흔히 '식체' --＞ 위마비(위배출시간 지연) nature

[문형철]

Abstract |

Gastroparesis is a preval‎ent condition that produces symptoms of delayed gastric emptying in the absence of physical blockage. The most common etiologies of gastroparesis are idiopathic, diabetic, and postsurgical disease, although some cases stem from autoimmune, paraneoplastic, neurologic or other conditions. Histologic examination of gastric tissues from patients with severe gastroparesis reveals heterogeneous and inconsistent defects in the morphology of enteric neurons, smooth muscle and interstitial cells of Cajal, and increased levels of inflammatory cells. Diagnosis is most commonly made by gastric emptying scintigraphy; however, wireless motility capsules and nonradioactive isotope breath tests have also been validated. A range of treatments have been used for gastroparesis including dietary modifications and nutritional supplements, gastric motor stimulatory or antiemetic medications, endoscopic or surgical procedures, and psychological interventions. Most treatments have not been subjected to controlled testing in patients with gastroparesis. The natural history of this condition is poorly understood. Active ongoing research is providing important insights into the pathogenesis, diagnosis, treatment and outcomes of this disease.

위마비는 

신체적 장애가 없는 상태에서 

위 내용물의 배출이 지연되는 증상을 일으키는 흔한 질환입니다. 

위마비의 가장 흔한 원인은 

특발성, 

당뇨병, 

수술 후 질환이지만, 

일부 사례는 자가면역, 부신생식, 신경학적 또는 기타 질환에서 비롯됩니다. 

심한 위마비 환자의 위 조직을 조직학적으로 검사한 결과, 

장 신경세포, 평활근, 카잘의 간질 세포의 형태에 

이질적이고 일관되지 않은 결함이 있으며, 

염증 세포의 수치가 증가하는 것으로 나타났습니다. 

진단은 

위 배출 신티그래피로 가장 일반적으로 이루어지지만, 

무선 운동성 캡슐과 비방사성 동위원소 호흡 검사도 검증되었습니다. 

위마비에는 

식이요법, 

영양 보충제, 

위 운동 자극제 또는 구토 방지제, 

내시경 또는 수술, 심리 치료 등 다양한 치료법이 사용되고 있습니다. 

대부분의 치료법은 

위마비 환자를 대상으로 한 통제된 실험을 거치지 않았습니다. 

이 질환의 자연적 경과는 잘 알려져 있지 않습니다. 

활발하게 진행되고 있는 연구가 

이 질환의 병인, 진단, 치료, 결과에 대한 중요한 통찰을 제공하고 있습니다.

Introduction

Patients with gastroparesis present with symptoms of impaired gastric emptying, and diagnostic testing reveals evidence of delayed gastric emptying in the absence of a physical blockage. The most common etiologies of gastroparesis are diabetic, idiopathic and postsurgical disease. For men and women respectively, the preval‎ence of definite gastroparesis (defined by typical symptoms of gastroparesis with evidence of delayed gastric emptying) is 9.6 and 37.8 per 100,000 persons and its ageadjusted incidence is 2.4 and 9.8 per 100,000 personyears, respectively.1 From 1995–2004, hospitalizations attributable to a primary diagnosis of gastroparesis increased by 158%.2 Duration of hospital stay and hospital charges related to this disorder also rose during this time. One study estimated inpatient costs associated with severe gastroparesis to be US$7,000 per month while another noted increased mortality from the condition.1,3 Studies over the last 5 years have defined clinical factors and characterized histopathologic findings associated with gastroparesis suggesting a heterogeneous pathogenesis. The role of gastric emptying testing has also been reeval‎uated and our understanding of the benefits of different treatments for this disease has been expanded. This Review is timely because of the impressive volume of new research that has been published or presented internationally over the past 5 years.

소개

위마비 환자는 

위 배출 장애의 증상을 보이며, 

진단 검사 결과 신체적 장애가 없는 상태에서 위 배출이 지연된다는 사실이 밝혀집니다. 

위마비의 가장 흔한 원인은 

당뇨병, 특발성 질환, 수술 후 질환입니다. 

남성과 여성의 경우, 

명확한 위마비(위마비의 전형적인 증상과 함께 위 배출 지연의 증거가 있는 것으로 정의됨)의 유병률은 

100,000명당 각각 9.6명, 37.8명이고, 연령 조정 발생률은 2.4명, 9명입니다. 100,000명당 8명입니다.1 

1995년부터 2004년까지, 

위마비증의 일차 진단으로 인한 입원 건수는 158% 증가했습니다.2 

이 질환과 관련된 입원 기간과 병원 비용도 이 기간 동안 증가했습니다. 

한 연구에서는 

중증 위마비 환자의 입원 비용이 월 7,000달러에 달한다고 추정했으며, 

또 다른 연구에서는 이 질환으로 인한 사망률이 증가한다고 지적했습니다.1,3 

지난 5년 동안의 연구에서는 

위마비와 관련된 임상적 요인을 규명하고 조직병리학적 소견을 특성화하여 

이 질환의 이질적인 병인을 시사했습니다. 

위 배출 검사의 역할도 재평가되었고, 

이 질병에 대한 다양한 치료법의 이점에 대한 이해가 확대되었습니다. 

이 리뷰는 지난 5년 동안 국제적으로 발표되거나 발표된 새로운 연구의 양이 인상적이어서 시기적절합니다.

Presentation

A range of symptoms are reported in gastroparesis. More than 90% of patients report nausea, 68–84% experience vomiting, and 60% describe early satiety.4 Pain is reported by 46–90% of patients, and is the predominant symptom of gastroparesis in 19% of individuals; pain impairs quality of life and is characterized as epigastric, constant, meal induced and nocturnal in 43%, 38%, 72% and 74% of patients, respectively.5 Bloating is a common symptom—it is reported by 80% of patients with gastroparesis and is the predominant symptom in 8% of patients.6 Severe bloating impairs quality of life and is associated with female sex. Bloating is shown to correlate with the intensity of other gastroparesis symptoms. Heartburn may occur as a result of gastroparesisassociated increased lower esophageal sphincter relaxations. Symptoms of gastroparesis are often persistent, but some patients experience episodic symptom flares that are separated by asymptomatic periods mimicking cyclic vomiting syndrome.7 Many patients with gastroparesis are obese; few are underweight.8 However, an assessment of food consumption patterns in a large gastroparesis cohort revealed that daily caloric intake in such patients averaged <60% of recommended levels and 64% of patients consumed caloriedeficient diets.9

Deficiencies in vitamins A, B6, C and K, as well as iron, potassium and zinc were prominent. In patients with diabetic gastroparesis, variably delayed gastric emptying promotes unpredictable duodenal food delivery and therefore increases the risk of hypoglycemic and hyperglycemic excursions in these patients. In one study, insulinrequiring patients with type 1 or type 2 diabetes and delayed gastric emptying were at much higher risk of early postprandial hypoglycemic reactions than patients with diabetes but without clinically significant delayed gastric emptying.10 Other complications are also reported for this condition. Gastroparesis of all etiologies is the main cause of bezoar formation, with most other cases occurring after bariatric surgery.11 Bezoars may increase gastroparesis symptoms or produce a palpable epigastric mass, gastric ulcers, a gastric perforation, or small bowel obstruction. One study has reported evidence of small intestinal bacterial overgrowth in 60% of patients with gastroparesis by the measurement of hydrogen or methane levels in the breath after glucose ingestion.

Such bacterial overgrowth was related to disease duration but not to gastric emptying rates.12 Future studies testing antibiotic responses will define the role of this complication in gastroparesis. Quantification of symptom severity and characterization of symptom profiles of gastroparesis are aided by surveys like the Gastroparesis Cardinal Symptom Index (GCSI).13 The GCSI is a subset of the Patient Assessment of Upper Gastrointestinal Symptoms (PAGISYM) and consists of three subscales (nausea and vomiting, postprandial fullness and early satiety, and bloating) scored by recall of symptoms over the preceding 2 weeks. One concern of the standard GCSI survey is that a 2week recall period might bias scoring by favoring symptoms of the past few days over those experienced 2 weeks ago. A new variant designed to address this issue, the GCSI daily diary (GCSI DD), shows significant daytoday symptom variability in patients with gastroparesis; however mean GCSIDD scores correlate closely with GCSI scores from the 2week recall.14 The Patient Assessment of Upper Gastrointestinal Disorders Quality of Life (PAGIQOL) provides numerical values for quality of life in patients with disordered gut motility.15 By using these surveys, investigators can stratify patients with gastroparesis into subgroups on the basis of severity of symptoms and predominant symptoms. Forthcoming investigations will determine if such surveys help to predict outcomes of directed treatments for specific clinical presentations of gastroparesis.

발표

위마비에는 다양한 증상이 보고됩니다. 

환자의 90% 이상이 메스꺼움을 호소하고, 

68-84%는 구토를 경험하며, 

60%는 조기 포만감을 호소합니다.4 

통증은 환자의 46-90%가 호소하며, 

19%의 개인에게서 위마비의 주요 증상으로 나타납니다. 

통증은 삶의 질을 저하시키고 

상복부 통증, 

지속적인 통증, 

식사 유발성 및 야행성 복부팽창은 

각각 43%, 38%, 72%, 74%의 환자에서 발생합니다.5 

복부팽창은 흔한 증상입니다. 

위마비 환자의 80%가 이 증상을 보고하고 있으며,

 8%의 환자에서 가장 두드러지는 증상입니다.6 

심한 복부팽창(severe bloating)은 

삶의 질을 저하시키고 

여성에게서 더 자주 발생합니다. 

복부팽창은 

다른 위마비 증상의 강도와 상관관계가 있는 것으로 나타났습니다. 

위마비 때문에 

하부 식도 괄약근이 이완되는 경우가 많아 속쓰림이 발생할 수 있습니다. 

위마비의 증상은 종종 지속되지만, 

일부 환자는 주기적 구토 증후군을 모방하는 무증상 기간이 있는 간헐적 증상 발작을 경험합니다.7 

많은 위마비 환자가 비만이고, 

저체중 환자는 거의 없습니다.8 

그러나 

대규모 위마비 집단의 음식 섭취 패턴을 평가한 결과, 

이러한 환자의 일일 열량 섭취량은 권장량의 평균 60% 미만이고, 

64%의 환자가 열량 부족 식단을 섭취하는 것으로 나타났습니다.9

비타민 A, B6, C, K뿐만 아니라 

철분, 칼륨, 아연의 결핍이 두드러졌습니다. 

당뇨병성 위마비 환자의 경우, 

위 배출이 다양하게 지연되어 십이지장으로의 음식 전달이 예측할 수 없게 되고,

 따라서 이러한 환자들에게 저혈당과 고혈당 위험이 증가합니다. 

한 연구에 따르면, 

인슐린을 필요로 하는 제1형 또는 제2형 당뇨병 환자들과 위 배출 지연이 있는 환자들은 

임상적으로 유의미한 위 배출 지연이 없는 당뇨병 환자들보다 

식후 저혈당 반응의 위험이 훨씬 더 높았습니다.10 

이 상태에 대한 다른 합병증도 보고되었습니다. 

모든 원인의 위마비증은 

담석 형성의 주요 원인이며, 

대부분의 다른 경우는 비만 수술 후에 발생합니다.11 

담석은 

위마비증 증상을 증가시키거나 만져지는 상복부 덩어리, 

위궤양, 

위 천공 또는 소장 폐쇄를 유발할 수 있습니다. 

한 연구에 따르면, 

포도당 섭취 후 호흡에서 수소 또는 메탄 수치를 측정하여 

위마비 환자의 60%에서 소장 세균 과다 증식증이 나타났습니다.

이러한 세균 과다 증식증은 

질병 지속 기간과 관련이 있지만 

위 배출률과는 관련이 없습니다.12 

향후 항생제 반응을 테스트하는 연구는 

위마비에서 이러한 합병증의 역할을 정의할 것입니다. 

위마비 증상의 심각도를 정량화하고 

위마비 증상 프로파일을 특성화하는 데는 

위마비 주요 증상 지수(GCSI)와 같은 설문 조사가 도움이 됩니다.13 

GCSI는 상부 위장관 증상 환자 평가(PAGISYM)의 하위 집합이며, 

지난 2주 동안의 증상 회상으로 점수를 매긴 

세 가지 하위 척도(메스꺼움과 구토, 식후 포만감과 조기 포만감, 복부팽만감)로 구성되어 있습니다. 

표준 GCSI 설문 조사의 한 가지 우려 사항은 

2주간의 회상 기간이 2주 전에 경험한 증상보다 

최근 며칠 동안 경험한 증상을 선호하는 편향된 점수를 산출할 수 있다는 것입니다. 

이 문제를 해결하기 위해 고안된 새로운 변형인 GCSI 일일 일기(GCSI DD)는 위마비 환자의 일상적인 증상 변동성을 보여줍니다. 그러나 평균 GCSIDD 점수는 2주 회상 GCSI 점수와 밀접한 상관 관계가 있습니다.14 환자 상부 위장관 장애 삶의 질 평가(PAGIQOL)는 장 운동 장애가 있는 환자의 삶의 질에 대한 수치적 값을 제공합니다.15 이러한 설문 조사를 통해 연구자들은 위마비의 증상의 심각성과 주요 증상에 따라 위마비 환자를 하위 그룹으로 분류할 수 있습니다. 향후 연구에서는 이러한 설문 조사가 위마비의 특정 임상 증상에 대한 직접적인 치료의 결과를 예측하는 데 도움이 되는지 여부를 결정할 것입니다.

위마비증은 위 내용물의 배출이 지연되는 만성 증상을 유발합니다. 또한, 위장 외 합병증을 촉진할 수 있으며, 심각한 이환율과 의료 서비스 이용을 초래합니다. ■ 당뇨병성, 특발성 및 수술 후 위마비증은 가장 흔한 질병 원인입니다. ■ 조직 병리학은 장 신경세포, 평활근 및 카잘의 간질 세포의 형태학적 결함을 보여줍니다. 또한, 신경 전달 물질의 손실과 염증 세포의 증가 수준은 이질적인 병인을 시사합니다. 질병 ■ 위 배출을 측정하는 기술(위 배출 신티그래피, 무선 운동성 캡슐 모니터링, 호흡 검사 등)이 위마비의 진단에 사용되고 있지만, 여전히 논란이 존재 ■ 위마비 치료에는 운동 촉진제, 구토 방지제, 내시경 및 수술 기법, 영양 및 심리 개입 등이 포함되지만, 그 효과를 확인하기 위해서는 통제된 실험이 여전히 필요하다 ■ 진행 중인 연구는 위마비의 자연적 경위를 규명하고 있다

Etiology

Gastroparesis has many potential etiologies (Box 1). In a singlecenter study of 146 patients with gastroparesis, the etiology of the condition was diabetes in 29%, idiopathic in 36% and postsurgical in 13%.4 A multicenter database investigation of 571 patients with gastroparesis revealed that 64% had idiopathic gastroparesis and 31% had diabetic gastroparesis.

원인
위마비에는 많은 잠재적 원인이 있습니다(박스 1). 

위마비 환자 146명을 대상으로 한 단일 센터 연구에서, 

이 질환의 원인은 당뇨병이 29%, 

특발성이 36%, 

수술 후가 13%였습니다.4 

위마비 환자 571명을 대상으로 한 다기관 데이터베이스 조사에 따르면,

 64%는 특발성 위마비,

 31%는 당뇨병성 위마비였습니다.

Idiopathic gastroparesis

Idiopathic gastroparesis is the most common form of gastroparesis. In a series of 243 patients, mean age 41 years, 88% female [who reported more severe symptoms], gastric emptying was severely delayed in 28%, and predominant symptoms of gastroparesis were nausea (34%), vomiting (19%) and pain (23%).8 Severe anxiety and depression were present in 36% and 18% of individuals, respectively. 50% of patients reported acute symptom onset and 19% noted an initial infectious prodrome, such as acute gastroenteritis, food poisoning or respiratory infection. In most patients with gastroparesis reporting an infectious prodrome, offending organisms are not characterized, but rotavirus, Norwalk virus, Hawaii virus, parvovirus and Lyme disease have been implicated in a small number of cases. In one report, a patient developed gastroparesis in addition to cardiac conduction defects and bladder dysfunction after an infection in what seemed to be a case of postinfectious generalized dysautonomic syndrome.16 Cytomegalovirus, EpsteinBarr virus, varicella zoster virus and herpes simplex virus may be causative in the setting of immunosuppression. Gastroparesis may also develop after tetanus, anthrax and hepatitis vaccination, and after failed syphilis treatment in the setting of HIV infection.17

Idiopathic gastroparesis may present in a similar way to functional dyspepsia, leading some experts to speculate if they can be reliably distinguished from each other. Some patients with functional dyspepsia develop symptoms after a viral prodrome and 25–50% exhibit delayed gastric emptying on diagnostic testing. The postprandial distress subtype of functional dyspepsia, as well as chronic idiopathic nausea and functional vomiting are three Rome III criteria diagnoses of functional gastroduodenal disorders that have similar symptom characteristics to idiopathic gastroparesis.18 In a large study of patients with idiopathic gastroparesis, 86% met the Rome III criteria for diagnosis of functional dyspepsia.8 Presentation of a patient with a predominant symptom of upper abdominal pain has been promoted as representative of functional dyspepsia, whereas presentation of clinically significant nausea with little pain is touted to be more characteristic of idiopathic gastroparesis.19 This view is, however, inconsistent with the observation that symptomatic predominance of pain is equally preval‎ent in patients with diabetic and idiopathic gastroparesis;20 no clinician considers symptomatic predominance of pain in diabetic gastroparesis as synonymous with functional dyspepsia. At present, the ability to distinguish idiopathic gastroparesis from functional dyspepsia is of limited clinical relevance as therapies for the two conditions have substantial overlap.18

Future investigations should strive to identify specific patient subsets that selectively respond to different therapies on the basis of determinations of gastric emptying and other potentially causative motor or sensory defects. Pathophysiologic studies in patients with idiopathic gastroparesis have identified several abnormalities. One investigation observed hypersensitivity to gastric balloon inflation in 29% of patients, which related to increases in upper abdominal pain, early satiety and weight loss compared with those without hypersensitivity. Impaired fundic accommodation (reported in 43% of patients) was more often associated with increased early satiety and loss of weight compared with those with normal accommodation.21 Vagus nerve integrity can be measured by assessing gastric acid output or pancreatic polypeptide responses to sham feeding. Vagal neuropathy is more severe in diabetic versus idiopathic gastroparesis, as indicated by observations that gastric pH is higher and pancreatic polypeptide responses to sham feeding are selectively impaired in patients with diabetic gastroparesis.22 In a preliminary study from a large multicenter database, erythrocyte sedimentation rates and C­reactive protein levels were shown to be increased in patients with severe idiopathic gastroparesis versus those with less severe disease, and increased levels of antinuclear antibodies were shown to relate to symptomatic predominance of nausea, raising the possibility that inflammatory factors may participate in the pathogenesis of this condition.23

특발성 위마비증

특발성 위마비증은 

가장 흔한 형태의 위마비증입니다. 

평균 연령 41세, 여성 88%[더 심한 증상을 보고한 환자] 243명의 환자 집단에서, 

위 배출이 28%에서 심하게 지연되었고, 

위마비의 주요 증상은 메스꺼움(34%), 구토(19%), 통증(23%)이었습니다. 8 

심각한 불안과 우울증은 

각각 36%와 18%의 개인에게서 나타났습니다. 

환자의 50%가 급성 증상 발병을 보고했고, 

19%는 급성 위장염, 식중독 또는 호흡기 감염과 같은 초기 전염성 전구 증상을 보고했습니다. 

전염성 전구 증상을 보고한 대부분의 위마비 환자에서 원인균은 밝혀지지 않았지만, 

로타바이러스, 노워크 바이러스, 하와이 바이러스, 파보바이러스 및 라임병이 

소수의 사례와 관련이 있는 것으로 밝혀졌습니다. 

한 보고서에 따르면, 

한 환자가 감염 후 전신성 자율신경실조증후군으로 보이는 증상을 겪은 후 

심장 전도 결함과 방광 기능 장애에 더해 위마비까지 발생했습니다.16 

사이토메갈로바이러스, 엡스타인바 바이러스, 수두 대상포진 바이러스, 단순포진 바이러스가 

면역 억제 환경에서 원인이 될 수 있습니다. 

위마비증은 

파상풍, 탄저병, 간염 예방접종 후, 그리고 HIV 감염 상태에서 매독 치료에 실패한 후에도 

발생할 수 있습니다.17

특발성 위마비증은 

기능성 소화불량과 유사한 방식으로 나타날 수 있기 때문에 

일부 전문가들은 이 두 가지가 서로 확실하게 구분될 수 있는지 추측하고 있습니다. 

기능성 소화불량증 환자 중 일부는 

바이러스성 전구증상이 나타난 후에 증상이 나타나며, 

25~50%는 진단 검사에서 위 배출 지연이 나타납니다. 

식후 불편감의 기능성 소화불량 하위 유형과 

만성 특발성 구역 및 기능성 구토는 

특발성 위마비증과 유사한 증상 특성을 가진 

기능성 위십이지장 장애의 로마 3 기준 진단 3가지입니다.18 

특발성 위마비증 환자를 대상으로 한 대규모 연구에서 

86%가 기능성 소화불량 진단을 위한 

로마 3 기준을 충족했습니다.8 

상복부 증상이 주된 환자의 증상 통증은 

기능성 소화불량증의 대표적인 증상으로 여겨져 왔지만, 

임상적으로 유의미한 메스꺼움과 함께 

통증이 거의 없는 증상은 특발성 위마비증의 특징으로 여겨지고 있습니다.19 

그러나 이러한 견해는 

통증의 증상이 당뇨병성 위마비증과 특발성 위마비증 환자 모두에게 

똑같이 널리 나타나는 것을 고려할 때 

일관성이 없습니다.20 

어떤 임상의도 

당뇨병성 위마비증에서 통증의 증상이 기능성 소화불량증과 동의어라고 생각하지 않습니다. 

현재 특발성 위마비증과 기능성 소화불량증을 구분하는 능력은 

두 질환에 대한 치료법이 상당히 겹치기 때문에 

임상적으로 제한적인 관련성을 가지고 있습니다.18

향후 연구에서는 

위 배출 및 기타 잠재적 원인인 운동 또는 감각 결함을 기준으로 

다양한 치료법에 선택적으로 반응하는 특정 환자 하위집단을 식별하는 데 주력해야 합니다. 

특발성 위마비증 환자의 병리 생리학적 연구에서 

몇 가지 이상이 확인되었습니다. 

한 연구에 따르면 

위 팽창에 대한 과민증은 

위 복부 통증, 조기 포만감, 체중 감소의 증가와 관련이 있는 것으로 나타났습니다. 

위 팽창에 대한 과민증은 

위 팽창에 대한 과민증이 없는 사람들에 비해 

위 팽창에 대한 과민증이 있는 사람들의 29%에서 관찰되었습니다. 

43%의 환자에서 보고된 

안저 조절 장애는 

정상 조절을 가진 사람들에 비해 조기 포만감 증가 및 체중 감소와 더 자주 관련이 있었습니다.21 

미주신경의 완전성은 

위산 배출량 또는 위약 섭취에 대한 췌장 폴리펩티드 반응을 평가함으로써 

측정할 수 있습니다. 

위식도 역류성 질환이 있는 당뇨병 환자에서 위산도가 더 높고, 

위식도 역류성 질환이 있는 당뇨병 환자에서 

위가 비어 있는 상태에 대한 췌장 폴리펩티드 반응이 선택적으로 손상된다는 관찰 결과가 나타내는 바와 같이, 

위식도 역류성 질환은 특발성 위식도 역류성 질환보다 당뇨병에서 더 심각합니다.22 

대규모 다기관 데이터베이스의 예비 연구에서 

적혈구 침강 중증 특발성 위마비 환자에서 

활성 단백질 수치가 증가하는 것으로 나타났으며, 

항핵 항체 수치의 증가는 메스꺼움의 증상 우세와 관련이 있는 것으로 나타났습니다. 

따라서 

염증 요인이 이 질환의 발병에 관여할 가능성이 있습니다.23

Diabetic gastroparesis

Diabetes is the condition that is most often complicated by gastroparesis. In one report, 18% of patients with diabetes noted upper gastrointestinal symptoms, which is higher than in healthy controls.24 Delayed gastric emptying is found in 27–65% of patients with longstanding type 1 diabetes and in up to 30% of patients with type 2 diabetes. In a preliminary report from a multicenter database of 129 patients with diabetic gastroparesis, patients with type 2 diabetes were older, had a higher body mass, and reported greater nausea, early satiety and constipation than patients with type 1 diabetes.25 In diabetics on hemodialysis, gastroparesis develops in those with orthostatic hypotension, a prior myocardial infarction or cerebrovascular accident, or peripheral gangrene, indicating the codevelopment of gastroparesis with vascular complications of disease.26 Diabetes as a result of chronic pancreatitis also causes gastroparesis. Regional gastric defects are demonstrable in patients with diabetic gastroparesis. Fasting and fed phasic antral contractions are reduced while postprandial antral diameter on ultrasonography is increased.27 Abnormally intense and prolonged pyloric contractility (referred to as pylorospasm) is observed in some patients with diabetic gastroparesis.28 Other patients exhibit abnormal jejunal phasic motor bursts that have been postulated to contribute to delayed gastric emptying.29

Fundic sensory thresholds to distention are enhanced and accommodation to meals is shown to be blunted in patients with diabetes and refractory gastrointestinal symptoms.30 However, studies of the esophagus have shown that impaired afferent nerve transmission relates to less rather than more upper gastrointestinal symptomatology.31 Extragastric factors have a role in delayed gastric emptying in patients with diabetes. Shamfeeding induced gastric acid production is decreased in diabetics, reflecting vagal neuropathic damage. In one study, 62% of patients with type 1 diabetes and gastroparesis showed autonomic neuropathy.32 Autonomic neuropathy severity scores correlate positively with gastric emptying times. However, a longitudinal followup study of 20 patients with diabetic gastroparesis (16 with type 1 diabetes) reported no progression of either liquid or solid phase scintigraphic gastric retention and no increase in gastrointestinal symptoms over a 12year period, even though the preval‎ence of autonomic dysfunction in this population increased from 35% at baseline to 80% at the end of the followup.33 Genetic factors, such as the mitochondrial DNA mutation 3243, predispose patients with type 2 diabetes to gastroparesis.34 Loss of glycemic control impairs gastric motor function; liquid gastric emptying is delayed when blood glucose is >15mmol/l (270mg/dl).35

Acute hyperglycemia can lead to the abolition of fasting migrating motor complex activity, increased fundic compliance, stimulation of pyloric motility, heightened gastric sensitivity, disruption of normal slow wave activity, blunting of gastric response to stimulation with the prokinetic drug erythromycin in healthy volunteers, and reductions of antral motility and induction of slow wave dysrhythmias in patients with diabetes.36–39 Furthermore, selected studies have shown that hyperglycemia reduces sensations of hunger in healthy individuals and patients with type 1 diabetes and increases reports of postprandial fullness in patients with diabetes who require insulin.39–41 Conversely, insulininduced hypoglycemia promotes acceleration of both solid and liquid gastric emptying in patients with type 1 diabetes.42 Finally, immunologic effects on motor function may have pathogenic roles in diabetic gastroparesis. Impaired contractility in response to direct smooth muscle stimulation in some patients with type I diabetes may result from L­type calcium channel antibodies.43

당뇨병성 위마비

당뇨병은 

위마비로 인해 가장 자주 복잡해지는 질환입니다. 

한 보고서에 따르면, 

당뇨병 환자의 18%가 상부 위장 증상을 호소했는데, 

이는 건강한 대조군보다 높은 수치입니다.24 

위 배출 지연은 

장기적인 제1형 당뇨병 환자의 27-65%에서, 

제2형 당뇨병 환자의 최대 30%에서 발견됩니다. 

다기관 데이터베이스에 등록된 129명의 당뇨성 위마비 환자들에 대한 예비 보고서에 따르면, 제2형 당뇨병 환자들은 제1형 당뇨병 환자들보다 나이가 많고, 체질량이 높으며, 메스꺼움, 조기 포만감, 변비 등의 증상이 더 많이 보고되었습니다.25 

혈액 투석 중인 당뇨병 환자들 투석, 위마비는 

기립성 저혈압, 이전의 심근경색 또는 뇌혈관 사고, 말초 괴저를 가진 사람들에게서 발생하며, 

이는 위마비와 혈관 합병증의 병발 발생을 나타냅니다.26 

만성 췌장염으로 인한 당뇨병도 

위마비를 유발합니다. 

당뇨병성 위마비 환자에서 국소 위 결손이 입증됩니다. 

금식 시와 식사 후 위 수축이 감소하는 반면, 

식사 후 초음파 검사에서 위 직경이 증가합니다.27 

당뇨병성 위마비 환자 중 일부에서는 

비정상적으로 강렬하고 장기간 지속되는 유문 수축(유문 연축이라고 함)이 관찰됩니다.28 

다른 환자들에서는 

비정상적인 공장 수축이 관찰되는데, 

이는 위 배출 지연에 기여하는 것으로 추정됩니다.29

팽창에 대한 감각 역치가 향상되고, 

당뇨병과 난치성 위장 증상을 보이는 환자에서 식사 조절 능력이 둔화된 것으로 나타났습니다.30

그러나

식도 연구에 따르면

구심성 신경 전달 장애가 상부 위장 증상의 증가보다는 감소와 관련이 있는 것으로 나타났습니다.31

위장 외적 요인은

당뇨병 환자의 위 배출 지연에 영향을 미칩니다.

위산 분비를 유도하는 위약의 효과는 당뇨병 환자의 경우 감소하는데,

이는 미주신경 신경병증의 손상을 반영합니다.

한 연구에 따르면,

제1형 당뇨병과 위마비 환자의 62%가 자율신경병증을 보였습니다.32

자율신경병증의 심각도 점수는

위 배출 시간과 양의 상관관계가 있습니다.

그러나

당뇨성 위마비 환자 20명(제1형 당뇨병 환자 16명)을 대상으로 한 종단적 추적 연구에 따르면,

12년 동안 액체 또는 고체 위잔류 신티그래피의 진행이 없었으며,

위장 증상도 증가하지 않았습니다.

이 집단의 자율 신경 기능 장애 유병률은

기준 시점의 35%에서 80%로 증가했지만 말입니다.

추적 조사 끝에 나온 결과의 %33 미토콘드리아 DNA 돌연변이 3243과 같은 유전적 요인은 제2형 당뇨병 환자에게 위마비를 유발할 수 있습니다.34 혈당 조절의 상실은 위 운동 기능을 손상시킵니다.

혈당이 15mmol/l(270mg/dl) 이상일 때

위액 배출이 지연됩니다.35

Gastric emptying of a digestible solid and liquid meal and oesophageal emptying of a solid bolus were measured with scintigraphic techniques in 20 randomly selected Type 2 (non-insulin-dependent) diabetic patients receiving oral hypoglycaemic therapy and 20 control subjects. In the diabetic patients, the relationships between oesophageal emptying, gastric emptying, gastrointestinal symptoms, autonomic nerve function and glycaemic control were examined. The percentage of the solid meal remaining in the stomach at 100 min (p less than 0.001), the 50% gastric emptying time for the liquid meal (p less than 0.05) and oesophageal emptying (p less than 0.05) were slower in the diabetic patients compared to the control subjects. Scores for upper gastrointestinal symptoms and autonomic nerve dysfunction did not correlate significantly (p greater than 0.05) with oesophageal, or gastric emptying. The 50% gastric emptying time for the liquid meal was positively related (r = 0.58, p less than 0.01) to the plasma glucose concentration at the time of the performance of the gastric emptying test and the lag period, before any solid food emptied from the stomach, was longer (p less than 0.05) in subjects with plasma glucose concentrations during the gastric emptying measurement greater than the median, compared to those with glucose concentrations below the median. These results indicate that delayed gastric and oesophageal emptying occur frequently in Type 2 diabetes mellitus and that delayed gastric emptying relates, at least in part, to plasma glucose concentrations. 소화 가능한 고체 및 액체 식사의 위 배출과 고형 덩어리의 식도 배출은 경구용 저혈당 요법을 받고 있는 무작위로 선택된 제2형(인슐린 비의존성) 당뇨병 환자 20명과 대조군 20명을 대상으로 신티그래피 기법으로 측정되었습니다. 당뇨병 환자들에서는 식도 배출, 위 배출, 위장 증상, 자율 신경 기능, 혈당 조절 간의 관계를 조사했습니다. 100분 후 위장에 남아 있는 고형식사의 비율(p<0.001), 액상식사의 50% 위 배출 시간(p<0.05), 식도 배출(p<0.05)은 대조군보다 당뇨병 환자에서 더 느렸습니다. 상부 위장관 증상 및 자율신경 기능 장애 점수는 식도 또는 위 배출과 유의미한 상관관계가 없었습니다(p>0.05). 액체 식사의 50% 위 배출 시간은 위 배출 검사 수행 시점의 혈장 포도당 농도와 양의 상관관계가 있었습니다(r=0.58, p<0.01). 위 배출 측정 중 혈장 포도당 농도가 중앙값보다 높았던 피험자에서 위 배출 지연 기간이 중앙값보다 낮은 피험자에 비해 더 길었습니다(p<0.05). 이러한 결과는 제2형 당뇨병 환자에서 위와 식도 배출 지연이 자주 발생하며, 위 배출 지연이 적어도 부분적으로는 혈장 포도당 농도와 관련이 있음을 나타냅니다.

급성 고혈당증은 

공복시 이동 운동 복합체의 활동을 중단시키고, 

안저 순응도를 증가시키며, 

유문 운동성을 자극하고, 

위 민감도를 증가시키며, 

정상적인 느린 파동 활동을 방해하고, 

건강한 지원자에게서 프로키네틱 약물인 에리스로마이신으로 자극했을 때 위 반응이 둔화되며, 

당뇨병 환자의 경우 위 운동성을 감소시키고 느린 파동 부정맥을 유발할 수 있습니다.36-39 

또한, 

일부 연구에서는 

고혈당증이 건강한 사람과 제1형 당뇨병 환자의 배고픔을 감소시키고, 

인슐린이 필요한 당뇨병 환자의 식후 포만감을 증가시킨다는 사실이 밝혀졌습니다.39-41 

반대로, 

인슐린으로 인한 저혈당증은 

제1형 당뇨병 환자의 고형 및 액체 위 배출을 촉진합니다.42 

마지막으로, 

운동 기능에 대한 면역학적 영향은 

당뇨병성 위마비에 병원성 역할을 할 수 있습니다. 

제1형 당뇨병 환자 중 일부는 

직접적인 평활근 자극에 대한 반응으로 수축력이 저하될 수 있는데, 

이는 L형 칼슘 채널 항체에 의해 발생할 수 있습니다.43

Postsurgical gastroparesis

Gastroparesis can occur as a consequence of many operations. Approximately 5% of individuals who undergo surgeries for peptic ulcer disease or gastric malignancy that include truncal or selective vagotomy develop delayed gastric emptying.44 The Roux stasis syndrome occurs after gastrojejunostomy and presents with delayed gastric emptying that occurs as a consequence of simultaneous or retrograde Roux limb contractions. Patients with this condition present with nausea, vomiting and pain. 4–40% of laparoscopic fundoplication procedures for GERD are complicated by vagal damage that may predispose to gastroparesis.45 However, in some cases it is unknown if pathologic degrees of delayed gastric emptying existed prior to the operation. Bariatric surgeries such as Rouxen­Y gastric bypass and sleeve gastrectomy, but not laparoscopic banding or vertical banded gastroplasty, increase gastric retention and lead to fundic distention that may increase reports of early satiety, anorexia and weight loss.46 Esophagectomy can also lead to gastroparesis in 11% of patients.47

Delayed gastric emptying occurs in 44% of patients undergoing pancreatoduodenectomy and contributes to prolonged hospitalizations; such patients with delayed gastric emptying have been stratified into three severity grades by the International Study Group of Pancreatic Surgery on the basis of the time after surgery that a nasogastric tube is needed and the time that oral intake can be resumed.48 Risk factors for delayed gastric emptying in those who have undergone pancreatic surgery include female sex, preoperative heart failure and postoperative complications. Gastroparesis attributable to vagal injury is also observed after radiofrequency ablation for atrial arrhythmias.49 Lastly, one study reported that 8% of postcholecystectomy patients developed gastroparesis, suggesting that operations that do not disrupt vagal activity also impair gastric motor function.4

수술 후 위마비

위마비는 많은 수술의 결과로 발생할 수 있습니다. 

위궤양이나 위암으로 인해 수술을 받은 사람들 중 

약 5%가 몸통 또는 선택적 미주신경 절개술을 받은 경우 위 배출 지연이 발생합니다.44 

루우 정체 증후군은 위장루술 후 발생하며, 동시 또는 역행성 루우 사지 수축의 결과로 발생하는 위 배출 지연이 나타납니다. 이 질환을 앓고 있는 환자는 메스꺼움, 구토, 통증을 호소합니다. 위식도 역류 질환에 대한 복강경 위저근 접합술의 4~40%는 위마비 유발 요인이 될 수 있는 미주신경 손상으로 인해 복잡해집니다. 그러나 어떤 경우에는 수술 전에 위 배출 지연의 병리학적 정도가 존재했는지 여부가 알려지지 않습니다. 루웬Y 위 우회술과 소매 위 절제술과 같은 비만 수술은 복강경 밴딩이나 수직 밴드 위성형술은 아니지만, 위 잔류량을 증가시키고, 조기 포만감, 거식증, 체중 감소에 대한 보고를 증가시킬 수 있는 위 팽창을 유발합니다.46 식도 절제술은 또한 11%의 환자들에게서 위 마비를 유발할 수 있습니다.47

위 배출 지연은 췌십이지장 절제술을 받은 환자의 44%에서 발생하며, 입원 기간을 연장하는 원인이 됩니다. 위 배출 지연이 있는 환자는 국제 췌장 수술 연구 그룹에 의해 3가지 중증도 등급으로 분류됩니다. 수술 후 위관 영양이 필요한 시간과 경구 섭취를 재개할 수 있는 시간의 기준입니다. 48 췌장 수술을 받은 사람들의 위 배출 지연의 위험 요소로는 여성, 수술 전 심부전, 수술 후 합병증이 있습니다. 심방 부정맥에 대한 고주파 절제술 후에도 미주신경 손상으로 인한 위마비가 관찰됩니다.49 

마지막으로, 

한 연구에 따르면 

담낭 절제술 후 환자의 8%가 위마비를 겪었는데, 

이는 미주신경 활동을 방해하지 않는 수술도 위 운동 기능을 손상시킬 수 있음을 시사합니다.4

Other causes of gastroparesis

Isolated development of delayed gastric emptying with preservation of normal transit in other gut regions can be a complication of selected disorders. Some studies have reported delayed liquid or solid gastric emptying in patients with GERD.50 Delayed gastric emptying is also observed in 60% of patients with pancreatic carcinoma and to a lesser degree in patients with other malignancies (for example gastric, gallbladder, esophageal and lung cancer, and leiomyosarcoma).51 Mechanisms of cancer associated gastroparesis include malignant infiltration of the vagus or autonomic nerves and autoantibody mediated myenteric damage. Ischemic gastroparesis results from celiac arterial thrombosis. Patients with median arcuate ligament syndrome develop compression of the celiac artery by a fibrous band with resultant blood flow restriction and present with nausea, vomiting, pain and delayed gastric emptying.52 A single report has suggested that ingesting caustic acidic or alkaline substances can also lead to prolonged gastric emptying.53

Other causes of delayed gastric emptying include abdominal irradiation and atrophic gastritis. Gastroparesis is found in conditions that produce generalized dysmotility. Delayed gastric emptying is reported in 40–67% of patients with scleroderma but is less common in patients with polymyositis or systemic lupus erythematosus.54 Gastric stasis is also observed in patients with amyloidosis, myotonic dystrophy and progressive muscular dystrophy.55,56 Intestinal pseudoobstruction is a condition that is very similar to gastroparesis and is defined by symptoms of abnormal small bowel retention in the absence of mechanical obstruction. It may be familial, postinfectious, autoimmune or paraneoplastic in etiology. Type 1 antineuronal nuclear, antiPurkinje cell cytoplasmic and ganglionic nicotinic acetylcholine receptor antibodies may be present in patients with paraneoplastic intestinal pseudoobstruction, reflecting an underlying immunologic basis of this condition.57 Chagas’ disease is a parasitic condition resulting from infection with Trypanosoma cruzi that causes gastroparesis and chronic intestinal pseudoobstruction. Chronic constipation and constipationpredominant IBS may also be associated with abnormal gastric emptying. A study has reported that 19–64% of patients with these conditions may have abnormal gastric emptying.58 Delayed gastric emptying is observed in neurologic diseases. One study has reported that more than 7% of patients with gastroparesis had Parkinson’s disease as a potential disease etiology.4

Gastric and/or small intestinal dysmotility is also noted in patients with stroke, meningioma, migraines, cervical spinal injury, neurofibromatosis, stiffman syndrome, Charcot–Marie– Tooth syndrome, familial dysautonomia, Shy–Drager syndrome, Guillain–Barré syndrome, multiple sclerosis and other demyelinating diseases.59–61 Other conditions also affect gastric emptying. Studies using nonradioactive methods report delayed gastric emptying in individuals with pregnancyrelated nausea. Gastroparesis is also a risk factor for hyperemesis gravidarum.62 Most studies observe normal or accelerated gastric emptying in patients with adult cyclic vomiting syndrome, although some of these individuals exhibit gastroparesis. Eating disorders such as anorexia nervosa and bulimia nervosa may have associated impaired gastric emptying or phasic antral contractility.63 Likewise, reduced antral contractions are reported in rumination syndrome. The ability of improved nutrition to accelerate gastric emptying in such conditions provides evidence that the contractile deficits are consequences rather than causes of gastric motor impairments.64 Delayed gastric emptying has been found in association with inactive Crohn’s disease.65

Hypothyroidism, hyperparathyroidism, cirrhosis, chronic renal failure, chronic pancreatitis and cystic fibrosis are also associated with gastroparesis.66–68 Patients with critical illness in the intensive care unit may exhibit delayed gastric emptying and this can influence feeding decisions. In physiologic studies, mechanically ventilated critically ill patients show increases in pyloric pressure waves and exaggerated reductions in antral motility in association with increased basal and nutrientstimulated cholecystokinin levels during duodenal nutrient perfusion.69,70 This mechanism may contribute to gastroparesis. Prescribed drugs can impair gastric function. In patients with diabetes, the glucagonlike peptide 1 analog exenatide delays both solid and liquid gastric emptying—a phenomenon that correlates with reductions in postprandial glucose excursions.71 The effects of this agent on gastric emptying are postulated to contribute to its therapeutic benefits. Tobacco, excessive alcohol intake and cannabis use are also associated with delayed gastric emptying.72,73 Cancer chemotherapy can produce long lasting impairments of gastric emptying.74 Finally, total parenteral nutrition impairs gastric emptying in part by inducing hyperglycemia; such impairment can be partly reversed by replacing half of the amino acid content of the nutrition supplement with branchedchain formulations.7

위마비의 다른 원인들

다른 장 부위의 정상적인 통과를 유지하면서 위 배출이 지연되는 증상이 단독으로 나타나는 경우도 있습니다. 

일부 연구에 따르면 

위식도 역류 질환 환자의 경우 

액체 또는 고형 음식의 위 배출이 지연되는 것으로 나타났습니다.50 

위 배출 지연은 

췌장암 환자의 60%에서 관찰되며, 

다른 악성 종양 환자(예: 위암, 담낭암, 식도암, 폐암, 평활근육종 등) 51 

암과 관련된 위마비의 메커니즘에는 

미주신경 또는 자율신경의 악성 침윤과 자가항체에 의한 장간막 손상이 포함됩니다. 

허혈성 위마비는 

복강동맥 혈전증으로 인해 발생합니다. 

중간 아치형 인대 증후군 환자는 섬유성 띠에 의해 복강 내 동맥이 압박되어 혈류 제한이 발생하고, 

메스꺼움, 구토, 통증, 위 배출 지연 등의 증상이 나타납니다.52 

한 보고서에 따르면 

부식성 산성 또는 알칼리성 물질을 섭취할 경우에도 

위 배출 지연이 발생할 수 있다고 합니다.53

위 배출 지연의 다른 원인으로는 

복부 방사선 조사와 위축성 위염이 있습니다. 

위마비는 

전신 운동 장애를 일으키는 질환에서 발견됩니다. 

위 배출 지연은 

경피증 환자의 40-67%에서 보고되지만, 

다발성 근염이나 전신성 홍반성 낭창 환자에서는 덜 흔합니다.54 

위 정체는 또한 다음 환자들에서 관찰됩니다. 

아밀로이드증, 근이영양증, 진행성 근이영양증.55,56 장폐색증은 

위마비와 매우 유사한 질환으로,

 기계적 장애가 없는 상태에서 소장의 비정상적인 정체 증상이 나타나는 것으로 정의됩니다. 

원인은 

가족성, 감염 후, 자가면역 또는 부신생식성일 수 있습니다. 

유형 1 항신경핵, 항푸르킨제 세포질 및 신경절 니코틴성 아세틸콜린 수용체 항체가 

부신생식성 장폐색증 환자에서 발견될 수 있으며, 

이는 이 질환의 근본적인 면역학적 기초를 반영합니다.57 

샤가스병은 트리파노소마 크루지(Trypanosoma cruzi)에 감염되어 발생하는 

기생충 질환으로, 

위마비 및 만성 장폐색증을 유발합니다. 

만성 변비 및 변비우세성 과민성 대장 증후군은

 위 배출 이상과 관련이 있을 수도 있습니다. 

한 연구에 따르면 

이러한 증상을 보이는 환자의 19~64%가 위 배출 이상 증상을 보일 수 있다고 합니다.58 

위 배출 지연은 신경학적 질환에서 관찰됩니다. 

한 연구에 따르면 위 마비 환자의 7% 이상이 파킨슨병을 잠재적 질병 원인으로 가지고 있다고 합니다.4

위 또는 소장 운동 장애는 

뇌졸중, 수막종, 편두통, 경추 손상, 신경섬유종증, 강직성 근긴장증후군, 

샤르코-마리-투스 증후군, 가족성 자율신경실조증, 샤이-드레거 증후군, 길랑-바레 증후군, 

다발성 경화증 및 기타 탈수초성 질환 환자들에게서도 관찰됩니다.59-61 

위 배출에 영향을 미치는 다른 질환들도 있습니다. 비방사성 방법을 사용한 연구에 따르면, 임신과 관련된 메스꺼움을 겪는 사람들은 위 배출이 지연되는 것으로 나타났습니다. 위마비증은 또한 임신 중 심한 구토증의 위험 요소입니다.62 대부분의 연구에서 성인 주기성 구토 증후군 환자의 경우 위 배출이 정상적이거나 가속화된 것으로 관찰되지만, 일부 환자는 위마비증을 보입니다. 

신경성 식욕부진증과 신경성 폭식증과 같은 섭식 장애는 

위 배출 장애 또는 위 수축과 관련이 있을 수 있습니다.63 

마찬가지로, 

반추 증후군에서는 위 수축이 감소하는 것으로 보고됩니다. 

이러한 상황에서 위 배출을 촉진하는 영양 개선 능력은 위 운동 장애의 원인이 아닌 결과라는 증거를 제공합니다.64 

위 배출 지연은 

비활성 크론병과 관련이 있는 것으로 밝혀졌습니다.65

갑상선 기능 저하증, 부갑상선 기능 항진증, 간경화, 만성 신부전, 만성 췌장염, 낭포성 섬유증도 

위마비와 관련이 있습니다.66-68 

중환자실에서 중증 질환을 앓고 있는 환자는 

위 배출이 지연될 수 있으며, 

이는 수유 결정에 영향을 미칠 수 있습니다. 

생리학 연구에 따르면, 기계적 인공호흡을 받는 중증 환자는 십이지장 영양관 관류 중 기저 및 영양 자극 콜레시스토키닌 수치가 증가하면서 유문 압력 파가 증가하고, 십이지장 운동성이 과도하게 감소하는 것으로 나타났습니다.69,70 이 메커니즘이 위마비에 영향을 미칠 수 있습니다. 처방약은 위 기능을 손상시킬 수 있습니다. 당뇨병 환자의 경우, 글루카곤 유사 펩타이드 1 유사체인 엑세나타이드가 고형 및 액체 위 배출을 지연시킵니다. 이 현상은 식후 포도당 변동 감소와 관련이 있습니다.71 위 배출에 대한 이 약제의 영향은 치료 효과에 기여하는 것으로 추정됩니다. 

담배, 과도한 알코올 섭취, 대마초 사용도 위 배출 지연과 관련이 있습니다.72,73 

암 화학 요법은 위 배출에 장기적인 손상을 일으킬 수 있습니다.74 

마지막으로, 완전 비경구 영양은 부분적으로 고혈당증을 유발하여 위 배출을 손상시킵니다. 

이러한 손상은 영양 보충제의 아미노산 함량의 절반을 분지 사슬 제형으로 대체함으로써 부분적으로 회복될 수 있습니다.7

Histopathology

Histologic study of excised full thickness gastric tissues from patients with gastroparesis provides insight into the causes of impaired gastric emptying. Vagus nerves from patients with diabetes exhibit variable levels of myelin degeneration. In tissues from 28 patients, lymphocytic infiltrates were observed in 7 patients and reductions in the number of nerve cell bodies, ganglion cells and interstitial cell of Cajal were observed in variable numbers of patients.76 In a large series of individuals with diabetic or idiopathic gastroparesis, full thickness gastric biopsy specimens revealed dysmorphic or absent interstitial cells of Cajal, abnormal immune infiltrates containing macrophages, decreased nerve fibers, and increased connective tissue with smooth muscle fibrosis.77 Findings from diabetic and idiopathic gastroparesis full thickness gastric tissue samples were similar except greater reductions in neuronal nitric oxide synthase expression‎ were found in tissues from patients with idiopathic gastroparesis. Examination of endoscopic gastric mucosal biopsy specimens from patients with diabetic gastroparesis reveals reduced density and abnormal morphology of mucosal nerves with deficient nerve fibers extending from gastric glands to the basal lamina.78 These findings raise the possibility that endoscopic diagnosis of enteric neuropathy may be clinically feasible in gastroparesis.

Diagnosis of presumed gastroparesis

Other conditions potentially causative of symptoms, such as gastric outlet obstruction, peptic ulcer disease, neoplasm, small bowel obstruction or IBD should be excluded by endoscopy or contrast radiology prior to conferring a diagnosis of gastroparesis.

Gastric motor testing methods

Gastric emptying scintigraphy uses a labeled isotope (Tc­99m sulfur colloid) bound to solid food to enable imaging of gastric motility and is the most widely employed test to diagnose gastroparesis. A drawback of this procedure is poor standardization of methods of testing and interpretation of results. In one publication, the reported diagnostic cutoff value for gastroparesis was >2, 1.5 and 1 standard deviations greater than the mean in 28%, 6.5% and 26% of surveyed hospitals, respectively; 40% of institutions did not define diagnostic criteria for gastroparesis.79 A uniform gastric emptying scintigraphy technique involving the consumption of toast, jam and a lowfat egg substitute labeled with Tc­99m sulfur colloid has been validated in healthy individuals (Figure 1).80 Gastric retention of >60% of the meal at 2h and/or >10% of the meal at 4h is outside the range of >95% of healthy individuals and these cutoff values are therefore used to confer a diagnosis of gastroparesis. This protocol has been endorsed by the American Neurogastroenterology and Motility Society and the Society of Nuclear Medicine.81 However, one study reported that 37% of patients with normal gastric emptying at 2 h showed delayed gastric emptying at 4h whereas 19% of individuals with delayed gastric emptying at 2 h had normal gastric emptying at 4 h.82 This study highlights the inconsistencies of diagnosis even with standardized methods. Some clinicians have proposed measuring blood glucose in patients with diabetes and suspected gastroparesis and not proceeding with gastric emptying scintigraphy until near euglycemia is achieved, as hyperglycemia can produce exaggerated delays in gastric emptying. A diagnostic method using a wireless motility capsule (WMC) that quantifies luminal pH and pressure offers an alternative to gastric emptying scintigraphy. In this method, gastric emptying is identified by a significant and sustained pH increase as the capsule passes from the antrum to the proximal small intestine (Figure 2). Unlike with gastric emptying scintigraphy, this pH increase reflects gastric emptying of an indigestible solid—a phenomenon that is usually controlled by resumption of the fasting migrating motor complex in the distal stomach. The correlation coefficient between WMC findings and gastric emptying scintigraphy findings at 4 h is 0.73 and the accuracy of WMC testing for the differentiation of patients with gastroparesis from healthy individuals is 0.83.83 By use of WMC, reduced numbers of contractions and motility indices are noted in the stomach and small bowel of patients with gastroparesis.84 In another study of WMC testing, diabetics with gastroparesis were shown to have delayed colon transit, which indicates that many patients with gastroparesis have generalized transit defects.85 For patients who have symptoms that suggest a generalized motility disorder involving multiple gut regions, WMC testing can measure gastric emptying and small bowel and colon transit in a single study. Breath tests using nonradioactive 13Clabeled substrates are proposed as alternatives to gastric emptying scintigraphy. These techniques measure 13CO2 in exhaled breath samples after duodenal processing of the consumed substrate. Findings of 13Coctanoate and 13Cacetate breath tests correlate well with those of gastric emptying scintigraphy.86 Another breath test using 13CSpirulina platensis, a blue green alga, mixed with eggs, crackers and water showed 89% sensitivity and 80% specificity versus gastric emptying scintigraphy for detecting delayed emptying when a multiple linear regression model was employed measuring combined breath test results at 150 and 180 min.87 Breath tests results may be unreliable in individuals with conditions that impair digestive, absorptive or pulmonary function. In one study, delayed 13CO2 excretion was similar in patients with diabetic gastroparesis and in patients with untreated celiac disease;86 it was unclear if delayed gastric emptying in the patients with celiac disease resulted from transit defects or impaired small bowel absorption. Other techniques to measure gastric emptying are useful in research. Ultrasound quantifies gastric accommodation, antral contractions, transpyloric flow, gastric emptying and meal distribution within the stomach. Two dimensional ultrasound methods are limited by operator variabilities and because only liquid gastric emptying can be measured. Three dimensional techniques offer more accurate estimates of gastric emptying because of superior delineation of gastric shape and volumes as a function of time.88 Half times of gastric emptying from such methodologies have been shown to closely correlate with values from gastric emptying scintigraphy in patients with gastroparesis.89 MRI measures gastric emptying of liquid and mixed solid/liquid meals and characterizes antral contractile propagation velocity and motility indices. Drawbacks of MRI include the need to perform testing while the patient is supine, lack of standardized methods of performance and protocols for calculating emptying rates and other motor parameters, and cost. Other technologies define factors other than delayed gastric emptying that are associated with symptoms in patients with presumed gastroparesis. Barium radiography documents impaired peristalsis, dilation and retained food residue.90 Antroduodenal manometry monitors luminal pressure during fasting and after meals and medications. This technique should be considered for patients with unexplained nausea, vomiting, abdominal pain or other symptoms suggestive of upper gut dysmotility, and in individuals who are unresponsive to appropriate medical therapy, or persons who are being considered for supplemental enteral or parenteral feeding or for intestinal resection or venting enterostomy to reduce symptoms. Manometry is useful to exclude small bowel 

dysmotility, including myopathic (contractile amplitude <30mmHg with normal morphology) and neuropathic (uncoordinated burst contractions) profiles, that may be identified in 17–85% of patients with delayed gastric emptying.29 Electrogastrography (EGG) characterizes myoelectric activity by the use of cutaneous electrodes that are placed over the stomach. EGGs in healthy individuals show uniform three cycles per min gastric slow wave patterns that increase in power (amplitude) after meals. EGG abnormalities include rhythm disruption for >30% of recording time such as tachygastria (>four cycles per min) and bradygastria (<2 cycles per min) and an impaired increase in amplitude with eating.91 Single photon emission computed tomography (SPECT) involves the intravenous administration of Tc­99m pertechnetate and provides three dimensional outlines of the proximal stomach to assess fundic accommodation. Satiety testing is performed by ingesting water or liquid nutrients until a sensation of maximal fullness is reported. Volumes ingested in patients with functional dyspepsia are decreased versus healthy controls; this finding may relate to blunting of the fundic accommodation reflex, heightened sensitivity to volume, delayed gastric emptying, or a combination of the three defects.92

Controversies of gastric motor testing

Poor correlation exists between symptoms and gastric emptying rates recorded by gastric motor testing, according to the findings of over two decades of small cohort studies.93 In a large study (425 patients with gastroparesis), no differences were noted in those with delayed versus normal gastric emptying with respect to symptoms, healthcare utilization, quality of life or depression.94 However, in patients with idiopathic gastroparesis, those with severely delayed gastric emptying (>35% gastric retention at 4h) had greater vomiting, anorexia and overall symptoms.8 Another investigation observed that early satiety, postprandial fullness and total GCSI scores predicted increased gastric retention at 2 h but not at 4 h.95 One study noted that fullness, bloating and pain recorded during gastric emptying scintigraphy are increased in those with delayed versus normal gastric emptying.96 However, there are no reports suggesting that any given symptom profile is specific for delayed versus normal gastric emptying. It should be recognized that most studies over the past 5 years include only patients with a predetermined lower cutoff for symptom severity, a factor that could limit the ability of gastric motor testing to detect a correlation between symptoms and gastric emptying rates.8,94 However, even some older studies that include asymptomatic patients with profound gastric emptying delays show no more than a modest correlation between symptoms and gastric emptying scintigraphy, which emphasizes the importance of other factors in symptom genesis.93 Symptoms of patients with rapid gastric emptying are similar to those who show delayed emptying on gastric scintigraphy. A study of diabetic patients with symptoms suggestive of upper gastrointestinal tract dysmotility reported that 36% exhibited delayed gastric emptying, 42% exhibited normal gastric emptying and 22% exhibited rapid gastric emptying.97 In a preliminary report, upper gastrointestinal symptoms were similar in patients with normal versus delayed emptying as measured by WMC.98 The results of gastric emptying scintigraphy reportedly do not influence clinical management, perhaps as a consequence of the poor correlation between symptoms and gastric emptying rates.99 Evidence, however, suggests that rate of gastric emptying does influence outcomes in diabetic patients with symptoms of gastroparesis. In diabetic patients, those with upper gastrointestinal symptoms and delayed gastric emptying had more hospitalizations and outpatient clinic and emergency department visits than similarly symptomatic individuals with normal gastric emptying.3 Solid food gastric emptying scintigraphy is considered to offer the most reliable diagnosis of gastroparesis. Studies over the past 2 years challenge this assumption. In a retrospective analysis from one study, 13 of 17 patients with symptoms of gastroparesis had normal solid gastric emptying but showed delayed liquid gastric emptying.100 In a prospective followup from the same study, 10 of 30 individuals with symptoms of gastroparesis and normal solid gastric emptying showed delayed liquid gastric emptying. In another study of 101 individuals with suspected gastroparesis, delays in solid gastric emptying were found in 16% of individuals, whereas delayed liquid gastric emptying was detected in 32%.101 Furthermore, 32% of individuals with normal solid emptying showed delayed liquid gastric emptying. As with methods of solid food gastric emptying scintigraphy, standardization of techniques to measure liquid gastric emptying is needed as nutritive and nonnutritive liquids empty at dramatically different rates both in healthy individuals and in patients with gastroparesis.102 A final issue relates to reproducibility of gastric motor testing. Intraindividual and interindividual coefficients of variation (COV) for gastric half emptying time with gastric emptying scintigraphy are 14% and 30%, respectively, in healthy individuals.75 Interindividual COV for WMC measures of gastric emptying are 28% for healthy controls and 34% for patients with gastroparesis. Intraindividual and interindiviudal COV for breath test measures of emptying at 120 min are 12% and 14%, respectively, in healthy individuals.86,87 It is uncertain how much of this variability stems from an inherent lack of biologic constancy in gastric emptying rate versus test result inconsistency.

Treatment of gastroparesis

Gastroparesis therapies include diet changes, medications to stimulate gastric emptying or reduce emesis, endoscopic or operative approaches, and psychological interventions. There is little in the literature to favor one approach over another for most patients. Furthermore, it has not been definitively established whether a number of therapies are superior to placebo. Most studies have examined the utility of treatments to reduce gastrointestinal symptoms of gastroparesis. Conversely, the utility of such modalities to improve nongastrointestinal manifestations of gastroparesis, including glycemic changes in diabetic patients, has not been established. Finally, many treatment trials have recruited patients predominantly from tertiary sites—results from such investigations may not be applicable to community cases of gastroparesis. Medication for gastroparesis can be administered in several different forms. In general, pills or capsules may be absorbed slowly due to slow gastric emptying or may be expelled during emesis. In patients with uncontrolled vomiting, better results may therefore be achieved with sublingual, liquid oral, rectal suppository, transdermal or parenteral formulations of medication. A classification of disease severity has been devised for gastroparesis to facilitate treatment selection.19 Patients with grade 1 gastroparesis present with intermittent, wellcontrolled symptoms but nutritional status is normal. These patients are managed by diet measures and the avoidance of drugs that predispose to gastric retention. Grade 2 gastroparesis is characterized by moderate symptoms that are treated with gastricmotor stimulating and antiemetic drugs. Patients with grade 3 gastroparesis are refractory to medical therapy, unable to sustain a healthy nutritional status and present frequently to emergency departments or inpatient services. Such patients receive intravenous fluids and medication, supplemental nutrition, and endoscopic or operative treatment for their disease. Grade 3 gastroparesis has been associated with increased depression and anxiety, highlighting the association of severe symptoms with psychological dysfunction.103 Triggers for hospitalization associated with gastroparesis include poor glycemic control, medication noncomplicance or intolerance, and adrenal insufficiency.104 Predictors of poor response to therapy included a high overall GCSI score, a high bloating subscale score of the GCSI, and increased abdominal distention.105 Disease etiology and gastric emptying rate are reported not to influence treatment response. The following sections describe the available options to treat gastroparesis. There has been limited investigation comparing outcomes from different therapies upon which rational treatment algorithms could be designed. Thus, decisions by clinicians to use these therapies rely on other factors, including their own experiences prescribing these agents, as well as the opinions of experts in the field.

Dietary and nonmedicinal measures

Ingesting small meals frequently, consuming a predominantly liquid diet, and avoiding indigestible solids and fatty meals can compensate for gastric impairments. In patients with type 1 diabetes, ingesting solids with small particle sizes accelerates gastric emptying and reduces changes in glucose levels.106 Dietary fiber contributes to bloating and bezoars and should be minimized in patients with gastroparesis from any etiology. Drugs that inhibit motility, including calcium channel antagonists, anticholinergics, opiates and exenatide, should be stopped if possible. In patients with diabetes, maintaining euglycemia is recommended to avoid effects of hyperglycemia. However, one study has reported that patients with type 1 diabetes with hemoglobin A1c values averaging 8% had less nausea and early satiety than patients with type 2 diabetes and hemoglobin A1c levels of 6.6%.25 This finding raises the possibility that glycemia has a limited impact on gastroparesis symptoms.

Prokinetic medications

Prokinetic drugs are the mainstay of therapy for patients with moderate or severe gastroparesis (Table 1). However, there are few direct comparisons of prokinetics in gastroparesis. A 1999 metaanalysis noted that erythromycin is most potent at stimulating gastric emptying, and erythromycin and domperidone are individually superior to metoclopramide for symptom control.107 No further comparisons of available prokinetic drugs have been published. Metoclopramide is a serotonin 5­HT4 receptor agonist, dopamine D2 antagonist, and direct gastrointestinal smooth muscle contractile agent that also reduces vomiting via brainstem D2 receptor antagonism and vagal and brainstem 5­HT3 receptor antagonism. The drug can be administered in pill, liquid, intravenous and subcutaneous preparations. Most studies report symptom reductions and stimulation of gastric emptying with this drug.108 Tolerance to its prokinetic action may develop, but effects to reduce vomiting persist, emphasizing the importance of the antiemetic effects of this drug. Adverse effects limit the use of metoclopramide in about onethird of patients. Fatigue, agitation, sleep disruption and symptoms relating to elevated circulating prolactin levels (such as galactorrhea and amenorrhea) are preval‎ent adverse effects. Dystonias are frequently reported, especially in patients <30 years old. Tardive dyskinesia, a difficultto treat form of dyskinesia that results in involuntary, repetitive body movements, is a catastrophic consequence of metoclopramide that occurs in 1–10% of patients who have been taking the drug for >3 months.109 Owing to the disabling nature of this complication, patients should be informed about its consequences and medical records should include documentation of this discussion. Erythromycin elicits occlusive antral contractions by activating receptors for motilin, the mediator of fasting antroduodenal contractility. The intense motility that is induced by this drug impairs gastric sieving, promoting the delivery of poorly triturated food residue into the duodenum.110 Oral pill, liquid and intravenous forms of this agent can be prescribed. Symptom reductions have been reported in controlled and openlabel studies.108 Tolerance to the prokinetic action of erythromycin occurs frequently due to motilin receptor downregulation. Adverse effects of the drug include abdominal pain, nausea, and vomiting. These effects are prominent at high drug doses that elicit spastic gastrointestinal contractions. Erythromycin also increases the risk of sudden death from cardiac arrhythmias.111 In a large database, sudden death rates in patients on erythromycin were elevated twofold over the general population and were further increased by the concomitant use of CYP3A inhibitors, including certain antipsychotics, antidepressants, cardiac antiarrhythmics, antifungals, calcium antagonists and antiemetics. Domperidone is a dopamine D2 receptor antagonist that does not cross the blood–brain barrier and acts only on peripheral sites; therefore, central neural adverse effects are negligible. The potent antivomiting effects of domperidone relate to its actions on brainstem structures outside the blood–brain barrier. Oral domperidone is approved in most countries except the USA. The drug is as efficacious as metoclopramide in reducing nausea and vomiting. In a systematic review of 11 articles and 17 abstracts, 64% of studies reported symptom reductions, 67% reported decreased hospitalizations, and 60% noted accelerated gastric emptying.112 The authors of this meta analysis concluded that there is level 3 evidence for domperidone efficacy in gastroparesis, that is, the evidence is insufficient owing to limited patient numbers or flaws in study design. This represents the authors’ assessment of study quality on the basis of their review of the medical literature. Given that it acts peripherally, domperidone is useful for the treatment of dysmotility in patients with Parkinson’s disease.113 Adverse reactions are seen less often with domperidone than with metoclopramide; however, symptoms related to hyperprolactinemia may still occur as a consequence of the porous blood–brain barrier in the pituitary gland. Domperidone prolongs electrocardiographic heartratecorrected QT intervals; an intravenous preparation was taken off the market because of fatal arrhythmias. One study noted increased sudden cardiac deaths in patients on oral domperidone.114 Domperidone was never approved by the FDA, but it can be obtained from foreign sources including pharmacies and internet websites, as well as compounding pharmacies in the USA. The FDA discourages such practices but makes domperidone available to clinicians who follow a multistep process that includes submission of both an Investigational New Drug application to the FDA and an Institutional Review Board proposal to the host institution. Other available gastricmotorstimulating drugs have been proposed as gastroparesis treatments. The 5­HT4 agonists tegaserod and cisapride were used prior to withdrawal due to cardiovascular complications. Bethanechol is a smooth muscle muscarinic receptor agonist that evokes nonpropulsive gastric contractions but does not accelerate gastric emptying.115 Adverse effects include abdominal cramping, emesis, wheezing, urinary urgency, low blood pressure and atrial fibrillation. The acetylcholinesterase inhibitor pyridostigmine has been shown to reduce symptoms in one individual with gastroparesis secondary to autoimmune disease.116 Clarithromycin and azithromycin are macrolides with similar effects to erythromycin. Intravenous azithromycin elicits higher amplitude and more prolonged antral responses compared with erythromycin.117 Oral azithromycin has been shown to reduce vomiting and improve glycemic control in patients with type 2 diabetes and gastroparesis.118 A 2010 study comparing azithromycin with erythromycin showed that azithromycin was equipotent at accelerating gastric emptying, had a longer duration of action, elicited fewer adverse effects, and did not interact with P450 systems; this interaction was considered to underlie the cardiac dysrhythmic actions of erythromycin.119 Novel investigational agents show promise in gastroparesis. 5­HT4 agonists with prokinetic effects include prucalopride and TD­5108.120 Mitemcinal, a motilin receptor agonist without antibacterial action, is shown to accelerate gastric emptying in animal models and in patients with gastroparesis.121 The drug showed benefits in a doubleblind trial that included patients with diabetes and gastroparesis symptoms that were only seen in individuals with a BMI <35 kg/m2 and a hemoglobin A1c level of <10%.122 New stimulants of acetylcholine release, such as acotiamide, are in testing.123 Investigations show that ghrelin, an endogenous mediator of food intake, has potent effects to stimulate gastric emptying. In diabetic patients with severe gastroparesis, the intravenous ghrelin agonist TZP­101 (ulimorelin) has been shown to reduce nausea, vomiting and overall symptoms compared with placebo (Figure 3).124 Oral ghrelin agonists are being eval‎uated. 

Antiemetic medications

Medications without motor stimulatory activity that act primarily as central antiemetic agents are often used for the treatment of gastroparesis, either alone or in conjunction with prokinetics. The dopamine antagonist thiethylperazine has been shown to reduce symptoms of gastroparesis in one patient with diabetes.125 In another patient with diabetes, who was followed for 4 months, the neurokinin NK1 antagonist aprepitant was shown to reduce symptoms of gastroparesis.126 In a retrospective analysis, 88% of patients with diabetes noted reduced nausea and vomiting during therapy with tricyclic antidepressant agents.127 Nearly onethird of these patients exhibited delayed gastric emptying, suggesting the potential utility of these agents in gastroparesis. Improved symptoms have also been reported with another antidepressant drug, mirtazapine, in patients with type I diabetes and gastroparesis.128 Antiemetics in other drug classes—including histamine H1 antagonists (for example, promethazine), serotonin 5­HT3 antagonists (for example, ondansetron) and cannabinoids (for example, dronabinol)—are commonly given to patients with gastroparesis; however, there is no evidence to support their use. The herbal extract STW5 (iberogast) has been shown to reduce symptoms in patient with functional dyspepsia and has been used in patients with gastroparesis owing to its effects to stimulate antral motility.129,130 Symptom benefits do not relate to accelerated gastric emptying, however, as gastrointestinal transit is slowed by this agent.131 Acupuncture is also reported to have a role in patients with diabetic gastroparesis. This therapy is reported to produce 75% reductions in GCSI scores and possible acceleration of gastric emptying in these individuals.132

Endoscopic treatment

Therapeutic endoscopy may be beneficial in some patients with gastroparesis. Uncontrolled series of endoscopic pyloric botulinum toxin injection report reduced symptoms and accelerated emptying in patients with idiopathic, diabetic and postsurgical gastroparesis.133–142 Another study reported that botulinum toxin decreased gastroesophageal reflux symptoms due to gastroparesis.143 A 5­month duration of efficacy has been noted with the use of this therapy. A large series (179 patients) has reported that response rates to a high dose of botulinum toxin (200 IU) were higher than with lower doses.144 Benefits were greater in women and in those with idiopathic disease, and a sustained response on repeated injections was noted in 76% of patients. By contrast, two blinded, controlled trials of 23 and 32 patients, respectively, did not note superior responses for botulinum toxin versus placebo for the treatment of gastroparesis; however, these studies were small and possibly underpowered.145,146 One study employed a crossover design and used a low dose of botulinum toxin, which is a concerning strategy given that motor effects of the agent persist for approximately 6 months.145 Endoscopic pneumatic pyloric dilation has anecdotal benefits in patients with postsurgical gastroparesis.147 Endoscopic venting gastrostomies are also reported to decrease hospitalizations associated with gastroparesis by reducing distentionevoked symptoms.148,149 For gastroesophageal reflux attributable to gastroparesis, one group has noted accelerated gastric emptying after administering radiofrequency therapy via the Stretta® (Mederi Therapeutics Inc., Delaware, CT) procedure to the lower esophageal sphincter.150 The purported benefits of this treatment may relate to its effects on adjacent proximal gastric function.

Figure 3 | Changes in nausea and/or vomiting Gastroparesis Cardinal Symptom Index (GCSI) subscale scores in patients with diabetes and severe gastroparesis following the intravenous administration of the ghrelin agonist TZP-101 (also known as ulimorelin). a | GCSI nausea/vomiting scores over 4 days of TZP-101 treatment (all doses [range 20–600μg/kg] and 80μg/kg dose shown) compared with placebo. b | GCSI vomiting scores over 4 days of TZP-101 treatment (all doses [range 20-600μg/kg] and 80μg/kg dose shown) compared with placebo. Nausea/vomiting GCSI subscale scores for days 2–4 were significantly different for the TZP-101 80 μg/ kg group versus placebo (P<0.001) and the TZP-101 all doses group versus placebo (P=0.004). Likewise, vomiting scores for days 2–4 are significantly lower for the TZP-101 80μg/kg group versus placebo (P=0.008) and TZP-101 all doses group versus placebo (P=0.005). Permission obtained from Wiley © Wo, J. M. et al. Aliment. Pharmacol. Ther. 33, 679–688 (2011).

Gastric electrical stimulation

Uncontrolled studies suggest that exogenously delivered electrical stimuli can reduce gastroparesis symptoms. On the basis of apparent benefits noted with an implanted electrical device that delivered low energy impulses, the gastric stimulator received approval from the FDA as a humanitarian use device and was granted a humanitarian device exemption (HDE) for the treatment of diabetic and idiopathic gastroparesis.151 For HDEs, the FDA restricts use to centers that grant Institutional Review Board approval. Series including between 2 and 55 patients have noted 80% reductions in nausea and vomiting for >1 year in diabetic, idiopathic and postsurgical gastroparesis.152–157 A larger report extended the benefits of this type of therapy to >10 years.158 Other conditions showing responses to gastric electrical stimulation include gastroparesis in patients with underlying immunosuppression, patients with intestinal pseudoobstruction, and patients with nausea and vomiting and normal gastric emptying.159 Electrical stimuli improve nutritional parameters, decrease medication use, improve glycemic control, enhance quality of life and reduce healthcare utilization.160 Predictors of nonresponse to this type of therapy include a nondiabetic etiology of disease, less severe vomiting, symptomatic predominance of pain, and opiate use.161 Many publications originate from a few centers and may include overlapping patient cohorts. Other centers have discontinued gastric electrical stimulation because of reported lesser benefits. Temporary gastric electrical stimulation by use of endoscopically placed electrodes has been advocated to predict responses to an implanted device.162 Adverse events associated with the gastric electrical stimulator include infections of the subcutaneous pocket in which the device is placed, lead breakage or dislodgement from the stomach, and bowel obstruction. These complications mandate explantation of the device in >10% of cases. Some reports state that up to 25% of patients have undergone subsequent gastrectomy after the insertion of a gastric electrical stimulator because of poor response.152 Two small trials have assessed gastric electrical stimulation in shamcontrolled fashion. In the first study, 33 individuals with idiopathic or diabetic gastroparesis underwent a 2­month, doubleblind, crossover, sham stimulationcontrolled phase (1 month of active stimulation and one month of sham stimulation in random order) followed by an openlabel active stimulation phase from the end of the crossover phase to the end of study at 12 months after surgery.163 During the blinded phase, weekly vomiting frequencies were lower with the device on (6.8, range 3.9–16.5) versus off (13.5, range 5.5–25.4) but total symptoms were unchanged. Nausea and vomiting decreased in patients with diabetic gastroparesis but not idiopathic gastroparesis; other symptoms did not decrease. It was commented that no differences in vomiting between active and inactive periods were reported in the initial submission of these data to the FDA, raising concern about post hoc changes in primary study end points before manuscript publication.164 In the second trial, 55 diabetic patients with gastroparesis underwent implantation of a gastric electrical stimulation device followed by activation in all patients for 6 weeks.165 Patients were then randomly allocated in blinded fashion to a 6 month crossover phase in which the device was on or off for 3 months each. After the crossover phase, stimulators were turned on in all patients. Weekly vomiting episodes decreased from 20 preoperatively to 4.8 before the crossover. During the crossover phase, vomiting frequencies were similar when devices were on (3.8) or off (4.3) (Figure 4). The authors hypothesized that initial symptom decreases in the first 6 weeks extended into the crossover, obscuring the benefits of active versus sham stimulation. However, an alternate explanation is that these data show a placebo effect. A third preliminary trial of similar design in patients with idiopathic gastroparesis noted comparable lack of benefit of active over sham stimulation.166 As with the controlled botulinum toxin trials, sample sizes in these studies may have been too small to detect modest treatment benefits. Research has focused on mechanisms of gastric stimulation. In animals and humans, gastric electrical stimulation acts on vagal pathways to increase proximal gastric accommodation and blunt visceral hypersensitivity but has no consistent effect on gastric emptying.167 Increases in discomfort threshold with gastric distention, decreases in sympathovagal balance measured by heart rate variability, and increased thalamic and caudate activity on positron emission tomography were noted in patients receiving gastric electrical stimulation.168 These findings emphasize the role of afferent and central neural pathways in the potential treatment benefits of this therapy. Novel gastric electrical stimulation methods are in development. True electrical gastric pacing with the induction of propagating contractions and acceleration of gastric emptying involves pulse widths 1,000fold longer than for neurostimulation. In a 1­month trial of electrical gastric pacing at 3.3 cycles per min in nine patients with refractory gastroparesis, intrinsic gastric slow wave activity was entrained, slow wave tachyarrhmias were abolished, gastric retention was decreased, and nausea and vomiting improved such that eight individuals no longer required supplemental enteric nutrition.169 The method was impractical because the sources of electrical current were too bulky for implantation. Multichannel sequential protocols have been devised that deliver electrical pulses to several electrode pairs implanted in the stomach wall with initial stimulation of the proximal gastric corpus and subsequent progressive stimulation in antegrade fashion to more distal sites in the antrum.170 Such methods have been shown to consume 1% of the energy of single channel methods in animal models, raising hope for future portable energy sources for this type of therapy.171 A preliminary study of dual channel sequential electrical gastric pacing in diabetic gastroparesis noted accelerated gastric emptying and symptom reductions.172 Another direction of research involves dual pulse stimuli with alternating delivery of short neurostimulation and long pacing pulses to elicit antiemetic and motor stimulatory effects with a single device.173 Percutaneous and endoscopic systems to implant electrodes in the gastric wall without surgery may broaden the applicability of electrical pacing technologies.174

Other surgical treatment

Other surgeries are rarely performed in patients with refractory gastroparesis. In anecdotal observations, pyloroplasty is reported to reduce symptoms in diabetic patients with gastroparesis. However, one preliminary report noted symptom benefits in only onethird of patients, indicating that this strategy has minimal utility.175 Completion gastrectomy provides enduring symptom relief in subsets of patients with postsurgical gastroparesis. Of 44 patients, 78% reported improved health with reduced pain, nausea and vomiting a mean of 5.6 years after completion gastrectomy, whereas 6% stated that their health had deteriorated.176 Complications (for example bowel obstruction, anastomotic leaks and strictures) occurred in 36% of these patients and the preval‎ence of osteoporosis increased from 17% to 67% postoperatively. Subtotal gastrectomy was performed in seven diabetic patients with gastroparesis in another study.177 Nongastrointestinal adverse events complicated the clinical course in three patients, two of whom died. The benefits of the surgery of this population were uncertain because of these poor outcomes. Pancreatic transplantation may slow progression of diabetic neuropathy and retinopathy, but its effects on gastroparesis are unproved. Finally, as with radiofrequency methods, laparoscopic fundoplication plus pyloroplasty is reported to improve gastric emptying (possibly by impairing fundic accommodation and decreasing intragastric volumes) and symptoms in some patients with gastroparesis and gastroesophageal reflux.178 Some clinicians consider gastroparesis to be a relative contraindication to fundoplication owing to risks of gas bloating and other complications. The decision to pursue this course should be individualized for each patient. Supplemental nutrition Some patients with gastroparesis who are unresponsive to medical therapy do well with initiation of intermittent or permanent enteral or parenternal nutrition. In diabetic gastroparesis, enteral nutrition delivered through a jejunostomy tube improves overall health.179 This measure also shows trends in reducing gastrointestinal symptomology and hospitalizations and enhancing nutrition. Patients who should be considered for enteral nutrition include those with severe malnutrition (>10% weight loss over 6 months) that has not responded to diet revision, patients with mineral or electrolyte disturbances, and individuals who are frequently hospitalizated for nutritional replenishment.19 Initiation of permanent total parenteral nutrition is usually needed only in patients with associated impairment of small intestinal motor function who cannot tolerate enteral feedings, although some patients with gastroparesis benefit from shortterm total parenteral nutrition to reverse rapid weight loss.

Psychological measures

Patients with gastroparesis may experience significant psychological sequelae. In a report from 1989, psychological impairment was shown to correlate with symptom severity in diabetics with gastroparesis.180 In a 2010 investigation of patients with diabetic or idiopathic gastroparesis, depression and anxiety severity was related to investigatorrated and patientrated gastroparesis severity.103 Medication use and hospitalizations, but not gastric emptying rates, paralleled increased depression and anxiety intensity. In another study, depression was associated with increases in EGG dysrhythmias.181 Despite these observations, the role of mental health specialists in managing gastroparesis is undefined.

Outcomes

Data on the natural history of gastroparesis are limited. In a preliminary report from a large registry, nausea, vomiting, fullness, early satiety and weight loss were shown to improve under the care of motility specialists after 48 weeks; however, symptoms of bloating and pain were unchanged.182 Healthcare utilization decreased over this time but the number of hospitalizations did not significantly change. In another study, many patients with postinfectious idiopathic gastroparesis demonstrated good prognoses with resolution of symptoms over several years.183 A preliminary report has noted a similar reduction in symptoms 48 weeks after presentation in patients reporting an infectious prodrome to their symptoms versus those who did not.184 Studies with longer followup are needed to define the clinical course of gastroparesis.

Conclusions

Over the past 5 years, considerable advances have been made in understanding gastroparesis and its diagnosis and eval‎uation. The clinical features of diabetic and idiopathic gastroparesis have been carefully characterized by analyses of questionnaires from large clinical databases. Rigorous histopathologic examinations of excised full thickness gastric tissues have shown that gastroparesis— particularly in its most severe forms—is quite heterogeneous, with variable dropout of enteric neurons and interstitial cells of Cajal, smooth muscle fibrosis, disruption of neurotransmitter synthesis, and increased inflammatory cell infiltration in the myenteric plexus. Standardized surveys quantifying severity of different symptoms of gastroparesis and quality of life are now widely employed in research. In the future, it is conceivable that such surveys may serve similar roles as the Rome criteria do for functional bowel disorders by stratifying patients by dominant symptoms (for example nausea and vomiting, bloating and distention, postprandial fullness and early satiety, and pain and discomfort) for enrollment in clinical trials. A validated method of gastric emptying scintigraphy has been endorsed by prominent gastrointestinal motility and nuclear medicine societies—a move that hopefully will lead to more widespread adoption of an accepted standard for diagnosing the condition. Other methods of eval‎uating gastric motor activity, including wireless capsules and breath tests, have been introduced and represent important alternatives to scintigraphy, especially in patients with symptoms that suggest a more generalized process involving the entire gastrointestinal tract and in individuals who should not receive radiation exposure. These new findings provide the foundation for further investigation in gastroparesis. As databases expand, clinical features of gastroparesis occurring as a consequence of other etiologies (for example postsurgical gastroparesis) will be further defined. Current knowledge of the natural history of gastroparesis is quite sparse and has been limited to less than 1 year of followup in large multicenter registries. Longterm characterization (over a several year period) of clinical features, medication requirements, serial gastric emptying measurements and healthcare utilization will be achieved by maintaining these ongoing databases. In particular, prolonged followup will provide insight into important pathogenic roles for infection, gastrointestinal inflammation and psychosocial factors. One area that has lagged over the past 5 years has been the development of new treatment options for gastroparesis. However, novel prokinetics in several drug classes (including ghrelin agonists, 5­HT4 agonists and cholinesterase inhibitors) show promise for this condition. Research is ongoing to assess if tricyclic antidepressants and antiemetic therapies (for example NK1 antagonists) will be effective to reduce symptoms of gastroparesis. The benefits of novel gastric electrical stimulation methods, including those that pace the stomach, will be explored. Finally, it is conceivable that single agent therapies may offer only limited symptom relief and that combining treatment modalities with different mechanisms of action (for example, a prokinetic plus an antidepressant) may provide optimal symptom control.