글루텐 과민증 탐구 jama

[문형철]

글루텐 과민증 jama.pdf

1.43MB

셀리악병(Celiac Disease)과 비셀리악 글루텐 민감증(Nonceliac Gluten Sensitivity, NCGS) 요약 (JAMA 리뷰 논문 기반)

📄 논문 제목:
"Celiac Disease and Nonceliac Gluten Sensitivity: A Review"
출처: JAMA, 2017년 8월 15일

---

IMPORTANCE

The preval‎ence of gluten-related disorders is rising, and increasing numbers of individuals are empirically trying a gluten-free diet for a variety of signs and symptoms. This review aims to present current evidence regarding screening, diagnosis, and treatment for celiac disease and nonceliac gluten sensitivity.

OBSERVATIONS

Celiac disease is a gluten-induced immune-mediated enteropathy characterized by a specific genetic genotype (HLA-DQ2 and HLA-DQ8 genes) and autoantibodies (antitissue transglutaminase and antiendomysial). Although the inflammatory process specifically targets the intestinal mucosa, patients may present with gastrointestinal signs or symptoms, extraintestinal signs or symptoms, or both, suggesting that celiac disease is a systemic disease. Nonceliac gluten sensitivity is diagnosed in individuals who do not have celiac disease or wheat allergy but who have intestinal symptoms, extraintestinal symptoms, or both, related to ingestion of gluten-containing grains, with symptomatic improvement on their withdrawal. The clinical variability and the lack of validated biomarkers for nonceliac gluten sensitivity make establishing the preval‎ence, reaching a diagnosis, and further study of this condition difficult. Nevertheless, it is possible to differentiate specific gluten-related disorders from other conditions, based on currently available investigations and algorithms. Clinicians cannot distinguish between celiac disease and nonceliac gluten sensitivity by symptoms, as they are similar in both. Therefore, screening for celiac disease must occur before a gluten-free diet is implemented, since once a patient initiates a gluten-free diet, testing for celiac disease is no longer accurate.

CONCLUSIONS AND RELEVANCE Celiac disease and nonceliac gluten sensitivity are common. Although both conditions are treated with a gluten-free diet, distinguishing between celiac disease and nonceliac gluten sensitivity is important for long-term therapy. Patients with celiac disease should be followed up closely for dietary adherence, nutritional deficiencies, and the development of possible comorbidities.

중요성
글루텐 관련 질환의 유병률이 증가하고 있으며, 

다양한 징후와 증상을 경험한 많은 사람들이 

글루텐 프리 식단을 시도하고 있습니다. 

이 리뷰는 

셀리악병과 비셀리악 글루텐 과민증의 선별, 진단, 치료에 관한 

현재의 증거를 제시하는 것을 목표로 합니다.

관찰 결과 

셀리악병은 

글루텐에 의해 유발되는 면역 매개성 장질환으로, 

특정 유전자형(HLA-DQ2 및 HLA-DQ8 유전자)과 

자가항체(항트랜스글루타민제 및 항엔도미실)가 특징입니다. 

염증 과정이 장 점막을 표적으로 삼지만, 

환자는 위장 징후나 증상, 장외 징후나 증상 또는 둘 다를 보일 수 있으며, 

이는 셀리악병이 전신 질환임을 시사합니다. 

비셀리악병 글루텐 과민증은 

셀리악병이나 밀 알레르기가 없지만, 

글루텐 함유 곡물의 섭취와 관련된 장 증상, 장 외 증상, 또는 둘 다를 가지고 있고, 

글루텐 섭취를 중단하면 증상이 호전되는 경우에 진단됩니다. 

비셀리악병 글루텐 과민증의 임상적 다양성과 검증된 바이오마커의 부재로 인해 

이 질환의 유병률을 파악하고, 진단을 내리고, 

추가 연구를 진행하기가 어렵습니다. 

그럼에도 불구하고, 현재 이용 가능한 조사와 알고리즘을 바탕으로 

특정 글루텐 관련 질환을 

다른 질환과 구별하는 것이 가능합니다. 

셀리악병과 비셀리악 글루텐 과민증은 

증상이 비슷하기 때문에 임상의는 증상을 보고 구분할 수 없습니다. 

따라서, 

글루텐 프리 식단을 시작하면 

셀리악병 검사가 더 이상 정확하지 않기 때문에, 

글루텐 프리 식단을 시작하기 전에 셀리악병 검사를 실시해야 합니다.

결론 및 관련성 

셀리악병과 비셀리악 글루텐 과민증은 흔한 질병입니다. 두 질환 모두 글루텐이 없는 식단으로 치료되지만, 장기적인 치료를 위해서는 셀리악병과 비셀리악 글루텐 과민증을 구분하는 것이 중요합니다. 셀리악병 환자는 식이 요법 준수, 영양 결핍, 가능한 동반 질환의 발생 여부를 면밀히 추적 관찰해야 합니다.

1. 셀리악병(Celiac Disease, CD) 개요

✅ 정의:
셀리악병은 **유전적으로 감수성이 있는 개인이 글루텐(Gluten)에 반응하여 발생하는 면역 매개 소장병증(enteropathy)**으로, 자가면역 질환입니다.

Celiac disease is a chronic, small-intestinal immunemediated enteropathy initiated by exposure to dietary gluten in genetically predisposed individuals and characterized by specific autoantibodies against tissue transglutaminase 2 (anti-tTG2), endomysium, and/or deamidated gliadin peptide.1 Although up to 40% of the population carries the genotypeHLA-DQ2 or HLA-DQ8, which is required for the development of celiac disease, only 2% to 3% ofHLA-DQ2 orHLA-DQ8 carriers subsequently develop celiac disease.2 Celiac disease, once considered a relatively rare gastrointestinal condition affecting almost exclusively young white children, can develop at any age and can affect almost any race. Celiac disease was first described by Samuel Gee in 1887. Wheat was hypothesized as the possible offending agent by William Dicke in 1941.3 The epidemiology, clinical presentation, pathophysiology, and management of the disease have changed since its initial description. There is strong evidence that celiac disease is an autoimmune disease triggered by the ingestion of gluten present in wheat, barley, and rye in genetically predisposed individuals. The preval‎ence of celiac disease in the general population is 1%, with regional differences (Table 1).4 Celiac disease can affect any human organ or tissue (Table 1 and Table 2).6

셀리악병은 

유전적 소인이 있는 개인에게 식이 글루텐에 노출되어 시작되는 

만성 소장 면역 매개 장질환으로, 

조직 트랜스글루타민화효소 2(anti-tTG2), 

근내막, 및/또는 탈아미노화 글리아딘 펩타이드에 대한 특이적 자가항체가 특징입니다. 1 

specific autoantibodies against tissue transglutaminase 2 (anti-tTG2), endomysium, and/or deamidated gliadin peptide.

셀리악병 발병에 필요한 

HLA-DQ2 또는 HLA-DQ8 유전자형을 가진 인구의 비율이 40%에 달하지만, 

HLA-DQ2 또는 HLA-DQ8 유전자형을 가진 사람들 

중 2~3%만이 셀리악병에 걸립니다.2 

한때 

셀리악병은 거의 어린 백인 아이들에게만 영향을 미치는 

비교적 드문 위장병으로 여겨졌지만, 

이제는 모든 연령대에서 발병할 수 있으며 

거의 모든 인종에게 영향을 미칠 수 있습니다. 

셀리악병은 1887년 사무엘 기에 의해 처음 설명되었습니다. 밀이 원인 물질일 수 있다는 가설은 1941년 윌리엄 디케에 의해 제기되었습니다.3 이 병의 역학, 임상 증상, 병태 생리학, 관리 방법은 최초 설명 이후로 많이 바뀌었습니다. 

셀리악병은 

유전적 소인이 있는 사람에게 

밀, 보리, 호밀에 함유된 글루텐을 섭취함으로써 유발되는 

자가면역질환이라는 강력한 증거가 있습니다. 

일반 인구에서 셀리악병의 유병률은 1%이며, 

지역마다 차이가 있습니다(표 1).4 

셀리악병은 

모든 인체 기관이나 조직에 영향을 미칠 수 있습니다(표 1과 표 2).6

Nonceliac gluten sensitivity is a term used to describe individuals who have intestinal signs or symptoms, extraintestinal signs or symptoms, or both, related to ingestion of gluten-containing grains (Table 2), with improvement when these are removed from a patient’s diet. The frequency of nonceliac gluten sensitivity is unknown owing to the lack of validated biomarkers, but it is thought to be more common than celiac disease. Wheat allergy, the third gluten-related disorder, which will not be addressed in this review, is defined as an adverse type-2 helper T-cell immunologic reaction to wheat proteins and typically presents soon after wheat ingestion, with signs of anaphylaxis such as swelling or itching of the mouth, throat, and skin; nasal congestion; watery eyes; and difficulty breathing. Wheat allergy is more common in children, with reported preval‎ence between 2% and 9% in children and 0.5% and 3% in adults.8 This review provides an evidence-based update of the pathophysiology, diagnosis, treatment, and implications of celiac disease and nonceliac gluten sensitivity.

비셀리악병 글루텐 과민증은 

글루텐 함유 곡물(표 2) 섭취와 관련된 

장 증상이나 징후, 또는 

장 외 증상이나 징후, 

또는 둘 다를 보이는 개인을 설명하는 데 사용되는 용어입니다. 

비셀리악병 글루텐 과민증의 빈도는 

검증된 바이오마커가 부족하기 때문에 알려지지 않았지만, 

셀리악병보다 더 흔한 것으로 여겨집니다. 

밀 알레르기는 

글루텐 관련 질환 중 세 번째로, 이 글에서는 다루지 않겠지만, 

밀 단백질에 대한 부작용인 제2형 헬퍼 T세포 면역 반응으로 정의되며, 

일반적으로 밀 섭취 직후에 입, 목, 피부의 부기나 가려움, 코 막힘, 눈물, 호흡 곤란 등의 아나필락시스 징후가 나타납니다. 

밀 알레르기는 어린이에게 더 흔하게 나타나며, 

어린이의 경우 2%에서 9% 사이, 

성인의 경우 0.5%에서 3% 사이로 보고되고 있습니다.8 

이 리뷰는 

셀리악병과 비셀리악 글루텐 과민증의 

병태생리학, 진단, 치료, 그리고 그 의미에 대한 근거 기반의 최신 정보를 제공합니다.

✅ 유전적 요인:

• CD 발병에는 HLA-DQ2 또는 HLA-DQ8 유전자형이 필요함.
• 일반 인구의 40%가 HLA-DQ2 또는 HLA-DQ8 유전자를 보유하지만, 
• 실제로 셀리악병이 발생하는 비율은 **2~3%**에 불과함.

Results

Pathophysiology

Gluten as Environmental Trigger of Gluten-Related Disorders Gluten is a mixture of gliadins and glutenins, complex proteins unusually rich in prolines and glutamines that are not completely digestible by intestinal enzymes.9 The final product of this partial digestion is a mix of peptides that can trigger host responses (increased intestinal permeability and innate +/− adaptive immune response) that closely resemble those instigated by the exposure to gastrointestinal pathogens10-13 (Figure 1).

결과 

병태생리학 

글루텐 관련 장애의 환경적 유발 요인 글루텐은 

글리아딘과 글루테닌의 혼합물로, 

장내 효소에 의해 완전히 소화되지 않는 프롤린과 글루타민이 풍부하게 함유된 

복합 단백질입니다. 9 

부분적인 소화 과정의 최종 산물은 

위장 병원체에 노출되었을 때 유발되는 것과 매우 유사한 

숙주 반응(장 투과성 증가 및 선천성 +/- 적응성 면역 반응)을 유발할 수 있는 

펩타이드의 혼합물입니다10-13(그림 1).

Normal Phsyiologic Events That Contribute to the Pathogenesis of Celiac Disease and Nonceliac Gluten Sensitivity.

Gluten Translocation From Lumen to Lamina Propria (Paracellular vs Transcellular) |

Previous studies have shown that gliadin can cause an immediate and transient increase in gut permeability.9,13 This permeating effect is secondary to the binding of specific undigestible gliadin fragments to the CXCR3 chemokine receptor with subsequent release of zonulin, a modulator of intercellular tight junctions (Figure 1).14 This process takes place in all individuals who ingest gluten. For the majority, these events do not lead to abnormal consequences. However, these same events can lead to an inflammatory process in genetically predisposed individuals when the immunologic surveillance system mistakenly recognizes gluten as a pathogen. Thus, this normal physiologic process is also essential to the development of celiac disease and nonceliac gluten sensitivity in at-risk individuals. Additionally, there is evidence that during the acute phase of celiac disease, gluten can also cross the intestinal barrier through the transcellular pathway via transferrin receptor CD71, once tolerance to gluten has been lost15 (Figure 1).

셀리악병과 비셀리악 글루텐 과민증의 발병에 기여하는 정상적인 생리적 사건 

글루텐이 내강에서 점막하층으로 이동(세포간 대 세포간) | 

이전 연구에 따르면 

글리아딘은 장 투과성을 즉각적이고 일시적으로 증가시킬 수 있습니다. 9,13 

이러한 침투 효과는 

소화되지 않는 글리아딘(Gliadin)의 특정 단편이 CXCR3 케모카인 수용체에 결합한 후 

세포 간 촘촘한 접합부 조절자인 조눌린(Zonulin)이 방출되는 것에 이차적인 효과입니다(그림 1).14 

이 과정은 글루텐을 섭취하는 모든 사람에게서 발생합니다. 대부분의 경우, 이러한 사건들은 특별한 결과로 이어지지 않습니다. 그러나 면역 감시 시스템이 글루텐을 병원체로 잘못 인식할 때, 유전적 소인이 있는 개인에게 염증 과정을 유발할 수 있습니다. 따라서, 이러한 정상적인 생리적 과정은 위험에 처한 개인에게 셀리악병과 비셀리악 글루텐 민감성을 유발하는 데 필수적입니다. 또한, 셀리악병의 급성기 동안에는 글루텐에 대한 내성이 사라지면 트랜스셀룰러 경로를 통해 장벽을 통과할 수 있다는 증거가 있습니다(그림 1).

The Innate Immune Response | 

Innate immunity plays a critical role in initiating celiac disease and possibly nonceliac gluten sensitivity. Cytokines such as interleukin (IL) 15 and interferon alfa can prime the innate immune response by polarizing dendritic cells and intraepithelial lymphocyte function.15,16 These mucosal events, along with the breach of the epithelial barrier function secondary to the gliadin-mediated zonulin release,14 lead to the passage of undigested peptides from the gut lumen to the lamina propria. Once gliadin crosses the epithelial barrier, neutrophil recruitment through IL8 production11,12,17 or a direct neutrophil chemoattractant effect18 causes a loss of tolerance to gluten in genetically susceptible individuals (Figure 1).

선천성 면역 반응 | 

선천성 면역은 

셀리악병과 셀리악병이 아닌 글루텐 과민증을 유발하는 데 중요한 역할을 합니다. 

인터루킨(IL) 15와 인터페론 알파 같은 사이토카인은 

수지상 세포와 상피내 림프구 기능을 분화시켜 

선천성 면역 반응을 촉진할 수 있습니다.15,16 

이러한 점막 사건은 

글리아딘에 의한 조눌린 방출로 인한 상피 장벽 기능의 파괴와 함께14, 

소화되지 않은 펩타이드가 장 내강에서 점막하층으로 통과하게 만듭니다. 

글리아딘이 상피 장벽을 통과하면, 

IL8 생산을 통한 호중구 모집11,12,17 또는 

직접적인 호중구 화학주성 효과18이 

유전적으로 글루텐에 민감한 개인에게 글루텐에 대한 내성을 잃게 만듭니다(그림 1).

Specific Events in Celiac Disease Pathogenesis

The Celiac Disease Adaptive Immune Response

The adaptive immune response is the consequence of a highly specific interplay between selected gluten peptides and major histocompatibility complex class II HLA-DQ2/8–restricted T-cell antigens and plays a role in celiac disease pathogenesis.19,20 The contact of CD4+ T cells in the lamina propria with gluten induces their activation and proliferation, leading to production of proinflammatory cytokines,metalloproteases, and keratinocyte growth factor, which induces cryptal hyperplasia and villous blunting secondary to intestinalepithelial cell death induced by intraepithelial lymphocytes.20,21 Celiac disease crypt hyperplasia has been hypothesized to be the consequence of an imbalance between continuous tissue damage due to the mucosal autoimmune insult described above and inability of the stem cells to compensate (Figure 1).

셀리악병 발병 기전에 관한 구체적인 사건들
셀리악병 적응 면역 반응

적응 면역 반응은 

선택된 글루텐 펩티드와 

주요 조직 적합성 복합체 클래스 II HLA-DQ2/8-제한 T세포 항원 사이의 

매우 구체적인 상호 작용의 결과이며, 

셀리악병 발병 기전에 중요한 역할을 합니다. 19,20 

장상피층에 있는 CD4+ T 세포가 

글루텐과 접촉하면 활성화와 증식이 유도되어, 

장 상피내 림프구에 의해 유발된 장 상피 세포의 사멸에 이은 

선동성 사이토카인, 금속단백질 분해효소, 각질세포 성장 인자의 생성을 유도하여, 

선상피 증식과 융모의 둔화를 유발합니다. 20,21 

셀리악병의 선와 증식은 

위에서 설명한 점막의 자가면역성 손상으로 인한 지속적인 조직 손상과 

줄기세포의 보상 능력 부족 사이의 불균형이 원인이라는 가설이 있습니다(그림 1).

A, 정상적인 융모-암포라 비율(3:1)을 가진 점막(왼쪽)과 셀리악병의 구조적 특징을 가진 점막(오른쪽). 

B, IEC 기저막에 발현된 유능한 밀착 접합체와 CD71 수용체. 

C, 특정 소화되지 않은 글루텐 조각이 CXCR3 수용체에 결합하여 조눌린의 방출과 글루텐 조각의 세포간 통과 증가. 

D, 유전적으로 민감한 개인의 경우, 층상피에 글루텐 조각이 존재하면 선천성 면역 반응(왼쪽)이 유발되어 손상된 세포에서 조직 트랜스글루타미나제(tTG)가 방출됩니다. 아미노산이 제거된 글루텐 조각은 CD4+T 세포(오른쪽)에 제시되어 TH2 반응을 활성화하여 B세포 증식을 유도하고, TH1 반응을 활성화하여 전염증성 사이토카인을 방출합니다. 자연살해(NK) 세포의 장 상피로의 이동, IEL의 증가, 그리고 궁극적으로 IEC의 상피측에 있는 IEC 및 CD71 발현의 자극, 그리고 글루텐 단편의 세포간 경로를 통한 추가 통과. 

Specific Events in Nonceliac Gluten Sensitivity Pathogenesis

The pathophysiology of nonceliac gluten sensitivity remains largely undetermined.In addition to gluten, α-amylase/trypsin inhibitors are suggested to play akey role in the innate immune response of glutenrelated disorders.22 A study by Sapone et al23 found that glutensensitive individuals without celiac disease have a significant reduction in T-regulatory cellmarkers compared with control patients and patients with celiac disease and an increase in the α and β classes of intraepithelial lymphocytes, with no increase in adaptive immunityrelated gut mucosal gene expression‎. These findings suggest an important role of the intestinal innate immune system in the pathogenesis of nonceliac gluten sensitivity without an adaptive immune response.24 This hypothesis is also supported by the lack of enteropathy with villous blunting in nonceliac gluten sensitivity, a feature detected in celiac disease as a sign of HLA-driven adaptive immune response.

비셀리악 글루텐 민감성 발병 기전의 특정 사건

비셀리악 글루텐 민감성의 병태생리학은 아직까지 거의 밝혀지지 않았습니다.

글루텐 외에도 α-아밀라제/트립신 억제제가

글루텐 관련 질환의 선천성 면역 반응에 중요한 역할을 하는 것으로 추정됩니다. 22

Sapone 등의 연구에 따르면23

셀리악병이 없는 글루텐 민감성 환자는 대조군과 셀리악병 환자들에 비해

T-regulatory cellmarkers가 현저히 감소하고,

적응성 면역 관련 장 점막 유전자 발현의 증가 없이 intraepithelial lymphocytes의

α 및 β 클래스가 증가하는 것으로 나타났습니다.

이 연구 결과는

비셀리악병 글루텐 과민증의 발병 기전에서

장의 선천성 면역체계가 중요한 역할을 한다는 것을 시사합니다.24

이 가설은

비셀리악병 글루텐 과민증에서 융모가 둔화되는 장 병증이 없다는 사실에 의해 뒷받침됩니다.

이는 셀리악병에서 HLA에 의한 적응성 면역반응의 징후로 나타나는 특징입니다.

✅ 병리 기전:

1. 글루텐 섭취 → 장 점막 투과성 증가 (Zonulin 단백질 조절 실패)
2. 미소융모(Villi) 손상 및 장벽 기능 손실 → 영양 흡수 장애
3. 면역 반응 활성화 → CD4+ T세포가 인터페론 감마(IFN-γ)와 TNF-α 방출 → 염증 및 조직 손상
4. 자가항체 생성: Anti-tTG2 (항-조직 트랜스글루타미나제), 항-내피미소체(anti-endomysial) 항체

✅ 증상:

• 소화기 증상: 복통, 설사, 복부 팽만, 체중 감소
• 비소화기 증상: 철 결핍성 빈혈, 골다공증, 피부염(Dermatitis Herpetiformis), 신경병증(Peripheral Neuropathy)
• 소아에서는 성장 장애, 사춘기 지연이 나타날 수 있음

Clinical Presentation

Celiac Disease

Historically, the classic presentation of celiac disease had been malabsorption manifesting as diarrhea and poor growth in childhood.25 It was presumed that the disease appeared when gluten was introduced, and the timing of the presentation of symptoms varied according to the intensity of the immune response. However, the development of highly sensitive and specific noninvasive tests6,26 facilitated a more accurate measurement of celiac disease preval‎ence, identified at-risk individuals and groups, and helped to establish that celiac disease is a systemic autoimmune disease and that onset can occur at any age,27 presenting with gastrointestinal manifestations, extraintestinal manifestations, or both (Table 2).28,2

임상 증상
셀리악병
역사적으로 셀리악병의 전형적인 증상은 소아기의 설사와 성장 부진으로 나타나는 흡수 장애였습니다.25 이 병은 글루텐이 도입될 때 발생하는 것으로 추정되며, 증상의 발현 시기는 면역 반응의 강도에 따라 달라집니다. 그러나 매우 민감하고 특이적인 비침습적 검사법6,26의 개발로 셀리악병의 유병률을 보다 정확하게 측정할 수 있게 되었고, 위험에 처한 개인과 집단을 식별할 수 있게 되었으며, 셀리악병이 전신 자가면역질환이며, 발병 연령에 관계없이 위장관 증상, 장외 증상, 또는 둘 다를 동반할 수 있다는 사실을 입증하는 데 도움이 되었습니다(표 2).28,2

Intestinal Manifestations

Gastrointestinal symptoms are more common in the pediatric age group. Children younger than 3 years are likely to present with diarrhea, loss of appetite, abdominal distention, and poor growth.30 Older children and adults may present with diarrhea, bloating, constipation, abdominal pain, or weight loss.31,32

Extraintestinal Manifestations

The etiology of extraintestinal manifestations is attributable toa combination of chronic inflammation, nutrient deficiencies, and possibly an adaptive immune response spreading from the intestinal mucosa to other tissues and organs. Poor growth, short stature, or delayed puberty may be the only presenting symptoms of pediatric celiac disease.6 Dental enamel defects are common in children who develop celiac disease before age7 years.33 Iron-deficiency anemia is a common presentation of celiac disease and is seen in 32% of adults and 9% of children.7,34,35 In women, studies suggest an increased risk of miscarriage.36,37 In addition to dermatitis herpetiformis, dermatologic conditions such as urticaria, psoriasis, and dry skin are more frequent in patients with celiac disease.38Up to 22% of patients with celiac disease have neurologic manifestations, psychiatric manifestations, or both.39,40 Peripheral neuropathy is frequent, compared with healthy controls. The etiology may be attributable to nutritional deficiencies suchas deficientvitaminB12, chronic inflammation, or an immune-basedmechanism.40In one study, neuropathy was diagnosed in 0.7% of patients with celiac disease, compared with 0.3% of controls.41 Refractory celiac disease is defined as persistent or recurrent malabsorptive symptoms and villous atrophy despite strict adherence to a gluten-free diet for at least 6 to 12 months. Patients with refractory celiac disease may go on to develop uncommon but severe complications such as ulcerative jejunitis and enteropathyassociated T-cell lymphoma.42

장 증상
소아 연령대에서 위장 증상이 더 흔하게 나타납니다. 3세 미만의 아이들은 설사, 식욕 부진, 복부 팽만감, 성장 부진을 겪을 가능성이 높습니다.30 좀 더 나이가 많은 아이들과 성인은 설사, 복부 팽만감, 변비, 복통, 체중 감소 등을 겪을 수 있습니다.31,32

장 외 증상

장외 증상의 원인은 만성 염증, 영양소 결핍, 그리고 장 점막에서 다른 조직과 기관으로 퍼지는 적응성 면역 반응의 조합에 기인합니다. 성장 부진, 키가 작거나 사춘기 지연이 소아 셀리악병의 유일한 증상일 수 있습니다.6 셀리악병에 걸린 7세 이전의 어린이에게서 흔히 나타나는 치아 법랑질 결손.33 철분 결핍성 빈혈은 셀리악병의 흔한 증상이며, 성인의 32%, 어린이의 9%에서 나타납니다.7,34,35 여성의 경우, 연구 결과에 따르면 유산 위험이 증가한다고 합니다. 36,37 피부염성 홍반 외에도 셀리악병 환자에게는 두드러기, 건선, 건성 피부와 같은 피부 질환이 더 자주 발생합니다.38 셀리악병 환자의 최대 22%는 신경학적 증상, 정신과적 증상 또는 둘 다를 보입니다.39,40 말초 신경병증은 건강한 대조군에 비해 빈번하게 발생합니다. 그 원인은 비타민B12 결핍과 같은 영양 결핍, 만성 염증, 면역 기반 메커니즘 때문일 수 있습니다.40 한 연구에서 셀리악병 환자의 0.7%가 신경병증을 앓고 있는 것으로 진단되었으며, 대조군의 경우 0.3%였습니다. 41 난치성 셀리악병은 최소 6~12개월 동안 글루텐이 없는 식단을 엄격하게 준수했음에도 불구하고 흡수 장애 증상이 지속되거나 재발하고 융모가 위축되는 경우로 정의됩니다. 난치성 셀리악병 환자는 궤양성 공장염 및 장병증 관련 T세포 림프종과 같은 드물지만 심각한 합병증이 발생할 수 있습니다.42

Nonceliac Gluten Sensitivity

The clinical symptoms of nonceliac gluten sensitivity begin after the ingestion of gluten-containing grains. Symptoms improve or disappear with withdrawal of these grains from the diet, and symptoms reappear after gluten challenge, usually within hours or days. The clinical gastrointestinal presentation of nonceliac gluten sensitivity is characterized by abdominal pain, bloating, bowel irregularity (diarrhea, constipation, or both), while extraintestinal manifestations include patient report of a “foggy brain,”which is described as slowed thinking, memory disturbance, or reduced level of alertness, along with headache, joint andmuscle pain, fatigue, depression, leg or arm numbness, dermatitis (eczema or skin rash),andanemia (Table 2).8,43

비셀리악 글루텐 민감성

비셀리악 글루텐 과민증의 임상 증상은

글루텐이 함유된 곡물을 섭취한 후에 시작됩니다.

이러한 곡물을 식단에서 제외하면

증상이 개선되거나 사라지고,

글루텐을 다시 섭취하면 증상이 보통 몇 시간 또는 며칠 내에 다시 나타납니다.

비셀리악 글루텐 과민증의 임상적 위장 증상은

복통, 복부팽만, 장의 불규칙(설사, 변비, 또는 둘 다)이 특징이며,

장외 증상으로는 환자가 “뇌가 흐릿하다”고 보고하는 증상이 있습니다.

이는 두통, 관절 및 근육통, 피로, 우울증, 다리 또는 팔의 저림, 피부염(습진 또는 피부 발진),

빈혈과 함께 느린 사고, 기억력 장애 또는 주의력 저하로 묘사됩니다(표 2).8,43

✅ 진단:

• 혈청 검사: Anti-tTG (IgA, IgG), Anti-EMA 검사
• 소장 조직검사: 융모 위축(Villous Atrophy), 상피 내 림프구 침윤(Increased IEL) 확인
• 유전자 검사: HLA-DQ2, HLA-DQ8 유전자 확인 (음성일 경우 CD 가능성 낮음)

Assessment and Diagnosis

Celiac Disease

There has been an increase in the availability and use of accurate noninvasive tools for the diagnosis of celiac disease in the last 20 years. Their performance has been recently and comprehensively reviewed.44,45 Recommendations for the use of each test and the sensitivityand specificityare summarized inTable 3.In practice,measurement of serum IgA antibodies to tissue transglutaminase (anti-tTG) (or IgG class in patients with IgA deficiency) is an excellent screening procedure with high sensitivity and specificity and is considered the first screening test that should be ordered in patients in whom celiac disease is suspected. The IgA antiendomysial antibody determination is 98% specific for active celiac disease, but it should be used only as a confirm‎atory test because of cost and subjective interpretation, which may contribute to the more variable sensitivity.44

Deamidated gliadin peptides—antibodies of the IgG class—have a sensitivity and specificity close to IgA anti-tTG antibodies and should be used as the initial screening test for patients withIgA deficiency.Given the highlyaccurate testsavailable, the firstgeneration antinative gliadin antibody test should no longer be used to eval‎uate for celiac disease.44HLA-DQ2 andHLA-DQ8 determinationmay be usefulwhen there is discrepancy between serologic studies and histologic findings to better assess whether celiac disease is possible, because the disease, except in rare cases, cannot develop in individualswhoare negative forHLA-DQ2andHLA-DQ8. 44 Figure 2 provides a diagnostic approach to celiac disease. Villous blunting on the small-intestinal biopsy can definitively establish the diagnosis of celiac disease and is recommended by the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition (NASPGHAN) and the American College of Gastroenterology (ACG).46,47 The characteristic histologic changes associated with celiac disease include an increased number of intraepithelial lymphocytes (>25 per 100 enterocytes), elongation of the crypts,and partial to totalvillousatrophy.48The EuropeanSociety for Pediatric Gastroenterology andHepatology (ESPGHAN) has proposed an algorithm for children whomeet specific criteria, for whom biopsy is not recommended.4 For the biopsy to be omitted, childrenmust have signsand symptoms suggesting celiac disease,a positive anti-tTG antibodies finding with a level greater than 10 times the upper limit of normal, a positive antiendomysial antibody finding obtained at a different time than the anti-tTG antibodies finding, and a HLA genotype compatible with celiac disease.4 Specific diagnostic procedures such as double-balloon enteroscopy, videocapsule endoscopy, or magnetic resonance imaging are rarely used and may be indicated in the workup of complicated celiac disease when there are discrepancies between serology and histology results or when a patient with celiac disease has persistent or worsening symptoms despite following a gluten-free diet.

진단과 진단
셀리악병
지난 20년 동안 셀리악병 진단을 위한 정확하고 비침습적인 도구의 가용성과 사용이 증가했습니다. 그들의 성능은 최근에 종합적으로 검토되었습니다.44,45 각 검사의 사용과 민감도 및 특이도에 대한 권장 사항은 표 3에 요약되어 있습니다. 실제로, 조직 트랜스글라민화 효소에 대한 혈청 IgA 항체(항-tTG) (또는 IgA 결핍 환자의 경우 IgG 클래스)의 측정은 높은 민감도와 특이도를 가진 우수한 선별 검사 절차이며, 셀리악병이 의심되는 환자에게 가장 먼저 시행해야 하는 선별 검사입니다. IgA 항체 결정은 활성 셀리악병에 대해 98%의 특이성을 보이지만, 비용과 주관적인 해석으로 인해 민감도가 더 다양해질 수 있으므로 확인 검사로서만 사용해야 합니다.44

탈아미노화 글리아딘 펩티드(IgG 클래스의 항체)는 IgA 항-tTG 항체에 가까운 민감도와 특이성을 가지고 있으므로 IgA 결핍 환자의 초기 선별 검사로 사용해야 합니다. 매우 정확한 검사법을 고려할 때, 1세대 항체 검사인 글리아딘 항체 검사는 더 이상 셀리악병을 평가하는 데 사용되어서는 안 됩니다.44 HLA-DQ2와 HLA-DQ8의 결정은 혈청학적 연구와 조직학적 소견 사이에 불일치가 있을 때 셀리악병의 가능성을 더 잘 평가하는 데 유용할 수 있습니다. 드문 경우를 제외하고, HLA-DQ2와 HLA-DQ8에 음성인 개인에게는 이 질병이 발병할 수 없기 때문입니다. 44 그림 2는 셀리악병에 대한 진단적 접근법을 제공합니다. 소장 생검에서 융모의 둔화는 셀리악병의 진단을 확실히 확립할 수 있으며, 북미 소아 위장병학회(NASPGHAN)와 미국 소화기학회(ACG)에서 권장합니다. 46,47 셀리악병과 관련된 조직학적 특징적인 변화로는 상피내 림프구 수 증가(장세포 100개당 25개 이상), 선와(crypt)의 연장, 부분적 또는 전체적인 융모 위축 등이 있습니다.48 유럽 소아 위장병 및 간장학회(ESPGHAN)는 특정 기준을 충족하는 어린이의 경우 생검을 권장하지 않는 알고리즘을 제안했습니다. 4 생검을 생략하기 위해서는, 아이가 셀리악병을 시사하는 징후와 증상이 있어야 하고, 정상 상한의 10배 이상의 항-tTG 항체 양성 반응이 있어야 하며, 항-tTG 항체 양성 반응과 다른 시기에 얻은 항내장근 항체 양성 반응이 있어야 하고, 셀리악병과 호환되는 HLA 유전자형이 있어야 합니다. 4 이중 풍선 장내시경, 비디오 캡슐 내시경, 자기공명영상과 같은 특정 진단 절차는 거의 사용되지 않으며, 혈청학 및 조직학 결과 사이에 불일치가 있거나 셀리악병 환자가 글루텐이 없는 식단을 따랐음에도 불구하고 증상이 지속되거나 악화되는 경우, 복잡한 셀리악병의 진단에 사용될 수 있습니다.

Nonceliac Gluten Sensitivity

No specific biomarkers have yet been identified and validated for nonceliac gluten sensitivity. Clinicians should suspect nonceliac gluten sensitivity in a patient who presents with gastrointestinal or extraintestinal symptoms (Table 2) that appear to improve with a gluten-free diet. Since these symptoms also can be seen with celiac disease and, to a lesser extent, with wheat allergy, these conditions need to be preliminarily excluded with serologic and histologic evidence to focus on the suspicion of nonceliac gluten sensitivity. Until biomarkers are identified and validated, the diagnosis of nonceliac gluten sensitivity is confirmed in a research setting with a doubleblind crossover gluten challenge.49 In a clinical setting, cliniciansmay suggest a blinded gluten challenge during which a patient is given approximately 8 g of gluten (corresponding to approximately 2 slices of bread) or placebo for 1 week each, separated by a 1-week gluten-free washout period. Symptoms are monitored throughout the challenge.49A blinded challenge is not generally feasible in a clinical setting; therefore, for patients with fluctuating symptoms, symptomatic assessment of a patient adhering vs not adhering to a gluten-free diet for at least 1 week is suggested.49

비셀리악 글루텐 민감성

비셀리악 글루텐 민감성에 대한 특정 바이오마커는 아직 확인되지 않았고 검증되지 않았습니다. 임상가들은 위장 또는 비위장 증상(표 2)을 보이며, 글루텐 프리 식단으로 증상이 호전되는 환자의 경우 비셀리악병 글루텐 민감성을 의심해야 합니다. 이러한 증상은 셀리악병과 밀 알레르기에서도 나타날 수 있기 때문에, 비셀리악병 글루텐 민감성을 의심하기 위해서는 혈청학적, 조직학적 증거를 통해 이러한 상태를 사전에 배제해야 합니다. 바이오마커가 확인되고 검증될 때까지, 비셀리악 글루텐 민감성 진단은 이중맹검 교차 글루텐 챌린지를 통해 연구 환경에서 확인됩니다.49 임상 환경에서, 임상의는 1주 동안 글루텐(빵 2조각에 해당하는 양) 또는 위약을 각각 1주씩 투여하는 맹검 글루텐 챌린지를 제안할 수 있습니다. 이 기간은 글루텐이 없는 1주간의 휴약 기간으로 구분됩니다. 증상은 도전 기간 내내 모니터링됩니다.49 맹검 도전은 일반적으로 임상 환경에서 실행하기 어렵습니다. 따라서 증상이 변동하는 환자의 경우, 최소 1주 동안 글루텐 프리 식단을 준수하는지 여부를 기준으로 증상을 평가하는 것이 좋습니다.49

✅ 치료:

• 엄격한 글루텐 프리 식이 (Gluten-Free Diet, GFD) 필요
• 영양 결핍 보충: 철분, 칼슘, 비타민 D 보충 필수
• 장기적 모니터링 필요: 골다공증, 갑상선 질환, 악성 종양(특히 장림프종) 발생 가능성 고려

---

2. 비셀리악 글루텐 민감증(Nonceliac Gluten Sensitivity, NCGS)

✅ 정의:
NCGS는 셀리악병이나 밀 알레르기가 없는 사람이 글루텐 섭취 시 위장관 및 비위장관 증상을 경험하는 상태입니다.

✅ 병리 기전:

• NCGS는 자가면역 질환이 아니며, HLA-DQ2/DQ8 연관성이 낮음.
• 셀리악병과 달리 소장 조직 손상이 없음.
• 일부 연구에서는 면역세포(Toll-like receptor 4 활성화) 및 장내 미생물총 변화가 관여할 가능성을 제시.

✅ 증상:

• 소화기 증상: 복부 팽만, 가스, 설사 또는 변비
• 비소화기 증상: 피로감, 두통, 집중력 저하(Brain Fog), 관절통, 우울감

✅ 진단:

• 특정 바이오마커 없음 → 셀리악병 및 밀 알레르지를 배제한 후 진단
• 글루텐 제거 후 증상 개선 여부로 판단
• 이중맹검 위약 대조 시험(Gluten Challenge Test)이 필요할 수 있음.

✅ 치료:

• 글루텐 프리 식이가 도움이 될 수 있으나, 엄격한 제한이 필요하지 않을 수 있음.
• 장기적 연구 부족으로 GFD 지속 필요성은 논란이 있음.

---

3. 셀리악병(CD)과 NCGS의 비교 요약

특징셀리악병(CD)비셀리악 글루텐 민감증(NCGS)

유전적 연관성	HLA-DQ2/DQ8 필수	HLA-DQ2/DQ8와 무관
자가면역 반응	O (자가항체 존재)	X
장 손상	융모 위축(Villous Atrophy)	없음
증상	위장관 + 전신 증상	위장관 + 신경학적 증상 (Brain Fog 등)
진단	혈청 검사 + 조직 검사	셀리악병/밀 알레르지 배제 후 임상적 판단
치료	엄격한 GFD 필수	필요 시 GFD 고려 가능

---

4. 임상적 의미 및 결론

✔️ 셀리악병(CD)은 장기적인 건강 문제(영양결핍, 골다공증, 암 위험 증가)와 관련되므로 조기 진단과 철저한 GFD가 필요.
✔️ NCGS는 면역 반응보다는 장내 미생물 변화 및 소화 문제와 연관될 가능성이 높으며, 개별 환자 맞춤형 접근이 필요.
✔️ 셀리악병이 의심되는 환자는 GFD를 시작하기 전에 반드시 적절한 진단 검사를 받아야 함.
✔️ GFD가 일반 건강 증진을 위한 식이법으로 사용되는 것은 근거가 부족하며, 불필요한 제한은 영양 불균형을 초래할 수 있음.