Metabolic Medicine Flashcards
Acromegaly: features
In acromegaly there is excess growth hormone secondary to a pituitary adenoma in over 95% of cases. A minority of cases are caused by ectopic GHRH or GH production by tumours e.g. pancreatic.
Features
coarse facial appearance, spade-like hands, increase in shoe size
large tongue, prognathism, interdental spaces
excessive sweating and oily skin: caused by sweat gland hypertrophy
features of pituitary tumour: hypopituitarism, headaches, bitemporal hemianopia
raised prolactin in 1/3 of cases → galactorrhoea
6% of patients have MEN-1
Complications
hypertension
diabetes (>10%)
cardiomyopathy
colorectal cancer
Addison’s disease
Autoimmune destruction of the adrenal glands is the commonest cause of primary hypoadrenalism in the UK, accounting for 80% of cases. This is termed Addison’s disease and results in reduced cortisol and aldosterone being produced.
Features
lethargy, weakness, anorexia, nausea & vomiting, weight loss, ‘salt-craving’
hyperpigmentation (especially palmar creases)*, vitiligo, loss of pubic hair in women, hypotension, hypoglycaemia
hyponatraemia and hyperkalaemia may be seen
crisis: collapse, shock, pyrexia
Other causes of hypoadrenalism
Primary causes
tuberculosis
metastases (e.g. bronchial carcinoma)
meningococcal septicaemia (Waterhouse-Friderichsen syndrome)
HIV
antiphospholipid syndrome
Secondary causes
pituitary disorders (e.g. tumours, irradiation, infiltration)
Exogenous glucocorticoid therapy
*Primary Addison’s is associated with hyperpigmentation whereas secondary adrenal insufficiency is not
Addison’s disease management - hydrocortisone + fludrocortisone
Important for meLess important
Addison’s disease: management
Patients who have Addison’s disease are usually given both glucocorticoid and mineralocorticoid replacement therapy.
This usually means that patients take a combination of:
hydrocortisone: usually given in 2 or 3 divided doses. Patients typically require 20-30 mg per day, with the majority given in the morning dose
fludrocortisone
Patient education is important:
emphasise the importance of not missing glucocorticoid doses
consider MedicAlert bracelets and steroid cards
discuss how to adjust the glucocorticoid dose during an intercurrent illness (see below)
Management of intercurrent illness
in simple terms the glucocorticoid dose should be doubled
the Addison’s Clinical Advisory Panel have produced guidelines detailing particular scenarios - please see the CKS link for more details
Carbimazole
Carbimazole is used in the management of thyrotoxicosis. It is typically given in high doses for 6 weeks until the patient becomes euthyroid before being reduced.
Mechanism of action
blocks thyroid peroxidase from coupling and iodinating the tyrosine residues on thyroglobulin → reducing thyroid hormone production
in contrast propylthiouracil as well as this central mechanism of action also has a peripheral action by inhibiting 5’-deiodinase which reduces peripheral conversion of T4 to T3
Adverse effects
agranulocytosis
crosses the placenta, but may be used in low doses during pregnancy
Corticosteroids
Corticosteroids are amongst the most commonly prescribed therapies in clinical practice. They are used both systemically (oral or intravenous) or locally (skin creams, inhalers, eye drops, intra-articular). They augment and in some cases replace the natural glucocorticoid and mineralocorticoid activity of endogenous steroids.
The relative glucocorticoid and mineralocorticoid activity of commonly used steroids is shown below:
Fludrocortisone
Minimal glucocorticoid activity, very high mineralocorticoid activity,
Hydrocortisone
Glucocorticoid activity, high mineralocorticoid activity,
Prednisolone
Predominant glucocorticoid activity, low mineralocorticoid activity
Dexamethasone / Betmethasone
Very high glucocorticoid activity, minimal mineralocorticoid activity
Side-effects
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.
Glucocorticoid side-effects
endocrine: impaired glucose regulation, increased appetite/weight gain, hirsutism, hyperlipidaemia
Cushing’s syndrome: moon face, buffalo hump, striae
musculoskeletal: osteoporosis, proximal myopathy, avascular necrosis of the femoral head
immunosuppression: increased susceptibility to severe infection, reactivation of tuberculosis
psychiatric: insomnia, mania, depression, psychosis
gastrointestinal: peptic ulceration, acute pancreatitis
ophthalmic: glaucoma, cataracts
suppression of growth in children
intracranial hypertension
neutrophilia
Mineralocorticoid side-effects
fluid retention
hypertension
Selected points on the use of corticosteroids:
patients on long-term steroids should have their doses doubled during intercurrent illness
the BNF suggests gradual withdrawal of systemic corticosteroids if patients have: received more than 40mg prednisolone daily for more than one week, received more than 3 weeks treatment or recently received repeated courses
Cushing’s syndrome: causes
It should be noted that exogenous causes of Cushing’s syndrome (e.g. glucocorticoid therapy) are far more common than endogenous ones.
ACTH dependent causes
Cushing’s disease (80%): pituitary tumour secreting ACTH producing adrenal hyperplasia
ectopic ACTH production (5-10%): e.g. small cell lung cancer
ACTH independent causes
iatrogenic: steroids
adrenal adenoma (5-10%)
adrenal carcinoma (rare)
Carney complex: syndrome including cardiac myxoma
micronodular adrenal dysplasia (very rare)
Pseudo-Cushing’s mimics Cushing’s
often due to alcohol excess or severe depression
causes false positive dexamethasone suppression test or 24 hr urinary free cortisol
insulin stress test may be used to differentiate
Diabetes mellitus (type 2): diagnosis
The diagnosis of type 2 diabetes mellitus can be made by either a plasma glucose or a HbA1c sample. Diagnostic criteria vary according to whether the patient is symptomatic (polyuria, polydipsia etc) or not.
If the patient is symptomatic:
fasting glucose greater than or equal to 7.0 mmol/l
random glucose greater than or equal to 11.1 mmol/l (or after 75g oral glucose tolerance test)
If the patient is asymptomatic the above criteria apply but must be demonstrated on two separate occasions.
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
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 cell turnover (see below)
Conditions where HbA1c may not be used for diagnosis:
haemoglobinopathies
haemolytic anaemia
untreated iron deficiency anaemia
suspected gestational diabetes
children
HIV
chronic kidney disease
people taking medication that may cause hyperglycaemia (for example corticosteroids)
Impaired fasting glucose and impaired glucose tolerance
A fasting glucose greater than or equal to 6.1 but less than 7.0 mmol/l implies impaired fasting glucose (IFG)
Impaired glucose tolerance (IGT) is defined as fasting plasma glucose less than 7.0 mmol/l and OGTT 2-hour value greater than or equal to 7.8 mmol/l but less than 11.1 mmol/l
Diabetes UK suggests:
‘People with IFG should then be offered an oral glucose tolerance test to rule out a diagnosis of diabetes. A result below 11.1 mmol/l but above 7.8 mmol/l indicates that the person doesn’t have diabetes but does have IGT.’
Diabetes mellitus (type 2): management
NICE updated its guidance on the management of type 2 diabetes mellitus (T2DM) in 2015. Key points are listed below:
HbA1c targets have changed. They are now dependent on what antidiabetic drugs a patient is receiving and other factors such as frailty
there is more flexibility in the second stage of treating patients (i.e. after metformin has been started) - you now have a choice of 4 oral antidiabetic agents
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 use of foods marketed specifically at people with diabetes
initial target weight loss in an overweight person is 5-10%
HbA1c targets
This is area which has changed in 2015
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 consideration for people who are older or frail, for adults with type 2 diabetes’
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 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
Patient already on treatment
Management of T2DM
HbA1c target
Already on one drug, but HbA1c has risen to 58 mmol/mol (7.5%)
53 mmol/mol (7.0%)
Diabetes Mellitus - Beyond metformin
Tolerates metformin:
metformin is still first-line and should be offered if the HbA1c rises to 48 mmol/mol (6.5%)* on lifestyle interventions
if the HbA1c has risen to 58 mmol/mol (7.5%) then a second drug should be added from the following list:
→ sulfonylurea
→ gliptin
→ pioglitazone
→ SGLT-2 inhibitor
if despite this the HbA1c rises to, or remains above 58 mmol/mol (7.5%) then triple therapy with one of the following combinations should be offered:
→ metformin + gliptin + sulfonylurea
→ metformin + pioglitazone + sulfonylurea
→ metformin + sulfonylurea + SGLT-2 inhibitor
→ metformin + pioglitazone + SGLT-2 inhibitor
→ OR insulin therapy should be considered
Criteria for glucagon-like peptide1 (GLP1) mimetic (e.g. exenatide)
if triple therapy is not effective, not tolerated or contraindicated then NICE advise that we consider combination therapy with metformin, a sulfonylurea and a glucagonlike peptide1 (GLP1) mimetic if:
→ BMI >= 35 kg/m² and specific psychological or other medical problems associated with obesity or
→ BMI < 35 kg/m² and for whom insulin therapy would have significant occupational implications or
weight loss would benefit other significant obesityrelated 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
Cannot tolerate metformin or contraindicated
if the HbA1c rises to 48 mmol/mol (6.5%)* on lifestyle interventions, consider one of the following:
→ sulfonylurea
→ gliptin
→ pioglitazone
if the HbA1c has risen to 58 mmol/mol (7.5%) then a one of the following combinations should be used:
→ gliptin + pioglitazone
→ gliptin + sulfonylurea
→ pioglitazone + sulfonylurea
if despite this the HbA1c rises to, or remains above 58 mmol/mol (7.5%) then consider insulin therapy
Starting insulin
metformin should be continued. In terms of other drugs NICE advice: ‘Review the continued need for other blood glucose lowering therapies’
NICE recommend starting with human NPH insulin (isophane, intermediate acting) taken at bed-time or twice daily according to need
Risk factor modification
Blood pressure
target is < 140/80 mmHg (or < 130/80 mmHg if end-organ damage is present)
ACE inhibitors are first-line
Antiplatelets
should not be offered unless a patient has existing cardiovascular disease
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 on
Thiazolidinediones
Thiazolidinediones are a class of agents used in the treatment of type 2 diabetes mellitus. They are agonists to the PPAR-gamma receptor and reduce peripheral insulin resistance. Rosiglitazone was withdrawn in 2010 following concerns about the cardiovascular side-effect profile.
The PPAR-gamma receptor is an intracellular nuclear receptor. It’s natural ligands are free fatty acids and it is thought to control adipocyte differentiation and function.
Adverse effects
weight gain
liver impairment: monitor LFTs
fluid retention - therefore contraindicated in heart failure. The risk of fluid retention is increased if the patient also takes insulin
recent studies have indicated an increased risk of fractures
bladder cancer: recent studies have shown an increased risk of bladder cancer in patients taking pioglitazone (hazard ratio 2.64)
Diabetes mellitus DM1
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 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 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 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 pregnancy, during pregnancy and while breastfeeding
Blood glucose targets
5-7 mmol/l on waking and
4-7 mmol/l before meals at other times of the day
Type of insulin
offer multiple daily injection basal–bolus insulin regimens, rather than twice‑daily mixed 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
offer rapid‑acting insulin analogues injected before meals, rather than rapid‑acting soluble human or animal insulins, for mealtime insulin replacement for adults with type 1 diabetes
Metformin
NICE recommend considering adding metformin if the BMI >= 25 kg/m²
Diabetic foot disease
Diabetic foot disease is an important complication of diabetes mellitus which should be screen for on a regular basis. NICE produced guidelines relating to diabetic foot disease in 2015.
It occurs secondary to two main factors:
neuropathy: resulting in loss of protective sensation (e.g. not noticing a stone in the shoe), Charcot’s arthropathy, dry skin
peripheral arterial disease: diabetes is a risk factor for both macro and microvascular ischaemia
Presentations
neuropathy: loss of sensation
ischaemia: absent foot pulses, reduced ankle-brachial pressure index (ABPI), intermittent claudication
complications: calluses, ulceration, Charcot’s arthropathy, cellulitis, osteomyelitis, gangrene
All patients with diabetes should be screened for diabetic foot disease on at least an annual basis
screening for ischaemia: done by palpating for both the dorsalis pedis pulse and posterial tibial artery pulse
screening for neuropathy: a 10 g monofilament is used on various parts of the sole of the foot
NICE recommend that we risk stratify patients:
Low risk
• no risk factors except callus alone
Moderate risk
- deformity or
- neuropathy or
- non-critical limb ischaemia.
High risk
- previous ulceration or
- previous amputation or
- on renal replacement therapy or
- neuropathy and non-critical limb ischaemia together or
- neuropathy in combination with callus and/or deformity or
- non-critical limb ischaemia in combination with callus and/or deformity.
All patients who are moderate or high risk (I.e. any problems other than simple calluses) should be followed up regularly by the local diabetic foot centre.
Diabetic neuropathy
Diabetes typically leads to sensory loss and not motor loss in peripheral neuropathy. Painful diabetic neuropathy is a common problem in clinical practice.
NICE updated it’s guidance on the management of neuropathic pain in 2013. Diabetic neuropathy is now managed in the same way as other forms of neuropathic pain:
first-line treatment: amitriptyline, duloxetine, gabapentin or pregabalin
if the first-line drug treatment does not work try one of the other 3 drugs
tramadol may be used as ‘rescue therapy’ for exacerbations of neuropathic pain
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
Gastrointestinal autonomic neuropathy
Gastroparesis
symptoms include erratic blood glucose control, bloating and vomiting
management options include metoclopramide, domperidone or erythromycin (prokinetic agents)
Chronic diarrhoea
often occurs at night
Gastro-oesophageal reflux disease
caused by decreased lower esophageal sphincter (LES) pressure
Diabetic ketoacidosis
Diabetic ketoacidosis (DKA) may be a complication existing type 1 diabetes mellitus or be the first presentation, accounting for around 6% of cases. Rarely, under conditions of extreme stress, patients with type 2 diabetes mellitus may also develop DKA.
Whilst DKA remains a serious condition mortality rates have decreased from 8% to under 1% in the past 20 years.
Pathophysiology
DKA is caused by uncontrolled lipolysis (not proteolysis) which results in an excess of free fatty acids that are ultimately converted to ketone bodies
The most common precipitating factors of DKA are infection, missed insulin doses and myocardial infarction.
Features
abdominal pain
polyuria, polydipsia, dehydration
Kussmaul respiration (deep hyperventilation)
Acetone-smelling breath (‘pear drops’ smell)
Diagnostic criteria
American Diabetes Association (2009)
Joint British Diabetes Societies (2013)
Key points
glucose > 13.8 mmol/l
pH < 7.30
serum bicarbonate <18 mmol/l
anion gap > 10
ketonaemia
Key points
glucose > 11 mmol/l or known diabetes mellitus
pH < 7.3
bicarbonate < 15 mmol/l
ketones > 3 mmol/l or urine ketones ++ on dipstick
Management
fluid replacement: most patients with DKA are deplete around 5-8 litres. Isotonic saline is used initially. Please see an example fluid regime below.
insulin: an intravenous infusion should be started at 0.1 unit/kg/hour. Once blood glucose is < 15 mmol/l an infusion of 5% dextrose should be started
correction of hypokalaemia
long-acting insulin should be continued, short-acting insulin should be stopped
Glycosylated haemoglobin
Glycosylated haemoglobin (HbA1c) is the most widely used measure of long-term glycaemic control in diabetes mellitus. HbA1c is produced by the glycosylation of haemoglobin at a rate proportional to the glucose concentration. The level of HbA1c therefore is dependant on
red blood cell lifespan
average blood glucose concentration
A number of conditions can interfere with accurate HbA1c interpretation:
Lower-than-expected levels of HbA1c (due to reduced red blood cell lifespan)
Higher-than-expected levels of HbA1c (due to increased red blood cell lifespan)
Sickle-cell anaemia
GP6D deficiency
Hereditary spherocytosis
Vitamin B12/folic acid deficiency
Iron-deficiency anaemia
Splenectomy
HbA1c is generally thought to reflect the blood glucose over the previous ‘3 months’ although there is some evidence it is weighed more strongly to glucose levels of the past 2-4 weeks. NICE recommend ‘HbA1c should be checked every 3-6 months until stable, then 6 monthly’.
The relationship between HbA1c and average blood glucose is complex but has been studied by the Diabetes Control and Complications Trial (DCCT). A new internationally standardised method for reporting HbA1c has been developed by the International Federation of Clinical Chemistry (IFCC). This will report HbA1c in mmol per mol of haemoglobin without glucose attached.
From the above we can see that average plasma glucose = (2 * HbA1c) - 4.5
Graves’ disease: management
Despite many trials there is no clear guidance on the optimal management of Graves’ disease. Treatment options include titration of anti-thyroid drugs (ATDs, for example carbimazole), block-and-replace regimes, radioiodine treatment and surgery. Propranolol is often given initially to block adrenergic effects
ATD titration
carbimazole is started at 40mg and reduced gradually to maintain euthyroidism
typically continued for 12-18 months
patients following an ATD titration regime have been shown to suffer fewer side-effects than those on a block-and-replace regime
Block-and-replace
carbimazole is started at 40mg
thyroxine is added when the patient is euthyroid
treatment typically lasts for 6-9 months
The major complication of carbimazole therapy is agranulocytosis
Radioiodine treatment
contraindications include pregnancy (should be avoided for 4-6 months following treatment) and age < 16 years. Thyroid eye disease is a relative contraindication, as it may worsen the condition
the proportion of patients who become hypothyroid depends on the dose given, but as a rule the majority of patient will require thyroxine supplementation after 5 years
Hashimoto’s thyroiditis
Hashimoto’s thyroiditis (chronic autoimmune thyroiditis) is an autoimmune disorder of the thyroid gland. It is typically associated with hypothyroidism although there may be a transient thyrotoxicosis in the acute phase. It is 10 times more common in women
Features
features of hypothyroidism
goitre: firm, non-tender
anti-thyroid peroxidase and also anti-Tg antibodies
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
Subacute thyroiditis (de Quervain's) Riedel thyroiditis After thyroidectomy or radioiodine treatment Drug therapy (e.g. lithium, amiodarone or anti-thyroid drugs such as carbimazole) Dietary iodine deficiency
Secondary hypothyroidism (rare)
From pituitary failure
Other associated conditions
Down’s syndrome
Turner’s syndrome
coeliac disease
Hypothyroidism management
Key points
initial starting dose of levothyroxine should be lower in elderly patients and those with ischaemic heart disease. The BNF recommends that for patients with cardiac disease, severe hypothyroidism or patients over 50 years the initial starting dose should be 25mcg od with dose slowly titrated. Other patients should be started on a dose of 50-100mcg od
following a change in thyroxine dose thyroid function tests should be checked after 8-12 weeks
the therapeutic goal is ‘normalisation’ of the thyroid stimulating hormone (TSH) level. As the majority of unaffected people have a TSH value 0.5-2.5 mU/l it is now thought preferable to aim for a TSH in this range
women with established hypothyroidism who become pregnant should have their dose increased ‘by at least 25-50 micrograms levothyroxine’* due to the increased demands of pregnancy. The TSH should be monitored carefully, aiming for a low-normal value
there is no evidence to support combination therapy with levothyroxine and liothyronine
Side-effects of thyroxine therapy
hyperthyroidism: due to over treatment
reduced bone mineral density
worsening of angina
atrial fibrillation
Interactions
iron, calcium carbonate
absorption of levothyroxine reduced, give at least 4 hours apart
Subacute (De Quervain’s) thyroiditis
Subacute thyroiditis (also known as De Quervain’s thyroiditis and subacute granulomatous thyroiditis) is thought to occur following viral infection and typically presents with hyperthyroidism.
There are typically 4 phases;
phase 1 (lasts 3-6 weeks): hyperthyroidism, painful goitre, raised ESR
phase 2 (1-3 weeks): euthyroid
phase 3 (weeks - months): hypothyroidism
phase 4: thyroid structure and function goes back to normal
Investigations
thyroid scintigraphy: globally reduced uptake of iodine-131
Management
usually self-limiting - most patients do not require treatment
thyroid pain may respond to aspirin or other NSAIDs
in more severe cases steroids are used, particularly if hypothyroidism develops
