Changing Concept of Crohn's Disease.
P.K.Ghatak, MD
Crohn's disease is a chronic ulcerative granulomatous inflammation of the isolated segments of ilium, associated with some systemic manifestations. The cause of this inflammation has shifted several times -from syphilis, tuberculosis, autoimmune, genetics, rouge colon bacterial antigen derived immune reaction and unknown.
The Journal of the American Medical Association (JAMA) in October 1932 published a paper authored by Dr. B. B. Crohn describing a comprehensive summary of 14 cases of chronic diarrheal disease with histopathological findings. It was a new disease. He called the disease regional ileitis and speculated the etiology was a mycobacterial infection. The medical community named it Crohn's disease.
A review of literature showed Crohn was not the first person to publish this new disease. A short list of publications of the same illness appeared prior to the JAMA article is presented below. Most of these are autopsy findings of patients with similar symptoms described by Dr. Crohn.
It is said that Alfred the great of England and King of France Louis XIII died of complications of regional ileitis. Antonio Benivieni in the fourteen century described autopsy findings of a chronic diarrheal disease as seen in regional ileitis. In 1769 Giovanni B. Morgagni described a similar case. In 1905 Wilmannis and 1907 Monyiham reported cases in BMJ. In 1909 Braun, 1911 Schmidt, 1912 Groto and 1924 Lawon published similar cases in German medical journals.
In 1912 Dr. Kennedy Dalziel of Glasgow, Scotland worked on regional ileitis. It is now known that Dr Crohn worked based on Dalziel. Crohn, however, presented a comprehensive clinical and histopathological findings.
Characteristic features of Crohn's disease.
Men and females are equally affected, there is genetic predisposition, but the precise nature of genetic mutation is unknown. Usual age of beginning of symptoms is late 20s. Exacerbation and remissions are features of Crohn's disease. Campy abdominal pain in mid and lower abdomen and frequent bowel movements of blood mixed stool are initial symptoms. Other symptoms are a low grade fever, sclerites of eyes, joint pains, loss of weight.
Pathological feedings-Skip lesions are typical (segments of ilium are inflamed and in between sections of ilium are completely normal). Granulomatous inflammation of all the layers of ilium is a typical finding. The villi are atrophic and lymph follicular hypertrophy of the submucosal and, muscular and serosal layers are thickened with granuloma formation. Fissures and sinus tracts are distinguishing features. Abscess formation, peritonitis and fistular communication with urinary bladder and colon are complications.
Diagnosis of Crohn's disease is not difficult and usually made by endoscopy and biopsy of the lesions of the small intestine.
Another inflammatory bowel disease, Ulcerative colitis, should be excluded first because Crohn's disease can affect anywhere in the GI tract-from the mouth to the anus. Endoscopy in ulcerative colitis shows extensive inflammation of the entire colon and lesions are limited to the lining membrane of the colon only, sparing the other parts of the colon wall. And biopsy revealed acute necrotic lesion of epithelium of the colon, and no granulomas. Since granuloma is the distinguishing feature of Crohn's diseases, a short review of granuloma is presented here.
Granuloma.
Macrophages and other immune cells appear at the site of invasion by infectious pathogens or the presence of a foreign body in the tissue. The macrophages encircle it and try to contain it from spreading. If macrophages fail to destroy it, more macrophages gather around it and summons other immune cells. The inflamed area takes the shape of a nodule. The center is formed by clusters of macrophages and the surrounded by layers of immune cells, chiefly by lymphocytes. In certain infections, the cells in the center of the nodule become necrotic, and in others no necrosis occur. The first one is called Narcotizing granuloma, a typical finding in M.TB infection; the second one is called Non-narcotizing granuloma with no central necrosis, a typical finding in Sarcoidosis and Crohn's disease.
Causes of granuloma.
Bacterial infection. Example- Listeria, Bacteriodes, Q fever.
Mycobacteria tuberculosis are paratuberculosis (Non-TB mycobacteria).
Virus infection. eg.- Epstein Barr virus, Cytomegalo virus, measles and mumps.
Unknown antigen. -eg.- Scarcoidosis.
Fugal infection. -eg.- Histoplasma capsulatum, Aspergillus species,
Parasite. -eg.- Schistosoma sp.
Foreign body. - Surgical sutures, talk, silicone and thorns.
Cancer cells.
Autoimmune diseases. -eg.- Lupus erythematosus, scleroderma.
Special category,- Granulomatous agiitis, eg, Giant cell arteritis, Wegener's granulomatosis.
Etiology of Crohn's disease (CD).
The list of pathogen mentioned above are just a few in each category. After a diagnosis is CD is made, the first thing to do is to find any known pathogen is responsible for a granulomatous lesion in the GI tract. Microbiology and image studies are usually enough to exclude a known pathogen.
Heredity and gene mutation.
Mutations of several genes are suspected, but few are positively linked to CD disease. Mutation of NOD2 gene (nucleotide binding oligomerization domain containing intra -cytoplasmic protein 2) which encodes a protein involved in apoptosis (cell death) is linked to CD.
ATGs (autophagy-related genes) encodes many cytokines. When ATGs mutate proinflammatory activities proceed unchecked and result in inflammatory bowel disease.
A large section of each chromosome has no active gene, known as Junk genes. Newly discovered ETS2 gene, among the junk gene found to encode a protein which enhance Macrophage's activities. Drugs that suppress ETS2 gene helps to heal of CD lesions in the bowel. It is now postulated that mutated ETS2 gene is another inherited gene in the etiology of CD.
Mutation of these two genes and many other gene mutation are inherited by autosomal recessive and autosomal dominant modes.
Gut Bacteria.
Over 1000 different species of bacteria are present in the gut of any healthy adult. Among them the dominant species are Firmicutes, Bacteriodes, and Actinobacteria and less are colonies of Protobacteria, Fusobacteria, Cyanobacteria, and Verrucomicrobacteria. Intestinal epithelium enter into a symbiotic relationship with these bacteria. Disruption of this relationship may happen due to antibiotic therapy and ingestion of other medications, certain illnesses, change in dietary habits, eating highly processed food and other environmental factors. Less abundant bacterial species multiply under this changed environment and break the intestinal barrier and invade the intestinal tissue. This results in activation of the adaptive immune responses and generate excess pro-inflammatory cytokines and produce tissue necrosis and inflammation.
Bacterial antigen trigger antibodies by B-cells. Antibodies attacks normal tissues instead of pathogen due to error of Th-2 cells (thymic 2) and antigen complex may also trigger antibody production and tissue damage, a feature of autoimmune bowel disease.
Multiple factors.
Until a definitive etiology of CD is identified, a complex association of heredity susceptible gene mutation, disrupted intestinal microbiome, environmental factors, unidentified infective pathogen, autoimmunity and unknown factors are contributing to the development of CD.
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