A Case of Abrupt Onset Autoimmune Type 1 Diabetes Mimicking Fulminant Type 1 Diabetes

Transcription

1 Endocrine Journal 2009, 56 (9), NOTE A Case of Abrupt Onset Autoimmune Type 1 Diabetes Mimicking Fulminant Type 1 Diabetes Shinya MAKINO #, Sumio HAMADA ##, Masanobu IWATA # and Masayoshi FUJIWARA # # Department of Internal Medicine, Osaka Gyomeikan Hospital, Kasugade-naka, Konohana-ku, Osaka , Japan ## Hamada Clinic, Nishikujo, Konohana-ku, Osaka , Japan Abstract. A 63-year-old male was admitted to our hospital with diabetic ketoacidosis. He had flu-like symptoms 10 days before admission and developed thirst, polyuria and anorexia with 9 kg of body weight loss in a week. Plasma glucose level on admission was 983 mg/dl and HbA1c was 7.5%. Despite high levels of serum pancreatic enzymes, lack of severe abdominal pain and no morphological change of pancreas in the abdominal CT scan eliminated the complication of classical acute pancreatitis. These findings suggested the diagnosis of fulminant type 1 diabetes. However, urinary and plasma C-peptide levels showed that insulin secretion was not completely depleted at onset. Furthermore, an examination of isletrelated antibodies revealed the presence of high titer anti-gad antibody. His HLA typing showed that DRB1*0901- DQB1*0303 and A24 were present. He has been doing well with continuation of insulin therapy. Over two years after onset, his plasma C-peptide level was gradually lowered, and anti-gad antibody was still positive. Taken together, this is a rare case of abrupt onset autoimmune type 1 diabetes with transient but apparent exocrine pancreatic impairment at onset. Similar cases should be accumulated to clarify pathophysiological similarities and/or differences between fulminant type 1 diabetes and abrupt onset autoimmune type 1 diabetes. Key words: Type 1 diabetes, Fulminant, Autoimmune, Pancreatic enzyme (Endocrine Journal 56: , 2009) TYPE 1 diabetes mellitus is caused by loss of insulin secreting capacity due to destruction of the pancreatic beta cells, and is subdivided into autoimmune (type 1A) and idiopathic (type 1B) diabetes [1]. The onset of type 1 diabetes is known to be acute especially in children, whereas it may be insidious or may occur over a time frame of weeks or even months in older patients [2]. Fulminant type 1 diabetes (FT1DM) is a novel clinical entity which is characterized by an extremely abrupt onset of the disease and remarkably acute destruction of pancreatic beta cells with urinary C-peptide secretion less than 10 µg/day: however, more than 90% of FT1DM patients were adolescent or adult [3-5]. Although FT1DM is basically classified into type 1B diabetes as indicated by absence of Received Mar. 9, 2009; Accepted Aug. 7, 2009 as K09E-074 Released online in J-STAGE as advance publication Aug. 13, 2009 Correspondence to: Shinya Makino, M.D., Department of Internal Medicine, Osaka Gyomeikan Hospital, Kasugadenaka, Konohana-ku, Osaka , Japan. makinos@ares.eonet.ne.jp islet-related autoantibodies, two atypical cases showing the mixed characteristics of FT1DM and autoimmune type 1 diabetes (i.e. anti-gad antibody positivity) have been reported [6, 7]. Here we report a 63-year-old case of abrupt onset autoimmune type 1 diabetes, mimicking FT1DM. In addition to the above mentioned two autoimmune cases [6, 7], the present case draws an attention in terms of differential diagnosis between typical FT1DM and this rapidly progressive form of autoimmune type 1 diabetes. Case Report A 63-year-old male was admitted to our hospital with diabetic ketoacidosis on December 23 in His medical history revealed that he had been suffering from hypertension and angina pectoris for 7 years, but there was no sign of diabetes. The HbA1c level in June, 2006 was 5.5%, while fasting plasma glu-

2 1114 MAKINO et al. Fig. 1. Clinical course. Computed tomography scanning images of pancreas shows that there are no morphological signs of acute pancreatitis such as enlargement of the pancreas, pancreatic necrosis, or peripancreatic or pancreatic fluid collections [26]. PSTI: pancreatic secretory trypsin inhibitor cose level was 79 mg/dl and 89 mg/dl on February 8 in 2006 and on November 18 in 2006, respectively (Figure 1). He had flu-like symptoms 10 days before admission and developed thirst, polyuria and anorexia with 9 kg of body weight loss in a week. Random plasma glucose level 5 days before or on admission was 473 or 983 mg/dl and HbA1c was 6.7% or 7.5%, respectively. He drank a large amount of Japanese tea, but not sweetened beverage during the abrupt onset of diabetes, eliminating the possibility of soft drink ketosis [8-10]. Physical examination on admission showed that his skin and tongue were dry due to the dehydration. His height was 161 cm and weight was 62.5 kg. Blood pressure was 104/56 mmhg. Laboratory findings revealed a red blood cell count of 408 x 10 4 /mm 3, hemoglobin at 13.5 g/dl, and hematocrit at 39.2%. The white blood cell count was /mm3 with 84% neutrophils, and his platelet count was 32.1 x 10 4 / mm 3. Serum electrolytes were the following: Na 120 meq/l; K 5.9 meq/l; Cl 88mEq/L and Ca 8.6 mg/dl. Serum BUN was 79.8 mg/dl; creatinine, 2.96 mg/dl; and uric acid, 11.3 mg/dl. Total serum protein was 7.6 g/dl with 60.4% albumin; GOT, 11 IU/L; GPT, 17 IU/ L; LDH, 247 IU/L; γ-gtp, 83 IU/L; and total cholesterol, 221 mg/dl. Arterial blood gas analysis revealed ph, 7.059; PaO 2, mmhg; PaCO 2, 8.5 mmhg; HCO 3, 2.3 meq/l and base excess of meq/l. Plasma ketone body was remarkably elevated (14880 µmol/l; normal range, ). Despite high levels of serum pancreatic enzymes (Figure 1), lack of severe abdominal pain and no morphological change of pancreas in the abdominal CT scan indicated that the diagnosis of coexisting acute

3 ABRUPT ONSET AUTOIMMUNE DM 1115 pancreatitis [11] was unlikely (Figure 1). These overall findings suggested the diagnosis of FT1DM. However, urinary and plasma C-peptide levels showed that insulin secretion was not depleted (urinary C-peptide on 5 th hospital day, 14.6 µg/day; random plasma C-peptide on admission, 2.68 ng/ml). Furthermore, an examination of autoimmune antibody revealed the presence of high titer anti-glutamic acid decarboxylase (GAD) antibody (116.0 U/mL). Other autoimmune antibodies such as islet cell antibody (ICA), insulin autoantibody (IAA) or anti-insulinoma-associated antigen 2 (IA-2) antibody were not detected. Thyroid autoantibodies to throid peroxidase and thyroglobulin were negative. His HLA type was A02, A24, B35, B46 in class I antigen, and DRB1*0803, DRB1*0901, DQB1*0601, DQB1*0303 in class II antigen. Intensive insulin therapy was initiated and plasma glucose level was normalized and ketoacidosis disappeared in a couple of days. Oral intake was initiated a day after admission, but increased serum pancreatic enzyme levels gradually lowered back to the normal range in 2-3 weeks only by the treatment for diabetes (Figure 1). Laboratory findings on January 10 in 2007 were the following: a red blood cell count 375 x 10 4 /mm 3 ; hemoglobin 12.2 g/dl; hematocrit 37.3%; BUN 16.7 mg/dl and creatinine, 0.74 mg/dl. The HbA1c level has been controlled at % over units/day insulin. He has not developed major diabetic complications such as neuropathy, nephropathy or retinopathy in the course of the disease. One year after the abrupt onset of diabetes, GAD antibody was 7.3 U/mL and fasting plasma C-peptide was 0.82 ng/ ml. Two years after the onset, GAD antibody was still positive (11.3 U/mL) and plasma C-peptide was 0.61 ng/ml and 0.90 ng/ml before and 6 min after intravenous glucagon (1mg) injection, respectively. As shown in Figure 1, the clinical course indicates the diagnosis of autoimmune type 1 diabetes which shows slow progression of pancreatic beta cell destruction despite abrupt onset with ketoacidosis. Discussion Imagawa et al. [4] described difference between FT1DM and nonfulminant autoimmune type 1 diabetes for their clinical characteristics. According to their report, FT1DM accounts for around 20% of the ketosisonset type 1 diabetes cases in Japan and has more se- vere metabolic derangement than in autoimmune type 1 diabetes [4]. The following findings in the present case meet the proposed criteria for FT1DM [5]: (1) the extremely abrupt onset (around a week) with the presence of ketoacidosis at diagnosis, (2) plasma glucose level 288 mg/dl (16.0 mmol/l) and HbA1c level <8.5% at first visit, (3) elevated serum pancreatic enzyme levels, and (4) preceding flu-like symptoms. However, the presence of high titer anti-gad antibody at onset and the gradual functional destruction of pancreatic beta cells over two years after the onset of the disease definitively eliminate the diagnosis of FT1DM. Thus, the present case is diagnosed as abrupt onset autoimmune type 1 diabetes. A long-term subclinical insulitis with the presence of islet-related autoantibodies usually precede the onset of overt diabetes in typical autoimmune type 1 diabetes [2, 12]. In this case, although the presence or absence of islet-related autoantibodies before the onset of overt diabetes is uncertain, advanced flu-like symptoms at the onset of diabetes suggest that putative viral infection could induce innate immune responses to develop the additional destruction of beta cells in patients with preceded subclinical insulitis. Alternatively, it is possible that these viral infection might trigger novel production of islet-related autoantibodies [13] as well as rapid beta cell destruction in some individuals including our patient who show abrupt onset of autoimmune type 1 diabetes. Although his urinary C-peptide level (14.6 µg/day) did not meet the criteria for FT1DM (<10µg/day) at onset, it might be low enough to develop overt diabetes along with viral infection-associated insulin resistance. Despite having HLA-A24, known to be associated with rapid destruction of beta cell function [14], insulin secretion in this patient was gradually depleted over around 2 years after clinical onset. It is known that, in general, beta cell function is not completely destroyed at onset and the rate of beta cell destruction is relatively slow in autoimmune type 1 diabetes [15, 16], consistent with the autoimmune characteristics of this case. Exocrine pancreatic involvement at clinical onset is more frequently observed in FT1DM than in acute (but not extremely abrupt) onset autoimmune type 1 diabetes [4]. Although diabetic ketoacidisis per se is known to induce non-specific elevation of serum pancreatic enzymes [17-20], there may be the damage of the exocrine pancreas through viral-associated inflammation

4 1116 MAKINO et al. in FT1DM [3, 5, 21]. More studies including the pancreas histology will be needed to clarify whether patients with abrupt onset autoimmune type 1 diabetes also exhibit nonspecific inflammation to the exocrine pancreas as well as the specific insulitis. Susceptibility and resistance to the development of type 1 diabetes is known to depend largely on the genetic background [2]. According to previous HLA reports [5, 22-24], HLA DRB1*0901-DQB1*0303 haplotype, which was seen in this patient, appears to be associated with autoimmune type 1 diabetes rather than FT1DM in Japan. Interestingly, class II HLA haplotypes (DRB1*0803, DRB1*0901, DQB1*0601, DQB1*0303) in a FT1DM patient with positive anti-gad antibody was identical to those seen in this patient [7], although frequency of DRB1*0803- DQB1*0601 or genotypic combination (DRB1*0901- DQB1*0303/ DRB1*0803-DQB1*0601) was not different between type 1 diabetes and control [22]. In conclusion, we report the rapidly progressing autoimmune type 1 diabetes with advanced flu-like symptoms and exocrine pancreatic involvement at onset, mimicking FT1DM. Viral infection may trigger the immune response leading either to non-specific alpha and beta cell destruction by T cells in typical FT1DM patients [5, 25] or to the specific insulitis through the production of islet-related antibodies in patients with abrupt onset autoimmune type 1 diabetes. Similar cases should be accumulated to clarify pathophysiological similarities and/or differences between FT1DM and abrupt onset autoimmune type 1 diabetes. Acknowledgements The authors wish to thank medical technologists of Osaka Gyomeikan Hospital and Fukuyama Medical Laboratories Inc. for their technical support. References 1. Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. (1997) Diabetes Care 20: Eisenbarth GS, Polonsky KS, Buse JB (2003) Type 1 diabetes mellitus. In: Reed Larsen P, Kronenberg HM, Melmed S, Polonsky KS (Eds) Williams Textbook of Endocrinology 10 th edition. Saunders, Philadelphia, Imagawa A, Hanafusa T, Miyagawa J, Matsuzawa Y (2000) A novel subtype of type 1 diabetes mellitus characterized by a rapid onset and an absence of diabetes-related antibodies. Osaka IDDM Study Group. N Engl J Med 342: Imagawa A, Hanafusa T, Uchigata Y, Kanatsuka A, Kawasaki E, Kobayashi T, Shimada A, Shimizu I, Toyoda T, Maruyama T, Makino H (2003) Fulminant type 1 diabetes: a nationwide survey in Japan. Diabetes Care 26: Imagawa A, Hanafusa T (2006) Fulminant type 1 diabetes mellitus. Endocr J 53: Kahara T, Takamura T, Ando H, Sakurai M, Ota T, Misaki T, Oba S, Iguchi M, Komori K, Kobayashi K (2003) Fulminating onset type 1 diabetes with positivity for anti-gad antibody and elevated pancreatic exocrine enzyme concentrations. Intern Med 42: Shimada A, Oikawa Y, Shigihara T, Senda T, Kodama K (2002) A case of fulminant type 1 diabetes with strong evidence of autoimmunity. Diabetes Care 25: Umpierrez GE, Casals MM, Gebhart SP, Mixon PS, Clark WS, Phillips LS (1995) Diabetic ketoacidosis in obese African-Americans. Diabetes 44: Tanaka K, Moriya T, Kanamori A, Yajima Y (1999) Analysis and a long-term follow up of ketosis-onset Japanese NIDDM patients. Diabetes Res Clin Pract 44: Matsui J, Tamasawa N, Tanabe J, Kasai N, Murakami H, Matsuki K, Suda T (2005) Clinical characteristics of Japanese youth-onset type 2 diabetes with ketonuria. Diabetes Res Clin Pract 70: Nair S, Yadav D, Pitchumoni C (2000) Association of diabetic ketoacidosis and acute pancreatitis: observations in 100 consecutive episodes of DKA. Am J Gastroenterol 95: Shimada A, Charlton B, Taylor-Edwards C, Fathman CG (1996) Beta-cell destruction may be a late consequence of the autoimmune process in nonobese diabetic mice. Diabetes 45: Jun HS, Yoon JW (2003) A new look at viruses in type 1 diabetes. Diabetes Metab Res Rev 19: Nakanishi K, Kobayashi T, Murase T, Nakatsuji T, Inoko H, Tsuji K, Kosaka K (1993) Association of HLA-A24 with complete beta-cell destruction in IDDM. Diabetes 42: Kobayashi T, Itoh T, Kosaka K, Sato K, Tsuji K (1987) Time course of islet cell antibodies and beta-cell function in non-insulin-dependent stage of type I diabetes. Diabetes 36:

5 ABRUPT ONSET AUTOIMMUNE DM Zimmet PZ, Tuomi T, Mackay IR, Rowley MJ, Knowles W, Cohen M, Lang DA (1994) Latent autoimmune diabetes mellitus in adults (LADA): the role of antibodies to glutamic acid decarboxylase in diagnosis and prediction of insulin dependency. Diabet Med 11: Knight AH, Williams DN, Ellis G, Goldberg DM (1973) Significance of hyperamylasaemia and abdominal pain in diabetic ketoacidosis. Br Med J 21: Warshaw AL, Feller ER, Lee KH (1977) On the cause of raised serum-amylase in diabetic ketoacidosis. Lancet 1: Vinicor F, L/M/ L, Karn RC, Merritt AD (1979) Hyperamylasemia in diabetic ketoacidosis: sources and significance. Ann Intern Med 91: Yadav D, Nair S, Norkus EP, Pitchumoni CS (2000) Nonspecific hyperamylasemia and hyperlipasemia in diabetic ketoacidosis: incidence and correlation with biochemical abnormalities. Am J Gastroenterol 95: Rayfield EJ, Seto Y (1978) Virus and the pathogenesis of diabetes mellitus. Diabetes 27: Kawabata Y, Ikegami H, Kawaguchi Y, Fujisawa T, Shintani M, Ono M, Nishino M, Uchigata Y, Lee I, Ogihara T (2002) Asian-specific HLA haplotypes reveal heterogeneity of the contribution of HLA-DR and -DQ haplotypes to susceptibility to type 1 diabetes. Diabetes 51: Murao S, Makino H, Kaino Y, Konoue E, Ohashi J, Kida K, Fujii Y, Shimizu I, Kawasaki E, Fujiyama M, Kondo S, Tanaka K, Tarumi Y, Seto I, Kato K, Ohno K, Kusunoki Y, Ebisui O, Takada Y, Tanabe K, Takemoto K, Onuma H, Nishimiya T, Osawa H (2004) Differences in the contribution of HLA-DR and -DQ haplotypes to susceptibility to adult- and childhoodonset type 1 diabetes in Japanese patients. Diabetes 53: Imagawa A, Hanafusa T, Uchigata Y, Kanatsuka A, Kawasaki E, Kobayashi T, Shimada A, Shimizu I, Maruyama T, Makino H (2005) Different contribution of class II HLA in fulminant and typical autoimmune type 1 diabetes mellitus. Diabetologia 48: Sayama K, Imagawa A, Okita K, Uno S, Moriwaki M, Kozawa J, Iwahashi H, Yamagata K, Tamura S, Matsuzawa Y, Hanafusa T, Miyagawa J, Shimomura I (2005) Pancreatic beta and alpha cells are both decreased in patients with fulminant type 1 diabetes: a morphometrical assessment. Diabetologia 48: Balthazar EJ, Robinson DL, Megibow AJ, Ranson JH (2000) Acute pancreatitis: value of CT in establishing prognosis. Radiology 174: