Crohn's disease

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Crohn's disease
Other namesCrohn disease, Crohn syndrome, granulomatous enteritis, regional enteritis, Leśniowski-Crohn disease
immunosuppressants such as azathioprine, methotrexate[1]
PrognosisSlightly increased risk of death[11]
Frequency3.2 per 1,000 (developed world)[12]
Named after

Crohn's disease is a type of

small bowel cancer.[1]

Although the precise causes of Crohn's disease (CD) are unknown, it is believed to be caused by a combination of environmental,

antigens.[14][16] While Crohn's is an immune-related disease, it does not seem to be an autoimmune disease (the immune system is not triggered by the body itself).[17] The exact underlying immune problem is not clear; however, it may be an immunodeficiency state.[16][18][19]

About half of the overall risk is related to genetics, with more than 70 genes involved.[1][20] Tobacco smokers are three times as likely to develop Crohn's disease as non-smokers.[6] It often begins after gastroenteritis.[1] Other conditions with similar symptoms include irritable bowel syndrome and Behçet's disease.[1]

There is no known cure for Crohn's disease.

Treatment options are intended to help with symptoms, maintain remission, and prevent relapse.[1] In those newly diagnosed, a corticosteroid may be used for a brief period of time to improve symptoms rapidly, alongside another medication such as either methotrexate or a thiopurine used to prevent recurrence.[1] Cessation of smoking is recommended for people with Crohn's disease.[1] One in five people with the disease is admitted to the hospital each year, and half of those with the disease will require surgery at some time during a ten-year period.[1] While surgery should be used as little as possible, it is necessary to address some abscesses, certain bowel obstructions, and cancers.[1] Checking for bowel cancer via colonoscopy is recommended every few years, starting eight years after the disease has begun.[1]

Crohn's disease affects about 3.2 per 1,000 people in Europe and North America;

developed world.[23] Rates have, however, been increasing, particularly in the developing world, since the 1970s.[22][23] Inflammatory bowel disease resulted in 47,400 deaths in 2015,[24] and those with Crohn's disease have a slightly reduced life expectancy.[1] It tends to start in adolescence and young adulthood, though it can occur at any age.[25][1][3][26] Males and females are equally affected.[3]

Name controversy

The disease was named after

terminal ileum of the small intestine, the area most commonly affected by the illness.[27] Why the disease was named after Crohn has controversy around it.[28][29] While Crohn, in his memoir, describes his original investigation of the disease, Ginzburg provided strong evidence of how he and Oppenheimer were the first to study the disease.[30]

Signs and symptoms

Signs and symptoms
Crohn's disease Ulcerative colitis
Defecation Often porridge-like,[31]
sometimes steatorrhea		 Often mucus-like
and with blood[31]
Tenesmus Less common[31] More common[31]
Fever Common[31] Indicates severe disease[31]
Fistulae Common[32] Seldom
Weight loss Often More seldom

Gastrointestinal

aphthous ulcer on the mucous membrane of the mouth
in Crohn's disease.

Many people with Crohn's disease have symptoms for years before the diagnosis.

gastrointestinal disease and the depth of tissue involvement, initial symptoms can be more subtle than those of ulcerative colitis. People with Crohn's disease experience chronic recurring periods of flare-ups and remission.[34]
The symptoms experienced can change over time as inflammation increases and spreads. Symptoms can also be different depending on which organs are involved. It is generally thought that the presentation of Crohn's disease is different for each patient due to the high variability of symptoms, organ involvement, and initial presentation.

Perianal

skin tags are also common in Crohn's disease, and may appear with or without the presence of colorectal polyps.[35] Fecal incontinence
may accompany perianal Crohn's disease.

Intestines

The intestines, especially the colon and terminal ileum, are the areas of the body affected most commonly.

bowel movements per day, and may need to awaken at night to defecate.[1][37][38][39] Visible bleeding in the feces is less common in Crohn's disease than in ulcerative colitis, but is not unusual.[1] Bloody bowel movements are usually intermittent, and may be bright red, dark maroon, or even black in color. The color of bloody stool depends on the location of the bleed. In severe Crohn's colitis, bleeding may be copious.[37]

Stomach and esophagus

The stomach is rarely the sole or predominant site of CD. To date there are only a few documented case reports of adults with isolated gastric CD and no reports in the pediatric population. Isolated stomach involvement is very unusual presentation accounting for less than 0.07% of all gastrointestinal CD.[40] Rarely, the esophagus and stomach may be involved in Crohn's disease. These can cause symptoms including difficulty swallowing (dysphagia), upper abdominal pain, and vomiting.[41]

Oropharynx (mouth)

The mouth may be affected by recurrent sores (

aphthous ulcers). Recurrent aphthous ulcers are common; however, it is not clear whether this is due to Crohn's disease or simply that they are common in the general population. Other findings may include diffuse or nodular swelling of the mouth, a cobblestone appearance inside the mouth, granulomatous ulcers, or pyostomatitis vegetans. Medications that are commonly prescribed to treat CD, such as anti-inflammatory and sulfa-containing drugs, may cause lichenoid drug reactions in the mouth. Fungal infection such as candidiasis is also common due to the immunosuppression required in the treatment of the disease. Signs of anemia such as pallor and angular cheilitis or glossitis are also common due to nutritional malabsorption.[42]

People with Crohn's disease are also susceptible to

angular stomatitis, an inflammation of the corners of the mouth, and pyostomatitis vegetans.[43]

Systemic

Like many other chronic, inflammatory diseases, Crohn's disease can cause a variety of

growth failure is common. Many children are first diagnosed with Crohn's disease based on inability to maintain growth.[44] As it may manifest at the time of the growth spurt in puberty, as many as 30% of children with Crohn's disease may have retardation of growth.[45] Fever may also be present, though fevers greater than 38.5 °C (101.3 °F) are uncommon unless there is a complication such as an abscess.[1] Among older individuals, Crohn's disease may manifest as weight loss, usually related to decreased food intake, since individuals with intestinal symptoms from Crohn's disease often feel better when they do not eat and might lose their appetite.[44] People with extensive small intestine disease may also have malabsorption of carbohydrates or lipids, which can further exacerbate weight loss.[46]

Extraintestinal

Crohn's disease can affect many organ systems beyond the gastrointestinal tract.[47]

Complications
Crohn's
disease		 Ulcerative
colitis
Nutrient deficiency Higher risk
Colon cancer
risk		 Slight Considerable
Prevalence of extraintestinal complications[48][49][50]
Iritis/uveitis
 Females 2.2% 3.2%
Males 1.3% 0.9%
Primary sclerosing
cholangitis		 Females 0.3% 1%
Males 0.4% 3%
Ankylosing
spondylitis		 Females 0.7% 0.8%
Males 2.7% 1.5%
Pyoderma
gangrenosum		 Females 1.2% 0.8%
Males 1.3% 0.7%
Erythema nodosum Females 1.9% 2%
Males 0.6% 0.7%

Visual

Inflammation of the interior portion of the eye, known as uveitis, can cause blurred vision and eye pain, especially when exposed to light (photophobia).[51] Uveitis can lead to loss of vision if untreated.[47]

Inflammation may also involve the white part of the eye (

episclera), which causes conditions called scleritis and episcleritis, respectively.[51]

Other very rare ophthalmological manifestations include: conjunctivitis, glaucoma, and retinal vascular disease.[52]

Gallbladder and liver

Crohn's disease that affects the ileum may result in an increased risk of gallstones. This is due to a decrease in bile acid resorption in the ileum, and the bile gets excreted in the stool. As a result, the cholesterol/bile ratio increases in the gallbladder, resulting in an increased risk for gallstones.[51] Although the association is greater in the context of ulcerative colitis, Crohn's disease may also be associated with primary sclerosing cholangitis, a type of inflammation of the bile ducts.[53]

Liver involvement of Crohn's disease can include

Nonalcoholic fatty liver disease (nonalcoholic steatohepatitis, NAFLD) are relatively common and can slowly progress to end-stage liver disease. NAFLD sensitizes the liver to injury and increases the risk of developing acute or chronic liver failure following another liver injury.[52]

Other rare hepatobiliary manifestations of Crohn's disease include: cholangiocarcinoma, granulomatous hepatitis, cholelithiasis, autoimmune hepatitis, hepatic abscess, and pericholangitis.[52]

Renal and urological

Nephrolithiasis, obstructive uropathy, and fistulization of the urinary tract directly result from the underlying disease process. Nephrolithiasis is due to calcium oxalate or uric acid stones. Calcium oxalate is due to hyperoxaluria typically associated with either distal ileal CD or ileal resection. Oxalate absorption increases in the presence of unabsorbed fatty acids in the colon. The fatty acids compete with oxalate to bind calcium, displacing the oxalate, which can then be absorbed as unbound sodium oxalate across colonocytes and excreted into the urine. Because sodium oxalate only is absorbed in the colon, calcium-oxalate stones form only in patients with an intact colon. Patients with an ileostomy are prone to formation of uric-acid stones because of frequent dehydration. The sudden onset of severe abdominal, back, or flank pain in patients with IBD, particularly if different from the usual discomfort, should lead to inclusion of a renal stone in the differential diagnosis.[52]

Urological manifestations in patients with IBD may include ureteral calculi, enterovesical fistula, perivesical infection, perinephric abscess, and obstructive uropathy with hydronephrosis. Ureteral compression is associated with retroperitoneal extension of the phlegmonous inflammatory process involving the terminal ileum and cecum, and may result in hydronephrosis severe enough to cause hypertension.[52]

Immune complex glomerulonephritis presenting with proteinuria and hematuria has been described in children and adults with CD or UC. Diagnosis is by renal biopsy, and treatment parallels the underlying IBD.[52]

Amyloidosis (see endocrinological involvement) secondary to Crohn's disease has been described and is known to affect the kidneys.[52]

Pancreatic

Pancreatitis may be associated with both UC and CD. The most common cause is iatrogenic and involves sensitivity to medications used to treat IBD (3% of patients), including sulfasalazine, mesalamine, 6-mercaptopurine, and azathioprine. Pancreatitis may present as symptomatic (in 2%) or more commonly asymptomatic (8–21%) disease in adults with IBD.[52]

Cardiovascular and circulatory

Children and adults with IBD have been rarely (<1%) reported developing pleuropericarditis either at initial presentation or during active or quiescent disease. The pathogenesis of pleuropericarditis is unknown, although certain medications (e.g., sulfasalazine and mesalamine derivatives) have been implicated in some cases. The clinical presentation may include chest pain, dyspnea, or in severe cases pericardial tamponade requiring rapid drainage. Nonsteroidal anti-inflammatory drugs have been used as therapy, although this should be weighed against the hypothetical risk of exacerbating the underlying IBD.[52]

In rare cases, cardiomyopathy, endocarditis, and myocarditis have been described.[52]

Crohn's disease also increases the risk of

deep venous thrombosis, while difficulty breathing may be a result of pulmonary embolism
.

Respiratory

hypopharynx.[55] Hoarseness, sore throat, and odynophagia are other symptoms of laryngeal involvement of Crohn's disease.[56]

Considering extraintestinal manifestations of CD, those involving the lung are relatively rare. However, there is a wide array of lung manifestations, ranging from subclinical alterations, airway diseases and lung parenchymal diseases to pleural diseases and drug-related diseases. The most frequent manifestation is bronchial inflammation and suppuration with or without bronchiectasis. There are a number of mechanisms by which the lungs may become involved in CD. These include the same embryological origin of the lung and gastrointestinal tract by ancestral intestine, similar immune systems in the pulmonary and intestinal mucosa, the presence of circulating immune complexes and auto-antibodies, and the adverse pulmonary effects of some drugs.[57] A complete list of known pulmonary manifestations include: fibrosing alveolitis, pulmonary vasculitis, apical fibrosis, bronchiectasis, bronchitis, bronchiolitis, tracheal stenosis, granulomatous lung disease, and abnormal pulmonary function.[52]

Musculoskeletal

Crohn's disease is associated with a type of rheumatologic disease known as seronegative spondyloarthropathy.[51] This group of diseases is characterized by inflammation of one or more joints (arthritis) or muscle insertions (enthesitis).[51] The arthritis in Crohn's disease can be divided into two types. The first type affects larger weight-bearing joints such as the knee (most common), hips, shoulders, wrists, or elbows.[51] The second type symmetrically involves five or more of the small joints of the hands and feet.[51] The arthritis may also involve the spine, leading to ankylosing spondylitis if the entire spine is involved, or simply sacroiliitis if only the sacroiliac joint is involved.[51]

Crohn's disease increases the risk of osteoporosis or thinning of the bones.[51] Individuals with osteoporosis are at increased risk of bone fractures.[58]

Dermatological

A single lesion of erythema nodosum

Crohn's disease may also involve the skin, blood, and

septal panniculitis.[59]

Pyoderma gangrenosum is a less common skin problem, occurring in under 2%,[60] and is typically a painful ulcerating nodule.[59][47]

Clubbing, a deformity of the ends of the fingers, may also be a result of Crohn's disease.[citation needed]

Other very rare dermatological manifestations include:

Sweet's syndrome is connected to Crohn's disease.[52]

Neurological

Crohn's disease can also cause

seizures, stroke, myopathy, peripheral neuropathy, headache, and depression.[61]

Central and peripheral neurological disorders are described in patients with IBD and include peripheral neuropathies, myopathies, focal central nervous system defects, convulsions, confusional episodes, meningitis, syncope, optic neuritis, and sensorineural loss. Autoimmune mechanisms are proposed for involvement with IBD. Nutritional deficiencies associated with neurological manifestations, such as vitamin B12 deficiency, should be investigated. Spinal abscess has been reported in both a child and an adult with initial complaints of severe back pain due to extension of a psoas abscess from the epidural space to the subarachnoid space.[52]

Psychiatric and psychological

Crohn's disease is linked to many psychological disorders, including depression and anxiety, denial of one's disease, the need for dependence or dependent behaviors, feeling overwhelmed, and having a poor self-image.[62]

Many studies have found that patients with IBD report a higher frequency of depressive and anxiety disorders than the general population; most studies confirm that women with IBD are more likely than men to develop affective disorders and show that up to 65% of them may have depression and anxiety disorder.[63][64]

Endocrinological or hematological

red blood cells, is also more common in Crohn's disease and may cause fatigue, a pale appearance, and other symptoms common in anemia
.

Secondary amyloidosis (AA) is another rare but serious complication of inflammatory bowel disease (IBD), generally seen in Crohn's disease. At least 1% of patients with Crohn's disease develop amyloidosis. In the literature, the time lapse between the onset of Crohn's disease and the diagnosis of amyloidosis has been reported to range from 1 to 21 years.

immunosuppressant treatments or sulfasalazine. Plasma erythropoietin levels often are lower in patients with IBD than expected, in conjunction with severe anemia.[52]

thromboembolic events resulting from a hypercoagulable state in patients with IBD can lead to pulmonary embolism or thrombosis elsewhere in the body. Thrombosis has been reported in 1.8% of patients with UC and 3.1% of patients with CD. Thromboembolism and thrombosis are less frequently reported among pediatric patients, with three patients with UC and one with CD described in case reports.[52]

In rare cases, hypercoagulation disorders and portal vein thrombosis have been described.[52]

Malnutrition symptoms

People with Crohn's disease may develop anemia due to

small bowel bacterial overgrowth syndrome, which can produce micronutrient deficiencies.[67][68]

Complications

Intestinal damage

Histopathology of a non-necrotizing granuloma of colonic mucosa in a patient with Crohn's disease, H&E stain. It is seen as an aggregate of histiocytes in the center of the image, having ample eosinophilic cytoplasm.

Crohn's disease can lead to several mechanical complications within the

perianal area. Crohn's is responsible for 10% of vesicoenteric fistulae, and is the most common cause of ileovesical fistulae.[72]

Symptoms caused by

small bowel obstruction or disease involving the stomach, pylorus, or duodenum.[37]

Intestinal granulomas are a walled-off portions of the intestine by macrophages in order to isolate infections. Granuloma formation is more often seen in younger patients, and mainly in the severe, active penetrating disease.[73] Granuloma is considered the hallmark of microscopic diagnosis in Crohn's disease (CD), but granulomas can be detected in only 21–60% of CD patients.[73]

Cancer

Crohn's disease also increases the risk of

colon cancer.[75] Screening for colon cancer with colonoscopy is recommended for anyone who has had Crohn's colitis for at least eight years.[76]

Some studies suggest there is a role for chemoprotection in the prevention of colorectal cancer in Crohn's involving the colon; two agents have been suggested,

mesalamine preparations.[77] Also, immunomodulators and biologic agents used to treat this disease may promote developing extra-intestinal cancers.[78]

Some cancers, such as acute myelocytic leukaemia have been described in cases of Crohn's disease.[52] Hepatosplenic T-cell lymphoma (HSTCL) is a rare, lethal disease generally seen in young male patients with inflammatory bowel disease. TNF-α Inhibitor treatments (infliximab, adalimumab, certolizumab, natalizumab, and etanercept) are thought to be the cause of this rare disease.[79]

Endoscopic image of colon cancer identified in the sigmoid colon on screening colonoscopy for Crohn's disease

Major complications

Major complications of Crohn's disease include

hemorrhage, which in rare cases may be fatal.[80][81]

Other complications

Individuals with Crohn's disease are at risk of

total parenteral nutrition (TPN). Most people with moderate or severe Crohn's disease are referred to a dietitian for assistance in nutrition.[82]

meteorism, flatulence, and abdominal pain, mimicking acute flare in these patients.[68]

Pregnancy

Crohn's disease can be problematic during

sperm count or otherwise adversely affect a man's fertility.[83]

Ostomy-related complications

Common complications of an

ostomy (a common surgery in Crohn's disease) are: mucosal edema, peristomal dermatitis, retraction, ostomy prolapse, mucosal/skin detachment, hematoma, necrosis, parastomal hernia, and stenosis.[84]

Etiology

The

Autoinflammatory diseases are diseases where the innate immune system, or the immune system we are genetically coded with, is designed to attack our own cells.[86] Crohn's disease likely has involvement of both the adaptive and innate immune systems.[87]

Autoinflammatory theory

Crohn's disease can be described as a multifactorial autoinflammatory disease. The etiopathogenesis of Crohn's disease is still unknown. In any event, a loss of the regulatory capacity of the immune apparatus would be implicated in the onset of the disease. In this respect interestingly enough, as for

autosomal-dominant disease. All this new knowledge in the pathogenesis of Crohn's disease allows us to put this multifactorial disease in the group of autoinflammatory syndromes.[86]

Some examples of how the innate immune system affects bowel inflammation have been described.

CD4+ T cell apoptosis, thus avoiding the T cell response to normal bowel micro bacteria. Further studies of IBD patients compared with non-IBD patients found that the expression of MHC II by ILC3 was significantly reduced in IBD patients, thus causing an immune reaction against intestinal cells or normal bowel bacteria and damaging the intestines. This can also make the intestines more susceptible to environmental factors, such as food or bacteria.[87]

The thinking is that because Crohn's disease has strong innate immune system involvement and has NOD2 mutations as a predisposition, Crohn's disease is more likely an autoinflammatory disease than an autoimmune disease.[87]

Immunodeficiency theory

A substantial body of data has emerged in recent years to suggest that the primary defect in Crohn's disease is actually one of relative

monogenic disorders impairing phagocyte function.[89]

Risk factors

Risk factors
Crohn's disease Ulcerative colitis
Smoking Higher risk for smokers Lower risk for smokers[90]
Age Usual onset between
15 and 30 years[91]		 Peak incidence between
15 and 25 years

While the exact cause or causes are unknown, Crohn's disease seems to be due to a combination of environmental factors and genetic predisposition.[92] Crohn's is the first genetically complex disease in which the relationship between genetic risk factors and the immune system is understood in considerable detail.[93] Each individual risk mutation makes a small contribution to the overall risk of Crohn's (approximately 1:200). The genetic data, and direct assessment of immunity, indicates a malfunction in the innate immune system.[94] In this view, the chronic inflammation of Crohn's is caused when the adaptive immune system tries to compensate for a deficient innate immune system.[95]

Genetics

CARD domains (red) connected via helical linker (blue) with central NBD domain (green). At C-terminus LRR domain (cyan) is located. Additionally, some mutations which are associated with certain disease patterns in Crohn's disease are marked in red wire representation.[96]

Crohn's has a genetic component.[97] Because of this, siblings of known people with Crohn's are 30 times more likely to develop Crohn's than the general population.[98]

The first mutation found to be associated with Crohn's was a

SLC11A1.[107]
There is considerable overlap between susceptibility loci for IBD and
mycobacterial infections.[108] Genome-wide association studies have shown that Crohn's disease is genetically linked to coeliac disease.[109]

Crohn's has been linked to the gene

waste product in cells, and is also associated with Parkinson's disease.[110]

Immune system

There was a prevailing view that Crohn's disease is a primary

Th17 cytokine response.[112][113]

In 2007, the ATG16L1 gene was implicated in Crohn's disease, which may induce

parasites inside the body and that the lack thereof due to modern hygiene standards has weakened the immune system. Test subjects were reintroduced to harmless parasites, with positive responses.[114]

Microbes

It is hypothesized that maintenance of

GI tract is dysregulated, either as a result or cause of immune dysregulation.[115][116]

There is an apparent connection between Crohn's disease,

secondary infections.[121]

NOD2 is a gene involved in Crohn's genetic susceptibility. It is associated with

TNF-α.[123][124]

Other studies have linked specific strains of enteroadherent E. coli to the disease.[125] Adherent-invasive Escherichia coli (AIEC), more common in people with CD,[126][127][125] have the ability to make strong biofilms compared to non-AIEC strains correlating with high adhesion and invasion indices[128][129] of neutrophils and the ability to block autophagy at the autolysosomal step, which allows for intracellular survival of the bacteria and induction of inflammation.[130] Inflammation drives the proliferation of AIEC and dysbiosis in the ileum, irrespective of genotype.[131] AIEC strains replicate extensively inside macrophages inducing the secretion of very large amounts of TNF-α.[132]

Mouse studies have suggested some symptoms of Crohn's disease, ulcerative colitis, and irritable bowel syndrome have the same underlying cause. Biopsy samples taken from the colons of all three patient groups were found to produce elevated levels of a serine protease.[133] Experimental introduction of the serine protease into mice has been found to produce widespread pain associated with irritable bowel syndrome, as well as colitis, which is associated with all three diseases.[134] Regional and temporal variations in those illnesses follow those associated with infection with the protozoan Blastocystis.[135]

The "cold-chain" hypothesis is that

psychrotrophic bacteria such as Yersinia and Listeria species contribute to the disease. A statistical correlation was found between the advent of the use of refrigeration in the United States and various parts of Europe and the rise of the disease.[136][137][138]

There is also a tentative association between Candida colonization and Crohn's disease.[139]

Still, these relationships between specific pathogens and Crohn's disease remain unclear.[140][141]

Environmental factors

The increased incidence of Crohn's in the

milk protein, and an increased ratio of omega-6 to omega-3 polyunsaturated fatty acids.[142]
Those who consume vegetable proteins appear to have a lower incidence of Crohn's disease. Consumption of fish protein has no association.[142] Smoking increases the risk of the return of active disease (flares).[6] The introduction of hormonal contraception in the United States in the 1960s is associated with a dramatic increase in incidence, and one hypothesis is that these drugs work on the digestive system in ways similar to smoking.[143] Isotretinoin is associated with Crohn's.[144][145][146]

Although

stress is sometimes claimed to exacerbate Crohn's disease, there is no concrete evidence to support such claim.[3] Still, it is well known that immune function is related to stress.[147] Dietary microparticles, such as those found in toothpaste, have been studied as they produce effects on immunity, but they were not consumed in greater amounts in patients with Crohn's.[148][149] The use of doxycycline has also been associated with increased risk of developing inflammatory bowel diseases.[150][151][152] In one large retrospective study, patients who were prescribed doxycycline for their acne had a 2.25-fold greater risk of developing Crohn's disease.[151]

Pathophysiology

Pathophysiology
Crohn's disease Ulcerative colitis
Cytokine response Associated with
Th17[153]
 Vaguely associated with
Th2

During a colonoscopy, biopsies of the colon are often taken to confirm the diagnosis. Certain characteristic features of the pathology seen point toward Crohn's disease; it shows a transmural pattern of inflammation, meaning the inflammation may span the entire depth of the intestinal wall.[1]

Granulomas, aggregates of macrophage derivatives known as giant cells, are found in 50% of cases and are most specific for Crohn's disease. The granulomas of Crohn's disease do not show "caseation", a cheese-like appearance on microscopic examination characteristic of granulomas associated with infections, such as tuberculosis. Biopsies may also show chronic mucosal damage, as evidenced by blunting of the intestinal villi, atypical branching of the crypts, and a change in the tissue type (metaplasia). One example of such metaplasia, Paneth cell metaplasia, involves the development of Paneth cells (typically found in the small intestine and a key regulator of intestinal microbiota) in other parts of the gastrointestinal system.[154][155]

Diagnosis

The diagnosis of Crohn's disease can sometimes be challenging,

Giant (multinucleate) cells, a common finding in the lesions of Crohn's disease, are less common in the lesions of lichen nitidus.[157]

  • Endoscopic image of Crohn's colitis showing deep ulceration
    Endoscopic image of Crohn's colitis showing deep ulceration
  • CT scan showing Crohn's disease in the fundus of the stomach
    CT scan showing Crohn's disease in the fundus of the stomach
  • Section of colectomy showing transmural inflammation
    Section of colectomy showing transmural inflammation
  • Resected ileum from a person with Crohn's disease
    Resected ileum from a person with Crohn's disease

Classification

Distribution of gastrointestinal Crohn's disease.

Crohn's disease is one type of inflammatory bowel disease (IBD). It typically manifests in the gastrointestinal tract and can be categorized by the specific tract region affected.

Gastroduodenal Crohn's disease causes inflammation in the stomach and the first part of the small intestine called the duodenum. Jejunoileitis causes spotty patches of inflammation in the top half of the small intestine, called the jejunum.[158] The disease can attack any part of the digestive tract, from mouth to anus. However, individuals affected by the disease rarely fall outside these three classifications, with presentations in other areas.[1]

Crohn's disease may also be categorized by the behavior of disease as it progresses. These categorizations formalized in the Vienna classification of the disease.

Inflammatory disease (or nonstricturing, nonpenetrating disease) causes inflammation without causing strictures or fistulae.[159][160]

Endoscopy

A

gastroenterologist can also perform a biopsy, taking small samples of tissue for laboratory analysis, which may help confirm a diagnosis. As 30% of Crohn's disease involves only the ileum,[1] cannulation of the terminal ileum is required in making the diagnosis. Finding a patchy distribution of disease, with involvement of the colon or ileum, but not the rectum, is suggestive of Crohn's disease, as are other endoscopic stigmata.[161]
The utility of capsule endoscopy for this, however, is still uncertain.[162]

Radiologic tests

A

small bowel follow-through may suggest the diagnosis of Crohn's disease and is useful when the disease involves only the small intestine. Because colonoscopy and gastroscopy allow direct visualization of only the terminal ileum and beginning of the duodenum, they cannot be used to evaluate the remainder of the small intestine. As a result, a barium follow-through X-ray, wherein barium sulfate suspension is ingested and fluoroscopic images of the bowel are taken over time, is useful for looking for inflammation and narrowing of the small bowel.[161][163] Barium enemas, in which barium is inserted into the rectum and fluoroscopy is used to image the bowel, are rarely used in the work-up of Crohn's disease due to the advent of colonoscopy. They remain useful for identifying anatomical abnormalities when strictures of the colon are too small for a colonoscope to pass through, or in the detection of colonic fistulae (in this case contrast should be performed with iodate substances).[164]

small bowel as well as looking for complications, though it is more expensive and less readily available.[167] MRI techniques such as diffusion-weighted imaging and high-resolution imaging are more sensitive in detecting ulceration and inflammation compared to CT.[168][169]

Blood tests

A complete blood count may reveal anemia, which commonly is caused by blood loss leading to iron deficiency or by vitamin B12 deficiency, usually caused by ileal disease impairing vitamin B12 absorption. Rarely autoimmune hemolysis may occur.[170] Ferritin levels help assess if iron deficiency is contributing to the anemia. Erythrocyte sedimentation rate (ESR) and C-reactive protein help assess the degree of inflammation, which is important as ferritin can also be raised in inflammation.[171]

Other causes of anemia include medication used in treatment of inflammatory bowel disease, like azathioprine, which can lead to cytopenia, and sulfasalazine, which can also result in folate deficiency. Testing for Saccharomyces cerevisiae antibodies (ASCA) and antineutrophil cytoplasmic antibodies (ANCA) has been evaluated to identify inflammatory diseases of the intestine[172] and to differentiate Crohn's disease from ulcerative colitis.[173] Furthermore, increasing amounts and levels of serological antibodies such as ASCA, antilaminaribioside [Glc(β1,3)Glb(β); ALCA], antichitobioside [GlcNAc(β1,4)GlcNAc(β); ACCA], antimannobioside [Man(α1,3)Man(α)AMCA], antiLaminarin [(Glc(β1,3))3n(Glc(β1,6))n; anti-L] and antichitin [GlcNAc(β1,4)n; anti-C] associate with disease behavior and surgery, and may aid in the prognosis of Crohn's disease.[174][175][176][177]

Low serum levels of vitamin D are associated with Crohn's disease.[178] Further studies are required to determine the significance of this association.[178]

Comparison with ulcerative colitis

The most common disease that mimics the symptoms of Crohn's disease is ulcerative colitis, as both are inflammatory bowel diseases that can affect the colon with similar symptoms. It is important to differentiate these diseases, since the course of the diseases and treatments may be different. In some cases, however, it may not be possible to tell the difference, in which case the disease is classified as indeterminate colitis.[1][37][38]

Diagnostic findings
Crohn's disease Ulcerative colitis
Terminal ileum
involvement		 Commonly Seldom
Colon involvement Usually Always
Rectum involvement Seldom Usually (95%)[90]
Involvement around
the anus		 Common[179] Seldom
Bile duct involvement No increase in rate of primary sclerosing cholangitis Higher rate[180]
Distribution of disease Patchy areas of inflammation (skip lesions) Continuous area of inflammation[90]
Endoscopy Deep geographic and serpiginous (snake-like)
ulcers
 Continuous ulcer
Depth of inflammation May be transmural, deep into tissues[179][181] Shallow, mucosal
Stenosis Common Seldom
Granulomas on biopsy May have non-
intestinal crypt granulomas[179][182][183]
 Non-peri-
intestinal crypt granulomas not seen[184]

Differential diagnosis

Other conditions with similar symptoms as Crohn's disease includes intestinal

intestinal villi atrophy.[187][188]

Management

Main article: Management of Crohn's disease
Management
Crohn's disease
Ulcerative colitis
Mesalazine Less useful[189] More useful[189]
Antibiotics Effective in long-term[190] Generally not useful[191]
Surgery Often returns following
removal of affected part		 Usually cured by removal
of colon

There is no cure for Crohn's disease and

acute
problem and its symptoms, then maintaining remission of the disease.

Lifestyle changes

Certain lifestyle changes can reduce symptoms, including dietary adjustments, elemental diet, proper hydration, and smoking cessation. Recent reviews underlined the importance to adopt diets that are best supported by evidence, even if little is known about the impact of diets on these patients.[193][194] Diets that include higher levels of fiber and fruit are associated with reduced risk, while diets rich in total fats,

terminal ileum, cobalamin injections. Smoking may worsen symptoms and the course of the disease, and stopping is recommended. Alcohol consumption can also worsen symptoms, and moderation or cessation is advised.[192]

Medication

Acute treatment uses medications to treat any infection (normally

Clostridium difficile.[197]

Medications used to treat the symptoms of Crohn's disease include

certolizumab,[199] vedolizumab, ustekinumab,[200] natalizumab,[201][202]risankizumab-rzaa, and upadacitinib[203] Hydrocortisone should be used in severe attacks of Crohn's disease.[204] Biological therapies are medications used to avoid long-term steroid use, decrease inflammation, and treat people who have fistulas with abscesses.[36] The monoclonal antibody ustekinumab appears to be a safe treatment option, and may help people with moderate to severe active Crohn's disease.[205] The long term safety and effectiveness of monoclonal antibody treatment is not known.[205] The monoclonal antibody briakinumab is not effective for people with active Crohn's disease and it is no longer being manufactured.[205]

The gradual loss of blood from the gastrointestinal tract, as well as chronic inflammation, often leads to anemia, and professional guidelines suggest routinely monitoring for this.[206][207][208]

Immunosuppressant therapies, infection risks and vaccinations

Many patients affected by Crohn's disease need immunosuppressant therapies, which are known to be associated with a higher risk of contracting opportunistic infectious diseases and of pre-neoplastic or neoplastic lesions such as cervical high-grade dysplasia and cancer.[209][210] Many of these potentially harmful diseases, such as Hepatitis B, Influenza, chickenpox, herpes zoster virus, pneumococcal pneumonia, or human papilloma virus, can be prevented by vaccines. Each drug used in the treatment of IBD should be classified according to the degree of immunosuppression induced in the patient. Several guidelines suggest investigating patients’ vaccination status before starting any treatment and performing vaccinations against Vaccine-preventable disease when required.[211][212] Compared to the rest of the population, patients affected by IBD are known to be at higher risk of contracting some

vaccine-preventable diseases such as flu and pneumonia.[213]
Nevertheless, despite the increased risk of infections, vaccination rates in IBD patients are known to be suboptimal and may also be lower than vaccination rates in the general population.[214][215]

Surgery

Crohn's cannot be cured by surgery, as the disease eventually recurs, though it is used in the case of partial or full blockage of the intestine.[216] Surgery may also be required for complications such as obstructions, fistulas, or abscesses, or if the disease does not respond to drugs. After the first surgery, Crohn's usually comes back at the site where the diseased intestine was removed and the healthy ends were rejoined; it can also come back in other locations. After a resection, scar tissue builds up, which can cause strictures, which form when the intestines become too small to allow excrement to pass through easily, which can lead to a blockage. After the first resection, another resection may be necessary within five years.[217] For patients with an obstruction due to a stricture, two options for treatment are strictureplasty and resection of that portion of bowel. There is no statistical significance between strictureplasty alone versus strictureplasty and resection in cases of duodenal involvement. In these cases, re-operation rates were 31% and 27%, respectively, indicating that strictureplasty is a safe and effective treatment for selected people with duodenal involvement.[218]

Postsurgical recurrence of Crohn's disease is relatively common. Crohn's lesions are nearly always found at the site of the resected bowel. The join (or anastomosis) after surgery may be inspected, usually during a colonoscopy, and disease activity graded. The "Rutgeert's score" is an endoscopic scoring system for postoperative disease recurrence in Crohn's disease. Mild postsurgical recurrences of Crohn's disease are graded i1 and i2, moderate to severe recurrences are graded i3 and i4.[219] Fewer lesions result in a lower grade. Based on the score, treatment plans can be designed to give the patient the best chance of managing the recurrence of the disease.[220]

intestinal transplant surgery may be considered; though the number of transplant centres offering this procedure is quite small and it comes with a high risk due to the chance of infection and rejection of the transplanted intestine.[222]

Bile acid diarrhea is another complication following surgery for Crohn's disease in which the terminal ileum has been removed. This leads to the development of excessive watery diarrhea. It is usually thought to be due to an inability of the ileum to reabsorb bile acids after resection of the terminal ileum and was the first type of bile acid malabsorption recognized.[223]

Microbiome modification

The use of oral

controlled trials were available in 2020, with no clear overall evidence of higher remission nor lower adverse effects, in people with Crohn's disease receiving probiotic supplementation.[224]

Mental health

Crohn's may result in

mood disorders, especially in young people who may have stunted growth or embarrassment from fecal incontinence.[225] Counselling as well as antidepressant or anxiolytic medication may help some people manage.[225]

As of 2017[update] there is a small amount of research looking at

cognitive behavioural therapy.[226]

Alternative medicine

It is common for people with Crohn's disease to try

herbal
and nutritional supplements.

Prognosis

Crohn's disease is a

chronic condition for which there is no known cure. It is characterised by periods of improvement followed by episodes when symptoms flare up. With treatment, most people achieve a healthy weight, and the mortality rate for the disease is relatively low. It can vary from being benign to very severe, and people with CD could experience just one episode or have continuous symptoms. It usually reoccurs, although some people can remain disease-free for years or decades. Up to 80% of people with Crohn's disease are hospitalized at some point during the course of their disease, with the highest rate occurring in the first year after diagnosis.[11] Most people with Crohn's live a normal lifespan.[238] However, Crohn's disease is associated with a small increase in risk of small bowel and colorectal carcinoma (bowel cancer).[239]

Epidemiology

The percentage of people with Crohn's disease has been determined in

Crohn's & Colitis Foundation of America cites this number as approx 149:100,000; NIH cites 28 to 199 per 100,000.[240][241] Crohn's disease is more common in northern countries, and with higher rates still in the northern areas of these countries.[242] The incidence of Crohn's disease is thought to be similar in Europe but lower in Asia and Africa.[240] It also has a higher incidence in Ashkenazi Jews[1][243] and smokers.[244]

Crohn's disease begins most commonly in people in their teens and 20s, and people in their 50s through to their 70s.[1][37][26] It is rarely diagnosed in early childhood. It usually affects female children more severely than males.[245] However, only slightly more women than men have Crohn's disease.[246] Parents, siblings or children of people with Crohn's disease are 3 to 20 times more likely to develop the disease.[247] Twin studies find that if one has the disease there is a 55% chance the other will too.[248]

The incidence of Crohn's disease is increasing in Europe[249] and in newly industrialised countries.[250] For example, in Brazil, there has been an annual increase of 11% in the incidence of Crohn's disease since 1990.[250]

History

Main article: List of people diagnosed with Crohn's disease

Inflammatory bowel diseases were described by Giovanni Battista Morgagni (1682–1771) and by Scottish physician Thomas Kennedy Dalziel in 1913.[251]

Ileitis terminalis was first described by Polish surgeon

Mount Sinai Hospital, described fourteen cases in 1932, and submitted them to the American Medical Association under the rubric of "Terminal ileitis: A new clinical entity". Later that year, he, along with colleagues Leon Ginzburg and Gordon Oppenheimer, published the case series "Regional ileitis: a pathologic and clinical entity". However, due to the precedence of Crohn's name in the alphabet, it later became known in the worldwide literature as Crohn's disease.[27]

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Further reading

External links

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