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Keywords:

  • amyloidosis (hereditary);
  • inborn errors of metabolism;
  • transplantation (liver and heart);
  • transthyretin

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Genetics
  5. Clinical symptoms of TTR amyloidosis
  6. Age of onset
  7. Somatic and autonomic polyneuropathy
  8. Heart complications
  9. Gastrointestinal disturbances
  10. Kidney complication
  11. Carpal tunnel syndrome
  12. Eye complications
  13. Diagnosis
  14. Transplantation as a treatment for transthyretin amyloidosis
  15. Neuropathy, gastrointestinal disturbances and kidney failure
  16. The heart after transplantation
  17. Complications from the eye and central nervous system after transplantation
  18. What about genetic testing and counselling
  19. Conflict of interest statement
  20. References

Abstract. Suhr OB, Svendsen IH, Andersson R, Danielsson Å, Holmgren G, Ranløv PJ (Umeå University Hospital, Umeå, Sweden; Rigshospitalet, København Ø, Denmark; Örnsköldsviks Hospital, Örnsköldsvik, Sweden; and Hørsholm Hospital, Hørsholm, Denmark). Hereditary transthyretin amyloidosis from a Scandinavian perspective (Review). J Intern Med 2003; 254: 225–235.

Hereditary transthyretin (TTR) amyloidosis is a rare often fatal form of systemic amyloidosis, that until recently was considered intractable, with the patients dying from the disease 5–15 years after onset. The phenotype of the disease varies according to the type of mutation, but generally the heart and/or the nervous system is affected. Liver and in some cases heart transplantation has now been shown to stop the progress of the disease, but the outcome depends on the patients’ status at the time of operation, as no substantial improvement of the patients’ symptoms has been noted after the procedure. Thus an early diagnosis is of importance for the outcome.

In the following, we summarize our knowledge of the amyloidogenic TTR mutations found in the Scandinavian countries, their symptoms, how to settle the diagnosis and the outcome of transplantation. Besides, the problems arising from our capability to genetically test asymptomatic members of affected families for the trait will be discussed.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Genetics
  5. Clinical symptoms of TTR amyloidosis
  6. Age of onset
  7. Somatic and autonomic polyneuropathy
  8. Heart complications
  9. Gastrointestinal disturbances
  10. Kidney complication
  11. Carpal tunnel syndrome
  12. Eye complications
  13. Diagnosis
  14. Transplantation as a treatment for transthyretin amyloidosis
  15. Neuropathy, gastrointestinal disturbances and kidney failure
  16. The heart after transplantation
  17. Complications from the eye and central nervous system after transplantation
  18. What about genetic testing and counselling
  19. Conflict of interest statement
  20. References

Hereditary transthyretin (TTR) amyloidosis is a systemic amyloidosis, caused by mutated TTR. Only four different amyloidogenic TTR (ATTR) mutations are known in Scandinavia (Table 1), and the number of affected patients is low, thus, the disease is generally of little concern to the health care system. Until recently the disease was considered intractable, and the patients died within 5–15 years after the diagnosis was established [1, 2]. However, liver transplantation is currently an accepted and in the majority of cases an effective treatment, but the results are depending on an early diagnosis and intervention, especially for patients with the neuropathic forms of TTR amyloidosis [3].

Table 1.  Amyloidogenic transthyretin (ATTR) mutations found in Scandinavia
ATTRCountrySymptoms
Val30MetSweden, FinlandPeripheral neuropathy, autonomic neuropathy, heart conduction disturbances, gastrointestinal dysfunction, nephrotic syndrome and kidney failure, amyloid deposits in the eye, carpal tunnel syndrome
Ala45SerSwedenRestrictive heart failure, carpal tunnel syndrome
Tyr69HisSwedenSevere migraine, hemiparesis, epileptic seizures, dysartry, hallucinations, dementia
Leu111MetDenmarkRestrictive heart failure. Carpal tunnel syndrome (may precede heart symptoms with several years)

On a worldwide basis, until now, more than 80 ATTR have been discovered. However, nonmutated TTR is the precursor protein for the senile systemic amyloidosis, signifying that wild-type (normal) TTR under certain unknown conditions has the capacity to form amyloid [4]. TTR is a tetramer and function as a carrier protein for the thyroid hormone and the retinol binding protein. The half-life of TTR is approximately 3 days [5], why attempts to treat TTR amyloidosis by removal of TTR from the plasma by plasmapheresis and filtering have proved unsuccessful [6].

A decreased stability of the tetramer is typical for ATTR mutations. It is suggested that a separation of the tetramer into monomers is required for amyloid formation, and that the monomer undergoes conformational changes and assembles into the typical beta-pleated sheaths common for all types of amyloid fibrils [7]. Experience based on experimental amyloid animal models suggests that the formation of amyloid fibrils from conformational altered TTR monomers may be triggered and mediated by as yet ill-defined intercellular agents, i.e. ‘amyloid enhancing factors’ [8–11]. However, for TTR amyloidosis, as for all other types of amyloidosis, the amyloid generating process is not fully elucidated.

The different TTR mutations give rise to a variety of systemic amyloidosis with different phenotypes [12]. From a global perspective, the ATTR mutation with leucine substituting valine at position 122 (ATTR Val122Leu) is the most common, and it causes a late onset cardiac amyloidosis in patients of African origin [13]. From a Scandinavian point of view the ATTR Val30Met is the most widespread mutation with a focus in northern Sweden, but sporadic cases are known from all over Sweden, and a case from Finland has also emerged [1, 14]. ATTR Val30Met gives rise to a neuropathic form of amyloidosis: familial amyloidotic polyneuropathy (FAP), Portuguese type (Fig. 1) [15]. Single families with the mutation are found worldwide, but endemic areas are present in Portugal, Sweden, Japan and Brazil [1, 15–17]. Although the mutation is the same in the endemic areas, the phenotype of the disease varies considerably; thus indicating that some ill-defined environmental and/or genetic factors may operate in the pathogenesis [18].

image

Figure 1. First diagnosed patient with familial amyloidotic polyneuropathy in Sweden. The peripheral muscle wasting is clearly seen. The patient had suffered from disease for 14 years.

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In Denmark, the ATTR Leu111Met causes a primarily cardiac amyloidosis: familial amyloidotic cardiomyopathy (FAC), with clinical onset in the forth or fifth decade of life [2, 19, 20]. This mutation has at present only been found in three Danish families, apparently unrelated and originating from different parts of the country [21].

In Sweden, two additional mutations have recently been identified. One (ATTR Ala45Ser) is characterized by slowly progressing cardiomyopathy with a relatively late onset. One family only has been found [22]. The other (ATTR Tyr69His) is characterized by central nervous system (CNS) disturbances: severe migraine, hemiparesis, epileptic seizures hallucinations and dementia, symptoms that mimics those of cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL). However, this mutation has been excluded. ATTR Tyr69His was initially observed in Pennsylvania (USA) and Canada in families originating from Sweden (M. Benson, Indianapolis, USA, personal communication). Also for this mutation only one Swedish family is known. As little as yet is known about these latter two mutations, they will not be discussed in details.

Genetics

  1. Top of page
  2. Abstract
  3. Introduction
  4. Genetics
  5. Clinical symptoms of TTR amyloidosis
  6. Age of onset
  7. Somatic and autonomic polyneuropathy
  8. Heart complications
  9. Gastrointestinal disturbances
  10. Kidney complication
  11. Carpal tunnel syndrome
  12. Eye complications
  13. Diagnosis
  14. Transplantation as a treatment for transthyretin amyloidosis
  15. Neuropathy, gastrointestinal disturbances and kidney failure
  16. The heart after transplantation
  17. Complications from the eye and central nervous system after transplantation
  18. What about genetic testing and counselling
  19. Conflict of interest statement
  20. References

The FAP is an autosomal dominantly inherited disease with a variable penetrance. Until the genetic mutation was identified, it was believed that homozygous carriers would not survive until birth. However, the identification of the mutant TTR made population studies possible, and this has had a profound impact on our knowledge of the disease. Several homozygous patients have been identified in Sweden, and their disease is not more severe or rapidly progressing than that of the heterozygous [23, 24]. Moreover, from population studies it is even obvious that asymptomatic homozygous individuals do exist. Similar results are reported from Japan [25]. Furthermore, areas with a high frequency of the trait in the population are not necessarily those with a high number of patients. In Lycksele, Sweden, the frequency of the trait in the population is approximately 10%, but only a few overt FAP cases are known, and the disease in that area is generally slowly progressing, with cases who have had the disease for more than 20 years still with only minor symptoms. In contrast, the largest concentration of symptomatic patients is in the Skellefteå area, where the frequency of the trait is 2.6%, and the onset and progress of the disease in that area – compared with Lycksele – is earlier and more rapid [26].

In Portugal, patients with the compound heterozygous variant TTR: ATTR Val30Met/119Met, have been identified. Their main characteristics are a slowly progressing disease with a late onset. It has been shown that the tetramer with the non-ATTR Thr119Met polymorphism is more stable than the wild-type TTR. Furthermore, the tetramer of ATTR Val30Met/Thr119Met is more stable than the ATTR Val30Met variant [27]. These findings support the suggestion that tetrameric instability is an amyloidogenic factor [7]. However, investigations of Swedish and Japanese late onset cases have failed to reveal individuals with this compound variant, but in Japan, the ATTR Arg104His appears to have similar properties [28, 29]. Pronounced variation between age at onset and progress rate of the different mutations has been noted but no genetic factor beside the TTR gene has been identified that influences penetrance, onset or the progress rate of the disease.

Lately, monozygous ATTR Val30Met twins has been identified in Sweden and Spain [30, 31]. Of the Swedish twins, one is severely ill and has undergone liver transplantation, whereas his brother shows no signs of amyloid disease 11 years after onset of his brother's disease. In the Spanish cases substantial variation of onset and type of symptoms was noted. Thus, other factors than the genetic trait appears to be decisive for the development of FAP.

In the endemic areas, a maternal anticipation of FAP has been described, with a marked earlier onset of the disease for carriers who inherited the trait from their mother [32–34]. However, the importance of this observation has been questioned, as the onset of the disease is unchanged in Sweden during the last decades, and, furthermore, no patient has got the disease before puberty [35].

Three Danish FAC families have been identified. In the most thoroughly described family – from Djursland, counting 125–130 members with one-fourth being carriers – the penetrance of the trait appears to be invariably high, almost 100% [2, 20, 21]. As in FAP, the inheritance of FAC is autosomal dominant.

Unfortunately, because of raised legal and ethical obstacles recently, no systematic registration and follow-up of the remaining two Danish FAC families has been possible. The families identified originate from three different rural areas of Denmark, and no connection between them apparently exists. This mutation has not been found in any other country, inside or outside Scandinavia; a remarkable feature in light of the for centuries high rate of immigration between the Scandinavian countries. However, it is even more remarkable than the more widespread ATTR Val30Met (Swedish) trait never has been found in Denmark or Norway.

Clinical symptoms of TTR amyloidosis

  1. Top of page
  2. Abstract
  3. Introduction
  4. Genetics
  5. Clinical symptoms of TTR amyloidosis
  6. Age of onset
  7. Somatic and autonomic polyneuropathy
  8. Heart complications
  9. Gastrointestinal disturbances
  10. Kidney complication
  11. Carpal tunnel syndrome
  12. Eye complications
  13. Diagnosis
  14. Transplantation as a treatment for transthyretin amyloidosis
  15. Neuropathy, gastrointestinal disturbances and kidney failure
  16. The heart after transplantation
  17. Complications from the eye and central nervous system after transplantation
  18. What about genetic testing and counselling
  19. Conflict of interest statement
  20. References

Transthyretin amyloidosis is a group of systemic disorders with a very variable clinical presentation. In several mutations, a restrictive cardiomyopathy is the predominant and earliest symptom, whereas in others, a peripheral and/or autonomic polyneuropathy is dominating [12]. CNS involvement is rare, although TTR is produced locally in the brain by the choroid plexus. Amyloid deposits are found in the meninges whereas CNS symptoms have been described in surprisingly few mutations such as the ATTR Asp18Gly, Ser64Phe and Val30Gly and lately in Sweden the Tyr69His mutation [36–38].

Endocrine dysfunction has been observed in FAP, but it appears to be of little clinical importance [39, 40].

Somatic and autonomic polyneuropathy

  1. Top of page
  2. Abstract
  3. Introduction
  4. Genetics
  5. Clinical symptoms of TTR amyloidosis
  6. Age of onset
  7. Somatic and autonomic polyneuropathy
  8. Heart complications
  9. Gastrointestinal disturbances
  10. Kidney complication
  11. Carpal tunnel syndrome
  12. Eye complications
  13. Diagnosis
  14. Transplantation as a treatment for transthyretin amyloidosis
  15. Neuropathy, gastrointestinal disturbances and kidney failure
  16. The heart after transplantation
  17. Complications from the eye and central nervous system after transplantation
  18. What about genetic testing and counselling
  19. Conflict of interest statement
  20. References

In FAP, peripheral polyneuropathy is the initial symptom in the majority of cases. The patients complain of disturbed temperature sensation, and often hyperalgesia, where even the pressure from the blanket at night can be painful. Walking is impaired as a result of motor polyneuropathy, and is often accompanied by a decreased deep sensation which explains why the patient acquires painless fracture and Charcot joint (Fig. 2) [1]. The polyneuropathy progresses relentlessly, and in the end stage of the disease the patients are bedridden or confined to a wheelchair unable to care for themselves. Histopathological examination of nerve biopsies demonstrates a destruction of the peripheral nerves by amyloid infiltration.

image

Figure 2. (A) Familial amyloidotic polyneuropathy patient with a Charcot joint and medial fracture of the right knee. (B) X-ray from the patient showing the joint and fracture.

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The autonomic nervous system is also affected [43]. Impotence and urinary retention are common findings in FAP. Spectral analysis of heart rate variability has demonstrated a profound reduction of autonomic activity in late stages of the disease [44]. The autonomic nervous system appears to be earlier and more severely involved in Japanese than in Swedish patients [45]. A pronounced ortostatic hypotension with fainting and even a reverse blood flow in the carotic artery has been observed in Japanese patients after tilting [46]. However, such reactions are less common in Swedish cases.

For the ATTR Tyr69His mutation only symptoms relating to the CNS has been found. In the Danish variant, FAC, neuropathy prior to cardiomyopathy has not been observed during the natural course of the disease.

Heart complications

  1. Top of page
  2. Abstract
  3. Introduction
  4. Genetics
  5. Clinical symptoms of TTR amyloidosis
  6. Age of onset
  7. Somatic and autonomic polyneuropathy
  8. Heart complications
  9. Gastrointestinal disturbances
  10. Kidney complication
  11. Carpal tunnel syndrome
  12. Eye complications
  13. Diagnosis
  14. Transplantation as a treatment for transthyretin amyloidosis
  15. Neuropathy, gastrointestinal disturbances and kidney failure
  16. The heart after transplantation
  17. Complications from the eye and central nervous system after transplantation
  18. What about genetic testing and counselling
  19. Conflict of interest statement
  20. References

The heart is affected in three of the four Scandinavian TTR mutations. In the Danish FAC, the patients develop a restrictive cardiomyopathy, with a diastolic dysfunction as the first sign of disease (Fig. 3) [21], but later on, a systolic dysfunction with heart failure supervenes. Ischaemic symptoms in the form of angina pectoris are often present because of amyloid deposits in the coronary arteries.

image

Figure 3. Early echocardiographic mitral valve velocity pattern in a asymptomatic carrier of the ATTR Leu111Met mutation: familial amyloidotic cardiomyopathy (FAC). A pattern of abnormal relaxation can be seen characterized by: a decreased A/E ratio and a prolonged isovolumetric relaxation time (>100 ms). Typical finding of a restrictive cardiomyopathy with diastolic dysfunction in FAC. (B) For comparison: schematic drawing of normal mitral flow velocity pattern showing a biphasic filling pattern with a greater early peak (E) and a smaller late peak (A) flow velocity. Deceleration time (DT) is the time interval required for the E velocity decline from peak to baseline. Isovolumetric relaxation time (IVRT) is the time interval from aortic valve closure (AVC) to onset of forward transmitral (OFTF).

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The ATTR Ala45Ser mutation found in Sweden is also characterized by cardiomyopathy, but it develops later in life, and the rate of progression appears to be slower than the Danish variant [22].

In FAP, disturbances of the conduction system are typical symptoms of heart involvement [47–49]. Sino-atrial and atrial-ventricular conduction abnormalities are noted, and the patients often develop Adam-Stokes attacks that require pacemaker treatment, symptoms that rarely are observed in FAC. Cardiac failure is very rarely observed in FAP, probably because the patients die from other complications of the disease.

Gastrointestinal disturbances

  1. Top of page
  2. Abstract
  3. Introduction
  4. Genetics
  5. Clinical symptoms of TTR amyloidosis
  6. Age of onset
  7. Somatic and autonomic polyneuropathy
  8. Heart complications
  9. Gastrointestinal disturbances
  10. Kidney complication
  11. Carpal tunnel syndrome
  12. Eye complications
  13. Diagnosis
  14. Transplantation as a treatment for transthyretin amyloidosis
  15. Neuropathy, gastrointestinal disturbances and kidney failure
  16. The heart after transplantation
  17. Complications from the eye and central nervous system after transplantation
  18. What about genetic testing and counselling
  19. Conflict of interest statement
  20. References

Gastrointestinal complications are invariably present during the course of FAP [1, 50], and they have a profound impact on survival for Swedish patients [51]. In some cases, gastrointestinal disturbances are present even before the onset of peripheral polyneuropathy [52]. The initial symptoms are constipation and/or nausea and vomiting. Later on, bouts of diarrhoea supervene, and subsequently the patient's diarrhoea becomes continuous, often with faecal incontinence [50, 52]. The patients develop malabsorption, severe malnutrition and opportunistic infections which often leads to the patients death [50, 51]. The gastrointestinal malfunction is probably the result of a impaired gastrointestinal motility, where gastric retention is a common finding [53]. However, examination of the enteric nervous system of the gut has failed to demonstrate any destruction of enteric nerves and ganglions [54], although the mucosal neuroendocrine cell content is decreased [55].

In a study comparing Japanese and Swedish cases, diarrhoea was the first gastrointestinal symptom in the majority of Japanese patients, whereas constipation and nausea/vomiting were more common in Swedish cases. A short time interval between onset of neuropathy and onset of gastrointestinal complications was correlated with a decreased survival for Swedish patients, whereas no such correlation was noted for Japanese [18]. Thus, substantial differences in phenotype exist between different populations with ATTR Val30Met amyloidosis.

Gastrointestinal disturbances are not recorded during the natural history of FAC patients.

Kidney complication

  1. Top of page
  2. Abstract
  3. Introduction
  4. Genetics
  5. Clinical symptoms of TTR amyloidosis
  6. Age of onset
  7. Somatic and autonomic polyneuropathy
  8. Heart complications
  9. Gastrointestinal disturbances
  10. Kidney complication
  11. Carpal tunnel syndrome
  12. Eye complications
  13. Diagnosis
  14. Transplantation as a treatment for transthyretin amyloidosis
  15. Neuropathy, gastrointestinal disturbances and kidney failure
  16. The heart after transplantation
  17. Complications from the eye and central nervous system after transplantation
  18. What about genetic testing and counselling
  19. Conflict of interest statement
  20. References

Amyloid deposits in the kidneys are commonly found in FAP [56], but not in FAC. FAP patients have a steadily decreasing kidney function [57]. The initial finding is proteinuria and subsequently the patients develop a nephrotic syndrome and kidney failure. The amyloid infiltration and denervation of the bladder, with ascending infections caused by urinary retention contributes probably to the development of kidney failure [58].

Diagnosis

  1. Top of page
  2. Abstract
  3. Introduction
  4. Genetics
  5. Clinical symptoms of TTR amyloidosis
  6. Age of onset
  7. Somatic and autonomic polyneuropathy
  8. Heart complications
  9. Gastrointestinal disturbances
  10. Kidney complication
  11. Carpal tunnel syndrome
  12. Eye complications
  13. Diagnosis
  14. Transplantation as a treatment for transthyretin amyloidosis
  15. Neuropathy, gastrointestinal disturbances and kidney failure
  16. The heart after transplantation
  17. Complications from the eye and central nervous system after transplantation
  18. What about genetic testing and counselling
  19. Conflict of interest statement
  20. References

The diagnosis of TTR amyloidosis rest on the finding of typical clinical symptoms, identification of amyloid deposits and detection of mutated TTR. However, the symptoms are variable for the different mutations, but the diagnosis should be suspected in patients with polyneuropathy or restrictive cardiomyopathy of unknown aetiologies, likewise in patients with symptoms suggestive of CADASIL but without the mutation. The patients should be examined for amyloid deposits either in the skin, rectal mucosa and/or in the subcutaneous fat [60]. Fine needle fat aspiration may also give the diagnosis [61]. Repeated biopsies may be required to settle the diagnosis. The biopsies have to be stained with Congo red and examinated under polarized light to disclose the typical apple green birefringence of amyloid deposits (Fig. 5).

image

Figure 5. Congo red staining of subcutaneous fat biopsies. The typical apple green birefringence of the amyloid deposits under examination in polarized light is clearly visualized.

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Biopsies from an effected organ may also be helpful, i.e. heart biopsy in conjunction with heart catherization in a patient with cardiomyopathy of unknown aetiology. Testing for mutated TTR can be performed by gene sequencing or, by PCR analysis if the mutation is known and DNA available [62]. TTR in plasma samples can also be analysed by mass spectrometry for alteration of the molecular weight signalling the presence of mutated TTR [63]. However, this method does not identify the mutation per se. All methods are available through the Amyloid team, Departments of Medicine and Clinical Genetics, Umeå University Hospital, Sweden.

Transplantation as a treatment for transthyretin amyloidosis

  1. Top of page
  2. Abstract
  3. Introduction
  4. Genetics
  5. Clinical symptoms of TTR amyloidosis
  6. Age of onset
  7. Somatic and autonomic polyneuropathy
  8. Heart complications
  9. Gastrointestinal disturbances
  10. Kidney complication
  11. Carpal tunnel syndrome
  12. Eye complications
  13. Diagnosis
  14. Transplantation as a treatment for transthyretin amyloidosis
  15. Neuropathy, gastrointestinal disturbances and kidney failure
  16. The heart after transplantation
  17. Complications from the eye and central nervous system after transplantation
  18. What about genetic testing and counselling
  19. Conflict of interest statement
  20. References

No effective treatment for TTR amyloidosis, apart from liver transplantation, has been reported. The rationale behind the procedure is that TTR is mainly produced by the liver. Small amounts are also produced locally in the brain and eye. CNS complications, however, have not been reported in FAP or FAC. The local production in the eye, does not cause severe problems, as the amyloid deposits are effectively removed and the patient's vision restored by vitrectomy.

Liver transplantation has now been performed since 1990, when the first Swedish FAP patient was transplanted with encouraging result [5, 64]. Since then, TTR amyloidosis has become an accepted indication for liver transplantation and is now carried out worldwide [3]. As FAP patients’ liver is normal and well functioning apart from its production of ATTR, it has been reused for other patients, the so-called sequential or domino procedure [65]. So far, no report of amyloid disease in a recipient of an FAP liver has been presented, and biopsies from recipients intestine has not shown amyloid deposits [66].

Neuropathy, gastrointestinal disturbances and kidney failure

  1. Top of page
  2. Abstract
  3. Introduction
  4. Genetics
  5. Clinical symptoms of TTR amyloidosis
  6. Age of onset
  7. Somatic and autonomic polyneuropathy
  8. Heart complications
  9. Gastrointestinal disturbances
  10. Kidney complication
  11. Carpal tunnel syndrome
  12. Eye complications
  13. Diagnosis
  14. Transplantation as a treatment for transthyretin amyloidosis
  15. Neuropathy, gastrointestinal disturbances and kidney failure
  16. The heart after transplantation
  17. Complications from the eye and central nervous system after transplantation
  18. What about genetic testing and counselling
  19. Conflict of interest statement
  20. References

It appears that the progression of FAP patients’ somatic and autonomic polyneuropathy is halted by liver transplantation [67–72]. However, improvement is not to be expected and deterioration has in fact been reported for some advanced cases [67, 69]. Quality of life after transplantation is also depending on an early transplantation before the patients develops severe neurological and/or gastrointestinal complications [73]. This emphasizes the recommendation that transplantation should be performed whilst the patient still is reasonably neurologically intact.

Although the patients’ nutritional status normally improves after transplantation [72], no improvement of gastrointestinal complications, such as malabsorption has been found [74]. The decreased number of neuroendocrine cells noted in intestinal biopsies before transplantation became normal after the procedure, but no correlation with improved gastrointestinal function was recorded [75]. An impaired nutritional status before transplantation forecast a decreased chance of survival, and at present such patients will mostly fail to qualify as candidates for transplantation [76].

Kidney function deteriorates in conjunction with the operation, but thereafter it appears to remains stable [77]. For patients with an early onset of kidney failure, who have an otherwise good nutritional status, combined liver and kidney transplantation has successfully been performed [72].

The heart after transplantation

  1. Top of page
  2. Abstract
  3. Introduction
  4. Genetics
  5. Clinical symptoms of TTR amyloidosis
  6. Age of onset
  7. Somatic and autonomic polyneuropathy
  8. Heart complications
  9. Gastrointestinal disturbances
  10. Kidney complication
  11. Carpal tunnel syndrome
  12. Eye complications
  13. Diagnosis
  14. Transplantation as a treatment for transthyretin amyloidosis
  15. Neuropathy, gastrointestinal disturbances and kidney failure
  16. The heart after transplantation
  17. Complications from the eye and central nervous system after transplantation
  18. What about genetic testing and counselling
  19. Conflict of interest statement
  20. References

One of the big question marks has been the outcome of heart complications. Differences exist between the various mutations and for several a continuous increasing cardiomyopathy have been observed [78, 79]. Regarding FAP, reports have been contradictory. In two studies, decreased or unchanged heart size was found, whereas a continuous increase was reported from Sweden [78–80]. In a Japanese study of cardiac TTR amyloid, 50% of the amyloid in nontransplanted patients’ hearts consisted of wild-type TTR. In contrast, the amyloid in a liver transplanted patient's heart with progressive cardiomyopathy after the transplantation consisted of 80% wild-type TTR [81]. Thus wild-type TTR can assemble into amyloid in the heart without the presence of mutated TTR. This is also the case in senile systemic amyloidosis [4].

It has been suggested that a liver transplant applied well before amyloid is deposited in the heart will prevent ensuing cardiomyopathy. However, with our present techniques – including percutaneous myocardial biopsies – it is not unlikely that small amyloid deposits scattered randomly in the myocardium will be missed. Furthermore, Swedish FAP patients with normal heart dimensions on echocardiography, and no signs of amyloid deposits nevertheless developed cardiomyopathy after transplantation [80].

Three transplantations have been performed for the Danish FAC. One patient underwent heart transplant only, and although the immediate result was encouraging, the patient succumbed 5 years later. Before death he suffered from recurrent cardiomyopathy, gastrointestinal disturbances (mainly oesophageal dysfunction) and symptoms consistent with an autonomic and peripheral polyneuropathy (severe ortostatic hypotension, peripheral pareses), the latter symptoms not normally associated with FAC. The first minute deposits of amyloid were detected in myocardial biopsies 2 years after transplantation. That unfortunate patient provided us with a new information: the natural history of FAC, not obscured by early death from cardiomyopathy. Thus FAC patients appear to develop neurological complications, but normally they die from cardiomyopathy before development of these complications. The next two patients underwent a combined heart and liver transplantation. One patient survived the transplantation and is currently in good health and employed full-time [82]. Yearly repeated myocardial biopsies show no signs of recurrent amyloid.

Reports have emerged regarding heart dysrhythmia after transplantation in FAP patients [83]. In the cited report and in our series, patients have developed dysrhythmia after transplantation, and pacemaker implant was required in several cases. This may be linked to a progressing post-transplant cardiomyopathy. No dysrhythmia after heart/liver transplantation has been observed in FAC.

Complications from the eye and central nervous system after transplantation

  1. Top of page
  2. Abstract
  3. Introduction
  4. Genetics
  5. Clinical symptoms of TTR amyloidosis
  6. Age of onset
  7. Somatic and autonomic polyneuropathy
  8. Heart complications
  9. Gastrointestinal disturbances
  10. Kidney complication
  11. Carpal tunnel syndrome
  12. Eye complications
  13. Diagnosis
  14. Transplantation as a treatment for transthyretin amyloidosis
  15. Neuropathy, gastrointestinal disturbances and kidney failure
  16. The heart after transplantation
  17. Complications from the eye and central nervous system after transplantation
  18. What about genetic testing and counselling
  19. Conflict of interest statement
  20. References

As TTR is synthesized locally in the eye, amyloid deposits in the corpus vitrium may occur after transplantation, and several cases have also been reported [84, 85]. For the CNS, a few reports concerning central nervous complications after transplantation has emerged, but not for any of the mutations found in Scandinavia [78].

What about genetic testing and counselling

  1. Top of page
  2. Abstract
  3. Introduction
  4. Genetics
  5. Clinical symptoms of TTR amyloidosis
  6. Age of onset
  7. Somatic and autonomic polyneuropathy
  8. Heart complications
  9. Gastrointestinal disturbances
  10. Kidney complication
  11. Carpal tunnel syndrome
  12. Eye complications
  13. Diagnosis
  14. Transplantation as a treatment for transthyretin amyloidosis
  15. Neuropathy, gastrointestinal disturbances and kidney failure
  16. The heart after transplantation
  17. Complications from the eye and central nervous system after transplantation
  18. What about genetic testing and counselling
  19. Conflict of interest statement
  20. References

One of the crucial questions today, with the increasing identification of the genetic abnormalities responsible for hereditary diseases, is whether asymptomatic individuals should undergo gene testing for hereditary diseases present in the family history. Such a test may have consequences not only for the tested individual, but also for his/hers relatives, as the detection of a genetic trait for a severe disease will have a profound impact on all family members.

Considering FAP, an early diagnosis appears to be important for an acceptable result of liver transplantation. The questions tied to offer genetic testing to members of affected families have therefore expectedly been raised. Before decision of testing the penetrance of the genetic trait, the prospects of available treatment and/or preventive strategies should be taken into consideration. For Swedish FAP, the genetic trait is common in the endemic areas, but the penetrance is low, and even in families with several generations of affected individuals, carriers of the trait may not develop the disease [26, 32]. Furthermore, we can at present offer neither efficient medical treatment nor acceptable preventive strategies. Genetic diagnosis without histopathological confirmation may lead to liver transplantation of patients with other, unrelated forms of polyneuropathy. For the time being, in affected families we recommend positive biopsy before genetic testing.

From Portugal nerve damage has been demonstrated in asymptomatic individuals years and in some instances even decades before they developed clinical symptoms [86]. A characteristic feature of the biopsies was accumulation of TTR, and it has been suggested that this pre-amyloid material may be toxic. As these patients were asymptomatic we, for symptomatic patients, require the presence of amyloid deposits before considering liver transplantation.

However, for the Danish FAC families the problem of genetic testing is different. It may in some ways also be easier to accept genetic testing of asymptomatic members of FAC families, as the Danish ATTR Leu111Met trait shows a much higher penetrance, apparently 100% [20, 21]. Unfortunately, the only treatment of overt cardiac amyloidosis is a combined liver and heart transplantation, a considerable surgical procedure carrying a substantial risk. At present, we cannot know with certainty whether an early liver transplantation, before cardiac amyloid deposits have developed in the carrier, will prevent the otherwise inevitable and fatal cardiomyopathy. As mentioned above, the possibility of a continued build-up of amyloid fibrils from wild-type (normal) TTR in the myocardium cannot be excluded.

The actual knowledge presents an ethical problem to consider: is it acceptable to advise an asymptomatic individual to undergo a liver transplantation in order to prevent or hopefully to prevent later development of cardiomyopathy? Should a (myocardial) biopsy with small amyloid deposits present be required – following the practice in Swedish FAP? Should a liver transplantation not be performed before patterns of early diastolic relaxation appears in an echocardiogram (Fig. 3)? Could it be considered ethical to perform a liver transplantation in a TTR-Met111 carrier with a normal echocardiogram and no trace of amyloid in a myocardial biopsy? Unfortunately, in Denmark ethically motivated legal restrictions have so far prevented the necessary continued search for and investigations of the remaining carriers of the FAC trait. It seems that the time has come to reconsider the currently operating restrictions, or at least inform members of affected families of their major health problem and its possible solutions.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Genetics
  5. Clinical symptoms of TTR amyloidosis
  6. Age of onset
  7. Somatic and autonomic polyneuropathy
  8. Heart complications
  9. Gastrointestinal disturbances
  10. Kidney complication
  11. Carpal tunnel syndrome
  12. Eye complications
  13. Diagnosis
  14. Transplantation as a treatment for transthyretin amyloidosis
  15. Neuropathy, gastrointestinal disturbances and kidney failure
  16. The heart after transplantation
  17. Complications from the eye and central nervous system after transplantation
  18. What about genetic testing and counselling
  19. Conflict of interest statement
  20. References
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