Endocrine Flashcards
fxWhat is primary vs secondary vs congenital hypothyroidism?
primary hypothyroidism: there is a problem with the thyroid gland itself, for example an autoimmune disorder affecting thyroid tissue (see below)
secondary hypothyroidism: usually due to a disorder with the pituitary gland (e.g.pituitary apoplexy) or a lesion compressing the pituitary gland
congenital hypothyroidism: due to a problem with thyroid dysgenesis or thyroid dyshormonogenesis
What is the most common cause of hypothyroidism in the developed vs the devoloping world??
Hashimoto’s thyroiditis
most common cause in the developed world autoimmune disease, associated with type 1 diabetes mellitus, Addison's or pernicious anaemia may cause transient thyrotoxicosis in the acute phase 5-10 times more common in women
Iodine deficiency
the most common cause of hypothyroidism in the developing world
What is hashimotos thyroiditis? what is found o/e? what antibodies are assoc.?
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 (TPO) and also anti-thyroglobulin (Tg) antibodies
What associations are there with hashimotos thyroiditis?
other autoimmune conditions e.g. coeliac disease, type 1 diabetes mellitus, vitiligo
Hashimoto’s thyroiditis is associated with the development of MALT lymphoma
What diagnosis would be likely if there was a painful goitre and raised ESR with hypothyroidism?
Subacute thyroiditis (de Quervain’s)
associated with a painful goitre and raised ESR
What is subacute thyroiditis? what are the four phases?
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
What are the investigations and management of subacute thyroiditis?
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
What is riedel thyroiditis? What does this cause on examination?
Riedel thyroiditis
fibrous tissue replacing the normal thyroid parenchyma causes a painless goitre
On examination a hard, fixed, painless goitre is noted. It is usually seen in middle-aged women. It is associated with retroperitoneal fibrosis.
How can pregnancy affect thyroid function?
Postpartum thyroiditis - hypothyroidism
What is the most common cause of hyperthyroidism in pregnancy?
What is the management?
Graves’ disease is the most common cause of thyrotoxicosis in pregnancy. It is also recognised that activation of the TSH receptor by HCG may also occur - often termed transient gestational hyperthyroidism. HCG levels will fall in the second and third trimester
Management
propylthiouracil has traditionally been the antithyroid drug of choice however, propylthiouracil is associated with an increased risk of severe hepatic injury 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 associated with an increased risk of congenital abnormalities. At the beginning of the 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 thyrotrophin receptor stimulating antibodies should be checked at 30-36 weeks gestation - helps to determine the risk of neonatal thyroid problems block-and-replace regimes should not be used in pregnancy radioiodine therapy is contraindicated
How is hypothyroidism managed in pregnancy?
Key points
thyroxine is safe during pregnancy
serum thyroid-stimulating hormone measured in each trimester and 6-8 weeks post-partum
women require an increased dose of thyroxine during pregnancy
by up to 50% as early as 4-6 weeks of pregnancy
breastfeeding is safe whilst on thyroxine
What drugs can cause thyroid dysfunctions
Drugs
lithium - hypo amiodarone - either
What is the most common cause of hyperthyroidism?
Graves’ disease
most common cause of thyrotoxicosis as well as typically features of thyrotoxicosis other features may be seen including thyroid eye disease It is typically seen in women aged 30-50 years
What 3 features are seen in graves but not in other forms of graves disease?
Features seen in Graves’ but not in other causes of thyrotoxicosis
eye signs (30% of patients)
exophthalmos
ophthalmoplegia
pretibial myxoedema
thyroid acropachy, a triad of:
digital clubbing
soft tissue swelling of the hands and feet
periosteal new bone formation
What autoantibodies are found in graves disease? what is found on thyroid scintigraphy?
Autoantibodies
TSH receptor stimulating antibodies (90%) anti-thyroid peroxidase antibodies (75%)
Thyroid scintigraphy
diffuse, homogenous, increased uptake of radioactive iodine
What is the general management of grave’s disease?
Anti-thyroid drugs have emerged as the most popular first-line therapy for Graves’ disease in 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
propranolol is used to help block the adrenergic effects
NICE Clinical Knowledge Summaries recommended that patients with Graves’ disease are referred to secondary care for ongoing treatment.
NICE suggest carbimazole should be considered in primary care if patients symptoms are not controlled with propanolol
Describe two regimes of anti-thyroid drug therapy for graves disease?
ATD therapy
carbimazole is started at 40mg and reduced gradually to maintain euthyroidism
typically continued for 12-18 months
the major complication of carbimazole therapy is agranulocytosis
an alternative regime is termed 'block-and-replace'
carbimazole is started at 40mg
thyroxine is added when the patient is euthyroid
treatment typically lasts for 6-9 months
patients following an ATD titration regime have been shown to suffer fewer side-effects than those on a block-and-replace regime
What is the mechanism of action of carbimazole? what adverse effects exist?
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
When is radioiodine treatment used for graves disease? what are contraindications?
Radioiodine treatment
often used in patients who relapse following ATD therapy or are resistant to primary ATD 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
What is a toxic multinodular goitre? does this cause hypo or hyper thyroidism?
Toxic multinodular goitre
autonomously functioning thyroid nodules that secrete excess thyroid hormones
What is sick euthyroid and what TFTs are assoc?
Common in hospital inpatients. Changes are reversible upon recovery from the systemic illness and no treatment is usually needed
T4 - low
TSH - low
What are the 3 main types of thyroid antibody?
A number of thyroid autoantibodies can be tested for (remember the majority of thyroid disorders are autoimmune). The 3 main types are:
Anti-thyroid peroxidase (anti-TPO) antibodies TSH receptor antibodies Thyroglobulin antibodies
Which antibodies are seen in Graves disease? which ones are assoc. with hashimoto?
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 thyroiditis.
What is seen on nuclear scintigraphy with toxic multinodular goitre?
Other tests include:
nuclear scintigraphy; toxic multinodular goitre reveals patchy uptake
What is the treatment of thyrotoxicosis?
Patients with thyrotoxicosis may be treated with:
propranolol: this is often used at the time of diagnosis to control thyrotoxic symptoms such as tremor carbimazole: blocks thyroid peroxidase from coupling and iodinating the tyrosine residues on thyroglobulin → reducing thyroid hormone production. Agranulocytosis is an important adverse effect to be aware of radioiodine treatment
Who is affected by thyroid eye disease and why does this occur?
Thyroid eye disease affects between 25-50% of patients with Graves’ disease.
Pathophysiology
it is thought to be caused by an autoimmune response against an autoantigen, possibly the TSH receptor → retro-orbital inflammation the inflammation results in glycosaminoglycan and collagen deposition in the muscles
What can be done to prevent thryoid eye disease?
Prevention
smoking is the most important modifiable risk factor for the development of thyroid eye disease radioiodine treatment may increase the inflammatory symptoms seen in thyroid eye disease. In a recent study of patients with Graves' disease around 15% developed, or had worsening of, eye disease. Prednisolone may help reduce the risk
What features are seen with thyroid eye disease?
Features
the patient may be eu-, hypo- or hyperthyroid at the time of presentation exophthalmos conjunctival oedema optic disc swelling ophthalmoplegia inability to close the eyelids may lead to sore, dry eyes. If severe and untreated patients can be at risk of exposure keratopathy
What symptoms/signs of thyroid eye disease would prompt urgent opthalmologist review?
For patients with established thyroid eye disease the following symptoms/signs should indicate the need for urgent review by an ophthalmologist (see EUGOGO guidelines):
unexplained deterioration in vision awareness of change in intensity or quality of colour vision in one or both eyes history of eye suddenly 'popping out' (globe subluxation) obvious corneal opacity cornea still visible when the eyelids are closed disc swelling
What is the management of thyroid eye disease?
Management
topical lubricants may be needed to help prevent corneal inflammation caused by exposure steroids radiotherapy surgery
What is subclinical hyperthyroidism? how is this managed?
Subclinical hyperthyroidism is an entity which is gaining increasing recognition. It is defined as:
normal serum free thyroxine and triiodothyronine levels with a thyroid stimulating hormone (TSH) below normal range (usually < 0.1 mu/l)
Management
TSH levels often revert to normal - therefore levels must be persistently low to warrant intervention a reasonable treatment option is a therapeutic trial of low-dose antithyroid agents for approximately 6 months in an effort to induce a remission
what is the risk of progressing to hypothyroidism in subclinical hypothyroidism?
Significance
risk of progressing to overt hypothyroidism is 2-5% per year (higher in men) risk increased by the presence of thyroid autoantibodies
What is the management of subclinical hypothyroidism?
TSH is > 10mU/L and the free thyroxine level is within the normal range
consider offering levothyroxine if the TSH level is > 10 mU/L on 2 separate occasions 3 months apart
TSH is between 5.5 - 10mU/L and the free thyroxine level is within the normal range
if < 65 years consider offering a 6-month trial of levothyroxine if:
the TSH level is 5.5 - 10mU/L on 2 separate occasions 3 months apart,and
there are symptoms of hypothyroidism
in older people (especially those aged over 80 years) follow a 'watch and wait' strategy is often used
if asymptomatic people, observe and repeat thyroid function in 6 months
What is the management of hypothyroidism? What is the therapeutic goal? How to manage pregnant ladies with established hypothyroidism?
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
What are the side effects of thyroxine therapy? What interactions exist?
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
What investigations are indicated when considering T1DM? 4. Is HbA1c useful?
urine should be dipped for glucose and ketones
fasting glucose and random glucose
HbA1c is not as useful for patients with a possible or suspected diagnosis of T1DM as it may not accurately reflect a recent rapid rise in serum glucose
C-peptide levels are typically low in patients with T1DM
diabetes-specific autoantibodies are useful to distinguish between type 1 and type 2 diabetes
What is HbA1c?
glycosylated haemoglobin HbA1c - reflects glucose over 3mths
What causes lower than expected HbA1c levels?
Sickle-cell anaemia
GP6D deficiency
Hereditary spherocytosis
Haemodialysis
What causes higher than expected HbA1c levels?
Vitamin B12/folic acid deficiency
Iron-deficiency anaemia
Splenectomy
What 4 antibodies are tested when considering T1DM? what are the association?
Antibodies to glutamic acid decarboxylase (anti-GAD) - Present in around 80% of patients with T1DM
Islet cell antibodies (ICA, against cytoplasmic proteins in the beta cell) - Present in around 70-80% of patients with T1DM
Insulin autoantibodies (IAA) - Presence in T1DM correlates strongly with age, found in over 90% of young children with T1DM but only 60% of older patients
Insulinoma-associated-2 autoantibodies (IA-2A)
What is the diagnostic criteria for T1DM if symptomatic? what if asymptomatic?
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.
Do all patient suspected of T2DM need to get antibody levels checked?
patients suspected of type 2 diabetes, if they over the age of 40 years and respond well to oral hypoglycaemic agents do not need to undergo further testing for type 1 diabetes. For those in whom there is a doubt, C-peptide levels and diabetes-specific autoantibodies are the investigations of choice.
How often is HbA1c checked in T1DM?
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
Describe self-monitoring of BMs and the target levels of patients with T1DM?
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
What types of insulin is used in T1DM? when is metformin added?
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
What is diagnostic criteria for T2DM?
If the patient is symptomatic: CKS
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.
When HbA1c is used for 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)
What is impaired fasting glucose? what is impaired glucose tolerance? what causes this?
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.'
Causes:
impaired fasting glucose (IFG) - due to hepatic insulin resistance
impaired glucose tolerance (IGT) - due to muscle insulin resistance
patients with IGT are more likely to develop T2DM and cardiovascular disease than patients with IFG
What is pre-diabetes?
Fasting glucose - 6.1-6.9
HbA1c - 42-47
or impaired glucose tolerance
What is the management of pre-diabetes?
Management
lifestyle modification: weight loss, increased exercise, change in diet at least yearly follow-up with blood tests is recommended NICE recommend metformin for adults at high risk 'whose blood glucose measure (fasting plasma glucose or HbA1c) shows they are still progressing towards type 2 diabetes, despite their participation in an intensive lifestyle-change programme'
What dietary advice is recommended for patients with T2DM?
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%
What are HbA1c targets for patients on lifestyle measures or single drug therapy?
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%)
When would you add another drug to a patient with T2DM and what is the HbA1c target?
HbA1c rises to 58
Already on one drug, but HbA1c has risen to 58 mmol/mol (7.5%), aim for HbA1c 53 mmol/mol (7.0%)
Describe the first line management of T2DM?
Metformin
Add SGLT2 inhibitor if have high risk CVD (QRisk >10) / Established CVD or Chronic heart failure
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
What is the first line therapy for T2DM if there is contraindications to metformin?
If metformin is contraindicated
if the patient has a risk of CVD, established CVD or chronic heart failure:
SGLT-2 monotherapy
if the patient doesn't have a risk of CVD, established CVD or chronic heart failure:
DPP‑4 inhibitor or pioglitazone or a sulfonylurea
SGLT-2 may be used if certain NICE criteria are met
What is the second line treatment of T2DM?
Dual therapy - add one of the following:
metformin + DPP-4 inhibitor metformin + pioglitazone metformin + sulfonylurea metformin + SGLT-2 inhibitor (if NICE criteria met)
What is the third line treatment of T2DM?
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
When would you offer DPP4 inhibitor to treat T2DM?
NICE guidelines on DPP-4 inhibitors
NICE suggest that a DPP-4 inhibitor might be preferable to a thiazolidinedione (pioglitazone) if further weight gain would cause significant problems, a thiazolidinedione is contraindicated or the person has had a poor response to a thiazolidinedione
Describe common adverse effects of sulfonylureas? (gliclazide) What are rarer adverse effects?
Common adverse effects
hypoglycaemic episodes (more common with long-acting preparations such as chlorpropamide) weight gain
Rarer adverse effects
hyponatraemia secondary to syndrome of inappropriate ADH secretion bone marrow suppression hepatotoxicity (typically cholestatic) peripheral neuropathy
Sulfonylureas should be avoided in breastfeeding and pregnancy.
When is a GLP-1 mimetic added?
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 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
