-year old male patient from Korea:59 Hwang Geun Cho containing Corydalis speciosa. Jaundice. ALT 531 U/L with subsequent decline after cessation of the herb down to 146 U/ L. Unintentional reexposure two months after discharge: ALT 381 U/L. ALTb , 5N and ALTr o 2ALTb R positive reexposure. Ji Xue Cao 7. N 61-year old Argentinian woman:60 Ji Xue Cao (Centella asiatica,syn.Gotu Kola) tablets for 30 days. Jaundice. ALT 1193 U/L and two months after cessation 18 U/L. Unintentional reexposure seven months later : ALT 481 U/L. ALTb , 5N and ALTr o 2ALTb R positive reexposure. 8. N 52-year old female patient from Argentina:60 Ji Xue Coa (Centella asiatica) for six months. Jaundice. Not further quantified elevated hepatic enzymes at beginning and after cessation. Unintentional reexposure one year later : ALT 1694 U/L. ALTb not availabe R uninterpretable reexposure. Jin Bu Huan 9. N 66-year old US woman:63 Jin Bu Huan 2 tablets at night 2 to 3 times a week for 12 weeks. Fever,nausea,fatigue for the past 5 weeks. ALT 782 U/L (normal , 35) with R 18.7,ALT declined to 47 U/L following cessation. Reexposure: ALT 941 U/L. ALTb , 5N and ALTr o 2ALTbR positive reexposure. 10. N 46-year old US man:63 Jin Bu Huan 3 tablets 3 times a week intermittently for 6 months. Fever,headaches,fatigue, tender hepatomegaly. ALT 394 U/L (normal , 35) 2 weeks after cessation with R 24.2,ALT subsequently 48 U/L. Reexposure: ALT 100 U/L. ALTb , 5 N and ALTr o 2ALTbR positive reexposure. 11. N 50-year old US woman:64 Jin Bu Huan 2–3 tablets daily or intermittently for around 24 days. Fever. ALT 830 U/L and 330 U/L after cessation. Reexposure: ALT 540 U/L. ALTb o 5N and ALTr , 2ALTb R negative reexposure. 12. N 70-year old US woman:64 Jin Bu Huan 3 to 4 tablets at night 3 to 5 times a week for 31 days. Chills and fever 12 days after start of use,subsequently low-grade fever,malaise. ALT 408 U/L initially,263 U/L after 2- week cessation, 67 U/L after 6-week cessation. Reexposure after 1 month: ALT 77 U/L. ALTb , 5N but ALTr , 2ALTb R negative reexposure. Lu Cha 13. N 56-year old French woman:82 Mincifit1 14 ml/d containing green tea (Camellia sinensis,TCM Lu Cha) and Cassia sp. extracts for 15 days. Jaundice. ALT 54N with R 54.0,ALT normalization 2 months after cessation. Reexposure 5 years later with Dynasvelte forte1 8–12 g/d for 21 days (Green tea, Coffea Arabica,and chromium): ALT 99N. ALTb , 5N and ALTr o 2ALTb R positive reexposure. 14. N 45-year old Spanish man:83 Green tea infusion (6 cups/day) over 4 months. Asthenia and jaundice of 10 days duration prior to cessation. ALT 1613 U/L (normal , 40) with R 14.3,ALT normalized within 2 months of cessation. Reexposure 6 weeks later: ALT 1460 U/L after 1 month of reuse. ALTb , 5N and ALTr o 2ALTb R positive reexposure. Continued
90 Journal of Clinical and Translational Hepatology 2014 vol. 2 | 80–94 Teschke R.: Traditional Chinese medicine induced liver injury
Table 3. Continued
Case Reexposure tests in cases of suspected herbal TCM induced liver injury
15. N 37-year old Hispanic woman from the US:84 Green tea-containing product with various other herbal extracts for 4 months. Jaundice. ALT 1788 U/L (normal , 40) with R 21.7,ALT 92 U/L after withdrawal. Reexposure one year later for one month: ALT 1131 U/L. ALTb , 5N and ALTr o 2ALTb R positive reexposure. 16. N 23-year old Spanish woman:85 Green tea (Camellia sinensis) for 21 days. Jaundice after 19 days. ALT 56.9N with R 34.7,ALT 0.35N 3 months after withdrawal. Reexposure: ALT values not available. ALTb , 5N but ALTr not available R uninterpretable reexposure. 17. N 26-year old Spanish woman:85 Green tea for 121 days. Jaundice. ALT 32.1N with R 42.2,ALT dechallenge values not available. Reexposure: ALT values not available. Both ALTb and ALTr not available R uninterpretable reexposure. 18. N 38-year old French woman:86 Green tea (6 caps Tealine1/d,containing also white and red tea) for 20 days. Symptoms not reported. ALT values not available. Reexposure: ALT value not available. Both ALTb and ALTr not available R uninterpretable reexposure. Ma Huang 19. N 33-year old US woman:89 Unknown daily dose of Ma Huang for around 4 weeks. Nausea,vomiting,abdominal discomfort after use for several days,jaundice under continuing Ma Huang use for another 3 weeks. ALT 832 U/L (normal , 65) with R 9.8. ALT dechallenge values not available. Intentional reexposure with a single dose 1 week after discharge: ALT 1586 U/L. Both ALTb and ALTr not available R uninterpretable reexposure. Polygonum multiflorum 20. N 61-year old Korean man:97 Unknown dose of Polygonum multiflorum Thunb for 1 day. Myalgia. ALT 818 U/L with R 21.6,180 U/L after 9 days of cessation and ALTb , 5N as likely assumed. Reexposure after 11.5 months with a single dose of P. multiflorum Thunb: ALT 1520 U/L. ALTb , 5N and ALTr o 2ALTb R positive reexposure. Shou Wu Pian 21. N 5-year old Netherland girl:96 Shou Wu Pian (3 tablets daily) for 4 months. Jaundice. ALT 1543 U/L (normal , 39 U/ L),5 weeks after cessation 50 U/L. Reexposure with 2 tablets Shou Wu Pian daily for 1 month: ALT 1277 U/L. ALTb , 5N and ALTr o 2ALTb R positive reexposure. Xiao Chai Hu Tang 22. N 51-year old Japanese woman:107 7.5 g of Xia Chai Hu Tang daily for 7 weeks. Jaundice,with preexisting mild elevations of aminotransferases. ALT 855 U/L (normal , 35) with R 35.9,ALT decrease to 139 U/L upon cessation. Reexposure: ALT 186 U/L. ALTb , 5N but ALTr , 2ALTbR negative reexposure. 23. N 52-year old Japanese woman:107 Xia Chai Hu Tang 7.5 g daily for 6 weeks. Jaundice,preexistent ALT activity of 180 U/L (normal , 35). ALT 600 U/L,near normal 2.5 months after withdrawal. Reexposure: ALT 162 U/L. ALTb , 5N and ALTr o 2ALTb R positive reexposure. 24. N 58-year old Japanese woman:107 Xia Chai Hu Tang 7.5 g daily for 3 months. Symptoms not reported. ALT 246 U/L (normal , 35) with R 5.0,ALT fell to near normal after 2 months of withdrawal. Intentional 7-day reexposure: ALT 265 U/L. ALTb , 5N and ALTr o 2ALT R positive reexposure. 25. N 42-year old Japanese woman:107 Xia Chai Hu Tang 7.5 g daily for an unspecified time period for hepatitis A infection. Symptoms not specified,ALT 2 165 U/L (normal , 35) initially dropped with treatment to 42 U/L and increased 3 weeks after initiation of treatment. ALT 1335 U/L with normalization within 2 months after withdrawal. Intentional 2- day reexposure: ALT 195 U/L ALTb , 5N and ALTr o 2ALTb R positive reexposure.
Compilation of some clinical details and laboratory values for assessment of reported positive reexposure test results in 25 cases with suspected herbal hepatotoxicity by TCM products.24,25,48,54,57,59,60,63,64,82–86,89,96,97,107 Data are derived from a previous report,which may provide additional deta ils.17 Unless otherwise stated,reexposure was commonly unintentional. Criteria for a positive reexposure test result were used as described in Table 2,restricted to criteria provided for th e hepatocellular type of liver injury. Accordingly,essential data are the ALT levels at baseline before reexposure (ALTb) and the ALT levels during reexposure (ALTr). Response to reexposure is positive if ALTr o 2ALTb and ALTb , 5N,with N as the upper limit of the normal value. Other combinations lead to negative or uninterpretable results. Serum enzyme activities were provided in U/L or multiples of N. Details for calculation of the R value were presented previously.17 Abbreviation: ALT,alanine aminotransferase; AST,aspartate aminotranferase; N,upper limit of normal; R,ratio; TCM,Traditional Chi nese Medicine. arsenic,mercury,and lead. 6,116 These shortcomings are well Quan Xie (dry polypides of the Scorpio Buthus martensii),30 recognized1–12,14,116 and require efforts by manufacturers Sang Hwang (Phellinus linteus,mushroom), 27,28 Song Rong and regulatory agencies (Table 1).117 (Agaricus blazei,Himematsutake as Japanese Kampo Of additional concern is the potential hepatotoxicity of Medicine,mushroom), 119 Wu Gong (dried polypites of the non-herbal TCM elements.10,27,28,30,62,118–122 They are com- centipede Scolopendra subspinipes mutilans),30 Wu Shao monly used in connection with herbal TCM products,10,30 and She (syn. Wu Xiao She,Sheng Wu Shao She,parts of the even named as such.10 Known or potentially hepatotoxic non- snake Zaocys dhumnades),30 and Yu Dan (fish gallblad- herbal TCM elements are Bai Hua She (venom of the Chinese der).120–122 viper Agkistrodon acutus),30 Jiang Can (dried larvae of Finally and most importantly,the use of a few TCM Bombyx Batryticatus,infected by Batrytis bassiana),30 Ling products caused serious hepatotoxicity in some suscep- Yang Qing Fei (antelope horn),30 Liyu Danzhi (carp juice),118 tible patients resulting in a severe clinical course with
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[46] Lin TJ,Su CC,Lan CK,Jiang DD,Tsai JL,Tsai MS. Acute poisonings with [75] Kumana CR,Ng M,Lin HJ,Ko W,Wu PC,Todd D. Hepatic veno-occlusive Breynia officinalis - an outbreak of hepatotoxicity. J Toxicol Clin Toxicol disease due to toxic alkaloid in herbal tea. Lancet 1983;2:1360–1361. doi: 2003;41: 591–594. doi: 10.1081/CLT-120023760. 10.1016/S0140-6736(83)91112-1. [47] http://livertox.nih.gov/ChiRYun.htm,accessed 10 January 2014. [76] Culvenor CC,Edgar JA,Smith LW,Kumana CR,Lin HJ. Heliotropium [48] Allen BR,Parkinson R,Hollman A,Jones R,Harper JI,Davies EG, et al. lasiocarpum Fisch and Mey identified as cause of veno-occlusive disease Chinese herbs for eczema. Lancet 1990;336:177. doi: 10.1016/0140- due to herbal tea. Lancet 1986;1:978. doi: 10.1016/S0140- 6736(90)91696-8. 6736(86)91084-6. [49] Graham-Brown R. Toxicity of Chinese herbal remedies. Lancet [77] Chen MY,Cai JT,Du Q. Hepatic veno-occlusive disease associated with the 1992;340:673. Reply: Rustin M,Atherton D. 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Gastroenterol Clin Biol 2004;28;404–406. doi: 10.1016/ Kampo Med 2010;61:828–833. doi: 10.3937/kampomed.61.828. S0399-8320(04)94944-5. [56] Linnebur SA,Rapacchietta OC,Vejar M. Hepatotoxicity associated wi th [83] Jimenez-Saenz M,Martinez-Sanchez Mdel C. Acute hepatitis associat ed chinese skullcap contained in Move Free Advanced dietary supplement: two with the use of green tea infusions. J Hepatol 2006;44:616–617. doi: case reports and review of the literature. Pharmacotherapy 2010;30:258– 10.1016/j.jhep.2005.11.041. 262. [84] Bonkovsky HL. Hepatotoxicity associated with supplements containing [57] Yang L,Aronsohn A,Hart J,Jensen D. Herbal hepatotoxicity from Chine se Chinese green tea (Camellia sinensis). Ann Intern Med 2006:144:68–71. skullcap: A case report. World J Hepatol 2012;4:231–233. doi: 10.7326/0003-4819-144-1-200601030-00020. [58] Dhanasekaran R,Owens V,Sanchez W. Chinese skullcap in Move Free [85] Garcı´a-Corte´s M,Borraz Y,Lucena MI,Pela ´ez G,Salmero´n J,Diago M, et al. arthritis supplement causes drug induced liver injury and pulmonary Liver injury induced by ‘‘natural remedies’’: an analysis of cases submitted infiltrates. Case Reports Hepatol 2013; Article ID 965092. doi: org/ to the Spanish Liver Toxicity Registry. Rev Esp Enferm Dig 2008;100:688– 10.1155/2013/965092 695. [59] Kang HS,Choi HS,Yun TJ,Lee KG,Seo YS,Yeon JE, et al. A case of acute [86] Sarma DN,Barrett ML,Chavez ML,Gardiner P,Ko R,Mahady GB, et al. cholestatic hepatitis induced by Corydalis speciosa Max. Korean J Hepatol Safety of green tea extract: a systematic review by the US Pharmacopeia. Drug Saf 2008;31:469–484. doi: 10.2165/00002018-200831060-00003. 2009;15:517–523. [87] Navarro VJ,Bonkovsky HL,Hwang SI,Vega M,Barnhart H,Serrano J. [60] Jorge OA,Jorge AD. Hepatotoxicity associated with the ingestion of Centella Catechins in dietary supplements and hepatotoxicity. Dig Dis Sci 2013;58: asiatica. Rev Esp Enferm Dig 2005;97:115–124. doi: 10.4321/S1130- 2682–2690. doi: 10.1007/s10620-013-2687-9. 01082005000200006. [88] Rossi S,Navarro VJ. Herbs and liver injury: a clinical perspective. C lin [61] Kim YJ,Ryu SL,Shim JW,Kim DS,Shim JY,Park MS, et al. A pediatric case of Gastroenterol Hepatol 2014; in press. DOI: 10.1016/j.cgh.2013.07.030. toxic hepatitis induced by Hovenia dulcis. Pediatr Gastroenterol Hepatol [89] Nadir A,Agrawal S,King PD,Marshall JB. Acute hepatitis associated w ith Nutr 2012;15:111–116. doi: 10.5223/pghn.2012.15.2.111. the use of a Chinese herbal product,ma-huang. Am J Gastroenterol 1996; [62] Chau TN. Drug-induced liver injury: an update. Medical Bulletin 2008;13: 91:1436–1438. 23–26. [90] Reuben A,Koch DG,Lee WM,Acute Liver Failure Study Group. Drug- [63] Woolf GM,Petrovic LM,Rojter SE,Wainwright S,Villamil FG,Katkov WN , induced acute liver failure: Results of a U.S. multicenter,prospective s tudy. et al. Acute hepatitis associated with the Chinese herbal product Jin Bu Hepatology 2010;52:2065–2076. doi: 10.1002/hep.23937. Huan. Ann Intern Med 1994;121:729–735. doi: 10.7326/0003-4819-121- [91] Borum ML. Fulminant exacerbation of autoimmune hepatitis after the use of 10-199411150-00001. Ma Huang. Am J Gastroenterol 2001;96:1654–1655. [64] Horowitz RS,Feldhaus K,Dart RC,Stermitz FR,Beck JJ. The clinical [92] Skoulidis F,Alexander GJ,Davies SE. Ma huang associated acute liver spectrum of Jin Bu Huan toxicity. Arch Intern Med 1996;156:899–903. doi: failure requiring liver transplantation. Eur J Gastroenterol Hepatol 2005;17: 10.1001/archinte.1996.00440080101012. 581–584. [65] Divinsky M. Case report: Jin Bu Huan – not so benign herbal medicine. Can [93] Joshi D,Cross TJ,Wong VS. Acute drug induced hepatitis secondary to a Fam Physician 2002;48:1640–1642. weight loss product purchased over the internet. Nutr J 2007;6:13. [66] Picciotti A,Campo N,Brizzolara R,Giusto R,Guido G,Sinelli N, et al. Chronic [94] http://livertox.nih.gov/ShouWuPian.htm,accessed 10 January 201 4. hepatitis induced by Jin Bu Huan. J Hepatol 1998;28:165–167. doi: [95] Ca´rdenas A,Restrepo JC,Sierra F,Correa G. Acute hepatitis due to shen- 10.1016/S0168-8278(98)80217-1. min: a herbal product derived from Polygonum multiflorum.JClin [67] http://livertox.nih.gov/JinBuHuan.htm,accessed 10 January 2014 . Gastroenterol 2006;40:629–632. doi: 10.1097/00004836-200608000- [68] Wu GL,Yu GY,Chen J. Clinical analysis of hepatic veno-occlusive dise ase 00014. induced by Sedum aizoon. Zhongguo Zhong Yao Za Zhi 2008; 33: 2402– [96] Panis B,Wong DR,Hooymans PM,De Smet PA,Rosias PP. Recurrent toxic 2404. hepatitis in a Caucasian girl related to the use of Shou-Wu-Pian,a Chinese
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herbal preparation. J Pediat Gastroenterol Nutr 2005;41:256–258. doi: [109] Teschke R,Wolff A,Frenzel C,Schwarzenboeck A,Schulze J,Eickhoff A. 10.1097/01.MPG.0000164699.41282.67. Drug and herb induced liver injury: Council for International Organizations [97] Jung KA,Min HJ,Yoo SS,Kim HJ,Choi SN,Ha CY, et al. Drug-induced liver of Medical Sciences scale for causality assessment. World J Hepatol 2014; injury: Twenty five cases of acute hepatitis following ingestion of 6:17–32. Polygonum multiflorum Thun. Gut Liver 2011;5:493–499. doi: 10.5009/ [110] Chau TN,Cheung WI,Ngan T,Lin J,Lee KW,Poon WT,et al. Causality gnl.2011.5.4.493. assessment of herb-induced liver injury using multidisciplinary approach [98] Valente G,Sanges M,Campione S,Bellevicine C,De Franchis G,Sollazz oR, and the Roussel Uclaf Causality Assessment Method (RUCAM). Clin Toxicol et al. Herbal hepatotoxicity: a case of difficult interpretation. Eur Rev Med (Phila) 2011;49:34–39. doi: 10.3109/15563650.2010.537662. Pharmacol Sci 2010;14:865–870. [111] Teschke R,Schulze J,Schwarzenboeck A,Eickhoff A,Frenzel C. Herba l [99] But PP,Tomlinson B,Lee KL. Hepatitis related to the Chinese medicine hepatotoxicity: suspected cases assessed for alternative causes. Shou-wu-pian manufactured from Polygonum multiflorum. Vet Hum Toxicol Eur J Gastroenterol Hepatol 2013;25:1093–1098. 1996;38:280–282. [112] Teschke R,Frenzel C,Wolff A,Eickhoff A,Schulze J. Drug induced liv er [100] Park GJ,Mann SP,Ngu MC. Acute hepatitis induced by Shou-Wu-Pian,a injury: accuracy of diagnosis in published reports. Ann Hepatol 2014;13: herbal product derived from Polygonum multiflorum. J Gastroenterol 248–255. Hepatol 2001;16:115–117. doi: 10.1046/j.1440-1746.2001.02309.x. [113] Zhang L,Yang X,Sun Z,Qu Y. Retrospective study of adverse events of [101] Battinelli L,Daniele C,Mazzanti G,Mastroianni CM,Lichtner M,Col etta S, Polygonum multiflorum and risks control. Zhongguo Zhong Yao Za Zhi Costantini S. New case of acute hepatitis following the consumption of Shou 2009;34:1724–1729. Wu Pian,a Chinese herbal product derived from Polygonum multiflorum. [114] Sangsuwan C,Udompanthurak S,Vannasaeng S,Thamlikitkul V. Ann Intern Med 2004;140:587–588. Randomized controlled trial of Tinospora crispa for additional therapy [102] Laird AR,Ramchandani N,deGoma EM,Avula B,Khan IA,Gesundheit N. in patients with type 2 diabetes mellitus. J Med Assoc Thai 2004;87:543– Acute hepatitis associated with the use of an herbal supplement 546. (Polygonum multiflorum) mimicking iron-overload syndrome. Clin [115] Bjo¨rnsson ES,Bergmann OM,Bjo ¨rnsson HK,Kvaran RB,Olafsson S. Gastroenterol 2008;42:861–862. doi: 10.1097/MCG.0b013e3181492515 Incidence,presentation and outcomes in patients with drug-induced live r [103] Furukawa M,Kasajima S,Nakamura Y,Shouzushima M,Nagatani N, injury in the general population of Iceland. Gastroenterology 2013;144: Takinishi A, et al. Toxic hepatitis induced by Show-Wu-Pian,a Chinese 1419–1425. doi: 10.1053/j.gastro.2013.02.006. herbal preparation. Inter Med 2010;49:1537–1540. doi: 10.2169/inter- [116] Ko RJ. Adulterants in Asian patent medicines. N Engl J Med 1998;339:847. nalmedicine.49.3509. [117] Zhang L,Yan J,Liu X,Ye Z,Yang X,Meyboom R, et al. Pharmacovigilance [104] Aiba T,Takahashi T,Suzuki K,Okoshi S,Nomoto M,Uno K, et al. Liver injury induced by a Japanese herbal medicine,sairei-to (TJ-114,Bupleurum and practice and risk control of Traditional Chinese Medicine drugs in China: Hoelen combination,Chai-Ling-Tang). J Gastroenterol Hepatol 2007;22: Current status and future perspective. J Ethnopharmacol 2012;140:519– 762–763. doi: 10.1111/j.1440-1746.2006.03373.x 525. doi: 10.1016/j.jep.2012.01.058. [105] Tsuda T,Yashiro S,Gamo Y,Watanabe K,Hoshino T,Oikawa T, et al. [118] Son HS,Kim GS,Lee SW,Kang SB,Back JT,Nam SW, et al. Toxic hepatitis Discrepancy between clinical course and drug-induced lymphocyte stimula- associated with carp juice ingestion. Korean J Hepatol 2006;12:103–106. tion tests in a case of saireito-induced liver injury accompanied by Sjo¨gren [119] Mukai H,Watanabe T,Ando M,Katsumata N. An alternative medicine, syndrome. J Altern Complement Med 2010;16:501–505. doi: 10.1089/ Agaricus blazei,may have induced severe hepatic dysfunction in cancer acm.2009.0183 patients. Jpn J Clin Oncol 2006;36:808–810. [106] Cohen SM,Heywood E,Pillai A,Ahn J. Hepatotoxicity associated with the [120] Chan DW,Yeung CK,Chan MK. Acute renal failure after eating raw fish g all use of White Flood,a nutritional supplement. Practical Gastroenterolog y bladder. BMJ 1985:290:897. doi: 10.1136/bmj.290.6472.897. 2012; October issue:45–48. [121] Xuan BH,Thi TX,Nguyen ST,Goldfarb DS,Stokes MB,Rabenou RA. [107] Itoh S,Marutani K,Nishijima T,Matsuo S,Itabashi M. 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94 Journal of Clinical and Translational Hepatology 2014 vol. 2 | 80–94 Review Article
Hepatotoxicity Secondary to Chemotherapy
Alla Grigorian and Christopher B. O’Brien
Divisions of Liver and GI Transplantation, University of Miami School of Medicine, Miami, FL, USA
Abstract enzyme activities (alanine aminotransferase’’ (ALT), aspar- tate aminotransferase (AST), alkaline phosphatase (ALP), The difficult problem faced by multiple generation of practi- and c-glutamyltransferase (GGT)) into mild (grade 1) if .ULN cing physicians is determining the cause of abnormal liver (upper limits of normal) to 2.56ULN; moderate (grade 2) if function tests in cancer patients on chemotherapy. .2.5 to 56ULN; severe (grade 3) if .5to206ULN; and life- Hepatotoxicity from chemotherapy occurs frequently from threatening (grade 4) if .206ULN; and with no definition for an unpredictable or idiosyncratic reaction. Despite remark- fatal (grade 5). Similarly, they graded serum total bilirubin able advances in our understanding of the mechanisms of concentration as mild if .ULN to 1.56ULN, moderate if .1.5 action, pharmacodynamics, and interrelationships between to 36ULN, severe if .3to86ULN, and life-threatening if the liver and chemotherapy, the underlying etiology of .86ULN. Although this grading system is commonly used, hepatic toxicity for various agents remains unexplained. this practice has been questioned since the elevation of Here, we present a concise review of the broad differential enzymes by itself does not always reflect dysfunction of the diagnosis for abnormal liver function tests (LFTs) in oncology liver and can therefore be misleading. patients. E 2014 The Second Affiliated Hospital of Chongqing Medical University. Published by XIA & HE Publishing Ltd. All rights National Institute of Health Drug Induced Liver Injury reserved. (DILI) network
Introduction The National Institute of Health funded DILI network experts proposed to use clinical measures instead of laboratory In the complex world of cancer therapy, the administration of values and defined liver injury as follows: level 1 (mild) if medications intentionally designed to be cytotoxic inevitably patient has isolated elevation of ALT and or ALP, level 2 causes negative consequences. The liver is the primary site of (moderate) in presence of elevated bilirubin and coagulo- metabolism for many of these drugs, and this liver-drug pathy, level 3 (serious) if it results in hospitalization or interaction must be accounted for while dosing chemother- disability to do usual work; level 4 as acute liver failure, in apy. Preexisting liver disease can impair the process of which another organ that is dependent on liver function recovery after injury,1 and in preparation for chemotherapy, shows dysfunction (brain, encephalopathy; kidney, renal oncologists need to assess both liver function and potential insufficiency; etc.); and level 5 as death or liver transplanta- liver involvement by the cancer. tion.2 They also proposed a scale of increasing likelihood, ranging from unlikely to definite, of a suspected case of liver Guidelines for monitoring potential hepatotoxicity injury to be related to the imputed drug.
National Cancer Institute (NCI) common toxicity criteria for adverse events Dose modification guidelines
Close liver function monitoring is advised for patients starting Liver metabolized agents new chemotherapy regimen. It remains controversial how often liver testing should be performed and what constitutes liver dysfunction. The NCI in the ‘‘Common Toxicity Criteria There is agreement on the need for dose reduction for agents for Adverse Events’’ has classified elevations of serum that are dependent upon liver metabolism for clearance from the circulation. The major chemotherapeutic agents in this group include methotrexate, sorafenib, dactinomycin, ifosfa- Keywords: Hepatotoxicity; Drugs; Cancer; Chemotherapy; Liver. mide, gemcitabine, etoposide, irinotecan, procarbazine, 6- Abbreviations: 5-FU, 5-fluorouracil; 5FUDR, fluorodeoxyuridine; 6-MP, 6- mercaptopurine, cytarabine, crizotinib, and cyclophosphamide. mercaptopurine; 6-TG, 6-thioguanine; ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; AZA, azathioprine; DILI, drug induced liver injury; GGT, c-glutamyltransferase; HCC, hepatocellular Chemotherapy to be used with caution carcinoma; IBD, inflammatory bowel disease; MTX, methotrexate; NCI, National Cancer Institute; ULN, upper limits of normal; VOD, veno-occlusive disease. Received: 4 March 2014; Revised: 6 May 2014; Accepted: 22 May 2014 Certain chemotherapeutic agents must be used with extreme q DOI of original article: 10.14218/JCTH.2014.00011. caution in patient with preexisting liver disease. These Correspondence to: Alla Grigorian, Divisions of Liver and GI Transplantation, include the anthracyclines, taxanes, vinca alkaloids, temsir- University of Miami School of Medicine, 1500 NW. 12th Ave, Suite 1101, Miami, FL 33136, USA. Tel: +1-305-243-6956, Fax: +1-305-243-6681, Email: a.grigorian@ olimus, imatinib, axitinib, lapatinib, erlotinib, nilotinib, pazo- med.miami.edu panib, ponatinib, and ruxolitinib.
Journal of Clinical and Translational Hepatology 2014 vol. 2 | 95–102 Grigorian A. et al.: Hepatotoxicity secondary to chemotherapy
Overall guidelines transformation, veno-occlusive disease/sinusoidal obstruc- tion, and fulminant hepatic failure. Table 1 lists proposed The clinical presentations of hepatotoxicity vary from asymp- mechanisms of hepatic injury for commonly used chemother- tomatic, increase of liver chemistries, overt cholestatic apeutics; it is based mainly on evidence derived from case- hepatitis, progression to fibrosis and cirrhosis, malignant series and case reports.
Table 1. Chemotherapy drugs and liver side effects
Biliary Nodular Hyperplasia Veno-Occlusive Drug Hepatitis Cholestasis Stricture Steatosis Fibrosis Disease Actinomycin Rare Rare Arsenic Asparaginase Common Common Azathioprine Rare Rare Bleomycin Rare Bortezomib Rare Busulfan Rare Rare Rare Capecitabine Rare Carmustine Common Chlorambucil Rare Cyclophosphamide Rare Common Cytarabine Rare Common Dacarbazine Rare Docetaxel Rare Doxorubicin Rare Rare Rare Erlotinib Common Etoposide Rare Rare Floxuridine Common Common Common Fluorouracil Rare Common Rare Gefitinib Rare Gemcitabine Rare Rare Hydroxyurea Rare Ifosfamide Rare Imatinib Common Interferon Common Interleukin Common Irinotecan Rare Lomustine Rare Melphalan Rare Rare Mercaptopurine Rare Rare Methotrexate Common Common Mitomycin Rare Rare Oxaliplatin Rare Rare Common Paclitaxel Rare Pazopanib Common Procarbazine Rare Regorafenib Rare Sorafenib Rare Rare Streptozocin Rare Thioguanine Rare Rare Topotecan Rare Vincristine Rare Vinorelbine Rare
96 Journal of Clinical and Translational Hepatology 2014 vol. 2 | 95–102 Grigorian A. et al.: Hepatotoxicity secondary to chemotherapy
Since there are no perfect laboratory tests that will predict Another study retrospectively evaluated the surgical specimen the likelihood of serious liver injury prior to administration of with focus on liver parenchyma not involved by the resected the drug, clinicians are tasked with detecting the early signs tumor.13 Overall, sinusoidal obstruction was present in 39 of injury and determining whether the drug should be stopped patients (10%), steatosis in 134 (35%), and steatohepatitis in due to hepatotoxicity or to continue chemotherapy if hepatic 16 (4%). A recent study which attempted to stratify patients adaptation and tolerance development are likely. In most based on degree of hepatic dysfunction reported no difference cases of DILI, the only effective treatment is discontinuation in the 5-FU clearance in patients with elevated bilirubin.14 of the causal agent and supportive care. In the context of life- threatening disease, the risk and benefit need to be Fluorodeoxyuridine (5FUDR) calculated based on the individual patient and disease course. In a study comparing regional intra-arterial versus contin- Specific chemotherapy uous systemic therapy with 5FUDR in patients with colorectal liver metastasis, there was considerable hepatotoxicity, Anti-metabolites including chemical hepatitis in 79% of patients and biliary sclerosis is 21% of patients. The small gain in survival seen 6-Mercaptopurine (6-MP) with regional therapy was offset by toxicity of intra-arterial FUDR.15 In later studies, biliary toxicity called for reduction of The largest series, Present et al. reported long-term results of the dose and the duration of therapy with more than half of 6-MP use in 396 patients with inflammatory bowel disease patients requiring treatment termination due to drug toxi- (IBD). There were 11 cases of hepatitis and one case of city.16 It is still a matter of debate whether bile duct injury is recurrence of jaundice after reinstitution of the drug.3 Severe related to drug toxicity or ischemia.17 cholestasis associated with the use of conventional doses of 6-MP has also been reported after liver transplantation.4 The Capecitabine most common pattern of described injury is intrahepatic cholestasis. Jaundice resolved with discontinuation of the Capecitabine is a drug that undergoes preferential conversion drug. Cases of fulminant hepatic failure occurred with the to 5-fluorouracil within the tumor. A study of 14 patients doses of medication far exceeding the current recommended investigated the pharmacokinetics of the drug in patients with dose of 1.5 mg/kg body weight per day. hepatic dysfunction and concluded that mild to moderate hepatic dysfunction had no clinically significant influence.18 Azathioprine (AZA) This was confirmed in a recent study, which examined the impact of hepatic dysfunction on the safety and pharmacol- Despite being the parental drug of 6-MP, AZA has been linked ogy of gemcitabine/capecitabine in patients with advanced to little hepatotoxicity. Nevertheless, caution is advised since pancreatico-biliary cancer. Eight patients with hepatic dys- cholestatic liver injury appears to be possible after prolonged function and bilirubin elevation (ranging 1.2–6.6 mg/dL) use. Fulminant liver failure was reported in one patient after were included. Combination therapy was well tolerated, and eight years of dose AZA therapy at levels higher than the hepatic dysfunction was not associated with drug-related currently recommended dose.5 AZA related hepatotoxicity toxicity.19 was also reported in liver transplant recipients.6 Gemcitabine 6-Thioguanine (6-TG) In a Phase I trial in patients with hepatic dysfunction, 25 6-TG was reported to cause hepatic vascular disease7 and to patients were divided in two groups: elevated AST and mildly present significant risk for nodular hyperplasia and early and moderately elevated bilirubin. AST levels ranged from 37 fibrosis.8 to 530 U/L, and bilirubin from normal up to 5.7 mg/dL. The most common dose limiting side effect was transient eleva- Cytarabine tion in baseline bilirubin in seven patients from the second group. The authors of this trial recommended decreasing the Despite various degrees of hepatic enzyme abnormalities in initial dose of medication in patients with elevated baseline 42 out of 116 patients in a study,9 the definite association bilirubin.20 This conclusion was not confirmed in a retro- with the drug administration was not confirmed. This finding spective review of treatment with gemcitabine in seven was echoed in a subsequent study with high dose of the drug. patients with hepatic dysfunction and bilirubin elevation (total Abnormalities in liver function occurred in 14 (22%) patients bilirubin.4.5 mg/dL). Full dose of gemcitabine in this study (severe in three), but no treatment modifications were did not result in further deterioration of liver function.21 required.10 Nevertheless, there are reports of severe drug- induced hepatic cholestasis related to cytarabine therapy.11 Methotrexate (MTX)
5-Fluorouracil (5-FU) With MTX therapy, the incidence of abnormalities in hepatic function tests for ALT and AST were reported to be 14% and 5-Fluorouracil is commonly used in combination regimen for 8%, respectively.22 This finding was replicated recently with a neoadjuvant chemotherapy in patients with colorectal liver recent meta-analysis where the pooled frequency of liver metastasis prior to surgical resection. In a study of 107 patients enzyme abnormalities was 10.2%.23 In a historic report, of assigned to receive 5-FU, no significant hepatic toxicity was the use of ‘‘antifolics’’ and ‘‘antipurins’’ in children with acute observed in a group receiving 5-FU orally and was seen leukemia was associated with fibrosis in 80% of children infrequently in those receiving the drug intravenously.12 based on histology and clinical evidence of liver disease in
Journal of Clinical and Translational Hepatology 2014 vol. 2 | 95–102 97 Grigorian A. et al.: Hepatotoxicity secondary to chemotherapy almost all cases.24 Cases of hepatocellular carcinoma (HCC) fever, and a rise in transaminases.39 In a study analyzing the in long-term survivors of childhood leukemia have been toxicity data for 511 children, 64 (12.5%) had at least one reported.25 In addition, methotrexate induced cirrhosis has episode of hepatotoxicity and 41 satisfied the criteria for VOD, resulted in liver transplantation in a number of patients.26 with 94% overall survival in this group.40 Despite the concerns spanning half of a century for the potential risk for hepatic cirrhosis with the use of methotrex- Bleomycin ate in nonmalignant diseases such as psoriasis,27 later studies in patients with rheumatoid arthritis28 alleviated Studies with bleomycin described mild transient abnormalities some of the fears. However, ‘‘word of caution’’ still requires in liver enzymes with a return to baseline upon cessation of drug very close patient monitoring, in particular in those with treatment and no specific pathological liver abnormalities.41 concurrent obesity and diabetes.29 Doxorubicin/Adriamycin Alkylating agents Adriamycin dosing in hepatic dysfunction received attention Busulfan because of reported excessive life –threatening toxicity, as demonstrated with liver test abnormalities, in eight Oral Busulfan has been implicated in severe cases of hepatic patients.42 The investigators reduced the dose of the drug veno-occlusive disease.30 In a study with intravenous in the subsequent nine patients to 50% of the dose in patients Busulfan in 55 pediatric patients, mild to moderate transient with bilirubin of 1.2–3.0 mg and 75% of the dose if bilirubin elevation in liver enzymes and bilirubin was described. measured .3.0 mg. This approach succeeded and was Although veno-occlusive disease (VOD) occurred in up to 15 adopted by clinical community. In contrast, liver cirrhosis % of patients, reported cases were mild and resolved in ten did not seem to affect drug metabolism in a study of seven days after diagnosis.31 patients, three of which had biopsy proven cirrhosis.43
Cyclophosphamide Mitomycin
Cyclophosphamide is used in the most liver toxic myeloa- Mitomycin can cause transient jaundice44 and has been blative regimen, and when combined with total body irradia- implicated in VOD.45 tion, has been reported to result in VOD in 38% of the patients.32 The hepatotoxicity appeared to be greatly poten- Dacarbazine tiated by radiation. Cyclophosphamide was demonstrated in seven patients with liver dysfunction to have a significantly Dacarbazine was associated in one report with hepatic longer half-life.33 necrosis with thrombotic occlusion of the small vessels in two of sixty-eight patients (3%).46 Chlorambucil Nitrosoureas There are few available reports regarding liver toxicity of chlorambucil, but the largest one found jaundice in 7.2% Carmustine patients undergoing treatment for lymphoma and leukemia.34 With carmustine, liver enzymes were elevated, unexplained Ifosfamide by the primary disease, in 26% of patients.47
Ifosfamide is not commonly associated with hepatotoxicity. In Lomustin one phase II trial of 19 patients with HCC in the background of viral hepatitis and cirrhosis (bilirubin ,3.0 mg/dL), direct In a trial of lomustin with 142 patients with advanced solid intra-arterial delivery of the drug to the tumor was reported tumors, reports of transient hepatic toxicity was reported to worsen liver function in two patients.35 much less frequently and consisted of elevation of ALP, ALT, and AST in two patients.48 Melphalan Streptozotocin Hepatotoxicity with melphalan has been reported infre- quently. Its use has been associated with transient elevation In a study of streptozotocin with 88 patients with advanced of transaminases36 and VOD.37 In the past decade, isolated malignancy, hepatotoxicity, manifesting as elevation of hepatic perfusion of the liver for metastatic disease was transaminases, was demonstrated in 13 (15%). The enzymes advocated and more severe hepatotoxicity was observed in a rapidly returned to normal after discontinuation of therapy, study where 16 of 71 patients exhibited level 3–4 hepatic and no signs of hepatocellular necrosis were found on toxicity after one week of treatment.38 histological examination.49
Antitumor antibiotics Taxanes
Actinomycin Paclitaxel
Hypersensitivity reaction to actinomycin has been reported In a study of paclitaxel with 81 patients with solid tumors and with acute presentation and a sharp drop in platelet count, abnormal hepatic function, three groups were evaluated
98 Journal of Clinical and Translational Hepatology 2014 vol. 2 | 95–102 Grigorian A. et al.: Hepatotoxicity secondary to chemotherapy based on the level of bilirubin and AST.50 The elevation of prior to resection of hepatic colorectal metastasis. It has been bilirubin above 1.5 mg/dL with any level of AST predicted linked to the development of steatohepatitis, which contrib- drug-related toxicity with 24 hour infusion, and dose reduc- uted to increased postoperative mortality in a large cohort of tion was recommended. The study with 3-hour infusion patients.61 confirmed a higher incidence of toxicities in severe liver dysfunction groups (bilirubin .2.0 mg/dL). The study Etoposide included two patients with liver cirrhosis.51 Topoisomerase II inhibitor Etoposide had been described to Docetaxel cause severe hepatocellular injury.62 Studies in patients with impaired hepatic function (bilirubin up to 23 mg/dL) showed In a study of 42 patients with moderate hepatic impairment, no change in etoposide clearance.63 the docetaxel dose had to be reduced due to increased incidence of drug-related toxicities following treatment.52 Platinum agents However, in a study of patients with hepatic dysfunction secondary to metastatic breast cancer, almost half of group A pilot study of 11 patients with hepatic dysfunction (bilirubin allowed initial dose escalation due to improved liver function .1.5 times ULN) due to breast cancer metastatic to the liver as an indicator of the tumor response to treatment.53 reported normalization of the liver function tests, a marker of tumor responsiveness, to administered therapy in ten Vinca alkaloids patients.64
Vincristine Oxaliplatin
Transient elevation of transaminases following vincristine Oxaliplatin associated hepatic vascular injury has been therapy has been described, and it seems to be greatly described in multiple studies. A large series that evaluated potentiated by radiation therapy.54 Since neurotoxicity, the 153 liver resection specimens found sinusoidal congestion of most feared side effect, has been shown to be dose various degrees in 44 patients, perisinusoidal fibrosis and dependent, much attention has been paid its reduced fibrotic venular occlusion in 21 patients, nodular regenerative elimination in liver dysfunction. A study of 39 patients hyperplasia in seven patients, and hepatic steatosis in 75 suggested that elevation in ALP is the most sensitive patients.65 Another study assessed the risk of preoperative parameter in predicting reduced clearance.55 chemotherapy in patients undergoing liver resection for colorectal cancer metastasis. Out of 166 patients treated Vinorelbine with oxaliplatin, 11% developed sinusoidal dilatation. No increase in postoperative morbidity was found, suggesting In a study of oral and intravenous vinorelbine, the drug this histopathology finding does not independently increase exposure was not affected by mild to moderate hepatic the operative risk.66 dysfunction (bilirubin ,3.0 mg/dL).56 In contrast, another A phase I study administered reduced schedule dose of study assessed patients with impaired liver function due to oxaliplatin to 47 patients with impaired liver function, metastatic disease and established that increased systemic including 16 patient with severe dysfunction (bilirubin exposure with high risk of toxicity occurred in the group with .3.0 mg/dL). No dose limiting toxicities were observed in hyperbilirubinemia (.1.5 mg/dL).57 any cohort of the patients with escalation of the dose to the conventionally used level.67 Topoisomerase inhibitors Tyrosine kinase inhibitors Topotecan The discovery of targeted inhibition of tyrosine kinase (a family Rapid transient elevation of serum bilirubin without signifi- of proteins frequently dysregulated in various cancers) cant elevation in transaminases was noticed in patients in a marked a breakthrough in the fight against cancer. The unique phase I trial of topotecan.58 Due to its known hepatic route of properties of these medications helped to avoid conventional elimination, a study of 21 patients (mean bilirubin 4.3 mg/dL) toxicities, while hepatotoxicity emerged as a dose-limiting was conducted to establish dosing guidelines in patients with event. The risk of grade 3 hepatic adverse events with TKIs has impaired liver function.59 No increase in toxicity was been reported in the range of 1% to 12%.68 observed, and worsening of hepatic function in several patients was attributed to disease progression. This study Erlotinib concluded that no dose adjustment is necessary with impaired liver function. Transient grade 1–2 hyperbilirubinemia was reported in a phase I clinical trial of erlotinib.69 However, in a recent study, Irinotecan grade 3–4 bilirubin elevation was described in 47% of patients with preexisting moderate hepatic dysfunction.70 Dose reduction was suggested for irinotecan in patients with elevated baseline bilirubin and transaminases, as one study Gefitinib showed an increased incidence of neutropenia and dose- limiting elevation in transaminases in a group with hepatic Use of Gefitinib in treatment of advanced metastatic non- dysfunction (AST 134–394 U/l, bilirubin 0.7–5.5 mg/dl).60 small cell lung cancers was linked with grade 3 elevation of Irinotecan is used in a preoperative chemotherapy regimen ALT 2% of 147 patients receiving medication.71
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Imatinib recommended in patients with moderate to severe hepatic impairment defined as bilirubin.1.5 ULN. In a study of 89 patient with solid cancers and liver dysfunction, up to 58% of patients with moderate to severe Hydroxyurea HD, defined as bilirubin .1.5 ULN, had to be withdrawn from 72 the study prematurely due to progressive elevation of LFTs. Hepatotoxicity appears to be uncommon with hydroxyurea, Another study of 551 patients with chronic myeloid leukemia but there is case report of a self-limiting hepatitis81 that treated with Imatinib reported elevation of serum amino- recurred upon drug reintroduction. transferases in 43% of patients, with grade 3–4 in 5%.73 Procarbazine Pazopanib Liver toxicity is not commonly reported with procarbazine, Due to concern of hepatotoxicity, a phase I study attempted although it has been implicated in the development of hepatic to define the appropriate dose of Pazopanib in patients with granulomas.82 solid tumors and lymphoma and hepatic dysfunction. It was concluded that no dose reduction was necessary in mild cases Conclusions and reduced dose can be used in patients with moderate dysfunction, defined as bilirubin elevation 1.5–3X ULN.74 Collateral damage to the liver in cancer therapy is not uncommon. Hepatotoxicity from chemotherapy occurs fre- Sorafenib quently in an unpredictable or idiosyncratic fashion, ,and preexisting liver disease increases this risk. The pattern of In a phase I study of sorafenib in patients with hepatic presentation can vary from that of an inflammatory hepatitis, dysfunction, dose limiting elevation of bilirubin occurred in 10 cholestasis, steatosis, and finally a vascular presentation as out of 72 patients, leading to recommendation to lowering the hepatic VOD. The severity ranges from asymptomatic liver dose to half in patients with bilirubin .1.5 6 ULN and not function test elevation, acute liver failure, or a progressive reaching conclusive safe dose guidelines in patients with fibrosis culminating in end stage liver disease. Various groups bilirubin .36 ULN.75 have produced liver toxicity classifications that lay out dose modification guidelines for various chemotherapeutic agents. Immunotherapy Nevertheless, with knowledge and caution, many potential side effects and serious damage to the recipient can be avoided. Interferon
In patients receiving high-dose Interferon therapy for mela- Conflict of interest noma, 63% had hepatic toxicities (all grades). If AST or ALT levels increased .5 times normal, this was considered dose- None limiting toxicity with recommended dose modifications.76 Author contributions Interleukin-2 Writing this article (AG, CBO). With interleukin-2 therapy, profound reversible intrahepatic cholestasis was reported in 261 retrospectively and 10 prospectively evaluated patients with cancer, with normal- References ization, on average, in 5.6 days.77 [1] Senior JR. Unintended hepatic adverse events associated with cancer chemo- Miscellaneous agents therapy. Toxicol Pathol 2010;38:142–147. doi: 10.1177/0192623309351719. [2] Fontana RJ, Watkins PB, Bonkovsky HL, Chalasani N, Davern T, Serrano J, et al. Drug-induced liver injury network (DILIN) prospective study: Arsenic trioxide Rationale, design, and conduct. Drug Safety 2009;32:55–68. doi: 10.2165/00002018-200932010-00005. In a study examining of the use of arsenic trioxide for newly [3] Present DH, Meltzer SJ, Krumholtz MP, Wolke A, Korelitz BI. 6- Mercaptopurine in the management of inflammatory bowel disease: short- diagnose promyelocytic leukemia, severe hepatotoxicity and long-term toxicity. Ann Intern Med 1989;111:641–649. doi: 10.7326/ resulted in the death of two out of 11 treatment naı¨ve 0003-4819-111-8-641. patients.78 [4] Kontorinis N, Agarwala K, Gondolesia G, Fiel MI, O’Rourke M, Schianoa TD. Diagnosis of 6 mercaptopurine hepatotoxicity post liver transplantation utilizing metabolite assays. Am J Transplant 2004;4:1539–1542. doi: Asparaginase 10.1111/j.1600-6143.2004.00543.x. [5] Barrowman JA, Kutty PK, Ra MU, Huang SN. Sclerosing hepatitis and Liver enzyme abnormalities with asparaginase were reported azathioprine (letter). Dig Dis Sci 1986;31:221–222. doi: 10.1007/BF01300713. in 33 out of 35 patients in an early study, where liver biopsies [6] Sterneck M, Wiesner R, Ascher N, Roberts J, Ferrell L, Ludwig J, et al. found reversible fatty metamorphosis in two patients.79 Azathioprine hepatotoxicity after liver transplantation Hepatology 1991;14: 806–810. doi: 10.1002/hep.1840140511. [7] Satti MB, Weinbren K, Gordon-Smith EC. 6-thioguanine as a cause of toxic Bortezomib veno-occlusive disease of the liver. J Clin Pathol 1982;35:1086–1091. doi: 10.1136/jcp.35.10.1086. Bortezomib was studied in 61 patients with advanced malig- [8] Geller SA, Dubinsky MC, Poordad FF, Vasiliauskas EA, Cohen AH, Abreu MT, 80 et al. Early hepatic nodular hyperplasia and submicroscopic fibrosis associated nancies and varying degrees of hepatic dysfunction. Since with 6-thioguanine therapy in inflammatory bowel disease. Am J Surg Pathol liver failure was reported in one patient, dose adjustment was 2004;28:1204–1211. doi: 10.1097/01.pas.0000128665.12063.97.
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Clin Pharmacol Ther 1996;59:32–40. doi: 10.1016/S0009-9236(96)90021-1. study by the National Cancer Institute Organ Dysfunction Working Group. J [58] Rowinsky EK, Kaufmann SH, Baker SD, Miller CB, Sartorius SE, Bowling MK, Clin Oncol 2008;26:563–269. doi: 10.1200/JCO.2007.11.0304. et al. A phase I and pharmacological study of Topotecan infused over [73] O’Brien SG, Guilhot F, Larson RA, Gathmann I, Baccarani M, Cervantes F, 30 minutes for five days in patients with refractory acute leukemia. Clin et al. Imatinib compared with interferon and low-dose cytarabine for newly Cancer Res 1996;2:1921–1930. diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med 2003;348: [59] O’Reilly S, Rowinsky E, Slichenmyer W, Donehower RC, Forastiere A, Ettinger 994–1004. doi: 10.1056/NEJMoa022457. D, et al. Phase I and pharmacologic studies of topotecan in patients with [74] Shibata SI, Chung V, Synold TW, Longmate JA, Suttle AB, Ottesen LH, et al. impaired hepatic function. J Natl Cancer Inst 1996;88:817–824. doi: Phase I study of pazopanib in patients with advanced solid tumors and 10.1093/jnci/88.12.817. hepatic dysfunction: a National Cancer Institute Organ Dysfunction Working [60] Venook AP, Enders Klein C, Fleming G, Hollis D, Leichman CG, Hohl R, et al.A Group study. Clin Cancer Res 2013;19:3631–3639. doi: 10.1158/1078- phase I and pharmacokinetic study of irinotecan in patients with hepatic or 0432.CCR-12-3214. renal dysfunction or with prior pelvic radiation: CALGB 9863. Ann Oncol [75] Miller AA, Murry DJ, Owzar K, Hollis DR, Kennedy EB, Abou-Alfa G, et al. 2003;14:1783–1790. doi: 10.1093/annonc/mdg493. Phase I and pharmacokinetic study of sorafenib in patients with hepatic or [61] Vauthey JN, Pawlik TM, Ribero D, Wu TT, Zorzi D, Hoff PM, et al. renal dysfunction: CALGB 60301. J Clin Oncol 2009;27:1800–1805. doi: Chemotherapy regimen predicts steatohepatitis and an increase in 90-day 10.1200/JCO.2008.20.0931. mortality after surgery for hepatic colorectal metastases. J Clin Oncol 2006; [76] Kirkwood JM, Bender C, Agarwala S, Tarhini A, Shipe-Spotloe J, Smelko B, 24:2065–2072. doi: 10.1200/JCO.2005.05.3074. et al. Mechanisms and management of toxicities associated with high-dose [62] Tran A, Housset C, Boboc B, Tourani JM, Carnot F,Berthelot P.Etoposide (VP 16– interferon alfa-2b therapy. J Clin Oncol 2002;20:3703–3718. doi: 10.1200/ 213) induced hepatitis. Report of three cases following standard-dose treat- JCO.2002.03.052. ments. J Hepatol 1991;12:36–39. doi: 10.1016/0168-8278(91)90905-Q. [77] Fisher B, Keenan AM, Garra BS, Steinberg SM, White DE, DiBisceglie AM, [63] Arbuck SG, Douglass HO, Crom WR, Goodwin P, Silk Y, Cooper C, et al. et al. Interleukin-2 induces profound reversible cholestasis: a detailed Etoposide pharmacokinetics in patients with normal and abnormal organ analysis in treated cancer patients. J Clin Oncol 1989;7:1852–1862. function. J Clin Oncol 1986;4:1690–1695. [78] Niu C, Yan H, Yu T, Sun HP, Liu JX, Li XS, Wu W, et al. Studies on treatment of [64] Sharma RA, Decatris MP, Santhanam S, Roy R, Osman AE, Clarke CB, et al. acute promyelocytic leukemia with arsenic trioxide: remission induction, Reversibility of liver failure secondary to metastatic breast cancer by follow-up, and molecular monitoring in 11 newly diagnosed and 47 relapsed vinorelbine and cisplatin chemotherapy. Cancer Chemother Pharmacol acute promyelocytic leukemia patients. Blood 1999;94:3315–3324. 2003;52:367–370. doi: 10.1007/s00280-003-0679-8. [79] Haskell CM, Canellos GP, Leventhal BG, Carbone PP, Block JB, Serpick [65] Rubbia-Brandt L, Audard V, Sartoretti P, Roth AD, Brezault C, Le Charpentier AA, et al. L-asparaginase: therapeutic and toxic effects in patients with M, et al. Severe hepatic sinusoidal obstruction associated with oxaliplatin- neoplastic disease. N Engl J Med 1969;281:1028–1034. doi: 10.1056/ based chemotherapy in patients with metstatic colorectal cancer. Ann Oncol NEJM196911062811902. 2004;15:460–466. doi: 10.1093/annonc/mdh095. [80] LoRusso PM, Venkatakrishnan K, Ramanathan RK, Sarantopoulos J, Mulkerin [66] Wolf PS, Park JO, Bao F, Allen PJ, DeMatteo RP, Fong Y. Preoperative D, Shibata SI, et al. Pharmacokinetics and safety of bortezomib in patients chemotherapy and the risk of hepatotoxicity and morbidity after liver resection for metastatic colorectal cancer: a single institution experience. J with advanced malignancies and varying degrees of liver dysfunction: phase Am Coll Surg 2013;216:41–49. doi: 10.1016/j.jamcollsurg.2012.08.030. I NCI Organ Dysfunction Working Group Study NCI-6432. 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102 Journal of Clinical and Translational Hepatology 2014 vol. 2 | 95–102 Review Article
Pathology of Alcoholic Liver Disease
Romulo Celli1 and Xuchen Zhang2
1Department of Pathology, Yale University School of Medicine, New Haven, CT, USA; 2Pathology and Laboratory Service, VA Connecticut Health System and Department of Pathology, Yale University School of Medicine, West Haven, CT, USA
Abstract (i.e. steatosis). The role of the pathologist is to assimilate the diverse morphologic data from a given liver biopsy and to Alcohol-attributable burden on global health is increasing, clearly determine progression of the disease and, if possible, and the relationship between population alcohol consumption its etiology. and liver-related deaths is strong. Longstanding scientific and Specifically, the role of liver biopsy in ALD is 1) to clinical workhas led to a relatively thorough, if not complete, corroborate clinical findings in establishing diagnosis and 2) understanding of the effects of alcohol consumption on the to estimate disease severity using semi-quantitative tools of liver. Pathologic features of alcoholic liver disease (ALD) are disease grade and stage. recognized by pathologists and used to assist clinicians in The objective of this review is to survey the gross and diagnosing and determining severity of disease in patients microscopic features of ALD and, in doing so, to provide suspected of ALD. In this review, we discuss the pathologic clinicians with a reference for the interpretation of liver biopsy manifestations of ALD and provide salient points on their pathology reports. Additionally, we review the benefits and pathophysiology. In addition, the benefits and indications of limitations of obtaining a liver biopsy and provide a pre- liver biopsy and important differential diagnoses, including liminary set of indications for this clinical test. features distinguishing these entities, are reviewed. E 2014 The Second Affiliated Hospital of Chongqing Medical Major pathologic features of ALD University. Published by XIA & HE Publishing Ltd. All rights reserved. Steatosis
Introduction Steatosis is the abnormal accumulation of mono-/di-/trigly- cerides and fatty acids in hepatocytes in the form of lipid 2 There is a strong relationship between population alcohol droplets. In normal lipid metabolism, plasma free fatty acids consumption and liver-related deaths. In 2010, nearly 50% (FFA)—unbound or attached to lipoprotein particles—are of the world’s population consumed alcohol in some form. shuttled to the liver and either oxidized for fuel at the During that year more than one million deaths worldwide hepatocyte mitochondrion or stored as triglycerides. were attributed to liver cirrhosis, and 47.9% of those were Triglycerides are exported as VLDL particles or organized into caused by chronic alcohol use.1 lipid droplets and kept indefinitely within the hepatocyte. As a pathologic entity, alcoholic liver disease (ALD) can be Sufficient accumulation of lipid droplets leads directly to defined as the manifold gross and microscopic manifestations hepatocellular damage. An increase in plasma FFA concen- of regular alcohol consumption on the liver. ALD is recognized tration is seen in non-alcohol and alcohol-induced steatosis as a progressive disease that worsens with chronic alcohol and is a likely contributing mechanism to pathologic liver fat 3 intake. Likewise, the pathological effects comprise a wide accumulation. In addition, alcohol-induced steatosis stimu- spectrum: from the banal and reversible steatosis to the lates a series of pathophysiologic disturbances. The oxidation severe and irreversible cirrhosis. The natural consequence of of ethanol, for example, reduces nicotinamide adenine such phenotypic heterogeneity within a disease process is the dinucleotide (NADH), which suppresses the oxidative presentation of certain pathologic features that are more mechanism of the mitochondria. Ethanol has also been specific for ALD (i.e. Central Hyaline Sclerosis) than others shown, primarily in cell culture and animal models, to stimulate hepatic lipogenesis via activation of transcription factors such as sterol response element binding proteins Keywords: Alcoholic liver disease; Steatosis; Steatohepatitis; Pathology. (SREBP’s), which regulate the expression of genes involved in Abbreviations: ALD, alcoholic liver disease; ASH, non-alcoholic fatty liver lipid biosynthesis.4 disease; CK8/18, cytokeratins 8 and 18; EASL, European Association for the Study of the Liver; FFA, free fatty acids; H&E, hematoxylin and eosin; NADH, Steatosis is the earliest and most common finding in ALD 5 nicotinamide adenine dinucleotide; NAFLD, non-alcoholic fatty liver disease; and is reversed upon cessation of alcohol consumption. It is NASH, non-alcoholic steatohepatitis; PDGF, platelet-derived growth factor; ROS, estimated that normal liver parenchyma consists of up to 5% reactive oxygen species; TGF- b1, transforming growth factor beta 1; TIMP-1, lipids. Therefore, by convention, a hepatic lipid deposition tissue inhibitors of metalloproteinase-1; TNFR2, TNF receptor 2; VLDL, very low- 6 density lipoprotein. greater than 5% is considered pathologic. Received: 3 March 2014;Revised: 14 April 2014;Accepted: 16 April 2014 Steatosis presents with distinct gross and histological q DOI of original article: 10.14218/JCTH.2014.00010. characteristics. Grossly, diffuse involvement of the liver by Correspondence to: Xuchen Zhang, Pathology and Laboratory Service, VA steatosis appears as generalized enlargement of the liver Connecticut Health System and Yale University School of Medicine, 950 Campbell Ave. West Haven, CT 06516, USA. Tel: +1-203-932-5711, Fax: +1-203-937-4704, with a yellow-tinged appearance that looks and feels E-mail: [email protected] ‘‘greasy’’ to the touch. Microscopically, steatosis begins in
Journal of Clinical and Translational Hepatology 2014 vol. 2 | 103–109 Celli R. et al.: Pathology of alcoholic liver disease zone 3 (perivenular/centrilobular) and extends outwards complications of liver disease (cirrhosis, hepatocellular carci- with increasing severity.7 Steatosis can be classified into noma). However, studies involving both humans and animal microvesicular (small-droplet) or macrovesicular (large-dro- models have demonstrated that steatosis may progress plet) types. Of the two, microvesicular steatosis is less directly to fibrosis or cirrhosis without the characteristic prevalent and is characterized by hepatocytes with centrally inflammatory changes of steatohepatitis.2 For this reason, placed nuclei and small vesicular fat droplets located circum- pathologists should examine even purely steatotic livers for the ferentially around the nucleus. Macrovesicular steatosis is presence/degree of fibrosis. This will lead to a more compre- characterized by hepatocytes that contain nuclei displaced to hensive assessment of a patient’s particular riskfor progres- one side of the cell by the large fat droplets (Fig. 1A). Rupture sion to cirrhosis and its sequelae. of fat-laden hepatocytes can give rise to the appearance of lipogranulomas—microscopic foci of inflammation around fat Steatohepatitis droplets (Fig. 1B). These typically are seen singly and are often dispersed throughout the parenchyma. Chronic inflam- Steatohepatitis is a histologic pattern that can be seen in matory cells may be seen scattered within the lobules, but chronic ethanol users. It is characterized by a set of they should not be present in significant density due to diagnostic features, which may present in different stages steatosis alone. In general, these characteristics make of severity.8 Diagnostic features of steatohepatitis are steatosis a readily identifiable pattern, but they are highly parenchymal inflammation, hepatocyte damage, and fibrosis. non-specific as there are no features of ethanol-induced This histologic pattern can be caused by the direct effect of steatosis that can help distinguish it from non-alcoholic fatty alcohol (ASH) or multiple non-alcohol related etiologies (non- liver disease (NAFLD). alcoholic steatohepatitis, NASH). In general, these changes Classically, steatosis is considered a riskfactor for disease are seen in a perivenular distribution in the earliest form of progression to steatohepatitis and other more serious the disease, and they extend throughout the lobules as the
Fig. 1. 1A: Steatosis - Large-droplet (macrovesicular) and small-droplet (microvesicular) steatosis (200X, H&E stain); 1B: Lipogranuloma - extracellular lipid surrounded by chronic inflammatory cells (200X, H&E stain); 1C: Neutrophilic inflammation - Steatohepatitis with a predominantly neutrophilic inflammatory infiltrate (arrow showing clusters of neutrophils, 200X, H&E stain); 1D: Mallory bodies - dense ropy eosinophilic skeins of cytokeratin filaments within cytoplasm of hepatocytes (arrow showing intra- cytoplasmic Mallory body, 400X, H&E stain); 1E: Ballooning degeneration of hepatocytes - swollen and enlarged hepatocytes with an intracytoplasmic rarefied, ‘‘stringy’’ or ‘‘wispy’’ appearance (arrow showing hepatocytes with ballooning degeneration, 400X, H&E stain); 1F: Perisinusoidal fibrosis - fibrosis in a ‘‘chicken-wire’’ pattern (arrow showing blue-colored perisinusoidal fibrosis, 400X, Trichrome stain)
104 Journal of Clinical and Translational Hepatology 2014 vol. 2 | 103–109 Celli R. et al.: Pathology of alcoholic liver disease disease progresses. Despite similarities in nomenclature, the Activation of stellate cells leads to increase cell size and ASH histopathologic diagnosis can be seen in the chronic proliferation. These cells also gain the ability to destroy alcoholic with or without the acute clinical syndrome termed normal intercellular matrix and replace it with dense base- alcoholic hepatitis. In other words, ASH is not synonymous ment membrane-like collagen. Additionally, they increase the with alcoholic hepatitis, but patients with alcoholic hepatitis production of inflammatory cytokines, attracting more typically have ASH.9 inflammatory cells and causing increased hepatocyte damage Inflammation in ASH has a varying amount of lobular via a positive feedbackmechanism. 18 Light microscopic involvement, with no specific zonal distribution. It is typically evidence of this process appears as dense collagen due to neutrophil-rich (Fig. 1C),8 although rarely it involves chronic fibrosis. In particular, the process of fibrosis typically pro- inflammatory cells such as lymphocytes. Satellitosis can be ceeds in a perisinusoidal and pericellular fashion, creating a present and appears as inflammatory cells encircling distinctive ‘‘chicken-wire’’ pattern10 more easily seen with damaged hepatocytes.10 Neutrophilic infiltration has been collagen stains such as trichrome or reticulin (Fig. 1F). These attributed to the increase of chemokines, such as IL-8 and IL- stains are particularly useful when pale hematoxylin and 17, in both the serum and the liver parenchyma.11,12 It has eosin (H&E) stained sections make identification of collagen been hypothesized that their function is to clear the liver of difficult. dying hepatocytes, and the baseline phagocytic function of In ASH, portal tracts may show small collections of these neutrophils has been reported to be decreased in lymphocytes, but portal tract findings should not be the most human alcoholic patients.13 This could explain in part why conspicuous feature of the biopsy. If larger, denser, and more infection is a major cause of mortality among patients with frequent collections are seen, then other chronic hepatitides alcoholic hepatitis. should be considered as the primary or concomitant pathol- There are multiple morphologic manifestations of hepato- ogy. ALD is strongly associated with other chronic hepatic cyte damage in ASH. Mallory-Denkbodies (also knownas diseases epidemiologically, especially hepatitis B and C.19,20 Mallory’s hyaline, alcoholic hyaline, or Mallory bodies) are Comorbid hepatic diseases are common enough to warrant another classic, albeit non-specific finding, of alcoholic significant consideration each time a slide is examined. steatohepatitis. The presence of Mallory-Denkbodies reflects intracellular oxidative stress and can signal other liver Steatofibrosis-cirrhosis pathology, including non-alcoholic steatohepatitis; Wilson disease; cholestatic conditions such as primary biliary There are multiple interplaying factors that contribute to the cirrhosis; or exposure to certain drugs (such as amiodarone). development of diffuse fibrosis-cirrhosis in ALD. Broadly, They are characterized by ropy eosinophilic material within alcohol-induced hepatocyte damage leads to hepatic stellate the hepatocyte cytoplasm (Fig. 1D), which is composed of cell activation. As discussed previously, activated stellate cells misfolded and cross-linked cytokeratins 8 and 18 (CK8/18)14 develop a myofibroblastic phenotype and the capacity to lay as well as the ubiquitination-proteasome proteins ubiquitin, down basement-membrane like collagen.21 Thickcollagen p62, heat-shockproteins (HSPs) 70 and 25, and other strands can be seen around the central vein as well as coursing peptides. Immunohistochemical staining with CK8/18, ubi- through the hepatic lobules in a perisinusoidal and pericellular quitin, or p62 antibodies is useful for the identification of fashion, inhibiting diffusion of key nutrients to and from the inconspicuous Mallory-Denkbodies. 10 Of note, both CK8 and hepatocytes and sinusoidal blood. This leads to starvation and CK18 are able to bind to the TNF receptor 2 (TNFR2), thereby focal atrophy of nearby hepatocytes. This, in turn, leads to an influencing TNF-a–induced activation of apoptosis and neu- increase in scarring and thickening of the fibrous septa over trophilic inflammation through NF-kB activation.15 Thus, the time. Simultaneously, as a response to hepatic injury, there accumulation of Mallory-Denkbodies may not simply be a by- will be other areas of hepatocyte regeneration. The visible product of hepatocellular toxic damage but may also con- result of this interplay between fibrosis, hepatocyte atrophy, tribute to the perpetuation or advancement of inflammatory and focal regeneration is the appearance of cirrhotic nodules. injury.16 Another invariably present finding that reflects These nodules can be classified as micronodular or macro- cellular damage is hepatocyte ‘‘ballooning’’. Ballooned hepa- nodular depending on their size (larger or smaller than 3 mm). tocytes appear swollen or enlarged, with an intracytoplasmic Grossly, a liver that was once steatotic (enlarged and yellow/ rarefied ‘‘stringy’’ or ‘‘wispy’’ appearance (Fig. 1E). In con- brown in color) becomes cirrhotic (shrunken-often ,1kg- trast to steatotic hepatocytes, which have an entirely clear brown, firm, and nodular). cytoplasm, ballooned cells have some wispy cytoplasmic Although more likely to develop from ASH, fibrosis may content remaining. Apoptotic cells (also termed-apoptotic also develop in the purely steatotic liver.16,22 In this scenario, bodies or acidophilic bodies) are small hepatocytic cellular fibrosis is the direct result of the injurious effects of alcohol, remnants with hyperchromatic condensed nuclei and a dense rather than secondary inflammation. This process typically eosinophilic rim. They are often scattered in areas affected by takes longer than the more aggressive natural history of ASH- inflammation. Apoptotic cells, ballooning hepatocytes, and induced fibrosis. A separate and equally important point is Mallory-Denkbodies represent the hallmarksof hepatocyte that a cirrhotic liver may lose all of its fat content in the damage in ASH. process of fibrosis. This increases the difficulty of determining The pattern of fibrosis in early ASH is often, although not etiology in an end stage liver. exclusively, centrilobular. The presence of centrilobular/ perivenular fibrosis confers an increased riskfor progression Other pathologic findings of ALD to cirrhosis.10,17 Hepatic stellate cells (previously Ito cells) under normal conditions have lipid-storing function and are Cholestasis responsible for producing the majority of intercellular col- lagen (fibrosis). This occurs following hepatic stellate cell Histologic cholestasis is more often seen in ASH than NASH activation by inflammation and hepatocyte damage (Fig. 3). and can be a key feature when distinguishing between these
Journal of Clinical and Translational Hepatology 2014 vol. 2 | 103–109 105 Celli R. et al.: Pathology of alcoholic liver disease entities. Microscopically (Fig. 2A), cholestasis can take the to mitochondrial dysfunction, and an identical histologic form of inspissated bile—within canaliculi or intra-hepato- pattern can be seen in Reye’s syndrome, tetracycline toxicity, cyte—termed bile ‘‘plugs’’ or ‘‘thrombi.’’ Another feature of and fatty liver of pregnancy.7,26 cholestasis is bile ductular proliferation. Also known as ductular reaction, this histologic feature is composed of an Megamitochondria increase in bile ductular profiles within fibrotic portal tracts or along the fibrous septa of bridging fibrosis or cirrhosis. It is Megamitochondria represent eosinophilic sphere-like intra- 23 frequently accompanied by neutrophils. Cholestasis can be cytoplasmic forms of this organelle on H&E staining seen in all stages (steatosis, ASH, or cirrhosis) of ALD and (Fig. 2C).27 While not specific for ALD, they provide a ranges in severity. Its presence microscopically has been diagnostic clue, particularly when found in the center of the associated with worse prognosis in patients with clinical lobule. Their presence is related to the amount of daily 24 25 alcoholic hepatitis and histologic ASH. ethanol use and to the length of abstinence before the time of biopsy.28 Alcoholic foamy degeneration Perivenular fibrosis-central hyaline sclerosis Alcoholic foamy degeneration, originally described by Uchida et al in 1983, is an uncommon pattern of microvesicular The criteria for the interpretation of perivenular fibrosis steatosis (Fig. 2B), which has been described as classically include extending at least two-thirds the perimeter of the centrilobular26 and at times diffuse.7 Clinically, the patient terminal hepatic venule with the fibrous rim measuring over may present with acute hepatotoxicity and markedly elevated 4 mm in thickness.17,29 In its extreme form, perivenular serum gamma-glutamyl transaminase levels, with or without fibrosis can cause the necrosis of adjacent hepatocytes elevation of the transaminases.26 The pathogenesis is related and fibrous thickening and obliteration of the central
Fig. 2. Hepatic Stellate Cell (HSC) activation. Both alcohol and inflammation damage the liver and induce stellate cell activation. Apart from a phenotypic enlargement of the cell and nucleus, the stellate cells gain the capacity to degrade normal intercellular matrix and replace it with fibrous tissue (collagen). Additionally, they are able to proliferate and migrate to areas of injury, as well as attract more inflammatory cells, leading to further liver damage and HSC activation. ROS- reactive oxygen species; PDGF- platelet-derived growth factor; MCP-1- monocyte chemotactic protein-1; TGF- b1- Transforming growth factor beta 1; TIMP-1- tissue inhibitors of metalloproteinase-1.
106 Journal of Clinical and Translational Hepatology 2014 vol. 2 | 103–109 Celli R. et al.: Pathology of alcoholic liver disease
Fig. 3. 3A: Cholestasis – hepatocytic and canalicular cholestasis (arrow showing canalicular steatosis, 400X, H&E stain); 3B: Foamy cell degeneration – enlarged hepatocytes with diffuse microvesicular steatosis (200X, H&E stain); 3C: Megamitochondria – multiple eosinophilic sphere-like megamitochondria in the cytoplasm of hepatocytes (arrow showing megamitochondria in hepatocyte, 400X, H&E stain); 3D: Central hyaline sclerosis – central venule with fibrosis and obliteration of its lumen (arrow showing obliterated central venule, 400X, trichrome stain). venule—referred to as central hyaline sclerosis (Fig. 2D).30 and serum marker tests have been developed that correlate When diffuse, this unique lesion may cause pre-cirrhotic well with biopsy results.18,33 portal hypertension.31 Pathologic differential diagnosis Siderosis The differential diagnoses of pathologic ALD depend on the An iron stain (i.e. Prussian blue) reveals an increase in specific parenchymal changes seen. For example, alcohol- parenchymal iron in later stage ALD, particularly within induced macrovesicular steatosis is indistinguishable from Kupffer cells. Alcohol increases iron absorption in the gut. the steatosis seen in the metabolic syndrome. The presence Significant siderosis, including significant iron staining within of microvesicular steatosis, which is less common and due to hepatocytes, should prompt consideration of a concurrent mitochondrial oxidative stress, raises a differential diagnosis process such as hereditary hemochromatosis. which includes fatty liver of pregnancy, Reye’s syndrome, and Grading and staging of ALD the effect of anti-retroviral therapies in AIDS patients. Clinical history and other relevant clinical data are essential in As we have sought to demonstrate, there are many variables differentiating the causes of these similar patterns. to scrutinize in the analysis of any liver biopsy. Consequently, In the case of steatohepatitis, the most important a system that would standardize the scoring of these differential diagnosis is NASH, itself an etiologically diverse variables in concert for the purpose of disease staging and entity. Besides clinical history, which may or may not be prognostication would be welcome. In the absence of a useful in distinguishing between these two frequent diseases, consensus method for semi-quantitative scoring of ALD there are clues in the biopsy tissue that may suggest one severity, many pathologists have adopted the system pro- etiology over the other. For example, in ASH, necroinflamma- posed originally by Brunt et al.32 for use in NASH. In this tion is generally more prominent; meaning that there are system, the severity of parenchymal necroinflammatory more widespread neutrophilic infiltration, lipogranulomas, activity is reflected by the grade of the lesion. Grade has central hyaline sclerosis, and significantly increased density been shown to correlate with patient AST and ALD levels.32 of Mallory-Denkbodies. Although the presence of Mallory- Mild activity (grade 1) represents steatosis involving up to Denkbodies in general is largely non-specific, a biopsy with a 66% of lobules and mild steatohepatitis, while severe grade 3 high enough density of these may be considered ASH until represents panlobular steatosis and florid steatohepatitis. proven otherwise. Cholestasis is another feature that is more The severity of architectural distortions (fibrosis) is reflected commonly present in ASH than NASH and may be used as a by increasing stage. Stage 1 represents pericellular fibrosis diagnostic clue. It is important to remember that a definitive (focal or extensive), while the higher stages 3 and 4 diagnosis can only be made following acquisition of a represent bridging fibrosis and cirrhosis, respectively. thorough clinical history.34 Also, it is not uncommon that a Biopsy is required for the diagnosis of histologic ALD or patient may share these diseases, with morphologic overlap ASH. In terms of staging fibrosis, novel non-invasive imaging making their distinction nearly impossible.
Journal of Clinical and Translational Hepatology 2014 vol. 2 | 103–109 107 Celli R. et al.: Pathology of alcoholic liver disease
Indication for liver biopsy in the setting of ALD Conflict of interest
With the advent of new technologies and other methods that None allow for non-invasive evaluation of liver parenchyma,35 it is useful to critically review the role of liver biopsy in the setting Author contributions of ALD. There are no precise indications for the use of this study, and this remains a source of active discussion.36 For Reviewing the literature and drafting the manuscript (RC), example, some argue that liver biopsy is a diagnostic aid and providing overall intellectual input into the design and editing not necessary in establishing the diagnosis or determining the final version of the manuscript (XZ),approval of the final the prognosis of alcoholic hepatitis. Furthermore, they version to be published (RC,XZ). believe how much weight to put on the biopsy depends on the acuity of the clinical situation and the turn-around time of the particular histology lab. 9,36,37 Others argue that biopsy, REFERENCES in addition to the correct clinical context, is a key component of the diagnostic gold standard of alcoholic hepatitis.38 As [1] Rehm J, Samokhvalov AV, Shield KD: Global burden of alcoholic liver part of their recently published clinical practical guidelines, diseases. J Hepatol 2013;59:160–168. doi: 10.1016/j.jhep.2013.03.007. [2] Mavrelis PG, Ammon HV, Gleysteen JJ, Komorowski RA, Charaf UK: Hepatic the European Association for the Study of the Liver (EASL) free fatty acids in alcoholic liver disease and morbid obesity. 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[12] McClain CJ, Barve S, Deaciuc I, Kugelmas M, Hill D: Cytokines in alcoholic transjugular approach is favored in patients with hepatic liver disease. Semin Liver Dis 1999;19:205–219. doi: 10.1055/s-2007- coagulopathy. 1007110. [13] Stadlbauer V, Mookerjee RP, Hodges S, Wright GA, Davies NA, Jalan R: Effect of probiotic treatment on deranged neutrophil function and cytokine Conclusions responses in patients with compensated alcoholic cirrhosis. J Hepatol 2008;48:945–951. doi: 10.1016/j.jhep.2008.02.015. Liver biopsy plays an important role in the real-time clinical [14] Stumptner C, Omary MB, Fickert P, Denk H, Zatloukal K: Hepatocyte assessment of patients. Tissue histology not only yields cytokeratins are hyperphosphorylated at multiple sites in human alcoholic hepatitis and in a mallory body mouse model. Am J Pathol 2000;156:77–90. diagnostic information but also important information about doi: 10.1016/S0002-9440(10)64708-6. the patient’s overall disease progression. Clear and open [15] Caulin C, Ware CF, Magin TM, Oshima RG: Keratin-dependent, epithelial communication between the pathologist and the treating resistance to tumor necrosis factor-induced apoptosis. J Cell Biol 2000;149: clinician is key to successfully work through the oftentimes 17–22. doi: 10.1083/jcb.149.1.17. [16] Crawford JM: Histologic findings in alcoholic liver disease. Clinics in liver complex clinico-pathological data and to arrive at the disease 2012;16:699–716. doi: 10.1016/j.cld.2012.08.004. best decisions (from microscope-to-bedside) for a given [17] Worner TM, Lieber CS: Perivenular fibrosis as precursor lesion of cirrhosis. patient. JAMA 1985;254:627–630. doi: 10.1001/jama.1985.03360050065027. From steatosis to steatohepatitis and from Mallory bodies [18] Vera M, Nieto N: Hepatic stellate cells and alcoholic liver disease. Rev Esp Enferm Dig 2006;98:674–684. doi: 10.4321/S1130-01082006000900005. to megamitochondria—the morphologic heterogeneity of ALD [19] Rosman AS, Waraich A, Galvin K, Casiano J, Paronetto F, Lieber CS: is as varied as it is difficult to manage. It is only after decades Alcoholism is associated with hepatitis C but not hepatitis B in an urban of investigation by laboratory scientists and clinical physi- population. Am J Gastroenterol 1996;91:498–505. cians alike that the mechanisms of disease and the associa- [20] Caldwell SH, Jeffers LJ, Ditomaso A, Millar A, ClarkRM, Rabassa A, Red dy KR, De Medina M, Schiff ER: Antibody to hepatitis C is common among patients tions between microscopic morphology and clinical with alcoholic liver disease with and without riskfactors. Am J Gastroent erol syndromes have started to come into focus. However, much 1991;86:1219–1223. workis left to be done. Future studies may takeadvantage of [21] Friedman SL: Hepatic fibrosis – overview. Toxicology 2008;254:120–129. emerging molecular/genomic technologies in order to eluci- doi: 10.1016/j.tox.2008.06.013. date the clinically important markers of this disease.42 With [22] Lee UE, Friedman SL: Mechanisms of hepatic fibrogenesis. Best Pract Res Clin Gastroenterol 2011;25:195–206. doi: 10.1016/j.bpg.2011.02.005. time, better understanding should lead to better clinical [23] Tung BY, Carithers RL, Jr.: Cholestasis and alcoholic liver disease. Clin Liver outcomes. Dis 1999;3:585–601. doi: 10.1016/S1089-3261(05)70086-6.
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[24] Nissenbaum M, Chedid A, Mendenhall C, Gartside P: Prognostic-Significance Poynard T: Diagnostic and prognostic values of noninvasive biomarkers of of Cholestatic Alcoholic Hepatitis. Dig Dis Sci 1990;35:891–896. doi: fibrosis in patients with alcoholic liver disease. Hepatology 2009;49:97–105. 10.1007/BF01536804. doi: 10.1002/hep.22576. [25] Spahr L, Rubbia-Brandt L, Genevay M, Hadengue A, Giostra E: Early liver [34] Diehl AM, Goodman Z, IshakKG: Alcohollikeliver disease in nonalcoho lics. biopsy, intraparenchymal cholestasis, and prognosis in patients with alco- A clinical and histologic comparison with alcohol-induced liver injury. holic steatohepatitis. BMC gastroenterol 2011;11:115. doi: 10.1186/1471- Gastroenterology 1988;95:1056–1062. 230X-11-115. [35] Friedrich-Rust M, Ong MF, Herrmann E, Dries V, Samaras P, Zeuzem S, [26] Suri S, Mitros FA, Ahluwalia JP: Alcoholic foamy degeneration and a markedly Sarrazin C: Real-time elastography for noninvasive assessment of liver elevated GGT: a case report and literature review. Dig Dis Sci 2003;48: fibrosis in chronic viral hepatitis. AJR Am J Roentgenol 2007;188:758–764. 1142–1146. doi: 10.1023/A:1023781132498. doi: 10.2214/AJR.06.0322. [27] Bruguera M, Bertran A, Bombi JA, Rodes J: Giant mitochondria in [36] Forrest EH, Gleeson D: Is a liver biopsy necessary in alcoholic hepatitis? J hepatocytes: a diagnostic hint for alcoholic liver disease. Gastroenterology Hepatol 2012;56:1427–1428. doi: 10.1016/j.jhep.2011.12.028. 1977;73:1383–1387. [37] Dhanda AD, Collins PL, McCune CA: Is liver biopsy necessary in the [28] Junge J, Horn T, Christoffersen P: Megamitochondria as a diagnostic marker management of alcoholic hepatitis? World J Gastroenterol 2013;19:7825– for alcohol induced centrilobular and periportal fibrosis in the liver. Virchows 7829. doi: 10.3748/wjg.v19.i44.7825. Arch A Pathol Anat Histopathol 1987;410:553–558. [38] Potts JR, Verma S: Alcoholic hepatitis: diagnosis and management in 2012. [29] Nakano M, Worner TM, Lieber CS: Perivenular fibrosis in alcoholic liver injury: Expert Rev Gastroent 2012;6:695–710. doi: 10.1586/egh.12.57. ultrastructure and histologic progression. Gastroenterology 1982;83:777–785. [39] Tannapfel A, Dienes HP, Lohse AW: The indications for liver biopsy. Dtsch [30] Edmondson HA, Peters RL, Reynolds TB, Kuzma OT: Sclerosing Hyaline Necrosis of the Liver in the Chronic Alcoholic. A Recognizable Clinical Arztebl Int 2012;109:477–483. Syndrome. Ann Intern Med 1963;59:646–673. doi: 10.7326/0003-4819- [40] Bouchier IA, Hislop WS, Prescott RJ: A prospective study of alcoholic liver 59-5-646. disease and mortality. J Hepatol 1992;16:290–297. doi: 10.1016/S0168- [31] Yip WW, Burt AD: Alcoholic liver disease. Semin Diagn Pathol 2006;23:149– 8278(05)80659-2. 160. doi: 10.1053/j.semdp.2006.11.002. [41] Mathurin P, Duchatelle V, Ramond MJ, Degott C, Bedossa P, Erlinger S, [32] Brunt EM, Janney CG, Di Bisceglie AM, Neuschwander-Tetri BA, Bacon BR: Benhamou JP, Chaput JC, Rueff B, Poynard T: Survival and prognostic factors Nonalcoholic steatohepatitis: a proposal for grading and staging the in patients with severe alcoholic hepatitis treated with prednisolone. histological lesions. Am J Gastroenterol 1999;94:2467–2474. doi: Gastroenterology 1996;110:1847–1853. doi: 10.1053/gast.1996.v110. 10.1111/j.1572-0241.1999.01377.x. pm8964410. [33] Naveau S, Gaude G, Asnacios A, Agostini H, Abella A, Barri-Ova N, Dauvois B, [42] Beyoglu D, Idle JR: The metabolomic window into hepatobiliary disease. Prevot S, Ngo Y, Munteanu M, Balian A, Njike-Nakseu M, Perlemuter G, J Hepatol 2013;59:842–858. doi: 10.1016/j.jhep.2013.05.030.
Journal of Clinical and Translational Hepatology 2014 vol. 2 | 103–109 109 Review Article
Clinical Application of Transient Elastography in the Diagnosis of Liver Fibrosis: an Expert Panel Review and Opinion
Expert Panel on Liver Stiffness Measurement
Abstract Liver transient elastography (TE) is a newly developed non-invasive technique for diagnosis of liver fibrosis. It can be Liver fibrosis evaluation is pivotal for treatment decisions and used to assess the state of liver fibrosis by liver stiffness prognosis assessment in patients with chronic liver disease. measurement (LSM). TE techniques (for example, Fibroscan) Liver transient elastography (TE) is a newly developed non- offer better diagnostic performance for liver cirrhosis than invasive technique for diagnosis of liver fibrosis. It can assess serum biological markers including FibroTest, FibroMeter, the state of liver fibrosis by liver stiffness measurements, and HepaScore, APRI, API, FIB-4, Forns Index, Hui Index, and 1–7 offers better performance for the diagnosis of liver cirrhosis Compensated Cirrhosis Index (CCI), and it has been than serum biological markers. It has now been approved for approved for clinical use in China. To assist in the optimal clinical use in China. The aim of this review is to provide a application of this technique in clinical practice, the China guide for clinicians to apply this technique appropriately. The Foundation for Hepatitis Prevention and Control has brought recommendations are made under the auspices of China together experts to develop Expert Opinions on the Diagnosis Foundation for Hepatitis Prevention and Control, and have of Liver Fibrosis with Transient Elastography. The panel been prepared by a panel experts, who have reviewed and discussed and finalized the draft in November 2012 based summarized the clinical studies on TE in order to develop on progress in clinical practice, and growing evidence in the these recommendations. field. E 2014 The Second Affiliated Hospital of Chongqing Medical University. Published by XIA & HE Publishing Ltd. All rights The statistical basis for assigning cutoff values reserved. Ideally, the diagnostic cutoff values of non-invasive diagnosis should have a high negative predictive value (NPV) and low Introduction negative likelihood ratio (NLR) to rule out a diagnosis as well as a high positive predictive value (PPV) and high positive It is well established that many patients with chronic hepatitis likelihood ratio (PLR) to confirm a diagnosis. There are and even early cirrhosis may have no specific symptoms, necessary in order to avoid mis-diagnosis of liver fibrosis or signs, or biochemical abnormallities. Once symptoms or signs missed diagnosis of advanced fibrosis and cirrhosis. To ensure are detected, most cases already have well-established liver the accuracy of the diagnosis, it is necessary to adopt low cirrhosis, and even hepatic failure. Timely assessment and cutoffs to exclude the diagnosis and high cutoffs to confirm detection of advanced liver fibrosis and early diagnosis of the diagnosis. When the measured values fall in the gray zone cirrhosis are critical steps in managing chronic liver disease. between the high and low cutoffs, liver biopsy is still The use of liver biopsy, the current ‘‘gold standard’’ for necessary.8–9 Statistical analysis showed that cutoff values diagnosis of liver fibrosis/cirrhosis, suffers from limitations with a PLR . 10.0 afford sufficient confidence to confirm the such as low acceptability, invasiveness, risks of repeated diagnosis, whereas cutoff values with a NLR , 0.1 provide sampling, sampling error, and inter-observer and intra- enough confidence to rule out a disease. Therefore, the observer variability. Therefore, it is important to develop determination of high and low cutoff values should meet non-invasive diagnostic techniques for the diagnosis of liver these special requirements. fibrosis. Recommendations for the application of TE in noninvasive diagnosis of liver fibrosis Keywords: Transient elastography; Liver fibrosis; Diagnosis; Expert opinion. Abbreviations: AUC, area under receiver operating characteristics curve; AUROC, area under the receiver operating characteristic curve; CCI, Operational requirements Compensated Cirrhosis Index; CHB, chronic hepatitis B; LSM, liver stiffness measurement; NLR, negative likelihood ratio; NPV, negative predictive value; The operation of TE is mainly affected by obesity and narrow PLR, positive likelihood ratio; PPV, positive predictive value; TE, transient intercostal space. TE usually fails in patients with ascites. elastography. Received: 17 February 2014; Revised: 24 May 2014; Accepted: 30 May 2014 Operational failure or unreliable test results are indepen- q DOI of original article: 10.14218/JCTH.2014.00008. dently associated with operator experience of , 500 exam- Correspondence to: Jin-Lin Hou, Department of Infectious Disease and inations and patient characteristics of BMI . 30 kg/m2, age . Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou 52 years, female gender, hypertension, and type 2 dia- 510515, China. Email: [email protected]; Ji-Dong Jia, Liver Research Center, 10 Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China. betes. Abdominal obesity (abdominal circumference . Email: [email protected] 80 cm in women and . 90 cm in men) is also an independent
110 Journal of Clinical Translational Hepatology 2014 vol. 2 | 110–116 Expert Panel on Liver Stiffness Measurement: TE in the diagnosis of liver fibrosis risk factor for operational failure or unreliable results.11 In Diagnostic cutoff values patients with BMI o 28.0 kg/m2, and an abdominal circum- ference o 102 cm, an XL probe yields higher success rates A. Chronic hepatitis B: than the M probe.12–13 An XL probe can generate reliable The area under the receiver operating characteristic curve results in 51.6–61% of patients for whom the M probe is (AUROC) values for significant liver fibrosis (Metavir Fo2), 12–14 unable to obtain reliable detection results. The S probe is advanced liver fibrosis (Fo3), and cirrhosis (F54) due to suitable for patients with narrow intercostal space and chronic hepatitis B (CHB) were 0.78–0.87, 0.87–0.93, and children. However this probe is associated with significantly 0.84–0.96, respectively (Table 1).7,29–33 It is possible to higher failure rates in children under 5 years of age.15 It determine whether cirrhosis is present in more than 78% of remains to be determined whether there are differences in patients with normal bilirubin levels, and whether advanced the detection results obtained with the S probe or the M liver fibrosis is present in 80% of these patients. Increased probe. The reliability of LSM depends mainly on the ratio of bilirubin levels exert a significant impact on the diagnostic the interquartile range, and the median of detection values performance of TE: only 41% of patients can be identified as (IQR/M), where IQR/M f 0.10 suggests very reliable results, having cirrhosis, and 53% can be identified as having 0.10 , IQR/M f 0.30 or IQR/M . 0.30 with median LSM , advanced liver fibrosis.7,33 The diagnostic performance of 34 7.1 kPa suggests reliable results, and IQR/M . 0.30 and TE at cutoff values of 10.1 kPa (NLR 0.15 and PLR 7.3), median LSM o 7.1 kPa suggest unreliable results.16 12.9 kPa (PLR 7.33, NLR 0.52), 14.1 kPa (PLR 5.6, NLR 0.19), Recommendation 1: TE operators should receive standard and 11 kPa (PLR 7.3, NLR 0.28) is unsatisfactory for diagnosis training and have relatively constant annual volumes of cases of liver cirrhosis in patients with normal ALT levels,5,35–36 to ensure the reliability of test results. suggesting that the cutoff value for confirming cirrhosis Recommendation 2: The M probe should be the first choice should be higher than 14.1 kPa, and the cutoff value for for TE measurements. For overweight or obese patients from excluding cirrhosis should be less than 11 kPa. At cutoff whom TE cannot obtain reliable results, the XL probe may be values of 10.2 kPa and 8.1 kPa, NLR values were 0.15 and considered. The S probe may be considered for patients with 0.15, and PLR values were 9.0 and 4.6, respectively, for the narrow intercostal space or for children. diagnosis of advanced liver fibrosis,35–36 suggesting that the Recommendation 3: Test results must meet all the high cutoff value for advanced liver fibrosis should be slightly following conditions to be considered valid: at least 10 valid higher than 10.2 kPa, while the lower cutoff value should be tests, success rate . 60%, and IQR/M , 0.3. less than 8.1 kPa. Most cutoff values that help establish the diagnosis of significant liver fibrosis offer no clinical value due 5,29,34–36 Influencing factors to a PLR , 5.0 or NLR . 0.2. Recommendation 6: In patients with abnormal bilirubin LSM is influenced by factors such as hepatic necroinflamma- levels, LSM o 29.2 kPa suggests cirrhosis, LSM o 17.0 kPa tory activity (manifested as elevated levels of transaminases suggests advanced liver fibrosis, LSM , 9.1 kPa excludes or bilirubin),17–18 extrahepatic cholestasis,19–20 hepatic cirrhosis, and LSM , 7.8 kPa excludes advanced liver fibrosis. venous congestion,21–22 and food intake,23–24 and LSM Patients with LSM values in the grey zone can be measured decreases along with reductions in ALT and bilirubin again after bilirubin levels return to normal, using normal levels.17–18 bilirubin cutoffs for diagnosis, or will require liver biopsy. Recommendation 4: TE should be performed after fasting Recommendation 7: In patients with normal bilirubin or at least 2 hours postprandially, and ALT and bilirubin levels, LSM o 17.5 kPa suggests cirrhosis, LSM o 12.4 kPa levels should be considered to make a hierarchical diag- (10.6 kPa if ALT , 26 upper normal limit) suggests advanced nosis. Extrahepatic cholestasis and heart failure should be liver fibrosis, LSM , 10.6 kPa rules out cirrhosis, LSM o ruled out. 9.4 kPa suggests significant fibrosis, and LSM , 7.4 kPa rules out advanced liver fibrosis. If clinical decision-making is difficult for patients with LSM between 7.4–9.4 kPa, a liver Normal reference values biopsy should be considered. Recommendation 8: In patients with normal aminotrans- The normal reference ranges in healthy living liver donors ferase levels, LSM o 12.0 kPa suggests cirrhosis, LSM o and kidney donors in South Korea have been reported to be 9.0 kPa suggests advanced liver fibrosis, LSM , 9.0 kPa rules 3.7–7.0 kPa in men, and 3.3–6.8 kPa in women.25 Normal out cirrhosis, and LSM , 6.0 kPa rules out advanced liver LSM values of adult male residents without notable liver fibrosis. If clinical decision-making is difficult for patients disease in Guangdong have been found to vary with age with LSM between 6.0–9.0 kPa, a liver biopsy should be (age , 60 years: 5.2 ± 1.3 kPa; age 60 years: 5.9 ± o considered. 1.8 kPa).26 The normal reference range in a South Asia Given the significant impact of abnormal bilirubin levels on population was found to be 3.2–8.5 kPa, and lean or obese the diagnostic performance of TE, the measurement should people have higher values than those with normal BMIs.27 be performed when bilirubin levels return to normal, and The normal reference range in people with no significant interventions may be taken based on clinical virology data as liver disease in Hong Kong was found to be 2.8–7.4 kPa.28 shown in Fig. 1. Because the number of individuals with high BMI who develop fatty liver in the population is increasing, and it is B. Chronic hepatitis C: not grouped into the liver disease population, current normal The AUROC of LSM for hepatitis C cirrhosis is 0.90– reference values do not take into account for the impact of 0.972,5,37–39 (Table 2), which is better than that for other high BMIs. non-invasive diagnostic modalities of liver fibrosis including Recommendation 5: The normal reference range of LSM FibroTest, APRI, Lok index, platelet count, and AST/ALT should be 2.8–7.4 kPa. ratio.38 In a large sample study (n 5 913), the NLR and PLR
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Table 1. Data on cut-off values for liver fibrosis assessment by transient elastography (kPa) in Patients with Chronic Hepatitis B
Fibrosis stages Cutoff Sensitivity Specificity (Metavir) Authors (n) Stratification AUC value (%) NPV (%) NLR (%) PPV (%) PLR
29 F4 Marcellin (173) 0.93 11.0 93 99 0.08 87 38 7.0 18.2 57 96 0.44 97 67 19 30 Chan (161) Normal ALT 0.96 9.0 100 100 0 77 60 3.0 ora fCiia rnltoa Hepatology Translational Clinical of Journal 12.0 60 87 0.42 95 82 12.9 Abnormal ALT 0.94 8.4 96 98 0.07 54 40 2.1 13.4 75 92 0.27 93 78 11.1 7 Chen (315) Normal bilirubin 0.90 10.6 93 98 0.09 76 49 3.9 16.9 59 90 0.45 94 72 10.2
Abnormal bilirubin 0.84 9.1 100 100 0 47 48 1.9 fibrosis liver of diagnosis the in TE Measurement: Stiffness Liver on Panel Expert 29.2 23 0 0.73 98 88 14.7 31 Vigano (217) -9.4 98 -0.02 - -- 13.1 ---95 -14 32 Jia 0.90 17.5 60 95 0.43 93 55 8.91 29 Fo3 Marcellin (173) 0.93 8.1 86 95 0.16 85 65 5.7 10.5 72 91 0.29 95 84 14.4 30 Chan (161) Normal ALT 0.90 6.0 93 88 0.15 47 62 1.8 9.0 71 79 0.29 100 100 2014 Abnormal ALT 0.87 7.5 96 94 0.07 59 65 2.3 12.0 51 68 0.5 98 96 25.5
o.2|110–116 | 2 vol. 32 Jia 0.88 12.4 58 81 0.44 95 86 12.3 33 Chen (226) ALT,26ULN 0.92 7.4 92 93 0.11 73 72 3.4 10.6 82 81 0.19 92 88 10.5 ALTo26ULN 0.89 7.5 93 91 0.11 65 89 2.6 12.7 64 69 0.38 96 95 15.3 33 Fo2 Chen (226) 0.86 5.0 99 88 0.04 --- 9.8 ---95 97 11.0 31 Vigano (217) -6.2 94 -0.10 - -- 9.4 ---96 -14
AUC: area under receiver operating characteristics curve; NPV: negative predictive value, NLR, negative likelihood ratio; PPV, positive predictive value; PLR, positive likelihood ration Expert Panel on Liver Stiffness Measurement: TE in the diagnosis of liver fibrosis
Fig. 1 Transient elastography for diagnosis of patients with HBV virus infection at different stages of liver fibrosis were 0.31 and 6.77, respectively, at the recommended cutoff and the diagnostic cutoffs of the M probe differed by 1–2 kPa value of 12.9 kPa, suggesting the cutoff value for confirma- from those of the XL probe.13 tive diagnosis of cirrhosis should be higher than 12.9 kPa.5 At Recommendation 10: Advanced liver fibrosis may be a cutoff value of 14.6 kPa, the PLR was as high as 21.5, considered for patients with LSM o 9.8 kPa, and clinical confirming the diagnosis of cirrhosis. The cutoff values for intervention should be taken. Patients with LSM between 7.9– significant fibrosis suggested by a number of studies provide 9.8 kPa need to undergo liver biopsy to determine the stage insufficient evidence to confirm or exclude the diagnosis of of liver fibrosis. Patients with LSM , 7.9 kPa should receive significant fibrosis (Table 2), and the cutoff values for regular LSM monitoring and BMI reduction intervention. confirmative diagnosis of significant fibrosis should be higher Recommendations 11: The XL probe may be considered in than 7.1 kPa. patients who fail using the M probe, and the diagnostic cutoff Recommendation 9: LSM o 14.6 kPa suggests cirrhosis, value should be lowered by 1–2 kPa. whereas LSM , 9.3 kPa excludes cirrhosis. LSM o 9.3 kPa All the recommended diagnostic cutoff values for various suggests advanced liver fibrosis, whereas LSM ,7.3 kPa rules liver diseases are summarized in Table 3. out advanced liver fibrosis. LSM o 7.3 kPa suggests sig- nificant fibrosis. Prospects of clinical application of TE
C. Non-alcoholic fatty liver disease In the course of antiviral therapy, LSM decline does not solely The diagnostic performance of TE for advanced fibrosis reflect the reversal of liver fibrosis. It is also associated with and cirrhosis in non-alcoholic fatty liver is superior to AST/ALT decreased necroinflammation scores.41 Various antiviral ratio, APRI, FIB-4, BARD and NAFLD fibrosis scores, and other drugs may exert different effects on improving liver necroin- non-invasive serum markers, with AUROC values of TE for flammation, and further studies are needed to determine the oF2, oF3, and F4 liver fibrosis being 0.84, 0.93, and 0.95, cutoff values of TE for determining liver fibrosis stages in respectively. The NLR was 0.12 at a cutoff value of 7.9 kPa for patients receiving antiviral therapy. A large-scale, commu- the diagnosis of oF3 fibrosis, and 0.09 at a cutoff value of nity-based study that included 1190 patients over 45 years of 10.3 kPa for the diagnosis of cirrhosis. The PLR was 8.9 at a age showed that 89 patients with LSM . 8 kPa (of whom nine cutoff value of 9.6 kPa for thhe diagnosis of oF3 fibrosis.40 had LSM . 13 kPa) had a certain chronic liver disease, and Measured LSM valuses obtained with the XL probe are lower that liver biopsy confirmed the presence of liver cirrhosis in than those obtained with the M probe (6.8 kPa vs. 7.8 kPa),12 the nine patients with LSM . 13 kPa,42 suggesting that TE can
Journal of Clinical Translational Hepatology 2014 vol. 2 | 110–116 113 114
Table 2. Data-on cut-off value for liver fibrosis assessment by transient elastography (kPa) in Patients with Chronic Hepatitis B
Fibrosis stages Author Disease Cutoff Sensitivity NPV Specificity PPV (Metavir) (n) rate AUC value (%) (%) NLR (%) (%) PLR
37 F4 Castera (297) 23.6% 0.96 12.5 83 95 0.18 95 85 16.6 38 Ziol (251) -0.97 14.6 86 97 0.15 95 78 21.5 5 Degos (913) 13.8% 0.9 12.9 72.2 95.3 0.31 89.3 52 6.8 39 Ferraioli (195) 16.4% 0.97 12.3 81.3 96.3 0.2 95.7 78.8 18.9 ora fCiia rnltoa Hepatology Translational Clinical of Journal 9.3 93.8 98.7 0.07 92.0 69.0 11.8 39 oF3 Ferraioli (195) 26.1% 0.95 9.3 74.5 91.4 0.3 96.5 88.4 21.5 7.3 94.1 97.6 0.07 85.4 69.6 6.5 1 oF2 Castera (183) 74% 0.83 7.1 67 48 0.37 89 95 6.1 38 Ziol (251) -0.79 8.8 56 56 0.48 91 88 6.2 5 Degos (913) 28% 0.75 5.2 90 66 0.32 32 68 1.3 fibrosis liver of diagnosis the in TE Measurement: Stiffness Liver on Panel Expert 39 Ferraioli (195) 49.7% 0.86 6.9 69.1 74.6 0.34 89.8 87.0 6.8
AUC, area under receiver operating characteristics curve; NPV, negative predictive value; NLR, negative likelihood ratio; PPV, positive predictive value; PLR, positive likelihood ration
Table 3. Suggested cut-off values s for transient elastography according to disease
Diseases 2014 Causes Liver cirrhosis Advanced liver fibrosis Significant fibrosis o.2|110–116 | 2 vol. HBV Abnormal bilirubin levels LSM o 29.2 Yes LSM o 17.0 Yes – LSM , 9.1 No LSM , 7.8 No Normal bilirubin levels LSM o 17.5 Yes LSM o 12.4 Yes LSM o 9.4 Yes LSM , 10.6 No LSM , 7.4 No Normal aminotransferase levels LSM o 12.0 Yes LSM o 9.0 Yes – LSM , 9.0 No LSM , 6.0 NO HCV LSM o 14.6 Yes LSM o 9.3 Yes LSM o 7.3 Yes LSM , 9.3 No LSM , 7.3 No NAFLD – LSM o 9.8 # Yes –
HBV, hepatitis B virus; HCV, hepatitis C virus, NAFLD, non-alcoholic fatty liver disease; LSM, liver stiffness measurement; ‘‘—‘‘, no recommendation; #, the diagnostic cutoff value should be lowered by 1–2 kPa when XL probe was used in patients who fail with M probe Expert Panel on Liver Stiffness Measurement: TE in the diagnosis of liver fibrosis identify liver cirrhosis, and reveal previously undiagnosed formula for advanced liver fibrosis in chronic hepatitis B. Aliment Pharmacol chronic liver disease in the general population. The increase Ther 2010;31:1095–1103. doi: 10.1111/j.1365-2036.2010.04276.x. [5] Degos F, Perez P, Roche B, Mahmoudi A, Asselineau J, Voitot H, et al. in LSM is associated with higher risk of hepatocellular Diagnostic accuracy of FibroScan and comparison to liver fibrosis biomarkers carcinoma development,43–44 but there is no reliable cutoff in chronic viral hepatitis: a multicenter prospective study (the FIBROSTIC value for the prediction of hepatocellular carcinoma. The study). J Hepatol 2010;53:1013–1021. doi: 10.1016/j.jhep.2010.05.035. [6] Poynard T, Ngo Y, Munteanu M, Thabut D, Ratziu V. Noninvasive markers of AUROC of LSM for the prediction of hepatic decompensation is hepatic fibrosis in chronic hepatitis B. Curr Hepat Rep 2011;10:87–97. doi: 0.90–0.92, and the AUROC of LSM for the prediction of Child- 10.1007/s11901-011-0096-0. Pugh C cirrhosis is 0.91.45–46 However, further research is [7] Chen YP, Liang XE, Dai L, Zhang Q, Peng J, Zhu YF, et al. Improving transient required to establish the predictive value of LSM for the elastography performance for detecting hepatitis B cirrhosis. Dig Liver Dis 2012;44:61–66. doi: 10.1016/j.dld.2011.08.004. progression of liver disease. High-risk esophageal varices [8] Sebastiani G, Alberti A. Non-invasive fibrosis biomarkers reduce but not (moderate and severe grade, mild grade with liver decom- substitute the need for liver biopsy. World J Gastroenterol 2006;12:3682– pensation) require early clinical intervention to prevent 3694. bleeding. However, LSM offers limited value for prediction of [9]Manning DS, Afdhal NH. Diagnosis and quantitation of 47–48 fibrosis.Gastroenterology 2008;134:1670–1681. doi: 10.1053/j.gas- high-risk esophageal varices (AUROC, 0.71–0.73), and tro.2008.03.001. the combined use of LSM and other non-invasive indicators [10] Caste´ra L, Foucher J, Bernard PH, Carvalho F, Allaix D, Merrouche W, et al. seems to improve the predictive performance.47,49–50 Pitfalls of liver stiffness measurement: a 5-year prospective study of 13369 As TE measurements are affected by many factors, this examinations. Hepatology 2010;51:828–835. [11] Wong GL, Wong VW, Chim AM, Yiu KK, Chu SH, Li MK, et al. Factors technique may produce diagnoses inconsistent with other associated with unreliable liver stiffness measurement and its failure with diagnostic methods. For example, liver cirrhosis with mild transient elastography in the Chinese population. J Gastroenterol Hepatol necroinflammation can present a low LSM. When different 2011;26:300–305. doi: 10.1111/j.1440-1746.2010.06510.x. non-invasive diagnostic methods produce inconsistent diag- [12] Myers RP, Pomier-Layrargues G, Kirsch R, Pollett A, Duarte-Rojo A, Wong D, et al. Feasibility and diagnostic performance of the FibroScan XL probe for noses, abdominal ultrasography, platelet count, and other liver stiffness measurement in overweight and obese patients. Hepatology clinical data can also be analyzed to help establish a definite 2012;55:199–208. doi: 10.1002/hep.24624. diagnosis. For patients in whom a definite diagnosis cannot be [13] Wong VW, Vergniol J, Wong GL, Foucher J, Chan AW, Chermak F, et al. Liver stiffness measurement using XL probe in patients with nonalcoholic fatty reached due to TE values in the gray zone, serum biomarkers liver disease. Am J Gastroenterol 2012;107:1862–1871. may provide complementary diagnostic parameters. When [14] de Le´dinghen V, Wong VW, Vergniol J, Wong GL, Foucher J, Chu SH, et al. used in combination with TE, serum biomarkers, and imaging Diagnosis of liver fibrosis and cirrhosis using liver stiffness measurement: examinations (sequential or parallel diagnosis), the conse- comparison between M and XL probe of FibroScan. J Hepatol 2012;56:833– 839. doi: 10.1016/j.jhep.2011.10.017. quence of misdiagnosis or missed diagnosis should be [15] Engelmann G, Gebhardt C,Wenning D, Wu¨hlE, Hoffmann GF, Selmi B, et al. considered. Sequential measurements raises the sensitivity, Feasibility study and control values of transient elastography in healthy but may lead to higher misdiagnosis rates due to lower children. Eur J Pediatr 2012;171:353–360. specificity, whereas parallel measurements can increase [16] Boursier J, Zarski JP, de Ledinghen V, Rousselet MC, Sturm N, Lebail B, et al. Determination of reliability criteria of liver stiffness evaluation by transient specificity and increase diagnostic reliability, but may also elastography. Hepatology 2013;57:1182–1191. doi: 10.1002/hep.25993. increase the risk of missed diagnosis by reducing sensitivity. [17] Liang XE, Chen YP, Zhang Q, Dai L, Zhu YF, Hou JL, et al. Dynamic evaluation of liver stiffness measurement to improve diagnostic accuracy of liver Liver stiffness assessment expert panel: Zhuang Hui, cirrhosis in patients with chronic hepatitis B acute exacerbation. J Viral Hepat Hou Jinlin, Jia Jidong, Wei Lai, Ren Hong, Wang Guiqiang, Lu 2011;18:884–891. doi: 10.1111/j.1365-2893.2010.01389.x. Lungen, Fan Jiangao, Niu Junqi, Xie Qing, Ning Qin, Dou [18] Wong GL, Wong VW, Choi PC, Chan AW, Chim AM, Yiu KK, et al. Increased liver stiffness measurement by transient elastography in severe acute Xiaoguang, Li Jie, Ma Hong, You Hong, Shu Jianchang, and exacerbation of chronic hepatitis B. J Gastroenterol Hepatol 2009;24: Chen Yongpeng (secretary). 1002–1007. doi: 10.1111/j.1440-1746.2009.05779.x. [19] Harata M, Hashimoto S, Kawabe N, Nitta Y, Murao M, Nakano T, et al. Liver stiffness in extrahepatic cholestasis correlates positively with bilirubin and Conflict of interest negatively with alanine aminotransferase. Hepatol Res 2011;41:423–429. doi: 10.1111/j.1872-034X.2011.00797.x. None [20] Millonig G,Reimann FM, Friedrich S, Fonouni H, Mehrabi A, Bu¨chlerMW, et al. Extrahepatic cholestasis increases liver stiffness (FibroScan) irrespective of fibrosis. Hepatology 2008;48:1718–1723. doi: 10.1002/hep.22577. [21] Colli A, Pozzoni P, Berzuini A, Gerosa A, Canovi C, Molteni EE, et al. Author contributions Decompensated chronic heart failure: increased liver stiffness measuredby means of transient elastography. Radiology 2010;257:872–878. doi: Writing the paper (all authors). 10.1148/radiol.10100013. [22] Millonig G, Friedrich S, Adolf S, Fonouni H, Golriz M, Mehrabi A, et al. Liver stiffness is directly influenced by central venous pressure. J Hepatol 2010; References 52:206–210. doi: 10.1016/j.jhep.2009.11.018. [23] Mederacke I, Wursthorn K, Kirschner J, Rifai K, Manns MP, Wedemeyer H, et al. Food intake increases liver stiffness in patients with chronic or resolved [1] Caste´ra L, Vergniol J, Foucher J, Le Bail B, Chanteloup E, Haaser M, et al. hepatitis C virus infection. Liver Int 2009;29:1500–1506. doi: 10.1111/ Prospective comparison of transient elastography, Fibrotest, APRI, and liver j.1478-3231.2009.02100.x. biopsy for the assessment of fibrosis in chronic hepatitis C. Gastroenterology [24] Arena U, Platon ML, Stasi C, Moscarella S, Assarat A, Bedogni G, et al. Liver 2005;128:343–350. doi: 10.1053/j.gastro.2004.11.018. stiffness is influenced by a standardized meal in patients with chronic hcv [2] Shaheen AA, Wan AF, Myers RP. FibroTest and FibroScan for the predictionof hepatitis at different stages of fibrotic evolution. Hepatology 2013;58:65– hepatitis C-related fibrosis: a systematic review of diagnostic test accuracy. 72. doi: 10.1002/hep.26343. Am J Gastroenterol 2007;102:2589–2600. doi: 10.1111/j.1572- [25] Kim BK, Kim SU, Choi GH, Han WK, Park MS, Kim EH, et al. ‘‘Normal’’ liver 0241.2007.01466.x. stiffness values differ between men and women: a prospective study for [3] Kim SU, Ahn SH, Park JY, Kang W, Kim do Y, Park YN, et al. Liver stiffness healthy living liver and kidney donors in a native Korean population. measurement in combination with noninvasive markers for the improved J Gastroenterol Hepatol 2012;27:781–788. doi: 10.1111/j.1440- diagnosis of B-viral liver cirrhosis. J Clin Gastroenterol 2009;43:267–271. 1746.2011.06962.x. doi: 10.1097/MCG.0b013e31816f212e. [26] Chen YP, Liang XE, Zhang Q, Dai M, Hou JL. Age influencing liver stiffness [4] Wong GL, Wong VW, Choi PC, Chan AW, Chan HL. Development of a non- measurements in Chinese male general populations. J Hepatol 2010;52: invasive algorithm with transient elastography (Fibroscan) and serum test S162. doi: 10.1016/S0168-8278(10)60397-2.
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[27] Das K, Sarkar R, Ahmed SM, Mridha AR, Mukherjee PS, Das K, et al. ‘‘Normal’’ patients with chronic hepatitis C. Hepatology 2005;41:48–54. doi: 10.1002/ liver stiffness measure (LSM) values are higher in both lean and obese hep.20506. individuals: a population-based study from a developing country. Hepatology [39] Ferraioli G,Tinelli C, Dal Bello B, Zicchetti M, Lissandrin R, Filice G, et al. 2012;55:584–593. doi: 10.1002/hep.24694. Performance of liver stiffness measurements by transient elastography in [28] Wong GL, Chan HL,Choi PC, Chan AW, Lo AO, Chim AM, et al. Association chronic hepatitis. World J Gastroenterol 2013;19:49–56. between anthropometric parameters and measurements of liver stiffness by [40] Wong VW, Vergniol J, Wong GL, Foucher J, Chan HL, Le Bail B, et al. Diagnosis transient elastography. Clin Gastroenterol Hepatol 2013;11:295–302. doi: of fibrosis and cirrhosis using liver stiffness measurement in nonalcoholic 10.1016/j.cgh.2012.09.025. fatty liver disease. Hepatology 2010;51:454–462. doi: 10.1002/hep.23312. [29] Marcellin P, Ziol M, Bedossa P, Douvin C, Poupon R, de Le´dinghen V, et al. [41] Wong GL, Wong VW, Choi PC, Chan AW, Chim AM, Yiu KK, et al. On-treatment Non-invasive assessment of liver fibrosis by stiffness measurement in monitoring of liver fibrosis with transient elastography in chronic hepatitis B patients with chronic hepatitis B. Liver Int 2009;29:242–247. doi: patients. Antivir Ther 2011;16:165–172. doi: 10.3851/IMP1726. 10.1111/j.1478-3231.2008.01802.x. [42] Roulot D, Costes JL, Buyck JF, Warzocha U, Gambier N, Czernichow S, et al. [30] Chan HL, Wong GL, Choi PC, Chan AW, Chim AM, Yiu KK, et al. Alanine Transient elastography as a screening tool for liver fibrosis and cirrhosis in a aminotransferase-based algorithms of liver stiffness measurement by community-based population aged over 45 years. Gut 2011;60:977–984. transient elastography (Fibroscan) for liver fibrosis in chronic hepatitis B. J doi: 10.1136/gut.2010.221382. Viral Hepat 2009;16:36–44. doi: 10.1111/j.1365-2893.2008.01037.x. [43] Masuzaki R, Tateishi R, Yoshida H, Goto E, Sato T, Ohki T, et al. Prospective [31] Vigano`M, Paggi S, Lampertico P, Fraquelli M, Massironi S, Ronchi G, et al. risk assessment for hepatocellular carcinoma development in patients with Dual cut-off transient elastography to assess liver fibrosis in chronic hepatitis chronic hepatitis C by transient elastography. Hepatology 2009;49:1954– B: a cohort study with internal validation. Aliment Pharmacol Ther 2011;34: 1961. doi: 10.1002/hep.22870. 353–362. doi: 10.1111/j.1365-2036.2011.04722.x. [44] Jung KS, Kim SU, Ahn SH, Park YN, Kim do Y, Park JY, et al. Risk assessment [32] Jia JD, Hou JL, Ding HG, Chen JM, Xie Q, Wang YM, et al. Liver stiffness of hepatitis B virus–related hepatocellular carcinoma development using measured by transient elastography can predict liver fibrosis in Chinese liver stiffness measurement (FibroScan). Hepatology 2011;53:885–894. patients with chronic hepatitis B. Hepatol Int 2010;4:22. doi: 10.1002/hep.24121. [33] Chen YP, Liang XE, Zhang Q, Peng J, Zhu YF, Wen WQ, et al. Larger biopsies [45] Foucher J, Chanteloup E, Vergniol J, Caste´ra L, Le Bail B, Adhoute X, et al. evaluation of transient elastography for detecting advanced fibrosis in Diagnosis of cirrhosis by transient elastography (FibroScan): a prospective patients with compensated chronic hepatitis B. J Gastroenterol Hepatol study. Gut 2006;55:403–408. doi: 10.1136/gut.2005.069153. 2012;27:1219–1226. doi: 10.1111/j.1440-1746.2012.07122.x. [34] Kim SU, Kim do Y, Park JY, Lee JH, Ahn SH, Kim JK, et al. How can we enhance [46] Chen YP, Liang XE, Zhang Q, Dai L, Peng J, Hou JL. Transient elastography the performance of liver stiffness measurement using FibroScan in diagnos- accurately predicts the severity of disease in patients with chronic hepatitis ing liver cirrhosis in patients with chronic hepatitis B? J Clin Gastroenterol B. Chin J Intern Med 2011;50:758–762. (in Chinese) 2010;44:66–71. doi: 10.1097/MCG.0b013e3181a95c7f. [47] Chen YP, Zhang Q, Dai L, Liang XE, Peng J, Hou JL. Is transient elastography [35] Kim BK, Kim SU, Kim HS, Park JY, Ahn SH, Chon CY, et al. Prospective valuable for high-risk esophageal varices prediction in patients with validation of FibroTest in comparison with liver stiffness for predicting liver hepatitis-B-related cirrhosis? J Gastroenterol Hepatol 2012;27:533–539. fibrosis in Asian subjects with chronic hepatitis B. PLoS One 2012;7:35825. doi: 10.1111/j.1440-1746.2011.06889.x. doi: 10.1371/journal.pone.0035825. [48] Pineda JA, Recio E, Camacho A, Macı´as J, Almodo´var C, Gonza´lez-Serrano M, [36] Cardoso AC, Carvalho-Filho RJ, Stern C, Dipumpo A, Giuily N, Ripault MP, et al. Liver stiffness as a predictor of esophageal varices requiring therapy in et al. Direct comparison of diagnostic performance of transient elastography HIV/hepatitis C virus-coinfected patients with cirrhosis. J Acquir Immune in patients with chronic hepatitis B and chronic hepatitis C. Liver Int 2012; Defic Syndr 2009;51:445–449. doi: 10.1097/QAI.0b013e3181acb675. 32:612–621. doi: 10.1111/j.1478-3231.2011.02660.x. [49] Wang JH, Chuah SK, Lu SN, Hung CH, Chen CH, Kee KM, et al. Transient [37] Caste´ra L, Le Bail B, Roudot-Thoraval F, Bernard PH, Foucher J, Merrouche W, elastography and simple blood markers in the diagnosis of esophageal et al. Early detection in routine clinical practice of cirrhosis and oesophageal varices for compensated patients with hepatitis B virus-related cirrhosis. varices in chronic hepatitis C: comparison of transient elastography J Gastroenterol Hepatol 2012;27:1213–1218. doi: 10.1111/j.1440- (FibroScan) with standard laboratory tests and non-invasive scores. 1746.2012.07132.x. J Hepatol 2009;50:59–68. doi: 10.1016/j.jhep.2008.08.018. 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116 Journal of Clinical Translational Hepatology 2014 vol. 2 | 110–116 Review Article
Maternal-Fetal Hepatitis E Transmission: Is It Underestimated?
Maysaa El Sayed Zaki1, Mohammed Magdy Abd El Razek2 and Hassan Magdy Abd El Razek1
1Clinical Pathology, Mansoura Faculty of Medicine, Egypt; 2Mansoura University Hospital, Egypt
Abstract in only 1% to 2% of cases, whereas for person-to-person transmission in hepatitis Ait is 15%.18 Transplacental trans- Hepatitis E virus (HEV) is an enterically transmitted virus; and mission of HEVin the third trimester of pregnancy has been several modes of transmission have been proposed, including described; and in affected newborns it is associated with a blood transfusion, person to person transmission, and high perinatal mortality.19,20 transplacental transmission. HEVduring pregnancy is asso- HEVis considered an enterically transmitted self-limiting ciated with an unfavorable prognosis for mothers and in acute viral hepatitis. It also has been reported to cause acute severe cases can cause acute fulminate hepatitis and death. viral hepatitis, especially among travelers to endemic areas, Transplacental transmission of HEVusually results in unfa- and to cause a small percentage of sporadic fulminant hepatic vorable outcomes of pregnancy, mainly fetal loss, preterm failure (FHF) in persons without history of travel to endemic labor, and hepatic dysfunction in neonates. In this review, we areas. Overall, serological studies highlight a global distribu- will summarize the effects of HEVon maternal-fetal health in tion of this virus.16 various clinical situations. E 2014 The Second Affiliated Hospital of Chongqing Medical Hepatitis E in pregnancy University. Published by XIA & HE Publishing Ltd. All rights reserved. The course of Hepatitis E in pregnancy is different than the mild self constraining infection described in other popula- Introduction tions. Hepatitis E has both a high prevalence and rigorous course in pregnant women in some geographic regions of HEV 21,22 Hepatitis E virus (HEV) is a small RNA virus responsible for endemic countries, such as Northern India. However, in hepatitis E. HEVis a spherical, non-enveloped, single Egypt, an HEVendemic country, it has been shown to have a 23 stranded, positive-sense 59-capped RNA of 7.2 kb. It consists benign course with little or no morbidity. Similar findings of short 59 and 39 untranslated regions (UTRs) and three were shown in pregnant women in western countries, where partially overlapping open reading frames (ORF) called ORF1, they suffer less morbidity and mortality. HEVinfection during ORF2, and ORF3.1 There are five known major genotypes of pregnancy could result in rigorous complications, which may HEV, and they differ according to geographical distribution. lead to fetal and/or maternal mortality, abortion, premature Genotype I includes Asian (India, Burma, Nepal, China- distribution, or death of a live-born baby soon after birth. The Xinjiang, Pakistan) strains2–8 and African (Chad, Algeria, severity of the complications depends on the rigor of the 9–12 infection, stratified as acute viral hepatitis (AVH) or acute Tunisia, Morocco, Egypt, Namibia) strains, genotype II 24,25 includes US and Japanese strains,13 genotype III includes liver failure (ALF). Mexican and African (Nigeria) strains,14,15 genotype IV(4) In a large-scale prospective study from Northern India on includes Chinese (Shanga) and Japanese strains,13 and maternal and fetal outcomes of HEV, approximately 60% of genotype V(5) includes European strains. 14,15 The disease viral hepatitis in pregnant women was due to HEVinfection. is endemic in large parts of developing countries in Asia, Moreover, FHF was more likely among HEV-infected women 16 (55%), who were at 2.7 time’s greater risk than non-HEV Africa, and Latin America. infected women (20%). Maternal mortality secondary to FHF Contamination of drinking water is the most common was higher in the HEVinfected group (41%) compared to the mode for the spread of HEV. Studies indicate that hepatitis E non-HEVgroup (7%). 22 may be a zoonotic disease with pigs and rats serving as In addition, sporadic HEVinfection is associated with reservoirs for human infection.17 Person-to-person transmis- incremented incidence and astringency in pregnant women. sion of HEVbetween family members has been documented HEValone contributed to a subset of patients with acute viral hepatitis all over the world. Importantly, prevalence and the Keywords: Hepatitis E virus; Vertical transmission; Prevention. astringency of HEVinfection in pregnant women did not differ Abbreviations: ALF, acute liver failure; AVH, acute viral hepatitis; CDC, Center significantly in various stages of gestation.26 However, it was for Disease Control; FDA, Food and Drug Administration; FHF, fulminant hepatic failure; HBV, hepatitis B virus; HEV, hepatitis E virus; Ig, immunoglobulin; ORF, reported that high mortality was associated with infection in open reading frame; UTR, untranslated region. the third trimester.26 In one case of second trimester ascites Received: 28 January 2014; Revised: 3 March 2014; Accepted: 6 March 2014 q due to fetal HEVinfection, the ascites resolved in utero, and DOI of original article: 10.14218/JCTH.2014.00006. healthy infant was born at 38 weeks of gestation.27,28 Correspondence to: Maysaa El SayedZaki, Clinical Pathology, Mansoura Faculty of Medicine, El Gomhoria street, Mansoura 35516, Egypt. Tel: +20-502258877, Incremented maternal and fetal mortality has been Fax: +20-502247042, Email:[email protected] reported by many groups, mainly from developing countries.
Journal of Clinical and Translational Hepatology 2014 vol. 2 | 117–123 Zaki M.E. et al.: Hepatitis E, pregnancy
Poor prenatal care and maternal nutrition appear to have outcomes were seen in other studies. Newborn babies of contributed significantly to the incremented astringency of infected mothers developed a syndrome of fatal FHF, and this infection in these countries.29 syndrome occurred in some babies with anicteric hepati- In Egypt, where prevalence of anti-HEVin rural commu- tis.20,22 We could not find any reports of assiduous HEV nities is very high, rigorous HEV-caused AVH in pregnant infection in infants born to mothers with hepatitis E. This is women has not been reported. In one study, the anti-HEV consistent with the natural history of hepatitis E infection in prevalence in a series of pregnant women was 84%, with no adults, where, by convention, it occurs in a self-circumscrib- evidence for AVH.30 The differences in the outcome of HEVin ing pattern.39 Although chronic HEVinfections have been different geographical areas could be the result of early reported primarily in immunosuppressed and immunocom- childhood immunity acquired from HEVexposures that may promised populations,39–57 there are no reports of chronic modify subsequent exposure to the virus. Alternatively, the HEVinfection in pregnant women or infants. Theoretically, predominant HEVgenotypes in Egypt may be less virulent than among immunocompromised pregnant women or neonates, those in Asia.30,31 The studies from developed countries differ such infections could occur. Pregnant women may be coin- over maternal-fetal outcomes of pregnancy associated with fected with other hepatotropic pathogens,58–65 but how such viral hepatitis. The pregnancy state associated with hepatitis E coinfections influence vertical HEVtransmission and out- has not been linked to rigorous course with adequate nutrition. comes has not yet been studied. The astringency of HEV This is in contrast to the clinical course of hepatitis B virus infection in the mother and baby may be linked. Findings from (HBV) infection acquired perinatally by neonates. This is likely an anterior study suggested that fetal disease influenced the due to the different pathogenic effects of both viruses. Liver course of maternal HEVinfection and provided a clear injury is caused by immune replication of the host against the relationship between FHF of the fetus and mother.54 pathogen in hepatitis B,32 whereas liver injury in HEVis related Tables 1 and 2 summarize the different incidence of HEV to direct cytopathogenic alterations in liver cells.33 infection in pregnancy and vertical transmission. There is a relationship between HEVgenotype and the unpropitious effects of HEVinfection in pregnancy. Hepatitis E Pathogenesis of hepatitis E in pregnancy caused by HEVgenotype 1 has consistently been observed to engender these negative effects in pregnancy. Although HEV Diminished cellular immunity, manifested by decreased genotype 2 was implicated in acute liver failure in a pregnant CD4,increased CD8, and reduced CD4/CD8 ratio, may be woman during an outbreak in Namibia,34 the potential of the leading cause of astringency of HEVinfection during genotypes 2–4 to cause adverse outcomes in pregnant pregnancy.65 Moreover, increased levels of steroid that women, given exposure, remains controversial. influence viral replication and expression may cause the rigor of HEVinfection. Steroid hormones are immunosuppressive Hepatitis E vertical transmission and mediate lymphocyte apoptosis through NF-kB. NF-kBisa dimeric transcription factor that has varied roles in liver There is emerging concerns from epidemiologic and clinical development, liver regeneration, and immune replication.28 studies suggesting that vertical transmission of HEVmay When HEVinfection occurs, a cytotoxic immune replication occur frequently from infected mothers and contribute to (Th1) may be elicited in Th2 partial pregnant women. FHF is poor perinatal health outcomes in addition to the effects of always associated with high HEVviral load, leading to maternal morbidity and mortality.34 vigorous Th1 replication. If this elevated Th1 immune The risk of vertical transmission of HEVinfection from replication remains inadequate to control a high viral load, it mother to infant was 100% in an antecedent study of a series is possible that Th1 replication will increase but that cytotoxic of pregnant women. There may, however, have been selec- immune replication may result in reduced fetal defenses and tion errors. The babies born to mothers with active disease eventually fetal death.29 either were either preterm or had anicteric hepatitis. This It has been theorized that fetal infection in the uterus may high transmission rate denotes the importance of vertical itself leads to adverse maternal outcomes.54 Such upside- transmission of HEVinfection. 35 In another study, vertical down vertical effects have been posited to occur with other transmission of HEVwas in 33% of newborns born to infected viral infections as well in animal models.66 For example, it women in the third trimester of pregnancy. HEVinfection was was demonstrated in a murine model of herpes infection that determined with detection of HEV-RNA or immunoglobulin fetal inflammatory replications to viral replication in the (Ig)M anti-HEVantibodies. 36,37 placenta may predispose the mother to morbidity and reduce Vertically transmitted HEV infection is known to cause the mother’s capacity for sustaining the pregnancy.67,68 A acute hepatitis in neonates, but the clinical course and prior study highlighted that hormone receptor mitigated duration of viremia is unclear.38 HEVin neonates is self- inflammatory replications at the fetomaternal interface could constraining and does not run a chronic or prolonged clinical affect pregnancy outcomes in human hepatitis E.69 Fig. 1 course. This finding is consistent with another study by summarizes the outcome of HEVinfection during pregnancy Khuroo et al., 2009 that found HEV-infected neonates at birth associated with different immune responses and HEVgeno- survived when the infection cleared.38 The clinical profile of types. HEVinfected babies customarily varies from elevated liver enzymes alone, elevated bilirubin alone, and combination Laboratory diagnosis of hepatitis E elevated bilirubin and elevated liver enzymes. Elevated bilirubin (unconjugated) could be due to physiological jaun- During acute HEVinfection, serological studies showed that dice, which occurs in neonates. However, a pattern of serum anti-HEVIgM becomes detectable days before the onset of bilirubin (commixed pattern) identified in three babies from symptoms and vanishes over a 4–6 month period.70 Anti- this study was inconsistent with physiological jaundice and HEVIgG appears soon after the IgM replication and may more consistent with an HEVinfection. Nevertheless, fatal persist for up to 12 years after infection.71 Fig. 2 summarizes
118 Journal of Clinical and Translational Hepatology 2014 vol. 2 | 117–123 Zaki M.E. et al.: Hepatitis E, pregnancy
Table 1. Incidence of HEV infection in pregnancy and its consequences
HEVpregnancy incidence Severity Mortality Patra et al.,23 2007-India Among 200 pregnant women -Fulminant hepatic failure Maternal mortality was greater screened for HEV, 60% of (FHF) (relative risk, 6.0 [CI, 2.7 to them had positive markers -Obstetric complications 13.3]; P , 0.001) for HEV. weremore common, such as antepartum hemorrhage, intrauterine fetal death, and preterm delivery Stoszek et al.,31 2006-Egypt Anti-HEVscreening among No clinical disease No mortality 2,428 women was 84% Khuroo&Kamili,39 2009-India HEVin 205 (49.6%) FHF, cerebral edema, and dis- FHF died [25 (53.2%) pregnant seminated intravascular coagu-women and 25 (69.5%) non- lation pregnant women (P50.06)]. Tsega et al.,27 1993-Ethiopia 19(59%) of 34 pregnant FHF Maternal death with FHF women had HEVinfection Premature deliveries as a direct result of acute viral hepatitis Kumar et al.,36 2001-United Out of 469 mothers, 93 (20%) FHF, non-fulminant acute Fetal outcomes with FHF Arab Emirates were anti-HEVpositive and 28 viral hepatitis (30%) were HEV-RNA positive and symptomatic with on-going infection. Rayis et al.,41 2013-Sudan 38 pregnant women with FHF, post partum hemorrhage, Maternal deaths due FHF with outbreaks intrauterine fetal death hepatic encephalopathy was the most common cause of death among these patients. Zaki et al.,38 2013-Egypt HEVIgG (31%) in 29 Mild hepatic disorders No death
Table 2. Vertical transmission of HEV from infected mother to neonates and its consequences
Consequences of vertical hepatitis E Frequency of transmission from affected transmission mother to neonate Kumar et al.,36 2001 Acute viral hepatitis with complete recov- 100% ery, limited early neonatal deaths Kumar et al.,37 2004 Preterm birth 33% Zaki et al.,38 2013 Respiratory distress syndrome 33% preterm birth sepsis Hepatosplenomegaly Khuroo et al.,39 2009 icteric hepatitis, 79% anicteric hepatitis, and neonatal death All surviving babies had self-limiting dis- ease and none had prolonged viremia. Khuroo et al.,21 1995 Icteric neonatal hepatitis, - non icteric neonatal hepatitis, hypothermia, and hypoglycaemia and died within 24 h; massive hepatic necrosis. Patra et al.,23 2007 Intrauterine fetal death - Still birth Preterm Rayis et al.,41 2013 Intrauterine fetal death - Preterm
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the virological markers and clinical symptoms in the weeks after infection. This figure is a modification of one from the Center for Disease Control (CDC). Several commercial assays are available internationally; however, no assay is currently approved by the US Food and Drug Administration (FDA). In addition to serological assays, nucleic acid amplification methods can be used to identify HEVRNA both in the blood and stool of infected individuals. In a human volunteer experiment, HEVRNA was detectable in blood at the apex of eccentric liver function tests starting from two weeks before and up to one week after onset of jaundice. HEVRNA appeared in stool later than in blood and vanished from stool within two weeks after it became undetectable in blood.72 Fig. 3 summarizes laboratory pro- cedures used in the diagnosis of HEV.
HEV therapeutic modalities
To date, there are no efficient treatments for hepatitis E in pregnancy. Experimental use of ribavirin to treat acute hepatitis has promising results in non-pregnant patients,73– 75 but unfortunately, this drug is contraindicated in pregnancy because of consequential embryocidal and/or teratogenicef- fects.76 Several researchers have suggested that early induced distribution or even pregnancy termination may be considered to preserve the life of the mother.54,77 However, this line of treatment to avert death in women who present with astringent disease has not been studied systematically. Given the high rate of miscarriage, stillbirth, and premature distribution in pregnancies affected by astringent hepatitis E, the net impact of such a strategy on neonatal morbidity and mortality is questionable.
HEV aversion and control strategies
Aversion measures typically involve amelioration of unsanitary conditions and provision of safe to drink water.Efforts to reduce Fig. 1. Effects of HEV infection in pregnancy person-to-person transmission of HEVneeds to focus on hand
Fig. 2. Appearance of virological markers and symptoms of HEV infection according to weeks after infection.
120 Journal of Clinical and Translational Hepatology 2014 vol. 2 | 117–123 Zaki M.E. et al.: Hepatitis E, pregnancy
Author contributions
Conception and designing of the article, acquisition of data, analysis and interpretation of data (MESZ); drafting the article or revising (MMAER, H,AER).
References
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Journal of Clinical and Translational Hepatology 2014 vol. 2 | 117–123 123 Review Article
Management of Hepatitis C Before and After Liver Transplantation in the Era of Rapidly Evolving Therapeutic Advances
Chalermrat Bunchorntavakul1 and K. Rajender Reddy2
1Division of Gastroenterology and Hepatology, Department of Medicine, Rajavithi Hospital, College of Medicine, Rangsit University, Bangkok, Thailand; 2Hospital of the University of Pennsylvania, University of Pennsylvania, Philadelphia, PA, USA
Abstract to have a neutral or small beneficial impact on HCV recurrence. Donor interleukin 28 B (IL28B) polymorphisms Management of hepatitis C (HCV) in liver transplantation (LT) appear to impact the course and treatment outcomes in population presents unique challenges. Suboptimal graft recurrent HCV. Retransplantation should be considered for survival in HCV+ LT recipients is attributable to universal patients with reasonable survival probability. HCVrecurrence following LT. Although eradication of HCV E 2014 The Second Affiliated Hospital of Chongqing Medical prior to LT is ideal for the prevention of HCVrecurrence it is University. Published by XIA & HE Publishing Ltd. All rights often limited by adverse events, particularly in patients with reserved. advanced cirrhosis. Antiviral therapy in LT candidates needs careful monitoring, and prophylaxis with HCVantibodies is Introduction ineffective. Early antiviral therapy after LT has been investi- gated, but no clear benefit has been demonstrated. Protocol Chronic hepatitis C virus (HCV) infection is the leading cause liver biopsy is generally recommended in HCV+ LT recipients, of cirrhosis and hepatocellular carcinoma (HCC) worldwide. and antiviral therapy can be considered in those with severe/ As a consequence, it is the most common indication for liver progressive HCVrecurrence. Sustained virological response transplantation (LT) in the United States, Japan, and many (SVR) can be achieved in approximately 30% of LT recipients countries in Europe. Despite advances in anti-viral therapy, with pegylated interferon/ribavirin (PEG-IFN/RBV) with sur- current estimates indicate that the prevalence of HCVand its vival benefit, but adverse effects are common. Favorable associated complications will continue to rise over the next patient characteristics for response to therapy include non-1 two decades.1,2 RecurrenceofHCVintheallograftis genotype, previously untreated, low baseline HCV-RNA, and universal, occurring soon after liver transplantation, and donor IL28B genotype CC. Direct acting antiviral (DAA)- may be associated with accelerated progression to cirrhosis, based triple therapy is associated with higher rates of SVR, graft loss, and death.2,3 Therefore, management of chronic but with similar or slightly higher rates of side effects, and HCVinfection before and after LT is an important component immunosuppressive regimens need to be closely monitored of current and future clinical practice. and adjusted during the treatment period. Notably, the safety Current approaches to the management of HCVpatients and efficacy of HCVtreatment are very likely to improve with before and after LT fall into four broad categories based on the newer generation DAA. The benefit of immunosuppressive time of intervention: (1) treatment of patients with cirrhosis strategy on the natural history HCVrecurrence has not been awaiting LT; (2) prophylaxis defined as initiation of therapy at well elucidated. Based upon available evidence, cyclosporine the time of LTand continued post-LTwith the goal of preventing A (CSA), mycophenolate mofetil (MMF), and sirolimus appear recurrent infection; (3) early post-LT (within the first 6 months after LT); and (4) HCVtherapy for established disease. 4 Keywords: Hepatitis C; Liver transplantation; Prevention; Treatment; The overall outcome of antiviral therapy in this setting is Interferon; Protease inhibitors; Immunosuppression. suboptimal; however, it can be successfully utilized in Abbreviations: ACR, acute cellular rejection; AIH, autoimmune hepatitis; ATG, selected populations with careful monitoring. Unique chal- anti-thymocyte globulin; AUC, area under the curve; BOC, boceprevir; CR, lenges and issues in the LT population in the context of HCV chronic rejection; CSA, cyclosporine A; CTP, Child-Turcotte-Pugh; DAA, direct acting antivirals; EVR, early virological response; HCC, hepatocellular carcinoma; therapy include the tolerability of pegylated-interferon (PEG- HCIG, hepatitis C immunoglobulins; HCV, hepatitis C virus; IMPDH, inosine IFN) and ribavirin (RBV) and more recently of the direct monophosphate dehydrogenase; LADR, low accelerating dosage regimen; LT, acting antivirals (DAA), the need to modify immunosuppres- liver transplantation; MELD, Model of End-stage Liver Disease; MMF, mycophe- sive regimens during DAA therapy because of drug-drug nolate mofetil; mTOR, mammalian target of rapamycin; PEG-IFN, pegylated interferon; RBV, ribavirin; RT, retransplantation; RV R, rapid virological response; interactions, the risk of graft rejection, and the role of genetic SVR, sustained virological response; TK, terminal elimination half-life; TAC, polymorphisms on response to therapy.5 tacrolimus; TVR, telaprevir; UNOS/SRTR, United Network of Organ Sharing/ Scientific Registry of Transplant Recipients. Received: 01 January 2014; Revised: 13 February 2014; Accepted: 20 February Natural history of hepatitis C before and after LT 2014 q DOI of original article: 10.14218/JCTH.2014.00002. Approximately 15–20% of patients with HCV-related cirrhosis Correspondence to: K. Rajender Reddy, 2 Dulles, 3400 Spruce Street, Hospital of the University of Pennsylvania, Philadelphia, PA 19104, USA. Tel: +1-215-662- evolve to hepatic decompensation and/or develop HCC 6 4311, E-mail: [email protected] within 10 years. If these complications are left untreated,
124 Journal of Clinical and Translational Hepatology 2014 vol. 2 | 124–133 Bunchorntavakul C. et al.: Hepatitis C before and after liver transplantation prognosis is poor and these patients will require LT as a life- within 10 years and approximately 50% developing liver saving procedure. In addition, graft and patient survival are failure shortly thereafter (Fig. 1).2–6,11 significantly reduced in HCV-positive recipients compared to A subset of patients (2–9%) may develop post-LT chole- HCV-negative recipients, a difference mainly accounted for by static hepatitis C, which is characterized by persistent recurrence of HCVinfection in the graft. 7 HCVrecurrence is cholestasis of at least 4 weeks in duration, high HCV-RNA, almost universal and its severity depends on several host, hepatocyte ballooning, rapid progression to graft failure, and, viral, donor, and transplant factors (Table 1).2,8–10 in the absence of biliary and hepatic artery complications, 12 Following LT, the liver graft is re-infected upon reperfusion, sepsis and drug-related cholestasis. This complication is and is accompanied by a rise in HCVviral load that peaks usually resistant to antiviral therapy and leads to death in around 3–4 months. Most patients develop features of acute more than 50% of patients within the first year after LT; hepatitis between 4 and 12 weeks after LT.4 Though serum retransplantation (RT) is associated with poor out- 2,12,13 transaminases and HCV-RNA generally settle down to normal comes. or near normal range, spontaneous viral clearance has not Due to the lack of sensitivity and specificity of serum been observed.2–4 At the end of the first year, HCV-RNA levels transaminases in determining the severity of recurrent are, on an average, 10-20-fold higher than pre-LT levels. hepatitis, HCVrecipients ideally should undergo protocol liver Histological evidence of chronic hepatitis C is encountered in biopsies in order to determine disease severity and prognosis 50–80% of patients after 6–12 months.2,3,11 The natural starting from around 6–12 months and then annually following LT. Early post-LT histology has been consistently course of hepatitis C is accelerated in liver transplant 2,3 recipients, with more than 40% progressing to cirrhosis predictive of subsequent fibrosis progression. Several preliminary studies have suggested that non-invasive mar- kers, especially transient elastography, correlated well with Table 1. Factors associated with an increased incidence and/or increased the degree of graft fibrosis and outcomes in HCV+ LT severity of recurrence in HCV following liver transplantation recipients.14–17 A recent study of 144 HCV-infected and 48 Risk factors for severe HCVrecurrence non-HCV-infected LT recipients reported that the liver stiff- ness measurement at one year after LT is a valuable predictor Pre-transplant factors of liver-related outcomes in recurrent HCV(cumulative Host factors probabilities of liver decompensation five years after LT were 8% for patients with liver stiffness measurement ,8.7 kilo- # Advanced age (.50 years) pascals versus 47% for patients with o 8.7 kilopascals; # Reduced immune responses (T-cells, natural killer p , 0.001) and can be used in clinical practice to identify cells) the best candidates for antiviral therapy.18 This tool can be # Non-CC IL28B genotypes very useful as an alternative or complementary test to * # Cryoglobulinemia invasive protocol biopsies for monitoring post-LT recurrent hepatitis C and to identify the best candidates for antiviral Viral factors therapy. However, studies with a longer follow-up period and # Genotype 1 larger sample size are needed to confirm these preliminary # High HCV-RNA levels results. Nevertheless, the decision to intervene therapeuti- # HIVco-infection cally has varied across centers and is mostly tailored to the severity of liver disease, although a strategy to treat all with Donor factors any degree of recurrent hepatitis has also been pursued.
# Advanced donor age (.35 years) # Liver steatosis Management of hepatitis C before and after LT # Non-CC IL28B genotypes # HLA mismatch* The goal of HCVmanagement in the setting of LT is to prevent # High liver iron concentration* or cure recurrent HCVdisease. Current approaches can be divided into four broad categories according to the time of 4 Transplant factors intervention (Fig. 2).
# Prolonged cold ischemic time (.12 hours) Management of hepatitis C in LT candidates # Preservative injury Management of patients with HCVcirrhosis awaiting LT aims Post-transplant factors to attain sustained virological response (SVR), slow liver # Early / high HCV-RNA levels disease progression, and prevention of liver graft infection. # Rejection episode(s) Successful viral eradication in patients with cirrhosis inde- # Corticosteroids: pulse therapy, high accumulation pendently reduces the likelihood of clinical decompensation dose, early/ rapid withdrawal and improves survival, which may then facilitate, delay, or, in 4,19 # CMVand HHV-6*infection a small proportion of patients, avoid LT. Furthermore, high # OKT3, ALG*, ATG* pre-LT HCV-RNA levels are strongly associated with poor graft # Post-LT diabetes mellitus* and patient survival and are driven by HCVrecurrence. Taken together, these findings support the necessity to treat HCV *Possible risk factor (limited and/or controversial data) prior to LT. Notably, in patients who achieved SVR prior to LT, Abbreviations: HCV, hepatitis C virus; LT, liver transplantation; HIV, human the incidence of HCVrecurrence is very low (0–20%). 2–4,9,19 immunodeficiency virus; HLA, human leukocyte antigen CMV, cytomegalovirus; HHV, human herpes virus; ALG, anti-lymphocyte globulins; ATG, anti-thymocyte Several uncontrolled and controlled prospective studies globulins have evaluated the efficacy and safety of antiviral therapy
Journal of Clinical and Translational Hepatology 2014 vol. 2 | 124–133 125 Bunchorntavakul C. et al.: Hepatitis C before and after liver transplantation
Fig. 1. Natural history of HCV in non-transplant and liver transplant populations. Abbreviations: HCV, hepatitis C virus; LT, liver transplantation; RT, retransplantation with IFN or PEG-IFN and RBVin LT candidates. SVRwas and efficacy of DAA-based triple therapy in cirrhosis and LT achieved in 7–30% of patients with HCVgenotype 1, whereas candidates are limited. Adverse effects of treatment, parti- 44–57% of patients with genotype 2/3 achieved SVR.4,20 cularly anemia, are more frequently observed with BOC and Predictors of SVR were genotypes 2/3, early virological TVR therapies.24–27 Though treatment-induced anemia is response (EVR), low HCV-RNA, adherence to full dose(s)/ generally manageable by dose reduction and erythropoi- duration of treatment, and IL28B genotype CC.21 Everson et esis-stimulating agent, severe anemia could develop more al. treated 124 patients with decompensated cirrhosis by a frequently and lead to treatment discontinuation in more low accelerating dosage regimen (LADR) using either IFN vulnerable cirrhotic patients. Cure rates in patients with 1.5 MU thrice weekly or PEG-IFN alfa-2b 0.5 mg/kg once advanced fibrosis were significantly lower than in patients weekly plus RBV600 mg/day, and gradually increased the with mild to moderate fibrosis, although results were still doses every two weeks until they reached the maximum encouraging.20 However, there is no data available regarding tolerated or target standard doses. SVR was 13% in patients the efficacy of BOC and TVR in patients with decompensated with genotype 1 and 50% in those patients with non-1 cirrhosis, where safety is the major concern.20 A French genotypes. Adverse events were frequent in patients with Cohort (CUPIC Study Group) of compensated HCVcirrhosis cirrhosis awaiting LT, which led to dose reduction in 40–70% treated with BOC or TVR (N5674) reported a high incidence and treatment discontinuation in 13–40% of patients.4 The of serious adverse events (40%), severe complications, incidence of infections, particularly spontaneous bacterial death (6%), and a difficult management of anemia peritonitis in patients not receiving quinolone prophylaxis, (63%).29 Death or severe complications were related to was significantly higher in patients on antiviral therapy than platelets count f100,000/mm3 (OR 3.11, 95% CI; 1.30– in those who did not receive therapy.22 Treatment-induced 7.41) and albumin ,3.5 g/L (OR 6.33, 95%CI; 2.66–15.07), cytopenias have commonly been managed by dose reduction with a risk of 44% in patients with both.29 and hematopoietic growth factors. In the foreseeable future, IFN-free DAA regimens are Currently, four direct-acting antivirals, including bocepre- likely to become available and expected to have high efficacy vir (BOC), telaprevir (TVR), simeprevir, and sofosbuvir, have with low side effects,30 which are perhaps worthy options for been approved for the treatment of HCVgenotype 1 as part of managing HCVin LT candidates. There was a recent case a three-drug combination with PEG-IFN/RBV. These DAA- report using all-oral DAA (initially TVR and RBV and then BOC based triple therapies have been shown to improve virological and RBV) in the pre-transplant period, to prevent reinfection outcomes in HCVgenotype 1 patients, with an SVRof up to of the liver graft after LT for advanced HCV-related cirrho- 65–86% in treatment naı¨ve patients and 29–83% in previous sis.31 A preliminarily report of the multi-center, open-label relapsers/non-responders.23–28 However, the data on safety Phase 2 Study (N561) evaluating sofosbuvir plus RBV(taken
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Fig. 2. Summary of available HCV management options before and after liver transplantation. Abbreviations: HCV, hepatitis C virus; LT, liver transplantation; PEG-IFN, pegylated interferon; RBV, ribavirin, LADR, low accelerated dose regimen; SVR, sustained virologic response; G, genotype; HCC, hepatocellular carcinoma; IFN, interferon; DAA, direct acting antivirals; HCIG, Hepatitis C immune globulin; IV, intravenous; IL, interleukin; IMS, immunosuppressive drugs; CSA, cyclosporine A; MMF, mycophenolate mofetil; mTOR, the mammalian target of rapamycin inhibitors; LSM, liver stiffness measurement for 24–48 weeks before LT) to prevent HCVrecurrence Prophylactic therapy following LT has shown promising results.32 Participants had well-compensated liver disease (the median MELD score was Immune globulin containing virus-specific antibodies have 8) and were listed for LT due to HCC; 73% had HCVgenotype been shown to be effective in the treatment of several viral 1, 13% had genotype 2, 12% had genotype 3, and 2% had diseases, as well as in the prevention of recurrent hepatitis B genotype 4. More than 90% of patients who received after LT.4 In animal studies, immune globulin enriched in treatment had undetectable HCV-RNA at the time of LT. antibody to HCV(HCIG) was able to neutralize infectious Among those with undetectable HCVat LT, 64% maintained inoculates and delay or prevent HCVinfection. 34 Therefore, viral suppression at 12 weeks post-LT.32 Sofosbuvir/RBVwas HCIG might have a role in preventing recurrent HCVafter LT. generally safe and well-tolerated with 11 serious adverse Unfortunately, clinical studies of HCVantibody therapy events reported during the study (none of which were using polyclonal HCIG34 and anti-E2 monoclonal antibody35 considered related to sofosbuvir).32 have not proven to be effective. In a Phase II study of Taken together, antiviral therapy with PEG-IFN/RBVin the monoclonal antibody HCV-AbXTL68, 24 patients were rando- setting of HCVcirrhosis should be used in properly selected mized to receive 2–4 infusions of either placebo, low-dose populations with careful monitoring by those experienced in HCV-AbXTL68, or high-dose HCV-AbXTL68 during the first hepatitis C treatment. Given the high rate of serious adverse 24 hours after LT, followed by daily infusions for six days, events among patients with more advanced liver disease, weekly infusions for three weeks, and either two or four weekly treatment is contraindicated when the Child-Turcotte-Pugh infusions for eight weeks. Significant HCV-RNA reduction was (CTP) score is .11 or the Model of End-stage Liver Disease achieved in a dose-related manner, although all patients (MELD) score is .25, whereas treatment should be consid- became viremic after LT.35 Preliminary data suggested that ered if CTP f7 or MELD f18.3,33 DAA-based triple therapy high-dose intravenous silibinin given immediately after LT may should not be used in LT candidates outside of carefully prevent HCVrecurrence. 36 However,this approach needs to be designed clinical trials, and IFN-free regimens are required further evaluated. Recently, a Cochrane Systematic Review for this vulnerable population. (included 10 trials; 441 HCV+ LTrecipients) reported that there
Journal of Clinical and Translational Hepatology 2014 vol. 2 | 124–133 127 Bunchorntavakul C. et al.: Hepatitis C before and after liver transplantation were no significant differences in mortality rates, worsening of proportion (21–43%) of LT recipients who achieved end-of- fibrosis, HCVrecurrence, serious adverse events, or graft treatment response.19,43,44 Two-thirds of patients required rejection between intervention and control groups.37 dose reductions of either IFN or RBVand one-fourth discon- Therefore, at present, there is no demonstrated role for tinued treatment early.3 Baseline factors associated with SVR antiviral or HCVantibody therapy in the management of HCV included non-1 genotype, previously untreated, low baseline patients undergoing LT. HCV-RNA, adherence to therapy, and donor IL28B genotype CC.8,10,21,43,45–47 On-treatment predictors matched those in Early post-transplant or preemptive antiviral therapy the non-transplant setting; achievement of rapid virological response (RVR) was a good predictor of SVR, and failure to Preemptive antiviral strategy typically initiates antiviral treat- achieve EVR was highly predictive for non-SVR.43,48 ment within the first two months after LT. The rationale for this The use of DAA with PEG-IFN and RBVin the management approach is supported by the experience from the treatment of post-transplant recurrent HCVis challenging. As in non- of acute hepatitis C in the non-transplant population, where cirrhotic cases, one could speculate that DAA might also SVR rates are very high when therapy is initiated early.4 improve SVR rates in HCV patients in the post-LT state. Therefore, intervening at an early time point with relatively However, caution must be exercised due to limited data on low HCV-RNA levels in the absence of significant histological efficacy and safety of DAA in this population. changes in the graft might lead to better treatment outcomes Another challenge in utilizing DAA in LT recipients is the in recurrence HCVinfection. The majority of clinical studies of potential drug interaction with immunosuppressive agents. preemptive therapy in LTrecipients was uncontrolled and used TVR and BOC, as well as many other DAAs, are substrates and a combination of conventional IFN/RBV.4,20 Overall results possibly weak inhibitors of cytochrome P450 3A4.4,49 Lessons have been somewhat disappointing; rates of SVR varied from HIVpatients have demonstrated that protease inhibi- between 5–33% in genotype 1 and 14–100% in genotype 2/ tors, particularly when boosted by ritonavir, can lead to a 3 patients.4,20 More recent controlled studies have evaluated profound increase in serum levels of calcineurin inhibitors and the efficacy of 48-week therapy in the early post-LT (mean 3– sirolimus.50 A recent pharmacokinetic study demonstrated 4 months) with standard dose38 and escalating dose regimen that co-administration of telaprevir significantly increased the of PEG-IFN/RBV;39 SVR was achieved in 13–35% of dose-normalized exposure (AUC) and terminal elimination patients.4,38,39 Preemptive treatment was associated with half-life (TK) of both cyclosporine (CSA) (AUC increased high rates of treatment dose reduction (28–85%) and ,4.6-fold; mean TK increased from 12 to 42 hours) and discontinuation (0–37%). Furthermore, transplant-related tacrolimus (TAC) (AUC increased ,70-fold; mean TK factors, such as high levels of immunosuppression, can increased from 40.7 to 196 hours).51 Subsequent clinical decrease the likelihood of HCVeradication, and post-surgical studies have demonstrated that BOC and TVR could be and infectious complications may preclude patients as treat- administered in LT recipients with close monitoring of ment candidates. immunosuppressive drug levels.52–57 BOC induced a reduc- A recent multi-center, randomized controlled trial of 115 tion in the estimated oral clearance of CSA of 50%, of TAC of patients comparing early treatment (10–26 weeks after LT) up to 80%, and of everolimus of 50%.53,56 With TVR, the and treatment of established histologic HCVrecurrence doses of CSA, sirolimus, and TAC were reduced by 2.5, 7, and (Phoenix trial) with PEG-IFN/RBVshowed similar SVRrates 22-fold, respectively.55 A recent multi-center cohort study in both treatment groups (22% vs. 21%, respectively). included 37 HCV+ LT recipients treated with BOC (n 5 18) or Survival, adverse events, dose reduction, and acute cellular TVR (n 5 19) and noted ETR rates of 72% (13/18) and 40% rejection (ACR) rates were no different between the groups.40 (4/10), and SVR12 rates of 20% (1/5) and 71% (5/7) with Thus it appears that there is no established role of early post- TVR and BOC, respectively. The doses of CSA (1.8±1.1-fold LT HCVtherapy. with BOC and 3.4±1.0-fold with TVR) and TAC (5.2±1.5-fold with BOC and 23.8±18.2-fold with TVR) were reduced in all Treatment of established HCV recurrence patients during the treatment. The most common adverse effect was anemia (92%). Treatment was discontinued in 16 Antiviral therapy is considered in LT recipients who develop patients (43%) (11 due to treatment failure and 5 due to significant or progressive recurrent HCVdisease, as defined adverse events). Infections occurred in 10 patients (27%), by moderate to severe necroinflammatory activity (grade 3– with three fatal outcomes (8%). Another smaller series 4) and/or significant fibrosis (stage 2–4) on histologic reported a SVR rate of 56% (5/9) with TVR-based triple evaluation.33 Treatment of recurrent HCVin LT recipients, therapy for LT recipients with recurrent HCV(most of them particularly with successful viral eradication, is associated were previously treated with PEG-IFN/RBV).58 with a reduced risk of graft failure.41 Five-year survival has There is limited data on the interaction between DAA and been reported to be significantly greater in patients with SVR mammalian target of rapamycin (mTOR) inhibitors. than non-responders (93% vs. 69%, respectively).42 Recognizing that sirolimus carries a black box warning for The majority of data on efficacy and safety of treatment use in LT,59 it may be sensible to avoid this agent altogether in come from retrospective and uncontrolled studies, and few patients receiving TVR or BOC.52 Consideration might be randomized controlled studies have been performed to given to everolimus use in place of sirolimus if an mTOR date.43–45 The majority of patients included were genotype inhibitor is indicated.52 The shorter half-life of everolimus 1, and most studies employed a reduced dose of RBV(400– may make management of drug-drug interactions easier than 800 mg/day) and/or PEG-IFN, as well as hematopoietic sirolimus.52 growth factors. The pooled estimate of SVR from prospective Newer generations of DAA are associated with higher studies was 24–40%.4 Biochemical and histological responses potency, more convenient dosing, and less drug-drug inter- were observed in approximately 50% of treated patients. actions, characteristics that are necessary and ideal for use in Remarkably, virologic relapse occurred in a substantial LT recipients.49 Simeprevir and faldeprevir are mild-moderate
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CYP3A4 and OATP1B1 inhibitors, which are likely to have dosing strategies of currently-approved concomitant pro- potential but mild drug-drug interactions with calcineurin tease inhibitor and immunosuppressive agents during HCV inhibitors and other OATP1B1 substrates.49 Therefore, a therapy are summarized in Table 2. small change in calcineurin inhibitor level, as well as 49 unconjugated hyperbilirubinemia, may be expected. Special aspects of HCV treatment after LT Daclatasvir is metabolized by hepatic CYP3A without clinical evidence of CYP3A inhibition or induction,49 and sofosbuvir is excreted by the kidney. Although these two protease Rejection and autoimmune complications inhibitors are not expected to lead to clinically significant drug-drug interactions in LT recipients, confirmatory studies HCVinfection itself is associated with a variety of auto- immune phenomena.63 Due to the potent immunomodula- are needed.49 Of importance are the recent preliminary tory effects of IFN, the risk of graft rejection and other results of a multi-center, open-label Phase 2 Study (N540) immune complications remain a concern. Additionally, it has evaluating 24-week sofosbuvir plus RBVfor treatment of been suggested that the improvement in hepatic microsomal established HCVrecurrence after LT found at week four and at function during antiviral therapy may lead to a decrease in the end of treatment that all participants had undetectable serum levels of immunosuppressive agents, which in turn HCV-RNA.60 Four weeks after completing treatment, 77% still may place patients at a higher risk for ACR.64 The reported had sustained viral suppression (SVR4). No baseline factors incidence of ACR following IFN-based therapy in HCV-positive were found that predicted which patients would relapse.60 LT recipients ranges from 0–25%.4 Among controlled studies, While these response rates are promising, it is still early to the occurrence and severity of ACR was not significantly estimate the rate of SVR as relapse could occur four weeks different from that of untreated HCV-positive LT recipients.64 after cessation of therapy. Serious adverse events were A typical manifestation of ACR during IFN-based therapy is a reported in 15% of patients (5% led to treatment disconti- secondary increase in serum transaminases after an initial nuation), and no interactions were reported between sofos- 60 improvement with treatment and concomitant low or nega- buvir and any immunosuppressive agents. tive serum HCV-RNA.64 Nevertheless, this is neither specific Taken together, DDA-based therapy is feasible for LT nor sensitive, and the accurate diagnosis of ACR requires 54,57,58 recipients with severe HCVrecurrence. Higher rates prompt liver biopsy. Mild forms of ACR can be managed by of SVR (more than 50%) can be expected with BOC- and TVR- augmenting baseline immunosuppression, while moderate/ based therapy, but close monitoring for side effects and severe form of ACR may require high-dose intravenous immunosuppressive drug levels are warranted. The use of corticosteroids. The question of whether or not antiviral newer protease inhibitors, such as simeprevir, faldeprevir, therapy should be discontinued at the onset of ACR, daclatasvir, and sofosbuvir, will likely be associated with particularly in those responding to therapy, remains unclear. improved SVR rates in LT recipients as well as fewer drug Intuitively, it appears that a safe strategy would be to interactions and side effects. However, optimization of agents discontinue HCVtherapy, unless ACR evolved with low trough and duration of therapy will require further study, and it is levels of immunosuppressive agents, and their doses have likely that IFN-free regimens will be associated with a better been augmented. In that case, HCVtherapy can be continued safety profile in this population. Recently, cases of severe or restarted after ACR has been treated. recurrent cholestatic HCVfollowing LT that were successfully Chronic rejection (CR) is a rare but serious complication in managed by daclastasvir plus PEG-IFN/RBVfor 24 weeks 61 LT recipients. The incidence of CR in HCV-positive LT and daclastavir plus sofosbuvir (without IFN) for 24 weeks62 recipients varies between 4–8% in the absence of treat- have been reported. In both, the treatment regimens were ment.65 Several uncontrolled studies have suggested that CR well-tolerated, and calcineurin inhibitors trough levels may be related to IFN-based therapy (incidence range 4– reached the targeted therapeutic range during and after 17%).64,66 CR is generally detected after one year of therapy treatment.61,62 Based on available data, the interactions and and is often observed concurrent with the absence or low
Table 2. Empiric recommended dosing strategies of concomitant protease inhibitors and immunosuppressive agents during HCV therapy [Adapted from Charlton M, Dick T. J Hepatol 2014;60:6–8.)
Empiric dose changes* Mechanism of interaction Drug and exposure effect BOC TVR SMV SFV
Cyclosporine Inhibits CYP3A4: q drug exposure Q 50% Q 75% No data (smallQ) Not necessary Tacrolimus Inhibits CYP3A4: q drug exposure Q 75% Q 90% No data (small Q) Not necessary Sirolimus Inhibits CYP3A4: q drug exposure Black box warning for use in liver transplant. Recommend everolimus, if mTOR inhibitor indicated. Everolimus Inhibits CYP3A4: q drug exposure Q 50% Likely Q 75% No data (small Q) Not necessary MMF No published data, no change known No empiric dose adjustments necessary Azathioprine No published data, no change known No empiric dose adjustments necessary Prednisolone No published data, no change known No empiric dose adjustments necessary
*Empiric dose changes should be done in conjunction with therapeutic drug monitoring. Abbreviations: BOC, boceprevir; TVR, telaprevir; SMV, simeprevir; SFV, sofosbuvir; CYP3A4, cytochrome P450 3A4; mTOR, mammalian target of rapamycin; MMF, mycophenolate mofetil
Journal of Clinical and Translational Hepatology 2014 vol. 2 | 124–133 129 Bunchorntavakul C. et al.: Hepatitis C before and after liver transplantation levels of hepatitis C viremia. Notably, the majority of patients in HCVrecurrence between TAC and CSA regimens, but TAC had not experienced ACR during treatment and yet evolved to increased graft and patient survival in HCVtransplanted CR.64 As in ACR, the diagnosis of CR requires liver biopsy. The patients.72 Interestingly, a synergistic role of CSA in combi- pathogenesis of CR remains unclear, and most patients who nation with antiviral therapy has been suggested. Sugawara had graft failure secondary to CR required RT.64 It should be et al. reported on 21 living-donor LT patients with HCV noted that IFN-related CR may be partly preventable by recurrence that were treated with PEG-IFN/RBVwhile main- ensuring that the immunosuppressant dose is not reduced tained on a TAC-based regimen. Among eight patients who during antiviral therapy.66 had no virologic response after six months of treatment and Autoimmune hepatitis (AIH)-like hepatitis after LT has were switched from TAC to CSA, five patients (63%) became been reported in HCVpatients, particularly with IFN-based HCV-RNA negative within three months of conversion.73 therapy.19,64,67 The histological hallmarks can somewhat Recently, a pilot study from Firpi et al. randomized 38 resemble classical AIH, including plasma cell-predominant patients with HCVrecurrence treated with TAC to either periportal infiltrates with interface hepatitis or so called continue TAC or switch to CSA before initiation of PEG-IFN/ plasma cell-rich hepatitis. Increased serum transaminase RBV.74 A modest HCV-RNA drop with a trend toward better levels are seen during, or after HCVtherapy, or in some virologic responses in the CSA group was observed; although cases, without a history of antiviral therapy. Autoantibodies statistical significance was not reached.74 Taken together, the are often absent or present with low titers. The majority of impact of CSA on HCVrecurrence or on antiviral therapy cases rapidly respond to increased immunosuppression with response appears to be neutral or beneficial.4 Therefore, the or without discontinuation of antiviral therapy.19,64,67 Adding utilization of CSA in all HCV+ LT recipients must be deliberated everolimus may also be an option.68 Whether this AIH-like with the caveat that TAC appears to be an overall better hepatitis is a variant of ACR or is de novo AIH is a matter of immunosuppressive agent.72,75 The strategy to switch from debate.67 TAC to CSA before antiviral therapy needs to be further validated. Immunosuppressive regimens Data from in vitro studies suggest that mycophenolate mofetil (MMF) could have an antiviral effect against HCV The impact of immunosuppressive agents on HCVviremia, through inhibition of inosine monophosphate dehydrogenase histologic recurrence, and treatment outcomes has been (IMPDH) and enhance the effect of CSA and IFN-based 3,76 extensively debated. Immunosuppressive agents may facil- therapy. However, neither an effect on HCV-RNA nor itate HCVreplication and enhance HCVdisease progression. serum transaminases has been clearly demonstrated in 3,76 High-dose intravenous corticosteroid for the treatment of clinical studies. An analysis from United Network of ACR has been accompanied by a transient increase in HCV- Organ Sharing/Scientific Registry of Transplant Recipients RNA and an increased incidence of severe HCVrecurrence. 2,3 (UNOS/SRTR) database suggests that addition of MMF to However, in a randomized controlled trial of 312 HCV+ LT TAC-based regimen is associated with improved long-term 77 recipients with a steroid-free arm (induction by daclizumab), outcomes after LT in patients with and without HCV. A there were no differences in HCVrecurrence and graft randomized, multicenter trial conducted in Japan (N575) survival between steroid-free and steroid utilizing regi- comparing TAC plus MMF to TAC plus steroids in HCV+ mens.69 Therefore, there is no indication, specifically for recipients of living donor LT has reported similar outcomes HCV, to avoid oral corticosteroids in the early postoperative (survival, ACR, recurrent HCVand HCC) at five years in the 78 period. two groups. Treatment of steroid-resistant ACR with anti-CD 3 mono- mTOR inhibitors, such as sirolimus and everolimus, have clonal antibody, OKT3, is a strong risk factor for both the time anti-proliferative, anti-inflammatory, and possible antiviral to development and the severity of recurrent HCV.2,3,9 Based effects, which may translate to a lower rate of HCVdisease 79,80 on limited data, other induction antibody therapies, such as evolving to cirrhosis. A retrospective analysis of 141 anti-thymocyte globulins (ATG), anti-lymphocyte globulins, HCV+ LT recipients demonstrated that a sirolimus-based daclizumab, and basiliximab, have been noted to have little regimen did not significantly delay the time to develop severe 79 effect on recurrent HCV.2,3,9 recurrence of HCVafter LT. In contrast, in a prospective Some immunosuppressive agents have antiviral and anti- cohort of 67 patients (39 received sirolimus, 28 received inflammatory properties, which may in turn alleviate HCV calcineurin inhibitors), the sirolimus group had significantly 81 disease progression. Cyclosporine A (CSA) has been shown to lower HCV-RNA levels and increased survival. In addition, have antiviral effect against HCVby inhibiting interactions two independent retrospective studies (N51274 and 313) between cyclophilin B and NS5B-RNA-dependent-RNA poly- have demonstrated with sirolimus a reduction in the degree merase. This effect has not been demonstrated with TAC. of fibrosis and the rate of progression in HCV+ LT recipi- 82,83 Whether this in vitro data can translate into the clinical arena ents. However, an analysis of 26,414 patients (12,589 remains controversial. In a randomized controlled trial of 95 with HCV) in the UNOS/SRTR database suggested a link HCV+ LT recipients comparing CSA-based and TAC-based between sirolimus use and risk of death and graft loss after LT 84 regimens, CSA was associated with lower rates of severe HCV in HCVpatients that was not seen in patients without HCV. recurrence (46% vs. 80%) and graft loss (6% vs. 13%, These conflicting data warrant further and well-designed respectively) after a three year follow-up.70 However, a longitudinal studies to delineate the impact of sirolimus on recent prospective controlled trial (253 HCV+ LT recipients) HCVrecurrence. with seven year follow-up reported conflicting results. There was no significant difference in severity of HCVrecurrence, Donor and recipient genetic background SVR rates (in those 69 patients who received antiviral therapy), and graft and patient survival between CSA and Genetic variation in the IL28B gene, which encodes the TAC groups.71 Recent meta-analyses suggested no difference antiviral cytokine IFN-e¨3, is strongly associated with SVR in
130 Journal of Clinical and Translational Hepatology 2014 vol. 2 | 124–133 Bunchorntavakul C. et al.: Hepatitis C before and after liver transplantation patients with chronic HCVinfection treated with PEG-IFN/ HCV+ LT recipients, and antiviral therapy may be considered RBV. A genome-wide association study of more than 1,600 in those with severe/progressive HCVrecurrence. SVRcan be patients infected with HCVgenotype 1 found the rate of SVR achieved in approximately 30% of LT recipients with PEG-IFN/ following PEG-IFN/RBVtreatment to be approximately 80%, RBV. However, adverse effects are common and about one- 40%, and 25% in IL28B genotypes CC, CT, and TT, quarter of patients discontinue treatment prematurely. respectively.85 Following LT, IL28B polymorphisms have been Survival benefit is evident in those patients who achieve associated with histological recurrence and treatment SVR. Favorable patient characteristics for response to therapy response.8,10,46,47 Recipient CC genotype has been shown include non-1 genotype, previously untreated, low baseline to be an independent predictor of delayed HCVrecurrence at HCV-RNA, and donor IL28B genotype CC. DAA-based triple two and five years after LT and was associated with slower therapy is associated with higher rates of SVR, but with progression of fibrosis.8,10 Following HCVrecurrence, treat- similar or slightly higher rates of side effects, and immuno- ment response has a stronger association with the CC suppressive regimens need to be adjusted and closely genotype of the donor than the recipient.21,46,47 Although monitored for the levels during the treatment period. IL28B polymorphisms predict post-LT recurrence and clear- Notably, the safety and efficacy of HCVtreatment are very ance of HCV, these findings have not yet been demonstrated likely to improve with newer generation DAA. The impact of to improve graft or patient survival. Therefore, the use of immunosuppressive strategy on the natural history HCV IL28B in donor selection, particularly in the context of live recurrence has not been well elucidated. Based upon avail- donor LT and in the management of HCV, warrants further able evidence, CSA, MMF, and sirolimus appear to have a study. neutral or small beneficial impact on HCVrecurrence. Donor IL28B polymorphisms appear to impact the course and Retransplantation (RT) treatment outcomes in recurrent HCV. Retransplantation should be considered for patients with reasonable survival Following HCVrecurrence after primary LT, RT remains the probability. only option for patients with decompensated cirrhosis. Regardless of HCVstatus, RT is associated with decreased patient and graft survival compared with primary LT.86 Conflict of interest However, it is unclear whether HCVis an independent risk factor for survival or not. It is generally accepted that None progression to cirrhosis is faster after RT than after primary LT, particularly in patients with severe hepatitis C recurrence Author contributions (cholestatic hepatitis and graft failure within the first year).86 UNOS data from 1994–2005 demonstrated that despite Literatures reviewing, manuscript drafting, figures and tables improved outcomes with RT overall, HCVpatients continue creating (CB), conceptualization and critically revision of the to have worse patient and graft survival rates compared to manuscript (KRR). non-HCVpatients. 87 Additional variables such as increased severity of illness pre-RT may account for decreased survival in this group following RT. As a result, the role of RT in HCV+ References LT recipients remains controversial due to concerns of accelerated recurrence leading to rapid graft loss. A score [1] Davis GL, Alter MJ, El-Serag H, Poynard T, Jennings LW. Aging of hepatitis C specifically designed for to predict survival after RT for HCV virus (HCV)-infected persons in the United States: a multiple cohort modelof 88 HCVprevalence and disease progression. Gastroenterology 2010;138:513 – has been proposed. This score includes variables from the 521. doi: 10.1053/j.gastro.2009.09.067. first transplant (recipient age), second transplant (donor age, [2] Gane EJ. The natural history of recurrent hepatitis C and what influences this. creatinine, INR, and serum albumin), and the interval Liver Transpl 2008;14 (Suppl 2):36–44. doi: 10.1002/lt.21646. between both transplants. The area under the ROC (receiver [3] Watt K, Veldt B, Charlton M. A practical guide to the management of HCV operating characteristic) curve was 0.643 at three years, and infection following liver transplantation. Am J Transplant 2009;9:1707–1713. [4] Bunchorntavakul C, Bonnel AR, Reddy KR. Management of hepatitis before survivals were 71%, 56%, and 37% for scores ,30, 30 to 40, and after liver transplantation. In: Arroyo V, editor. Management of Hepatitis 88 and .40, respectively. In an era of organ shortage, the use C: International Hepatology Updates Series. Barcelona: Permanyer of well-validated prognostic scores is recommended to limit Publications; 2011. RT to patients with reasonable survival probability.86 [5] Reddy KR, Bunchorntavakul C. Managing hepatitis C: before and after liver transplantation. Indian J Transplant 2011;5:72–76. [6] Alberti A, Vario A, Ferrari A, Pistis R. Review article: chronic hepatitis C– Conclusions natural history and cofactors. Aliment Pharmacol Ther 2005;22 (Suppl 2): 74–78. doi: 10.1111/j.1365-2036.2005.02602.x. Management of hepatitis C in LT population presents unique [7] Forman LM, Lewis JD, Berlin JA, Feldman HI, Lucey MR. The association between hepatitis C infection and survival after orthotopic liver transplanta- challenges. Suboptimal graft survival in HCV+ LT recipients is tion. Gastroenterology 2002;122:889–896. doi: 10.1053/gast.2002.32418. attributable to universal HCVrecurrence following LT. [8] Charlton MR, Thompson A, Veldt BJ, Watt K, Tillmann H, Poterucha JJ, et al. Eradication of HCVbefore LT is ideal to prevent HCV Interleukin-28B polymorphisms are associated with histological recurrence recurrence, but is often limited by adverse events, particu- and treatment response following liver transplantation in patients with hepatitis C virus infection. Hepatology 2011;53:317–324. doi: 10.1002/ larly in patients with advanced cirrhosis. Antiviral therapy in hep.24074. LT candidates needs careful monitoring and DAA-based triple [9] Roche B, Samuel D. Risk factors for hepatitis C recurrence after liver therapy is generally not recommended, except by those who transplantation. J Viral Hepat 2007;14 (Suppl 1):89–96. doi: 10.1111/ have experience with such therapy. 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Journal of Clinical and Translational Hepatology 2014 vol. 2 | 124–133 131 Bunchorntavakul C. et al.: Hepatitis C before and after liver transplantation
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Journal of Clinical and Translational Hepatology 2014 vol. 2 | 124–133 133 ReviewArticle
Interaction Between the Neglected Tropical Disease Human Schistosomiasis and HCV Infection in Egypt: a Puzzling Relationship
Mahmoud M. Bahgat1,2
1Immunology and Infectious Diseases Group, Therapeutic Chemistry Department, the Centre of Excellence for Advanced Sciences, the National Research Centre, Dokki, Cairo, Egypt; 2Research Group of Biomarkers for Infection and Immunity, Institute of Experimental Infection Research, TWINCORE Centre for Experimental and Clinical Infection Research, Hannover, Germany
Abstract both the immune system and liver pathology. E 2014 The Second Affiliated Hospital of Chongqing Medical Egypt has the highest prevalence of chronic hepatitis C virus University. Published by XIA & HE Publishing Ltd. All rights (HCV) infection and seropositivity worldwide, and it has been reserved. proposed that this enhanced susceptibility to HCV is related to coinfection with schistosomiasis. Although currently, there Introduction are no studies regarding the actual prevalence of both human schistosomiasis and schistosomiasis/HCV coinfection evi- Helminth infections are one of the most common parasitic dences strongly support that eliminating human schistoso- diseases found in tropical countries worldwide.1 The highest miasis from Egypt is necessary to reduce both HCV prevalence of such infections occur in underdeveloped prevalence and liver pathology. The present reviewhighlights regions with poor hygiene and inadequate water supply and the significant impact of the neglected tropical disease human sanitation. These populations often live on less than 2 US schistosomiasis on both susceptibility of Egyptians to HCV dollars per day. Helminthic infections are the most neglected coinfection, severity of the resulting liver pathology, and poor of tropical diseases.1 Schistosomiasis, in particular, has been response to antiviral therapy. The immune evasion mechan- endemic in Egypt and other African countries located along isms exerted by the HCV-NS3/4A protease domain, and the the Nile River since antiquity.2 During the first half of the 20th possible impact of immune evasion mechanisms exerted by century, up to 80% of the residents in impoverished Egyptian proteases of larval, worm and egg stages of the parasite villages were infected with schistosome parasites, an incident Schistosoma on human susceptibility to HCV infection are that made a writer at that time declare, ‘‘No other people on discussed. In addition, schistosome immune evasion earth suffer the consequences of bilharzial infection to the mechanisms may include immunosuppression that in turn extent of the Egyptian farmers’’.2 Risk factors for active prevents clearance of HCV viremia and leads to relapsing HCV schistosomiasis transmission, including improper water and infection and severe liver pathology. I propose the generation sanitation facilities and bodies of stagnant water contami- of a replicon system from the most prevailing genotype (HCV- nated with infected intermediate snail hosts, existed in poor 4a) in Egypt and establishing its replication on hepatoplas- Egyptian villages and dramatically contributed to the estab- toma or immune cells in presence of bilharzial antigens. lishment of disease endemicity.2 Globally, chronic morbidities Finally, the use of a humanized small animal model that can associated with repeated schistosomiasis infection include acquire both HCV and S. mansoni infections will be important impaired child growth and development, chronic liver inflam- to further understand in real time the impact of coinfection on mation, anemia, and other nutritional deficiencies. It has been estimated that up to 56 million disability adjusted life years are lost annually, a value that exceeds the estimated Keywords: Egypt; Neglected tropical disease; Human schistosomiasis; HCV; 3 Coinfection; Immune evasion mechanisms; HCV protease; Schistosome pro- global burden of malaria. teases. Prior to the availability of oral praziquantel, the primary Abbreviations: HCC, hepatocellular carcinoma; HCV, hepatitis C virus; HCV-4a, treatment for schistosomiasis in Egypt was tartar emetic HCV genotype 4a; INF- c, interferon gamma; IPS-1, interferon-beta promoter (potassium antimony tartrate) administered parenterally.2 stimulator 1; IRF-3, IFN regulatory factor 3; ISGs, IFN-stimulated genes; MAVS, mitochondrial anti-viral signaling protein; NS, nonstructural protein; RIG-I, Hundreds of thousands of Egyptian farmers received the retinoic-acid inducible gene I; TNF- a, tumor necrosis factor alpha; TLR3, Toll- medication following World War I, which was, although highly like receptor 3; VISA, virus-induced signaling adaptor. toxic, often effective in curing schistosomiasis. The drug Received: 08 December 2013; Revised: 21 February 2014; Accepted: 26 exerted its action via inhibition of DNA synthesis,4 and side February 2014 q DOI of original article: 10.14218/JCTH.2013.00028. effects included nausea, vomiting, coughing, acute circulatory 5 Correspondence to: Mahmoud M. Bahgat, Research Group of Biomarkers for failure, and electrocardiographic changes. Unfortunately, this Infection and Immunity, Institute of Experimental Infection Research, TWINCORE drug was dispensed without due attention to sterilization of Centre for Experimental and Clinical Infection Research, Feodor-Lynen-Straße 7-9 needles between patients and resulted in an unanticipated D - 30625 Hannover, Germany. Tel: +49 511-22 00 2-7172, Fax: +49 511-22 00 6–12 27-186, E-mails: [email protected]; mahmoud-bahgat.riad@ epidemic of hepatitis C virus (HCV) transmission. During helmholtz-hzi.de this period, human blood and multiple syringe use were
134 Journal of Clinical Translational Hepatology 2014 vol. 2 | 134–141 Bahgat M.M.: Connection between human Schistosomiasis and HCV infection in Egypt not known as possible routes for transmission of other frequently complicated by underlying S. mansoni coinfection, infections.12 It has recently become evident that the parent- which has been associated with increased HCV morbidity and eral administration of tartar emetic using non sterilized chronicity.62–64 syringes resulted in widespread transmission of both HCV Taken together, these findings make clear that although and HBV.13 Given the prevalence of schistosomiasis/HCV schistosomiasis is an extremely neglected tropical disease, it coinfection in Egyptians, higher susceptibility of this popula- has contributed significantly to the spread of, the suscept- tion was proposed.14,15 Two years ago, the prevalence of ibility to, and the pathological consequences of HCV infection. chronic HCV infections and seropositivity among Egyptians The present reviewfocuses on the immune evasion was reported to be one in 10 people, whereas the global rate mechanisms of both schistosome parasites and HCV that was one in 50 people.16 In contrast, the seroprevalence of HCV might underlie the higher susceptibility of, and the severe and schistosomiasis in neighboring Sudan is much lower, and disease outcome in, coinfected Egyptian patients. Also high- the reason for this difference is still unclear.17 lighted the poor anti-viral therapy outcome among coinfected Over the last decade, most papers published regarding subjects and proposed several future strategies that may human schistosomiasis began with a similar version of the help in resolving the puzzling relationship between human following paragraph: ‘‘Schistosomiasis is the second most schistosomiasis and HCV infection. important parasitic infection after malaria and affects more than 200 million people in 74 countries.18 It is endemic, with Helminth infections switch immune response to favor high prevalence and morbidity rates in many countries, secondary viral infection especially those in Africa, such as Egypt,19 Kenya20 and Sudan12,22 and in South America, mainly Brazil.23 The largest Helminth infections exert profound suppressive effects on the epidemiological survey in Egypt mentioned the prevalence of host’s immune response, which enable their worms to evade Schistosoma haematobium in Upper Egypt (where it is the defense mechanisms and survive in the blood, lymphatics, endemic) to be around 7.8%, while the prevalence of S. intestine, body cavities, or other tissues for years.65–67 mansoni in Lower Egypt (where it is endemic) was found to be Chronically infected filarial and schistosome patients present around 36.4%.19 When one carefully looks at the dates of the clinically with impaired immune responses, as demonstrated references for global prevalence of the human schistosomiasis, by reduced production of IL-5 and IFN-c, and occasionally IL- it becomes apparent that all results are outdated and represent 4.68–71 Although some elements of such immune suppression more a history than a description of the current status. are reversible upon drug-mediated parasite clearance,70–72 The main reasons for this is that human schistosomiasis, drug treatments do not induce protective immunity against among other helminth infections, became an extremely parasite challenge, and individuals can rapidly become re- neglected tropical disease.1 During the 1990’s, the WHO, infected upon re-exposure to the infective stages of these the Egyptian Government in collaboration with the USAID,24 parasites. Therefore, innovative strategies to induce long- and the EU allocated large funds to establish relationships term protective immunity and to develop vaccines against between scientists from endemic countries for human schis- helminth infections which can counteract infection-induced tosomiasis and collaborators form Europe and the USA. These immune suppression are still lacking. Recently, serum CCL11 funds were extremely useful in training young scientists and and CCL17 were identified as serological indicators of human establishing an infrastructure in Egypt that enabled labora- multiple helminth infections. They were determined to be tories to seriously begin research on the control of human primarily driven by S. mansoni infection as these biomarkers schistosomiasis. Unfortunately, the majority of the funds was significantly correlated with fecal bilharzia egg counts and spent on characterizing vaccine candidates, an aim which is bilharzial induced IL10.73 Besides modulation of the immune to date still not achieved, and not on setting up concrete response, helminth infections cause chronic disease, including hygienic plans to eliminate human schistosomiasis from fatigue, iron deficiency anemia, growth stunting, malnutrition, Egypt. Candidate schistosome antigens that were evaluated and poor cognitive development.74 Both the immune suppres- for their protective potential against schistosomiasis infection sive effects and the severe pathological consequences result- and their capacity to stimulate various host immune ing from chronic helminth infections represent risk factors that responses are listed in table 1 (reviewed in 25).26–49 By the increase host predisposition to secondary viral infections. end of the 1990’s, the funds expired, Western countries excluded human schistosomiasis from their research prio- Schistosomiasis infection induces TH2 responses that rities, and Egypt declared schistosomiasis as a minor or no enhance both susceptibility to HCV infection and longer existing health problem. The dramatic absence of both progression of liver pathology international funding schemes and political willingness to help contributed to an extreme neglect of human schistosomiasis One possible reason for both enhanced susceptibility to HCV and other helminth, soil-, and mosquitoes-borne diseases in infection and liver pathology is the shift in the immune Egypt over the last twenty years. response and corresponding cytokine release. While mount- The early schistosomiasis tartar emetic control campaign ing a successful immune response against HCV infection 8–13 which resulted in HCV transmission led to the highest would be characterized by a TH1 immunological profile that prevalence rates globally of HCV in Egypt,17 with many cases triggers a robust antiviral response and a reduction in host developing into chronic liver cirrhosis and hepatocellular fibrosis, schistosomiasis triggers a TH2 cytokine response, carcinoma (HCC). Schistosoma and HCV appear to act which not only suppresses TH1 cytokine release (thereby synergistically in coinfected patients, causing more severe hindering cellular and antiviral immunity) but also promotes 15,52,54,75–79 liver disease progression compared to either pathogen subsequent TH2 responses and fibrogenesis. 50–60 alone. Since praziquantel became the oral drug of choice Such suppression of TH1 cytokines in case of S. mansoni/ to control human schistosomiasis,61 no injectable drugs are HCV coinfection was reported to be mediated by antigens used for infection treatment. Nevertheless, HCV infection is shed from dead parasite worms or eggs, and therefore did not
Journal of Clinical Translational Hepatology 2014 vol. 2 | 134–141 135 Bahgat M.M.: Connection between human Schistosomiasis and HCV infection in Egypt
Table 1. Candidate schistosome antigens, their capacity to stimulate various host immune responses, and their protective potential against schistosomiasis infection
Induced immune Reduction of Reduction of Antigen Form response egg count (%) worm count (%) References
Sm-p80 DNA vaccine Th1, IgG, IgG2a and 84 59 26 IgG2b TSP-2 Recombinant protein IgG, IgG1 and IgG2a ,65 57 27,28 Sm29 Recombinant protein Th1, IgG, IgG1 and 60 51 29,30 IgG2a Sm200 (ECL) DNA vaccine IgG, IgG1. IgG2a ND 38.1 13 Sm 25 Peptide vaccine IgG Significant Significant 32,33 Glutathione peroxidase DNA prime vaccinia ND ND 85 34 virus boost Sm21.7 Recombinant protein ND ND 41–70 35 Cu/Zn superoxide DNA vaccine ND ND 44–60 34 dismutase Filamin DNA vaccine Th1/2, IgG, IgG1, ND 44–57 36 2a and 2b Sm fimbrin + Sm 21.7 Multivalent DNA IgG 41.5 (Liver) 55.6 56 37 vaccine (Intestine) Sm-p80 DNA vaccine Th1/Th17, IgG ND 47 38 Sm 23 DNA vaccine IgG ND 44 39,40 Sm 21.7 DNA vaccine IgG 62 (liver) 67 41.53 41 (intestine) Fimbrin Recombinant protein ND ND 39.4–41.6 42 Sm 22.6 Recombinant protein Th1/Th2, IgG, IgG1 ND 34.5 43 IgG2a TSP-1 Recombinant protein IgG, IgG1 and IgG2a 52 (liver) 69 34 26,27 (feces) Stomatin like protein-2 Recombinant protein Th1 IgG, IgG1 No significant 30–32 44 . IgG2a difference Sm 20.8 DNA vaccine ND ND 28.5–30.8 45 Sm28GST DNA vaccine +plasmid Th1, IgG 29.6% (liver) 22.6 46 containing IL-18 27.5% (intestine) Dif 5 DNA vaccine ND ND 22 47 SmIg Recombinant protein Th1/Th2, IgG ND No significant difference 48 Sm21.6 Recombinant protein Th1/Th2b IgG, ND No significant difference 49 IgG1 . IgG2 require an active parasitic infection.34 The shift in immune responses compared to T-cells in blood from Egyptian 56,76 response from TH1toTH2 can be confirmed by high plasma patients positive only for anti-HCV antibodies. The levels of the profibrotic cytokines IL-4 and IL-13 and anti- authors concluded that the presence of S. mansoni eggs in inflammatory cytokine IL-10.75–77,80–84 the liver inhibited local intrahepatic T-cell responses against Consistent with this, it was reported that impaired HCV infection and consequently promoted persistent viral interferon gamma (INF- c) and tumor necrosis factor alpha infection and accelerated the clinical course of HCV in HCV/S. (TNF- a) production as well as impaired maturation of mansoni coinfected humans. This could at that time provide a dendritic cells in a HCV patient who underwent liver trans- possible explanation for why coinfected patients have a plantation resulted in an inadequate immune response to higher incidence of cirrhosis and HCC than those matched viral progression and caused relapsing HCV infection.85 In for age, disease duration, and viral genotype with chronic 53 addition, induction of T- cells from infected humans with HCV mono-infection. human T cell lymphotropic virus type 1 by three recombinant schistosome antigens, namely Sm29, ShTSP2 (tetraspanin), Immune evasion mechanisms by both HCV and S. and PIII, caused downregulation of IFN- c production, which mansoni proteases enhance relapsing HCV infection in turn enhanced virus propagation.86 Similarly, T-cell and severe liver pathology responses in blood from positive Egyptian patients for both anti-HCV and anti-Schistosoma antibodies showed a signifi- Although escape from adaptive immunity is a key to long cant decrease in core-specific T-cell IFN- c, IL-4, and IL-10 term persistence of HCV infection, evasion of innate antiviral
136 Journal of Clinical Translational Hepatology 2014 vol. 2 | 134–141 Bahgat M.M.: Connection between human Schistosomiasis and HCV infection in Egypt responses is crucial in establishing a persistent infection in organic molecules120,121 or by inducing specific immunity the first place.87 As a main player in innate immunity against against DNA constructs encoding worm proteases122 resulted viruses, the IFN system is key in curtailing pathogens by in partial protection against S. mansoni infection as demon- putting infected and neighboring cells into an antiviral strated by either reduction in worm burden or egg counts. state.88 HCV has been known for long time to be highly sensitive to treatment with type I IFNs,89,90 and to date, IFN- Response of HCV/schistosoma coinfected patients to a is the major component of HCV therapy. Since HCV is IFN- a therapy sensitive to IFN and can still manage to establish persistent infection, this suggests that the virus may have evolved Treatment of HCV with pegylated interferon and ribavirin mechanisms to circumvent the innate antiviral defense represents the cornerstone and the standard of care for the system. In fact, the viral serine protease domain, nonstruc- management of the prevailing HCV genotype 4a (HCV-4a) in tural protein (NS) 3/4A, was found to suppress activation of Egypt.123 HCV-4a has been reported to be one of the most IFN regulatory factor 3 (IRF-3), a central antiviral transcrip- difficult genotypes to treat.123 One possible reason for this is tion factor promoting the production of IFN-b and a plethora the great diversity of virus quasi species present in each of IFN-stimulated genes (ISGs), most prominently ISG56,91 patient, which provides a reservoir of mutations that enable in response to viral infection or treatment with double- virus-escape from anti-viral therapy.124,125 A very recent stranded ribonucleic acid.87,92 study conducted on Egyptian patients clearly demonstrated a Further identification of cellular targets of the HCV protease significant association between positive serology for schisto- indicated that it interferes with both Toll-like receptor 3 somal infection and failure to HCV treatment despite anti- (TLR3)–mediated signaling through cleavage of the essential schistosomal therapy with praziquantel.126 This further sup- adaptor TRIF (Toll/interleukin receptor domain containing ports that bilharzial infection complicates HCV disease adapter-inducing interferon b)93,94, mitochondrial antiviral progression and treatment. signaling protein95 and TLR-independent activation of IRF-3 by the cytosolic pathways of retinoic-acid inducible gene I (RIG-I) and MDA5 (melanoma differentiation associated Conclusions protein 5) by inactivating the signaling adaptor CARDIF (also known as interferon-beta promoter stimulator 1 [IPS-1], The lack of recent data regarding the actual prevalence of mitochondrial anti-viral signaling protein [MAVS] and/or both human schistosomiasis and schistosomiasis/HCV coin- virus-induced signaling adaptor [VISA]).96 This indicated that fection clearly highlights the urgent need for active surveil- both pathways may play a role in controlling HCV infection, lance studies for both pathogens in Egypt. I believe that most likely, in different sets of cells because TLR3 was shown eliminating human schistosomiasis will significantly contri- to be essential for IFN production in plasmacytoid dendritic bute to the reduction of both HCV prevalence and liver cells, whereas RIG-I triggers IFN secretion upon viral infection pathology among Egyptians and, as proposed by others, in conventional dendritic cells and other tissues.97 More advocate plans for the elimination of human schistosome recently, the preferential abrogation of the RIG-I-mediated parasites from Egypt.127,128 The present reviewhighlights the pathway following proteolytic cleavage of CARDIF by the HCV significant impact of the neglected tropical disease human NS3/4A protease ectopically expressed in human primary schistosomiasis on both susceptibility of Egyptian patients to hepatocytes was reported. The TLR3-mediated pathway was HCV coinfection, severity of the resulting liver pathology, and affected to a lesser extent and in a protease-independent poor response to antiviral therapy. In addition to the exerted manner.98 In support of the impairment of innate anti-HCV immune evasion mechanisms by the HCV-NS3/4A protease, I responses, IRF3-dependent genes, type IFN-b, type III IL28A/ discuss for the first time the possible impact of immune IL29 and chemokine CCL5 were significantly downregulated in evasion mechanisms exerted by proteases of larval, worm, association with a global decrease of CARDIF adaptor in liver and egg stages of the parasite Schistosoma on human biopsies and corresponding purified hepatocytes of chronic susceptibility to HCV infection. In addition, schistosome HCV patients.99 Altogether, these data suggest that HCV- NS3/ immune evasion mechanisms are among the suppressive 4A protease is an attractive anti-HCV drug target, and there- tactics of the parasite that prevents clearance of HCV viremia fore, I and others molecularly characterized this protease and and leads to both relapsing HCV infection and severe liver reported on selective serine protease inhibitors as potential pathology. anti-HCV therapeutics.90,100–103 In fact, developing in vitro and in vivo models would A variety of proteases of various classes and clades were enable the study of the impact of HCV-4a alone or in also reported to be differentially expressed in various combination with live schistosome stages (schistosomula, developmental stages of the schistosome parasites.104–110 worms and eggs) on liver pathogenesis and immune modula- These were also demonstrated to be implicated in the evasion tion. The in vitro system requires generation of a replicon of the host immune mechanisms for the sake of establishing system129 from the most prevailing genotype (HCV-4a) in chronic bilharzial infection. Cercarial and schistosomular Egypt and establishment of its replication on hepatoplastoma proteases were reported for their capacity to cleave both or immune cells in presence of bilharzial antigens.60 The ideal complement molecules111–115 and immunoglobulin E116,117 in vivo system would be a humanized small animal model that and in this way prevented host mediated parasite killing by can acquire both HCV and S. mansoni infections in order to such molecules. Furthermore, helminth cysteine proteases study the impact of coinfection on both the immune system were recently reported to inhibit TRIF-dependent activation and liver pathology in real-time.130,131 of macrophages via degradation of TLR3, which represents an Last but not least, both international collaborative and additional immune evasion mechanism by parasite worms.118 funding initiatives are needed to help resolve the puzzling In murine systems, inhibition of schistosome proteases relationship between human schistosomiasis and HCV using either specific inhibitors,119 newly synthesized small infections.
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