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Candida Albicans Infection

Close-up shows inflammation and yellowish white patches of roof and back of the mouth caused by candidiasis. Uvula is greatly swollen, hanging near the level of the tongue. Courtesy: Wikipedia.
Close-up shows inflammation and infected patches on roof and back of the mouth caused by candidiasis. Uvula is swollen, hanging near the tongue. Courtesy: Wikimedia.

What Is Candida Albicans Infection?

Candida albicans infection, called candidosis or candidiasis, is an opportunistic invasion of mucous membrane or skin by candida albicans, an endogenous yeast found in 40 to 80% of normal human beings. A former name for this small, budding fungus is monilia albicans.

Opportunistic means that yeast living on mucosal and skin surfaces does not invade (infect) unless these tissues become unhealthy and therefore cannot protect themselves.

Q: How does candida albicans cause infection?

A: Candida albicans lives on the mucosal surfaces and skin in most people without causing infection (colonizes) because of our normal defenses against invasion. In fact, candida albicans is a very effective colonizer of humans. For example, Russell and Lay found that 47% of 1-month-old infants were orally colonized with candida albicans, and 49% were colonized with other fungi.

During growth within the intestinal tract, the organism senses pH (acidity), oxygen, carbon sources, and the presence of surfaces allowing it to optimize gene expression for a particular environment. With these mechanisms for sensing, candida albicans is able to efficiently colonize humans in infancy.1

Candida Infection Of The Esophagus on X-ray. Courtesy Radiology Assistant.nl
Candida Infection Of The Esophagus (White Area) On X-ray. Courtesy Radiology Assistant.nl

Lowered host defenses allow yeast already present on mucosal and skin surfaces to take advantage and can grow rapidly, becoming pathogenic (disease producing) so that infection results.

Infection is characterized by superficial, irregular white patches on mucosal surfaces and possible invasion of the bloodstream by a filamentous form (thread-like structures) that can rapidly develop.

Candida albicans is unique among oral pathogens in its ability to invade cornified layers of stratified squamous epithelium of the tongue, mouth surfaces, hard and soft palate, esophagus, and gut. Stratified squamous epithelium is the tough surface cells that ordinarily protect underlying tissues from damage or invasion by microbes.

Candida albicans is also capable of invading the lungs and causing pneumonia and septicemia, which is the spread of infection into the bloodstream.

Here is a time honored simple do-it-youself test for infection of the mouth or throat: First thing in the morning before brushing your teeth or eating, fill a small see through glass with water then gently spit onto the surface. If after an hour the spit remains on the water surface, it is unlikely you have candida in the mouth. If it grows legs downward, it indicates that yeast is growing. If the spit sinks to the bottom, you have this problem. Yeast in the mouth can quickly travel down the esophagus and into the gut.

Medical diagnosis. Difinitive diagnosis for the oral cavity is made by your clinician by swabbing the areas of your mouth and/or throat and viewing under a microscope for evidence of candida.

Infections of the esophagus and gut require inspection by gastroscopy or endoscopy procedure and the taking of samples to be examined under microscope. This examination also give the opportunity to rule out other problems. Barium swallow can show the extent of infection and any disfiguration of the esophagus that results.

What Is Candida Albicans Infection In Celiac Disease and/or Gluten Sensitivity?

Sources:
  1. Rosenbach A, Dignard D, Pierce JV, Whiteway M, Kumamoto CA. Adaptations of Candida albicans for growth in the mammalian intestinal tract. Eukaryot Cell. 2010 Jul;9(7):1075-86. doi: 10.1128/EC.00034-10. Epub 2010 Apr 30. [↩]

Crohn’s Disease

Endoscopic image of Crohn'sDisease showing deep ulceration in sigmoid colon.
Endoscopic Image of Crohn’s Disease Showing Deep Ulceration in the Sigmoid Colon.

What Is Crohn’s Disease?

Crohn’s disease is an inflammatory bowel disease characterized by patchy inflamed areas involving the full thickness of the intestinal wall that can occur anywhere in the intestinal tract, in addition to, mucosal disease.

In Crohn’s disease there is ongoing immune activation which produces inflammation and ulceration but the cause is not known and the severity varies among patients. At diagnosis of Crohn’s disease, factors predictive of subsequent 5-year aggressive disease are an age below 40 years, the presence of perianal disease, and the initial requirement for steroids.1

Dysbiosis is a factor that develops in and worsens Crohn’s disease and stress is a factor in both of these conditions. Psychological stress activates multiple physiological processes aimed at maintaining balance within the body. These physiological processes also have the capacity to influence the composition of microbial communities in the digestive tract, and research now indicates that exposure to stressful stimuli leads to gut microbiota dysbiosis.2

While the relative abundance of many different bacterial types can be altered during stressor exposure, findings in nonhuman primates and laboratory rodents, as well as humans, indicate that bacteria in the genus Lactobacillus are consistently reduced in the gut during stress.2

Q: Is there a cure for Crohn’s disease?

A: Presently, Crohn’s disease cannot be cured. This condition has a course of remissions, when symptoms subside, and flares, when symtpoms get worse. Treatment is aimed to reduce flares and promote remission.

What Is Crohn’s Disease In Celiac Disease and/or Gluten Sensitivity?

Sources:
  1. Beaugerie L, Seksik P, Nion-Larmurier I, Gendre JP, Cosnes J. Predictors of Crohn’s disease. Gastroenterology. 2006;130:650–656. [↩]
  2. Galley JD, Bailey MT. Impact of stressor exposure on the interplay between commensal microbiota and host inflammation. Gut Microbes. 2014 May 1;5(3):390-396. Epub 2014 Apr 1. [↩] [↩]

Colitis, Collagenous

Collagenous Colitis.
Microscopic Image Showing a Pink Collagen Band in Collagenous Colitis.

What Is Collagenous Colitis?

Collagenous colitis is a disease of the large intestine (colon) that is characterized by microscopic inflammation of the surface mucosal lining and an abnormally thickened collagen band of tissue that develops wthin the lining of the colon.

The thicker than normal layer of collagen of at least 10 µm (reference value: 2–7 µm) can vary in different locations. Inflammation occurs with increased numbers of lymphocytes (white blood cells) and plasma cells and epithelial (surface cell) damage. These changes can only be seen under microscopic examination of multiple biopsied tissue samples taken during a colonoscopy procedure.

Q: What is collagen?

A: Collagen is a strong, fibrous protein found in connective tissue of the colon and many other tissues such as tendons. The normal basement membrane in the bowel consists mainly of collagen type IV, laminin, and fibronectin. The increased collagen band observed in collagenous colitis consists basically of collagen type I and III, which are the subtypes produced by repair functions, indicating a reactive origin to some irritant or drug.1

The biopsies should preferably be taken from the ascending colon, since the pathological hallmarks may be absent in the descending colon, and in the normally occurring thicker collagen layer in the rectosigmoid region.1 Inflammation of the ileum (last segment of the small intestine next to colon) is common.2

Endoscopy and radiological (x-ray) examinations are usually normal.3

Autoimmune disorders are frequently seen in adult patients with collagenous colitis.4 In the study below by Koskela et al. concomittent autoimmune diseases were present in 53% of patients with collagenous colitis.5

Importantly, the finding of collagenous colitis in patients with autoimmune diseases may reflect the treatment with NSAIDs (non-steroidal anti-inflammatory drugs), such as Ibuprofin and aspirin, PPIs (proton pump inhibitors), and other drugs. However, if secondary forms of collagenous colitis are not taken into consideration, underlying, treatable diseases may be overlooked, while only the gastrointestinal symptoms are treated symptomatically or with budesonide (a steroid).6

Treatment with budesonide steroid is efficacious irrespective of bile acid malabsorption.7

Budesonide at a mean dose of 4.5 mg/day maintained clinical remission for at least 1 year in the majority of patients with collagenous colitis and preserved health-related quality of life without safety concerns. Treatment extension with low-dose budesonide beyond 1 year may be beneficial given the high relapse rate after budesonide discontinuation.8

See below for nutritional deficiency problems caused by steroid usage and steps to be taken for correction.

What Is Collagenous Colitis In Celiac Disease and/or Gluten Sensitivity?

Sources:
  1. Ohlsson B. New insights and challenges in microscopic colitis. Therap Adv Gastroenterol. 2015 Jan;8(1):37-47. doi: 10.1177/1756283X14550134. [↩] [↩]
  2. Bjørnbak C, Engel PJ, Nielsen PL, Munck LK. Microscopic colitis: clinical findings, topography and persistence of histopathological subgroups. Aliment Pharmacol Ther. 2011 Nov;34(10):1225-34. doi: 10.1111/j.1365-2036.2011.04865.x. [↩]
  3. Abdo AA, Urbanski SJ, Beck PL. Lymphotcytic and collagenous colitis: the emerging entity of microscopic colitis. An update on pathophysiology, diagnosis and management. Canadian Journal of Gastroenterology. Jul 2003;17(7):425-32. [↩]
  4. Leung ST, Chandan VS, Murray JA, Wu TT. Collagenous gastritis: histopathologic features and association with other gastrointestinal diseases. Am J Surg Pathol. 2009 May;33(5):788-98. doi: 10.1097/PAS.0b013e318196a67f. [↩]
  5. Koskela RM, Niemela SE, Karttunen TJ, Lehtola JK. Clinical characteristics of collagenous and lymphocytic colitis. Scandanavian Journal of Gastroenterology. Sep 2004;39(9):837-45. [↩]
  6. Ohlsson B. New insights and challenges in microscopic colitis. Therap Adv Gastroenterol. 2015 Jan;8(1):37-47. doi: 10.1177/1756283X14550134. [↩]
  7. Bjørnbak C, Engel PJ, Nielsen PL, Munck LK. Microscopic colitis: clinical findings, topography and persistence of histopathological subgroups. Aliment Pharmacol Ther. 2011 Nov;34(10):1225-34. doi: 10.1111/j.1365-2036.2011.04865.x. [↩]
  8. Münch A, Bohr J, Miehlke S, et al. Low-dose budesonide for maintenance of clinical remission in collagenous colitis: a randomised, placebo-controlled, 12-month trial. Gut. 2014 Nov 25. pii: gutjnl-2014-308363. doi: 10.1136/gutjnl-2014-308363. [↩]

Vitamin B1 (Thiamin) Deficiency

thiamin deficiency What Is Thiamin?

Thiamin, also called vitamin B1, is an essential vitamin that is required to convert foodstuffs into energy and for the health and proper functioning of the nervous, muscular and cardiovascular systems.

In the bloodstream, 90% of active thiamin (TPP) is carried by red blood cells while 10% is transported in the bloodstream as free thiamin and thiamin monophosphate bound mostly to the protein albumin.

In the diet, animal food sources provide active thiamin while plant food sources provide free thiamin.1

Urinary excretion of thiamin cannot be detected when vitamin intake is below the required levels. On the other hand, when intake exceeds saturation in the body, thiamin and/or its metabolites are actively excreted into urine to prevent excessive toxicity of the vitamins.2

In patients who have thiamin deficiency, the most common conditions that bring them to a clinician include neuropathies, depression, myalgia, cardiomyopathies or takes diuretics and/or eat a high carbohydrate diet.3

What Is Thiamin Deficiency In Celiac Disease and/or Gluten Sensitivity?

Sources:
  1. Kathleen Mahan and Sylvia Escott-Stump, ed. Krause’s Food, Nutrition & Diet Therapy, 10th Edition. Philadelphia, PA. USA: W.B. Saunders Company, 2000. [↩]
  2. Shibata K, Hirose J, Fukuwatari T. Relationship Between Urinary Concentrations of Nine Water-soluble Vitamins and their Vitamin Intakes in Japanese Adult Males. Nutr Metab Insights. 2014 Aug 5;7:61-75. doi: 10.4137/NMI.S17245. [↩]
  3. Spectracell Labs, Inc. [↩]

Irritable Bowel Syndrome (IBS)

What Is Irritable Bowel Syndrome? Irritable bowel syndrome (IBS) is a motility disorder without anatomic cause involving the entire gastrointestinal tract that is characterized by these four features: 1) Abdominal pain usually relieved by defecation… 

Gluten Sensitive Enteropathy (Active Celiac Disease)

canstockphoto17997339What Is Gluten Sensitive Enteropathy?

Gluten sensitive enteropathy is active celiac disease characterized by inflammation of the small intestinal mucosa that results from an inherited immunologic intolerance to ingested gluten.

Q: What does the inflammation do to the mucosa in the small intestine?

A: Inflammation is a cell level immune response to gluten that has these effects on the mucosa:

  • Damages the barely visible villi (multitudinous finger-like structures) by causing atrophy or loss.
  • Likely affects the structural support and microcirculation of the villus, leading to collapse of the villus.
  • Elongates the crypts between villi. The thickening of the crypt is not so much a response to loss of surface enterocytes but represents inflammation of the mucosa.1
  • Increases round cells in the lamina propria and surface epithelial cells leaving few, irregular microvilli (brush border) on the surface of villi.
  • Damage is most intense in the duodenum and decreases toward the large intestine.
  • The extent of the damage to the intestine determines the malabsorptive consequences of the disease. Both gastric and small intestinal permeability are disrupted in patients with celiac disease.2
  • Relationship between active celiac disease and intestinal permeability: There is a clear association between degree of mucosal damage and the intestinal-permeability ratio, and a normal ratio generally implies near-normal small intestinal structure. A raised intestinal permeability of the mucosal lining (leaky gut) could predispose to a high absorption of gluten and exacerbate an existing lesion and hence convert a latent to an overt enteropathy.3
  • Relationship between active celiac disease and tight junction proteins: A study of intestinal permeability showed that the expression of all junction proteins of the small intestinal lining (occludin, claudin 3, zonula occludens 1, and E-cadherin) was already decreased in early stage celiac disease when compared with non-celiac controls, showing leaky gut and confirming the above earlier study by Johnston et al. Junction protein expression correlated positively with mucosal villus structure and negatively with the number of intraepithelial lymphocytes (IELs), the intensity of small-intestinal autoantibody deposits, and serum autoantibodies. The expression of claudin 3 showed a negative correlation with diarrheal score.4
  • Relationship between active celiac disease and inflammation. In celiac disease there is an over production of inflammatory interleukin-15 (IL-15) which inhibits the correct removal of damaged intraepithelial lymphocytes caused by the reaction to gluten. Serum levels of IL-15 are directly correlated with the seriousness of tissue damage.5

  • Relationship between active celiac disease and gut microbiota. Results of a study investigating intestinal microbiota (normal bacterial residents) in patients with celiac disease suggest that with lower levels of the genus bifidobacteria, celiac patients have an imbalance in the intestinal microbiota even while on a gluten-free diet. This fact could favor the pathological process of the disorder. The concentration of bifidobacteria per gram of feces was significantly higher in healthy subjects (2.5 ± 1.5 x107 CFU/g) when compared to celiac patients (1.5 ± 0.63 x108 CFU/g).6

  • Relationship between active celiac disease and endoscopy technique. The most severe degree of villous atrophy was detected when distal duodenal biopsy specimens were taken in addition to a duodenal bulb biopsy specimen from either the 9- or 12-o’clock position (96.4% sensitivity; 95% CI, 79.7%-100%). The difference between the 12-o’clock position biopsy and the 3-o’clock position biopsy in detecting the most severe villous atrophy was 92% (24/26 patients) versus 65% (17/26 patients).7
  • Relationship between active celiac disease and diet adherence. Patients with consistent gluten free diet adherence experience symptomatic responses to dietary gluten (SRDG) faster and more severe in comparison to their prior gluten exposure possibly demonstrating an adept immunological response. Anxiety and depression also enhance the speed of symptom onset and co-existing visceral hypersensitivity is a risk factor for severe reactions to dietary gluten.8
  • Relationship between active celiac disease and atrial fibrillation: Patients with celiac disease, verified by intestinal biopsy, are at increased risk of atrial fibrillation. This observation is consistent with previous findings that elevation of inflammatory markers predicts atrial fibrillation.9

How Prevalent Is Gluten Sensitive Enteropathy?

Sources:
  1. Murray JA, the widening spectrum of celiac disease. American Journal of Clinical Nutrition. Mar 1999; 69(3):354-365. [↩]
  2. Murray JA, the widening spectrum of celiac disease. American Journal of Clinical Nutrition. Mar 1999; 69(3):354-365. [↩]
  3. Johnston SD, Smye M, Watson RGP. Intestinal permeability and morphometric recovery in coeliac disease. Lancet. Jul 28, 2001;358(9278):259, 2p. [↩]
  4. Rauhavirta T, Lindfors K, Koskinen O, Laurila K, Kurppa K, Saavalainen P, Mäki M, Collin P, Kaukinen K. Impaired epithelial integrity in the duodenal mucosa in early stages of celiac disease. Transl Res. 2014 Sep;164(3):223-31. doi: 10.1016/j.trsl.2014.02.006 [↩]
  5. Stazi AV, Trinti B. Selenium status and over-expression of interleukin-15 in celiac disease and autoimmune thyroid diseases. Ann Ist Super Sanita. 2010;46(4):389-99.DOI: 10.4415/ANN_10_04_06. [↩]
  6. Golfetto L, de Senna FD, Hermes J, Beserra BT, França Fda S, Martinello F. Lower bifidobacteria counts in adult patients with celiac disease on a gluten-free diet. Arq Gastroenterol. 2014 Apr-Jun;51(2):139-43. [↩]
  7. Kurien M, Evans KE, Hopper AD, Hale MF, Cross SS, Sanders DS. Duodenal bulb biopsies for diagnosing adult celiac disease: is there an optimal biopsy site? Gastrointest Endosc. 2012 Jun;75(6):1190-6. doi: 10.1016/j.gie.2012.02.025. [↩]
  8. Barratt SM, Leeds JS, Sanders DS. Factors influencing the type, timing and severity of symptomatic responses to dietary gluten in patients with biopsy-proven coeliac disease. J Gastrointestin Liver Dis. 2013 Dec;22(4):391-6. [↩]
  9. Emilsson L, Smith JG, West J, Melander O, Ludvigsson JF. Increased risk of atrial fibrillation in patients with coeliac disease: a nationwide cohort study. Eur Heart J. 2011 Oct;32(19):2430-7. doi: 10.1093/eurheartj/ehr167. [↩]

Gas

intest (2)What Is Obnoxious Gas?

Obnoxious gas, or flatus, is gas that is not only offensive when passed but also lingers in the air longer than ordinary gas does.

Gas is a natural digestive product within the colon that is composed mainly of hydrogen and carbon dioxide gases. These gases are given off in the necessary bacterial breakdown of undigested fermentable food entering the colon from the small intestine.

Q: What makes gas obnoxious?

A: The production of obnoxious gas depends on the type and quantity of undigested food residue that is passed into the colon from the small intestine, dysfunctional motility instead of normal peristalsis, and dysbiosis. Dysbiosis is the condition of  having unhealthy or insufficient populations of microbes responsible for digesting (fermenting) foodstuffs in the lower gut or colon. 

Gases produced by intestinal microbes may modulate intestinal motor function (muscle movement) in individuals with functional bowel disease. Methane, produced by enteric bacteria in the human gut, is associated with slowed intestinal transit and constipation.1

What Is Obnoxious Gas In Celiac Disease and/or Gluten Sensitivity?

Sources:
  1. Jahng J, Jung IS, Choi EJ, Conklin JL, Park H. The effects of methane and hydrogen gases produced by enteric bacteria on ileal motility and colonic transit time. Neurogastroenterol Motil. 2012 Feb;24(2):185-90, e92. doi: 10.1111/j.1365-2982.2011.01819.x. Epub 2011 Nov 20.

    Methane is produced in the colon by intestinal methanogens (microbes) that metabolize hydrogen, one of the end products of normal anaerobic (meaning without oxygen) bacterial fermentation.  Fermentation of the undigested starchy part of carbohydrates produces hydrogen in the intestine, which is the food for methane production by intestinal methanogens.

    Hydrogen and methane are excreted in the flatus and in breath giving the opportunity to indirectly measure their production using breath testing. ((Triantafyllou K, Chang C, Pimentel M. Methanogens, Methane and Gastrointestinal Motility. J Neurogastroenterol Motil. 2014 Jan;20(1):31-40. Epub 2013 Dec 30. [↩]

Vitamin B3 (Niacin) Deficiency

SumptuousTuna For Niacin.
Sumptuous Tuna For Niacin.

What Is Vitamin B3 (Niacin)?

Niacin is an essential water-soluble B vitamin that is required by all cells of the body.

During digestion of food containing it, niacin (the form in food) is changed in the small intestines to the active form niacinamide (niacin plus an amide group), which is then absorbed into the bloodstream. 

Niacinamide is converted by the body into co-enzymes which are present in all cells. These are niacinimide adenine dinucleotide (NAD) and NADP. NADP is formed when the body adds a phosphate to NAD.

Q: How do these enzymes work?

A: These enzymes function in oxidation-reduction reactions essential for release of energy from carbohydrates, fats, and proteins and are needed as components for more than 200 enzymes involved in metabolism.

In addition to producing energy, niacinamide is essential for healthy skin and the mucosal lining of the digestive tract, normal functioning of the brain and nervous system, and production of steroid hormones in adrenal glands and hormones in sex glands.  Functions are more fully described below.

Urinary excretion of niacin cannot be detected when vitamin intake is below the required levels. On the other hand, when intake exceeds saturation in the body, the vitamin and/or its metabolites are actively excreted into urine to prevent excessive toxicity of the vitamins.1

What Is Niacin Deficiency In Celiac Disease and/or Gluten Sensitivity?

Sources:
  1. Shibata K, Hirose J, Fukuwatari T. Relationship Between Urinary Concentrations of Nine Water-soluble Vitamins and their Vitamin Intakes in Japanese Adult Males. Nutr Metab Insights. 2014 Aug 5;7:61-75. doi: 10.4137/NMI.S17245. eCollection 2014. [↩]

Vitamin B12 Deficiency

Clams Are Chock Full of Vitamin B12.
Lovely Clams For Vitamin B12.

What Is Vitamin B12?

Vitamin B12, also called cobalamin, is a highly complex vitamin that functions in two coenzyme forms: adenosylcobalamin and methylcobalamin.

These forms of the vitamin play important roles in the physical and chemical processes by which amino acids become proprionate, proprionate that becomes acetate,  and single carbons.

Q: Why are these steps important?

A: These steps are essential for normal function in the workings of all cells, especially for those of the digestive tract, bone marrow and nervous tissue.

Vitamin B12 is mainly excreted through bile into the duodenum (first part of the small intestine) for excretion in stool.1 However, if vitamin B12 is needed, it is reabsorbed in the ileum (end of the small intestine) while excess is excreted in stool and very little in urine.2

The blood level of vitamin B12 in healthy people ranges between 140 and 750 pg/ml.

What Is Vitamin B12 Deficiency In Celiac Disease and/or Gluten Sensitivity?

Sources:
  1. Shibata K, Hirose J, Fukuwatari T. Relationship Between Urinary Concentrations of Nine Water-soluble Vitamins and their Vitamin Intakes in Japanese Adult Males. Nutr Metab Insights. 2014 Aug 5;7:61-75. doi: 10.4137/NMI.S17245. [↩]
  2. Shinton N K. Vitamin B 12 and folate metabolism. Br Med J. Feb 26, 1972; 1(5799): 556–559. [↩]

Lymphoma, Enteropathy-Associated T-Cell (EATL) 

A real photomicrograph of carcinoma of the esophagus. Panorama of 6 photos of a slide at 40x through the microscope. Some areas may appear blurry due to shallow DOF.
A real photomicrograph of carcinoma of the esophagus. Panorama of 6 photos of a slide at 40x through the microscope. Some areas may appear blurry due to shallow DOF.

What Is Cancer Of The Esophagus?

C ancer of the esophagus is a malignancy arising in the stratified squamous cell lining of any part of the esophagus and having a poor prognosis.

This tumor first invades the deeper layers of the esophagus which includes the layer beneath the mucosa (submucosa) and muscle before it may invade structures close to it including the aorta and trachea. Later, it may spread to organs further away such as the liver, lungs and bones.

Q: What is the stratified squamous cell lining of the esophagus?

A: Stratified squamous cells are flat epithelial cells that are composed of several layers, called the epithelium. This type of epithelium forms the surface mucosa that lines the inside of the esophagus.

The esophagus itself is a muscular tube that transports swallowed substances to the stomach. It begins at the cricoid cartilage (Adam’s apple) as a continuation of the pharynx in the throat and ends at the lower esophageal sphincter (LES).

The LES is a circular muscle surrounding the junction of the esophagus and stomach. The LES opens to allow swallowed food and liquids to enter the stomach and closes to prevent their travelling back into the esophagus.

Who is Affected in the General Population?

Esophageal cancer is the fifth leading cause of death in men from cancer worldwide.1

What Is Cancer Of The Esophagus In Celiac Disease and/or Gluten Sensitivity?

Sources:
  1. Feldman M, Friedman LS, Brandt LJ. Sleisenger & Fordtran’s Gastrointestinal and Liver Disease. ed 9. Philadelphia: Saunders; 2010. pp. 745–767. [↩]