Introduction – the challenge
Gastroparesis is commonly defined on the basis of the combination of symptoms and delayed gastric emptying, in the absence of mechanical obstruction. Therein lies a major challenge to attempts to provide accurate data on the incidence or prevalence of this disorder which must include (i) a definition of what symptoms are to be regarded as relevant, (ii) an accurate measurement of gastric emptying rate and (iii) appropriate testing to exclude gastric outlet or small bowel obstruction.
Symptoms indicative of gastroparesis
Traditionally, nausea and vomiting have been regarded as the “classical” symptoms of gastroparesis; more recent literature reveals a more inclusive approach with the NIH consensus group incorporating nine symptoms: nausea, retching, vomiting, stomach fullness, inability to finish a meal, excessive fullness, loss of appetite, bloating and abdominal distension in their Gastroparesis Cardinal Symptom Index (GCSI) . It can be readily appreciated that these symptoms overlap with functional gastrointestinal disorders such as functional dyspepsia and irritable bowel syndrome . The more recent adoption of abdominal pain as a symptom of gastroparesis further complicates the use of symptoms as a clinical indicator of gastroparesis. Up to 89% of individuals with gastroparesis are reported to complain of upper abdominal pain and in the NIH cohort this pain was moderate to severe in 66% and did not correlate with gastric emptying rate . Not surprisingly many consume opiates which further confuses attempts to interpret gastric emptying studies; forty-one per cent of 583 patients in one report from the Gastroparesis Clinical Research Consortium (GpCRC) Registry were taking opioids . Additional symptoms may be relevant in specific clinical contexts – hypoglycemia in diabetes due to delayed emptying of nutrients and on-off phenomena in Parkinson’s disease due to unpredictable delivery of dopaminergic medications. Taking all of these factors together renders a diagnosis of gastroparesis on the basis of symptoms alone nigh impossible. Indeed, symptoms have proven very poor predictors of gastric emptying rate and symptom patterns and severity were very similar when subjects with nausea and vomiting with and without gastric emptying delay were compared .
Tests of gastric emptying
There is no shortage of test modalities which have been proposed as valuable in the assessment of gastric emptying rate: plain radiographs, breath tests, radionuclide scintigraphy, ultrasonography, magnetic resonance imaging, pharmacological approaches and SPECT imaging . Because of cost and availability some are clearly unsuitable for large scale epidemiological studies and only one, radionuclide scintigraphy, has been validated in a large multicenter study . Its utility in the general population is also limited by the involvement of radiation exposure. Though this technique is by far the most widely used worldwide in clinical practice its comparability between centers is limited by differences in study meal, protocol and interpretation.
The final hurdle that confronts any attempt at an epidemiological study of gastroparesis is the accurate definition of the phenotype. How thoroughly has gastric outlet obstruction or low grade small bowel obstruction been excluded? How accurately are underlying causes defined? Have iatrogenic causes, such as opiates, anticholinergics and calcium channel blockers, been diligently documented?
Incidence and prevalence
True population-based studies on the incidence and prevalence of gastroparesis are rare. Up until very recently the figures for incidence and prevalence of 6.3 per 100,000 persons per year and 24.2 per 100,000 inhabitants (0.0242%), respectively, obtained by the Rochester Epidemiology Study in Olmsted County, Minnesota were the best estimates available to us . Now, Syed and colleagues in a cross-sectional population-based study based on a total of 43,827,910 medical records surveyed between 1999 and 2014 documented an overall prevalence of 0.16% ; a much higher figure, yes, but still well short of prior estimates of 3–5% of the population . In this study, rates for those with type 1 and type 2 diabetes mellitus were higher at 4.59% and 1.31%, respectively . Across all categories, women and Caucasians had the highest prevalence of gastroparesis . It must also be noted that the diagnosis of gastroparesis was confirmed by gastric emptying study and esophago-gastro-duodenoscopy in only 14% . At our institution, an 800-bed tertiary referral hospital, 1292 patients were admitted with gastroparesis as the admission diagnosis over a 5-year period. A random sample of 285 from this total were studied in detail; while 63% had undergone a gastric emptying study, only 20% had completed the recommended 4-hour protocol and 58% were on a narcotic at the time of the study . These “real world” observations illustrate the difficulties of defining gastroparesis in any context.
The rates described by Syed and colleagues are also consistent with an earlier population-based, historical cohort study, again from the Rochester Epidemiology Project, where cumulative proportions developing gastroparesis over a 10-year period were 5.2% in type 1 diabetes, 1.0% in type 2 diabetes, and 0.2% in controls . It must be remembered that one was a cross sectional and the other a cohort study .
In another questionnaire-based study of 15,000 adults in the community, diabetes was associated with an increased prevalence of several upper and lower gastrointestinal symptoms – 5.2% of diabetics (mostly type 2) and 3.5% of non-diabetics suffered from nausea; equivalent rates for vomiting were 1.7% and 1.1% . Though gastric emptying rate was not studied, these symptom rates are again similar to the gastroparesis rates described above. It should be noted that other community-based surveys failed to document an increased prevalence of upper gastrointestinal symptoms in diabetics or between type 1 and type 2 disease .
What can we conclude from population-bases studies? Though available data are limited and subject to all of the aforementioned problems with definition, it is evident that gastroparesis, whether in diabetics or in non-diabetics, is not as common as clinical series based on hospitalization or clinic visits would suggest . Though incidence is higher in type 1 than type 2 diabetes, the latter is much more common and increasing rapidly around the world; instances of gastroparesis related to type 2 diabetes are likely to greatly outnumber those related to type 1 diabetes for the foreseeable future.
It is also evident that the incidence of gastroparesis is on the increase ; while some of this may reflect changes in diagnostic practice (and even include some misdiagnoses), trends are consistent and suggest that gastroparesis is on the rise. Global increases in obesity and diabetes are certainly contributory.
What can we learn from clinic/hospital-based studies?
Some of the most detailed data come from the many studies produced by the National Institute of Diabetes and Digestive and Kidney Diseases Gastroparesis Clinical Research Consortium and derived from several academic medical centers across the US. What have these studies revealed?
Idiopathic gastroparesis is more common than all other causes (at least in the US).
In a Consortium study of 416 patients with gastroparesis, 254 had idiopathic gastroparesis, and 137 had diabetic gastroparesis (78 had type 1, and 59 had type 2 diabetes) . Symptoms that prompted evaluation more often featured vomiting for those with diabetic gastroparesis and abdominal pain for those with idiopathic gastroparesis. More than 50% of patients with type 1 DM had severe retention (>35% at 4 hours); these individuals also used prokinetic agents more frequently, had more hospitalizations and were more likely to be implanted with a gastric electric stimulator . Data on the prevalence of idiopathic gastroparesis from the rest of the world is scant – in a comparison of experiences with gastric electrical stimulation between the US and Europe it was noticeable how few subjects with idiopathic gastroparesis were implanted in Europe in comparison to the US ; whether this reflects a real difference in prevalence or variations in diagnostic criteria or management strategies is unclear. It is undoubted that the category “idiopathic” gastroparesis includes a heterogeneous population which may range from extreme forms of a functional disorder to enteric neuropathology . Most problematic are those with functional dyspepsia who undergo a gastric emptying study and are found to exhibit a mild-to-moderate delay; is this gastroparesis?
Gastroparesis, regardless of etiology is more common in females.
Data from 718 adult patients with gastroparesis from another NIDDK Gastroparesis Consortium Study revealed a remarkable female predominance; 84% vs 16% . Women were also more likely to be labeled as idiopathic (69%) than men (46%). This has been a consistent finding in many other studies , regardless of location or etiology of gastroparesis. In the Olmsted county study, for example, what they defined as definite gastroparesis was 4-fold more common in females than in males .
Diabetic gastroparesis is more common in blacks and Hispanics.
In the aforementioned study, a higher proportion of non-Hispanic blacks (60%) and Hispanics (59%) had gastroparesis of diabetic etiology than non-Hispanic whites (28%). Blacks also had more severe retching and vomiting and were more likely to have been hospitalized in the past year (66%) .
Hospitalizations and health care unitization
While the community prevalence and incidence of gastroparesis may not be as high as our experience as hospital-based gastroenterologists with a special interest in motility disorders would suggest, it is evident that hospitalization rates for this disorder are on the increase and that patients with an admission diagnosis of gastroparesis consume a disproportionate amount of health care expenditure. Even as long ago as 2006, a 138% increase in hospitalization rates for gastroparesis had been noted in the Olmsted county study which incorporated admissions where gastroparesis was either a primary or secondary admission diagnosis . More recently, Nusrat and Bielefeldt, using data from the National Inpatient Sample, documented a more than 18-fold increase in hospitalization rate for gastroparesis between 1994 and 2009 but cautioned that much of this increase may relate to changes in awareness and a shift in diagnostic category and away from functional diagnoses, in particular, rather than to an actual gastroparesis epidemic . Similar trends were noted in another study that tracked admission rates between 1997 and 2013 .
Not surprisingly, opioid use is a strong predictor of health care resource utilization . Again, reflective perhaps of the severity of their gastroparesis and the prevalence of comorbidities, hospitalization rates are higher for those with type 1 than type 2 diabetes and for those diabetics with upper gastrointestinal symptoms who also have delayed (rather than normal) gastric emptying . Readmission rates are also high; data from the National Readmissions Database revealed that the 30 and 90-day readmission rates for individuals with a primary diagnosis of gastroparesis were 26.8% and 45.6%, respectively .
Based on all of the above it should come as no surprise that gastroparesis is associated with marked impairments in quality of life, ability to work and income .
A further contributor to the increasing health care costs related to gastroparesis are emergency department visits; between 2006 and 2013 emergency department visits for gastroparesis and their related costs more than doubled in the US .
Long-term outcomes – morbidity and mortality
Recent data from the NIDDK consortium indicate that the outcome for those with gastroparesis is not good; over a median follow-up period of 2.1 y, only 28% of 262 patients treated for gastroparesis at centers of expertise experienced a reduction of their gastroparesis-related symptoms . Male sex, age over 50 years, initial infectious prodrome, antidepressant use, and a four-hour gastric retention in excess of 20% on a gastric emptying study were the factors predictive of symptom reduction whereas being overweight or obese, a history of smoking, use of pain modulators and the presence of moderate to severe abdominal pain, severe gastroesophageal reflex or moderate to severe depression predicted a failure to improve .
Reported mortality rates related to gastroparesis in the literature are highly variable, ranging from as low as 4% to as high as 40% . Several studies support an association between gastroparesis and increased long-term mortality . For example, in the Olmsted county study the estimated 5-year survival for those with gastroparesis was only 67% in comparison to an expected 81% survival. Predictors of mortality included older age at diagnosis and diabetes as the cause of gastroparesis . In their review, Camilleri and colleagues concluded that patients with type 1 or 2 diabetes with symptoms of gastroparesis (including bloating, early satiety, nausea, vomiting, retching and postprandial fullness) and in whom there was a documented delay in gastric emptying were more likely to suffer co-morbid cardiovascular disease, hypertension, and retinopathy . These complications are most likely due to poor diabetic control rather than to gastroparesis per se . This conclusion is supported by admission data collected from the Nationwide Inpatient Sample of the Agency for Healthcare Research and Quality and Nationwide Emergency Department Sample – inpatient deaths among patients with a primary or secondary diagnosis of gastroparesis were more often due to a co-morbid condition, rather than gastroparesis itself . Among diabetics, short and longer term outlook, in terms of symptoms, morbidity and mortality are worse for those with type 1 than type 2 disease .
Global or regional variations
Data on global or regional variations in regard to any aspect of gastroparesis are very scarce. In a study in the US, Blielefeldt noted very dramatic variations between states in relation to care for, and outcomes from, gastroparesis . For example, admission rates for gastroparesis were four-fold higher in Maryland compared to Utah with mortality rates varying to a similar extent from 0.5 ± 0.1/100,000 in Colorado to 2.3 ± 0.1/100,000 in Florida. Similarly dramatic rates were noted for interventions such as endoscopy, gastrostomy and nutritional support. A variety of demographic, health care delivery and insurance status factors influenced these variations .
Gastroparesis, a diagnosis that rests on the combination of certain (though non-specific symptoms), a demonstrated delay in gastric emptying and the absence of any obstructing lesion in the gastrointestinal tract will inevitably pose challenges for the epidemiologist. Not surprisingly, therefore, truly accurate population estimates of incidence and prevalence are lacking. Available data does permit some conclusions, however: gastroparesis, though not common, is increasing in prevalence and incidence, is especially common among females and contributes disproportionately to impaired quality of life, health care utilization and costs . The latter alone should prompt research into its true incidence and prevalence, facilitated, one hopes, by the advent of diagnostic approaches that could be applied accurately to large numbers of the general population.