Download Endocrine complications in thalassemia major

Endocrine complications in
thalassemia majorDiabetes mellitus
Dr. K W Wong
QEH
15th July 2004
Introduction
• Part I
– Classification
– Epidemiology
– Pathogenesis
– Clinical presentation
– Diagnosis
– Management
– DM complications
Introduction
• Part I
– Associated endocrine problems
– Survival
• Part II
– Diabetic thalassemic patients - a local
hospital experience
Classification
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Type I DM
Type II DM
Other specific types
Gestational diabetes
Classification
• Other specific types
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genetic causes of impaired -cell function
genetic defects of insulin action
secondary to pancreatic disease e.g. thalassemia
secondary to other endocrine disease
secondary to drugs of toxins
secondary to infection
other forms of immune disorder
rare genetic disorders
Epidemiology
• Limited data on prevalence of DM in
thalassemic patients
• Study in Italy: 2.3-24%
• QMH study in 1995: 5.9%
• QEH, PWH, PMH study in 2002: 8.6%
• prevalence varies and higher if studies
involving older patients
Epidemiology
• Age of onset of DM: teenagers
• Male > Female
Pathogenesis
• Not completely understood
• Combination of insulin deficiency and
insulin resistance
Pathogenesis
(contributing factors):
• Pancreatic dysfunction
• Liver dysfunction
– Fe deposition
– Co-existing chronic liver disease
– Hepatitis virus
• Genetic factor
–no distinct HLA typing can be found
• Autoimmune factor
Pathogenesis (Pancreatic
dysfunction)
Thalassemia  Repeated blood
transfusion  Iron overload  Damage
pancreatic cells  Pancreatic
dysfunction  Compensatory increase
in insulin secretion   cell exhaustion
 Insulin deficiency
Pathogenesis (Liver
dysfunction)
• Fe deposition
– Thalassemia  Repeated blood
transfusion  Iron overload 
Damage hepatic cells  ??  Insulin
resistance
• Co-existing chronic liver disease
– well recognised association between
cirrhosis and DM
Pathogenesis (Liver
dysfunction)
• Hepatitis virus
– 28% of patients with thalassemia major
developed DM shortly after acute viral
hepatitis
De Sanctis V. Insulin Dependent Diabetes in thalassemia. Arch. Dis. Child 1988; 63: 58-62.
– Prevalence of DM in thalassemia patients
with positive HCV Antibody was higher
(50%) than those with negative antibody
(9.5%)
Curyssoula. High prevalence of diabetes mellitus among adult beta thalassemia patients in
chronic hepatitis C. Europe J. of gastroenterology & hepatology. 1999; 11:1033-1036.
Pathogenesis
(Autoimmune factor)
The frequency of insulin cell antibodies
positive subjects among diabetic
thalassemic individuals (41.6%) was
high
Monge L.The possible role of autoimmunity in the pathogenesis of diabetes in betal thalassemia
major. Diabetes Metab (Paris) 2001; 27: 149-154.
CHO metabolism in
thalassemia
Normal insulin secretion  Decrease in
insulin secretion and decrease in insulin
sensitivity  Compensatory increase in
secretion to maintain CHO homeostasis
 Insulin secretion fails to keep pase
Normal  IGT (present for months and
can be up to 5 years) DM
Clinical presentations
• Asymptomatic : glycosuria,
hyperglycemia
• Classical symptoms: polyuria,
polydipsia, unexplained weight loss
• Acute complications: DKA
Diagnosis
In the absence of unequivocal
hyperglycemia with acute metabolic
decompensation, needed to repeat
testing on a different day
• Symptoms + random plasma glucose
level >/ 11.1mmol/L
• Fasting plasma glucose >/7mmol/L
• 2-hr plasma glucose >/11.1 during
OGTT test
Screening
No guideline
• History taking
• Urine monitoring of glucose every 4
weeks
• Spot sugar annually
Management
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Education
Diet
Exercise
Medication
– insulin (dosage similar as other DM
patients)
– oral hypoglycemic drugs
• DM control
Management-Oral
hypoglycemic drugs
• long term treatment with glyburide
(glibenclamide) can reverse excessive
insulin response to oral glucose
Jones TW. Correction of hyperinsulinemia by glyburide treatment in nondiabetic patients with
thalassemia major. Pediatr Res 1993; 33: 497-500
• improvement of OGTT in 73% of
patients treated with glibenclamide
versus 43% of patients on diet
treatment
Ladis. J.Glucose disturbance in regulation with glibenclamide in thalassemia. J. of Paed. Endo.
& Metabolism. 1998; 11: 867-869
Management-DM control
No guideline
• spot sugar 3 monthly
• fructosamine annually
• annual complication DM screening
– serum creatinine level
– lipid profile
– visual assessment by ophthalmologist
– 24 hr urine for microalbumin
Management-Prevention
• Intensive chelation may be able to
reverse islet cell damage and decrease
insulin requirement
DM Complications
• Acute
– hypoglycemia
– DKA
• Chronic
– macrovascular : atherosclerosis
– microvascular : retinopathy,
nephropathy, neuropathy
DM complications-retinopathy
• 12/46 (26%) patients suffers from
diabetic retinopathy in thalassemic
patients with diabetes duration of 9+/4.5 years.
• Less frequent and milder degree when
compared with type I DM
• Hypogonadism may be a protective
factor
Incorvaia C. Prevalence of retinopathy in diabetic thalassemic patients. J. of Paed. Endo. &
Metab. 1998; 11: 879-883.
DM complicationsnephropathy
• 5/9 (58%) patients developed
microalbuminuria after a mean duration
of overt diabetes of 3.6+/-2years
• Early development and accelerated
course of diabetic nephropathy
• Iron-derived free radicals cause high
oxidative stress to kidney
Loebstein. Diabetic nephropathy in hypertransfused patient with beta thalassemia with the role
of oxidative stress. Diabetes Care 1998; 21(8): 1306-1309.
Diabetic thalassemic patients:
associated endocrine problems
23/29 have other endocrine problems
• 5/23 hypoparathyroidism
• 19/23 hypogonadism
• 14/23 hypothyroidism
• 14/23 hypoparathyroidism
• 0/23 adrenal failure
De Sanctis V. Insulin Dependent Diabetes in thalassemia. Arch. Dis. Child 1988; 63: 58-62.
Diabetic thalassemic patients:
survival
• 14/29 patients died within 3 years of
developing overt diabetes
De Sanctis V. Insulin Dependent Diabetes in thalassemia. Arch. Dis. Child 1988; 63: 58-62.
• 34% still alive 8 years after diagnosis of
diabetes
De Sanctis V. Multicentre study on prevalence of endocrine complications in thalassemia
major. Endocrinology 1995; 42: 581-586
mainly caused by refractory heart failure