Celiac Disease and
Malabsorptive Disorders
Jamile’ Wakim-Fleming MD, FACG
CHAPTER SECTION LINKS
Definition of Celiac Disease
Celiac disease (CD) is an immune mediated disorder that develops in genetically susceptible individuals when gluten, a major protein found in wheat, barley and rye is ingested in the diet. Also called non-tropical sprue, celiac sprue, or gluten sensitive enteropathy, CD is primarily an enteropathy characterized by small bowel mucosal inflammation and villous atrophy that results in nutrient malabsorption, wasting and diarrhea. These symptoms define the classical or the typical symptoms of CD (Table 1).
Table 1: Typical Symptoms of Celiac Disease
| Type | Symptoms | Serology | Villous Atrophy |
|---|---|---|---|
| Classical CD | malabsorption | abnormal | yes |
| Atypical CD | extraintestinal | abnormal | yes |
| Silent CD | no symptoms | abnormal | yes |
| Latent CD | no symptoms | abnormal | no villous atrophy |
| Potential CD | symptoms | abnormal | Increase IEL only |
| Refractory CD | symptoms | abnormal | villous atrophy but no response to 6m GFD |
| Collagenous | symptoms | abnormal | villous atrophy and failure of therapy |
Any organ system may be involved in CD, and patients may develop extra-intestinal manifestations also called atypical manifestations such as anemia, bone disease, infertility, unfavorable outcomes of pregnancy, lymphoma and liver disease. The clinical presentation may include a wide range of symptoms, or even lack of symptoms as in silent CD, but patients may have abnormal celiac serology (endomysial antibodies (EMA) and human tissue transglutaminase antibodies (HtTG)) and varying degrees of small bowel involvement on biopsy. A definition of the various forms of CD based on clinical, pathological and serological findings is listed in Table 1.
Genetical susceptibility defines individuals who possess the gene pair encoding the major histocompatibility complex Class II HLA DQ2 or DQ8. These genes are virtually required for CD to occur, and lack of these genes makes CD very unlikely.
Prevalence and Epidemiology
Recent availability of highly sensitive and specific serological tests such as endomysial antibodies and human tissue transglutaminase antibodies (EMA and hTTG) has made it possible to assess the true prevalence of CD. Epidemiological studies using such tests along with small bowel biopsies report a higher prevalence of CD than previously thought. Prevalence in Western Europeans and in the USA, is reported to range between 1/250 and 1/133, and is higher in relatives of individuals with CD, occurring in 1/22 in first-degree relatives and in 1/39 in second-degree relatives. It is rarely, if ever, reported in people with pure ethnic backgrounds from Africa, the Caribbean, China, and Japan. Women are affected more commonly than men, but there is no age predilection.
Other than individuals with family relatives with CD, individuals at increased risk include those with Down syndrome, Turner syndrome, diabetes mellitus type 1, thyroid disease, lymphocytic colitis and autoimmune disorders (Table 2).
| Table 2: Patients at risk for celiac disease and should be tested: |
|---|
| Gastrointestinal /classical symptoms: diarrhea, weight loss, abdominal distension, failure to thrive. |
| Autoimmune diseases, type 1 Diabetes Mellitus, thyroid disorders, IBD, sjogren syndrome, microscopic colitis, inflammatory bowel disease. |
| First degree relatives |
| Liver enzyme elevation |
| Down syndrome |
| Williams syndrome |
| Iron deficiency anemia |
| Osteoporosis |
| Delayed puberty |
| Infertility |
| Irritable bowel syndrome |
Pathophysiology
Celiac disease is a multifactorial and a multisystem disorder involving a genetic predisposition, environmental exposure of gluten to the small bowel mucosa, and an immunologic response to gluten.
Genetic: The majority (>90%) of individuals with CD possess the Human Leukocyte Antigens (HLA) DQ2 haplotype, and 5% to 10% possess the DQ8 haplotype, conferring a negative predictive value greater than 98%. These haplotypes are encoded within the HLA class II region of the major histocompatibility complex on chromosome 6p. However about 40% of the general population carry these haplotypes without having the disease, which makes their presence necessary but not sufficient for its development. Other non-HLA genes have been proposed but their role in influencing the disease has not been clearly defined.
Environmental: It was a serendipitous observation that children with CD improved during World War II when cereals used to make bread were scarce, and relapsed after the war when the supply of these cereals was reinstituted. Risk for developing CD is increased with the introduction of gluten in the diet of infants before the age of 4 months. Grains that activate the disease contain gluten (prolamins and glutenins also called gliadins) and include wheat, barley and rye. Grains that do not activate the disease include rice, corn, sorghum and millet. Oats contain a very small proportion of prolamins and should be avoided initially.
Immunologic: Exposure of the upper small bowel mucosa to gluten in susceptible individuals precipitates an inflammatory reaction characterized by infiltration of the lamina propria and the epithelium with inflammatory cells which eventually leads to destruction and atrophy of the mucosa.
Ingestion of gluten induces the antigen precipitating cells, which express HLA DQ2/DQ8, in lamina propria to sensitize T lymphocytes in both lamina propria and in epithelium. Activated T lymphocytes, particularly CD8+ intraepithelial lymphocytes expressing δ/Υ receptors, become abundant and their number increases about sixfold. These in turn activate B lymphocytes and other lymphocytes to secrete immunoglobulins, cytokines, interferons, tumor necrosis factor and other inflammatory mediators notably IL15, and cause damage to the enterocytes resulting in villous atrophy. Additionally, tissue transglutaminase tTG, a ubiquitous intracellular enzyme which is released by inflammatory and endothelial cells, deamidates glutamine residues in gluten to glutamic acid, which is negatively charged. This in turn facilitates further reactivation of more lymphocytes, potentially affecting more organ systems in the body.
Clinical Manifestations
Celiac disease exhibits a spectrum of clinical and pathological manifestations. Left untreated CD may progress to involve multiple organ systems with severe complications and nutritional deficiencies.
Symptoms may manifest in infancy and as early as cereals are introduced in the diet. Crampy abdominal pain, steatorrhea, failure to thrive, apathy and irritability, muscle wasting and hypotonia are described. Any of these symptoms should trigger a diagnostic work up. Catch –up growth is well documented once gluten-free diet is introduced.
In adults, the clinical symptoms are variable and not specific. The classical symptoms of malabsorption are less and less encountered since testing with serological antibodies has become available and diagnosis recognized before the full blown clinical wasting occurs. On the other hand, atypical presentations are increasingly recognized and becoming more common.
Patients with CD may exhibit weakness, fatigue and dyspnea as a result of vitamin B12, folate and iron deficiency anemias; bone fractures, muscular atrophy and tetany as a result of osteoporosis and osteopenia due to vitamin D and calcium deficiencies; peripheral neuropathy and ataxia as a result of cerebellar and posterior column inflammatory damage; secondary hyperparathyroidism, edema, petechia and dermatitis herpetiformis. Infertility is observed in men and women. Amenorrhea, intrauterine growth retardation, and unfavorable outcomes of pregnancy have been reported. Liver enzyme abnormalities and nonspecific hepatitis have been incidentally recognized in patients with CD, but also advanced liver disease and cirrhosis have been reported with improvement of the liver disease upon withdrawal of gluten from the diet. It is generally accepted that patients with abnormal elevation of liver enzymes should be tested for celiac disease.
Dermatitis herpetiformis may be the clinical presentation of a latent CD. It is characterized by a papulo-vesicular rash that is intensely pruritic affecting the buttocks, extensor surfaces of elbows and knees. It is characterized by granular IgA deposits in the dermo-epidermal junction. Most patients have abnormalities of the intestinal mucosa. Treatment consists of withdrawing gluten from the diet, if skin lesions do not improve dapsone may be added at 1-2 mg /day.
Other manifestations of CD include weight gain and obesity, gastroesophageal reflux disease, irritable bowel syndrome with abdominal pain and constipation, pancreatitis, myocarditis, aphtous ulcers of the oral mucosa, lymphocytic/collagenous colitis, hyposplenism and asymptomatic IgA nephropathy. There is a mildly increased risk for gastrointestinal malignancies and lymphomas in CD patients than in the general population.
Diagnosis
Once the clinical suspicion in patients at risk factors is raised, the initial step toward a diagnosis is to obtain celiac serology antibody testing. This should be followed by a small bowel biopsy. Testing should be done on a gluten containing diet.
The most sensitive and specific serological tests are endomysial antibody IgA EMA and human tissue transglutaminase antibody (IgA HtTG). Sensitivities and specificities are higher than 85% and 97% respectively for EMA and 90% and 97% respectively for HtTG. Gliadin antibodies have lower sensitivities and specificites and are not recommended for screening, however gliadin antibodies may have a role in monitoring adherence to a gluten-free diet.
About 2%-5% of patients with CD have selective IgA deficiency, in which case serum IgG TTG or IgG EMA should be performed.
Pathological changes on small bowel biopsy are characterized by a spectrum of abnormalities described by Marsh and known as the Marsh criteria. (Table 3). The hallmark of CD is Marsh 3 or villous atrophy. However, this might be patchy or present in other disorders as in hypo-gammaglobulinemia, acute infectious gastroenteritis or milk intolerance. Additionally, there is growing evidence that CD may be diagnosed when changes of earlier phase, such as Marsh I or Marsh II, are seen on biopsy.
| Table 3: Histological spectrum of intestinal involvement in CD |
|---|
| Marsh 0 or type 0: preinfiltrative or normal |
| Marsh I or type 1: infiltrative lesion. Increased intraepithelial lymphocytes |
| Marsh II or type 2: hyperplastic lesion. (type 1 plus crypt hyperplasia) |
| Marsh III or type 3: destructive lesion. (type 2 plus villous atrophy) |
| Marsh IV or type 4: hypoplastic lesion seen in T cell lymphoma |
So how is diagnosis of celiac disease established in less than typical signs and symptoms?
The wide range of clinical manifestations of the disease coupled with less than Marsh 3 on biopsy makes the diagnosis of CD a bit challenging for the clinician. In these situations, and genetic testing and/or gluten challenge might be necessary for a definite diagnosis. We describe a few scenarios that might be encountered in a clinical setting and propose the following diagnostic work up:
- Positive serology and villous atrophy: Diagnosis established. Patient should be treated.
- Positive serology and normal small bowel mucosa biopsy: Disease is considered latent. Biopsy should be repeated after a gluten challenge or a few months later on a normal diet.
- Positive serology and increased intraepithelial lymphocytes (IEL): Potential celiac disease. Repeat biopsy after a gluten challenge or in a few months on a normal diet or obtain HLA typing. If any is positive start a gluten-free diet.
- Normal serology and normal biopsy: Look for other causes of patients’ symptoms.
- Normal serology and villous atrophy: Exclude other causes of villous atrophy, exclude immunodeficiency, IgA deficiency.
Gluten challenge should be done in patients who embarked on a gluten-free diet empirically without serological or pathological abnormalities. It can also be done in patients with latent celiac and in patients with potential celiac disease. Gluten should be started in small increments beginning with one slice of bread and doubling this amount every 3 days if tolerated until at least 10 gm of gluten are ingested daily or the equivalent of 4 slices of bread after which serological test and small bowel biopsy should be repeated and signs and symptoms observed. If tests remain negative, patients should remain on a normal diet.
Who should be screened for celiac disease?
Although CD is fairly common, underdiagnosed and may lead to serious complications, mass screening is not yet recommended. Screening with EMA and TtG may be warranted in patients with high risk factors, notably first-degree relatives of patients with the disease.
Complications
Refractory sprue: Patients with refractory disease have persistent symptoms despite 6 months of gluten-free diet (GFD). Glucocorticoids and at times immunosuppressants are indicated to induce remission. Patients often progress to ulcerative jejunitis or malignancy.
Malignancy: Includes intestinal lymphoma such as enteropathy associated intestinal lymphoma (EATL). It is usually not responsive to GFD. Other malignancies include various carcinomas along the gastrointestinal tract.
Ulcerative jejunoileitis: Consists of ulcers and strictures of the small bowel requiring surgical resections.
Acute celiac crisis: Is rare and usually occurs when patients undergo rapid and non-incremental gluten challenge. It is characterized by severe diarrhea, electrolyte abnormalities and metabolic acidosis. Glucocorticoids and volume replacement are often required.
Collagenous sprue: Defines CD that is refractory to therapy and characterized by the deposition of collagen in subepithelial regions of the small bowel with a thickness greater than 10 mm. Prognosis is very grim.
Treatment
Treatment consists of withdrawing gluten from the diet for life. It entails eliminating wheat, barley and rye. This allows healing of the small bowel mucosa and restitution of nutritional status. Oats may initially be withdrawn in severely symptomatic patients until symptoms begin to resolve.
Lactose-containing products may worsen gastrointestinal symptoms and should be avoided in these situations until restitution of a normal mucosa. Vitamins D and B12, folic acid, calcium, iron and nutritional deficiencies should be replaced as necessary. Prevention of bone loss and pneumococcal vaccination due to hyposplenism are necessary. Complications of CD should be managed appropriately and increased vigilance in recognizing and managing lymphoma and cancer is important.
Adherence to a gluten-free diet is often difficult because of cost and lack of palatability and because it requires patient’s commitment and perseverance. Therefore, alternative therapies are increasingly in demand and trials are ongoing to assess for their efficacy. These therapies include gluten-degrading enzymes, modified grains that lack immunogenic compounds, zonulin inhibitors that decrease intestinal permeability, and anti-inflammatory/ immunotherapy.
Referral of patients to nutritional counseling for education and for monitoring adherence and response to therapy is essential in order to safeguard and good outcome. Patient information on gluten-containing and gluten-free foods is available on various web sites along with a wide variety of gluten-free cooking recipes.
Response to gluten-free diet is assessed by clinical and serological improvement. There is no clear consensus on whether a repeat small bowel biopsy is necessary. However, this may be indicated in cases where adherence to diet is proven but response to diet is equivocal or lacking.
Other Malabsorptive Disorders
The small intestine is the site of absorption of nutrients necessary to maintain life. Several disorders including CD affect the intestinal mucosa and/or the intestinal chyme and may cause malabsorption and wasting. These may be classified into small bowel mucosal diseases and luminal or digestive diseases. Potential etiologies may include infectious causes as in parasitic or bacterial and viral enteritis, iatrogenic causes by means of surgical resection of the small bowel or administration of medications, structural defects as in strictures causing stasis with bacterial overgrowth, and lack of digestive enzymes in the brush border and/or the lumen of the gastrointestinal tract. (Table 4 and 5).
Table 4: Differential Diagnosis of Celiac Disease, Malabsorption Due to Mucosal Abnormalities
| Disease | Etiology | Diagnosis | Therapy |
|---|---|---|---|
| Tropical sprue | Nonspecific enterotoxigens | Acute enteric infection in visitors of endemic locales | antibiotics |
| Whipple disease | Tropheryma whippelli | Small bowel biopsy, PAS+ laden macrophages | antibiotics |
| Disaccharidase deficiency( lactose intolerance) | Lactase deficiency of villous epithelial cells | Hydrogen breath test | Avoidance of milk products |
| Abetalipoproteinemia | Autosomal recessive inability to synthesize abetalipoproteins | Absence in plasma of chlomicrons, Very low density lipoproteins and low density lipoproteins Burr cells on blood smear | |
| Crohn’s disease | Autoimmune disorder of the GI tract | Clinical, endoscopic and histological | 5 ASA and immunosuppressants |
| Eosinophilic gastroenteritis, mastocytosis | inflammation | histological | Steroids |
| Gastrectomy | Surgical/iatrogenic | Clinical history, B12 deficiency | B12 supplementation |
| Short gut syndrome | Surgical/iatrogenic | Clinical history | Nutrient supplementation |
| Graft vs. host disease | Iatrogenic | Clinical history | Withdrawal of offending agents |
| Giardia | Protozoa | Histological | antibiotics |
| AIDS | Infectious agents, AIDS enteropathy | Histological possibly | Antibiotics, antiretroviral therapy |
| Table 5: Differential diagnosis of celiac disease, malabsorption due to defective intraluminal digestion |
|---|
| Pancreatic insufficiency, chronic pancreatitis, cystic fibrosis: lack of pancreatic enzymes. |
| Zollinger Ellison syndrome, inactivation of pancreatic enzymes by excess gastric acid secretion. |
| Gastrectomy, Ileal resection or short gut syndrome. |
| Cholestatic liver disease and severe chronic liver disease. |
| Parasitic infestation. |
| Lymphoma. |
| Bacterial overgrowth. |
| Drugs: Bile salt binders(decrease micelle formation), antacids ( chelation), Metothrexate( villlus blunting)sulfasalazine( inhibits folate hydrolase). |
Conclusion
CD is a multisystem disorder with a wide range of clinical presentations. Clinicians should have a heightened awareness to these presentations and a low threshold for testing with EMA and TtG antibodies. Education and surveillance of patients on a gluten-free diet are crucial in order to safeguard adherence to the diet and potential prevention of further complications of the disease.
Other malabsorptive disorders should be included in the differential diagnosis of CD, bearing in mind the similarities in signs and symptoms – even pathological findings – on biopsy. Further testing may be required and a multidisciplinary approach may be necessary for a definite diagnosis.
Suggested Readings
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