Thinking Clearly About Fecal Microbiota Transplantation & Hepatic Encephalopathy

An intriguing open-label randomized clinical trial (JS Bajaj et al. Hepatology 2017; 66: 1727-38) showed that fecal microbiota transplantation (FMT) was helpful in hepatic encephalopathy.

Background: It is well-recognized that changing bacteria flora can be beneficial in patients with hepatic encephalopathy (HE) associated with cirrhosis.  This has been shown with prior treatments with both lactulose and rifaximin.  It is clear that FMT can improve microbial dysbiosis, particularly in patients with Clostridium difficile.  In this study, the authors randomized 20 patients to either standard of care (SOC) or to SOC & FMT (single enema) with a 5-month follow-up. SOC patients received lactulose and rifaximin.

Key findings:

  • No FMT patients and 5 SOC patients developed further HE
  • Cognition improve in the FMT, but not the SOC, group
  • FMT was associated with increased microbial diversity

Since this was a small study, a bigger trial with longer follow-up is needed.

My take: This intriguing study suggests that FMT, or similar more selected modification of bacterial flora, could be helpful in reducing hepatic encephalopathy among patients with cirrhosis.

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South Kaibab Trail, Grand Canyon

Liver Update -January 2015

Briefly noted:

1. Gastroenterology 2014; 147: 1327-37 (editorial 1216-18).  “Probiotic VSL#3 reduces liver disease severity and hospitalization in patients with cirrhosis: a randomized, controlled trial.” 66 patients received VSL#3 (9 x 10 to the 11th bacteria), 64 patients received placebo -both groups studied for 6 months. Treatment with lactulose and rifaximin were withdrawn a week prior to study entry. Key findings: ‘fewer hospitalizations for severe encephalopathy, better quality of life, and decreases in Child-Turcotte-Pugh class and Model for End-Stage Liver Disease.’  Hazard ratio for preventing hospitalization with VSL#3 was 0.52. However, the findings did not show that VSL#3 reached a statistically-significant reduction in recurrence rate for hepatic encephalopathy. No adverse events were noted.

2. NY Times: Gilead sued over cost of Sovaldi.

3. N Engl J Med 2014; 371:2375-2382.  Link to abstract: Interferon-free Antiviral Regimen for HCV after Liver Transplantation:  “Treatment with the multitargeted regimen of ombitasvir–ABT-450/r and dasabuvir with ribavirin was associated with a low rate of serious adverse events and a high rate of sustained virologic response among liver-transplant recipients with recurrent HCV genotype 1 infection, a historically difficult-to-treat population.

4. “Transplantation Traffic –Geography as Destiny for Transplant Candidates” NEJM 2014; 271: 2450-52.  Describes ongoing geographic inequality in organ distribution and obstacles to improving allocation.

5. Liver Transpl 2015; 21: 57-62. Immediate Extubation After Pediatric Liver Transplantation –feasible in 67% according to this retrospective review.

Local Law Office  --Truth in Advertising?

Local Law Office –Truth in Advertising?

PEG vs Lactulose in Hepatic Encephalopathy

In a study (JAMA Intern Med. Published online September 22, 2014. doi:10.1001/jamainternmed.2014.4746) with 50 participants, PEG was more effective than standard therapy of lactulose for hepatic encephalopathy.  PEG vs Lactulose (HELP study) Abstract.

Here’s an excerpt:

Design, Setting, and Participants  The HELP (Hepatic Encephalopathy: Lactulose vs Polyethylene Glycol 3350-Electrolyte Solution) study is a randomized clinical trial in an academic tertiary hospital of 50 patients with cirrhosis (of 186 screened) admitted for HE.

Interventions  Participants were block randomized to receive treatment with PEG, 4-L dose (n = 25), or standard-of-care lactulose (n = 25) during hospitalization…

Results  Thirteen of 25 patients in the standard therapy arm (52%) had an improvement of 1 or more in HESA score, thus meeting the primary outcome measure, compared with 21 of 23 evaluated patients receiving PEG (91%) (P < .01)… The median time for HE resolution was 2 days for standard therapy and 1 day for PEG (P = .01). Adverse events were uncommon, and none was definitely study related.

Conclusions and Relevance  PEG led to more rapid HE resolution than standard therapy, suggesting that PEG may be superior to standard lactulose therapy in patients with cirrhosis hospitalized for acute HE.

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Hepatology Update (Part 2) -Summer 2014

Hepatology 2014; 60: 715-33.  This publication is the AASLD Practice Guideline for Hepatic Encephalopathy in Chronic Liver Disease.  The recommendations are too extensive to summarize.  Here’s one: despite concerns about efficacy, “lactulose is the first choice for treatment of episodic” overt hepatic encephalopathy.  Rifaximin is an effective add-on therapy to lactulose for prevention of OHE recurrence. AASLD Guidelines Website

Hepatology 2014; 60: 679-86. Using the Drug-Induced Liver Injury Network between 2004-2012, the authors identified 22 cases of hepatotoxicity attributed to statins.  Median age was 60 years.  The latency to onset of symptoms varied from 34 days to 10 years with a median of 155 days. Nine patients had a cholestatic hepatitis pattern and 12 had hepatocellular injury, including six with an autoimmune phenotype. Severity: nine required hospitalization, four had evidence of hepatic failure and one died.

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Probiotics for Hepatic Encephalopathy

A recent open-label, randomized prospective study (Clin Gastroenterol Hepatol 2014; 12: 1003-08) indicates that probiotics (VSL#3) can be effective as primary prophylaxis of hepatic encephalopathy (HE) in at risk patients with cirrhosis.

While cirrhosis-related HE is an uncommon problem in pediatric gastroenterology/hepatology, there are few effective therapeutic options.  This study randomly assigned the 160 patients to groups given probiotics three times daily or to controls (no test article).  These patients were studied extensively including psychometric analysis, glucose hydrogen breath tests, critical flicker fusion, and lactulose hydrogen breath tests to assess orocecal transit time.

Key result: Three months of probiotics reduced HE scores.  Seven probiotic subjects developed overt HE which was significantly lower than the 14 patients in the control group (P<.05).

Bottomline: Probiotics may reduce the development of overt HE in patients with cirrhosis.

Rifaximin for Crohn’s disease?

Rifaximin (Xifaxan®) shows promise as a new treatment for Crohn’s disease (Gastroenterology 2012; 142: 473-81).  Rifaximin is an oral medication with minimal systemic absorption; it has a good track record in a number of GI indications, including bacterial gastroenteritis (traveler’s diarrhea), bacterial overgrowth in irritable bowel disease, and hepatic encephalopathy.  There are a few reasons why rifaximin would be considered a good candidate treatment for Crohn’s disease:

  • The pathophysiology of Crohn’s disease involves interaction of adherent bacteria to the intestinal mucosa and with the immune system
  • Other antimicrobials have shown benefit for Crohn’s disease
  • Animal models do not manifest Crohn’s disease when in a bacteria-free environment

In this study of 402 patients with moderate-to-severe Crohn’s disease, a multicenter randomized double-blind trial examined efficacy and safety of rifaximin at doses of 400mg, 800mg, and 1200mg twice daily.  The primary end point was remission based on Crohn’s Disease Activity Index (CDAI).

At the end of the 12-week treatment period, 62% of the 800mg group were in remission compared to 43% of the placebo group.  This difference was maintained 12 weeks afterwards with 45% maintaining remission compared with 43% of patients receiving placebo.  When looking at the other dosing regimens, at 12 weeks, 54% of the 400mg group and 47% of the 1200mg group were in remission based on CDAI.

Clinical response, but not remission, occurred in 56% of placebo patients compared with 63% for 400mg patients, 72% for 800mg patients, and 57% of 1200mg patients.  This trial may have been hampered by patient selection in that the placebo response was high.  This may be due to the fact that ~50% of patients had a low CRP value at baseline.

Safety was good in all patient groups.  However, one rifaximin-treated patient developed C difficile infection.

The fact that a clear dose response was not evident suggests the need for more studies.

Additional Rifaximin References:

  • -NEJM 2011; 364: 22 (pg 81-editorial).  About 10% improvement over placebo in pts with IBS-D.  (see abstract below).  Effects lasted up to 3 months.
  • -JPGN 2009; 49: 400-04. helped symptoms in 61% of IBD pts. n=23 (12 w Crohn). dose 10-30mg/kg/day.
  • -Aliment Pharm Ther 2005; 22: 31-35. Use in SBBO. n=90; 1200mg/day x 7 days. NL glucose breath test in 60% (vs 17% in low dose group); no side effects.
  • -Ann Intern Med 2006; 145: 557-563. double-blind, randomized controlled trial, n=87 for IBS. 400mg tid x 10days. Rx resulted in greater IBS improvement, ~40% improvement vs 20% w placebo during 10 week study
  • -IBD 2006; 12: 335. open-label use of rifaximim (400mg BID) for 30 pts c UC flare on ASA products resulted in clinical remission in 23 of 30.
  • -J Infect 2011; 62: 34-38. Rx may lead to resistant staphylococci.
  • -Hepatology 2010; 52: 1484. Review.

Additional Crohn’s Antibiotic/Probiotic References:

  • -IBD 2009; 15; 17. 40% response to Cipro in treatment of peranal fistulas. n=25. No response to metronidazole.
  • -IBD 2008; 14: 1597, 1585. No proven role for probiotics and IBD except pouchitis (after Abx)
  • -Clin Gastro & Hep 2008; 6: 145. Pouch problems reviewed -excellent review.
  • -IBD 2006; 12: 335. open-label use of rifaximim (400mg BID) for 30 pts c UC flare on ASA products resulted in clinical remission in 23 of 30.
  • -Curr Med Res Opinion 2005; 8: 1165-70. Rx for traveler’s diarrhea.  May be useful for Crohn’s as well.
  • -Gastroenterology 2005; 128: 856. Use of ornidazole prophylaxis reduced recurrence p-op from 37.5% to 8%.
  • -IBD 2004; 10: 318-325. antibiotics & IBD review.
  • -Gastroenterology 2004; 127: 412-21. adherent-invasive E. coli associated with ileal mucosa in 22% of Crohn’s (n=63) ileal mucosa vs. 6% of controls (n=16); higher colonization noted in neo-terminal ileums (36%).