3   Why would Ann require fluid and electrolyte replacement?

4   What is IBD?

5   What could have caused Ann’s CD?

6   What symptoms could Ann experience as a result of her CD?

7   What investigations would Ann have in order to diagnose her CD?

8   What medicines are available to help manage Ann’s CD?

9   Why were azathioprine and methotrexate tried?

10   What are biological therapies and how do they work?

11   What complications might occur in the course of Ann’s CD, and what is the role of surgery?

12   How might people like Ann adjust their lifestyle?

ANSWERS

1 What is diarrhoea and what are the principles for self-medication?

Most attacks of acute uncomplicated diarrhoea are self-limiting and it is recommended that the person abstain from food and that they drink plenty of fluids. Self-medication in otherwise healthy adults may be considered necessary to relieve discomfort and social dysfunction; however, seeking medical advice is important if the diarrhoea does not improve within 48 hours, if the faeces contain blood, or if there is severe abdominal pain and vomiting (BMA 2005).

2 How does loperamide ease diarrhoea?

A The main types of drugs for non-specific diarrhoea are opioids, bulk-forming and adsorbent agents. Loperamide, a synthetic opioid (bought over the counter), has a direct effect on the large intestine wall, decreasing its activity. This increases the amount of time substances stay in the intestine, allowing more water to be absorbed. Loperamide is taken orally in tablet, capsule or liquid form immediately after each loose bowel movement but should be used with caution when diarrhoea is caused by infection and avoided in those under 12 (Prosser et al. 2000; BNF 2012).

3 Why would Ann require fluid and electrolyte replacement?

A Chemically, an electrolyte is a substance that, when in fluid, dissociates into electrically charged ions. The positive or negative charge carried by these ions is what allows our body’s cells to use electrolytes to carry electrical impulses throughout the body. Electrolytes are crucial in maintaining the body’s ability to transmit nerve impulses and contract muscles. Electrolytes also serve other biological functions, including water balance and distribution to working cells as well as acid–base balance.

Prolonged diarrhoea can result in dehydration and electrolyte imbalance and so a priority is the prevention or reversal of fluid and electrolyte depletion. The absorption of water occurs passively in the colon, following the active transport of sodium. As a result there is normally a net secretion of potassium and bicarbonate into the colon, hence the significant hypokalaemia often observed in severe diarrhoea (Long and Scott 2005; Karch 2010).

4 What is IBD?

A IBD includes ulcerative colitis and CD. Both chronic, non-contagious disorders, these cause inflammation in the GI tract. In ulcerative colitis, inflammation is limited to the superficial layers of the colon. CD, also known as ileitis or regional enteritis, mainly affects the ileum and the colon but any area from the mouth to the anus can be involved. Normal healthy bowel may be present between patches of diseased and inflamed bowel. The whole layer of the GI tract can be involved, starting in the sub-mucosa and spreading to the mucosa and serosa.

A

•   The exact cause of CD is unknown. Genetic susceptibility, an abnormal immune reaction and environmental factors have all been highlighted. CD is more common in developed countries such as the UK and the USA and affects mainly white adults. Men and women are roughly equally affected. Its onset is typically between the ages of 16 and 30, although any age can be affected. CD is characterized by long periods of remission followed by periods where the symptoms flare up. There is no way of predicting when a remission may occur or when symptoms will return, and there is no prevention. Smoking is a significant factor. Smokers are twice as likely to develop CD and experience more severe symptoms compared with non-smokers (NHS Choices 2011).

•   CD runs in families, but is genetically complicated and multifactorial. A susceptibility gene at the IBD 1 locus on chromosome 16 has been identified as NOD2/CARD15. Mutations of this gene are associated with CD and a dysfunctional immune response.

•   In certain genetically susceptible individuals, a previous infection with the measles virus or bacteria related to the mycobacterial species commonly found in cows, sheep and goats may be implicated in CD.

•   There is strong evidence that an abnormal reaction by the body’s immune system occurs in CD. The GI mucosa is exposed to abundant antigens in the form of ‘friendly bacteria’ (commensals) and those derived from ingested food. The immune system has to recognize commensals, allowing them to do their job without attacking them, while eliminating harmful antigens. The intestinal immune system differs from systemic immunity in that the response to foreign antigens is downregulated, resulting in a state of controlled physiological inflammation: harmful antigens are eliminated, helpful ones are not. This is achieved through a balance of T-helper-–1 lymphocytes which produce pro-inflammatory cytokines, kept in check with T-helper-–2 lymphocytes. These dampen the T1 response by producing anti-inlammatory cytokines such as interleukin 10 and TGFb which promote mucosal healing. In genetically susceptible people, the immune system mistakes ‘helpful’ microbes and normal flora in the lumen of the intestines for foreign or invading substances, and launches an attack. T-helper-–1 lymphocytes are sent to the lining of the intestines. Here they are activated, making increased amounts of a special antibody called tumour necrosis factor alpha (TNFalpha). This cytokine intensifies inflammation by killing all bacteria, friendly or not, ultimately leading to ulceration and injury of the intestines.

•   TNFalpha, present in high levels in CD, causes most of the associated inflammation. This is a key point to remember, as will be seen later. CD has a distinct profile of cytokine production. There is a predominant synthesis of type 1 helper T-cell cytokines, including IFN-γ and TNF-α.

6 What symptoms could Ann experience as a result of her CD?

A Because CD can affect any part of the intestine its symptoms may vary greatly from patient to patient, making diagnosis a challenge. The most common symptoms are:

•   bloating;

•   cramping;

•   persistent diarrhoea (with blood and mucus in the faeces);

•   unintentional weight loss;

•   fatigue;

•   mild fever.

Additional symptoms and complications include:

•   anal pain;

•   skin lesions;

•   uveitis;

•   boils;

•   anaemia;

•   malabsorption;

•   rectal abscess;

•   fissures;

•   arthritis.

The most common complications are fistulas and intestinal blockage caused by thickening of the intestinal wall due to swelling and scar tissue.

7 What investigations would Ann have in order to diagnose her CD?

A There is no single test to establish the diagnosis of CD. Other conditions are ruled out through a combination of information from the patient’s history, physical examination (including a range of laboratory tests), X-rays and endoscopy findings. X-ray tests can often confirm or disprove the diagnosis of CD and may include barium studies of the upper and lower GI tract. Barium coats the small intestine, making signs of CD show up more.

Colonoscopy (with biopsy) is commonly used to diagnose CD and determine the extent and location of inflammation, bleeding or ulcers. The wall of the ileum, rectum and the entire colon can be observed through a lighted tube inserted through the anus. Stool specimens are examined for pathogenic organisms to rule out infection and to show if there is bleeding in the intestines (C. difficile had been ruled out by Ann’s GP).

Blood tests can identify anaemia caused by bleeding, and a high white blood cell count, which is a sign of inflammation or infection somewhere in the body. Raised erythrocyte sedimentation rate and C reactive protein levels may indicate active disease (Talley et al. 2008).

8 What medicines are available to help manage Ann’s CD?

A There is currently no cure for CD. The goals of treatment are to suppress the inflammatory response, allowing the intestinal tissue to heal (induce remission), correct nutritional deficiencies, relieve symptoms and prolong (maintain) periods of remission.

Treatment employs several groups of drugs including aminosalicylates (5-ASA) cortico-steroids (hydrocortisone, budesonide and prednisolone) and drugs that suppress the immune response. Aminosalicylates and corticosteroids are the backbone of treatment for acute, mild to moderate attacks (BNF 2012). These are now outlined.

AMINOSALICYLATES

Aminosalicylates are aspirin-like compounds known to reduce inflammation in the colon, and may be continued as a maintenance therapy providing long-term relief. The exact mechanism is unknown. A variety of aminosalicylate preparations are available and sulfasalazine is a popular choice. This is a pro-drug activated in the bowel to release 5-aminosalicylic acid and sulapyridine.

As an alternative to steroid medications, sulfasalazine can be used to treat mild cases of CD, and acute, mild to moderate CD affecting the rectum (proctitis) or lower colon can be treated with local application of an aminosalicylate in suppository or retention enema form, together with a local corticosteroid. Disease that is more widespread in the intestine or unresponsive to rectal treatment requires oral treatment. More moderate disease requires corticosteroid tablets.

Asacol is the proprietory name for a prescription-only preparation of the aminosalicylate drug mesalazine. Mesalazine (5-aminosalicylic acid) is a unique compound that releases aspirin in the large intestine for a direct anti-inflammatory effect. It is used when the more commonly used drug sulfasalazine has not worked or cannot be tolerated. Side-effects of mesalazine-containing medications include nausea, vomiting, heartburn, diarrhoea and headache. Particularly troublesome side-effects should be reported as the dose may need adjusting (Ford and Roach 2010).

CORTICOSTEROIDS

Used to treat moderate to severely active CD, corticosteroid (steroid) drugs are a type of hormone medication used to help reduce inflammation. They non-specifically suppress the immune system. Prednisone and methylprednisolone are available orally, intravenously and rectally. During the earliest stages of CD, when symptoms are at their worst, corticosteroids are usually prescribed in large doses. These are gradually lowered once symptoms are controlled and should not be stopped suddenly. Steroids are not used as a maintenance medication as they have significant short- and long-term side-effects. These include greater susceptibility to infection and osteoporosis, acne, weight gain, oedema, mood changes, insomnia, diabetes, muscle cramps and stiffness.

Budesonide is a slow-release steroid used specifically to treat CD. Causing fewer side-effects than prednisolone, it may be less effective. If budesonide is not effective or if symptoms are more severe, prednisolone is used; this has been known to cause mental health problems in an estimated 5% of people.

ANTIBIOTICS

These are used if there is an additional bacterial infection. Ampicillin, sulfonamides, cephalosporin, tetracycline or metronidazole may be prescribed.

A Azathioprine (Imuran) is an immunosuppressive (immunomodulator) drug affecting the immune response and is used in the treatment of CD for severe symptoms that have not responded sufficiently to corticosteroids. It helps reduce inflammation on a long-term, maintenance basis, often in combination with corticosteroids when symptoms relapse. It is thought to enhance the action of corticosteroids. Azathioprine is a pro-drug that is metabolized to 6-mercaptopurine (6MP) (both agents are available), effective in treating severe CD and maintaining remissions. The precise action of 6MP is not known but a T-cell suppressant action is thought to be one of the main mechanisms. Depending on the severity of symptoms, azathioprine can be given as a tablet or an injection. Azathioprine may cause nausea, vomiting and diarrhoea, joint pain, bone marrow suppression and occasionally pancreatitis, which resolve on drug withdrawal.

Methotrexate is used in chronically active CD which is resistant to or dependent on steroids. It is given intravenously at a dose of 25mg weekly for 16 weeks, during which time steroids are reduced. Daily folic acid supplementation is recommended. This drug is also used for rheumatoid arthritis and is associated with a range of side-effects including liver damage.

10 What are biological therapies and how do they work?

A A growing range of biological therapies include infliximab (Remicade) and adalimumab (Humera). These are used to treat moderate to severe CD that does not respond to standard therapies, and in the treatment of open, draining fistulas. They work by targeting the tumour necrosis factor alpha (TNFalpha) antibodies responsible for most of the inflammation associated with CD. Some studies suggest that biological therapies may enhance the effectiveness of immunosuppressive medications (NICE 2010).

Infliximab (licensed since 1998) is a chimeric (a blend consisting of 75% human, 25% mouse protein) monoclonal antibody. It is given through an IV infusion over the course of two hours. Depending on how well symptoms respond to treatment, one infusion may suffice, although three infusions given every eight weeks may be necessary.

Around one in four people have an allergic reaction to infliximab so close monitoring is essential. Resuscitation facilities are necessary as anaphylactic shock (as in Ann’s case) is not unknown. It is not recommended for people who have previously had tuberculosis (TB), hepatitis or heart disease.

Ann is currently prescribed Humira (adalimumab, licensed in 2007), a synthetic man-made protein. Similar to human protein, it is indicated for adult patients with moderate to severely active CD who have had an inadequate response to conventional therapy, or those intolerant to previous treatment with infliximab (NICE 2010).

Adalimumab is taken by injection every other week, and works by attaching to the tumour necrosis factor and blocking its effects, reducing the inflammation and relieving symptoms associated with CD. It can be administered at home by the patient or family member once instructed by a health care professional. Its common side-effects include pain, swelling, redness and itching at the site of the injection, headache, nausea, vomiting, skin rash, muscle, joint and bone pain, respiratory tract infections such as colds, a runny nose and pneumonia (lung infection).

Corticosteroids, immunsuppressants, infliximab and adalimumab increase vulnerability to infection so people with shingles or chickenpox should not be prescribed these drugs.

A The most common complications are fistulas and intestinal blockage caused by thickening of the intestinal wall due to swelling and inflammation. In more advanced or complicated cases of CD, or when symptoms cannot be controlled using medication, surgery may be recommended. An estimated 60–75% of sufferers will require surgery. Because CD often recurs after surgery, those considering surgery should carefully weigh its benefits and risks compared with other treatments. Surgery may be restricted to a resection, or require an ileostomy.

12 How might people like Ann adjust their lifestyle?

A It is important that people with CD follow a nutritious diet. Some people find that certain foods make their symptoms worse and decide to try a different diet, although no special diet has been proven effective in the prevention and treatment of CD. In cases where symptoms are severe, a liquid diet (elemental diet) may be recommended. Nutritional and vitamin support may be required during active phases.

While CD is a serious chronic disease with many complications, it is not considered a fatal illness. Most people with the illness may continue to lead useful and productive lives, even though they may be hospitalized from time to time, or need to take medications. In between flare-ups of the disease, many individuals feel well and may be relatively free of symptoms.