High-dose ursodeoxycholic acid therapy for nonalcoholic steatohepatitis: a double-blind, randomized, placebo-controlled trial


  • Potential conflict of interest: Nothing to report.


In uncontrolled clinical studies, ursodeoxycholic acid (UDCA) had a beneficial effect on nonalcoholic steatohepatitis (NASH). However, a large controlled trial using UDCA (13-15 mg/kg/day) was unable to confirm these results. Accordingly, a randomized, placebo-controlled study was initiated with a high dose of UDCA (23-28 mg/kg/day). The allocation of patients and the evaluation of liver histology were performed according to a modified Brunt score and the nonalcoholic fatty liver disease activity score (NAS). With the modified Brunt score, 185 patients with histologically proven NASH were randomized [intention to treat (ITT)], and 147 were treated per protocol (PP). With the NAS, 137 patients were confirmed to have NASH, 48 had borderline NASH, and 1 did not have NASH. The treatment time was 18 months. At entry, the treatment groups were comparable. A second biopsy sample was obtained from 139 of 185 patients (NAS: 107/137). The primary criterion for evaluation was a change in the liver histology; the secondary criteria were single histological variables and liver biochemistry. Significant differences in the overall histology could not be detected between the two treatment groups with the modified Brunt score (P = 0.881) or NAS (P = 0.355). Only lobular inflammation improved significantly (P for the modified Brunt score = 0.011, P for NAS = 0.005). In subgroup analyses, significant improvements in lobular inflammation were also observed in males, younger patients up to 50 years of age, slightly overweight patients, and patients with hypertension and an increased histology score. The fibrosis score did not change (P for ITT = 0.133, P for PP = 0.140). With the exception of γ-glutamyl transferase, UDCA did not improve laboratory data. Conclusion: High-dose UDCA failed to improve the overall histology in patients with NASH in comparison with placebo. Hepatology 2010

Histologically, nonalcoholic steatohepatitis (NASH) has been characterized by steatosis, ballooning of hepatocytes, lobular and portal tract inflammation, fibrosis, the absence of lipogranulomas, glycogenated nuclei, and Mallory-Denk bodies. Currently, the definition of NASH is based on three variables significantly associated with the diagnosis of NASH: steatosis, ballooning, and lobular/portal inflammation.1 Lobular fibrosis, portal/periportal fibrosis, bridging fibrosis, and cirrhosis characterize the staging of NASH.1 The nonalcoholic fatty liver disease activity score (NAS) is the sum of the steatosis, lobular inflammation, and hepatocellular ballooning scores.2 In therapy studies, the NAS allows an assessment of overall histological changes. Imaging procedures and routine laboratory data are not diagnostic.

NASH is often associated with type 2 diabetes and dyslipidemia.3 The disease can progress to liver cirrhosis,4, 5 and the development of liver cancer is possible.6 The pathogenesis of NASH is not well understood. Most patients are insulin-resistant and have a decreased carbohydrate oxidation rate,7 increased tumor necrosis factor-α levels,8 reduced expression of adiponectin,9 and increased de novo lipogenesis. Augmentation of free radicals and induction of lipid peroxidation are observed with the ability to stimulate the synthesis of extracellular matrix in stellate cells.10

To date, there is no proven medical therapy for NASH. Clinical studies using antihyperlipidemic agents,11, 12 substances influencing tumor necrosis factor-α13 or oxidative stress,14 have had variable effects. Thiazolidinediones reduce insulin resistance, activate the oxidation of free fatty acids,15 and improve liver function tests and liver histology but also increase the risk of bone fracture, whereas rosiglitazone increases the risk of myocardial infarction and induces weight gain.16-18 The endocannabinoid receptor antagonist rimonabant, affecting body weight, fibrogenesis, and lipogenesis,19, 20 increases the risk of neuropsychiatric side effects. Positive effects of betaine have not been shown, except for steatosis.21 Only exercise and body weight reduction22 have a positive effect on NASH.

Because ursodeoxycholic acid (UDCA) lowers biliary and serum concentrations of hydrophobic bile acids, lowers tumor necrosis factor-α levels in chronic cholestasis,23 is said to reduce oxidative stress, and has antiapoptotic properties,24 UDCA could have a beneficial effect on NASH. Additionally, smaller open-label clinical studies have shown that UDCA positively influences liver function tests and liver histology,25-27 but in a 2-year prospective, double-blind trial with 166 patients, neither laboratory data nor liver histology improved at the dosage of 13 to 15 mg/kg of body weight/day.28 Because the dosage of UDCA may have been too low and a reduction of body weight could have contributed to the results, we initiated a multicenter, placebo-controlled, double-blind trial with a high dose of UDCA and without a weight-lowering diet.


ALT, alanine aminotransferase; AP, alkaline phosphatase; AST, aspartate aminotransferase; BMI, body mass index; GGT, γ-glutamyl transferase; ITT, intention to treat; NAS, nonalcoholic fatty liver disease activity score; NASH, nonalcoholic steatohepatitis; NS, not significant; PP, per protocol; SD, standard deviation; UDCA, ursodeoxycholic acid.

Patients and Methods

Study Design

The study was planned as a multicenter, randomized, placebo-controlled, double-blind study. Patients were enrolled from 25 medical centers in Germany (n = 22) and Greece (n = 3). Patients of both sexes, 18 years old and older, were included. A UDCA dose of 23 to 28 mg/kg of body weight or placebo was administered daily in three divided doses. No special diet was recommended. The total treatment time for each patient was 18 months. The primary objective was improvement of liver histology. Data were evaluated according to the modified Brunt score, which included lobular, portal/periportal, and bridging fibrosis (staging) and steatosis, lobular inflammation, and ballooning (grading), and according to the NAS, which validated steatosis, lobular inflammation, and ballooning of hepatocytes (grading).

Evaluation According to a Modified Brunt Score.

Inclusion and Exclusion Criteria

The diagnosis of NASH was accepted when three of the following five criteria were proven by liver biopsy: steatosis, hepatocellular ballooning, lobular inflammation, Mallory-Denk bodies, and lobular portal/peripertal fibrosis. Data on Mallory-Denk bodies were collected as inclusion criterion to pinpoint the accuracy of diagnosis, but they were not used for evaluation. A 4-point scale [(0) none, (1) mild, (2) moderate, and (3) severe; for steatosis, (0) <5%, (1) 5%-30%, (2) 30%-70%, and (3) >70% of fat-containing cells] for each of the four criteria resulted in a sum score ranging from 0 to 12. One point was added in case of prominent lobular fibrosis, and 2 points were added in case of bridging fibrosis (maximum score = 14 points). Biopsy samples were taken within 1 month prior to inclusion or after the final visit. The biopsy sample had to be 20 mm long (in all or in fragments) with a minimum diameter of 0.8 mm. The review of the specimens was done by a single pathologist who was blinded to the assigned treatment. For inclusion in the study, the sum score of a patient had to be 6 points at least. Additional inclusion criteria are summarized in Table 1. Exclusion criteria were as follows: liver cirrhosis; hepatitis B or C markers; antinuclear antibody/smooth muscle antibody titers >1:160; cholestatic liver diseases; Wilson's disease; α1-antitrypsin deficiency; hemochromatosis; a history of human immunodeficiency virus; a recent intake of potential liver-toxic drugs or drugs interacting with UDCA; treatment with UDCA, glitazones, metformin, vitamin E, and angiotensin II receptor antagonists in the last 3 months prior to study entry; ethanol consumption >70 g/week (confirmed by a family member); a mean corpuscular volume >101 fL; pregnancy, lactation, or insufficient contraception in fertile women; and patients considered to be unreliable or not compliant.

Table 1. Inclusion Criteria
  • *

    The inclusion variables were used according to the NAS.

  • To make the inclusion criteria safer, data on Mallory-Denk bodies and waist circumference were collected in addition.

  • When a patient did not meet three of the four criteria of metabolic syndrome, he was also included when one of the three parameters of point 6 was present.

1. Written, informed consent prior to the study start
2. Patients of both sexes (≥18 years old)
3. Diagnosis of NASH with three of the following criteria proven by biopsy (the histology sum score had to be at least 6 points):
  Lobular inflammation*
  Mallory-Denk bodies
4. ALT level at least 1.5 times the upper limit of normal (persistently for at least 3 months)
5. Three of four criteria of metabolic syndrome:
  Waist circumference > 102 cm in men and > 88 cm in women
  Fasting glucose > 110 mg/dL
  Dyslipidemia (high-density lipoprotein cholesterol < 40 mg/dL in men and < 50 mg/dL in women and/or fasting triglycerides ≥ 150 mg/dL)
  Arterial pressure > 130/85 mm Hg or pharmacological treatment
6. Type 2 diabetes (sufficiently controlled), or hypertriglyceridemia, or BMI > 25 kg/m2
7. Alcohol consumption < 70 g/week (confirmed by a third person)
Patient Selection and Management

A total of 451 patients underwent screening, which included baseline liver biopsy; 186 of these were randomized. Results were analyzed for the intention to treat (ITT) and per protocol (PP) treated sets. The ITT set comprised 186 patients. Because of major protocol violations, 39 patients dropped out. As such, the PP set comprised 147 patients (Fig. 1). Sixty (32%) of the randomized patients and 44 (30%) who finished the study were female. Liver biopsy samples before study entry were obtained from 185 of 186 patients; 139 of the 185 patients (75.1%) underwent biopsy for a second time at the end of the study. The UDCA and placebo groups did not significantly differ with respect to the parameters assessed at the baseline (Tables 2 and 3), with the exception of the age variable.

Figure 1.

Patient selection and management.

Table 2. Baseline Values of the ITT Set (n = 186)
VariableUDCAPlaceboP Value
  1. Abbreviation: NS, not significant.

Gender, n (%)   
 Male63 (66.32)63 (69.33)NS
 Female32 (33.68)28 (30.77)NS
Ethnic origin, n (%)   
 Caucasian89 (93.68)88 (98.70)NS
 Other6 (6.7)3 (3.3)NS
Age (years), mean (range)41.45 (18-71)45.02 (18-73)0.044
Age, n   
 ≤50 years6456NS
 >50 years3035NS
Weight (kg), mean (range)95.4 (63-135)91.7 (63-122)NS
BMI, n   
 ≤30 kg/m25150NS
 >30 kg/m24341NS
Hypertension, n (%)26 (27.37)26 (28.57)NS
Type 2 diabetes, n (%)10 (10.53)11 (12.09)NS
Smoking habit, n (%)   
 None76 (80)77 (84.62)NS
 Occasional9 (9.47)5 (5.49)NS
 Regular10 (1.53)9 (9.89)NS
Alcohol, n (%)   
 None48 (50.53)38 (41.67)NS
 Occasional47 (49.47)53 (58.24)NS
Total bilirubin (3-22 μmol/L), n (mean/SD)95 (11.86/5.78)91 (11.38/7.48)NS
AST (14-36 U/L), n (mean/SD)95 (58.90/30.32)91 (60.99/25.34)NS
ALT (9-52 U/L), n (mean/SD)95 (100.19/53.00)91 (109.50/58.07)NS
AP (38-126 U/L), n (mean/SD)95 (165/48.30)91 (173/45.00)NS
GGT (12-43 U/L), n (mean/SD)95 (87.45/71.72)91 (90.90/84.66)NS
Albumin (39-50 g/L), n (mean/SD)95 (46.38/4.33)91 (46.63/4.37)NS
Triglycerides (maximum 2.28 mmol/L), n (mean/SD)95 (2.35/1.26)91 (2.29/1.26)NS
Cholesterol (maximum 200 mg/dL), n (mean/SD)95 (148.05/102.05)91 (162.57/94.42)NS
Glucose (3.64-5.88 mmol/L), n (mean/SD)95 (5.59/.2.36)91 (5.60/2.37)NS
Iron (8.8-32.4 μmol/L), n (mean/SD)95 (19.48/6.56)91 (19.53/6.12)NS
Table 3. Baseline Values of Liver Histology (ITT set)
VariableUDCAPlaceboP Value
  • *

    Lobular, portal/periportal, and bridging.

Modified Brunt scoren = 94n = 91 
 Overall histology, mean/SD7.0/1.147.3/1.230.061
 Steatosis, mean/SD2.0/0.542.1/0.570.298
 Ballooning, mean/SD1.5/0.501.6/0.500.270
 Lobular inflammation, mean/SD1.6/0.591.6/0.560.543
 Fibrosis, mean/SD*1.2/0.411.2/0.420.118
NASn = 69n = 68 
 Overall histology, mean/SD5.6/0.725.7/0.800.369
 Steatosis, mean/SD2.2/0.432.3/0.510.231
 Ballooning, mean/SD1.6/0.501.7/0.470.092
 Lobular inflammation, mean/SD1.8/0.551.7/0.550.267

Patients were seen for inclusion into the study after 6, 12, and 18 months (final examination) and were subjected to physical examination and blood sampling. Evaluation via telephone was carried out at 3-, 9-, and 15-month intervals. UDCA and placebo were shipped to the participating medical centers and were handed to randomized patients upon entry into the study after 6 and 12 months. Regular drug intake was determined by phone calls. Unused drugs were returned to the medical centers during visits, and this made calculation of patient compliance possible. Duplex ultrasonography was performed at entrance into the study and after 6, 12, and 18 months.

Primary Criterion for Evaluation: The primary criterion for efficacy was an overall improvement of liver histology after 18 months. Pre-post differences of the sum scores were compared in each group, and this was followed by a comparison of the UDCA and placebo groups.

Secondary Criteria for Evaluation: The pre-post differences of each of four histological criteria were compared and this was followed by comparison of the UDCA and placebo groups. Further pre-post differences for the liver function tests and for the other clinical parameters were evaluated. Subgroup analyses comparing the secondary variables of the UDCA group with those of the placebo group included age (<50 years and ≥50 years), inflammation (sum score >7 points), improvement of alanine aminotransferase (ALT; by ≥50%), body mass index (BMI; ≤30 kg/m2 and >30 kg/m2), and blood pressure (<130/85 mm Hg and ≥130/85 mm Hg). Because in the UDCA group only 10 patients and in the placebo group only 11 patients presented with type 2 diabetes, diabetes was not used for subgroup analysis.

Symptoms and Adverse Effects

Symptoms such as fatigue, malaise, pruritis, right upper quadrant abdominal discomfort, right upper quadrant abdominal pain, and tenderness were assessed by the investigator on each visit. The sum scores of symptoms were determined according to a scale ranging from 0 to 3 (none, mild, moderate, and severe). The assessment of the safety and tolerability profile of UDCA included adverse events, laboratory data, liver biopsy, and ultrasonography. Adverse events were registered throughout the study and were coded according to MedDRA version 10.1, and the number of patients was compared between the treatment groups.

Evaluation According to NAS.

Although our study was started 3 years before publication of the NAS,2 a second evaluation was performed according to the NAS, a score in which steatosis, lobular inflammation, and hepatocellular ballooning are used as variables. The definition of NASH according to the NAS was applied to all randomized patients, and the response to therapy was assessed with the NAS. Liver biopsy samples were obtained from 137 patients; 107 (78%) underwent biopsy a second time. A 4-point scale for steatosis [(0) <5%, (1) 5%-33%, (2) >33%-66%, and (3) >66%] and lobular inflammation [(0) no foci, (1) <2 foci, (2) 2-4 foci, and (3) >4 foci] and a 3-point scale for ballooning [(0) none, (1) few, and (2) many] resulted in a maximal sum score of 8. An NAS ≥ 5 correlated with the diagnosis of NASH (n = 137), patients with scores <3 were diagnosed as not having NASH (n = 1), and patients with scores of 3 and 4 were diagnosed as having borderline NASH (n = 48; Fig. 1). The follow-up, symptoms, and adverse effects were assessed as described previously.

Data Management and Statistical Analysis

Biochemical measurements were conducted at the Central Laboratories of Dr. Spranger and Partner (Ingolstadt, Germany). Data were evaluated with SAS version 9.1 statistical software. Statistical analysis was performed by Sonja Kaftan at the Institute for Research and Development (IFE Europe GmbH, Essen, Germany).

Sample Size Calculation.

Fisher's exact test with a two-sided significance level of 0.050 is 80% capable of detecting a difference between a group 1 proportion of 0.3 and a group 2 proportion of 0.1 when the sample size in each group is 69. With a protocol violation rate of approximately 15% taken into account, 170 patients should be enrolled.

Statistical Analysis of Primary Efficacy Variables.

Pre-post differences between the histology sum scores at the baseline and at the study end were calculated for each group by the two-sided Wilcoxon rank sum test with an α-level of 5%.

Statistical Analysis of Secondary Efficacy Variables.

Pre-post differences between each of the histological criteria and pre-post differences between each of the liver function tests and the other clinical parameters were compared with the Wilcoxon rank sum test. For the comparison of each of the parameters between the treatment groups, Fisher's exact test was used.

UDCA (500-mg Ursofalk tablets) and placebo were provided by Dr. Falk Pharma GmbH (Freiburg, Germany). The placebo was identical in shape, color, and size. The patient information leaflet for study participation was prepared by IFE Europe. Before enrollment into the study, written, informed consent was obtained from each patient. The study was approved by the ethics committee of the University of Frankfurt (Frankfurt, Germany) on June 4, 2002 and by Landesärztekammer (LAEK) Hessen on June 25, 2002 according to §40 Arzneimittelgesetz (AMG), and it was in compliance with the Declaration of Helsinki.


The first patient entered the study in August 2002, and the last one completed it in April 2008. Thirty-nine of the 186 patients were removed from the ITT set because of major protocol violations. Opening of the emergency code envelope occurred for two patients. For six patients, the first biopsy sample was older than 1 month, and two patients had antinuclear antibody/smooth muscle antibody titers >1:160. For seven patients, the aspartate aminotransferase (AST) or ALT level was less than 1.5 times the upper limit of normal, and they did not have simultaneous findings indicative of metabolic syndrome. In one patient, type 2 diabetes could not be controlled sufficiently. One patient had concomitant medication (bezafibrate) for more than 48 days. In 9 patients, the date of the final visit was later than 90 days, and 11 patients were not compliant. In one patient, the first liver biopsy sample was missing; therefore, he was not included in the histological evaluation. Mean compliance was 95.50% in the ITT set [standard deviation (SD) = 10.05] and 94.66% in the placebo group (SD = 13.73).

During the study, the body weight of the patients remained constant in both groups (Fig. 2). The overall sum score of liver histology between the UDCA and placebo groups did not change significantly in the ITT set or in the PP set (PP set not shown), regardless of whether the modified Brunt score or NAS was applied (Table 4). There was a placebo effect shown by the decrease in the sum score in the placebo group. Accordingly, the primary endpoint of the study was not achieved. Of the single variables, only lobular inflammation improved when the modified Brunt score and NAS were applied (Table 4). Staging had not changed at 18 months from the baseline in the UDCA and placebo groups (P for the ITT set = 0.133; PP set not shown; Table 4).

Figure 2.

Mean weights at the baseline and on the final visit (ITT set, n = 186). Differences were not significant (NS) between the UDCA and placebo groups or within each group at the onset of therapy and at the study end.

Table 4. Liver Histology at 18 Months from Treatment Onset and Pre-Post Therapy Differences (ITT Set)
VariableUDCAPlaceboP Value
  • *

    Lobular, portal/periportal, and bridging.

Modified Brunt scoren = 94n = 91 
 Overall histology   
 Lobular inflammation   
NASn = 69n = 68 
 Overall histology   
 Lobular inflammation   

In subgroup analyses of the secondary variables in UDCA-treated patients (ITT and PP sets), significant improvement in lobular inflammation in comparison with placebo-treated patients could be allocated to males (P < 0.011), patients ≤50 years old (P < 0.002), patients with a BMI ≤30 kg/m2 (P < 0.023), patients with a blood pressure ≥130/85 mm Hg (P < 0.018), patients with a histology sum score >7 (P < 0.005), patients with an ALT level ≥ 80 U/L at the baseline (P < 0.025), and patients in whom the decrease in ALT after 18 months of therapy was at least 50% of the baseline (P < 0.004). In patients with a BMI ≤30 kg/m2, centrilobular fibrosis also improved significantly (P < 0.046; PP set not shown). In patients of the placebo group in whom the ALT level after 18 months had dropped by at least 50%, lobular inflammation was just below significance (P = 0.07).

During therapy, levels of AST, ALT, alkaline phosphatase (AP), and γ-glutamyl transferase (GGT) improved in both treatment groups, but differences between the two treatment groups were not significant, except for GGT (Table 5). Subgroup analyses did not provide any significant differences (data not shown).

Table 5. Pre-Post Differences in the Laboratory Data at 18 Months After Treatment Onset (ITT Set)
Variable*UDCAPlaceboP Value
  • *

    For normal values, see Table 2.

Total bilirubin, mean/SD0.15/0.89−0.24/0.910.061
AST, mean/SD−16.46/30.83−14.30/28.840.917
ALT, mean/SD−40.63/58.37−38.15/62.600.851
AP, mean/SD−10.52/47.65−9.43/43.880.792
GGT, mean/SD−52.42/64.19−16.84/53.98<0.0001
Albumin, mean/SD0.22/3.62−0.66/4.260.289
Triglycerides, mean/SD−0.18/1.19−0.17/1.210.828
Cholesterol, mean/SD−85.09/109.04−88.29/105.530.973
Glucose, mean/SD−0.19/2.24−0.08/2.490.193
Iron, mean/SD−0.31/7.83−0.58/7.500.530

The sum score of symptoms was not different between the two study groups at the baseline and at the end of the study. In both groups, symptoms revealed a numerical decrease over the study period. Subgroup analyses showed that only in patients with a BMI ≤30 kg/m2 did right upper quadrant abdominal discomfort improve significantly (P < 0.032) in the PP set. No safety issues were raised during this long-term study with the high dose of UDCA. A total of 28 adverse drug reactions were reported in 21 patients; 16 adverse drug reactions occurred in the UDCA group, and 12 occurred in the placebo group. Diarrhea was the predominant reaction in the UDCA group and occurred more often in comparison with the placebo group (11 events versus 1 event). All reactions except one (fatigue in the UDCA group) were documented with mild or moderate intensity, and all reactions were transient. No patient dropped out because of drug reactions or died during the course of the study.


The aim of this study was to investigate the effect of high-dose UDCA on liver histology and on liver function tests in patients with NASH.

Our study has shown that a high dose of UDCA (23-28 mg/kg of body weight/day) over a treatment time of 18 months was unable to improve overall liver histology in comparison with placebo, and this confirms the results of an earlier study using a lower dose over a period of 24 months.28 For the evaluation of histological changes, we used a scoring system that included steatosis, lobular inflammation, ballooning, and fibrosis (suitable for grading and staging)1 and the NAS.2 The results obtained with the two scoring systems were highly similar. With the modified Brunt score, progress from one histological stage of the disease to the next was not observed. Lobular inflammation was the only variable that improved regardless of the scoring system applied. However, because lobular inflammation just missed significance in a subgroup of the placebo group, even this result is not firm. This could explain why liver function tests remained unchanged between the two treatment groups, except for GGT. In contrast to our observations, in a recent study with 126 patients treated with UDCA (30 mg/kg/day) over a period of 12 months, UDCA significantly improved ALT, AST, and GGT levels; data on liver histology were not given.29

Why did UDCA not affect NASH despite previous investigations showing positive results? First of all, in most of the studies, the number of patients was too small, the treatment time was too short, or a control group was missing. Second, a positive effect of UDCA on the suggested pathogenetic mechanisms has been shown in only a few investigations with a small number of experimental animals and a few patients. Finally, the anticipation of an effect of UDCA on NASH probably depends on an incorrect assumption. Until now, positive effects of UDCA have been observed only in primary biliary cirrhosis,30 but NASH does not present with features of biliary liver diseases.

Our study has two drawbacks. First, NASH possibly is a patchy disease with unevenly distributed histological lesions,31, 32 and second, intrarater agreement on lobular inflammation and hepatocyte ballooning is only moderate to good.33, 34 In other words, the two variables would often make the diagnosis difficult with a second biopsy sample; furthermore, there are no data on whether the two variables indicate a progressive and more severe course of the disease.34 Therefore, the evaluation of second biopsy samples taken months or years later from a different region of the liver often renders an assessment of positive or negative therapy effects difficult or even impossible.

With respect to the patchy character of NASH and the problems of intrarater agreement for hepatocyte ballooning and lobular inflammation,34 the question arises whether it would not be better to include a larger spectrum of clinical and histological variables (e.g., insulin resistance, cytokines, and lobular and portal fibrosis) and to prolong the treatment time and increase the number of biopsy procedures. However, the latter consideration could be questionable from an ethical perspective.


The NASH study group includes the following members: Ulrich F. H. Leuschner, M.D. (Interdisziplinäres Facharztzentrum Sachsenhausen, Frankfurt, Germany); Birgit Lindenthal, M.D. (Zentrum der Inneren Medizin, Johann Wolfgang Goethe-Universität, Frankfurt, Germany); Günter Herrmann, M.D. (Klinikum Ludwigsburg, Pathologisches Institut, Ludwigsburg, Germany); Joachim C. Arnold, M.D. (Medizinische Klinik, Diakoniekrankenhaus, Rotenburg/Wümme, Germany); Martin Rössle, M.D. (Praxiszentrum für Gastroenterologie, University Hospital, Freiburg, Germany); Hans-Jörg Cordes, M.D. (Interdisziplinäres Facharztzentrum Sachsenhausen, Frankfurt, Germany); Stefan Zeuzem, M.D. (Zentrum der Inneren Medizin, Johann Wolfgang Goethe-Universität, Frankfurt, Germany); Jasper Hein, M.D. (Private Praxis, Innere Medizin, Marburg, Germany); Thomas Berg, M.D. (Medizinische Universitäts-Klinik und Poliklinik II, Leipzig, Germany); Hanns Löhr, M.D. (Private Praxis, Gastroenterologic, Hepatologie, Wiesbaden, Germany); Bernd Möller, M.D. (Leberzentrum Berlin, Germany); Stefan Pape, M.D. (Endopraxis Paderborn, Germany); Irini Vafiadi-Zoubouli, M.D. (Laiko Hospital, Athens, Greece); Epaminondas Tsianos, M.D. (Hospital of Ioannina Dourouti, General District University, Ioannina, Greece); Kurt Grüngreiff, M.D., Ph.D. (Private Praxis, Innere Medizin, Gastroenterologie, Magdeburg, Germany); Elias Kouroumalis, M.D. (Department of Gastroenterology, General District University Hospital of Heraklion Voutes, Heraklion, Greece); and Matthias Pirlich, M.D. (Elisabeth Klinik Berlin, Germany). Markus Menges, M.D., PhD, (Evangelisches Diakoniewerk, Schwäbisch Hall, Germany); Dietrich Hüppe, M.D., (Private Praxis, Gastroenterologie, Hepatologie, Herne, Germany); Karl M Teubner, M.D., (Private Praxis, Ambulante Gastroenterologie, Stuttgart, Germany) Johanna Preiss, M.D., (Private Praxis, Innere Medizin, Herne, Germany); Axel Holstege, M.D., (Medizinische Klinik L Klinikum Landshut, Landshut, Germany); Manfred Lutz, M.D., PhD, (Caritasklinik, Saarbrücken, Germany); Lutz T Dieekmann, M.D., (Private Praxis, Innere Medizin, Gastroenterologie, Wittenberge, Germany); Karl J Goerg, M.D., (St. Josef Krankenhaus, Wuppertal, Germany); and Werner Swobodnik, M.D., (Private Praxis, Gastroenterologie, Vilshofen, Germany).