Pathology: Adaptation, Injury, Death (Part 2) Flashcards
Describe hydropic degeneration
Injured cells tend to swell with water, which follows sodium that the injured cell is unable to pump out fast enough. Also called ballooning degeneration.
If ischemia goes on too long, the result is beyond injury; it is the death of the tissue or the organ, termed _________.
Infarction.
The earliest gross pathologic change in ischemic organs is often a __________ of ________.
darkening of color
Define and distinguish hypoxia from ischemia.
Hypoxia is deprivation of oxygen, such as low oxygen concentration in blood (hypoxemia) that is still adequately perfused unlike in ischemia when blood is simply not reaching an organ. Hypoxia IS a component of ischemia but ischemia is not always the cause of hypoxia.
Hypoxia induces the transcription factor:
hypoxia-inducible-factor-1 (HIF-1)
HIF-1 does what to counteract hypoxia?
enhances anaerobic glycolysis, stimulates cell survival pathways and promotes new blood vessel formation.
What causes the sodium pumps needed to keep potassium in and sodium out of cells to shut down, leading to further problems? (This also lets excess calcium in)
Depletion of ATP. ‘cause Na ATPase pumps, yo!
Lack of ATP shuts down protein synthesis, leading to the accumulation of misfolded ________, which can progress to the ________ _________ response.
Proteins; unfolded protein response
Injury to a mitochondrion leads to formation of a high-conductance channel in its membrane referred to as the ____ ______ ________ _____, which wrecks 3 things. Name the three things.
mitochondrial permeability transition pore
- membrane potential
- oxidative phosphorylation
- ATP production capacity
Deranged oxidative phosphorylation secondary to mitochondrial injury generates excess:
reactive oxygen species
Name the reactive oxygen species.
superoxide, hydrogen peroxide, and hydroxyl ion
Superoxide and hydroxyl ions are free radicals that react in pathologic ways by:
attacking the double bonds on unsaturated fatty acids in membrane lipids (peroxidation), by oxidizing the amino acid side chains in proteins (sometimes forming abnormal cross-links with other proteins), and by breaking and cross-linking DNA.
The highly reactive peroxynitrite (ONOO) is derived from what molecule found in the blood stream?
Nitric Oxide (NO)
What are responsible for donating or accepting free electrons during intracellular reactions and catalyzing free radical formation?
metals like iron and copper
Describe the condition of oxidative stress.
Derives from the presence of reactive oxygen species and free radicals. Such an important mechanism of injury that some liken oxygen to a low grade slow poison.
This compound is responsible for a cell’s normal disposal of the free radical hydrogen peroxide
catalase
This compound is responsible for a cell’s normal disposal of the free radical superoxide.
superoxide dismutase
This compound is responsible for a cell’s normal disposal of the free radicals hydroxyl ion and hydrogen peroxide
Glutathione peroxidase
NAPQI, a toxic product of Tylenol (acetaminophen) metabolism when accumulated in hepatocytes, can be detoxified by:
conjugation to glutathione
How does alcohol impair the liver’s natural defenses to NAPQI, leading to acetaminophen toxicity when consumed with Tylenol?
EtOH impairs methionine metabolism needed to generate glutathione and induces CYP-450 enzymes that increase acetaminophen metabolism to NAPQI.
Lowering or raising metabolic rate decreases injury caused by ischemia or hypoxia?
lowering
Describe reperfusion injury.
refers to the exacerbation of free radical injury sometimes caused by the restoration of blood flow, which brings oxygen to cells with damaged mitochondria or overwhelmed scavenging capacity, resulting in the production of reactive oxygen species by those injured mitochondria or simply more reactive oxygen species than can be scavenged.
How is calcium influx an important mechanism of cell injury?
It opens the mitochondrial transition pore and activates phospholipases (damaging membranes), proteases, endonucleases and ATPases.
When does injury to a cell become irreversible?
The point of no return is thought to be passed when mitochondrial injury is so severe that the cell cannot generate the energy (ATP) to repair itself. Also correlated with outer membrane damage so severe that the cell cannot keep enough of its constituents in to continue functioning.
How long can the brain be ischemic before infarcting?
4 mins
How long can the heart be ischemic before infarcting?
20 mins
How long can the liver be ischemic before infarcting?
2 hours
The most sensitive and specific blood tests for myocardial damage are the cardiac-specific proteins:
What are their functions?
Troponin T and Troponin I.
Regulate calcium mediated contraction of cardiac myocytes.
Are Troponins usually detectible in the blood at any concentration?
No.
At what time point, following irreversible injury, will you find troponins in the blood?
3 hrs
Given a patient has suffered a single discrete episode of myocardial infarction, describe the levels of troponin in their serum over the course of two weeks.
Appears: 3 hrs
Peaks: 24 hrs
Elevated: 10 days
What is creatine phosphokinase (creatine kinase)?
An enzyme that catalyzes the transfer of phosphate from creatine phosphate to ADP.
Where is CK concentrated?
muscle and brain tissue
MM CK homodimers are present predominantly in:
striated muscle (skeletal/cardiac)
BB CK homodimers are present in:
brain, lung and many other tissues
MB heterodimers are present primarily in:
cardiac muscle (a little in skeletal m.)
Given irreversible myocardial injury, describe the concentrations of CK MB in the bloodstream:
Appears: 3 hrs
Peaks: 24 hrs
Elevated: 48 hrs
Describe the time/release of AST following acute MI.
Appears: 24 hrs
Peaks: 48 hrs
Elevated: 4 days
Describe the time/release of lactate dehydrogenase following necrotic myocardium.
Appears: 24 hrs
Peaks: 72 hrs
Elevated: 7 days
What method is often used for diagnosing injury of the pancreas?
blood testing for enzymes (amylase, lipase). Although elevated levels not always due to pancreatic injury and low levels not always clear of pancreatic injury. i.e. poor sensitivity/specificity
How is renal injury diagnosed?
urine output and presence of waste products in bloodstream
How is lung injury diagnosed?
functional assessment
How is gastric injury diagnosed?
bleeding into lumen of stomach visualized via NG tube
How is colon injury diagnosed?
blood in stool, colonoscopy for specifics
How is small intestinal injury diagnosed?
distal ileum: scope
proximal duodenum: scope
jejumum: capsule camera (not very helpful) Usually don’t know there is a problem before it is too late.
Renal failure can cause a two-fold increase in serum amylase (should be excreted in urine), mimicking injury to this organ:
Pancreas
Salivary gland inflammation causes elevated levels of what enzyme that breaks down CHO?
amylase
Tumors of the lung and ovaries can produce elevated levels of this pancreatic enzyme:
amylase
Ischemic bowel releases this enzyme from the intestinal lumen into the bloodstream:
amylase
Uncontrolled diabetes mellitus can cause elevated levels of this enzyme in the bloodstream:
amylase
Acute appendicitis can cause a mild increase of this enzyme in the serum:
amylase
Describe the time/release of serum amylase following acute pancreatitis.
Rise: 6-12 hrs
Return to normal: 3-5 days if uncomplicated
In acute pancreatitis, serum lipase levels remain elevated longer or shorter than amylase levels?
Longer (8-14 days)
Which is more sensitive/specific for the Dx of acute pancreatitis, serum elevation of amylase or lipase?
Lipase
ALT catalyzes the interconversion of:
Glu and Ala
AST catalyzes the interconversion of:
Glu and Asp
Injury to this organ is most likely to elevate the ALT:AST serum ratio.
Liver
If ALT levels go up in the blood, think _______ is damaged!
Liver!
Acute hepatic injury due to viral infection or acetaminophen overdose causes an elevation in this outer cell membrane enzyme found in greatest number in hepatocytes.
Gamma-glutamyltransferase (GGT): for transfering AAs from blood into liver cells
These two diseases cause a greater elevation of GGT out of proportion to ALT:AST ratios:
- bile backup due to hepatic/common bile duct obstruction.
2. Alcoholic liver disease (in part because EtOH is a potent inducer of GGT synthesis by the hepatocytes.)
Describe the function of Alkaline phosphatase (ALP).
A phosphatase that transfers inorganic phosphate from donor to receptor molecules at an alkaline pH.
Cholestatic liver disease causes elevated _____ out of proportion to ALT and AST.
ALP
Alcoholic liver disease causes more elevation of which enzyme? ALT:AST, ALP, GGT
GGT
Malignant tumors in the liver cause more elevation of which enzyme: ALP, GGT, ALT:ASP
ALP
Lactate Dehydrogenase (LDH) serves what function?
catalyzes the conversion of lactate to pyruvate by removing two hydrogens.
Skeletal muscle injury causes LDH levels to drop or rise?
Rise
What impact does acute MI have on serum LDH levels?
Increases
What impact does acute pulmonary infarct have on serum LDH levels?
Increases
Malignant tumors have what impact on serum LDH levels?
Increases. Especially when metastasized to the liver.
Hepatitis has what impact on serum LDH levels?
Increases
Hemolysis has what impact on serum LDH levels?
Increases
