A pain in the gut: a look at the diagnosis of gastrointestinal disease
A pain in the gut: a look at the diagnosis of gastrointestinal disease
Accurate diagnosis of GI disease is fundamental for appropriate patient management. Focusing on four common diseases, Carolyne Horner describes how a selection of commercial kits may supplement diagnostic methods and support diagnosis.
In simple terms, the gastrointestinal (GI) tract is a flexible tube with an entrance at one end (mouth), a sphincter-controlled exit (anus) at the other, with a series of organs (pharynx, oesophagus, stomach, small intestine and large intestine) in between. Add to that the closely regulated function of the pancreas, gall bladder and liver, the enteric nervous system, not to mention the 100 trillion microorganisms that form the teeming intestinal microbiota,1?and the GI tract emerges as a complex, interacting system associated with a correspondingly complex range of disorders and diseases.
?Tummy troubles
Diseases of the GI tract are diverse, ranging from acute foodborne infection, chronic inflammatory bowel disease (IBD), to life-threatening colorectal cancer (Fig 1). Gastrointestinal disease may be mild and transitory causing a minor inconvenience, or may be severe and affect the quality of life of the patient on a daily basis, or may even require life-changing surgery, such as removal of a section of colon and the need for a stoma bag.
???????????While diverse in nature, common symptoms are non-specific and overlap between different diseases (Table 1). Patients with ‘Red Flag’ symptoms, such as rectal bleeding, unintentional weight loss and iron-deficiency anaemia, are those that require referral to secondary care for investigations for IBD and colorectal cancer.2
???????????Gastrointestinal disease may be divided into communicable diseases, those with an infectious aetiology, and non-communicable diseases, which may be further categorised as functional or structural diseases.3?Functional GI diseases, a complex group compromising >30 chronic conditions,4?are those in which the GI tract is not functioning correctly but looks ‘normal’ on internal inspection (Fig 2a). Examples include infant colic, irritable bowel syndrome (IBS) and dyspepsia, but could also encompass stress, lactose intolerance and the effect of certain medications.3?Structural GI diseases, on the other hand, are those in which the intestine is not functioning properly and is showing abnormal features (Fig 2b). Examples include diverticular disease, polyps, colorectal cancer, IBD and haemorrhoids.3
Getting to the bottom of gastrointestinal disease
Given the range and complexity of gastrointestinal disease, an accurate diagnosis is fundamental for appropriate disease management; however, other benefits include:
Options available to guide a differential diagnosis for the patient presenting to primary care with unresolving GI symptoms due to gastroenteritis, IBS or IBD, and colorectal cancer, will be discussed in more detail.
Communicable gastrointestinal disease
Infectious gastrointestinal diseases are associated with various causative agents, including viruses, bacteria and parasites.5?Gastroenteritis, a common example of infectious GI disease, typically presents as acute diarrhoea and/or vomiting accompanied by non-inflammatory infection of the upper bowel or inflammatory infection of the colon.6?In most cases, the infection is short-lived and self-limiting; however, immunocompromised patients, including those at the extremes of age, are at risk of persistent infection.
???????????Gastroenteritis is an important healthcare burden in terms of morbidity and mortality, public health, economic and social costs. Globally, diarrhoeal diseases are ranked the fifth leading cause of disability-adjusted life-years (DALYS).7?In the UK, it is estimated that there are 17 million cases of GI infection every year.8?By way of an indication of economic and social costs, the Food Standards Agency estimated that in a single year (2018) foodborne disease (comprising 13 pathogens) cost UK society approximately ￡9.1 billion, a much higher estimate than previously reported (￡1.5 billion).9?Of the total cost to society, ￡7.1 billion was calculated to represent the human cost of pain, grief and suffering.5
Conventional versus contemporary diagnosis
Owing to the diversity of agents causing gastroenteritis, the importance of a thorough clinical history (eg recent travel, contact with animals, hospital admission) cannot be underestimated. Guided by this information and the patient setting (community or hospital), diagnostic algorithms are used to identify the most likely infectious agent in a judicious manner.10
???????????When required, centralised laboratory microbiological investigation of a faecal sample, using microscopy and culture, remains the basis for diagnosis of gastroenteritis. Microscopy is commonly used for detection of faecal parasites, such as?Cryptosporidium?and?Giardia.10?Detection and identification of parasitic ova and cysts by microscopy, however, is a labour-intensive, highly skilled technique with low sensitivity,10?particularly as the majority of the samples tested will be negative for faecal parasites. Selective culture largely remains the routine method of diagnosis of bacterial GI pathogens. Bacterial culture is slow and requires specialist culture media and particular growth requirements to screen out pathogenic bacteria from normal intestinal flora.10
???????????Molecular detection methods offer advantages over the aforementioned phenotypic methods in terms of speed and sensitivity, and multiplex polymerase chain reaction (PCR) methods are used routinely for diagnosis of viral gastroenteritis. The development of syndromic testing platforms, those in which a single test can simultaneously target a broad range of pathogens (bacteria plus viral plus parasite targets) causing overlapping signs and symptoms, are driving change in the way that GI pathogens are detected. Unlike conventional multiplex PCR methods, syndromic testing, such as BioFire FilmArray from bioMérieux, or modular panel options, such as EntericBio from Serosep, offers rapid detection of a range of GI pathogens direct from a faecal sample. Molecular syndromic testing is not without its disadvantages,11?however, and is unlikely to be a solution for all laboratories.
???????????Commercial kits that detect specific faecal antigens are a non-molecular alternative with improved sensitivity compared with conventional phenotypic methods. Kits from manufacturers such as TECHLAB are available for rapid detection of faecal antigens specific for agents of gastroenteritis including faecal parasites, and other common causes of foodborne illness, such as?Campylobacter. An enzyme immunoassay (EIA) format is available for high-throughput sample processing, usually providing results in under two hours. Alternatively, individual immunochromatographic lateral-flow assays can detect the presence of specific faecal antigens within 10 minutes, and individual tests based on membrane EIA technology can provide superior results in <30 minutes. Detection of faecal antigen may supplement existing diagnostic algorithms, decrease turnaround times and improve laboratory workflow.
Intestinal inflammation
With similar abbreviations, similar symptoms and a similar relapsing and remitting course, IBS and IBD are two very different clinical conditions that are difficult to differentiate by clinical symptoms alone. Correct diagnosis is paramount, however, for appropriate patient management.
???????????Irritable bowel syndrome, a non-inflammatory condition, is characterised by abdominal pain associated with defaecation, and a change in stool frequency and/or form for six months or more.11. Owing to the lack of specific biomarkers indicative of the disease, diagnosis of IBS is based on clinical history and symptoms.11?Commonly a diagnosis by exclusion, use of diagnostic algorithms are encouraged to support judicious use of investigations.12,13?Management of IBS focuses on patient education, lifestyle and dietary changes, and antispasmodic drugs (Table 2).2
???????????Inflammatory bowel disease, on the other hand, is a disease of chronic inflammation. Largely encompassing two diseases: Crohn’s disease, potentially affecting the whole of the GI tract, and ulcerative colitis, which is limited to the colon and rectum, symptoms of IBD include abdominal pain, recurring bloody diarrhoea and unexplained weight loss.14?Owing to mucosal damage following chronic inflammation, patients with IBD are at risk of other diseases, particularly colorectal cancer.15?The aim of IBD management is to heal inflammation during periods of active disease and maintain remission.16?Drugs used to manage IBD are different to those used to manage IBS, and, in some cases, surgery may be required (Table 2).16
Faecal leucocyte markers
Faecal leucocyte markers are molecules released from neutrophils during intestinal inflammation; the presence of these markers in a faecal sample enables differentiation between IBS and IBD.17?Two examples are calprotectin, a calcium-binding protein,18?and lactoferrin, an iron-binding protein.19?Faecal leucocyte markers are more specific for intestinal inflammation than C-reactive protein (CRP); however, these markers may also be raised in association with other causes of intestinal inflammation, such as infective colitis (due to?Campylobacter, amoebiasis,?Clostridioides difficile), diverticulitis, certain medications, and colorectal cancer.
Rapid diagnostic solutions
While centralised laboratory detection and quantification of faecal leucocyte markers by enzyme-linked immunosorbent assay (ELISA) is the gold standard, rapid detection of these markers during patient consultation has the following benefits:
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As faecal leucocyte marker levels correlate with IBD activity,18–20?they can be used to discriminate between active disease and remission without the need for invasive investigations, which are not without patient risk or complications.21?Currently, there is no agreed cut-off value to distinguish between active disease and remission;22?however, the suggested range for endoscopically active IBD is 50–280 μg/g.17
???????????Analyser-based options, such as QuantumBlue by Buhlmann and CalFast from Eurospital,22?are available for quantitative detection of calprotectin, while individual immunochromatographic lateral- flow tests, such as Lactoferrin EZ VUE (TECHLAB) and a dual calprotectin and lactoferrin lateral-flow test provide results direct from a faecal sample within 10 minutes.
Is it cancer?
Colorectal cancer is difficult to differentiate from other GI tract diseases, such as diverticulitis, IBS, IBD, haemorrhoids and anal cancer, by clinical symptoms alone. Colorectal cancer is the fourth most common GI cancer in the UK, with almost 43,000 new cases diagnosed per year.23?Most colorectal cancers develop from polyps, growths on the inner mucosa of the large intestine that protrude into the bowel (Fig 2b). Most polyps are benign but those of the adenomatous type are associated with malignancy.24?Physical examination of the abdomen, digital rectal examination, full blood count and liver function tests are used to aid diagnosis. Colonoscopy is the gold standard method of diagnosis for colorectal cancer, which enables biopsy of lesions for histological investigation.25
???????????In the UK, 54% of colorectal cancer cases are preventable and most patients diagnosed early have a good prognosis; 53% of patients diagnosed with colorectal cancer survived for ≥10 years.23?To this end, a national bowel cancer screening programme was introduced in England in 2006. Every two years individuals aged 50–74 years and registered with a GP, are sent a kit to collect a faecal sample at home and return by post to the laboratory. Following the introduction of this screening programme, bowel cancer mortality has decreased by 15%.26
Faecal immunochemical tests
Detection of faecal occult blood by faecal immunochemical testing (FIT) is the preferred method for colorectal cancer screening, replacing guaiac faecal occult blood tests (gFOBT). Faecal immunochemical tests use antibodies specific for the globin moiety of human faecal haemoglobin (f-Hb). They offer sampling advantages over gFOBTs, have a lower detection of f-Hb (0.02 mg Hb/g compared with 0.6 mg Hb/g faeces gFOBT) and a higher sensitivity of detection for colorectal cancer.27
???????????In addition to population screening of largely asymptomatic individuals, FIT is also recommended by the National Institute for Health and Care Excellence (NICE) for use in primary care for symptomatic patients at low risk of colorectal cancer (ie those without rectal bleeding) if they “are aged 50 or over with unexplained abdominal pain or weight loss; are aged under 60 with changes in their bowel habit or with iron-deficiency anaemia; or are aged 60 and over and have anaemia even in the absence of iron deficiency”.25?In this population of symptomatic patients at low risk, based on testing a single faecal sample and a cut-off value of 10 μg Hb/g faeces, high-throughput laboratory assay with OC-Sensor (Mast Group) had a sensitivity of 92.1% (95% confidence interval [CI] 86.9–95.3%), and HM-JACKarc (Alpha Laboratories) had a sensitivity of 100% (95% CI 71.5–100%) for detection of colorectal cancer.28
Decentralised FIT
The faecal immunochemical test from Aidian QuikReadgo offers a decentralised rapid diagnostic solution for detection of faecal occult blood. The analyser-based test provides individual results in less than three minutes, enabling immediate clinical decision-making for referral or other intervention. Results may be provided qualitatively (a positive result indicated by f-Hb >15 μg/g of faeces) or quantitively measuring f-Hb between 10 μg/g to 200 μg/g faeces. Once added to the sampling buffer, the analyte remains stable, allowing a patient to take a sample at home and return for it testing within five days.29
Future opportunities for diagnosis
Given the immensely complex and interacting nature of the GI tract, there are many avenues of innovation still to be explored that may lead to advancement of diagnostics for gastrointestinal disease. Three exciting possibilities are listed below:
All's well that ends well
Accurate diagnosis of GI disease is crucial for timely, appropriate patient management. Likewise, there is an urgent need to streamline clinical pathways and use resources judiciously in order to maintain the necessary level of services in an already stretched healthcare system. Careful evaluation and application of commercial kits may supplement existing diagnostic algorithms and support rapid diagnosis, providing options for triage of patients with gastrointestinal disease in primary care
Article is from Pathology in Practice which you can see here
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References
https://www.pathologyinpractice.com/story/37817/a-pain-in-the-gut-a-look-at-the-diagnosis-of-gastrointestinal-disease
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