Endocrine (240) Flashcards
1
Q
Endocrine system made up of?
A
DUCTLESS endocrine glands
2
Q
How are endocrine signals terminated? (2)
A
Either by
- Metabolic inactivation in liver
- Inactivation at sites of action
3
Q
Complementary protein actions? Antagonistic actions?
A
- Complementary e.g. = adrenaline, cortisol and glucagon all prevent hypoglycaemia and hypokalaemia during short-term intense exercise
- Antagonistic = insulin vs glucagon
4
Q
Specific carrier proteins for hormones? (3)
General carrier proteins? (2)
A
Specific
- Cortisol-binding globulin = binds cortisol
- Thyroxine-binding globulin = binds thyroxine T4
- Sex-steroid binding globulin = binds testosterone and oestradiol
General
* Albumin
* Transthyretin
(both bind steroids + thyroxine)
5
Q
Why can bound hormone not cross capillary wall?
A
Too large = only free hormone can cross capillary wall to activate receptors in target tissues (i.e. BIOPHASE)
6
Q
What controls rate of secretion?
A
HPA negative feedback loop
- Hypothalamus (secretes CRF) -> Anterior pituitary (secretes ACTH) -> adrenal cortext (secretes cortisol) -> inhibits pituitary and hypothalamus
7
Q
Plasma concentration of hormone equal to?
A
Plasma concentration = rate of secretion - rate of elimination
8
Q
Half life of amines e.g. adrenaline? Proteins and peptides? Steroids and thyroid hormones?
A
- Amines = seconds
- Proteins and peptides = minutes
- Steroids and thyroid hormones = hours to days (due to extensive protein binding suppressing elimination)
9
Q
Hormone receptor types? (3)
A
- GPCR - activated by amines and some proteins/peptides
- Receptor kinases - some proteins/peptides e.g. insulin
- Nuclear receptors - subdivided into class 1 (steroid hormones, located in cytoplasm bound to heat shock proteins), class 2 (activated by lipids, found in nucleus) and hybrid class (activated by thyroid hormone T3)
10
Q
Gs and Gi protein signalling? Gq11?
A
Gs and Gi (adrenaline, CRF, glucagon) = adenylyl cyclase, cAMP + PKA
Gq (angiotensin II, thyrotropin releasing hormone, gonadotropin releasing hormone) = PLC, PKC, IP3, CICR
11
Q
Signalling via receptor kinases e.g.?
A
Insulin!
- Binding of insulin causes autophosphorylation of intracellular tyrosine residues
- IRS1 proteins recruited and also phosphorylated
- Activates protein kinase B which produces metabolic effects
12
Q
Look at pharmacology table of endocrine glands and their secretions!
A
…
13
Q
Cells of the pancreas? (2)
A
- Exocrine tissue = acinar cells
* Islets = a cells, B cells, d-cells, PP- cells
14
Q
Function of pancreatic islets? (4)
A
- Beta cells = secrete insulin
- Alpha cells = secrete glucagon
- Delta cells = secrete somatostatin
- PP cells - secrete pancreatic polypeptide
15
Q
Explain synthesis of insulin? (2)
A
- Synthesised in RER of pancreatic B cells as preproinsulin
* Cleaved to form insulin
16
Q
Explain structure of insulin (2)
A
- 2 polypeptide chains (A chain + B chain) linked by disulphide bonds
- C peptide is connected to insulin as a byproduct of cleavage but has no known physiological function
17
Q
Insulin preparations? (5)
A
- Ultra shot-acting = lispro
- Short-acting = regular
- Intermediate = NPH + lente
- Long-acting = ultralente
- Ultra long-acting = glargine
18
Q
What is lispro insulin?
A
Ultra short-acting = lysine and proline swap positions, making much more unstable (so less time spent in blood)
19
Q
Features of lispro insulin? (5)
A
- Monomeric
- Not antigenic
- Most rapidly acting insulin!!
- Injected within 15 minutes of starting meal
- Must be used in combination with other insulin preparations as very very short-acting!!
20
Q
What is insulin glargine?
Administration?
A
Ultra long-acting - asparagine swapped to glycine on A chain + 2 arginine residues added to B-chain
* Administered as single bedtime dose
21
Q
Explain process of insulin secretion (6)
A
- Glucose enters B cells thru GLUT2 transporter and is phosphorylated by glucokinase
- Increased metabolism of glucose leads to increase in intracellular ATP
- ATP inhibits K+ channel (kATP) preventing K+ from exiting cell
- Depolarisation of cell membrane
- Depolarisation opens voltage-gated Ca++ channels
- Increased intracellular Ca++ concentration causes release of insulin from vesicles
22
Q
When should B cells secrete insulin?
A
Should only secrete insulin in response to blood glucose rising above 5mM (Beta cells are lost in T1DM)
23
Q
How many phases does insulin release occur in?
Why?
A
2 phases (2nd phase dependent on effectiveness of 1st phase) * Reserve pools of insulin are important (i.e. only 5% of insulin granules available for immediate release) so entire insulin store isn't depleted
24
Q
Mechanism of action of sulphonurea in T2DM?
A
Mimic the action of ATP to depolarise beta cells
25
What 2 proteins are kATP channels made up?
* Kir6 and SUR1
26
What has the opposite effect of ATP (and thus sulphonourea) on beta cells?
Diazoxide - inhibits insulin secretion by STIMULATING kATP!!!
27
What are SURs?
Second line tx for T2DM
28
What is maturity-onset diabetes of the young (MODY)?
| What gene mutations can cause MODY? (6)
Monogenic diabetes with genetic defect in β cell function (results in impaired insulin secretion!!)
* Glucokinase
* Hepatocyte nuclear factor-4a
* Hepatocyte nuclear factor -1a
* Insulin promoter factor 1
* Hepatocute nuclear factor 1B
* Neurogenic differentiation factor 1
29
What does impaired glucokinase activity lead to?
MODY2
30
Why is robust genetic screening to differentiate between MODY and T1DM important??
MODY can be treated with sulphonylurea rather than insulin!! Type 1 diabetics cannot
31
What is type 1 diabetes?
MODY?
Type 2 diabetes?
* Type 1 = loss of B cells (req endogenous insulin)
* MODY = defective glucose sensing in pancreas + loss of insulin secretion
* Type 2 diabetes = hyperglycaemia and hyperinsulinaemia (reduced insulin sensitivity in tissues)
32
Biological effects of insulin? (9)
STIMULATES
* Amino acid uptake in muscle
* DNA synthesis
* Protein synthesis
* Growth
* Glucose uptake in muscle + adipose tissue
* Lipogenesis in adipose tissue and liver
* Glycogen synthesis in liver and muscle
INHIBITS
* Lipolysis
* Gluconeogenesis in liver
33
What are the 2 pathways by which insulin mediates its effects? (2)
Pathway 1
* IRS-1 -> PI3K -> PKB -> glycogen synthesis + cell growth
Pathway 2
* IRS-1 -> Ras -> MAP kinase pathway -> gene expression + cell growth
34
What is leprechaunism (Donohue syndrome)?
| S/s? (3)
Rare autosomal recessive - mutation in insulin receptor causing SEVERE INSULIN RESISTANCE!!
* Elvin facial appearance
* Growth retardation
* Absence of subcutaneous fat + decreased muscle mass
35
Rabson Mendenhall syndrome?
| S/s? (4)
Rare autosomal recessive - SEVERE INSULIN RESISTANCE
* Developmental abnormalities
* Acanthosis nigricans (hyperpigmentation)
* Fasting hypoglycaemia (due to hyperinsulinaemia)
* Diabetic ketoacidosis
36
Diabetic ketoacidosis symptoms? (4)
* Vomiting
* Dehydration
* Increased HR
* Acetone smell on breath
37
How are ketone bodies formed?
| When are ketone bodies formed? (2)
Formed in liver mitochondria from acetyl-CoA from B oxidation of fats
* Insulin normally inhibits lipolysis and prevents ketone body overload
* In T1DM - DKA is a danger is insulin injection is missed!!
* Rarer in T2DM but can occur as insulin resistance increases!!
38
Tx for DKA?
Insulin + rehydration
39
What is diabetes mellitus?
a group of metabolic diseases characterized by hyperglycemia resulting from defects in insulin secretion/insulin action
40
Diabetes Dx? (4)
* HbA1c = >48m/m
* Fasting glucose = >7 mmol
* 2-hr glucose in OGTT = >11.1 mmol
* Random glucose = >11.1 mmol
41
Gestational diabetes mellitus?
diabetes diagnosed in the second or third trimester of pregnancy that was not clearly overt diabetes prior to gestation
42
Clinical presentation T1DM? (4)
| Symptoms? (4)
* Pre-school + during puberty
* Severe weight loss
* Acute onset
* Ketonuria + metabolic acidosis
4Ts
* Toilet
* Thirsty
* Tired
* Thinner
43
T2DM clinical presentation? (4)
* Middle-aged/elderly
* Obese
* Insidious onset
* Evidence of micro-vascular disease (unlike T1DM)
44
Testing criteria for DM in asymptomatic adults? (9)
* Obese
* First-degree relative with diabetes
* High risk race (e.g. Asian)
* History of CVD
* Hypertension
* High cholesterol
* Women with PCOS
* Physical inactivity
* Other clinical conditions associated with insulin resistance (e.g. Rabson Mendenhall syndrome)
45
Risk factors for T2DM? (6)
* Obesity
* FH
* Gestational diabetes
* Ethnicity
* PHx of MI/stroke
* Medications e.g. antipsychotics
46
Symptoms of diabetes mellitus? (8)
* Thirst
* Polyuria
* Thrush
* Fatigue
* Blurred vision
* Infections
* Weight loss
* T2DM = neuropathy + retinopathy
47
Useful discriminatory tests between type 1 and type 2? (4)
Type 1 associated with
* Autoimmine markers (GAD)
* Ketones
* C-peptide in plasma
* HLA association with DQA and DQB genes
48
How to differentiate between late-onset type 1 diabetes and 'typical' type 2 diabetes?
Type 1 diabetes = KETOSIS
49
Type 3 diabetes?
Gestational diabetes = any degree of glucose intolerance arising or diagnosed during pregnancy
50
Type 4 diabetes? (4)
* Pancreatic disease e.g. pancreatitis, haemochromatosis, CF
* Endocrine disease e.g. Cushing's, acromegaly, phaeochromocytoma
* Drug-induced = glucocorticoids, diuretics, B-blockers
* Genetic diseases = CF, myotonic dystrophy, Turner's syndrome
51
Features of monogenic diabetes (e.g. MODY)? (5)
* FH
* Renal cysts
* Young onset
* GAD negative
* C-peptide positive
52
What is HbA1c?
Measure of blood glucose over past 2-3 months
53
Complications of diabetes mellitus? (3)
* Macro-vascular = heart disease + stroke (70% die from CVD)
* Micro-vascular = retinopathy, nephropathy, neuropathy
* Psychological = depression/anxiety
54
Pathophysiology T2DM?
Genetic predisposition + obesity -> insulin resistance
* Compensatory B cell hyperplasia = normoglycaemia
* B cell failure (early) = impaired glucose tolerance
* B cell failure (late) = diabetes
55
What does B cell dysfunction in T2DM lead to?
| What does chronic hyperglycaemia lead to?
Hyperglycaemia
| * Microvascular disease!
56
Complications of diabetes? (5)
* Macrovascular = IHD + stroke
* Microvacular = neuropathy, nephropathy, retinopathy
* Dementia
* Erectile dysfunction
* Psychiatric
57
Types of diabetic neuropathy? (4)
* Peripheral = pain/loss of feeling in feet, hands
* Autonomic = changes in bowel, bladder function, sexual response, sweating, HR, BP
* Proximal = pain in thighs, hips/buttocks, leading to weakness in legs (amyotrophy)
* Focal neuropathy = sudden weakness in one nerve or group of nerves causing muscle weakness or pain e.g. carpal tunnel, foot drop, bells palsy
58
Neuropathy risk factors? (8)
* Increased length of diabetes
* Poor glycaemic control
* Type 1 > type 2
* High cholesterol
* Smoking
* Alcohol
* Genes
* Mechanical injury
59
What is peripheral neuropathy associated with increased risk of?
Increased risk of focal osteoporosis due to bone resorption
60
Tx painful neuropathy? (5)
* Amitriptyline
* Duloxetine
* Gabapentin
* Pregabalin
* Capsaicin cream (if cannot tolerate oral)
61
What is charcot foot?
Complication of peripheral neuropathy (rockerbottom feet)
62
What group is most commonly affected by diabetic proximal neuropathy?
What is proximal neuropathy associated with?
Elderly T2D
| * Associated with marked weight loss
63
What is gastroparesis?
S/s?
Complication?
Associated with diabetic autonomic neuropathy - slow stomach emptying
* Nausea
* Vomiting
* Bloating
* Loss of appetite
Complications = Can make blood glucose levels fluctuate due to abnormal digestion!
64
Tx gastropesis? (5)
* Glycaemic control
* Smaller more frequent food portions (low fat, low fibre)
* Promotility drugs like metoclopramide
* Botulinum toxin
* Gastric pacemaker
65
What is gustatory sweating?
| Tx?
Caused by autonomic neuropathy, profuse sweating at night or when eating
Tx
* topical glycopyrrolate
* clonidine
* botulinum toxin
66
What happens to BP and HR in autonomic neuropathy?
* BP = may drop sharply after sitting or standing, causing syncope
* HR = raised
67
Screening for neuropathy? (5)
* Diabetic foot screening
* Nerve conduction studies or electromyography
* HR
* Ultrasound of bladder
* Gastric emptying studies
68
What is diabetic nephropathy?
Also known as?
Hallmark?
progressive kidney disease caused by damage to the capillaries in the kidneys' glomeruli
* Kimmelsteil-Wilson syndrome or nodular glomerulosclerosis
* Microvascular changes (angiopathy of capillaries)
69
Complications of diabetic nephropathy? (3)
* Hypertension
* Decline in renal function (decreased GFR)
* Accelerated vascular disease
70
What is used to screen for nephropathy?
albumi creatinine ratio (ACR) to screen for diabetic kidney disease
71
Tx and Ix for microalbuminuria? (6)
* Monitor serum creatinine
* Check for retinopathy
* Screen for PVD
* Screen for IHD
* Smoking cessation
* Glycaemic control
* Tx hypertension
72
Risk factors for nephropathy progression?
* Hypertension
* Cholesterol
* Smoking
* Glycaemic control
* Albuminuria
73
Tx nephropathy? (3)
* BP maintained at <130/80
* ACE-I or ARB
* Glycaemic control
74
Diabetic eye disease e.g.? (4)
* Diabetic Retinopathy
* Cataract- clouding of the lens (develops earlier in people with diabetes)
* Glaucoma- increase in fluid pressure in the eye leading to optic nerve damage. 2 x more common in diabetes
* Acute hyperglycaemia- visual blurring (reversible)
75
Stages of retinopathy? (4)
* Mild non-proliferative (background retinopathy) - haemorrhage
* Moderate non-proliferative (hard exudate, haemorrhages)
* Severe non-proliferative (IRMA, venous beading, haemorrhages)
* Proliferative (new vessel formation)
76
Retinopathy terminology? (4)
* Haemorrages: Dot/ Blot/ Flame
* Cotton Wool Spots: Ischaemic Areas
* Hard Exudates: Lipid break down products
* IRMA: Intra-retinal microvascular abnormalities (abnormalities of blood vessels)
77
Complications of diabetic retinopathy? (2)
* Secondary glaucoma
| * Retinal detachment
78
Retinopathy tx? (3)
* Laser
* Virectomy
* Anti-VEGF (only tx that can help regain vision)
79
What is the cause of erectile dysfunction in diabetics?
Vascular + neuropathy
80
Diabetic screening?
* Risk assessment then fasting blood glucose
* High risk groups (impaired glucose tolerance, previous gestational diabetes) should be recalled annually for a fasting venous (plasma) glucose measurement
* Other high risk groups (PCOS, FH of T2DM, obese) should be screened OPPORTUNISTICALLY
81
When should you consider a diagnosis of diabetes in a patient? (7)
* thirst and polyuria
* unexplained weight loss or tiredness
* pruritus vulvae, balanitis or recurrent UTIs
* recurrent infections
* blurring of vision (usually an osmotic effect and not permanent)
* discoloured or ulcerated feet
* Acutely unwell- vomiting/abdominal pain (children)
82
How to make diagnosis of diabetes? (3)
1. Classical symptoms (e.g. polyuria, polydipsia, unexplained weight loss) plus one of the following:
* random plasma venous glucose concentration ≥11.1 mmol/L or
* fasting venous plasma glucose concentration ≥7.0 mmol/L or
* venous plasma glucose concentration ≥11.1 mmol/L (2 hour sample in OGTT)
2. No symptoms i.e. incidental finding of glycosuria or hyperglycaemia
* Diagnosis should not be based on a single venous plasma glucose measurement
* Additional testing on another day with a value in the diabetic range is essential
* If fasting or random values are not diagnostic, the 2-hour value should be used
3. If ketonuria is present with:
Severe symptoms i.e. vomiting and dehydration, urgent hospital admission is required
83
when is oral glucose tolerance test (OGTT) carried out?
| Process?
If fasting glucose 6.1 - 6.9
* Initial fasting glucose
* 75g anhydrous glucose
* Repeat plasma glucose at 2 hrs
84
What diabetics should be referred to secondary care? (5)
* Definite or likely Type 1 diabetes (urgent telephone referral to on-call Paediatric or Adult Diabetes Team)
* Patients with low or low normal BMI
* All children
* Patients who are pregnant or planning a pregnancy
* Pre-existing Chronic Renal Impairment
* Seriously consider if patient under age of 40 at diagnosis of * Type 2 diabetes (especially if strong family history of diabetes)
85
What is the golden rule of type 1 diabetes?
Insulin should NEVER be omitted due to the risk of Diabetic Ketoacidosis (DKA)
ALWAYS check for ketones
86
Mx for DKA? (5)
* Increase insulin dose by 10% if blood glucose levels elevated (consider STAT dose of rapid insulin i.e. 10-20% of patient's total daily dose)
* 100-200 ml of fluid every hour + regular intake of carbs
* If unable to eat, consider 200 ml of sugary drink e.g. fruit juice
* Glucose monitoring 4 times per hour
* Ketone monitoring (after STAT delivered, recheck ketones in 1-2 hrs)
87
Clinical signs of ketoacidosis? (4)
* Dehydration
* Abdominal pain
* Vomiting
* Kussmaul
88
What medications should not be taken on "sick days" i.e. fever, vomiting, diarrhoea? (4)
* ACEIs + ARBS
* Diuretics
* Metformin
* NSAIDs
89
What is DKA?
disordered metabolic state that usually occurs in the context of an insulin deficiency accompanied by an increase in the counter-regulatory hormones i.e. glucagon, adrenaline, cortisol and growth hormone
90
Pathophysiology DKA?
* Insulin deficiency
* Stress hormone activation
* Lipolysis -> ketogenesis -> acidosis
* Decreased glucose uptake
* Proteolysis
* Glycogenolysis
* Lead to hyperglycaemia -> glycosuria -> electrolyte loss -> dehydration -> decreased renal function
91
Dx DKA? (4)
* Ketonaemia >3mmol/L
* Ketonuria >2+ on dipstick
* Blood glucose > 11 mmol/L
* Bicarbonate <15 mmol/L or venous pH <7.3
92
Causes of death from DKA? (4)
Adults
* Hypokalaemia
* Aspiration pneumonia (vomiting)
* ARDS
Children
* Cerebral oedema
93
Conditions associated with DKA? (2)
* Sepsis
| * Gastroeteritis
94
Classical biochemistry of DKA at diagnosis? (9)
* Glucose - ~40 mmol/L (from 11 - 100)
* Potassium often raised (but beware low potassium!!)
* Creatinine raised
* Sodium low
* Raised lactate
* Blood ketones >5
* Bicarbonate <10 in severe cases
* Amylase raised
* Raised WCC
95
Tx DKA? (5)
* Fluid 0.9% NaCL (then dextrose one glucose falls to 15)
* Insulin
* Potassium
* Monitor K+
* Prophylactic LMWH (thrombus)
96
How are ketone levels monitored? (2)
Blood Ketone testing
* Optium meter
* Measures beta-hydroxybutyrate
* Meter range 0 - 8mmol/L
* < 0.6 mmol/L normal
Urine ketone testing
* Measures acetoacetate
* Indicates levels of ketones 2-4 hours previously
* Ketonuria persists after clinical improvement due to mobilisation of ketones from fat tissue
97
Pathophysiology of Hyperglycaemic Hyperosmolar Syndrome?
osmotic diuresis leads to hyperosmolar state
98
Biochemical diagnosis HHS? (5)
* Hypovolaemia
* Hyperglycaemia >30 mmol
* No ketonaemia (differentiate from DKA)
* Bicarbonate >15 mmol/L or venous pH >7.3 (again, different from DKA)
* Osmolality >320 mosmol/kg
99
Features of HHS? (3)
* Diabetes often not known at presentation
* Older patients (or young afro-caribbean)
* Associated with:CVD, sepsis, medication like steroids/diuretics
100
Compare DKA to HHS? (6)
DKA
* Younger
* Type 1
* Cause = Insulin deficiency
* Precipitant = insulin omission
* Mortality = <2%
* Tx= insulin
HHS
* Older
* Type 2
* Cause = diuretics, steroids, fizzy drinks
* Precipitant = infection
* Mortality = 10-50%
* Tx = diet, OHA
101
Differences in tx of HHS vs DKA? (3)
* Give fluids more cautiously in HHS due to increased risk of fluid overload
* May not req insulin
* Consider 0.45% saline to avoid rapid fluctuations of sodium
102
Tx alcohol-induced keto-acidosis? (4)
* IV pabrinex (high dose vitamins)
* IV fluids - dextrose
* IV anti-emetics
* Insulin usually not required
103
Biochemical dx alcoholic ketoacidosis? (4)
* Dehydration
* Ketonaemia > 3 mmol or ketonuria >2
* Bicarbonate <15 mmol or venous pH <7.3
* Glucose normal
104
Pathophysiology alcohol-induced ketoacidosis? (5)
* Ethanol broken down ino acetaldehyde by ADH
* Acetaldehyde then broken down into acetate by ALDH
* Acetate then loses water and CO2 to become acetoacetate
* Acetoacetate becomes Beta-OHB!!
105
Target in-patient blood sugar for T1DM?
6-10 mmol (accept range of 4-12)
106
where does lactate come from?
| What does clearance require?
Lacate is end product of anaerobic glucose metabolism - comes from RBCs, skeletal muscle, brain + renal medulla
* Clearance = hepatic uptake and aerobic conversion to pyruvate then glucose
107
Ion gap?
[Na + K] - [HCO3 + Cl]
| Normal range in 10-18
useful for deeming cause of acidosis
108
Type A lactic acidosis?
Associated with tissue hypoxaemia e.g. sepsis, haemorrhage
109
Type B lactic acidosis?
* Associated with liver disease, leukaemic states, diabetes
110
Clinical features lactic acidosis? (3)
| Lab findings?(5)
* Hyperventilation
* Mental confusion
* Coma
Lab
* Reduced bicarbonate
* Raised anion gap
* Glucose often raised
* Absence of ketonaemia
* Raised phosphate
111
Tx lactic acidosis? (4)
* Tx underlying condition e.g. sepsis, diabetes
* Fluids
* Antibiotics
* Withdraw offending medication (METFORMIN)
112
What is MODY?
Ax?
Age of onset?
Maturity Onset diabetes of the Young - non-insulin dependent diabetes!!
* Autosomal dominant inheritance (genetic cause rather than autoimmune destruction of B cells)
* <25 years of age
113
Genetic defects associated with MODY? (3)
* Glucokinase
* Transcription factors - HNF1a, NHF4a, HNF1B
* MODY X
114
What is glucokinase?
First step in glycolysis
115
Insulin secretion in patients with glucokinase mutations?
Sigmoid curve (glucose against insulin secretion) is shifted to the right so require greater volume of glucose to secrete insulin
i.e. have high fasting glucose!! (can produce plenty of insulin after a meal however so will not have high rise after meal)
116
Difference between glucokinase mutations and transcription factor mutations? (2)
* Have glucokinase mutations from birth!
* Transcription factor genes will progress over time (at birth - won't have high glucose)
* Glucokinase - fasting glucose is high but after meal, it decreases
* HNF - have normal fasting glucose but is high after glucose challenge
117
Features of glucokinase mutations? (4)
| Features of transcription factor mutations? (4)
Glucokinase
* Onset at birth
* Stable hyperglycaemia
* Diet treatment - NO NEED FOR INSULIN in glucokinase MODY!!
* Complications rare
Transcription factor
* Adolescence/young adult onset
* Progressive hyperglycaemia
* 1/3 diet, 1/3 OHA, 1/3 Insulin (similar to T2)
* Complications frequent
118
What OHA is effective in treating HNF MODY?
| Why does it work?
Sulphonylureas e.g. gliclazide
* the sites of defect in HNF MODY are mitochondria, L-PK and Glut 2
* The K+ channel is unaffected so sulphonylureas work best
119
What tests are used to differentiate T1DM from MODY? (2)
* Antibodies
| * C-peptide level (MODY will have high C peptide compared to T1)
120
Neonatal diabetes?
| Types? (2)
Requires insulin treatment within first 3 months of life
* Transient neonatal diabetes (TNDM) - usually diagnosed <1 week, resolves around 12 weeks, stop insulin
* Permanent neonatal diabetes (PNDM) - usually diagnosed 0-6 weeks, lifelong insulin
121
What mutation is associated with neonatal diabetes?
| Tx?
KATP channel - insensitive to insulin, no insulin secretion as channel cannot close
* Therefore, best tx is sulphonylureas as they can close channel independent of insulin
122
Histology of type 1 diabetes? Type 2 diabetes?
* Type 1 diabetes - lymphocytes attacking pancreatic islet
| * Type 2 - amyloid deposition
123
Highest risk genetype for type 1 diabetes?
HLA DR3 or DR4
124
Islet auto-antibodies T1DM? (4)
* IA-2
* IAA
* GAD
* ZnT8
125
Maternal factors T1DM? (3)
Auto-immune trigger factors T1DM? (4)
Accelerating factors? (5)
Maternal
* ABO mismatch
* Age
* Infection
Triggers
* Viral infection!
* Vit D deficiency
* Diet
* Environmental toxins
Accelerating factors
* Infection
* Insulin resistance
* Puberty!
* Weight!
* Stress
126
What is checked at annual review of diabetic patients? (5)
* Weight
* BP
* Bloods - HbA1c (monitored regularly anyway), creatinine, lipids
* Retinal screening
* Foot risk
127
Differential diagnoses in someone presenting under 30 years wit diabetes? (6)
* Type 1
* MODY
* LADA
* Mitochondrial gene mutations
* Amylin gene mutations
* Type 2 (unusual)
128
Describe normal secretion of insulin?
Biphasic in response to meal
* rapid pase of pre-formed insulin lasts 5-10 mins
* slow phase over 1-2 hrs
129
What are children diagnosed with diabetes under the age of 6 likely to have?
Monogenic rather than Type 1 Diabetes
130
What is LADA?
| Also known as? (2)
Latent onset diabetes of adulthood - presence of elevated levels of auto-antibodies in newly-diagnosed patients who did not initially require insulin
* slowly progressive type 1
* type 1.5 diabetes
131
When to suspect LADA? (7)
* young adults 25 to 40
* Males
* Usually non-obese
* Auto-antibody positive
* Associated auto-immune conditions
* Non-insulin requiring at diagnosis
* Sub-optimal control on oral agents
132
Significance of cystic fibrosis?
Prone to develop diabetes
133
What is DIDMOAD or Wolfram syndrome?
DIDMOAD (diabetes insipidus, diabetes mellitus, optic atrophy, and deafness), is a rare autosomal-recessive genetic disorder that causes childhood-onset diabetes mellitus, optic atrophy, and deafness
134
Bardet-Biedl Syndrome features? (7)
| Cause?
* Often very obese
* Polydactyly
* Hypogonadal
* Visual impairment
* Hearing impairment
* Mental retardation
* Diabetes
Cause = consanguineous parents
135
Autoimmune conditions associated with diabetes? (6)
* Thyroid
* Coeliacs
* Pernicious anaemia
* Addison's disease
* IgA deficiency
* IPEX syndrome
136
What does thyroid gland secrete? (3)
* Thyroxine
* Tri-iodothyronine
* Calcitonin
137
What do the 4 parathyroid glands secrete?
Parathyroid hormone (PTH)
138
Describe the anatomy and location of the thyroid gland (5)
* Highly vascular
* 5th cervical - 1st thoracic vertebrae (2nd-4th tracheal rings)
* H to U shape
* Isthmus sometimes absent (2 separate lobes)
* Increases in size during pregnancy/menstruation
139
Describe the innervation, blood supply and drainage of the thyroid gland? (3)
* Innervation = autonomic (parasympathetic from vagus + sympathetic from superior, middle and inferior ganglia of synpathetic trunk)
* Blood supply = superior (from external carotid) and inferior thyroid (subclavian - thyrocervical trunk) arteries + sometimes thyroidea IMA!!
* Drainage - superior, middle (internal jugular) + inferior thyroid vein (brachiocephalic vein)
140
What is the thyroid gland supported by? Posteromedial aspect?
Ligaments + strap muscles
| * Posteromedial aspect supported by posterior suspensory ligament (Berry ligament)
141
Which cells secrete calcitonin?
Parafollicular C cells of the thyroid gland
142
Synthesis, storage and release of thyroid hormones? (5)
* Iodine taken up by follicle cells
* Iodine attached to tyrosine residues on thyroglobulin to form MIT and DIT
* Coupling of MIT + DIT to form T3 - triiodothyronine
* Coupling of 2 DITs to form thyroxine (T4)
* Stored in colloid thyroglobulin til required
143
Percentage of thyroid hormones secreted? Significance of T3?
* T4 (thyroxine) - 90%
* T3 (triiodothyronine) - 10%
T3 is 4 x more potent than T4
* T3 = major biologically active thyroid hormone
144
Explain thyroid hormone release and transport (4)
* TSH causes T3 and T4 to be secreted from colloid thyroglobulin
* T3 and T4 are hydrophobic (lipophillic) so bind to plasma proteins
* Unbound is biologically active form
* T4 converted to T3 and binds to nuclear receptor in target cell to affect protein synthesis
145
Which plasma proteins are T3 and T4 bound to in blood? (3)
* Thyroxine binding globulin (70%)
* Thyroxine binding prealbumin (20%)
* Albumin (5%)
146
Why is free T3 and T4 measured as opposed to total hormone concentration?
Metabolic state correlates more closely with the free than with the total concentration in the plasma
147
What does increased TBG result in? What causes increased TBG?
Increase TOTAL T4 but not free T4
* Pregnancy
* Hep A
* Billiary cirrhosis
* Acute intermittent porphyria
* Heroin
148
What does decreased TBG result in? What causes decreased TBG?
Decreased TOTAL T4 but not free T4
* Adrogens
* Glucocorticoids (Cushings)
* Acromegaly
* Chronic liver disease
* Carbamzepine
149
Physiological effects of thyroid hormones? (5)
* Metabolism
* Growth
* Development
* Reproduction
* Behaviour
150
What is the effect of thyroid hormones on metabolic rate and thermogenesis?
* Increase metabolic rate (increase number and size of mitochondria, increase ATP hydrolysis, increase synthesis of respiratory chain enzymes)
* Increase thermogenesis (30% of temp regulation due to thyroid hormone)
151
Effect of thyroid hormone on carbohydrate metabolism? Lipid metabolism? Protein metabolism?
* Carb = increase in blood glucose due to stimulation of glycogenolysis and gluconeogenesis, increase in glucose uptake into cells
* Lipid = mobilise fats from adipose tissue + increase fatty acid oxidation
* Protein - increase protein synthesis
152
How does thyroid hormone affect growth and development? (3)
* Growth - growth hormone releasing hormone (GHRH) requires thyroid hormone
* Development of foetal brain - myelinogenesis and axonal growth require thyroid hormones
* CNS activity - hypothyroid slows intellectual functions, hyperthyroid results in nervousness + hyperkinesis
153
Sympathomimetic action of thyroud hormones?
| Tx for hyperthyroidism?
Thyroid hormones increase responsiveness to adrenaline and noradrenaline by increasing number of receptors
* cardiovascular response also increased - increased rate and force
Note = propanolol used to treat symptoms in initial stages of hyperthyroidism
154
Thyroid hormone regulation? (3)
* Thyrotrophin releasing hormone (TRH) from hypothalamus stimulates thyroid stimulating hormone from anterior pituitary
* TSH stimulates release of T3 and T4 from thyroid gland
* T3 and T4 exert negative feedback control of release of TRH and TSH
155
What environmental factors can affect thyroid hormone regulation? (3)
* Low temperatures = stimulates TRH release so increased T3 and T4
* Stress = inhibits TRH and TSH release
* Circadian rhythm - thyroid hormones highest late at night, lowest in morning
156
Tissue level regulation of thyroid hormone?
DeIodinase enymes - addition or removal of iodine atom in outer ring activates and deactivates T3 and T4
157
Types of deiodinase enzymes? (3)
* Type I (D1) - found in liver and kidney
* Type II (D2) - found in heart, skeletal muscle, CNS, fat, thyroid + pituitary
* Type III (D3) - found in foetal tissue, placenta + brain (except pituitary)
158
Function of D2?
Activates T4 --> T3 in tissues
159
Causes of thyroid hormone deficiency (hypothyroidism)? (3)
* Primary gland failure - can cause goitre
* Secondary to TRH or TSH (no goitre)
* Lack of iodine in diet - can cause goitre
160
Symptoms of hypothyroidism? (7)
* Reduced metabolism
* Slow pulse rate
* Fatigue, lethargy
* Cold intolerance
* Weight gain
* Adults = myxoedema (puffy face, hands, feet)
* Children - cretinism (dwarfism and limited mental function)
161
What can cause hyperthyroidism? What is this?
| Symptoms? (2)
Grave's disease
* Autoimmune disease involving thyroid stimulating immunoglobulin (acts like TSH but is unchecked by T3 and T4)
* Exophthalmos - bulging eyes due to carbohydrate build up behind eyes
* Goitre - enlarged thyroid gland
162
Symptoms of hyperthyroidism? (6)
* Increased metabolism
* Very fast pulse
* Increased nervousness
* Insomnia
* Sweating and heat intolerance
* Weight loss
163
Describe embryological development of thyroid?
| Abnormalities associated with this process?
* Develops from evagination of pharyngeal epithelium
* Descent from foramen caecum to normal location along thyroglossal duct
Abnormalities
* Failure of descent (lingual thyroid)
* Excessive descent (retrosternal location in mediastinum)
* Thyroglossal duct cyst
164
Explain anatomy of thyroid gland
* Composed of follicles, each follicle surrounded by epithelial cells
* Centre of each follicle contains amorphic pink material containing thyroglobulin
* Occasional scattered C cells (parafollicular cells)
165
Explain how thyroid hormones increase BMR
* TSH binds to TSH receptor on surface of thyroid epithelial cells
* G proteins activated with conversion of GTP to GDP + production of cAMP
* cAMP increases production + release of T3 + T4
* Bind to thyroid response element on target genes
* Stimulates transcription of genes = increased BMR
166
Thyroid pathologies? (4)
* Hyperthyroidism (thyrotoxicosis)
* Goitre
* Neoplasia
* Hypothyroidism
167
Causes of thyroid inflammation? (6)
* Grave's disease
* Hashimoto's thyroiditis
* Infection
* subacute lymphocytic thyroiditis
* De quervain's thyroiditis
* Riedel's thyroiditis
168
Autoimmune thyroiditis? (2)
* CTLA-4 - negative regulator of T cell responses, polymorphism results in reduced function
* PTPN-22 - inhibits T cell function
169
Hyperthyroidism also known as? What is it?
| Ax? (6)
Thyrotoxicosis
* excess T3 + T4
Ax
* 85% due to Grave's
* Hyperfunctioning nodules
* Tumours (adenoma, carcinoma)
* TSH secreting pituitary adenoma (rare)
* ectopic production (struma ovarii)
* factitious (exogenous intake)
170
Epidemiology of Grave's disease?
* Female > male
| * 20-40 years old
171
Antibodies involved in Grave's disease?
* Thyroid stimulating immunoglobulins (relatively specific for Grave's disease)
* Thyroid growth stimulating immunoglobulin
* TSH binding inhibitor immunoglobulin
172
Grave's disease triad?
* Hyperthyroidism with enlargement of thyroid
* Eye changes (exophthalmos)
* Pretibial myxoedema
173
Histology Grave's?
Scalloping
174
Hypothyroidism?
Ax? (4)
Associated with?
Low levels of T3 + T4
* Majority due to Hashimoto's thyroiditis
* Iodine deficiency
* Drugs (lithium)
* Congenital
Associated with HLA-Dr3 and DR5
175
Hashimoto's epidemiology?
* F >M
| * 40 - 50 yrs
176
Histology hashimoto's?
unlike Grave’s, have a lot of thyroid hormone (more retention rather than release) and no scalloping
177
Goitre?
| Ax?
Enlargement of thyroid gland
| * Lack of dietary iodine
178
Thyroid neoplasms? (2)
* Follicular adenomas
| * Carcinomas (papillary, follicular, medullary, anaplastic)
179
What are follicular adenomas?
Difficulty?
What is a possible complication?
Benign lesions encapsulated by collagen
* They are difficult to distinguish from multi-nodular goitre + follicular carcinoma
Possible complication = thyrotoxicosis as they can secrete thyroid hormones independent of TSH
180
Thyroid carcinoma epidemiology?
| What are they derived from?
Can affect any age group - including children!!
| * Derived from follicular epithelium (EXCEPT medullary - from C cells)
181
Ax thyroid carcinomas?
Environment
* Radiation
* Iodine deficiency
Genetics
* Papillary = MAP kinase
* Follicular = P13K
* Anaplastic = multiple mutations incl. p53
* Medullary = MEN2
182
Papillary carcinoma?
Features? (2)
S/s? (4)
Most common thyroid cancer
* Solitary nodule (sometimes lymph node metastasis)
* Psammoma bodies (calcified)
S/s
* hoarseness, dysphagia, cough, dyspnoea
NOTE = haematogenous spread is uncommon but usually to lung!!
183
Follicular carcinoma?
Features? (3)
Difference from papillary?
Second most common thyroid cancer
* Slow-growing, painless + non-functional
Difference
* MUCH greater potential for haematogenous spread!!! (less lymphatic spread)
* Bone, lungs, liver
184
What are minimally invasive follicular carcinomas difficult to distinguish from?
Adenomas
185
Medullary carcinoma associated with?
Features?
S/s? (3)
Most cases are sporadic but can be associated with multiple endocrine neoplasia (MEN)
* Usually solitary nodules but familial cases are multi-nodular
S/s
* neck mass
* local effects (e.g. dysphagia)
* Paraneoplastic syndrome = diarrhoea, Cushing's syndrome
186
Tx medullary carcinoma?
Total thyroidectomy
187
Features of anaplastic carcinoma? (3)
| Why is it dangerous?
* Very aggressive, undifferentiated, tends to affect older patients (usually with a Hx of thyroid cancer)
Very poor prognosis due to rapid growth and involvement of neck structures = DEATH
188
Midline swellings of the neck? (3)
| How to differentiate?
Thyroid, thyroglossal cyst, dermoid cyst
If moves on swallowing = thyroid
If moves on sticking out tongue = thyroglossal cyst
189
Anterior triangle swellings of neck? (4)
lymph nodes, branchial cyst, salivary glands, carotid body tumour
190
Posterior triangle swellings of neck? (2)
lymph nodes, cystic hygroma (developmental lymphatic anomaly)
191
Appearance of branchial cyst?
| Risk of surgery?
Half-filled hot water bottle
| * risk of injuring internal jugular vein
192
Tx cystic hygroma?
Voluntary C-section
193
Ix solitary thyroid nodule? (3)
* TSH
* isotope scan
* USS
194
What is water balance controlled by? Effect?
ADH
Makes you pee less as it causes water to be reabsorbed from renal tubules
195
How is urine concentration measured?
As osmolality
High osmolality = concentrated urine
Low osmolality = dilute urine
196
What is the process called by which ADH causes water reabsorption from the kidneys?
Countercurrent multiplication
197
What is metabolic syndrome? (6)
* Impaired glucose regulation or diabetes
* Insulin resistance
* Raised BP
* Raised cholesterol
* Central obesity (makes >90, females >85)
* Microalbuminuria (>20 mcg/minute)
198
Cushing's syndrome?
Excess cortisol
199
Lifetime risk of diabetes following gestational diabetes?
30%
200
What proportion of patients with acromegaly also have diabetes?
1/3rd
201
What is glibenclamide?
Sulphonylurea
202
Pioglitazone?
TZD
203
Which antidiabetic medication can cause the Somogyi effect?
Insulin
| * post-hypoglycaemic hyperglycaemia
204
Which class of drug impairs the efficacy of sulphonylureas?
Corticosteroids
205
What is the poyol pathway?
| What are its effects? (3)
Also known as the aldose-reductase pathway
* series of biochemical reactions that occur in the prescence of raised intracellular glucose
* Involved in retinopathy, neuropathy, and nephropathy
206
Why is poyol pathway normally inactive?
Aldose reductase has a very high Km compared to glycolytic enzyme glucokinase (therefore will not process glucose unless there is a significant excess)
207
What is the function of aldose reductase? What then happens?
Converts glucose into sorbitol (the glucose that isn't converted becomes glycating sugars)
* sorbitol dehydrogenase converts sorbitol to fructose
208
What are Advanced Glycation End-products?
Synthesised in the aldose reductase pathway (glycating sugars bind to proteins) - can cause damage
209
What is sodium balance controlled by?
Steroids from adrenals i.e. mineralocorticoid activity
210
What is mineralocorticoid activity?
Which steroids have mineralocorticoid activity?
How does mineralcorticoid activity affect Na concentation?
Refers to Na+ reabsorption in renal tubules in exchange for K+/H+
* Aldosterone (main one!)
* Cortisol
Too much mineralocorticoid activity means sodium gain
Too little mineralocorticoid activity means sodium loss
211
Concentration of sodium inside cell as opposed to outside cell?
Outside cell = 140 mmol/L
| Inside cell = 4 mmol/L
212
What is the consequence of sodium loss?
Water loss
213
Causes of hyponatraemia?
Either due to too little sodium or too much water
Too little sodium
* Adrenal/kidney
* Gut - vomiting etc
* Skin - severe burns
Too much water
* Decreased H20 excretion e.g. SIADH
* Increased water intake e.g. compulsive water drinking
214
Causes of hypernatraema?
Either too much sodium or too little water
Too much sodium
* Increase Na+ intake (near-drowning)
* Malicious
* Decrease in Na+ excretion
Too little water
* Water loss e.g. diabetes insipidus
* Decrease water intake
215
Tx hyponatraemia?
| Tx hypernatraemia?
Hypo
* Too little sodium = give sodium
* Too much water = fluid restrict
Hyper
* Too much sodium = loop diuretic
* Too little water = give 5% dextrose
216
Dx hypo/hypernatraemia?
```
Hypo = Na <120
Hyper = Na >160
```
217
S/s hyper/hyponatraemia? (5)
* Altered consciousness
* Confusion
* Nausea
* Vomiting
* Fitting
218
2 kinds of stimuli for ADH release?
| Examples? (3)
```
Osmotic = in health
Non-osmotic = in disease
```
Non-osmotic stimuli
* Hypovolaemia/hypotenison
* Pain
* Nausea/vomiting
219
How to differentiate between hyponatraemia and pseudohyponatraemia?
Measure serum osmolality
220
Ax Addison's disease?
| S/s? (4)
Adrenal insufficiency so can't make steroids (loss of sodium thus water)
* Dizziness
* Excess pigmentation (due to excess ACTH from pituitary, stimulates melanocyte-stimulating hormone)
* Tiredness
* Poor appetite
* Postural hypotension
221
What is normally the cause of too much water?
| Clinical signs?
ADH secreted in response to non-osmotic stimulus
* Often don't have symptoms of hyponatraemia
* However, U+Es show Na to be low (due to water excess)
222
Ax diabetes insipidus?
| Tx?
* Disruption of pituitary so can't secrete ADH from posterior pituitary
* Lots of water lost in urine as cannot be reabsorbed by kidneys
* Na is high reflecting water deficit
Tx = exogenous ADH
223
TSH also known as?
| How is it released?
Thyrotropin
| * Released by thyrotroph cells in anterior pituitary in response to thyrotropin releasing hormone (TRH)
224
What percentage of thyroid hormone released is T4? T3?
```
T4 = 80%
T3 = 20%
```
225
TSH and free T3/4 in primary hypothyroidism? Hyperthyroidism?
Hypothyroidism
* Free T3/4 = low
* TSH high
Hyperthyroidism
* Free T3/4 = high
* TSH low
226
What is meant by secondary hypo/hyperthyroidism?
| TSH and free T3/4 in SECONDARY hypothyroidism? Hyperthyroidism?
Hypothalmic/pituitary disease
Hypo
* Free T3/T4 low
* TSH low
Hyper
* Free T3/4 high
* TSH high
227
What is myxoedema? What about pretibial myxoedema?
Myxoedema = severe HYPOthyroidism and is a medical emergency!!
* Pretibial myxoedema = rare sign of Grave's disease, which causes HYPERthyroidism
228
Causes of primary hypothyroidism? (3)
* Goitrous - Hashimoto's, iodine deficiency, drug-induced (lithium, amiodarone)
* Non-goitrous = atrophic thyroiditis, post-ablative therapy/radiotherapy
* Self-limiting = withdrawal of antithyroid drugs, post-partum thyroiditis
229
Causes of secondary hypothyroidism? (5)
Diseases of hypothalamus and pituitary gland
* Infectious
* Malignant
* Trauma
* Congenital
* Drug-induced
230
What is hashimoto's thyroiditis?
| Features? (2)
Autoimmune destruction of thyroid gland and so reduced thyroid hormone production (most common cause of hypothyroid in Western world)
* Antibodies against thyroid peroxidase (TPO)
* T-cell infiltrate
231
Clinical features of hypothyroidism? (9)
Hair and skin
* sparse hair
* Dull, expressionless face
* Periorbital puffiness
* pale cool skin that feels doughy to touch
* Vitiligo
* Hypercarotenaemia (jaundice-like yellowing of the skin in palms of hands and soles of feet)
Thermogenesis = cold intolerance
Fluid retention = pitting oedema
Cardiac = reduced HR, pericardial effusion, worsening of CCF
Metabolic = hyperlipidaemia, decreased appetite, weight gain
GI
* constipation
Respiratory
* deep hoarse voice, macroglossia, sleep apnoea
Neurology
* decreased intellectual/motor activities, depression muscle stiffness, carpal tunnel
Reproductive
* Menorrhagia + later amenorrhoea
* Hyperprolactinaemia
232
Lab investigations for primary hypotheyroidism?
* Raised TSH and decreased fT4/3!!
* Increased MCV
* Increased creatine kinase
* Increased cholesterol
* Hyponatraemia
* Hyperprolactinaemia
233
Thyroid autoantibodies (including Grave's disease)? (3)
* Anti-TPO
* Anti-thyroglobulin antibody
* TSH receptor antibody
234
Mx primary hypothyroidism?
* Younger patients = levothyroxine at 50-100 ug daily
* Elderly with history of IHD = levothyroxine at 25-50 ug daily
Important notes
* TSH should be checked 2 months after any dose change
* Once stabilised, TSH should be checked every 12-18 months
* Normal metabolic rate should be restored GRADUALLY - rapid restoration can cause cardiac arrhythmias
* TSH level is irrelevant in SECONDARY hypothyroidism as there is a decrease in TSH production (titrate dose of levothyroxine to fT4 level)
235
What is levothyroxine?
| Pregnancy?
T4 (T3 therapies rarely used + no benefit with combo of T4+T3)
* Dose requirements increase in pregnancy due to increased TBG
236
Myxoedema coma epidemiology?
| Dx myxoedema coma?
Elderly women with untreated hypothyroidism (mortality up to 60% despite early diagnosis and tx)
* ECG = bradycardia, T wave inversion, prolongation of QT interval, low voltage
* Type 2 respiratory failure
* Adrenal failure (10% of patients)
237
Tx myxoedema coma? (6)
* ABC
* Passively rewarm
* Cardiac monitoring
* Monitor urine output, blood sugar, oxygen
* Broad spectrum antibiotics (can be caused by infection)
* Thyroxine
238
What is thyrotoxicosis?
State arising when tissues are exposed to excess thyroid hormone
239
S/s thyrotoxicosis? (10)
Cardiac = AF, cardiac failure (very rare)
Sympathetic = tremor, sweating
CNS = anxiety, nervousness, sleep disturbance, irritability
GI = frequent loose stools
Vision
* Lid retraction
* Double vision
* Proptosis (Grave's)
Hair and skin
* Brittle, thin hair
* rapid fingernail growth
Reproductive
* lighter infrequent periods
Muscles = muscle weakness (esp. in thighs and upper arms)
Metabolism = weight loss despite increased appetite
Thermogenesis = intolerance to heat
240
Causes of thyrotoxicosis? (5)
(remember: hyperthyroidism refers to overactivity of the thyroid gland!!)
ASSOCIATED WITH HYPERTHYROIDISM
Excessive thyroid stimulation
* Grave's disease
* Hashitotoxicosis
* Thyrotropinaemia (very rare)
* Thyroid cancer
* Choriocarcinoma (trophoblast tumour)
Thyroid nodules with autonomous function
* toxic solitary nodule
* toxic multinodular goitre
NOT ASSOCIATED WITH HYPERTHYROIDISM
* Thyroiditis (de quervain's, post-partum thyroiditis, drug-induced)
* Exogenous thyroid hormones (over-treatment with levothyroxine)
* Ectopic thyroid tissue (struma ovarii)
241
What can affect lifetime risk of Grave's disease? (2)
* Smoking
| * Sisters and children of women with Grave's disease have a 5-8% risk
242
Lab Ix of Grave's disease?
* Decreased TSH and increased fT4/3
* Hypercalcaemia and increased ALK PHOS (grave's associated with osteoporosis)
* Leucopenia
* TSH receptor antibody
243
Clinical signs specific to Grave's disease? (4)
* Pretibial myxoedema
* Thyroid acropachy
* Thyroid bruit (associated with large goitres - but not heard in other goitrous conditions)
* Grave's eye disease (associated with smoking) - can be severe and sight-threatening
244
Tx for Grave's eye disease?
```
Mild = lubricants
Severe = steroids, radiotherapy, surgery
```
245
Features of nodular thyroid disease? (3)
Tests? (4)
Older patients
Insidious onset
Asymmetrical goitre
Tests
* increased fT4/3, decreased TSH (or normal)
* antibody negative
* Scintigraphy = high uptake
* Thyroid US
246
Thyroid storm?
S/s? (3)
Tx? (5)
EMERGENCY associated with hyperthyroid patients with acute infection/illness or recent thyroid surgery
* HYPERthermia
* Respiratory and cardiac collapse
* Exaggerated reflexes
Tx
* Lugol's iodine, glucocorticoids, PTU, B-blockers, fluids
247
Mechanism of hyperthyroid (antithyroid) drugs?
| Examples? (2)
Inhibition of TPO therefore blocking thyroid hormone synthesis
* Carbimazole (1st line)
* Propylthiouracil (1st line only in 1st trimester of pregnancy as carbimazole has risk of aplasia cutis)
248
Side effects of antithyroid drugs? (3)
Generally well tolerated
* Allergic reaction
* PTU associated with cholestatic jaundice + fulminant hepatic failure
* AGRANULOCYTOSIS - very dangerous!! (risk highest in first 6 weeks)
249
B-blockers for treatment of?
Mechanism?
Drug of choice?
Hyperthyroidism - especially in immediate symptomatic relief of thyrotxic symptoms
* Reduced activity of sympathetic NS
* Drug of choice = propanolol
250
What is the 1st choice of treatment for relapsed Grave's disease and nodular thyroid disease?
Risks? (3)
Radioiodine
* Contraindicated in pregnancy
* Contraindicated in active thyroid eye disease
* High risk of hypothyroidism when used in Grave's disease
251
When is thyroidectomy carried out?
| Risks of surgery? (3)
When radioiodine is contraindicated (usually treatment for relapsed Graves and nodular thyroid disease)
* Recurrent laryngeal nerve palsy
* Hypothyroidism
* Hypoparathyroidism
252
Ax subacute thyroiditis?
| Tx?
May be triggered by viral infection (so will have viral symptoms like fever)
* Usually self-limiting
253
Non-thyroidal illness also known as? What is it?
| Course of disease?
Sick euthyroid syndrome
* refers to impact of intercurrent illness on HPT axis
* TSH typically suppressed initially then rises during recovery
254
Hormone subtypes? (3)
* Proteins and peptides = insulin, GH, prolactin
* Steroids = derived from cholesterol e.g. cortisol, testosterone
* Tyrosine tryptophan derivatives = adrenaline, thyroid hormones, melatonin
255
Example of steroid hormone receptors?
Oestrogen + androgen receptors
256
How is pituitary function assessed in thyroid disease since TSH cannot be used? (6)
* 9am cortisol (random measurement is of little value)
* FT4, FT3
* Prolactin
* IGF1 (may indicate GH hypersecretion)
* LH, FSH
* Imaging
257
What is prolactin secreted by?
Prolactin (PRL) secreted by lactotroph cells of anterior pituitary
258
Tests to check adrenal function? (2)
* Synacthen Test (adrenal insufficiency)
| * Dexamethasome suppression test (Cushings)
259
S/s Cushing's syndrome? (9)
* Cushingoid facies (moon face)
* Acne
* Hirsutism
* Abdominal striae & centripetal obesity
* Interscapular & supraclavicular fat pads
* Proximal myopathy
* Osteoporosis
* Hypertension
* Impaired glucose tolerance
260
Ax cushings syndrome? (4)
Cushing's disease = pituitary cushings
* tumour from corticotroph cells of anterior pituitary
ACTH-independent Cushing's
* adrenal tumour
Ectopic ACTH = malignancy
Exogenous steroids
261
How is Cushing's diagnosed?
First carry out dexamethasone suppression test
* Failure to suppress = Cushing's
To determine cause, measure ACTH
* ACTH low = adrenal origin
* ACTH raised = need to distinguish between pituitary origin (Cushing's disease) + ectopic ACTH
Rise in cortisol and ACTH on CRH test indicated pituitary source
262
Endocrinology of pregnancy? (5)
* Ovum = oestrogen
* corpus luteum = progesterone
* Implantation = HCG (pregnancy test)
* Placenta = human placental lactogen (hPL), placental progesterone, placental oestrogen
* Pituitary = prolactin (lactogen)
263
Pathophysiology gestational diabetes?
* Progesterones + hPL cause insulin resistance in the mother
| * if predisposed, results in raised blood glucose + gestational diabetes
264
When does foetal organogenesis occur?
Starts at 5 weeks
265
Which complications can diabetes lead to in pregnancy? (5)
* Congenital malformation
* Prematurity
* Intra-uterine growth retardation (IUGR)
* Macrosomia (large foetus)
* Polyhydramonios (too much amniotic fluid)
* Intrauterine death
266
Diabetic complications for foetus? (5)
* Respiratory distress
* Hypoglycaemia - fits
* Hypocalcaemia - fits
* CNS defects (anencephaly, spina bifida)
* Caudal regression syndrome
* Genital and GI abnormalities e.g. ureteric duplication
267
How does diabetes in pregnancy lead to macrosomia?
* Meternal hyperglycaemia
* Foetal hyperglycaemia
* Foetal hyperinsulinaemia
* Leads to macrosomia (in 3rd trimester foetus produces own insulin which is a MAJOR growth factor!!)
* Can lead to neonatal hypoglycaemia - fits
268
Management of type 1 and type 2 diabetes in pregnancy? (6)
* Optimise blood sugar control
* Folic acid 5mg
* Consider change from tablets to insulin
* Regular eye checks (accelerated retinopathy)
* Avoid ACE-I and statins (for BP use Labetalol, Nifedipine, methyldopa)
* Monitor HbA1c, BP
269
Tx during labour for mother with T1DM, T2DM or GDM?
Maintain good blood glucose during labour - IV insulin and IV dextrose
270
Tx GDM? (2)
* Lifestyle
* Metformin
(may need insulin)
271
Dx gestational diabetes?
* 6 week post-natal fasting glucose or GTT
| * DM should have resolves - if not, they have T2DM
272
Implications of gestational diabetes?
* After 10-15 years, 50% have increased risk of T2DM (especially for obese)
* T1DM (<5%)
273
Prevention of diabetes after GDM? (4)
* Keep weight as low as possible
* Healthy diet
* Aerobic exercise
* Annual fasting glucose
274
When does gestational diabetes usually present?
Later in pregnancy - 3rd trimester
275
Implications of thyroid disease in pregnancy?
* Hypo and hyperthyroidism causes anovulatory cycles (reduced fertility)
* Maternal thyroxine important for neonatal development
* Increased demand on thyroid during pregnancy
276
Mx hypothyroidism in pregnancy?
* Increase thyroxine dose by 25mcg as soon as pregnancy suspected!
* Check TFTs monthly for first 20 weeks then 2 monthly until birth
* Aim for TSH <3 mU/1
277
Complications of untreated hypothyroidism in pregnancy? (
* Preeclampsia
* Abruption
* Post-partum haemorrhage
* Preterm labour
* Neuropsychological development (increased risk of IQ < 85)
278
What is a possible effect of hCG in pregnancy?
hCG effect mimics hyperthyroidism biochemically (raised fT4, low TSH)
* Increases thyroxine
* Suppresses TSH
(because hCG and TSH have similar structures)
279
What is it important to distinguish hyperthyroidism from in pregnancy?
Gestational hCG-associated thyrotoxicosis
* Hyperemesis gravidarum
* Not TRab antibody positive
* Resolves by 20 wks gestation
280
Complications of hyperthyroidism in pregnancy? (5)
* Infertility
* Spontaneous miscarriage
* Stillbirth
* Thyroid crisis in labour
* Transient neonatal thyrotoxicosis
281
Ax thyrotoxicosis in pregnancy? (3)
* Grave's disease
* Toxic multinodular goitre, toxic adenoma
* Thyroiditis
282
S/s hyperthyroidism pregnancy? (4)
Difficult to distinguish from hyperemesis of pregnancy
* Nausea + vom
* tachycardia
* warm and sweaty
* lack of wt gain
283
Mx hyperthyroidism pregnancy? (3)
* Wait and see - if hyperemesis, will settle, Graves may settle as pregnancy suppresses autoimmunity
* B-blockers if needed
* LOW DOSE anti-thyroid drugs (propylthiouracil 1st trimester, carbimazole 2/3rd trimester, wait as late as possible)
284
Why is carbimazole avoided in 1st trimester? (4)
* Embryopathy
* Scalp abnormalities
* GI abnormalities
* Choanal and oesophageal atresia
285
Why is it important to check TRab antibodies in pregnancy?
TRab antibodies can cross the placenta and cause neonatal transient hyperthyroidism (ideally check during 3rd trimester)
286
Post-partum thyroiditis?
* Transiently thyrotoxic -> hypothyroid
* Small, diffuse, non-tender goitre
* Hypothyroid phase associated with postnatal depression
287
Histology anterior pituitary? (4)
| Posterior?
Anterior
* Islands of cells
* Acidophils (somatophils (GH), mammotrops (PRL))
* Basophils (corticotrophs (ACTH), thyrotrophs (TSH), gonadotrophs (FSH/LH))
* Chromophobe
Posterior
* non-myelinated axons of neurosecretory neurons
288
Pathology of anterior pituitary? (2)
Hyperfunction
* Adenoma
* Carcinoma
Hypofunction
* Surgery/radiation
* Haemorrhage
* Ischaemic necrosis (sheehan syndrome)
* Tumours
* Sarcoidosis
289
Pathology of posterior pituitary? (2)
* Diabetes insipidus - lack of ADH secretion, can lead to life threatening dehydration
* SIADH - ectopic secretion of ADH by tumours or primary disorder in the pituitary
290
Pituitary adenoma derived from?
Ax? (2)
Classification?
Complications of large adenomas? (3)
Derived from cells of anterior pituitary
* Ax = sporadic or associated with MEN1
* Classify by hormone produced (prolactin, ACTH, FSH/LH)
Large adenomas
* visual field defects
* pressure atrophy of surrounding tissues
* infarction can lead to panhypopituitarism
291
Functional pituitary adenomas? (3)
Prolactinoma
* Most common
* Infertility, lack of libido, amenorrhea
GH
* second most common
* increase in insulin-like growth factors
* gigantism or acromegaly
ACTH secreting
* Cushing's disease
* Bilateral adenocortical hyperplasia
292
Ax pituitary hypofunction?
* Granulamatous inflammation - sarcoidosis
* Infarction - Sheehan's syndrome
* Primary or metastatic tumours
293
Craniopharyngioma derived from?
Features? (3)
S/s? (3)
Remnants of Rathke's pouch
* Slow growing
* cystic
* may calcify
S/s
* headaches
* visual disturbances
* children may have growth retardation
294
Tx craniopharyngioma?
| Risk?
Great prognosis
* Tx = radiation
SCC may develop following radiation but rare
295
Paired hormones? (5)
* ACTH (central) -> cortisol (peripheral)
* TSH (central) -> thyroxine (peripheral)
* LH/FSH (central) -> testosterone/oestrogen (peripheral)
* GH (central) -> IGF-1 (peripheral)
* Prolactin (central)
296
What is the general rule for dynamic endocrine tests?
* Too much hormone = do test that tries to suppress the hormone
* Too little hormone = test that tries to stimulate hormone
297
Examples of dynamic pituitary function tests (stimulation)? (3)
* Synacthen (synthetic ACTH) = if cortisol doesn't rise to 500, adrenal insufficiency !!
* Insulin stress test = stimulates cortisol (>500) and GH (>7ug/l), purposely trying to make patient hypo
* Water deprivation test = if serum osmolality <2, diabetes insipidous
298
What is a microadenoma? Macroadenoma?
* Microadenoma = <1 cm
| * Macroadenoma = >1 cm
299
Complications of non-functioning pituitary adenoma? (2)
Too big
* Compression of optic chiasma (bitemporal hemianopia)
* Compression on cranial nerves 3, 4, 6 (disrupts eye movement)
Too little hormones
* Hypoadrenalism (lack of cortisol)
* Hypothyroidism
* Hypogonadism (lack of FSH, LH)
* Diabetes insipidous if affects post. pituitary
* GH deficiency
300
Physiological causes of raised prolactin? (4)
| Drug-induced causes of raised prolactin? (2)
Physiological
* breast-feeding
* pregnancy
* stress
* sleep
Drugs
* Dopamine antagonists e.g. metoclopramide
* Antipsychotics
301
Pathological causes of raised prolactin? (3)
* Hypothyroidism (TRH stimulates prolactin)
* Stalk lesions (prevent action of dopamine)
* Prolactinoma!!!
302
Dx prolactinoma?
* MRI pituitary
* If prolactin >5,000, nearly always prolactinoma
* visual fields (bitemporal hemianopia)
303
S/s prolactinoma? (2)
Females
* EARLY presentation
* Galctorrhoea (production from breast)
* Ammenorrhoea
* Infertility
Males
* LATE presentation
* Impotence
* Visial field abnormal
* Headache
* Ant pit malfunction (other hormones squeezed out)
304
Tx prolactinoma?
| Side effects? (3)
Dopamine agonists
* Carbergoline most common (least side effects) - oral once or twice per week
Side effects
* nausea/vom
* low mood
* fibrosis
305
Acromegaly?
| S/s? (8)
GH excess
* Giant
* Thickened soft tissues (large jaw, large hands)
* Sleep apnoea
* Hypertension, cardiac failure
* Headaches (VASCULAR effect, NOT due to tumour!!)
* Diabetes mellitus
* Visual field disturbance
* Colon cancer
306
Tests for acromegaly? (3)
IGF-1
Suppression test = glucose tolerance test (remember insulin is stimulating test)
* Normal = GH suppresses to <0.4 ug/l
* Acromegaly = GH remains >1 ug/l
Visual field test
MRI pituitary scan
307
Tx acromegaly? (4)
1st line = pituitary surgery
2nd line = somatostatin analogues (relieves headache in 1 hr)
* sandostatin, lanreotide
3rd line = dopamine agonists (only if struggling with somatostatin analogue)
* Cabergoline
Last line = GH antagonist
* Pegvisomant
* Blocks GH activity, however, tumour does not decrease in size
308
Side effects of somatostatin analogues? (3)
* Local stinging
* Flatulence, diarrhoea, abdominal pains
* GALLSTONES (as somatostatin stops gallbladder contracting)
309
Acromegaly follow-up? (5)
* Achieve clinically safe levels of GH (<0.4 post GTT and <2ug random)
* Check other pituitary hormones, especially thyroid!!
* Cancer surveillance (colon)
* Cardio risk factors (BP, lipids, glucose)
* Sleep apnoea
310
Cushing's syndrome?
| S/s? (5)
Excess cortisol
* protein loss - myopathy, osteoporosis, thin skin (striae, bruising)
* Diabetes + obesity (due to altered carb + lipid metabolism)
* Psychosis, depression
* Excess mineralocorticoid - hypertension, oedema
* Excess androgen = virilism, hirtuism, acne, amenorrhea
311
How to differentiate cushings from obesity? (6)
* Thin skin
* Striae (rapid weight gain)
* Proximal myopathy + central obesity (lemon on sticks)
* Frontal balding in women
* Conjunctival oedema (chemosis)
* Osteoporosis
312
Screening Cushing's? (3)
Overnight 1mg dexamethasone suppression test (oral)
* Normal = <50mmol cortisol next morning
* Cushings = >100
Urine free cortisol
* Normal = <250
Diurnal cortisol variation
313
Definitive test for cushings?
Low dose DST
* 2 day 2mg dexamethasone suppression test
* Normal = cortisol <50
* Cushing's = >130
314
Ax Cushing's? (4)
* Pituitary = Cushing's disease (all others are cushing's syndrome)
* Adenoma of adrenal
* Ectopic
* Pseudo - alcohol and depression, steroid medication
315
CRH test?
Suggestive of pituitary disease if:
* 50% increase in ACTH
* 20% increase in cortisol
316
Tx Cushing's? (4)
* Pituitary = hypophysectomy, external radiotherapy (if reoccurs), bilateral adrenalectomy
* Adrenal = adrenalectomy
* Ectopic = remove source or bilateral adrenalectomy
* Drug tx (if other tx fails) = metyrapone, ketoconazole, pasireotide
317
Pan hypopituitarism?
Anterior pituitary
* Growth hormone = growth failure
* TSH = hypothyroidism
* LH/FSH = hypogonadism
* ACTH = hypoadrenal
* Prolactin
Posterior pituitary
* Diabetes insipidous
318
Causes of hypopituitarism? (6)
* Pituitary tumours
* Secondary metastatic lesions (lung, breast)
* Local brain tumours - astrocytoma, meningioma, glioma
* Granulomatous diseases = TB, sarcoid
* Trauma
* Autoimmume = sheenan (post-pregnancy)
319
S/s anterior hypopituitarism? (9)
* Menstrual irregularities (F)
* Infertility, impotence
* Gynaecomastia (M)
* Abdominal obesity
* Loss of facial hair (M)
* Loss of axillary and pubic hair (M&F)
* Dry skin and hair
* Hypothyroid faces
* growth retardation (children)
320
Dx panhypopituitarism?
Synacthen test and Insulin tolerance test best for steroid axis
(remember LSH and FSH should be high in post-menopausal women)
321
Tx hypopituitarism? (5)
Replacement therapy
* Thyroxine
* Hydrocortisone
* ADH
* GH
* Sex steroids (HRT, the pill, testosterone)
322
Testosterone replacement? (3)
| Risks? (3)
* IM injection every month (sustanon)
* Skin gel (testogel)
* Prolonged IM injection every 3 months (nebido)
Risks
* Prostate enlargement (does not cause prostate cancer but if already have cancer, can make it grow)
* Polycytheamia - monitor FBC
* Hepatitis (only for oral tablets) - monitor LFTs
323
Causes of cranial diabetes insipidus? (3)
* Familial - DIDMOAD
* Acquired - idiopathic or RTA
* RARE = tumour, sarcoid, meningitis
324
Dx diabetes insipidus?
Water deprivation test
* Check serum osmolalities for 8hr, then 4hrs after giving IM DDAVP (desmopressin)
* If serum osmol >2 = normal
* if not = DI (if it improves after DDAVP it is DI)
then do vasopressin stimulation test
if respond = brain problem
if dont respond = renal problem
325
Tx diabetes insipidus? (3)
* Desmospray - nasally
* Desmopressin oral
* Desmopressin injection (only used in emergencies or post-pituitary surgery)
326
menopause hormones?
very high LH and FSH (no negative feedback as ovaries not functioning)
327
what inhibits prolactin?
dopamine
328
anterior pituitary gland derived from? Called?
| Secretes?
derived from Rathke's pouch
called adenohypophysis
secretes TSH, ACTH, FSH, LH, GH and prolactin
329
posterior pituitary gland called?
derived from?
secretes?
neurohypophysis
extension of hypothalamus
secretes ADH + oxytocin
330
sheehan syndrome?
occurs after severe PPH
| ischaemic necrosis of pituitary gland resulting in panhypopituitarism
331
what can cause hyperfunction anterior pituitary?
| hypofunction?
```
hyperfunction = adenoma or carcinoma
hypofunction
* surgery/radiation
* haemorrhage
* sheehan syndrome
* tumours
* sarcoid, TB, histiocytosis X
```
332
posterior pituitary hypofunction vs hyperfunction
hypofunction = diabetes insipidus (lack of ADH that can lead to life threatening dehydration)
hyperfunction = SIADH
* ectopic secretion of ADH by tumours or primary disorder in pituitary
333
pathology of adrenal gland
hyperfunction = hyperplasia, adenoma or carcinoma
hypofunction
* acute = waterhouse-friderichsen
* chronic = addison's disease
334
adrenocortical hyperplasia congenital vs acquired
congenital (CAH) = enzyme deficiency
* autosomal recessive
* increased androgen production = masculinisation + precocious puberty
acquired
* pituitary adenoma (cushing's)
* ectopic ACTH (small cell)
335
adrenocortical tumours in children?
li-fraumeni syndrome
336
adrenocortical tumours epidemiology? S/s?
Adult males
(in children suspect li fraumeni)
* asymptomatic
* primary hyperaldosteronism (conn's), cushing's, virilisation
337
adrenocortical carcinoma
usually small, well-circumscribed
yellow
rarely functional
338
adrenococrtical carcinoma
prognosis?
rare
functional - conn's, cushings, virilisation
50% dead in 2 years
339
primary hyperaldosteronism Ax?
conn's syndrome
| adenoma
340
adrenocortical hypofunction Ax
primary
| secondary = hypopituitarism, steroids
341
primary adrenocortical insufficiency Ax?
acute = rapid withdrawal of steroid treatment, Addison's crisis (infection), massive adrenal haemorrhage (DIC, sepsis, anticoagulants)
chronic = Addison's disease
342
Ax Addison's disease?
3 common causes = autoimmune adrenalitis, infections (TB, histoplasma, HIV), metastatic malignancy from lung or breast
unusual causes = amyloid, sarcoid, haemochromatosis
343
Addison's symptoms?
| signs?
```
weakness + fatigue
anorexia
vomiting + diarrhoea
weight loss
pigmentation (palmar creases, buccal)
```
signs
* hyperkalaemia + hyponatraemia!! (hypotension)
* hypoglycaemia
344
Addison's crisis Ax?
| S/s?
infection, trauma, surgery
* vomiting
* abdominal pain
* hypotension --> shock
* death
345
which cells secrete catecholamines?
| therefore what can cause hypersecretion?
chromaffin cells from adrenal medulla
adrenal medullary tumours e.g. neuroblastoma, phaeochromocytoma (differentiate from adrenocortical tumours)
346
phaeochromocytoma?
S/s?
Dx?
Associated with?
adrenal medullary tumour derived from chromaffin cells
S/s = hypertension, palpitations, sweating, headache
Dx = urinary excretion of catecholamines
associated with MEN2
347
why is phaeochromocytoma called 10% tumour?
```
10% are extra-adrenal
10% are bilateral
10% are malignant
10% not associated with hypertension
25% are familial (MEN2)
```
348
osteoporosis?
progressive skeletal disease characterised by:
low bone mass
bone fragility
fracture
349
risk factors osteoporosis?
early menopause
| drugs = GLUCOCORTICOIDS, aromatase inhibitors
350
Dx osteoporosis?
DEXA scan
normal > -1
osteopenia -1 to -2.5
osteoporosis >-2.5
severe osteoporosis -2.5 with fragility fracture
351
2ndry causes osteoporosis?
endocrine - hyperthyroidism, hyperparathyroidism, cushing's
GI - coeliac, IBD, liver disease, chronic pancreatitis
resp - CF, COPD
CKD
352
Tx osteoporosis?
lifestyle advice = avoid smoking + alcohol, calcium (2-3 portions dairy)
drug Tx
* calcium + vit D supplements
* bisphosphonates (alendronate and risedronate)
* denosumab
* HRT
NOTE - calcium supplements should not be taken within 2 hours of bisphosphonates
353
examples of bisphosphonates
duration of Tx?
complications?
alendronate, risedronate, zoledronic acid (useful if intolerant to oral bisphosphonates)
```
Tx = 5 years
complications = osteonecrosis of jaw, oesophageal cancer, atypical fractures
```
354
desonumab
mechanism
side effects?
monoclonal antibody used in tx of osteoporosis
inhibits osteoclasts
S/E = hypocalcaemia, eczema, cellilitis (injection)
355
teriparatide?
used in severe osteoporosis
356
Paget's disease of bone
s/s
complication?
affects long bones, pelvis, lumbar spine + skull (i.e. like midline bones)
* bone pain
* deformity
* deafness
* compression neuropathies
osteosarcoma is a rare complication
357
Dx Paget's disease of bone?
| Tx?
```
Dx = high ALK PHOS + high uptake on isotope bone scan
Tx = analgesia + bisphosphonates
```
358
osteogenesis imperfecta?
S/s?
Tx?
autosomal dominant disorder (COL1A) affecting bone
* blue sclerae
* dentogenesis imperfecta
* fractures in childhood
* hearing loss
Tx = no cure, surgery to correct deformities, bisphosphontes
NOTE - important differential for suspected NAI
359
key precursor for aldosterone, cortisol + testosterone?
| where are they produced?
cholesterol
| adrenal glands
360
regulation of cortisol production?
HPA axis (negative feedback)
361
renin angiotensin system activation?
regulates aldosterone
| activated in response to low BP (causes vasoconstriction + release of aldosterone)
362
whats likely diagnosis?
21 year old female "unwell" for few months - weight loss + amenorrhoea
acutely unwell over past 48 hours with vomiting + diarrhoea
on examination = dark skin, dehydrated, hypotensive, hyperkalaemia + hyponatraemia
classic presentation of Addison's disease
363
adrenal insufficiency Ax?
```
primary = Addison's disease, CAH, adrenal TB, malignancy
secondary = lack of ACTH, iatrogenic, pituitary/hypothalamic disorder
```
364
Addison's disease Ax?
| associated with?
commonest cause of primary adrenal insufficiency!!
autoimmune destruction of adrenal cortex
associated with other autoimmune diseases e.g. T1DM, thyroid, pernicious anaemia
365
Dx addison's?
| Tx?
hyponatraemia
hyperkalaemia
hypoglycaemia
short synacthen test!!
* <550 mmol after ACTH = Addison's
Tx = hydrocortisone (as corticol replacement), fludrocortisone (as aldosterone replacement)
366
how to differentiate between addisons and secondary adrenal insufficiency?
so Tx?
```
clinical features similar (weight loss, nausea, fatigue, weakness) except:
skin pale (no increased ACTH)
aldosterone production intact (regulated by RAS)
```
so only Tx is hydrocortisone (fludrocortisone is unnecessary)
367
```
likely diagnosis?
34 y/o male
1 year history of HTN
no other PMHx
no regular medications
O/E
* BP 168/98 mmHg
* renal function normal but plasma potassium low
```
primary aldosteronism (Conn's or bilateral adrenal hyperplasia)
368
what is primary aldosteronism?
| s/s?
uncontrolled production of aldosterone
significant hypertension
hypokalaemia
metabolic alkalosis
369
Ax primary aldosteronism?
| Dx?
adrenal adenoma = Conn's syndrome
bilateral adrenal hyperplasia (commonest cause)
rare causes = genetic mutations or unilateral hyperplasia
Dx step 1 = confirm aldosterone excess
* plasma aldosterone and renin ratio raised = do saline suppression test
if failure to suppress = PA
step 2 = confirm subtype
* adrenal CT for adenoma
370
Tx primary aldosteronism
surgical for adrenal adenoma = laparoscopic adrenalectomy
| drugs if bilateral adrenal hyperplasia = spironolactone or eplerenone
371
congenital adrenal hyperplasia?
| Dx?
enzyme defects autosomal recessive
* increased androgen production = virilisation
* low mineralocirticoids
Dx = 17 OH progesterone
372
s/s CAH in males? females?
| Tx?
males = adrenal insufficiency, poor weight gain, same biochemical pattern as Addison's disease
females - genital ambiguity, acne, hirsutism
Tx in children = glucocorticoid replacement, surgical correction, achieve maximum growth potential
In adults = control androgen excess, restore fertility
373
complications phaemochromocytoma?
LVF
stroke
shock
parlytic ileus of bowel
374
biochemical abnormalities phaeochromocytoma?
| Tx?
```
hyperglycaemia
low K+
high haematocrit
mild hypercalcaemia
lactic acidosis
```
suspect when you have hypertension + hyperglycaemia
Tx = surgery, a-blocker, b-blocker
375
endocrine causes of hypertension?
conn's
cushing's
phaeochromocytoma
376
Tx DKA?
fluids
insulin
POTASSIUM
377
Ax hyponatraemia?
| Hypernatraemia?
hypo = SIADH, compulsive water drinking
hyper = diabetes insipidus, severe dehydration
378
Tx SIADH?
loop diuretics - furosemide
379
kallmans syndrome?
Dx?
differential?
Tx?
hypothalamic pituitary failure
low levels FSH/LH
oestrogen deficiency
amenorrhoea
Dx = negative progesterone challenge test
stress, anorexia, pituitary tumours, drugs (steroids/opiates)
Tx = FSH + LH injections, GnRH
380
PCOS?
```
normal FSH, excess LH
oligo/amenorrhoea
normal oestrogen
insulin resistance
increased testosterone
```
381
high FSH/LH, low oestrogen + amenorrhoea
menopausal
382
Turner's syndrome
premature ovarian failure
wide chest
shorter than average
no puberty
383
causes of primary hypogonadism in males
klinefelters syndrome
| cryptochordism
384
klinefelters syndrome
Dx?
S/s
most common cause of primary hypogonadism in males
it is NOT inherited
Dx = karyotyping
S/s
* small, firm testes, infetility, learning disability, breast development, wide hips
385
Kallman's syndrome?
| S/s?
genetic disorder characterised by isolated GnRH deficiency + anosmia
```
associated with
small penile size +/- undescended testicles
red green colour blindness
cleft lip
unilateral renal agenesis
```
386
Ix if suspect hypogonadotrophic hypogonadism?
| Tx?
measure AM testosterone
if normal = reassure patient
if low = measure LH/FSH
* high = hypergonadotrophic hypogonadism (primary) e.g. klinefelter's
* low = hypogonadotrophic hypogonadism (secondary) e.g. Kallmann's, prader willi
Testosterone replacement therapy
