Chronic lymphocytic thyroiditis in children
Introduction
Introduction to chronic lymphocytic thyroiditis in children Chronic lymphocytic thyroiditis (CLT), also known as autoimmune thyroiditis, is a chronic inflammatory autoimmune disease with its own thyroid tissue as an antigen. Japan's Kyushu University Hashimoto first (1912) reported four cases in the German medical journal and named Hashimoto (Hashimotosthyroiditis, HT), the most common thyroid inflammation in the clinic. In recent years, the incidence rate has increased rapidly. It has been reported that it has similar morbidity to hyperthyroidism. This disease is the most common cause of goiter and acquired hypothyroidism in children and adolescents. basic knowledge The proportion of illness: 0.0035% Susceptible people: children Mode of infection: non-infectious Complications: systemic mucinous edema
Cause
Causes of chronic lymphocytic thyroiditis in children
Genetic factors (30%):
It has become a consensus that CLT is produced by the interaction of genetic factors and non-genetic factors. The production of thyroid autoantibodies is related to autosomal dominant inheritance. In Europe and North America, HLA-B8 and DR3, DR5 are more common in CLT patients. The Japanese were more common with HLA-B35. Xu Chun et al. used PCR-SSCP to detect allele polymorphisms in HLA-DQA1 and DQB1 loci in 30 Han Chinese CLT patients, and found that the frequency of DQA1-0301 was significantly higher than that of normal controls. It is speculated that it may be a susceptibility gene in Chinese disease. A US research institute analyzed the genes of 56 Caucasian families with autoimmune thyroid disease and identified six genes associated with autoimmune thyroid disease. The AITD-1 gene located on chromosome 6 is associated with Graves disease and CLT; CLT-1 on chromosome 13 and CLT-2 on chromosome 12 are associated with the pathogenesis of CLT, after which they used Genomic screening method studied a Chinese American family with 27 family members and found that D1IS4191 and D9S175 are related to CLT, so it is believed that there are different genetic susceptibility to CLT among different races, Tomer et al. Studies have shown that an important decision thyroid autoantibodies gene located on chromosome 2q33, activation pathway essential co-stimulatory factor CTLA-4 gene is very likely that genes on chromosome thyroid antibodies 2q33.
Immunological factors (25%):
The mechanism by which immunological factors cause thyroid damage is not fully understood. At present, the following mechanisms are preferred:
(1) Defects in congenital immune surveillance: The number and quality of organ-specific inhibitory T lymphocytes are abnormal, and T lymphocytes can directly attack thyroid follicular cells.
(2) Humoral immune-mediated autoimmune mechanism: HK cells can attack thyroid follicular cells in synergy with anti-thyroid antibodies. When antigen-antibody binds, its complex exists in target cell target, activated HK cells and antibodies. The Fc fragment reacts to kill target cells. This antibody-dependent cytotoxicity of HK cells is activated by thyroglobulin-thyroglobulin antibody complex in CLT and kills with specific cytotoxicity. Thyroid follicular cells, in addition, TPOAb itself plays a cytotoxic role in thyroid tissue.
(3) The lytic effect of anti-thyroid antibodies bound to complement on follicular cells.
(4) Lymphocyte-mediated toxicity, anti-thyroid antibody triggers and activates it.
(5) CLT patients are often accompanied by other autoimmune diseases such as pernicious anemia, systemic lupus erythematosus, rheumatoid arthritis, type I diabetes, chronic active hepatitis, etc., which also prove the existence of autoimmune factors.
Environmental factors (25%):
Infection and dietary iodide are the two major environmental factors in the development of CLT. Wenzel et al. used western blotting to study the anti-Yersinia bacterial antibodies in serum of CLT patients. The frequency of this antibody was significantly higher than that of patients with non-autoimmune thyroid disease. In contrast to the normal control group, Yerinia bacteria in the small intestine and colon were associated with the development of CLT.
In areas with iodine deficiency or iodine-rich areas, the incidence of CLT increases, indicating that iodine plays an important role in the pathogenesis of CLT. In excess, genetically susceptible animals can develop thyroiditis, but if iodine is not depleted in the thyroid gland, Can prevent the development of severe thyroiditis, the mechanism has not yet been elucidated, Rose et al found that the addition of iodine in the diet, CLT thyroid damage significantly increased, the incidence of CLT increased, thyroglobulin iodization, T cell proliferation in CLT, the main Increased potency of the pathogenic antigen-Tg autoantigen and increased systemic immune response can lead to CLT.
Apoptosis (5%):
Recent studies have found that the expression of proapoptotic protein-Fas in thyroid cells of CLT patients is increased, indicating that CLT is involved in apoptosis. Fas protein, also known as AOP-1 or CD95, is a type I membrane protein and belongs to nerve growth factor. (nerve growth factor, NGF), tumor necrosis factor (TNF) family, expressed by lymphocytes, human Fas gene is located on the 10th pair of chromosomes, Fas-L protein is a ligand of Fas, type II cross Membrane proteins belong to the TNF family. Fas-L is abundantly expressed in activated T cells and NK cells. The binding of Fas-L to Fas can initiate a series of signal transduction systems in the cell leading to cell death. The Fas pathway is CD8-mediated. The main mechanism of cytotoxicity, studies have shown that thyroid cell destruction in CLT is associated with Fas-induced apoptosis, and cytotoxic T cells express Fas and FasL-mediated thyroid cell apoptosis, which may be the triggering factor for CLT thyroid cell destruction. First, Hammoned et al. found that the degree of apoptosis and apoptotic nucleus in CLT thyroid gland increased significantly compared with Graves disease, multiple nodular goiter and normal thyroid tissue. CLT thyroid cells and glandular infiltrating lymphocytes expressed Fas, while Graves disease, multiple nodular goiter and normal thyroid tissue did not. Dong (2002) also found 38.1% of 21 CLT patients. Patients with Fas gene mutations, except for one exception, other Fas gene abnormalities are frameshift mutations, which cause a loss of function in a region related to apoptotic cell conduction in the cytoplasm, although currently related to Fas and FasL in CLT There are still many controversies about the role, but they are present in the thyroid gland and have been recognized for their function.
Pathogenesis
Pathological change
(1) Macroscopic view: In typical cases, bilateral thyroid diffuse enlargement, in some cases, the enlargement of one leaf gland is obvious, the gland enlargement is about 2 to 5 times of normal, the surface is smooth or fine nodular, and the capsule Complete, thickened, with little adhesion to the surrounding tissue, the cut surface is slightly raised, the texture is tough like rubber, showing obvious or inconspicuous lobulated, gray or grayish yellow, lack of luster due to less gelatin content, similar to hyperplastic lymph nodes There is no bleeding, calcification or necrosis. In the middle and late stages, it may be nodular due to extensive fibrosis, and the texture is hard. Some cases adhere to the surrounding tissues.
(2) Microscopic examination: The main histological features are thyroid follicular destruction, atrophy, decreased glial content in the lumen, follicular epithelial eosinophilia (Fig. 1) and interstitial lymphocytes, plasma cell infiltration, and prominent Lymphoid follicle formation in the germinal center and varying degrees of fibrosis.
The infiltration of lymphocytes is distributed in the lobules, and there are more between the follicles and the lobes, and there are fewer between the lobes. The lymphocytes between the follicles often form lymphoid follicles or diffuse distribution with germinal centers. The lymphoid follicles are mainly composed of small lymphocytes. It is composed of lymphocytes transformed at various levels in the germinal center, while the diffusely distributed lymphocytes mainly surround the degenerated epithelium, sometimes a small amount of lymphocytes invade into the follicles, between the epithelial cells and the basement membrane, and even invade In the follicular cavity, in addition to small lymphocytes, there are also many different plasma cells, tissue cells, immunoblasts and multinucleated giant cells, and the ratio of lymphoid tissue to thyroid tissue varies, usually around 1/3.
Thyroid follicular atrophy, a small amount of colloid or no gelatin in the follicular cavity, degeneration and destruction of epithelial cells, disintegration of the basement membrane, reduction or absence of some follicular gelatin, enlargement of epithelial cells, columnar or cubic Rich in cytoplasm, eosinophilic, fine-grained, deep nuclear staining, varying in size, degenerative and deformed. This eosinophil is called Hürthle cell, and eosinophilic change of follicular epithelial cells. It is the histological feature of this disease, but it has different understanding of the formation, function and significance of eosinophilic changes. Histologically, there is a transitional form of follicular epithelial cell compensatory hyperplasia and eosinophilic transformation. Under electron microscope, cytoplasmic mitochondria increase. Immunohistochemistry demonstrated that the enzymatic activity of cytosolic thyroglobulin was enhanced, indicating that eosinophilic changes may be gradually evolved from proliferating follicular epithelial cells, which are not unique signs of Hashimoto's thyroiditis, other thyroid diseases, Such as thyroid atrophy, multinodular goiter and thyroid tumors can also be seen, adolescent patients with cell eosinophilic and lymphoid follicles are not obvious, occasionally macrophages and foreign bodies In the follicles, occasionally seen covering squamous cysts, often a large number of peripheral lymphocytes, with branchial cyst morphology very similar.
2. The histological type can be divided into three types according to the difference of lymphocyte infiltration and fibrous tissue proliferation in the lesion:
(1) Lymphoid type: mainly lymphocyte infiltration, fibrous tissue proliferation is not obvious, characterized by extensive lymphocyte replacement of thyroid parenchyma, only a few follicular residues, degenerative thyroid follicles are also less, so the thyroid gland The size is large and soft, and it is also manifested as thyroid dysfunction. This type of child and young people are more common.
(2) fibrous type: connective tissue hyperplasia, extensive replacement of thyroid parenchyma by dense connective tissue, fibrous tissue secondary to glassy changes, infiltration of lymphocytes is not obvious, follicular atrophy or squamous, this type accounts for 12.5% of all cases This type mainly occurs in middle-aged people and has symptoms of hypothyroidism.
(3) Fibrous-lymphoid type: lymphoid tissue and connective tissue are hyperplasia. The typical Hashimoto's thyroiditis is diffusely changed under the microscope, but there are also cases of obvious nodular growth. The nodular epithelial component is present. Hyperplastic changes, another morphological change in Hashimoto's thyroiditis is one or more distinct hyperplastic nodules composed entirely of eosinophils, eosinophils forming follicles or a solid arrangement.
3. Electron microscopy eosinophils are filled with mitochondria and lysosomes. Eosinophils can not secrete T3, T4 or thyroglobulin. The gelatin in the follicular cavity is significantly reduced and red stained. The interstitial can be fibrotic in different degrees. Squamous metaplasia of follicular cells occurs, a phenomenon that is particularly pronounced in fibrous types.
4. Immunohistochemistry The keratin of the thyroid inflammatory thyroid follicular cells, especially high molecular weight keratin, S-100 protein, HLA-DR and N-acetyl--D galactosamine are more immunohistochemically positive than normal cells. high.
Prevention
Prevention of chronic lymphocytic thyroiditis in children
The disease is an autoimmune disease. Recently, it has been diagnosed with various examination methods. The key is that clinicians should improve their understanding of the disease, reduce misdiagnosis, missed diagnosis, timely correct treatment, prevent unnecessary surgery, or occur. complication.
Complication
Complications of chronic lymphocytic thyroiditis in children Complications, systemic mucinous edema
If the disease progresses, the hypothyroidism may occur after a few years, manifested as thyroid atrophy, mucinous edema, slow heart rate, body aches, fatigue, lack of activity, thick skin and so on.
Symptom
Chronic lymphocytic thyroid symptoms in children Common symptoms Goiter, hypothyroidism, hypothyroidism, hyperthyroidism, small ear swelling
Mostly slow onset, no special feeling, often due to thyroid enlargement, the initial stage of the disease is often diffuse enlargement of the thyroid gland, more right lobe than the left lobe, smooth surface, soft texture, no nodules, with the course of the disease Goiter is obvious, with nodules, moderate hardness or hardness, no tenderness, normal thyroid function, 8% can cause hyperthyroidism, about 60% of patients have symptoms of hypothyroidism, due to high degeneration and fibrosis of follicular epithelium Permanent low.
Chronic lymphatic thyroiditis, which often occurs in other autoimmune diseases, is part of the disease called autoimmune polyglandular syndrome, and Carpente reports autoimmune thyroid disease (CLT.Grave spontaneous mucinous edema). Addison disease and insulin-dependent diabetes mellitus (IDDM), and pointed out that these invaded glands have lymphocytic infiltration, which is common in women, female: male ratio is about 2:1, and Danmak studies propose these patients with HLA-Bg Related to type (A1), the most common polygland syndrome in pediatrics is IDDM with autoimmune thyroid disease, most commonly with CLT goiter, normal thyroid function, positive thyroid antibody, and regular determination of thyroid in such patients. Functional and blood antibody levels are extremely important.
There have also been reports of autoimmune thyroid disease with pernicious anemia and Cetrophie gastrointestinal inflammation. Florida recently reported 88 cases of adult goiter and thyroiditis patients, found that serum gastrointestinal wall cells antibody is 14%, have pernicious anemia, and some patients Patients with autoimmune thyroid disease are associated with some or all of the hair loss.
Examine
Examination of chronic lymphocytic thyroiditis in children
1. Determination of thyroid function: Serum T3, T4, FT3, FT4 are generally normal or low, even in patients with hyperthyroidism symptoms, T3, T4 levels are often normal.
2. Determination of serum TSH concentration: serum TSH level can reflect the metabolic state of patients. Generally, TSH is normal in normal thyroid function, but it is elevated in hypothyroidism. However, some patients with normal T3 and T4 may also have elevated TSH, probably due to Thyroid dysfunction and modern compensatory TSH increase to maintain normal thyroid function. CLT should be highly suspected when TSH is higher than normal. In recent years, there have been more and more reports on subclinical hypothyroidism. Diagnosis of subclinical A The reduction index is an increase in TSH levels. It has been reported that after 20 years of follow-up observation, 55% of subclinical hypothyroidism CLT women can develop clinical hypothyroidism. The initial rate of hypothyroidism is the rate of hypothyroidism. 2.6% (33%) per year, the rate of hypothyroidism in the initial increase in TSH was 2.1% (27%) per year. It was also reported that CLT was associated with subclinical hypothyroidism and TSH was >20 nU/ml. 25% of each year can progress to clinical hypothyroidism, while those with mild TSH can return to normal.
3.131I absorption rate test: can be lower than normal, but also higher than normal, most patients are at normal levels.
4. Anti-thyroid antibody assay: Anti-thyroglobulin antibody (TGAb) and anti-thyroid microsomal antibody (TMAb) assays are helpful in diagnosing CLT. In recent years, TPO (peroxidase) has been proven to be the antigen of TMAb in the past. Fixed complement, "cytotoxic" effect, and confirmed that TPOAb causes thyroid follicular cell damage by activating complement, antibody-dependent cell-mediated cytotoxicity and sensitizing T cell killing. TPO-Ab can directly interact with TPO. Binding, inhibits the activity of TPO, and TPO is a key enzyme in the synthesis of thyroxine. TPOAb has replaced TMAb for the diagnosis of CLT. The positive rate of TGAb and TPOAb combined detection can reach more than 90%. For single detection, TPOAb determination It is superior to TGA in the diagnosis of CLT. According to reports in the literature, 80% of CLT patients are positive for TGAb, while 97% of patients have positive TPAAb, but it has also been reported that the positive rate of TGA and TPOAb in CLT patients is less than 50%. The First Affiliated Hospital of Sun Yat-sen University summarized 335 cases of CLT confirmed by postoperative pathological examination, of which only half of cases were positive for TGAb and TPOAb.
5. The potassium perchlorate excretion test is positive, and the iodine release rate is >10%.
6. Cytological examination: Fine needle aspiration cytology (FNAC) and histological examination of tissue cryosection have a decisive role in the diagnosis of CLT. CLT can be diffuse parenchymal atrophy, lymphocytic infiltration and fibrosis under the microscope. Thyroid cells slightly increased in eosinophilic staining, namely Hurthle cells.
7. Other examinations: ESR increased, flocculation test was positive, gamma globulin IgG increased, blood beta lipoprotein increased, and lymphocyte count increased.
8. B-ultrasound: The sound image is as follows: (1) The diffuse enlargement of the two thyroid glands is generally symmetrical, and may also be mainly swollen on one side and thickened in the isthmus.
(2) The surface is uneven, forming a nodular surface, the shape is stiff, the edge becomes dull, and the probe is pressed with a hard object.
(3) The gland is uneven and low echo, see suspicious nodule-like echo, but the boundary is unclear, can not be repeated on multiple cut surfaces, sometimes only shows partial echo reduction, and some visible fine line-like strong echo formation irregularity The network looks like a change.
(4) There may be small cystic changes inside.
9. Color Doppler sound image shows that the blood flow in the thyroid is rich, sometimes almost fire, the upper thyroid artery flow rate is high, the inner diameter is thicker, but the arterial flow velocity and resistance index are significantly lower than hyperthyroidism, and the frequency bandwidth, diastolic phase The amplitude is increased, and there is no symptoms of hyperthyroidism, which can be identified.
10. Thyroid nuclides scan showed thyroid enlargement but reduced iodine intake, uneven distribution, if there is a large nodular shape, it can be cold nodules.
11. Positron emission tomography (PET) using 18-fluoro-deoxyglucose (Fluorine-18-fluorodeoxyglucose, 18F-FDG) for PET examination, non-invasive examination of tissue glucose metabolism, can be used to diagnose each Tumor, diffuse 18F-FDG absorption in thyroid examination may suggest thyroiditis, activation of the lymphoid tissue of the thyroid may be the cause of 18F-FDG absorption, but should be distinguished from thyroid cancer because 18F-FDG/PET differentiates thyroid Malignant tumors and CLT are still difficult and should be identified in combination with other clinical tests.
Diagnosis
Diagnosis and diagnosis of chronic lymphocytic thyroiditis in children
diagnosis
1. Diagnostic criteria Currently, the diagnostic criteria for CLT have not been unified. In 1975, Fisher proposed five diagnostic protocols, namely
1 thyroid diffuse enlargement, tough, uneven surface or nodules;
2TGAb, TMAb positive;
3 blood TSH increased;
4 thyroid scan has irregular concentration or sparse;
5 potassium perchlorate excretion test is positive, 2 out of 5 can be diagnosed as CLT, with 4 can be diagnosed, generally in clinical as long as typical CLT clinical manifestations, serum TGAb, TPOAb positive can be clinically diagnosed as CLT For patients with atypical clinical manifestations, high titer anti-thyroid antibody assay is needed to diagnose. For these patients, if serum TGAb and TPOAb are positive, the necessary imaging examination should be given and the thyroxine should be diagnosed. Treatment should be confirmed by FNAC or frozen section histology if necessary.
2. Atypical performance It is worth noting that the clinical manifestations of CLT are often not typical, or combined with other thyroid diseases or autoimmune diseases, the main atypical manifestations are:
(1) Hashimoto's hyperthyroidism: Graves disease and CLT are combined and can be transformed into each other. Patients may have clinical manifestations of hyperthyroidism, high titers of TGAb and TPOAb, and may have TSAb positive, 131I absorption rate of thyroid is increased, and no Inhibited by T4, pathology has both GD and CLT characteristic changes.
(2) exophthalmia type: mainly invasive exophthalmos, may be associated with goiter, normal thyroid function, TGAb, TPOAb positive, some patients can detect TSAb (thyroid stimulating antibody) and pro-ocular immunoglobulin.
(3) subacute thyroid type: clinical manifestations similar to subacute thyroiditis, acute onset, rapid thyroid enlargement and pain, 131I absorption rate is normal, T3, T4 normal, TGAb, TPOAb high titer positive.
(4) Adolescent type: CLT accounts for about 40% of adolescent goiter. Adolescent CLT has normal thyroid function, TGAb, TPOAb titer is low, clinical diagnosis is difficult, and some patients have slower goiter, called adolescent hyperplasia. Type, thyroid tissue lacks eosinophils, often without systemic and other local symptoms, patients with hypothyroidism can affect growth and development.
(5) associated with thyroid tumor type: often manifested as solitary nodules, hard, TGAb, TPOAb titer is higher, the nodules may be part of thyroid tumor or thyroid cancer, the surrounding part is CLT, CLT combined with thyroid cancer The rate was 0.5% to 26.0%. The First Affiliated Hospital of Sun Yat-sen University of Guangzhou (1998) reported that 13% (9/69) of a group of CLTs had thyroid cancer, and Gyory (1999) reported that CLT combined tumors accounted for 11.8% (14/118). Therefore, when the following conditions are encountered in the clinic, the possibility of combining tumors should be considered, and FNAC or excisional biopsy should be performed:
1 thyroid pain is obvious, thyroxine treatment is invalid;
2 After the thyroxine treatment, the gland does not shrink but increases;
3 thyroid enlargement with enlarged neck lymph nodes and compression symptoms;
4 There is a single cold nodule in the gland, which is asymmetrical and hard.
(6) fibrotic type (atrophic type): patients with a longer course of disease may have extensive or partial fibrosis of the thyroid gland, manifested as thyroid atrophy, hard texture, TGAb and TPOAb may be destroyed by thyroid, fibrosis is not high, thyroid function Also reduced, tissue sections showed the same as CLT, often misdiagnosed as primary hypothyroidism or thyroid cancer, which is one of the main causes of mucinous edema in adults.
(7) Complicated with other autoimmune diseases: manifested as multiple autoimmune diseases, such as CLT with Addisons disease, diabetes, pernicious anemia, idiopathic hypoparathyroidism, myasthenia gravis, systemic lupus erythematosus and other diseases Some people also call "autoimmune polyglandular failure syndrome" or "polygranulomatous failure syndrome", such as multiple endocrine neoplasia syndrome type II (Addison disease, AITD, type I diabetes, hypogonadism) One of the performances.
(8) Hashimoto encephalopathy: severe and rare. Since the first case was reported in 1966, only about 50 cases have been reported in the world. The etiology and pathogenesis are unclear. The clinical manifestations can be:
1 vasculitis type: characterized by repeated episodes of stroke-like episodes.
2 diffuse progression: there may be disturbance of consciousness, confusion, lethargy or coma, abnormal cerebrospinal fluid examination, increased protein content, increased monocytes, positive thyroid antibody, especially TPOAb titer, thyroid hormone levels are generally normal Or low, EEG can be abnormal, the treatment of this disease with corticosteroids, thyroxine also has a good effect.
Differential diagnosis
Mainly should be differentiated from simple goiter and Grave disease.
The diagnosis of chronic lymphatic thyroiditis with temporary hyperthyroidism and Grave disease is very difficult in pediatric clinical practice. If there is a prominent eye, Grave disease should be considered. The best differential diagnosis test is: 131I uptake test, if iodine is taken 6h, 24h iodine rate is low or normal should consider CLT; if 6h and 24h increase iodine rate is considered Grave disease, T3 inhibition test, Grave disease is not inhibited, serum thyroid-stimulated immunoglobulin is a characteristic of Grave disease, More reliable evidence for the diagnosis of this disease.
Thyroid biopsy has certain value in the identification of simple goiter and thyroid tumor.
