Ahmad Hormati Assistant Professor of Gastroenterology Qom University of Medical Sciences. Email:...

Ahmad HormatiAhmad Hormati

Assistant Professor of Assistant Professor of GastroenterologyGastroenterology

Qom University of Medical Qom University of Medical Sciences.Sciences.

Email: Email: [email protected]@yahoo.com

http://hormatigi.irhttp://hormatigi.ir//

MALABSORPTION MALABSORPTION SYNDROMESYNDROME

Epidemiology, and Epidemiology, and clinical manifestations clinical manifestations

of celiac disease in of celiac disease in adultsadults

Celiac disease occurs primarily in Celiac disease occurs primarily in whites of whites of northern European northern European

ancestryancestry . .

Although classically a disease of Although classically a disease of infants, celiac disease now often infants, celiac disease now often presents later, between the ages presents later, between the ages

of of 10 and 40 years10 and 40 years

Formerly, epidemiological studies using Formerly, epidemiological studies using serologic assays for serologic assays for IgA antibodies to gliadin IgA antibodies to gliadin

and endomysium and endomysium with biopsy verification with biopsy verification established established prevalences of 1:300 to 1:500 prevalences of 1:300 to 1:500 in in

most countries where celiac disease is most countries where celiac disease is prevalentprevalent..

The identification of tissue transglutaminase The identification of tissue transglutaminase (TG2) as endomysial autoantigen allowed the (TG2) as endomysial autoantigen allowed the

development of a highly sensitive and specific development of a highly sensitive and specific serological test and population based screening. serological test and population based screening.

Anti-TG2-based screening programs Anti-TG2-based screening programs revealed a revealed a higher prevalence higher prevalence of celiac of celiac

disease, disease, reaching 1 percent or morereaching 1 percent or more, thus , thus demonstrating a large number of undiagnosed demonstrating a large number of undiagnosed

celiac patients in the "normal" populations of celiac patients in the "normal" populations of affected countriesaffected countries..

Patients with celiac disease may present with Patients with celiac disease may present with classic symptomsclassic symptoms related to malabsorption, related to malabsorption,

including diarrhea, steatorrhea, weight loss, including diarrhea, steatorrhea, weight loss, and nutrient or vitamin deficienciesand nutrient or vitamin deficiencies . .

They may also exhibit only They may also exhibit only minor minor gastrointestinal complaintsgastrointestinal complaints, have , have

nongastrointestinal manifestationsnongastrointestinal manifestations, or , or be be asymptomaticasymptomatic..

Numerous conditions have been associated Numerous conditions have been associated with celiac disease including with celiac disease including dermatitis dermatitis

herpetiformisherpetiformis, , diabetes mellitusdiabetes mellitus, and , and selective IgA deficiencyselective IgA deficiency..

CLASSIFICATIONCLASSIFICATION Classic diseaseClassic disease::

includes the following three featuresincludes the following three features : :villous atrophyvillous atrophysymptoms of malabsorption symptoms of malabsorption such as such as

steatorrhea, weight loss, or other signs of nutrient steatorrhea, weight loss, or other signs of nutrient or vitamin deficiencyor vitamin deficiency

resolution of the mucosal lesions resolution of the mucosal lesions and and symptoms upon withdrawal of gluten-containing symptoms upon withdrawal of gluten-containing

foods, usually within a few weeks to monthsfoods, usually within a few weeks to months . .

Patients with classic disease present with Patients with classic disease present with diarrhea, weight loss, or malabsorption, and diarrhea, weight loss, or malabsorption, and

possess antibodies against gliadin and especially possess antibodies against gliadin and especially tissue transglutaminasetissue transglutaminase..

CLASSIFICATIONCLASSIFICATION Atypical celiac diseaseAtypical celiac disease::

Patients with atypical disease exhibit only Patients with atypical disease exhibit only minor gastrointestinal complaintsminor gastrointestinal complaints . .

They can display They can display anemiaanemia, , dental enamel dental enamel defectsdefects, , osteoporosisosteoporosis, , arthritisarthritis, , increased increased

transaminasestransaminases, , neurological symptomsneurological symptoms, , or or infertilityinfertility . .

However, most of these patients show severe However, most of these patients show severe mucosal damage and possess the celiac mucosal damage and possess the celiac

specific antibody patternspecific antibody pattern..

CLASSIFICATIONCLASSIFICATION Asymptomatic (silent) celiac diseaseAsymptomatic (silent) celiac disease: :

Patients are often Patients are often recognized incidentally recognized incidentally

based upon screenings for antibodies based upon screenings for antibodies against gliadin or tissue transglutaminaseagainst gliadin or tissue transglutaminase . .

Although these patients Although these patients very often display the very often display the characteristic architectural remodelling of the characteristic architectural remodelling of the

intestinal mucosa seen in celiac disease intestinal mucosa seen in celiac disease (ie, crypt (ie, crypt hyperplasia and villous atrophy), they hyperplasia and villous atrophy), they do not do not

show clinical symptomsshow clinical symptoms . .

Often minor symptoms Often minor symptoms (eg, fatigue) (eg, fatigue) are only are only realized after introduction of a gluten free dietrealized after introduction of a gluten free diet..

CLASSIFICATIONCLASSIFICATION Latent celiac diseaseLatent celiac disease

There are some patients who have There are some patients who have normal jejunal mucosa normal jejunal mucosa and minor symptoms or and minor symptoms or no symptoms no symptoms at one or more time at one or more time

points while on a normal, gluten-containing dietpoints while on a normal, gluten-containing diet . .

Two variants of what has been called latent celiac disease Two variants of what has been called latent celiac disease have been identifiedhave been identified::

Celiac disease was present before, usually in childhood; the Celiac disease was present before, usually in childhood; the patient recovered completely with a gluten-free diet, remaining patient recovered completely with a gluten-free diet, remaining

"silent" even when a normal diet was reintroduced. About 20 "silent" even when a normal diet was reintroduced. About 20 percent of such patients continue to have latent disease percent of such patients continue to have latent disease

(asymptomatic with normal villous architecture) into adulthood, (asymptomatic with normal villous architecture) into adulthood, while the others re-develop variable degrees of villous atrophy . while the others re-develop variable degrees of villous atrophy . Latency may be transient Latency may be transient and thus regular follow up of such and thus regular follow up of such

patients is warrantedpatients is warranted..

A normal mucosa was diagnosed at an earlier occasion while A normal mucosa was diagnosed at an earlier occasion while ingesting a normal diet, but celiac disease developed lateringesting a normal diet, but celiac disease developed later..

CLINICAL MANIFESTATIONSCLINICAL MANIFESTATIONSGastrointestinal manifestationsGastrointestinal manifestations — Patients may — Patients may

present with classic signs, including diarrhea with bulky, present with classic signs, including diarrhea with bulky, foul-smelling, floating stools due to steatorrhea and foul-smelling, floating stools due to steatorrhea and

flatulenceflatulence . .

These symptoms are paralleled by the These symptoms are paralleled by the consequences of consequences of malabsorption,malabsorption, such as growth failure in children, such as growth failure in children,

weight loss, severe anemia, neurologic disorders from weight loss, severe anemia, neurologic disorders from deficiencies of B vitamins, and osteopenia from deficiency deficiencies of B vitamins, and osteopenia from deficiency

of vitamin D and calciumof vitamin D and calcium . .

However, there is a shift from fewer patients presenting However, there is a shift from fewer patients presenting with classic celiac disease to with classic celiac disease to more patients with more patients with

atypical symptoms atypical symptoms or an asymptomatic presentationor an asymptomatic presentation

Adult patients with undiagnosed celiac disease Adult patients with undiagnosed celiac disease rarelyrarely present with profuse diarrhea and severe metabolic present with profuse diarrhea and severe metabolic

disturbances (disturbances (celiac crisisceliac crisis))

CLINICAL MANIFESTATIONSCLINICAL MANIFESTATIONSSubclinical diseaseSubclinical disease most patients have mild most patients have mild

and unspecific symptoms, such as fatigue, borderline and unspecific symptoms, such as fatigue, borderline iron deficiency or otherwise unexplained elevations in iron deficiency or otherwise unexplained elevations in

serum aminotransferases, or no symptoms at all. serum aminotransferases, or no symptoms at all. Those without any specific complaints may be Those without any specific complaints may be

diagnosed during screening programs or during diagnosed during screening programs or during endoscopy performed for other reasonsendoscopy performed for other reasons. .

Establishing the diagnosis of subclinical celiac disease Establishing the diagnosis of subclinical celiac disease is ofis of

potential importance potential importance for four reasonsfor four reasons : :

the danger of malignancythe danger of malignancythe presence of unsuspected nutritional deficienciesthe presence of unsuspected nutritional deficienciesthe association with low-birth weight infants in the association with low-birth weight infants in

affected mothersaffected mothersthe occurrence of autoimmune disordersthe occurrence of autoimmune disorders . .

Nongastrointestinal manifestationsNongastrointestinal manifestations

Neuropsychiatric diseaseNeuropsychiatric disease

Neurologic symptoms most often include Neurologic symptoms most often include headacheheadache, , dysthymiadysthymia, and , and peripheral neuropathyperipheral neuropathy

Peripheral neuropathiesPeripheral neuropathies, characterized by burning, tingling, and , characterized by burning, tingling, and numbness in hands and feet, found in 50% of patients and may precede numbness in hands and feet, found in 50% of patients and may precede

the diagnosis of celiac diseasethe diagnosis of celiac disease

A A gluten free diet gluten free diet has been shown to have a favorable effect on has been shown to have a favorable effect on headache and dysthymia, but headache and dysthymia, but not on peripheral neuropathiesnot on peripheral neuropathies

The correlation of celiac disease with depression is still unclear. A similar The correlation of celiac disease with depression is still unclear. A similar discrepancy in the association of celiac disease with epilepsy was noteddiscrepancy in the association of celiac disease with epilepsy was noted..

Other cause of neuropathy:In some patients, neurologic deficits can Other cause of neuropathy:In some patients, neurologic deficits can result from vitamin deficiencies, such as deficiencies in vitamins B1 result from vitamin deficiencies, such as deficiencies in vitamins B1

(thiamine), B2 (riboflavin), B3 (niacin), B6 (pyridoxine), B12 (cobalamine), (thiamine), B2 (riboflavin), B3 (niacin), B6 (pyridoxine), B12 (cobalamine), and E. However, vitamin deficiency syndromes are uncommon in the and E. However, vitamin deficiency syndromes are uncommon in the

absence of severe and extensive small bowel involvement. In addition, absence of severe and extensive small bowel involvement. In addition, neuropathies may be associated with lymphomaneuropathies may be associated with lymphoma

Nongastrointestinal Nongastrointestinal manifestationsmanifestations

Arthritis Arthritis — A higher prevalence of osteoarthritis has — A higher prevalence of osteoarthritis has been described in celiac disease, but whether there is a been described in celiac disease, but whether there is a

causal relationship is unclearcausal relationship is unclear..

Iron deficiencyIron deficiency — Celiac disease may be a — Celiac disease may be a surprisingly frequent cause of iron deficiency anemia. surprisingly frequent cause of iron deficiency anemia.

The incidence was The incidence was 20 percent 20 percent in the subgroup of in the subgroup of nonresponders to supplemental ironnonresponders to supplemental iron..

Some reports have suggested that celiac disease can be Some reports have suggested that celiac disease can be associated with occult gastrointestinal bleeding. associated with occult gastrointestinal bleeding.

However, the positive results with colorimetric tests may However, the positive results with colorimetric tests may have been due to have been due to excess loss of intestinal cellsexcess loss of intestinal cells

and/or and/or malabsorption of peroxidase-containing malabsorption of peroxidase-containing foodsfoods rather than loss of red blood cells . Furthermore, rather than loss of red blood cells . Furthermore,

one study found that occult bleeding was no more one study found that occult bleeding was no more common in patients with celiac disease compared with a common in patients with celiac disease compared with a

control population . control population . Thus, occult gastrointestinal Thus, occult gastrointestinal bleeding may not be a major contributor to iron bleeding may not be a major contributor to iron

deficiencydeficiency..

Nongastrointestinal Nongastrointestinal manifestationsmanifestations Metabolic bone diseaseMetabolic bone disease — Metabolic bone — Metabolic bone

disease is common in celiac disease and can occur disease is common in celiac disease and can occur in patients without gastrointestinal symptomsin patients without gastrointestinal symptoms

In In adultsadults, , loss of bone density in the peripheral loss of bone density in the peripheral skeleton may persistskeleton may persist despite apparent despite apparent

normalization at axial skeletal sites after patients normalization at axial skeletal sites after patients are on a gluten free dietare on a gluten free diet. .

In contrast, in a study of 30 In contrast, in a study of 30 childrenchildren and and adolescents maintained on a long-term gluten-free adolescents maintained on a long-term gluten-free

diet (average 10.7 years), bone mineral density and diet (average 10.7 years), bone mineral density and serum markers of bone metabolism serum markers of bone metabolism completely completely

normalizednormalized . .

Data suggest that the Data suggest that the risk of fractures is only risk of fractures is only slightly increasedslightly increased in patients with celiac disease in patients with celiac disease..

Nongastrointestinal Nongastrointestinal manifestationsmanifestations

HyposplenismHyposplenism — Several case reports have described — Several case reports have described hyposplenism in association with celiac disease the hyposplenism in association with celiac disease the

pathogenesis of which is unknown. pathogenesis of which is unknown. Prophylactic Prophylactic pneumococcal vaccination pneumococcal vaccination has been suggestedhas been suggested . .

Kidney diseaseKidney disease — — Glomerular IgA deposition is Glomerular IgA deposition is commoncommon, occurring in as many as one-third of patients. , occurring in as many as one-third of patients. The great majority of affected patients have The great majority of affected patients have no clinical no clinical

manifestations manifestations of renal disease, perhaps because there of renal disease, perhaps because there is is no associated activation of complementno associated activation of complement

Idiopathic pulmonary Idiopathic pulmonary hemosiderosishemosiderosis — Coexistence of celiac disease and — Coexistence of celiac disease and

idiopathic pulmonary hemosiderosis, also known as idiopathic pulmonary hemosiderosis, also known as Lane-Lane-Hamilton syndromeHamilton syndrome, has been reported in a number of , has been reported in a number of

cases, and introduction of a gluten-free diet has been cases, and introduction of a gluten-free diet has been associated with remission of pulmonary symptoms in associated with remission of pulmonary symptoms in

several patientsseveral patients..

RISK OF MALIGNANCY AND RISK OF MALIGNANCY AND MORTALITYMORTALITY

A number of observational studies have noted A number of observational studies have noted a a small absolute increase in overall small absolute increase in overall

mortality mortality in patients with celiac disease in patients with celiac disease compared with the general populationcompared with the general population . .

Estimates of the magnitude of risk have Estimates of the magnitude of risk have differed in various reports, many of which differed in various reports, many of which

were small, based upon referral populations, were small, based upon referral populations, and had several and had several methodologic limitationsmethodologic limitations. . In addition, the increase in some studies was In addition, the increase in some studies was

limited to non-Hodgkin's lymphomalimited to non-Hodgkin's lymphoma..

ASSOCIATED CONDITIONSASSOCIATED CONDITIONS Dermatitis herpetiformisDermatitis herpetiformis

Dermatitis herpetiformis is a condition characterized by pruritic Dermatitis herpetiformis is a condition characterized by pruritic papulovesicles over the external surface of the extremities and on the papulovesicles over the external surface of the extremities and on the

trunktrunk

The diagnosis is confirmed histologically by the demonstration of The diagnosis is confirmed histologically by the demonstration of granular IgA depositsgranular IgA deposits along the nonaffected subepidermal along the nonaffected subepidermal

basement membranebasement membrane..

Similar to celiac disease, antibodies against tissue transglutaminase Similar to celiac disease, antibodies against tissue transglutaminase (anti-tTG) are elevated in patients with the disease. The (anti-tTG) are elevated in patients with the disease. The

autoantibodies are directed autoantibodies are directed mainly against epidermal mainly against epidermal transglutaminasetransglutaminase, which shows high sequence homology to tTG, which shows high sequence homology to tTG

Dermatitis herpetiformis is common among patients with celiac Dermatitis herpetiformis is common among patients with celiac diseasedisease

Although the Although the celiac disease in patients with dermatitis celiac disease in patients with dermatitis herpetiformis is often asymptomaticherpetiformis is often asymptomatic, , the skin lesions in most the skin lesions in most

patients respond to gluten withdrawalpatients respond to gluten withdrawal

Herpetiform clusters of vesicles on an erythematous, edamatous base with

crusts and postinflammatory pigmentation on the upper back and

shoulder.

Dermatitis herpetiformis

ASSOCIATED CONDITIONSASSOCIATED CONDITIONS Diabetes mellitusDiabetes mellitus Celiac disease is closely associated with type 1 diabetes Celiac disease is closely associated with type 1 diabetes

mellitusmellitus . .

Between Between 2.6 and 7.8 percent 2.6 and 7.8 percent of adults with type 1 of adults with type 1 diabetes had IgA autoantibodies to endomysium or to tissue diabetes had IgA autoantibodies to endomysium or to tissue

transglutaminasetransglutaminase ; ;mostmost such patients were proven to such patients were proven to have celiac disease have celiac disease

with small bowel biopsywith small bowel biopsy. . ManyMany such patients had such patients had no overt clinical no overt clinical

manifestations manifestations of celiac diseaseof celiac disease . .

Type 1 diabetes and celiac disease share multiple genetic Type 1 diabetes and celiac disease share multiple genetic loci such as HLA-DR3, HLA-DQ2 (HLA-DQ8) and several loci such as HLA-DR3, HLA-DQ2 (HLA-DQ8) and several

genetic variations . This suggests that type 1 diabetes and genetic variations . This suggests that type 1 diabetes and celiac disease have celiac disease have common features in their common features in their

pathogenesis pathogenesis such as tissue damage from autoimmunity such as tissue damage from autoimmunity or intolerance to dietary antigensor intolerance to dietary antigens . .

ASSOCIATED CONDITIONSASSOCIATED CONDITIONS Whether Whether a gluten-free diet improves diabetesa gluten-free diet improves diabetes

in diabetic patients with celiac disease is in diabetic patients with celiac disease is unclearunclear

Furthermore, the very early supplementation of Furthermore, the very early supplementation of newborns diet with gluten (<3 months) showed an newborns diet with gluten (<3 months) showed an

increased risk for islet autoantibodies, which increased risk for islet autoantibodies, which precede type 1 diabetes mellitusprecede type 1 diabetes mellitus

prospective clinical studies are required to clarify prospective clinical studies are required to clarify the relationship between celiac disease, type 1 the relationship between celiac disease, type 1 diabetes, and other secondary autoimmunitiesdiabetes, and other secondary autoimmunities..

ASSOCIATED CONDITIONSASSOCIATED CONDITIONS Selective IgA deficiencySelective IgA deficiency

An association between selective IgA deficiency and celiac An association between selective IgA deficiency and celiac disease appears to be well-established as screening disease appears to be well-established as screening

programs have detected celiac disease in up to programs have detected celiac disease in up to 8 percent 8 percent of patientsof patients

On the other hand, selective IgA deficiency occurs in On the other hand, selective IgA deficiency occurs in 1 to 2 1 to 2 percent percent of patients with celiac diseaseof patients with celiac disease

Screening for celiac disease in patients with IgA deficiency Screening for celiac disease in patients with IgA deficiency is best done using an is best done using an IgG test for tissue IgG test for tissue

transglutaminasetransglutaminase..

Down syndrome Down syndrome — There appears to be a — There appears to be a strong strong association association between Down syndrome and celiac disease. between Down syndrome and celiac disease.

The prevalence of biopsy proven celiac disease has been The prevalence of biopsy proven celiac disease has been reported to be as high as 16 percent, representing a reported to be as high as 16 percent, representing a 20-20-

fold increasefold increase compared with the general population compared with the general population

ASSOCIATED CONDITIONSASSOCIATED CONDITIONS Liver diseaseLiver disease celiac disease may be associated with celiac disease may be associated with nonspecific nonspecific

mild chronic elevation in serum mild chronic elevation in serum aminotransferase aminotransferase levels (AST ranging from 29 to levels (AST ranging from 29 to

80, and ALT ranging from 60 to 130 with the ALT 80, and ALT ranging from 60 to 130 with the ALT usually slightly greater than ASTusually slightly greater than AST . .

A meta-analysis found that in patients with cryptogenic A meta-analysis found that in patients with cryptogenic hypertransaminasemia, hypertransaminasemia, celiac serologies were celiac serologies were

positive in positive in six percent six percent and and duodenal biopsies duodenal biopsies suggested celiac disease suggested celiac disease in four percentin four percent

In addition, the meta-analysis found abnormal serum In addition, the meta-analysis found abnormal serum transaminases in 27 percent of patients with newly transaminases in 27 percent of patients with newly

diagnosed celiac disease. When a gluten free diet was diagnosed celiac disease. When a gluten free diet was followed, serum transaminases normalized in 63 to 90 followed, serum transaminases normalized in 63 to 90

percent of patients within a yearpercent of patients within a year . .

ASSOCIATED CONDITIONSASSOCIATED CONDITIONS

Celiac disease has also been associated with Celiac disease has also been associated with advanced liver diseaseadvanced liver disease

One report, for example, focused on four patients with One report, for example, focused on four patients with severe liver disease (due to congenital liver fibrosis, severe liver disease (due to congenital liver fibrosis,

massive steatosis, and progressive hepatitis of unclear massive steatosis, and progressive hepatitis of unclear origin) and untreated celiac disease. Hepatic dysfunction origin) and untreated celiac disease. Hepatic dysfunction

reversed in all patients following a gluten-free dietreversed in all patients following a gluten-free diet

Although the number of patients studied is small, these Although the number of patients studied is small, these data suggest that data suggest that celiac disease may contribute to celiac disease may contribute to

or be the cause of serious liver diseaseor be the cause of serious liver disease, which may , which may improve following a gluten-free dietimprove following a gluten-free diet..


The association between celiac disease and The association between celiac disease and primary primary biliary cirrhosis (PBC) biliary cirrhosis (PBC) has also been described has also been described

in other reportsin other reports . .

Two studies suggested a prevalence of 6 to 11 percent Two studies suggested a prevalence of 6 to 11 percent in patients with PBC , although these may be in patients with PBC , although these may be

overestimatesoverestimates . .No cases of celiac disease were detected in 65 No cases of celiac disease were detected in 65

patients with PBC in a study from Italypatients with PBC in a study from Italy. .

Recognition of celiac disease in patients with PBC may Recognition of celiac disease in patients with PBC may be important since both diseases impact negatively be important since both diseases impact negatively

upon bone mineralization and are risk factors for upon bone mineralization and are risk factors for osteoporosisosteoporosis

ASSOCIATED CONDITIONSASSOCIATED CONDITIONS Thyroid diseaseThyroid disease — There is an increased incidence — There is an increased incidence

of autoimmune thyroid disease among patients with of autoimmune thyroid disease among patients with celiac disease. celiac disease. Hypothyroidism is more frequent Hypothyroidism is more frequent

than hyperthyroidismthan hyperthyroidism..

Gastroesophageal reflux diseaseGastroesophageal reflux disease — An — An association of celiac disease with gastroesophageal association of celiac disease with gastroesophageal

reflux disease (GERD) has been reportedreflux disease (GERD) has been reported . .

Eosinophilic esophagitisEosinophilic esophagitis — The incidence of — The incidence of eosinophilic esophagitis is increased in both children eosinophilic esophagitis is increased in both children

and adults with celiac disease (age-adjusted and sex-and adults with celiac disease (age-adjusted and sex-adjusted SIR 16.0, 95% CI 8.7-25.5) .A diagnosis of adjusted SIR 16.0, 95% CI 8.7-25.5) .A diagnosis of

eosinophilic esophagitis should be considered in eosinophilic esophagitis should be considered in patients with celiac disease and dysphagia or patients with celiac disease and dysphagia or

persistent refluxpersistent reflux..


Inflammatory bowel diseaseInflammatory bowel disease

Several case series have demonstrated an association Several case series have demonstrated an association between celiac disease and inflammatory bowel disease, between celiac disease and inflammatory bowel disease,

more frequently with ulcerative colitis than Crohn’s more frequently with ulcerative colitis than Crohn’s diseasedisease

In one case-control study, the In one case-control study, the risk of IBD in patients with risk of IBD in patients with celiac celiac disease was disease was elevated 10-fold elevated 10-fold while the while the risk of risk of

celiac disease in patients with IBD celiac disease in patients with IBD was was comparable to comparable to controlscontrols

One study demonstrated that first-degree relatives of One study demonstrated that first-degree relatives of patients with celiac disease may be at a fivefold increased patients with celiac disease may be at a fivefold increased

risk of developing ulcerative colitis as compared to the risk of developing ulcerative colitis as compared to the general populationgeneral population


Menstrual and reproductive issuesMenstrual and reproductive issues — Women — Women with untreated celiac disease may have an with untreated celiac disease may have an

increased frequency of reproductive increased frequency of reproductive abnormalitiesabnormalities: later menarche, earlier : later menarche, earlier

menopause, secondary amenorrhea, recurrent menopause, secondary amenorrhea, recurrent miscarriage, and infertilitymiscarriage, and infertility

Male infertilityMale infertility, characterized by abnormalities in , characterized by abnormalities in sperm motility and morphology as well as a sperm motility and morphology as well as a

biochemical picture of biochemical picture of androgen resistance androgen resistance (high (high serum testosterone and high LH concentrations), serum testosterone and high LH concentrations),

has been reported in celiac diseasehas been reported in celiac disease

ASSOCIATED CONDITIONSASSOCIATED CONDITIONS Myocarditis and cardiomyopathyMyocarditis and cardiomyopathy Two reports from Italy suggest that celiac disease, which is often Two reports from Italy suggest that celiac disease, which is often

clinically unsuspected, accounts for as many as clinically unsuspected, accounts for as many as 5 percent of 5 percent of patients with autoimmune myocarditis or idiopathic patients with autoimmune myocarditis or idiopathic

dilateddilated

Atrophic glossitisAtrophic glossitis — Oral lesions (erythema or atrophy) and a — Oral lesions (erythema or atrophy) and a soreness or burning sensation of the tongue have been described soreness or burning sensation of the tongue have been described

in association with celiac disease and respond to a gluten free diet in association with celiac disease and respond to a gluten free diet . . Oral symptoms are frequent in patients with classical Oral symptoms are frequent in patients with classical

celiac diseaseceliac disease, thus the involvement of the oral cavity is a , thus the involvement of the oral cavity is a helpful tool in diagnosis of celiac diseasehelpful tool in diagnosis of celiac disease..

PancreatitisPancreatitis — A large database study described an increased — A large database study described an increased risk of pancreatitis (both acute and chronic) in patients with celiac risk of pancreatitis (both acute and chronic) in patients with celiac

disease diagnosed in adulthood . disease diagnosed in adulthood . Further studies are needed Further studies are needed to to clarify the strength of the association and potential mechanisms clarify the strength of the association and potential mechanisms

that underlie itthat underlie it..

Ischemic heart diseaseIschemic heart disease — Some studies suggest that patients — Some studies suggest that patients with celiac disease are at increased risk for ischemic heart diseasewith celiac disease are at increased risk for ischemic heart disease

..

Diagnosis of celiac Diagnosis of celiac diseasedisease

Categories of celiac diseaseCategories of celiac diseaseThe classical formThe classical form, characterized by fully developed villous , characterized by fully developed villous

atrophy and features of intestinal malabsorptionatrophy and features of intestinal malabsorption..The atypical formThe atypical form, characterized by fully developed villous , characterized by fully developed villous

atrophy in the setting of milder clinical features such as iron atrophy in the setting of milder clinical features such as iron deficiency, osteoporosis, short stature, and/or infertility. Despite deficiency, osteoporosis, short stature, and/or infertility. Despite

the historical title of "atypical", this form is the most commonthe historical title of "atypical", this form is the most common..The silent form The silent form in which villous atrophy is found after testing in which villous atrophy is found after testing

asymptomatic patients (eg, because of a family history of celiac asymptomatic patients (eg, because of a family history of celiac disease or during an upper endoscopy performed for another disease or during an upper endoscopy performed for another

reason)reason)..A potential form A potential form in those who have never had a biopsy in those who have never had a biopsy

consistent with celiac disease, but show serologic and/or consistent with celiac disease, but show serologic and/or immunologic abnormalities characteristic for the disorder. This is immunologic abnormalities characteristic for the disorder. This is

most often detected in patients with a family history of celiac most often detected in patients with a family history of celiac diseasedisease..

A latent form A latent form in patients who had a previous diagnosis of in patients who had a previous diagnosis of celiac disease that responded to gluten withdrawal but retained celiac disease that responded to gluten withdrawal but retained

normal villous architecture after gluten reintroduction. The latent normal villous architecture after gluten reintroduction. The latent form also refers to patients with elevated IgA tTG serology but form also refers to patients with elevated IgA tTG serology but

normal intestinal mucosa who may subsequently develop celiac normal intestinal mucosa who may subsequently develop celiac diseasedisease..

WHO SHOULD BE TESTEDWHO SHOULD BE TESTED

.1.1 Those with gastrointestinal Those with gastrointestinal symptomssymptoms

chronic or recurrent diarrheachronic or recurrent diarrheaMalabsorptionMalabsorptionweight lossweight lossabdominal distension or bloatingabdominal distension or bloatingpatients with symptoms suggestive for IBSpatients with symptoms suggestive for IBSsevere lactose intolerancesevere lactose intolerance..

WHO SHOULD BE TESTEDWHO SHOULD BE TESTED.2.2Individuals without other explanations Individuals without other explanations

for signs and symptomsfor signs and symptoms Iron deficiency anemiaIron deficiency anemiafolate or vitamin B12 deficiencyfolate or vitamin B12 deficiencypersistent elevation in serum aminotransferasespersistent elevation in serum aminotransferases , ,short statureshort stature delayed pubertydelayed pubertyrecurrent fetal lossrecurrent fetal loss low birthweight infantslow birthweight infantsreduced fertilityreduced fertility persistent aphthous stomatitispersistent aphthous stomatitis dental enamel hypoplasiadental enamel hypoplasia idiopathic peripheral neuropathyidiopathic peripheral neuropathy nonhereditary cerebellar ataxianonhereditary cerebellar ataxiarecurrent migraine headachesrecurrent migraine headaches..

WHO SHOULD BE TESTEDWHO SHOULD BE TESTED

.3.3Symptomatic individuals at high Symptomatic individuals at high risk for celiac diseaserisk for celiac disease

patients with type 1 diabetes mellituspatients with type 1 diabetes mellitus other autoimmune disordersother autoimmune disordersfirst- and second-degree relatives of first- and second-degree relatives of

individuals with celiac diseaseindividuals with celiac diseasepatients with Turner, Down, or Williams patients with Turner, Down, or Williams

syndromessyndromes..

WHO SHOULD NOT BE TESTEDWHO SHOULD NOT BE TESTED

.1.1screening of the screening of the general population general population is is not recommendednot recommended . .

.2.2Screening of patients with Screening of patients with osteoporosisosteoporosis is also not recommended in the is also not recommended in the consensus statement since the consensus statement since the

prevalence of celiac disease is not prevalence of celiac disease is not significantly increased among the significantly increased among the

general population of patients with general population of patients with osteoporosisosteoporosis..

Serologic evaluationSerologic evaluation As a general rule, testing should begin with serologic As a general rule, testing should begin with serologic

evaluation. As will be discussed below, the most sensitive evaluation. As will be discussed below, the most sensitive and specific tests are and specific tests are IgA anti tissue IgA anti tissue

transglutaminase transglutaminase and and IgA endomysial antibodyIgA endomysial antibody, , which have equivalent diagnostic accuracywhich have equivalent diagnostic accuracy..

By contrast, antigliadin antibody tests are no longer used By contrast, antigliadin antibody tests are no longer used routinely because of their lower sensitivity and specificityroutinely because of their lower sensitivity and specificity..

However, a second generation AGA test (However, a second generation AGA test (Deamidated Deamidated Gliadin Peptide [DGPGliadin Peptide [DGP]) yielded far higher diagnostic ]) yielded far higher diagnostic

accuracy (sensitivity 94 percent, specificity 99 accuracy (sensitivity 94 percent, specificity 99 percent) .the combination of anti-tTG and DGP serology percent) .the combination of anti-tTG and DGP serology

may become a powerful non-invasive pairing for serologic may become a powerful non-invasive pairing for serologic diagnosis of celiac diseasediagnosis of celiac disease . .

Serologic testing may not be as accurate in children less Serologic testing may not be as accurate in children less than age five and is less accurate before age twothan age five and is less accurate before age two..

Testing on a gluten-rich dietTesting on a gluten-rich diet All diagnostic tests should be performed while the All diagnostic tests should be performed while the

patient is on a gluten-rich dietpatient is on a gluten-rich diet . .

Some patients may have already begun a low gluten Some patients may have already begun a low gluten diet before undergoing formal evaluation and thus diet before undergoing formal evaluation and thus

may have normal results from antibody testing. Such may have normal results from antibody testing. Such patients should be advised to consider patients should be advised to consider resuming a resuming a

gluten-rich diet for 2 to 12 weeks gluten-rich diet for 2 to 12 weeks before antibody before antibody titers are drawntiters are drawn

Antibody levels remain elevated for varying lengths of Antibody levels remain elevated for varying lengths of time (time (1 to 12 months1 to 12 months) after patients with celiac ) after patients with celiac

disease begin a gluten-free diet. disease begin a gluten-free diet. Thus, antibody Thus, antibody testing in patients who have only recently testing in patients who have only recently

begun a gluten-free diet is reasonable begun a gluten-free diet is reasonable and may and may yield a positive result, although testing while on a yield a positive result, although testing while on a

gluten containing diet is preferable to exclude celiac gluten containing diet is preferable to exclude celiac diseasedisease..

Small bowel biopsySmall bowel biopsyPatients with a positive IgA endomysial or Patients with a positive IgA endomysial or

transglutaminase antibody test should undergo a transglutaminase antibody test should undergo a small bowel biopsysmall bowel biopsy . .

ExceptionsExceptions are those who have are those who have biopsy-proven biopsy-proven dermatitis herpetiformis dermatitis herpetiformis in whom the diagnosis in whom the diagnosis

can be established without a small bowel biopsycan be established without a small bowel biopsy..

Multiple biopsies should be obtained from the Multiple biopsies should be obtained from the duodenal bulb duodenal bulb and the and the secondsecond and and third third portion portion

of the duodenumof the duodenum

Duodenal bulb biopsies Duodenal bulb biopsies should be clearly labeled should be clearly labeled as such to help ensure that the pathologist takes as such to help ensure that the pathologist takes

into account the different mucosal architecture of into account the different mucosal architecture of the bulb to avoid false positive reports of villous the bulb to avoid false positive reports of villous

atrophyatrophy . .

Small bowel biopsySmall bowel biopsyThe exact minimal number of duodenal The exact minimal number of duodenal

biopsies needed to make a diagnosis of celiac biopsies needed to make a diagnosis of celiac disease is uncertain, although some experts disease is uncertain, although some experts

believe that believe that at least fourat least four should be obtained should be obtained

The duodenal mucosa may appear atrophic The duodenal mucosa may appear atrophic with with loss of foldsloss of folds, contain , contain visible fissuresvisible fissures, ,

have a have a nodular appearance nodular appearance or the folds may or the folds may be be scallopedscalloped but such findings are not but such findings are not

universally present and may be seen with universally present and may be seen with other disordersother disorders

Staining techniques and high resolution Staining techniques and high resolution magnification endoscopy can help identify magnification endoscopy can help identify

areas of villous atrophy for biopsyareas of villous atrophy for biopsy..

A. The second duodenum is characterized

by circular folds termed valvulaeconniventes or Kerckring's valves. The

mucosa has a granular appearance. Thejunction of the second and third

duodenum(inferior duodenal angle )is seen in the

distance. B. The mucosa may have afrosty white appearance.

C. The duodenalmucosa is characterized by slender

villicomposed of goblet cells.

Marsh-Oberhuber classificationMarsh-Oberhuber classification

Marsh 0 (preinfiltrative): Marsh 0 (preinfiltrative): less than 30 less than 30 intraepithelial lymphocytes (IELs) per 100 enterocytes, intraepithelial lymphocytes (IELs) per 100 enterocytes,

normal villi and crypts. This finding represents to normal villi and crypts. This finding represents to normal histologynormal histology..

Marsh 1 (infiltrative): Marsh 1 (infiltrative): more than 30 IELs per more than 30 IELs per 100 100 enterocytes, enterocytes, normal villi and cryptsnormal villi and crypts . .

This finding is nonspecific and can occur in early or This finding is nonspecific and can occur in early or mild celiac disease, but it may also be seen in healthy mild celiac disease, but it may also be seen in healthy

individuals, in patients with small intestinal bacterial individuals, in patients with small intestinal bacterial overgrowth, in Crohn’s disease, in other autoimmune overgrowth, in Crohn’s disease, in other autoimmune

disorders, in patients infected with Helicobacter pylori, disorders, in patients infected with Helicobacter pylori, in patients taking nonsteroidal antiinflammatory in patients taking nonsteroidal antiinflammatory

drugs, and in a variety of other situationsdrugs, and in a variety of other situations . .

Marsh 2 (infiltrative-hyperplastic): Marsh 2 (infiltrative-hyperplastic): more than more than 30 IELs per 100 enterocytes, 30 IELs per 100 enterocytes, normal villinormal villi, , crypt crypt

hyperplasiahyperplasia

Marsh 3a (flat destructive): Marsh 3a (flat destructive): more than 30 IELs more than 30 IELs per 100 enterocytes, per 100 enterocytes, mild villous atrophymild villous atrophy, ,

crypt hyperplasiacrypt hyperplasia

Marsh 3b (flat destructive): Marsh 3b (flat destructive): more than 30 IELs more than 30 IELs per 100 enterocytes, per 100 enterocytes, moderate villous moderate villous

atrophyatrophy, crypt hyperplasia, crypt hyperplasia

Marsh 3c (flat destructive): Marsh 3c (flat destructive): more than 30 IELs more than 30 IELs per 100 enterocytes, per 100 enterocytes, total villous atrophytotal villous atrophy, ,

crypt hyperplasiacrypt hyperplasia

Marsh 4 (atrophic-hypoplastic): Marsh 4 (atrophic-hypoplastic): more than 30 more than 30 IELs per 100 enterocytes, total villous atrophy, IELs per 100 enterocytes, total villous atrophy,

crypt hypoplasiacrypt hypoplasia

The diagnosis is The diagnosis is presumptivelypresumptively established when there is concordance established when there is concordance between the serologic results and the between the serologic results and the

biopsy findingsbiopsy findings . .

It is It is confirmedconfirmed when symptoms resolve when symptoms resolve subsequently on a gluten-free diet. subsequently on a gluten-free diet.

Demonstration of histologic Demonstration of histologic normalization is not always requirednormalization is not always required..

Suggestive clinical features but Suggestive clinical features but negative serologic testsnegative serologic tests

There are three main possibilities in those with There are three main possibilities in those with suggestive clinical features but negative serologic suggestive clinical features but negative serologic

teststests::The individual may have The individual may have selective IgA deficiencyselective IgA deficiency..The individual may The individual may already be on a low gluten dietalready be on a low gluten diet..The patient The patient may not have celiac disease may not have celiac disease in which case in which case

other causes of symptoms or villous atrophy should be other causes of symptoms or villous atrophy should be considered (table 1 and algorithm 2)considered (table 1 and algorithm 2)..

here are occasional patients in whom the diagnosis is here are occasional patients in whom the diagnosis is unclear despite the above. Such patients can unclear despite the above. Such patients can

undergo undergo testing for HLA testing for HLA haplotypes associated with haplotypes associated with celiac disease. More than 99 percent of patients with celiac disease. More than 99 percent of patients with celiac disease have HLA DQ2 and/or DQ8 compared celiac disease have HLA DQ2 and/or DQ8 compared

with about 40 percent of the general population. with about 40 percent of the general population. Thus, Thus, celiac disease is highly unlikely in celiac disease is highly unlikely in

patients without these haplotypespatients without these haplotypes

Positive serologic tests but negative small Positive serologic tests but negative small bowel biopsiesbowel biopsies

False positive tTGFalse positive tTG results are rare but do occur and results are rare but do occur and are are usually low titer usually low titer (typically less than twice the (typically less than twice the

upper limit of normal). upper limit of normal). Repeating the test using an Repeating the test using an assay that uses human tTG assay that uses human tTG as the capture antigen as the capture antigen

may resolve the discrepancy since older tTG tests using may resolve the discrepancy since older tTG tests using non-human tTG have more frequently been associated non-human tTG have more frequently been associated

with false positive resultswith false positive results . .

The intestinal biopsy should be reviewed The intestinal biopsy should be reviewed by a by a pathologist familiar with CD to look for subtle pathologist familiar with CD to look for subtle

abnormalities of CD such as an increase in IELsabnormalities of CD such as an increase in IELs . .

If these two steps do not reconcile the results, the If these two steps do not reconcile the results, the patient can be placed on a high gluten diet and, patient can be placed on a high gluten diet and,

after 6 to 12 weeks, numerous additional after 6 to 12 weeks, numerous additional biopsies obtainedbiopsies obtained from multiple sites in the mid and from multiple sites in the mid and distal duodenum since CD enteropathy can be patchy distal duodenum since CD enteropathy can be patchy

and missed due to sampling error. As noted above, and missed due to sampling error. As noted above, staining techniques and high resolution magnification staining techniques and high resolution magnification

endoscopy can help identify areas of villous atrophy for endoscopy can help identify areas of villous atrophy for biopsybiopsy..

Some patients have a positive serologic Some patients have a positive serologic test and only mild histologic changes test and only mild histologic changes

supportive of celiac disease. Patients with supportive of celiac disease. Patients with mild villous atrophy mild villous atrophy appear to appear to benefit benefit

from a gluten-free dietfrom a gluten-free diet . .

The response to gluten-free diet in The response to gluten-free diet in patients with an patients with an increase in increase in

intraepithelial lymphocytes intraepithelial lymphocytes but but normal villi is normal villi is less clearless clear

IgA EMA, IgA tTG, and IgA AGA levels IgA EMA, IgA tTG, and IgA AGA levels fall with treatmentfall with treatment ; ;

as a result, these assays can be used as a result, these assays can be used as a noninvasive means of as a noninvasive means of

monitoring the response to a gluten-monitoring the response to a gluten-free dietfree diet

IgA endomysial assayIgA endomysial assayEndomysial antibodies bind to connective tissue surrounding Endomysial antibodies bind to connective tissue surrounding

smooth muscle cellssmooth muscle cells

Frozen sections of monkey esophagus were initially used for Frozen sections of monkey esophagus were initially used for the assaythe assay . .

Currently, Currently, many laboratories use sections of human many laboratories use sections of human umbilical cord umbilical cord which are more readily available. Serum IgA which are more readily available. Serum IgA endomysial antibodies bind to the endomysium, producing a endomysial antibodies bind to the endomysium, producing a

characteristic staining pattern, which is visualized by characteristic staining pattern, which is visualized by indirect indirect immunofluorescenceimmunofluorescence . .

The test result is The test result is reported simply as positive or negative reported simply as positive or negative since even low titers of serum IgA endomysial antibodies are since even low titers of serum IgA endomysial antibodies are

specific for celiac disease. The target antigen has been specific for celiac disease. The target antigen has been identified as a tissue transglutaminaseidentified as a tissue transglutaminase

IgA endomysial antibody testing is IgA endomysial antibody testing is moderately sensitive moderately sensitive and and highly specifichighly specific for untreated celiac disease . Serum levels of for untreated celiac disease . Serum levels of

IgA endomysial antibody fall on a gluten-free diet and the IgA endomysial antibody fall on a gluten-free diet and the test test often becomes negative in treated patientsoften becomes negative in treated patients. .

Anti-tissue transglutaminase Anti-tissue transglutaminase antibodiesantibodies The antigen against which antiendomysial The antigen against which antiendomysial

antibodies are directed is a tissue transglutaminase antibodies are directed is a tissue transglutaminase (tTG)(tTG)

Anti-tTG antibodies were Anti-tTG antibodies were highly sensitive and highly sensitive and specific specific for the diagnosis of celiac disease in most for the diagnosis of celiac disease in most

reportsreports

ELISA tests for IgA anti-tTG antibodies are now ELISA tests for IgA anti-tTG antibodies are now widely availablewidely available and are easier to perform and and are easier to perform and less costly less costly than the immunofluorescence assay than the immunofluorescence assay

used to detect IgA endomysial antibodiesused to detect IgA endomysial antibodies..

The diagnostic The diagnostic accuracyaccuracy of IgA anti-tTG of IgA anti-tTG immunoassays has been immunoassays has been improved further by improved further by

the use of human tTG the use of human tTG in place of the non-human in place of the non-human tTG preparations used in earlier immunoassay kitstTG preparations used in earlier immunoassay kits..

Antigliadin antibody assaysAntigliadin antibody assaysGliadin is a component of the wheat storage protein Gliadin is a component of the wheat storage protein

glutengluten . .

Purified gliadin is readily available and is used as the Purified gliadin is readily available and is used as the antigen for enzyme-linked immunosorbent assays antigen for enzyme-linked immunosorbent assays

(ELISA) to detect serum antigliadin antibodies(ELISA) to detect serum antigliadin antibodies..

positive predictive value in a general population is positive predictive value in a general population is relatively poorrelatively poor

Antigliadin antibody test results are reported as a titer Antigliadin antibody test results are reported as a titer or level. A or level. A high titer of antigliadin antibody is high titer of antigliadin antibody is

somewhat more specific somewhat more specific for celiac disease than a low for celiac disease than a low titer, but titer, but some normal individuals have high serum some normal individuals have high serum

levels of antigliadin antibodylevels of antigliadin antibody . .

Antigliadin antibody levels decrease during treatment Antigliadin antibody levels decrease during treatment with a gluten-free dietwith a gluten-free diet..

Assay sensitivity and specificityAssay sensitivity and specificity A systematic review of the literature estimated A systematic review of the literature estimated

that the that the sensitivitysensitivity and and specificityspecificity of IgA of IgA endomysial and IgA tissue transglutaminase endomysial and IgA tissue transglutaminase

antibodies were antibodies were over 95 percentover 95 percent and and close to close to 100 percent100 percent, respectively, respectively

The following data come from our experienceThe following data come from our experience::IgA endomysial antibodies – sensitivity IgA endomysial antibodies – sensitivity 85 to 98 85 to 98

percent; specificity 97 to 100 percentpercent; specificity 97 to 100 percentIgA tissue transglutaminase antibodies – sensitivity IgA tissue transglutaminase antibodies – sensitivity

90 to 98 percent90 to 98 percent; specificity 95 to 97 percent; specificity 95 to 97 percentIgA antigliadin antibodies – sensitivity 80 to 90 IgA antigliadin antibodies – sensitivity 80 to 90

percent; specificity 85 to 95 percentpercent; specificity 85 to 95 percentIgG antigliadin antibodies – sensitivity 75 to 85 IgG antigliadin antibodies – sensitivity 75 to 85

percent; specificity 75 to 90 percentpercent; specificity 75 to 90 percent

Assay sensitivity and specificityAssay sensitivity and specificity

It is also important to consider the likelihood It is also important to consider the likelihood that the patient has the disease since, at a that the patient has the disease since, at a

given sensitivity and specificity, the given sensitivity and specificity, the pretest pretest probability of disease determines the probability of disease determines the

positive and negative predictive values positive and negative predictive values of of the testthe test

In addition to laboratory variation, the In addition to laboratory variation, the sensitivity of these tests may depend sensitivity of these tests may depend

upon the severity of the diseaseupon the severity of the disease..In one report, as an example, serum antibodies In one report, as an example, serum antibodies

were determined in 101 patients with biopsy were determined in 101 patients with biopsy proven celiac disease . The sensitivity of IgA proven celiac disease . The sensitivity of IgA

endomysial antibodies varied for 100 percent in endomysial antibodies varied for 100 percent in patients with total villous atrophy to only 31 patients with total villous atrophy to only 31 percent in those with partial villous atrophypercent in those with partial villous atrophy..

Role of antibodies in disease Role of antibodies in disease pathogenesispathogenesis

Antigliadin antibodies Antigliadin antibodies do do not appear to be essential for not appear to be essential for the pathogenesis the pathogenesis of celiac disease . Furthermore, many of celiac disease . Furthermore, many

normal individuals have increased IgA and/or IgG antigliadin normal individuals have increased IgA and/or IgG antigliadin levelslevels

In contrast, In contrast, IgA endomysial antibodies IgA endomysial antibodies are rarely found in are rarely found in the absence of gluten-sensitive enteropathy. However, patients the absence of gluten-sensitive enteropathy. However, patients

with celiac disease who lack these antibodies do with celiac disease who lack these antibodies do notnot differ in differ in their clinical presentation from those who are antibody positivetheir clinical presentation from those who are antibody positive . .

antibodies against antibodies against tissue transglutaminase tissue transglutaminase are of are of some some pathogenetic importancepathogenetic importance. Furthermore, tissue . Furthermore, tissue

transglutaminase enzymatically alters gliadin peptides to transglutaminase enzymatically alters gliadin peptides to increase their propensity to induce helper T-cell activation when increase their propensity to induce helper T-cell activation when

presented by DQ2 or DQ8 on antigen presenting cellspresented by DQ2 or DQ8 on antigen presenting cells . .

Individuals with celiac disease also have increased levels of Individuals with celiac disease also have increased levels of serumserum antibodies against other food proteins antibodies against other food proteins such as beta-such as beta-

lactoglobulin, casein, and ovalbumin . It is lactoglobulin, casein, and ovalbumin . It is not clear not clear whether whether this reflects a general aberrant immune responsiveness to food this reflects a general aberrant immune responsiveness to food antigens or results from enhanced systemic exposure to these antigens or results from enhanced systemic exposure to these

proteins because of increased small intestinal permeabilityproteins because of increased small intestinal permeability..

CLINICAL APPLICATION OF SEROLOGIC CLINICAL APPLICATION OF SEROLOGIC TESTSTESTS

Three different clinical circumstances Three different clinical circumstances should be considered when using serologic should be considered when using serologic studies in the diagnosis and management studies in the diagnosis and management

of celiac diseaseof celiac disease::

.1.1Evaluation of individuals with a Evaluation of individuals with a low pretest low pretest probability probability for celiac disease. Such patients for celiac disease. Such patients

may have undergone testing for celiac may have undergone testing for celiac disease during evaluation of common disease during evaluation of common

disorders such as irritable bowel syndrome, disorders such as irritable bowel syndrome, reduced fertility or osteoporosisreduced fertility or osteoporosis..

.2.2Evaluation of individuals with Evaluation of individuals with a moderate or a moderate or high pretest probabilityhigh pretest probability for celiac disease for celiac disease

.3.3Monitoring adherence and response Monitoring adherence and response to a to a gluten-free dietgluten-free diet

Individuals with a low risk for Individuals with a low risk for celiac diseaseceliac disease

AsymptomaticAsymptomatic patients patients without a family history of without a family history of celiac disease celiac disease or laboratory or clinical evidence for or laboratory or clinical evidence for

malabsorption can be considered to be low riskmalabsorption can be considered to be low risk

In the low-risk setting, the In the low-risk setting, the IgA endomysial antibody IgA endomysial antibody test has the highest diagnostic accuracy test has the highest diagnostic accuracy but is a little but is a little

more costly than the IgA tTG ELISA test.As noted above, more costly than the IgA tTG ELISA test.As noted above, the serum IgA tissue transglutaminase and IgA endomysial the serum IgA tissue transglutaminase and IgA endomysial

tests have similar sensitivities. A tests have similar sensitivities. A negative result for negative result for either test has a high negative predictive value either test has a high negative predictive value in in this situation and may obviate the need for small bowel this situation and may obviate the need for small bowel

biopsybiopsy..

IgG DGP IgG DGP testing can be used in patients with testing can be used in patients with IgA IgA deficiencydeficiency..

The specificities of the IgA endomysial and IgA tissue The specificities of the IgA endomysial and IgA tissue transglutaminase tests are high. Thus, their transglutaminase tests are high. Thus, their positive positive

predictive values are high even in low-risk predictive values are high even in low-risk populations populations In contrast, the specificities of IgA and IgG In contrast, the specificities of IgA and IgG

antigliadin tests are lower, and positive results have a low antigliadin tests are lower, and positive results have a low positive predictive value in low-risk populationspositive predictive value in low-risk populations

Individuals with a moderate or high risk for Individuals with a moderate or high risk for celiac diseaseceliac disease

When the pretest probability of celiac disease is When the pretest probability of celiac disease is perceived to be high (ie, greater than 5 percent), perceived to be high (ie, greater than 5 percent),

diagnosis is based upon diagnosis is based upon serologic tests and serologic tests and histologyhistology . .

Celiac disease is frequently associated with dermatitis Celiac disease is frequently associated with dermatitis herpetiformis, Down syndrome, selective IgA deficiency, herpetiformis, Down syndrome, selective IgA deficiency,

and other conditions that have autoimmune features and other conditions that have autoimmune features such as type 1 diabetes mellitus, thyroid disease, and such as type 1 diabetes mellitus, thyroid disease, and

autoimmune liver disease. Patients with autoimmune liver disease. Patients with these these conditions conditions or or a family history of celiac disease a family history of celiac disease can can be considered as being at increased risk. be considered as being at increased risk. Patients with Patients with suggestive clinical features suggestive clinical features such as severe diarrhea, such as severe diarrhea,

weight loss, or persistent anemia can also be weight loss, or persistent anemia can also be considered to be at high riskconsidered to be at high risk..

We recommend performing We recommend performing both IgA endomysial (or both IgA endomysial (or TTG) and small bowel biopsy TTG) and small bowel biopsy prior to dietary prior to dietary

treatmenttreatment . .

SCREENING IN ASYMPTOMATIC SCREENING IN ASYMPTOMATIC INDIVIDUALSINDIVIDUALS

Screening studies suggest that the incidence of CD in Screening studies suggest that the incidence of CD in whites of northern European ancestry may be as high as whites of northern European ancestry may be as high as

1:100 to 1:2501:100 to 1:250 . .

The benefit of population screening include: a reduction in The benefit of population screening include: a reduction in risk for enteropathy-associated T-cell lymphoma, a reversal risk for enteropathy-associated T-cell lymphoma, a reversal

of unrecognized nutritional deficiency states, resolution of of unrecognized nutritional deficiency states, resolution of mild or ignored intestinal symptoms, avoidance of other mild or ignored intestinal symptoms, avoidance of other autoimmune disorders, an improvement in general well-autoimmune disorders, an improvement in general well-

being, and a possible reduction in mortalitybeing, and a possible reduction in mortality..

Asymptomatic individuals may not be sufficiently motivated Asymptomatic individuals may not be sufficiently motivated to adhere to a strict gluten-free diet. There may also be to adhere to a strict gluten-free diet. There may also be

adverse psychological effects when asymptomatic adverse psychological effects when asymptomatic individuals receive a diagnosis of a chronic incurable individuals receive a diagnosis of a chronic incurable condition that demands substantial lifestyle changescondition that demands substantial lifestyle changes..

For these reasons, For these reasons, widespread screening of widespread screening of asymptomatic individuals is not generally advocated asymptomatic individuals is not generally advocated at this timeat this time, even in populations in which the prevalence , even in populations in which the prevalence

of celiac disease is highof celiac disease is high . .

OTHER NONINVASIVE TESTS FOR THE OTHER NONINVASIVE TESTS FOR THE DIAGNOSIS OF CELIAC DISEASEDIAGNOSIS OF CELIAC DISEASE

A variety of hematologic and biochemical abnormalities A variety of hematologic and biochemical abnormalities may be found in individuals with untreated celiac may be found in individuals with untreated celiac

disease including iron deficiency, folic acid deficiency, disease including iron deficiency, folic acid deficiency, and vitamin D deficiency. These abnormalities reflect and vitamin D deficiency. These abnormalities reflect

nutritional deficiency states secondary to enteropathy-nutritional deficiency states secondary to enteropathy-induced malabsorption. Although relevant to patient induced malabsorption. Although relevant to patient evaluation and management, evaluation and management, none is sufficiently none is sufficiently

sensitive or specificsensitive or specific to serve as useful screening or to serve as useful screening or diagnostic toolsdiagnostic tools

An oral xylose and/or lactulose absorption test, fecal fat An oral xylose and/or lactulose absorption test, fecal fat evaluation, small bowel radiographic study, or capsule evaluation, small bowel radiographic study, or capsule

endoscopy may also be abnormal in untreated celiac endoscopy may also be abnormal in untreated celiac disease, but will disease, but will not provide a specific diagnosisnot provide a specific diagnosis

HLA typing may be useful in patients who are already on HLA typing may be useful in patients who are already on a gluten-free diet without having achieved a firm a gluten-free diet without having achieved a firm

diagnosis. Those without HLA DQ2 or DQ8 are very diagnosis. Those without HLA DQ2 or DQ8 are very unlikely to have celiac diseaseunlikely to have celiac disease

SUMMARY AND SUMMARY AND RECOMMENDATIONSRECOMMENDATIONS

An approach to diagnosis of celiac disease is summarized in An approach to diagnosis of celiac disease is summarized in the following algorithm (algorithm 1). All testing should be the following algorithm (algorithm 1). All testing should be

performed while patients are on a gluten-containing dietperformed while patients are on a gluten-containing diet..

IgA deficiency is more common in celiac disease (2 to 5 IgA deficiency is more common in celiac disease (2 to 5 percent) than in the general population (<0.5 percent). The percent) than in the general population (<0.5 percent). The

IgA EMA and IgA tTG serology tests will be falsely negative in IgA EMA and IgA tTG serology tests will be falsely negative in untreated celiac disease in patients with IgA deficiency. As a untreated celiac disease in patients with IgA deficiency. As a result, result, total serum IgA total serum IgA can be measured in addition to IgA can be measured in addition to IgA EMA or IgA tTG especially when there is heightened clinical EMA or IgA tTG especially when there is heightened clinical

suspicion for celiac disease and IgA markers are negativesuspicion for celiac disease and IgA markers are negative . .

If total IgA levels are abnormally low, an IgG-based assay If total IgA levels are abnormally low, an IgG-based assay should be used to test for celiac disease. The IgG antigliadin should be used to test for celiac disease. The IgG antigliadin assay has been traditionally used in this circumstance but is assay has been traditionally used in this circumstance but is not ideal since it yields frequent false positive results. Thus, not ideal since it yields frequent false positive results. Thus,

serum IgG tTG or IgG DGP tests are preferableserum IgG tTG or IgG DGP tests are preferable. . Negative results upon testing for HLA DQ2 or DQ8 can also Negative results upon testing for HLA DQ2 or DQ8 can also

help exclude the diagnosis in this settinghelp exclude the diagnosis in this setting..

SUMMARY AND SUMMARY AND RECOMMENDATIONSRECOMMENDATIONS

A few controversies remain regarding confirmation of the A few controversies remain regarding confirmation of the diagnosisdiagnosis . .

SomeSome authorities recommend that a repeat small intestinal authorities recommend that a repeat small intestinal biopsy should be obtained 6 to 24 months after beginning a biopsy should be obtained 6 to 24 months after beginning a

gluten-free diet to demonstrate histologic improvementgluten-free diet to demonstrate histologic improvement . .

SomeSome also recommended a repeat small bowel biopsy (after also recommended a repeat small bowel biopsy (after a gluten rechallenge) following a gluten-free dieta gluten rechallenge) following a gluten-free diet . .

We do We do not believe that these approaches are not believe that these approaches are generally required generally required unless the diagnosis remains uncertain unless the diagnosis remains uncertain

based upon the serologic profile, histology and clinical based upon the serologic profile, histology and clinical response. Furthermore, these approaches are not response. Furthermore, these approaches are not

recommended in a consensus statement issued by the NIHrecommended in a consensus statement issued by the NIH

Management of Management of celiac disease in celiac disease in

adultsadults

IndicationsIndications — A gluten-free diet is — A gluten-free diet is recommended in patients with celiac recommended in patients with celiac

disease (disease (classic diseaseclassic disease, , atypical celiac atypical celiac diseasedisease, and , and asymptomatic or silent asymptomatic or silent

celiac celiac disease)disease)..

Patients with Patients with latent celiac disease latent celiac disease (positive IgA endomysial antibody, but (positive IgA endomysial antibody, but

normal small bowel biopsy) are normal small bowel biopsy) are currently currently not advised to be on a gluten-free diet not advised to be on a gluten-free diet

but should continue to be monitored and but should continue to be monitored and rebiopsied if symptoms developrebiopsied if symptoms develop . .

dietary advicedietary adviceFoods containing Foods containing wheat, rye, and barley wheat, rye, and barley should should

be be avoidedavoided..

Soybean or tapioca flours, rice, corn, buckwheat, Soybean or tapioca flours, rice, corn, buckwheat, and potatoes are safeand potatoes are safe..

Read labels on prepared foods and condiments Read labels on prepared foods and condiments carefully, paying particular attention to additives carefully, paying particular attention to additives

such as stabilizers or emulsifiers that may contain such as stabilizers or emulsifiers that may contain glutengluten..

Dairy products may not be well tolerated initially Dairy products may not be well tolerated initially since many patients with celiac disease can have since many patients with celiac disease can have

secondary lactose intolerance. As a result, secondary lactose intolerance. As a result, lactose-lactose-containing products containing products should initially be should initially be

avoided avoided in patients whose symptoms appear to be in patients whose symptoms appear to be worsened by themworsened by them..

dietary advicedietary adviceOatOat consumption should be limited to consumption should be limited to 50 to 60 50 to 60

g/day g/day in in patients with mild disease patients with mild disease upon upon presentation or presentation or whose disease is in remissionwhose disease is in remission

after a stringent gluten-free diet. The latter after a stringent gluten-free diet. The latter patients should be followed carefully for clinical or patients should be followed carefully for clinical or

serologic evidence of disease recurrence after serologic evidence of disease recurrence after reintroducing oatsreintroducing oats . .

Patients with Patients with severe disease severe disease should should avoid oats avoid oats altogetheraltogether..

Although gluten is also found in oats, the toxicity Although gluten is also found in oats, the toxicity of oats in celiac disease is now in doubt because of oats in celiac disease is now in doubt because some studies suggest that pure oat flour can be some studies suggest that pure oat flour can be

tolerated without disease recurrencetolerated without disease recurrence

Is strict gluten avoidance Is strict gluten avoidance necessarynecessary??

the ability to tolerate gluten in the diet is the ability to tolerate gluten in the diet is highly highly variablevariable among patients among patients . .

While some patients are exquisitely sensitive to While some patients are exquisitely sensitive to even small amounts of gluten, other patients can even small amounts of gluten, other patients can

tolerate the reintroduction of small amounts in tolerate the reintroduction of small amounts in their diet after achieving remissiontheir diet after achieving remission..

Despite this variable response, Despite this variable response, several several arguments favor encouraging strict arguments favor encouraging strict

adherence to a gluten-free diet adherence to a gluten-free diet in most in most patients with established celiac disease patients with established celiac disease

regardless of clinical symptomsregardless of clinical symptoms

MONITORING THE RESPONSE TO A MONITORING THE RESPONSE TO A GLUTEN-FREE DIETGLUTEN-FREE DIET

Approximately Approximately 70 percent 70 percent of patients have of patients have noticeable noticeable clinical improvement within two clinical improvement within two

weeksweeks

As a general rule, As a general rule, symptoms improve faster than symptoms improve faster than histologyhistology, especially when biopsies are obtained in , especially when biopsies are obtained in

the proximal intestinethe proximal intestine . .

The reason is incompletely understood; however, a The reason is incompletely understood; however, a possible explanation is that the possible explanation is that the less severely less severely

damaged distal small intestine recovers faster damaged distal small intestine recovers faster than the proximal intestine, which is typically more than the proximal intestine, which is typically more

severely affected due to relatively increased severely affected due to relatively increased exposure to glutenexposure to gluten


We suggest that patients be evaluated We suggest that patients be evaluated four to six weeksfour to six weeks following the initiation following the initiation

of a gluten-free diet at which time a of a gluten-free diet at which time a complete blood countcomplete blood count, , folatefolate, , B12B12, , iron iron

studiesstudies, , liver chemistriesliver chemistries, and , and serologic serologic testing testing should be performedshould be performed . .

It is important to note that It is important to note that women often women often experience breast tenderness experience breast tenderness for for

three months three months after starting a gluten-free after starting a gluten-free diet and reassurance should be provideddiet and reassurance should be provided..


(1(1Serologic testingSerologic testing

with increased use of IgA tTG for initial diagnosis with increased use of IgA tTG for initial diagnosis this assay is now also increasingly used in this assay is now also increasingly used in

monitoring response to gluten-free dietmonitoring response to gluten-free diet..

A normal baseline value is A normal baseline value is typically reached typically reached within 3 to 12 months within 3 to 12 months depending upon the depending upon the

pre-treatment concentrationspre-treatment concentrations..

Normal IgA tTG levels do not reliably indicate Normal IgA tTG levels do not reliably indicate recovery from villous atrophyrecovery from villous atrophy

Conversely, if the levels do not fall as Conversely, if the levels do not fall as anticipated, the patient is usually continuing to anticipated, the patient is usually continuing to

ingest gluten either intentionally or inadvertentlyingest gluten either intentionally or inadvertently

(2(2Small bowel biopsySmall bowel biopsy

The need for a follow-up biopsy in patients The need for a follow-up biopsy in patients with clinical improvement with clinical improvement has been has been

debateddebated, especially since serologic testing , especially since serologic testing can be used to monitor recovery and can be used to monitor recovery and

compliance with the dietcompliance with the diet..

Some authorities rely on clinical Some authorities rely on clinical improvement and changes in serologic improvement and changes in serologic

markers, reserving re-biopsy for markers, reserving re-biopsy for nonresponsive patients in whom there nonresponsive patients in whom there

remains diagnostic uncertainty, or those remains diagnostic uncertainty, or those who wish to confirm mucosal healingwho wish to confirm mucosal healing

The The author's practice author's practice is to is to repeat a small intestinal repeat a small intestinal biopsy in all patients three to four months biopsy in all patients three to four months after after

beginning a gluten-free diet to demonstrate histologic beginning a gluten-free diet to demonstrate histologic improvementimprovement . .

If improvement in small intestinal morphology is not If improvement in small intestinal morphology is not seenseen, but symptomatic improvement has occurred, the diet , but symptomatic improvement has occurred, the diet

should be continued and the small intestinal biopsy should should be continued and the small intestinal biopsy should be repeated after six to nine monthsbe repeated after six to nine months . .

Although histological improvement is usually seen, Although histological improvement is usually seen, persistent abnormalities have been described, even in persistent abnormalities have been described, even in

patients with symptomatic improvement . The significance patients with symptomatic improvement . The significance is at the moment unclear, but this may be due to is at the moment unclear, but this may be due to low level low level

gluten contaminationgluten contamination, a , a persistent immune response persistent immune response or or other unknown mechanisms. other unknown mechanisms. Other diagnosesOther diagnoses, after a first , after a first

check for check for poor compliancepoor compliance, or , or inadvertent ingestion inadvertent ingestion of of gluten should be considered in these patients (see 'Other gluten should be considered in these patients (see 'Other

diagnoses' below)diagnoses' below)..

(3(3Gluten rechallengeGluten rechallenge

Gluten rechallenge Gluten rechallenge is unnecessary is unnecessary according to a consensus statement according to a consensus statement issued by the National Institutes of Health and Guidelines issued by the issued by the National Institutes of Health and Guidelines issued by the

European Society of Paediatric Gastroenterology and Nutrition (ESPGAN)European Society of Paediatric Gastroenterology and Nutrition (ESPGAN)

According to the ESPGAN guidelines, gluten rechallenge should only be According to the ESPGAN guidelines, gluten rechallenge should only be used in equivocal cases such as when used in equivocal cases such as when no initial biopsy was performedno initial biopsy was performed, ,

biopsies were inadequate or atypicalbiopsies were inadequate or atypical, , in communities with high rates of in communities with high rates of other enteropathiesother enteropathies, or , or in situations when patients plan to abandon a in situations when patients plan to abandon a

gluten-free diet in an uncontrolled waygluten-free diet in an uncontrolled way . .

Gluten rechallenge should be performed after Gluten rechallenge should be performed after obtaining a control obtaining a control biopsy biopsy on a gluten-free diet and on a gluten-free diet and repeat biopsies should be obtained repeat biopsies should be obtained

three to six months later three to six months later with the recognition that with the recognition that relapse can take relapse can take five to seven years or morefive to seven years or more..

A rare hazard in giving a gluten rechallenge is the development of A rare hazard in giving a gluten rechallenge is the development of fulminant diarrhea, with resulting dehydration, acidosis, and other fulminant diarrhea, with resulting dehydration, acidosis, and other

metabolic disturbances (a condition known as "metabolic disturbances (a condition known as "gliadin shockgliadin shock") Such ") Such patients patients should be treated with glucocorticoidsshould be treated with glucocorticoids . .

There is a suggestion that use of gluten challenge in young children may There is a suggestion that use of gluten challenge in young children may be associated with an increased likelihood of development of be associated with an increased likelihood of development of

autoimmune disorders such as autoimmune disorders such as IDDMIDDM..

NONRESPONDERSNONRESPONDERS

Nonresponders are individuals who have Nonresponders are individuals who have persistent persistent symptoms symptoms or or serologicserologic and/or and/or histologic abnormalities histologic abnormalities

after two years after two years on a gluten-free dieton a gluten-free diet . .

The The majority majority of patients with celiac disease of patients with celiac disease respondrespond to a to a gluten-free diet but approximately gluten-free diet but approximately 5 percent 5 percent of individuals of individuals

do notdo not . .

In patients who are incomplete responders or In patients who are incomplete responders or nonresponders, it is important to consider that not all nonresponders, it is important to consider that not all

clinical features of celiac disease respond at the same rateclinical features of celiac disease respond at the same rate

Furthermore, Furthermore, bone loss bone loss due to secondary due to secondary hyperparathyroidism and hyperparathyroidism and peripheral neuropathy peripheral neuropathy may may

only improve partially only improve partially despite a gluten-free dietdespite a gluten-free diet[ [

Patients who do not respond to a gluten-Patients who do not respond to a gluten-free diet fall into five main categoriesfree diet fall into five main categories::

(1(1Patients with poor compliance or Patients with poor compliance or inadvertent gluten ingestioninadvertent gluten ingestion

(2(2Patients with clinical or histologic features Patients with clinical or histologic features that overlap with celiac disease but are that overlap with celiac disease but are

caused by other disorderscaused by other disorders(3(3Patients with concurrent disordersPatients with concurrent disorders(4(4Patients with refractory spruePatients with refractory sprue(5(5Patients with ulcerative jejunitis or Patients with ulcerative jejunitis or

intestinal lymphomaintestinal lymphoma

11))Poor compliance or Poor compliance or inadvertent gluten ingestioninadvertent gluten ingestion

The The most common reasons most common reasons for a lack of for a lack of response are poor compliance or inadvertent response are poor compliance or inadvertent

gluten ingestiongluten ingestion

In patients who continue to have symptoms or In patients who continue to have symptoms or persistent histologic abnormalities, or in those in persistent histologic abnormalities, or in those in whom serum antibody titers have not declined, a whom serum antibody titers have not declined, a

meticulous dietary history should be obtained, meticulous dietary history should be obtained, and dietary counseling pursued with a dietitian and dietary counseling pursued with a dietitian

specifically trained and experienced in celiac specifically trained and experienced in celiac diseasedisease..

22))Other diagnosesOther diagnoses An erroneous diagnosis of celiac sprue An erroneous diagnosis of celiac sprue

may result from false positive serology, may result from false positive serology, specifically IgA antigliadin antibodiesspecifically IgA antigliadin antibodies . .

Diseases associated with small bowel Diseases associated with small bowel villous atrophy should be excluded in villous atrophy should be excluded in

patients with persistent symptoms who patients with persistent symptoms who do not show histologic improvementdo not show histologic improvement

33))Concurrent disordersConcurrent disordersOther concurrent diagnoses should be considered in Other concurrent diagnoses should be considered in

patients who, despite apparent compliance, continue patients who, despite apparent compliance, continue to have symptoms or do not have histologic to have symptoms or do not have histologic

improvementimprovement

)1)1 Concomitant or secondary lactose intolerance Concomitant or secondary lactose intolerance is a is a possible cause of continued diarrhea and flatulencepossible cause of continued diarrhea and flatulence

(2(2Patients with celiac disease may have concurrent bowel Patients with celiac disease may have concurrent bowel disturbances such as disturbances such as irritable bowel syndromeirritable bowel syndrome, ,

which affects a large proportion of the general which affects a large proportion of the general populationpopulation . .

)3)3 Small bowel bacterial overgrowthSmall bowel bacterial overgrowth, which may , which may respond to antibiotics, develops in a small percentage respond to antibiotics, develops in a small percentage

of patients with celiac diseaseof patients with celiac disease(4(4Some patients have Some patients have coexisting pancreatic coexisting pancreatic

insufficiencyinsufficiency)5)5 Microscopic colitis Microscopic colitis is found in is found in 4 percent 4 percent of patients of patients

with celiac disease, which represents a with celiac disease, which represents a 70-fold 70-fold increase increase in risk. These patients had more severe in risk. These patients had more severe

villous atrophy and frequently required glucocorticoids villous atrophy and frequently required glucocorticoids or immunosuppressive drugs to treat the diarrheaor immunosuppressive drugs to treat the diarrhea

44))Refractory sprueRefractory spruePatients with refractory sprue (also referred to as Patients with refractory sprue (also referred to as

"unclassified sprue") fall into two clinical categories"unclassified sprue") fall into two clinical categories: : Patients who have no initial response Patients who have no initial response to a gluten-free to a gluten-free

dietdietPatients who experience initial clinical Patients who experience initial clinical

improvement improvement on a gluten-free diet, but, after a period of on a gluten-free diet, but, after a period of remission, develop disease refractory to gluten abstinenceremission, develop disease refractory to gluten abstinence

Refractory sprue has also been subdivided into two Refractory sprue has also been subdivided into two immunologic categoriesimmunologic categories: :

Type 1Type 1 in which there is a in which there is a normal population of normal population of intraepithelial lymphocytesintraepithelial lymphocytes..

Type 2Type 2 in which there is an in which there is an aberrant or premalignant aberrant or premalignant population of intraepithelial lymphocytespopulation of intraepithelial lymphocytes based based

upon clonality analysis of T-cell receptors and upon clonality analysis of T-cell receptors and immunophenotyping. Type 2 can progress to enteropathy-immunophenotyping. Type 2 can progress to enteropathy-associated T-cell lymphoma, which may present clinically associated T-cell lymphoma, which may present clinically

as ulcerative jejunitisas ulcerative jejunitis

Patients with Patients with type 1 disease have a less severe presentation type 1 disease have a less severe presentation and a much better prognosis than patients with type 2 diseaseand a much better prognosis than patients with type 2 disease

Furthermore, Furthermore, type 1 does not appear to evolve into type 2type 1 does not appear to evolve into type 2 . .

An illustrative study compared outcomes in 41 patients with type An illustrative study compared outcomes in 41 patients with type 1 disease to 50 patients with type 2 disease [66]. Five-year 1 disease to 50 patients with type 2 disease [66]. Five-year

survival was higher in the type 1 group (96 versus 58 percent). survival was higher in the type 1 group (96 versus 58 percent). Most deaths were due to development of T-cell lymphoma (which Most deaths were due to development of T-cell lymphoma (which

developed in one-half of patients during follow-up). No patient developed in one-half of patients during follow-up). No patient with type 1 disease developed type 2 disease during an average with type 1 disease developed type 2 disease during an average

five years follow-upfive years follow-up . .

Refractory sprue (particularly type 2) can be severe and Refractory sprue (particularly type 2) can be severe and associated with associated with progressive malabsorption and deathprogressive malabsorption and death. A . A

subset of patients develops subepithelial collagen deposition, a subset of patients develops subepithelial collagen deposition, a condition referred to as condition referred to as "collagenous sprue"collagenous sprue""

The cause of refractory sprue is unknownThe cause of refractory sprue is unknown..

It is possible that some patients with this condition develop It is possible that some patients with this condition develop sensitivity to a dietary constituent other than glutensensitivity to a dietary constituent other than gluten

However, identification of the responsible antigens in most However, identification of the responsible antigens in most patients is difficult and unrewarding. As a result, treatment patients is difficult and unrewarding. As a result, treatment has focused on immunosuppression, which has traditionally has focused on immunosuppression, which has traditionally

relied upon glucocorticoidsrelied upon glucocorticoids . .

The dose of glucocorticoids required varies among The dose of glucocorticoids required varies among patients, and not all patients respond. In severely ill patients, and not all patients respond. In severely ill

patients, we usually begin with hydrocortisone (100 mg IV patients, we usually begin with hydrocortisone (100 mg IV Q6H). Oral dosing (such as 40 to 60 mg of Q6H). Oral dosing (such as 40 to 60 mg of

prednisolone daily) can be used in patients who are prednisolone daily) can be used in patients who are tolerating an oral diet. After a few weeks, the dose can be tolerating an oral diet. After a few weeks, the dose can be reduced by 5 to 10 mg per day in responding patients and reduced by 5 to 10 mg per day in responding patients and

subsequently tapered to the subsequently tapered to the lowest dose that keeps the lowest dose that keeps the patient in remissionpatient in remission..

Experience with alternative immunosuppressant therapy in Experience with alternative immunosuppressant therapy in patients who require high doses of glucocorticoids is limited to patients who require high doses of glucocorticoids is limited to

case reports and clinical experiencecase reports and clinical experience . .

However, azathioprine and 6-mercaptopurine appear to be However, azathioprine and 6-mercaptopurine appear to be effective steroid-sparing agentseffective steroid-sparing agents

Oral budesonide (9 mg, range 6 to 12 mg) has been effective in Oral budesonide (9 mg, range 6 to 12 mg) has been effective in case seriescase series

Other dugs used in case seriesOther dugs used in case series : :emental diet in patients with type 1 refractory sprueemental diet in patients with type 1 refractory spruesmall intestinal release mesalaminesmall intestinal release mesalaminetype 2 disease following treatment with alemtuzumab, an anti-type 2 disease following treatment with alemtuzumab, an anti-

CD52 monoclonal antibodyCD52 monoclonal antibodyCladribine in patients with type 2 refractory sprueCladribine in patients with type 2 refractory sprue

55))Ulcerative jejunitis and Ulcerative jejunitis and intestinal lymphomaintestinal lymphoma

Ulcerative jejunitis and lymphoma should Ulcerative jejunitis and lymphoma should be considered in patients with refractory be considered in patients with refractory

sprue unresponsive to glucocorticoidssprue unresponsive to glucocorticoids . .

The conditions are thought to share a The conditions are thought to share a similar pathogenesis, since both have similar pathogenesis, since both have

aberrant T-cell monoclonalityaberrant T-cell monoclonality

The disease most commonly presents in The disease most commonly presents in middle-aged patients with underlying celiac middle-aged patients with underlying celiac

diseasedisease..

Patients with Patients with ulcerative jejunitis ulcerative jejunitis have multiple chronic, have multiple chronic, benign-appearing ulcers, most frequently in the benign-appearing ulcers, most frequently in the jejunumjejunum . .

Clinical manifestations are similar to severe celiac disease; Clinical manifestations are similar to severe celiac disease; patients may present with new or recurrent symptoms of patients may present with new or recurrent symptoms of

malabsorption, lassitude, anorexia, weight loss, abdominal pain, malabsorption, lassitude, anorexia, weight loss, abdominal pain, diarrhea, and fever despite being on a gluten-free dietdiarrhea, and fever despite being on a gluten-free diet

Intestinal stricturing can develop with resulting small bowel Intestinal stricturing can develop with resulting small bowel obstructionobstruction . .

Evaluation should begin with an abdominal computed Evaluation should begin with an abdominal computed tomography (CT) enterography or magnetic resonance (MR) tomography (CT) enterography or magnetic resonance (MR) enterography scan and upper endoscopy, which, if negative, enterography scan and upper endoscopy, which, if negative,

should be followed by a capsule endoscopyshould be followed by a capsule endoscopy . .

Ulcerative jejunitis responds poorly to a gluten-free diet and is Ulcerative jejunitis responds poorly to a gluten-free diet and is associated with an associated with an unfavorable prognosisunfavorable prognosis. Up to one-third of . Up to one-third of

patients die from complications. The prognosis can be improved patients die from complications. The prognosis can be improved if the ulcerated or strictured segment can be resectedif the ulcerated or strictured segment can be resected..

Lymphoma Lymphoma should be suspected in patients with celiac should be suspected in patients with celiac disease presenting with the clinical features described above disease presenting with the clinical features described above

for ulcerative jejunitisfor ulcerative jejunitis . .

Among patients who initially responded to a gluten-free diet, Among patients who initially responded to a gluten-free diet, the diagnostic dilemma is whether the return of symptoms is the diagnostic dilemma is whether the return of symptoms is

due to dietary lapses or the development of lymphomadue to dietary lapses or the development of lymphoma . .

Clinical manifestations more suggestive of lymphoma, such as Clinical manifestations more suggestive of lymphoma, such as fever, hepatomegaly, splenomegaly, duodenal mass(es), or fever, hepatomegaly, splenomegaly, duodenal mass(es), or

ascites,ascites, may help the diagnostic conundrum, but their may help the diagnostic conundrum, but their presence implies more advanced diseasepresence implies more advanced disease . .

Other presentations of lymphoma include Other presentations of lymphoma include acute perforation, acute perforation, gastrointestinal obstruction, or, less commonly, gastrointestinal obstruction, or, less commonly,

gastrointestinal hemorrhagegastrointestinal hemorrhage..

A A full-thickness surgical intestinal biopsy full-thickness surgical intestinal biopsy may be may be required to establish the diagnosis in patients in whom clinical required to establish the diagnosis in patients in whom clinical

suspicion is high, but radiographic and endoscopic testing is suspicion is high, but radiographic and endoscopic testing is inconclusiveinconclusive

Five-year survival is approximately 10 Five-year survival is approximately 10 percent, with the worst outcomes in patients percent, with the worst outcomes in patients

with previously diagnosed celiac diseasewith previously diagnosed celiac disease

Favorable outcomes with multidrug therapy Favorable outcomes with multidrug therapy occur only in patients who have minimal occur only in patients who have minimal

gastrointestinal symptoms prior to the gastrointestinal symptoms prior to the diagnosis of lymphoma, and can tolerate diagnosis of lymphoma, and can tolerate

therapytherapy

Patients should also be maintained on a Patients should also be maintained on a gluten-free dietgluten-free diet..

OTHER ASPECTS OF OTHER ASPECTS OF MANAGEMENTMANAGEMENT

Repletion of nutritional deficienciesRepletion of nutritional deficiencies Specific dietary deficiencies such as iron, folic acid, Specific dietary deficiencies such as iron, folic acid,

calcium, vitamin D and, rarely, thiamine, vitamin calcium, vitamin D and, rarely, thiamine, vitamin B6 and B12 deficiency should be tested for and B6 and B12 deficiency should be tested for and

correctedcorrected . .Mineral deficiencies including magnesium, zinc, Mineral deficiencies including magnesium, zinc,

copper and selenium may also occur depending on copper and selenium may also occur depending on the disease severity and dietary intakethe disease severity and dietary intake . .

A gluten-free diet may induce A gluten-free diet may induce troublesome troublesome constipationconstipation since it is low in roughage. This since it is low in roughage. This usually responds to usually responds to fiber supplementation fiber supplementation

with psyllium seed huskswith psyllium seed husks..

OTHER ASPECTS OF OTHER ASPECTS OF MANAGEMENTMANAGEMENT Prevention of bone lossPrevention of bone loss — Bone loss (principally osteopenia and — Bone loss (principally osteopenia and

less often osteoporosis) is common in celiac disease, and can less often osteoporosis) is common in celiac disease, and can occur in patients without gastrointestinal symptomsoccur in patients without gastrointestinal symptoms

Much of the bone loss is related to Much of the bone loss is related to secondary secondary hyperparathyroidismhyperparathyroidism, which is probably due to vitamin , which is probably due to vitamin

D deficiencyD deficiency . .

Patients with advanced disease may have bone pain, Patients with advanced disease may have bone pain, pseudofractures, or deformity, but the pseudofractures, or deformity, but the majority of patients are majority of patients are

asymptomatic asymptomatic or have only raised serum levels of alkaline or have only raised serum levels of alkaline phosphatase or hypocalcemiaphosphatase or hypocalcemia

It can only be partially reversed with a gluten-free diet; It can only be partially reversed with a gluten-free diet; loss of loss of bone density in the peripheral skeleton may persist despite bone density in the peripheral skeleton may persist despite

apparent normalization at axial skeletal apparent normalization at axial skeletal sitessites

Patients diagnosed with celiac disease should be evaluated for Patients diagnosed with celiac disease should be evaluated for bone loss using a DEXA (dual energy x-ray absorptiometry) scan. bone loss using a DEXA (dual energy x-ray absorptiometry) scan.

Monitoring by repeat DEXA scan after one year is useful in patients Monitoring by repeat DEXA scan after one year is useful in patients with osteopenia since it permits estimation of the rate of change of with osteopenia since it permits estimation of the rate of change of

bone mineral densitybone mineral density

OTHER ASPECTS OF OTHER ASPECTS OF MANAGEMENTMANAGEMENT

Pneumococcal vaccinationPneumococcal vaccination — Celiac disease is — Celiac disease is associated with hyposplenism.Therefore, prophylactic associated with hyposplenism.Therefore, prophylactic

administration of pneumococcal vaccine is administration of pneumococcal vaccine is recommendedrecommended . .

Dermatitis herpetiformisDermatitis herpetiformis — Celiac disease is — Celiac disease is associated with a number of skin disorders of which associated with a number of skin disorders of which

dermatitis herpetiformis is the most commondermatitis herpetiformis is the most commonImprovement in dermatitis herpetiformis following Improvement in dermatitis herpetiformis following

withdrawal of gluten may be withdrawal of gluten may be considerably delayed (6 considerably delayed (6 to 12 monthsto 12 months) compared to the response of the ) compared to the response of the

intestinal manifestations of the disease . As a result, intestinal manifestations of the disease . As a result, treatment with sulfones (such as dapsone) in addition treatment with sulfones (such as dapsone) in addition

to gluten avoidance may be necessary to achieve rapid to gluten avoidance may be necessary to achieve rapid controlcontrol. .

SCREENING FAMILY SCREENING FAMILY MEMBERSMEMBERS

Relatives of patients with celiac disease are at Relatives of patients with celiac disease are at increased risk for having celiac diseaseincreased risk for having celiac disease

The risk is highest among The risk is highest among monozygotic twins monozygotic twins (approximately 75 percent) , (approximately 75 percent) , HLA-identical siblings HLA-identical siblings (approximately 40 percent), and among (approximately 40 percent), and among first-degree first-degree

relatives relatives of families with at least two affected of families with at least two affected siblings (17 percent)siblings (17 percent)

Among first-degree relatives, the risk has varied from Among first-degree relatives, the risk has varied from 5 to 11 percent in various reports5 to 11 percent in various reports . .

Thus, screening of first-degree relatives (particularly Thus, screening of first-degree relatives (particularly siblings) should be consideredsiblings) should be considered . .

MALABSORPTION SYNDROMEMALABSORPTION SYNDROME

This occurs when the normal digestion and absorption of food is interrupted.

PATHOPHYSIOLOGICAL )MECHANISM(:

-Is divided into:

A( Intraluminal stage

Impaired hydrolysis and solubilization of nutrients in the small intestine.

1 )Impaired fat absorption:

i( Pancreatic lipase is necessary for triglyceride hydrolysis in duodenum.

Pancreatic enzyme deficiency leads to fat malabsorption.

ii( Inactivation of pancreatic lipase by low gastric luminal

pH – fat malabsorption.

iii( Interruption of enterohepatic circulation of bile salt – impaired micelle formation – fat malabsorption.

Absorption of fat soluble vitamins may be impaired as well.

2 )Impaired carbohydrate absorption:

Most diseases that causes carbohydrate malabsorption do so by affecting intestinal stage.

But amylase catalyse hydrolysis of starch to

oligosaccharides .

3 )Impaired protein absorption:

Hydrolysis of polypeptides occurs mainly in small intestine by action of pancreatic enzyme trypsin, chymotrypsin.

Deficiency of pancreatic proteases – impaired protein absorption.

Diseases like :

Chronic pancreatitis

Cystic fibrosis

Ca. pancreatic resection

- Protein malnutrition

B) Intestinal stageB) Intestinal stage

1 )Abnormalities of small intestinal mucosa.

Lactase deficiency

e.g. Congenital or acquired

Result – malabsorption of lactose.

Acquired:- i( Coeliac disease

ii( Crohn’s disease

iii( Infective enteritis

2 )Impaired epithelial cell transport:

Many diseases cause loss of intestinal surface area

- malabsorption of many nutrients.

e.g. i( Coeliac disease

ii( Tropical spure

iii( Extensive surgical resection

iv( Drugs

C) Lymphatic transportC) Lymphatic transport::

Lymphatic obstruction – fat malabsorption

e.g. i( Intestinal lymphangiectasia

iii( Tuberculous enteritis

iv( Intestinal lymphoma

D)D) Decreased availability of ingested nutrients and

cofactors for absorption.

i( Vitamin B12 malabsorption if intrinsic factor is deficient. e.g. gastrectomy, antiparietal cell Ab.

ii( Bacterial overgrowth –can bind B12.

iii( Patient infected with fist tapeworm – B12 deficiency.

CLINICAL MANIFESTATIONS

History:

Diarrhea/steatorrhoea Weight loss Symptoms of anaemia

Diarrhoea – bulky, floating, malodorous stool – difficult to flush .

Weight loss – may be profound, usually associated with anorexia .

Anaemia – B12, iron, folate malabsorption.

Patient may complain of dizziness, dyspnoea and fatigue

Important part of history:

Recent travel - giardiasis

Drug abuse/multiple blood transfusions or ethanol

abuse

surgical resection

- small bowel

- gastric

Malabsorption + chronic lung disease = cystic fibrosis

Fever + weight loss = TB, lymphoma.

O/E:

Normal.

Pallor - muscle wasting

Sign of vitamin deficiency

glossitis – B deficiency

ecchymoses

parasthesia

tetany

Investigations:

General:

- CBC

- Blood film

- Ca.

- B12, folate

- Iron study

- LFT, PT, PTT

Investigations:

Specific:

Tests of fat absorption:

Quantitative fecal fat

Patient should be on daily diet containing 80-100 grams of fat.

Fecal fat estimated on 72 H collection.

6 grams or more of fat/day is abnormal.

May be due to: - Pancreatic

- Small intestinal

- Hepatobiliary disease

1414C-Triolein TestC-Triolein Test::

Is triglyceride which is hydrolysed by pancreatic lipase .

absorption of metabolism ↑ 14CO2

lung

Tests for pancreatic function:

1 )Bentiromide test:

Chymotrypsin

PABA + pepside

PABA absorbed and conjugated in liver

urine excretion

2 )Schilling test

3( Pancreatic stimulation test Secretin stimulation –

4( Radiographic techniques: - Plain abdominal X-ray - U/S abdomen - ERCP - CT abdomen

Carbohydrate absorption test

1 )Hydrogen breath test

Hydrogen excretion ↑ in

bacterial overgrowth

small intestinal malabsorption

Carbohydrate absorption test

2 )D-xylose test

5-carbon sugar excreted unchanged in urine

25 grams given

Urine collected for 5 hours

Normally 25% is excreted

In patients with fat malabsorption, this test

differentiates pancreatic from small intestinal malabsorpton.

D-xylose is normal in pancreatic disease

Serum level of D-xylose at 1-2 hours after ingestion can be measured .

Test for bacterial overgrowth:Test for bacterial overgrowth:

1)1) Intestinal aspiration and cultureIntestinal aspiration and culture

2)2) Breath testBreath test

3)3) C-D xylose breath testC-D xylose breath test

1)1) Radiography of small intestine:Radiography of small intestine:

Barium swallow and follow-through Barium swallow and follow-through –– to to seesee

- Blind loop- Blind loop

- Stricture- Stricture

- J. diverticular- J. diverticular

2)2) Intestinal mucosal biopsy:Intestinal mucosal biopsy:

- using crossby capsule- using crossby capsule- endoscopy- endoscopy

Coeliac disease:Coeliac disease:- Villous atrophy- Villous atrophy

Tropical spure:Tropical spure:- short villi and increased lymphocyte- short villi and increased lymphocyte

Selection of tests in evaluation malabsorption

Quantitaive fecal fatQuantitaive fecal fat

Normal Abnormal

D-xylose test

Normal Abnormal

Abd. Radiograph14 C-D-xylose test

Bentiromide test

CT-abd. Normal

Small intestinal Bx

Abnormal

• Jej culture

• Tetracyclin

•Then repeat breath test

Classification of Malabsorption Classification of Malabsorption SyndromeSyndrome

A.A. Inadequate digestion:Inadequate digestion:• Postgastrectomy steatorrhea.Postgastrectomy steatorrhea.• Exocrine Pancreatic insufficiency.Exocrine Pancreatic insufficiency.• Reduced bile salt concentration in Reduced bile salt concentration in

intestine:intestine:I.) Liver DiseaseI.) Liver Disease

II.) CholestasisII.) Cholestasis

III.) Bacterial over growthIII.) Bacterial over growth

IV.) Interruption of enterohepatic circulation of IV.) Interruption of enterohepatic circulation of bile salt.bile salt.

B.B. Inadequate absorptive surface:Inadequate absorptive surface:• ResectionResection• Diseased intestineDiseased intestine

C.C. Lymphatic obstruction.Lymphatic obstruction. e.g Lymphomae.g Lymphoma

D.D. Primary mucosal defects. Primary mucosal defects.• CrohnCrohn’’s diseases disease• Coeliac diseaseCoeliac disease• Tropical SprueTropical Sprue• Disaccharide DeficiencyDisaccharide Deficiency• LymphomaLymphoma• TBTB

Malabsorption due to bacteral over Malabsorption due to bacteral over growth of small bowelgrowth of small bowel

Normal small intestine is bacterial sterile due to: Normal small intestine is bacterial sterile due to:

AcidAcid Int. peristalsis (major)Int. peristalsis (major) ImmunoglobulinImmunoglobulin

Cause of bacterial growth.Cause of bacterial growth. e.g.e.g.

Small intestinal diverticuliSmall intestinal diverticuli Blind loopBlind loop StricturesStrictures DM/ SclerodermaDM/ Scleroderma

PathophysiologyPathophysiology

1)1) Bacterial over growth: Metabolize bile salt Bacterial over growth: Metabolize bile salt resulting in deconjugation of bile salt resulting in deconjugation of bile salt

Bile SaltBile Salt Impaired intraluminal micelle formationImpaired intraluminal micelle formation Malabsorption of fat. Malabsorption of fat.

2)2) Intestinal mucosa is damaged byIntestinal mucosa is damaged by Bacterial invasionBacterial invasion ToxinToxin Metabolic productsMetabolic products Damage villi Damage villi may cause total villous atrophy. may cause total villous atrophy.

Clinically:Clinically: SteatorrheaSteatorrhea AnaemiaAnaemia B12 def.B12 def.Reversed of symptom after antibiotic Reversed of symptom after antibiotic

treatment.treatment. Diagnosis:Diagnosis: Breath testBreath test Cxylose testCxylose test Culture of aspiration (definitive)Culture of aspiration (definitive)Treatment:Treatment: Antibiotic Antibiotic TetracyclinTetracyclin CiproflexacinCiproflexacin MetronidazoleMetronidazole AmoxilAmoxil

Intestinal LymphomaIntestinal Lymphoma

Primary 2Primary 2ndnd Affect male = 50 Y.Affect male = 50 Y. Feature of malabsorptionFeature of malabsorption Biopsy resemble coeliac sprue Biopsy resemble coeliac sprue Abdominal painAbdominal pain FeverFeverIncomplete respond to gluten free diet.Incomplete respond to gluten free diet.Absent features of generalized lymphoma.Absent features of generalized lymphoma.

Malabsorption may be due to:Malabsorption may be due to: Diffuse small intestinal mucosa disease.Diffuse small intestinal mucosa disease. Obstruction of lymphatic channelsObstruction of lymphatic channels Stenosis Stenosis bacterial overgrowth. bacterial overgrowth. FeverFever

Diagnosis:Diagnosis: History/Endoscopic Biopsy - History/Endoscopic Biopsy - CT scan of abdomenCT scan of abdomen LaparotomyLaparotomySome form secretion Some form secretion - heavy chain - heavy chain Ig A.Ig A.

Complication:Complication: PerforationPerforation BleedingBleeding Intestinal obstructionIntestinal obstruction

Treatment:Treatment: Chemotherapy Chemotherapy SurgerySurgery

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Ahmad Hormati Assistant Professor of Gastroenterology Qom University of Medical Sciences. Email:...

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