Coeliac Disease

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Onto today's topic:

While eating gluten-free can be just a lifestyle choice, for those with coeliac disease it is not a choice but a necessity. Now, perhaps with the combination of advanced medicine, wheat consumption, and migratory patterns, the diagnosis and worldwide distribution of coeliac disease is on the rise. So let’s get to know one of the most common genetic diseases: coeliac disease.

Essentially coeliac disease is an abnormality of the small intestine mucosa due to a reaction to gluten, a protein found in cereals. As mentioned previously, it is a genetic disease; HLA-DQ2 (chromosome 6) is found in 80~90% of patients compared with 20% in the general population. Coeliac disease can also be associated with HLA-DQ8 (up to 40% of Caucasians carry the HLA alleles but will never develop the disease.) When gluten is digested, it is broken down into gliadin, which is the toxic factor to those with coeliac disease—the body attacks the gliadin and in the process damages its own villi; interestingly, unlike other autoimmune diseases, coeliac disease is the only autoimmune disease in which the antigen is actually recognized. However, like other autoimmune diseases, when you get one, you tend to get more than one—coeliac disease is associated with other autoimmune diseases, especially Sjogren’s disease and thyroid disease.

Once thought to be a disease only affecting Caucasians, coeliac disease is now diagnosed worldwide. It is more commonly found in women. Family histories reveal that 10~15% of first-degree relatives will also be affected. Coeliac disease can present any time from infancy (when cereals introduced—peak presentation) to the elderly; it can lay dormant until triggered by certain events (immigration or sickness or other).

A classic presentation of coeliac disease would be the combination of diarrhea, weight loss, anemia, symptoms of vitamin/mineral deficiency, and failure to thrive in infants. More common current presentations include bloating, gas, and iron deficiency. The symptoms improve when gluten is eliminated from the diet and deteriorate when gluten is reintroduced. Because the disease is usually more severe in the proximal bowel, iron, calcium, and folic acid deficiency is more common (as these are absorbed proximally) than B12 deficiency (absorbed in ileum). Coeliac disease can be associated with non-GIT conditions such as dermatitis herpetiformis skin eruptions (large vesicles with yellow liquid), epilepsy, myopathy, depression, paranoia, infertility, bone fractures, or metabolic bone disease.

The golden standard of diagnosis is small bowel mucosal biopsy (usually from duodenum) showing increased intraepithelial lymphocytes (earliest pathologic finding), crypt hyperplasia, and villous atrophy (which can also be seen in small bowel overgrowth, Crohn’s disease, lymphoma, Giardia, and HIV); however, serological tests can also be performed. Serum anti-tTG (tissue transglutaminase) antibody, IgA, is 90~98% sensitive, 94~97% specific. IgA deficient patients have false-negative anti-tTG; therefore, measure serum IgA concomitantly via serum quantitative protein electrophoresis and incorporate serum testing tTG and/or DGP (deamidated gliadin peptide) IgG in IgA deficiencies. There will be evidence of malabsorption; these can be either localized or generalized, such as steatorrhea, low levels of ferritin/iron saturation, iron, calcium, albumin, cholesterol, carotene, and vitamin B12. Consider CT enterography to visualize small bowel to rule out lymphoma.

Gluten-free diets should not be started before serological tests and biopsy. Gluten is found in barley, rye, some oats, and wheat (mnemonic BROW) and should be avoided in the patient’s diet; however, sometimes oats are allowed if it is grown in soil without cross-contamination by other grains. Rice and corn flour are acceptable. Supplementary of iron, folate, and other vitamins/minerals should be added as necessary. If there is a poor response to diet change, consider alternate diagnosis, concurrent disease (e.g. microscopic colitis, pancreatic insufficiency), development of intestinal (enteropathy-associated T-cell) lymphoma (symptoms include abdominal pain, weight loss, and palpable mass), or development of diffuse intestinal ulceration, characterized by aberrant intraepithelial T-cell population (precursor to lymphoma).

Coeliac disease is associated with increased risk of lymphoma, carcinoma (e.g. small bowel and colon; small increase compared with general population), and autoimmune diseases. The risk of lymphoma may be lowered by gluten-free diet.

Inflammatory Bowel Disease Part 2

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This week we continue to explore inflammatory bowel disease:

Ulcerative colitis is defined as an inflammatory disease affecting colonic mucosa anywhere from the rectum (ALWAYS involved) to the cecum, causing anything from proctitis (rectum-only) to pancolitis (entire colon); inflammation limited to rectum or left colon is more common than pancolitis. On colonoscopy, the inflammation seen is diffuse, continuous, and confined to the mucosa. The incidence of ulcerative colitis is 2~10/100,000 and prevalence is 35~100/100,000. This makes it more common than Crohn’s disease. Two-thirds of patients have disease onset by age 30, with a second peak after age 50; like Crohn’s disease, the distribution is equal between male and female patients. There is a small hereditary contribution—15% of cases have 1^st degree relative with disease. Risk is LESS in smokers.

The hallmark clinical feature of ulcerative colitis is rectal bleeding. Diarrhea can also be present, as well as abdominal cramps/pain (especially with defecation), tenesmus, urgency, and incontinence; systemic symptoms include fever, anorexia, weight loss, and fatigue. The severity of the colonic inflammation correlates with the symptoms (e.g. stool volume, amount of blood in stool). Patients with ulcerative colitis present with characteristic exacerbations and remissions; 5% of cases are fulminant.

Although there is no single confirmatory test, sigmoidoscopy with mucosal biopsy is often sufficient for diagnosis, but a colonoscopy would be helpful in determining the extent of disease (but contraindicated in severe exacerbation). CT colonography (formerly barium enema) can be done if colonoscopy not possible. Stool culture and microscopy and C. Difficile toxin assay should be done to exclude infectious causes.

The mainstay of treatment is 5-ASA derivatives (suppository and enema form in acute treatment; oral form can be used in maintaining remission) and corticosteroids (IV for acute disease; suppositories/enemas/topical applications can be used for disease distal to splenic flexure) for mild to moderate disease; the use of 5-ASA medications such as sulfasalazine or mesalamine may decrease rate of colorectal cancer. Immunosuppressants (e.g. 6-MP) and biologics (e.g. infliximab) are used in hospitalized patients with severe ulcerative colitis; biologics can also be used for outpatients with moderate to severe disease, particularly those that are steroid-unresponsive or steroid-dependent. Azathioprine can also be used in those who are steroid-dependent, but they are most commonly used to maintain remission while corticosteroids are being withdrawn; when given together with biologics, azathioprine increases the efficacy of biologics and decreases the likelihood of tolerance to biologics (around 10% chance/year). Diet change is of little value in decreasing inflammation but may alleviate symptoms. Anti-diarrheal medications are generally not used in ulcerative colitis. When all else fails, colectomy is a curative option; bowel continuity can be restored with ileal pouch-anal anastomosis (IPAA). Other indications of colectomy include toxic megacolon, uncontrollable bleeding, pre-cancerous changes detected by endoscopy/colonoscopy/biopsy, overt malignancy, or inability to taper corticosteroids.

Complications of ulcerative colitis are similar to that of Crohn’s disease, except that there are more liver problems involved in ulcerative colitis (especially primary sclerosing cholangitis in men). There is a greater risk of colorectal cancer in ulcerative colitis; the risk increases with duration and extent of disease and also increases with active mucosal inflammation and development of sclerosing cholangitis. Thusly, regular colonoscopy and biopsy in pancolitis of ≥ 8 years is indicated. Toxic megacolon (traverse colon diameter > 6cm on abdominal x-ray) with immediate danger of perforation is also a major complication! This is lethal and requires immediate treatment using steroids +/- surgery.

A comprehensive list of complications of ulcerative colitis is as follows:

Urinary calculi

Liver problems

Cholelithiasis

Epithelial problems

Retardation of growth/sexual maturation

Arthralgia

Thrombophlebitis

Iatrogenic complications

Vitamin deficiencies

Eye problems

Colorectal cancer

Obstruction

Leakage (perforation)

Iron deficiency

Toxic megacolon

Inanition (wasting)

Strictures

In patients with only proctitis, the disease usually runs a benign course. However, most patients present in chronic relapse pattern. More colonic involvement in the first year of onset correlates with increased severity of attacks and increased colectomy rate. Post colectomy most patients can have normal life expectancy.

The biggest difference between Crohn’s disease and ulcerative colitis is that Crohn’s disease can affect any part of the GIT where as ulcerative colitis is limited to the large intestines.

And as promised... the bonus chart of extra-intestinal manifestations of IBD!

Inflammatory Bowel Disease Part 1

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Onto this week's topic:

Inflammatory bowel disease refers to a group of three conditions: Crohn’s disease, ulcerative colitis, and indeterminate colitis. These conditions cause the intestines to become inflamed. The mechanism is thought to be that of autoimmune reaction where the body doesn’t recognize itself and ends up attacking itself, but the exact cause may be a combination of environmental and/or infectious and/or other factors. Genetics play a big part—there is increased risk of both Crohn’s disease and ulcerative colitis in relatives of patients with either disease, especially siblings; the risk is even higher if the disease onset is early in life. Additionally, Crohn’s disease is associated with CARD15/NOD2 gene mutation.

Crohn’s Disease is defined as a chronic, transmural inflammatory disorder potentially affecting the entire gut from mouth to anus (“gum to bum”). It has an incidence of 1~6/100,000 (number of newly diagnosed cases in a given time) and a prevalence of 10~100/100,000 (number of cases in the population at a given time). Onset of disease tends to be either before 30 (most common) or around 60 years of age; both sexes are equally affected, although the incidence is increasing (relative to ulcerative colitis) in young females. It is more common in Caucasians and Ashkenazi Jews.

Because it can occur anywhere in the GIT, the natural history can be unpredictable. The most common presentation is recurrent episodes of abdominal cramps, diarrhea, and weight loss. The most common site affected is the ileum and ascending colon; ileitis can present with post-prandial pain, vomiting, and RLQ mass—it may also mimic acute appendicitis—but linear ulceration leading to mucosal islands and classic “cobblestone” appearance on endoscopic finding will confirm Crohn’s disease. Fissures, fistulas, and abscesses are commonly in Crohn’s disease; deep fissures run risk of perforation into contiguous viscera, leading to the formation of fistulae and abscesses—enteric fistulae may communicate with skin, bladder, vagina, and other parts of bowel. Extra-intestinal manifestations are more common with colonic involvement. Granulomas are in 50% of surgical specimen. Young age, perianal disease, and need for corticosteroid therapy are indicators of poor prognosis.

Investigations include colonoscopy (more common) or endoscopy (less common) with biopsy; this should be done only when acute flare up has calmed down. In the meantime, CT/MRI enterography can be done to visualize the small bowel. CRP will be elevated in most new cases, and it is a useful factor to monitor when evaluating patient’s response to treatment. Stool cultures for bacteria, ova and parasites, and C. Difficile toxin should be done to exclude other causes of inflammatory diarrhea.

Management can be divided into the following categories:

·      Acute exacerbation

o   Fluids only

o   Antibiotics—metronidazole or ciprofloxacin

§  Works well for perianal disease

§  Can sometimes cause flare ups when discontinued

o   5-ASA—sulfasalazine or mesalamine

§  Efficacy controversial

§  Most evidence for mild colonic disease

o   Corticosteroids—prednisolone

§  Starting dose 40mg PO

§  IV methylprednisolone if severe

§  No proven role for steroids in maintaining remission

§  May mask intra-abdominal sepsis

o   Immunosuppressives—6-mercaptopurine (6-MP), azathioprine (Imuran), methotrexate (used less often)

§  Used to maintain remission than to treat inflammation

§  Used to decrease chance of relapse when corticosteroids are being withdrawn

§  May take more than 3 months to achieve beneficial effect

§  Usually continued for several years

§  May help heal fistulae and decrease disease activity

§  Side-effects:

·      Vomiting

·      Pancreatitis

·      Bone marrow suppression

·      Increased risk of malignancy

o   Biologics—infliximab (Remicade) IV, adalimumab (Humira) SC

§  Antibodies to TNF-α

§  Proven efficacy for treatment of fistulae and patients with medically refractory Crohn’s disease

§  First-line immunosuppressive therapy with infliximab and azathioprine more effective than used either alone

·      Surgical treatment

o   Usually reserved for complications such as fistulae, obstruction, abscess, perforation, bleeding, and medically refractory disease

o   Resection of bowel

o   Complications

§  <100cm ileum resection can lead to bile salt malabsorption and watery diarrhea—can be treated with cholestyramine or anti-diarrheal like loperamide

§  >100cm ileum resection can lead to steatorrhea—needs dietary fat restriction

§  If less than 50% or < 200cm of functional small intestines remain, then there is risk of developing short bowel syndrome *Short bowel syndrome (SBS, or simply short gut) is a malabsorption disorder caused by a lack of functional small intestine. The primary symptom is diarrhea, which can result in dehydration, malnutrition, and weight loss.

·      Lifestyle changes

o   Quit smoking!

o   No evidence that any specific diet that can change the natural history of Crohn’s disease, but some diet changes may improve symptoms

o   Anti-diarrheal agents—loperamide (Imodium), diphenoxylate (Lomotil), and codeine

§  Symptom relief

§  Decrease bowel motility

§  Should NOT be used during acute exacerbation or severe colitis due to risk of toxic megacolon.

o   Electrolyte replenishment in those with extensive small bowel involvement or extensive resection

§  Vit. D

§  Calcium

§  Magnesium

§  Zinc

§  Iron

§  Vit. B12

Complications include intestinal obstruction/perforation, fistula formation, and malignancy (although Crohn’s has a lower risk than that of ulcerative colitis). Prognosis is hard to predict due to highly variable course of disease, but there is increased mortality if disease onsets within the first 4~5 years of life, especially with more proximal disease. Surveillance colonoscopy is required (same as ulcerative colitis) if more than 1/3 of colon involved.