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Metabolic and endocrine disorders
Diabetic neuropathy
Diabetic neuropathy can take several forms.
Somatic neuropathies—Somatic neuropathies may take
the following forms:
• Distal symmetrical polyneuropathy: this commonly
affects the lower limbs first, with numbness and
paraesthesia of the feet, spreading up the leg, before
then affecting the hands (‘glove and stocking’
pattern). Symptoms are predominantly sensory with
early loss of vibration sense and absent ankle jerks.
In advanced cases the loss of pain sensation may
lead to the development of punched-out chronic
ulcers at pressure points in areas of thick callus,
and may cause arthropathy (see later). The patient’s
foot may then become infected and eventually
gangrenous.
• Mononeuritis: may be due to entrapment or ischaemia.
Commonly involved nerves include the third cranial
nerve, ulnar nerve and lateral popliteal nerve. More
than one nerve can be involved, causing mononeuritis
multiplex.
• Diabetic amyotrophy: painful asymmetrical weakness
and wasting of the quadriceps muscles due to
lumbosacral plexopathy and polyradiculopathy. The
patient may recover.
Autonomic neuropathies—This may lead to symptoms
of postural hypotension (i.e. dizziness on standing), impotence, diarrhoea and urinary retention. Gastroparesis
causing vomiting can be a very troubling symptom for
patients.
PATIENT SAFETY
Patients can have a lack of awareness of the
symptoms of hypoglycaemia. Find out whether
your patient has hypoglycaemic episodes and
whether he or she is are aware of them. This is
particularly important to do before the start of
treatment with any β-blockers, which can mask
hypoglycaemic awareness.
RED FLAG
The infected diabetic foot requires urgent and
aggressive assessment and treatment with broadspectrum antibiotics. Investigations need to be
performed to assess the underlying blood supply
(through Doppler studies and angiography) and to
see whether there is an underlying osteomyelitis.
If arterial perfusion is poor, medical treatment is
rarely effective, and surgical debridement and
amputation is often required.
COMMUNICATION
Explain to your patients the importance of
inspecting their feet for any cuts or blisters which
can become infected. Tell them to always wear
well-fitting shoes, not to walk barefoot and to see a
chiropodist regularly.
Skin
Complications occurring in the skin include:
• Lipoatrophy: this is loss of fat at insulin injection
sites. It is much rarer now that human insulin has
replaced bovine or porcine insulin. The patient
should be advised to vary the injection sites because
the absorption of insulin at sites of atrophy is
unpredictable.
• Acanthosis nigricans: hyperpigmented velvety
thickening of skin folds, predominantly in the neck,
axilla and groin areas. It is common, and has a strong
association with insulin resistance.
• Necrobiosis lipoidica: these are irregular, painless ovoid
plaques with a yellow atrophic centre and red to purple
edge. They are found on the skin of the tibia, and occur
in approximately 1% of people with type 1 diabetes.
Infections, such as boils and candida, are more common.
Diabetic feet
Diabetic foot problems are due to a combination of neuropathy and peripheral vascular disease. Diabetes predisposes
patients to infection, which may affect the soft tissue and
even bone (osteomyelitis) of ulcerated feet. This is a common reason for presentation and admission.
Sensory neuropathy causes ulcers over pressure points
(e.g. metatarsal heads) and can cause joint deformity because of the lack of pain and proprioception (e.g. pes cavus,
Charcot joints). Peripheral vascular disease, which may be
due to small and/or large vessel occlusion, affects the toes
primarily.
308
Infections
Common infections are of the urinary tract and skin, and
candidiasis. Tuberculosis is also more common in people
with diabetes. Susceptibility to infection is due to several
factors, including a reduced immune response due to hyperglycaemia, tissue ischaemia secondary to vascular disease and increased portals of entry, such as ulcers.
Management
Successful management of diabetic patients requires a
high level of patient education and motivation, and this is
achieved through regular follow-up with a multidisciplinary
Diabetes mellitus
3333
team involving doctors, nurses, ophthalmologists, dietitians
and chiropodists/podiatrists. The aims of continued assessment of diabetic patients are ongoing education, assessment
of glycaemic control and assessment of complications.
COMMUNICATION
Adolescent patients often find it especially difficult
to achieve good control of their diabetes. Give
these patients your special attention. Some
hospitals offer transition clinics where there is an
emphasis on multidisciplinary involvement and
focus on addressing the patient’s social needs.
Peer support groups are often extremely valuable
for patients.
The Diabetes Control and Complications Trial in type 1 diabetic patients and the UK Prospective Diabetes Study in
type 2 diabetic patients demonstrated that tight control of
blood glucose (aiming for a glycated haemoglobin (HbA1c)
fraction of 6.5%–7.5%, 48–58 mmol/mol) reduces microvascular complications. This needs to be balanced against
the increased risk of hypoglycaemic episodes.
The UK Prospective Diabetes Study also demonstrated
that tight control of blood pressure reduces both macrovascular and microvascular complications. This and other trials have suggested that the aim should be a blood pressure
below 130/80 mmHg. This emphasizes the need for a global
assessment of a diabetic patient’s cardiovascular risk factors
and aggressive management of all of them.
Many patients now monitor their own blood glucose
concentrations using blood glucose strips and an electronic
meter. These records should be examined, together with any
corresponding hypoglycaemic symptoms. The HbA1c fraction should be checked every 3–6months depending on the
level of control.
Microvascular complications must be monitored:
• Visual acuity checks together with examination of the
optic fundi for retinopathy.
• The feet should be examined for neuropathy, ischaemic
changes and infection.
• Nephropathy should be sought by monitoring of urea
and electrolyte levels, and by testing for albuminuria.
Type 2 diabetes is usually treated initially with oral hypoglycaemic drugs if dietary measures are unsuccessful, although
many of these patients will require insulin at some point. Type
1 diabetes is treated with injectable insulin from the outset.
of postprandial hypoglycaemia. Patients should be encouraged to take regular exercise and reduce energy intake to
help achieve and maintain ideal body weight. This often
proves to be very difficult. Studies suggest that bariatric surgery for weight loss is an effective therapy in type 2 diabetes,
and may lead to remission.
Oral hypoglycaemic agents
Treatment with these is usually started when diet and lifestyle measures fail to offer adequate control, although some
organizations now suggest that metformin therapy should
be started at diagnosis. Metformin is the first-line drug as it
reduces cardiovascular risk in obese patients and does not
cause weight gain. The next step is usually the addition of
a sulphonylurea, thiazolidinedione, newer agents (see later)
or insulin either alone or in combination. Acarbose is used
less frequently now. When choosing, with your patient,
which agent to use, you must consider side effects, contraindications and the patient’s lifestyle and circumstances.
Biguanides
Metformin is the only available biguanide, and is the firstline therapy for patients without contraindications. It exerts
its effect mainly by decreasing gluconeogenesis and increasing peripheral utilization of glucose; some residual islet cell
function is required. Gastrointestinal side effects are common, including nausea and diarrhoea. There is a risk of lactic acidosis and, although this is rare, metformin should be
avoided in patients with predisposing conditions, including
renal failure, heart failure and liver disease.
PATIENT SAFETY
Stop the use of metformin when the estimated
glomerular filtration rate (eGFR) is less than 30 mL/
min per 1.73 m2, because of the increased risk
of lactic acidosis. Metformin use should also be
stopped during sepsis. The 2009 guidelines from
the Royal College of Radiologists state that there is
no need to stop the use of metformin in association
with the use of iodinated contrast agents in
patients with normal serum creatinine level and
or an eGFR greater than 60 mL/min per 1.73m2. If
creatinine level is above the normal range or eGFR
is less than 60 mL/min per 1.73m2, then a decision
to hold metformin use for 48 hours should be
considered with the clinical team.
Diet and lifestyle
The diet should be low in fat (to help delay the progression
of atherosclerosis) and low in refined sugars, but high in
complex carbohydrates (such as starch) and high in fibre,
which among other benefits helps to lower the incidence
Sulphonylureas
These drugs act mainly by augmenting insulin secretion,
and therefore some residual pancreatic beta-cell activity is
required. There are several sulphonylureas, but all are probably equally effective, and are used as second-line therapy or
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Metabolic and endocrine disorders
first-line therapy when metformin is contraindicated. The
most frequent and significant side effect is hypoglycaemia,
which may persist longer than expected because of the long
half-life of some sulphonylureas. Elderly patients and individuals with renal impairment are particularly prone to hypoglycaemia. The sulphonylureas tend to encourage weight
gain, and this can be a problem in obese patients, whose
insulin resistance may worsen even more.
Meglitinides; rapid-acting insulin secretagogues
These include repaglinide and nateglinide, and are
short-acting stimulators of insulin and can be given before
a main meal. They are used generally in combination with
metformin, and their main risk is of hypoglycaemia.
Thiazolidinediones
Pioglitazone is currently the only licensed thiazolidinedione, and can be added as second-line or third-line therapy. It increases insulin sensitivity. The main side effect is
fluid retention, and it is contraindicated in heart failure.
There is also a slightly higher risk of fractures and bladder
cancer.
Dipeptidyl peptidase 4 inhibitors
These include sitagliptin, saxagliptin and linagliptin, and
may work via several mechanisms, including increasing the
action of glucagon-like peptide 1. They are generally well
tolerated, although gastrointestinal side effects can occur
and there may be an increased risk of pancreatitis. They are
used as second-line therapy.
Glucagon-like peptide 1 agonists
This group of injection-only drugs includes exenatide, and
functions by mimicking the action of glucagon-like peptide
1. They are administered once weekly. They are used as a
third-line therapy.
Acarbose
Acarbose, an inhibitor of intestinal α-glucosidases, delays
the digestion of starch and sucrose and hence the increase in
blood glucose levels that follows a carbohydrate- containing
meal. It may be used as an adjunctive therapy but often
causes intolerable flatulence.
Insulin
All type 1 diabetic patients are treated with insulin, and
many type 2 diabetic patients require insulin to achieve
satisfactory glycaemic control. Mixtures of available insulin
preparations may be required to maintain good control, and
these will differ for individual patients. Requirements may
be affected by variations in lifestyle, other medications and
concurrent illness such as infection.
Patients should aim for blood glucose concentrations
between 4 and 10 mmol/L for most of the time, while accepting that on occasions they will be above or below
these values. They should be advised to look for ‘peaks’
and ‘troughs’ of blood glucose and to adjust their insulin
dosage only once or twice weekly. Animal insulin, human insulin and insulin analogues are available, and the
preparations may be short-acting (Actrapid, Humulin
S), intermediate-acting (Insulatard, Humulin I) or longacting (Lantus). If possible, a ‘basal-bolus’ regimen is used:
a once-daily injection of a medium-acting or long-acting
insulin, with short-acting or rapid-acting insulin injection
before or with meals. This most closely resembles the physiological changes in insulin levels, but requires education
and commitment. In some patients twice-daily injections
of ‘biphasic insulin’ (mixtures of a short-acting and an
intermediate-acting insulin, e.g. Novomix or Humulin M3)
are better (Fig.33.3).
Some patients may have an insulin pump, which gives
them a continuous insulin infusion. Pancreatic transplant may be performed if the patient meets the criteria,
in patients undergoing renal transplant, in which case it
is performed simultaneously, or if the patient has very labile and problematic diabetes, particularly hypoglycaemic
unawareness.
Diabetes and surgery
Patients who have diabetes should be first on the operating list and should fast on the morning of surgery.
Diet-controlled diabetic patients simply require careful
monitoring of glucose levels. Oral agents should be avoided
on the morning of surgery and can be recommenced with
the first meal postoperatively. If glucose levels are poorly
controlled, if oral intake will be problematic postoperatively,
or if the procedure is long, intravenous (IV) administration
of insulin may be required (see later).
For patients already using insulin, IV administration
of insulin is started early on the day of the operation, with
use of a variable rate insulin sliding scale. Depending on
the protocol, the patient’s normal long-acting bolus medication may be continued. The IV insulin regimen usually
consists of a 1 unit per millilitre infusion of soluble insulin in 0.9% saline (i.e. 50 units of Actrapid in 50 mL 0.9%
NaCl). The capillary glucose level is checked on an hourly
or 2-hourly basis, and the rate of insulin infusion is changed
accordingly. While the patient is fasting, a 5% dextrose with
20 mmol/L KCl infusion must always be running concurrently with the insulin infusion and other fluid and electrolyte requirements should supplement this infusion. When
patients start to eat and drink, their normal insulin regimen
may be restarted.
COMMUNICATION
Patients are often well informed about their
diabetes. Ensure that any modifications to their
therapy are discussed with and explained to them.
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Diabetes mellitus
• Soluble insulin = short-acting insulin preparation
Typical blood glucose
profile in a nondiabetic
LunchBreakfast
Dinner
Night-time fast
person
3333
One injection per day
Lente
Two injections per day
SolubleSoluble
Isophane Isophane
Four injections per day
SolubleSolubleSoluble
• Lente = long-acting insulin preparation
• Isophane = medium-acting insulin preparation
Fig.33.3 Examples of different insulin regimens.
Diabetic emergencies
Hypoglycaemia
Symptoms of hypoglycaemia include sweating, hunger
and tremor (autonomic symptoms) and very low glucose concentrations may cause drowsiness, seizures, transient neurological symptoms and loss of consciousness.
Hypoglycaemia is very common in diabetic patients, but
there are many causes:
• drugs: excessive insulin or sulphonylureas;
• alcohol binges, especially with decreased food intake;
• endocrine causes: pituitary insufficiency, Addison
disease and insulinomas;
• liver failure.
Certain specific investigations can help differentiate between the causes:
• Measurement of insulin and C-peptide levels;
C-peptide is produced from the breakdown of
proinsulin, and its level will be raised only with
endogenous hyperinsulinaemia, suggesting an
insulinoma.
• Sulphonylurea levels.
• Short Synacthen (tetracosactide) test for Addison
disease.
Management—This should be approached in relation
to whether the patient is conscious or not. If the patient
is conscious, give high-sugar-containing foods orally (e.g.
Lucozade, biscuits or glucose gel), followed by complex
carbohydrate. If the patient is unconscious, begin with an
Prevents ketoacidosis and
symptoms but not flexible
enough to achieve close
glycaemic control in most
patients
Usual treatment in newly
diagnosed patients
Allows a close control of
Isophane
blood glucose and a more
variable lifestyle
ABCDE approach, and then commence an IV infusion of
glucose. This needs to be a glucose concentration of greater
than 10%; typically 100 mL of 20% dextrose is used. If no
IV access is possible, then 1 mg of glucagon can be given
intramuscularly (IM). Recheck the blood glucose level every 10 minutes following treatment, and repeat treatment
as needed. Treat the underlying cause. In diabetic patients,
issues surrounding education and awareness of hypoglycaemia should be addressed when the patient has recovered
from the acute event.
CLINICAL NOTES
Glucagon is a polypeptide hormone produced
by the alpha cells of the pancreatic islets of
Langerhans. It increases plasma glucose level by
mobilizing glycogen stored in the liver, and will be
useful only in patients with adequate glycogen
stores.
CLINICAL NOTES
Following treatment of a hypoglycaemic episode,
do not omit the patient’s next dose of insulin,
although a dose reduction may be needed.
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Metabolic and endocrine disorders
PATIENT SAFETY
Be careful with insulin prescribing. Careful
handwriting is essential, write out the dose in
full (i.e. ‘15 units’ rather than ‘15 U’. If any shortacting insulin dose is greater than 25 units or any
intermediate-acting/long-acting insulin dose is
greater than 50 units, stop and check if this is
correct.
Diabetic ketoacidosis
DKA occurs in type 1 diabetes. It may be the mode of first
presentation of diabetes, or it may be precipitated by an inadequate insulin dose or an intercurrent illness (e.g. infection or myocardial infarction). There is usually a gradual
deterioration over hours to days.
Symptoms include polyuria, polydipsia, abdominal pain
and vomiting. There may be evidence of the underlying
cause. Patients often hyperventilate to compensate for the
metabolic acidosis (Kussmaul respiration), and their breath
smells of ketones (like nail varnish remover). There are physical signs of dehydration. As the condition worsens, lethargy,
confusion, drowsiness and ultimately coma may occur.
CLINICAL NOTES
The diagnosis of diabetic ketoacidosis requires all
three of the following to be present:
• the patient to be known to have diabetes
or be hyperglycaemic (serum glucose level
>11 mmol/L)
• the presence of ketones (serum ketone level
>3 mmol/L or 2+ on urine dipstick test)
• an acidosis (pH <7.3; reference range 7.35–7.45)
When investigating the cause of a patient’s acidosis, ask
yourself could this be DKA? How severe is it? What has
triggered it (e.g. sepsis, myocardial infarction)?
Investigations include:
• Blood tests: full blood count (FBC), urea and
electrolytes (U&Es), bone profile, liver function tests
(LFTs), C-reactive protein (CRP), bicarbonate and
glucose. If you are considering myocardial infarction,
then include troponin.
• Arterial blood gas: perform an arterial measurement
initially; following this venous blood gas can be taken
to give the pH and potassium level quickly—this is
important in monitoring response to treatment.
• Bedside capillary glucose and capillary ketones (only
some hospitals will have facilities for bedside ketone
measuring).
• Urine dipstick: look for ketones.
• Culture and sensitivity: blood, urine and swab of any
wound/ abscess.
• ECG (evidence of silent myocardial infarction).
• Chest X-ray (CXR): look for underlying pneumonia/
pulmonary oedema.
Management—Correction of dehydration takes precedence. Make sure you have at least two wide-bore cannulas;
using one cannula, fluid-resuscitate the patient and through
the other run a slow fixed-rate insulin infusion. Patients
with DKA are potassium-depleted overall but the serum
concentration may be normal or high as the acidosis causes
potassium to move out of the intracellular compartment.
Therefore the serum potassium concentration can fall precipitously as acidosis is corrected, and it must be monitored
closely and replaced.
Between 6 and 9 litres of IV fluid may be required, and
the first 2 L can be given over the first hour. An IV infusion
of insulin, 0.1 units/kg per h is commenced. Once the blood
glucose level drops to around 15 mmol/L, 0.9% saline is
generally replaced with dextrose to prevent too precipitous
a fall in the glucose level. The aim of insulin treatment is
to suppress ketogenesis as well as reduce the blood glucose
level. In children, fluid requirements need to be calculated
more accurately as cerebral oedema may occur with overaggressive fluid administration.
The patient should be catheterized, and fluid balance
needs to be monitored very carefully. A nasogastric tube
may need to be inserted to reduce the risk of aspiration from
the gastric stasis that occurs in this condition. Prophylactic
low-molecular-weight heparin is given as there is a significant risk of venous thromboembolism.
If there is evidence of infection, broad-spectrum antibiotics are used, and attempts should be made to identify the
precipitant. The levels of the inflammatory markers may rise
in the absence of infection. The patient should be observed
very closely, with a low threshold for admission to the highdependency or intensive care unit. IV insulin administration
should be continued until there are no detectable ketones, the
acidosis is corrected and the patient is eating and drinking.
HINTS AND TIPS
Search your hospital’s guidelines; there will
be a protocol for intravenous insulin and fluid
prescription in diabetic ketoacidosis.
COMMUNICATION
Diabetic ketoacidosis is life-threatening. Spend
time to counsel your patient about the severity of
the condition, and ensure your patient knows about
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Obesity and metabolic syndrome
3333
sick day rules (not omitting insulin during the time
of intercurrent illness). Individuals with diabetes
should be told to monitor their blood glucose level
and check for ketone production during intercurrent
illness or traumatic events (e.g. surgery) to try to
spot diabetic ketoacidosis early.
Hyperosmolar hyperglycaemic state
This occurs in type 2 diabetes. The patient is often elderly
and may not be known to have diabetes. The precipitants
are as for DKA but onset is more gradual, usually over days.
By the time of presentation, blood glucose level is usually
very high (higher than in DKA) and plasma osmolality is
increased with significant hypernatraemia. Polyuria leads
to severe dehydration. Neurological symptoms such as confusion, seizures and coma may occur. Ketoacidosis almost
never occurs as there is enough endogenous insulin remaining to suppress ketone formation. However, an initial check
for ketones should be performed. When investigating, again
look at the severity of the hyperosmolar state and look for
an underlying precipitant. In your investigations include:
• blood tests: FBC, serum glucose, U&Es, bone profile,
LFTs, CRP, bicarbonate;
• plasma osmolality, which should be calculated;
• bedside capillary glucose (and ketones, if available at
the bedside);
• capillary and urine analysis for ketones;
• ECG (look for evidence of a myocardial infarction);
• further investigations directed at finding the
underlying cause (e.g. blood cultures, urine culture,
CXR, troponin).
Management—Rehydration is usually achieved with
normal saline. IV administration of insulin should only be
commenced when the glucose level is not falling with IV
fluids alone, and is given at a lower dose than for DKA. If
the sodium concentration is very high, it may be tempting
to give hypotonic saline. However, this is not used as it can
cause cerebral oedema and myelinolysis by lowering the
osmolality too quickly, and because these patients are so
volume depleted their total body stores of sodium are low
and require replacement (see Chapter31). Invasive cardiovascular monitoring may be required. Patients are at very
high risk of venous thromboembolism, so be suspicious and
treat this if it is present or suspected; in other cases ensure a
prophylactic dose of low-molecular-weight heparin is used.
The mortality rate is up to 50%.
HINTS AND TIPS
Osmolality can be calculated: 2(Na + K) + glucose
+ urea.
OBESITY AND METABOLIC
SYNDROME
According to the WHO global estimates, in 1980, 6% of
adult males and 8% of adult females were obese. In 2014,
these figures had increased to 38% and 40%, respectively.
There is certainly a growing problem among children also.
This trend constitutes an enormous public health issue,
with widespread changes in dietary and exercise patterns
required.
Obesity is defined as a body mass index (BMI) greater
than 30 kg/m2. The normal range is 19–25 kg/m2. Central
adiposity – an increased waist circumference to height ratio – is associated with greater health risks, including type
2 diabetes mellitus, cardiovascular disease, dyslipidaemia,
hypertension, osteoarthritis and cancer. There are several definitions of metabolic syndrome, each comprising a
combination of hypertension, low high-density lipoprotein
(HDL) level, hypertriglyceridaemia, raised fasting glucose
level, insulin resistance and obesity. In every consultation
obesity should be addressed and patients should be given
lifestyle and dietary advice. Those patients with a BMI
greater than 28 kg/m2 with comorbid conditions that may
benefit from weight reduction and those with a BMI greater
than 30 kg/m2 are considered for drug therapy after exercise, diet and behavioural intervention has been tried. Drug
therapy includes orlistat, which works by inhibiting the
absorption of fat in the intestine and therefore causes side
effects of steatorrhoea, urgency and oily spotting. Orlistat
use may be continued beyond 3months if there is evidence
of more than 5% weight loss.
Morbidly obese patients with a BMI greater than 40 kg/
m2 (or greater than 35kg/m2 with comorbidity) in whom
there has been a failure to lose weight despite all conservative measures at a specialist clinic may be considered for
surgery. This takes two forms: malabsorptive surgery, where
bypass procedures are performed (e.g. gastric bypass), or
restrictive surgery (e.g. gastric banding or sleeve gastrectomy), where the size of the stomach is reduced. Endoscopic
procedures which cause early satiety (e.g. placement of an
intragastric balloon) have also been used but risk development of gastric ulcers.
CLINICAL NOTES
Following bariatric surgery, particularly following
bypass procedures, patients are at high risk of
nutritional deficiencies, so watch for iron, calcium,
zinc, folate and vitamin D deficiency. Hyperoxaluria
can occur, with reduced intestinal oxalate
absorption. This can predispose to renal stone
formation.
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Metabolic and endocrine disorders
HINTS AND TIPS
Dumping syndrome is commonly asked about
in examinations. It is a neurohormonal reaction
triggered by sugar after a gastric bypass procedure
and causes dizziness, flushing, palpitations and
diarrhoea.
LIPID DISORDERS
Hypercholesterolaemia is widely prevalent in Western societies. In the United Kingdom, two-thirds of the adult
population have a serum total cholesterol concentration
above 5.0 mmol/L. There is an association between serum
cholesterol and cardiovascular risk. Low-density lipoprotein (LDL) particles are the main carriers of cholesterol to
the liver and peripheries; LDL levels are positively associated with cardiovascular risk. HDLs are involved in ‘reverse
cholesterol transport’ from the peripheries to the liver, and
levels are inversely related to cardiovascular risk.
When you are assessing patients, it is more important to
assess their overall cardiovascular risk to guide your advice
and management decisions rather than focus on individual
risk factors (see later). In this way therapy may be targeted
at those with most to gain.
Aetiology and pathophysiology
The genetics of hyperlipidaemia are complicated; most
commonly it is polygenic, with high serum cholesterol
concentrations and normal triglyceride concentrations. It
is greatly influenced by dietary lipid intake. ‘Monogenic’
forms are less common; some of these are discussed next.
Primary hyperlipidaemia
Familial combined hyperlipidaemia has a prevalence of 1
in 100 and is associated with high cholesterol and/or high
triglyceride concentrations. It is heterogeneous, and the
causative gene has not been identified.
Familial hypercholesterolaemia is an autosomal dominant condition and is due to LDL receptor deficiency, resulting in an increase in the level of LDL particles in the
circulation. The prevalence of heterozygotes is approximately 1 in 500. Homozygotes (prevalence of 1 in 250,000)
can have serum cholesterol levels of up to 30 mmol/L or
more and may develop coronary artery disease in their
teenage years.
Familial hypertriglyceridaemia is also an autosomal
dominant condition, and can cause pancreatitis. Patients
may have eruptive xanthomata. Triglyceride levels may also
be raised in diabetes, alcoholism and obesity.
Other types of dyslipidaemia are rare. Cases of primary
hyperlipidaemia are generally managed by lipid specialists.
CLINICAL NOTES
Interpret the results along with the family
history; consider the possibility of familial
hypercholesterolaemia if the total cholesterol level
is greater than 7.5 mmol/L and there is a family
history of premature coronary heart disease.
Secondary hyperlipidaemia
Causes include diabetes mellitus, excess alcohol consumption, hypothyroidism, chronic kidney disease, cholestasis
(such as in primary biliary cirrhosis), Cushing syndrome,
nephrotic syndrome, obesity and synthetic oestrogens.
HINTS AND TIPS
On clinical examination look for arcus senilis,
a white ring in the corneal margin, and tendon
xanthomata, hard nontender nodular enlargements
of the Achilles tendon or knuckles. These signs are
associated with familial hypercholesterolaemia.
Investigations
Measure both total cholesterol and HDL cholesterol to achieve
the best estimate of cardiovascular risk. Before starting any
lipid modification therapy for primary prevention of cardiovascular disease, perform a full lipid screen. This should include total cholesterol, HDL cholesterol, non-HDL cholesterol
and triglycerides. This does not need to be a fasting sample.
CLINICAL NOTES
Investigate the patient for secondary causes: check
thyroid function, liver function, serum glucose level
and cortisol level, and if serum albumin level is low,
look for evidence of proteinuria.
Management
Causes of secondary hyperlipidaemia should be treated.
Dietary measures should be tried, including reduction
of total energy and saturated fat intake. However, the average fall in total cholesterol concentration with a general
lipid-lowering diet is only 2%. Drug treatment is aimed at
high-risk patients and in consideration of other cardiovascular risk factors.
The use of lipid-lowering therapy should form part of
an integrated approach to the assessment and treatment
of cardiovascular risk, including interventions directed at
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Thyroid disease
3333
smoking, lifestyle, obesity, blood pressure and use of antiplatelet therapy.
Lowering of lipid levels appears to reduce cardiovascular
risk regardless of baseline serum cholesterol levels. However,
the absolute risk reduction is greater if the patient's risk of cardiovascular disease is higher. Guidelines aim to target those
groups at highest cardiovascular risk to maximize gains.
Primary prevention
Risk assessment tools to estimate the patient’s 10-year risk
of developing cardiovascular disease should be used to identify high-risk individuals for primary prevention. These risk
calculators include the Framingham risk score and QRISK2
but caution needs to be taken as they provide only an estimate of risk. A risk of cardiovascular disease greater than
20% over 10years is defined as high risk, and dietary modification and lipid-lowering treatment should be started.
Patients in certain high-risk groups should be treated regardless of their calculated risk. These include individuals
with severe hypertension (blood pressure >160/100 mmHg),
and those aged more than 75years if they also smoke or are
hypertensive.
COMMUNICATION
Clinical judgement must always be used, and
a patient-centred approach is essential as lipid
lowering medications, such as statins, are taken
life long and are taken life-long and will only be
effective if the patient takes the tablets.
muscle pain may be due to a nocebo effect. Other side effects
include headache, altered LFT values (which occasionally necessitates stopping therapy) and gastrointestinal effects (e.g.
abdominal pain, nausea and vomiting).
COMMUNICATION
Tell patients to avoid drinking grapefruit juice with
simvastatin/atorvastatin as drug levels can increase
through the inhibition of cytochromes P450. Watch
out for other drug interactions.
Ezetimibe—This drug reduces the intestinal absorption
of cholesterol. It may be used when a statin is not tolerated
or in addition to a statin to achieve target levels.
Fibrates—Their main action is to decrease serum triglyceride levels. Current clinical guidelines recommend
fibrates as the treatment of choice for severe isolated hypertriglyceridaemia. However, where high triglyceride levels
coexist with high cholesterol levels, statins are still first-line
therapy. They can also cause a myositis, especially when
taken in combination with a statin. They are not recommended in chronic kidney disease or diabetes.
Additional lipid-regulating drugs—Other drugs include cholestyramine, nicotinic acid and omega fish oils.
These are not recommended by the National Institute for
Health and Care Excellence but may occasionally be used
in specialist clinics.
Plasmapheresis in combination with additional pharmacological treatment is proven in managing homozygous
hyperlipidaemia.
Secondary prevention
This is targeted at those patients who already have known
coronary heart disease or ‘coronary heart disease equivalents’, including other atherosclerotic vascular disease,
diabetes, chronic kidney disease and inherited dyslipidaemias. Therapy aims to achieve a total cholesterol level below
4 mmol/L and an LDL level below 2 mmol/L.
Drugs
Statins—The statins competitively inhibit
3- hydroxy-3-methylglutaryl coenzyme A reductase, an enzyme involved in cholesterol synthesis, especially in the
liver. They are usually first-line therapy. There is evidence
that statins produce important reductions in cardiovascular
events in high-risk patients. They should be used with caution
in those with a history of liver disease, and LFT results should
be checked after treatment has started. Side effects include
reversible myositis, and treatment should be stopped if there
are symptoms of myopathy or a significantly raised creatine
kinase level. Patients should therefore be advised to report
unexplained muscle pain, tenderness and weakness. A recent
study suggested that many of these episodes of intercurrent
RED FLAGS
Refer a patient for urgent specialist review if a
patient has a triglyceride concentration greater than
20 mmol/L that is not the result of excess alcohol
consumption or poor glycaemic control. Individuals
with a total cholesterol level greater than 9 mmol/L or
non-high-density lipoprotein cholesterol level greater
than 7.5 mmol/L should be seen by a lipid specialist.
THYROID DISEASE
The control of thyroid hormone production and release is
outlined in Fig 33.4. Thyroid disorders are common, and include both overactive and underactive thyroid, and thyroid
cysts, which may be benign or malignant. Some of these
disorders will present with an enlarged thyroid gland (i.e. a
goitre). Thyroid disease is discussed in detail in Chapter17,
and here we focus on the management of thyroid disease.
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Metabolic and endocrine disorders
Hypothalamus
–
+
pituitary gland
Thyroid gland
hypothalamus–pituitary–thyroid axis. TRH, Thyrotrophinreleasing hormone; TSH, thyroid-stimulating hormone.
Anterior
+
TSH
TRH
–
+ T
T
4
3
Hypothyroidism
Hypothyroidism results from deficiency of thyroxine (T4)
or triiodothyronine (T3).
Management
Thyroxine sodium (normally levothyroxine, T4 replacement) is the treatment of choice for maintenance therapy.
Usual maintenance dosages are between 100 and 200 μg
daily. The initial dose is usually 50 μg, increased as necessary
over a few weeks, and even lower doses (25 μg) are started
in elderly patients or patients with cardiac disease to avoid
worsening angina or precipitating a myocardial infarction.
Treatment is monitored by serum thyroid-stimulating hormone (TSH) level and serum T4 level and is nearly always
lifelong except in cases of subacute or silent thyroiditis. It is
sometimes necessary to rule out adrenal insufficiency (e.g.
in secondary hypothyroidism) before starting treatment, as
giving thyroxine can precipitate an adrenal crisis if there is
concomitant glucocorticoid deficiency.
CLINICAL NOTES
Subclinical hypothyroidism (i.e. raised thyroidstimulating hormone level but normal thyroxine
level) is treated with levothyroxine only if the
patient is at high risk of progressing to overt
hypothyroidism. These high-risk groups include
individuals with thyroid antibodies, a history
of previous radioiodine treatment or a thyroidstimulating hormone level greater than 10 mU/L.
PATIENT SAFETY
Overtreating hypothyroidism with levothyroxine can
result in atrial fibrillation and osteoporosis, and can
worsen angina or cardiac failure in a patient with
existing cardiac disease.
Hyperthyroidism
Thyrotoxicosis is the condition resulting from raised levels
of circulating free T4 and free T3.
Management
Treatment options include drugs, radioiodine and surgery.
Most patients younger than 50 years with Graves disease
receive a course of an antithyroid drug as the initial treatment. There is a significant risk of relapse after drug treatment, and it is more likely in younger patients and those
with a large goitre. Relapse after a period of drug therapy
should be treated with iodine-131 (radioiodine) or subtotal thyroidectomy. Subtotal thyroidectomy is often recommended in young patients with large goitres to remove the
neck swelling.
Toxic adenoma or toxic multinodular goitre is treated
with radioiodine or surgery. All options should be discussed with the patient, and a joint decision should be
made. β-Blockers are useful to ameliorate the symptoms of
thyrotoxicosis.
Antithyroid drugs
In the United Kingdom, carbimazole is the most commonly
used drug. It is metabolized to methimazole, the active
agent. Propylthiouracil may be used in patients who have
sensitivity reactions to carbimazole and is preferred in pregnancy. Both drugs act primarily by interfering with the synthesis of thyroid hormones.
The daily dose of carbimazole is adjusted according to
response and then maintained until the patient becomes
euthyroid, usually after 4–8weeks. The dose may then be
gradually reduced to a maintenance dose, again adjusted
according to response. Patients are advised to report any
infectious symptoms immediately as agranulocytosis is a
rare complication. More common side effects of this drug
include a rash and pruritus.
If symptoms are profound, a combination of higher-dose
carbimazole and exogenous T4 daily may be used in a ‘block
and replace’ regimen. A euthyroid state may be achieved
more quickly with this regimen. Treatment with either of
these regimens is usually for 18months followed by longterm monitoring.
Iodine may be given 10–14days before surgery, in addition to carbimazole, to assist control and to reduce vascularity of the thyroid.
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Thyroid disease
3333
The B blocker, Propranolol is useful for the rapid relief
of thyrotoxic symptoms before a euthyroid state is achieved.
β-Blockers are also useful for the control of supraventricular
arrhythmias secondary to thyrotoxicosis.
Radioiodine
This is commonly used for adenomas or toxic multinodular goitre. Radioactive sodium iodide (Na
centrated by the thyroid and causes cell damage and cell
death. Hypothyroidism may therefore develop at any stage
after treatment, and so the patient should be under regular follow-up. Radioiodine is used increasingly for the
treatment of thyrotoxicosis at all ages, particularly where
medical therapy or adherence is a problem, in patients with
cardiac disease and in patients who relapse after thyroidectomy. Contraindications include pregnancy and breastfeeding. Pregnancy is safe 4months or more after treatment.
Radioiodine may worsen the ophthalmopathy of Graves
disease.
131
I) is con-
Subtotal thyroidectomy
This is more commonly performed for adenoma or multinodular goitre than for Graves disease, in which it is reserved for those with a large or obstructive goitre. The aim
of surgery is to remove sufficient thyroid tissue to cure
hyperthyroidism. One year later, approximately 80% of
patients are euthyroid, 15% are hypothyroid and 5% have
relapsed. Complications include hypoparathyroidism, recurrent laryngeal nerve damage and bleeding into the neck
causing laryngeal oedema.
Thyroid emergencies
Thyrotoxic crisis (‘thyroid storm’)
This is an uncommon, life-threatening exacerbation of thyrotoxicosis with a mortality of up to 20% with treatment.
Precipitating factors include thyroid surgery, radioiodine,
withdrawal of antithyroid drugs, iodinated contrast agents
and acute illnesses (e.g. stroke, infection, trauma and
DKA). In addition to general symptoms, common features
include hyperpyrexia, severe tachycardia and psychiatric
symptoms, including anxiety, delirium or psychosis. It requires emergency treatment with oxygen, IV fluids because
of profuse sweating, β-blockers for control of tachycardia
(may need to be given IV), IV hydrocortisone (which inhibits peripheral T4 conversion to T3), oral administration
of iodine solution (to block release of thyroid hormone)
and propylthiouracil (to prevent new synthesis of thyroid
hormones).
Myxoedema coma
This is uncommon. It is typically seen in the elderly, and
is precipitated by infection, myocardial infarction, treatment with sedatives or inadequate heating in cold weather.
Most patients have hypothermia and are hypotensive with
heart failure, hyponatraemia, hypoxia and hypercapnia.
Treatment is with T3 intravenously because of its rapid
action. Hydrocortisone IV is also given, particularly if
pituitary hypothyroidism is suspected. Supportive measures are also needed, including IV fluids, antibiotics, ventilation and slow rewarming. T4 can be substituted after
2–3 days if there is a clinical improvement. Mortality is
up to 20%.
Parathyroid disease
The parathyroid gland is located on the back of the thyroid
gland and is generally made up of four small glands. These
glands produce parathyroid hormone (PTH) from the chief
cells. PTH is integral in the control of calcium and phosphate homeostasis in the body. Many conditions are associated with disorders of the parathyroid gland. These can be
divided into those causing hypoparathyroidism and those
causing hyperparathyroidism.
Hypoparathyroidism
Hypoparathyroidism results in hypocalcaemia and hyperphosphataemia. This occurs as a low PTH level,
downregulates calcium release from the skeleton, downregulates activation of vitamin D in the kidney and suppresses phosphate excretion. In normal conditions the
low serum calcium level and high serum phosphate level
would trigger PTH production from the parathyroid
gland.
Aetiology
Hypoparathyroidism is most commonly iatrogenic following surgery to the neck. Other causes are rare. Primary
(idiopathic) hypoparathyroidism is an autoimmune disorder associated with vitiligo, Addison disease, pernicious
anaemia and other autoimmune diseases, and it may be
part of autoimmune polyendocrine syndrome (see later).
Infiltration due to metabolic disease such as Wilson disease
and haemochromatosis can cause destruction of the parathyroid gland, but this is very uncommon. Rare mutations
can cause inherited abnormalities of parathyroid development, such as in DiGeorge syndrome, when it is associated
with intellectual impairment, cardiac abnormalities and
thymic hypoplasia.
Pseudohypoparathyroidism is a syndrome of variable
end-organ (kidney and bone) resistance to PTH. It is associated with intellectual impairment, short stature, a round
face and short metacarpals and metatarsals.
Other causes of hypocalcaemia include chronic renal
failure and osteomalacia. In acutely ill patients, acute pancreatitis and rhabdomyolysis can cause hypocalcaemia.
Causes are summarized in Table33.2.
Clinical features
These include the symptoms of hypocalcaemia, classically
circumoral paraesthesiae and cramps (see Chapter31).
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