PEPTIC ULCER DISEASE
Case vignette
A 56-year-old man presents with severe nocturnal epigastric pain. The pain was initially relieved by food ingestion and antacids. However, lately the pain has been recalcitrant and progressive. He also complains of fatigue and exertional retrosternal discomfort. He is a heavy smoker and consumes alcoholic spirits on a regular basis. He is on aspirin. On examination there was tenderness to deep palpation in the epigastric region. He also had conjunctival pallor. His pulse rate was 110 bpm and irregularly irregular.
Approach to the patient
Peptic ulcer disease is a common associated morbidity in the long case.
History
Enquire about the initial presentation—the symptoms of epigastric pain, dyspepsia, reflux and anorexia. It is important to obtain details about any previous or current gastrointestinal bleeding. A medication history should be obtained, to exclude causative agents, such as aspirin or NSAIDs. Ask when and how the diagnosis was made and whether the patient has had a gastroscopy. Ask how the patient has been treated in the past and whether they have ever been tested for Helicobacter pylori. A history of gastrointestinal bleeding becomes an issue if the patient has a comorbid condition that would require anticoagulation or antiplatelet therapy, such as coronary stenting or AF. Be alert to features that may indicate the possibility of gastric carcinoma, such as significant weight loss, persistent vomiting or jaundice in the setting of liver secondaries.
Examination
The patient may have epigastric tenderness. A mass lesion in the abdomen should alert to neoplasia. Do not forget to look for signs of anaemia.
Figure 12.1 Scanning electron micrographs of a 48-h culture of H. pylori (A, B), and infection of cultured AGS cells for 24 h (C, D) or 48 h (E, F). A, blebs (→) protrude from the spiral-shaped bacterial body. B, numerous vesicles (→) are visible on the bacterial surface. C, bacteria are tightly embodied in a dense network of extended microvilli. Spirals are attached horizontally (→) or perpendicularly (arrowhead). D, H. pylori displays various shapes when attached to the cell surface: the spiral (white→), U-shaped (white arrowhead), doughnut (black→), or coccoid form (black arrowhead)
(reprinted from Heczko U, Smith V C, Mark Meloche R et al 2000 Characteristics of Helicobacter pylori attachment to human primary antral epithelial cell. Microbes and Infection 2:8)
Figure 12.2 Foveolar cells with ‘cobblestoning’. The changes are patchy and often mild. When the cells bulge out, resembling cobblestones, the appearance is almost always diagnostic of H. pylori infection
(reprinted from Robin W J 2000 Gastric pathology associated with Helicobacter pylori. Gastroenterology Clinics of North America 29:47)
Figure 12.3 Duodenal ulcer
(courtesy of Dr George Ostapowicz)
Investigations
All patients who present with symptoms suggestive of peptic ulcer disease or a diagnosis of peptic ulcer disease should be tested for H. pylori infection. This is achieved by performing the rapid urease test in those undergoing endoscopy and by serology. However, in individuals under age 50 without alarm symptoms, it is reasonable to treat without investigation and assess response (in both H. pylori positive and H. pylori negative individuals).
Negative tests can be confirmed with non-endoscopic tests, such as the urea breath test or the stool antigen test. The urea breath test can be accurately interpreted only if antisecretory therapy has been withheld for a minimum of 2 weeks prior to the test.
However, negative tests do not necessarily need confirmation (realising that serology may only be 70–80% accurate). In such situations it would be reasonable to treat with a proton pump inhibitor (PPI) initially. If there is no response or symptoms return, further investigation with gastroscopy is indicated.
If the patient has had an acute event, check the full blood count (looking for anaemia) and electrolyte profile (looking for an elevation in blood urea level that is disproportionate to the creatinine level). In this situation gastroscopy is definitely indicated.
Management
1. If the test is positive for H. pylori the patient has to be treated for 7–14 days with a triple-therapy combination. Currently prepared combinations include PPI (omeprazole or esomeprazole) together with amoxycillin and clarithromycin. Metronidazole is substituted in penicillin allergies. Bismuth is an agent only rarely used in resistant cases, generally as part of quadruple therapy.
2. The cure of infection is confirmed with a urease breath test performed 2 weeks after the completion of therapy. If there is ulcer disease without the presence of H. pylori, it is enough to treat with a PPI alone for 4–6 weeks. Therapy may be required for a longer period for large ulcers.
3. All gastric ulcers have to be biopsied during endoscopy, to exclude gastric carcinoma. The patient should be followed up with repeat gastroscopy a few weeks after the completion of the curative treatment, to confirm ulcer healing.
INFLAMMATORY BOWEL DISEASE
Case vignette
A 33-year-old female presents to hospital with high fevers and severe abdominal pain in the background of anorexia and weight loss. She was diagnosed with Crohn’s disease 3 years ago upon investigation for chronic fevers, diarrhoea, weight loss, abdominal pain, nausea and vomiting. Her Crohn’s disease is managed with long-term mesalazine therapy. She is also on cipramil for depression.
On examination she has tenderness with guarding in the left lower quadrant and aphthous ulceration in the oral mucosa. She is cushingoid. Investigations reveal a mild anaemia, leucocytosis, thrombocytosis and significantly elevated CRP. Abdominal CT reveals an abscess in the sigmoid region. She is commenced on high-dose antibiotics and steroids. The abscess is drained percutaneously under CT guidance.
While in hospital her symptoms improve. However, on the third day in hospital she develops severe retrosternal chest pain that radiates to the neck and jaw. ECG reveals ST segment elevation in the septal leads. She also complains of severe left calf pain and tenderness. She is commenced on a heparin infusion and subsequently taken to the cardiac catheterisation laboratory. Angiography shows evidence of slow coronary flow in the left anterior descending artery. Otherwise the coronary anatomy is normal with no evidence of any occlusive disease in any artery. She has a peak troponin I level of 20 and echocardiography shows significant hypokinesis of the anteroseptal region of the left ventricle, suggesting significant myocardial damage or stunning. Lower limb Doppler studies reveal DVT of the left leg.
1. How would you describe the interrelationship between the different aspects of her clinical picture?
2. What further investigations would you require to ascertain the certain aetiology of her myocardial infarction?
3. What is your comprehensive plan of management for this patient?
4. Describe your planned discussion with her about her prognosis, long-term management and available supportive care.
Approach to the patient (ulcerative colitis and Crohn’s disease)
Knowledge of the basic principles of management of ulcerative colitis and Crohn’s disease will be very useful because inflammatory bowel disease can make patients ideal long cases with multifaceted issues.
History
Ask when and how the initial presentation was made and what investigations led to the diagnosis. Take a detailed history of gastrointestinal symptoms, such as abdominal pain, diarrhoea, tenesmus, per rectum bleeding, rectal mucous discharge, anorexia, nausea and vomiting. Ask about constitutional symptoms and weight loss. The combination of symptoms such as per rectal bleeding and mucus together with tenesmus and constipation with the absence of systemic symptoms is very suggestive of ulcerative proctitis. Episodes of abdominal pain and bloating, together with vomiting a few hours after food ingestion are symptoms suggestive of small bowel involvement, especially terminal ileal Crohn’s disease.
Ask about systemic features such as oral ulcers, arthritis, biliary colic (uncommon), pyoderma gangrenosum and erythema nodosum. Ask how often acute exacerbations happen and how they are treated. It is very important to obtain a detailed medication history, enquiring about current therapy as well as agents tried previously. Ask about adverse effects associated with medications, especially corticosteroids. Take a detailed smoking history, as smoking prevents exacerbation of ulcerative colitis but precipitates Crohn’s disease. Check the family history, as Crohn’s disease especially tends to be familial. The clinical features alone often may not differentiate between Crohn’s disease and ulcerative colitis.
Once the precise disease entity is identified, it is important to localise the possible areas of involvement in the gastrointestinal tract. Ask about any diagnosis of gastrointestinal malignancy. Risk of malignancy, especially colorectal cancer, is increased in individuals with inflammatory bowel disease, especially ulcerative colitis.
The social aspects of inflammatory bowel disease are extremely important. Enquire about how the disease affects the patient’s social, academic and occupational life. Ask about how it affects relationships, particularly with the patient’s partner. Effects on sexual and reproductive function and cosmetic effects of surgery are key questions that should be addressed, particularly in the young patient. Ask about available social support and try to gain a good understanding of the level of insight the patient has into their condition, the treatment given and the side effects experienced. Depression is common among patients suffering from inflammatory bowel disease, and this should be enquired about. Pregnancy and management of inflammatory bowel disease is an important area, where many questions can be asked. Ask about how the patient is managing with the ileostomy or the colostomy (if they have had a colectomy). Some patients may have had an ileal pouch created after colectomy. In such patients, ask about symptoms of pouchitis and issues of continence. Ask whether the patient belongs to a support group such as a Crohn’s or colitis association.
Examination
Look for wasting and stunted growth. Assess the level of hydration and nutrition. Note the signs suggestive of malnutrition if present. Look for peripheral stigmata such as finger clubbing, arthritis, oral ulcers, jaundice, pyoderma gangrenosum (Fig 12.4) and erythema nodosum (Fig 12.5). Do not miss uncommon signs such as iritis and jaundice (sclerosing cholangitis, though very rare), if present. Examine the abdomen, looking for surgical scars, colostomy or ileostomy bags, distension, right upper or lower quadrant tenderness, generalised abdominal tenderness, guarding and rigidity. A palpable mass lesion could suggest an abscess, a phlegmon (especially in the right lower quadrant) or a malignancy. Check the character of bowel sounds. Ask for the findings of the per rectum examination. Per rectal examination may show perianal skin tags (Crohn’s disease especially), discharging sinuses or fistulae (Crohn’s disease) and blood.
Differential diagnoses in inflammatory bowel disease
• Infective colitis (Shigella, Salmonella, Campylobacter) (CMV colitis in the immunocompromised)
• Ulcerative colitis
• Crohn’s disease
• Pseudomembranous colitis (Clostridium difficile colitis)
• Radiation colitis
• Ischaemic colitis—especially in older individuals and/or those with vascular disease
Ulcerative colitis
Investigations
1. Stool microscopy—looking for white and red cells, organisms, parasite ova or cysts, and the results of stool culture
2. Full blood count—looking for anaemia and leucocytosis (and rarely haemolysis)
3. Electrolyte profile—looking for hypokalaemia, and elevated levels of urea and creatinine if the patient has lost body fluids (only relevant if significant diarrhoea present but always useful in establishing a baseline)
4. Liver function test results once again—to establish the baseline and monitor regularly (patients with ulcerative colitis can rarely develop primary sclerosing cholangitis and very rarely develop cholangiocarcinoma)
5. Iron studies—looking for iron deficiency
6. Results of sigmoidoscopy and biopsy and the result of colonoscopy
Figure 12.6 Barium enema of ulcerative colitis showing pseudopolyposis, lack of haustral markings and straightening of ascending and transverse colon
(reprinted from Kanski J, Pavesio C, Tuft S 2005 Ocular inflammatory disease, Elsevier, fig 8.41)
7. Plain X-ray (both supine and erect views)—useful in acute colitis to check for colonic oedema (thumb-printing) and to exclude megacolon, or to assess for proximal constipation in proctitis
8. Abdominal CT may be useful in acute presentations with unusual features (such as severe pain, high fever and abdominal signs) to exclude complications
Management
Acute ulcerative colitis
The management objective is to induce remission.
1. Mild to moderate pancolitis (or subtotal colitis)—treat with oral aminosalicylic acid (ASA) agents. Specific agents used for the purpose of disease control include sulfasalazine, olsalazine and mesalazine. All three agents can be used to treat active disease as well as to maintain remission. Olsalazine and mesalazine are prescribed for patients who cannot tolerate the sulfa component of sulfasalazine. Olsalazine is made up of two molecules of aminosalicylic acid combined, and mesalazine is a coated aminosalicylic acid preparation that releases the active ingredient in the terminal ileum.
2. Severe pancolitis—treat with prednisone (prednisolone). However, if the patient is severely ill, treatment with IV hydrocortisone is indicated.
3. Antibiotics (e.g. metronidazole) may be a useful adjunct therapy, especially if there is a suspicion of sepsis.
4. Steroid enemas can also be used in this setting.
5. Patients admitted to hospital require prophylactic anticoagulation (unfractionated heparin or low molecular weight heparin).
Maintenance of remission
1. Steroids should be weaned over 8–12 weeks upon achieving remission. Long-term or frequent steroid use should be avoided.
2. ASA agents have been shown to decrease the risk of relapse in ulcerative colitis and should be used in all confirmed cases for at least a few years.
3. In individuals who relapse on ASA, a second-line agent such as azathioprine or 6-mercaptopurine should be used (or this option should at least be discussed with the patient).
Advanced management of severe acute ulcerative colitis resistant to IV corticosteroids (upon being treated for at least 7 days)
1. IV cyclosporin infusion (continuously for 10–14 days)—in some patients infliximab may be used instead to prevent or delay the need for colectomy.
2. Azathioprine can also be commenced but in itself is not useful as its effect is delayed for 6–8 weeks or longer.
3. Patients with severe ulcerative colitis require close monitoring with daily or twice-daily medical reviews, daily FBC, electrolytes and abdominal X-ray.
4. A surgical review is recommended, and surgeons should be notified of the patient. Any significant deterioration or development of toxic megacolon, even if within the first few days of IV steroid therapy, requires urgent surgical assessment and possible emergency colectomy.
5. Toxic megacolon is a medical and surgical emergency, and treatment should be commenced with IV corticosteroids and IV antibiotics. The patient should be kept ‘nil by mouth’. They should be rolled to the prone position regularly and urgent referral should be made to the surgeon to assess the need for colectomy.
6. Because of their propensity to develop colonic carcinoma, patients who have had ulcerative colitis for more than 10 years should be screened for malignancy every 2 years with colonoscopy and multiple biopsies. Strong consideration should be given to colectomy in patients whose biopsy shows mucosal dysplasia.
7. Patients need emotional and social support to cope with this chronic and distressing condition.
8. Patients with a stoma need counselling and the help of a qualified stoma nurse or therapist.
Crohn’s disease
Investigations
1. Stool investigation for microscopy and culture—looking for white and red cells, pathogenic bacteria, parasitic ova and cysts
2. Full blood count—looking for anaemia and leucocytosis and inflammatory markers (CRP, ESR)
3. Liver function tests, serum vitamin B12 levels and iron studies
5. Individuals with known (terminal ileum abnormal on colonoscopy) or suspected small bowel disease should undergo small bowel imaging, including small bowel series or enema (this is of relatively low sensitivity), CT or MRI enteroclysis.
Wireless capsule endoscopy can show small bowel mucosal abnormalities (see box) suggestive of Crohn’s disease but should be avoided if strictures are suspected (where capsule may not pass through, necessitating surgical removal).
6. Sigmoidoscopy and biopsy may be of use on specific occasions. This is not generally used in the initial approach, as disease is frequently proximal to the sigmoid colon. It is of use occasionally to reassess activity of known distal disease.
7. Abdominal X-ray (with barium), CT of the abdomen—abdominal CT may show areas of small bowel inflammation, phlegmon or other complications. This is useful in acute and non-acute settings.
8. Immunological markers—ANCA and anti-saccharomyces cerevisiae antibody (ASCA) (occasionally used to help differentiate between ulcerative colitis and Crohn’s)
Management
The hallmark feature of Crohn’s disease is transmural inflammation. Mucosal changes are typically patchy in distribution. Histopathology also may reveal granulomatous lesions seen in < 50% of cases.
Figure 12.7 Colonic Crohn’s disease
(courtesy of Dr George Ostapowicz)
Acute luminal disease
The primary objective is to induce remission. Also ensure rehydration, restoration of electrolytes, and adequate nutrition.
1. Mild Crohn’s—oral ASA agents as outlined above may be of some help. Note that in suspected ileal disease, mesalazine should be used, as the other agents are released only in the colon.
2. Moderate to severe Crohn’s—oral prednisone (or prednisolone) is indicated. If the patient is significantly ill, requiring hospital admission, therapy with IV hydrocortisone should be considered. Antibiotics (e.g. metronidazole) may be a useful adjunct, especially if there is suspicion of infection or mass/phlegmon. In resistant disease, tumour necrosis factor antibody (TNF Ab) such as infliximab may be tried.
3. An elemental or semi-elemental diet may help achieve better disease control.
4. Complications such as collections or phlegmons may require surgical treatment.
Maintenance of remission
1. Steroids should be weaned over 8–12 weeks. Long-term or frequent steroid use should be avoided as they do not maintain remission.
2. ASA agents may be of some benefit in mild cases but the overall evidence for their benefit is dubious. In individuals who relapse on ASA (this is quite likely) or present with severe disease, especially if complications are involved, a second-line agent such as azathioprine or 6-mercaptopurine should be offered—this is effective in maintaining remission or decreasing disease activity in a significant percentage of patients.
3. Patients with luminal disease in whom second-line agents are ineffective can be treated with methotrexate or TNF Ab such as infliximab.
4. Perianal disease may require the use of antibiotics such as metronidazole and ciproflaxacin (4–6 weeks). Surgical involvement is necessary and specific treatment may include drainage of collections or more involved surgical procedures.
Treatment with second-line agents such as azathioprine may result in fistula closure. In resistant cases, TNF Ab such as infliximab may be effective (50–60%).
6. Surgery is not curative, but ultimately many patients require a surgical procedure. Surgery has a role in the treatment of complications: stricture(s), masses/phlegmons, collections, fistulae, severe perianal disease. May involve hemicolectomy, total colectomy, small bowel resection and ‘ostomy’ or pouch creation.
Complications of Crohn’s disease
• Oral mucosa—aphthous ulcers, gum and mouth pain, cheilitis, sialadenitis
• Skin—erythema nodosum, pyoderma gangrenosum
• Joints—seronegative spondyloarthropathy, large joint arthritis in the periphery, ankylosing spondylitis, sacroilitis
• Eyes—uveitis, episcleritis, iritis
• Vascular system—thromboembolism (venous as well as arterial, as was the case in the above case vignette—a DVT and paradoxical embolism via a possible patent foramen ovale (PFO))
• Abdominal—abscess, draining sinuses, fistula formation, perforation, peritonitis, obstruction, cancer (small bowel, colon)
• Kidneys—amyloidosis and associated renal failure
• Liver—primary sclerosing cholangitis
• Skeletal system—osteoporosis
• Respiratory—pulmonary embolism
• Haematological—haematinic deficiency anaemia, autoimmune haemolytic anaemia
Microscopic colitis: lymphocytic, collagenous
This is a relatively uncommon condition that occurs more frequently in older patients.
Presentation Usually painless chronic diarrhoea. Sometimes diarrhoea is severe.
Aetiology Unknown, but could be associated with some drugs, especially NSAIDs.
Diagnosis Colonoscopy and biopsy. Macroscopic appearance of the large bowel is normal.
Management Treatment is often suboptimal and the exact duration unknown. Suspected precipitants should be withdrawn. Therapeutic agents used include antidiarrhoeals (loperamide), ASA agents and cholestyramine. Budesonide can be effective but has potential adverse effects, especially if long term. Azathioprine has rarely been used but can only be justified in very severe diarrhoea.
COELIAC DISEASE
Approach to the patient
History
This is familial enteropathy due to hypersensitivity to the gliadin component of gluten. Ask about initial diagnosis and age of diagnosis. Most often coeliac disease manifests and is diagnosed in childhood and early adulthood. Presenting symptoms could be abdominal pain, anorexia, diarrhoea, constipation, bloating, steatorrhoea and constant flatulence. Ask about growth failure during childhood. Patients may also have weight loss and pallor, fatigue and/or dyspnoea due to anaemia. Ask about associated conditions such as IgA deficiency, diabetes mellitus, autoimmune thyroid disease and rare associations such as pernicious anaemia and liver disease. Gastrointestinal lymphoma is a very rare but dreaded complication. If any of these conditions are present, you should enquire about therapy and the response to therapy.
A pathological fracture due to metabolic bone disease (osteopenia and osteoporosis), though not very common, should not be overlooked. Ask about arthritis and, if present, the details thereof. Ask about problems with fertility and menstrual irregularities in the young female. Some patients may have had recurrent spontaneous abortions. Ask about neurological symptoms such as ataxia and epilepsy. Some patients may have anxiety and/or depression. Ask whether the patient has sought help for the psychological manifestations. Check the patient’s family history. Ask how the disease has been treated and the response to therapy.
Examination
In the physical examination look for evidence of malnutrition and short stature. Conjunctival, palmar crease or mucosal pallor may suggest anaemia. Examine the skin and mouth for the classic rash of dermatitis herpetiformis. Examine the abdomen for tenderness or masses.
Investigations
1. Serological tests for auto antibodies—IgA antihuman tissue transglutaminase and IgA-endomysial antibody. Always check IgA levels, as a deficiency will give a false negative result.
2. Small bowel biopsy—looking for the histological features of villous atrophy (Fig 12.8) (blunted villii), hyperplastic crypts, loss of height in the surface enterocytes. There is infiltration of the epithelium by lymphocytes. These changes improve once the patient is commenced on a gluten-free diet.
3. Renal function indices—looking for chronic renal failure due to IgA nephropathy (uncommon)
4. Full blood count—looking for anaemia. If anaemia is present, check the haematinics for Fe deficiency, B12 deficiency (this is uncommon, as the terminal ileum is not typically affected) and folate deficiency. Also consider serum levels of calcium, parathyroid hormone (PTH), vitamin D, vitamin A.
5. Liver function indices—looking for mild elevation of liver enzyme levels
6. Bone densitometry—looking for osteoporosis
Management
1. The mainstay of treatment is a gluten-free diet. The patient should be referred to a qualified dietitian, and given ample education and counselling.
2. Haematinic replacement and replacement of other nutrients.
3. Prophylactic immunisation against meningococcus and pneumococcus is indicated in patients who have hyposplenism, which is not too uncommon with coeliac disease.
4. Non-responders to a gluten-free diet may require corticosteroid therapy.
