Hypothyroidism:Normal Thyroid State: Synthesis and release of thyroid hormone is controlled by TSH released from the anterior pituitary TSH is controlled by the release of thyroid releasing hormone (TRH) from the hypothalamus and a negative feedback loop to the pituitary Thyroid hormone production is dependent on adequate iodine intakeNormal Thyroid State: Thyroid hormone is reversibly bound to various proteins including thyroxin-binding globulin (TBG) Free unbound portions are biologically active T4 is the predominant circulating hormone T4 is deiodinated to T3 T3 is biologically more active than T4 but has a shorter half-lifeHypothyroidism: 1.8% of total population. Second only to DM as most common endocrine disorder. Incidence increases with age. More common in females. 2-3% of older women.Causes of Hypothyroidism:Non-Goitrous Causes: Post-ablative (radio-iodine, surgery) Congenital developmental defect Atrophic thyroiditis Post radiation (e.g., for lymphoma)Causes of Hypothyroidism: GoitrousChronic thyroiditis (Hashimotos thyroiditis)Iodine deficiencyDrugs (amiodarone, ASA, iodides, lithium, IFN)Heritable biosynthetic defectsMaternally transmitted antithyroid agents, iodides

PituitaryPanhypopituitarismIsolated TSH deficiencyHypothalamic:NeoplasticInfilterative (sarcoidosis)Congenital defectsInfection (encephalitis)Causes of Hypothyroidism: Self-limitingFollowing withdrawal of suppressive thyroid therapySubacute and chronic thyroiditis with transient hypothyroidismPostpartum thyroiditisSymptoms and Signs: Non-specific. May be confused with other conditions especially in postpartum depression and elderly. Maintain high index of suspicion. In older patients, hypothyroidism may be confused with Alzheimer’s and depression. Patient may end up getting treated for depression. Clinical Features – Adult: Insidious, non specific onset Fatigue, lethargy, constipation Cold intolerance Muscle stiffness, cramps, carpel tunnel syndrome Menstrual irregularities Slowing of intellectual and motor activities Decreasing appetite and weight gainClinical Features – Adult: Dry skin, hair loss Deep hoarse voice Decreasing visual acuity Obstructive sleep apnoeaClinical Features – Myxoedema: Dull expressionless face, sparse hair

Periorbital puffiness, macroglossiaPale cool skin that feels rough and doughy Enlarged heart Megacolon / intestinal obstruction Psychiatric symptoms e.g Depression, psychosisClinical Features – Myxoedema: Cerebellar ataxia Prolonged relaxation phase of deep tendon reflexes Peripheral neuropathy EncephalopathyCommon signs and symptoms:S/S % pt’s affected:Weakness 99Skin changes 97Slow speech 91Eyelid edema 90Cold sensation 89Decreased sweating 89Cold skin 83Thick tongue 82Facial edema 79Coarse hair 76Skin pallor 67Forgetfulness 66Constipation 61Diagnosis:In Primary Hypothyroidism; TSH is high. Free thyroid hormone are depressed. In Secondary Hypothyroidism: Both TSH and free thyroid hormones are low.Anti bodies in hypothyroidism:Anti bodies: Anti thyroid peroxidase [ anti microsomal] antibodies Anti thyroglobulin antibodies. Anti TSH receptor (blocking) antibody In primary hypothyroidism; - up to 12 % pts do have anti gastric parietal cell

antibodies.- these pts can develop pernicious anemia. Thyroid Hormone Replacement: Thyroxin can cause increases in resting heart rate and blood pressure So replacement should start at low doses in older and patients at risk for cardiovascular compromise Treatment of Hypothyroidism:Need for replacementPatients >50 or high risk of Cardiac DiseaseMonitor TSH - Primary hyperthyroidism orFree T4 - Secondary hypothyroidism, every 6-8 Weeks and adjust dosesMonitoring thyroid function: Most patients can be followed by serial TSH measurements. Changes in TSH levels lag behind serum thyroid levels. So TSH should not be checked sooner than four weeks after adjusting doses. Full effect of replacement on TSH may not become apparent until eight weeks. Patients with pituitary insufficiency, T3 and T4 can be followed. Goal is to keep thyroid hormone level in middle to upper range of normal. Frequency: TSH or Free T4 monitored yearly. No data supports the practice. Usually once stable dosage is established, it remains stable until 60-70 years. In elderly serum albumin levels may decrease, so dosage may have to be decreased by 20%. Less frequent monitoring in young patients and annually in elderly.Increased thyroxin Requirements:

Pregnancy Gastrointestinal Disorders- Mucosal diseases of the small bowel (e.g.,sprue)- After jejunoileal bypass and small-bowel resection- Diabetic diarrhoea Conditions That May Block Deiodinase Synthesis- Selenium deficiency- CirrhosisIncreased thyroxin Requirements: Drugs That Interfere with Thyroxin AbsorptionCholestyramine,Sucralfate,Aluminum hydroxide,Calcium carbonate, Ferrous sulphate Drugs That Increase the Cytochrome P450 Enzyme (CYP3A4)Rifampicin, Carbamazepine, EstrogenPhenytoin, Sertraline, ? Statins Drugs That Block T4 to T3Conversion AmiodaroneDecreased thyroxin Requirements: Aging (65 years and older) Androgen therapy in womenSubclinical Hypothyroidism: TSH > 10 Antithyroid antibody positive Previous treatment of Grave’s disease Symptomatic Six to 12 monthly TSH measurement.

Management of Diabetes Mellitusand Role of analogues By Dr Bilal bin Younis (MRCP)UK:

Disease burden of DM per hour: New Cases – 4,100 Deaths – 810 Amputations – 230 Kidney Failure – 120 Blindness - 55

The Rise of the Diabetes in Asia: Percentage increase in T2DM would be highest (170%) in India in next 20 years Our multi-site Indo-US collaborative study: 1/10 in Delhi and 1/5 Indian in US is a diabetic. In 2007: India-40 million DM, Pakistan: 7 million DM

Prevalence: India 6%, Pakistan: 8.3% In SEAR, WPR: Pakistan stands 10th place in prevalence

Ave Age of onset:

Natural History of Type 2 Diabetes:

Defined glycaemic targets in T2DM:Glucose control Healthy ADA1 AACE2 JDS3

HbA1c (%) <6 <7 £ 6.5 5.8―6.4

Mean FPG mmol/l (mg/dl)

<5.6 (<100)

5―7.2(90―130)

<6 (<110)

5.6―6.6 (100―119)

Mean postprandial PG mmol/l (mg/dl)

<7.8 (<140)

<10* (<180)

<7.8** (<140)

―

         

0

20

40

60

80

100

120

mill

ion 140

160

N. America Europe AustralasiaS America Africa Middle East Asia

0

50

100

150

200

250

-10 -5 0 5 10 15 20 25 30

50100150200250300350

Years of Diabetes

Insulin Resistance

Insulin LevelBeta cell failure

Post Meal Glucose

Developing Diabetes

% o

f N

orm

al F

un

cti

on

(11.1 mmol/L)

(7.0 mmol/L)

It’s a

matter of

time!

Proposed Algorithm ofTherapy for Type 2 Diabetes:

Tier 1: Well-validated core therapies:

Type 2 Clinical Pathway:

Oral Antihyperglycemic Monotherapy- Maximum Therapeutic Effect on A1C:

Reduction in A1C (%)Efficacy of OHAs Declines with Time: A1C rises at ~0.2% to 0.3% yearly stable therapy This rate is the same as for diet alone, sulfonylureas, and metformin b-Cell function declines at the same rate with all these treatments Combination treatments are routinely neededSelected Clinical Trials Showing Benefits of Intensive Glycemic Control:

DCCT 1441 (type 1)Kumamoto Study 110 (type 2)UKPDS 5102 (type 2)Summary of Intervention Studies:Risk Reduction With Treatment:Blood pressure treatment 20%–40%

20%–50%Lipid treatment – 25%–55Glucose treatment 12%–35%*

10%–20%*Correlation of A1c and Complication Risk: UKPDS:Risk reduction in complications per each 1% reduction in mean A1c

Oral agent

2 Oral agents

3 Oral agents

Add Insulin Earlier in the Algorithm

Severe symptoms

Severe hyperglycaemia

KetosisPregnancy

Inadequate nonpharmacologic

therapy

At diagnosis:Life Style

+Metformin

Life Style +Metformin +

Basal Insulin

Life Style +Metformin +

Sulfonylurea

+ Intensive Insulin

Step 1 Step 2 Step 3

Tier 2: Less Well-validated core therapies

Life Style +Metformin +

Pioglitazone No Hyperglycemia

Oedema /CHFNausea/Vomiting

Life Style +Metformin +

GLP-1 agonist No Hyperglycemia

Weight loss Nausea/Vomiting

Life Style +Metformin +

Pioglitazone+

Sulfonylurea

Life Style +Metformin +

Basal Insulin

Oral Agent StageOral Agent Stage

Fasting < 200 mg/dL (11.1 mmol/L)Casual < 250 mg/dL (13.9 mmol/L)HbA1c <8%

Fasting < 200 mg/dL (11.1 mmol/L)Casual < 250 mg/dL (13.9 mmol/L)HbA1c <8% Medical Nutrition Stage

Medical Nutrition Stage

Fasting 200–300 mg/dL (11.1 – 16.7 mmol/L)Casual 250–350 mg/dL (13.9 – 19.4 mmol/L)HbA1c 8-11%

Fasting 200–300 mg/dL (11.1 – 16.7 mmol/L)Casual 250–350 mg/dL (13.9 – 19.4 mmol/L)HbA1c 8-11%

Insulin ResistanceSensitizers

~1%

Insulin DeficiencySecretagogues

~2%

Combination Oral Agent Stage

Combination Oral Agent/Insulin Stage

Combination Oral Agent Stage

Combination Oral Agent/Insulin StageSecretagogue + Sensitizer

Oral Agent + Insulin

~2-4%

> 4%

Entry Criteria TherapiesLowers HbA1c

Fasting > 300 mg/dL (16.7 mmol/L)Casual > 350 mg/dL (19.4 mmol/L)HbA1c > 11%

Fasting > 300 mg/dL (16.7 mmol/L)Casual > 350 mg/dL (19.4 mmol/L)HbA1c > 11%

Physiologic Insulin Stage 4 Basal/Bolus Insulin

RA - RA - RA - G

Insulin Resistance: HTN, Dyslipidemia,

Obesity

Insulin Deficiency: Symptomatic, Lean

Note: Each stage requires a pre-Note: Each stage requires a pre-set BG target: and a timeline to set BG target: and a timeline to reach that goalreach that goal

International Diabetes CenterInternational Diabetes Center

-0.50 -1.0

-1.5

-2.0

Nateglinide

Reduction in A1C (%)

Glipizide GITS

Glimepiride

Repaglinie

Pioglitazoe

Acarbose

Metformin

Rosiglitazoe

Trial Total Subjects

Glycemic Responses in the UKPDS:

50% of sulphonylurea-treated patients with T2DM required insulin after 6 years to achieve glycaemic targetInsulin added when FPG >6 mmol/l (>108 mg/dl)

Percentages of patients on different glucose lowering therapy

Normal Insulin Secretion:

Time (Hours)Insulin Action: comparison of new Insulin Analogs

From Orals to Insulin:

UKPDS Group. Lancet. 1998;352:837-853

10-Year Cohort9

8

7

6

00 3 6 9

Years

12

10-year median7.9%

10-year 10-year medianmedian7.0% 7.0%

50

25

0

Time since randomisation (years)

2 3 4 5 61

SU

-tre

ate

d p

ati

ents

re

quir

ing a

ddit

ional

insu

lin (

%)

n=826HbA1c <7% at 6 years

Insu

lin a

lone

SU ±

insu

lin

35

47

20

25

0

Diabetes Care:Dose Calculation and Adjustment Begin modestly with 0.3 to 0.5 U/kg/day insulin (total) 2/3 of this dose in the morning and 1/3 in the evening 2/3 of the insulin should be NPH and 1/3 should be regular or simply use 70/30 combination Begin with loose control and tighten with experience Tight control is dependant on the stage of the diseaseType 2: Insulin Adjustment Guidelines:Insulin Pattern Adjustments Adjust insulin from 3- days pattern Determine which insulin is responsible for pattern Adjust by 2-4 units Adjust only one dose at a time Correct hypoglycemia first. If total dose >1.5 U/Kg. Consider over insulization If hyperglycemia throughout the day, correct highest SMBG first; if all within 50 mg/dl, correct AM first.Type 2: Insulin Start (cont):R/N – 0 –R/N –0LP/N – 0 –LP/N – 0At Diagnosis or from Oral TherapyCalculate total dose at 0.3 U/kg based on current weight

AM MIDDAY PM BTDistribution2/3 0 1/3 0R/N or LP/N ratio 1:2 1:1 -Pre-mixed insulin, 70/30 AM and 50/50 PM,may be used for patients unable to draw insulin correctlyRefer patient for nutrition and diabetes education

Control of Blood sugar Insulin vs non insulin:

Controlled vs Uncontrolled:

Normal Insulin Secretion:

Conventional Insulin Stage 2R/N-0-R/N-0 or RA/N-0-RA/N-0:

R/N – 0 –R/N – 0 or LP/N –0 – LP/N – 0

pm R or LP 2-4 U (f)

pm R or LP 1-2 U (f)

pm R or LP 1-2 U (e)BEDTIME

>250 mg/dl160-250 mg/dl< 100 mg/dlIf BG

am N 2-4 U (f.h)

am N 1-2 U (f.h) am N 1-2U (d.e)P.M.

am R or LP 2-4 U (f.g)

am N 1-2 U (f.h) am R or LP 1-2 u.(c.e.)

MIDDAY

Pm N 1-2 u (a.b.)

pm N 1-2 u (a) Pm N 1-2 u (a.b.)A.M.

> 250 mg/dl140-250 mg/dl< 80 mg/dl If BG

Management of Hyperglycemia Common Oral + Insulin Combinations:

Duration of action in type 2 diabetes:

Objectives and design of Hermansen treat-to-target study:

Hermansen treat-to-target study: HbA1c and FPG :Hermansen treat-to-target trial: Change in weight by baseline BMI

Hermansen treat-to-target trial: Overall hypoglycaemia

Hermansen treat-to-target trial: weight change

Philis-Tsimikas study: Weight change at 20 weeks detemir pm vs. NPH pm

Clean switch’ type 2 diabetes patients: change in HbA1c

7

8

9

A1C%

Met

9.7

7.2

9.7

Glim

7.6

1 or 2 Oral Agents +

Glargine

Oral

8.6

7.0

Combinationtherapy

Baselinemonotherapy

22.1 (2.6)

24.0 (0)

16.8 (6.8)

19.4 (6.9)

12.0 (8.5)

10.2 (7.4)

Detemir

Glargine

1.4 U/kg0.8 U/kg0.4 U/kg

Insulin detemir twice-daily

NPH twice-daily

Existing OADs continued (both groups)

n=237

Insulin titrated to target: fasting and pre-dinner PG ≤6 mmol/l

24 weeks

n=238

Baseline BMI

-0.5 £25 >25-27 >27-29 >29-31 >31

Mean

weig

ht

chan

ge (

kg)

35

36

34

39

55

37

42

50

69

76

0.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

NPH insulinn = patient numbers in each BMI category

0

400

800

1200

1600

2000Insulin detemir (n=237)

NPH insulin (n=238)

All Major Minor confirmed Symptomaticunconfirmed

908

1688

1 8

387

755519

923

**

**

**

** p<0.001

80

81

82

83

84

85

86

-2 1 3 5 7 9 11 13 15 17 19 21 23Weeks

Weig

ht

(kg

)

p=0.005

Weig

ht

ch

an

ge

(kg

) 1.6

0.7

1.5

1.0

0.5

Insulin detemir pm NPH insulin pm

2.0

Clean switch’ type 2 diabetes patients: change in nocturnal hypoglycaemia

Clean switch’ type 2 diabetes patients:

Insulin-naïve type 2 diabetes patients:

change in HbA1c:

Change in HbA1c and weight in three comparable treat-to-target trials:Summary: Detemir vs. NPH in basal + OADTherapy:

Comparable glycaemic control Significantly fewer minor hypoglycaemic events: 53% reduction Significantly fewer minor nocturnal hypoglycaemic events: 65% reduction Significantly less weight gain: (0.7 vs. 1.6 kg) No significant differences between detemir am and pm regarding HbA1c, hypoglycaemia and weight changeSummary cont: In randomised clinical trials in insulin naïve T2DM patients: Insulin detemir is equally effective in achieving glycaemic control in comparison to NPH Insulin detemir exerts significantly lower risk of overall and nocturnal hypoglycaemia in comparison to NPH Insulin detemir once-daily results in significantly less weight gain than NPH

OCD Spectrum disordersand their treatment:

Obsessive-Compulsive Disorder: Affects Almost 3% Of World’s Population

8.1

7.9

7.4

7.5

7.6

7.7

7.8

7.9

8.0

8.1

8.2

Baseline Threemonths

Mean

HbA

1c

(%)

(n=152)

–0.2%

*

NPH insulin

Mean

HbA

1c

(%)

(n=97)

–0.6%8.1

7.5

7.4

7.5

7.6

7.7

7.8

7.9

8.0

8.1

8.2

Baseline Threemonths

†

PREDICTIVETM data on file

*

n=175 n=118Events

per

pati

ent-

year

Events

per

pati

ent-

year

-81%

*p<0.001

-75%

†p<0.05

†

1.6

0.4

0

1

2

3

4

5

6

7

8

Baseline Three months

6.9

1.3

0

1

2

3

4

5

6

7

8

Baseline Three months

NPH insulin

*

n=160 n=101

Mean

weig

ht

(kg

)

Mean

weig

ht

(kg

)

-0.7

-0.5*

89.3

88.6

88

89

90

Baseline Three months

84.6

84.1

84

84.5

85

85.5

86

Baseline Three months

DetemirNPH insulin

Mean H

bA

1c

(%)

(n=1799)

-1.3%

8.9

7.6

7.37.57.77.98.18.38.58.78.9

Baseline

Three months

Start Anytime From Preschool To Adulthood Typically Between 20-24 Many Different Forms Of OCD – Differ From Person To Person Cause Of OCD Is Still Unknown Better When Diagnosed Early

Definition: Specific criteria to be clinically diagnosed Anxiety disorder with presence of obsessions or compulsions ego dystonic – realize thoughts and actions are irrational or excessive Must take up more than 1 hour a day Must disrupt daily routine Symptoms can’t result from effects of other medical conditions or substancesObsessions Repetitive And Constants Thoughts, Images, Or Impulses That Cause Anxiety Or Distress Thoughts, Images, Or Impulses Not About Real-life Problems Try To Ignore Or Counter Act Thoughts, Images, Or Impulse Thoughts, Images, Or Impulses “Recognized As A Product Of One’s Own Mind And Not Imposed From Without”Compulsions: Repetitive behaviors or mental acts person does in reaction to obsessions behaviors or mental acts done to avoid or decrease distress behaviors or mental acts are clearly excessive or not realistic History: 14th & 15th century thought people were possessed by the devil and treated by exorcism 17th century thought people were cleansing their guilt

18th century finally considered medical issue 20th century began treating with behavioral techniquesTheories: Scientist split into 2 groups Psychological disorder where people are responsible for feelings they have Abnormalities in the brainCauses: Serotonin is involved in regulating anxiety Abnormality in the neurotransmitter serotonin__In order to send chemical messages serotonin must bind to the receptor sites located on the neighboring nerve cells__OCD suffers may have blocked or damaged receptor sites preventing serotonin from functioning to full potential Possible genetic mutation __Some people suffering have mutation in the human serotonin transporter gene

OCD and the Brain: PET scans show people with OCD have different brain activity from others Another theory: miscommunication between the orbital frontal cortex, the caudate nucleus, and the thalamus Caudate nucleus doesn’t function properly and causes thalamus to become hyperactive and sends “never-ending” worry signals between OFC and thalamus à OFC responds by increasing anxiety

Comorbidity : Has excessive comorbidity with other diseases Common diseases: Depression, Schizophrenia, Tourette Syndrome Depression is the most common Many people with OCD suffered from depression first 2/3 of OCD patients develop depression à makes OCD symptoms worse and more difficult to treat People with OCD common diagnosed as Schizophrenic à hard to separate obsessions from delusionsTreatment: Only completely curable in rare cases Most people have some symptom relief with treatment Treatment choices depend on the problem and patients preferences Most common treatments:---Behavioral Therap

--- Cognitive Therapy--- MedicationCognitive-Behavioral Therapy: Cognitive: change the way they think to deal with their fears Behavioral: change the way they react to “anxiety-provoking” situations Exposure and Response Prevention--- Slowly learning to tolerate anxiety associated with not performing ritual behavior Psychotherapy--- Talking with therapist to discover what causes the anxiety and how to deal with symptoms--- Systematic Desensitization--- Learning cognitive strategies to deal with anxiety then gradual exposure to feared object Medication: Antidepressants because of common depression Selective Serotonin Reuptake Inhibitors (SSRIs): alter the levels of neurotransmitter serotonin in the brain which helps brain cells communicate with one another---- Prevents excess serotonin from being pumped back into original neuron that released it---- Then can bind to receptor sites of nearby neurons and send chemical message that can help regulate anxiety and obsessive compulsive thoughts---- Most effective drug treatment helping about 60% of patientsConclusion: OCD is a complicated issue Most cases are incurable Best form of treatment is CBT in combination with medication Most important thing that can be done to discover more about OCD and its treatments is to research the brain

The WHO predicts that by 2020, Major Depressive Disorder is expected to move from 4th to 2nd place in terms of greater global disease burden.” Mean overall prevalence of anxiety and depressive disorders in the community population was 34% (range 29-66% for women and 10-33% for men).”