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Fulminant type 1 diabetes: a novel clinical entity requiring special attention by all medical practitioners
Toshiaki Hanafusa and Akihisa Imagawa S U M M A RY
Fulminant type 1 diabetes is a recently discovered subtype of type 1 diabetes It is defined as diabetes in which the process of -cell destruction and the progression of hyperglycemia and ketoacidosis are extremely rapid The pathogenesis of this disease remains to be clarified, but the involvement of both genetic background–especially human leukocyte antigen genes–and viruses has been suggested Fulminant type 1 diabetes has the following clinical characteristics: duration of hyperglycemic symptoms is 4 days on average; there is a high prevalence of preceding common-cold-like and gastrointestinal symptoms; there is a near-normal level of glycated hemoglobin in spite of very high plasma glucose levels associated with ketoacidosis; the disease is sometimes related to pregnancy; and there are increased serum pancreatic enzyme levels, absent C-peptide levels, but virtually no detectable autoantibodies against constituents of pancreatic cells The presence of the above characteristics
strongly indicates the diagnosis of fulminant type 1 diabetes Once the diagnosis of this disease is suspected, treatment of diabetic ketoacidosis must be started immediately, as in all other cases of type 1 diabetes Otherwise, the death of the patient is likely to occur within 24 h All medical practitioners must remember that this extremely rapidly progressing type of diabetes does exist, and they must pay special attention not to overlook it
KEYWORDS autoimmunity, HLA, ketoacidosis, type 1 diabetes, virus
This article offers the opportunity to earn one Category 1 credit toward the AMA Physicians Recognition Award
INTRODUCTION
REVIEW CRITERIA We searched PubMed for relevant publications using the search terms type 1 diabetes and fulminant
CME
T Hanafusa is a Professor, and A Imagawa an Assistant Professor, of the First Department of Internal Medicine in the Osaka Medical College, Osaka, Japan T Hanafusa is Chief, and A Imagawa is a Sub-Chief, of the Diabetes, Endocrinology and Metabolism Section
Correspondence
First Department of Internal Medicine, Osaka Medical College, 2-7 Daigaku-machi, Takatsuki 569-8686, Japan hanafusa@pohosaka-medacjp
Received 13 December 2005 Accepted 31
July 2006
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Type 1 diabetes results from destruction of pancreatic cells Destruction of most of the -cell mass leads to marked depletion of insulin Since insulin is the only hormone that lowers blood glucose levels in the human body, depletion of insulin therefore results in marked hyperglycemia Insulin also has antilipolytic effects, and thus its absence increases lipolysis and causes ketosis followed by ketoacidosis Without proper treatment, ketoacidosis leads to death of the patient According to the classification made by the American Diabetes Association and the World Health Organization,1,2 type 1 diabetes is further divided into two categories: autoimmune type 1A and idiopathic type 1B diabetes Type 1A diabetes is now believed to result from destruction of cells by autoreactive immunocytes; however, little is known even now about type 1B diabetes For the last 5 years or so, accumulating evidence has indicated the presence of a new clinical entity–a very rapidly progressing form of type 1 diabetes35 This form is now called fulminant type 1 diabetes, because the disease progresses very rapidly Since the first description
of this disease,3 many interesting results have been emerging In this review we provide a comprehensive description of our current knowledge about this life-threatening disease This novel clinical entity is extremely important for all physicians, especially clinical practitioners, because if it is disregarded or not caught, it quickly results in the death of the patient
DEFINITION AND GENERAL CONCEPT: WHAT IS FULMINANT DIABETES?
Fulminant type 1 diabetes is defined as diabetes in which the process of -cell destruction and, therefore, progression of hyperglycemia and ketoacidosis are extremely rapid The
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duration of the disease from a normal -cell mass and normoglycemia to almost total destruction of cells and ketoacidosis is considered to be only a few days, and rarely exceeds 1 week Without appropriate therapy, the death of the patient is inevitable, as in all other cases of type 1 diabetes This rapid aggravation contrasts strikingly with the slow progression of type 1A diabetes, in which it takes at least several years from the initial appearance of
autoantibodies in the peripheral blood to the clinical onset of ketoacidosis Figure 1 In our original study,3 we collected a group of patients with an extremely rapidly progressing diabetes without anti-GAD glutamic acid decarboxylase antibodies; however, when we collected many additional cases of extremely rapidly progressing diabetes in the following nationwide survey in Japan, a small proportion of such patients turned out to have antiGAD antibodies, though in most of such cases the titer was low and the duration of positivity was short This additional finding led us to change our original definition of fulminant type 1 diabetes, and the absence of detectable autoantibodies is not included in the new definition
EPIDEMIOLOGY Prevalence
100 Fulminant Autoimmune
Hypothetical
-cell
mass
20 Insulinrequiring state 0 Years 1 week Time
Figure 1 Schematic process showing the destruction of the hypothetical -cell mass in fulminant type 1 diabetes and type 1A autoimmune diabetes
25
20 Number of patients
15
In a hospital-based preliminary study of 5 years duration, the prevalence of fulminant type 1 diabetes was 196 11 out of 56 patients who had type 1 diabetes with ketosis-onset
or ketoacidosis-onset3 A nationwide survey, conducted in Japan, followed and showed that the prevalence of this type of diabetes was 194 43 out of 222 patients who had type 1diabetes with ketosis-onset or ketoacidosis-onset5 In a regional, hospital-based study for diabetes in the Japanese region of Ehime, the prevalence of fulminant type 1 diabetes among acute-onset type 1 diabetic patients in whom insulin treatment was initiated within 3 months was 148 9 out of 616 These lines of epidemiological evidence have confirmed that in Japan fulminant diabetes accounts for 1520 of type 1 diabetes cases that feature the onset of ketosis or ketoacidosis
Age at onset
10
5
0
9
9
9
9
9
9
0 9
9 70 7
10 1
20 2
30 3
40 4
50 5
Age years
Figure 2 Distribution of ages at onset of fulminant type 1 diabetes The white columns depict males and the gray columns depict females The light gray bars show pregnant patients or those who recently gave birth Adapted, with permission, from Hanafusa et al16 Permission obtained from the Japan Diabetes Society Hanafusa T et al 2005 J Japan Diab Soc 48 Suppl 1: A1A13
The onset age of fulminant type 1 diabetes ranges from 1 to 80 years old Figure 2
The mean age of the patients at onset of the disease
is 391 157 years mean SD; Table 1 Among 161 patients, only 14 87 were under 20 years of age, indicating that more than 90 of patients
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Table 1 Clinical characteristics at onset in patients with fulminant type 1 diabetes in comparison with those with autoimmune type 1A diabetes
Characteristic Age BMI kg/m2 Family history of type 1 Family history of type 2 diabetesa diabetesa Fulminant type 1 DM 391 157 207 39 1/160 25/119 9/85 Autoimmune type 1A DM 301 162 188 28 2/135 33/102 17/51 P value 00001 00001 NS NS 001
Regional variation
Association with other autoimmune diseases
Data are mean SD or numbers of patients positive/negative Adapted, with permission, from Imagawa et al5 Copyright 2003 American Diabetes Association from Diabetes Care, Vol 26, 2003; 23452352 aFamily history of type 1 or type 2 diabetes given for first-degree relatives Abbreviations: DM, diabetes mellitus NS, not significant
Within Japan, fulminant type 1 diabetes occurs all over the countrys
islands and there is no area of significant accumulation; however, there seems to be a large difference in the prevalence of fulminant diabetes between Japan and other countries Reports of patients with this type of diabetes are extremely rare from outside Japan, and especially rare from Western countries811 Only a limited number of patients whose clinical course resembles that of fulminant type 1 diabetes have been reported in other ethnic groups1215
Year-to-year variation
39 25 Number of patients 20 15 10 5 0
For the last 10 years, there seems to be a trend of an increase in the number of new-onset fulminant type 1 diabetes cases in Japan Figure 3;16 however, this trend could be partly attributable to the increasing interest in this disease among doctors in Japan The apparent increase, therefore, does not seem to be significant
Seasonal variation
Year
Figure 3 Year-to-year variation in number of patients with fulminant type 1 diabetes from 1990 to 2000 Dark gray columns indicate the number of patients seen in 10 diabetes centers, whereas light gray columns indicate the number of patients reported from other hospitals Adapted, with permission, from Hanafusa et al16 Permission
obtained from the Japan Diabetes Society Hanafusa T et al 2005 J Japan Diab Soc 48 Suppl 1: A1A13
Fulminant type 1 diabetes develops most frequently in May, according to a nationwide survey of the disease in Japan Figure 4 Even so, the incidence of the disease in May does not exceed the double of the average incidence during the year At present the seasonal variation of fulminant diabetes is thus not considered significant
Association with pregnancy
91
93
95
98
19 90
19 92
19 94
19 96
19 97
19 99
19
19
19
19
20
00
with this disease are over 20 years old, although some childhood onset occurs7 This pattern also makes a remarkable contrast with the onset of type 1A diabetes, which is most prevalent in adolescence
Male-to-female variation
The proportions of male and female patients with fulminant type 1 diabetes are nearly the same: among 161 patients, 78 were female and 83 were male; however, female patients tend to develop fulminant diabetes at significantly younger ages than male patients–the age at onset in female patients is 351 158 years and that in males is 428 148 years P 00015
The development of fulminant type 1 diabetes sometimes associates with
pregnancy By the time of the nationwide survey, 14 female patients had developed diabetes during pregnancy or just after delivery Among them, only one case was associated with autoimmune type 1A diabetes; the other 13 were associated with fulminant type 1 diabetes The difference is remarkable, and association with pregnancy could be regarded as one of many characteristics of fulminant diabetes5,17,18 In most patients with fulminant type 1 diabetes associated with pregnancy PF, the onset of diabetes is in the third trimester or immediately after delivery The prognosis for the fetus is extremely poor The differences in clinical and genetic characteristics between PF and fulminant type 1 diabetes not associated with pregnancy NPF are reported elsewhere19 Briefly, compared with NPF, PF shows significantly
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Number of patients
lower values in the incidence of abdominal symptoms, lower glycated hemoglobin HbA1c levels, and lower arterial pH The prevalence of the human leukocyte antigen HLA; see Box 1 genotypes is also slightly different between
PF and NPF19
GENETIC BACKGROUND
20
15
10
Accumulating evidence strongly suggests that different genotypes of HLA confer susceptibility or resistance to the development of type 1 diabetes20 In Japanese people, HLADR4DQ4 usually encoded by DRB10405 DQB10401 and DR9DQ3 encoded by DRB10901DQB10303 have been reported to confer susceptibility to type 1 diabetes, whereas DR2DQ1 encoded by DRB11501/1502 DQB10602/0601 has been shown to confer resistance On the other hand, in Caucasians, HLA-DR4DQ1 encoded by DRB10401 DQB10302 and DR3DQ2 encoded by DRB10301DQB10201 but not DR4DQ4 confer susceptibility to type 1 diabetes, and DR2 DQ1 encoded by DRB11501DQB10602 confers resistance, as in Japanese people20,21 As a part of the nationwide survey, HLA-A, HLA-DR and HLA-DQ serotypes were investigated in 91 patients with fulminant diabetes and 81 patients with type 1A diabetes together with 190 normal controls22 The distribution of HLA-A was not different between patients with fulminant or type 1A diabetes and controls Regarding class II HLA, DR4DQ4 was observed in 418 of patients and was significantly more frequent in patients with fulminant diabetes, whereas both DR2DQ1 and DR8DQ1 were less
frequent In type 1A diabetes, DR2DQ1 was extremely rare, whereas DR9DQ3 was significantly more frequent In the combination analysis, homozygosity for DR4DQ4 in fulminant type 1 diabetes and DR9DQ3 in typical type 1A diabetes indicated high odds ratios 133 and 133, respectively for disease These results suggest that the class II HLA genotype also contributes to the development of fulminant type 1 diabetes, but that the susceptibility or resistance of different HLA genotypes to type 1 diabetes is distinct between fulminant and typical type 1A diabetes The HLA-DR4DQ4 haplotype is common in Japanese people but rare in Caucasian populations, and this difference might contribute to the different incidence of fulminant diabetes between Japanese and Caucasian people
5
0
N ov
Au g
Se p
M ay
Fe
Ja
Month
Figure 4 Seasonal variation of fulminant type 1 diabetes Numbers of patients include both patients seen in 10 diabetes centers and those reported from other hospitals Adapted, with permission, from Hanafusa et al16 Permission obtained from the Japan Diabetes Society Hanafusa T et al 2005 J Japan Diab Soc 48 Suppl 1: A1A13
Box 1 The human leukocyte antigen system
Human leukocyte
antigen HLA is a group of molecules encoded by the genes in the HLA complex also called the MHC in a region on a short arm of chromosome 6 in humans Two main classes of HLA molecules are class I HLA-A, -B, and -C and class II HLA-DR, -DQ, and -DP Most of the HLA loci genes are polymorphic, making a set of HLA molecules in each individual extremely heterogeneous HLA molecules play a critical role in immunological specificity; for example, presentation of antigens to the immune system, killing of antigen-bearing target cells by cytotoxic T lymphocytes, and rejection of transplanted tissues Certain HLA types are known to associate with susceptibility or resistance to various autoimmune diseases including type 1A diabetes This association is often utilized in exploring the strategies for prediction and prevention of the disease In type 1A diabetes, for example, siblings and/or offspring of patients with type 1 diabetes were followed in terms of appearance of islet autoantibodies and development of diabetes, and those who have susceptible HLA types were shown to have higher risk of developing islet autoimmunity and diabetes than those who have not
PATHOLOGY
In the pancreas of patients
with fulminant type 1 diabetes, the area of insulin-positive cells is markedly reduced and almost no remaining cells can be seen In type 1 diabetes, cells are always reduced in number, but in type 1A diabetes some cells still remain In addition, in contrast to type 1A diabetes, glucagoncontaining cells are also significantly reduced in fulminant type 1 diabetes In fulminant type 1 diabetes, it is therefore concluded that both and cells are greatly reduced in number23 Insulitis–infiltration of lymphocytes and/or other immunocytes inside and/or around the
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Table 2 Symptoms at onset in fulminant type 1 diabetes in comparison with those in autoimmune type 1A diabetes
Characteristic Duration of the disease days Symptoms Thirst Body weight loss kg Flu-like symptoms total Fever Sore throat Cough Headache Abdominal symptoms total Nausea or vomiting Upper abdominal pain Lower abdominal pain Disturbance of consciousness Association with pregnancya 937 35 27 717 600 252 120 115 725 654 392 110 452
210 933 55 37 269 ND ND ND ND 75 ND ND ND 53 15
al5
CLINICAL FEATURES
Fulminant type 1 DM 44 31
Autoimmune type 1A DM 364 251
P value NA
NS 00001 00001 NA NA NA NA 00001 NA NA NA 00001 00003
Data are mean SD or Adapted, with permission, from Imagawa et Copyright 2003 American Diabetes Association from Diabetes Care, Vol 26, 2003; 23452352 aIndicates percent female subjects ages 1349 years who had type 1 diabetes during or after pregnancy in this study 13 out of 62 fulminant diabetic subjects and 1 of the autoimmune diabetic subjects Abbreviations: DM, Diabetes mellitus; NA, not applicable; ND, not determined; NS, not significant
pancreatic islet–was not a common feature in biopsy specimens of the pancreas in patients with fulminant type 1 diabetes a few months after onset3,24 This was apparently different to the finding in patients with type 1A diabetes, in which insulitis is frequently seen;25,26 however, we unpublished observation and others27 have found insulitis in autopsy samples of the pancreas from patients with fulminant diabetes who died shortly after onset The different result concerning the presence or absence of insulitis between biopsy and autopsy samples
could be attributable to the difference in time of examination and/or the amount of tissue available for study Another interesting pathological feature in the pancreas of patients with fulminant type 1 diabetes is lymphocytic infiltration in the exocrine pancreas tissue3 The infiltration by lymphocytes is in good accordance with the elevated serum level of exocrine pancreatic enzymes in these patients, as will be described later; however, neither massive infiltration of polymorphonucleocytes nor edema or bleeding in the exocrine pancreatic tissue is observed, indicating that the diagnosis of acute pancreatitis could not be made
There are some characteristic symptoms preceding the onset of fulminant type 1 diabetes Table 2 shows the symptoms seen at or immediately before onset of the disease In this type of diabetes, the duration from the start of symptoms associated with hyperglycemia, such as thirst, polyuria, polydipsia or body weight loss, to a demonstration of hyperglycemia is mostly less than 7 days with an average of 44 31 days, which is much shorter than that 364 251 days in type 1A diabetes This marked difference suggests the striking rapidity of the disease progression
in fulminant type 1 diabetes The most prevalent symptom around the onset of fulminant type 1 diabetes is thirst 937; however, remarkable symptoms observed just before the onset of the disease are common-cold-like symptoms 717 and abdominal symptoms 725 Among the common-cold-like symptoms, the most prevalent symptom is fever 600, which is followed by sore throat 252 and cough 120 Among several abdominal symptoms, the most common ones are nausea or vomiting 654, upper-abdominal pain 392 and lower-abdominal pain 110 Disturbance in consciousness–ranging from slight drowsiness to deep coma–is seen nearly half 452 of the patients with fulminant type 1 diabetes Cardiopulmonary arrest was seen in one patient with fulminant type 1 diabetes in a series of nationwide surveys It occurred within 24 h after the patients first visit to the general practitioners clinic The patients main complaint was fatigue, and the diagnosis of diabetes was not made at first The correct diagnosis of fulminant diabetes was confirmed after successful cardiopulmonary resuscitation The cause of cardiopulmonary arrest remains to be clarified; however, there are some case reports of fulminant type 1 diabetes
associated with cardiac disorders, such as T-wave inversion, atrial fibrillation or cardiac arrest of unknown origin28,29 The presence of such cases indicates the possibility that some patients with fulminant type 1 diabetes die from cardiac arrest during an acute phase, most probably within 24 h, of disease onset and that the death is not suspected to result from this type of diabetes
LABORATORY FINDINGS
Table 3 summarizes the laboratory findings at onset of fulminant type 1 diabetes and compares them with those of type 1A diabetes
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The plasma glucose level at onset of fulminant type 1 diabetes ranged from 285 to 2,112 mg/dl mean 800 360 mg/dl Interestingly, in contrast to very high plasma glucose levels, the HbA1c level is almost normal at the onset of fulminant type 1 diabetes–it ranged from 47 to 84 64 09 This remarkable imbalance between very high plasma glucose level and near-normal HbA1c level could be explained by the very short length of the disease duration in fulminant type 1 diabetes; the HbA1c level reflects the average
of plasma glucose levels during the preceding 1 to 2 months, so a very high plasma glucose level for only a few days as seen in fulminant type 1 diabetes is too short a time period for HbA1c to be elevated The near-normal HbA1c level despite a very high plasma glucose level in patients with ketoacidosis is the key characteristic for diagnosis of fulminant type 1 diabetes, because both HbA1c and plasma glucose levels are almost invariably elevated at the onset of ketoacidosis in type 1A diabetes Plasma ketone bodies are elevated ketosis without exception at the onset of fulminant type 1 diabetes Arterial blood gas had a pH below 735 acidosis in more than 90 of the patients with this disease Ketoacidosis is therefore usually seen at onset of this type of diabetes Serum levels of exocrine pancreas enzymes pancreas-type amylase, elastase-1 and lipase are also almost invariably elevated at the onset of fulminant type 1 diabetes This elevation does not necessarily mean that the disease is associated with acute pancreatitis In most cases, abdominal CT scans and/or abdominal echograms show no evidence of pancreatic swelling, which is usually seen in acute pancreatitis In some rare cases,
however, swelling of the pancreas could be seen in CT scans and/or echograms before the onset of overt diabetes30 These abnormalities resemble acute pancreatitis, but symptoms of exocrine dysfunction such as diarrhea or stools with elevated fat content are not long-standing, and increased serum pancreatic enzyme levels and swelling of the pancreas disappear after the treatment for diabetic ketoacidosis alone Changes in the pancreas of patients with fulminant type 1 diabetes are therefore not like those in acute pancreatitis Among serum electrolytes, sodium and chloride levels are markedly decreased and potassium is increased These changes are more severe than those in autoimmune type 1A
Table 3 Laboratory data in fulminant type 1 diabetes
Characteristic Plasma glucose mg/dl Arterial pH HbA1c 24-h urinary CPR g/day Serum CPR during fasting nmol/l Serum CPR after stimulation nmol/l CPR nmol/l Elevation in serum pancreatic enzyme levels Amylase Elastase-1 Lipase Na mEq/l K Cl mEq/l mEq/l Fulminant type 1 DM 800 360 7125 0125 64 09 43 40 010 007 010 010 003 003 98/2 74/54 54/9 50/9 131 9 55 12 94 10 49 83 44 51 198 60 182 162 7/138 0/43 5/63 6/59 Autoimmune type 1A DM
434 213 7309 0124 122 22 210 148 023 013 040 026 020 020 17/26 11/81 1/37 5/38 137 4 43 08 101 5 22 17 26 33 215 64 118 88 114/14 31/24 13/64 24/64 P value 00001 00001 NA NA NA NA NA 00001 00001 00001 00001 00001 00001 00001 0004 0003 NS 0002 00001 00001 NS 001
AST IU/l ALT IU/l Total cholesterol mg/dl Triglyceride mg/dl Antibodies Anti-GAD Anti-IA-2 Anti-thyroglobulin Anti-microsome
Data are mean SD, , or number of patients positive/negative Adapted, with permission, from Imagawa et al5 Copyright 2003 American Diabetes Association from Diabetes Care, Vol 26, 2003; 23452352 Abbreviations: ALT, alanine transaminase; AST, aspartate transaminase; CPR, C peptide; DM, diabetes mellitus; GAD, glutamic acid decarboxylase; HbA1c, glycated hemoglobin; IA-2, islet-cell-associated antigen 2; IU, international units; mEQ, milliequivalent; NA, not applicable; NS, not significant
diabetes, indicating the more-severe metabolic derangement in fulminant type 1 diabetes More severe ketonemia, hyponatremia and hyperkalemia in fulminant type 1 diabetes could all be attributable to the greater degree of insulinopenia in this type of diabetes Serum aspartate transaminase AST and
alanine transaminase ALT levels are elevated in many patients at the onset of fulminant type 1 diabetes Elevation of AST and ALT levels is sometimes seen after the start of insulin treatment following diabetic ketoacidosis,31 but the exact reason for this phenomenon is not yet clear Autoantibodies against various constituents of pancreatic cells, for example ICA islet cell antibodies, anti-GAD antibody, IAA insulin
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Box 2 Screening and diagnostic criteria for fulminant type 1 diabetes
Findings strongly suggesting the diagnosis of fulminant type 1 diabetes mellitus Ketosis or ketoacidosis within a week after the onset of hyperglycemic symptoms Plasma glucose level 160 mmol/l 288 mg/dl at first visit Criteria for definite diagnosis of fulminant type 1 diabetes mellitus Fulminant type 1 diabetes mellitus is confirmed when all the following three findings are present: 1 Occurrence of diabetic ketosis or ketoacidosis soon around 7 days after the onset of hyperglycemic symptoms elevation of urinary and/or serum ketone bodies at first visit 2
Plasma glucose level 160 mmol/l 288 mg/dl and glycated hemoglobin level 85 at first visit 3 Urinary C-peptide excretion 10 g/day or fasting serum C-peptide level 03 ng/ml 010 nmol/l and 05 ng/ml 017 nmol/l after intravenous glucagon or after meal load at onset Other findings in fulminant type 1 diabetes mellitus Islet-related autoantibodies such as antibodies to glutamic acid decarboxylase, islet-associated antigen 2 and insulin are undetectable in general Duration of the disease before the start of insulin treatment can be 1 to 2 weeks Elevation of serum pancreatic enzyme levels amylase, lipase or elastase-1 is observed in 98 of the patients Flu-like symptoms fever, upper respiratory symptoms, etc or gastrointestinal symptoms upper abdominal pain, nausea and/or vomiting, etc precede the disease onset in 70 of patients The disease can occur during pregnancy or just after delivery
Adapted, with permission, from Hanafusa et al16 Permission obtained from the Japan Diabetes Society Hanafusa T et al 2005 J Japan Diab Soc 48 Suppl 1: A1A13
are important because, if they are met, treatment should be started immediately in order to save the patients life Criteria for diagnosing fulminant
type 1 diabetes must enable a definitive diagnosis The fulfillment of these criteria is important for future analysis of this disease, since the inclusion of definite cases only is necessary to elucidate the pathogenesis and characterize the pathophysiology of this disease Ketoacidosis occurs during fulminant type 1 diabetes and at the onset of autoimmune type 1A diabetes, but can also be induced by sugarcontaining soft drinks,36 or by acute pancreatitis; however, in most cases these situations can be clearly differentiated from fulminant type 1 diabetes, which has no autoantibodies, no previous history of intake of a large amount of sugar-containing soft drinks, and no preserved insulin, morphological signs of pancreas swelling or marked elevation of serum pancreatic enzyme levels, respectively Since the occurrence of fulminant type 1 diabetes is often preceded by common-cold-like symptoms and/or abdominal symptoms, the patients are often misdiagnosed with acute infections and/or acute gastritis or gastroenteritis In emergency clinics, special attention should therefore be paid not to overlook the presence of ketoacidosis caused by this type of diabetes
TREATMENT
autoantibody,
and anti-IA-2 islet-associated antigen 2, are usually undetectable even at the onset of disease In exceptional cases of fulminant type 1 diabetes, however, anti-GAD antibodies are detected, usually at a low titer and sometimes transiently32 The plasma C-peptide level is markedly decreased in patients with fulminant type 1 diabetes The C-peptide level is very low not only after fasting but also after stimulation with glucagons, indicating almost complete loss of pancreatic cells In some patients with fulminant type 1 diabetes, antibodies against various viruses were detected3335 Among these viruses, enteroviruses coxsackie viruses, echoviruses, etc and herpes viruses seem to be frequently associated with the disease This issue will be discussed later in relation to pathogenesis
DIAGNOSIS
Criteria for screening and diagnosing fulminant type 1 diabetes are listed in Box 216 The screening criteria must be designed so as not to overlook patients with this disease The criteria
When the diagnosis of fulminant type 1 diabetes is made or strongly suspected, treatment of the patient must be started immediately, as in all other cases of type 1 diabetes Otherwise, the disease will quickly
deteriorate, leading to the death of the patient usually within 24 h The treatment for fulminant type 1 diabetes does not differ from that for autoimmune type 1 diabetes At onset, when ketoacidosis is present, intravenous infusion of saline and of regular insulin should be started Once the acute phase of ketoacidosis is over, usually multiple insulin injections should be administered, using daily or twice-daily injections of either a very-long-acting insulin analog or intermediate-acting insulin, together with thrice-daily injections at each meal of either a very-rapid-acting insulin analog or regular insulin37 In some patients, continuous subcutaneous insulin infusion therapy using a portable pump is necessary to control the plasma glucose levels38
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CLINICAL COURSE
As the deficiency of insulin-secretory capacity is probably nearly complete after the onset of fulminant type 1 diabetes,39 glycemic control is generally difficult in this disease Reflecting the difficulty in glycemic control, the HbA1c level, which is near-normal at onset of
the disease, increases even after the improvement of glycemic control following the start of insulin therapy in this type of diabetes5 The time required for normalization of serum pancreatic enzyme levels depends on the degree of elevation of the enzymes, but it usually takes 2 to 3 weeks, irrespective of the application of special treatment for acute pancreatitis
PATHOGENESIS
It is strongly suggested that certain class II HLA types confer susceptibility to fulminant type 1 diabetes The role of class II HLA has been emphasized in the context of the antigenpresenting process in typical autoimmune type 1A diabetes,17 but it is not known how certain class II HLAs can contribute towards the molecular mechanisms of -cell destruction in fulminant type 1 diabetes One possibility is that, as in type 1A diabetes, the HLA molecule is associated with the immune reaction seen in fulminant diabetes, but another possibility is that HLA molecules could interact with viruses, as has been shown in mice40 Similarly to the results in the general population that are described above, small pilot studies of patients with fulminant type 1 diabetes suggest that DR4DQ4, which is encoded by DRB10405
DQB10401, confers susceptibility to the disease in this population41,42 It has long been suspected that viruses might play some role in the pathogenesis of type 1 diabetes A model in which diabetes is induced in mice by infection with encephalomyocarditis virus is reported to resemble human fulminant type 1 diabetes43 In fact, there have been many case reports in which occurrence of fulminant diabetes is associated with evidence of various viral infections3335 Among many viruses, enteroviruses coxsackie viruses, echo viruses, etc and herpes viruses seem to be frequently associated with fulminant diabetes There is one report that clearly documents the association between fulminant type 1 diabetes and human herpes virus 6 HHV-633 In this patient, the diabetes occurred in close association with reactivation of HHV-6 during the course of hypersensitivity syndrome, which is the disease known to occur together with
reactivation of HHV-6 Similar cases of fulminant diabetes together with hypersensitivity syndrome have also been reported44,45 Interestingly, it was observed, using a method for detecting antibodies that specifically recognize a group of enteroviruses, that titers of specific
IgA antibodies were significantly higher in patients with fulminant type 1 diabetes than in patients with type 1A diabetes46 This finding suggests that recurrent enterovirus infections precede fulminant diabetes and might indicate that patients with this disease are susceptible to enterovirus infections Although viruses are possible pathogenic agents, immune reactions might also play a role in the development of fulminant type 1 diabetes47 T lymphocytes capable of responding to GAD are detected using a sensitive assay in the peripheral blood of patients with this disease48 The presence of these T cells, however, does not necessarily mean that autoimmunity plays a primary role in the pathogenesis of fulminant diabetes Insulitis is observed in autopsy samples of the pancreas from patients who died immediately after the diagnosis of fulminant type 1 diabetes, but the presence of insulitis, or the presence of immunocytes in and/or around the islet, does not necessarily mean that the cause of -cell destruction is autoimmunity49 Immune mechanisms include not only autoimmunity but also other mechanisms such as antivirus immunity following viral infection of pancreatic cells, as shown in
the encephalomyocarditis-virus-infected mouse model50 It thus remains to be clarified whether fulminant type 1 diabetes belongs to type 1A or type 1B The mechanism for the involvement of the exocrine pancreas is also not clear Viruses affecting both endocrine and exocrine pancreatic tissues, for example the encephalomyocarditis virus in mice, might be a possible explanation In one case of fulminant diabetes, the presence of autoantibodies against exocrine pancreatic tissue has been described51
CONCLUSIONS
Fulminant type 1 diabetes is a novel clinical entity established within insulin-deficient type 1 diabetes This disease develops in apparently healthy subjects The rate of aggravation is so rapid that the diagnosis must be quickly and correctly made Once the diagnosis of this disease is strongly suspected, the treatment of diabetic ketoacidosis must be started immediately
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Otherwise, the death of the patient is likely to occur within 24 h In conclusion, all medical practitioners must remember that fulminant type 1 diabetes–an extremely
rapidly progressing type of diabetes–does exist and they must pay special attention not to overlook this disease
KEY POINTS
Fulminant type 1 diabetes is defined as diabetes in which the progression from normoglycemia to hyperglycemia accompanied with ketoacidosis is extremely rapid Without appropriate therapy, the death of the patient is inevitable within several days Clinical features include common-cold-like and/or abdominal symptoms preceding disease onset, disease duration of less than 1 week from the start of hyperglycemia, a nearnormal glycated hemoglobin level, no residual insulin secretory capacity, a lack of anti-islet autoantibodies, and elevation of pancreatic enzyme levels; association with pregnancy is not rare Human leukocyte antigen DR4DQ4 confers susceptibility to the disease, and viruses are suspected to be involved in the pathogenesis
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Fulminant type 1 diabetes at onset should be treated the same as other diabetic ketoacidosis with intravenous infusion of saline and regular insulin; this treatment should be followed by an intensive insulin therapy including continuous subcutaneous insulin infusion
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References 1 American Diabetes Association 1997 Report of the expert committee on the diagnosis and classification of diabetes mellitus Diabetes Care 20: 11831197 2 Alberti KG and Zimmet PZ 1998 Definition, diagnosis and classification of diabetes mellitus and its complications Part 1: diagnosis and classification of diabetes mellitus: provisional report of a WHO consultation Diabet Med 15: 539553 3 Imagawa A et al 2000 A novel subtype of type 1 diabetes mellitus characterized by a rapid onset and an absence of diabetes-related antibodies N Engl J Med 342: 301307 4 Imagawa A et al 2000 A proposal of three distinct subtypes of type 1 diabetes mellitus based on clinical and pathological evidence Ann Med 32: 539543 5 Imagawa A et al 2003 Fulminant type 1 diabetes: a nationwide survey in Japan Diabetes Care 26: 23452352 6 Murao S et al 2004 Differences in the contribution of HLA-DR and -DQ haplotypes to susceptibility to adult-onset and childhood-onset type 1 diabetes in Japanese patients Diabetes 53: 26842690 7 Urakami T et al 2002 A subtype of markedly abrupt onset with absolute insulin deficiency in idiopathic type 1 diabetes in Japanese children Diabetes Care 25: 23532354
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Pozzilli P et al 2000 No evidence of rapid onset Japanese Type I diabetes in Caucasian patients Diabetologia 43: 1332 Weets I et al 2002 Relation between disease phenotype and HLA-DQ genotype in diabetic patients diagnosed in early adulthood J Clin Endocrinol Metab 87: 25972605 Maldonado M et al 2003 Ketosis-prone diabetes: dissection of a heterogeneous syndrome using an immunogenetic and -cell functional classification, prospective analysis, and clinical outcomes J Clin Endocrinol Metab 88: 50905098 Balasubramanian K et al 2003 High frequency of type 1B idiopathic diabetes in north Indian children with recent-onset diabetes Diabetes Care 26: 2697 Vreugdenhil GR et al 2000 Acute onset of type I diabetes mellitus after severe echovirus 9 infection: putative pathogenic pathways Clin Infect Dis 31: 10251031 Jung TS et al 2004 A Korean patient with fulminant autoantibody-negative type 1 diabetes Diabetes Care 27: 30233024 Taniyama M et al 2004 A Filipino patient with fulminant type 1 diabetes Diabetes Care 27: 842843 Foulis AK et al 1988 Massive synchronous B-cell necrosis causing type 1 insulin-dependent diabetes–a unique histopathological case report
Diabetologia 31: 4650 Hanafusa T et al 2005 Report of Japan diabetes society committee on fulminant type 1 diabetes mellitus: epidemiological and clinical analysis and proposal of diagnostic criteria [Japanese] J Japan Diab Soc 48 Suppl 1: A1A13 Shimizu I et al 2003 Association of fulminant type 1 diabetes with pregnancy Diabetes Res Clin Pract 62: 3338 Otsubo M et al 2002 Nonimmune fulminant type 1 diabetes presenting with diabetic ketoacidosis during pregnancy Obstet Gynecol 99: 877879 Shimizu I et al 2006 Clinical and immunogenetic characteristics of fulminant type 1 diabetes associated with pregnancy J Clin Endocrinol Metab 91: 471476 Eisenbarth GS et al 2003 Type 1 Diabetes Mellitus In Williams Textbook of Endocrinology, edn 10, 14851504 Eds Larsen PR et al Philadelphia: WB Saunders Ikegami H and Ogihara T 1996 Genetics of insulindependent diabetes mellitus Endocr J 43: 605613 Imagawa A et al 2005 Different contribution of class II HLA in fulminant and typical autoimmune type 1 diabetes mellitus Diabetologia 48: 294300 Sayama K et al 2005 Pancreatic and cells are both decreased in patients with fulminant type 1 diabetes: a morphometrical assessment Diabetologia 48: 15601564
Yamazaki M and Hayashi T 2002 Rapid-onset type 1 diabetes mellitus without pancreatic exocrine dysfunction Ann Intern Med 137: 145146 Itoh N et al 1993 Mononuclear cell infiltration and its relation to the expression of major histocompatibility complex antigens and adhesion molecules in pancreas biopsy specimens from newly diagnosed insulin-dependent diabetes mellitus patients J Clin Invest 92: 23132322 Moriwaki M et al 1999 Fas and Fas ligand expression in inflamed islets in pancreas sections of patients with recent-onset type I diabetes mellitus Diabetologia 42: 13321340 Tanaka S et al 2000 A novel subtype of type 1 diabetes mellitus N Engl J Med 342: 18351838
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28 Uto Y et al 2002 A case of fulminant type 1 diabetes mellitus detected after cardiac arrest due to diabetic ketoacidosis [Japanese] J Japan Diab Soc 45: 689693 29 Kobayashi T et al 2005 A case of fulminant type 1 diabetes with ECG changes in the first trimester of pregnancy [Japanese] J Jpn Soc Intensive Care Med 12: 2530 30 Fukui K et al 2002 A case of diabetes mellitus after
acute pancreatitis with histological findings compatible to non-autoimmune fulminant type 1 diabetes [Japanese] J Japan Diab Soc 45: 759765 31 Takaike H et al 2004 Transient elevation of liver transaminase after starting insulin therapy for diabetic ketosis or ketoacidosis in newly diagnosed type 1 diabetes mellitus Diabetes Res Clin Pract 64: 2732 32 Iwaoka T 2003 A case of fulminant type 1 diabetes with transiently positive anti-GAD antibodies Endocr J 50: 225231 33 Sekine N et al 2001 Rapid loss of insulin secretion in a patient with fulminant type 1 diabetes mellitus and carbamazepine hypersensitivity syndrome JAMA 285: 11531154 34 Nagaoka T et al 2001 Insulin-dependent diabetes mellitus following acute pancreatitis caused by herpes simplex virus: a case report [Japanese] J Japan Diab Soc 44: 335340 35 Nishida W et al 2005 A case of fulminant type 1 diabetes associated with high titer of coxsackie B3 virus antibody [Japanese] J Japan Diab Soc 48 Suppl 1: A23A27 36 Yamada K and Nonaka K 1996 Diabetic ketoacidosis in young obese Japanese men Diabetes Care 19: 671 37 Sano H et al 2005 Efficacy of intensive insulin therapy using ultra long acting insulin analog in fulminant type 1
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39 Yamaguchi H et al 2003 Prospective study of the capacity of insulin secretion of fulminant type 1 diabetic patients from the onset of diabetes [Japanese] J Japan Diab Soc 46: 211215 40 Wykes MN et al 1993 Murine cytomegalovirus interacts with major histocompatibility complex class I molecules to establish cellular infection J Virol 67: 41824189 41 Tanaka S et al 2002 Association of HLA-DQ genotype in autoantibody-negative and rapid-onset type 1 diabetes Diabetes Care 25: 23022307 42 Nakamura T et al 2003 HLA-DRDQ haplotype in rapid-onset type 1 diabetes in Japanese Diabetes Care 26: 16401641 43 Shimada A and Maruyama T 2004 Encephalomyocarditis-virus-induced diabetes model resembles fulminant type 1 diabetes in humans Diabetologia 47: 18541855 44 Ohta K et al 2001 A case of fulminant type 1 diabetes mellitus during steroid therapy for hypersensitivity syndrome [Japanese] J Japan Diab
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Acknowledgments
We are indebted to Drs N Itoh, J Miyagawa and Y Matsuzawa for discussions, also to the doctors of the Osaka IDDM study group and the Committee of the Japan Diabetes Society on the Research of Fulminant Type 1 Diabetes
Mellitus for collaboration This study was supported by the a grant-in-aid for scientific research from the Japan Society for the Promotion of Science, a grant-in-aid from the Japan Medical Association, and a grant from the Japan Diabetes Society
Competing interests
The authors declared they have no competing interests
JANUARY 2007 VOL 3 NO 1 HANAFUSA AND IMAGAWA
NATURE CLINICAL PRACTICE ENDOCRINOLOGY METABOLISM 45
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