Back to Basics: Endocrinology Diabetes, Obesity and Thyroid.

Back to Basics: Back to Basics: EndocrinologyEndocrinology

Diabetes, Obesity and Diabetes, Obesity and

ThyroidThyroid

Diagnosis of DiabetesDiagnosis of Diabetes

What are the CDA criteria for the What are the CDA criteria for the diagnosis of diabetes?diagnosis of diabetes?

Who should be screened for type 2 Who should be screened for type 2 diabetesdiabetes

Which type of diabetes has a stronger Which type of diabetes has a stronger genetic component type 1 or type 2?genetic component type 1 or type 2?

Which type of diabetes only presents Which type of diabetes only presents in the elderly population?in the elderly population?

Screening for Type 2 Screening for Type 2 DiabetesDiabetes

5.7-6.9 mmol/L plus risk factor(s) for diabetes/IGT

2hPG in a 75-g OGTT

Every 3 years in individuals 40 years of age Earlier and/or more frequently in individuals with

additional risk factors

FPG

CDA 2003 Clinical Practice Guidelines. Can J Diabetes 2003;27:S11

Definitions of Impaired Fasting Glucose (IFG) and Impaired Glucose Tolerance

(IGT) and Diabetes

Fas

ting

Glu

cose

(mm

ol/

L)

3.5

4.5

5.5

6.5

7.5

8.5

3 4 6 8 10 12 14

2-h Post-load Glucose (mmol/L)

Diabetes

IFG + IGT

NormalGlucose

IGT

IFG6.1

6.9

7.8 11.1

* 1. ADA Diabetes Care 2006;29(Suppl 1):S47,2. CDA Can J Diabetes 2003;27(Suppl 2):S7, 3.WHO 1999 NDC/NCS.99.2 accessed Mar 2 2006 from www.who.int

5.6*

The World Wide Epidemic:The World Wide Epidemic:Prevalence of DiabetesPrevalence of Diabetes

5%

8%

14%

4%

3%

The Worldwide Epidemic:The Worldwide Epidemic:Diabetes TrendsDiabetes Trends

30

135177

221

300

370

0

50

100

150

200

250

300

350

400

Mil

lion

s w

ith

Dia

bete

s

1985 1995 2000 2010 2025 2030Sources: www.who.intwww.idfZimmet P. et al Nature: 414, 13 Dec 2001

The Diabetes The Diabetes Epidemic Epidemic in Canadain Canada

Prevalence, Risk Factors, Prevalence, Risk Factors,

and and

Current Cost ImplicationsCurrent Cost Implications

The Canadian Epidemic: The Canadian Epidemic: Prevalence in Canada, 1994/95 to Prevalence in Canada, 1994/95 to

2000/01, by Province2000/01, by Province 1996 - 1997

2.53.1

3.23.20

3.203.23.2

3.40

4.60

4.6

Prevalence (%)

1.30 to 2.903.00 to 3.403.50 to 3.90

4.00 to 4.405.00 to 5.405.50 to 5.90No data

3.10

1998 - 1999

3.4

4.4

3.13.13.1

3.33.6

4.0

5.2

3.1

2000 - 2001

1.3

3.43.9

4.0

4.0

4.14.2

5.0

5.1 5.2

5.8

3.2

1994 - 1995

2.7

2.8

2.83.0

3.13.1

3.2

3.50

3.6

3.90

Source: Statistics Canada: CANSIM II

Diabetes Risk Diabetes Risk FactorsFactors

Modifiable Risk FactorsModifiable Risk FactorsPhysical Activity Physical Activity

Obesity Obesity DietDiet

&&

Non-Modifiable Risk FactorsNon-Modifiable Risk FactorsEthnicityEthnicity

Family HistoryFamily History

Diabetes Risk Factors:Diabetes Risk Factors:ModifiableModifiable

0

1

2

Rel

ativ

e Ris

k

>7 4 to 7 2 to 4 .5 to 2 <0.5

Hours per week

Physical Activity: Relative Risk For Developing Diabetes

Source: Choi B, Shi F. Diabetologia 2001, 44:1221-1231.

0

0.5

1

1.5

2

rela

tive

ris

k

5 4 3 2 1quintiles based on fat/fibre content

Healthy Diet: Relative Risk for Developing DM



0

10

20

30

40

Rela

tive R

isk

<23 23-25 25-30 30-35 <35

BMI = wt/ (ht)2

Obesity: Relative Risk For Developing DM



Relative risk for developing type 2 is Relative risk for developing type 2 is cumulative.cumulative. A physically inactive individual (less than 30 A physically inactive individual (less than 30

min/wk of exercise) min/wk of exercise) who consumes an unhealthy dietwho consumes an unhealthy diet and is modestly overweight (BMI 25-30) and is modestly overweight (BMI 25-30) would have a 30-fold increased (1.8*2*8) risk of would have a 30-fold increased (1.8*2*8) risk of

developing type 2 DM compared to the general developing type 2 DM compared to the general population, population,

which would translate to a lifetime risk of which would translate to a lifetime risk of nearly 100%nearly 100%

REF: Atlas of Diabetes 2nd Ed, Part 2, JS Sklyer, EditorREF: Atlas of Diabetes 2nd Ed, Part 2, JS Sklyer, Editor


Run away from diabetes

The Epidemic: The Epidemic: Non-Modifiable Non-Modifiable

Risk FactorsRisk FactorsEthnicityEthnicity

AgeAge

Family History / GeneticsFamily History / Genetics

The Epidemic: The Epidemic: Ethnic Groups at High Ethnic Groups at High

Risk for DMRisk for DM Aboriginal Aboriginal

LatinoLatino

South East AsianSouth East Asian

AsianAsian

African DescentAfrican Descent

77.1% of Canada’s immigrant 77.1% of Canada’s immigrant population are coming from population are coming from populations which from high risk populations which from high risk ethnic groupsethnic groups

7.3% 7.3% LatinosLatinos Central and South America, 7.3%Central and South America, 7.3%

57.0% Asian 57.0% Asian 12.8% African Decent12.8% African Decent

Caribbean and Bermuda, 5.5%Caribbean and Bermuda, 5.5% Africa, 7.3%Africa, 7.3%

Diabetes Risk Factors: Non-Modifiable Other High-risk Groups in Canada

REF: Statistics Canada, 1996 Census

Type 2 Diabetes is NOT a Type 2 Diabetes is NOT a Mild DiseaseMild Disease

Stroke

2- to 4-fold increase in cardiovascular mortality and stroke3

Cardiovascular Disease

8/10 diabetic patients die from CV events4

Diabetic Neuropathy

Leading cause of non-traumatic lower extremity amputations5

Diabetic Retinopathy

Leading cause of blindness in

working-age adults1

Diabetic Nephropathy

Leading cause of end-stage renal

disease2

1. Fong DS et al. Diabetes Care 2003; 26(Suppl 1):S99-S102. 2. Molitch ME et al. Diabetes Care 2003; 26(Suppl 1):S94-S98. 3. Kannel WB et al. Am J Heart 1990; 120:672-6. 4. Gray RP and Yudkin JS. In: Textbook of Diabetes. 1997. 5. Mayfield JA, et al. Diabetes Care 2003; 26(Suppl 1):S78-S79.

Diabetes Complications: Diabetes Complications: MacrovascularMacrovascular

DM is a major risk factor for cardiac DM is a major risk factor for cardiac diseasedisease

Acute MI occurs 15-20 years earlier Acute MI occurs 15-20 years earlier in those with DMin those with DM

Heart disease accounts for Heart disease accounts for approximately 50% of all deaths approximately 50% of all deaths among people with diabetes in among people with diabetes in industrialized countries industrialized countries

REF: Diabetes in Ontario, An ICES Practice Atlas, 2002

Several large epidemiological Several large epidemiological studies have found a strong studies have found a strong relationship between relationship between glucose level and subsequent coronary glucose level and subsequent coronary

events, even at ‘pre-diabetes’ levels events, even at ‘pre-diabetes’ levels (IGT and IFG)(IGT and IFG)

glucose levels that are only modestly glucose levels that are only modestly elevated place patients at risk. elevated place patients at risk.

REF: Coutiho M. et al Diabetes Care 1999;22:233-240.& DECODE Study Group. Arch Intern Med 2001;161:397-404.

Diabetes Complications:Diabetes Complications: MacrovascularMacrovascular

Diabetes Complications: Macrovascular

Relationship between FPG and CHD

REF: Coutinho et al. Diabetes Care 1999;22:233-40.

Metaregression - 20 prospective studies n = 95,783 - follow-up 12.4 yrsFPG > 6 mmol/L: RR 1.38 (1.06-1.67)

Fasting glucose (mmol/L)

Rel

ativ

e R

isk

2.5

2

1.5

14 5 6 7 8 9

Diabetes….Diabetes…. Is the leading cause of non traumatic Is the leading cause of non traumatic

amputationamputation Increases the risk of amputation by 20 Increases the risk of amputation by 20

foldfold those living in the north or in low income those living in the north or in low income

neighborhoods and those with poor access neighborhoods and those with poor access to physician services are at particular risk to physician services are at particular risk for amputation.for amputation.


Diabetes Complications: Diabetes Complications: MicrovascularMicrovascular – Amputation– Amputation

DiabetesDiabetes Is a leading cause of adult-onset Is a leading cause of adult-onset

blindnessblindness Prevalence of diabetic retinopathy is ~ Prevalence of diabetic retinopathy is ~

70% in persons with type 1 and 40% 70% in persons with type 1 and 40% with person with type 2 diabetes. with person with type 2 diabetes.


Diabetes Complications: Diabetes Complications: MicrovascularMicrovascular – Retinopathy– Retinopathy

Diabetes Diabetes Is the leading cause of ESRDIs the leading cause of ESRD Increases the risk of developing ESRD Increases the risk of developing ESRD

by up to 13-foldby up to 13-fold

Refs: Meltzer S, et al CMAJ 1998; 159 (8 suppl):S1-S29, &

Parchman ML, et al Medical Care 2002; 40(2):137-144.

Diabetes Complications: Diabetes Complications: MicrovascularMicrovascular - - NephropathyNephropathy

Prevention strategiesPrevention strategies

Primary PreventionPrimary Prevention Prevent diabetes through reduction of Prevent diabetes through reduction of

modifiable risk factors in general modifiable risk factors in general populationpopulation

Secondary PreventionSecondary Prevention Screening those at high-risk for diabetesScreening those at high-risk for diabetes

Tertiary PreventionTertiary Prevention Upon diagnosis of diabetes, prevention of Upon diagnosis of diabetes, prevention of

complications morbidity, and mortalitycomplications morbidity, and mortality

REF: Diabetes Blueprint

Primary Prevention Primary Prevention ModelModel

GoalGoal Reducing modifiable risk factors for diabetesReducing modifiable risk factors for diabetes

Target Target General population & high-risk groups General population & high-risk groups

MessagesMessages Healthy lifestyle choicesHealthy lifestyle choices

Current Delivery Models of Primary Current Delivery Models of Primary PreventionPrevention Population HealthPopulation Health Primary CarePrimary Care

REF: Health Canada

Primary Prevention Model: Primary Prevention Model: Population HealthPopulation Health – National – National

CDS

Health Canada

NADA

GoalGoal Early identification of those with Early identification of those with

dysglycemia dysglycemia Target Target

High-risk individuals and groups High-risk individuals and groups MessagesMessages

Diabetes awarenessDiabetes awareness Current delivery model of secondary Current delivery model of secondary

prevention relies on primary careprevention relies on primary care

Secondary PreventionSecondary Prevention

Secondary Prevention: Secondary Prevention: Is It Effective?Is It Effective?

Yes….Yes…. Patients diagnosed with IGT can be Patients diagnosed with IGT can be

prevented from progressing to type 2 prevented from progressing to type 2 diabetes diabetes 58% reduction with lifestyle changes (DPP, 58% reduction with lifestyle changes (DPP,

DPS) DPS) 30% reduction with medication (DPP, Stop 30% reduction with medication (DPP, Stop

NIDDM) NIDDM)

Tertiary Prevention: Tertiary Prevention: Is it Effective?Is it Effective?

Yes…Yes… Strong evidence for tertiary prevention Strong evidence for tertiary prevention

particularly for microvascular diseaseparticularly for microvascular disease DCCT, UKPDSDCCT, UKPDS

How to translate this evidence into How to translate this evidence into practice?practice?

Tertiary PreventionTertiary Prevention

GoalsGoals Glucose, blood pressure, and lipid Glucose, blood pressure, and lipid

control to reduce the development of control to reduce the development of complicationscomplications

Complication screening for early Complication screening for early identification and managementidentification and management

Why are Obesity and Type 2 DM

Increasing in Frequency? More sedentary lifestyles More sedentary lifestyles Worldwide changes in urbanization and nutritionWorldwide changes in urbanization and nutrition Aging population due to demographic growth rates Aging population due to demographic growth rates

(baby boomers) and increased life expectancy (baby boomers) and increased life expectancy

www.who.int and www.idf.org accessed March 16, 2006

19901985

1994

< 10%

< 10% - 14.9%

> 15%

No data

1996 1998

Source: Katzmarzyk PT, CMAJ Apr. 16, 2002; 166 (8)

Obesity by Province: BMI Obesity by Province: BMI 3030

ObesityObesity The most common metabolic condition in The most common metabolic condition in

industrialized nationsindustrialized nations Statistics Canada: 48% of Canadians Statistics Canada: 48% of Canadians

between ages 20-64 yr are overweight between ages 20-64 yr are overweight (BMI>25)(BMI>25)

Associated with dyslipidemia, impaired Associated with dyslipidemia, impaired glucose tolerance and insulin resistanceglucose tolerance and insulin resistance

Risk factor for developing metabolic Risk factor for developing metabolic syndrome, type 2 Dm, cardiovascular syndrome, type 2 Dm, cardiovascular diseasedisease

Huge economic costsHuge economic costs

Obesity in Canada: 1978/79 to 2004

Data from Canadian Community Health Survey www.statcan.ca/Daily/English/050706/d050706a.htm

Quick Facts:Quick Facts:

% of obese children increased from 3% to 8%

Among adults, the increase was even more dramatic: from 14% to 23%, a total of 5.5 million people

About 30% of baby boomers (aged 45 to 64) are obese

Canada’s Food guide to Canada’s Food guide to healthy eatinghealthy eating

Promote a diet with 30% or less Promote a diet with 30% or less energy from fat, 15-20% energy energy from fat, 15-20% energy from protein and 50-55% from from protein and 50-55% from complex carbohydratescomplex carbohydrates

Despite a decrease from 40% of Despite a decrease from 40% of energy from fat in U.S. diet in 1965 energy from fat in U.S. diet in 1965 to 34% in 1991, incidence of obesity to 34% in 1991, incidence of obesity increasedincreased

Why is it Important to Why is it Important to Recognize the Recognize the

Metabolic Syndrome?Metabolic Syndrome?A prevalent condition associated with:A prevalent condition associated with: Significantly increased CVD risksSignificantly increased CVD risks Significantly increased risks for type 2 diabetesSignificantly increased risks for type 2 diabetes

It is treatable and preventableIt is treatable and preventable

Clinical Features of the Clinical Features of the Metabolic SyndromeMetabolic Syndrome

Abdominal obesityAbdominal obesity HyperglycemiaHyperglycemia Atherogenic dyslipidemiaAtherogenic dyslipidemia HypertensionHypertension Proinflammatory stateProinflammatory state Prothrombotic stateProthrombotic state

IDF Classification of the IDF Classification of the Metabolic SyndromeMetabolic Syndrome

5.6 mmol/L 5.6 mmol/L Fasting glucoseFasting glucose

130 Syst. or diast. 130 Syst. or diast. 85 mm Hg or Rx 85 mm Hg or RxBlood pressureBlood pressure

1.10 1.10 WomenWomen

0.900.90 MenMen

1.71.7HDL cholesterolHDL cholesterol

Men Men Waist C.Waist C. WomenWomen

94 cm 94 cm (37 in)(37 in) 80 cm 80 cm (31.5 in)(31.5 in)

90 cm 90 cm (35 in)(35 in) 80 cm 80 cm (31.5 in)(31.5 in)

85 cm 85 cm (33 in)(33 in) 90 cm 90 cm (35 in)(35 in)

Central obesityCentral obesity Europids, Mid-eastEuropids, Mid-east S. Asians, ChineseS. Asians, Chinese JapaneseJapanese

Cut PointsCut Points

Plus any 2 of the following for diagnosis:Plus any 2 of the following for diagnosis:

Inadequate evidence to recommend routine measurement of insulin resistance (e.g., plasma insulin), proinflammatory state, or prothrombotic state in the diagnosis of the metabolic syndrome

TriglyceridesTriglycerides

Risk FactorsRisk Factors

Metabolic SyndromeMetabolic Syndrome

A common condition associated with A common condition associated with increased cardiovascular disease risksincreased cardiovascular disease risks

Treatment is aimed at lifestyle Treatment is aimed at lifestyle modification to achieve desirable body modification to achieve desirable body weight and reduce abdominal obesityweight and reduce abdominal obesity

Multiple medical therapy may be Multiple medical therapy may be required to achieve metabolic targets required to achieve metabolic targets (lipids, glucose and BP)(lipids, glucose and BP)

Lifestyle modification benefits Lifestyle modification benefits everyone!everyone!

Therapeutic Therapeutic strategies for the strategies for the management of management of type 2 diabetes.type 2 diabetes.

Targets for Metabolic Targets for Metabolic Control: Control:

Glucose ControlGlucose Control (2003 CDA (2003 CDA Guidelines)Guidelines)Normal Range Normal Range

(consider if (consider if can be can be achieved achieved safely)safely)

Target for Target for Most PatientsMost Patients

A1CA1C 6.06.0 7.07.0

PreprandialPreprandial 4.0 – 6.04.0 – 6.0 4.0 – 7.04.0 – 7.0

2 h 2 h PostprandialPostprandial 5.0 – 8.05.0 – 8.0 5.0 – 10.05.0 – 10.0

Risk categories and target lipid levels

III-9

Clinical assessment and initiation of nutrition and physical activity

A1C <9% A1C ≥9%

BMI ≥25 BMI <25

Metformin (first-line)TZD

SecretagogueInsulin

Acarbose

MetforminTZD

SecretagogueInsulin

Acarbose

2 agents:Metformin

TZDSecretagogue

InsulinAcarbose

Insulin

Achieve Target A1C Achieve Target A1C within 6within 6––12 Months12 Months

Timely adjustments/additions should be made to attain target A1C within 6–12 months.

Canadian Diabetes Association Clinical Practice Guidelines Expert Committee. Can J Diabetes 2003;27(Suppl 2):S1–152.

Oral Medications Oral Medications to Treat Type 2 to Treat Type 2

DiabetesDiabetes

Oral Medications Oral Medications to Treat Type 2 to Treat Type 2

DiabetesDiabetes

Major Classes of Major Classes of MedicationsMedications

1. Drugs that sensitize 1. Drugs that sensitize the body to insulin the body to insulin and/or control hepatic and/or control hepatic glucose productionglucose production

2. Drugs that stimulate 2. Drugs that stimulate the pancreas to make the pancreas to make more insulinmore insulin

3. Drugs that slow the3. Drugs that slow the absorption of starchesabsorption of starches

ThiazolidinedioneThiazolidinedioness

BiguanidesBiguanides

SulfonylureasSulfonylureasMeglitinidesMeglitinides

Alpha-glucosidase Alpha-glucosidase inhibitorsinhibitors

ThiazolidinedionesThiazolidinediones Thiazolidinediones decrease insulin resistance by Thiazolidinediones decrease insulin resistance by

making muscle and adipose cells more sensitive to making muscle and adipose cells more sensitive to insulin. They also suppress hepatic glucose insulin. They also suppress hepatic glucose production.production.

EfficacyEfficacy Decrease fasting plasma glucose ~1.9-2.2 mmol/LDecrease fasting plasma glucose ~1.9-2.2 mmol/L Reduce A1C ~0.5-1.0%Reduce A1C ~0.5-1.0% 6 weeks for maximum effect6 weeks for maximum effect

Other EffectsOther Effects Weight gain, edema Weight gain, edema Hypoglycemia (if taken with insulin or agents that stimulate Hypoglycemia (if taken with insulin or agents that stimulate

insulin release)insulin release) Contraindicated in patients with abnormal liver function or Contraindicated in patients with abnormal liver function or

CHFCHF Improves HDL cholesterol and plasma triglycerides; usually Improves HDL cholesterol and plasma triglycerides; usually

LDL neutralLDL neutral Medications in this Class: pioglitazone (Actos), Medications in this Class: pioglitazone (Actos),

rosiglitazone (Avandia), rosiglitazone (Avandia),

BiguanidesBiguanides Biguanides decrease hepatic glucose production and Biguanides decrease hepatic glucose production and

increase insulin-mediated peripheral glucose uptake.increase insulin-mediated peripheral glucose uptake. EfficacyEfficacy

Decrease fasting plasma glucose 3.3-3.9 mmol/LDecrease fasting plasma glucose 3.3-3.9 mmol/L Reduce A1C 1.0-2.0%Reduce A1C 1.0-2.0%

Other EffectsOther Effects Diarrhea and abdominal discomfortDiarrhea and abdominal discomfort Risk of Lactic acidosis in those at risk (renal failure, CHF)Risk of Lactic acidosis in those at risk (renal failure, CHF) Cause small decrease in LDL cholesterol level and triglyceridesCause small decrease in LDL cholesterol level and triglycerides No specific effect on blood pressureNo specific effect on blood pressure No weight gain, with possible modest weight lossNo weight gain, with possible modest weight loss Contraindicated in patients with impaired renal function Contraindicated in patients with impaired renal function

(eGFR<33 ml/min)(eGFR<33 ml/min) Medications in this Class: metformin (Glucophage), Medications in this Class: metformin (Glucophage),

metformin hydrochloride extended release metformin hydrochloride extended release (Glumetza)(Glumetza)

SulfonylureasSulfonylureas Sulfonylureas increase endogenous insulin Sulfonylureas increase endogenous insulin

secretionsecretion EfficacyEfficacy

Decrease fasting plasma glucose 3.3-3.9 mmol/LDecrease fasting plasma glucose 3.3-3.9 mmol/L Reduce A1C by 1.0-2.0%Reduce A1C by 1.0-2.0%

Other EffectsOther Effects HypoglycemiaHypoglycemia Weight gain Weight gain No specific effect on plasma lipids or blood pressureNo specific effect on plasma lipids or blood pressure Generally the least expensive class of medicationGenerally the least expensive class of medication

Medications in this Class:Medications in this Class: glyburide (DiaBeta), glimepiride (Amaryl), gliclizide glyburide (DiaBeta), glimepiride (Amaryl), gliclizide

(Diamicron)(Diamicron)

MeglitinidesMeglitinides Meglitinides stimulate insulin secretion Meglitinides stimulate insulin secretion

(rapidly and for a short duration) in the (rapidly and for a short duration) in the presence of glucose.presence of glucose.

EfficacyEfficacy Decreases peak postprandial glucoseDecreases peak postprandial glucose Decreases plasma glucose 3.3-3.9 mmol/LDecreases plasma glucose 3.3-3.9 mmol/L Reduce A1C 1.0-2.0%Reduce A1C 1.0-2.0%

Other EffectsOther Effects Hypoglycemia (although may be less than with Hypoglycemia (although may be less than with

sulfonylureas if patient has a variable eating schedule)sulfonylureas if patient has a variable eating schedule) Weight gain Weight gain No significant effect on plasma lipid levelsNo significant effect on plasma lipid levels Safe at higher levels of serum Cr than sulfonylureasSafe at higher levels of serum Cr than sulfonylureas

Medications in this Class: repaglinide Medications in this Class: repaglinide (Gluconorm), nateglinide (Starlix)(Gluconorm), nateglinide (Starlix)

Alpha-glucosidase Alpha-glucosidase InhibitorsInhibitors Alpha-glucosidase inhibitors block the Alpha-glucosidase inhibitors block the

enzymes that digest starches in the small enzymes that digest starches in the small intestineintestine

EfficacyEfficacy Decrease peak postprandial glucose 2.2-2.8 mmol/LDecrease peak postprandial glucose 2.2-2.8 mmol/L Decrease fasting plasma glucose 1.4-1.7 mmol/LDecrease fasting plasma glucose 1.4-1.7 mmol/L Decrease A1C 0.5-1.0%Decrease A1C 0.5-1.0%

Other EffectsOther Effects Flatulence or abdominal discomfort Flatulence or abdominal discomfort No specific effect on lipids or blood pressureNo specific effect on lipids or blood pressure No weight gainNo weight gain Contraindicated in patients with inflammatory bowel Contraindicated in patients with inflammatory bowel

disease or cirrhosisdisease or cirrhosis Medications in this Class: acarbose Medications in this Class: acarbose

(Glucobay)(Glucobay)

Treatment of Type 2 Treatment of Type 2 DiabetesDiabetes

DiagnosisDiagnosis

Therapeutic Lifestyle ChangeTherapeutic Lifestyle Change

Combination Therapy - Oral Drug with InsulinCombination Therapy - Oral Drug with Insulin

Combination Therapy - Oral Drugs OnlyCombination Therapy - Oral Drugs Only

MonotherapyMonotherapy

Insulin TherapyInsulin Therapy

Normal Pancreatic Normal Pancreatic FunctionFunction

Meal Meal Meal

Bolus: At mealtime, insulin is rapidly released

in response to food.

Basal: Beta cells secrete small amounts of insulinthroughout the day.

Basal Insulin

Bolus Insulin

• Expected insulin changes during the day Expected insulin changes during the day for individuals with a healthy pancreasfor individuals with a healthy pancreas..

*Insulin effect images are theoretical representations and are not derived from clinical trial data.

Action Profiles of Bolus Action Profiles of Bolus & Basal Insulins& Basal Insulins

Pla

sm

a In

sulin

lev

els

HoursNote: action curves are approximations for illustrative purposes. Actual patient response will vary.

regular 6-10 hours

NPH 12–20 hours

lispro/aspart 4–6 hours

BASAL INSULINS

detemir ~ 6-23 hours (dose dependant)

glargine ~ 20-26 hours

Mayfield, JA.. et al, Amer. Fam. Phys.; Aug. 2004, 70(3): 491 Plank, J. et.al. Diabetes Care, May 2005; 28(5): 1107-12

BOLUS INSULINS

• Expected insulin changes during the day Expected insulin changes during the day • for individuals with a healthy pancreas.for individuals with a healthy pancreas.

*Insulin effect images are theoretical representations and are not derived from clinical trial data

Mayfield, JA. et al., Amer. Fam. Phys.; Aug. 2004, 70(3): 489-500

BID NPH and Regular BID NPH and Regular Insulin Therapy - Insulin Therapy -

Compared to Normal Compared to Normal PhysiologyPhysiology

Bolus needs: Regular

Basal needs: NPH

Meal Meal Meal

• Expected insulin changes during the day Expected insulin changes during the day • for individuals with a healthy pancreas.for individuals with a healthy pancreas.

*Insulin effect images are theoretical representations and are not derived from clinical trial data.

Multiple Daily Injections Multiple Daily Injections (MDI) – (MDI) –

Strive to Mimic Normal Strive to Mimic Normal PhysiologyPhysiology

MDI insulin therapy addresses:

Bolus needs: Lispro, Aspart Basal needs: Glargine, Detemir

Meal Meal Meal

Insulin RegimensInsulin RegimensType 2Type 2

Usually – a single bedtime injection Usually – a single bedtime injection of basal insulin added to OAD. of basal insulin added to OAD.

Occasionally - twice daily injections Occasionally - twice daily injections of basal insulin with OAD.of basal insulin with OAD.

Twice daily injection of “pre-mixed” Twice daily injection of “pre-mixed” insulin (split mix without mixing).insulin (split mix without mixing).

Intensive insulin – basal/bolusIntensive insulin – basal/bolus 40% basal/20% mealtime with each meal40% basal/20% mealtime with each meal

Case 1Case 1

Breakfast Lunch Dinner Bedtime

9.5 7.5 7.1 7.0

Is this patient well controlled? Does this patient require insulin?If “yes”… How would you start insulin here? How do you titrate the insulin dose? What do you do with the oral agents?

55 year old, 84 kg, BMI 29, T2DM 5 yrs, 55 year old, 84 kg, BMI 29, T2DM 5 yrs, A1C = 7.5% A1C = 7.5% On metformin, glyburide, TZD (thiazolidinedione)On metformin, glyburide, TZD (thiazolidinedione)

Case 1 - Bedtime InsulinCase 1 - Bedtime Insulin

Breakfast Lunch Dinner Bedtime

Start with 10 units1, or use 0.1- 0.2 units/kg and titrate2 Ex. 84 kg X 0.1 = 8 units OR 84 kg X 0.2 = 17 units Continue metformin, glyburide. Continuing TZD would be

off-label in Canada

NPH, Glargine or Detemir - 10 units

55 year old, 84 kg, BMI 29, T2DM 5 yrs, 55 year old, 84 kg, BMI 29, T2DM 5 yrs, A1C = A1C = 7.5% 7.5% On metformin, glyburide, TZDOn metformin, glyburide, TZD

- - -

1 Riddle et.al., Diabetes Care, 2003, 26(11):3080-862 CDA 2003 CPG, Can J Diabetes 27(Suppl 2):S135

Dosage Initiation & Dosage Initiation & Titration for Once-Daily Titration for Once-Daily

Insulin RegimensInsulin Regimens Initial dose of insulin at bedtime (Glargine, Detemir, Initial dose of insulin at bedtime (Glargine, Detemir,

NPH)NPH) - - Safe starting dose should equal fasting blood Safe starting dose should equal fasting blood

glucose glucose in mmol/L. in mmol/L. For example: Fasting glucose = 10 For example: Fasting glucose = 10 mmol/Lmmol/L Starting Insulin Dose = 10 unitsStarting Insulin Dose = 10 units

Self-adjustment of insulin dosesSelf-adjustment of insulin doses - Measure fasting glucose daily during first - Measure fasting glucose daily during first

weeks or weeks or months; after reaching target, months; after reaching target, frequency of testing can frequency of testing can reduce to once a weekreduce to once a week

-- If fasting glucose exceeds 5.5 mmol/L on three If fasting glucose exceeds 5.5 mmol/L on three consecutive FPG measurements, increase consecutive FPG measurements, increase

bedtime bedtime insulin dose by 2 units insulin dose by 2 units Yki-Jarvinen, H., Diabetes Care 2001, 24(4): 758-67

Hypoglycemia – Hypoglycemia – RecognitionRecognition

Hypoglycemia = development of symptoms or a plasma Hypoglycemia = development of symptoms or a plasma glucose <4.0 mmol/L.glucose <4.0 mmol/L.

Symptoms of hypoglycemiaSymptoms of hypoglycemia

AutonomicAutonomic NeuroglycopenicNeuroglycopenicTremblingTremblingPalpitationsPalpitationsSweatingSweatingAnxietyAnxiety

HungerHungerNauseaNauseaTinglingTingling

Difficulty Difficulty concentrating concentrating Vision changesVision changesDifficulty speakingDifficulty speakingHeadacheHeadacheDizzinessDizziness

ConfusionConfusionWeaknessWeaknessDrowsinessDrowsinessTirednessTiredness

Severity of hypoglycemiaSeverity of hypoglycemiaMild: Mild: Autonomic symptoms are present. The individual is Autonomic symptoms are present. The individual is able to self-treat.able to self-treat.Moderate: Moderate: Autonomic and neuroglycopenic symptoms are Autonomic and neuroglycopenic symptoms are present. The individual is able to self-treat.present. The individual is able to self-treat.Severe: Severe: Individual requires assistance of another person. Individual requires assistance of another person. Unconsciousness may occur. Plasma glucose is typically Unconsciousness may occur. Plasma glucose is typically <2.8 mmol/L. <2.8 mmol/L.

CDA 2003 CPG, Can J Diabetes 27(Suppl 2):S43

Type 2 Diabetes and Type 2 Diabetes and DyslipidemiaDyslipidemia

Dyslipidemic Profile in Type Dyslipidemic Profile in Type 2 Diabetes2 Diabetes

Type 2 diabetes is associated with a Type 2 diabetes is associated with a lipid profile that increases CV risk:lipid profile that increases CV risk:

Low levels of HDL cholesterolLow levels of HDL cholesterol Elevated triglyceridesElevated triglycerides Raised concentrations of free fatty acidsRaised concentrations of free fatty acids Increased small, dense, and more atherogenic Increased small, dense, and more atherogenic

LDL particlesLDL particles Total LDL levels remain relatively unchangedTotal LDL levels remain relatively unchanged Raised total cholesterol / HDL cholesterol ratioRaised total cholesterol / HDL cholesterol ratio

Pyorala K, et al. Diabetes Care. 1997;20:614-620.

Paolisso G, Howard BV. Diabet Med 1998;15:360-366. Haffner SM, et al. Diabetes Care. 1999;22:562-568.

LDL Atherogenicity in LDL Atherogenicity in Type 2 DiabetesType 2 Diabetes

Total LDL cholesterol concentrations Total LDL cholesterol concentrations similar to those in nondiabetic similar to those in nondiabetic controls, BUT…controls, BUT…

Important qualitative changes in LDLImportant qualitative changes in LDL Shift in LDL subfraction distribution to Shift in LDL subfraction distribution to

smaller denser particles (pattern B)smaller denser particles (pattern B) Increased susceptibility to oxidationIncreased susceptibility to oxidation Glycation of LDL apo BGlycation of LDL apo B

Adapted from Chait A, Bierman EL. Joslin's Diabetes Mellitus 13th ed. Philadelphia: Lea & Febiger; 1994:648-664.Haffner SM. Diabetes Care. 1998;2:160-178.

Reduce LDL-C to target for high risk patients Reduce LDL-C to target for high risk patients (< 2.0 mmol/L)(< 2.0 mmol/L)

Combinations of lipid-lowering medications can Combinations of lipid-lowering medications can and should be used to achieve lipid targetsand should be used to achieve lipid targets

Statin + cholesterol absorption inhibitorsStatin + cholesterol absorption inhibitors

Statin + fibratesStatin + fibrates

Statin + niacinStatin + niacin

Cholesterol absorption inhibitors + fibratesCholesterol absorption inhibitors + fibrates

Treatment optionsTreatment options

Vascular Protection Through Vascular Protection Through a a

Multifaceted ApproachMultifaceted Approach For ALL High-risk Patients with Diabetes • ACEI• ASA (clopidogrel if intolerance)• Lifestyle management: No smoking, healthy diet / weight, physical activity

Blood Pressure Control

Aim for BP < 130/80 mm Hg

If BP >130/80 mm Hg despite ACEI:Treat as per hypertension recommendations (CHEP/CHS)

Glycemic Control

Aim for A1C < 7.0%(< 6.0% if achievable safely)

If AIC > 7%: Treat as per glycemiarecommendations (CDA)

High CV risk

Renal Protection•Treat as per nephropathy recommendations (CDA)

Lipid Control

Adapted from Can J Diabetes. 2003;27:S58-S65.

When monotherapy fails to achieve lipid targets, the addition of a second drug from another class should be considered

Aim forLDL ≤ 2.0 andTC:HDL < 4.0

Smoking Cessation advice.

Diabetic Diabetic NephropathyNephropathy

Diabetic NephropathyDiabetic Nephropathy Over 40% of new cases of Over 40% of new cases of

end-stage renal disease end-stage renal disease (ESRD) are attributed to (ESRD) are attributed to diabetes. diabetes.

In 2001, 41,312 people with In 2001, 41,312 people with diabetes began treatment for diabetes began treatment for end-stage renal disease in end-stage renal disease in U.S.U.S.

In 2001, it cost $22.8 billion In 2001, it cost $22.8 billion in public and private funds to in public and private funds to treat patients with kidney treat patients with kidney failure.failure.

Minorities experience higher Minorities experience higher than average rates of than average rates of nephropathy and kidney nephropathy and kidney diseasedisease

Incidence of ESRD Resulting from Primary

Diseases (1998)

43%

23%

12%

3%

19%

Diabetes

Hypertension

Glomerulonephritis

Cystic Kidney

Other Causes

Screening for Diabetic Screening for Diabetic NephropathyNephropathy

Test When Normal Range

Blood Pressure1

Each office visit <130/80 mm/Hg

Urinary Albumin1

Type 2: Annually beginning at diagnosis Type 1: Annually, 5-years post-diagnosis

<30 mg/day 30 g/mgcreatinine

1American Diabetes Association: Nephropathy in Diabetes (Position Statement). Diabetes Care 27 (Suppl.1): S79-S83, 2004

ACR </= 2.8 for womenACR </= 2.0 for men

Treatment of Diabetic Treatment of Diabetic NephropathyNephropathy

Hypertension Control -Hypertension Control - Goal: lower Goal: lower blood pressure to <130/80 mmHg blood pressure to <130/80 mmHg Antihypertensive agentsAntihypertensive agents

Angiotensin-converting enzyme (ACE) Angiotensin-converting enzyme (ACE) inhibitorsinhibitors

captopril, enalapril, lisinopril, benazepril, captopril, enalapril, lisinopril, benazepril, fosinopril, ramipril, quinapril, perindopril, fosinopril, ramipril, quinapril, perindopril, trandolapril, moexipriltrandolapril, moexipril

Angiotensin receptor blocker (ARB) therapy Angiotensin receptor blocker (ARB) therapy candesartan cilexetil, irbesartan, losartan candesartan cilexetil, irbesartan, losartan

potassium, telmisartan, valsartan, esprosartan potassium, telmisartan, valsartan, esprosartan

Beta-blockersBeta-blockers

Glycemic Control Glycemic Control Preprandial plasma glucose 90-130 mg/dlPreprandial plasma glucose 90-130 mg/dl A1C <7.0%A1C <7.0% Peak postprandial plasma glucose <180 Peak postprandial plasma glucose <180

mg/dlmg/dl Self-monitoring of blood glucose (SMBG)Self-monitoring of blood glucose (SMBG) Medical Nutrition TherapyMedical Nutrition Therapy

Restrict dietary protein to RDA of 0.8 Restrict dietary protein to RDA of 0.8 g/kg body weight per day g/kg body weight per day

Treatment of Diabetic Treatment of Diabetic Nephropathy (cont.)Nephropathy (cont.)

Treatment of Diabetic Treatment of Diabetic Nephropathy (cont.)Nephropathy (cont.)

Treatment of End-Stage Treatment of End-Stage Renal Disease (ESRD)Renal Disease (ESRD)

There are three primary treatment There are three primary treatment options for individuals who options for individuals who experience ESRD:experience ESRD:

1. Hemodialysis1. Hemodialysis

2. Peritoneal Dialysis2. Peritoneal Dialysis

3. Kidney Transplantation3. Kidney Transplantation

How Can You Prevent How Can You Prevent Diabetic Kidney Diabetic Kidney

Disease?Disease? Maintain blood pressure <130/80 Maintain blood pressure <130/80

mm/Hgmm/Hg Maintain preprandial plasma glucose 4-Maintain preprandial plasma glucose 4-

7 mmol/L7 mmol/L Maintain postprandial plasma glucose Maintain postprandial plasma glucose

<10 mmol/L<10 mmol/L Maintain A1C <7.0%Maintain A1C <7.0% Use ACE inhib or ARB if ACR is Use ACE inhib or ARB if ACR is

elevated even if normotensiveelevated even if normotensive Use antiplatelet therapyUse antiplatelet therapy

Diabetic Diabetic RetinopathyRetinopathy

Diabetic RetinopathyDiabetic Retinopathy

• Diabetic retinopathy is the most common cause of new cases of blindness among adults 20-74 years of age.

• During the first two decades of disease, nearly all patients with type 1 diabetes and over 60% of patients with type 2 diabetes have retinopathy

Risks of Diabetic Risks of Diabetic Retinopathy Related Retinopathy Related

Vision LossVision Loss Duration of diabetes diseaseDuration of diabetes disease type 1 patients experience a 25% rate of type 1 patients experience a 25% rate of

retinopathy after 5 years of disease, and 80% at retinopathy after 5 years of disease, and 80% at 15 years of disease15 years of disease11

Up to 21% of newly diagnosed type 2 patients Up to 21% of newly diagnosed type 2 patients have some degree of retinopathy at time of have some degree of retinopathy at time of diagnosisdiagnosis11

PubertyPuberty PregnancyPregnancy Lack of appropriate ophthalmic examinationLack of appropriate ophthalmic examination

1American Diabetes Association: Retinopathy in Diabetes (Position Statement). Diabetes Care 27 (Suppl.1): S84-S87, 2004

Retinopathy ScreeningRetinopathy Screening Type 1 diabetes - screen within 3-5 Type 1 diabetes - screen within 3-5

years of diagnosis after age 10years of diagnosis after age 1011

Type 2 diabetes - screen at time of Type 2 diabetes - screen at time of diagnosisdiagnosis11

Pregnancy - women with preexisting Pregnancy - women with preexisting diabetes should be screened prior to diabetes should be screened prior to conception and during first trimesterconception and during first trimester11

Follow-up annually; less frequent Follow-up annually; less frequent exams (2-3 yrs) may be consideredexams (2-3 yrs) may be considered11

Examination Methods - Dilated indirect Examination Methods - Dilated indirect ophthalmoscopy coupled with ophthalmoscopy coupled with biomicroscopy and seven-standard field biomicroscopy and seven-standard field steroscopic 30° fundus photographysteroscopic 30° fundus photography11

1American Diabetes Association: Retinopathy in Diabetes (Position Statement). Diabetes Care 27 (Suppl.1): S84-S87, 2004

Natural History of Natural History of Diabetic RetinopathyDiabetic Retinopathy

Mild nonproliferative Mild nonproliferative diabetic retinopathy diabetic retinopathy (NPDR)(NPDR)

Moderate NPDRModerate NPDR Severe NPDRSevere NPDR Very Severe NPDRVery Severe NPDR Proliferative diabetic Proliferative diabetic

retinopathy (PDR)retinopathy (PDR)

Diabetic Diabetic ketoacidosisketoacidosis

TYPE 1 Diabetes

10%

Beta cell destruction (usually autoimmune)

Low or absent

Required for survival

Often <30 (but can occur at any age)

Usually lean

Smaller

Acute, severe

Yes

No

Proportion of diabetes cases

Pathogenesis

Endogenous insulin secretion

Need for insulin therapy

Age of onset

Body habitus

Genetic component

Symptoms at onset

Ketoacidosis

Long-term complications present at dx?

TYPE 2 Diabetes

90%

Insulin resistance, relative insulin deficiency

Variable

Required in <50%, to improve control rather than for survival

Often >40

Often obese

Very large

Often mild, slow onset

Rare

Retinopathy ~20%, CVD relatively common

Diagnostic criteriaDiagnostic criteria

HyperglycemiaHyperglycemia Glucose >11.1 mmol/l; usually > 15 mmol/lGlucose >11.1 mmol/l; usually > 15 mmol/l

metabolic acidosis (increased anion gap)metabolic acidosis (increased anion gap) pH < 7.35pH < 7.35 decreased bicarbonate <15 (best estimation decreased bicarbonate <15 (best estimation

with venous)with venous) positive serum ketonespositive serum ketones

Urine ketones: may be absent in early stagesUrine ketones: may be absent in early stages

Insulin deficiencyInsulin deficiency

Decreased peripheral glucose Decreased peripheral glucose utilizationutilization

increased glucose productionincreased glucose production liver - gluconeogenesis (from liver - gluconeogenesis (from

aminoacids, glycerol), glycogenolysisaminoacids, glycerol), glycogenolysis increased ketogenesisincreased ketogenesis

increased lipolysis in adipocytes - increased lipolysis in adipocytes - provides free fatty acids for ketones and provides free fatty acids for ketones and glycerol for gluconeogenesisglycerol for gluconeogenesis

Clinical featuresClinical features

Hyperglycemia: thirst, polyuria, Hyperglycemia: thirst, polyuria, circulatory collapsecirculatory collapse

Ketosis: “acetone breath’Ketosis: “acetone breath’ Acidosis/ compensatory respiratory Acidosis/ compensatory respiratory

alkalosis: tachypneaalkalosis: tachypnea

DKA: Precipitating Causes

Consequences of DKAConsequences of DKA

HyperglycemiaHyperglycemia osmotic diuresisosmotic diuresis

dehydrationdehydration loss of K, Na, HCO3 in urineloss of K, Na, HCO3 in urine

hyperosmolar state hyperosmolar state increase free water into blood increase free water into blood hyponatremia, hyponatremia,

cerebral dehydration cerebral dehydration decreased level of decreased level of consciousnessconsciousness

acidosisacidosis compensatory respiratory alkalosiscompensatory respiratory alkalosis K shifts (hyperkalemia)K shifts (hyperkalemia)

Laboratory Calculations Laboratory Calculations for diagnosis and for diagnosis and

treatmenttreatment Serum osmolalitySerum osmolality 2(Na + K) + glucose +BUN2(Na + K) + glucose +BUN

serum Naserum Na for each 3-4 mmol/l increase in glucose, Na for each 3-4 mmol/l increase in glucose, Na

should decrease by 1should decrease by 1 anion gapanion gap

Na -(Cl+HCO3)Na -(Cl+HCO3) compensation for metabolic acidosiscompensation for metabolic acidosis If suspect other causes for acidosis; If suspect other causes for acidosis;

meausre serum lactate and salicylatemeausre serum lactate and salicylate

TreatmentTreatment

GOAL: GOAL: replace volume lossreplace volume loss stop ketone productionstop ketone production replace K loss (K initially high but falls replace K loss (K initially high but falls

rapidly with treatment)rapidly with treatment) lower serum glucoselower serum glucose

**Need to correct INSULIN DEFICIENCYNeed to correct INSULIN DEFICIENCY

*Look for precipitating cause and treat*Look for precipitating cause and treat

FluidFluid NS 1L per hour first 2 hours, then 1L over 4 hrsNS 1L per hour first 2 hours, then 1L over 4 hrs NS until glucose < 15 NS until glucose < 15 then D5/NS or D5 depending if still replacing then D5/NS or D5 depending if still replacing

volumevolume insulininsulin

intravenousintravenous 50 units regular in 500 normal saline (0.1U/ml)50 units regular in 500 normal saline (0.1U/ml) Bolus 0.1 unit per kg body weight (IM/IV)Bolus 0.1 unit per kg body weight (IM/IV) Infusion 0.1 unit/kg/hourInfusion 0.1 unit/kg/hour Glucoscans q1h, adjust IV rate and IV D5Glucoscans q1h, adjust IV rate and IV D5* Do not stop insulin infusion until acidosis/ AG * Do not stop insulin infusion until acidosis/ AG

correctedcorrected bicarbonate generally avoidedbicarbonate generally avoided potassiumpotassium

start when K 4.5-5.0, 20 mmol/Lstart when K 4.5-5.0, 20 mmol/L

Hyperosmolar non-Hyperosmolar non-ketotic stateketotic state

Severe hyperglycemia generally in DM Severe hyperglycemia generally in DM type 2type 2

dehydrationdehydration serum hyperosmolalityserum hyperosmolality lack of significant ketosis (still some lack of significant ketosis (still some

circulating insulin)circulating insulin)

* takes less insulin to prevent ketosis than * takes less insulin to prevent ketosis than to stop hyperglycemiato stop hyperglycemia

Stressor - increased insulin Stressor - increased insulin resistanceresistance

relative insulin deficiencyrelative insulin deficiency increased glucose production, increased glucose production,

decreased utilizationdecreased utilization reduced renal excretion of glucose reduced renal excretion of glucose

secondary to renal disease, aging secondary to renal disease, aging kidneyskidneys

Treatment of HONKTreatment of HONK

Correct increased serum osmolality Correct increased serum osmolality Blood glucose will fall in response to Blood glucose will fall in response to

fluid repletionfluid repletion If Na>155 mmol/L, start 0.45% NS If Na>155 mmol/L, start 0.45% NS

as initial fluidas initial fluid Insulin infusion only if persistent Insulin infusion only if persistent

hyperglycemia after fluid repletehyperglycemia after fluid replete

ThyroidThyroid

Average weight 20 gms (~0.7 ounces)

Thyroid GlandThyroid GlandThyroid GlandThyroid Gland

Thyroid Hormone ReviewThyroid Hormone Review

Tetraiodothyronine Tetraiodothyronine (T4)(T4) and and triiodothyronine triiodothyronine (T3)(T3) released from thyroid released from thyroid gland in ratio gland in ratio 20:120:1

T3 is the active form T3 is the active form or thyroid hormoneor thyroid hormone

20% of T3 from 20% of T3 from thyroid gland, 80% thyroid gland, 80% from extra-thyroidal from extra-thyroidal conversion by conversion by 5’deiodinase enzyme5’deiodinase enzyme

Thyroid Review cont…Thyroid Review cont…

T4 converted to T3 by T4 converted to T3 by 5’deiodinase5’deiodinase enzyme in enzyme in target tissuestarget tissues

5’deiodinase also converts 5’deiodinase also converts T4 to T4 to rT3 (inactive form)rT3 (inactive form)

rT3 production rT3 production upregulated (at the upregulated (at the expense of T3) in acute or expense of T3) in acute or chronic illnesschronic illness

Thyroid hormones exert a Thyroid hormones exert a variety of effects including variety of effects including inotropic and chronotropicinotropic and chronotropic effects on the heart (direct effects on the heart (direct and permissive via and permissive via upregulation of B-upregulation of B-adrenergic receptors), adrenergic receptors), vasodilation,vasodilation, increased increased heat production.heat production.

Review: Hypothalamic-Review: Hypothalamic-Pituitary AxisPituitary Axis

Review: Hypothalamic-Review: Hypothalamic-Pituitary AxisPituitary Axis

What can go wrong?What can go wrong?

FunctionalFunctional HypothyroidismHypothyroidism

HyperthyroidismHyperthyroidism

StructuralStructural NodulesNodules

CancerCancer

BothBoth

Can exacerbate pre-Can exacerbate pre-existing medical existing medical conditions.conditions.

FatigueFatigue Slow heart rateSlow heart rate ConstipationConstipation Menstrual Menstrual

IrregularitiesIrregularities Dry Skin, Coarse Hair Dry Skin, Coarse Hair Cold IntoleranceCold Intolerance

HypothyroidismHypothyroidism

Signs of HypothyroidismSigns of Hypothyroidism Pseudomyotonic reflexes (95%)Pseudomyotonic reflexes (95%)

Hypothermia or cold skin (83%)Hypothermia or cold skin (83%)

Skin changes (79%) – nonpitting waxy dry edema, Skin changes (79%) – nonpitting waxy dry edema, dependant edema (30%)dependant edema (30%)

Coarse hair (76%), loss of axillary and pubic hair Coarse hair (76%), loss of axillary and pubic hair (30%), loss of scalp and facial hair (18%)(30%), loss of scalp and facial hair (18%)

Pallor (24%)Pallor (24%)

Abdominal distension (18%)Abdominal distension (18%)

Goiter (16%)Goiter (16%)

Pericardial effusion, dull facial expression, Pericardial effusion, dull facial expression, unsteady gait, husky voice, periorbital puffiness, unsteady gait, husky voice, periorbital puffiness, bradycardia, narrow pulse pressure, macroglossia, bradycardia, narrow pulse pressure, macroglossia, CTS, thyroidectomy scarCTS, thyroidectomy scar

LabsLabs – macrocytic anemia, hyponatremia, – macrocytic anemia, hyponatremia, elevated CPK, AST, LDH dyslipidemia, low FT4elevated CPK, AST, LDH dyslipidemia, low FT4

LEVOTHYROXINE

•T4 preparation exact chemical structure of human

thyroxine

• stable, cheap, widely available

• one of the most commonly prescribed drugs

•half life is ~ 7 days

DOSAGE ADJUSTMENT

• evaluate clinical response

• measure TSH ~ 6 weeks after change in dose

• adjust dose by 0.025 mg (0.012 mg)

• once TSH is in target range, repeat annually

RISKS OF OVER TREATMENTWITH THYROID HORMONES

• induce symptoms of hyperthyroidism

• may accelerate bone loss in those at risk

• exacerbate angina

• risk of atrial fibrillation

• increased heart rate and myocardial contractility•Important to keep the T3 level in the target range

THYROID HORMONE REPLACEMENTIN PREGNANCY

• requirements can increase by 25 - 50%

• must monitor TSH every 8 weeks and and 6 weeks after dosage adjustment

• target TSH in normal range

• post pregnancy - requirements return to pre-pregnancy dose

THYROIDITIS

Thyroiditis with pain and tenderness:

• acute infectious (rare)

• subacute granulomatous thyroiditis (common, viral)

SUBACUTE GRANULOMATISTHYROIDITIS

• subacute thyroiditis or DeQuervains’ thyroiditis, likely viral

• three phases: hyperthyroid,hypothyroidrecovery phase

• treatment: NSAID or prednisone, • -blocker for hyperthyroid symptoms L-T4 not usually necessary

POST-PARTUM THYROIDITIS

• lymphocytic thyroiditis up to 1 year post-partum, usually 6 weeks after delivery

• usually mild phases of hyper/hypothyroidism

• anti-thyroid peroxidase antibodies elevated

• usually resolves but can recur after future pregnancies

HYPERTHYROIDISM

Symptoms Signs

Nervousness Restlessness

Heat intolerance Warm, moist skin

Insomnia Tremor

Sweating Diffuse goitre

Diarrhea Bruit

OTHER OTHER MANIFESTATIONSMANIFESTATIONS

dermopathydermopathy

onycholysisonycholysis

gynecomastiagynecomastia

palmar erythemapalmar erythema

spider angiomataspider angiomata

myopathymyopathy

periodic periodic paralysisparalysis

vitiligovitiligo

HYPERTHYROIDISM -MOST COMMON CAUSES

• Graves’ Disease

• Toxic nodular goitresolitary nodular or multinodular

• hyperthyroid phase of subacute thyroiditis

• excessive administration of thyroid hormone

HYPERTHYROIDISM -UNCOMMON CAUSES

• choriocarcinoma or hydatidiform moles (HCG)• thyroid carcinoma

toxic carcinomatous nodule from widespread metastasis

• struma ovarii• associated with acromegaly• related to polyostotic fibrous dysplasia• induced by iodine• TSH-producing pituitary adenoma• T3 toxicosis

LABORATORY TESTING

Graves’ Toxic Toxic Thyroiditisnodular nodule

FT4

FT3

TSH

RAIU

ETIOLOGY OF GRAVESDISEASE

• autoimmune disorder

• TSI bind to hTSH-R

TSHor Ab

GRAVES’ DISEASE

• most common cause of hyperthyroidism

• females 4: males 1

• autoimmune disorder

• thyroid stimulating immunoglobulin (TSI)

• genetic factors

AUTOIMMUNE DISEASES ASSOCIATED WITHGRAVES’ AND HASHIMOTO’S DISEASES

Graves’ disease

• Hashimoto’s thyroiditis• Pernicious anemia• Addison’s disease• Diabetes mellitus• Vitiligo• Myasthenia gravis• Rheumatoid arthritis• Idiopathic thrombocytopenic purpura

Hashimoto’s thyroiditis

• Graves’ disease• Pernicious anemia• Sjögren’s syndrome• Addison’s disease• Rheumatoid arthritis

GRAVES’ DISEASE -MANIFESTATIONS

• hyperthyroidism

• ophthalmopathy

• “pretibial myxedema”

Graves DermopathyGraves Dermopathy

Accumulation of Accumulation of polysaccharides – polysaccharides – glycosglycosaminoglycanaminoglycanss

Usually on anterior Usually on anterior tibiatibia

Can be painful, Can be painful, usually has red usually has red appearanceappearance

Graves’ OphthalmopathyGraves’ Ophthalmopathy

Thyroid stareThyroid stare chemosischemosis ProptosisProptosis Improves with Improves with

treatment of treatment of hyperthyroidismhyperthyroidism

GRAVES’ DISEASE - TREATMENT

• antithyroid drugs propylthiouracil methimazole

• radioactive iodine Complications:

recurrence hypothyroidism

• subtotal thyroidectomy Complications:

recurrence hypothyroidism vocal cord palsy hypoparathyroidism

Hyperthyroidism and pregnancy

•Start propylthiouraci if needed, (methimazole is second choice).

•Target free T4 and free T3 to the upper range of normal

•Refer to Endocrinology

•Ensure women with history of Graves’ disease inform their doctor’s with each pregnancy.

Subclinical Subclinical HyperthyroidismHyperthyroidism

40 y.o woman c/o fullness in neck, otherwise will40 y.o woman c/o fullness in neck, otherwise will

TSH is <0.1 mU/LTSH is <0.1 mU/L fT4 is 18 pmol/L, fT3 is 4.8 pmol/LfT4 is 18 pmol/L, fT3 is 4.8 pmol/L no palpable nodule, slight goitreno palpable nodule, slight goitre

Do you need to do more? Only if becomes Do you need to do more? Only if becomes symptomatic or is high risk for atrial fib. or symptomatic or is high risk for atrial fib. or osteoporosisosteoporosis

Subclinical Hyperthyroidism

• Increase risk of atrial fibrillation

• May have mild symptoms of hyperthyroidism

• increased risk of bone loss

• Treat if symptoms or has other risk factors for

AF or osteoporosis

• Most cases of subclinical hyperthyroidism

resolve within 1 year without treatment

THYROID NODULAR DISEASETHYROID NODULAR DISEASE

Prevalence of thyroid nodulesPrevalence of thyroid nodules 4% on palpation (most are 2cm)4% on palpation (most are 2cm) 67% by ultrasound67% by ultrasound 50% by autopsy50% by autopsy ~30,000 palpable nodules found ~30,000 palpable nodules found

annuallyannually Rarely malignant, ~5%Rarely malignant, ~5%

CAUSES OF THYROID NODULES

• Common causes: colloid nodule (nodular goitre) cyst benign neoplasm papillary carcinoma

Uncommon causes: granulomatous thyroiditis infections cancer: follicular, medullary, anaplastic, metastatic (breast, renal, GI), lymphoma

Thyroid Nodule or Nodules

Fine Needle Aspiration Biopsy

Benign solid Thyroid Nodule

Observation for 1 Year

Thyroid Ultrasonography

Size Decreased Size Unchanged Size Increased

Continue Observation Fine NeedleAspiration Biopsy

Benign Nodule Malignant orSuspicious Nodule

L-Thyroxine SuppressiveTherapy for 1 Year

Surgery

Thyroid Ultrasonography

Size decreased or

unchanged

Size Increased

Surgery

Continue L-ThyroxineTherapy

Decision making for treatment of patients with benign thyroid nodules

Castro, M. R. et. al. Ann Intern Med 2005;142:926-931

Ultrasonography-guided fine-needle aspiration with needle tip accurately placed in the nodule

TREATMENT OF THYROIDNODULES

Toxic Nodule

• antithyroid drugs

• radioactive iodine

• surgery

• Ethanol injection

Nontoxic Nodule

• observation

• thyroxine suppression

• surgery

Thyroid Cancer Thyroid Cancer UpdateUpdate

OutlineOutline

What types?What types?

How common?How common?

Treat?Treat?

Follow-up?Follow-up?

Question 1Question 1

Thyroid cancer is the most rapidly Thyroid cancer is the most rapidly increasing cancer among Canadians increasing cancer among Canadians age 20-44.age 20-44.

TrueTrue

FalseFalse


One is considered “cured” after One is considered “cured” after being disease-free for 10 years being disease-free for 10 years and no further follow-up is and no further follow-up is required.required.

TrueTrue

FalseFalse

Thyroid CancerThyroid Cancer

Differentiated Differentiated Papillary (83%)Papillary (83%) Follicular (9%)Follicular (9%)

Medullary (2%)Medullary (2%)

AnaplasticAnaplastic

LymphomaLymphoma

“Cancer Care Ontario: Cancer in Young Adults in Canada, May 2006

How common?How common?

~3400 cases in Canada in 2006 ~3400 cases in Canada in 2006

33rdrd most common in young adults most common in young adults

Most rapidly growing Most rapidly growing

2-3 times more prevalent in women2-3 times more prevalent in women



Prognosis = good!Prognosis = good!

Age at diagnosis Age at diagnosis (<45 yrs)(<45 yrs)

Tumour size Tumour size

RecurrenceRecurrence

MetastasesMetastases

Pathologic featuresPathologic features

Cumulative RecurrenceCumulative Recurrenceand Cancer Death After Initial and Cancer Death After Initial

TherapyTherapy

Mazzaferri. Am J Med. 1994; 97:418–428.

4040

Patients at risk Patients at risk (n)(n)

13551355 10751075 568568 185185 1010

Years after initial therapy

00 1010 2020 3030 4040

Cum

ulat

ive

per

cent

00

1010

2020

3030

RecurrenceRecurrence

Cancer deathCancer death

At 30 years:

Recurrence 30%

Cancer death 8%

Therefore …Therefore …

Thyroid cancer prevalence is increasing Thyroid cancer prevalence is increasing

– particularly in young adults– particularly in young adults

Prognosis is generally goodPrognosis is generally good

Death from thyroid cancer is uncommonDeath from thyroid cancer is uncommon

Recurrence can happen even years after Recurrence can happen even years after

diagnosis diagnosis

TreatmentTreatment

TreatmentTreatment

1. THYROIDECTOMY1. THYROIDECTOMY

To remove the cancer and the To remove the cancer and the

rest of the thyroidrest of the thyroid

To provide information about the To provide information about the

cancer (size etc)cancer (size etc)

TreatmentTreatment2.2. RADIOIODINE REMNANT ABLATIONRADIOIODINE REMNANT ABLATION

Iodine is taken up by thyroid cellsIodine is taken up by thyroid cells

Radioiodine in large dose will destroy any Radioiodine in large dose will destroy any

remaining thyroid cells (normal and cancer)remaining thyroid cells (normal and cancer)

Works better when cells are “hungry” for Works better when cells are “hungry” for

iodineiodine

Must have a high TSH (means hypothyroid)Must have a high TSH (means hypothyroid)

Withdrawal of hormone is usual for treatmentWithdrawal of hormone is usual for treatment

Whole body scan 1 week laterWhole body scan 1 week later

TreatmentTreatment

3.3. THYROID REPLACEMENT (Thyroxine)THYROID REPLACEMENT (Thyroxine)

To replace missing thyroid hormoneTo replace missing thyroid hormone

Give a little “extra” to push down TSH Give a little “extra” to push down TSH

to not stimulate any remaining cells to not stimulate any remaining cells

(thyroid hormone suppression therapy)(thyroid hormone suppression therapy)

TreatmentTreatment

3. THYROID REPLACEMENT3. THYROID REPLACEMENT

Target TSH to <0.5 mIU/L for mostTarget TSH to <0.5 mIU/L for most

May consider TSH 0.3 – 2 long term May consider TSH 0.3 – 2 long term

in some casesin some cases

Thyroid CancerThyroid Cancer

Ensure suppressed TSHEnsure suppressed TSH Follow thyroglobulin as tumor Follow thyroglobulin as tumor

markermarker Periodic CXR, US neck Periodic CXR, US neck Stimulated thyroglobulin levels Stimulated thyroglobulin levels raise TSH by hypothyroidism or raise TSH by hypothyroidism or

ThyrogenThyrogen (rhTSH injection) (rhTSH injection) Iodine body scans (not always used)Iodine body scans (not always used)


Thyroid cancer is the most rapidly Thyroid cancer is the most rapidly increasing cancer among Canadians increasing cancer among Canadians age 20-44.age 20-44.

TrueTrue

FalseFalse


One is considered “cured” after One is considered “cured” after being disease-free for 10 years being disease-free for 10 years and no further follow-up is and no further follow-up is required.required.

TrueTrue

FalseFalse

Thank you!Thank you!

Back to Basics: Endocrinology Diabetes, Obesity and Thyroid.

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