Ⅵ Gastrointestinal Diseases

Disease of the Small Intestine

JMAJ 47(10): 462–467, 2004

Hiroaki TAKEDA

Associate Professor, Division of Endoscopy, Yamagata University School of Medicine

Abstract: Recent information on the small intestine is summarized. Concerning digestion and absorption, ␣-glycosidase inhibitor, which slows the absorption of carbohydrate, has become commercially available as a diabetic drug, and a number of transporters, such as peptide transporter (PepT1) that is involved in the efficient absorption of nitrogen source as well as drug absorption, have been discovered. In addition, a group of growth factors that are involved in the formation and regeneration of the small intestine have been found, and the importance of intraepithelial lymphocytes and glutamine has become known. In addition, the possibility that cells derived from the bone marrow might behave as a part of the epithelium of the digestive tract has been reported and has gained interest. Concerning intestinal motility, progress has been made in the analysis of interstitial cells of Cajal and various neurotransmitters. C-kit-positive stromal tumors were thoroughly investigated. The concept of GIST has been established and imatinib therapy for GIST has already begun. Although there is room for improvement in enteroscopy, is useful in the diagnosis of small intestinal diseases. The advance- ment of technology including virtual endoscopy is expected. In the area of surgery, the spread of laparoscopic surgeries as a minimally invasive approach has been marked. Key words: Peptide transporter; Stem cells; Gastrointestinal stromal tumor (GIST); Enteroscopy; CT

Introduction with the autonomic nerves and endocrine system. However, it is also an organ where a The small intestine, which plays a role in the direct approach such as endoscopy is difficult. absorption of nutrients that are essential to Recent information on the small intestine, maintain life, is an important immune organ that has been summarized firstly in terms of basic serves as a barrier against foreign antigens, and research and secondly in terms of clinical its functions are while intricately interrelated research.

This article is a revised English version of a paper originally published in the Journal of the Japan Medical Association (Vol. 129, No. 4, 2003, pages 460–464). The Japanese text is a transcript of a lecture originally aired on November 6, 2002, by the Nihon Shortwave Broadcasting Co., Ltd., in its regular program “Special Course in Medicine”.

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Basic Research transporters are mostly specific to the small intestine. It has become evident that various 1. Digestion and absorption transcription factors such as Cdx2 are involved Food is degraded into glucose, amino acids, in the phenotypic expression specific to the and others by digestive enzymes, and it is small intestine. Small intestinal epithelium finally absorbed into the body through the differentiates from stem cells that exist near villous epithelium in the small intestine. Carbo- the bottom of the intestinal crypt, and the hydrate is hydrolyzed by ␣-glycosidase during entire villus is thus formed through the matu- the membrane digestion. The ␣-glycosidase ration process of these cells. However, the inhibitor, which slows the hydrolysis of carbo- mechanism by which the small intestinal hydrate, is presently used in the treatment of mucosa acquires properties specific to the small diabetes, because it prevents the blood glucose intestine, is not yet clearly understood. This is level from rapidly increasing. one of the major research themes today. In addition to simple diffusion, various In addition to transcription factors, various substrate-specific transporters are also em- growth factors such as epidermal growth factor ployed in the absorption process of each nutri- (EGF) and insulin-like growth factor-1 (IGF-1) ent from the villous epithelium into the body are involved in this process. Among such efficiently. Thus far, a number of transpor- growth factors, glucagon-like peptide-2 (GLP-2) ters such as sodium-glucose cotransporters in particular has drawn attention because its (SGLT1), glucose transporters (GLUT2) that strong action for mucosa proliferation action function by facilitated diffusion, transporters has been proven through experiments.2) More- of various amino acids, and sodium-dependent over, stimulation by foreign antigens that has bile acid transporters (BAT) have been entered from the mouth and the presence of reported, and their properties are being intraepithelial lymphocytes are also factors revealed at a molecular biological level. Con- that cannot be ignored in the formation of cerning absorption of nitrogen sources, the mucosa. functions and regulation of peptide trans- In fact, the number of intraepithelial lym- porters (PepT1), which can absorb nitrogen phocyte count in the small intestinal mucosa sources in the form of oligopeptides, have decreases over a short period in patients who become clear. PepT1 is known to have unique receive parenteral nutrition, followed by a characteristics, such as maintaining its func- decrease in secretory IgA and finally causing tions even in various pathological conditions villous atrophy. This induces bacterial trans- and being involved in the absorption of some location and increases the patient’s suscepti- antibiotics. bility to serious infections. To prevent such More recently, monocarboxylic acid trans- villous atrophy and infections, administering porter (MCT1) and non-sodium-dependent glutamine and dietary fibers are effective. organic anion transporters (OATP) have been With regard to differentiation and prolifera- newly discovered, and it is expected that many tion of mucosa, one recent report concerning more transporters will be revealed in the the regeneration of the intestinal tract was future. These transporters may be applied not particularly noteworthy. The report showed only to absorption of nutrients but also to that bone-marrow-derived cells might serve as drug delivery.1) stem cells for gastrointestinal mucosa when gastrointestinal mucosa has been seriously 2. Process of villus formation and damaged.3) Since intestinal disorders caused by regeneration of mucosa radiotherapy and carcinostatics often make As mentioned above, expression of nutrient treatment difficult to continue, exploring

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methods that can be used not only to prevent Clinical Research mucosal disorders but also to rapidly repair and regenerate mucosa is a very important 1. Enteral nutrition and project from a clinical standpoint. home parenteral nutrition The number of patients with severe mal- 3. Gastrointestinal motility and absorption due to short-bowel syndrome and autonomic nerves Crohn’s disease is increasing each year. In The small intestine transports food by peri- Japan, nutritional management using enteral staltic movement, which is appropriately regu- nutrition is the first choice followed by home lated according to hunger, the ingestion of parenteral nutrition (HPN). food, and other conditions. While it is known According to a survey done by an HPN that sympathetic nerves (noradrengic) and Research Group, 149 out of 355 patients were parasympathetic nerves (cholinergic) serve as given HPN each year due to a benign disease. It autonomic nerves associated with gastro- is striking that the majority of these patients, intestinal motility, the mechanisms of intestinal (132 cases) are able to return to work or to live motility are also becoming more clearly under- at home because of HPN, which confirms the stood. In particular, a nervous system that is benefits derived from HPN.4) operated by nonadrenergic and noncholinergic In contrast, due to the patients who require transmitters has been found in the intestinal nutritional management by enteral nutrition wall. and HPN over one year, new problems Specifically, there is a nervous system that concerning vitamins and trace elements have is sensitive to various substances including surfaced. For example, well-known trace ele- vasoactive intestinal poly-peptide (VIP), nitric ment deficiencies such as copper deficiency and oxide (NO), 5-hydroxytryptamine (5-HT), and selenium deficiency cause anemia and heart calcitonin gene-related peptide (CGRP), and dysfunction, respectively. Conversely, the excess each of these substances is closely involved in manganese has become a problem, as studies regulating gastrointestinal motility and secre- have shown that manganese is deposited in the tion. The actions of 5-HT (serotonin) for secre- brain. Effective management methods of trace tion have drawn attention thus far, and it is elements that do not cause deficiency or excess thought that changes in the sensitivity to 5-HT must be established through prescriptions and may cause abnormal intestinal motility. over-the-counter supplements of trace elements.

Although 5-HT3 receptor antagonists have already been put to clinical use as antiemetics 2. Tumors of the small intestine for chemotherapy, a clinical attempt has been Neoplastic diseases in the small intestine are made to use them for diarrhea-type irritable not very common. In general, non-epithelial bowel syndrome based on the idea that they tumors are more common than epithelial suppress intestinal motility. It is also becoming tumors. Recently, new information on stromal- clear that peristaltic movement of the digestive cell-derived tumors has become available. tract is regulated by the motilin level during Conventionally, it has been thought that hunger. The cause is still unknown as for intes- stroma-derived tumors were mostly leiomyoma tinal pseudo-obstruction, which makes food or leiomyosarcoma, and tumors originating intake impossible due to a marked decrease in from the nervous system were distinguished intestinal motility, but a marked decrease in by immunostaining. Recently, however, the interstitial cells of Cajal has been reported in tumor originating from interstitial cells of Cajal some patients. has drawn attention. This tumor has been narrowly defined as a gastrointestinal stromal

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Table 1 Immunohistological Diagnosis of become an imaging method that is very easy to Gastrointestinal Stromal Tumors use. Although there was a tendency to shun overdependence on CT, the situation seems to (ם) GIST c-kit have somewhat changed with the appearance (ם) desmin ,(ם) SMA ,(מ) Leiomyoma c-kit of helical CT, and CT is now viewed essential in (ם) S-100 ,(מ) Neurogenic tumor c-kit (SMA: smooth muscle actin) acute abdomen examinations. (Excerpt from Fletcher, C.D. et al.: Hum Pathol 2002; 33: Contrast-enhanced CT is the first-line test 459Ð465) for ileus, which is a disease that is encountered on a daily basis, and location of obstruction, degree of obstruction, and condition of intes- tumor (GIST). tinal ischemia can be grasped by CT. Makita, Interstitial cells of Cajal, which are dis- et al., have established six types of findings and tributed in the muscularis propria throughout reported that diagnosis of cases with intestinal the digestive tract, serve as pacemaker cells necrosis was possible at a sensitivity of 94% for intestinal motility. Since interstitial cells of and a specificity of 89%.7) This method has also Cajal are c-kit- and CD34-positive cells, c-kit made it possible for physicians to quickly deter- and CD34 are used as markers for diagnosis mine surgical need. It is also particularly useful (Table 1). Re-evaluation of stromal tumors by for confirming diseases that are difficult to find, this diagnostic method has revealed that many such as obturator hernia. of the tumors that had been considered to be Another new and noteworthy form of leiomyoma were tumors that had originated applied technology is virtual CT. With the from the interstitial cells of Cajal (GIST).5) popularization of hardware and software, the While GIST itself is said to be most commonly daily clinical application of virtual CT will found in the stomach, it is a representative become a common procedure in the near neoplastic disease of the small intestine where future. non-epithelial tumors are common. There is also a malignant GIST, and metastatic cases 4. Enteroscopy with this type of tumor have a very poor In the field of endoscopy, a relatively thin prognosis. push type video enteroscope has become Recently, it has been reported that tyrosine popular and it is utilized for diagnosis or treat- kinase inhibitor (imatinib), which has been ment of the upper jejunum. While the use is developed to treat chronic myelocytic leuke- somewhat limited, as the small intestinal wall is mia, also inhibits the tyrosine kinase of GIST weak, treatment such as polypectomy is pos- and exhibits a contractionary effect against sible by using this method. Attempts at deeper tumors.6) Although the use of this drug has insertion of the enteroscope by using of a already become available in Japan, there sliding tube and a balloon have been reported. remain unresolved problems concerning indi- Although widespread use of enteroscopy is cations and adverse drug effects. One should hoped for, a remote-controlled capsule endo- note that the term GIST is occasionally used scopy, which is swallowed by the patient, has broadly to refer to stromal-cell-derived tumors. been developed recently. This method awaits clinical application in the very near future. 3. Recent developments in While diagnosis and treatment of hemor- diagnostic imaging rhage from the small intestine often seem diffi- Since popularization of helical CT has dra- cult, perioperative endoscopy has been known matically reduced the amount of time required to be useful in identifying the source of small for exposure and improved resolution, CT has intestinal hemorrhage. In addition, when lapa-

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rotomy is performed in patients with Peutz- inflammatory bowel disease but also following Jeghers syndrome, it is recommended that laparotomy, and adhesion-induced ileus should small intestinal polyps be thoroughly searched be avoided when it can be helped. In recent and treated by perioperative endoscopy so that years, a carboxyl methylcellulose membrane intussusception may be prevented. has become popular in preventing adhesion, serving as an effective adhesion prevention 5. Inflammatory bowel disease method. In fact, when patients with ulcerative A representative inflammatory bowel dis- colitis and familial adenomatous polyposis ease of the small intestine is Crohn’s disease, were randomly allocated to a group that used and the number of patients with the disease has the membrane and a group that did not use the been increasing yearly in Japan. While the true membrane in first-stage surgery, an exami- cause of the disease is still unknown, an abnor- nation of the degree of adhesion during the mality was discovered in 2001 in a gene called second-stage surgery revealed that adhesion NOD2, which is one of the innate immune had been prevented significantly in the group mechanisms. This abnormality was seen in that used the membrane.9) approximately 10% of patients in Western 8) countries. However, this gene abnormality Conclusion has not been found in Japan. A topic of interest in the area of treatment Since peptides common to both the central is that monoclonal antibody therapy against nervous system and the small intestine have tumor necrosis factor ␣ (TNF␣), a representa- been discovered, the small intestine is called tive inflammatory cytokine, is now covered by the second brain. It works while intricately Japan’s national insurance system as of May interrelating with the endocrine, the nervous, 2002. Insurance coverage is applicable for cases and the immune systems. The study of this with external fistulae or cases in which inflam- organ is a major field with many topics remain- mation could not be relieved by other methods. ing to be explored. However, as concerns for adverse drug reac- tions have been emphasized since the begin- REFERENCES ning and it has been pointed out that the treatment is not easy to use in cases with a 1) Tamai, I., Sai, Y., Ono, A. et al.: Immunohisto- strong stenosis, the type of cases in which the chemical and functional characterization of treatment would be appropriate needs to be pH-dependent intestinal absorption of weak determined in the future. organic acids by the monocarboxylic acid transporter MCT1. J Pharm Pharmacol 1999; In the field of surgery, it seems that laparo- 51: 1113–1121. scopic surgery is being used more widely. 2) Jasleen, J., Ashley, S.W., Shimoda, N. et al.: Laparoscopic surgery reduces invasiveness and Glucagon-like peptide 2 stimulates intestinal makes it possible for patients to return to work epithelial proliferation in vitro. Dig Dis Sci earlier, and the procedure is not inferior in its 2002; 47: 1135–1140. effectiveness compared to open surgery. In 3) Okamoto, R., Yajima, T., Yamazaki, M. et al.: addition, prevention of short-bowel syndrome Damaged epithelia regenerated by bone caused by resection, a surgical method called marrow-derived cells in the human gastro- intestinal tract. Nat Med 2002; 8: 1011–1017. strictureplasty rather than resection, is recom- 4) Home Parenteral Nutrition (HPN) Research mended to relieve the stenosis in cases of Group: Home Parenteral Nutrition (HPN) Crohn’s disease. Registration Status, Year 2000 Investigation Intestinal adhesion has been a major prob- Report, 2000. (in Japanese) lem for quite some time not only in cases with 5) Hirota, S., Isozaki, K., Moriyama, Y. et al.:

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