Mechanisms of disease Flashcards
Give four other complications of gallstones and explain why they occur.
Biliary colic and jaundice – due to impaction of a stone in the common bile duct leading to biliary obstruction.
Pancreatitis – inflammation of the pancreas due to impaction of a gallstone distal to the opening of the pancreatic duct.
Cholecystitis – inflammation of the gallbladder caused by impaction of a stone in the neck of the gall bladder or cystic duct.
Gallstone ileus – this is intestinal obstruction by a gallstone that has entered the gut through a fistulous connection with the gallbladder.
Mucocele - an over distended gallbladder filled with mucoid material. Usually non- inflammatory, it results from outlet obstruction of the gallbladder and is commonly caused by an impacted stone in the neck of the gallbladder or in the cystic duct.
Predisposition to carcinoma of the gallbladder – pathogenesis unclear but could be due to repeated trauma to gallbladder epithelium resulting in increased epithelial turnover and increased risk of mutations occurring during DNA replication.
What are the 4 types of chemotherapy agents?
Antimetabolites- mimic normal substrates involved in DNA replication
Alkylating agents - cross-link the two strands of the DNA helix.
Antibiotics - inhibits DNA topoisomerase, which is needed for DNA synthesis, while bleomycin causes double-stranded DNA breaks.
Plant-derived drugs - blocks microtubule assembly and interferes with mitotic spindle formation.
What is a TIA?
Transient ischaemic attack, usually secondary to microemboli originating from the heart or carotid or vertebral arteries.
What is Scrofula?
TB nodes in cervical region.
Local complications of inflammation
- Swelling e.g. airway (acute epiglottis), enclosed spaces - acute bacterial meningitis -> raised intracranial pressure -> ischaemia +/-coning
- Inappropriate inflammation e.g. hypersensitivity reactions
- Exudation of fluid e.g. pericardial space following MI -> tamponade (prevents pumping of heart) • Loss of fluid, shock e.g. burns
- Prolonged pain and loss of function
- Digestion of host tissues by harmful enzymes released by neutrophils e.g. vascular damage in glomerulonephritis.
What is a saddle embolus?
A large embolus straddling the pulmonary artery bifurcation.
This results in blockage of pulmonary arterial blood flow to the lungs and sudden death.
What is the name of the process that distal nerve fibres undergo following damage?
Wallerian degeneration.
Summarise the laboratory diagnosis of alcoholic liver disease
Acute alcoholic liver disease – a hepatic picture is seen.
Chronic alcoholic liver disease – fulminant liver failure is seen.
Raised bilirubin, raised alkaline phosphatase, raised gamma GT (glutamyl transpeptidase).
(NB: See raised alkaline phosphatase and gamma GT with damage to bile canaliculus (these are plasma membrane enzymes)).
Which benign tumours cause a high serum calcium and how?
Which benign tumours cause a high serum calcium and how? Primary parathyroid adenomas produce hyperparathyroidism. There is an increase in parathyroid hormone which results in:
- Raised serum ionised calcium and bone resorption
- Hypophosphataemia
- Increased excretion of calcium and phosphate in the urine
Classically the symptoms are of painful bones (fractures), renal stones, Abdominal groans (constipation, peptic ulcers, pancreatitis, gallstones) and psychic moans (depression, lethargy, seizures).
What is a Ranke complex?
This is seen in ‘healed’ primary tuberculosis comprising of a ghon focus and an ipsilateral calcified hilar node.
What are the six hallmarks of cancer?
Self-sufficient growth signals: e.g. HER2 gene amplification (breast cancer)
Resistance to anti-growth signals: e.g. CDKN2A gene deletion
(cyclin dependant kinase inhibitor ) (Melanoma)
Grow indefinitely: e.g. Telomerase gene activation (most cancers)
Induce new blood vessels: e.g. Activation of VEGF expression (many cancers)
Resistance to apoptosis: e.g. BCL2 gene translocation (lymphoma)
Invade & produce metastases: e.g. E-cadherin mutation (gastric cancer)
What are the stages of scar formation?
Seconds - minutes: haemostasis
Minutes - hours: acute inflammation
1-2 days: chronic inflammation
3 days: granulation tissue forms
7-10 days: early scar
Weeks – 2 years: scar maturation
Which stem cells divide permanently in order to replenish losses?
labile stem cells
How does Helicobacter pylori cause gastritis?
Causes gastritis by stimulating production of pro-inflammatory cytokines and by directly injuring epithelial cells and increasing acid secretion.
Acute appendicitis is a mysterious disease. Its cause is poorly understood. What predisposing factors have been described?
Presence of seeds or pinworms in the appendix.
Impaction of the neck of the appendix by a faecolith.
Lymphoid hyperplasia within the wall of the appendix (occurs in childhood and some viral infections such as adenovirus and measles).
Tumour within the appendix.
What is a pressure sore and why do they occur?
Pressure sores (also known as bed sores, pressure ulcers and decubitus ulcers (decubitis is the act of lying down)) are ulcerated areas of skin caused by continuous pressure from the weight of the body on that area resulting in skin ischaemia .
They are most common over bony prominences (where the bones are close to the skin) such as heels, sacrum, elbows, hips, back of the head and shoulders.
There is compression of the skin and underlying tissues and blood vessels can be damaged.
What makes cells monoclonal?
A collection of cells is monoclonal if they all originated from a single founding cell.
Why does LDL have a longer half life than other lipoproteins?
LDLs do not have apoC or apoE so are not efficiently cleared by liver (Liver LDL-Receptor has a high affinity for apoE).
What are the 3 different types of cell signalling?
Autocrine – the same secreting and responding cell
Paracrine – secreting cell and responding cell are different
Endocrine- Endocrine organs synthesise hormones-conveyed through blood stream- target organs distant from site of synthesis
What is a corneal arcus and what is its significance?
A greyish-white ring opacity at the periphery of the cornea. They are due to lipid infiltration of the corneal stroma.
They can occur in healthy elderly people when they have no significance. If they occur in younger people they are an indication of hypercholesterolaemia, especially homozygous familial hypercholesterolaemia.
What are the main cellular and non-cellular constituents of granulation tissue?
What is its function?
Granulation tissue – cellular constituents: macrophages, other inflammatory cells, fibroblasts, myofibroblasts, endothelial cells; non-cellular constituents: exudate fluid, fibrin, extracellular matrix proteins (e.g. collagen).
Function of granulation tissue – tissue repair and walling off the wound to try to prevent any infection present from spreading. New vessels bring cells and substances for healing. Granulation tissue contracts and helps close the wound.
List four of the possible complications of meningitis.
Cerebral abscess Subdural empyema
Cerebral thrombophlebitis
Cerebral infarction due to obliterative endarteritis of local arteries
Disseminated intravascular coagulation (DIC)
Neurological damage including:
- Sensorineural hearing loss
- Cranial nerve palsies
- Epilepsy
- Learning and behavioural difficulties
- Focal neurological deficits
Obstructive hydrocephalus due to subarachnoid adhesions blocking flow of CSF. This can result in neurological damage.
Adrenal haemorrhage (Waterhouse-Friderichsen syndrome) causing adrenocortical insufficiency – pathogenesis unclear
Summarise the laboratory diagnosis of hepatitis
Laboratory diagnosis:
- Raised serum ALT, AST and LDH. These are cytosolic hepatocellular enzymes and their presence in the blood indicates poor hepatocyte integrity.
- Raised bilirubin (often conjugated) – indicates poor biliary excretory function.
- Decreased albumin, raised PT (reliant on factors 2,7,9,10 produced by the liver), raised ammonia – these findings indicate poor hepatocyte function.
In a lung suffering from a pulmonary embolism, what colour will the tissue be?
It will be red.
The lung has a dual blood supply.
Occlusion of the main blood supply causes an infarct.
The collateral arterial supply is insufficient to rescue the tissue but does allow blood to enter the dead tissue creating a red infarct.
Also the lung has loose stroma which allows bleeding to occur into the infarct.
What is Acute ITP?
Immune thrombocytopenic purpura – an idiopathic condition that presents with a purpuric rash and low platelets. Patients produce autoantibodies against platelet membrane glycoproteins. The onset is abrupt but often preceded by a viral illness. It usually resolves spontaneously in 6 months.
Are there any tumour markers of value in monitoring cancers of the large intestine?
Carcinoembryonic antigen (CEA).
What are the complications of fibrous repair?
Formation of adhesions : Compromising organ function or blocking tubes, e.g., intestinal obstruction following abdominal surgery
Loss of function: Due to replacement of specialised functional parenchymal cells by scar tissue, e.g., healed myocardial infarction with non-contracting area of myocardium
Chemical mediator groups
VASOACTIVE AMINES
Histamine: Mast cells, basophils + platelets
Serotonin (5-HT): Platelets
VASOACTIVE PEPTIDES
Bradykinin: From plasma precursor kininogen, causes: ↑ vascular permeability, dilatation of blood vessels and pain
Prostaglandins: From membrane phospholipids by cyclo-oxygenase, vasodilatation
Factors from neutrophils and platelets:
C3a, C5a, IL-1, f
What is DIC?
It is characterised by activation of coagulation resulting in formation of microthrombi in the microcirculation. There is consumption of clotting factors and platelets and activation of fibrinolysis. This in turn leads to haemorrhage.
The following processes come into play:
- Microthrombi formation causing tissue ischaemia .
- Haemorrhage – this may be very severe and is seen from mucous membranes and into the skin or internal organs including the brain.
- Microangiopathic haemolytic anaemia – as red blood cells squeeze through vessels narrowed by microthrombi.
Why do aortic aneurysms occur?
The media of the aorta is weakened by atheroma and no longer has elastic recoil as elastin fibres are destroyed by atherosclerosis.
Laplace’s law – for a given pressure, increased radius requires increased wall thickness to accommodate a stable wall tension.
4 main systemic effects of inflammation
1. Pyrexia
- Bacterial endotoxins
- Pyrogenic cytokines, e.g. TNF, IL-2, from macrophages and neutrophils, act on anterior hypothalamus, ↑ synthesis of prostaglandin E2 (why aspirin reduces fever)
2. Leucocytosis (↑ WCC)
– Macrophages + endothelial cells release colony-stimulating factors so BM produces more leucocytes
– IL-1 and TNFa accelerate release from BM
– Bacterial infections = ↑neutrophils
– viral = ↑lymphocytes
3. Acute phase response in liver
Constitutional symptoms (malaise, anorexia, nausea)
– acute phase proteins: fibrinogen, CRP (C-reactive protein), alpha1 antitrypsin, Haptoglobin, Serum amyloid A protein
– reduced protein synthesis
4. Shock = circulatory failure (clinical syndrome)
• Due to spread of microorganisms and toxins (septic shock). Often fatal
What is the difference between lobar and bronchopneumonia?
Lobar pneumonia affects all or part of a lobe with other areas generally normal.
Bronchopneumonia is especially seen in young and old patients. It has a patchy distribution and generally involves more than one lobe.
How is Hodgkin’s disease staged?
- Single node/groups
- Two or more groups on the same side of the diaphragm
- Disease both sides of the diaphragm
- Involvement of extralymphatic organs, e.g. liver, lung, bone marrow
Name the 4 growth factors
- Epidermal growth factor
- Vascular endothelial growth factor
- Platelet-derived growth factor
- Granulocyte colony stimulating factor
What is the molecular defect in this Heterozygous familial hypercholesterolaemia?
Underproduction or malproduction of LDL clearance receptor in the liver.
What causes Ehlers-Danlos syndrome?
Defective conversion of procollagen to tropocollagen
Name the 4 cancer screen programmes in the UK
Cervical Screening - 25-64 year old women
Breast Screening - 50 -70 year old women every 3 years
Bowel Cancer Screening - 60-69 year old men and women.
Bowel scope screening programme - 55 year olds
Which malignancies are associated with Helicobacter pylori gastritis?
Gastric adenocarcinoma.
MALT (mucosa associated lymphoid tissue) lymphoma.
What is a polyp?
A growth, usually benign, with a stalk, protruding from a mucus membrane.
Neutrophil extravasation (emigration) different receptors/chemical mediators at each stage:
ROLLING: selectins expressed by endothelial cells bind to carbohydrate ligands (sLex) on neutrophils. Increased by several cytokines secreted by macrophages, mast cells and endothelial cells e.g. IL-1 and TNF
ADHESION: integrins expressed by neutrophils bind to integrin ligands on the endothelium. C5a, leukotriene B4, IL-1 and TNF increase expression.
DIAPEDESIS: chemotaxins e.g. C5a, leukotriene B4, bacterial peptides stimulate neutrophils to migrate through the inter-endothelial cell junctions
What are the two main processes seen in necrosis?
- Denaturation of intracellular proteins
- Enzymatic digestion by lysosomes inherent to the dying cell and lysosomes of leukocytes that are part of the inflammatory reaction
What is gangrene?
The clinical term used to describe visible necrosis.
May be wet, dry, or gaseous
What are myofibroblasts and what is their function?
Fibroblasts that develop a contraction phenotype.
They resemble smooth muscle cells and are intermediate between fibroblasts and smooth muscle cells.
They contract and help close the wound
What is vascular endothelial growth factor?
- Potent inducer of blood vessel development (vasculogenesis) and role in growth of new blood vessels (angiogenesis) in tumours, chronic inflammation and wound healing
What are the 4 stages of haemostasis?
Vascular spasm
Primary haemostasis - formation of unstable platelet plug
Secondary haemostasis - stabilisation of plug with fibrin (blood coagulation system)
Dissolution of clot and vessel repair (fibrinolysis)
What is a pipelle biopsy?
A process for taking a biopsy of the endometrium using a plastic tube (the pipelle ) inserted through the cervical os and which uses suction to obtain endometrial tissue.
What are the 4 roles of neutrophils in acute inflammation?
Neutrophils migrate to site of injury by chemotaxis
Phagocytose and kill microorganisms
Eliminate foreign material and necrotic tissue
Produce growth factors for repair
Briefly describe how breast cancer is graded.
Bloom-Richardson grading system which assesses tubule (glandular) formation, nuclear pleomorphism and mitotic rate within the tumour, i.e. how well differentiated the tumour is.
Describe what is meant by the term acid fast
Retains stains even on treatment with a mixture of acid and alcohol.
Which three alterations must occur before carcinoma cells can invade surrounding tissue?
altered adhesion, stromal proteolysis and motility
How are prostatic carcinomas graded?
Gleason grading – based on the pattern of glandular differentiation.
What is the name of a benign tumour of glandular epithelium?
Adenocarcinoma
What is the hallmark of reversible cell injury?
Swelling of the cell
What are growth factors?
- Local mediators involved in cell proliferation
- Coded by proto oncogenes
- Polypeptides that act on the cell surface
- Local hormones
- They stimulate cell proliferation but may also affect cell locomotion, contractility, differentiation and angiogenesis.
What occurs in healing by secondary intention?
Considerable wound contraction must take place to close wound
Substantial scar formation, new epidermis often thinner than usual
Takes longer than healing by primary intention
What are the mechanisms of vascular leakage?
Endothelial cell contraction: Chemical mediators e.g. histamine, C5a, NO
Endothelial cell injury: Direct e.g. trauma, chemicals, microbial toxins or ndirect e.g. toxic oxygen species and proteolytic enzymes from neutrophils
Structural re-organisation of cytoskeleton: Cytokine mediated e.g. interleukin-1, TNF
Transcytosis: VEGF induces ↑ channels in endothelial cells
What is a Pleomorphism?
Variation in size and shape, occurs in neoplastic cells and nuclei.
What is anaplasia?
Lack of differentiation (‘to form backwards’).
Main steps involved in invasion of extracellular matrix
- Detachment of tumour cells from one another by unzipping of the anchor protein E-cadherin.
- Degradation of the extracellular matrix by collagenase attacking the collagen fibres of the basement membrane
- Loss of adhesion of cells from integrins: this process should induce apoptosis but fails to in tumour cells.
- Migration of tumour cells through the extracellular matrix.
What are the clinical features of ulcerative colitis?
Inflammation is limited to mucosa and submucosa
Crypt abscesses common
Distorted crypt architecture very common
Significant increased risk of colon cancer
Often most severe in distal colon
Colectomy often indicated
4 main systemic effects of acute inflammation
Pyrexia
Leucocytosis (↑ WCC)
Acute phase response in liver
Shock = circulatory failure (clinical syndrome)
What happens during primary haemostasis?
- Formation of primary haemostat plug
- Platelets adhere to subendothelial structures via von Willebrand factor (VWF)
- adhere to each other (aggregation)
- form a platelet plug held to together by insoluble fibrin
How is asbestos thought to cause cancer?
It is an initiator and a promoter (it is proinflammatory).
It generates free radicals. It absorbs toxic elements onto the fibres.
Name the 3 irreversible nuclear changes
pkynosis
karyorrhexis
karyolysis
What is ‘proud flesh’? If necessary how is it treated?
Hypertrophy of granulation tissue that grows above the surface of the surrounding skin and blocks reepithelialisation . It is treated by cautery or surgical removal.
Summary of role of neutrophils in acute inflammation
- Neutrophils migrate to site of injury by chemotaxis
- Phagocytose and kill microorganisms
- Eliminate foreign material and necrotic tissue
- Produce growth factors for repair
- Activated neutrophils may release toxic metabolites and enzymes causing damage to normal host tissue
What is platelet-derived growth factor?
- Stored in platelet alpha granules and released on platelet activation
- Also produced by macrophages, endothelial cells, smooth muscle cells and tumour cells
- Causes migration and proliferation of fibroblasts, smooth muscle cells and monocytes
Which other staging methods are used for other specific cancers?
Dukes staging for colorectal cancers
Ann Arbor staging for lymphomas
- Rare type of cancer that usually affects the bones of children and adolescents –
- Benign tumour of cartilage –
- Often produces CEA –
- Commonest cause of cancer death in the UK –
- Has a known association with Aspergillus flavus –
- Tumour that can produce 5HT –
- Tumour that is usually benign in the ovary and malignant in the testis –
- Associated with EBV –
- Malignant tumour of blood vessels –
- A cancer of the skin that rarely metastasises –
- Malignant tumour of skeletal muscle –
- Benign tumour of melanocytes –
- Produces vanillyl mandelic acid –
- Another name for nephroblastoma –
- Tumour, often within the skin and frequently associated with HIV infection –
- Tumour of the thyroid gland that can produce calcitonin -
- Common tumour of the bladder–
- Associated with asbestos exposure –
- Often produces human chorionic gonadotropin –
- Type of lung tumour most often associated with ectopic production of ADH –
- Rare type of cancer that usually affects the bones of children and adolescents – Ewing’s sarcoma
- Benign tumour of cartilage – chondroma
- Often produces CEA – colon cancer
- Commonest cause of cancer death in the UK – lung cancer
- Has a known association with Aspergillus flavus – hepatocellular carcinoma
- Tumour that can produce 5HT – carcinoid tumour
- Tumour that is usually benign in the ovary and malignant in the testis – teratoma
- Associated with EBV – Burkitt’s lymphoma
- Malignant tumour of blood vessels – angiosarcoma
- A cancer of the skin that rarely metastasises – basal cell carcinoma
- Malignant tumour of skeletal muscle – rhabdomyosarcoma
- Benign tumour of melanocytes – naevus
- Produces vanillyl mandelic acid – phaeochromocytoma
- Another name for nephroblastoma – Wilm’s tumour
- Tumour, often within the skin and frequently associated with HIV infection – Kaposi’s sarcoma
- Tumour of the thyroid gland that can produce calcitonin - medullary carcinoma
- Common tumour of the bladder– transitional cell carcinoma
- Associated with asbestos exposure – malignant mesothelioma
- Often produces human chorionic gonadotropin – choriocarcinoma
- Type of lung tumour most often associated with ectopic production of ADH – small cell carcinoma
What is Trousseau’s syndrome? Why does it occur?
It is the increased risk of thromboembolism in disseminated cancers.
It occurs as tumours produce inflammation and tissue injury causing release of procoagulants.
Some also produce and release mucin which is also a procoagulant.
What are oncogenes?
are abnormally activated versions of normal genes called proto-oncogenes. Only one allele of each proto-oncogene needs to be activated to favour neoplastic growth.
What does healing by “first intention” mean?
Healing by first intention - the healing that is seen in a clean wound opposed by sutures. The wound consists of a narrow space and there is limited epithelial and soft tissue destruction.
By what mechanisms can malignant tumours cause high serum calcium and which tumours can do this?
- Ectopic secretion of PTH-related protein in a paraneoplastic syndrome:
- Paraneoplastic syndrome = a disease or symptom that is the consequence of the presence of cancer in the body, but is not due to the local presence of cancer cells. These phenomena are mediated by humoral factors (by hormones or cytokines) excreted by tumour cells or by an immune response against a tumour.
- Seen in carcinomas of breast, lung (especially squamous cell bronchogenic carcinoma), kidney and ovary. • = humoral hypercalcaemia of malignancy.
- Destruction of bone tissue:
- Primary tumours of bone, e.g. multiple myeloma, leukaemia.
- Diffuse skeletal metastases, e.g. breast cancer.
Examples of some antiinflammatories
Aspirin / NSAIDs e.g. naproxen, meloxicam
Antihistamines
Corticosteroids
Leukotriene antagonists e.g. Montelukast
TNF alpha antagonists e.g. Infliximab
Complement system
- Inactive enzymatic proteins (e.g. C3a, C5a) made in liver, present in blood
- Activated by variety of mechanisms: proteolytic enzymes from necrotic cells, anitgen-antibody complexes in infection, gram -ve bacterial (classic and alternate pathways, respectively) and by products of kinin and fibrinolytic systems.
What is a scar?
Healing with the formation of fibrous connective tissue.
Are there any blood tests that might help in identifying sarcoidosis?
Serum calcium concentration and serum angiotensin converting enzyme (ACE) levels are both raised in sarcoidosis.
What does triple negative mean and what implications does this have for the treatment of the patient?
Triple negative cancers do not express oestrogen receptor (ER), progesterone receptor (PR) or Her2 receptors.
Therefore, these cancers do not respond to endocrine treatment or treatment with Herceptin (trastuzumab). However, they often show a better response to chemotherapy than some other breast cancers.
What does mitochondrial membrane damage result in?
i. Loss of the electron transport chain (inner mitochondrial membrane)
ii. Cytochrome C leaking into cytosol (activates apoptosis)
Why is DVT often asymptomatic?
Because collateral venous channels open up to aid circulation.
What is a blastoma
tumours arise from precursor cells and are composed of cells with immature characteristics seen in developing (embryonic) stages. Generally a tumour of infants /children. eg nephroblastoma, neuroblastoma, pulmonary blastoma, retinoblastoma
What is the cause of liquefactive necrosis?
degradation of tissue by enzymes
What types of giant cell do you know and when are they commonly seen?
Langhans type giant cells – seen in tuberculosis.
Touton giant cells – seen in lesions containing a lot of fat.
Foreign body giant cells – generated in response to the presence of a large foreign body
The illustration below comes from the patient’s liver biopsy. What is indicated by the arrow?
An apoptotic cell (also called Councilman bodies in the liver).
What process has occurred?
Why is the intestine this colour?
Explain why might this have happened?
What process has occurred?
Haemorrhagic (red) infarction.
Why is the intestine this colour ?
Because numerous vascular anastomoses are present within the small bowel. Occlusion of the main blood supply causes an infarct.
The collateral arterial supply is insufficient to rescue the tissue but does allow blood to enter the dead tissue creating a red infarct.
Explain why might this have happened?
Due to loss of blood supply which can be caused by:
- Embolism from an atrial or ventricular mural thrombus
- Thrombosis of a mesenteric artery secondary to atherosclerosis
- Intestinal adhesions wrapped around the bowel occluding the blood supply
- Volvulus with resulting occlusion of blood supply
Compare reversible and irreversible cell injuries
