An article on Thyroid Disorders Submitted by Dr.Tariq Azeez President Pakistan Society of Family Physicians

1. Hypothyroidism: Panhypopituitarism
Normal Thyroid State: Isolated TSH deficiency
Synthesis and release of thyroid Hypothalamic:
hormone is controlled by TSH Neoplastic
released from the anterior pituitary Infilterative (sarcoidosis)
TSH is controlled by the release of Congenital defects
thyroid releasing hormone (TRH) Infection (encephalitis)
from the hypothalamus and a negative Causes of Hypothyroidism:
feedback loop to the pituitary Self-limiting
Thyroid hormone production is Following withdrawal of suppressive
dependent on adequate iodine intake thyroid therapy
Normal Thyroid State: Subacute and chronic thyroiditis with
Thyroid hormone is reversibly transient hypothyroidism
bound to various proteins including Postpartum thyroiditis
thyroxin-binding globulin (TBG) Symptoms and Signs:
Free unbound portions are Non-specific.
biologically active May be confused with other
T4 is the predominant circulating conditions especially in postpartum
hormone depression and elderly.
T4 is deiodinated to T3 Maintain high index of suspicion.
T3 is biologically more active than In older patients, hypothyroidism
T4 but has a shorter half-life may be confused with Alzheimer’s
Hypothyroidism: and depression.
1.8% of total population. Patient may end up getting treated
Second only to DM as most common for depression.
endocrine disorder. Clinical Features – Adult:
Incidence increases with age. Insidious, non specific onset
More common in females. Fatigue, lethargy, constipation
2-3% of older women. Cold intolerance
Causes of Hypothyroidism: Muscle stiffness, cramps, carpel
Non-Goitrous Causes: tunnel syndrome
Post-ablative (radio-iodine, surgery) Menstrual irregularities
Congenital developmental defect Slowing of intellectual and motor
Atrophic thyroiditis activities
Post radiation (e.g., for lymphoma) Decreasing appetite and weight gain
Causes of Hypothyroidism: Clinical Features – Adult:
Goitrous Dry skin, hair loss
Chronic thyroiditis (Hashimotos Deep hoarse voice
thyroiditis) Decreasing visual acuity
Iodine deficiency Obstructive sleep apnoea
Drugs (amiodarone, ASA, iodides, Clinical Features – Myxoedema:
lithium, IFN) Dull expressionless face, sparse hair
Heritable biosynthetic defects Periorbital puffiness,
Maternally transmitted antithyroid macroglossiaPale cool skin that feels
agents, iodides rough and doughy
Pituitary Enlarged heart

2. Megacolon / intestinal obstruction Thyroxin can cause increases in
Psychiatric symptoms e.g resting heart rate and blood pressure
Depression, psychosis So replacement should start at low
Clinical Features – Myxoedema: doses in older and patients at risk for
Cerebellar ataxia cardiovascular compromise
Prolonged relaxation phase of deep Treatment of Hypothyroidism:
tendon reflexes Need for replacement
Peripheral neuropathy Patients >50 or high risk of Cardiac
Encephalopathy Disease
Common signs and symptoms: Monitor TSH - Primary
S/S % pt’s affected: hyperthyroidism or
Weakness 99 Free T4 - Secondary hypothyroidism,
Skin changes 97 every 6-8 Weeks and adjust doses
Slow speech 91 Monitoring thyroid function:
Eyelid edema 90 Most patients can be followed by
Cold sensation 89 serial TSH measurements.
Decreased sweating 89 Changes in TSH levels lag behind
Cold skin 83 serum thyroid levels.
Thick tongue 82 So TSH should not be checked
Facial edema 79 sooner than four weeks after adjusting
Coarse hair 76 doses.
Skin pallor 67 Full effect of replacement on TSH
Forgetfulness 66 may not become apparent until eight
Constipation 61 weeks.
Diagnosis: Patients with pituitary insufficiency,
In Primary Hypothyroidism; T3 and T4 can be followed.
TSH is high. Goal is to keep thyroid hormone
Free thyroid hormone are depressed. level in middle to upper range of
In Secondary Hypothyroidism: normal.
Both TSH and free thyroid Frequency:
hormones are low. TSH or Free T4 monitored yearly.
Anti bodies in hypothyroidism: No data supports the practice.
Anti bodies: Usually once stable dosage is
Anti thyroid peroxidase [ anti established, it remains stable until
microsomal] antibodies 60-70 years.
Anti thyroglobulin antibodies. In elderly serum albumin levels may
Anti TSH receptor (blocking) decrease, so dosage may have to be
antibody decreased by 20%.
In primary hypothyroidism; Less frequent monitoring in young
- up to 12 % pts do have anti gastric patients and annually in elderly.
parietal cell Increased thyroxin Requirements:
antibodies. Pregnancy
- these pts can develop pernicious Gastrointestinal Disorders
anemia. - Mucosal diseases of the small bowel
Thyroid Hormone Replacement: (e.g.,sprue)

3. - After jejunoileal bypass and small-
bowel resection
- Diabetic diarrhoea
Conditions That May Block
Deiodinase Synthesis
- Selenium deficiency
- Cirrhosis
Increased thyroxin Requirements:
Drugs That Interfere with Thyroxin
Absorption
Cholestyramine,Sucralfate,Aluminum
hydroxide,Calcium carbonate,
Ferrous sulphate
Drugs That Increase the Cytochrome
P450 Enzyme (CYP3A4)
Rifampicin, Carbamazepine, Estrogen
Phenytoin, Sertraline, ? Statins
Drugs That Block T4 to T3
Conversion Amiodarone
Decreased thyroxin Requirements:
Aging (65 years and older)
Androgen therapy in women
Subclinical Hypothyroidism:
TSH > 10
Antithyroid antibody positive
Previous treatment of Grave’s
disease
Symptomatic
Six to 12 monthly TSH
measurement.

4. Management of Diabetes Mellitus Prevalence: India 6%, Pakistan:
and Role of analogues By Dr Bilal bin 8.3%
Younis (MRCP)UK: In SEAR, WPR: Pakistan stands
160 10th place in prevalence
million
140
120
100
80
60
40
20
0
N. America S America Europe Australasia
Africa Middle East Asia
Disease burden of DM per hour: Ave Age of onset:
New Cases – 4,100
Deaths – 810 50
40
Amputations – 230 30
20
Kidney Failure – 120 10
Females 39 yrs
Males 42 yrs
Blindness - 55 0
Females Males
age of age of
Onset Onset
Natural History of Type 2 Diabetes:
350
300 Post Meal Glucose
250
200 (11.1 mmol/L)
150 (7.0 mmol/L)
100
50
% of Normal Function
250
200 Insulin Resistance
150
100
Developing Insulin Level
50 Diabetes
sa f
Beta cell failure
0
0 5 10 15 20 25 30
It’ r o
-10 -5
Years of Diabetes
Defined glycaemic targets in T2DM:
atte e!
Glucose control Healthy ADA1 AACE2 JD
m m HbA1c (%) <6 <7 ≤ 6.5 5.8
ti
The Rise of the Diabetes in Asia:
Mean FPG
mmol/l (mg/dl)
<5.6
(<100)
5―7.2 <6
(90―130) (<110)
5.6
(10
Percentage increase in T2DM would
be highest (170%) in India in next 20 Mean postprandial <7.8 <10* <7.8** ―
years PG mmol/l (mg/dl) (<140) (<180) (<140)
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

5. Nateglinide
Acarbose
Repaglinie
Rosiglitazoe
Pioglitazoe
Glimepiride
Glipizide GITS
Metformin
0 -0.5 -1. -1. -2.
0 5 0
Reduction in A1C
(%)
Reduction in A1C (%)
Proposed Algorithm of Efficacy of OHAs Declines with Time:
Therapy for Type 2 Diabetes: A1C rises at ~0.2% to 0.3% yearly
Inadequate stable therapy
nonpharmacologic
therapy This rate is the same as for diet
alone, sulfonylureas, and metformin
β-Cell function declines at the same
Severe
symptoms
Severe
hyperglycae
Oral 2 Oral 3 Oral
mia
Ketosis
Pregnancy
agent agents agents
rate with all these treatments
Combination treatments are
routinely needed
Add Insulin Earlier in the Algorithm
Selected Clinical Trials Showing
Tier 1: Well-validated core therapies: Benefits of Intensive Glycemic
Life Style +Metformin
+ +
Control:
At diagnosis:
Life Style
Basal Insulin Intensive Insulin
Trial Total
+
Metformin Life Style +Metformin Subjects
+
Sulfonylurea DCCT 1441
Step 1
Tier 2: Less Well-validated core therapies
Step 2 Step 3
(type 1)
Life Style +Metformin Life Style +Metformin Kumamoto Study 110
+ +
Pioglitazone
No Hyperglycemia
Oedema
Pioglitazone
+ (type 2)
UKPDS 5102
/CHF
Nausea/Vomiting Sulfonylurea
(type 2)
Life Style +Metformin
+ Life Style +Metformin
GLP-1 agonist
Summary of Intervention Studies:
+
No Hyperglycemia
Weight loss
Basal Insulin
Nausea/Vomiting
Type 2 Clinical Pathway: Risk Reduction With Treatment:
Entry Criteria Therapies Lowers Blood pressure treatment 20%–40%
HbA1c
Insulin Deficiency:
Symptomatic, Lean
Insulin Resistance:
HTN, Dyslipidemia,
Obesity
20%–50%
Fasting < 200 mg/dL (11.1 mmol/L)
Casual < 250 mg/dL (13.9 mmol/L)
HbA1c <8%
Medical Nutrition Stage ~1%
Lipid treatment – 25%–55
Fasting 200–300 mg/dL
(11.1 – 16.7 mmol/L)
Oral Agent Stage
Insulin Deficiency Insulin Resistance ~2% Glucose treatment 12%–35%*
Secretagogues Sensitizers
Casual 250–350 mg/dL
(13.9 – 19.4 mmol/L)
HbA1c 8-11%
10%–20%*
Combination Oral Agent Stage
Secretagogue + Sensitizer
Correlation of A1c and
~2-4%
Note: Each stage requires a pre-
set BG target: and a timeline to
Combination Oral Agent/Insulin Stage
Oral Agent + Insulin
Complication Risk: UKPDS:
reach that goal
Risk reduction in complications per
Fasting > 300 mg/dL (16.7 mmol/
L)
Physiologic Insulin Stage 4
Basal/Bolus Insulin > 4% each 1% reduction in mean A1c
Casual > 350 mg/dL (19.4 RA - RA - RA - G
mmol/L)
HbA1c > 11%
International Diabetes Center
50
Oral Antihyperglycemic Monotherapy
- Maximum Therapeutic Effect on
40
A1C: 30
20
10
0

6. Glycemic Responses in the UKPDS:
9 10-Year Cohort
8 10-year
median 7.9%
7
10-year
median 7.0%
6
0
0 3 6 9 1
2
Year
UKPDS Group. Lancet. 1998;352:837-853
s
50% of sulphonylurea-treated patients
with T2DM required insulin after 6
years to achieve glycaemic target Normal Insulin Secretion:
Insulin added when FPG >6 mmol/l 50
(>108 mg/dl) 40
30
20
10
50
requiring additional insulin
n=826 HbA1c <7% 0
0 2 4 6 8 10 12 14 16 18 20 22 24
at 6 years
SU-treated patients
47
Time (Hours)
(%)
25 35
25
Insulin Action:
20
comparison of new Insulin Analogs
Insulin levels (U/ml)
140
e
in
on
0
ul
0
Rapid(Lispro, Aspart)
al
s
120
in
1 2 3 4 5 6
lin
±
su
SU
In
Time since randomisation (years) 100
80 Regular
Percentages of patients on different 60
glucose lowering therapy 40 Intremediate (NPH)
20
1 OAD 37% 0 Long (UL,HOE)
12
15
3
6
9
2 OAD 34% Hours
3 OAD 3%
Insulin Alone
18%
Insulin + OAD
8%
From Orals to Insulin:

7. Diabetes Care: R/N – 0 –R/N – 0 or LP/N –0 – LP/N – 0
Dose Calculation and Adjustment If BG < 80 mg/dl 140-250 mg/dl > 250 mg/dl
Begin modestly with 0.3 to 0.5 U/kg/ A.M. Pm N 1-2 u (a.b.) pm N 1-2 u (a)
Pm N 1-2 u
(a.b.)
day insulin (total) am R or LP 1-2 u. am R or LP
MIDDAY am N 1-2 U (f.h)
2/3 of this dose in the morning and (c.e.) 2-4 U (f.g)
am N 2-4 U
1/3 in the evening P.M. am N 1-2U (d.e) am N 1-2 U (f.h)
(f.h)
 2/3 of the insulin should be NPH If BG < 100 mg/dl 160-250 mg/dl >250 mg/dl
and 1/3 should be regular or simply BEDTIME pm R or LP 1-2 U (e)
pm R or LP 1-2
U (f)
pm R or LP
2-4 U (f)
use 70/30 combination
Control of Blood sugar Insulin vs non
 Begin with loose control and tighten
insulin:
with experience
 Tight control is dependant on the 350
stage of the disease 300
250
Type 2: Insulin Adjustment 200
150
Guidelines: 100
50
253.5mg
312mg
Insulin Pattern Adjustments 0
insulin(alone
Adjust insulin from 3- days pattern or
combination)
Determine which insulin is
Controlled vs Uncontrolled:
responsible for pattern
Adjust by 2-4 units 100%
Adjust only one dose at a time 90%
80%
Correct hypoglycemia first. 70%
If total dose >1.5 U/Kg. Consider 60%
50% controlled (200mg%and
over insulization 40%
30%
less)
If hyperglycemia throughout the 20%
10% Uncontrolled( More than
day, correct highest SMBG first; if all 0%
200mg%)
14 %Controlled
within 50 mg/dl, correct AM first.
Type 2: Insulin Start (cont):
R/N – 0 –R/N –0
LP/N – 0 –LP/N – 0
At Diagnosis or from Oral Therapy
Calculate total dose at 0.3 U/kg based
on current weight
AM MIDDAY PM BT
Distribution2/3 0 1/3 0
R/N or LP/N ratio 1:2 1:1 -
Pre-mixed insulin, 70/30 AM and
50/50 PM,may be used for patients Normal Insulin Secretion:
unable to draw insulin correctly
Refer patient for nutrition and
diabetes education 50
40
30
20
10
0
Conventional Insulin Stage 2
0 2 4 6 8 10 12 14 16 18 20 22 24
R/N-0-R/N-0 or RA/N-0-RA/N-0:

8. 50
40 n = patient numbers in each BMI
category NPH insulin
3.5
36 37
39
30 3.0 50
76
2.5 35
Mean weight change (kg)
20 2.0 34
1.5
55
10 1.0 69
42
0.5
0 0.0
0 2 4 6 8 10 12 14 16 18 20 22 24 -0.5 ≤25 >25-27 >27-29 >29-31 >31
Baseline BMI
Management of Hyperglycemia
Common Oral + Insulin Hermansen treat-to-target trial:
Combinations: Overall hypoglycaemia Insulin detemir (n=237)
2000 **
A1C 1 or 2 Oral Agents NPH insulin (n=238)
% + 1688
9.7 9.7
Glargine Baseline
1600
9 monotherapy **
8.6 1200 923
908
**
Combination 800 755
8 therapy 519
7.6 387
400
7.2 1 8
7 7.0 0
All Major Minor confirmed Symptomatic
unconfirmed
** p<0.001
Met Glim Oral
Duration of action in type 2 diabetes: Hermansen treat-to-target trial:
0.4 U/kg 0.8 U/kg 1.4 U/kg
weight change
86
Detemir 12.0 (8.5) 16.8 (6.8) 22.1 (2.6)
85
Glargine 10.2 (7.4) 19.4 (6.9) 24.0 (0)
Weight (kg)
84
Objectives and design of Hermansen
treat-to-target study: 83
Insulin detemir twice-daily 82
n=237
81
80
NPH twice-daily
-2 1 3 5 7 9 11 13 15 17 19 21 23
n=238 Weeks
Existing OADs continued (both groups)
24 weeks Philis-Tsimikas study: Weight change
Insulin titrated to target: at 20 weeks detemir pm vs. NPH pm
fasting and pre-dinner PG ≤6 mmol/l p=0.005
2.0
Weight change
Hermansen treat-to-target study: 1.5
HbA1c and FPG :
(kg)
1.6
1.0
Hermansen treat-to-target trial:
Change in weight by baseline BMI 0.5 0.7
Insulin detemir pm NPH insulin pm
Clean switch’ type 2 diabetes patients:
change in HbA1c

9. Comparable glycaemic control
Mean HbA1c (%)
Mean HbA1c (%)
NPH insulin
8.2
*
8.2
†
Significantly fewer minor
–
8.1
8.1
8.1
8.1
–0.6% hypoglycaemic events: 53% reduction
8.0 8.0
7.9
7.9
7.9 Significantly fewer minor nocturnal
7.8
7.7
7.8
7.7
hypoglycaemic events: 65% reduction
7.6 7.6
7.5
Significantly less weight gain: (0.7
7.5 7.5
7.4
Baseline Three
7.4 vs. 1.6 kg)
Baseline Three
months
(n=152)
months
(n=97)
No significant differences between
PREDICTIVE
detemir am and pm regarding HbA1c,
TM
data on file
Clean switch’ type 2 diabetes patients: hypoglycaemia and weight change
change in nocturnal hypoglycaemia Summary cont:
*
In randomised clinical trials in
8 8 Events per patient-year
7 6.9 7
NPH insulin
insulin naïve T2DM patients:
6
5 -81%
6
5
Insulin detemir is equally effective in
Events per patient-year
4 4 † achieving glycaemic control in
3 3
2
1.3
2
1.6
-75%
comparison to NPH
1
0
1
0
0.4 Insulin detemir exerts significantly
Baseline Three months Baseline Three months lower risk of overall and nocturnal
n=175 n=118
*p<0.001
†p<0.05
hypoglycaemia in comparison to NPH
Insulin detemir once-daily results in
Clean switch’ type 2 diabetes patients:
Detemi significantly less weight gain than
NPH
r
90
*
86
insulin NPH
Mean weight (kg)
Mean weight (kg)
85.5
89.3 -0.7
*
89 85 -0.5 OCD Spectrum disorders
88.6
84.5
84.6
and their treatment:
84.1
88 84
Baseline Three months Baseline Three months
n=160 n=101
Insulin-naïve type 2 diabetes patients:
change in HbA1c:
Mean HbA1c (%)
8.9
8.
8.
8. -1.3%
8.
8.
7.
7. 7.6
7.
7.
Baselin Three
(n=1799)
Change in HbA1c and weight in three
comparable treat-to-target trials:
Summary: Obsessive-Compulsive Disorder:
Detemir vs. NPH in basal + OAD Affects Almost 3% Of World’s
Therapy: Population

10. Start Anytime From Preschool To 18th century finally considered
Adulthood Typically Between 20-24 medical issue
Many Different Forms Of OCD – 20th century began treating with
Differ From Person To Person behavioral techniques
Cause Of OCD Is Still Unknown Theories:
Better When Diagnosed Early Scientist split into 2 groups
Psychological disorder where people
Definition: are responsible for feelings they have
Specific criteria to be clinically Abnormalities in the brain
diagnosed Causes:
Anxiety disorder with presence of Serotonin is involved in regulating
obsessions or compulsions anxiety
ego dystonic – realize thoughts and Abnormality in the neurotransmitter
actions are irrational or excessive serotonin
Must take up more than 1 hour a __In order to send chemical messages
day serotonin must bind to the receptor
Must disrupt daily routine sites located on the neighboring nerve
Symptoms can’t result from effects cells
of other medical conditions or __OCD suffers may have blocked or
substances damaged receptor sites preventing
Obsessions serotonin from functioning to full
Repetitive And Constants Thoughts, potential
Images, Or Impulses That Cause Possible genetic mutation
Anxiety Or Distress __Some people suffering have
Thoughts, Images, Or Impulses Not mutation in the human serotonin
About Real-life Problems transporter gene
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
OCD and the Brain:

11. PET scans show people with OCD --- Medication
have different brain activity from Cognitive-Behavioral Therapy:
others Cognitive: change the way they
Another theory: miscommunication think to deal with their fears
between the orbital frontal cortex, the Behavioral: change the way they
caudate nucleus, and the thalamus react to “anxiety-provoking”
Caudate nucleus doesn’t function situations
properly and causes thalamus to Exposure and Response Prevention
become hyperactive and sends “never- --- Slowly learning to tolerate anxiety
ending” worry signals between OFC associated with not performing ritual
and thalamus ◊ OFC responds by behavior
increasing anxiety 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
Comorbidity : Inhibitors (SSRIs): alter the levels of
Has excessive comorbidity with
neurotransmitter serotonin in the
other diseases brain which helps brain cells
Common diseases: Depression,
communicate with one another
Schizophrenia, Tourette Syndrome ---- Prevents excess serotonin from
Depression is the most common
being pumped back into original
Many people with OCD suffered
neuron that released it
from depression first ---- Then can bind to receptor sites of
2/3 of OCD patients develop
nearby neurons and send chemical
depression ◊ makes OCD symptoms message that can help regulate anxiety
worse and more difficult to treat and obsessive compulsive thoughts
People with OCD common ---- Most effective drug treatment
diagnosed as Schizophrenic ◊ hard to helping about 60% of patients
separate obsessions from delusions Conclusion:
Treatment: OCD is a complicated issue
Only completely curable in rare Most cases are incurable
cases Best form of treatment is CBT in
Most people have some symptom combination with medication
relief with treatment Most important thing that can be
Treatment choices depend on the done to discover more about OCD and
problem and patients preferences its treatments is to research the brain
Most common treatments:
---Behavioral Therap
--- Cognitive Therapy

12. 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).”