Week 11 - Disorders of the Endocrine Pancreas and Thyroid Flashcards
What is another name for the islets of Langerhans?
Pancreatic islets
List the cell types found in the pancreatic islets. What substance does each cell type secrete?
- alpha cells - produce glucagon (increases blood glucose levels)
- beta cells - produce insulin (decrease blood glucose levels)
- delta cells - produce somatostatin (growth-hormone inhibiting hormone)
- pancreatic peptide cells - produce pancreatic peptides (inhibit gallbladder contraction and pancreatic exocrine secretion)
What is the normal range for blood glucose (mmol/L)?
- according to Diabetes Australia: 4.0-7.8 mmol/L
Describe how insulin and glucagon maintain blood glucose levels within the normal range
- Stimulus: high blood glucose levels
- pancreas release insulin (beta cells)
- insulin acts on liver
- stimulate glycogen formation
- insulin acts on somatic/tissue cells
- stimulate uptake of glucose
- result: blood glucose levels return to normal range
- Stimulus: low blood glucose levels
- pancreas releases glucagon (alpha cells)
- glucagon acts on the liver
- stimulate conversion of glycogen to glucose
- result: blood glucose levels return to normal range
List the effects that insulin and glucagon have on fat and protein metabolism
- insulin
- fats
- inhibits gluconeogenesis (stops conversion of AAs or fatty acids to glucose)
- in adipose tissue: stimulates conversion of glucose to fat (storage)
- protein
- stimulates cellular uptake of AAs
- stimulates protein synthesis
- fats
- glucagon
- fats
- stimulates gluconeogenesis (encourages conversion of AAs or fatty acids into glucose)
- protein
- stimulates uptake of AAs
- stimulates gluconeogenesis
- fats
Name the hormonal mechanism by which insulin acts
- insulin is an amino-acid-based hormone
- therefore, it acts via second messenger systems
- more specifically, it utilise the tyrosine kinase second messenger system
Name the hormonal mechanism by which glucagon acts
- amino-acid based hormone
- second messenger system
- cyclic AMP second messenger system
Suggest why diabetes is such an important disease to diagnose and manage effectively
- the complications arising from unmanaged diabetes can be fatal or lead to a poorer quality of life
Define the term diabetes
- diabetes is a condition related to hyperglycaemia (high blood glucose levels)
- can be absolute or relative
- diabetic patients are said to be ‘glucose intolerant’ as the body is unable to metabolize intake of glucose normally
- classified as:
- primary
- type 1 diabetes
- type 2 diabetes
- gestational diabetes
- secondary (known cause for disease)
- pancreatic disease (e.g. cystic fibrosis)
- primary
- diagnosed if:
- random blood sugar is >11.1 mmol/L
- fasting blood sugar level is >7 mmol/L
Differentiate primary diabetes from secondary diabetes
- primary diabetes is the most common form of the disease, and includes type 1 and type 2 diabetes
- secondary diabetes is diagnosed when there is a known cause or pathology for the diabetes. For example, pancreatic diseases such as cystic fibrosis, where excessive mucous production leads to blocking of exocrine glands, can lead to an inability to metabolise glucose
Compare the aetiology of Type 1 diabetes with that of Type 2 diabetes. Which factors are most significant for each type?
- Type 1 Diabetes
- moderate genetic link (identical twin is 50% likely to have it) (though environmental factors are more significant)
- autoimmune component
- viral infection
- combine hypothesis (virus triggers autoimmune response in genetically vulnerable patient)
- Type 2 Diabetes
- much strong genetic link (identical twin is 100% likely to have it; related to genetic coding of beta cells and insulin receptors)
- obesity (inflammatory mechanisms)
- metabolic syndrome
- 3 out of:
- hypertension
- increased weight circumference
- increased TAGs
- decreased HDLs
- abnormal blood glucose
- 3 out of:
- smoking (30-40% higher risk)
- age (70% in >50 years old)
Summarise the proposed role that obesity plays in the aetiology of Type 2 diabetes
- excessive caloric intake leads to:
- accumulation of adipose tissue
- increased adipose tissue releases excessive proinflammatory cytokines
- leads to chronic low grade inflammation
- proinflammatory cytokines impair intracellular signalling
- causes target cells to become less responsive to insulin
- also, linked to damaging the beta cells of the pancreas
- obesity is also linked to decreased insulin receptor density
- collectively, this leads to insulin resistance
How do insulin levels change as Type 2 diabetes progresses from its early to late stage? Can you explain why this occurs?
- early stage:
- insulin levels are elevated above normal to compensate for the insulin resistance (compensatory hyperinsulinemia)
- late stage:
- insulin levels drop below normal due to beta cell exhaustion (insulinpaenia)
Discuss how a patient might present with previously undiagnosed Type 1 Diabetes.
- florrid (quick) onset of symptoms
- three poly’s
- polyphagia (increased hunger)
- polyuria (increased urination)
- polydipsia (increased thirst)
- weight loss and fatigue (‘starvation in the midst of plenty’ due to inability to absorb glucose)
- vulvitis, balanitis (inflammation of glans penis)
- increased gluconeogensis (leading to muscle wasting and weakness)
Outline the symptomatology that might make you consider Type 2 as a possible diagnosis. Can you explain why these features present so differently to Type 1 diabetes?
- insidious onset occurs over months to years
- co-morbidities (metabolic syndrome)
- diabetic vascular disease
- diabetic neuropathy
- hyperglycaemia and glycosuria can increase risk for infection:
- skin infections
- recurrent UTIs
- vulvitis, balantitis
- suspect Type 2, not Type 1, if onset is slow
Hypoglycaemia and ketoacidosis coma are both acute, life-threatening, complications of diabetes. Compare these two acute complications, based on their trigger factors, the metabolic changes that occur and the clinical features.
- Hypoglycaemia
- trigger factors:
- inappropriate use of insulin
- missed, delayed or inadequate meals
- alcohol or drug use
- excessive exercise
- metabolic changes
- low blood glucose levels due to excessive insulin
- clinical features
- CNS features
- drowsiness, confusion, speech difficulties, inability to concentrate
- ANS features
- sweating, trembling, pounding heart, hunger, anxiety, nausea
- Severe hypo
- coma, convulsions, brain damage, stroke
- CNS features
- trigger factors:
- DKA
- triggers factors:
- stress
- inadequate insulin
- infection
- alcohol/drug abuse
- stress
- metabolic changes:
- blood glucose is not accessible
- excessive fatty acids are utilised as a source of glucose
- results in excessive aceytl CoA
- leads to by-product formation of ketones
- ketones lower pH level, leading to DKA
- clinical features:
- early SSx related to hyperglycaemia: polydipsia, polyuria, nausea, vomiting
- acetone breath
- respiratory compensation (increased RR)
- mental disturbance (range from inattention to coma)
- peripheral vasodilation (hypotension, hypothermia)
- triggers factors:
Describe how the chronic complications of diabetes can potentially manifest
- diabetic vascular disease (umbrella term for range of blood vessel pathologies)
- diabetic macroangiopathy = atherosclerosis (lead to AMI, stroke, PVD)
- diabetic microangiopathy = arteriolosclerosis (leads to neuropathy)
- diabetic foot
- infected, non-healing wounds/ulcers
- diabetic neuropathy
- due to pathological changes:
- thickened basement membrane of intra-neural capillaries
- axonal degeneration
- patchy demyelination
- sensory polyneuropathy
- paraesthesia, pain, ataxia
- motor neuropathy
- generalized muscle wasting or weakness
- mononeuropathy
- involvement of a single peripheral nerve
- autonomic neuropathy
- can produce a spectrum of features:
- postural hypotension, tachycardia
- dysphagia, nausea, vomiting
- diarrhoea/constipation
- impotence, sweating
- can produce a spectrum of features:
- due to pathological changes:
Explain why diabetic patients have a 25-fold increased risk for lower limb amputation
These factors, which are manifestations of diabetes, lead to an increased risk of diabetic foot:
- diabetic vascular disease
- reduce tissue healing capacity
- open wound increases risk of infection
- diabetic neuropathy
- inability to feel pain and realise the open wound
- hyperglycaemia and ketosis
- reduce immune function (increasing risk of infection)
When left untreated, may result in gangrenous necrosis (amputation is required)
What is the pharmacological treatment for Type 1 diabetes?
- exogenous insulin (help to regulate high blood glucose levels)
Explain why some Type 2 diabetic patients require insulin in the advanced stages of the disease
- when beta cell exhaustion occurs, type 2 diabetics require insulin to regulate high blood glucose levels
Describe how lifestyle modification can contribute to the management of Type 2 diabetes
- weight loss increases the concentration of insulin receptors and glucose tolerance (thereby, improving insulin sensitivity)
- foods with low GI can prevent dramatic changes in blood glucose levels (levels are more sustained)
- limit caloric and fat intake (limit accumulation of adipose tissue -> pro-inflammatory cytokines)
- frequent, small meals (avoid major spike in blood glucose levels)
List the drug classes that can be used as oral hypoglycaemic agents
- biguanides (first line therapy)
- sulphonylureas
- thiazolidinediones
- alpha-glucosidase inhibitors
Which oral hypoglycaemic agent is used as the first line pharmacological treatment for Type 2 diabetes? List the effects
biguanides (e.g. metformin)
- stimulate glucose uptake and utilization
- inhibit gluconeogenesis
- inhibit intestinal absorption of glucose
Describe the endocrine cells that exist in the thyroid gland. What substances do these cells secrete?
- follicle (hollow, spherical cell) is surrounded by follicular cells, and contain colloid
- follicular cells - secrete thyroglobulin
- parafollicular cells - secrete calcitonin (minor effects on storage of calcium in bones)
List the two hormones that are collectively referred to as the “thyroid hormones”
- T3 - triiodothyronine
- T4 - tetraiodothyronine
Explain how thyroid hormones are synthesised. Where does this take place? What molecules and enzymes are required?
- thyroglobulin is found in follicular cells
-
iodide is actively transported into follicular lumen from bloodstream
- oxidized to iodine (I2) and attached to tyrosine molecule (residue of thyroglobulins) by thyroid peroxidases
- T1 and T2 are linked together to form T3 and T4
Outline the mechanism for the release of thyroid hormones. How are thyroid hormones transported in the circulation?
- HYPOTHALAMUS releases THYROTROPHIN RELEASING HORMONE
- ANTERIOR PITUITARY GLANDS releases THYROID STIMULATING HORMONE
- FOLLICULAR CELLS release T3 and T4
Name the hormonal mechanism by which the thyroid hormones act upon target cells
Direct gene activation
Where are thyroid hormone receptors located within target cells?
within nucleus, attached to DNA
Which of the thyroid hormones is considered most biologically active?
T3 (stronger affinity to thyroid receptors)
Summarise the effects of the thyroid hormones
- gene transcription
- increase basal metabolic rate
- increases body heat production
- catecholamine effect (similar to adrenaline and noradrenaline)
- regulate normal cardiac function
- increase blood pressure
- regulates normal development and function of:
- nervous systems
- musculoskeletal system
- reproductory system
- digestive system
- integumentary system
Briefly describe the function of calcitonin
- minor role in calcium storage within bones
- decrease calcium levels in blood (when high)
Which hormone is predominantly responsible for the regulation of calcium levels in the ECF?
Parathyroid hormone (increase calcium levels when low in blood)
List some differentials for a palpable lump or generalised enlargement of the thyroid.
For each cause, indicate whether thyroid function would be (i) normal (euthyroid) (ii) hypothyroid or (iii) hyperthyroid
- simple (non-toxic) goitre (i)
- simple diffuse (goitre is soft and symmetrical)
- simple multinodular (goitre can become very large, pain and swelling from haemorrhage)
- hypothyroidism
- Hashimoto’s thyroiditis (diffuse, large and firm) (ii)
- thyrotoxicosis (iii)
- toxic diffuse (2-3x normal size + audible bruit)
- toxic multinodular
- toxic solitary (adenoma - benign)
- thyroid cancer (firm and non-tender goitre) (i)
What is another term for the condition “Simple goitre”? How is this condition defined?
Non-toxic goitre
- enlargement of the thyroid gland, where thyroid function is maintained within a normal range
Describe some causes of a simple goitre.
- iodine deficiency (leading cause)
- ingestion of goitrogens (lithium, smoking, certain foods)
- pregnancy
- OCP
- early stage of Hashimoto’s thyroiditis
Summarise the aetiology of Hashimoto’s thyroiditis. What factors may precipitate this disorder?
- It is an autoimmune disorder, characterized by lymphocyte-mediated inflammation and fibrosis, leading to hypothyroidism
- precipitating factors include:
- high dose iodine supplementation
- exposure to radiation
- certain drugs: lithium
Consider the pathophysiology associated with Hashimoto’s thyroiditis. Describe the antibodies that are produced in this disorder.
- also known as ‘chronic lymphocytic thyroiditis’
- secretion of IgG autoantibodies
- some directed against thyroglobulin
- others directed against thyroid peroxidases
- however, the levels of these autoantibodies do not correlate with the severity of the disease
Outline the clinical features of Hashimoto’s thyroiditis.
-
goitre
- only seen in early stages
- diffuse, enlarged and firm
- neck tightness + symptoms of compression
-
reduced metabolic rate
- tiredness, cold intolerance, weight gain, depression
- digestive system: constipation
- reproductive system: menstrual irregularity
- nervous system: bradycardia
- integumetary system: dry, flaky skin and hair, alopecia, xanthelasma
-
glycosaminoglycan (GAG) accumulation
- accumulate in various tissues of the body due to reduced rate of protein breakdown
- GAG accumulation in skin (non-pitting form of oedema = myxedema)
- skin of hands, feet, eyelids
- in CVS, increased risk for angina and hypotension
What is the pharmacological treatment for Hashimoto’s thyroiditis?
- thyroid replacement therapy (oral and usually for life)
Discuss the aetiology of Graves’ disease. What risk factors have been associated with this disease?
- autoimmune disorder cause hyperthyroidism
- risk factors:
- family history
- high dose iodine supplementation
- major stressors, leading to an autoimmune response
- ? role of infection
Describe the antibodies that are produced in Graves’ disease
- autoantibodies (TSH-reactive B cell) attack thyroid stimulating hormone receptors
- this stimulates thyroid follicular cells to produce:
- goitre
- increased T3 and T4
- note: auto-antibody levels in Graves disease do fluctuate with the severity of the disease
Outline the clinical features of Graves’ disease
-
goitre
- diffuse, enlarged + audible bruit
-
thyroxicosis features
- increased metabolic rate - heat intolerance, weight loss
- GIT manifestations - polyphagia, polydipsia
- cardiorespiratory - palpiations, AF
- neurological - nervousness, emotional reliability, psychosis, tremor, hyper-reflexia
- reproductive - menstrual irregularities, loss of libido
-
ocular changes
- GAG accumulation leading to extraocular mm swelling
- lid retraction, corneal ulceration, conjunctivitis
-
skin changes
- pre-tibial skin myxedema (marked thickening of overlying skin)
Discuss how Graves’ disease may be managed (i) pharmacologically and (ii) surgically
- pharmacologically
- anti-thyroid drugs (inhibit thyroid perioxidases)
- beta-blockers
- radioactive iodine (treatment of choice)
- surgery
- sub-total thyroidectomy (preferred)
Describe the clinical features (and any information in the case history) that might make you suspect a thyroid malignancy
- non-tender and firm nodule (recent onset or enlarging)
- dysphagia, hoarseness, Horner’s syndrome (from compression of large tumour)
- symptoms of metastatic spread
- cervical lymph node enlargement
- spread into trachea, lungs
