- A small proportion of patients will have an upper gastrointestinal causes of diarrhoea.
Unfortunately, the guidelines are not clear as to which patients should have an upper gastrointestinal endoscopy. 2,3
a. Coeliac disease: delayed diagnosis and the implications.
In a series of 825 coeliac disease patients, 32% reported a diagnostic
delay of more than 10 years, despite many having diarrhoea.
4 Serological testing for coeliac disease is now widely available. A
delayed diagnosis has implications for long term bone health and
quality of life.
A paper evaluating 20 referral centres estimated the risk of developing
a neoplasm among non-diagnosed coeliac patients and whether
this risk correlates with the age of patients at diagnosis of coeliac
disease. They found the Standardised Incidence Ration (SIR) for all
cancers resulted to be 1.3 (95% CI = 1.0–1.7 p < 0.001). The specific
SIRs for non Hodgkin lymphoma was 4.7 (95% CI = 2.9–7.3 p < 0.001),
for the small bowel carcinoma 25 (95% CI = 8.5–51.4 p < 0.001), for
non Hodgkin lymphoma 10 (95% CI = 2.7–25 p = 0.01), stomach
carcinoma 3 (95% CI = 1.3–4.9 p < 0.08). This paper concluded that
the gluten-free diet is likely to protect from the development of
malignancies in CD patients, since the higher the age at diagnosis of
CD the higher the risk of developing a malignancy.
b. Angiotensin-receptor II blockade (ARB) causes sprue-like enteropathy
A systematic review revealed a total of 82 case reports and case series
as well as 5 comparative studies, including 248 cases6. The ARBs listed in
the case reports were olmesartan (233 users; 94.0%), telmisartan
(5 users; 2.0%), irbesartan (4 users; 1.6%), valsartan (3 users; 1.2%),
losartan (2 users; 0.8%) and eprosartan (1 user; 0.4%). The periods
between ARB initiation and onset of symptoms ranged from 2 weeks to
13 years. Histologic results were reported in 218 cases, in which 201
cases (92.2%) were villous atrophy and 131 cases (60.1%) were
intraepithelial lymphocytosis. Complete remission of symptoms
after discontinuation of ARB was reported in 233 (97.4%) of the
239 patients. Seven cases (2.8%) reported recurrence of symptoms
after restarting olmesartan; rechallenge was not reported for the
non-olmesartan ARBs.
c. Not considering rarer upper gastrointestinal causes
Whipple’s disease, autoimmune enteropathy, tropical sprue,
pancreatic insufficiency, amyloid, intestinal lymphangectasia and hormonal
secreting causes (VIPoma, Gastrinoma, Carcinoid) should be considered in
patients with refractory diarrhoea.
2. Microscopic colitis (MC) – Missed when routine colonic biopsies are not
performed in the evaluation of diarrhoea
Microscopic colitis is an inflammatory disease of the colon and a frequent
cause of chronic or recurrent watery diarrhea. MC consists of two subtypes,
collagenous colitis (CC) and lymphocytic colitis (LC). While the primary
symptom is diarrhoea, other signs and symptoms such as abdominal pain,
weight loss, and dehydration or electrolyte abnormalities may also be present
depending on disease severity.7 In MC, the colonic mucosa usually appears
normal on colonoscopy, and the diagnosis is made by histologic findings
of intraepithelial lymphocytosis with (CC) or without (LC) a prominent
subepithelial collagen band. The prevalence of MC ranges from 10%-20%
in patients undergoing colonoscopy for chronic watery diarrhea.8,9
Risk factors: 10,11,12,13
- Female gender
- Cigarette smoking
- Increasing age
- Concomitant autoimmune disease
- Medications (NSAIDs, proton pump inhibitors (PPIs), statins, and selective serotonin reuptake inhibitors (SSRIs)
There is an association with Coeliac Disease with a 50-70 times greater risk
of MC. Between 2%-9% of patients with MC have CD.14,15
3. Overlooking over the counter medications/ Herbal medications/dietary
triggers 16
a. Over the counter medications:
- Magnesium containing medications - Typically affecting motility. Usually magnesium carbonate, magnesium chloride, magnesium gluconate and magnesium oxide.
- Proton pump inhibitors – seen in 3.5% of patients.17 The mechanism is possibly related to alterations in bacterial flora and a direct pro-kinetic effect. The presence of small intestinal bacterial overgrowth (SIBO) in a previous study was 50% of patients using PPIs, 24.5% of patients with Irritable bowel syndrome (IBS) and 6% of healthy control subjects; there was a statistically significant difference between patients using PPIs and those with IBS or healthy control subjects (P < .001). 18 Therapy for SIBO will resolve symptoms in most patients if they fail to respond to medication withdrawal.
- Fish oil/ Krill oil/ Flaxseed oil – The incidence has not been well studied but rises with higher doses. Often a dose reduction may be sufficient to reduce symptoms.
b. Herbal remedies/herbal teas/Traditional Chinese medicine:
Herbal tea can contain sennosides, which are hydroxyanthracene
glycosides derived from senna leaves. Diclofenac and caffeine have also
been found in traditional Chinese medicine. 17
c. Dietary triggers:
- Sorbitol/Mannitol (candy, chewing gums, and sugar-free items).
- Fructose: Present in fruit and honey but also candy and soft drinks.
- Lactose: When standardising for country size, the global prevalence estimate of lactose malabsorption was 68% (95% CI 64–72) in a recent systematic review and meta-analysis. The prevalence ranged from 28% (19–37) in western, southern, and northern Europe to 70% (57–83) in the Middle East.18
- Alcohol
- Liquorice
- Caffeine
Keeping these factors in mind can be useful in evaluating those patients
whose chronic diarrhoea has proven refractory. |
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REFERENCES
- Daoud D, Bouin M, Bellemare L, Nemer M. Prevalence of chronic diarrhea amongst patients followed in gastroenterology. [Published online ahead of print March 1, 2018]. J Can Assoc Gastroenterol.
- Arasaradnam RP, Brown S, Forbes A, et al. Gut Epub ahead of print:
- Shen, Bo et al.The role of endoscopy in the management of patients with diarrhea. Gastrointestinal Endoscopy, Volume 71, Issue 6, 887 - 892
- Fuchs V, et al. Factors associated with long diagnostic delay in celiac disease. Scand J Gastroenterol 2014; 49: 1304–1310.
- Silano, M., Volta, U., Mecchia, A.M. et al. Delayed diagnosis of coeliac disease increases cancer risk.BMC Gastroenterol 7, 8 (2007).
- Kamal et al. Angiotensin II receptor blockers and gastrointestinal adverse events of resembling sprue-like enteropathy: a systematic review, Gastroenterology Report, Volume 7, Issue 3, June 2019, Pages 162–167
- Nyhlin N et al.Long-term prognosis of clinical symptoms and health-related quality of life in microscopic colitis: a case-control study. Aliment Pharmacol Ther. 2014;39:963-72.
- Tong J et al.Incidence, prevalence, and temporal trends of microscopic colitis: a systematic review and meta-analysis. Am J Gastroenterol. 2015;110:265-76.
- Olesen M et al.Microscopic colitis: a common diarrhoeal disease. An epidemiological study in Orebro, Sweden, 1993-1998. Gut. 2004;53(3):346-50.
- Macaigne G et al.Microscopic colitis or functional bowel disease with diarrhea: a French prospective multicenter study. Am J Gastroenterol. 2014; 09(9):1461-70.
- Verhaegh BP et al.High risk of drug-induced microscopic colitis with concomitant use of NSAIDs and proton pump inhibitors. Aliment Pharmacol Ther. 2016;43(9):1004-13.
- Masclee GM et al. Increased risk of microscopic colitis with use of proton pump inhibitors and non-steroidal anti-inflammatory drugs. Am J Gastroenterol. 2015;110:749-59.
- Zylberberg H et al.Medication use and microscopic colitis: a multicentre retrospective cohort study Ailment Pharmacol Ther. 2021 Jun;53(11)1209-15.
- Stewart M et al.The association of coeliac disease and microscopic colitis: a large population-based study. Aliment Pharmacol Ther. 2011;33(12):1340-9.
- Green PHR et al.An association between microscopic colitis and coeliac disease Clin Gastroenterol Hepatol. 2009;7(11):1210-6.
- Sweetser, Seth. "Evaluating the patient with diarrhea: a case-based approach."Mayo Clinic Proceedings. Vol. 87. No. 6. Elsevier, 2012.
- Kam, Peter & Liew, S. (2002). Traditional Chinese herbal medicine and anaesthesia. Anaesthesia. 57. 1083-9.
- Storhaug et al. "Country, regional, and global estimates for lactose malabsorption in adults: a systematic review and meta-analysis." The Lancet Gastroenterology & Hepatology 2.10 (2017): 738-746.
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Article by Dr Dev Segarajasingam
Dr Segarajasingam is a gastroenterologist with subspecialty interests in small bowel investigations and endoscopic ultrasound. He has extensive experience in capsule endoscopy and enteroscopy.
Click here to read more about Dr Dev Segarajasingam
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