Summary of results

This is the first study to use a national primary care population-based database to explore sex, socioeconomic and regional differences in the prevalence of hereditary HHT and provide national prevalence figures for the UK. The 2010 point prevalence for HHT in the UK is 1.06/10 000 (or 1/9400) which has remained relatively stable between 2000 and 2010. The prevalence estimate is higher when Read codes likely to be associated with HHT are included (1/8700) and is higher still if the prevalence in women is considered to be more representative of the population as a whole (1/7800). The prevalence increases with age. The diagnosed prevalence ratio of HHT was 59% higher in women than in men and 74% higher in those from the least deprived socioeconomic group compared with those in the most deprived group. In addition, we have demonstrated a substantial geographical variation in the diagnosed prevalence of HHT across the UK.

Strengths and weaknesses

This is the first population-based study of HHT using a primary care database in the UK general population. With a total of 365 HHT prevalent cases identified in 2010, our study sample size is almost four times larger than the last UK estimate undertaken in 1992,13 is nationally representative and comparable in size with epidemiological studies conducted in other countries.6 ,14 ,15 We have been able to stratify our prevalence estimates by sex, age group, deprivation status and geographical location without the risk of bias that may occur either from low response rates (as have been observed in previous surveys of HHT prevalence in the UK13) or from case series in specialist centres which may lack a denominator population or represent cases referred for specialist care with potentially more severe disease.

There are potential limitations to the study which should be addressed. The first is that of the validity of the HHT diagnoses, which are recorded by general practitioners in the THIN database whilst the clinical diagnosis is generally made in secondary care. In practice, we are reasonably confident that the vast majority of these diagnoses will be correct with the increasing involvement of clinical geneticists in the screening and diagnosis of HHT which should result in more reliable information being conveyed to the primary care practitioner, and hence entered into the database. It seems very unlikely that a primary care practitioner would enter a diagnosis of HHT into the database unless it was supported by correspondence from secondary care. The consistency of our calculated prevalence of HHT with other comparable estimates from previous studies also supports the reliability of our findings. One further limitation that complicates all studies of HHT prevalence at present is the likelihood of undiagnosed individuals with HHT at large in the community. This may explain the higher prevalence of PAVMs as defined by radiological criteria (and by inference, HHT) in patients who were participating in a recent Japanese CT screening program for lung cancer16 than we observed in our dataset which did not use this radiological definition of the disease. Diagnosis is often confounded by the heterogeneous clinical presentation of HHT due to its variable genetic penetrance and expressivity.17 An average time lag of 25 years separates disease onset and first definite diagnosis.18 Hence, our prevalence estimates represent those with diagnosed HHT, and are likely to be lower than the true prevalence defined as all individuals with a mutation compatible with the disease. The fact that our data show the prevalence of the disease has been stable in both sexes over the last decade would suggest that the consistency in coding practice over this period has been maintained.

We used the Townsend score which is a deprivation index based on area as it was not possible to access individual-level deprivation data. This score presumes that individuals living within a geographical area have a similar deprivation status which may not be the case. However, there is evidence to suggest that the Townsend scores calculated at a district level are good proxy measures for individual levels of deprivation.19

Interpretation of results

Reasons for the marked sex difference between the diagnosed prevalence of HHT require careful consideration. One study from the Dutch Antilles showed a 33% increased prevalence ratio of a ‘definite’ diagnosis of HHT in women compared with men (using the Curacao criteria),15 and a recent US paper found a female:male ratio of 1.54, with HHT being diagnosed more commonly in women.20 Other studies have reported a more balanced distribution between sexes.14 ,17 Given HHT is an autosomal dominant disorder, the offspring of affected individuals will have a 50% chance of inheriting a mutation and this should not per se be associated with a sex bias. Our data show a significant difference in diagnosis of HHT in women compared with men, which appears to be greatest between the ages of 15 and 49. One possible explanation for this observation is that the higher diagnosed prevalence of HHT in women we observed is due to a difference in access to healthcare resources. Women have significantly higher rates of consultation with primary care providers during the ages of 15–70 years with many consultations due to issues surrounding contraception, pregnancy and childcare, and this may explain an increased ascertainment of symptomatic women with HHT.21 ,22 A possible alternative explanation for the disparity between sexes may be that the expression of the HHT phenotype is more common in women with the gene mutation. Little is known about the role of other genetic factors (such as moderator genes) or environmental factors that may modify the HHT phenotype but there is limited evidence that symptoms such as epistaxis may be amenable to treatment via manipulation of oestrogen and progesterone levels.23 During pregnancy there is an increased risk of developing complications of HHT24 ,25 and it has been suggested that this may represent a modification of the HHT vasculature by female hormones or be secondary to the haemodynamic changes of pregnancy. Clarifying whether the sex differential in diagnosis of HHT is due solely to behavioural factors or may be partly due to biological reasons is an important area for further research.

The reduced prevalence of diagnosed HHT in those from lower socioeconomic groups has multiple potential explanations which encompass controversial issues such as the proximity and quality of healthcare services provided in more deprived areas, and differentials in individuals’ thresholds for accessing these services across different socioeconomic groups. It is internationally recognised that health and healthcare access inequities vary along social gradients26 and one study looking at health-seeking behaviour in those from more deprived areas with asthma found that these populations reported a higher prevalence of respiratory symptoms but had lower consultation rates for those symptoms.27 Explanations such as varying access to healthcare, differing perceptions of symptom severity or less positive views of healthcare services were postulated to explain this disparity.27 ,28

Finally, we observed an almost twofold difference in diagnosed prevalence throughout the UK; least common in the West Midlands and most common in the South West. A pattern of geographical variability has been seen in other studies, most notably in the landmark French paper which first identified a particularly high concentration of affected individuals in the Ain, Jura and Deux-Sevres regions of the country.29 They attributed their findings to a local founder effect when an initial new mutation had given rise to a cluster of affected individuals that then gradually moved by diffusion to involve other nearby regions.30 It is not possible to say whether our findings could represent genetic clusters of the disease in the UK or if they are the result of variations in local primary or secondary care recording practice or access to healthcare resources. Further work should try to address this as there may be regions of the UK with a disproportionate under-diagnosis of HHT, thus exposing individuals to the avoidable risk of the complications of this disease.

Comparison with existing literature

Table 4 provides a summary of the HHT prevalence estimates of different studies conducted worldwide over the last 25 years. Each study has investigated different populations using different methodologies which, in part, explains the differing results. Certain areas such as the Dutch Antilles and the Ain region of France have shown particularly high prevalence of the disease. Elsewhere, most studies indicate a prevalence between 1 and 1.6/10 000 (or between 1/6000 and 1/10 000) and our study estimate falls within this range, although data from individuals with health insurance in the USA provide estimates as low as 1/33 000.20 Our findings with respect to age are consistent with previous work, with the prevalence of HHT being higher in older age groups, suggesting that the disease has an age-related penetrance17 or alternatively that the likelihood of diagnosis is related to longevity. No other studies have looked at the prevalence of diagnosis by deprivation status and most studies have been restricted to a small geographical area excepting the epidemiological data from France which also show a wide variation in prevalence depending on geographical location.29 ,31 ,32 Further research should consider the influence of disease severity on the diagnosed prevalence rate and its potentially confounding effect on our observations with respect to sex, socioeconomic status and geographical location.

Implications

This is the first contemporary study in a representative UK population to estimate the prevalence of HHT and suggests that it is much more common than previously thought, and similar to the prevalence seen in other countries. Assuming that the prevalence of HHT in men is the same as for women, the ‘true’ estimate of total prevalence would be closer to 1.28/10 000 or 1/7800 (the figure calculated for women alone). A similar approach extrapolating the ‘true’ prevalence from women living in the South West of the UK (the health authority with the highest crude prevalence of HHT) estimates a prevalence of 1.9/10 000 and would equate to at least 11 800 cases of HHT in a population of 62.3 million in 2010.35 The lower diagnostic rate of HHT in men and those from less affluent social backgrounds suggests a sociological role (or alternatively a biological role) in the presentation of HHT, while the previously unreported regional differences is an observation that requires validation in other datasets. Future research would ideally draw on a national rare disease database with integrated clinical information and genetic samples allowing greater understanding of the presentation of the disease, the genotype–phenotype relationship in HHT and the influences upon it of moderator genes and external environmental factors.