Abrupt onset of type 1 diabetes mellitus during recombinant
interferon-alpha 2b therapy in a patient with chronic
hepatitis B

[病例].重组干扰素alpha-2b治疗慢性乙型肝炎突然发作1型糖尿病

A 33-year-old woman with a body mass  index  (BMI) of  
22.49 kg/m2 
was treated with recombinant human IFN-α 
2b at a dosage of  3 million units  (MU) once every other 
day from April 2006 because of  hepatitis B. Ten months 
after  IFN-α 2b  treatment, both hepatitis B  e  antigen 
(HBeAg)  and HBV DNA became negative,  and  serum 
aminotransferases  returned  to normal. However, 13 mo 
after  initiation of   IFN-α 2b  treatment  (reaching 585 
MU of   total dose  in May 2007),  the patient  complained 
of  weakness, polydipsia, polyuria  and  a  rapid weight 
loss  (5 kg within 10 d). She was  then  admitted  to our 
hospital. Her  clinical data on  admission  are  shown  in 
Table 1. Urinalysis  showed  glucosuria  and ketonuria. 
Fasting plasma  glucose  and  glycosylated hemoglobin 
(HbA1c) were 31.7 mmol/L  (570.6 mg/dL)  and 10.0%, 
respectively. Arterial blood gas analysis showed metabolic 
acidosis. Serum  asparate  aminotransferase  (AST)  and 
alanine aminotransferase (ALT) were within normal range. 
Hepatitis B  surface  antigen  (HBsAg)  and  anti-HB  core 
antibody  (HBcAb)  in  serum were positive. The  fasting 
plasma C-peptide  level was  low. The curve of  C-peptide 
response  to 75  g  glucose  load was  flat  (Table 2). The 
serum  ICAb was positive  (Figure 1). The patient had 
no  family history of   type 1 DM or other  autoimmune 
disorders. She had no  symptoms of  other  autoimmune 
diseases. Other  autoantibodies  including  thyroid 
peroxidase  antibody  (TPOAb),  thyroglobulin  antibody 
(TgAb),  antinuclear  antibody  (ANA),  anti-dsDNA 
antibody,  anti-RNP,  anti-SSA,  anti-SSB,  and  rheumatoid 
factor (RF) were all negative. Taken together, clinical and 
laboratory data  confirmed  the diagnosis of   type 1 DM 
with ketoacidosis. Administration of  IFN was immediately 
terminated. Her  clinical  condition  improved with diet 

therapy,  intravenous fuids  and  insulin  therapy  (isophane
protamine  biosynthetic  human  insul in, Novol in®
   
R, Novo Nordisk, Denmark). Ketonuria disappeared after
12 h  insulin  therapy  for. Following normalization of   the
acute metabolic disturbances,  intensive  insulin  therapy
was recommended with four daily doses of  subcutaneous
insulin: each before every meal and  last at bedtime. Four
days later, fasting plasma glucose decreased to 5.6 mmol/L   
(100 mg/dL). Five months  after  cessation of   IFN-α 2b
therapy,  the patient  remained  insulin dependent with  a
daily requirement of  20 units Novolin®
30R. The plasma
C-peptide level was still low. Serum HbA1c level was 6.5%.
Serum  aminotransferase was normal,  and  serum HBV
DNA remained undetectable.

Table 1  Laboratory fndings in the patient on admission
Laboratory fndings
Urinalysis
   Glucose (+++)
   Ketobody (++++)
   Protein (-)
CBC
   RBC 3.94 × 1012
/L
   Hb 124 g/L
   WBC  5.1 × 109
/L
   Plt   62 × 109
/L
Blood chemistry
   Fasting plasma glucose 31.7 mmol/L (570.6 mg/dL)
   Arterial blood gas analysis
      pH  7.314
      PCO2          35.1 mmHg
      PO2
        70.6 mmHg
      HCO3
-
           11.5 mmol/L
      BE            -3.6 mmol/L
   TP     87.1 g/L
   ALB  48 g/L
   AST    36 IU/L
   ALT    40 IU/L
   ALP    98 IU/L
   GGT     21 IU/L
Serology
   HbA1c 10.0%
   HBs Ag (+)
   HBs Ab (-)
   HBe Ag (-)
   HBe Ab (-)
   HBcAb (+)
   HBV DNA (PCR) < 1000 copies/mL
   IgG  18.37 g/L
   IgA    2.79 g/L
   IgM   1.87 g/L
   TSH 0.636 mIU/mL
   FT3         4.03 pmol/L
   FT4     16.3 pmol/L
   TPOAb (-)
   TgAb (-)
   ANA (-)
   Anti-DNA Ab (-)
   RF (-)

患者女性，33岁，BMI=22.49kg/m2。由于患有慢性乙型肝炎，患者于2006年4月起开始接受重组人类α-干扰素2b(IFN-α 2b)治疗，每次300万单位，一日一次。IFN-α 2b治疗10个月后，患者乙肝病毒e抗原(HBeAg)和乙肝病毒脱氧核糖核酸(HBV-DNA)转阴，血清转氨酶回复至正常水平。但是IFN-α 2b起始治疗第13个月时（至2007年5月，累积剂量5亿8500万单位），患者主诉虚弱、烦渴、多尿和体重迅速下降（10日减少5kg），于是到西安交通大学第一附属医院就诊。
入院时实验室检查。尿常规发现糖尿(+++)和酮体(++++)。空腹血糖和糖化血红蛋白分别为31.7mmol/L(570.6mg/dl)和10.0%。动脉血气分析提示代谢性酸中毒：PCO2 35.1mmHg，PO2 70.6mmHg，HCO3- 11.5mmol/L，BE -3.6mmol/L。血清乙肝表面抗原和核心抗体阳性。空腹C肽水平下降，75克OGTT试验后C肽反应呈平直曲线。
患者没有T1DM或自身免疫性疾病家族史，也没有其他自身免疫性疾病症状。甲状腺过氧化物酶体抗体、抗核抗体、双链DNA抗体、核糖核蛋白抗体、SSA抗体及SSB抗体阴性，类风湿因子阴性。总观之，患者临床表现及实验室检查结果符合T1DM合并酮症酸中毒，与此同时，IFN治疗立即停止。在接受饮食控制、静脉补液及胰岛素(Isophane Protamine)治疗后，患者临床状况明显好转，12小时后酮尿消失。在患者急性酸中毒得到纠正后，胰岛素强化治疗改为1日4次，三餐前及睡前皮下注射。4日后，患者空腹血糖降至5.6mmol/L(100mg/dl)。IFN-α 2b治疗停止5个月后，患者胰岛素需用量保持20U/d，C肽水平依然较低，HbA1c为6.5%，转氨酶正常，HBV-DNA依然为依性。

IFN-α  has  di f ferent  biologic  ef fects  (ant ivi ral ,
antiproliferative,  immunomodulatory),  and has been
used  in  treatment of   chronic  viral hepatitis  for nearly
20 years. IFN-α acts on many  target cells and organs.
The thyroid represents the main target for autoimmunity
associated with IFN-α therapy. Although several reports
indicate  a beneficial  effect on  glucose metabolism,
IFN-α has been considered  to have a variety of  effects
on pancreatic beta  cells.  In  1992, Fabris  et  al

repor ted  the  first  case of   type  1 DM  in  a  chronic
hepatitis C patient  treated with  IFN-α  and  concluded
that  IFN  could  trigger  autoimmune destruction of  
pancreatic beta cells.
IFN-α  therapy-induced  autoimmunity of  pancreatic
beta  cells has been  evaluated  in  some  studies.
The prevalence of   ICAb, GADAb,  insulin  autoantibody
(IAA),  and/or  tyrosine-like phosphatase  autoantibody
(IA2Ab)  is not  generally  increased  in patients with
chronic viral infection prior to IFN-α therapy compared
with normal control subjects. In 50% of   the previously
reported patients, markers of  pancreatic  autoimmunity
predated  treatment,  the majority of   cases having  a  ge-
netic predisposition  (HLA-DR3/-DR4 was positive).
However, after IFN-α treatment, the prevalence of  pan-
creatic autoantibodies may increase from 3% to 7% with
type 1 DM developed  in a few cases. Therefore, IFN-α
therapy may induce type 1 DM in genetically and immu-
nologically predisposed individuals.
The exact mechanism underlying the development of  
type 1 DM in chronic viral hepatitis patients treated with
IFN-α is unclear. A variety of  mechanisms may account
for the effect of  IFN-α on pancreatic beta cell dysfunc-
tion. First,  IFN-α  activates  the oligoadenylate  syn-
thase-RnaseL pathway and the protein kinase R pathway,
thus inducing apoptosis of  pancreatic beta cells. Second,
IFN-α may stimulate a counter  regulatory hormone se-
cretion  (growth hormone,  glucagon,  etc.),  thus  resulting
in  impaired  glucose  tolerance. Third,  regarding  type  1
DM, IFN-α may favor the development of  Th1 immune
reaction  and  thereby  contribute  to  the development of  
autoimmune disease by activating CD4  lymphocytes se-
creting IL-2, IFN-γ, and tumor necrosis factor. IFN-α is
also associated with over-expression of  MHC classⅠan-
tigens in human islets of  pancreas. In addition to IFN-α,
HCV infection can increase the frequency of  pancreatic
autoimmunity. That is why IFN-α-induced type 1 DM is
relatively rare in chronic hepatitis B patients.
Transient  insulin dependency was observed  in  some
cases and permanent insulin administration was required
in the other reported cases. These data demonstrate that
in some cases the autoimmune attack is at least partially
reversible with interruption of  interferon therapy.
In conclusion, development of  type 1 DM should be
considered as one of  the risk consequences after IFN-α
therapy. In order to avoid it, administration of  IFN-α in
special patients should be evaluated, weighing the risk of  
diabetes and  the beneft of   the  treatment. We conclude
that patients having positive  islet  autoantibodies, HLA-
DR3/-DR4,  impaired  glucose  regulation, or positive
family history of  diabetes mellitus, should be considered
to have a higher risk of  developing type 1 DM following
IFN-α  treatment. Physicians  should be  cautious of  
the use of  IFN therapy.

[ 本帖最后由 宇宙的琴弦 于 2008-8-20 17:41 编辑 ]

IFN-α具有多种不同的生物学效应（抗病毒、抑制细胞增殖和免疫调节），用于慢性病毒性肝炎的治疗已有近20年的历史。IFN-α对多种靶细胞或器官产生生物学效应，在治疗自身免疫性疾病的过程中，IFN-α的主要靶器官是甲状腺。虽然有些报道提示IFN-α对糖代谢有益，但IFN-α仍被认为对胰岛β细胞具有多种不同影响。1992年，Fabris等报道了第1个IFN-α治疗慢性丙型肝炎过程中患者突发T1DM的病例，Fabris等认为IFN具有催化免疫系统破坏胰岛β细胞的作用。
部分研究评估了IFN-α治疗对胰岛β细胞自身免疫反应的作用，相比于对照组，接受IFN-α治疗的慢性病毒性肝炎患者没有表现出胰岛细胞抗体、谷氨酸脱羧酶抗体、胰岛素抗体和/或酪氨酸样磷酸酶自身抗体普遍升高。50%的报告病例中，患者胰岛自身免疫指标出现早于干扰素治疗，这些患者多数存在遗传易感性（HLA-DR3/DR4阳性）。但IFN-α治疗可使少数T1DM患者胰岛自身抗体阳性率升高大约3%~7%，因此IFN-α治疗可能会诱发遗传、免疫易感个体发生T1DM。
IFN-α治疗慢性病毒性肝炎引起T1DM的确切机制至今不明，IFN-α的多种生物学机制可能参与了导致胰岛细胞缺陷的过程。首先，IFN-α可激活寡聚腺苷酸合成酶-RNA酶L(RnaseL)途径和蛋白激酶R途径，从而引起胰岛β细胞凋亡；其次，IFN-α可能对激素（生长激素、胰升糖素等）分泌起负向调作用，最终导致糖耐量损伤；第三，IFN-α可能会助长Th1自身免疫反应，通过激活CD4+淋巴细胞分泌IL-2、IFN-γ和肿瘤坏死因子促进自身免疫性疾病的形成。IFN-α可能与人类胰岛MHC I类抗原过度表达有关，此外，丙肝病毒感染可以加重胰腺自身免疫，这也是IFN-α引起T1DM在慢性乙型肝炎患者中相对少见的主要原因。
部分病例中也可见一过性胰岛素缺乏，其他病例均需要永久使用胰岛素治疗。这些证据表明在部分病例中，及时停止干扰素治疗可以达到至少部分缓解自身免疫反应的作用。

3楼中最后一句“HBV-DNA依然为依性。”

是不是打错了?

应该是“HBV-DNA依然为阴性。”吧.....