Flashcards in 1 - What is Rheumatology and Phenotype of Systemic Inflammation Deck (51):
What is Rheumatology a subspecialty of?
What are the key areas of expertise of a Rheumatologist?
Systemic Auto-immune and Auto-inflammatory Conditions
What is the overlap between musculoskeletal medicine and auto-immune/auto-inflammtory diseases?
The bright side of having a systemic inflammatory response
Defense against infection
Hemostasis/Homeostasis after acute tissue damage/injury
The dark side of having a systemic inflammatory response
Overly excessive inflammatory response
Pleiotropic effects of inflammatory mediators
Inflammation is NECESSARY to clear the infection
Prevent entrenchment or dissemination (bacteremia has high mortality rate)
Inflammation CAUSES most of the irreparable damage to the joint. UGH
This also happens in ARDS and post-inflammatory changes after encephalitis or CVA
Systemic Inflammatory Response - Immune Effectors
Systemic Inflammatory Response - Cytokines
Cytokines - Effect on Bone Marrow
Cytokines - Effect on CNS
Cytokines - Effect on Liver
Synthesis of Acute Phase Reactants
Reduced albumin synthesis
Cytokines - Effect on Muscle
Reduced glucose uptake
Cytokines - Effect on Adipose
Free Fatty Acid Release
Cytokines - Effect on Blood Vessels
Endothelium primed for leukocyte transmigration
Cytokines - Effect on ReticuloEndothelial System
Migration of dendritic cells to lymph nodes
Acute Phase Reactants - Induced in response to
Cytokines and other extra-cellular signals
Acute Phase Reactants - Importance in systemic inflammatory response
Varies depending on reactant
Pro-inflammatory vs. Anti-inflammatory
Acute Phase Reactants - Test characteristics
Circulate in much higher concentrations than cytokines, easily identified as markers for disease processes.
Examples of Acute Phase Reactants
Serum Amyloid A
Mannose binding lectin
Macrophages produce TNF-α and IL-1
These induce IL-6
This induces the liver to produce the above.
Lab Measures of Acute Phase Reactants
C-Reactive Protein (CRP)
Erythrocyte Sedimentation Rate (ESR)
Pentamer of 23kDa subunits
Synthesized by hepatocytes under cytokine (primarily IL-6) stimulation
Binds to macrophages to induce inflammatory cytokines
Binds to endothelial cells to expose tissue factor
May have putative anti-inflammatory effects
Primarily used to measure the inflammatory response in patients
Erythrocyte Sedimentation Rate
The rate at which RBCs will migrate over an hour, the distance they will travel in an upright tube in that time.
What increases the ESR?
Temperature of sample
Increase in plasma proteins(immunoglobulins, fibrinogen, etc)
Microcytic anemia or variable RBC size
Increase in plasma viscosity
What decreases the ESR?
Sickle cell anemia
You see an elevated or depressed ESR. What do you ask?
Is this because of a response to cytokines?
Is this because of another factor unrelated to inflammation?
Proposed benefits of fever during infection
Inhibition of bacterial growth
Facilitates killing by macrophages and PMNs
How do exogenous pyrogens and microbes cause a fever?
They stimulate leukocytes to produce endogenous pyrogens
Mostly monocytes/macrophages and neutrophils
Fever during Infection - Mechanism
Endogenous pyrogens circulate
Endogenous pyrogens signal the CNS (multiple redundant mechanisms)
Prostaglandins (PGE2) are synthesized
This elevates the thermostatic set point of the hypothalamus (No PGE receptor = no fever)
Fever is dampened by poorly-understood endogenous anti-pyrogens
Fever during Chronic Inflammatory Diseases - Mechanism
Same process as during infection, except instead of endogenous pyrogens triggering it, we have exogenous pyrogens:
Anemia of Inflammation
Anemia of Chronic Disease (previous name)
Associated with chronic infections, inflammatory diseases, neoplastic disorders
Affects Iron, Erythropoietin, RBC survival
NOT resolved by exogenous Fe or Erythropoietin.
Anemia of Inflammation - Levels
Circulating iron is normal (Lecturer said normal, slide said decreased)
Iron binding capacity is decreased
Whole body iron stores are normal or increased
Blunted response to endogenous and exogenous erythropoietin
RBC life span is reduced
NOT resolved by exogenous Fe or Erythropoietin
Anemia of Inflammation - Mechanism
IL-6 levels are high
This raises hepcidin levels
This destroys ferroportin
This causes less iron to be absorbed, and for iron to get trapped in hepatocytes and macrophages.
Treat with an IL-6 inhibitor!
Small peptide/hormone (25aa)
Synthesized in liver
Expressed primarily in liver (less in kidney, heart, muscle, brain)
Negative regulator of iron homeostasis
Mutations in hepcidin lead to severe juvenile hemochromatosis
Hepcidin knockout leads to
Multi-organ iron overload
Hepcidin overexpression leads to
Severe Fe deficiency anemia
How does Hepcidin regulate iron?
In the duodenum, where iron is absorbed, hepcidin destroys ferroportin channels in the setting of iron excess.
This prevents the basal translocation of further iron into the bloodstream, when we already have too much.
This means iron is trapped in the hepatocytes, rather than allowed into the bloodstream.
Iron can also be trapped in macrophages due to this process.
What are the regulators of Hepcidin?
Serum Iron (low serum iron suppresses hepcidin, high serum iron induces hepcidin)
Inflammation (IL-6 via NF-κB) - THIS IS THE PRIMARY REGULATOR
Cachexia - Definition
Loss of lean (non-fat) mass in the setting of systemic inflammation
Distinct from frank wasting (not associated with malnutrition, the fat is unaffected or even INCREASED)
Related to, but distinct from aging-associated sarcopenia
Cachexia - Mechanism
Cytokine-driven (TNF-α, IL-6, IL-1)
Degradation mediated through NF-κB
Reduced physical activity
Effects of altered hormone signaling/insulin not well studied
Energy Metabolism - Normal
Glucose & Free Fatty Acids are essential sources of energy during infection, acute injury, healing
Energy Metabolism - Acute Inflammation
Cytokines facilitate release of glucose & free fatty acids into circulation
These target liver, adipose & skeletal muscle
Energy Metabolism - Chronic exposure to the cytokines of acute inflammation leads to:
Atherogenic lipid profile
(particularly in the setting of energy excess and other CV risk factors)
TNF-α and Glucose Metabolism
Adipose - Acts through p55 receptor:
Free Fatty Acid Release
Increased hepatic gluconeogenesis
Increased triglyceride production (synergized under IL-1, IL-6)
Increased VLDL production, enriched with triglyceride, decreased clearance
Skeletal Muscle - Acts through the p55 receptor in combination with the free fatty acids released from the adipose tissue:
Altered insulin-signaled glucose uptake
TNF-α and reduced insulin-stimulated glucose uptake in skeletal muscle - Mechanism
Inhibition of auto-phosphorylation of the insulin receptor
Apo A-1 (a component of HDL) promotes reverse cholesterol process
Inflammation results in accumulation of oxidants in HDL
This inactivates Apo A-1
This also facilitates the formation of oxidized LDL
Chronic Inflammation - Steps of Atherogenesis/Thrombosis
Chronic inflammation is linked to all stages of atherogenesis/thrombosis
Endothelial dysfunction (earliest stage)
Atheroma formation (potentiated by other CVD risk factors)
Plaque instability and rupture (results in MI)
Atherogenesis/Thrombosis - Effects (direct or indirect) of cytokines on the vasculature
Up-regulate vascular adhesion molecules
Activate and recruit macrophages
Upregulate other pro-inflammatory cytokines
Remodel vascular matrix (MMPs, TIMPs)
Regulate the apoptosis of vascular SMCs
Induce pro-coagulant state (PAI-1)
Modulate glucose metabolism
Modulate fat/lipid metabolism
Antagonize anti-inflammatory pathways
"Thin capped fibroatheroma"
Rupture is prone to a plaque weak at the "shoulders"
Shoulders with few SMC, PG, collagen
More macrophages and infiltrating t-cells