Endocrinology

Metabolic syndrome

Unfortunately there are a number of competing definitions of the metabolic

syndrome around at the present time. It is thought that the key
pathophysiological factor is insulin resistance.

SIGN recommend using criteria similar to those from the American Heart
Association. The similarity of the International Diabetes Federation criteria
should be noted. For a diagnosis of metabolic syndrome at least 3 of the
following should be identified:

 elevated waist circumference: men > 102 cm, women > 88 cm

 elevated triglycerides: > 1.7 mmol/L
 reduced HDL: < 1.03 mmol/L in males and < 1.29 mmol/L in females

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  raised blood pressure: > 130/85 mmHg, or active treatment of
hypertension
 raised fasting plasma glucose > 5.6 mmol/L, or previously diagnosed
type 2 diabetes

The International Diabetes Federation produced a consensus set of

diagnostic criteria in 2005, which are now widely in use. These require the
presence of central obesity (defined as waist circumference > 94cm for
Europid men and > 80cm for Europid women, with ethnicity specific values
for other groups) plus any two of the following four factors:

 raised triglycerides level: > 1.7 mmol/L, or specific treatment for this
lipid abnormality
 reduced HDL cholesterol: < 1.03 mmol/L in males and < 1.29 mmol/L in
females, or specific treatment for this lipid abnormality
 raised blood pressure: > 130/85 mm Hg, or active treatment of
hypertension
 raised fasting plasma glucose > 5.6 mmol/L, or previously diagnosed
type 2 diabetes

High LDL levels are not part of the World Health Organization or International
Diabetes Federation diagnostic criteria

In 1999 the World Health Organization produced diagnostic criteria which

required the presence of diabetes mellitus, impaired glucose tolerance,
impaired fasting glucose or insulin resistance, AND two of the following:

 blood pressure: > 140/90 mmHg

 dyslipidaemia: triglycerides: > 1.695 mmol/L and/or high-density
lipoprotein cholesterol (HDL-C) < 0.9 mmol/L (male), < 1.0 mmol/L
(female)
 central obesity: waist:hip ratio > 0.90 (male), > 0.85 (female), and/or
body mass index > 30 kg/m2
 microalbuminuria: urinary albumin excretion ratio > 20 mg/min or
albumin:creatinine ratio > 30 mg/g

Other associated features include:

 raised uric acid levels

 non-alcoholic fatty liver disease
 polycystic ovarian syndrome

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Decisions on primary prevention of cardiovascular disease should be made
using standard tools and are not dependant on whether a diagnosis of
metabolic syndrome is made.

Prediabetes and impaired glucose regulation

Prediabetes is defined by a HbA1c of 42-47 mmol/mol (6.0-6.4%)

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. 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.

Terminology

 Diabetes UK currently recommend using the term prediabetes when

talking to patients and impaired glucose regulation when talking to
other healthcare professionals
 research has shown that the term 'prediabetes' has the most impact
and is most easily understood

Identification of patients with prediabetes

 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 type 2 diabetes

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  patients identified at high risk should have a blood sample taken
 a fasting plasma glucose of 5.5-6.9 mmol/l or an HbA1c level of 42-47
mmol/mol (6.0-6.4%) indicates high risk

NICE recommend metformin for adults at high risk 'whose blood glucose

measure (fasting plasma glucose or HbA1c) shows they are still progressing
towards type 2 diabetes, despite their participation in an intensive lifestyle-
change programme'.

Management

 lifestyle modification: weight loss, increased exercise, change in diet

 at least yearly follow-up with blood tests is recommended
 NICE recommend metformin for adults at high risk 'whose blood
glucose measure (fasting plasma glucose or HbA1c) shows they are still
progressing towards type 2 diabetes, despite their participation in an
intensive lifestyle-change programme'

Impaired fasting glucose and impaired glucose tolerance

There are two main types of IGR:

 impaired fasting glucose (IFG) - due to hepatic insulin resistance

 impaired glucose tolerance (IGT) - due to muscle insulin resistance
 patients with IGT are more likely to develop T2DM and cardiovascular
disease than patients with IFG

Definitions

 a fasting glucose greater than or equal to 6.1 but less than 7.0 mmol/l
implies impaired fasting glucose (IFG)
 impaired glucose tolerance (IGT) is defined as fasting plasma glucose
less than 7.0 mmol/l and OGTT 2-hour value greater than or equal to 7.8
mmol/l but less than 11.1 mmol/l
 people with IFG should then be offered an oral glucose tolerance test
to rule out a diagnosis of diabetes. A result below 11.1 mmol/l but above
7.8 mmol/l indicates that the person doesn't have diabetes but does have
IGT.

Patients with impaired glucose tolerance are more likely to develop

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diabetes than patients with impaired fasting glycaemia

Drug-induced impaired glucose tolerance

Drugs which are known to cause impaired glucose tolerance include:

 thiazides, furosemide (less common)

 steroids
 tacrolimus, ciclosporin
 interferon-alpha
 nicotinic acid
 atypical antipsychotics e.g. olanzapine

Beta-blockers cause a slight impairment of glucose tolerance. They should

also be used with caution in diabetics as they can interfere with the
metabolic and autonomic responses to hypoglycaemia
Bendroflumethiazide is more likely than beta-blockers to cause impaired
glucose tolerance.

Diabetes mellitus (type 2): diagnosis

Diabetes diagnosis: fasting > 7.0, random > 11.1 - if asymptomatic need two
readings

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The diagnosis of type 2 diabetes mellitus 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.

If the patient is symptomatic:

 fasting glucose greater than or equal to 7.0 mmol/l

 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 two separate occasions.

In 2011 WHO released supplementary guidance on the use of HbA1c on the

diagnosis of diabetes:

 a HbA1c of greater than or equal to 6.5% (48 mmol/mol) is diagnostic of

diabetes mellitus
 a HbAlc value of less than 6.5% does not exclude diabetes (i.e. it is not
as sensitive as fasting samples for detecting diabetes)
 in patients without symptoms, the test must be repeated to confirm the
diagnosis
 it should be remembered that misleading HbA1c results can be caused
by increased red cell turnover (see below)

Conditions where HbA1c may not be used for diagnosis:

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  haemoglobinopathies
 haemolytic anaemia
 untreated iron deficiency anaemia
 suspected gestational diabetes
 children
 HIV
 chronic kidney disease

Impaired fasting glucose and impaired glucose tolerance

A fasting glucose greater than or equal to 6.1 but less than 7.0 mmol/l
implies impaired fasting glucose (IFG)

Impaired glucose tolerance (IGT) is defined as fasting plasma glucose less

than 7.0 mmol/l and OGTT 2-hour value greater than or equal to 7.8 mmol/l
but less than 11.1 mmol/l

Diabetes UK suggests:

 'People with IFG should then be offered an oral glucose tolerance test
to rule out a diagnosis of diabetes. A result below 11.1 mmol/l but above
7.8 mmol/l indicates that the person doesn't have diabetes but does have
IGT.'

Glycosylated haemoglobin

Glycosylated haemoglobin (HbA1c) is the most widely used measure of long-

term glycaemic control in diabetes mellitus. HbA1c is produced by the
glycosylation of haemoglobin at a rate proportional to the glucose
concentration. The level of HbA1c therefore is dependant on

 red blood cell lifespan

 average blood glucose concentration

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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 red blood cell lifespan) increased red blood cell lifespan)

Sickle-cell anaemia Vitamin B12/folic acid deficiency

GP6D deficiency  Iron-deficiency anaemia
Hereditary spherocytosis Splenectomy

HbA1c is generally thought to reflect the blood glucose over the previous '2-3
months' although there is some evidence it is weighed more strongly to
glucose levels of the past 2-4 weeks
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 standardised method for reporting HbA1c has been
developed by the International Federation of Clinical Chemistry (IFCC). This
will report HbA1c in mmol per mol of haemoglobin 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

11 17.5

12 19.5

From the above we can see that average plasma glucose = (2 * HbA1c) - 4.5

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Diabetes mellitus: management of type 2

NICE updated its guidance on the management of type 2 diabetes mellitus

(T2DM) in 2009. Key points are listed below:

Dietary advice

 encourage high fibre, low glycaemic index sources of carbohydrates

 include low-fat dairy products and oily fish
 control the intake of foods containing saturated fats and trans fatty
acids
 limited substitution of sucrose-containing foods for other
carbohydrates is allowable, but care should be taken to avoid excess
energy intake
 discourage use of foods marketed specifically at people with diabetes
 initial target weight loss in an overweight person is 5-10%

 HbA1c

 the general target for patients is 48 mmol/mol (DCCT = 6.5%). HbA1c

levels below 48 mmol/mol (DCCT = 6.5%) should not be pursued
 however, individual targets should be agreed with patients to
encourage motivation
 HbA1c should be checked every 2-6 months until stable, then 6
monthly

Blood pressure

 target is < 140/80 mmHg (or < 130/80 mmHg if end-organ damage is
present)
 ACE inhibitors are first-line

The NICE treatment algorithm has become much more complicated following
the introduction of new therapies for type 2 diabetes. We suggest reviewing
this using the link provided. Below is a very selected group of points from the
algorithm:

 NICE still suggest a trial of lifestyle interventions first*

 usually metformin is first-line, followed by a sulfonylurea if the HbA1c
remains > 48 mmol/mol (DCCT = 6.5%)

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  if the patient is at risk from hypoglycaemia (or the consequences of)
then a DPP-4 inhibitor or thiazolidinedione should be considered rather
than a sulfonylurea
 meglitinides (insulin secretagogues) should be considered for patients
with an erratic lifestyle
 if HbA1c > 58 mmol/mol (DCCT = 7.5%) then consider human insulin
 metformin treatment should be continued after starting insulin
 exenatide should be used only when insulin would otherwise be
started, obesity is a problem (BMI > 35 kg/m^2) and the need for high
dose insulin is likely. Continue only if beneficial response occurs and is
maintained (> 1.0 percentage point HbA1c reduction and weight loss >
3% at 6 months)

Starting insulin

 usually commenced if HbA1c > HbA1c > 58 mmol/mol (DCCT = 7.5%)

 NICE recommend starting with human NPH insulin (isophane,
intermediate acting) taken at bed-time or twice daily according to need

Other risk factor modification

 current NICE guidelines suggest giving aspirin to all patients > 50

years and to younger patients with other significant risk factors.
However, recent evidence does not support this approach. The 2010
SIGN guidelines do not advocate the use of aspirin for primary
prevention in diabetics
 following the 2014 NICE lipid modification guidelines only patients with
a 10-year cardiovascular risk > 10% (using QRISK2) should be offered a
statin. The first-line statin of choice is atorvastatin 20mg on

*many local protocols now recommend starting metformin upon diagnosis.

Neither metformin nor pioglitazone cause hypoglycaemia.

Following the recent NICE type 2 diabetes mellitus guidelines , lower risk
patients do not automatically need to be offered a statin, even if they are
over the age of 40 years. 

Aspirin should be given to all type 2 diabetic patients > 50 years and to
younger patients with other significant risk factors.

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Non-serious gastrointestinal adverse effects of metformin are common
especially when starting the medication. The frequency and degree of
persistence of adverse effects are dose dependent, but they usually improve
with continued use and are minimised if metformin is started at a low dose,
taken with food, and slowly titrated upwards.

If blood glucose is inadequately controlled by lifestyle interventions (diet and

exercise) and monotherapy (HbA1c greater than or equal to 6.5% (48
mmol/mol) or other individually agreed higher limit) CKS recommend the
following:
Review adherence to diet, lifestyle, and monotherapy. 

If adherence to lifestyle measures is optimum, titrate the drug up to the

optimum dose

 Switch to modified-release metformin if compliance or tolerability is a

problem with metformin.
 Switch to a once-daily sulfonylurea if compliance is a problem with a
twice-daily sulfonylurea.
 If taking a sulfonylurea alone, add metformin.
 If metformin is contraindicated or not tolerated, add a gliptin
(saxagliptin, sitagliptin, or vildagliptin) or pioglitazone.
 If metformin, a gliptin, and pioglitazone are contraindicated or not
tolerated, refer to a specialist for possible initiation of liraglutide

Pioglitazone can cause fluid retention and is therefore contraindicated in

patients with heart failure.

First-line drugs: 

 Metformin
 Sulphonylureas (e.g. gliclizide)
 Use both in combination if HbA1c remains high despite monotherapy

Second-line drugs: 

 Generally used if metformin / gliclizide not tolerated

 DPP4-inhibitors (e.g. sitagliptin)
 Glitazones (e.g. pioglitazone)

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If HbA1c remains high on oral agents:

 Insulin
 Incretin analogues (e.g. exanetide): an alternative to insulin in obese
patients

Target cholesterol for type 2 diabetics (NICE) >>>  40% reduction in non-HDL
cholesterol

 Dapagliflozin is a SGLT-2 inhibitor which causes increased renal

glucose loss to control diabetic glycaemia. It may cause recurrent
urinary infections due to high urinary glucose load
 Since the regulation of glucose and insulin is affected by many
physiological variables, there are many targets for drugs to influence
glycaemic homeostasis. Older oral hypoglycaemic drugs such as the
sulphonylureas (gliclazide, etc) work by directly stimulating insulin
release from pancreatic beta cells, whereas biguanides like metformin
inhibit glucose mobilisation from hepatic stores and improve glucose
handling. Metformin is associated with lactic acidosis and
sulphonylureas are associated with increased incidence of hepatitis
and jaundice. 
A class of oral hypoglycaemic agent known as the thiazolidinediones
(pioglitazone, etc) also improve glucose processing by increasing
upregulation of genes which augment glucose and fat metabolism. This
occurs by stimulation of the nuclear signalling protein peroxisome
proliferator-activated receptor gamma (PPAR-). Thiazolidinediones
have fallen out of vogue of late due to concerns about heart failure and
ischaemic heart disease.
A more novel treatment for hyperglycaemia is the use of incretins
which are gastrically derived peptides which also stimulate insulin
secretion from beta cells. The two main peptides of use are glucose
like peptide 1 (GLP-1) and gastric inhibitory peptide (GIP) both of which
synergistically stimulate beta cell insulin release and inhibit alpha cell
glucagon release, causing a fall in blood glucose. Incretin drugs of this
class include exenatide and liraglutide and are usually given as
subcutaneous daily injections. In vivo, GLP-1 and GIP are rapidly
deactivated by the enzyme dipeptidyl peptidase-4 (DPP-4) which limits
their use (although the synthetic incretin analogue drugs are not
deactivated by this enzyme). Drugs which can inhibit DPP-4 are useful
in controlling blood glucose since they allow physiological gut
incretins to stimulate insulin release. Examples of these drugs include

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 sitagliptin, saxagliptin, etc. Rarely DPP-4 inhibitors and PPAR-
modulators can cause hepatitis, pancreatitis and pancytopaenia.
Previous pancreatitis is a relative contraindication to their use.
Dapagliflozin is a renal SGLT-2 (sodium glucose transporter) inhibitor
which has only recently obtained UK and US licensing authority. It
causes an increase in glucose excretion by the kidney to lower serum
glucose concentrations. SGLT-2 is a sodium/glucose co-transporter
protein in the nephrons proximal tubule which reabsorbs glucose from
the renal filtrate. These drugs cause heavy urinary glucose loss and
can cause recurrent urinary infections and candidiasis as well as
hypoglycaemia, crystalluria and renal failure due to osmotic diuresis.

Insulin therapy: side-effects

Hypoglycaemia

 patients should be taught the signs of hypoglycaemia: sweating,

anxiety, blurred vision, confusion, aggression
 conscious patients should take 10-20g of a short-acting carbohydrate
(e.g. a glass of Lucozade or non-diet drink, three or more glucose
tablets, glucose gel)
 every person treated with insulin should have a glucagon kit for
emergencies where the patient is not able to orally ingest a short-
acting carbohydrate.

Give intramuscular glucagon

 patients who have frequent hypoglycaemic episodes may develop

reduced awareness. If this develops then allowing glycaemic control to
slip for a period of time may restore their awareness

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beta-blockers reduce hypoglycaemic awareness

It is potentially dangerous to place anything inside the mouth of an

unconscious patient as they may not be protecting their airway properly.

Protamine sulphate is used in heparin overdose.

Lipodystrophy

 typically presents as atrophy of the subcutaneous fat

 can be prevented by rotating the injection site

Thiazolidinediones

Thiazolidinediones are absolutely contraindicated in heart failure

There is increasing evidence thiazolidinediones increase the risk of fractures

Thiazolidinediones are a new class of agents used in the treatment of type 2

diabetes mellitus. They are agonists to the PPAR-gamma receptor and
reduce peripheral insulin resistance. Rosiglitazone was withdrawn in 2010
following concerns about the cardiovascular side-effect profile.
The PPAR-gamma receptor is an intracellular nuclear receptor. Its natural
ligands are free fatty acids and it is thought to control adipocyte
differentiation and function.
Adverse effects

 weight gain
 liver impairment: monitor LFTs
 fluid retention - therefore contraindicated in heart failure. The risk of
fluid retention is increased if the patient also takes insulin
 recent studies have indicated an increased risk of fractures
 bladder cancer: recent studies have showed an increased risk of
bladder cancer in patients taking pioglitazone (hazard ratio 2.64)

NICE guidance on thiazolidinediones

 only continue if there is a reduction of > 0.5 percentage points in

HbA1c in 6 months

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Sulfonylureas
Sulfonylureas are oral hypoglycaemic drugs used in the management of type
2 diabetes mellitus. They work by increasing pancreatic insulin secretion
and hence are only effective if functional B-cells are present. On a molecular
level they bind to an ATP-dependent K+(KATP) channel on the cell membrane of
pancreatic beta cells.

Common adverse effects

 hypoglycaemic episodes (more common with long acting preparations

such as chlorpropamide)
 weight gain

Rarer adverse effects

 syndrome of inappropriate ADH secretion

 bone marrow suppression
 liver damage (cholestatic)
 photosensitivity
 peripheral neuropathy

Sulfonylureas should be avoided in breast feeding and pregnancy.

Metformin

Metformin is a biguanide used mainly in the treatment of type 2 diabetes

mellitus. It has a number of actions which improves glucose tolerance (see
below). Unlike sulphonylureas it does not cause hypoglycaemia and weight
gain and is therefore first-line, particularly if the patient is overweight.
Metformin is also used in polycystic ovarian syndrome and non-alcoholic
fatty liver disease
NICE recommend that the metformin dose should be reviewed if the
creatinine is > 130 µmol/l (or eGFR < 45 ml/min) and stopped if the creatinine
is > 150 µmol/l (or eGFR < 30 ml/min)
Metformin should be stopped following a myocardial infarction due to the
risk of lactic acidosis. It may be introduced at a later date. Diabetic control
may be achieved through the use of a insulin/dextrose infusion (e.g. the
DIGAMI regime)

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Mechanism of action

 increases insulin sensitivity

 decreases hepatic gluconeogenesis
 may also reduce gastrointestinal absorption of carbohydrates

Adverse effects 

 gastrointestinal upsets are common (nausea, anorexia, diarrhoea),

intolerable in 20%
 reduced vitamin B12 absorption - rarely a clinical problem
 lactic acidosis* with severe liver disease or renal failure

Contraindications**

 chronic kidney disease: NICE recommend that the dose should be

reviewed if the creatinine is > 130 �mol/l (or eGFR < 45 ml/min) and
stopped if the creatinine is > 150 �mol/l (or eGFR < 30 ml/min)
 metformin may cause lactic acidosis if taken during a period where
there is tissue hypoxia. Examples include a recent myocardial infarction,
sepsis, acute kidney injury and severe dehydration
 iodine-containing x-ray contrast media: examples include peripheral
arterial angiography, coronary angiography, intravenous pyelography
(IVP); there is an increasing risk of provoking renal impairment due to
contrast nephropathy; metformin should be discontinued on the day of
the procedure and for 48 hours thereafter
 alcohol abuse is a relative contraindication

*it is now increasingly recognised that lactic acidosis secondary to

metformin is rare, although it remains important in the context of exams

**metformin is now sometimes used in pregnancy, for example in women

with polycystic ovarian syndrome.

Metformin should be titrated slowly, leave at least 1 week before increasing

dose

Gastrointestinal side-effects are more likely to occur if metformin is not

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slowly titrated up. The BNF advises leaving at least 1 week before increasing
the dose.

A 59-year-old man with a history of type 2 diabetes mellitus and benign

prostatic hypertrophy develops urinary retention associated with acute renal
failure. Which one of the following drugs should be discontinued?

Metformin

As the patient has developed acute renal failure metformin should be

stopped due to the risk of lactic acidosis. In the long term paroxetine may
also need to be stopped as SSRIs can contribute to urinary retention.
If a patient is intolerant to standard metformin then modified-release
preparations should be tried. There is some evidence that these produce
fewer gastrointestinal side-effects in patients intolerant of standard-release
metformin.

Diabetes mellitus: GLP-1 and the new drugs

Exenatide causes vomiting>>>The major adverse effect is nausea and

vomiting

Meglitinides - stimulate insulin release - good for erratic lifestyle

Meglitinides stimulate insulin release and are particularly useful for post-
prandial hyperglycaemia or an erratic eating schedule, as patients take them
shortly before meals

A number of new drugs to treat diabetes mellitus have become available in

recent years. Much research has focused around the role of glucagon-like
peptide-1 (GLP-1), a hormone released by the small intestine in response to
an oral glucose load
Whilst it is well known that insulin resistance and insufficient B-cell
compensation occur other effects are also seen in type 2 diabetes mellitus
(T2DM). In normal physiology an oral glucose load results in a greater release
of insulin than if the same load is given intravenously - this known as the
incretin effect. This effect is largely mediated by GLP-1 and is known to be
decreased in T2DM.
Increasing GLP-1 levels, either by the administration of an analogue
(glucagon-like peptide-1, GLP-1 mimetics, e.g. exenatide) or inhibiting its

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breakdown (dipeptidyl peptidase-4 ,DPP-4 inhibitors - the gliptins), is
therefore the target of two recent classes of drug.

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

Exenatide is an example of a glucagon-like peptide-1 (GLP-1) mimetic. These

drugs increase insulin secretion and inhibit glucagon secretion. One of the
major advances of GLP-1 mimetics is that they typically result in weight loss,
in contrast to many medications such as insulin, sulfonylureas and
thiazolidinediones.
Exenatide must be given by subcutaneous injection within 60 minutes before
the morning and evening meals. It should not be given after a meal.

Liraglutide is the other GLP-1 mimetic currently available. One 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 a

sulfonylurea. Standard release exenatide is also licensed to be used with
basal insulin alone or with metformin. Please see the BNF for a more
complete list of licensed indications.

NICE state the following:

Consider adding exenatide to metformin and a sulfonylurea if:

 BMI >= 35 kg/m� in people of European descent and there are

problems associated with high weight, or
 BMI < 35 kg/m� and insulin is unacceptable because of occupational
implications or weight loss would benefit other comorbidities.

Patients do not need to have been on insulin prior to using exenatide

NICE like patients to have achieved a 1% reduction in HbA1c and 3% weight

loss after 6 months to justify the ongoing prescription of GLP-1 mimetics.

The major adverse effect of GLP-1 mimetics is nausea and vomiting. The
Medicines and Healthcare products Regulatory Agency has issued specific
warnings on the use of exenatide, reporting that is has been linked to severe
pancreatitis or renal impairement in some patients.

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

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Hypoglycaemia is rare in patients taking dipeptidyl peptidase-4 inhibitors.

Key points

 oral preparation
 trials to date show that the drugs are relatively well tolerated with no
increased incidence of hypoglycaemia
 do not cause weight gain

NICE guidelines on DPP-4 inhibitors

 continue DPP-4 inhibitor only if there is a reduction of > 0.5 percentage

points in HBA1c in 6 months
 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 or the person has had a
poor response to a thiazolidinedione.

Although nasopharyngitis and pancreatitis are both side effects of sitagliptin,

nasopharyngitis is more common. Sitagliptin is considered to be weight
neutral. 

Common side effects:

 gastro-intestinal disturbances
 peripheral oedema
 nasopharyngitis
 upper respiratory tract infections

Less common side effects:

 dry mouth
 anorexia
 headache
 drowsiness
 dizziness
 hypoglycaemia
 osteoarthritis

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Reported:

 Pancreatitis
 Stevens-Johnson syndrome
 Rash
 Cutaneous vasculitis

Diabetes mellitus: Ramadan

During Ramadan, one-third of the normal metformin dose should be taken
before sunrise and two-thirds should be taken after sunset.
Research suggests that the vast majority (around 80%) of Muslims with
diabetes will fast during Ramadan

Around 4 out of 5 patients Muslim patients with type 2 diabetes

mellitus fast during Ramadan

We know that 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. The BMJ published an excellent and comprehensive review of this
issue in 20101.

It is important that we can give appropriate advice to Muslim patients to

allow them safely observe their fast. This is particularly important from 2014
as Ramadan is due to fall in the long days of the summer months for several
years henceforth. 
Clearly it is a personal decision whether a patient decides to fast. It 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. 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. Around 79% of Muslim
patients with type 2 diabetes mellitus fast Ramadan 2.There is an excellent
patient information leaflet from Diabetes UK and the Muslim Council of
Britain which explores these options in more detail.

If a patient with type 2 diabetes mellitus does decide to fast:

 they should try and and eat a meal containing long-acting

carbohydrates prior to sunrise (Suhoor)
 patients should be given a blood glucose monitor to allow them to
check their glucose levels, particularly if they feel unwell

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  for patients taking metformin the expert consensus is that the dose
should be split one-third before sunrise (Suhoor) and two-thirds after
sunset (Iftar)
 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 after sunset
 no adjustment is needed for patients taking pioglitazone

Side-effects of common drugs: diabetes drugs

The table below summarises characteristic (if not necessarily the most
common) side-effects of drugs used to treat diabetes mellitus

Drug Side-effect

Metformin � Gastrointestinal side-effects

� Lactic acidosis

Sulfonylureas � Hypoglycaemic episodes

� Increased appetite and weight gain
� Syndrome of inappropriate ADH secretion
� Liver dysfunction (cholestatic)

Glitazones � Weight gain

� Fluid retention
� Liver dysfunction
� Fractures

Key trials: diabetes mellitus

The following table summarises some of the key trials that have altered the
approach to diabetes mellitus:

UKPDS The United Kingdom Prospective Diabetes Study was a seminal trial of over 5,000
patients with type 2 diabetes mellitus. Patients were followed for an average of 10 years
to establish whether control of blood glucose levels was associated with clinical
benefits (reduced macrovascular and microvascular complications) and whether there
was an advantage to any particular type of drug treatment. UKPDS also had a blood
pressure control arm to establish whether this had an impact on complication rates.

Main results

21
  UKPDS confirmed the importance of tight glycaemic and blood pressure control
in type 2 diabetics
 both macrovascular and microvascular complications were

reduced in patients with tight glycaemic control

The Diabetes Control and Complications Trial involved 1,400 patients with type 1
diabetes mellitus in the US and Canada between 1983 and 1993.

Main results

DCCT  DCCT showed a significant reduction in microvascular complications for patients

who had tight glycaemic control

there was a higher incidence of hypoglycaemia in the group who had tight glycaemic
control
The Diabetes Reduction Assessment with ramipril and rosiglitazone Medication trial
looked at whether patients with impaired fasting glucose (IFG) and/or impaired glucose
tolerance (IGT) could be stopped from developing type 2 diabetes by using either
ramipril and rosiglitazone.
DREAM
The study showed that the onset of type 2 diabetes may be delayed by rosiglitazone
therapy.

MODY
MODY is inherited in an autosomal dominant fashion so a family history is
often present

Maturity-onset diabetes of the young (MODY) is characterised by the

development of type 2 diabetes mellitus in patients < 25 years old. It is
typically inherited as an autosomal dominant condition. Over six different
genetic mutations have so far been identified as leading to MODY.
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
 due to a defect in the HNF-1 alpha gene

MODY 2

22
  20% of cases
 due to a defect in the glucokinase gene

Features of MODY

 typically develops in patients < 25 years

 a family history of early onset diabetes is often present
 ketosis is not a feature at presentation
 patients with the most common form are very sensitive to
sulfonylureas, insulin is not usually necessary

Glycaemic index

The glycaemic index (GI) describes the capacity of a food to raise blood
glucose compared with glucose in normal glucose-tolerant individuals. Foods
with a high GI may be associated with an increased risk of obesity and the
post-prandial hyperglycaemia associated with such foods may also increase
the risk of type 2 diabetes mellitus.

Classification Examples

High GI White rice (87), baked potato (85), white bread (70)

Medium GI Couscous (65), boiled new potato (62), digestive biscuit (59), brown rice (58)

Low GI Fruit and vegetables, peanuts

The glycaemic index is shown in brackets. Glucose, by definition, would have

a glycaemic index of 100

Diabetic neuropathy

NICE updated it's guidance on the management of neuropathic pain in 2013.

Diabetic neuropathy is now managed in the same way as other forms of
neuropathic pain:

 first-line treatment: amitriptyline, duloxetine, gabapentin or pregabalin

 if the first-line drug treatment does not work try one of the other 3
drugs
 tramadol may be used as 'rescue therapy' for exacerbations of
neuropathic pain

23
  topical capsaicin may be used for localised neuropathic pain (e.g. post-
herpetic neuralgia)
 pain management clinics may be useful in patients with resistant
problems

Amitriptyline would normally be first choice but if there is history of benign

prostatic hyperplasia , it is better to avoid amitriptyline due to the risk of
urinary retention.

Gastroparesis

 symptoms include erratic blood glucose control, bloating and vomiting

 management options include metoclopramide, domperidone or
erythromycin (prokinetic agents)

Skin disorders associated with diabetes

Note whilst pyoderma gangrenosum can occur in diabetes mellitus it is rare

and is often not included in a differential of potential causes

Necrobiosis lipoidica

 shiny, painless areas of yellow/red/brown skin typically on the shin

 often associated with surrounding telangiectasia

Infection

 candidiasis
 staphylococcal

Neuropathic ulcers

Vitiligo

Lipoatrophy

Granuloma annulare*

24
  papular lesions that are often slightly hyperpigmented and depressed
centrally

*it is not clear from recent studies if there is actually a significant

association between diabetes mellitus and granuloma annulare, but it is
often listed in major textbooks

Pregnancy: diabetes mellitus

Diabetes mellitus may be a pre-existing problem or develop during

pregnancy, gestational diabetes. It complicates around 1 in 40 pregnancies.
NICE updated the guidance in 2015

Risk factors for gestational diabetes

 BMI of > 30 kg/m�

 previous macrosomic baby weighing 4.5 kg or above
 previous gestational diabetes
 first-degree relative with diabetes
 family origin with a high prevalence of diabetes (South Asian, black
Caribbean and Middle Eastern)

Screening for gestational diabetes

 women who've 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
 women with any of the other risk factors should be offered an OGTT at
24-28 weeks

Diagnostic thresholds for gestational diabetes

 these have recently been updated by NICE, gestational diabetes is

diagnosed if either:
 fasting glucose is >= 5.6 mmol/l
 2-hour glucose is >= 7.8 mmol/l

Management of gestational diabetes

25
  newly diagnosed women should be seen in a joint diabetes and
antenatal clinic within a week
 women should be taught about selfmonitoring of blood glucose
 advice about diet (including eating foods with a low glycaemic index)
and exercise should be given
 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
 if at the time of diagnosis the fasting glucose level is >= 7 mmol/l
insulin should be started
 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
 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

 weight loss for women with BMI of > 27 kg/m^2

 stop oral hypoglycaemic agents, apart from metformin, and commence
insulin
 folic acid 5 mg/day from pre-conception to 12 weeks gestation
 detailed anomaly scan at 20 weeks including four-chamber view of the
heart and outflow tracts
 tight glycaemic control reduces complication rates
 treat retinopathy as can worsen during pregnancy

Targets for self monitoring of pregnant women (pre-existing and gestational

diabetes)

Time Target

Fasting 5.3 mmol/l

1 hour after meals 7.8 mmol/l, or:

26
Time Target

2 hour after meals 6.4 mmol/l

Pregnancy: diabetes - complications

Maternal complications

 polyhydramnios - 25%, possibly due to fetal polyuria

 preterm labour - 15%, associated with polyhydramnios

Neonatal complications

 macrosomia (although diabetes may also cause small for gestational

age babies)
 hypoglycaemia (secondary to beta cell hyperplasia)
 respiratory distress syndrome: surfactant production is delayed
 polycythaemia: therefore more neonatal jaundice
 malformation rates increase 3-4 fold e.g. sacral agenesis, CNS and CVS
malformations (hypertrophic cardiomyopathy)
 stillbirth
 hypomagnesaemia
 hypocalcaemia
 shoulder dystocia (may cause Erb's palsy)

Diabetes mellitus: hypertension management

Type 2 diabetes blood pressure target

 no organ damage: < 140 / 80

 end-organ damage: < 130 / 80

Hypertension in diabetics - ACE-inhibitors are first-line regardless of age

NICE recommend the following blood pressure targets for type 2 diabetics:

 if end-organ damage (e.g. renal disease, retinopathy) < 130/80 mmHg

 otherwise < 140/80 mmHg

27
A 2013 Cochrane review casted doubt on the wisdom of lower blood pressure
targets for patients with diabetes. It compared patients who had tight blood
pressure control (targets < 130/85 mmHg) with more relaxed control (< 140-
160/90-100 mmHg). Patients who were more tightly controlled had a slightly
reduced rate of stroke but otherwise outcomes were not significantly
different.
Because ACE-inhibitors have a renoprotective effect in diabetes they are the
first-line antihypertensives recommended for NICE. Patients of African or
Caribbean family origin should be offered an ACE-inhibitor plus either a
thiazide diuretic or calcium channel blocker. Further management then
reverts to that of non-diabetic patients, as discussed earlier in the module.
Remember than autonomic neuropathy may result in more postural
symptoms in patients taking antihypertensive therapy.
The routine use of beta-blockers in uncomplicated hypertension should be
avoided, particularly when given in combination with thiazides, as they may
cause insulin resistance, impair insulin secretion and alter the autonomic
response to hypoglycaemia

Subclinical hyperthyroidism

Subclinical hyperthyroidism is an entity which is gaining increasing

recognition. It is defined as:

 normal serum free thyroxine and triiodothyronine levels

 with a thyroid stimulating hormone (TSH) below normal range (usually
< 0.1 mu/l)

Causes

 multinodular goitre, particularly in elderly females

 excessive thyroxine may give a similar biochemical picture

The importance in recognising subclinical hyperthyroidism lies in the

potential effect on the cardiovascular system (atrial fibrillation) and bone
metabolism (osteoporosis). It may also impact on quality of life and increase
the likelihood of dementia

Management

 TSH levels often revert to normal - therefore levels must be

persistently low to warrant intervention

28
  a reasonable treatment option is a therapeutic trial of low-dose
antithyroid agents for approximately 6 months in an effort to induce a
remission

Graves' disease: management

Despite many trials there is no clear guidance on the optimal management of

Graves' disease. 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

 carbimazole is started at 40mg and reduced gradually to maintain

euthyroidism
 typically continued for 12-18 months
 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

 carbimazole is started at 40mg

 thyroxine is added when the patient is euthyroid
 treatment typically lasts for 6-9 months

The major complication of carbimazole therapy is agranulocytosis

Radioiodine treatment

 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
 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

It is well documented that radioiodine therapy can precipitate thyroid eye

disease but a majority of patients eventually require thyroxine replacement

29
Carbimazole

Carbimazole is used in the management of thyrotoxicosis. It is typically

given in high doses for 6 weeks until the patient becomes euthyroid before
being reduced.

Mechanism of action

 blocks thyroid peroxidase from coupling and iodinating the tyrosine

residues on thyroglobulin → reducing thyroid hormone production
 in contrast propylthiouracil as well as this central mechanism of action
also has a peripheral action by inhibiting 5'-deiodinase which reduces
peripheral conversion of T4 to T3

Adverse effects

 agranulocytosis
 crosses the placenta, but may be used in low doses during pregnancy

A rare but serious side effect of carbimazole is agranulocytosis so patients

must be counselled regarding this. If the patient develops any symptoms of
an infection, particularly sore throat or fever then must seek urgent medical
review and a FBC must be performed to check the neutrophil count. 

Subclinical hypothyroidism

Basics

 TSH raised but T3, T4 normal

 no obvious symptoms

Significance

 risk of progressing to overt hypothyroidism is 2-5% per year (higher in

men)
 risk increased by presence of thyroid autoantibodies

30
Treat if

 TSH > 10
 thyroid autoantibodies positive
 other autoimmune disorder
 previous treatment of Graves' disease

Hypothyroidism: management

Iron reduces the absorption of thyroxine

 Levothyroxine must be taken 30 minutes before food as it's absorption may

be affected by food, caffeine or other medications.

A TSH value between 0.5 to 2.5 mU/l is now considered preferable. Dosage
changes should of course also take account of symptoms

Key points

 initial starting dose of levothyroxine should be lower in elderly patients

and those with ischaemic heart disease. The 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. 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. As the majority of unaffected people have a TSH
value 0.5-2.5 mU/l it is now thought preferable to aim for a TSH in this
range
 women with established hypothyroidism who become pregnant should
have their dose increased 'by at least 25-50 micrograms
levothyroxine'* due to the increased demands of pregnancy. 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

 hyperthyroidism: due to over treatment

 reduced bone mineral density

31
  worsening of angina
 atrial fibrillation

Interactions

 iron: absorption of levothyroxine reduced, give at least 2 hours apart

A 43-year-old woman presents for follow-up in clinic. She was diagnosed with
Hashimoto's thyroiditis four months ago and is currently being treated with
levothyroxine 75 mcg od. What is the single most important blood test to
assess her response to treatment?

TSH

Amiodarone and the thyroid gland

Around 1 in 6 patients taking amiodarone develop thyroid dysfunction

Amiodarone-induced hypothyroidism

The pathophysiology of amiodarone-induced hypothyroidism (AIH) is thought

to be due to the high iodine content of amiodarone causing a Wolff-Chaikoff
effect*

Amiodarone may be continued if this is desirable

Amiodarone-induced thyrotoxicosis

Amiodarone-induced thyrotoxicosis (AIT) may be divided into two types:

AIT type 1 AIT type 2

Pathophysiolog Excess iodine-induced thyroid hormone Amiodarone-related destructive

y synthesis thyroiditis

Goitre Present Absent

32
 AIT type 1 AIT type 2

Management Carbimazole or potassium perchlorate Corticosteroids

Unlike in AIH, amiodarone should be stopped if possible in patients who

develop AIT

*an autoregulatory phenomenon where thyroxine formation is inhibited due

to high levels of circulating iodide

Hashimoto's thyroiditis

Hashimoto's thyroiditis = hypothyroidism + goitre + anti-TPO

The combination of a goitre with hypothyroidism points to a diagnosis of

Hashimoto's. De Quervain's thyroiditis typically causes a painful goitre.

Hashimoto's thyroiditis is an autoimmune disorder of the thyroid gland. It is

typically associated with hypothyroidism although there may be a transient
thyrotoxicosis in the acute phase. It is 10 times more common in women

Features

 features of hypothyroidism
 goitre: firm, non-tender
 anti-thyroid peroxidase and also anti-Tg antibodies

This patient has Hashimoto's thyroiditis, as evidenced by the

hypothyroidism, goitre and anti-thyroid peroxidase antibodies. De Quervain's
thyroiditis typically causes a painful goitre and a raised ESR. Around 90% of
patients with Grave's disease have anti-TSH receptor stimulating antibodies.

33
Thyroid function tests

Thyroid stimulating hormone (TSH) 0.3 mu/l

8 pmol/l
Free T4
This patient has hypothyroidism. The vast majority of cases are primary
hypothyroidism with a high TSH and low T4. The common causes are:

 Autoimmune (Hashimoto's disease, atrophic)

 Iodine deficiency
 Thyroiditis (post-viral, post-partum)
 Iatrogenic (thyroidectomy, radioiodine, drugs)

Secondary hypothyroidism is very rare and results in a low TSH and low T4.
In these cases pituitary insufficiency is most likely and therefore an MRI of
the gland should be performed.

Diagnosis TSH Free T4 Notes

Thyrotoxicosis (e.g. Graves' disease) Low High In T3 thyrotoxicosis the free T4 will be
normal

Primary hypothyroidism (primary atrophic High Low

hypothyroidism)

Secondary hypothyroidism Low Low Replacement steroid therapy is required

34
Diagnosis TSH Free T4 Notes

prior to thyroxine

Sick euthyroid syndrome* Low* Low Common in hospital inpatients

* T3 is particularly low in these patients

Subclinical hypothyroidism High Normal

Poor compliance with thyroxine High Normal

Steroid therapy Low Norm

al

A 64-year-old man recently discharged from hospital following

treatment for a pneumonia:

TSH 0.4 mU/l

Free T4 8.1 pmol/l

35
 Sick euthyroid syndrome

A 43-year-old woman presents with a tender goitre:

TSH <0.05 mU/l

Free T4 21.7 pmol/l

Subacute (De Quervain's) thyroiditis

Subacute thyroiditis (also known as De Quervain's thyroiditis) is thought to

occur following viral infection and typically presents with hyperthyroidism

Features

 hyperthyroidism
 painful goitre
 raised ESR

Management

 usually self-limiting - most patients do not require treatment

 thyroid pain may respond to aspirin or other NSAIDs
 in more severe cases steroids are used, particularly if hypothyroidism
develops
 globally reduced uptake on iodine-131 scan
 A 34-year-old woman presents with palpitations and feeling hot all the
time. On examination she has a non-tender goitre. Bloods show the
following:

36
 A 34-year-old woman presents with palpitations and feeling hot all the
time. On examination she has a non-tender goitre. Bloods show the
following:

TSH <0.05 mU/l

Free T4 22 pmol/l
Graves' disease

Graves' disease is a much more likely diagnosis than subacute (De Quervain's) thyroiditis which is
associated with a tender goitre and raised ESR.

A 52-year-old woman who was diagnosed as having primary atrophic

hypothyroidism 12 months ago is reviewed following recent thyroid
function tests (TFTs):

TSH 12.5 mU/l

Free T4 14 pmol/l

She is currently taking 75mcg of levothyroxine once a day. How should these
results be interpreted?

Poor compliance with medication

37
The TSH level is high. This implies that over recent days/weeks her body is
thyroxine deficient. However, her free T4 is within normal range. The most
likely explanation is that she started taking the thyroxine properly just
before the blood test. This would correct the thyroxine level but the TSH
takes longer to normalise.

Primary hyperparathyroidism

The PTH level in primary hyperparathyroidism may be normal

In exams primary hyperparathyroidism is stereotypically seen in elderly

females with an unquenchable thirst and an inappropriately normal or raised
parathyroid hormone level. It is most commonly due to a solitary adenoma

Causes of primary hyperparathyroidism 

 80%: solitary adenoma

 15%: hyperplasia
 4%: multiple adenoma
 1%: carcinoma

Features - 'bones, stones, abdominal groans and psychic moans'

 polydipsia, polyuria
 peptic ulceration/constipation/pancreatitis
 bone pain/fracture
 renal stones
 depression

38
  hypertension

Associations

 hypertension
 multiple endocrine neoplasia: MEN I and II

Investigations

 raised calcium, low phosphate

 PTH may be raised or normal
 technetium-MIBI subtraction scan

39
Bilateral hand radiographs in a middle-aged woman demonstrating
generalised osteopenia, erosion of the terminal phalyngeal tufts (acro-
osteolysis) and sub-periosteal resorption of bone particularly the radial
aspects of the 2nd and 3rd middle phalanges. These changes are consistent
with a diagnosis of hyperparathyroidism.

The most likely diagnosis here is primary hyperparathyroidism caused by

parathyroid adenoma or hyperplasia. The classical biochemical findings are a
high serum calcium and low phosphate. The parathyroid hormone level is
either high or inappropriately normal. 

Secondary hyperparathyroidism is caused by chronic hypocalcaemia (e.g.

chronic kidney disease). Serum calcium is low or normal which parathyroid
normal levels are high. Tertiary hyperparathyroidism develops from
secondary hyperparathyroidism and results in autonomous parathyroid
production. It is usually seen patients with end-stage renal disease.

Sarcoidosis and type 1 renal tubular acidosis are rare causes of

hypercalcaemia.

Treatment

 total parathyroidectomy

A 72-year-old woman presents with polyuria and polydipsia. Investigations

reveal the following: 

40
Fasting glucose 4.5 mmol/l

Calcium 2.88 mmol/l

Phosphate 0.75 mmol/l

Parathyroid 6 pmol/L (normal range =

hormone 0.8 - 8.5)

What is the most likely underlying diagnosis?

Primary hyperparathyroidism

Despite a raised calcium level the parathyroid hormone level is

inappropriately normal. This points towards a diagnosis of primary
hyperparathyroidism and the other causes (such as myeloma) would lead to
a suppression of parathyroid hormone.

Vitamin D supplementation

Vitamin D supplementation has been a hot topic for a number of years now.
The muddied waters are now slightly clearer following the release of the
following:

 2012: letter by the Chief Medical Officer regarding vitamin D

supplementation
 2013: National Osteoporosis Society (NOS) release UK Vitamin D
guideline

The following groups should be advised to take vitamin D supplementation:

 all pregnant and breastfeeding women should take a daily supplement

containing 10µg of vitamin D
 all children aged 6 months - 5 years. Babies fed with formula milk do
not need to take a supplement if they are taking more than 500ml of
milk a day, as formula milk is fortified with vitamin D
 adults > 65 years
 'people who are not exposed to much sun should also take a daily
supplement'

41
Testing for vitamin D deficiency

The key message is that not many people warrant a vitamin D test. The NOS
guidelines specify that testing may be appropriate in the following
situtations:

 patients with bone diseases that may be improved with vitamin D

treatment e.g. known osteomalacia or Paget's disease
 patients with bone diseases, prior to specific treatment where
correcting vitamin deficiency is appropriate e,g, prior to intravenous
zolendronate or denosumab
 patients with musculoskeletal symptoms that could be attributed to
vitamin D deficiency e.g. bone pain ?osteomalacia

Patients with osteoporosis should always be given calcium/vitamin D

supplements to testing is not considered necessary. People who are at
higher risk of vitamin D deficiency (see above) should be treated anyway so
again testing is not necessary.
Calcium levels should be monitored after commencing vitamin D because it
can unmask underlying hyperparathyroidism - hypercalcaemia can occur. For
this reason vitamin D may not be suitable for patients with renal calculi,
granulomatous disease, or bone metastases. The National Osteoporosis
Society suggests checking serum calcium at one month. Vitamin D levels do
not need routinely checked after commencing replacement. 

Addison's disease: management

Addison's disease management - hydrocortisone + fludrocortisones

Patients on long-term steroids should have their doses doubled during

intercurrent illness

Patients who have Addison's disease are usually given both glucocorticoid
and mineralocorticoid replacement therapy.

This usually means that patients take a combination of:

 hydrocortisone: usually given in 2 or 3 divided doses. Patients typically

require 20-30 mg per day, with the majority given in the morning dose
 fludrocortisone

42
Patient education is important:

 emphasise the importance of not missing glucocorticoid doses

 consider MedicAlert bracelets and steroid cards
 discuss how to adjust the glucocorticoid dose during an intercurrent
illness (see below)

Management of intercurrent illness

 in simple terms the glucocorticoid dose should be doubled

 the Addison's Clinical Advisory Panel have produced guidelines
detailing particular scenarios .

Patients with Addison's have little or no endogenous steroid

production. During illness the body usually increases cortisol
production as a stress response. Therefore hydrocortisone doses are
typically doubled while such patients are unwell. Fludrocortisone is
less important and the dose is typically kept the same as normal.

Double the hydrocortisone dose, keep the same fludrocortisone

dose

43
This woman has Addison's disease as she has failed a short synacthen test.
Synacthen is a synthetic adrenocorticotrophic hormone (ACTH) analogue
which should stimulate cortisol secretion from the adrenal glands.

The most common cause of Addison's disease in industrialised nations is

autoimmune disease. Tuberculosis (TB) is the most common cause
worldwide but given the patient's Welsh ethnicity and the absence of any TB
risk factors it is less likely in this case. Metastatic disease, amyloidis and
Waterhouse Friderichsen syndrome are all less common causes of Addison's
disease.

44
Hyponatraemia and hyperkalaemia in a patient with lethargy is highly
suggestive of Addison's disease. The thyroxine level is slightly low and she
may indeed have co-existing hypothyroidism but this would not explain the
hyperkalaemia

The short synacthen test is the best test to diagnose Addison's disease

Primary hyperaldosteronism

Primary hyperaldosteronism was previously thought to be most commonly

caused by an adrenal adenoma, termed Conn's syndrome. However, recent
studies have shown that bilateral idiopathic adrenal hyperplasia is the cause
in up to 70% of cases. Differentiating between the two is important as this
determines treatment. Adrenal carcinoma is an extremely rare cause of
primary hyperaldosteronism

Features

 hypertension
 hypokalaemia (e.g. muscle weakness)
 alkalosis

Investigations

 high serum aldosterone

 low serum renin
 high-resolution CT abdomen

45
  adrenal vein sampling

Management

 adrenal adenoma: surgery

 bilateral adrenocortical hyperplasia: aldosterone antagonist e.g.
spironolactone

CT abdomen showing a right-sided adrenal adenoma in a patient who

presented with hypertension and hypokalaemia. The adenoma can be seen
'next to' or 'below' the liver.

46
Corticosteroids

Corticosteroids are amongst the most commonly prescribed therapies in

clinical practice. They are 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.

The relative glucocorticoid and mineralocorticoid activity of commonly used

steroids is shown below:

Minimal Predominant Very high

glucocorticoid Glucocorticoid glucocorticoid glucocorticoid
activity, very high activity, high activity, low activity, minimal
mineralocorticoid mineralocorticoid mineralocorticoid mineralocorticoid
activity, activity, activity activity

Fludrocortisone Hydrocortisone Prednisolone Dexamethasone

Betmethasone

Side-effects

The side-effects of corticosteroids are numerous and represent the single

47
greatest limitation on their usage. Side-effects are more common with
systemic and prolonged therapy.

Glucocorticoid side-effects

 endocrine: impaired glucose regulation, increased appetite/weight

gain, hirsutism, hyperlipidaemia
 Cushing's syndrome: moon face, buffalo hump, striae
 musculoskeletal: osteoporosis, proximal myopathy, avascular necrosis
of the femoral head
 immunosuppression: increased susceptibility to severe infection,
reactivation of tuberculosis
 psychiatric: insomnia, mania, depression, psychosis
 gastrointestinal: peptic ulceration, acute pancreatitis
 ophthalmic: glaucoma, cataracts
 suppression of growth in children
 intracranial hypertension

Proximal myopathy is common with longer term steroid use.

Psychiatric problems are common with longer term steroid use.

Mineralocorticoid side-effects

 fluid retention
 hypertension

Selected points on the use of corticosteroids:

 patients on long-term steroids should have their doses doubled during

intercurrent illness
 the BNF suggests gradual withdrawal of systemic corticosteroids if
patients have: received more than 40mg prednisolone daily for more
than one week, received more than 3 weeks treatment or recently
received repeated courses

48
Hyperlipidaemia: management

NICE recommend the following when considering the use of statins in

patients with type 2 diabetes mellitus:

Measure total cholesterol, high-density lipoprotein (HDL) cholesterol, and

non-HDL cholesterol (total cholesterol minus HDL cholesterol) levels after 3
months of atorvastatin treatment. The aim of treatment is to achieve a
greater than 40% reduction in baseline non-HDL cholesterol levels. 

If a greater than 40% reduction in non-HDL cholesterol is not achieved:

 Discuss adherence and timing of dose.

 Reinforce adherence to diet and lifestyle measures.
 Consider increasing the dose of atorvastatin if the person is judged to
be at higher risk of CVD because of comorbidities or risk score, or
using clinical judgement.

If a greater than 40% reduction in non-HDL cholesterol is still not achieved

after appropriate dose titrations of atorvastatin, or because dose titration is
limited by adverse effects:

 Ezetimibe, co-administered with atorvastatin, can be considered for

people with primary hypercholesterolaemia (consider seeking
specialist advice).

Offer atorvastatin 20 mg for the primary prevention of CVD to people with

type 2 diabetes who have a 10% or greater 10-year risk of developing CVD.

In 2014 NICE updated their guidelines on lipid modification. This proved

highly controversial as it meant that we should be recommending statins to a
significant proportion of the population over the age of 60 years. Anyway, the
key points of the new guidelines are summarised below.

Primary prevention - who and how to assess risk

A systematic strategy should be used to identify people aged over 40 years

who are likely to be at high risk of cardiovascular disease (CVD), defined as a
10-year risk of 10% or greater. 

NICE recommend we use the QRISK2 CVD risk assessment tool for patients

49
aged <= 84 years. Patients >= 85 years are at high risk of CVD due to their
age. QRISK2 should not be used in the following situations as there are more
specific guidelines for these patient groups:

 type 1 diabetics
 patients with an estimated glomerular filtration rate (eGFR) less than
60 ml/min and/or albuminuria
 patients with a history of familial hyperlipidaemia

NICE suggest QRISK2 may underestimate CVD risk in the following

population groups:

 people treated for HIV

 people with serious mental health problems
 people taking medicines that can cause dyslipidaemia such as
antipsychotics, corticosteroids or immunosuppressant drugs
 people with autoimmune disorders/systemic inflammatory disorders
such as systemic lupus erythematosus

Measuring lipid levels

When measuring lipids both the total cholesterol and HDL should be
checking to provide the most accurate risk of CVD. A full lipid profile should
also be checked (i.e. including triglycerides) before starting a statin. The
samples does not need to be fasting.

In the vast majority of patient the cholesterol measurements will be fed into
the QRISK2 tool. If however the patient's cholesterol is very high we should
consider familial hyperlipidaemia. NICE recommend the following that we
should consider the possibility of familial hypercholesterolaemia and
investigate further if the total cholesterol concentration is > 7.5 mmol/l and
there is a family history of premature coronary heart disease. They also
recommend referring people with a total cholesterol > 9.0 mmol/l or a non-
HDL cholesterol (i.e. LDL) of > 7.5 mmol/l even in the absence of a first-
degree family history of premature coronary heart disease.

Interpreting the QRISK2 result

Probably the headline changes in the 2014 guidelines was the new, lower
cut-off of 10-year CVD risk cut-off of 10%. 

50
NICE now recommend we offer a statin to people with a QRISK2 10-year risk
of >= 10%

Lifestyle factors are of course important and NICE recommend that we give
patients the option of having their CVD risk reassessed after a period of time
before starting a statin.

Atorvastatin 20mg should be offered first-line.

Special situations

Type 1 diabetes mellitus

 NICE recommend that we 'consider statin treatment for the primary

prevention of CVD in all adults with type 1 diabetes'
 atorvastatin 20 mg should be offered if type 1 diabetics who are:
 → older than 40 years, or
 → have had diabetes for more than 10 years or
 → have established nephropathy or
 → have other CVD risk factors

Chronic kidney disease (CKD)

 atorvastatin 20mg should be offered to patients with CKD

 increase the dose if a greater than 40% reduction in non-HDL
cholesterol is not achieved and the eGFR > 30 ml/min. If the eGFR is <
30 ml/min a renal specialist should be consulted before increasing the
dose

Secondary prevention

All patients with CVD should be taking a statin in the absence of any
contraindication.

Atorvastatin 80mg should be offered first-line.

Follow-up of people started on statins

NICE recommend we follow-up patients at 3 months

51
  repeat a full lipid profile
 if the non-HDL cholesterol has not fallen by at least 40% concordance
and lifestyle changes should be discussed with the patient
 NICE recommend we consider increasing the dose of atorvastatin up to
80mg

Lifestyle modifications

These are in many ways predictable but NICE make a number of specific
points:

Cardioprotective diet

 total fat intake should be <= 30% of total energy intake

 saturated fats should be <= 7% of total energy intake
 intake of dietary cholesterol should be < 300 mg/day
 saturated fats should be replaced by monounsaturated and
polyunsaturated fats where possible
 replace saturated and monounsaturated fat intake with olive oil,
rapeseed oil or spreads based on these oils
 choose wholegrain varieties of starchy food
 reduce their intake of sugar and food products containing refined
sugars including fructose
 eat at least 5 portions of fruit and vegetables per day
 eat at least 2 portions of fish per week, including a portion of oily fish
 eat at least 4 to 5 portions of unsalted nuts, seeds and legumes per
week

Physical activity

 each week aim for at least 150 minutes of moderate intensity aerobic
activity or 75 minutes of vigorous intensity aerobic activity or a mix of
moderate and vigorous aerobic activity
 do musclestrengthening activities on 2 or more days a week that work
all major muscle groups (legs, hips, back, abdomen, chest, shoulders
and arms) in line with national guidance for the general population

Weight management

 no specific advice is given, overweight patients should be managed in

keeping with relevant NICE guidance

52
Alcohol intake

 again no specific advice, other than the general recommendation that

males drink no more than 3-4 units/day and females no more than 2-3
units/day

Smoking cessation

 smokers should be encouraged to quit

Familial hypercholesterolaemia

Familial hypercholesterolaemia (FH) is an autosomal dominant condition that

is thought to affect around 1 in 500 people. It results in high levels of LDL-
cholesterol which, if untreated, may cause early cardiovascular disease
(CVD). FH is caused by mutations in the gene which encodes the LDL-
receptor protein.

Clinical diagnosis is now based on the Simon Broome criteria:

 in adults total cholesterol (TC) > 7.5 mmol/l and LDL-C > 4.9 mmol/l or
children TC > 6.7 mmol/l and LDL-C > 4.0 mmol/l, plus:
 for definite FH: tendon xanthoma in patients or 1st or 2nd degree
relatives or DNA-based evidence of FH
 for possible FH: family history of myocardial infarction below age 50
years in 2nd degree relative, below age 60 in 1st degree relative, or a
family history of raised cholesterol levels

Management

 the use of CVD risk estimation using standard tables is not appropriate
in FH as they do not accurately reflect the risk of CVD
 referral to a specialist lipid clinic is usually required
 the maximum dose of potent statins are usually required
 first-degree relatives have a 50% chance of having the disorder and
should therefore be offered screening. This includes children who
should be screened by the age of 10 years if there is one affected
parent
 statins should be discontinued in women 3 months before conception
due to the risk of congenital defects

53
Hirsutism and hypertrichosis

Porphyria cutanea tarda is a cause of hypertrichosis rather than hirsutism.

/hirsutism is often used to describe androgen-dependent hair growth in

women, with hypertrichosis being used for androgen-independent hair growth

Polycystic ovarian syndrome is the most common causes of hirsutism. Other

causes include: 

 Cushing's syndrome
 congenital adrenal hyperplasia
 androgen therapy
 obesity: due to peripheral conversion oestrogens to androgens
 adrenal tumour
 androgen secreting ovarian tumour
 drugs: phenytoin

Assessment of hirsutism

 Ferriman-Gallwey scoring system: 9 body areas are assigned a score of

0 - 4, a score > 15 is considered to indicate moderate or severe
hirsutism

Management of hirsutism

 advise weight loss if overweight

 cosmetic techniques such as waxing/bleaching - not available on the
NHS
 consider using combined oral contraceptive pills such as co-cyprindiol
(Dianette) or ethinylestradiol and drospirenone (Yasmin). Co-cyprindiol
should not be used long-term due to the increased risk of venous
thromboembolism
 facial hirsutism: topical eflornithine - contraindicated in pregnancy and
breast-feeding

Causes of hypertrichosis

54
  drugs: minoxidil, ciclosporin, diazoxide
 congenital hypertrichosis lanuginosa, congenital hypertrichosis
terminalis
 porphyria cutanea tarda
 anorexia nervosa

Obesity: therapeutic options

The primary mode of action of orilistat is to inhibit pancreatic lipases, which

in turn will decrease the absorption of lipids from the intestine

The management of obesity consists of a step-wise approach:

 conservative: diet, exercise

 medical
 surgical

Orlistat is a pancreatic lipase inhibitor used in the management of obesity.

Adverse effects include faecal urgency/incontinence and flatulence. A lower
dose version is now available without prescription ('Alli'). NICE have defined
criteria for the use of orlistat. It should only be prescribed as part of an
overall plan for managing obesity in adults who have:

 BMI of 28 kg/m^2 or more with associated risk factors, or

 BMI of 30 kg/m^2 or more
 continued weight loss e.g. 5% at 3 months
 orlistat is normally used for < 1 year

Sibutramine

 withdrawn January 2010 by the European Medicines Agency due to an

increased risk of cardiovascular events
 centrally acting appetite suppressant (inhibits uptake of serotonin and
noradrenaline at hypothalamic sites that regular food intake)
 adverse effects include hypertension (monitor blood pressure and
pulse during treatment), constipation, headache, dry mouth, insomnia
and anorexia
 contraindicated in psychiatric illness, hypertension, IHD, stroke,
arrhythmias

Rimonabant, a specific CB1 cannabinoid receptor antagonist, was withdrawn

55
in October 2008 after the European Medicines Agency warned of serious
psychiatric problems including suicide

Haemochromatosis: features

Haemochromatosis is an autosomal recessive disorder of iron absorption and

metabolism resulting in iron accumulation. It is caused by inheritance of
mutations in the HFE gene on both copies of chromosome 6*. It is often
asymptomatic in early disease and initial symptoms often non-specific e.g.
lethargy and arthralgia

Epidemiology

 1 in 10 people of European descent carry a mutation genes affecting

iron metabolism, mainly HFE
 prevalence in people of European descent = 1 in 200

Presenting features

 early symptoms include fatigue, erectile dysfunction and arthralgia

(often of the hands)
 'bronze' skin pigmentation
 diabetes mellitus
 liver: stigmata of chronic liver disease, hepatomegaly, cirrhosis,
hepatocellular deposition)
 cardiac failure (2nd to dilated cardiomyopathy)
 hypogonadism (2nd to cirrhosis and pituitary dysfunction -
hypogonadotrophic hypogonadism)
 arthritis (especially of the hands)

Questions have previously been asked regarding which features are

reversible with treatment:

Irreversible complications

Reversible complications  Liver cirrhosis**

 Diabetes mellitus
 Cardiomyopathy  Hypogonadotrophic hypogonadism
 Skin pigmentation  Arthropathy

56
*there are rare cases of families with classic features of genetic
haemochromatosis but no mutation in the HFE gene

**whilst elevated liver function tests and hepatomegaly may be reversible,

cirrhosis is not

Haemochromatosis: investigation

Screening for haemochromatosis

 general population: transferrin saturation > ferritin

 family members: HFE genetic testing

Serum transferrin saturation is currently the preferred investigation for

population screening. However, the patient has a sibling with
haemochromatosis and therefore HFE gene analysis is the most suitable
investigation. In clinical practice this would be combined with iron studies
as well
Haemochromatosis is an autosomal recessive disorder of iron absorption and
metabolism resulting in iron accumulation. It is caused by inheritance of
mutations in the HFE gene on both copies of chromosome 6*. The British
Committee for Standards in Haematology (BCSH) published guidelines for the
investigation and management of haemochromatosis in 2000

There is continued debate about the best investigation to screen for

haemochromatosis. The 2000 BCSH guidelines suggest:

 general population: transferrin saturation is considered the most useful

marker. Ferritin should also be measured but is not usually abnormal in
the early stages of iron accumulation
 testing family members: genetic testing for HFE mutation

These guidelines may change as HFE gene analysis become less expensive

Screening for haemochromatosis

 general population: transferrin saturation > ferritin

 family members: HFE genetic testing

57
The British Committee for Standards in Haematology (BCSH) guidelines
recommend measuring the transferrin saturation first as this is the most
specific and sensitive test for iron accumulation. They also recommend that
serum ferritin is measured but this marker is not usually abnormal in the
early stages of iron accumulation.

Diagnostic tests

 molecular genetic testing for the C282Y and H63D mutations

 liver biopsy: Perl's stain

Typical iron study profile in patient with haemochromatosis

 transferrin saturation > 55% in men or > 50% in women

 raised ferritin (e.g. > 500 ug/l) and iron
 low TIBC

Monitoring adequacy of venesection

 BSCH recommend 'transferrin saturation should be kept below 50% and

the serum ferritin concentration below 50 ug/l'

Joint x-rays characteristically show chondrocalcinosis

*there are rare cases of families with classic features of genetic

haemochromatosis but no mutation in the HFE gene

58
Prolactin and galactorrhoea

Causes of raised prolactin - the p's

 pregnancy
 prolactinoma
 physiological
 polycystic ovarian syndrome
 primary hypothyroidism
 phenothiazines, metoclopramide, domperidone

Bromocriptine is a treatment for galactorrhoea, rather than a cause

Selective serotonin reuptake inhibitors such as fluoxetine have rarely been

associated with hyperprolactinaemia but the most likely cause in this patient
is metoclopramide. Cimetidine is generally associated with gynaecomastia,
rather than galactorrhoea ('very rare', according to the BNF).
Prolactin is secreted by the anterior pituitary gland with release being
controlled by a wide variety of physiological factors. Dopamine acts as the
primary prolactin releasing inhibitory factor and hence dopamine agonists
such as bromocriptine may be used to control galactorrhoea. It is important
to differentiate the causes of galactorrhoea (due to the actions of prolactin

59
on breast tissue) from those of gynaecomastia

Features of excess prolactin

 men: impotence, loss of libido, galactorrhoea

 women: amenorrhoea, galactorrhoea

Causes of raised prolactin

 prolactinoma
 pregnancy
 oestrogens
 physiological: stress, exercise, sleep
 acromegaly: 1/3 of patients
 polycystic ovarian syndrome
 primary hypothyroidism (due to thyrotrophin releasing hormone (TRH)
stimulating prolactin release)

Drug causes of raised prolactin

 metoclopramide, domperidone
 phenothiazines
 haloperidol
 very rare: SSRIs, opioids

patient who has a prolactinoma , symptomatic patients are treated

medically with dopamine agonists (e.g. bromocriptine) which inhibit the
release of prolactin from the pituitary gland. Surgery is performed for
patients who cannot tolerate or fail to respond to medical therapy. A trans-
sphenoidal approach is generally preferred unless there is significant extra-
pituitary extension. Radiotherapy is rarely performed and octreotide is a
somatostatin analogue used in the treatment of acromegaly.

A 52-year-old man presents to his GP as he is concerned about a discharge

from his nipples. Which one of the following drugs is most likely to be
responsible?

Ranitidine
Isoniazid
Digoxin
Spironolactone
Chlorpromazine >>> a phenothiazine ( antipsychotic).

60
Each of the other four drugs may be associated with gynaecomastia rather
than galactorrhoea.

Gynaecomastia

Gynaecomastia describes an abnormal amount of breast tissue in males and

is usually caused by an increased oestrogen:androgen ratio. It is important
to differentiate the causes of galactorrhoea (due to the actions of prolactin
on breast tissue) from those of gynaecomastia

Causes of gynaecomastia

 physiological: normal in puberty

 syndromes with androgen deficiency: Kallman's, Klinefelter's
 testicular failure: e.g. mumps
 liver disease
 testicular cancer e.g. seminoma secreting hCG
 ectopic tumour secretion
 hyperthyroidism
 haemodialysis
 drugs: see below

Drug causes of gynaecomastia

 spironolactone (most common drug cause)

 cimetidine
 digoxin
 cannabis
 finasteride
 gonadorelin analogues e.g. Goserelin, buserelin
 oestrogens, anabolic steroids

Very rare drug causes of gynaecomastia

 tricyclics
 isoniazid
 calcium channel blockers
 heroin

61
  busulfan
 methyldopa

Goserelin is a gonadorelin analogue used in the treatment of advanced

prostate cancer. Tamoxifen may be used to treat gynaecomastia.

Erectile dysfunction

As part of assessment for erectile dysfunction Clinical knowledge

Summaries (CKS) recommend that all men have their 10-year cardiovascular
risk calculated by measuring lipid and fasting glucose serum levels. 

Testosterone, lipids, fasting glucose

Free testosterone should also be measured in the morning between 9 and

11am. If free testosterone is low or borderline, it should be repeated along
with follicle-stimulating hormone, luteinizing hormone and prolactin levels. If
any of these are abnormal refer to endocrinology for further assessment.

Opinion on testosterone measurement differs between some experts but

CKS advises universal measurement of testosterone in men with erectile
dysfunction as recommended by the British Society for Sexual Medicine and
the European Association of Urology.

Hyponatraemia

Hyponatraemia may be caused by water excess or sodium depletion. Causes

of pseudohyponatraemia include hyperlipidaemia (increase in serum volume)
or a taking blood from a drip arm. Urinary sodium and osmolarity levels aid
making a diagnosis

Urinary sodium > 20 mmol/l

Sodium depletion, renal loss (patient often hypovolaemic)

 diuretics
 Addison's
 diuretic stage of renal failure

62
Patient often euvolaemic

 SIADH (urine osmolality > 500 mmol/kg)

 hypothyroidism

Urinary sodium < 20 mmol/l

Sodium depletion, extra-renal loss

 diarrhoea, vomiting, sweating

 burns, adenoma of rectum

Water excess (patient often hypervolaemic and oedematous)

 secondary hyperaldosteronism: heart failure, cirrhosis

 reduced GFR: renal failure
 IV dextrose, psychogenic polydipsia

63
Hyponatraemia: correction

Central pontine myelinolysis

 demyelination syndrome caused by rapid correction of chronic

hyponatraemia
 may lead to quadriparesis and bulbar palsy
 diagnosis: MRI brain

A sodium result of 118 mmol/L falls into the category of severe

hyponatraemia (less than 125 mmol/L). Emergency admission is indicated
because hyponatraemia is potentially life threatening, particularly when it is
severe and/or of acute onset (over a period of less than 48 hours). This is due
to swelling of brain cells when water moves from the extracellular to the
intracellular compartment because of differences in the osmolality between
brain and plasma. Cerebral oedema and raised intracranial pressure can lead

64
to seizures, coma or cardio-respiratory arrest.

Hyponatraemia can be classified by biochemical severity and rate of onset:

Biochemical severity

 mild hyponatraemia = serum sodium 130-135 mmol/L

 moderate hyponatraemia = serum sodium 125-129 mmol/L
 severe hyponatraemia = serum sodium less than 125 mmol/L

Rate of onset

 acute = hyponatraemia duration for less than 48 hours

 chronic = hyponatraemia duration for 48 hours or more.

65