Contents
- Summary
- More Information
- Ulcerative Colitis
- Crohn’s Disease
Summary
Summary table of Crohn’s disease vs Ulcerative Colitis.
Crohn’s | UC | ||||
Incidence | 5-10 per 100 000 | 10 to 20 per 100 000 | |||
Mean age of onset | 26 Can also present in children – failure to thrive and also in those in their 60’s | 34 | |||
Male: Female | 1.2 : 1 | 1 : 1.2 | |||
Affects | Any part of GI-tract, most commonly the terminal ileum. Also commonly affects the rectum, but not the colon | Only colon, usually more distal regions are worse affected | |||
Mortality | Low | Lower | |||
Surgery required in | 50-80% | 20% | |||
Skip lesions | Yes | No | |||
Mucosal Layers | Deeper | More superficial | |||
Complications | Fistula, abscess, stricture. Most commonly the fistulae come from the anus to the peri-anal region and the produce pus | Rare. Toxic megacolon | |||
pANCA | Negative | Positive | |||
Race | Most common in Caucasians | Most common in Caucasians | |||
Protective factors | High residue, low sugar diet, relatives with Crohn’s means you have an INCREASED RISK | Smoking, appendicectomy, high reside low sugar diet | |||
Pathology | Thought to be very similar in both diseases. In genetically susceptible individuals there is an adverse reaction to bacterial lipopolysaccharide. Normally the reaction against this is self limiting, but in IBD patients once the inflammation starts it may not stop. Thus ultimately it is a kind of autoimmune disease – and the inflammation ends up damaging the gut wall. The diseases follow a relapsing and remising course. | ||||
Symptoms | Right iliac fossa mass/pain – this is present even when there is no abscess, abdominal discomfort, blood in the stools, vitamin B12 and iron deficiencies – Crohn’s commonly affects the small intestine and thus can cause malabsorption. | Diarrhoea due to excess mucus production. often also contains blood. Abdominal discomfort, bloating . symptoms usually less severe than Crohn’s | |||
Extra-intestinal symptoms | These are generally the same for both conditions. They include; large joint arthritis, irisitis (like conjunctivitis, but worse), erythema nodosum (red rashes on the shins, more common in UC), ulcers on mucous membranes (mouth and vagina – more common in Crohn’s), cholangitis, pyoderma gangrenosum – this is nasty dead black necrotic tissue. Most commonly found on the legs and around the stoma, renal stones, gallstones, fatty liver, fat wrapping – only occurs in Crohn’s – this is where the messenetric fat spreads around the intestine Crohn’s disease is associated with an increased risk of bowel cancer –this is typically adenocarcinoma of the distal ileum | ||||
Signs | The acute presentation may be mistaken for appendicitis. However, a good history may reveal some facts pointing to a background acute disease. | May be few in mild disease.may include weight loss and malaise. In an acute attack there can be fever, malaise, iron def anaemia, raised WBC, platelets and ESR, hypoalbuminaemia | |||
Barium swallow | This is the most useful test. It can show areas of stricture, shortening of small bowel, fistulas and abscesses | PR | Blood | ||
CT | Will shows areas of wall thickening, strictures and abscesses | CT | Thickened bowel wall | ||
Colonoscopy | Not that useful but can biopsy. Also may help you differentiate pseudopolyps from true polyps | Barium enema | Reduced haustral folds due to fibrosis | ||
CLUBBING! | |||||
Treatment | Cessation of smoking may induce remission in some patients. 5-ASA compounds are not typically used Immunosuppresants used in severe disease. 80% of Crohn’s patients will eventually require surgery. Many require B12 and iron supplements. Low residue diets and low fat diets can help reduce symptoms. Patients may need to be given supplements of the fat soluble vitamins (A D E K). patients are often given antibiotics to reduce the intestinal flora and diarrhoea – metronidazole Infliximab is used in patients that don’t respond to other types of treatment. 70% of Crohn’s patients will respond to it. It is particularly useful in perianal disease | Mild disease: 5-ASA Moderate disease: steroid to initiate remission, then 5-ASA for maintenance Severe disease: trial steroid for 5-7 days. If no remission, then operate immediately. Try to maintain remission with 5-ASA, if not then immunosuppressants may be used. Steroids are often given as a rectal foam | |||
In 10% of cases it is not possible to differentiate from Crohn’s disease or UC, and thus these patients are said to have indeterminate colitis.
Drugs
Drug | Mechanism | Side-effects | Info |
Sulfasalazine* (ASA) | Not fully understood. Thought to trap free radicals released in the inflammatory process | Headache, nausea, vomiting, oligpspermia (low semen volume, but not reduced sperm count), rashes, nephrotoxicity | Can both initiate and maintain remission. Other 5-ASAs include mesalazine and olsalazine. Both are thought to be less effective than sulfasalazine. |
| Corticosteroids | Effective at quickly getting symptoms under control. | Minimal in short-term use. Common in long-term or multiple use patients. | Used in acute flares of moderate to severe disease that has not responded to other treatments. |
Azathioprine | Immunomodulator. Inhibits purine synthesis. reduces the turnover rate of quickly dividing cells | Nausea, vomiting skin rashes, and other similar to other immunosupressants. | Side effects tend to reduce after 6 weeks. Immunomodulators are useful for maintaining remission, but slow to induce remission. Azathioprine is usually the first line immunomodulator. Widely used for maintenance of remission, particularly in CD |
Methotrexate | Immunomodulator. Inhibits the metabolism of folic acid. Reduces the turnover rate of quickly dividing cells | Similar to above | Not licensed for Crohn’s. Evidence for its efficacy is not as good as azathioprine, particularly for UC. |
Infliximab and other monoclonal antibodies | Monoclonal antibody – this is an antibody to TNFα. Prevents TNF alpha binding to its binding site, and thus reduces inflammation. | Not licensed for UC. Other examples of monoclonal antibodies include adalimumab, vedolizumab. | |
| Cyclosporin | Immunosuppressant. Inhibits T cell division. A calcineurin inhibitor – as is Tacrolimus. | Nephrotoxicity, hypertension, hepatic dysfunction, tremor, headache, anorexia, nausea, vomiting, gum hypertrophy, excessive hair growth | Generally a last resort in patients whom are not responding to high dose IV steroids. |
*this is actually a combination of an ASA compound and a sulphapyridine. The sulphapyridine makes the drug pH sensitive, thus it is activated at the right place in the bowel (i.e. the colon).
Surgery
Crohn’s | Bowel resection – patients will often have to have several resections during their lifetime. Thus when you operate, you should be as conservative as possible. you should remove the affected area, and 2cm either side. Big wide resections do not decrease the recurrence rate. you should try to avoid small bowel syndrome by resecting too large an area Stricturoplasty In the case of a severe stricture, you can cut the bowel lengthways along the stricture, and then sew it back together to widen the strictured part. Surgery is generally reserved for stricutres, fistulas, disease that does not respond to drug treatments. Abscesses are generally treated by percutaneous drainage and not by surgery Fistulas can exist between parts of the bowel, e.g. between the small and large intestines. These can affect absorption After surgery many patients will have a massive initial improvement in symptoms. |
UC | The whole colon has to be removed, otherwise the disease will return in the part of the colon you have not taken out. You can either have a permanent ileostomy (rare) or a temporary one (restorative protocolectomy). In the restorative surgery, the colon is removed (1% chance of sexual dysfunction in males) and the end of the ileum is then folded over one itself to create a ‘pouch’. This pouch becomes the rectum. It requires two separate operations. One to create the pouch, the other to connect the pouch to the anus. It can be done in one, but this increases the risk of sepsis. After the operation, patients will have to empty the bowel about 5-6 times a day, but there will not usually be urgency. There are often n other symptoms, and thus for many patients, this is better than the symptoms they experiences during exacerbations of UC. Most patients will take anti-diarrhoeal agents at some point. |
Toxic megacolon – this is where the colon becomes massively distended. It can induce tachycardia and shock, and may also present with fever. It is a medical emergency, and if it does not respolve, will require surgery to prevent perforation
More Information
There are two major types of non-specific inflammatory disease: Crohn’s disease and Ulcerative colitis. There is a great degree of overlap between the two diseases – in 10% of cases in cannot be determined which disease is present.
In such cases, the condition is known as indeterminate colitis and tends to look more like UC than Crohn’s, but it may involve skip lesions, or a rare variant of UC.
In cases where indeterminate colitis has to be surgically managed, then a colectomy and pouch formation is usually best advised, although the pouch failure rate is higher than in UC.
Both diseases follow a relapsing and remitting course.
In patients with a negative faecal occult blood test (FOBT) and negative faecal calprotectin, a diagnosis of IBD is very unlikely.
Comparison
- Crohn’s is very rare in the developing world, whilst UC, although still rare is becoming more common.
- Both disease are most common in young adults. There is also a second incidence peak in the 7th decade.
- Crohn’s mean age of onset is 26
- UC mean age of onset is 34.
- Incidence of UC – 10-20 per 100 000
- Incidence of Crohn’s – 5-10 per 100 000
- The main distinction is that ulcerative colitis only involves the colon, whilst Crohn’s disease can involve any part of the GIt from the mouth to the anus. Crohn’s most commonly affects the distal ileum, however, differentiating between the two diseases can be difficult when Crohn’s also involves the large bowel.
- Crohn’s tends to affect the terminal ileum more than anywhere else. ‘Satellite ‘ lesions may occur in the skin, distal from the main affected region, but these are rare. It is also quite rare for any region outside of the small and large intestine to be affected.
- Both diseases are more present in the west than the rest of the world. Non-whites are less likely to suffer, whilst there is a specifically high incidence amongst the Jewish community.
- Crohn’s disease is slightly more common in females than males
- Crohn’s is very slightly more common in females – M:F – 1-12, but the exact opposite ratio is true for UC.
- Test for pANCA is different in each disease – test is positive in UC and negative in Crohn’s.
- Surgery is required in about 20%of UC, but 50-80% of crohns.
- Crohn’s has ‘skip lesions’ whilst UC occurs in one continuous band of inflammation.
- Crohn’s disease affects deeper layers of the mucosa than UC
- Crohn’s can cause complications such as fistulation and structuring that are rarely seen in UC.
- The extra-intestinal symptoms of Crohn’s and UC are the same.
- Mortality of slightly higher for Crohn’s than UC, although both are relatively low.
Aetiology
- High concordance in identical twins(50% chance if you have twin with disease – 10% chance if sibling, 1/1000 in general population)
- 10% of patients have a relative who also suffers from IBD
- Associated with other auto-immune diseases
- UC is more common in non-smokers and ex-smokers
- Crohn’s is more likely in smokers than non-smokers (3-4x).
- Associated with low-residue, high refined sugar diet
- Appendicectomy protects against UC.
- Bacteria! Certain bacteria trigger the disease.
Therefore you get the disease as a result of bacterial antigens in genetically susceptible people.
Ulcerative Colitis
Epidemiology
- Most often affects Caucasians in temperate climates.
- It is very rare in Africa and Asia
- It is roughly 2-3x more common than Crohn’s. Although the incidence of Crohn’s is increasing.
- Incidence varies somewhat across developed contires, however some of this difference can be attributed to the fact that some countries class proctitis as a separate disease, whilst some say it is just UC confined to the rectum.
- Similar incidence between males and females.
Pathology
- There is continuous inflammation, that tends to be worse distally and the rectum is almost always involved.
- The inflammation is generally confined to the mucosa and submucosa. It is this inflammation that leads to excess production of mucous and triggers the diarrhoea.
The disease will develop as a result of an environmental trigger in a genetically susceptible individual. There are many cellular stages involved in the course of the disease, and these stages will probably be the target for future clinical intervention. The mechanism is thought to be the same in both UC and Crohn’s.
- Initially, bacterial or dietary antigens are taken up by M cells and pass into the lamina proporia through a ‘leaky’ gap between cells or through a lesion.
- The antigens are picked up by antigen presenting cells in the lamina proporia, causing them to secrete pro-inflammatory cytokines, such as TNF-α and IL-12 and IL-18.
- This effect, coupled with the presentation of antigens to the CD4+ T cells, results in activation of TH1 cells. These secrete further cytokines, attracting many more T cells to the region. This build up of T cells will lead to a full blown inflammatory response, including increased vascular adhesion and all that stuff. This can lead to ulceration and stricture formation.
- There may also be accompanying fever, malaise and anorexia.
In normal patients, this process is self-limiting, but in genetically susceptible individuals, something goes wrong, whereby it does not stop, and massive inflammation, ulceration and structuring can occur. It is thought that the main culprit in initiating this response in a genetically susceptible individual is bacterial lippolysaccharide.
In Crohn’s disease, two specific mutations have been identified; the CARD 15 and NOD-2 genes on chromosome 16 are thought to be responsible in some patients.
Basically, there is just massive inflammation of parts of the bowel wall, with resulting strictures and ulcers.
Crohn’s affects much deeper layers of bowel than UC. Therefore Crohn’s disease can fistulate, but UC cannot. There are four main types of fistulae. Complex severe fistulating Crohn’s is a death threat. Strictures are also a common complication that you cannot get in UC.
Proctitis – this refers UC that occurs only in the last 6 inches of the rectum. It also refers to any form of inflammation in the rectum.
Proctocolitis – means inflammation in the colon and rectum – i.e. more generalised than proctitis
Pancolitis – inflammation affecting the whole of the colon.
Clinical Features
- These vary widely depending on the severity of the disease.
- The most common presentation is bloody diarrhoea in an otherwise fit patient. There may also be mucous and pus in the stool, and some slight abdominal discomfort.
- Tenesmus may occur if the rectum is involved.
- Patients with protosigmoiditis may also have tenesmus.
- There may be generally symptoms of malaise and anorexia.
- Abdominal pain often results from stricture – it comes on after eating – as a result the patient eats less – and may lose weight.
- Urgency and tenesmus – these are related to inflammation of the rectum.
- clubbing
There are many other vague symptoms affecting various areas of the body:
- Mucous membranes – Ulcers in mouth and vagina
- Joints – Arthralgia / arthritis in large joints. 10% with IBD get arthritis in the large joints – knees, shoulders, elbows and spine.
- Eyes – Iritis – a deeper inflammation than conjunctivitis. It is inflammation of the iris. 5-10% of IBD sufferers will get this.
- kin
- Erythema nodosum – painful itchy raised round lumps in the skin 1-5cm. 5% of IBD sufferers will have these. Most commonly on the legs.
- Pyoderma gangrenosum – pussy dead tissue – a black necrotis ulcerating mass. Most commonly on the legs or around the stoma. 2% of IBD sufferes will have this.
- Bile ducts / Liver – Cholangitis. This is one of the biggest killers in IBD – death results from liver failure. It occurs in less than 1% of cases of IBD.
Some patients may only ever have one attack, and then be in remission for the rest of their life. 10% of patients will have chronic disease for the rest of their life – i.e. it never goes into remission.
Disease confined to the rectum is generally not pathologically problematic; however it causes ‘inconvenient’ symptoms, such as urgency, tenesmus and blood mixed with the stool. This type of the disease is known as proctitis.
Acute attack
This will cause bloody diarrhoea and the patient may pass liquid stools up to 20x a day. Sometimes they pass only mucous / blood (i.e. no faeces). This trend may also continue during the night ans is very disabling for the patient.
Other signs of an acute attack include:
- Fever (>37.5’)
- Tachycardia (>90bpm)
- ESR >30mm/hour
- Anaemia – <10g/dl haemoglobin
- Albumin – <30g/L
The disease often starts off in the rectum and then progresses up the colon. Very occasionally the distal ileum will be affected, but this is thought to be chronic inflammation as a result of incompetence of the ileocaecal valve, rather than direct pathology affecting this part of the small bowel.
Generally, there are very few signs, and often few symptoms. The symptoms will be related to the part of the bowel that is affected.
Smoking actually decreases your risk of UC! If you have been diagnosed with UC, and then stop smoking, you increase your risk of relapse.
Examination
- There are no obvious signs to look for in UC. The bowel may be slightly distended and tendr to palpation. The anus is usually normal.
- Rectal examination will usually show the presence of blood.
Investigations
PR exam – this may show blood on the glove
Rigid sigmoidoscopy – this will often show abnormal inflamed bleeding mucosa. There may also be ulceration and friability. In very rare cases, the rectum is not involved in the disease and thus the sigmoidoscopy will be normal.
Blood tests – in acute attacks, the following may be observed
- Raised white cell count
- Raised platelets
- Iron deficiency anaemia
- Raised ESR
- Raised CRP
- Hypoalbuminaemia (in more severe disease)
- pANCA may be positive – in Crohn’s disease this is usually negative.
Stool samples – should always be taken to exclude infective causes of colitis.
Plain AXR– may show the presence of air in the colon and colonic dilatation.
Ultrasound – may show thickening of the wall and the presence of free fluid in the abdominal cavity
CT –often used in acute attacks
Most of the imaging techniques above are only used in acute attacks – but this is when the patient presents anyway!
Colonoscopy – is unusual as an investigation in Crohn’s as it should not be performed during an acute attack. In gives a better view of what’s going on than a barium enema. In long-standing chronic disease it is used to assess the extent of the disease. In patients with disease of more than 10 years, colonoscopy should be performed to obtain biopsies of the affected areas to rule out the possibility of malignancy. It is particularly difficult to pick up malignancy on scans due to the appearance of the disease on such tests – i.e. the pathology of normal UC seen on a scan could ‘hide’ the presence of malignancy.
Barium enema – this will show the macroscopic extent of the disease as well as any ulceration. It will show loss of haustral and possibly a shortened colon as a result of scarring and fibrosis.
Rectal biopsy – this may show inflammatory infiltrates, goblet cell depletion, mucous ulcers and crypt abscesses.
Complications
- Perforation
- Bleeding
- Toxic megacolon
- Venous thrombosis – you should consider prophylaxis in hospital once diagnosis is confirmed
- Colon cancer – there is a 15% risk in patients who have had a pancolitis for 20 years or more.
Treatment
Corticosteroids
Common examples include; hydrocortisone, prednisolone and dexamethasone
These can be given orally, IV, or by enema.
They are effective at inducing a remission, but not at maintaining it.
They have many side effects, and this is the main reason why they are not used long-term to maintain the remission. Steroids are very effective at what they do, but the side effects can be nasty.
They are produced naturally by the body in small amounts, and are synthesised as required by the pituitary gland in response to circulating ACTH levels. They are released in a definite circadian rhythm, with the highest levels of secretion in the morning, that gradually reduce throughout the day, until the very low levels at night.
Mechanism
These products enter cells passively via diffusion, and will then bind with cytoplasmic receptors, causing a conformational changes in the receptor, which exposes a DNA binding site. This new complex will then migrate to the nucleus, and bind to a receptor and will cause a change in gene transcription.
About 1% of genes can be regulated in this fashion.
As well as their DNA effects, glucocorticoids cause transduction effects one they have bound to their ligand, but are still floating around in the cytoplasm. The effects caused through this pathway are thought to be those involved in the anti-inflammatory property of steroids.
An activated glucocorticoid receptor will cuse release of the protein annexin-1 which has potent effects on the movement of leukocytes.
The effects on inflammation happen very quickly (within minutes) as opposed to the effects on DNA transcription which occur over a much longer time frame.
Metabolic actions
- Carbohydrates – Glucocorticoids cause a decrease in the utilization of circulation glucose, and an increase in gluconeogenesis. This leads to a tendency for hyperglycaemia. There is also an increase in glucose storage, which is probably a result of increased secreted insulin as a response to the hyperglycaemia.
- Proteins – causes increased catabolism and decreased anabolism – i.e. they cause an overall increase in ‘metabolism’ – breakdown of products to release energy, but a decrease in ‘growth’. Overall there is an increase in protein breakdown, and a decrease in protein synthesis – which can lead to muscle ‘wasting’.
- Fats – has an effect on lypolitic hormones, and causes a redistribution of fat, like that seen in Cushing’s syndrome (e.g. Moon face and buffalo hump)
- Electrolytes – glucocorticoids tend to reduce the amount of calcium in the body by reducing its uptake from the GIt, and increasing its excretion by the kidneys. This can induce osteoperosis. Glucocorticoids are also likely to cause sodium retention and potassium loss.
Regulatory actions
Hypothalamus and anterior pituitary – causes a feedback effect resulting in reduced release of endogenous glucocorticoids
Cardiovascular system – reduced vasodilation and decreased fluid exudation (oozing)
Musculoskeletal system – decreased osteoblast, and decreased osteoclast activity
Inflammation and immunity –
- Acute inflammation – decreased influx and activity of leukocytes
- Chronic inflammation – decreased activity of mononuclear cells, decreased angiogenesis (development of new blood vessels)
- Lymphoid tissues – decreased action of B and T cells, and decreased release of inflammatory mediators by T cells.
- Decreased production of cytokines
- Decreased expression of COX-2 and thus decreased prostaglandin synthesis
- Decreased generation of nitric oxide
- Decreased histamine release from basophils
- Decreased production of IgG
- Decreased complement components in the blood
- Increased anti-inflammatory factors such as IL-10 and annexin-1
- Overall, this results in decreased immune response – both to acquired auto-immune problems, but also to the protective role of the immune system.
Glucocorticoids are the ‘Holy grail’ of treating inflammation. They act on both the late and early stage reactions – and thus are effective in chronic inflammation. They will reverse virtually any type of inflammation, whatever the cause.
They are also useful after graft surgery – because they can suppress the response against the ‘foreign’ tissue.
It is interesting to note that natural levels of glucocorticoids actually rise when our immune system is more active. It is thought this occurs to prevent our immune system from ‘getting out of control’ and threatening homeostasis. Cortisone is a glucocorticoid – its levels have been shown to be high when we are stressed – thus reducing the immune response in times of stress. Note that cortisone and prednisone are inactive until they are converted into hydrocortisone and prednisolone in vivo.
Corticosteroids are inactive in the liver and elsewhere in the body.
Unwanted effects
These are most likely to occur with large and/or prolonged doses.
- Poor wound healing
- Peptic ulceration
- Cushing’s syndrome – which is basically a manifestation of all the metabolic and systemic effects described above.
- Diabetes – as a result of the hyperglycaemia
- Weakness and muscle wasting
- Stunted growth in children – particularly if the treatment is continued for more than 6 months – even if the dose is low.
- CNS effects – often the patient may experience euphoris, but it can also manifest as depression. In depressed patients, the depression may be due to a disruption of the circadian rhythm secretion of the steroids.
- Oral thrush (candidasis) often occurs when the drugs are taken orally, as a result of suppression of local inflammatory processes.
Sudden withdrawal after treatment can result in adrenal insufficiency as a result of the patient’s inability to synthesis corticosteroids. Phased withdrawal patterns should always be followed.
Pharmacokinetics
Corticosteroids can be taken by pretty much any route imaginable! Usually, when they are not given orally, this is to avoid systemic effects.
When systemic therapy is necessary, taking the drug on alternate days has been shown to reduce the risk of side effects.
Endogenous corticosteroids are carried in the blood by corticosteroid-binding globulin (CBG) and albumin. About 77% is carried by CBG. However, when the drug is administered, much of it travels unbound. Bound steroids are inactive – so I guess this means the binding, in normal circumstances – acts as a storage and buffer system.
Hydrocortisone has a half life on 90 minutes, but its effects are present for 2-8 hours after administration.
5-ASA compounds
5-ASA compounds are recommended for:
- First line treatment (induction of remission) of mild to moderate UC
- Mainting remission in UC
- They are less effective in Crohn’s disease
Those with mild to moderate UC should be treated as a first line with an amino-salicylate. They are effective at both inducing and maintaining remission. They are less effective in Crohn’s than in UC, especially when there is no colonic involvement in the Crohn’s disease. The most commonly used form of these is sulfasalazine. Other examples include mesalazine and olsalazine.
- Note that sulfasalazine is metabolised to mesalazine in the gut
5-ASA are absorbed in the gut, and may be nephrotoxic.
- About 20% of sulfasalazine is absorbed by the small intestine.
- The rest remains in the gut lumen and travels to the large intestine, where the bond between the two components (sulphapryridine and mesalazine) is broken by floral bacteria. In some drugs the breaking of this bond is pH dependent – i.e. it breaks at a certain pH, and thus is targeted to a certain part of the GIt. It is not until this bond is broken that the compound has a therapeutic effect. Very little of 5-ASA is absorbed, and it exerts its effect from the lumen itself.
- Sulphapyridine is absorbed, and it metabolised by the liver.
- In some patients, the pH of the colon may be affected by the disease, and as a result, some preparations of 5-ASA in certain patients may pass into the faeces intact.
- The drug can also be given without the sulfapyridine component, and in such cases it is known as mesalazine. However, this is nearly all absorbed in the gut when given orally, and as such it is clinically less effective than sulfasalazine.
The usually dose of sulfasalazine is 2-4g daily. This will benefit about 80% of patients with mild to moderate colitis. It is never used alone in severe colitis. It may be used to try to achieve remission (dose of 4g daily) and then to maintain the remission with a dose of 2g daily.
It can be safely continued during pregnancy.
Mechanism
This is very poorly understood. It is thought that it acts by trapping free radicals, and thus reducing the response of inflammatory cells, and reducing cytokine release.
These drugs are particularly useful at targeting the bowel.
Unwanted Effects
Sulphapyridine
- Headache
- Nausea
- Vomiting
- Rashes
- Oligospermia – low semen volume – NOT a low sperm count
- Agranulocytosis – reduced granulocytes (WBC’s) in the blood
5-ASA
- Nausea, diarrhoea, abdominal pain
- Headache and flushing
- Nephrotoxicity – chronic interstitial nephritis and renal impairment
- Skin rashes
Immunosuppressants
These may be used in severe cases of UC that do not respond to other treatments.
These drugs are often not as effective in Crohn’s, and as such they may often not be licensed for use in Crohn’s, although some practitioners try to give them anyway and get round the rules.
Examples include azathioprine and cyclosporin. They are more commonly used after organ transplant to suppress the host’s immune system.
When used to treat UC they may allow a lower dose of steroid to be used.
Cyclosporin inhibits T cell division, by inhibiting production of IL-2. Cyclosporin also inhibits other activated protein kinases that are activated by IL-1 and TNFα.
It is usually given orally. It has many unwanted effects including:
- Nephrotoxicity. Almost always occurs. The damage caused is usually temporary but can be permanent.
- Hypertension – occurs in about 50% of people as a result of fluid retention
- Hepatic dysfunction
- Tremor
- Headache
- Excessive hair growth and gum hypertrophy
- Anorexia, nausea, vomiting
Azathioprine works by inhibiting the synthesis of purine, and thus inhibiting the proliferation of quickly dividing cells, particularly leukocytes. Side effects are similar to cyclosporin. It is also important to note that because these drugs suppress the immune system, you are at greater risk of succumbing to infection.
Often the side-effects of these drugs will lessen after 6 weeks of use (particularly the nausea, vomiting and skin rashes).
Azathioprine is actually the same drug as 6-mercaptopurine – azathioprine is the pro-drug of this.
Methotrexate is another drug given in UC be not licensed for Crohn’s. It inhibits the metabolism of folic acid, and thus slows the division of quickly dividing cells.
Monoclonal Antibody – aka TNFα antibody
Infliximab is the first of these to be approved for treatment of Crohn’s. it is not licensed for treatment of UC. Infliximab inhibits the binding of TNFα to its receptors, and thus prevents the release of IL-1 and IL-6. TNFα is crucial to the inflammatory cascade. Stopping it will help reduce leukocyte migration, infiltration and activation.
Even in Crohn’s it is only 33% effective. In UC it is much less effective. It costs £1000 a dose and you need a dose every 6-8 weeks. Although its side-effects are rare, they can be serious.
It is given IV roughly every 8 weeks.
Generally, infliximab is used to obtain remission, and remission is maintained with an immunosuppressant.
Some studies have also shown that Infliximab can actually close fistulae in Crohn’s.
Unwanted effects
- Dyspnoea and headache
- Fever, chills, pruritis and urticaria after infusion (15% of people)
- Increased risk of serious infection.
- 12% of patients will develop antibodies to double-stranded DNA as a result of the apoptosis induced by this drug.
Surgery
This is used as a last resort. For many patients with severe chronic UC, the idea of a stoma is much more appealing than having to live with the severe symptoms of UC. However, you cannot remove just the affected part, as the disease will return in part of the colon that you haven’t removed, so you must remove the whole colon.
Surgery is also used in cases of perforation, toxic megacolon, dysplasia and acute attack where there has been no improvement for 72 hours on other treatment.
Toxic megacolon – this is where deeper layer of the bowel become affected, and the colon can become massive and may perforate. It is diagnosed when the diameter of the colon has stretch to more than 6cm.
An acute attack may involve tachycardia, pyrexia and heavy bleeding.
Dysplasia – if there are signs of dysplasia at two separate locations in the colon where the mucosa has turned flat, then this is an indication for surgery to avoid the possibility of malignancy.
Note that perforation is less likely in UC than in Crohn’s due to the fact that UC does not affect as many layers of bowel mucosa.
Also, surgery may be performed if after 5-7 days on steroids, the improvement is so mild that remission is unlikely to be obtainable. You should not keep a patient on steroids for a longer period than this if they show no or little improvement, because their condition is likely to deteriorate, and may deteriorate to such a stage that they become inoperable.
Good resuscitation and management during an acute attack, with subsequent early surgery gives a mortality rate of only 3%.
On the other hand, colonic dilation followed by perforation has a mortality of 33%.
About ½ of patients with severe acute colitis will recover with drug treatment alone, however, many of these will experience further similar attacks in the future and will ultimately require surgery.
Pre-operative management
It is very important that the site of the proposed stoma is marked on the patient carefully and discuss with the patient. You don’t want to end up with a stoma that is in a natural skin crease, as this can be very leaky and difficult to manage by the patient.
Equally, you don’t want to end up with a stoma that is below the level of the waist of the trousers, particularly in men who like to wear their trousers high.
Surgical Options
Restorative proctocolectomy – this involves total removal of the colon and rectum, however, the anal canal and sphincter and associated nerves are left in place for anastomosis. It is possible to perform the whole procedure in one go, but this is associated with higher morbidity and mortality (probably due to the steroids the patient will be on to trea the UC), and so is usually carried out in two or three steps. You need to leave in at least 2cm of anus to rejoin the bits together later on. This surgery carries a 1% risk of sexual dysfunction in males.
The best thing about this surgery is that it will only require a temporary stoma. It will usually involve two operations. In the first, the rectum and colon are removed, and a pouch created with the terminal ileum. This will then be left for about 6 months to ‘bed in’. During this period, the patient will have to have a stoma. This temporary form of stoma is known as a loop ileostomy. After this time, the pouch (which now performs the job of a ‘rectum’) will be joined to the anal canal to create a continuous bowel. The stoma can be removed at this stage.
After this procedure, 80& of patients will make a full recovery, and 20% will experience some morbidity. Complications include; sepsis (which may involve breakdown of the anastomosis), small bowel obstructions, and ileostomy problems.
After surgery, most patients will have continued improvement of symptoms for the first 18months. They will defecate 5-6 times a day, and can usually hold off (i.e. there is not urgency).
There may be faecal spotting for 25% of patients during the day, and 40% at night, however full blown incontinence is rare.
50% of patients will use antidiarrheal agents at some stage.
In 2% of patients, the pouch will fail completely, and have to be taken out.
Some patients will experience ‘pouchitis’ where there is diarrhoea, abdominal cramps, tenesmus, fever and a general feeling of unwell. This is usually treated with metronidazole.
Complete protocolectomy and permanent ileostomy – luckily, this is now rarely performed. It is generally used in elderly patients with poor anal sphincter control, those with advanced stage rectal cancer and in those unwilling to undergo the more complex and lengthy treatment that involves anastomosis.
The ileo-anal pouch
This is where part of the ileum is folded back on itself to form a little pouch that will eventually go on to perform the job of a rectum.
The ileum is folded back on itself, then stapled together, and the internal walls removed, so that you have a ‘pouch’ that is twice the thickness of normal ileum, and it forms a reservoir. You can also fold the ileum over more times to form a bigger reservoir. The pouches are named according to how many times the ileum has been folded over to create them; 2 folds (j-pouch), 3 folds (s-pouch), 4 folds (w-pouch).
This is allowed to fully heal before being attached to the rectum as this greatly reduces the risk of infection from faeces passing through the pouch.
Emergency surgery options
The ideal option is subtotal colectomy with ileostomy as it allows the possibility of later anastomosis. A restorative protocolectomy is not advisable at this stage due to the higher mortality, and the fact that in an acute situation, you may not know if it is Crohn’s or UC that is present.
The splenic flexure is the most dangerous area in an emergency colectomy due to the risk of perforation.
Management of UC
How to use the above treatments
Before you manage the patient, you have to asses how serious the condition is. There are three classifications for the severity of the disease, mild, moderate and severe. The disease can be classed according to the Truelove and Witts criteria:
Mild | Moderate | Severe | |
Motions per day | <4 | 4-6 | >6 |
Rectal bleeding | Small | Moderate | Large |
Temp at 6am | Apyrexial | 37.1-37.8 | >37.8 |
Pulse | <70 | 70-90 | >90 |
Haemoglobin | >11g/dL | 10.5-11g/dL | <10.5g/dL |
ESR | <30mm/h | – | >30mm/h |
Inducing Remission
Mild UC
- 5-ASAs are recommended first line and will induce remission in about 30-45% of patients.
- If this is ineffective, then start on oral steroids (e.g. prednisolone 20-40mg/day), or if the disease is distal, give steroid foams.
- If there is improvement, then reduce the steroids gradually (“Tapering regimen”). If there is no improvement, then treat as moderate UC
- 5-ASA compounds are more effective at maintaining remission than inducing remission
Moderate UC
- Give oral prednisolone (starting at 40mg/day), reducing the dose by 10mg/week if there is improvement, and a 5-ASA, and twice daily steroid enemas.
- If the patient improves then gradually decrease the steroids, if not, then treat as severe UC.
Severe UC
- This is where the patient will usually be systemically unwell. They will generally have greater than 6 motions per day.
- Give hydrocortisone 600mg IV every 6 hours.
- Give rectal steroids every 12 hours
- Consider nil-by-mouth
- Give electrolytes and consider blood transfusion in those with severe anaemia.
- Monitor temp, pulse BP and stools.
- Examine them twice daily and check for tenderness, bowel sounds and distension (i.e. you are basically checking it is not perforation, or toxic megacolon is not forming)
- If they improve after 5 days, then treat as moderate UC. If they do not, then consider ciclosporin or infliximab or surgery.
Novel therapies
- Cyclosporin may be given as a very short course to try and induce remission. Long courses are not advised due to risk of nephropathy
- Infliximab is not really advised due to lack of evidence, but may be attempted
- Nicotine for some reason gives better results than a placebo. This also links in with the fact that smoking is a protective factor for UC.
Maintaining Remission
- Once remission has been achieved 5-ASA will maintain remission in up to 70% of patients after one year, although this fall to 50-60% of patients over time
- Sulfasalazine is generally the drug of choice, but in patients where this is not well tolerated, newer 5 ASA’s such as olsalazine may be given. Sulfasalazine should also be avoided in young men where it can induce temporary infertility (reversed when sulfasalazine is ceased)
Administering steroids topically
Suppository – Rectum only
Foam – 30cm
Liquid enema – will go as far as the splenic flexure.
Course and prognosis of the disease
10-15% of patients will have continuous chronic disease and will rarely achieve remission for any period of time.
5-10% will have an initial acute attack that requires surgery. Virtually nobody will have one attack then relapse permanently.
Extensive disease is more likely to relapse than distal disease, and is also therefore morelikely to be treated by colectomy.
90% of patients are able to cope without the disease affecting their daily living beyond acceptable levels (i.e. they still hold down a normal job etc.)
Mortality compared with that of the general population is almost identical
Risk of mortality in a severe acute attack is about 2%.
Crohn’s Disease
In contrast to UC, this will cuase skip lesions – where there are unaffected parts of bowel in between affected bits. In UC, there are just continuous affected bits.
Crohn’s is basically a condition of young adults, with most diagnosise occurs between the gaes of 20-29. There is a second incidence peak in the 7th decade. Crohn’s is also known to affect young children.
The main symptoms of Crohn’s are abdominal pain, diarrhoea (which may contain blood), vomiting and weight loss. The initial onset may mimic appendicitis in terms of its symptoms.
The disease is probably brought on by a combination of 3 factors – genetic susceptibility, environmental factors (in this case mainly dietary) and the patient’s own immune response.
Symptoms
- Diarrhoea – generally caused by inflammation in the rectum.
- Abdominal pain
- Weight loss (and failure to thrive in children)
- Fever, malaise and anorexia may be present in active disease.
- Can also cause constipation if the disease is in the terminal ileum, or if the disease causes a blockage.
Signs
- Abdominal tenderness
- Right iliac fossa mass. 70% of Crohn’s affects the terminal ileum – and there may often be an abscess. Even without an abscess there will be pain in this region.
- Perianal abscesses, fistulae, skin tags. The fistulas go from the lower bowel just out to the perianal region, and they secrete lots of stuff.
- Anal / rectal strictures
- The rectum is rarely affected, although the anus often is
- It commonly causes fistulating and / or stricutring disease.
- The mesentery becomes thickened, and mesenteric fat will creep along the sides of the bowel wall towards the anti-mesenteric border. This is called fat wrapping.
- The disease involves all layers of the bowel wall.
- Often the inflammatory and ulcerating nature of the disease can give the bowel a cobblestone appearance, and there may be many pseudopolyps.
- Fistulation and abscesses result from full-thickness penetration of the ulcers.
- The bowel can become thickened due to fibrosis, leading to stricture formation.
- Perianal disease often leads to skin tags, deep fissures, and perianal fistulas and abscesses that come from the anal canal. These fistulas can leak.
- Lymphatic infiltrate is normally seen in all layers of the bowel.
Systemic signs- these are pretty much identical to those seen in UC.
- Clubbing
- Large joint arthirits
- Conjunctivitis
- Fatty liver
- Renal stones
- Pyoderma gangrenosum
Crohn’s disease and cancer
Crohn’s disease is associated with an increased risk of GI malignancy. Typically the cancers will be adenocarcinomas that arise in the distal ileum and have a very poor prognosis. The value of a screening program for cancers secondary to Crohn’s is highly debatable due to the inaccessibility of the small bowel.
Types of Crohn’s
Generally, Crohn’s can be divided into 3 types:
- Colonic (25%)
- Ileocaecal (40%)
- Small intestine alone (30%)
The duodenum is affected in about 2% of cases, and the stomach even more rarely. Where the stomach and duodenum is affected, there may be symptoms of B12 and iron deficiencies.
In lots of cases of Crohn’s there is malabsorption of various things due to structuring and fibrosis (leading to shortening) of the small intestine.
Symptoms
- Diarrhoea (90%)
- Abdominal pain (55%)
- Anorexia, nausea, vomiting
There will often be a long history, although some cases present acutely. Of in the acute presentation, the disease may be mistaken for appendicitis, and the true disease is only discovered on operation. However, a good history taking is likely to reveal some sort of lengthy history which will favour the diagnosis towards Crohn’s.
Investigations
- Barium swallow – this will show strictures, gross mucosal changes and the presence of fistulas. It is also good for showing the length of the bowel. Small bowel enema will give better definition.
- Colonoscopy – allows for a good view of the colon and for biopsies to be taken. These may show histological abnormalities (e,g, inflammation and granulomas) and even when the bowel appears normal. It is also possible to take biopsies of the terminal ileal orifice when imaging of this region is inconclusive. This type of imaging is preferred to barium enema as it allows biopsy, and you can see more.
- CT – can show fistulas, thickening of the bowel wall and abscesses.
- Stool samples should be taken to exclude infective diarrhoea.
Blood tests
- Serum iron and B12 if you suspect anaemia
- CRP (will be raised if disease is active)
- LFT
- U+E
- FBC
- ESR (will be raised if disease is active)
- WCC (will be raised if disease is active)
- Hb (will be decreased in active disease)
- Albumin (will be decreased if disease is active)
Management
The severity of the disease is harder to asses than in UC. Generally, the higher the following results, the more severe the disease: ESR, temperature, pulse, CRP, WCC.
Stopping the patient smoking is technically the best method to maintain remission. It is associated with a more benign course of the disease, and also reduced re-lapse rate after surgery.
Nutritional Management
Managing the diet of the patient may help reduce the symptoms. A low residue diet should be advised in those with stricture, and a low-fat diet may help to reduce steatorrhea.
Many patients also have vitamin deficiencies, particularly of B12 and iron, and these should be treated accordingly.
In patients with extensive disease of the small bowel, then there may also be deficiencies of the fat soluble vitamins; A, D, E, K. In patients with particularly severe disease (usually those with a shortened bowel) then parenteral nutrition may be advised as a temporary solution until surgery can be undertaken.
Elemental diet
This is a diet made up of single amino acids and it is antigen free. It is not as effective at inducing remission as steroids, but does still have some effect.
Low residue diet
Will not induce remission on its own, but has been shown to be beneficial alongside other treatments.
Unlike UC, Crohn’s will not be treated if it is asymptomatic – i.e. you won’t give 5-ASA’s during periods of remission in an attempt to maintain the remission. This is because there is no evidence that they are more effective than a placebo as a treatment to maintain remission. In cases of chronic disease, then the drug of choice to maintain ‘remission’ is azathioprine.
Mild attacks
- In these cases, the patient will be symptomatic but systemically well. Give 30mg/day prednisolone and gradually reduce the dose if the patient improves. Probably doesn’t need hospital admission, but will need to check up on them at clinic every 2 weeks or so.
Severe Attacks
- In these cases the patient may have severe symptoms as well as being systemically unwell with tachycardia and fever. An abdominal mass may be present.
- The treatment is pretty similar to that of a severe attack in UC, except that antibiotics may also be given IV ; usually a cephalosporin and metronidazole. These are to try and correct any bacterial overgrowth that may be present.
- You may also want to consider parenteral nutrition in severe fistulating disease where resection is the next step.
Severe Chronic disease
- This is disease where the patient will have a flare-up whenever the prednisolone dose is dropped below 15mg/day. These patients should be considered for immunosuppressant therapy with azathioprine or 6-mercaptopurine. It may take up to 16 weeks on azathioprine before a beneficial effect is seen.
- Pancreatitis and bone marrow suppression as side effects of azathioprine are rare.
- Interestingly, patients who develop the diarrhoea / nausea etc side effects of azathioprine are able to tolerate 6-metcaptopurine.
- Patients who fail to respond to immunosuppressant may be given a weekly intramuscular injection of methotrexate. This will have some sort of effect in 66% of patients.
- Finally, the last line (before surgery) is infliximab. This is given at a dose of 5mg/Kg over a 2 hour infusion, as this method has been shown to be most effective. This will have an effect in 70% of patients.
Surgery
About 80% of Crohn’s patient’s will require surgery at some point in their life. This is much more than for UC.
Surgery for Crohn’s is not as simple as it is for UC. The basic principles are as follows:
You should remove the most affected part(s) of the bowel and make an end to end anastomosis, you should try to leave 2cm at either side of non-diseased tissue, however in extensive disease this is not necessary (and may not be possible) and so you may end up having inflamed tissue being anastomosed.
Big wide resections do not decrease the recurrence rate.
Surgery should generally be conservative to avoid small bowel syndrome, particularly as many patients will require more than one resection during their lifetime. Therefore surgery is generally restricted to patients with:
- Fistulating disease
- Stricture causing obstruction
- Disease that has not responded to any of the above therapies
- Acute and chronic blood loss (rare)
- Abscess removal (rare – most are now drained percutaneously)
For disease at the distal ileum, there is a 25% chance the patient will need further surgery within 5 years.
Recurrence of the disease is common after surgery, however, for those with a stricture causing obstruction, the patient will notice a massive and immediate improvement in symptoms after surgery.
Nearly all patients will develop an ulcer within 12 months on the ileal side of an ileocolic anastomosis.
As an alternative to resection, a strictureplasty may be performed in patients with structuring disease. This is where the strictured piece of bowel is cut longitudinally along its anti-messenteric side, and then sutured transversely.
The worse the inflammation before surgery, the higher the chance of recurrence.
Surgery for fistulas and abscesses
These two complications often co-exist.
Often abscesses can be seen on CT, and then drained via CT guided percutaneous drainage.
Many fistulas are asymptomatic and only discovered upon surgery. You can have:
- Ileosigmoid fistulas – due to ileal disease
- Enterovesical fistuals – causing reccurnet urinary tract infections and pneumaturia
Usually these fistulas are just sewn up locally as the bowel is removed.
Crohn’s Colitis
i.e. Crohn’s in the colon.
Symptoms
- Bloody diarrhoea
- Urgency
- Frequency
Clinical features
Fibrosis and stricture often lead to large bowel obstruction. There may be fistulas – to the vagina and bladder.
Perianal disease up to 50% of Crohn’s patients will have this, particularly those with anal disease. There may be painful anal ulcers, and complex perianal fistulas, but usually the condition is not that painful. Abscesses can be very difficult to live with as they mean its painful to sit down and to walk, and the patient’s quality of life can suffer as a result. Some of the fistulas may open out onto the perineum, and their structure is often very complex. Stricture at the anal ring is also very common.
In cases of this, surgery should be pretty much avoided at all costs to try and maintain the anal sphincter. Dietary modification will be of benefit, and regular drainage will probably be necessary.
Antibiotics will often be given to prevent infection, and infliximab is becoming quite a common treatment when this type of disease is present.
A seton is sometimes used. This is where a thread of nylon is threaded up the fistula and out through the anus and tightened in a tight loop. The loop will be tightened every 10 days or so. This basically cuts through the fistula slowly, and then the tissue behind the seton heals over. Eventually it will cut all the way through to the anal canal, and the fistula will have gone. This is a painful treatment, and is also quite risky as it may destroy the anal sphincter, but it is a useful alternative to surgery.
As well as healing up the fistula, the seton acts as a drain. Basically, fistulas are problematic because they turn into abscesses which then may become infected and painful. This occurs because once a fistula has formed, one end of it will then heal over, and thus create a cavity. This cavity will be full of bacteria that can now thrive, and thus form an abscess. If you keep the fistula as an open loop, it prevents a cavity being formed.
Complications of Crohn’s
- Obstruction – due to fibrosis or inflammatory oedema.
- Fistulas – commonly to neighbouring loops of small bowel (which probably won’t cause too much harm) but also to the bladder and vagina. They may also go from the small bowel to the large bowel.
- Perforation
- Abscess formation
- Haemorrhage
- Gallstones – particularly after the terminal ileum has been resected as treatment for the disease. This resection interrupts hepatic circulation, and leads to depletion of bile salts and gallstone formation.
- Renal stones
- Adenocarcinoma of the small bowel – with very poor prognosis.
- Osteoporosis – many patients have reduced bone density at the time of diagnosis. This is thought to be as a result of the combination of chronic inflammation and poor nutrition.
Prognosis for Crohn’s disease
Generally, the mortality is quite good, being only a 2x the risk of the general population.
However, as you have probably gathered, there is serious morbidity.
Mortality is not greatly increased during the first 15 years of the disease but then gets progressively worse.
After surgery, 30% of patients will have recurrence of the disease within 5 years, and 50% within 10 years. Half of these will require further surgery.
Actual mortality of Crohn’s disease is about 10-15%.
Smoking – why does it have opposite effects on these two diseases?
It is thought that the beneficial effect seen in UC is due to the nicotine present in the cigarettes, but that the negative effect seen in Crohn’s is a result of reduction of blood flow in the mesenteric arteries. This second method (i.e. the detrimental effect of smoking) is thought to be the mechanism by which smoking has a negative effect on many diseases.
Anti diarrhoeal agents
These should be avoided at all costs, due to the chance of precipitating toxic megacolon.
Loperamide – Immodium
This is a very common anti-diarrhoea drug and is available OTC in the UK.
It is an opiod receptor agonist, acting on µ-opiod receptors of the myenteric plexus of theGIt. It has the same effect on bowel movements as an opiod.
It basically prolongs the transit time of stuff in the colon by reducing propulsive movements of the small intestine and colon. This prolonged transit time provides the opportunity for enhanced absorption of fluids.
Most opioids have short half-lives, however, loperamide has an intermediate half-life giving it an advantage over similar treatments because it has a longer duration of action. It also has a quicker onset.
It has a very high first-pass metabolism, and thus is quite specific for the gut, and systemic effects are not seen.
Toxic megacolon is a complication of intestinal conditions. It is life-threatening. It is characterised by an extremely distended colon, with accompanying abdominal distension, fever, abdominal pain, tachycardia and sometimes shock.
Decompression should be attempted, and you should try to prevent the patient from swallowing air. If the situation has not improved after 24hours, then partial or total resection of the colon may be necessary to prevent perforation.
Codeine should also be avoided for the same reasons.
Flashcard
References
- Murtagh’s General Practice. 6th Ed. (2015) John Murtagh, Jill Rosenblatt
- Clinical Update for General Practitioners and Physicians – Inflammatory Bowel Disease – GESA
- Oral 5‐aminosalicylic acid for induction of remission in ulcerative colitis – Cochrane Systematic Review
- Oxford Handbook of General Practice. 3rd Ed. (2010) Simon, C., Everitt, H., van Drop, F.
If I’m not mistaken, “Cessation of smoking may induce remission in some patients” in the table at the beginning should be under ulcerative colitis not Crohn’s.
Thanks