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Personal ESA 2 Mechanisms of Disease > Session 2 > Flashcards

Session 2 Flashcards

0
Q

What effects does Calcium have?

A

Can cause local inflammation

May have general toxic effects on body

May appear in high concentrations in blood and aid in diagnosis

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1
Q

What are the molecules released by Injured and Dying Cells?

A

Calcium

Potassium

Enzymes

Myoglobin

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2
Q

What effect does Potassium have?

A

Very toxic to the heart

Some injuries can cause damage to heart by high blood [K+] such as heart injury (infarct), mass necrosis elsewhere in the body, tumour lysis syndrome after chemotherapy and tourniquet shock

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3
Q

Why is measuring enzymes useful?

A

Can help with the timing and evolution of tissue damage

Enzymes with lowest molecular weight are released first

Particularly applies to heart and liver; measurement of enzymes can be used to follow progress and find location (on organ) of damage

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4
Q

What effect does release of myoglobin have?

A

Myoglobin is abundant in striated muscle and myocardium

When released, it can block up renal tubules causing renal failure.

A classic sign is very dark brown urine

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5
Q

Give examples of Apoptosis

A

Can be a normal physiological process occurring when cells which are no longer needed are removed to remain a steady state, during hormone controlled involution (shrinkage of an organ due to old age or when inactive e.g. Of the womb after childbirth) and in cytotoxic T cell killing of virus-infected or neoplastic cells (tumours)

Also seen in embryogenesis - helps sculpt the body during development

Also occurs when a cell is damaged beyond repair (particularly its DNA)

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6
Q

Describe Apoptosis

A

Active process that requires energy

Membrane integrity is maintained - no leakage of cell contents and therefore apoptosis does not induce inflammation

No lysosomal enzymes involved

Very quick

Affects single cells or small clusters of cells

3 Key Phases: Initiation, Execution and Degradation/Phagocytosis

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7
Q

What does apoptosis look like under light microscopy?

A

Cells are shrunken and appear intensely eosinophilic (pink)

Chromatin condensation

Pyknosis

Nuclear fragmentations

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8
Q

What does apoptosis look like under electron microscopy?

A

Cytoplasmic blebbing which progresses to fragmentation into membrane-bound apoptotic bodies which contain cytoplasm, organelles and often nuclear fragments.

Apoptotic bodies eventually removed by macrophage phagocytosis.

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9
Q

Describe the Initiation and Execution Phases of Apoptosis

A

Triggered by two key mechanisms intrinsic and extrinsic which both culminate in the activation of caspases.

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10
Q

What is the intrinsic mechanism?

A

Aka mitochondrial

All the apoptotic machinery is within the cell and the mitochondrion is a key player.

There are various triggers for intrinsic apoptosis (e.g. DNA damage or the withdrawal of growth factors or hormones)

p53 is important

The triggers lead to increased mitochondrial permeability resulting in the release of Cytochrome C from mitochondria. This interacts with APAF1 and caspase 9 to form an apoptosome that activates various downstream caspases

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11
Q

What is the extrinsic mechanism?

A

Aka receptor-mediated apoptosis

Caused by external ligands such as TRAIL or Fas which bind to death receptors.

This leads to caspase activation independently of mitochondria

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12
Q

What are Caspases?

A

Proteases that mediate the cellular effects of apoptosis.

They act by cleaving proteins, breaking up the cytoskeleton and initiating the degradation of DNA.

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13
Q

Describe the Degradation/Phagocytosis Phase of Apoptosis

A

Cell breaks into membrane bound fragments called apoptotic bodies.

They express molecules on their surfaces that induce the phagocytosis of the apoptotic bodies by either neighbouring cells or phagocytes.

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14
Q

What are some important apoptotic molecules?

A

p54: mediates apoptosis in response to DNA damage

Cytochrome C, APAF1 and Caspase 9 together are apoptosomes

Bcl-2 prevents cytochrome C release from mitochondria therefore INHIBITING apoptosis

Death ligands e.g. TRAIL

Death receptors e.g. TRAIL-R

Caspases: effector molecules of apoptosis e.g. Caspase 3

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15
Q

Why can abnormal cellular accumulations occur and what can they consist of?

A

Metabolic processes can become deranged and often occur with sub lethal or chronic injury. If a cell can’t metabolise something it will remain in the cell. They can consist of:

Normal cellular constitutents e,g. Water and electrolytes, lipids, proteins, carbohydrates

Abnormal substances either exogenous such as minerals or endogenous such as the products of normal metabolism.

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16
Q

How can fluid accumulate?

A

Via oncosis - vacuoles or hydropic swelling due to osmotic disturbance of the cell e.g. Reduced blood supply

Can be a problem to the organ or the whole body e.g. A swollen brain could compress brain stem leading to restricted blood flow to the brain.

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17
Q

Explain about Lipid Accumulation

A

Steatosis (fatty change) is the accumulation of TAGs.

Often seen in the liver.

Common causes: alcohol abuse, diabetes mellitus, obesity and toxins such as carbon tetracholoride.

Mild steatosis doesn’t appear to have any effect on cell function

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18
Q

Describe Cholesterol Accumulation

A

Accumulates within smooth muscle cells and macrophages within atherosclerotic plaques.

Stored as membrane-bound droplets and are insoluble, can’t be broken down.

Microscopically these cells seem to have foamy cytoplasm hence they are called foam cells

Cholesterol is also seen in macrophages within the skin and tendons of people with acquired and hereditary hyperlipidaemias.

The macrophages form small masses called xanthomas

19
Q

Describe Protein accumulation

A

Seen as eosinophilic droplets or aggregates in the cytoplasm

Mallory’s hyaline is a damaged protein which is seen in hepatocytes in alcoholic liver disease and is due to accumulation of altered keratin filaments

20
Q

What happens in alpha1-anti trypsin deficiency?

A

In alpha-1 antitrypsin deficiency (genetic), liver produces a misfolded alpha-1antitrypsin which cannot be packaged by the ER and accumulates within the ER and is not secreted by the liver.

The systemic deficiency means proteases within the lungs can act unchecked and patients with the condition can develop emphysema (air sacs of the lungs are damaged and enlarged causing breathlessness) as lung tissue is broken down

21
Q

Describe the effect of pigment accumulation

A

Can be normal cellular constituents e.g. Melanin

Or exogenous e.g. Carbon/coal dust (urban air pollutant).

Once inhaled, macrophages phagocytose it within lung tissue (blackened lung tissue - anthracosis) or it can be seen as blackened peri bronchial lymph nodes (which are filters so pigments accumulate in them) which contain macrophages which have migrated from the lungs. The black discolouration is irreversible.

22
Q

What could happen in coal miners (particular high exposure to urban air pollutants)?

A

The lungs can become fibrotic or emphysematous. This is known as coal worker’s pneumoconiosis

23
Q

What happens to the pigments in a skin tattoo?

A

Exogenous pigments are phagocytosed by macrophages within the dermis and remain there indefinitely

24
Q

Explain about Lipofuscin

A

Yellow brown endogenous pigment seen in ageing cells which doesn’t cause any injury to the cell.

It is a sign of previous free radical injury and lipid peroxidation

Rare in cells with a high turnover rate e.g. Endothelial cells

25
Q

Explain about Haemosiderin (endogenous pigment)

A

Derived from haemoglobin, yellow-brown, contains iron

Forms when there is a systemic or local excess or iron e.g. In the skin and subcutaneous tissues as a bruise.

If there is a systemic overload of iron, Haemosiderin is deposited in many organs. This is called haemosiderosis. Seen in conditions such as haemolytic anaemias, blood transfusions and hereditary Haemochromatosis

When haemosiderosis is severe, liver, heart and pancreas damage can occur - endocrine dysfunction

26
Q

Explain about Hereditary Haemochromatosis

A

Genetically inherited disorder which results in increased intestinal absorption of dietary iron.

Treatment - bleed regularly

27
Q

Explain about Bilirubin

A

Endogenous pigment

Bile pigment eliminated from the body within bile

Deposited in tissues causing jaundice when in excess e.g. In haemolytic anaemia or in abnormal liver function

28
Q

How can carbohydrate accumulation occur?

A

Deficiency of critical enzymes causes carbohydrate metabolism dysfunction and hence accumulations of carbohydrates

29
Q

What is Pathological Calcification?

A

The abnormal deposition of calcium salts within tissues

Can be either Dystrophic or Metastatic

30
Q

Explain about Dystrophic Calcification

A

Local

Occurs in an area of dying tissue, in atherosclerotic plaques, in ageing or damaged heart valves and in tuberculous lymph nodes

No abnormality in calcium metabolism or serum calcium concentration

Can cause organ dysfunction e,g, in atherosclerosis or calcified heart valves

May be asymptomatic

Aortic valves can calcify but pulmonary valves never calcify

More common than metastatic

31
Q

Explain about Metastatic Calcification

A

General, body-wide

Deposited in normal tissues when there is hypercalcaemia secondary to disturbances in calcium metabolism.

Usually asymptomatic

32
Q

What are the causes of metastatic calcification?

A

Increased secretion of PTH resulting in bone resorption. This may be due to parathyroid tumours of ectopic secretion of PTH related protein (PTHrP) by malignant tumours

Destruction of bone secondary to primary tumours of bone e.g. Leukaemia metastasis to bone, Paget’s disease or immobilisation

Vitamin D related disorders

Renal failure

33
Q

What happens in Paget’s Disease?

A

The normal cycle of bone renewal and repair is disrupted - bone is replaced at a faster rate than usual. Bones become weakened and deformed - the bones are enlarged but weak and brittle.

Both genetic and environmental factors (possible viral triggers) involved.

34
Q

Explain about Cellular Ageing?

A

As cells game they accumulate damage to cellular constituents and DNA.

May also accumulate Lipofuscin pigment and misfolded proteins

Decline in their ability to replicate - after a certain number of divisions, cells reach REPLICATIVE SENESCENCE.

35
Q

What is Replicative Senescence

A

Thought to be related to the length of chromosomes

Telomeres (ends of chromosomes) are shortened with each replication When the telomeres reach a critical lengt, the cell can no longer divide.

Germ cells and stem cells contain enzyme telomerase which maintains the original length of the telomeres so they can continue to replicate.

Many cancer cells produce telomerase and so have the ability to replicate multiple times.

36
Q

What can Chronic Excessive Alcohol Intake result in?

A

Psychological and physical dependence on alcohol.

Metabolic tolerance to alcohol can occur due to induction of CYP2E1.

CYP2E1 increases the rate of metabolism of ethanol and also increases the rate of metabolism of other drugs that are metabolised by this enzyme

37
Q

Explain the mechanism of alcohol metabolism

A

Ethanol is metabolised by alcohol dehydrogenase, cytochrome p450 enzyme CYP2E1 and catalase to acetaldehyde

Acetaldehyde is metabolised by aldehyde dehydrogenase to acetic acid

Women have lower concentration of alcohol dehydrogenase so they have a higher blood alcohol concentration then men who have drunk the same.

~50% of oriental people have reduced activity of aldehyde dehydrogenase which results in a build of acetaldehyde when they drink alcohol. Resulting symptoms include facial flushing.

38
Q

What 3 major effects on the liver does excessive alcohol intake have?

A

Fatty change: steatosis which can be so marked as to cause Hepatomegaly. This happens acutely, is reversible and generally asymptomatic.

Acute alcoholic hepatitis- as alcohol and its metabolites are directly toxic, can result in inflammation of the liver with focal hepatocyte necrosis, the formation of Mallory bodies (Mallory’s hyaline) and a neutrophilic infiltrate. Symptoms: fever, liver tenderness and jaundice. Usually irreversible

Cirrhosis occurs in 10-15% of alcoholics. Hard shrunken liver and histologically appears as micro nodules of regenerating hepatocytes surrounded by bands of collagen. Reversible and serious, sometimes fatal.

39
Q

How is Paracetamol normally metabolised and how is an overdose metabolised?

A

Usually detoxified in the liver by sulphonation and glucuronidation

Small amounts are metabolised by cytochrome p450 oxidation (CYP2E1) to a highly toxic metabolite NAPQI

NAPQI detoxified by conjugation with glutathione

If a large dose is ingested, glutathione is depleted and NAPQI accumulates

40
Q

How is NAPQI toxic to the liver?

A

Binds with sulphydryl groups on liver cell membranes, eventually causing hepatocyte necrosis and liver failure

With a large paracetamol overdose, massive liver necrosis occurs after 3-5 days - can be fatal

41
Q

What groups of people have lower reserves of glutathione?

A

Those who took alcohol with the paracetamol overdose

Alcohol dependent

Malnourished

People on enzyme inducing drugs e,g, carbamazepine

People who are HIV positive or who have AIDs

42
Q

What is NAC?

A

N-acetylcysteine

Antidote

Increases availability of hepatic glutathione

To decide whether NAC is required, measure the serum concentration of paracetamol from 4 hours after overdose.

The prothrombin time (or the INR) measured 24 hours after the overdose is a guide to the severity of the liver damage in these patients.

43
Q

What does aspirin do?

A

Aspirin acetylates platelet cyclooxygenase and blocks platelets’ ability to make thromboxane A2, which is a substance that activates platelet aggregation.

44
Q

What are the major consequences of Aspirin Overdose?

A

Aspirin stimulates the respiratory centre which results in respiratory alkalosis (hyperventilation elevates the blood pH). Compensatory mechanisms result in metabolic acidosis. A fall in serum pH indicates serious poisoning.

Aspirin overdose also interferes with carbohydrate, fat and protein metabolism and oxidative phosphorylation –> increase in lactate, pyruvate and ketone bodies all of which contribute to acidosis.

As platelet cyclooxygenase is inhibited there is decreased platelet aggregation and petechiae may be present.

Acute erosive gastritis producing GI bleeding (affects mucus production - mucus protects GI lining)

45
Q

What is petechiae?

A

Pinpoint round spots that appear on the skin as a result of bleeding under the skin

46
Q

Compare structural changes in oncosis/necrosis and apoptosis

A

Personal ESA 2 Mechanisms of Disease (11 decks)

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