The Inflammatory Bowel Diseases Health And Social Care Essay
Inflammation is the local physiological response to injury from endogeneous and exogeneous factors and is not, in itself a disease, but is a manifestation of disease . Inflammation may have beneficial or harmful effects. A controlled inflammatory response is beneficial; but detrimental if deregulated [12, 13]. Inflammation aims at restoring impaired homeostasis. Each of the specific organs in the gastrointestinal tract (GIT) can be susceptible to inflammation. Inflammation of the GIT remains a serious concern in clinical setting .
1.2 Types of GI inflammation
Inflammation can occur in any part of the GIT. GI inflammation can be sub-divided as glossitis, oesophagitis, gastritis, ileitis, colitis, gastroenteritis, ulcerative colitis & Crohn’s colitis, appendicitis, pancreatitis, amongst others and is characterised by a plethora of signs and symptoms.
1.2.1 Inflammatory Bowel Diseases (IBD)
Crohn's disease (CD) and Ulcerative Colitis (UC) are idiopathic, chronic, relapsing and immunologically mediated inflammatory conditions . UC and CD have multiple similarities, including gastrointestinal inflammation and unknown aetiology . Environmental factors such as smoke exposure, diet, oral contraceptives, NSAIDs, microbial influences, immunologic deregulation and genetic factors influence IBD [16, 17].
22.214.171.124 Crohn’s Disease (CD)
Crohn's disease is a chronic granulomatous inflammation of the GIT and has relapsing nature [16, 18]. CD inflammation is triggered by Th1 cells whereby IL-12 is increased in the mucosa, leading to increased Th1 response and increased IFN-γ, which up-regulates macrophages leading of a cycle of uncontrolled inflammation . CD can occur anywhere along the GIT from the oropharynx to the perianal area. However, 3 mostly involved sites include: ileum alone, colon alone, or combined small and large intestine involvement [16, 19].
126.96.36.199 Ulcerative colitis (UC)
The pathogenesis of UC is still poorly understood . In UC, the inflammatory response and morphologic changes remain confined to the colon and rectum [16, 19]. Inflammation is limited primarily to the mucosa by polymorphonuclear leukocytes and mononuclear cells and histological findings are crypt abscesses, distortion of mucosal glands, and goblet cell depletion . The immune response is represented principally by secretion of IL-5 and IL-13 . Increased expression of IL-5 and the Th2 contribution may be helping the antibody response, because in UC, there is an increase in IgG plasma cells presumably mediated by T cells .
Gastritis is the inflammation of the gastric mucosa and includes acute and chronic forms of inflammation . Gastritis can be classified as acute, chronic, atrophic, lymphocytic and granulomatous gastritis . Causes are infection with Helicobacter pylori, an autoimmune (Type A Gastritis) and chemical gastritis resulting from ingestion of NSAIDs or a reflux of the duodenal contents into the stomach .
Pancreatitis is the inflammation of the pancreas and causes include gallstones, alcoholism, genetic causes, ischemia, autoimmune or idiopathic . Substance P, the proinflammatory neuropeptide and neurokinin-1 receptor are associated in development of local and systemic inflammation in acute pancreatitis. Inflammation is initiated by activation of intracellular proteolytic enzyme zymogens in the acinar cell. When protective mechanisms of the body are overcome, tissue injury causes leakage of chymotrypsin and elastase enzymes into pancreatic tissue and activated proteases and lipase break down cell and tissue membranes; leading to oedema, haemorrhage and necrosis. Inflammatory mediators are also released, finally resulting in chronic pancreatitis [24, 25].
Acute appendicitis is characterised by development of inflammation at a local level, followed by a more generalized inflammatory response. Inflammatory markers like white blood cell count and C-reactive protein are poorly reliable to confirm presence of acute appendicitis, due to their low specificity . The cause of acute appendicitis is unknown but is probably multifactorial; though luminal obstruction, dietary and familial factors have all been suggested .
1.3 Signs and symptoms of GI inflammation
Table 1.1: Signs and symptoms of GI inflammation
Type of GI inflammation
The clinical symptoms can vary significantly depending on the disease location. The symptoms range from abdominal pain and diarrhoea, rectal bleeding, fever and weight loss. Other symptoms include bloody stools, strictures, and fistula to skin or adjacent organs. Oesophageal involvement and gastroduodenal involvement are rare [16, 19].
Consistent features of UC are presence of blood and mucus mixed with stool, accompanied by lower abdominal cramping which is most intense during passage of bowel movements .
Abdominal pain is the cardinal symptom .
Abdominal pain is the primary complaint of patients with acute appendicitis .
Clinical signs and symptoms such as pain, nausea, vomiting, flatulence, abdominal discomfort, red blood in stool, black stools, blood in vomit and fatigue are noted [22, 28]. However, gastritis can also be asymptomatic .
Acute gastroenteritis is characterised by diarrhoea, which may be accompanied by nausea, vomiting, fever, and abdominal pain .
1.4 Biomarkers for GI inflammation and respective laboratory test
GI inflammation can be detected by invasive or non-invasive methods. Invasive techniques include endoscopy and colonoscopy while non-invasive methods include the use of serological and faecal biomarkers, whose levels are modified in inflammation. Faecal biomarkers such as calprotectin, lactoferrin, lysosyme, polymorphonuclear elastase, myeloperoxidase, eosinophil Protein X or leukocytes are used as biomarkers of gastrointestinal inflammation. C-Reactive Protein and Erythrocyte Sedimentation Rate (ESR) are other diagnostic markers of inflammation; however, they are not specific for GI inflammation [30, 31, 32]. To detect GI inflammation, faecal biomarkers are preferred mainly because faecal biomarker testing measures proteins originating in the intestinal mucosa, meaning that they should reflect purely gastrointestinal inflammation. The main advantage of faecal biomarkers is this specificity for the bowel. In addition, analysing stool sample is less invasive than colonoscopy, and elimination of the need for colonoscopy is crucial, especially with paediatric patients .
Calprotectin is a calcium binding-neutrophil derived protein which can be measured in the faeces after mucosal damage due to inflammation, which causes influx of neutrophils into the gut lumen. Calprotectin is primarily a non-specific marker of inflammation in the gastrointestinal tract [8, 9, 10]. Calprotectin is not actively secreted from neutrophils; instead, it is released following cell death or cell disruption. Once released, calprotectin induces apoptosis in other cells, and as a result of which, calprotectin level from apoptotic neutrophils increases during cell activation and turnover under inflammatory conditions. As the calprotectin sits in the intestine, it is absorbed by faecal material passing through and this accounts for the existence of calprotectin in stool without being attached to the neutrophil . Plasma calprotectin increases 5-40 fold in infectious and inﬂammatory conditions. Faecal calprotectin is a useful non-invasive marker and amount of calprotectin in faeces is proportional to neutrophil migration to the gastrointestinal mucosa [35, 36]. There is a strong correlation between calprotectin level and mucosal inflammation . Faecal calprotectin is stable against degradation for up to 1 week at room temperature and no changes have been found by storing faeces at -200C [36, 10]. A four‐day faecal excretion of 111Indium‐labelled granulocytes is the ‘gold standard’ for assessing intestinal inflammation. However, this test is costly to perform, exposes the patient to radiation and incurs problems of complete faecal collection over a four‐day period. A strong positive correlation between faecal calprotectin and faecal excretion of 111Indium‐labelled neutrophils has been shown; supporting the hypothesis that faecal calprotectin reflects the migration of neutrophils through inflamed gastrointestinal mucosa [37, 38]. A cut-off value of 50 μg/g is considered to be useful for all age groups over 4 years old . In children of 4-12 years, calprotectin levels range from 25-35 mg/kg while in kids of 1-4 years, calprotectin cut-off value is within 53-119 mg/kg .
Table 1.2: Advantages and limitations of calprotectin as a marker of GI inflammation
Advantage of calprotectin
It is a non-invasive marker and is particularly useful in paediatric cases .
It is stable for upto 1 week at room temperature .
Calprotectin is a sensitive, stable marker that is unaffected by medication, dietary supplements, or enzymatic degradation . Calprotectin is resistant to colonic bacterial degradation.
Calprotectin can be conveniently assessed in small quantity of stool sample .
Limitation of calprotectin
Since levels of faecal calprotectin increase in any condition that causes neutrophil migration to the gut, including neoplasm and infections, the sensitivity of faecal calprotectin is not as high as desired. Thus, whether inflammatory or neoplastic, the cause of elevated calprotectin must be ascertained by endoscopy or radiography [38, 39].
In addition, it is a non-specific marker and thus cannot predict in which part of the GI tract is the inflammation .
Furthermore, any bleeding in the body over 100 ml, including menstrual bleedings, might increase faecal calprotectin levels .
Increased faecal calprotectin levels have been reported after the use of NSAIDs as well as with increasing age .
Lactoferrin is an iron binding glycoprotein of the transferrin family. Lactoferrin is a prominent component of secondary granules of neutrophils and can reflect the activity of polymorphonuclear neutrophils. It is a specific and sensitive indicator in the evaluation of intestinal inflammation [41, 42]. Neutrophils are nonspecific inflammatory cells, which are recruited to any site of inflammation. During intestinal inflammation polymorphonuclear neutrophils infiltrate the mucosa, resulting in an increase of lactoferrin's concentration in faeces, and its presence is proportional to neutrophil translocation to the GIT. Since calprotectin and lactoferrin constitute a high proportion of the cytosolic proteins of neutrophils, these proteins appear in stools, and are very stable in this environment. Thus, measurement of these biomarkers provides a reliable criterion for the degree of inflammation in the bowel [33, 43].
Table 1.3: Advantages and limitations of lactoferrin as a marker of GI inflammation
Advantage of lactoferrin
Lactoferrin has excellent stability in faeces at room temperature for 4 days [43, 39].
Elevated faecal lactoferrin is a sensitive and specific marker of intestinal inflammation in patients with chronic intestinal disease [41, 44].
Faecal lactoferrin assessment is a measure of mucosal inflammatory activity that may be detected at a level insufficient to cause an increase in ESR and CRP .
Limitation and disadvantage of lactoferrin
The main disadvantage of faecal lactoferrin is that, as it occurs with calprotectin, it can increase after the use of NSAIDs, probably due to the associated induced enteropathy. Therefore, stopping NSAID treatment should be recommended before taking faecal samples for lactoferrin determination .
Furthermore, after a stool sample has been stored for more than 48 hours at room temperature, the faecal concentrations of lactoferrin are approximately 90% of their original levels .
Microscopic examination of a stained faecal smear has been used as a diagnostic tool for detection of intestinal inflammation . Faecal leukocyte testing detects large bowel inflammation or disruption, conditions that allow leukocytes into stool. Faecal leukocytes result from a breach of the colonic mucosa. Stool from patients with acute intestinal inflammation with ulcerated, or disrupted mucosal epithelium allows neutrophils into the colonic lumen, resulting in faecal leukocytes. Faecal leukocyte testing is thus used to evaluate large bowel mucosa inflammation and disruption . The main disadvantage is that the procedure requires fresh stool (tested within 1 hour of collection, or refrigerated for up to 4 hours), which is difficult to achieve in practice .
1.4.4 C Reactive Protein (CRP)
CRP is produced mainly in hepatocytes in response to acute phase stimuli like inflammation and its production is stimulated by IL-6, IL-1β and TNF-α, originating from the inflamed tissues. CRP is normally present in trace levels in serum but increases rapidly and dramatically in response to a variety of infectious or inﬂammatory conditions Genetic variation, age and sex affect the CRP levels. CRP concentration may increase rapidly up to 1000-fold in inflammation [47, 48].
Table 1.4: Advantages and limitations of CRP as a marker of GI inflammation
Advantage of CRP
No anti-inflammatory or immunosuppressive drug has proven to affect CRP production. Therefore, modifications of CRP response during treatment occur only as a result of the effect of the drug on the underlying inflammation or disorder .
The short half-life of CRP ensures that the concentrations quickly decrease once the acute-phase stimulus disappears. This makes CRP a very valuable marker to detect and follow-up inflammation .
Disadvantage of CRP
It is a nonspecific marker of inflammation 
1.4.5 Erythrocyte Sedimentation Rate (ESR)
ESR can be used to identify low-grade inflammation . The test measures the distance erythrocytes fall after an hour in a vertical column of anticoagulated blood under the influence of gravity . Women and elderly people tend to have higher ESR levels .
Table 1.5: Advantages and limitations of ESR as a marker of GI inflammation
Advantage of ESR
Inexpensive, quick and easy to perform 
Disadvantage of ESR
Affected by a variety of factors including anaemia and red cell size .
Not sensitive enough for screening .
ESR is non-specific and its increase does not indicate the exact location of inflammation and also, it can be affected by other conditions besides inflammation. Thus, ESR must be used in conjunction with other tests .
The test is best carried out within two hours of blood collection although a delay of up to 6 hours is permissible provided that the blood is kept at 4oC 
1.5 Drug use and GI inflammation
It is a well-known fact that side effect and/ or adverse effect of drug therapy could be its effect on the GIT. Several drugs can exacerbate and accentuate gastrointestinal inflammation. Drugs are more likely to mediate inflammation especially when taken on long term basis. In cases where risk factors for inflammation are already present, drugs can act as a propellant for gastrointestinal inflammation.
Though anti-inflammatory, NSAIDs can mediate GI inflammation. Non-selective NSAIDs inhibit both cyclooxygenase-1 & 2 and ultimately inhibiting prostaglandin biosynthesis. However, prostaglandins protect the gastric mucosa and since prostaglandin is not formed, protection to gastric mucosa is no longer conferred. As a result, the stomach undergoes auto-digestion by gastric acid and this mediates inflammation [54, 55].
Chronic NSAID use may be associated, although rarely, with oesophagitis, ulceration, or stricture formation. In the large bowel, NSAID use may lead to development of non-specific colitis. NSAIDs may also cause exacerbation of UC or CD, if the associated arthropathy in IBD is treated with NSAIDs . Local and/or systemic effects of NSAIDs on mucosal cells might lead to increased intestinal permeability, which is a prerequisite for colitis . Prolonged NSAID ingestion is associated with type C gastritis . Conventional acidic NSAIDs frequently cause small bowel inflammation and after treatment with NSAIDs, increased level of faecal calprotectin level above the upper limit is observed .
Angiotensin-converting enzyme (ACE) inhibitors and diuretics are associated with acute pancreatitis and the risk increases with higher daily doses and was highest in first 6 months of therapy. Calcium channel blockers and potassium sparing diuretics increase risk of acute pancreatitis while loop and thiazide diuretic do not . ACE inhibitors and Calcium channel antagonists can induce ischemic colitis . Lisinopril is associated with intermediate likelihood of inducing microscopic colitis .
188.8.131.52 Hypoglycaemic agents
Sitagliptin or exenatide increases 6-fold the risk of pancreatitis . Glyburide can produce an acute hepatitis-like illness and gliclazide induced acute hepatitis has been reported [64, 65]. Patients taking metformin have been reported to develop pancreatitis. There are reports of pancreatitis in patients using acarbose, chlorpropamide, exenatide, glimepiride, glicazide, insulin, metformin, miglitol, pioglitazone and rosiglitazone . Thiazolidenedione ligands, reduce TH1 inflammation in intestinal inflammation [67, 68].
Among fluoroquinolones, only ciprofloxacin is associated with serious hepatitis. Trimethoprim/sulfamethoxazole-induced hepatitis and pancreatitis are often reported [69, 70]. Clindamycin may cause pseudomembranous colitis and oesophagitis [71, 72]. Antibacterials such as doxycycline, tetracycline and clindamycin are the offending agents in more than 50% cases of oesophagitis . Large oral doses of chlortetracycline, chloramphenicol, and oxytetracycline can induce mucous membrane reactions such as glossitis .
Imipramine can probably cause gastroenteritis . Venlafaxine therapy can lead to drug-induced hepatitis . There is a possible causal relationship with sertraline usage and acute pancreatitis .
1.6 Factors affecting GI inflammation
Smoking adversely affects human health. Components in cigarette smoke modulate the immune system through modification of pro/anti-inflammatory cytokines, which can contribute to inflammation. Furthermore, cigarette smoke contains reactive oxygen species, which combine with decreased activity of antioxidant enzymes to produce additional proinflammatory effect . Cigarette smoke and nicotine can aggravate colon and stomach inflammation . Smoking is also a risk factor for reflux oesophagitis as it predisposes to oesophageal mucosal damage [80, 81]. Smoking also confers a strong, independent and dose-dependent risk of pancreatitis, being more pronounced when combined with alcohol .
1.6.2 Alcohol consumption
By interfering with the body’s natural defences against influx of gut microbiota, heavy alcohol consumption contributes to systemic inflammation. Chronic alcohol use impairs gut microfloral balance, affects gut barrier function, and the brain’s ability to regulate inflammation in the periphery. With impairment of these defences, systemic inflammation follows and this can damage host tissues, beyond the local injury to the gut [83, 84]. Alcoholism is responsible for acute pancreatitis and generally, alcoholic pancreatitis requires drinking alcohol for more than 5 years. Abstinence from alcohol delays the progression to chronic pancreatitis . Alcohol also causes chronic gastritis and pancreatitis [82, 85].
Physical and psychological stresses both trigger and/or modify gastrointestinal disorders. The brain-gut axis provides the anatomical basis through emotions and environmental influence, modulate gastrointestinal function through regulation of gastrointestinal immune system and mucosal inflammation . Stress increases the intestinal permeability to large antigenic molecules, leading to mast cell activation, degranulation and colonic mucin depletion. Furthermore, stress leads to increased susceptibility to colonic inflammation and plays key role in exacerbating and accentuating intestinal inflammation [87, 88]. Patients with high prolonged stressful life events have higher recurrence rate of colitis as compared to lower recurrence in low stress patients .
1.6.4 Central Obesity
WHO defines obesity as an abnormal or excessive fat accumulation in adipose tissue, to the extent that health is impaired . The cut-off value of waist circumference for central obesity in males is 90 cm while in females, it is 80cm . Obesity is associated with chronic low-grade inflammation. The inflammatory process is mainly in adipose tissue. With increasing obesity, there is decrease in adiponectin levels and thus, increase in systemic inflammation . The recognition that abdominal fat is immunologically active, sheds new light on the pathogenesis of obesity-related gastrointestinal conditions, including inflammatory conditions . Excessive accumulation of adipocytes in abdomen leads to chronic inflammation . Central obesity correlates more strongly with disease states compared with total body fat . Obesity is increasingly recognised as risk factor for various benign and malignant gastrointestinal conditions . There is increased gut inflammatory activity in obese children otherwise normal, with an evidence of worsening intestinal inflammation with the grade of obesity . Similarly, faecal calprotectin is elevated in obese adults, implying whole gut inflammation. Increased inflammatory activity at tissue level in normal subjects associated with obesity was noted and this represents the mechanism linking obesity to GI disorders [7, 93]. Adipokines influence gut permeability and hence exposure to luminal antigens which initiate the immune response. Inflammatory mediators increase uptake of proteins from the gut, which is due to increased local expression of TNF-α .
1.6.5 Food intake
There is an inverse relationship between faecal calprotectin with fibre intake and vegetable consumption . Fruit polyphenols have anti-inflammatory properties and prevent GI disorders . Consumption of fish (rich in n-3 fatty acids) has anti-inflammatory activity on gastrointestinal mucosa [95, 96]. Nuts and seeds are rich in unsaturated fat and other nutrients that may reduce inflammation .
1.6.6 Socioeconomic status
Low socioeconomic status is associated with significantly elevated levels of IL-6, CRP and TNF-α as compared to high socioeconomic status. Factors such as smoking, alcohol and obesity explain this inverse association between socioeconomic status and inflammatory markers . However, a higher socioeconomic status is more prevalent in IBD patients versus controls .
Appendectomy has immune-modulating effect and decreases risk of developing UC [100, 101].