Patient: Description (onset, main symptoms, hospital visited, etc.): 5 years ago, I felt dyspnea during exercise (I was a middle-distance runner for 10 years), and in June 2009, I was examined and diagnosed with “tracheobronchial amyloidosis” at Peking Union Medical College Hospital. His current symptoms are dyspnea with light exercise. The cough is persistent with pus sputum and sometimes fever. I saw Dr. Ma Lingguo’s excellent medical skills on the Internet, and I hope to get Dr. Ma’s advice or treatment.
Ma Lingguo, Department of Otolaryngology, Shenzhen People’s Hospital.
I once treated a patient with severe laryngotracheal amyloidosis, the patient had a tracheotomy for breathing difficulties and has been cured after laser surgery. Please send me the details of fiberoptic bronchoscopy, CT, etc. Only when I see the complete case information can I give the most appropriate treatment plan.
Patient: Dr. Ma Lingguo, I am sending you my medical records from Peking Union Medical College Hospital, and I would like to ask you to give me further diagnosis in your busy schedule. Thank you!
Ma Lingguo, Department of Otolaryngology, Shenzhen People’s Hospital: The information you provided has been read in detail, there is extensive amyloidosis in both trachea and bronchi. If the amyloid hyperplasia is large enough to cause respiratory distress, surgical removal can be considered to relieve respiratory distress. Surgical removal is only indicated for amyloidosis with more limited hyperplasia, and if there is extensive hyperplasia, surgery will not be able to help. Therefore, in cases like yours, the best way is to take your medication on time, review it regularly, and deal with any problems early.
Patient: Thank you, Dr. Ma, for your reply in your busy schedule. I will follow your advice and review regularly. Thanks again!
Also, please ask Dr. Ma, what medicine can effectively delay the proliferation of amyloid tissue in this condition of mine? Where can I buy it?
Ma Lingguo, Department of Otolaryngology, Shenzhen People’s Hospital.
There is no effective drug to delay amyloid proliferation, and titanium tracheal stents should not be used until absolutely necessary, because they are easily dislocated and not easy to remove. The following is some relevant information to share with you.
Amyloidosis (Amyloidosis) is a heterogeneous group of diseases in which proteins are deposited between cells in an abnormal fibrous structure, causing structural and functional changes in tissues and organs resulting in corresponding clinical manifestations. The name “amyloidosis” was given to a group of fibers that react similarly to starch when exposed to iodine and sulfuric acid, and has been used ever since. Amyloidosis can be hereditary or acquired; the deposition can be localized or systemic; the course of the disease can be benign or malignant.
1.The composition and pathogenesis of amyloid
The biochemical composition, peptide subunits, and origin of different types of amyloid protein fibers vary, but they all have a nearly identical core structure, the β-sheet. Amyloid is composed of three main components: (1) amyloid fibrils: amyloid fibrils are the partially hydrolyzed and broken fragments of their corresponding precursor proteins, and different types of amyloidosis have different precursor proteins. (ii) Glycosam-inoglycan GAG: GAG binds to amyloid fibrils in a non-covalent way and has a role in promoting protein fibril formation. (iii) Substance P: serum amyloid Pcomponent SAP is a highly stable, protease-resistant glycoprotein that binds to amyloid in a calcium-dependent manner and contributes to amyloid stabilization in vivo. Some immune cells and cellular factors are involved in the development of acquired amyloidosis. It has been shown that a monoclonal subpopulation of plasma cells that consistently produce λ or κ light chains is associated with the development of light chain amyloidosis; that macrophages cleave certain types of immunoglobulins in an abnormal manner, contributing to the development of light chain amyloidosis; that interleukin-1 (IL-1) contributes to the development of hepatic SAA (serum amyloid A protein serum amyloi dapolipoprotein SAA); and that interleukin-1 (IL-1) contributes to the development of amyloidosis. The synthesis of hepatic SAA (serum amyloi d apolipoprotein SAA) is involved in the development of reactive amyloidosis; amyl oid enhancing factor AEF is involved in the hydrolysis of the precursor protein and the deposition of its fragments, which to some extent determines the susceptibility of patients to amyloidosis. To date, the pathogenesis of amyloid fibrils is not fully understood, but studies have shown that amyloid fibrils can damage tissues and organs in three ways: (1) by causing destruction of normal tissue structures through physical presence. (2) Damage the structure and function of tissues and organs through cytotoxic effects. (3) Inducing apoptosis.
2.Clinical manifestations of amyloidosis
The clinical manifestations of amyloidosis are varied, depending on the extent, degree and location of amyloid material deposition. The common non-specific symptoms in patients with systemic amyloidosis are: fatigue and weakness (54%), weight loss (45%), swelling (41%), and dyspepsia (33%), and all tissues and organs of the body can develop amyloidosis and show corresponding manifestations. (1) Kidney: kidney damage is often irreversible and can be characterized by varying degrees of proteinuria and hematuria until uremia. ②Liver: Involvement is very common, often manifesting as hepatomegaly and abnormal liver function, but biliousness is rare. (③) Heart: amyloidosis mainly involves the heart, manifesting as restrictive cardiomyopathy, congestive heart failure and cardiac arrhythmia. (iv) Gastrointestinal tract: the manifestations are due to direct deposition of amyloid or corresponding vegetative nerve involvement, which may manifest as dysfunction, ulceration, bleeding, diarrhea, or obstruction; megalingual is characteristic but rare. (5) Nervous system: peripheral nerves (such as carpal tunnel syndrome) and plant nerve dysfunction are the main manifestations. (6) Skin and mucous membranes: The skin and mucous membranes are often involved, but most of them have no clinical manifestations, and waxy papules or plaques that are mildly raised above the skin surface are more characteristic. (7) Respiratory system: often asymptomatic, a few may show obstructive lesions of the upper respiratory tract and interstitial lung changes.
3.Classification of amyloidosis
The classification of amyloidosis is quite complicated. The classification according to the biochemical properties of protein fiber precursors can partially reflect the nature of the disease, but the operability is poor. A working classification that integrates the mode of acquisition, biochemical properties and clinical characteristics of the disease is of great value. In the working classification, acquired amyloidosis accounts for more than 90% of all amyloidosis. See the attached table for details.
4.Diagnosis of amyloidosis
The clinical manifestations of amyloidosis are diverse and mostly non-characteristic, sometimes they are part of the manifestations of the underlying disease, which should be alerted and examined as soon as possible when the disease is suspected.
4.1 Histological diagnosis Biopsy and specific tissue staining are the most important indicators for the diagnosis of amyloidosis. Congo red staining of tissue sections shows characteristic green birefringence (polarized light microscopy) or red-green birefringence (cross-polarized light microscopy). Histological examinations that are widely used are abdominal subcutaneous fat aspiration and rectal mucosal biopsy, skin and gingival biopsy are also commonly used. After the diagnosis of amyloidosis is established, immunohistochemical tests should be performed to clarify the biochemical type of amyloidosis. Potassium permanganate staining with Congo red staining is valuable for type AA and AH amyloidosis.
Schedule Working classification of amyloidosis
Acquired amyloidosis
1.Light chain amyloidosis (AL type)
2.reactive amyloidosis (AA type)
3.Age-related amyloidosis (AS type)
4.Dialysis-related amyloidosis (AH type)
5.Limited amyloidosis (AE type)
6.Other
Hereditary amyloidosis
1.Familial polyneurogenic amyloidosis (FAP type)
2, visceral amyloidosis (Ostertag type)
3.Hereditary cerebral hemorrhage with amyloidosis (Lcelandic type)
4.Familial Mediterranean fever (Dutch type)
(FMF type)
5.Other
Chromosomal recessive inheritance, remaining hereditary amyloidosis
All are autosomal dominant
4.2 SAP scintigraphy is the only method available for systemic monitoring of amyloidosis. When a certain amount of amyloid is present in the body, radiolabeled SAP can be rapidly and specifically localized to the site of amyloid deposition, allowing qualitative and quantitative diagnosis of amyloidosis, with a sensitivity of 100% for type AA and 90% for type AL. The SAP scintigraphy allows to understand the different distribution patterns of different types of amyloidosis: the relationship between the amount of deposition and organ function; the natural regression of amyloidosis and the determination of its outcome. It has diagnostic value in amyloidosis that is not histologically certain. Histology and SAP scintigraphy are complementary techniques, with SAP providing a noninvasive, macroscopic diagnosis and histology being more sensitive and precise for the confirmation of amyloidosis and the determination of biochemical types.
4.3 Other tests Cardiac amyloidosis is difficult to determine by histology and SAP scintigraphy, but the combination of electrocardiography and bidirectional echocardiography has a high sensitivity, with the electrocardiogram often showing low voltage and pathological Q waves in the thoracic leads, and the bidirectional echocardiogram showing diffuse hyperrefractive granular highlights. After the diagnosis of amyloidosis is established, the primary disease should be actively investigated; in 15% of patients with AL, the primary disease cannot be diagnosed by cytological and immunological examination of bone marrow, blood and urine, and the immunoglobulin gene rearrangement can be examined by DNA blotting or PCR. When hereditary amyloidosis is suspected, a gene deletion or mutation should be identified and confirmed by a gene lineage survey. Very few patients can only be diagnosed by protein amino acid sequence analysis in the lesion.
5.Treatment principles of amyloidosis
To date, there is no specific method to eliminate amyloid deposits. The focus of clinical management is to reduce the supply of amyloid precursor protein. A rational treatment plan should include the following four aspects: (1) control of the primary disease; (2) reduction of amyloid fibrillar precursor production, such as the use of immunosuppressive agents to control the acute inflammatory response in patients with AA amyloidosis and combination chemotherapy to inhibit the production of antibody light chains in AL amyloidosis. In situ liver transplantation to reduce the production of protein fibrillar precursors in hereditary amyloidosis, and early renal transplantation in patients with end-stage renal failure to facilitate the clearance of β2 microglobulin. ③Promote the regression of amyloid foci, there is no specific method. (4) Symptomatic supportive therapy: Symptomatic supportive therapy can delay target organ failure, improve the quality of life and prolong survival; organ failure that has already occurred, such as renal failure, intractable heart failure, renal and heart transplantation is of some value. Some amyloidosis can be prevented, such as colchicine to prevent FMF amyloidosis and early kidney transplantation to prevent H A amyloidosis.
6. Clinical aspects of common amyloidosis syndromes
6.1 Systemic AL amyloidosis Among the primary causes of AL amyloidosis, 80% are “benign” clonal globulinemia, 10% are multiple myeloma, and the remaining 10% are malignant lymphoma and macroglobulinemia. The clinical manifestations of systemic AL amyloidosis are complex, and all organs except the brain can be involved, with cardiac, renal, and peripheral nerve involvement being the most common, and the periorbital vascular purpura causing the “black eye sign” and the giant tongue sign being specific. This is the most common and least prognostic form of amyloidosis, with an average survival of 12 to 15 months. Treatment of AL amyloidosis focuses on inhibition of B-cell proliferation, with the best regimen being MP (Marfannan + prednisolone), which is 50% effective, VAD (vincristine + adriamycin + dexamethasone) and high-dose Marfannan + PBST (autologous peripheral blood hematopoietic stem cells). The efficiency of VAD (vincristine + adriamycin + dexamethasone) and high-dose Marfan + PBST (autologous peripheral blood stem cell transplantation) can reach 85%. The new anthracycline antibiotic I-DOX may be more effective, and interferon is only effective in myeloma-induced AL amyloidosis.
6.2 Systemic reactive amyloidosis AA amyloidosis can be combined with any pathological stimulus that causes a sustained inflammatory response. Diseases with AA amyloidosis include: (1) rheumatic diseases: including rheumatoid arthritis, juvenile arthritis, psoriasis and psoriatic arthritis, Reiter′s syndrome, adult Still′s disease, leukoarthrosis, and Crohn′s disease. ② chronic infections: including leprosy, tuberculosis, bronchiectasis, decubitus ulcer, chronic pyelonephritis, osteomyelitis, Whipple′s disease. ③Neoplastic diseases: including Hodgkin’s lymphoma, renal tumor, lung, intestinal and urogenital tract tumor, basal cell carcinoma, hairy cell leukemia.
There is no linear relationship between the amount of AA amyloidosis deposition and the severity of clinical manifestations, but renal involvement is most common, with 30% of patients having hepatomegaly, splenomegaly, and adrenal enlargement. The prognosis for AA amyloidosis is not optimistic, with survival rates of 50% and 25% after 5 and 15 years, respectively, and death due to renal failure. Treatment emphasizes control of the underlying disease. The use of cytotoxic drugs such as benzodiazepine and cyclophosphamide has significantly improved the prognosis.
6.3 Geriatric systemic amyloidosis Asymptomatic systemic amyloidosis due to wild-type TTR (Transthyretin) is present in more than 25% of the elderly and generally does not require treatment.
6.4 Dialysis-associated amyloidosis is seen in patients with renal failure on hemodialysis and peritoneal dialysis, where amyloid material (β2 microglobulin) is deposited mainly in joints, periarticular tissues, and bone, causing joint pain, carpal tunnel syndrome, and bone cysts. Renal transplantation is the most important treatment, and NSAIDs and adrenocorticosteroids can control most symptoms.
6.5 Restricted amyloidosis Restricted amyloidosis mostly occurs in the skin, respiratory tract, and genital tract and can be cured by surgical excision.
6.6 Hereditary systemic amyloidosis Hereditary systemic amyloidosis is rare, but can exist in many forms, and is caused by mutations in certain genes that regulate protein production, and is usually inherited in an autosomal dominant pattern. It is characterized by progressive peripheral and vegetative neuropathy and varying degrees of visceral amyloid deposits. Since 1997, four cases have been treated with liver transplantation, and three have had good results.
The diagnosis and treatment of laryngeal amyloidosis
Fudan University Eye, Ear, Nose and Throat Hospital Journal of Otolaryngology Published:2007-04-03
[Abstract] Laryngeal amyloidosis most often involves the supraglottic region, and the ventricular zone is most frequently involved, and the lesions are multifocal. The clinical manifestations are insidiously developing, and hoarseness is the most common symptom. Congo red staining is the most classic and specific histochemical test. The goals of treatment are twofold: (1) to ensure adequate respiratory access; and (2) to improve or restore the quality of articulation.
Amyloidosis is a general term for a group of diseases caused by the deposition of pathological protein substances between the cells of tissues and organs. 1851 Virchow used the term “amyloid” when describing this diseased tissue that reacts amyloidly with iodine and sulfuric acid [1]. The disease rarely affects the head and neck and the respiratory tract, but the lesions that do occur in this region are mainly in the larynx. We summarize the recent literature on laryngeal amyloidosis (LA). The clinical manifestations, diagnosis and treatment methods are reviewed as follows.
I. Clinical manifestations
Since the first case of LA was reported by Burow and Neumann in 1875, there have been case reports or mass reports of this disease in China and abroad [1-5]. Thompson et al [3] reported 11 cases of LA treated, 8 males and 3 females had hoarseness. The lesions were polypoid or granulomatous, with an average length of about 1.6 cm. 4 cases involved only the vocal cords, 1 case involved only the ventricular cords, and 6 cases were trans-vocal [3]. Lewis et al [6] reported 22 cases of LA, 11 cases in each sex, aged 29-85 years, with a mean of 56 years. Hoarseness was the most common symptom (18/22), and some cases had laryngeal stridor, fullness and choking. O’Halloran and Lusk [1] summarized 300 cases of LA reported in the literature since 1875, with only 3 cases in children, the youngest being an 8-year-old girl.
LA most often involves the supraglottic region, while the ventricular zone is most frequently involved, followed by the infraglottic region, laryngeal chambers, vocal cords, and aryepiglottic folds. Lewis et al [6] reported that only 5 of 22 cases had lesions limited to one area of the larynx, while the remaining 17 cases were multifocal. 6 cases had tracheal amyloidosis in addition to laryngeal involvement, and 1 patient with multifocal LA of the larynx had amyloidosis of the turbinates and anterior nasal cavity. Green et al [7] reported 1 case of LA with amyloidosis involving the entire pharyngeal lymphatic ring.
The clinical manifestations of LA develop insidiously, often over a period of months to years between the onset of symptoms and hospitalization, with hoarseness being the most common symptom. There is no racial difference, and the age of presentation is generally 40-60 years, while the age range of patients is 8-80 years [1].
II. Diagnosis of LA
1, Classification of amyloidosis.
It is usually divided into systemic or localized according to the anatomical site involved in the lesion, and into primary, secondary and familial according to clinical characteristics. As the biochemical nature of amyloidosis is better understood, modern classification is based on the relationship between the clinicopathological features and the biochemical composition of the fibrin deposits. The AA type (amyloid A protein) is seen in secondary amyloidosis and undulant fever. The most frequent amyloidosis is systemic amyloidosis due to multiple myeloma, which is of the AL(κ or λ light chain)/concomitant myeloma type, which rarely involves the larynx; LA is usually a primary, focal lesion of the AL(κ or λ light chain)/primary type [1].
2, Pathology and clinical diagnosis of LA
The presence of amyloid, an eosinophilic substance characterized by a glycoprotein component, in tissues is called amyloidosis [9]. The cause of amyloidosis and the intrinsic relationship between the different protein components or protein precursors and the clinical manifestations are not known. Substance P (P component) is a glycoprotein that is present in almost all forms of amyloidosis and is not clinically specific. Positive staining for substance P can be used as an indicator to confirm the correct diagnosis of amyloidosis [6].
Amyloidosis can be distinguished from other eosinophilic infiltrates by a series of histochemical stains: amyloid tissue produces a brownish-black color with iodine, a purplish-red color with methyl viologen, and a yellow fluorescence with thioflavin under UV light. The most classic and specific histochemical test is Congo red staining, catalyzed by potassium permanganate, which produces apple green birefringence and dichroism under polarized light. The gold standard for diagnosis by electron microscopy is the detection of characteristic fibrin – taut, linear unbranched fibers, 7.5-10 nm wide [1].
The diagnosis must be made by directly assessing the extent of the local lesion and determining whether it is systemic amyloidosis. A thorough endoscopic examination of the entire respiratory tract, including the nose, nasopharynx, larynx, trachea, and bronchi, with attention to the multifocal tendency of the disease, is recommended. Recommended tests include: blood count, BUN (urea nitrogen), creatinine, liver function tests, urinalysis, sedimentation, urine immunoelectrophoresis, tuberculin test, and chest radiograph. A detailed history should be taken to distinguish familial amyloidosis syndrome from endocrine disorders such as thyroid adenoma. These tests have a very low positive rate in LA [1, 3, 6, 10].
LA appears endoscopically as a diffusely swollen, occasionally submucosal nodular mass without ulceration and is often yellow, translucent and paraffin-like . Vocal fold movement may be weakened by the lesion masses but not paralyzed [1, 3].
III. Treatment and prognosis of LA
The treatment of LA has two goals: first, to ensure adequate respiratory access; second, to improve or restore the quality of articulation. When LA causes clinical symptoms, surgical excision of the diseased tissue is the mainstay, while reducing trauma to surrounding structures. Local or systemic steroids are ineffective, and radiotherapy is contraindicated because it is not therapeutic and has significant side effects. There are two routes of surgical resection, with a large body of literature reporting good results in endoscopic resection of LA and the use of lasers making the treatment of the disease more convenient. In cases with severe laryngeal obstruction, a tracheotomy is required prior to endoscopic laser resection. The vast majority of cases are suitable for the endoscopic route, and the procedure can be repeated if necessary. The extralaryngeal approach mainly refers to laryngectomy, while the supraglottic lateral approach is suitable for removal of large supraglottic lesions [11], and Kennedy and Patel [11] reported that preoperative CT 2D reconstruction is useful for understanding the extent of the lesion and for surgical planning.
LA is a benign lesion and does not usually result in death. Deng Yaxin et al [12] reported a case that survived for more than 30 years from the time of diagnosis. The lesion extended to the root of the tongue, the posterior lateral wall of the pharynx, the whole larynx and part of the trachea, and it was difficult to remove all of them, so only a tracheotomy was performed and he was able to take care of himself despite his 86 years of age. Many reports show that the course of LA progresses slowly, even for several years without progression. There are reports of no change in lesion size after 17 years of observation [1]. There are no reports of malignant transformation of the disease, nor of focal amyloidosis to systemic amyloidosis. In view of this, clinical observation can be used in older, frail cases with small lesions and no respiratory tract obstruction.
References
[Amyloidosis of the larynx in a child.
[2].Mazzantiti D,Pazzagli M,Cagno Mc,et al.Long-term survival in primary amyloid osis of the laryngotracheobronchial tract by treating complications only.Monald i Arch Chest Disease, 2000,55(2):114-116.
[3].Thompson LD,Derringer GA, Wenig BM,et al.Amyloidosis of the larynx:A cl inicopathologic study of 11 cases.Modern Pathology,2000,13(5):528-535 .