Fulminant type 1 diabetes (FTlD) is a new subtype of type 1 diabetes first reported by Japanese scholar Imagawa in 2000 and is tentatively classified as type 1B. The onset of the disease is usually preceded by prodromal symptoms such as upper respiratory tract infection or gastrointestinal discomfort within one to two weeks. The onset of the disease is rapid, with rapid destruction of pancreatic islet B cells, and diabetic ketosis (DK) or DKA occurs within one week of the onset of hyperglycemia, with high blood glucose and near normal HbA1c, often accompanied by elevated serum pancreatic enzyme levels. Some patients have transient changes in ECG, and in severe cases, rhabdomyolysis and acute renal failure may occur, which may lead to death if improper or untimely treatment.
Clinical analysis
(I) Epidemiology
The incidence of this disease is predominantly in the yellow population, especially in the Japanese, which may be related to their better knowledge of this disease. In recent years, the disease has also been reported in other Asian countries and among Caucasians and Hispanic Americans. imagawa et al. showed that FTlD accounted for 20% of patients seen with DKA in a Japanese population. the study also showed that the disease accounted for 7.1% of adults with type l diabetes, but the incidence of the disease was less in children with type 1 diabetes than in adults. According to Korean statistics, FTlD accounts for 1.33% of newly diagnosed type 1 diabetes mellitus in patients under 16 years of age.
The age of onset of the disease ranged from l to 80 years, with a mean of (39.1 ± 15.7) years, which is greater than type 1A. Imagawa et al. found that the BMI at the onset of FTlD was higher than that of type 1A [(20.7±3.9 versus 18.8±2.8) kg/m2].
In addition, according to a Japanese survey, FT1D often develops in May, which is twice as often as the general month, while a survey of women of childbearing age from China showed that pregnancy-associated FT1D (fulminant type 1 diabetes associated with pregnancy, PF) was associated with non-pregnancy-associated FTlD_( fhlminant type 1 diabetes not associated with pregnancy (NPF) showed no regional or seasonal differences. The prevalence has increased in recent years in all regions. It may be related to the increased awareness of the disease among clinicians, but the real incidence and prevalence need further statistics.
(B) Etiology and pathogenesis
The specific pathogenesis of the disease is not fully understood, but it is generally believed that viral infection, autoimmunity and pregnancy may be related to the development of the disease on the basis of genetic background. Studies have shown that human leukocyte antigen (HLA) CII is the susceptibility gene for FT1D and type 1A, but there are differences between the two HLAC II haplotypes, with the main susceptible haplotype for FTlD being DRBl*0405CDQBl*0401 and the susceptible haplotype for type 1A being DRBl*0901CDQBl*0301.
On the basis of genetic susceptibility, viral infection is a key factor in triggering FT1D. A national survey in Japan found that serum IgA antibody titers of echovirus were significantly higher in FT1D patients compared with type 1A and normal controls. Immunohistochemical tests demonstrated that enterovirus capsids were found in islet cells and pancreatic exocrine tissues of FT1D patients and that viral pattern recognition receptors (pattem recognition receptors) were significantly expressed in islet cells and monocytes infiltrating islets, whereas they were not expressed or were minimally expressed in type 1A patients and normal controls.
Autoimmunity also plays an important role in the pathogenesis of FT1D. Viral infection triggers an autoimmune response, and the molecular mechanism may be that cytokines or cytotoxins such as chemokine ligand 10, gamma interferon and interleukin 18, which are significantly expressed in β-cells during viral infection, interact to activate immune responses mediated by dendritic cells, macrophages and autoimmune T cells. β-cell apoptosis is triggered through endogenous and exogenous pathways, and β-cell endoplasmic reticulum stress is also a factor in activating the endogenous apoptotic pathway.
The vast majority of the literature reports negative islet related autoantibodies (IRA) at the onset of FT1D patients. A national survey in Japan showed a GADCAb positivity rate of only 4.7% with low titers: however, one paper reported an increase in peripheral blood glutamic acid decarboxylase-reactive T cells in patients with late GADCAb conversion, and whether this correlates with FT1D remains to be further investigated.
Recently, it has been reported that the incidence of FT1D in patients with drug-induced hypersensitivity syndmme (DIHS) is higher than that in the general population, and the mean age of onset is older, 53.4 years. The mean time from the appearance of DIHS to the development of FT1D was 39.9 d, and the susceptibility gene was HLAB62. It is assumed that the immune response triggered by DIHS is associated with the development of the disease on the basis of genetic susceptibility. The mechanism may be the release of inflammatory cytokines by T lymphocytes and macrophages-mediated immune response, which destroy islet B cells and lead to the development of the disease.
Pregnant women are a high-risk group for this disease, and almost all new type 1 diabetes during pregnancy are FT1D. it was found that PF patients have a significant difference between their HLAC II haplotype and NPF. in addition to the trait of HLA antigens, the development of PF is related to the special physiological changes during pregnancy, which may be related to the development of this disease, but the specific mechanism needs further study.
(C) Clinical manifestations
1. Prodromal symptoms: 70% of patients often have cold-like symptoms or gastrointestinal discomfort before the onset of the disease, mostly within 2 weeks before the onset of the disease. Cold-like symptoms such as fever, headache, cough, sore throat, etc.; gastrointestinal discomfort, the most common are abdominal pain, diarrhea, nausea, vomiting, etc.. In addition, hypoglycemic symptoms may appear before the onset of the disease, probably due to the rapid destruction of β cells and the release of the synthesized insulin in the blood within a short period of time, which has been confirmed in animal models.
2. Hyperglycemia and metabolic disorder manifestation: manifested as severe hyperglycemic symptoms such as irritable thirst, excessive drinking and polyuria. Almost all patients develop DK within 1 week of the onset of hyperglycemic symptoms, and about 90% of them have DKA, whose acidosis is significantly more severe than that of type lA. At the onset, blood glucose is very high while HbA1c is mostly close to normal, about half of the patients have HbA1c<6< span="">.2%_12, insulin and C-peptide levels are significantly reduced, and IRA is usually undetectable.
3. Other systemic manifestations: (1) Serum pancreatic enzyme levels were elevated in 98% of patients. However, CT and ultrasound examination of the pancreas are mostly without obvious abnormalities, very few patients may have pancreatic edema, some scholars found pathological changes in the pancreas through autopsy, but this is different from acute pancreatitis. Most patients may have mildly elevated serum glutamate transaminase and glutamic oxalacetic transaminase;
(2) A significant number of patients may have elevated serum CK, CKCMB, troponin, BNP, and even heart failure, which is more common in elderly patients. The inflammatory response, acidosis, electrolyte disturbance, especially high fatty acid and other internal environmental disturbances during DKA can affect myocardial cell conduction and cell membrane depolarization, and in some patients can also cause transient coronary spasm and transient ST-segment elevation on ECG, which is easily misdiagnosed as acute Myocardial infarction;
(3) The combination of acute pulmonary edema, cerebral edema, and rhabdomyolysis leading to acute l renal failure has also been reported.
It is generally believed that the above-mentioned manifestations are related to the disturbance of the internal environment, microcirculatory disorders, and ischemia and hypoxia in DKA, which often indicate the severity of the disease. If the treatment is timely and appropriate, with the correction of hyperglycemia and DKA, the above abnormalities can be completely recovered.
(IV) Diagnosis and differential diagnosis
According to the criteria proposed by the Japanese Diabetes Society in 2004, the following 3 points must be met to confirm the diagnosis of FT1D: (1) development of DK or DKA within l weeks of the onset of hyperglycemic symptoms (elevated blood or urine ketone bodies at the first visit); (2) blood glucose ≥288 mg/dl and HbA1c <8.5< span="">% at the first visit; (3) urine C-peptide value <10 mg/d at the onset, or FCP<0.3ng/ml and <0.5ng/ml after stimulation (glucagon or feeding).
Other common clinical features are: (1) 70% of patients have flu-like symptoms or gastrointestinal symptoms before the onset of the disease: (2) elevated blood glucose appears within 1 to 2 weeks of the onset of prodromal symptoms; (3) 98% of patients have elevated levels of serum pancreatic enzymes (amylase, lipase, elastase C1 and phospholipase): (4) IRA is often negative; (5) it can develop during pregnancy or after delivery.
The disease needs to be differentiated from the following diseases: (1) mainly with lA type, lA type has a younger age of onset, higher HbA1c level at onset, IRA can be positive, combined with the onset characteristics of FT1D should not be difficult to differentiate. (2) FT1D with gastrointestinal symptoms and elevated blood and urine amylase, especially in combination with gallstone disease, should be distinguished from secondary diabetes mellitus due to severe pancreatitis, DKA. In the latter case, abdominal symptoms and signs are more obvious. Blood amylase is elevated more than 3 times the upper limit of normal, and pancreatic cT or ultrasound, etc. generally have corresponding changes of acute pancreatitis. (3) FT1D combined with myocardial enzymatic abnormalities and electrocardiographic changes should be distinguished from acute myocardial infarction. The latter often has risk factors for coronary heart disease. Chest pain is more intense and characteristic, myocardial enzymology and ECG may show a series of characteristic dynamic changes, and troponin elevation is obvious. In some patients, ECG changes need to be differentiated from bundle branch block and atrial fibrillation. In general, FT1D ECG changes are mostly transient and disappear with the correction of metabolic disorders.
(E) Treatment
1. Treatment of hyperglycemia and metabolic disorders: Once the disease is suspected. It should be treated immediately and actively, and there are no special principles for the treatment of DKA. When DKA is corrected. Due to the extremely poor β-cell function and high blood glucose fluctuation, it is emphasized to control blood glucose with insulin intensive treatment program, and basal insulin is best to choose long-acting. Conditions allow, continuous subcutaneous insulin infusion therapy can be considered. It can be supplemented with metformin and alpha glucosidase inhibitors to reduce blood glucose fluctuation and insulin dose. In addition, special careful management and good diabetes education are needed.
2. Treatment of comorbidities: When there are elevated serum pancreatic enzymes, abnormal liver and kidney functions and electrocardiogram changes, no special treatment is needed for mild cases, but close observation is required. Generally, it will improve with the correction of hyperglycemia and DKA. In severe cases, such as combined heart failure, rhabdomyolysis and acute renal failure, comprehensive treatment measures are required while correcting metabolic disorders.
(F) Prognosis
FT1D has a rapid onset and is very dangerous, with a poor prognosis. There is no statistical data on the mortality rate of this disease. β-cells of FT1D patients are almost completely destroyed, and islet function is much worse than that of type 1A, and so far there is no report of p-cell function recovery. The incidence of severe hypoglycemia is also higher due to the extremely poor β-cell function in this disease.
The incidence of microvascular complications in FTlD is higher than that of type lA. The Japanese FT1D committee conducted a 5-year follow-up of 4l cases of FT1D and 76 cases of type 1A patients nationwide and found that: the HbA1c of the two was comparable, but the incidence of microangiopathy in this disease was significantly higher than that of type 1A, with the incidence of diabetic retinopathy, peripheral neuropathy and diabetic nephropathy being 9.8%, 12.2% and 12.2%, respectively, while that of type 1A was 0%, 1.3% and 2.6%, respectively. 1.3% and 2.6%, respectively. However, another 10-year survey of 16 FT1D and 60 type lA patients found no difference in the cumulative incidence of microangiopathy between the two.
IV. Diagnosis, treatment, follow-up and clinical characteristics of the cases in this paper
The 2 cases in the first volume of this paper fully met the diagnostic criteria for FTl D, so the diagnosis was clear.
After the correction of DKA in the 2 patients was changed to 4 times daily insulin intensive glucose lowering, the blood glucose still fluctuated greatly and was prone to hypoglycemia, showing the characteristics of brittle diabetes mellitus. This was related to the extremely low function of pancreatic β-cells. After supplemented with α-glucosidase inhibitor and metformin, it can improve hyperglycemia, reduce hypoglycemia and blood glucose fluctuation, and reduce insulin dosage. 2 patients were discharged with insulin dosage of 0.57 U・kg-1・d-1 and 0.73 U・kg-1・d-1, including case 1 with glycine insulin dosage of 0.2 U・kg-1・d-1 and Novalis 0.37 U・kg-1・d-1 The dosage of case 2 came with 0.25 U・kg-1・d-1, 0.48 U・kg-1・d-1 of Novalis, 0.5 g qd of oral metformin extended-release tablets and 0.2 mg qd of voglibose.
Follow-up of 2 patients. Case 1 moved out of the hospital about 20 d after discharge and had good glycemic control at the telephone follow-up. Case 2 had relatively poor compliance with treatment and had changed the treatment regimen in a foreign hospital during the period, and the HbA1c tended to rise gradually. 2 patients were followed up at about 1 month and 7 months after the onset of the disease, respectively, and neither of them showed any signs of improvement in islet β-cell function. In case 2, which was dynamically observed for 7 months, there was no significant difference in pancreatic β-cell function at more than 2 months from the time of onset, but it showed a significant decrease at 7 months. The reason for this is that it is unclear whether the onset factors continue to produce damage to the islet β-cells or the effect of glucotoxicity at a later stage, but the latter is presumed to be more likely, judging from the trend of no change at the beginning and a decline at the end. 2 patients with diabetes mellitus remain negative on follow-up for autoantibodies.
The two patients in this paper: (1) had cold-like symptoms or gastrointestinal symptoms before the onset of the disease, respectively; (2) had elevated blood glucose within l weeks of the onset of prodromal symptoms; (3) were negative for IRA; and (4) had elevated serum pancreatic enzyme (amylase and lipase) levels. These are all consistent with the most common clinical features of FT1D described previously. However, the age of onset for both was 58 and 62 years, respectively, which was significantly higher than the mean age of onset reported in the literature (39.1 years), and in addition the month of onset was close, around October. In addition, the onset months were close to each other, around October, and the season of prevalence (May) was also different from that reported in Japan.
In this paper, two patients were older and both were initially misdiagnosed as type 2 diabetes mellitus. Case 1 was once misdiagnosed as acute myocardial infarction. The cases in this paper and the literature suggest that (1) older patients with first-onset diabetes should be alerted to the possibility of FT1D when they present with rapidly progressing severe DKA; (2) when patients with DKA present with ECG changes and elevated pancreatic enzymes similar to acute myocardial infarction, this often indicates a serious condition, and the differential diagnosis should be made with caution and the possibility of FT1D should be taken into account; (3) for patients with the above respiratory or gastrointestinal symptom onset, conventional (3) for the above respiratory or gastrointestinal symptoms onset, conventional treatment is not effective, the deterioration of the condition especially the emergence of hyperglycemic symptoms should be timely determination of blood glucose, to avoid blind input of sugary liquid, delaying the diagnosis and treatment; (4) the disease is more serious pancreatic B-cell damage than lA type, large blood glucose fluctuations, high incidence of microangiopathy, should be particularly strengthened management of diabetes mellitus, delaying the onset of complications.