Monthly Archives: September 2012

RFA doesn’t always work for Barrett’s

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As noted previously in a related blog (Preventing Cancer in patients with Barrett’s Esophagus), Barrett’s esophagus (BE) is not a frequent issue in pediatric gastroenterology.  However, some esophageal problems that start in childhood can predispose to this condition later in life. Certainly, BE is a frequent clinical issue in adult gastroenterology.

Three articles in this month’s Gastroenterology provide some useful information.

  • Gastroenterology 2012; 143: 564-66
  • Gastroenterology 2012; 143: 567-75
  • Gastroenterology 2012; 143: 576-81

An editorial on these three articles is available on page 524.

The first reference describes three cases of high-grade dysplasia and adenocarcinoma that developed after ‘successful’ radiofrequency ablation (RFA).  Thus, the authors advocate continued surveillance following RFA and caution in using RFA to patients with low-risk BE.

The second reference describes an elaborate model to determine if RFA is cost-effective.  Based on their assumptions, “initial RFA might not be cost-effective for patients with BE without dysplasia.”   Though, the authors indicate that one of the cost savings was that RFA was more effective and less costly than endoscopic surveillance.  The authors acknowledge that their analysis is limited by assumptions and that the only alternative would be a large multicenter randomized trial with a long followup.

The third study examined 37 RFA patients.  22 were classified as complete responders and 15 were incomplete; complete responders had no intestinal metaplasia after fewer than 3 ablation sessions.  Risks for persistent intestinal metaplasia were uncontrolled weakly acidic reflux despite twice-daily PPI therapy, longer length of BE, and larger hiatal hernias.

Congenital hepatic fibrosis

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In a previous blog entry (Hepatic ciliopathies), I briefly discussed congenital hepatic fibrosis (CHF).  A more detailed review and handy reference: Srinath A, Shneider BL. JPGN 2012; 54: 580-87.

This invited review details information related to 1230 CHF patients from 155 articles (available at http://links.lww.com/MPG/A88).  Median and mean age of diagnosis were 2 and 11.2 years respectively.

Distribution of CHF cases/associated conditions: 118 isolated CHF, 788 autosomal recessive polycystic kidney disease, 315 with Caroli disease/syndrome, 9 with type V choledochal cyst

Clinical problems:

  • Sequelae of portal hypertension in 409 patients: 164 with varices, 74 with bleeding varicose, 81 underwent portosystemic shunting.  Portal hypertension itself was identified in 71-97% depending on the patient subset examined.
  • Cholangitis in 152 patients –often recurrent.  This was fatal in 3 of 23 children after renal transplantation.
  • Malignancy in 21 patients (2%). 19 were cholangiocarcinoma.  Of these cases, 10/19 had Caroli disease/syndrome, 7 had isolated CHF, 1 had ARPKD, and 1 had Type V choledochal cysts. Youngest patient with cholangiocarcinoma was 33 years, all other cases involved patients >40 years.

Transplantation: Isolated kidney 91 (95% in ARPKD), Isolated liver 173 (87% had Caroli), Combined 23.  Three renal patients subsequently had combined transplantation.

Other important points:

  • CHF is not ‘typically associated with progressive hepatic insufficiency.’ Only rarely is hepatic synthetic function compromised
  • Predisposition to cholangitis may affect transplantation decisions and timing

Increased bile acids in diarrhea-predominant IBS

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The role for bile acids in causation of irritable bowel gets a closer look in a recent publication (Clin Gastroenterol Hepatol 2012; 10: 1009-15).

This study randomly selected 52 participants (26 with diarrhea-predominant IBS, 26 with constipation predominant IBS) from a cohort of 700 IBS patients followed at the Mayo clinic along with 26 healthy volunteers.  The ages of the patients ranged from 29-51. Subsequently, these patients underwent additional testing following a 4-day high fat diet.  Of note, 5 of the IBS-D patients had a history of cholecystectomy compared with one patient in the other two groups.

In these patients, bile acid concentrations were measured in the stool and serum levels of 7α-hydroxy-4-cholesten-3-one (C4).In the IBS-D patients, serum levels of C4 were significantly higher than in the other two groups.  38% of the IBS-D group had elevated C4 levels; these elevated levels correlated with increased stool concentrations of bile acids.

The authors note that bile acid malabsorption has been identified frequently in patients with unexplained chronic diarrhea and that these patients often respond to bile acid sequestration (eg. cholestyramine or colesevelam).  Another interesting finding was that obesity was associated with elevated bile acid levels. Overall, the cohort with IBS-D had an average BMI of 29.5.

So, what conclusions can be drawn?

  • Serum C4 levels may be using in identifying patients with bile acid malabsorption
  • Bile acid sequestration agents may be worth a try in some cases of IBS-D and this study provides a rationale

Additional references:

-Alim Pharmacol Ther 2009; 30: 707-17.  Bile acid malabsorption in IBS-D.

Extended data with entecavir & annotated HBV management references

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Long-term data for entecavir continue to look good (Clin Gastroenterol Hepatol 2012; 10: 1047-1050).

With this study, the authors performed a post hoc analysis of 94 Asian patients with hepatitis B e antigen-positve (HBeAg+) nucleus(t)ice analogue-naive patients who received 5 years of entecavir therapy.  By five years, 66 patients remained in the study; of the other 28: 11 withdrew consent, 4 completed treatment, 5 died, 2 were lost to followup, 2 had minimal virologic response, and 4 had other reasons.

Results:

  • 63 of 66 (95%) patients who completed 5 years of therapy had HBV DNA < 300 copies/mL
  • 50 of 66 (76%) had normalized levels of alanine aminotransferase
  • 26 of 65 (40%) had HBeAg loss
  • 12 of 65 (18%) had HBeAg seroconversion
  • No resistance to entecavir was detected

Related blog entries:

References on Hepatitis B Management:

  • –Chronic Hepatitis B: Update_2009 AASLD Practice Guidelines
  • -Clin Gastroenterol Hepatol 2011; 9: 85. Mgt recommendations.
  • -Hepatology 2010; 52: 2192. Consensus guidelines suggest that IFN is treatment of choice in pediatric pts (<16yrs) due to resistance among nucleosides and lack of pediatric studies with these agents along with PEG-IFN. Does not recommend Rx for immune tolerant (NL ALT, HBeAg+, HBV >20K), inactive dz (NL ALT, HBeAg-Neg, HBV <2K), mild disease. Reactivation (HBeAg-Neg, HBV>2K IU/mL & +ALT1.5ULN or >60) & Immune active (+ALT1.5ULN or >60, HBeAg+, HBV >20K) can be treated if mod-severe dz.
  • -JPGN 2009; 48: 399-404. For children, IF +HBeAg/HBV DNA> 20,000 IU/mL & ALT>2 x ULN, Rx post 3months (sooner if decompensating). IF +HBeAg/HBV DNA> 20,000 IU/mL & ALT<2 x ULN or if inactive replication, then monitor. Consider: Follow yearly U/S, q6mo AFP.  IF HBV DNA <20K U/mL & NL ALT: no Rx, monitor q6-12mo. IF HBV DNA >20K U/mL & NL ALT, low rate of HBeAg conversion, young pts often immunotolerant, consider biopsy, esp if >35yrs.  IF HBV DNA >20K U/mL & incr ALT, then Rx options entecavir, tenofovir, PEG interferon alfa-2a preferred.
  • Hepatology 2009; 49: May 2009 supplement -Entirely on management of HBV: S1-S199. NIH Consensus conference. S8: “Reasonable to monitor this group ((younger than 40/HBeAg+) without therapy unless evidence of progressive liver disease is found” S10 Table 1 -Criteria for determining Rx. Generally not indicated: immune-tolerant phase (High HBV DNA but normal ALT or little activity on Bx).S119: “almost all of the oral agents are superior to interferon-based therapy in achieving other clinical endpoints…and in achieving biochemical and histological improvement…in addition, with longer use, oral agents can equal and exceed the level of pegIFN-associated HBeAg & HBsAg serologic responses w/o the need for injections, side effects…”
  • -Hepatology 2009; 49: 699. German Rx guidelines: IF HBV DNA+ & Cirrhosis –>Rx. IF HBV DNA >10 to 4th and any of the following: ALT >2X, F2 + inflammation, Risk HCC/extrahep dz—>Rx. If none of these reeval q6-12mo

Additional entecavir/tenofovir references:

  • -Gastroenterol 2011; 141: 1212. Entecavir effective as monotherapy post OLT.
  • -Hepatology 2010; 53: 763. No resistance with tenofovir over 2yrs. n=641 (HBe+ & HBe-neg)
  • -Gastroenterol 2011; 140: 132. n=365. Excellent efficacy of tenofovir over 3 yr Rx for HBV. 87% of HBeAg-neg with undetectable HBV & 74% of HBeAg-pos. 8% of HBeAg-pos lost HBsAg & 34% lost HBeAg.
  • -Hepatology 2009; 51: 73. n=131. Tenofovir Rx.
  • -Clin Gastroenterol Hepatol 2010; 9: 274. Use of entecavir (long term) reverses fibrosis in HBV
  • -Hepatology 2010; 52: 886. Long term entecavir Rx (>6yrs) with good efficacy & improved histology (96%), n=69.
  • -Hepatology 2009; 49: 1503. Long term entecavir Rx with LOW resistance. n=608 @ yr1, 108 @ yr5. Resistance ~1%
  • -Hepatology 2009; 50: 1064. Entecavir less effective in pts with combined LAM/ADV resistance.
  • -Hepatology 2008; 48: 99. Entecavir for lamivudine-refractory HBV thru 96 weeks. n=141 entecavir, n=145 lam. Entecavir fairly effective (81% had NL Alt, 10% HBeAg seroconversion) 6/77 in 2nd yr developed resistance much higher than those in studies who never rec’d lamivudine
  • -NEJM 2007; 356: 2614. Use entecavir with caution in pts coinfected w HIV -may select for resistant organisms in those not on fully sppressive antiretroviral regimens.
  • -NEJM 2006; 354: 1001, 1011, 1074. Hepatitis B patients: At 48 weeks, Entecavir-Rx’d HBeAg+ had 72% histologic response, 67% c undetectable HBV DNA, and 68% normalized ALT (n=314/314 entecavir/lamivudine pts). At 48 weeeks among HBeAG-neg, 90% in entecavir group (n=296 vs. 287 lamivudine pts) w/o detectable HBV DNA, 78% c Nl ALT, 70% c histologic improvement. Entecavir has caused cancer in mice.
  • -Hepatology 2006; 44: 1656. Entecavir had highly potent efficacy in reducing HBV DNA levels to <300 copies/mL. Study of 673 Rx’d pts. In HBeAg+, 69% were HBV DNA-neg at 48 weeks, & 82% at 96 weeks; in HBeAg-neg, 93% at 48 weeks & 96% at 96 weeks were HBV DNA neg. Low level of resistance due potent HBV DNA levels.

Life in the balance (book)

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While a recent blog (“There is More to Life Than Death”) referred to the complexity of  population-based medical decisions when relying solely on mortality, clearly mortality matters a lot.  In the same NEJM issue, an article highlights the difference that expanded Medicaid coverage has on mortality in adults (NEJM 2012; 367: 1025).

Traditionally, Medicaid has covered only low-income children, parents, pregnant women, and disabled persons.  In the past decade, several states expanded coverage to include nondisabled adults without dependent children.  This study examined these efforts in three states (New York, Arizona & Maine).  Then, effects on mortality were examined from 1997-2007 in these states as well as bordering states who did not expand coverage.  This time period allowed data to be analyzed five years prior to change and five years afterwards.

Findings:

  • By broadening eligibility requirements, there was a 25% increase in Medicaid coverage.
  • States with Medicaid expansions reduced all-cause mortality by 19.6 deaths per 100,000 adults; this was a relative reduction of 6.1%.
  • Mortality reductions were greatest for older adults (35-64), nonwhites, and residents of poorer counties.
  • The authors note that these changes do not prove causality.  However, there are implications for the affordable care act which allows expansion of eligibility up to 138% of the federal poverty level.

Despite apparent improvement in mortality, the cost, logistics and politics of expanding medical coverage remain unclear. In Georgia, the decisions on expanding medical coverage are quite controversial (see links below). My view: I think everyone in this country needs at least basic medical coverage.  This saves lives.

Deal rejects expansion of Medicaid | www.ajc.com

Expand Medicaid? – Blogs – Atlanta Journal-Constitution

 

Interpreting industry-funded studies

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Yesterdays’ blog entry discussed how patient selection affects the external validity of studies (According to the study which you would never qualify for…).  Today, we look at how physicians interpret studies based on a relevant article (NEJM 2012; 367: 1119-27).

In a randomized study, 269 respondents (from a pool of 503 board-certified internists)were presented with a series of three hypothetical abstracts (27 in all) and were queried about their confidence in the results.  The presumption was that “the methodologic rigor of a trial, not its funding disclosure, should be a primary determinant of its credibility.”  One of the questions that was asked was the following: “Do you think that pharmaceutical company funding is likely to influence the outcome of scientific studies…in favor of the drug in question?”

Results:

  • Physicians were more likely to identify high-rigor trials as rigorous (odds ratio, 3.95); in turn, physicians were more willing to prescribe drugs reported in high-rigor trials.
  • Physicians were less likely to view a trial as having a high level of rigor if funding source was a pharmaceutical company (odds ratio 0.63).

Both the article and the editorial (pages 1152-53) indicate a good deal of concern that industry-funded studies are “downgraded” as compared to NIH-funded studies.  Though, is it really surprising?  There have been well-publicized controversies with industry-funded research:

  • Withholding of critical data and negative results (eg. rofecoxib Alzheimer studies)
  • Ghostwritten articles (eg. promotion of gabapentin)

In addition, the perception is that industry-sponsored studies are more prone to bias due to a financial stake in the outcome.

Due to these previous problems, gaining full confidence in industry-funded studies could take a long time.  As stated by Friedrich Nietzsche:

“I’m not upset that you lied to me, I’m upset that from now on I can’t believe you”

A much more expansive discussion on the issue of industry-funded studies can be found at the following link (thanks to Jeff Lewis for this):

http://www.guardian.co.uk/business/2012/sep/21/drugs-industry-scandal-ben-goldacre

I think if the authors of the study and the NEJM editor read this link they might change their tune from “Believe the data” to “Missing data poisons the well for everybody.”  A particularly insightful example in the link includes how the industry withheld negative data on paroxetine in pediatric patients for commercial reasons.

You really should read the attached link to understand why skepticism of industry-funded studies is justified.

Additional references:

  • -Am Heart J 2012; 164: 186-93.  Rofecoxib: under-reporting of cardiovascular events in Alzheimer studies.
  • -JAMA 2008; 299: 1800-12.  Promotion of rofecoxib with guest authorship.
  • -Ann Intern Med 2006; 145: 284-93.  Promotion of gabapentin.

According to the study which you would never qualify for…

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When I give patients advice on treatment, I rely on well-designed studies to help select the medications/treatments that are most likely to be effective.  It is interesting to ponder how applicable these studies are and how closely they reflect the patient population that I’m seeing.  A recent article indicates that in a tertiary referral center for inflammatory bowel disease, the majority of patients would be excluded from participation in these studies (Clin Gastroenterol Hepatol 2012; 10: 1002-07).

These authors performed a retrospective cohort study of patients presenting to the Mount Sinai Medical Center between January 2008 and June 2009.  For Crohn’s disease (CD) patients, the authors selected 7 published randomized control trials of biological therapy for patients with moderate-severe disease (ACCENT 1, CLASSIC 1, CHARM, PRECISE 1, ENCORE, ENACT, and SONIC).  For Ulcerative Colitis (UC), they selected ACT 1 and ACT 2 trials for moderate-severe UC.

Only 31.1% of 206 patients with IBD would have been eligible to participate in any of the selected RCTs.  The average age of their patients was about 35 and did not differ significantly among patients who would qualify compared to those who would not.

Among the CD patients, the inflammatory phenotype was most likely to qualify; 37 patients with inflammatory disease behavior would have been eligible.  While only 54% (37 of 68) of the inflammatory phenotype would have qualified, this accounted for 86% of the total population who would have qualified (only 34% of the entire CD cohort would have been eligible for study participation).

Among the UC patients, there were no disease characteristics or demographics associated with eligibility; that is, there was a similar distribution of disease extents, Mayo scores, disease duration, gender, and age among the patients who qualified and those who did not.

Reasons for exclusion: stricturing or penetrating disease, steroid dosing, comorbities, concomitant therapies, or prior exposure to biologics.

The authors note that the results from this study mirror that from similar studies with other chronic diseases including rheumatoid arthritis, chronic obstructive pulmonary diseases, and congestive heart failure.

When the authors looked at the trial-ineligible patients, 60% had a response to biological therapy. The response rates for ineligible patients (compared to eligible patients) were lower for CD patients but not for UC patients (Figure 2 in study).

While stringent criteria for eligibility limit the external validity of the study results, these criteria are in place for multiple reasons.  Less rigid selection criteria would require larger study populations, longer duration studies, and greater costs.

The issue of study applicability is even a bigger problem in pediatrics.  This is primarily due to fewer high quality studies in children. As such, many clinical judgements require extrapolation from adult studies.

Related blog post:

Interpreting industry-funded studies

Portopulmonary Hypertension

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A useful update: Liver Transpl 2012; 18: 881-91.

Definition: When pulmonary artery hypertension (PAH), mean pulmonary artery pressure (MPAP) ≥ 25 mm Hg, occurs in the setting of of portal hypertension and no alternative cause of the PAH exists (eg, collagen vascular disease, congenital heart disease, or certain drugs), it is known as portopulmonary hypertension (POPH).

  • Mild POPH: MPAP < 35 mm Hg
  • Moderate POPH: MPAP ≥ 35 mm Hg & <45 mm Hg
  • Severe POPH:  MPAP ≥ 45 mm Hg

Patients with moderate POPH and severe POPH, if not improved with medical therapy, have high mortality rates and these are generally considered contraindications for liver transplantation.

POPH is associated with high pulmonary vascular resistance ≥ 240 dyn(sec)(cm¯5 ) and with  pulmonary wedge pressure < 15 mm Hg.

Difference between POPH and hepatopulmonary syndrome:

From the following link: Portopulmonary hypertension and hepatopulmonary syndrome “Abnormal intrapulmonary vascular dilatation, the hallmark of hepatopulmonary syndrome, can cause profound hypoxaemia that can be very difficult to treat. By contrast, portopulmonary hypertension results from excessive pulmonary vasoconstriction and vascular remodelling that eventually leads to right-heart failure.”

Pathophysiology: unclear.  Most but not all cases are associated with cirrhosis.

Frequency: 6-8% of cirrhotic patients.

Diagnosis: while dyspnea may be present, routine screening with echocardiography is part of liver transplantation evaluation.

Prognosis: retrospective study from Mayo clinic (n=74, 1994-2007) noted 5-hr survival of 14% for untreated patients, 45% treated with vasodilators, and 67% who underwent liver transplantation.

Treatments: Table 6 in article.

  • PDE5 Inhibitors (oral): Tadalfil, Sildenafil
  • Endothelin Receptor antagonists (oral): Ambrisentan, Bosentan
  • Prostacyclins (IV): EPO, Trepostinil
  • Prostacyclins (Inhalation): Iloprost , Tyvaso
  • Liver transplantation: 79 patients with LT for POPH 2007-2011

Beta-blockers may have adverse effect.

Noncirrhotic POPH: Worldwide, infection with Schistosoma mansion is likely the most common reason; severe disease may occur in 10% of the 200 million people who are infected.  When noncirrhotic POPH occurs without cirrhosis or Schistosoma mansion, this requires a high degree of clinical suspicion as well as awareness of this disorder.

Additional references:

**Hepatology 2008; 48: 13, 196. POPH: pulmonary arterial htn associated w portal htn:

  • -resting pulm artery pressure > 25mmHg
  • -pulm capillary wedge pressure <15mmHg
  • -pulm vascular resistance >240dynes(s)(cm to -5)
  • -measure c trans thoracic echocardiography
  • -female sex, autoimmune dz were risk factors
  • -avg age associated was 53yrs whereas idiopathic PAH avg age is 36yrs

**NEJM 2008; 358: 2378. Review. Hepatopulmonary Syndrome – New England Journal of Medicine  Hepatopulmonary syndrome, a separate but related condition characterized by hypoxemic respiratory insufficiency due to increased intrapulmonary shunting
**Liver Tx 2007; 13: 680. Hepatopulmonary syndrome experience at CHOA

Sirolimus and transplant mortality

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A surprise to me was a recent study which identified sirolimus as a risk factor for increased mortality and graft loss in HCV-positive liver transplant patients (Liver Transpl 2012; 18: 1029-36, commentary 1003-1004).

Sirolimus mechanism of action: inhibits mammalian target of rapamycin (mTOR) which is a phosphoinositide 3-kinase which affects cell proliferation, angiogenesis, and immune function.  For transplant patients, sirolimus blocks interleukin-2-induced stimulation of T lymphocytes.

Black box warnings for sirolimus: FDA warns that sirolimus can increase risk of hepatic artery thrombosis, graft loss, and death with de novo sirolimus-based treatment.

What’s different about HCV transplants? HCV reinfection occurs immediately during liver transplantation and “unlike all other indications, graft survival and patient survival have not improved” (between 1991-2001).  HCV transplant survival continues to be 10-15% lower than non-HCV transplant survival.  Immunosuppression allows more rapid progression of HCV; this allows ~20% of recipients to develop cirrhosis within 5 years of transplantation.

The authors of the study analyzed 26,414 patients (12,589 with hepatitis C virus) from the Scientific Registry of Transplant Recipients (SRTR) database; all recipients were >18 years.  Among this database, 1685 liver transplant recipients received sirolimus; in the majority, it was administered along with a calcineurin inhibitor.  A multivariate analysis of patient mortality showed the following were risk factors for increased mortality:

  • recipient age
  • donor age
  • hepatocellular carcinoma
  • diabetes
  • creatinine

Tacrolimus-based immunosuppression was associated with superior survival. Whereas, the use of sirolimus was associated with increased mortality in patients with HCV, even when adjusting for confounding variables (eg. renal function, and cancer).  In patients who received sirolimus at baseline, the adjusted HR for mortality at 3 years was 1.29 (p=0.0053).  In non-HCV patients, the adjusted HR for the sirolimus group was 1.09  (p=0.40).  Also, duration of exposure to sirolimus was directly correlated with worse outcomes.  Why?

This is not clear.  It is recognized that the study has several limitations.  Due to the nature of the SRTR database, there is not adequate information on how sirolimus may have affected viral load, histologic progression or causes of death.  Despite attempts to control for risk factors, it is possible that the sirolimus group did have higher disease severity.  Nevertheless, sirolimus effects on multiple cellular functions may have deleterious consequences in certain subsets of patients.

GI & Nutrition Problems in Rett Syndrome

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A nationwide survey of 983 patients with Rett syndrome identifies a high prevalence of GI and nutritional problems (Motil KJ et al. JPGN 2012; 55: 292-98).

Parents from 983 female patients with Rett syndrome responded to the study questionnaire; this was a 59% response rate from the 1666 families in the North American Rett Database.  Patients included those who fulfilled clinical criteria for diagnosis or who had MECP2 gene (methyl-CpG-binding-protein).

Prevalence of GI problems were listed in article’s Table 2 and included the following:

  • Gastrointestinal problems 92%
  • Feeding problems 81%
  • Constipation 80%
  • Poor weight gain 38%
  • Gastroesophageal reflux 39%

Z-scores for height-for-age, weight-for-age, and BMI are presented for ages 0-40 (see Table 1) -these are all significantly lower than age-matched healthy children.

Important findings:

  • Surgical interventions were common: 11% had fundoplication, 28% gastrostomy, 3% and cholecystectomy
  • Many gastrointestinal symptoms improved with age.  However, short stature, gastrostomy tube, and bone health issues were more common in older patients.
  • Bone fractures are 3- to 4-fold higher than in healthy children

Addtional references:

  • -J Pediatr 2010; 156: 135.  Longevity in Rett syndrome –about 1/2 survive to age 40.
  • -Ann Neurol 2010; 68: 944-50.  Rett diagnostic criteria
  • -JPGN 2007; 45: 582-90.  Growth/feeding issues in Rett syndrome