1 case of extremely rare autoimmune disease

Preface

Endocrine diseases and their immune disorders are inextricably linked, and systemic manifestations of endocrine diseases and autoimmune diseases has exceeded the boundaries of different systems, it can be expressed as a multi-system, multi-organ involvement, complex and diverse clinical manifestations

Laboratory physicians play a vital role in the diagnosis and treatment of endocrine diseases and autoimmune diseases

Case history

The patient is female, 42 years old

He was treated with methimazole and oral brompistigmine; after 2 months, the chest CT thymoma disappeared; on June 22, 2016, due to dry mouth, polydipsia, polyphagia, weight loss and blurred vision, random blood glucose was measured 20mmol/L, he was admitted to the hospital with " diabetes ", and insulin intensive treatment was given after admission

During the hospitalization, there was a twitch of limbs, eyes turned up, foaming at the mouth, and loss of consciousness.

Discharged after blood sugar stabilized, discharge diagnosis: Diabetes ( type 1 diabetes is considered first), Graves disease, convulsions pending investigation (Epilepsy considerations), ptosis (myasthenia gravis considerations)

On October 27, 2018, the limbs twitched once again at night, and the traits were similar to the previous time.

Family history: Wushu

Test case analysis

At the time of admission, blood and stool routines were normal; urine routine: glucose 2+↑, ketone bodies -, white blood cells -; biochemistry: liver and kidney functions, electrolytes were normal; thyroid function was normal, thyroid peroxidase antibody>1300.

Table 1 Results of insulin and C-peptide release test

Note: Normal reference value: fasting insulin 20.

Clinical case analysis

When the patient was first treated, the thyroid function was checked outside the hospital, combined with thyroid color Doppler ultrasound and thyroid ECT examination, the clinical diagnosis of Graves disease was clear

Epilepsy occurs outside the hospital during hospitalization, after a blood glucose monitoring, ruled out hypoglycemia

Treatment process: After admission, methimazole tablets 10mg, 1 time/day, levothyroxine sodium tablets 25ug1/day; insulin pump continuous infusion of insulin (insulin lispro); immune globulin 20g, intravenous infusion × 5 days, After 28 days, 10 g of immunoglobulin was injected intravenously for 5 days

In the third month, recheck the cerebrospinal fluid GAD>2000IU/ml

Knowledge development

01

Type 1 diabetes (T1DM) and autoimmune thyroid disease (AITD)

T1DM and AITD are relatively common autoimmune endocrine diseases, both of which are caused by autoimmune attacks against the body's endocrine tissues mediated by organ-specific T lymphocytes

This case started with typical hyperthyroid hormoneemia, and the examination was in line with AITD, followed by typical symptoms of diabetes.
Insulin/C peptide release test showed insulin deficiency and GAD positive.
It was in line with T1ADM, and the diagnosis of APS III was clear
.
TIDM and AITD are more likely to occur in the same individual, and have a tendency to familial aggregation, suggesting that the two have a close relationship in genetic pathogenesis [2]
.

Abnormal immune regulation is the most fundamental cause of disease in TIDM and AITD, and genetic susceptibility also plays a role through immune regulation
.
Therefore, immunomodulatory therapy is the fundamental strategy for the treatment of T1DM and AITD
.
When APS is combined with Graves hyperthyroidism, it needs to be treated with isotope or methimazole.
Among them, 131I has a better effect because patients with APS have a strong immune response and drug treatment is prone to relapse
.

02

AITD and thymoma

Thymoma is one of the most common mediastinal tumors
.
The occurrence of thymoma is often accompanied by the loss of autoimmune tolerance and the emergence of autoimmune diseases.
Therefore, thymoma is associated with a variety of autoimmune diseases, including myasthenia gravis, systemic lupus erythematosus, hypogammaglobulinemia, and AITD and others [3]
.
There are also reports in the literature of autoimmune encephalitis (AE) and limbic encephalitis (LE) [4-5]
.
The mechanism is not very clear
.

Interestingly, Lohwasser et al.
[6] reported that the anti-thyroid drug carbimazole was used to treat Graves disease with enlarged thymus, and CT examination showed that the anterior mediastinum mass disappeared after normal thyroid function
.
In this case, after methimazole treatment for 2 months, the thymus mass disappeared, which may be related to the strong immunosuppressive effect of antithyroid drugs on patients with Graves disease
.

03

GAD-mediated limbic encephalitis (LE)

APS can also affect other non-endocrine systems, and can cause autoimmune encephalitis (AE) when it affects the nervous system
.
Those who meet limbic encephalitis in AE are called limbic encephalitis (LE)
.
At present, the prevalence of AE accounts for 10% to 20% of encephalitis cases.
Anti-NMDAR encephalitis is the most common, accounting for about 80% of AE patients.
GAD-mediated limbic encephalitis is rare
.

GAD is an inhibitory neurotransmitter and the main rate-limiting enzyme in the synthesis of gamma aminobutyric acid (GABA).
Studies have found that this antibody is one of the important immune markers of T1DM, and this antibody can mediate limbic encephalitis.
There is a strong correlation with persistent epilepsy in the body [7]
.

The specific mechanism of action is still unclear.
Only some animal experiments in vivo and in vitro have found that GAD antibody can inhibit the release of aminobutyric acid, which may damage neurons and interfere with the synthesis of neurotransmitters in the brain, thereby causing neurological diseases
.

GAD antibody can also cause continuous repetitive muscle activity, abnormal conditioned firing, and enhance the excitability of anterior horn neurons; it can also reduce the level of NMDA-mediated nitric oxide in the cerebellar nucleus and reduce the number of glutamate synapses
.
The clinical manifestations of GAD-mediated limbic encephalitis include type 1 diabetes-related symptoms, muscle weakness, abnormal mental behavior, seizures (originating in the temporal lobe), and near memory impairment as the main symptoms.
EEG and neuroimaging show consistent The limbic system is involved, and the cerebrospinal fluid examination reveals inflammatory changes.
In this case, the main manifestations are epileptic seizures and EEG changes
.

In the diagnosis of LE, it is necessary to exclude infectious diseases, metabolic and toxic encephalopathy, Hashimoto's encephalopathy, central nervous system tumors, genetic diseases, and neurodegenerative diseases
.
The treatment of GAD-mediated limbic encephalitis refers to autoimmune encephalitis, including: immunotherapy, symptomatic treatment, supportive treatment, rehabilitation treatment, and anti-tumor treatment such as tumor resection for patients with tumors
.

Summary

The medical model of modern medicine, which uses organs for division and diagnosis and treatment, has played a positive role in improving the level of specialist diagnosis and treatment.
However, it is undeniable that the purely organ-centered diagnostic thinking mode not only hinders the treatment of diseases, but also makes us deviate.
The general direction of clinical research work
.

Clinical specialists must have a good foundation in internal medicine and integrated concepts.
When making a clinical diagnosis, they must consider various professions, from the outside to the inside, from this to the other, to explore the internal connection of the disease and find the root cause of the disease
.
The systemic manifestations of autoimmune diseases have broken through the boundaries of different systems, and can manifest as multi-system and multi-organ involvement, with complex and diverse clinical manifestations
.

The involvement of the endocrine system and the non-endocrine system of APS patients is often sequential rather than simultaneous.
Clinicians must have a holistic concept and scientific and meticulous clinical thinking in the diagnosis and treatment of the disease, take the patient as the center and pay attention to all clinical manifestations of the patient.
Propose diagnosis ideas
.
Laboratory physicians must be closely integrated with the clinic, combined with modern laboratory technology, and actively carry out relevant test items and verify clinical diagnosis to avoid missed diagnosis and misdiagnosis, so that patients can receive early treatment
.

Expert Reviews

Test reviews

Expert: Zhu Jin, Director, Chief Technician and Master's Tutor of the Department of Laboratory Medicine, Quzhou Hospital Affiliated to Wenzhou Medical University (Quzhou People's Hospital)
.

Comments: This case entered the hospital with hyperthyroidism for the first time, and then the imaging examination found thymoma, and the clinical treatment effect was good
.
Two months later, he was admitted to the hospital again with diabetes (type 1 diabetes considered first), Graves disease, convulsions pending investigation (consideration of epilepsy), ptosis (consideration of myasthenia gravis), and the cause of epilepsy was not clear at the time of discharge
.

Two years later, the epilepsy had another seizure.
Through the interpretation of the commonly used item "anti-glutamate decarboxylase antibody (GAD)" in laboratory tests, the patient's clinical course was very well connected, and the final diagnosis of "autoimmune polyendocrine syndrome" (APS Ⅲ) combined with marginal encephalitis (GAD-mediated) and thymoma" provides key evidence
.

The diagnosis and treatment of this case suggests the importance of applying integrated medical concepts in the clinical diagnosis and treatment process
.
Laboratory physicians understand modern testing technology, actively carry out related testing items, closely integrate clinical practice, use professional knowledge to interpret test results, and work with clinicians to make the final diagnosis of the disease
.
This case is clinically rare, reflecting the high guiding value of laboratory diagnosis results for clinical work in integrated medicine
.

Clinical Comments

Expert: Li Chengjiang, chief endocrinologist, professor, master tutor of the First Affiliated Hospital of Zhejiang University School of Medicine, former director of the Department of Endocrinology, and appointed chairman of the Endocrinology Branch of Zhejiang Medical Association
.

Comments: Autoimmune polyendocrine syndrome (APS Ⅲ type) combined with marginal encephalitis (GAD-mediated) and thymoma are clinically rare, and they are easily misdiagnosed and missed
.
In the diagnosis and treatment of this case, clinicians have applied holistic concepts and scientific and rigorous clinical thinking well, centered on patients, paid attention to details in the manifestations of common endocrine diseases, combined endocrine diseases and autoimmune diseases, and put forward diagnostic ideas
.
Laboratory physicians must be closely integrated with the clinic, combined with modern testing technology, and actively carry out relevant testing items, peel off the cocoon, remove the falsehood and preserve the truth, and finally be diagnosed.
It has high guidance for clinical work and high clinical research value
.