Endocrinology Flashcards
1
Q
bonWhat are normal serum ionized calcium levels?
A
1.1 mmol/L
2
Q
What is hypoparathyroidism
A
Decrease in PTH production by parathyroid glands.
3
Q
Aetiology of hypoparathyroidism
A
Surgical excision
Radiation
Magnesium deficiency (Mg needed for PTH release).
DiGeorge Syndrome
Polyglandular Type 1 Autoimmune Syndrome
Haematomachrosis, Wilson’s Disease
4
Q
What is pseudohypoparathyroidism
A
End-organ resistance to PTH
5
Q
Genetic aetiology of pseudohypoparathyroidism
A
GNAS-1 inactivating mutation
Autosomal dominant, maternal transmission.
Encodes for Gs protein
There is inactivation of adenylyl-cyclase when PTH binds to receptor.
6
Q
What disease is related to aetiology of pseudohypoparathyroidism?
A
Type 1 Albright Hereditary Dystrophy
7
Q
What happens in type 1 Albright hereditary dystrophy?
A
Mutation with deficient Ga subunit on G-proteins.
8
Q
Pathophysiology of pseudohypoparathyroidism
A
PTH is produced but does not have an effect.
Due to negative feedback loop, more PTH is produced to try and overcome the resistance.
9
Q
Clinical presentation of pseudohypoparathyroidism
A
Short stature, round faces.
Obesity
Mild learning difficulties
Subcutaneous ossification & short fourth metacarpals
Also associated with T1 Albright Hereditary Osteodystrophy
10
Q
What is pseudopseudohypoparathyroidism
A
Autosomal dominant, paternally transmitted mutation in GNAS gene.
No end-organ resistance due to maternal gene still causing renal responsiveness.
11
Q
What is primary hyperparathyroidism
A
Parathyroids producing excess PTH
12
Q
Lab findings for pseudopseudohypoparathyroidism
A
Normal PTH, Ca, Ph,
13
Q
Aetiology of primary hyperparathyroidism
A
80% due to benign adenoma of a single parathyroid.
15-20% due to all 4 gland hyperplasia.
Very unlikely to be malignant neoplasms.
14
Q
Clinical presentation of hyperparathyroidism
A
Osteitis fibrosis cystica, osteoporosis
Kidney stones
Confusion
Constipation
Acute pancreatitis
Polyuria
15
Q
What is secondary hyperparathyroidism?
A
Parathyroids producing excess PTH in response to another condition such as Vit.D deficiency, CKD causing hypocalcaemia.
16
Q
Aetiology of secondary hyperparathyroidism
A
CKD, vitamin D deficiency
17
Q
Lab findings for secondary hyperparathyroidism
A
High PTH, low Ca, low phosphate
18
Q
What is tertiary hyperparathyroidism?
A
Occurs after many years of secondary hyperparathyroidism.
Autonomic PTH secretion not limited by feedback.
19
Q
What is hypocalcaemia?
A
Low total serum calcium.
20
Q
How does calcium exist in the blood?
A
45% is in ionized form.
40% is bound to albumin
15% exist within ion complexes
21
Q
Formula for corrected calcium
A
Total calcium + 0.02 (40 - serum albumin).
22
Q
Aetiology of hypocalcaemia
A
pse
23
Q
Symptoms of hypocalcaemia
A
Paresthesia (skin tingling)
Muscle spasms (hands, feet, larynx, premature labour)
Seizures
Basal ganglia calcification
Cataracts
ECG abnormalities - long QT interval.
24
Q
What are the 2 signs of hypocalcaemia?
A
Chvostek’s sign
Trousseau’s sign
25
What is Chvostek's sign?
Tapping over facial nerve causes muscle spasms.
26
What is trousseau's sign?
Inflate blood pressure cuff of 20mmHg over systolic BP for 5 minutes to see if there are carpal muscle spasms.
27
What is hypercalcaemia?
Abnormally high serum calcium
28
Aetiology of hypercalcaemia
Malignancy
Primary hyperparathyroidism
Milk-alkali syndrome due to high milk and antacid consumption
Thiazides
Adrenal insufficiency
Bone immobilisation
29
How can malignancy cause hypercalcaemia?
Bone destruction due to cancer can cause Ca release.
Some tumours can cause PTHrP (PTH related peptide) which can mimic effects of hyperparathyroidism
Lymphomas can cause unrestrained Vit.D activation.
30
Clinical presentation of acute hypercalcaemia
Polyuria
Thirst
Nausea
Constipation
Confusion
Short QT-interval on ECG
31
Lab findings for primary hyperparathyroidism
High PTH, high Ca, low phosphate
32
Lab findings for hypercalcaemia of malignancy
Low PTH, high Ca, low-high phosphate
33
Lab findings for familial hypocalciuric hypercalcaemia
Normal/high PTH, high Ca, low phosphate
34
Lab findings for tertiary hyperparathyroidism
High PTH, high Ca, high phosphate
35
Lab findings for pseudohypoparathyroidism
High PTH, low Ca, high phosphate
36
Pathophysiology of hypocalciuric hypercalcaemia
Defective G-coupled Ca sensing receptors in tissues.
Results in higher Ca levels to suppress PTH production.
37
What is goitre?
Palpable & visible thyroid enlargement
38
What is the most common cause of goitre?
Iodine deficiency, the thyroid gland enlarges to absorb more iodine.
39
Can goitre be present in hypo or hyperthyroidism?
Both
40
What types of goitre are there?
Diffuse, multinodular, solitary nodule,
41
What is primary hypothyroidism?
Absence/dysfunction of the thyroid gland resulting in reduced T3/T4 production.
42
What is secondary/tertiary hypothyroidism?
Reduced T3/T4 levels normally caused by pituitary/hypothalamic dysfunction.
43
Aetiology of primary hypothyroidism
Hashimoto's thyroiditis
Iodine deficiency
Thyroidectomy
Radioactive iodine therapy
44
Drug-related aetiology of hypothyroidism
Antithyroid thonamides (PTU, carbimazole)
Amiodarone
Interferon
Lithium - inhibits T3/T4 production.
45
Aetiology of secondary hypothyroidism
Non-functioning pituitary adenoma
Sheehan's syndrome
46
Neonatal aetiology of hypothyroidism
Thyroid agenesis
Thyroid ectopia
Thyroid dyshormonogenesis
47
Clinical presentation of hypothyroidism
Bradycardia
Weight gain
Dry hair + hair loss - esp in lateral third of eyebrows.
Puffy faces
Delayed reflexes
Cold skin
Depressed mood
Constipation
Abnormal uterine bleeding
48
Investigation/results for primary hypothyroidism
High TSH
Low free T3 and T4
High LDL
Could have anti-TPO antibodies.
49
Investigation/results for secondary hypothyroidism
Low TSH
Low free T3 and T4
Could be caused by pituitary excision or things that decrease pituitary function.
50
Managment of hypothyroidism
Replacement therapy with levothyroxine (synthetic T4)
51
What initial dosage of levothyroxine is given to young adults
100 mcg daily
52
What initial dosage of levothyroxine is given to patients with ischaemic heart disease
25-50 mcg daily
Levothyroxine can cause cardia arrhythmias and worsen angina.
53
How is hypothyroidism replacement therapy monitored?
Clinical assessment every 6-8 weeks.
54
What is the pathophysiology of Hashimoto's thyroiditis?
Presence of thyroid peroxidase antibodies (TPO-Ab) causes inactivation of enzyme and hypothyroidism.
Can have goitre in early phase.
55
What is hyperthyroidism
Excess of thyroid hormones in blood
56
3 mechanisms for thyrotoxicosis
Overproduction thyroid hormone
Leakage of preformed hormone from thyroid
Ingestion of excess thyroid hormone
57
Aetiology of hyperthyroidism
Graves’ disease (75- 80% of all cases)
Toxic multinodular goitre
Toxic solitary adenoma
De Quervain's thyroidism
Lithium
Amiodarone
58
Clinical presentation of hyperthyroidism
Tachycardia
Weight loss
Hyperreactivity
Anxiety
Warm, moist skin
Exopthalmos, lid lag
Increased appetite + defaecation
Abnormal uterine bleeding
59
Investigation of hyperthyroidism
Thyroid function tests
Imaging - ultrasound
Supporting antibody tests - anti TSHR, anti TPO, antithyroglobulin
Radioiodine uptake
60
TFT values for primary hyperthyroidism
Low serum TSH
High free T3 and T4
61
TFT values for secondary/tertiary hyperthyroidism
High TSH for high free T3 and T4
62
What supporting antibody tests would be requested for hyperthyroidism?
TSH receptor stimulating antibodies.
TPO antibodies and thyroglobulin antibodies
63
What would a raised TSHR antibody result mean?
Diagnostic for Grave's disease.
64
What is the most common cause of hyperthyroidism?
Grave's disease
65
Pathophysiology of Grave's disease
Thyroid stimulating immunoglobulins bind to TSH receptors (TSHR-antibodies).
Cause excess TSH production resulting in hyperthyroidism and diffuse goitre.
Can rarely cause hypothyroidism (myxedema).
66
Clinical presentation of Grave's disease
Diffuse goitre (smooth, even on both sides)
Acropachy (similar appearance to clubbing)
Pretibial myxoedema (protein depositon in subcutaeneous tissue).
Exopthalmos (Grave's opthalmopathy)
67
What condition also comes with Grave's disease?
Grave's opthalmopathy
68
Pathophysiology of Grave's opthalmopathy
Lymphocyte infiltration of retroorbital space.
Causing glycoasaminoglycan deposition
Results in extra-ocular muscle swelling and retro-orbital inflammation.
69
Clinical presentation of Grave's opthalmopathy
Exopthalmos (protruding eyes beyond orbit).
Vision impairment due to swelling muscles compressing optic nerve.
70
What is toxic, multinodular goitre
Areas of distended, hyperfunctioning follicular cells.
71
What is toxic adenoma
Benign, solitary growth on thyroid.
72
What are some conditions associated with thyroid autoimmunity?
Pernicious anaemia
Myasthenia gravis
T1DM
Addison's disease
73
What drug is used for symptomatic control in hyperthyroidism?
Beta blockers, ex. propanalol.
74
What are the 2 management regimens for hyperthyroidism?
Gradual dose titration
Block and replace regimen
75
What is done during first-line gradual dose titration?
20-40 mg daily carbimazole, with dose adjustment for 12-18 months.
76
What is done during the block and replace regimen?
Full dose of antithyroids like carbimazole 40mg given to fully suppress thyroid.
Thyroid activity replaced with levothyroxine 100 mcg daily.
77
What are 2 antithyroid drugs
Carbamizole, propylthiouracil
78
What drug can be used as second line hyperthyroidism treatment?
Propylthiouracil
79
What is the pharmacodymanics of carbamizole?
Inhibits thyroid peroxidase enzyme.
80
What is the pharmacodynamics of propylthiouracil?
Inhibits 4-diodenase which prevents peripheral T4->T3 conversion
81
What class of drugs are propylthiourcil and carbimazole?
Thionamides
82
Side effects of thionamides
Rash, agranulocytosis - can present as mouth ulcers, sore throats, hepatitis
83
What is thyroiditis?
Autoimmune destruction of the thyroid.
84
Pharmacodynamics of radioactive iodine therapy
Radioiodine uptake by thyroid releases ionizing radiation and destroys cells.
85
When is radioiodine therapy contraindicated?
During pregnancy and breastfeeding.
86
What drugs are contraindicated in thyrotoxicosis?
Aspirin - increases T4 levels
Symptomatic management - paracetamol.
87
What surgical management for hyperthyroidism is available?
Full/partial thyroidectomy
88
Clinical Presentation of Hypothyroidism in Pregnancy
Usually predates the pregnancy
Weight gain
Cold intolerance, dry skin.
Poor concentration
Poor sleep pattern
Constipation
Tiredness
89
Complications of Hypothyroidism in Pregnancy
Gestational hypertension and pre-eclampsia
Post partum haemorrhage
Preterm delivery (if left untreated)
Neonatal goitre (if left untreated)
Neonatal respiratory distress (if left untreated)
90
What are some features to look out for when screening for hypothyroidism in pregnancy?
Age >30
BMI >40
Miscarriage preterm labour
Personal or family history
Goitre
Anti TPO
Type 1 DM
Head and neck irradiation
Amiodarone, Lithium or contrast use
91
Managment of pre-existing hypothyroidism in pregnancy
Pre-conception counselling (ideal pre-conception TSH <2.5 mIU/L)
Increase thyroxine dose by 30 %
Arrange TFT early pregnancy and titrate
92
Management of new presentation of hypothyroidism in pregnancy
Start thyroxine 50-100mcg daily
Measure TFT at 4-6 week
93
Complications of Hyperthyroidism in Pregnancy
Intra-uterine growth restriction
Preeclampsia
Preterm delivery
Low birth weight
Risk of miscarriage
94
Complications of Hyperthyroidism in Pregnancy
Intra-uterine growth restriction
Preeclampsia
Preterm delivery
Low birth weight
Risk of miscarriage
95
What congenital abnormalities does carbimazole increase the chance of?
Aplasia cutis, Choanal atresia, Intestinal anomalies
96
What is looked at for thyroid autoantibody measurement during pregnancy?
TSHR antibodies
during 22-26 weeks.
97
Pathophysiology of foetal thyrotoxicosis
Occurs due to TSHR stimulating antibodies crossing the placenta and acting on the baby.
98
Management of foetal thyrotoxicosis
Carbimazole to the mother.
99
Pathophysiology of gestational thyrotoxicosis
High hCG levels in first trimester allows for stimulation of TSH receptors.
100
Lab values for gestational thyrotoxicosis
Slightly low TSH, high T3 and T4.
101
Pathophysiology of amiodarone induced hypothyroidism
Iodine presence causes inhibitory effect on thyroid hormone synthesis.
Inability of gland to escape Wolf-Chaikoff effect.
102
What is the Wolf-Chaikoff effect?
Sudden exposure to increased iodine inactivates thyroid peroxidase enzyme and reduced T3/T4 secretion.
103
Pathophysiology of amiodarone induced thyrotoxicosis
Iodine excess causes Jod-basedow phenomenon and hyperthyroidism.
104
What is the Jod-Basedow phenomoneon
When iodine-deficient patients get increased exposure to iodine resulting in hyperthyroidism.
105
What endocrine disorders is ipilumimab associated with?
Hypophysitis and hypothyroidism.
106
Where is the V1a vasopressin receptor?
Blood vessels
107
Where is the V1b vasopressin receptor?
Anterior pituitary
108
Where is the V2 vasopressin receptor?
Renal tubules
109
What is the relationship between plasma osmolality and vasopressin release?
Increase in plasma osmolality causes linear increase in vasopressin release.
110
What is the relationship between urine osmolality and vasopressin release?
Vasopressin release causes exponential increase in urine osmolality.
111
What is the formula for plasma osmolality calculation?
2 x [Na] + [Glucose] + [Urea]
112
What is normal plasma osmolality?
282-295 mOsmol/kg.
113
Aeitiology of diabetes insipidus
Vasopressin deficiency or resistance
114
What urine volume excludes diabetes insipidus?
<3L a day
115
Lab values when diagnosing diabetes insipidus
High plasma osmolality, low urine osmolality
Plasma osmolality >300 mOsmol/kg, urine osmolality <200 mOsmol/kg
116
What diagnostic test is used to investigate diabetes insipidus?
Water deprivation test
117
What is expected in the water deprivation test of a patient with diabetes insipidus?
Plasma osmolality rises with low urine osmolality
118
Genetic aetiology of cranial diabetes insipidus
Wolfram syndrome
Familial isolated vasopressin deficiency
119
Acquired aetiology of cranial diabetes insipidus
Craniopharyngioma, TB, aneurysm, meningitis, head trauma
120
What is seen in the water deprivation test with cranial diabetes insipidus?
Plasma osmolality decreases and urine osmolality increases >50% upon administration of desmopressin.
121
Management of cranial diabetes insipidus
Administer desmopressin
122
What are the methods of administering desmopressin?
Tablets 100-600 mcg/day
IM injection 1-2 mcg/day
Nasal spray 10-20 mcg/day
123
Pharmacodynamics of desmopressin
Synthetic vasopressin, activates V2 receptor.
124
Aetiology of nephrogenic diabetes insipidus
Renal resistance to vasopressin
125
Genetic aetiology of nephrogenic diabetes insipidus
X-linked V2 receptor defect
Autosomal - Aquaporin 2 channel defect
126
Acquired aeitiology of nephrogeneic diabetes insipidus
Hypercalcaemia, renal tubulopatheis, lithium use.
127
What diagnoses nephrogenic diabetes insipidus in the water deprivation test?
Continued increase in plasma osmolality and low urine osmolality despite desmopressin administration.
128
Management of nephrogenic diabetes insipidus
Thiazide diuretics, e.g benzofluomethiazide - causes temporary hypovolemia and increased sodium excretion.
129
What is hyponatraemia?
Serum sodium <135 mmol/L
130
What is severe hyponatraemia?
Serum sodium <125 mmol/L
131
What is the normal range for serum sodium levels?
135-144 mmol/L
132
Clinical presentation of hyponatraemia and SIADH
Headache
Irritability
Nausea / vomiting
Mental slowing
Unstable gait / falls
Confusion / delirium / disorientation
133
Management of hypervolaemic/normovolaemic hyponatraemia
Fluid restrict to 1L/24/hrs
134
Management of hypovolemic hyponatraemia
Saline replacement
135
Aetiology of SIADH
Small cell carcinoma of the lung
Pneumonia
Meningitis
Medications: Thiazide diuretics, desmopressin, SSRIs
136
Pathophysiology of SIADH
Too much ADH, when it should not be being secreted
Causes water retention and hyponatraemia
137
Investigation results of SIADH
Low serum osmolality
High urine osmolality and sodium (>30 mmol/L)
Euvolemic hyponatraemia
Normal thyroid and adrenal function
138
Management of SIADH
Fluid restriction <1L/24 hour
Sometimes demeclocycline/tolvaptan which inhibits vasopressin action.
If Na <115 mmol/L administer IV 150ml of 3% hypertonic saline
139
Pharmacodynamics of tolvaptan
Selective V2 receptor antagonist that competes with ADH.
140
What is chronic demyelination syndrome?
Massive demyelination of descending axons.
141
Aetiology of chronic demyelinaton syndrome
Sudden high increase in serum sodium when there has been chronic hyponatraemia.
142
What is the sodium increase rate that provides a risk of chronic demyelination syndrome?
>18mmol in 48 hours
143
What is acromegaly?
Excess production of growth hormone
144
Pathophysiology of Acromegaly
Excess growth hormone production causes release of insulin like growth factor 1 (IGF-1) from liver.
This stimulates skeletal and soft tissue growth giving rise to ‘giant-like’ appearance and symptoms
145
Clinical Presentation of Acromegaly
Acral enlargement - increased hand size
Widening of supraorbital ridge
Coarsening of features.
Excessive sweating
Increased weight
Amenorrhea
Voice deepening
Arthralgia (joint pain) and backache
Snoring
VFD - bitemporal hemianopia
Headaches
146
Comorbidities of Acromegaly
Hypertension
Cardiomyopathy
Cerebrovascular events
Sleep apnoea
Arthritis
T2DM
147
Investigation of acromegaly
FL: Raised plasma IGF-1 levels
Diagnostic:
Oral glucose tolerance test
148
What are normal serum GH levels?
<0.5 ng/L
149
What is a normal result of the glucose tolerance test?
In normal individuals, glucose administration should suppress GH levels.
150
What would patients with acromegaly show on glucose tolerance tests?
No suppression of GH levels after glucose administration.
151
What are the management options for acromegaly?
First line: Surgical management
Radiotherapy
Medical management
152
Surgical management of acromegaly
Trans-sphenoidal surgery for pituitary removal
Causes rapid fall in GH
153
What is conventional radiotherapy for acromegaly?
Fractional (small) doses given daily for 5-6 weeks.
154
What is a benefit of conventional radiotherapy?
Is tolerated by optic nerves.
155
What is stereotactic radiotherapy?
Single dose of precise radiation is administered towards the tumour.
156
What drug classes are used in the medical management of acromegaly?
Dopamine receptor agonists
GH receptor antagonists
Somatostatin analogues - daily subcut injection
157
Example of dopamine receptor agonist
Cabergoline
158
Example of somatostatin analogue
Octreotide
159
Example of GH receptor antagonist
Pegvisomant
160
What hormone inhibits prolactin?
Dopamine
161
Aetiology of hyperprolactinaemia
Prolactinoma
Pregnancy
Pituitary stalk compression
Dopamine antagonists
162
Clinical presentation of prolactinoma
Headaches
Visual field defects
163
Clinical presenation of hyperprolactinaemia
Amenorrhea
Galactorrhea
Decreased libido
164
Management of prolactinoma
Dopamine agonists ex. cabergoline, bromocriptine
165
Examples of non-functional pituitary tumours.
Pituitary adenoma
Craniopharyngioma
Rathke's cyst
Meningioma
Lymphocytic hypophysitis
166
Effects of pituitary tumours
Headhaces due to raised ICP
Visual field defects
CSF rhinorrhea
Cranial nerve palsies
167
What is a common visual field defect caused by pituitary tumours?
Bitemporal hemianopia
168
What is the preffered method for pituitary imaging?
MRI
169
What is MRI useful for visualizing?
Vascular and soft tissue structures
170
What does a T1 weighted MRI scan highlight?
Images of fat.
Structures such as fatty marrow and orbital fat show up as bright images.
171
What does a T2 weighted MRIs scan highlight?
Structures with high water content, such as CSF and cystic lesions.
172
What is a CT scan useful for visualizing?
Bony structures and calcifications within soft tissue.
173
What pituitary tumours are better seen with CT?
Craniopharyngiomas and meningiomas.
174
Clinical presentation of a craniopharyngioma
Headaches, visual field defects, growth failure
175
What is the embryological origin of a Rathke's cyst and a craniopharyngioma?
Rathke's pouch
176
What are some signs of an aggressive pituitary adenoma?
Large size
Cavernous sinus invasion
Lobulated suprasellar margins
177
What is the hormonal relationship between glucagon and insulin?
Insulin secretion causes paracrine inhibition of glucagon secretion and vice versa.
178
What is the process of insulin secretion?
- Glucose enters the beta cell through GLUT2 transporter.
- Glucokinase metabolises the glucose.
- ATP release causes closure of potassium pumps.
- This depolarizes the cell membrane causing voltage gated Ca channel opening.
- Influx of Ca causes insulin vesicle migration and exocytosis.
179
Mechanism of peripheral insulin action?
- Insulin binds to insulin receptor in peripheral tissue.
- Triggers intracellular signalling cascades that cause mobilisation of GLUT4 transporter vesicles.
- These integrate into the plasma membrane and allow for glucose uptake into the cell.
180
What is diabetes mellitus?
Disorder of carbohydrate metabolism characterized by hyperglycaemia.
181
What are the different types of diabetes?
T1DM
T2DM (including gestational and medication induced)
Maturity onset diabetes of youth (MODY).
Pancreatic Diabetes
Endocrine Diabetes (cushings/acromegaly)
Malnutrition Related Diabetes
182
What is T1DM?
Autoimmune disease characterised by autoimmune beta cell destruction causing insulin deficiency.
183
Epidemiology of T1DM
Usually affects those <30
Patients are usually lean.
High prevalence in Northern Europe.
184
Pathophysiology of DM
Decreased peripheral uptake of glucose
Decreased paracrine glucagon inhibiton
Increased glycogenolysis and lipolysis.
Increasing plasma glucose concentration
185
Clinical presentation of of T1DM
Polyuria and/or glycosuria
Polydipsia
Unexplained weight loss
Polyphagia
Ketonuria/ketosis
186
Explanation of T1DM symptoms
Polyuria and glycosuria to excrete glucose once it goes above renal threshold.
Polydipsia due to high plasma osmolality and osmotic diuresis causing dehydration.
Weight loss due to lipolysis and skeletal muscle breakdown.
Polyphagia due to inability for glucose to enter cells causing hunger.
Ketonuria/ketosis due to increased FFA oxidation into ketones.
187
What is T2DM?
Peripheral post-receptor insulin resistance
188
Non-modifiable risk factors for T2DM
Increasing age (usually >30)
Male gender
South Asian/Afro-Carribean descent
189
Modifiable risk factors for T2DM
Obesity
Sedentary lifestyle
Hypertension
Alcoholism
190
Clinical presentaton of T2DM
Polyuria and/or glycosuria
Polydipsia
Unexplained weight loss
Polyphagia
Acanthosis nigricans
191
What is the identical twin concordance for DM?
>90% concordance in T2DM
60% concordance in T1DM.
192
What immune components are associated with T1DM?
HLA-4 and HLA-3
193
Investigation of DM
Random plasma glucose > 11.1 mmol/L
Fasting plasma glucose > 7mmol/L
Haemoglobin A1c (HbA1c) > 48mmol/mol (>6.5%)
Oral glucose tolerance test >11.1 mmol/L
194
What is the oral glucose tolerance test
Patient is given 75g of glucose and has serum levels measured 2 hours later.
195
What does HbA1c represent?
Average levels of blood glucose attached to haemoglobin over the last 3-4 months.
3-4 months due to RBC turnover rate.
196
Management of T1DM.
Basal-bolus insulin therapy.
197
Examples of short-acting insulins
Lispro, aspart, glulisine.
198
Examples of long-acting insulins
Detemir, degludec.
199
First line pharmacological management for T2DM
Oral metformin 500 mg
1 with breakfast then increase to 1 with each meal/day.
200
Drug class and pharamcodynamics of metformin
Biguanide.
Inhibits mitochondrial glycerol-3-phosphate
dehydrogenase (mGPD) to prevent hepatic gluconeogenesis.
201
Side effects of metformin
Lactic acidosis
Diarrhoea
Anorexias
202
Contraindications of metformin
Patients with hepatic and renal insufficiency because there is a risk of lactic acidosis.
203
Pharmacodynamics of sulfonylureas
Stimulate insulin release by binding to sulfonylurea receptors on B cells that close K+ channels and allow for membrane depolarisation.
204
Examples of sulfonylureas
Gliclazide, glyburide
205
Side effects of sulfonylureas
Weight gain
Hypoglycemia in renally impaired patients.
206
Pharmacodynamics of thiazolidenediones
Binds to PPAR-gamma receptor to increase insulin sensitivity and increasing adiponectin levels.
207
Side effects of thazolidenediones
Increased risck of heart failure, fractures, weight gain,
208
Examples of thiazolidenediones
Pioglitazone, rosiglitazone.
209
Examples of incretins
GLP-1 (glucagon like peptide)
GIP (glucose-dependent insulinotropic peptide)
210
First line management for T2DM
Lifestyle advice
211
Examples of GLP-1 analogues
Exenatide, Liraglutide, Semaglutide
212
Side effects of incretins
Nausea, vomiting, pancreatitis.
213
What enzyme degrades incretins?
Dipeptyl peptidase (DPP4)
214
What type of inhibition is performed by DPP-4 inhibitors?
Competitive enzyme inhibition.
215
Examples of DPP-4 inhibitors
Vildagliptin, sitagliptin.
216
Pharmacodynamics of SGLT-2 inhbitors.
Block reabsorption of glucose through SGLT-2 co-transporter in proximal convoluted tubule.
217
Examples of SGLT-2 inhibitors
Canagliflozin, dapagliflozin
218
Side effects of DPP-4 inhibitors
Respiratory and urinary infections.
219
Side effects of SGLT-2 inhbitors
Genital thrush
UTIs
Glycosuria
Euglycaemic ketoacidosis
220
How do SGLT-2 inhitors cause euglycaemic ketoacidosis?
Increased glycosuria makes the body think it is in a fasting state.
Leads to increased lipolysis, fatty acid oxidation., ketogenesis, and acidosis.
221
Aetiology of diabetic ketoacidosis
Mostly type 1 diabetes.
Uncontrolled, chronic T2DM.
Interruption of insulin therapy
Infection/Illness
Myocardial Infarction
222
Pathophysiology of diabetic ketoacidosis
Absence of insulin and disinhibition of glucagon causes greater lipolysis and fatty acid oxidation into ketones.
Ketones are acidic and lower blood pH.
223
Clinical presentation of diabetic ketoacidosis
Dehydration & polydipsia
Polyuria
Nausea/vomiting
Kussmaul breathing
Fruity/pear drop smelling breath due to exhaled acetone
Delirium
224
Managment of diabetic ketoacidosis
Rehydration (IV 0.9% saline, 3L in first 3 hrs)
Insulin administration + glucose to prevent hypoglycaemia
Electrolyte replacement ( IV K+)
225
Why does K+ need to be replaced during diabetic ketoacidosis?
Insulin can cause hypokalaemia by causing K influx into cells, and K+ loss can occur due to vomiting.
226
Complications of diabetic ketoacidosis
Coma
Cerebral oedema (if too much fluids given)
Adult respiratory distress syndrome
Thromboembolism – venous and arterial (DVT, PE, etc).
Aspiration pneumonia (in drowsy/comatose patients)
Death
227
Investigation of diabetic ketoacidosis
Ketonaemia: Ketones ≥ 3mmol/L (31mg/dL)
Hyperglycaemia: Serum glucose > 11 mmol/L
Acidosis: Blood pH < 7.3 or HCO3 < 15 mmol/L
228
Pathophysiology of hyperglycaemic hyperosmolar state
Profound hyperglycemia --> excessive osmotic
diuresis --> dehydration and high serum osmolality
229
Aetiology of hyperglycaemic hyperosmolar state
T2DM
230
Investigation of hyperosmolar hyperglycaemic state
Hyperglycaemia, high serum osmolality
No ketones unlike DKA
231
When can T2DM lead to diabetic ketoacidosis?
Increased stress on pancreatic B-cells due to insulin insensitivity can cause cell decline in prolonged T2DM and result in decreased insulin production and ketoacidosis.
232
Why does T2DM not normally result in diabetic ketoacidosis?
Even low concentrations of insulin can prevent and fatty acid oxidation and ketogenesis.
233
What is level 1 hypoglycaemia?
Alert value
Plasma glucose <3.9 mmol/l (70 mg/dl) and no symptoms
234
What is level 2 hypoglycaemia?
Serious biochemical
Plasma glucose <3.0 mmol/l
(55 mg/dl)
235
Aetiology of hypoglycaemia in diabetics
Insulin/sulphonylurea treatment
Missed meals
236
Aetiology of hypoglycaemia inon-diabetics
Exogenous insulin
Hypopituitarism
Insulinoma
Liver failure
Adrenal insufficiency
237
Autonomic symptoms of hypoglycaemia
Trembling, palpitations, sweating, anxiety
238
Neuroglycopenic symptoms of hypoglycaemia
Dizziness, seizures, confusion, difficulty speaking
239
Managment of hypoglycaemia
15g fast acting carbohydrate/glucose (juice, bread etc.)
If no improvement after 3 cycles of carbs, IM glucagon.
If still unresponsive, IV glucose 10%.
240
Pathophysiology of microvascular complications of diabetes
Increase of advanced glycation end products (AGE) causes tissue inflammation and injury.
Excess glucose is metabolised into sorbitol via polyol pathway.
Increased levels of sorbitol and fructose cause changes to vascular permeability and capillary structure.
Hyperglycaemia inactivates autoregulatory mechanisms to limit blood flow causing endothelial cell damage which can lead to microvascular occlusion.
241
Examples of microvascular complications of diabetes
Diabetic retinopathy, neuropathy, nephropathy.
242
Pathophysiology of diabetic neuropathy
Damage to blood vessels supplying the nerves causes decreased nerve conduction velocity and segmental demyelination.
243
Clinical presentation of diabetic neuropathy
Burning pain
Parasthesia
Feeling like walking on glass/cotton wool
‘Glove and stocking’ sensory loss
Orthostatic hypotension
Erectile dysfunction
244
What is tested in diabetic neuropathy screening?
Sensation, vibration perception, ankle reflexes.
245
How is sensation tested in diabetic neuropathy screening?
10 gm monofilament, neurotips
246
How is vibration perception screened for diabetic neuropathy?
Tuning fork, biothesiometer (applies vibrational voltage, those detecting only above 30 V are considered at high risk for foot ulceration.
247
Management of diabetic neuropathy
Tricyclic antidepressants / SSRIs
Anticonvulsants (carbamazepine, Gabapentin)
Opiods (Tramadol, oxycodone)
IV lignocaine
248
What is peripheral vascular disease?
Decreased perfusion to distal extremities due to macrovascular complications.
249
Investigation of peripheral vascular disease
Doppler ultrasound
250
What occurs in a doppler study?
Measures ankle brachial index, a marker of lower extremity circulation.
251
Management of peripheral vascular disease
Continued light walking of the foot to allow collateral vessel formation.
Smoking cessation
May require surgical intervention.
252
Aetiology of diabetic foot ulcers
Peripheral vascular disease + diabetic neuropathy
253
Pathophysiology of diabetic foot ulcers
Ischaemia due to PVD causes necrosis and ulceration.
Neuropathy causes painless onset of symptoms.
254
Clinical presentation of ischaemic diabetic foot ulcers
Due to PVD
Pain during rest
Claudication (pain upon movement)
Cold, pulseless upon examination.
Ulceration is normally on heels/toes.
255
Clinical presentation of neuropathic diabetic foot ulcers
Due to diabetic neuropathy.
Painless onset.
Clawing of toes, high arching of foot.
Warm with bounding pulses.
Ulceration is normally on the plantar surface.
256
Management of diabetic foot ulcers
Ensure ulcerated foot is non-weight bearing.
Bypass surgery if ischaemia.
Broad spectrum antibiotics if infection occurs.
Persisting issues can result in amputation of foot.
257
What is the most common cause of blindness in the working population?
Diabetic retinopathy
258
Risk factors for diabetic retinopathy
Long-term diabetes
Hypertension
Pregnancy
Insulin treatment.
259
Stages of diabetic retinopathy
Non-proliferative (R1), pre-proliferative (R2), proliferative (R3)
260
Pathophysiology of R1
Pericyte and smooth muscle cell loss cause micro-aneurysms - red dots.
Hemorrhage of the aneurysms are seen as blots.
Clearing of blood into veins leaves protein and lipid deposits - exudate in imaging.
261
Pathophysiology of of R2
Venous loops and beading.
Multiple haemorrhages
262
Pathophysiology of R3
VEGF release causes neovascularization.
Results in appearance of intraretinal microvascular abnormalities (IRMAs).
Pre-retinal and vitreous haemorrhage - can lead to blindness.
Risk of retinal detachment.
263
Pathophysiology of diabetic maculopathy
Non-proliferative retinopathy can affect vision if within the macular region.
Classification is if exudate is within 1 disc diameter of macula.
Can cause retinal thickening and loss of central vision.
264
Management of diabetic retinopathy
Intravitreal injection
Laser photocoagulation
265
What does intravitreal injection entail?
Injection anti-VEGF drugs such as ranibizumab.
Can control proliferative retinopathy and maculopathy.
266
What does laser photocoagulation entail?
Targets new vessels of proliferative retinopathy.
Panretinal photocoagulation is used if vessels have developed on the optic disk, where the peripheral retina is targeted.
267
Side effects of laser photocoagulation.
Risk of reduced night and peripheral vision.
268
Pathophysiology of diabetic nephropathy
Hyperglycemia causes afferent arteriole dilation.
This results in greater intraglomerular pressure and shearing forces.
Causes basement membrane hypertrophy and reduces filtration capacity, allowing more molecules through.
269
Clinical presentation of diabetic nephropathy
Gradually increasing albuminuria.
Microalbuminuria → macroalbuminuria → consistent proteinuria.
270
Management of diabetic nephropathy
Antihypertensive therapy can slow progression.
ACE inhibitors such as ramipril and ARBs such as candesartan.
271
What drugs should be reduced for diabetic nephropathy
Metformin and insulin due to impaired renal clearance.
272
How is C-peptide presence in diabetes?
Absent in T1DM, present in T2DM.
273
Aetiology of precocious puberty
CNS tumours
Congenital adrenal hyperplasia
Leydig cell tumours
274
Pathophysiology of precocius puberty
Early activation of HPG system causes increased GnRH production.
Increased androgen production can also cause early development.
275
Aetiology of delayed puberty
Hypergonadotropic hypogonadism (primary)
Hypogonadotropic hypogonadism (secondary)
276
Aetiology of hypergonadotropic hypogonadism (primary hypogonadism)
Klinefelter's syndrome (47XXY), Turner syndrome (45X), gonadal injury.
277
Aetiology of hypogonadotropic hypogonadism (secondary hypogonadism)
Kallman syndrome
278
What is delayed puberty?
Lack of secondary sexual characteristics by age 13 in females and age 14 in males.
279
What is precocious puberty?
Presence of secondary sexual characteristics before age 8 in females and age 9 in males.
280
Clinical presentation of Turner's syndrome
Recurrent middle ear infection
Webbing of neck
Short stature
Cardiac defects
281
Clinical presentation of Klinefelter's syndrome
Azoospermia (no sperm in ejacualte)
Tall stature
Gynecomastia
282
What is the genetic defect in Klinefelter syndrome
47 XXY
283
Clinical presentation of Kallman syndrome
Micropenis
Gonads have not dropped.
Impaired sense of smell
Single kidney development
284
Management of delayed/precocious puberty?
Oestrogen/testosterone replacement therapy
285
What is hypokalaemia?
Hypokalaemia is defined as a serum potassium level <3.5 mmol/L
286
Aetiology of hypokalaemia
BAD LOAD
Bleh (vomiting)
Aldosterone (Conn's)
Diarrhoea
Laxatives
Overdose on insulin
Alkalosis
Diuretics
287
Clinical presentation of hypokalaemia
Muscle weakness, hyporeflexia, cramps, Tetany (intermittent muscle spasm), palpitations, light headedness, arrythmias, Constipation
288
Investigation of hypokalaemia
ECG
U + E
CMP (comprehensive metabolic panel)
289
How would hypokalaemia present on an ECG?
Small or inverted T waves, Prominent U wave
Long PR + QT interval, ST depression.
Torsades de pointes
290
Management of mild hypokalaemia
Usually asymptomatic (3.0-3.4mmol/L)
Oral replacement- consider IV
291
Management of severe hypokalamia
<2.5mmol/L
IV replacement 40mmol KCl in 1L 0.9 NaCl
292
What is hyperkalaemia?
Hyperkalaemia is defined as a serum potassium value >5.5mmol/L
293
Aetiology of hyperkalaemia
FRAMED
Failure (renal)
Rhabdomyolysis
Addison's (adrenal insufficiency)
Metabolic acidosis
Excess administration
Drugs (spironolactone, NSAIDs, ACEi/ARBs).
294
Clinical presentation of hyperkalaemia
Muscle weakness and paralysis, arrhythmia, chest pain, light headiness
295
Investigation of hyperkalaemia
Metabolic panel
ECG
Urine electrolytes
296
What can an ECG show for hyperkalaemia?
Tall tented T waves
Long PR interval
Small P waves
Wide QRS complex
Ventricular fibrillations
Sine wave
297
Management of hyperkalaemia with ECG changes
Administer IV calcium gluconate/chloride to stabilise cardiac membrane.
298
Management of hyperkalaemia without ECG changes
Combined insulin/dextrose infusion with nebulised salbutamol
299
Management of acute severe hyperkalaemia
IV calcium gluconate + IV insulin/dextrose
300
What is carcinoid syndrome?
Disease caused by enterochromaffin like cell tumour which releases serotonin into the the circulation.
301
Aetiology of carcinoid syndrome
Small intestine malignancy (Most common) metastesizing to liver.
- Appendix most common GI tract site
302
Pathophysiology of carcinoid syndrome
Normally the serotonin secretedy by GI carcinoid tumours reach portal circualtion and are inactivated by the liver.
With hepatic metastsis, this is not possible and it is released into systemic circulation.
303
Clinical presentation of carcinoid syndrome
Flushing, diarrhoea, abdominal cramps, bronchospasm (wheezing, asthma), fibrosis (heart valve dysfunction, palpitations
304
Investigation of carcinoid syndrome
1st line: Urinary 5-hydroxyindoleacetic acid test - elevated levels
CXR + Chest/pelvic CT- Helps locate primary tumours
305
Management of carcinoid syndrome
Surgery- Resection of tumour is the only cure for carcinoid tumours so it is vital to find the primary tumour.
Debulking, embolization, or radiofrequency ablation for hepatic masses/metastases can decrease symptoms
Somatostatin analogues- Octreotide, blocks release of tumour mediators and counters peripheral effects
306
What are common areas for neuroendocrine tumours?
GI tract, parathyroids, thyroid, adrenal glands
307
What is a common feature of neuroendocrine cells?
Share a common function through amine precursor uptake decarboxylase.
308
What is a neuroblastoma?
Most common adrenal medulla tumour in children below 4 years.
Originates from neural crest cells.
309
Clinical Presentation of Neuroblastoma
Abdominal distension
Firm, irregular mass that crosses midline.
Normally normotensive.
310
Investigation of Neuroblastoma
High serum Homovanillic acid (HVA) and vanillylmandelic acid (VMA) levels.
HVA and VMA are catecholamine metabolites.
311
What is a phaemochromocytoma?
Most common tumour of the adrenal medulla in adults.
Derived from chromaffin cells (which arise from neural crest cells).
312
Pathophysiology of Phaemochromocytoma
Secrete catecholamines such as adrenaline, noradrenaline and dopamine.
313
Clinical Presentation of Phaemochromocytoma
Episodic hypertension,
Pain (headache), pressure, perspiration, palpitations (tachycardia), pallor.
314
Investigation of Phaemochromocytoma
Raised urine and serum catecholamines.
Raised urine and serum catecholamine metabolites such as HVA (homovanillic acid) and VMA (vanillymandelic acid).
Abdominal CT
315
Management of Phaeomochromocytoma
Surgical tumour removal.
Prior to surgery:
Administer alpha antagonists such as phenoxybenzamine
Follow with beta blockers like propanalol.
Alpha blockade must be achieved before beta blockers to prevent hypertensive crisis.
316
How are MEN genes inherited?
Autosomal dominant inheritance.
317
What can mutations in MEN genes cause?
Neuroendocrine tumours.
318
What are the different MEN genes?
MEN1
MEN2A
MEN2B
319
What can be caused by MEN1 mutations?
Pituitary tumours (Prolactinoma/acromegaly)
Pancreatic endocrine tumours
Parathyroid adenomas
320
What can be caused by MEN2A mutations?
Parathyroid hyperplasias.
Medullary thyroid carcinoma (C-cell tumour increasing calcitoni release).
Phaemochromocytoma
321
What can be caused by MEN2B mutations?
Phaemochromocytoma
Medullary thyroid carcinoma
Oral/intestinal ganglioneuromatosis.
322
What are 3 examples of pancreatic tumours?
Insulinomas
Glucagonaomas
Somatostatinomas
323
Pathophysiology of insulinoma
Pancreatic B-cell tumour
Causes overproduction of insulin resulting in hypoglycaemia.
324
Clinical Presentation of Insulinoma
Whipple triad: Hypoglycaemic symptoms during fasting/exercise, low blood glucose during the symptoms, and resolution of symptoms upon glucose intake.
Inappropriately high insulin levels during hypoglycaemia.
325
Treatment of Insulinoma
Surgical resection.
326
What cells are affected in a glucagonoma?
Pancreatic alpha cells
327
Clinical Presentation of Glucagonoma
Migratory necrolytic dermatitis
Diabetes
Deep vein thrombosis
Declining weight
Depression
Diarrhoea
328
Treatment of Glucagonoma
Surgical resection
Ocreotide (somatostatin analogue)
329
What cells are affected in a somatostatinoma?
Pancreatic delta cells
330
Pathophysiology of Somatostainomas
Overproduction of somatostatin causes decreased insulin, glucagon, secretin and cholecystokinin activity.
331
Clinical Presentation of Somatostatinomas
Diarrhoea/Steatorrea
Diabetes
Gall stones
332
Treatment of Somatostatinoma
Surgical resection
Somatostatin analogues
333
ATCH Dependent Aetiology of Cushing's Syndrome
Cushing’s disease: Increased ACTH production, normally caused by pituitary adenomas (most common ACTH-dependent cause).
Ectopic ACTH production where neoplasms elsewhere in the body produce excess glucocorticoids. - small cell lung carcinoma
334
ATCH Independent Aetiology of Cushing's Syndrome
Oral steroid use
Adrenal adenoma
335
Clinical Presentation of Cushing's Syndrome
entral obesity/weight gain (increased cholesterol)
Mood changes
Red/purple abdominal, axillary striae
Moon face (face swollen into rounded shape)
Buffalo hump (fatty hump between shoulders)
Hirsutism (thick black hair appearance for women on face, back, etc.)
Amenorrhea
Hypertension
Increased risk of infection due to cortisol suppressing immune system
336
Investigation of Cushing’s Syndrome
GS, FL: Low Dose Dexamethasone Suppression Test:
Administration of 0.5-1g dexamethasone (a glucocorticoid medication) at 11pm.
Check cortisol levels next morning 9am.
Normal patients would show cortisol suppression <50nmol/L due to negative feedback.
Cortisol >50nmol/L = Cushing’s
If high, proceed to high dose dexamethasone test (use 8g).
24 hr Urinary Free Cortisol Measurement:
Could be alternative to LDDS.
Does not give indication of underlying cause - can be altered by external factors.
Imaging:
MRI Pituitary if pituitary adenoma
Chest/abdominal CT if ectopic neoplasms.
337
Management of Cushing's Syndrome
Iatrogenic
Cessation of steroid medications.
Cushing’s Disease
Trans-sphenoid surgical removal of the tumour.
Adrenal/Ectopic Tumour
Adrenalectomy
Resection of tumour
Cortisol Hypersecretion
Metyrapone, ketoconazole - 11b hydroxylase blocker.
Are used pre-op.
338
What is Nelson's Syndrome
Complication of bilateral adrenalectomy resulting in enlargement of functional pituitary adenomas.
Results in increased ACTH production and hyperpigmentation.
