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Not All That Flattens Villi Is Celiac Disease: A Review of Enteropathies

      Abstract

      Enteropathies can be overwhelming for clinicians. There is a wide spectrum of diseases involved; their effect on patients can be severe; and their underlying cause can be obscure. In this article, we outline a practical approach to enteropathies that are most common and not to be missed and is applicable to general and specialist physicians.

      Abbreviations and Acronyms:

      CD (celiac disease), CVID (common variable immune deficiency), HIV (human immunodeficiency virus)
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      Learning Objectives: On completion of this article, you should be able to (1) identify the most common causes of villous atrophy, (2) describe the not to miss diagnoses of villous atrophy, and (3) recommend appropriate work-up and testing for the clinical situation.
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      In their editorial and administrative roles, Karl A. Nath, MBChB, Terry L. Jopke, Kimberly D. Sankey, and Jenna M. Pederson, have control of the content of this program but have no relevant financial relationship(s) with industry.
      Dr Murray is a board member of Celimmune. He is a consultant for Boehringer Ingelheim, Inova Diagnostics, BioLineRx, GlaxoSmithKline, ImmusanT, Institute for Protein Design (PvP Biologics), Takeda Pharmaceutical, Innovate Biopharmaceuticals, Intrexon, MediBeacon, UCB (Atlanta), Allakos, and Rockwell Medical. He has received a research grant from the Broad Medical Research Program at the Crohn’s and Colitis Foundation of America, the National Institutes of Health, and the Oberkotter Foundation. He has received money for patents from Miomics. He has received royalties from Torax.
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      Diseases of the small intestine, termed enteropathies, are a common cause of diarrhea.
      • Murray J.A.
      • Rubio-Tapia A.
      Diarrhoea due to small bowel diseases.
      The small intestine functions as both an absorptive and a secretory organ. When damaged, both absorptive failure and secretion excess can occur.
      • Murray J.A.
      • Rubio-Tapia A.
      Diarrhoea due to small bowel diseases.
      Features of clinically significant enteropathy include diarrhea and malabsorption, leading to weight loss. Oily, pale, foul-smelling, or bulky stools; postprandial bowel movements; and bloating are suggestive of steatorrhea.
      • Murray J.A.
      • Rubio-Tapia A.
      Diarrhoea due to small bowel diseases.
      Enteropathies are of particular interest to internists and gastroenterologists alike because the differential diagnosis is challenging and extensive. Thus, a thorough systemic evaluation is required to identify both the cause and direct therapy.
      Numerous patients present with diarrhea, but not all have an enteropathy. We must identify the more serious cases because of the potentially significant effect on morbidity and mortality. The malabsorption associated with enteropathies can be severe, and at times it can require parenteral nutrition. In certain cases, namely, collagenous sprue and Whipple disease, enteropathy can be fatal. It is important to determine the cause of enteropathy because although certain principles of management, such as corticosteroids, are similar in different etiologies, there are also unique therapeutic options that depend on the underlying diagnosis.
      Although there are myriad causes of enteropathy, we will limit the scope of this article to those that cause villous atrophy, thereby creating an environment of malabsorption resulting in clinically significant weight loss and possible nutritional deficiencies in addition to diarrhea. We will focus on the high-yield etiologies that are the most common (celiac disease [CD], medications, collagenous sprue, and common variable immune deficiency) and on the not to miss diagnoses (human immunodeficiency virus [HIV], tropical sprue, giardiasis, Whipple disease, and viral infection). As such, this article will not address small-bowel ischemia, food allergies, Crohn disease, abetalipoproteinemia, amyloidosis, eosinophilic enteritis, tuberculosis, Zollinger-Ellison syndrome, gastric metaplasia, lymphoproliferative diseases, autoimmune enteropathy, small intestinal bacterial overgrowth, and others.
      • Rubio-Tapia A.
      • Murray J.A.
      Classification and management of refractory coeliac disease.
      Items from this list will be briefly highlighted in our comprehensive table (Table), but not discussed. Relative frequencies of causes of villous atrophy not including CD are shown in Figure 1.
      TableCauses of Villous Atrophy
      Information from Am J Gastroenterol,
      • DeGaetani M.
      • Tennyson C.A.
      • Lebwohl B.
      • et al.
      Villous atrophy and negative celiac serology: a diagnostic and therapeutic dilemma.
      Gut,
      • Aziz I.
      • Peerally M.F.
      • Barnes J.
      • et al.
      The clinical and phenotypical assessment of seronegative villous atrophy; a prospective UK centre experience evaluating 200 adult cases over a 15-year period (2000-2015).
      and Aliment Pharmacol Ther.
      • Pallav K.
      • Leffler D.A.
      • Tariq S.
      • et al.
      Noncoeliac enteropathy: the differential diagnosis of villous atrophy in contemporary clinical practice.
      CategoryDiagnosisHistorical cluesStudy resultsTreatment
      AutoimmuneCeliac diseaseWorsens with dietary gluten (wheat, barley, rye)Positive TTG, EMA, range from inflammation to villous atrophy on biopsyGluten-free diet
      Crohn diseaseOther areas of the gastrointestinal tract involvedElevated ESR, CRP levels, characteristic biopsyImmunosuppression, steroids, immunotherapy
      Autoimmune or immune-mediated enteropathyOther autoimmune disease, mesenteric lymphadenopathyPositive anti-enterocyte antibodyImmunosuppression, steroids—budesonide
      Medication-relatedAngiotensin receptor blockerHypertension, medication listLack of autoantibodies, HLA DQ2 or DQ8 presentDiscontinue the offending agent
      NeoplasticImmunoproliferative small intestinal lymphomaYoung men, Middle Eastern or Mediterranean populations, low socioeconomic status, previous enteric infectionsImmunostains on biopsyHematologist consult for consideration of chemotherapy
      Enteropathy-associated T-cell lymphomaHistory of celiac disease, resurgence of symptoms despite a gluten-free dietImmunostains on biopsyHematologist consult for consideration of chemotherapy
      Diffuse large B-cell lymphomaWeight loss, fevers, night sweats, older adults, history of IBD or Epstein-Barr virusImmunostains on biopsyHematologist consult for consideration of chemotherapy
      InfiltrativeAmyloidosisPseudo-obstruction, diarrhea or constipation, macroglossia, neuropathy, periorbital purpura after proctoscopyCongo red stain on biopsy or subcutaneous fat pad aspirateLimited options, experimental therapies
      Eosinophilic enteritisAllergies, food intolerancesElevated IgE levels, infiltration of eosinophils, eosinophiliaCorticosteroids
      Collagenous sprueOlder women, can be secondary product of other primary diseaseThick band of the subepithelial collagen on histopathologyGluten-free diet, corticosteroids—budesonide
      InfectiousHIVWeight loss, changes in fat distributionLow CD4 count, positive HIV testAntiretroviral therapy
      Tropical sprueTravel to the tropics (especially Cuba, Haiti, Puerto Rico, the Dominican Republic, India, Vietnam, Burma, Malaysia, and Indonesia, but not China, Africa, the Middle East, the Bahamas, or Jamaica)Low folate and/or vitamin B12Tetracyclines and folic acid (3-6 mo)
      GiardiasisCamping, sick contacts, day care center exposureGiardia antigen in stool, O&P stool microscopyMetronidazole or similar tinidazole medications
      Whipple diseaseEye involvement, fevers, arthralgias, ataxia, cognitive impairmentIntracellular organisms on periodic acid–Schiff stain, PCRCeftriaxone or penicillin G and then TMP/SMX or doxycycline and hydroxychloroquine
      TuberculosisEndemic area, fever, night sweatsTuberculin skin test, QuantiFERON Gold test, acid-fast stainRIPE therapy—rifampin, isoniazid, pyrazinamide, ethambutol
      Viral infection/post-viral syndromeRecent self-limiting illnessOther negative studiesSupportive care
      Small intestinal bacterial overgrowthAbnormal structure or function (motility) of small bowel, no weight lossElevated hydrogen or methane on breath testAntibiotics—rifaximin and others
      Helicobacter pylori (can rarely lead to celiac-like changes, usually lymphocytic enteritis)Residence in a developing countryH pylori stool antigen detected, CO2 detected on urea breath test, positive serology, biopsy with presence of urease, culture and histology consistent with H pyloriQuadruple therapy—bismuth, metronidazole, tetracycline, proton pump inhibitor
      InflammatoryPeptic duodenitisPeptic ulcer diseaseUlcer visible on endoscopy or positive H pylori testProton pump inhibitor
      Diet-relatedMalnutritionWeight loss, failure to thriveLow albumin, prealbumin, hemoglobin, vitamin and mineral, sodium, BUN, creatinine levelsSupportive care, nutritional support
      Food allergyAtopy, numerous allergiesReaction on skin test, elevated IgE levels, trial elimination dietsAllergen avoidance
      IschemicSmall bowel ischemiaCardiovascular disease history, thrombotic conditions, hypovolemia, dialysisIschemia or occlusion seen on CT angiographyPain control, hemodynamic support, anticoagulation, antibiotics, surgical exploration
      OtherCommon variable immune deficiencyRecurrent sinopulmonary infections, autoimmune cytopeniasLow IgG, IgA, or IgM levels, lack of response to pneumococcal vaccine, absence of plasma cells on biopsyIntravenous immunoglobulin (for recurrent infections) and corticosteroids (for enteropathy)
      Radiation enteritisPrevious cancer therapy with radiationPallor, friability, telangiectasias on endoscopyDietary modification, antidiarrheal agents, bile acid resins, surgical resection
      Idiopathic or unclassified sprueNo response to a gluten-free dietOther negative studiesSteroids and/or immunosuppression
      BUN = blood urea nitrogen; CRP = C-reactive protein; CT = computed tomography; EMA = endomysial antibody; ESR = erythrocyte sedimentation rate; HIV = human immunodeficiency virus; HLA = human leukocyte antigen; IBD = inflammatory bowel disease; O&P = ova and parasite; PCR = polymerase chain reaction; TMP/SMX = trimethoprim/sulfamethoxazole; TTG = tissue transglutaminase.
      Figure thumbnail gr1
      Figure 1Frequencies of causes of villous atrophy other than CD. CD = celiac disease; CVID = common variable immune deficiency; HIV = human immunodeficiency virus; SIBO = small intestinal bacterial overgrowth; TB = tuberculosis.
      Adapted from Am J Gastroenterol,
      • DeGaetani M.
      • Tennyson C.A.
      • Lebwohl B.
      • et al.
      Villous atrophy and negative celiac serology: a diagnostic and therapeutic dilemma.
      Gut,
      • Aziz I.
      • Peerally M.F.
      • Barnes J.
      • et al.
      The clinical and phenotypical assessment of seronegative villous atrophy; a prospective UK centre experience evaluating 200 adult cases over a 15-year period (2000-2015).
      and Aliment Pharmacol Ther.
      • Pallav K.
      • Leffler D.A.
      • Tariq S.
      • et al.
      Noncoeliac enteropathy: the differential diagnosis of villous atrophy in contemporary clinical practice.

      Common Causes of Villous Atrophy

      We begin by addressing some of the most common causes of enteropathy.

      Celiac Disease Including Seronegative

      Celiac disease (CD) is an autoimmune disorder involving chronic inflammation of the small intestine due to an immune reaction against ingested gluten. Seropositive and seronegative CD are the most common causes of enteropathy causing villous atrophy. Celiac disease affects roughly 1% of the population and is largely undiagnosed.
      • Murray J.A.
      • Rubio-Tapia A.
      Diarrhoea due to small bowel diseases.
      The broad range of presentations may partially explain this deficit in diagnosis. Although classical CD presents with malabsorption, it can also present with atypical symptoms, such as elevated liver enzymes and infertility, or with no symptoms. These nonclassical presentations are increasing in frequency, particularly in the undiagnosed cohort.
      Current guidelines recommend case finding for detection of CD, which involves testing individuals with either classical or nonclassical symptoms, or associated at-risk conditions such as autoimmune diseases or Down syndrome.
      • Rubio-Tapia A.
      • Hill I.D.
      • Kelly C.P.
      • Calderwood A.H.
      • Murray J.A.
      American College of Gastroenterology. ACG clinical guidelines: diagnosis and management of celiac disease.
      A family history of CD is a significant risk factor and should be sought in the history and prompt evaluation. An initial screening test for CD includes tissue transglutaminase antibodies.
      • Rubio-Tapia A.
      • Hill I.D.
      • Kelly C.P.
      • Calderwood A.H.
      • Murray J.A.
      American College of Gastroenterology. ACG clinical guidelines: diagnosis and management of celiac disease.
      Gliadin antibodies are no longer recommended, although deamidated gliadin antibodies can be helpful in indeterminate cases. Routinely, IgA isotype antibodies are used; all individuals should be screened for IgA deficiency and, if present, should be tested with IgG isotype antibodies. In cases of positive serology or negative serology with high clinical suspicion for CD, the criterion standard diagnostic test, upper endoscopy with multiple bulb and distal duodenum biopsies should be performed.
      • Rubio-Tapia A.
      • Hill I.D.
      • Kelly C.P.
      • Calderwood A.H.
      • Murray J.A.
      American College of Gastroenterology. ACG clinical guidelines: diagnosis and management of celiac disease.
      Histologic changes consistent with CD range from inflammation to villous atrophy and are stratified using the Marsh-Oberhuber classification.
      • Rubio-Tapia A.
      • Hill I.D.
      • Kelly C.P.
      • Calderwood A.H.
      • Murray J.A.
      American College of Gastroenterology. ACG clinical guidelines: diagnosis and management of celiac disease.
      Once diagnosed, the recommended treatment is a lifelong gluten-free diet after receiving instructions and education from a dietitian with expertise.
      • Rubio-Tapia A.
      • Hill I.D.
      • Kelly C.P.
      • Calderwood A.H.
      • Murray J.A.
      American College of Gastroenterology. ACG clinical guidelines: diagnosis and management of celiac disease.
      Generally, patients respond well to this, and if they do not, detailed investigation into inadvertent gluten contamination should be performed before evaluating for alternative diagnoses.
      Most cases of CD will have positive serology, but there is a minority in which serology will be negative (5%-10%), termed seronegative CD. This is defined by negative celiac serology, positive histologic findings, and permissive human leukocyte antigen DQ2 and DQ8 haplotypes
      • Ierardi E.
      • Losurdo G.
      • Piscitelli D.
      • et al.
      Seronegative celiac disease: where is the specific setting?.
      and is suggested to be the most common cause of villous atrophy in the setting of negative celiac serology.
      • Volta U.
      • Caio G.
      • Boschetti E.
      • et al.
      Seronegative celiac disease: shedding light on an obscure clinical entity.
      Although the reason for seronegativity is unknown, one hypothesis is that antibodies are trapped in the small intestinal mucosa and do not pass into the bloodstream, in which they could be detected by serological tests. In addition, those who are already limiting gluten in their diets or those who are IgA deficient may inadvertently be grouped into this category. Management of seronegative CD is similar to that of seropositive CD with a strict gluten-free diet.
      • Ierardi E.
      • Losurdo G.
      • Piscitelli D.
      • et al.
      Seronegative celiac disease: where is the specific setting?.

      Medications

      Diarrhea is a common adverse effect of several medications, and certain drugs damage the small intestine itself, resulting in medication-induced enteropathy. Mycophenolate mofetil, azathioprine, methotrexate, and nonsteroidal anti-inflammatory drugs are well-recognized culprits.
      • Freeman H.J.
      Drug-induced sprue-like intestinal disease.
      More recently, olmesartan-associated enteropathy has been identified.
      • Rubio-Tapia A.
      • Herman M.L.
      • Ludvigsson J.F.
      • et al.
      Severe spruelike enteropathy associated with olmesartan.
      It is typically classified by severe malabsorptive symptoms commonly leading to nutritional deficiencies and electrolyte abnormalities.
      • Hujoel I.A.
      • Rubio-Tapia A.
      Sprue-like enteropathy associated with olmesartan: a new kid on the enteropathy block.
      Most cases have either human leukocyte antigen DQ2 or DQ8 haplotype. Histologic features, including villous atrophy and a subepithelial collagenous layer consistent with collagenous sprue, can be found in the small bowel, gastric, and colonic mucosa.
      • Hujoel I.A.
      • Rubio-Tapia A.
      Sprue-like enteropathy associated with olmesartan: a new kid on the enteropathy block.
      Diagnosis requires these histologic findings, negative celiac serology, lack of response to a gluten-free diet, and improvement after discontinuing olmesartan.
      • Rubio-Tapia A.
      • Herman M.L.
      • Ludvigsson J.F.
      • et al.
      Severe spruelike enteropathy associated with olmesartan.
      Treatment involves withdrawal of the drug, and in severe cases topical or systemic corticosteroids. Although controversial, some evidence, including a case report on valsartan, suggests that enteropathy may be a class-related drug effect.
      • Hujoel I.A.
      • Rubio-Tapia A.
      Sprue-like enteropathy associated with olmesartan: a new kid on the enteropathy block.

      Collagenous Sprue

      Collagenous sprue is a rare condition that is part of a family of collagenous gastroenteritides that includes collagenous gastritis and colitis, the latter being the most common.
      • Freeman H.J.
      Update on collagenous sprue.
      Classically this is a disease of older women, and although the etiology of the collagen deposits is not known, in some cases it is felt to be the pathological consequence of another disease process, such as CD, tropical sprue, or medication-associated enteropathy.
      • Freeman H.J.
      Update on collagenous sprue.
      • Rubio-Tapia A.
      • Talley N.J.
      • Gurudu S.R.
      • Wu T.T.
      • Murray J.A.
      Gluten-free diet and steroid treatment are effective therapy for most patients with collagenous sprue.
      Collagenous sprue is characterized by histologic findings of villous atrophy and a distinct layer of the subepithelial collagen in the small bowel mucosa (usually >20 μm). The presentation can be severe with significant malnutrition. Treatment is targeted at the associated condition (if known) and often also includes topical corticosteroids or immunosuppressants. It is uncommon to have treatment lead to resolution, and previous case reports detail a high risk of mortality, but resolution can potentially be seen in those cases in which the underlying etiology is reversible, such as in the case of comorbid CD or medication-associated enteropathies.
      • Freeman H.J.
      Update on collagenous sprue.
      • Rubio-Tapia A.
      • Talley N.J.
      • Gurudu S.R.
      • Wu T.T.
      • Murray J.A.
      Gluten-free diet and steroid treatment are effective therapy for most patients with collagenous sprue.

      Common Variable Immune Deficiency

      Common variable immune deficiency (CVID) is a rare disorder that can be either congenital or acquired and can therefore occur at any age. This disease involves deficient production of immunoglobulins and is characterized by low levels of at least 2 serum isotypes (other isotypes are IgG, IgE, IgA, IgM, and IgD), frequently IgA.
      • Malamut G.
      • Verkarre V.
      • Suarez F.
      • et al.
      The enteropathy associated with common variable immunodeficiency: the delineated frontiers with celiac disease.
      Typically, individuals present with frequent respiratory tract infections and poor response to vaccinations. Diarrhea and malabsorption are common symptoms, and individuals are at risk for intestinal infections (eg, recurrent giardiasis) and small intestinal bacterial overgrowth. In one-third to one-half of cases of CVID, gastrointestinal symptoms are associated with villous atrophy (more commonly partial as opposed to severe), felt to be secondary to dysregulation of the intestinal immune system.
      • Malamut G.
      • Verkarre V.
      • Suarez F.
      • et al.
      The enteropathy associated with common variable immunodeficiency: the delineated frontiers with celiac disease.
      Common variable immune deficiency is diagnosed by measuring serum immunoglobulins, and CVID enteropathy is characterized by villous atrophy on histologic examination with little to no plasma cells.
      • Malamut G.
      • Verkarre V.
      • Suarez F.
      • et al.
      The enteropathy associated with common variable immunodeficiency: the delineated frontiers with celiac disease.
      Nodular lymphoid hyperplasia is a common finding. Management of the underlying CVID involves intravenous immunoglobulin therapy in certain cases, although this does not help the gastrointestinal involvement and resultant symptoms.
      • Malamut G.
      • Verkarre V.
      • Suarez F.
      • et al.
      The enteropathy associated with common variable immunodeficiency: the delineated frontiers with celiac disease.
      Aggressive treatment of associated gastrointestinal tract infections is recommended. Budesonide may be effective for gastrointestinal symptoms after infection has been ruled out.
      • Malamut G.
      • Verkarre V.
      • Suarez F.
      • et al.
      The enteropathy associated with common variable immunodeficiency: the delineated frontiers with celiac disease.

      Not To Miss Diagnoses of Villous Atrophy

      Next we shift our discussion to diagnoses that should not be missed.

      Human Immunodeficiency Virus

      Wasting syndrome—manifested as weight loss, malnutrition, and diarrhea—and opportunistic enteric infections are well-known complications of HIV. A lesser known consequence, although common in HIV, is dysfunction of the small intestine in the absence of microorganism infection—termed HIV enteropathy. It is debatable whether this enteropathy results from direct damage to the mucosa by the virus or immunological disturbances such as the markedly low level of CD4+ T cells in the intestinal mucosa.
      • Zeitz M.
      • Ullrich R.
      • Schneider T.
      • Kewenig S.
      • Hohloch K.
      • Riecken E.O.
      HIV/SIV enteropathy.
      Human immunodeficiency virus enteropathy results in partial villous atrophy, epithelial hypoproliferation, and enterocyte dysfunction leading to decreased brush border enzyme activity causing malabsorption.
      • Zeitz M.
      • Ullrich R.
      • Schneider T.
      • Kewenig S.
      • Hohloch K.
      • Riecken E.O.
      HIV/SIV enteropathy.
      This entity improves with antiretroviral therapy. It is important to search for HIV as a cause of enteropathy because the infection has devastating consequences and potential for spread if undetected and untreated.

      Tropical Sprue

      Tropical sprue is an enteropathy that affects travelers to and residents of certain tropical regions. Endemic areas include locations between 30° north and south of the equator, but all nations are not affected equally.
      • Gray G.M.
      Tropical sprue.
      It is uncommon in travelers with visits of less than 2 weeks; typically afflicted travelers have stayed for a month or longer. The pathogenesis of tropical sprue is unclear but thought to be infectious (exact pathogen unknown) in nature, with subsequent bacterial overgrowth attacking the structure of the small bowel.
      • Turner J.R.
      The gastrointestinal tract.
      The resultant intestinal injury affects absorption, particularly of carbohydrates, fat, vitamin B12, and especially folate. It presents with malabsorption, borborygmi, and sequelae of nutritional deficiencies. Intestinal biopsies reveal villous atrophy to a lesser degree than in CD, which supports the diagnosis, but ultimately, response to treatment confirms it.
      • Turner J.R.
      The gastrointestinal tract.
      Treatment is with antibiotics (commonly tetracycline) and folate supplementation for a duration of 3 to 6 months.
      • Sweetser S.
      Diarrhea, malabsorption, and small-bowel disorders.
      This condition is not to be missed because it can be detected from the history of travel and requires a long course of treatment. In addition, if not managed with behavior change or improved precautions, it can recur, as reexposure to the pathogen is not only possible but likely for those living in the tropics.

      Giardiasis

      Another infection to be mindful of is Giardia intestinalis (also called giardia lamblia or duodenalis). It is a food- and waterborne parasite with broad geographic reach; it is the leading parasite responsible for enteric infections in the United States.
      • Painter J.E.
      • Gargano J.W.
      • Collier S.A.
      • Yoder J.S.
      Centers for Disease Control and Prevention
      Giardiasis surveillance—United States, 2011-2012.
      It is frequently found in areas with limited water treatment capacity and poor sanitary conditions.
      • Painter J.E.
      • Gargano J.W.
      • Collier S.A.
      • Yoder J.S.
      Centers for Disease Control and Prevention
      Giardiasis surveillance—United States, 2011-2012.
      It can also be transmitted fecal-orally.
      • Turner J.R.
      The gastrointestinal tract.
      The parasite has 2 forms: cysts and trophozoites. Cysts are infectious and can be ingested and excreted.
      • Painter J.E.
      • Gargano J.W.
      • Collier S.A.
      • Yoder J.S.
      Centers for Disease Control and Prevention
      Giardiasis surveillance—United States, 2011-2012.
      Trophozoites are pear-shaped multi-flagellated forms and localize to the small intestine in which they attach to the surface but do not invade.
      • Turner J.R.
      The gastrointestinal tract.
      Illness is characterized by bloating, flatulence, abdominal cramping, watery diarrhea, malabsorption, and weight loss. Diagnosis is made by stool examination (detection of giardia antigen) or detection of the characteristically shaped organisms by the pathologist. Villous atrophy can be present on small intestinal biopsy.
      • DeGaetani M.
      • Tennyson C.A.
      • Lebwohl B.
      • et al.
      Villous atrophy and negative celiac serology: a diagnostic and therapeutic dilemma.
      This diagnosis is not to be overlooked, as it is a frequent occurrence in the United States and readily treatable with nitroimidazoles.

      Whipple Disease

      The gram-positive bacteria Tropheryma whipplei cause this rare multisystem infection. It predominantly affects middle-aged white men.
      • Sweetser S.
      Diarrhea, malabsorption, and small-bowel disorders.
      The most common presenting symptom is steatorrhea or diarrhea, resulting in weight loss. This gastrointestinal disturbance is due to impaired lymphatic transport caused by bacteria and can be present years before other areas of the body are attacked.
      • Turner J.R.
      The gastrointestinal tract.
      Beyond the small bowel, it can involve essentially any organ system. Its variable systemic presentation can include arthritis, fever, cardiac valve issues, and central nervous system disease such as myoclonus, dementia, oculomasticatory myorhythmia that is pathognomonic of Whipple disease (jaw contractions accompanied by synchronous pendulum-like vergence oscillations in the eyes).
      • Sweetser S.
      Diarrhea, malabsorption, and small-bowel disorders.
      It is diagnosed by endoscopy with intestinal biopsy, revealing characteristic periodic acid–Schiff stain–positive T whipplei bacteria within macrophages and/or polymerase chain reaction.
      • Sweetser S.
      Diarrhea, malabsorption, and small-bowel disorders.
      Slides will also reveal disrupted villous architecture usually affecting the duodenum and jejunum.
      • Turner J.R.
      The gastrointestinal tract.
      The optimal treatment is uncertain. The initial phase requires intravenous antibiotics for several weeks (ceftriaxone or penicillin G) followed by a long oral maintenance phase (trimethoprim/sulfamethoxazole or doxycycline plus hydroxychloroquine).
      • Fenollar F.
      • Lagier J.C.
      • Raoult D.
      Tropheryma whipplei and Whipple’s disease.
      This diagnosis is not to be missed, because the prognosis is poor and it can be fatal.

      Viral Infection

      Perhaps both the most common and overlooked causes of enteropathy are an active viral infection or a post-viral syndrome. Viruses are the main culprit for acute infectious gastroenteritis. Norovirus, rotavirus, adenovirus, and astrovirus are some of the pathogens responsible for outbreaks.
      • Turner J.R.
      The gastrointestinal tract.
      Diarrhea can be accompanied by nausea, vomiting, fevers, and abdominal pain. Although the incubation, infectious, and symptomatic (2-8 days) periods are short, with the illness being self-limited, effects to the gastrointestinal system can sometimes be lasting.
      • Turner J.R.
      The gastrointestinal tract.
      Viral gastroenteritis can cause abnormal villous shortening, loss of the brush border, compensatory crypt hyperplasia, and lymphocyte infiltration.
      • Turner J.R.
      The gastrointestinal tract.
      These changes are temporary and rarely documented because of the short course of illness. Bacterial illnesses such as salmonella, cholera, shigella, typhoid, yersinia, and others also affect the small intestine, but not as often as viral infections. This category is a reminder not to overdiagnose, because viral enteritis is an exceedingly common cause of self-limited diarrhea, which can be elicited through the history and presence of sick contacts.

      General Approach to Enteropathy

      When a patient presents with an enteropathy causing clinically significant diarrhea, malabsorption, and weight loss and is found to have villous atrophy, it is reasonable to begin by assessing for CD. Celiac disease is by far the most common cause of villous atrophy (79%-93% of cases) in the United States.
      • Aziz I.
      • Peerally M.F.
      • Barnes J.
      • et al.
      The clinical and phenotypical assessment of seronegative villous atrophy; a prospective UK centre experience evaluating 200 adult cases over a 15-year period (2000-2015).
      If CD is deemed unlikely, we recommend revisiting the history and considering further testing as outlined in Figure 2. Also examine the biopsy specimen to rule out artifact such as a wholly flattened slide due to operator error during preparation. If just the villi are flat, check the report or ask the pathologist to re-review the slide for clues. Special stains can also be requested. Many diseases seen by staining are rare or suggested by the history; these studies should be reserved for the appropriate clinical scenario. The biopsy of tropical sprue and medication-associated enteropathy mimic CD. Working in a stepwise fashion by evaluating for CD and if negative, performing tests on serum and biopsy, as guided by clinical suspicion, is our suggested approach to working up an enteropathy.
      Figure thumbnail gr2
      Figure 2Villous atrophy algorithm. CD = celiac disease; CVID = common variable immune deficiency; EMA = endomysial antibody; HIV = human immunodeficiency virus; HLA = human leukocyte antigen; H pylori = Helicobacter pylori; SIBO = small intestinal bacterial overgrowth. aRituximab has been associated with a form of CVID.

      Treatment

      After an etiology is uncovered, treatment is dictated by the underlying cause. Corticosteroids are frequently useful, as they help subdue inflammation. Guidelines are often practical sources for current clinical information.
      • Rubio-Tapia A.
      • Hill I.D.
      • Kelly C.P.
      • Calderwood A.H.
      • Murray J.A.
      American College of Gastroenterology. ACG clinical guidelines: diagnosis and management of celiac disease.
      The Table references treatment options.

      Conclusion

      Enteropathies encompass a wide spectrum of illness; they cause diarrhea, nutritional deficiencies, and weight loss. A detailed and careful approach can often reveal the underlying cause. An example of such a work-up is described in this article, featuring the most common and not to miss enteropathies. We hope that it is of particular use in scenarios in which CD is not the final diagnosis and so it may broaden the differential diagnosis and awareness of other illnesses, because not all that flattens is CD.

      Supplemental Online Material

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