GLYCOSYLATED HEMOGLOBIN (HbA1C)

 Is the most widely used measure of long-term glycemic control in diabetes mellitus
 HbA1c is produced by the glycosylation of hemoglobin at a rate proportional to the glucose
concentration
 Level of HbA1c therefore is dependent on:
o Red blood cell lifespan
o Average blood glucose concentration
 A number of conditions can interfere with accurate HbA1c interpretation:

Lower-than-expected levels of HbA1c (due to Higher-than-expected levels of HbA1c (due to

reduced RBC lifespan) increased red blood cell lifespan)
Sickle-cell anemia Vitamin B12/ folic acid deficiency
G6PD deficiency Iron-deficiency anemia
Hereditary spherocytosis Splenectomy

 HbA1c is generally thought to reflect the blood glucose over the previous 3 months, although
there is some evidence it is weighed more strongly to glucose levels of the past 2-4 weeks
 NICE recommend HbA1c should be checked every 3-6 months until stable, then 6 monthly
 The relationship between HbA1c and average blood glucose is complex, but has been studied by
the Diabetes Control and Complications Trial (DCCT)
 A new internationally standardized method for reporting Hba1c has been developed by the
International Federation of Clinical Chemistry (IFCC) – will report HbA1c in mmol/ mol of
hemoglobin without glucose attached

HbA1c (%) Average plasma glucose (mmol/L) IFCC-HbA1c (mmol/mol)

5 5.5
6 7.5 42
7 9.5 53
8 11.5 64
9 13.5 75
10 15.5 Average plasma glucose
11 17.5 = (2 x HbA1c) – 4.5
12 19.5

DIABETES MELLITUS: A VERY BASIC INTRODUCTION

 May be defined as a chronic condition characterized by abnormally raised levels of blood

glucose
 Poorly treated type 1 diabetes mellitus can still result in significant morbidity and mortality (as a
result of diabetes ketoacidosis)

1
  Main focus of diabetes management now is reducing the incidence of macrovascular (ischemic
heart disease, stroke) and microvascular (eye, nerve and kidney damage) complications

TYPE NOTES SYMPTOMS & SIGNS MANAGEMENT

Type 1 diabetes mellitus Autoimmune disorder Weight loss Patients always
(T1DM) where the insulin- Polydipsia require insulin to
producing beta cells of Polyuria control the blood
the islets of Langerhans sugar levels – due to
in the pancreas are May present with there is absolute
destroyed by the diabetic ketoacidosis: deficiency of insulin
immune system  Abdominal with no pancreatic
Results in an absolute pain tissue left to stimulate
deficiency of insulin  Vomiting with drugs
resulting in raised  Reduced
glucose levels consciousness
Patients tend to develop level
T1DM in childhood/
early adult life and
typically present unwell,
possibly in diabetic
ketoacidosis
Type 2 diabetes mellitus Most common cause of Often picked up Majority of patients
(T2DM) diabetes in the incidentally on routine with T2DM controlled
developed world blood tests using oral medication
Caused by a relative Polydipsia First-line drug for vast
deficiency of insulin due polyuria majority of patients is
to an excess of adipose metformin
tissue 2nd line: Sulfonylureas,
(in simple terms, there gliptins, pioglitazone
is not enough insulin to If oral medication is
‘go around’ all the not controlling the
excess fatty tissue, blood glucose to a
leading to blood glucose sufficient degree, then
creeping up) insulin is used
Prediabetes This term used for
patients who do not yet
meet the criteria for a
formal diagnosis of
T2DM to be made, but
are likely to develop the
condition over the next
few years
Therefore, require
closer monitoring and
lifestyle interventions
such as weight loss
Gestational diabetes Some pregnant women
develop raised glucose

2
 levels during pregnancy
Important to detect as
untreated it may lead to
adverse outcomes for
the mother and baby
Maturity onset diabetes A group of inherited
of the young genetic disorders
(MODY) affecting production of
insulin
Results in younger
patients developing
symptoms similar to
those with T2DM, i.e.
asymptomatic
hyperglycemia with
progression to more
severe complications
such as diabetic
ketoacidosis
Latent autoimmune The majority of patients Diagnosis may be
diabetes of with autoimmune- aided through a
adults (LADA) related diabetes present Glutamic Acid
younger in life Decarboxylase (GAD)
There are however a autoantibodies test
small group of patients and evidence of other
who develop such autoimmune diseases
problems later in life
These patients are often
misdiagnosed as having
T2DM

Patients are typically

younger and without an
increased body habitus
(in contrast to T2DM)

Insulin not usually

required in the early
stages of the disease (in
contrast to T1DM)
Other types Any pathological
process which damages
the insulin-producing
cells of the pancreas
may cause diabetes to
develop
Examples: Chronic

3
 pancreatitis,
hemochromatosis

Drugs may also cause

raised glucose levels
Common example:
Glucocorticoids –
commonly result in
raised blood glucose
levels

 Polyuria and polydipsia – due to water being ‘dragged’ out of the body due to the osmotic
effects of excess blood glucose being excreted in the urine (glycosuria)
 4 main ways to check blood glucose:
o Finger-prick bedside glucose monitor
o One-off blood glucose – may either be fasting or non-fasting
o HbA1c – measures amount of glycosylated hemoglobin and represents the average
blood glucose over the past 2-3 months
o Glucose tolerance test – fasting blood glucose taken after which a 75g glucose load is
taken, then after 2 hours a second blood glucose reading is then taken
 Diagnostic criteria are determined by WHO:
o If the patient is symptomatic:
 Fasting glucose ≥ 7.0 mmol/L
 Random glucose ≥ 11.1 mmol/L (or after 75g OGTT)
o If the patient is asymptomatic:
 The above criteria apply
 But must be demonstrated on two separate occasions
 In 2011 WHO released supplementary guidance on the use of HbA1c on the diagnosis of
diabetes:
o Hba1c of ≥ 48 mmol/mol (6.5%) is diagnostic of diabetes mellitus
o A HbA1c value of < 48 mmol/mol (6.5%) does not exclude diabetes (i.e. it is not as
sensitive as fasting samples for detecting diabetes)
o In patients without symptoms, the test must be repeated to confirm the diagnosis
o Should be remembered that misleading HbA1c results can be caused by increased red
cell turnover
 Principle of managing diabetes mellitus:
o Drug therapy to normalize blood glucose levels
o Monitoring for and treating any complications related to diabetes
o Modifying any other risk factors for other conditions such as cardiovascular disease

DRUG CLASS MECHANISM OF ROUTE MAIN SIDE- NOTES

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 ACTION EFFECTS
INSULIN Direct Subcutaneous Hypoglycemia Used in all patients
replacement of Weight gain with T1DM and some
endogenous Lipodystrophy patients with poorly
insulin controlled T2DM

Can be classified
according to source
(analogue, human
sequence and
porcine) and duration
of action (short,
immediate, long-
acting)
Metformin Increases insulin Oral Gastrointestinal First-line medication
sensitivity upset
Decreases hepatic Lactic acidosis Cannot be used in
gluconeogenesis patients with an eGFR
of <30ml/min
Sulfonylureas Stimulate Oral Hypoglycemia e.g. Gliclazide,
pancreatic beta Weight gain Glimepiride
cells to secrete Hyponatremia
insulin
Thiazolidinediones PPAR-gamma Oral Weight gain Only currently
receptor agonists: Fluid retention available
Activate PPAR- thiazolidinedione is
gamma receptor Pioglitazone
in adipocytes to
promote
adipogenesis and
fatty acid uptake
DPP-4 inhibitors (- Increases incretin Oral Generally well
gliptins) levels which tolerated but
inhibit glucagon increased risk of
secretion pancreatitis
SGLT-inhibitors (- Inhibits Oral Urinary tract Typically result in
gliflozins) reabsorption of infection weight loss
glucose in the
kidney
GLP-1 agonists (- Incretin mimetic Subcutaneous Nausea and Typically result in
tides) which inhibits vomiting weight loss
glucagon Pancreatitis
secretion

DIABETES MELLITUS: PATHOPHYSIOLOGY

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  Type 1 diabetes mellitus:
o Autoimmune disease – autoimmune destruction of the Beta-cells of the pancreas
o Antibodies against beta cells of pancreas
o Identical twins show a genetic concordance of 40%
o Associated with HLA-DR3 and DR4; HLA DR4 > HLA DR3
o Inherited in a polygenic fashion
o Various antibodies such as islet-associated antigen (IAA) antibody and glutamic acid
decarboxylase (GAD) antibody are detected in patients who later go on to develop type I
DM – their prognostic significance is not yet clear
 Type 2 diabetes mellitus:
o Thought to be caused by a relative deficiency of insulin and the phenomenon of insulin
resistance
o Age, obesity and ethnicity are important etiological factors
o There is almost 100% concordance in identical twins and no HLA associations
 Hemochromatosis is an example of secondary diabetes

PREDIABETES AND IMPAIRED GLUCOSE REGULATION

 Prediabetes is a term which is increasingly used where there is impaired glucose levels which are
above the normal range but not high enough for a diagnosis of diabetes mellitus
o The term includes patients who have been labelled as having either impaired fasting
glucose (IFG) or impaired glucose tolerance (IGT)
 Diabetes UK estimate that around 1 in 7 adults in the UK have prediabetes
 Many individuals with prediabetes will progress on to developing type 2 diabetes mellitus
(T2DM) and they are therefore at greater risk of microvascular and macrovascular complications
 Diabetes UK currently recommend using the term prediabetes when talking to patients and
impaired glucose regulation when talking to other healthcare professionals
 Identification of patients with prediabetes:
o NICE recommend using a validated computer-based risk assessment tool for all adults
aged 40 and over, people of South Asian and Chinese descent aged 25-39, and adults
with conditions that increase the risk of T2DM
o Patients identified at high risk should have a blood sample taken
o A fasting plasma glucose of 6.1 – 6.9 mmol/L or an HbA1c level of 42-47 mmol/mol (6.0-
6.4%) indicates high risk
 Management:
o Lifestyle modifications: weight loss, increased exercise, change in diet
o At least yearly follow-up with blood tests is recommended
o NICE recommend metformin for adults at high risk ‘whose blood glucose measure
(fasting plasma glucose or HbA1c) shows they are still progressing towards T2DM,
despite their participation in an intensive lifestyle-change programme’

IMPAIRED FASTING GLUCOSE AND IMPAIRED GLUCOSE TOLERANCE

6
  There are 2 main types of impaired glucose regulation:
o Impaired fasting glucose (IFG): Due to hepatic insulin resistance
o Impaired glucose tolerance (IGT): Due to muscle insulin resistance
o Patients with IGT are more likely to develop T2DM and cardiovascular disease than
patients with IFG
 Definitions:
o Impaired fasting glucose = Fasting glucose ≥6.1 but <7.0mmol/L
o Impaired glucose tolerance (IGT) = Fasting plasma glucose <7.0 mmol/L, and OGTT 2-
hour value ≥7.8 mmol/L but <11.1 mmol/L
o People with IFG should then be offered an OGTT to rule out a diagnosis of diabetes
 Result <11.1 mmol/L but above 7.8mmol/L indicates that the person does not
have diabetes but does have IGT

DIABETES MELLITUS (TYPE 2): DIAGNOSIS

 Diagnosis can be made by either a plasma glucose or a HbA1c sample

 Diagnostic criteria vary according to whether the patient is symptomatic (polyuria, polydipsia
etc.) or not
 Diabetes diagnosis: Fasting > 7.0, random >11.1; If asymptomatic will need two readings
 If the patient is symptomatic:
o Fasting glucose greater than or equal to 7 mmol/L
o Random glucose greater than or equal to 11.1 mmol/L (or after 75g oral glucose
tolerance test)
 If the patient is asymptomatic, the above criteria apply, but must be demonstrated on 2
separate occasions:

 In 2011 WHO released supplementary guidance on the use of HbA1c on the diagnosis of
diabetes:
o Hba1c of ≥ 48 mmol/mol (6.5%) is diagnostic of diabetes mellitus

7
 o A HbA1c value of < 48 mmol/mol (6.5%) does not exclude diabetes (i.e. it is not as
sensitive as fasting samples for detecting diabetes)
o In patients without symptoms, the test must be repeated to confirm the diagnosis
o Should be remembered that misleading HbA1c results can be caused by increased red
cell turnover
 Conditions where HbA1c may not be used for diagnosis:
o Hemoglobinopathies
o Hemolytic anemia
o Untreated iron deficiency anemia
o Suspected gestational diabetes
o Children
o HIV
o Chronic kidney disease
o People taking medication that may cause hyperglycemia (for example corticosteroids)
 Impaired fasting glucose (IFG): A fasting glucose ≥ 6.1, but less than 7 mmol/L
o Diabetes UK suggests that people with IFG should then be offered OGTT to rule out
diagnosis of diabetes
 Impaired glucose tolerance (IGT): Fasting plasma glucose less than 7 mmol/L and OGTT 2-hour
value ≥ 7.8 mmol/L but less than 11.1 mmol/L

DIABETES MELLITUS: MANAGEMENT OF TYPE 1

 The long-term management of type 1 diabetics is an important and complex process requiring
the input of many different clinical specialties and members of the healthcare team
 NICE released guidelines on diagnosis and management of type 1 diabetes in 2015
 HbA1c:
o Should be monitored every 3-6 months
o Adults should have a target of HbA1c level of 48 mmol/mol (6.5%) or lower – but take
into account factors such as the person’s daily activities, aspirations, likelihood of
complications, comorbidities, occupation and history of hypoglycemia
 Self-monitoring of blood glucose:
o Recommend testing at least 4 times a day, including before each meal and before bed
o More frequent monitoring is recommended if frequency of hypoglycemic episodes
increases/ during periods of illness/ before, during and after sport/ when planning
pregnancy, during pregnancy and while breastfeeding
 Blood glucose targets:
o 5-7 mmol/L on waking and
o 4-7 mmol/L before meals at other times of the day
 Type of insulin:
o Offer multiple daily injection basal-bolus insulin regimens, rather than twice-daily mixed
insulin regimes, as the insulin injection regime of choice for all adults

8
 o Twice-daily insulin detemir is the regime of choice
o Once-daily insulin glargine or insulin detemir is an alternative
o Offer rapid-acting insulin analogues injected before meals, rather than rapid-acting
soluble human or animal insulins, for mealtime insulin replacement for adults with type
1 diabetes
 Metformin: NICE recommend considering adding metformin if the BMI ≥25 kg/m2

DIABETES MELLITUS: MANAGEMENT OF TYPE 2 (UPDATED NICE GUIDELINES 2015)

 Key points:
o HbA1c targets have changed – now dependent on what antidiabetic drugs a patient is
receiving and other factors such as frailty
o There is more flexibility in the 2nd stage of treating patients (i.e. after metformin has
been started) – with a choice of 4 oral antidiabetic agents
 In average patient who is taking Metformin for T2DM, can titrate up metformin and encourage
lifestyle changes to aim for a HbA1c of 48 mmol/mol (6.5%), but should only add a second drug
if the HbA1c rises to 58 mmol/mol (7.5%)
 Dietary advice:
o Encourage high fiber, low glycemic index sources of carbohydrates
o Include low-fat dairy products and oily fish
o Control intake of foods containing saturated fats and trans fatty acids
o Limited substitution of sucrose-containing foods for other carbohydrates is allowable,
but care should be taken to avoid excess energy intake
o Discourage use of foods marketed specifically at people with diabetes
o Initial target weight loss in an overweight person is 5-10%
 HbA1c targets:
o Individual targets should be agreed with patients to encourage motivation
o HbA1c should be checked every 3-6 months until stable, then 6 monthly
o NICE encourage to consider relaxing targets on ‘a case-by-case basis, with particular
consideration for people who are older or frail, for adults with type 2 diabetes’
o In 2015, the guidelines changed so HbA1c targets are now dependent on treatment –
practical examples:
 A patient is newly diagnosed with HbA1c and wants to try lifestyle treatment
first – agreed a target of 6.5%
 You review a patient 6 months after starting Metformin – HbA1c is 51
mmol/mol (6.8%)  you increase his Metformin from 500mg BD to 500mg TDS
and reinforce lifestyle factors

9
Management of T2DM HbA1c target
Lifestyle 48 mmol/mol (6.5%)
Lifestyle + Metformin 48 mmol/mol (6.5%)
Includes any drug which may cause hypoglycemia (e.g. lifestyle + 53 mmol/mol (7.0%)
Sulfonylurea)
Already on one drug, but HbA1c has risen to 58 mmol/mol (7.5%) 53 mmol/mol (7.0%)

 Tolerates metformin:
o Metformin is still first-line and should be offered if the HbA1c rises to 48 mmol/mol
(6.5%) on lifestyle interventions
o If the HbA1c has risen to 58 mmol/mol (7.5%), then a second drug should be added from
the following list:
 Sulfonylurea
 Gliptin
 Pioglitazone
 SGLT-2 inhibitor
o If despite this the HbA1c rises to, or remains above 58 mmol/mol (7.5%), then triple
therapy with one of the following combinations should be offered:
 Metformin + gliptin + sulfonylurea
 Metformin + pioglitazone + sulfonylurea
 Metformin + sulfonylurea + SGLT-2 inhibitor
 Metformin + pioglitazone + SGLT-2 inhibitor
 OR insulin therapy should be considered
 Criteria for glucagon-like peptide1 (GLP1) mimetic (e.g. exenatide) – Exenatide generally causes
weight loss and is therefore useful in obese diabetics (NICE BMI criteria of 35 kg/m2):
o If triple therapy is not effective, not tolerated or contraindicated, then NICE advise to
consider combination therapy with metformin, a sulfonylurea and a glucagon-like
peptide 1 (GLP1) mimetic if:
 BMI ≥35 kg/m2 and specific psychological or other medical problems associated
with obesity or
 BMI <35 kg/m2 and for whom insulin therapy would have significant
occupational implications or
 Weight loss would benefit other significant obesity-related comorbidities – only
continue if there is a reduction of at least 11 mmol/mol (1.0%) in HbA1c and a
weight loss of at least 3% of initial body weight in 6 months
 Practical examples:
o You review an established type 2 diabetic on maximum dose metformin – her HbA1c is
55 mmol/mol (7.2%)  you do not add another drug as she has not reached the
threshold of 58 mmol/mol (7.5%)
o A type 2 diabetic is found to have a HbA1c of 62 mmol/mol (7.8%) at annual review,
who currently on maximum dose metformin  add on a sulfonylurea
 Cannot tolerate metformin or contraindicated:

10
 o If the HbA1c rises to 48 mmol/mol (6.5%) on lifestyle interventions, consider one of the
following:
 Sulfonylurea
 Gliptin
 Pioglitazone – contraindicated by history of bladder cancer and may contribute
to patient’s obesity
o If the HbA1c has risen to 58 mmol/mol (7.5%), then one of the following combinations
should be used:
 Gliptin + pioglitazone
 Gliptin + sulfonylurea
 Pioglitazone + sulfonylurea
o If despite this the HbA1c rises to, or remains above 58 mmol/mol (7.5%), then consider
insulin therapy
 Starting insulin:
o Metformin should be continued – ‘review the continued need for other blood glucose
lowering therapies’
o NICE recommend starting with human NPH insulin (isophane, intermediate acting) taken
at bed-time or twice daily according to need
o NPH plus a short-acting insulin should be considered (particularly if the person’s HbA1c
is 75 mmol/mol [9.0%] or higher) – may be administered either separately or as a pre-
mixed (biphasic) human insulin preparation
o Insulin detemir or insulin glargine should be considered as an alternative to NPH insulin
if:
 The person needs assistance from a carer or healthcare professional to inject
insulin and the use of insulin detemir or insulin glargine would reduce the
frequency of infections from twice to once daily, OR
 The person’s lifestyle is restricted by recurrent symptomatic hypoglycemic
episodes, OR
 The person would otherwise need twice-daily NPH insulin injections in
combination with oral antidiabetic drugs

Risk factor modification:

 Blood pressure
o Target is <140/80 mmHg (or <130/80 mmHg if end organ damage is present)
o ACE inhibitors are first-line
 Antiplatelets – should not be offered unless patient has existing cardiovascular disease
 Lipids:
o Following the 2014 NICE lipid modification guidelines, only patients with a 10-year
cardiovascular risk >10% (using QRISK2) should be offered a statin
o First-line statin of choice is Atorvastatin 20mg ON (as primary prevention)
o Atorvastatin 80mg ON as secondary prevention (for patients with known ischemic heart
disease OR cerebrovascular disease OR peripheral arterial disease)

11
SULFONYLUREAS

 Works by increasing pancreatic insulin secretion, hence only effective if functional B-cells are
present
o On a molecular level, they bind to an ATP-dependent K+ (K ATP) channel on the cell
membrane of pancreatic beta cells
o Work via mimicking the role of ATP on potassium-ATP channels from the outside – act
to block these channels causing membrane depolarization and thus opening of voltage-
gated calcium channels  results in stimulation of insulin release
o When used acutely, they increase insulin secretion and decrease insulin clearance in the
liver; Due to this stimulation of insulin secretion, they can cause hypoglycemia leading
to serious complication of neuroglycopenia  resulting lack of glucose supply to the
brain can cause confusion and possible coma (treatment through oral glucose,
intramuscular glucagon or intravenous glucose)
o If the tissue is exposed chronically to sulfonylureas, there is no acute increase in insulin
release but a decrease in plasma glucose concentration does remain; Chronic exposure
to sulfonylureas does also lead to down-regulation of their receptors
 E.g. Glibenclamide (Gliclazide), Tolbutamide
 Common adverse effects:
o Hypoglycemic episodes (more common with long-acting preparations such as
chlorpropamide)
o Weight gain – Sulfonylureas stimulate pancreas to release more insulin, therefore
allowing for the utilization of more glucose
o Long-term administration they also have an extrapancreatic action – side effects:
hypoglycemia, cholestatic jaundice, diarrhea
 Rarer adverse effects:
o Hyponatremia secondary to syndrome of inappropriate ADH secretion
o Bone marrow suppression
o Hepatotoxicity (typically cholestatic)
o Peripheral neuropathy
 Sulfonylureas should be avoided in breastfeeding and pregnancy

THIAZOLIDINEDIONES

 Agonists to the PPAR-gamma receptor  reduces peripheral insulin resistance

 PPAR-gamma receptor is an intracellular nuclear receptor
 Natural ligands are free fatty acids and it is thought to control adipocyte differentiation and
function
 Adverse effects:
o Weight gain
o Liver impairment: monitor LFTs

12
 o Fluid retention – therefore contraindicated in heart failure; Risk of fluid retention
increased if patient also takes insulin
o Recent studies have indicated an increased risk of fractures
o Bladder cancer: recent studies shown an increased risk of bladder cancer in patients
taking pioglitazone (hazard ratio 2.64)

NORMAL RENAL PHYSIOLOGY

 In the normal kidney, up to 180g/ day of glucose is filtered by the renal glomerulus and virtually
all of it is reabsorbed in the proximal convoluted tubule
 This reabsorption is carried out by two sodium-dependent glucose co-transporter (SGLT)
proteins, SGLT1, which reabsorbs 10%, and SGLT2, which reabsorbs the remaining 90%
 While SGLT1 is expressed elsewhere in the body, SGLT2 is expressed solely in the kidney, making
it an attractive target for novel diabetic treatments
 SGLT2 inhibitors have been shown to enhance renal glucose excretion by inhibiting renal glucose
reabsorption with consequent improvements in HbA1c and insulin resistance
o They also have been shown to have protective effects in the progression of chronic
kidney disease, blood pressure lowering effects, and reduce cardiovascular events in
high risk type II diabetic patients

SGLT-2 INHIBITORS

 Reversibly inhibit sodium-glucose co-transporter 2 (SGLT-2) in the renal early proximal

convoluted tubule  reduce glucose reabsorption and increase urinary glucose excretion
(additional approximately 70g of glucose a day is excreted)
o Due to an increased amount of glucose being secreted in the urine, these medications
are contraindicated in patients with recurrent thrush
o The increased amount of glucose in the urine is thought to predispose to bacterial
growth
o Should also be noted that urine dipstick will test positive for glucose
 Slight diuresis caused by increased glucose excretion may also improve blood pressure, but also
increased glucose in the urine can also cause adverse effects such as urinary tract or genital
infections
 SGLT-2 inhibitors promote increased glucose excretion, corresponds to a calorie load of 200-400
kcal/ day
o In some patients, this results in dramatic weight loss, although on average this equates
to 1-2% reduction in weight over 6 months
 Associated with increased urate excretion, rather than an increase in serum uric acid

13
  SGLT-2 inhibitors are recognized to increase total cholesterol (both HDL and LDL), although
cardiovascular outcome studies as yet do not suggest this translates into increased risk of MACE
events
 SGLT-2 inhibitors do not slow gastric emptying
 Examples: Canagliflozin, Dapagliflozin, Empagliflozin
 Important adverse effects:
o Urinary and genital infection (secondary to glycosuria)
 Fournier’s gangrene has also been reported
o Normoglycemic/ euglycemic diabetic ketoacidosis
o Increased risk of lower-limb amputation: feet should be closely monitored
o Increased total cholesterol
 Patients taking SGLT-2 drugs often lose weight, which can be beneficial in type 2 diabetes
mellitus
 Trials are ongoing, but SGLT2 inhibitors are not currently licensed as an adjunct in patients with
type 1 diabetes

MEGLITINIDES

 Examples: Repaglinide, Nateglinide

 Increase pancreatic insulin secretion  stimulates insulin release
 Similar to Sulfonylureas – Bind to an ATP-dependent K+ (K-ATP) channel on the cell membrane
of pancreatic beta cells
 Often used for patients with an erratic lifestyle/ eating schedule, also particularly useful for
post-prandial hyperglycemia (as patients take them shortly before meals)
 Adverse effects: Weight gain, hypoglycemia (less compared to sulfonylureas)

DIABETES MELLITUS: GLP-1 AND THE NEW DRUGS

 Glucagon-like peptide-1 (GLP-1) is a hormone released by the small intestine in response to an

oral glucose load
 It is well known that insulin resistance and insufficient B-cell compensation occur, other effects
are also seen in type 2 diabetes mellitus (T2DM)
o In normal physiology, an oral glucose load results in a greater release of insulin than if
the same load is given intravenously  known as the incretin effect
o This effect is largely mediated by GLP-1 and is known to be decreased in T2DM
 Increasing GLP-1 levels, either by administration of an analogue (glucagon-like peptide-1, GLP-1
mimetics, e.g. Exenatide) or inhibiting its breakdown (dipeptidyl-peptidase-4, DPP-4 inhibitors –
the gliptins), is therefore the target of 2 recent classes of drugs

14
Glucagon-like peptide-1 (GLP-1) mimetics (e.g. Exenatide)

 Increase insulin secretion and inhibit glucagon secretion

 Major advantage: Typically results in weight loss (in contrast to many medications such as
insulin, sulfonylureas, thiazolidinediones)
o Sometimes used in combination with insulin in T2DM to minimize weight gain
 Exenatide must be given by subcutaneous injection within 60 minutes before the morning and
evening meals – should not be given after a meal
 Liraglutide (the other GLP-1 mimetic)
o One of the main advantages of liraglutide over exenatide is that it only needs to be
given once a day
 Both exenatide and liraglutide may be combined with metformin and sulfonylurea
o Standard release exenatide is also licensed to be used with basal insulin alone or with
metformin
 Consider adding exenatide to metformin and sulfonylurea if:
o BMI ≥ 35 kg/m2 in people of European descent and there are problems associated with
high weight, OR
o BMI < 35 kg/m2 and insulin is unacceptable because of occupational implications or
weight loss would benefit other comorbidities
 Aim: To achieve 11 mmol/mol (1%) reduction in HbA1c and 3% weight loss after 6 months (to
justify the ongoing prescription of GLP-1 mimetics)
 Major adverse effect of GLP-1 mimetics: Nausea and vomiting
 The Medicines and Healthcare products Regulatory Agency has issued specific warnings on use
of exenatide, reporting that is has been linked to increased risk of severe pancreatitis and renal
impairment in some patients

Dipeptidyl peptidase-4 (DPP-4) inhibitors (e.g. Vildagliptin, Sitagliptin)

 Key points:
o Oral preparation
o Trials to date show that the drugs are relatively well tolerated with no increased
incidence of hypoglycemia
o Do not cause weight gain
 NICE guidelines on DPP-4 inhibitors:
o NICE suggest that a DPP-4 inhibitor might be preferable to a thiazolidinedione if further
weight gain would cause significant problems/ a thiazolidinedione is contraindicated/
the person has had a poor response to a thiazolidinedione

ACARBOSE

 An inhibitor of intestinal alpha-glucosidases

15
  Results in decreased absorption of starch and sucrose
 Acarbose prevents the degradation and absorption of complex carbohydrates into glucose  an
increased carbohydrate load will be delivered to the colon  in the colon, bacteria digest the
complex carbohydrates, causing gastrointestinal side-effects such as flatulence and diarrhea
 Excessive flatulence is the most commonly reported side-effect, thus often the reason for
discontinuation of the drug (Metformin can also cause gastrointestinal side-effects, but it is
often diarrhea rather than excessive flatulence)

DIABETIC MEDICATIONS - SUMMARY

DRUGS MECHANISM OF ACTION ADVERSE EFFECTS

Metformin Reduces hepatic gluconeogenesis,
increases peripheral glucose uptake and
also reduces the absorption of
carbohydrate in the gut
Sulphonylureas (e.g. Act by closing ATP-sensitive K-channels
Gliclazide) in pancreatic beta cells  causes
increased stimulation of insulin
secretion by pancreatic B-cells and
decreases hepatic clearance of insulin
 increase insulin release from
pancreas
Thiazolidinediones/ PPARγ (gamma) agonists  cause
Glitazones (e.g. increased insulin sensitivity
Pioglitazone)
Upregulation of transcription of insulin
-also an insulin responsive genes, leading to an increase
sensitizer in glucose transporters and insulin
receptors at the surface of the cell
Sitagliptin, Vildagliptin Dipeptidyl peptidase-4 (DPP-4) inhibitor
(DPP-4 inhibitors) This enzyme breaks down the incretins
GLP-1 and GIP  increases insulin
secretion and suppresses glucagon
secretion  decrease glucagon release
from pancreas
Increased appetite and weight
gain
Syndrome of inappropriate ADH
secretion (Sulphonylureas,
particulary long-acting ones
such as chlorpropamide are
well-established causes of
SIADH)
Liver dysfunction (cholestatic)
Weight gain
Fluid retention
Decompensation of pre-existing
heart failure
Liver dysfunction
Fractures
Pancreatitis

By preventing GLP-1 and GIP

inactivation, increased insulin is
secreted by the pancreas
Gliflozin/ SGLT-2 Inhibits sodium-glucose co-transporter-
inhibitors (e.g. 2 (SGLT2) in the proximal convoluted
Dapagliflozin) tubule of the nephron of kidneys 
stop glucose reabsorption  meaning it
is excreted in the urine

16
 Acarbose Decrease glucose absorption in the gut
DIABETIC NEUROPATHY

 Diabetes typically leads to sensory loss and not motor loss in peripheral neuropathy
 Painful diabetic neuropathy is a common problem in clinical practice
 NICE updated guidelines on management of neuropathic pain in 2013 – Diabetic neuropathy
now managed in the same way as other forms of neuropathic pain:
o First-line treatment: Amitriptyline, Duloxetine, Gabapentin or Pregabalin
 Avoid amitriptyline in patients with history of benign prostatic hyperplasia – due
to the risk of urinary retention
o If the first-line drug treatment does not work, try one of the other 3 drugs
o Tramadol may be used as ‘rescue therapy’ for exacerbations of neuropathic pain
o Topical capsaicin may be used for localized neuropathic pain (e.g. post-herpetic
neuralgia)
o Neither codeine or naproxen are recommended in neuropathic pain
o Pain management clinics may be useful in patients with resistant problems

GASTROINTESTINAL AUTONOMIC NEUROPATHY

 Gastroparesis
o Symptoms include erratic blood glucose control, bloating and vomiting
o Management options include metoclopramide, domperidone or erythromycin
(prokinetic agents)
 Chronic diarrhea – often occurs at night
 Gastro-esophageal reflux disease – Caused by decreased lower esophageal sphincter (LES)
pressure

DIABETIC FOOT

 Diabetic foot disease is an important complication of diabetes mellitus which should be screen
for on a regular basis
 NICE produced guidelines relating to diabetic foot disease in 2015
 It occurs secondary to 2 main factors:
o Neuropathy: resulting in loss of protective sensation (e.g. not noticing a stone in the
shoe), Charcot’s arthropathy, dry skin
o Peripheral arterial disease: Diabetes is a risk factor for both macro and microvascular
ischemia
 Presentations:
o Neuropathy: loss of sensation
o Ischemia: Absent foot pulses, reduced ankle-brachial pressure index (ABPI), intermittent
claudication

17
 o Complications: Calluses, ulceration, Charcot’s arthropathy, cellulitis, osteomyelitis,
gangrene
 All patients with diabetes should be screened for diabetic foot disease on at least an annual
basis:
o Screening for ischemia: Done by palpating for both the dorsalis pedis pulse and posterial
tibial artery pulse
o Screening for neuropathy: A 10g monofilament is used on various parts of the sole of
the foot
 NICE recommend that we risk stratify patients:

LOW RISK MODERATE RISK HIGH RISK

No risk factors  Deformity OR  Previous ulceration OR
except callus  Neuropathy OR  Previous amputation OR
alone  Non-critical limb ischemia  On renal replacement therapy OR
 Neuropathy and non-critical limb
ischemia together OR
 Neuropathy in combination with
callus and/or deformity OR
 Non-critical limb ischemia in
combination with callus and/or
deformity

 All patients who are moderate or high risk (i.e. any problems other than simple calluses), should
be followed up regularly by the local diabetic foot center

DIABETIC KETOACIDOSIS

 May be a complication of existing type 1 diabetes mellitus or be the first presentation,

accounting for around 6% of cases
 Rarely, under conditions of extreme stress, patients with type 2 diabetes mellitus may also
develop DKA
 Whilst DKA remains a serious condition, mortality rates have decreased from 8% to under 1% in
the past 20 years
 Pathophysiology: DKA is caused by uncontrolled lipolysis (not proteolysis) resulting in an excess
of free fatty acids that are ultimately converted to ketone bodies
 Most common precipitating factors of DKA: Infection, missed insulin doses and myocardial
infarction
 Features:
o Abdominal pain
o Polyuria, polydipsia, dehydration
o Kussmaul respiration (deep hyperventilation)
o Acetone-smelling breath (‘pear drops’ smell)

18
  Diagnostic criteria:

American Diabetes Association (2009) Joint British Diabetes Societies (2013)

 Glucose >13.8 mmol/L  Glucose >11 mmol/L or known diabetes
 pH < 7.30 mellitus
 Serum bicarbonate <18 mmol/L  pH < 7.3
 Anion gap >10  bicarbonate <15 mmol/L
 Ketonaemia  ketones >3 mmol/L or urine ketones ++
on dipstick

 Management:
o Fluid replacement: Most patients with DKA are deplete around 5-8 litres. Isotonic saline
is used initially
 Slower infusion may be indicated in children/ young adults (aged 18-25 years)
as they are at greater risk of cerebral edema; often need 1:1 nursing to monitor
neuro-observations, headache, irritability, visual disturbance, focal neurology
etc. – usually occurs 4-12 hours following commencement of treatment but can
present at any time (if there is any suspicion, a CT head and a senior review
should be sought)
o Insulin: An intravenous infusion should be started at 0.1 unit/kg/hour. Once blood
glucose is <15 mmol/L, an infusion of 5% dextrose should be started
o Correction of hypokalemia
o Long-acting insulin should be continued, short-acting insulin should be stopped

JBDS example of fluid replacement regime for patient with a systolic BP on admission 90mmHg and over

FLUID VOLUME
0.9% sodium chloride 1L 1000ml over 1st hour
0.9% sodium chloride 1L with potassium chloride 1000ml over next 2 hours
0.9% sodium chloride 1L with potassium chloride 1000ml over next 2 hours
0.9% sodium chloride 1L with potassium chloride 1000ml over next 4 hours
0.9% sodium chloride 1L with potassium chloride 1000ml over next 4 hours
0.9% sodium chloride 1L with potassium chloride 1000ml over next 6 hours

JBDS potassium guidelines:

Potassium level in first 24 hours (mmol/L) Potassium replacement in mmol/L of infusion

solution
Over 5.5 Nil
3.5 – 5.5 40
Below 3.5 Senior review as additional potassium needs to
be given

19
  Complications of DKA and its treatment:
o Gastric stasis
o Thromboembolism
o Arrhythmias secondary to hyperkalemia/ iatrogenic hypokalemia
o Iatrogenic due to incorrect fluid therapy: Cerebral edema, hypokalemia, hypoglycemia
o Acute respiratory distress syndrome
o Acute kidney injury

HYPEROSMOLAR HYPERGLYCEMIC STATE

 Medical emergency which is extremely difficult to manage and has a significant associated
mortality
 Hyperglycemia results in osmotic diuresis, severe dehydration and electrolyte deficiencies
 HHS typically presents in the elderly with T2DM, however the incidence in younger adults is
increasing (can be the initial presentation of T2DM)
 It is extremely important to differentiate HHS from diabetic ketoacidosis as the management is
different, and treatment of HHS with insulin (e.g. as part of a DKA protocol) can result in adverse
outcomes
 HHS has a higher mortality than DKA, and may be complicated by vascular complications such as
myocardial infarction, stroke or peripheral arterial thrombosis
o Seizures, cerebral edema and central pontine myelonolysis (CPM) are uncommon but
documented complications of HHS
 Whilst DKA presents within hours of onset, HHS comes on over many days, and consequently
the dehydration and metabolic disturbances are more extreme
 Pathophysiology:
o Hyperglycemia results in osmotic diuresis with associated loss of sodium and potassium
o Severe volume depletion results in a significant raised serum osmolarity (typically >320
mosmol/kg), resulting in hyperviscosity of blood
o Despite these severe electrolyte losses and total body volume depletion, the typical
patient with HHS, may not look as dehydrated as they are, because hypertonicity leads
to preservation of intravascular volume
 Clinical features:
o General: Fatigue, lethargy, nausea and vomiting
o Neurological: Altered level of consciousness, headaches, papilloedema, weakness
o Hematological: Hyperviscosity (may result in myocardial infarctions, stroke and
peripheral arterial thrombosis)
o Cardiovascular: Dehydration, hypotension, tachycardia
 Diagnosis:

20
 o Hypovolemia
o Marked hyperglycemia (>30 mmol/L) without significant ketonemia or acidosis
o Significantly raised serum osmolarity (<320 mosmol/kg)

A precise definition of HHS does not exist, however the above 3 criteria are helpful in distinguishing
between HHS and DKA. It is also important to remember that a mixed HHS/ DKA picture can occur

 Management goals:
o Normalize the osmolality (gradually)
o Replace fluid and electrolyte losses
o Normalize blood glucose (gradually)

Management Notes
Fluid  Fluid losses in HHS are estimated to be between 100-220 ml/kg (e.g. 10-
replacement 22 litres in an individual weighing 100kg)
 Rate of rehydration will be determined by assessing the combination of
initial severity and any pre-existing co-morbidities (e.g. heart failure and
chronic kidney disease). Caution is needed, particularly in the elderly,
where too rapid rehydration may precipitate heart failure but insufficient
may fail to reverse an acute kidney injury
 Intravenous 0.9% sodium chloride solution is the first line fluid for
restoring total body fluid
 If serum osmolarity is not declining despite positive balance with 0.9%
sodium chloride, then the fluid should be switched to 0.45% sodium
chloride solution which is more hypotonic relative to the HHS patients
serum osmolarity
 IV fluid replacement should aim to achieve a positive balance of 3-6 litres
by 12 hours and the remaining replacement of estimated fluid losses
within the next 12 hours  vigorous initial fluid replacement will result in
a gradual decline in plasma glucose and serum osmolarity
 Rapid decline is potentially harmful, therefore insulin should NOT be used
in the first instance unless there is significant ketonemia or acidosis
Monitoring  The key parameter in managing HHS is the osmolality to which glucose
response to and sodium are the main contributors
treatment  Rapid changes of serum osmolarity are dangerous and can result in
cardiovascular collapse and central pontine myelinolysis (CPM)
 A reduction of serum osmolarity will cause a shift of water into the
intracellular space, inevitably results in a rise in serum sodium (fall in
blood glucose of 5.5 mmol/L will result in a 2.4 mmol/L rise in sodium);
Rising sodium is only a concern if the osmolality is NOT declining
concurrently
 Rapid changes must be avoided – a safe rate of fall of plasma glucose
between 4-6 mmol/hour is recommended; the rate of fall of plasma
sodium should not exceed 10 mmol/L in 24 hours
 A target blood glucose of between 10-15 mmol/L is a reasonable goal
 Complete normalization of electrolytes and osmolality may take up to 72
hours
Insulin  Fluid replacement alone with 0.9% sodium chloride solution will result in

21
 a gradual decline of blood glucose and osmolarity
 Insulin treatment prior to adequate fluid replacement may result in
cardiovascular collapse as the water moves out of the intravascular space,
with a resulting decline in intravascular volume
 A steep decline in serum osmolarity may also precipitate CPM
 Measurement of ketones is essential for determining if insulin is required
 If significant ketonemia is present (3-beta-hydroxybutyrate is more than
1mmol/L), this indicates relative hypoinsulinemia and insulin should be
started at time zero (e.g. mixed DKA/ HHS picture) – recommended
insulin dose is a fixed rate intravenous insulin infusion given at 0.05
units/kg/ hour
 If significant ketonemia is not present (3-beta-hydroxybutyrate is less
than 1 mmol/L), then do NOT start insulin
Potassium  Patients with HHS are potassium deplete but less acidotic than those with
DKA, so potassium shifts are less pronounced
 Hyperkalemia can be present with acute kidney injury
 Patients on diuretics may be profoundly hypokalemic
 Potassium should be replaced or omitted as required

DIABETES MELLITUS: RAMADHAN

 Type 2 diabetes mellitus is more common in people of Asian ethnicity and a significant
proportion of those patients in the UK will be Muslim
 Important to given appropriate advice to Muslim patients to allow them safely observe their fast
 It is a personal decision whether a patient decides to fast
o May however be worthwhile exploring the fact that people with chronic conditions are
exempt from fasting or may be able to delay fasting to the shorter days of the winter
months
o It is however known that many Muslim patients with diabetes do not class themselves
as having a chronic/ serious condition which should exempt them from fasting
o Around 79% of Muslim patients with T2DM fast Ramadan
 If a patient with T2DM does decide to fast:
o They should try and eat a meal containing long-acting carbohydrates prior to sunrise
(Suhoor)
o Patients should be given a blood glucose monitor to allow them to check their glucose
levels, particularly if they feel unwell
o For patients taking metformin, the expert consensus is that the dose should be split 1/3
before sunrise (Suhoor) and 2/3 after sunset (Iftar)
o Expert consensus also recommends switching once-daily sulfonylureas to after sunset
 For patients taking twice-daily preparations such as Gliclazide, it is
recommended that a larger proportion of the dose is taken after sunset
o No adjustment is needed for patients taking Pioglitazone

22
PREGNANCY: DIABETES MELLITUS

 Diabetes mellitus may be a pre-existing problem or develop during pregnancy, gestational

diabetes
 It complicates up to 1 in 20 pregnancies
 NICE estimate the following breakdown:
o 87.5% have gestational diabetes
o 7.5% have type 1 diabetes
o 5% have type 2 diabetes
 Risk factors for gestational diabetes:
o BMI of >30 kg/m2
o Previous macrosomic baby weighing 4.5kg or above
o Previous gestational diabetes
o First-degree relative with diabetes
o Family origin with a high prevalence of diabetes (South Asian, black Caribbean, and
Middle Eastern)
 Screening for gestational diabetes:
o Women who have previously had gestational diabetes: Oral glucose tolerance test
(OGTT) should be performed as soon as possible after booking and at 24-28 weeks if the
first test is normal
 NICE also recommend that early self-monitoring of blood glucose is an
alternative to the OGTTs
o Women with any of the other risk factors should be offered an OGTT at 24-28 weeks
 Diagnostic thresholds for gestational diabetes:
o Fasting glucose is ≥ 5.6 mmol/L
o 2-hour glucose is ≥ 7.8 mmol/L
 Management of gestational diabetes:
o Newly diagnosed women should be seen in a joint diabetes and antenatal clinic within a
week
o Women should be taught about self-monitoring of blood glucose
o Advice about diet (including eating foods with a low glycemic index) and exercise should
be given
o If the fasting plasma glucose level is <7 mmol/L, a trial of diet and exercise should be
offered
 If glucose targets are not met within 1-2 weeks of altering diet/ exercise,
metformin should be started
 If glucose targets are still not met, insulin should be added to diet/ exercise/
metformin
o If at the time of diagnosis the fasting glucose is ≥ 7 mmol/L, insulin should be started
o If the plasma glucose level is between 6 – 6.9 mmol/L, and there is evidence of
complications such as macrosomia or hydramnios, insulin should be offered

23
 o Glibenclamide should only be offered for women who cannot tolerate metformin or
those who fail to meet the glucose targets with metformin but decline insulin treatment
 Management of pre-existing diabetes:
o Weight loss for women with BMI of >27 kg/m2
o Stop oral hypoglycemic agents, apart from metformin, and commence insulin
o Folic acid 5mg/day from pre-conception to 12 weeks gestation
o Aspirin 75mg/day from 12 weeks until the birth of the baby, to reduce risk of pre-
eclampsia
o Detailed anomaly scan at 20 weeks including four-chamber view of the heart and
outflow tracts
o Tight glycemic control reduces complication rates
o Treat retinopathy as can worsen during pregnancy
 Targets for self-monitoring of pregnant women (pre-existing and gestational diabetes):
o Fasting: 5.3 mmol/L
o 1 hour after meals: 7.8 mmol/L OR
o 2 hours after meals: 6.4 mmol/L

Metformin is the first-line therapy of choice for diabetes in pregnancy

 Versus insulin initiation at the point of diagnosis, those patients treated with metformin gained
less weight during pregnancy and suffered slightly fewer episodes of hypoglycemia
 No difference in the primary endpoint of adverse fetal outcomes, and women treated with
metformin first preferred this option, even though most eventually progressed to insulin in
addition to oral therapy
 NICE recommend metformin as first-line option where fasting glucose is less than 7 mmol/L
despite dietary modifications
 Although glibenclamide is safe in pregnancy, it does not limit weight gain and control is inferior
to insulin therapy  therefore only an option in patients who refuse metformin and insulin
 There is no evidence to support the use of SGLT-2 inhibitors such as Dapagliflozin in pregnancy

HYPOGLYCEMIA

 Causes:
o Insulinoma – increased ratio of proinsulin to insulin
o Self-administration of insulin/ sulfonylureas
 Raised insulin with low c-peptide level points to a diagnosis of insulin abuse
 C-peptide levels would be raised in patients following sulfonylurea abuse
o Liver failure
o Addison’s disease
o Alcohol
 Other possible causes in children:

24
 o Nesidioblastosis – beta cell hyperplasia
 Physiological response to hypoglycemia:
o Hormonal response: the first response of the body is decreased insulin secretion 
followed by increased glucagon secretion
 Growth hormone and cortisol are also released but later
o Sympathoadrenal response: Increased catecholamine-mediated (adrenergic) and
acetylcholine-mediated (cholinergic) neurotransmission in the peripheral autonomic
nervous system and in the central nervous system
 Patients with alcoholic liver disease have depleted glycogen stores, therefore, treatment with
glucagon does not improve blood glucose
o Hypoglycemia in patients with alcoholic liver disease does not respond to glucagon
o Treatment: 100ml IV Glucose 20%

INSULINOMA

 An insulinoma is a neuroendocrine tumor deriving mainly from pancreatic islets of Langerhans

cells
 Most common pancreatic endocrine tumor
 10% malignant, 10% multiple
 Of patients with multiple tumors, 50% have MEN-1
 Insulinoma is diagnosed with supervised prolonged fasting
 Features:
o Hypoglycemia: typically early in the morning or just before meal, e.g. diplopia, weakness
etc.
o Rapid weight gain may be seen
o High insulin, raised proinsulin: insulin ratio
o High C-peptide
 Diagnosis:
o Supervised, prolonged fasting (up to 72 hours) – normally the investigation of choice
o CT pancreas
 Management:
o Surgery
o Diazoxide and somatostatin if patients are not candidates for surgery

MATURITY-ONSET DIABETES OF THE YOUNG (MODY)

 Characterized by development of type 2 diabetes mellitus in patients <25 years old

 Typically inherited as an autosomal dominant condition
 Over 6 different genetic mutations have so far been identified as leading to MODY

25
  It is thought that around 1-2% of patients with diabetes mellitus have MODY, and around 90%
are misclassified as having either type 1 or type 2 diabetes mellitus
 MODY 3 – 60% of cases:
o Due to a defect in the HNF-1 alpha gene
o Associated with an increased risk of HCC
 MODY 2 – 20% of cases:
o Due to defect in the glucokinase gene
 Features of MODY:
o Typically develops in patients <25 years
o A family history of early onset diabetes is often present
o Ketosis is not a feature at presentation
o Patients with the most common form are very sensitive to sulfonylureas, insulin is not
usually necessary

DVLA: DIABETES MELLITUS

 DVLA guidelines (October 2011) – following standards need to be met (also apply to patients
using other hypoglycemic inducing drugs such as sulfonylureas):
o There has not been any severe hypoglycemic event in the previous 12 months
o The driver has full hypoglycemic awareness
o Driver must show adequate control of the condition by regular blood glucose
monitoring, at least twice daily and at times relevant to driving
o Driver must demonstrate an understanding of the risks of hypoglycemia
o There are no other debarring complications of diabetes
 From a practical point of view, patients on insulin who want to apply for a Group 2 (HGV) license
need to complete a VDIAB1I form
o Patients on insulin may now hold a HGV license if they meet strict DVLA criteria
 Other specific points for group 1 drivers:
o If on insulin, then patient can drive a car as long as they have hypoglycemic awareness,
not more than 1 episode of hypoglycemia requiring the assistance of another person
within the preceding 12 months and no relevant visual impairment – drivers normally
contacted by DVLA
o If on tablets or Exenatide, no need to notify DVLA
 If tablets may induce hypoglycemia (e.g. sulfonylureas), then there must not
have been more than 1 episode of hypoglycemia requiring assistance of another
person within the preceding 12 months
o If diet controlled alone, then no requirement to inform DVLA

26
METABOLIC SYNDROME

 It is thought that the key pathophysiological factor is insulin resistance

 SIGN recommend using criteria similar to those from the American Heart Association – similar to
International Diabetes Federation criteria – For a diagnosis of metabolic syndrome, at least 3 of
the following should be identified:
o Elevated waist circumference: men >102cm, women >88cm
o Elevated triglycerides: >1.7 mmol/L
o Reduced HDL: <1.03 mmol/L in males and <1.29 mmol/L in females
o Raised blood pressure: >130/85 mmHg, or active treatment of hypertension
o Raised fasting plasma glucose >5.6 mmol/L, or previously diagnosed type 2 diabetes
 WHO 1999 diagnostic criteria – required the presence of diabetes mellitus, impaired glucose
tolerance, impaired fasting glucose or insulin resistance, AND two of the following:
o Blood pressure: >140/90 mmHg
o Dyslipidemia: Triglycerides >1.695 mmol/L and/or high-density lipoprotein cholesterol
(HDL-C) <0.9 mmol/L in males, <1.0 mmol/L in females
o Central obesity: Waist:hip ratio >0.9 in males, >0.85 in females, and/or body mass index
>30 kg/m2
o Microalbuminuria: urinary albumin excretion ratio >20mg/min or albumin:creatinine
ratio >30mg/g
 Other associated features include:
o Raised uric acid levels
o Non-alcoholic fatty liver disease
o Polycystic ovarian syndrome

REMNANT HYPERLIPIDEMIA

 Rare cause of mixed hyperlipidemia (raised cholesterol and triglyceride levels)

 Also known as Fredrickson type III hyperlipidemia, broad-beta disease and
dysbetalipoproteinemia
 Associated with apo-e2 homozygosity
 High incidence of ischemic heart disease and peripheral vascular disease
 Thought to be caused by impaired removal of intermediate density lipoprotein from the
circulation by the liver
 Features:
o Yellow palmar creases
o Palmar xanthomas

27
 o Tuberous xanthomas
 Management: Fibrates are first-line treatment

OBESITY: THERAPEUTIC OPTIONS

 Management of obesity consists of a step-wise approach:

o Conservative: diet, exercise
o Medical
o Surgical
 Orlistat – a pancreatic lipase inhibitor used in the management of obesity
o Mechanism of action: Works by inhibiting gastric and pancreatic lipase to reduce the
digestion of fat, in turn will decrease the absorption of lipids from the intestine
o Adverse effects: Fecal urgency/ incontinence and flatulence
o A lower dose version is now available without prescription
 NICE have defined criteria for the use of Orlistat – should only be prescribed as part of an overall
plan for managing obesity in adults who have:
o BMI of 28 kg/m2 or more with associated risk factors, or
o BMI of 30 kg/m2 or more
o Continued weight loss e.g. 5% at 3 months
o Orlistat is normally used for <1 year

28
DYNAMIC PITUITARY FUNCTION TESTS

 Used to assess patients with suspected primary pituitary dysfunction

 Insulin, TRH and LHRH are given to patient following which the serum glucose, cortisol, growth
hormone, TSH, LH and FSH levels are recorded at regular intervals
 Prolactin levels are also sometimes measured
 Dopamine antagonist tests using metoclopramide may also be used in the investigation of
hyperprolactinoemia
o Normal response is at least a 2-fold rise in prolactin
o A blunted prolactin response suggests a prolactinoma
 A normal dynamic pituitary function test has the following characteristics:
o GH level rises >20mu/L
o Cortisol level rises >550 mmol/L
o TSH level rises by >2mu/L from baseline level
o LH and FSH should double

WATER DEPRIVATION TEST

 Method:
o Prevent patient drinking water
o Ask patient to empty bladder
o Hourly urine and plasma osmolalities
 Dramatic improvement seen in the ability of kidneys to concentrate urine following
administration of DDAVP – points towards diagnosis of cranial diabetes insipidus

Starting plasma osm. Final urine osm. Urine osm. Post-

DDAVP
Normal Normal >600 >600
Psychogenic polydipsia Low >400 >400
Cranial DI High <300 >600
Nephrogenic DI High <300 <300

29
THYROID FUNCTION TESTS

DIAGNOSIS TSH FREE T4 NOTES

Thyrotoxicosis (e.g. Low High In T3 thyrotoxicosis, the free T4
Graves’ disease) will be normal
Primary High Low
hypothyroidism
(primary atrophic
hypothyroidism)
Secondary Low Low Replacement steroid therapy is
hypothyroidism required prior to thyroxine
Sick euthyroid Low (TSH may be Low Common in hospital inpatients
syndrome/ non- normal in some cases) T3 is particularly low in these
thyroidal illness patients
Subclinical High Normal
hypothyroidism
Poor compliance with High (implies that over Normal Most likely that she started
thyroxine recent days/weeks, her taking the thyroxine properly just
body is thyroxine before the blood test – would
deficient) correct the thyroxine level, but
the TSH takes longer to normalise
Steroid therapy Low Normal

THYROTOXICOSIS: CAUSES AND INVESTIGATION

 Graves’ disease accounts for around 50-60% of cases of thyrotoxicosis

 Acute fibrillation is a complication of hyperthyroidism, thus patients with AF should have their
thyroid function assessed
 Causes:
o Graves’ disease
o Toxic nodular goiter
o Acute phase of subacute (de Quervain’s) thyroiditis
o Acute phase of post-partum thyroiditis
o Acute phase of Hashimoto’s thyroiditis (later results in hypothyroidism)
o Amiodarone therapy
 Investigations:

30
 o TSH down, T4 and T3 up
 TSH is the best biochemical marker to assess response to treatment (however
a significant proportion of patients of whom TSH monitoring alone is
insufficient)
 TSH may remain suppressed for several weeks as continued production of
thyroid stimulating immunoglobulins seen in Grave’s disease reduces the need
for the pituitary to secrete TSH
o Thyroid autoantibodies
o Other investigations are not routinely done but includes isotope scanning

GRAVES’ DISEASE: FEATURES

 Graves’ disease is the most common cause of thyrotoxicosis

 Typically seen in women aged 30-50 years
 Features:
o Typical features of thyrotoxicosis
o Specific signs limited to Grave’s
 Eye signs (30% of patients): Exophthalmos, ophthalmoplegia (absence of eye
signs does not exclude Graves’ disease)
 Pretibial myxedema
 Thyroid acropachy

31
  Whilst Grave’s disease is the most common cause of thyrotoxicosis, it would NOT cause a tender
goiter
 Autoantibodies:
o TSH receptor stimulating antibodies (90%)
o Anti-thyroid peroxidase antibodies (75%)

GRAVES’ DISEASE: MANAGEMENT

 Treatment options include: Titration of anti-thyroid drugs (ATDs, for example Carbimazole),
block-and-replace regimes, radioiodine treatment and surgery
 Propranolol is often given initially to block adrenergic effects
 ATD titration:
o Carbimazole is started at 40mg and reduced gradually to maintain euthyroidism
o Typically continued for 12-18 months
o Patients following an ATD titration regime have been shown to suffer fewer side-effects
than those on a block-and-replace regime
 Block-and-replace:
o Carbimazole is started at 40mg
o Thyroxine is added when patient is euthyroid
o Treatment typically lasts for 6-9 months
 Major complication of Carbimazole therapy is agranulocytosis
 Radioiodine treatment:
o Contraindications include pregnancy (should be avoided for 4-6 months following
treatment) and age <16 years
 Thyroid eye disease is a relative contraindication, as it may worsen the condition
o The proportion of patients who become hypothyroid depends on the dose given, but as
a rule, the majority of patient will require thyroxine supplementation after 5 years

SUBACUTE (DE QUERVAIN’S) THYROIDITIS

 Subacute thyroiditis (also known as De Quervain’s thyroiditis and subacute granulomatous

thyroiditis) – thought to occur following viral infection and typically presents with
hyperthyroidism
 Thyrotoxicosis with tender goiter = subacute (De Quervain’s thyroiditis)
 Can present with pain and dysphagia
 May lead to high, normal or low thyroid levels, as well as raised ESR
 There are typically 4 phases:
o Phase 1 (lasts 3-6 weeks): Hyperthyroidism, painful goiter, raised ESR
o Phase 2 (1-3 weeks): Euthyroid

32
 o Phase 3 (weeks – months): Hypothyroidism
o Phase 4: Thyroid structure and function goes back to normal
 Investigations: Thyroid scintigraphy – globally reduced uptake of iodine-131
 Management:
o Usually self-limiting – most patients do not require treatment
o Thyroid pain may respond to aspirin or other NSAIDs
o In more severe cases, steroids are used, particularly if hypothyroidism develops

CARBIMAZOLE

 Used in the management of thyrotoxicosis

 Typically given in high doses for 6 weeks until the patient becomes euthyroid before being
reduced
 Mechanism of action:
o Blocks thyroid peroxidase from coupling and iodinating the tyrosine residues on
thyroglobulin  reducing thyroid hormone production
o In contrast to propylthiouracil, other than the central mechanism of action, also has a
peripheral action by inhibiting 5’-deiodinase which reduces peripheral conversion of T4
to T3
 Adverse effects:
o Agranulocytosis
o Crosses the placenta, but may be used in low doses during pregnancy

THYROID STORM

 A rare but life-threatening complication of thyrotoxicosis

 Typically seen in patients with established thyrotoxicosis and is rarely seen as the presenting
feature
 Iatrogenic thyroxine excess does not usually result in thyroid storm
 Thyrotoxic storm is treated with beta-blockers, propylthiouracil and hydrocortisone
 Precipitating events:
o Thyroid or non-thyroidal surgery
o Trauma
o Infection
o Acute iodine load e.g. CT contrast media
 Clinical features include:
o Fever >38.5 degrees Celcius
o Tachycardia
o Confusion and agitation
o Nausea and vomiting
o Hypertension

33
 o Heart failure
o Abnormal liver function test – jaundice may be seen clinically
 Management:
o Symptomatic treatment e.g. Paracetamol
o Treatment of underlying precipitating event
o Beta-blockers: Typically IV Propanolol – to treat the tachycardia (would be
contraindicated in patients suffering from asthma)
o Anti-thyroid drugs: e.g. Methimazole or Propylthiouracil – help reduce the effect of
raised serum thyroid hormones that are causing symptoms
o Lugol’s iodine
o Dexamethasone – e.g. 4mg IV qds; Blocks the conversion of T4 to T3
 Hydrocortisone – used to treat any underlying adrenal insufficiency which is
more common in patients suffering from hyperthyroidism, and can also help to
reduce serum thyroid hormone levels

TOXIC MULTINODULAR GOITRE

 Describes a thyroid gland that contains a number of autonomously functioning thyroid nodules
resulting in hyperthyroidism
 Nuclear scintigraphy: Patchy uptake
 Treatment of choice: Radioiodine therapy

HYPOTHYROIDISM: FEATURES

 General:
o Weight gain
o Lethargy
o Cold intolerance
 Skin:
o Dry (anhydrosis), cold, yellowish skin
o Non-pitting edema (e.g. hands, face)
o Dry, coarse scalp hair, loss of lateral aspect of eyebrows
 Gastrointestinal: Constipation
 Gynecological: Menorrhagia
 Neurological:
o Decreased deep tendon reflexes
o Carpal tunnel syndrome
 A hoarse voice is also occasionally noted
 Myxoedemic coma – presenting features: confusion, bradycardia, hypotension

34
 o Patients suffering from a myxoedemic coma due to secondary hypothyroidism are at risk
of hypopituitarism due to location of the lesion – thus patients are treated as presumed
adrenal insufficiency until it has been ruled out
o Treated with Thyroxine and Hydrocortisone
 Levothyroxine is used to replace the low levels of thyroid hormone
 Hydrocortisone is given to treat adrenal insufficiency

HYPOTHYROIDISM: MANAGEMENT

 Initial starting dose of Levothyroxine should be lower in elderly patients and those with ischemic
heart disease
o BNF recommends that for patients with cardiac disease, severe hypothyroidism or
patients over 50 years, the initial starting dose should be 25mcg OD with dose slowly
titrated
o Other patients should be started on a dose of 50-100mcg OD
 Following a change in thyroxine dose, thyroid function tests should be checked after 8-12 weeks
 The therapeutic goal is ‘normalisation’ of the thyroid stimulating hormone (TSH) level –
preferably to aim for TSH value 0.5-2.5 mU/L
 Women with established hypothyroidism who become pregnant should have their dose
increased ‘by at least 25-50mcg Levothyroxine’ due to the increased demands of pregnancy
o The TSH should be monitored carefully, aiming for a low-normal value
 There is no evidence to support combination therapy with levothyroxine and liothyronine
 Side effects of thyroxine therapy:
o Hyperthyroidism: due to over treatment
o Reduced bone mineral density
o Worsening of angina
o Atrial fibrillation
 Interactions: Iron – absorption of levothyroxine reduced, given at least 2 hours apart

SUBCLINICAL HYPERTHYROIDISM

 Defined as:
o Normal serum free thyroxine and triiodothyronine levels
o With a thyroid stimulating hormone below normal range (usually <0.1 mU/L)
 Causes:
o Multinodular goiter, particularly in elderly females
o Excessive thyroxine may give a similar biochemical picture

35
  Potentially affects cardiovascular system (supraventricular arrhythmias/ atrial fibrillation) and
bone metabolism (osteoporosis), may also impact on quality of life and increase likelihood of
dementia
 Management:
o TSH levels often revert to normal – therefore levels must be persistently low to warrant
intervention
o A reasonable treatment option is therapeutic trial of low-dose antithyroid agents for
approximately 6 months in an effort to induce a remission

SUBCLINICAL HYPOTHYROIDISM

 Basics: TSH raised, but T3, T4 normal; No obvious symptoms

 Significance:
o Risk of progressing to overt hypothyroidism is 2-5% per year (higher in men)
o Risk increased by the presence of thyroid autoantibodies
 Management:
o Not all patients require treatment
o TSH is between 4-10 mU/L and the free thyroxine level is within the normal range:
 If <65 years old with symptoms suggestive of hypothyroidism, given a trial of
Levothyroxine. If there is no improvement in symptoms, stop Levothyroxine
 In older people (especially those aged over 80 years), follow a ‘watch and wait’
strategy, generally avoiding hormonal treatment
 If asymptomatic people, observe and repeat thyroid function in 6 months
o TSH is >10mU/L and the free thyroxine level is within the normal range:
 Start treatment (even if asymptomatic) with Levothyroxine if ≤70 years
 In older people (especially those aged over 80 years), follow a ‘watch and wait’
strategy, generally avoiding hormonal treatment

HASHIMOTO’S THYROIDITIS

 Hashimoto’s thyroiditis (chronic autoimmune thyroiditis) is an autoimmune disorder of the

thyroid gland
 Hashimoto’s thyroiditis is associated with thyroid lymphoma
 Typically associated with hypothyroidism, although there may be a transient thyrotoxicosis in
the acute phase
 It is 10 times more common in women
 Features:
o Features of hypothyroidism

36
 o Goiter: firm, non-tender
o Anti-thyroid peroxidase and also anti-Tg antibodies

RIEDEL’S THYROIDITIS

 A rare cause of hypothyroidism

 Characterized by dense fibrous tissue replacing the normal thyroid parenchyma and by
extension of this fibrosis to adjacent structures of the neck
 Most patients are euthyroid, but hypothyroidism is noted in approximately 30% of cases
 On examination: A hard, fixed, painless goiter is noted
 May present with painless neck lump and symptoms of hypothyroidism such as weight gain,
tiredness, fatigue and intolerance
 Usually seen in middle-aged women
 Associated with retroperitoneal fibrosis
 NOT associated with hyperthyroidism, ascites or photosensitivity/ atrial fibrillation

SICK EUTHYROID SYNDROME

 A reversible state of abnormal thyroid function tests due to a non-thyroidal illness, without pre-
existing hypothalamic-pituitary or thyroid gland dysfunction
 By definition, after recovery of the non-thyroidal illness, thyroid function tests should revert
back to normal
 Causes of sick euthyroid include:
o Myocardial infarctions
o Starvation
o Burns
o Trauma
o Surgery
o Malignancy
o Diabetic ketoacidosis
o Any organ failure
o Any inflammatory conditions

37
  Pathology postulated is the down regulation of type 1 deiodinase, reducing the peripheral
conversion of T4 to T3 and thus reducing the basal metabolic rate during periods of stress
o Upregulation of type 3 deiodinase to inactive (reverse) T3 also aids to reducing basal
metabolic rate
 In sick euthyroid syndrome (now referred to as non-thyroidal illness), it is often said that
everything (TSH, thyroxine and T3 is low)
 In the majority of cases however, the TSH level is within the normal range (inappropriately
normal given the low thyroxine and T3)
 Changes are reversible upon recovery from the systemic illness, hence no treatment is usually
needed

SKIN DISORDERS ASSOCIATED WITH THYROID DISEASE

 Skin manifestations of hypothyroidism:

o Dry (anhydrosis), cold, yellowish skin
o Non-pitting edema (e.g. hands, face)
o Dry, coarse scalp hair, loss of lateral aspect of eyebrows
o Eczema
o Xanthomata
 Skin manifestations of hyperthyroidism:
o Pretibial myxedema: Erythematous, oedematous lesions above the lateral malleoli
 There are however case reports of it been found in hypothyroid patients,
especially the diffuse non-pitting variety
o Thyroid acropachy: Clubbing
o Scalp hair thinning
o Increased sweating
 Pruritus can occur in both hyper- and hypothyroidism

THYROID EYE DISEASE

 Affects between 25-50% of patients with Graves’ disease

 Pathophysiology:
o It is thought to be caused by an autoimmune response against an autoantigen, possibly
the TSH receptor  retro-orbital inflammation
o The inflammation results in glycosaminoglycan and collagen deposition in the muscles
 Prevention:
o Smoking is the most important modifiable risk factor for the development of thyroid eye
disease

38
 o Radioiodine treatment may increase inflammatory symptoms seen in thyroid eye
disease – in a recent study of patients with Graves’ disease, around 15% developed, or
had worsening of eye disease; Prednisolone may help reduce the risk
 Features:
o The patient may be eu-, hypo- or hyperthyroid at the time of presentation
o Exophthalmos
o Conjunctival oedema
o Optic disc swelling
o Ophthalmoplegia
o Inability to close the eye lids may lead to sore, dry eyes; If severe and untreated,
patients can be at risk of exposure keratopathy
 Severity of thyroid eye disease is not related to the degree of thyrotoxicosis in Graves’ disease
 Management:
o Topical lubricants may be needed to help prevent corneal inflammation caused by
exposure
o Steroids
o Radiotherapy
o Surgery
 For patients with established thyroid eye disease, the following symptoms/ signs should indicate
the need for urgent review by an ophthalmologist (EUGOGO guidelines):
o Unexplained deterioration in vision
o Awareness of change in intensity or quality of color vision in one or both eyes
o History of eye suddenly ‘popping out’ (globe subluxation)
o Obvious corneal opacity
o Cornea still visible when the eyelids are closed
o Disc swelling

PREGNANCY: THYROID PROBLEMS

 In pregnancy, there is an increase in the levels of thyroxine-binding globulin (TBG)

o Causes an increase in the levels of total thyroxine, but does not affect the free thyroxine
level

THYROTOXICOSIS

 Untreated thyrotoxicosis increases the risk of fetal loss, maternal heart failure and premature
labour
 Graves’ disease is the most common cause of thyrotoxicosis in pregnancy
o May present first or become worse during pregnancy and the post-natal period
 It is also recognized that activation of the TSH receptor by HCG may also occur – often termed
transient gestational hyperthyroidism
 HCG levels will fall in second and third trimester

39
  Exophthalmos is a specific sign seen in Graves’ disease and not in other hyperthyroid conditions
 In post-partum thyroiditis, the woman initially develops hyperthyroidism immediately after birth
followed by normal or sometimes decreased thyroid levels
 Management:
o Propylthiouracil has traditionally been antithyroid drug of choice
o However, propylthiouracil is associated with an increased risk of severe hepatic injury
o Propylthiouracil is used in the first trimester of pregnancy in place of Carbimazole (as
the latter drug may be associated with an increased risk of congenital abnormalities),
then at the beginning of 2nd trimester, should be switched back to Carbimazole
o Maternal free thyroxine levels should be kept in the upper third of the normal reference
range to avoid fetal hypothyroidism
o Thyrotrophin receptor stimulating antibodies should be checked at 30-36 weeks
gestation – helps to determine the risk of neonatal thyroid problems
o Block-and-replace regimes should not be used in pregnancy
o Radioiodine therapy is contraindicated

HYPOTHYROIDISM

 Thyroxine is safe during pregnancy

 Serum thyroid stimulating hormone measured in each trimester and 6-8 weeks post-partum
 Some women require an increased dose of thyroxine during pregnancy
 Breastfeeding is safe whilst on thyroxine

THYROID CANCER

 Features of hyperthyroidism or hypothyroidism are not commonly seen in patients with thyroid
malignancies as they rarely secrete thyroid hormones

TYPE PERCENTAGE NOTES

Papillary 70% Often young females – excellent prognosis

 Usually contain a mixture of papillary and colloidal filled

follicles
 Histologically tumor has papillary projections and pale
empty nuclei
 Seldom encapsulated
 Lymph node metastasis predominate
 Hematogenous metastasis rare
 Also appears to be associated with the RET oncogene
Follicular 20%

40
 Follicular Usually present as a solitary thyroid nodule
adenoma Malignancy can only be excluded on formal histological
assessment

Follicular May appear macroscopically encapsulated, microscopically

carcinoma capsular invasion is seen (without this finding, the lesion is a
follicular adenoma)
Vascular invasion predominates
Multifocal disease rare
Medullary 5% Cancer of parafollicular (C) cells – secrete calcitonin, part of MEN-
2; C cells derived from neural crest and not thyroid tissue

 Serum calcitonin levels often raised

 Familial genetic disease accounts for up to 20% cases
 Associated with RET oncogene
 Both lymphatic and hematogenous metastasis are
recognized, nodal disease is associated with a very poor
prognosis
Anaplastic 1%  Most common in elderly females
 Local invasion is common feature
 Not responsive to treatment, can cause pressure
symptoms
 Treatment is by resection where possible, palliation may
be achieved through isthmusectomy and radiotherapy;
chemotherapy is ineffective
Lymphoma Rare Associated with Hashimoto’s thyroiditis

 Management of papillary and follicular cancer:

o Total thyroidectomy
o Followed by radioiodine (I-131) to kill residual cells
o Yearly thyroglobulin levels to detect early recurrent disease

Anaplastic thyroid cancer

 Anaplastic thyroid cancer – aggressive, difficult to treat and often causes pressure symptoms
 A highly aggressive, locally invasive tumor
 Typically presents in older patients with a rapidly increasing mass or lymph node
 Anaplastic tumors invades local surrounding tissues causing compression symptoms including:
pain, shortness of breath and dysphagia
 The aggression of the tumor often leads to lymphovascular invasion and subsequent bone and
lung metastasis
 The cancer originates from follicular cells, which are poorly differentiated and have a high
mitotic rate
 The prognosis is poor with a 5-year survival rate quoted between 7-14%
 Treatment is usually palliative, with combination of radiotherapy and chemotherapy

41
PENDRED’S SYNDROME

 Autosomal recessive genetic disorder

 Characterized by bilateral sensorineural deafness, with mild hypothyroidism and a goiter
 The patients tend to present with progressive hearing loss and delay in academic progression
 Often head trauma tends to make the sensorineural deafness worse, leading to patients having
to avoid contact sports
 In Pendred syndrome, there is a defect in the organification of iodine, leading to
dyshormonogenesis
o However thyroid symptoms are often mild in Pendred syndrome
o Patients are often clinically euthyroid, presenting only with goiter
o Thyroid function tests are also often normal, requiring perchlorate discharge test to aid
diagnosis
 Syndrome can be diagnosed via genetic testing (Pendred syndrome (PDS) gene, chromosome 7),
audiometry and MRI imaging to look for characteristic one and a half turns in the cochlea,
compared to the normal 2 ½ turns
 Treatment: Thyroid hormone replacement and cochlear implants

HYPERCALCEMIA: CAUSES

 2 conditions account for 90% of cases of hypercalcemia:

o Primary hyperparathyroidism: commonest cause in non-hospitalised patient
o Malignancy: commonest cause in hospitalized patient; may be due to number of
processes, including bone metastases, myeloma, PTHrP from squamous cell lung cancer
 Other causes include:
o Sarcoidosis
 Other causes of granulomas may lead to hypercalcemia e.g. Tuberculosis and
histoplasmosis
o Vitamin D intoxication
o Acromegaly
o Thyrotoxicosis
o Milk-alkali syndrome
o Drugs: thiazides, calcium containing antacids
o Dehydration
o Addison’s disease
o Paget’s disease of the bone – calcium usually normal, but hypercalcemia may occur with
prolonged immobilization

42
PRIMARY HYPERPARATHYROIDISM

 In exams, primary hyperparathyroidism is stereotypically seen in elderly females with an

unquenchable thirst and an inappropriately normal or raised parathyroid hormone level
 Most commonly due to a solitary adenoma
 Causes of primary hyperparathyroidism:
o 80%: solitary adenoma
o 15%: Hyperplasia
o 4%: multiple adenoma
o 1%: carcinoma
 Features – ‘bones, stones, abdominal groans and psychic moans’
o Polydipsia, polyuria
o Peptic ulceration/ constipation/ pancreatitis
o Bone pain/ fracture
o Renal stones
o Depression
o Hypertension
 Associations:
o Hypertension
o Multiple endocrine neoplasia: MEN I and II
 Investigations:
o Raised calcium, low phosphate
o PTH may be raised or (inappropriately, given the raised calcium) normal
o Technetium-MIBI subtraction scan
o Pepperpot skull is a characteristic X-ray finding of hyperparathyroidism
 Treatment:
o Definitive management: Total parathyroidectomy
o Conservative management may be offered if the calcium level is less than 0.25mmol/L
above the upper limit of normal AND the patient is >50 years AND there is no evidence
of end-organ damage
o Calcimimetic agents such as cinacalcet are sometimes used in patients who are
unsuitable for surgery
 Circumstances which parathyroidectomy should be considered in primary hyperparathyroidism:
o Age under 50 years
o Adjusted serum calcium concentration that is 0.25 mmol/L or more above the upper
end of the reference range
o Estimated glomerular filtration rate (eGFR) less than 60 mL/min/1.73m2 (this threshold
depends on other factors, such as age)
o Renal stones or presence of nephrocalcinosis on ultrasound or CT
o Presence of osteoporosis or osteoporotic fracture
o Symptomatic disease

43
  X-ray changes of hyperparathyroidism: Hand radiographs demonstrating generalized
osteopenia, erosion of the terminal phalangeal tufts (acro-osteolysis) and subperiosteal
resorption of bone particularly the radial aspects of the 2nd and 3rd middle phalanges

DISEASE
Primary hyperparathyroidism
Secondary hyperparathyroidism
Tertiary hyperparathyroidism
Pseudohypoparathyroidism
NOTES
PTH over-secretion usually from a parathyroid adenoma
Both PTH and calcium are elevated
Surgery to remove adenoma is the most effective treatment
Conservative measures such as bisphosphonates can be used
Occurs in chronic kidney disease typically
Can be secondary to Vitamin D deficiency
PTH released due to low calcium, high phosphate and lack of
Vitamin D activation by diseased kidneys
PTH level high with calcium levels being low or normal
Medical management primarily: Phosphate binders, calcium and
vitamin D supplementation
Autonomous hypersecretion of PTH due to hypertrophied
parathyroid glands
Occurs after a period of long-standing secondary
hyperparathyroidism
Treatment involves parathyroidectomy
Caused by PTH resistance
Associated with low calcium and high PTH levels
MEN1 is a rare hereditary disorder involving multiple types of
endocrine tissue neoplasia

HYPOPARATHYROIDISM

 Primary hypoparathyroidism:
o Decrease PTH secretion
o E.g. secondary to thyroid surgery
o Low calcium, high phosphate
o Treated with alfacalcidol
 Main symptoms of hypoparathyroidism are secondary to hypocalcemia:
o Tetany: Muscle twitching, cramping and spasm
o Perioral paraesthesia
o Trousseau’s sign: carpal spasm if the brachial artery occluded by inflating blood pressure
cuff and maintaining pressure above systolic
o Chvostek’s sign: Tapping over parotid causes facial muscles to twitch

44
 o If chronic: Depression, cataracts
o ECG: Prolonged QT interval
 Pseudohypoparathyroidism:
o Target cells being insensitive to PTH
o Due to abnormality in a G protein
o Associated with: Low IQ, short stature, shortened 4th and 5th metacarpals
o Low calcium, high phosphate, high PTH
o Diagnosis is made by measuring urinary cAMP and phosphate levels following an
infusion of PTH
 In hypoparathyroidisim, this will cause an increase in both cAMP and phosphate
levels
 In pseudohypoparathyroidism type I, neither cAMP nor phosphate levels are
increased
 In pseudohypoparathyroidism type II, only cAMP is raised
 Pseudopseudohypoparathyroidism: Similar phenotype to pseudohypoparathyroidism, but
normal biochemistry

PSEUDOHYPOPARATHYROIDISM

 Caused by target cell insensitivity to parathyroid hormone (PTH) due to a mutation in a G-

protein
 In type I pseudohypoparathyroidism, there is a complete receptor defect whereas in type II, the
cell receptor is intact
 Pseudohypoparathyroidism is typically inherited in an autosomal dominant fashion
 Bloods:
o PTH: high
o Calcium: low
o Phosphate: high
 Features:
o Short fourth and fifth metacarpals
o Short stature
o Cognitive impairment
o Obesity
o Round face
 Investigation: Infusion of PTH followed by measurement of urinary phosphate and cAMP
measurement
o Can help to differentiate between type I (neither phosphate or cAMP levels rise) and II
(cAMP rises but phosphate levels do not change)

45
CORTICOSTEROIDS

 Corticosteroids are amongst the most commonly prescribed therapies in clinical practice
 Used both systemically (oral or intravenous) or locally (skin creams, inhalers, eye drops, intra-
articular)
 They augment and in some cases replace the natural glucocorticoid and mineralocorticoid
activity of endogenous steroids

Minimal glucocorticoid Glucocorticoid activity, Predominant Very high

activity, very high high mineralocorticoid glucocorticoid activity, glucocorticoid activity,
mineralocorticoid activity low mineralocorticoid minimal
activity activity mineralocorticoid
activity
Fludrocortisone Hydrocortisone Prednisolone Dexamethasone,
Betmethasone

 Prednisolone can cause neutrophilia through:

o Demargination of neutrophils via the endovascular lining
o Delayed migration of neutrophils into tissue
o Release of immature neutrophils from bone marrow

During bacterial infection, there is an increased ‘left shift’ seen on microscopy. In ‘left shift’, neutrophils
are produced and released from the bone marrow at an equal rate to their consumption in the
circulation

With steroid use, ‘left shift’ generally does not occur due to increased production and release of
neutrophils from the bone marrow, but no neutrophil consumption

 Side effects of corticosteroids – more common with systemic and prolonged therapy

46
  Glucocorticoid side-effects:
o Endocrine: Impaired glucose regulation, increased appetite/ weight gain, hirsutism,
hyperlipidemia
o Cushing’s syndrome: moon face, buffalo hump, striae
o Musculoskeletal: Osteoporosis/ osteopenia, proximal myopathy, avascular necrosis of
the femoral head
o Immunosuppression: Increased susceptibility to severe infection, reactivation of
tuberculosis
o Psychiatric: Insomnia, mania, depression, psychosis
o Gastrointestinal: Peptic ulceration, acute pancreatitis
o Ophthalmic: Glaucoma, cataracts
o Suppression of growth in children
o Intracranial hypertension
o Neutrophilia
 Mineralocorticoid side-effects:
o Fluid retention
o Hypertension
 Other points:
o Patients on long-term steroids should have their doses doubled during intercurrent
illness
o BNF suggests gradual withdrawal of systemic corticosteroids if patients have received
more than 40mg Prednisolone daily for more than 1 week or received more than 3
weeks treatment or recently received repeated courses
o There are some situations where it is important to combine high glucocorticoid (anti-
inflammatory) activity with minimal mineralocorticoid (fluid-retention) effects – a good
example is the use of dexamethasone for patients with raised intracranial pressure
secondary to brain tumors

CUSHING’S SYNDROME

 Features:
o Weight gain
o Hirsutism
o Depression
o Hypertension

CUSHING’S SYNDROME: CAUSES

 Note that exogenous causes of Cushing’s syndrome (e.g. glucocorticoid therapy) are far more
common than endogenous ones
 Cushing’s disease is the most common, non-iatrogenic, cause of Cushing’s syndrome

47
  ACTH dependent causes:
o Cushing’s disease (80%): pituitary tumor secreting ACTH producing adrenal hyperplasia
o Ectopic ACTH production (5-10%): e.g. small cell lung cancer
 ACTH independent causes:
o Iatrogenic: steroids
o Adrenal adenoma (5-10%)
o Adrenal carcinoma (rare)
o Carney complex: syndrome including cardiac myxoma
o Micronodular adrenal dysplasia (very rare)
 Pseudo-Cushing’s:
o Mimics Cushing’s
o Often due to alcohol excess or severe depression
o Causes false positive dexamethasone suppression test or 24 hour urinary free cortisol
o Insulin stress test may be used to differentiate

CUSHING’S SYNDROME: INVESTIGATIONS

 Investigations divided into confirming Cushing’s syndrome and then localizing the lesion
 Hypokalemic metabolic alkalosis may be seen, along with impaired glucose tolerance
 Ectopic ACTH secretion (secondary to small cell lung cancer) – characteristically associated with
very low potassium levels
 Insulin stress test  to differentiate between the Cushing’s and pseudo-Cushing’s
 2 most commonly used tests to confirm Cushing’s syndrome:
o Overnight dexamethasone suppression test (most sensitive)
o 24-hour urinary free cortisol

Localization tests

 First-line localization test is 9am and midnight plasma ACTH (and cortisol) levels
o If ACTH is suppressed, then a non-ACTH dependent cause is likely such as an adrenal
adenoma
 Both low- and high-dose dexamethasone suppression tests may be used to localize the
pathology resulting in Cushing’s syndrome

Cortisol result Interpretation

Not suppressed by low-dose dexamethasone
Not suppressed by low-dose, but suppressed by
high-dose dexamethasone
Not suppressed by low- or high-dose
dexamethasone
Cushing’s syndrome not due to primary causes,
i.e. likely secondary to corticosteroid therapy
Cushing’s disease
Ectopic ACTH syndrome likely

 CRH stimulation

48
 o If pituitary source, then cortisol rises
o If ectopic/ adrenal, then no change in cortisol
 Petrosal sinus sampling of ACTH may be needed to differentiate between pituitary and ectopic
ACTH secretion

INSULIN STRESS TEST

 Used in the investigation of hypopituitarism

 Occasionally used to differentiate Cushing’s from pseudo-Cushing’s
 IV insulin given, GH and cortisol levels measured
 With normal pituitary function, GH and cortisol should rise
 Contraindications:
o Epilepsy
o Ischemic heart disease
o Adrenal insufficiency

ADDISON’S DISEASE

 Autoimmune destruction of the adrenal glands is the commonest cause of primary

hypoadrenalism in the UK, accounting for 80% of cases
 This is termed Addison’s disease – results in reduced cortisol and aldosterone being produced
 Addison’s is adrenocortical insufficiency due to the dysfunction/ destruction of the adrenal
cortex – affects both glucocorticoid (metabolism of glucose etc.) and mineralocorticoid (salt
balance) function
 Dehydroepiandrosterone is the most abundant circulating adrenal steroid
o Adrenal glands are the main source of DHEA in females
o Loss of functioning adrenal tissue as in Addison’s disease may result in symptoms
secondary to androgen deficiency, such as loss of libido
 Deficiency of glucocorticoids, mineralocorticoids, as well as lower levels of androgens, which are
usually produced in females by the zona reticularis of the adrenal cortex  leads to thinning of
hair grown at puberty, which is androgen dependent
o Scalp hair is unaffected
 Patients with Addison’s disease are prone to developing hypoglycemia due to loss of the
glucogenic effect of glucocorticoids, thus glucose level must be checked if given sudden
deterioration in GCS
 Commonest cause in the developed world is autoimmune adrenalitis
o Other causes include destruction of the cortex by infections such as TB, or metastasis
o Other causes damage to the adrenal gland:
 Infiltration of the adrenal gland by amyloidosis
 Hemorrhage into the adrenal gland
 Autoimmune adrenal failure
 Infiltration of the adrenal gland by tuberculosis
 Features:

49
 o Lethargy, weakness, anorexia, nausea and vomiting, weight loss, ‘salt-craving’
o Hyperpigmentation (especially palmar creases), vitiligo, loss of pubic hair in women,
hypotension, hypoglycemia
o Hyponatremia and hyperkalemia may be seen
o Crisis: collapse, shock, pyrexia

Primary Addison’s is associated with hyperpigmentation, whereas secondary adrenal insufficiency is not

Other causes of hypoadrenalism

 Primary causes:
o Tuberculosis
o Metastases (e.g. bronchial carcinoma)
o Meningococcal septicaemia (Waterhouse-Friderichsen syndrome)
o HIV
o Antiphospholipid syndrome
 Secondary causes:
o Pituitary disorders (e.g. tumors, irradiation, infiltration)
o Exogenous glucocorticoid therapy

ADDISON’S DISEASE: INVESTIGATIONS

 In a patient with suspected Addison’s disease, the definite investigation is an ACTH stimulation
test (short Synacthen test)
o Short Synacthen test is a method of excluding adrenal insufficiency – excludes only
primary adrenal failure, and does not exclude cortisol deficiency secondary to failure of
the pituitary to produce ACTH (e.g. pituitary failure due to damage by an enlarging
pituitary malignancy)
o Plasma cortisol is measured before and 30 minutes after given IM Synacthen 250
microgram
o If the cortisol post ACTH rises to >420 nmol/L at 30 minutes, the adrenal response to
ACTH is adequate and Addison’s disease (adrenal failure) can be excluded
 Adrenal autoantibodies such as anti-21-hydroxylase may also be demonstrated
 If an ACTH stimulation test is not readily available (e.g. in primary care), then sending a 9am
serum cortisol can be useful:
o >500 nmol/L makes Addison’s very unlikely
o <100 nmol/L is definitely abnormal (makes Addison’s disease or hypoadrenalism likely)
o 100-500 nmol/L (inconclusive) should prompt a ACTH stimulation test to be performed

Whilst 9am cortisol can be useful in the diagnosis of Conn’s, patients typically require plasma renin:
aldosterone level

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  Associated electrolyte abnormalities are seen in around 1/3 of undiagnosed patients:
o Hyperkalemia
o Hyponatremia
o Hypoglycemia
o Metabolic acidosis
 Most important first step in therapy is corticosteroid replacement
o Although features of hypothyroidism may co-exist with hypoadrenalism, commencing
thyroxine may worsen any adrenal crisis
o Fluid replacement with normal saline is unlikely to be effective without commencing
hydrocortisone therapy
o Oral fludrocortisone is added to hydrocortisone in patients who are corticosteroid
replete, but still suffer from symptoms of hyponatremia or volume depletion

ADDISONIAN CRISIS

 Addisonian crisis is a medical emergency

 Causes:
o Sepsis or surgery causing an acute exacerbation of chronic insufficiency (Addison’s,
Hypopituitarism)
o Adrenal hemorrhage e.g. Waterhouse-Friderichsen syndrome (fulminant
meningococcemia)
o Steroid withdrawal
 Signs/ symptoms of Addisonian crisis:

Neurological Hemodynamic Biochemical

 Syncope  Hypotension  Hyponatremia
 Confusion  Hypothermia  Hyperkalemia
 Lethargy  Hypoglycemia
 Convulsions

 Management:
o Hydrocortisone 100mg IM or IV
 IV Dexamethaosone is often preferred as this will not interfere with cortisol
assays needed for a short synacthen test, unlike hydrocortisone
o 1L normal saline infused over 30-60 minutes or with dextrose if hypoglycemic
o Continue hydrocortisone 6 hourly until patient is stable
 No fludrocortisone is required because high cortisol exerts weak
mineralocorticoid action

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 o Oral replacement may begin after 24 hours and be reduced to maintenance over 3-4
days

AUTOIMMUNE POLYENDOCRINOPATHY SYNDROME

 Addison’s disease (autoimmune hypoadrenalism) is associated with other endocrine deficiencies

in approximately 10% of patients
 There are 2 distinct types of autoimmune polyendocrinopathy syndrome (APS), with type 2
(sometimes referred to as Schmidt’s syndrome) being much more common
 APS type 2 has a polygenic inheritance and is linked to HLA DR3/ DR4 – patients have Addison’s
disease plus either:
o Type 1 diabetes mellitus
o Autoimmune thyroid disease
 APS type 1 is occasionally referred to as Multiple Endocrine Deficiency Autoimmune Candidiasis
(MEDAC) – a very rare autosomal recessive disorder caused by mutation of AIRE1 gene on
chromosome 21
 Features of APS type 1 (2 out of 3 needed):
o Chronic mucocutaneous candidiasis (typically first feature as young child)
o Addison’s disease
o Primary hypoparathyroidism (usually the first endocrine manifestation)
 Vitiligo can occur in both types

GYNAECOMASTIA

 Describes an abnormal amount of breast tissue in males

 Usually caused by an increased oestrogen: androgen ratio
 Important to differentiate the causes of galactorhea (due to the actions of prolactin on breast
tissue) from those of gynecomastia
 Causes of gynecomastia:
o Physiological: normal in puberty
o Syndromes with androgen deficiency: Kallman’s, Klinefelter’s
o Testicular failure: e.g. mumps
o Liver disease
o Testicular cancer e.g. seminoma secreting beta-hCG
o Ectopic tumor secretion
o Hyperthyroidism (Gynaecomastia is not a feature of hypothyroidism)
o Hemodialysis
o Drugs:
 Spironolactone (most common drug cause)

52
  Cimetidine
 Digoxin
 Cannabis
 Finasteride
 Gonadorelin analogues e.g. Goserelin, Buserelin (Goserelin is used in the
treatment of advanced prostate cancer)
 Oestrogens, anabolic steroids
 Very rare drug causes of gynecomastia:
o Tricyclics
o Isoniazid
o Calcium channel blockers
o Heroin
o Busulfan
o Methyldopa
 Tamoxifen may be used to treat gynecomastia

PROLACTIN AND GALACTORRHEA

 Prolactin is secreted by the anterior pituitary gland with release being controlled by a wide
variety of physiological factors
 Prolactin is unique amongst the pituitary hormones – being tonically inhibited by the
hypothalamus (under continuous inhibition)
 Features of excess prolactin:
o Men: Impotence, loss of libido, galactorrhea
o Women: Amenorrhea, galactorrhea
 Causes of raised prolactin – the P’s:
o Prolactinoma
o Pregnancy
o Oestrogens
o Physiological: stress, exercise, sleep
o Acromegaly: 1/3 of patients
o Polycystic ovarian syndrome
o Primary hypothyroidism (due to thyrotrophin releasing hormone (TRH) stimulating
prolactin release)
 Drug causes of raised prolactin:
o Metoclopramide, domperidone
o Phenothiazines
o Haloperidol

53
 o Very rare: SSRIs, opioids
 Dopamine acts as the primary prolactin releasing inhibitory factor, hence dopamine agonists
such as bromocriptine may be used to control galactorrhea
 Cabergoline (a dopamine agonist) – more commonly used in the medical management of
prolactinoma (as opposed to acromegaly)

ACROMEGALY: FEATURES

 There is excess growth hormone secondary to a pituitary adenoma in over 95% of cases
 A minority of cases are caused by ectopic GHRH or GH production by tumors e.g. pancreatic
 Growth hormone stimulates insulin growth factor-1 release from the liver
 Somatostatin directly inhibits the release of growth hormone  somatostatin analogues are
used to treat acromegaly
 Features:
o Coarse facial appearance, spade-like hands, increase in shoe size
o Large tongue, prognathism, interdental spaces
o Excessive sweating and oily skin: caused by sweat gland hypertrophy
o Features of pituitary tumor: hypopituitarism, headaches, bitemporal hemianopia
o Raised prolactin in 1/3 of cases  galactorrhea
o 6% of patients have MEN-1
 Patients with acromegaly have an increased incidence of colorectal polyps and colorectal
carcinoma
o Recommended that patients with acromegaly have an initial colonoscope at age 40, and
enter a surveillance program based on the results of the colonoscopy
 Carpal tunnel syndrome and sleep apnea are classic complications of acromegaly
 Complications:
o Hypertension – associated with systemic rather than pulmonary hypertension
o Diabetes (>10%)
o Cardiomyopathy
o Colorectal cancer

ACROMEGALY: INVESTIGATIONS

 Growth hormone (GH) levels vary during the day and are therefore not diagnostic
 1st line investigation: Serum IGF-1 levels – now overtaken the oral glucose tolerance test
(OGTT) with serial GH measurements
 OGTT test is recommended to confirm the diagnosis if IGF-1 levels are raised
o In normal patients, GH is suppressed to <2 mu/L with hyperglycemia
o In acromegaly, there is no suppression of GH
o May also demonstrate impaired glucose tolerance which is associated with acromegaly
 Endocrine Society guidelines suggest:

54
 o Recommend measurement of IGF-1 levels in patients with typical clinical manifestations
of acromegaly, especially those with acral and facial features
o In patients with elevated or equivocal serum IGF-1 levels, we recommend confirmation
of the diagnosis by finding lack of suppression of GH to <1 microgram/L following
documented hyperglycemia during an oral glucose load
 Serum IGF-1 may also be used to monitor disease
 A pituitary MRI may demonstrate a pituitary tumor

ACROMEGALY: MANAGEMENT

 Trans-sphenoidal surgery is the first-line treatment for acromegaly in the majority of patients
 Somatostatin analogue – e.g. Octreotide
o Directly inhibits the release of growth hormone
o Effective in 50-70% of patients
o May be used as an adjunct to surgery
o Results in reduced growth hormone levels and reduction in tumor size
 Dopamine agonists – e.g. Bromocriptine
o First effective medical treatment for acromegaly, however now superseded by
somatostatin analogue
o Effective only in a minority of patients
 Pegvisomant – a GH receptor antagonist; prevents dimerization of the GH receptor
o Once daily S/C administration
o Very effective – decreases IGF-1 levels in 90% of patients to normal
o Does not reduce tumor volume therefore surgery still needed if mass effect
 External irradiation is sometimes used for older patients or following failed surgical/ medical
treatment

PITUITARY ADENOMA

 A benign tumor of the pituitary gland

 They are common (10% of all people), but in most cases will never be found (asymptomatic) or
are found as an incidental finding
 Account for around 10% of adult brain tumors
 Pituitary adenoma can be classified according to:
o Size (a microadenoma is <1cm and a macroadenoma is >1cm)
o Hormonal status (a secretory/ functioning adenoma produces and excess of a particular
hormone and a non-secretory/ functioning adenoma does not produce a hormone to
excess)
 Prolactinomas are the most common type – they produce an excess of prolactin
o After prolactinomas, non-secreting adenomas are the next most common, then GH
secreting and then ACTH secreting adenomas

55
  Pituitary adenomas typically cause symptoms by:
o Excess of hormone (e.g. Cushing’s disease due to excess ACTH, acromegaly due to
excess GH or amenorrhea and galactorrhea due to excess prolactin)
o Depletion of a hormone (s) (due to compression of the normal functioning pituitary
gland)
o Stretching of the dura within/ around pituitary fossa (causing headaches)
o Compression of the optic chiasm (causing a bitemporal hemianopia due to crossing
nasal fibers)
 Alternatively, pituitary adenomas, particularly microadenomas, can be an incidental finding on
neuroimaging and therefore called a ‘pituitary incidentaloma’
 Hormones secreted:
o Prolactin – 35%
o No obvious hormone, ‘non-functioning’, ‘chromophobe’ – 30%
o Growth hormone – 20%
o Prolactin and growth hormone – 7%
o ACTH – 7%
o Others: TSH, LH, FSH – 1%
 Non-functioning pituitary tumors – present with hypopituitarism and pressure effects
o Whilst the prolactin level is slightly raised, this can be caused by the pressure effects of
the tumor preventing dopamine (which inhibits prolactin release) from reaching the
normal prolactin-producing cells
o Much higher levels would be expected with a prolactinoma
 Investigation requires:
o A pituitary blood profile (including: GH, prolactin, ACTH, FH, LSH, and TFTs)
o Formal visual field testing
o MRI brain with contrast
 Differential diagnoses include:
o Pituitary hyperplasia
o Craniopharyngioma
o Meningioma
o Brain metastases
o Lymphoma
o Hypophysitis
o Vascular malformation (e.g. aneurysm)
 Treatment may include a combination of:
o Hormonal therapy (e.g. bromocriptine is the first line treatment for prolactinomas)
o Surgery (e.g. trans-sphenoidal transnasal hypophysectomy)
o Radiotherapy

PRIMARY HYPERALDOSTERONISM

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  Primary hyperaldosteronism was previously thought to be most commonly caused by an adrenal
adenoma, termed Conn’s syndrome
o Recent studies shown that bilateral idiopathic adrenal hyperplasia is the cause in up to
70% of cases
o Differentiating between the 2 is important as this determines treatment
 Adrenal carcinoma is an extremely rare cause of primary hyperaldosteronism
 Aldosterone is elevated in bilateral renal artery stenosis due to reduced renal perfusion – high
renin levels also seen as renal perfusion is permanently reduced, despite hypertension, due to
the stenotic renal arteries
 Features:
o Hypertension
o Hypokalemia (e.g. muscle weakness) – A classical feature in exams, but studies suggest
this is seen in only 10-40% of patients
o Alkalosis
 Investigations:
o 2016 Endocrine Society recommend that a plasma aldosterone/ renin ratio is the first-
line investigation in suspected primary hyperaldosteronism
 Aldosterone is high in primary hyperaldosteronism, however, serum renin is
usually low in primary hyperaldosteronism due to the resulting hypertension
causing excessive renal perfusion  resulting in decreased renin production
(negative feedback mechanism)
 Will show high aldosterone levels alongside low renin levels (negative feedback
due to sodium retention from aldosterone)
o Following this, a high-resolution CT abdomen and adrenal vein sampling is used to
differentiate between unilateral and bilateral sources of aldosterone excess
 Medications that can cause false-negative renin: aldosterone ratio results are:
o Angiotensin-converting enzyme inhibitors (e.g. Ramipril or Lisinopril) – due to
interference with the RAAS (renin-angiotensin-aldosterone system)
o Angiotensin receptor blockers (e.g. Losartan)
o Direct renin inhibitors (e.g. Aliskiren)
o Aldosterone antagonists (e.g. Spironolactone or Eplerenone)
 Management:
o Adrenal adenoma: Surgery
o Bilateral adrenocortical hyperplasia: Aldosterone antagonist e.g. Spironolactone

PHAEOCHROMOCYTOMA

 A rare catecholamine secreting tumor

 About 10% are familial and may be associated with MEN type II, neurofibromatosis and von
Hippel-Lindau syndrome
 Basics:

57
 o Bilateral in 10%
o Malignant in 10%
o Extra-adrenal in 10% (most common site = organ of Zuckerkandl, adjacent to the
bifurcation of the aorta)
 Features are typically episodic:
o Hypertension (around 90% of cases, may be sustained) – episodic hypertension,
associated with bursts of catecholamine release
o Headaches
o Palpitations
o Sweating
o Anxiety
 Tests: 24-hour urinary collection of metanephrines (sensitivity 97%) (replaced 24-hour urinary
collection of catecholamines with sensitivity of 86%)
o Three 24-hour collections are needed as some patients have intermittently raised levels
 Surgery is the definitive management – but patient must first however be stabilized with
medical management:
o Alpha-blocker (e.g. phenoxybenzamine)
 Phenoxybenzamine is a non-selective alpha-adrenoceptor antagonist and should
be started before a beta-blocker is introduced

PHaechromocytoma – give PHenoxybenzamine before beta-blockers

o Beta blocker (e.g. propranolol)

MULTIPLE ENDOCRINE NEOPLASIA

 MEN is inherited as an autosomal dominant disorder

MEN TYPE I MEN TYPE IIa MEN TYPE IIb

3 P’s: Medullary thyroid cancer (70%) Medullary thyroid cancer
 Parathyroid (95%):
Hyperparathyroidism 2 P’s: 1 P:
due to parathyroid  Parathyroid (60%)  Phaeochromocytoma
hyperplasia  Phaeochromocytoma
 Pituitary (70%) Marfanoid body habitus
 Pancreas (50%): e.g. Neuromas
Insulinoma, gastrinoma
(leading to recurrent
peptic ulceration)

Also: Adrenal and thyroid

MEN1 gene RET oncogene RET oncogene

Most common presentation =

hypercalcemia
Peptic ulceration, galactorrhea,

58
hypercalcemia = multiple
endocrine neoplasia type 1

High incidence of parathyroid

tumors and hypercalcemia
make serum calcium a useful
indicator of MEN type 1 in
suspected individuals

 When differentiating between MEN 2A and 2B, it is worth remembering that MEN 2B has similar
characteristics as MEN 2A - Thyroid carcinoma, adrenal tumors, parathyroid hyperplasia
 But in addition, MEN 2B typically have a Marfanoid appearance and mucosal neuromas, as well
as the absence of hyperparathyroidism
 MEN type 1 is characterized by pancreatic neuroendocrine tumors, pituitary adenoma and
parathyroid hyperplasia

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MENSTRUAL CYCLE

 May be divided into the following phases:

o Menstruation: Day 1-4
o Follicular phase (proliferative phase): Day 5-13
o Ovulation: Day 14
o Luteal phase (secretory phase): Day 15-28

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 Follicular phase (proliferative Luteal phase (secretory phase)
phase)
Ovarian histology A number of follicles develop Corpus luteum

One follicle will become

dominant around the mid-
follicular phase
Endometrial histology Proliferation of endometrium Endometrium changes to
secretory lining under influence

61

Hormones A rise in FSH results in
development of follicles which
in turn secrete oestradiol
of progesterone
Progesterone secreted by
corpus luteum rises through the
luteal phase (Progesterone is
secreted by the corpus luteum
following ovulation)

When the egg has matured, it If fertilization does not occur,

secretes enough oestradiol to the corpus luteum will
trigger acute release of LH, in degenerate and progesterone
turn leads to ovulation levels fall

Oestradiol levels also rise again

during the luteal phase
Cervical mucus Following menstruation, the Under the influence of
mucus is thick and forms a plug progesterone, it becomes thick,
across the external os scant and tacky

Just prior to ovulation, the

Basal body temperature
mucus becomes clear, acellular,
low viscosity. It also becomes
‘stretchy’ – a quality termed
spinnbarkeit
Falls prior to ovulation due to Rises following ovulation in
the influence of oestradiol response to higher
progesterone levels

AMENORRHEA

 May be divided into primary (failure to start menses by the age of 16 years) or secondary
(cessation of established, regular menstruation for 6 months or longer)
 Causes of primary amenorrhea:
o Turner’s syndrome
o Testicular feminization
o Congenital adrenal hyperplasia

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 o Congenital malformations of the genital tract
 Secondary amenorrhea – defined as when menstruation has previously occurred, but has now
stopped for at least 6 months
 Causes of secondary amenorrhea (after excluding pregnancy):
o Hypothalamic amenorrhea (e.g. stress, excessive exercise)
o Polycystic ovarian syndrome (PCOS)
o Hyperprolactinemia
o Premature ovarian failure
o Thyrotoxicosis (hypothyroidism may also cause amenorrhea)
o Sheehan’s syndrome
o Asherman’s syndrome (intrauterine adhesions)
 Initial investigations:
o Exclude pregnancy with urinary or serum beta-HCG
o Gonadotrophins: low levels indicate a hypothalamic cause, while raised levels suggest
an ovarian problem (e.g. premature ovarian failure)
o Prolactin
o Androgen levels: Raised levels may be seen in PCOS
o Oestradiol
o Thyroid function tests

HYPOTHALAMIC AMENORRHEA

 Energy deficit:
o Weight loss
o Exercise-induced
 Suppression GnRH secretion:
o Decreased gonadotrophin pulsation
o Low or normal LH secretions, low estradiol
o FSH usually in normal range (FSH would be raised in premature ovarian failure)
o Mimics prepubertal state

POLYCYSTIC OVARIAN SYNDROME: FEATURES AND INVESTIGATIONS

 PCOS is a complex condition of ovarian dysfunction thought to affect between 5-20% of women
of reproductive age
 Etiology of PCOS is not fully understood

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  Both hyperinsulinemia and high levels of luteinizing hormone are seen in PCOS and there
appears to be some overlap with the metabolic syndrome
 Features:
o Subfertility and infertility
o Menstrual disturbances: Oligomenorrhea and amenorrhea
o Hirsutism, acne (due to hyperandrogenism)
o Obesity
o Acanthosis nigricans (due to insulin resistance)
 Clitoromegaly is seen occasionally in PCOS, but is normally associated with very high androgen
levels
o If clitoromegaly is found, then further investigations to exclude an ovarian or adrenal
androgen secreting tumor are required
 Investigations:
o Pelvic ultrasound: Multiple cysts on the ovaries
o FSH, LH, prolactin, TSH and testosterone are useful investigations
 Raised LH: FSH ratio is a ‘classical’ feature, but no longer thought to be useful in
diagnosis
 Prolactin may be normal or mildly elevated
 Testosterone may be normal or mildly elevated; However, if markedly raised
consider other causes
o Check for impaired glucose tolerance

POLYCYSTIC OVARIAN SYNDROME: MANAGEMENT

 PCOS is a complex condition of ovarian dysfunction thought to affect between 5-20% of women
of reproductive age
 General management:
o Weight reduction if appropriate
o If a women requires contraception, then a combined oral contraceptive (COC) pill may
help regulate her cycle and induce a monthly bleed
 Hirsutism and acne:
o A COC pill may be used to help manage hirsutism. Possible options include a 3rd
generation COC which has fewer androgenic effects or co-cyprindiol which has an anti-
androgen action; Both of these types of COC may carry increased risk of venous
thromboembolism
o If does not respond to COC, then topical eflornithine may be tried
o Spironolactone, flutamide and finasteride may be used under specialist supervision
 Infertility:
o Weight reduction if appropriate
o Management of infertility in patients with PCOS should be supervised by specialist

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 o 2007 trial published in the NEJM suggested Clomifene was the most effective
treatment for infertility (Clomifene superior to Metformin in treating infertility in
PCOS)
 Potential risk of multiple pregnancies with anti-oestrogen therapies such as
clomifene
 Clomifene works by occupying hypothalamic oestrogen receptors without
activating them  interferes with the binding of oestradiol and thus prevents
negative feedback inhibition of FSH secretion
o Metformin is also used, either combined with clomifene or alone, particularly in patients
who are obese
 Mechanism of action of Metformin in PCOS: Increases peripheral insulin
sensitivity (majority of patients with PCOS have a degree of insulin resistance
which in turn can lead to complicated changes in the hypothalamic-pituitary-
ovarian axis)
o Gonadotrophins

PREMATURE OVARIAN FAILURE

 Defined as the onset of menopausal symptoms and elevated gonadotrophin levels before the
age of 40 years
 Occurs in around 1 in 100 women
 Causes:
o Idiopathic – the most common cause
o Chemotherapy
o Autoimmune
o Radiation
 Features similar to those of the normal climacteric, but the actual presenting problem may
differ:
o Climacteric symptoms: Hot flushes, night sweats
o Infertility
o Secondary amenorrhea
o Raised FSH, LH levels

HORMONE REPLACEMENT THERAPY: ADVERSE EFFECTS

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  Hormone replacement therapy involves the use of a small dose of oestrogen (combined with a
progestogen in women with a uterus) to help alleviate menopausal symptoms
 Side-effects:
o Nausea
o Breast tenderness
o Fluid retention and weight gain
 HRT: Unopposed oestrogen increases risk of endometrial cancer
 Potential complications:
o Increased risk of breast cancer: Increased by addition of a progestogen
o Increased risk of endometrial cancer: Reduced by addition of a progestogen, but not
eliminated completely (BNF states that the additional risk is eliminated if a progestogen
is given continuously)
o Increased risk of venous thromboembolism: Increased by the addition of a progestogen
o Increased risk of stroke – BNF states that stroke risk is the same regardless of whether
the HRT preparation contains progesterone
o Increased risk of ischemic heart disease if taken more than 10 years after menopause
 Breast cancer:
o In the Women’s Health Initiative (WHI) study, there was a relative risk of 1.26 at 5 years
of developing breast cancer
o The increased risk relates to duration of use
o Breast cancer incidence is higher in women using combined preparations compared to
oestrogen-only preparations
o The risk of breast cancer begins to decline when HRT is stopped and by 5 years, it
reaches the same level as in women who have never taken HRT

CONGENITAL ADRENAL HYPERPLASIA

 Group of autosomal recessive disorders

 Affect adrenal steroid biosynthesis
 In response to resultant low cortisol levels, the anterior pituitary secretes high levels of ACTH
 ACTH stimulates the production of adrenal androgens that may virilize a female infant
 Causes:
o 21-hydroxylase deficiency (90%) – most common cause
o 11-beta hydroxylase deficiency (5%)
o 17-hydroxylase deficiency (very rare)

ENZYMES DEFICIENCY

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  17-beta-hydroxysteroid dehydrogenase deficiency – Results in a rare condition of sexual
development, resulting in ambiguous male genitalia or female external genitalia at birth in a
46XY individual
o Patients also have hypothyroidism, cryptorchidism, metabolic disorders and are infertile
 5-alpha reductase deficiency – An autosomal recessive condition that affects male sexual
development resulting in a genetically male individual, with usually either female or ambiguous
genitalia
o Some individuals may have micropenis with hypospadias

KALLMANN’S SYNDROME

 A recognized cause of delayed puberty secondary to hypogonadotrophic hypogonadism

 Usually inherited as an X-linked recessive trait
 Kallmann’s syndrome thought to be caused by failure of GnRH-secreting neurons to migrate to
the hypothalamus
 The clue given in many questions is lack of smell (anosmia) in a boy with delayed puberty
 Features:
o ‘delayed puberty’
o Hypogonadism, cryptorchidism
o Anosmia
o Sex hormone levels are low
o LH, FSH levels are inappropriately low/ normal
o Patients are typically of normal or above average height
o Cleft lip/ palate and visual/ hearing defects are also seen in some patients

Klinefelter’s – LH & FSH raised

Kallmann’s – LH & FSH low-normal – LH and FSH levels are inappropriately low-normal given the low
testosterone concentration, which point towards a diagnosis of hypogonadotrophic hypogonadism

KLINEFELTER’S SYNDROME

 Associated with karyotype 47, XXY

 Features:
o Often taller than average
o Lack of secondary sexual characteristics
o Small, firm testes
o Infertile
o Gynaecomastia – increased incidence of breast cancer

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 o Elevated gonadotrophin levels but low testosterone
 Diagnosis is by karyotype (chromosomal analysis)

ANDROGEN INSENSITIVITY SYNDROME

 X-linked recessive condition

 Due to end-organ resistance to testosterone causing genotypically male children (46XY) to have
a female phenotype
 Complete androgen insensitivity syndrome is the new term for testicular feminization syndrome
 Features:
o Primary amenorrhea
o Undescended testes causing groin swellings
o Breast development may occur as result of conversion of testosterone to oestradiol
 Diagnosis: Buccal smear or chromosomal analysis to reveal 46XY genotype
 Management:
o Counselling – raise child as female
o Bilateral orchidectomy (increased risk of testicular cancer due to undescended testes)
o Oestrogen therapy

BARTTER’S SYNDROME

 An inherited cause (usually autosomal recessive) of severe hypokalemia due to defective

chloride absorption at the Na+ K+ 2Cl- cotransporter (NKCC2) in the ascending loop of Henle
 Associated with normotension (unlike other endocrine causes of hypokalemia such as Conn’s,
Cushing’s and Liddle’s syndrome which are associated with hypertension)
 Features:
o Usually presents in childhood, e.g. failure to thrive
o Polyuria, polydipsia
o Hypokalemia
o Normotension
o Weakness
 Loop diuretics work by inhibiting NKCC2 – think of Bartter’s syndrome as like taking large doses
of furosemide

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GITELMAN’S SYNDROME

 A rare autosomal recessive disorder

 Due to a defect in the thiazide-sensitive Na+ Cl- transporter in the distal convoluted tubule
(pathogenesis similar to the mechanism of a thiazide diuretic)
 Characterized by hypokalemia-hypomagnesemia and alkaline urine/ metabolic alkalosis
 Features:
o Normotension
o Hypokalemia
o Hypocalciuria
o Hypomagnesemia
o Metabolic alkalosis

LIDDLE’S SYNDROME

 A rare autosomal dominant condition

 Associated with hypertension and hypokalemic alkalosis
 Thought to be caused by disordered sodium channels in the distal tubules  increased
reabsorption of sodium
 Treatment: Either amiloride or triamterene

NEPHROPATHY MUTATION TARGETING CHANNEL

Bartter syndrome Mutation causing a defect in the Na-K-Cl co-
transporter
Liddle’s syndrome Mutation causing a defect in epithelial sodium
channels located in the DCT

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URINARY INCONTINENCE

 A common problem, affecting around 4-5% of the population

 More common in elderly females
 Risk factors:
o Advancing age
o Previous pregnancy and childbirth
o High body mass index
o Hysterectomy
o Family history
 Classification:
o Overactive bladder (OAB)/ urge incontinence: due to detrusor overactivity
o Stress incontinence: Leaking small amounts when coughing or laughing
o Mixed incontinence: Both urge and stress
o Overflow incontinence: Due to bladder outlet obstruction, e.g. due to prostate
enlargement
 Initial investigations:
o Bladder diaries should be completed for a minimum of 3 days
o Vaginal examination to exclude pelvic organ prolapse and ability to initiate voluntary
contraction of pelvic floor muscles (‘Kegel’ exercises)
o Urine dipstick and culture
o Urodynamic studies
 Management depends on whether urge or stress UI is the predominant picture:

URGE INCONTINENCE IS PREDOMINANT STRESS INCONTINENCE IS PREDOMINANT

 Bladder retraining (lasts for a minimum  Pelvic floor muscle training: NICE
of 6 weeks, the idea is to gradually recommend at least 8 contractions
increase the intervals between voiding) performed 3 times per day for a
 Bladder stabilizing drugs: Anti- minimum of 3 months
muscarinics are first-line; NICE  Surgical procedures: e.g. retropubic mid-
recommend Oxybutynin (immediate urethral tape procedures
release), Tolterodine (immediate release)
or Darifenacin (once daily preparation)
Immediate release Oxybutynin should however
be avoided in ‘frail older women’
 Mirabegron (a beta-3 agonist) – may be
useful if there is concern about
anticholinergic side-effects in frail elderly
patients

 NICE (February 2015) outlines treatment steps for management of overactive bladder symptoms
in men:
o If non-pharmacological measures fail, an anticholinergic agent is first-line
 In older men, tolterodine is preferred to oxybutynin as oxybutynin has a greater
risk of causing confusion (cognitive impairment), falls and general decline

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 o If anticholinergics fail or are contraindicated, mirabegron may be trialled – mechanism
of action of Mirabegron: Via beta-adrenoreceptor-mediated relaxation of the bladder
wall (MIrabegron is a beta-3 agonist)
o Tamsulosin – an alpha-blocker; Indicated if the patient has obstructive symptoms, rather
than symptoms of overactive bladder
o Finasteride – a 5-alpha reductase inhibitor; Indicated if the patient has obstructive
symptoms and an enlarged prostate with a high risk of progression
o Desmopressin – a synthetic vasopressin analogue that acts in the collecting duct of the
nephron; sometimes used off-label for nocturnal urinary incontinence

PELVIC INFLAMMATORY DISEASE

 A term used to describe infection and inflammation of the female pelvic organs including the
uterus, fallopian tubes, ovaries and the surrounding peritoneum
 It is usually the result of ascending infection from the endocervix
 Causative organisms:
o Chlamydia trachomatis – the most common cause
o Neisseria gonorrhea
o Mycoplasma genitalium
o Mycoplasma hominis
 Features:
o Lower abdominal pain
o Fever
o Deep dyspareunia
o Dysuria and menstrual irregularities may occur
o Vaginal or cervical discharge
o Cervical excitation
o Perihepatitis (Fitz-Hugh Curtis syndrome) occurs in around 10% of cases – characterized
by right upper quadrant pain and may be confused with cholecystitis
 Investigation: Screen for Chlamydia and Gonorrhea
 Management:
o Due to the difficulty in making an accurate diagnosis, and the potential complications of
untreated PID, consensus guidelines recommend having a low threshold for treatment
(recommend treatment once diagnosis of PID is suspected, rather than waiting for
results of swabs)
o Oral Ofloxacin + oral metronidazole or intramuscular ceftriaxone + oral doxycycline +
oral metronidazole
o RCOG guidelines suggest that in mild cases of PID, intrauterine contraceptive devices
may be left in. The more recent BASHH guidelines suggest that the evidence is limited
but that Removal of the IUD should be considered and may be associated with better
short term clinical outcomes

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  Complications:
o Infertility – the risk may be as high as 10-20% after a single episode
o Chronic pelvic pain
o Ectopic pregnancy

CERVICAL CANCER

 Around 50% of cases of cervical cancer occur in women under the age of 45 years, with
incidence rates for cervical cancer in the UK are highest in people aged 25-29 years, according to
Cancer Research UK
 May be divided into:
o Squamous cell cancer (80%)
o Adenocarcinoma (20%)
 Features:
o May be detected during routine cervical cancer screening
o Abnormal vaginal bleeding: Postcoital, intermenstrual or postmenopausal bleeding
o Vaginal discharge
 Human papillomavirus (HPV) – particularly serotypes 16, 18 & 33 is by far the most important
factor in the development of cervical cancer
 Other risk factors include:
o Smoking
o Human immunodeficiency virus
o Early first intercourse, many sexual partners
o High parity
o Lower socioeconomic status
o Combined oral contraceptive pill
 Mechanism of HPV causing cervical cancer:
o HPV 16 &18 produces the oncogenes E6 and E7 genes respectively
o E6 inhibits the p53 tumor suppressor genes
o E7 inhibits RB suppressor gene

HUMAN PAPILLOMA VIRUS VACCINATION

 It has been known for a long time that the human papilloma virus (HPV) which infects the
keratinocytes of the skin and mucous membranes is carcinogenic
 There are dozens of strains of HPV – the most important to remember are:
o 6 & 11: causes genital warts
o 16 & 18: Linked to a variety of cancers, most notably cervical cancer
 HPV infection is linked to:

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 o Over 99.7% of cervical cancers
o Around 85% of anal cancers
o Around 50% of vulval and vaginal cancers
o Around 20-30% of mouth and throat cancers
 There are other risk factors important in developing cervical cancer such as smoking, combined
oral contraceptive pill use and high parity
 Testing for HPV has been integrated into the cervical cancer screening programme
o If a smear is reported as borderline or mild dyskaryosis, the origical sample is tested for
HPV
o If HPV negative, the patient goes back to routine recall
o If HPV positive, the patient is referred for colposcopy
 In 2012, Gardasil replaced Cervarix (Cervarix protected against HPV 16 & 18, but not 6 & 11) as
the vaccine used
o Gardasil protects against HPV 6, 11, 16 & 18
o Was initially just given to girls, but from September 2019, boys were given the vaccine
as well
 From September 2019, all 12- and 13-year old girls AND boys in school year 8 will be offered
the human papillomavirus (HPV) vaccine (prior to their first sexual exposure)
o The vaccine is normally given in school
o Given as 2 doses – girls have the second dose between 6-24 months after the first,
depending on local policy
o Currently no catch-up vaccination programme for women/ heterosexual men who were
not offered the vaccine at age 12
 HPV vaccination is currently recommended to men who have sex with men under 45 years old –
to reduce their risk of anal, throat and penile cancers as well as genital warts
 Transgender men (who were assigned female at birth) who have sex with men are also eligible
for vaccination (although do not require it if previously vaccinated)
 Injection site reactions are particularly common with HPV vaccines

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