case 13 - tiredness Flashcards
what main conditions can cause tiredness?
- blood-related = anaemia, underactive thyroid, coeliac disease, diabetes, glandular fever
- head-related = depression, anxiety
- sleep-related = chronic fatigue syndrome, sleep apnoea, restless legs syndrome
what’s the difference between tiredness and fatigue?
- tiredness = can be relieved by sleep and rest
- fatigue = overwhelming tiredness that cannot be relieved by sleep and rest
what type of anaemias are associated with tiredness?
- iron-deficiency anaemia (most common)
- vitamin B12 or folate deficiency anaemia
who is at a high risk of developing iron-deficiency anaemia?
- women with heavy periods (menorrhagia)
- pregnant women
what is the most common cause of anaemia in men and postmenopausal women?
problems with the stomach and intestines
e.g. ulcer OR taking NSAIDs
why and how can NSAIDs cause anaemia?
- decrease the activity of blood platelets = decreased clot formation
- increased risk of bleeding and ulcer formation
what is an ulcer?
a localised sore in the skin or mucous membrane (stomach, small intestine, oesophagus)
besides anaemia, which (opposite) blood condition can cause tiredness?
haemochromatosis
what is haemochromatosis?
- rare inherited condition
- build-up of iron in the body leading to iron-overload
- deposition in the liver, joints, pancreas etc
who does haemochromatosis affect most?
men and women between 30-60
what is sleep apnoea?
a condition where your throat narrows or closes during sleep and repeatedly interrupts your breathing
what does sleep apnoea result in?
loud snoring
decrease in blood oxygen levels
what is the main symptoms/impact of sleep apnoea?
waking up often during the night
feeling exhausted the next day (due to disrupted sleep)
who is affected by sleep apnoea the most?
overweight middle-aged men
what factors worsen sleep apnoea?
increased alcohol and smoking
what is an underactive thyroid?
thyroid hormone (T3 and T4) deficiency
due to reduced production by the thyroid gland
besides tiredness, what are the additional symptoms of an underactive thyroid?
- weight gain
- aching muscles
- dry skin
- low mood
what is an underactive thyroid alternatively known as?
hypothyroidism
how can an underactive thyroid be diagnosed?
blood test (to test TSH, T4 levels)
who is most likely to be affect by hypothyroidism?
women as they get older
what is coeliac disease?
autoimmune condition wherein the immune system overreacts to the gluten ingested in the diet
what is gluten?
a protein in wheat, barley and rye
which foods are gluten-rich?
can be found in foods like pasta, bread, cakes and cereals
besides tiredness, what are the symptoms of coeliac disease?
- diarrhoea
- anaemia
- bloating
- weight loss
how is coeliac disease diagnosed?
blood test
what is chronic fatigue syndrome?
severe and disabling fatigue for at least 4 months
what is chronic fatigue alternatively known as?
myalgic encephalomyelitis
besides tiredness, what are the other symptoms of ME?
muscle or joint pain
which diabetes is tiredness a symptom of?
type 1 and type 2 diabetes both
besides tiredness, what are the symptoms of diabetes (type 1)?
- polydipsia
- polyuria
- nocturia
- weight loss
what is glandular fever/mononucleosis?
a common viral infection that causes fatigue, fever, sore throat and swollen glands
who is most affected by glandular fever?
teenagers and young adults
how long does glandular fever last?
symptoms usually clear up in 4-6 weeks but fatigue can linger for several more months
how and why can depression cause tiredness?
core symptoms = anergia, anhedonia, low mood
can also cause disruption to sleep + early waking up = more tiredness during the day
what is restless legs syndrome?
an overwhelming urge to move your legs, which can keep you awake at night
what are the symptoms of restless legs syndrome?
an overwhelming urge to move legs at night
unpleasant crawling sensation
deep ache in legs
legs may jerk spontaneously through the night
what is GAD?
- generalised anxiety disorder
- long-term condition that causes you to feel uncontrollably anxious about a wide range of situations and issues, rather than one specific event
who is most commonly affected by GAD?
common, affects women slightly more than men
to the nearest 10%, what percentage of patients who present to a GP with fatigue have a diagnosis made?
approx 66%
to the nearest 10%, what percentage of patients who present to a GP have a condition that is detected on blood tests?
- approx <10%
- history and physical examination are important
how many GP consultations are due to fatigue?
approx 7%
name five other possible differential diagnoses
jet lag disorder
pregnancy
(chronic) heart failure
insomnia
vitamin D deficiency
what is important to consider when thinking of possible differential diagnoses?
- frequency e.g. common to rare
- consequence e.g. less serious (e.g. nutritional deficiencies) to very serious (e.g. cancers)
how do you narrow down to fewer/a maximum of two differential diagnoses?
asking more questions to get a more comprehensive history
which of the following blood tests would be ordered to investigate hypothyroidism?
FBC
U&E
vitamin D
TFTs
HbA1c
CRP
coeliac screen
autoimmune screen
EBV serology
FBC (full blood count)
U&E (urea & electrolytes)
vitamin D
TFTs (thyroid function tests)
HbA1c
why would a FBC be done to investigate tiredness?
to test for classic signs of anaemia, haematological malignancy and WBC levels for signs of infection
why would a U&E be done to investigate tiredness?
look at electrolyte abnormalities and eGFR
why would a vitamin D test be done to investigate tiredness?
to test for vitamin D deficiency
why would TFTs be done to investigate tiredness?
to test for possible hypothyroidism
why would HbA1c be done to investigate tiredness?
to test for abnormal glucose levels which could indicate diabetes
why wouldn’t an autoimmune screen be done to investigate tiredness?
can be an extensive test that requires loads of time and effort so more justification is needed before requesting one
what do the following blood test results indicate and why?
indicate primary hypothyroidism due to the reduced fT3 and fT4 levels and the elevated TSH levels
what are the symptoms of hypothyroidism?
explain the mechanism of action of primary hypothyroidism, using the HPA axis
decreased production of thyroid hormones by the thyroid gland causes a compensatory increase of TSH due to the negative feedback loop
what is primary hypothyroidism?
- low levels of blood thyroid hormone due to destruction of the thyroid gland
- destruction can be due to autoimmunity, surgery, radiation, medication etc
what is secondary hypothyroidism?
pituitary produces insufficient TSH (more common)
what would be the expected TFT results for a patient with primary hypothyroidism?
low fT3 and fT4
elevated TSH
what would be the expected TFT results for a patient with secondary hypothyroidism?
low fT3 and fT4
low TSH
differentiate between primary and secondary hypothyroidism
primary = due to direct damage to the pituitary gland
secondary = due to pituitary or hypothalamic damage/disease
what is tertiary hypothyroidism?
when the hypothalamus produces insufficient thyrotropin-releasing hormone (TRH)
reducing TSH and therefore fT3 and fT4 production downstream
what is the most common type of autoimmune hypothyroidism?
Hashimoto’s thyroiditis
how can you differentiate between secondary and tertiary hypothyroidism?
practically impossible to do so as TRH levels are immeasurable (as it is in the portal circulation, not the systemic circulation)
name the immune cells
eosinophils
basophils
neutrophils
macrophages
dendritic cells
natural killer (NK) cells
B lymphocytes
T lymphocytes
name the antigen-presenting cells
macrophages
dendritic cells
B cells
explain the mechanism by which immune cells attack the thyroid cells in Hashimoto’s disease
what are the ‘foreign’ antigens recognised by APCs in Hashimoto’s?
either TPO (thyroid peroxidase) or thyroglobulin
how do APCs interact with T helper cells when a foreign antigen is recognised?
the TPO/Tg is presented in the MHC II molecules of APC to the TCRs of T helper cells
what are MHC I molecules?
receptors on the surfaces of almost all somatic cells that present endogenous antigens to cytotoxic T cells
what are MHC II molecules?
receptors on the surfaces of all antigen-presenting cells (dendritic cells, B cells, macrophages) that present exogenous antigens to T helper cells
what is a TCR and what does it interact with?
protein complex found on the surface of T cells and is responsible for recognising and binding to foreign antigens
interacts with antigens presented on the MHC II molecules of APCs
what is T cell co-stimulation?
a secondary signal which T cells rely on to activate an immune response in the presence of an antigen-presenting cell
= specifically when B7 on APCs binds to CD28 on T helper cells
how does a T cell process the foreign antigen in Hashimoto’s?
presents the TPO/Tg foreign antigen to the MHC IIs of B cells via the TCRs
how do T helper cells interact with B cells when a foreign antigen is recognised?
- the TPO/Tg foreign antigen is presented on the TCRs molecules of T cells to the MHC IIs of the B cells
- simultaneously, B-cell co-stimulation takes place when CD40L on T cells binds to CD40 on B cells
what is B cell co-stimulation?
- a secondary signal which B cells rely on to activate an immune response
- when CD40L on T cells binds to CD40 on B cells
which receptors interact in T cell co-stimulation?
B7 on APCs with CD28 on T helper cells
which receptors interact in B cell co-stimulation?
CD40L on T helper cells with CD40 on B cells
how do B cells respond after activation and B cell co-stimulation in Hashimoto’s?
produce anti-TPO/anti-thyroglobulin (anti-Tg) antibodies to attack the thyrocytes
what are anti-TPO antibodies?
antibodies that are produced against and attack the thyroid peroxidase (TPO) enzyme, which normally facilitates the production of thyroxine
what are anti-thyroglobulin antibodies?
antibodies produced against thyroglobulin (store for the inactive forms of the thyroid hormone in the follicular cells)
how are thyrocytes attacked in Hashimoto’s?
upon activation, T helper cells can further activate cytotoxic T cells that go on to attack the thyrocytes
differentiate between exogenous and endogenous antigens
exogenous = antigens that enter from outside the body, such as bacteria, fungi, protozoa, and free viruses (MHC II)
endogenous = antigens found within the cytosol of human cells such as viral proteins, proteins from intracellular bacteria, and tumor antigens (MHC I)
what is immune tolerance and where does it occur?
central tolerance (both B cells and T cells) = the process of eliminating any self-reactive B/T lymphocytes
- B cell central tolerance occurs in the bone marrow: negative selection only
- T cell central tolerance occurs in the thymus: positive and negative selection both
how does immune tolerance take place in terms of adaptive immunity?
during development, B cells in the bone marrow and T cells in the thymus are exposed to the entire protein repertoire of the body = to prevent them from recognising self antigens as foreign AND any self-reactive lymphocytes are destroyed early on
(central tolerance in the primary lymphoid organs)
how does immune tolerance take place in terms of innate immunity?
- granulocytes (neutrophils, basophils, eosinophils), macrophages and dendritic cells only attack cells that display PAMPs (pathogen-associated molecular patterns)
- NK cells attack only cells that do not display MHC I molecules (which all somatic cells display normally)
why do normal granulocytes, dendritic cells and macrophages not attack body cells?
only attack cells that display PAMPs (pathogen-associated molecular patterns)
why do normal natural killer cells not attack body cells?
natural killers cells attack only cells that do not display MHC I molecules (which all somatic cells display normally)
when do autoimmune diseases occur?
when the immune system attacks the body’s own cells, considering them to be foreign
(can be due to molecular mimicry, environmental triggers, genetic predisposition, high stress levels)
what is molecular mimicry?
when a foreign cells display antigens that resemble host antigens and so host antigens are mistaken as being foreign and responded to inappropriately
what are T regulatory cells and why are they important?
a subpopulation of suppressive T cells, T regulatory cells (Treg cells) are potent mediators of self-tolerance + essential for the suppression of triggered immune responses if the antigen is a host antigen
what are the steps to addressing tiredness in a GP setting?
- step 1 = define type of tiredness
- step 2 = why did this patient present?
- step 3 = screen for red flags
- step 4 = explore any psychosocial triggers
- step 5 = examine the patient
- step 6 = initial bloods
- step 7 = management of persisting unexplained tiredness with normal initial bloods
what are the types of tiredness?
drowsiness, short of breath, weakness
which one is more worrying?
1) ‘i feel okay when i wake up, but it gets worse as i do things’
2) ‘i feel rubbish when i wake up, but it gets better as i do things’
first one is more worrying = exertional tiredness is far more likely to be physical
what is important to assess initially when a patient presents with tiredness?
look for functional impairment (e.g. unable to make dinner for family)
what are the red flag symptoms associated with tiredness?
- lymphadenopathy
- unintentional weight loss
- specific malignancy features (lung, breast, colon, upper GI and gynae)
- joint pains and muscle aches
- focal neurology
- infective symptoms (glandular fever, TB, lyme disease)
what are possible psychosocial triggers for tiredness?
workload, money, family, mood, drugs & alcohol
how is a patient usually examined for tiredness?
dependent on history but at minimum: pulse, blood pressure and BMI
which bloods are taken initially from a patient presenting with tiredness?
FBC, TFTs, ESR, glucose
notes
- FBC = not just for anaemia, but also for iron deficiency and haematological malignancy
- in non-anaemia, menstruating women, treating a low ferritin can improve tiredness
- lymphomas often have normal WBC count in early stages
answer the following question posed by a patient with hypothyroidism:
‘what are the side effects of treatment? how can i cope with them?’
levothyroxine doesn’t usually have any side effects as the tablets are simply replacing a missing hormone
side effects would usually occur if you’re taking too much levothyroxine which can cause problems including sweating, chest pain, headaches, diarrhoea and vomiting
(if symptoms develop then you should consult your doctor)
answer the following question posed by a patient with hypothyroidism:
‘what are the chances that someone else in my family will get an underactive thyroid? does it run in families?’
underactive thyroid is often caused by an autoimmune disease that can run through families
what are some common causes of an underactive thyroid gland?
- autoimmune damage, Hashimoto’s thyroiditis
- temporarily after giving birth
- radioactive iodine treatment or surgery to correct hyperthyroidism
- antithyroid drugs
- medicines like lithium and amiodarone
- some cough medicines containing large amounts of iodine
- some health foods taken in excess e.g. kelp
- malfunction of the pituitary gland
- radiation for head and neck cancers, not so common in UK
- congenital hypothyroidism = present from birth
what is the spectrum of symptoms experienced due to an underactive thyroid gland?
some people don’t notice symptoms or have very mild symptoms that gradually develop
while others feel tired and low, have dry skin and hair loss
what is hormone replacement therapy for an underactive thyroid called?
levothyroxine (tablet)
how is levothyroxine taken?
tablet once a day on an empty stomach, usually before breakfast
how is the optimal dose of levothyroxine determined?
needs to be adjusted carefully to prevent administering too much
begin with a low dose that is gradually increased as required with regular monitoring through blood tests
how long does levothyroxine take to improve symptoms?
may take several weeks/months before you notice any difference in your symptoms
will have regular thyroid function tests during this time to inform dose adjustment
what can too much levothyroxine cause?
atrial fibrillation (abnormal heartbeat) or thinning of bones
how are patients with mildly underactive thyroid glands managed?
might not need to take thyroxine straight away
= may have your thyroid level checked regularly
what is congenital hypothyroidism?
hypothyroidism being present from birth
in some babies, the thyroid gland is underdeveloped and so there is a lack of thyroid hormone
how can hyperthyroidism lead to hypothyroidism?
treatment for hyperthyroidism (radioactive iodine therapy, surgery, antithyroid drugs) can lead to hypothyroidism if administered in excess
how is hypothyroidism diagnosed?
physical examination and blood tests
- physical examination = look for enlarge thyroid gland, brittle nails, hair loss, dry skin etc
- TFTs = assess TSH levels and fT3 and fT4 levels; can also test for thyroid antibodies (to confirm if the cause is autoimmune)
what is mild thyroid failure?
when the level of hypothyroidism so small that there are no obvious symptoms and can only be detected by blood test
what is mild thyroid failure also known as?
subclinical hypothyroidism
how is mild thyroid failure/subclinical hypothyroidism detected and diagnosed?
can be discovered as a result of blood tests for another autoimmune disorder or because there is a history of thyroid disorders in the family
blood test = raised TSH with a normal fT4
how should subclinical hypothyroidism be managed?
regular thyroid function test and consult doctor if noticing any symptoms
what is levothyroxine?
a synthetic version of the thyroxine produced by the thyroid gland
what are the side effects of levothyroxine?
very pure, has negligible side effects when taken in the correct dose
how is levothyroxine dose determined normally?
doses are dependent upon the person’s body weight and their blood test results
most patients require between 100 and 150mcg a day, but the dose can be lower than 75mcg or up to
300mcg a day, depending on your needs
how is levothyroxine dose determined in severe hypothyroidism?
if severe hypothyroidism or risk of heart problems, doctor will start cautiously + increase dose gradually.
which drugs can decrease levothyroxine absorption and how is this prevented?
calcium, iron, orlistat and multivitamin tablets
prevented by taking on an empty stomach
which substances can decrease levothyroxine absorption and how?
grapefruit, as it increases acidity in the stomach
what happens if you miss a dose of levothyroxine?
your body has a big reservoir of thyroxine so you will not notice a difference
what are the desired blood results for patients with hypothyroidism?
- a TSH reading in the lower part of the reference range
- fT4 reading towards the upper part or even slightly above the reference range
what is combined LT3 and LT4 therapy?
combo therapy of levothyroxine and tri-iodothyronine (LT4 and LT3) may be considered as an experimental approach under the supervision of an accredited endocrinologist
= if symptoms persist despite levothyroxine administration
why is LT3 not commonly prescribed?
not always available on the NHS
no solid evidence to suggest it has a better clinical outcome
what is the difference between brands of levothyroxine?
differences in fillers and bulking agents between the various brands of tablets
= why some people prefer specific brands of levothyroxine over others when they are all structurally the same
how does levothyroxine dose change when planning a pregnancy?
when planning = let doc know + have TFTs before
when pregnant = increased levothyroxine daily dose by 25-50mcg + then have regular TFTs
what is the risk of complications in a pregnant woman with hypothyroidism?
even if thyroid levesl not ideal = risk of pregnancy complications only slightly higher
who looks after patients with hypothyroidism?
GP and endocrinologist
what happens in Hashimoto’s thyroiditis?
variant of hypothyroidism, caused by autoimmunity
thyroid gets infiltrated by white cells (lymphocytic infiltration) and slowly loses its function = usually enlarges but may not
what are the two forms of autoimmune thyroidits?
Graves’ disease and Hashimoto’s thyroiditis
differentiate between Graves’ disease and Hashimoto’s thyroiditis
Graves’ = autoimmune hyperthyroidism
Hashimoto’s = autoimmune hypothyroidism
what are common triggers of Graves’ and Hashimoto’s?
stress factors
pregnancy
genetic predisposition
why is Hashimoto’s disease frequently missed?
because of undue reliance on blood tests
= fT4 usually decrease but doesn’t have to
= TSH usually rises but may be normal or low
which test conclusively helps diagnose Hashimoto’s and why?
antibody test
= any level of thyroid antibodies usually suggests an autoimmune process at work
why may thyroid antibody levels decrease?
as the damage becomes chronic
what causes hypometabolism in Hashimoto’s?
low thyroid function
how does mild Hashimoto’s present clinically?
may be nothing obvious and only noticed during a general blood test
what are the two ways Hashimoto’s can present?
goitrous autoimmune thyroiditis (enlarging of the thyroid gland)
atrophic autoimmune thyroiditis (shrinking of the thyroid gland)
explain how goitrous autoimmune thyroidits can occur
- progressive lymphocytic infiltration enlarges the thyroid
- the gland itself becomes a mass of fibrous tissue
- gland enlarges into goitre
explain how atrophic autoimmune thyroidits can occur
- antibodies block the TSH receptors in the thyroid and on the basis that what you don’t use, you lose, the glandular tissue shrinks
what triggers goitrous autoimmune thyroidits?
lymphocytic infiltration of the of the glandular tissue
what triggers atrophic autoimmune thyroidits?
antibodies block the TSH receptors in the thyroid
differentiate between Hashimoto’s and hypothyroidism
Hashimoto’s = specifically autoimmune hypothyroidism
hypothyroidism = can have other causes besides autoimmune ones
(treatment same)
what is the most common cause of hypothyroidism in the developed world?
a) subacute thyroiditis
b) Hashimoto’s thyroiditis
c) thyroidectomy
d) drugs
e) iodine deficiency
b) hashimoto’s thyroiditis
most common cause of primary hypothyroidism in the UK
what is the most common cause of hypothyroidism in the developing world?
a) postpartum thyroiditis
b) Hashimoto’s thyroiditis
c) Graves’ disease
d) subacute thyroiditis (de Quervain’s)
e) iodine deficiency
e) iodine deficiency
iodine deficiency is the most common cause of hypothyroidism in the DEVELOPING world
why does subclinical hypothyroidism present with raised TSH and normal fT4?
more TSH is needed to produce a normal level of thyroid hormone which is why TSH is slightly raised
