Amyloidosis

Amyloidosis is the term for a group of rare diseases in which abnormal proteins deposit as amyloid in tissues and organs.

Amyloid is produced when abnormal proteins in the body “misfold” and collect together in various tissues and organs. As the amyloid builds up, it starts to cause organ damage and impair quality of life.

Thanks to research, we are learning more about the different types of amyloidosis, developing new treatments for them and raising awareness to help everyone affected by it.

The differents types of Amyloidosis

AA amyloidosis

In AA amyloidosis a protein called serumamyloid A serum (SAA) is produced in excessive quantities by the liver. This AAS protein circulates in over-large quantities in the blood. It folds badly and forms amyloid fibrils which are deposited in the different organs.

The most affected organs are the kidneys, the digestive tract (stomach and intestines), the liver and the salivary glands.

SAA protein is a protein of inflammation so that any situation causing chronic inflammation can bring about an excessive production of SAA. The most frequent situations are chronic infections (particularly lung infections), chronic inflammatory rheumatism (rheumatoid arthritis, spondyloarthritis), chronic inflammatory diseases of the intestine (Crohn’s disease, ulcerative colitis), auto-inflammatory diseases of genetic origin, like familial Mediterranean fever and rarer causes such as certain tumours.

The symptoms encountered during AA amyloidosis are often vague and not very specific at first.

When there is advanced kidney failure, patients can suffer from oedema of the ankles, frothy urine and intense fatigue. When the digestive tract is affected diarrhoea may occur.

The most serious complication of AA amyloidosis is terminal kidney failure which may require renal dialysis.

INFLAMMATORY DISEASES ASSOCIATED WITH AA AMYLOIDOSIS

Chronic infections

  • Bacterial infections :
    Tubercolosis, Leprosy, Syphilis, Osteomyelitis, Bronchiectasis, cystic, fibrosis, Frequent urinary infections, Xanthogranulomatous pyelonephritis, Endocarditis, Whipple’s disease, Chronic skin, infections, Infection of a prosthesis, Agammaglobulinemia, Hypogammaglobulinemia
  • Infections due to parasites or fungus
  • Viral infections :
    HIV : humain immunodeficiency virus

Chronic inflammatory diseases

  • Joint diseases (rheumatic) :
    Rheumatoid arthritis, Chronic juvenile arthritis, Ankylosing spondylitis, Psoriatic arthritis, SAPHO syndrome (synovitis, acne, pustulosis, hyperostosis, osteitis, Polyarticular gout
  • Inflammatory diseases of the digestive tract :
    Crohn’s disease, Ulcerative colitis
  • Genetic auto-inflammatory diseases :
    Familial Mediterranean fever, TRAPS, Cryopyrin related diseases, Mevalonate kinase deficiency
  • Rare inflammatory diseases :
    Castleman’s disease, Still’s disease, Schnitzler syndrome, Dermatoses: psoriasis, epidermolysis, Sarcoidosis
  • Auto-immune diseases :
    Systemic lupus erythematosus, Mixed connective tissue disease, Polymyositis
  • Vasculitis :
    Takayasu’s disease, Horton’s disease, Behçet’s disease, Other rare vasculitis

Tumours

  • Malignant tumours :
    Kidney cancer, Horton’s disease, Hodgkin’s disease, Waldenström’s disease

Obesity

The symptoms of AA amyloidosis may be mistaken for those of more frequent diseases affecting the kidneys, heart, lungs or liver and thus delay the diagnosis of amyloidosis. Indeed, patients often see several doctors before they are diagnosed.

The only way to obtain with certainty a diagnosis of amyloidosis is by carrying out a biopsy.

Once amyloidosis has been found in an organ, it is necessary to find out which kind of amyloidosis it is, using further techniques. In the case of AA amyloidosis, it is necessary in the biopsy to look for deposits of protein SAA, which also needs to be measured in the blood to see if there is too large a quantity in the bloodstream. Another inflammation protein is also measured, reactive protein C.

It is also useful to look at former levels of CRP to see whether they have been high for a long time. Generally, in AA amyloidosis, there has been inflammation for several years before the formation of amyloidosis finally occurs.

The purpose of the treatment is to decrease the surplus in the bloodstream of the misfolded protein SAA.

To prevent the amyloidosis from worsening, it is necessary to stop the production of protein SAA by the liver. This means that the inflammation must be stopped and therefore the disease causing the inflammation has to be cured. To do so, specific treatments are available for the different inflammatory diseases: in the case of familial Mediterranean fever for example patients are given lifelong colchicine treatment.

Other treatments vary according to the disease and may include antibiotics (in case of infectious diseases), corticoids or biotherapies.

So far, no effective treatment has been found to get rid of the amyloid fibrils already formed in the AA amyloidosis.

Finally, a kidney can sometimes be transplanted in case of terminal kidney failure on patients who are otherwise in good health.

Preventive treatment is very important, especially when the patients have had a genetic auto-inflammatory disease since their childhood. Treatment against inflammation is prescribed for the whole of their lives to ensure that they do not develop amyloidosis. Every year, they are required to undergo blood and urine tests to see whether amyloidosis is present.

In cases of confirmed AA amyloidosis, the patient must be closely monitored by the doctor who is following his or her inflammatory disease, the general practitioner and a specialist in AA amyloidosis.

AL (or immunoglobulin related) amyloidosis is a rare disease linked to deposits in the different organs of a part (the light chain) of an abnormal antibody known as monoclonal in the form of fibrils. Fibrils are insoluble and are deposed in the organs and prevent them from functioning properly.

These deposits can affect all the organs except the brain and consequently the symptoms differ greatly depending on which organ is affected.

It is estimated that there are 500 to 700 new cases in France every year. The average age for diagnosis is about 65.

Unlike other forms of amyloidosis, AL amyloidosis is not a hereditary disease but an acquired one.

Plasma cells and B cells produce antibodies, or immunoglobulins, the tools which defend the body. They are made of two heavy chains and two light chains.

Sometimes a plasma cell or a B cell can become immortal, multiply and form clones. All the plasma cells and B cells thus produced therefore secrete the same antibody which is said to be monoclonal. Most of the time this is of no consequence but, in about one case out of a hundred, the light chains – sub-parts of the monoclonal antibodies – can build up one on top of the other to form the fibrils which constitute the deposits of amyloidosis.

By studying the bone marrow, various blood diseases can be diagnosed according to the nature and number of cells. In 90% of causes, the cells are those which in their normal state produce antibodies to defend against infections i.e plasma cells. When there are only a small number in the bone marrow, less than 10%, we speak of simple monoclonal immunoglobulin. When they represent more than 10% of the cells, we speak of myeloma.

Simple monoclonal immunoglobulin is a relatively frequent phenomenon and it becomes increasingly frequent with age, affecting 5% of people around 60 years old, with up to 10% in people over 80.

Myeloma is a much less frequent blood cancer but when it is combined with amyloidosis it does not usually develop much. This is known as indolent myeloma.

They are multiple and depend on the organs that are affected.

The most frequently affected organ is the kidney, concerning two thirds of patients. The kidney is a filter responsible for eliminating toxins produced by the body and present in the blood. Deposits of amyloidosis damage the filter and allow proteins which do not usually get into the urine, to be evacuated, mainly albumin. Loss of albumin in urine lowers the amount in the blood causing oedema in the legs or more wide spread. After a while, the kidney functions less and less efficiently and kidney failure occurs making it necessary sometimes to put the patient on dialysis.

The most serious cases are those where the heart is affected, concerning 60% of patients. The deposits of amyloidosis thicken the heart muscle and make it less supple. The consequence is a so-called “restrictive” heart condition because the heart is unable to fill up and the cardiac outputis slower causing fatigue and breathlessness, firstly with effort then even when the patient is resting.

The other consequence of cardiac deposits is disturbances to electric circulation in the heart with the appearance of abnormal heartbeat, either too fast or too slow, or cardiac arrest. This can require a pacemaker, a battery placed under the skin to control the heartbeat.

About 20% of patients have a neurological condition which is manifested by abnormal sensations in the feet then legs, thighs and hands. Affected nerves can also cause digestive problems and a decrease in blood pressure when moving from a lying to a standing position, causing dizziness and possibly falls.

The digestive tract may also be affected with diarrhoea or constipation or bleeding. The tongue can also be the seat of amyloid deposits which make it thicker and modify the taste of food.

The presence of amyloidosis in the small blood vessels of the skin can cause bleeding particularly in areas which move like the eyelids which can have bruises which contribute to the diagnosis of amyloidosis.

All these forms of AL amyloidosis are said to be systemic, meaning that they affect different organs by the depositing of light chains. There are also forms of localised amyloidosis in which a small population of cells produces a monoclonal light chain and deposits it around them without any dissemination. These forms are rarer and generally less serious and are usually located in just one place: conjunctiva of the eye, the larynx and bronchial tubes, the bladder, digestive tract etc.

Diagnosis requires a biopsy.

Amyloidosis is recognised in biopsies thanks to Congo Red staining. Then typing is carried out to differentiate AL amyloidosis from another form, particularly a hereditary one.

Once the amyloidosis diagnosis has been made it is necessary to determine which blood disease is responsible for the production of monoclonal antibodies and this requires puncturing the marrow at the level of the sternum (myelogram) and other biological examinations.

Then a detailed check-up has to be carried out on the organs affected by amyloidosis, particularly the heart with an ultrasound scan and if necessary an cardiac MRI scan, a dosing of blood markers for heart condition, BNP or NT-proBNP and troponin, an electrocardiogram and sometimes the recording of the heartbeat for 24 hours (Holter-ECG).

Other examinations will be made to assess the functioning of the kidneys and liver, dosing of creatinine, albumin, proteinuria, liver enzymes. Imagery can also be used, like an ultrasound scan of the abdomen or a scanner.

Treatment aims first to eliminate the cells which produce monoclonal antibodies by chemotherapy protocols most often derivatives of those of myeloma. The most frequently used ones are MDex and VCD.

MDex is a combination of two medicines: Melphalan (also called Alkeran) and dexamethasone which is a powerful corticosteroid.

VCD combines bortezomib therapy (or Velcade), cyclophosphamide (Endoxan) and dexamethasone. Bortezomib can also be added to MDex if the response is insufficient.

The effectiveness of the treatment is monitored on the dosage of free light chains determined by a blood test. To enable the amyloidosis to get better the light chains have to be reduced as much as possible. The test used to measure the free light chains should be carried out in a hospital if possible as the cost cannot be reimbursed and is charged to the patient if it is done in a private laboratory.

When a good response is obtained with a sufficient decrease in the number of free light chains, the damage will decrease more or less rapidly depending on which organs are affected and will vary from one patient to another.

In patients who do not respond (insufficient decrease of the free light chains) or in case of a relapse, other molecules may be used, particularly those in the category of IMIDs. The most commonly used one is lenalidomide (or Revlimid) generally combined with a dose of dexamethasone each week.

Among several new treatments which are being tested in AL amyloidosis, the most promising is a monoclonal antibody, Daratumumab. Daratumumab is produced in a laboratory to recognize and eliminate plasma cells, which produce light chains. It is currently tested in a protocol in France in patients with insufficient response after treatment.

Finally, several treatments to eliminate amylose deposits more quickly are under development. Several therapeutic trials using antibodies directly or indirectly recognizing amyloid deposits and likely to recruit immunity cells to remove amyloid deposits have been conducted or are in progress. NEOD001 was the most advanced but 2 trials that included more than 300 patients failed to demonstrate efficacy in heart disease and the product was removed by the laboratory that developed it. Two other antibodies are being tested in England and the United States.

Follow-up care is fundamental for AL amyloidosis patients.

  • During the treatment the patient has to be monitored to make sure it is effective with the dosage of free light chains in the blood (or monoclonal antibodies if the light chains are not numerous at the time of diagnosis) for each cycle of treatment and the different biological tests to ensure that it is well tolerated.
  • Check-ups after the treatment every two or three months to detect any relapse involving an increase in the free light chains which could be cause for a new course of treatment.
  • Finally, regular check-ups during and after the treatment of different markers to seek an improvement in the organs affected by amyloidosis.

The prognosis of AL amyloidosis is very dependent on the type and seriousness of the damage to the organ, particularly the heart and has improved greatly in the past fifteen years with the introduction of new molecules (bortezomib, lenalidomide etc….) which ensure a haematological response (i.e on free light chains) in more than 80% of patients.

If patients with the most serious heart conditions can unfortunately still die in a few weeks, the survival rate of other patients is very good with most often a gradual improvement of the affected organs if the treatment began before irreversible damage was caused by amyloidosis.

AL amyloidosis

Cardiac amyloidosis

We talk of cardiac amyloidosis when the heart can no longer function correctly because amyloid fibrils have accumulated inside it. This cardiac infiltration gradually alters the structure and function of the myocardium. Several proteins can be responsible and give their name to the disease (e.g. Type AL cardiac amyloidosis). We cannot a priori speak of a “single” cardiac amyloidosis as there are several diseases which can lead to the production of fibrillar proteins

Which diseases are responsible for cardiac amyloidosis?

Depending on which protein is involved, the other organs that are affected and the means of transmission (hereditary or otherwise), we may distinguish different types of amyloidosis that can be at the origin of cardiac amyloidosis.

Type Protein concernedOrgans concernedCause
Acquired AmyloidosisAL amyloidosisLight chain of immuno-globulin (antibodies)heart, kidneys, liver, nervessurplus production of immunoglobulin
 Senile amyloidosisTransthyretinheart, carpal tunnel, ears, lumbar canalageing
 AA Amyloidosis Serum Amyloid ASerum Amyloid Ararely the heart, kidney, liver, nervesInflammatory disease
Hereditary amyloidosisHereditary Transthyretin Amyloidosismutated transthyretinheart, nerves carpal tunnel, eye, kidneymutation of the transtheretin gene
 Other mutated proteinsfibrinogen, ApoAI ApoAII, gelsolinvariable depending on gene mutation of the diseasethe protein concerned Lyzozyme

The main types of amyloidosis affecting the heart are AL amyloidosis, senile amyloidosis and certain hereditary forms of amyloidosis including transthyretin amyloidosis.

Consequently, cardiac amyloidosis can be isolated or integrated into a disease affecting several other organs and therefore associated with numerous symptoms.

The clinical manifestations of the disease are due to two distinct forms of damage to the heart by the amyloid deposit: damage to the heart muscle and a disorder of the rhythm and cardiac conduction.

Deposits in the heart muscle

These deposits are responsible for a thickening of the heart known as “myocardial hypertrophy”. The consequence is that it becomes very rigid, limiting its capacity to fill up. Later it becomes difficult for the heart to contract. This lowers the cardiac output giving rise to various symptoms that go by the name of “heart failure”:

Breathlessness during effort, then while resting (talking or lying down)

  • Tiredness in case of effort, then during resting
  • Water retention/ oedema particularly in the legs, weight increase.
  • Palpitations
  • Deposits in the electric circuit

They disrupt the heart rate, making it either too rapid or too slow and can even lead to cardiac arrest. This disorder can require the fitting of a pacemaker under the skin to control the heartbeats or a defibrillator. The symptoms can include:

  • Feeling faint
  • Syncope
  • Palpitations

Cardiac amyloidosis is looked for in two types of situation:

  • When faced with symptoms like those we have just described. Certain tests are then able to show up heart disorders that indicate cardiac amyloidosis. Thickening of the heart, or myocardial hypertrophy, is highlighted by trans-thoracic echocardiography and an cardiac MRI. A heartbeat disorder is shown up by a standard electrocardiogram (ECG – recording the electric signals of the heart) and an extended one, also called a Holter-Electrocardiogram (Holter ECG). When the disorders have been highlighted, the presence of amyloid deposits must be proved by a biopsy. The heart is then the first or only organ to be affected by amyloidosis.
  • In a patient already affected by a known amyloidosis when he or she develops telling symptoms or during an annual heart check-up. Once again echocardiography, cardiac MRI, ECG and Holter ECG are used.

The definitive diagnosis is based on evidence of a deposit on the biopsy sample. In a case where heart damage appears during the development of an already-known amyloidosis, it is not always necessary to carry out a new biopsy.

Amyloidosis is recognised on biopsies thanks to Congo Red staining. Typing is then carried out to differentiate the various kinds of amyloidosis.

 Deposits of transthyretin amyloidosis (senile amyloidosis or hereditary TTR amyloidosis) can be revealed by a nuclear imagery examination called a DPD/HMDP scintigraphy. Their identification does not always mean that the biopsy will be waived.

Once amyloidosis has been diagnosed, it is necessary to carry out a detailed check-up of the affected organs, which will vary according to their type.

The treatment offered depends on the type of amyloidosis and the associated symptoms.  Medical care will include two major types of treatment: those which aim to alleviate the symptoms and prevent complications and those which aim to stop the formation of amyloid fibrils. 

Treatment for alleviating the symptoms

Symptomatic treatments are not specific for amyloidosis. The symptoms of heart failure are treated by diuretics (such as FUROSEMIDE) and a salt-free diet. Heart rhythm disorders, linked to electrical defects can be treated or prevented by a pacemaker. Incidentally, some medication may worsen the symptoms and have to be stopped: for example, beta-blockers (medication which slow down the heart beat) or vasodilators (medication which dilates the blood vessels). Finally, in some cases when the heart becomes very rigid and can no longer contract, the blood stagnates and forms clots which can block arteries far from the heart causing a stroke or pulmonary embolism. To prevent these kinds of complication, the physician may prescribe anti-coagulant treatment to thin the blood.

Anti-amyloid treatments

On the other hand, treatments to stop the formation of amyloid fibrils are adapted to the type of amyloidosis.

Monitoring is fundamental in the care of a patient with amyloidosis. Its purpose is to follow the progression of the heart condition, to ensure the effectiveness and absence of toxicity of the medication prescribed and to detect as early as possible any damage to other organs. This involves regular detailed clinical examinations, examinations using imagery (ultrasound scan, MRI) and biological tests (dosage of free light chains in the blood, cardiac markers: BNP, NT-proBNP); markers for kidney damage: proteinuria, micro-albuminuria, urinary test strips).

The frequency of the consultations is variable: once or twice a year in the case of a stable pathology, more frequent in case of problems with the control of the disease or therapeutic modifications which need to be revalued. The prognosis of cardiac amyloidosis depends largely on the type of amyloidosis concerned and which other organs are affected. In any case, cardiac amyloidosis is a serious disease. Nevertheless, when it is detected and treated in time, its progression can be stopped for a considerable length of time. In some cases, a gradual improvement in the heart condition is even possible if the treatment began before any irreversible damage was caused by amyloid deposits.

Hereditary (also called familial) transthyretin amyloidosis is a rare disease due to an anomaly (mutation) of part of your DNA (gene). This gene produces a protein, transthyretin or TTR. TTR amyloidosis mainly affects the nerves (neuropathy), the heart, but also, more rarely, the eyes and the kidneys.

More than 500 cases have been diagnosed in France, in most of the departments in metropolitan France and in the overseas territories. This disease concerns adults (from 20 to 88 years old). The age when the disease begins is very variable: around 30 in northern Portugal (where many families are affected) or later (around 60 on average) for non-Portuguese patients.

This is a potentially very serious, debilitating disease if the subject does not receive specialized treatment and care.

The presence of a mutation on the coding gene for the synthesis of transthyretin is nearly always responsible. Nearly all the transthyretin is synthesized by the liver.

The TTR protein in its normal state usually serves to transport substances in the blood: the thyroid hormone (thyroxine) and the binding protein of retinol. It circulates in the form of a molecule called tetramer with four identical components. When the gene mutates, the protein produced undergoes a modification. Its four components are dislocated and deposited in the form of a toxic amyloid substance in the tissues and organs, thus altering their functions.

Manifestations linked to a neuropathy (affection of the peripheral nervous system)

These revealing manifestations are very varied, which explains largely why diagnosis is delayed. They indicate a malfunctioning of the peripheral sensory, motor and vegetative nerves.

This can be:

  • A loss of sensitivity in the feet, predominantly on sensibility to temperature and pain; spontaneous and intense pain (like “burning”) or unpleasant sensations (paresthesia) non-perceived or non-healing wound or sore.
  • Weakness in the feet or more rarely the hands making walking or precise gestures difficult. Walking difficulties or loss of balance in older patients.
  • Vegetative disorders may also occur by lesions in the nerves which command the digestive, genital, cardiovascular and urinary systems with respectively: nausea, slow digestion, loss of appetite or more rarely vomiting, constipation, diarrhoea, or alternation between diarrhoea and constipation, erection disorders, dizziness, fainting just after getting up, difficulties in urinating….

As the disease evolves, the sensitivity disorders spread gradually to the knees and then to the hands: the weakness in the limbs is accentuated and the vegetative disorders get worse.

  • Weight loss: involuntary weight loss of more than 5kgs over six months is also usual; it can be inaugural.

Manifestations related to heart disease

A heart condition is very frequent particularly when the disease starts late in life and depending on the type of mutation undergone by the gene responsible for the disease. These manifestations are silent for many years, hence the importance of regular heart check-ups.

These can be:

  • Conductive disorders: a risk of extreme slowing down of the heart beat or even cardiac arrest which may require the implantation of a pacemaker. This proves necessary in nearly one third of cases during the evolution of the disease.
  • Cardiac infiltration by the deposits of amyloidosis leading to increased thickness and rigidity of the heart, breathlessness in case of effort (heart failure).
  • An attack oh the nerves of the cardiovascular system (low blood pressure, juste efter getting up, loss of normal variations of the heartbeat, anomalies on the MIBG scintigraphy.

When the heart starts to be affected by amyloidosis, the patient is not always aware of the problem, so detection of the heart condition is indispensable and requires a thorough initial check-up. Early detection is extremely important because it conditions a rapid treatment as soon as the anomalies have been shown up.

Manifestations concerning the eyes

There are several types of eye condition which depend on where the amyloid deposits are situated in the eye and vary considerably from one patient to another.

  • Deposits in the vitreous body occur in 20 to 30% of cases during the disease. They are manifested most often by the perception of “floating bodies” or “flying flies”. If the deposits are dense, they can cause sight impairment.
  • Glaucoma is secondary to amyloid deposits in the evacuation mechanism of the aqueous humour. This obstacle to resorption of the aqueous humour is accompanied by gradual increased pressure inside the eye which cannot be felt by the patient. However, it causes irreversible damage to the optic nerve causing disorders of the visual field. Without adapted treatment, glaucoma leads to permanent sight loss. Glaucoma concerns about 20% of the patients affected with amyloidosis.
  • Dryness of the eye is very frequent in the case of amyloidosis patients. This is manifested by a stinging feeling or foreign body sensation. This is due to a malfunctioning of the tear glands infiltrated by amyloidosis.

For all these reasons, it is indispensable for the patient to have a systematic eye test followed by regular check-ups of the vitreous disorders (visual acuity and eye fundus), glaucoma (ocular tension and if there is the slightest doubt the visual field and an analysis of the fibres in the optic nerve by OCT) and dryness of the eye.

Less common manifestations

Kidneys condition (proteinuria, kidney failure) or in exceptional cases damage to the meninges with headaches and confusion. 

The diagnosis of amyloid neuropathy can be difficult and is often delayed, bearing in mind that the disorders are irreversible. It is easier among patients of Portuguese origin where there is a quasi- constant medical history, providing there is genetic screening and regular follow-up care. It is more difficult in all the other patients for whom there is no family history of the disease in over half the cases. Delay in diagnosis can vary from 3 to 6 years as a cause of neuropathy other than amyloidosis is initially suspected as causing the patient’s health problems.

Diagnosis relies currently on three elements:

  • Information collected during medical consultations with a neurologist trained for this rare disease. All this information can be put together thanks to questioning to detect neurological manifestations, by a neurological clinical examination to look for certain particularly distinctive signs or by data from an electromyogram.

Other elements will bring arguments in the cardiological field thanks to an electrocardiogram and a cardiac ultrasound scan.

A similar family history found in one of the parents is not a reliable indication as it is to be found in fewer than 50% of patients of non-Portuguese origin.

  • A genetic test – after a simple blood test- indispensable for asserting the presence of a mutation of the transthyretin gene responsible for amyloidosis. The blood sample is sent to the molecular biology laboratory of Kremlin Bicêtre university hospital.
  • A biopsy to demonstrate the presence of abnormal deposits of amyloid substances.

From what moment is a patient detected as carrying a mutated transthyretin gene actually considered to be ill?

This subject is of major importance for several reasons.

Indeed, the disorders caused by the disease are usually irreversible and the earlier anti-amyloid treatments are administered, the more effective they are. However, the disease takes hold insidiously, making it difficult to put a precise date to it and we know that most carriers of the mutated transthyretin gene will develop the disease one day.

To identify this moment, there consequently needs to be a concerted effort on the part of patients carrying the mutation, specialised doctors trained for this disease and certain complementary examinations if necessary to confirm the presence of amyloidosis, hence the importance for carriers of mutations to take stock of the situation regularly by means of an annual check-up. If all the conditions together lead to the assertion that the disease has started, then an anti-amyloid treatment is initiated by the specialised medical doctor.

We still see the children of patients who had an amyloid neuropathy twenty years ago arriving in specialised consultation units. They even arrive at a very advanced stage of the disease whereas they were diagnosed as being positive during genetic tests performed several years before.

Familial transmission and genetic counseling

Screening in families with amyloid neuropathy is fundamental in the detection and monitoring carriers of genetic mutation likely to develop the disease later in life.

The genetic anomaly responsible for amyloidosis is transmitted in the family from parents to children. Each child has a one-in-two risk of receiving the abnormal gene from the parent who is affected (autosomal, dominant transmission) and therefore of developing the disease later in life. The disease will develop in a large majority of people with the genetic anomaly as the risk increases with age.

The treatment of a patient suffering from hereditary amyloid neuropathy requires specialist care from a pluri-disciplinary team composed of a minimum of a neurologist, a cardiologist, an ophthalmologist and a geneticist.

The treatment includes anti-amyloid treatment if possible, treatment of the manifestations of the disease, medico-social care and genetic advice for the detection and care for carriers of a mutation of the TTR gene.

Anti- amyloid treatments

Their purpose is to prevent the formation of new deposits of amyloidosis by stabilising Transthyretin and blocking its production. The treatments available so far are only able to slow down the progression and even to stop it but not to get rid of the symptoms already present.

  1. a) Liver transplant

The purpose of a liver transplant is to remove the main organ producing abnormal TTR protein even if the liver is functioning perfectly well otherwise. A liver transplant is a complicated operation that needs to be performed in a specialized centre.

This treatment has been offered to over 2000 patients worldwide. It has been effective in stopping the progression of the disease in a large majority of cases (70%) treated in their early stages. It is not advised for patients who developed the disease late in life or for carriers of a certain type of mutation. It cannot be performed on patients over 70 years old.

In spite of the transplant, the disease sometimes continues to develop in the nervous system and the heart. This deterioration can be explained by an accumulation of non-mutated (wild) TTR after a liver transplant in subjects over 50.

  1. b) “Anti-amyloid” medication

Tafamidis ® (Vindaqel ®) is the only medication currently authorized by the French authorities. It is a stabilizer of mutated transthyretin which slows down the progression of the disease. It is a tablet which is taken daily. It is well tolerated and must be prescribed by a neurologist who is familiar with the disease. Other medicines are currently being developed and tested for patients who are not candidates fot a liver transplant. They aim at inhibiting the production of both the mutated transthyretin protein and normal TTR protein by blocking its production by the cells of the liver.

  1. c) Medication repressing the expression of the TTR gene

Medication has been developed to control and reduce the expression of the Transthyretin gene. These molecules are administered by repeated intravenous or subcutaneous injections. They block most of the mutated and wild transthyretin by the cells of the liver. Two important international studies are being carried out currently to test the effectiveness of these medicines on the progression of the neuropathy.

Treatment of the manifestations of the disease

It is very important to correct the manifestations of the disease to ensure everyday comfort and improve the patients’ quality of life.

Neurological manifestations

Nervous (neuropathic) pain is treated by specific painkillers. Recently, local treatments have been developed using a patch to be applied to painful areas. Special precautions need to be taken to protect insensitive legs and feet from burns and wounds.

For vegetative disorders, there exist corrective treatments, mainly in the form of diets and medication.

For motor disorders, physiotherapy is indispensable.

Cardiac manifestations

It may be necessary to implant a pacemaker to protect the patient from sudden cardiac arrest.

Ophtalmological manifestations

When it is responsible for impaired vision, vitreous damage may be treated by a surgical ablation of the vitreous body (vitrectomy) which will remove the amyloid deposits and recover the patient’s sight. It is most often combined with ablation of the lens. Glaucoma is treated with eye drops which lower ocular tension. When the latter are ineffective, it is possible to use laser treatment or glaucoma surgery (trabeculectomy) to lower ocular tension. Dryness of the eye is treated with drops which replace tears (lachrymal substitutes).

Hereditary transthyretin amyloidosis is a chronic disease. Regular monitoring of the disease by a multi-disciplinary team including a neurologist, a cardiologist and a hepatologist in case of a liver transplant, as well as other specialists depending on each case, is indispensable. It is necessary for the patient to have a neurological check-up every six to twelve months to monitor the evolution of the neuropathy. Depending on the associated vegetative disorders, other specialists may also be consulted (gastroenterologist, urologist). A heart check-up including at least one clinical examination, an ECG, a cardiac ultrasound scan, a dosing of BNP and troponin and possibly a 24-hour ECG recording in outpatients is carried out every year and, if necessary, a check on the functioning of the pacemaker every six months. The check-up may be completed at varying intervals according to the gravity of the heart condition and its evolution. In case of a liver transplant, a close watch will be kept by the transplant physicians Concerning the reference centre (NNERF), sessions with a psychologist are organised both at CHB Paul Brousse and in the Neurology Department, if necessary completed by social assistance, ergo-therapy or physiotherapy.

How does familial amyloid neuropathy develop?

Without treatment the disease evolves inexorably towards the worsening of sensory and motor deficiencies, vegetative disorders and often a heart condition, which all cause disabilities. Death occurs within approximately ten years. A liver transplant can halt the disease, especially if it is carried out early in the development of the disorders. It has doubled the survival rate among subjects affected with Met30 mutation and younger people (under 50) at an early stage. Available “anti-amyloid” medication has slowed down the progression of the disease; we do not yet have any information concerning their impact on the survival rate.

Hereditary Transthyretin amyloidosis

Localised amyloidosis

Most forms of amyloidosis are characterised by damage to several tissues and organs and are known as systematic or, better, multi-systematic forms. Nonetheless, some forms of amyloidosis affect only one organ. 

They are nearly always cases of AL (or immunoglobulin related) amyloidosis. The amyloidosis deposit formed of light chains of antibodies is made in contact with a proliferation of plasma cells located in a specific organ. No light chain of immunoglobin enters the blood stream and consequently the deposits are not constituted in other organs.

The symptoms of these kinds of amyloidosis are directly linked to the affected organs 

  • Dysphonia with a gradual modification of the voice, coughing, breathlessness in the case of the upper airways (trachea, bronchial tubes).
  • Presence of blood in the urine, urination disorders, lower abdominal pain in the case of urinary amyloidosis.

These are very rare diseases and their diagnosis is hardly ever evoked by physicians who think first of a more common disease, particularly the presence of a tumour. 

As with all forms of amyloidosis, their diagnosis is based on a biopsy of the affected organs. Therefore, it is a specialist in pathological anatomy who discovers in the biopsies that there is no tumor but rather amyloid deposits. These deposits are rarely characterised precisely in immunohistochemistry, a technique which can determine what kind of amyloidosis is present. It is essential to be able to assert the local nature of the lesions and to be sure that there is no amyloidosis in the other organs. This question can best be answered by a clinical examination and simple additional tests.

Treatment is discussed on a case-by-case basis according to the effect of the amyloidosis on the functions of the affected organ. Surgery may be prescribed to remove some of the deposits. For certain lesions radiotherapy may be used. Systemic medication is rarely prescribed. In certain forms of amyloidosis of the bladder, local medical treatment can be used.

Evolution is very variable and requires local monitoring by a specialist for the organ which has been affected, for example an otolaryngologist in the case of amyloidosis of the larynx, and general check-ups to ensure that the amyloidosis remains localised.

In hereditary amyloidosis, the abnormally (misfolded) protein which accumulates in the body is caused by genetic mutation. The most frequent hereditary amyloidosis is secondary to mutations in the gene the protein transthyretin which mainly attacks peripheral nerves and the heart.

Beside transthyretin amyloidosis, there are several other forms of hereditary amyloidosis caused by the mutation of other proteins. These are the rarest forms of multisystemic amyloidosis, i.e. those which affect several organs.

The proteins involved in these forms are: the alpha chain of fibrinogen, several proteins belonging to the family of apolipoproteins: A1, A2, A4, C2, C3 lysozyme, gelsolin (see table).

Classification of hereditary forms of amyloidosis

Amyloid proteinPrecusorName of Amyloidosis
ATTRMutated TransthyretinFamilial amyloidosis
AApoAlApolipoprotein AIApolipoprotein AI amyloidosis
AApoAllApolipoprotein AIIApolipoprotein AII amyloidosis
AApoAlVApolipoprotein AIVApolipoprotein AIV amyloidosis
A β)2Mβ 2-Microglobinβ 2-Microglobin amyloidosis
AGelGelsolinGelsolin amyloidosis
AfibFibrinogen α chainFibrinogen α chain amyloidosis
AlysLysozymeLysozyme amyloidosis
ALect2Leucocyte chemotactic factor 2ALect2 Amyloidosis
AcysCystatin CCystatin C amyloidosis
AkerKerato-epithelinFamilial corneal dystrophy
AlacLactoferrinLactoferrin corneal amyloidosis

Rare forms of hereditary amyloidosis chiefly affect the kidneys. As with other diseases affecting the kidneys, there are no symptoms for a long time. The patient is therefore unaware of his or her condition whereas amyloidosis gradually builds up in the kidneys. The delayed clinical symptoms are swollen ankles, rise in blood pressure and the usual symptoms caused by kidney failure when it is serious (tiredness, pallor, breathlessness, itching).

These forms are very rare and have no specific clinical characteristics. What is peculiar is the hereditary character of the disease, with the presence of other cases of amyloidosis in the family, in a patient’s ascendants, siblings or children. This distribution is linked to the means of genetic transmission of the disease which is “dominant”. In the presence of several cases of amyloidosis in a family, we should think firstly of transthyretin amyloidosis but also of these rarer forms of the disease.

However, other cases of amyloidosis in the family are not always recognized and, in some cases, the patient may be the only subject affected. We think of these genetic forms after excluding more frequent forms.

As we have seen, the disease is often evoked in the presence of a biological anomaly reflecting a kidney condition: the presence of excess protein in the urine and an increase in blood creatinine which defines kidney failure.

Apart from the kidney which is the main target organ, all the other organs can potentially be affected too, depending on the nature of the abnormal protein.

As is the case for all forms of amyloidosis, the diagnosis requires a tissue sample or biopsy taken from an easily accessible tissue like accessory salivary glands or the digestive tract. Indeed, deposits are frequent there whereas no symptoms are present.

However, occasionally, there is no suspicion of amyloidosis because in this case we are faced with the rarest forms of a rare disease. In such cases, it is usually a renal biopsy which is performed, the only way of knowing what is in the kidney.

Then the presence of amyloidosis needs to be confirmed with the Congo Red staining. A more thorough examination of these deposits with specific antibodies (a test only available in a few specialized laboratories) can help the diagnosis when it shows that the deposits are not recognized by the antibodies which react with the most frequently found proteins but are recognised by antibodies which react with the proteins in question in these rare forms.

It is necessary to carry out a survey of the family’s medical history to detect these asymptomatic cases and enable an affected subject to receive genetic counselling is she wishes to have children.

In French law, screening must take place during a genetic consultation, after a prior discussion with a psychologist. It concerns only adults (over eighteen years old). Firstly, the screening will concern the patient’s siblings (brothers and sisters) and any children over eighteen.

The result of the genetic analysis can only be issued after a period of several weeks and several preliminary sessions with the psychologist to prepare the patient for the announcement of the results.

If the result of the genetic test proves negative, the patient has no risk of ever developing the disease, nor will s/he transmit it to children and descendants. If the result is positive, s/he is likely to develop the disease and transmit it to his or her children. In this case a medical check-up is recommended to look for initial signs of the disease (kidney condition).

The treatment consists of two parts.

The first one is the treatment of the kidney condition. When the kidneys no longer function, the patients can be put on dialysis. In most cases, a kidney transplant is possible, but the disease can then affect the transplanted kidney.

But the real purpose of the treatment is to stop the production of the mutated protein which is causing the disease. This can be envisaged when the protein is produced by the liver, as is the case for transthyretin. A liver transplant can then be proposed. Therefore, this treatment can be envisaged in cases of amyloidosis by mutation of the fibrinogen alpha chain. On the other hand, it cannot be carried out in forms linked to the lysozyme, because this protein is produced by numerous tissues.

The evolution of these diseases is very variable, notably concerning affected kidneys the functioning of which can worsen slowly or, on the contrary, rapidly. In all cases the kidney disease needs to be monitored.

Rare hereditary amyloidosis

The journey of a patient from the first symptoms to the implementation of treatment through the diagnosis, can sometimes look like an obstacle course.
This path can be very different depending on where you live, as clinical trials and knowledge of the disease are not the same everywhere.
Discover two testimonials below, one from a patient in France and the other from a patient in Mexico, as examples of two very different trajectories.

A PATIENT IN FRANCE

It’s a story that will take your breath away, literally more than figuratively. It is a story about the breath of life that leaves you little by little without you knowing why. A story whose origin is unknown but whose end is known. A fruitless quest that leads you, with heavy legs and shortness of breath, from specialist to specialist, to all the “-ologists” in the repertoire, three, four years of medical wandering… until chance places you on the path of Professor D, the one who knows the invisible enemy that has slyly begun the invasion of your body, stiffened your heart and is attempting an incursion into your kidneys, your stomach or your liver… The enemy advances in disguise and in order to flush him out for sure, you must submit to a long series of tests and examinations, more or less unpleasant, more or less painful. 

A PATIENT IN MEXICO

To be born and to live in Venezuela has been a real honour, son of Eulogio R. D. and Justina O. L. I am 49 years old and the fourth of 6 siblings. I was born in 1972 on the 21st of May. According to my siblings and my mother I was always a bit sickly, to the point that I once had peritonitis and it was serious. In retrospect I always remember my dad being very skinny and sick, but he used to say that people have to die of something. As several years passed his health condition worsened and he visited several doctors, vitamins, x-rays, hospitalisation, fluid retention, loss of vision, recurrent falls, weakness, diarrhoea, kidney failure and death in January 1992. Cause of death: Chronic Kidney Failure. On several occasions my mother and sister were told by doctors; You should watch your children because this can be hereditary, that kidney failure, so for any discomfort associated with the kidneys there was never a shortage of a concoction or medication to relieve the colic.

Useful links

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To be constantly up to date with the information we give you, we have chosen to direct you to the official international site which records it.

The site www.clinicaltrials.gov establishes an exhaustive report on the studies in progress:

https://clinicaltrials.gov/ct2/results?cond=Amyloidosis

Clinical trials can be initiated in one or more investigating centers and in one or more countries.

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https://www.amyloidosisalliance.org/