QJM Advance Access originally published online on April 4, 2006
QJM 2006 99(5):327-334; doi:10.1093/qjmed/hcl037
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Life expectancy in patients with hereditary haemorrhagic telangiectasia
1From the Department of Internal Medicine and Public Health, 2Department of Statistical Sciences, 3Geriatrics-MIDIM, and 4Unit of Medical Genetics, University of Bari, Bari, Italy
Address correspondence to Professor C. Sabbà, Department of Internal Medicine and Public Health, University of Bari, Bari, Italy. email: c.sabba{at}dimimp.uniba.it
Received 24 November 2005 and in revised form 3 February 2006
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Background: There are few data on life expectancy in patients with hereditary haemorrhagic telangiectasia (HHT), a disorder with life-threatening complications.
Methods: Seventy HHT patients provided data on age and age at death of their HHT-affected parent, which was compared with that of the parent's non-affected partner.
Results: At the time of the study, 40 HHT parents (57.1%) vs. 36 (51.4%) non-HHT parents had died (p = 0.404). Median age at death was lower in HHT vs. non-HHT parents (63.2 vs. 70.0 years, respectively). The mortality of HHT parents showed an early peak in the under 50s and a late peak at 60–79 years. HHT was the main risk factor influencing life expectancy after 30 years (p < 0.05). No differences in survival probability were found in HHT patients with respect to sex (p = 0.37), or ENG vs. ALK-1 genotype (p < 0.9).
Discussion: Life expectancy appears to be significantly lower in HHT patients than in their partners. Prevention of HHT complications with screening programs could increase life expectancy.
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Introduction |
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In clinical practice, life expectancy and quality of life are important parameters when evaluating the potential benefits and burdens of treatment. Moreover, knowledge concerning the influence of a particular illness on life expectancy may affect the physician's behaviour in dealing with such disease. Hereditary haemorrhagic telangiectasia (HHT), or Rendu-Osler-Weber disease, is a dominantly inherited disorder. Emergencies are not uncommon and can be lethal, but it is also a chronic and often socially disabling disease.
HHT is caused by mutations in the endoglin (HHT1), ALK-1 (HHT2) or SMAD4 genes (HHT-JP, an HHT juvenile polyposis combined syndrome);1–3 another locus (HHT3) has recently been identified.4 These gene mutations largely account for familial cases, but de novo mutations have also been reported that are responsible for sporadic cases.5–7 The prevalence of the disease is currently estimated at 1 in 8000.8–10 HHT is characterized by angiodysplastic lesions (telangiectases and arteriovenous malformations or AVMs) that may affect many organs.8 The disease displays age-related penetrance,11,12 with manifestations developing throughout the patient's lifetime that may vary between affected individuals and even among members of the same family.13,14
Generally, spontaneous and recurrent epistaxis is the initial symptom, but the onset of HHT often includes life-threatening complications as a result of visceral involvement (brain, lungs, liver).8,15 Nosebleeds and gastrointestinal bleeding telangiectases may result in severe anaemia, requiring blood transfusions in older patients. Rarely, these bleeding episodes can also cause hemorrhagic shock. Pulmonary and cerebral arteriovenous malformations (PAVMs and CAVMs) may be clinically silent, but they can often result in sudden morbidity and mortality. PAVMs result in a direct right-to-left shunt with impairment of the filtering capabilities of the lung, thereby permitting the passage of thrombi and bacteria through the capillary bed, causing transient ischaemic attacks (TIAs), emboli, stroke or brain abscess. Bleeding with haemoptysis or haemothorax is less frequent, but may be fatal during pregnancy. CAVMs can also be responsible for haemorrhagic strokes, with disabling consequences or death. The heart is rarely affected; the most common condition is a high-output heart failure, due to arteriovenous shunting in the liver. Clinical manifestations of liver involvement are related to the type of shunting present (high-output heart failure, portal hypertension, portosystemic encephalopathy, biliary disease) and may require liver transplantation.15–24
Because of this risk of complications from acute catastrophic events, such as rupture of arteriovenous malformations resulting in early death, it has been presumed that mortality is higher and life expectancy lower in HHT patients, compared to non-affected individuals, but this hypothesis has been investigated in only one study.25 The present study assessed the life expectancy of patients with HHT.
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This retrospective study was based on familial medical histories of 70 HHT patients referred to our University Interdepartmental Research Centre for Rendu-Osler-Weber disease. The initial group consisted of 131 consecutive patients seen between June 2001 and February 2004, whose diagnosis of HHT was based on the presence of three out of four established clinical diagnostic criteria (recurrent epistaxis, mucocutaneous telangiectases, visceral arteriovenous malformations or AVMs, family history)26 and subsequently submitted to genetic analysis.
The life expectancy of an individual is genetically related to the length of life of their parents.27,28 We interviewed HHT patients with affected parents (presence of at least three diagnostic criteria), to discover: (i) the age of living parents, (ii) the age at death of deceased parents, and (iii) the cause of their death, if known.
The final patient cohort consisted of 70 patients whose clinical diagnosis was confirmed by genetic analysis, and who had a parent with HHT. We excluded 21 patients with molecular analysis still in progress, and 12 who asserted that neither of their parents had ever demonstrated any symptom of HHT. In addition, given that siblings share the same parents, only one individual per sibship was included in the study, to avoid redundancy in the data.
The parents with HHT were then compared with their non-affected partners (controls). In our sample, there were no patients whose parents were both affected (this latter condition has been reported in cases of consanguineous marriages).29,30
Statistical analysis
All statistical evaluations used the SPSS package (v. 11.0). p values <0.05 were considered statistically significant. The Kolmogorov normality test and the Shapiro-Wilk test were used to verify the appropriate application of parametric tests. The distribution functions of the two populations (HHT and controls) were assessed using the Kolmogorov-Smirnov test.
The difference between percentages of deaths in the two groups was evaluated and verified with the normal Z test for frequencies, since both groups were larger than 30 units. The difference between the location parameters (which are identified with the median age of death, since the comparison between mean age of death is not applicable) was verified with the Mann-Whitney test and confirmed with the less powerful, but more adaptable, median test (Fisher's exact test). To confirm the difference between the age-of-death in couples studied, the t-test for dependent samples was used, since distribution of such difference is normally distributed.
The survival analysis in the two populations was performed with the Kaplan-Meier method, and verified by the Breslow and Mantel-Haenzsel tests (best known as log-rank test). The influence of the HHT mutation (or other prognostic factors) was assessed with a semi-parametric Cox model; to verify this model, the test of maximum likelihood and the Wald test were used.
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Results |
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A total of 40/70 HHT parents (57.1%) and 36/70 (51.4%) of their non-affected partners had already died at the time of this analysis, a difference which did not reach statistical significance (Z test, HHT vs. non-HHT, p = 0.404). Table 1 shows the causes of death in the HHT group.
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The mean age of death of HHT parents was lower than that for the normal parents (63.2 years, SD 16.1, SE 2.5 vs. 70.0 years, SD 13.4, SE 2.3, respectively). However, age of death was not normally distributed in both groups, as shown by both the Kolmogorov test (HHT p < 0.02 and non-HHT p < 0.1) and the Shapiro-Wilk test (HHT p < 0.02 and non-HHT p < 0.03). These findings are illustrated in Figures 1 and 2. The HHT group had an early peak in the under-50 age group and a late peak at 60–79 years, whereas the non-HHT group only peaked in the 70–79-year age group. Thus the statistical analysis of the age of death distribution required non-parametric tests. Since the two distribution functions are statistically similar, as shown by the Kolmogorov-Smirnov test (standardized value 1.105, p < 0.20), the Mann-Whitney and median tests were used to verify the significance of the above difference; both statistical tests rejected the hypothesis of equality between the median age of death, the former test at p < 0.05 and the latter at p < 0.02. This means that the median age of death is not similar in both populations (HHT and non-HHT parents).
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Figure 3 illustrates cumulative survival, assessed using the Kaplan-Meier method31 (Table 2). The difference between the two groups of parents was statistically verified by Breslow test and Mantel-Haenzsel log-rank test (p < 0.03 with the former test, p < 0.05 with the latter).
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Mortality risk in HHT parents (14% cumulative death rate at the age of 50 years) was higher than in the controls (3%), and this risk increased significantly in the 70-year-old subjects (51% probability of death in HHT parents vs. 27% in controls). At this age, an HHT subject has a ratio of death probability to survival probability (odds ratio, OR) approaching 1 vs. OR 0.38 for non-HHT patients. Non-HHT subjects approach OR 1 only when they are 75 years old, when the OR for HHT patients is >1.6.
The semi-parametric Cox model confirms that HHT is the main risk factor negatively influencing life expectancy from the age of 30 years (p < 0.05). In this group of HHT parents, there was no significant difference in survival probability between men and women (p = 0.37), nor between HHT1 subjects with genotype ENG and HHT2 subjects with genotype ALK-1 (p < 0.9).
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Discussion |
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The possibility of severe complications in HHT has suggested an increased mortality in these patients.13 This was recently documented in a study on the prevalence and mortality of HHT patients based on two cross-sectional surveys in combination with a long-term follow-up study. The authors concluded that in young patients, HHT was associated with an increased early mortality, which was fully attributable to the disease (in patients aged <60 years at inclusion (in 1974), the mortality rate in 1995–1997 was twice than expected).25
In the present study, as expected, the absolute number of deaths was similar to that of HHT patients when compared with their healthy partners (HHT vs. non-HHT, p = 0.404), given that the probability of death is obviously equal to 100% in the long term for all subjects. Nevertheless, the average lifespan of HHT patients is shorter than that for the control group (63.2 vs. 70.0 years, respectively), with a decrease in life expectancy approaching 6.8 years.
A double peak for mortality was observed in HHT patients. The mortality peak in the under-50s seems to be due to major acute complications, which, however, can also be the cause of death in the 60–79-year age group, in addition to chronic organ involvement (Table 1). Maternal complications occurring during pregnancy led to the deaths of two young women at childbirth, due to haemorrhage from PAVMs, caused by the increased blood flow and alterations in the vascular tone related to pregnancy, and haemorrhage from CAVMs, due to the increased intracranial pressure during vaginal delivery or from AVMs in the uterus.22,32 The death related to haemothorax can be attributed to spontaneous rupture and bleeding of the PAVM.
Although HHT is basically a haemorrhagic disease, thromboembolic complications are not uncommon (myocardial infarction, pulmonary thromboembolism). PAVMs, and the use of either female hormones or antifibrinolytic agents in the management of bleeding,33,34 may increase the risk of thrombotic events in these patients. The stroke death was a likely consequence of paradoxical brain embolism associated with a right-to-left shunt from PAVMs. With regard to the myocardial infarction, it was not clear whether it was induced by thromboembolic complications or by severe anaemia from epistaxis, which could potentially account for the ischaemia, due to decreased haemoglobin levels and subsequent impaired oxygen-carrying capacity. Severe anaemia was the cause of death in patients with frequent and severe nosebleeds, while we presume that the gastrointestinal bleedings might have contributed to anaemia in patients without epistaxis. Respiratory failure was probably induced by untreated PAVMs causing ipoxaemia with progressive dyspnoea in later life. Liver involvement (HAVMs) probably determined high output heart failure, portal hypertension and cirrhosis (the latter could be responsible for liver cancer).35,36
The difference in survival between the two populations (HHT parents and their healthy partners) can most likely be attributed to the presence of HHT, which was the main risk factor influencing life expectancy from the age of 30 years (Kaplan-Meier, p < 0.03). The cumulative risk of death at any given age in adult HHT patients is higher than that for controls, and this probability increases dramatically in the 70-year-old age group, in accordance with data illustrating that HHT complications increase with age.11,37 Our results are also agree with those of other authors,25 who reported a significant increase in cumulative mortality rate for HHT patients with respect to normal individuals.
In our study, non-HHT partners, rather than the general population, were used as a control group, thus permitting us to compare life expectancy between HHT and non-HHT individuals who shared the same lifestyle and socio-economic conditions. Since this device reduces the effect of environmental factors on lifespan, it may be an effective tool for evaluating the impact on life expectancy of other adult-onset autosomal dominant diseases. Nevertheless, these data may have a bias introduced by the a priori exclusion of individuals who died because of acute HHT-related complications at a young age, or who avoided bearing children due to extremely severe disease symptoms. Since several sudden life-threatening events have been reported in young patients,38,39 resulting in deaths or serious motor and cognitive impairment, our results probably underestimate the actual decrease in life expectancy due to HHT.
No significant difference in life expectancy (p = 0.37) was observed between sexes or between HHT1 patients and HHT2 patients (p < 0.9) with regard to survival probability. This result is surprising, since HHT1 is reported to be associated with a higher frequency of pulmonary arteriovenous malformations, and to cause more severe clinical manifestations, while HHT2 is believed to have a lower penetrance and milder disease manifestations.13,14,40
Early detection and treatment of arteriovenous malformations (AVMs) would almost certainly increase life expectancy in HHT, suggesting a need for genetic screening of all HHT patients and their at-risk relatives, even in asymptomatic patients, in order to reduce morbidity and mortality. In particular, every attempt should be made to discover and treat cerebral and pulmonary arteriovenous malformations.22,41,42 The adoption of measures such as early genetic investigation for mutation identification38 and presymptomatic diagnosis of PAVMs and CAVMs including prenatal diagnosis of fetal arteriovenous malformations through appropriate screening programmes,36 would be expected to improve life expectancy in HHT patients.
No treatment can prevent the development of telangiectasic lesions in HHT patients, and thus the complete elimination of premature death in HHT is not currently realistic. However, the severity of the complications should be taken into account when considering prevention. The most appreciable benefits, in terms of lifespan, would be probably obtained by the use of screening programs. Reducing disease burden through prevention might also have a large impact on health-related quality of life, because it might eliminate possible disabilities, such as the consequences of stroke or brain abscess.
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