Seminar 7 - Endocrine Disease and Its Complications Flashcards
Which tests can be done to identify the specific type of diabetes
Often T1 is diagnosed on Hx and PC alone (e.g., DKA)
If in doubt, GAD/IA2 antibodies [and c-peptide] may help
What is Cushing’s syndrome
A disease resulting from chronic excess of glucocorticoids
Why is endometrial cancer often diagnosed early
Post-menopausal bleeding is a common symptom which many women know to have checked so it often leads to early detection and good prognosis.
Which differentials must you consider when diagnosing osteoporosis
Metastatic bone malignancy
Osteomalacia – Difficult to differentiate clinically
Multiple myeloma – Symptoms include bone pain as well as those of anaemia and renal failure
Cervical cancer can affect your sex life - true or false
True
Can be due to treatment side effects or psychological/emotional
Also cannot have vaginal sex for a time after surgery
What is the precursor lesion for serous endometrial carcinoma
Endometrial intraepithelial carcinoma.
What determines the outcome of breast cancer
The stage at presentation
Biological features - e.g. whether it is ER, HER2 of triple neg
Histological type
Which type of adjuvant therapies are available for breast cancer
Chemotherapy
Biological therapies - trastuzumab/Herceptin
Endocrine therapies - tamoxifen
List the macroscopic features of osteoporosis
Trabecular bone is most noticeably affected, but there may also be thinning of the cortical bone
Flattening of vertebral bodies
Will also find artefacts of previous fractures e.g. hip prothesis
What is hyperosmolar hyperglycaemia syndrome
Hypovolaemia and hyperglycaemia without significant acidosis or ketonemia (non-ketotic state)
Also hyperosmolar.
List symptoms that may be seen in advanced stage endometrial cancer
Patients may experience: pain in the back, legs or pelvis, loss of appetite, tiredness and nausea
In which age group is secondary systemic hypertension more common
More common in younger persons, with a prevalence close to 30% in those 18 to 40 years of age with hypertension
List the pathological features of Cervical adenocarcinoma
Characterised by proliferation of glandular epithelium composed of malignant endocervical cells.
These cells have large hyperchromatic nuclei (darker appearance) and relatively mucin depleted cytoplasm.
Describe the epidemiology of cervical cancer
4th most common cancer in women worldwide.
570,000 new cases in 2018 of which more than 50% will be fatal.
50 years ago, it was the leading cause of cancer death in women.
Death rate decreased by 75%
In the UK, less than 1% of those with a cervix will develop cervical cancer in their lifetime
What is insulitis
The leukocytic infiltrates in islets seen in T1DM
Contributes to destruction of the islets
Diffuse thickening of the basement membrane underlies the development of which diabetic complications
Diabetic nephropathy, retinopathy and some forms of neuropathy
Development of end-stage renal disease is more common in which type of diabetes
Type 1
ESRD occurs in >75% of T1 diabetics (vs. 40% T2) within 20 years of developing nephropathy.
List cardiovascular causes of secondary systemic hypertension
Coarctation of the aorta Polyarteritis nodosa Increased intravascular volume Increased cardiac output Rigidity of the aorta
Which symptoms of diabetes are caused by the lack of anabolic action from insulin
Results in catabolic effects so you get:
Increased appetite
Weight loss
Muscle weakness
How does angiotensin II stimulate aldosterone secretion
It sodium resorption via Na+/K+ pump activity at basolateral membrane in the distal convoluted tubules which increases blood volume
This increase in BV triggers aldosterone secretion from the adrenal glands
What is happening to the global prevalence of diabetes
It is rising
rose from 108 million (1980) to 422 million (8.5%; 2014
List the microscopic features of serous endometrial carcinomas
Can have a papillary growth pattern or even be predominately glandular in growth pattern.
Glandular pattern can be differentiated form the similar endometroid tumours by the cytologic features.
Marked cytologic atypia including; high nucleus: cytoplasm ratio, atypical mitotic figures, hyperchromasia and prominent nucleoli.
In which ethnic groups is breast cancer most common
Risk is highest for European women
4-7x greater risk than rest of population
What are the 3 main groups of breast cancer and how are they grouped
Grouped by protein expression
HER2+ – positive for HER2 and +/- for ER
Triple negative – negative for ER, HER2 and PR
Luminal – ER + and HER2 negative
List the pathological features of Cervical squamous cell carcinoma
Composed of nests or tongues of malignant epithelium.
Can be keratinising or non keratinising.
These nests can invade the underlying cervical stroma.
List complications of testicular cancer metastasis
Lung – haemorrhage and blockage of clearance which lead to potential infection, sepsis or respiratory failure
Liver – if severe enough may reduce liver function and lead to liver failure
Brain – has the potential to bleed, cause seizures and raise the ICP
Premature birth or miscarriage due to cervical excision surgery is common -true or false
False
It is rare - only occurs in 2% of women who have had the procedure
How do Selective Oestrogen Receptor Modulator (SERM) work in osteoporosis
Only appears effective in reducing vertebral fractures
How can you differentiate well differentiated endometroid endometrial carcinoma from endometrial hyperplasia
Can be differentiated from hyperplasia by presence of complex growth patterns (e.g. papillary) or desmoplastic stroma
In which % of secondary hypertension patients have Cushing’s
~80% of adult patients
~47% in children
What additional risks need to be addressed in DKA
Is a NG tube required?
Monitor K+
Prescribe LMWH
Source sepsis if present: CXR, cultures
Does diabetic neuropathy mainly effect sensory or motor neurons
Sensory
Which medications can increase the risk of cervical cancer
Oral contraceptives
Increase risk in those already infected with HPV
How does the brain regulate food intake
BY responding to signals received from fat (adipose) tissue, the pancreas, and the digestive tract
These signals are transmitted by hormones—such as leptin, insulin, and ghrelin—and other small molecules (controlled by genes)
The brain coordinates these signals with other inputs and responds with instructions to the body: either to eat more and reduce energy use, or to do the opposite
Which hormones are commonly released by Leydig cell tumours
Cells commonly release androgens, estrogen and corticosteroids
Which of the consequences of chronic hyperglycemia contribute to diabetic microangiopathy
PKC activation
AGE production
Where will immature cells be found in HSIL
In the top 2/3 of the epithelium
What are Squamous Intraepithelial Lesions
Cervical precursor lesion associated again with the high-risk HPVs
List common causes of secondary systemic hypertension in children and adolescents (birth to 18 years)
Renal parenchymal disease
Coarctation of the aorta
Breast cancer is due to genetic factors alone - true or false
False
Exact aetiology not well understood but thought to be due to genetic and environmental factors
List potential complications of testicular cancer treatment
Generic chemotherapy complications
Fertility concerns - if only one removed it should be fine, sperm banking can be done and testosterone can be replaced with meds
Surgical complications inc; retrograde ejaculation, impotence and loss of genital and groin sensation
Radiotherapy complications – blistering and peeling around effected site, infertility of healthy testicle effected, increased risk of future cancer, damage to organs and blood vessels near by
How does acute limb ischaemia present
6 Ps – Pain, pallor, pulselessness, paraesthesia, paralysis, poikilothermia (perishingly cold)
List the mechanisms promoting b-cell dysfunction in T2DM
B-cells exhaust their capacity to adapt to insulin resistance and altered BG levels.
Excess FFAs compromise b-cell function and diminish insulin release.
Impact of chronic hyperglycaemia (glucotoxicity)
Abnormal incretin effect: reduced GIP and GLP-1
Amyloid deposition within islets.
What is the most common malignancy in women worldwide
Breast cancer
Also the deadliest
1.7million women are diagnosed annually with 1/3 succumbing to the disease – 20% mortality rare
Most cases of PAD are asymptomatic - true or false
True
Where does the HPV virus mature in the cervix
The mature squamous cells
How are endometroid endometrial carcinomas staged
Currently endometrial cancer is graded based on gland differentiation and presence of squamous foci are largely ignored
Describe the trend with obesity
It is increasing!
Tripled worldwide since 1975
In 2016, more than 1.9 billion adults, 18 years and older, were overweight
List the pancreatic changes that may be seen in T2DM
Subtle decrease in islet cell mass - only seen on special morphometric studies
Amyloid deposits within the islets
Describe the macroscopic features of a testicular choriocarcinoma
Primary tumours are usually small and most often <5cm in diameter
It very common on the cut surface to see both haemorrhage and necrosis
Which symptoms of DKA are caused by ketone bodies themselves
Flushed Vomiting Abdo pain + tenderness Breathless (Kussmaul’s breathing) May have ketone smelling breath but not always
How does hypothyroidism cause renal dysfunction
You gets a reduced kidney-to-body weight ratio which lowers free water clearance and reduces GFR
This causes hyponatremia and leads to higher blood volume
increases BP
How does hypothyroidism increase peripheral vascular resistance
T3 has a vasodilatory effect on vascular muscle cells
This is deficient in hypothyroid so you get peripheral vasoconstriction
Also associated with increased arterial stiffness
Which drugs can cause hypoglycaemia in non-diabetics
insulin oral hypoglycaemics aspirin poisoning ACE-I B-blockers quinine sulphate insulin-like growth factor.
List the main symptoms of hyperthyroidism
Hair thinning/loss Goiters Excessive sweating Shortness of breath High blood pressure
List causes of estrogenic stimulation
Obesity
Menopause
PCOS
Functioning granuloma cell tumours of the ovaries
Excessive ovarian cortical function (stromal hyperplasia)
Prolonged administration of estrogenic substances - oestrogen replacement therapy
What is osteomalacia
Softening of the bones due to inadequate mineralisation, most commonly due to vitamin D deficiency
How does reduced physicals activity cause osteoporosis
Mechanical forces on bone stimulate bone remodelling, therefore immobility or lack of exercise will increase the rate of bone loss
Also contributes to senile osteoporosis as aging is associated with reduced activity
How does renal artery stenosis lead to secondary systemic hypertension
Causes decreased glomerular flow and pressure in afferent arteriole of the glomerulus
This induces renin secretion which causes an increase in blood volume & vascular tone via angiotensin & aldosterone pathways (increase CO & TPR)
List risk factors for testicular cancer
Cryptorchidism Fx of testicular cancer – although most affected males have none Klinefelters syndrome HIV Carcinoma in Situ of the testes Previous testicular cancer – 3-4% risk of another Caucasian Tall ( no link to body weight) Aged 20-34
What effect does insulin have on the striated muscle
Increases glucose uptake, glycogen synthesis and protein synthesis
Which age group is typically affected by serous endometrial carcinoma
Older women
Aged 65-75
Which breast cancers are usually incurable
Those presenting with distant mets
Luckily this is rare
How can sleep apnoea cause secondary systemic hypertension
May be related to sympathetic activation and hormonal changes associated with repeated periods of apnea-induced hypoxia, hypercapnea and stress associated with loss of sleep
If blood results show hypoglycaemia and hyperinsulinemia what is the likely cause
Sulphonylurea or insulin injection
no detectable c-peptide [only released w/ endogenous insulin]
How is SIL graded
Based on the location of these atypical and immature cells
Normal location is in the basal layer
LSIL will have them in the bottom 1/3 of epithelium
HSIL will have them in the top 2/3 as well
What are the main precursor lesions for breast cancer
ductal carcinoma in situ and lobular carcinoma in situ
How is LSIL managed
May just be followed up with repeat tests - chance of regression on its own
May do local ablation of cervix if worried about patient not following up.
Which membrane protein is recruited in the kidney by ADH
Aquaporin 2
Why do hypos need to be reversed quickly
If not you risk neurological damage
Which is more common sporadic of familial breast cancers
Sporadic are much more common
When are GIP and GLP-1 released
Both are released following food ingestion
List the features of proliferative diabetic retinopathy
New vessel formation on fundus - this is the characteristic finding
Can have rubeosis iridis (new vessels on the iridio-corneal angle)
Which specific HPV strains cause the majority of cervical cancer cases
HPV-16 causes 60% of cancer cases and HPV-18 causes another 10%.
In which type of diabetes is DKA more common
Type 1
Less common in T2 due to higher level of portal vein insulin which prevents unrestricted hepatic fatty acid oxidation, keeping ketone bodies in check
Which stains can you do to test for SIL
You can perform in situ hybridisation to look for viral DNA . The majority will be found in upper mature layers and tells you about viral load.
Can also stain for cell proliferation markers and if these are present outside the normal basal location it suggests SIL.
How does Ca2+ nutritional state cause osteoporosis
If Ca2+ intake is insufficient during a period of rapid bone growth (e.g. adolescence), then peak bone mass will be reduced, increasing the risk of osteoporosis later in life
Related to vitamin D deficiency and fluctuations in PTH
Describe the 3 cells that are seen in spermatocytic tumours
Type 1 – they are medium in size and have a round nucleus. They also have spireme type chromatin with occasional nucleoli and the cytoplasm tends to be eosinophilic
Type 2 – these cells tend to be smaller and the chromatin is dense and has a narrow edge of eosinophilc cytoplasm meaning that it looks like a secondary spermatocyte
Type 3 – these are giant cells which are scattered throughout and can either be uninucleate or multinucleate
Describe the life expectancy with breast cancer
It is possible to have a normal life expectancy with breast cancer but can be as low as 10% survival at 5yrs depending on the above features
Huge variation
What is the management for T1DM
Blood glucose and ketone monitoring
Insulin: usually basal [once daily] bolus [with meals] regimen.
Carbohydrate estimation.
Regular check of glycaemic control – HbA1c
Record severe hypoglycaemic episodes or admission with DKA
How is glucose used in the adipose tissue
Primarily used as a substrate for lipid synthesis (stored as triglycerides)
It inhibits triglyceride hydrolysis & lipid release; promoting amino acid uptake & protein synthesis, whilst inhibiting proteolysis.
List other variants of kidney disease seen in diabetics (beside glomerular disease)
Hyalinizing arteriolar sclerosis
Increases susceptibility to pyelonephritis and papillary necrosis and causes various tubular lesions
What happens to the incretin effect in T2 diabetics
It becomes seriously blunted - reduced satiety
Describe treatment for a stage one testicular seminoma
Orchidectomy and single dose of chemo
Potentially radiotherapy also, to reduce recurrence
How can superficial cervical cancer be managed
Treated with cone excision alone.
May also get a large loop excision or trachelectomy (removal of cervix).
Usually for stage 1A or B and aims to remove all cancer.
Sometimes node dissection if in local nodes affected.
Describe stage II serous endometrial carcinoma
Carcinoma involves the corpus and cervix.
Describe the series of events that occur in the baroreceptors when arterial pressure suddenly rises
Vessel walls passively expand
Receptors depolarize - respond to stretch
Increases firing frequency of AP
Vasomotor center inhibits sympathetic drive
and increases vagal tone on SA node of heart
SA node is slowed by Ach
HR slows down
CO decreases
BP decreases
Describe genetic susceptibility in T1DM
30% risk of inheriting T1DM from both parents, and 3x more likely if only father.
40-50% of T1 diabetics are HLA-DR3/DR4 compound heterozygotes.
Those with DR3 or DR4 AND a DQ8 haplotype have highest inherited risk for T1D.
Several non-HLA genes also confer susceptibility – tandem repeats in promoter region of insulin gene and polymorphisms in CTLA4 and PTPN22 causing altered T-cell selection and regulation.
How does phaechromocytoma cause secondary systemic hypertension
Causes high level of circulating catecholamines
This leads to α-adrenoreceptor mediated systemic vasoconstriction + β-adrenoreceptor mediated cardiac stimulation (arrhythmia) Can elevate arterial pressure
How do you diagnose diabetes
Fasting blood glucose ⩾ 7.0mmol/L or
Random blood glucose ⩾ 11.1mmol/L
And symptoms, OR repeat test.
What are the main causes of hypoglycaemia in non-diabetics
EXogenous drugs, alcohol
Pituitary insufficiency
Liver failure
Addison’s disease
Islet cell tumours (insulinoma) and immune hypoglycaemia
Non-pancreatic neoplasms, e.g., fibrosarcoma, hemangiopericytomas.
Use EXPLAIN to remember
What is the main cause of endometrioid endometrial carcinoma
Prolonged and unopposed estrogenic stimulation of the endometrium
Describe the microscopic features of a testicular spermatocytic tumour
They contain 3 cellular populations that are intermixed
They lack inflammatory cells and synctiotrophoblasts
They don’t mix with other GCT types and don’t appear in extra testicular sites
List common causes of secondary systemic hypertension in older adults (65 years and older)
Renal artery stenosis secondary to atherosclerosis
Renal failure
Describe the morphology of non-specialised adenocarcinoma of the breast
Usually 2-3cm in size
Lumps are usually hard, irregular, radio dense and have a desmoplastic stromal reaction
Cutting the tumour creates a grating sound due to small central foci or streaks of chalky white desmoplastic stroma or calcification
Less commonly they can present as well circumscribed and made of sheets of tumour cells - scarce stromal reactions or be almost unperceivable as are made of scattered neoplastic glands or single tumour cells invading fibrofatty tissue
What is dry gangrene
sterile process where tissue becomes mummified
Describe well differentiated endometroid endometrial carcinoma
Composed almost entirely of well formed glands
Serous endometrial carcinoma is associated with a thin physique - true or false
True
What is peripheral artery disease
Specifically refers to the occlusion of the arteries through the formation of atherosclerotic plaques,
Post-pubertal teratomas can progress to what
Teratomas with somatic type malignant transformation
Usually in the form of squamous cell carcinoma, mucin secreting adenoma, sarcoma or another cancer
If not all those HPV get cancer, what other factors influence development
It has been suggested that other factors such as immune status and exposure to other carcinogens may influence whether it progresses.
Describe the obesity grades of the BMI system
Grade 1 overweight (commonly called overweight) - BMI of 25-29.9 kg/m2
Grade 2 overweight (commonly called obesity) - BMI of 30-39.9 kg/m2
Grade 3 overweight (commonly called severe or morbid obesity) - BMI ≥40 kg/m2
Describe the macroscopic features of a testicular embryonal carcinoma
Locally aggressive and often invade the epidydimis, spermatic cord and vascular and lymphatic systems
The cut surface has a variegated appearance due to foci of haemorrhage and necrosis
What is the pathogenesis of T1DM
Genetically susceptible individuals + environmental stimulus leads to b-cell destruction.
Autoantibodies for islet cell antigens attack the cells
What is the gold standard test for peripheral arterial stiffness
Pulse wave velocity (PWV)
If increased its a sign of early vascular ageing
List rarer gene mutations that can cause familial breast cancers
Rarer tumour suppressor genes with germline mutations
Tp53, PTEN, STK11, CDH1, PALPB2, ATM, CHEK2
Describe the appearance of diffuse mesangial sclerosis seen in diabetic nephropathy
lesion consisting of diffuse increase in mesangial matrix
Matrix depositions are PAS-positive, may be nodular as disease progresses
Expansion of mesangium correlates with deteriorating renal function.
How does age affect incidence of osteoporotic fractures
As age increases so does incidence
How do you diagnose endometrial cancer
Diagnosed by histological examination of tissue sample taken via biopsy or curettage (usually with hysteroscopy).
Where is cortisol secreted from
zona fasciculata of adrenal cortex
How does excess thyroid hormone secretion affect the kidneys
Increased kidney mass due to hypertrophy of renal compartments
How does cervical cancer spread
Advanced cancer spreads by direct invasion to contiguous tissue (: paracervical soft tissue, bladder, ureters, rectum and vagina)
It can invade local lymph nodes which then allow for spread to local and distant nodes.
Distant metastases may be seen in liver, lungs, bone marrow and others.
List the macroscopic features of endometroid endometrial carcinoma
Can form a localised polypoid mass or diffusely affect the endometrial lining.
If it invades the broad ligament it can form a palpable mass.
List the microscopic features of osteoporosis
Bone is histologically normal, though there may be noticeably increased osteoclast activity depending on aetiology (seen as pitting on bone surface)
Trabecular bone thins and loses interconnections so vertical trabeculae become more prominent
Describe the volume dependent mechanisms by which sodium retention cause high BP
Excess extracellular volume leads to increased perfusion of peripheral tissues
This stimulates vasoconstriction and increases TPR
Extracellular volume expansion leads to production of ouabain-like steroids that induce vasoconstriction -> increase TPR
What are the most common testicular tumours
Germ cell
Sex chord stromal
When is glucagon released
When glucose is gone
It’s levels fall after a large glucose load
Which cell/tissue types may be found in a teratoma
Islands of cartilage, neural tissue, squamous epithelium lining epidermal like surfaces with or without skin adnexal structures, muscle bundles, bronchial epithelium , structures that look like the thyroid gland, and bits of intestinal wall or brain substance
Describe the epidemiology of testicular choriocarcinomas
1% of GCTS
Highly malignant
Describe endometrial adenosarcomas
Low grade malignancy .
Presents with large polypoid growths that can prolapse through the cervix.
Identified by malignant appearing stroma alongside benign but abnormally shaped glands.
Nearly always confined to the pelvis.
Recurs in 1/4 of cases.
Older women are most effected by which type of breast cancer
Luminal cancer
<2% are HER2+ or Triple neg
Endometrial adenosarcomas are most common in women of what age
In their 40s and 50s
Where is aldosterone secreted from
zona glomerulosa of adrenal gland
How can risk assessment be beneficial for osteoporosis patients
Assessing falls risks in vulnerable or diagnosed populations may reduce the disease burden by reducing the overall number of fractures sustained
What is Addison’s disease
An uncommon disorder resulting from progressive destruction of adrenal cortex - leads to hypofunction
The adrenal glands do not produce enough of the hormone cortisol (& aldosterone) - Chronic adrenocortical insufficiency
Affects about 1 in 100,000 people
Describe the appearance of hepatocyte steatosis caused by obesity
It ranges from that with no evidence of liver injury to non-alcoholic steatohepatitis (NASH) with evidence of inflammation and hepatocyte injury with/without fibrosis.
What is endothelin 1
Most potent vasoconstrictor peptide with marked hypertensive, mitogenic & atherogenic effects
How are Squamous Intraepithelial Lesions classified
As either low or high grade
LSIL = mild dysplasia
HSIL - moderate and severe dysplasia and carcinoma in situ
What are the main causes of hypoglycaemia in diabetic
Insulin or sulphonylurea treatment
Accidental or non-accidental overdose
Increased activity
Missed meal
How are breast cancers staged
Using the Nottingham grading scale
Grades 1-3
How does osteoporosis present
Insidious onset – patients are asymptomatic until fractures occur, and presentation depends on which bones are affected
Fragility fractures
Vertebral fractures -> Back pain, loss of height, deformities (kyphosis)
Which age group is most commonly affected by endometrial carcinoma
Peak is post-menopausal women 55-65
What is Raynaud’s phenomenon
Extremities becoming pale due to decreased blood flow in cold weather
Caused by vasospasm
Do all HPV infections lead to cancer
No
Majority will not cause any symptoms or damage.
How do hyperglycaemia and insulin deficiency lead to glomerulosclerosis
They alter the GBM, largely via non-enzymatic glycation of proteins. Subsequent haemodynamic changes
cause increased GFR, glomerular capillary pressure, and glomerular hypertrophy, which culminate in glomerulosclerosis.
Which endometrial carcinoma is classed as type 2
Serous endometrial carcinoma
The majority of mutations in endometroid endometrial carcinoma act on which pathway
Act to increase signalling by the PI3K/AKT pathway
This enhances the expression of target genes which can be turned on by oestrogen (have oestrogen receptors) in the endometrium.
Removal of which precursor lesion will reduce future risk of invasive cancer
DCIS
Same cannot be said for LCIS
Describe the appearance of nodular glomerulosclerosis (Kimmelstiel-Wilson disease)
Ovoid/spherical lesions
Often laminated
PAS-positive nodules of matrix found in the periphery of a glomerulus.
Sorbitol accumulation in the lens has what effect
Cataract formation
Seen in diabetics
How can cervical cancer be prevented
The HPV vaccine can prevent up to 70% of cases
What are the most important targets of insulin
Striated muscle cells
“beige” adipocytes are another target.
What pressures do the carotid sinus baroreceptors respond to
Respond to pressures ranging from 60-180mmHg
Describe the progression of HSILs
Has a high risk of progressing to cervical carcinoma
Where is ADH released from
Posterior pituitary
It is stored here but made in the hypothalamus
How does Cushing’s suppress vasodilatory systems
Glucocorticoids inhibit NOS synthesis which produces the vasodilator NO
As a result TPR increases and so does BP
Glucocorticoids also inhibit production of prostacyclin (another potent vasodilator in vascular endothelium)
Decreased PGE2 & kallikrein
Mutations in which gene is commonly seen in serous endometrial carcinoma
Highly associated with mutations in the TP53 tumour suppressor gene (present in over 90% of these tumours).
These mutations are also found in the precursor lesion which suggests they are an early occurrence in the natural history of these tumours.
Also have high chromosomal instabaility – a feature of TP53 cancers.
List the features of nephrotic syndrome
Proteinuria >3g/day Hypoalbinaemia (<30) Oedema Hypercholesterolaemia Usually normal renal function
What is meant by a mixed testicular tumour
Tumour is composed of >1 type of GCT
Accounts for 60% of all GCTs
List symptoms of Cushing’s
Psychosis Impaired memory Sleep disturbance Depression and anxiety Hypertension Dyslipidaemia Obesity Facial and abdominal fat accumulation Diabetes - impaired glucose tolerance Muscle and skin atrophy Osteoporosis
Which conditions of adrenocortical hyperfunction can cause secondary systemic hypertension
Cushing syndrome
Primary aldosteronism
Congenital adrenal hyperplasia
Licorice ingestion
Describe the epidemiology of endometrial carcinoma
Accounts for 7% of all invasive cancer in women.
Used to be much less common than cervical but the screening program and increased incidence of endometrial cancer in young women has switched this.
There were 380,000 new cases in 2018 worldwide
List potential complications of radiotherapy
skin breakdown, angiosarcoma of the breast skin, breast and arm lymphoedema, radiation fibrosis of the breast, chronic radiation pneumonitis, chronic pericarditis, chronic discolouration of the effected area, osteoporosis
How does behaviour contribute to obesity
Inactivity and not getting enough exercise
Not burning off enough calories
People in the UK are much less active now
Which haplotype has the greatest risk of T1DM
DR3 or DR4 AND a DQ8 haplotype
18- fold increase
Describe the microscopic features of a testicular choriocarcinoma
These tumours are mainly composed of syncytiotrophoblasts and cytotrophoblasts
What is the purpose of neoadjuvant therapy in breast cancer
Used to downstage cancer, reduce nodal involvement and improve surgical outcomes
Can be chemotherapy, endocrine therapy or biologic therapy but not radiotherapy
Young women are most effected by which type of breast cancer
Mainly have HER2+ or Triple neg
Rarely affected by luminal cancer
How can you treat osteoporosis
Bisphosphonates – Inhibit osteoclastic bone resorption
Denosumab – Anti-RANKL monoclonal antibody
Hormone Therapy - Selective Oestrogen Receptor Modulator (SERM) or HRT
List common causes of secondary systemic hypertension in middle aged adults (40-64)
Hyper aldosteronism
Obstructive sleep apnoea
Cushing’s syndrome
Phaeochromocytoma
What are the main types of testicular sex chord stromal tumours
Leydig and Sertoli cell tumours
Leydig cell tumours are the most common of the 2 in children and adults
What effect does insulin have on the liver
Decreases gluconeogenesis
Increased glycogen synthesis and lipogenesis
How do you treat hypoglycaemia
If conscious, orientated & able to swallow: 15-20g quick-acting CHO snack (200ml orange juice) and recheck BG after 20-25mins (repeat up to 3 times).
If conscious but uncooperative, squirt glucose gel between teeth & gums.
If unconscious/unresponsive to above measures: glucose IV (10% at 200ml/hr if conscious; 200ml/15mins if unconscious) or give glucagon 1mg IV/IM (wont work in malnourished patients).
How do you diagnose a hypo
Bloods: glucose, insulin, c-peptide, plasma ketones (symptomatic).
If endogenous hyperinsulinism suspected – insulin, c-peptide, proinsulin, beta-hydroxybutyrate.
How does Addison’s disease affect BP
Lack of cortisol and aldosterone secretion reduces the BP
How can the incretin effect be harnessed to treat T2 DM
Efforts to restore incretin function can lead better control of BG and promotes weight loss (by restoring satiety)
This has led to development of DPP4-inhibitors and GLP-1 agonists for T2D treatment.
PTEN mutations (tumour suppressor) have been identified in both hyperplastic lesions and the carcinoma - true or false
True
This suggests suggesting some of the mutations occur before it becomes cancerous
Describe the glucose levels inside and outside of insulin dependent cells in diabetes
low glucose inside cell, high glucose outside cell
Seen in skeletal muscle, adipose tissues, liver
What is the main underlying cause for all diabetes complications
Persistent hyperglycaemia
Leads to glucotoxicity
List the microscopic features of endometroid endometrial carcinoma
Endometrioid microscopic pattern with glandular, cribriform, and papillary features
These cancers have 3 histological patterns of glandular growth: well differentiated, moderately differentiated and poorly differentiated
Some tumours have foci of squamous differentrion (around 20%)
Describe stage 1 cervical cancer
Carcinoma is confined to the cervix.
Further divided into:
1a – preclinical carcinoma diagnosed only by microscopy
1a1 – stromal invasion no deeper than 3mm and no wider than 7mm (also called superficially invasive)
1a2 – depth of stromal invasion between 3mm and 5mm, no wider than 7mm (horizontal invasion
1b – Histologically invasive carcinoma, still confined to cervix but greater than 1a2
Which nerve signals to the veins can lead to a drop in BP
Decrease sympathetic tone on veins
Compliance increases so venous pressure decreases
This causes VR to decrease and CO decreases as a result
Overall BP decreases
What happens when AQP2 fuses with the apical membrane in the kidney tubules
AQP-2 gene expression increases
Collecting duct epithelium becomes permeable to water
More H2O resorbed through osmosis
This leads to more concentrated urine
BV returns to normal (increased arterial pressure)
How is intermittent claudication managed
Encourage patients to continue walking - may find supervised exercise programmes beneficial
In patients with lifestyle-limiting disease, additional pharmacological treatment should be offered
Cilostazol – Vasodilator with antiplatelet action
contraindicated in CCF and recent ACS
What is metabolic syndrome
It is a cluster of conditions that occur together, increasing your risk of heart disease, stroke and type 2 diabetes.
The conditions include increased blood pressure, high blood sugar, excess body fat around the waist, and abnormal cholesterol or triglyceride levels.
Causes abnormalities of glucose and lipid metabolism coupled with hypertension and evidence of a systemic pro-inflammatory state.
Crystalloids of Reinke are characteristic of which tumour type
Leydig cell tumours
What is the most common subtype of germ cell tumour in the testes
Seminomas
Long standing diabetes is associated with which eye diseases
Raised intra-ocular pressure = glaucoma
Damage to the optic nerve
What initial tests would you do in a middle aged adult with secondary systemic hypertension
Renin and aldosterone levels
TSH
Polysomnography if OSA suspected cause
24hr urinary cortisol and fractionated metanephrines if above tests inconclusive
How do serous endometrial carcinomas develop
The tumours begin as surface epithelial neoplasms which then extend into adjacent glands and later the endometrial stroma.
They also have a propensity to break off and travel through the fallopian tubes and implant on peritoneal structures.
What initial tests would you do in an older adult with secondary systemic hypertension
Renal artery doppler MRA with contrast CT angiography TSH Urinalysis
How does angiotensin 2 act on the blood brain barrier
Acts on AT receptors there - particularly high density in brain areas responsible for CVS regulation
Acts on 3 circumventricular organs of brain which send signals to other areas of brain
This increases SNS activity and modulates baroreflex sensitivity -> increase BP
What factor affects the prevalence of diabetic neuropathy
Duration of disease
Up to 50% of all diabetics have it but in those who have had diabetes for >15years prevalence is up to 80%
What is DKA
Diabetic ketoacidosis
A disordered metabolic state usually occurring in the context of an absolute or relative insulin deficiency accompanied by an increase in the counter-regulatory hormones (glucagon, adrenaline, cortisol, GH).
Describe the epidemiology of PAD
Around 20% of >60s in the UK are estimated to have some degree of PAD
But this is difficult to quantify as roughly half these patients will be asymptomatic
Describe the epidemiology of testicular yolk sac tumours
Prepubertal ones tend to be pure with good prognosis
Most common tumour in <3yrs
But post-pubertal are mixed
List the macroscopic features of serous endometrial carcinomas
Large and bulky tumours (may look larger as typically occur in atrophic uteri).
May have deeply invaded the myometrium.
Endometrial adenosarcomas need to be differentiated from which other condition
Diagnosis mainly involves differentiating from benign polyps.
They have the same gross appearance but the cancer has malignant stroma and benign but abnormally shaped glands.
List the pathological features of Cervical neuroendocrine tumours
Appears similar to small cell lung cancer but will also test positive for high-risk HPV.
At which point does maximal carotid sinus sensitivity occur
Maximal carotid sinus sensitivity occurs near the normal mean arterial pressure
Therefore, very small changes in arterial pressure around this set point alters receptor firing
How can stress lead to secondary systemic hypertension
Emotional stress activates the sympathetic nervous system
You get an increase in norepinephrine release from sympathetic nerves in heart and blood vessels which increases CO and TPR
Adrenal medulla secretes more catecholamines -this activate sympathetic nervous system and increases circulating angiotensin II, aldosterone, vasopressin
All increase TPR
List common symptoms of testicular cancer
Most cases present with a testicular lump or enlarged testicle - usually hard, within the testicle, non transluminal and able to be gotten above
Usually painless but may have episodic pain due to haemorrhage
Dragging sensation in the scrotum
A hydrocele may also be present and potentially filled with blood stained fluid – it can also invade into the scrotum
Describe the effect of TP53 mutations
Leads to accumulation of altered p53 proteins
What initial tests would you do in a child/adolescent with secondary systemic hypertension
Urinalysis
Urine culture
Renal ultrasound
Echo if above tests not conclusive
What treatments may become available for endometrial cancer in the future
A lot of research is going into biological agents that target specific pathways associated with these cancers. At the moment inhibitors of the PI3K/AKT pathway are in clinical trials
How does ADH act on the renal collecting ducts to increase BP
Acts on them via V3 receptors
This increase water permeability (cAMP-dependent mechanism) and therefore decrease urine formation
This causes an increase blood volume & CO so arterial pressure increases
Gluconeogenesis is a constantly occurring process - true or false
True
It provides energy to tissues such as skeletal muscle, brain and adipose tissue, cardiac muscle – tissues requiring glucose but can’t make it themselves.
Which endometrial carcinoma is classed as type 1
Endometroid endometrial carcinoma
Describe the microscopic features of a Leydig cell tumour
Histologically cells look like normal Leydig cells - round or polygonal cell outlines, usually large, round and central nucleus and cytoplasm is granular and eosinophilic
Lipid droplets, vacoules or lipofuscin pigment are found in the cells cytoplasm along with rod shaped crystalloids of Reinke which are characteristic of this tumour and seen in about ¼ of them
What are the symptoms of endometrial cancer
May be asymptomatic.
Main symptom is abnormal vaginal bleeding: either irregular or post-menopausal.
Less common symptoms are pain in the lower abdomen and pain during sex
Why is the transformation zone susceptible to cancer development
Immature squamous cells developing here which are highly susceptible to HPV infection (major cause of cervical cancer)
How are endometrioid endometrial carcinomas managed
Endometroid carcinomas are typically treated with surgery (often a hysterectomy)
They may also receive adjuvant radiotherapy to prevent recurrence and chemotherapy if it has spread outside of the uterus.
Breast cancer affects which age groups
Rare in women <25yrs and more common after 30
Which part of the cervix can be seen on speculum examination
The ectocervix
Which glomerular lesions are seen in diabetic nephropathy
Capillary basement membrane thickening
Diffuse mesangial sclerosis
Nodular glomerulosclerosis (Kimmelstiel-Wilson disease)
What innervates the carotid sinus baroreceptors
The sinus nerve of hering
Branch of the glossopharyngeal nerve which synapses in the NTS in the medulla
List the pathological features of Cervical adenosquamous cancer
Composed of a mix of malignant squamous and glandular epithelium.
Describe stage III serous endometrial carcinoma
Carcinoma extends outside of the uterus but not outside the true pelvis.
What is osteoporosis
A skeletal disease characterised by low bone mineral density and abnormal bone architecture, resulting in increasingly fragile bone and elevated fracture risk
Where do most cervical cancers form
The transformation zone
What are the most common sites of fracture in osteoporosis
vertebrae, proximal femur and distal radius
Describe the volume independent mechanisms by which sodium retention cause high BP
increased vascular stiffness & increased central sympathetic outflow
What are the risk factors for obesity
Increased production and intake of energy-dense foods that are high in fat and sugars
Decrease in physical activity - increasingly sedentary nature of many forms of work, modes of transportation, and increasing urbanization
Dietary habits
Social deprivation
Income
Ethnicity
What is the definition of obesity
“an accumulation of adipose tissue of sufficient magnitude to impair health”
Overweight and obesity are terms that refer to an excess of body fat and usually relate to increased weight-for-height
Secondary systemic hypertension is the most common type of hypertension seen - true or false
False
Makes up only a small fraction (5-10%) of hypertensive cases
ADH is first secreted into which vessel
inferior hypophyseal artery
Why does serous endometrial carcinomas have a poor prognosis
They also have a propensity to break off and travel through the fallopian tubes and implant on peritoneal structures
Therefore often outside of the uterus by the time of diagnosis
Endocrine therapy can be extended for how long
Both forms of adjuvant endocrine therapy can be extended and so are used for more than 5yrs but postmenopausal women get acromatase inhibitors and premenopausal get tamoxifen
Even if low risk of recurrence post menopausal women can still get extended endocrine therapy
How does endometroid endometrial carcinoma progress and spread
Start with precursor lesions then develop into the carcinoma.
Spread generally occurs by direct invasion of myometrium and other surrounding structures/organs.
Eventually it will spread to the regional lymph nodes.
Late stages involves metastases to the lungs, liver, bones and other organs.
List the biochemical signs of DKA
Ketonaemia >3mmol/L, or significant ketonuria (>2+ on urine stick)
BG >11.0mmol/L (or known diabetes)
Bicarbonate <15mmol/L or venous pH <7.3.
Autoantibodies against islet antigens are found in most T1 diabetics - true or false
True
However, it is unclear if the autoantibodies are causing the injury or if they are merely a consequence of islet injury
If causing injury there may be a role for antibodies in the treatment of the disease
What other diseases can HPV cause other than cervical cancer
Also causes other cancers such as vulvar, penile, anal, vaginal and oropharyngeal
Low risk strains can cause genital warts
Which lifestyle factors can increase the risk of cervical cancer
Cigarette smoking
Linked to 20% of cases
Where does coarctation of the aorta most commonly occur
just distal to left subclavian artery in the arch of aorta
Where is leptin produced
Fat cells
Which biochemical factors must be monitored in HHS
Monitor and chart BG, osmolality and Na every 1-2hrs
Monitor fluid input and output
How are serous endometrial carcinomas managed
Serous carcinomas are aggressive in nature so usually treated with chemotherapy even if there is no evidence of spread yet alongside the other treatments.
How does Cushing’s affect β-Adrenergic Receptors
Increases their sensitivity to catecholamines
The SNS is upregulated and you get increased vascular tone
This increased BP
Obese people are at higher risk of a severe response to COVID - true or false
True - a clear link has already been established
It increases the risk of dying from the disease by nearly 50% and may make vaccines less effective
What determines the prognosis of serous endometrial carcinoma
Highly dependent on the stage
How does angiotensin II raise BP
Acts on the AT1 receptor to induce vascular contraction
Stimulates aldosterone secretion
Increases sodium resorption
Acts on the blood brain barrier
If blood results show low or undetectable insulin and no excess ketones what is the likely cause of the hypo
Non-pancreatic neoplasm
Anti-insulin receptor antibodies
What is acute limb ischaemia
Sudden occlusion of vessels which threatens limb viability
Usually due to thromboembolism
What are the subtypes of endometrial carcinoma
Endometrioid Endometrial Carcinoma
Accounts for 80-85% of cases
Also called type 1 carcinoma
Serous Endometrial Carcinoma
Account for 15% of cases
Also called type 2 carcinoma
What types of HPV are covered by the vaccine
Protects against both high and low risk HPV - reduces cancer and warts.
There are different types of HPV vaccine but the most comprehensive is Gardasil 9 (it covers HPV-16,18,31,33,45,52 and 58 and low risk HPV-6 and 11)
List consequences of bisphosphonate treatment
Osteonecrosis of the jaw and atypical fractures are known risks
Which symptoms of DKA are caused by osmotic disruption
Thirst, polyuria
Dehydration
Fatigue
How is advanced cervical cancer managed
Advanced lesions also treated with radiation and chemotherapy.
Pelvic exenteration may be done if other options have failed. This is removal of pelvic organs and some surrounding tissues.
Advanced cancer is often considered incurable/palliative, so patients are treated with chemo and a drug called Avastin (bevacizumab) to try and control the cancer.
Describe the progression of LSILs
Low-grade doesn’t directly progress to invasive cancer, in fact many cases will spontaneously regress.
Only a small percentage move onto high-grade.
What investigations are performed if a smear test comes back abnormal
You get a colposcopy to examine the cervix and identify the lesion.
Acetic acid is applied as this causes abnormal epithelium to show up as white spots.
Abnormal areas can then be biopsied.
How is critical limb ischaemia managed
If patient is suitable for revascularisation, this can be achieved via endovascular or surgical methods
If not patients should be closely monitored in case amputation required and risk factors managed
How does sleep deprivation and circadian disruption contribute to T2DM
CD impairs glucose haemostasis by affecting both insulin secretion and action
Association found between circadian-controlled genes and T2D
Disruption of “clock” genes not only affects insulin secretion & action but also activity level and feeding behaviors
This leads to increased risk of hyperglycaemia and diabetes
Which neurological conditions can cause secondary systemic hypertension
Psychogenic - brought on by stress
Increased cranial pressure
Sleep apnoea
Acute stress, including surgery
What are the complications of endometrial cancer treatment
Typical side effects of hysterectomy, chemo and radiotherapy
Progesterone therapy can cause mild nausea, mild muscle cramps and weight gain
How is advanced breast cancer managed
A combination of chemotherapy, endocrine therapy and biological therapy rather than surgery due to the nature of the disease
List some of the clinical consequences of obesity
Cardiovascular - Coronary artery disease, hypertension, LVH, cor pulmonale, obesity-associated cardiomyopathy, accelerated atherosclerosis, and pulmonary hypertension of obesity
Respiratory - OSA,greater predisposition to respiratory infections, increased incidence of bronchial asthma, and Pickwickian syndrome (obesity hypoventilation syndrome)
Gastrointestinal - Gall bladder disease (cholecystitis, cholelithiasis e.g. gallstones), non-alcoholic steatohepatitis (NASH), fatty liver infiltration, and reflux oesophagitis
Cancer
Depression and stress
Arthritis
What is the common mechanism of death from testicular cancer
Complications of metastasis
Describe the macroscopic features of a testicular seminoma
Bulky mass up to 10X size of normal testes
Homogenous gray/white lobulated cut surface without haemorrhage or necrosis
Can extend to epididymis, spermatic cord and scrotal sac
What does the AGE-RAGE complex cause in diabetics
Release of cytokines + growth factors.
ROS generated in endothelial cells.
Increased procoagulant activity on ECs + macrophages.
Increased proliferation of vascular SMCs + ECM synthesis
In the UK how many people will develop cervical cancer in their lifetime
Less than 1% of those with a cervix
Protein linking by AGEs has what effects
Proteins cross-linked by AGEs resist digestion so they accumulate in the cells
Can also reduce elasticity of vessels - type 1 collagen
Which genes/proteins have been linked to post-menopausal osteoporosis
RANKL – Expressed by osteoblasts
RANK – Facilitates osteoclast formation, function and differentiation
OPG – Secreted by osteoblasts and inhibits the RANKL-induced activation of RANK
What treatment is offered to carriers of the BRACA genes
Prophylactic mastectomy and salpingoophrectomy
Reduces mortality
How does chronic hyperglycaemia cause oxidative stress + destruction of polyol pathways
Glucose metabolised into sorbitol (polyol) then fructose (uses up NADH).
Less NADH means less GSH (antioxidant) and increased cellular susceptibility to oxidative stress
List the main metabolic complications of diabetes
Hypoglycaemia
Diabetic ketoacidosis (DKA)
Hyperglycaemic Hyperosmolar Syndrome (HHS)
Which cervical cancer precursor lesion is more common LSIL or HSIL
LSIL is much more common
What is the underlying mechanism of insulin resistance in T2DM
Functional deficits in insulin signalling pathway
How is invasive cervical cancer treated
More invasive cancers get hysterectomy and lymph node dissection (typically 1B or 2A).
Locally advanced may also get radiation and chemotherapy.
What is the average age of cervical cancer patients
Between 45-50
Which ethnic groups have the most rapidly increasing rates of T2DM
Populations such as East Asian, South Asian, and Middle Easterns
However, they do not show comparable increases in obesity
Describe stage I serous endometrial carcinoma
Carcinoma is confined to the corpus uteri itself.
Why is the slow progression of cervical cancer beneficial
Gives plenty time for detection and treatment
HHS patients are at high risk of which vascular complication
Foot ulceration
Protect heels and perform daily foot checks.
What are the characteristic symptoms of Addison’s disease
Weight loss- decreased appetite Abdominal pain Muscle weakness Fatigue Shaking/tremors Depression Low BP Sometimes darkening of skin - hyperpigmentation
Which genetic factors are associated with T2DM
1st degree relatives have 5/10-fold increased risk of developing T2D vs. no FH – when matched for age and weight.
There is a higher concordance rate in monozygotic twins (>90%) compared with T1D.
At least 30 loci that confer minimal-modest increase in lifetime risk – most are involved in adipose tissue function, islet b-cell function and obesity
What is the precursor lesion for endometrioid endometrial carcinoma
Endometrial hyperplasia
Most cancers develop on a background of this
Describe how Advanced glycation end products (AGEs) are formed in diabetes
The result of a non-enzymatic reaction between glucose-derived metabolites & amino acids
Form the AGE-RAGE complex
AGEs can cross-link ECM proteins
What is diabetes mellitus
A group of metabolic disorders sharing the common feature of hyperglycaemia caused by defects in insulin secretion, action, or most commonly, both.
Describe treatment for a stage one non-seminoma testicular cancer
orchidectomy + short course of chemo and potential radiotherapy
If blood results show low insulin and high ketones what is the likely cause of the hypo
Alcohol
Pituitary insufficiency
Addison’s
BRACA cancers typically develop at what age
Over 70
Describe the role of the hypothalamus in the control of energy balance
It receives input from the body about energy stores:
if they are inadequate, triggers anabolic circuits(increase food intake and decrease expenditure)
If they are adequate catabolic circuits
Acts like a conductor
Describe how diabetes leads to ketoacidosis
The insulin deficiency causes stress hormone activation which blocks any residual insulin action and stimulates glucagon release
This leads to increased lipolysis so more FFAs sent to the liver
They get oxidised in hepatocytes and ketone bodies are produced
Also causes poor glucose utilisation, more proteolysis and glycogenolysis
All lead to hyperglycaemia, glucosuria and then osmotic diuresis and electrolyte loss
This causes dehydration + worsened renal function.
If urinary excretion of ketones is compromised by dehydration then you get systemic metabolic ketoacidosis
List the risk factor for hyperosmolar hyperglycaemia syndrome
T2 > T1DM
CVS event (stroke or MI)
Sepsis
Medications: glucocorticoids & thiazides.
How do you treat HHS
Fluid replacement - carefully!
Low dose IV insulin if significant ketonaemia
Prophylactic LMWH
Identify and treat underlying precipitants such as sepsis
Which afferent arteriole secretion can increase renin secretion in the kidney
NO, PGE2, PGI2
What is the typical mechanism of death in cervical cancer
Most patients with advanced cancer die due to consequences of local invasion such as ureter obstruction, pyelonephritis and uraemia.
These complications usually kill before the distant mets do.
State the waist circumference scale for men
Desirable = Less than 94 cm (<37”)
High = Between 94-102 cm (37”-40”)
Very high = More than 102 cm (>40’’)
Cervical cancer treatments can lead to fertility problems - true or false
True
radiotherapy, chemotherapy and the hysterectomy can all affect it
List the grades of the Nottingham Score system for breast cancer
Grade 1 ( well differentiated) – grows in a tubular or cribiform pattern, has small uniform nuclei and a low proliferative rate
Grade 2 ( moderately differentiated) – they have areas where cells grow as solid clusters or single infiltrating cells and have greater levels of nuclear polymorphism and high numbers of mitotic figures
Grade 3 ( poorly differentiated) – invade as ragged nests or solid sheets of cells and have enlarged irregular nuclei. Its common to have a high proliferative rate and areas if tumour necrosis.
List the different types of germ cell tumour of the testes
Seminoma, yolk sac, embryonal carcinoma, spermatocytic, teratoma, choriocarcinoma
What are the common manifestations of diabetic nephropathy
Typically glomerular disease leading to proteinuria, with/without nephrotic syndrome
Earliest manifestations: microalbuminuria (>30mg and <300mg/day).
How is early or locally advanced breast cancer managed
Mostly with breast surgery - conservative or mastectomy
May have radiotherapy if risk of recurrence or if nodal disease and unclear margins following mastectomy
List the microscopic features of PAD
Atherosclerotic plaques within vasculature
Evidence of ischaemia in skeletal muscle - Inflammation, necrosis, fibrosis
How does diabetic retinopathy present
Blurry vision
Floaters
Blindness
List the features of pre-proliferative diabetic retinopathy
Cotton wool spots
Dot & blot haemorrhages
Abnormalities in venous calibre
Which type of testicular cancer tends to metastasize earlier
Non seminoma GCTs
This is because they spread through the blood more commonly
How does nodal involvement affect survival in breast cancer
In terms of 5-year survival
No nodes = 70%
1-3 nodes = 35-40%
10 nodes = 10-15%
What common complication of vascular disease is more common in diabetics
Gangrene of the lower extremities
100x more common in diabetes
What is circadian disruption
A misalignment between endogenous circadian rhythm and the cycle/rhythm created by individual behaviors
What symptoms of testicular cancer metastasis may be seen on presentation
Cough, chest pain and haemoptysis from lung metastasis
Cervical lymphadenopathy
Abdominal masses and back ache from para aortic node metastasis
Obesity is the second biggest preventable cause of cancer - true or false
True
It is only behind smoking
List some of the clinical features of breast cancer
New lump within breast or axilla
Thickening or swelling of any part of the breast
Irritation or dimpling of the skin
Redness or flaky skin at the nipple
Discharge from the nipple inc. blood but excluding breast milk
Nipple retraction or inversion
Any general changes to the shape or size of the breast
Any pain in the area of the breast
Describe type 2 DM
Caused by a combination of peripheral resistance to insulin action & a secretory response by pancreatic b-cells that is inadequate to overcome insulin resistance (“relative insulin deficiency”)
Approx. 90-95% of diabetics have T2D, and the vast majority are overweight.
How can pregnancy cause secondary systemic hypertension
Release of oestrogen
Pre-eclampsia - Develops during the third trimester of pregnancy and causes hypertension due to increased blood volume and tachycardia (increase CO)
When does incidence of HPV infection peak
Between the ages of 20-24
This is due to start of sexual activity
State the waist circumference scale for women
Desirable = Less than 80 cm (<31”)
High = Between 80-88 cm (31”-34”)
Very high = More than 88 cm (>34”)
Describe the pathogenesis of testicular germ cell tumours
Starts with a primordial germ cell with an acquired defect in differentiation
Leads to activation of growth factor receptor signaling usually because of activating mutations in KIT receptor tyrosine kinase which then causes proliferation and creates germ cell neoplasia in situ
The germ cell neoplasia in situ develops in utero and remains dormant then is activated at puberty by hormonal influences stimulating germ cell growth
Reduplication of the short arm of ch12 ( isochromosome 12p) then creates the invasive tumour
Which common management is offered to all PAD patients
Single antiplatelet therapy, Reduction of any modifiable risk factors
Monitoring for the development of further circulatory system disease
How does CKD cause hypertension via the sympathetic nervous system
The sodium retention cause by the angiotensin II secretion in turn causes overactivity of the sympathetic nervous system
This stimulates renin production
Renal ischemia also leads to renal afferent nerve excitation through adenosine
Which environmental factors can contribute to the development of T1DM
Antecedent viral infections suspected but neither the type of virus nor how it promotes islet-specific autoimmunity is known.
Seasonality – winter months have highest incidence of new diagnoses.
Maternal factors and weight gain are also important factors.
Describe the epidemiology of testicular seminomas
Makes up >50% of all GCTs
Most common in the 4th decade
What type of inheritance does familial breast cancer (BRACA) usually follow
Autosomal dominant
Describe the microscopic features of a Sertoli cell tumour
The tumour cells are arranged in distinctive trabeculae that tend to form cord like structures and tubules
What is the most common invasive cancer of the female genital tract
Endometrial carcinoma
Describe the action of ADH in the kidney tubules
It binds to ADH receptors in the basolateral membrane
This activates adenylate cyclase which converts ATP into cAMP
This in turn activates protein kinase A which allows trafficking of AQP-2 vesicles
The AQP-2 fuses with the apical membrane and increases water uptake
How does Cushing’s result in endothelin release and what is the result
Catabolic effect of hypercortisolism promotes endothelial damage & increases vascular permeability
This leads to endothelin 1 hypersecretion which causes endothelial dysfunction (associated with arterial hypertension)
Which afferent arteriole secretion can inhibit renin secretion from the kidney
Endothelins
Describe the macroscopic anatomy of the cervix
It connects the top of vagina and lower part of womb.
Made up of the external vaginal section called ectocervix and the internal endocervical canal
What is the purpose of adjuvant therapy in breast cancer
Carried out after surgery to reduce the risk of recurrence
Describe the microscopic features of a testicular embryonal carcinoma
Cells grow in alveolar or tubular patterns occasionally with papillary folds
The neoplastic cells are large and anaplastic, epithelial in appearance and have prominent nucleoli within a hyperchromatic nucleus
Mitotic figures, tumour giant cells, pleomorphism and indistinct borders are also all often seen in the cells
Less differentiated lesions may have sheets of cells with cleft like spaces
List risk factors for PAD
HTN, hyperlipidaemia, diabetes, age, male gender, evidence of CHD
What are the main mechanisms of death in osteoporosis
Consequences of fractures
Hospitalisation +/- immobilisation due to treatment of fractures leads to complications such as pneumonias, PEs etc.
Describe how insulin treatment is used in HHS
Start low dose IV insulin (0.05units/kg/hr) only if significant ketonaemia at presentation
Or
If BG falling at rate of <5mmol/hr despite adequate fluid replacement.
Aim to maintain BG level 10-15mmol/L for 1st 24hrs
What are the immediate complications of cervical cancer surgery
Patients can experience pain, must avoid sex and heavy lifting and may require a catheter whilst healing
Describe the macroscopic features of a Leydig cell tumour
Usually <5cm and well circumscribed
Cut surface is distinctively gold brown and homogenous
What is secondary systemic hypertension
A type of hypertension with an underlying and potentially reversible cause
Can the location of the squamocolumnar junction change
Yes
It can change slightly with age and hormone levels but in general it moves upwards into the canal with time
This is known as squamous metaplasia - glandular is slowly replaced
Which islet autoantigens are targeted by T cells in T1DM
Insulin (IAA)
Glutamic acid decarboxylase (GAD; b-cell enzyme)
and others e.g., islet-antigen 2 (IA2).
List the typical biochemical signs of HHS
Hypovolaemia
Hyperglycaemia (>30mmol/L; higher than DKA, median ~60)
No major acidosis or ketonaemia.
Hyperosmolar (osmolality >320 osmolal/kg), i.e., significant dehydration.
Significant renal impairment
Na+ may be raised on admission.
Describe the metastatic pattern seen in HER2+ breast cancer
70% mets to bone, 45% to viscera and 30% to brain but its common to see mets in each.
They have a bimodal relapse pattern with early and late peaks 10 years apart
Describe neuropathic pain
Shooting/burning sensation
Tingling/numbness
Hyperalgesia
Allodynia
Where is ghrelin produced
Stomach
How is glucose used in the muscle cells
Glucose is either stored as glycogen or oxidised to generate ATP
List the common symptoms of hypothyroidism
Depression Brain fog Fatigue Muscle cramps Cold intolerance Weight gain Dry skin
Co-morbidities are more common in HHS - true or false
True
All patients should be screened for things like vascular events or sepsis
What is critical limb ischaemia
Severe occlusion of arteries in the limbs
Where are the baroreceptors located
They are mechanoreceptors located in the carotid sinus and the aortic arch
List the pathological characteristics of SIL
Characterised by nuclear atypia (enlargement, hyperchromia, coarse chromatin granules and variation in shape/size).
Also have cytoplasmic halos which are due to perinuclear vacuoles which are created by HPV proteins.
How does the lack of cortisol seen in Addison’s disease affect BP
Loss of permissive actions on catecholamines - they usually enhance cardiac contractility (raise CO) and increase AV node conduction velocity (raise HR)
When you have catecholamines insufficiency you get decreasing CO & HR and BP decreases
Describe the pathogenesis of osteoporosis
It is a multifactorial disease due to an imbalance between osteoclast resorption and osteoblast formation of bone
Describe how T cells become autoreactive in T1DM
The initial activation of these cells is thought to occur in the peri-pancreatic lymph nodes.
Activated T cells travel to pancreas and cause b-cell injury.
T-cell populations implicated:
Th1 cells – may secrete cytokines incl. TNF, IFN-g that injure b-cells.
CD8+ CTLs – kill b-cells directly.
What controls renin release from the kidney
Renal perfusion pressure in afferent arteriole
GFR
Renal sympathetic nerve activation
Secretion of various inhibitory or promoting compounds from afferent arteriole
Why are obese people more likely to develop coronary heart disease
Obese individuals have hypertriglyceridemia and low HDL levels
What can be used as a marker of b-cell function in diabetes
C-peptide
It is secreted in equal amounts as insulin on stimulation
How does Cushing’s affect the RAAS system
Glucocorticoids increases angiotensinogen which affects angiotensin II which in turn increase BP
Plasma renin activity & plasma renin concentration are generally normal or suppressed -> an overall increase throughout in the system just not via renin
Showed an increased pressor response to angiotensin II -> increased sensitivity to the agent
Which people are at risk of circadian disruption
Shift workers
Those with sleep disorders
Any other conditions that restrict night-time sleep and daytime wakefulness
What is the role of the nucleus tractus solitarius (NTS) located in medulla of brainstem
It modulates the activity of sympathetic and parasympathetic (vagal) neurons in the medulla
This regulates the autonomic control of the heart and BP
Which environmental factors can cause T2DM
Obesity - especially central or visceral
Sedentary lifestyle - independent of obesity
Sleep deprivation and circadian disruption
How do you calculate osmolality
2[Na] + urine + glucose
Describe the microscopic features of a testicular seminoma
Made of sheets of seminoma cells divided into poorly demarcated lobules by fibrous septae containing lymphocytic infiltrate
Made of seminoma cells
Occasionally have poorly demarcated granulomas as part of an immune reaction to the lesion
List the features of background diabetic retinopathy
Microaneurysms
Microhaemorrhages
Hard exudates
Describe treatment for stage 3-4 testicular cancer
3-4 cycles of chemo, surgery and potentially radiotherapy
Surgery also done for effected nodes/tissues
Which gene mutations are associated with endometrioid endometrial carcinoma
PTEN, PI3K are the main 2
FGF2 (growth factor) and many more
What is the most common cause of death in diabetics
MI
How does obesity negative impact resistance
Free fatty acids (FFAs) – inverse correlation between fasting FFAs and insulin sensitivity.
Adipokines - sparse in obesity
Inflammation – in response to excess nutrients; excess FFAs activate inflammasome
Leads to IL-1 beta release and b-cell dysfunction
Liver steatosis – high levels of FFAs cause hepatocyte steatosis
Which conditions are Sertoli cell tumours associated with
Carney Complex
Peutz-Jeghers syndrome
Familial adenomatous polyposis
List the symptoms of DKA
High BG and ketones in the urine Excessive thirst Urinating more often and in larger amounts Sudden loss of weight Stomach pain and nausea Vomiting Dehydration - dry mouth, sore throat, dark eye circles Deep heavy breathing - Kussamauls Fruity breath Drowsiness and unconsciousness
What proportion of patients presenting with intermittent claudication will progress to critical limb ischemia
Around 20%
Hyaline arteriosclerosis is specific to DM - true or false
False
More prevalent and severe but not specific for DM
Also often seen in the elderly and those with hypertension
How do the SIL classifications compare to the CIN classification
LSIL = CIN I
HSIL is CINII -CINIII
What regulates the remodelling of bone in osteoporosis
Cytokines – IL-1, 6 & 11
Calcitrophic hormones – PTH, 1,25-hiydroxyvitamin D, calcitonin, oestrogen
Colony-stimulating factors – stimulates monocytes to become osteoclasts
What are the symptoms of cervical cancer
Often no symptoms and just picked up by screening.
Vaginal bleeding that is unusual for patient (including after the menopause, after sex, or between regular periods).
Changes to vaginal discharge (looking or smelling different)
Pain or discomfort during sex
Unexplained pain in your lower back or pelvis.
What are the consequences of osteoporotic fractures of the hip
In the UK, 20% of osteoporotic hip fractures are fatal with a further 50% left with significantly reduced quality of life
Which group are most prone to osteoporotic fractures
Caucasian women are the most prone to osteoporotic fractures, with the lifetime risk of a fragility fracture sitting at around 40%
How do genetics contribute to obesity
Studies show that genetics contribute towards the development of obesity. However, it is very rare that genetics are the sole cause and usually mutations have a very small effect
Most commonly implicated gene isMC4R - causes children to feel extremely hungry and become obese due to overeating
Describe the pathogenesis of Her2+ cancers
Strongly associated with a pathway which amplifies the HER2 gene on ch 17
HER2 is a receptor kinase responsible for promoting cell differentiation and apposing apoptosis through stimulation of RAS and p-13K-akt signalling pathways
What is the precursor lesion of cervical adenocarcinoma
Adenocarcinoma in situ.
What are the 3 components of the neurohumoral regulation of energy balance
Peripheral system - leptin, ghrelin, insulin
Central processing system - (arcuate nucleus of hypothalmus – first order neurons and second order neurons…-
The efferent system (split into two pathways – anabolic and catabolic
What is the unique metastasis feature of testicular GCTs
The histological cell type of distant metastasis or recurrent disease can differ from the original cell type
This is because they come from pluripotent germ cells
What is the typical triad of diabetes symptoms
Polydipsia
Polyuria
Polyphagia
Describe the anatomy of the endometrium
Lines the internal cavity if the uterus.
It is composed of glands embedded in a cellular stroma.
Undergoes physiological and morphological changes during the menstrual cycle (in response to steroid hormones)
Proliferative phase of rapid growth followed by a secretory phase where glands become active and then degeneration and shedding before cycle starts again.
Classical manifestations of T1DM are typically seen once around 50% of b-cells have been destroyed - true or false
False
It is actually >90% destroyed before it presents
How do AGEs affect LDL
It can trap it in large vessels reducing its efflux and contributing to cholesterol deposition in the intima, thus accelerating atherogenesis
Can trap other non-glycated or interstitial proteins too
Describe stage 2 cervical cancer
Carcinoma extends beyond cervix but not as far as the pelvic wall.
Carcinoma involves the vagina but not lower 1/3
How is acute limb ischaemia managed
Systemic anticoagulation
Assess limb for viability:
If viable - revascularisation via endovascular or surgical methods
Not viable – Amputation required
List commonly used measures for obesity
BMI
Waist circumference
NICE recommends using them in conjunction with each other
Standard lab tests include LFT, Thyroid function tests and fasting glucose and HbA1c
More specific tests if specific cause suspected - e.g.
24-hour urinary free-cortisol test is needed only whenCushing syndromeis suspected
What is metabolic syndrome
It is a cluster of conditions that occur together, increasing your risk of heart disease, stroke and type 2 diabetes.
The conditions include increased blood pressure, high blood sugar, excess body fat around the waist, and abnormal cholesterol or triglyceride levels.
Characterised by abnormalities of glucose and lipid metabolism coupled with hypertension and evidence of a systemic pro-inflammatory state.
What is included in an annual diabetes exam
Smoking cessation, diet and lifestyle advice
BP lowering - Target <140/80 mmHg; optimal <130/80
Cholesterol lowering - <5mmol/l; optimal <4mmol/l
HbA1c test
Eye exam
Foot exam
Guardian drugs to delay complications of diabetes - Aspirin, ACE-inhibitors, ARBs, statins
Which other cancers, beside breast, do BRACA mutations increase the risk of
Ovarian - mainly BRACA 1
Prostate
Pancreatic
How does ADH cause vasoconstriction
Binds to V1 receptors on vascular smooth muscle to cause vasoconstriction through IP3 signal transduction & Rho-kinase pathway (protein kinase C)
This mobilizes intracellular calcium stored in ER to cause vasoconstriction
Overall increase arterial pressure
How does hyperthyroidism cause hypertension
Causes an increase in expression of myocardial sarcoplasmic reticulum calcium-dependent ATP + A decrease in the expression of its inhibitor phospholamban
This increases heart rate & cardiac contractility - CO increases by 250%
Which type of adipocytes accumulate in obesity
Beige
Not white
What is the primary effect of aldosterone
Increase the number of open sodium channels in luminal membrane of the principal cells in cortical collecting tubule of the kidney
This causes increased sodium resorption and therefore increased sodium & water retention
Describe the effect of Hexosamine pathways + fructose-6-phosphate generation seen in diabetes
Hyperglycaemia induces a flux of glycolytic intermediates via hexosamine pathway
These cause cell damage and enhance oxidative stress
Give examples of bisphosphonates
alendronic acid, risedronate sodium, ibandronic acid
What is the prognosis of endometrial stromal tumours
5-year survival for low grade is 50% and is lower for the higher grades
What is happening to the prevalence of T2DM
It is increasing due to the increasing rates of obesity
Occurring more often in children and young people
Describe the prognosis of cervical cancer
Prognosis depends on the stage and subtype.
For superficial carcinoma 5-year survival is 100%.
Drops to less than 20% if the cancer spreads outside the pelvis.
What facilitates glucose uptake into the pancreas and what is the effect
GLUT2 (insulin-independent) glucose transporters
Occurs in the pancreatic b cells
This uptake increases intracellular Ca2+ which stimulates insulin secretion
What is the most common type of invasive breast cancer
Adenocarcinoma
Which cells does HPV enter
HPV enters immature basal epithelial cells.
Large number in transformation zone which is why it is so vulnerable
Other areas include squamous cell trauma and repair (as virus can access the basal cells
How do you diagnose osteoporosis
Duel-energy X-ray Absorptiometry (DXA) – Taken at the hip to correlate with T-score, but may be less predictive of fracture risk at other sites
Bone biopsy can be taken to differentiate between osteoporosis and osteomalacia as these can be difficult to distinguish clinically
How does the lack of aldosterone seen in Addison’s disease affect BP
Aldosterone affects sodium & potassium ion equilibrium and thus sodium resorption in DCT to increase blood volume
If lacking it hinders kidney’s ability to filter salt and water
This lowers blood volume and CO and decreases BP
List some of the psychological features of obesity
attitudes to food, eating disorders such as binge eating,
How should you replace the losses in DKA
0.9% NaCl
1L in 1hr, then 1L over 2hrs, 1L over 4hrs, 1L over 8hrs.
If glucose falls to ~15, switch to dextrose.
Give insulin
Give potassium
3-5mmol/kg deficit typical, plasma K+ falls w/ treatment as K+ enters cells.
Don’t add K+ to 1st bag, thereafter, add K+ according to most recent VBG result
List secondary causes of osteoporosis
Many conditions can lead to it including diabetes (poor blood sugar control and insulin dependence), malabsorption, malnutrition, heavy alcohol use, CKD (impaired Ca2+ homeostasis), immobilisation
List the macroscopic features of osteoporosis
Trabecular bone is most noticeably affected, but there may also be thinning of the cortical bone
Flattening of vertebral bodies
Will also find artefacts of previous fractures e.g. hip prothesis
Once a patient has recovered from a hypo (BG returned >4 mmol/L what further treatment is requires
Long-acting CHO (slice of toast).
Describe the pathogenesis of luminal breast cancers
Due to ER positivity oestrogen exposure is their main driver
Oestrogen increases several growth factors for epithelial cells and regulates the genes for epithelial cells within the breast and therefore plays a role in this cancers development
Once there is a clonal population of ER + mutated cells further oestrogen exposure enhances transformation from a precursor lesion to fully malignant cells
What is Conn’s syndrome
Primary aldosteronism
An endocrine disorder characterized by excessive secretion of the hormone aldosterone from adrenal glands
What is the fundamental cause of obesity
a chronic imbalance between calories consumed and calories expended
What is the most common type of cancer in the breast
Adenocarcinoma
About 1/3 can be further classified into special histological types
What type of epithelium covers the ectocervix
Mature squamous epithelium
It extends up to the external os and is continuous with vaginal walls
Describe the stages of T1DM development
Stage 1 – those at risk for T1D have 100% functional b-cell mass. They will have developed 2 or more autoantibodies but are still normoglycemic and pre-symptomatic.
Stage 2 – increasingly worse glucose tolerance due to progressive loss of b-cell mass; no frank symptoms.
Stage 3 – classic manifestations of disease seen, this is typically once >90% of b-cells have been destroyed
Which cancers are obese patients more susceptible to
lymphoma, leukemia, melanoma and multiple myeloma, and carcinomas of the esophagus, stomach, colon, gallbladder, thyroid, prostate, breast and endometrium
How does diabetic neuropathy lead to ulcer formation
Loss of pain sensation can result in formation of cutaneous ulcers which heal poorly due to microvascular disease
Which people are most at risk of HHS
Older people
Younger individuals in non-Caucasian group.
List examples of peripheral vascular diseases
Chronic venous insufficiency -> Varicose veins, venous ulcers
Thrombosis e.g. DVT
Raynaud’s Phenomenon
What molecular marker is Luminal Breast cancer positive for
Er positive, her 2 negative
What difficulties do obese bodies present at autopsy
Physical difficulties - more sets of hands/robust equipment required to handle the larger bodies
Accelerated putrefaction
Quality of autopsy can suffer as difficult to position bodies for normal examinations
Some conditions may be more difficult to demonstrate at autopsy than in an individual with a normal body mass index
List examples of surgical interventions for PAD
thrombectomy, bypass, arterial repair
How does Cushing’s cause vasoconstriction via calcium elevation
Glucocorticoids downregulates the expression of Na+, Ca2+ exchanger in vascular smooth muscle cells
This elevates cytosolic Ca2+ which in turn causes vasoconstriction
Describe poorly differentiated endometroid endometrial carcinoma
More than 50% of the tumour is solid growth.
Why are testicular tumours not often biopsied
There is a potential of seeding tumour cells
Instead orchidectomy on the presumption of malignancy is often done
List the symptoms of autonomic neuropathy (may be seen in diabetics)
bladder, bowel, erectile dysfunction and postural hypotension.
What causes widespread endothelial dysfunction in diabetics
Caused by persistent hyperglycaemia and insulin resistance
Feature of macrovascular disease
How do you calculate CO
CO = SV x HR
Large adenocarcinomas of the breast can invade which other structures
Pectoralis muscle - become fixed
The skin - causing dimpling
The centre of the breast - causes nipple retraction
How does Cushing’s cause secondary hypertension
Activation of RAAS - increase in angiotensinogen
Via the mineralocorticoid activity of cortisol
Enhancement of cardiovascular reactivity to vasoconstrictors
Increased β-Adrenergic Receptor Sensitivity to Catecholamines
Suppression of vasodilatory systems
Insulin resistance & sleep apnea
Do you still need a smear test if you have had the HPV vaccine
YES
not all strains of HPV covered
Can still get cancer
What are the two main metabolic defects seen in T2DM
Insulin resistance
B-cell dysfunction
How are testicular sex chord stromal tumours classified
Differentiation and histogenesis
Which exogenous hormones can cause secondary systemic hypertension
Glucocorticoids
Oestrogen - including pregnancy-induced and oral contraceptives
Sympathomimetics and tyramine-containing foods
Monoamine oxidase inhibitors
What is the leading cause of adult blindness in the US
Diabetic retinopathy
How does Cushing’s result in polycythemia and what is the effect
Cortisol increases serum concentration of erythropoietin which has a vasoconstrictor effect
It also leads to polycythemia
Combined these factors increase BP
List the pathological features of diabetic neuropathy
Axonal loss
Axonal regeneration
Demyelination (in some).
Small axons affected more severely – thickening of endoneurial arterioles (increased deposition of BM material)
Describe the structure of syncytiotrophoblasts
They are large multinucleated cells with abundant eosinophilic vacuolated cytoplasm containing hCG
Readily detected by immunohistochemistry
Seen in testicular choriocarcinomas
Which underlying processes have been implicated in the development of diabetic neuropathy
Non-enzymatic protein glycation, polyol damage and diabetic microvascular disease
Describe the structure of cytotrophoblasts
They are more regular and usually polygonal
Have a clear cytoplasm with distinct borders. These cells have a single nucleus that is quite uniform in structure and the cells tend to grow in cords or sheets.
Seen in testicular choriocarcinomas
Describe the sex distribution of MI in diabetics
Occurs in men and women at the same rate
What is renin
A proteolytic enzyme produced by renal juxta-glomerular cells
How do endocrine influences cause osteoporosis
Oestrogen loss stimulates increased secretion of pro-inflammatory cytokines within the blood and bone marrow, leading to increased bone resorption via osteoclast recruitment and activity
Seen after the menopause
List primary causes of osteoporosis
Senile osteoporosis
Post-menopausal
Idiopathic
Why do triple negative cancers have a poorer outcome than the others
No biological treatments are available
How does insulin resistance in Cushing’s cause HTN
The hyperinsulinemia causes increased sympathoadrenal system activity + local RAAS activation + vascular hypertrophy
This all increases TPR and leads to HTN
Also get sodium and water retention
In which states does PAD become symptomatic
Intermittent claudication
Critical limb ischaemia
Acute limb ischaemia
The most profound diabetic eye changes occur in which part of the eye
The retina
Describe the microscopic features of a testicular yolk sac tumour
Pre and Post pubertal Tumours have the same histology
Cells composing the tumours tend to be medium sized cuboidal, flattened or spindle cells arranged in a lace like pattern with less atypia than embryonal carcinoma
In half of these tumours Schiller Duval Bodies are seen - capillary in the centre of a mesodermal core and both visceral and parietal layers of cells that look like primitive glomeruli
Additionally eosinophilic and hyaline like globules containing AFP and a1- antitrypsin are also seen
Which proportion of diabetics will develop retinopathy
60-80% of patients develop diabetic retinopathy 15-20yrs after diagnosis
How does diabetes lead to eye disease
Neovascularisation due to hypoxia-induced VEGF expression of retina.
DM-induced hyperglycaemia causes sorbitol formation + accumulation
This causes acquired opacification of the lens (cataract).
What is the external cervical os
The entrance to the endocervical canal.
What is the action of renin
It cleaves plasma angiotensinogen into angiotensin I
This can then be converted to angiotensin II by ACE
Key to the RAAS system
Explain how a cervical smear is carried out
Speculum inserted into vagina to view cervix
A brush is scraped over the transformation zone and cells are smeared or spun down onto a slide
Fixed, stained (Papanicolaou method) and cell structure analysed
How can hypothyroidism cause hypertension
Increase in peripheral vascular resistance
Causes renal dysfunction
Hormonal changes can impact BP - ADH and adrenoreceptor effects
Endothelial dysfunction
What are the results of insulin resistance in T2DM
Failure to inhibit endogenous glucose production = high fasting BG.
Failure of glucose reuptake + glycogen synthesis in skeletal muscle following a meal = high postprandial BG.
Failure to inhibit activation of lipases in adipose tissue = excess triglyceride breakdown in adipocytes + high levels of circulatory FFAs.
Why do Cushing’s patients develop insulin resistance
The chronic glucocorticoid exposure leads to hyperinsulinemia and eventual resistance
List the different types of diabetes mellitus
Type 1
Type 2
Gestational
Specific types due to another cause e.g., monogenic diabetes syndromes (neonatal diabetes, maturity onset diabetes of the young [MODY]), diseases of the exocrine pancreases (e.g., CF), and drug- or chemical-induced diabetes (e.g., with glucocorticoid use, in HIV/AIDS treatment, or after organ transplantation).
Where is glucose produced in the body
In the liver
Which mutations are associated with endometrial stromal tumours
Several chromosomal abnormalities, particularly translocations, have been found to be specific for these malignancies (i.e., JAZF1 gets fused to SUZ12).
Which proportion of germ cell neoplasias progress to invasive cancer
Around 70%
How does hypothyroidism affect α1-adrenoreceptors and β-adrenoreceptors and what are the effects
Density of α1-adrenoreceptors is increased = their action is smooth muscle cell contraction, causing vasoconstriction in the blood vessels
β-adrenoreceptors are reduced in vascular beds - this can induce low cardiac output, renin secretion from the kidneys, low lipolysis and anabolism in skeletal muscle
What is the hallmark of macrovascular disease in diabetes
Accelerated atherosclerosis involving the aorta and large-med sized arteries
List potential complications of Herceptin
neutropenia, tremors, raised or lowered BP, mild heart failure
How does angiotensin II cause vascular contraction
Acts on the AT1 receptor to cause widespread vasoconstriction
This increases TPR and therefore BP
List the 4 main negative effects that glucotoxicity has on peripheral tissues
Advanced glycation end products (AGEs) formed
PKC activation
Oxidative stress + destruction of polyol pathways
Hexosamine pathways + fructose-6-phosphate generation
All involve an increased flux through metabolic pathways and generating harmful precursors that contribute to end-organ damage
How does HPV replicate in the cervix
Replication requires the virus to move these cells out of the resting phase of the cell cycle so that the DNA synthesis mechanisms within the cell can be used to replicate the viral DNA
HPV does this using the viral E6 and E7 proteins which interfere with key tumour suppressor genes such as P53 and RB.
What effect do elevated GIP and GLP-1 have
This causes increased insulin secretion from b-cells, reduced glucagon secretion from a-cells and delayed gastric emptying (promotes satiety).
Called the incretin effect
How do age related changes cause osteoporosis
Reduced production and activity of osteoblasts leads to decreased bone formation
List common causes of secondary systemic hypertension in young adults (19-39 y/o)
Thyroid dysfunction
Renal artery stenosis secondary to fibromuscular dysplasia
Describe the natural progression of cervical cancer
Relatively slow progression from squamous precursor lesions to invasive carcinoma - can take decades
Progression time from in-situ lesions to invasive adenocarcinoma and neuroendocrine is much shorter
Will start with direct spread to nearby tissues before spreading through lymph nodes and metastasizing
Describe the macroscopic features of a testicular spermatocytic tumour
Circumscribed fleshy lesions that can by myxoid potentially with cystic regions
Where is the transformation zone of the cervix
In the squamocolumnar junction
It is the area where the cell types change
Describe how amyloid deposits form in the islets in T2DM
Begins in and around capillaries and between cells.
At advanced stages, islets can be virtually obliterated.
Amyloid acts as a diffusion barrier which leads to a secretory + absorptive defect.
Fibrosis may be seen too.
What is the most common subtype of cervical carcinoma
Squamous cell carcinoma
Accounts for 80% of cases
Persistent or recurrent HPV infection increases cervical cancer risk - true or false
True
List symptoms of diabetes
Polydipsia Polyuria Polyphagia If severe DKA can be the presenting event Weight loss Muscle weakness Fatigue & somnolence Blurred vision Candida infection - pruritus vulvae and balanitis
Which aspects of diabetes contribute to cardiovascular risk
Glucotoxicity - CV risk increases as HbA1c does
Hypertension – found in 75% of T2 diabetics
~40% of diabetics will develop CKD which increases risk of CVD.
Obesity / metabolic syndrome
Exact cause of most testicular cancers is unknown - true or false
True
How can you prevent osteoporosis
Achieving peak bone mass and then minimising loss of bone mass
Diet supplementation with Ca2+ and vitamin D is recommended for all at risk patients
Encouraging exercise, particularly resistance exercises
What is the usual role of the BRACA genes
BRACA genes are tumour suppressor genes
So mutations in them leads to loss of function = cancer
Describe the macroscopic features of a Sertoli cell tumour
They are firm small nodules with a gray-white to yellow homogenous cut surface
List additional symptoms seen in advanced cervical cancer
Advanced cancer can cause different symptoms as it affects different organs.
Haematuria, bone pain, oedema, changes to bladder/bowel habit, weight loss, loss of appetite, fatigue are just some of the symptoms you may see.
List risk factors for breast cancer
Age >50 or post menopause
Family Hx ( BRACA cancers ted to run in families)
Previous breast lump (benign, ductal/lobular carcinoma in situ, atypical ductal hyperplasia, previous invasive carcinoma)
Dense breast tissue – more cells to malfunction + makes mammography challenging
High oestrogen exposure – early periods, late menopause, late/no pregnancy, HRT, contraceptive pill
Obesity – post menopause will increase oestrogen levels
Alcohol
Radiation to chest
What triggers insulin release
High levels of blood glucose
Excessive weight and and obesity are precursors of the metabolic syndrome - true or false
True
What is the greatest threat to health in the developed world
Obesity
Poor diet contributing to more disease than physical inactivity, smoking and alcohol combined!
Most of the world’s population live in countries where overweight and obesity kills more people than underweight
List causes of endometrioid endometrial carcinoma
Prolonged and unopposed estrogenic stimulation of the endometrium Obesity Hypertension Diabtetes Specific gene mutations
How does obesity cause endometrioid endometrial carcinoma
It increases synthesis of oestrogen from androgen precursors.
Excess oestrogen is the major cause
List potential complications of acromatase inhibitors
osteoporosis, high cholesterol
When would you see pancreatic islets with reduced insulin content and preserved architecture
Recent-onset T1DM
Insulin‐deficient islets seem to be preserved in size in early stages
Which nerve signals to the arterioles can lead to a drop in BP
Decrease sympathetic tone on arterioles
This caused vasodilation and so TPR decreases leading to a decrease in BP
Describe the lipostat
This is an internal set point for fat content
It senses the quantity of energy stores (adipose tissue) and appropriately regulates intake and expenditure - like a thermostat regulates temperature
Are endometrial stromal tumours likely to recur
Yes
Around 1/2 of tumours will recur but it is hard to predict which ones will.
List the subtypes of cervical carcinoma
Squamous cell carcinoma - 80%
Adenocarcinoma 0 15%
Rare - adenosquamous and neuroendocrine
What is detected on a cervical smear test
Highly effective in detecting cervical precursor lesions (some of which will progress if not treated).
Also able to detect low stage cancers which are highly curable (at that stage).
Can also test for the presence of HPV DNA in the smear sample (higher sensitivity but low specificity)
An average woman has what chance of developing breast cancer
Most have a 1/8 chance of developing the disease
What are the incretins
They are a hormone class involved in glucose haemostasis and satiety
Describe the behaviour of the HPV that causes HSIL
The HPV is more disruptive to the cell cycle so there is greater proliferation and effect on host cells.
The disrupted cell cycle may become irreversible and lead to malignant phenotype
List the symptoms of mononeuropathy (may be seen in diabetics)
foot-drop, wrist-drop, or isolated CN palsies
Describe the microscopic features of a testicular teratoma
Huge variety of cell and tissue types possible
The elements its made from can either be mature resembling adult tissue or immature resembling foetal or embryonic tissue
What additionally symptom may be present in Leydig cell tumours
Gyneacomastia in adults
In children sexual precocity due to hormonal release
List the macroscopic features of PAD
Evidence of gangrene or amputated digits/ limbs
Arterial ulcers – ‘punched-out’ appearance, may be associated with loss of leg hair
Evidence of atherosclerosis on dissection of vessels
Most testicular cancers have which genetic abnormality
Most have an isochromosome 12p
Except prepubertal teratomas and spermatocytic GCTs
What is the leading cause of cervical cancer
HPV infection
Specifically the 15 strains with high oncogenic risk
How does chronic kidney disease lead to secondary systemic hypertension
It damages the nephrons in the kidneys and they cannot excrete normal amounts of sodium
This leads to sodium and water retention and an increase in blood volume (increase CO)
There is an elevation in arterial pressure as the kidney attempts to increase renal perfusion and restore glomerular filtration
This increase systemic pressure
Describe how ADH release is triggered by changes in osmolarity
Osmoreceptors in hypothalamus detects ECF osmolarity
If osmolarity of the plasma increases, water moves out from the osmoreceptor cells into the surrounding ECS to balance osmolarity
This causes the osmoreceptor cells to depolarize and create an AP
This AP causes depolarization of supraoptic nucleus cells
Subsequent AP travels down hypothalamo-hypophyseal tract to depolarize the posterior pituitary gland and release ADH
Where is PAD most commonly seen
most commonly in the legs
How is the RAAS system affected by chronic kidney disease
Reduced blood flow in peritubular capillaries downstream of sclerosed glomeruli caused glomeruli to hypersecrete renin
This increases circulating angiotensin II levels
A II promotes sodium reabsorption
The net loss of GFR also impairs sodium excretion so you get retention which causes HTN
Fewer functioning glomeruli in CKD so need to increase GFR
There is an increase arterial pressure helps bolster perfusion pressure and GFR
What process may occur after hysterectomy
If ovaries removed on hysterectomy you will go through menopause after surgery.
will get the normal symptoms
What drug can be used for a T2 diabetic with CKD
Metformin can be used
SUs and SGLT2 inhibitors are contraindicated
Use a DPP-4 inhibitor but at a reduced dose.
How does environment contribute to obesity
Modern environments encourage inactivity and less than healthier choices
e.g. encourage cars over walking and high availability of unhealthy food choices
Called the obesogenic environment
List potential complications of tamoxifen
thrombosis and endometrial cancer
Serous endometrial carcinoma usually occurs on a background of what
Usually occur on a background of endometrial atrophy.
How can hypothyroidism cause endothelial dysfunction and what is the effect
You get downregulation of vasodilatory NO production in hypothyroidism
Less dilation = higher BP
How many fractures are caused by osteoporosis each year
Worldwide, osteoporosis leads to around 9 million fractures per year
In 2000, fragility fractures were estimated to cost the NHS £1.8 billion and were projected to reach £2.2 billion in 2025
What are the two classifications of diabetic retinopathy
non-proliferative and proliferative
Describe the appearance of hyaline sclerosis
Markedly thickened arterioles
How do you treat dehydration in HHS
Use 0.9% saline (±K) for fluid replacement WITHOUT insulin
The fluid alone will reduce BG which will reduce osmolality
Rehydrate slowly over 48hrs
What is intermittent claudication
Inadequate blood flow during exercise
What is the the most common presenting complaint for diabetic retinopathy
Distal symmetrical polyneuropathy of lower extremities
Will then progress to upper extremities = “glove and stocking” distribution
The proinflammatory state in metabolic syndrome is caused by what
It seems to be caused by activation of the inflammasome by free fatty acids and excess levels of lipids in cells and tissues stimulating interleukin 1 which induces inflammation.
Describe the structure of a seminoma cell
Classically they are round or polyhedral
The cytoplasm is either clear or has a watery appearance and may contain glycogen which can vary in its amount.
The nucleus tends to be large and central and may have 1-2 prominent nucleoli.
The cell membrane is usually distinct.
List endocrine causes of secondary systemic hypertension
Adrenocortical hyperfunction Exogenous hormones Pheochromocytoma Acromegaly Hyperthyroidism (thyrotoxicosis) Pregnancy-induced (preeclampsia)
Can cervical cancer be screened for
Yes
Can screen for cervical cancer and its precursors using smear or Pap tests.
Chronic hyperglycaemia in diabetes has what effect on insulin independent tissues
Causes glucose to accumulate in the tissues
Includes blood vessels, nerves, kidneys, eyes, CNS
What are the downstream effects of PKC activation in chronic hyperglycaemia
Production of VEGF, TGF-B, and procoagulant PAI-1 by vascular endothelium
These molecules are involved in angiogenesis & BM matrix
Contributes to microangiopathy
Define hypoglycaemia
Plasma glucose <3mmol/L
What are adipokines
Adipose cytokines
Normally released in response to altered fat metabolism, incl. leptin & adiponectin (role in lowering BG)
Describe stage 3 cervical cancer
Carcinoma has extended to the pelvic wall. On rectal examination there is no cancer-free space between the tumour and pelvic wall.
The tumour involves the lower 1/3 of vagina
List some of the common side effects of chemo/radiotherapy
Dry or broken skin, pain, tiredness, hair loss and nausea.
Many more
Where is insulin produced
Pancreas
How does endometrioid endometrial carcinoma develop from the precursor lesion
A stepwise accumulation of genetic mutations in tumour suppressor genes and oncogenes which leads to cancer
Which conditions are Leydig cell tumours associated with
Klinefelters
Cryptorchidism hereditary leiomyomatosis
Renal cell carcinoma syndrome
What is metabolic syndrome
Metabolic syndrome = obesity + hyperglycaemia + raised serum cholesterol and triglycerides
Describe the epidemiology of testicular embryonal carcinomas
Peaks between 20-30yrs
Can be mixed or pure form
Tend to be more aggressive
Describe type 1 DM
An autoimmune disease characterised by pancreatic b-cell destruction & an absolute deficiency of insulin
Accounts for ~5-10% of diabetes and is the most common subtype diagnosed in patients <20
What effect does insulin have on the adipose tissue
Increases glucose uptake, lipogenesis
Decreases lipolysis
Which type of pain is typically caused by diabetic neuropathy
Neuropathic
Early stage testicular cancer may be managed with what single treatment
orchidectomy alone
Are most testicular sex chord stromal tumours benign or malignant
Most are benign
Only 10% are malignant
Describe moderately differentiated endometroid endometrial carcinoma
Well formed glands mixed with areas of solid cell sheets (these sheets make up 50% or less of tumour)
Why has the death rate of cervical cancer fallen
Mostly due to the cervical screening programme
Describe the mechanisms of death from PAD
Patients diagnosed with PAD are 3-6x more likely to die from a cardiac cause than the general population
Critical limb ischaemia – 5 yr mortality is around 50%
May lead to sepsis from infected gangrene or ulcers
Amputation as a result of PAD is associated with significant disability and mortality
Which serum biomarkers are produced in testicular cancer
Lactate dehydrogenase – is proportionate to tumour
AFP and HCG
Elevated in 80% of non seminomatous GCTs. Only 15% of seminomatous GCTs will produce HCG.
How does critical limb ischaemia present
Limb pain at rest which may wake patients from sleep
May lead to ulcers and gangrene in affected limb
How does intermittent claudication present
Pain on exertion which resolves with rest
Describe the behaviour of the HPV that causes LSIL
Caused by HPV infections with lots of viral replication but little effect on host cells.
A weakened immune system can increase the risk of cervical cancer - true or false
True
Makes it harder to fight HPV which increases risk
Those with HIV are asked to get a smear every year as a result
Name the 2 most important incretins
GIP
GLP-1
Both are released following food ingestion
Endometrial cancer is uncommon in which age group
The under 40s
Describe the epidemiology of testicular spermatocytic tumours
These are rare GCT, compromising 1-2%
Affect men >65yrs
Describe stage 0 cervical cancer
This is Carcinoma in Situ (CIN III or HSIL)
List the consequences of macrovascular disease in diabetes
MI Heart failure Peripheral artery disease TIA or stroke Aortic aneurism Overt proteinuria and end-stage renal failure
How do most testicular cancers spread
They most commonly spread through the lymphatic system firstly to retroperitoneal para aortic nodes and subsequently to mediastinal and supraclavicular nodes
Haematogenous spread does occur (usually later in disease process) and is usually to lung but can also be to liver, brain and bone
How does obesity lead to T2DM
Risk for diabetes increases as BMI increases.
Especially caused by central or visceral obesity
Highlighted by certain populations having increased rates of T2D but no comparable increase in obesity – suggests risk is related to distribution of fat not just quantity of it.
Biological therapy is used in what type of breast cancer
HER2+ cancers
Used alongside surgery, chemo and radiotherapy
What is found in the transformation zone of the cervix
Immature squamous cells
They develop in this region as the cell type changes
How does coarctation of the aorta cause secondary systemic hypertension
Reduces distal arterial pressures and elevates arterial pressure in the head and arms
This reduces systemic arterial pressure, activates RAAS and increases the blood volume
How does ADH reach the kidney tubules
Travels through the bloodstream to the kidney tubules where it diffuses from plasma in peritubular capillary across into the peritubular fluid
Does primary aldosteronism cause oedema
No
Pressure natriuresis and volume expansion takes over and counteracts the aldosterone induced sodium resorption
How does obesity link to poverty
In Scotland there are substantial inequalities in the risk of overweight and obesity between children living in the least and most deprived areas in Scotland – and evidence to suggest that this gap is widening
More common in deprived area
What proportion of diabetes cases are linked to obesity
Globally, 44% of cases of diabetes are attributable to overweight and obesity
The risk for type 2 diabetes rises exponentially with high BMI
How does hypoglycaemia present
Usually rapid onset May be accompanied by odd behaviour (e.g. aggression) Sweating Dizziness Tachycardia Palpitations Seizures
Can progress to loss of consciousness
Familial breast cancers make up the majority of cases - true or false
False
They are responsible for the minority of cancers
What can cause Cushings
Adrenal causes
Nonadrenal causes - pituitary adenomas
Exogenous steroids
List the typical signs and symptoms of HHS
Diabetes may be known, often not.
High refined CHO intake pre-event.
Onset is slow w/ polyuria over 2-3w + progressive dehydration.
What factor do the baroreceptors respond to
Stretching of the arterial walls
When does the incidence of HPV infection start to decline
From age 25 onwards
This is because women develop immunity or enter relationship
List potential complications of HHS therapy
Fluid overload - cerebral oedema etc.
How does CKD cause hypertension
Activation of RAAS
Overactivity of the sympathetic nervous system
Endothelial dysfunction (including impaired NO production), oxidative stress and elevated endothelin levels are implicated
How does GFR affect renin release
If GFR is low the macula densa cells release prostaglandin E2 and nitric oxide
This causes vasodilation and increased renin release
Describe gestational DM
Diabetes diagnosed in the 2nd/3rd trimester of pregnancy that was not clearly overt diabetes prior to gestation.
How can you calculate BP
BP = CO x TPR
What causes testicular germ cell tumours
Potentially caused by environmental and genetic factors
Environmental factors – in utero exposure to pesticides and nonsteroidal estrogens
Genetic Factors – multiple gene loci have been located including ligand for receptor tyrosine kinases KIT and BAK, important in apoptosis and gonadal development, and variants in genes for sex hormone metabolism
Insulin resistance predates hyperglycaemia in T2DM - true or false
True
It is usually accompanied by compensatory b-cell hyperfunction in the early stages
Describe the prevalence of obesity in Scotland
In 2018,two thirds(65%) of adults in Scotland were overweight, including28%who were obese
When would you see an increase in number and size of pancreatic islets
This is characteristic of nondiabetic new-borns of mothers with diabetes
Presumed to be a response (hyperplasia) of foetal islets to the maternal hyperglycaemia
What determines the rate of complications from PAD
The size and location of the occlusion – a large femoral stenosis will require more dramatic treatment than infrapopliteal lesions
Describe the appearance of endometrial stromal tumours
Stroma gives rise to neoplasms that look like normal stromal cells.
Get benign stromal nodules and endometrial stromal sarcoma (low- and high-grade versions).
What breaks down GIP and GLP-1
Circulating GIP and GLP-1 are degraded by enzymes called dipeptidyl peptidases (DPPs), esp. DPP-4.
What is osteopenia
Decreased bone mineral density, but not to the extent of osteoporosis
T-score between -1 and -2.5
How does renal perfusion pressure affect renin release
A pressure decrease (due to reduced blood flow) stimulates renin release
List the common precipitants for DKA
Infection
Illicit drugs & alcohol
Non-adherence w/ treatment
Newly diagnosed diabetes.
What is the main complication of HHS
Renal impairment
Therefore fluids must be prescribed carefully due to increased risk of overload
Obesity is associated with hyperinsulinemia - true or false
True
Due to insulin resistance
significantly increase the risk of hypertension and diabetes
Which cancer can be treated by progesterone hormone therapy
Some endometrial cancers
List renal causes of secondary systemic hypertension
Acute glomerulonephritis Chronic renal disease Polycystic kidney disease Renal artery stenosis Renal vasculitis Renin-producing tumours
What is the T-score and how is it relevant to osteoporosis
T-score – no. of SD away from the mean reference value for bone density in young, healthy adults
T-score < -2.5 is classes as osteoporosis
Is HPV common in the population
Yes
Around 8/10 will have it at some point and most do not cause any symptoms or damage.
Which endometrial cancer is always classed as grade 3
serous endometrial carcinoma
Describe the metastatic pattern seen in luminal breast cancer
Most mets go to bone (70%)
Some go to viscera ( 25%) and brain (10%)
They have a low rate of recurrence but long survival is possible with bone mets
Describe the pathogenesis of sex chord stromal tumours
Arise due to poor gonadal development
Mutations and polymorphisms create altered functioning Sertoli and Leydig cells then environmental and lifestyle factors impact development in the early years
The hormonal balance is then disrupted by the dysfunctional cells creating altered germ cell differentiation resulting in the neoplasm
List potential complications of mastectomy
bleeding, infection, lymphoedema, hard scar tissue formation, shoulder pain and stiffness, numbness under the arm
Baroreceptors only respond to sudden rises in BP, not drops - true or false
False
They also respond to sudden reductions in arterial pressure e.g. suddenly stand up or following hemorrhage
Describe the macroscopic features of a testicular teratoma
Usually 5-10cm in diameter
Heterogenous appearance made of multiple tissue types and potentially have solid, cystic and cartilaginous areas
All of said different cell types will be embedded in a wall of fibrous or myxoid stroma
How can serum biomarkers be used in testicular cancer
In diagnosis
To assess tumour burden – using lactate dehydrogenase
To assess treatment response
To monitor for metastasis
How does renal sympathetic nerve activation affect renin release
Acts on B1 adrenergic receptor of JG cells
This increases intracellular cAMP which in turn increases renin release
Describe how ADH release is triggered by changes in blood volume
If blood volume decreases then venous return does too
This decreases the stretch in the atrium which represses the atrial volume receptors (firing decreases)
This is picked up by the CVS centre and then the hypothalamus
Stimulates ADH production
What is the management for T2DM
1st line: metformin (SU if intolerant or osmotic symptoms)
2nd line: add one of: sulphonylurea (SU) OR SGLT2 inhibitor OR DPP-4 inhibitor OR thiazolidinediones (TZDs).
3rd line: add either an additional oral agent from another class OR an injectable agent (GLP-1 agonist or basal insulin).
What is the role of insulin
Insulin increases rate of glucose transport into certain cells, providing a source of energy and metabolic intermediates for the biosynthesis of building blocks such as lipids, nucleotides and amino acids.
List the pancreatic changes that may be seen in T1DM
Decreased number of islets - especially. in advancing disease; most of the islets are small & inconspicuous
Leukocytic infiltration of the islets - can be present at any time, primarily T lymphocytes
At which age does cervical screening start and how often do you get it
Invited before 25th birthday
Ages 25-49 get it every 3 years
50-64 is every 5 years
65+ only get tested if 1 of last 3 tests was abnormal
Who gets the HPV vaccine in Scotland
All girls and boys by ages 11-12 in Scotland.
Can pay to have it if outwith this group (i.e. missed it at school)
Is obesity more common in men or women
A greater proportion of men were overweight or obese than women
What is the main mechanism of b-cell destruction in T1DM
Failure of self-tolerance (in T-cells) for islet antigens
These autoreactive T cells attack islet autoantigens
Skeletal muscle + adipose tissue make up which proportion of body weight
2/3
What type of epithelium covers the endocervix
Columnar, mucus secreting epithelium.
How does HPV cause cancer
Viral proteins interfere with tumour suppressor genes such as p53
Enhances the cell cycle and reduces the cell’s ability to repair DNA damage and promotes cellular immortalization.
Overall, you get increased proliferation of cells that are more likely to acquire mutations and therefore lead to cancer
What are the consequences of vertebral osteoporotic fractures
significant pain and disability, and decreased life expectancy
What causes PKC activation in chronic hyperglycaemia
Excessive activation due to de novo synthesis of messenger (DAG) in PKC activation process
How do most breast cancers develop (in terms of genetics)
Can evolve through several pathways that allow collection of driver mutations in the epithelial cells followed by mutagenesis and an outgrowth of normal clones
How do genetic factors cause osteoporosis
Rarely directly cause osteoporosis, but certain gene polymorphisms (RANK, RANKL, OPG) may lead to variation in peak bone mass
All listed mutations encode osteoclast regulators
Describe how the mineralocorticoid activity of cortisol can lead to increased BP (as seen in Cushing’s)
Cortisol binds to both glucocorticoid & MR but MR is protected from this binding by by 11β-HSD2 (modulates corticosteroid hormone action at tissue level)
However, excess cortisol as per Cushing’s can exceed the protective capacity of 11β-HSD2 to inactivate the steroid to cortisone
This makes it available to bind to MR where it can mimic excess aldosterone
This causes sodium & water retention and increased blood volume
What is a PAS stain
PAS is a staining method used to identify polysaccharides including glycogen
Endocrine therapy is used in what type of breast cancer
ER+ cancers
tamoxifen for for premenopausal women/men
Or as acromatase inhibitors for post menopausal women
List the mechanisms by which BP is regulated
Baroreceptors
ADH
RAAS
How does age affect bone mass
Peak bone mass reached between 25-30
After this, bone mass is lost at approximately 0.7%/year in both men and women
Aside from retinopathy, which eye disease can occur as a result of diabetes
Central Retinal Vein Occlusion (CRVO) due to endothelial dysfunction Vitreous haemorrhage (assoc. w/ proliferative retinopathy) Ischaemic optic neuropathy (vessel occlusion).
What is happening to the incidence and mortality rates from breast cancer
They are both rising
Now second only to lung cancer
List the potential complications of cervical cancer surgery
After excisional surgery patients may have pain, bleeding, discharge changes, cervical stenosis due to scarring, infection and may experience premature birth or miscarriage.
Cervix and womb removal also increases risk of lymphocysts/lymphoceles which are fluid filled swellings in the abdomen, bladder issues and lymphedema.
What is peripheral vascular disease
An umbrella term covering diseases of the arteries, veins and lymphatics
Primarily in the limbs, face and neck
How do you diagnose PAD
Ankle-Brachial Pressure Index (ABPI) – Ratio of the systolic blood pressure in the ankle to that in the upper arm
< 0.5 – Severe PAD
0.5-0.8 – Moderate PAD
0.8-1.3 – No evidence of disease
>1.3 – May be falsely high reading due to calcification of arteries
What innervates the aortic arch baroreceptors
The aortic nerve
Combines with the vagus nerve and travels to the NTS in the medulla
Describe the epidemiology of testicular germ cell tumours
Most effect Caucasian males between ages of 15-45yrs
They are the most common cancer in this demographic
Their incidence is increasing for unknown reasons
They are less common in African and Asian populations
List causes of osteoporosis
Age-related changes Reduced physicals activity Genetic factors Ca2+ nutritional state Endocrine influences
Describe stage IV serous endometrial carcinoma
Carcinoma extends out of the true pelvis or involves the mucosa of the bladder or rectum.
Where will immature cells be found in LSIL
Confined to the bottom 1/3 of epithelium
Which nerve signals to the heart can lead to a drop in BP
Decrease sympathetic, increase parasympathetic (vagal) tone on heart
HR and contractility will decrease - this lowers CO and therefore BP
High chromosomal instability is associated with which cancers
It is a feature of cancers caused by TP53 mutations
What factor can increase the risk of mutation in luminal cancers
Oestrogen exposure during pregnancy and menstruation
This is because it increases breast epithelial cell proliferation and therefore increases risk
Which genes are implicated in obesity
ADIPOQ - produced by fat cells and promotes energy expenditure
FTO - promotes food intake
Leptin - produced by fat cells
Leptin receptors - when bound to leptin inhibits appetite
MC4R - stimulates appetite
Describe the epidemiology of testicular teratomas
Occurs at any age
Adult forms make up 2-3% of GCTs
They’re usually mixed and malignant
Infant forms are second in frequency to yolk sac tumours, tend to be pure and not assoc. with germ cell neoplasia in situ
Which genes are responsible for the majority of familial breast cancers
Caused by a single gene mutation with moderate to high penetrance usually in BRACA 1 (ch 17q21) or BRACA 2 (ch 13q12.3)
There are multiple different locations on these genes the mutation can occur which will effect penetrance, susceptibility to other cancers and age of onset
Describe stage 4 cervical cancer
Carcinoma has extended beyond the true pelvis or has involved the mucosa of the bladder or rectum.
This stage also includes those that have metastasized.
Which ethnicities are at greater risk of developing end-stage renal disease as a consequence of diabetic nephropathy
Native Americans, Hispanics and African Americans
Greater risk than non-Hispanic Caucasians with T2D
Why were boys included in the HPV vaccination scheme
Originally given to just girls to reduce cervical cancer incidence
Boys now included to reduce HPV spread and to prevent HPV cancers of the anus and oropharynx
How does hypothyroidism affect ADH levels and what is the effect
Increased ADH
This leads to water retention and an increased blood volume = higher BP
Where do most breast cancers arise
The terminal ductal lobular unit
What is the ideal range for HbA1c
48-58mmol/mol
Describe the metastatic pattern seen in triple negative breast cancer
40% mets go to bone, 35% to viscera and 25% to brain, again common to find mets in each.
If they are to relapse will be in the first 8yrs ( rare after this), if they do have mets then survival is uncommon
HHS is more common in which type of diabetes
T2
Higher level of portal vein insulin prevents unrestricted hepatic fatty acid oxidation and ketogenesis - glucose isn’t used up that way
The sustained hyperglycaemia brings chronic dehydration and leads to HHS
List potential causes of unexpected sudden death in an obese
cardiomegaly, pulmonary thromboembolism, or ischemic heart disease may be the most probable diagnosis
List is extensive and not limited to obesity caused disease
What initial tests would you do in a young adult with secondary systemic hypertension
MRA with contrast
CT angiography
TSH
Echo if above tests not conclusive
Is obesity preventable
YES
What is the trend in childhood obesity
Prevalence of children at risk of obesity has remained relatively stable - 70% are a healthy weight
However, children in theUKare becoming obese at earlier ages and staying obese longer
Do environmental factors have a role in development of T1DM
Yes
Must play a role since concordance rate in monozygotic twins is only ~50%.
How does the sleep apnoea in Cushing’s cause HTN
Increased sympathetic tone during hypoxemic episodes worsens the HTN
What is the squamocolumnar junction
The meeting point of the two types of epithelium of the cervix (squamous and columnar)
List examples of endovascular interventions for PAD
percutaneous transluminal angioplasty with balloon dilation, stents etc.
Describe the series of events that occur in the baroreceptors when arterial pressure suddenly drops
Causes decreased baroreceptor firing
This leads to disinhibition of sympathetic activity within medulla so sympathetic activity originating within rostral ventrolateral medulla increases
This causes vasoconstriction (increase TPR)
Tachycardia occurs to increase CO
Positive inotropy -> BP increases and restored
Describe the pathogenesis of triple negative cancers
These cancers tend to have tp53 mutations giving rise to inefficient cell arrest and apoptosis increasing the ability for cancerous mutations to collect
The detection of HPV from cervical smears is not recommended in women under 30 - true or false
True
Not as useful in women under 30 as high incidence of infection in this age group anyway
Aortic arch baroreceptors are less sensitive than the carotid sinus ones - true or false
True
They have a higher pressure threshold so are less sensitive
