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Copyright2003 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written PermissionAlternative Medicine Review Volume 8, Number 3 2003 Page 247

Review Ulcerative Colitis

AbstractUlcerative colitis (UC), a subcategory ofinflammatory bowel disease, afflicts 1-2 millionpeople in the United States, and many moreworldwide. Although the exact cause ofulcerative colitis remains undetermined, thecondition appears to be related to acombination of genetic and environmentalfactors. While conventional treatments can beeffective in maintaining remission anddecreasing the length of active diseaseperiods, the treatments are not without sideeffects, and a significant number of peoplesuffering from UC fail to respond to even thestrongest drugs. This article reviews potentialunconventional treatments transdermalnicotine, heparin, melatonin, DHEA, probiotics,fiber, dietary changes, botanicals, essentialfatty acids, and other nutrients that may beconsidered in conjunction with conventionalapproaches or as part of a comprehensivealternative treatment protocol. In addition thisreview addresses risk factors, pathogenesis,nutrient deficiencies, conventional treatmentapproaches, and extra-intestinal manife-stations of the disease.(Altern Med Rev 2003;8(3):247-283)

IntroductionInflammatory bowel disease (IBD) en-

compasses several chronic inflammatory condi-tions, most significantly ulcerative colitis (UC) andCrohns disease (CD). While these two conditionsshare many common features diarrhea, bloody

stools, weight loss, abdominal pain, fever, andfatigue each has unique features (Table 1). Acomplete discussion of Crohns disease will beaddressed in a future article. This review focuseson ulcerative colitis and associated risk factors,pathogenesis, nutrient deficiencies, conventionaltreatment approaches, natural treatment ap-proaches, and extra-intestinal manifestations of thedisease.

Description and SymptomologyUlcerative colitis affects the colon and

rectum and typically involves only the innermostlining or mucosa, manifesting as continuous ar-eas of inflammation and ulceration, with no seg-ments of normal tissue. The Crohns and ColitisFoundation of America defines several varietiesof UC. Disease involving only the most distal partof the colon and the rectum is termed ulcerativeproctitis; disease from the descending colon downis referred to as limited or distal colitis; and dis-ease involving the entire colon is called pancolitis.1

Kathleen A. Head, ND Technical Advisor, ThorneResearch, Inc.; Editor-In-Chief, Alternative MedicineReview.Correspondence address: Thorne Research, PO Box 25,Dover, ID 83825 E-mail: [email protected]

Julie S. Jurenka, MT (ASCP) Research Assistant,Alternative Medicine Review; Technical Assistant, ThorneResearch, Inc.

Inflammatory Bowel Disease Part I:Ulcerative Colitis Pathophysiology andConventional and Alternative Treatment

OptionsKathleen A. Head, ND and

Julie S. Jurenka, MT (ASCP)

Alternative Medicine Review Volume 8, Number 3 2003

Ulcerative Colitis Review

Copyright2003 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written Permission

Table 1. Comparison between Symptoms of Ulcerative Colitis and CrohnsDisease

Sign/Symptom

Area of intestinal tract affected

Diarrhea

Abdominal pain/cramping

Blood in stool

Fatigue

Fever

Physical examination

Weight loss/anorexia

Appetite

Risk of colon cancer

Ulcerative Colitis

Any part of inner most lining of colon, continuous with no "patches" of normal tissue

Typically four episodes per day

Mild tenderness, lowerabdominal cramping

Present; amount depends on disease severity

Result of excessive blood loss and anemia

Low-grade in severe cases

Rectal exam may show peri-anal irritation, fissures, hemorrhoids, fistulas, and abscesses

Weight loss in more severe cases

Often decreased during periods of disease exacerbation

Increased

Crohns Disease

Lower ileum most common but can flare up anywhere, including the colon; "patches" of normal tissue between affected areas; can affect entire intestinal wall

Typically four episodes per day

Moderate to severe abdominaltenderness in right lower quadrant

Present; amount depends on disease severity

Result of excessive blood loss, anemia, and poor nutrient absorption

Low-grade in severe cases

Peritoneal irritation, abdominal or pelvic mass

Weight loss and anorexia common due to poor digestion and intestinal absorption

Often decreased during periods of disease exacerbation

Increased

Alternative Medicine Review Volume 8, Number 3 2003 Page 249



UC may be insidious, with gradual onsetof symptoms, or the first attack may be acute andfulminate. More mild symptoms include a progres-sive loosening of the stool, abdominal cramping,and diarrhea. As the disease progresses from mildto more severe, the patient may also experienceweight loss, fatigue, loss of appetite that may re-sult in nutrient deficiencies, mucus in the stool,severe rectal bleeding, fever, and anemia.1,2

Epidemiology and Risk FactorsIt is estimated that 1-2 million Americans

suffer from IBD; approximately half of these haveulcerative colitis. UC can occur anytime in life,but is usually diagnosed prior to age 30. The dis-ease appears to affect men and women equally.Approximately 20 percent of people with UC havea close relative with IBD.1 Caucasians have ahigher incidence of UC, with Jewish people ofEuropean descent 3-6 times more likely to developthe disease.3 Regions with a low incidence of UCinclude Asia, Japan, Africa, and South America.4

Breast feeding,5,6 appendectomy,7,8 andsmoking,8,9 are associated with reduced risk of UC.Consumption of a Western diet,10-12 left-hand-edness,13,14 and depression15,16 may increase riskfor ulcerative colitis.

Diagnosis of Ulcerative ColitisSince the early symptoms of UC are simi-

lar to irritable bowel syndrome (IBS), Crohnsdisease, diverticulitis, and colorectal cancer, acomplete patient history is essential. In addition,it is initially necessary to rule out infectious causesof diarrhea and cramping with stool cultures andova and parasite analysis. Other tests that may beperformed early in the diagnostic process are fe-cal occult blood and a complete blood count (CBC)to check for intestinal blood loss and anemia. IfUC is not ruled out, confirmation is usually viaeither flexible sigmoidoscopy or colonoscopy.1,3

Factors in the Etiopathogenesis ofUlcerative Colitis

Although the exact cause of ulcerativecolitis remains undetermined, the condition ap-pears to be related to a combination of genetic andenvironmental factors. Whole genome scans havefound susceptibility genes for UC on chromo-somes 1 and 4, although these loci have not beenuniformly confirmed.17

Among the pathological findings associ-ated with UC are an increase in certain inflamma-tory mediators, signs of oxidative stress, a de-ranged colonic milieu, abnormal glycosaminogly-can (GAG) content of the mucosa, decreased oxi-dation of short chain fatty acids (SCFAs), in-creased intestinal permeability, increased sulfideproduction, and decreased methylation. While noone factor has been identified as the initial triggerfor ulcerative colitis, pieces of the puzzle havebeen elucidated; fitting them together to create acomplete picture remains to be accomplished.

Inflammatory MediatorsDiffering cytokine and other inflamma-

tory-mediator profiles have been identified for UCand CD. The classic lesions of UC, involving themucosal layer with extensive epithelial damage,abundant neutrophils, and crypt abscesses have ledto a search for an immune mechanism to explainthe epithelial damage.18

While it has been hypothesized that CDis a T-helper 1 (Th1) dominated (cell-mediated)immune reaction, there is evidence UC ischaracterized by T-helper 2 (Th2) (humoral)domination.17 The picture is far from clear,however (see Kidd P. Altern Med Rev 2003;8(3))Enhanced humoral immunity in UC is evidencedby high levels of immune globulins andautoantibodies. Mucosal plasma cells frompatients with UC have demonstrated high levelsof immune globulins, especially IgG1.19Autoantibodies, including anticolon andantineutrophil antibodies, have been detected inthe serum of UC patients.20,21 Das et al haveidentified protein on colonic epithelium (40 kDa)that elicits an IgG antibody response.22 Halstensenet al found evidence of immune globulins and




complement on theapical surface ofcolonic enterocytes more evidence of apotential auto-immune response.23

The cyto-kine profile in UCpatients providesmore evidence of anexaggerated Th2response elevatedinterleukin-5 (IL-5)but no significantelevation ofinterferon-gamma(IFN-) and othercytokines associatedwith an overactiveTh1 response.24Other researchershave reportedelevated IL-8 in themucosa of UCpatients compared tocontrols or patientswith CD.25 Othercytokines associatedwith generalizedinflammation IL-1,IL-6, and tumornecrosis factor-alpha(TNF-) are foundelevated in both inflammatory bowel conditions.18Table 2 compares cytokine profiles typically seenin UC and CD.

Animal models of colitis have yielded evi-dence of both Th1- and Th2-mediated conditions.In a mouse model, Th1 cytokine responses yieldedacute transmural and focal lesions, whereas Th2cytokine responses resulted in diffuse atrophicchanges in crypts and the mucosal layer. The au-thors conclude that in the animal model Th1 re-sponses more closely resemble inflammation as-sociated with CD, while Th2 responses inducedlesions resembling UC.26

While antibodies and complement may beassociated with lesions of UC, the colon damagemay also be the direct result of an exaggerated T-cell response. In another mouse model of colitis,it was established that a bacterially associatedantigen could stimulate pre-committed Th1 or Th2cells to mount an inflammatory reaction in thecolon. Lamina propria cells recovered from Th2-stimulated mice produced IL-4 and -10, but nodetectable IFN-.27

TNF-, although not specific to UC, maybe a means of monitoring disease activity. Com-pared to healthy controls (n=10) or children withdiarrhea (n=14) (mean TNF- 58- and 45 pg/g,respectively), children with active UC or CD had

Table 2. Cytokine Profiles: Comparison between UlcerativeColitis and Crohns Disease

Cytokine

IL-1

IL-2

IL-6

IL-8

Interferon-gamma

Tumor necrosis factor-alpha

Ulcerative Colitis

Normal in serum; raised in mucosa

Normal in serum and mucosa


Undetectable in serum; high in mucosa

Serum levels not known; normal in mucosa

Serum levels high; mucosa levels high

Crohns Disease


Raised in serum and mucosa

Raised in serum and mucosa

Undetectable in serum; mucosa levels not reported

Serum levels not known; high in mucosa

Serum levels high; mucosa levels high

Adapted from: MacDonald TT, Murch SH. Aetiology and pathogenesis of chronic inflammatory bowel disease. Ballieres Clin Gastroenterol 1994;1:1-34.




significantly higher levels of stool TNF-. Thisstudy looked at only four children with UC andfound levels of this cytokine ranged from 276-5,982 pg/g. In patients with inactive disease, lev-els fell to those of controls.28

In another study, frequency of TNF--se-creting cells from intestinal mucosal biopsy speci-mens was analyzed. Although levels were higherin children with UC than normal subjects, theywere not higher than in children with non-specificintestinal inflammation.29

Oxidative Stress inUlcerative Colitis

Signs of increasedoxidative stress are in evi-dence in the intestinal mu-cosa of patients with ulcer-ative colitis and may be sec-ondary to inflammation. Onestudy examined signs of oxi-dative stress and plasma an-tioxidant levels in controlscompared to patients withUC and CD. Oxidative DNAdamage was noted in bothIBD groups compared tocontrols, measured by pro-duction of 8-hydroxy-deoxy-guanosine (8-OHdG). UCpatients were found to havesignificantly lower plasmalevels of vitamins A and Eand several carotenoids com-pared to controls (Table 3);there were no differencesbetween UC and CDgroups.30

Other researchershave also found increasedoxidative stress in ulcerativecolitis patients. Mucosal bi-opsies of UC patients were

analyzed and shown to have increased reactiveoxygen intermediates, DNA oxidation products (8-OHdG), and iron in inflamed tissue compared tocontrols. Decreased levels of copper and zinc,cofactors for the endogenous antioxidant super-oxide dismutase, were also observed.31 In addi-tion, increased protein carbonyls in inflamed mu-cosa were noted. The authors speculate this sup-ports the theory that free radicals can produce dam-age to mucosal proteins in IBD.

A theory proposed by several researchersinvolves TNF- production of reactive oxygenspecies (ROS); ROS in turn activate nuclear fac-tor-kappa B (NF-kB), which then enhances fur-ther TNF- production, propagating a viciouscycle (Figure 1).

Table 3. Plasma Antioxidant Levels in InflammatoryBowel Disease

Antioxidant

Retinol

Alpha tocopherol

Lutein

Zeaxanthin

Lycopene

Beta cryptoxanthin

Alpha carotene

Beta carotene

Ulcerative Colitis (n=43)

1.8 0.1 (p




The Role ofGlycosaminoglycans

The gastrointestinal (GI) extra-cellular matrix is composed of the pro-teins collagen and elastin, and groundsubstance that includes glycosaminogly-cans (GAGs). GAGs are abundant in thebasement membrane, lamina propria, andsubmucosa of the GI tract. The compo-sition of GAGs may significantly affectboth the permeability of the colon andimmune/inflammatory reactions. Analy-sis of diseased, resected colons yieldedaltered GAG content in the colon of pa-tients with IBD and colonic neoplasiacompared to tissue from undiseased co-lons. In histologically normal colon tis-sue the majority of GAG content con-sists of chondroitin- and dermatin sul-fate, with smaller amounts of hyaluronicacid and heparan sulfate. Ulcerative coli-tis yielded a distinctly abnormal distri-bution of GAGs, with significantlygreater amounts of total glycosaminogly-cans, heparan sulfate, and hyaluronicacid than control tissue. Colonicneoplasias were also found to containthese abnormal GAG profiles, but to agreater extent than UC tissue.32

Other researchers report the alterations arelimited to the mucosa in UC, with substantial lossof GAGs from the subepithelial basal lamina.These researchers hypothesize that alterations innegatively charged sulfated compounds could sig-nificantly affect the passage of substances throughthe colonic mucosa, contributing to leakage ofproteins and fluids, thrombosis, and extensive re-modeling observed in UC and other inflammatorybowel conditions.33

The importance of altered glycosamino-glycan content of colonic tissue to the pathogenesisof UC is not completely understood. Whether it isa result of, or cause of, inflammation remains tobe determined. Some researchers hypothesizethese alterations may contribute to theinflammatory process since hyaluronic acid can

interact directly with lymphocytes, inhibitmacrophage response to cytokines, and enhancephagocytosis. GAG content has been associatedwith alteration in the distribution of macrophagesreactive to TNF-.34

Extracellular matrix proteins areimportant for maintaining the integrity of the gutwall as it is constantly challenged by antigens andmicrobes.

Figure 1. The Potential Role of Reactive OxygenSpecies in Inflammation

TUMOR NECROSISFACTOR-ALPHA

REACTIVEOXYGEN SPECIES

NUCLEARFACTOR-KAPPA B

A theory proposed by several researchers involves TNF- production of reactive oxygen species, which in turn activate nuclear factor-kappa B (NF-kB), which then enhances further TNF- production, setting up a vicious cycle.

increases produces

activates




Colonic Milieu: Bacterial Profile,Effect on Gut Permeability, Sulfur,Nitric Oxide, and Short Chain FattyAcidsThe Significance of the ColonicMicroflora

Despite considerable study of fecal mi-croflora in inflammatory bowel disease, no con-sistent pathogenic enteric bacteria have been iden-tified, with the exception of Clostridium difficile(specific to patients with antibiotic-associatedcolitis).

Research results have varied and may, atleast in part, be due to differences in specimenlocation. Some researchers have linked variousEnterobacteraceae, especially Escherichia coli,with colitis. An examination of fecal samples col-lected from 23 patients with active ulcerative coli-tis, 15 with UC in remission, and 20 from patientswith other types of colitis, found 35 percent ofpatients with active UC and 27 percent of patientswith UC in remission harbored one or more inva-sive or adhesive fecal coliform bacteria, comparedwith five percent of patients with other types ofcolitis and five percent of normal controls(p




Despite the inability to isolate a specificpathogen, there is considerable evidence that bac-teria play a role in colitis: (1) bowel lesions ap-parently occur more frequently in areas of high-est bacterial concentration; (2) normal enteric bac-teria are necessary for disease expression in ani-mal models; (3) patients with UC who have hadileal pouch-anal anastomosis surgery developmucosal lesions only after bacterial colonization;and (4) therapeutic manipulation of colonic florawith anti- or probiotics can result in symptomimprovement.41

There are several mechanisms wherebycolonic bacteria may influence the course of ul-cerative colitis. The beneficial effects are discussedin the treatment section. Pathogenic mechanismsmay involve: (1) an overwhelming presence of

specific pathogenic bacteria; (2) subtle imbalancesin the ratio of beneficial to pathogenic bacteria(dysbiosis); (3) a defective mucosal barrier; and(4) alterations in the gut immune response.41 Patho-genic bacteria may secrete enterotoxins capableof altering gut permeability and causing systemiceffects, elaborate immunosuppressive proteins thatinterfere with normal gut immune responses, andmay directly interfere with epithelial cell metabo-lism (e.g., metabolism of SCFAs). A possible cas-cade of events is illustrated in Figure 2.

Because no specific pathogen has beenimplicated in UC, alterations in gut immunity mayplay a significant role. A popular theory amongresearchers is that UC is characterized by an ab-normal host response to normal colonic bacteria,i.e., a cross-reactivity between antibodies pro-duced against bacteria and mucosal proteins. Ani-mal models and human studies of colitis supportthis theory, demonstrating inflammatory reactionsto commensal anaerobes. In a mice study an ab-normal T-cell response to an enteric bacterial strainwas implicated as a mechanism for colitis patho-genesis. The researchers further demonstrated abacterial antigen could contribute to either an ab-normal Th1 or Th2 response that progressed tocolitis.27

Subjects with normal bowel functionelaborate IgA as the primary immunoglobulin inthe intestines, offering the first line of defenseagainst antigens (bacteria, allergens, etc.). Re-searchers have found patients with IBD tend toproduce high concentrations of IgG by intestinallymphocytes, when compared to controls withIBS. IgG antibodies, directed at cytoplasmic pro-teins from normal commensal bacteria, were evi-dent in patients with UC but not in controls.42 Anoverreaction to normal enteric microflora, result-ing in an autoimmune response, may be an im-portant aspect of chronic ulcerative colitis.

Gut PermeabilityAn impaired colonic mucosal barrier lead-

ing to increased intestinal permeability has beendemonstrated in patients with UC. Local leaks dueto apoptosis of colonic epithelium comprise theprimary lesion in mild UC. Moderate-to-severe

Figure 2. The PotentialEffect of Bacteria onInflammation and GutPermeability

Bacterial Components

Intestinal immuneand epithelial cells

CytokinesReactive oxygen species

Nitric oxideProteases

Eicosanoids

Local mucosal damage

activation

secretion




UC is characterized not only by extensive localleaks but also by highly permeable ulcerous le-sions.43

Patients with UC have also demonstrateddecreased colonic mucin species IV compared tobiopsy specimens from normal controls.44 An invitro study demonstrated a possible interactionbetween bacterial peptides and the mucosa in UC,resulting in depletion of mucus secretion by gob-let cells.45

Medical therapy (unspecified) leading toremission not only results in decreased inflamma-tion but also improved gut barrier integrity.46

The Sulfur-Butyric Acid ConnectionButyric acid, a four-carbon short chain

fatty acid, and several other SCFAs, including pro-pionic and acetic acids, are produced in a healthycolon by fermentation of fiber and other carbohy-drates. Butyric acid provides the primary fuel forcolonocytes. Proper ion transfer, mucus synthe-sis, phase II detoxification, and lipid synthesis forcell membrane integrity in the colonocytes dependon butyrate oxidation.47 Impaired metabolism ofSCFAs has been implicated as a factor in UC.

Hond et al compared butyrate metabolismin healthy controls with that of 25 hospitalizedpatients with severe ulcerative colitis and 11 UCpatients in remission. They measured butyratemetabolism after rectal instillation of 14C-labeledbutyrate by measuring 14C02 in the breath. Patientswith active UC had significantly lower butyrateoxidation than patients in remission (who had nor-mal butyrate oxidation) or controls. Three patientswith inactive disease had decreased butyrate oxi-dation and interestingly, all three relapsed withina few weeks.48 Perhaps decreased oxidation ofSCFAs is a good predictor of possible relapse andoccurs before other signs of inflammation. Be-cause normal oxidation was observed in patientsin remission, faulty SCFA oxidation is likely tobe a result rather than a primary cause of ulcer-ative colitis.

Other researchers compared the rate ofbutyrate, glucose, and glutamine oxidation to car-bon dioxide in colonoscopy biopsy specimensfrom 15 patients with quiescent or mild colitis tospecimens from 28 controls with normal colonic

mucosa. Butyrate, but not glucose or glutamine,oxidation was significantly impaired in the UCpatients compared to controls, even though thedisease was mild.49

High concentrations of sulfate-reducingbacteria with concomitant elevation of hydrogensulfide have been noted in patients with UC. Hy-drogen sulfide can potentially damage the gutmucosa by inhibiting butyrate oxidation in themitochondria, essentially starving the colonocyte(Figure 3). In experiments on human colonocytesisolated from colectomy patients, hydrogen sul-fide and other sulfur compounds inhibited butyrateoxidation by 75 percent in the distal colon and 43percent in the ascending colon. The authors of thestudy conclude that the metabolic effects of so-dium hydrogen sulfide on butyrate oxidation alongthe length of the colon closely mirror metabolicabnormalities observed in active ulcerativecolitis.50

Figure 3. A PotentialMechanism for HydrogenSulfide Toxicity

Sulfate-reducing bacteriaDietary sulfur

Hydrogen sulfide

Metabolism of butyric acidand other SCFAs

Colonocytes

inhibits

starving




Animal studies on rabbits and guinea pigshave demonstrated that feeding sulfated polysac-charides (such as carrageenan), but not unsulfatedpolysaccharides, can induce lesions similar to ul-cerative colitis.51

Researchers note higher counts of sulfur-reducing bacteria in the feces of patients with ac-tive UC than in patients in remission.52 A com-monly used drug for treatment of ulcerative coli-tis, 5-aminosalicylic acid (5-ASA; mesalamine)has been shown to lower sulfide concentrationsin feces.53

Methylation is believed to be an impor-tant route for sulfide detoxification in thecolonocyte.54 A study was conducted to determineif methyl donors could reverse the damaging ef-fect of sulfides on colonocytes. Isolatedcolonocytes from rat and human specimens weretested by measuring the oxidation of butyrate inthe presence of hydrogen sulfide, followed by in-troduction of methyl donors to the suspension.Sulfide toxicity was reversible most potently byS-adenosylmethionine 1,4 butane disulfonate(stable form of SAMe), followed by DL-methion-ine-S-methyl-sulfonium and L-methionine. Me-thyl donors may have therapeutic value in UC.55

Interestingly, hyperhomocysteinemia, acondition of inadequate methylation, has beenfound to occur more commonly in patients withIBD (17 of 64; 26.5%) than controls (4 of 121;3.3%).56 Other researchers confirm homocysteinelevels tend to be higher in IBD (8.7 mmol/L) thanin healthy controls (6.6 mol/L).57 Whilehyperhomocysteinemia may likely be, at least inpart, a result of folate or vitamin B12 deficiencyassociated with the disease process or medicationsused, it may also be a contributing factor to thepathogenesis of UC.

At least two in vitro studies have attemptedto determine whether activity of certain enzymesinvolving sulfur metabolism are up- or down-regulated in UC. One found thiolmethyltransferase(TMT) activity did not seem to be associated withsulfide-induced colonocyte toxicity.54 A second invitro study found TMT activity was significantlyhigher in UC. The authors speculate TMT might beup-regulated in UC in an attempt to detoxify excesshydrogen sulfide.58

Potential sulfate toxicity may have impli-cations for diet as both an etiological and thera-peutic factor. The Western diet, which by oneanalysis contains an average of 16.6 mmol sul-fate/day compared to the rural African diet thatcontains an average of 2.7 mmol sulfate/day,51 hasbeen implicated as one of the risk factors in ulcer-ative colitis. Sulfur may be acquired in the diet byconsumption of food preservatives and additivessuch as sulfites, sulfur dioxide, and carrageenan,and foods high in sulfur amino acids (eggs, wholemilk, cheese, meat, cruciferous vegetables, onions,and garlic). The effects of low-sulfur diets on UCare discussed in the dietary treatment section.

Similar to sulfides, nitrogen derivativesmay inhibit butyrate metabolism. An in vitro studyfound nitric oxide interfered with fatty acid me-tabolism in colonocytes. However, co-administra-tion of peroxide and sulfide was necessary to causeinjury to the colonocyte.59

NSAIDs as a Causative FactorNon-steroidal anti-inflammatory drugs

(NSAIDs) are believed to cause colitis as well asexacerbate existing disease by increasing perme-ability and contributing to colonic bleeding. Basedon previous animal studies demonstratingibuprofen inhibited SCFA oxidation in isolatedmitochondria of mouse liver,60 Roediger andMillard studied ibuprofens effect on colonocytesfrom rats and humans and found that, at concen-trations of 2.0-7.5 mmol/L, ibuprofen selectivelyinhibited oxidation of butyrate.61 This concentra-tion may not occur at doses typically consumed.

Other NSAIDs have been implicated inacute episodes and relapses of proctocolitis. Fourcases were reported, involving flufenamic acid,mefenamic acid, naproxen, and ibuprofen.62,63

Dietary Factors in the Etiology ofColitis

Several studies have examined dietary riskfactors for the development of ulcerative colitis.Table 5 summarizes the results.




An Italian study of 104 patients with UCand CD found, using a dietary recall questionnaire,that total carbohydrate, refined sugar, and starchintakes immediately prior to onset of the diseasewere significantly higher in both UC and CD pa-tients than in healthy controls. Total protein in-take was significantly higher in UC but notCrohns patients.12

A case-control Netherlands study of 43recently-diagnosed (within the previous sixmonths) UC patients and 43 age- and gender-matched controls examined dietary intakes for fiveyears prior to the study using a cross-check di-etary history method. Fat intake was determinedby adipose tissue fatty acid composition. In thisstudy, high intakes of vitamin B6 and mono- andpolyunsaturated fats were associated with in-creased risk. No significant differences in com-position of adipose tissue were noted. The con-nection between vitamin B6 and increased UC riskis baffling and may be an anomaly.64

A study in Israel compared the pre-illnessdiet of 87 recently diagnosed IBD patients (54 withUC and 33 with CD) with 144 controls. Odds ra-tios for developing IBD were determined for vari-ous foods. High sucrose intake was associated withrisk for both UC and CD, while fat (especiallyanimal fat) was associated with increased risk forUC only. Interestingly, fructose intake was nega-tively associated with risk for IBD.65

Pre-illness dietary habits of Swedish pa-tients with IBD (145 with UC, 152 with CD, and305 controls) were examined in a case-controlstudy. The most significant finding was an in-creased relative risk for IBD associated with fastfood consumption. Eating fast food twice weeklyresulted in a relative risk of 3.9 for UC. Coffeeintake was associated with protection, althoughthe researchers believed this could have beenmerely an artifact. Because the questionnaire wassent to participants as long as four years after thedate of diagnosis asking them to recall what theyhad eaten five years previously, the data may beflawed.10

Table 5. Dietary Risk Factors for Ulcerative Colitis

Study

Italian

Dutch

Israeli

Swedish

Subjects

104 UC and CD patients compared to healthy controls

43 UC patients compared to 43 age- and gender-matched controls

54 UC patients, 33 CD patients, and 144 controls

145 UC patients, 152 CD patients, and 305 controls

Method

Dietary recall questionnaire

Cross-check dietary history

Pre-illness dietary history

Dietary recall questionnaire

Increased Risk

Refined sugarStarchTotal protein

Mono- and polyunsaturated fats Vitamin B6 (artifact?)

SucroseFat (especially animal fat)

Fast food (twice weekly resulted in relative risk of 3.9)

Decreased Risk

Fructose

Coffee (artifact?)




Cows milk sensitivity has been evaluatedas an etiology of UC. Serum from patients withseveral conditions, including 51 with UC, wascompared to that of 38 healthy controls. Antibod-ies to the principal cows milk proteins were ana-lyzed, including casein, -lactalbumin, and -lac-toglobulin. Antibody titers from patients with UCdid not differ from controls or patients with otherconditions. The authors conclude, At the presenttime there is little evidence to suggest that milkallergy is a factor in the etiology of ulcerative coli-tis.66 Other researchers have found no increasein IgG antibodies to folate-binding protein ofcows milk in patients with UC compared to con-trols.67

Conventional Treatment ofUlcerative Colitis

Conventional drugs for ulcerative colitisinclude aminosalicylates, corticosteroids, antibi-otics, and immunomodulators. The most commonprotocols include aminosalicylates for maintain-ing remission and corticosteroids during acuteepisodes.

Aminosalicylates include sulfasalazine(azulfadine) and 5-ASA-only medications mesalamine, balsalazide, and olsalazine.Sulfasalazine consists of a 5-ASA molecule boundto sulfapyridine. Sulfapyridine is absorbed sys-temically after being cleaved from 5-ASA and isresponsible for the majority of side effects associ-ated with sulfasalazine. Drugs in this class haveanti-inflammatory effects by inhibition of IL-1,IL-2, and NF-kB.68,69 In addition, they impairmonocyte and lymphocyte function and provideantioxidant activity.70 Another potential mecha-nism may involve inhibition of sulfide production.In vitro, 5-ASA has been found to inhibit sulfideproduction. Patients with UC not on 5-ASA drugsappear to have higher fecal levels of sulfide thancontrols,71 although 5-ASA appears to inhibit oxi-dation of butyrate, potentially interfering withnormal SCFA metabolism.72 The implications forlong-term use remain to be elucidated. These drugsmay also be used as suppositories or enemas fordistal colitis and proctitis.

Side effects occur in 30 percent of patientstaking sulfasalazine and include nausea, vomit-ing, headaches, rash, fever, agranulocytosis, pan-creatitis, nephritis, hepatitis, and male infertility.In addition, the sulfa portion of the drug interfereswith folic acid absorption, so this vitamin shouldbe supplemented in patients taking sulfasalazine.The 5-ASA medications lacking the sulfa moietyare associated with fewer side effects, althoughdiarrhea and abdominal pain have been reportedwith these medications.70

Corticosteroids are the mainstay for acuteepisodes of UC. Their potent immunosuppressiveeffects include inhibition of the arachidonic acidcascade, IFN-, and IL-1, -2, -4, -5, -6, and -8.While a dose-response curve is evident with pred-nisone, doses over 40 mg/day do not confer in-creased benefit.70 Topical steroids may be admin-istered rectally via suppository or enema for dis-tal proctocolitis.

Side effects of short-term steroid use in-clude fluid retention, weight gain, and moodswings. Long-term use increases the risk for cata-racts, osteoporosis, myopathy, conditions associ-ated with immune suppression, and adrenal insuf-ficiency.

Antibiotics have been prescribed for UC;however, unlike with Crohns disease, they havebeen largely ineffective. Among the drugs triedare vancomycin, metronidazole, tobramycin, andciprofloxacin. In some studies antibiotics haveresulted in initial improvement that has not beenmaintained over the long term.70

A new category of drugs, immune modu-lator drugs, including azathioprine and 6-mercap-topurine, is being explored for patients dependenton steroids. These drugs exert their effects by in-hibiting proliferation of lymphocytes and ribo-nucleotide synthesis. Their anti-inflammatory ef-fects are due to suppression of natural killer (NK)cell activity and T-cell function. While effective,they are associated with significant side effects,including pancreatitis, fever, rashes, arthralgias,nausea, and diarrhea.70

Cyclosporin, billed as the greatest treat-ment advance for UC in 10 years, inhibits T-helper activity by blocking IL-2, -3, and -4, TNF-, and IFN-. It is particularly useful for patients




with severe UC for whom steroids are no longereffective. Not only does it have a higher responserate than steroids, its remission rate is consider-ably more impressive. Cyclosporin has significantpotential toxicity, including paresthesias, tremor,hypertension, nausea, vomiting, headaches, sei-zures, and nephrotoxicity. The combination ofcyclosporin with steroids and immunomodulatorsincreases the risk for opportunistic infections suchas Pneumocystis carinii.70

Less Conventional Treatments forUlcerative ColitisConnection between Smoking,Nicotine, and UC

Epidemiological data have found smok-ing may confer some level of protection from UC.Thirty newly diagnosed UC patients were matchedfor age, sex, and marital and economic status withhealthy controls. Patients with UC were threetimes less likely to smoke but seven times morelikely to have quit smoking an average of 27months prior to diagnosis.73

Because of the possible link betweensmoking and protection from UC, a number ofstudies have been conducted using transdermalnicotine patches or nicotine gum for the treatmentof ulcerative colitis. A small, double-blind, cross-over trial examined seven UC patients individu-ally (single-patient trial) for eight weeks. Therapywas alternated every two weeks between nicotinegum (20 mg/day) and placebo gum. Evaluationwas on the basis of self-reported symptoms andproctoscopic exam. Three of seven patients, allformer smokers, demonstrated significant enoughimprovement to warrant incorporating nicotinegum into their treatment regimens.74

The effectiveness of transdermal patcheshas been examined in several double-blind trials.Seventy-two patients with active UC wererandomized to receive either daily 15-25 mgtransdermal nicotine patches or placebo patchesfor six weeks. All patients remained on previousmedications mesalamine in all patients and low-dose glucocorticoids in 12 patients. Seventeen of35 patients in the nicotine group experienced

complete remission, compared to nine of 37 in theplacebo group. The nicotine group also had greaterimprovement in clinical signs, symptoms, andhistological findings, and decreased stoolfrequency, abdominal pain, and urgency. Twenty-three patients in the nicotine group experience sideeffects (mainly lightheadedness, nausea, headache,and sleep disturbances), compared to only 11 inthe placebo group.75

A study published the following year, in-volving some of these same researchers, did notfind significant positive effects from the use oftransdermal nicotine. Eighty UC patients in remis-sion were assigned in double-blind fashion to ei-ther transdermal nicotine (15 mg patch for 16hours daily) or placebo patch for six months. Assoon as a maintenance dose of nicotine wasreached, mesalamine was discontinued in all pa-tients. No significant differences in number of re-lapses were noted between groups. The research-ers observed serum nicotine levels were lower thanexpected in the active treatment group, which mayreflect poor compliance.76

Several small Italian studies yielded somepositive findings. In seven of 10 patients with re-lapsing UC on mesalamine who did not toleratesteroids well, 15 mg transdermal nicotine dailyfor four weeks resulted in clinical remission thatpersisted for as long as three months after nico-tine withdrawal.77

Another small study compared the effectsof transdermal nicotine with those of prednisonein patients on mesalamine maintenance therapy.Patients in clinical relapse were randomly assignedto add either prednisone or transdermal nicotineto mesalamine for five weeks. The first 15 in eachgroup with clinical and endoscopic signs ofremission were followed for six months. Therelapse rate was 20 percent in the nicotine groupand 60 percent in the prednisone group.78 In afurther evaluation, follow-up continued for 12months with patients in remission due to eithernicotine or prednisone. If patients relapsed, theywere crossed over to the other treatment regimen.After 12 months, relapse occurred in 14 of 15patients originally on prednisone and seven of 15on nicotine.79




Transdermal nicotine has been comparedto oral mesalamine in the treatment of distal coli-tis. Thirty patients who failed to respond tomesalamine enemas (4 g at bedtime) were ran-domly assigned to 15 mg transdermal nicotinedaily or 800 mg mesalamine three times daily forfour weeks. Clinical and sigmoidoscopic remis-sion was observed in 12 of 15 patients on nico-tine, but only five of 15 on oral mesalamine.80

Transdermal nicotine appears to offer ef-fective co-treatment for UC, both for patients dur-ing relapse and for maintaining remission. In thenegative study, patients were asked to discontinuemesalamine, unlike other studies where patientsremained on their maintenance treatment. Al-though nicotines mechanism of action is un-known, it may exert its effects through inflamma-tory mediators,81 changes in mucus production,82or alterations in blood flow.83

Heparin: An Unexpected FindPatients with UC have a greater risk of

developing coagulation problems such as deepvein thrombosis (DVT). In treating patients forDVT with heparin, an unexpected improvementin UC was noted. Heparin consists of a group ofGAGs that have anticoagulant as well as poten-tial anti-inflammatory effects.

In a pilot study, 16 hospitalized UC pa-tients unresponsive to high-dose steroid treatmentwere given intravenous (IV) heparin at standardanticoagulant dosages. Within one week, 12 of 16experienced significant clinical improvement; andwithin four weeks these 12 were in complete re-mission.84

In a prospective study, 13 patients withsevere UC and four with CD in a hospital settingwere treated with sulfasalazine (which they hadalready been taking at the time of hospitalization)and continuous heparin IV for two weeks, fol-lowed by home injections of heparin for anothersix weeks. Significant improvement in clinicalsymptoms and laboratory signs of inflammation C-reactive protein and erythrocyte sedimenta-tion rate were seen in patients with UC, but notCD. Seven UC patients achieved complete remis-sion after four weeks.85

Another small pilot study examined thesafety and effectiveness of heparin in an outpa-tient setting. Twelve UC patients, who had notresponded well to steroids, self administered hep-arin (dalteparin sodium 5,000 units by subcutane-ous injection) twice daily. Eleven of the 12 pa-tients improved; six attained complete remissionafter 12 weeks. No serious adverse events oc-curred.86

Based on positive results from small, pi-lot trials, a multicenter, randomized trial was con-ducted. Hospitalized patients received either IVheparin or methylprednisolone for 10 days. After10 days, 69 percent in the steroid group but nonein the heparin group had achieved remission. C-reactive protein was decreased in the steroid butnot heparin group. Thirty-one percent of the ste-roid group experienced rectal bleeding by day 10compared to 90 percent in the heparin group. Twopatients in the heparin group experienced rectalbleeding severe enough to require a blood trans-fusion.87 More extensive study to examine the ef-fectiveness and safety of heparin for UC is indi-cated.

Melatonin and the GastrointestinalTract

The amount of melatonin found in the GItract can be 10-100 times the levels found in theblood and 400 times that found in the pineal gland.Although the GI tract may act as a sink for extra-gastrointestinal derived melatonin, there is evi-dence pointing to de novo synthesis in the GI tractas well.88

While it is still theoretical and no clinicalstudies have been conducted to determine its effi-cacy, melatonin may provide some benefit in ul-cerative colitis. Intraperitoneal injections (150 g/kg) of melatonin to mice with dextran-inducedcolitis resulted in resolution of rectal bleeding andoccult blood in all cases. Frequency and severityof lesions in the mucosa were significantly reducedon histological exam.89

There are several mechanisms wherebymelatonin might exert potential benefit. Locationof melatonin in the intestinal villae supports the




hypothesis that it is integral in transport of elec-trolytes across cell membranes. Melatonin hasbeen noted in vitro to relieve spasm in isolated ratintestinal tissue.90

Melatonin may exert benefit in IBD byinteracting with inflammatory mediators. Mucosaladdressin cell adhesion molecule-1 (MAdCAM-1) is induced by TNF- and believed to be in-volved in inflammation associated with IBD. Inan in vitro study, melatonin, in amounts 5-50 timesthe usual 3 mg nightly dose, inhibited TNF--in-duced MAdCAM-1.91 Furthermore, oxidativestress is considered to be important in the patho-genesis of UC, and melatonin is a significant freeradical scavenger.88

Effect of Estrogens in UCData on the relationship between estro-

gen and ulcerative colitis has been conflicting, withpregnancy increasing risk of UC flare-ups in se-vere, uncontrolled colitis, but not in milder casesor those in remission.92 In animals 17-estradiolhas been found to decrease inflammation in someexperimental models of colitis, but to increase in-flammation in others.93 Whether exogenous estro-gen would be beneficial or detrimental to womenwith ulcerative colitis remains to be determined.

Dehydroepiandrosterone (DHEA)Dehydroepiandrosterone sulfate

(DHEAS) levels have been found to be low inpeople with chronic inflammatory conditions. Astudy examined serum DHEAS and cortisol lev-els in 64 patients with UC, 115 patients with CD,and 66 healthy subjects. DHEAS levels were lowerin both groups of IBD patients than in controls,and even lower in patients with a history of corti-costeroid use.94

Another controlled study compared theeffects of acute and chronic inflammation onDHEA levels. Thirteen patients undergoingcardiothoracic surgery (representing acute inflam-mation) were compared to 61 patients with IBD(21 with UC; representing chronic inflammation)and 120 controls. While DHEA was elevated inpatients with acute inflammation, it was decreasedin IBD patients with chronic inflammation.95

DHEA, at least in animal models, has beenshown to inhibit proinflammatory cytokines, in-cluding TNF-, providing a potential beneficialmechanism of action in chronic inflammation.96

Diet, Probiotics, Specific Nutrients,and Botanicals in the Treatment ofUCCorrecting Nutrient Deficiencies orExcesses

Ulcerative colitis is associated with sev-eral nutritional deficiencies. Geerling et al dem-onstrated, in a clinical study of 69 patients withIBD (46 with UC), that beta-carotene, magnesium,selenium, iron, copper, and zinc were significantlylower in newly diagnosed patients than in con-trols.97 The low levels of antioxidants, such as caro-tenoids, selenium, and zinc, may be attributed toincreased oxidative stress contributing to increasedconsumption of antioxidants by the inflamed in-testinal tissue.

Vitamin A and CarotenoidsCarotenoids and retinol play an essential

role in enhancing the mucosal integrity of the gut.Low levels of retinol binding protein (RBP) areseen in IBD, resulting in a secondary decrease inserum retinol levels. Decreases in RBP may bedue to excessive protein loss from diarrhea asso-ciated with IBD. Patients with most active dis-ease demonstrated the lowest levels of serum ret-inol and RBP. Because zinc is required for thesynthesis of RBP, a zinc deficiency may negativelyimpact vitamin A metabolism and result in hypo-vitaminosis A. Retinol absorption rates were alsodecreased in patients with severe UC, but not inpatients with mild-to-moderate disease.98 In theGeerling study, serum beta-carotene concentra-tions were significantly lower in UC patients thanin controls.97

A study of IBD patients, including 35 withUC, examined serum retinol and carotenoid lev-els as well as the prevalence of the Leiden muta-tion, a newly discovered genetic marker of UCand CD. Mozsik concluded that (1) retinoids andcarotenoids play an essential role in maintaining




mucosal integrity in the gastrointestinal tract; (2)serum levels of vitamin A are significantly lowerin UC, while alpha- and beta-carotene levels arenearly the same as that of controls; and (3) an in-verse relationship exists between the prevalenceof the Leiden mutation and serum retinol values.99

One study found beta-carotene was thecarotenoid most significantly reduced in UC, withonly 50 percent of the plasma concentration ofcontrols. The extent of disease activity also influ-enced some antioxidant levels to varying degrees,with lycopene and zeaxanthin demonstrating thelargest difference between active disease and re-mission in ulcerative colitis patients.30 In an ani-mal model of colitis, lycopene, but not beta-caro-tene, significantly reduced signs of inflamma-tion.100

Vitamin EVitamin E levels have also been found to

be low in some patients with IBD. One study foundlow levels only during active disease, possiblyreflective of increased oxidative stress observedduring inflammation.30

Vitamin CMuch of the research on IBD has focused

on the etiology of the inflammatory process andthe role oxidative stress plays in damaging intes-tinal tissue. An Australian study examined colonicbiopsies from IBD patients and measured mucosalconcentrations of reduced and total ascorbic acid.In UC patients, mucosal total ascorbic acid con-tent decreased by 73 percent and reduced-ascor-bic acid by 41 percent. Enzymatic reduction ofdehydroascorbic acid decreased significantly ininflamed mucosa of UC patients, indicating in-flamed mucosa is less able to maintain reduced-ascorbic acid concentrations. The researchers pos-tulated that oxidative stress caused by inflamma-tory cells contributed to significant loss of anti-oxidant buffering capacity, retarding tissue recov-ery.101

Vitamin KInflammatory bowel disease has also been

shown to be associated with vitamin K deficiencythat can result in abnormal prothrombin.102,103 Con-sequently, a highly sensitive antigen assay, usingthis prothrombin abnormality, was developed forthe diagnosis of vitamin K deficiency. In a studyof 58 patients with chronic GI disease or resec-tion, 31 percent (18 patients) demonstrated a vita-min K deficiency. All patients had either conven-tionally treated UC or CD involving the ileum.Abnormal prothrombin levels returned to normalwith vitamin K administration. Vitamin K defi-cient patients also demonstrated significantlylower plasma vitamin E levels.103

Folic AcidFolic acid status in ulcerative colitis pa-

tients may be influenced by a number of factors,including reduced dietary intake, red cell hemoly-sis secondary to chronic drug therapy,104 chronicdiarrhea,105 and sulfasalazine therapy that inter-feres with absorption of folate.106 Impaired intes-tinal transport and absorption results in structuralalteration of intestinal mucosal cells, thus promot-ing further malabsorption and cell transforma-tion.105,107

As mentioned, folate deficiency may beassociated with high homocysteine levels oftenseen in UC patients. A Greek study examined se-rum folate and homocysteine levels in 108 IBDpatients, 53 of whom had UC. It was determinedthat UC patients had significantly higher homocys-teine levels, while folate levels were lower whencompared to control subjects.108

CalciumCalcium deficiency in UC patients may

result from a variety of factors, including de-creased dietary intake, malabsorption, entericlosses, associated vitamin D deficiency, and cor-ticosteroid treatment.109 In a study of 152 patientswith IBD (73 controls), males especially had lowercalcium intakes than control subjects. The dailydietary calcium intake was below 1,000 mg in 53percent of patients and below 400 mg in 9.2 per-cent of patients. Forty-seven percent of patients




avoided lactose in their diet, compared to 11 per-cent of control subjects.110

IronIron deficiency and resultant anemia is

frequent in UC due to chronic GI bleeding.109 Ironstatus in UC patients is most accurately measuredby serum ferritin, with levels below 18 ng/mLbeing highly predictive of iron deficiency. In astudy of 24 patients with UC, plasma iron levelswere significantly reduced compared to controls,particularly in patients with moderately severeUC.111

Conversely, the mucosal iron concentra-tion has been observed to be significantly in-creased in the presence of inflammation, at leastin part due to overproduction of free radicals viaincreased levels of free hemoglobin from mucosalulceration and bleeding.112 Furthermore, researchon preneoplastic colonic mucosa of UC patientshas demonstrated immunoreactivity to the majoriron-binding proteins, lactoferrin, transferrin, andferritin. Increased expression of these proteins andsubsequent iron accumulation may trigger a self-perpetuating cycle, resulting in further tissue dam-age and a trend toward neoplastic progression. Ironchelation has been found effective in experimen-tal models of inflammation.111 In view of higheriron concentrations in intestinal mucosa, ironsupplementation in UC should be avoided if pos-sible. Treatment goals should be to curb iron lossby healing the gut, providing antioxidants tocounter pro-oxidant effects of mucosal iron, andchelate free iron if necessary.

MagnesiumMagnesium deficiency is prevalent in UC

patients, but whether it is a result of disease viamalabsorption and intestinal loss, or a causativefactor from decreased intake remains unclear. Ina dietary history study of 54 UC patients, highmagnesium intake was shown to reduce the riskof inflammatory bowel disease, suggesting an as-sociation between low pre-illness dietary intakesand subsequent development of UC.65 Anotherstudy demonstrated that in 46 newly diagnosedUC patients, serum magnesium concentrations

were significantly lower than in controls, suggest-ing a possible etiological role for magnesium de-ficiency.97 Despite sometimes-normal serum mag-nesium levels, intracellular magnesium concen-trations are frequently low in UC patients.109

SeleniumLike magnesium, serum and plasma sele-

nium levels are significantly (p




colonic mucosa resulting in a continuouscycle of inflammation in IBD.120 Zinc supple-mentation may result in a copper deficiency;therefore, supplementing small amounts ofcopper may be indicated.

See Table 6 for suggested supplemen-tation of vitamins and minerals.

Dietary TreatmentElemental Diet

An elemental diet is comprised offree-form or predigested amino acids. Someimprovement in UC has been noted in patientson these diets, but is thought to be a result ofthe diets influence on intestinal microfloracomposition rather than enhanced nutritionalstatus. Evidence of the effectiveness of el-emental diets is limited. A review of 11 ran-domized trials evaluating various diets usedin UC patients revealed no positive treatmenteffect in the two trials utilizing elemental di-ets.121 Compliance is also difficult. Hospital-ization is often necessary for proper admin-istration, and relapse is common once thepatient resumes a normal diet. The diets arealso unpalatable to many patients and thehyperosmolality frequently causes diarrhea.

Elimination/Hypoallergenic DietFood allergies have long been con-

sidered in the etiology of UC, with most re-search focusing on allergy to cows milk pro-tein. Recent research demonstrates, however,there is no consistent evidence of lactose in-tolerance among patients with active ulcer-ative colitis.122-124

Other highly allergenic foods may beresponsible for exacerbation of UC, and elimi-nation diets seem to hold the most promisefor therapeutic benefit. A small study of 18 UCpatients demonstrated an elimination diet exclud-ing commonly known allergenic foods resulted insignificantly fewer UC symptoms (primarily di-arrhea and rectal bleeding) in nine patients on theelimination diet compared to nine patients con-suming a normal diet. Foods that seemed to elicit

symptoms included citrus fruits, dairy, pork, to-matoes, pineapple, shellfish, spiced or curriedfoods, apples, grapes, and melon. In addition tothe decrease in symptoms, four patients in thisstudy attained remission on the elimination dietand eight months later three were still symptomfree, despite reverting to a normal diet.125

Table 6. Correcting Nutrient Deficiencies inUC

Nutrient

Vitamin A

Beta carotene

Vitamin E

Vitamin C

Vitamin K

Folic acid

Calcium

Iron

Magnesium

Selenium

Zinc

Copper

Suggested Supplementation

10,000-25,000 IU daily*

25,000-100,000 IU daily

400-800 IU daily

500-1,000 mg daily

500 mcg-1 mg daily

400 mcg-1 mg daily

500-1,000 mg daily**

30-60 mg daily***

300-500 mg daily

200-400 mcg daily

15-45 mg daily

1-3 mg daily

* Do not exceed 7,500 IU if pregnant** Citrate or citrate malate forms*** Supplement only if anemic




Elimination of Sulfur-containing AminoAcids

Based on the known contribution of sul-fides to the pathogenesis of UC, a pilot study wasconducted on eight patients taking sulfasalazinefor maintenance and prednisolone for acute attacks(four who had suffered a first acute attack and fourwith chronic UC). The patients were asked toeliminate dietary sources of sulfur-containingamino acids, including eggs, cheese, whole milk,ice cream, mayonnaise, soy milk, mineral water,sulfited drinks such as wine and cordials, nuts, andcruciferous vegetables. They were also asked todecrease intake of red meat, substituting chicken,fish, and skim milk as protein sources. During the12-month follow-up, the patients experienced norelapses or attacks (expected relapse rate onsulfasalazine was 22.6 percent). In addition, allshowed marked histological improvement. Thenumber of bowel movements daily in the fourchronic UC patients decreased from an averageof 6/day to 1.5/day. Two patients stopped the diet,but resumed it when they noticed adverse ef-fects.126 A larger controlled trial is warranted.

Fiber in the DietFiber can be therapeutically beneficial for

people with UC. Diets with a low fiber contenthave been associated with increased risk of UC,suggesting a high-fiber diet may protect againstdisease or relapse.127 Low-fiber diets are frequentlyhigh in refined carbohydrates thought to promotemuscle spasm, resulting in increased pressure inthe colonic lumen, further facilitating the diseaseprocess.128 This suggests that a high-fiber diet,composed of complex rather than refined carbo-hydrates, may be a better option for UC patients.During periods of disease exacerbation, however,the amount and type of fiber may have to be de-creased until overt inflammation subsides. Dietshigh in fiber may also promote advantageous in-testinal flora composition via increased butyrateproduction.129

The effects of specific types of fiber havebeen examined in both animal models and clini-cal studies of UC. In a rat model, animals receiv-ing five-percent Plantago ovata (PO; psyllium)

seeds experienced an increase in SCFA produc-tion (mainly butyrate), restored colonic glutathionelevels, lower TNF- and nitric oxide synthase lev-els, and recovery of damaged colonic mucosa,when compared with untreated colitic rats.130

In a randomized clinical trial of 105 ul-cerative colitis patients in remission, subjects weregiven 10 g PO seeds twice daily, 500 mgmesalamine three times daily, or a mesalamine andPO combination, with the desired outcome beingremission for 12 months. In the PO group, 13 of35 patients relapsed, compared to 13 of 37 patientsin the mesalamine group. In the PO plusmesalamine group, only seven of 30 patients re-lapsed, suggesting a greater benefit with the com-bination treatment than either PO or mesalaminealone. To determine the effect of PO intake onSCFA production, a separate group of seven pa-tients was given the seeds for three months. FecalSCFA were measured at trial entry and at threemonths. PO administration resulted in significantlyhigher butyrate, acetate, and total SCFA levels. Ithas been suggested butyrate has a protective ef-fect against colon carcinogenesis.131

Psyllium husk (referred to as ispaghulahusk in the study) has the ability to absorb 40 timesits own weight in moisture. A double-blind, pla-cebo-controlled trial of 29 UC patients in remis-sion, but reporting disturbances in bowel habits,demonstrated 4 g psyllium husk twice daily (orplacebo low-fiber crushed crispbread) for fourmonths resulted in symptomatic improvement in69 percent of patients on psyllium compared to24 percent in the control group. Symptom assess-ment was by questionnaire at onset and at two andfour months.132

Germinated barley foodstuff (GBF) is aprotein-rich insoluble prebiotic fiber made frombrewers spent grain, containing glutamine-richprotein and hemicellulose. Prebiotics enhance pro-duction of beneficial microflora. GBF is producedby the Kirin Brewing Company in Japan and hasreceived approval from the Japanese Ministry ofHealth and Welfare as a food for specific use inulcerative colitis therapy. Animal and human stud-ies by a group of Japanese researchers have shownGBF to increase stool butyrate levels and inhibit




pro-inflammatory cytokine production,133,134 in-crease levels of beneficial intestinal bacteria,135increase stool-forming ability in the colon,136 de-crease diarrhea,137 prevent mucosal damage,138 andpossibly improve the mucosal barrier of the co-lon.139

Larch arabinogalactan is a polysaccharidepowder derived from the wood of the larch tree(Larix species) and comprised of approximately98-percent arabinogalactan. Arabinogalactans aremost abundant in Larix occidentalis (Westernlarch), a deciduous pine tree native to the Pacificand Inland Northwest.140 Larch arabinogalactan isapproved by the U.S. Food and Drug Administra-tion as a source of dietary fiber, and has beenshown to increase SCFA production (primarilybutyrate) via its vigorous fermentation by intesti-nal microflora.141 Because butyrate is a primaryenergy source for colonic epithelial cells, it mayprotect the intestinal mucosa from disease.142 Al-though no studies have been conducted to date,larch arabinogalactan administration may be ofbenefit in UC patients by virtue of increased fecalbutyrate levels and improved intestinal microfloracomposition.

ProbioticsAs previously discussed, an abnormal host

immune response to certain intestinal microflora isbelieved to play a part in the pathogenesis of UC. Inaddition, UC patients with active disease frequentlyhave reduced amounts of obligate anaerobes such asBifidobacteria, Eubacteria, and Clostridia, as well asreductions in facultative organisms and micro-aer-obes, when compared to UC patients in remission.39Consequently, researchers have examined the effectsof probiotic supplementation in UC patients.Probiotic bacteria may include Lactobacilli, Strep-tococci, Bifidobacteria, and certain E. coli subspe-cies. Probiotics may be effective in UC because oflactic acid production, which reduces luminal con-tent pH, inhibiting growth of putrefactive or harm-ful bacteria.143 Another possible explanation is bac-teriocin production, resulting in a direct antibacte-rial action.144 For a probiotic to be effective, it mustbe safe and well-tolerated, arrive in the intestinal tractin a viable form, and adhere securely to the intesti-nal mucosa.145

Both animal and clinical studies revealseveral probiotics may aid in achieving UC re-mission. Nineteen UC patients were treated withLactobacillus plantarum 299v or placebo afterfour weeks of being unresponsive to conventionaltherapies. Of the 10 patients receiving the probioticsolution, seven achieved clinical and colonoscopicremission. No patients in the placebo groupachieved remission.146

In an uncontrolled, open trial Venturi etal administered a combination probiotic prepara-tion called VSL-3, which contained three strainsof Bifidobacteria, four Lactobacilli strains, as wellas Streptococcus salivarius, subspeciesthermophilus, to UC patients in remission. Patientswere supplemented for a period of 12 months. Ofthe 20 patients in the treatment group, 15 remainedin remission for one year, four relapsed, and onewas lost to follow-up. Levels of fecal Streptococ-cus salivarius ssp. thermophilus, Lactobacilli, andBifidobacteria were significantly increased in all20 patients, as compared to baseline. These re-sults suggest that colonization of the intestinal tractby the VSL-3 preparation may aid in maintainingremission in UC patients.147

In a double-blind study, Kruis et al gaveE. coli (Nissle strain 1917) or mesalazine to 116patients with quiescent UC and demonstrated thatthe E. coli strain was as effective as mesalazine inpreventing relapse.148 The two agents were alsocompared in a study of 120 patients with activedisease, and it was concluded the E. coli strainwas equally effective to mesalazine in preventingrelapse in these patients.149

A small, randomized clinical trial exam-ined the use of Bifidobacteria-fermented milk(BFM) as a dietary adjunct in the treatment of UC.Eleven patients received 100 mL/day BFM for oneyear, at which time colonoscopies, blood mark-ers, and examinations of intestinal flora were per-formed. Statistical analysis revealed a significantreduction in disease exacerbation in the BFMgroup compared to controls, suggesting BFMsupplementation was successful in preventing re-lapse and maintaining remission.150




Specific NutrientsEssential Fatty Acids

Changes in omega-3 and -6 fatty acid pro-files have been observed in UC patients.151,152These changes may influence fatty acid synthesisby colonic tissue as well as membrane lipid com-position of luminal cells,153 potentially playing apart in disease pathogenesis. A study of 73 patientswith active IBD assessed plasma fatty acid pat-terns and actually found a marked increase inomega-3 fatty acids, particularly docosahexanoicacid (DHA), suggesting that during active diseaseincreased biosynthesis may accompany increasedconsumption resulting from a response to inflam-mation. Omega-6 fatty acids, especiallydihomogammalinolenic acid (DGLA), were foundto be decreased in UC patients.152

With few exceptions, a review of omega-3 fatty acid studies demonstrates they exert a ben-eficial effect in UC patients.154-157 In a randomized,double-blind, controlled trial of 96 ulcerative coli-tis patients, 4.5 g eicosapentanoic acid (EPA) wasadministered daily for one year. Control subjectswere given an olive oil placebo. Twenty of 96 pa-tients entered the trial during relapse, and 16 ofthat 20 achieved remission with EPA. Patients re-ceiving EPA attained remission sooner than pa-tients in the placebo group (median 102 days ver-sus 141 days on placebo), although the results werenot statistically significant. Patients receiving EPA,however, experienced a significant reduction insteroid medication requirement and a 50-percentreduction in leukotriene B4 (LTB4) synthesisthroughout the trial.158

Three separate studies conducted byAlmallah et al examined various effects of a six-month supplementation with 3.2 g EPA and 2.4 gDHA in 18 patients with distal proctocolitis; con-trol subjects received sunflower oil. The earliestof the three studies investigated the role of omega-3 fatty acids in the modulation of natural cytotox-icity and disease activity. Over the six-month pe-riod, analysis revealed omega-3 supplementationsignificantly reduced the number of circulating NKcells and lymphokine activated killer (LAK) cellswhen compared to the placebo group.159

Some of the same researchers examinedhistological and clinical effects of omega-3 supple-mentation and found a significant reduction in thenumber of certain T-lymphocyte subsets (CD3)and activated cells (HLA-DR) in the intestinalmucosa. The supplemented group also had a sig-nificantly reduced percentage of rectal mucosalcells containing IgM when compared to controls.Histological scores, disease activity, and sigmoi-doscopic scores also improved in the omega-3supplemented group compared to placebo. Theresearchers concluded omega-3 supplementationfor six months suppressed immune reactivity aswell as disease activity in proctocolitis patientsreceiving omega-3 fatty acids.160

A third evaluation examined the possiblemechanisms involved in the inhibition of naturalcytotoxicity observed in the earlier studies. Aftersix months of supplementation with omega-3 fattyacids, laboratory assessment revealed that keyhumoral mediators, specifically LTB4 and IL-2,both known to enhance NK-cell activity, were sig-nificantly reduced in serum samples of patientswith proctocolitis when compared to patients re-ceiving placebo. Clinical assessment showed areduction in disease activity as evidenced by re-duced symptomology and improved sigmoido-scope scores.161

Not all studies have found positive ben-efits from supplementation with omega-3 fattyacids. In a double-blind, placebo-controlled studyof 63 UC patients with quiescent disease, admin-istration of EFAs (1.6 g gamma-linolenic acid, 270mg EPA, and 45 mg DHA per day) for one yearfailed to prolong remission when compared tocontrols (500 mg/day sunflower oil). 162 It shouldbe noted, however, the dosages in this study wereextremely low.

In a second study, omega-3 fatty acids (5.4g daily) were compared to sulfasalazine (2 g daily)in 10 patients with mild-to-moderate UC over atwo-month period. Treatment with omega-3 fattyacids resulted in an increase in disease activity asevidenced by increased platelet counts, erythro-cyte sedimentation rate, C-reactive protein, andtotal fecal nitrogen excretion. Patients in thesulfasalazine group did not experience any sig-nificant changes in these laboratory parameters.




Table 7. Summary of Omega-3 Fatty Acids for Ulcerative ColitisAuthors

Middleton et al. 2002

Dichi et al. 2000

Almallah, El-Tahir et al. 2000

Almallah et al. 1998

Hawkey et al. 1992

Almallah, Ewen et al. 2000

Stenson et al. 1992

Lorenz et al. 1989

Loeschke, Uberschaer et al. 1996

Salomon et al. 1990

Subjects

63 patients with quiescent disease

10 with mild to moderate active UC

18 with active distal proctocolitis

18 with active distal proctocolitis

96 patients in remission or relapse

18 patients with active distal proctocolitis

18 with active UC

10 with active UC

64 with active but quiescent disease

10 patients with mild-to-moderate UC

Duration

12 months

4 months

6 months

6 months

12 months

6 months

4 months

7 months

24 months

2 months

Design

Randomized, double-blind, placebo-controlled

Randomized, cross-over study

Double-blind, randomized, placebo-controlled study




Multi-center, randomized, double-blind, placebo-controlled, cross-over study

Double-blind, placebo-controlled, cross-over study

Double-blind, placebo-controlled study

Uncontrolled, open trial

Dosage

1.6 g GLA, 270 mg EPA, 45 mg DHA daily

5.4 g fish oil daily

3.2 g EPA and 2.4 g DHA daily


4.5 g EPA daily




5.1 g daily omega-3 fatty acids

2.7 g EPA daily

Outcome

Did not prolong the period of disease remission

Increased disease activity compared to sulfasalazine; (increased pH, ESR, CRP, fecal nitrogen)

Decreased serum LTB4 and IL2; inhibition of NK cytotoxicity

Decreased circulating levels of LAK and NK cells; suppressed cytotoxicity and reduced disease activity

Decreased serum LTB4 levels and decreased steroid use

Decreased CD3, HLA, and IgM expression (in situ immune reactivity); improvement in disease activity and histological scores

Decreased LTB4 levels; improved histological scores; weight gain

Decreased disease activity; improved morphological scores on endoscopy

Increased time to relapse initially; did not prevent relapse over long-term

Decreased disease activity; improved morphological score on endoscopy.; reduced steroid dosages




It was concluded that sulfasalazine treatment wassuperior to omega-3 fatty acids in patients withmild-to-moderate UC.163 See Table 7 for a sum-mary of omega-3 fatty acid studies in ulcerativecolitis.

Short Chain Fatty AcidsBecause of the vital role they play in the

maintenance of colonic integrity and energy me-tabolism, SCFA supplementation using butyrateenemas has been the focus of several studies inUC patients. Enema administration is thought toenhance and prolong the contact of butyrate withthe colonic cells when compared to other routesof administration. The use of butyrate enemas inUC patients has produced varied results, makingconclusions regarding their effectiveness difficult.Harig et al administered enemas containing so-dium salts of butyrate, propionate, and acetate topatients with diversion colitis (microscopicallyindistinguishable from UC) twice daily over a six-week period and demonstrated an improvementin inflammation and a significant reduction insymptoms.164

In a multicenter trial, 51 patients withchronically active mild-to-moderate distal UC re-ceived enemas of either butyrate plus 5-ASA orsaline plus 5-ASA twice daily. After eight weeksendoscopic and histological parameters, labora-tory data, stool frequency and consistency, andother UC symptoms were assessed. The adminis-tration of 5-ASA plus butyrate was significantlymore effective than 5-ASA plus saline in achiev-ing disease improvement or remission.165

Two six-week studies reported either sta-tistically insignificant166 or no improvement167 inUC disease activity or remission status in patientssupplemented with butyrate enemas, when com-pared to a saline enema placebo.

GlutamineIn addition to being the main fuel source

for the mucosal cells in the ileum,168 glutamine isalso utilized by colonocytes as a respiratory fuelsource.169 A rat study investigated the effect ofvarious agents (prednisolone, 5-ASA, L-glutamine, or SCFAs) applied by enema twice

daily for seven days after induction of colitis withtrinitrobenzene sulfonic acid in ethanol. L-glutamine enemas provided the most benefit whencompared to the other agents, resulting in a de-crease in severity of colitis and lipid peroxidation,without altering mucosal absorption capacity.None of the other three agents yielded such com-prehensive benefit.170

Research using other animal models ofUC has shown glutamine addition to elementaldiets decreases endotoxin levels171 and promotesmore rapid healing of colonic lesions.172

Phosphatidylcholine/PhosphatidylinositolResearch using a rat model of induced

colitis indicates oral supplementation with phos-phatidylcholine (PC) prevents collagen depositionand subsequent stricture formation in inflamedcolonic tissue. Two of 15 rats fed 100 mg PC dailydeveloped strictures, compared to 12 of 16 coliticrats not receiving PC. Non-colitic control rats hadno stricture development. In addition, collagenaseactivity in colonic tissue was significantly higherin colitic rats given PC than in non-colitic rats andcolitic rats receiving no PC. The authors concludethe reduced rate of stricture formation in the treatedrats was due to PC enhancement of collagen break-down.173

A study of rats with acetic-acid inducedcolitis investigated the therapeutic benefits ofcolonically administered PC and phosphatidyl-inositol (PI). Both phospholipids were found tohave therapeutic benefit when given in a dose-dependent and time-dependent manner over athree-day period. Beneficial effect (prevention ofcolitis induction and reduction of mucosal perme-ability) was most pronounced when either PC orPI was given to rats immediately after colitis in-duction (acetic acid administration). Both phos-pholipids resulted in significant mucosal recov-ery and decreased permeability.174

Superoxide DismutaseUC is characterized by signs of increased

oxidative stress in the intestinal mucosa that maybe secondary to inflammation. Superoxidedismutase (SOD) is a scavenger of free radicals,




and as such may have therapeutic application inUC. An animal study examined the effects oflecithinized-SOD (PC-SOD) administered intra-venously to 114 rats with induced UC; control ratswere given purified water. The SOD was boundto lecithin to enhance tissue affinity. Rats receiv-ing PC-SOD showed a decrease in bloody stoolsas well as decreased inflammatory cell infiltrationand erosion in the colon. Blood leukocyte levelswere also decreased. By scavenging oxygen freeradicals, PC-SOD is thought to prevent colonictissue damage in this UC model.175

Botanicals and FlavonoidsOver 20 different botanicals have been

used alone or in combination in both animal mod-els and clinical trials of UC. Clinical trials havebeen conducted on a Ginkgo biloba extract(Cedemin), Boswellia serrata, and a botanicalcombination. Animal studies or case reports offerpreliminary information on the potential efficacyof flavonoids, bromelain, and other plant extracts.

Ginkgo bilobaIn a small open trial, 10 patients with mild-

to-moderate UC were given Cedemin enemasnightly for three weeks. Three of 10 patientsachieved remission and two experienced someimprovement, but these results were not statisti-cally better than placebo.176 It was hypothesizedthat the mechanism responsible for Cedeminseffect in patients who improved or attained remis-sion was due to the extracts inhibition of plate-let-activating factor (PAF), which mediates mu-cosal inflammation.177

Boswellia serrataAn open, non-randomized clinical trial of

30 patients with chronic colitis investigated theeffect of Boswellia serrata gum resin (BWGR)for six weeks on various UC disease parameters.Achieving remission was the primary goal of treat-ment. Stool properties, histopathology of colonicmucosa, sigmoidoscopic scores, and various labo-ratory markers of anemia and inflammation wereassessed at the beginning and end of the trial.Twenty of 30 patients received 900 mg daily of

BWGR in three divided doses. Ten control patientsreceived 3 mg daily sulfasalazine in divided doses.Eighteen of 20 patients receiving BWGR showedan improvement in one or more of the parametersassessed, particularly in sigmoidoscopic scores,and 14 achieved remission. This was compared tofour of 10 patients in the control group receivingsulfasalazine. After statistical analysis of resultsfor all parameters measured, the degree of im-provement was not statistically significantly bet-ter for BWGR-treated patients than for patientsreceiving sulfasalazine.178

Combination Herbal TreatmentAnother study examined the effectiveness

of an herbal combination, containing Taraxacumofficinale, Hypericum perforatum, Melissaofficinalis, Calendula officinalis, and Foeniculumvulgare, on 24 patients with chronic non-specificcolitis. By day 15 of the study, 23 patients had acomplete resolution of pain in the large intestine.In addition, diarrhea resolved and fecal contentnormalized.179

Peumus boldusA rat study compared the efficacy of bol-

dine an alkaloid from Peumus boldus, an ever-green tree found in Chile to 5-ASA. The studyinvestigated boldines cytoprotective and anti-in-flammatory properties in mucosal tissue of ratswith induced colitis. Boldine was found to havean anti-inflammatory effect in the colon as evi-denced by reduced colonic neutrophil infiltration,protection against edema and cell death, and en-hanced fluid absorption in the colon.180 Clinicalstudies may be indicated.

Plant Sterols and SterolinsSterols and sterolins (phytosterols) are fats

present in all plants, including fruits and veg-etables. Beta-sitosterol (BSS) is the major phy-tosterol in higher plants, along with its glycosidebeta-sitosterolin (BSSG). In in vitro, animal, andhuman studies a proprietary BSS:BSSG mixturehas shown promise in normalizing T-cell functionand dampening overactive antibody responses.Since T cells from patients with UC manifest a




cytokine profile compatible with an over-activeTh2 response, it is possible that administration ofa BSS:BSSG mixture might prove beneficial inUC patients. Dampening of Th2 leads to decreasedlevels of IL-4, IL-6, and IL-10, which are involvedin B-lymphocyte differentiation and inflamma-tion.181

BromelainBromelain is a proteolytic enzyme ob-

tained from the pineapple stem. Its anti-inflam-matory properties are attributed to fibrinolysis andinhibition of platelet aggregation. Two case reportsindicate it may be of benefit in UC patients. Twowomen with UC refractive to conventional treat-ment reported a reduction in diarrhea after takingbromelain and one reported a decrease in the num-ber of bowel movements and the appearance ofblood in the stool when compared to pre-brome-lain status. In both cases, endoscopy performedafter bromelain supplementation revealed healedmucosa.182 Although these anecdotal reports areof interest, more extensive clinical investigationis indicated.

Flavonoids: Quercetin and RutinQuercetin and rutin have both been the

subject of study in patients with UC, based on theirantioxidant, anti-inflammatory, mast-cell stabiliz-ing, and free-radical scavenging properties. Quer-cetin and its glycosides, rutin and quercitrin, werefound to counteract glutathione depletion in co-lonic tissue and inhibit colonic inflammation in arat model of induced colitis. Quercitrin also re-duced adhesions, colonic weight, and colonic sur-face damage by 30-45 percent, although it did notattenuate disease severity. This study indicates apotential protective effect in the intestinal mucosameriting further study.183

Potential Sequelae of UlcerativeColitis

Patients with UC are at higher risk fordeveloping a number of secondary conditions, in-cluding colon cancer, osteoporosis, kidney stones,gallstones, and liver disease.

Colon CancerPersons with UC have an increased risk

for colon cancer. Although aspects of the diseaseitself, such as inflammation and alterations inGAG content, may be partially responsible for theincreased risk, certain medications used in its treat-ment may be co-carcinogens. In a dimethylhydra-zine (DMH) rat model of colitis, metronidazole,sulfasalazine, and low-dose 5-ASA (30 mg/kgdaily) increased number and/or size of tumors. Onthe other hand, high-dose 5-ASA (60 mg/kg daily)inhibited tumor size. Olsalazine at 60 mg/kg dailyhad no effect.181 Another study of sulfasalazine onDMH-induced carcinogenesis found sulfasalazine,at doses similar to human therapeutic doses, al-tered the character of the tumors without affect-ing incidence.185

Sulfasalazine was chosen by the NationalCancer Institute for carcinogenicity and toxicitystudies. The two-year NTP Toxicology and Car-cinogenesis Study for Salicylazosulfapyridinefound large doses of sulfasal

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