SciELO - Scientific Electronic Library Online

vol.74 issue3Single port laparoscopic colostomy using the glove techniqueMethicillin-resistant Staphylococcus aureus (MRSA) isolation in breast abscesses in a Public Maternity author indexsubject indexarticles search
Home Pagealphabetic serial listing  

Services on Demand




  • Have no cited articlesCited by SciELO

Related links

  • Have no similar articlesSimilars in SciELO


Medicina (Buenos Aires)

Print version ISSN 0025-7680

Medicina (B. Aires) vol.74 no.3 Ciudad Autónoma de Buenos Aires June 2014



Association of diffuse idiopathic skeletal hyperostosis and aortic valve sclerosis


Alberto O. Orden1,4, José M. David2, Rosana P. Díaz1, Norma N. Nardi3, Aida C. Ejarque4, Adriana B. Yöchler4

1Servicio de Medicina Interna,
2Servicio de Cardiología,
3Servicio de Reumatología, Clínica San Camilo,
4Servicio de Reumatología, Hospital Aeronáutico Central, Buenos Aires, Argentina

Postal address: Dr. Alberto O. Orden, Alfredo Bufano 2423, 1416 Buenos Aires, Argentina


The principal objective of this investigation was to analyze the association between diffuse idiopathic skeletal hyperostosis (DISH) and the presence of aortic valve sclerosis (AVS). For this study we used results from 1000 consecutive outpatients (473 males), older than 50 years of age (average 67.6 years), that had been examined with Doppler echocardiogram and anterior and lateral chest radiographs. Overall, 195 patients (19.5%) were diagnosed with DISH and 283 (28.3%) with AVS. DISH was more prevalent than AVS in males (66.7% vs. 42.6%, p< 0.0001) and in older patients (73.6 ± 9 years vs. 66.1 ± 9 years, p < 0.0001). Furthermore, 55.4% of patients with dorsal DISH presented aortic sclerosis calcification vs. 21.7% of patients free of DISH (OR = 4.47; 95% CI = 3.22-6.21). The adjusted odds ratio (OR) was calculated by sex and age resulting in 3.04 (95% CI = 2.12-4.36; p < .0001). A statistically significant association was found between DISH and AVS in accordance to age and sex. The biological plausibility of this association is based on similar risk factors, pathogenic mechanisms and vascular complications.

Key words: Diffuse idiopathic skeletal hyperostosis; Aortic valve sclerosis

Asociación de hiperostosis esquelética idiopática difusa y esclerosis valvular aórtica. El objetivo principal fue analizar la asociación entre la hiperostosis esquelética idiopática difusa (DISH) y la presencia de esclerosis valvular aórtica (AVS). Se evaluaron los resultados de 1000 pacientes ambulatorios consecutivos (473 varones), mayores de 50 años (promedio, 67.6 años), que habían sido examinados con un ecocardiograma Doppler y radiología torácica anterior y lateral. Globalmente, 195 pacientes (19.5%) tuvieron diagnóstico de DISH y 283 (28.3%) de AVS. DISH fue más prevalente que AVS en varones (66.7% vs. 42.6%, p < 0.0001) y en pacientes de mayor edad (73.6 ± 9 años vs. 66.1 ± 9 años, p < 0.0001). Además, 55.4% de los pacientes con DISH dorsal presentaron AVS vs. 21.7% de los pacientes sin DISH (OR = 4.47; 95% CI = 3.22-6.21). El odds ratio (OR) ajustado por sexo y edad fue 3.04 (95% CI = 2.12-4.36; p < 0.0001). Se encontró una asociación estadísticamente significativa entre DISH y AVS, que se mantuvo después de ajustar por sexo y edad. La plausibilidad biológica de esta asociación se basa en los factores de riesgo, mecanismos patogénicos y complicaciones vasculares compartidos.

Palabras clave: Hiperostosis esquelética idiopática difusa; Esclerosis valvular aórtica


Diffuse idiopathic skeletal hyperostosis (DISH; also known as Forestier and Rotés-Querol disease) is a condition characterized by the calcification or ossification of soft tissues, mainly entheses, ligaments and joint capsules. The classical site of this condition is the spine, of which the lower thoracic segment is the most affected. Soft tissue ossification is the most characteristic feature (Fig. 1). However, DISH is not limited to the spine and can independently involve multiple peripheral sites. Extra-spinal enthesis ossifications are frequent, and the presence of these can lead to a diagnosis of DISH1, 2.

Fig.1.- Dorsal DISH.

Bone proliferation (exostoses) and vascular calcifications are common in elderly patients, but it is not clear if these phenomena have a shared etiology. A derivative study from the Framingham Heart Study showed that osteophytes from the lumbar spine and calcifications of the abdominal aorta were present in the same patients, even after adjusting for age and other co-variables. The inclusion of subjects with DISH (7.0% of the sample) did not affect the analysis3.
The cause of DISH is unknown, but several risk factors are involved; these are based on the frequency of association with different metabolic diseases, including hyperinsulinemia with or without diabetes mellitus, obesity, hyperuricemia, dyslipidemia, hypertension and long-term isoretinol use4-6. DISH is associated with an increased incidence of coronary and cerebrovascular disease risk factors, and patients with DISH are significantly more likely to present with metabolic syndrome than are non-DISH patients7. These reports are common but not uniform in all studies6, 8, 9.
Aortic valve stenosis (AS) due to calcification is the main indication for replacement surgery in Europe and the United States of America. Valve calcification occurs in a wide range of diseases from aortic sclerosis (AVS), defined as a focal thickening with increased echogenicity of the aortic valve surfaces and returning velocities of < 2.5 m/s, to severe stenosis with thickening and calcification, leading to ventricular outflow obstruction with returning velocities of > 4 m/s10, 11.
Several studies have shown that AVS risk factors, which include dyslipidemia, hypertension and diabetes, are also common to atherosclerosis. These disorders share pathological characteristics such as endothelial damage, lipid deposition, and inflammatory infiltration, which is why early aortic valve lesions appear similar to atheromata. Scleral calcification is an active biological process, similar to vascular calcification, and it is supported by mechanical tension and inflammation. It is associated with the synthesis of extracellular matrix proteins such as metalloproteinases, tenascin-C, osteopontin and bone sialoprotein. The coexistence of neoangiogenesis, T lymphocyte infiltration, adhesion molecules and HSP60 gene expression indicate an active immunomediated process12.
DISH and AVS share risk factors, comorbidities and pathogenic mechanisms1, 2, 4-9, 11-23. Clinical observations of aortic valve involvement in DISH patients led to the aim of the present study: to analyze, in outpatients, the association between DISH that is diagnosed with conventional dorsal chest radiography and the presence of aortic valve involvement according to Doppler echocardiography.

Materials and Methods

Outpatients over 50 years of age underwent a bidimensional Doppler echocardiogram. Anterior and lateral chest radiograph for any clinical indication (i.e., arterial hypertension) were included.
Patients with prosthetic heart valves were excluded, as well as those previously diagnosed with ankylosing spondylitis or sacroiliitis.
The echocardiograms were performed with a Vivid I echocardiograph (General Electric, Fairfield, CT, USA), and sclerosis and valve calcification were determined according to the recommendations of the EAE/ASE14. The echocardiographers were unaware of the radiographic results.
The radiographs were taken with CR technology (digital radiography) and GE Legacy equipment. The radiographic technique was as follows: the patient was positioned at a 1.70 m distance, after which the anterior thorax was imaged at 70 kV/400 mA/0.004 s and the lateral thorax at 80 kV/400 mA/0.08 s. The images were stored for later availability in the Carestream PACS package, v 11.3 (Carestream Health Inc./Vue Solutions, Rochester, NY, USA).
DISH was diagnosed according to Resnick's criteria24. Three independent observers performed the diagnoses without knowing the echocardiographic results.
For the statistical analysis, the data are shown as means ± standard deviations for numerical variables and as percentages for categories. The Chi-square test was applied to compare proportions, and Student's t-test to compare means. Logistic regression was used to calculate odds ratios (OR) with 95% confidence intervals (CI). Age and sex were adjusted in a multiple logistic regression analysis. A value of p < 0.05 was considered significant. The analysis was performed with the Stata 11.0 program (StataCorp LP, College Station, TX, USA).
The study was approved by the Ethics and Teaching-Research Committees of the participating institutions.


Doppler echocardiogram and anterior and lateral chest radiograph results of 1000 patients over 50 years of age were analyzed. Demographic data (age and sex), aortic and mitral valve echocardiographic data (normality, scleral calcification, stenosis and insufficiency) and the presence or absence of DISH was recorded.
A description of the sample is presented in Table 1. Table 2 shows the comparison between the DISH and Non-DISH groups.

TABLE 1.- Sample description

TABLE 2.- Comparison of DISH and Non-DISH groups

Overall, 55.4% of the patients with dorsal DISH had AVS, versus 21.7% of the patients without DISH (OR = 4.47, 95% CI = 3.22-6.21). The adjusted OR (for age and sex) was 3.04 (95% CI = 2.12-4.36; p < 0.0001).
To avoid statistical biases when comparing groups of different sizes, random samples of 395 patients without DISH and 195 patients with DISH were taken (Non-DISH:DISH ratio = 2:1). The AVS frequency in the Non-DISH group was 20.2% (n = 78) vs. 55.4% in the DISH group. The OR was 4.90 (95% CI = 3.36-7.14; p < 0.0001). The adjusted OR (for age and sex) was 3.48 (95% CI = 2.31-5.24: p < 0.0001).


In 1950, Forestier and Rotés-Querol published a study about a condition named "senile vertebral ankylosing hyperostosis", which was distinguished as a different disease entity from spondyloarthropathy and ankylosing spondylitis25. In 1975, Resnick published an extensive study of the extraspinal locations of the condition, showing its high prevalence and suggesting its current name, "Diffuse Idiopathic Skeletal Hyperostosis (DISH)"26.
Posterior longitudinal ligament ossification (OPLL) of the spine is most frequent in Japanese and other Asian populations; it was present in 50% of studied cases and considered as a DISH variant27, 28.
Initially, Forestier and Rotés-Querol considered DISH a "spectacular but innocuous radiographic alteration" (Fig. 1)29. Progressively, spinal rigidity of varying degrees, dynamic overload of the mobile segment and space occupation syndromes (esophageal, tracheal or laryngeal compression, or medullar compromise with or without spinal fractures) were described30-34. Finally, hyperostosis was shown to be caused by manifestations in peripheral structures such as the shoulders, hips and feet29.
The global prevalence, according to studies of different populations and countries (including Finland, Budapest, Israel, Korea, Naples, The Netherlands, South Africa and the USA), varies from 3.6% to 28%, depending on the diagnostic criteria and study population. This condition has been observed in 2.4 to 5.4% of patients older than 40 years of age and in 11.2% of patients above 70 years of age in radiological studies; these findings have been confirmed in necropsy series. DISH prevalence increases with age. Accordingly, the condition is present in 10% of men between 50 and 54 years of age and 36% of men above 75 years of age, and in 1.9% of women between 50 and 54 years of age and 26% of women above 75 years of age. The male/female prevalence ratio is 2:1 and decreases with age15, 34-42.
The DISH classification criteria have not been fully defined, but classification requires at least 2 (according to Forestier) or 3 (according to Resnick) criteria in the presence of disk preservation and the absence of spondylitis and sacroiliitis. Utsinger considered 3 bridges to indicate a definitive diagnosis, with or without other involved entheses16, 17, 24, 26, 43. A recent attempt at consensus was positive only for exuberant new bone formation and the presence of intervertebral bridges. There was a perfect consensus with regard to the spine. There was no consensus on the constitutional, demographic and metabolic factors required for the definition of DISH18.
In recent years, there has been a dramatic change in the understanding of aortic valve calcification mechanisms that led to acknowledgment of this disease as an active process similar to atherosclerosis10-12.
Population studies such as the Helsinki Ageing Study, which included subjects between 55 and 71 years of age, and the Cardiovascular Health Study, a prospective study of subjects over 65 years of age in the United States, showed AVS prevalence rates between 21% and 26% in adults over 65 years of age and aortic stenosis prevalence rates of 2% to 7%, depending on the exact definition of outflow obstruction10-12.
Extracellular matrix mineralization or calcification is regulated under physiological conditions and is generally limited to bone tissues. In pathological conditions, ectopic calcification can occur1 when calcium and phosphate concentrations in the extracellular fluid exceed the saturation point (metastastic calcification)2, consequent to the substitution or transition of damaged, degenerated or necrotic tissues due to mineral deposition or3 due to mesenchymal cell transdifferentiation in bone tissues (ectopic calcification)19.
The initiation process and the relationship between the metabolic conditions and new bone formation in DISH are unknown. Neoformation is believed to be the result
of abnormal osteoblastic growth activation. This increase in growth continues beyond bone function, due to several growth factors. Insulin-like growth factor I stimulates alkaline phosphate and type II collagen activity in osteoblasts, while growth hormones can induce the local production of insulin-like growth factor I and insulin-like growth factor binding proteins in chondrocytes and osteoblasts20, 21. Because ossification begins at certain sites, El Miedany et al. suggested that hypervascularization might indicate the process1.
Several systemic hormones such as 1,25-dihydroxyvitamin D, parathyroid hormone (PTH), insulin and leptin and local growth factors such as transforming growth factor-β (TGF-β) and bone morphogenic protein (BMP) have been studied. These might participate in the initiation and evolution of the ossification of the spine ligament (OSL) 13, 16, 19, 27.
The underlying mechanism of aortic stenosis calcification has been investigated in clinicopathological studies; these have shown that calcified deposits are associated with the mineralization of devitalized cells and subcellular vesicles, as well as with protein deposition in the extracellular matrix of the bone (ECM). These proteins, including osteocalcin, osteopontin, osteonectin, matrix Gla protein, bone morphogenic protein, matrix metalloproteinase-2 (MMP-2) and matrix metalloproteinase-9 (MMP-9), are present in cardiovascular calcification, including calcified valves, but are not present in normal cardiovascular tissue23.
Although the results were adjusted for age and sex, the study had limitations. Prospective studies that register hypertension, diabetes and metabolic syndrome are required to rule out any bias in the studied association between DISH and AVS and to reinforce this hypothesis. The instability of the statistical results in comparisons of different groups (case/control ratio over 4) is another limitation. A second analysis with a control sample was used to demonstrate a closer relationship between the groups; this resulted in non-significant modifications.
In summary, the present study shows a statistically significant association between DISH and AVS, even after adjusting for age and sex. The biological plausibility of this association is based on the previously exposed risk factors, co-morbidities and physiopathological mechanisms. This finding encourages the performance of other studies in which variables that could reinforce the validity of this association are controlled, and basic studies that explore existing biological mechanisms behind the probable shared genesis of these manifestations.

Acknowledgements: The authors would like to thank Dr. Marina Khoury for her assistance with statistical processing and Lic. María Angélica Orden for her technical assistance.

Conflict of interest: None to declare.


1. El Miedany YM, Wassif G, el Baddini M. Diffuse idiopathic skeletal hyperostosis (DISH): is it of vascular aetiology? Clin Exp Rheumatol 2000;18: 193-200.         [ Links ]

2. Mader R, Sarzi-Puttini P, Atzeni F, et al. Extraspinal manifestations of diffuse idiopathic skeletal hyperostosis. Rheumatology (Oxford) 2009; 48: 1478-81.         [ Links ]

3. Karasik D, Kiel DP, Kiely DK, et al. Abdominal aortic calcification and exostoses at the hand and lumbar spine: the Framingham Study. Calcif Tissue Int 2006; 78: 1-8.         [ Links ]

4. Mader R, Lavi I. Diabetes mellitus and hypertension as risk factors for early diffuse idiopathic skeletal hyperostosis (DISH). Osteoarthritis Cartilage 2009; 17: 825-8.         [ Links ]

5. Kiss C, Szilágyi M, Paksy A, et al. Risk factors for diffuse idiopathic skeletal hyperostosis: a case-control study. Rheumatology (Oxford) 2002; 41: 27-30.         [ Links ]

6. Sencan D, Elden H, Nacitarhan V, Sencan M, Kaptanoglu E. The prevalence of diffuse idiopathic skeletal hyperostosis in patients with diabetes mellitus. Rheumatol Int 2005; 25: 518-21.         [ Links ]

7. Mader R, Novofestovski I, Adawi M, et al. Metabolic syndrome and cardiovascular risk in patients with diffuse idiopathic skeletal hyperostosis. Semin Arthritis Rheum 2009; 38: 361-5.         [ Links ]

8. Mader R, Dubenski N, Lavi I. Morbidity and mortality of hospitalized patients with diffuse idiopathic skeletal hyperostosis. Rheumatol Int 2005; 26: 132-6.         [ Links ]

9. Burner TW, Rosenthal AK. Diabetes and rheumatic diseases. Curr Opin Rheumatol 2009; 21: 50-4.         [ Links ]

10. Cawley PJ, Otto CM. Prevention of calcific aortic valve stenosis-fact or fiction? Ann Med 2009; 41: 100-8.         [ Links ]

11. Olszowska M. Pathogenesis and pathophysiology of aortic valve stenosis in adults. Pol Arch Med Wewn 2011; 121: 409-13.         [ Links ]

12. Mazzone A, Epistolato MC, De Caterina R, et al. Neoangiogenesis, T-lymphocyte infiltration, and heat shock protein-60 are biological hallmarks of an immunomediated inflammatory process in end-stage calcified aortic valve stenosis. J Am Coll Cardiol 2004; 43: 1670-6.         [ Links ]

13. Berthelot JM, Le Goff B, Maugars Y. Pathogenesis of hyperostosis: a key role for mesenchymatous cells? Joint Bone Spine 2013 May 31. doi: 10.1016/j.jbspin. 2013.03.013.         [ Links ]

14. Baumgartner H, Hung J, Bermejo J, et al. EAE/ASE. Echocardiographic assessment of valve stenosis: EAE/ASE recommendations for clinical practice. Eur J Echocardiogr 2009; 10:1-25.         [ Links ]

15. Julkunen H, Heinonen OP, Knekt P, Maatela J. The epidemiology of hyperostosis of the spine together with its symptoms and related mortality in a general population. Scand J Rheumatol 1975; 4: 23-7.         [ Links ]

16. Mazières B. Diffuse idiopathic skeletal hyperostosis (Forestier-Rotés-Querol disease): What's new? Joint Bone Spine 2013 Apr 5. doi: 10.1016/j.jbspin.2013 .02.011.         [ Links ]

17. Utsinger PD. Diffuse idiopathic skeletal hyperostosis. Clin Rheum Dis 1985; 11: 325-51.         [ Links ]

18. Mader R, Buskila D, Verlaan JJ, et al. Developing new classification criteria for diffuse idiopathic skeletal hyperostosis: back to square one. Rheumatology (Oxford) 2013; 52: 326-30.         [ Links ]

19. Atzeni F, Sarzi-Puttini P, Bevilacqua M. Calcium deposition and associated chronic diseases (atherosclerosis, diffuse idiopathic skeletal hyperostosis, and others). Rheum Dis Clin North Am 2006; 32: 413-26.         [ Links ]

20. Denko CW, Malemud CJ. Role of the growth hormone/insulin-like growth factor-1 paracrine axis in rheumatic diseases. Semin Arthritis Rheum 2005; 35: 24-34.         [ Links ]

21. Denko CW, Malemud CJ. Body mass index and blood glucose: correlations with serum insulin, growth hormone, and insulin-like growth factor-1 levels in patients with diffuse idiopathic skeletal hyperostosis (DISH). Rheumatol Int 2006; 26: 292-7.         [ Links ]

22. Tanaka H, Nagai E, Murata H, et al. Involvement of bone morphogenic protein-2 (BMP-2) in the pathological ossification process of the spinal ligament. Rheumatology (Oxford) 2001; 40: 1163-8.         [ Links ]

23. Jian B, Jones PL, Li Q, Mohler ER 3rd, Schoen FJ, Levy RJ. Matrix metalloproteinase-2 is associated with tenascin-C in calcific aortic stenosis. Am J Pathol 2001; 159: 321-7.         [ Links ]

24. Resnick D, Niwayama G. Radiographic and pathologic features of spinal involvement in diffuse idiopathic skeletal hyperostosis (DISH). Radiology 1976; 119: 559-68.         [ Links ]

25. Forestier J, Rotés-Querol J. Senile ankylosing hyperostosis of the spine. Ann Rheum Dis 1950; 9: 321-30.         [ Links ]

26. Resnick D, Shaul SR, Robins JM. Diffuse idiopathic skeletal hyperostosis (DISH): Forestier's disease with extraspinal manifestations. Radiology 1975; 115: 513-24.         [ Links ]

27. Yamada K, Inui K, Iwamoto M, et al. High serum levels of menatetrenone in male patients with ossification of the posterior longitudinal ligament. Spine (Phila Pa 1976) 2003; 28: 1789-93.         [ Links ]

28. Epstein N. Ossification of the cervical posterior longitudinal ligament: a review. Neurosurg Focus 2002; 13: ECP1.         [ Links ]

29. Rotés-Querol J. Clinical manifestations of diffuse idiopathic skeletal hyperostosis (DISH). Br J Rheumatol 1996; 35: 1193-4.         [ Links ]

30. Castellano DM, Sinacori JT, Karakla DW. Stridor and dysphagia in diffuse idiopathic skeletal hyperostosis (DISH). Laryngoscope 2006; 116: 341-4.         [ Links ]

31. Ebo DG, Uytterhaegen PJ, Lagae PL, et al. Choking, sore throat with referred otalgia and dysphagia in a patient with diffuse idiopathic skeletal hyperostosis (DISH). Acta Clin Belg 2005; 60: 98-101.         [ Links ]

32. Sreedharan S, Li YH. Diffuse idiopathic skeletal hyperostosis with cervical spinal cord injury -a report of 3 cases and a literature review. Ann Acad Med Singapore 2005; 34: 257-61.         [ Links ]

33. Lee SH. Spinal subarachnoid hematoma with hyperextension lumbar fracture in diffuse skeletal hyperostosis: a case report. Spine (Phila Pa 1976) 2009; 34: E673-6.         [ Links ]

34. Kim SK, Choi BR, Kim CG, et al. The prevalence of diffuse idiopathic skeletal hyperostosis in Korea. J Rheumatol 2004; 31: 2032-5.         [ Links ]

35. Westerveld LA, van Ufford HM, Verlaan JJ, et al. The prevalence of diffuse idiopathic skeletal hyperostosis in an outpatient population in The Netherlands. J Rheumatol 2008; 35: 1635-8.         [ Links ]

36. Pappone N, Lubrano E, Esposito-del Puente A, et al. Prevalence of diffuse idiopathic skeletal hyperostosis in a female Italian population. Clin Exp Rheumatol 2005; 23: 123-4.         [ Links ]

37. Kiss C, O'Neill TW, Mituszova M, et al. Prevalence of diffuse idiopathic skeletal hyperostosis in Budapest, Hungary. Rheumatology (Oxford) 2002; 41: 1335-6.         [ Links ]

38. Weinfeld RM, Olson PN, Maki DD, et al. The prevalence of diffuse idiopathic skeletal hyperostosis (DISH) in two large American Midwest metropolitan hospital populations. Skeletal Radiol 1997; 26: 222-5.         [ Links ]

39. Boachie-Adjei O, Bullough PG. Incidence of ankylosing hyperostosis of the spine (Forestier's disease) at autopsy. Spine 1987; 12: 739-43.         [ Links ]

40. Cassim B, Mody G, Rubin D. The prevalence of diffuse idiopathic skeletal hyperostosis in African blacks. Br J Rheumatol 1990; 29: 131-2.         [ Links ]

41. Bloom RA. The prevalence of ankylosing hyperostosis in a Jerusalem population--with description of a method of grading the extent of the disease. Scand J Rheumatol 1984; 13: 181-9.         [ Links ]

42. Julkunen H, Knekt P, Aromaa A. Spondylosis deformans and diffuse idiopathic skeletal hyperostosis (DISH) in Finland. Scand J Rheumatol 1981; 10: 193-203.         [ Links ]

43. Arlet J, Mazieres B. La maladie hyperostosique. Rev Med Interne 1985; 6: 553-64.         [ Links ]

Received: 11-XI-2013
Accepted: 4-III-2014

Creative Commons License All the contents of this journal, except where otherwise noted, is licensed under a Creative Commons Attribution License