24 December 2020
13:54
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)
· following this a high-resolution CT abdomen and adrenal vein sampling is used to differentiate between unilateral and bilateral sources of aldosterone excess
· Adrenal Venous Sampling (AVS) can be done to identify the gland secreting excess hormone in primary hyperaldosteronism
Management
· adrenal adenoma: surgery
· bilateral adrenocortical hyperplasia: aldosterone antagonist e.g. spironolactone
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| © Image used on license from Radiopaedia | |
CT abdomen showing a right-sided adrenal adenoma in a patient who presented with hypertension and hypokalaemia. The adenoma can be seen 'next to' or 'below' the liver.
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24 December 2020
13:54
SGLT-2 inhibitors
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 excretion.
Examples include canagliflozin, dapagliflozin and empagliflozin.
Important adverse effects include
· urinary and genital infection (secondary to glycosuria). Fournier’s gangrene has also been reported
· normoglycaemic ketoacidosis
· increased risk of lower-limb amputation: feet should be closely monitored
Patients taking SGLT-2 drugs often lose weight, which can be beneficial in type 2 diabetes mellitus.
From <https://www.passmedicine.com/review/textbook.php?s=#>
24 December 2020
13:54
Graves' disease: features
Graves' disease is the most common cause of thyrotoxicosis. It is typically seen in women aged 30-50 years.
Features
· typical features of thyrotoxicosis
· specific signs limited to Grave's (see below)
Features seen in Graves' but not in other causes of thyrotoxicosis
· eye signs (30% of patients)
o exophthalmos
o ophthalmoplegia
· pretibial myxoedema
· thyroid acropachy, a triad of:
o digital clubbing
o soft tissue swelling of the hands and feet
o periosteal new bone formation
Autoantibodies
· TSH receptor stimulating antibodies (90%)
· anti-thyroid peroxidase antibodies (75%)
From <https://www.passmedicine.com/review/textbook.php?s=#>
Corneal involvement in Grave's disease indicates severe eye pathology
Important for meLess important
The severity of Grave's eye disease can be graded using the mnemonic NOSPECS
· No signs / symptoms
· Only signs (e.g: upper lid retraction)
· Signs & symptoms (including soft-tissue involvement)
· Proptosis
· Extra-ocular muscle involvement
· Corneal involvement
· Sight loss due to optic nerve involvement
Therefore the correct answer is corneal involvement.
From <https://www.passmedicine.com/question/questions.php?q=0#>
24 December 2020
13:55
Primary hyperparathyroidism
In exams, primary hyperparathyroidism is stereotypically seen in elderly females with an unquenchable thirst and an inappropriately normal or raised parathyroid hormone level. It is most commonly due to a solitary adenoma
Causes of primary hyperparathyroidism
· 80%: solitary adenoma
· 15%: hyperplasia
· 4%: multiple adenoma
· 1%: carcinoma
Features - 'bones, stones, abdominal groans and psychic moans'
· polydipsia, polyuria
· peptic ulceration/constipation/pancreatitis
· bone pain/fracture
· renal stones
· depression
· 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
· 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
· calcimimetic agents such as cinacalcet are sometimes used in patients who are unsuitable for surgery
| | |
| © Image used on license from Radiopaedia | |
Bilateral hand radiographs in a middle-aged woman demonstrating generalised osteopenia, erosion of the terminal phalangeal tufts (acro-osteolysis) and subperiosteal resorption of bone particularly the radial aspects of the 2nd and 3rd middle phalanges. These changes are consistent with a diagnosis of hyperparathyroidism.
From <https://www.passmedicine.com/review/textbook.php?s=#>
24 December 2020
13:55
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
From <https://www.passmedicine.com/review/textbook.php?s=#>
hyperpigmentation could be caused by the stimulant effect of excess ACTH on the melanocytes to produce melanin
Investigation
ACTH stimulation test (Short synacthen (tetracosactide) test)
How it is done:
Baseline cortisol and ACTH levels are performed. Synthetic ACTH 0.25mg is given IM or IV. 30 and 60 minutes after the injection, blood samples are drawn for cortisol levels.
Cortisol usually increase >600 after 30 minutes
Management:
Glucocorticoid replacement with hydrocortisone and fludrocortisone to replace mineralocorticoid
Patient may present with adrenal crisis if undiagnosed with appreciable mortality. An acute adrenal crisis can manifest with vomiting, abdominal pain, and hypovolaemic shock
24 December 2020
13:55
Cushing's syndrome: investigations
Investigations are divided into confirming Cushing's syndrome and then localising the lesion. A hypokalaemic metabolic alkalosis may be seen, along with impaired glucose tolerance. Ectopic ACTH secretion (e.g. secondary to small cell lung cancer) is characteristically associated with very low potassium levels. An insulin stress test is used to differentiate between true Cushing's and pseudo-Cushing's
Tests to confirm Cushing's syndrome
The two most commonly used tests are:
· overnight dexamethasone suppression test (most sensitive)
· 24 hr urinary free cortisol
Localisation tests
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
Both low- and high-dose dexamethasone suppression tests may be used to localise the pathology resulting in Cushing's syndrome. These tests may be interpreted as follows:
| Cortisol following low-dose dexamethasone | Cortisol following high-dose dexamethasone | ACTH | Interpretation |
| ↓ | ↓ | ↔ | Normal |
| ↔ | ↔ | ↓ | Cushing's syndrome due to other causes (e.g. adrenal adenomas) |
| ↔ | ↓ | ↑ | Cushing's disease (i.e. pituitary adenoma → ACTH secretion) |
| ↔ | ↔ | ↑ | Ectopic ACTH syndrome likely |
CRH stimulation
· if pituitary source then cortisol rises
· if ectopic/adrenal then no change in cortisol
Petrosal sinus sampling of ACTH may be needed to differentiate between pituitary and ectopic ACTH secretion
From <https://www.passmedicine.com/review/textbook.php?s=#>
Suppression after high dose dexamethasone indicates pituitary source
High ACTH excludes adrenal source
Needs pituitary imaging, preferably MRI Corticotrophin releasing hormone test can be used to confirm pituitary source in difficult cases if imaging inconclusive. Should see an exaggerated ACTH and cortisol response at 30 mins post injection. Inferior petrosal sinus sampling will help confirm pituitary source
If pituitary adenoma identified then transsphenoidal surgery ± radiotherapy first choice
24 December 2020
13:55
Diabetes mellitus: sick day rules
The following are key messages that should be given to all patients with diabetes if they become unwell:
· Increase frequency of blood glucose monitoring to four hourly or more frequently
· Encourage fluid intake aiming for at least 3 litres in 24hrs
· If unable to take struggling to eat may need sugary drinks to maintain carbohydrate intake
· It is useful to educate patients so that they have a box of 'sick day supplies' that they can access if they become unwell
· Access to a mobile phone has been shown to reduce progression of ketosis to diabetic ketoacidosis
If a patient is taking oral hypoglycaemic medication, they should be advised to continue taking their medication even if they are not eating much. Remember that the stress response to illness increases cortisol levels pushing blood sugars high even without much oral intake. The possible exception is with metformin, which should be stopped if a patient is becoming dehydrated because of the potential impact upon renal function.
If a patient is on insulin, they must not stop it due to the risk of diabetic ketoacidosis. They should continue their normal insulin regime but ensure that they are checking their blood sugars frequently. Patients should be able to check their ketone levels and if these are raised and blood sugars are also raised they may need to give corrective doses of insulin. The corrective dose to be given varies by patient, but a rule of thumb would be total daily insulin dose divided by 6 (maximum 15 units). NHS Scotland have produced a useful flowsheet for patients to follow:
http://www.diabetesinscotland.org.uk/ketocard/ketosheet.pdf
Possible indications that a patient might require admission to hospital would include:
· Suspicion of underlying illness requiring hospital treatment eg myocardial infarction
· Inability to keep fluids down - admit if persisting more than a few hours
· Persistent diarrhoea
· Significant ketosis in an insulin dependent diabetic despite additional insulin
· Blood glucose persistently >20mmol/l despite additional insulin
· Patient unable to manage adjustments to usual diabetes management
· Lack of support at home e.g. a patient who lives alone and is at risk of becoming unconscious
From <https://www.passmedicine.com/review/textbook.php?s=#>
24 December 2020
13:55
Hypercalcaemia: causes
Two conditions account for 90% of cases of hypercalcaemia:
· 1. Primary hyperparathyroidism: commonest cause in non-hospitalised patients
· 2. Malignancy: the commonest cause in hospitalised patients. This may be due to number of processes, including; bone metastases, myeloma, PTHrP from squamous cell lung cancer
Other causes include
· sarcoidosis*
· vitamin D intoxication
· acromegaly
· thyrotoxicosis
· Milk-alkali syndrome
· drugs: thiazides, calcium containing antacids
· dehydration
· Addison's disease
· Paget's disease of the bone**
*other causes of granulomas may lead to hypercalcaemia e.g. Tuberculosis and histoplasmosis
**usually normal in this condition but hypercalcaemia may occur with prolonged immobilisation
From <https://www.passmedicine.com/review/textbook.php?s=#>
24 December 2020
13:58
Thyroid function tests
The interpretation of thyroid function tests is usually straightforward:
| Diagnosis | TSH | Free T4 | Notes |
| Thyrotoxicosis (e.g. Graves' disease) | Low | High | In T3 thyrotoxicosis the free T4 will be normal |
| Primary hypothyroidism (primary atrophic hypothyroidism) | High | Low | |
| Secondary hypothyroidism | Low | Low | Replacement steroid therapy is required prior to thyroxine |
| Sick euthyroid syndrome* | Low** | Low | Common in hospital inpatients T3 is particularly low in these patients |
| Subclinical hypothyroidism | High | Normal | |
| Poor compliance with thyroxine | High | Normal | |
| Steroid therapy | Low | Normal |
| | |
| |
Venn diagram showing how different causes of thyroid dysfunction may manifest. Note how many causes of hypothyroidism may have an initial thyrotoxic phase.
*now referred to as non-thyroidal illness
**TSH may be normal in some cases
From <https://www.passmedicine.com/review/textbook.php?s=#>
24 December 2020
13:58
Diabetes mellitus: a very basic introduction
Diabetes mellitus is one of the most common conditions encountered in clinical practice and represents a significant burden on the health systems of the developed world. It is now estimated that 8% of the total NHS budget is now spent on managing patients with diabetes mellitus.
What is diabetes mellitus?
Diabetes mellitus may be defined as a chronic condition characterised by abnormally raised levels of blood glucose.
Why is the management of diabetes mellitus so important?
Before the advent of insulin therapy untreated type 1 diabetes would usually result in death. 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.
| Type | Notes |
| Type 1 diabetes mellitus (T1DM) | Autoimmune disorder where the insulin-producing beta cells of the islets of Langerhans in the pancreas are destroyed by the immune system This results in an absolute deficiency of insulin resulting in raised glucose levels Patients tend to develop T1DM in childhood/early adult life and typically present unwell, possibly in diabetic ketoacidosis |
| Type 2 diabetes mellitus (T2DM) | This is the most common cause of diabetes in the developed world. It is caused by a relative deficiency of insulin due to an excess of adipose tissue. In simple terms there isn't enough insulin to 'go around' all the excess fatty tissue, leading to blood glucose creeping up. |
| Prediabetes | 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 the next few years. They, therefore, require closer monitoring and lifestyle interventions such as weight loss |
| Gestational diabetes | Some pregnant develop raised glucose levels during pregnancy. This is important to detect as untreated it may lead to adverse outcomes for the mother and baby |
| Maturity onset diabetes of the young (MODY) | A group of inherited genetic disorders affecting the production of insulin. Results in younger patients developing symptoms similar to those with T2DM, i.e. asymptomatic hyperglycaemia with progression to more severe complications such as diabetic ketoacidosis |
| Latent autoimmune diabetes of adults (LADA) | The majority of patients with autoimmune-related diabetes present younger in life. There are however a small group of patients who develop such problems later in life. These patients are often misdiagnosed as having T2DM |
| Other types | Any pathological process which damages the insulin-producing cells of the pancreas may cause diabetes to develop. Examples include chronic pancreatitis and haemochromatosis. Drugs may also cause raised glucose levels. A common example is glucocorticoids which commonly result in raised blood glucose levels |
Symptoms and signs
The presentation of diabetes mellitus depends very much on the type:
| Type 1 DM | Type 2 DM |
| Weight loss Polydipsia Polyuria May present with diabetic ketoacidosis · abdominal pain · vomiting · reduced consciousness level | Often picked up incidentally on routine blood tests Polydipsia Polyuria |
Remember that the polyuria and polydipsia are due to water being 'dragged' out of the body due to the osmotic effects of excess blood glucose being excreted in the urine (glycosuria).
Investigations
There are 4 main ways to check blood glucose:
· a finger-prick bedside glucose monitor
· a one-off blood glucose. This may either be fasting or non-fasting
· a HbA1c. This measures the amount of glycosylated haemoglobin and represents the average blood glucose over the past 2-3 months
· 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
The diagnostic criteria are determined by WHO.
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.
In 2011 WHO released supplementary guidance on the use of HbA1c for the diagnosis of diabetes:
· a HbA1c of greater than or equal to 6.5% (48 mmol/mol) is diagnostic of diabetes mellitus
· 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)
· 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
| | |
| |
Diagram showing the spectrum of diabetes diagnosis
Management
The principle of managing diabetes mellitus are as follows:
· drug therapy to normalise blood glucose levels
· monitoring for and treating any complications related to diabetes
· modifying any other risk factors for other conditions such as cardiovascular disease
Type 1 diabetes
· patients always require insulin to control the blood sugar levels. This is because there is 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
Type 2 diabetes
· the majority of patients with type 2 diabetes are controlled using oral medication
· the first-line drug for the vast majority of patients is metformin
· second-line drugs include sulfonylureas, gliptins and pioglitazone. Please see the table below for further information
· if oral medication is not controlling the blood glucose to a sufficient degree then insulin is used
The table below shows some of the main drugs used in the management of diabetes mellitus:
| Drug class | Mechanism of action | Route | Main side-effects | Notes |
| Insulin | Direct replacement for endogenous insulin | Subcutaneous | Hypoglycaemia Weight gain Lipodystrophy | Used in all patients with T1DM and some patients with poorly controlled T2DM Can be classified according to source (analogue, human sequence and porcine) and duration of action (short, immediate, long-acting) |
| Metformin | Increases insulin sensitivity Decreases hepatic gluconeogenesis | Oral | Gastrointestinal upset Lactic acidosis* | First-line medication in the management of T2DM Cannot be used in patients with an eGFR of < 30 ml/min |
| Sulfonylureas | Stimulate pancreatic beta cells to secrete insulin | Oral | Hypoglycaemia Weight gain Hyponatraemia | Examples include gliclazide and glimepiride |
| Thiazolidinediones | Activate PPAR-gamma receptor in adipocytes to promote adipogenesis and fatty acid uptake | Oral | Weight gain Fluid retention | Only currently available thiazolidinedione is pioglitazone |
| DPP-4 inhibitors (-gliptins) | Increases incretin levels which inhibit glucagon secretion | Oral | Generally well tolerated but increased risk of pancreatitis | |
| SGLT-2 inhibitors (-gliflozins) | Inhibits reabsorption of glucose in the kidney | Oral | Urinary tract infection | Typically result in weight loss |
| GLP-1 agonists (-tides) | Incretin mimetic which inhibits glucagon secretion | Subcutaneous | Nausea and vomiting Pancreatitis | Typically result in weight loss |
NICE provide guidelines on how drug therapy should be used in T2DM:
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| |
*common in exams, much less common in clinical practice
From <https://www.passmedicine.com/review/textbook.php?s=#>
24 December 2020
13:58
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
From <https://www.passmedicine.com/review/textbook.php?s=#>
24 December 2020
13:58
Parathyroid glands and disorders of calcium metabolism
Hyperparathyroidism
| Disease type | Hormone profile | Clinical features | Cause |
| Primary hyperparathyroidism | · PTH (Elevated) · Ca2+ (Elevated) · Phosphate (Low) · Urine calcium : creatinine clearance ratio > 0.01 | · May be asymptomatic if mild · Recurrent abdominal pain (pancreatitis, renal colic) · Changes to emotional or cognitive state | Most cases due to solitary adenoma (80%), multifocal disease occurs in 10-15% and parathyroid carcinoma in 1% or less |
| Secondary hyperparathyroidism | · PTH (Elevated) · Ca2+ (Low or normal) · Phosphate (Elevated) · Vitamin D levels (Low) | · May have few symptoms · Eventually may develop bone disease, osteitis fibrosa cystica and soft tissue calcifications | Parathyroid gland hyperplasia occurs as a result of low calcium, almost always in a setting of chronic renal failure |
| Tertiary hyperparathyroidism | · Ca2+ (Normal or high) · PTH (Elevated) · Phosphate levels (Decreased or Normal) · Vitamin D (Normal or decreased) · Alkaline phosphatase (Elevated) | · Metastatic calcification · Bone pain and / or fracture · Nephrolithiasis · Pancreatitis | Occurs as a result of ongoing hyperplasia of the parathyroid glands after correction of underlying renal disorder, hyperplasia of all 4 glands is usually the cause |
Differential diagnoses
It is important to consider the rare but relatively benign condition of benign familial hypocalciuric hypercalcaemia, caused by an autosomal dominant genetic disorder. Diagnosis is usually made by genetic testing and concordant biochemistry (urine calcium : creatinine clearance ratio <0.01-distinguished from primary hyperparathyroidism).
Treatment
Primary hyperparathyroidism
Indications for surgery
· Elevated serum Calcium > 1mg/dL above normal
· Hypercalciuria > 400mg/day
· Creatinine clearance < 30% compared with normal
· Episode of life threatening hypercalcaemia
· Nephrolithiasis
· Age < 50 years
· Neuromuscular symptoms
· Reduction in bone mineral density of the femoral neck, lumbar spine, or distal radius of more than 2.5 standard deviations below peak bone mass (T score lower than -2.5)
Secondary hyperparathyroidism
Usually managed with medical therapy.
Indications for surgery in secondary (renal) hyperparathyroidism:
· Bone pain
· Persistent pruritus
· Soft tissue calcifications
Tertiary hyperparathyroidism
Allow 12 months to elapse following transplant as many cases will resolve
The presence of an autonomously functioning parathyroid gland may require surgery. If the culprit gland can be identified then it should be excised. Otherwise total parathyroidectomy and re-implantation of part of the gland may be required.
References
1. Pitt S et al. Secondary and Tertiary Hyperparathyroidism, State of the Art Surgical Management. Surg Clin North Am 2009 Oct;89(5):1227-39.
2. MacKenzie-Feder J et al. Primary Hyperparathyroidism: An Overview. Int J Endocrinol 2011; 2011: 251410.
From <https://www.passmedicine.com/review/textbook.php?s=#>
24 December 2020
13:58
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.
Thyrotoxicosis
Untreated thyrotoxicosis increases the risk of fetal loss, maternal heart failure and premature labour
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
Hypothyroidism
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
o by up to 50% as early as 4-6 weeks of pregnancy
· breastfeeding is safe whilst on thyroxine
From <https://www.passmedicine.com/review/textbook.php?s=#>
24 December 2020
13:58
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
From <https://www.passmedicine.com/review/textbook.php?s=#>
24 December 2020
13:58
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
| | |
| |
Venn diagram showing how different causes of thyroid dysfunction may manifest. Note how many causes of hypothyroidism may have an initial thyrotoxic phase.
From <https://www.passmedicine.com/review/textbook.php?s=#>
24 December 2020
13:59
Hyperosmolar hyperglycaemic state
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 diabetes mellitus (T2DM), however the incidence in younger adults is increasing. It can be the initial presentation of T2DM.
It is extremely important to differentiate HHS from diabetic ketoacidosis (DKA) as the management is different, and treatment of HHS with insulin (e.g. as part of a DKA protocol) can result in adverse outcomes. The first 24 hours of treatment is very labour intensive so these 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 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 the dehydration and metabolic disturbances are more extreme.
Pathophysiology
· Hyperglycaemia results in osmotic diuresis with associated loss of sodium and potassium
· 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.
Clinical features
· General: fatigue, lethargy, nausea and vomiting
· Neurological: altered level of consciousness, headaches, papilloedema, weakness
· Haematological: hyperviscosity (may result in myocardial infarctions, stroke and peripheral arterial thrombosis)
· Cardiovascular: dehydration, hypotension, tachycardia
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 in distinguishing between HHS and DKA. It is also important to remember that a mixed HHS / DKA picture can occur.
Management
The goals of management of HHS can be summarised as follows:
· 1. Normalise the osmolality (gradually)
· 2. Replace fluid and electrolyte losses
· 3. Normalise blood glucose (gradually)
Fluid replacement
· Fluid losses in HHS are estimated to be between 100 - 220 ml/kg (e.g. 10-22 litres in an individual weighing 100 kg).
· The rate of rehydration will be determined by assessing the combination of initial severity and any pre-existing co-morbidities (e.g. heart failure and chronic kidney disease). Caution is needed, particularly in the elderly, where too rapid rehydration may precipitate heart failure but insufficient may fail to reverse an acute kidney injury.
· Intravenous (IV) 0.9% sodium chloride solution is the first line fluid for restoring total body fluid.
· 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.
· 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 more hypotonic relative to the HHS patients serum osmolarity
· IV fluid replacement should aim to achieve a positive balance of 3-6 litres by 12 hours and the remaining replacement of estimated fluid losses within the next 12 hours.
· Existing guidelines encourage vigorous initial fluid replacement and this alone (without insulin) will result in a gradual decline in plasma glucose and serum osmolarity. A rapid decline is potentially harmful (see below) therefore insulin should NOT be used in the first instance unless there is significant ketonaemia or acidosis
· The aim of treatment should be to replace approximately 50% of estimated fluid loss within the first 12 hours and the remainder in the following 12 hours. However this is just a guide, and clinical judgement should be applied, particularly in patient with co-morbidities such as heart failure and chronic kidney disease (which may limit the speed of correction).
Monitoring response to treatment
· The key parameter in managing HHS is the osmolality to which glucose and sodium are the main contributors. Rapid changes of serum osmolarity are dangerous and can result in cardiovascular collapse and central pontine myelinolysis (CPM).
· Guidelines suggest that serum osmolarity, sodium and glucose levels should be plotted on a graph to permit appreciation of the rate of change. They should be plotted hourly initially.
· Not all laboratories have readily available access to serum osmolarity measurements. If not available then a calculated osmolarity can be estimated with 2Na + glucose + urea
· Fluid replacement alone (without insulin) will gradually lower blood glucose which will 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 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 for each 5.5 mmol/L fall in blood glucose this would suggest insufficient fluid replacement. Rising sodium is only a concern if the osmolality is NOT declining concurrently.
· Rapid changes must be avoided. A safe rate of fall of plasma glucose of between 4 and 6 mmol/hr is recommended. The rate of fall of plasma sodium should not exceed 10 mmol/L in 24 hours.
· A target blood glucose of between 10 and 15 mmol/L is a reasonable goal.
· Complete normalisation of electrolytes and osmolality may take up to 72 hours.
Insulin
· Fluid replacement alone with 0.9% sodium chloride solution will result in a gradual decline of blood glucose and osmolarity
· Because most patients with HHS are insulin sensitive (e.g. it usually occurs in T2DM), administration of insulin can result in a rapid decline of serum glucose and thus osmolarity.
· Insulin treatment prior to adequate fluid replacement may result in cardiovascular collapse as the water moves out of the intravascular space, with a resulting decline in intravascular volume.
· A steep decline in serum osmolarity may also precipitate CPM.
· Measurement of ketones is essential for determining if insulin is required.
· If significant ketonaemia is present (3ÎČ-hydroxy butyrate is more than 1 mmol/L) this indicates relative hypoinsulinaemia and insulin should be started at time zero (e.g. mixed 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 (3ÎČ-hydroxy butyrate is less than 1 mmol/L) then do NOT start insulin.
Potassium
· Patients with HHS are potassium deplete but less acidotic than those with DKA so potassium shifts are less pronounced
· Hyperkalaemia can be present with acute kidney injury
· Patients on diuretics may be profoundly hypokalaemic
· Potassium should be replaced or omitted as required
From <https://www.passmedicine.com/review/textbook.php?s=#>
24 December 2020
13:59
Hypoglycaemia
Causes
· insulinoma - increased ratio of proinsulin to insulin
· self-administration of insulin/sulphonylureas
· liver failure
· Addison's disease
· alcohol
Other possible causes in children
· nesidioblastosis - beta cell hyperplasia
Physiological response to hypoglycaemia
· hormonal response: the first response of the body is decreased insulin secretion. This is followed by increased glucagon secretion. Growth hormone and cortisol are also released but later
· sympathoadrenal response: increased catecholamine-mediated (adrenergic) and acetylcholine-mediated (cholinergic) neurotransmission in the peripheral autonomic nervous system and in the central nervous system
From <https://www.passmedicine.com/review/textbook.php?s=#>
Causes of hypoglycaemia can be remembered by the mnemonic EXPLAIN
· Exogenous drugs (typically sulfonylureas or insulin)
· Pituitary insufficiency
· Liver failure
· Addison's disease
· Islet cell tumours (insulinomas)
· Non-pancreatic neoplasms
From <https://www.passmedicine.com/question/questions.php?q=0>
EXPLAIN:
· Exogenous drugs such alcohol, aspirin poisoning, pentamidine, quinine sulfate, ACE-inhibitor
· Pituitary insufficiency
· Liver failure
· Addison's disease
· Islet cell tumours eg insulinoma
· Non-pancreatic neoplasms
From <https://www.passmedicine.com/question/questions.php?q=0>
From <https://www.passmedicine.com/question/questions.php?q=0>
24 December 2020
13:59
MODY
· MODY is a rare form of diabetes often termed monogenic with an autosomal dominant inheritance.
The key features of MODY are:
· Being diagnosed with diabetes under the age of 25.
· Absence of ketoacidosis
· Having a parent with diabetes, with diabetes in two or more generations.
· Not necessarily requiring insulin.
MODY is very rare compared with type 1 and type 2 diabetes – experts estimate that only 1–2% of people with diabetes (20-40,000 people) in the UK have it. But because MODY is so rare, doctors may not be aware of it, so it’s estimated that about 90% of people with it are mistakenly diagnosed with type 1 or type 2 diabetes at first.
There are many genes identified with MODY. Some of the known genes are
HNF 1 Alpha, HNF 4 Alpha, HNF 1 Beta and Glucokinase
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.
MODY 3
· 60% of cases
· due to a defect in the HNF-1 alpha gene
· is associated with an increased risk of HCC
MODY 2
· 20% of cases
· due to a defect in the glucokinase gene
MODY 5
· rare
· due to a defect in the HNF-1 beta gene
· liver and renal cysts
Features of MODY
· typically develops in patients < 25 years
· 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 usually necessary
From <https://www.passmedicine.com/review/textbook.php?s=#>
24 December 2020
13:59
Myxoedema coma
Myxoedema coma typically presents with confusion and hypothermia.
Myxoedema coma is a medical emergency requiring treatment with
· IV thyroid replacement
· IV fluid
· IV corticosteroids (until the possibility of coexisting adrenal insufficiency has been excluded)
· electrolyte imbalance correction
· sometimes rewarming
From <https://www.passmedicine.com/review/textbook.php?s=#>
24 December 2020
13:59
Pituitary adenoma
A pituitary adenoma is a benign tumour of the pituitary gland. They are common (10% of all people1) but in most cases will never be found (asymptomatic) or are found as an incidental finding. They account for around 10% of adult brain tumours2.
It is recommended that all patients with a pituitary incidentaloma, including those without symptoms, undergo clinical and laboratory evaluations for hormone hypersecretion and hypopituitarism.
Pituitary adenomas can be classified according to:
· size (a microadenoma is <1cm and a macroadenoma is >1cm)
· hormonal status (a secretory/functioning adenoma produces and excess of a particular hormone and a non-secretory/functioning adenoma does not produce a hormone to excess)
Prolactinomas are the most common type and they produce an excess of prolactin. After prolactinomas, non-secreting adenomas are the next most common, then GH secreting and then ACTH secreting adenomas.
Pituitary adenomas typically cause symptoms by:
· excess of a hormone (e.g. Cushing’s disease due to excess ACTH, acromegaly due to excess GH or amenorrhea and galactorrhea due to excess prolactin)
· depletion of a hormone(s) (due to compression of the normal functioning pituitary gland)
o non-functioning tumours, therefore, present with generalised hypopituitarism
· stretching of the dura within/around pituitary fossa (causing headaches)
· compression of the optic chiasm (causing a bitemporal hemianopia due to crossing nasal fibers)
Alternatively, pituitary adenomas, particularly microadenomas, can be an incidental finding on neuroimaging and therefore called a ‘pituitary incidentaloma’.
Investigation requires:
· a pituitary blood profile (including: GH, prolactin, ACTH, FH, LSH and TFTs)
· formal visual field testing
· MRI brain with contrast
Differential diagnoses include:
· pituitary hyperplasia
· craniopharyngioma
· meningioma
· brain metastases
· lymphoma
· hypophysitis
· vascular malformation (e.g. aneurysm)
Treatment may include a combination of:
· hormonal therapy (e.g. bromocriptine is the first line treatment for prolactinomas)
· surgery (e.g. transsphenoidal transnasal hypophysectomy)
o e.g. if progression in size
· radiotherapy
From <https://www.passmedicine.com/review/textbook.php?s=#>
criteria for surgical removal of a pituitary mass:
· A visual field deficit due to the lesion.
· Other visual abnormalities, such as ophthalmoplegia or neurological compromise due to compression by the lesion.
· Lesion abutting or compressing the optic nerves or chiasm on MRI.
· Pituitary apoplexy with visual disturbance.
· Hypersecreting tumours other than prolactinomas
From <https://www.passmedicine.com/question/questions.php?q=0>
24 December 2020
13:59
Prolactin and galactorrhoea
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
Causes of raised prolactin
· prolactinoma
· pregnancy
· oestrogens
· physiological: stress, exercise, sleep
· acromegaly: 1/3 of patients
· polycystic ovarian syndrome
· primary hypothyroidism (due to thyrotrophin releasing hormone (TRH) stimulating prolactin release)
Drug causes of raised prolactin
· metoclopramide, domperidone
· phenothiazines
· haloperidol
· very rare: SSRIs, opioids
From <https://www.passmedicine.com/review/textbook.php?s=#>
24 December 2020
13:59
Sick euthyroid syndrome
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).
Changes are reversible upon recovery from the systemic illness and hence no treatment is usually needed.
From <https://www.passmedicine.com/review/textbook.php?s=#>
24 December 2020
13:59
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.
Structure and function
The thyroid gland is one of the largest endocrine organs in the body. It is a bi-lobed structure which is found in the anterior neck. As with many endocrine organs, it is part of a hypothalamus-pituitary-end organ system with negative feedback cycles to maintain normal circulating levels of the hormone, in this case thyroxine and triiodothyronine.
On a simple level the hypothalamus secretes thyrotropin-releasing hormone (TRH) which stimulates the anterior pituitary to secrete thyroid-stimulating hormone (TSH). This then acts on the thyroid gland increasing the production of thyroxine (T4) and triiodothyronine (T3), the two main thyroid hormones. These then act on a wide variety of tissues, helping to regulate the use of energy sources, protein synthesis, and controls the body's sensitivity to other hormones.
How are thyroid problems classified?
Hypothyroidism may be classified as follows:
· 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
Whilst there are a number of causes thyrotoxicosis the vast majority are primary in nature. Congenital thyrotoxicosis is not seen and secondary hyperthyroidism is rare, account for less than 1% of cases.
What causes thyroid problems?
The majority of thyroid problems seen in the developed world are a consequence of autoimmunity.
The table below shows the different autoimmune problems which cause thyroid dysfunction:
| Hypothyroidism | Thyrotoxicosis | |
| Most common cause | 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 | Graves' disease · most common cause of thyrotoxicosis · as well as typically features of thyrotoxicosis other features may be seen including thyroid eye disease |
| Other causes | Subacute thyroiditis (de Quervain's) · associated with a painful goitre and raised ESR Riedel thyroiditis · fibrous tissue replacing the normal thyroid parenchyma · causes a painless goitre Postpartum thyroiditis Drugs · lithium · amiodarone Iodine deficiency · the most common cause of hypothyroidism in the developing world | Toxic multinodular goitre · autonomously functioning thyroid nodules that secrete excess thyroid hormones Drugs · amiodarone |
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:
| | |
| |
Venn diagram showing how different causes of thyroid dysfunction may manifest. Note how many causes of hypothyroidism may have an initial thyrotoxic phase.
Symptoms and signs
Thyroid disorders can present in a large variety of ways. Often (but not always) the symptoms present are the opposite depending on whether the thyroid gland is under or over active, for example hypothyroidism may result in weight gain whilst thyrotoxicosis normally leads to weight loss
| Feature | Hypothyroidism | Thyrotoxicosis |
| General | Weight gain Lethargy Cold intolerance | Weight loss 'Manic', restlessness Heat intolerance |
| Cardiac | - | Palpitations, may even provoke arrhythmias e.g. atrial fibrillation |
| Skin | Dry (anhydrosis), cold, yellowish skin Non-pitting oedema (e.g. hands, face) Dry, coarse scalp hair, loss of lateral aspect of eyebrows | Increased sweating Pretibial myxoedema: erythematous, oedematous lesions above the lateral malleoli Thyroid acropachy: clubbing |
| Gastrointestinal | Constipation | Diarrhoea |
| Gynaecological | Menorrhagia | Oligomenorrhea |
| Neurological | Decreased deep tendon reflexes Carpal tunnel syndrome | Anxiety Tremor |
Investigations and diagnosis
The principle investigation is 'thyroid function tests', or TFTs for short:
· these primarily look at serum TSH and T4 levels
· 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 thyroxine) but the TSH level is high, because the hypothalamus/pituitary has detected low levels of T4 and is trying to get the thyroid gland to produce more
· TSH levels are more sensitive than T4 levels for monitoring patients with existing thyroid problems and are often used to guide treatment
The table below shows how thyroid function tests are interpreted:
| Diagnosis | TSH | Free T4 | Notes |
| Thyrotoxicosis (e.g. Graves' disease) | Low | High | |
| Primary hypothyroidism (e.g. Hashimoto's thyroiditis) | High | Low | |
| Secondary hypothyroidism | Low | Low | |
| Sick euthyroid syndrome | Low | Low | Common in hospital inpatients. Changes are reversible upon recovery from the systemic illness and no treatment is usually needed |
| Subclinical hypothyroidism | High | Normal | This is a common finding and represents patients who are 'on the way' to developing hypothyroidism but still have normal thyroxine levels. Note how the TSH levels, as mentioned above, are a more sensitive and early marker of thyroid problems |
| Poor compliance with thyroxine | High | Normal | Patients who are poorly compliant may only take their thyroxine in the days before a routine blood test. The thyroxine levels are hence normal but the TSH 'lags' and reflects longer term low thyroxine levels |
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
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.
Other tests include:
· nuclear scintigraphy; toxic multinodular goitre reveals patchy uptake
Treatment
This clearly depends on the cause. For patients with hypothyrodism thyroxine is given in the form of levothyroxine to replace the underlying deficiency.
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
From <https://www.passmedicine.com/review/textbook.php?s=#>
24 December 2020
13:59
Acromegaly: management
Trans-sphenoidal surgery is the first-line treatment for acromegaly in the majority of patients.
If a pituitary tumour is inoperable or surgery unsuccessful then medication may be indicated:
· somatostatin analogue
o directly inhibits the release of growth hormone
o for example octreotide
o effective in 50-70% of patients
· pegvisomant
o GH receptor antagonist - prevents dimerization of the GH receptor
o once daily s/c administration
o very effective - decreases IGF-1 levels in 90% of patients to normal
o doesn't reduce tumour volume therefore surgery still needed if mass effect
· dopamine agonists
o for example bromocriptine
o the first effective medical treatment for acromegaly, however now superseded by somatostatin analogues
o effective only in a minority of patients
External irradiation is sometimes used for older patients or following failed surgical/medical treatment
From <https://www.passmedicine.com/review/textbook.php?s=#>
24 December 2020
13:59
Addison's disease: investigations
In a patient with suspected Addison's disease the definite investigation is an ACTH stimulation test (short Synacthen test). Plasma cortisol is measured before and 30 minutes after giving Synacthen 250ug IM. Adrenal autoantibodies such as anti-21-hydroxylase may also be demonstrated.
If an ACTH stimulation test is not readily available (e.g. in primary care) then sending a 9 am serum cortisol can be useful:
· > 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
Associated electrolyte abnormalities are seen in around one-third of undiagnosed patients:
· hyperkalaemia
· hyponatraemia
· hypoglycaemia
· metabolic acidosis
From <https://www.passmedicine.com/review/textbook.php?s=#>
24 December 2020
13:59
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
From <https://www.passmedicine.com/review/textbook.php?s=#>
24 December 2020
14:00
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 is the most common causes
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
From <https://www.passmedicine.com/review/textbook.php?s=#>
24 December 2020
14:00
DVLA: diabetes mellitus
Until recently people with diabetes who used insulin could not hold a HGV licence. The DVLA changed the rules in October 2011. The following standards need to be met (and also apply to patients using other hypoglycaemic inducing drugs such as sulfonylureas):
· there has not been any severe hypoglycaemic event in the previous 12 months
· the driver has full hypoglycaemic awareness
· the driver must show adequate control of the condition by regular blood glucose monitoring*, at least twice daily and at times relevant to driving
· the driver must demonstrate an understanding of the risks of hypoglycaemia
· here are no other debarring complications of diabetes
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 within the preceding 12 months and no relevant visual impairment. Drivers are normally contacted by DVLA
· 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 hypoglycaemia requiring the assistance of another person within the preceding 12 months
· if diet controlled alone then no requirement to inform DVLA
*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 meters with a memory function to measure and record blood glucose levels for at least 3 months prior to submitting their application
From <https://www.passmedicine.com/review/textbook.php?s=#>
24 December 2020
14:00
Hypothyroidism: features
General
· Weight gain
· Lethargy
· Cold intolerance
Skin
· Dry (anhydrosis), cold, yellowish skin
· Non-pitting oedema (e.g. hands, face)
· Dry, coarse scalp hair, loss of lateral aspect of eyebrows
Gastrointestinal
· Constipation
Gynaecological
· Menorrhagia
Neurological
· Decreased deep tendon reflexes
· Carpal tunnel syndrome
A hoarse voice is also occasionally noted.
From <https://www.passmedicine.com/review/textbook.php?s=#>
24 December 2020
14:00
Kallmann's syndrome
Kallmann's syndrome is a recognised cause of delayed puberty secondary to hypogonadotropic hypogonadism. It is usually inherited as an X-linked recessive trait. Kallmann'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
· 'delayed puberty'
· hypogonadism, cryptorchidism
· anosmia
· sex hormone levels are low
· LH, FSH levels are inappropriately low/normal
· patients are typically of normal or above average height
Cleft lip/palate and visual/hearing defects are also seen in some patients
From <https://www.passmedicine.com/review/textbook.php?s=#>
24 December 2020
14:00
Klinefelter's syndrome
Klinefelter's syndrome is associated with karyotype 47, XXY.
Features
· often taller than average
· lack of secondary sexual characteristics
· small, firm testes
· infertile
· gynaecomastia - increased incidence of breast cancer
· elevated gonadotrophin levels but low testosterone
Diagnosis is by karyotype (chromosomal analysis).
From <https://www.passmedicine.com/review/textbook.php?s=#>
24 December 2020
14:00
Obesity: therapeutic options
The management of obesity consists of a step-wise approach:
· conservative: diet, exercise
· medical
· surgical
Orlistat is a pancreatic lipase inhibitor used in the management of obesity. Adverse effects include faecal urgency/incontinence and flatulence. A lower dose version is now available without prescription ('Alli'). NICE have defined criteria for the use of orlistat. It should only be prescribed as part of an overall plan for managing obesity in adults who have:
· BMI of 28 kg/m^2 or more with associated risk factors, or
· BMI of 30 kg/m^2 or more
· continued weight loss e.g. 5% at 3 months
· orlistat is normally used for < 1 year
From <https://www.passmedicine.com/review/textbook.php?s=#>
24 December 2020
14:00
Prediabetes and impaired glucose regulation
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 impaired glucose tolerance (IGT). Diabetes UK estimate that around 1 in 7 adults in the UK have prediabetes. Many individuals with prediabetes will progress on to developing type 2 diabetes mellitus (T2DM) and they are therefore at greater risk of microvascular and macrovascular complications.
Terminology
· Diabetes UK currently recommend using the term prediabetes when talking to patients 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 understood
Identification of patients with prediabetes
· 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
| | |
| |
Diagram showing the spectrum of diabetes diagnosis
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'
Impaired fasting glucose and impaired glucose tolerance
There are two main types of IGR:
· 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
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
From <https://www.passmedicine.com/review/textbook.php?s=#>
24 December 2020
14:00
Subclinical hypothyroidism
Basics
· TSH raised but T3, T4 normal
· no obvious symptoms
Significance
· risk of progressing to overt hypothyroidism is 2-5% per year (higher in men)
· risk increased by the presence of thyroid autoantibodies
Management
Not all patients require treatment. NICE Clinical Knowledge Summaries (CKS) have produced guidelines. Note that not all patients will fall within the age boundaries given and hence these are guidelines in the broader sense.
TSH is between 4 - 10mU/L and the free thyroxine level is within the normal range
· if < 65 years with symptoms suggestive of hypothyroidism, give a trial of levothyroxine. If there is no improvement in symptoms, stop levothyroxine
· 'in older people (especially those aged over 80 years) follow a 'watch and wait' strategy, generally avoiding hormonal treatment'
· if asymptomatic people, observe and repeat thyroid function in 6 months
TSH is > 10mU/L and the free thyroxine level is within the normal range
· start treatment (even if asymptomatic) with levothyroxine if <= 70 years
· 'in older people (especially those aged over 80 years) follow a 'watch and wait' strategy, generally avoiding hormonal treatment'
From <https://www.passmedicine.com/review/textbook.php?s=#>
24 December 2020
14:00
Sulfonylureas
Sulfonylureas are oral hypoglycaemic drugs used in the management of type 2 diabetes mellitus. They work by increasing pancreatic insulin secretion and hence are only effective if 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
· 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.
From <https://www.passmedicine.com/review/textbook.php?s=#>
24 December 2020
14:00
Thyroid eye disease
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
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
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
Management
· topical lubricants may be needed to help prevent corneal inflammation caused by exposure
· steroids
· radiotherapy
· surgery
Monitoring patients with established thyroid eye disease
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
From <https://www.passmedicine.com/review/textbook.php?s=#>
24 December 2020
14:00
Toxic multinodular goitre
Toxic multinodular goitre describes a thyroid gland that contains a number of autonomously functioning thyroid nodules resulting in hyperthyroidism.
Nuclear scintigraphy reveals patchy uptake.
The treatment of choice is radioiodine therapy.
From <https://www.passmedicine.com/review/textbook.php?s=#>
24 December 2020
14:00
Acromegaly: investigations
Growth hormone (GH) levels vary during the day and are therefore not diagnostic.
Serum IGF-1 levels have now overtaken the oral glucose tolerance test (OGTT) with serial GH measurements as the first-line test. The OGTT test is recommended to confirm the diagnosis if IGF-1 levels are raised.
The Endocrine Society guidelines suggest the following:
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 ÎŒg/L following documented hyperglycemia during an oral glucose load.
Serum IGF-1 may also be used to monitor disease
Oral glucose tolerance test
· in normal patients GH is suppressed to < 2 mu/L with hyperglycaemia
· in acromegaly there is no suppression of GH
· may also demonstrate impaired glucose tolerance which is associated with acromegaly
A pituitary MRI may demonstrate a pituitary tumour.
From <https://www.passmedicine.com/review/textbook.php?s=#>
24 December 2020
14:01
Combined deficiency of magnesium and calcium
Magnesium is required for both PTH secretion and its action on target tissues. Hypomagnesaemia may both cause hypocalcaemia and render patients unresponsive to treatment with calcium and vitamin D supplementation.
Magnesium is the fourth most abundant cation in the body. The body contains 1000mmol, with half contained in bone and the remainder in muscle, soft tissues and extracellular fluid. There is no one specific hormonal control of magnesium and various hormones including PTH and aldosterone affect the renal handling of magnesium.
Magnesium and calcium interact at a cellular level also and as a result decreased magnesium will tend to affect the permeability of cellular membranes to calcium, resulting in hyperexcitability.
From <https://www.passmedicine.com/review/textbook.php?s=#>
24 December 2020
14:01
Congenital adrenal hyperplasia
Overview
· group of autosomal recessive disorders
· affect adrenal steroid biosynthesis
· in response to resultant low cortisol levels the anterior pituitary secretes high levels of ACTH
· ACTH stimulates the production of adrenal androgens that may virilize a female infant
Cause
· 21-hydroxylase deficiency (90%)
· 11-beta hydroxylase deficiency (5%)
· 17-hydroxylase deficiency (very rare)
| | |
| Image sourced from Wikipedia | |
From <https://www.passmedicine.com/review/textbook.php?s=#>
24 December 2020
14:01
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 20101.
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 Council of Britain which explores these options in more detail.
If a patient with type 2 diabetes mellitus does decide to fast:
· they should try and and eat a meal containing long-acting carbohydrates prior to sunrise (Suhoor)
· patients should be given a blood glucose monitor to allow them to check their glucose levels, particularly if they feel unwell
· for patients taking metformin the expert consensus is that the dose should be split one-third before sunrise (Suhoor) and two-thirds after sunset (Iftar)
· expert consensus also recommends switching once-daily sulfonylureas to after sunset. For patients taking twice-daily preparations such as gliclazide it is recommended that a larger proportion of the dose is taken after after sunset
· no adjustment is needed for patients taking pioglitazone
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 Care 2004;27:2306-11.
From <https://www.passmedicine.com/review/textbook.php?s=#>
24 December 2020
14:01
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
From <https://www.passmedicine.com/review/textbook.php?s=#>
24 December 2020
14:01
Growth hormone therapy
NICE guidance recommended growth hormone therapy for the following indications
· proven growth hormone deficiency
· Turner's syndrome
· Prader-Willi syndrome
· chronic renal insufficiency before puberty
Key points
· given by subcutaneous injection
· treatment should be discontinued if there is a poor response in the first year of therapy
Adverse effects
· headache
· benign intracranial hypertension
· fluid retention
From <https://www.passmedicine.com/review/textbook.php?s=#>
24 December 2020
14:01
Hypoparathyroidism
Primary hypoparathyroidism
· decrease PTH secretion
· e.g. secondary to thyroid surgery*
· low calcium, high phosphate
· treated with alfacalcidol
The main symptoms of hypoparathyroidism are secondary to hypocalcaemia:
· tetany: muscle twitching, cramping and spasm
· perioral paraesthesia
· Trousseau's sign: carpal spasm if the brachial artery occluded by inflating the blood pressure cuff and maintaining pressure above systolic
· Chvostek's sign: tapping over parotid causes facial muscles to twitch
· if chronic: depression, cataracts
· ECG: prolonged QT interval
Pseudohypoparathyroidism
· target cells being insensitive to PTH
· due to abnormality in a G protein
· associated with low IQ, short stature, shortened 4th and 5th metacarpals
· low calcium, high phosphate, high PTH
· diagnosis is made by measuring urinary cAMP and phosphate levels following an infusion of PTH. In hypoparathyroidism this will cause an increase in both cAMP and phosphate levels. In pseudohypoparathyroidism type I neither cAMP nor phosphate levels are increased whilst in pseudohypoparathyroidism type II only cAMP rises.
Pseudopseudohypoparathyroidism
· similar phenotype to pseudohypoparathyroidism but normal biochemistry
*this may seem an oxymoron, but most medical textbooks classify hypoparathyroidism which is secondary to surgery as being 'primary hypoparathyroidism'
From <https://www.passmedicine.com/review/textbook.php?s=#>
24 December 2020
14:01
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
| | |
| |
Venn diagram showing how different causes of thyroid dysfunction may manifest. Note how many causes of hypothyroidism may have an initial thyrotoxic phase.
Secondary hypothyroidism (rare)
From pituitary failure
Other associated conditions
· Down's syndrome
· Turner's syndrome
· coeliac disease
From <https://www.passmedicine.com/review/textbook.php?s=#>
24 December 2020
14:01
Insulin
Insulin is a peptide hormone, produced by beta cells of the pancreas, and is central to regulating carbohydrate and fat metabolism in the body. Insulin causes cells in the liver, skeletal muscles, and fat tissue to absorb glucose from the blood. In the liver and skeletal muscles, glucose is stored as glycogen, and in fat cells (adipocytes) it is stored as triglycerides.
Structure
The human insulin protein is composed of 51 amino acids, and has a molecular weight of 5808 Da. It is a dimer of an A-chain and a B-chain, which are linked together by disulfide bonds.
Synthesis
Pro-insulin is formed by the rough endoplasmic reticulum in pancreatic beta cells. Then pro-insulin is cleaved to form insulin and C-peptide. Insulin is stored in secretory granules and released in response to Ca2+.
Function
Basics
· Secreted in response to hyperglycaemia
· Glucose utilisation and glycogen synthesis
· Inhibits lipolysis
· Reduces muscle protein loss
· Increases cellular uptake of potassium (via stimulation of Na+/K+ ATPase pump)
From <https://www.passmedicine.com/review/textbook.php?s=#>
24 December 2020
14:01
Insulin stress test
Basics
· used in investigation of hypopituitarism
· IV insulin given, GH and cortisol levels measured
· with normal pituitary function GH and cortisol should rise
Contraindications
· epilepsy
· ischaemic heart disease
· adrenal insufficiency
From <https://www.passmedicine.com/review/textbook.php?s=#>
24 December 2020
14:01
Insulin therapy
Insulin therapy revolutionised the management of diabetes mellitus when it was developed in the 1920's. It is still the only available treatment for type 1 diabetes mellitus (T1DM) and is widely used in type 2 diabetes mellitus (T2DM) where oral hypoglycaemic agents fail to gain adequate control.
It can sometimes seem daunting to understand the various types of insulin but it is important you have a basic grasp to avoid potential harm to patients.
Classification of insulin
By manufacturing process
· porcine: extracted and purified from pig pancreas
· human sequence insulin: either produced by enzyme modification of porcine insulin (emp) or biosynthetically by recombinant DNA using bacteria (crb, prb) or yeast (pyr)
· analogues
By duration of action
| Onset | Peak | Duration | |
| Rapid-acting insulin analogues | 5 mins | 1 hour | 3-5 hours |
| Short-acting insulin | 30 mins | 3 hours | 6-8 hours |
| Intermediate-acting insulin | 2 hours | 5-8 hours | 12-18 hours |
| Long-acting insulin analogues | 1-2 hours | Flat profile | Up to 24 hours |
| Premixed preparations | - | - | - |
Patients often require a mixture of preparations (e.g. both short and long acting) to ensure stable glycaemic control throughout the day.
Rapid-acting insulin analogues
· the rapid-acting human insulin analogues act faster and have a shorter duration of action than soluble insulin (see below)
· may be used as the bolus dose in 'basal-bolus' regimes (rapid/short-acting 'bolus' insulin before meals with intermediate/long-acting 'basal' insulin once or twice daily)
· insulin aspart: NovoRapid
· insulin lispro: Humalog
Short-acting insulins
· soluble insulin examples: Actrapid (human, pyr), Humulin S (human, prb)
· may be used as the bolus dose in 'basal-bolus' regimes
Intermidate-acting insulins
· isophane insulin
· many patients use isophane insulin in a premixed formulation with
Long-acting insulins
· insulin determir (Levemir): given once or twice daily
· insulin glargine (Lantus): given once daily
Premixed preparations
· combine intermediate acting insulin with either a rapid-acting insulin analogue or soluble insulin
· Novomix 30: 30% insulin aspart (rapid-acting), 70% insulin aspart protamine (intermediate-acting)
· Humalog Mix25: 25% insulin lispro (rapid-acting), 75% insulin lispro protamine (intermediate-acting); Humalog Mix50: 50% insulin lispro, 50% insulin lispro protamine
· Humulin M3: biphasic isophane insulin (human, prb) - 30% soluble (short-acting), 70% isophane (intermediate-acting)
· Insuman Comb 15: biphasic isophane insulin 9human, prb) - 30% soluble (short-acting), 70% isophane (intermediate-acting)
Administration of insulin
The vast majority of patients administer insulin subcutaneously. It is important to rotate injection sites to prevent lipodystrophy. Insulin pumps are available ('continuous subcutaneous insulin infusions') which delivers a continuous basal infusion and a patient-activated bolus dose at meal times.
Intravenous insulin is used for patients who are acutely unwell, for example with diabetic ketoacidosis. Inhaled insulin is available but not widely used and oral insulin analogues are in development but have considerable technical hurdles to clear.
From <https://www.passmedicine.com/review/textbook.php?s=#>
24 December 2020
14:01
Insulinoma
An insulinoma is a neuroendocrine tumour deriving mainly from pancreatic Islets of Langerhans cells
Basics
· most common pancreatic endocrine tumour
· 10% malignant, 10% multiple
· of patients with multiple tumours, 50% have MEN-1
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
· high C-peptide
Diagnosis
· supervised, prolonged fasting (up to 72 hours)
· CT pancreas
Management
· surgery
· diazoxide and somatostatin if patients are not candidates for surgery
From <https://www.passmedicine.com/review/textbook.php?s=#>
24 December 2020
14:01
Prolactinoma
Prolactinomas are a type of pituitary adenoma, a benign tumour of the pituitary gland.
Pituitary adenomas can be classified according to:
· size (a microadenoma is <1cm and a macroadenoma is >1cm)
· hormonal status (a secretory/functioning adenoma produces and excess of a particular hormone and a non-secretory/functioning adenoma does not produce a hormone to excess)
Prolactinomas are the most common type and they produce an excess of prolactin.
Features of excess prolactin
· men: impotence, loss of libido, galactorrhoea
· women: amenorrhoea, infertility, galactorrhoea, osteoporosis
Diagnosis
· MRI
Management
· in the majority of cases, symptomatic patients are treated medically with dopamine agonists (e.g. cabergoline, bromocriptine) which inhibit the release of prolactin from the pituitary gland
· surgery is performed for patients who cannot tolerate or fail to respond to medical therapy. A trans-sphenoidal approach is generally preferred unless there is a significant extra-pituitary extension
From <https://www.passmedicine.com/review/textbook.php?s=#>
24 December 2020
14:01
PTH
A hormone is a chemical messenger which is secreted by an endocrine gland and designed to generate a specific response by binding to a cellular receptor. This receptor may be intracellular (commonly steroid hormone receptors) or on the cell surface membrane.
Parathyroid hormone (PTH) is a polypeptide hormone secreted from the parathyroid gland. It has an important role in calcium homeostasis. It acts on cell-surface receptors to generate a coordinated response throughout the body and maintain blood calcium within a narrow range.
It is vital that calcium does not rise too high or fall too low, as hyper- and hypo- calcaemia can have serious consequences. Calcium enters the body through the intestines and leaves through urine and faeces. The main reservoir of calcium in the body is the bone, containing about 1 kg of complexed calcium and phosphate. In the blood, calcium exists in three main forms:
· free calcium
· bound to albumin
· complexed with anions
It is free calcium which is physiologically active and can travel into cells to exert a function.
Structure and function
PTH, a single-chain polypeptide containing 84 amino acids, is secreted from the Chief cells of the parathyroid glands, located on the posterior aspect of the thyroid. It is generated in response to low levels of calcium in the blood, where it travels to effector organs to increase levels of the electrolyte back to normal concentrations.
Effector organs associated with PTH include the bone and kidney:
· At the bone PTH acts to increase the activity of osteoclastic cells, which are responsible for bone resorption. In this way, the bone releases some of its calcium, and phosphate, stores into the bloodstream.
· At the kidney PTH as two actions. One is to increase the hydroxylation and activation of vitamin D in the proximal convoluted tubules. Another in to increase calcium reabsorption from the distal convoluted tubules and increase phosphate excretion.
Active vitamin D has a similar action to PTH, however, it is a steroid hormone. One of its unique actions is to increase dietary calcium absorption from the intestine by increasing expression of calcium-binding hormone.
Regulation
While PTH is very important in maintaining adequate levels of calcium in the bloodstream, it is equally as important that its actions don't cause hypercalcaemia. Regulation is therefore vital. This is achieved through a negative feedback loop:
· calcium levels in the blood fall, which is detected by the parathyroid gland
· chief cells secrete PTH into the blood
· calcium is released from bone and reabsorbed from the renal tubules, causing its level to rise
· increased calcium levels are detected by the parathyroid gland, which decreases PTH secretion
Clinical relevance
Primary hyperparathyroidism is a condition in which the parathyroid gland is overactive. This is often due to hyperplasia, an adenoma or malignancy. Symptoms of hypercalcaemia develop, which includes renal calculi, constipation, polyuria, abdominal pain and low mood. One treatment is surgical removal of the glands.
PTHrp is a polypeptide which has a similar structure to PTH, hence its name 'related peptide'. It can be secreted from cancer cells, notably squamous cell bronchial carcinoma, to cause hypercalcaemia. PTHrp has all the same effects as PTH, however it cannot activate vitamin D.
From <https://www.passmedicine.com/review/textbook.php?s=#>
24 December 2020
14:02
Stress response: Endocrine and metabolic changes
· Surgery precipitates hormonal and metabolic changes causing the stress response.
· Stress response is associated with: substrate mobilization, muscle protein loss, sodium and water retention, suppression of anabolic hormone secretion, activation of the sympathetic nervous system, immunological and haematological changes.
· The hypothalamic-pituitary axis and the sympathetic nervous systems are activated and there is a failure of the normal feedback mechanisms of control of hormone secretion.
A summary of the hormonal changes associated with the stress response:
| Increased | Decreased | No Change |
| Growth hormone | Insulin | Thyroid stimulating hormone |
| Cortisol | Testosterone | Luteinizing hormone |
| Renin | Oestrogen | Follicle stimulating hormone |
| Adrenocorticotrophic hormone (ACTH) | ||
| Aldosterone | ||
| Prolactin | ||
| Antidiuretic hormone | ||
| Glucagon |
Sympathetic nervous system
· Stimulates catecholamine release
· Causes tachycardia and hypertension
Pituitary gland
· ACTH and growth hormone (GH) is stimulated by hypothalamic releasing factors, corticotrophin releasing factor (CRF) and somatotrophin (or growth hormone releasing factor)
· Perioperative increased prolactin secretion occurs by release of inhibitory control
· Secretion of thyroid stimulating hormone (TSH), luteinizing hormone (LH) and follicle stimulating hormone (FSH) does not change significantly
· ACTH stimulates cortisol production within a few minutes of the start of surgery. More ACTH is produced than needed to produce a maximum adrenocortical response.
Cortisol
· Significant increases within 4-6 hours of surgery (>1000 nmol litre-1).
· The usual negative feedback mechanism fails and concentrations of ACTH and cortisol remain persistently increased.
· The magnitude and duration of the increase correlate with the severity of stress and the response is not abolished by the administration of corticosteroids.
· The metabolic effects of cortisol are enhanced:
Skeletal muscle protein breakdown to provide gluconeogenic precursors and amino acids for protein synthesis in the liver
Stimulation of lipolysis
'Anti-insulin effect'
Mineralocorticoid effects
Anti-inflammatory effects
Growth hormone
· Increased secretion after surgery has a minor role
· Most important for preventing muscle protein breakdown and promote tissue repair by insulin growth factors
Alpha Endorphin
· Increased
Antidiuretic hormone
· An important vasopressor and enhances haemostasis
· Renin is released causing the conversion of angiotensinogen to angiotensin I
· Angiotensin II formed by ACE on angiotensin 1, which causes the secretion of aldosterone from the adrenal cortex. This increases sodium reabsorption at the distal convoluted tubule
Insulin
· Release inhibited by stress
· Occurs via the inhibition of the beta cells in the pancreas by the α2-adrenergic inhibitory effects of catecholamines
· Insulin resistance by target cells occurs later
· The perioperative period is characterized by a state of functional insulin deficiency
Thyroxine (T4) and tri-iodothyronine (T3)
· Circulating concentrations are inversely correlated with sympathetic activity and after surgery there is a reduction in thyroid hormone production, which normalises over a few days.
Metabolic effect of endocrine response
Carbohydrate metabolism
· Hyperglycaemia is a main feature of the metabolic response to surgery
· Due to increase in glucose production and a reduction in glucose utilization
· Catecholamines and cortisol promote glycogenolysis and gluconeogenesis
· Initial failure of insulin secretion followed by insulin resistance affects the normal responses
· The proportion of the hyperglycaemic response reflects the severity of surgery
· Hyperglycaemia impairs wound healing and increase infection rates
Protein metabolism
· Initially there is inhibition of protein anabolism, followed later, if the stress response is severe, by enhanced catabolism
· The amount of protein degradation is influenced by the type of surgery and also by the nutritional status of the patient
· Mainly skeletal muscle protein is affected
· The amino acids released form acute phase proteins (fibrinogen, C reactive protein, complement proteins, a2-macroglobulin, amyloid A and ceruloplasmin) and are used for gluconeogenesis
· Nutritional support has little effect on preventing catabolism
Lipid metabolism
Increased catecholamine, cortisol and glucagon secretion, and insulin deficiency, promotes lipolysis and ketone body production.
Salt and water metabolism
· ADH causes water retention, concentrated urine, and potassium loss and may continue for 3 to 5 days after surgery
· Renin causes sodium and water retention
Cytokines
· Glycoproteins
· Interleukins (IL) 1 to 17, interferons, and tumour necrosis factor
· Synthesized by activated macrophages, fibroblasts, endothelial and glial cells in response to tissue injury from surgery or trauma
· IL-6 main cytokine associated with surgery. Peak 12 to 24 h after surgery and increase by the degree of tissue damage Other effects of cytokines include fever, granulocytosis, haemostasis, tissue damage limitation and promotion of healing.
Modifying the response
· Opioids suppress hypothalamic and pituitary hormone secretion
· At high doses the hormonal response to pelvic and abdominal surgery is abolished. However, such doses prolong recovery and increase the need for postoperative ventilatory support
· Spinal anaesthesia can reduce the glucose, ACTH, cortisol, GH and epinephrine changes, although cytokine responses are unaltered
· Cytokine release is reduced in less invasive surgery
· Nutrition prevents the adverse effects of the stress response. Enteral feeding improves recovery
· Growth hormone and anabolic steroids may improve outcome
· Normothermia decreases the metabolic response
References
Deborah Burton, Grainne Nicholson, and George Hall
Endocrine and metabolic response to surgery .
Contin Educ Anaesth Crit Care Pain (2004) 4(5): 144-147 doi:10.1093/bjaceaccp/mkh040
From <https://www.passmedicine.com/review/textbook.php?s=#>
24 December 2020
14:02
Subclinical hyperthyroidism
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)
Causes
· multinodular goitre, particularly in elderly females
· excessive thyroxine may give a similar biochemical picture
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 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
From <https://www.passmedicine.com/review/textbook.php?s=#>
24 December 2020
14:02
Sulfonylureas: side-effects
Common adverse effects
· hypoglycaemic episodes (more common with long acting preparations such as chlorpropamide)
· weight gain
Rarer adverse effects
· syndrome of inappropriate ADH secretion
· bone marrow suppression
· liver damage (cholestatic)
· peripheral neuropathy
From <https://www.passmedicine.com/review/textbook.php?s=#>
24 December 2020
14:02
Thyrotoxicosis: causes and investigation
Graves' disease accounts for around 50-60% of cases of thyrotoxicosis.
Causes
· 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)
· amiodarone therapy
Investigation
· TSH down, T4 and T3 up
· thyroid autoantibodies
· other investigations are not routinely done but includes isotope scanning
| | |
| |
Venn diagram showing how different causes of thyroid dysfunction may manifest. Note how many causes of hypothyroidism may have an initial thyrotoxic phase.
From <https://www.passmedicine.com/review/textbook.php?s=#>
24 December 2020
14:02
Thyrotoxicosis: features
General
· Weight loss
· 'Manic', restlessness
· Heat intolerance
Cardiac
· palpitations, tachycardia
· high-output cardiac failure may occur in elderly patients, a reversible cardiomyopathy can rarely develop
Skin
· Increased sweating
· Pretibial myxoedema: erythematous, oedematous lesions above the lateral malleoli
· Thyroid acropachy: clubbing
Gastrointestinal
· Diarrhoea
Gynaecological
· Oligomenorrhea
Neurological
· Anxiety
· Tremor
From <https://www.passmedicine.com/review/textbook.php?s=#>
22 December 2020
20:56
Diabetes mellitus: management of type 2
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%) |
Drug treatment
The 2015 NICE guidelines introduced some changes into the management of type 2 diabetes. There are essentially two pathways, one for patients who can tolerate metformin, and one for those who can't:
| | |
| |
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:
o sulfonylurea
o gliptin
o pioglitazone
o 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:
o metformin + gliptin + sulfonylurea
o metformin + pioglitazone + sulfonylurea
o metformin + sulfonylurea + SGLT-2 inhibitor
o metformin + pioglitazone + SGLT-2 inhibitor
o 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:
o BMI >= 35 kg/m² and specific psychological or other medical problems associated with obesity or
o 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
Practical examples
· you review an established type 2 diabetic on maximum dose metformin. Her HbA1c is 55 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 a HbA1c of 62 mmol/mol (7.8%) at annual review. They are currently on maximum dose metformin. You elect to add a sulfonylurea
Cannot tolerate metformin or contraindicated
· if the HbA1c rises to 48 mmol/mol (6.5%)* on lifestyle interventions, consider one of the following:
o sulfonylurea
o gliptin
o pioglitazone
· if the HbA1c has risen to 58 mmol/mol (7.5%) then a one of the following combinations should be used:
o gliptin + pioglitazone
o gliptin + sulfonylurea
o 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
Hypertension
· blood pressure targets are the same as for patients without type 2 diabetes (see table below)
· ACE inhibitors are first-line
| Clinic BP | ABPM / HBPM | |
| Age < 80 years | 140/90 mmHg | 135/85 mmHg |
| Age > 80 years | 150/90 mmHg | 145/85 mmHg |
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
| | |
| |
Graphic showing choice of statin.
*this is a bit confusing because isn't the diagnostic criteria for T2DM HbA1c 48 mmol/mol (6.5%)? So shouldn't all patients be offered metformin at diagnosis? Our interpretation of this is that some patients upon diagnosis will elect to try lifestyle measures, which may reduce their HbA1c below this level. If it then rises to the diagnostic threshold again metformin should be offered
From <https://www.passmedicine.com/question/questions.php?q=0#>
21 December 2020
21:48
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
JBDS example of fluid replacement regime for patient with a systolic BP on admission 90mmHg and over
| Fluid | Volume |
| 0.9% sodium chloride 1L | 1000ml over 1st hour |
| 0.9% sodium chloride 1L with potassium chloride | 1000ml over next 2 hours |
| 0.9% sodium chloride 1L with potassium chloride | 1000ml over next 2 hours |
| 0.9% sodium chloride 1L with potassium chloride | 1000ml over next 4 hours |
| 0.9% sodium chloride 1L with potassium chloride | 1000ml over next 4 hours |
| 0.9% sodium chloride 1L with potassium chloride | 1000ml over next 6 hours |
Please note that slower infusion may be indicated in young adults (aged 18-25 years) as they are at greater risk of cerebral oedema.
JBDS potassium guidelines
| Potassium level in first 24 hours (mmol/L) | Potassium replacement in mmol/L of infusion solution |
| Over 5.5 | Nil |
| 3.5-5.5 | 40 |
| Below 3.5 | Senior review as additional potassium needs to be given |
Complications of DKA and its treatment
· gastric stasis
· thromboembolism
· arrhythmias secondary to hyperkalaemia/iatrogenic hypokalaemia
· iatrogenic due to incorrect fluid therapy: cerebral oedema*, hypokalaemia, hypoglycaemia
· acute respiratory distress syndrome
· acute kidney injury
* children/young adults are particularly vulnerable to cerebral oedema following fluid resuscitation in DKA and often need 1:1 nursing to monitor neuro-observations, headache, 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
From <https://www.passmedicine.com/review/textbook.php?s=#>
22 December 2020
16:16
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.'
From <https://www.passmedicine.com/question/questions.php?q=0>
21 December 2020
21:48
Addisonian crisis
Causes
· sepsis or surgery causing an acute exacerbation of chronic insufficiency (Addison's, Hypopituitarism)
· adrenal haemorrhage eg Waterhouse-Friderichsen syndrome (fulminant meningococcemia)
· steroid withdrawal
Management
· hydrocortisone 100 mg im or iv
· 1 litre normal saline infused over 30-60 mins or with dextrose if hypoglycaemic
· continue hydrocortisone 6 hourly until the patient is stable. No fludrocortisone is required because high cortisol exerts weak mineralocorticoid action
· oral replacement may begin after 24 hours and be reduced to maintenance over 3-4 days
From <https://www.passmedicine.com/review/textbook.php?s=#>
Features of an addisonian crisis:
· Hyponatraemia
· Hyperkalaemia
· Hypoglycaemia
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22 December 2020
19:10
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:
| Minimal glucocorticoid activity, very high mineralocorticoid activity, | Glucocorticoid activity, high mineralocorticoid activity, | Predominant glucocorticoid activity, low mineralocorticoid activity | Very high glucocorticoid activity, minimal mineralocorticoid activity |
| Fludrocortisone | Hydrocortisone | Prednisolone | Dexamethasone Betmethasone |
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
From <https://www.passmedicine.com/question/questions.php?q=0>
22 December 2020
20:51
Phaeochromocytoma
Pheochromocytoma
Phaeochromocytoma is a rare catecholamine secreting tumour. About 10% are familial and may be associated with MEN type II, neurofibromatosis and von Hippel-Lindau syndrome
Basics
· bilateral in 10%
· malignant in 10%
· extra-adrenal in 10% (most common site = organ of Zuckerkandl, adjacent to the bifurcation of the aorta)
Features are typically episodic
· hypertension (around 90% of cases, may be sustained)
· headaches
· palpitations
· sweating
· anxiety
Tests
· 24 hr urinary collection of metanephrines (sensitivity 97%*)
· this has replaced a 24 hr urinary collection of catecholamines (sensitivity 86%)
Surgery is the definitive management. The patient must first however be stabilized with medical management:
· alpha-blocker (e.g. phenoxybenzamine), given before a
· beta-blocker (e.g. propranolol)
*BMJ 2012; 344 doi: http://dx.doi.org/10.1136/bmj.e1042 (Published 20 February 2012
Labetalol has both alpha and beta action
From <https://www.passmedicine.com/question/questions.php?q=0>
22 December 2020
18:01
Thyroid cancer
Features of hyperthyroidism or hypothyroidism are not commonly seen in patients with thyroid malignancies as they rarely secrete thyroid hormones
Main points
| Type | Percentage | |
| Papillary | 70% | Often young females - excellent prognosis |
| Follicular | 20% | |
| Medullary | 5% | Cancer of parafollicular (C) cells, secrete calcitonin, part of MEN-2 |
| Anaplastic | 1% | Not responsive to treatment, can cause pressure symptoms |
| Lymphoma | Rare | Associated with Hashimoto's thyroiditis |
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
Further information
| Type | Notes |
| Papillary carcinoma | · Usually contain a mixture of papillary and colloidal filled follicles · Histologically tumour has papillary projections and pale empty nuclei · Seldom encapsulated · Lymph node metastasis predominate · Haematogenous metastasis rare |
| Follicular adenoma | · Usually present as a solitary thyroid nodule · Malignancy can only be excluded on formal histological assessment |
| Follicular carcinoma | · May appear macroscopically encapsulated, microscopically capsular invasion is seen. Without this finding the lesion is a follicular adenoma. · Vascular invasion predominates · Multifocal disease raree |
| Medullary carcinoma | · C cells derived from neural crest and not thyroid tissue · Serum calcitonin levels often raised · Familial genetic disease accounts for up to 20% cases · Both lymphatic and haematogenous metastasis are recognised, nodal disease is associated with a very poor prognosis. |
| Anaplastic carcinoma | · Most common in elderly females · Local invasion is a common feature · Treatment is by resection where possible, palliation may be achieved through isthmusectomy and radiotherapy. Chemotherapy is ineffective. |
From <https://www.passmedicine.com/question/questions.php?q=0>
21 December 2020
21:48
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 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
From <https://www.passmedicine.com/review/textbook.php?s=#>
22 December 2020
19:45
Diabetes mellitus: GLP-1 drugs
A number of drugs to treat diabetes mellitus have become available in recent years. Much 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
Whilst it is well known that insulin resistance and insufficient B-cell compensation occur other 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 decreased in T2DM.
Increasing GLP-1 levels, either by the administration of an analogue (glucagon-like peptide-1, GLP-1 mimetics, e.g. exenatide) or inhibiting its breakdown (dipeptidyl peptidase-4 ,DPP-4 inhibitors - the gliptins), is therefore the target of two recent classes of drug.
Glucagon-like peptide-1 (GLP-1) mimetics (e.g. exenatide)
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 that they typically result in weight loss, in contrast to many medications such as insulin, sulfonylureas and thiazolidinediones. They are sometimes used in combination with insulin in T2DM to minimise weight gain.
Exenatide must be given by subcutaneous injection within 60 minutes before the morning and evening meals. It should not be given after a meal.
Liraglutide is the other GLP-1 mimetic currently available. One the main advantages of 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 release exenatide is also licensed to be used with basal insulin alone or with metformin. Please see the BNF for a more complete list of licensed indications.
NICE state the following:
Consider adding exenatide to metformin and a sulfonylurea if:
· 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 weight loss would benefit other comorbidities.
NICE like patients to have achieved a > 11 mmol/mol (1%) reduction in HbA1c and 3% weight loss after 6 months to justify the ongoing prescription of GLP-1 mimetics.
The major adverse effect of GLP-1 mimetics is nausea and vomiting. The Medicines and Healthcare products Regulatory Agency has issued specific warnings on the use of exenatide, reporting that is has been linked to severe pancreatitis in some patients.
Dipeptidyl peptidase-4 (DPP-4) inhibitors (e.g. Vildagliptin, sitagliptin)
Key points
· DPP-4 inhibitors increase levels of incretins (GLP-1 and GIP)
· oral preparation
· trials to date show that the drugs are relatively well tolerated with no increased incidence of hypoglycaemia
· do not cause weight gain
NICE guidelines on DPP-4 inhibitors
· NICE suggest that a DPP-4 inhibitor might be preferable to a thiazolidinedione if further weight gain would cause significant problems, a thiazolidinedione is contraindicated or the person has had a poor response to a thiazolidinedione
From <https://www.passmedicine.com/question/questions.php?q=0#>
22 December 2020
19:14
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.
| HBA1c (%) | Average plasma glucose (mmol/l) | IFCC-HbA1c (mmol/mol) |
| 5 | 5.5 | |
| 6 | 7.5 | 42 |
| 7 | 9.5 | 53 |
| 8 | 11.5 | 64 |
| 9 | 13.5 | 75 |
| 10 | 15.5 | |
| 11 | 17.5 | |
| 12 | 19.5 |
From the above we can see that average plasma glucose = (2 * HbA1c) - 4.5
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21 December 2020
21:48
Gynaecomastia
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 galactorrhoea (due to the actions of prolactin on breast tissue) from those of gynaecomastia
Causes of gynaecomastia
· physiological: normal in puberty
· syndromes with androgen deficiency: Kallman's, Klinefelter's
· testicular failure: e.g. mumps
· liver disease
· 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
· finasteride
· GnRH agonists e.g. goserelin, buserelin
· oestrogens, anabolic steroids
Very rare drug causes of gynaecomastia
· tricyclics
· isoniazid
· calcium channel blockers
· heroin
· busulfan
· methyldopa
From <https://www.passmedicine.com/review/textbook.php?s=#>
22 December 2020
20:23
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
o absorption of levothyroxine reduced, give at least 4 hours apart
*source: NICE Clinical Knowledge Summaries
From <https://www.passmedicine.com/question/questions.php?q=0#>
22 December 2020
19:12
Multiple endocrine neoplasia
The table below summarises the three main types of multiple endocrine neoplasia (MEN). MEN is inherited as an autosomal dominant disorder.
Men-2 Men-1
| MEN type I | MEN type IIa | MEN type IIb |
| 3 P's Parathyroid (95%): hyperparathyroidism due to parathyroid hyperplasia Pituitary (70%) Pancreas (50%): e.g. insulinoma, gastrinoma (leading to recurrent peptic ulceration) Also: adrenal and thyroid | Medullary thyroid cancer (70%) 2 P's Parathyroid (60%) Phaeochromocytoma | Medullary thyroid cancer 1 P Phaeochromocytoma Marfanoid body habitus Neuromas |
| MEN1 gene Most common presentation = hypercalcaemia | RET oncogene | RET oncogene |
| | |
| |
Venn diagram showing the different types of MEN and their associated features
From <https://www.passmedicine.com/question/questions.php?q=0>
21 December 2020
21:48
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)
From <https://www.passmedicine.com/review/textbook.php?s=#>
22 December 2020
19:53
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
From <https://www.passmedicine.com/question/questions.php?q=0#>
5 clinical features:
Enlarged hands and feet
Change in glove, ring or shoe size.
Coarse, enlarged facial features.
Coarse, oily, thickened skin.
Excessive sweating and body odour.
Small outgrowths of skin tissue (skin tags)
A deep, husky voice due to enlarged vocal cords and sinuses
Enlarged lips
Enlarged tongue
Prognathism, protrusion of lower jaw
Increase in inter dental spacing
Malocclusion of teeth
Visual field defect due to pituitary enlargement (Bi temporal hemianopia)
Test: Glucose tolerance test
Treatment:
Any 4 of the following:
Pituitary surgery or Tran-sphenoidal pituitary adenomectomy
Radiotherapy
Dopamine receptor agonists
Somatostatin analogues
Pegvisomant (growth hormone receptor antagonist)
Tuesday, 22 December 2020
23:33
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 (TPO) and also anti-thyroglobulin (Tg) antibodies
Associations
· other autoimmune conditions e.g. coeliac disease, type 1 diabetes mellitus, vitiligo
· Hashimoto's thyroiditis is associated with the development of MALT lymphoma
| | |
| |
Venn diagram showing how different causes of thyroid dysfunction may manifest. Note how many causes of hypothyroidism may have an initial thyrotoxic phase.
21 December 2020
21:48
Thyroid storm
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 thyroxine excess does not usually result in thyroid storm.
Precipitating events:
· thyroid or non-thyroidal surgery
· trauma
· infection
· acute iodine load e.g. CT contrast media
Clinical features include:
· fever > 38.5ÂșC
· tachycardia
· confusion and agitation
· nausea and vomiting
· hypertension
· heart failure
· abnormal liver function test - jaundice may be seen clinically
Management:
· symptomatic treatment e.g. paracetamol
· treatment of underlying precipitating event
· beta-blockers: typically IV propranolol
· anti-thyroid drugs: e.g. methimazole or propylthiouracil
· Lugol's iodine
· dexamethasone - e.g. 4mg IV qds - blocks the conversion of T4 to T3
From <https://www.passmedicine.com/review/textbook.php?s=#>
22 December 2020
20:52
Insulin therapy: side-effects
Hypoglycaemia
· patients should be taught the signs of hypoglycaemia: sweating, anxiety, blurred vision, confusion, aggression
· conscious patients should take 10-20g of a short-acting carbohydrate (e.g. a glass of Lucozade or non-diet drink, three or more glucose tablets, glucose gel)
· every person treated with insulin should have a glucagon kit for emergencies where the patient is not able to orally ingest a short-acting carbohydrate
· patients who have frequent hypoglycaemic episodes may develop reduced awareness. If this develops then allowing glycaemic control to slip for a period of time may restore their awareness
· beta-blockers reduce hypoglycaemic awareness
Lipodystrophy
· typically presents as atrophy/lumps of subcutaneous fat
· can be prevented by rotating the injection site
· may cause erractic insulin absorption
From <https://www.passmedicine.com/question/questions.php?q=0#>
22 December 2020
17:06
Graves' disease: features
Graves' disease is the most common cause of thyrotoxicosis. It is typically seen in women aged 30-50 years.
Features
· typical features of thyrotoxicosis
· specific signs limited to Grave's (see below)
Features seen in Graves' but not in other causes of thyrotoxicosis
· eye signs (30% of patients)
o exophthalmos
o ophthalmoplegia
· pretibial myxoedema
· thyroid acropachy, a triad of:
o digital clubbing
o soft tissue swelling of the hands and feet
o periosteal new bone formation
Autoantibodies
· TSH receptor stimulating antibodies (90%)
· anti-thyroid peroxidase antibodies (75%)
From <https://www.passmedicine.com/question/questions.php?q=0>
22 December 2020
17:08
SGLT-2 inhibitors
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 excretion.
Examples include canagliflozin, dapagliflozin and empagliflozin.
Important adverse effects include
· urinary and genital infection (secondary to glycosuria). Fournier’s gangrene has also been reported
· normoglycaemic ketoacidosis
· increased risk of lower-limb amputation: feet should be closely monitored
Patients taking SGLT-2 drugs often lose weight, which can be beneficial in type 2 diabetes mellitus.
From <https://www.passmedicine.com/question/questions.php?q=0>
Wednesday, 23 December 2020
00:27
Myxoedema coma
Myxoedema coma typically presents with confusion and hypothermia.
Myxoedema coma is a medical emergency requiring treatment with
· IV thyroid replacement
· IV fluid
· IV corticosteroids (until the possibility of coexisting adrenal insufficiency has been excluded)
· electrolyte imbalance correction
· sometimes rewarming
22 December 2020
19:28
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 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
From <https://www.passmedicine.com/question/questions.php?q=0>
31 December 2020
19:58
Levothyroxine not associated with diabetes
31 December 2020
20:05
Levothyroxine is not associated with inducing diabetes. In patients with diabetes starting thyroxine, doses of antidiabetic drugs including insulin may need to be increased.
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