Inflammatory bowel disease
|Inflammatory bowel diseases|
|Classification and external resources|
|eMedicine||med/1169 emerg/106 oph/520|
The inflammatory bowel disease (IBD) is a group of inflammatory conditions of the colon and small intestine. Crohn's disease and ulcerative colitis are the principal types of inflammatory bowel disease. It is important to note that not only does Crohn's disease affect the small intestine and large intestine, it can also affect the mouth, oesophagus, stomach and the anus.
The chief types of inflammatory bowel disease are Crohn's disease and ulcerative colitis (UC). Inflammatory bowel diseases fall into the class of autoimmune diseases, in which the body's own immune system attacks elements of the digestive system.
Accounting for far fewer cases are other forms of IBD, which are not always classified as typical IBD:
The way doctors can tell the difference between Crohn's disease and UC is the location and nature of the inflammatory changes. Crohn's can affect any part of the gastrointestinal tract, from mouth to anus (skip lesions), although a majority of the cases start in the terminal ileum. Ulcerative colitis, in contrast, is restricted to the colon and the rectum. Microscopically, ulcerative colitis is restricted to the mucosa (epithelial lining of the gut), while Crohn's disease affects the full thickness of the bowel wall ("transmural lesions").
Lastly, Crohn's disease and ulcerative colitis present with extra-intestinal manifestations (such as liver problems, arthritis, skin manifestations and eye problems) in different proportions.
Rarely, a definitive diagnosis neither of Crohn's disease nor of ulcerative colitis can be made because of idiosyncrasies in the presentation. In this case, a diagnosis of indeterminate colitis may be made. Although a recognised definition, not all centres refer to this.
Signs and symptoms
|Crohn's disease||Ulcerative colitis|
and with blood
|Tenesmus||Less common||More common|
|Fever||Common||Indicates severe disease|
|Weight loss||Often||More seldom|
In spite of Crohn's and UC being very different diseases, both may present with any of the following symptoms: abdominal pain, vomiting, diarrhea, rectal bleeding, severe internal cramps/muscle spasms in the region of the pelvis and weight loss. Anemia is the most prevalent extraintestinal complication of inflammatory bowel disease. Associated complaints or diseases include arthritis, pyoderma gangrenosum, primary sclerosing cholangitis, and non-thyroidal illness syndrome (NTIS). Associations with Deep vein thrombosis (DVT) and Bronchiolitis obliterans organizing pneumonia (BOOP) have also been reported. Diagnosis is generally by assessment of inflammatory markers in stool followed by colonoscopy with biopsy of pathological lesions.
||Crohn's disease||Ulcerative colitis|
|Terminal ileum involvement||Commonly||Seldom|
|Bile duct involvement||No increase in rate of primary sclerosing cholangitis||Higher rate|
|Distribution of Disease||Patchy areas of inflammation (Skip lesions)||Continuous area of inflammation|
|Endoscopy||Deep geographic and serpiginous (snake-like) ulcers||Continuous ulcer|
|Depth of inflammation||May be transmural, deep into tissues||Shallow, mucosal|
|Granulomas on biopsy||May have non-necrotizing non-peri-intestinal crypt granulomas||Non-peri-intestinal crypt granulomas not seen|
|Crohn's disease||Ulcerative colitis|
|Cytokine response||Associated with Th17||Vaguely associated with Th2|
IBD is a complex disease which arises as a result of the interaction of environmental and genetic factors. It is increasingly thought that alterations to enteral bacteria can contribute to inflammatory gut diseases IBD affected individuals have been found to have 30-50 percent reduced biodiversity of commensalism bacteria such as a decrease in Firmicutes (namely Lachnospiraceae) and Bacteroidetes. Further evidence of the role of gut flora in the cause of inflammatory bowel disease is that IBD affected individuals are more likely to have been prescribed antibiotics in the 2-5 year period before their diagnosis than unaffected individuals. The enteral bacteria can be altered by environmental factors, such as Concentrated milk fats (a common ingredient of processed foods and confectionery) or oral medications such as antibiotics and oral iron preparations.
The genetic contribution is poorly understood and seems to arise from the small contribution of dozens of genes. In 2012 163 IBD susceptibility loci were confirmed which means that 163 alleles that can increase the susceptibility to the disease. These 163 loci explain from an 8.2% to a 13.6% of variance in Crohn’s disease and 4.1% to 7.5% in ulcerative colitis.
The 163 loci were related with 300 known genes. The functional enrichment analysis of this group of genes using Gene Ontology showed that there are many genes related with cytokine production, lymphocyte activation and the response to bacterial infection. In an effort to identify likely causal genes a probabilistic causal gene network was constructed. Here a sub-network including NOD2, Il10 and CARD9 seems to indicate a close relationship between IBD and genes related with host interaction with bacteria. Of particular relevance is the presence of the gene HCK which seems to play an important role anti-inflammation. In the figure beside there is a NOD2-focused cluster in the causal gene sub-network.
|Crohn's disease||Ulcerative colitis|
|Mesalazine||Less useful||More useful|
|Antibiotics||Effective in long-term||Generally not useful|
|Surgery||Often returns following
removal of affected part
|Usually cured by removal
CD and UC are inflammatory diseases, and are not medically curable. Surgery can essentially cure ulcerative colitis if the large intestine is removed (though medical treatment and endoscopic surveillance may be necessary if a stump of rectum is left behind). A jpouch can be created from the small intestine, this serves as the rectum and prevents the need for a permanent ileostomy. Further complications can arise with a jpouch in the form of pouchitis which manifests itself by symptoms, somewhat similar to UC. Surgery cannot cure Crohn's disease.
Medical treatment of IBD is individualized to each patient. The choice of which drugs to use and by which route to administer them (oral, rectal, injection, infusion) depends on factors including the type, distribution, and severity of the patient's disease, as well as other historical and biochemical prognostic factors, and patient preferences. For example, mesalazine is more useful in ulcerative colitis than in Crohn's disease. Generally, depending on the level of severity, IBD may require immunosuppression to control the symptom, such as prednisone, TNF inhibition, azathioprine (Imuran), methotrexate, or 6-mercaptopurine.
Often, anti-inflammatory steroids are used to control disease flares and were once acceptable as a maintenance drug. In use for several years in Crohn's disease patients and recently in patients with ulcerative colitis, biologicals have been used such as TNF inhibitors. Severe cases may require surgery, such as bowel resection, strictureplasty or a temporary or permanent colostomy or ileostomy. Ulcerative colitis can be cured by removing the entire large intestine and the rectum, and while this cannot get rid of extra-intestinal symptoms, the disease cannot recur without a large intestine. In Crohn's disease, surgery involves removing the worst inflamed segments of the intestine and connecting the healthy regions, but unfortunately, it does not cure Crohn's or eliminate the disease, as at some point after the first surgery, Crohn's disease recurs in the healthy parts of the intestine, usually at the resection site. (For example, if a patient with Crohn's disease has an ileocecal anastomosis, in which the caecum and terminal ileum are removed and the ileum is joined to the ascending colon, their Crohn's will nearly always flare-up near the anastomosis or in the rest of the ascending colon).
Usually the treatment is started by administering drugs with high anti-inflammatory effects, such as prednisone. Once the inflammation is successfully controlled, the patient is usually switched to a lighter drug to keep the disease in remission, such as Asacol, a mesalazine. If unsuccessful, a combination of the aforementioned immunosuppression drugs with a mesalazine (which may also have an anti-inflammatory effect) may or may not be administered, depending on the patient. Budesonide is the easiest medication for the elderly and children.
A relatively new treatment option is fecal bacteriotherapy (FBT), which has been used to successfully treat IBD in several small studies. There is evidence from case series of patients with ulcerative colitis responding favourably to fecal microbiota transplant with cure or significant remission persisting for up to 13 years post treatment. Individuals whose onset of ulcerative colitis is associated with antibiotic use or colonic infection are the most likely to benefit from fecal microbiota transplant.
There is evidence of an infections contribution to inflammatory bowel disease in some patients and this subgroup of patients may benefit from antibiotic therapy. Anaemia is a common finding in both ulcerative colitis and Crohn's disease. Due to raised levels of inflammatory cytokines which lead to the increased expression of hepcidin, parenteral iron is the preferred treatment option as it bypasses the gastrointestinal system, has lower incidence of adverse events and enables quicker treatment. Hepcidin itself is also an anti-inflammatory agent. In the murine model very low levels of iron restrict hepcidin synthesis, worsening the inflammation that is present. Enteral nutrition has been found to be efficient to improve hemoglobin level in patients with inflammatory bowel disease, especially combined with erythropoietin.
Due to the fact that the disease might be triggered by the blooms of a rare type of gut bacteria some anti-bacterial drugs like chloroxine might be able to dispense the problem. A wider study is needed to confirm this.
|Nutrient deficiency||Higher risk|
|Colon cancer risk||Slight||Considerable|
|Prevalence of extraintestinal complications|
While IBD can limit quality of life because of pain, vomiting, diarrhea, and other socially undesired symptoms, it is rarely fatal on its own. Fatalities due to complications such as toxic megacolon, bowel perforation and surgical complications are also rare.
While patients of IBD do have an increased risk of colorectal cancer, this is usually caught much earlier than the general population in routine surveillance of the colon by colonoscopy, and therefore patients are much more likely to survive.
A recent literature review by Gandhi et al. described that IBD patients over the age of 65 and females are at increased risk of coronary artery disease despite the lack of traditional risk factors.
The goal of treatment is toward achieving remission, after which the patient is usually switched to a lighter drug with fewer potential side effects. Every so often, an acute resurgence of the original symptoms may appear; this is known as a "flare-up". Depending on the circumstances, it may go away on its own or require medication. The time between flare-ups may be anywhere from weeks to years, and varies wildly between patients - a few have never experienced a flare-up.
Life with IBD can be challenging, however, it should not impede your ability to live a normal life. Patients with IBD can go to college, hold a normal job, get married, have children etc. As is the nature of any chronic, unpredictable disease, there will be ups and downs. The progress made in IBD research and treatment is astounding and will only improve in the years to come.
Although living with IBD can be difficult, there are numerous resources available to help families navigate the ins and out of IBD. The Crohn's and Colitis Foundation of America (CCFA) is an excellent resource. CCFA is a vital resource to getting questions answered and finding support about life with IBD.
Globally, as of 2010, IBD resulted in 34,000 deaths.
The following treatment strategies are not used routinely, but appear promising in most forms of inflammatory bowel disease.
Initial reports suggest that "helminthic therapy" may not only prevent but even control IBD: a drink with roughly 2,500 ova of the Trichuris suis helminth taken twice monthly decreased symptoms markedly in many patients. It is even speculated that an effective "immunization" procedure could be developed—by ingesting the cocktail at an early age.
In 2005 New Scientist published a joint study by Bristol University and the University of Bath on the apparent healing power of cannabis on IBD. Reports that cannabis eased IBD symptoms indicated the possible existence of cannabinoid receptors in the intestinal lining, which respond to molecules in the plant-derived chemicals. CB1 cannabinoid receptors – which are known to be present in the brain – exist in the endothelial cells which line the gut, it is thought that they are involved in repairing the lining of the gut when damaged.
The team deliberately damaged the cells to cause inflammation of the gut lining and then added synthetically produced cannabinoids; the result was that gut started to heal: the broken cells were repaired and brought back closer together to mend the tears. It is believed that in a healthy gut, natural endogenous cannabinoids are released from endothelial cells when they are injured, which then bind to the CB1 receptors. The process appears to set off a wound-healing reaction, and when people use cannabis, the cannabinoids bind to these receptors in the same way.
Previous studies have shown that CB1 receptors located on the nerve cells in the gut respond to cannabinoids by slowing gut motility, therefore reducing the painful muscle contractions associated with diarrhea. The team also discovered another cannabinoid receptor, CB2, in the guts of IBD sufferers, which was not present in healthy guts. These receptors, which also respond to chemicals in cannabis, appear to be associated with apoptosis – programmed cell death – and may have a role in suppressing the overactive immune system and reducing inflammation by mopping up excess cells.
Alicaforsen is a first generation antisense oligodeoxynucleotide designed to bind specifically to the human ICAM-1 messenger RNA through Watson-Crick base pair interactions in order to subdue expression of ICAM-1. ICAM-1 propagates an inflammatory response promoting the extravasation and activation of leukocytes (white blood cells) into inflamed tissue. Increased expression of ICAM-1 has been observed within the inflamed intestinal mucosa of ulcerative colitis, pouchitis and Crohn's sufferers where ICAM-1 over production correlated with disease activity. This suggests that ICAM-1 is a potential therapeutic target in the treatment of these diseases.
In 2014, an alliance among the Broad Institute, Amgen and Massachusetts General Hospital formed with the intention to "collect and analyze patient DNA samples to identify and further validate genetic targets."
- Baumgart DC, Carding SR (2007). "Inflammatory bowel disease: cause and immunobiology.". The Lancet 369 (9573): 1627–40. doi:10.1016/S0140-6736(07)60750-8. PMID 17499605.
- Baumgart DC, Sandborn WJ (2007). "Inflammatory bowel disease: clinical aspects and established and evolving therapies.". The Lancet 369 (9573): 1641–57. doi:10.1016/S0140-6736(07)60751-X. PMID 17499606.
- Xavier RJ, Podolsky DK (2007). "Unravelling the pathogenesis of inflammatory bowel disease.". Nature 448 (7152): 427–34. doi:10.1038/nature06005. PMID 17653185.
- "IBD Facts".
- "Crohn's & Colitis Foundation of America".
- internetmedicin.se > Inflammatorisk tarmsjukdom, kronisk, IBD By Robert Löfberg. Retrieved Oct 2010 Translate.
- Hanauer SB, Sandborn W (2001-03-01). "Management of Crohn's disease in adults" (PDF). American Journal of Gastroenterology 96 (3): 635–43. doi:10.1111/j.1572-0241.2001.03671.x. PMID 11280528. Retrieved 2009-11-07.
- Wang GF, Ren JA, Liu S, Chen J, Gu GS, Wang XB, Fan CG, Li JS (July 2012). "Clinical characteristics of non-perianal fistulating Crohn's disease in China: a single-center experience of 184 cases.". Chinese medical journal 125 (14): 2405–10. PMID 22882911.
- Stein J, Hartmann F, Dignass AU (2010). "Diagnosis and management of iron deficiency anemia in patients with IBD". Nature Reviews Gastroenterology & Hepatology 7 (11): 599–610. doi:10.1038/nrgastro.2010.151. PMID 20924367.
- Liu S, Ren J, Zhao Y, Han G, Hong Z, Yan D, Chen J, Gu G, Wang G, Wang X, Fan C, Li J (February 2013). "Nonthyroidal illness syndrome: is it far away from Crohn's disease?". Journal of Clinical Gastroenterology 47 (2): 153–9. doi:10.1097/MCG.0b013e318254ea8a. PMID 22874844.
- Warner, Jennifer (February 22, 2011). Martin, Laura J., ed. "Inflammatory Bowel Disease Health Center". WebMD. Retrieved 14 October 2014.
- Kornbluth A, Sachar DB (July 2004). "Ulcerative colitis practice guidelines in adults (update): American College of Gastroenterology, Practice Parameters Committee". American Journal of Gastroenterology 99 (7): 1371–85. doi:10.1111/j.1572-0241.2004.40036.x. PMID 15233681. Archived from the original on April 6, 2008. Retrieved 2009-11-07.
- Broomé U, Bergquist A (February 2006). "Primary sclerosing cholangitis, inflammatory bowel disease, and colon cancer". Seminars in Liver Disease 26 (1): 31–41. doi:10.1055/s-2006-933561. PMID 16496231.
- Shepherd NA (August 2002). "Granulomas in the diagnosis of intestinal Crohn's disease: a myth exploded?". Histopathology 41 (2): 166–8. doi:10.1046/j.1365-2559.2002.01441.x. PMID 12147095.
- Mahadeva U, Martin JP, Patel NK, Price AB (July 2002). "Granulomatous ulcerative colitis: a re-appraisal of the mucosal granuloma in the distinction of Crohn's disease from ulcerative colitis". Histopathology 41 (1): 50–5. doi:10.1046/j.1365-2559.2002.01416.x. PMID 12121237.
- Elson CO, Cong Y, Weaver CT, Schoeb TR, McClanahan TK, Fick RB, Kastelein RA (2007). "Monoclonal anti-interleukin 23 reverses active colitis in a T cell-mediated model in mice". Gastroenterology 132 (7): 2359–70. doi:10.1053/j.gastro.2007.03.104. PMID 17570211.
- Andy Coghlan (2012). "Milk fats clue to inflammatory bowel disease". New Scientist.
- Mukhopadhya I, Hansen R, El-Omar EM, Hold GL (20 February 2012). "IBD—what role do Proteobacteria play?". Nature Reviews Gastroenterology & Hepatology 9 (4): 219–230. doi:10.1038/nrgastro.2012.14. PMID 22349170.
- Aroniadis OC, Brandt LJ (January 2013). "Fecal microbiota transplantation: past, present and future". Curr. Opin. Gastroenterol. 29 (1): 79–84. doi:10.1097/MOG.0b013e32835a4b3e. PMID 23041678.
- Kotanko P, Carter M, Levin NW (August 2006). "Intestinal bacterial microflora-a potential source of chronic inflammation in patients with chronic kidney disease". Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association 21 (8): 2057–60. doi:10.1093/ndt/gfl281. PMID 16762961.
- Jostins L, Ripke S, Weersma RK, Duerr RH, McGovern DP, Hui KY, et al. (Nov 1, 2012). "Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease". Nature 491 (7422): 119–24. doi:10.1038/nature11582. PMC 3491803. PMID 23128233.
- Henderson, P; Anderson, NH; Wilson, DC (May 2014). "The diagnostic accuracy of fecal calprotectin during the investigation of suspected pediatric inflammatory bowel disease: a systematic review and meta-analysis.". The American journal of gastroenterology 109 (5): 637–45. doi:10.1038/ajg.2013.131. PMID 23670113.
- Pages 152-156 (Section: Inflammatory bowel disease(IBD)) in: Elizabeth D Agabegi; Agabegi, Steven S. (2008). Step-Up to Medicine (Step-Up Series). Hagerstwon, MD: Lippincott Williams & Wilkins. ISBN 0-7817-7153-6.
- Feller M, Huwiler K, Schoepfer A, Shang A, Furrer H, Egger M (2010). "Long-term antibiotic treatment for Crohn's disease: systematic review and meta-analysis of placebo-controlled trials". Clin. Infect. Dis. 50 (4): 473–80. doi:10.1086/649923. PMID 20067425.
-  Section "Antibiotics and Ulcerative Colitis" in: Prantera C, Scribano ML (2009). "Antibiotics and probiotics in inflammatory bowel disease: why, when, and how". Curr. Opin. Gastroenterol. 25 (4): 329–33. doi:10.1097/MOG.0b013e32832b20bf. PMID 19444096.
- Fecal Microbiota Transplants Effective Treatment for C. Difficile, Inflammatory Bowel Disease, Research Finds
- Borody TJ, Torres M, Campbell J, Leis S, Nowak N (2011). "Reversal of inflammatory bowel disease (IBD) with recurrent fecal microbiota transplants (FMT)". Am J Gastroenterol (Abstracts Submitted for the 76th Annual Scientific Meeting of the American College of Gastroenterology, Washington, DC, October 28 - November 2, 2011) 106: S366, abstract 979.
- Ohkusa T, Sato N (March 2005). "Antibacterial and antimycobacterial treatment for inflammatory bowel disease". J. Gastroenterol. Hepatol. 20 (3): 340–51. doi:10.1111/j.1440-1746.2004.03472.x. PMID 15740475.
- Pagani A, Nai A, Corna G, Bosurgi L, Rovere-Querini P, Camaschella C, Silvestri L (July 2011). "Low hepcidin accounts for the proinflammatory status associated with iron deficiency". Blood 118 (3): 736–46. doi:10.1182/blood-2011-02-337212. PMID 21628413.
- Liu S, Ren J, Hong Z, Yan D, Gu G, Han G, Wang G, Ren H, Chen J, Li J (February 2013). "Efficacy of erythropoietin combined with enteral nutrition for the treatment of anemia in Crohn's disease: a prospective cohort study". Nutrition in clinical practice : official publication of the American Society for Parenteral and Enteral Nutrition 28 (1): 120–7. doi:10.1177/0884533612462744. PMID 23064018.
- "Research Supports Promise of Cell Therapy for Bowel Disease". Wake Forest Baptist Medical Center. 28 February 2013. Retrieved 5 March 2013.
- Greenstein AJ, Janowitz HD, Sachar DB (September 1976). "The extra-intestinal complications of Crohn's disease and ulcerative colitis: a study of 700 patients". Medicine (Baltimore) 55 (5): 401–12. doi:10.1097/00005792-197609000-00004. PMID 957999.
- Roifman I, Sun YC, Fedwick JP, Panaccione R, Buret AG, Liu H, Rostom A, Anderson TJ, Beck PL (February 2009). "Evidence of endothelial dysfunction in patients with inflammatory bowel disease". Clin. Gastroenterol. Hepatol. 7 (2): 175–82. doi:10.1016/j.cgh.2008.10.021. PMID 19121648. Retrieved 2013-09-14.
- Gandhi S, Narula N, Marshall JK, Farkouh M (1 October 2012). "Are Patients with Inflammatory Bowel Disease at Increased Risk of Coronary Artery Disease?". The American Journal of Medicine 125 (10): 956–962. doi:10.1016/j.amjmed.2012.03.015. PMID 22840916.
- Lozano R, Naghavi M, Foreman K, Lim S, Shibuya K, Aboyans V, et al. (Dec 15, 2012). "Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the Global Burden of Disease Study 2010". Lancet 380 (9859): 2095–128. doi:10.1016/S0140-6736(12)61728-0. PMID 23245604.
- Summers RW, Elliott DE, Qadir K, Urban JF, Thompson R, Weinstock JV (2003). "Trichuris suis seems to be safe and possibly effective in the treatment of inflammatory bowel disease". Am. J. Gastroenterol. 98 (9): 2034–41. doi:10.1111/j.1572-0241.2003.07660.x. PMID 14499784.
- Furrie E, Macfarlane S, Kennedy A, Cummings JH, Walsh SV, O'neil DA, Macfarlane GT (2005). "Synbiotic therapy (Bifidobacterium longum/Synergy 1) initiates resolution of inflammation in patients with active ulcerative colitis: a randomised controlled pilot trial". Gut 54 (2): 242–9. doi:10.1136/gut.2004.044834. PMC 1774839. PMID 15647189.
- Kruis W, Fric P, Pokrotnieks J, Lukás M, Fixa B, Kascák M, Kamm MA, Weismueller J, Beglinger C, Stolte M, Wolff C, Schulze J (2004). "Maintaining remission of ulcerative colitis with the probiotic Escherichia coli Nissle 1917 is as effective as with standard mesalazine". Gut 53 (11): 1617–23. doi:10.1136/gut.2003.037747. PMC 1774300. PMID 15479682.
- Wright K, Rooney N, Feeney M, Tate J, Robertson D, Welham M, Ward S (2005). "Differential expression of cannabinoid receptors in the human colon: cannabinoids promote epithelial wound healing". Gastroenterology 129 (2): 437–53. doi:10.1053/j.gastro.2005.05.026. PMID 16083701.
- Bennett CF, Condon TP, Grimm S, Chan H, Chiang MY (April 1994). "Inhibition of endothelial cell adhesion molecule expression with antisense oligonucleotides". J. Immunol. 152 (7): 3530–40. PMID 7511650.
- Jones SC, Banks RE, Haidar A, Gearing AJ, Hemingway IK, Ibbotson SH, Dixon MF, Axon AT (1995). "Adhesion molecules in inflammatory bowel disease". Gut 36 (5): 724–30. doi:10.1136/gut.36.5.724. PMC 1382677. PMID 7541009.
- van Deventer SJ, Wedel MK, Baker BF, Xia S, Chuang E, Miner PB (2006). "A Phase II dose ranging, double-blind, placebo-controlled study of alicaforsen enema in subjects with acute exacerbation of mild to moderate left-sided ulcerative colitis". Alimentary Pharmacology & Therapeutics 23 (10): 1415–25. doi:10.1111/j.1365-2036.2006.02910.x. PMID 16669956.
- Thomas S, Baumgart DC (2012). "Targeting leukocyte migration and adhesion in Crohn's disease and ulcerative colitis". Inflammopharmacology 20 (1): 1–18. doi:10.1007/s10787-011-0104-6. PMID 22205271.
- "Amgen, MGH, Broad form IBD Therapeutics Initiative". News: Discovery & Development. Gen. Eng. Biotechnol. News (paper) 34 (4). p. 14.