Fecal microbiota transplant

Fecal microbiota transplant

Escherichia coli at 10,000× magnification
Synonyms fecal bacteriotherapy, fecal transfusion, fecal transplant, stool transplant

Fecal microbiota transplant (FMT), also known as a stool transplant,[1] is the process of transplantation of fecal bacteria from a healthy individual into a recipient. FMT involves restoration of the colonic microflora by introducing healthy bacterial flora through infusion of stool, e.g. by enema, orogastric tube or by mouth in the form of a capsule containing freeze-dried material, obtained from a healthy donor. A limited number of studies have shown it to be an effective treatment for patients suffering from Clostridium difficile infection (CDI), whose effects can range from diarrhea to pseudomembranous colitis.

Due to an epidemic of CDI in North America and Europe, FMT has gained increasing prominence, with some experts calling for it to become first-line therapy for CDI. In 2013 a randomized, controlled trial of FMT from healthy donors showed it to be highly effective in treating recurrent C. difficile in adults, and more effective than vancomycin alone. FMT has been used experimentally to treat other gastrointestinal diseases, including colitis, constipation, irritable bowel syndrome, and neurological conditions such as multiple sclerosis and Parkinson's. In the United States, the Food and Drug Administration (FDA) has regulated human feces as an experimental drug since 2013.

Definition

Fecal microbiota transplantation or FMT is the transfer of fecal material containing bacteria and natural antibacterials from a healthy individual into a diseased recipient.[2] Previous terms for the procedure include fecal bacteriotherapy, fecal transfusion, fecal transplant, stool transplant, fecal enema, and human probiotic infusion (HPI). Because the procedure involves the complete restoration of the entire fecal microbiota, not just a single agent or combination of agents, these terms have now been replaced by the new term fecal microbiota transplantation.[2]

Medical uses

Clostridium difficile infection

Fecal microbiota transplant is approximately 85 percent to 90 percent effective in those for whom antibiotics have not worked or in whom the disease recurs following antibiotics.[3][4]

Most people with CDI recover after just one treatment.[2][5][6]

A 2009 study found that fecal microbiota transplant was an effective and simple procedure that was more cost-effective than continued antibiotic administration and reduced the incidence of antibiotic resistance.[7]

Once considered to be "last resort therapy" by some medical professionals due to its unusual nature and invasiveness compared with antibiotics, perceived potential risk of infection transmission, and lack of Medicare coverage for donor stool, position statements by specialists in infectious diseases and other societies[2] have been moving toward acceptance of FMT as standard therapy for relapsing CDI and also Medicare coverage in the United States.[8]

It has been recommended that endoscopic FMT be elevated to first-line treatment for people with clinical deterioration and severe relapsing C. difficile infection.[6]

Ulcerative colitis and other gastrointestinal conditions

While C. difficile is easily eradicated with a single FMT infusion, this generally appears to not be the case with ulcerative colitis. Published experience of ulcerative colitis treatment with FMT largely shows that multiple and recurrent infusions are required to achieve prolonged remission or cure.[9]

Side effects

Side effects, at least initially, appear to be few but further study was needed as of 2016.[10] They have included bacterial blood infections, fever, exacerbation of IBD in people who also had that condition, and mild GI which generally resolved soon after the procedure including flatulence, diarrhea, irregular bowel movements, abdominal distension/bloating, abdominal pain/tenderness, constipation, cramping, and nausea.[10]

Technique

A team of international gastroenterologists and infectious disease specialists have published formal standard practice guidelines for performing FMT which outline in detail the FMT procedure, including preparation of material, donor selection and screening, and FMT administration.[2] There is preliminary evidence that the fecal transplant may also be delivered in the form of a pill.[11]

Donor selection

Preparing for the procedure requires careful selection and screening of the donor and excluding those who test positive for certain diseases as well as any donor carrying any pathogenic gastrointestinal infectious agent. Although a close relative is often the easiest donor to obtain and have tested, there is no reason to expect this to affect the success of the procedure as genetic similarities or differences do not appear to play a role.[2] Indeed, in some situations, use of a close relative as a donor may be a disadvantage as they may be an asymptomatic carrier of C. difficile. Donors must be tested for a wide array of bacterial and parasitic infections.[2] In more than 370 published reports there has been no reported infection transmission.[12]

Specimen preparation

Approximately 200 to 300 grams (7.1 to 10.6 ounces) of fecal material is recommended per treatment for optimum results. Fresh stools have been recommended to be used within six hours, however frozen stool samples can also be used without loss of efficacy. There is evidence that the relapse rate is 2 fold greater when water is used as opposed to saline as the dilution agent. There is also some evidence that using infusions of greater than 500 millilitres (18 imperial fluid ounces; 17 US fluid ounces) produces a higher success rate compared to infusions using less than 200 ml (7.0 imp fl oz; 6.8 US fl oz) of prepared solution. Research is needed to determine whether certain mixing methods such as using an electric blender reduce the efficacy of treatment via oxygenating the solution and killing obligate anaerobes.[13] The fecal transplant material is then prepared and administered in a clinical environment to ensure that precautions are taken.[14]

Administration

Numerous techniques have been published, and choice depends on suitability and ease. The procedure involves single or multiple infusions of bacterial fecal flora originating from a healthy donor by enema,[15] through a colonoscope,[16] or through a nasogastric or nasoduodenal tube.[17] There does not appear to be any significant methodological difference in efficacy between the various routes. A recent study[18] has shown that fecal transplant through colonoscopy has a better outcome than transplant performed with a nasogastric or nasoduodenal tube, with a success rate of 90 percent of patients treated with transplant by colonoscopy versus 81 percent[19] of patients treated with transplant by NG tube.

Autologous restoration of gastrointestinal flora

A modified form of fecal microbiota transplant (autologous restoration of gastrointestinal flora—ARG) commenced development as of 2009.[20] An autologous fecal sample, provided by the patient before anticipated medical treatment with antibiotics, is stored in a refrigerator. Should the patient subsequently develop C. difficile infection the sample is extracted with saline and filtered. The filtrate is freeze-dried and the resulting solid enclosed in enteric-coated capsules. Administration of the capsules is hypothesised to restore the patient's original colonic flora and combat C. difficile. However using one's own original colonic flora which made them susceptible to the CDI infection in the first place obviously holds a foreseeable disadvantage. As such, it is likely that following treatment the patient will still remain susceptible to C. difficile colonisation. In comparison, the introduction of donor flora facilitates colonisation with a more robust, C. difficile-resistant flora.

Standardised filtrate

Researchers have also produced a standardised filtrate composed of viable fecal bacteria in a colourless, odorless form.[21] The preparation has been shown to be as effective at restoring missing and deficient bacterial constituents as crude homogenised FMT.[22]

Public stool bank in the United States

In 2012, a team of researchers from the Massachusetts Institute of Technology founded OpenBiome, the first public stool bank in the United States[23] OpenBiome provides clinicians with frozen, ready-to-administer stool samples for use in treating C. difficile, and supports clinical research into the use of fecal transfer for other indications.

Mechanism of action

The hypothesis behind fecal microbiota transplant rests on the concept of bacterial interference, i.e. using harmless bacteria to displace pathogenic organisms. In the case of CDI, the C. difficile pathogen is identifiable. However, in the case of other conditions such as ulcerative colitis, no single culprit has yet been identified.

In patients with relapsing CDI, the mechanism of action may be the restoration of missing components of the flora including Bacteroidetes and Firmicutes.[24][25][26] The introduction of normal flora results in durable implantation of these components.[27]

Another postulated mechanism entails the production of antimicrobial agents (Bacteriocins) by the introduced colonic flora to eradicate C. difficile. This may be a similar mechanism to that of Vancomycin which originates from soil bacteria, and Bacillus thuringiensis which has been proven to produce bacteriocins specific for C. difficile.[28] The potential combination of replacing missing components and antimicrobial products manufactured by the incoming flora are likely to be the mechanisms curing CDI.

In the case of ulcerative colitis, it is likely that a shared infectious mechanism is at play, where the offending infective agents are still unknown. Given the response to FMT, it is scientifically plausible that an infection persists but cannot be identified.

History

The concept of treating fecal diseases with fecal matter originated in China millennia ago. Fourth century Chinese medical literature mentions it to treat food poisoning and severe diarrhea. 1200 years later Li Shizhen used "yellow soup" (aka "golden syrup") which contained fresh, dry or fermented stool to treat abdominal diseases.[29] "Yellow soup" was made of fecal matter and water, which was drunk by the patient.[30]

The consumption of "fresh, warm camel feces has been recommended by Bedouins as a remedy for bacterial dysentery; its efficacy probably attributable to the antimicrobial subtilisin produced by Bacillus subtilis was anecdotally confirmed by German soldiers of the Afrika Korps during World War II".[31]

The first description of FMT was published in 1958 by Ben Eiseman and colleagues, a team of surgeons from Colorado, who treated four critically ill patients with fulminant pseudomembranous colitis (before C. difficile was the known cause) using fecal enemas, which resulted in a rapid return to health.[15] In 2003, a case series involving 18 people was published.[32][33] Stool transplants are about 90 percent effective in those with severe cases of Clostridium difficile colonization, in whom antibiotics have not worked.[3]

Since that time various institutions have offered FMT as a therapeutic option for a variety of conditions. At the Centre for Digestive Diseases in Sydney, Australia, FMT has been offered as a treatment option for more than 20 years. In May 1988, the CDD treated the first idiopathic colitis patient with FMT which resulted in a durable clinical and histological cure.[34] Since that time, a number of publications have reported the successful treatment of ulcerative colitis with FMT,[35][36][37][38][39] with clinical trials now underway in this indication.

Regulation

Interest in FMT surged in 2012 and 2013, as measured by the number of clinical trials and scientific publications.[40] The first rigorous, head-to-head study (randomized controlled trial) published in January 2013 showed FMT was superior to antibiotics for patients with recurring C. difficile.[41]

In the United States, the FDA announced in February 2013 that it would hold a public meeting entitled "Fecal Microbiota for Transplantation" which was held on May 2–3, 2013.[42][43] In May 2013 the FDA also announced that it had been regulating human feces as a drug.[44] The American Gastroenterological Association (AGA), the American College of Gastroenterology (ACG), the American Society for Gastrointestinal Endoscopy (ASGE), and the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition (NASPGHAN) sought clarification, and the FDA Center for Biologics Evaluation and Research (CBER) stated that FMT falls within the definition of a biological product as defined in the Public Health Service Act and the definition of a drug within the meaning of the Federal Food, Drug, and Cosmetic Act.[45] It argued since FMT is used to prevent, treat, or cure a disease or condition, and intended to affect the structure or any function of the body, "a product for such use" would require an Investigational New Drug (IND) application.[45]

In July 2013, the FDA issued an enforcement policy ("guidance") regarding the IND requirement for using FMT to treat C. difficile infection unresponsive to standard therapies (78 FR 42965, July 18, 2013).[46]

In February 2014, a gastroenterologist, a biological engineering professor from Massachusetts Institute of Technology (MIT), and an MIT microbiology PhD candidate, with the latter two being co-founders of the stool bank OpenBiome, recommended that for medical use, human stool should be considered a tissue not a drug, and argued that although the strict requirements protect patients it also limits access to care and that if stool was treated as a tissue product or given its own classification like blood it would keep patients safe, ensure broad access, and facilitate research.[44]

In March 2014, the FDA issued a proposed update (called "draft guidance") that, when finalized, is intended to supersede the July 2013 enforcement policy for FMT to treat C. difficile infections unresponsive to standard therapies. It proposed an interim discretionary enforcement period, if 1) informed consent is used, mentioning investigational aspect and risks, 2) stool donor is known to either patient or physician, and 3) if stool donor and stool are screened and tested under the direction of the physician (79 FR 10814, February 26, 2014).[47] Some doctors and patients have been worried that the proposal, if finalized, would shutter the handful of stool banks which have sprung up, using anonymous donors and ship to providers hundreds of miles away.[40][48][49]

As of 2015 FMT for recurrent C. difficile infections can be done without mandatory donor and stool screening, whereas FMT for other indications cannot be performed without an IND.[44]

Other animals

Elephants, hippos, koalas, and pandas are born with sterile intestines, and to digest vegetation need bacteria which they obtain by eating their mothers' feces, a practice termed coprophagia. Other animals eat dung.[50]

In veterinary medicine fecal microbiota transplant has been known as "transfaunation" and is used to treat ruminating animals, like cows and sheep, by feeding rumen contents of a healthy animal to another individual of the same species in order to colonize its gastrointestinal tract with normal bacteria.[51]

Research

Cultured intestinal bacterial are being studied as an alternative to fecal microbiota transplant.[52]

References

  1. ↑ Rowan, Karen (October 20, 2012). "'Poop Transplants' May Combat Bacterial Infections". LiveScience.com. Retrieved October 20, 2012.
  2. 1 2 3 4 5 6 7 Bakken, Johan S.; Borody, Thomas; Brandt, Lawrence J.; Brill, Joel V.; Demarco, Daniel C.; Franzos, Marc Alaric; Kelly, Colleen; Khoruts, Alexander; Louie, Thomas; Martinelli, Lawrence P.; Moore, Thomas A.; Russell, George; Surawicz, Christina (December 1, 2011). "Treating Clostridium difficile Infection With Fecal Microbiota Transplantation". Clinical Gastroenterology and Hepatology. 9 (12): 1044–1049. PMC 3223289 Freely accessible. PMID 21871249. doi:10.1016/j.cgh.2011.08.014.
  3. 1 2 Burke KE, Lamont JT (August 2013). "Fecal Transplantation for Recurrent Clostridium difficile Infection in Older Adults: A Review.". Journal of the American Geriatrics Society. 61 (8): 1394–8. PMID 23869970. doi:10.1111/jgs.12378.
  4. ↑ Drekonja, D; Reich, J; Gezahegn, S; Greer, N; Shaukat, A; MacDonald, R; Rutks, I; Wilt, TJ (May 5, 2015). "Fecal Microbiota Transplantation for Clostridium difficile Infection: A Systematic Review.". Annals of Internal Medicine. 162 (9): 630–8. PMID 25938992. doi:10.7326/m14-2693.
  5. ↑ Kelly CR; De Leon L; Jasutkar N (2012). "Fecal Microbiota Transplantation for relapsing Clostridium difficile infection in 26 patients: methodology and results". J Clin Gastroenterol. 46 (2): 145–149. PMID 22157239. doi:10.1097/MCG.0b013e318234570b.
  6. 1 2 Brandt LJ; Borody TJ; Campbell J. (Sep 2011). "Endoscopic Fecal Microbiota Transplantation: first-line treatment for severe Clostridium difficile infection?". J Clin Gastroenterol. 45 (8): 655–657. PMID 21716124. doi:10.1097/MCG.0b013e3182257d4f.
  7. ↑ Bakken JS (Dec 2009). "Fecal bacteriotherapy for recurrent Clostridium difficile infection". Anaerobe. 15 (6): 285–289. PMID 19778623. doi:10.1016/j.anaerobe.2009.09.007.
  8. ↑ Floch MH (2010). "Fecal Bacteriotherapy, Fecal Transplant and the Microbiome". J Clin Gastroenterol. 44 (8): 529–530. PMID 20601895. doi:10.1097/MCG.0b013e3181e1d6e2.
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  10. 1 2 Baxter, M; Colville, A (February 2016). "Adverse events in faecal microbiota transplant: a review of the literature.". The Journal of hospital infection. 92 (2): 117–27. PMID 26803556. doi:10.1016/j.jhin.2015.10.024.
  11. ↑ Preeti Malani (October 4, 2013). "Fecal transplant pill effective against recurrent Clostridium difficile infection". news@JAMA.
  12. ↑ Borody TJ, Khoruts A (December 20, 2011). "Fecal microbiota transplantation and emerging applications". Nature Reviews Gastroenterology & Hepatology. 9 (2): 88–96. PMID 22183182. doi:10.1038/nrgastro.2011.244.
  13. ↑ Smits LP; Bouter KE; de Vos WM; Borody TJ; Nieuwdorp M (November 2013). "Therapeutic potential of fecal microbiota transplantation". Gastroenterology. 145 (5): 946–53. PMID 24018052. doi:10.1053/j.gastro.2013.08.058.
  14. ↑ Borody TJ, Leis S, Pang G et al. Fecal Bacteriotherapy in the treatment of recurrent Clostridium difficile infection. UpToDate
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  16. ↑ Lund-Tonnesen S, Berstad A, Schreiner A, et al. (1998). "Clostridium-difficile-associated diarrhea treated with homologous feces". Tidsskr nor Laegeforen. 118 (7): 1027–1030. PMID 9531822.
  17. ↑ Persky SE, Brandt LJ (2000). "Treatment of recurrent Clostridium-difficile-associated diarrhea by administration of donated stool directly through a colonoscope". Am J Gastroenterol. 95 (11): 3283–3285. PMID 11095355. doi:10.1111/j.1572-0241.2000.03302.x.
  18. ↑ Cammarota, G.; Masucci, L.; Ianiro, G.; Bibbò, S.; Dinoi, G.; Costamagna, G.; Sanguinetti, M.; Gasbarrini, A. (2015). "Randomised clinical trial: faecal microbiota transplantation by colonoscopy vs. vancomycin for the treatment of recurrent Clostridium difficile infection". Aliment Pharmacol Ther. 41 (9): 835–843. PMID 25728808. doi:10.1111/apt.13144.
  19. ↑ van Nood E; Vrieze A; Nieuwdorp M; et al. (Jan 2013). "Duodenal infusion of donor feces for recurrent Clostridium difficile". N Engl J Med. 368 (5): 407–15. PMID 23323867. doi:10.1056/NEJMoa1205037.
  20. ↑ Martin WJ (2009). "Encapsulated Medicines for Iatrogenic Diseases". British Patent Application: GB0916335.3.
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  22. ↑ Hamilton MJ; Weingarden AR; Unno T; Khoruts A; Sadowsky MJ (2013). "High-throughput DNA sequence analysis reveals stable engraftment of gut microbiota following transplantation of previously frozen fecal bacteria". Gut Microbes. 4 (2): 1–11. doi:10.4161/gmic.23571.
  23. ↑ Smith, Peter Andrey (February 17, 2014). "A New Kind of Transplant Bank". The New York Times. Retrieved July 10, 2014.
  24. ↑ Chang JY, Antopoulos DA, Kalra A, et al. (2008). "Decreased diversity of the fecal microbiome in recurrent Clostridium difficile-associated diarrhea". J Infect Dis. 197 (3): 438. PMID 18199029. doi:10.1086/525047.
  25. ↑ Khoruts A, Dicksved J, Jansson JK, et al. (2010). "Changes in the composition of the human fecal microbiome after bacteriotherapy for recurrent Clostridium difficile-associated diarrhea". J Clin Gastroenterol. 44 (5): 354–360. PMID 20048681. doi:10.1097/MCG.0b013e3181c87e02.
  26. ↑ Tvede M, Rask-Madsen J (1989). "Bacteriotherapy for chronic relapsing Clostridium difficile diarrhoea in six patients". Lancet. 333 (8648): 1156–1160. doi:10.1016/S0140-6736(89)92749-9.
  27. ↑ Grehan MJ, Borody TJ, Leis SM, et al. (2010). "Durable alteration of the colonic microbiota by the administration of donor fecal flora". J Clin Gastroenterol. 44 (8): 551–561. PMID 20716985. doi:10.1097/MCG.0b013e3181e5d06b.
  28. ↑ Rea MC; Dobson A; O'Sullivan O; Crispie F; Fouhy F; Cotter PD; Shanahan F; Kiely B; Hill C; Ross RP (March 15, 2011). "Effect of broad- and narrow-spectrum antimicrobials on Clostridium difficile and microbial diversity in a model of the distal colon". Proc Natl Acad Sci U S A. 108 (Suppl 1): 4639–4644. PMC 3063588 Freely accessible. PMID 20616009. doi:10.1073/pnas.1001224107.
  29. ↑ Henning Gerke (December 2014). "Whats the lowdown on 'fecal transplantation'?". Health at Iowa. U of Iowa. Retrieved January 14, 2015.
  30. ↑ "Therapeutic Poop: Hope for Cure of Childhood Diarrhea Comes Straight from the Gut". The Johns Hopkins Children's Center. The Johns Hopkins University. July 29, 2013.
  31. ↑ Lewin, Ralph A. (2001). "More on merde". Perspectives in Biology and Medicine. 44 (4): 594–607. PMID 11600805. doi:10.1353/pbm.2001.0067.
  32. ↑ Aas, Johannes (March 1, 2003). "Recurrent Clostridium difficile Colitis: Case Series Involving 18 Patients Treated with Donor Stool Administered via a Nasogastric Tube". Clinical Infectious Diseases. 36: 580–5.
  33. ↑ Seekatz, Anna (May–June 2014). "Recovery of the Gut Microbiome following Fecal Microbiota Transplantation". mBio. 5 (3): 1–9.
  34. ↑ Borody TJ, Campbell J (2011). "Fecal microbiota transplantation: current status and future directions". Expert Rev Gastroenterol Hepatol. 5 (6): 653–655. PMID 22017691. doi:10.1586/egh.11.71.
  35. ↑ Bennet JD; Brinkman M (1989). "Treatment of ulcerative colitis by implantation of normal colonic flora". Lancet. 1 (8630): 164. doi:10.1016/s0140-6736(89)91183-5.
  36. ↑ Borody T; Warren E; Leis S; Surace R; Ashman O (2003). "Treatment of ulcerative colitis using fecal bacteriotherapy". J Clin Gastroenterol. 37 (1): 42–47. PMID 12811208. doi:10.1097/00004836-200307000-00012.
  37. ↑ Borody TJ; Warren EF; Leis SM; Surace R; Ashman O; Siarakis S (2004). "Bacteriotherapy using fecal flora: toying with human motions". J Clin Gastroenterol. 38 (6): 475–83. PMID 15220681. doi:10.1097/01.mcg.0000128988.13808.dc.
  38. ↑ Borody TJ, Torres M, Campbell J, et al. (2011). "Reversal of inflammatory bowel disease (IBD) with recurrent fecal microbiota transplants (FMT)". Am J Gastroenterol. 106: S352.
  39. ↑ Borody TJ; Paramsothy S; Agrawal G (2013). "Fecal Microbiota Transplantation: Indications, Methods, Evidence and Future Directions". Curr Gastroenterol Rep. 15 (8): 337. doi:10.1007/s11894-013-0337-1.
  40. 1 2 "FDA struggles to regulate fecal transplants". CBS News. Associated Press. June 26, 2014.
  41. ↑ van Nood E; Vrieze A; Nieuwdorp M; Fuentes S; Zoetendal EG; de Vos WM; Visser CE; Kuijper EJ; Bartelsman JF; Tijssen JG; Speelman P; Dijkgraaf MG; Keller JJ (January 16, 2013). "Duodenal Infusion of Donor Feces for Recurrent Clostridium difficile". N Engl J Med. 368 (5): 407–15. PMID 23323867. doi:10.1056/NEJMoa1205037.
  42. ↑ "Public Workshop: Fecal Microbiota for Transplantation". Food and Drug Administration. March 10, 2014.
  43. ↑ 78 FR 12763, February 25, 2013
  44. 1 2 3 Smith, Mark B.; Kelly, Colleen; Alm, Eric J. (February 19, 2014). "Policy: How to regulate faecal transplants". Nature.
  45. 1 2 AGA Confirms IND is Required for Fecal Microbiota Transplantation, American Gastroenterological Association, May 6, 2013, archived from the original on May 10, 2013
  46. ↑ "Guidance for Industry: Enforcement Policy Regarding Investigational New Drug Requirements for Use of Fecal Microbiota for Transplantation to Treat Clostridium difficile Infection Not Responsive to Standard Therapies". Food and Drug Administration. July 2013.
  47. ↑ "Draft Guidance for Industry: Enforcement Policy Regarding Investigational New Drug Requirements for Use of Fecal Microbiota for Transplantation to Treat Clostridium difficile Infection Not Responsive to Standard Therapies". Food and Drug Administration. March 2014.
  48. ↑ Gabrielle Emanuel (March 7, 2014). "MIT Lab Hosts Nation's First Stool Bank, But Will It Survive?". WBUR-FM.
  49. ↑ Ratner, Mark (May 8, 2014). "Fecal transplantation poses dilemma for FDA". Nature Biotechnology. 32 (5): 401–402. doi:10.1038/nbt0514-401.
  50. ↑ "BBC Nature — Dung eater videos, news and facts". Bbc.co.uk. n.d. Retrieved November 27, 2011.
  51. ↑ DePeters EJ; George LW (September 26, 2014). "Rumen transfaunation". Immunology Letters. 162 (2 Part A): 69–76. PMID 25262872. doi:10.1016/j.imlet.2014.05.009.
  52. ↑ Dupont, HL (October 2013). "Diagnosis and management of Clostridium difficile infection.". Clinical Gastroenterology and Hepatology. 11 (10): 1216–23; quiz e73. PMID 23542332. doi:10.1016/j.cgh.2013.03.016.
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