19th July 2023

Lower GI Pathology

Diseases of the Small Bowel

This section focuses on diseases that predominantly affect the small bowel – the duodenum, jejunum and/or the ileum. As the small bowel is the main site of absorption of nutrients and minerals for the body, disease within this part of the bowel often results in malabsorption and secondary malnutrition. Please refer to the topic “Infection and Inflammation” for detail on inflammatory bowel disease.

Coeliac Disease

Coeliac disease is a chronic autoimmune systemic condition characterised by intolerance to gliadin in gluten and prolamins in wheat, barley and rye. Exposure to these allergens causes a pro-inflammatory response resulting in villous atrophy in the proximal small bowel mucosa, reducing its ability to perform its absorption functions. It can present in childhood following introduction of gluten into the diet or adulthood – this is now the most common timing of presentation, with the average age of diagnosis in the UK around 40 years old. Typical symptoms include abdominal pain, bloating, diarrhoea, weight loss, failure to thrive, fatigue, arthralgia and pallor. Clues within the presentation to suggest possible coeliac disease include anaemia (secondary to iron +/or B12 +/or folate deficiency), dermatitis herpetiformis (blistering skin rash on extensor sites), aphthous ulcers, buttock wasting or faltering growth. Patients will typically have raised IgA tissue transglutaminase antibodies (anti-tTGA) and IgA endomysial antibodies (anti-EMA IgA). These should be checked alongside total IgA levels, as those with IgA deficiency may get false negative results. The gold standard for diagnosis is endoscopy with small intestine biopsies – this requires continued gluten-containing diet for at least 6 weeks prior to endoscopy. Eliminating gluten from the diet is the mainstay of treatment. Those diagnosed with dermatitis herpetiformis should be offered dapsone. Complications include mineral deficiencies – namely calcium, B12, folate, iron, vitamin D, osteoporosis, hyposplenism and small bowel lymphoma.

Small Intestine Bacterial Overgrowth (SIBO)

SIBO is excessive colonisation of the small bowel with bacteria – usually coliforms, which produce gas from fermenting carbohydrates. This causes GI symptoms – most commonly abdominal bloating and pain, flatulence and diarrhoea. Risk factors include previous bowel resection or gastric bypass, connective tissue disorders (systemic sclerosis, Ehlers-Danlos, rheumatoid arthritis) and medications (narcotics and PPIs). The excessive bacteria impair the small bowel’s absorptive function, causing vitamin and nutrient deficiencies, including vitamin B12, vitamin D and iron. Folate levels, however, tend to be elevated due to its synthesis by the bacteria. The gold standard diagnostic test used to be a culture of duodenal aspirates; however, its invasive nature and expense has resulted in the most up-to-date guidelines recommending hydrogen breath testing with either glucose or lactulose as the first line investigation. SIBO can be treated with a course of broad-spectrum antibiotics – most commonly rifaximin 550mg three times daily for 14 days.

Bile Acid Malabsorption (BAM)

BAM is a chronic condition caused by failed reabsorption of bile in the terminal ileum and subsequent accumulation in the colon, where it stimulates water and electrolyte secretion. It can be idiopathic or occur secondary to ileal dysfunction (resection or Crohn’s disease), coeliac disease, pancreatic insufficiency, bacterial overgrowth or following cholecystectomy. BAM presents with chronic non-bloody greasy pungent diarrhoea. It can be diagnosed using the selenium homocholic acid taurine (SeHCAT) test, however, this is no longer recommended by NICE. Other tests that aid diagnosis include a trial of treatment – 48-hour total stool bile acid levels or fasting C4 levels. The mainstay of treatment is implementing a low-fat diet and oral bile acid binders – most commonly cholestyramine.

Neuroendocrine Neoplasms (NENs) of the GI Tract 

GI NENS, previously called neuroendocrine tumours (NETs), are rare slow growing tumours of enterochromaffin cells. Most occur sporadically, however, some occur as part of a genetic syndrome, including MEN1 (10% of all GI NENs), Von Hippel Lindau, Neurofibromatosis-1 and Tuberous Sclerosis. GI NENs are most commonly found in the small bowel, rectum, pancreas, stomach and appendix. Most are non-functional and asymptomatic, leading to delays in diagnosis. Functional NENs (approximately 40%) release large amounts of vasopressor peptides into the circulation causing symptoms. Carcinoid syndrome, affecting <10% of NEN patients, predominantly occurs when the tumour metastasises to the liver and releases hormones including serotonin. This leads to the classic symptoms of Carcinoid syndrome – diarrhoea, flushing, wheeze and abdominal pain. Fibrosis of the right-sided heart valves and right-sided heart failure (carcinoid heart syndrome) can also occur. Other functional NENs that secrete specific hormones are shown in table 1.

Table 1: Functional Neuroendocrine Neoplasms of the GI Tract

Functional NENs can be investigated using a 24-hour urine 5-HIAA test, where levels will be raised. The validity of this test can be affected by foods and drugs that contain or trigger the release of serotonin, causing false positives. Diagnosis is made by CT/MRI abdominal imaging or on histology from biopsies taken during endoscopy. Management is complex and requires regional MDT discussion but typically:

• Localised and resectable tumours – endoscopic or surgical resection
• Functional tumours –monthly somatostatin analogue subcutaneous injections (usually octreotide or lanreotide)
• Metastatic tumours – somatostatin analogues, radionuclide therapy (MIBG), chemotherapy, and embolisation of hepatic metastases

Peutz-Jeghers Syndrome (PJS)

PJS is a rare condition characterised by multiple hamartomatous polyps throughout the GI tract, most commonly affecting the jejunum. It is caused by a mutation in the STK11 gene, 50% occurring de novo and 50% inherited in an autosomal dominant fashion. Around 50% of patients will present in their 1st or 2nd decade of life with bowel obstruction. Other symptoms include GI bleeding (overt or presenting as iron deficiency anaemia), abdominal pain and distension. A hallmark sign is pigmented macules on the buccal mucosa, perioral areas, lips, fingers and toes. Diagnosis is confirmed with genetic testing. Polyps can be resected under endoscopic guidance. Patients have a 93% lifetime risk of malignancy – intestinal most commonly (39% colorectal cancer, 19% small bowel cancer) but also extra-intestinal (breast, pancreatic and ovarian/testicular cancer).

Whipple’s Disease

Whipple’s disease is a rare disease caused by infection with Tropheryma whipplei – a gram positive actinobacteria. It most commonly affects middle-aged men. Early symptoms include abdominal pain, joint pain, weight loss, diarrhoea, lymphadenopathy, steatorrhoea and skin hyperpigmentation. The disease later spreads and affects the central nervous system (CNS) and heart. CNS symptoms include synchronised abnormal ocular and masticatory movements, abnormal facial movements, memory or consciousness impairment, seizures and ataxia. Cardiac manifestations include endocarditis or myocarditis. Diagnosis is made based on jejunal biopsies taken at upper GI endoscopy (PAS-positive granules in the villi) or by PCR of CSF or lymph nodes (positive for T.Whipplei DNA). Initial treatment of Whipple’s disease is 2 weeks of IV ceftriaxone or benzylpenicillin. This is followed by a 1-year maintenance treatment of oral co-trimoxazole. If there is CNS involvement, oral doxycycline and hydroxychloroquine are added.

Diseases of the Large Bowel

This section focuses on diseases that predominantly affect the large bowel aka the colon. The colon is the main site of water reabsorption and uses peristaltic and high amplitude propagating contractions to move its contents along the tract and eventually result in defecation. Disease within this part of the GI tract results in symptoms including change in stool form and/or frequency, abdominal pain and PR bleeding. Please note:

• Some of the common large bowel diseases, including infective gastroenteritis and inflammatory bowel disease, will be covered in the topic “Infection and Inflammation”.
• Ischaemic bowel diseases, which affect both the small and large bowel, will be combined and only covered in this section to avoid duplication.

Colorectal Cancer (CRC)

CRC is the 3rd most common cancer in the Western world. The most common histology type is adenocarcinoma. Risk factors include increasing age, male gender, Caucasian or Black ethnicity, family history, obesity, physical inactivity and high red meat consumption. Symptoms depend on the site of the tumour but include abdominal pain, PR bleeding and change in bowel habit. Signs include an unexplained iron deficiency anaemia, palpable abdominal or rectal masses and evidence of weight loss. The gold standard investigation for diagnosis is colonoscopy with biopsy, however, CT colonography can be used if colonoscopy is contraindicated or inappropriate. Once a confirmed diagnosis is made, a staging CT of the chest, abdomen and pelvis is required. Management involves an MDT-based decision, considering factors including TNM staging, the patient’s performance status and patient preference. Localised CRC is usually managed with curative surgical resection and is only avoided if the risks outweigh the benefits. This may be preceded or followed up by radiotherapy and/or chemotherapy. Advanced metastatic or inoperable tumours will be managed with a palliative approach, including palliative surgery, chemotherapy and hormone therapy. In the UK, bowel cancer screening is offered to everyone aged 60 to 74 years old every 2 years in the form of a home Faecal Immunochemical Test (FIT).

Hereditary Non-Polyposis Colorectal Cancer (HNPCC)

HNPCC, aka Lynch syndrome, is an autosomal dominant inherited condition that increases the risk of various malignancies – most commonly CRC(60-80%). It is caused by a defect in a mismatch repair gene, usually MSH2 or MLH1 (90%), causing microsatellite instability. It is the most common hereditary CRC syndrome, responsible for 1-3% of all CRCs. Other malignancies that are commonly associated with HNPCC include endometrial, ovarian, small bowel and liver cancer. The Amsterdam clinical criteria aids diagnosis alongside molecular genetic testing for germline mutations. Patients with HNPCC undergo 2 yearly colonoscopy screening, with the onset of screening determined by the causative gene mutation. All patients should be offered aspirin, which reduces the risk of developing CRC. If a high risk gene mutation is identified, subtotal bowel resection should be considered.

Familial Adenomatous Polyposis (FAP) 

FAP is a rare autosomal dominant condition characterised by the development of hundreds to thousands of colonic polyps by aged 30-40 years. FAP results from a mutation in the APC tumour suppressor gene on chromosome 5. 80% of cases are familial. Without definitive treatment, almost all FAP patients will develop CRC by the age of 40. Those with FAP may be identified through family genetic screening or by presenting with symptoms such as abdominal pain, PR bleeding or symptoms of bowel obstruction. These patients should undergo colonoscopy at the time of diagnosis and then regularly to assess the polyp burden. Patients invariably require total colectomy or proctocolectomy to reduce their CRC risk. Gardner’s syndrome is a variant of FAP where, in addition to colonic polyps, patients are prone to develop extra-intestinal tumours, including desmoid tumours, osteomas, thyroid and skin tumours (lipomas, fibromas and epidermoid cysts).

Diverticular Disease 

Diverticula are small outpouchings of bowel mucosa and submucosa through its outer muscular layer. Risk factors for diverticula formation include increased age, reduced physical activity, raised BMI, low fibre diet and certain medications (NSAIDs and steroids). When symptoms develop that can be attributed to the diverticula, this is termed diverticular disease – this may include intermittent colicky left iliac fossa pain, bloating, constipation and painless fresh red PR bleeding. Acute diverticulitis occurs if the diverticula becomes inflamed – the patient may develop a fever, elevated leu leukocytes and CRP, and tenderness on the PR exam. Diagnosis of acute diverticulitis is made by CT abdomen with contrast. Endoscopy should be avoided during acute inflammation due to the risk of perforation. Diverticula increases the risk of lower GI complications, including abscess or fistula formation, bowel obstruction, GI bleeding, bowel perforation and peritonitis. Disease management depends on the presentation:

Table 2: Management of diverticula-related disease

Angiodysplasia 

Angiodysplasia is the presence of vascular malformations in the GI tract, most commonly the ascending colon and caecum. This results in fragile blood vessels that are prone to leaking, causing GI bleeding. This disease predominantly affects older patients but is also found in those with aortic stenosis, end stage renal failure requiring dialysis, left ventricular assist devices and Von Willebrand disease. Patients may be asymptomatic, or present with GI bleeding and/or symptoms of iron deficiency anaemia. Diagnosis is made during endoscopy (upper GI, colonoscopy and/or capsule endoscopy) or CT angiography if persistent active GI bleeding. Management involves stabilisation with fluid and blood products if bleeding causes haemodynamic instability and, if persistent, uncontrollable bleeding, treatment options include mesenteric angiography and embolisation, colonoscopy with electrocautery, photocoagulation, clipping or epinephrine injections, or surgical bowel resection.

Colitis

Colitis is inflammation of the colon. It occurs secondary to different underlying pathologies:

• Ulcerative colitis/Crohn’s colitis (as part of IBD) – please see “Infection and Inflammation” topic
• Microscopic colitis – please see “Infection and Inflammation” topic
• Infective colitis – please see “Pseudomembranous Colitis” section
• Ischaemic colitis – please see “Ischaemic Bowel Disease” section

Pseudomembranous Colitis

Pseudomembranous colitis is acute inflammation of the colon secondary to infection with Clostridium difficile – a gram positive toxin-producing anaerobic rod. It has a strong association with prolonged use of broad-spectrum antibiotics, which disrupt the normal bowel flora and allow Clostridium difficile to colonise. The most common culprit antibiotics are 3rd/4th generation cephalosporins, ciprofloxacin, clindamycin, carbapenems and broad-spectrum penicillins. Other risk factors include increased age, prolonged hospital stay, PPI use, immunosuppression and previous Clostridium difficile infection. Symptoms include new onset pungent diarrhoea, abdominal pain, fever, nausea and vomiting. The classification of Clostridium difficile infection severity is shown in table 3:

Table 3: Public Health England Classification of Clostridium difficile Infection Severity

Stool samples should be sent for PCR and enzyme immunoassay in all suspected cases of Clostridium difficile. If clinical signs suggest toxic megacolon or bowel perforation, abdominal imaging is necessary. Patients need to be isolated with enhanced PPE for contacts and handwashing with soap and water until 48 hours after diarrhoea has resolved. Care is supportive, with antimicrobial use guided by frequency of reinfection, as shown in tavle 4.

Table 4: Management of Clostridium difficile Infection in Adults

Ischaemic Bowel Disease 

Ischaemic bowel disease is a heterogeneous group of conditions characterised by reduced blood flow to the bowel, resulting in ischaemia which may lead to infarction and necrosis. Ischaemic colitis affects the large bowel, whilst mesenteric ischaemia affects the small bowel.

Ischaemic Colitis

This is the most common type of bowel ischaemia, caused mainly by arterial (but occasionally venous) embolism or thrombus. It usually affects the watershed areas of the large bowel that lack a collateral blood supply – the splenic flexure and rectosigmoid junction. Risk factors include older age, recent cardiac or vascular surgery, irritable bowel syndrome and constipation. It often presents with sudden onset worsening left iliac fossa pain, often with concurrent passage of loose bloody stool. CT abdomen and pelvis with contrast is often the first line investigation, however, findings may not be specific or diagnostic. Colonoscopy may be required to confirm the diagnosis. Most cases resolve spontaneously. If there are persistent symptoms, patients may require hospital admission with a course of antibiotics, low molecular weight heparin, bowel rest and monitoring. Surgical intervention is required for associated complications (peritonitis, massive GI bleeding, fulminant colitis) – usually segmental bowel resection with stoma formation.

Acute Mesenteric Ischaemia (AMI)

AMI is a medical emergency where the small bowel becomes acutely ischaemic from one of the following 4 mechanisms: acute arterial embolism (50%), intestinal hypoperfusion (20-30%), arterial thrombosis (15-25%) or mesenteric venous thrombosis (5%). It typically affects older patients with cardiovascular risk factors, including atrial fibrillation, previous myocardial infarction, atherosclerosis, smoking and congestive heart failure. It presents with sudden onset severe periumbilical pain out of keeping with examination findings. 90% of patients will have leukocytosis. In suspected cases, an urgent contrast CT abdomen and pelvis and CT angiography are required. Once AMI is confirmed, early surgical and intensive care review is needed. Antibiotics should be started as the intestinal mucosal barrier can be damaged by ischaemia causing bacterial translocation. Management options include interventional radiology (IR)-guided endovascular treatment (thrombolysis, transjugular intrahepatic portosystemic shunt and thrombectomy) or urgent laparotomy with bowel resection if there is bowel infarction, perforation or peritonitis.

Chronic Mesenteric Ischaemia (CMI)

CMI is caused by chronic hypoperfusion of the small bowel, usually because of progressive atherosclerosis. It is more common in older female patients with risk factors including atherosclerosis, left ventricular dysfunction, chronic low blood pressure and constipation. It usually presents with recurrent episodes of mild self-limiting generalised abdominal pain, worse after eating, associated with weight loss from food avoidance. Signs include an abdominal bruit and electrolyte and nutrient deficiencies. Diagnosis is confirmed on CT angiography. Asymptomatic patients can be managed with lifestyle interventions, antiplatelet and lipid-lowering therapies. If symptomatic, surgical or IR-guided revascularisation can be performed.

Functional Bowel Disorders (FBDs)

Definition and Pathophysiology 

FBDs are a group of conditions characterised by chronic GI tract symptoms for which no pathology can be found by conventional testing means. While previously defined as “lacking organic cause”, research has now demonstrated a correlation with abnormal gut-brain communications. This occurs secondary to abnormalities in GI motility, visceral hypersensitivity, altered mucosal and immune function, altered gut microbiota, and altered CNS processing. Risk factors include female gender, adolescents/young adults, and concomitant chronic psychiatric conditions (e.g., anxiety, depression, OCD), chronic pain syndromes (e.g., fibromyalgia) or functional conditions (e.g., chronic fatigue syndrome). They are the most commonly encountered GI pathologies in both primary and secondary care, therefore, it is important to recognise, diagnose and treat early.

Classification

The most common and well-known functional bowel disorder is Irritable Bowel Syndrome (IBS), estimated to affect 10-20% of the UK population. However, there are other FBDs which are defined according to the Rome IV criteria, shown in table 5.

Table 5: The Rome IV Diagnostic Criteria of FBDs

Assessment 

To formally diagnose an FBD, an organic cause for the patient’s symptoms must be excluded. A thorough history should exclude any red flag symptoms (such as GI bleeding, anaemia, unintentional weight loss) whilst also assessing lifestyle factors (diet, exercise, stress levels) and psychological state. Blood and stool testing is often required before attributing the patient’s symptoms to an FBD and managing them as such accordingly.

Management 

FBDs should be managed with a biopsychosocial approach involving a multidisciplinary team to deliver holistic care that is patient-specific with the aim of ameliorating symptoms and improving quality of life. Patients should be informed of an FBD diagnosis early with a thorough explanation that FBDs are chronic, often relapsing conditions and are, therefore, incurable and hard to treat. Management strategies, therefore, do not have curative intent and instead focus on improving symptom control and reducing their impact on the sufferer’s daily life, as shown in table 6.

Table 6: Management of FBDs