Wk9 - Endocrinology Flashcards
Define DM
“A metabolic disorder of multiple aetiology characterized by chronic hyperglycaemia with disturbances of carbohydrate, protein and fat metabolism resulting from defects in insulin secretion, insulin action, or both.”
Presentation of DM
Hyperglycaemmia:
Glycosuria - Depletion of Energy Stores
Tired, weak, weight loss, difficulty concentrating, irritability
Glycosuria - Osmotic Diuresis
Polyuria, polydipsia, thirst, dry mucous membranes, reduced skin turgor, postural hypotension
Glucose Shifts - Swollen Ocular Lenses
Blurred vision
Insulin deficiency & complications:
Ketone Production -
Nausea, vomiting, abdominal pain, heavy/rapid breathing, acetone breath, drowsiness, coma
Depletion of Energy Stores (ie. Muscle) - Weakness, polyphagia, weight loss, growth retardation in young
Complications (T2DM) - Macrovascular, Microvascular, Neuropathy, Infection
WHO criteria for DM
Fasting plasma glucose of >=7.0 mmol/L
Random plasma glucose of >=11.1 mmol/L
One abnormal values diagnostic if symptomatic
Two abnormal values if diagnostic if asymptomatic
HbA1c 6.5% or 48 mmol/mol
Diabetes should not be diagnosed on the basis of glycosuria or a BM stick
OGTT only required for diagnosis if IFG or GDM
Classifying primary diabetes
1) Type 1 DM
Immune pathogenesis
Severe insulin deficiency
2) Type 2 DM
Combination of insulin resistance and insulin deficiency
Diagnosis of DM
Plasma ketone metres (Beta-hydroxybutyric acid)
Islet autoantibodies:
Markers of autoimmune process associated with T1DM
Present in 80% of T1DM if combination of glutamic acid decarboyxylase (GAD) and insulinoma-associated antigen -2 (IA2) measured (<1% of MODY)
Some patients with phenotype of T2DM have positive antibodies (progress more quickly to insulin). Most useful 3-5 years from diagnosis (overlap with T2DM/MODY before, especially in obese)
C-peptide:
Secreted in equimolar concentrations to insulin
Useful marker of endogenous insulin secretion
Most useful 3-5 years from diagnosis (overlap with T2DM/MODY before especially in obese)
Can be measured in blood or urine (urine c peptide/creatinine ratio)
Pathogenesis of type 1 DM
Chronic, progressive metabolic disorder characterised by hyperglycaemia and the absence of insulin secretion.
Type 1 diabetes results from autoimmune destruction of the insulin-producing beta cells in the islets of Langerhans.
Occurs in genetically susceptible subjects and is probably triggered by one or more environmental agents.
Reports have linked each of the following factors to an increased risk of T1DM (no associations have been verified and many have been contradicted):
●Viral infections, particularly enterovirus infections
●Immunizations
●Diet, especially exposure to cow’s milk at an early age
●Higher socioeconomic status
●Obesity
●Vitamin D deficiency
●Perinatal factors such as maternal age, history of preeclampsia, neonatal jaundice and low birth weight (reduced risk)
Disease progression of T1DM
Genetic risk
Immune activation - beta cells are attacked
Immune response - development of a single autoantibody…..
Epidemiology of T1DM
Lifetime risk of developing T1DM:
No family history – 0.4 percent
Offspring of an affected mother – 1 to 4 percent
Offspring of an affected father – 3 to 8 percent
Offspring with both parents affected – reported as high as 30 percent
Non-twin sibling of affected patient – 3 to 6 percent
Dizygotic twin – 8 percent
Monozygotic twin – 30 percent within 10 years of diagnosis of the first twin, and 65 percent concordance by age 60 years 5% of DM.
Pathogenesis of T2DM
90% of DM.
Chronic, progressive metabolic disorder characterised by hyperglycaemia, insulin resistance and relative impairment of insulin deficiency
Common with a prevalence that rises markedly with increasing levels of obesity
Most likely arises through a complex interaction among many genes and environmental factors
Epidemiology of T2DM
Prevalence varies remarkably among ethnic groups living in the same
39% have at least one parent with the disease
Lifetime risk for a first-degree relative of a is 5 -10 times higher than that of age- and weight-matched without family history of diabetes.
Environment explains why Pima Indians in Mexico are less than one-fifth that in United States Pima Indians (6.9 versus 38 percent).
Pathogenesis and epidemiology of T2DM
1-2% of DM (often unrecognised)
Caused by change in a single gene (monogenic). Autosomal dominant (50% chance of inheriting)
6 genes have been identified accounting for 87% of UK MODY (HNF1-A around 70%)
3 main features:
- Often <25yrs onset
- Runs in families from one generation to next
- Managed by diet, OHAs, insulin (not always)
Pathogenesis and epidemiology of GDM
Carbohydrate intolerance with onset, or diagnosis, during pregnancy
Studies show that appropriate interventions reduce adverse outcomes in pregnancy
Risk factors include high body mass index, previous macrosomic baby or gestational diabetes, or family history of, or ethnic prevalence of, diabetes
All women with risk factors should have an OGTT at
24 to 28 weeks. Internationally agreed criteria for gestational diabetes using 75 g OGTT:
Fasting venous plasma glucose ≥ 5.1 mmol/l, or
One hour value ≥ 10 mmol/l, or
Two hours after OGTT ≥ 8.5 mmol/l
Recall causes of secondary DM
Secondary Diabetes
1) Genetic Defects of beta-cell function
2) Genetic defects in insulin action
3) Disease of exocrine pancreas
- Pancreatitis/Carcinoma/CF/Haemochromatosis
4) Endocrinopathies
- Acromegaly/Cushings/Phaeochromocytoma
5) Immunosuppressive agents
- Glucocorticoids/Tacrolimus/Ciclosporin
6) Anti Psychotics – Cloazpine/Olanzipine
7) Genetic syndromes associated with DM
- Down’s Syndrome Friedreich’s Ataxia, Turner’s
- Myotonic Dystrophy, Kleinfelter’s Syndrome.
Pathophysiological basis of insulin secretion
Insulin is produced in beta cells which constitute 75% of the islets of Langerhans of the pancreas
Insulin, as well as C peptide, are released by exocytosis into the portal venous system which leads it directly to the liver (50%)
The principal stimulant of insulin secretion is glucose
With a basal secretion of approximately 40 microgram/h under fasting conditions, there are increases of secretion linked to meals
The aim of the treatments by exogenous insulin is to approach the physiological curve of secretion.
Human vs analogue insulin ….
-
Insulin pens
More convenient and easier to transport than traditional vial and syringe
Repeatedly more accurate dosages
Easier to use for those with impairments in visual and fine motor skills
Less injection pain (as polished and coated needles are not dulled by insertion into a vial of insulin before a second insertion into the skin)
Can be used without being noticed
Continuous Subcutaneous Insulin infusion (CSII)
CSII or ‘pump therapy’ can potentially provide significant improvement in glycaemic control and quality of life for some people with Type 1 diabetes.
Pumps have the potential to make it easier to achieve glucose control with less danger of severe and incapacitating hypoglycaemia. However, the efficacy of this compared to SMBG is still debatable.
Specific but infrequent complications of CSII therapy include reactions and occasionally infections at the cannula site, tube blockage and pump malfunction.
CSII therapy is expensive, incurring costs for batteries, reservoirs, infusion sets, insulin, lancets, test strips and glucometers.
Curative treatment for T1DM
Islet cell transplant - harvest islets from pancreas and then inject them - immunosuppressive drugs needed
Pancreatic transplant
Physiological hierachy of hypoglycaemia
4.6 mmol/l - inhibition of insulin release - general malaise: headache, nausea
3.8 mmol/l - release of counterrgulatory hormones glucagon and adrenaline – onset of autonomic symptoms (most occur ~3 mmol/l) - sweating, palpitations, shaking, nausea, anxiety, hunger
BUT 70-80% of readings at this level no symptoms
2.5 -2.8 mmol/l - impairment of cognitive function and concentration, inability to perform complex tasks - confusion, drowsiness, odd behaviour, speech difficulty, incoordination, weakness, visual change, dizziness, tiredness
<2mmol/l – EEG changes, seizures
<1.5 mmol/l - coma, convulsions
Severity scale of hypoglycaemia
MILD: autonomic
MODERATE: autonomic and neuroglycopaenic
MODERATE: autonomic and nueroglycopaenic
SEVERE: autonomic and neuroglycopaenic
Hypos and driving
CBG> 5mmol/l before driving (5 TO DRIVE), carry CHO, identifiers
If between 4-5 mmol/l – eat before driving
2 hours at a time
Do not drive if feeling hypo or CBG <4 mmol/l
If hypo: 1 hour before driving (from onset) and CBG>5
Group 1 entitlement: on insulin
Adequate hypo awareness
Notify if >1 severe hypo whilst awake in 12 months or most recent <3months when filling form
CBG monitoring evidence
Not a danger to the public
Acuity and visual fields OK
Group 1 entitlement: tablets risk of hypos e.g. sulphonylureas
Hypo guidance as above
CBG diary for driving
Group 2 entitlement: IRDM
Full hypo awareness and understanding of risks
No severe hypos in 12 months
CBG monitoring evidence: 3 months of recordings
Not a danger to the public
Acuity and visual fields OK
Group 2 entitlement: tablets risk of hypos
No severe hypos in 12 months
Full hypo awareness and understanding of risks
CBG checks at least twice daily and more often for driving
Definition of DKA
Features and diagnosis of DKA
Defintion:
- DKA is an acute metabolic complication of diabetes that is potentially fatal and requires prompt medical attention for successful treatment.
- It is characterised by absolute insulin deficiency and is the most common acute hyperglycaemic complication of type 1 DM
Clinical diagnosis with diagnostic criteria
Mainly T1DM but now recognise ketosis prone T2DM
4.6 to 8 episodes per 1000 people with diabetes
Mortality: fallen from 7.96% to 0.67% in UK. 5% worldwide
Mortality in young: cerebral oedema 70-80% deaths
Mortality in adults: severe hypokalaemia, ARDS, illness causing
decompensation
1) Metabolic acidosis: venous bicarbonate < 18mmol
H+ > 45 mEq/L
pH < 7.3
2) Plasma glucose: > 13.9mmol/l
3) Urinary / plasma ketones: ≥2+ urinary / >3mmol/L
Metabolic acidosis, hyperglycaemia and ketonuria or ketonaemia
Pathophysiology od DKA
Absolute or relative insulin deficiency
+
Increase in stress hormones
–>
- Lipolysis: FFAs: ketogenesis
- Gluconeogenesis: severe hyperglycaemia
- Osmotic diuresis + acidosis: dehydration
Clinical features of DKA
Osmotic Symptoms Weight Loss Breathlessness – Kussmaul respiration Abdominal pains, especially in children Leg cramps Nausea and vomiting Confusion
Precipitating factors of DKA
ACute illness (MI, trauma, pancreatitis)
NEw-onset DM
Insulin omission
Infections (pneumonia and UTIs are most common)
Steroids CSII pump failure Substance abuse Deliberate omission of insulin dose - weight management, avoidance of hypo, escaping domestic situation, depression, attention seeking Eating disorder
Typical key losses in DKA
DKA treatment
Complications of DKA
Key losses: 6-8L of water Sodium Chloride Potassium
Treatment:
Always consider and treat the precipitant
Fluid: restoration of circulatory volume: crystalloid (saline solution)
Clearance of ketones: 10% dextrose
Potassium
Insulin
Complications: hypoglycaemia, hypokalaemia (associated with cardiac arrhythmias)
Definition of HHS
Features and diagnosis of HHS
HHS is characterised by profound hyperglycaemia, hyperosmolality and volume depletion in the absence of significant ketoacidosis
Hypovolaemia
Very high blood glucose > 30mmol/L
Serum osmolality >320mOsmol/l
Bicarbonate usually > 15mmol/l
Absence of significant ketones
Ketoacidosis not present
May proceed to coma: watch GCS
Precipitating factors for HHS
Infection - 60%
Poor compliance - 30%
Drugs
Treatment of HHS
Treat the precipitant
Fluid
0.9% sodium chloride
Aim for a positive fluid balance of 3-6L by 12 hours
Only switch to 0.45% sodium chloride if osmolality not falling despite
positive fluid balance
Rate of fall in sodium should not exceed 10mmol in 24 hours
Insulin
Rate of fall no more than 5mmol/L/hr
Only start when glucose not falling with fluid alone
Low dose insulin 0.05units/kg/hr
Other
LMWH
Foot protection
Microvascular, foot and macrovascular ocmplications of diabetes
Retinopathy (eyes):
A leading cause of blindness in the working population in the developed world
First microvascular complication for patients with diabetes
Nephropathy (kidneys):
Will affect 30-40% of patients with diabetes;
23% of patients starting dialysis have diabetes as the primary case, but poorer survival on it
Neuropathy/foot disease:
Life-time risk for a foot ulcer is 25%
80% of non-traumatic amputations occur in patients with diabetes
Cardiovascular disease (CVD):
Increased risk of CVD
Duration of diabetes and female gender increase risk
Management of microvascular, foot and macrovascular ocmplications of diabetes
Retinopathy (eyes):
Annual photographic retinal screening with triggers for ophthalmology referral
Nephropathy (kidneys):
Annual monitoring of renal function and urinary albumin excretion, referral to renal team if nephropathy progesses e.g. CKD4; macroalbuminuria
Neuropathy/foot disease:
Annual foot-screening (minimum) with risk stratification and referral to podiatry/vascular as appropriate e.g. progressive neuropathy, structural change, ischaemia
Cardiovascular disease (CVD):
Keep BP <130/80, lower if nephropathy
Statin therapy if T2DM and age >40 regardless of DM duration and baseline cholesterol. Consider in T1DM especially if complications
MOA of metformin
Side effects of biiguanides
Metformin is part of the biguanide class
MOA:
Increases the activity of AMP-dependent protein kinase (AMPK)
This inhibits gluconeogenesis
Decreases insulin resistance.
Side effects: Diarrhoea Nausea Vomiting Taste disturbances Lack of apetite Risk of lactic acidosis in patients with renal failure
Not recommended in pregnancy and renal failure
MOA of sulphonylureas
Side effects
MOA of sulphonylureas (e.g. Cliclazide, Glimepiride):
Stimulates B cells of the pancreas to produce more insulin
Increases cellular glucose uptake and glycogenesis; reduces gluconeogensis
Gliclazide is short acting (12 hours approx)
Glimepiride is long acting)
Side effects: Hypoglycaemia Rashes Nausea Vomiting Stomach pain Indigestion Weight gain
Renally excreted so accumulates with renal failure
Avoid alcohol
Hypopitiutarism
Failure of (anterior) pituitary function
Can affect single hormonal axis or all hormones (panhypopituitarism)
Leads to secondary gonadal/thyroid/adrenal failure
Need multiple hormone replacement
Causes of hypopituitarism
Tumours (most common) Radiotherapy Infarction / haemorrhage (apoplexy) - Associated headache / visual disturbance - Assoc PPH (Sheehan’s syndrome) Infiltration (eg sarcoid) Trauma Lymphocytic hypophysitis
Anterior pituitary hromone replacement
Deficiency Replacement ACTH - hydrocortisone TSH - thyroxine FSH/LH - testosterone (males) - oestrogen (females) GH - growth hormone PRL - no replacement
Causes of high prolactin
Prolactinomas
Physiological
Lactation / pregnancy
Drugs (that block dopamine)
Tricyclics / antiemetics / antipsychotics
“stalk” effect
Due to loss of inhibitory dopamine
Macro vs micro adenoma
Macro >1cm
Micro <1cm
Pituitary tumours - types
Non-functioning (majority) - dont produce any hormones
Functioning Prolactin (prolactinoma) GH (acromegaly) ACTH (Cushing’s disease) TSH (TSHoma)
Others
Craniopharyngioma, pituitary cancer, Rathke’s cyst
Problems associated with non-functioning pituitary tumours
Commonest (25 % of all pit tumours)
No hormonal release
But cause problems Visual field defects Headache Stops other pituitary hormones working Eye movement problems
Investigation and treatment of non-functioning pituitary tumour
Investigation Imaging Visual field assessment Prolactin Other pituitary hormones
Treatment
Surgery
RT
Medical management unhelpful
Clinical features of prolactinoma
Pituitary tumours releasing prolactin
Micro < 1 cm
Macro > 1 cm
Clinical features Galactorrhoea Headaches Mass effect Visual field defect
Amenorrhoea / erectile dysfunction
(Gonadotrophic hormones are the ones first affect)
Prolactinomas diagnosis & treatment
Serum prolactin
Usually > 6000
MRI pituitary
Test remaining pituitary function
Gonadal function and thyroid hormones most affected
Medical
Dopamine agonists
eg cabergoline / bromocriptine / quinagolide
Surgery
VF compromise
Failure of medical therapy
Prolactinomas in pregnancy
Pituitary gland gets bigger in pregnancy
Dopamine agonists contraindicated
[prolactin] unhelpful
Can’t do serial MRI in pregnancy
Monitor visual fields if macroprolactinoma
Features of acromegaly
Pituitary tumour secreting Growth Hormone
Post puberty ie after growth plates fused
Gigantism
Features Sweats and headaches Alteration of facial features Increased hand and feet size Visual impairment Cardiomyopathy Inc. Inter-dental space
Diagnosis of acromegaly
Rare
20 new cases per year in Scotland
Usually macroadenoma
Diagnosis
Glucose tolerance test:
- Glucose should suppress GH so if present, GH will still be high regardless of oral administration of glucose
- Measure IGF-1 as has long half-life and is more useful than a random GH
Then MRI
Acromegaly treatment
First line- surgery
Often tumour can’t be fully removed
Drugs
- Somatostatin analogue: Octreotide; Before and after surgery
- Dopamine agonist
- GH receptor agonist: Pegvisomant ; £££
Radiotherapy
- Residual tumour / ongoing symptoms
Gene mutation causes Acromegaly
AIP gene
What is cushings disease?
Diagnosis
Pituitary tumour releasing ACTH
One of the causes of Cushing’s syndrome
wt gain / thin skin / easy bruising / BP / osteoporosis
Diagnosis- try to suppress it
- Dexamethasone suppression testing
Treatment of cushings disease
Surgery first line
If surgery fails / inappropriate / refused Bilateral adrenalectomy Medical therapy Ketoconazole / metyrapone Radiotherapy
Signs and symptoms of cushings disease
Buffalo hump Hypertension Moon face, with red (plethoric) cheecks Increased abdo fat Easy bruising...
Features of TSHoma
Pituitary tumour releasing TSH
Rare
Causes high TSH and high fT4
Clinical features and differential diagnosis of diabetes insipidus
ADH deficiency- central or cranial Clinical features polydipsia chronic excessive thirst accompanied by excessive fluid intake polyuria urine output > 3 L/day Differential diagnosis Nephrogenic diabetes insipidus Psychogenic polydipsia
Investigation:
Water deprivation test - deprived of fluids for 8 hours and plasma and urine osmolality measured every 2-4 hours. Then give synthetic ADH (desmopressin). If cranial DI, the urine osmolality will increase after given desmopressin; There will be no change in urine osmolality with nephrogenic DI.
Causes of central diabetes insipidus
deficiency of ADH idiopathic trauma pituitary tumour pituitary surgery pregnancy familial other Wegeners, sarcoidosis, histiocytosis X, lymphocytic panhypophysitis
