Endocrinology Part 3 Flashcards
What is MODY?
Maturity-onset diabetes of the young- MODY
- Commonest type of monogenic diabetes (~1% diabetes)
- Diagnosed <25y
- Autosomal dominant
- Non-insulin dependent
- Single gene defect altering beta cell function
- Tend to be non-obese
Talk about transcription factors in MODY.
Hepatic nuclear factor (HNF) mutations alter insulin secretion, reduce beta cell proliferation.
What are the different types of MODY?
- HNF1A mutation (MODY 3)
- Very sensitive to sulphonylurea treatment (tablet), so often do not need insulin (~80%) - HNF4A mutation (MODY 1)
- FH, young age of onset, non-obese, Sus, AND
- Macrosomia (>4.4kg at birth)
- Neonatal hypoglycaemia - Glucokinase gene (GCK) mutation (MODY 2)
- GCK is the glucose-sensor of beta cells, rate determining step in glucose metabolism, controlling the release of insulin
- Higher set point, but still tight glycaemic control
- Mild diabetes, no treatment required
MODY is usually misdiagnosed as what type of diabetes?
Diabetes type 1 or young onset Type 2 diabetes
Compared MODY with Type 1 DM and Type 2 DM.
MODY: non-insulin depedence, +/- obesity, diagnosis < 25 yo, 1 parent affected
Type 1 DM: insulin dependence, +/- obesity, diagnosis < 25 yo, 0-1 parent affected
Type 2 DM: non-insulin dependence, +++ obesity, unusual before 25 yo, 1-2 parent affected
Which patients might be MODY?
- Parent affected with diabetes
- Absence of islet autoantibodies
- Evidence of non-insulin dependence
- Good control on low dose insulin
- No ketosis
- Measurable C-peptide
- Sensitive to sulphonylurea
Talk about C-peptide in different type of diabetes.
- Not present in synthetic insulin
- C-peptide longer half-life, 30 vs 3 mins
- In Type 1 diabetes, C-peptide is negative within 5 years (due to complete autoimmune beta cell destruction)
- Type 2 and MODY, C-peptide persists
Talk about permanent neonatal diabetes.
- Diagnosed <6 months (usually de novo):
> Signs:
> Small babies, epilepsy, muscle weakness - Mutations encode Kir6.2 and SUR1 subunits of the beta cell ATP sensitive potassium channel
- Rising ATP closes the channel as a result of hyperglycaemia, depolarising the membrane and insulin is secreted
- Mutations prevent closure of the channel, and thus beta cells unable to secrete insulin
- Sulphonylureas close the KATP channel
What is maternally inherited diabetes and deafness (MIDD)?
- Mutation in mitochondrial DNA
- Loss of beta cell mass
- Similar presentation to Type 2
- Wide phenotype
What is lipodystrophy?
- Selective loss of adipose tissue
- Associated with insulin resistance, dyslipidaemia, hepatatic steatosis, hyperandrogenism, PCOS
What are some examples of diseases of the exocrine pancreas?
- Inflammatory (acute and chronic pancreatitis)
- Hereditary Haemochromatosis
- Deposition (Amyloidosis / cystinosis)
- Pancreatic Neoplasia
- Cystic Fibrosis
Talk about inflammatory (pancreatitis)
Acute – usually transient hyperglycaemia, due to increased glucagon secretion
Chronic pancreatitis:
- Alcohol
- Alters secretions, formation
of proteinaceous plugs that
block ducts and act as a foci
for calculi formation
- Stop alcohol, treat with insulin
Talk about Hereditary Haemochromatosis.
Autosomal recessive – triad of cirrhosis, diabetes and bronzed hyperpigmentation
Excess iron deposited in liver, pancreas, pituitary, heart and parathyroids
Most need insulin
What are the 2 deposition diseases that are commonly seen in the pancreas?
Amyloidosis / cystinosis
Talk about pancreatic neoplasia.
- Common cause of cancer death
- 4-5 resections per week at STH
- Require sc insulin
- Prone to hypoglycaemia due to loss of glucagon function
- Frequent small meals, enzyme replacement
- Insulin pumps
Talk about cystic fibrosis.
- Cystic fibrosis transmembrane conductance regulator (CFTR) gene located on chromosome 7q22
- Regulates chloride secretion
- Viscous secretions lead to duct obstruction, and fibrosis
- Incidence is 25 to 50% in adults
- Ketoacidosis rare
- Insulin treatment required
- CF survival better, so microvascular complications increasing
- Insulin improves:
> Body weight
> Reduces infections
> Lung function
> Improves quality of life, and ?survival
What are some examples of endocrine causes of diabetes?
- potentially reversible
> Acromegaly
> Cushing syndrome
> Pheochromocytoma
Talk about acromegaly induced diabetes.
- Excessive secretion of growth hormone
- Similar to Type 2
- Insulin resistance rises, impairing insulin action in liver and peripheral tissues
Talk about Cushings syndrome-induced diabetes.
- Increased insulin resistance, reduced glucose uptake into peripheral tissues
- Hepatic glucose production increased through stimulation of gluconeogenesis via increased substrates (proteolysis and lipolysis)
Talk about pheochromocytoma-induced diabetes.
Pheochromocytoma:
Pheochromocytoma is a type of neuroendocrine tumor that grows from cells called chromaffin cells. These cells produce hormones needed for the body and are found in the adrenal glands. If you have a pheochromocytoma, the tumor releases hormones that may cause high blood pressure, headache, sweating and symptoms of a panic attack.
- Catecholamine, predominately epinephrine excess
- Increased gluconeogenesis
- Decreased glucose uptake
Talk about drug-induced diabetes.
Glucocorticoids increase insulin resistance
Thiazides / protease inhibitors (HIV) / antipsychotics – mechanisms not clearly understood
Less insulin induced vasodilatation in muscle leading to reduced glucose delivery to muscle beds, reducing opportunity of muscle to clear glucose from the blood
Describe the HPA axis
Hypothalamus - Pituitary Gland (ACTH) - Adrenal - Cortisol
What is the time period for the acrophase (peak) and nadir phase (lowest point) for cortisol circadian rhythm?
Acrophase (peak)
- 0832h (0759h - 0905h)
Nadir phase (lowest point)
- 0018h (2339h – 0058h)
What is circadian system?cr
Circadian rhythms are physical, mental, and behavioral changes that follow a 24-hour cycle. These natural processes respond primarily to light and dark and affect most living things
What is the primary ‘zeitgeber’ of the body clock/ circadian rhythm?
(zeitgeber - a rhythmically occurring natural phenomenon which acts as a cue in the regulation of the body’s circadian rhythms.)
Light - changes in the quantity and quality of light at dawn or dusk
eye - then feedback to the suprachiasmatic nuclei in the brain
Central body clock controls peripheral body clock.
true/ false?
True
Suprachiasmatic Nuclei - Muscle, heart, lung, brain, hormones, liver, kidney, stomach
Glucocorticoids are a secondary messenger from central to peripheral clocks
Talk about adrenal insufficiency.
- Primary – Addison’s Disease (93-140/M)
− Autoimmune adrenalitis >60% of cases
− APS type 1 10-15% of cases
− CAH 1:15000 live births
− Adrenoleukodystrophy
− Mets, haemorrhage, infection
− Infection (TB), infiltration (Amyloid) - Secondary – Hypopituitarism (150-280/M)
− Pituitary macroadenoma/Cranio
− Apoplexy
− Hypophysitis
− Mets, infiltration, infection
− Radiotherapy
− Congenital - Tertiary – Suppression of HPA
− Steroids, oral, inhaler, creams
What are the diagnosis for adrenal insufficiency?
- History
− Symptoms: fatigue, weight loss, poor recovery from illness, adrenal crisis, headache
− Past History: TB, post partum bleed, cancer
− Family History: Autoimmunity, congenital disease
− Treatment: Any steroids! Etomidate, Ketoconazole - Signs
− Pigmentation and pallor
− Hypotension - Biochemistry
− Low Na, high K
− Eosinophilia
− Borderline elevated TSH
Talk about the biochemical investigation for adrenal insufficiency?
- 0900 Cortisol and ACTH
− Cortisol > 500 nmol/l AI unlikely
− Cortisol < 100 nmol/l AI likely
− ACTH > 22 pmol/l primary
− ACTH < 5 pmol/l secondary - Renin / Aldo
− Elevated renin in primary - Synacthen Test
− 250ug IV measure 0’ & 30’
− > 500-550 nmol/l AI unlikely
What is a synacthen test? A synacthen test uses a special chemical (synacthen) to test how well the adrenal glands make cortisol. It involves stimulating the adrenal glands and then checking to see if they respond.
Talk about the investigation for causes of adrenal insufficiency?
- Primary
− Adrenal antibodies
− Very long-chain fatty acids
− 17-OHP
− Imaging
− Genetic - Secondary
− Any steroids???
− Imaging
− Genetic
Talk about the treatment for adrenal insuffiency.
- Goal: Mirror the normal physiological state
- Hydrocortisone (pharmaceutical name for cortisol) twice or three times daily at a dose to replace cortisol levels 15-25mg
- In primary adrenal insufficiency also replace aldosterone with fludrocortisone
Talk about adrenal crisis.
Common Presentation of adrenal insufficiency:
− Hypotension and cardiovascular collapse
− Fatigue
− Fever
− Hypoglycaemia
− Hyponatraemia and hyperkalaemia
In patients on treatment with glucocorticoids:
− Incidence 5-10 / 100 patient years
− Mortality 0.5 / 100 patient years
What is the management for adrenal crisis?
- Take bloods if possible for cortisol and ACTH
- Immediate hydrocortisone 100mg IV, IM, (SC)
- Fluid resuscitation (1L N/Saline 1 hour)
- Hydrocortisone 50-100mg IV/IM 6 hourly
- In primary start fludrocortisone 100-200ug (when HC <50mg)
- When patient stable wean to normal replacement over 24-
72h:
− 50mg orally TDS
− 20mg orally TDS
− 10mg orally TDS - Sick day rules!!
Talk about “sick day rules” for adrenal insufficiency.
- Always carry 10 x 10mg tablets hydrocortisone
- If unwell with fever or flu like illness double dose of steroids
- If in doubt double dose of steroids
- If vomiting or increasingly unwell take emergency injection
of hydrocortisone 100mg IM (SC) - If unable to have injection take hydrocortisone 20mg and repeat if vomit
- Go to emergency room / ring ambulance
- You cannot harm yourself in the short-term taking extra steroid
- Carry steroid card and medic-alert
What is the current Hydrocortisone therapy for adrenal insufficiency?
Current three times daily hydrocortisone therapy.
Talk about Adrenal Insufficiency: Increased morbidity and mortality.
- Standardised Mortality Ratio – 2.7
- Quality of Life - Impaired
- Cardiovascular risk - Increased
- Osteoporosis – Low BMD (Bone Mineral Density)
What is the current and new therapies for adrenal insuffiency?
- Hydrocortisone
– Chronobiology approach (Chronocort® in development) (microparticulate to tackle the challenge of gut length and transit time
What is diabetes mellitus?
A disorder of carbohydrate metabolism characterised by hyperglycaemia
How can diabetes mellitus cause morbidity and mortality?
Acute hyperglycaemia which if untreated leads to acute metabolic emergencies diabetic ketoacidosis (DKA) and hyperosmolar coma (Hyperglycaemic Hyperosmolar State)
Chronic hyperglycaemia leading to tissue complications (macrovascular and microvascular)
Side effects of treatment- hypoglycaemia
Talk about impaired insulin secretion and insulin resistance.
- Genes and environment
2a) impaired insulin secretion
2b) insulin resistance - impaired glucose tolerance
- Type 2 diabetes
- Progressive hyperglycaemia and high free fatty acids
What are the complications for diabetes mellitus type 2?
- Diabetic Retinopathy
- Diabetic Nephropathy
> Leading cause of
end-stage renal disease - 2-4 fold increase in CV mortality and stroke
- 8/10 people with diabetes die from CVD
- DPN (Diabetic Peripheral Neuropathy)
> Leading cause of non-traumatic
lower extremity amputations
What are the 6 common CVD seen in patients with DM2?
- stable angina
- unstable angina
- non-fatal MI
- unheralded coronary death
- HF (heart failure)
- ischaemic stroke
Talk about the mechanism of CVD in diabetes patients.
Hyperglycaemia - subclinical atherosclerosis - atherosclerotic clinical events - acute and chronic coronary syndromes, stroke, peripheral artery disease
What are the different drugs at different sites for DM2?
- GI Tract
- Delay gastric emptying
- Inhibition of glucagon release
- Inhibition of glucose absorption
- Stimulation of GLP-1 release
Drugs : pramlintide, alpha glucosidase inhibitor - Pancreatic beta cells
- Acute stimulation of insulin release
- stimulation of insulin biosynthesis
- inhibition of beta cells apoptosis
- stimulation of beta cell differentiation
Drugs: sulfonylurea, meglitinides, GLP1/DPP-IV inhibitors - Liver
- Inhibition of glucose production
- Increase in hepatic insulin sensitivity
Drugs: metformin - Muscle
- Increase in muscle insulin sensitivity
Drugs: Thiazolidinediones - Adipose tissue
- Suppression of NEFA release
- Fat redistribution (visceral to subcutaneous)
- Modulation of adipokine release
Drugs: Thiazolidinediones
Talk about the structure in Diabetes Care 2002?
- Healthy eating, weight control, increased physical activity, diabetes education
- metformin
- SU/ TZD/ Glinides
- Insulin
What are the lifestyle interventions for DM2?
- Compliance
- Lifestyle and patient education
- 30 min exercise a day
- Dietitian
- Local education programmes (e.g. Desmond and Xpert)
Desmond : Diabetes Education and Self-Management for Ongoing and Newly Diagnosed people
Xpert: X-PERT is a six-week group education programme for patients with Type 2 Diabetes. It has been developed to help patients understand more about diabetes and how they can manage it through lifestyle changes. It is suitable for anyone newly diagnosed and those who have had diabetes for a while but want to learn more.
