World J Gastroenterol. Dec 7, 2011; 17(45): 4971–4978.
Published online Dec 7, 2011. doi: 10.3748/wjg.v17.i45.4971
Burden of celiac disease in the Mediterranean area
Luigi Greco, Laura Timpone, Abdelhak Abkari, Mona Abu-Zekry, Thomas Attard, Faouzi Bouguerrà, Paskal Cullufi, Aydan Kansu, Dusanka Micetic-Turk, Zrinjka Mišak, Eleftheria Roma, Raanan Shamir, and Selma Terzic
This article has been cited by other articles in PMC.
AIM: To estimate the burden of undiagnosed celiac disease (CD) in the Mediterranean area in terms of morbidity, mortality and health cost.
METHODS: For statistics regarding the population of each country in the Mediterranean area, we accessed authoritative international sources (World Bank, World Health Organization and United Nations). The prevalence of CD was obtained for most countries from published reports. An overall prevalence rate of 1% cases/total population was finally estimated to represent the frequency of the disease in the area, since none of the available confidence intervals of the reported rates significantly excluded this rate. The distribution of symptoms and complications was obtained from reliable reports in the same cohort. A standardized mortality rate of 1.8 was obtained from recent reports. Crude health cost was estimated for the years between symptoms and diagnosis for adults and children, and was standardized for purchasing power parity to account for the different economic profiles amongst Mediterranean countries.
RESULTS: In the next 10 years, the Mediterranean area will have about half a billion inhabitants, of which 120 million will be children. The projected number of CD diagnoses in 2020 is 5 million cases (1 million celiac children), with a relative increase of 11% compared to 2010. Based on the 2010 rate, there will be about 550 000 symptomatic adults and about 240 000 sick children: 85% of the symptomatic patients will suffer from gastrointestinal complaints, 40% are likely to have anemia, 30% will likely have osteopenia, 20% of children will have short stature, and 10% will have abnormal liver enzymes. The estimated standardized medical costs for symptomatic celiac patients during the delay between symptom onset and diagnosis (mean 6 years for adults, 2 years for children) will be about €4 billion (€387 million for children) over the next 10 years. A delay in diagnosis is expected to increase mortality: about 600 000 celiac patients will die in the next 10 years, with an excess of 44.4% vs age- and sex-matched controls.
CONCLUSION: In the near future, the burden of CD will increase tremendously. Few Mediterranean countries are able to face this expanding epidemic alone.
Keywords: Pediatric, Celiac disease, Short stature, Anemia, Osteopenia, Purchasing power parity, Standardized mortality rate, Mediterranean area
Recent epidemiological studies show that the prevalence of celiac disease (CD) is underestimated not only in Europe, but also among the populations of Mediterranean regions such as the Middle East and North Africa[1-3], where its prevalence is similar to that recently observed in Western countries. Indeed, in these two regions, a very high prevalence of CD has recently been reported both in the general population and in at-risk groups. These high frequencies are associated with the widespread consumption of wheat and barley[1,5] and the high frequency of the DR3-DQ2 CD-predisposing haplotypes in these populations[6,7]. But these factors alone do not satisfactorily account for the spread of the CD epidemic in recent years[8,9]. The prevalence of CD among the general population varies from 0.14% to 1.17%[10-20]: 1%-1.3% in Turkey[10-12], 0.6%-0.96% in Iran[13,14], 0.5% in Egypt, 0.6% in Tunisia and Israel[16-19], and < 0.5% in Jordan, Lebanon and Kuwait[5,20]. Among high-risk groups [including patients with a positive family history, insulin-dependent diabetes mellitus (IDDM), thyroiditis] the prevalence of CD ranges from 2.4% to 44%, assessed by serological markers and biopsy[21-24].
Egypt, and indeed all North African countries, were significant producers of wheat, and largely used barley for beer brewing; they were considered the “granary”of Romans for over 4 centuries. Bread, mostly made of wheat flour and called “the survival” in some local languages, has been a staple food for thousands of years. Similarly, the widespread use of couscous [from grossly milled durum wheat (Triticum durum)] dates back over 2000 years. But the use of wheat and other gluten-containing cereals is also increasing in the countries where it has been a staple for centuries[25,26].
The diffusion of pasta across all the Mediterranean countries is relatively recent and stems from the industrial development of grain processing. Unfortunately, a side effect of this positive dispersal may be the enormous increase in gluten intolerance, which is at a truly epidemic level. CD is now a widespread public health problem that also involves the populations of developing countries, as well as China and India[27,28]. However, this epidemic is not fully recognized since a sizeable number of cases are neither diagnosed nor cared for. In many Mediterranean countries, few cases are diagnosed because of the low level of awareness, knowledge and skill to deal with the problem, the lack of diagnostic resources and the attribution of CD symptoms to other, similar, illnesses[5,20]. The low awareness of CD often leads to a delay in diagnosis, which contributes to an excess of medical costs (CD includes growth failure, infant malnutrition, gastrointestinal diseases, anemia and more than 20 associated symptoms and conditions) and mortality.
All partners taking part in this study agreed that, to date, the best available estimation of CD-associated medical cost was that reported by Long et al, and supported by Hershcovici et al. The annual medical cost in the year preceding the diagnosis of CD, excluding diagnostic costs, was estimated to be $5023/patient, $1764 more than the cost of the same patients in the year after diagnosis. In the four years preceding the diagnosis of symptomatic CD, the direct medical cost was estimated to be $11 037/patient. For a symptom- and age-matched control individual, not affected by CD, the cost after 4 years was estimated at $7073, with a difference of $3964 (about $1000/patient per year). This difference is due to increased in-patients admissions, out-patient cost, laboratory tests, radiology, and office visits. The diagnosis of CD resulted in a 30% reduction in direct medical expenditure. A similar 30% reduction in direct medical costs after diagnosis of CD was reported by Green et al; the mean medical expenditure decreased from $8502 per capita to $7133 for the 2 years after diagnosis of CD.
The CD epidemic is the largest epidemic of food-induced permanent disease in the Euro-Mediterranean region. Very few countries of this region are able to face this expanding problem. The aim of this study was to estimate what the burden of CD will be in the near future, and how the CD epidemic will affect morbidity, mortality and health costs. We aim to provide stakeholders with a reliable prediction of the incoming picture of CD in the Mediterranean area, and so enable them to take action to face this epidemic.
MATERIALS AND METHODS
For statistics regarding each country in the Mediterranean area, we accessed authoritative international sources (World Bank, World Health Organization and United Nations). Population size, median age, number of children (0-14 years), population growth rate, birth rate, death rate, infant mortality rate and literacy were retrieved and validated across multiple sources. The projected population from 2010 to 2020 was computed by adopting the 2008 growth rate as a constant over the following decade because the predicted rate of change of the growth rate would have not significantly affected our estimate. The number of children was incremented yearly by the birth rate and corrected for the infant mortality rate although mortality from 1 to 14 years is minimal in all the countries included in this evaluation.
The prevalence of CD among the populations of Mediterranean countries, such as the Middle East and North Africa[1-3], is similar to that recently observed in Western countries. The prevalence of CD among the general population varies from 0.14% to 1.17%[10-20]: 1%-1.3% in Turkey[10-12], 0.6%-0.96% in Iran[13,14], 0.5% in Egypt, 0.6% in Tunisia and Israel[16-19], and < 0.5% in Jordan, Lebanon and Kuwait[5,20]. An overall prevalence rate of 1% cases/total population was finally estimated to better represent the frequency of the disease in the area, since none of the available confidence intervals of the reported rates significantly excluded this 1% rate. The rate of symptomatic vs asymptomatic patients was obtained from several reliable reports from the area[3,9,10,17]. In summary, 85% of symptomatic patients are likely to suffer from gastrointestinal symptoms, which include diarrhea, abdominal pain, vomiting, irritable bowel, and gastritis[5,13,20,32-37]. Among the non-gastrointestinal complaints, the available estimates suggest 20% of children are affected by short stature[5,20,33-35,37], 40% of all cases are affected by anemia[5,20,32,36,37], 30% are afflicted by osteopenia[32,33,35,37], and 10% by abnormal liver enzymes[37,38].
Mortality has been reported in excess of 1.8 compared to age- and sex-matched controls[31,39,40]. The risk of cancer in undiagnosed adults is significantly increased and the mortality is almost doubled in the total cohort of affected persons compared with the general population[41,44].
Crude medical costs
Crude health costs were estimated for the years between symptoms and diagnosis only for symptomatic adults and children, and were standardized for purchasing power parity (PPP) to account for the different economic profile among Mediterranean countries. Since gross national product is different across countries, the PPP is based on the law of one price; in the absence of transaction costs, identical goods will have the same price in different markets. The PPP equalizes the purchasing power of different currencies for a given basket of goods, thereby providing a standardized estimate of cost across countries.
We assume that the cohort of CD without symptoms does not increase the average medical cost compared to non CD individuals (but this should also be revised, since a significant number of patients identified by screening had a posteriori clinical symptoms). Therefore, medical costs are estimated only for 1:7 adults and 1:5 children with CD symptoms.
For each individual adult we assigned (on the basis of the reports cited and the clinical experience of the study partners), a minimal period of 6 years of delay between symptom onset and diagnosis of the disease[45,46], while this delay was two years for each assigned child with CD[9,20]. During that period an adult with CD required, in excess of age- and sex-matched controls, at least: 2 in-patient admissions, 1 out-patient admission, 3 primary medical consultations, 2 specialized consultations, and 4 laboratory tests. Similarly, children needed at least: 1 in-patient admission and 1 out-patient admission, 3 medical consultations, 1 specialized consultation and 2 laboratory tests (Table (Table11).
Excess need of health resources before the diagnosis of celiac disease
Estimated medical costs
The costs of health services were estimated based on the 2007 costs of the Italian National Health Service (NHS) which is similar to that of several European countries. We summed the total costs of the medical services required for each child or adult patient to obtain a standardized cost/per patient before the diagnosis of CD was made (Table (Table1).1). In this way, we obtained an estimation of the financial load (only for medical expenses) of symptomatic patients. The estimated cost according to the Italian NHS was then standardized for each country according to its PPP index. The total load of medical expenses for each country was calculated by multiplying the individual cost by the number of symptomatic patients estimated (adults and children).
Summary of reference data
(1) CD prevalence = 1%; incidence: new cases/year estimated at 1% of the live births, corrected for infant mortality rate; (2) symptomatic adults: 1 of every 7 cases, children 1:5 cases; (3) mortality of the total CD cohort: standardized mortality rate 1.8 compared to age- and sex-matched population; (4) delay between symptoms and diagnosis: adults 6 years, children 2 years; (5) associated conditions: 10%-15% of the total cohort - autoimmune disorders 30% (Turkey 1.9%, Iran 33%) and IDDM 10% (6.7%-18.5%); (6) complications: 16% of symptomatic CD patients; and (7) non gastrointestinal symptoms: short stature 20% (only children), anemia 40% (20%-80%), osteopenia 30% (30%-50%), abnormal liver function 10% (Turkey 38%, Iran 25%)
Table Table22 shows the population growth, number of children aged 0-14 years and the predicted figures for the year 2020, calculated based on a constant growth rate. The Mediterranean area will have about half a billion individuals by the year 2020, more than 100 million of which will be children aged 0-14 years. This estimate is likely to be in the low range, since some countries with a large population are likely to grow at a higher rate than this estimate before the year 2010.
Populations now and after 10 years
Table Table33 shows the prevalence of CD in each country in 2010 and the predicted prevalence in 2020. Within 10 years, the Mediterranean area will have to face more than 5 million cases of CD, one million of which will be in children. The large majority will not have clear symptoms and their diagnosis and care will be significantly delayed. Among the adult CD population, about 550 000 will present symptoms, while only 240 000 out of the 1 million estimated celiac children will be symptomatic. Table Table44 shows the estimated number of clinical complaints associated with the CD epidemic. It is likely that more than 48 000 children will be affected by growth failure, there will be 317 000 cases of anemia and 238 000 individuals will be afflicted with osteopenia. Table Table55 shows the estimated financial burden of the CD epidemic. There is no scope for a detailed calculation of costs, which will be related more to the availability of and access to medical services than to the actual cost of the service, but these figures help to understand the financial burden of the undiagnosed disease. European countries may not be impressed by these estimates but, for several other Mediterranean countries, these predicted costs might be a consistent load to the gross national product. More than €4 billion is a prudent estimate; only crude medical costs are included, not individual or social cost.
Prevalence of celiac disease in the next 10 years1
Symptoms and diseases associated with symptomatic cases
Excess cost of undiagnosed symptomatic celiac patients
Table Table66 shows the estimated number of deaths in the celiac disease cohort and the excess of deaths compared to age- and sex-matched controls. At the present rate, there will be more than 250 000 CD-related deaths in the Mediterranean area in 2020.
Excess mortality in undiagnosed cases2
Celiac disease is a very common chronic disease that affects adults and children in all wheat-consuming countries. It has also recently been reported in countries where its prevalence was previously unknown, such as China. For more than two decades, we have been discussing the difference in the prevalence of CD among countries in Europe, North America and South America, and the conclusion is that there is no country where CD prevalence is significantly different from the overall prevalence of about 1%. Interestingly, the prevalence, at a global level, is not related either to the amount of wheat consumed by each country or to the prevalence of the human leukocyte antigen (HLA) DR3-DQ2 and DR4-DQ8 haplotype worldwide.
An excess prevalence of CD has been reported in an isolated population in North Africa and in a large population in Sweden, but again it is plausible that this excess prevalence reflects a bias related to the cohort rather than a true excess. The prevalence of CD is increasing worldwide, including in Europe, China and India. The only region where it has not yet been described is Central Africa, and this may be explained by the absence in this region of HLA predisposing haplotypes, and of polymorphisms of the major non-HLA genes, namely SH2B3, IL12A, SCHIP, IL18RAP, and IL1RL1, among others[47,48]. Recently, Barada et al from Lebanon produced a comprehensive report of the situation in the countries that face the Mediterranean Sea, thereby increasing the awareness of CD in the area.
The EUROMED program supports several health-promoting activities across the Mediterranean, such as the surveillance of infectious diseases program and the Program for Transplants and Oncology EuroMed (Cancer Registries Network, Cancer screening and early diagnosis program, Mediterranean Transplant Network). Italy has requested that the CD epidemic be included in these programs (www.eeas.europa.eu/euromed/index_en.htm). The first step in facing this epidemic is to estimate the burden of CD in the area. Here we provide a reliable and simple picture of the present situation and a prediction of the development of the CD epidemic in the next 10 years, up to 2021.
The prediction obtained by simple straightforward calculations is impressive. Mediterranean countries will have to be prepared to deal with a considerable number of CD patients in the near future. There will be more than 5 million cases, one million of which will be children. But, more than the overall figures, each country will be especially concerned about the national figures. Our estimates are conservative figures, since we estimated a constant population growth over the next ten years, whereas the faster growing countries may have a more rapid growth rate than slower growing countries. Data on symptoms and common clinical problems are available only for symptomatic individuals, while a considerable percentage of so-called “asymptomatic” subjects notoriously report significant complaints a posteriori. A limitation of this study is related to the uncertainties inherent in any prediction given the wide confidence intervals of rates. However, the starting 1% prevalence rate is not only very robust, because of innumerable replications, but it also probably underestimates rather than overestimates the problem[4,28,50]. The rate of symptomatic versus asymptomatic individuals is also fairly conservative.
The financial burden estimate is not aimed to acquire more precision; we provide a gross figure for the spectrum of resources needed in each country for the services required by symptomatic patients. The priority issue is the availability of services; in many African countries, services are mostly only available in large cities and specialized health institutions. In the rural areas, the availability of services can be far less than that required. Hence, the cost of these services should, sadly, be subtracted from the total financial burden. This impending cohort of CD patients does require, and moreover will require, access to health services as inpatients or outpatients, for medical consultations, laboratory tests and, after diagnosis, financial support for a lifelong gluten-free diet. There is universal concern and many countries demand the expertise and support for dissemination of know how and capacity building for the management of CD.
The EuroMed - MEDICEL project (www.medicel.unina.it) offers a platform to analyze the problem and develop strategies, but active national plans are required to face the burgeoning epidemic, and the heavy burden that it will place on the health and the finances of the population.
This project was supported by Italian Ministry of Health, Direction of International Affairs, Project MEDICEL.
The incidence of celiac disease (CD) (i.e., permanent gluten intolerance), is increasing in all countries in which there is awareness of this intolerance. In all Western countries, including the United States and South America, the observed prevalence of the disease went from 1:1000 individuals to more than 1:100 individuals in two decades. However, large series of cases have recently been reported from “new” countries like India, China, North Africa and the Middle East. Celiac disease is expanding over and above any predicted trend, and has taken on the semblance of a real epidemic.
This expanding “epidemic” raises a series of unanswered research questions related to the following hot topics: (1) the weight of environmental factors in the increase of CD; (2) the genetic profile associated with predisposition to CD; (3) population differences in terms of genetic and environmental factors; and (4) the development of “sensitivity” to gluten.
Innovations and breakthroughs
In next 10 years, the Mediterranean area will have about half a billion inhabitants, 120 million of whom will be children. The projected number of CD cases in 2020 will be 5 million cases (1 million celiac children), with a relative increase of 11% compared to 2010. At a 2010 constant rate, there will be about 550 000 symptomatic adults and 240 000 sick children: 85% of patients will suffer from gastrointestinal complaints, 40% are likely to have anemia, 30% will be afflicted with osteopenia, 20% of children will have short stature and 10% will have abnormal liver enzymes. The estimated standardized medical costs for symptomatic celiac disease during the years of delay between onset of symptoms and diagnosis (mean: 6 years for adults, 2 years for children) will be about €4 billion (€387 million for the children) over the next 10 years. A delay in diagnosis is expected to increase mortality; about 600 000 deaths will occur among individuals affected by CD in the next 10 years, with an excess of 44.4% compared to age- and sex-matched controls.
The data produced in this study provide a picture of the cohort of patients affected by CD that will develop over the next 10 years in each country of the Mediterranean Basin. Stakeholders and health professionals in each country now have the figures with which it is possible to base adequate plans to face this epidemic. The diagnostic protocol must be simplified and made available not only in specialized centers, usually in large cities, but it should be especially important in rural districts.
CD: Celiac disease is a permanent intolerance to gluten based on a genetic predisposition; Projected prevalence: The number of celiac cases that are expected to be present over the next 10 years; Excess mortality: Undiagnosed celiac cases have twice the risk of death compared to age- and sex-matched controls. If the expected cases are not diagnosed, there will be more than 200 000 excess deaths in the Mediterranean area; Growth failure: 20% of children (about 50 000) with undiagnosed CD are affected by weight loss and short stature, due to a growth failure.
The paper is well written and deals with an important problem people are continuously facing.
Supported by European Laboratory for Food Induced Diseases, Federico II University of Naples
Peer reviewer: Ron Shaoul, MD, Director, Pediatric Gastroenterology and Nutrition Unit, Meyer Children’s Hospital, Rambam Medical Center, PO Box 9602, Haifa 31096, Israel
S- Editor Sun H L- Editor Rutherford A E- Editor Li JY
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