Gastrointestinal System

Diagnosis and reasoning

This middle aged gentleman has presented with a complex constellation of symptoms and signs.

In such patients, the first step of the diagnostic approach should be to attempt to classify these findings into discrete (and logical) groups; this gives us the following:

- There is evidence of a sensory neuropathy affecting the distal lower limbs in a bilateral and symmetric manner.

- The history of malodorous and bulky stools is suspicious of steatorrhea.

- There is a background of constitutional symptoms such as weakness, fatigability and significant weight loss.

Note that the above symptoms involve multiple organ systems - the peripheral system and the gastrointestinal tract (GI).

If we consider the differential diagnosis of symmetric (distal) sensory neuropathy, the list of conditions is wide indeed.

However, in practice, the most common are diabetes mellitus, hypothyroidism, alcoholism, deficiency of vitamins such as cobalamin, thiamine or folate, and connective tissue disorders.

The list of diseases causing steatorrhea is similarly wide; however, the most common causes are diseases of the pancreas such as chronic pancreatitis, pancreatic tumors or exocrine pancreatic insufficiency; and diseases of the small bowel such as inflammatory bowel disease or celiac disease.

When these disparate lists are considered together, several potential diagnoses become apparent:

- This could be a malabsorptive condition. Thus, malabsorption of fat would result in steatorrhea, while malabsorption of water soluble vitamins would result in a deficiency of thiamine, folate or cobalamin.

- Diabetes in association with chronic pancreatitis; here, the pancreatic insufficiency would explain the impaired fat digestion, while diabetic neuropathy would account for the CNS findings.

- Alcoholism complicated by chronic pancreatitis; note that alcohol reduces gastrointestinal absorption of cobalamin.

However, observe the presence of a megaloblastic anemia with hypersegmented neutrophils in the blood film; this is strongly suggestive of either cobalamin or folate deficiency, making the second diagnosis above unlikely.

In addition, there is no history of alcohol abuse or a previous history suggestive of episodes of pancreatitis; this makes the third diagnosis unlikely.

Thus, a malabsorptive disorder is the most likely underlying etiology.

Assaying the serum cobalamin and folate levels demonstrates the presence of vitamin B12 deficiency; the fecal fat analysis gives objective evidence of steatorrhea. Thus the clinical diagnosis gains further credence.

Cobalamin is absorbed from the terminal ileum; unfortunately, many diseases can affect this region of the bowel, including celiac disease, Crohn’s disease, intestinal tuberculosis, Whipples disease and tropical sprue.

However, the terminal ileum is amenable to endoscopic inspection - thus an ileoscopy and biopsy is a good path towards rapid resolution of the diagnosis.

Endoscopy reveals inflammation and multiple ulcerations involving the ileum and proximal ascending colon, indicating the presence of inflammatory bowel disease (IBD). The biopsy findings are suggestive of Crohn's disease, clinching the diagnosis.

Controlled-release oral glucocorticoids (such as Budesonide) are recommended as the primary therapy in patients with mild to moderate active Crohn’s disease which is localized to the ileum and/or the right colon.

Note that NSAIDs are probably best avoided in these individuals, as they may provoke disease activity (via mechanisms which are unclear).

Vitamin B12 should be administered in view of the deficiency. Surgical resection is not indicated right now.


Crohn’s disease (CD) is an inflammatory bowel disease of unclear etiology, characterized by transmural inflammation and 'skip' lesions (i.e. isolated lesions) which may involve the entire gastrointestinal tract from the mouth to the perianal region.

Ulcerative Colitis (UC) is the other major form of inflammatory bowel disease; in this, there is superficial and diffuse inflammation of the colonic mucosa and submucosa, which almost invariably affects the rectum and extends proximally and contiguously along the colon.

CD is a chronic relapsing disease which is almost always incurable, with most patients requiring lifelong therapy.

The incidence and prevalence in the United States are estimated to be 20.2 cases per 100,000 person-years and 201 per 100,000 person-years respectively.

While the disease may occur at any age, the incidence is bimodal, with one peak in the second and third decades of life, and a smaller peak in the fifth decade.

Simultaneous involvement of both the ileum and colon is the most common clinical pattern, being found in 35% of patients; isolated colonic involvement (32%), isolated small bowel involvement (28%) and gastroduodenal disease (5%) are the next most common.

Although the pathogenesis of CD is poorly understood, a number of risk factors such as genetic susceptibility, immunoregulatory defects, smoking, diet (processed, fried, and sugary foods), and Nonsteroidal Anti Inflammatory Drugs (NSAIDs) have been identified.

Due to the insidious nature of the disease, patients can have symptoms for many years prior to diagnosis; fatigue, prolonged diarrhea with abdominal pain, fever, weight loss, and gastrointestinal bleeding are the most common.

Approximately one third of patients have perianal disease (which is quite uncommon in UC); these include abscesses, anal fissures, anorectal fistulas, and perianal skin tags.

Extraintestinal manifestations include anemia, inflammatory arthropathies, aphthous ulcers of the mouth, cholelithiasis, ocular involvement (such as uveitis or scleritis), erythema nodosum, osteoporosis, nephrolithiasis, and venous thromboembolism.

Crohn's disease is often tricky to diagnose clinically, because of the heterogeneous presentation, often insidious onset, and overlap of symptoms with other forms of inflammatory bowel disease.

The diagnosis is usually established via the presence of supportive endoscopic or imaging findings, in a patient with a compatible clinical picture.

Characteristic endoscopic findings include skip lesions, cobblestoning (serpiginous and linear ulcers), strictures, and aphthous ulcers of the distal ileum or colon; these are distinct from those of UC.

Wireless capsule endoscopy can be used for evaluation of CD affecting the small bowel; however, this should be avoided in suspected cases of intestinal stricture.

Imaging is most useful in the evaluation of upper GI disease; endoscopic ultrasonography (EUS) and MRI are valuable for the diagnosis of perirectal complications.

Laboratory tests help in assessing disease activity, identifying complications, and monitoring the response to therapy.

Key therapeutic goals include control of symptoms, induction of clinical remission, maintenance of remission with minimal adverse effects, and improvement of quality of life.

Two main strategies are currently employed in the management of CD; the conventional “step up” approach begins with corticosteroids or 5-aminosalicylate (5-ASA), and advances to immunomodulators or anti–tumor necrosis factor (TNF) agents based on severity of disease,

The early, aggressive, “top-down” approach begins with tumour necrosis factor (TNF) alfa inhibitors in combination with immunomodulators.

Note that the which of the above strategies is optimal is still a matter of controversy.

In the step-up approach, glucocorticoids, 5-aminosalicylate (5-ASA) and antibiotics are currently recommended for achieving remission in mild to moderate disease; immunomodulators (such as azathioprine, mercaptopurine or methotrexate) can be used as add on drugs to induce remission and maintenance.

Note that (long term therapy with) corticosteroids should not be used for maintenance of remission.

TNF-alfa inhibitors (Infliximab and adalimumab) decrease mucosal production of inflammatory cytokines, and are used in patients with severe active CD, who have not responded to complete and adequate therapy with a corticosteroid or an immunosuppressive agent.

Patients on TNF-alfa inhibitors should have their disease reassessed at least every 12 months to determine whether ongoing treatment is still clinically appropriate.

Abscesses should be drained as appropriate; chronic fistulae and perianal fissures are usually treated with antibiotics and immunosuppressives or anti-TNF agents.

Note that most patients with CD will eventually require surgery for refractory disease, intractable hemorrhage, perforation, obstruction, abscesses, intestinal dysplasia, bowel cancer or unresponsive fulminant disease.

It is essential to properly educate the patients and their families about the disease, side effects, complications, and importance of nutrition.

As mentioned earlier, CD can affect almost any site in the gastrointestinal tract. However, once established, the location of disease does not tend to change over time, although it's behavior may.

Thus, surgery may be curative in a limited population of patients, in whom CD is limited to the colon - if the entire colon is removed.

The complications of CD are linked to it's transmural inflammatory nature; these include deep ulceration leading to fistulization (by way of the sinus tracts penetrating the serosa), micro perforations, abscess formation, adhesions, malabsorption, and acute or subacute intestinal obstruction.

Poor prognostic indicators include a young age at diagnosis, perianal disease, upper GI tract involvement, multiple extraintestinal manifestations, active tobacco use, and perforating (ie. fistulizing disease); these patients are believed to benefit from “top down” therapy.

At least half of patients will require surgical treatment in the first ten years of the disease; approximately 80% will require surgery within their lifetime.

Around 10% to 20% of patients experience prolonged remission after the initial presentation; less than 5% of patients will have a continuous course of active disease.

The lifetime risk of fistula development has been reported to range from 20% to 40%.

Estimates from different population-based studies show these individuals to have a mortality ranging from no increased risk to a five-fold increase compared to the general population; this is higher in the first 2 years following diagnosis, and in patients with upper GI disease.

The risk of developing colorectal cancer is similar to that for individuals with UC who have the same extent of colonic involvement.

Take home messages

1. CD is a chronic, relapsing IBD which is usually incurable.

2. Clinical diagnosis is often tricky, due to the insidious nature of symptoms and overlap with other forms of IBD.

3. While CD can affect almost any site in the GI tract, once established, the location of disease usually does not tend to change over time, although the behavior may.

4. The "step up" approach and "top down" approach are the two main management strategies; which is more effective is still a matter of controversy.


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