ENDOCRINOLOGY Serum IGF-1 may also be used to monitor disease

Acromegaly: Oral glucose tolerance test

• in normal patients GH is suppressed to < 2 mu/L with hyperglycaemia

In acromegaly there is excess growth hormone secondary to a pituitary adenoma in over 95% of
• in acromegaly there is no suppression of GH
cases. A minority of cases are caused by ectopic GHRH or GH production by tumours e.g.
• may also demonstrate impaired glucose tolerance which is associated with acromegaly
pancreatic.

Features
A pituitary MRI may demonstrate a pituitary tumour.
• coarse facial appearance, spade-like hands, increase in shoe size
Management
• large tongue, prognathism, interdental spaces
• excessive sweating and oily skin: caused by sweat gland hypertrophy
Trans-sphenoidal surgery is the first-line treatment for acromegaly in the majority of patients.
• features of pituitary tumour: hypopituitarism, headaches, bitemporal hemianopia
• raised prolactin in 1/3 of cases → galactorrhoea
If a pituitary tumour is inoperable or surgery unsuccessful then medication may be indicated:
• 6% of patients have MEN-1

• somatostatin analogue
o directly inhibits the release of growth hormone
Complications
o for example octreotide
o effective in 50-70% of patients
• hypertension
• pegvisomant
• diabetes (>10%)
o GH receptor antagonist - prevents dimerization of the GH receptor
• cardiomyopathy
o once daily s/c administration
• colorectal cancer
o very effective - decreases IGF-1 levels in 90% of patients to normal
Investigations o doesn't reduce tumour volume therefore surgery still needed if mass effect
• dopamine agonists
Growth hormone (GH) levels vary during the day and are therefore not diagnostic. o for example bromocriptine
o the first effective medical treatment for acromegaly, however now superseded by
Serum IGF-1 levels have now overtaken the oral glucose tolerance test (OGTT) with serial GH somatostatin analogues
measurements as the first-line test. The OGTT test is recommended to confirm the diagnosis if o effective only in a minority of patients
IGF-1 levels are raised.

External irradiation is sometimes used for older patients or following failed surgical/medical
The Endocrine Society guidelines suggest the following:
treatment
1.1 We recommend measurement of IGF-1 levels in patients with typical clinical manifestations of
acromegaly, especially those with acral and facial features.
...
1.5 In patients with elevated or equivocal serum IGF-1 levels, we recommend confirmation of the
diagnosis by finding lack of suppression of GH to < 1 μg/L following documented hyperglycemia Acute phase proteins
during an oral glucose load.
• CRP*
• procalcitonin

• ferritin Autoimmune destruction of the adrenal glands is the commonest cause of primary
• fibrinogen hypoadrenalism in the UK, accounting for 80% of cases. Addison's is adrenocortical insufficiency
• alpha-1 antitrypsin due to the dysfunction/destruction of the adrenal cortex. It affects both glucocorticoid
• caeruloplasmin
(metabolism of glucose etc.) and mineralocorticoid (salt balance) function. The commonest
• serum amyloid A
cause in the developed world is autoimmune adrenalitis. Other causes include destruction of the
• serum amyloid P component**
• haptoglobin cortex by infections such as TB, or metastasis.
• complement
Signs/symptoms of Addisonian crisis:

During the acute phase response the liver decreases the production of other proteins
Neurological
(sometimes referred to as negative acute phase proteins). Examples include:

• syncope
• albumin
• confusion
• transthyretin (formerly known as prealbumin)
• lethargy
• transferrin (while serum ferritin and ceruluplasmin increases)
• convulsions
• retinol binding protein
• cortisol binding protein
Haemodynamic

*Levels of CRP are commonly measured in acutely unwell patients. CRP is a protein synthesised • hypotension
in the liver and binds to phosphocholine in bacterial cells and on those cells undergoing • hypothermia
apoptosis. In binding to these cells it is then able to activate the complement system. CRP levels
Biochemical
are known to rise in patients following surgery. However, levels of greater than 150 at 48 hours
post operatively are suggestive of evolving complications.
• hyponatraemia
**plays a more significant role in other mammals such as mice • hyperkalaemia
• hypoglycaemia

Management of Addisonian crisis (medical emergency):

• intravenous fluids
• corticosteroids (e.g iv dexamethasone)

Note: iv dexamethasone is often preferred as this will not interfere with cortisol assays needed
for a short synacthen test, unlike hydrocortisone.

Features
Addison's disease

• lethargy, weakness, anorexia, nausea & vomiting, weight loss, 'salt-craving'

 • hyperpigmentation (especially palmar creases)*, vitiligo, loss of pubic hair in women, If an ACTH stimulation test is not readily available (e.g. in primary care) then sending a 9 am
hypotension, hypoglycaemia serum cortisol can be useful:
• hyponatraemia and hyperkalaemia may be seen
• crisis: collapse, shock, pyrexia • > 500 nmol/l makes Addison's very unlikely
• < 100 nmol/l is definitely abnormal
• 100-500 nmol/l should prompt a ACTH stimulation test to be performed

Other causes of hypoadrenalism

Associated electrolyte abnormalities are seen in around one-third of undiagnosed patients:
Primary causes
• hyperkalaemia
• hyponatraemia
• tuberculosis
• hypoglycaemia
• metastases (e.g. bronchial carcinoma)
• metabolic acidosis
• meningococcal septicaemia (Waterhouse-Friderichsen syndrome)
• HIV
• antiphospholipid syndrome

Addisonian crisis
Secondary causes
Causes
• pituitary disorders (e.g. tumours, irradiation, infiltration)
• sepsis or surgery causing an acute exacerbation of chronic insufficiency (Addison's,
Hypopituitarism)
Exogenous glucocorticoid therapy • adrenal haemorrhage eg Waterhouse-Friderichsen syndrome (fulminant
meningococcemia)
*Primary Addison's is associated with hyperpigmentation whereas secondary adrenal • steroid withdrawal
insufficiency is not

Management

• hydrocortisone 100 mg im or iv
• 1 litre normal saline infused over 30-60 mins or with dextrose if hypoglycaemic
Investigations • continue hydrocortisone 6 hourly until the patient is stable. No fludrocortisone is
required because high cortisol exerts weak mineralocorticoid action
In a patient with suspected Addison's disease the definite investigation is an ACTH stimulation • oral replacement may begin after 24 hours and be reduced to maintenance over 3-4
test (cosyntopin/short Synacthen test). Plasma cortisol is measured before and 30 minutes after days
giving Synacthen 250ug IM. If the cortisol post ACTH rises to > 420 nmol/L at 30 minutes, the
adrenal response to ACTH is adequate and Addison’s disease (adrenal failure) can be excluded.

However, this excludes only primary adrenal failure and does not exclude cortisol deficiency
secondary to failure of the pituitary to produce ACTH Adrenal autoantibodies such as anti-21- Alkaline phosphatase
hydroxylase may also be demonstrated.
Causes of raised alkaline phosphatase (ALP)

• liver: cholestasis, hepatitis, fatty liver, neoplasia

• Paget's
• osteomalacia Investigation and management
• bone metastases
• hyperparathyroidism
Initial investigations
• renal failure
• physiological: pregnancy, growing children, healing fractures
• exclude pregnancy with urinary or serum bHCG
• full blood count, urea & electrolytes, coeliac screen, thyroid function tests
• gonadotrophins
The table below splits the causes according to the calcium level
o low levels indicate a hypothalamic cause where as raised levels suggest an
ovarian problem (e.g. Premature ovarian failure)
Raised ALP and raised calcium Raised ALP and low calcium o raised if gonadal dysgenesis (e.g. Turner's syndrome)
Bone metastases Osteomalacia • prolactin
Hyperparathyroidism Renal failure • androgen levels
o raised levels may be seen in PCOS
• oestradiol

Management
Amenorrhoea
Amenorrhoea may be divided into: • primary amenorrhoea:
o investigate and treat any underlying cause
• primary: defined as the failure to establish menstruation by 15 years of age in girls with o with primary ovarian insufficiency due to gonadal dysgenesis (e.g. Turner's
normal secondary sexual characteristics (such as breast development), or by 13 years of syndrome) are likely to benefit from hormone replacement therapy (e.g. to
age in girls with no secondary sexual characteristics prevent osteoporosis etc)
• secondary: cessation of menstruation for 3-6 months in women with previously normal
and regular menses, or 6-12 months in women with previous oligomenorrhoea

• secondary amenorrhoea
o exclude pregnancy, lactation, and menopause (in women 40 years of age or
Causes
older)
o treat the underlying cause
Secondary amenorrhoea (after excluding
Primary amenorrhoea
pregnancy)
• gonadal dysgenesis (e.g. Turner's syndrome) - hypothalamic amenorrhoea (e.g. secondary *hypothyroidism may also cause amenorrhoea
the most common causes stress, excessive exercise)
• testicular feminisation polycystic ovarian syndrome (PCOS)
• congenital malformations of the genital tract hyperprolactinaemia
• functional hypothalamic amenorrhoea (e.g. premature ovarian failure
secondary to anorexia) thyrotoxicosis*
• congenital adrenal hyperplasia Sheehan's syndrome
• imperforate hymen Asherman's syndrome (intrauterine
adhesions)
Androgen insensitivity syndrome
APS type 1 is occasionally referred to as Multiple Endocrine Deficiency Autoimmune Candidiasis
Androgen insensitivity syndrome is an X-linked recessive condition due to end-organ resistance (MEDAC). It is a very rare autosomal recessive disorder caused by mutation of AIRE1 gene on
to testosterone causing genotypically male children (46XY) to have a female phenotype. chromosome 21
Complete androgen insensitivity syndrome is the new term for testicular feminisation syndrome
Features of APS type 1 (2 out of 3 needed)
Features
• chronic mucocutaneous candidiasis (typically first feature as young child)
• 'primary amennorhoea' • Addison's disease
• undescended testes causing groin swellings • primary hypoparathyroidism
• breast development may occur as a result of conversion of testosterone to oestradiol

Vitiligo can occur in both types

Diagnosis

• buccal smear or chromosomal analysis to reveal 46XY genotype

Management

• counselling - raise child as female

• bilateral orchidectomy (increased risk of testicular cancer due to undescended testes)
• oestrogen therapy

Autoimmune polyendocrinopathy syndrome Bartter's syndrome

Addison's disease (autoimmune hypoadrenalism) is associated with other endocrine deficiencies Bartter's syndrome is an inherited cause (usually autosomal recessive) of
in approximately 10% of patients. There are two distinct types of autoimmune severe hypokalaemia due to defective chloride absorption at the Na+ K+ 2Cl- cotransporter
polyendocrinopathy syndrome (APS), with type 2 (sometimes referred to as Schmidt's syndrome) (NKCC2) in the ascending loop of Henle. It should be noted that it is associated
being much more common. with normotension (unlike other endocrine causes of hypokalaemia such as Conn's, Cushing's
and Liddle's syndrome which are associated with hypertension).
APS type 2 has a polygenic inheritance and is linked to HLA DR3/DR4. Patients have Addison's
disease plus either: Loop diuretics work by inhibiting NKCC2 - think of Bartter's syndrome as like taking large doses
of furosemide
• type 1 diabetes mellitus
• autoimmune thyroid disease Features

• usually presents in childhood, e.g. Failure to thrive • abnormal vaginal bleeding: postcoital, intermenstrual or postmenopausal bleeding
• polyuria, polydipsia • vaginal discharge
• hypokalaemia
• normotension
• weakness Human papillomavirus (HPV), particularly serotypes 16,18 & 33 is by far the most important
factor in the development of cervical cancer. Other risk factors include:
Liddle's syndrome
• smoking (Women who smoke are at a two-fold increased risk of developing cervical
Liddle's syndrome is a rare autosomal dominant condition that causes hypertension and cancer than women who do not)
hypokalaemic alkalosis. It is thought to be caused by disordered sodium channels in the distal • human immunodeficiency virus
tubules leading to increased reabsorption of sodium. • early first intercourse, many sexual partners
• high parity
Treatment is with either amiloride or triamterene • lower socioeconomic status
• combined oral contraceptive pill*
Gitelman's syndrome

Gitelman's syndrome is due to a defect in the thiazide-sensitive Na+ Cl- transporter in the distal Mechanism of HPV causing cervical cancer
convoluted tubule.
• HPV 16 & 18 produces the oncogenes E6 and E7 genes respectively
Features (polyelectrolyte disturbance) • E6 inhibits the p53 tumour suppressor gene
• E7 inhibits RB suppressor gene
• normotension
• hypokalaemia
• hypocalciuria *the strength of this association is sometimes debated but a large study published in the Lancet
• hypomagnesaemia (2007 Nov 10;370(9599):1609-21) confirmed the link
• metabolic alkalosis ( decrease hydrogen like other electrolytes)

Congenital adrenal hyperplasia

Cervical cancer
Overview
Around 50% of cases of cervical cancer occur in women under the age of 45 years, with
incidence rates for cervical cancer in the UK are highest in people aged 25-29 years, according
• group of autosomal recessive disorders
to Cancer Research UK. It may be divided into:
• affect adrenal steroid biosynthesis
• in response to resultant low cortisol levels the anterior pituitary secretes high levels of
• squamous cell cancer (80%)
ACTH
• adenocarcinoma (20%)
• ACTH stimulates the production of adrenal androgens that may virilize a female infant
• Should be considered in all infants with failure to thrive especially those with episodes of
acute adrenal insufficiency, salt wasting and hypertension.
Features

• may be detected during routine cervical cancer screening

Cause

• 21-hydroxylase deficiency (90%)

• 11-beta hydroxylase deficiency (5%)
• 17-hydroxylase deficiency (very rare)

17-hydroxylase deficiency features

• non-virilising in females
• inter-sex in boys
• hypertension

Congenital hypothyroidism

Congenital hypothyroidism affects around 1 in 4000 babies. If not diagnosed and treated within
the first four weeks it causes irreversible cognitive impairment

Features

Congenital adrenal hyperplasia features • prolonged neonatal jaundice

21-hydroxylase deficiency features • delayed mental & physical milestones
• short stature
• virilisation of female genitalia postnatally [at birth female have ambiguous • puffy face, macroglossia
genitalia(female pseudohermaphroditism), enlarged clitoris and partial or complete • hypotonia
fusion of labia]
• precocious puberty in males postnatally ( macrogenitosomia at birth)
• 60-70% of patients have a salt-losing crisis at 1-3 wks of age ( hypotension, dehydration Children are screened at 5-7 days using the heel prick test
hyperkalemia and hyponatremia)

11-beta hydroxylase deficiency features

• virilisation of female genitalia

• precocious puberty in males
• hypertension
• hypokalaemia
Corticosteroids
Corticosteroids are amongst the most commonly prescribed therapies in clinical practice. They
• can have Biphasic presentation with salt losing during infancy and mineralocorticoid
are used both systemically (oral or intravenous) or locally (skin creams, inhalers, eye drops, intra-
excess during childhood/adulthood.
articular). They augment and in some cases replace the natural glucocorticoid and o peptic ulceration
mineralocorticoid activity of endogenous steroids. o acute pancreatitis
• ophthalmic
The relative glucocorticoid and mineralocorticoid activity of commonly used steroids is shown o glaucoma
below: FHP-BD o cataracts
• dermatologic: acne (Systemic glucocorticoids can cause drug-induced acne. This is
Minimal glucocorticoid Predominant Very high glucocorticoid characterised as monomorphic papular rash without comedones or cysts. This does not
Glucocorticoid activity,
activity, very high glucocorticoid activity, activity, minimal respond to acne treatment but improves on drug discontinuation)
high mineralocorticoid
mineralocorticoid low mineralocorticoid mineralocorticoid • suppression of growth in children
activity,
activity, activity activity • intracranial hypertension
Dexamethasone • neutrophilia
Fludrocortisone Hydrocortisone Prednisolone
Betmethasone

Mineralocorticoid side-effects
Side-effects
• fluid retention
• hypertension
The side effects of corticosteroids are numerous and represent the single greatest limitation on
their usage. Side-effects are more common with systemic and prolonged therapy.
Selected points on the use of corticosteroids:
Glucocorticoid side-effects
• patients on long-term steroids should have their doses doubled during intercurrent
• endocrine illness
o impaired glucose regulation • longer-term systemic corticosteroids suppress the natural production of endogenous
o increased appetite/weight gain steroids. They should therefore not be withdrawn abruptly, as this may precipitate an
o hirsutism Addisonian crisis
o hyperlipidaemia • the BNF suggests gradual withdrawal of systemic corticosteroids if patients have:
• Cushing's syndrome o received more than 40mg prednisolone daily for more than one week
o moon face o received more than 3 weeks of treatment
o buffalo hump o recently received repeated courses
o striae
• musculoskeletal
o osteoporosis
o proximal myopathy
o avascular necrosis of the femoral head
• immunosuppression
o increased susceptibility to severe infection
o reactivation of tuberculosis
• psychiatric
o insomnia
o mania
o depression
o psychosis
• gastrointestinal

Cushing's syndrome:
It is useful to bear in mind the possible causes:
Causes
It should be noted that exogenous causes of Cushing's syndrome (e.g. glucocorticoid therapy)
are far more common than endogenous ones. • iatrogenic: corticosteroid therapy
Cushing's disease is the most common, non-iatrogenic, cause of Cushing's syndrome • ACTH-dependent causes
ACTH dependent causes o Cushing's disease (a pituitary adenoma → ACTH secretion)
o ectopic ACTH secretion secondary to a malignancy
• Cushing's disease (80%): pituitary tumour secreting ACTH producing adrenal hyperplasia • ACTH-independent causes
• ectopic ACTH production (5-10%): e.g. small cell lung cancer is the most common causes o adrenal adenoma

ACTH independent causes

General findings consistent with Cushing's syndrome
• iatrogenic: steroids
• adrenal adenoma (5-10%)
• adrenal carcinoma (rare) A hypokalaemic metabolic alkalosis may be seen, along with impaired glucose tolerance.
• Carney complex: syndrome including cardiac myxoma (Carney complex is a rare genetic
disorder characterized by multiple benign tumors (multiple neoplasia) most often Ectopic ACTH secretion (e.g. secondary to small cell lung cancer) is characteristically associated
affecting the heart, skin and endocrine system and abnormalities in skin coloring with very low potassium levels.
(pigment) resulting in a spotty appearance to the skin of affected areas)
• micronodular adrenal dysplasia (very rare)

Tests to confirm Cushing's syndrome

Pseudo-Cushing's

• mimics Cushing's The two most commonly used tests are:

• often due to alcohol excess or severe depression
• causes false positive dexamethasone suppression test or 24 hr urinary free cortisol • overnight dexamethasone suppression test
• insulin stress test may be used to differentiate o this is the most sensitive test and is now used first-line to test for Cushing's
syndrome
o patients with Cushing's syndrome do not have their morning cortisol spike
suppressed
Cushing's syndrome investigations • 24 hr urinary free cortisol

This section will consider:

• the general lab findings consistent with Cushing's syndrome Localisation tests
• tests to confirm whether a patient indeed has Cushing's syndrome
• tests to find the underlying cause of Cushing's syndrome
The first-line localisation is 9am and midnight plasma ACTH (and cortisol) levels. If ACTH is
suppressed then a non-ACTH dependent cause is likely such as an adrenal adenoma

High-dose dexamethasone suppression test

The high-dose dexamethasone suppression test may be used to localise the pathology resulting What is diabetes mellitus?
in Cushing's syndrome. This test may be interpreted as follows:
Diabetes mellitus may be defined as a chronic condition characterised by abnormally raised
levels of blood glucose.
Cortisol ACTH Interpretation

Not suppressed Suppressed Cushing's syndrome due to other causes (e.g. adrenal adenomas) Why is the management of diabetes mellitus so important?

Suppressed Suppressed Cushing's disease (i.e. pituitary adenoma → ACTH secretion)

Before the advent of insulin therapy untreated type 1 diabetes would usually result in death.
Not suppressed Not suppressed Ectopic ACTH syndrome Poorly treated type 1 diabetes mellitus can still result in significant morbidity and mortality (as a
result of diabetic ketoacidosis). However, the main focus of diabetes management now is
reducing the incidence of macrovascular (ischaemic heart disease, stroke) and microvascular
(eye, nerve and kidney damage) complications.
Other tests
CRH stimulation

• if pituitary source then cortisol rises Type Notes

• if ectopic/adrenal then no change in cortisol
Autoimmune disorder where the insulin-producing beta cells of the islets of
Langerhans in the pancreas are destroyed by the immune system
Petrosal sinus sampling of ACTH may be needed to differentiate between pituitary and ectopic
Type 1 diabetes This results in an absolute deficiency of insulin resulting in raised glucose
ACTH secretion.
mellitus (T1DM) levels
An insulin stress test is used to differentiate between true Cushing's and pseudo-Cushing's.
Patients tend to develop T1DM in childhood/early adult life and typically
present unwell, possibly in diabetic ketoacidosis
Nelson's syndrome is a rare clinical manifestation that occurs as a complication of bilateral
adrenalectomy, which is a procedure used to control hypercortisolism in patients with Cushing's This is the most common cause of diabetes in the developed world. It is
disease. It is associated with a clinical triad of hyperpigmentation, excessive adrenocorticotropin Type 2 diabetes caused by a relative deficiency of insulin due to an excess of adipose tissue.
secretion, and a corticotroph adenoma mellitus (T2DM) In simple terms there isn't enough insulin to 'go around' all the excess fatty
tissue, leading to blood glucose creeping up.

This term is used for patients who don't yet meet the criteria for a formal
diagnosis of T2DM to be made but are likely to develop the condition over
Prediabetes
the next few years. They, therefore, require closer monitoring and lifestyle
Diabetes mellitus: a very basic introduction interventions such as weight loss
Diabetes mellitus is one of the most common conditions encountered in clinical practice and
Some pregnant develop raised glucose levels during pregnancy. This is
represents a significant burden on the health systems of the developed world. It is now
Gestational diabetes important to detect as untreated it may lead to adverse outcomes for the
estimated that 8% of the total NHS budget is now spent on managing patients with diabetes
mother and baby
mellitus.
Maturity onset A group of inherited genetic disorders affecting the production of insulin.

Type Notes due to the osmotic effects of excess blood glucose being excreted in the urine (glycosuria).

diabetes of the Results in younger patients developing symptoms similar to those with
young (MODY) T2DM, i.e. asymptomatic hyperglycaemia with progression to more severe Investigations

complications such as diabetic ketoacidosis

There are 4 main ways to check blood glucose:
The majority of patients with autoimmune-related diabetes present younger
Latent autoimmune
in life. There are however a small group of patients who develop such • a finger-prick bedside glucose monitor
diabetes of adults • a one-off blood glucose. This may either be fasting or non-fasting
problems later in life. These patients are often misdiagnosed as having
(LADA) • a HbA1c. This measures the amount of glycosylated haemoglobin and represents the
T2DM.
average blood glucose over the past 2-3 months
Any pathological process which damages the insulin-producing cells of the • a glucose tolerance test. In this test, a fasting blood glucose is taken after which a 75g
glucose load is taken. After 2 hours a second blood glucose reading is then taken
pancreas may cause diabetes to develop. Examples include chronic
pancreatitis and haemochromatosis.
Other types
The diagnostic criteria are determined by WHO.
Drugs may also cause raised glucose levels. A common example is
glucocorticoids which commonly result in raised blood glucose levels If the patient is symptomatic:

• fasting glucose greater than or equal to 7.0 mmol/l (7*18=126mg/dl)

• random glucose greater than or equal to 11.1 mmol/l (200mg/dl) (or after 75g oral
glucose tolerance test)

Symptoms and signs

If the patient is asymptomatic the above criteria apply but must be demonstrated on two
The presentation of diabetes mellitus depends very much on the type:
separate occasions.

Type 1 DM Type 2 DM In 2011 WHO released supplementary guidance on the use of HbA1c for the diagnosis of
diabetes:
Weight loss
Polydipsia • a HbA1c of greater than or equal to 6.5% (48 mmol/mol) is diagnostic of diabetes
Polyuria mellitus
Often picked up incidentally on routine blood tests • 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)
May present with diabetic ketoacidosis Polydipsia
• in patients without symptoms, the test must be repeated to confirm the diagnosis
Polyuria
• it should be remembered that misleading HbA1c results can be caused by increased red
• abdominal pain cell turnover
• vomiting
• reduced consciousness level

Remember that the polyuria and polydipsia are due to water being 'dragged' out of the body
 looking after a patient with type 1 diabetes.

HbA1c

• should be monitored every 3-6 months

• adults should have a target of HbA1c level of 48 mmol/mol (6.5%) or lower. NICE do
however recommend taking into account factors such as the person's daily activities,
aspirations, likelihood of complications, comorbidities, occupation and history of
hypoglycaemia

Self-monitoring of blood glucose

• recommend testing at least 4 times a day, including before each meal and before bed
• more frequent monitoring is recommended if frequency of hypoglycaemic episodes
increases; during periods of illness; before, during and after sport; when planning
Diagram showing the spectrum of diabetes diagnosis pregnancy, during pregnancy and while breastfeeding

Blood glucose targets

• 5-7 mmol/l on waking and

Management • 4-7 mmol/l before meals at other times of the day

The principle of managing diabetes mellitus are as follows:

Type of insulin
• drug therapy to normalise blood glucose levels
• monitoring for and treating any complications related to diabetes • offer multiple daily injection basal–bolus insulin regimens, rather than twice-daily mixed
• modifying any other risk factors for other conditions such as cardiovascular disease insulin regimens, as the insulin injection regimen of choice for all adults
• twice-daily insulin detemir is the regime of choice. Once-daily insulin glargine or insulin
detemir is an alternative
Type 1 diabetes • offer rapid-acting insulin analogues injected before meals, rather than rapid-acting
soluble human or animal insulins, for mealtime insulin replacement for adults with type 1
diabetes
Diabetes mellitus: management of type 1
The long-term management of type 1 diabetics is an important and complex process requiring
the input of many different clinical specialties and members of the healthcare team. A diagnosis Metformin
of type 1 diabetes can still reduce the life expectancy of patients by 13 years and the micro and
macrovascular complications are well documented.
• NICE recommend considering adding metformin if the BMI >= 25 kg/m²
NICE released guidelines on the diagnosis and management of type 1 diabetes in 2015. We've
only highlighted a very select amount of the guidance here which will be useful for any clinician

• patients always require insulin to control the blood sugar levels. This is because there is Drug class Mechanism of action Route Main side-effects Notes
an absolute deficiency of insulin with no pancreatic tissue left to stimulate with drugs
• different types of insulin are available according to their duration of action Stimulate pancreatic Hypoglycaemia
Examples include
Sulfonylureas beta cells to secrete Oral Weight gain
gliclazide and glimepiride
insulin Hyponatraemia
Type 2 diabetes
Activate PPAR-gamma
• the majority of patients with type 2 diabetes are controlled using oral medication receptor in adipocytes Only currently available
• the first-line drug for the vast majority of patients is metformin Weight gain
Thiazolidinediones to promote Oral thiazolidinedione is
• second-line drugs include sulfonylureas, gliptins and pioglitazone. Please see the table Fluid retention
adipogenesis and pioglitazone
below for further information
• if oral medication is not controlling the blood glucose to a sufficient degree then insulin fatty acid uptake
is used
Generally well
Increases incretin
DPP-4 inhibitors (- tolerated but
levels which inhibit Oral
The table below shows some of the main drugs used in the management of diabetes mellitus: gliptins) increased risk of
glucagon secretion
pancreatitis
Drug class Mechanism of action Route Main side-effects Notes
Inhibits reabsorption
SGLT-2 inhibitors (- Urinary tract Typically result in weight
Used in all patients with of glucose in the Oral
gliflozins) infection loss
T1DM and some patients kidney
with poorly controlled
Incretin mimetic which Nausea and
T2DM GLP-1 agonists (- Typically result in weight
inhibits glucagon Subcutaneous vomiting
tides) loss
Hypoglycaemia secretion Pancreatitis
Direct replacement for Can be classified
Insulin Subcutaneous Weight gain
endogenous insulin according to source
Lipodystrophy
(analogue, human NICE provide guidelines on how drug therapy should be used in T2DM:
sequence and porcine)
and duration of action
(short, immediate, long-
acting)

First-line medication in
the management of
Increases insulin
Gastrointestinal T2DM
sensitivity
Metformin Oral upset
Decreases hepatic
Lactic acidosis* Cannot be used in
gluconeogenesis
patients with an eGFR of
< 30 ml/min
 If the patient is asymptomatic the above criteria apply but must be demonstrated on two
separate occasions.

Diagram showing the spectrum of diabetes diagnosis

In 2011 WHO released supplementary guidance on the use of HbA1c on the diagnosis of
diabetes:

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

mellitus
*common in exams, much less common in clinical practice • a HbAlc value of less than 48 mmol/mol (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
Diabetes mellitus (type 2): diagnosis cell turnover (see below)
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. Conditions where HbA1c may not be used for diagnosis:

If the patient is symptomatic: • haemoglobinopathies

• haemolytic anaemia
• fasting glucose greater than or equal to 7.0 mmol/l (126) • untreated iron deficiency anaemia
• random glucose greater than or equal to 11.1 mmol/l (or after 75g oral glucose tolerance • suspected gestational diabetes
test) • children
• HIV
• chronic kidney disease
• people taking medication that may cause hyperglycaemia (for example corticosteroids)

The National Institute for Health and Care Excellence (NICE) recommends that in adults
Impaired fasting glucose and impaired glucose tolerance with type 2 diabetes:

• Neutral Protamine Hagedorn (NPH) insulin [also known as isophane insulin]

A fasting glucose greater than or equal to 6.1 but less than 7.0 mmol/l implies impaired fasting (injected once or twice daily according to need) should be offered.
glucose (IFG) • NPH plus a short-acting insulin should be considered (particularly if the person’s
HbA1c is 75 mmol/mol [9.0%] or higher). This may be administered either
Impaired glucose tolerance (IGT) is defined as fasting plasma glucose less than 7.0 mmol/l and separately or as a pre-mixed (biphasic) human insulin preparation.
OGTT 2-hour value greater than or equal to 7.8 mmol/l but less than 11.1 mmol/l • Insulin detemir or insulin glargine should be considered as an alternative to NPH
insulin if:
Diabetes UK suggests:
• → The person needs assistance from a carer or healthcare professional to inject
• 'People with IFG should then be offered an oral glucose tolerance test to rule out a insulin and the use of insulin detemir or insulin glargine would reduce the
diagnosis of diabetes. A result below 11.1 mmol/l but above 7.8 mmol/l indicates that frequency of injections from twice to once daily, or
the person doesn't have diabetes but does have IGT.' • → The person's lifestyle is restricted by recurrent symptomatic hypoglycaemic
episodes, or
• → The person would otherwise need twice-daily NPH insulin injections in
combination with oral antidiabetic drugs.

Diabetes mellitus: management of type 2

NICE updated its guidance on the management of type 2 diabetes mellitus (T2DM) in 2022. This
update reflected the advances in drug therapy and improved evidence regarding newer
therapies such as SGLT-2 inhibitors.

It's worthwhile thinking of the average patient who is taking metformin for T2DM, you can
titrate up metformin and encourage lifestyle changes to aim for a HbA1c of 48
mmol/mol (6.5%), but should only add a second drug if the HbA1c rises to 58 mmol/mol (7.5%)

Dietary advice

• 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 the use of foods marketed specifically at people with diabetes
• initial target weight loss in an overweight person is 5-10%
 • in 2015 the guidelines changed so HbA1c targets are now dependent on treatment:

Lifestyle or single-drug treatment

Management of T2DM HbA1c target

Lifestyle 48 mmol/mol (6.5%)

Lifestyle + metformin 48 mmol/mol (6.5%)

Includes any drug which may cause hypoglycaemia (e.g. lifestyle + sulfonylurea) 53 mmol/mol (7.0%)

Practical examples

• a patient is newly diagnosed with HbA1c and wants to try lifestyle treatment first. You
agree on a target of 48 mmol/mol (6.5%)
• you review a patient 6 months after starting metformin. His HbA1c is 51 mmol/mol
(6.8%). You increase his metformin from 500mg bd to 500mg tds and reinforce lifestyle
factors

HbA1c targets

This is an area which has changed in 2015

Patient already on treatment
• individual targets should be agreed with patients to encourage motivation
• HbA1c should be checked every 3-6 months until stable, then 6 monthly
• NICE encourage us to consider relaxing targets on 'a case-by-case basis, with particular Management of T2DM HbA1c target
consideration for people who are older or frail, for adults with type 2 diabetes'

Management of T2DM HbA1c target • if standard-release metformin is not tolerated then modified-release metformin should
be trialled
Already on one drug, but HbA1c has risen to 58 mmol/mol (7.5%) 53 mmol/mol (7.0%)

SGLT-2 inhibitors

• should also be given in addition to metformin if any of the following apply:

o the patient has a high risk of developing cardiovascular disease (CVD, e.g. QRISK
≥ 10%)
o the patient has established CVD
o the patient has chronic heart failure
Initial drug therapy
• metformin should be established and titrated up before introducing the SGLT-2 inhibitor
• SGLT-2 inhibitors should also be started at any point if a patient develops CVD (e.g. is
diagnosed with ischaemic heart disease), a QRISK ≥ 10% or chronic heart failure

If metformin is contraindicated

• if the patient has a risk of CVD, established CVD or chronic heart failure:
o SGLT-2 monotherapy
• if the patient doesn't have a risk of CVD, established CVD or chronic heart failure:
o DPP-4 inhibitor or pioglitazone or a sulfonylurea
o SGLT-2 may be used if certain NICE criteria are met

Further drug therapy if HbA1c targets are not met

Simplified initial management of type 2 diabetes mellitus

Metformin remains the first-line drug of choice in type 2 diabetes mellitus.

• metformin should be titrated up slowly to minimise the possibility of gastrointestinal

upset
 Third-line therapy

If a patient does not achieve control on dual therapy then the following options are possible:

• metformin + DPP-4 inhibitor + sulfonylurea

• metformin + pioglitazone + sulfonylurea
• metformin + (pioglitazone or sulfonylurea or DPP-4 inhibitor) + SGLT-2 if certain NICE
criteria are met
• insulin-based treatment

Further therapy
If triple therapy is not effective or tolerated consider switching one of the drugs for a GLP-1
mimetic:

• BMI ≥ 35 kg/m² and specific psychological or other medical problems associated with
obesity or
• BMI < 35 kg/m² and for whom insulin therapy would have significant occupational
Simplified further management of type 2 diabetes mellitus if HbA1c targets are not met implications or weight loss would benefit other significant obesity-related comorbidities
• only continue if there is a reduction of at least 11 mmol/mol [1.0%] in HbA1c and a
weight loss of at least 3% of initial body weight in 6 months

If the HbA1c has risen to 58 mmol/mol (7.5%) then further treatment is indicated. Given the
GLP-1 mimetics should only be added to insulin under specialist care
large number of drug therapy options, medication choices depend on individual clinical
circumstances (comorbidities, contraindications, weight) and patient preference.
Starting insulin

• metformin should be continued. In terms of other drugs NICE advice: 'Review the
continued need for other blood glucose-lowering therapies'
Second-line therapy
• NICE recommend starting with human NPH insulin (isophane, intermediate-acting) taken
at bed-time or twice daily according to need
Dual therapy - add one of the following:

• metformin + DPP-4 inhibitor Practical examples

• metformin + pioglitazone
• metformin + sulfonylurea • you review an established type 2 diabetic on maximum dose metformin. Her HbA1c is 55
• metformin + SGLT-2 inhibitor (if NICE criteria met) mmol/mol (7.2%). You do not add another drug as she has not reached the threshold of
58 mmol/mol (7.5%)
• a type 2 diabetic is found to have an HbA1c of 62 mmol/mol (7.8%) at annual review.
They are currently on maximum dose metformin. You elect to add a sulfonylurea

Diabetes mellitus: GLP-1 drugs

A number of drugs to treat diabetes mellitus have become available in recent years. Much Consider adding exenatide to metformin and a sulfonylurea if:
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 • BMI >= 35 kg/m² in people of European descent and there are problems associated with
high weight, or
• BMI < 35 kg/m² and insulin is unacceptable because of occupational implications or
Whilst it is well known that insulin resistance and insufficient B-cell compensation occur other
weight loss would benefit other comorbidities.
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 NICE like patients to have achieved a > 11 mmol/mol (1%) reduction in HbA1c and 3% weight
decreased in T2DM. loss after 6 months to justify the ongoing prescription of GLP-1 mimetics.

Increasing GLP-1 levels, either by the administration of an analogue (glucagon-like peptide-1, The major adverse effect of GLP-1 mimetics is nausea and vomiting. The Medicines and
GLP-1 mimetics, e.g. exenatide) or inhibiting its breakdown (dipeptidyl peptidase-4 ,DPP-4 Healthcare products Regulatory Agency has issued specific warnings on the use of exenatide,
inhibitors - the gliptins), is therefore the target of two recent classes of drug. reporting that is has been linked to severe pancreatitis in some patients.

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

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

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 Key points
that they typically result in weight loss, in contrast to many medications such as insulin,
• dipeptidyl peptidase-4, DPP-4 inhibitors increase levels of incretins (GLP-1 and
sulfonylureas and thiazolidinediones. They are sometimes used in combination with insulin in
GIP) by decreasing their peripheral breakdown
T2DM to minimise weight gain. • oral preparation
• trials to date show that the drugs are relatively well tolerated with no increased incidence
Exenatide must be given by subcutaneous injection within 60 minutes before the morning and of hypoglycaemia
evening meals. It should not be given after a meal. • do not cause weight gain

Liraglutide is the other GLP-1 mimetic currently available. One the main advantages of
NICE guidelines on DPP-4 inhibitors
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
• NICE suggest that a DPP-4 inhibitor might be preferable to a thiazolidinedione if further
release exenatide is also licensed to be used with basal insulin alone or with metformin. Please weight gain would cause significant problems, a thiazolidinedione is contraindicated or
see the BNF for a more complete list of licensed indications. the person has had a poor response to a thiazolidinedione

NICE state the following:

Risk factor modification

Hypertension

• blood pressure targets are the same as for patients without type 2 diabetes (see
table below)
• ACE inhibitors or angiotensin II receptor blockers (ARB) are first-line
o an ARB is preferred if the patient has a black African or African–Caribbean family
origin

Clinic BP ABPM / HBPM

Age < 80 years 140/90 mmHg 135/85 mmHg

Graphic showing choice of statin.
Age > 80 years 150/90 mmHg 145/85 mmHg
NICE specifically state that we should not use QRISK2 for type 1 diabetics. Instead, the following
criteria are used for starting on statins:
Antiplatelets
• older than 40 years, or
• should not be offered unless a patient has existing cardiovascular disease • have had diabetes for more than 10 years or
• have established nephropathy or
• have other CVD risk factors
Lipids

• 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 OD Diabetes mellitus: 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 2010 1.

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 Ramadan2.There is an excellent patient information leaflet from Diabetes UK and the Muslim • neuropathy: resulting in loss of protective sensation (e.g. not noticing a stone in the
Council of Britain which explores these options in more detail. shoe), Charcot's arthropathy, dry skin
• peripheral arterial disease: diabetes is a risk factor for both macro and microvascular
If a patient with type 2 diabetes mellitus does decide to fast: ischaemia

• they should try and and eat a meal containing long-acting carbohydrates prior to sunrise
(Suhoor) Presentations
• patients should be given a blood glucose monitor to allow them to check their glucose
levels, particularly if they feel unwell • neuropathy: loss of sensation
• for patients taking metformin the expert consensus is that the dose should be split one- • ischaemia: absent foot pulses, reduced ankle-brachial pressure index (ABPI), intermittent
third before sunrise (Suhoor) and two-thirds after sunset (Iftar) claudication
• expert consensus also recommends switching once-daily sulfonylureas to after sunset. • complications: calluses, ulceration, Charcot's arthropathy, cellulitis, osteomyelitis,
For patients taking twice-daily preparations such as gliclazide it is recommended that a gangrene
larger proportion of the dose is taken after after sunset
• no adjustment is needed for patients taking pioglitazone
All patients with diabetes should be screened for diabetic foot disease on at least an annual
basis
1. Management of people with diabetes wanting to fast during Ramadan BMJ 2010;340:c3053
2. Salti I et al. Results of the Epidemiology of Diabetes and Ramadan (EPIDIAR) study. Diabetes • screening for ischaemia: done by palpating for both the dorsalis pedis pulse and
Care 2004;27:2306-11. posterial tibial artery pulse
• screening for neuropathy: a 10 g monofilament is used on various parts of the sole of the
foot
Diabetes pathophysiology

Type 1 DM NICE recommend that we risk stratify patients:

• autoimmune disease Low risk Moderate risk High risk

• antibodies against beta cells of pancreas • previous ulceration or
• HLA DR4 > HLA DR3 • previous amputation or
• various antibodies such as islet-associated antigen (IAA) antibody and glutamic acid • on renal replacement therapy or
• deformity or
decarboxylase (GAD) antibody are detected in patients who later go on to develop type • neuropathy and non-critical limb ischaemia together
• no risk factors except • neuropathy or
1 DM - their prognostic significance is not yet clear or
callus alone • non-critical limb
• neuropathy in combination with callus and/or
ischaemia.
deformity or
• non-critical limb ischaemia in combination with
Diabetic foot disease callus and/or deformity.

Diabetic foot disease is an important complication of diabetes mellitus which should be screen All patients who are moderate or high risk (I.e. any problems other than simple calluses) should
for on a regular basis. NICE produced guidelines relating to diabetic foot disease in 2015. be followed up regularly by the local diabetic foot centre.

It occurs secondary to two main factors:

Diabetic ketoacidosis
Diabetic ketoacidosis (DKA) may be a complication of existing type 1 diabetes mellitus or be the Management
first presentation, accounting for around 6% of cases. Rarely, under conditions of extreme stress,
patients with type 2 diabetes mellitus may also develop DKA. Main principles of management

Whilst DKA remains a serious condition mortality rates have decreased from 8% to under 1% in • fluid replacement
o most patients with DKA are deplete around 5-8 litres
the past 20 years.
o isotonic saline is used initially, even if the patient is severely acidotic
o please see an example fluid regime below.
Pathophysiology • insulin
o an intravenous infusion should be started at 0.1 unit/kg/hour
• DKA is caused by uncontrolled lipolysis (not proteolysis) which results in an excess of free o once blood glucose is < 15 mmol/l (270) an infusion of 5% dextrose should be
fatty acids that are ultimately converted to ketone bodies started
• correction of electrolyte disturbance
o serum potassium is often high on admission despite total body potassium being
The most common precipitating factors of DKA are infection, missed insulin doses low
and myocardial infarction. o this often falls quickly following treatment with insulin resulting in hypokalaemia
o potassium may therefore need to be added to the replacement fluids
Features o if the rate of potassium infusion is greater than 20 mmol/hour then cardiac
monitoring may be required
• long-acting insulin should be continued, short-acting insulin should be stopped
• abdominal pain
• polyuria, polydipsia, dehydration
• Kussmaul respiration (deep hyperventilation)
• Acetone-smelling breath ('pear drops' smell)
JBDS example of fluid replacement regime for patient with a systolic BP on admission
90mmHg and over

Diagnostic criteria
Fluid Volume

American Diabetes Association (2009) Joint British Diabetes Societies (2013) 0.9% sodium chloride 1L 1000ml over 1st hour

Key points 0.9% sodium chloride 1L with potassium chloride 1000ml over next 2 hours
Key points

• glucose > 13.8 mmol/l 0.9% sodium chloride 1L with potassium chloride 1000ml over next 2 hours
• glucose > 11 mmol/l or known diabetes mellitus
• pH < 7.30
• pH < 7.3
• serum bicarbonate <18 mmol/l 0.9% sodium chloride 1L with potassium chloride 1000ml over next 4 hours
• bicarbonate < 15 mmol/l
• anion gap > 10
• ketones > 3 mmol/l or urine ketones ++ on dipstick
• ketonaemia 0.9% sodium chloride 1L with potassium chloride 1000ml over next 4 hours

Fluid Volume Complications

0.9% sodium chloride 1L with potassium chloride 1000ml over next 6 hours
Complications may occur from DKA itself or the treatment:

• gastric stasis
Please note that slower infusion may be indicated in young adults (aged 18-25 years) as they are
• thromboembolism
at greater risk of cerebral oedema. • arrhythmias secondary to hyperkalaemia/iatrogenic hypokalaemia
• iatrogenic due to incorrect fluid therapy: cerebral oedema*, hypokalaemia,
hypoglycaemia
JBDS potassium guidelines • acute respiratory distress syndrome
Potassium level in first 24 hours (mmol/L) Potassium replacement in mmol/L of infusion solution • acute kidney injury

Over 5.5 Nil

* children/young adults are particularly vulnerable to cerebral oedema following fluid
3.5-5.5 40
resuscitation in DKA and often need 1:1 nursing to monitor neuro-observations, headache,
Below 3.5 Senior review as additional potassium needs to be given irritability, visual disturbance, focal neurology etc. It usually occurs 4-12 hours following
commencement of treatment but can present at any time. If there is any suspicion a CT head
and senior review should be sought

Resolution
Diabetic neuropathy

DKA resolution is defined as:

Peripheral neuropathy
• pH >7.3 and
• blood ketones < 0.6 mmol/L and Diabetes typically leads to sensory loss and not motor loss. Sensory loss typically results in a
• bicarbonate > 15.0mmol/L 'glove and stocking' distribution, with the lower legs affected first due to the length of the
sensory neurons supplying this area. Painful diabetic neuropathy is also a common problem in
clinical practice.
Further points
NICE updated it's guidance on the management of neuropathic pain in 2013. Diabetic
• both the ketonaemia and acidosis should have been resolved within 24 hours. If this neuropathy is now managed in the same way as other forms of neuropathic pain:
hasn't happened the patient requires senior review from an endocrinologist
• if the above criteria are met and the patient is eating and drinking switch to • first-line treatment: amitriptyline, duloxetine, gabapentin or pregabalin
subcutaneous insulin • if the first-line drug treatment does not work try one of the other 3 drugs
• the patient should be reviewed by the diabetes specialist nurse prior to discharge • tramadol may be used as 'rescue therapy' for exacerbations of neuropathic pain
• 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 given his history of benign prostatic hyperplasia it is
better to avoid amitriptyline due to the risk of urinary retention. From a practical point of view patients on insulin who want to apply for a Group 2 (HGV) licence
need to complete a VDIAB1I form.

Other specific points for group 1 drivers:

• if on insulin then patient can drive a car as long as they have hypoglycaemic awareness,
not more than one episode of hypoglycaemia requiring the assistance of another person
Gastrointestinal autonomic neuropathy within the preceding 12 months and no relevant visual impairment. Drivers are normally
contacted by DVLA
Gastroparesis • if on tablets or exenatide no need to notify DVLA. If tablets may induce hypoglycaemia
(e.g. sulfonylureas) then there must not have been more than one episode of
• symptoms include erratic blood glucose control, bloating and vomiting hypoglycaemia requiring the assistance of another person within the preceding 12
• management options include metoclopramide, domperidone or erythromycin (prokinetic months
agents) • if diet controlled alone then no requirement to inform DVLA

Chronic diarrhoea *to demonstrate adequate control, the Secretary of State's Honorary Medical Advisory Panel on
Diabetes Mellitus has recommended that applicants will need to have used blood glucose
• often occurs at night meters with a memory function to measure and record blood glucose levels for at least 3
months prior to submitting their application

Gastro-oesophageal reflux disease

• caused by decreased lower esophageal sphincter (LES) pressure Disorders of sex development
The table below lists the most common disorders of sex development:

Name Karyotype Notes

X-linked recessive condition. Defect in androgen receptor results
in end-organ resistance to testosterone causing genotypically
DVLA: diabetes mellitus Androgen insensitivity
46 XY male children (46XY) to have a female phenotype. Rudimentary
syndrome
vagina and testes present but no uterus. Testosterone,
Until recently people with diabetes who used insulin could not hold a HGV licence. The DVLA oestrogen and LH levels are elevated
changed the rules in October 2011. The following standards need to be met (and also apply to
Autosomal recessive condition. Results in the inability of males
patients using other hypoglycaemic inducing drugs such as sulfonylureas):
to convert testosterone to dihydrotestosterone (DHT).
5-α reductase deficiency 46 XY
Individuals have ambiguous genitalia in the newborn period.
• there has not been any severe hypoglycaemic event in the previous 12 months
Hypospadias is common. Virilization at puberty.
• the driver has full hypoglycaemic awareness
Individual has testes but external genitalia are female or
• the driver must show adequate control of the condition by regular blood glucose Male
46 XY ambiguous. may be secondary to androgen insensitivity
monitoring*, at least twice daily and at times relevant to driving pseudohermaphroditism
syndrome
• the driver must demonstrate an understanding of the risks of hypoglycaemia
• here are no other debarring complications of diabetes Female Individual has ovaries but external genitalia are male (virilized) or
46 XX
pseudohermaphroditism ambiguous. May be secondary to congenital adrenal hyperplasia
True hermaphroditism 46 XX or 47 Very rare, both ovarian and testicular tissue are present

Name Karyotype Notes • 'delayed puberty'

XXY • hypogonadism, cryptorchidism
• anosmia
• sex hormone levels are low
Disorders of sex hormones • LH, FSH levels are inappropriately low/normal
The table below summarises the findings in patients who have disorders of sex hormones: • patients are typically of normal or above average height

Disorder LH Testosterone
Cleft lip/palate and visual/hearing defects are also seen in some patients
Primary hypogonadism (Klinefelter's syndrome) High Low
Hypogonadotrophic hypogonadism (Kallman's syndrome) Low Low
Androgen insensitivity syndrome High Normal/high
Testosterone-secreting tumour Low High Androgen insensitivity syndrome

Androgen insensitivity syndrome is an X-linked recessive condition due to end-organ resistance

Klinefelter's syndrome
to testosterone causing genotypically male children (46XY) to have a female phenotype.
Complete androgen insensitivity syndrome is the new term for testicular feminisation syndrome
Klinefelter's syndrome is associated with karyotype 47, XXY
Features
Features
• 'primary amenorrhoea'
• often taller than average • undescended testes causing groin swellings
• lack of secondary sexual characteristics • breast development may occur as a result of conversion of testosterone to oestradiol
• small, firm testes
• infertile
• gynaecomastia - increased incidence of breast cancer Diagnosis
• elevated gonadotrophin levels
• buccal smear or chromosomal analysis to reveal 46XY genotype

Diagnosis is by chromosomal analysis

Management

• counselling - raise child as female

Kallman's syndrome • bilateral orchidectomy (increased risk of testicular cancer due to undescended testes)
• oestrogen therapy
Kallman's syndrome is a recognised cause of delayed puberty secondary to hypogonadotrophic
hypogonadism. It is usually inherited as an X-linked recessive trait. Kallman's syndrome is
thought to be caused by failure of GnRH-secreting neurons to migrate to the hypothalamus.

The clue given in many questions is lack of smell (anosmia) in a boy with delayed puberty

Features
Dynamic pituitary function tests • premenopausal women may have a change intermenstrual bleeding
A dynamic pituitary function test is used to assess patients with suspected primary pituitary • pain and discharge are unusual features
dysfunction

Insulin, TRH and LHRH are given to the patient following which the serum glucose, cortisol, Investigation
growth hormone, TSH, LH and FSH levels are recorded at regular intervals. Prolactin levels are
also sometimes measured* • women >= 55 years who present with postmenopausal bleeding should be referred
using the suspected cancer pathway
A normal dynamic pituitary function test has the following characteristics: • first-line investigation is trans-vaginal ultrasound - a normal endometrial thickness (< 4
mm) has a high negative predictive value
• GH level rises > 20mu/l • hysteroscopy with endometrial biopsy
• cortisol level rises > 550 mmol/l
• TSH level rises by > 2 mu/l from baseline level
• LH and FSH should double Management

• localised disease is treated with total abdominal hysterectomy with bilateral salpingo-
*dopamine antagonist tests using metoclopramide may also be used in the investigation of oophorectomy. Patients with high-risk disease may have post-operative radiotherapy
hyperprolactinaemia. A normal response is at least a twofold rise in prolactin. A blunted • progestogen therapy is sometimes used in frail elderly women not consider suitable for
prolactin response suggests a prolactinoma. surgery

*the combined oral contraceptive pill and smoking are protective

Endometrial cancer

Endometrial cancer is classically seen in post-menopausal women but around 25% of cases
occur before the menopause. It usually carries a good prognosis due to early detection

The risk factors for endometrial cancer are as follows*:

Ezetimibe
• obesity
• nulliparity Ezetimibe is a lipid-lowering drug which inhibits cholesterol receptors on enterocytes,
• early menarche decreasing cholesterol absorption in the small intestine.
• late menopause
• unopposed oestrogen. The addition of a progestogen to oestrogen reduces this risk (e.g. NICE produced guidelines in 2016 on the use of ezetimibe in primary heterozygous-familial and
In HRT). The BNF states that the additional risk is eliminated if a progestogen is given non-familial hypercholesterolaemia
continuously
• diabetes mellitus • Ezetimibe monotherapy is recommended as an option for treating primary
• tamoxifen hypercholesterolaemia in adults in whom initial statin therapy is contraindicated or who
• polycystic ovarian syndrome cannot tolerate statin therapy
• hereditary non-polyposis colorectal carcinoma • Ezetimibe, coadministered with initial statin therapy, is recommended as an option for
treating primary hypercholesterolaemia in adults who have started statin therapy when:
o serum total or LDL cholesterol concentration is not appropriately controlled
Features either after appropriate dose titration of initial statin therapy or because dose
titration is limited by intolerance to the initial statin therapy
• postmenopausal bleeding is the classic symptom

o a change from initial statin therapy to an alternative statin is being considered. • statins should be discontinued in women 3 months before conception due to the risk of
congenital defects

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 Fibrates
the LDL-receptor protein.
Fibrates are used in the management of hyperlipidaemia, particularly raised triglycerides.
Case finding:
Fibrates work through activating PPAR alpha receptors resulting in an increase in LPL activity
• NICE suggest that we should suspect FH as a possible diagnosis in adults with: reducing triglyceride levels. (Thiozolidinidiones act on nuclear PPAR gamma receptors)
o a total cholesterol level greater than 7.5 mmol/l(7.5*38.76=290) and/or
o a personal or family history of premature coronary heart disease (an event before Adverse effects:
60 years in an index individual or first-degree relative)
• children of affected parents: • gastrointestinal side-effects are common
o if one parent is affected by familial hypercholesterolaemia, arrange testing in • increased risk of thromboembolism
children by age 10
o if both parents are affected by familial hypercholesterolaemia, arrange testing in
children by age 5

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 Galactosaemia
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- Galactosaemia is a rare autosomal recessive condition caused by the absence of galactose-1-
based evidence of FH phosphate uridyl transferase. This results in intracellular accumulation of galactose-1-phosphate
• 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 Features
levels
• jaundice
• failure to thrive
Management • hepatomegaly
• cataracts
• the use of CVD risk estimation using standard tables is not appropriate in FH as they do • hypoglycaemia after exposure to galactose
not accurately reflect the risk of CVD • Fanconi syndrome
• referral to a specialist lipid clinic is usually required
• high-dose statins are usually used first-line Diagnosis
• 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 • urine reducing substances
if there is one affected parent
 Gestational diabetes
Management is with a galactose free diet Diabetes mellitus may be a pre-existing problem or develop during pregnancy, gestational
diabetes. It complicates up to 1 in 20 pregnancies. NICE estimates the following breakdown:

• 87.5% have gestational diabetes (Remove the first 8 then 7 to get the below percentages)
• 7.5% have type 1 diabetes
• 5% have type 2 diabetes

Gestational diabetes

Gestational diabetes is the second most common medical disorder complicating pregnancy
(after hypertension), affecting around 4% of pregnancies.

Risk factors for gestational diabetes

• BMI of > 30 kg/m²

• 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

• the oral glucose tolerance test (OGTT) is the test of choice

• women who've previously had gestational diabetes: 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 (100.8mg/dl) mmol/L
• 2-hour glucose is >= 7.8 (140.4) mmol/L

Management of gestational diabetes Targets for self monitoring of pregnant women (pre-existing and gestational
diabetes)
• newly diagnosed women should be seen in a joint diabetes and antenatal clinic within a
week
• women should be taught about self-monitoring of blood glucose
• advice about diet (including eating foods with a low glycaemic index) and exercise Time Target
should be given Fasting 5.3 mmol/l
• if the fasting plasma glucose level is < 7 mmol/l a trial of diet and exercise should be 1 hour after meals 7.8 mmol/l, or:
offered 2 hour after meals 6.4 mmol/l
o if glucose targets are not met within 1-2 weeks of altering diet/exercise
metformin should be started
o if glucose targets are still not met insulin should be added to Glycaemic index
diet/exercise/metformin
o gestational diabetes is treated with short-acting, not long-acting, insulin
The glycaemic index (GI) describes the capacity of a food to raise blood glucose compared with
• if at the time of diagnosis the fasting glucose level is >= 7 mmol/l insulin should be glucose in normal glucose-tolerant individuals. Foods with a high GI may be associated with an
started increased risk of obesity and the post-prandial hyperglycaemia associated with such foods may
• if the plasma glucose level is between 6-6.9 mmol/l, and there is evidence of also increase the risk of type 2 diabetes mellitus.
complications such as macrosomia or hydramnios, insulin should be offered
• glibenclamide should only be offered for women who cannot tolerate metformin or
Classification Examples
those who fail to meet the glucose targets with metformin but decline insulin treatment
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)
Management of pre-existing diabetes Low GI Fruit and vegetables, peanuts

• weight loss for women with BMI of > 27 kg/m^2 The glycaemic index is shown in brackets. Glucose, by definition, would have a glycaemic index
• stop oral hypoglycaemic agents, apart from metformin, and commence insulin of 100
• 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 Glycosylated haemoglobin
• treat retinopathy as can worsen during pregnancy 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

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
 o digital clubbing
HbA1c is generally thought to reflect the blood glucose over the previous '3 months' although o soft tissue swelling of the hands and feet
there is some evidence it is weighed more strongly to glucose levels of the past 2-4 weeks. NICE o periosteal new bone formation
recommend 'HbA1c should be checked every 3-6 months until stable, then 6 monthly'.

The relationship between HbA1c and average blood glucose is complex but has been studied by Autoantibodies
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 • TSH receptor stimulating antibodies (90%)
(IFCC). This will report HbA1c in mmol per mol of haemoglobin without glucose attached. • anti-thyroid peroxidase antibodies (75%)

HBA1c Average plasma glucose

IFCC-HbA1c (mmol/mol) Thyroid scintigraphy
(%) (mmol/l)
5 5.5
• diffuse, homogenous, increased uptake of radioactive iodine
6 7.5 42
7 9.5 53
8 11.5 64 Graves' disease management
9 13.5 75 Despite many trials, there is no clear guidance on the optimal management of Graves' disease.
10 15.5 Treatment options include anti-thyroid drugs (ATDs, for example carbimazole), radioiodine
11 17.5 treatment and surgery.
12 19.5
Anti-thyroid drugs have emerged as the most popular first-line therapy for Graves' disease in
From the above we can see that average plasma glucose = (2 * HbA1c) - 4.5] recent years. Factors that particularly support their use include anti-thyroid drugs significant
symptoms of thyrotoxicosis, or patients with a significant risk of hyperthyroid complications (e.g.
elderly patients, cardiovascular disease).

Initial treatment to control symptoms

Graves' disease: • propranolol is used to help block the adrenergic effects

Graves' disease is the most common cause of thyrotoxicosis. It is typically seen in women aged
30-50 years.
NICE Clinical Knowledge Summaries recommended that patients with Graves' disease are
Features referred to secondary care for ongoing treatment.

• typical features of thyrotoxicosis • NICE suggest carbimazole should be considered in primary care if patients symptoms are
• specific signs limited to Grave's (see below) not controlled with propanolol

Features seen in Graves' but not in other causes of thyrotoxicosis

ATD therapy
• eye signs (30% of patients)
• carbimazole is started at 40mg and reduced gradually to maintain euthyroidism
o exophthalmos
• typically continued for 12-18 months
o ophthalmoplegia
• the major complication of carbimazole therapy is agranulocytosis
• pretibial myxoedema
• an alternative regime is termed 'block-and-replace'
• thyroid acropachy, a triad of:

o carbimazole is started at 40mg • finasteride

o thyroxine is added when the patient is euthyroid • GnRH agonists e.g. goserelin, buserelin
o treatment typically lasts for 6-9 months • oestrogens, anabolic steroids
o patients following an ATD titration regime have been shown to suffer fewer side-
effects than those on a block-and-replace regime
Very rare drug causes of gynaecomastia

Radioiodine treatment • tricyclics

• isoniazid
• often used in patients who relapse following ATD therapy or are resistant to primary ATD • calcium channel blockers
treatment • heroin
• contraindications include pregnancy (should be avoided for 4-6 months following • busulfan
treatment) and age < 16 years. Thyroid eye disease is a relative contraindication, as it • methyldopa
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 Hashimoto's thyroiditis
Hashimoto's thyroiditis (chronic autoimmune thyroiditis) is an autoimmune disorder of the
Graves' disease may manifest itself or worsen during pregnancy and the post-natal period. 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

Gynaecomastia Features
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 • features of hypothyroidism
galactorrhoea (due to the actions of prolactin on breast tissue) from those of gynaecomastia • goitre: firm, non-tender
• anti-thyroid peroxidase (TPO) and also anti-thyroglobulin (Tg) antibodies
Causes of gynaecomastia

• physiological: normal in puberty Associations

• syndromes with androgen deficiency: Kallman's, Klinefelter's
• testicular failure: e.g. mumps • other autoimmune conditions e.g. coeliac disease, type 1 diabetes mellitus, vitiligo
• liver disease • Hashimoto's thyroiditis is associated with the development of MALT lymphoma
• 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
 • increased risk of endometrial cancer
o oestrogen by itself should not be given as HRT to women with a womb
o reduced by the addition of a progestogen but not eliminated completely
o the BNF states that the additional risk is eliminated if a progestogen is given
continuously
• increased risk of venous thromboembolism
o increased by the addition of a progestogen
o transdermal HRT does not appear to increase the risk of VTE
o NICE state women requesting HRT who are at high risk for VTE should be referred
to haematology before starting any treatment (even transdermal)
• increased risk of stroke
• increased risk of ischaemic heart disease if taken more than 10 years after menopause

Hungry bone syndrome

• Hungry bone syndrome is an uncommon entity but can occur after parathyroidectomy if
the hyperparathyroidism has been long-standing. The mechanism is thought to be this:
high pre-operative levels of parathyroid hormone provide a constant stimulus for
osteoclast activity creating the hypercalcaemic state by de-mineralizing the bones. This
process can result in x-ray changes very similar to metastatic lytic lesions if left untreated.
Venn diagram showing how different causes of thyroid dysfunction may manifest. Note how Upon removal of the parathyroid adenoma the hormone levels fall rapidly (they have a
many causes of hypothyroidism may have an initial thyrotoxic phase. very short half-life) and the osteoclast activity is subsequently diminished and the bones
rapidly begin re-mineralisation - 'hungry bone syndrome'. This process can be
Hormone replacement therapy: adverse effects uncomfortable and also result in systemic hypocalcaemia.
Hormone replacement therapy (HRT) involves the use of a small dose of oestrogen (combined
with a progestogen in women with a uterus) to help alleviate menopausal symptoms. Hypercalcaemia causes
Two conditions account for 90% of cases of hypercalcaemia:
Side-effects
• 1. Primary hyperparathyroidism: commonest cause in non-hospitalised patients
• nausea • 2. Malignancy: the commonest cause in hospitalised patients. This may be due to
• breast tenderness number of processes, including;
• fluid retention and weight gain o PTHrP from the tumour e.g. squamous cell lung cancer
o bone metastases
o myeloma,: due primarily to increased osteoclastic bone resorption caused by
Potential complications local cytokines (e.g. IL-1, tumour necrosis factor) released by the myeloma cells

• increased risk of breast cancer

o increased by the addition of a progestogen Other causes include
o in the Women's Health Initiative (WHI) study there was a relative risk of 1.26 at 5
years of developing breast cancer • sarcoidosis*
o the increased risk relates to the duration of use • vitamin D intoxication
o the risk of breast cancer begins to decline when HRT is stopped and by 5 years it • acromegaly
reaches the same level as in women who have never taken HRT • thyrotoxicosis

• Milk-alkali syndrome • Encourage mobilization where possible to avoid exacerbating the

• drugs: thiazides, calcium containing antacids, lithium hypercalcaemia.
• dehydration • Advise the person to report any symptoms of hypercalcaemia.
• Addison's disease
• Paget's disease of the bone**
• Acidosis (inc amount of free calcium bcx albumin buffer acidosis and replaces H+ ions)
• Familial hypocalciuric hypocalcemia is a benign cause of hypercalcemia (Urine Hypocalcaemia: causes and management
Ca<200mg/day and a Ca:Cr of <0.01 due to loss of functional mutation in CaSR gene) The clinical history combined with parathyroid hormone levels will reveal the cause of
hypocalcaemia in the majority of cases

*other causes of granulomas may lead to hypercalcaemia e.g. Tuberculosis and histoplasmosis Causes

**usually normal in this condition but hypercalcaemia may occur with prolonged immobilisation • vitamin D deficiency (osteomalacia …Osteomalacia causes hypocalcaemia associated with
a low serum phosphate, rather than a raised phosphate level.)
• chronic kidney disease
• hypoparathyroidism (e.g. post thyroid/parathyroid surgery)
• pseudohypoparathyroidism (target cells insensitive to PTH)
Hypercalcaemia management • rhabdomyolysis (initial stages)
The initial management of hypercalcaemia is rehydration with normal saline, typically 3-4
• magnesium deficiency (due to end organ PTH resistance)
litres/day. Following rehydration bisphosphonates may be used. They typically take 2-3 days to
• massive blood transfusion
work with maximal effect being seen at 7 days
• acute pancreatitis

Other options include:

Contamination of blood samples with EDTA may also give falsely low calcium levels.
• calcitonin - quicker effect than bisphosphonates
• steroids in sarcoidosis
Management

Loop diuretics such as furosemide are sometimes used in hypercalcaemia, particularly in patients
• acute management of severe hypocalcaemia is with intravenous replacement. The
who cannot tolerate aggressive fluid rehydration. However, they should be used with caution as
preferred method is with intravenous calcium gluconate, 10ml of 10% solution over 10
they may worsen electrolyte derangement and volume depletion.
minutes
• intravenous calcium chloride is more likely to cause local irritation
HOME ADVICE • ECG monitoring is recommended
In the context of hypercalcaemia secondary to malignancy the below advice is • further management depends on the underlying cause
suggested by NICE:
Hypocalcaemia: features
• Advice about maintaining good hydration (drinking 3-4 L of fluid per day), As extracellular calcium concentrations are important for muscle and nerve function many of the
provided there are no contraindications (such as severe renal impairment or heart features seen in hypocalcaemia seen a result of neuromuscular excitability
failure).
• Reassure that a low calcium diet is not necessary, as intestinal absorption of Features
calcium is usually reduced.
• Advise the person to avoid any drugs or vitamin supplements that could • tetany: muscle twitching, cramping and spasm
• perioral paraesthesia
exacerbate the hypercalcaemia.
• if chronic: depression, cataracts
• ECG: prolonged QT interval
Trousseau's sign

• carpal spasm if the brachial artery occluded by inflating the blood pressure cuff and
maintaining pressure above systolic
• wrist flexion and fingers are drawn together
• seen in around 95% of patients with hypocalcaemia and around 1% of normocalcaemic
people

Chvostek's sign

• tapping over parotid causes facial muscles to twitch

• seen in around 70% of patients with hypocalcaemia and around 10% of normocalcaemic
people

Hyperkalaemia
Plasma potassium levels are regulated by a number of factors including aldosterone, acid-base
balance and insulin levels. Metabolic acidosis is associated with hyperkalaemia as hydrogen and
potassium ions compete with each other for exchange with sodium, ions across cell membranes
Causes of hyperkalaemia
and in the distal tubule. ECG changes seen in hyperkalaemia include tall-tented T waves, small P
waves, widened QRS leading to a sinusoidal pattern and asystole, short QT, prolonged PR, • Decrease urinary excretion: acute kidney injury, drugs, type IV RTA, adrenal enzyme
bradycardia. deficiency, Addison’s disease or adrenelectomy, NSAIDs (dec aldosterone secretion)
• drugs*: potassium sparing diuretics, ACE inhibitors, angiotensin 2 receptor
blockers, spironolactone (mineralocorticoid receptor antagonist), ciclosporin (block
aldosterone), heparin, Digoxin, succinylcholine, TMP/SMX
• metabolic acidosis (H+ Compete with K+ and stays in serum in excess and also cellular
buffering…..K moves out in exchange for excess H in serum ***)
• Tissue breakdown: rhabdomyolysis, Tumor lysis syndrome, seizures and severe exercise
• massive blood transfusion
• insulin deficiency
• Periodic paralysis: mild brief episodes of muscle weakness and mild increase in K;
diagnosis with recurrent attacks and family history

Foods that are high in potassium:

• salt substitutes (i.e. Contain potassium rather than sodium)

• bananas, oranges, kiwi fruit, avocado, spinach, tomatoes

*beta-blockers interfere with potassium transport into cells and can potentially cause
hyperkalaemia in renal failure patients - remember beta-agonists, e.g. Salbutamol, are
sometimes used as emergency treatment

**both unfractionated and low-molecular weight heparin can cause hyperkalaemia. This is
thought to be caused by inhibition of aldosterone secretion Magnesium deficiency may also cause hypokalaemia. In such cases, normalizing the potassium
level may be difficult until the magnesium deficiency has been corrected

*** for every 0.1 point dec in PH the K level inc by 0.7 points because of transcellular shift
Hypokalaemia and hypertension
Clincal Presentation:
For exams it is useful to be able to classify the causes of hypokalaemia in to those associated
with hypertension, and those which are not
• Ascending muscle weakness with flaccid paralysis (K>6.5)
• Arrhythmias
Hypokalaemia with hypertension
Treatment:
• Cushing's syndrome
• Calcium gluconate • Conn's syndrome (primary hyperaldosteronism)
• Liddle's syndrome
• Sodium bicarbonate: alkalosis drives K inside cells ( don’t give in same IV line with Ca)
• 11-beta hydroxylase deficiency*
• Glucose and insulin (IV not subcutaneous)
• Renal artery stenosis
• Diuretics and beta 2 agonists
• Cation exchange resins
• Dialysis Carbenoxolone, an anti-ulcer drug, and liquorice excess can potentially cause hypokalaemia
associated with hypertension
*The differential for hypertension with low potassium includes Conn's, Cushing's, renal artery stenosis and
Liddle's. The first step in this case should be further simple investigations. Quantifying the renin and
angiotensin levels will help to distinguish the cause here, before going on to more specialised tests.

Cushing's and Conn's would be associated with a high aldosterone and a low renin, renal artery stenosis
Hypokalaemia
would be associated with a high renin and aldosterone, Liddle's is associated with a low renin and
aldosterone.
Potassium and hydrogen can be thought of as competitors. Hyperkalaemia tends to be
associated with acidosis because as potassium levels rise fewer hydrogen ions can enter the cells
Hypokalaemia without hypertension
Hypokalaemia with alkalosis (CCTV-Loop)
• diuretics
• vomiting • GI loss (e.g. Diarrhoea, vomiting)
• thiazide and loop diuretics • renal tubular acidosis (type 1 and 2**)
• Cushing's syndrome • Bartter's syndrome
• Conn's syndrome (primary hyperaldosteronism) • Gitelman syndrome

Hypokalaemia with acidosis (DRA-Dka) *21-hydroxylase deficiency, which accounts for 90% of congenital adrenal hyperplasia cases, is
not associated with hypertension
• diarrhoea **type 4 renal tubular acidosis is associated with hyperkalaemia
• renal tubular acidosis
• acetazolamide
• partially treated diabetic ketoacidosis
 Hyperlipidaemia: management
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.

Graphic showing choice of statin.

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
Pseudohyperkalaemia
at high risk of cardiovascular disease (CVD), defined as a 10-year risk of 10% or greater.
Pseudohyperkalaemia is a rise in serum potassium that occurs due to excessive leakage of
potassium from cells, during or after blood is taken. It is a laboratory artefact and does not
NICE recommend we use the QRISK2 CVD risk assessment tool for patients aged <= 84 years.
represent the true serum potassium concentration. The majority of potassium is intracellular and
Patients >= 85 years are at high risk of CVD due to their age. QRISK2 should not be used in the
thus leakage from cells can significantly impact serum levels. In this case the potassium is
following situations as there are more specific guidelines for these patient groups:
released as the large numbers of platelets aggregate and degranulate.
• type 1 diabetics
Causes include:
• patients with an estimated glomerular filtration rate (eGFR) less than 60 ml/min and/or
albuminuria
• haemolysis during venipuncture (excessive vacuum of blood drawing, prolonged
• patients with a history of familial hyperlipidaemia
tourniquet use or too fine a needle gauge)
• delay in the processing of the blood specimen
• abnormally high numbers of platelets, leukocytes, or erythrocytes (such as
NICE suggest QRISK2 may underestimate CVD risk in the following population groups:
myeloproliferative disorders)
• familial causes
• people treated for HIV
• people with serious mental health problems
• people taking medicines that can cause dyslipidaemia such as antipsychotics,
Measuring an arterial blood gas will give a quick and accurate measure of true serum potassium.
corticosteroids or immunosuppressant drugs
For obtaining a lab sample, using a lithium heparin tube, requesting a slow spin (on the lab
centrifuge) and walking the sample to the lab should ensure an accurate result.

• people with autoimmune disorders/systemic inflammatory disorders such as systemic Special situations
lupus erythematosus
Type 1 diabetes mellitus

• NICE recommend that we 'consider statin treatment for the primary prevention of CVD in
all adults with type 1 diabetes'
Measuring lipid levels • atorvastatin 20 mg should be offered if type 1 diabetics who are:
o older than 40 years, or
o have had diabetes for more than 10 years or
When measuring lipids both the total cholesterol and HDL should be checked to provide the o have established nephropathy or
most accurate risk of CVD. A full lipid profile should also be checked (i.e. including triglycerides) o have other CVD risk factors
before starting a statin. The samples do not need to be fasting.

In the vast majority of patients the cholesterol measurements will be fed into the QRISK2 tool. If Chronic kidney disease (CKD)
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 • atorvastatin 20mg should be offered to patients with CKD
hypercholesterolaemia and investigate further if: • 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
• the total cholesterol level greater than 7.5 mmol/L and/or
• there is a personal or family history of premature coronary heart disease (an event before
60 years in an index person or first-degree relative [parents, siblings, children])
Secondary prevention

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

Interpreting the QRISK2 result Atorvastatin 80mg should be offered first-line.

Probably the headline change in the 2014 guidelines was the new, lower cut-off of 10-year CVD
risk cut-off of 10%.
Follow-up of people started on statins

NICE now recommend we offer a statin to people with a QRISK2 10-year risk of >= 10% NICE recommend we follow-up patients at 3 months

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. • repeat a full lipid profile
• if the non-HDL cholesterol has not fallen by at least 40% concordance and lifestyle
Atorvastatin 20mg should be offered first-line. changes should be discussed with the patient
• NICE recommend we consider increasing the dose of atorvastatin up to 80mg
Lifestyle modifications • smokers should be encouraged to quit

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

Cardioprotective diet Hyperlipidaemia: secondary causes

Causes of predominantly hypertriglyceridaemia
• total fat intake should be <= 30% of total energy intake
• saturated fats should be <= 7% of total energy intake • diabetes mellitus (types 1 and 2)
• intake of dietary cholesterol should be < 300 mg/day • obesity
• saturated fats should be replaced by monounsaturated and polyunsaturated fats where • alcohol
possible • chronic renal failure
• replace saturated and monounsaturated fat intake with olive oil, rapeseed oil or spreads • drugs: thiazides, non-selective beta-blockers, unopposed oestrogen
based on these oils • liver disease
• choose wholegrain varieties of starchy food
• reduce their intake of sugar and food products containing refined sugars including
fructose Causes of predominantly hypercholesterolaemia
• 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 • nephrotic syndrome
• eat at least 4 to 5 portions of unsalted nuts, seeds and legumes per week • cholestasis
• hypothyroidism

Physical activity Remnant hyperlipidaemia

• each week aim for at least 150 minutes of moderate-intensity aerobic activity or 75 Overview
minutes of vigorous-intensity aerobic activity or a mix of moderate and vigorous aerobic
activity • rare cause of mixed hyperlipidaemia (raised cholesterol and triglyceride levels)
• do muscle-strengthening activities on 2 or more days a week that work all major muscle • also known as Fredrickson type III hyperlipidaemia, broad-beta disease and
groups (legs, hips, back, abdomen, chest, shoulders and arms) in line with national dysbetalipoproteinaemia
guidance for the general population • associated with apo-e2 homozygosity
• high incidence of ischaemic heart disease and peripheral vascular disease
• thought to be caused by impaired removal of intermediate density lipoprotein from the
Weight management circulation by the liver

• no specific advice is given, overweight patients should be managed in keeping with

relevant NICE guidance Features

• yellow palmar creases

Alcohol intake • palmer xanthomas
• tuberous xanthomas
• again no specific advice, other than the general recommendation: men and women are
advised not to drink more than 14 units a week on a regular basis
Management

Smoking cessation

• fibrates are first line treatment Hyponatraemia

Hyponatraemia may be caused by water excess or sodium depletion. Causes of
>>Evolocumab (trade name Repatha) is a monoclonal antibody medication designed for the
[3]
pseudohyponatraemia include hyperlipidaemia (increase in serum volume) or a taking blood
treatment of hyperlipidemia. from a drip arm. Urinary sodium and osmolarity levels aid making a diagnosis
Evolocumab is a fully human monoclonal antibody that inhibits proprotein convertase
subtilisin/kexin type 9 (PCSK9). PCSK9 is a protein that targets LDL receptors for degradation and its
inhibition thereby enhances the liver's ability to remove LDL-C, or "bad" cholesterol, from the Urinary sodium > 20 mmol/l
blood.[4]
Sodium depletion, renal loss (patient often hypovolaemic)

• diuretics: thiazides, loop diuretics

Hypernatraemia • Addison's disease
• diuretic stage of renal failure
Causes of hypernatraemia • ACEIs
• Cerebral salt wasting
• Insensible Losses: increase skin loss (sweating, burns, fever and exercise), respiratory
infections.
• GI losses: osmotic diarrhea and infectious diarrhea Patient often euvolaemic
• Transcellular Shift: rhabdomyolysis or seizures causes the muscles to avidly take water
and result in Increase serum sodium • SIADH (urine osmolality > 500 mmol/kg)
• Renal causes: Nephrogenic & central diabetes insipidus, osmotic diuresis e.g. • hypothyroidism
hyperosmolar non-ketotic diabetic coma, diuretics, mannitol
• excess IV saline

Symptoms:
Urinary sodium < 20 mmol/l
Symptoms are primarily neurologic which include lethargy, weakness irritability, seizures and
coma

Sodium depletion, extra-renal loss

Treatment:
Hypernatraemia should be corrected with great caution. Although brain tissue can lose sodium
• diarrhoea, vomiting, sweating
and potassium rapidly, lowering of other osmolytes (and importantly water) occurs at a slower
• burns, adenoma of rectum
rate, predisposing to cerebral oedema, resulting in seizures, coma and death1. Although there
are no clinical guidelines by NICE or Royal College of Physicians at present, it is generally
accepted that a rate of no greater than 0.5 mmol/hour correction is appropriate 1.
Water excess (patient often hypervolaemic and oedematous)

**Rapid correction of hypERnatremia causes cERebral edema

• secondary hyperaldosteronism: heart failure, liver cirrhosis
• nephrotic syndrome
**Rapid correction of hyPONatremia causes central PONtine myelinolysis or osmotic
• IV dextrose
myelinolysis
• psychogenic polydipsia

Hyponatraemia treatment
Untreated, severe hyponatraemia may result in cerebral oedema, which in turn can cause brain
herniation. It is therefore important to promptly identify and treat hyponatremia appropriately.
However, the particular management for each patient is based on a number of factors listed Chronic hyponatreamia without severe symptoms
below. Further to this, over-rapid correction may result in osmotic demyelination syndrome.
If a hypovolemic cause is suspected

Principles • normal, i.e. isotonic, saline (0.9% NaCl)

• this may sometimes be given as a trial
o if the serum sodium rises this supports a diagnosis of hypovolemic
Management of hyponatremia is complicated and primarily based on the following parameters: hyponatraemia
o if the serum sodium falls an alternative diagnosis such as SIADH is likely
• duration of hyponatremia: is it acute or chronic?
o acute: develops over a period of < 48 hours
o chronc: develops over a period > 48 hours If a euvolemic cause is suspected
• severity of hyponatremia: what is the sodium level?
o mild: 130-134 mmol/L • fluid restrict to 500–1000 mL/day
o moderate: 120-129 mmol/L • consider medications:
o severe: < 120 mmol/L o demeclocycline
• symptoms: is the patient symptomatic? Usually depends, how fast levels drop o vaptans (see below)
o severe symptoms usually appear with <120mEq
o early symptoms may include: headache, lethargy, nausea, vomiting, dizziness,
confusion, and muscle cramps If a hypervolemic cause is suspected
o late symptoms may include: seizures, coma, and respiratory arrest
• the suspected aetiology of the hyponatraemia:
o hypovolemic hyponatraemia/clinically dehydrated: diuretic stage of renal failure, • fluid restrict to 500–1000 mL/day
diuretics, Addisonian crisis • consider loop diuretics
o euvolemic hyponatraemia: SIADH • consider vaptans
o hypervolaemic hyponatraemia: heart failure, liver failure, nephrotic syndrome

Acute hyponatreamia with severe symptoms

Management Patients with acute, severe (<120 mmol/L) or symptomatic hyponatraemia require close
monitoring, preferably in an HDU or above setting.

Initial steps in all patients Hypertonic saline (typically 3% NaCl) is used to correct the sodium level more quickly than
would be done in patients with chronic hyponatraemia.

• exclude a spurious result (e.g. blood taken from a drip arm)

• review medications that may cause hyponatraemia

Notes on specific medications patients are best managed in either a medical high dependency unit.

HHS has a higher mortality than DKA and may be complicated by vascular complications such as
myocardial infarction, stroke or peripheral arterial thrombosis. Seizures, cerebral oedema and
Vasopressin/ADH receptor antagonists (vaptans):
central pontine myelinolysis (CPM) are uncommon but documented complications of HHS.
Whilst DKA presents within hours of onset, HHS comes on over many days, and consequently
• these act primarily on V2 receptors - antagonism of V2 receptors results in selective
the dehydration and metabolic disturbances are more extreme.
water diuresis, sparing the electrolytes
• They should be avoided in patients who have hypovolemic hyponatremia
Pathophysiology
• Vasopression/ADH receptor antagonists can stimulate the thirst receptors leading to the
desire to drink free water. They can be hepatotoxic in patients with underlying liver • Hyperglycaemia results in osmotic diuresis with associated loss of sodium and potassium
disease. • Severe volume depletion results in a significant raised serum osmolarity (typically > than
320 mosmol/kg), resulting in hyperviscosity of blood.
• Despite these severe electrolyte losses and total body volume depletion, the typical
patient with HHS, may not look as dehydrated as they are, because hypertonicity leads to
preservation of intravascular volume.
Complications of treatment

Clinical features
Osmotic demyelination syndrome (central pontine myelinolysis)
• General: fatigue, lethargy, nausea and vomiting
• can occur due to over-correction of severe hyponatremia • Neurological: altered level of consciousness, headaches, papilloedema, weakness
• to avoid this, Na+ levels are only raised by 4 to 6 mmol/l in a 24-hour period • Haematological: hyperviscosity (may result in myocardial infarctions, stroke and
• symptoms usually occur after 2 days and are usually irreversible: dysarthria, dysphagia, peripheral arterial thrombosis)
paraparesis (weakness of lower limbs) or quadriparesis, seizures, confusion, and coma • Cardiovascular: dehydration, hypotension, tachycardia

patients are awake but are unable to move or verbally communicate, also called 'Locked-in
syndrome’ Diagnosis

• 1. Hypovolaemia
• 2. Marked Hyperglycaemia (>30 mmol/L) without significant ketonaemia or acidosis
• 3. Significantly raised serum osmolarity (> 320 mosmol/kg)
• Note: A precise definition of HHS does not exist, however the above 3 criteria are helpful
Hyperosmolar hyperglycaemic state in distinguishing between HHS and DKA. It is also important to remember that a mixed
HHS / DKA picture can occur.
Hyperosmolar hyperglycaemic state (HHS) is a medical emergency which is extremely difficult to
manage and has a significant associated mortality. Hyperglycaemia results in osmotic diuresis,
severe dehydration, and electrolyte deficiencies. HHS typically presents in the elderly with type 2 Management
diabetes mellitus (T2DM), however the incidence in younger adults is increasing. It can be the
initial presentation of T2DM. The goals of management of HHS can be summarised as follows:

It is extremely important to differentiate HHS from diabetic ketoacidosis (DKA) as the • 1. Normalise the osmolality (gradually)
management is different, and treatment of HHS with insulin (e.g. as part of a DKA protocol) can o the serum osmolality is the key parameter to monitor
result in adverse outcomes. The first 24 hours of treatment is very labour intensive so these o if not available it can be estimated by 2 * Na+ + glucose + urea
 • 2. Replace fluid and electrolyte losses • Fluid replacement alone (without insulin) will gradually lower blood glucose which will
• 3. Normalise blood glucose (gradually) reduce osmolality
• A reduction of serum osmolarity will cause a shift of water into the intracellular space.
This inevitably results in a rise in serum sodium (a fall in blood glucose of 5.5 mmol/L will
Fluid replacement result in a 2.4 mmol/L rise in sodium). This is not necessarily an indication to give
hypotonic solutions. If the inevitable rise in serum Na+ is much greater than 2.4 mmol/L
• Fluid losses in HHS are estimated to be between 100 - 220 ml/kg (e.g. 10-22 litres in an for each 5.5 mmol/L fall in blood glucose this would suggest insufficient fluid
individual weighing 100 kg). replacement. Rising sodium is only a concern if the osmolality is NOT declining
• The rate of rehydration will be determined by assessing the combination of initial concurrently.
severity and any pre-existing co-morbidities (e.g. heart failure and chronic kidney • Rapid changes must be avoided. A safe rate of fall of plasma glucose of between 4 and 6
disease). Caution is needed, particularly in the elderly, where too rapid rehydration may mmol/hr is recommended. The rate of fall of plasma sodium should not exceed 10
precipitate heart failure but insufficient may fail to reverse an acute kidney injury. mmol/L in 24 hours.
• Intravenous (IV) 0.9% sodium chloride solution is the first line fluid for restoring total • A target blood glucose of between 10 and 15 mmol/L is a reasonable goal.
body fluid. • Complete normalisation of electrolytes and osmolality may take up to 72 hours.
• It is important to remember that isotonic 0.9% sodium chloride solution is already
relatively hypotonic compared to the serum in someone with HHS. Therefore in most
cases it is very effective at restoring normal serum osmolarity. Insulin
• If the serum osmolarity is not declining despite positive balance with 0.9% sodium
chloride, then the fluid should be switched to 0.45% sodium chloride solution which is • Fluid replacement alone with 0.9% sodium chloride solution will result in a gradual
more hypotonic relative to the HHS patients serum osmolarity decline of blood glucose and osmolarity
• IV fluid replacement should aim to achieve a positive balance of 3-6 litres by 12 hours • Because most patients with HHS are insulin sensitive (e.g. it usually occurs in T2DM),
and the remaining replacement of estimated fluid losses within the next 12 hours. administration of insulin can result in a rapid decline of serum glucose and thus
• Existing guidelines encourage vigorous initial fluid replacement and this alone (without osmolarity.
insulin) will result in a gradual decline in plasma glucose and serum osmolarity. A rapid • Insulin treatment prior to adequate fluid replacement may result in cardiovascular
decline is potentially harmful (see below) therefore insulin should NOT be used in the collapse as the water moves out of the intravascular space, with a resulting decline in
first instance unless there is significant ketonaemia or acidosis intravascular volume.
• The aim of treatment should be to replace approximately 50% of estimated fluid loss • A steep decline in serum osmolarity may also precipitate CPM.
within the first 12 hours and the remainder in the following 12 hours. However this is just • Measurement of ketones is essential for determining if insulin is required.
a guide, and clinical judgement should be applied, particularly in patient with co- • If significant ketonaemia is present (3β-hydroxy butyrate is more than 1 mmol/L) this
morbidities such as heart failure and chronic kidney disease (which may limit the speed indicates relative hypoinsulinaemia and insulin should be started at time zero (e.g. mixed
of correction). DKA / HHS picture). The recommended insulin dose is a fixed rate intravenous insulin
infusion given at 0.05 units per kg per hour.
• If significant ketonaemia is not present (3β-hydroxy butyrate is less than 1 mmol/L) then
Monitoring response to treatment do NOT start insulin.

• The key parameter in managing HHS is the osmolality to which glucose and sodium Potassium
are the main contributors. Rapid changes of serum osmolarity are dangerous and can
result in cardiovascular collapse and central pontine myelinolysis (CPM). • Patients with HHS are potassium deplete but less acidotic than those with DKA so
• Guidelines suggest that serum osmolarity, sodium and glucose levels should be plotted potassium shifts are less pronounced
on a graph to permit appreciation of the rate of change. They should be plotted hourly • Hyperkalaemia can be present with acute kidney injury
initially. • Patients on diuretics may be profoundly hypokalaemic
• Not all laboratories have readily available access to serum osmolarity measurements. If • Potassium should be replaced or omitted as required
not available then a calculated osmolarity can be estimated with 2Na + glucose + urea

Hyperuricaemia
Physiological response to hypoglycaemia
Increased levels of uric acid may be seen secondary to either increased cell turnover or reduced
renal excretion of uric acid. Hyperuricaemia may be found in asymptomatic patients who have • hormonal response: the first response of the body is decreased insulin secretion. This is
not experienced attacks of gout followed by increased glucagon secretion. Growth hormone and cortisol are also
released but later
Hyperuricaemia may be associated with hyperlipidaemia and hypertension. It may also be seen • sympathoadrenal response: increased catecholamine-mediated (adrenergic) and
in conjunction with the metabolic syndrome acetylcholine-mediated (cholinergic) neurotransmission in the peripheral autonomic
nervous system and in the central nervous system
Increased synthesis

• Lesch-Nyhan disease Features

• myeloproliferative disorders
• diet rich in purines • blood glucose levels and the severity of symptoms are not always correlated, especially
• exercise in patients with diabetes.
• psoriasis • blood glucose concentrations <3.3 mmol/L (60) cause autonomic symptoms due to the
• cytotoxics release of glucagon and adrenaline (average frequency in brackets):
o Sweating
o Shaking
Decreased excretion o Hunger
o Anxiety
• drugs: low-dose aspirin, diuretics, pyrazinamide o Nausea
• pre-eclampsia • blood glucose concentrations below <2.8 mmol/L(50) cause neuroglycopenic symptoms
• alcohol due to inadequate glucose supply to the brain:
• renal failure o Weakness
• lead o Vision changes
• Down’s Syndrome o Confusion
o Dizziness
• Severe and uncommon features of hypoglycaemia include:
o Convulsion
o Coma
o

Hypoglycaemia
Management of hypoglycaemia
Causes
• the following guidelines are based on the BNF hypoglycaemia treatment summary.
• insulinoma - increased ratio of proinsulin to insulin • in the community (for example, diabetes mellitus patients who inject insulin):
• self-administration of insulin/sulphonylureas o Initially, oral glucose 10-20g should be given in liquid, gel or tablet form
• liver failure o Alternatively, a propriety quick-acting carbohydrate may be given: GlucoGel or
• Addison's disease Dextrogel.
• alcohol o A 'HypoKit' may be prescribed which contains a syringe and vial of glucagon for
• nesidioblastosis - beta cell hyperplasia IM or SC injection at home
• in a hospital setting:
 o If the patient is alert, a quick-acting carbohydrate may be given (as above)
o If the patient is unconscious or unable to swallow, subcutaneous or intramuscular Features
injection glucagon may be given.
o Alternatively, intravenous 20% glucose solution may be given through a large • short fourth and fifth metacarpals
vein • short stature
• cognitive impairment
Patients with alcoholic liver disease have depleted glycogen stores, therefore, treatment with • obesity
glucagon does not improve blood glucose. • round face

Investigation
Hypoparathyroidism
• infusion of PTH followed by measurement of urinary phosphate and cAMP measurement
Primary hypoparathyroidism - this can help differentiate between type I (neither phosphate or cAMP levels rise) and II
(cAMP rises but phosphate levels do not change)
• decrease PTH secretion
• e.g. secondary to thyroid surgery*
• low calcium, high phosphate *it was previously thought to be an X-linked dominant condition
• treated with alfacalcidol

Pseudopseudohypoparathyroidism
The main symptoms of hypoparathyroidism are secondary to hypocalcaemia:
• similar phenotype to pseudohypoparathyroidism but normal biochemistry
• tetany: muscle twitching, cramping and spasm
• perioral paraesthesia
• Trousseau's sign: carpal spasm if the brachial artery occluded by inflating the blood *this may seem an oxymoron, but most medical textbooks classify hypoparathyroidism which is
pressure cuff and maintaining pressure above systolic secondary to surgery as being 'primary hypoparathyroidism'
• Chvostek's sign: tapping over parotid causes facial muscles to twitch
• if chronic: depression, cataracts
• ECG: prolonged QT interval Hypophosphataemia

Causes
Pseudohypoparathyroidism
• alcohol excess
Pseudohypoparathyroidism is caused by target cell insensitivity to parathyroid hormone (PTH) • acute liver failure
due to a mutation in a G-protein. In type I pseudohypoparathyroidism • diabetic ketoacidosis
there is a complete receptor defect whereas in type II the cell receptor is intact. • refeeding syndrome
• primary hyperparathyroidism
Pseudohypoparathyroidism is typically inherited in an autosomal dominant fashion*
• osteomalacia
Bloods

• PTH: high Consequences

• calcium: low
• red blood cell haemolysis
• phosphate: high

• white blood cell and platelet dysfunction

• muscle weakness and rhabdomyolysis
• central nervous system dysfunction

Hypothyroidism: causes

Hypothyroidism affects around 1-2% of women in the UK and is around 5-10 times more
common in females than males.

Primary hypothyroidism

Hashimoto's thyroiditis

• most common cause

• autoimmune disease, associated with IDDM, Addison's or pernicious anaemia
• may cause transient thyrotoxicosis in the acute phase
• 5-10 times more common in women
Venn diagram showing how different causes of thyroid dysfunction may manifest. Note how
many causes of hypothyroidism may have an initial thyrotoxic phase.
Subacute thyroiditis (de Quervain's)

Riedel thyroiditis Secondary hypothyroidism (rare)

After thyroidectomy or radioiodine treatment

Drug therapy (e.g. lithium, amiodarone or anti-thyroid drugs such as carbimazole) From pituitary failure

Dietary iodine deficiency Other associated conditions

• Down's syndrome
• Turner's syndrome
• coeliac disease

Hypothyroidism features
General

• Weight gain
• Lethargy
• Cold intolerance
 • the therapeutic goal is 'normalisation' of the thyroid stimulating hormone (TSH) level. As
Skin 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
• Dry (anhydrosis), cold, yellowish skin increased 'by at least 25-50 micrograms levothyroxine'* due to the increased demands of
• Non-pitting oedema (e.g. hands, face) pregnancy. The TSH should be monitored carefully, aiming for a low-normal value
• Dry, coarse scalp hair, loss of lateral aspect of eyebrows • there is no evidence to support combination therapy with levothyroxine and liothyronine
• Myxoedemic coma is treated with thyroxine and hydrocortisone

Gastrointestinal
Side-effects of thyroxine therapy

• Constipation • hyperthyroidism: due to over treatment

• reduced bone mineral density
• worsening of angina
Gynaecological • atrial fibrillation

• Menorrhagia Interactions

• iron, calcium carbonate

Neurological o absorption of levothyroxine reduced, give at least 4 hours apart

• Decreased deep tendon reflexes Insulin stress test

• Carpal tunnel syndrome
Basics

A hoarse voice is also occasionally noted. • used in investigation of hypopituitarism

• IV insulin given, GH and cortisol levels measured
• with normal pituitary function GH and cortisol should rise
Hypothyroidism: management
Key points
Contraindications

• initial starting dose of levothyroxine should be lower in elderly patients and those with • epilepsy
ischaemic heart disease. The BNF recommends that for patients with cardiac disease, • ischaemic heart disease
severe hypothyroidism or patients over 50 years the initial starting dose should be • adrenal insufficiency
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

Insulinoma • adverse effects include weight gain and hypoglycaemia (less so than sulfonylureas)

An insulinoma is a neuroendocrine tumour deriving mainly from pancreatic Islets of Langerhans Glucosidase inhibitors (acarbose, meglitol)
cells
Acarbose is an inhibitor of intestinal alpha glucosidases, which results in decreased absorption
Basics of starch and sucrose. Since acarbose prevents the degradation and absorption of complex
carbohydrates into glucose, an increased carbohydrate load will be delivered to the colon. In the
• most common pancreatic endocrine tumour colon, bacteria digest the complex carbohydrates, causing gastrointestinal side-effects such as
• 10% malignant, 10% multiple flatulence and diarrhoea. Excessive flatulence is the most commonly reported side effect and is
• of patients with multiple tumours, 50% have MEN-1 often the reason for discontinuation of the drug.

Features

• of hypoglycaemia: typically early in morning or just before meal, e.g. diplopia, weakness
etc
• rapid weight gain may be seen
• high insulin, raised proinsulin:insulin ratio Menstrual cycle
• high C-peptide • The menstrual cycle may be divided into the following phases:

Days
Diagnosis Menstruation 1-4
supervised, prolonged fasting (up to 72 hours) Follicular phase (proliferative phase) 5-13
Ovulation 14
• CT pancreas
Luteal phase (secretory phase) 15-28

Management

• surgery
• diazoxide and somatostatin if patients are not candidates for surgery

*Cryptorchidism is more suggestive of Kallman's than Klinefelter's syndrome

Meglitinides
Meglitinides (e.g. repaglinide, nateglinide)

• increase pancreatic insulin secretion

• like sulfonylureas they bind to an ATP-dependent K+(KATP) channel on the cell membrane
of pancreatic beta cells
• often used for patients with an erratic lifestyle
 Follicular phase (proliferative phase) Luteal phase (secretory phase)
Progesterone secreted by corpus
luteum rises through the luteal phase.
A rise in FSH results in the development of
follicles which in turn secrete oestradiol
If fertilisation does not occur the
Hormones corpus luteum will degenerate and
When the egg has matured, it secretes enough
progesterone levels fall
oestradiol to trigger the acute release of LH. This
in turn leads to ovulation
Oestradiol levels also rise again
during the luteal phase
Following menstruation the mucus is thick and
forms a plug across the external os
Under the influence of progesterone
Cervical mucus
Just prior to ovulation the mucus becomes clear, it becomes thick, scant, and tacky
acellular, low viscosity. It also becomes 'stretchy'
- a quality termed spinnbarkeit
Basal body Falls prior to ovulation due to the influence of Rises following ovulation in response
temperature oestradiol to higher progesterone levels

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: (weight, FBS, BP, Lipids2)

• 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
• 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
Further details are given in the table below

Follicular phase (proliferative phase) Luteal phase (secretory phase) The International Diabetes Federation produced a consensus set of diagnostic criteria in 2005,
A number of follicles develop. which are now widely in use. These require the presence of central obesity (defined as waist
Ovarian circumference > 94cm for Europid men and > 80cm for Europid women, with ethnicity specific
Corpus luteum values for other groups) plus any two of the following four factors:
histology One follicle will become dominant around the
mid-follicular phase
Endometrium changes to secretory • raised triglycerides level: > 1.7 mmol/L, or specific treatment for this lipid abnormality
Endometrial • reduced HDL cholesterol: < 1.03 mmol/L in males and < 1.29 mmol/L in females, or
Proliferation of endometrium lining under influence of
histology specific treatment for this lipid abnormality
progesterone

• raised blood pressure: > 130/85 mm Hg, or active treatment of hypertension • 20% of cases
• raised fasting plasma glucose > 5.6 mmol/L, or previously diagnosed type 2 diabetes • due to a defect in the glucokinase gene

In 1999 the World Health Organization produced diagnostic criteria which required the presence MODY 5
of diabetes mellitus, impaired glucose tolerance, impaired fasting glucose or insulin resistance,
AND two of the following: • rare
• due to a defect in the HNF-1 beta gene
• blood pressure: > 140/90 mmHg • liver and renal cysts
• 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 > Features of MODY
30 kg/m2
• microalbuminuria: urinary albumin excretion ratio > 20 mg/min or albumin:creatinine • typically develops in patients < 25 years
ratio > 30 mg/g • 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
Other associated features include: usually necessary

• raised uric acid levels

• non-alcoholic fatty liver disease
• polycystic ovarian syndrome

MODY
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.
Multiple endocrine neoplasia

MODY 3 The table below summarises the three main types of multiple endocrine neoplasia (MEN). MEN
is inherited as an autosomal dominant disorder.
MEN type I MEN type IIa MEN type IIb
• 60% of cases
• due to a defect in the HNF-1 alpha gene
• is associated with an increased risk of HCC
• metformin has been shown to be inferior to sulphonylureas in MODY type 1.

MODY 2
 MEN type I MEN type IIa MEN type IIb Neuroblastoma
Medullary thyroid Neuroblastoma is one of the top five causes of cancer in children, accounting for around 7-8%
3 P's
cancer of childhood malignancies. The tumour arises from neural crest tissue of the adrenal medulla
Parathyroid (95%): hyperparathyroidism due to Medullary thyroid cancer
(the most common site) and sympathetic nervous system.
parathyroid hyperplasia (70%)
1P
Pituitary (70%)
Phaeochromocytoma Median age of onset is around 20 months
Pancreas (50%): e.g. insulinoma, gastrinoma 2 P's
(leading to recurrent peptic ulceration) Parathyroid (60%)
Marfanoid body Features
Phaeochromocytoma
habitus
Also: adrenal and thyroid • abdominal mass
Neuromas
MEN1 gene • pallor, weight loss
RET oncogene RET oncogene • bone pain, limp
Most common presentation = hypercalcaemia • hepatomegaly
• paraplegia
• proptosis

Investigation

• raised urinary vanillylmandelic acid (VMA) and homovanillic acid (HVA) levels
• calcification may be seen on abdominal x-ray
• biopsy

• Venn diagram showing the different types of MEN and their associated features

The high incidence of parathyroid tumours and hypercalcaemia make serum calcium a useful
indicator of MEN type 1 in suspected individuals

Obesity: therapeutic options • urinary symptoms e.g. Urgency

The management of obesity consists of a step-wise approach: • early satiety
• diarrhoea
• conservative: diet, exercise
• medical
• surgical Investigations

Orlistat is a pancreatic lipase inhibitor used in the management of obesity. Adverse effects • CA125
include faecal urgency/incontinence and flatulence. A lower dose version is now available o NICE recommends a CA125 test is done initially. Endometriosis, menstruation,
without prescription ('Alli'). NICE have defined criteria for the use of orlistat. It should only be benign ovarian cysts and other conditions may also raise the CA125 level
prescribed as part of an overall plan for managing obesity in adults who have: o if the CA125 is raised (35 IU/mL or greater) then an urgent ultrasound scan of the
abdomen and pelvis should be ordered
• BMI of 28 kg/m^2 or more with associated risk factors, or o a CA125 should not be used for screening for ovarian cancer in asymptomatic
• BMI of 30 kg/m^2 or more women
• continued weight loss e.g. 5% at 3 months • ultrasound
• orlistat is normally used for < 1 year

Diagnosis is difficult and usually involves diagnostic laparotomy

Management

Ovarian cancer • usually a combination of surgery and platinum-based chemotherapy

Ovarian cancer is the fifth most common malignancy in females. The peak age of incidence is 60
years and it generally carries a poor prognosis due to late diagnosis.
Prognosis
Pathophysiology
• 80% of women have advanced disease at presentation
• around 90% of ovarian cancers are epithelial in origin, with 70-80% of cases being due to • the all stage 5-year survival is 46%
serous carcinomas
• interestingly, it is now increasingly recognised that the distal end of the fallopian tube is
often the site of origin of many 'ovarian' cancers *It is traditionally taught that infertility treatment increases the risk of ovarian cancer, as it
increases the number of ovulations. Recent evidence however suggests that there is not a
significant link. The combined oral contraceptive pill reduces the risk (fewer ovulations) as does
Risk factors having many pregnancies.

• family history: mutations of the BRCA1 or the BRCA2 gene

• many ovulations*: early menarche, late menopause, nulliparity
Pendred's syndrome
Pendred is an autosomal recessive genetic disorder that is characterised by bilateral
sensorineural deafness, with mild hypothyroidism and a goitre. The patients tend to present with
Clinical features are notoriously vague
progressive hearing loss and delay in academic progression. Often head trauma tends to make
the sensorineural deafness worse, leading to patients having to avoid contact sports.
• abdominal distension and bloating
• abdominal and pelvic pain
In Pendred syndrome there is a defect in the organification of iodine, leading to
dyshormonogenesis. However thyroid symptoms in pendred syndrome are often mild and
patients are often clinically euthyroid, presenting only with a goitre. Thyroid function tests are
also often normal, requiring the perchlorate discharge test to aid diagnosis. Pituitary adenoma
A pituitary adenoma is a benign tumour of the pituitary gland. They are common (10% of all
The syndrome can be diagnosed via genetic testing (Pendred syndrome (PDS) gene, people1) but in most cases will never be found (asymptomatic) or are found as an incidental
chromosome 7), audiometry and MRI imaging to look for characteristic one and a half turns in finding. They account for around 10% of adult brain tumours2.
the cochlea, compared to the normal two and a half turns.
Pituitary adenomas can be classified according to:
Treatment is with thyroid hormone replacement and cochlear implants.
• size (a microadenoma is <1cm and a macroadenoma is >1cm)
Phaeochromocytoma • hormonal status (a secretory/functioning adenoma produces and excess of a particular
Phaeochromocytoma is a rare catecholamine secreting tumour. About 10% are familial and may hormone and a non-secretory/functioning adenoma does not produce a hormone to
be associated with MEN type II, neurofibromatosis and von Hippel-Lindau syndrome excess)

Basics
Prolactinomas are the most common type and they produce an excess of prolactin. After
• bilateral in 10% prolactinomas, non-secreting adenomas are the next most common, then GH secreting and
• malignant in 10% then ACTH secreting adenomas.
• extra-adrenal in 10% (most common site = organ of Zuckerkandl, adjacent to the
bifurcation of the aorta) Pituitary adenomas typically cause symptoms by:

• excess of a hormone (e.g. Cushing’s disease due to excess ACTH, acromegaly due to
Features are typically episodic excess GH or amenorrhea and galactorrhea due to excess prolactin)
• depletion of a hormone(s) (due to compression of the normal functioning pituitary
• hypertension (around 90% of cases, may be sustained) gland)
• headaches o non-functioning tumours, therefore, present with generalised hypopituitarism
• palpitations • stretching of the dura within/around pituitary fossa (causing headaches)
• sweating • compression of the optic chiasm (causing a bitemporal hemianopia due to crossing nasal
• anxiety fibers)

Tests Alternatively, pituitary adenomas, particularly microadenomas, can be an incidental finding on

neuroimaging and therefore called a ‘pituitary incidentaloma’.
• 24 hr urinary collection of metanephrines (sensitivity 97%*)
• this has replaced a 24 hr urinary collection of catecholamines (sensitivity 86%) Investigation requires:

• a pituitary blood profile (including: GH, prolactin, ACTH, FH, LSH and TFTs)
Surgery is the definitive management. The patient must first however be stabilized with medical • formal visual field testing
management: • MRI brain with contrast

• alpha-blocker (e.g. phenoxybenzamine), given before a

• beta-blocker (e.g. propranolol) Differential diagnoses include:

• pituitary hyperplasia normal or mildly elevated. Testosterone may be normal or mildly elevated - however, if
• craniopharyngioma markedly raised consider other causes
• meningioma • check for impaired glucose tolerance
• brain metastases
• lymphoma
• hypophysitis
• vascular malformation (e.g. aneurysm) Polycystic ovarian syndrome: management

General
Treatment may include a combination of:
• weight reduction if appropriate
• hormonal therapy (e.g. bromocriptine is the first line treatment for prolactinomas) • if a women requires contraception then a combined oral contraceptive (COC) pill may
• surgery (e.g. transsphenoidal transnasal hypophysectomy) help regulate her cycle and induce a monthly bleed (see below)
o e.g. if progression in size
• radiotherapy
Hirsutism and acne

• a COC pill may be used help manage hirsutism. Possible options include a third
Polycystic ovarian syndrome (Stein-Leventhal Syndrome) generation COC which has fewer androgenic effects or co-cyprindiol which has an anti-
androgen action. Both of these types of COC may carry an increased risk of venous
Polycystic ovary syndrome (PCOS) is a complex condition of ovarian dysfunction thought to thromboembolism.
affect between 5-20% of women of reproductive age. The aetiology of PCOS is not fully • if doesn't respond to COC then topical eflornithine may be tried
understood. Both hyperinsulinaemia and high levels of luteinizing hormone are seen in PCOS • spironolactone, flutamide and finasteride may be used under specialist supervision
and there appears to be some overlap with the metabolic syndrome.

Features Infertility

• subfertility and infertility • weight reduction if appropriate

• menstrual disturbances: oligomenorrhea and amenorrhoea • the management of infertility in patients with PCOS should be supervised by a specialist.
• hirsutism, acne (due to hyperandrogenism) There is an ongoing debate as to whether metformin, clomifene or a combination should
• obesity be used to stimulate ovulation
• acanthosis nigricans (due to insulin resistance) • a 2007 trial published in the New England Journal of Medicine suggested clomifene was
• Clitoromegaly is seen occasionally in PCOS but is normally associated with very high the most effective treatment. There is a potential risk of multiple pregnancies with anti-
androgen levels. If clitoromegaly is found then further investigations to exclude an oestrogen* therapies such as clomifene. The RCOG published an opinion paper in 2008
ovarian or adrenal androgen secreting tumour are required. and concluded that on current evidence metformin is not a first line treatment of choice
in the management of PCOS
• metformin is also used, either combined with clomifene or alone, particularly in patients
Investigations who are obese
• gonadotrophins
• pelvic ultrasound: multiple cysts on the ovaries (ovarian cysts are the most consistent
feature)
• FSH, LH, prolactin, TSH, and testosterone are useful investigations: raised LH:FSH ratio is *work by occupying hypothalamic oestrogen receptors without activating them. This interferes
a 'classical' feature but is no longer thought to be useful in diagnosis. Prolactin may be with the binding of oestradiol and thus prevents negative feedback inhibition of FSH secretion
Prediabetes and impaired glucose regulation
Management
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 • lifestyle modification: weight loss, increased exercise, change in diet
impaired glucose tolerance (IGT). Diabetes UK estimate that around 1 in 7 adults in the UK have • at least yearly follow-up with blood tests is recommended
prediabetes. Many individuals with prediabetes will progress on to developing type 2 diabetes • NICE recommend metformin for adults at high risk 'whose blood glucose measure (fasting
mellitus (T2DM) and they are therefore at greater risk of microvascular and macrovascular plasma glucose or HbA1c) shows they are still progressing towards type 2 diabetes, despite
complications. their participation in an intensive lifestyle-change programme'

Terminology

• Diabetes UK currently recommend using the term prediabetes when talking to patients Impaired fasting glucose and impaired glucose tolerance
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 There are two main types of IGR:
understood
• impaired fasting glucose (IFG) - due to hepatic insulin resistance
• impaired glucose tolerance (IGT) - due to muscle insulin resistance
Identification of patients with prediabetes • patients with IGT are more likely to develop T2DM and cardiovascular disease than
patients with IFG
• 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
• patients identified at high risk should have a blood sample taken
• a fasting plasma glucose of 6.1-6.9 mmol/l or an HbA1c level of 42-47 mmol/mol (6.0-
6.4%) indicates high risk 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

Pregnancy: thyroid problems

In pregnancy, there is an increase in the levels of thyroxine-binding globulin (TBG). This causes
an increase in the levels of total thyroxine but does not affect the free thyroxine level. Elevated
oestrogen levels produced in pregnancy stimulate the expression of thyroid binding
Diagram showing the spectrum of diabetes diagnosis globulin (TBG) from the liver. As TBG binds to free thyroxine (fT4) and free triiodothyronine
(fT3), an increase in TBG results in an initial lowering of fT4 and fT3. This in turn causes a

secondary increase in thyroid-stimulating hormone (TSH). The net result is a new equilibrium Premature ovarian insufficiency
between free and bound thyroid hormones with an increase in bound-T3 and T4 but an overall
unaffected fT3 and fT4 level Premature ovarian insufficiency is defined as the onset of menopausal symptoms and elevated
gonadotrophin levels before the age of 40 years. It occurs in around 1 in 100 women.

Thyrotoxicosis Causes of premature menopause include:

• idiopathic
Untreated thyrotoxicosis increases the risk of fetal loss, maternal heart failure and premature
o the most common cause
labour.
o there may be a family history
• bilateral oophorectomy
Graves' disease is the most common cause of thyrotoxicosis in pregnancy. It is also recognised
o having a hysterectomy with preservation of the ovaries has also been shown to
that activation of the TSH receptor by HCG may also occur - often termed transient gestational
advance the age of menopause
hyperthyroidism. HCG levels will fall in the second and third trimester
• radiotherapy
• chemotherapy
Management
• infection: e.g. mumps
• propylthiouracil has traditionally been the antithyroid drug of choice • autoimmune disorders
• however, propylthiouracil is associated with an increased risk of severe hepatic injury • resistant ovary syndrome: due to FSH receptor abnormalities
• therefore NICE Clinical Knowledge Summaries advocate the following: 'Propylthiouracil is
used in the first trimester of pregnancy in place of carbimazole, as the latter drug may be
Features are similar to those of the normal climacteric but the actual presenting problem may
associated with an increased risk of congenital abnormalities. At the beginning of the
differ
second trimester, the woman should be switched back to carbimazole'
• maternal free thyroxine levels should be kept in the upper third of the normal reference
range to avoid fetal hypothyroidism
• climacteric symptoms: hot flushes, night sweats
• thyrotrophin receptor stimulating antibodies should be checked at 30-36 weeks
• infertility
gestation - helps to determine the risk of neonatal thyroid problems
• secondary amenorrhoea
• block-and-replace regimes should not be used in pregnancy
• raised FSH, LH levels
• radioiodine therapy is contraindicated
o e.g. FSH > 40 iu/l
o elevated FSH levels should be demonstrated on 2 blood samples taken 4–6
weeks apart
• low oestradiol
Hypothyroidism
o e.g. < 100 pmol/l

Key points Management

• thyroxine is safe during pregnancy • hormone replacement therapy (HRT) or a combined oral contraceptive pill should be
• serum TSH measured in each trimester and 6-8 weeks post-partum offered to women until the age of the average menopause (51 years)
• women require an increased dose of thyroxine during pregnancy o it should be noted that HRT does not provide contraception, in case spontaneous
o by up to 50% as early as 4-6 weeks of pregnancy (It is most appropriate to start ovarian activity resumes
with small increments of 25-50mcg and then adjust the dose further based on
the TSH results)
• breastfeeding is safe whilst on thyroxine
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
o e.g. muscle weakness
o this is a classical feature in exams but studies suggest this is seen in only 10-40%
of patients
• alkalosis

Investigations

• the 2016 Endocrine Society recommend that a plasma aldosterone/renin ratio is the
first-line investigation in suspected primary hyperaldosteronism
o should show high aldosterone levels alongside low renin levels (negative
feedback due to sodium retention from aldosterone)
CT abdomen showing a right-sided adrenal adenoma in a patient who presented with
• following this a high-resolution CT abdomen and adrenal vein sampling is used to
hypertension and hypokalaemia. The adenoma can be seen 'next to' or 'below' the liver.
differentiate between unilateral and bilateral sources of aldosterone excess
o if the CT is normal adrenal venous sampling (AVS) can be used to distinguish
between unilateral adenoma and bilateral hyperplasia

*Medications that can cause false negative renin:aldosterone ratio results are the following: Primary hyperparathyroidism
In exams, primary hyperparathyroidism is stereotypically seen in elderly females with an
• Angiotensin-converting enzyme inhibitors (e.g. ramipril or lisinopril). unquenchable thirst and an inappropriately normal or raised parathyroid hormone level. It is
• Angiotensin receptor blockers (e.g. losartan). most commonly due to a solitary adenoma
• Direct renin inhibitors (e.g aliskiren).
• Aldosterone antagonists (e.g. spironolactone or eplerenone). Causes of primary hyperparathyroidism

• 80%: solitary adenoma

• 15%: hyperplasia
• 4%: multiple adenoma
Management • 1%: carcinoma

• adrenal adenoma: surgery

• bilateral adrenocortical hyperplasia: aldosterone antagonist e.g. spironolactone Around 80% of patients are asymptomatic and are diagnosed on routine blood tests. The

symptomatic features of primary hyperparathyroidism may be remembered by the

mnemonic: 'bones, stones, abdominal groans and psychic moans':

• polydipsia, polyuria
• depression
• anorexia, nausea, constipation
• peptic ulceration
• pancreatitis
• bone pain/fracture
• renal stones
• hypertension

Associations

• hypertension
• multiple endocrine neoplasia: MEN I and II

Investigations

• raised calcium, low phosphate

• PTH may be raised or (inappropriately, given the raised calcium) normal
• technetium-MIBI subtraction scan
• pepperpot skull is a characteristic X-ray finding of hyperparathyroidism

Treatment (1mg/dl=0.25mmol/L for calcium)

• the definitive management is total parathyroidectomy

• conservative management may be offered if the calcium level is less than 0.25 mmol/L
above the upper limit of normal AND the patient is > 50 years AND there is no evidence
of end-organ damage
• patients not suitable for surgery may be treated with cinacalcet, a calcimimetic
o a calcimimetic 'mimics' the action of calcium on tissues by allosteric activation of
the calcium-sensing receptor
Bilateral hand radiographs in a middle-aged woman demonstrating generalised osteopenia,
The NICE guidelines (NG 132) state that all patients with symptomatic hyperparathyroidism or
erosion of the terminal phalangeal tufts (acro-osteolysis) and subperiosteal resorption of bone
with an adjusted calcium level above 2.85 mmol/mL should be referred to a surgeon with expertise
particularly the radial aspects of the 2nd and 3rd middle phalanges. These changes are
in parathyroid surgery in the first instance.
consistent with a diagnosis of hyperparathyroidism.
Primary hyperparathyroidism
Causes of raised prolactin
• PTH over-secretion usually from a parathyroid adenoma
• both PTH and calcium are elevated • prolactinoma
• surgery to remove the adenoma is the most effective treatment • pregnancy
• oestrogens
• conservative measures such as bisphosphonates can be used
• physiological: stress, exercise, sleep
• acromegaly: 1/3 of patients
• polycystic ovarian syndrome
Secondary hyperparathyroidism
• primary hypothyroidism (due to thyrotrophin releasing hormone (TRH) stimulating
prolactin release)
• occurs in chronic kidney disease typically
• can be secondary to vitamin D deficiency
• PTH released due to low calcium, high phosphate and lack of vitamin D activation Drug causes of raised prolactin
by diseased kidneys
• PTH level high with calcium levels being low or normal • metoclopramide, domperidone
• medical management primarily: phosphate binders, calcium and vitamin D • phenothiazines
supplementation • haloperidol
• very rare: SSRIs, opioids

Tertiary hyperparathyroidism
Causes of raised prolactin - the p's
• autonomous hypersecretion of PTH due to hypertrophied parathyroid glands
• occurs after a period of long standing secondary hyperparathyroidism • pregnancy
• treatment involves parathyroidectomy. • prolactinoma
• physiological
• polycystic ovarian syndrome
Prolactin and galactorrhoea • primary hypothyroidism
• phenothiazines, metoclopramide, domperidone, haloperidol, opiods
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 on breast tissue) from those of gynaecomastia

Features of excess prolactin

• men: impotence, loss of libido, galactorrhoea

• women: amenorrhoea, galactorrhoea

Renal tubular acidosis Type 1 RTA (distal)

All three types of renal tubular acidosis (RTA) are associated with hyperchloraemic metabolic
acidosis (normal anion gap). • inability to generate acid urine (secrete H+) in distal tubule
• causes hypokalaemia
• complications include nephrocalcinosis and renal stones
• causes include idiopathic, rheumatoid arthritis, SLE, Sjogren's, amphotericin B toxicity,
analgesic nephropathy

Type 2 RTA (proximal)

• decreased HCO3- reabsorption in proximal tubule

• causes hypokalaemia
• complications include osteomalacia
• causes include idiopathic, as part of Fanconi syndrome, Wilson's disease, cystinosis,
outdated tetracyclines, carbonic anhydrase inhibitors (acetazolamide, topiramate)

Type 3 RTA (mixed)

• extremely rare
• caused by carbonic anhydrase II deficiency
• results in hypokalaemia

Type 4 RTA (hyperkalaemic)

• reduction in aldosterone leads in turn to a reduction in proximal tubular ammonium

excretion
• causes hyperkalaemia
 • causes include hypoaldosteronism, diabetes >> Due to an increased amount of glucose being secreted in the urine, these medications are
contra-indicated in patients with recurrent thrush. The increased amount of glucose in the urine is
>>Lightwood–Albright syndrome is a neonatal form of renal tubular acidosis. It is thought to predispose to bacterial growth.
characterized by distal renal tubular acidosis that occurs as a result of bicarbonate wasting and
the inability to excrete hydrogen ions. By definition, it is a transient process and has no
particular disease course.

Riedel's thyroiditis

Riedel's thyroiditis is a rare cause of hypothyroidism characterised by dense fibrous tissue

replacing the normal thyroid parenchyma. On examination a hard, fixed, painless goitre is noted. SIADH
It is usually seen in middle-aged women. It is associated with retroperitoneal fibrosis.
The syndrome of inappropriate ADH secretion (SIADH) is characterised by hyponatraemia
secondary to the dilutional effects of excessive water retention.

Causes of SIADH

Category Examples
• small cell lung cancer
SGLT-2 inhibitors Malignancy • also: pancreas, prostate
SGLT-2 inhibitors reversibly inhibit sodium-glucose co-transporter 2 (SGLT-2) in the renal
proximal convoluted tubule to reduce glucose reabsorption and increase urinary glucose • stroke
excretion. • subarachnoid haemorrhage
Neurological • subdural haemorrhage
Examples include canagliflozin, dapagliflozin and empagliflozin. • meningitis/encephalitis/abscess

Important adverse effects include • tuberculosis

Infections • pneumonia
• urinary and genital infection (secondary to glycosuria). Fournier’s gangrene has also been
reported • sulfonylureas*
• normoglycaemic ketoacidosis • SSRIs, tricyclics
• increased risk of lower-limb amputation: feet should be closely monitored • carbamazepine
Drugs
• vincristine
• cyclophosphamide
Patients taking SGLT-2 drugs often lose weight, which can be beneficial in type 2 diabetes
mellitus. • positive end-expiratory pressure (PEEP)
Other causes • porphyrias
>> SGLT-2 inhibitors are recognised to increased total cholesterol, (both HDL and LDL), although
cardiovascular outcome studies as yet do not suggest this translates into increased risk of MACE
events. Management

• correction must be done slowly to avoid precipitating central pontine myelinolysis Subacute (De Quervain's) thyroiditis
• fluid restriction Subacute thyroiditis (also known as De Quervain's thyroiditis and subacute granulomatous
• demeclocycline: reduces the responsiveness of the collecting tubule cells to ADH thyroiditis) is thought to occur following viral infection and typically presents with
• ADH (vasopressin) receptor antagonists have been developed hyperthyroidism.

There are typically 4 phases;

*the BNF states this has been reported with glimepiride and glipizide.
• phase 1 (lasts 3-6 weeks): hyperthyroidism, painful goitre, raised ESR
• phase 2 (1-3 weeks): euthyroid
Sick euthyroid syndrome (everything low) • phase 3 (weeks - months): hypothyroidism
• phase 4: thyroid structure and function goes back to normal
In sick euthyroid syndrome (now referred to as non-thyroidal illness) it is often said that
everything (TSH, thyroxine and T3) is low. In the majority of cases however the TSH level is
within the >normal range (inappropriately normal given the low thyroxine and T3). Investigations

Changes are reversible upon recovery from the systemic illness and hence no treatment is • thyroid scintigraphy: globally reduced uptake of iodine-131
usually needed.

Management
Skin disorders associated with thyroid disease
• usually self-limiting - most patients do not require treatment
• thyroid pain may respond to aspirin or other NSAIDs
Skin manifestations of hypothyroidism
• in more severe cases steroids are used, particularly if hypothyroidism develops
• dry (anhydrosis), cold, yellowish skin
• non-pitting oedema (e.g. hands, face)
• dry, coarse scalp hair, loss of lateral aspect of eyebrows
• eczema Subclinical hyperthyroidism
• xanthomata Subclinical hyperthyroidism is an entity which is gaining increasing recognition. It is defined as:

• normal serum free thyroxine and triiodothyronine levels

Skin manifestations of hyperthyroidism • with a thyroid stimulating hormone (TSH) below normal range (usually < 0.1 mu/l)

• pretibial myxoedema: erythematous, oedematous lesions above the lateral malleoli Causes
• thyroid acropachy: clubbing
• scalp hair thinning • multinodular goitre, particularly in elderly females
• increased sweating • excessive thyroxine may give a similar biochemical picture

Pruritus can occur in both hyper- and hypothyroidism 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 Sulfonylureas
intervention Sulfonylureas are oral hypoglycaemic drugs used in the management of type 2 diabetes
• a reasonable treatment option is a therapeutic trial of low-dose antithyroid agents for mellitus. They work by increasing pancreatic insulin secretion and hence are only effective if
approximately 6 months in an effort to induce a remission 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

Subclinical hypothyroidism
Basics • hypoglycaemic episodes (more common with long-acting preparations such as
chlorpropamide)
• TSH raised but T3, T4 normal • weight gain
• no obvious symptoms

Rarer adverse effects

Significance
• hyponatraemia secondary to syndrome of inappropriate ADH secretion
• risk of progressing to overt hypothyroidism is 2-5% per year (higher in men) • bone marrow suppression
• risk increased by the presence of thyroid autoantibodies • hepatotoxicity (typically cholestatic)
• peripheral neuropathy

Management Sulfonylureas should be avoided in breastfeeding and pregnancy.

Not all patients require treatment. NICE Clinical Knowledge Summaries (CKS) have produced T2DM medications
guidelines. Note that not all patients will fall within the age boundaries given and hence these Drugs used
are guidelines in the broader sense.
• sulphonylureas
• metformin (biguanide)
TSH is between 4 - 10mU/L and the free thyroxine level is within the normal range
• alpha-glucosidase inhibitors (acarbose)
• if < 65 years with symptoms suggestive of hypothyroidism, give a trial of levothyroxine. If • SGLT 2 mimetics (glitazones)
there is no improvement in symptoms, stop levothyroxine • DPP4 inhibitors
• 'in older people (especially those aged over 80 years) follow a 'watch and wait' strategy, • thiozolidinidiones
generally avoiding hormonal treatment' • insulin
• if asymptomatic people, observe and repeat thyroid function in 6 months • meglitinides

TSH is > 10mU/L and the free thyroxine level is within the normal range Thiazolidinediones
Thiazolidinediones are a class of agents used in the treatment of type 2 diabetes mellitus. They
• start treatment (even if asymptomatic) with levothyroxine if <= 70 years are agonists to the PPAR-gamma receptor and reduce peripheral insulin resistance.
• 'in older people (especially those aged over 80 years) follow a 'watch and wait' strategy, Rosiglitazone was withdrawn in 2010 following concerns about the cardiovascular side-effect
generally avoiding hormonal treatment' profile.

The PPAR-gamma receptor is an intracellular nuclear receptor. It's natural ligands are free fatty Further information
acids and it is thought to control adipocyte differentiation and function.

Adverse effects
Type Notes
• weight gain • Usually contain a mixture of papillary and colloidal filled follicles
• liver impairment: monitor LFTs • Histologically tumour has papillary projections and pale empty nuclei
• fluid retention - therefore contraindicated in heart failure. The risk of fluid retention is Papillary • Seldom encapsulated
increased if the patient also takes insulin carcinoma • Lymph node metastasis predominate
• recent studies have indicated an increased risk of fractures • Haematogenous metastasis rare
• bladder cancer: recent studies have shown an increased risk of bladder cancer in patients
taking pioglitazone (hazard ratio 2.64) • Usually present as a solitary thyroid nodule
Follicular
• Malignancy can only be excluded on formal histological assessment
adenoma

• May appear macroscopically encapsulated, microscopically capsular invasion is

Thyroid cancer seen. Without this finding the lesion is a follicular adenoma.
Follicular
Features of hyperthyroidism or hypothyroidism are not commonly seen in patients with thyroid • Vascular invasion predominates
carcinoma
malignancies as they rarely secrete thyroid hormones • Multifocal disease raree

Main points • C cells derived from neural crest and not thyroid tissue
• Serum calcitonin levels often raised
Type Percentage Medullary • Familial genetic disease accounts for up to 20% cases
Papillary 70% Often young females - excellent prognosis carcinoma • Both lymphatic and haematogenous metastasis are recognised, nodal disease is
associated with a very poor prognosis.
Follicular 20%
Medullary 5% Cancer of parafollicular (C) cells, secrete calcitonin, part of MEN-2
• Most common in elderly females
Anaplastic 1% Not responsive to treatment, can cause pressure symptoms • Local invasion is a common feature
Lymphoma Rare Associated with Hashimoto's thyroiditis Anaplastic
• Treatment is by resection where possible, palliation may be achieved through
carcinoma
isthmusectomy and radiotherapy. Chemotherapy is ineffective.
Management of papillary and follicular cancer

• total thyroidectomy
• followed by radioiodine (I-131) to kill residual cells
• yearly thyroglobulin levels to detect early recurrent disease

Thyroid disorders: a very basic introduction

Disorders of thyroid function are very commonly encountered in clinical practice. Around 2% of
the UK population has hypothyroidism (an under active thyroid gland) whilst around 1% have
thyrotoxicosis (an over active gland). Both hypothyroidism and hyperthyrodism (also known as
thyrotoxicosis) are around 10 times more common in women than men.
How are thyroid problems classified? Hypothyroidism Thyrotoxicosis
Hashimoto's thyroiditis
Hypothyroidism may be classified as follows:
• most common cause in the Graves' disease
• primary hypothyroidism: there is a problem with the thyroid gland itself, for example an developed world
autoimmune disorder affecting thyroid tissue (see below) Most • autoimmune disease, associated with • most common cause of thyrotoxicosis
• secondary hypothyroidism: usually due to a disorder with the pituitary gland common type 1 diabetes mellitus, Addison's • as well as typically features of
(e.g.pituitary apoplexy) or a lesion compressing the pituitary gland cause or pernicious anaemia thyrotoxicosis other features may be
• congenital hypothyroidism: due to a problem with thyroid dysgenesis or thyroid • may cause transient thyrotoxicosis in seen including thyroid eye disease
dyshormonogenesis the acute phase
• 5-10 times more common in women

Whilst there are a number of causes thyrotoxicosis the vast majority are primary in nature. Subacute thyroiditis (de Quervain's)
Congenital thyrotoxicosis is not seen and secondary hyperthyroidism is rare, account for less
than 1% of cases.
• associated with a painful goitre and
raised ESR

What causes thyroid problems?

Riedel thyroiditis

The majority of thyroid problems seen in the developed world are a consequence of Toxic multinodular goitre
autoimmunity. • fibrous tissue replacing the normal
thyroid parenchyma
The table below shows the different autoimmune problems which cause thyroid dysfunction: • causes a painless goitre • autonomously functioning thyroid
nodules that secrete excess thyroid
Other hormones
causes Postpartum thyroiditis

Drugs Drugs

• amiodarone
• lithium
• amiodarone

Iodine deficiency

• the most common cause of

hypothyroidism in the developing
world

It should be remembered that a lot of the conditions mentioned above don't always cause either

hypothyroidism or hyperthyroidism, there is sometimes some overlap, as shown below: Investigations and diagnosis

The principle investigation is 'thyroid function tests', or TFTs for short:

• these primarily look at serum TSH and T4 levels

Symptoms and signs • T3 can be measured but is only useful clinically in a small number of cases
• remember that TSH and T4 levels will often be 'opposite' in cases of primary hypo- or
hyperthyroidism. For example in hypothyroidism the T4 level is low (i.e. not enough
Thyroid disorders can present in a large variety of ways. Often (but not always) the symptoms thyroxine) but the TSH level is high, because the hypothalamus/pituitary has detected
present are the opposite depending on whether the thyroid gland is under or over active, for low levels of T4 and is trying to get the thyroid gland to produce more
example hypothyroidism may result in weight gain whilst thyrotoxicosis normally leads to weight • TSH levels are more sensitive than T4 levels for monitoring patients with existing thyroid
loss problems and are often used to guide treatment

Feature Hypothyroidism Thyrotoxicosis

Weight gain The table below shows how thyroid function tests are interpreted:
Lethargy Weight loss
General 'Manic', restlessness Free
Diagnosis TSH Notes
T4
Cold intolerance Heat intolerance Thyrotoxicosis (e.g. Graves'
Low High
disease)
Palpitations, may even provoke arrhythmias
Cardiac - Primary
e.g. atrial fibrillation
hypothyroidism (e.g. High Low
Dry (anhydrosis), cold, yellowish Hashimoto's thyroiditis)
skin Increased sweating
Secondary hypothyroidism Low Low
Common in hospital inpatients. Changes are reversible upon
Non-pitting oedema (e.g. hands, Pretibial myxoedema: erythematous, oedematous
Skin Sick euthyroid syndrome Low Low recovery from the systemic illness and no treatment is usually
face) lesions above the lateral malleoli
needed
Dry, coarse scalp hair, loss of lateral Thyroid acropachy: clubbing This is a common finding and represents patients who are 'on
aspect of eyebrows the way' to developing hypothyroidism but still have normal
Subclinical hypothyroidism High Normal
thyroxine levels. Note how the TSH levels, as mentioned above,
Gastrointestinal Constipation Diarrhoea
are a more sensitive and early marker of thyroid problems
Gynaecological Menorrhagia Oligomenorrhea
Patients who are poorly compliant may only take their thyroxine
Decreased deep tendon reflexes Anxiety
Poor compliance with in the days before a routine blood test. The thyroxine levels are
Neurological High Normal
thyroxine hence normal but the TSH 'lags' and reflects longer term low
Carpal tunnel syndrome Tremor
thyroxine levels

• Anti-thyroid peroxidase (anti-TPO) antibodies

• TSH receptor antibodies
• Thyroglobulin antibodies

There is significant overlap between the type of antibodies present and particular diseases, but
generally speaking TSH receptor antibodies are present in around 90-100% of patients with
Graves' disease and anti-TPO antibodies are seen in around 90% of patients with Hashimoto's • radioiodine treatment may increase the inflammatory symptoms seen in thyroid eye
thyroiditis. disease. In a recent study of patients with Graves' disease around 15% developed, or had
worsening of, eye disease. Prednisolone may help reduce the risk
Other tests include:

• nuclear scintigraphy; toxic multinodular goitre reveals patchy uptake Features

• the patient may be eu-, hypo- or hyperthyroid at the time of presentation

• exophthalmos
• conjunctival oedema
Treatment • optic disc swelling
• ophthalmoplegia
This clearly depends on the cause. For patients with hypothyrodism thyroxine is given in the • inability to close the eyelids may lead to sore, dry eyes. If severe and untreated patients
form of levothyroxine to replace the underlying deficiency. can be at risk of exposure keratopathy

Patients with thyrotoxicosis may be treated with:

Management
• propranolol: this is often used at the time of diagnosis to control thyrotoxic symptoms
• topical lubricants may be needed to help prevent corneal inflammation caused by
such as tremor
exposure
• carbimazole: blocks thyroid peroxidase from coupling and iodinating the tyrosine
• steroids
residues on thyroglobulin → reducing thyroid hormone production. Agranulocytosis is an
• radiotherapy
important adverse effect to be aware of
• surgery
• radioiodine treatment

Thyroid eye disease Carbimazole

Carbimazole is used in the management of thyrotoxicosis. It is typically given in high doses for 6
Thyroid eye disease affects between 25-50% of patients with Graves' disease.
weeks until the patient becomes euthyroid before being reduced.
Pathophysiology
Mechanism of action
• it is thought to be caused by an autoimmune response against an autoantigen, possibly
• blocks thyroid peroxidase from coupling and iodinating the tyrosine residues on
the TSH receptor → retro-orbital inflammation
thyroglobulin → reducing thyroid hormone production
• the inflammation results in glycosaminoglycan and collagen deposition in the muscles
• 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
Prevention to T3

• smoking is the most important modifiable risk factor for the development of thyroid eye
disease

• heart failure
Adverse effects • abnormal liver function test - jaundice may be seen clinically

• agranulocytosis Management:
• crosses the placenta, but may be used in low doses during pregnancy
• symptomatic treatment e.g. paracetamol
• treatment of underlying precipitating event
• beta-blockers: typically IV propranolol
Monitoring patients with established thyroid eye disease • anti-thyroid drugs: e.g. methimazole or propylthiouracil
• Lugol's iodine
For patients with established thyroid eye disease the following symptoms/signs should indicate • dexamethasone - e.g. 4mg IV qds - blocks the conversion of T4 to T3
the need for urgent review by an ophthalmologist (see EUGOGO guidelines):
Thyrotoxicosis: causes and investigation
• unexplained deterioration in vision Graves' disease accounts for around 50-60% of cases of thyrotoxicosis.
• awareness of change in intensity or quality of colour vision in one or both eyes
• history of eye suddenly 'popping out' (globe subluxation) Causes
• obvious corneal opacity
• cornea still visible when the eyelids are closed
• disc swelling • Graves' disease
• toxic nodular goitre
• acute phase of subacute (de Quervain's) thyroiditis
• acute phase of post-partum thyroiditis
• acute phase of Hashimoto's thyroiditis (later results in hypothyroidism)
Thyroid storm • amiodarone therapy
Thyroid storm is a rare but life-threatening complication of thyrotoxicosis. It is typically seen in
patients with established thyrotoxicosis and is rarely seen as the presenting feature. Iatrogenic
Investigation
thyroxine excess does not usually result in thyroid storm.

Precipitating events:
• TSH down, T4 and T3 up
• thyroid autoantibodies
• thyroid or non-thyroidal surgery
• other investigations are not routinely done but includes isotope scanning
• trauma
• infection
• acute iodine load e.g. CT contrast media

Toxic multinodular goitre

Clinical features include: Toxic multinodular goitre describes a thyroid gland that contains a number of autonomously
functioning thyroid nodules resulting in hyperthyroidism.
• fever > 38.5ºC
• tachycardia Nuclear scintigraphy reveals patchy uptake.
• confusion and agitation
• nausea and vomiting The treatment of choice is radioiodine therapy.
• hypertension
 • bladder retraining (lasts for a minimum of 6 weeks, the idea is to gradually increase the
Urinary incontinence intervals between voiding)
Urinary incontinence (UI) is a common problem, affecting around 4-5% of the population. It is • bladder stabilising drugs: antimuscarinics are first-line
more common in elderly females. o NICE recommend oxybutynin (immediate release), tolterodine (immediate
release) or darifenacin (once daily preparation)
Risk factors o Immediate release oxybutynin should, however, be avoided in 'frail older women'
• mirabegron (a beta-3 agonist) may be useful if there is concern about anticholinergic
• advancing age side-effects in frail elderly patients
• previous pregnancy and childbirth
• high body mass index
• hysterectomy If stress incontinence is predominant:
• family history
• pelvic floor muscle training
o NICE recommend at least 8 contractions performed 3 times per day for a
Classification minimum of 3 months
• surgical procedures: e.g. retropubic mid-urethral tape procedures
• overactive bladder (OAB)/urge incontinence • duloxetine may be offered to women if they decline surgical procedures
o due to detrusor overactivity o a combined noradrenaline and serotonin reuptake inhibitor
o the urge to urinate is quickly followed by uncontrollable leakage ranging from a o mechanism of action: increased synaptic concentration of noradrenaline and
few drops to complete bladder emptying serotonin within the pudendal nerve → increased stimulation of urethral striated
• stress incontinence: leaking small amounts when coughing or laughing muscles within the sphincter → enhanced contraction
• mixed incontinence: both urge and stress
• overflow incontinence: due to bladder outlet obstruction, e.g. due to prostate Uterine fibroids
enlargement Fibroids are benign smooth muscle tumours of the uterus. They are thought to occur in around
• functional incontinence 20% of white and around 50% of black women in the later reproductive years.
o comorbid physical conditions impair the patient’s ability to get to a bathroom in
time Associations
o causes include dementia, sedating medication and injury/illness resulting in
decreased ambulation • more common in Afro-Caribbean women
• rare before puberty, develop in response to oestrogen

Initial investigation
Features
• bladder diaries should be completed for a minimum of 3 days
• vaginal examination to exclude pelvic organ prolapse and ability to initiate voluntary • may be asymptomatic
contraction of pelvic floor muscles ('Kegel' exercises) • menorrhagia
• urine dipstick and culture o may result in iron-deficiency anaemia
• urodynamic studies • lower abdominal pain: cramping pains, often during menstruation
• bloating
• urinary symptoms, e.g. frequency, may occur with larger fibroids
Management depends on whether urge or stress UI is the predominant picture. If urge • subfertility
incontinence is predominant: • rare features:
o polycythaemia secondary to autonomous production of erythropoietin

Diagnosis Some of the complications such as subfertility and iron-deficiency anaemia have been
mentioned previously.
• transvaginal ultrasound
Other complications

• red degeneration - haemorrhage into tumour - commonly occurs during pregnancy

Management

Asymptomatic fibroids Water deprivation test

The water deprivation test is designed to help evaluate patients who have polydipsia.
• no treatment is needed other than periodic review to monitor size and growth
Method

Management of menorrhagia secondary to fibroids • prevent patient drinking water

• ask the patient to empty their bladder
• levonorgestrel intrauterine system (LNG-IUS) • hourly urine and plasma osmolalities
o useful if the woman also requires contraception
o cannot be used if there is distortion of the uterine cavity
• NSAIDs e.g. mefenamic acid Starting plasma osm. Final urine osm. Urine osm. post-DDAVP
• tranexamic acid Normal Normal > 600 > 600
• combined oral contraceptive pill Psychogenic polydipsia Low > 400 > 400
• oral progestogen Cranial DI High < 300 > 600
• injectable progestogen Nephrogenic DI High < 300 < 300

Treatment to shrink/remove fibroids >>Alcohol bingeing can lead to ADH suppression in the posterior pituitary gland subsequently
leading to polyuria. This is similar to cranial diabetes insipidus or partial cranial diabetes
• medical
o GnRH agonists may reduce the size of the fibroid but are typically useful for insipidus and typically causes hypernatremia with a raised serum osmolality and decreased urine
short-term treatment osmolality.
o ulipristal acetate has been in the past but not currently due to concerns about
rare but serious liver toxicity.
• surgical
o myomectomy: this may be performed abdominally, laparoscopically or
hysteroscopically
o hysteroscopic endometrial ablation
o hysterectomy
• uterine artery embolization

Prognosis and complications

Fibroids generally regress after the menopause.