Development Of Fulminant Type Research Articles

Development of Fulminant Type 1 Diabetes Mellitus in the Course of Treatment with Atezolizumab for Hepatocellular Carcinoma.

A 71-year-old woman with recurring stage IV hepatocellular carcinoma (HCC) was admitted to our hospital while being treated with atezolizumab and bevacizumab and complained of fatigue, vomiting, and appetite loss. The following were noted on admission: serum glucose level, 633 mg/dL; metabolic acidemia (HCO3- of 19.5 mmol/L); remarkably low serum and urinary C-peptide levels (0.16 ng/mL and ≤1.5 μg/day, respectively); and urinary ketone body level, 4,197 μmol/L. She was diagnosed with atezolizumab-induced fulminant type 1 diabetes mellitus (T1DM), and insulin therapy improved the symptoms. To our knowledge, this a novel report of atezolizumab-induced fulminant T1DM in an HCC patient.

Immune checkpoint therapy and type 1 diabetes.

Type 1 diabetes is caused by destruction of insulin-producing beta cells of the pancreas. The etiology of type 1 diabetes is immune-mediated by either an organ-specific autoimmune mechanism in autoimmune type 1 diabetes or a still unknown but probably immune-mediated mechanism in fulminant type 1 diabetes. Immunomodulation is therefore expected to accelerate or inhibit type 1 diabetes. Recent progress in anti-cancer therapy by immune-checkpoint blockade, such as anti-PD-1 and anti-CTLA4 monoclonal antibodies, has markedly improved the prognosis of patients with advanced cancers. These drugs activate anti-tumor immunity by blocking inhibitory signals of T lymphocytes. Activation of immunological pathways, however, is expected to accelerate immune-mediated diseases. In fact, the development of autoimmune-thyroid diseases and type 1 diabetes, including fulminant type 1 diabetes, has been reported in patients treated with immune checkpoint blockers. The development of fulminant type 1 diabetes is a major concern because of its abrupt onset and very rapid progression, leading to death unless proper treatment is initiated immediately after diagnosis. In this review, the development of type 1 diabetes with immune-checkpoint therapy and its etiological background are discussed.

Development of fulminant Type 1 diabetes with thrombocytopenia after influenza vaccination: a case report

Fulminant Type 1 diabetes was originally reported as idiopathic Type 1 diabetes. Involvement of viral infections in the pathogenesis of fulminant T1D has been suggested, but the development of fulminant Type 1 diabetes after influenza vaccination has not been reported. We report a case of fulminant Type 1 diabetes with thrombocytopenia following influenza vaccination. A 54-year-old man was admitted to hospital with hyperglycaemia and diabetic ketosis. Seven days before admission, he received a seasonal influenza vaccine for the prevention of influenza infection. On admission, blood glucose was 29 mmol/L and HbA1c 40 mmol/mol (5.9%). Fasting and 2-h C-peptide immunoreactivity were <0.0333 nmol/L and 0.0999 nmol/L, respectively. Anti-GAD and anti-IA-2 antibodies were negative, so no autoimmunity seemed to participate in the etiology. ELISPOT assay also showed no association with T cell-mediated autoimmunity. HLA genotypes were consistent with susceptibility to fulminant Type 1 diabetes. After the abrupt onset of diabetes, he showed mild thrombocytopenia, which has been observed for approximately 5 years after diabetes development. This is the first description of fulminant Type 1 diabetes after influenza vaccination. Our observation raises the possibility that influenza vaccination might trigger this condition via the TLR7 pathway.

A case of fulminant type 1 diabetes mellitus after influenza B infection

A 64-years-old man referred to a hospital because of high-grade fever. He was diagnosed as having influenza B by “POCTEM Influenza A/B”, a rapid influenza diagnostic kit which detect some antigens of influenza virus. Six days after medication of oseltamivir phosphate, his flu-symptoms disappeared, but he complained sever thirsty. And after 2 days, he suffered from loss of consciousness and was admitted to the hospital. Laboratory data on admission showed diabetes ketoacidosis, slight elevation of HbA1c level despite sever hyperglycemia, and increase of serum amylase concentration. Anti GAD antibody and anti IA-2 antibody were not detected. Urinary C-peptide excretion was undetectable and serum C-peptide levels were also undetectable after glucagon and arginin load, suggesting disappearance of endogeneous insulin secretion. Class II HLA was susceptible to fulminant type1 diabetes. Based on these findings, we diagnosed him with fulminant type1 diabetes. In Japan, only three viruses in three cases have been reported to be the trigger in the development of fulminant type 1 diabetes. They were human herpes virus 6, herpes simplex virus and Coxsackie B3 virus. This is the fourth report of fulminant type 1 diabetes developed after the established diagnosis of viral infection and the first after influenza B virus infection. The fact that fulminant type 1 diabetes developed after the infection of such a common virus suggest that factors within host will play more important roles than virus itself in the etiology of fulminant type 1 diabetes.

Genetics of Fulminant Type 1 Diabetes

Fulminant type 1 diabetes exhibits distinct clinical futures from "classic" autoimmune type 1 diabetes. Although the etiology of fulminant type 1 diabetes is not fully elucidated, class II HLA could contribute to the development of fulminant type 1 diabetes. In Japanese patients with "classic" type 1 diabetes, DRB1*0405-DQB1*0401 and DRB1*0901-DQB1*0303 are major susceptible HLA-DR-DQ haplotypes, whereas DRB1*1502-DQB1*0601 and DRB1*1501-DQB1*0602 are protective. In contrast, only DRB1*0405-DQB1*0401, but not DRB1*0901-DQB1*0303, is a susceptible haplotype in fulminant type 1 diabetes. In addition, neither DRB1*1502-DQB1*0601 nor DRB1*1501-DQB1*0602 are protective haplotypes in fulminant type 1 diabetes. In genotypic combination analysis, the homozygotes of DRB1*0405-DQB1*0401 are associated with both fulminant type 1 diabetes and "classic" type 1 diabetes, whereas the homozygotes of DRB1*0901-DQB1*0303 are associated with only "classic" type 1 diabetes. These findings suggest a different contribution of class II HLA in the mechanisms of beta cell damage between fulminant and "classic" type 1 diabetes. To further address the pathogenesis of fulminant type 1 diabetes, HNF-1alpha gene mutation and mutation of the mitochondrial DNA were analyzed in patients with fulminant type 1 diabetes admitted to our department during the period from 1990 to 2000. Neither mutations of HNF-1alpha gene nor A-to-G mutation at nucleotide position 3,243 of the mitochondrial tRNA(LEU(UUR)) gene were identified in these patients. These results suggest that the HNF-1alpha gene mutation and mutation of the mitochondrial DNA are not likely associated with diabetic patients with fulminant clinical symptoms at disease onset. In this article we will summarize the current findings on the genetics of Japanese patients with fulminant type 1 diabetes.

Pancreatic exocrine and endocrine events occur concomitantly but independently during the course of fulminant type 1 diabetes

Although pancreatic exocrine enzymes are often elevated in patients with fulminant type 1 diabetes, the onset of this elevation and its significance in disease development remain unclear. We therefore investigated the significance of elevated serum enzyme concentrations and pancreatic swelling in the development of fulminant type 1 diabetes. Serum pancreatic exocrine enzymes, including amylase, elastase-I, lipase and trypsin, were measured during the course of the disease in 11 patients with fulminant type 1 diabetes (3 men and 8 women; a range of age 24–73 years, median 33 years; a range of HbA 1c at onset 4.5–6.7%, median 6.0%), all of whom developed ketotic diabetes requiring intensive insulin therapy within a month. At least one pancreatic exocrine enzyme was elevated in each patient during the course of the disease. The concentration of enzymes on admission could not be correlated with urinary excretion of C-peptide. The time course of increase in serum amylase varied in these patients. In conclusion, neither the level of serum amylase nor the swelling of pancreas was associated with the onset or severity of fulminant type 1 diabetes. The pancreatic exocrine and endocrine events may occur concomitantly but independently during the course of fulminant type 1 diabetes.