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Over the years it has been clear that various Helicobacter species are able to colonize the gastrointestinal tract of humans and animals. Helicobacter species are commonly found in the mucus layer of the gut and in the hepatobiliary system of diverse animal hosts. Infection would lead to a local inflammatory response and would sometimes be associated with diseases. Examples of such diseases would be the inflammatory bowel diseases commonly seen in mice and humans. Such diseases are known as Ulcerative colitis and Crohn's disease. Also, inflammation of the gastrointestinal region due to Helicobacter infection has shown to cause hepatitis and hepatocarcinoma which eventually leads to liver cancer. This is especially so in Helicobacter Hepaticus infection in mice (Fox et al., 2011).
4.2 Helicobacter Hepaticus as an agent to study inflammatory bowel disease in humans
Inflammatory bowel disease is usually due to chronic inflammation. Chronic inflammation that is restricted to the large bowel is usually ulcerative colitis whereas, chronic inflammation anywhere in the gastrointestinal tract is known as Crohn's disease. Etiopathogenesis of inflammatory bowel disease is poorly understood. However there are two possible explanations for the disease. One of them would be that the disease is due to an abnormal and uncontrolled immune response to luminal antigen. The second would be the disease is due to an appropriate immune response to an enteric pathogen (Anagnostides et al., 1991). In recent times there have been developed models of inflammatory bowel disease which comes in the form of mice. Such mice have been genetically bred and modified appropriately to study the abnormal immune response when presented with a single enteric pathogen. This is where Helicobacter Hepaticus plays a key role in the study of inflammatory bowel disease as it is known to be related to the human pathogen known as Helicobacter Pylori which already has a long term standing in promoting inflammatory bowel disease. Helicobacter Hepaticus initiates and causes hepatitis and hepatocellular carcinoma (Fox et al., 1996), (Ward et al., 1994) in certain strains of mice and has been related with colitis in immunodeficient mice (Ward et al., 1996). This is because it is already known that Helicobacter Hepaticus infections are endemic in myriad mouse colonies in various laboratories around the globe (Shames et al., 1995). In the studies conducted by Rachel J. Cahill et al, it showed that Helicobacter Hepaticus causes the development of severe inflammatory bowel disease in the experimental mice. The paper also concluded that such diseases were similar to the human disease and requires the presence of only a single pathogenic bacterial species in this case it is Helicobacter Hepaticus. In their mice model the immunological response and Helicobacter Hepaticus caused the development of inflammatory bowel disease. Therefore, Helicobacter Hepaticus together with various kinds of mice models are essential in the study of human inflammatory bowel disease (Cahill et al., 1997).
4.3 Pathology of Helicobacter Hepaticus infections
4.3.1 The normal intestine
A normal gastrointestinal tract would be one where it is a hollow tube which consists of three layers. They are known as the mucosa, submucosa, muscularis propria and loose areolar tissue which are covered by mesothelium. For the colon region, the surface of the mucosa is flat and would have crypts as straight tubes which are parallel to each other. The crypt base would be above a layer of smooth muscle cell (muscularis mucosae), which differentiates the mucosa from the submucosal connective tissue. The crypt organization is seen throughout the colon except in certain areas such as when the zones transition to the small intestinal mucosa or to the squamous epithelium. For the small intestine, the surface area is irregular due to the presence of finger-like projections known as the villi. When normal these projections would be uniform in both shape and size. When observing the ileum, the villi seen there are taller and the crypts are less deep when compared to the jejunum. Villi and crypts are covered with a single-cell layer of columnar epithelium.
4.3.2 Inflammatory Bowel Disease - Clinical features of Crohn's Disease
Crohn's disease is the chronic inflammation of the gastrointestinal tract. It can happen anywhere along the gastrointestinal tract from the mouth to the anus. The usual three main sites of inflammation would be the small intestine alone, the colon alone, or a combination of small and large intestine involvement. The terminal ileum is the most commonly affected area. Various studies have shown that other parts of the gastrointestinal tract may also be involved such as the duodenum, oesophagus, stomach and mouth. The clinical features or symptoms of Crohn's disease can differ a lot depending on the site of the disease. The primary symptoms of Crohn's disease would be abdominal pain and diarrhoea. The other common symptoms would include fever and weight loss. Due the the various locations that may be affected in the gastrointestinal tract other symptoms such as bloody stools, strictures and fistulas to the skin or neighbouring organs can be observed. Although rare, esophageal involvement would have deep ulcerations, stenosis or pseudopolyps. Where there is esophageal involvement there would also be other accompanying symptoms such as dysphagia, heartburn or chest pain (Decker et al., 2001).
The common symptoms seen with gastruduodenal involvement would be upper abdominal pain, weight loss, nausea, vomiting and hematemesis. Strictures are the main pathological finding with this sort of involvement. Other frequent symptoms would be edema, aphthous ulcerations and irregular mucosal thickening (Nugent & Roy, 1989), (T. Yamamoto, 1999).
There are multiple causes of weight loss. This is due to partial obstruction in the gastrointestinal tract which would in turn lead to loss of appetite due to the increasing pain. Persistent pain can also be due to acute inflammation or abscesses. Due to the damage done to the gastrointestinal tract (villi) due to inflammation or other detrimental mechanisms there can also be weight loss due to malabsorption if the small bowel is involved. There can also be other complications when there is small bowel disease involvement and this happens in the form of fistulas that can also include the vagina, skin or bladder. In Crohn's colitis there can also be rectal bleeding and diarrhea. Strictures can form leading to obstruction and distention. Perianal involvement happens when there is inflammation and fistulisation within the anal crypt glands. Skin tags, fissure and perianal scarring can be observed here. Main symptoms would be pain, purulent drainage and problems with bowel movement (defecation). Extraintestinal manifestations are also seen in Crohn's disease. This is usually affects the various systems such as the dermatologic system, ocular system, hepatobiliary system and the joints. For the dermatological systems there can be erythema nodosum and pyoderman gangrenosum. For the ocular system it would include uveitis and epsicleritis. Joint problems would include ankylosing spondylitis, sacral ileitis, and peripheral polyarthropathy. The hepatobiliary system would have sclerosing cholangitis.
4.3.3 Inflammatory Bowel Disease -Gross features of Crohn's Disease
Crohn's disease can affect different segments of the gastrointestinal tract. The appearances are similar even at differing regions. Any involvement of the upper gastrointestinal tract is uncommon. The length of the segments that are affected is variable and the lesions observed are separated by uninvolved 'skip areas'. Macroscopic lesions are visible on the mucosal and serosal side of the bowel wall. Fistulas are usually associated with strictures and thus, we can categorize them to two types: the perforating type and the non-perforating type. Lesions of different sizes are present. The mucosa can either appear normal or show multiple small (1-2 mm in size) punctiform, rounded nodules or superficial erosions known as 'aphthoid lesions'. Given enough time, the erosions would give rise to bigger longtudinal ulcers which are also known as serpiginous ulcers (Rutgeerts et al., 1984).
With the combination of longitudinal and transvers ulceration within edematous mucosa it would cause a characteristic 'cobblestone' aspect. Ulcerations are commonly seen on the mesenteric border of the small intestine. These ulcerations can become deeply situated fissuring ulcers which can reach the muscularis propria or even pass through the muscularis and form abscesses or fistulas between involved affected segments and neighbouring organs or unaffected loops. Histological experiments have showed that fistulas are composed of granulation tissue encompassing the lumen. These tissues are filled up mostly by nuclear debris and inflammatory cells such as neutrophils (Dvorak et al., 1980).
When there is high grade stenosis, it would often be linked with severe ulcerations with complete loss of the mucosa (Figure 2).
As Crohn's disease is a transmural disease, the bowel wall is thickened with involvement of the submucosa, the muscularis prorpia, the subserosa and mesenteric fat. Serosal surfaces would reveal
conspicuous distended blood vessels and may display fibrous exudate with or without adhesions to adjacent loops. Also, mesenteric fats would partially surround the intestine which extends from the mesenteric attachment anteriorly and posteriorly. This occurrence is known as 'fat wrapping' and is specific in Crohn's disease (Figure 3).
There would be fibrous strands within the mesenteric fat. It radiates from the intestine and the surrounding thickened, hypertrophied fat lobules (Sheehan et al., 1992). Mesenteric lymph nodes would be swollen in Crohn's disease but this feature can also be seen in Ulcerative Colitis (Cook, 1972).
Other gross features would be inflammatory pseudopolyps of the colon and small intestine. They would be tall mucosal outgrowths.
4.3.4 Inflammatory Bowel Disease - Microscopic features of Crohn's Disease
In the histological sections of Crohn's Disease, granulomas are present (Chambers & Morson, 1979).
Granulomas are defined as an accumulation of monocyte and macrophage cells and other inflammatory cells with or without giant cells (Figure 4).
The macrophages are seen as large cells with a lot of pale eosinophilic cytoplasm and large oval nuclei. They are seen in clusters. Due to their epithelial-like morphology they are coined as epitheloid cells. Such cells can be closely packed and have sarcoid-like appearance but a 'looser' expanded form of granuloma is the more common case (Figure. 5).
The giant cells that are seen may contain calcified conchoids bodies (Cook & Dixon, 1973).
The inflammatory cells that are present would be lymphocytes - usually the CD4+ T cells. In the case with granulomas in Crohn's disease the diagnostic value of it is usually accepted however, its clinical and prognostic significance remains unclear as there are conflicting views.
There are many types of microscopic lesions in Crohn's disease. Such lesions develop as focal lesions in the back area of normal mucosa. At the initiating stage of the disease the lesions would have epithelial patchy necrosis or ahpthoid ulcers. Other components would have the occurrence of a naked surface of the dome area overlying a mucosal lymph follicle and loss of M cells. Also, ulcers seen at the base of crypts would have neutrophils streaming into the gastrointestinal lumen which would eventually lead to mountain peak ulcers, abnormal villous and damage to the small capillaries with loss of surface summit lesions (Figure. 6 & 7). In normal circumstances there would be limiting necrosis in surface epithelial cells. In spite of all these characteristic lesions seen in Crohn's Disease granulomas hold a more diagnostic value than that of mucosal lesions as such lesions can be also be seen in other forms of diseases in the gastrointestinal tract.
4.3.5 Inflammatory Bowel Disease - Clinical Features of Ulcerative colitis
With ulcerative colitis, the inflammation is limited to the mucosa and sub-mucosa. Also, ulcerative colitis is a continuous disease with no skip lesions between areas of disease. The region of occurrence in ulcerative colitis is almost always at the rectum. However, there are chances that the disease will continue proximally from the rectum. There are chances whereby the small intestine can be affected. Usually there are four major categories of colonic involvement in the case of ulcerative colitis. The first is proctitis which is the rectum-only involvement. Second is Proctosignoiditis which has not only rectal involvement but it would also have sigmoid region involvement as well. Third is the left-sided colitis which is when the disease extends from the rectum all the way to the splenic flexure. Fourth would be Pancolitis which is the term given when there is inflammation which goes past the splenic fexure and can extend to the cecum (Farmer et al., 1993).
Due to the extent of the disease there can be varying symptoms. The common symptoms in ulcerative colitis would be rectal bleeding, bloody diarrhoea, abdominal pain, fever, weight loss and malaise. Symptoms of proctitis would be that of bloody stools and/or painful straining. When ulcerative colitis extends more proximally there would be lower abdominal pain and in severe cases there would be nausea, vomiting, weight loss, malnutrition and anemia. There are also extraintestinal manifestations in ulcerative colitis that are similar to that of Crohn's disease. Pyoderma gangrenosum is however closely related to ulcerative colitis than in Crohn's disease and erythema nodosum is more associated to Crohn's disease. Also, toxic megacolon is one of the severe life threatening complications in ulcerative colitis. When this occurs there would be abdominal distension, abdominal tenderness, fever, increased white blood cell count, anaemia, hypotension and altered levels of consciousness (Sheth & LaMont, 1998).
In ulcerative colitis inflammation of the gastrointestinal tract can be observed throughout the bowel wall with necrosis and the degeneration of myocytes. There can be a chance for perforation when the disease has progress so far that the bowel wall is so thin due to distension and necrosis.
Colorectal cancer is also observed more in ulcerative colitis than in Crohn's disease.
4.3.6 Inflammatory Bowel Disease - Gross Features of Ulcerative colitis
In ulcerative colitis, it starts from the rectum and can spread proximally to other regions of the colon. For pancolitis the disease progression would halt at the leocecal valve but is some cases it is limited to the distal ileitis (Both et al., 1983).
The ileal lesions seen are due to the continuation of colonic lesions. This can be observed under the microscope when there are diffuse inflammatory lesions with shortening of the villi. In severe cases there can be diffuse duodenitis and extensive involvement of the upper small bowel.
Gross appearance in ulcerative colitis always varies with its activity. The lesions seen in ulcerative colitis are commonly limited to the mucosa. Acute forms of ulcerative colitis would have a mucosal surface that is wet and the mucus would be filled with petechial haemorrhages. Various sized ulcers would appear and would be small, rounded and superficial in nature. These ulcers can however, develop to become more extensive and undermine the mucosa. When this occurs the mucosal bridges with an underlying inflammatory infiltrate would develop. When these mucosal ulcers are healed eventually, there would be the development of pseudopolyps(reddish nodules). These pseudopolyps are usually small and may have filiform configuration (Figure. 8)
Pseudopolyps are common in the sigmoid and descending colon. Advanced stages of ulcerative colitis would be presented with the entire bowel becoming fibrotic, narrowed and shortened.
4.3.7 Inflammatory Bowel Disease - Microscopic Features of Ulcerative colitis
Under the microscope ulcerative colitis is seen with an inflammatory reaction with distinct structural abnormalities of the mucosa. Inflammation can be observed when there is increased intensity of lamina propria cellular infiltrate. For the case of ulcerateive colitis this infiltrate is more extensive and can extend towards the deeper parts (Figure. 9).
Commonly, there would be accumulation of plasma cells near the mucosal base. When there are neutrophils observed within the epithelial structures, such as the crypt lumen and wall with crypt damage it can be a determining factor for diagnosing ulcerative colitis. In infectious colitis cryptitis and crypt abscesses can be observed. One can determine ulcerative colitis microscopically when there are mucosal ulcerations and erosions, mucin depletion, Paneth cell metaplasia and the diffuse thickening of the muscularis mucosae (Figure. 10).
In most cases, ulcerative colitis is distinguished by a special distribution of inflammation and architectural distortion with increased intensity from the proximal region to the distal colon.
4.4 Helicobacter Hepaticus and extra-intestinal tumor
From the information gathered it is well known that Helicobacter Hepaticus can induce inflammatory bowel diseases. However, it has also been shown that Helicobacter Hepaticus infection in mice can initiate sustained inflammation and carcinoma of the liver in A/Jr mice (these mice serves as an animal model for the study of human cancers with viral hepatitis and Helicobacter pylori chronic gastristis.) In mice that are infected with Helicobacter Hepaticus the inflammatory lesions followed one of two courses. This in turn results in the necrogranulomatous lobular and/or lymphocytic portal hepatitis. The histological observations seen in these mice had correlations with human hepatitis. These histopathological pictures were taken from an experiment on a group of mice as seen in the table (Figure. 11A & 11B)
Where there is lubular hepatitis, necroinflammatory lessions would consist mainly of Kupffer cells and the recruitment of macrophages that surrounds and infiltrating foci of spotty or confluent hepatocellular necrosis (Figure. 12).
The result of this, lead to translobular coagulative necrosis in extreme cases. Even with much inflammation neutrophils and lymphocytes made a small contribution to the lobular lesions. These lobular lesions were frequent but not always around the terminal hepatic venules. However, fibrosis was not a main feature of the disease. In portal hepatitis it mainly included lymphocytoid cells forming expansile nodular lesions. In females uncomplicated portal hepatitis was most common. As microorganisms such as bacteria are rarely seen in portal regions, it is still likely that these lesions formed due to circulating antigens or cytokines from the lower bowel. Also, lobular necrogranulomatous lesions were observed throughout. However, chronic portal inflammation was not fully developed until 12 months of age. When portal mononuclear infiltrates disrupted the hepatic limiting plate it would result in interface hepatitis (Figure. 13).
In reactive portal lymphatic vessel, lymphocytoid cells would accumulate causing these vessels to expand. Larger lesions they would infiltrate bile ductules thereby inducing epithelial loss, hypertrophy and atypia (Figure. 13). In some cases expansile aggregates would organize into follicles which are consistent with "tertiary lymphoid tissue" (Figure. 14)(Shomer et al., 2003).
However, inflammation of the colon and cecum seen in these immunocompetent mice were rather mild (Rogers et al., 2004).
Typhlocolitis was observed only in mice that were infected at or before 3 weeks of age. As the morphological changes were not severe, microarray experiments conducted have proven that lower bowel colonization of A/Jr mice with Helicobacter Hepaticus would induce transcriptional responses (Rogers et al., 2004). Male mice that were at twelve months of age that had severe lobular hepatitis developed dysplastic and proliferative lesions that were akin to those that were documented (Boutin et al., 2004; Ward et al., 1994) .
Dysplastic foci were observed to be multifocal and would frequently fuse into the adjacent zones of more normal hepatocytes. Sometimes the expansile dysplastic nodules were strongly delineated from the less affected lobules (Figure 15).
The inflammation was mainly observed at the perimeter of dysplastic nodules. Within the foci where there was cellular alteration there would be oval cell hyperplasia with the common pseudocholoangiole formation (Figure. 16) (Rogers et al., 2004) (Price & Morson, 1975).