Celiac Disease (Clinical)

Epidemiology and Etiology

Epidemiology^[1,2,6,8,12]

• Previously thought to affect mostly White population of European descent, but has been increasingly diagnosed in Northern Africa, Middle East, and Asia ASIA Spinal Cord Injuries
• Prevalence Prevalence The total number of cases of a given disease in a specified population at a designated time. It is differentiated from incidence, which refers to the number of new cases in the population at a given time. Measures of Disease Frequency worldwide: approximately 1%
• More common in women
• Bimodal age distribution, but more common in childhood:
  • 8‒12 months of age
  • 3rd–4th decades of life
• Family history Family History Adult Health Maintenance is positive in 10%‒15% of patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship.
• 99% of individuals with celiac disease Celiac disease Celiac disease (also known as celiac sprue or gluten enteropathy) is an autoimmune reaction to gliadin, which is a component of gluten. Celiac disease is closely associated with HLA-DQ2 and HLA-DQ8. The immune response is localized to the proximal small intestine and causes the characteristic histologic findings of villous atrophy, crypt hyperplasia, and intraepithelial lymphocytosis. Celiac Disease have HLA DR3-DQ2 and/or HLA-DR4-DQ8.
• Celiac disease Celiac disease Celiac disease (also known as celiac sprue or gluten enteropathy) is an autoimmune reaction to gliadin, which is a component of gluten. Celiac disease is closely associated with HLA-DQ2 and HLA-DQ8. The immune response is localized to the proximal small intestine and causes the characteristic histologic findings of villous atrophy, crypt hyperplasia, and intraepithelial lymphocytosis. Celiac Disease is associated with:
  • Down and Turner syndromes
  • Moderately increased risk of small bowel Small bowel The small intestine is the longest part of the GI tract, extending from the pyloric orifice of the stomach to the ileocecal junction. The small intestine is the major organ responsible for chemical digestion and absorption of nutrients. It is divided into 3 segments: the duodenum, the jejunum, and the ileum. Small Intestine: Anatomy lymphoma Lymphoma A general term for various neoplastic diseases of the lymphoid tissue. Imaging of the Mediastinum
  • Autoimmune thyroid Thyroid The thyroid gland is one of the largest endocrine glands in the human body. The thyroid gland is a highly vascular, brownish-red gland located in the visceral compartment of the anterior region of the neck. Thyroid Gland: Anatomy disease
  • Type 1 Type 1 Spinal Muscular Atrophy diabetes Diabetes Diabetes mellitus (DM) is a metabolic disease characterized by hyperglycemia and dysfunction of the regulation of glucose metabolism by insulin. Type 1 DM is diagnosed mostly in children and young adults as the result of autoimmune destruction of β cells in the pancreas and the resulting lack of insulin. Type 2 DM has a significant association with obesity and is characterized by insulin resistance. Diabetes Mellitus
• Underdiagnosed: Approximately 5% of patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship diagnosed with irritable bowel syndrome Irritable bowel syndrome Irritable bowel syndrome (IBS) is a functional bowel disease characterized by chronic abdominal pain and altered bowel habits without an identifiable organic cause. The etiology and pathophysiology of this disease are not well understood, and there are many factors that may contribute. Irritable Bowel Syndrome or microscopic colitis Colitis Inflammation of the colon section of the large intestine, usually with symptoms such as diarrhea (often with blood and mucus), abdominal pain, and fever. Pseudomembranous Colitis have celiac disease Celiac disease Celiac disease (also known as celiac sprue or gluten enteropathy) is an autoimmune reaction to gliadin, which is a component of gluten. Celiac disease is closely associated with HLA-DQ2 and HLA-DQ8. The immune response is localized to the proximal small intestine and causes the characteristic histologic findings of villous atrophy, crypt hyperplasia, and intraepithelial lymphocytosis. Celiac Disease.^[7]

Etiology^[1,2,6,8]

Environmental, immunologic, and genetic factors contribute to the disease process:

• Environmental
  • Triggered by gliadin Gliadin Simple protein, one of the prolamins, derived from the gluten of wheat, rye, etc. May be separated into 4 discrete electrophoretic fractions. It is the toxic factor associated with celiac disease. Celiac Disease, which is a component of gluten Gluten Prolamins in the endosperm of seeds from the triticeae tribe which includes species of wheat; barley; and rye. Celiac Disease (found in wheat, barley, and rye)
  • The only autoimmune disease in which the antigen Antigen Substances that are recognized by the immune system and induce an immune reaction. Vaccination is known
• Immunologic
  • Involves both innate and adaptive immune response Adaptive immune response Immune responses against pathogens are divided into the innate and adaptive immune response systems. The adaptive immune response, also called the acquired immune system, consists of 2 main mechanisms: the humoral- and cellular-mediated immune responses. Adaptive Immune Response ( type 4 Type 4 Spinal Muscular Atrophy hypersensitivity reaction)
  • Autoantibodies Autoantibodies Antibodies that react with self-antigens (autoantigens) of the organism that produced them. Blotting Techniques:
    • Immunoglobulin A ( IgA IgA Represents 15-20% of the human serum immunoglobulins, mostly as the 4-chain polymer in humans or dimer in other mammals. Secretory iga is the main immunoglobulin in secretions. Immunoglobulins: Types and Functions) anti-tissue transglutaminase 
    • Anti-endomysial Anti-endomysial Celiac Disease
    • Anti-deamidated gliadin peptide Anti-deamidated gliadin peptide Celiac Disease
• Genetics Genetics Genetics is the study of genes and their functions and behaviors. Basic Terms of Genetics: associated with HLA-DR3-DQ2 and HLA-DR4-DQ8

Pathophysiology

Gluten Gluten Prolamins in the endosperm of seeds from the triticeae tribe which includes species of wheat; barley; and rye. Celiac Disease peptides trigger Trigger The type of signal that initiates the inspiratory phase by the ventilator Invasive Mechanical Ventilation the innate immune response Innate Immune Response Immunity to pathogens is divided into innate and adaptive immune responses. The innate immune response is the 1st line of defense against a variety of pathogens, including bacteria, fungi, viruses, and parasites. In essentially the same form, the innate type of immunity is present in all multicellular organisms. Innate Immunity: Barriers, Complement, and Cytokines in intestinal epithelial cells, leading to T cell–mediated mucosal damage of the proximal small intestine Small intestine The small intestine is the longest part of the GI tract, extending from the pyloric orifice of the stomach to the ileocecal junction. The small intestine is the major organ responsible for chemical digestion and absorption of nutrients. It is divided into 3 segments: the duodenum, the jejunum, and the ileum. Small Intestine: Anatomy (distal duodenum Duodenum The shortest and widest portion of the small intestine adjacent to the pylorus of the stomach. It is named for having the length equal to about the width of 12 fingers. Small Intestine: Anatomy and proximal jejunum Jejunum The middle portion of the small intestine, between duodenum and ileum. It represents about 2/5 of the remaining portion of the small intestine below duodenum. Small Intestine: Anatomy).^[2,8]

1. Presence of gliadin Gliadin Simple protein, one of the prolamins, derived from the gluten of wheat, rye, etc. May be separated into 4 discrete electrophoretic fractions. It is the toxic factor associated with celiac disease. Celiac Disease → release of tissue transglutaminase (tTG) (intracellular enzyme) → deaminated gliadin Gliadin Simple protein, one of the prolamins, derived from the gluten of wheat, rye, etc. May be separated into 4 discrete electrophoretic fractions. It is the toxic factor associated with celiac disease. Celiac Disease
2. Antigen-presenting cells Antigen-presenting cells A heterogeneous group of immunocompetent cells that mediate the cellular immune response by processing and presenting antigens to the T-cells. Traditional antigen-presenting cells include macrophages; dendritic cells; langerhans cells; and B-lymphocytes. Follicular dendritic cells are not traditional antigen-presenting cells, but because they hold antigen on their cell surface in the form of immune complexes for b-cell recognition they are considered so by some authors. Adaptive Immune Response process and present this to T cells T cells Lymphocytes responsible for cell-mediated immunity. Two types have been identified – cytotoxic (t-lymphocytes, cytotoxic) and helper T-lymphocytes (t-lymphocytes, helper-inducer). They are formed when lymphocytes circulate through the thymus gland and differentiate to thymocytes. When exposed to an antigen, they divide rapidly and produce large numbers of new T cells sensitized to that antigen. T cells: Types and Functions → T helper cell and plasma Plasma The residual portion of blood that is left after removal of blood cells by centrifugation without prior blood coagulation. Transfusion Products cell activation
3. Plasma Plasma The residual portion of blood that is left after removal of blood cells by centrifugation without prior blood coagulation. Transfusion Products cells release anti-tTG, anti-endomysial Anti-endomysial Celiac Disease, and anti-deamidated gliadin Gliadin Simple protein, one of the prolamins, derived from the gluten of wheat, rye, etc. May be separated into 4 discrete electrophoretic fractions. It is the toxic factor associated with celiac disease. Celiac Disease antibodies Antibodies Immunoglobulins (Igs), also known as antibodies, are glycoprotein molecules produced by plasma cells that act in immune responses by recognizing and binding particular antigens. The various Ig classes are IgG (the most abundant), IgM, IgE, IgD, and IgA, which differ in their biologic features, structure, target specificity, and distribution. Immunoglobulins: Types and Functions.
4. T helper cells → cytokine release → intraepithelial lymphocytosis Lymphocytosis WBCs develop from stem cells in the bone marrow and are called leukocytes when circulating in the bloodstream. Lymphocytes are 1 of the 5 subclasses of WBCs. Lymphocytosis is an increase in the number or proportion of the lymphocyte subclass of WBCs, often as a result of an immune response to infection (known as reactive lymphocytosis). Lymphocytosis and activation of fibroblasts Fibroblasts Connective tissue cells which secrete an extracellular matrix rich in collagen and other macromolecules. Sarcoidosis → matrix proteases Proteases Proteins and Peptides → intestinal destruction, including loss of the brush border Brush border Tubular System, crypt hyperplasia Crypt hyperplasia Celiac Disease, and villous atrophy Villous Atrophy Giardia/Giardiasis 
5. This process causes impaired absorption Absorption Absorption involves the uptake of nutrient molecules and their transfer from the lumen of the GI tract across the enterocytes and into the interstitial space, where they can be taken up in the venous or lymphatic circulation. Digestion and Absorption of fat, fat-soluble vitamins, and minerals Minerals Electrolytes → malabsorption Malabsorption General term for a group of malnutrition syndromes caused by failure of normal intestinal absorption of nutrients. Malabsorption and Maldigestion

Clinical Presentation

Clinical manifestations^[1,2,6–8]

Gastrointestinal (GI) symptoms:

• Diarrhea Diarrhea Diarrhea is defined as ≥ 3 watery or loose stools in a 24-hour period. There are a multitude of etiologies, which can be classified based on the underlying mechanism of disease. The duration of symptoms (acute or chronic) and characteristics of the stools (e.g., watery, bloody, steatorrheic, mucoid) can help guide further diagnostic evaluation. Diarrhea (most common symptom)
• Steatorrhea Steatorrhea A condition that is characterized by chronic fatty diarrhea, a result of abnormal digestion and/or intestinal absorption of fats. Diarrhea (bulky, foul-smelling, floating stool)
• Bloating Bloating Constipation and flatulence
• Abdominal cramping Abdominal cramping Norovirus

Extraintestinal manifestations:

• Weight loss Weight loss Decrease in existing body weight. Bariatric Surgery and muscle wasting Muscle Wasting Duchenne Muscular Dystrophy
• Fatigue Fatigue The state of weariness following a period of exertion, mental or physical, characterized by a decreased capacity for work and reduced efficiency to respond to stimuli. Fibromyalgia and weakness
• Failure to thrive Failure to Thrive Failure to thrive (FTT), or faltering growth, describes suboptimal weight gain and growth in children. The majority of cases are due to inadequate caloric intake; however, genetic, infectious, and oncological etiologies are also common. Failure to Thrive in infants and children
• Impaired iron Iron A metallic element with atomic symbol fe, atomic number 26, and atomic weight 55. 85. It is an essential constituent of hemoglobins; cytochromes; and iron-binding proteins. It plays a role in cellular redox reactions and in the transport of oxygen. Trace Elements and folate Folate Folate and vitamin B12 are 2 of the most clinically important water-soluble vitamins. Deficiencies can present with megaloblastic anemia, GI symptoms, neuropsychiatric symptoms, and adverse pregnancy complications, including neural tube defects. Folate and Vitamin B12 absorption Absorption Absorption involves the uptake of nutrient molecules and their transfer from the lumen of the GI tract across the enterocytes and into the interstitial space, where they can be taken up in the venous or lymphatic circulation. Digestion and Absorption → anemia Anemia Anemia is a condition in which individuals have low Hb levels, which can arise from various causes. Anemia is accompanied by a reduced number of RBCs and may manifest with fatigue, shortness of breath, pallor, and weakness. Subtypes are classified by the size of RBCs, chronicity, and etiology. Anemia: Overview and Types
• Impaired vitamin K Vitamin K A lipid cofactor that is required for normal blood clotting. Several forms of vitamin K have been identified: vitamin K 1 (phytomenadione) derived from plants, vitamin K 2 (menaquinone) from bacteria, and synthetic naphthoquinone provitamins, vitamin K 3 (menadione). Vitamin k 3 provitamins, after being alkylated in vivo, exhibit the antifibrinolytic activity of vitamin k. Green leafy vegetables, liver, cheese, butter, and egg yolk are good sources of vitamin k. Fat-soluble Vitamins and their Deficiencies (fat soluble) absorption Absorption Absorption involves the uptake of nutrient molecules and their transfer from the lumen of the GI tract across the enterocytes and into the interstitial space, where they can be taken up in the venous or lymphatic circulation. Digestion and Absorption → prothrombin Prothrombin A plasma protein that is the inactive precursor of thrombin. It is converted to thrombin by a prothrombin activator complex consisting of factor Xa, factor V, phospholipid, and calcium ions. Hemostasis deficiency → bleeding diathesis Bleeding diathesis Wiskott-Aldrich Syndrome
• Hypocalcemia Hypocalcemia Hypocalcemia, a serum calcium < 8.5 mg/dL, can result from various conditions. The causes may include hypoparathyroidism, drugs, disorders leading to vitamin D deficiency, and more. Calcium levels are regulated and affected by different elements such as dietary intake, parathyroid hormone (PTH), vitamin D, pH, and albumin. Presentation can range from an asymptomatic (mild deficiency) to a life-threatening condition (acute, significant deficiency). Hypocalcemia and vitamin deficiencies → motor Motor Neurons which send impulses peripherally to activate muscles or secretory cells. Nervous System: Histology weakness, paresthesias Paresthesias Subjective cutaneous sensations (e.g., cold, warmth, tingling, pressure, etc.) that are experienced spontaneously in the absence of stimulation. Posterior Cord Syndrome, sensory Sensory Neurons which conduct nerve impulses to the central nervous system. Nervous System: Histology loss
• Dermatitis herpetiformis Dermatitis herpetiformis Rare, chronic, papulo-vesicular disease characterized by an intensely pruritic eruption consisting of various combinations of symmetrical, erythematous, papular, vesicular, or bullous lesions. The disease is strongly associated with the presence of hla-b8 and hla-dr3 antigens. A variety of different autoantibodies has been detected in small numbers in patients with dermatitis herpetiformis. Celiac Disease (pruritic papules, vesicles Vesicles Female Genitourinary Examination, and bullae Bullae Erythema Multiforme on the extensor surface of extremities)
• Atrophic glossitis, oral mucosal lesions
• Impaired amino acid Amino acid Amino acids (AAs) are composed of a central carbon atom attached to a carboxyl group, an amino group, a hydrogen atom, and a side chain (R group). Basics of Amino Acids absorption Absorption Absorption involves the uptake of nutrient molecules and their transfer from the lumen of the GI tract across the enterocytes and into the interstitial space, where they can be taken up in the venous or lymphatic circulation. Digestion and Absorption → peripheral edema Peripheral edema Peripheral edema is the swelling of the lower extremities, namely, legs, feet, and ankles. Edema
• Amenorrhea Amenorrhea Absence of menstruation. Congenital Malformations of the Female Reproductive System, delayed menarche Menarche The first menstrual cycle marked by the initiation of menstruation. Menstrual Cycle, and infertility Infertility Infertility is the inability to conceive in the context of regular intercourse. The most common causes of infertility in women are related to ovulatory dysfunction or tubal obstruction, whereas, in men, abnormal sperm is a common cause. Infertility
• Bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Bones: Structure and Types loss, ↑ risk of fractures caused by vitamin D deficiency Vitamin D Deficiency A nutritional condition produced by a deficiency of vitamin D in the diet, insufficient production of vitamin D in the skin, inadequate absorption of vitamin D from the diet, or abnormal conversion of vitamin D to its bioactive metabolites. It is manifested clinically as rickets in children and osteomalacia in adults. Fat-soluble Vitamins and their Deficiencies

Associated conditions

Celiac disease Celiac disease Celiac disease (also known as celiac sprue or gluten enteropathy) is an autoimmune reaction to gliadin, which is a component of gluten. Celiac disease is closely associated with HLA-DQ2 and HLA-DQ8. The immune response is localized to the proximal small intestine and causes the characteristic histologic findings of villous atrophy, crypt hyperplasia, and intraepithelial lymphocytosis. Celiac Disease is also associated with:

• Diabetes Diabetes Diabetes mellitus (DM) is a metabolic disease characterized by hyperglycemia and dysfunction of the regulation of glucose metabolism by insulin. Type 1 DM is diagnosed mostly in children and young adults as the result of autoimmune destruction of β cells in the pancreas and the resulting lack of insulin. Type 2 DM has a significant association with obesity and is characterized by insulin resistance. Diabetes Mellitus mellitus ( type 1 Type 1 Spinal Muscular Atrophy)
• Selective immunoglobulin A ( IgA IgA Represents 15-20% of the human serum immunoglobulins, mostly as the 4-chain polymer in humans or dimer in other mammals. Secretory iga is the main immunoglobulin in secretions. Immunoglobulins: Types and Functions) deficiency
• Autoimmune thyroid Thyroid The thyroid gland is one of the largest endocrine glands in the human body. The thyroid gland is a highly vascular, brownish-red gland located in the visceral compartment of the anterior region of the neck. Thyroid Gland: Anatomy diseases
• Gastroesophageal reflux disease Gastroesophageal Reflux Disease Gastroesophageal reflux disease (GERD) occurs when the stomach acid frequently flows back into the esophagus. This backwash (acid reflux) can irritate the lining of the esophagus, causing symptoms such as retrosternal burning pain (heartburn). Gastroesophageal Reflux Disease (GERD)
• Inflammatory bowel disease and microscopic colitis Colitis Inflammation of the colon section of the large intestine, usually with symptoms such as diarrhea (often with blood and mucus), abdominal pain, and fever. Pseudomembranous Colitis
• Autoimmune myocarditis Autoimmune myocarditis Type IV Hypersensitivity Reaction
• Idiopathic Idiopathic Dermatomyositis dilated cardiomyopathy Dilated Cardiomyopathy Dilated cardiomyopathy (DCM) is the most common type of non-ischemic cardiomyopathy and a common cause of heart failure (HF). The cause may be idiopathic, familial, or secondary to a variety of underlying conditions. The disease is characterized by the enlargement of 1 or both ventricles and reduced systolic function. Dilated Cardiomyopathy

Diagnosis

Diagnosis generally involves a combination of serologic testing and biopsy Biopsy Removal and pathologic examination of specimens from the living body. Ewing Sarcoma in the setting of suggestive history and symptoms. Specialist referral (e.g., gastroenterology) is necessary to help confirm the diagnosis.

Serologic testing

Tests:^[4–6,12]

• Tissue transglutaminase (tTG)-IgA antibody: 
  • Single preferred test for diagnosis (96% sensitivity and specificity Sensitivity and Specificity Binary classification measures to assess test results. Sensitivity or recall rate is the proportion of true positives. Specificity is the probability of correctly determining the absence of a condition. Epidemiological Values of Diagnostic Tests) 
  • Not accurate if the patient is on a gluten-free diet
• Total IgA IgA Represents 15-20% of the human serum immunoglobulins, mostly as the 4-chain polymer in humans or dimer in other mammals. Secretory iga is the main immunoglobulin in secretions. Immunoglobulins: Types and Functions also recommended:
  • Rules out IgA deficiency IgA deficiency A dysgammaglobulinemia characterized by a deficiency of immunoglobulin a. Selective IgA Deficiency, which affects the accuracy of the above tests
  • If IgA-deficient → check IgG-deamidated gliadin Gliadin Simple protein, one of the prolamins, derived from the gluten of wheat, rye, etc. May be separated into 4 discrete electrophoretic fractions. It is the toxic factor associated with celiac disease. Celiac Disease peptide (DGP-IgG) and tTG-IgG
  • Note: IgG IgG The major immunoglobulin isotype class in normal human serum. There are several isotype subclasses of igg, for example, igg1, igg2a, and igg2b. Hypersensitivity Pneumonitis isotype testing is not specific in the absence of IgA deficiency IgA deficiency A dysgammaglobulinemia characterized by a deficiency of immunoglobulin a. Selective IgA Deficiency.
• Other antibodies Antibodies Immunoglobulins (Igs), also known as antibodies, are glycoprotein molecules produced by plasma cells that act in immune responses by recognizing and binding particular antigens. The various Ig classes are IgG (the most abundant), IgM, IgE, IgD, and IgA, which differ in their biologic features, structure, target specificity, and distribution. Immunoglobulins: Types and Functions:
  • IgA IgA Represents 15-20% of the human serum immunoglobulins, mostly as the 4-chain polymer in humans or dimer in other mammals. Secretory iga is the main immunoglobulin in secretions. Immunoglobulins: Types and Functions anti-endomysial Anti-endomysial Celiac Disease antibody (EMA) 
  • IgA IgA Represents 15-20% of the human serum immunoglobulins, mostly as the 4-chain polymer in humans or dimer in other mammals. Secretory iga is the main immunoglobulin in secretions. Immunoglobulins: Types and Functions deamidated gliadin Gliadin Simple protein, one of the prolamins, derived from the gluten of wheat, rye, etc. May be separated into 4 discrete electrophoretic fractions. It is the toxic factor associated with celiac disease. Celiac Disease peptide (DGP): almost as sensitive as tTG but detects antibodies Antibodies Immunoglobulins (Igs), also known as antibodies, are glycoprotein molecules produced by plasma cells that act in immune responses by recognizing and binding particular antigens. The various Ig classes are IgG (the most abundant), IgM, IgE, IgD, and IgA, which differ in their biologic features, structure, target specificity, and distribution. Immunoglobulins: Types and Functions to gliadin Gliadin Simple protein, one of the prolamins, derived from the gluten of wheat, rye, etc. May be separated into 4 discrete electrophoretic fractions. It is the toxic factor associated with celiac disease. Celiac Disease instead of autoantibodies Autoantibodies Antibodies that react with self-antigens (autoantigens) of the organism that produced them. Blotting Techniques
  • Antigliadin antibody (AGA): false positive False positive An FP test result indicates that a person has the disease when they do not. Epidemiological Values of Diagnostic Tests results in 15%–20%

Additional recommendations for serologic testing:^[4–6,12] 

• Serologic tests are obtained with patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship on a gluten-containing diet.
• In children < 2 years of age:
  • There has been concern that tTG and EMA antibodies Antibodies Immunoglobulins (Igs), also known as antibodies, are glycoprotein molecules produced by plasma cells that act in immune responses by recognizing and binding particular antigens. The various Ig classes are IgG (the most abundant), IgM, IgE, IgD, and IgA, which differ in their biologic features, structure, target specificity, and distribution. Immunoglobulins: Types and Functions may be less sensitive, but recent guidelines still indicate tTG-IgA as the initial test of choice.
  • DGP antibodies Antibodies Immunoglobulins (Igs), also known as antibodies, are glycoprotein molecules produced by plasma cells that act in immune responses by recognizing and binding particular antigens. The various Ig classes are IgG (the most abundant), IgM, IgE, IgD, and IgA, which differ in their biologic features, structure, target specificity, and distribution. Immunoglobulins: Types and Functions were previously recommended in this group, but current guidelines only recommend if IgA deficiency IgA deficiency A dysgammaglobulinemia characterized by a deficiency of immunoglobulin a. Selective IgA Deficiency is present.
• For those with negative serology Serology The study of serum, especially of antigen-antibody reactions in vitro. Yellow Fever Virus but high likelihood of celiac disease Celiac disease Celiac disease (also known as celiac sprue or gluten enteropathy) is an autoimmune reaction to gliadin, which is a component of gluten. Celiac disease is closely associated with HLA-DQ2 and HLA-DQ8. The immune response is localized to the proximal small intestine and causes the characteristic histologic findings of villous atrophy, crypt hyperplasia, and intraepithelial lymphocytosis. Celiac Disease (e.g., type 1 Type 1 Spinal Muscular Atrophy diabetes Diabetes Diabetes mellitus (DM) is a metabolic disease characterized by hyperglycemia and dysfunction of the regulation of glucose metabolism by insulin. Type 1 DM is diagnosed mostly in children and young adults as the result of autoimmune destruction of β cells in the pancreas and the resulting lack of insulin. Type 2 DM has a significant association with obesity and is characterized by insulin resistance. Diabetes Mellitus, Down syndrome Down syndrome Down syndrome, or trisomy 21, is the most common chromosomal aberration and the most frequent genetic cause of developmental delay. Both boys and girls are affected and have characteristic craniofacial and musculoskeletal features, as well as multiple medical anomalies involving the cardiac, gastrointestinal, ocular, and auditory systems. Down syndrome (Trisomy 21), family history Family History Adult Health Maintenance), perform duodenal biopsy Biopsy Removal and pathologic examination of specimens from the living body. Ewing Sarcoma.
• In children (and symptomatic patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship who cannot, or choose not to, undergo biopsy Biopsy Removal and pathologic examination of specimens from the living body. Ewing Sarcoma confirmation), a diagnosis can be made with both:
  • tTG > 10 times the upper limit Limit A value (e.g., pressure or time) that should not be exceeded and which is specified by the operator to protect the lung Invasive Mechanical Ventilation of normal
  • Positive EMA from a second blood sample

Endoscopy Endoscopy Procedures of applying endoscopes for disease diagnosis and treatment. Endoscopy involves passing an optical instrument through a small incision in the skin i.e., percutaneous; or through a natural orifice and along natural body pathways such as the digestive tract; and/or through an incision in the wall of a tubular structure or organ, i.e. Transluminal, to examine or perform surgery on the interior parts of the body. Gastroesophageal Reflux Disease (GERD) and duodenal biopsy Biopsy Removal and pathologic examination of specimens from the living body. Ewing Sarcoma

Endoscopy Endoscopy Procedures of applying endoscopes for disease diagnosis and treatment. Endoscopy involves passing an optical instrument through a small incision in the skin i.e., percutaneous; or through a natural orifice and along natural body pathways such as the digestive tract; and/or through an incision in the wall of a tubular structure or organ, i.e. Transluminal, to examine or perform surgery on the interior parts of the body. Gastroesophageal Reflux Disease (GERD) and biopsies are recommended to confirm the diagnosis in children and adults.

If serologic testing is positive → proceed with upper endoscopy Endoscopy Procedures of applying endoscopes for disease diagnosis and treatment. Endoscopy involves passing an optical instrument through a small incision in the skin i.e., percutaneous; or through a natural orifice and along natural body pathways such as the digestive tract; and/or through an incision in the wall of a tubular structure or organ, i.e. Transluminal, to examine or perform surgery on the interior parts of the body. Gastroesophageal Reflux Disease (GERD) with duodenal biopsy Biopsy Removal and pathologic examination of specimens from the living body. Ewing Sarcoma:^[4–6,12]

• Because histologic changes may be patchy, multiple biopsies are performed, requiring:
  • 1 or 2 biopsies of the duodenal bulb 
  • ≥ 4 biopsies of the distal duodenum Duodenum The shortest and widest portion of the small intestine adjacent to the pylorus of the stomach. It is named for having the length equal to about the width of 12 fingers. Small Intestine: Anatomy 
• Endoscopic features:
  • Atrophic mucosa
  • Fissures
  • Scalloping
  • Submucosal vascularity
• Histology:
  • Increased intraepithelial lymphocytes Intraepithelial lymphocytes T lymphocytes with limited diversity of receptors (e.g., alpha e integrins) in the epidermis of the skin and the mucosal linings. They recognize common microbes via t-cell receptors and pathogen-associated molecular pattern molecules and function as effector cells for innate immunity. Activation of intraepithelial lymphocytes is a marker for various gastrointestinal diseases (e.g., celiac disease; hairy cell leukemia; and enteropathy-associated t-cell lymphoma). Adaptive Cell-mediated Immunity
  • Crypt hyperplasia Crypt hyperplasia Celiac Disease
  • Villous atrophy Villous Atrophy Giardia/Giardiasis

If serology Serology The study of serum, especially of antigen-antibody reactions in vitro. Yellow Fever Virus and biopsy Biopsy Removal and pathologic examination of specimens from the living body. Ewing Sarcoma results are discordant:^[4,6] 

• Positive serology Serology The study of serum, especially of antigen-antibody reactions in vitro. Yellow Fever Virus and nondiagnostic biopsy Biopsy Removal and pathologic examination of specimens from the living body. Ewing Sarcoma → perform HLA-DQ2/DQ8 typing
  • If negative, celiac disease Celiac disease Celiac disease (also known as celiac sprue or gluten enteropathy) is an autoimmune reaction to gliadin, which is a component of gluten. Celiac disease is closely associated with HLA-DQ2 and HLA-DQ8. The immune response is localized to the proximal small intestine and causes the characteristic histologic findings of villous atrophy, crypt hyperplasia, and intraepithelial lymphocytosis. Celiac Disease is excluded and an alternative diagnosis should be explored.
  • If positive, a high-gluten diet ( gluten Gluten Prolamins in the endosperm of seeds from the triticeae tribe which includes species of wheat; barley; and rye. Celiac Disease challenge: > 10 g/ day, or ≥ 4 slices of gluten-containing bread per day) is recommended. Repeat biopsy Biopsy Removal and pathologic examination of specimens from the living body. Ewing Sarcoma (at multiple sites) in 6–12 weeks.
• Negative serology Serology The study of serum, especially of antigen-antibody reactions in vitro. Yellow Fever Virus and abnormal biopsy Biopsy Removal and pathologic examination of specimens from the living body. Ewing Sarcoma → perform HLA-DQ2/DQ8 typing
  • If negative, likely not celiac disease Celiac disease Celiac disease (also known as celiac sprue or gluten enteropathy) is an autoimmune reaction to gliadin, which is a component of gluten. Celiac disease is closely associated with HLA-DQ2 and HLA-DQ8. The immune response is localized to the proximal small intestine and causes the characteristic histologic findings of villous atrophy, crypt hyperplasia, and intraepithelial lymphocytosis. Celiac Disease.
  • If positive, place patient on a gluten-free diet for 12–24 months, and repeat biopsy Biopsy Removal and pathologic examination of specimens from the living body. Ewing Sarcoma afterward. Mucosal healing is seen in celiac disease Celiac disease Celiac disease (also known as celiac sprue or gluten enteropathy) is an autoimmune reaction to gliadin, which is a component of gluten. Celiac disease is closely associated with HLA-DQ2 and HLA-DQ8. The immune response is localized to the proximal small intestine and causes the characteristic histologic findings of villous atrophy, crypt hyperplasia, and intraepithelial lymphocytosis. Celiac Disease.
  • No mucosal response indicates a non-celiac cause of villous atrophy Villous Atrophy Giardia/Giardiasis.

Evaluation of malabsorption Malabsorption General term for a group of malnutrition syndromes caused by failure of normal intestinal absorption of nutrients. Malabsorption and Maldigestion^[4,9,12]

• Electrolytes Electrolytes Electrolytes are mineral salts that dissolve in water and dissociate into charged particles called ions, which can be either be positively (cations) or negatively (anions) charged. Electrolytes are distributed in the extracellular and intracellular compartments in different concentrations. Electrolytes are essential for various basic life-sustaining functions. Electrolytes
  • Hypokalemia Hypokalemia Hypokalemia is defined as plasma potassium (K+) concentration < 3.5 mEq/L. Homeostatic mechanisms maintain plasma concentration between 3.5-5.2 mEq/L despite marked variation in dietary intake. Hypokalemia can be due to renal losses, GI losses, transcellular shifts, or poor dietary intake. Hypokalemia
  • Hypocalcemia Hypocalcemia Hypocalcemia, a serum calcium < 8.5 mg/dL, can result from various conditions. The causes may include hypoparathyroidism, drugs, disorders leading to vitamin D deficiency, and more. Calcium levels are regulated and affected by different elements such as dietary intake, parathyroid hormone (PTH), vitamin D, pH, and albumin. Presentation can range from an asymptomatic (mild deficiency) to a life-threatening condition (acute, significant deficiency). Hypocalcemia
  • Hypomagnesemia Hypomagnesemia A nutritional condition produced by a deficiency of magnesium in the diet, characterized by anorexia, nausea, vomiting, lethargy, and weakness. Symptoms are paresthesias, muscle cramps, irritability, decreased attention span, and mental confusion, possibly requiring months to appear. Deficiency of body magnesium can exist even when serum values are normal. In addition, magnesium deficiency may be organ-selective, since certain tissues become deficient before others. Electrolytes
• ↓ Albumin Albumin Serum albumin from humans. It is an essential carrier of both endogenous substances, such as fatty acids and bilirubin, and of xenobiotics in the blood. Liver Function Tests
• ↓ Cholesterol Cholesterol The principal sterol of all higher animals, distributed in body tissues, especially the brain and spinal cord, and in animal fats and oils. Cholesterol Metabolism
• ↓ Hemoglobin
• ↑ PT/INR and PTT ( partial thromboplastin time Partial thromboplastin time The time required for the appearance of fibrin strands following the mixing of plasma with phospholipid platelet substitute (e.g., crude cephalins, soybean phosphatides). It is a test of the intrinsic pathway (factors VIII, IX, XI, and XII) and the common pathway (fibrinogen, prothrombin, factors V and X) of blood coagulation. Hemostasis)
• ↓ Iron Iron A metallic element with atomic symbol fe, atomic number 26, and atomic weight 55. 85. It is an essential constituent of hemoglobins; cytochromes; and iron-binding proteins. It plays a role in cellular redox reactions and in the transport of oxygen. Trace Elements, ferritin Ferritin Iron-containing proteins that are widely distributed in animals, plants, and microorganisms. Their major function is to store iron in a nontoxic bioavailable form. Each ferritin molecule consists of ferric iron in a hollow protein shell (apoferritins) made of 24 subunits of various sequences depending on the species and tissue types. Hereditary Hemochromatosis
• ↓ Vitamin B₁₂
• ↓ Folate Folate Folate and vitamin B12 are 2 of the most clinically important water-soluble vitamins. Deficiencies can present with megaloblastic anemia, GI symptoms, neuropsychiatric symptoms, and adverse pregnancy complications, including neural tube defects. Folate and Vitamin B12
• ↑ Fecal fat

Management and Prognosis

• US guidelines:
  • AGA Clinical Practice Update on Diagnosis and Monitoring of Celiac Disease Celiac disease Celiac disease (also known as celiac sprue or gluten enteropathy) is an autoimmune reaction to gliadin, which is a component of gluten. Celiac disease is closely associated with HLA-DQ2 and HLA-DQ8. The immune response is localized to the proximal small intestine and causes the characteristic histologic findings of villous atrophy, crypt hyperplasia, and intraepithelial lymphocytosis. Celiac Disease^[3]
  • ACG clinical guidelines: diagnosis and management of celiac disease Celiac disease Celiac disease (also known as celiac sprue or gluten enteropathy) is an autoimmune reaction to gliadin, which is a component of gluten. Celiac disease is closely associated with HLA-DQ2 and HLA-DQ8. The immune response is localized to the proximal small intestine and causes the characteristic histologic findings of villous atrophy, crypt hyperplasia, and intraepithelial lymphocytosis. Celiac Disease^[4]
• UK guidelines:
  • National Institute for Health and Care Excellence: Coeliac disease^[5]
  • British Society of Gastroenterology (BSG) guidelines on the diagnosis and management of adult coeliac disease^[6]

Management^[3–6,12]

• Education about the disease
• The mainstay of treatment is a lifelong gluten-free diet.
  • Consultation with a dietitian is recommended.
  • Avoid barley, rye, and wheat.
  • Clinical improvement is seen in most patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship within 2 weeks.
  • The most common reason for treatment failure is incomplete removal of gluten Gluten Prolamins in the endosperm of seeds from the triticeae tribe which includes species of wheat; barley; and rye. Celiac Disease from the diet, either because of poor adherence or inadvertent gluten Gluten Prolamins in the endosperm of seeds from the triticeae tribe which includes species of wheat; barley; and rye. Celiac Disease ingestion in:
    • Breading and coating mixes
    • Croutons
    • Energy bars
    • Imitation bacon or seafood
    • Processed lunch meats
    • Soy sauce
    • Supplements including probiotics and vitamins
    • Alcoholic Alcoholic Persons who have a history of physical or psychological dependence on ethanol. Mallory-Weiss Syndrome (Mallory-Weiss Tear) beverages made from grains
• Many individuals with celiac disease Celiac disease Celiac disease (also known as celiac sprue or gluten enteropathy) is an autoimmune reaction to gliadin, which is a component of gluten. Celiac disease is closely associated with HLA-DQ2 and HLA-DQ8. The immune response is localized to the proximal small intestine and causes the characteristic histologic findings of villous atrophy, crypt hyperplasia, and intraepithelial lymphocytosis. Celiac Disease also have secondary lactose intolerance Lactose intolerance Lactose intolerance (LI) describes a constellation of symptoms due to lactase deficiency (LD), the enzyme located in the brush border of the absorptive cells in the small intestine. Lactose is the disaccharide present in milk and requires hydrolysis by lactase to break it down into its 2 absorbable constituents, glucose and galactose. Lactose intolerance typically presents with bloating, abdominal cramping, diarrhea, and flatulence. Lactose Intolerance.
• Constipation Constipation Constipation is common and may be due to a variety of causes. Constipation is generally defined as bowel movement frequency < 3 times per week. Patients who are constipated often strain to pass hard stools. The condition is classified as primary (also known as idiopathic or functional constipation) or secondary, and as acute or chronic. Constipation due to diet changes can be treated with fiber supplements.
• Additional management:
  • Evaluate for bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Bones: Structure and Types loss:
    • Related to secondary hyperparathyroidism Secondary hyperparathyroidism Abnormally elevated parathyroid hormone secretion as a response to hypocalcemia. It is caused by chronic kidney failure or other abnormalities in the controls of bone and mineral metabolism, leading to various bone diseases, such as renal osteodystrophy. Hyperparathyroidism due to vitamin D deficiency Vitamin D Deficiency A nutritional condition produced by a deficiency of vitamin D in the diet, insufficient production of vitamin D in the skin, inadequate absorption of vitamin D from the diet, or abnormal conversion of vitamin D to its bioactive metabolites. It is manifested clinically as rickets in children and osteomalacia in adults. Fat-soluble Vitamins and their Deficiencies
    • May be reversed with a gluten-free diet
    • Evaluate with a DEXA DEXA Osteoporosis scan
  • Pneumococcal vaccination Vaccination Vaccination is the administration of a substance to induce the immune system to develop protection against a disease. Unlike passive immunization, which involves the administration of pre-performed antibodies, active immunization constitutes the administration of a vaccine to stimulate the body to produce its own antibodies. Vaccination: recommended owing to hyposplenism Hyposplenism Asplenia associated with celiac disease Celiac disease Celiac disease (also known as celiac sprue or gluten enteropathy) is an autoimmune reaction to gliadin, which is a component of gluten. Celiac disease is closely associated with HLA-DQ2 and HLA-DQ8. The immune response is localized to the proximal small intestine and causes the characteristic histologic findings of villous atrophy, crypt hyperplasia, and intraepithelial lymphocytosis. Celiac Disease
  • Screen 1st-degree relatives: Consider serologic testing, especially if symptoms are present.
  • Investigational agents: transglutaminase 2 inhibitors are being studied.

Monitoring response to therapy^[3–6,12]

• Repeat IgA IgA Represents 15-20% of the human serum immunoglobulins, mostly as the 4-chain polymer in humans or dimer in other mammals. Secretory iga is the main immunoglobulin in secretions. Immunoglobulins: Types and Functions anti-tTG antibody and IgA IgA Represents 15-20% of the human serum immunoglobulins, mostly as the 4-chain polymer in humans or dimer in other mammals. Secretory iga is the main immunoglobulin in secretions. Immunoglobulins: Types and Functions ( IgG IgG The major immunoglobulin isotype class in normal human serum. There are several isotype subclasses of igg, for example, igg1, igg2a, and igg2b. Hypersensitivity Pneumonitis) DGP 3–6 months after diagnosis, then every 6–12 months. 
  • ↓ Levels are expected
  • If levels do not decline, suspect gluten Gluten Prolamins in the endosperm of seeds from the triticeae tribe which includes species of wheat; barley; and rye. Celiac Disease ingestion.
• Duodenal biopsy Biopsy Removal and pathologic examination of specimens from the living body. Ewing Sarcoma after 2 years on a gluten-free diet:
  • Evaluates mucosal healing
  • With dietary compliance Compliance Distensibility measure of a chamber such as the lungs (lung compliance) or bladder. Compliance is expressed as a change in volume per unit change in pressure. Veins: Histology, most adults reach complete mucosal healing.
• Identify and treat any nutritional deficiencies.
  • Vitamins A, D, and E
  • B vitamins— thiamine Thiamine Also known as thiamine or thiamin, it is a vitamin C12H17N4OSCl of the vitamin B complex that is essential to normal metabolism and nerve function and is widespread in plants and animals Water-soluble Vitamins and their Deficiencies (B₁), folic acid (B₉), B₆, and B₁₂
  • Copper Copper A heavy metal trace element with the atomic symbol cu, atomic number 29, and atomic weight 63. 55. Trace Elements, zinc Zinc A metallic element of atomic number 30 and atomic weight 65. 38. It is a necessary trace element in the diet, forming an essential part of many enzymes, and playing an important role in protein synthesis and in cell division. Zinc deficiency is associated with anemia, short stature, hypogonadism, impaired wound healing, and geophagia. It is known by the symbol zn. Trace Elements, iron Iron A metallic element with atomic symbol fe, atomic number 26, and atomic weight 55. 85. It is an essential constituent of hemoglobins; cytochromes; and iron-binding proteins. It plays a role in cellular redox reactions and in the transport of oxygen. Trace Elements, magnesium Magnesium A metallic element that has the atomic symbol mg, atomic number 12, and atomic weight 24. 31. It is important for the activity of many enzymes, especially those involved in oxidative phosphorylation. Electrolytes, and selenium Selenium An element with the atomic symbol se, atomic number 34, and atomic weight 78. 97. It is an essential micronutrient for mammals and other animals but is toxic in large amounts. Selenium protects intracellular structures against oxidative damage. It is an essential component of glutathione peroxidase. Trace Elements
  • PT/INR (to evaluate vitamin K Vitamin K A lipid cofactor that is required for normal blood clotting. Several forms of vitamin K have been identified: vitamin K 1 (phytomenadione) derived from plants, vitamin K 2 (menaquinone) from bacteria, and synthetic naphthoquinone provitamins, vitamin K 3 (menadione). Vitamin k 3 provitamins, after being alkylated in vivo, exhibit the antifibrinolytic activity of vitamin k. Green leafy vegetables, liver, cheese, butter, and egg yolk are good sources of vitamin k. Fat-soluble Vitamins and their Deficiencies)
• 6–12 month follow-up for those exhibiting the expected response (to gluten-free diet), which includes:
  • Improvement of symptoms
  • Seroconversion Seroconversion The appearance of antibodies against causative agents in the blood of individuals during the course of an infection or following immunization. HIV Infection and AIDS
  • Histologic improvement
  • Correction of nutritional deficiencies

Nonresponsive celiac disease Celiac disease Celiac disease (also known as celiac sprue or gluten enteropathy) is an autoimmune reaction to gliadin, which is a component of gluten. Celiac disease is closely associated with HLA-DQ2 and HLA-DQ8. The immune response is localized to the proximal small intestine and causes the characteristic histologic findings of villous atrophy, crypt hyperplasia, and intraepithelial lymphocytosis. Celiac Disease^[4–6]

• Celiac disease Celiac disease Celiac disease (also known as celiac sprue or gluten enteropathy) is an autoimmune reaction to gliadin, which is a component of gluten. Celiac disease is closely associated with HLA-DQ2 and HLA-DQ8. The immune response is localized to the proximal small intestine and causes the characteristic histologic findings of villous atrophy, crypt hyperplasia, and intraepithelial lymphocytosis. Celiac Disease with persistent signs and symptoms, or laboratory test results consistent with the disease in spite of adhering to gluten-free diet for 6–12 months
• A small percentage of individuals do not respond to a gluten-free diet or relapse Relapse Relapsing Fever after responding.
• Approach:
  • Confirm that the patient is not inadvertently ingesting gluten Gluten Prolamins in the endosperm of seeds from the triticeae tribe which includes species of wheat; barley; and rye. Celiac Disease; requires a thorough evaluation by the dietitian.
  • Review and confirm diagnosis with supporting evidence.
    • Small bowel Small bowel The small intestine is the longest part of the GI tract, extending from the pyloric orifice of the stomach to the ileocecal junction. The small intestine is the major organ responsible for chemical digestion and absorption of nutrients. It is divided into 3 segments: the duodenum, the jejunum, and the ileum. Small Intestine: Anatomy biopsy Biopsy Removal and pathologic examination of specimens from the living body. Ewing Sarcoma findings and serology Serology The study of serum, especially of antigen-antibody reactions in vitro. Yellow Fever Virus results
    • Presence of HLA-DQ2 or HLA-DQ8
    • Biopsy-proven dermatitis herpetiformis Dermatitis herpetiformis Rare, chronic, papulo-vesicular disease characterized by an intensely pruritic eruption consisting of various combinations of symmetrical, erythematous, papular, vesicular, or bullous lesions. The disease is strongly associated with the presence of hla-b8 and hla-dr3 antigens. A variety of different autoantibodies has been detected in small numbers in patients with dermatitis herpetiformis. Celiac Disease
    • Clinical or histologic response to gluten-free diet
    • Strong family history Family History Adult Health Maintenance of celiac disease Celiac disease Celiac disease (also known as celiac sprue or gluten enteropathy) is an autoimmune reaction to gliadin, which is a component of gluten. Celiac disease is closely associated with HLA-DQ2 and HLA-DQ8. The immune response is localized to the proximal small intestine and causes the characteristic histologic findings of villous atrophy, crypt hyperplasia, and intraepithelial lymphocytosis. Celiac Disease
  • Repeat endoscopic biopsy Biopsy Removal and pathologic examination of specimens from the living body. Ewing Sarcoma. Results may show:
    • Inflammatory enteropathy Enteropathy IPEX Syndrome with villous atrophy Villous Atrophy Giardia/Giardiasis: Consider refractory disease, gluten Gluten Prolamins in the endosperm of seeds from the triticeae tribe which includes species of wheat; barley; and rye. Celiac Disease ingestion, or other causes of villous atrophy Villous Atrophy Giardia/Giardiasis.
    • Normal or near normal histology: Consider alternative diagnosis.
• Consider other causes of small intestinal villous atrophy Villous Atrophy Giardia/Giardiasis.
  • Autoimmune enteropathy Enteropathy IPEX Syndrome
  • Tropical or collagenous sprue
  • Hypogammaglobulinemia Hypogammaglobulinemia Selective IgA Deficiency and combined variable Variable Variables represent information about something that can change. The design of the measurement scales, or of the methods for obtaining information, will determine the data gathered and the characteristics of that data. As a result, a variable can be qualitative or quantitative, and may be further classified into subgroups. Types of Variables immunodeficiency Immunodeficiency Chédiak-Higashi Syndrome ( CVID CVID Common variable immune deficiency (CVID), also known as humoral immunodeficiency, is a disorder of the immune system characterized by reduced serum levels of immunoglobulins g, a, and m. Common Variable Immunodeficiency (CVID))
  • Crohn disease
  • Eosinophilic enteritis Enteritis Inflammation of any segment of the small intestine. Lactose Intolerance
  • Peptic duodenitis
• Consider an alternative or concurrent disease, such as:
  • Irritable bowel syndrome Irritable bowel syndrome Irritable bowel syndrome (IBS) is a functional bowel disease characterized by chronic abdominal pain and altered bowel habits without an identifiable organic cause. The etiology and pathophysiology of this disease are not well understood, and there are many factors that may contribute. Irritable Bowel Syndrome
  • Small bowel Small bowel The small intestine is the longest part of the GI tract, extending from the pyloric orifice of the stomach to the ileocecal junction. The small intestine is the major organ responsible for chemical digestion and absorption of nutrients. It is divided into 3 segments: the duodenum, the jejunum, and the ileum. Small Intestine: Anatomy bacterial overgrowth Bacterial overgrowth Lactose Intolerance (may or may not have villous atrophy Villous Atrophy Giardia/Giardiasis)
  • Pancreatic insufficiency
  • Food intolerances
  • Microscopic colitis Colitis Inflammation of the colon section of the large intestine, usually with symptoms such as diarrhea (often with blood and mucus), abdominal pain, and fever. Pseudomembranous Colitis (specialist referral for possible immunosuppressants Immunosuppressants Immunosuppressants are a class of drugs widely used in the management of autoimmune conditions and organ transplant rejection. The general effect is dampening of the immune response. Immunosuppressants) 
  • Ulcerative jejunitis 
  • Intestinal lymphoma Lymphoma A general term for various neoplastic diseases of the lymphoid tissue. Imaging of the Mediastinum

Refractory disease^[4]

• Persistent or recurrent malabsorptive symptoms and signs with villous atrophy Villous Atrophy Giardia/Giardiasis in small bowel Small bowel The small intestine is the longest part of the GI tract, extending from the pyloric orifice of the stomach to the ileocecal junction. The small intestine is the major organ responsible for chemical digestion and absorption of nutrients. It is divided into 3 segments: the duodenum, the jejunum, and the ileum. Small Intestine: Anatomy biopsy Biopsy Removal and pathologic examination of specimens from the living body. Ewing Sarcoma despite a strict gluten-free diet for > 12 months (in the absence of other disorders)
• Affects 1%–2% of those with celiac disease Celiac disease Celiac disease (also known as celiac sprue or gluten enteropathy) is an autoimmune reaction to gliadin, which is a component of gluten. Celiac disease is closely associated with HLA-DQ2 and HLA-DQ8. The immune response is localized to the proximal small intestine and causes the characteristic histologic findings of villous atrophy, crypt hyperplasia, and intraepithelial lymphocytosis. Celiac Disease
• Management generally involves immunosuppression.
• Differentiation of the type is important for management and prognosis Prognosis A prediction of the probable outcome of a disease based on a individual’s condition and the usual course of the disease as seen in similar situations. Non-Hodgkin Lymphomas:
  • Type 1 Type 1 Spinal Muscular Atrophy: normal intraepithelial lymphocytes Intraepithelial lymphocytes T lymphocytes with limited diversity of receptors (e.g., alpha e integrins) in the epidermis of the skin and the mucosal linings. They recognize common microbes via t-cell receptors and pathogen-associated molecular pattern molecules and function as effector cells for innate immunity. Activation of intraepithelial lymphocytes is a marker for various gastrointestinal diseases (e.g., celiac disease; hairy cell leukemia; and enteropathy-associated t-cell lymphoma). Adaptive Cell-mediated Immunity:
    • Less severe presentation
    • Better prognosis Prognosis A prediction of the probable outcome of a disease based on a individual’s condition and the usual course of the disease as seen in similar situations. Non-Hodgkin Lymphomas
    • Does not evolve into type 2
    • Initial treatment consists of glucocorticoids Glucocorticoids Glucocorticoids are a class within the corticosteroid family. Glucocorticoids are chemically and functionally similar to endogenous cortisol. There are a wide array of indications, which primarily benefit from the antiinflammatory and immunosuppressive effects of this class of drugs. Glucocorticoids (such as prednisone Prednisone A synthetic anti-inflammatory glucocorticoid derived from cortisone. It is biologically inert and converted to prednisolone in the liver. Immunosuppressants).
    • Immunosuppressants Immunosuppressants Immunosuppressants are a class of drugs widely used in the management of autoimmune conditions and organ transplant rejection. The general effect is dampening of the immune response. Immunosuppressants such as azathioprine Azathioprine An immunosuppressive agent used in combination with cyclophosphamide and hydroxychloroquine in the treatment of rheumatoid arthritis. According to the fourth annual report on carcinogens, this substance has been listed as a known carcinogen. Immunosuppressants can be given if there is no response to steroids Steroids A group of polycyclic compounds closely related biochemically to terpenes. They include cholesterol, numerous hormones, precursors of certain vitamins, bile acids, alcohols (sterols), and certain natural drugs and poisons. Steroids have a common nucleus, a fused, reduced 17-carbon atom ring system, cyclopentanoperhydrophenanthrene. Most steroids also have two methyl groups and an aliphatic side-chain attached to the nucleus. Benign Liver Tumors.
  • Type 2: aberrant or premalignant population of intraepithelial lymphocytes Intraepithelial lymphocytes T lymphocytes with limited diversity of receptors (e.g., alpha e integrins) in the epidermis of the skin and the mucosal linings. They recognize common microbes via t-cell receptors and pathogen-associated molecular pattern molecules and function as effector cells for innate immunity. Activation of intraepithelial lymphocytes is a marker for various gastrointestinal diseases (e.g., celiac disease; hairy cell leukemia; and enteropathy-associated t-cell lymphoma). Adaptive Cell-mediated Immunity:
    • Associated with progressive malabsorption Malabsorption General term for a group of malnutrition syndromes caused by failure of normal intestinal absorption of nutrients. Malabsorption and Maldigestion and death in 55% of cases (causes of which include sepsis Sepsis Systemic inflammatory response syndrome with a proven or suspected infectious etiology. When sepsis is associated with organ dysfunction distant from the site of infection, it is called severe sepsis. When sepsis is accompanied by hypotension despite adequate fluid infusion, it is called septic shock. Sepsis and Septic Shock, malnutrition Malnutrition Malnutrition is a clinical state caused by an imbalance or deficiency of calories and/or micronutrients and macronutrients. The 2 main manifestations of acute severe malnutrition are marasmus (total caloric insufficiency) and kwashiorkor (protein malnutrition with characteristic edema). Malnutrition in children in resource-limited countries, and lymphoma Lymphoma A general term for various neoplastic diseases of the lymphoid tissue. Imaging of the Mediastinum).
    • Severe malnutrition Malnutrition Malnutrition is a clinical state caused by an imbalance or deficiency of calories and/or micronutrients and macronutrients. The 2 main manifestations of acute severe malnutrition are marasmus (total caloric insufficiency) and kwashiorkor (protein malnutrition with characteristic edema). Malnutrition in children in resource-limited countries may require parenteral nutrition Parenteral nutrition The administering of nutrients for assimilation and utilization by a patient who cannot maintain adequate nutrition by enteral feeding alone. Nutrients are administered by a route other than the alimentary canal (e.g., intravenously, subcutaneously). Central Venous Catheter.
    • Treatment includes glucocorticoids Glucocorticoids Glucocorticoids are a class within the corticosteroid family. Glucocorticoids are chemically and functionally similar to endogenous cortisol. There are a wide array of indications, which primarily benefit from the antiinflammatory and immunosuppressive effects of this class of drugs. Glucocorticoids and other immunosuppressants Immunosuppressants Immunosuppressants are a class of drugs widely used in the management of autoimmune conditions and organ transplant rejection. The general effect is dampening of the immune response. Immunosuppressants (e.g., azathioprine Azathioprine An immunosuppressive agent used in combination with cyclophosphamide and hydroxychloroquine in the treatment of rheumatoid arthritis. According to the fourth annual report on carcinogens, this substance has been listed as a known carcinogen. Immunosuppressants).
    • In severe illness: hydrocortisone Hydrocortisone The main glucocorticoid secreted by the adrenal cortex. Its synthetic counterpart is used, either as an injection or topically, in the treatment of inflammation, allergy, collagen diseases, asthma, adrenocortical deficiency, shock, and some neoplastic conditions. Immunosuppressants 100 mg IV every 6 hours can be started.
    • For those on an oral diet: oral prednisolone Prednisolone A glucocorticoid with the general properties of the corticosteroids. It is the drug of choice for all conditions in which routine systemic corticosteroid therapy is indicated, except adrenal deficiency states. Immunosuppressants 40–60 mg daily can be given (taper to the lowest dose that maintains remission Remission A spontaneous diminution or abatement of a disease over time, without formal treatment. Cluster Headaches).

Prognosis Prognosis A prediction of the probable outcome of a disease based on a individual’s condition and the usual course of the disease as seen in similar situations. Non-Hodgkin Lymphomas^[8]

• Excellent prognosis Prognosis A prediction of the probable outcome of a disease based on a individual’s condition and the usual course of the disease as seen in similar situations. Non-Hodgkin Lymphomas for those who respond to treatment
• Complications associated with increased mortality Mortality All deaths reported in a given population. Measures of Health Status:
  • Increased risk of lymphoma Lymphoma A general term for various neoplastic diseases of the lymphoid tissue. Imaging of the Mediastinum and GI cancer
    • 6%–8% of patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship
    • Manifests after 20–40 years with the disease
  • Collagenous sprue
    • Refractory disease with subepithelial Subepithelial Membranoproliferative Glomerulonephritis collagen Collagen A polypeptide substance comprising about one third of the total protein in mammalian organisms. It is the main constituent of skin; connective tissue; and the organic substance of bones (bone and bones) and teeth (tooth). Connective Tissue: Histology deposition
    • Leads to severe malabsorption Malabsorption General term for a group of malnutrition syndromes caused by failure of normal intestinal absorption of nutrients. Malabsorption and Maldigestion
  • Ulcerative jejunitis
    • Associated with refractory celiac disease Celiac disease Celiac disease (also known as celiac sprue or gluten enteropathy) is an autoimmune reaction to gliadin, which is a component of gluten. Celiac disease is closely associated with HLA-DQ2 and HLA-DQ8. The immune response is localized to the proximal small intestine and causes the characteristic histologic findings of villous atrophy, crypt hyperplasia, and intraepithelial lymphocytosis. Celiac Disease
    • Aberrant T cell monoclonality causing multiple, chronic ulcers in the jejunum Jejunum The middle portion of the small intestine, between duodenum and ileum. It represents about 2/5 of the remaining portion of the small intestine below duodenum. Small Intestine: Anatomy
    • Can lead to intestinal obstruction Intestinal obstruction Any impairment, arrest, or reversal of the normal flow of intestinal contents toward the anal canal. Ascaris/Ascariasis due to strictures

Differential Diagnosis

• Irritable bowel syndrome Irritable bowel syndrome Irritable bowel syndrome (IBS) is a functional bowel disease characterized by chronic abdominal pain and altered bowel habits without an identifiable organic cause. The etiology and pathophysiology of this disease are not well understood, and there are many factors that may contribute. Irritable Bowel Syndrome ( IBS IBS Irritable bowel syndrome (IBS) is a functional bowel disease characterized by chronic abdominal pain and altered bowel habits without an identifiable organic cause. The etiology and pathophysiology of this disease are not well understood, and there are many factors that may contribute. Irritable Bowel Syndrome): a functional bowel disease presenting with recurrent abdominal pain Abdominal Pain Acute Abdomen and altered bowel habits. Irritable bowel syndrome Irritable bowel syndrome Irritable bowel syndrome (IBS) is a functional bowel disease characterized by chronic abdominal pain and altered bowel habits without an identifiable organic cause. The etiology and pathophysiology of this disease are not well understood, and there are many factors that may contribute. Irritable Bowel Syndrome is a diagnosis of exclusion, and celiac disease Celiac disease Celiac disease (also known as celiac sprue or gluten enteropathy) is an autoimmune reaction to gliadin, which is a component of gluten. Celiac disease is closely associated with HLA-DQ2 and HLA-DQ8. The immune response is localized to the proximal small intestine and causes the characteristic histologic findings of villous atrophy, crypt hyperplasia, and intraepithelial lymphocytosis. Celiac Disease should be ruled out with a negative IgA IgA Represents 15-20% of the human serum immunoglobulins, mostly as the 4-chain polymer in humans or dimer in other mammals. Secretory iga is the main immunoglobulin in secretions. Immunoglobulins: Types and Functions tissue transglutaminase. Treatment includes reassurance Reassurance Clinician–Patient Relationship, dietary modifications, and symptom-control measures.
• Inflammatory bowel disease (IBD): includes Crohn disease and ulcerative colitis Colitis Inflammation of the colon section of the large intestine, usually with symptoms such as diarrhea (often with blood and mucus), abdominal pain, and fever. Pseudomembranous Colitis; characterized by chronic inflammation Chronic Inflammation Inflammation of the GI tract due to a cell-mediated immune response to the GI mucosa. Symptoms include diarrhea Diarrhea Diarrhea is defined as ≥ 3 watery or loose stools in a 24-hour period. There are a multitude of etiologies, which can be classified based on the underlying mechanism of disease. The duration of symptoms (acute or chronic) and characteristics of the stools (e.g., watery, bloody, steatorrheic, mucoid) can help guide further diagnostic evaluation. Diarrhea, abdominal pain Abdominal Pain Acute Abdomen, weight loss Weight loss Decrease in existing body weight. Bariatric Surgery, and extraintestinal manifestations. Diagnosis includes imaging, endoscopy Endoscopy Procedures of applying endoscopes for disease diagnosis and treatment. Endoscopy involves passing an optical instrument through a small incision in the skin i.e., percutaneous; or through a natural orifice and along natural body pathways such as the digestive tract; and/or through an incision in the wall of a tubular structure or organ, i.e. Transluminal, to examine or perform surgery on the interior parts of the body. Gastroesophageal Reflux Disease (GERD), and biopsy Biopsy Removal and pathologic examination of specimens from the living body. Ewing Sarcoma. Celiac antibody serology Serology The study of serum, especially of antigen-antibody reactions in vitro. Yellow Fever Virus will be negative. Treatment involves steroids Steroids A group of polycyclic compounds closely related biochemically to terpenes. They include cholesterol, numerous hormones, precursors of certain vitamins, bile acids, alcohols (sterols), and certain natural drugs and poisons. Steroids have a common nucleus, a fused, reduced 17-carbon atom ring system, cyclopentanoperhydrophenanthrene. Most steroids also have two methyl groups and an aliphatic side-chain attached to the nucleus. Benign Liver Tumors, aminosalicylates, immunomodulators, and biologic agents Biologic Agents Immunosuppressants.
• Chronic pancreatitis Pancreatitis Inflammation of the pancreas. Pancreatitis is classified as acute unless there are computed tomographic or endoscopic retrograde cholangiopancreatographic findings of chronic pancreatitis. The two most common forms of acute pancreatitis are alcoholic pancreatitis and gallstone pancreatitis. Acute Pancreatitis: persistent inflammation Inflammation Inflammation is a complex set of responses to infection and injury involving leukocytes as the principal cellular mediators in the body’s defense against pathogenic organisms. Inflammation is also seen as a response to tissue injury in the process of wound healing. The 5 cardinal signs of inflammation are pain, heat, redness, swelling, and loss of function. Inflammation, fibrosis Fibrosis Any pathological condition where fibrous connective tissue invades any organ, usually as a consequence of inflammation or other injury. Bronchiolitis Obliterans, and irreversible cell damage to the pancreas Pancreas The pancreas lies mostly posterior to the stomach and extends across the posterior abdominal wall from the duodenum on the right to the spleen on the left. This organ has both exocrine and endocrine tissue. Pancreas: Anatomy. Alcohol and biliary obstruction are common causes. Patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship may have steatorrhea Steatorrhea A condition that is characterized by chronic fatty diarrhea, a result of abnormal digestion and/or intestinal absorption of fats. Diarrhea, abdominal pain Abdominal Pain Acute Abdomen, and other malabsorption Malabsorption General term for a group of malnutrition syndromes caused by failure of normal intestinal absorption of nutrients. Malabsorption and Maldigestion symptoms. Imaging will show an atrophic pancreas Pancreas The pancreas lies mostly posterior to the stomach and extends across the posterior abdominal wall from the duodenum on the right to the spleen on the left. This organ has both exocrine and endocrine tissue. Pancreas: Anatomy, dilated ducts, and calcifications. Celiac disease Celiac disease Celiac disease (also known as celiac sprue or gluten enteropathy) is an autoimmune reaction to gliadin, which is a component of gluten. Celiac disease is closely associated with HLA-DQ2 and HLA-DQ8. The immune response is localized to the proximal small intestine and causes the characteristic histologic findings of villous atrophy, crypt hyperplasia, and intraepithelial lymphocytosis. Celiac Disease antibody testing will be negative. Therapy includes alcohol cessation, diet changes, pain Pain An unpleasant sensation induced by noxious stimuli which are detected by nerve endings of nociceptive neurons. Pain: Types and Pathways control, and treatment of pancreatic insufficiency.
• Lactose intolerance Lactose intolerance Lactose intolerance (LI) describes a constellation of symptoms due to lactase deficiency (LD), the enzyme located in the brush border of the absorptive cells in the small intestine. Lactose is the disaccharide present in milk and requires hydrolysis by lactase to break it down into its 2 absorbable constituents, glucose and galactose. Lactose intolerance typically presents with bloating, abdominal cramping, diarrhea, and flatulence. Lactose Intolerance: an intolerance to lactose-containing foods due to lactase deficiency Lactase deficiency Lactose Intolerance. Symptoms include crampy abdominal pain Abdominal Pain Acute Abdomen, bloating Bloating Constipation, nausea Nausea An unpleasant sensation in the stomach usually accompanied by the urge to vomit. Common causes are early pregnancy, sea and motion sickness, emotional stress, intense pain, food poisoning, and various enteroviruses. Antiemetics, and diarrhea Diarrhea Diarrhea is defined as ≥ 3 watery or loose stools in a 24-hour period. There are a multitude of etiologies, which can be classified based on the underlying mechanism of disease. The duration of symptoms (acute or chronic) and characteristics of the stools (e.g., watery, bloody, steatorrheic, mucoid) can help guide further diagnostic evaluation. Diarrhea. Diagnosis is based on the association with lactose-containing foods and a lactose hydrogen breath test Hydrogen breath test Lactose Intolerance. Management includes restriction of dietary lactose and enzyme replacement Enzyme replacement Therapeutic replacement or supplementation of defective or missing enzymes to alleviate the effects of enzyme deficiency (e.g., glucosylceramidase replacement for gaucher disease). Severe Combined Immunodeficiency (SCID). It is common for patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship with celiac disease Celiac disease Celiac disease (also known as celiac sprue or gluten enteropathy) is an autoimmune reaction to gliadin, which is a component of gluten. Celiac disease is closely associated with HLA-DQ2 and HLA-DQ8. The immune response is localized to the proximal small intestine and causes the characteristic histologic findings of villous atrophy, crypt hyperplasia, and intraepithelial lymphocytosis. Celiac Disease to have concurrent lactose intolerance Lactose intolerance Lactose intolerance (LI) describes a constellation of symptoms due to lactase deficiency (LD), the enzyme located in the brush border of the absorptive cells in the small intestine. Lactose is the disaccharide present in milk and requires hydrolysis by lactase to break it down into its 2 absorbable constituents, glucose and galactose. Lactose intolerance typically presents with bloating, abdominal cramping, diarrhea, and flatulence. Lactose Intolerance.
• Small intestinal bacterial overgrowth Bacterial overgrowth Lactose Intolerance: excessive bacteria Bacteria Bacteria are prokaryotic single-celled microorganisms that are metabolically active and divide by binary fission. Some of these organisms play a significant role in the pathogenesis of diseases. Bacteriology growing in the small intestine Small intestine The small intestine is the longest part of the GI tract, extending from the pyloric orifice of the stomach to the ileocecal junction. The small intestine is the major organ responsible for chemical digestion and absorption of nutrients. It is divided into 3 segments: the duodenum, the jejunum, and the ileum. Small Intestine: Anatomy due to alterations in intestinal anatomy or motility Motility The motor activity of the gastrointestinal tract. Gastrointestinal Motility. Symptoms can range from mildly symptomatic to chronic diarrhea Diarrhea Diarrhea is defined as ≥ 3 watery or loose stools in a 24-hour period. There are a multitude of etiologies, which can be classified based on the underlying mechanism of disease. The duration of symptoms (acute or chronic) and characteristics of the stools (e.g., watery, bloody, steatorrheic, mucoid) can help guide further diagnostic evaluation. Diarrhea, weight loss Weight loss Decrease in existing body weight. Bariatric Surgery, and malabsorption Malabsorption General term for a group of malnutrition syndromes caused by failure of normal intestinal absorption of nutrients. Malabsorption and Maldigestion. Individuals with this condition may or may not have villous atrophy Villous Atrophy Giardia/Giardiasis. Bacterial cultures and breath tests can distinguish this condition from celiac disease Celiac disease Celiac disease (also known as celiac sprue or gluten enteropathy) is an autoimmune reaction to gliadin, which is a component of gluten. Celiac disease is closely associated with HLA-DQ2 and HLA-DQ8. The immune response is localized to the proximal small intestine and causes the characteristic histologic findings of villous atrophy, crypt hyperplasia, and intraepithelial lymphocytosis. Celiac Disease. Treatment includes antibiotics and correction of nutritional deficiencies.
• Microscopic colitis Colitis Inflammation of the colon section of the large intestine, usually with symptoms such as diarrhea (often with blood and mucus), abdominal pain, and fever. Pseudomembranous Colitis: a chronic inflammatory disease of the colon Colon The large intestines constitute the last portion of the digestive system. The large intestine consists of the cecum, appendix, colon (with ascending, transverse, descending, and sigmoid segments), rectum, and anal canal. The primary function of the colon is to remove water and compact the stool prior to expulsion from the body via the rectum and anal canal. Colon, Cecum, and Appendix: Anatomy; can be categorized as collagenous or lymphocytic colitis Colitis Inflammation of the colon section of the large intestine, usually with symptoms such as diarrhea (often with blood and mucus), abdominal pain, and fever. Pseudomembranous Colitis. Patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship tend to be middle-aged with chronic, watery diarrhea Watery diarrhea Rotavirus, abdominal pain Abdominal Pain Acute Abdomen, and bloating Bloating Constipation. A colonoscopy Colonoscopy Endoscopic examination, therapy or surgery of the luminal surface of the colon. Colorectal Cancer Screening will appear normal, but inflammatory cells, cryptitis, or a subepithelial Subepithelial Membranoproliferative Glomerulonephritis collagen Collagen A polypeptide substance comprising about one third of the total protein in mammalian organisms. It is the main constituent of skin; connective tissue; and the organic substance of bones (bone and bones) and teeth (tooth). Connective Tissue: Histology band will be seen on biopsy Biopsy Removal and pathologic examination of specimens from the living body. Ewing Sarcoma, differentiating the condition from celiac disease Celiac disease Celiac disease (also known as celiac sprue or gluten enteropathy) is an autoimmune reaction to gliadin, which is a component of gluten. Celiac disease is closely associated with HLA-DQ2 and HLA-DQ8. The immune response is localized to the proximal small intestine and causes the characteristic histologic findings of villous atrophy, crypt hyperplasia, and intraepithelial lymphocytosis. Celiac Disease. Treatment includes trigger Trigger The type of signal that initiates the inspiratory phase by the ventilator Invasive Mechanical Ventilation avoidance, glucocorticoids Glucocorticoids Glucocorticoids are a class within the corticosteroid family. Glucocorticoids are chemically and functionally similar to endogenous cortisol. There are a wide array of indications, which primarily benefit from the antiinflammatory and immunosuppressive effects of this class of drugs. Glucocorticoids, and symptom management.