Gastroenterology
Endoscopy [link]
Oesophagogastroduodenoscopy [link]
Conventional enteroscopy [link]
Double-balloon enteroscopy [link]
Wireless capsule endoscopy [link]
Flexible sigmoidoscopy & colonoscopy [link]
Endoscopic retrograde cholangiopancreatography [link]
Endoscopic ultrasound [link]
Tests for Helicobacter pylori[link]
Faecal occult blood [link]
Serological & faecal testing in inflammatory bowel disease [link]
Tumour markers [link]
Investigations for small bowel pathology [link]
Tests of small bowel absorption [link]
Tests for bacterial overgrowth [link]
Tests of pancreatic exocrine function [link]
Testing for neuroendocrine tumours [link]
Gastrointestinal physiology [link]
Non-invasive liver investigations [link]
Liver biopsy [link]
Investigations of ascitic fluid [link]
Endoscopy
This allows direct visualization of the gastrointestinal tract mucosa and offers further diagnostic investigations to obtain tissue for histology, cytology, or microbiology, as well as therapeutic possibilities.
Consent (general)
Consent is a vital component of the endoscopy process. Patients should receive written information before attending for the procedure. This should describe pre-test preparation, the procedure itself, risks and possible complications, after-care advice (particularly for those patients requiring sedation), and contact details in the event of problems and include the consent form that the patient will be asked to sign.
Sedation
While the majority of oesophagogastroduodenoscopy (OGD) procedures can be performed using local anaesthetic spray to the oropharynx, sedation will be required for more complex or prolonged procedures. An IV combination of a sedative with amnesic effects such as midazolam or diazepam is usually combined with an analgesic such as pethidine or fentanyl. Finally, hyoscine butylbromide (Buscopan®) may act to reduce intestinal motility, which is useful for colonoscopy, endoscopic retrograde cholangiopancreatography (ERCP), or enteroscopy. An alternative to hyoscine butylbromide (Buscopan®) is glucagon which may be used for patients with glaucoma or ischaemic heart disease where hyoscine butylbromide (Buscopan®) is contraindicated.
Antibiotic prophylaxis
Guidelines have recently changed with prophylaxis indicated for percutaneous endoscopic gastrostomy or jejunostomy palcement, those patients undergoing ERCP where biliary drainage is unlikely to be achieved at the first procedure or finally for those with severe neutropenia (<0.5 109/L) and/or severe immunocompromise undergoing procedures with a high risk of bacteraemia such as oesophageal dilatation or variceal sclerotherapy.
Anticoagulation guidelines
For diagnostic OGD, colonoscopy, flexible sigmoidoscopy and enteroscopy, including simple biopsies and thermocoagulation techniques, it is possible to continue anticoagulation as long as the international normalized ratio (INR) is within the therapeutic range. However, therapeutic procedures such as PEG placement, ERCP, polypectomy, or dilatation require normal coagulation and specialist advice should be sought.
Risks and points for consent
Table 7.1 shows the common complications of endoscopic procedures with morbidity and mortality figures for each.
Table 7.1 Risks and complications of most commonly performed endoscopic procedures
Procedure | Risks | Morbidity for each complication | Overall mortality | Other issues |
|---|---|---|---|---|
OGD | Perforation Haemorrhage | 0.03% 0.002% | 0.0001% | Greatest risk for therapeutic procedures Cardiorespiratory sedation-related complications 0.005% |
Flexible sigmoidoscopy/colonoscopy | Perforation Haemorrhage | 0.005% 0.001% | 0.001% | Cardiorespiratory complications related to sedation—0.01% |
Colonic polypectomy | Perforation Haemorrhage | 0.06%, 0.26% | 0.007% | As above |
PEG placement | Perforation Haemorrhage Infection | Overall risk 5–10% | 1–2% | 30-day mortality of approximately 10% (often resulting from underlying condition) |
ERCP | Perforation Haemorrhage Cholangitis Pancreatitis | 1.1%, 0.9% 5%, 3.8% Cardiorespiratory complications related to sedation—2.3% | 1.0% | Greatest risks overall with dilated bile duct, placement of stent and high dose buscopan Risk of pancreatitis greatest with age <40 yrs, placement of stent and dilated bile duct |
Further reading
Allison M. BSG Antibiotic prophylaxis in gastrointestinal endoscopy. 2009. 
www.bsg.org.uk. (British Society of Gastroenterology).
Christensen M, Matzen P, Schulze S, Rosenberg J. Complications of ERCP: A prospective study. Gastrointest Endosc 2004; 60: 721–31
Find This Resource
Green J (ed). Complications of gastrointestinal endoscopy. 2006. www.bsg.org.uk (British Society of Gastroenterology guidelines)
Veitch AM, Baglin TP, Gershlick AH, et al. Guidelines for the management of anticoagulant and antiplatelet therapy in patients undergoing endoscopic procedures. Gut 2008. 57: 1322–9
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Oesophagogastroduodenoscopy
• Endoluminal visualization of oropharynx to second part of duodenum.
• Allows direct testing for Helicobacter pylori.
• In preparation for OGD, patients should not eat for 4–6 h beforehand with clear fluids allowed up to 2 h before the procedure.
• They should remain nil-by-mouth for at least 30 min afterwards to allow local anaesthetic spray or sedation to wear off.
• Stop proton pump inhibitors 2 weeks before elective diagnostic OGD to prevent masking of appearances (risk of partial healing and thus misdiagnosing malignant oesophageal or gastric ulcers).
Alternative investigations
As an alternative procedure to OGD or enteroscopy, barium swallow, meal, or follow through may be performed depending upon symptoms (for oesophageal, gastric, or duodenal, and jejunal pathology, respectively). Investigations are limited by their lower sensitivity for mucosal pathology and inability to obtain tissue for histology or H. pylori testing.
Indications
Symptoms/signs
• Dysphagia.
• Haematemesis and melaena.
• Dyspepsia despite appropriate therapy.
• Iron deficiency anaemia (Fig. 7.1a).
• Weight loss.
• Vomiting or nausea.
• Investigation of suspected giardia to obtain duodenal aspirates.
• Investigation of suspected coeliac disease to obtain duodenal/jejunal biopsies.
• Investigation to obtain histology and cultures of H. pylori.
• Abnormal barium swallow, meal, or early follow through.
Table 7.6 Ascitic fluid aspiration—practical procedure
Patient | Lies on his/her back tilting towards side planned for aspiration |
Percussion | Used to find shifting dullness in left or right lower quadrant |
Chlorhexidine | Used to clean the site |
Lignocaine | 2–3mL of 1% used to infiltrate a site in the left or right lower quadrant where shifting dullness is detected. It should be possible to aspirate ascitic fluid using a standard 19G needle. |
50mL syringe | Sterile 19G needle placed through the same site to obtain the samples required. |
Rare complications | Include bowel perforation, secondary bacterial peritonitis or haemorrhage |
).Surveillance/screening
• Ensures healing of oesophageal and gastric ulceration.
• Barrett’s oesophagus.
• Establishes response to a gluten-free diet in coeliac disease.
• Diagnosis of polyps in familial polyposis syndromes.
Therapeutic
• Treatment of bleeding lesions (peptic ulceration, angiodysplasia, varices, vascular malformations).
• Palliation of oesophageal cancers using stent placement, argon plasma coagulation or Nd:Yag laser therapy.
• Placement of PEG or jejunostomy tubes (Fig. 7.1b).
• Direct placement of nasogastric or nasojejunal feeding tubes.
• Dilatation of strictures of the oesophagus or pylorus.
• Polypectomy.
• Placement of luminal stents
Conventional enteroscopy
• Similar to OGD, but allows views of distal duodenum and jejunum using a 2.4m instrument.
• An overtube allows less looping, but increases complications.
• Preparation as for OGD; usually requires sedation, analgesia, and hyoscine butylbromide (Buscopan®).
Double-balloon enteroscopy
• Allows views of entire small bowel from oral or rectal approach.
• Preparation is as for OGD or colonoscopy, and requires sedation, analgesia, and buscopan.
• Consists of two balloons, one attached to distal endoscope and one to a transparent overtube sliding over the endoscope allowing movement forward by telescoping the small bowel by gripping and pleating it over the endoscope.
Alternative investigations
Diagnosis
Barium investigations are limited by a lower sensitivity for mucosal pathology. Wireless capsule endoscopy is a more effective (but less frequently available) alternative. Sonde enteroscopy uses a thinner endoscope with a balloon at its tip passing through the entire small bowel over 6–8 h, with examination occurring on withdrawal of the instrument after deflation of the balloon. However, each of these is limited by an inability to obtain tissue or provide therapeutic interventions.
Treatment (and diagnosis)
Double-balloon enteroscopy allows visualization and treatment of any lesions within the full length of the small bowel, and may replace conventional enteroscopy. Conventional enteroscopy will diagnose and treat lesions within the upper small bowel (to jejunum), but is limited by patient tolerance. Intra-operative enteroscopy allows complete examination of the entire small bowel and therapeutic possibilities via an enterotomy.
Indications for enteroscopy
Symptoms/signs
• Investigation of obscure gastrointestinal bleeding (following non-diagnostic OGD and colonoscopy).
• Investigation of lesions found on barium follow-through/computed tomography (CT) scan abdomen.
• Investigation of severe iron deficiency anaemia (following non-diagnostic OGD and colonoscopy).
• Therapeutic.
• Treatment of bleeding lesions found at enteroscopy or by wireless capsule endoscopy (WCE).
• Polypectomy.
Wireless capsule endoscopy
• Allows imaging of the entire small bowel by using an 11 × 27mm capsule (‘M2A’) with up to 7.5 h of battery life.
• When swallowed, the capsule transmits images to aerials attached by adhesive pads to the abdominal wall and stored on a recorder attached round the waist.
• Propelled by the patient’s own peristalsis so symptom-free.
• Views of the distal small bowel are improved by using one sachet of sodium picosulfate 1 day beforehand to remove residue.
• Specialist procedure, but with a higher diagnostic yield than other small bowel investigations.
• Prior barium small bowel imaging may be advisable to rule out stricturing, where WCE could precipitate obstruction.
Indications
• WCE has a role in visual diagnosis, but is unable to obtain samples for subsequent analysis or allow therapeutic management.
• Occult gastrointestinal bleeding with non-diagnostic OGD and colonoscopy.
• Possible small bowel polyposis (e.g. Peutz–Jegher syndrome).
• Unexplained diarrhoea and malabsorption not diagnosed by other methods.
Points for consent
• 1–2% risk of obstruction reported especially if stricturing (e.g. small bowel Crohn’s disease) or previous small bowel surgery.
• Contraindicated in patients with a pacemaker.
Further reading
Mylonaki M, Fritscher-Raven A, Swain CP. Wireless capsule endoscopy: a comparison with push enteroscopy in patients with gastroscopy and colonoscopy negative gastrointestinal bleeding. Gut 2003; 52: 1122–6
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Swain P. Wireless capsule endoscopy. Gut 2003; 52: 48–50
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Table 7.2 Diagnostic yield of small bowel investigations for occult bleeding lesions
Sensitivity | Specificity | Diagnostic yield | |
|---|---|---|---|
Enteroscopy | 37% | 97% | 30–32% |
Wireless capsule endoscopy | 64% | 92% | 55–68% |
Flexible sigmoidoscopy & colonoscopy
• Allows examination from anus to splenic flexure (flexible sigmoidoscopy) or from anus to caecum/terminal ileum (colonoscopy).
• Flexible sigmoidoscopy may be performed without sedation.
• Colonoscopy usually requires a sedation and analgesia together with smooth muscle relaxant (buscopan).
• Preparation for flexible sigmoidoscopy: phosphate enema 30–60 min prior to the procedure.
• Preparation for colonoscopy: oral preparation using 2 sachets of sodium picosulfate on the day before the procedure with a low residue diet for the 3 days pre-procedure.
Alternative investigations
Alternative procedures are radiological: barium enema or CT colonography. Neither allows tissue to be taken, for histotopy nor polypectomy, nor other therapeutic procedure to be performed. Sensitivity is lower for detecting adenomas using CT colonography than colonoscopy; for lesions ≤10mm, sensitivity is 55% against 99% for colonoscopy. Colonoscopy is ‘gold standard’ for investigating likely colon cancer, diarrhoea, anaemia, and rectal bleeding.
Indications
Symptoms and signs
• Rectal bleeding (bright red = flexible sigmoidoscopy and dark red = colonoscopy), but beware as some right-sided colonic lesions do present with bright red bleeding.
• Positive faecal occult bloods (colonoscopy).
• Abnormal barium enema (depends upon site of pathology found).
• Iron deficiency anaemia (colonoscopy).
• Diarrhoea (colonoscopy with biopsies).
Surveillance/screening
• Extensive ulcerative colitis or colonic Crohn’s disease for more than 8 yrs.
• High risk of adenomatous colonic polyps, or carcinoma, or previous history of adenomatous polyps or carcinoma.
• Familial polyposis syndrome (FAP), hereditary non-polyposis colorectal carcinoma (HNPCC), or other family cancer syndromes.
Therapeutic
• Treatment of bleeding lesions (angiodysplasia, vascular abnormalities, haemorrhoids).
• Dilatation of benign strictures.
• Palliation of malignant strictures (placement of stents, argon plasma coagulation, or Nd:Yag laser therapy).
• Decompression of sigmoid volvulus and non-malignant toxic megacolon.
• Endoscopic mucosal resection of tumours.
Endoscopic retrograde cholangiopancreatography
• Side-viewing endoscope used to find the ampulla of Vater, and guide cannulation of the biliary and pancreatic ducts by injecting radio-opaque contrast medium to allow visualization of the ducts using fluoroscopy.
• Magnetic resonance cholangiopancreatography (MRCP) has replaced ERCP in 1° diagnosis. ERCP is used for interventional procedures and to obtain biopsy and cytology specimens.
• ERCP requires sedation, an analgesic and buscopan.
Alternative investigations
MRCP allows imaging of the biliary and pancreatic systems and is the best (and safest) option for diagnosis, although no therapeutic procedures are possible. A percutaneous transhepatic cholangiogram (PTC) allows imaging, stent placement and drainage of a dilated biliary tree using a trans-abdominal approach. PTC is indicated if therapeutic ERCP fails.
Indications
Symptoms and signs
• Endoscopic diagnosis of periampullary polyps, and tumours.
• Obtaining bile/brushings for cytology in suspected cholangiocarcinoma.
• Investigation of dilated ducts found on ultrasound scan with contraindications to MRCP.
• Assessment of sphincter of Oddi pressures in suspected sphincter of Oddi dysfunction syndromes (SOD).
Therapeutic
• Biliary stenting:
• Palliation of pancreatic, ampullary and cholangiocarcinomas.
• Treatment of biliary leak following surgery.
• Benign biliary stricture.
• Biliary sphincterotomy:
• Gaining access to perform diagnostic or therapeutic procedures.
• Choledocholithiasis.
• Ampullary carcinoma.
• Treatment of a biliary leak following surgery.
• Treatment of SOD.
• Treatment of acute severe pancreatitis secondary to gallstones.
• Pancreatic stenting:
• Drainage of pseudocysts (via stomach).
• Following sphincterotomy for SOD (as this increases risk of pancreatitis in short-term).
• Pancreatic sphincterotomy:
• Pancreatic stone disease.
• Gaining access prior to stent placement.
• Minor duct papillotomy in pancreatic divisum to prevent pancreatitis.
Endoscopic ultrasound
• Combines endoscopy with ultrasound imaging to allow visualization of organs such as the pancreas and accurate assessment of degree of invasion of luminal tumours.
• Higher frequency ultrasound probe allowed by proximity of probe to organ results in increased spatial resolution compared with transabdominal ultrasound, CT or magnetic resonance (MR) scanning.
• Two different modes of imaging are possible: radial—which allows a 360° view around the shaft of the instrument—or linear—which is in line with the endoscope and allows 90° up to 270° views.
• Specialist technique provided in few centres.
• Pre-procedure preparation is as for OGD or ERCP.
• Consent procedures differ, depending upon indications and potential pathology.
Alternative investigations
Transabdominal ultrasound, CT and MRI scanning allow views of the pancreas and liver, but do not allow such fine detail for diagnosis or therapy.
Indications
• Staging of oesophageal, gastric, pancreatic, and distal biliary tumours.
• Diagnosis and staging for gastrointestinal stromal tumours.
• Fine needle aspiration of ‘Trucut’ biopsy of mediastinal or coeliac axis lymph nodes, pancreatic lesions, or submucosal lesions.
• Defining mucosal abnormalities, such as Barrett’s oesophagus.
• Coeliac axis nerve block to treat pancreatic pain (chronic pancreatitis or pancreatic carcinoma).
• Evaluation and treatment of pancreatic pseudocysts.
• Detection of common bile duct stones.
Further reading
Allum WH, Griffin SM, Watson A, et al. Guidelines for the management of oesophageal and gastric cancer. Gut 2002; 50 (suppl V): v1–23
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Soriano A, Castells A, Ayuso C, et al. Preoperative staging and tumor resectability assessment of pancreatic cancer: prospective study comparing endoscopic ultrasonography, helical computed tomography, magnetic resonance imaging, and angiography. Am J Gastroenterol 2004; 99: 492–501
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Tests for Helicobacter pylori
Indications for testing
• ‘Test and treat’: patients <55 yrs of age with a low probability of significant pathology and dyspeptic symptoms do not require OGD. Non-invasive testing for H. pylori allows treatment of those found to be positive to assess effect on symptoms. Although it is essential that all patients with alarm symptoms (weight loss, anaemia, or dysphagia) should undergo urgent OGD.
• Ensure effective eradication in patients with confirmed peptic ulceration or MALT-lymphoma.
Non-invasive tests
Serology
Serum IgG antibodies to H. pylori may be detected by ELISA with sensitivity of 90% and a specificity of 70–90%. IgG levels take up to 1 year to fall so are not useful to confirm response to eradication. Other organisms may cause cross-reactivity. False negatives occur in elderly or immunocompromised patients.
Urea breath test
Expired air is collected after ingestion of 13C-labelled urea. If H. pylori present, bacterial urease breaks down urea → ammonium and bicarbonate then → carbon dioxide and ammonia. Expired 13CO2 is collected into a tube 30 min after ingestion, measured by mass spectrophotometer, and compared with one collected prior to ingestion. This test is almost 100% sensitive and specific, and remains the gold standard to confirm eradication.
Invasive tests (performed at OGD)
Investigations are based on biopsy samples. H. pylori density is usually greatest in the antrum, but during acid suppression the greatest concentration is found in the corpus. Colonization is patchy so may yield sampling errors.
Histology
H. pylori can be detected on routine histology using the modified Giemsa stain. Sensitivity is 85% with a specificity of almost 100%.
Culture
This is useful in those few patients who have failed eradication to establish antibiotic sensitivities. Sensitivity is over 95% with specificity of almost 100%.
Rapid urease test
A biopsy is placed into a urea solution containing phenol red. H. pylori contains urease, releasing ammonia from urea thus changing pH, detected as a colour change with phenol red dye turning from straw to pink/purple. Commercial kits such as the Campylobacter-like organism (CLO) test are available. Specificity is 97%, and sensitivity between 70 and 95%.
Further reading
Calam J. Clinicians guide to Helicobacter pylori. Chapman and Hall Medical, London, 1996
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Gatta L, Perna F, Ricci C et al. A rapid immunochromatographic assay for Helicobacter pylori in stool before and after treatment. Aliment Pharmacol Ther 2004; 15: 469–74
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Faecal occult blood
Indications
• Population screening for colorectal neoplasms in UK started 2006–2008 with a planned screening programme from Department of Health for 60–69-yr-olds every 2 yrs. Full colonoscopy is performed for those with positive results. Mortality from colorectal carcinoma is decreased by 15–18%.
• Pre-menopausal women to establish whether iron-deficiency anaemia is related to gastrointestinal blood loss (in all other groups, the gastrointestinal (GI) tract should be investigated in iron-deficiency anaemia using OGD and colonoscopy).
Investigation
• Simple and inexpensive, performed by the patient in their own home.
• Samples taken onto test card from 3 consecutive bowel motions and card sent to screening centre.
• Test card uses the ‘guaiac’ reaction with pseudoperoxidase in haemoglobin causing a colour change in an indicator dye.
• Dietary changes advised (avoid red meat, horseradish, broccoli, and turnips as these have high perioxidase activity, which may cause false positive results) and vitamin C tablets (high ascorbic acid activity).
Results
• Sensitivity of the non-hydrated test is 70%; this increases to 90% with rehydration, but at the loss of specificity. Sensitivity improves with the number of samples taken.
• Individuals who are positive require full colonoscopy.
• Multicentre UK trial invited 486,355 for screening using FOB (take up 56%), finding 2% FOB positive and of these, 10.9% have carcinoma, 35% adenoma, and 54.1% to be normal
Limitations
Polyps and carcinomas may bleed intermittently, but FOB are more likely to be positive with early-stage cancers than polyps.
Further reading
Hardcastle JD, Chamberlain JO, Robinson MHE, et al. Randomised controlled trial of faecal-occult-blood screening for colorectal cancer. Lancet 1996; 348: 1472–7
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Tappenden P et al. Option appraisal of population-based colorectal cancer screening programme in England. Gut 2007; 56: 677–84
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Serological & faecal testing in inflammatory bowel disease
At present, there are no tests that are sufficiently sensitive or specific to confidently diagnose either ulcerative colitis or Crohn’s disease, but antibodies to Saccharomyces cerevisiae (ASCA) and perinuclear antineutrophil cytoplasmic antibodies (pANCA) cannot be measured in isolation as the sensitivity and specificity of each increases if the other serological marker is negative.
Perinuclear antineutrophil cytoplasmic antibodies
Occur in the serum of 50–80% of patients with histologically confirmed ulcerative colitis, but only 10% of those with Crohn’s disease. This is likely to be genetically determined. These antibodies are particularly associated with 1° sclerosing cholangitis in association with ulcerative colitis. Overall sensitivity is 55.3% with a specificity of 88.5%. In a paediatric cohort with negative ASCA, sensitivity increased to 70.3% with 93.4% sensitivity.
Antibodies to Saccharomyces cerevisiae
Found in 60% of patients with Crohn’s disease, but only 5% of those with ulcerative colitis. In Crohn’s disease, the presence of high titres of ASCA appears to be associated with early age of onset, and both fibrostenosing and fistulating disease types. Here, sensitivity is 54.6% with specificity of 92.8% if pANCA is negative.
Faecal calprotectin
This is a neutrophil granulocyte cytosol protein which acts as a marker of intestinal inflammation. It is positively correlated with inflammation scores in Crohn’s disease and ulcerative colitis. However, it is non-specifically elevated in neoplasia and radiation proctitis. At present it is available in few centres and it identifies a group of patients who require further investigation from those with probable irritable bowel syndrome who do not. Sensitivity for diagnosing pathology is 93% with specificity of 100%. This is likely to become more widely available with easier assays and a reduction in price compared with the cost implications of avoiding tests such as colonoscopy for those patients who do not require them.
Faecal lactoferrin
This is a neutrophil-derived protein, which acts as a marker of intestinal inflammation. As for calprotectin, it aims to use non-invasive testing to differentiate those who require intestinal imaging, such as colonoscopy, from those more likely to have functional disease, such as irritable bowel syndrome. It is not as effective as calprotectin in this regard as sensitivity for diagnosing pathology is 82% and specificity is 84%.
Further reading
Reese GE. et al. Diagnostic precision of anti-Saccharomyces cervisiae antibodies and perinuclear antineutrophil cytoplasmic antibodies in inflammatory bowel disease. Am J Gastroenterol. 2006; 101: 2410–22
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Schröder O, et al. Prospective evaluation of faecal neutrophil-derived proteins in identifying intestinal inflammation: combination of parameters does not improve diagnostic accuracy of calprotectin. Aliment Pharmacol Ther. 2007; 26: 1035–42
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Tumour markers
• As a result of generally low sensitivities and specificities, these should not be first-line investigations.
• They are best used for tracking patients following diagnosis of carcinoma through subsequent surgery, and chemo-radiotherapy when levels should fall to normal unless disease recurrence.
Carcinoembryonic antigen
• ↑ in 60% of those with localized colorectal carcinoma and 80–100% of those with metastatic disease.
• Non-specific and non-diagnostic—also ↑ in bronchial carcinoma, heavy smokers, inflammatory bowel disease.
• Levels do not relate to tumour load, but a rising level, which was previously low or normal, may imply recurrence of colorectal carcinoma.
α-fetoprotein
• Normally produced by fetal liver.
• High levels in non-pregnant adults imply hepatocellular carcinoma (raised in over 90% cases).
• ↑ Serological concentrations in pregnancy suggest neural tube defect.
• Blood levels may be ↑ in hepatocyte regeneration, acute viral hepatitis, cirrhosis, choriocarcinoma, and teratoma.
• May be used 6 monthly (with liver ultrasound scan) to screen cirrhotic patients for development of hepatocellular carcinoma
Carbohydrate antigen 19-9 (CA 19-9)
• ↑ in pancreaticobiliary obstruction with the highest levels in pancreatic carcinoma.
• Levels >40IU/L have 75–90% sensitivity and 80–95% specificity for ductal pancreatic carcinoma.
• Serum levels may be elevated in jaundice, cholangitis, choledocholithiasis, and chronic pancreatitis.
Cancer antigen 125 (Ca 125)
• Glycoprotein antigen to an epidermal growth factor receptor ([link] sEGFR).
• Blood levels ↑ with menstruation, endometriosis, pelvic inflammatory disease, pregnancy, and ascites.
• Highest levels with ovarian malignancy, but also ↑ with ovarian, pancreas, breast, lung, and colon cancers.
• 20% ovarian cancers have little/no expression of Ca 125.
• Useful in monitoring response of ovarian carcinoma to treatment (if initially positive) as rising level Ca 125 precedes clinical recurrence by up to 3 months (>90% cases).
• As isolated values lack sensitivity and specificity, serial Ca 125 readings may be used to achieve specificity of 99.6%, but with a sensitivity of only 80%.
Investigations for small bowel pathology
General investigations
Presenting features of small bowel pathology include diarrhoea (or steatorrhoea), abdominal pain, weight loss, and nutritional deficiencies. Investigation of diarrhoea is shown in Fig. 7.4. Occasionally, occult GI bleeding may originate in the small bowel and an algorithm for investigation of anaemia is shown in Fig. 7.5.
Serology
Anti-endomysial antibodies (almost 100% sensitivity for coeliac disease, but may be false –ve in presence of a low IgA)—this can be confirmed using duodenal or jejunal biopsies, which would reveal partial villous atrophy. Now largely replaced by anti-tissue transglutaminase (see Endomysial & tissue transglutaminase antibodies, [link]).
Endoscopy
OGD and enteroscopy allow views of the proximal small intestine to obtain tissue and allow therapeutic possibilities. Wireless capsule endoscopy permits diagnosis from the whole small intestine, but does not allow therapeutic options.
Radiology
Barium follow-through involves ingestion of dilute barium with images taken every 10–30 min until barium reaches the caecum. Small bowel enema (enteroclysis) uses insertion of a nasoduodenal tube to infuse barium slowly, with this column followed continuously using fluoroscopy. Both studies define structural abnormalities. Small bowel enema allows more focused views of areas of interest, such as the terminal ileum (Fig. 7.2).
Nuclear medicine
Radiolabelled white cell scintigraphy for inflammation/infection
This uses 99m-technetium-hexamethylpropyleneamine oxide (99mTc-HMPAO) to show intensity and extent of inflammation or infection 1 & 3 h after injection of autologous, radiolabelled leucocytes, and is used in Crohn’s disease and ulcerative colitis to delineate disease extent (Fig. 7.3). False negative results occur, particularly with small bowel Crohn’s disease. There is a sensitivity of 96% and specificity of 97% for inflammatory bowel disease, and a sensitivity of 85–100% and specificity of 100% for detecting abscesses.
Radionuclide studies to detect Meckel’s diverticulum
Intravenous 99mTc pertechnate accumulates in gastric mucosa with a time course of 5–60 min. Uptake in ectopic mucosa (e.g. Meckel’s diverticulum) occurs simultaneously. Imaging at 5–10 min intervals up to 2 h after injection allows localization of the site of ectopic mucosa. False positives are caused by early gastric emptying and duplication cysts. Sensitivities vary from 90% in children to 60% in adults. (See Meckel’s scan: ectopic gastric mucosa localization, [link].)
Tests of small bowel absorption
Tests of carbohydrate malabsorption
D-xylose tolerance test
Xylose is absorbed from the proximal small bowel, and urinary excretion and blood levels reflect absorption. It is used mainly in paediatric practice and has a low sensitivity.
Tests of fat malabsorption
Patients with fat malabsorption secondary to small bowel diseases, such as coeliac disease or tropical sprue, may malabsorb between 10 and 20g/day of fat, while patients with pancreatic insufficiency may malabsorb 30–50g/24 h. A normal faecal fat excretion is less than 6g/day (17mmol/day).
3-day faecal fat
• Unpleasant test, fallen into disuse, but remains gold standard.
• Fat content measured in a 3-day faecal collection.
• Patient takes standard diet of 100g fat/day.
• Does not differentiate small bowel and pancreatic malabsorption.
Bile salt malabsorption
SeHCAT scan
• The labelled bile acid 75selenium homotaurocholate (SeHCAT) is administered orally. Retention is measured at 7 days by whole body counting.
• Retention >15% SeHCAT is normal (less indicates malabsorption).
• Useful second line investigation in patients with diarrhoea of unknown aetiology.
Tests for bacterial overgrowth
Deep duodenal/jejunal aspiration
• Samples may be collected through the biopsy channel at OGD.
• Scanty bacteria are present in normal upper small bowel.
• Numbers in excess of 106/mL of aspirated fluid are pathological.
• This technique may culture Giardia and Strongyloides spp.
Hydrogen breath tests
Rationale
In mammals, the only source of breath hydrogen is bacterial fermentation of carbohydrates. Hydrogen is absorbed from the intestinal lumen and expired during breathing. In bacterial overgrowth, hydrogen production can occur in the small intestine, as well as in the colon.
Method
• A mouthwash is given beforehand to reduce contamination by oral bacteria.
• Test dose of glucose (50g) and breath hydrogen measured.
• An early peak (e.g. 40 min) suggests bacterial overgrowth.
Limitations
• Sensitivity 60–90% with specificity of 80%.
• False negatives result from variations in microflora present in the small intestine or antibiotic administration within 3 weeks.
• False positives occur in patients with impaired glucose tolerance, those with rapid transit to the colon, and smokers.
• Patients should avoid eating pulses for 48 h prior to the test (normal digestion of pulses liberates excess hydrogen).
14C-glycocholic acid test
Rationale
• Bacteria act to deconjugate radiolabelled bile salts to produce radioactive glycine, which is metabolized in the liver to 14CO2.
• An early peak suggests bacterial overgrowth in the small intestine or rapid transit to the colon.
Limitations
• Difficult to distinguish between small bowel overgrowth and other causes of bile salt malabsorption, e.g. ileal dysfunction, unless faecal bile acid excretion is measured.
• Ileal dysfunction leads to a late peak in 14CO2 and high faecal bile acids, while bacterial overgrowth results in increased and early breath excretion of 14CO2 and low faecal bile acid excretion (<5%).
Tests of pancreatic exocrine function
Symptoms of pancreatic exocrine dysfunction include diarrhoea or steatorrhoea and weight loss. Investigations aim to determine the degree of pancreatic insufficiency; however, both biochemical and particularly radiological investigations are unreliable in mild disease. Fat malabsorption may occur in small bowel or pancreatic disease and diagnosis may prove difficult as a result (see Tests of small bowel absorption, [link]). A diagnostic algorithm for investigation of diarrhoea is shown in Fig. 7.4.
Faecal testing
Elastase
Elastase is a proteinase produced by pancreatic acinar cells and remains undegraded during gut transit. Immunoassay of faeces allows measurement of elastase in a random faecal sample. Levels of >200μg/g faeces are normal, 100–200 represents mild insufficiency and <100 is diagnostic of severe disease. Specificity is 93%, while sensitivity is 63, 100, and 100% for mild, moderate, and severe disease, respectively. False positives may occur with high volume watery stools. This test is not affected by pancreatic enzyme supplements.
Direct investigations
Secretin test
Direct intubation of the duodenum allows collection of pancreatic juice following intravenous injection of a hormonal secretogogue. Secretin injection allows measurement of volume and bicarbonate content, cholecystokinin (CCK) injection allows measurement of amylase, trypsin, and lipase. This test is highly sensitive and specific, even with mild pancreatic disease, but is not widely available.
Indirect investigations
Both tests are more sensitive and specific with more advanced dysfunction.
PABA test
A synthetic peptide (N-benzoyl-L-tyrosol p-aminobenzoic acid (PABA)) is given orally. In normal patients, pancreatic chymotrypsin hydrolyses this peptide to yield free PABA, which is absorbed, metabolized, and excreted in urine. In the presence of pancreatic insufficiency, free PABA levels are reduced, and thus absorption and excretion are lower. This results in lower urinary PABA and a lower serum concentration.
Pancreolauryl test
Fluorescein dilaurate (an ester) is taken orally with a set diet. In the presence of normal pancreatic function, arylesterases release fluorescein, which is absorbed, partially conjugated in liver, and excreted in urine. A 24 h urine collection for excreted levels shows close correlation with pancreatic exocrine function.
Testing for neuroendocrine tumours
Carcinoid and carcinoid syndrome
Urinary 5-hydroxyindole acetic acid (5HIAA)
• 24 h collection of urine for 5HIAA.
• High levels imply carcinoid syndrome.
• High specificity, but false positives result from serotonin-rich bananas, tomatoes, or drugs such as phenothiazines.
Further investigations
Abdominal CT scan with biopsy of liver metastases may confirm the diagnosis. The 1° tumour is identified in only 50–70%. Radiolabelled octreotide scintigraphy establishes tumour extent in difficult cases as most carcinoid tumours express somatostatin receptors.
.)Hormone-secreting pancreatic tumours
• Pancreatic islet-cell tumours that produce vasoactive peptide hormones.
• Measured using fasting gut hormone assays: insulin (paired with a serum glucose sample), glucagon, vasoactive intestinal peptide (VIP), pancreatic polypeptide (PP), gastrin, and somatostatin.
• Single tumours often secrete more than one type of hormone.
• Up to 50% of these slow-growing tumours are thought to be non-functional.
• Several types of tumour occur as part of the multiple endocrine neoplasia syndrome type 1 (MEN-1).
• Concurrent therapy with a proton pump inhibitor will falsely raise serum gastrin levels.
Gastrointestinal physiology
pH monitoring
Indications
• Assessment of gastro-oesophageal reflux disease (GORD).
• Atypical symptoms such as asthma or non-cardiac chest pain.
• Before consideration of anti-reflux surgery.
• Poorly controlled GORD to confirm diagnosis on or off treatment.
Investigation
An ambulatory 24 h test that places a pH electrode through the nose to sit 5cm above the lower oesophageal sphincter. This is connected to a portable microprocessor that records episodes where the pH dips below 4. The patient fills in a simultaneous event diary, to correlate symptoms and episodes of low pH. For most patients, H2 receptor antagonists and proton pump inhibitors are stopped 7 days beforehand. A few patients require testing on medication to establish treatment response.
Oesophageal manometry
Indications
• Diagnosis and assessment of motility disorders suggested by symptoms/OGD/barium swallow findings.
• Defining the precise location of the lower oesophageal sphincter prior to 24 h pH monitoring.
• Before consideration of anti-reflux surgery.
Investigation
A static test using a nasogastrically-placed multiple channel, water perfused catheter, which is gradually withdrawn during a series of wet and dry swallows. Pressure is measured through the length of the oesophagus, at the upper and lower oesophageal sphincter and the duration and frequency of contractions are recorded (see Table 7.3).
Table 7.3 Results
Non-specific motility disorder | Abnormal and incomplete peristalsis with normal body contractions |
Achalasia | Incomplete relaxation and high pressure of lower oesophageal sphincter with aperistalsis of the oesophageal body |
Nutcracker oesophagus | High amplitude and duration of contractions, normal peristalsis |
Oesophageal spasm | Disordered peristalsis with simultaneous prolonged contractions throughout |
Gastric emptying
Scintigraphy using the radioactive tracer 99mtechnetium displays gastric movements with a range of test meals (liquid to solid) to quantify gastric emptying and intestinal filling over time. This confirms dysmotility although in practice, barium and endoscopic studies provide enough information (see Gastric emptying studies, [link]).
Intestinal transit studies
Intestinal transit may be established using 50 radio-opaque plastic markers inside a pH-sensitive gel capsule, which is designed to release its contents in the terminal ileum. An abdominal radiograph at 100 h should show less than 20% of markers present in the colon. A rarely used alternative is radioactive indium-labelled polystyrene pellets with gamma camera recording of the pellet’s progress through the intestine. These investigations are useful to determine colonic transit in suspected slow transit constipation. Normal transit from mouth to anus is 1–3 days.
Anorectal manometry
A water-perfused catheter measures anorectal pressures to assess voluntary and involuntary sphincter squeeze pressures and reflex responses to balloon distension in the rectum. Readings allow assessment of rectal sensation, spinal reflexes, and internal and external sphincter integrity. These tests are useful for assessment of faecal soiling, incontinence and chronic constipation.
Sphincter of Oddi manometry
A water-perfused pressure catheter is used during ERCP to measure sphincter of Oddi pressures to formally diagnose SOD (a triad of abnormal liver function, biliary type abdominal pain and dilatation of the biliary tree in the absence of a physical cause such as gallstone disease). Diagnosis is confirmed by high resting pressure, retrograde peristalsis and a failure of contrast to drain from the biliary tree within 45 min. Although patients with SOD have an increased risk of pancreatitis after ERCP, biliary sphincterotomy may relieve symptoms of pain.
Non-invasive liver investigations
Basic liver function testing
These are basic serological screening tests that establish whether liver inflammation, infection, or obstruction is present.
Alanine transaminase
Alanine transaminase (ALT: cytosol enzyme specific to the liver) and aspartate transaminase (AST: mitochondrial enzyme also present in heart, muscle, kidney and brain)—both enzymes are present in hepatocytes and leak into blood with liver cell damage.
Alkaline phosphatase
Alkaline phosphatase (ALP: canalicular and sinusoidal membranes of liver but also bone, intestine, placenta)—specific isoenzymes for ALP are produced by different tissues but a simultaneously raised γ-glutamyl transpeptidase (γGT) and ALP implies a hepatic origin. Extra- and intrahepatic cholestasis may cause raised ALP, and result from benign or malignant disease with or without raised bilirubin. Highest levels result from 1° biliary cirrhosis and hepatic metastases.
γ-glutamyl transpeptidase
γGT (microsomal enzyme)—activity can be induced by drugs, such as phenytoin, rifampicin, and alcohol. Mild elevation of γGT is common with even a small alcohol intake and isolated elevation does not imply liver disease. It rises in parallel with ALP in cholestasis.
Albumin
A protein that is synthesized in the liver. Plasma concentration partially results from functional capacity within the liver. However, it has a serum half-life of 20 days and may be normal in early phases of acute liver disease. Hypoalbuminaemia may also arise from an increased volume of distribution (sepsis, overhydration, pregnancy); increased excretion or degradation (nephrotic syndrome, protein-losing enteropathy); haemorrhage; or catabolic states such as malignancy or burns.
Prothrombin time
Test of plasma clotting activity and reflects the activity of vitamin K-dependent clotting factors synthesized by the liver. Prothrombin time (PT) may be elevated in acute or chronic liver disease. In vitamin K deficiency with normal liver function, PT will return to normal within 18 h of administration of parenteral vitamin K.
Bilirubin
In liver disease, a raised bilirubin is usually associated with other liver function abnormalities. There are many causes of raised serum bilirubin. Bilirubin may be conjugated or unconjugated, although in practice, this conjugation state only differentiates congenital hyperbilirubinaemias. In Gilbert’s syndrome (the most common, benign cause of an isolated raised serum bilirubin) an elevated unconjugated bilirubin, which rises during fasting and mild illness diagnoses the condition.
Specific biochemical tests
These are summarized in Table 7.4, with serological tests, diagnosis, and definitive investigations required to confirm the diagnosis. The best investigations for an individual patient are established from history, examination, and basic biochemical parameters.
Table 7.4 Specific biochemical tests
Test | Condition | Findings | More specific tests |
|---|---|---|---|
Serum ferritin Serum iron Transferrin saturation | Haemochromatosis | Serum iron >30μmol/L Serum ferritin >500μg/L Transferrin sat >60% | HFE gene testing (83–90% patients have Cys 282 Tyr mutation; 25% have His 63 Asp; 187G in complete linkage disequilibrium with Cys 282 Tyr). Liver biopsy—with dry weight of iron |
Urinary copper excretion Serum copper Caeruloplasmin | Wilson’s disease | Serum copper and caeruloplasmin levels are usually reduced, but can be normal α1-antitrypsin | Liver biopsy—with dry weight of copper |
α1-antitrypsin | α1-antitrypsin def. | Levels of <10% of normal in homozygotes and 60% in heterozygotes | Liver biopsy and lung function testing for emphysema |
AMA | Primary biliary cirrhosis | Antimitochondrial antibodies present in titres >1/160 specific M2 antibody (possible non-specific ↑ ANA/SMA) ↑ serum IgM and ALP | Liver biopsy |
ANA/SMA | Type I autoimmune hepatitis | ↑ ANA ± SMA ↑ total IgG | Liver biopsy |
Anti-LKM1 or anti-liver cytosol anti-bodies | Type II autoimmune hepatitis | ↑ Antibodies titres ↑ Total IgG | Liver biopsy |
Fasting cholesterol and glucose, glycosylated haemoglobin | Non-alcoholic fatty liver disease/non-alcoholic Steatohepatitis | Impaired glucose tolerance | Liver biopsy |
Specific virological tests
Hepatitis A
• Acute infection: —positive IgM antibodies to hepatitis A (HAV).
• Chronic infection: does not occur.
• Markers of clearing virus: positive IgG antibodies to HAV and anti-HAV IgM.
Hepatitis B
Acute infection with subsequent clearing of virus
• HBsAg appears in blood from 6–12 weeks after infection then disappears.
• HBeAg appears early then declines rapidly.
• Anti-HBs appears late and indicates immunity.
• Anti-HBc is the first antibody to appear and IgM anti-HBc may persist for many months as the only marker of ongoing viral replication when HBsAg has disappeared and anti-HBs is not yet detectable.
• Anti-HBe appears after anti-HBc and indicates decreased infectivity.
Acute infection leading to chronic hepatitis B
• HBsAg persists and indicates chronic carrier state.
• HBeAg persists, correlating with increased severity and infectivity.
• Anti-HBe indicates seroconversion (if this occurs) with disappearance of HBeAg and a rise in ALT.
• HBV DNA suggests continued viral replication.
Hepatitis C
• Acute infection: hepatitis C HCV RNA is positive 1–2 weeks after infection with HCV antibodies developing after ~12 weeks.
• Chronic infection: more than 50% patients with persistent HCV RNA, which can be measured as viral load.
• Hepatitis C has 6 genotypes that determine response to treatment.
Investigation of liver disease
Fig. 7.7 shows an algorithm for investigation of liver disease. This differentiates obstructive from parenchymal liver disease to suggest further investigation and treatment.
Liver biopsy
• Obtains tissue for diagnosis of diffuse or localized parenchymal disease.
• Severity of histological liver dysfunction cannot be predicted from basic LFTs.
• Consent should be obtained based on risks.
• Transjugular liver biopsy overcomes many contraindications.
Indications
• Unexplained persistently abnormal LFTs.
• Staging of disease in hepatitis B or C infection, and prior to considering antiviral treatment.
• Acute hepatitis of unknown aetiology.
• Cirrhosis of unknown aetiology.
• Alcohol-related liver disease.
• 1° biliary cirrhosis/chronic active hepatitis.
• Targeted liver biopsy of lesions (not if resection/transplant is a possibility).
• Pyrexia of unknown origin.
• Haemochromatosis/Wilson’s disease.
• Storage diseases.
• Post-liver transplant to rule out acute or chronic rejection.
Methods for obtaining tissue: (risks and benefits)
Percutaneous with or without ultrasound viewing (Table 7.5)
• Standard method for obtaining tissue.
• Ultrasonography of liver and biliary tree pre-procedure to identify anatomical variations increasing risk and to rule out obstruction.
• Most complications <2 h, but can occur up to 24 h.
• No evidence that direct ultrasound-guided biopsy is safer and ultrasound should be used only if a targeted biopsy is required.
Contraindications
• An uncooperative or confused patient.
• PT prolonged by >3 s, platelets <80 × 109/L or bleeding diathesis.
• Ascites.
• Hydatid cysts (risks of anaphylaxis and abdominal seeding).
• Extrahepatic cholestasis.
• Higher risk of bleeding if amyloidosis present.
Minor complications
Shoulder tip pain, minor intra-abdominal bleeding, or mild abdominal pain (up to 30%)—usually settles with analgesia.
Major complications
• Perforation (0.01–0.001%: pneumothorax, gallbladder puncture, kidney, colon).
• Intra-abdominal haemorrhage; haemobilia (0.05%: a triad of biliary colic, jaundice and melaena within 3 days of liver biopsy).
• Mortality varies between 0.001–0.0001% and results from intraperitoneal haemorrhage or biliary peritonitis.
• Risk of tumour seeding if a malignant lesion is biopsied: if curative resection/transplantation is planned, needle biopsy should be avoided.
Transjugular
• Specialist technique carried out using fluoroscopic guidance.
• Catheter passes from the right internal jugular vein, through the right atrium and inferior vena cava, and into the hepatic veins.
• Patient holds his/her breath while the biopsy needle is advanced through the catheter then rapidly pushed forward by 1–2cm into the liver to obtain a small core of liver parenchyma.
• Safe technique with few complications (1.3–2% morbidity and 0.5% mortality) usually performed in higher risk patients.
• Complications range from neck haematoma, puncture of intrathoracic arteries, transient Horner’s syndrome, cardiac arrhythmias, infection, and perforation of the liver capsule.
• Test of choice in patients excluded from percutaneous biopsy by coagulopathy, bleeding diathesis, ascites, portal hypertension, and amyloidosis.
• Transjugular cannulation allows measurement of portal venous pressures.
Laparoscopic
• Allows sampling of the liver when an operation is planned.
• Allows targeted biopsies, as well as parenchymal biopsies.
• Bleeding is directly controlled and perforation is avoided.
• Risks of surgery and anaesthesia should be considered.
Table 7.5 Percutaneous liver biopsy—practical procedure
Procedure | Should be carried out by an experienced doctor using aseptic precautions |
Check | Clotting, FBC, and take G&S within 24 h before procedure (cancel if platelets <80 × 109/L or PT prolonged >3 s) |
Patient | Lies flat on his/her back |
Liver margins | Delineated using percussion or ultrasound |
1% lidocaine | 5mL injected at the point of maximal dullness down to the liver capsule through intercostal space in expiration |
Menghini or Trucut needle | Used to obtain sample with patient’s breath held in expiration (up to 2 passes may be used). Menghini needles use suction, have a lower rate of complications and allow more rapid biopsy, but have a lower yield for tissue than Trucut (a cutting needle) |
Sample | Placed into 10% formalin (or into a dry pot to estimate dry weight of iron or copper or for culture) |
Patient | Nurse in supine position or right lateral for >6 h with regular BP and pulse measurements (every 15 min for 2 h, every 30 min for the next 2 h then hourly) with urgent medical review if any sign of deterioration |
If stable | At 6 h, the patient can be discharged home as long as s/he can return to hospital within 30 min and have a responsible adult with him/her overnight |
Investigations of ascitic fluid
Investigation requires diagnostic aspiration
• 10mL is sent for cell count, Gram stain, Ziehl–Neelsen (ZN) stain culture (add 10mL to a pair of blood culture bottles to increase diagnostic yield).
• 10mL is sent for cytology.
• 10mL for biochemical investigation of protein, glucose, lactate dehydrogenase (LDH), triglycerides (if chylous ascites is suspected), and amylase if pancreatic ascites is suspected.
Results
Cell count
• Polymorphonuclear leucocytes (neutrophils) >250cells/mm3 suggest underlying spontaneous bacterial peritonitis (or 2° infection).
• Total leucocytes of >500cells/mm3 imply bacterial peritonitis (SBP) if a specific neutrophil count is not available.
• Lymphocyte count >500cells/mm3 implies tuberculous peritonitis (with raised protein, positive ZN stain/TB culture and low glucose).
Gram stain and culture
• Gram staining for early identification of bacteria and bacterial culture allows targeting of antimicrobial therapy.
Protein
• Using ascitic fluid protein levels to aid diagnosis is best achieved using the serum ascites albumin gradient (SAAG) by subtracting ascites albumin concentration from serum albumin concentration. Levels ≥11g/L suggest cardiac failure, cirrhosis, and nephrotic syndrome, while levels <11g/L suggest malignancy, tuberculosis or pancreatitis as causes.
• Risk of spontaneous bacterial peritonitis is greatest if ascitic protein <10g/L.