Introduction:
POEMSSyndrome is a rare multisystem disease with unclear etiology and pathogenesis. It is mainly characterized by polyneuropathy (P), organmegamega (o), endocrinopathy (E), and single disease. Clonal gamma globulin disease (M, also known as M-protein) and skin changes (S). The disease was first described by Crow in 1956 and subsequently described by Fukase in 1968. Nakanishi et al. call it Crow-Fukase syndrome. Takatsuki first confirmed and comprehensively described the disease, so it is also known as Takatsuki syndrome. Bardwick et al. collectively referred to the first letter of the above five major manifestations as POEMS syndrome. POEMS syndrome patients are often accompanied by osteosclerotic bone damage, biopsy can be seen in malignant plasma cells, so it is a special type of plasma cell disease, and POEMS syndrome may be a paraneoplastic syndrome.
Cause:
(1) Causes of the disease
The cause of the disease is unclear. Recent studies suggest that human herpesvirus type 8, HHV-8 infection is associated with POEMS syndrome-related multicentric Castleman disease (MCD). Belec et al investigated the HHV-8 infection in 18 patients with POEMS syndrome (9 with MCD). HHV-8 DNA sequences were detected in 7/13 (54%) and circulating anti-HHV-8 antibodies were detected in 9/18 (50%). Of the POEMS patients with MCD, 6/7 (85%) detected DNA sequences and 7/9 (78%) detected antibodies. MCD is a non-neoplastic lymphoproliferative disorder with unclear meaning. It is characterized by proliferation of vascular follicular lymph nodes in primary polylymphoid organs and may be associated with various immunodeficiency states, including rheumatoid arthritis and Hodgkin's disease. Disease and B-cell non-Hodgkin's lymphoma, human immunodeficiency virus (HIV) infection, and POEMS syndrome. HHV-8 infection was first discovered in acquired immunodeficiency syndrome (AIDS), and non-AIDS-related Kaposi sarcoma (Kaposis sarcoma), and thereafter also in primary exudative lymphoma (primary effusion lym-phoma) ), MCD lymph nodes and peripheral blood mononuclear cells and multiple myeloma bone marrow dendritic cells. A substance similar to human interleukin-6 (IL-6) is present in the HHV-8 genome, while IL-6 as a growth factor may be in Kaposi sarcoma, primary exudative lymphoma, multiple myeloma, MCD And plays a role in the pathogenesis of POEMS syndrome.
(two) pathogenesis
The pathogenesis is unclear, and the excessive production of proinflammatory cytokines and vascular endothelial growth factor (VEGF) may play an important role in the pathogenesis of this disease. Excessive production of pro-inflammatory cytokines and attenuation of their antagonistic responses are associated with this disease. These pro-inflammatory cytokines mainly include IL-1, TNF-α and IL-6. They are functionally related to each other. IL-1 and TNF-a have mutual stimulatory effects, and they all stimulate the production of IL-6. IL-6 is rarely directly toxic, and it is involved as an important cofactor. IL-1 is an early inflammatory mediator produced by mononuclear macrophages that acts on almost all tissues, including the immune, neurological, and endocrine systems, and has a broad impact on systems as they are released in large amounts in the blood circulation. IL-1a is mainly present in cells, while IL-1β is mainly secreted into extracellular fluid. Gherardi et al found that 14/15 patients with POEMS syndrome had elevated serum IL-1β levels, 10 patients had increased TNF-α, and 10 patients had increased IL-6 levels. Serum IL-1β, TNF-α, and IL-6 levels were higher in patients with multiple myeloma without neuropathy, while IL-2 and interferon gamma (IFN-γ) levels were normal. The level of metastatic growth factor β1 (TGF-β1) is low. The primary site of activation of these cytokines and the cause of activation have not been established. Lymph nodes may be sites of overproduction of IL-1β, but are more likely to reflect systemic activation of the monocyte/macrophage system. Similarly, normal levels of IL-2 and TNF-[alpha] suggest activation of macrophages rather than activation of T cells. However, activation of cytokine production is associated with plasma cell cloning or its secreted product, as POEMS syndrome patients with solitary plasmacytoma can be completely relieved after surgery or local radiotherapy. Therefore, it has been suspected that monoclonal gamma globulin disease or its lambda light chain triggers the production of a pro-nuclear/macrophage system, a pro-inflammatory cytokine. It may also be that in the case of multiple myeloma patients, in vitro bone marrow cells produce IL-6, IL-1 and TNF-α, and the tumor cells themselves can also produce cytokines. TGF-β1 is one of the inhibitory cytokines. In vitro animal experiments have shown that inhibition of TGF-β1 production is associated with severe systemic inflammatory responses. TGF-β1 has been shown to antagonize pro-inflammatory cytokines and act as an inactivation factor for monocytes/macrophages by reducing the production of hydrogen peroxide and nitric oxide and the production of IL-6 and TNF-α. kick in. Overproduction of IL-1β, TNF-a, and IL-6 and a decrease in TGF-β1 levels reflect an imbalance in cytokine production and its antagonism, ie, TGF-β1 is insufficient to buffer the deleterious effects of cytokines.
Because TNF-α, IL-1β, and IL-6 have overlapping biological activities and synergistic effects, it is difficult to attribute a symptom to the action of a single cytokine. However, studies suggest that long-term elevation of TNF-α levels and inflammatory demyelinating neuropathy, hepatosplenomegaly, endocrine disorders (including low testosteroneemia, gonadotropin-releasing release, adrenal insufficiency, hypothyroidism Associated with hyperprolactinemia, skin changes (such as hairy, clubbing) and other clinical manifestations (such as edema, lipase inhibition with weight loss, hypertriglyceridemia, and diarrhea). Elevated levels of IL-1β can act on the central nervous system, causing activation of the sympathetic nerves of anorexia and brown adipose tissue, leading to cachexia; activation of the opioid pro-opiomelanocortin gene, leading to skin pigmentation. Overproduction of IL-1β can also explain multiple endocrine abnormalities (including impaired glucose tolerance, behavioral and psychiatric disorders, and accelerated atherosclerosis). Elevated levels of IL-6 are associated with plasma cell proliferation and gamma globulin disease, thrombocytosis, Castlerman's disease, hemangioma, and microangiopathic glomerular lesions. IL-1β and TNF-α are strong osteoclast activating factors, while TGF-β can stimulate bone formation, but the latter does not coincide with the observed bone sclerosis. However, it is curious that low concentrations of IL-1 can stimulate bone formation in vitro, and IL-1 can upregulate TGF-β surface receptors, so osteosclerosis may be due to local cytokine-induced complex metabolic disorders of the bone.
It has recently been recognized that the overproduction of vascular endothelial growth factor is associated with the pathogenesis of this disease. Vascular endothelial growth factor (VEGF) is a potent and multifunctional cytokine that induces angiogenesis and microvascular permeability enhancement, so it is also known as vascular permeability factor (VPF). It acts directly and selectively on vascular endothelial cells via two vascular endothelial growth factor receptors. The source of vascular endothelial growth factor is still unclear. Vascular endothelial growth factor can be secreted either by tumor cells or by plasma cells and macrophages in chronic inflammatory lesions. Bone damage may be a source of elevated vascular endothelial growth factor levels due to decreased levels of vascular endothelial growth factor after local excision and radiotherapy. Vascular endothelial growth factor may also be secreted by swollen lymph nodes, as 19/30 lymph node specimens are damaged by Castleman's disease in a group of cases reported by Japan. Elevated levels of vascular endothelial growth factor may also be caused by circulating and proliferation of plasma cells in the bone.
The physiological role of vascular endothelial growth factor may explain the organ enlargement, edema, skin damage and multiple neuropathy. The enlarged organs are usually the liver, spleen and lymph nodes. Common vascular follicular lymph node proliferation, characterized by significant vascular proliferation, lymphoid sinus cell proliferation and large mature plasma cells. Vascular endothelial growth factor is a mitogenic factor in dermal microvascular endothelial cells that can explain skin thickening. The pathology of a patient with thickened skin showed thickening of the arterioles and capillary walls but no significant necrotizing vasculitis, suggesting a low degree of occlusive microvascular disease or vascular disease. Vascular endothelial growth factor may cause multiple neuropathy, but may not be direct, as nervous system tissue does not express vascular endothelial growth factor messenger RNA and vascular endothelial growth factor receptor. Vascular endothelial growth factor may affect the blood-nerve barrier by increasing microvascular permeability, resulting in increased intra-neuronal pressure after edema. After the increase in blood-nerve barrier permeability, serum components that are toxic to nerves such as complement and thrombin may cause neurological damage. Vascular endothelial growth factor can also cause an increase in bone density, which can explain changes in bone sclerosis. Osteogenesis is dependent on angiogenesis. Osteoblasts and bone tissue express vascular endothelial growth factor, which is an important regulator of osteoblast differentiation. Vascular endothelial growth factor also promotes mesangial proliferation and glomerular capillary thickening. The role of vascular endothelial growth factor in endocrine expression remains unclear.
IL-1β and IL-6 can stimulate vascular endothelial growth factor production. The combined effects of vascular endothelial growth factor and cytokines are thought to play a special role in the development of various clinical manifestations of this disease.
symptom:
The onset of the disease is insidious, and the progress is slow. The main clinical manifestations can be summarized into the following 6 groups.
1. Progressive multiple peripheral neuropathy is often the first symptom, which is characterized by symmetrical movement and sensory disturbance of the limbs. The lower limbs are heavier than the upper limbs, and the distal end is heavier than the proximal end. There are often foot drop, muscle atrophy and tendon reflexes weakened or disappeared. Feeling disorder, some patients have only movement disorders. Cranial nerve damage is mainly optic disc edema.
2. The swelling of the organs is mainly liver and/or splenomegaly, but the liver function is normal, and there are few manifestations of esophageal varices and hypersplenism. Some patients may have lymphadenopathy.
3. The skin changes with diffuse pigmentation (93%), mainly in the limbs and head and face, the areola is black, and there is thickening, necrosis and hairy (81%). Some patients may have skin changes similar to dermatomyositis or scleroderma.
4. Endocrine changes manifest as endocrine gland dysfunction, male breast development, impotence. Female breast enlargement, galactorrhea, amenorrhea. Can also be accompanied by abnormal glucose tolerance and hypothyroidism, edema is more common, mostly depressed, and often the first symptom. Some patients may have pleural effusion, ascites, hypothermia (76%), hyperhidrosis (66%) and clubbing (56%), similar to proliferative glomerulonephritis, acute arterial occlusion, pulmonary hypertension, Thrombocytopenia and true erythrocytosis. Occasionally see the pericardial effusion.
5. The most common plasma cell proliferative disease is osteosclerotic myeloma, followed by extramedullary plasmacytoma, and osteolytic multiple myeloma is rare.
6. Clinical auxiliary examination features
(1) Serological examination: serum protein electrophoresis may have M protein (75%), but the increase is not significant, mostly IgG, a few are IgA. Most of its components are lambda light chains, which are rarely kappa chains. Some patients may have double clones (biclonal), polyclonal albumen (polyclonal albumen), antinuclear antibodies and rheumatoid factor positive.
(2) Cerebrospinal fluid examination: cerebrospinal fluid protein is elevated and the number of cells is normal.
(3) Urine test: There may be a Bence-Jones protein.
(4) bone marrow puncture: visible plasma cell proliferation, ossifying myeloma when the proportion of plasma cells is more than 5%, multiple myeloma (osteolytic) more than 10%. Lymph node biopsy can be seen in plasmacytoma or plasma cell proliferation.
(5) X-ray examination: including bone hardening changes, osteolytic changes or both, of which bone hardening is the most common. Mainly involving the pelvis, clavicle, ribs, tibia, femur, thoracolumbar vertebrae and skull. X-ray manifests as skeletal hyperplasia or destruction.
(6) EMG examination: neurogenic damage, slowing of both motor and sensory conduction.
The syndrome is complicated and diverse due to multiple organ damage, and early diagnosis is often difficult. More than 3 of the above 6 major clinical manifestations are required to be diagnosed. Among them, multiple peripheral neuropathy, visceral enlargement and blood M protein positive are particularly important. Therefore, patients with unexplained peripheral nerve damage, edema (mainly with lower limbs, face), and enlarged organs should think of the possibility of this syndrome, and conduct relevant tests as soon as possible to facilitate diagnosis.
However, the rate of misdiagnosis of this syndrome is higher. The main reasons are: rational understanding and perceptual knowledge are not enough, the diagnosis often unilaterally focuses on the specialty diseases, neglecting detailed medical history inquiry and comprehensive physical examination.
complication:
Almost all cases have plasma cell proliferative diseases, the most common is sclerosing myeloma, followed by extramedullary plasmacytoma, and osteolytic multiple myeloma is rare. Followed by endocrine dysfunction, heart failure and cachexia.
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