ENDOCRINE AND METABOLIC DISORDERS

RCW Wong

Endocrine and metabolic disorders

Endocrine glands regulate homeostasis by secretion of hormones which affect many organ systems

Metabolism - process body uses to get or make energy from food.

Metabolic disorders occur when abnormal chemical reactions disrupt this process.

too much or too little of some substances occurs when some organs, e.g. liver or pancreas,

become diseased or do not function normally.

Endocrine glands

Hypothalamus Pituitary Pineal Thyroid Parathyroid Thymus Pancreas Adrenal Sex organsMainly regulated in negative feedback

loop

Endocrine disorders

Pituitary tumours –gigantism, acromegaly, diabetes insipidus

Diabetes mellitus Adrenal insufficiency Thyroid disorders- hypo or hyperthyroid Parathyroid-hypo or hyper Tumours- multiple endocrine neoplasia,

phaeochromocytoma

Inherited disorders of metabolism

Acid lipase disease Barth syndrome Central pontine

myelinosis Phenylketonuria Lesch-Nyhan disease G6PD deficiency Pompe disease Mitochondrial

myopathies Muscular dystrophy

Lipid storage disease Mucolipidosis Mucopolysaccharidos

is Porphyria Hereditary fructose

intolerance Type I glycogen

storage disease Hypercholesterolemi

a Diabetes mellitus

type I

Acquired disorders of metabolism

Diabetes mellitus Type II Hypercholesterolemia Metabolic syndrome /Syndrome X

Important disorders

Diabetes mellitus Adrenocortical hypofunction Thyroid disorders G6PD

Diabetes mellitus

Diabetes mellitus

Diabetes mellitus (DM) is a heterogenous disorder of metabolism due to absolute or relative deficiency of insulin

It affects 9% of the population aged 18-69 years in Singapore causing multi-organ damage and dysfunction

Associated with 9.3% of all deaths National Health Survey 1998, Epidemiology and Disease Control, Department of Ministry of Health, Singapore.

Classification of diabetes

Type 1 (primary diabetes-insulin dependant diabetes mellitus)-due to severe insulin deficiency caused by destruction of the pancreatic beta cells

Type 2 (primary diabetes -non-insulin dependent diabetes mellitus)-due to varying degrees of insulin resistance and insulin deficiency

Classification of diabetes

Gestational diabetes-diabetes that is first recognized or occurs during pregnancy

Miscellanous group- includes diabetes caused by chronic pancreatitis, drugs like steroids, hemochromatosis, acromegaly

Signs and Symptomsof diabetes mellitus

Type I mainly juvenile and occasionally non-obese individuals/elderly when hyperglycaemia first appears

Polyuria Polydipsia Rapid weight loss associated with

hyperglycaemia Postural hypotension Muscle weakness Ketoacidosis Ketonuria

Signs and Symptomsof diabetes mellitus

Type II (mainly over 40 and obese) Polyuria Polydipsia Non-ketotic form of diabetes Candidal vaginitis in women Chronic skin infections Generalized pruritus Associated with hypertension, hyperlipidemia

and atherosclerosis

Known risk factors

positive family history Hypertension Overweight previous gestational diabetes impaired glucose tolerance plasma HDL-cholesterol less than

0.9mmol/L and plasma trigylceride above 2.8 mmol/L

Diagnosis

Based on clinical history symptoms and lab analysis

Lab analysis

Urinanalysis: a) Glucosuria- certain drugs like salicylates,

ascorbic acids can give false negative results. A normal renal threshold and a reliable bladder is essential for interpretation.

b) KetonuriaCapillary blood glucose measurements by

bedside (Hypocount) in a hospital setting requires rigorous quality control programs and certification of personnel to avoid errors

Lab analysis

Fasting plasma glucose- Repeated fasting plasma glucose over 7 mmol/L and /or random plasma glucose over 11 mmol/L in an asymptomatic individual is enough for diagnosis. In symptomatic persons, only one of the above values is required.

Glucose tolerance test: gold standard for diagnosis of diabetes but not always necessary

Lab analysis

Glycosylated haemoglobin (HbA1c): HbA1c is abnormally high in diabetics with chronic hyperglycaemia. The normal value should be 4-6% of total haemoglobin. This reflects the state of gycaemia in the preceeding 8-12 weeks

Attempts to use this for diagnosis of diabetes are controversial as the sensitivity in detecting diabetes with this test is only 85% i.e. diabetes cannot be excluded by a normal value. However, elevated levels are quite specific (91%) in identifying diabetes

Therapy for type 1 diabetes consists of dietary management and insulin.

Therapy for type 2 diabetes consists of dietary management and possibly oral hypoglycemic agents or insulin

Management of diabetic pts

The clinician should assess the disease severity, including the presence of chronic complications of DM e.g. IHD, renal disorders, neuropathy.

The degree of control, the types of medication (dosage, duration) and past history of acute infections and hospital admissions should be noted.

Minor surgery/outpatients

Routine dental treatment or minor oral surgery (under local anaesthesia [LA]) can be carried out in well-controlled diabetics

Schedule such patients first thing in the morning after breakfast and after their routine anti-diabetic medication

Minor surgery/outpatients

Keep appointments short; watch out for signs of hypoglycaemia (in the dental setting, a collapse of a known diabetic is usually due to hypoglycaemia since ketoacidosis takes some time to develop).

Onset of hypoglycaemia requires termination of the procedure and administration of a sweetened drink.

If unconscious, give 1mg glucagon IM followed by a glucose drink. Alternatively, if an IV line can be secured, give 50ml of 50% dextrose intravenously

Minor surgery/outpatients

Diabetic ketoacidosis (DKA) occurs in patients with type 1 disease because of stress or worsening glucose control, which produces hyperglycemia that causes osmotic diuresis, leading to severe dehydration and hyponatremia

Minor surgery/outpatients

Post-operative antibiotics may be considered after surgical procedures, if infection is a concern

If patients are unable to take their normal diet post-operatively, their insulin or oral hypoglycaemic medication may need to be reduced. Patients must be told to monitor their blood glucose at home, as is usually done.

 

GA/ major surgery

For diabetics/pts with hyperglycaemia/suspected diabetes undergoing major oral surgery procedures (under GA), consultation with the anaesthetist and physician/endocrinologist is essential.

A regime needs to be worked out to ensure good blood glucose control preoperatively, perioperatively and postoperatively. (Glucose/Insulin Sliding scale)

Start hypocount measurements 6 hourly and target insulin therapy on a sliding scale.

Sliding Scale insulin protocol

Hypocount readings (mmol/L)

Subcutaneous insulin dosage  

4-6 4 units  6.1-8

6 units 

8.1-10 8 units  10.1-12 10 unitsMore than 12 12 units

Adrenocortical hypofunction

Introduction

Medulla secretes epinephrine and norepinephrine into adrenal veins when stimulated

Cortex secretes steroids regulating metabolism, vascular tone, cardiac contractility, TBW/Na/K balance, androgenic function

Adrenal Physiology

Cyclic secretion controlled by time of day, HPA axis, renin-angiotensin system, serum potassium levels

Stress increases basal glucocorticoid and mineralcorticoid levels 5-10 fold Occurs within minutes

Adrenal Failure

Basal failure results in adrenal insufficiency Leads to insidious wasting disease

Stress failure results in adrenal crisis Life-threatening Absence of glucocorticoids is most critical

Corticosteroids

Three classes (by effect):GlucocorticoidsMineralcorticoidsAndrogenic steroids

Glucocorticoids

Regulate fat, glucose, protein metabolism Catecholamine and b-adrenergic receptor

synthesis Maintain vascular tone and cardiac

contractility Control endothelial integrity/vascular

permeability

Glucocorticoids

Cortisol Controlled by HPA axis Hypothalamus CRH and arginine

vasopressin in circadian rhythm (max 2-4am) Anterior Pituitary ACTH Adrenal cortex cortisol Peak @ 8am; declines throughout day

Glucocorticoids

Cortisol 25mg produced daily (non-stressed) 5-10% free and physiologically active Remainder bound to cortisol-binding globulin

Becomes uncoupled in times of stress Negatively feeds back to control

hypothalamus Role in adrenal insufficiency

Adrenal Insufficiency

Primary = failure of adrenal glands Secondary = failure of HPA axis

Usually due to chronic exogenous glucocorticoid administration

pituitary failure Tertiary = Hypothalamic dysfunction

Primary Adrenal Insufficiency

Loss of all three types of adrenal steroids 90% of glands must be destroyed to

manifest clinically High functional reserve

Adrenoleukodystrophy = X-linked inherited d/o of very-long-chain fatty acid metabolism Progressive neurological symptoms from

demyelination

Primary Adrenal Insufficiency

Addison disease = autoimmune Thrombosis/hemorrhage Sepsis, DIC, antiphospholipid syndrome

Infiltrative diseases Bilateral cancer metastasis Amyloidosis, hemosiderosis (rare)

Primary Adrenal Insufficiency

TB = m.c. infectious cause worldwide HIV = m.c. infectious cause in US

50% have degree of destruction Only 5% have clinical symptoms of A.I. CMV infection, ketoconazole use, macrophage-

released cytokines are risk factors

Secondary Adrenal Insufficiency

HPA axis failure deficiency of glucocorticoids and adrenal

androgens mineralcorticoids are unaffected

#1 cause=chronic exogenous glucocorticoid suppresses diurnal CRH/AV release both time- and dose-related reversible

recovery may take up to a year

Secondary Adrenal Insufficiency

Less common causes Postpartum necrosis (Sheehan syndrome) Adenoma hemorrhage(s) Pituitary destruction from head trauma typically have associated focal neurological

changes, visual deficits, diabetes insipidus or panhypopituitarism

Secondary Adrenal Insufficiency

MYTHBUSTERS! Short course (2-3 weeks) is unlikely to

suppress the HPA axis Daily doses of prednisone 5mg or less

are unlikely to cause secondary insufficiency

Management

adrenocortical crisis and collapse if the patient is subjected to trauma, stress (pain/ anxiety induced), and general anaesthesia

The associated medical condition which required the patient to be placed on systemic corticosteroids can complicate dental care as well. This includes asthma, autoimmune disorders and recipients of organ transplant

Management

Patients on systemic corticosteroids or those who have had steroids within the previous year may need supplemental steroid for “stressful” clinical procedures (extensive dental procedures, oral surgery).

Steroid supplementation is not normally required for routine dental procedures.

Management

Stress reducing protocols should be implemented which involve achieving good pain control intraoperatively and postoperatively

Blood pressure should be monitored during procedure and post-operatively (half-hourly for two hours post-operatively)

Management

Corticosteroid supplementation may be considered in :

patients currently on systemic corticosteroids

patients who were on systemic corticosteroids in the past 2 weeks to one month or who have been on it for more than one month in the past year where the amount of corticosteroids taken above is/was more than the equivalent of 7.5mg prednisolone daily

Corticosteroid cover regime

Treatment under LA (routine non-surgical dental treatment)

No supplementation required

Treatment under LA (minor Oral Surgery)

Double oral steroid dose* or give 25-50mg hydrocortisone hemisuccinate IV

Treatment under GA The target is for 50-100mg hydrocortisone hemisuccinate (within 1 hr of surgery) and 24-48 hrs post-operatively.Given as :Pre-op: 100mg hydrocortisone IV on inductionPost-op: 50mg hydrocortisone IV 8hrly

* oral dose to be taken within 2hrs of surgery

Adrenal Crisis

CLINICAL PRESENTATION Life-threatening emergency May be primary or secondary HYPOTENSION

Typically resistant to catecholamine and IV fluid resuscitation

THYROID DISORDERSHYPERTHYROIDISMHYPOTHYROIDISM

THYROID HORMONES

Metabolism in all body organs Stimulate the heart

heart rate stroke volume cardiac output blood flow

HYPERTHYROIDISM

INCREASED THYROID HORMONES: Hypermetabolism sympathetic nervous system activity Effects protein, lipid and carbohydrate

metabolism

EFFECTS ON PROTEIN METABOLISM

Protein synthesis and degradation More breakdown than buildup Leads to loss of protein Called negative nitrogen balance

EFFECTS ON GLUCOSE

Glucose tolerance decreased Leads to hyperglycemia

EFFECTS ON FAT METABOLISM

fat metabolism body fat appetite food intake; food intake does not meet

energy demands weight nutritional deficiencies with prolonged

disease

CAUSES OF HYPERTHYROIDISM

1. Graves disease2. TOXIC MULTINODULAR GOITER: multiple

thyroid nodules, milder disease3. EXOGENOUS HYPERTHYROIDISM:

excessive use of thyroid replacement hormones

4. THYROID STORM: untreated or poorly controlled hyperthyroidism; life threatening

WHO GETS IT

Most often women between 20-40 yrs

ASSESSMENT

Recent wgt loss Increased appetite Increase in # BM/day ****heat intolerance Diaphoresis even when temperatures

comfortable for others Palpitations/chest pain Dyspnea with or without exertion

ASSESSMENT

VISUAL PROBLEMS MAY BE EARLIEST PROBLEM:

Infiltrative Exophthalmopathy (abnormal eye appearance or function)

Blurring/double vision/tiring of eyes Increased tears Photophobia Eyelid retraction(eyelid lag) Globe lag (eyeball lag)

GOITER

Thyroid gland may be 4 X normal Bruits (turbulence from increased blood

flow) heard with stethoscope

CARDIAC PROBLEMS

systolic BP tachycardia dysrhythmia

FURTHER SYMPTOMS

Fine, soft, silky hair Smooth, moist skin Muscle weakness Hyperactive deep tendon reflexes Tremors of hands Restless, irritable, mood swings Decreased attention span Fatigued, inability to sleep

LABORATORY ASSESSMENT

IN HYPERTHYROIDISM: T3 T4 TSH in Graves disease Radioactive Thyroid Scan Ultrasonography: used to determine

goiter or nodules ECG: tachycardia

DRUG THERAPY

***antithyroid drugs: thioamides propylthiouracil (PTU) methimazole (Tapazole) carbimazole (Neo-Mercazole)

ACTION: blocks thyroid hormone production; takes time

control of cardiac manifestations (tachycardia, palpitations, diaphoresis, anxiety) until hormone production reduced: beta-adrenergic blocking drugs: propranolol (Inderal, Detensol)

DRUG THERAPY

Iodine preparations: Lugol’s Solution SSKI (saturated solution of potassium

iodide) Potassium iodide tablets, solution, and

syrupACTION:

decreases blood flow through the thyroid gland

This reduces the production and release of thyroid hormone

Takes about 2 wks for improvement Leads to hypothyroidism

DRUG THERAPY

Lithium Carbonate ACTION: inhibits thyroid hormone release NOT USED OFTEN BECAUSE OF SIDE

EFFECTS: depressions, diabetes insipidus, tremors

DRUG THERAPY

RADIOACTIVE IODINE THERAPY: Receives RAI in form of oral iodine Takes 6-8 Weeks for symptomatic relief Additional drug therapy used during this

type of treatment Not used on pregnant women

SURGICAL MANAGEMENT

Why use surgery? Used to remove large goiter causing

tracheal or esophageal compression Used for pts who do not have good

response to antithyroid drugsTWO TYPES OF SURGERIES: 1. Total thyroidectomy (must take lifelong

thyroid hormone replacement)2. Subtotal thyroidectomy

Dental management of hyperthyroid pt

The patient’s current clinical disease state, the degree of control and stability, the current medication and the presence of associated complications such as cardiac disease should be established and documented. If there is any suspicion that the disease is poorly controlled, defer dental treatment and consult the physician.

Dental management of hyperthyroid pt

Avoid any dental treatment for patients with thyrotoxicosis until the condition is stabilised

Routine dental treatment can be carried out for patients who have well-controlled disease (euthyroid) without concurrent medical problems

Aim for short, stress and pain free dental sessions.

Dental management of hyperthyroid pt

Minimise or avoid use of vasoconstrictors (especially those with uncontrolled or poorly controlled disease)

Some patients may have concurrent cardiac problems such as atrial fibrillation. These patients may be warfarinised and there may be risk for persistent bleeding. Consult physician

Carbimazole has been known to cause agranulocytosis. This may present with fever and abrupt onset of oropharyngeal ulcerations. Refer to physician

Dental management of hyperthyroid pt

A thyroid storm, an uncommon event in the dental outpatient setting, is an acute exacerbation of the hyperthyroid state

Known provoking factors include infection/sepsis, major surgical and GA procedures, pain/anxiety and abrupt discontinuation of anti-thyroid medication (and -blockers)

Clinical presentations are extreme irritability/nervousness, increase in body temperature and risk of developing life-threatening cardiac arrthymias. This is a medical emergency requiring expert attention.

Hypothyroidism- Causes

Cells damaged; no longer function Cells might be normal, person doesn’t

ingest enough iodide & tyrosine needed to make thyroid hormones

SYMPTOMS

Blood levels of thyroid hormones are low Decreased metabolic rate Hypothalamus and anterior pituitary

gland make stimulatory hormones (TSH) as compensation

Thyroid gland enlarges forming goiter

MYXEDEMA DEVELOPS

With low metabolism metabolites build up inside the cells which increases mucous and water leading to cellular edema

Edema changes client’s appearance Nonpitting edema appears everywhere

especially around the eyes, hands, feet, between shoulder blades

Tongue thickens, edema forms in larynx, voice husky

INCIDENCE OF HYPOTHYROIDISM

30-60 yrs of age Mostly women

ASSESSMENT

Increased sleeping (14-16 hours daily) Generalized weakness Anorexia Muscle aches Paresthesias Constipation Cold intolerance Decreased libido, woman:difficulty

becoming pregnant, changes in menses;men/impotence

ASSESSMENT

Coarse features Edema around eyes and face Blank expression Thick tongue Overall muscle movement is slow Lethargic, apathetic, drowsy, poor

attention span, poor memory

LABORATORY ASSESSMENT

T3 T4 TSH

TREATMENT

LIFELONG THYROID HORMONE REPLACEMENT

levothyroxine sodium (Synthroid, T4, Eltroxin)

IMPORTANT: start at low does, to avoid hypertension, heart failure and MI

Teach about S&S of hyperthyroidism with replacement therapy

Dental management of hypothyroid pt

Stable, well controlled hypothyroid pts do not need any special precautions for routine dental treatment under LA

Avoid routine prescribing of CNS depressants in severe untreated hypothyroidism for example, benzodiazepines and narcotic analgesics as they may result in over-reactions like CNS, CVS and respiratory overdepression. Judicious use in euthyroid individuals should not be a major problem

Myxedema coma (hypothermia, bradycardia, hypotension) can be precipitated by infections, surgery, GA and drugs mentioned above

MYEXEDEMA COMA

Rare serious complication of untreated hypothyroidism

Decreased metabolism causes the heart muscle to become flabby

Leads to decreased cardiac output Leads to decreased perfusion to brain

and other vital organs Leads to tissue and organ failure LIFE THREATENING EMERGENCY WITH

HIGH MORTALITY RATE

PROBLEMS SEEN WITH MYXEDEMA COMA

Coma Respiratory failure Hypotension Hyponatremia Hypothermia hypoglycemia

G6PD deficiency

WHAT IS IT?

• An inherited condition in which patients are excessively susceptible to the development of hemolytic anemia.  It is the most common enzymatic disorder of RBCs in humans.

•  • Affected individuals lack the ability to tolerate

biochemical oxidative stress, and red cell hemolysis is the most important clinical consequence.

• First noted in African-American soldiers who developed acute hemolytic anemia with hemoglobinuria following primaquine ingestion.

WHO WORKING GROUPS

• Class I: severely deficient, associated with chronic nonspherocytic hemolytic anemia

• Class II: severely deficient (1%-10% residual activity), associated with acute intermittent hemolytic anemia (G6PD Mediterranean)

• Class III: moderately deficient (10%-60% residual activity) - intermittent hemolysis usu assoc with infection or drugs (G6PD A)

• Class IV: normal activity (60%-150%)

• Class V: increased activity (>150%)

WHO GETS IT?

An X-linked disorder that therefore typically affects men.

Over 400 million people worldwide affected with highest prevalence in individuals of African, Mediterranean and Asian heritage. Since this is an X-linked gene, prevalence among females is higher but they are generally asymptomatic.

**Confers anti-malarial protection - unknown mechanism

How does it present?

Usually asymptomatic but can also vary from episodic anemia to chronic hemolysis.  The presentation depends on the biochemistry of the variant.  There are over 500 different mutations identified thus far.

acute hemolytic anemia congenital nonsperocytic hemolytic anemia neonatal hyperbilirubinemia favism

Acute hemolytic anemia

Asymptomatic at steady state without anemia or abnormal morphology.

Sudden destruction of deficient erythrocytes 2-4 days after offending "event" leads to jaundice, pallor, dark urine, +/- back pain.  Abrupt drop in H/H to <4 g/dL and PBS with microspherocytes, cell fragments or bite cells.  Sequestration of damaged red cells in liver and spleen.

Increase in reticulocytes within 5 days, maximal at 7-10 days with reversal of anemia even without removal of offending drug.

In G6PD Mediterranean, hemolysis more severe and can continue even after drug d/c'd.

HOW DOES IT WORK?

• G6PD is required by all cells to protect from damage by oxidation. It catalyses the first step in the HMP pathway (glucose-6-P oxidized to 6-phosphogluconate) which is linked to the reduction of NADP to NADPH, which is used to generate reduced glutathione. 

•  • For the red cell, this is the sole source of

protection against oxidant damage in the form of free radicals generated by the conversion of oxy- to deoxyhemoglobin and by peroxides generated by phagocytosing granulocytes. 

•  

cont'd

Normal red cells generate NADPH in response to oxidant stress; this capacity is impaired in patients with G6PD deficiency. Failure to withstand oxidant stress damage to sulphydryl groups in hemoglobin and the red cell membrane causes hemolysis.  Cells in other tissues and organs have alternate pathways for the generation of NADPH and can withstand such oxidant stress. But not so in the simple RBC. 

The activity of all red cell enzymes, including G6PD, is highest in young red cells (reticulocytes), and progressively declines as the cell ages.

PRECIPITANTS

• Infections (salmonella, E.coli, beta-hemolytic strep, rickettsiae, viral hepatitis)

 • Medications (next slide)

• Metabolic abnormalities (DKA) 

Pharmacological Class

Drugs

Analgesics Aspirin (acetylsalicyclic acid)Phenacetin (acetophenetidin)

Antibiotics Quinolones:ciprofloxacin,moxifloxacin, norfloxacin, ofloxacin, nalidixic acid)Sulphonamides and Sulfones:co-trimoxazole (Bactrim)sulphapyridine, sulphadimidine, sulphacetamide, sulphanilamide, sulphoxone, sulphafurazonedapsone.Others:nalidixic acidnitrofurans chloramphenicolp-aminosalicylic acid

Antimalarials chloroquine, primaquine, pamaquine

Cardiovascular procainamide, quinidine

Miscellaneous vitamin Cvitamin K analoguesmethylene bluetoluidine blueprobenecidnaphthalene (mothballs)