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MEETING REVIEW
Best of DDW 2004
Highlights from the 2004 Digestive Disease Week
May 15-20, 2004, New Orleans, LA
[Rev Gastroenterol Disord. 2004;4(3):129-161]
© 2004 MedReviews, LLC
Key words: 5-Aminosalicylic acid • Barrett’s esophagus • Cholestatic liver disease • Colonoscopy •
Crohn’s disease • Endoscopic retrograde cholangiopancreatography • Endoscopic therapy •
Endoscopic ultrasound • Extracorporeal shock wave lithotripsy • Fine-needle aspiration • Gastroesophageal
reflux disease • Helicobacter pylori • Hepatitis C • Hepatocellular carcinoma • Inflammatory bowel disease •
Irritable bowel syndrome • Liver transplantation • Nonalcoholic fatty liver disease • Pancreatic stones •
Probiotics • Ulcerative colitis • Viral hepatitis • Virtual colonoscopy
T
en of our contributing editors potential for biologic therapies to treat reported expanded data from a group
were among the attendees at the ulcerative colitis and of conventional of 32 patients with severe, steroid-
2004 Digestive Disease Week therapies to reduce disease-related refractory ulcerative colitis treated
(DDW) meetings in New Orleans. Here complications, such as cancer. The with 2 daily doses of visilizumab
they highlight the most noteworthy most impressive results arise from at either 15 g/kg or 10 g/kg.2 Of
presentations in their respective areas early trials of anti-CD3 monoclonal note, because of the potential risk of
of expertise, including novel treat- antibodies to treat severe ulcerative reactivating Epstein-Barr virus (EBV)
ments for ulcerative colitis, Crohn’s colitis, but additional low-tech bio- infections, all patients were negative
disease, and irritable bowel syn- logics (“probiotics”) and conventional for exposure to EBV. The initial ther-
drome; advances in liver disease and therapies such as mesalamine are apies induced a “cytokine-release
transplantation; new insights into also highlighted in this summary. syndrome” consisting of fatigue,
Helicobacter pylori; updates on endo- nausea, vomiting, fever, chills, and
scopic therapy for gastroesophageal Anti-CD3 Monoclonal Antibody dehydration, which occurred in 75%
reflux disease and Barrett’s esopha- Based on a preliminary report from to 100% of patients treated with the
gus; and the latest technologies in DDW 2003, Plevy and colleagues1 15 g/kg dose. A smaller proportion
the screening, diagnosis, and therapy described remarkable initial results (38%-75%) of patients receiving the
of gastrointestinal cancers. with visilizumab (Nuvion; Protein 10 g/kg dose also developed the
Design Labs [PDL], Fremont, CA), a cytokine release syndrome, despite
Medical Therapies for humanized anti-CD3 monoclonal anti- pretreatment with corticosteroids and
Ulcerative Colitis body administered to patients with acetaminophen. Subsequent to the
DDW 2004 included a series of severe, steroid-refractory ulcerative acute cytokine release symptoms,
reports describing the expanding colitis. This year, the same group most of the patients rapidly
VOL. 4 NO. 3 2004 REVIEWS IN GASTROENTEROLOGICAL DISORDERS 129Best of DDW 2004 continued
improved, were discharged within 1 14 days of ≥ 30 mg of prednisone) els tested. Treatment with the
to 3 days after visilizumab infusions, and 10 patients with severe disease daclizumab antibody product was
and were followed up to and a poor predictor of response after well tolerated. Although PDL has
1 year. Sixty-three percent of the 3 days of intravenous hydrocortisone, reportedly discontinued the program
15 g/kg dosing group remained 400 mg/d, or incomplete response after for daclizumab in ulcerative colitis,
relapse-free and off steroids after 7 days of intravenous hydrocortisone. positive results in asthma will con-
12 months. At the time of the meet- Patients were treated with a single 40 tinue to be pursued.
ing, 56% of patients in the 10 g/kg mg intravenous dose of basiliximab There are numerous differences
group were remaining in the study in addition to their ongoing steroid between these 2 trials with discrepant
and only 22% relapsed after a mean therapy. At the 8-week endpoint of results. The most important was
of 5 months. Post anti-CD3 infusion, the trial, 14 of 20 patients (70%) in the the placebo control group in the
T cell depletion persisted from 1 hour steroid-resistant group had achieved daclizumab study. In addition, the
basiliximab trial enrolled only steroid-
resistant patients and used a totally
Recent evidence suggests that antibodies to the interleukin-2 receptor may clinical index. In the placebo-con-
act as a steroid sensitizer in resistant ulcerative colitis. trolled daclizumab trial, a sigmoido-
scopic index was included in the Mayo
index, which may also have been a
to 2 weeks and returned to baseline a clinical remission (UCSS ≤ 2) as did more difficult endpoint to achieve.
levels within 2 to 6 weeks. EBV titers 5 of 10 patients in the severe group,
were noted to have risen in 80% of with the nonresponders either receiv- Novel Drug Therapies
patients but returned to baseline levels ing cyclosporine or proceeding to Otsuka America Pharmaceutical
as T cell numbers returned to normal. colectomy. The investigators reported (Rockville, MD) has entered into the
Despite the transient T cell depletion, no infusion reactions, although 2 field of ulcerative colitis with the ini-
no serious infectious complications patients developed herpes zoster. tial trial of OPC-6535, a novel thia-
were observed. The remarkable and Overall, the authors reported an 80% zole class of agents that inhibit cyclic
rapid efficacy and long-term response improvement rate and 63% remission adenosine monophosphate with phos-
suggest that either depletion of an rate and called for a large, random- phodiesterase-4 inhibitory properties.6
activated T cell population or, perhaps, ized, controlled trial. In vitro and animal trials have
repopulation by a T regulatory cell Protein Design Labs performed demonstrated that this compound
population may account for the ben- such a trial with a different anti- has neutrophil inhibitory properties,
efits. Future trials will continue to CD25 antibody: daclizumab (marketed including prevention of adhesion
explore optimal dosing regimens, as Zenapax). In a press release during and production of leukotriene B4,
long-term efficacy, and the potential DDW, PDL reported on a randomized, lysozyme, myeloperoxidase, superox-
risk of infections (including reactiva- double-blind, placebo-controlled phase ide, and platelet activating factor. In
tion of EBV) in these steroid-refrac- II clinical trial that enrolled 159 a multicenter, double-blind, placebo-
tory patients. patients at approximately 40 sites in controlled trial, 186 patients with
North America and Europe.5 Patients mild to moderate ulcerative colitis—
Ups and Downs With with active ulcerative colitis were including patients on stable doses of
Anti-CD25 Therapy randomized to receive daclizumab at 5-aminosalicylic acid (ASA) agents—
Recent evidence suggests that antibod- 1 mg/kg at a 4-week interval for a received oral dosing of either placebo
ies to the interleukin-2 (IL-2) receptor total of 2 doses, 2 mg/kg every 2 or OPC-6535 at doses of
may act as a steroid sensitizer in resist- weeks for a total of 4 doses, or 25 mg/d or 50 mg/d. Although the
ant ulcerative colitis.3 In a follow-up placebo. The primary study objec- primary endpoint of clinical improve-
report at DDW by Creed and cowork- tives were safety and achievement of ment—reduction of the Disease
ers,4 the initial series of patients remission, defined by the proportion Activity Index (DAI) by 3 points—was
treated with basiliximab (chimeric of patients who achieved remission not achieved because of a high, 40%
anti-CD25 monoclonal antibody) was after 8 weeks according to the Mayo placebo response, secondary end-
expanded to 20 steroid-resistant score. The primary efficacy endpoint points of reduced rectal bleeding and
patients (ulcerative colitis symptom in the study did not meet statistical physician global assessments were met,
score [UCSS] ≥ 6 despite at least significance at either of the dose lev- as was the total change in DAI scores.
130 VOL. 4 NO. 3 2004 REVIEWS IN GASTROENTEROLOGICAL DISORDERSBest of DDW 2004
Patients receiving an average con- ratio (OR) of colorectal cancer (OR = to induce remissions in subsequent
comitant 5-ASA dose greater than 0.25; 95% CI, 0.15-0.40) or any neo- controlled trials. Although the concept
2.2 g/d (27% of patients were receiving plasia (OR = 0.47; 95% CI, 0.24-0.92), of helminth therapy in preventing
more than 2.4 g/d) improved equally thus supporting the role of 5-ASA in the development of IBD (and other
to those not receiving concomitant both maintaining remissions and autoimmune disorders) is distinct
medications, and in post hoc analyses, lowering the risk of developing neo- from the potential of these probiotics
patients with more moderate disease plasia in ulcerative colitis. to treat ongoing inflammation, the
activity did demonstrate statistically novelty and apparent benignity pro-
superior results according to the Low-Tech Biologics vide a contrast to the manufactured,
improvement in DAI and remission at In contrast to the “high-tech” manu- high-tech, high-cost, and potentially
the 50 mg dose. There were early cases factured proteins described above, or toxic monoclonal antibody therapies.
of headache and nausea that subse- to conventional medical therapy to [Stephen B. Hanauer, MD]
quent studies have demonstrated can treat ulcerative colitis, the group from
be reduced by incremental increases in the University of Iowa has been Treatment of Crohn’s Disease
dose over a week. Large phase III exploring the potential of helminth Azathioprine and 6-Mercaptopurine
induction and maintenance trials with therapy to ameliorate inflammatory Azathioprine withdrawal in patients
this new class of drugs are in progress. bowel disease (IBD).10 Summers and with Crohn's disease maintained in
associates11 described the results of prolonged remission under treatment
Old Drugs a randomized, controlled trial of is associated with a high risk of
Gionchetti and colleagues7 performed Trichuris suis, a pig whipworm that relapse. A randomized trial of aza-
an open trial in 16 patients with pou- does not produce disease in humans, thioprine withdrawal in patients
chitis refractory to 1 month of antibi- for treatment of ulcerative colitis. In with Crohn’s disease in remission for
otic therapy that was treated with an
8-week course of budesonide, 9 mg
daily. Twelve of the 16 patients (75%) Summers and associates described the results of a randomized, controlled
went into remission within 8 weeks, trial of Trichuris suis, a pig whipworm that does not produce disease in
and both overall pouchitis activity humans, for treatment of ulcerative colitis.
scores and “quality of life” improved,
thus affording another option of ther-
apy for this difficult group of patients. the study, 54 patients with active > 42 months on azathioprine failed
Additionally, there is expanding evi- ulcerative colitis were randomized to to demonstrate noninferiority for aza-
dence for the chemopreventive proper- receive 2500 T. suis ova or placebo, thioprine withdrawal (n = 43, relapse
ties of 5-ASA in ulcerative colitis. The given orally in a charcoal solution rate of 21.3% over 18 months) com-
Mt. Sinai group led by Victoria Croog8 every 2 weeks for 12 weeks. At the pared with continued azathioprine
reported on a group of 321 patients conclusion of the trial, 43% of (n = 37, relapse rate 7.9%).12 After the
without dysplasia who have been patients treated with helminth ova 18-month withdrawal trial ended,
undergoing colonoscopic surveillance had a decrease of at least 4 points in 23 of 37 patients assigned to contin-
since 1996. The investigators reported DAI compared with 17% of patients ued azathioprine then discontinued
that 16.5% of the patients developed randomized to the placebo solution. azathioprine; thus 66 patients discon-
any neoplasia, although 5-ASA users Remission rates were not reported. Of tinued azathioprine (43 + 23).13 The
had significantly lower rates of pro- interest, no worms or ova were cumulative probability of relapse at 18,
gression to advanced neoplasia and reported in the stool; however, Dr. 36, and 54 months was 19%, 53%, and
likely (P = .12) to any neoplasia. Summers did report seeing worms in 60%, respectively. Among the patients
Similarly, Velayos and colleagues9 the colons of a few patients undergo- who relapsed after azathioprine with-
performed a meta-analysis from obser- ing colonoscopy. drawal, retreatment with azathioprine
vational studies evaluating the asso- These optimistic results must be was successful in 96%. Azathioprine
ciation of oral 5-ASA use and the confirmed in larger controlled trials, withdrawal is associated with a high
development of dysplasia or cancer. and a dose response requires testing. risk of relapse, even if patients have
Their pooled analysis of 6 studies Although these results are most been in remission for 42 months or
involving 1031 subjects found that intriguing, it remains to be determined more; therefore, azathioprine with-
the use of 5-ASA reduced the odds whether pig whipworms will be able drawal cannot be recommended.
VOL. 4 NO. 3 2004 REVIEWS IN GASTROENTEROLOGICAL DISORDERS 131Best of DDW 2004 continued
Azathioprine and 6-mercapto- infliximab monotherapy induction that prednisone, but not infliximab
purine use for IBD is associated with as compared with 20 of 25 patients or other immunosuppressive agents,
an increased risk of lymphoma. Six (80%) who received combination was an independent predictor of seri-
studies designed to determine whether induction therapy with infliximab plus ous infections. In this large registry,
cancer is an adverse event of azathio- azathioprine (P > .10). At 1 year, 13 of infliximab had a safety profile similar
prine or 6-mercaptopurine therapy for 20 patients (65%) were successfully to other Crohn’s disease treatments.
IBD have been performed. A meta- maintained on infliximab monother- The effectiveness of immunosup-
analysis of these 6 studies was per- apy as compared with 16 of 25 patients pression in suppressing the formation
formed to determine whether these (64%) receiving azathioprine mainte- of antibodies to infliximab in Crohn's
agents are associated with an increased nance therapy (P > .10). Overall, induc- disease. On-demand or episodic
risk of lymphoma.14 Eleven cases of tion of remission with the combination infliximab treatment is associated
lymphoma were identified, yielding a of infliximab and azathioprine was with the formation of antibodies to
pooled standardized incidence ratio not superior to infliximab alone in a infliximab (ATI) in up to 61% of
of 4.18 (95% CI, 2.07-7.51). These
data suggest an approximately 4-fold
increased risk of lymphoma among Azathioprine withdrawal is associated with a high risk of relapse, even if
patients with IBD treated with aza- patients have been in remission for 42 months or more; therefore, aza-
thioprine or 6-mercaptopurine. Based thioprine withdrawal cannot be recommended.
on incidence rates of lymphoma in the
United States, the results suggest that
1 additional lymphoma will result group of patients with active steroid- patients, resulting in infusion reac-
from between 300 and 4500 person- dependent Crohn’s disease, and main- tions and loss of efficacy. Concomitant
years of follow-up, depending on the tenance therapy with infliximab was immunosuppression reduces the risk
age of the patient. This low absolute as effective as azathioprine. of ATI formation. It is unknown
risk suggests that the risk–benefit Safety of infliximab in Crohn’s whether azathioprine (including 6-
ratio of azathioprine and 6-mercap- disease: data from the TREAT reg- mercaptopurine) or methotrexate are
topurine with respect to the risk of istry. The TREAT (Crohn’s Therapy, equally effective for this treatment
developing lymphoma is acceptable Resource, Evaluation and Assessment indication. In the study by Noman
for most patients. Tool) registry comprises 5807 patients and colleagues,17 153 patients with
with Crohn’s disease who are being Crohn’s disease treated with inflix-
Infliximab prospectively followed to determine imab on demand were divided into
A prospective, randomized trial of the safety of infliximab (2850 have 3 groups: 1) infliximab monotherapy
infliximab and azathioprine for the received infliximab and 2957 have (n = 59), 2) infliximab plus azathio-
induction and maintenance of remis- not).16 The mean follow-up is 0.9 years. prine (n = 65), and 3) infliximab plus
sion of steroid-dependent Crohn's Infusion reactions occurred in 5.4% methotrexate (n = 29). Infliximab and
disease. Forty-five patients with active of 11,504 infusions, severe reactions ATI concentrations (Prometheus
steroid-dependent Crohn’s disease in 0.16%. Mortality was similar for Laboratories, San Diego, CA) were
were randomized to induction treat- infliximab-treated patients and con- determined serially. Antibodies to
ment with infliximab monotherapy trols (0.53 per 100 patient-years vs infliximab were detected during fol-
5 mg/kg at 0, 2, and 6 weeks, fol- 0.51). The incidence of neoplasms in low-up in 73% of patients receiving
lowed by maintenance therapy with the 2 groups was similar (0.53 per monotherapy with episodic inflix-
infliximab 5 mg/kg every 8 weeks for 100 patient-years in infliximab- imab, compared with 48% in patients
1 year or combination induction treated patients vs 0.49 in controls). receiving azathioprine plus episodic
treatment with infliximab 5 mg/kg The incidence of serious infections infliximab and 38% in patients
at weeks 0, 2, and 6 plus azathioprine was 1.27 per 100 patient-years with- receiving methotrexate plus episodic
2.5 mg/kg/d, followed by maintenance in 3 months of an infliximab infu- infliximab. Both azathioprine and
therapy with azathioprine 2.5 mg/kg.15 sion versus 0.85 in patients who had methotrexate significantly reduce
Steroids were rapidly tapered and dis- not received an infliximab infusion the frequency of ATI formation in
continued by week 6. Sixteen of 20 within the previous 3 months (relative patients receiving episodic infliximab
patients (70%) achieved remission and risk [RR] = 1.51; 95% CI, 0.86-2.65; therapy. There were no significant
steroid withdrawal at week 6 with P = .11). Logistic regression showed differences in the frequency of ATI
132 VOL. 4 NO. 3 2004 REVIEWS IN GASTROENTEROLOGICAL DISORDERSBest of DDW 2004
formation between patients treated ment-limiting acute or delayed infu- 2 doses, and 6 mg/kg every 4 weeks
with azathioprine and those treated sion reactions, or loss of efficacy. The for 2 doses showed a significant
with methotrexate. fully human IgG1 monoclonal anti- short-term benefit for natalizumab in
body to TNF, adalimumab, was admin- patients with active Crohn’s disease.20
Adalimumab istered to 24 patients with Crohn’s A large phase III study in 905
A randomized, double-blind, place- disease who had previously received patients with active Crohn’s disease
bo-controlled trial of the human and responded to the infliximab but (ENACT-1 [Evaluation of Natalizumab
anti–tumor necrosis factor- mon- who no longer had a sustained as Continuous Therapy]) failed to show
oclonal antibody adalimumab for response and/or could not tolerate a benefit for natalizumab 300 mg
the induction of remission in infliximab because of acute or every 4 weeks for 3 doses, primarily
patients with moderate to severely delayed infusion reactions.19 Patients because of an unexpectedly high
active Crohn’s disease. Adalimumab were treated with subcutaneous adal- placebo response rate.21 Initial post hoc
is a fully human IgG1 monoclonal imumab, 80 mg loading dose at week exploratory analyses of the ENACT-1
antibody that targets tumor necrosis 0 followed by 40 mg every other trial demonstrated significant effects
factor (TNF). In the study by Hanauer week through week 12. The dose of for subgroups of patients with CRP
and associates,18 299 infliximab-naïve adalimumab was increased to 40 mg concentrations elevated above the
patients with active Crohn’s disease weekly if patients did not have a normal range and patients taking
were randomized to receive 1 of
4 treatments administered subcuta-
neously at week 0 and week 2 (week Adalimumab is effective in the treatment of active Crohn’s disease.
0/week 2): 160 mg/80 mg adali-
mumab, 80 mg/40 mg adalimumab,
40 mg/20 mg adalimumab, or place- complete clinical response at week 4. immunosuppressive medications. In
bo/placebo. At week 4, 30% of All 24 patients were able to tolerate this study, an additional post hoc
patients who received adalimumab adalimumab (including 14 who pre- subgroup analysis was performed to
80 mg/40 mg or 160 mg/80 mg viously experienced treatment-limit- determine whether natalizumab is
achieved remission (Crohn’s Disease ing acute hypersensitivity reactions potentially of benefit to patients with
Activity Index [CDAI] < 150) com- and 6 who previously experienced active Crohn’s disease who have pre-
pared with 12% who received placebo, delayed hypersensitivity reactions viously been treated with infliximab.22
P = .004 (primary endpoint for the with infliximab). Nineteen patients Of the 905 patients in the ENACT-1
study). Statistically significant results required dose escalation to 40 mg induction study, 360 had previously
were not dependent on baseline C- weekly. At week 12, clinical response been treated with infliximab. Clinical
reactive protein (CRP) concentration. (decrease in CDAI score ≥ 100 points) response (decrease in CDAI ≥ 70
The remission rates at week 4 for occurred in 59% of patients and points) at week 10 (time of primary
each of the 4 dose groups were: remission (CDAI < 150) in 29% of endpoint) in this subgroup occurred
placebo, 12%; 40 mg/20 mg, 18% patients. Among patients with fistulas, in 54% of natalizumab-treated
(P > .05 vs placebo); 80 mg/40 mg, fistula improvement (closure of ≥ 50% patients compared with 35% in the
24% (P > .05 vs placebo); and 160 of fistulas) occurred in 56% of patients placebo group (P = .004). A trend
mg/80 mg, 36% (P < .05 vs placebo). and complete fistula closure occurred toward increased clinical remission
Adalimumab is effective in the treat- in 33% of patients. (33% for natalizumab vs 22% for
ment of active Crohn’s disease. placebo, P = .064) was also observed.
An open-label study of the human Natalizumab Natalizumab may be of benefit as an
anti-TNF monoclonal antibody adal- Efficacy assessment of natalizumab induction agent in patients with
imumab in subjects with prior loss in patients with Crohn’s disease and active Crohn’s disease who have pre-
of response or intolerance to inflix- prior history of anti-TNF therapy: viously been treated with infliximab.
imab for Crohn’s disease. Infliximab results from ENACT-1. Natalizumab, A phase III, double-blind, placebo-
is a chimeric IgG1 monoclonal anti- a humanized IgG4 monoclonal anti- controlled study of the efficacy,
body to TNF with significant potential body to 4 integrin, blocks trafficking safety, and tolerability of Antegren
for immunogenicity. With repeated of leukocytes to the gut. A phase II (natalizumab) in maintaining clinical
episodic administration, many patients study of intravenous natalizumab at response and remission in Crohn’s
treated with infliximab develop treat- 3 mg/kg, 3 mg/kg every 4 weeks for disease (ENACT-2). The 339 patients
VOL. 4 NO. 3 2004 REVIEWS IN GASTROENTEROLOGICAL DISORDERS 133Best of DDW 2004 continued
who responded to natalizumab in the bo, with either a 4-week interval had a CRP concentration > 10 mg/L
phase III induction study (ENACT-1) between the first and second injec- (n = 35). At day 56, the remission
were re-randomized in a natalizumab tions (cohort 1) or no interruption rates (CDAI < 150) were 0%, 54%,
withdrawal study during which they (cohort 2). In cohort 2, patients and 57% for the placebo, 4 mg/kg,
received maintenance therapy with receiving 3 mg/kg showed signifi- and 10 mg/kg groups, respectively
natalizumab 300 mg or placebo every cantly increased rates of clinical (P < .05 for both the 4 mg/kg
4 weeks through 12 months (the response (decrease in CDAI score and 10 mg/kg groups vs placebo).
ENACT-2 trial).23 At 6 months, 61% ≥ 100 points) compared with placebo Fontolizumab may be of benefit as
of natalizumab-treated subjects con- (75% vs 25%, P = .032) and remission an induction agent in patients with
tinued to meet the criteria for clinical (CDAI < 150) (38% vs 0%, P = .066). active Crohn’s disease who have ele-
response as compared with 29% of Treatment with 3 mg/kg anti–IL-12 vated CRP concentrations.
subjects re-randomized to receive monoclonal antibody was signifi- [William J. Sandborn, MD]
Advances in Liver Disease
Treatment with 3 mg/kg anti–IL-12 monoclonal antibody was significantly Liver Transplantation
more effective than placebo for induction of clinical improvement and Nearly 15,000 hepatologists and gas-
remission in patients with active Crohn’s disease. troenterologists attended DDW 2004.
Here, we present a number of abstracts
presented to the members of the
placebo, P < .001 (primary study end- cantly more effective than placebo American Association for the Study
point). Forty-four percent of patients for induction of clinical improvement of Liver Diseases (AASLD).
in the natalizumab treatment group and remission in patients with active Patients are usually curious about
maintained clinical remission at 6 Crohn’s disease. how long the liver allograft (and they)
months, compared with 26% in the will last following liver transplanta-
placebo group (P = .003). In addition, Fontolizumab tion. This has been difficult informa-
55% of natalizumab-treated subjects Fontolizumab (HuZAF), a humanized tion to come by because United
taking steroids in ENACT-1 re-ran- anti–IFN- antibody, has clinical Network of Organ Sharing (UNOS)
domized to natalizumab in ENACT-2 activity and excellent tolerability in global survival data and most center-
were withdrawn from steroids at 6 moderate to severe Crohn’s disease. based reports focus on short-term
months, compared with 25% re-ran- IFN- is a cytokine that is elevated in (1-5–year) survival. Given the rapid
domized to placebo (P < .001). patients with active Crohn’s disease progress in immunosuppressive regi-
Natalizumab was significantly more and is believed to play a role in the mens and surgical techniques that have
effective than placebo for mainte- Th1 inflammatory response charac- dramatically improved survival over
nance of response, remission, and teristic of this disorder. In the study the past 2 decades, a running short-
steroid sparing at 6 months. by Hommes and colleagues,25 133 term survival figure is probably more
patients with active Crohn’s disease relevant to the patient facing liver
Anti–IL-12 Antibody were randomized to treatment with transplantation than are long-term
Anti–IL-12 treats active Crohn’s fontolizumab (a humanized mono- data. Nonetheless, the abstract by
disease. IL-12 is the pivotal cytokine clonal antibody to IFN-) at doses Smith and colleagues26 at Duke
driving the T-helper type 1 (Th1) of 4 mg/kg or 10 mg/kg, or placebo. University Medical Center on median
inflammatory response (TNF and The first 42 patients received a liver allograft survival is of interest.
interferon gamma [IFN-]) in patients single treatment; the subsequent 91 The UNOS scientific registry was
with Crohn’s disease. In the study by patients received 2 infusions (days 0 queried for survival of all grafts from
Mannon and coworkers,24 79 patients and 28). A nonsignificant trend 1988 through 1996 (19,717 trans-
with active Crohn’s disease were treat- in response at day 28 was observed: plants). Median graft survival (esti-
ed in a phase II placebo-controlled 33% versus 38% versus 44% for mated time at which 50% of grafts
trial with a human anti–IL-12 (anti- the placebo, 4 mg/kg, and 10 mg/kg had been lost) was calculated by
p40) monoclonal antibody (ABT- groups, respectively (P = .660 for Kaplan-Meier analysis. Median graft
874/J695). Patients were randomized 4 mg/kg and P = .375 for 10 mg/kg). survival in recipients who received
to 7 weekly subcutaneous injections Post hoc analyses were performed transplants for autoimmune hepati-
of 1 or 3 mg/kg of ABT-874 or place- in patients who received 2 doses and tis, cholestatic liver disease (primary
134 VOL. 4 NO. 3 2004 REVIEWS IN GASTROENTEROLOGICAL DISORDERSBest of DDW 2004
biliary cirrhosis [PBC] or primary transplantation between 1988 and 50 patients treated with pegylated
sclerosing cholangitis [PSC]), alcoholic 2001. As previously reported by oth- interferon and weight-based ribavirin
liver disease, or chronic hepatitis C ers, hepatitis C was associated with (800-1400 mg/d). By week 12, the
was 13.4, 12.6, 9.2, and 9.1 years, decreased 5-year patient and graft hemoglobin had fallen to less than
respectively. Primary grafts lasted far survival compared with other indica- 12 g/dL in 59% and to less than
longer than retransplants (12.0 vs tions; this was seen with transplanta- 10 g/dL in 26%. Thirteen patients met
1.5 years), irrespective of the etiology tion of liver alone (70% vs 73% and criteria for growth factor support
of liver failure. These data confirm 62% vs 70%, respectively) or sequen- (darbepoetin 3 g/kg every other week)
other data that show graft survival is tial liver-kidney transplantation (54% and 10 of 13 required support within
lower in patients who receive trans- vs 67% and 58% vs 74%, respectively), the first 12 weeks. Hemoglobin levels
plants for chronic hepatitis C. It is but not when both organs were trans- rose by an average of 1.27 g/dL, and
not clear how these numbers will planted at the same time (69% vs 66% 83% of supported patients were able
change in the era of MELD (Model for and 66% vs 60%, respectively). The to maintain the prescribed dose of
ribavirin. These data are quite similar
to those recently reported by Afdahl
Clearly, growth factors provide a valuable tool to maintain early antiviral and colleagues,29 in which 88% of
drug dosing when this is critical to achieving a treatment response. erythropoietin-treated patients were
However, this approach may be very expensive. able to maintain a full ribavirin dose
versus only 60% treated without
growth factor support.
End-Stage Liver Disease) priority and presence of diabetes reduced 5-year Clearly, growth factors provide a
with more effective patient manage- patient and graft survival in recipients valuable tool to maintain early
ment, including evolving immuno- of livers alone (67% vs 74%, respec- antiviral drug dosing when this is
suppressive regimens and antiviral tively) but did not affect survival for critical to achieving a treatment
treatment for recurrent hepatitis C. combined transplants, either simulta- response. However, this approach may
Finally, the graft survives only if the neous or sequential. In conclusion, be very expensive. Del Rio and col-
host survives, so improving long-term renal insufficiency in patients with leagues30 formulated a decision model
graft survival requires aggressive hepatitis C and diabetes may be an to examine the impact of erythropoi-
management of common risk factors indication for combined liver-kidney etin treatment on the cost for achieving
and comorbidities, such as diabetes, transplantation. Survival is better sustained viral response to combina-
hypertension, hyperlipidemia, smok- when these organs are transplanted tion therapy. Some of the assumptions
ing, and obesity. simultaneously instead of sequentially of the model might be questioned,
as the second organ fails. The mech- such as waiting until 4 weeks to ini-
Hepatitis C anisms that explain these observations tiate growth factor treatment and
Chronic hepatitis C is the main indi- need to be further investigated. reducing the ribavirin dose instead of
cation for liver transplantation, and increasing the erythropoietin dose if
diabetes is the major indication for Viral Hepatitis there was not a satisfactory hemo-
renal transplantation. Diabetes is Ribavirin causes a hemolytic anemia globin increase after 4 weeks.
quite common in patients with and results in a dose-dependent reduc- Nonetheless, it was projected that
chronic hepatitis C. Many patients tion in hemoglobin levels during the growth factor treatment of patients
referred for transplantation already first 8 weeks of treatment. Between with at least a 3 g/dL hemoglobin fall
have end-organ effects of diabetes 9% and 23% of patients require rib- would increase sustained viral
that sometimes require consideration avirin dose reductions, and this may response in genotype 1 patients.
of combined liver-kidney transplan- significantly reduce both early and However, this strategy resulted in an
tation. Bajaj and colleagues27 at the sustained viral responses. Furthermore, incremental cost of $185,236 to
Medical College of Wisconsin exam- anemia contributes to fatigue and $202,043 per sustained viral respon-
ined the UNOS database to look at other treatment-related symptoms. der. These costs, if confirmed, are
survival in cadaveric grafts of liver Therefore, several strategies to reduce simply too high to support unrestricted
alone or liver-kidney (either simulta- early dose reductions are being studied use of erythropoietin in all treated
neous or sequential) in recipients with and were reported at DDW 2004. patients with anemia. Growth factor
chronic hepatitis C who underwent Younassi and colleagues28 studied support should be carefully considered
VOL. 4 NO. 3 2004 REVIEWS IN GASTROENTEROLOGICAL DISORDERS 135Best of DDW 2004 continued and perhaps restricted to those patients group at Boehringer Ingelheim but drops in aminotransferase levels with hepatic fibrosis who are at higher Pharmaceuticals who reported the suggest an anti-inflammatory action; risk of progressive liver injury. results of a 2-day course of treatment therefore, caution is warranted. Longer Another strategy for reducing ane- with their protease inhibitor BILN 2061 courses of treatment are required to mia is to replace ribavirin with at the 2002 meeting of the AASLD.32 determine histologic effects on inflam- another drug that might achieve sim- The drug caused marked but transient mation and fibrosis, as well as any ilar antiviral effect without causing inhibition of HCV RNA, but further impact on viral levels. It is helpful anemia. Viramidine is a synthetic development was slowed by animal to recall the experience with IL-10 in nucleoside analogue that is orally model toxicity and resistance in a cell- which short courses resulted in strik- bioavailable and concentrates in the based system. Since then, progress has ing reductions in hepatic fibrosis, but liver, where it is converted to ribavirin, been slow. longer courses inhibited viral specific resulting in lower systemic ribavirin Schiff and colleagues33 at several immunity, resulting in enhanced HCV levels and less hemolysis. Gish and other institutions reported a dose- replication and disease progression.34 colleagues31 reported on a controlled finding study with IDN-6556, an It will be exciting to hear about sub- trial comparing treatment with pegy- antiapoptotic caspase inhibitor that sequent studies with IDN-6556. lated interferon and viramidine (400, is also being studied as an agent to Coinfection with HCV is common 600, or 800 mg twice daily) to stan- reduce transplant allograft preserva- in patients with human immunodefi- dard treatment with pegylated inter- tion injury. The effect of inhibiting ciency virus (HIV) infection. Several feron and ribavirin (1000-1200 mg/d). The rate of fall of hepatitis C virus (HCV) RNA was slightly slower Despite the fact that few candidate drugs have shown much promise, in the viramidine-treated subjects, there remains considerable optimism and excitement about development but after 24 weeks of therapy, the of new drugs that inhibit the hepatitis C replicative enzymes. proportion of subjects with more than a 2 log drop in virus was the same in all groups (83%). The propor- apoptosis in the setting of virus- studies have suggested that liver dis- tion in each group with undetectable induced liver disease is not known. ease from HCV infection progresses virus was also similar after 24 weeks. Although the drug might reduce more rapidly in this setting, and it As predicted, the proportion of patients inflammation and resulting fibrosis, has recently been observed that deaths with a fall in hemoglobin to less than it could just as well reduce apoptosis from liver disease are common in 10 g/dL was far less in those who of virus-infected cells or activated coinfected patients.35,36 It is not clear received viramidine (400 or 600 mg stellate cells, thereby promoting the whether the observed severity of liver twice weekly—0% and 800 mg twice progression of liver injury. Despite disease in coinfected patients is weekly—7%, vs 24% in the ribavirin- these uncertainties about the action simply a result of the impact of HIV treated group). Other symptoms were of the drug, results from this study on the HCV infection or whether similar, which was somewhat surpris- show that 14 days of IDN-6556 sig- other factors explain the difference. ing given the lower incidence of ane- nificantly lowered serum aspartate Alcohol use and low CD4 counts mia in the viramidine groups. This aminotransferase (AST) and alanine have been shown to be major factors study was not powered to look at aminotransferase (ALT) levels in all in liver-related mortality in coinfect- sustained viral responses, but trials dose groups, though twice-daily dos- ed patients.37 In fact, the combination studying those issues are currently ing at the highest dose (100 mg twice of infection in the era before highly under way. daily) was most effective and nor- active antiretroviral therapy (HAART), Despite the fact that few candidate malized AST or ALT in all 6 subjects alcohol use, and low CD4 count were drugs have shown much promise, studied at that dose. Of 48 patients associated with a 12-fold higher there remains considerable optimism enrolled in the study, only 1 had mortality risk. However, El-Serag and and excitement about development of a change in HCV RNA of more than colleagues38 performed a retrospective new drugs that inhibit the hepatitis C 1 log, and that subject (100 mg twice analysis of 16,439 HIV-infected replicative enzymes, including the daily) cleared HCV RNA. The drug patients (4761 of whom were HCV serine protease, helicase, and RNA- was well tolerated. Thus, it appears co-infected) in the Veterans Admin- dependent RNA polymerase. The first that IDN-6556 does not affect viral istration hospital system. Annual encouraging report came from the replication, at least with short courses, mortality in the coinfected group was 136 VOL. 4 NO. 3 2004 REVIEWS IN GASTROENTEROLOGICAL DISORDERS
Best of DDW 2004
6.27% compared with 12.22% in the of lamivudine resistance increases resistance at weeks 48, 96, and 144
HIV-monoinfected group. After con- with the duration of treatment, it has was 0%, 3.0%, and 5.9%, respectively.
trolling for age, race, gender, year of drawbacks in patients with hepatitis In conclusion, long-term adefovir
diagnosis, and HIV severity, the rela- B e antigen (HBeAg)-negative chronic results in profound and sustainable
tive risk of death in the coinfected hepatitis B. Adefovir dipivoxil, on the suppression of HBV DNA and ALT
group in the HAART era was 0.83 other hand, has potent antiviral levels in most patients with the
compared with patients infected with activity against hepatitis B virus HBeAg-negative variant of chronic
HIV alone. (HBV) and is active against lamivu- hepatitis B. Drug-resistant mutations
Common epidemiologic risk fac- dine-resistant mutations of HBV. occur late and are uncommon. Thus,
tors explain the high prevalence of Furthermore, adefovir-resistant muta- adefovir appears to be a more attrac-
HCV infection in HIV-infected patients. tions are uncommon. Hadziyannis tive antiviral agent than lamivudine
It appears that HIV alone does not and associates42 previously reported when long-term therapy is anticipated.
explain progressive liver disease in the results of a 48-week randomized [Gary L. Davis, MD]
coinfected patients. Rather, coinfect- trial comparing adefovir 10 mg/d to
ed patients, like HCV-monoinfected placebo in patients with HBeAg-neg- More From the AASLD
Some of the studies of greatest interest
in the areas of hepatocellular carci-
The importance of screening and surveillance, earlier diagnosis with noma, cholestatic liver disease, and
improved tests, and more aggressive and novel forms of therapy are rec- nonalcoholic fatty liver disease are
ognized as major unmet needs in patients with cirrhosis at risk for or reviewed here.
having developed hepatocellular carcinoma.
Hepatocellular Carcinoma
Hepatocellular carcinoma (HCC) is
patients, often have other risk factors, ative chronic hepatitis B. After 48 the most common primary malignant
such as alcohol use, male gender, and weeks, original placebo recipients were tumor involving the liver. The inci-
age more than 40 years, that put them crossed over to treatment and the dence of HCC has risen dramatically
at increased risk of progressive liver adefovir arm continued treatment. The in the United States and Europe over
disease. Several studies recently pub- original placebo and adefovir arms the past decade secondary to high
lished in abstract form have shown have now completed 96 and 144 prevalence rates of chronic hepatitis C,
that HCV infection may be successful- weeks of treatment, respectively, and with many patients having developed
ly treated with pegylated interferon Hadziyannis’ group43 reported the advanced disease that increases the
and ribavirin, although the sustained updated results at DDW 2004. risk for HCC. The importance of
viral response rate is 15% to 20% less Treatment with adefovir over 144 screening and surveillance, earlier
than in those without HIV infec- weeks resulted in significant and diagnosis with improved tests, and
tion.39-41 Thus, HIV-coinfected indi- continued reductions of HBV DNA more aggressive and novel forms of
viduals, and indeed all HCV-infected levels, with an increasing proportion therapy are recognized as major unmet
patients, should be counseled to avoid becoming undetectable (mean log needs in patients with cirrhosis at risk
alcohol. Treatment should be consid- change in HBV DNA: -3.47 at 96 for or having developed HCC.
ered in coinfected patients with ade- weeks, -3.63 at 144 weeks; percent Several papers presented at the
quate CD4 counts, and the decision with undetectable HBV DNA by poly- AASLD brought new knowledge
to initiate therapy should be based on merase chain reaction [PCR]: 71% at regarding HCC. It has long been rec-
histologic injury, risk of progressive 96 weeks, 79% at 144 weeks). Serum ognized that chronic HBV is a major
liver injury, and absence of con- ALT levels were normal in 73% at risk factor for the development of
traindications to therapy. 96 weeks and 69% at 144 weeks. The HCC. Recent studies have shown that
Patients who have HBeAg-negative drug continues to appear safe. Elevated mutations in the HBV basal core pro-
chronic hepatitis B often do not have serum creatinine (≥ 0.5 mg/dL above moter and precore viral regions may
the sustained suppression of virus baseline) appeared in 3 of the 170 be predictive indicators for the devel-
necessary for discontinuation of study participants and resolved in opment of HCC. In an ongoing long-
antiviral therapy. Therefore, these 1 with continued therapy and the term study of 1536 Alaska Natives
patients require long-term suppres- other 2 after stopping the drug. with chronic HBV infection, it had
sive treatment. Because the prevalence The cumulative incidence of adefovir been shown previously that there was
VOL. 4 NO. 3 2004 REVIEWS IN GASTROENTEROLOGICAL DISORDERS 137Best of DDW 2004 continued
an unusually high distribution of role for Helicobacter pylori in hepa- sound every 6 months and AFP every
genotype F in this population and tocarcinogenesis associated with HBV 3 months, with evaluation of an ele-
a significant association between and HCV infections to help explain vated AFP level with either CT or MRI.
genotype F and HCC.44 The aim of the the variable rates of HCC in different PIVKA-II was evaluated in a random
study by Simonetti and colleagues45 regions.47 A PCR test using H. pylori subset of 112 of the 143 patients,
was to determine the prevalence of primers and urease B primers in liver including 75 with low AFP levels and
basal core promoter and precore tissue was used to study patients with 37 with high AFP levels. Results of
mutations in this cohort of patients HCC associated with HBV or HCV this study showed that baseline AFP
with HCC. No association was found infection. Controls consisted of in cirrhotics with HCV infection is not
between either of these mutations and patients with metastatic liver cancer, a good predictor of the risk of HCC
the occurrence of HCC, indicating cirrhosis, or a normal liver. PCR using and has a 96% false-positive rate. In
that patients with chronic HBV infec- the H. pylori primers was positive in addition, serial monitoring with AFP
tion and genotype F are not at higher 87% of patients with HCC, 36% with detected only 14% of HCC. On the
risk of HCC if they have either of metastatic liver cancer, and 0% among other hand, PIVKA-II reduced the
these 2 mutations. those with cirrhosis or a normal liver. false-positive rate seen with AFP and
Another study examined the preva- Similarly, PCR analysis with urease B had a better predictive value. Thus,
lence rate of occult HBV infection in primers was positive in 83% of HCC the combination of AFP with PIVKA-
II may help improve the outcomes of
screening strategies in HCC in high-
There is a major need to make an earlier diagnosis of HCC in high-risk risk patients with cirrhosis secondary
patients undergoing regular screening or surveillance. to chronic hepatitis C. In a related
presentation, Tateishi and colleagues49
presented a systematic review of the
patients with HCC from a region with a cases versus 7% of patients with diagnostic accuracy of tumor markers
low prevalence of chronic hepatitis B.46 metastatic liver cancer, and none of for small HCC. The authors evaluated
Occult HBV infection was defined by the patients with cirrhosis or a nor- the diagnostic ability of AFP, PIVKA-
the presence of HBV DNA in either mal liver. These data are preliminary II, and lens culinaris agglutinin reac-
the serum or the liver of individuals and provocative, but suggest the tive fraction of AFP (AFP-L3). After
with a negative hepatitis B surface potential role for H. pylori in hepato- reviewing all relevant articles regard-
antigen (HBsAg). Although a high carcinogenesis. ing these 3 tumor markers and calcu-
prevalence rate of occult HBV infec- There is a major need to make an lation of receiver operator curves, it
tion has been reported in patients earlier diagnosis of HCC in high-risk was shown that AFP was less useful
with HCC from Asia, little informa- patients undergoing regular screening in the diagnosis of small HCC than was
tion is available on the prevalence of or surveillance. Although commonly PIVKA-II and AFP-L3.
occult HBV infection in HCC patients used, serum -fetoprotein (AFP) has Another paper addressed the chal-
from a low-prevalence region of significant limitations in both sensi- lenge in making an accurate diagnosis
chronic hepatitis B. In this retrospec- tivity and specificity. Many patients of HCC based on the increased sensi-
tive study of 19 cases of primary with cirrhosis secondary to HCV tivity of modern CT and MRI scanners,
liver cancer, including 18 typical HCC infection will have elevations of AFP particularly the difficulty in distin-
cases, from Baltimore, Maryland, without evidence of HCC. Preliminary guishing hypervascular pseudolesions
occult HBV was found in 3 of 19 evidence had suggested that the addi- (HPLs) from true HCC. Byrnes and
cases (16%).46 In all cases, HBV DNA tion of a second tumor marker, des-- coworkers50 conducted a study to
copy numbers were low, with each carboxyprothrombin (protein induced evaluate the fate of arterial-enhancing
case containing less than 10 copies/g vitamin K absence or antagonist II nodules on MRI in cirrhotic livers. A
liver DNA. In summary, occult HBV [PIVKA-II]) was associated with a total of 101 arterial-enhancing nodules
infection was found in 16% of HCC higher risk of HCC. In a prospective were identified on the initial MRI of
cases in a low HBV prevalence region. study of 453 patients, Kalmowitz and 28 patients with cirrhosis, and these
A third paper provided novel infor- associates48 evaluated baseline AFP patients were followed longitudinally.
mation regarding potential patho- and PIVKA-II levels and the risk for This study is ongoing, but preliminary
genetic mechanisms of HCC. Data were subsequent development of HCC. analysis of data showed that 94% of
presented that showed a potential Patients were followed with ultra- arterial-enhancing nodules within
138 VOL. 4 NO. 3 2004 REVIEWS IN GASTROENTEROLOGICAL DISORDERSBest of DDW 2004
the cirrhotic liver remained stable or In another study, the role of and has been increasingly recognized
regressed over time, and were most colchicine for the treatment of PBC, in the pediatric population. In an
likely consistent with HPLs. The which has remained controversial, was interesting study, Schwimmer and
authors concluded that nodule growth studied by a careful analysis of pub- coworkers55 sought to analyze differ-
remains the sole discriminating feature lished data. Vela and associates54 ences in children with pediatric ver-
between HCC and HPL, and follow-up systematically searched the literature sus adult-type NASH histology. Type
with serial MRI is a necessary part of for prospective controlled trials of 1, or adult-type, NASH was defined
tumor surveillance in these patients. colchicine for PBC and performed as steatosis with ballooning degener-
The final provocative study on new a meta-analysis. They were able ation and/or perisinusoidal fibrosis
diagnostic tests showed that a tumor to identify 6 controlled trials with with or without lobular inflammation
proliferation marker was associated
with recurrence of HCC following liver
transplantation.51 The authors studied Based on the growing epidemic of obesity in the United States and the
the expression of minichromosome Western world, nonalcoholic fatty liver disease has become the most com-
maintenance protein-2 and cyclin A mon cause of chronic liver disease. The disease is not isolated to adults
in 67 patients who received trans- and has been increasingly recognized in the pediatric population.
plants for HCC. On mean follow-up
of 47.5 months (range, 6-196 months),
minichromosome maintenance pro- 389 subjects for their meta-analysis. and without portal inflammation or
tein-2 was the strongest independent Their pooled analysis of controlled fibrosis. Type 2, or pediatric-type,
factor associated with tumor recur- trials suggests that colchicine is indeed NASH was defined as steatosis with
rence. The authors speculate that tumor an effective treatment for decreasing portal inflammation and/or fibrosis
biopsy to assess proliferative activity mortality, delaying the need for liver without perisinusoidal fibrosis or
may improve the current patient transplantation, and preventing the lobular inflammation. Type 2 NASH
selection criteria for liver transplan- development of major complications was found to be associated with male
tation for HCC, which is currently of cirrhosis. The only caution in their gender, greater adiposity, and non-
based on the Milan criteria of either conclusions was that this beneficial white race. Further studies are need-
1 tumor of < 5 cm in diameter or up effect might not be observed outside ed to define differences in pathogen-
to 3 tumors < 3 cm in diameter.52 of a trial setting. esis and natural history and treatment
response in both children and adults,
Cholestatic Liver Disease Nonalcoholic Fatty Liver Disease particularly children with type 1 and
Osteoporosis is a well-recognized Nonalcoholic fatty liver disease type 2 NASH.
complication of PBC. Limited pilot (NAFLD) encompasses a spectrum of Another study attempted to address
studies have suggested that alen- conditions characterized histological- the true prevalence rate of NAFLD in
dronate might improve bone mineral ly by macrovesicular hepatic steatosis the United States. There are as of yet
density (BMD) in patients with PBC, and clinically by features of the meta- no established noninvasive criteria for
but no randomized placebo-controlled bolic syndrome without excessive the diagnosis of NAFLD, making it
trial has been conducted to date. Zein consumption of alcohol. There are 2 difficult to assess its true prevalence
and colleagues53 presented a study in general subtypes of NAFLD: fatty liver, rate. Huang and colleagues56 compared
which 27 patients with PBC and osteo- which appears to be benign and not the prevalence of metabolic syndrome
porosis were enrolled in a double- progressive, and nonalcoholic steato- in patients with biopsy-proven NAFLD
blind, randomized, placebo-controlled hepatitis (NASH), which is associated with a matched controlled population,
trial. Patients with PBC and osteo- with inflammation and fibrosis and and determined the prevalence of
porosis were randomized to receive may progress to advanced fibrosis, NAFLD among these controls using
alendronate 70 mg/wk or placebo end-stage liver disease, and HCC. various biochemical criteria. They
over the course of 1 year, with mon- Based on the growing epidemic of compared 71 NAFLD patients seen
itoring of BMD. This carefully con- obesity in the United States and the over the past 2 years with National
ducted study showed that alendronate Western world, NAFLD has become Health and Nutrition Examination
was well tolerated and improved the most common cause of chronic Survey (NHANES) III controls. They
BMD in patients with PBC and osteo- liver disease. found that patients with biopsy-
porosis when compared with placebo. NAFLD is not isolated to adults proven NAFLD were significantly
VOL. 4 NO. 3 2004 REVIEWS IN GASTROENTEROLOGICAL DISORDERS 139Best of DDW 2004 continued more likely to have the metabolic proven NASH. Huang and coworkers59 substantial decline in hospitalizations syndrome, but 29% of controls also sought to determine whether dietary for complicated peptic ulcer disease had criteria indicating the presence of intervention would be an effective in the United States.60 Complicated metabolic syndrome. Thus, the exact method of improving histologic fea- peptic ulcer disease hospitalizations prevalence of NAFLD in the United tures of NASH. Patients with a BMI declined from 166,725 in 1998 to States remains unknown, as various > 25 kg/m2 and biopsy-proven NASH 139,597 in 2001. There were 2 sharp biochemical criteria can produce dis- received standardized nutritional periods of decline: the first in 1996 parate values ranging from 2.4% to counseling weekly for 2 months, (11%), coinciding with the National 10%, based on laboratory criteria. biweekly for 4 months, and then Institutes of Health (NIH) consensus It has long been recognized that monthly for 6 months, aimed at reduc- conference on H. pylori, and the sec- both alcohol and obesity are associ- ated with hepatic steatosis, but the combined effect of these 2 factors The authors’ novel conclusion was that the risk of alcohol-related liver on liver injury remains unknown. Ruhl injury was limited to persons who were either overweight or obese, based and Everhart57 examined the relation- on body mass index. ship between alcohol consumption and obesity in adult patients with elevated serum ALT levels from 13,607 patients ing insulin resistance and promoting ond in 1999 (8%), coinciding with who participated in NHANES III. gradual weight loss. Baseline liver the release of COX-2 specific Elevated ALT levels, as a surrogate biopsy was available, and then repeat- inhibitors in the United States. for liver injury, was associated with ed at month 12. Two thirds of the Reinfection after H. pylori eradi- consumption of more than 2 drinks patients with NASH (10/15) displayed cation: a study in Alaskan Natives. per day and overweight and obesity. histologic improvement, and no patient Reinfection with H. pylori was studied The authors’ novel conclusion was demonstrated disease progression in in a group of Alaskan Natives who that the risk of alcohol-related liver this small, 1-year study. Because had undergone successful eradication.61 injury was limited to persons who were there is no specific pharmacologic Ninety-five patients were followed for either overweight or obese, based on therapy proven to be beneficial for 2 years or until reinfection was doc- body mass index (BMI). NASH, this structured approach to umented. Reinfection occurred in 14 In another provocative study, car- weight loss warrants further study. subjects (14.5% cumulative reinfec- diac abnormalities were identified [Emmet B. Keeffe, MD] tion rate at 2 years). Multivariate as a new manifestation of NAFLD. analysis of risk factors demonstrated Goland and associates58 studied 26 H. pylori that a diagnosis of peptic ulcer dis- patients with NAFLD compared with DDW 2004 provided new insights into ease at entry into the study and failure an age- and gender-matched control the epidemiology, pathology, diagnosis, to graduate from high school were group. All patients underwent an and treatment of H. pylori infection. factors related to reinfection. There echocardiographic study and also was no significant difference in the had a normal exercise test. There was Epidemiology prevalence of infection in family a highly significant difference in intra- Several aspects of the epidemiology members. Five of 9 household ventricular septum thickness, left of H. pylori infection remain uncer- members (56%) of reinfected individ- ventricular mass, and left ventricular tain, particularly the spread of infec- uals were infected with H. pylori, diastolic function. The authors con- tion within and across families, the whereas 43 of 96 household members cluded that further investigation is effect of H. pylori eradication on the (45%) of individuals who were not required on a larger cohort of patients, incidence of complications of peptic reinfected had evidence of H. pylori but these preliminary studies suggest ulcer disease, and the incidence of infection by breath test (P = .73). that patients with NAFLD have early reinfection with H. pylori. These data suggest that the presence features of left ventricular diastolic Decreasing rates of complicated of infected individuals in the family dysfunction. peptic ulcer disease. An analysis of setting does not account for reinfec- Finally, a small pilot study sug- the Nationwide Inpatient Sample tion. Surrogate markers of socioeco- gested that dietary intervention was (a large sample of community hospi- nomic status (such as high school an effective approach to improving talizations in the United States) education) appear to be better pre- histology in patients with biopsy- demonstrated that there has been a dictors of reinfection. 140 VOL. 4 NO. 3 2004 REVIEWS IN GASTROENTEROLOGICAL DISORDERS
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