Chapter 1 - Growth Adaptations, Cellular Injury, and Cell Death

Question 1

What is the mechanism of the increase size in the Left Ventricle?

Answer 1

Hypertrophy

Hyperplasia is not possible in permanent tissues, cardiac muscle, skeletal muscle, and nerves.

Question 2

What is the purpose of the Ubiquitine-Proteosome pathway?

Answer 2

Degradation of the cytoskeleton.

Important part of atrophy and the mechanism of cell size decrease.

Filaments are tagged by ubiquitine and removed by proteosomes.

Question 3

What is the mechanism of Hypertrophy?

Answer 3

Gene activation, protein synthesis and organelle production.

Question 4

What is the mechanism of Hyperplasia?

Answer 4

Generation from Stem cells.

Question 5

Which Pathologic Hyperplasia does not increase the risk for cancer?

Answer 5

Benign prostatic hyperplasia.

Question 6

What is the pathology pictured?

Answer 6

Barrett esophagus, the squamous cells of the esophagus undergoes metaplasia and becomes collumnar cells.

Question 7

Which pathologic metaplasia does not increase the risk of cancer?

Answer 7

Apocrine metaplasia of the breast.

Question 8

Which vitamin may be involved in Promyelocytic leukemia?

Answer 8

Vitamin A

15’ - 17’ translocation involves the retinoic acid receptor alpha which hinders the maturation of promyelocytes. It responds to ATRA (All-Trans Retinoic Acid) treatment.

Question 9

Which deficency causes the metaplasia pictured?

Answer 9

Vitamin A deficency

Vit A deficency leads to metaplasia of the conjunctive (squamous to stratified keratinizing). It is called Keratomalacia.

Question 10

Case: 16 year old male presents with a hard immobile mass in the right upper arm. Looking through his file you see that he had previously visited due to a bike accident three weeks previous where he had hurt his arm, but there had been no fracture on the x-rays. Worried that you may have missed something you order a new x-ray. What does it show?

Answer 10

Myositis ossificans

It is a form of mesenchymal metaplasia which is caused by imflamation of the muscle following trauma. It turns the muscle to bone.

Can be differantiated from osteosarcoma due to the normal viewing of the bone and the fact that the tumor is not connecte to the bone.

Question 11

How can you distinguish Myositis ossificans from osteosarcome in an x-ray?

Answer 11

• Normal bone
• Distinct separation between the tumour and the bone.

It is a form of mesenchymal metaplasia which is caused by imflamation of the muscle following trauma. It turns the muscle to bone.

Question 12

What is the two most common mechanisms of dysplasia?

Answer 12

- Longstanding pathologic hyperplasia

- Metaplasia

Question 13

What are the common causes of Cellular injury?

Answer 13

- Inflammation

- Nutritional deficency

- Nutritional excess

- Hypoxia

- Trauma

- Genetic mutations

Question 14

What are the common causes of Hypoxia?

Answer 14

- Ischemia

- Hypoxemia

- Decreased O₂-carrying capacity

Question 15

What is Ischemia, and what causes it?

Answer 15

Ischemia is decreased blood flow through an organ. Has three common causes:

• Decreased arterial perfusion (atherosclerosis)
• Decreased venous drainage (e.g., Budd-Chiari, teticular hemorraghic infarction)
• Shock (generalised hypotension)

Question 16

Case: 22 year old patient presents with intense abdominal pain in the upper right quadrant. The patient has severe nausea and is quite jaundice.

The patient history is mostly unremarkable except a previous diagnosis of polycytemia vera. What illness is the patient presenting with?

Answer 16

Budd-Chiari syndrom

Embolous of the hepatic vein, causes infarction of the liver and may be fatal. Commonly caused by polycytemia vera (increased red bloodcells -> increased blood viscosity) or Lupus anticoagulant (causes hypercoagulant state)

Question 17

What is Budd-Chiari Syndrome?

Answer 17

Embolous of the hepatic vein, causes infarction of the liver and may be fatal. Commonly caused by polycytemia vera (increased red bloodcells -> increased blood viscosity) or Lupus anticoagulant (causes hypercoagulant state)

Question 18

What is the mechanism behind testicular hemorraghic infarction?

Answer 18

The testicular cord consists of a among others a thick walled artery and a thin walled vein. During testicular torsion the artery remains open but clamps off the vein. This leads to hypoxia through decreased venous drainage.

Question 19

What are the 5 types of shock?

Answer 19

- Anaphylactic

- Cardiogenic

- Hypovolemic

- Neurogenic

- Septic

Question 20

What is Hypoxemia?

Answer 20

It is low partial preassure of oxygen in the blood (P_aO₂)

Question 21

What causes hypoxemia?

Answer 21

FiO₂ → P_AO₂ → P_aO₂ → S_aO₂

Decreased FiO₂: High altitude

Decreased P_AO₂: Increased P_ACO₂ (hypoventilation, COPD)

Decreased P_aO₂: Diffusion defect (interstitial pulmonary fibrosis)

Question 22

What causes low O₂-carrying capacity of the blood?

Answer 22

• Anemia (P_aO₂ normal, S_aO₂ normal)
• Carbon monoxide poisioning (P_aO₂ normal, S_aO₂ low)
• Methemoglobinemia (P_aO₂ normal, S_aO₂ low)

Question 23

Case: You are called out to a house fire together with the paramedics. There is only one person in the building, an elderly lady who had been found sleeping in her bedroom. The firedepartment had been alerted to the fire by a neighbour. The fire had not yet reached the bedroom of the house when the firefighters broke through the window. The woman is upset and shaken, but says she feel fine except for a light headache. You decide to take her to the hospital. What treatment should you give?

Answer 23

If possible the patient should be put in a hyperbaric chamber to combat the carbonmonoxide poisioning she might have developed due to smoke inhalation, while sleeping in a confined room (closed window). Headache is an early sign. It also causes dizziness, confusion, and redness of the skin. If a hyperbaric chamber is not availible she should be put on oxygen therapy.

Question 24

What are the characteristic symptoms of carbonmonoxide posioning?

Answer 24

Cherry-red apparanca of the skin, this is caused by the tightly bound hemoglobin. It is paradoxical though because the patient is hypoxic.

OBS! Early sign is headache!

Question 25

What are the characteristic symptoms of Methemoglobinemia?

Answer 25

Cyanosis with Chocolate coloured blood

Question 26

What is the treatment for Methemoglobinemia?

Answer 26

Methylane blue it turns the Fe³⁺ back to Fe²⁺

Question 27

How does Hypoxia cause cellular injury?

Answer 27

Disruption of the electron transport chain leads to decreased ATP, which affects:

• Na⁺-K⁺ pump → cellular swelling
• Ca²⁺ pump → Increased Ca²⁺ → enzyme activation
• Aerobic glycosylation → Increased lactic acid → decreased pH → presipitation of proteins and DNA

Question 28

What are the findings of reversible injury?

Answer 28

Swelling

• Cytosol swelling → loss of microvilli and cellular blebbing
• RER swelling → Dissociation of ribosomes → decreased protein synthesis

Question 29

What are the findings of irreversible injury?

Answer 29

Membrane damage

• Plasma membrane damage → enzyme leakage (troponines), and Ca²⁺ influx.
• Mitochondrial membrane damage → Loss of electron transport chain and cytochrome C leakage causing apoptosis
• Lysosome membrane damage → Intracellular enzyme leakage causing intracellular damage (effect increased by increased intracellular Ca²⁺)

Question 30

What is the morphological hallmark of cell death?

Answer 30

Loss of nucleus

Question 31

What is the mechanism of nucleus loss?

Answer 31

- Pyknosis: nuclear condensation

- Karyorrhexis: fragmentation

- Karyolysis: dissolution

Question 32

What are the characteristics of Necrosis?

Answer 32

• Many cells
• Followed by acute inflammation
• Always pathological

Question 33

What are the two causes of inflammation?

Answer 33

- Infection

- Necrosis

Question 34

Which 6 types of necrosis are there?

Answer 34

- Coaglative: Ischemic infarction, pale wedge shaped.

- Liquefactive: Enzymatic lysis

- Gangrenous: Mumifiation, dry or wet

- Caseous: Cottage cheese, granulomatous inflammation

- Fat: Chalky white, saponification

- Fibrinoid: Blood vessels

Question 35

What is characteristic for the type of necrosis pictured?

Answer 35

Coagulative necrosis

Characteristic: Ischemic infarction of almost all organs. Often wedge shaped (due to branching vessels) and pale.

Question 36

What is characteristic for the type of necrosis pictured?

Answer 36

Liquefactive necrosis

Enzymatic lysis of cells. Characteristic for brain infarction (proteolytic enzymes from the microglial cells), abcesses (proteolytic enzymes from neutrophils), and Pancreatitis (pancreatic enzymes digests itself. The surrounding fat undergoes fat necrosis)

Question 37

What is characteristic for the type of necrosis pictured?

Answer 37

Gangrenous necrosis

Resembles mumified tissue. Affects lower limb and GI tract. May be dry or wet. Wet is with a superimposed infection on top.

Question 38

What is characteristic for the type of necrosis pictured?

Answer 38

Fat necrosis

Chalky white apparance due to calcium deposition. Characteristic of trauma (breast) and pancreatitis (surrpunding tissue)

Saponification (dystrophic calcification of dead or dying tissue) Normal serum calcium and phosphate levels.

Metastatic calcification (not necesarrily cancer) deposition due to High serum calcium and phosphate levels.

Question 39

What is characteristic for the type of necrosis pictured?

Answer 39

Caseous necrosis

Granulomatous inflammation resembles “chunky” liquefactive necrosis. Associated with fungal infections and tubercolosis.

Question 40

What is characteristic for the type of necrosis pictured?

Answer 40

Fibrinoid necrosis

Necrosis of blood vessels, causes protein leakage into the vessel wall showing as bright pink on Histology.

Caused by Malignant hypertension, vasculitis, and Pre-eclampsia.

Question 41

What is the mechanism behind a red infarction?

Answer 41

Blood reenters loose infarcted tissue. (e.g., testicular hemorraghic infarction)

Question 42

What are the characteristics of apoptosis?

Answer 42

- Few cells

• Genetically programed
• ATP dependent

Question 43

Which are the three pathways of apoptosis activation?

Answer 43

Intrinsic: DNA damage → inactivation of Bcl2 → destabilization of mitochondria → release of cytochrome C → Caspase activation.

Extrinsic: FAS ligand binds to CD95 (Death receptor) → Caspase activation. OR TNF binds TNF receptor → Caspase activation.

Cytotoxic (CD8⁺ T-cell mediated): Perforins create pores in the virally infected cell → Granzymes enters pores → Caspase activation

Question 44

What is the pathway of free radicals production?

Answer 44

Question 45

What causes pathological production of free radicals?

Answer 45

- Ionizing radiation - ^.OH

- Inflammation - O₂^-.

- Metals - ^.OH

- Drugs and chemicals

Question 46

What causes free radical damage?

Answer 46

- Peroxidation of lipids

- Oxidation of DNA

Question 47

Which protective measures against free radicals does the body use?

Answer 47

- Antioxidants (glutathione, and vitamins A, C, and E)

- Metal carrier proteins (e.g., transferrin) hinders metal in reacting in the Fenton reaction.

**- Enzymes**:
Superoxide dismutase (mitochondria) O<sub>2</sub><sup>-.</sup> → H<sub>2</sub>O<sub>2</sub>

Glutathione peroxidase (mitochondria) GSH + free radical → GSSH + H₂O

Catalase (peroxisomes) H₂O₂ → O₂ + H₂O

Question 48

Case: 50 year old male presents with malaise, abdominal distention and pain, and a slight jaundice to the eyes and skin.

When taking a medical history he reports that his son is also similarily affected. He suffers from hypertension, is a smoker (1 pack a day) and drinks moderatly. He owns a family run dry cleaning store, and has recently started remodeling his home.

Tests shows hypocoagulability and fatty streaks on the liver. What is the cause of his symptoms?

Answer 48

Answer: Free radical injury caused by CCL₄ exposure. CCL₄ is used in the dry cleaning industry.

CCL₄ is converted to CCL₃ by the p450 system of the liver. It results in cell injury with cellular swelling. Swelling of the RER reduces protein production leading to hypocoagubility, but most notably decreased apolipoproteins which leads to fatty change.

Question 49

Why does the cardiac enzymes keep rising after the occlusion, which caused an ischemic episode, is removed?

Answer 49

Reperfusion injury

when blood flow is reestablished it brings with it oxygen and inflammatory cells which together produces free radicals. This increases the area of injury.

Question 50

What is an amyloid?

Answer 50

A misfolded ß-plated sheet protein which is deposited in the extracellular space and damages the tissue. It often deposits around blood vessels and is stained congo red on histological staining. Turns characteristically apple green under polarised light.

Question 51

Which amyloid is connected with primary systemic amyloidosis? What type of illness is associated with it?

Answer 51

AL amyloid (immunoglobulin light chain)

Plasma cell dyscrasias (e.g., multiple myeloma)

Question 52

Which amyloid is connected with secondary systemic amyloidosis? What type of illness is associated with it?

Answer 52

AA amyloid (serum amyloid associated protein)

Acute phase reactant: Chronic inflammatory states (e.g., Rheumatoid arthritis, Lupus, Ulcerative collitis, Chron’s, Osteomyilitis), malignancy, Familial medeterrainian fever.

Question 53

Case: 33 year old female originally from Spain presents with severe chest pain, feet swelling, fever and proteinuria.

The EKG shows an arrythmia, but cardiac markers are negative. She has an enlarged liver and spleen and her kidney tests indicate damage. You perform a tissue biopsy. Which type of staining should you apply?

Your test confirms your suspision. How should you treat the patient?

Answer 53

Congo red

The patient has famillial medetarainian fever (rare!) a form of secondary amyloidosis. It causes fever and serosal inflammation (pericardium, appendix, etc.) it might threrefore mimic a MI, appendicitis, arthritis etc.

The amyloid affected tissues can not be treated, and must be transplanted.

Question 54

What are the clinical findings of amyloidosis?

Answer 54

- Neprhotic syndrome

- Restrictive cardiomyopathy or arrythmia

- Tounge enlargment, malabsorption, and hepatosplenomegally

Question 55

Match the disease and the amyloid:

Disease: Alzheimers disease, Dialysis associated amyloidosis, Familial amyloid cardiomyopathy, Medullary carcinoma of the thyroid, Non-insulin dependent diabetes mellitus, Senile cardiac amyloidosis.

Amyloid: Aß amyloid, Amylin, ß2-microglobulin, Calcitonin, Mutated serum transthyretin, Non-mutated serum transthyretin

Answer 55

Disease - Amyloid

AD - Aß amyloid

DAA - ß2-microglobulin

FAD - MST

MCotT - Calcitonin

NIDDM - Amylin

SCA - NMST