Incidence of hereditary amyloidosis and autoinflammatory diseases in Sweden: endemic and imported diseases
© Hemminki et al.; licensee BioMed Central Ltd. 2013
Received: 17 January 2013
Accepted: 26 August 2013
Published: 3 September 2013
Amyloidoses are a heterogeneous group of progressive diseases caused by tissue deposition of misfolded proteins. According to the International Classification of Diseases, hereditary amyloidosis is divided into neuropathic and non-neuropathic forms. In Sweden, neuropathic heredofamilial amyloidosis has been identified as familial amyloidotic polyneuropathy (FAP), a fatal disease that is treated by liver transplantation. The non-neuropathic form includes familial autoinflammatory diseases. As no incidence data on these hereditary diseases are available and as even diagnostic data on non-neuropathic forms are lacking we determined the incidence of these diseases and characterized non-neuropathic conditions.
Patients were identified using data from the Swedish Hospital Discharge Register and from the Outpatient Register for 2001 through 2008. All patients discharged with hereditary amyloidosis diagnoses were included and standardized incidence rates were calculated.
Non-neuropathic disease was diagnosed in 210 patients, with an incidence of 2.83 per million. FAP was diagnosed in 221 patients, with an incidence of 2.02 per million. Two northern provinces that are home to 5% of the Swedish population accounted for 77% of FAP cases; the incidence in one of them, West Bothnia, was 100 times that in the rest of Sweden. Approximately 98% of non-neuropathic disease patients were immigrants, most of whom were from the Eastern Mediterranean area. Young Syrian descendants had the highest incidence rate, which was over 500-fold higher than that in individuals with Swedish parents. Even the early onset of these conditions identified them as familial autoinflammatory diseases.
FAP cases were highly concentrated in the two northernmost provinces. Non-neuropathic familial autoinflammatory diseases were of early-onset and immigrant origin most likely related to periodic fever syndromes. Paradoxically, FAP has remained endemic, in spite of population movements within the country, while familial autoinflammatory diseases, with an incidence exceeding that of FAP, were brought into the country as a result of immigration mainly from the Eastern Mediterranean area.
KeywordsHospitalization Heritable amyloidosis Periodic fever syndrome Mutation
Amyloidosis is a heterogeneous group of diseases characterized by fibrillar protein deposits called amyloids in a single organ or multiple organs . The disease nomenclature is based on the precursors of the amyloid fibrils for which at least 28 different proteins have been identified [1, 2]. Amyloidosis presents in sporadic and familial forms, but incidence or prevalence data are largely lacking for all forms of the disease [3, 4]. The most common and widespread form of hereditary amyloidosis is familial amyloidotic polyneuropathy (FAP), which is caused by transthyretin mutations leading to amyloid accumulation in critical organs and tissues, such as peripheral nerves, the digestive tract, the heart, and the kidneys [5, 6]. The prevalence of this dominantly inherited amyloidosis is highest in Portugal, Sweden and Japan. Case numbers show large regional differences and the penetrance varies by mutation type and geography . FAP is a progressive fatal disease that can be alleviated through liver transplantation, as the liver is the site of transthyretin synthesis . FAP liver transplantations are carried out on a worldwide basis, and are coordinated by The Familial Amyloidotic Polyneuropathy World Transplant Registry (http://www.fapwtr.org) . As of the end of 2010, 1,900 FAP transplantations had been performed. Other dominant hereditary forms of amyloidosis include apolipoprotein AI- and II-, gelsolin-, cystatin C-, lysozyme-, and fibrinogen A-related diseases, all of which are extremely rare and have relatively early onset and distinct geographical locations [5, 6]. Fibrinogen A is reported to be the most common type of hereditary renal amyloidosis . There are no data on hereditary amyloidosis other than FAP in Sweden, except that an expert review stated that gelsolin and apolipoprotein-related familial patients have been identified .
Reactive amyloidosis is a systemic form of the disease in which serum acute phase protein, amyloid A is the amyloid precursor. Reactive amyloidosis occurs as a secondary condition in patients with chronic inflammation or cancer. Many rheumatoid arthritis patients are diagnosed with reactive amyloidosis during the course of their disease . Periodic fever syndromes and other inflammasome-related autoinflammatory conditions may also cause reactive amyloidosis [13–16]. Even though reactive amyloidosis may not be familial, it is a clinical manifestation of hereditary periodic fever syndromes which include pyrin-associated familial Mediterranean fever (FMF), cryopyrin-associated periodic syndrome, mevalonate kinase deficiency, and tumor necrosis factor receptor-associated periodic syndrome . FMF is common in the Eastern Mediterranean area but rare elsewhere, as are the other periodic fever syndromes. A European registry on autoinflammatory diseases included 1049 patients with monogenic diseases but it reported only one patient in Sweden . These diseases are normally diagnosed before age 20 years; the kidneys and the gastrointestinal tract are the vulnerable organs when the patients have developed amyloidosis [2, 7, 13]. According to the 10th revision of the International Classification of Diseases, hereditary autoinflammatory diseases are classified together with hereditary renal amyloidosis as ‘non-neuropathic heredofamilial amyloidosis‘, code E85.0. However, the development of amyloidosis in hereditary autoinflammatory disease patients depends on the severity of the condition and may be rare in patients responding to treatment, which for FMF includes colchicine [6, 18, 19]. Thus code E85.0 does not distinguish between patients with or without amyloidosis.
In this paper we addressed the lack of incidence data on these hereditary diseases using nationwide hospital discharge and outpatient data from Sweden for 2001 through 2008. The results showed that the patient characteristics for ‘non-neuropathic heredofamilial amyloidosis‘, code E85.0 showed identity with hereditary autoinflammatory diseases and we use this disease designation in the following text. There was no evidence for patients with hereditary renal amyloidosis which would also be covered by code E.85.0. In agreement, a Swedish review of 1000 consecutive kidney transplant patients revealed 189 ‘clear’ hereditary renal disorders but none were hereditary renal amyloidosis; the two amyloidosis patients belonged to a FAP pedigree from Northern Sweden . The data also suggested that ‘neuropathic heredofamilial amyloidosis‘ patients (code E85.1) suffered from FAP and we use this term in the text. The results were unexpected, FAP remains a local endemic disease and hereditary autoinflammatory diseases were imported by immigrants, which reiterates the importance of international health. Some 15% of the Swedish population is born outside Sweden .
Amyloidosis patients were identified using the Swedish Hospital Discharge Register (2001–2008) and the Outpatient Register (2001–2008). The Hospital Discharge Register has had nationwide coverage since 1987 and regional coverage since 1964. In order to ensure that the reported incidence data only included newly diagnosed cases, anyone who had been diagnosed with amyloidosis prior to 2001 was excluded. Information from the registers was linked at the individual level via the national 10-digit civic registration number assigned to each resident in Sweden for his or her lifetime. In the linked dataset, civic registration numbers were replaced with serial numbers to ensure the anonymity of all individuals.
The 10th revision of the International Classification of Diseases was used to identify disease cases using the following diagnostic codes: E85.0 for hereditary autoinflammatory disease, E85.1 for FAP and E85.2 for unspecified heredofamilial amyloidosis. Although amyloidosis diagnosis should be based on the demonstration of amyloid fibrils in tissue biopsies, it is likely that for diagnostic group E85.0, the periodic fever symptoms rather than demonstration of amyloidosis fibrils were the bases of diagnoses. The reason is the ambiguous assignment of hereditary autoinflammatory disease into this amyloidosis code. On the other hand, FAP should be correctly diagnosed and the types of transthyretin mutations are largely known in the pedigrees .
Sex: Males or females. Geographic region of residence was divided into: (1) large cities (cities with a population of more than 200,000, i.e., Stockholm, Gothenburg, and Malmö); (2) Southern Sweden; and (3) Northern Sweden. Sweden is divided into 25 provinces. The border between Northern and Southern Sweden has traditionally been drawn at Dalälven (the Dal River, north of Stockholm), which we used to define the geographic boundary between Southern and Northern Sweden. The dataset included information on people from 64 countries and regions of birth according to the available classification.
Person-years were calculated from the start of follow-up on 1 January 2001 until diagnosis of the relevant disease, death, emigration, or the end of the study (31 December 2008). All hereditary diseases, newly diagnosed during the follow-up period, were considered, irrespective of their possible kinship. In order to guarantee that the patients were newly diagnosed, anyone hospitalized prior to 2001 with a related diagnosis were excluded. Age-, gender-, region of residence-, immigration status-, and diagnosis subtype-specific incidence rates were calculated for the whole follow-up period. Relative weights used to calculate incidence rates were based on the European Standard Population for 2000. We used SAS version 9.2 for the statistical analyses.
This study was approved by the Ethics Committee of Lund University, Sweden. All data were anonymous and no informed consents could be obtained.
Case numbers and incidence rates (per million person years) for hereditary diseases in Sweden, 2001-2008
Subtype (ICD-10 code)
Hereditary autoinflammatory disease (E85.0)
Familial amyloidotic polyneuropathy (FAP, E85.1)
Heredofamilial amyloidosis, unspecified (E85.2)
Case numbers and incidence rates (per million person years) for the hereditary diseases by region of residence
Hereditary autoinflammatory disease (E85.0)
Familial amyloidotic polyneuropathy (FAP, E85.1)
Heredofamilial amyloidosis, unspecified (E85.2)
Västerbotten (West Bothnia)
Norrbotten (North Bothnia)
Case number and incidence rates (per million person years) for hereditary autoinflammatory disease by birth country of the first generation
Second generation of compatriot parents
The United Arab Emirates
The advantages of the present study include nationwide coverage in a country with universal access to medical services of high diagnostic standards. Amyloidosis diagnostics are time-consuming and it has been reported that a small proportion of hereditary amyloidosis is misdiagnosed as the common immunoglobulin light chain amyloidosis . However, FAP is well known in Sweden and, moreover, two thirds of the patients were discharged more than once with the same specific amyloidosis subtype which implies consistent diagnostics. Also, the striking finding showing the precise geographic location of FAP cases and the immigrant dominance of hereditary autoinflammatory disease testify to a high diagnostic accuracy. Based on the similar geographic location, approximately similar age distribution and interchanged diagnosis in many patients of FAP and unspecified heredofamilial amyloidosis, they may be the same disease, with a joint incidence of 2.28 per million, somewhat less than that of hereditary autoinflammatory disease (2.83 per million). These incidence rates refer to inpatients and outpatients for years 2001 to 2008.
Swedish neuropathic heredofamilial amyloidosis (FAP) is caused by any of three identified transthyretin mutations. However, even for the same mutation penetrance and manifestations vary . The mean age of onset has been reported to be 56 years, which is somewhat lower than what we found here (the median age at diagnosis was 67 years for men and 57 years for women). The likely explanation is that symptoms do not immediately lead to hospitalization, but once patients are hospitalized amyloidosis is fulminant. However, considering the variable penetrance of FAP, the present incidence rates underestimate the incidence of FAP. Our data showed that 77% of the Swedish FAP patients were diagnosed in the two northernmost provinces of Sweden (West and North Bothnia), which together account for slightly more than 5% of the Swedish population. The incidence of FAP was over 100-fold higher in West Bothnia than in the rest of the country (excluding North Bothnia), in spite of large population movements within Sweden since the Second World War.
Autoinflammatory diseases are caused by dysfunction of the inflammasome complex of the innate immune system [13, 14]. They include several monogenic diseases such as pyrin-associated FMF, cryopyrin-associated periodic syndrome, mevalonate kinase deficiency, and tumor necrosis factor receptor-associated periodic syndrome. Many of these diseases are diagnosed by pediatricians and, for example, 80% of FMF cases occur before age 20 years . FMF is, according to a review, almost always restricted to Turks, Armenians, Arabs and non-Ashkenazi Jews or emigrants with these ethnicities and, according to this source, no cases have been described in individuals of Scandinavian origin . Autoinflammatory conditions may give rise to reactive amyloidosis, which may manifest initially as renal problems; the amyloid precursor is serum amyloid A, the normal and not a mutated protein [13–16, 18]. Our first clue that code E85.0 included periodic fever syndromes was the overwhelming proportion of patients who were immigrants from the Eastern Mediterranean area, with the incidence being highest in first-generation Syrian immigrants (109 per million) and their descendants (136 per million). In endemic areas, rates have been estimated to be as high as 1,000 per million . The relatively early age of onset also supported the disease identity of periodic fever syndrome; the highest incidence rates were in the 20 to 29 years age group in second-generation immigrants (median age at diagnosis 14 years). However, it is important to note that the immigrant populations originating from the Eastern Mediterranean area are relative newcomers to Sweden and their oldest descendants are still young adults . Thus, the calculated median ages at hospitalization are likely to be too high in the first generation immigrants who entered Sweden at around age 25 years and who could have the disease already at immigration. The delay between first disease episodes and diagnosis was over 7 years in the Eurofever registry . The calculated median ages may be too low for the young second generation because of the age truncation (still a young population).
An obvious question resulting from the above findings is whether native Swedes have indigenous hereditary autoinflammatory or related diseases. Among the 210 identified patients, 95 were born in Sweden but for only nine (2.3%) had both parents been born in Sweden. However, we were unable to confirm parental ethnicity. Recent data demonstrated that some inflammasome-related conditions appear to have indigenous origins in Sweden. Cryopyrin-associated periodic syndrome cases diagnosed in adulthood have been reported and common inflammasome-related NLRP3 and CARD8 polymorphisms have been described, although without evidence on disease susceptibility [15, 16]. Cases of pediatric periodic fever, aphthous stomatitis, pharyngitis and adenitis (PFAPA) have also been described in Sweden, but the disease is apparently not heritable; mevalonate kinase deficiency has not been diagnosed in ethnic Swedes . Taken together, the available data suggest that hereditary autoinflammatory disease, as described in the present study, is a disease of immigrants originating from the Eastern Mediterranean area.
In conclusion, this nationwide hospital in- and outpatient study showed an incidence of 2.02 per million for FAP and 2.83 per million for hereditary autoinflammatory disease. Both of these diseases showed distinct characteristics. FAP cases were concentrated in the two northernmost provinces of Sweden, suggesting that this disease entity only constitutes FAP with transthyretin mutations and practically excluding other types of diseases. Hereditary autoinflammatory disease was found to be an early-onset disease of immigrant origin. However, the identities of the type(s) of periodic fevers could not be established. Paradoxically, FAP has remained endemic, in spite of population movements, while hereditary autoinflammatory disease has been brought into the country as a result of population movements. We have recently shown that Swedish FAP patients have an increased risk of non-Hodgkin lymphoma (Hemminki et al. unpublished observation).
Familial amyloidotic polyneuropathy
This work was supported by the EU FP7/2007-2013 grant 260715, the Swedish Council for Working Life and Social Research and Deutsche Krebshilfe. The funding bodies had no influence on the contents of this article.
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