AL amyloidosis

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Classification according to ICD-10
E85 Amyloidosis
ICD-10 online (WHO version 2019)
Affected patient with periorbital amyloid purpura, which occurs in approx. 15% of cases.

In the AL amyloidosis (also light chain amyloidosis ) is a special form of hematological disease amyloidosis , wherein the lower mold described here is the most common occurrence of the systemic amyloidosis and interchangeably as a primary amyloidosis is referred to. It is distinguished from the light chain storage disease (light-chain deposition disease). The acronym AL stands for " A myloid consisting of L eichtketten ". These light chains, which in its free form of a malignant plasma cell - clone are formed are the cause of the disease. However, free light chains are also found in low concentrations as natural protein in the serum of healthy patients. AL amyloidosis can be referred to as plasma cell dyscrasia , lymphoplasmocytic disease or monoclonal gammopathy . In most cases, AL amyloidosis occurs in isolation, but is also associated with multiple myeloma and other monoclonal gammopathies in 10–15% of cases .

distribution

AL amyloidosis is one of the so-called rare diseases . No exact data are known for the German-speaking area, as there is no corresponding register for this disease. However, it can be assumed that the incidence is around 5–13 people per 1,000,000 inhabitants per year, as has already been described for the North American population and in Great Britain. Men are affected somewhat more frequently than women, although the likelihood of an illness increases with age, similar to monoclonal gammopathy of unclear significance (MGUS). The median age at diagnosis is 63–64 years.

root cause

Production of intact immunoglobulins and free light chains by plasma cells.

The cause of the disease are monoclonal free light chains (of the lambda (λ) or kappa (κ) type) or their fragments, which are produced and excreted by a form of malignant B cells (the so-called monoclonal plasma cells). These tend to aggregate due to misfolding . These aggregates form fibrils in AL amyloidosis , which can usually be deposited extracellularly in almost all organs . As a result, their function is increasingly impaired, which leads to the typical appearance of the disease (see section Clinical Appearance ). The amino acid sequence and the three-dimensional structure of the light chains can be impaired or even shortened in affected patients. As a result, a β-sheet may be formed in the three-dimensional structure rather than the usual α-helix . This structural abnormality favors aggregation and is of diagnostic importance in the detection of misfolded free light chains using Congo red (see section Examination methods ).

Regarding the formation of fibrils in detail, the process of aggregation proves to be highly complex, wherein the intracellular protein - homeostasis (proteostasis), extracellular chaperones , as well as matrix components, metal ions , shear , limited proteolysis and cell interactions may play a role . In the majority of affected patients (80%) a monoclonal free light chain of type λ is the cause of the disease. A translocation of chromosomes 11 and 14 (t (11; 14)) can be detected cytogenetically in> 50% of all patients . Other known genetic aberrations are the translocation t (4; 14), gain 1q21 and deletion 17p13.

Disease emergence

As already described in the previous section, cytogenetic changes are known and are considered to be the initiators of the development of the disease. It has also been shown that the production of monoclonal free light chains occurs many years before the subsequent deposition occurs and patients present to the doctor with symptoms. This makes it difficult to differentiate between malignant and non-malignant diseases and can no longer be reconciled with the classic view of the significance of monoclonal gammopathies. As soon as a monoclonal gammopathy of unclear significance has been diagnosed, in which there is an increased concentration of a free light chain, regular, close examination of the affected patients is recommended, as the risk of developing AL amyloidosis is increased. "Screening" using cardiac and renal biomarkers serves as the diagnostic tool of choice (see also the section on prevention and early detection ).

Clinical manifestations

Similar to other monoclonal gammopathies, the symptoms of AL amyloidosis perceived by the patient are typical but also very unspecific. Many patients complain of tiredness and weakness as well as bone pain. Even edema , a paresthesia and weight loss can be observed in affected patients at the time of initial presentation may. Such a clinical appearance can serve to initiate further investigations. The deposits in organs typical of AL amyloidosis - especially in the kidneys and in the heart - as well as a polyneuropathy as the cause of the paresthesia can be confirmed or refuted here. Deposits in the kidney and / or heart can be e.g. B. in a nephrotic syndrome or a non- ischemic cardiomyopathy with hypertrophy in the echocardiography . If there is impairment of kidney function, AL amyloidosis can also be counted as part of the group of monoclonal gammopathies of renal significance . In addition to the key symptoms mentioned above , hepatomegaly or increased levels of alkaline phosphatase without morphological abnormalities as well as proteinuria can be present, which is often incorrectly assigned to the multiple myeloma with cast nephropathy .

forecast

According to a Swedish study, the median survival of affected patients is around 3 years. Up to 30% of all patients even die within the first year of diagnosis. If left untreated, around 80% of patients will die within the first two years of diagnosis, in most cases due to cardiac dysfunction. The earlier the diagnosis is made, the better the prognosis for affected patients.

When diagnosing and initiating therapy before advanced cardiomyopathy has developed, a hematological response and a response at the organ level is possible, which is also reflected in the longer survival of the patient. * With modern therapeutic agents, the disease can often be well controlled if therapy is initiated in good time.

Investigation methods

A comprehensive diagnostic work-up should be carried out in consideration of the severity of the disease in the event of an urgent suspicion. Due to the unspecific symptoms, which are often present in older patients, an expression of suspicion may therefore come up late. Similar to other monoclonal gammopathies, the diagnosis includes a number of different laboratory parameters, imaging methods and histological examinations in addition to the basic anamnesis with physical examination. Recommendations can be found in publications by various national and international research societies. For example, all patients who are already diagnosed with monoclonal gammopathy of unclear significance are advised of the potential presence of AL amyloidosis. The currently recognized diagnostic spectrum is made up as follows:

Laboratory parameters

Central laboratory parameters for the detection of monoclonal free light chains in suspected AL amyloidosis are:

With negative serum and urine immunofixation electrophoresis and normal rFLC, AL amyloidosis is unlikely and further investigations are only recommended if there is urgent suspicion.

Kidney biopsy with renal amyloid deposits.
Heart muscle biopsy - Congo red staining for amyloid in cardiac amyloidosis.

Other possible examinations are:

Imaging diagnostics

  • Projection radiography or more sensitive, albeit more radiation-intensive, low-dose CT for diagnosing osteolyses and assessing stability
  • CT of the chest
  • Spirometry for suspected pulmonary amyloidosis
  • MRI if soft tissue manifestations are suspected
  • Transthoracic echocardiography , EKG
  • If necessary, a cardiac MRI and a 24-hour ECG (for arrhythmias and limited heart rate variability)
  • Sonography of the abdomen (determination of liver and spleen size, residual urine measurement)
  • Neurological / electrophysiological examination

Cytological / histological examinations

In addition to the Congo red staining of a tissue biopsy, samples from the past 1–2 years can often be used for subsequent staining if such samples are already available. A biopsy is an integral part of a clear diagnosis. In the case of a positive result (polarization-optical birefringence in green or red-yellowish color), the amyloid must be typed (immunohistologically or, if necessary, by means of mass spectrometry ) in order to confirm the underlying amyloidosis, since the Congo red color is not specific for AL amyloidosis.

therapy

The most effective therapy option consists of a combination of autologous stem cell transplantation (if the general condition of the patient allows this procedure) and simultaneous chemotherapy, comparable to that which is also used for multiple myeloma. The administration of melphalan and dexamethasone has been shown to be effective for patients who are not suitable for an autologous stem cell transplant. In contrast, a combination of dexamethasone and bortezomib was found to be particularly suitable for a certain group of other patients. Therapy decisions, including the most suitable combination of therapeutic agents, must always be made by the treating doctor individually for each patient.

Prevention and early detection

Due to the complexity of the development of the disease and the lack of understanding about it, no generally applicable measures for the prevention of the disease are known. Certain environmental factors such as obesity , pesticides , radiation , autoimmune diseases and frequent inflammation and infections are considered risk factors for the monoclonal gammopathy of unclear significance that precedes AL amyloidosis. In MGUS patients, a strongly abnormal quotient of free light chains (kappa / lambda <0.01 or> 100) was identified as a risk factor for progression to AL amyloidosis (as well as multiple myeloma).

An early diagnosis of the disease or of the non-malignant precursor MGUS is crucial for the course of the disease and the patient's condition. A late diagnosis of the disease, which is often due to the often misinterpreted symptoms, is the reason for the high proportion of those affected (approx. 25%) with an advanced stage of the disease. The formation of the first fibrils favors the formation of further deposits, which is why immediate therapy is necessary is to prevent further negative consequences. The more the production of pathogenic free light chains can be prevented, the more positive the general condition of the patient to be expected. Even low concentrations of pathogenic free light chains can still be sufficient for the formation of further deposits. Amyloid glasses are considered to be resistant to degradation, but seem to be gradually reabsorbed by the body if the therapy response is good.

Since the cardiac consequences of AL amyloidosis are particularly serious and mean a short life expectancy for those affected, the experts of the Amyloidosis Research Consortium generally recommend that all patients with heart failure (with concentric hypertrophy or NYHA I-II or with both findings) are present increased free light chains are investigated. In the presence of MGUS with an abnormal quotient of the free light chains, experts recommend a "screening" of these patients for the biomarkers NT-proBNP (presymptomatically abnormal in cardiological complications) and albumin (presymptomatically abnormal in renal complications). A serious course of the disease can thereby be prevented under certain circumstances and thus a better quality of life can be achieved.

It has been shown that patients in risk groups (age, MGUS findings are already available, heart failure, etc.) benefit from regular examinations, since a malignant disease can be detected early and appropriate measures can be taken.

Web links

Individual evidence

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