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Year 2 - Semester 2 > Endocrinology - Week 4 > Flashcards

Endocrinology - Week 4 Flashcards

1
Q

what contributes to calories in

A

food and absorption

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2
Q

what contributes to calories out

A

basal metabolic rate, thermogenesis, non purposeful activity, exercise

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3
Q

heritability of obesity

A

40-70%

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4
Q

what are the efferents of the hypothalamus

A 
pituitary which goes on to:
gonads - sex steroids
adrenal cortex - cortisol
thyroid - thyroxine
growth hormone

autonomic NS
parasympathetic - insulin
sympathetic - adrenaline

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5
Q

what are afferents of the hypothalamus

A
  • Conscious control
  • Fatty acids, glucose, hormones
  • Leptin
  • Ghrelin
  • Insulin
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6
Q

when is leptin treatment for obesity effective

A

• Ineffective when leptin is high
o Idiopathic obesity

• Effective when [leptin] is low
o Leptin deficiency (rare)
o Anorexia nervosa
o Lipodystrophy

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7
Q

what are the actions of leptin

A 
•	Satiety
•	Hypothalamic-pituitary-gonadal axis
o	Puberty
o	Fertility
•	Hypothalamic-pituitary-adrenal axis
•	Hypothalamic-pituitary-thyroid axis

• Peripheral actions??
o Adipocytes, pancreatic islets, immune cells, …

PROBABLY MOST IMPORTANT IN LOW ENERGY STATES
AS SURVIVAL SIGNAL

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8
Q

what are some causes of secondary obesity

A
  • Hypothyroidism
  • Cushing’s syndrome - usually iatrogenic
  • Hypothalamic disease
•	Others 
o	Drugs (oestrogen, beta blockers, tricyclic antidepressants, sodium valproate) 
o	Insulinoma, GH deficiency 
o	Genetic Disorders: e.g. Prader Willi syndrome, Bardet Biedl syndrome, leptin or leptin receptor deficiency, melanocortin 4 receptor defect, POMC deficiency
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9
Q

spotting endocrine disorders in obesity History

A

• Always obese/age of onset?
o Periods regular/ headache/ thirst, polyuria?
o Diet, eating pattern, alcohol, exercise?
o Drugs?
o Complications and effects on lifestyle

• Examination:
o Features of Cushing’s, hypothyroidism, hypothalamic disease, syndromes
o BP

• Investigations:
o TFTs › Blood glucose
o ?o/n dex suppression test

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10
Q

why is obesity bad for you

A
  • Breathlessness, Sleep apnoea
  • Cancers (breast, endometrium, ovary, colon, gallbladder)
  • Gallstones, NAFLD
  • Incontinence
  • Varicose veins
  • Arthritis
  • Social & Psychological
  • Heart attack
  • Hypertension
  • Diabetes mellitus
  • Infertility & hirsutis
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11
Q

describe fat distribution

A

Fat distribution – Apples and Pears
Central Visceral Android ‘Apple’ HIGH RISK
Peripheral Subcutaneous Gynoid ‘Pear’ LOW RISK

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12
Q

what is important about visceral fat

A
  • different metabolism or secretion

* releases direct to liver

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13
Q

what is lawrence syndrome

A

“Lipoatrophic” Diabetes

•	Generic IR complications 
o	Acanthosis nigricans 
o	Hyperandrogenism 
o	Female subfertility 
o	Precocious puberty 
o	Diabetes mellitus 
o	Soft tissue overgrowth
•	Lipotoxic complications 
o	Severe dyslipidaemia 
o	NAFLD, cirrhosis, HCC 
o	Premature atherosclerosis 
o	Diabetes mellitus
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14
Q

describe adipokines

A
  • Secreted from adipocytes or macrophages in adipose tissue
  • Manipulations in mice demonstrate potent effects on insulin sensitivity in other tissues
  • Correlated with increased insulin sensitivity in other tissues in humans
  • Many candidates published – variable importance in subsequent studies
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15
Q

what are the endocrine consequences of obesity

A

• Altered steroid metabolism in adipose tissue:
o Increased oestrone and oestradiol
 Hirsutism and infertility
 Hormone-sensitive cancers
o increased reactivation of cortisol from cortisone

•	Altered substrate flux and adipose inflammation 
o	Insulin resistance 
	Hyperglycaemia 
	Dyslipidaemia, Fatty Liver 
	Subfertility

• Altered hypothalamic function
o Anovulatory menstrual cycles
 Subfertility

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16
Q

describe diabetes and its epidemiology

A
  • Affects 5% of total population
  • Affects 10% of people over 65
  • Around 3.2 million people are known to have diabetes
  • Many people have undiagnosed diabetes
  • About 25% require insulin therapy

Diabetes mellitus is a condition associated with an elevated blood glucose. This is a consequence of deficiency of INSULIN, or of its reduced action, or of a combination of both.

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17
Q

describe insulin

A
  • Hormone secreted in pancreas (islets)
  • Anabolic hormone
  • Essential for fuel storage and cell growth
  • Promotes uptake of glucose into cells for energy
  • Prevents breakdown of fat and protein
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18
Q

describe pancreatic cells

A

Alpha cell Glucagon 11%
Beta cell Insulin 85%
Delta cell Somatostatin 3%
F cell Pancreatic polypeptide 1%

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19
Q

describe the structure of insulin

A

Insulin has an alpha and beta subunit which are linked by disulphide bonds and C-peptide. This is proinsulin. Prior to release by cells, C-peptide is cleaved away to leave insulin and free C-peptide. This is done by b-cell peptidases.

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20
Q

how is Insulin Secretion from Beta Cells is Directly Coupled to Glucose Influx

A

Beta cells have GLUT 2 transporters which are insulin independent and let in glucose purely based on extracellular glucose concentration. This glucose is metabolised by the cell to give ATP. This ATP will inhibit K channels which then don’t pump K out of the cells. This leads to depolarisation of the membrane which in turn leads to voltage gated Ca channels to open and let Ca into the cell. Ca causes exocytosis of insulin granules into the bloodstream.

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21
Q

describe insulin release

A
  • Pro-insulin is converted to insulin and C-peptide in equimolar amounts
  • In response to ingestion of food, stored insulin is released first, followed by newly synthesised insulin
  • This gives a biphasic response of insulin secretion
  • C-peptide can be used as a measure of endogenous insulin secretion in people with diabetes
INSULIN from pancreas:
•	 Secreted into portal vein
•	 Acts first on LIVER
•	Passes through liver into systemic circulation
•	Acts on MUSCLE and FAT
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22
Q

what are the Principal Actions of Insulin

A 
↑ Glucose uptake in FAT and MUSCLE
↑ Glycogen storage in LIVER and MUSCLE
↑ Amino Acid uptake in MUSCLE
↑ Protein Synthesis
↑ Cell proliferation
↑ Lipogenesis in ADIPOSE TISSUE

↓Apoptosis
↓ Gluconeogenesis from 3-Carbon precursors
↓Ketogenesis (in LIVER)

Insulin Causes Translocation of GLUT 4 to Cell Membranes. This allows insulin-dependent glucose uptake into cells

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23
Q

what is the difference between insulin and glucagon

A

Insulin favours glycogenesis and inhibition of gluconeogenesis

Glucagon favours glycogenolysis and gluconeogenesis

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24
Q

what are some 3-carbon precursors

A

 Alanine (from ingested protein)
 Pyruvate (from muscle protein)
 Lactate (from muscle glycogen)
 Glycerol (from fat)

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25
Q

what are the 4 ways of being diagnosed with diabetes

A
  • Fasting plasma glucose > 7.0 mmol/l
  • 2hr plasma glucose in OGTT > 11.1 mmol/l
  • Random plasma glucose > 11.1 mmol/l
  • HbA1c > 48 mmol/mol
  • If the patient is asymptomatic, the same test should be repeated to confirm the diagnosis of diabetes
  • Do not delay urgent care waiting for a second test
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26
Q

describe Glycated Haemoglobin (HbA1c)

A

• Rate of formation of glycated haemoglobin is directly proportional to ambient blood glucose concentration
• Reflects integrated blood glucose (BG) concentrations during lifespan of erythrocyte (120 days)
• Blood sample can be taken at any time of day, irrespective of food consumption
Normal ≤41 mmol/mol
Pre-diabetes 42-47 mmol/mol
Diabetes ≥ 48mmol/mol

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27
Q

Situations where HbA1c should NOT be used as a Diagnostic Test

A

• Rapid onset of diabetes
– Suspected Type 1 Diabetes
– Children
– Drugs – steroids; antipsychotics

• Pregnancy
– Glucose levels can rise rapidly
– HbA1c is lower

•	Conditions where red cell survival may be reduced
–	Haemoglobinopathy
–	Haemolytic anaemia
–	Severe blood loss
–	Splenomegaly
–	Antiretroviral drugs

• Increased red cell survival
– Splenectomy

• Renal dialysis
– Reduced HbA1c, especially if treated with erythropoietin

• Iron and vitamin B12 deficiency
– Small effects on HbA1c

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28
Q

what is the glucose tolerance test

A
  • Used to assess state of glucose tolerance
  • 75g oral glucose load
  • No restriction or modification of carbohydrate intake for preceding three days
  • Fast overnight
  • Test is performed in morning – seated; no smoking
  • Blood samples for plasma glucose taken at 0hrs and 2 hrs
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29
Q

describe impaired glucose tolerance

A

Fasting plasma glucose: <7.0 mmol/l
2 hours after 75g oral glucose load: 7.8-11.0 mmol/l
• Affects 20% of population aged 40-65 years (UK)
• Increased mortality from cardiovascular disease (doubled)
• Natural history - 15% develop diabetes in 5 years, 15% return to normal
• Check fasting plasma glucose annually

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30
Q

what is impaired fasting glucose

A

(Fasting Hyperglycaemia)
Fasting plasma glucose: 6.0 – 6.9 mmol/l
• Intermediate state between normal glucose metabolism and diabetes
• Impaired glucose tolerance often present also (but not always)
• Found in 5% of population and prevalence increases with age
• Increased risk of vascular complications

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31
Q

what classes as a prediabetic state

A
  • Fasting blood glucose 6.0-6.9 mmol/l
  • 2 hr OGTT blood glucose 7.8-11.0 mmol/l
  • HbA1c 42-47 mmol/mol
  • Fasting hyperglycaemia and Impaired Glucose Tolerance often co-exist
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32
Q

what are risk factors for type 2

A 
•	Genetics
–	Race
•	Increasing age
•	Central obesity
•	Low birth weight
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33
Q

what is the extent of genetic risk for type 2

A

2x for one parent
5x for two parents
37x for two siblings

  • Genome-wide association studies have identified >400 gene variants associated with an increased risk of Type 2 diabetes
  • Most relate to beta cell function or mass, rather than obesity/insulin resistance
  • 40% of the overall risk of Type 2 diabetes is determined by genetic factors
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34
Q

what is type 2 diabetes

A

Type II diabetes is a combination of insulin resistance and beta cell dysfunction

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35
Q

why does diabetes incidence increase with age

A
  • Beta cell function reduces with age

* Obesity increases with age

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36
Q

what is the classical presentation of type 2

A
  • Asymptomatic – found on routine screening
  • Thirst, polyuria (osmotic symptoms)
  • Malaise, chronic fatigue
  • Infections, e.g. thrush (candidiasis); boils
  • Blurred vision
  • Complication as presenting problem (e.g. retinopathy, neuropathy)
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37
Q

describe metabolic syndrome

A 
linked to diabetes - very high cardiovascular disease risk
•	Central obesity
•	High BP
•	Fairly high triglycerides
•	Low HDL-cholesterol
•	Insulin resistance
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38
Q

what other disorders are linked to type 2

A
  • Obstructive Sleep Apnoea
  • Polycystic Ovarian Disease
  • Hypogonadotrophic Hypogonadism in men
  • Non-Alcoholic Fatty Liver Disease
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39
Q

what is the classical presentation of type 1

A
  • Polyuria, thirst
  • Fatigue, malaise
  • Weight loss
  • Blurred vision
  • Nausea, vomiting
  • Usual presentation is in childhood, adolescence or young adulthood
  • Can present at any age
  • Short history (weeks) of florid osmotic symptoms and rapid weight loss; Ketonuria/ketonaemia is usually present
  • High risk of metabolic decompensation – ketoacidosis
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40
Q

what is the pathogenesis of type 1

A
  • Genetic predisposition – HLA haplotypes (HLA-DR and HLA-DQ) as risk alleles
  • Environmental trigger
  • ? viral infection
  • ? chemical toxin
  • Autoimmune mechanism activated – can detect antibodies in blood to GAD, IA2 and/or ZnT8
  • Destruction of pancreatic beta cells - once 80% are destroyed you start having symptoms of hypoglycaemia

Much more likely to get type I diabetes in northern areas than southern Europe for example theory that certain viruses which trigger it live better in northern climates

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41
Q

what is the genetic risk of type 1

A

Relative with Type 1 diabetes Relative Risk

Father 9
Mother 3
Both parents 30

Non-HLA-identical Sibling 3
HLA-identical Sibling 16
Non-identical twin 20
Identical twin 35

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42
Q

what Autoimmune Disorders are Associated with Diabetes

A
  • Thyroid disease
  • Pernicious anaemia
  • Coeliac disease
  • Addison’s disease
  • Vitiligo
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43
Q

what effects on daily life does type 1 have

A 
•	Hypoglycaemia
–	Driving
–	Employment
•	Risks of Diabetic Ketoacidosis
•	Pregnancy
•	Childhood and adolescence
•	Complications
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44
Q

what are the causes of secondary diabetes

A

• Exocrine Pancreas Disorders
o Pancreatectomy
o Trauma
o Tumours

• Endocrinopathies
o Acromegaly
o Cushing’s
o Pheochromocytoma

• Drugs
o Steroid treatment
 Can often tip someone over the edge if they are susceptible to diabetes type II

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45
Q

describe monogenic diabetes

A
  • Big function altering mutations which lead to diabetes
  • Early-onset diabetes
  • Not insulin-dependent diabetes
  • Autosomal dominant inheritance
  • Obesity unusual
  • Caused by a single gene defect altering beta-cell function
  • 1-2% of ‘Type 2’ diabetes
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46
Q

what is home glucose monitoring

A

• Demonstrates glucose control throughout day (and night)
• Identifies hypoglycaemia (especially when asymptomatic)
• Provides information to adjust insulin dose
• Allows manipulation of insulin dose during
- intercurrent illness
- travel, sport, other activities
• Assists self-control of diabetes – improves glycaemic control

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47
Q

what is CGMS – Continuous Glucose Monitoring System

A
  • Wireless sensor and monitor communication
  • Hypo and hyperglycaemia alarms
  • “real time” glucose values

Freestyle Libre Flash Glucose Monitoring System

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48
Q

describe HbA1c as a monitoring tool

A

• Checked at the time of a visit to a diabetes clinic or GP surgery
• Allows evaluation of :
- efficacy of therapeutic regimen
- patient’s adherence to treatment
- risk of developing diabetic complications
• Enhances clinical decision-making if available at time of clinical consultation

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49
Q

what type of monitoring should type 1 do

A

HBGM - yes
CGMS/Libre - yes
HbA1c - yes
blood ketones - yes

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50
Q

what type of monitoring should type 2 insulin do

A

HBGM - yes
CGMS/Libre - no
HbA1c - yes
blood ketones - no

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51
Q

what type of monitoring should type 2 sulphonyurea do

A

HBGM - ?
CGMS/Libre - no
HbA1c - yes
blood ketones - no

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52
Q

what type of monitoring should other treatments do

A

HBGM - ?
CGMS/Libre - no
HbA1c - yes
blood ketones - no

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53
Q

what type of monitoring should gestational diabetes do

A

HBGM - yes
CGMS/Libre - no
HbA1c - no
blood ketones - no

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54
Q

what are the aims of Dietary Management in Diabetes

A
  • To achieve good glycaemic control
  • To reduce hyperglycaemia and avoid hypoglycaemia
  • To ensure adequate nutritional intake
  • To assist with weight management
  • To avoid aggravating diabetic complications

Reduce/eliminate refined carbohydrates and saturated fat
Restrict TOTAL caloric intake (portion size)
In order to
Increase insulin sensitivity
Lower blood glucose
Lower triglycerides/ LDL-cholesterol

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55
Q

what is a “healthy” diet in diabetes

A

 CARBOHYDRATE: 45-60% (unrefined, complex)
 FAT: <35% (monounsaturated 10-20%)
 PROTEIN: 10-15% (do not exceed 1g/kg body wt)
 High intake of dietary fibre (fruit, vegetables); low intake of salt

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56
Q

what is the dietary treatment in type 1 diabetes

A
  • At diagnosis insulin should be started immediately!
  • Dietary modification requires restriction of refined sugars and saturated fats
  • Diet is weight-maintaining for most people
  • Insulin dosage adjustment is based on carbohydrate content of meals
  • Structured education programmes are available, e.g. DAFNE (Dose Adjustment For Normal Eating)
  • Other lifestyle changes (regular exercise) are supplementary
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57
Q

describe indications and contraindications of oral hypoglycaemic drugs

A
  • Indications: Type 2 diabetes (if diet alone inadequate)
  • Insulin sensitisers in combination with insulin in Type 1 diabetes

• Contraindications:
o Ketoacidosis
o Severe intercurrent illness

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58
Q

describe sulphonyureas

A

(e.g. glipizide, gliclazide)
• stimulate secretion of endogenous insulin in beta cells
• used in non-obese patients (may be insulin-deficient)
• used as monotherapy or in combination with metformin, glitazone or insulin
• choice of sulfonylurea is based on duration of action and method of elimination
• promote weight gain
• main adverse effect is hypoglycaemia

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59
Q

describe biguanide

A

(metformin)
• decreases hepatic glucose production
• increases insulin sensitivity in muscle
• encourages weight loss
• effective as monotherapy or in combination with sulfonylurea, glitazone or insulin
• side-effects include nausea and diarrhoea
• contraindicated in renal impairment (risk of lactic acidosis)

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60
Q

describe glucose prandial regulators

A

(Glinides)
• Repaglinide (MEGLITINIDE)
• Nateglinide (AMINO ACID DERIVATIVE)
• Insulin secretagogues – direct effect on beta cells
• Stimulate rapid endogenous insulin release when given with meals
• Side-effects include weight gain and hypoglycaemia
• Lower risk of hypoglycaemia than sulfonylureas

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61
Q

describe alpha glucosidase inhibitors

A

(e.g. Acarbose; Miglitol)
• Delay digestion of carbohydrate and slow down postprandial absorption of glucose
• Do not cause weight gain
• Limited efficacy; can be used in combination
• Gastrointestinal side-effects are common, including bloating and flatulence

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62
Q

describe PPAR gamma activation in fat

A

Reduces Insulin Resistance in Liver and Muscle
Small insulin sensitive adipocytes
Lipolysis reduced

lowers plasma Free fatty acids
Adiponectin production raised
 reduces glucose output and increases glucose uptake
 Normoglycaemia

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63
Q

describe thiazolidinediones

A

(e.g. Pioglitazone) PPAR gamma agonist
• Slow onset of action - take 2-3 months to achieve maximal effect
• Promote weight gain - but redistribute body fat to reduce visceral depot
• Contraindicated in congestive cardiac failure; hepatic impairment May cause fractures

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64
Q

what is the incretin effect

A

Secretion of insulin is greater in response to oral glucose

Promoted by release of GI hormones “incretins”

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65
Q

describe glucagon-like peptide 1 (GLP-1)

A
  • Potent insulinotropic hormone (incretin) is released in response to meals
  • Rapidly degraded in plasma by enzyme Dipeptidyl Peptidase 4 (DPP- 4)
  • Plasma GLP-1 is lower in people with impaired glucose tolerance (IGT) and type 2 diabetes compared to healthy non-diabetic subjects
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66
Q

what are the GLP-1 physiological effects

A

• Upon ingestion of food…
• GLP-1 is secreted from the L-cells in the intestine
o Stimulates glucose-dependent insulin secretion
o Suppresses glucagon secretion
o Slows gastric emptying
o Reduces food intake
o Improves insulin sensitivity

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67
Q

what are the therapeutic forms of GLP-1

A

Incretin mimetic, synthetic exendin-4 (Exenatide)
GLP-1 analogue (Liraglutide)
DPP- 4 inhibitors (Gliptins)
EXENATIDE: synthetic form of Exendin-4. This was isolated from the salivary secretions of the lizard Heloderma suspectum
(Gila monster), and found to circulate as a meal-related peptide, with GLP-1 actions.

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68
Q

what are incretin mimetics

A

(e.g. Exenatide, Liraglutide
• Act like a GLP-1 peptide
• Have to be given by injection
• Promote weight loss
• Given in combination with either metformin or sulfonylurea
• Main side-effect is nausea
• Hypoglycaemia rare except when given with SU

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69
Q

what are gliptins

A

(e.g. sitagliptin; vildagliptin)
• DPP-4 inhibitors – inhibit degradation of incretin hormones and enhance their actions
• Oral route of administration
• Taken in combination with metformin
• Produce modest reduction in HbA1c
• Weight neutral
• Few side-effects, with minimal hypoglycaemia

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70
Q

what are Sodium-glucose Cotransporter-2 (SGLT2) Inhibitors

A

A class of FDA-approved drugs to lower blood sugar in type 2 diabetes. SGLT2 inhibitors include canagliflozin, dapagliflozin, and empagliflozin.

Empaglifozin acts as a glucuretic to remove glucose that would otherwise be reabsorbed

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71
Q

which drugs augment supply of insulin from pancreatic beta cells

A

sulphonyureas
prandial glucose regulators (glinides)
incretin mimetics

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72
Q

which drugs enhance insulin action and reduce resistance

A

metformin and thiazolidinediones

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73
Q

what drugs delay carbohydrate absorption

A

alpha glucosidase inhibitors

incretin mimetics

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74
Q

what are the indications for insulin therapy

A
  • Persistently elevated blood glucose and HbA1c on maximum doses of anti-diabetic drugs
  • Symptoms of hyperglycaemia and/or infections (e.g. candidiasis)
  • Non-fasting ketonuria
  • TYPE 1 DIABETES (ketosis-prone)
  • TYPE 2 DIABETES
  • Secondary failure to anti-diabetes drugs
  • Severe intercurrent illness
  • Metabolic complications (hyperosmolar states)
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75
Q

what is the problem with insulin therapy

A
  • Insulin has to be given by injection
  • Biological action is variable as insulin absorption is influenced by many factors (site of injection, ambient temperature, exercise, etc.)
  • Insulin has to be given several times daily
  • Insulin regimens are often complicated
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76
Q

what are the Types and Formulations of Insulin

A

• Short-acting Soluble
(Actrapid; Humulin-S)

• Intermediate-acting Isophane (NPH)
(Insulatard; Humulin-I)

Fixed mixtures are available containing combinations of soluble and isophane insulins e.g. 30% soluble with 70% isophane (Humulin M3)

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77
Q

what are insulin analogues

A

 Substitution of single amino acid in insulin chain
 Alters absorption characteristics of insulin

Time-action profile is modified by minor changes in amino acid sequence of insulin molecule

Fast-acting:		insulin lispro  (Humalog)
				insulin aspart  (Novorapid)
                                           insulin glulisine  (Apidra)
Long-acting:	            insulin glargine   (Lantus)
				insulin detemir    (Levemir)

Fixed mixtures include Humalog Mix 25 (25% fast-acting) and Novomix 30 (30% fast-acting)

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78
Q

what is the time-action characteristics of soluble insulin

A

onset of action - 30 mins

peak effect - 1-2 hours

duration of action - 7 hours

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79
Q

what is the time-action characteristics of fast acting analogue

A

onset of action - 5-10 mins

peak effect - 30-60 mins

duration of action - 3 hours

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80
Q

what is the time-action characteristics of isophane

A

onset of action - 3 hours

peak effect - 7 hours

duration of action - 12-14 hours

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81
Q

what is the time-action characteristics of long-acting analogue

A

onset of action - 1 hour

peak effect - none

duration of action - 19-32 hours

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82
Q

what does the choice between insulin regimens depend on

A
  • Targets for glycaemic control
  • Time-action profile of insulins
  • Ease and convenience of administration
  • Flexibility of regimen
  • Practical issues (e.g. disability, supply, species preference)
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83
Q

what insulin regimens are there

A

BASAL-BOLUS (Multiple injection): Short-acting or fast-acting insulin before meals; intermediate-acting or long-acting insulin once daily

TWICE DAILY: Soluble or fast-acting and isophane (NPH) insulins combined; free-mixing or fixed mixture

ONCE DAILY: Intermediate-acting or long-acting insulin, combined with anti-diabetic drugs (Type 2 diabetes)

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84
Q

what are the routes of adminitration for insulin

A
  • SUBCUTANEOUS - syringes, pens, pumps
  • intrapulmonary - inhaler (historical)
  • intravenous, intramuscular - injection (emergency use)
  • intraperitoneal - dialysate (renal failure)
  • transplanted islets - pancreatic islets
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85
Q

describe lipohypertrophy at insulin injection site

A
  • unsightly
  • slows insulin absorption
  • resolves if site avoided
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86
Q

what are the side effects of insulin therapy

A
  • HYPOGLYCAEMIA
  • WEIGHT GAIN
  • lipodystrophy at injection sites
  • peripheral oedema (salt & water retention)
  • insulin antibody formation (animal insulins)
  • local allergy (rare)
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87
Q

what are the signs and symptoms of hypoglycaemia

A
  • Palpitations
  • Trembling
  • Dizziness
  • Hunger
  • Sweating
  • Blurred vision
88
Q

what are the causes of Insulin-Induced Hypoglycaemia

A
  • Administration of too much insulin
  • Inadequate consumption of food
  • Increased physical exercise
  • Alcohol (without food)
89
Q

what are the Risk Factors for Severe Hypoglycaemia in Type 1 Diabetes

A
  • Duration of diabetes; Age ; Gender
  • Impaired awareness of hypoglycaemia
  • History of previous severe hypoglycaemia
  • Strict glycaemic control
  • Sleep
90
Q

what is the treatment for hypoglycaemia

A 
MILD   (self-treated)
		Oral fast-acting carbohydrate (10-15g)
			- glucose drink
			- glucose tablets, confectionery
		Oral supplementary snack (starch)
SEVERE   (external help required)
		Parenteral therapy
			- i.v. 20% dextrose (25-50g)
			- i.m. glucagon (1mg)
		Oral therapy
			- buccal glucose gel; jam, honey
91
Q

what are the morbidities for hypoglycaemia

A

CNS Coma; convulsions
Vascular events – stroke, transient

ischaemia
				Cognitive impairment (young children)
                                    Brain damage (rare)

CARDIAC Arrhythmias
Myocardial ischaemia/infarct

OTHER Accidents (including driving); Injuries

ACQUIRED SYNDROMES
Impaired awareness of hypoglycaemia
Counterregulatory hormonal deficiencies

92
Q

what are the microvascular complications of diabetes

A
  • nephropathy
  • peripheral neuropathy
  • retinopathy

erectile dysfunction also

93
Q

what are the macrovascular complications of diabetes

A
  • Ischaemic heart disease
  • Peripheral vascular disease
  • Cerebrovascular disease
94
Q

how do we stop progression?

A 
•	Good glycaemic control
-	HbA1c
-	Blood glucose monitoring
•	BP control
•	<140/90 with no microvascular disease (clinic)
•	<135/85 with target organ damage
95
Q

how do we screen for complications?

A

• Retinopathy screening

  • At least 2 yearly eyes
  • PAEP in some cases for higher risk
  • Urinary ACR annually
  • Annual foot examination
96
Q

describe hypoglycaemia

A
  • Inevitable that you will have a hypo at some point
  • Commonest diabetic emergency
  • Most episodes treated at home
  • Average person with Type 1 DM will experience 1000s of episodes of mild hypoglycaemia
  • 1-2 episodes of severe hypoglycaemia every year
  • Severe = need for external assistance
97
Q

what are the common causes of hypoglycaemia

A 
•	Patient error- 
–	too much insulin
–	too little carbohydrate
–	Missed/late meal
–	Exercise
•	Alcohol
•	(Same applies for patients on sulphonylureas eg gliclazide, glipizide)
98
Q

how do sulphonyureas work

A

encourage beta cells to produce more insulin by closing K-ATPase channel

99
Q

what are some less common causes of hypoglycaemia

A
  • Decreased insulin requirements e.g. weight loss
  • Liver disease, alcohol
•	Conditions associated with T1DM
–	Coeliac disease
–	Addison’s disease (cortisol important in counterregulation)
–	Hypothyroidism
–	(Hypopituitarism)
100
Q

what are some complications of diabetes

A

– Autonomic neuropathy
– Injection sites/lipohypertrophy
– Renal failure
– Counterregulatory failure

101
Q

what is the counteregulation for hypoglycaemia

A

• Glucagon
o Produced by alpha cells
o Should bring blood sugar up
• Epinephrine
• Cortisol (protective during prolonged hyperglycaemia)
• GH (protective during prolonged hyperglycaemia)

102
Q

what are the symptoms of hypoglycaemia

A 
autonomic 
sweating 
shaking
palpitations
hunger
neuroglycopenic 
confusion
drowsiness
difficulty speaking
odd behaviour
incoordination

non specific
nausea
headache

these are most common in young adults
children will often show behavioural change
elderly can have neurological symptoms

103
Q

what is important to remember about hypo symptoms

A

Symptoms can change due to changes in counterregulatory hormones – losing the ability to produce them in response to hypoglycaemia
When young. People might have symptoms of epinephrine release such as sweating and tremor before neurological symptoms, but as they get older and this response becomes deficient, they may be neurologically impaired before they get these symptoms

104
Q

what is the diagnosis of hypoglycaemia

A

• Whipple’s triad: 2 out of 3 of-
– Typical symptoms
– Biochemical confirmation (no agreed cut-off)
– Symptoms resolve with carbohydrate

• Remember ‘atypical’ presentations esp in elderly
– Hemiparesis
• In theory, confirm with laboratory blood glucose – but don’t delay treatment

105
Q

what is the management for hypoglycaemia

A
  • If alert, give sweet drink or dextrose tablet
  • If not alert give 20% dextrose iv (or Hypostop, Polycal)
  • If can’t get iv access, give 1mg im glucagon plus sweet drink (not effective in alcoholic hypo)
  • Follow-up rapid acting carbs with slow release carbs
  • 10% glucose infusion if long-acting insulin or SU.
  • If recovery not rapid, consider other cause.
  • Full cognitive recovery can lag by 45 mins (driving)
106
Q

what is the aftercare for hypoglycaemia

A

• Follow-up glucagon/dextrose with a starchy snack
• Patients presenting to hospital with hypo are
– Older
– Live alone
– Co-morbidity
– Sulfonylurea therapy
• Discharge if make full recovery and responsible adult at home – but not if sulfonylurea-induced
• Inform the diabetes team
• Close monitoring of blood glucose for next 72 hours
• Was there an obvious remedial cause?
• If not, cut right back on insulin doses

107
Q

describe the issues with driving

A

• DVLA issues advice letter to drivers on hyopglycaemia
• Drivers with insulin-treated diabetes should:
– Carry glc meter and rescue carbohydrate
– Check glc before driving (even short journeys)
– Test every 2h on long journeys. Regular snacks advised
– If glc is ≤ 5mmol/l, take a snack
– If glc ≤4mmol/l, do not drive
– Carry ID saying you have diabetes in case of accident
• If you have a hypo while driving
– Stop vehicle as soon as safe
– Switch off engine and remove keys from ignition
– Get out of driver’s seat
– Wait 45 mins after blood glc normal before driving
• Group 1 entitlement: car or motorcycle
• Extra standards for taxi drivers rest with local authority
• Group 2 entitlement: LGV or PCV. Stricter rules

108
Q

describe hyperglycaemia

A
  • Hyperglycaemic emergencies
  • Diabetic ketoacidosis develops in type 1 DM (or longstanding type 2 with insulin deficiency)
  • In type 2 diabetes, it is more usual to develop a hyperosmolar hyperglycaemic state

When you cannot use insulin in type I diabetes, you have hyperglycaemia but the cells cannot use it so have to produce ketones which are acidic and causes acidaemia. This causes osmotic diuresis and therefore hypovolaemia
Also muscle proteinolysis which just produces more glucose which we cant use and is excreted in the urine causing more water to be lost along with it
With a little bit of insulin, you don’t produce ketones but you do break down protein

109
Q

what are the principles of management of DKA

A

– Fluids: initially fast then slower, to rehydrate
– iv insulin: switch off ketone body production
– Monitor potassium: metabolic acidosis shifts K+ to extracellular space. As you give insulin, K+ moves into the cells and K+ falls
– Protocol driven
– Seek the precipitant. Commonly infection and errors/omissions
– Often no cause found.
– In 10% cases, DKA is first presentation of T1DM
– Try to prevent recurrence

110
Q

how do you diagnose DKA

A 
•	Polyuria, polydipsia
•	Hypovolaemia
–	 JVP down, down BP, high HR.
–	 ~5L fluid deficit
–	 Significant electrolyte deficit Na+ K+ and Cl-)
•	Abdo pain, N&V
•	Kussmaul resps, ketotic breath
•	Muscle cramps
•	There may be evidence of preciptant (eg sepsis)
111
Q

what to do after DKA

A

• Swap to s/c insulin once patient eating and drinking
• Ensure basal insulin given ≥ 1h before iv insulin stops
• Try to identify precipitant
• Don’t miss opportunity for pt education
– Sick day rules
– Adjusting insulin
• Involve DSN/dietician, ensure F/U
• Look out for any complications

112
Q

describe HONK

A
  • Usual finding is MARKED hyperglycaemia, raised osmolality and mild/no ketoacidosis
  • Mortality up to 33% (age, precipitant)
  • 2/3 cases in previously undiagnosed DM
  • Affects middle-aged or elderly type 2 DM

• DIAGNOSIS
 Hyperglycaemia (>30mmol/l, but often 60-90 mmol/l))
 Serum osmolality >320mmol/Kg
 No / mild ketoacidosis
 Severe dehydration and pre-renal failure common
• Calculated osmolality=2x(Na+K)+glc+urea.

•	Insidious onset
	Profound dehydration (9-10L deficit)
	Hypercoagulability (exclude CVA, DVT, PE)
	Confusion, coma, fits.
	Gastroparesis, N&V, haematemesis

• Management similar to DKA (protocols) but:
 Slower, prolonged rehydration
 Gradual reduction in Na+
 Gentler glucose reduction
 Anticoagulation vital: Prophylactic sc heparin
 Seek the precipitant (infection, MI etc)

113
Q

describe metoformin and safety

A

• Evidence that MF causes lactic acidosis is poor
• It does not increase lactate levels in T2DM
• It is excreted solely through the kidney
• Short t½ so rarely accumulates in absence of advanced RF
• Usually, tissue hypoxia is “trigger”
• Review of cases of MF-associated lactic acidosis 1995-2000 showed that no cases were caused solely with MF
• Cochrane review 2002 concluded that treatment with MF not associated with increased risk of lactic acidosis
• Stop MF if eGFR <30 (or worsening fast)
• Withdraw during tissue hypoxia but can reinstate later
 ‘Shock’
 MI, significant CCF
 Sepsis
 Dehydration
 Acute renal failure
• Withdraw for 3 days after iodine-containing contrast medium given. Check U/E before reinstating 48h later
• Withdraw 2 days before general anaesthetic and reinstate once renal function stable

114
Q

describe diabetes in childhood

A

In Scotland 300 children under the age of 15 years are diagnosed with T1D annually
1 in 4 are diagnosed in DKA (diabetic ketoacidosis)
Rising to 1 in 3 under the age of 5 years
The mortality & morbidity in DKA are related to the length of time between the onset of DKA and initiation of treatment: in the UK 10 children die and 10 children suffer permanent neurological disability per annum.

115
Q

what is the protocol for a child with diabetes

A 
THINK – Symptoms (4 x T’s)
Toilet –using more
Thirsty
Thinner
Tired
TEST- Immediately
Finger prick capillary glucose test
If result >11mmol/l
TELEPHONE – Urgently
Contact your local specialist team for a same day review

NO CHILD IS TOO YOUNG TO PRESENT WITH DIABETES – at 6 months can be diagnosed with type 1 – until then its monogenic diabetes

116
Q

what is it important to tell the family

A

 It is no-one’s ‘fault’
 Lifelong condition
 One that needs continued self care

117
Q

what is the presentation of type 1 in children

A
  • Glucose is a powerful osmotic agent
  • Subsequent POLYURIA & secondary POLYDIPSIA
  • NOCTURNAL ENURESIS – earliest symptom 89% aged 4 years +
  • DEHYDRATION [constipation in 10% under 5 years]
  • WEIGHT LOSS - 50% of age 10-14, but only 2% less than 2 years old
  • LETHARGY [10-20% all ages] & BEHAVIOURAL CHANGES
  • BLURRED VISION
  • VAGINAL CANDIDIASIS
118
Q

what is important to remember when giving insulin

A

 Normal insulin secretion: 0.7 – 0.9 units/kg/day
 Approx 30-40% total daily insulin is secreted during basal periods to suppress lipolysis, proteolysis + glycogenolysis
 Remember insulin is required 24 hours/day

119
Q

describe insulin treatment in children

A

 Must be started as soon as possible after diagnosis [usually within 6 hours if ketonaemia is present]
 Children can develop dehydration + acidosis within 24 hours of first presentation. Children < 2years old are most at risk. [30% newly diagnosed have had at least one related medical visit before the diagnosis]
 This is to prevent metabolic decompensation and diabetic ketoacidosis

120
Q

describe DKA in children

A

DKA: IS THE RESULT OF AN ABSOLUTE or RELATIVE DEFICIENCY OF INSULIN
• Newly diagnosed diabetes
In children with established TIDM – the risk is 1-10% per patient per year
• Infections
• Non compliance with treatment [75%]. Children whose insulin is administered by a responsible adult rarely have episodes of DKA
• Potential complication of insulin pump therapy

121
Q

what is the Pathophysiology of DKA in children

A
  • An accelerated catabolic state, impaired peripheral glucose utilization, increased lipolysis + ketogenesis
  • Hyperglycaemia + hyperketonaemia cause osmotic diuresis + dehydration
  • Dehydration becomes a major feature [vomiting - in child with diabetes vomiting is sign of insulin deficiency until proved otherwise]
  • Lactic acidosis from hypoperfusion
122
Q

what is the Clinical presentation of DKA in children

A
  • Dehydration
  • Nausea, vomiting + abdominal pain, mimicking an acute abdomen
  • Acidotic respiration [ Kussmaul ] ‘deep + sighing’
  • Altered conscious level
  • Biochemical data:
  • pH < 7.3 +/or bicarbonate < 15 mmol/L
  • Base excess: strongly negative
  • High anion gap
  • Hyperglycaemia
  • Hyperketonaemia
123
Q

what are the key aims in paediatric DKA management

A

 Meticulous monitoring of clinical condition of the patient and the biochemical data
 Correct dehydration SLOWLY [over 48 hours in those < 18 years]
 Correct acidosis SLOWLY + reverse ketosis – i.v insulin infusion and NOT bicarbonate therapy
 Restore BG to near normal
 Avoid complications of therapy: paediatric cerebral oedema

124
Q

describe sick day management in children

A

 Do not omit insulin. Always check blood ketone value.
 Switch off ketogenesis [requires additional insulin]
 Ensure sufficient carbohydrate substrate is available
 Achieve normoglycaemia: Febrile patients generally have an increased insulin requirement [25-50%],
 Patients with D+V with no ketonaemia may have a reduced insulin requirement. [20% in each dose given]
 Altered insulin doses may be required for up to one week after the intercurrent illness.
 Treat the current illness

125
Q

describe time in range

A

 There is a direct relationship between HbA1c and Time in Range: the higher the Time in Range the lower the HbA1c.
 The clinic TIR target is at 70% as this strongly correlates with an HbA1c of 53mmol/mol.
 It is also important to look at Time Below Range TBR (below 3.9mmol/l). It is recommended aiming for TBR below 4%.
 It is important to note that what may appear small success, i.e. 5% increase in TIR is actually significantly improving your/your child’s glycaemic control.

126
Q

what are the barriers to achieving target glycaemic control

A 
[HbA1c < 58 mmol/mol]
•	Day to day family life
•	Fear of hypoglycaemia and seizures
•	School day
•	Activities/ exercise/holidays
•	Insulin omission
•	Favourite injection sites [lipohypertrophy]
•	‘Diabulimia’ [deliberate insulin omission to lose weight]
127
Q

what is the guidance for appointments with young people

A

Get in the right mind set for the appointment
 Be non judgmental
 Be responsive, not reactive
 Compose yourself & be ready for anything!
Say hello, greet them by their name, smile & introduce yourself
• Check in with the YP
• Ask what they would like to get from the appointment
Give any relevant information & resources to take away
• Web addresses/ review together in clinic
Review the appointment
• Would you do anything differently next time?
• Check out – how are they feeling now?

128
Q

describe diabetes burnout

A

 A state of emotional exhaustion caused by the continuous distress of (& efforts to self manage) diabetes
 Described by health professionals as “difficult’, unmotivated’, ‘non-adherent’
 Signs of burnout are disengagement from self care tasks
 Rarely ‘open’ to any advice for change on offer
 Increases fears….but they feel unable to take control

129
Q

describe type 2 in young people

A

 An emerging problem.
 Frequency increased markedly in paediatric age group during past decade.
 Linked to increasing childhood obesity AND decreased physical activity
 Paediatric diabetes teams managing Type 1 must now recognise the vast differences between the treatment challenges of these 2 disorders.

130
Q

what are the numbers of diabetes in pregnancy

A

• 700,000 women deliver in England and Wales annually
• 5% have pre-existing or gestational diabetes
• 87.5% Gestational diabetes
• 7.5% T1DM
• 5% T2DM
If you have gestational DM in your first pregnancy, you can go on to develop type 2 DM fairly soon.

131
Q

what are the risks of diabetes in pregnancy

A

• Macrosomia
o 4.5 kg or more
• If you have macrosomia – shoulder dystocia
o Fracture humerus and or clavicle
• Anencephaly
• Prematurity – intrauterine growth retardation

In first trimester, you have the majority of your cardiac development and neural development which are glucose dependent processes – why pre-conception counselling is so important

Fetal outcomes in T1DM are
3-4x worse in stillbirth rate and perinatal mortality than normal

132
Q

what are risks to the baby of diabetes

A 
pre-existing diabetes
miscarriage
congenital malformation
stillbirth
neonatal death

gestational
neonatal hypoglycaemia
perinatal death
shoulder dystocia

both
fetal macrosomia
birth trauma
induction of labour or caesarean
transient neonatal mobidity
obesity and/or diabetes later in life for child
133
Q

maternal risks of diabetes

A
  • Miscarriage
  • Pre-eclampsia
  • Preterm labour
  • Intrapartum complications
  • Progression of microvascular complications
  • Severe hypoglycaemia
  • Ketoacidosis
  • Death
134
Q

what can we use for treatment in pregnancy

A

Can only use diet, metformin and insulin for glycaemic control as other drugs cross placenta

135
Q

what to do in the case of diabetes in pregnancy

A

• Pre-pregnancy planning for all patients with diabetes
Structured education
Dietetic, weight, exercise advice
Folic acid 5mg daily (until 12 weeks)
Renal and retinal assessment
• Optimise glycaemic control
Monthly HbA1c
HbA1c as low as possible and <53mmol/mol as minimum (SIGN), (lower with NICE-48)
Blood glucose meter, ketone testing in T1DM, hypoglycaemia management and awareness (remember glucagon)
• Review medications
stop statins, ACEi/ARB, oral hypoglycaemics
Continue metformin, (glibenclamide), commence insulin if required

• Balance between reducing renal, retinal and pregnancy complications vs risk of hypoglycaemia

136
Q

describe retinopathy in pregnancy

A
  • 43% of women with retinopathy show progression during pregnancy
  • Sight-threatening retinopathy rare (2%)
  • Risk factors are poor glycaemic control and uncontrolled hypertension
  • Pre-pregnancy screening, and during each trimester in pre-existing diabetes; early referral to ophthalmology
137
Q

describe gestational diabetes

A
  • Defined as “carbohydrate intolerance of variable severity with onset or first recognition during pregnancy”
  • Includes women with undiagnosed type 1, type 2 or monogenic (MODY) DM
  • Usually develops after 28 weeks gestation
  • Complications (all reduced by intensive management)
  • Macrosomia/shoulder dystocia (3%)
  • Neonatal hypoglycaemia (from neonatal hyperinsulinaemia)
  • Neonatal death (1%)
  • Late intra-uterine death (1%)
138
Q

what leads to macrosomia

A

Glucose crosses the placenta but insulin doesn’t so the baby makes its own insulin from 11 weeks – anabolic hormone which is what leads to macrosomia

139
Q

how do we screen for GDM

A

All women with risk factors or intermediate results in early pregnancy should have a 75g OGTT at 24-28 weeks

Risk factors
	BMI >30kg/m2
	Previous baby with birth weight > 4.5kg
	Previous GDM
	Family history of diabetes in a 1st degree relative
	Ethnic minority high risk population
140
Q

what is the diagnosis of GDM

A

• 75g OGTT: (oral glucose tolerance test)
Fasting glucose ≥5.1mmol/L (>7.0)
- 2 hour ≥ 8.5mmol/L (>11.1)

141
Q

what is the management of GDM

A 
•	HBGM
•	Dietetic input
•	Metformin / Insulin
	Fasting ≥5.5mM
	Pre-prandial ≥6mM
•	Weekly CTG and liquor volumes from 36 weeks
•	Induced at term
•	Insulin stopped once delivered
•	OGTT at 12 weeks,12 monthly screening for T2DM
142
Q

what are the goals for preexisting diabetes in pregnancy

A 
Pre-prandial 4-6mM
	1 hour post-prandial <8mM
	2 hour post-prandial <7mM
	Before bed <6mM
	Aspirin 75mg from 12-36 weeks (reduces pre-eclampsia risk)

60% will need metformin

143
Q

describe hypoglycaemia in pregnancy

A

• Insulin requirements change during pregnancy due to gestational hormones
• Hypoglycaemia
Common (14-45% of patients experience a severe hypo)
Occurs most often during 1st trimester
Risk factors include previous severe hypos, diabetes duration, impaired hypoglycaemia awareness, erratic control
Important that pre-pregnancy counseling includes hypoglycaemia re-education

144
Q

describe Intrapartum Care

A

• Pre-existing diabetes:
Usually IOL or elective C section at 37-38 weeks
• GDM: Labour induced before 40 weeks
Because of increased risk of IUD and other maternal/fetal complications
Increased risk of instrumental delivery and C Section (60%)

145
Q

describe Immediate Postnatal Care

A 
•	Neonatal care
	Hypoglycaemia
	Macrosomia
	Jaundice
	Respiratory distress syndrome
•	Maternal care
	Reduce insulin to pre-pregnancy doses
	Stop insulin in patients with GDM
	Avoid hypoglycaemia
	Breast feeding
146
Q

describe Postnatal Care

A

• Pre-pregnancy planning for next pregnancy!
• Encourage breastfeeding
• Adjust treatment regimen when necessary
• GDM: 50% 5 year risk of T2DM
Diet, weight, exercise advice
12 week OGTT
Annual screening for T2DM

147
Q

how do we measure growth

A 
•	Reliable measurement is critical
•	Expensive equipment not required
•	Height	
o	Wall mounted stadiometer preferred
o	Reproducible technique most important
•	Length	
o	In those less than 2 years or cannot stand 
o	Requires an assistant
•	Weight 
In underclothing or light clothing
148
Q

when do we measure growth

A
  • All children should have their height and weight charted when they visit their doctor for any reason
  • Serial measurements are most valuable as they allow assessment of rate of growth ( = growth velocity)
  • Need to plot and interpret the data
149
Q

what charts are available to us

A 
Growth charts
•	Plot height and weight
Height velocity charts
•	Assess rate of growth – cm/year
BMI charts
•	Identify BMI out with normal range
150
Q

what do we do with parents heights?

A 
•	Need height of each parent
o	For a girl: 
	plot mums height on chart
	plot dads height MINUS13 cm
o	For a boy:
	plot Dads height on chart
	plot Mums height PLUS 13 cm
Midpoint between the two = mid parental centile – plus or minus 6 cm
151
Q

what are the three stages of growth

A
  1. Infancy: 0 - ~2 years
  2. Childhood: 2 years – prepuberty
  3. Puberty: onset until reached final height and sexual maturation
152
Q

what is faltering growth?

A

“a baby or toddler is not growing at the rate that you would normally expect”
• 5% of children under the age of two at some point.
It is not a condition in itself – there are lots of different possible explanations, with feeding problems being the most common

153
Q

what is failure to thrive?

A 
•	Describes the pathological problem
•	Child not thriving – ie not gaining weight
Causes for lack of weight gain:
1.	Too little intake
2.	Failure to absorb
3.	Chronic disease
Poor weight gain CAUSES poor growth
154
Q

what causes abnormal growth between 2 and puberty

A 
•	Underlying pathological explanation!
Key indicators:
•	Stature out with parental target height
•	Slow growth or rapid growth
(not being short or tall!)
155
Q

whats in a history for growth disorders

A
  • Elicit the problem
  • duration, severity
  • emotional / psychological
  • Perinatal history
  • birth weight and length, gestation,
  • drugs, delivery, infection, jaundice,
  • oedema, hypoglycemia, micropenis
  • Family history
  • short stature, timing of puberty
  • heritable disease, endocrine disease
  • Systemic symptoms
  • chronic illness, neurological
  • nutritional review
  • Developmental history
  • Social circumstances
  • Diet
156
Q

whats in an examination for growth disorders

A

Measurement
• height, weight, head circumference,
• body proportions

Body habitus
• eg. broad chest, truncal obesity
• muscle bulk

Dysmorphism
• facial, midline defects, ears, palate,
• others

Hands and feet
• short metacarpals, clinodactyly,
• palmar creases, lymphoedema,
• clubbing

Neurological
• Visual fields, acuity, fundi,
• nystagmus

Puberty and genitalia
• Pubertal staging, penis size

Signs of systemic illness

157
Q

describe puberty

A

The period during which sexual maturation
occurs resulting in the capacity for reproduction
Involves:
Growth and maturation of primary sexual characteristics (gonads and genitals)
Appearance of secondary sexual characteristics (sexual hair, female breast development, voice change etc)
Stimulation of gonadal activity is by pulsatile
gonadotropin release from the pituitary gland

158
Q

describe puberty history

A

Often elicits limited information
Family history of puberty
Mother - menarche, growth spurt, cessation of growth
Father - growth spurt, shaving cessation of growth

History in the child
Onset and progression of pubertal characteristics
Pubic hair, axillary hair
Breast development - usually recalled
Onset of genital enlargement in boys - rarely recalled

159
Q

describe puberty examination

A

Parent present, privacy, appropriate simple explanation.

Girls				
Breast staging	       
Pubic hair			
Axillary hair			
Acne				
Body habitus			
Boys
Testicular volumes (or length)
Genital stage
Pubic hair	
Axillary hair
Acne
Facial hair
Body habitus

Self staging using growth chart pictures if examination declined

160
Q

what are normal ranges for girls

A 
Oestrogen production (ovaries enlarging)
•	Onset puberty = breast bud and onset of growth spurt = 10.5 years
•	End puberty = onset menses = 13 years
Normal range to start  = 8 - 13 yrs
Onset puberty before 8 yrs = precocious
Onset puberty after 13 yrs = delayed
Takes 2.5 yrs
•	Growth after onset menses ~ 6 cm
161
Q

what are normal ranges for boys

A

Testicular volumes = testosterone production
• Onset puberty = 4mls: age 11 yrs
• Onset growth spurt at 10 mls: age 13 yrs
• Adult male volumes of 25mls: age16 yrs

Normal range start = 9-14 yrs
• Onset puberty pre 9yrs = precocious
• Onset puberty after 14 yrs = delayed
Takes 5 yrs! Pubertal height gain 25 cm

162
Q

describe adrenarche

A

Onset of production of adrenal androgens – 2 years or more – prior to onset of puberty.
Due to maturation of adrenal cortex – zona reticularis
Begins by 6-8 yrs in normal individuals
Presence or absence does not influence onset of true puberty

163
Q

what are the clinical features of adrenarche

A

• Axillary and/or pubic hair, greasy hair & skin, acne, body odour
• >95% variant of normal
When should you worry?
• Sign of virilisation or rapid growth
Pathological diagnoses:
• Androgen secreting tumour or late onset CAH
Parents worry: onset of puberty – but ONLY if also signs of testicular enlargement or breast development

164
Q

describe menstruation

A

Occurs at end of sexual maturation – B4-5
Mean age = 13 years
Range of normal: 11-15 yrs
Irregular cycles common

There has been a large decline in age of onset of menstruation over the last 150 years due to nutrition

165
Q

what raises alarm bells to do with growth

A

Slow growth and thin?
• Chronic disease e.g Coelaic disease, IBD
Slow growth and fat?
• Endocrine problem e.g. hypothyroidism
Rapid growth in childhood?
• Sex steroid exposure e.g. precocious puberty

166
Q

describe precocious puberty

A

• Central precocious puberty: gonadotrophin dependent
– onset breast development before 8yrs
– Testicular volumes >3mls before 9yrs
• Pseudopuberty: gonadotrophin independent
– disharmonious pubertal events
– Eg vaginal bleeding without breast development

Central Precocious puberty:
Central activation of pubertal axis
Gonadal enlargement
Normal sequence of events

Precocious pseudopuberty:
Peripheral activation of sex steroids
Not centrally activated
Incomplete pubertal sequence
No gonadal enlargement
eg. congenital adrenal hyperplasia
ovarian tumour
167
Q

what concerns are raised by possible precocious sexual development

A
  • Possible sinister underlying cause
  • Psychologically unacceptable – embarrassment of inappropriately early sexual changes, excessive tall stature, early onset menstruation.
  • Long term sequelae – short stature (but only if age at onset is < 7yrs in girls and < 8 yrs in boys
168
Q

what concerns are raised by delayed or incomplete sexual development

A

Possibly a sinister underlying cause eg acquired hypothyroidism
• Emotional and psychological upset of immaturity, esp when associated with short stature
• Long term sequelae

169
Q

describe GH release

A
  • GH release controlled by a stimulatory factor – GHRH- Growth Hormone Releasing Hormone / Factor
  • GHRH - peptide synthesised by neurones in the arcuate nucleus, and released from neurosecretory terminals at the median eminence
  • Binds to specific G-protein coupled receptor on pituitary somatotrophs. Stimulates GH synthesis and release from stored pools
  • GH secretion is also controlled by an inhibitory factor – somatostatin
  • Somatostatin - peptide synthesised by neurosecretory neurones of the periventricular nucleus
  • Somatostatin inhibits secretion of GH from somatotrophs and inhibits the secretion of GHRH
170
Q

what else is GH regulated by

A

– Estrogen

– Thyroid hormone
• Hypothyroidism - poor growth, blunting of GH responses to stimuli & reduced pituitary GH levels

– Glucocorticoids
• Initial stimulatory effect but later suppressive effect

– Catecholamines
• Stimulatory effect

– Ghrelin
• Stimulatory effect

171
Q

describe how GH secretion varies

A

Growth hormone secretion is pulsatile and has circadian rhythm
• On average 10 pulses per day
• Peak in slow wave sleep (affected by ‘jet-lag’)
• Not affected by continuous GHRH administration or by inactivating mutations GHRH receptor
• Probably determined by somatostatin pulsatility

GH secretion is sexually dimorphic
• Women have higher mean GH levels than men during the day
• May reflect sex differences in somatostatin

GH levels decrease with ageing
• Decline with age
• Is there a role for GH in senescence, particularly altered body composition?
• GH levels are lower in obesity and are restored by massive weight loss

Exercise and GH
• Exercise - stimulant for GH secretion
• Occurs ~ 10-15 mins after start of exercise
• May be mediated by Ach, adrenaline, endogenous opioids

172
Q

describe GH signalling

A
  • One GH molecule binds to 2 GHR molecules leading to dimerisation
  • Activation of receptor-associated Janus kinase, followed by STAT phosphorylation
  • Translocates to nucleus and acts as a transcription factor
  • Insulin-like growth factor-1 (IGF-1) gene activation
173
Q

what are the physiological effects of GH

A

• Direct effects
– e.g. Adipocytes have GH receptors. GH stimulates them to break down TG & suppresses ability to take up circulating lipids

• Indirect effects
– Mediated primarily by IGF-1 secreted from the liver etc. in response to GH.
– Most growth promoting effects of GH due to IGF-1

174
Q

describe IGF-1

A
  • Liver is principle source of circulating IGF-1
  • Also produced by most other tissues
  • Autocrine/paracrine effect probably responsible for most linear growth
175
Q

describe the three phases of growth

A

Infancy period
• Rapid deceleration in growth velocity
• Largely nutritionally determined
Childhood period
• Largely determined by GH secretion
• Growth till 3 years is an additive combination of infancy and childhood components
• So.. good nutrition remains key in first 2-3 years of life
Puberty
• GH + sex steroids
• Sex steroids are anabolic and have an effect on GH secretion

176
Q

what are some causes of short stature and poor growth in childhood

A
  • Nutrition
  • Chronic disease (e.g. CF, asthma, IBD, coeliac, renal, liver)
  • Genetic conditions (Turner syndrome, Trisomy 21, Noonan syndrome, skeletal dysplasias)
  • Steroids (oral, topical, inhaled, endogenous)
  • Hypothyroidism
  • Psychosocial deprivation
a central cause is Pituitary abnormalities
–	GH deficiency
–	TSH deficiency
–	Gonadotrophin deficiency
–	Causes
–	Genetic
–	Tumours e.g. craniopharyngioma
–	Irradiation
–	Trauma
177
Q

describe child GH deficiency

A 
•	1:4000 children
•	Treatment - GH
•	Other rare conditions:
-	IGF-1 receptor abnormalities 
-	IGF-1 gene mutation
178
Q

describe adult GH deficiency

A

Adult growth hormone deficiency - 2-3 per 10,000 - 30% due to non-functioning pituitary adenoma

Symptoms
Decreased energy, Social isolation, Depressed mood, anxiety

Clinical features include
• Increased body fat
• Decreased muscle mass
• Decreased bone density, increased risk of fracture
• Impaired cardiac function
• Decreased insulin sensitivity and impaired glucose tolerance

But….
• Adult GH deficiency usually occurs in the context of other pituitary hormone abnormalities
• Symptoms may reflect multiple abnormalities (thyroid, glucocorticoids, gonadotrophins)

treatment
•	Controversial
•	Expensive +++
•	May improve 
–	QOL (quality of life)
–	Cardiovascular risk
–	Lipids
–	Exercise tolerance
–	Body composition
–	Bone health
179
Q

describe GH excess

A

• Tumour of pituitary (99%)
– Before epiphyses have fused: gigantism
– After growing ends of long bones have fused: acromegaly (prevalence 50-60 per million)
• Rare other causes inc. McCune-Albright

  • Untreated acromegaly - increase in morbidity, overall mortality at least 2x general population.
  • Early studies: > 50% of patients dead by 60yrs (diabetes, cardiovascular, respiratory or cerebrovascular disease)
  • Improved treatment of disease and complications means patients are surviving longer. May then be susceptible to other complications such as malignancy
180
Q

describe GH excess treatment

A
  • Aims: Normalise GH levels, reduce tumour size, preserve anterior pituitary function
  • Surgery – transphenoidal if possible (may use medical therapy to shrink tumour first)

• Drugs – if surgery fails
– Somatostatin analogues (octreotide, lantreotide, pasireotide)
– Long-acting GH receptor antagonist – pegvisomant. A modified recombinant GH molecule which prevents GH receptor dimerisation
– Dopamine agonists (if concurrent high prolactin – works in <10%)

• Radiotherapy - if surgery fails and control difficult

181
Q

describe the GH excess tests

A 
•	GH deficiency
–	Insulin tolerance test ITT (gold standard)
–	Arginine
–	Clonidine
–	Glucagon
–	Overnight GH sampling
182
Q

describe the difference between sperm and egg

A

sperm
• Constant fertility from puberty
• ~300 million per day from puberty
• Gradual decline with age

Egg
• Cyclical fertility, 3-5 days a month from puberty
• ~7 million follicles in utero, declines to 0 at menopause
• ~ 400 follicles are ovulated

183
Q

describe the growth of follicles (everything)

A

Eggs are within primordial follicles that are made in the ovary before birth and never get replenished
Every day, independent of the endocrine system, several primordial follicles activate and start growing
After about 110 days the follicles have grown to around 4-5 mm in size and at this stage they have become dependent of endocrine hormones for the next 14 days
Every day there are up to 20 follicles that have reached the stage when they become dependent on endocrine hormones (gonadotrophins)
They will grow under the influence of gonadotrophins and produce hormones. Most follicles will wither but the most mature follicle produces more and more hormones and survives to ovulate the egg
Gonadotrophins are produced in the pituitary under the influence of GnRH from the hypothalamus. There is feedback from estradiol, inhibin and prolactin
Oestrogen makes the endometrium grow and develop
This oestrogen comes from follicles in the ovary which are growing and producing more and more oestrogen

Granulosa cells are told to make oestrogen by FSH which binds to them
Cholesterol is changed through many steps to oestrogen and the step before estradiol is androgens. The enzyme which turns androgens to estradiol is aromatase.
Granulosa cells do not have the enzymes to make androgens from cholesterol. The theca cells make androgens which is stimulated by LH.

Follicles need less FSH as they get bigger and the oestrogen has negative feedback on FSH production so this means the smaller follicles cant get larger and therefore only one develops.

The high oestrogen leads to the LH surge which stimulates ovulation and then the follicle collapses and becomes the corpus luteum. – produces progesterone

Progesterone stops the endometrium growing and starts a secretory phase to nourish the embryo

184
Q

what is seen in Hypogonadotrophic Hypogonadism

A
  • LH low
  • FSH low
  • Estradiol low
  • Prolactin normal

In this case, the pituitary is working normally as prolactin is present, so it must be a problem with the hypothalamus. Low GnRH due to low body fat – body sensing it is not a good time to raise a child

History
• Weight loss, over exercise, stress, illness
Examination
• BMI
Management
• Lifestyle, pulsatile GnRH, FSH/LH injections

185
Q

what is seen in Premature ovarian insufficiency

A

LH high
FSH high
Estradiol low
Prolactin normal

Problem in the ovary – high FSH and LH but ovary not responding. Running out of eggs – hormones of the menopause – turners syndrome run out of eggs before puberty

History
•	Treatment, Family history, Menopausal symptoms
Examination
•	Atrophic vaginitis
Management
•	Egg Donation
186
Q

what is seen in Hyperprolactinaemia due to pituitary adenoma

A

LH low
FSH low
Estradiol low
Prolactin high

Pituitary issue as prolactin is abnormally high. This switches off gonadotrophin as you don’t want to get pregnant when you are breastfeeding – leads to leaking milk – Galactorrhea

History
•	Galactorrhoea
Examination
•	Galactorrhoea, Bitemporal hemianopia (MRI)
Management
•	Dopamine agonist (Bromocriptine
187
Q

what is seen in polycystic ovary syndrome

A 
LH high
FSH normal
Estradiol normal 
Prolactin normal 
A pathology where LH is higher than FSH. Will lead to increased androgens. These stop the follicles growing when they get to a certain size – called polycystic ovary syndrome but importantly they are not cysts!
History
•	Hirsuitism, acne, weight
Examination
•	BMI, Skin, (USS)
Management
•	Anti-estrogen (Clomifene citrate) this will get rid of oestrogen which would normally feedback to inhibit FSH so will increase FSH. But we only give it for the first 5 days of the cycle as otherwise the endometrium would not develop and  they couldn’t get pregnant
188
Q

describe the menopause and normal range

A

A woman’s ‘last spontaneous menstrual period’
Average age is 51 years
Normal range 45-55 years
Two key events:
Loss of fertility: quality and quantity of oocytes
Loss of ovarian hormonal function: estrogen (E) and progesterone (P)

189
Q

what is considered early and premature menopause

A

• Early Menopause < 45 years
• Premature Menopause < 40 years
=Premature Ovarian Insufficiency (POI)

190
Q

what are causes of Premature Ovarian Insufficiency (POI)

A 
•	IDIOPATHIC  (89%)	
•	autoimmune						
•	surgery / chemo or radiotherapy		
•	chromosomal					
•	 infections							
•	metabolic 
In general – TREAT early menopause  ie give oestrogen replacement
191
Q

what is the Biochemical profile of post-menopausal women

A 
ESTRADIOL  low
FSH    high
LH      high
- there may be many years of fluctuating  levels in the perimenopause
 -most women don’t need hormone tests
192
Q

what are predictors of the menopause

A
  • FSH – day 3 raised level
  • AMH – anti-Mullerian hormone: declines with age and useful marker of ovarian reserve
  • Inhibin B - declines with age and protein hormone marker of ovarian reserve
  • Ovarian antral follicle count by ultrasound
193
Q

what are symptoms of lack of oestrogen and what are other symptoms of menopause

A
  • Hot flushes and night sweats
  • Palpitations, faintness
  • Experienced by >80% of women
  • Debilitating, embarrassing and unpleasant
  • Severe sleep deprivation
other
•	Low mood
•	Poor memory and concentration
•	Mood swings
•	Lack of confidence
•	Low self esteem
•	Panic attacks
•	Tiredness
•	 Low energy
•	 Joint pains
•	 Skin / hair
194
Q

describe symptoms of urogenital ageing

A
  • Vaginal dryness and dyspareunia
  • Bladder neck symptoms: urgency, urge incontinence, nocturia, recurrent urinary infections
  • 30% of women admit that their UG symptoms strongly affect their daily lives
  • Embarrassment inhibits most women from seeking help
195
Q

what are issues with sexual functions in menopause

A
  • State of relationship
  • Lower sexual desire / libido
  • Orgasmic problems
  • Pain
  • Lack of testosterone?
196
Q

what are benefits of HRT

A
  • Improve quality of life:
  • relieve vasomotor symptoms
  • lift depressed mood
  • improve vaginal symptoms
  • Protection against osteoporosis (provided HRT is taken for long enough)
  • Protection against bowel cancer

TREAT EARLY MENOPAUSE

197
Q

what are risks of HRT

A
  • Side effects:
  • bleeding problems, bloatedness,
  • breast pain, ?? weight gain
  • Small extra risk of breast cancer with prolonged duration of use
  • Increased risk of venous thromboembolism: x2 fold increase
  • Small excess risk of stroke
198
Q

describe infertility epidemiology and causes

A 
•	Infertility now affects 1 in 7 couples 
•	Can be caused by 
o	STDs
o	Obesity/ low weight
o	Tobacco
199
Q

describe oxytocin effects

A
  • Oxytocin has major effects on smooth muscle contraction
  • milk ejection
  • contraction of uterus during childbirth
  • Secretion is stimulated in response to stimulation of nipples or uterine distension.
  • Oxytocin is used to induce labour
200
Q

describe hormones destined for the anterior pituitary

A

Synthesised by hypothalamic neuronsreleased from the hypothalamus into the hypophyseal portal system (Gonadotropin-releasing hormone)
• Pulsatile release
 prevents receptor desensitisation & downregulation
• Responds to ovarian hormonal feedback

201
Q

describe kisspeptin

A

Feeds back onto GnRH neurons themselves and regulate its secretion
• Kisspeptin gets signals from the gonads but also adrenal gland, fat (leptin) and environmental cues

202
Q

how are HPG hormones transported

A

Water soluble hormone transport
• GnRH
• FSH
• LH

Lipid soluble hormone transport
• Oestrogen
• Progesterone
• Need transport proteins

203
Q

how do gonadotrophins affect follicle development

A

No one knows what causes a primordial follicle to become a primary one but it is known that gonadotropins are important in the development from pre-antral follicle onwards
FSH – antral granulosa cell differentiation, proliferation & function
LH – theca cell androgen production, ovulation

204
Q

describe anti mullerian hormone

A
  • Made by granulosa cells
  • Absent in primordial follicles but present at later stages
  • Inhibitory effect on follicle development
  • Unaffected by gonadotropins/steroid hormones
  • reliable reflection of growing follicles

oestrogen and FSH induce the expression of the LH receptor on theca cells and the one with the most expression will be ovulated

205
Q

describe hormonal contraception

A

• Suppresses ovulation via negative feedback of progesterone
- secondary effects on female genital tract
• Combined pill – oestrogen provides additional feedback & promotes progesterone receptor expression
• During ‘off period’ own HPG axis is awakened

206
Q

describe milk production

A
  • Need suckling!
  • nerve impulses sent to the brain
  • Prolactin release from anterior pituitary
  • Alveoli swell and secrete milk
207
Q

describe milk release concequences

A
  • Boosts oxytocin synthesis & secretion from posterior pituitary
  • Myoepithelial cell contraction around alveoli = milk expulsion
  • Milk ejection reflex can be conditioned
208
Q

describe the relationship between milk production and fertility

A

Fertility is reduced during lactation

  • Lactation can continue for months
  • Menstruation & ovulation re-established by 3-6 months
  • ~50% of unprotected nursing mothers fall pregnant during 9 months of lactation
  • Negative feedback of prolactin on FSH/LH
209
Q

what is the epidemiology of reproductive disorders in males

A 
Cryptorchidism		   6-9% 		
Hypospadias		   0.4-0.9%	
Low sperm counts	  16-20% 	 
Testis germ cell cancer	   0.45%	 
Low adult Testosterone	 (Compensated Leydig cell failure  10%

Testicular dysgenesis syndrome is the most common reproductive disorders of
the developing and young adult male

It is the final, androgen-dependent phase that most commonly goes wrong

210
Q

describe the increase in testicular germ cell cancer

A
  • TGCC has its origins in fetal life
  • ‘Faulty’ Sertoli cells is the suspected cause
  • Sertoli cells are what determine sperm count
211
Q

why does sperm count matter

A

Falling sperm counts 1970 – 2010 - 52.4% decline
A male with a low sperm count + a female partner in her 30’s is a recipe for:
• Increased time to achieve a pregnancy
• Increased couple infertility
• Increased use of assisted reproduction, especially ICSI

212
Q

describe assisted reproduction

A
  • Assisted reproduction is at best ~30% successful
  • It gets increasingly ineffective with age
  • It is a bruising, traumatic process (especially for the female partner)
  • It can be expensive and there may be a significant waiting list

Progressive use of ICSI (intracytoplasmic sperm injection) in assisted reproduction
Use not confined to male factor infertility

213
Q

what are the big health unknowns with assisted reproduction

A
  • Animal studies have shown that variation in nutrition around the time of conception (before implantation) can dramatically alter metabolic function of the offspring in adulthood
  • These effects may be passed on to the next generation (grandchildren)
  • In IVF, embryos are cultured for several days
  • Sperm can also pass on epigenetic effects to offspring/grand-offspring which can alter their metabolism and health
  • Long-term effects of ICSI on health of offspring are largely unknown; sperm counts are 50% lower in ICSI-derived human males
214
Q

describe sertoli cell count

A

Sertoli cell (SC) number is the most important determinant of sperm count in men
SC number :
• Varies >100-fold between men (as does sperm count)
• Is mainly determined during fetal/early postnatal life

Maternal Diet, Lifestyle, exposures (such as smoking) leads to Subnormal testosterone production or action

215
Q

what is the anogental distance difference between males and females

A

Male AGD ~twice that of female

This is determined by androgens in the MPW (masculinisation programming window)

AGD in boys with cryptorchidism and hypospadias is much lower than normal boys

216
Q

what factors in first trimester may be responsible for testicular dysgenesis syndrome (TDS)?

A
  • > 90% of research effort in this area over the last 20 years has focussed on exposure to environmental contaminants/pollutants (‘endocrine disruptors’) - no convincing evidence
  • The biggest changes have been to maternal diet and lifestyle
  • Use of medicines during pregnancy has also increased substantially

Evidence in mice that paracetamol decreases testosterone in pregnancy which could lead to these conditions

217
Q

describe germ cell effects

A

Future fertility is absolutely dependent on germ cells from both sexes
Germ cells are the first cells to differentiate in the embryo and these fetal germ cells are the source of adult fertility (and potentially the health of resulting offspring)

With smoking for example, the mother (f0) is exposed, so is her fetus (f1) but so is are the fetus’ germ cells (f2)

Year 2 - Semester 2 (8 decks)

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