Lecture 1 – Pathology Introduction Mon. 08/16/10 Myocardial Infarction at 1 hour; H&E slide is “normal”
• “Clot-busters” or angioplasty can prevent infarction of the ventricular muscle
Myocardial Infarction – first 72 hours
• Coagulation necrosis of heart muscle and arrhythmias are generated • Coronary Care Unit- monitor and prevent and/or treat arrhythmias
Test q: When is a patient who has suffered an acute MI at greatest risk for fatal arrhythmias? Days 1-3. Test q: When is a MI patient at greatest risk for fatal arrhythmias? Days 1-3.
Test q: A patient suffers an MI and dies 30hr later in the coronary care unit. At autopsy, the infarcted area of the myocardium would most likely show: Coagulation necrosis w/neutrophil infiltration.
Test q: A 76y/o woman suffers a massive MI and dies in cardiogenic shock 20hr after its onset. Microscopic exam of her infarcted myocardium would
be expected to demonstrate which of the following? Coagulative necrosis w/few neutrophils.
Test q: A 76y/o man presents to the ER w/progressive substernal chest pain over the past 4 hr. He is short of breath and reports pain in his left jaw and
shoulder area. An initial ECG demonstrates ST elevation changes and a baseline troponin I level of 2.8ng/mL. Which of the following complications are you most concerned about occurring in this patient within the next 24hr? Ventricular arrhythmia.
Myocardial Infarction at 7 days: macrophages and fibroblasts on the H&E slide
• 1. Myocardium is destroyed • 2. Scar formation is incomplete
• 3. Aneurisms develop or ventricular wall may rupture • 4. Patient must avoid strenuous exercise and heavy lifting
Test q: A 49y/o male suffers an acute MI. He is treated w/angioplasty. Serum troponin I becomes elevated, but his recovery is otherwise uneventful.
He is discharged 5 days after onset of chest pain. At day 9 post-MI, what would be the appearance of the infarcted area of the myocardium?
Neutrophils, macrophages, and fibroblasts.
Test q: A patient is found dead at home. The patient has a history of angina. At autopsy the CK-MB was normal and the cardiac Troponin I was
elevated. The heart shows an area of coagulative necrosis with mixed inflammatory cells and evidence of new capillary growth and increased fibroblastic activity. The age of the infarct is approximately: 5 days – 1 week old. (Question was repeated with this answer: 3 days – 1 week old)
Test q: (slightly diff from one above) A patient is found dead at home. Patient has a history of angina. At autopsy, the CK-MB was normal and the
cardiac troponin I was elevated. The heart shows an area of coagulative necrosis with monocytes and evidence of new capillary growth and increased fibroblastic activity. The age of the infarct is approximately: 6-10 days old.
GROSS OBSERVATIONS
• Size • Consistency/texture • Color
• Shape • Location
SIZE
• Increased- HYPERTROPHY (increased cell size – e.g. muscle) or HYPERPLASIA (increased cell # - e.g. glands) • Decreased- ATROPHY (once normal, now smaller) or HYPOPLASIA (never normal in size)
• Accumulations of material may also increase the overall size of the organ; example: AMYLOIDOSIS
Test q: A 45 y/o woman is investigated for hypertension and is found to have a small right kidney. Contrast studies reveal stenosis of the right renal
artery. The size change in the right kidney is an example of which of the following adaptive changes? Atrophy.
Test q: A 45y/o man is evaluated for hypertension. Arteriography shows marked stenosis of the left renal artery. Unfortunately, he has an acute MI and
dies shortly after the procedure. At autopsy, the left kidney weighs only 30g and has a smooth capsule. The right kidney weighs 120g (normal is 150) with a pitted surface. The left kidney is best described as: Atrophic.
Test q: A 50y/o female w/a history of hypertension develops acute chest pain, arrest and cannot be resuscitated. At autopsy the free wall of the left
ventricle is noted to be 4.0cm in thickness. The best description of this change is: Hypertrophy. QUESTION REPEATED TWICE.
Test q: On a routine visit to the physician, an otherwise healthy 51y/o man has a BP of 150/95mmHg. If the patient’s hypertension remains untreated
for years, which of the following cellular alterations will most likely be seen in the myocardium? Hypertrophy.
Test q: A 60y/o male has been treated for hypertension for over 20 years. He has become increasingly short of breath over the past 2 years. An EKG
is normal. The left ventricle would most likely show: Hypertrophy.
Test q: A 60y/o male dies after a massive MI. He was known to be hypertensive. At autopsy the left renal artery is completely stenosed. The right
kidney is almost normal in size but shows many surface pits and scars, and on cut section shows very little cortex remaining. The left kidney would most likely show: Atrophy.
Test q: Following injury, which of the following restores functional capacity by hypertrophy? Cardiac muscle.
Hypertrophy of LV,
AMYLOIDOSIS causes heart and renal failure
• Pink, fluffy extracellular (protein) material in tissue stained with H&E
• Congo Red Stain- orange on light microscopy and Apple-green birefringence when polarized • Beta-Pleated Sheet by x-ray diffraction or EM
Test q: What is a diagnostic test for amyloid? Congo Red w/polarization
Test q: A 62y/o man dies following a 6-yr history of progressively worsening heart failure. At autopsy, the heart is found to have extensive infiltration of
the myocardium by an acellular, eosinophilic material. This extracellular material most likely represents: Amyloid.
Examples of Amyloid:
Disease Type of Amyloid
• Multiple myeloma Lambda or kappa (^ malignancy of plasma cells)
• Dialysis patients B-2 microglobulin
• Inflammation SAA
• Medullary CA Procalcitonin
(^ thyroid cancer – makes huge amounts of procalcitonin)
Lardaceous spleen: greasy appearance. Liver w/amyloid. Most hepatocytes replaced by this abnormal protein.
Test q: A 52y/o female on hemodialysis develops left heart failure and elevated
liver transaminases. A biopsy of liver shows acellular pink deposits which stain positively w/Congo red. The deposits contain: β-2 macroglobulin. (typo? should be microglobulin?) Normal (right) and hyperplastic (left) adrenal glands. Could be caused by pituitary tumor.
Normal (left) and atrophic (right) kidneys. The normal kidney has a smooth, capsular surface. The atrophic kidney has a rough, pitted surface due to destruction of glomeruli and scars pulling inward.
Amyloid – here, is procalcitonin.
SHAPE
• Shape of lesions may indicate the pathologic process
• Infarcts (tissue death, secondary to a thrombus) are wedge-shaped; arterial blood vessels distribute in an inverted “tree-like” fashion
Spleen Infarction COLOR
• Organs may acquire color or lose their natural color
• When liver accumulates FAT (as in alcoholism) it becomes enlarged and pale to
yellow-orange in color
• Also, when a SCAR forms in the myocardium of the heart (post MI), the color changes from red/tan to gray/white
LIVER COLORS (Gross)
• FAT Yellow/orange
• IRON Red (brick red)
• BILE Green
• MELANIN Black/brown
HEMOCHROMATOSIS
• 1. Genetic
• 2. Secondary (as opposed to genetic/primary)
A. Iron overload due to transfusions for anemias B. Increased oral intake (rare)
Above: can see brownish/red granules (iron).
Below: bile stains green
in liver. Caused by obstruction of bile ducts. Gross – green.
Microscopic – brown.
Above: nodules of malignant melanoma (black/brown).
thrombus started here, everything distal = infarct.
Infarct along IV septum. Takes weeks to develop this kind of scar. Remote infarct here, not acute infarct.
Below: too much iron.
Example of color change in melanoma (brown/black).
CONSISTENCY
•Organs become stiff, hard, soft, waxy or greasy in disease
•Alcoholism and hepatitis cause extensive fibrosis (cirrhosis/scar tissue) in the liver and the liver is pale, shrunken and firm with round NODULES (firm, circumscribed areas)
Cirrhosis/fibrosis of liver – scar tissue. Icteric sclera. Ascites. Esophageal varices.
LOCATION
•Some pathologic processes occur in specific locations (organ specific, tissue specific)
•For example, FAT NECROSIS occurs in the pancreas (enzymic fat necrosis) and breast (traumatic fat necrosis) •Also, tumors in the cortex of the kidney are usually glandular in origin (adenocarcinoma)
Above: Fat necrosis in pancreas.
Above: Tumor growing out of kidney cortex. Above: cysts – fluid-filled sacs. Almost always is renal cell carcinoma.
• CYST- fluid-filled sac; Ovary or Kidney cysts are “OK” • BULLA- fluid-filled sac in the lung or skin
• Uterus- LEIOMYOMAS in the myometrium;
ADENOCARCINOMAS in the endometrium
• METASTASES- multiple nodules of tumor
Leiomyoma in the uterus.
If in cervix, would be Liver metastases squamous cell carcinoma.
Test q: A 35y/o male alcoholic develops portal hypertension and esophageal varices.
You would expect the histopathology to show: hepatocytes surrounded by scar.
Test q: A 30y/o alcoholic male presents to the ER w/acute abdominal pain and vomiting
w/dehydration. Serum lipase is elevated. Phys exam shows esophageal varices. His EKG is normal.
-H&E stained slides of a liver biopsy would show: fibrosis and fatty change. -H&E stained slides of a pancreas biopsy would show: fat necrosis.
Fluid in peritoneal cavity. Distinguish w/wave sign. Bullae. Fluid-filled sacs in the lung. Spaces in lung but no capillaries for gas exchange.
TYPES OF NECROSIS
•COAGULATIVE Infarcts
•LIQUIFACTIVE Abscess
•CASEATION TB Granuloma
•FAT (ENZYMIC) Pancreas and breast
^ release lipase (pancreas), destroy tissue.
Old MI
Living heart
MI and acute
inflammation
(weeks, months old)
Abscess (pus pocket)
Brain abscess
Caseous
necrosis in TB
granuloma
(cottage cheese
appearance)
Granuloma w/central necrosis
Enzymic fat necrosis
Fat necrosis
of pancreas – tissue
totally destroyed but
no neutrophils
Lecture 2 – Adaptation, Injury, and Death of Cells (Part 1) Tues. 08/17/10 Pathology: the Study of Disease
• Etiology or cause: infection, genetic etc. and often mutifactoral • Pathogenesis: progression of the disease from start to finish • (Molecular and Morphologic Changes)
• Clinical Manifestations: signs and symptoms
At least two ways for cells to die – necrosis and apoptosis. Another is autophagy (will discuss later).
If membrane or organelles rupture, or if the
nucleus is destroyed, these changes are irreversible. In necrosis, almost always have neutrophils cleaning up the mess.
Cell Proliferation Varies
• Labile cells – continuously dividing/mitosing (epithelium, bone marrow)
• Stable cells – quiescent but can reenter cell cycle (in G0 stage; hepatocytes, smooth muscle, lymphocytes) • Permanent cells – nondividing (neurons, skeletal and cardiac muscle)
Test q: A 50y/o woman tests positive for HepA antibody. The
serum AST level is 275 U/L and ALT is 310 U/L. One month later, these enzyme levels have returned to normal. Which phase of the cell cycle describes the hepatocytes one month after infection? G0.
Test q: Examples of stable of quiescent cells (G0) are: Hepatocytes and smooth muscle. QUESTION REPEATED
TWICE.
Test q: All of the following are labile cells EXCEPT: fibroblasts. (Other choices were: epidermal keratinocytes,
endometrial glandular cells, bone marrow stem cells, and gastric mucosal cells.)
Test q: A 25y/o med student embarks on a drinking binge
after block exams and is hospitalized for acute alcohol toxicity. The serum AST level is 275U/L, and ALT is 310 U/L. One month later, these enzyme levels have returned to normal. Which phase of the cell cycle best describes the hepatocytes 1 month after the drinking episode? G0.
CELLULAR ADAPTATIONS:
STIMULUS CELL RESPONSE
• Increased demand (ex: left ventricle) Hyperplasia, hypertrophy
• Decreased nutrients Atrophy
• Chronic irritation (cigarette smoke) Metaplasia – one adult cell replaces another
• Hypoxia- acute, limited Reversible changes
Cardiac muscle hypertrophy and infarction: Hypertrophy of left ventricle in hypertension. If MI causes myocardial muscle to become hypoxic, you will get necrosis.
Hypertrophy
• Increase in cell size with subsequent increase in organ size
• Hypertrophy can be physiologic or pathologic
Causes of hypertrophy:
1. Increased functional demand (body builders; HT) 2. Hormonal stimulation
Physiologic reasons for hypertrophy, ex: pregnant uterus. Smooth muscle in uterine wall hypertrophies.
Hyperplasia:
• Increase in the number of cells in an organ, which may then increase organ size. • Physiologic or Pathologic
PHYSIOLOGIC HYPERPLASIA
1. Hormonal hyperplasia- female breast at puberty and in pregnancy 2. Compensatory hyperplasia- liver regeneration after partial resection
Test q: A 16y/o boy sustained blunt trauma to the abdomen when the vehicle he was driving struck a bridge abutment at high speed. Peritoneal lavage
shows a hemoperitoneum, and at laprotomy, a small portion of the left lobe of the liver is removed because of the injury. Several weeks later, a CT scan of the abdomen shows that the liver has nearly regained the size it was prior to injury. Which of the following processes best explains this CT scan finding? Hyperplasia.
Female Breast Tissue after Puberty: Lactating Breast during Pregnancy:
A few breast ducts present, arranged in lobules. Physiologic hyperplasia – many more glands to make milk (due to hormonal stimulation)
Causes of Pathologic Hyperplasia:
1. Excess hormone- endometrial hyperplasia due to estrogens 2. Growth factors- Warts (HPV 6, 11)
Hyperplasia is NOT a neoplastic process (tumor/cancer), but it may be fertlie soil for malignancy.
Atypical Hyperplasia (increased cells that look abnormal) in the endometrium
carries an increased risk for development of endometrial adenocarcinoma.
Normal uterus: relatively flat glandular lining Hyperplasia: much thicker
Test q: Which of the features of fibrocystic change is most associated with predisposition to
development of adenocarcinoma? Atypical hyperplasia.
Test q: A 69y/o man has had difficulty w/urination for the past 5 years. A digital rectal exam reveals that
the prostate gland is palpably enlarged to about twice normal size. A transurethral resection of the prostate is performed, and the microscopic appearance of the prostate “chips” obtained is that of large glands lined by 2 cell layers and with intervening stroma. Which of the following pathologic processes has most likely occurred in the prostate? Hyperplasia.
Endometrial hyperplasia
Normal proliferative endometrium: Endometrial hyperplasia: Endometrial adenocarcinoma:
Many more glands; cells. Atypical hyperplasia in endometrium: great risk for developing cancer. See similar changes in breast, prostate.
Atrophy:
Decrease in the size of a cell or organ by loss of cell substance
Causes (many more than just these): 1. Decreased workload
2. Loss of innervation 3. Decreased blood supply 4. Inadequate nutrition
5. Loss of endocrine stimulation 6. Pressure
Figure: Central skeletal muscle bundle is atrophic
Patient who had damage to skeletal muscle. Normal bundles on top and bottom of figure; abnormal in the middle. In the
mechanical injury to this muscle, the innervation of this muscle
bundle was severed – undergoes atrophy. Very prominent after trauma.
Atrophic brain: Normal brain:
As you get older, the sulci get bigger and the gyri get smaller.
Protein degradation is important in atrophy
A. Lysosomes with hydrolytic enzymes - or - B. The ubiquitin-proteasome pathway
Hypoplasia
Incomplete development of an organ so that it fails to reach adult size; most common example: hypoplastic left ventricle
Organ was never normal in size.
Hypoplastic left heart syndrome: Only a remnant of the LV
(vestigial) is there. Must have surgery very early on, may need heart transplant.
Metaplasia
A reversible change in which one ADULT cell type is replaced by another ADULT cell type. Reversible if stimulus is removed.
Causes of Metaplasia
• (USUALLY columnar epithelium changes to squamous) • Chronic irritation (cigarette smoke)
• Calculi (stones) in ducts • Vitamin A deficiency
Test q: A 40y/o male has been smoking since college. Biopsy of a suspicious area of the right upper lobe found on chest x-ray shows a squamous
epithelium lining the bronchial tree. There is no cytologic atypia. These changes are consistent with: Metaplasia.
A 67y/o smoker has shortness of breath and a chronic cough. His pulmonary function tests are abnormal and a bronchial biopsy is taken. The finding of stratified squamous epithelial cells lining the bronchus is indicative of which of the following? Metaplasia.
Test q: An experiment is conducted in which cells in
tissue culture are submitted to high levels of UV radiant energy. EM shows cellular damage in the form of increased cytosolic aggregates of denatured proteins. In situ hybridization reveals that protein components in these aggregates are also found in proteasomes. Which of the following substances is most likely to bind to the denatured proteins, targeting them for catabolism by cytosolic proteasomes? Ubiquitin.
Cervix- squamous epithelium of the endocervix replaces columnar (dysplasia and squamous CA may develop). Same thing happens in lung
• Barrett esophagus- gastric reflux results in columnar epithelium (glandular) replacing squamous epithelium in the esophagus (dysplasia and adenocarcinoma may occur)
Test q: After several years of gastric reflux, a 30y/o male develops Barrett’s Esophagus (syndrome). Histologically, the distal esophageal mucosa
shows: Columnar epithelium.
Test q: Secondary to gastric reflux, the distal esophagus exhibits replacement of squamous epithelium by columnar epithelium. This change is termed Metaplasia.
Test q: A 32y/o has heartburn and gastric reflux. Endoscopy reveals columnar epithelial metaplasia w/goblet cells in the lower esophagus. This patient is at risk for: Adenocarcinoma.
Squamous cells replace columnar cells: Glandular metaplasia:
Adenocarcinoma of the esophagus:
Esophagus: glandular epithelium (R) is metaplastic
(HIGH risk of adenocarcinoma)
Dysplasia:
Atypical proliferative changes due to chronic irritation or inflammation;
Premalignant change: unless there is some intervention, cells that undergo this change will become malignant
Metaplasia vs. Dysplasia: In metaplasia – if you take away stimulus, it goes away. Dysplasia – molecular change. (ex: HPV becomes incorporated into the host genome – not reversible change)
Figure (dysplasia in the cervix): 1st pic (left) = normal squamous epithelium (originally was columnar but underwent metaplasia to become squamous). If squamous epithelium gets infected by HPV, it will undergo dysplastic change. Nuclei get bigger and darker. “Mild” picture – only goes up a little. “Moderate” – goes up 2/3 of the picture. In “marked dysplasia” picture, could also be called “carcinoma in situ” – it’s already malignant but hasn’t punched through the BM yet. If you have just the metaplasia, it’s reversible. Dysplasia, however, will go on to malignancy unless it’s treated.
Test q: A transbronchial biopsy of lung shows a squamous epithelium with
increased nucleus:cytoplasm ratio, increased mitoses, and an overall disordered maturation. The basement membrane is intact. The epithelial changes are best described as: Dysplasia.
Causes of cell injury:
• Oxygen deprivation • Physical agents
• Chemical agents and drugs • Infectious agents
• Immunologic reactions • Genetic derangements • Nutritional imbalances
Cellular Changes Secondary to Injury:
Reversible Irreversible
Cellular swelling Lysosomes rupture
Cell membrane blebs Dense bodies in mitochondria Detached ribosomes Cell membrane rupture
Chromatin clumping Karyolysis, karyorrhexis, pyknosis • Karyolysis = the complete dissolution of the chromatin
matter of a dying cell due to the activity of DNAase. • Karyorrhexis = the destructive fragmentation of the
nucleus of a dying cell whereby its chromatin is distributed irregularly throughout the cytoplasm.
• Pyknosis = the irreversible condensation of chromatin in the nucleus of a cell undergoing necrosis or apoptosis. Listed above: Microscopic changes. If membranes are ruptured or if nucleus is significantly damaged, it is irreversible.
Test q: A 50 yo farmer is exposed to a pesticide that exhibits potent hepatotoxicity. Which is a reversible change in the hepatocytes? Cellular swelling. (NOT plasma membrane rupture, mitochondrial permeability, nuclear karyorrhexis, calcium influx into mitochondria)
Test q: A 17y/o boy w/HepA experiences mild nausea for about 1 week and develops very mild scleral icterus. On physical exam, he has minimal right
upper quadrant tenderness. Lab findings include a serum AST of 168U/L, ALT 175U/L, and total bilirubin 5.1mg/dL. The increase in this patient’s serum enzyme levels most likely results from which of the following changes in the hepatocytes? Cell membrane rupture.
Test q: A 55y/o male present to the ER w/crushing chest pain and EKG consistent with acute MI. Both troponin I and CKMB are markedly elevated at
24hr post-admission. What is the cellular change responsible for the elevated serum values? Cell membrane rupture.
Ruptured membranes or marked destruction of the nucleus = irreversible change. Others pictured above are reversible.
NECROSIS vs APOPTOSIS
• Necrosis- death of GROUPS of cells after injury; usually with inflammation (neutrophils). Accidental death. • Apoptosis- genetically controlled, ATP and enzyme-dependent death of individual cells; usually no inflammation.
Programmed cell death – are genetically programmed to die at a certain time or secondary to a certain stimulus.
Figure: NECROSIS vs APOPTOSIS
Necrosis – cell swells. Cell membrane ruptures, nucleus
disintegrates, organelles rupture. Neutrophils present.
Apoptosis – shrinks (cell and nucleus). Cell membrane
remains intact, gets compartmentalized into smaller bodies w/membranes and intact organelles. Theoretically is a way for a cell to preserve material. Finally, macrophages engulf the small bodies. No neutrophils around.
Cell Injury Principles
1. The cellular response to injurious stimuli depends on the type of injury, its duration and its severity. 2. The consequences of cell injury depend on the type,
state, and adaptability of the injured cell.
Susceptibility of Cells to Ischemic Necrosis High: Neurons (3-4 min) Must start CPR immediately.
Test q: A 25 yo man is electrocuted in a thunderstorm. He is successfully
resuscitated after being unresponsive for 6 minutes. Cells most likely to die during this event are: neurons.
Test q: Which of the following tissue types are most susceptible to ischemic necrosis? Neurons.
Intermediate: Myocardium, hepatocytes, renal epithelium (30 min-2hr) – the reason you can do angioplasty or clot
busters and still preserve part of the myocardium
Low: Fibroblasts, epidermis, skeletal muscle (many hours) – mesenchymal tissues.
Ischemia = not enough blood flow (so not enough oxygen). Can have hypoxia without ischemia (ex: CO poisoning), but if you have ischemia, you always have hypoxia. Test q: Total loss of blood supply to an organ or region of an organ is called: Ischemia.
Cell Injury Principles (cont’d from above)
3. The morphologic changes of cell injury become apparent only after some critical biochemical system within the cell has been deranged:
• Manifestations of lethal damage take more time to develop than those of reversible damage. • Ultrastructural alterations are visible earlier than light
microscopic changes.
Figure: A & B – may not see anything too abnormal until necrosis (C). Reversible Injury
• Cellular swelling – mainly seen in kidney • Fatty change – mainly seen in liver
Test q: Cloudy swelling, hydropic change, and fatty change are all examples of: Reversible cell injury.
Above: Normal kidney histology Above: normal tubules
Above: renal tubules exhibit cloudy swelling. Cell Above: tubules accumulate water.
membranes lose functional integrity. Take in too much fluid or lose too much fluid, and the electrolytes get out of balance. However, this is reversible.
Basically anything that increases triglycerides causes fatty change (if you make too many TGs, if you can’t transport them out of the liver, etc. – chronic alcoholism is most common reason). In fatty change and cloudy swelling, if the damage persists long enough, irreversible change will happen. Fatty change
liver is yellow/orange. If fatty change lasts long enough, the hepatocytes will die (get cirrhosis).
Fatty change
Hepatocytes filled with fat (triglyceride).
Figure: Hepatocytes filled with triglyceride. Nuclei pushed to the sides.
See big globules of fat. Fatty change is reversible if the person stops drinking – if you drink a 6-pack on Saturday night, your liver will undergo fatty change but it will reverse itself. Test q: Which of the following is an example of reversible cellular
change? Fatty change (NOT karyolysis, karyorrhexis, cell membrane rupture, or dense bodies in mitochondria) QUESTION REPEATED TWICE.
Rupture of cell membrane, organelle
membranes, significant change in the nucleus = irreversible damage. Everything else is
debatable.
Myocardial Infarction Markers
• Cardiac specific enzymes and proteins leak out of cells in 2 hours (CK, isoenzymes, LDH. troponin I and troponin T are most common)
• Morphologic (light microscopic) changes in 4-12 hours
Figure:
A = normal myocardium
B = coagulation necrosis (Muscle has lost its nuclei and
inflammatory cells are infiltrating. necrosis neutrophils)
NECROSIS
• Morphologic changes in GROUPS of cells that follow the death of living tissue; cells and PMNs leak lytic enzymes • CYTOPLASM: eosinophilia, vacuoles, calcification, myelin figures
• NUCLEUS: pyknosis, karyorrhexis, karyolysis
Patterns of Necrosis
• Coagulative - hypoxic death (except brain) – usually due to a thrombus. All tissue distal to the artery dies. Can still tell what the tissue is – can see it’s still heart muscle but a lot of the nuclei are gone (eventually all will disappear – all cells die at the same time because of blood supply cut off). Test q: A 56y/o male has left chest pain that
radiates to his left arm. Troponin I levels are elevated at 3hr; cardiac catheterization shows occlusion of the LAD artery. What is the diagnosis? Coagulation necrosis.
Test q: Coagulative necrosis usually results from: ischemia.
• Liquefactive - bacterial infections (influx of neutrophils and the enzymes they release); *also hypoxic death in brain tissue (infarction). Everything destroyed by neutrophils. Will only see neutrophils, if anything. Test q: A 70y/o female loses consciousness and later cannot speak or
move her right arm. The pattern of necrosis seen in the brain is: Liquefactive.
Test q: A 70y/o woman suffered an MI followed by a stroke due to focal cerebral
ischemia. Expected findings include: Coagulative necrosis in heart; liquefactive
necrosis in CNS. REPEATED x3!!
• Caseous - tuberculosis; will see macrophages
• Fat - enzymic or traumatic damage to fatty tissue; eg. Pancreatitis (enzymic) If pancreas damaged, enzymes leak and they will break down all the lipids in the pancreas, and that will combine w/calcium to produce calcium soaps. Saponification = fat changed into soap. Test q: Digestion of tissue w/soap formation and calcification is characteristic of: Enzymic fat necrosis
• Fibrinoid - immune complexes (Antigens and Igs) in the walls of arteries
Coagulation necrosis in the kidney.
See the roughly triangular-shaped infarct. Thrombus was at the bottom point of it – all the distal tissue died.
Test q: A well-demarcated lesion w/increased
cytoplasmic eosinophilia, karyolysis, and intact tissue architecture is characteristic of: Coagulative necrosis
Brain abscess with liquefactive necrosis.
Test q: An abscess is best defined as: a localized collection of pus.
Coagulative necrosis (A) – can
tell a glomerulus and tubules are present, but all the nuclei are gone (pale ghost of itself) – all tissue lost oxygen supply at the same time and therefore died at the same time. Liquefactive necrosis (B) in the
kidney – lots of neutrophils. Tissue in the middle totally destroyed.
Above: abscess; liquefactive necrosis. Above: caseous necrosis of lung
See neutrophils. Cottage cheese appearance.
Above: Granulomatous Inflammation with Central Necrosis. Above: Fat necrosis in pancreas. When the material Necrotic in the middle, has lots of multinucleated turns to soap, it calcifies and can be seen on a CT. giant cells around the periphery (bottom left).
Test q: A chest radiograph of an
asymptomatic, 37y/o man showed a 3-cm nodule in the middle lobe of the right lung. The nodule was excised with a pulmonary wedge resection, and sectioning showed the nodule to be sharply circumscribed with a soft, white center. Culture of tissue from the nodule grew
Mycobacterium tuberculosis. Which of the
following pathologic processes has most likely occurred in this nodule? Caseous necrosis.
Test q: A chest radiograph of an asymptomatic
37y/o man showed a 3cm nodule in the middle lobe of the right lung. The nodule was excised w/a pulmonary wedge resection, and
sectioning showed the nodule to be sharply circumscribed w/a soft, white center. Culture of tissue from the nodule grew Mycobacterium
tuberculosis. Which of the following pathologic
processes has most likely occurred in this nodule? Necrotizing granuloma (other choices were abscess, coag. necrosis, fat necrosis, and liquefactive necrosis.)
Test q: A 45y/o Gulf war veteran and lifelong resident of Indy develops a positive skin test for
tuberculosis. Chest x-ray shows a 3cm diameter nodule in the left lower lobe. Histopathology will most likely show: macropahges, lymphocytes, and fibroblasts.
Above: Fat necrosis (L) and normal pancreas (R). Above: Fibrinoid necrosis – seen in certain rheumatoid
and autoimmune diseases. See pink material deposited in the wall of the artery.
Mechanisms of Cell Injury
• Oxidative phosphorylation
• Mitochondrial damage (If you lose ATP, you lose membrane function and mitochondrial function.) • Influx of Ca++ (too much
will kill cells)
• Free radical formation
• Membrane damage
• DNA and Protein damage
Everything pictured above can result in necrosis.
Depletion of ATP
• Na+ pump fails- Na+ and water enter and K+ is lost; glycolysis depletes glycogen and lowers pH (loss of enzymic activity and fluid exchange messed up)
• Ca++ pump fails- Ca++ into cells (toxic – turns on enzymes that break down the cell)
• Decreased protein synthesis (ribosomes detach) • Unfolded protein response
Figure: Ischemic event (loss of blood supply due to a thrombosis)
tissue becomes anoxic because you don’t have oxygen as the terminal electron acceptor (so no ATP) lose Na pump, etc.
Mitochondrial Damage
• Increased cytosolic Ca++ • Decreased ATP (Hypoxia)
• Mitochondrial permeability transition (MPT)- pore that allows cytochrome C to escape; apoptosis is triggered and cell death occurs (sort of combo of necrosis/apoptosis destroying the cell)
Test q: A tissue preparation is experimentally subjected to a hypoxic environment. The cells
in this tissue begin to swell, and chromatin begins to clump in the nucleus. ATPases are activated, and ATP production decreases. Which of the following ions released from mitochondria leads to these findings and to eventual cell death? Ca2+
Test q: The cell membranes are ruptured and leaking. Water and calcium enter the cell. Calcium binds to mitochondria. At this point: the cell is irreversibly damaged.
Loss of Ca++ Homeostasis
• Extracellular Ca++ is 15X higher than cytosolic Ca++
• Loss of ATP increases intracellular Ca++
• Increased Ca++ activates many enzymes – phospholipases. proteases, endonucleases and ATPases
• Increased Ca++ also increases mitochondrial permeability triggering apoptosis
Figure (far right):
Enzymes chew up proteins, nucleus, etc. Also will disrupt mitochondria (decreasing ATP, leading to problems). All of these are interrelated.
Free Radical Formation
• Single unpaired electron; highly reactive – destroy chemical compounds
• Normal metabolism produces superoxide anion, hydrogen peroxide and hydroxyl ion; superoxide is produced in neutrophils • Lipid peroxidation of cell membranes • Protein fragmentation
• Breaks in DNA
Body has a lot of preventative mechanisms against ROS: superoxide dismutase, catalase, peroxidase, etc. Books say vitamins do the same thing, but this has been proven to be somewhat untrue (may have some related function but not primary function).
Major Antioxidants:
• Antioxidant Enzymes: superoxide dismutase, catalase, glutathione peroxidase
• Vitamins: A, E, ascorbic acid, glutathione. (Vitamins can be considered “antioxidants” but do not play major role.)
Membrane Permeability Defects:
• Plasma membrane • Mitochondrial membrane
• Lysosomal membrane- release of RNases, DNases and proteases
Anoxia is most common mechanism of membrane damage – if you can’t generate ATP, the Na and Ca pumps are disrupted. ROS is less common cause.
Hypoxia and Ischemia
• Hypoxia- deficiency of oxygen; causes: cardiorespiratory failure, anemia, CO poisoning; cell injury and death
• Ischemia- loss of blood supply (oxygen and nutrients); more rapidly and severely injures tissues than does hypoxia alone • AGAIN: Ischemia involves hypoxia, but you can have hypoxia
without ischemia.
Lecture 3 – Adaptation, Injury, and Death of Cells (Part 2) Fri. 08/20/10
Mechanisms of Cell Death:
Necrosis- groups of cells are killed by injurious agents Apoptosis- individual cells are induced to commit suicide Apoptosis (predetermined) Necrosis
ATP-dependent ATP not required
Cell membrane intact Cell membrane rupture
Organelles intact Organelles rupture
No inflammation Inflammation
Test q: Which of the following is characteristic of apoptosis? Energy dependence. (NOT cell membrane rupture, lysosome rupture, karyolysis, acute
inflammation)
Test q: Apoptosis is associated with all of the following EXCEPT: Local tissue inflammation. (the other choices were cleavage of chromatin by
endonucleases, activation of caspases, phagocytosis of apoptotic bodies, and chromatin condensation beneath the nuclear membrane)
NECROSIS: APOPTOSIS:
Rupture of cell/organelle membrane or rupture/lysis of Apoptosis – membrane recompartmentalizes, then
nucleus = dead cell. compartments are engulfed by macrophages
Apoptosis Morphology
• Cell shrinkage
• Chromatic condensation/reorganization of the nucleus • Plasma membrane wrinkles/blebs
• Fragmentation into apoptotic bodies • Phagocytosis of apoptotic cells/bodies
Test q: A 30y/o female w/metastatic breast carcinoma has
received several courses of chemotherapy. A post treatment biopsy shows individual neoplastic cells that exhibit nuclear fragmentation and cytoplasmic budding in cell that exhibit an overall decrease in size. The neoplastic cells responding to chemotherapy are exhibiting changes consistent with: apoptosis
Test q: A 54y/o man experienced onset of severe substernal chest pain over 3hr.
An ECG showed changes consistent w/an acute MI. After thrombolytic therapy w/t-PA, his serum creatine kinase (CK) level increased. Which of the following events most likely occurred after t-PA therapy? Free radical injury. (Robbins’ explanation: The reperfusion of damaged cells results in generation of oxygen-derived free radicals, however, causing a reperfusion injury. The elevation in the CK level is indicative of myocardial cell necrosis because this intracellular enzyme does not leak in large quantities from intact cells.)
Apoptotic Cells in H & E Sections
• Oval mass of intensely eosinophilic cytoplasm with dense chromatin fragments; occurs rapidly; no inflammation
• There is not tremendous shrinkage – may be hard to tell.
• Tend to be individual cells
Figure: Civatte Bodies
Civatte body = two cells undergoing apoptosis. Can do special stains for caspases, other intermediates, also (to visualize apoptosis).
PHYSIOLOGIC APOPTOSIS:
• Embryology- fingers and toes/maleness
• Hormone-dependent- endometrial cells shed on estrogen withdrawal; breast duct regression after weaning.
• When the hormone is taken away (don’t need the cells anymore), those cells undergo apoptosis. Breasts undergo hyperplasia, which would be dangerous if it didn’t go away. But it does disappear via apoptosis.
• Neutrophils (PMNs) disappear in acute inflammation
• Neutrophils only live 4 hr after they go into tissues – good thing bc they destroy everything w/enzymes. If they lived longer, we would be autodigested away.
• Figure: Apoptosis of Neutrophils
• Cytotoxic T cells eliminate virus-infected cells by inducing apoptosis
PATHOLOGIC APOPTOSIS:
• Radiation and anticancer drugs damage DNA and apoptosis follows (role of p53) • Hypoxia- apoptosis (if mild) or necrosis if the hypoxia is severe
• Decreased cell death in lymphomas (Bcl-2) APOPTOSIS IS BLOCKED BY BCL-2. • Misfolded proteins
Test q: A 40y/o man notices an increasing number of lumps in his groin and armpits. On physical exam, he has a generalized lymph node enlargement
and hepatosplenomegaly. An inguinal node biopsy shows a malignant tumor of lymphoid cells. Immunoperoxidase staining of the tumor cells w/antibody to BCL2 is positive. Which of the following mechanisms has most likely produced the lymphoma? Lack of apoptosis.
Test q: Which of the following results in increased apoptosis? Decreased of defective Bcl-2.
Test q: Prior to the start of a woman’s menstrual cycle, which protein decreases in mitochondrial cell membranes to allow for menses to proceed? Bcl2 Test q: An experiment introduces a “knockout” gene mutation into a cell line. The frequency of shrunken cells w/chromatin clumping and cytoplasmic
blebbing is increased, compared w/a cell line w/o the mutation. Overall survival of the mutant cell line is reduced. Which of the following genes is most likely to be affected by this mutation? Bcl-2. (other choices were Bax, C-myc, Fas, and p53)
Pathologic Apoptosis in Viral Infections APOPTOSIS AFTER RADIATION:
• HPV- E6 protein inactivates p53
• If p53 inactivated, you don’t get apoptosis (cells don’t die).
Test q: A 30y/o woman who has had multiple sexual partners sees her physician because she has had
vaginal bleeding and discharge for the past 5 days. Pelvic examination shows an ulcerated lesion arising from the squamocolumnar junction of the uterine cervix. A cervical biopsy is performed. Microscopic examination reveals an invasive tumor containing areas of squamous epithelium, with pearls of keratin. In situ hybridization shows the presence of HPV type 16 (HPV-16) DNA within the tumor cells. Which of the following molecular abnormalities in this tumor is most likely related to infection w/HPV-16? Decrease in p53 protein.
• EBV- makes Bcl-2-like substance (blocks apoptosis)
• HIV- infected cells make high levels of FasL which induce apoptosis in HIV-uninfected Tcells
Biochemical Events in Apoptosis
• Caspases (cysteine proteases) cleave the cytoskeleton and activate DNAses
• DNA breaks into 50- to 300-kilobase pieces; further broken into multiples of 200 base pairs by endonucleases (Ca++ and Mg++)- demonstrated as a “ladder pattern” on agarose gel; also proteases.
• Phosphatidylserine is exposed and attracts macrophages with little “collateral damage”
Figure: apoptosis. Caspases activate other
caspases, those activate proteases and nucleases = cell broken down. Red tags on bottom right – phosphotidyl serine tags – allow them to be phagocitized more easily.
The intrinsic Pathway of Apoptosis: Major mechanism.
• Increased mitochondrial permeability and release of pro-apoptotic molecules (cytochrome c)
• Pro:1. membrane- Bim, Bid, Bad and Bax, Bak 2. cytoplasm- Smac/DIABLO
• Anti: Bcl-2, Bcl-x
Figure 1-25: The intrinsic (mitochondrial) pathway of apoptosis.
A. Cell viability is maintained by the induction of anti-apoptotic proteins such as Bcl-2 by survival signals. These proteins maintain the integrity of mitochondrial membranes and prevent leakage of mitochondrial proteins. B. Loss of survival signals, DNA damage, and other insults activate sensors that antagonize the anti-apoptotic proteins and activate the pro-anti-apoptotic proteins Bax and Bak, which form channels in the mitochondrial membrane. The subsequent leakage of cytochrome C (and other proteins, not shown) leads to caspase activation and apoptosis.
Certain hormones in the environment can trigger apoptosis – involves the mitochondrial release of cytochrome c.
Test q: A 40 y/o man had undifferentiated carcinoma of the lung. Despite chemotherapy, the man died
of widespread metastases. At autopsy, tumors were found in many organs. Histologic examination
showed many foci in which individual tumor cells appeared shrunken and deeply eosinophilic. Their nuclei exhibited condensed aggregates of chromatin under the nuclear membrane. The process affecting these shrunken tumor cells was most likely triggered by the release of which of the following substances from mitochondria (into the cytosol)? Cytochrome c. QUESTION REPEATED x4!!
Figure: Intrinsic pathway.
Figure:
Extrinsic pathway.
Extrinsic Pathway:
• Activation of plasma membrane death receptors • TNFR1 and Fas
• Activation begins at cell membrane. Does not directly involve mitochondria. (Some stimuli do both. May start as a ligand, then activate the mitochondrial pathway.)
• Fas ligand (FasL in figure above, right) attaches to Fas receptor, then eventually activates caspase-8. • Caspase-9 is usually first in the intrinsic pathway
(above, left).
Control and Integration Stage:
• Specific proteins connect the “death signals” to proteolytic enzymes in the capase family responsible for “the
execution phase”.
• Can see in figure below that there are some intermediaries.
The Execution Stage:
• Caspases cleave cytoskeletal and nuclear matrix proteins and result in DNA cleavage into fragments giving “DNA Ladder pattern” by agarose gel electrophoresis.
• Can see ladder pattern in apoptosis (nuclear material – specific cleavage of nuclear components)
• Necrosis = smudge
Removal of Apoptotic Bodies:
• Apoptotic cells are coated by
Phosphatidyl serine (which “flips out”) or C1q leading to early recognition and
removal by macrophages – (makes the cell more attractive to macrophages).
Thrombospondin is an adhesive
DNA-damage and Apoptosis
• Radiation or chemotherapy damages DNA
• p53 accumulates
• Cell cycle arrested at G1 (allows repair) • If repair fails, p53 triggers apoptosis
• p53 = guardian of the genome. If there is damage to DNA, p53 shuts down cell cycle so cells can’t mitose. Then it induces DNA repair.
Figure: If you have active p53 and there is alteration to the
DNA, you can have potential repair. IF successful, go back to having normal cell. If not successful, apoptosis triggered.
Tumor Necrosis Factor and Cytotoxic Lymphocytes in Apoptosis
• Fas (CD95) –FasL induces apoptosis in lymphocytes that recognize “self”; Fas/FasL mutations may cause autoimmune disease
• TNF/TNFR1-TRADD-FADD causes caspase activation and APOPTOSIS; TNF activates NF-kB which aids cell SURVIVAL and is antiapoptotic • Foreign Ag-CTLs- lymphocytes produce PERFORMIN
which allows entry of GRANZYME which activates caspases; CTLs kill target cells
• If you could therapeutically trigger T lymphocytes to attack certain cells and send them into
apoptosis, could be therapeutic tool.
Dysregulated Apoptosis
• “Too little”: activity diminished in certain cancers • “Too much”: neurodegenerative diseases, ischemic
injury, virus-induced lymphocyte depletion
Defective Apoptosis
• 50% of human cancers have p53 mutations • Hormone-dependent tumors (breast, prostate)
• Follicular lymphomas and colon cancers express high levels of Bcl-2 (translocation of bcl-2 gene)
• HPV- protein E6 binds and inactivates p53
• EBV- proteins that mimic or increase production of Bbcl-2 • Autoimmune disorders
Test q: A 55y/o man visits the physician because of hemoptysis and worsening cough.
On physical examination, wheezes are auscultated over the right lung posteriorly. A chest radiograph shows a 6cm perihilar mass on the right. A fine-needle aspiration biopsy yields cells consistent with non-small cell bronchogenic carcinoma. Molecular analysis of the neoplastic cells show a p53 gene mutation. Which of the following mechanisms has most likely produced the neoplastic transformation? Loss of cell cycle arrest. REPEAT x2.
Test q: In a clinical trial, a chemotherapeutic agent is given to patients w/breast cancer
metastases. Samples of the cancer cells are obtained and assessed for the presence of death of tumor cells by apoptosis. Mutational inactivation of which of the following products is most likely to render tumor cells resistant to the effects of such an agent? p53. REPEAT x2.
Figure: Hasimoto’s thyroiditis can involve (A) A Bcl-2 decrease in
thyroid cells with a Bcl-2 increase in T-cells. (B) Bcl-2 decrease in thyroid cells. (C) Graves’ disease involves a Bcl-2 increase in thyroid cells with a Bcl-2 decrease in T-cells.
Increased Apoptosis
• Neurodegenerative diseases • Ischemic injury
• Death of virus-infected cells (hepatitis)
• AIDS (death of uninfected CD4 cells) • FasL+ tumors are MORE aggressive • Microorganisms induce apoptosis Most CD4 helper cells are not infected by virus. Only 1 in 1000 are infected. But they all end up dying, as seen in this figure. Pneumocystis pneumonia
• Pneumocystis causes pneumonia in AIDS (most common atypical pneumonia in AIDS patients) • Human macrophages are killed
before they can engulf the organisms • Apoptosis is triggered in
macrophages by polyamines
• Can see cluster of organisms in the alveolar space.
• Never see them inside the macrophages. Never get phagocytosed, just kill the macrophages.
Apoptosis Summary
• Normal part of the cellular machinery
• Pathology results when it is increased or decreased
• Future Study of Apoptosis: inflammation and repair (cell signaling); immune system; neoplasia; infectious diseases
• Future targets for new chemotherapeutic and antimicrobial agents
Clinical Applications
• Velcade (bortezomid)- blocks proteasomes in multiple myeloma; proteins accumulate which are toxic to myeloma cells
• Genasense (oblimersen)- blocks production of Bcl-2 in
lymphomas rendering them more susceptible to other anticancer drugs
Subcellular response to Injury
• Primary lysosome- hydrolytic enzymes • Lysosome/vacuole fusion- secondary
lysosome or phagolysosome • Heterophagy
• Autophagy - smaller components of the cell are destroyed if they become aberrant • Others- lipids, proteins, filaments, Ca++
Cytoskeletal Abnormalities
• Microtubules- 25 nm • Actin filaments (thin)- 8 nm • Myosin filaments (thick)- 15 nm • Intermediate- 10 nm
Abnormal Microtubules
• Sperm motility deficiency “YBCS syndrome” (microtubules in sperm become defective = can’t swim) • Immotile cilia syndrome (Kartagener’s Syndrome)
• Colchicine- disrupt microtubule formation and inhibit PMN migration; gout therapy • Vinca alkaloids- antitumor; disrupt the mitotic spindle
Intermediate Filaments (IM)
• Mallory bodies (alcoholic hyalin)- keratin IM • Neurofibrillary tangles- neurofilament IM seen in
Alzheimer’s Disease (below)
Intracellular Accumulations
1. Normal substance that cannot be metabolized- fatty liver (triglyceride)
2. Genetic defect in metabolism of a substance (alpha-1-antitrypsin deficiency and “storage diseases” like Gaucher’s)
3. No normal enzymes to degrade an abnormal substance (silica-silicosis)
Figure:
1. Fatty change. Cell will die – necrosis/cirrhosis of the liver. 2. Protein abnormality like amyloid – buildup can be toxic to cells 3. Enzyme deficiency (Gaucher’s, Tay-Sachs) – may get buildup of
cerebroside, etc.
4. Emphysema – can take up carbon (not toxic) but if exposed to silica – will get
silicosis, toxic to cell
Fatty Change (Steatosis)
• Triglycerides accumulates in parenchymal cells • Alcoholism, protein malnutrition, anoxia
1
2
3
4
Figure: Pale liver = fatty liver (just has been plasticized so color is not brilliant anymore) Below: Oil Red O Stain Below: Cerebroside in Gaucher’s Disease (spleen)
Gaucher’s – cerebroside is deposited in macrophages. Have problems w/reticulo-endothelial system. In Tay-Sachs,
ganglioside deposits in neurons.
Test q: The adult form of Gaucher’s disease: has marked splenomegaly due to glucocerebroside accumulation (QUESTION REPEATED TWICE) Test q: Accumulations of gangliosides in lysosomes is seen with: Tay Sachs disease.
Cholesterol Accumulation
• Atherosclerosis- smooth muscle cells and
macrophages (foam cells) • We saw infarcts that may
have been due to cholesterol accumulation and
atherosclerosis
Above: Silica in silicosis (polarized view) Above: Foam Cells in Atherosclerosis Protein Accumulation
• Renal failure- reabsorption of filtered protein in the proximal tubule accelerates
• Vesicles of protein fuse with lysosomes and appear as pink hyalin droplets in the tubules (=increased protein in tubules)
• Figure: Protein in renal tubules
Protein Folding Errors (failure of chaperones)
• Alpha-1-antitrypsin deficiency • Cystic fibrosis
• Familial hypercholesterolemia • Unfolded Protein Response-
caspase-12 is activated with apoptosis induction; Alzheimer’s, Huntington’s, Parkinson’s • Amyloidosis- amyloid not
eliminated
Hyaline change
• Homogenous, glassy, pink appearance
• Eg. Mallory alcoholic hyaline • #1 “pink” substance in
tissue = protein. • Fibrin – fibrinous
peritinitis – comes from all the protein in the blood
Hyaline change in hypertension (increased pink material in vessels)
Pigments – some pathologic, some not.
• Carbon (exogenous)
• Lipofuscin- lipid and phospholipid polymers complexed with protein; wear-and-tear pigment- liver and heart of aging patients
• Melanin- dihydroxyphenylalanine (from Tyr)
• Hemosiderin- iron-ferritin forms hemosiderin granules; hemosiderosis (in macrophages); hemochromatosis (in parenchymal cells)
Test q: A 25y/o male sickle cell patient has had several transfusions. He appears slightly
jaundiced and hepatitis is suspected. An aggressive resident performs a liver biopsy which is unremarkable except for hemosiderin in Kupffer cells. Hepatocytes do not exhibit necrosis and do not contain brown pigment. The best description is: Hemosiderosis.
Below: Lipofuscin. (slightly brownish, no path associated –
“Wear and tear pigment”)
Pathologic Calcification
• Dystrophic- calcification on necrotic tissue; serum Ca++ normal; atheromas, heart valves; psammoma body/asbestos body. if tissue dies and patient is still alive, it will probably calcify.
• Metastatic- calcification on living tissue. Hypercalcemia; parathyroid, skeletal metastases, vitamin D, renal failure; lungs, arteries
Test q: A 50y/o man from Guatemala recently immigrated to the US. He undergoes a routine physical as part of an employment requirement. A chest
X-ray shows a coin lesion (small nodule) in the right lower lobe. The radiologist notes focal calcifications in the nodule and a biopsy shows caseous necrosis w/focal calcification. These changes represent: dystrophic calcification.
Test q: A 70y/o man died suddenly and unexpectedly. At autopsy, multiple tissue sites were sample for microscopic analysis. Exam of the tissues
showed amorphous deposits of calcium salts in gastric mucosa, renal interstitium, and alveolar walls of lungs. Which of the following conditions is most likely to explain these findings? Chronic glomerulonephritis. (From Robbins. Explanation: The findings suggest metastatic calcification. Chronic renal disease reduced phosphate excretion increase in serum phosphate PTH increases Ca level Ca deposition.) Other choices were: Bacterial endocarditis, Disseminated TB, Generalized atherosclerosis, and Normal aging process.
Above: calcified heart valve. Above: dystrophic calcification. Dystrophic calcification after endocarditis. Tends to be bluish color.
Above: Asbestos bodies (aka ferruginous Above: metastatic calcification in lung. bodies– seen in mesothelioma)
Above: Iron/hemosiderin. Prussian blue stain.
Iron is usually granular and brown. If inside cells, is toxic. In hemachromatosis, see liver cells and pancreatic islet cells destroyed by iron.
Above: Psamomma body = dystrophic calcification. Seen in meningiomas of the brain. Also in papillary adenocarcinoma (ex: thyroid).
Cellular Aging
• Genetic
• Cellular damage over time
• We know that cells are programmed to die at a certain point. • Telomerase is associated. You can potentially live forever if you
have extra telomerase (see figures below).
Test q: Which of the following cells is most likely to
have highest telomerase activity? Stem cells. (Other choices were endothelial cells, smooth muscle cells, neutrophils, and erythrocytes.)
Test q: In human cells, telomerase activity is highest
in: stem cells. (Other choices were epithelial cells, mesenchymal cells, WBCs, and neurons)
Lecture 4: Week 1 in Review 08/20/10
The “Grandmother” Rules
1. You must “see” the pathology/disease and be shown it “several” times before you can recognize it. 2. Grandma (disease) does not always look the same
Q-1 Most of the inflammatory cells present in the lesions pictured are expected to be? A. Eosinophils B. Lymphocytes C. Macrophages D. Neutrophils E. Plasma cells Answer: D, neutrophils
• The CT and gross represent brain abscess and the microscopic shows sheets of neutrophils.
• Some cells show 3 lobes while others show 1 or 2. Remember, you are looking at a 2-dimensional image, so you cannot identify every cell.
Q 1A. Which microorganism most likely caused this lesion?
A. Mycobacterium tuberculosis
B. Streptococcus mitis C. Histoplasma capsulatum D. Mycoplasma pneumoniae
Answer: B, Streptococcus mitis
• Bacteria- neutrophils (abscess) • Fungi- macrophages (granuloma) • TB- macrophages (granuloma) • Virus/mycoplasma- lymphocytes TYPES OF NECROSIS: •COAGULATIVE Infarcts •LIQUIFACTIVE Abscess •CASEATION TB Granuloma
•FAT (ENZYMIC) Pancreas
•FAT (TRAUMATIC) Breast
Q-2 20-y.o female with nausea, vomiting, and right lower quadrant pain. No occult blood in stool and rebound tenderness. What lab test best predicts appendicitis? A. Increased amylase
B. Increased amylase and lipase C. Increased alkaline phosphatase D. Leukocytosis
E. Leukocytosis with “left shift” Answer: E, “left shift”
• Neutrophils are increased and immature forms (bands, metamyelocytes) are present
Test q: A 25y/o female presents w/abdominal pain, nausea, and vomiting. Appendicitis is suspected. Which of the following lab tests are consistent
with appendicitis? WBCs in the urine.
Q-3 The microscopic appearance (photo) of this lung biopsy is consistent with activation of:
A. Complement C5a B. Interferon-gamma C. Bradykinin D. Nitric Oxide E. Prostaglandin
Answer: B, interferon gamma
Q-4 A 38-y.o. female presented with abdominal pain and shock, dying after 36 hours. The images are consistent with:
A. Hepatitis B infection
B. Infarction of the small intestine C. Tuberculosis
D. Gangrenous cholecystitis E. Acute pancreatitis
Answer E, acute pancreatitis
• Fat necrosis with saponification and perhaps calcification with chronic enzymic fat necrosis Caseous necrosis of Lung This was a test q REPEATED TWICE!
Q-5 What lab tests might have been useful in the diagnosis of acute pancreatitis? (THIS WAS A TEST Q) A. Troponins
B. Alkaline phosphatase C. Transaminases (ALT, AST) D. Bilirubin
E. Amylase and lipase
Ans. E
Serum amylase is more sensitive (fewer false negatives); serum lipase is more specific (fewer false positives).
RR-1-1 Hepatitis A patient shows a bilirubin of 5.1 mg/dL and elevated AST (150) and ALT (180). Serum enzyme changes are due to?
A. Autophagy
B. Clumping of chromatin C. Cell membrane rupture D. Dispersion of ribosomes E. Swollen mitochondria
Ans. C
Transaminases are produced by hepatocytes. If serum levels are increased then the cells have been destroyed (cell membrane rupture)
RR-1-2. 16 y.o. in auto accident has resection ¼ of his liver. CT scan 8 weeks later shows normal liver size. Explain? A. Apoptosis B. Dysplasia C. Hyperplasia D. Hypertrophy E. Metaplasia Ans. C
Hepatocytes can re-enter the cell cycle and divide (hyperplasia).
The pattern of necrosis pictured in the spleen is?
A. Coagulation necrosis B. Liquefactive necrosis C. Caseous necrosis D. Enzymic fat necrosis E. Traumatic fat necrosis
Answer A, coagulation necrosis
Wedge-shaped pale infact; loss of nuclei histologically.
RR-1-9. 68 y.o. suddenly loses consciousness and later cannot speak. CT of the L parietal lobe is abnormal. Type of necrosis? A. Enzymic Fat B. Traumatic fat C. Coagulative D. Liquefactive E. Apoptosis Ans. D, liquefactive
Exception to the rule- ischemic events in the brain lead to liquefactive necrosis with a pocket of neutrophils and debris
Q-6 How old is this myocardial infarction?
A. 30 minutes B. 1 hour C. 2 hours D. A few days E. Several months
Test q: A 51y/o alcoholic man is admitted to the ER w/a 6hr history of severe epigastric pain
that radiates to his back. EKG is normal. Phys exam reveals tachycardia, hypotension, and low-grade fever consistent w/the early stage of shock. Which of the following serum measurements would be most useful in providing a diagnosis of his condition? Amylase. (Other choices: Aspartate aminotransferase, Myoglobin, Calcium, and Troponin I.
Test q: A 52y/o male presents to the ER w/a pathologic fracture of his femur. Additional
x-rays show small, “punched-out” defects in his skull. You would exprect the following lab test abnormality: Increased serum calcium,
Answer D, a few days
It usually takes 4-6 hours to see anything microscopically and probably longer to see gross changes; scars take several weeks to develop.
Contraction bands (above) are early changes. Above: 12-24 hr post-MI
Fibrous vs Fibrinous:
Fibrosis/fibrous Fibrinous
Fibroblasts/collagen Fibrin/liquid protein Scar, desmoplasia, sclerosis Pericarditis and peritonitis
Permanent Reversible, but may become fibrosis
Q-7 A 56-y.o. male has left chest pain that radiates to his left arm. Troponin I levels are elevated at 3 hours; cardiac cath. shows occlusion of the LAD artery. Etiology?
A. Enzymic fat necrosis B. Gall stones
C. Herpes zoster D. Esophageal spasm E. Coagulation necrosis (This was “Test q” on p13)
Answer E , coagulation necrosis
Although any of these can cause 6th dermatome pain, the radiating pain and elevated troponin level points to MI.
Fatal event
The plaque that initially ruptured continued to evolve while the patient was in the ER and lead to a completely obstructed LAD, which is fatal.
Myocardial Infarction Markers
Cardiac specific enzymes and proteins in 2-3 hours Morphologic (light microscopic) changes in 4-12 hours
Laboratory tests
ABGs BNP
CBC Coags
Serial Troponin I, Myoglobin, CK-MB CXR Electrolytes, glucose, Hgb A1c EKG Creatinine/BUN
ST elevation in the anterior leads V1 - 6, I and aVL. Reciprocal ST depression in the inferior leads
Lab Results:
• Myoglobin markedly elevated, Troponin I and CK-MB elevated. • BNP is 400
• Mild leukocytosis
• Ph 7.51, PaCO2 26, Pao2 90, Bicarb 21
• Patient was taken to cath lab, but unfortunately went into cardiogenic shock and died on the table.
More on Markers: Troponin I
– Is a specific indicator of MI
– Appears 4-6 hours post infarction, maybe not until 12 hours – Peaks at 16 hours and decrease in 9-10 days.
CK-MB
– MB fraction is specific for cardiac muscle, esp when there is no skeletal muscle damage in patient's history
– Appears to rise 4-6 hours post MI
– Not elevated in all patients until 12 hours post MI – Level returns to baseline in 36-48 hours
Myoglobin
– Elevates within 1-4 hours, most sensitive during early time period – Lacks specificity; any skeletal muscle injury
Other markers
• C-reactive protein (CRP), an acute phase reactant made in the liver, has been suggested as a predictor of risk of coronary heart disease. But, no better predictor than lipid levels, family history, physical exam
• Brain Natriuetic Peptide (BNP)- measure of heart failure, esp LV
Q-8 What drug therapy should the patient receive in the ER?
A. t-PA B. Aspirin C. Heparin D. Nitric oxide E. Vitamin K Answer A, tPA
• Tissue plasminogen activator (“clot buster”). Give within 3 hours of stroke or within 12 hours of MI (some positive change in 75%).
Q-9 Which of the following features of inflammation is affected by aspirin?
A. Vasodilation B. Chemotaxis C. Phagocytosis D. Leukocyte migration
E. Leukocyte release from the bone marrow
Q-10 On day 3 the MI patient developed CHF and died later that day. The lungs would show:
A. Fibrin and neutrophils in alveoli
B. Congested capillaries and transudate in alveoli
C. Heart failure cells in alveoli and fibrosis of alveolar walls
D. Subpleural hemorrhagic necrosis E. Purulent exudate in the pleural space
Answer: B BNP
• Beta natriuretic peptide is the active product of a split prohormone in response to atrial or ventricular wall stretch. • In this case it is a response to the acute congestive heart failure secondary to acute myocardial infarction. • <100 pg/mL CHF very unlikely
• 100-400 pg/mL indeterminate • >400 CHF likely
Q-11 What is the diagnosis in a 60-y.o. male with pitting edema in his legs, elevated AST and ALT and the following gross changes
A. Thrombocytopenia B. Portal vein thrombosis C. Renal failure
D. Bile duct obstruction E. Congestive heart failure
Answer B, congestive heart failure
Nutmeg (congested central veins) liver
Elevated transaminases indicate death of hepatocytes Right-sided failure is usually associated with left-sided failure-
pulmonary congestion also present with “heart-failure” cells (brown)
Q-12 When is the patient at greatest risk for fatal arrhythmias?
A. Days 1-3 B. Days 5-7 C. After 2 weeks D. After 4 weeks E. After 1 year Answer A, 1st 72 hours
Myocardial cells are dying and conduction pathways disrupted CCU, monitor, anti-arrhythmics
4-12 hours: beginning coagulation necrosis; edema; hemorrhage
The wavy part is the necrosis with edema between the remains of the muscle fibers.
Q-13 When is the patient at greatest risk for perforation (rupture) of the left ventricle? A. Days 1-3 B. Days 5-10 C. 2 weeks D. 4 weeks E. 1 year
Answer B, 5-10 (average 7) days
Heart muscle undergoes coagulation necrosis
Neutrophils enter to clear debris- enter at 12- 24 hours and persist 5 days At 5-7-10 days, the muscle is gone and fibroblasts have not made collagen (no scar); maximal weakness
Q-14 Six weeks post-MI, a 56-y.o. male has chest pain, SOB, precordial friction rub. He dies within days of heart failure. This late complication of infarction (photo) is? A. Granulomatous inflammation
B. Dressler’s syndrome This was a test q!
C. Metastatic carcinoma D. Ruptured LV
E. Viral infection
Answer B, fibrinous pericarditis – can see shaggy material on surface of pericardium.
Dressler’s syndrome is an autoimmune disorder that may occur months after MI.
Q-15 57-y.o. male with hx of MI presents 1 year later with abdominal pain and no bowel sounds. WBC is normal as is lipase and amylase. ??
A. Acute appendicitis with perforation B. Acute pancreatitis
C. Small intestine infarction D. Acute cholecystitis
E. Pseudomembranous enterocolitis
Answer C , infarction
It is likely the patient sufferd a mesenteric artery thrombosis. Or, another MI (abdominal pain may be seen in MI) with decreased cardiac output and infarction
Necrosis:
Cell membrane ruptures; organelles rupture; enzymatic digestion of the cell; inflammation
