Amyloidosis

from Wikipedia, the free encyclopedia
Classification according to ICD-10
E85 Amyloidosis
ICD-10 online (WHO version 2019)

The amyloidosis (from ancient Greek ἄμυλον AMYLON "power flour, starch") is a variable disease with accumulation of (partly abnormally altered) proteins usually extracellularly in the interstitium (intercellular space). These insoluble deposits are in the form of small fibers called fibrils (β-fibrils) and are known as amyloid . Amyloid is detected by microscopic examination of tissue samples that have previously been stained with Congo red. The amyloid deposits appear bright red in the bright field , in polarized light they show an apple-green birefringence .

The deposition of corpora amylacea in the prostate is considered to be the only non-pathological form of amyloid deposition in the body. Amyloidosis itself is not a single disease, but a pathological deposition process (through the aforementioned fribrillary protein deposits) that is triggered by various metabolic defects and - depending on the organ affected - can lead to various chronic diseases.

Amyloid means something like “starch-like”, because the deposits often turn blue when iodine is added , similar to the iodine-starch reaction . Rudolf Virchow first used the term in 1854 when he found atypical material in the livers of the deceased.

The incidence of systemic amyloidosis ( amyloidosis affecting the whole body as a multi-system disease) is about 1 case per 100,000 population per year. It mainly affects older patients around 65 years of age. The systemic disease is often fatal even with intensive treatment ( cytostatics , glucocorticoids ); only sometimes - depending on the biochemical cause - a treatment of the cause is possible.

The main forms of amyloidosis today are light chain amyloidosis (AL) and transthyretin-related ATTR amyloidosis.

In untreated AA amyloidosis (a type of amyloidosis in which the insoluble fibrils are amyloid A, whose precursor protein is an acute phase protein), the median survival time is 3 to 4 years. Healing is possible if the cause was an infection. Of all systemic forms of amyloidosis, AL amyloidosis is the most common.

Amyloid in the connective tissue layer (lamina propria) of the duodenum. Staining with Congo red . The amyloid deposits appear as bright red, structureless material in the connective tissue and around the blood vessels.
Amyloidosis - lymph nodes in polarized light

Cause and origin

Amyloidosis is based on a disorder in the folding of a normally soluble protein . Several different diseases can trigger the disease through overproduction, missing / reduced breakdown or impaired excretion of certain proteins. These proteins are usually present in dissolved form in the blood plasma . If their concentration increases, however, they also get into the surrounding tissue, where enzymes attack them. The agglomeration of the amino acid chains in the area of ​​the β-sheet structures causes insoluble complexes to form in the form of microscopic fibers ( fibrils ).

Since the fibrils are resistant to the defense mechanisms ( phagocytosis and proteolysis ), they can no longer be removed. According to more recent findings, however, the amyloid deposits can at least be reduced by removing the precursor proteins.

The amyloid deposits destroy the architecture of the organs and thereby lead to functional disorders. There is evidence that the deposits also have a direct toxic effect on cells.

diagnosis

The symptoms of amyloidosis are often non-specific, especially in the early stages of the disease. For this reason, the diagnosis is often only made at an advanced stage of the disease. Amyloidosis should be considered if proteinuria is not otherwise explained , and also in patients with cardiomyopathy , neuropathy , liver enlargement or in the presence of multiple myeloma .

Since, unless a scintigraphic proof of cardiac ATTR amyloidosis (transthyretin amyoloidosis) has been made if monoclonal gammopathy has been excluded, the exact composition of the amyloid must be known for the treatment, a biopsy (tissue sample) for histological amyloid detection with subtyping is usually required . This can be obtained from an infected organ (kidney, heart, stomach). A new discovery is that generalized amyloidoses can also be classified with biopsies from the subcutaneous fat tissue, a procedure that is less stressful for the patient. The small salivary glands , the gums , the rectum or the skin are other, less stressful extraction points . The histologically prepared samples are stained with Congo red and examined immunohistochemically . Amyloid binds the dye Congo red and then becomes visible with a greenish glow under polarized light . The electron microscope shows that the amyloid deposits consist of fibrils , irregularly arranged, thread-like structures of different lengths with a diameter between 8 and 15  nm .

If amyloidosis has been confirmed by tissue removal, a light chain disease should be searched for by bone marrow puncture , blood and urine tests . In the bone marrow there is a monoclonal increase in plasma cells , i.e. H. of plasma cells that produce either only kappa or only lambda chains for AL amyloidosis . The light chains can also be detected in serum or urine by immunoelectrophoresis .

The extent of amyloid deposits can be visualized by scintigraphy with radioactively labeled substances that bind to amyloid. Technetium Tc 99m pyrophosphate, technetium-labeled aprotinin and I-labeled serum amyloid P components bind to amyloid. The extent to which the heart is involved can be made visible by echocardiography or magnetic resonance imaging .

In many cases, the diagnosis is made by autopsy after death . An oversized tongue and characteristic, tough subcutaneous swellings point the pathologist to the correct diagnosis. Because of the bacon-like appearance of the cut surfaces of affected organs, they are also referred to as bacon liver , bacon spleen or bacon kidney . Just like Virchow, he can sprinkle the cut surface of any organ (including the tongue, heart) with Lugol's solution , which with amyloid gives it a characteristic brown color.

Classification

In the past, amyloidoses were classified as follows:

Type frequency Details
Primary amyloidosis Rare no association with other underlying diseases
cause unknown
mostly deposits of the so-called AL type (see below)
Familial amyloidosis Rare occurs frequently in combination with inherited diseases
e.g. B. familial Mediterranean fever
mostly deposits of the AA type
v. a. Kidney affected
Secondary amyloidosis most frequently Occurring exclusively with other underlying diseases
z. B. chronic infectious and non-infectious inflammation, tumors of the lymphatic system, prolonged dialysis
deposits of various amyloid subtypes
Age amyloidosis frequently
Deposits occurring in old age without an underlying disease a. AS amyloid
mainly affects the heart and brain

To date, ten different proteins have been detected in amyloid deposits (year of detection in brackets):

The amyloidoses are classified according to the protein involved, which can be differentiated immunohistochemically . The first A stands for "amyloid protein"; the second letter indicates the type of protein involved.

AA amyloidosis

This form is caused by serum amyloid A , a so-called acute phase protein . An increased formation of amyloid A occurs in familial Mediterranean fever, which is inherited as an autosomal recessive trait . Chronic infections (such as tuberculosis , leprosy or osteomyelitis ) and chronic non-infectious inflammations (e.g. ulcerative colitis , Crohn's disease , psoriasis , ankylosing spondylitis , collagenoses , rheumatoid arthritis ), as well as tumors (e.g. Hodgkin's disease , carcinomas ) also cause ) sometimes this effect emerges. The symptoms of AA amyloidosis are usually generalized in the body. The kidneys, spleen, liver, adrenal glands and always the gastrointestinal tract are particularly affected .

AL amyloidosis

The AL amyloidosis ( A myloid consisting of L eichtketten) is the most common systemic amyloidosis. It is a disease of the plasma cells , i.e. those cells in the bone marrow that are responsible for the production of antibodies (immunoglobulins) in healthy people . An antibody consists of two heavy and two light chains. During the immunoglobulin synthesis in the plasma cells, the light chains are always formed in excess, so that in addition to the intact antibodies, free light chains also get into the blood. In AL amyloidosis, there is a pathological increase in plasma cells, and thereby the formation of monoclonal free light chains or their fragments. These structurally altered light chains are deposited as amyloid. Lambda light chains are found about three times more frequently in the deposits than kappa light chains . Often the same proteins as so-called Bence Jones proteins can also be detected in the urine. A tumor of the lymphatic tissue ( lymphoma ) is usually responsible for the overproduction . It is very common in multiple myeloma (up to 15%) and Waldenström's disease . AL amyloidosis corresponds to the earlier "primary amyloidosis". It usually occurs locally in individual organs. The heart and kidneys are most commonly affected , but any other organ except the brain can be affected.

AE amyloidosis

Here protein hormones from endocrine ( inwardly excreting ) glands are affected; z. B. insulin or calcitonin . They come from hormone-producing tumors, such as certain tumors of the pancreas or the thyroid gland . Symptoms are localized and often affect the nerves, heart, kidneys, glands, lungs, or skin.

AB amyloidosis

It is derived from the B eta-2 microglobulin from, a protein that is under long-term dialysis accumulates. AB amyloidosis typically leads to carpal tunnel syndrome, as well as painful deposits in joints.

AP amyloidosis

Deposits of prealbumin (→ transthyretin ), the main localization is in the nerve and heart tissue.

AS amyloidosis

Various proteins that cause senile amyloidosis are brought together here. In many cases, the triggering proteins have not yet been characterized. A common occurrence is associated with Alzheimer's disease .

ATTR amyloidosis

Transthyretin (TTR) is a serum protein that is reduced in inflammatory conditions and is therefore referred to as an anti- acute phase protein . Transthyretin can be detected in old age amyloidosis. In addition, genetically modified variants of transthyretin can lead to hereditary amyloidoses with an autosomal dominant inheritance (hereditary ATTR amyloidosis, ATTRv amyloidosis). So far, more than 80 mutations are known. The deposits occur in the eyes, kidneys and heart and rarely in the central nervous system.

Apo A1 amyloidosis

Also autosomal dominant inheritance, which, however, can already be noticeable in the patient's early years. Frequently affected organs are the kidneys, the heart, the gastrointestinal tract, as well as polyneuropathies and autonomic neuropathies. There is no therapeutic option for this form of amyloidosis.

Symptoms

heart

The deposits of protein fibrils around the muscle fibers of the myocardium cause the heart muscles to stiffen ( restrictive cardiomyopathy ). This leads to cardiac insufficiency via a rapid deterioration in the heart's pumping capacity (heart failure, including heart failure if the pumping capacity is maintained ). Due to the deposits, the heart walls are thickened with normal or reduced size of the heart chambers . The heart failure can be associated with dyspnoea , peripheral edema , anasarca , pleural effusion , pericardial effusion , and hypotension . Often the level of the QRS complexes is reduced in the ECG ( low voltage ). If the conduction system of the heart is affected, cardiac arrhythmias can result. If the coronary arteries are affected, circulatory disorders can arise. In plasma cell dyscrasia, there is an unexplained increase in cardiac biomarkers .

kidney

The pathological proteins can accumulate around incoming and outgoing vessels ( vascularly accentuated amyloidosis ) or around the capillary vessels of the kidney corpuscle ( glomerular accentuated amyloidosis ). In most cases, the result is a greatly increased protein excretion (with edema, foaming urine up to nephrotic syndrome ) and a progressive loss of kidney function . In the case of vascularly accentuated amyloidosis (around 10% of cases), there can also be a loss of kidney function without an increased protein excretion in the urine being detectable. If dialysis treatment is required due to amyloidosis , the mean life expectancy for AL amyloidosis is 26 months; for AA amyloidosis, the prognosis is significantly better. The heart's involvement is decisive for the prognosis .

Digestive tract

The consequences of amyloidosis in the digestive tract can include macroglossia (enlargement of the tongue, hallmark of AL amyloidosis), difficulty swallowing ( dysphagia ), loss of appetite, fatigue and insufficient intake of food components ( malabsorption ) with weight loss, disorders in the mobility of the intestine with nausea, Bloating, meteorism, diarrhea , constipation, gastrointestinal bleeding, perforations, and intestinal obstruction. The liver is often enlarged (unexplained hepatomegaly ) and, as a result of increased liver stiffness, is rock-hard when palpated . In addition, ascites can develop . The blood test usually reveals a significant increase in alkaline phosphatase with only a moderate increase in transaminases .

Brain and nerves

Functional disorders of all kinds up to dementia can develop in the brain (see Alzheimer's disease ). The peripheral nerves often have very painful sensory or movement disorders. An attack on the autonomic nervous system leads to (orthostatic) dysregulation, a drop in blood pressure when standing ( orthostatic reaction ), a premature feeling of satiety as a result of reduced gastric emptying, erectile dysfunction , bladder emptying disorders and disorders of the bowel movement (intestinal motility disorders) with flatulence, abdominal pain and irregular stool. Symptoms of involvement of the peripheral and autonomic nervous system can show up as a variable picture of a (rapidly progressive) polyneuropathy. Lumbar spinal stenosis can also be a form of manifestation.

Soft tissue, eye

Soft tissue involvement manifests itself in carpal tunnel syndrome , biceps tendon rupture, nodes in the area of skin diseases of the joints ( arthropathy with joint swelling), muscle weakness, hair loss ( alopecia ), changes in the range of finger and toe nails ( nail dystrophy ), enlargement of the submandibular gland , dry eyes , reddened Dark circles or peri- orbital skin hemorrhages (purpura due to coagulation disorders), vitreous opacity, glaucoma, retinal angiopathy and hoarseness .

Endocrine system

In rare cases, AL amyloidosis can lead to disorders of the endocrine system as a result of amyloid deposits , which show up as hypothyroidism or adrenal glands in the hormone-producing glands .

lung

The formation of exudate can lead to a pleural effusion .

spleen

Also, splenomegaly (enlargement of spleen) may be of the systemic amyloidosis symptom.

therapy

General measures

Special therapy

AA amyloidosis

  • In patients with familial Mediterranean fever, lifelong use of colchicine can prevent the development of amyloidosis.
  • Experimental therapies are the administration of the TNF blocker etanercept and 1,3-propanedisulfonate , which is supposed to prevent fibril formation and dissolve fibril deposits.
  • Eprodisate is a negatively charged, low molecular weight sulfonated molecule that has structural similarities to heparan sulfate . Eprodisate inhibits the interaction between amyloid-forming proteins and glycosaminoglycans . In the mouse model, eprodisate inhibits the deposition of AA amyloid. In a randomized, double-blind, placebo-controlled study, eprodisate slowed the deterioration of kidney function in patients with AA amyloidosis.

AL amyloidosis

The aim of treatment is to reduce the production of abnormal light chains by inhibiting the multiplication of plasma cells .

  • The most effective treatment is high-dose chemotherapy with melphalan followed by the transfer of one's own blood stem cells ( autologous stem cell transplantation ). The mortality rate among treatment is 15-40%, the risk is increased in advanced cardiac involvement, decreased kidney function, involving more than two organs, severe hypotension and poor general health. Previous conventional chemotherapy with melphalan reduces the number of available stem cells; this should be taken into account when planning therapy.
  • The transfer of foreign bone marrow cells (allogeneic bone marrow transplantation ) is an experimental treatment and has so far only been carried out in a few cases. The mortality rate is 40%.
  • Conventional chemotherapy consists of oral administration of low-dose melphalan and prednisone for one week at intervals of 6 weeks. The effect on survival is moderate; the median patients survive on this therapy for about 18 months. Conventional chemotherapy reduces the number of stem cells in the bone marrow and thus reduces the chances of success of a later stem cell transplant. Therefore, before starting conventional chemotherapy, it should always be checked whether the patient is eligible for a stem cell transplant.
  • If the treatment does not respond or if it relapses, treatment with thalidomide in combination with dexamethasone can be attempted . Thalidomide, which has achieved notoriety under the trade name Contergan, may only be taken by women of childbearing age if special safety measures are observed because of the risk of fetal damage.
  • Experimental therapies are the administration of the proteasome inhibitor bortezomib and the thalidomide analogue lenalidomide . In animal experiments, 4-iodo-4-deoxy- doxorubicin binds to amyloid fibrils and is able to dissolve them, but studies on humans have so far been disappointing. The TNF-α inhibitor etanercept can relieve the symptoms of severe AL amyloidosis, but has no influence on the underlying plasma cell disease. In animal experiments, the amyloid load can be reduced by passive immunization with a monoclonal antibody against an epitope that is specific for amyloid-forming light chains.
  • The physicians Giampaolo Merlini and Giovanni Palladini started the first randomized clinical trial on epigallocatechin gallate in cardiac AL amyloidosis in 2012 in Pavia , Italy .

ATTR amyloidosis
  • A study at the Medical Clinic of Heidelberg University since April 2008 on the treatment of patients with transthyretin amyloidosis with epigallocatechin gallate showed improvements in heart function in some of the patients. The approach of Werner Hunstein and others is supported by other research results.

literature

  • Christoph Röcken et al: Interdisciplinary guidelines for the diagnosis and treatment of extracerebral amyloidoses . In: German Society for Amyloid Diseases e. V. (Ed.): German Medical Weekly . tape 131 , Suppl 2, 2006, p. 45-66 , doi : 10.1055 / s-2006-947836 .
  • Sandra Ihne, Caroline Morbach, Claudia Sommer, Andreas Geier, Stefan Knop, Stefan Störk: Amyloidosis - diagnosis and treatment of an underdiagnosed disease. In: Deutsches Ärzteblatt. Volume 117, No. 10, March 6, 2020, pp. 159-166.

Web links

Individual evidence

  1. ^ Wilhelm Pape , Max Sengebusch (arrangement): Concise dictionary of the Greek language. 3rd edition, 6th impression, Vieweg & Sohn, Braunschweig 1914. 1914, accessed on December 9, 2015 .
  2. ↑ Bouke PC Hazenberg: Amyloidosis: a clinical overview . tape 39 , no. 2 , May 2013, p. 323–345 , doi : 10.1016 / j.rdc.2013.02.012 ( rug.nl [PDF; accessed on September 8, 2019]).
  3. ^ G Merlini, V Bellotti: Molecular mechanisms of amyloidosis . In: N Engl J Med . tape 349 , no. 6 , 2003, p. 583-596 , doi : 10.1056 / NEJMra023144 .
  4. ↑ Merrill D Benson: LECT2 amyloidosis . In: Kidney International . tape 77 , no. 9 , May 2010, p. 757-759 , doi : 10.1038 / ki.2010.18 , PMID 20393490 .
  5. ↑ Sandra Ihne, Caroline Morbach, Claudia Sommer and others: Amyloidosis - diagnosis and therapy of an underdiagnosed disease. 2020, pp. 160 and 165.
  6. ↑ Keyur B. Shah et al: Amyloidosis and the Heart: A Comprehensive Review . In: Arch Intern Med . tape 166 , no. 17 , 2006, p. 1805–1813 , doi : 10.1001 / archinte.166.17.1805 .
  7. ↑ Vaishali Sanchorawala: light chain (AL) Amyloidosis: Diagnosis and Treatment . In: Clin J Am Soc Nephrol . tape 1 , no. 6 , 2006, p. 1331-1341 , doi : 10.2215 / CJN.02740806 .
  8. ↑ Bollee, Guillaume et al .: Presentation and Outcome of Patients with Systemic Amyloidosis Undergoing Dialysis . In: Clin J Am Soc Nephrol . tape 3 , no. 2 , 2008, p. 375-381 , doi : 10.2215 / CJN.02470607 .
  9. ↑ Berthold Jany, Tobias Welte: Pleural effusion in adults - causes, diagnosis and therapy. In: Deutsches Ärzteblatt. Volume 116, No. 21, (May) 2019, pp. 377-385, here: p. 379.
  10. ↑ LM Dember et al .: Eprodisate for the Treatment of Renal Disease in AA Amyloidosis . In: N Engl J Med . tape 356 , no. 23 , 2007, p. 2349-2360 , doi : 10.1056 / NEJMoa065644 , PMID 17554116 .
  11. ↑ A Phase II Open-label Randomized Study of Dietary Supplement With Epigallocatechin Gallate (EGCG) to Improve Cardiac Dysfunction in Patients With AL Amyloidosis Who do Not Require Chemotherapy (EpiCardiAL). ClinicalTrials.gov .
  12. ↑ SO Schönland: Advances in the diagnosis and therapy of amyloidoses . In: Deutsches Ärzteblatt . tape 103 , no. 34–35 , 2006, pp. 2237 ( aerzteblatt.de [PDF]).
  13. ↑ Domino transplant in the liver. (No longer available online.) According to German Foundation for Organ Transplantation, archived from the original on October 20, 2011 ; Retrieved August 5, 2010 .
  14. ↑ Derliz Mereles, Sebastian J. Buss, Stefan E. Hardt, Werner Hunstein, Hugo A. Katus: Effects of the main green tea polyphenol epigallocatechin-3-gallate on cardiac involvement in patients with AL amyloidosis . In: Clinical Research in Cardiology . tape 99 , no. 8 , 2010, p. 483-490 , doi : 10.1007 / s00392-010-0142-x .
  15. ↑ Jan Bieschke, Jenny Russ, Ralf P. Friedrich, Dagmar E. Ehrnhoefer, Heike Wobst, Katja Neugebauer, Erich E. Wanker: EGCG remodels mature α-synuclein and amyloid-β fibrils and reduces cellular toxicity . In: Proceedings of the National Academy of Sciences . tape 107 , no. 17 , 2010, p. 7710-7715 , doi : 10.1073 / pnas.0910723107 .
  16. ↑ Hereditary ATTR Amyloidosis with Polyneuropathy (hATTR-PN) ( Memento June 6, 2017 in the Internet Archive ), Alnylam website, accessed on June 7, 2017.
  17. ↑ Complete 18-Month Data from Ongoing Phase 2 OLE Study with Patisiran in Development for the Treatment of Hereditary TTR-Mediated Amyloidosis with Polyneuropathy (hATTR-PN) , PM Alnylam, April 20, 2016, accessed June 7 2017.
  18. ↑ Alnylam Reports Final 24-Month Results from Phase 2 Open-Label Extension Study of Patisiran, an Investigational RNAi Therapeutic in Development for the Treatment of Hereditary ATTR (hATTR) Amyloidosis ( Memento June 6, 2017 in the Internet Archive ), PM Alnylam from April 26, 2017, accessed June 7, 2017.