The “Other” Forms of Diabetes: Latent Autoimmune Diabetes of Adults Cystic Fibrosis Related...
-
Upload
jayson-rogers -
Category
Documents
-
view
214 -
download
0
Transcript of The “Other” Forms of Diabetes: Latent Autoimmune Diabetes of Adults Cystic Fibrosis Related...
The “Other” Forms of Diabetes:Latent Autoimmune Diabetes of Adults
Cystic Fibrosis Related DiabetesPost-Pancreatectomy Diabetes
EMILY BRENNAN
PGY-4 ENDOCRINOLGY
WEDNESDAY, MARCH 11, 2015
Objectives At the end of the lectures you will:
◦ Understand the definition of LADA, CFRD, and post-pancreatectomy diabetes
◦ Understand the pathophysiology behind LADA,CRFD and post-pancreatectomy diabetes
◦ Understand the implications for screening/diagnosis of these forms of diabetes
◦ Understand the clinical relevance and the differences in clinical management of these forms of diabetes
Case Mr. L.D. 57 year old male is referred by his family doctor for poorly controlled diabetes.
He was diagnosed about 4 months ago, and despite significant lifestyle modification and compliance with metformin and gliclazide, his sugars are still poor.
His BP is 124/78, HR 78. BMI 24.6. Unremarkable physical exam.
Most recent A1c is 9.1%
Started on insulin. Energy level much improved.
Sugars now controlled are low doses of MDI
LATENT AUTOIMMUNE DIABETES IN ADULTS
Diabetes and Antibodies Islet cell antibodies were discovered in 1974 in type 1 diabetes by Bottazzo et al.
Provided evidence that beta-cell destruction was autoimmune in nature, and leads to insulin deficiency
Thought to offer ‘evidence’ to differentiate between type 1 and type 2
Diabetes and Antibodies In 1978, Irvine et al, showed that 11% of patients with “type 2” diabetes were also positive for islet-cell cytoplasm antibodies (ICA)
Groop et al. 1986 found islet-cell antibodies in 14% of 154 patients aged 35 to 75 years who had been treated with diet and oral agents for at least 1 year
◦ Preserved beta-cell function◦ this subgroup had lower basal and stimulated C-peptide levels than ‘type 2s’◦ progressed more rapidly to insulin therapy
LADA: Definition Difficult to ‘define’
◦ Described over thirty years ago, but still a clinical controversy
Latent Autoimmune Diabetes in Adults (LADA)
Term coined in 1994 to describe patients with a slowly progressive form of type 1/autoimmune diabetes who could initially be treated without insulin
Heterogeneous disease that shares biochemical, genetic and phenotypic characteristics with both type 1 and 2 diabetes
Nomenclature
Latent Autoimmune Diabetes in Adults (LADA)
Progressive insulin-dependent diabetes
Latent type 1
Type 1 diabetes masquerading as type 2 diabetes
Type 1.5 diabetes
LADA DefinitionIn general, 3 criteria for “diagnosis of latent”:
◦ Adult age of diagnosis
◦ The presence of circulating islet autoantibodies
◦ No requirement for insulin for at least 6 months after diagnosis
Autoantibodies GAD (typically GAD65 isoform)
Insulinoma-associated (also called protein tyrosine phosphatase) antigen (IA-2A)
Cytoplasmic islet cell antibodies (ICA)
Zinc transporter 8
LADA: Pathophysiology Less understood than either type 1 or type 2 diabetes
Natural history of ‘pre-clinical’ LADA is unknown◦ Two extremes: longstanding islet cell autoimmunity and slowly progressive beta cell damage over many
years vs onset of islet autoimmunity in adult life with a shorter pre-clinical stage
LADA appears to be have both progressive autoimmune destruction of the beta-cells; however, insulin resistance may also contribute to the presentation of LADA
LADA: Pathophysiology
LADA: Genetics Less genetic epidemiology available for LADA; the focus is primarily on T1D and T2D
Family-based designs in linkage studies have had limited success to identify genetic factors
International HapMap project has offered new insight◦ Showed that T1D and T2D are distinct biological mechanisms; and none of the genes identified to date
in each of these disorders are associated with the other disease
LADA: Genetics T1DM Widely believed that LADA shares susceptibility genes with type 1 diabetes; small studies only available
HLA locus seen in T1DM is at 6p21◦ variation in this region accounts for half of the genetic risk for T1DM◦ this region coincides with the HLA class II genes which encode for the highly polymorphic antigen-
presenting proteins (primarily HLA-DRB1, DQA1, DQB1)◦ INS, CTLA4, and the protein tyrosine phosphatse-22 also confer susceptibility
HLA locus seen in T1D has also be seen in LADA; however, with some differences:◦ DQB1 *0201/*02302 is more common in T1DM than in LADA◦ Whereas the ‘protective genotypes’ *0602/X and 0603/X are more common in LADA◦ INS short class I variable number of tandem repeats has shown to confer equally strong susceptibility in
both T1DM and LADA
LADA: Genetics T2DM Transcription factor 7 (TCF7L2 gene) is the strongest locus for T2DM
TCF7L2 is also associated with LADA; interestingly, this has not been conclusively seen in T1DM
UKPDS Cohort UKPDS 70 - 2005
◦ Question: examine the prevalence of islet autoantibodies and their relationship to glycemic control over 10 years in patients diagnosed clinically with new onset type 2 diabetes
◦ Method: patient clinical characteristics and autoantibody status were determined at entry to the USPDS; before randomization to different glucose control policies.
◦ Follow-up: 10 years
◦ Patients had a clinical diagnosis of type 2 diabetes, defined as the absence of ketonuria
UKPDS 70 Cohort with 5102 newly diagnosed type 2 diabetes patients
UKPDS Baseline Characteristics
UKPDS 70
Ab+ closed circles
UKPDS 70
Ab+ on SU
Ab- on SU
Ab+ SUAb+ ConAb- SUAb- Con
UKPDS: Take Home Patients with autoantibody positivity exhibit:
◦ A phenotype closer to T1DM (lower BMI, lower BP, better lipid profile)
◦ Increased need for insulin to achieve glycemic control earlier than antibody negative patients
◦ Those who are antibody positive and on a SU had a higher rate of progression to insulin
Zhou et al (2013) In 2013:
◦ Multicenter study, retrospective analysis◦ Objective: characterize the Chinese LADA population ◦ 4880 subjects in China
◦ diabetes diagnosed at age > 30 years◦ enrolled within 1 year of diagnosis◦ did not develop DKA or insulin dependence for at least 6 months after diagnosis
Zhou et al (2013) LADA diagnosed in 5.9% based on + GAD65, the rest were classified as type 2
◦ LADA were leaner; lower fasting C-peptide, and less metabolic syndrome◦ North-South gradient (more LADA in the north)◦ HLA diabetes-susceptible haplotypes were more frequent in LADA◦ High GADA titer patients were phenotypically different than low GADA titer patients
Andersen et al (2013) Is there a difference in glycemic control in individuals with LADA versus T2DM and is it influenced by time on insulin therapy?
◦ Retrospective trial of 372 patients with LADA in Sweden◦ Age and sex-matched patients with type 2 DM were included as controls◦ Followed for 107 months
Andersen et al (2013) Outcomes
Andersen et al (2013) LADA were leaner than Type 2; longer time on insulin (53.3 vs 28.8)
LADA had poorer control at follow-up
They did not look at clinical outcomes; however, one can extrapolate more microvascular complications with higher A1c
Buzzetti et al (2007) Does the antibody titre matter?
2007 Italian trial:◦ Objective: define heterogeneity of LADA based on characterization of the antibodies◦ Used the NIRAD population and assessed antibody body status, HLA typing, and clinical characteristics◦ 4250 patients with T2DM
Buzzetti et al (2007)
Buzzetti et al (2007) Patients with high GAD antibody titers displayed:
◦ prominent traits of insulin deficiency ◦ a profile of more severe autoimmunity resulting in significantly higher A1C◦ significantly lower BMI◦ Lower total cholesterol, triglycerides◦ Lower prevalence of the metabolic syndrome
They look more like type 1 than type 2!
Treatment Apart from the UKPDS, studies on LADA have been small and underpowered
No consensus regarding ‘optimal’ treatment
Follow the CDA/ADA guidelines for T1DM
Suggested that patients with LADA should be initiated on insulin
Cochrane Review (2011) Objective: to compare interventions used for treatment of LADA
Selection criteria: RCT and controlled clinical trials evaluation interventions for LADA or T2DM with antibodies included
15 publications (10 studies) looking at 1019 who were followed for 3 months to 10 years◦ poor quality reporting◦ Small numbers of participants◦ No studies reported development of diabetic complications (looked at A1c and fasting blood glucose)◦ Significant heterogeneity
Cochrane Review (2011)
Cochrane Review Metabolic control (HbA1c) is improved using insulin compared to SU
Early pilot data that GAD65 may improve control
Insulin combined with Chinese medicine improved metabolic control when compared to SU
Vitamin D may protect beta-cells when given with insulin compared to insulin alone
LADA Adult-onset autoimmune diabetes is prevalent!
◦ likely more prevalent than T1DM
There is uncertainty regarding if the pathophysiology is distinct from T1DM or is there a clinical spectrum to ‘autoimmune diabetes’
It is not known whether the increasing prevalence of Type 2 diabetes is associated with an increasing prevalence of LADA
Does it matter? From a practical standpoint,
◦ If we are monitoring glucose, does measuring the antibodies matter?◦ No hard evidence that patients have more complications? (not studied)
◦ They do have worse HbA1c control post which would imply more microvascular complications
A list of diagnostic features for screening and defined clinical management regimens are unlikely to improve outcomes for adult-onset autoimmune patients who benefit from regular and careful clinical care with flexible treatment plans
Case: Ms. CF 42 year old female with a history of cystic fibrosis. She has had a prior lung transplant.
She is being followed for her diabetes. Last exacerbation was 2 months ago, required hospital admission. She struggles with frequent lows.
Physical exam: BP 112/62 HR 87. Weight 48.1. BMI 18.3
Her most recent A1c is 7.2%.
CYSTIC FIBROSIS RELATED DIABETES
Cystic Fibrosis Caused by mutations in the cystic fibrosis transmembrane conductance regulator (CRTR) protein
◦ Complex chloride channel and regulatory protein found in all exocrine tissues◦ Deranged transport of chloride and other CFTR-affected ions (Na and HCO3) result in thick, viscous
secretions in the lungs, pancreas, liver, intestine, and reproductive tract
CF is the most common recessive autosomal disease among Caucasians (1/2500-1/4000)
Cystic Fibrosis Related Diabetes (CFRD)
Significant advances in medical and nutritional treatments have led to improved survival, but increased the prevalence of other comorbidities:
◦ DM, bone diseases, depression
Diabetes is the most common morbidity in subjects with cystic fibrosis
CFRD: Epidemiology Can appear in infancy or adolescence
Increasing prevalence with age
Estimated to occur in approximately 50% of adult patients
CFRD: Pathophysiology
Certain mutations have higher occurrences of CRFD and more severe CF and pancreatic exocrine insufficiency
No known correlation with T1DM gene susceptibilities; however, some correlations with genes linked in T2DM have been found
CFRD: Pathophysiology
Pancreatic dysfunction is due to alterations in chloride channels◦ Viscous secretions cause obstruction of the exocrine pancreas with progressive fibrosis and fat
infiltration◦ This may lead to destruction and rupture of islets, which leads to loss of beta, alpha, and polypeptide
cells ◦ Postmortem studies have not found a greater loss of islets; however, amyloid polypeptide (seen in T2DM) was found in 69% of
CRRD patients and absent in non-DM patients
CFRD: Pathophysiology Primary issue that leads to DM is severe insulin deficiency (not absolute!)
Fasting insulin and C peptide may be normal, but there is a delay in the peak secretion of insulin during the OGTT (impaired first phase insulin and C-peptide secretion)
◦ In normal individuals this occurs at 30 and 60 minutes, while in CRFD the peak is observed in 90-120 minutes
CF patients also have an element of insulin resistance ◦ ?related to increased energy needs of CR patients create a physiologic balance between elevated hepatic
glucose production and high glucose demand◦ ?frequent use of glucocorticoids and constant infections may worsen this condition
Insulin resistance likely does not play as large a role as insulin deficiency
CFRD: Clinical Presentation Generally asymptomatic and may remain undetectable for up to 4 years prior to diagnosis
Spectrum of impaired glucose tolerance CFRD
In contrast to T1DM, insulin secretion is never totally absent
CFRD: Definition 1998 North American CFRD Committee Consensus:
2-hour glycemia >= 11.1 mmol/L in the OGTT
Divides the patients into those with or without fasting hyperglycemia ◦ FBG greater than/equal to 7 or less than 7 mmol/L◦ This classification was based on the fact that the prognosis can be different from the two groups ->
although, this has now been shown otherwise
CFRD: Screening
2-hr 75 gram OGTT (morning, during period of stable baseline health, 6 weeks after acute exacerbation)
Fasting blood glucose not acceptable (will miss up to half of patients)
HbA1c not sensitive enough in CFRD ◦ 6 studies showed low degree of correlation between A1C and glucose tolerance status
Begin annual screening at age 10 in all CF patients
CFRD: Screening For patients with continuous enteral feeds:
◦ Measure mid- and immediate postfeeding plasma glucose levels◦ CFRD represent if BG >= 11.1 mmol/L on two separate days
For patients during an acute exacerbation: (requiring IV antibiotics +/- glucocorticoids)◦ Screen by monitoring fasting and 2-h postprandial plasma glucose levels for the first 48 hours◦ If elevated glucose levels are found by SMBG, results must be confirmed on venous bloodwork
CFRD: RelevanceCFRD is associated with significant greater mortality
6 x increase in morbidity and mortality in those patients diagnosed with CFRD
CFRD: Morbidity Insulin deficiency and hyperglycemic negatively affect pulmonary disease
Nutritional condition and pulmonary function begin to deteriorate several years before CFRD diagnosis
Modest increases in sugars may influence pulmonary function◦ May promote growth of respiratory pathogens ◦ Catabolic effects of insulin deficiency may increase morbidity
US CF Foundation 2005 In 21, 047 patients in the US CF Foundation patient registry, between 1988 and 1992
Showed 54% increased in the risk of death in female patients with CFRD
Black = female no DMGreen = male no DMBlue = male + DMRed = female + DM
This was not confounded byCFTR genotype, age at CF diagnosis, BMI, steroid use or resp microbiology results
CF Population at University of Minnesota
Moran et al 2009◦ 527 patients at University of Minnesota
Mortality over time has decreased in CF with DM
In, the most recent time period, overall mortality still remains significantly higher in those with CFRD compared with those without diabetes, but the gap has considerably narrowed
Importantly, the mortality in the sex differences has disappeared.
CF Population at University of Minnesota
The improvement in the mortality is thought to be related to earlier detection and more aggressive treatment.
Also, CFRD without FH is now treated aggressively.
CF Population at University of Minnesota
CFRD: ADA Position Statement 2010
Should be treated with insulin therapy (Grade A)
Oral DM agents are not as effective as insulin to improve nutritional and metabolic outcomes in CFRD and are not recommended (Grade A)
No need to distinguish between CFRD with and without fasting hyperglycemia◦ both groups improve with insulin, and should receive insulin treatment
Strive to attain plasma glucose goals as per the ADA recommendations for all people with diabetes; higher or lower goals may be appropriate and should be individualized (Grade E)
CFRD: Dietary Recommendations
Common complications Hypoglycemia is common
◦ Occurs in the fasting and post-prandial state (usually not severe)◦ May reflect malnutrition and/or increased energy needs due to inflammation and infection◦ May be due to delayed and disordered insulin secretion◦ May have impaired glucagon secretion (alpha cell dysfunction), but should have normal catecholamine
response and normal hypoglycemic awareness
Microvascular complications appear typically after 5 years of CFRD and only after fasting hyperglycemia has developed
Multi-Disciplinary Approach CFRD is an expected complication as patients with CF grow older
Need to remember that the presence of another diagnosis – diabetes – for the families and the patients with CF is frequently difficult to accept and sometimes devastating.
Existence of multi-disciplinary teams with respirologist, physiotherapy, psychology and dietitian in addition to the endocrinologists is essential to promote the understanding of, and the adherence to the treatment and control of CFRD
Case: Mrs. CR 62 year old female with pancreatic mass found on CT.
Patient went for OR summer of 2014, and difficulties with bile leak post-operatively. Placed on TPN 24 hours a day for nutrition.
Blood sugars in hospital are 12-15.
Endocrine consulted to implement plan for diabetes management.
POST-PANCREATECTOMY DIABETES
Pancreatogenic DM Insulin is secreted by the beta cells (distributed evenly throughout the pancreas)
◦ Decreases glucose by: suppressing hepatic gluconeogenesis and glycogenolysis◦ Facilitates hepatic glycogen synthesis
Alpha cells (glucagon secreting cells) are located predominantly in the body and the tail of the pancreas
◦ maintain adequate glucose production by hepatocytes through stimulation of glycogenolysis and gluconeogenesis that together function as counter-regulatory mechanism to control hypoglycemia
Pancreatogenic DM Pancreatic polypeptide (PP) 36 amino-acid polypeptide localized to specific cells called PP cells
◦ Located mostly in the ventral pancreatic head and uncinated process
◦ In patients with low levels of plasma PP following pancreatic resection, hepatic glucose is not suppressed as it was in controls during an insulin infusion
◦ administration of PP to patients with PP deficiency was shown to improve their hepatic response
Pancreatogenic DM Loss of pancreatic parenchyma resulting from pancreatic resection causes an ‘extreme’ disruption in glucose homeostasis – different from T1DM or T2DM
◦ Pancreatogenic DM seldom causes ketoacidosis or severe hyperglycemia◦ does not have the insulin resistance of T2DM
Exogenous insulin administration frequently causes hypoglycemia ◦ Due to insulin sensitivity and reduced/lack of glucagon
Pancreatogenic DM: Pathophysiology
Differentiating Features
Pancreatogenic DM
Relevance:◦ Since the improved surgical procedures, post-op care and capacity for early diagnosis of disease has
prolonged life expectancy
Maeda and Hanazaki 2011
Burkhart et al (2014) Retrospective analysis of 1107 patients who underwent an pancreatectomy between 2006-2013
in New Jersey, US◦ Examined the incidence and characteristics of diabetes post-surgery◦ 257 of 691 surviving patients completed the surveys◦ Separated the patients into two groups: those with pre-existing DM versus those without
Burkhart et al (2014)
Burkhart et al (2014) Factors identified that were associated with increased risk (either development of pancreatogenic DM or worsening of preexisting condition):
◦ Increased insulin usage during the index hospitalization◦ Higher fasting blood glucose◦ Higher pre-operative HbA1c
Treatment There are no specific recommendations for the treatment of pancreatogenic DM
Choice of insulin versus non-insulin therapy depends on clinical presentation
Use the targets and recommendations set for T1DM and T2DM
If “mild”:◦ Frequent monitoring, follow-up, and lifestyle modification
If total pancreatectomy: results in insulin dependent pancreatogenic DM◦ Use insulin◦ Hypoglycemic attacks are partly related to the deficiency in pancreatic enzymes (does not occur until over 90% of pancreatic
exocrine function is lost)◦ Give pancreatic enzyme supplementation
TreatmentMetformin remains the first line agent
In patients with high risk of developing pancreatic carcinoma (chronic pancreatitis):Pancreatic carcinoma is characterized by overexpression of IGF-1 and G-protein coupled receptors and chronic hyperinsulinemia, which may enhance the development and growth of cancer
Pancreatogenic diabetes in the setting of chronic pancreatitis is considered ‘pre-malignant condition’, and treatments that employ insulin, insulin analogs, and insulin secretagogues may increase the risk of carcinoma by enhanced activation of these signally pathways
Metformin is the preferred drug, and should be used in in combination with insulin to reduce the insulin requirement (avoid SU, GLP-1 agonists, DPP4 inhibitor)
Comments/Questions?
References1. Andersen et al. Worse glycemic control in LADA patients than in those with type 2 diabetes, despite a longer time on insulin therapy. 2013.
Diabetoloigia. 56: 252-2582. Brophy et al. Interventions for latent autoimmune diabetes (LADA) in adults. Cochrane Review. 2011.3. Buzzeti, R et al. High titer of autoantibodies to GAD identifies a specific phenotype of adult-onset autoimmune diabetes. 2007. Diabetes Care.
30:93238.4. Burkhart et al. Incidence and severity of pancreatogenic diabetes after pancreatic resection. 2014. J gastrointesl Surg. 5. Cui. Pancreatogenic Diabetes: special considerations for management. 2011. Pancreatogeology. 11; 279-2946. Davis et al. UKPDS 70. Diabetologia. 2005. 48: 695-7027. De Noronha. Update on diagnosis and monitoring of cystic fibrosis-related diabetes mellitus (CFRD). 2011. Ar Bras Endocrinol Metab. 55(8):6138. Fourlanos et al. Latent autoimmune diabetes in adults (LADA) should be less latent. 2005. Diabetologia. 48:2206-22129. Gale. Latent autoimmue diabetes in adults: a guide for the perplexed. 2005 Diabetologia. 48:2195-219910. Laugesen E et al. Latent autoimmune diabetes of the adult: current knowledge and uncertainty. 2015. Diatbetic Medicine. (published online)11. Maeda and Hanazaki. Pancreatogenic diabetes after pancreatic resection. Pancreatology. 201112. Moran et al. Clinical care guidelines for Cystic Fibrosis-Related Diabetes. ADA Position Statement. 2010. Diabetes Care. 33(12): 2697-2708. 13. Moran et al. Cystic Fibrosis-Related Diabetes: Current trends in prevalence, incidence, and mortality. 2009. Diabetes Care. 32(9):1626-3114. Redondo, MJ. LADA: time for a new definition. 2013. Diabetes. 33915. Meada and Hanazaki. Pancretogenic diabetes after pancreatic resection. 2011. Pancreatology. 11:268-27616. Zhou et al. Frequency, immunogenetics, and clinical characteristics of latent autoimmune diabetes in China (LADA China study). 2013 Diabetes;
62;543