crohn_s trtmnt and path - alt med review 2004 copy

Alternative Medicine Review Volume 9, Number 4 2004

Crohns Disease Review

Copyright2004 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written Permission

AbstractCrohns disease, a subcategory ofinflammatory bowel disease, contributes tosignificant morbidity, particularly inindustrialized nations. It can affect people ofany age, but is more commonly diagnosed inadolescence and young adulthood.Inflammation and ulceration occur primarily inthe terminal ileum and colon, although anyportion of the intestinal tract can be affected.No etiology has been identified for Crohnsdisease, although a number of factorscontribute to its etiopathogenesis, includinggenetic, microbial, inflammatory, immune, andpermeability abnormalities. Conventionalmedications are not curative but can contributeto resolution of acute flare-ups and helpmaintain remission. Because significant sideeffects are associated with many of thesemedications, more natural interventions to helpmaintain remission should be considered.Associated nutrient deficiencies, dietaryinterventions, and nutrient and botanicalsupplementation are discussed.(Altern Med Rev 2004;9(4):360-401)

IntroductionDescription

Crohns disease (CD) is one of two mainforms of inflammatory bowel disease (IBD), theother being ulcerative colitis (UC). For a discus-sion of the pathophysiology and treatment of UC,see Alternative Medicine Review 2003;8(3). CDis a chronic, relapsing, transmural (affecting all

layers of the intestine) inflammation of uncertainetiology that can affect any portion of the diges-tive tract from mouth to anus, but is predominantlyseen in the terminal ileum and/or colon. Intestinalinflammation and ulceration in CD is asymmetri-cal and occurs in patches, with areas of healthytissue interspersed, and extends deeply into theintestinal wall, forming granulomatous lesions.The disease is named after Dr. Burrill B. Crohnwho, with his colleagues Ginzburg andOppenheimer, published a landmark paper in 1932describing the features of what is known today asCrohns disease. Several categories of CD havebeen described, defined by the portion of the di-gestive tract involved and the presenting symp-tomatology (Table 1).

Current statistics indicate 1-2 millionAmericans suffer from IBD, with approximatelyhalf of those cases diagnosed as Crohns disease.CD affects men and women equally, with a ma-jority of cases diagnosed in adolescents and youngadults ages 15-35 years. The disease, however, canaffect people at any age and approximately 10percent of cases are under age 18. Crohns dis-ease predominantly affects Caucasians; with aprevalence rate of 149 per 100,000, although therehas been a steady increase in reported cases of

Inflammatory Bowel DiseasePart II: Crohns Disease

Pathophysiology and Conventionaland Alternative Treatment Options

Kathleen Head, ND, and Julie Jurenka, MT(ASCP)

Kathleen A. Head, ND Technical Advisor, ThorneResearch, Inc.; Editor-In-Chief,Alternative Medicine Review.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.

Copyright2004 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written PermissionAlternative Medicine Review Volume 9, Number 4 2004 Page 361

Review Crohns Disease

CD and UC among African Americans. IBD islargely a disease of the industrialized world, es-pecially the United States and Europe, and is morecommon in urban areas and northern climates. CDhas a known genetic component, with 25 percentof Crohns patients having a family member withsome form of IBD. Statistics also indicate thosewith a sibling with IBD are 30 times more likelythan the general population to develop IBD.1

Signs and symptoms of CD are similar toUC, making diagnosis difficult. For a completecomparison of Crohns and UC signs and symp-toms, see Table 2. Patients diagnosed with CDpresent with some or all of the following symp-toms: frequent diarrhea, abdominal pain in thelower right quadrant appearing soon after meals,fatigue, loss of appetite, weight loss, fever, sto-matitis, and perianal fistula or fissures. Some pa-tients also present with rectal bleeding, arthritis,and erythema nodosum lesions on the extremities.1In pediatric cases of CD, growth failure is observedin 75 percent of patients.2

Risk FactorsRisk factors for CD include smoking, left-

handedness, adult appendectomy, and use of oralcontraceptives, nonsteroidal anti-inflammatorydrugs (NSAIDs), and antibiotics; demographicsalso affect the risk for CD.

Geographical, economical, educational,and occupational status can impact the risk.Crohns disease is more prevalent in developedcountries and is more common in white-collarworkers and individuals with indoor, sedentaryoccupations.3 It has been theorized that those withsedentary jobs have delayed intestinal transit time,resulting in increased contact between food anti-gens and the intestinal mucosa.

Several clinical and case-control studieshave determined smoking increases the risk ofdeveloping CD, and contributes to earlier diseaseonset, site of the disease, rate of relapse aftersurgery, and disease severity.4-6 Two studiesdemonstrate an association between childhoodsecond-hand smoke exposure and increased riskfor developing CD.7,8

Table 1. Subcategories of Crohns Disease1

Subcategory

Ileocolitis

Ileitis

Gastroduodenal Crohns Disease

Jejunoileitis

Crohns (Granulomatous) Colitis

Area Affected

The most common form of CD, affecting the ileum and colon

Affects only the ileum; fistulas or inflammatory abscesses possible

Affects the stomach and duodenum; bowel obstruction possible

Patchy areas of inflammation in the jejunum; fistulas possible

Affects only the colon and anus; anal fistulas, abscesses, and ulcers possible

Adapted from Crohns and Colitis Foundation of America, Inc. 2004http://www.ccfa.org/research/info/aboutcd




Table 2. Signs and Symptoms of CD and UC

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 or more 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 or more 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 9, Number 4 2004 Page 363



Previous antibiotic use appears to be a riskfactor for CD. A case-control study of 302 youngCD patients (< 25 years) compared to matchedcontrols investigated childhood risk factors for de-velopment of the disease. CD patients reportedmore frequent use of antibiotics in childhood andmore frequent upper respiratory infections thancontrol patients. Other factors that appeared to in-crease disease risk were history of eczema andconsumption of a low fiber diet.9 Another studydemonstrated a higher frequency of childhood in-fections, specifically pharyngitis, as well as morefrequent use of antibiotics for otitis media andpharyngitis, in CD patients compared to controls.10Utilizing the United Kingdoms General PracticeResearch Database, researchers at Queens Medi-cal Centre in Nottingham, England, found a sta-tistically significant association between Crohnsdisease and prior antibiotic use in 587 CD casesand 1,460 controls.11

Women taking oral contraceptives havetwice the risk of developing CD.12 Use of low-dose oral contraceptives does not appear to sig-nificantly influence the activity or course of thedisease, although contraceptives compound therisk of thromboembolic events, which is alreadyhigh due to hypercoagulation characteristic ofCD.13 There is also some evidence of NSAID-induced Crohns disease in the small and largebowel.14-16

Other factors that may increase the riskof developing Crohns disease are appendectomyin adulthood17,18 and left-handedness, with left-handed individuals having twice the risk of right-handed persons.19,20

DiagnosisDiagnosis of Crohns disease is often chal-

lenging due to its strong similarity to UC. It isvital, when diagnosing either form of IBD, to ob-tain an accurate patient history of symptomatol-ogy at the time of physical exam. Diagnostic im-aging to establish lesion type and extent of involve-ment include barium enema, small-bowel series,colonoscopy,21 and capsule endoscopy.22 Labora-tory tests and pathological examination of biopsiedintestinal tissue are also important for accurate

diagnosis. Tests performed often include completeblood count (CBC) to check for leukocytosis andanemia, erythrocyte sedimentation rate (ESR) andC-reactive protein (CRP) as markers of inflam-mation, stool cultures to rule out intestinal patho-gens, and IgG/IgA antibody levels to Saccharo-myces cerevisiae (SCA) and Mycobacteriumavium subspecies paratuberculosis (MAP). Theseantibodies have been shown to be positive in 60percent and 86 percent of CD patients, respec-tively, but are less frequently positive in UC pa-tients and rarely positive in healthy subjects.23

Perhaps the best tool for establishing andmonitoring disease severity and activity is theCrohns Disease Activity Index (CDAI). TheCDAI was developed in the National CooperativeCrohns Disease Study to provide assessable, uni-form clinical parameters with a consistent numeri-cal index of disease status (refer to patient hand-out at the end of this article).24,25 The CDAI is apatient assessment form incorporating both objec-tive and subjective information. Using establishedcriteria the physician calculates the CDAI score.CDAI scores > 150 indicate active disease with apoorer prognosis than scores < 150. Since theCDAI is not as accurate for monitoring diseaseactivity in children, a second scale known as thepediatric CDAI (PCDAI) was developed. ThePCDAI correlates disease severity and activity tolevels of serum albumin. The scoring is easy toperform, reproducible by different observers, andsensitive to changes in clinical status.26

Because there is no cure for Crohns dis-ease, conventional treatment has been aimed atsuppression of the inflammatory response and re-lief of symptoms of fever, diarrhea, and abdomi-nal pain. Once disease symptoms are stable, drugtherapy is employed to decrease the frequency ofdisease flares and maintain remission. Currentconventional treatment of CD includesaminosalicylates, corticosteroids, immune-modu-lating agents, and antibiotics. While reasonablyeffective in stabilizing disease and maintainingremission, many of these treatments are fraughtwith side effects and complications. Natural treat-ment options, as alternatives or complements toconventional therapy, are presented below.




EtiopathogenesisThe Genetic Component of CD

Several genes have been implicated in theetiology of CD, the most prominent of which arethe NOD2/CARD15 located on chromosome16,27,28 the OCTN1 gene located on chromosome5,29,30 and the DLG5 gene located on chromosome10.31 The exact mechanism responsible for NOD2/CARD15s role in the intestinal immune responseremains unclear, but mutations of the gene andresultant changes in its function may disrupt theintestinal mucosal barrier and the immune re-sponse to the bacterial milieu in the gut.27,32,33 Arecent study of 205 patients with diagnosed CDfrom northwestern France and 95 ethnicallymatched healthy controls revealed the R702 mu-tation of the NOD2 gene demonstrated a signifi-cant association with CD and was independentlyassociated with stricturing activity.34 In a study of512 German and British CD patients, an insertionpolymorphism in NOD2 conferred a significantlyincreased susceptibility to CD in these patients.28

The DLG5 gene has a lesser but signifi-cant impact on the risk for developing CD. Al-though the exact mechanism responsible has notbeen determined, DLG5 encodes a scaffoldingprotein important for maintaining epithelial integ-rity in various organs.31 DLG5 may interact addi-tively with the NOD2/CARD15 gene to increasesusceptibility to CD. Gene OCTN1 is located onchromosome 5q31, codes for an ion channel, andalso has a lesser impact on CD risk than NOD2/CARD15.35 Mutations in this gene may disrupt ionchannels via altered function of cation transport-ers and cell-to-cell signaling in the intestinal epi-thelium in Crohns patients.30

The TLR4 gene has recently been impli-cated in CD but is not associated with the chro-mosomal region previously linked to CD. TLR4codes for lipopolysaccharide (LPS) signaling, bac-terial recognition, and subsequent immune re-sponse to bacterial insult. In Crohns patients, theTLR4 gene is expressed in intestinal epithelialcells, macrophages, and dendritic cells of inflamedintestinal mucosa. Disruption of the LPS signal-ing pathway could result in an altered immuneresponse to pathogens and a subsequent increase

of intestinal inflammation. In two cohorts of 448Belgian patients diagnosed with CD (n=334,n=114) and 140 controls, it was demonstratedTLR4 polymorphisms enhance the relative risk ofdeveloping CD compared to controls. It was alsofound that polymorphisms of both TLR4 andNOD2 increased this risk.36 In 2001, a group ofHungarian researchers identified a genetic markerfor IBD, the Leiden point mutation, and concludedthe prevalence of this mutation was significantlyincreased in 49 CD patients compared to 57healthy controls (27.6% versus 5.3%), specificallyin central European patients compared to south-ern or northern European or American patients.37,38

Stress in the Etiology of CrohnsDisease

Research has demonstrated stress can bea contributing factor in Crohns disease. Themechanisms involved vary widely depending onthe animal model studied, but it can be concludedstress and other environmental factors affect boththe systemic and local immune status of the intes-tine. Stress signals are perceived by the centralnervous system (CNS), triggering transmission ofthe signal to the intestine via neuroendocrine me-diators. The hypothalamic-pituitary-adrenal axisand the sympathetic-adrenal-medullary axis canmodulate secretory, absorption, and barrier func-tions in the gut.39

CD is characterized by increased intesti-nal permeability and extensive animal research hasshown stress significantly influences intestinalpermeability.40 Factors involved in the effects ofstress on gut permeability include corticotropin-releasing factor (CRF), the autonomic nervoussystem, and the enteric nervous system. CRF isproduced and secreted by the hypothalamus, buthas also been found to be secreted in the coloniccrypts during times of stress, resulting in increasedintestinal permeability.41 The CNS also influencesthe degree of intestinal inflammation via the au-tonomic42 and enteric nervous systems.43

Stress can also contribute to exacerbationsof already existing disease. Two prospective stud-ies demonstrated psychological stress, anxiety, and




depression are associated with increased CD ac-tivity. In one study, 18 CD patients were followedprospectively at 8- to 12-week intervals for twoyears. Disease activity was measured using theCDAI, Beck Depression Inventory (BDI), andBeck Anxiety Inventory (BAI). The study revealeda strong association between BDI scores and cur-rent disease activity when measured simulta-neously. Both BDI- and BAI-score increases wereindependently associated with increased CDAIscores in a subsequent visit 8-12 weeks later.44

The second study involved 47 CD patientsin remission (after a documented flare) followedfor 18 months and assessed using the same scor-ing inventories as the first study. These research-ers also demonstrated psychological stress, anxi-ety, depression, and altered quality of life werelikely to influence further Crohns disease activ-ity following a relapse.45

Microbial FactorsAlthough a bacterial etiology of Crohns

disease has been postulated for decades, researchhas never revealed a specific responsible agent.Several possible mechanisms for a bacterial etiol-ogy in the development of CD have been proposed:(1) an immune response to a specific pathogenresulting in intestinal infection;46 (2) alterationsin normal bacterial content of the intestinal tract;47(3) a defective mucosal barrier and overwhelm-ing exposure to resident bacteria and their anti-gens and endotoxins;48,49 and (4) alterations to theintestinal immune response.46 Numerous bacteriaincluding Escherichia coli,50 viruses, and parasites(Table 3) have been implicated in CD, but nonehave been confirmed.

A 2003 study published inLancet examined a potential bacterialetiology. French researchers exam-ined evidence for the onset of in-creased rates of CD in Europe andNorth America beginning around1940 and found a corresponding in-crease in household refrigeration. Itappears certain bacteria, known aspsychotropic bacteria, are able togrow at the temperatures maintained

inside a refrigerator (-1 to +10 degrees Centigrade,or 30 to 50 degrees Fahrenheit). Referred to asthe Cold Chain Hypothesis, two psychotropic bac-teria Listeria monocytogenes and Yersiniaenterocolitica have been isolated from the le-sions of CD patients at higher rates than in con-trols.51,52 Both bacteria can be found in a wide va-riety of foods, including meats, dairy products, andvegetables.53,54 The researchers postulate consum-ing refrigerated food containing low levels of thesepsychotropic, pathogenic bacteria results in anover-active immune response, resulting in CD.55Additional research is warranted to confirm ordisprove this hypothesis.

Epidemiological data indicate an in-creased risk of Crohns disease in children withperinatal exposure to the measles virus.56 Subse-quent studies, however, have failed to detectmeasles-virus DNA in the intestinal tissue of CDpatients.57

MAP is perhaps the most researched bac-terial agent implicated in CD, with at least 20 stud-ies investigating either its role as a pathogenicagent or the effectiveness of antimicrobial therapyto treat it. Mycobacterium species as an etiologi-cal agent for gastrointestinal inflammation is nota new theory. As early as 1895, Johne andFrothingham reported findings from tissue analy-sis of a cow that had died of Crohns-like symp-toms. They identified a bacillus with much thesame staining characteristics as the tubercle ba-cilli; the disease in cattle became known as Johnesdisease.58 In 1901, a Scottish surgeon postulated,after operating on four patients with chronic en-teritis, that the disease he observed in the humanintestine might be the same as Johnes disease in

Table 3. Infectious Pathogens Implicated in Crohns Disease

Escherichia coliListeria monocytogenesYersinia enterocoliticaMycobacterium avium subspecies paratuberculosisMeasles virus




cattle. He was, however, unable to conclusivelyculture and identify the organisms from humantissue.59

In the 1980s Chiodini successfully iso-lated MAP from intestinal lesions of a small num-ber of CD patients.60,61 In 1992, an internationallyrecognized expert in CD, John Hermon-Taylor andcolleagues confirmed Chiodinis findings. Thestudy, involving 40 CD patients, 23 UC patients,and 40 controls (patients without IBD), isolatedMAP in 65 percent of patients with CD, 4.3 per-cent with UC, and 12.5 percent of control pa-tients.62 Other research has confirmed earlier find-ings of DNA insertion sequence (IS900) fromMAP in Crohns diseased tissues.63 Hermon-Tay-lor, aware MAP is ubiquitous in nature, especiallyin meats and dairy products, tested retail milk sup-plies in Great Britain. After culturing for 2.5 years,the IS900 MAP DNA sequence was isolated in 16percent of retail milk samples, easily facilitatingwidespread transmission to humans.64 Research-ers in Sweden confirmed this finding in 2002 whenthey revealed 19.7 percent of bulk milk samplesacross Sweden tested positive for IS900.65 A 2000meta-analysis by Hermon-Taylor and colleaguesof 18 peer-reviewed publications found nine otherstudies reporting the presence of MAP in the in-testine of CD patients, as well as several studiesin which MAP was not identified in Crohns pa-tients.66 Since that time, other researchers havedemonstrated MAP DNA presence in intestinaland blood samples in up to 92 percent of CD pa-tients compared to 26 percent of controls.67,68

Despite its prevalence in tissue and bloodof CD patients, the presence of MAP DNA doesnot prove causality. The isolation of MAP DNA isoften not reproducible with subsequent analysisof the same tissue. Conversely, MAP RNA isola-tion from Crohns-diseased tissue samples indi-cates the organism was viable at isolation and notfrom a contaminating source such as cows milk.Isolation of the MAP RNA sequence IS900 is morereproducible in human tissue, possibly because itis a much smaller molecule. In addition, becauseRNA has a very short half-life (in minutes),69 itspresence cannot be attributed to environmentalcontaminants.70

Antimicrobial therapy should be effectiveat controlling the disease, if MAP is a contribut-ing agent. Studies examining this premise haveyielded negative results.71-74 Negative results maybe because only single antibiotics or antibioticsineffective against MAP were used. MAP is nowknown to be resistant to most standard antituber-culous drugs. Since 1997 four open-label studieshave shown efficacy with a combination ofrifabutin and macrolide antibiotics for the treat-ment of CD.75-78

Inflammation/Immune ResponseAltered Immune Response

While it is unlikely a specific microbial an-tigen will be established as a consistent causativefactor in CD, an abnormal antibody response seemsto be a factor. The inflammation appears to be, atleast in part, a result of an overreaction to normalintestinal flora. Experts theorize either a microbialantigen may have precipitated the inflammationwhen elimination from the mucosa was unsuccess-ful, triggering ongoing inflammation, or an inherentdysregulation of the mucosal immunity exists, re-sulting in an overreaction to normal gut flora.79 Ineither case, it is thought the antigen persists due toan inability of phagocytes to break down the cellwalls of commensal microbes.

The presence of antibodies to microbial an-tigens in CD supports the theory that one aspect ofCD pathology involves an abnormal immune re-sponse to otherwise normal intestinal flora. For ex-ample, Crohns disease is characterized by elevationsin anti-Saccharomyces cerevisiae (brewers yeast)antibodies in 49-60 percent of cases.80 In addition,levels of protein-bound IgG (bound to proteins ofnon-pathogenic bacteria) have been found in the in-testinal mucosa of patients with active CD to be sig-nificantly higher than patients with UC, irritablebowel syndrome, or non-specific IBD.81

Zareie et al found mononuclear cells fromthe lamina propria of the gut mucosal cells in CDpatients were spontaneously activated, apparently bynormal gram-negative, luminal bacteria. Activationresulted in secretion of tumor necrosis factor-alpha(TNF-alpha) and subsequent epithelial changes.82




Cytokine PatternsA T-cell mediated immune response has

been identified in the mucosa of CD, in contrastto UC, and is postulated to be the primary pre-cipitating event.83 The ensuing production of in-flammatory cytokines can cause ulceration andincreased intestinal permeability.83

Animal models confirm the generally heldconsideration that CD is primarily a T-helper 1-(Th1) dominant condition. In murine models, dis-ease induced by a Th1 over-expression results inlesions histologically compatible with CD (includ-ing granulomas), while a T-helper 2- (Th2) medi-ated response results in lesions more closely re-sembling ulcerative colitis (including a lack ofgranulomas).84,85

As mentioned, the characteristic granulo-matous lesion seen in Crohns disease is evidenceof a cell-mediated immune response. In humanstudies, while chronic CD appears to involve pri-marily an overactive Th1 response characteristicof a cell-mediated phenomenon,86 some research-ers have determined divergent cytokine patternsat different stages of the disease.87 Chronic lesionsare associated with high levels of interleukin-2 (IL-2), interferon gamma (IFN-gamma),87 TNF-alpha,and interleukin-12 and -18 (IL-12 and IL-18).86Desreumaux et al, however, found a distinctly dif-ferent cytokine pattern in early CD. By examin-ing ileal biopsy specimens of 17 patients comparedto 11 controls, the researchers determined thatearly lesions were characterized by elevations ininterleukin-4 (IL-4) and decreases in IFN-gamma,87 a pattern more consistent with an over-active Th2 immune response.

Other researchers have found, at least inanimal models, the opposite may be true. In amouse model of ileitis (a CD-like enteritis), re-searchers found elevated Th2 cytokines, includ-ing IL-4, during the chronic phase of the disease.88

IL-18 is up-regulated in Crohns disease.Although typically considered to be an activatorof Th1 responses, IL-18 has actually been shownto be a pleiotropic cytokine capable of mediatingboth Th1 and Th2 responses, providing more po-tential evidence for divergent cytokine patterns inthe pathogenesis of CD.88

Another study examined human colonictissue samples and found IL-16 protein levels el-evated in CD patients but not UC patients. Thesame study found an anti-human IL-16 antibodycould suppress colonic injury in a murine modelof Crohns-like experimental colitis.89

Pro-inflammatory cytokines are normallykept in check by immunosuppressive cytokinessuch as transforming growth factor beta (TGF-beta). It is believed the transcription factor T-betis integral to controlling the balance between pro-and anti-inflammatory cytokines.90 T-bet is elabo-rated by Th1 cells, but not Th2 cells. IFN-gammais enhanced by T-bet. Neurath et al examined T-bet activity in lamina propria T-cells of patientswith CD as well as in animal models. The research-ers discovered T-bet over-expression in the laminapropria T-cell nucleus in patients with CD, but notUC or controls. In the animal models, T-bet over-expression was consistent with Th1-mediated coli-tis (animal model of CD), while a T-bet deficiencywas protective.

Tumor necrosis factor appears to play asignificant role in the pathogenesis of CD. Mu-cosal biopsies of children with IBD compared tocontrols found a significantly greater number ofTNF-alpha-secreting cells in patients with CDcompared to those with UC or non-specific bowelinflammation.91 A significant difference betweenmild-to-moderate and severe disease was alsonoted for the CD subgroup, with severe diseasedemonstrating a significantly greater percentageof TNF-secreting cells. In animal models ofCrohns ileitis, neutralization of TNF resulted insignificant decrease in inflammation.92 Indeed,suppression of TNF-alpha is the primary mecha-nism of action of the monoclonal antibody cat-egory of CD medications (see Conventional Treat-ments below). TNF-alpha contributes to gut in-flammation in several ways. It induces expressionof adhesion factors that allow for inflammatorycells to infiltrate and activates macrophages topromote release of other pro-inflammatory me-diators such as IFN-gamma.93

TNF-alpha concentrations in the stool canbe used to monitor disease activity in both CDand UC. Braegger et al compared 13 children with




active CD to children with inactive CD, UC, diar-rhea, and healthy controls. The average TNF con-centrations in the stools of children with activeCD ranged from 440-4,322 pg/g compared to arange of 40-84 pg/g in the children with diarrhea,inactive CD, and healthy controls.94

A tumor necrosis factor-like cytokine,TL1A, has recently been identified as a co-con-tributor to IFN-gamma production. Tissue fromIBD patients and controls was examined for thepresence of TL1A, which was found to be up-regu-lated in patients with IBD, particularly those withactive CD. It appears to be produced primarily inthe macrophages and T lymphocytes from thelamina propria in CD patients, with the amountpresent correlating with disease severity. The re-sult was a four-fold increase in IFN-gamma pro-duction. The authors concluded, Our study pro-vides evidence for the first time that the novelcytokine TL1A may play an important role in aTh1-mediated disease such as CD.95

Oxidative StressOxidative stress is thought to play a sig-

nificant role in the pathogenesis of inflammatorybowel disease, including CD. Endogenous anti-oxidants such as superoxide dismutase (SOD),glutathione, and catalase are normally able tocounteract oxidative stress in the intestinal mu-cosa. However, inflammation increases the de-mand for these important antioxidants and resultsin an imbalance between pro-oxidants and anti-oxidants, with subsequent mucosal damage.

In an Italian study, subjects (37 CD and46 UC patients) were compared to 386 healthycontrols. Oxidative DNA damage was measuredexamining the amount of 8-hydroxy-deoxy-gua-nosine (8-OhdG) present in blood. In addition,evaluation of plasma levels of vitamins A and Eand carotenoids demonstrated significant de-creases in patients with CD or UC compared tocontrols. The specific carotene found most sig-nificantly decreased was beta-carotene, withplasma levels only 50 percent of controls. No sig-nificant differences were noted between CD andUC patients. Levels of 8-OhdG were considerablyhigher in IBD patients than controls, illustratingincreased oxidative DNA damage.96

Researchers have studied the connectionbetween oxidative stress and immune-regulatedinflammatory factors. Reactive oxygen species(ROS) have been found to be involved in activa-tion of nuclear factor-kappaB (NF-kappaB), whichis necessary for encoding genes for TNF-alpha andsome of the interleukins involved in inflamma-tion. Antioxidant levels and inflammatory media-tors were examined in 26 CD patients comparedto 15 healthy controls. Selenium and glutathioneperoxidase (GSHPx) activity were both decreasedin CD patients, while TNF-alpha levels and ESRwere increased and negatively correlated with se-lenium and GSHPx. Selenium levels decreased inaccordance with disease activity, with the mostsevere disease manifestation exhibiting the low-est levels. These findings occurred in subjects whodid not have evidence of malabsorption, indicat-ing malabsorption is not the sole factor contribut-ing to selenium deficiency. The researchers con-clude, selenium supplementation in deficientpatient groups [should be] regarded as a potentialprotecting factor against oxidative burst, NF-kappaB activation and excessive inflammatory andimmune response.97

A study examining indices of oxidativestress and plasma levels of vitamins A and E in 20CD patients found higher peroxidative status andlower vitamin A and E levels compared to con-trols. Conservative surgery to remove bowel ob-structions resulted in improvements in vitamin Astatus and oxidative stress measured bythiobarbituric acid reactive substances (TBARS).98

A similar study found significantly higherlevels of breath-pentane and -ethane and F2-isoprostane (measurements of oxidative stress) in37 non-smoking CD patients compared to matchedcontrols. At the same time, plasma levels of vita-min C and the carotenoids alpha- and beta-caro-tene, lycopene, and beta-cryptoxanthin were sig-nificantly lower in CD patients.99

Pediatric patients also demonstrate signsof increased oxidative stress. In a study of 22 pe-diatric CD patients, malondialdehyde (MDA) lev-els were 70-percent higher than controls. Antioxi-dant levels were measured and only vitamin A wasfound significantly low, while alpha- and gamma-tocopherol and beta-carotene were no different




than controls. Red blood cell levels of glutathionewere higher in CD patients than controls. The re-searchers speculate these higher levels may be dueto an attempt to compensate for increased oxida-tive stress.100

Although oxidative stress is a factor in thepathogenesis of both UC and CD, the parametersmay vary between the two. Both UC and CD areassociated with increased levels of MDA, a signof lipid peroxidation. However, one study foundelevated levels of MDA in CD were associatedwith levels of the antioxidant metallothionein (ahydroxyl radical scavenger) and manganese-de-pendent SOD (active in the mitochondria);whereas, in UC the MDA levels were associatedwith catalase, GSHPx, and myeloperoxidase.Based on this data, the researchers suggest the like-lihood of the ROS hydroxyl radicals and super-oxide anions in the pathogenesis of CD, whilehydrogen peroxide and hypochlorous acid may bemore associated with UC.101 Antioxidants for thetreatment of CD are discussed below in the treat-ment section.

Intestinal PermeabilityConsiderable evidence supports the pres-

ence of increased small intestinal permeability(SIP) in Crohns disease. However, whether it is acontributing factor to the pathogenesis or a con-sequence of inflammation is not entirely clear.

Evidence for Genetic- and/orEnvironmentally-Induced IntestinalHyperpermeability Preceding DiseaseManifestation

Evidence that SIP precedes actual diseasemanifestation has been put forth by a number ofresearchers. Studies of CD patients and their first-degree relatives point to the possibility of a ge-netic- and/or environmentally-induced defect inintestinal permeability preceding the onset of full-blown disease. A case report in Gastroenterologydescribes a woman with a positive family historyof CD and a positive personal history of increasedSIP since age 13; at age 24 she developed CD. Inthis case, SIP appeared to precede disease mani-festation by at least 10 years.102

Examination of intestinal permeability inrelatives of CD patients sheds light on the poten-tial genetic influence of increased intestinal per-meability in the pathogenesis of CD. A study ex-amined intestinal permeability in 16 CD patientsand 26 first-degree relatives with whom they lived,compared with 32 healthy controls and their fam-ily members. Increased SIP was found in 37 per-cent of patients and 11 percent of first-degree rela-tives, significantly greater than controls. Becausethe patients were living with the relatives tested,it is impossible to know from this data whetherthe increased permeability was genetically or en-vironmentally induced. However, it does provideevidence of a defect in SIP, possibly precedingthe onset of inflammation.103 Interestingly, anotherstudy found a small increase in SIP in spouses ofCD patients, pointing to a possible environmentalcause.104

Another group of researchers, studying thefamilial connections in SIP and CD, tested SIP in39 CD patients, 34 healthy first-degree relatives,22 spouses, and 29 healthy controls, using thelactulose:mannitol test (Table 4). SIP was testedat baseline and then after dosing with acetylsali-cylic acid (aspirin) to induce increased permeabil-ity. The baseline SIP results found elevations in36 percent of CD patients, 23 percent of spouses,18 percent of relatives, and three percent of con-trols, indicating environment may play a greaterrole than genetics. On the other hand, after aspi-rin provocation, all participants experienced anincrease in permeability with 32 percent of pa-tients, 41 percent of first-degree relatives, 14 per-cent of spouses, and three percent of controls dem-onstrating an abnormally high response. This lat-ter data seems to point to genetic factors. The re-searchers suggest that baseline permeability maybe determined by environmental factors, whereasreaction to provocation by gut toxins such as as-pirin may be genetically determined.105 A similarstudy found exaggerated response to provocationby ibuprofen ingestion in first-degree relatives ofpediatric CD patients, with a greater increase inSIP in relatives than in healthy controls.106




An in vitro studyprovides a potentialmechanism by which in-creased SIP could contrib-ute to the etiology of CD.Mucosal samples fromnon-inflamed portions ofthe ileum of CD patientshad increased permeabilityto the common food aller-gen ovalbumin. The au-thors suggest this could in-crease the antigen load inthe mucosa leading to dis-ease initiation.107

Evidence for Inflammation as CausativeFactor of Increased SIP

Other research points to inflammation asthe causative factor for increased SIP in CD, im-plying the disease itself caused the increased per-meability. TNF-alpha appears to cause a rearrange-ment in key proteins associated with the tight junc-tions in the intestines of CD patients, resulting inincreased permeability.108 Inhibition of TNF-alphahas been found to reverse increased tight junctionpermeability.109

Common medications used to treat CD,including prednisone110 and infliximab,111 decreaseinflammatory cytokines including TNF-alpha andnormalize gut permeability.

SIP as a Predictor of Disease Activity andPotential for Relapse

Several studies indicate the permeabilityof the small intestine seems to be reflective of dis-ease activity and potential for relapse in CD. Onestudy of 39 CD patients found the effect of an el-emental diet on SIP was similar to SIP seen dur-ing disease remission in both instances signifi-cantly lower than during active disease.112

Wyatt et al followed 72 patients with in-active Crohns disease for one year, evaluating SIPusing the lactulose:mannitol ratio, and found 26of 37 patients with increased permeability experi-enced relapse, compared to only six of 35 withnormal permeability.113

Another study examined absorption ofmacromolecules (horseradish peroxidase) as a re-flection of increased intestinal permeability inmoderate-to-severe CD compared to mild diseaseand controls. The researchers found significantlyincreased permeability in moderate-to-severe CDbut not mild disease or controls. The authors con-clude disease activation seems to be associatedwith increased permeability, which they hypoth-esize is secondary to the disease process.114

Another study examined 50 patients withinactive CD; defined as a CDAI < 150. SIP wasassessed via the lactulose:rhamnose ratio. Of 18patients with increased permeability, eight re-lapsed during the one-year study, while only oneof 31 with normal SIP experienced a relapse.115

Evaluation of 132 CD patients in remis-sion who were followed every four months for twoyears supports the use of intestinal permeabilityas a predictor of relapse. Forty percent of patientsrelapsed during this period and increasedlactulose:mannitol ratio (signifying increased per-meability) and decreased serum iron were associ-ated with relapse. There was no association be-tween tendency to relapse and other disease pa-rameters such as white blood count, ESR, CRP, orother signs of inflammation.116

Another study of 27 CD patients in re-mission, compared to 22 healthy controls, failedto conclude intestinal permeability was a goodpredictor of relapse.117

Table 4. The Lactulose:Mannitol Test for Small IntestinalHyperpermeability

Patient swallows a solution of 5 g mannitol and 5 g lactuloseUrine is collected for six hoursAssay for total lactulose and mannitol < 14% mannitol = carbohydrate malabsorption>1% lactulose = disaccharide hyperpermeability

From: Bralley JA, Lord RS. Laboratory Evaluation in Molecular Medicine. Norcross, GA: Institute for Advances in Molecular Medicine; 2001:222.




A Generalized Permeability Defect inCD?

Whether SIP typically precedes diseasemanifestation or is a result of inflammation re-mains to be determined. It is probable increasedSIP precedes disease manifestation, but inflam-mation associated with active disease exacerbatesthe problem. However, the permeability defectmay be more generalized, as increased permeabil-ity has been noted in other tissues of CD patients.One group of researchers found increased pulmo-nary permeability in patients with Crohns disease.Unlike intestinal permeability, pulmonary perme-ability did not seem to be affected by disease ac-tivity.118

Gastroduodenal permeability (GDP),tested by sucrose excretion, has been found by twogroups of researchers to be increased in CD pa-tients. One study of 100 patients found GDP wassignificantly higher in CD patients than controls,and increased GDP was predictive of gastroduode-nal involvement.119 Another study found similarresults in a group of 50 CD patients. The research-ers also found higher gastric and intestinal per-meability were associated with a greater likelihoodof granulomatous involvement.120 Nutrients for thetreatment of increased intestinal permeability inCD are discussed below in the treatment section.

Other Abnormalities Contributing tothe Etiopathogenesis of CDPlatelet Abnormalities

Increased platelet count is a common fea-ture of active Crohns disease and contributes tothe increased incidence of thromboembolism seenin both CD and UC.121 In addition to increasedplatelet count, CD is characterized by increasedplatelet activation in the mesenteric vessels.122Although platelet function has historically beenconsidered to involve primarily blood clotting,there is considerable evidence for platelet involve-ment in inflammation. Platelets from inflamma-tory bowel-diseased tissues have been found toexpress a number of inflammatory mediators, in-cluding CD40L, a substance similar to tumor ne-crosis factor that directs platelets toward inflam-mation instead of aggregation.121 A sequence of

events has been postulated in which platelets trig-ger chemokine-mediated adhesion of white bloodcells to the endothelium, causing leukocyte mi-gration and subsequent focal inflammatory le-sions.121

Elevated HomocysteineHigher than normal incidence of

hypocoagulation states and subsequent thrombo-sis led investigators to examine homocysteine lev-els in IBD patients, since high homocysteine lev-els are known to contribute to risk for thromboem-bolism. Total homocysteine, vitamin B12, andfolate levels were tested in 64 IBD patients (25CD patients) and 121 controls. Seventeen of 64patients (26.5%) compared with three of 121 con-trols had hyperhomocysteinemia (defined ashomocysteinee 12.8 microM/L). Folate levelswere significantly lower in the IBD group, whilethere was no statistically significant difference inB12 levels between the two groups. There was alsono statistical difference between patients with CDor UC.123

In another study of 65 IBD patients (56with CD; 9 with UC), using 12.0 microM/L as thecutoff point, 10 patients (15.4%) demonstratedhyperhomocysteinemia compared to 3/138 (2.2%)in the control group. In this study, a vitamin B12deficiency was associated with high homocys-teine.124

Yet another study found elevated levelsof homocysteine in CD patients correlated withboth low folate and vitamin B12 levels, althoughthey were more strongly associated with lowfolate.125

Vitamin B6 is essential for the catabolismof homocysteine to cysteine, taurine, sulfate, andglutathione. Thus, deficiencies of vitamin B6 canalso result in hyperhomocysteinemia. The Jour-nal of Neurological Sciences reports a case of a39-year-old female CD patient with a history ofischemic stroke associated with a vitamin B6 de-ficiency and hyperhomocysteinemia along withinflammatory factors associated withhypercoagulation.126




Mitochondrial DysfunctionResearch on mitochondrial dysfunction as

a cause of chronic disease is in its infancy. Pre-liminary investigations point to the possible in-volvement of mitochondrial dysfunction in thepathogenesis of Crohns disease. As early as 1985,in vitro examination of rectal biopsy specimensprovide evidence of mitochondrial damage inCD.127 More recently, researchers elucidated apotential mechanism for the possible mitochon-drial dysfunction in CD. They determined TNF-alpha could enhance mitochondrial NF-kappaBexpression, down-regulating mitochondrial RNAexpression.128 A recent case report of a young girlwith CD demonstrated impaired oxidative phos-phorylation, with abnormalities in Complexes IIIand IV. In this case, the only medication that pro-vided therapeutic benefit was an anti-TNF-alphaantibody, infliximab.129 This child had numerousother health problems besides CD. Whether mito-chondrial dysfunction plays a central role in thepathogenesis of CD remains to be determined.

Conventional Treatment of CrohnsDisease

Conventional therapies utilized for thetreatment of Crohns disease include NSAIDS,corticosteroids, aminosalicylates and their deriva-tives, antibiotics, immunomodulatory drugs, andnumerous cutting edge therapies including mono-clonal antibody preparations, anti-sense nucleicacid drugs, mitogen-activated protein kinase in-hibitors, integrin antibody therapy, recombinantgrowth factors and hormones, and macrolide com-bination antibiotic therapy. Many of these drugsshow promise but are fraught with complicationsand side effects.

Anti-inflammatory AgentsNSAIDS and COX-2 Inhibitors

NSAIDS, such as aspirin, ibuprofen, andnaproxen sodium, act by inhibitingcyclooxygenase and blocking prostaglandin syn-thesis. Historically, they were used to treat the painand intestinal inflammation of IBD, until studiesdemonstrated they caused gastrointestinal erosion

and bleeding, protein loss enteropathy, bile acidmalabsorption, perforation, and strictures, wors-ening the course of IBD.130-132

Although still currently contraindicated inIBD, cyclooxygenase-2 (COX-2) selective inhibi-tors have been investigated as therapeutic agentsbecause they appear to cause less gastrointestinalinjury than regular NSAIDS. There is some evi-dence COX-2 inhibitors actually may be involvedin preserving intestinal mucosa and promotinghealing of gastrointestinal ulcers.133,134 One COX-2 inhibitor, rofecoxib (Vioxx) has recently beenremoved from the market due to safety concerns.A three-year clinical study revealed an increasedrelative risk for serious cardiovascular effects (in-cluding strokes and heart attacks) in patients tak-ing Vioxx longer than 18 months about twicethat observed in the placebo group. The trial in-vestigating the effect of rofecoxib in preventingthe recurrence of colorectal polyps was halted twomonths early. An increased risk of cardiovascularevents was not observed in patients takingrofecoxib for less than 18 months.135

AminosalicylatesOther anti-inflammatory agents widely

utilized for decades in treating IBD are theaminosalicylates, particularly sulfasalazine (com-prised of sulfapyridine, an antibacterial agent, and5-aminosalicylic acid, also known as mesalamine)or mesalamine alone. Research has shownsulfasalazine to be effective only in mild-to-mod-erate disease of the colon, but not for isolated smallbowel disease,136 and its use often results in folatedeficiency.137 A recent meta-analysis of slow-re-lease mesalamine (Pentasa) demonstrated it to besuperior to placebo for reducing the CDAI in mild-to-moderate CD.138 The slow-release forms ofmesalamine, Asacol and Pentasa, are released intothe small bowel as far as the distal ileum and tendto have fewer side effects than sulfasalazine.

CorticosteroidsOral corticosteroids reduce inflammation

and suppress the immune system. They comprisethe standard conventional treatment of moderate-to-severe CD or disease that is refractory to other




treatment. While useful for achieving remission,long-term use of steroids can have numerous sideeffects, ranging from edema, weight gain, insom-nia, night sweats, increased facial hair, acne, andmood disturbances, progressing to more seriouscomplications such as hypertension, osteoporosis,diabetes, increased risk of infection, depression,cataracts, and glaucoma.139 For many years thesteroid most frequently used to treat CD was pred-nisone; however, because of the extensive sideeffects, other options were explored. Budesonideis a topically active corticosteroid with low sys-temic bioavailability. When given orally it de-creases mucosal inflammation and then undergoesextensive first-pass metabolism in the liver, result-ing in far fewer side effects than other oral corti-costeroids, providing a safer option for childrenwith CD.140 Budesonide has also been shown tobe more effective than mesalamine in maintain-ing remission in adults with steroid-dependentCD.141

Other Immunosuppressive AgentsAzathioprine, 6-mercaptopurine (6-MP),

and methotrexate are widely used immunosuppres-sive drugs for IBD. The latter two are antimetabo-lite antineoplastic agents normally used to treatcancer, but have also demonstrated effectivenessin treating refractive CD. Azathioprine has beenshown to be effective for inducing remission insteroid-dependent CD, but has also been shownto cause side effects in significant numbers of pa-tients.142 According to the International Agency forResearch on Cancer, this substance is listed as aknown carcinogen.143 The immunosuppressiveagent 6-MP has demonstrated effectiveness inmaintaining remission in CD patients when ad-ministered without concomitant steroids.144 Low-dose methotrexate is sometimes used in Crohnspatients who have not responded to other drugtreatments and is reasonably effective in place ofsteroids.145 Side effects can range from nausea,diarrhea, and skin reactions,146 to more seriousproblems such as bone marrow suppression, lunglesions, kidney dysfunction, and hepatotoxicity(including liver fibrosis).146 Methotrexate has alsobeen shown to cause folic acid deficicieny.147 Allof these medications can take up to several months

to begin working, although methotrexate seemsto work more rapidly than the others. They can beuseful therapies for fistular disease and maintain-ing remission, but have little value in treating acuteflare-ups of CD.148

AntibioticsWhen a bacterial etiology was suggested

for CD, numerous studies investigated the effec-tiveness of antibiotic therapies, mostly with nega-tive results.71,74 Recent research has suggestedMAP as a potential pathogenic agent for CD andresearch utilizing combination anti-mycobacterialantibiotic therapy has been conducted for up to46 months. A long duration of therapy is indicatedbecause Mycobacterium species are very slowgrowing, making long-term therapy necessary.Two studies published in 2002 demonstrate theeffectiveness of a combination of rifabutin, a broadspectrum anti-tubercular agent and clarithromycin,a macrolide anti-mycobacterial antibiotic.77,78

Biologic TherapiesNumerous promising biologic therapies

are emerging, such as anti-TNF-alpha monoclonalantibodies, antibodies to integrins alpha4 and al-pha4-beta 7, interleukin antibodies, mitogen-acti-vated protein kinase inhibitors, anti-sense nucleicacids, recombinant growth factors, and colonystimulating factors.

Perhaps the most promising are the anti-TNF-alpha monoclonal antibodies, includinginfliximab, etanercept, adalimumab, CDP870,CDP571, and onercept. Exploring the mechanismsand efficacy of these drugs is beyond the scope ofthis article; for a brief description see Table 5.Infliximab has received the most attention in clini-cal trials and appears to be the most effective.Infliximab is a mouse-human IgG1 chimericmonoclonal antibody to TNF-alpha administeredintravenously. Infliximab is used to achieve clini-cal improvement and induce remission in patientswith moderate-to-severe luminal and fistular CDrefractory to other treatments. Infliximab exertsits beneficial effects by TNF-alpha neutralizationin mononuclear inflammatory cells, thereby induc-ing apoptosis.149 A single infusion of 5 mg/kg has




been shown to induce short-term (four-week) re-mission in 48 percent of patients150 and infliximabappears to have the greatest degree of efficacy inmaintaining remission for at least one year whendosed at 10 mg/kg body weight every eightweeks.151 Infliximab is fairly well-tolerated in mostpatients, although serious side effects include acuteinfusion reactions,152 serum sickness-like disease,drug-induced lupus, infectious events attributedto infliximab therapy, pneumonia, reactivation oflatent tuberculosis,153 and even death.154

Other anti-TNF-alpha monoclonal agentsunder investigation are CDP571, CDP870, andonercept, but all have failed phase 2 and 3 clinicaltrials despite showing a short-term clinical ben-efit.155-157 Future research on these drugs is uncer-tain. Adalimumab is a human monoclonal anti-body administered subcutaneously and appears tobe well-tolerated in most CD patients, particularlythose with reactions to infliximab. Phase 2 and 3trials with CD patients are currently underway.158

Table 5. Conventional Medications and their Mechanisms in Crohns Disease

Mechanisms of Action

Anti-inflammatory (slow-release topically to small bowel)

Anti-inflammatory; immunosuppressive

Suppress the immune response in Crohns

Damage cell wall of pathogenic agents; reduce bacterial load

TNF-alpha neutralization and apoptosis

Modulate lymphocyte migration to gut mucosa

Decrease inflammation by inhibiting inflammatory cytokines

Indirectly inhibit TNF-alpha

Decreases intestinal permeability; decreases mesenteric fat; increases amino acid and electrolyte absorption in intestine

Possible immunostimulation of neutrophils

Medication

Aminosalicylates

Corticosteroids

Other Immunosuppressive Agents

Antibiotics

TNF-alpha Monoclonal Antibodies

Anti-sense Agents

Anti-interleukins

Mitogen-activated Protein Kinase Inhibitors

Somatatropin

Sargramostim




Natalizumab and MLN-01 are othermonoclonal antibodies to gut glycoproteins, cur-rently in phase 2 and 3 trials.159-161 Several otheragents are in clinical trials.162

Nutrient Deficiencies in CrohnsDisease

A variety of nutrients have been found tobe deficient in CD patients. Causes include mal-absorption in the small intestine, increased nutri-ent need because of disease activity, low nutrientintake, nutrient loss due to chronic diarrhea or in-creased transit time, or effect of medications. Sev-eral studies have examined the specific nutrientdeficiencies associated with CD.

Studies Examining Multiple NutrientDeficiencies

A study measured serum, blood, and redblood cell levels of various nutrients in 24 CD pa-tients and 24 healthy controls. CD patients demon-strated significantly lower levels of vitamins A andE, thiamin, riboflavin, pyridoxine, and folic acidcompared to controls. Blood levels of pantothenicacid were significantly higher in CD patients, andthere were no statistically significant differences inlevels of vitamins B12 and C, nicotinic acid, andbiotin. No differences were noted on the basis of dis-ease activity, duration, or location.163

Another study examining multiple nutri-ent deficiencies found 85 percent of 279 CD pa-tients had deficiencies. Nutrients most frequentlyfound deficient were iron and calcium, with zinc,protein, vitamin B12, and folate deficiencies notedless frequently.164

Nutrient status, body composition, anddietary intakes were analyzed in 32 CD patientswith longstanding disease in remission andcompared to 32 matched controls. Regarding bodycomposition, bone mineral content wassignificantly lower in patients; percent body fatwas significantly lower in male CD patients.Patients had significantly lower dietary intakes offiber and phosphorus, while no other nutrientintakes were significantly different. Serum levelsof beta-carotene, vitamins C and E, selenium,

magnesium, and zinc, and glutathione peroxidaseactivity were also significantly lower in patientsthan controls. As noted in a previous study, therewas no correlation between nutrient status andduration of disease or extent of bowel resection.165

These same researchers conducted a studywith the same design on newly diagnosed patientswith IBD, 23 with CD. Even at diagnosis, bonemineral content was significantly lower in patientscompared to controls. While all nutrients testeddemonstrated slight decreases in patients, onlyvitamin B12, serum albumin (a reflection of pro-tein status), and glutathione peroxidase activity (areflection of antioxidant status) were significantlydecreased.166 These two studies seem to indicatethat, although nutrient status is negatively im-pacted at the time of diagnosis, longstanding dis-ease increases the extent of derangement.

A study published by the American Di-etetic Association examined the effect of dietarycounseling on nutrient status in CD. Subjects(n=137) were randomly assigned to one of twogroups. The treatment group received dietarycounseling monthly for six months, while the con-trol group received no counseling. Iron, vitaminB12, and folate levels were found to be low in asignificant portion of patients, with no significantdifferences between groups at study onset. Al-though dietary counseling was associated withnormalization of serum folate and total iron bind-ing capacity and moderate increases in intakes ofvitamin B12, folic acid, and iron, the laboratoryvalues as reflection of nutrient status did notchange significantly.167

Vitamin D Status in Crohns DiseaseA study of young CD patients (ages 5-22)

found low vitamin D (defined as serum concen-trations of 25-hydroxyvitamin D < 38 nmol/L) in16 percent of 112 subjects. Interestingly, the lowlevels did not significantly correspond to low bonemineral density (BMD) or dietary intakes. Fac-tors associated with hypovitaminosis D includedwinter season, African-American ethnicity, extentof glucocorticoid medication, and disease confinedto the upper gastrointestinal tract.168




Levels of serum vitamin D consideredlow have been inconsistent from study to study.Another study considered low plasma 25-hydroxyvitamin D to be less that 12 nmol/L. Inthis study, plasma vitamin D levels were exam-ined in 37 CD patients and levels were found tobe significantly lower in patients with active dis-ease compared to those with inactive disease.169

Studies on vitamin D status have also ex-amined active vitamin D levels. Recent researchfound circulating levels of 1,25-dihydroxyvitaminD were high in a large percentage of CD patients(42 percent of 138 subjects) compared to UC pa-tients (seven percent of 20 UC patients) and werepositively associated with disease activity. Lowlevels of 25-hydroxyvitamin D result in low se-rum calcium that in turn stimulates parathyroidhormone and a subsequent rise in 1,25-dihydroxyvitamin D levels to enhance calciumresorption from bone. High levels of active vita-min D were associated with significantly lowerBMD in CD patients compared to UC patients,independent of glucocorticoid use. The research-ers examined colonic biopsies of patients with UCand CD and found higher levels of 1alpha-hy-droxylase in CD mucosa. This enzyme converts25-hydroxy- to 1,25-dihydroxyvitamin D. Thus,it appears over-expression of this enzyme in theinflamed mucosa may be a cause of low BMD inCD.170

Vitamin K in Crohns DiseaseSerum vitamin K status was assessed in

32 CD patients and compared to reference rangesfrom 384 healthy controls. Levels were signifi-cantly lower in CD patients. Vitamin K is a co-factor for carboxylation of the protein osteocalcin,necessary for calcium binding to bone. Thus, de-ficiencies of vitamin K can contribute to os-teoporosis and measurements of free osteocalcin(uncarboxylated) reflect bone-vitamin K status.Levels of free osteocalcin were higher in CD pa-tients, while binding capacity of osteocalcin tohydroxyapatite was lower. High levels of freeosteocalcin were associated with low BMD in thelumbar spine.171

Water-soluble Vitamin DeficienciesB-complex Vitamins

As discussed previously, deficiencies ofvitamins B6 and B12 and folate in CD have beenassociated with increased homocysteine levels.Deficiencies may be associated with impairedabsorption or decreased dietary intake. A study offolate absorption in patients with Crohns diseasecompared 100 patients with 20 healthy controls.Serum folate levels were assessed after a loadingdose of folate and deemed normal in the 20 healthysubjects but in only 75 percent of the CD patients.Of the 25 patients with impaired folate absorp-tion, nine demonstrated almost no increase afteran oral dose, while 16 experienced an increase butstill below normal.172 In addition to impaired ab-sorption, CD patients frequently have diets devoidof fresh leafy green vegetables and fruits dietarysources of folate because of fear that these foodswill exacerbate symptoms.

Vitamin C in CDSeveral older studies focused on vitamin

C status in CD. A 1986 study of 137 patients withCD found low serum ascorbate levels in 11 per-cent of males and 37 percent of females; leuko-cyte ascorbate levels were low in 26 percent ofmales and 49 percent of females. The deficien-cies were not associated with disease activity. Inthis study the deficiencies were due in part to lowintake and were remedied by diet counseling.173Leukocyte ascorbate levels were found signifi-cantly lower than controls in two other stud-ies.174,175

Two studies examined ileal tissue levelsof vitamin C. The 1974 study found depressed tis-sue levels of ascorbate in CD patients with fistu-las compared to CD patients without fistulas orhealthy controls.176 The 1987 study found tissueascorbate levels higher in both fistulizing and non-fistulizing CD patients compared to controls.However, the levels in the patients with fistulaswere significantly lower than CD patients with-out fistulas. The authors speculate ascorbate isconcentrated in the tissues because of vitamin Csimportance in collagen formation. Those subjectto fistulas appear to be less efficient at mobilizing




ascorbate.177 One of the researchers conducted asubsequent study and found absorption of vitaminC was not impaired in either fistulizing or non-fistulizing CD patients compared to controls.178

Fat-Soluble Antioxidants: Vitamin A,Vitamin E, and Carotenoids

As mentioned previously, oxidative stressplays a significant role in the pathogenesis of CDand several antioxidants, including vitamins A andE, have been found to be low in CD patients. Stud-ies support the contention that vitamin E,179 vita-min A,180,181 and a combination of vitamins E andA,182 are low in CD patients. Low vitamin A ap-peared to be associated with low protein that con-tributes to a deficiency of retinol binding protein,181and both A and E were normalized when activedisease was brought under control.182

Carotenes, precursors to vitamin A, havebeen shown to be low in the CD population. A1987 study examining vitamin A/carotene levelsover a six-month period in 137 CD patients (70percent with inactive disease) found normal vita-min A status in all patients, while 20-25 percentof patients demonstrated low total serum caro-tenoids.183 A more recent study confirms low se-rum vitamin A and carotenoid (zeaxanthin, alpha-and beta-carotene, and lutein) levels in CD pa-tients compared to controls.184

Mineral DeficienciesZinc

Several studies note zinc deficiencies arecommon in CD. A study of 54 CD patients foundsignificant deficiencies in serum zinc, vitamin A,and retinol binding protein levels compared tohealthy controls. Zinc levels decreased in accor-dance with disease activity, patients with activedisease having significantly lower levels thanthose with inactive disease. Zinc deficiency is as-sociated with impaired metabolism of retinol bind-ing protein, resulting in a vitamin A deficiency.185

Other researchers have corroborated thetendency of zinc deficiency to parallel diseaseactivity in CD. A small study compared fivepatients with active CD to five patients withinactive disease and found serum zinc levels

significantly lower in those with active disease.Furthermore, low zinc levels seemed to be due toincreased body clearance, rather thanmalabsorption. Reasons for the increased zincclearance were not pursued.186

Another study found serum zinc levelsdeficient (defined as < 75 mcg/dL) in 17 of 50CD patients (34%). Low zinc levels were associ-ated with an increased tendency toward fistulaformation, with 65 percent (11/17) of CD patientswith low zinc levels experiencing fistula forma-tion.187 Thus, both low zinc and vitamin C levelshave been implicated in a tendency toward fistulaformation in CD patients.

Colonic mucosal biopsies of tissue fromCD patients found abnormally low levels of zincfrom uninflamed but not from inflamed tissue.188Increased levels in involved tissue may be due tothe need for more zinc as a co-factor for superox-ide dismutase.

Other Trace Mineral DeficienciesSerum levels of copper, zinc, and sele-

nium were examined in 47 CD patients and com-pared to 123 healthy controls. The patients hadsignificantly lower selenium and higher copperlevels than controls,189 supporting the premise ofincreased oxidative stress in the pathogenesis ofCD. There were no differences in serum zinc con-centrations between patients and controls. A simi-lar study examined children with Crohns disease(n=36) and found significantly lower levels ofselenium, copper, and zinc compared to controls.190

Iron Levels in CD: A Double-edgedSword

Iron deficiency is common in CD and isthought to be due to decreased dietary intake orchronic gastrointestinal bleeding. Lomer et al in-vestigated the seven-day diet diaries of 91 CDpatients in remission compared to 91 controls.Only 32 percent of CD patients compared to 42percent of controls consumed the recommendeddaily intake of iron. Patients tended to eat less fi-ber and iron-fortified cereal than controls.191




Supplementation with iron, however, maynot be a prudent recommendation in Crohnsdisease because it can exacerbate intestinal

inflammation and contribute to oxidative stress.While circulating iron may be decreased in patientswith IBD, mucosal levels may actually be

Table 6. Nutrient Deficiencies Associated with Crohns Disease

Nutrient

Vitamin A

Beta-carotene

Vitamin D

Vitamin E

Vitamin K

Vitamin C

Vitamin B1 (thiamine)Vitamin B2 (riboflavin)Vitamin B3 (niacin)Vitamin B12

Folic Acid

Biotin

Calcium

Magnesium

Iron

Zinc

Copper

Selenium

Daily Recommendation (adult)5,000-25,000 IU; not to exceed 7500 IU in pregnancy

25,000-100,000 natural mixed cis/trans beta-carotene

400-800 IU

400-800 IU

500 mcg-1 mg

500-1,000 mg

100 mg

100 mg

100 mg

1 mg

400-800 mcg

300 mcg-1 mg

1,000 mg

500 mg

Supplement with 50-75 mg daily well-absorbed form only if anemic; otherwise avoid supplementation

15-30 mg

Avoid unless supplementing with > 15 mg zinc for long period of time; then supplement with 1-2 mg

200-400 mcg

Status

Deficient

Deficient

Deficient

Deficient

Deficient

Deficient

Deficient

Deficient

Deficient

Deficient

Deficient

Deficient

Deficient

Deficient

Deficient in serum; elevated in gut mucosa

Deficient

Elevated

Deficient




increased.192 A small study examined the effect of120 mg/day ferrous fumarate in 10 patients withCD (eight with active disease; nine with irondeficiency anemia) compared to controls.Assessment after one week found eight of 10patients experienced gastrointestinal side effectsof diarrhea; the opposite effect occurred in thecontrol group fewer stools. Seven of 10 patientsexperienced increased abdominal pain and six of10 reported nausea, compared to none in thecontrol group. After one week of ferrous fumaratesupplementation, levels of reduced cysteine andglutathione (endogenous antioxidants) weresignificantly decreased in patients.193

Table 6 summarizes the nutrient deficien-cies associated with CD.

Due to extensive side effects associatedwith conventional medications and significantnutrient deficiencies in CD, the effort to maintainremission with dietary changes, nutrients, andbotanicals should be considered.

Dietary Interventions in CDPre-illness dietary habits may increase the

risk for developing Crohns disease in susceptibleindividuals.194 Research has demonstrated highsugar and carbohydrate intakes significantly im-pact the development of inflammatory bowel dis-ease. While researchers did not differentiate be-tween CD and UC, both di- and monosaccharideconsumption increased the risk of developing IBDin general.195 Sucrose was consistently associatedwith increased risk for IBD, and the trend was sta-tistically significant in CD patients. Patients withIBD had a significantly lower intake of fruit, fi-ber, and vegetables. Another study confirmed ahigher intake of total carbohydrates, starch, andrefined sugars in 104 patients, immediately priorto diagnosis of CD.196 A population-based, case-controlled Swedish study examining 152 CD casesfound a significant 3.4-fold increase in relative riskfor developing CD with consumption of fast food2-3 times weekly.197

Once Crohns disease has manifested,dietary disturbances result from significant lossof appetite and contribute to weight loss andnutrient deficiencies. Dietary rehabilitation of CD

patients depends on the extent of disease, presenceof intestinal stricturing, obstruction, or short bowel(due to surgery), and ability to consume foodorally.198 When strictures, obstruction, or shortbowel are present it may be necessary for thepatient to use enteral nutrition.

Enteral and Parenteral NutritionEnteral nutrition involves the provision of

liquid-formula diets by mouth or tube into thegastrointestinal tract.199 It is suggested that partialbowel rest, a restoration of nutritional status, anda reduction in immunological stimulation causedby whole protein can induce remission.

Parenteral nutrition, administering of nu-trients by a route other than the alimentary canal(e.g., intravenously, subcutaneously), is now sel-dom used for CD treatment, except in the mostextreme cases involving significant impairment ofabsorption or intestinal obstruction.200

Several diets of potential benefit to CDpatients are administered enterally, but all includeprotein, carbohydrates, electrolytes, vitamins, andminerals. In elemental diets the protein source isfrom amino acids or short-chain peptides; suchdiets were once considered the best form of en-teral feeding.201 Polymeric diets containing wholeprotein have a higher energy:osmolarity ratio thanelemental diets and have been shown to be espe-cially beneficial in treating children with CD.202Oligopeptide diets contain short-chain peptides of4-5 amino acids.203 Numerous studies have com-pared the benefits of enterally-fed elemental andpolymeric diets to steroid therapy for Crohns dis-ease (Table 7).204-209 The results are varied, withsome showing elemental diets superior to steroidsand vice versa. In general it can be concluded, atleast in the short-term, that an oral elemental dietis at least as effective as steroids in achieving ormaintaining remission of mild-to-moderately ac-tive CD in adults. Because of the potentially dev-astating effects of steroid therapy in growing chil-dren, enteral dietary therapy is almost always rec-ommended as a first-line treatment.210,211

In certain countries, epidemiological datashow an association between high dietary intakesof omega-6 polyunsaturated fatty acids (PUFAs)




and increased rates of Crohns disease.212 The roleof fatty acids in inflammation is well established andseveral studies have examined the therapeutic benefitof different types and amounts of dietary fat innutritional therapy. Fish oil studies are discussedbelow. Regarding other types of fats, researchindicates enteral feeds or other diets low in fat aremore effective in treating CD patients andmaintaining remission than diets high in fat.213 Thereis also some evidence that fat type can impact theeffectiveness of enteral nutrition. Due to its pro-inflammatory effect, high amounts of linoleic acid

(an omega-6 essential fatty acid) in an elemental dietwould be expected to show less benefit, a conclusionsupported by a meta-analysis conducted byMiddleton et al.214 Conversely, Gassull et al foundan enteral diet high in linoleic acid and low in oleicacid actually resulted in better patient remission rates(52%) than a high oleic acid/low linoleic acid diet(20%). The use of medium-chain triglycerides(MCTs) in varying amounts has also been studied.MCTs in enteral nutrition do not seem to show anydetriment or benefit over long-chain triglycerides,regardless of amount used.215

Table 7. Diet Therapies Compared to Steroid Medications in CD

First Author

Gonzalez-Hiux

Gorard

Malchow

OMorain

Riordan

Zoli

Study Duration

4 weeks

4 weeks

6 weeks

4 weeks

12 weeks

2 weeks

DietPatients

15

22

51

11

40

10

SteroidPatients

17

20

44

10

38

10

Diet

Polymeric Diet

Elemental Diet

Semi-elemental Diet

Elemental Diet

Elemental Diet

Elemental Diet

Steroid Dose

Prednisone70 mg/daywith tapering

Prednisolone52.5 mg/day with tapering

6-methyl Prednisolone48-12 mg/day (tapered)

Prednisolone 52.5 mg/day with tapering

Prednisolone 40 mg/day with tapering

Prednisolone 0.5 mg/kg/day

Results

12 of 15 diet patients achieved remission compared to 15 of 17 patients on steroids; relapse at one year = 66% in steroid patients versus 42% in diet patients.

Disease activity (SEM) decreased from 4.8 to 1.7 in diet patients vs. 5.3 to 1.9 in steroid patients.

32 of 44 patients on steroid therapy experienced decreased CDAI vs. 21 of 51 patients on dietary therapy.

Similar improvement in clinical score and ESR was experienced by both groups. Diet group showed more improvement in hemoglobin and albumin values. Diet group showed median remission length of 7.5 months vs. 3.8 months in steroid group. Relapse rate at 2 years was 79% for steroid group and 62% for diet group.

Diet group had significant improvements in CDAI, ESR, intestinal permeability, body mass index, and prealbumin levels. Steroid group improvements were noted in disease activity and fat free body mass.




Dietary FiberThe results of studies investigating the

beneficial effects of fiber in Crohns patients areinconclusive. In an Italian study, 70 CD patientswere randomly assigned to follow a low-residuediet or a normal Italian diet for 29 months. Nodifference in outcome was observed in the twogroups, and a lifting of dietary restrictions did notresult in symptom exacerbation.216 In a second,controlled trial in which 20 CD patients were givenan unrefined carbohydrate, fiber-rich diet or anexclusion diet (of foods they were intolerant to),70 percent (7 of 10) of patients on the exclusiondiet remained in remission for six months com-pared to zero percent (0 of 10) at six months onthe unrefined carbohydrate, fiber-rich diet.217

In one study, 162 patients with active CDwere assigned to a diet unrestricted in sugar andlow in fiber, and were compared to 190 active CDpatients given a low-sugar, high-fiber diet. Patientswere followed for approximately two years. As-sessment via history, physical exam, and labora-tory testing revealed no significant differencesbetween the two treatment groups, indicating thehigh-fiber diet did not benefit patients with activeCrohns.218 In another study 32 patients with CDwere placed on a fiber-rich diet in addition to con-ventional treatment. Another 32 matched CD pa-tients acted as controls and received no specificdietary instruction. After 52 months the treatmentgroup had significantly fewer and shorter hospi-talizations and required less intestinal surgery thanthe control group.219

Elimination DietsResearch on elimination diets in CD has

yielded inconclusive results. Elimination diets aredifficult to follow with high drop-out rates andpatients seem to have difficulty in identifyingfoods that trigger symptom exacerbation. Foodsensitivities often are not persistent and are diffi-cult to validate with subsequent blinded challenge.Remission rates in CD patients on elimination di-ets do not appear to be significantly better thanthose observed in patients on unrestricted diets.220

Probiotics in the Treatment of CDAlterations in the bacterial milieu of the

gut are common in Crohns disease. The use ofvarious probiotic bacteria to promote a balance ofappropriate intestinal flora has yielded mixed re-sults. Mechanisms associated with the beneficialeffects of probiotic therapy in CD include: (1) in-hibition of pathogenic bacteria via growth suppres-sion or epithelial binding;221 (2) improved epithe-lial and mucosal barrier function;222 and (3) alteredimmuno-regulation via stimulation of secretoryIgA or reduction in TNF-alpha.223,224

Saccharomyces boulardiiPlein et al demonstrated the efficacy of

Saccharomyces boulardii (Sb) in a randomized,double-blind, placebo-controlled study of 20 CDpatients. Patients were given 250 mg Sb threetimes daily for 10 weeks and evaluated via bowelmovement frequency and the CDAI index. Patientsreceiving Sb experienced a significant reductionin frequency of bowel movements (from 5.0 to3.3 per day) and CDAI index (193 to 107) by week10 of treatment.225

Another study utilizing Sb therapy in 32 CDpatients demonstrated a significant benefit of a com-bination of Sb and mesalamine compared tomesalamine alone. Relapse in the mesalamine-onlygroup was 37.5 percent at six months compared toonly 6.25 percent in the mesalamine-plus Sb group.226

E. coli (Nissle strain)Pathogenic E. coli that adhere to and in-

vade intestinal epithelial cells (IEC) have beenisolated from ileal lesions of Crohns patients.47Boudeau et al demonstrated the in vitro ability ofa non-pathogenic E. coli strain (Nissle 1917) toprevent pathogenic E. coli strains from adheringto and invading IEC. When IEC were co-infectedwith probiotic Nissle strain and pathogenic E. coli,the Nissle strain exhibited a dose- and time-de-pendent adhesion to IEC, which prevented adhe-sion of various pathogenic E. coli strains by 78.0-99.9 percent. When IEC were pre-incubated withNissle strain E. coli and pathogenic strains wereadded later, adhesion and invasion of pathogenicstrains was inhibited by 97.2-99.9 percent.221




Malchow et al conducted a double-blind,randomized, placebo-controlled trial investigatingthe efficacy of E. coli Nissle strain 1917 for in-ducing and maintaining remission in 28 patientswith colonic Crohns disease. Patients were ran-domized to either 60 mg prednisolone daily (witha standard tapering schedule) plus twice dailydoses of 2.5 x1010 probiotic Nissle strain E. coli(treatment group) or identical prednisolone therapyplus placebo (placebo group). The rate at whichremission was achieved was comparable in bothgroups (85.7% for treatment patients versus 91.7%for placebo patients), but only 33.3 percent of pa-tients in the E. coli treatment group relapsed atone year, compared to 63.6 percent in the placebogroup.227

Lactobacillus GGMalin et al investigated the effect of oral

Lactobacillus GG on the intestinal immunologi-cal barrier in a small study of 14 children withCD and seven control patients (hospitalized for

investigation of abdominal pain but with no evi-dence of intestinal disease). Lactobacillus GG wasadministered to patients and controls at 1010 colonyforming units mixed in liquid twice daily. Lacto-bacillus GG therapy significantly increased theIgA immune response in Crohns patients com-pared to controls, resulting in an improved mu-cosal barrier.223

Another study of Lactobacillus GG dem-onstrated that administration in children with mild-to-moderate stable CD improved gut barrier func-tion and clinical status after six months oftherapy.228 However, a randomized, double-blind,placebo-controlled trial of 45 post-surgery Crohnspatients given Lactobacillus GG for one year didnot show it to be more effective than placebo inpreventing disease recurrence.229

Antioxidants in CD TreatmentAs discussed previously, oxidative stress

is one of the pathogenic mechanisms involved inthe intestinal damage of CD. Figure 1 illustrates

Figure 1. Endogenous Neutralization of Free Radicals

Step 1. Superoxide anion(O2-)

Step 2.

or

Step 2.

Hydrogen Peroxide(H2O2)

Hydrogen Peroxide

Superoxide dismutase

(Mn, Cu, or Zn dependent)

Catalase or

Glutathione PeroxidaseWater(H2O)

if poorly metabolized

orMyeloperoxidase (MPO)

Metallothionein (MT)(scavenges OH-)

Hydroxyl radical(OH-)

Hypochlorous acid(OHCL)

This latter occurs if H2O2 formation exceeds its metabolism.

Hydrogen Peroxide(H2O2)




normal and deranged endogenous responses. Astudy examined mucosal tissue SOD levels andfound manganese-dependent SOD (Mn-SOD) wassignificantly higher in IBD patients, includingthose with CD 1.6-fold higher in non-inflamedtissue and almost 3-fold higher in inflamed tis-sue.230 These same researchers, in a follow-upstudy, found metallothionein levels were signifi-cantly lower in inflamed mucosa from C

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