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Achalasia: a critical review of epidemiological studies
THE AMERICAN JOURNAL OF GASTROENTEROLOGY Copyright © 1998 by Am. Coll. of Gastroenterology Published by Elsevier Science Inc.
Vol. 93, No. 12, 1998 ISSN 0002-9270/98/$19.00 PII S0002-9270(98)00567-X
Clinical reviews Achalasia: A Critical Review of Epidemiological Studies T. Podas, J. Eaden, M. Mayberry, and J. Mayberry Leicester General Hospital, Leicester, United Kingdom
Achalasia is one of the earliest recognized gastroenterological conditions. However, several centuries after it was first described, it remains also among the least understood. One of the main reasons for this is the relative rarity of the disease, which has resulted in limited opportunities to conduct investigative research. Few epidemiological studies have been conducted to date, and their data suggest a worldwide incidence estimated at between 0.03–1.1/105/yr. This review of the literature on the epidemiology of achalasia lends support to the idea that pooling of resources and collaboration at an international level is required, if any significant progress in the cause, treatment, and prevention of the disease is to be made. (Am J Gastroenterol 1998;93:2345–2347. © 1998 by Am. Coll. of Gastroenterology)
EPIDEMIOLOGY Incidence and prevalence studies The accurate definition of a disease is critical to distinguishing case from noncase. Classically, achalasia has been defined in terms of manometric abnormalities—although the emergence of “vigorous” achalasia has to some degree clouded the diagnosis. Endoscopy, and to a lesser extent radiology, provide less adequate means of identifying cases although helping to limit the number of cases where the manometric abnormalities are secondary to an underlying malignant process. In the case of achalasia, this limited availability of manometry has been a significant factor in preventing the widespread development of communitybased epidemiological studies. The lack of ready access to this facility has also meant that with one exception (1), it has been impossible to conduct prospective studies of incidence. Published studies have rather been retrospective and based on hospital records—a technique likely to underestimate the true frequency of the disease significantly. However, within these limitations, the reported incidence of achalasia has been fairly consistent across the western world, ranging from 0.4 to 1.1/105/yr in most studies (Table 1). Although many textbooks view achalasia as a disease of middle age, incidence studies from Britain (1– 4) and Israel (5) clearly show that there is a steady increase in the frequency of the condition throughout life. It is those over 70 yr of age who are most at risk; although in absolute figures their number is relatively small (4). At present, there is no reason to believe that there is a cohort phenomenon of susceptible people moving through the populations, but rather that achalasia is a disease of the elderly. If this is the case, it raises interesting questions as to its potential etiology. Certainly, the role of genetic predisposition seems minimal with two large community-based studies from Britain (6) and Israel (5) failing to identify any family clusters. Although early data from Israel (5) suggested that Jewish patients of Asian or African origin were most at risk, by 1983 the disease was clearly of similar prevalence in all
ACHALASIA Achalasia remains a disease without known cause, whose treatment is at best of limited effectiveness and whose prognosis is uncertain. The condition was first recognized in the 1600’s, and the usual approach to treatment of relieving the obstruction at the lower esophageal sphincter remains the cornerstone of management. Because of its comparative rarity, research on etiology has been limited, and for this reason there is no effective strategy for prevention. However, the infective etiology of Chagas disease has always held out hope that a similar origin might eventually be identified in achalasia. Certainly, much of the available evidence would point to a common origin for cases and away from a multifactorial cause. With this in mind, a critical approach to published work should help identify areas in which research could be concentrated.
Received July 14, 1998; accepted Aug. 3, 1998. 2345
2346
PODAS et al.
AJG – Vol. 93, No. 12, 1998 TABLE 1 Epidemiological Studies of Achalasia
Study Period
Incidence (Cases/ 105/yr)
Clear Statement of Case Definition (Yes/No)
Individual Cases Reviewed
Retrospective/ Prospective
Hospital/ CommunityBased Identification of Cases
11 31 ?
1925–64 1975–80 1986–89
0.6 0.6 ?
Yes No No
Yes No No
Retrospective Retrospective Retrospective
Hospital Hospital Hospital
48 53 25 152 162
1926–77 1966–83 1986–91 1980–84 1973–78 1979–83
0.4 0.5 0.8 1.0 0.8 1.1
Yes Yes Yes No Yes
Yes Yes Yes No Yes
Retrospective Retrospective Prospective Retrospective Retrospective
Hospital Hospital Hospital Hospital Hospital
25
1974–83
0.03
Yes
Yes
Retrospective
Hospital
No. of Cases USA Rochester (10) Virginia (11) United States (7) UK Cardiff, Wales (2) Nottingham, England (3) Edinburgh, Scotland (1) New Zealand (12) Israel (5) Zimbabwe (13) Bulawayo and Harare
groups, regardless of place of birth. This Israeli study was based on 162 cases in a population of 1.3 million. However, to identify regional or ethnic differences, much larger populations are required. In practice, in achalasia this has been associated with much less accurate case definition. In the three largest studies of disease distribution in the USA (7) and the UK (4, 8), diagnosis depended upon computerized analysis of hospital discharges or specialists recall of individual cases. Although all three studies pointed towards regional variations in the frequency of achalasia, such data must be interpreted with caution. They can easily be affected by incorrect coding—a problem often associated with uncommon conditions such as achalasia. Indeed, the question as to whether achalasia occurs with different rates in different communities remains open. It is perhaps surprising that there have been no retrospective case-controlled studies that have addressed the issue of etiology. Again, this reflects the difficulty of recruiting sufficient newly diagnosed cases and can probably only be overcome through a multicenter study. The main areas in which case reports would suggest such work might initially concentrate are: 1) Infections; and 2) Nutritional deficiency. Throughout this century there have been spasmodic reports linking achalasia to various infections. Perhaps the main stimulus has been the role of Trypanosoma cruzi in Chagas disease, but there is no comparable geographical or temporal clustering of patients with achalasia. Candidate viruses have included herpes and measles. However, the use of molecular medical techniques, such as polymerase chain reaction, has failed to substantiate any of these claims. Even the concept of a long delayed reaction to a viral infection, as is now being suggested for Crohn’s disease, does not easily fit our present understanding of this disease. With the emergence of cohort studies from countries such as Sweden and other parts of Europe, it may be possible to investigate the
role of infection in more detail. Twin registers could be valuable, but may be limited because of the rarity of the disease. In the 1930’s it was suggested that achalasia may be caused by a vitamin B deficiency (9). Although no subsequent study has supported this finding, the concept of degenerative changes is attractive and some interest has focused on the possibility that achalasia may be caused by central nervous system changes in the vagal and related nuclei. Such a view moves away from esophageal-targeted research and broadens the approach to etiology. CONCLUSION The etiology of achalasia remains a mystery. There is a clear place for case-control studies among well-defined patients. Again because of the disease’s rarity, it is unlikely that any research program will be effective unless it brings together a number of units in a multicentered approach. One purpose of this review is to call for a coordinated attempt to define the cause, clarify prognosis, and develop a strategy for an evidence-based approach to prevention and treatment. With this in mind, we would welcome approaches from centers interested in such an approved study. Reprint requests and correspondence: J. Mayberry, Gastrointestinal Research Unit, Leicester General Hospital, Gwendolen Road, Leicester LE5 4PW, UK.
REFERENCES 1. Howard PJ, Maher L, Pryde A, et al. Five year prospective study of the incidence, clinical features and diagnosis of alcoholism in Edinburgh. Gut 1992;33:1011–5. 2. Mayberry JF, Rhodes J. Achalasia in the city of Cardiff from 1926 – 1977. Digestion 1980;20:248 –52. 3. Mayberry JF, Atkinson M. Studies of incidence and prevalence of achalasia in the Nottingham area. Q J Med 1985;56:451– 6. 4. Mayberry JF, Atkinson M. Variations in the prevalence of achalasia in
AJG – December 1998
5. 6. 7. 8.
Great Britain and Ireland: An epidemiological study based on hospital admissions. Q J Med 1987;62:67–74. Arber N, Grossman A, Lurie B, et al. Epidemiology of achalasia in central Israel. Rarity of esophageal cancer. Dig Dis Sci 1993;38: 1920 –5. Mayberry JF, Atkinson M. A study of swallowing difficulties in first degree relatives of patients with achalasia. Thorax 1985;40:391–3. Sonnenberg A, Massey BT, McCarty DJ, et al. Epidemiology of hospitalisation for achalasia in the United States. Dig Dis Sci 1993; 38:2233– 44. Mayberry JF, Mayell MJ. Epidemiological study of achalasia in children. Gut 1988;29:90 –3.
ACHALASIA
2347
9. Stinson WD. Effect of thiamine chloride on cardiospasm and achalasia of the oesophagus. Ann Otol Rhinol Laryngol 1941;50:848 – 503. 10. Earlam RJ, Ellis FH, Nobrega FT. Achalasia of the oesophagus in a small urban community. Mayo Clin Proc 1969;44:478 – 83. 11. Galen EA, Switz DM, Zfass AM. Achalasia: Incidence and treatment in Virginia. Virginia Medical 1982;109:183– 6. 12. Mayberry JF, Atkinson M. Incidence of achalasia in New Zealand, 1980 –1984. An epidemiological study based on hospital discharges. J Gastroenterol Hepatol 1988;3:247–57. 13. Stein CM, Gelfand M, Taylor HG. Achalasia in Zimbabwean blacks. SAMJ 1985;67:261–2.
Vol. 93, No. 12, 1998 ISSN 0002-9270/98/$19.00 PII S0002-9270(98)00567-X
Clinical reviews Achalasia: A Critical Review of Epidemiological Studies T. Podas, J. Eaden, M. Mayberry, and J. Mayberry Leicester General Hospital, Leicester, United Kingdom
Achalasia is one of the earliest recognized gastroenterological conditions. However, several centuries after it was first described, it remains also among the least understood. One of the main reasons for this is the relative rarity of the disease, which has resulted in limited opportunities to conduct investigative research. Few epidemiological studies have been conducted to date, and their data suggest a worldwide incidence estimated at between 0.03–1.1/105/yr. This review of the literature on the epidemiology of achalasia lends support to the idea that pooling of resources and collaboration at an international level is required, if any significant progress in the cause, treatment, and prevention of the disease is to be made. (Am J Gastroenterol 1998;93:2345–2347. © 1998 by Am. Coll. of Gastroenterology)
EPIDEMIOLOGY Incidence and prevalence studies The accurate definition of a disease is critical to distinguishing case from noncase. Classically, achalasia has been defined in terms of manometric abnormalities—although the emergence of “vigorous” achalasia has to some degree clouded the diagnosis. Endoscopy, and to a lesser extent radiology, provide less adequate means of identifying cases although helping to limit the number of cases where the manometric abnormalities are secondary to an underlying malignant process. In the case of achalasia, this limited availability of manometry has been a significant factor in preventing the widespread development of communitybased epidemiological studies. The lack of ready access to this facility has also meant that with one exception (1), it has been impossible to conduct prospective studies of incidence. Published studies have rather been retrospective and based on hospital records—a technique likely to underestimate the true frequency of the disease significantly. However, within these limitations, the reported incidence of achalasia has been fairly consistent across the western world, ranging from 0.4 to 1.1/105/yr in most studies (Table 1). Although many textbooks view achalasia as a disease of middle age, incidence studies from Britain (1– 4) and Israel (5) clearly show that there is a steady increase in the frequency of the condition throughout life. It is those over 70 yr of age who are most at risk; although in absolute figures their number is relatively small (4). At present, there is no reason to believe that there is a cohort phenomenon of susceptible people moving through the populations, but rather that achalasia is a disease of the elderly. If this is the case, it raises interesting questions as to its potential etiology. Certainly, the role of genetic predisposition seems minimal with two large community-based studies from Britain (6) and Israel (5) failing to identify any family clusters. Although early data from Israel (5) suggested that Jewish patients of Asian or African origin were most at risk, by 1983 the disease was clearly of similar prevalence in all
ACHALASIA Achalasia remains a disease without known cause, whose treatment is at best of limited effectiveness and whose prognosis is uncertain. The condition was first recognized in the 1600’s, and the usual approach to treatment of relieving the obstruction at the lower esophageal sphincter remains the cornerstone of management. Because of its comparative rarity, research on etiology has been limited, and for this reason there is no effective strategy for prevention. However, the infective etiology of Chagas disease has always held out hope that a similar origin might eventually be identified in achalasia. Certainly, much of the available evidence would point to a common origin for cases and away from a multifactorial cause. With this in mind, a critical approach to published work should help identify areas in which research could be concentrated.
Received July 14, 1998; accepted Aug. 3, 1998. 2345
2346
PODAS et al.
AJG – Vol. 93, No. 12, 1998 TABLE 1 Epidemiological Studies of Achalasia
Study Period
Incidence (Cases/ 105/yr)
Clear Statement of Case Definition (Yes/No)
Individual Cases Reviewed
Retrospective/ Prospective
Hospital/ CommunityBased Identification of Cases
11 31 ?
1925–64 1975–80 1986–89
0.6 0.6 ?
Yes No No
Yes No No
Retrospective Retrospective Retrospective
Hospital Hospital Hospital
48 53 25 152 162
1926–77 1966–83 1986–91 1980–84 1973–78 1979–83
0.4 0.5 0.8 1.0 0.8 1.1
Yes Yes Yes No Yes
Yes Yes Yes No Yes
Retrospective Retrospective Prospective Retrospective Retrospective
Hospital Hospital Hospital Hospital Hospital
25
1974–83
0.03
Yes
Yes
Retrospective
Hospital
No. of Cases USA Rochester (10) Virginia (11) United States (7) UK Cardiff, Wales (2) Nottingham, England (3) Edinburgh, Scotland (1) New Zealand (12) Israel (5) Zimbabwe (13) Bulawayo and Harare
groups, regardless of place of birth. This Israeli study was based on 162 cases in a population of 1.3 million. However, to identify regional or ethnic differences, much larger populations are required. In practice, in achalasia this has been associated with much less accurate case definition. In the three largest studies of disease distribution in the USA (7) and the UK (4, 8), diagnosis depended upon computerized analysis of hospital discharges or specialists recall of individual cases. Although all three studies pointed towards regional variations in the frequency of achalasia, such data must be interpreted with caution. They can easily be affected by incorrect coding—a problem often associated with uncommon conditions such as achalasia. Indeed, the question as to whether achalasia occurs with different rates in different communities remains open. It is perhaps surprising that there have been no retrospective case-controlled studies that have addressed the issue of etiology. Again, this reflects the difficulty of recruiting sufficient newly diagnosed cases and can probably only be overcome through a multicenter study. The main areas in which case reports would suggest such work might initially concentrate are: 1) Infections; and 2) Nutritional deficiency. Throughout this century there have been spasmodic reports linking achalasia to various infections. Perhaps the main stimulus has been the role of Trypanosoma cruzi in Chagas disease, but there is no comparable geographical or temporal clustering of patients with achalasia. Candidate viruses have included herpes and measles. However, the use of molecular medical techniques, such as polymerase chain reaction, has failed to substantiate any of these claims. Even the concept of a long delayed reaction to a viral infection, as is now being suggested for Crohn’s disease, does not easily fit our present understanding of this disease. With the emergence of cohort studies from countries such as Sweden and other parts of Europe, it may be possible to investigate the
role of infection in more detail. Twin registers could be valuable, but may be limited because of the rarity of the disease. In the 1930’s it was suggested that achalasia may be caused by a vitamin B deficiency (9). Although no subsequent study has supported this finding, the concept of degenerative changes is attractive and some interest has focused on the possibility that achalasia may be caused by central nervous system changes in the vagal and related nuclei. Such a view moves away from esophageal-targeted research and broadens the approach to etiology. CONCLUSION The etiology of achalasia remains a mystery. There is a clear place for case-control studies among well-defined patients. Again because of the disease’s rarity, it is unlikely that any research program will be effective unless it brings together a number of units in a multicentered approach. One purpose of this review is to call for a coordinated attempt to define the cause, clarify prognosis, and develop a strategy for an evidence-based approach to prevention and treatment. With this in mind, we would welcome approaches from centers interested in such an approved study. Reprint requests and correspondence: J. Mayberry, Gastrointestinal Research Unit, Leicester General Hospital, Gwendolen Road, Leicester LE5 4PW, UK.
REFERENCES 1. Howard PJ, Maher L, Pryde A, et al. Five year prospective study of the incidence, clinical features and diagnosis of alcoholism in Edinburgh. Gut 1992;33:1011–5. 2. Mayberry JF, Rhodes J. Achalasia in the city of Cardiff from 1926 – 1977. Digestion 1980;20:248 –52. 3. Mayberry JF, Atkinson M. Studies of incidence and prevalence of achalasia in the Nottingham area. Q J Med 1985;56:451– 6. 4. Mayberry JF, Atkinson M. Variations in the prevalence of achalasia in
AJG – December 1998
5. 6. 7. 8.
Great Britain and Ireland: An epidemiological study based on hospital admissions. Q J Med 1987;62:67–74. Arber N, Grossman A, Lurie B, et al. Epidemiology of achalasia in central Israel. Rarity of esophageal cancer. Dig Dis Sci 1993;38: 1920 –5. Mayberry JF, Atkinson M. A study of swallowing difficulties in first degree relatives of patients with achalasia. Thorax 1985;40:391–3. Sonnenberg A, Massey BT, McCarty DJ, et al. Epidemiology of hospitalisation for achalasia in the United States. Dig Dis Sci 1993; 38:2233– 44. Mayberry JF, Mayell MJ. Epidemiological study of achalasia in children. Gut 1988;29:90 –3.
ACHALASIA
2347
9. Stinson WD. Effect of thiamine chloride on cardiospasm and achalasia of the oesophagus. Ann Otol Rhinol Laryngol 1941;50:848 – 503. 10. Earlam RJ, Ellis FH, Nobrega FT. Achalasia of the oesophagus in a small urban community. Mayo Clin Proc 1969;44:478 – 83. 11. Galen EA, Switz DM, Zfass AM. Achalasia: Incidence and treatment in Virginia. Virginia Medical 1982;109:183– 6. 12. Mayberry JF, Atkinson M. Incidence of achalasia in New Zealand, 1980 –1984. An epidemiological study based on hospital discharges. J Gastroenterol Hepatol 1988;3:247–57. 13. Stein CM, Gelfand M, Taylor HG. Achalasia in Zimbabwean blacks. SAMJ 1985;67:261–2.