HYPERTHYROIDISM

A Practical Approach to Diagnosis and Management

dr. Yunus Tanggo Sp.PD. PhD

Department of Internal Medicine, Universitas Kristen Indonesia General Hospital,
Jakarta, Indonesia
 LEARNING OBJECTIVES
• ANATOMI AND CLINICAL EXAMINATION
• PATHOPHYSIOLOGY
• CLINICAL SYMPTOM AND SIGN
• DIAGNOSIS
• MANAGEMENT
ANATOMI
CLINICAL EXAM. OF THYROID

• Have patient seated on a stool / chair

• Inspect neck before & after swallowing
• Examine with neck in relaxed position
• Palpate from behind the patient
• Use the tips of fingers for palpation
• Palpate firmly down to trachea
 PHYSIOLOGY
• The thyroid gland contains spherical follicles (50–500 μmin
diameter).
• Follicle cells synthesize the two iodine-containing thyroid hormones
thyroxine (T4, tetraiodothyronine and T3, triiodothyronine).
• T3 and T4 are bound to the glycoprotein thyroglobulin and stored
in the colloid of the follicles
• The synthesis and release of T3/T4 is controlled by the thyrotropin
releasing hormone, TRH)—thyrotropin stimulating hormone (TSH)
axis
• T3 and T4 influence physical growth, maturation and metabolism.
• The parafollicular cells (C cells) of the thyroid gland synthesize
calcitonin
Control of Thyroid Function
By a negative-feedback loop:
• The hypothalamus releases TRH
• TRH acts on the pituitary to release TSH
• TSH acts on the thyroid gland to release
T3 and T4 , that regulate metabolism

• TRH and TSH concentrations are

inversely related to the level of T3 & T4
• 99% circulating T3 & T4 is bound to
TBG. 1% circulate in the Free form,
(only the free forms are biologically
active)
 HYPERTHYROIDISM

• Hyperthyroidism is the result of excessive thyroid

function.

• Thyrotoxicosis is defined as the state of thyroid

hormone excess, However, the major etiologies of
thyrotoxicosis are hyperthyroidism caused by Graves’
disease, toxic multinodular goiter, and toxic
adenomas
 COMMON SYMPTOMS
1. Nervousness
2. Anxiety
3. Increased perspiration
4. Heat intolerance
5. Tremor
6. Hyperactivity
7. Palpitations
8. Weight loss despite increased appetite
9. Reduction in menstrual flow or oligo-menorrhea
 COMMON SIGNS
1. Hyperactivity, Hyper kinesis
2. Sinus tachycardia or atrial arrhythmia, AF, CHF
3. Systolic hypertension, wide pulse pressure
4. Warm, moist, soft and smooth skin- warm handshake
5. Excessive perspiration, palmar erythema, Onycholysis
6. Lid lag and stare (sympathetic over activity)
7. Fine tremor of out stretched hands – format's sign
8. Large muscle weakness, Diarrhea, Gynecomastia
Features of Graves’ disease. A. Facial appearance in Graves’ disease; lid retraction, periorbital edema, and
proptosis are marked. B. Thyroid dermopathy over the lateral aspects of the shins. C. Thyroid acropachy.
 Evaluation of thyrotoxicosis. aDiffuse goiter, positive TPO antibodies, ophthalmopathy,
dermopathy; bcan be confirmed by radionuclide scan. TSH, thyroid-stimulating hormone
 GRAVES DISEASE
• The most common cause of thyrotoxicosis (50-60%).
• Organ specific auto-immune disease
• The most important autoantibody is
– Thyroid Stimulating Immunoglobulin (TSI) or TSA
– TSI acts as proxy to TSH and stimulates T4 and T3
• Anti thyro peroxidase (anti-TPO) antibodies
• Anti thyro globulin (anti-TG) Anti Microsomal and other
• Autoimmune diseases - Pernicious Anemia, T1DM
• RA, Myasthenia Gravis, Vitiligo, Adrenal insufficiency.
GRAVES DISEASE

I 123 or TC 99m Normal v/s Graves

TOXIC MULTINODULAR GOITER (TMG)

• TMG is the next most common hyperthyroidism - 20%

• More common in elderly individuals – long standing goiter
• Lumpy bumpy thyroid gland
• Milder manifestations (apathetic hyperthyroidism)
• Mild elevation of FT4 and FT3
• Progresses slowly over time
• Clinically multiple firm nodules (called Plummer’s disease)
• Scintigraphy shows - hot and normal areas
TOXIC MULTINODULAR GOITER (TMG)
 SUB ACUTE THYROIDITIS (SAT)
• SAT is the next most common hyperthyroidism – 15%
• T4 and T3 are extremely elevated in this condition
• Immune destruction of thyroid due to viral infection
• Destructive release of preformed thyroid hormone
• Thyroid gland is painful and tender on palpation
• Nuclear Scintigraphy scan - no RIU in the gland
• Treatment is NSAIDs and Corticosteroids
 TOXIC SINGLE ADENOMA (TSA)
• TSA is a single hyper functioning follicular thyroid adenoma.
• Benign monoclonal tumor that usually is larger than 2.5 cm
• It is the cause in 5% of patients who are thyrotoxic
• Nuclear Scintigraphy scan shows only a single hot nodule
• TSH is suppressed by excess of thyroxines
• So the rest of the thyroid gland is suppressed

Nucleotide Scintigraphy
 AGE AND SEX
• Age
– Graves disease 20 to 40
– Toxic MNG > 50 yrs
– Toxic Single Adenoma 35 to 50
– Sub Acute Thyroiditis Any age
• Sex M : F ratio
– Graves Disease 1: 5 to 1:10
– Toxic MNG 1: 2 to 1: 4
NUCLEOTIDE SCINTIGRAPHY
 TREATMENT OPTIONS
• The hyperthyroidism of Graves’ disease is treated by reducing
thyroid hormone synthesis, using antithyroid drugs, or by
reducing the amount of thyroid tissue with radioiodine (131I)
treatment or by subtotal thyroidectomy.
• Antithyroid drugs are the predominant therapy in many
centers in Europe and Japan, whereas radioiodine is more
often the first line of treatment in North America.
• These differences reflect the fact that no single approach is
optimal and that patients may require multiple treatments
to achieve remission.
 TREATMENT OPTIONS
1. Symptom relief medications
2. Anti Thyroid Drugs – ATD
 Methimazole, Carbimazole
 Propylthiouracil (PTU)
3. Radio Active Iodine treatment – RAI Rx.
4. Thyroidectomy – Subtotal or Total
5. NSAIDs and Corticosteroids – for SAT
 SYMPTOM RELIEF
1. Rehydration is the first step
2. β – blockers to decrease the sympathetic excess
 Propranalol, Atenelol, Metoprolol
3. Rate limiting CCBs if β – blockers contraindicated
4. Treatment of CHF, Arrhythmias
5. Calcium supplementation
6. SSKI or Lugol solution for ↓ vascularity of the gland
 ANTI THYROID DRUGS (ATD)
Imp. considerations Methimazole Propylthiouracil
Efficacy Very potent Potent
Duration of action Long acting BID/OD Short acting QID/TID
In pregnancy Contraindicated Safely can be given
Mechanism of action Iodination, Coupling Iodination, Coupling
Conversion of T4 to T3 No action Inhibits conversion
Adverse reactions Rashes, Neutropenia Rashes, ↑Neutropenia
Dosage 20 to 40 mg/ OD PO 100 to 150mg qid PO
 HOW LONG TO GIVE ATD ?
• Reduction of thyroid hormones takes 2-8 weeks
• Check TSH and FT4 every 4 to 6 weeks
• In Graves, many go into remission after 12-18 months
• In such pts ATD may be discontinued and followed up
• 40% experience recurrence in 1 yr. Re treat for 3 yrs.
• Treatment is not life long. Graves seldom needs surgery
• MNG and Toxic Adenoma will not get cured by ATD.
• For them ATD is not the best. Treat with RAI.
 RADIO ACTIVE IODINE (RAI RX.)
• In women who are not pregnant
• In cases of Toxic MNG and TSA
• Graves disease not remitting with ATD
• RAI Rx is the best treatment of hyperthyroidism in adults
• The effect is less rapid than ATD or Thyroidectomy
• It is effective, safe, and does not require hospitalization.
• Given orally as a single dose in a capsule or liquid form.
• Very few adverse effects as no other tissue absorbs RAI
 RADIO ACTIVE IODINE (RAI RX.)
• I123 is used for Nuclear Scintigraphy (Dx.)
• I131 is given for RAI Rx. (6 to 8 milliCuries)
• Goal is to make the patient hypothyroid
• No effects such as Thyroid Ca or other malignancies
• Never given for children and pregnant/ lactating women
• Not recommended with patients of severe Ophthalmopathy
• Not advisable in chronic smokers
 SURGICAL TREATMENT
• Subtotal Thyroidectomy, Total Thyroidectomy
• Hemi Thyroidectomy with contra-lateral subtotal
• ATD and RAI Rx are very efficacious and easy – so
• Surgical treatment is reserved for MNG with
1. Severe hyperthyroidism in children
2. Pregnant women who can’t tolerate ATD
3. Large goiters with severe Ophthalmopathy
4. Large MNGs with pressure symptoms
5. Who require quick normalization of thyroid function
 PREOPERATIVE PREPARATION
• ATD to reduce hyper function before surgery
• βeta blockers to titrate pulse rate to 80/min
• SSKI 1 to 2 drops bid for 14 days
• This will reduce thyroid blood flow
• And there by reduce per operative bleeding
• Recurrent laryngeal nerve damage
• Hypo parathyroidism are complications
 DIETARY ADVICE
• Avoid Iodized salt, Sea foods
• Excess amounts of iodide in some
– Expectorants, x-ray contrast dyes,
– Seaweed tablets, and health food
supplements
– These should be avoided because
– The iodide interferes with or complicates
the management of both ATD and RAI Rx.
THANK YOU
 DIABETES MELLITUS
A Practical Approach to Diagnosis and Management

dr. Yunus Tanggo Sp.PD. PhD

Department of Internal Medicine, Universitas Kristen Indonesia General Hospital,
Jakarta, Indonesia
 LEARNING OBJECTIVES
• Knowing definition, sign and symptom,
classification of Diabetes Mellitus
• Management of type 2 Diabetes Mellitus
• Oral Hypoglycemic Agent
• Individualized Treatment of Diabetes Mellitus
 EPIDEMIOLOGY
 Diabetes is on the increase worldwide, especially in Western
Pacific countries. In 1995, there were 135 million people with
diabetes worldwide,with the number expected to rise to 330
million by 2025.

 Most of this increase will occur in developing countries where

an increase of 170% is expected (over 60% of the world’s
diabetic population)

 Inconjunction with increased obesity rates and

westernization of lifestyle
 DEFINITION OF DIABETES

Characterized by hyperglycaemia
• Defects in insulin production
• Autoimmune or other destruction of beta cells
• Insulin insensitivity
• Impaired action of insulin on target tissues
 CLASSIFICATION
1. Type 1 diabetes
– autoimmune
– LADA
– idiopathic
2. Type 2 diabetes
• Insulin resistance
• Deficiency of insulin
3. Other specific types
• MODY
• Defects in insulin action
• Diseases of the pancreas
• Endocrine disorders
• Drug- or chemical-induced
• Infections
• Uncommon forms of immune-mediated diabetes
• Other genetic syndromes
4. Gestational diabetes
 PATHOPHYSIOLOGY
INSULIN AND GLUCOSE DISPOSAL
Gluconeogenesis
Glycogenolysis
Insulin Glycogen synthesis

Blood glucose

Glycogen Glucose uptake

synthesis Free fatty acid release
INSENSITIVITY TO INSULIN IN TYPE 2 DIABETES
Glucose uptake
Glycolysis
Gluconeogenesis (amino acids)

Blood glucose

Glucose uptake
Protein degradation  amino acids

Glucose uptake
PATHOGENESIS OF TYPE 1 DIABETES

• Immunological activation

• Progressive beta-cell destruction

• Insufficient beta-cell function

• Dependent on exogenous insulin

• Risk of ketoacidosis
 PATHOGENESIS OF TYPE 1 DIABETES

• Genetic susceptibility

• Immune factors
– other autoimmune disease
– antigen-specific antibodies

• Environmental trigger
– viruses
– bovine serum albumin
– nitrosamines: cured meats
– chemicals: vacor (rat poison), streptozotin
PATHOGENESIS OF TYPE 1 DIABETES
Trigger

Immunological
Genetic abnormalities
Beta-cell
mass Clinical diabetes

Pre-diabetes ‘Honeymoon’

Chronic
phase
Time (months - years)
EPIDEMIOLOGY OF TYPE 1 DIABETES

• Age of onset peaks

– preschool
– puberty
• Autumn/winter peaks
TYPE 2 DIABETES
• 90%-95% of people with diabetes

• Insulin insensitivity and relative

insulin deficiency

• Obesity or overweight

• Complications often present at

diagnosis
PATHOGENESIS OF TYPE 2 DIABETES

• Multiple genes involved

• Hyperinsulinaemia
• Poor fetal nutrition   beta-cell
formation
• Low birth weight/weight change
• “Thrifty gene”
• 7% beta-cell loss
 THE NATURAL HISTORY OF TYPE 2 DIABETES

Beta-cell loss
 Insulin
Primary requirements
Insulin failure with age
requirements

Endogenous
insulin

Age (years)
 THE NATURAL HISTORY OF TYPE 2 DIABETES

Beta-cell loss

Hyper-  Insulin
insulinaemia requirements
Insulin with age
requirements
Insulin
insensitivity Endogenous
insulin

Age (years)
 THE NATURAL HISTORY OF TYPE 2 DIABETES

Secondary
Beta-cell loss failure

Hyper-  Insulin
insulinaemia Effect of oral requirements
Insulin drugs with age
requirements
Insulin
insensitivity Endogenous
insulin

Age (years)
EPIDEMIOLOGY OF TYPE 2 DIABETES

• Dramatic increase
• Aging population
• Disturbing trends parallel obesity
epidemic
• Especially in adolescents and minority
groups
• Increasing in young people
RISK FACTORS FOR TYPE 2 DIABETES

• Age > 40 years

• First-degree relative with diabetes
• Member of high risk population
• History of impaired glucose tolerance,
impaired fasting glucose
• Vascular disease
• History of gestational diabetes
• History of delivery of macrosomic baby
RISK FACTORS FOR TYPE 2 DIABETES

• Hypertension
• Dyslipidaemia
• Abdominal obesity
• Overweight
• Polycystic ovary disease
• Acanthosis nigricans
• Schizophrenia
SIGNS AND SYMPTOMS

– Polydipsia
– Polyuria
– Nocturia
– Visual disturbance
– Fatigue
– Weight loss
– Infections
 DIAGNOSING DIABETES

Normal Impaired fasting glucose* Diabetes

Impaired glucose
tolerance**
FPG <6.1mmol/L 6.1 to 6.9mmol/L* ≥7.0mmol/L
<110mg/dL 110 to 126mg/dL ≥126mg/dL
2hr PG <7.8mmol/L 7.8 to 11mmol/L** ≥11.1mmol/L
<126mg/dL 126 to 200mg/dL ≥200mg/dL

CDA 2003, ADA 2004, WHO 2002

 IMPAIRED GLUCOSE TOLERANCE
IMPAIRED FASTING GLUCOSE

• Intermediate states
• Increased risk of developing diabetes
• Prevention strategies to prevent or delay
progression
• Increased risk of cardiovascular disease
 PHARMACOLOGICAL MANAGEMENT
BLOOD GLUCOSE-LOWERING MEDICINES

• AIMS OF TREATMENT
– Reduce the symptoms of hyperglycaemia
– Limit adverse effects of treatment
– Maintain quality of life and psychological well-being
– Prevent or delay vascular complications of diabetes
 SITES OF ACTION BY THERAPEUTIC OPTIONS PRESENTLY
AVAILABLE TO TREAT TYPE 2 DIABETES
BRAIN
LIVER Endocannabinoid
Receptor Blockers
ADIPOSE TISSUE MUSCLE
Exenatide
Pramlinitide

PANCREAS
GLUCOSE PRODUCTION PERIPHERAL
Biguanides GLUCOSE UPTAKE
(Thiazolidinediones) INSULIN SECRETION
Sulfonylureas Thiazolidenediones
Meglitinides (Biguanides)
GLUCOSE Exenatide
ABSORPTION DPP4 Inhibitors
Insulin STOMACH
α-glucosidase inhibitors DELAYED EMPTYING
INTESTINE Exenatide,
Pramlintide

Adapted from Sonnenberg and Kotchen. Curr Opin Nephrol Hypertens 1998;7(5):551–5
 BIGUANIDES

Class Biguanides
Compound Metformin
Mechanism Activates AMP-kinase
Action(s) • Hepatic glucose production 
• Intestinal glucose absorption 
• Insulin action 
Advantages • No weight gain
• No hypoglycemia
• Reduction in cardiovascular events and mortality (UKPDS)
Disadvantages • Gastrointestinal side effects (diarrhea, abdominal cramping)
• Lactic acidosis (rare)
• Vitamin B12 deficiency
• Contraindications: reduced kidney function
Cost Low
 SULFONYLUREAS
Class Sulfonylureas
Compound • Glibenclamide/Glyburide
• Glipizide
• Gliclazide
• Glimepiride
Mechanism Closes KATP channels on β-cell plasma membranes
Action(s)  Insulin secretion
Advantages • Generally well tolerated
Disadvantages • Relatively glucose-independent stimulation of insulin
secretion: Hypoglycemia, including episodes necessitating
hospital admission and causing death
• Weight gain
• May blunt myocardial ischemic preconditioning
• Low “durability”
Cost Low
 GLINIDES

Class Meglitinides
Compound • Repaglinide
• Nateglinide
Mechanism Closes KATP channels on β-cell plasma membranes
Action(s) Insulin secretion 
Advantages Accentuated effects around meal ingestion
Disadvantages • Hypoglycemia, weight gain
• May blunt myocardial ischemic preconditioning
• Dosing frequency
Cost Medium
 THIAZOLIDINEDIONES

Class Thiazolidinediones (Glitazones)

Compound Rosiglitazone
Mechanism Activates the nuclear transcription factor PPAR-
Action(s) Peripheral insulin sensitivity 
Advantages No hypoglycemia
Disadvantages • LDL cholesterol 
• Weight gain
• Edema
• Heart failure
• Bone fractures
• Increased cardiovascular events (mixed evidence)
• FDA warnings on cardiovascular safety
• Contraindicated in patients with heart disease
Cost High
 α-GLUCOSIDASE INHIBITORS

Class α-Glucosidase inhibitors

Compound • Acarbose
• Miglitol
Mechanism Inhibits intestinal α-glucosidase
Action(s) Intestinal carbohydrate digestion (and
consecutively, absorption) slowed
Advantages • Nonsystemic medication
• Postprandial glucose 
Disadvantages • Gastrointestinal side effects (gas, flatulence,
diarrhea)
• Dosing frequency
Cost Medium
 INCRETIN MIMETICS
Class GLP-1 receptor agonists (incretin mimetics)
Compound • Exenatide
• Liraglutide
Mechanism Activates GLP-1 receptors (β-cells/endocrine pancreas;
brain/autonomous nervous system
Action(s) • Insulin secretion  (glucose-dependent)
• Glucagon secretion  (glucose-dependent)
• Slows gastric emptying
• Satiety 
Advantages • Weight reduction
• Potential for improved β-cell mass/function
Disadvantages • Gastrointestinal side effects (nausea, vomiting, diarrhea)
• Cases of acute pancreatitis observed
• C-cell hyperplasia/medullary thyroid tumors in animals
(liraglutide)
• Injectable
• Long-term safety unknown
Cost High
 INCRETIN MIMETICS
Class DPP-4 inhibitors (incretin enhancers)
Compound • Sitagliptin
• Vildagliptin
• Saxagliptin
• Linagliptin
Mechanism Inhibits DPP-4 activity, prolongs survival of endogenously
released incretin hormones
Action(s) • Active GLP-1 concentration 
Active GIP concentration 
• Insulin secretion 
• Glucagon secretion 
Advantages • No hypoglycemia
• Weight “neutrality”
Disadvantages • Occasional reports of urticaria/angioedema
• Cases of pancreatitis observed
• Long-term safety unknown
Cost High
 NO SINGLE CLASS OF ORAL ANTIHYPERGLYCEMIC
MONOTHERAPY TARGETS ALL KEY PATHOPHYSIOLOGIES

Alpha- DPP-4
Glucosidase Meglitinides SUs TZDs Metformin Inhibitors
Inhibitors
MAJOR PATHOPHYSIOLOGIES

Insulin
deficiency   
Insulin
resistance  
Excess hepatic
glucose output   
Intestinal
glucose
absorption
 
AS TYPE 2 DIABETES PROGRESSES,
INSULIN THERAPY IS NEEDED

HYPOTHETICAL MODEL

Insulin Insulin
Oral therapy
initiation initiation intensification

DISEASE PROGRESSION
 INDIVIDUALIZED TREATMENT OF
HYPERGLYCEMIA
• Patient-centered care is defined as an approach to
providing care that is respectful and responsive to
individual patient preferences, needs, values and
ensuring that patient values guide all clinical
decisions

• Patient who make final decisions regarding their

lifestyle choice, and to some degree the
pharmateucal interventions they use
INDIVIDUALIZED TREATMENT OF
HYPERGLYCEMIA
• Important of the patient in
medical decision.
• life style choices
• therapeutic choices regarding
to conditions ( co morbidities,
Age, access to drug for
diabetes)
• clinicians and patients act as
partners
• glycemic targets are flexible
 SUMARY
• Glycemic Targets And Glucose-lowering Therapies Must Be
Individualized
• Diet, Exercise And Education Remain The Foundation Of
T2DM Treatment Program
• Unless The Are Prevalent Contraindications, Metformin Is The
Optimal First Line Drug
• After Metformin Combination Of 1-2 Oral Or Insulin Is
Reasonable, Aiming To Minimize Side Effects
• All Treatment Decisions, Should Be Made In
Conjunction With The Patient, Focusing Preferences, Needs
And Tolerances Of Each Patients

• Comprehensive Cardiovascular Risk Reduction Must Be

A Major Focus Oh Therapy . Aggressive Management Of
Cardiovascular Risk Factor ( Bloodpressure , Lipid Therapy,
Antiplatelet Treatment And Smoking Cessation)
 COMPLICATIONS
ACUTE : DKA, HHS, HIPOGLYCEMIA
CHRONIC : MACROVASCULAR,
MICROVASKULAR,
NEUROPATHY