Umaprasanna S Karnam

Prevalence of occult celiac disease in patients with iron-deficiency anemia: a prospective study.

Background Occult celiac disease has been reported in 0 to 6% of adults presenting with iron-deficiency anemia. Most prior studies have been retrospective or screened only a selected population of patients with small bowel biopsies. To more accurately define the true prevalence of this disorder in patients presenting with iron-deficiency anemia (with or without stool hemoccult positivity), we initiated this prospective study. Methods Esophagogastroduodenoscopy with small bowel biopsies and colonoscopy were performed in all iron-deficiency anemia patients (including those with hemoccult-positive stools) referred to the gastroenterology service during a 2-year period (1998–2000). Inclusion criteria included iron-deficiency anemia as defined by a serum ferritin <25 ng/ml and anemia with hemoglobin <12 g/dl. Patients were excluded for documented prior erosive, ulcerative, or malignant disease of the gastrointestinal tract, previous gastrointestinal surgery, overt gastrointestinal bleeding within the past 3 months, or inability to access the duodenum for biopsy. All patients underwent upper endoscopy with more than two biopsies of the distal duodenum and colonoscopy. A serum immunoglobulin A antiendomysial antibody test was to be performed in those patients with a positive small bowel biopsy to confirm the diagnosis of celiac disease. Results One hundred five of 139 consecutive patients with iron-deficiency anemia met the inclusion criteria and were enrolled in the study. Fifty-seven men (mean age, 51.6 yr) and 48 women (mean age, 54.1 yr) constituted the study population. The demographics of this study population included 36 blacks, 38 Hispanics, and 22 whites. Nine patients were of mixed or unknown ethnic background. Forty-three and eight-tenths percent of the men and 37.5% of women had hemoccult-positive stools, accounting for a total of 40.9% of the study patients. Upper endoscopic findings included gastritis in 22.8%, gastric ulcers in 9.5%, duodenitis in 8.5%, esophagitis in 7.6%, Barrett’s ulcer in 2.8%, duodenal ulcer in 2.8%, gastric polyp in 2.8%, and celiac disease in 2.8%. Colonoscopic findings included colon polyps in 21.9%, diverticula in 10.4%, and hemorrhoids in 16.1%. Multiple findings were found in 32.3% of patients, and there were no findings in 28.5% of patients. Conclusion The prevalence of occult celiac disease in this prospective study of patients presenting with iron-deficiency anemia was 2.8%. A significant number of other gastrointestinal lesions amenable to therapy were also found on upper and lower endoscopy in these patients. Given the treatable nature of celiac disease, it should be screened for in patients with unexplained iron-deficiency anemia with or without hemoccult-positive stools.

Acquired hyperplastic gastric polyps in solid organ transplant patients

Abstract OBJECTIVE: We report a series of patients who developed hyperplastic gastric polyps after solid organ transplantation. METHODS: A retrospective review of patients with solid organ transplantation from January 1997 to December 1999 was performed. Patients with gastric polyps found during endoscopy were included. Demographic data, polyp characteristics (endoscopic and histological), time of endoscopy, and treatment regimens were analyzed. RESULTS: A total of 10 (seven men, three women) transplanted patients (six cardiac, three liver, and one kidney) with gastric polyps were identified. The median age was 61 yr (27–71 yr), and median time of endoscopy after transplantation was 11 months (3–28 months). Eight patients had endoscopy before or soon after transplantation, with no evidence of polyps. Nine patients had multiple polyps (three or more), and one had a single pedunculated polyp. Polyps were confined to the antrum in eight patients, antrum and body in one patient, and fundus in one patient. All polyps biopsied were found to be hyperplastic and without adenomatous or malignant changes. Cytomegalovirus serology was negative in nine patients. Each patient received standard immunosuppression that included a calcineurin inhibitor and steroids. Steroids were tapered and stopped by 3 months. Azathioprine was added in five patients and mycophenolate mofetil in one patient. CONCLUSIONS: The development of gastric polyps after organ transplantation has not been previously reported. The development of these gastric polyps (hyperplastic and multiple) is concerning as a malignant potential has been recognized in patients harboring multiple hyperplastic gastric polyps. The exact cause of these polyps is unknown. The association with immunosuppressive therapy as well as the natural history of these acquired hyperplastic gastric polyps needs further investigation.

CASE REPORT: Visceral Varicella Zoster After Bone Marrow Transplantation: An Obscure Cause of an “Acute Abdomen”

Reactivation of latent infection with the varicellazoster virus (VZV) is a common cause of morbidity and mortality after bone marrow transplantation (BMT) (1). The incidence of reactivation ranges from 17% to 52% with the highest rate of recrudescence (70%) occurring within the first six months of transplantation (1–3). In up to 90% of cases reactivation of latent virus is associated with the familiar vesicular skin eruption in a dermatomal distribution; however, in this immunosuppressed group, both cutaneous and visceral dissemination can occur (4). Visceral presentation with VZV infection has been reported in approximately 1% of bone marrow transplant recipients, the majority occurring after allogeneic transplantation. Although relatively uncommon, visceral VZV infection is likely underdiagnosed and is frequently lethal. A 50% mortality from adult respiratory distress syndrome, multiorgan failure, meningoencephalitis, fulminant hepatic failure, and/or severe pancreatitis has been reported (5). Diagnosis is difficult, as the characteristically poorly localized abdominal pain may precede the vesicular eruption by as many as 10 days. This report describes VZV presenting as acute abdomen without cutaneous signs of infection as a late complication of autologous BMT.

A toast to pentoxifylline.

The aim of this study was to evaluate the efficacy of pentoxifylline in patients with severe acute alcoholic hepatitis. Pentoxifylline is a nonselective phosphodiesterase inhibitor that decreases tumor necrosis factor (TNF) gene transcription. Elevated TNF levels have been found in the sera of patients with alcoholic hepatitis, and hence the rationale for this large scale study was to definitively address the therapeutic role of pentoxifylline in this disease. The study was conducted in the liver unit at the University of Southern California in patients with a history of heavy alcohol abuse and a clinical diagnosis of acute alcoholic hepatitis. Inclusion criteria for patients in the study were jaundice; Maddrey discriminant factor (DF) of ≥32 and one or more of the clinical or laboratory parameters of fever, palpable tender hepatomegaly, white blood cell count of >12,000/ml3 with predominantly neutrophilic differentiation, hepatic encephalopathy, and hepatic systolic bruit. Enrollment into the study was attempted within the first 10 days after admission. Exclusion criteria included concomitant bacterial infections, active GI hemorrhage, or severe cardiopulmonary disease, and clinical evidence of advanced alcoholic cirrhosis. A histological diagnosis was not required for inclusion in the study, as the investigators feared that severely ill, coagulopathic patients might not be able to undergo a percutaneous liver biopsy. The study was a prospective, double blind, randomized, placebo-controlled study. The two primary endpoints were the effect of pentoxifylline on 1) the short term survival (during the index hospitalization or over the 28-day study period) and 2) progression to hepatorenal syndrome (HRS). Secondary endpoints were the effect of pentoxifylline on 1) the course of laboratory parameters, including serum TNF levels, and 2) development of clinical complications of liver disease.One hundred two patients were enrolled and randomized to receive either pentoxifylline 400 mg t.i.d. for 4 wk or a placebo. Patients with previous hepatic decompensation (n = 22), hepatic encephalopathy (n = 10), and renal impairement (serum creatinine of >2.4 mg/dl, n = 9 patients) were also included. There were no significant differences between the two groups for any of the demographic or clinical variables. Among the pentoxifylline group, 78% received medication until the completion of 28 days or until death, whereas in the control group 92% received placebo capsules for 28 days or until death. The mean period of treatment was 21 (21.5 ± 9.5) days for both groups, thereby providing active treatment for a sufficient period. Reasons for discontinuation in the pentoxifylline group included headache, GI symptoms, and generalized skin rash.Plasma TNF levels were available for 60 patients (29 in the pentoxifylline group and 31 in the control group). Baseline TNF levels were above the normal range in all patients from both groups. There were no differences between the two groups at randomization or at any time during the treatment period in absolute values or in changes from baseline when all patients or only survivors of the two groups were compared. When only the nonsurvivors were compared, control patients had higher TNF values than pentoxifylline-treated patients at wk 1, 2, and 4.In this study, 25% and 46% in the pentoxifylline and control arms died (p = 0.037, reluctant risk [RR] = 0.59, 95% CI = 0.35–0.97) after a range of 5–54 days and 7–139 days, respectively. In the patients who died, hepatic failure with HRS had developed in 50% in the pentoxifylline group and 92% in the control group. New onset renal failure occurred in 11% and 43% in the pentoxifylline and control groups, respectively (p = 0.001, RR = 0.35, 95% CI = 0.15–0.77), and progressed to HRS in 80% and 90% of patients, respectively, in the two groups (p = 0.0015, RR = 0.32, 95% CI = 0.13–0.79). In multiple logistic regression analysis, two variables (DF and age) were independently associated with survival in the control group, and one variable (creatinine) in the pentoxifylline group. Three variables (creatinine, age, and treatment with pentoxifylline) were independently associated with survival in the two groups combined.

Bleeding gastric varices: stick to the sticky glue

In this prospective seminal study from Taiwan 74 cirrhotic patients with histories of gastric variceal bleeding were randomized to two groups. The group receiving endoscopic variceal obturation with butyl cyanoacrylate (GVO) comprised 31 patients, and the group receiving pneumatic-driven variceal ligation (GVL) comprised 29 patients. Treatment was repeated regularly until obliteration of gastric varices. All patients received emergent endoscopy within 12 h of admission to Kaohsiung Veterans General Hospital. The inclusion criteria of this study were that patients were cirrhotic, had histories of gastric variceal bleeding, and were between 20 and 70 yr of age. The definition of gastric variceal bleeding included 1) active spurting or oozing of blood from gastric varices during endoscopy and 2) stigmata of recent hemorrhage such as blood clots coating the gastric varices or the presence of hematocystic spots or white nipples on gastric varices. The exclusion criteria were 1) undetermined origin of bleeding from esophageal varices or gastric varices; 2) presence of deep jaundice (serum bilirubin > 10 mg/dl), hepatic encephalopathy, or hepatorenal syndrome; 3) association with advanced hepatocellular carcinoma, Okuda stage III, uremia, cerebrovascular accident, or other debilitating disease; 4) history of sclerotherapy or shunt operation; and 5) life expectancy < 24 h. Active bleeding occurred in 15 patients in the GVO group and 11 patients in the GVL group. The initial hemostasis rates (defined as no bleeding for 72 h after treatment) were 87% in the GVO group and 45% in the GVL group (p = 0.03). In both groups the sessions required to achieve variceal obliteration and obliteration rates were similar. However, rebleeding rates were significantly higher in the GVL group (54%) than in the GVO group (31%) (p = 0.0005). Treatment-induced ulcer bleeding was four times more common in the GVL group than in the GVO group (28% vs 7%, p = 0.03). The amount of blood transfusions was also higher in the GVL group (4.2 ± 1.3 U vs 2.6 ± 0.9 U) (p < 0.01). Twenty-nine percent of the GVO group patients died, compared to 48% of the GVL group (p = 0.05). The authors concluded that endoscopic obturation using cyanoacrylate was more effective and safer than band ligation in the management of bleeding gastric varices.

Hope or hype--cytokine therapy in ERCP-induced pancreatitis.

In a single-center study from Belgium, Deviere et al. reported the use of the anti-inflammatory cytokine interleukin (IL) 10 as prophylaxis against ERCP-induced pancreatitis. One hundred forty-four patients undergoing ERCP were randomized to receive either a placebo (group 0) or a single i.v. injection of 4 μg/kg (group 1) or 20 μg/kg (group 2) of IL-10 in a double-blinded manner. Seven patients were excluded on an intention to treat or per protocol basis. The primary endpoint of the study was the effect of IL-10 on serum hydrolases (amylase and lipase) measured at 4, 24, and 48 h after ERCP. Hyperhydrolasemia was defined as an increase in amylase and/or lipase levels more than three times normal values. The secondary endpoint was to evaluate changes in plasma cytokines (IL-6, IL-8, and tumor necrosis [TNF] serum levels) and the incidence of clinical acute pancreatitis. This was defined as hyperhydrolasemia associated with new or worsened abdominal pain persisting for more than 4 h after ERCP. The three groups were comparable for number of patients (groups 0, 1, and 2 consisted of 45, 48, and 44 patients, respectively) as well as for age, sex, underlying disease, indication for treatment, and baseline plasma levels of C-reactive protein, cytokines, and hydrolases. The authors found no significant difference in serum C-reactive protein, cytokine, and hydrolase plasma levels between the groups after ERCP. Overall, 43 of the 137 study patients developed hyperhydrolasemia. These were distributed as follows: 18 (40%) in group 0, 14 (29%) in group 1, and 11 (25%) in group 2 (p = 0.297, nonsignificant). Overall, 19 patients (of the entire study population) developed acute clinical pancreatitis and were distributed as follows: 11 (24.4%) in group 0, five (10.4%) in group 1, and three (6.8%) in group 2 (p = 0.038). Two severe cases were observed in the placebo group.Logistic regression identified three independent risk factors for post-ERCP pancreatitis: IL-10 administration (odds ratio [OR] = 0.46, 95% CI = 0.22–0.96, p = 0.039), pancreatic sphincterotomy (OR = 5.04, 95% CI = 1.53–16.61, p = 0.008), and acinarization (OR = 8.19, 95% CI = 1.83–36.57, p = 0.006). The authors conclude that a single i.v. dose of IL-10 30 min before the procedure independently reduces the frequency of post-ERCP pancreatitis.

43 – Effect of Gender on Pancreatic Disease

This chapter discusses pancreatic lesions that occur more frequently in men or women, evaluates the mechanisms by which they occur, and reviews their clinical course and therapy. Sex steroid hormones (SSH) including estrogens, progestagens, and androgens are responsible for sexual differentiation, and their major target organs are the mammary glands, urogenital tract, bone, cardiovascular and central nervous systems. Epidemiologic, clinical, and biochemical findings have shown the relationship between gender and prevalence of some tumors of the pancreas, the effect of pregnancy on insulin and glucose metabolism, and the identification of SSH receptors in pancreatic tissue. The study of gender-specific pancreatic lesions provides clues regarding their origin, development, tumoral behavior, prognosis, and more specific hormonal therapy. The varying effects of sex steroid hormones (SSH) in development and growth of pancreatic neoplasms may be related to the mechanism affecting carcinogenesis, and may be multifactorial and/or different for each hormone. Clinical trials designed to evaluate the response of cancer of the pancreas to hormonal therapy have been inconclusive.

Extending the sphincterotomy

Brand et al. prospectively studied the outcome of endoscopic sphincterotomy in 29 consecutive patients with biliary-type pain (two or more out of eight criteria), elevated liver enzyme levels (AST, ALP, or γ-glutamyltransferase), and no clear evidence of biliary pathology on transabdominal ultrasound and diagnostic endoscopic retrograde cholangiography. Elevated bilirubin levels (range = 1.3–7.2 mg/dl) were found in 18 patients. The majority of patients (n = 21) had gallbladders in situ. The findings from bile duct exploration after sphincterotomy were recorded, and pain (as measured by a visual analogue scale) and laboratory findings were assessed.The inclusion criteria for endoscopic sphincterotomy were 1) the presence of at least two of any eight characteristics associated with typical biliary-related pain (coliclike, located at the right upper abdomen, radiation to back or right shoulder, pain intensity > 4 on the visual analogue scale [possible range = 0–10], duration of pain > 30 min, postprandial pain, symptoms occurring at night, precise definition of onset and relief of pain), 2) elevated liver enzyme levels (AST, ALP, or γ-glutamyltransferase elevated more than 2-fold) in patients without histories of alcohol abuse or liver disease, and 3) absence of clear pathology on diagnostic endoscopic retrograde cholangiography—that is, no or only mild dilation of the biliary duct system (common bile duct ≤ 12 mm in patients who had undergone cholecystectomies, and ≤ 8 mm in patients with gallbladders in situ) as measured in relation to the diameter of the duodenoscope.Wire-guided sphincterotomy was successful in all patients, whereas uncomplicated pancreatitis occurred in one instance. In 16 patients (55%) there was macroscopic evidence of small stones (n = 2), sludge (n = 12), or both (n = 2) after bile duct exploration with a Dormia basket. In addition, microscopy revealed cholesterol crystals in four patients who had no macroscopic findings. All four patients with elevations of pancreatic enzymes before treatment and four of those eight patients with previous cholecystectomies demonstrated evidence of biliary pathology. The initial median pain intensity was 8 (range = 1–10); 26 patients became pain free within 3 months after endoscopic sphincterotomy. Twenty-six of 28 patients (93%) remained asymptomatic over a median follow-up period of 19 months (range = 12–26); one died of an unrelated malignancy 6 months after therapy.The authors concluded that endoscopic sphincterotomy may be acceptable therapy in patients with clinical presentations suggesting papillary or biliary origins of pain without further diagnostic workup.

Extending the sphincterotomy12

Brand et al. prospectively studied the outcome of endoscopic sphincterotomy in 29 consecutive patients with biliary-type pain (two or more out of eight criteria), elevated liver enzyme levels (AST, ALP, or γ-glutamyltransferase), and no clear evidence of biliary pathology on transabdominal ultrasound and diagnostic endoscopic retrograde cholangiography. Elevated bilirubin levels (range = 1.3–7.2 mg/dl) were found in 18 patients. The majority of patients (n = 21) had gallbladders in situ. The findings from bile duct exploration after sphincterotomy were recorded, and pain (as measured by a visual analogue scale) and laboratory findings were assessed. The inclusion criteria for endoscopic sphincterotomy were 1) the presence of at least two of any eight characteristics associated with typical biliary-related pain (coliclike, located at the right upper abdomen, radiation to back or right shoulder, pain intensity > 4 on the visual analogue scale [possible range = 0–10], duration of pain > 30 min, postprandial pain, symptoms occurring at night, precise definition of onset and relief of pain), 2) elevated liver enzyme levels (AST, ALP, or γ-glutamyltransferase elevated more than 2-fold) in patients without histories of alcohol abuse or liver disease, and 3) absence of clear pathology on diagnostic endoscopic retrograde cholangiography—that is, no or only mild dilation of the biliary duct system (common bile duct ≤ 12 mm in patients who had undergone cholecystectomies, and ≤ 8 mm in patients with gallbladders in situ) as measured in relation to the diameter of the duodenoscope. Wire-guided sphincterotomy was successful in all patients, whereas uncomplicated pancreatitis occurred in one instance. In 16 patients (55%) there was macroscopic evidence of small stones (n = 2), sludge (n = 12), or both (n = 2) after bile duct exploration with a Dormia basket. In addition, microscopy revealed cholesterol crystals in four patients who had no macroscopic findings. All four patients with elevations of pancreatic enzymes before treatment and four of those eight patients with previous cholecystectomies demonstrated evidence of biliary pathology. The initial median pain intensity was 8 (range = 1–10); 26 patients became pain free within 3 months after endoscopic sphincterotomy. Twenty-six of 28 patients (93%) remained asymptomatic over a median follow-up period of 19 months (range = 12–26); one died of an unrelated malignancy 6 months after therapy. The authors concluded that endoscopic sphincterotomy may be acceptable therapy in patients with clinical presentations suggesting papillary or biliary origins of pain without further diagnostic workup.Abstract Brand et al. prospectively studied the outcome of endoscopic sphincterotomy in 29 consecutive patients with biliary-type pain (two or more out of eight criteria), elevated liver enzyme levels (AST, ALP, or γ-glutamyltransferase), and no clear evidence of biliary pathology on transabdominal ultrasound and diagnostic endoscopic retrograde cholangiography. Elevated bilirubin levels (range = 1.3–7.2 mg/dl) were found in 18 patients. The majority of patients (n = 21) had gallbladders in situ. The findings from bile duct exploration after sphincterotomy were recorded, and pain (as measured by a visual analogue scale) and laboratory findings were assessed. The inclusion criteria for endoscopic sphincterotomy were 1) the presence of at least two of any eight characteristics associated with typical biliary-related pain (coliclike, located at the right upper abdomen, radiation to back or right shoulder, pain intensity > 4 on the visual analogue scale [possible range = 0–10], duration of pain > 30 min, postprandial pain, symptoms occurring at night, precise definition of onset and relief of pain), 2) elevated liver enzyme levels (AST, ALP, or γ-glutamyltransferase elevated more than 2-fold) in patients without histories of alcohol abuse or liver disease, and 3) absence of clear pathology on diagnostic endoscopic retrograde cholangiography—that is, no or only mild dilation of the biliary duct system (common bile duct ≤ 12 mm in patients who had undergone cholecystectomies, and ≤ 8 mm in patients with gallbladders in situ) as measured in relation to the diameter of the duodenoscope. Wire-guided sphincterotomy was successful in all patients, whereas uncomplicated pancreatitis occurred in one instance. In 16 patients (55%) there was macroscopic evidence of small stones (n = 2), sludge (n = 12), or both (n = 2) after bile duct exploration with a Dormia basket. In addition, microscopy revealed cholesterol crystals in four patients who had no macroscopic findings. All four patients with elevations of pancreatic enzymes before treatment and four of those eight patients with previous cholecystectomies demonstrated evidence of biliary pathology. The initial median pain intensity was 8 (range = 1–10); 26 patients became pain free within 3 months after endoscopic sphincterotomy. Twenty-six of 28 patients (93%) remained asymptomatic over a median follow-up period of 19 months (range = 12–26); one died of an unrelated malignancy 6 months after therapy. The authors concluded that endoscopic sphincterotomy may be acceptable therapy in patients with clinical presentations suggesting papillary or biliary origins of pain without further diagnostic workup.

Peginterferon is here to stay

The purpose of the first study was to compare the efficacy and safety of peginterferon alfa-2a (PEG IFN) administered once per wk for 48 wk s.c., with IFN alfa-2a administered three times/wk. The primary efficacy endpoints were a sustained virologic response (indicated by <100 copies/ml of hepatitis C virus [HCV]) at wk 72 and a sustained biochemical response (normalization of serum ALT to a value at or below the upper limit of normal) at wk 72. A subgroup of patients had liver biopsies done both pretreatment and 24 wk after cessation of treatment, and a histologic response (defined as a decrease of ≥2 points in the total Histological Activity Index score) was also assessed. In this study, 531 patients were randomly assigned to receive either 180 μg s.c. of PEG IFN once a wk for 48 wk (267 patients) or IFN alfa-2a 6 million U s.c. three times a wk for 12 wk followed by 3 million U s.c. three times/wk for 36 wk. In the PEG IFN group 223 of 267 patients (82.5%) completed treatment and 206 completed follow-up. In the IFN group 161 of 264 patients (61%) completed treatment and 154 completed follow-up. The baseline characteristics of the patients in the two treatment groups were similar. In an intent-to-treat analysis in which patients who missed the examination at the end of follow-up were considered as not having had a response, PEG IFN was associated with a higher rate of virologic response at wk 48 (69% vs 28%, p = 0.001) and at wk 72 (39% vs 19%, p = 0.001). The rate of sustained biochemical response at week 72 was also greater in the PEG IFN group (45% vs 25%, p = 0.001). In addition, the proportion of patients with both a sustained virologic and a biochemical response was higher in the PEG IFN group (38% vs 17%, p = 0.001). PEG IFN was associated with a 28% rate of sustained virologic response in patients infected with HCV genotype 1, whereas IFN alone resulted in <10% sustained virologic response in this subgroup. Sixty-six percent of the 531 patients had paired pre- and posttreatment liver biopsies. Histological improvement was observed in 63% of patients in the PEG IFN group and 55% of those in the IFN group. Independent factors associated with a sustained virologic response were identified as age of ≤40 yr, absence of cirrhosis or bridging fibrosis, body surface area of ≤2.0 m2, treatment with PEG IFN, HCV RNA level of ≤2 million copies/ml, pretreatment ALT quotient of >3 (ALT quotient being the average of the serum ALT values before treatment divided by the upper limit of normal), and HCV genotype other than 1. The frequency and severity of adverse effects were similar in the two groups. Psychiatric disorders were the most frequent serious adverse events, and significant anemia or thrombocytopenia was rare in both treatment groups.In the second study the efficacy and safety of PEG IFN alfa-2a in patients with HCV-related cirrhosis (76–79%) or bridging fibrosis (20–24%) were studied. In this multicenter, open label, randomized, parallel dose study, 271 patients with cirrhosis or bridging fibrosis were randomly assigned to receive treatment with 3 million U of IFN alfa-2a three times weekly (n = 88 patients), 90 μg of PEG IFN alfa-2a once weekly (n = 96), or 180 μg of PEG IFN alfa-2a once weekly (n = 87). Treatment was given for 48 wk and patients were observed thereafter for 24 more wk. Patients with decompensated cirrhosis, HIV infection, cancer, neutrophil count of <1,500/ml3, a platelet count of <75,000/ml3, and an alpha-fetoprotein of >100 ng/ml were excluded from the study. The primary endpoints and their definitions were similar to those in the study by Zeuzem et al. The secondary endpoints included virological and biochemical responses at the end of the 48-wk treatment period. Histological changes were also accessed on a 22-point Histological Activity Index (inflammation graded from 0 to 18 and fibrosis graded from 0 to 4) and defined as a positive response based on a ≥2 point decrease in the total score. Treatment was completed by 64, 78, and 67 patients, respectively, in the three groups, and follow-up was completed by 68, 79, and 74 patients, respectively, in the three groups.The rates of sustained virological response were 8%, 15%, and 30% in patients assigned to unmodified IFN alfa-2a, 90 μg of PEG IFN alfa-2a, and 180 μg of PEG IFN alfa-2a, respectively (p = 0.001 for comparison between the first and third groups). However, among patients infected with genotype 1, the response rates were 2%, 5%, and 13% in the three groups (genotype 1b had a 2-fold better response rate than 1a). It is also of note that a response at wk 12 predicted a sustained response. The rates of sustained biochemical response were 15%, 20%, and 34% in the three groups (p = 0.004 for comparison between the first and third groups). Among the patients who had paired liver biopsies, the histological responses were 31%, 44%, and 54% in patients assigned to unmodified interferon alfa-2a, 90 μg of PEG IFN alfa-2a, and 180 μg of PEG IFN alfa-2a, respectively (p = 0.02 for comparison between the first and third groups). A histological response correlated with a sustained virologic response (80–100%). The virological response was similar among patients with either bridging fibrosis or cirrhosis. Of interest, a histological response was also seen in about 26–35% of patients who did not have a sustained virological response. Even in the cohort of patients with a combination or poor prognostic factors (genotype 1, high baseline viral load of >2.0 million copies/ml), 10% of patients assigned to 180 μg of PEG IFN alfa-2a had a sustained virologic response.Safety parameters were carefully evaluated, and the proportion of patients with a neutrophil count of <500 ml3 at any time during the study was similar in the three groups (1–3%). No patient developed any serious infection or sepsis secondary to the neutropenia, and no patient had to discontinue treatment secondary to neutropenia. Even though a higher proportion of patients assigned to the higher doses of PEG IFN had a decrease in the platelet counts to <50,000/ml3, none of the patients had clinically significant bleeding secondary to the thrombocytopenia. A higher proportion of the patients assigned to the 180 μg of PEG IFN alfa-2a had myalgia and inflammation at the injection site. Four deaths were reported: two from hepatic failure, one from hepatic neoplasm, and one from suspected methadone overdose.