L26 - Cellular Response to Injury 2: Accumulations

What is Hepatic Lipidosis?

An energy imbalance overwhelms the liver's ability to metabolize and clear fatty acids → triglycerides accumulate inside hepatocytes

What are the 2 BASIC pathways that can lead to Hepatic Lipidosis?

1. Overload: too much fat is delivered/mobilized to the liver

2. Altered cell/metabolic function: liver cannot properly handle/metabolize fat

How can negative energy balance cause Hepatic Lipidosis?

Body mobilizes stored fat for energy → large amounts of fatty acids travel to the liver → liver becomes overwhelmed → triglycerides accumulate

What are Examples of fat mobilization causing Hepatic Lipidosis?

• Peri-parturient cows: negative energy balance

• Anorexic cats: stored fat mobilized to supply energy.

How can altered metabolism cause Hepatic Lipidosis?

Improper nutrient/fat handling can increase fatty-acid use or decrease the liver's ability to process fat

How can diabetes mellitus contribute to Hepatic Lipidosis?

Insufficient carbohydrate processing → preferential use of fatty acids → hepatic lipidosis

Is Hepatic Lipidosis usually Reversible?

Yes

• It is generally a reversible injury and a sign of cellular dysfunction

What can happen if Hepatic Lipidosis is prolonged?

• Hepatocellular injury/death

• Hepatic inflammation

• Additional metabolic changes

• Liver fibrosis

What is a Lysosomal Storage Disease (LSD)?

An inherited enzyme deficiency causes lysosomes to be unable to properly break down proteins, lipids, or carbohydrates → partially digested material accumulates inside cells

What happens to cells in Lysosomal Storage Diseases?

Material accumulates → interferes with normal cell function → may eventually cause cell death

What lysosomal processes can be disrupted in an LSD?

• Enzyme synthesis/fidelity

• Trafficking

• Fusion

Which tissues are preferentially affected by Lysosomal Storage Diseases?

1. Brain

2. Liver

3. Muscle

   
   

Why are neurons/brain commonly affected by Lysosomal Storage Diseases?

These tissues have rapid organelle turnover + high energy demands, making normal lysosomal recycling especially important

What determines which tissues are affected by a particular LSD?

Enzyme expression/activity + substrate production within that tissue

What is Extravascular Hemolysis?

RBC breakdown occurs inside macrophages → hemoglobin is released into a phagocytic cell

What is Intravascular Hemolysis?

RBCs rupture within the vasculature → hemoglobin is released directly into the blood.

What pigment is associated with Extravascular Hemolysis?

Hemosiderin → Yellow-brown pigment found within macrophages

What is a major clinical sign of Extravascular Hemolysis?

Icterus (jaundice)

What is a major clinical sign of Intravascular Hemolysis?

Hemoglobinuria

Why does Intravascular Hemolysis cause Hemoglobinuria?

RBCs rupture in circulation → free hemoglobin enters blood → kidneys filter the hemoglobin before macrophages can process it → hemoglobin appears in urine

What does Hemosiderin tell you about the timing of hemorrhage?

Hemosiderin takes time to form → indicates chronicity/older hemorrhage (days, weeks, or months)

What is icterus (jaundice)?

Yellow discoloration associated with accumulation of bilirubin in tissues

How does Extravascular Hemolysis lead to Icterus?

RBCs phagocytosed by macrophages → hemoglobin broken down → bilirubin produced → bilirubin is secreted/absorbed by tissues → icterus

What process does Hemolytic Icterus represent?

Severe extravascular hemolysis

Hepatic Lipidosis — 2 Pathways SUMMARY

Energy/metabolic imbalance → ↑ fatty acids to/within liver → liver overwhelmed → ↑ triglycerides in hepatocytes → hepatic lipidosis

Pathway	What happens?	Example
Overload	Too much fat delivered/mobilized to liver → liver can't process it all	Peri-parturient cow Anorexic cat
Altered cell/metabolic function	Improper handling/metabolism of fat	Diabetes Cell injury
End result	→ Triglycerides accumulate in hepatocytes	Hepatic lipidosis

Intravascular vs. Extravascular Hemolysis SUMMARY

INTRA = IN the blood → Hb reaches kidney → hemoglobinuria
EXTRA = macrophages → bilirubin → icterus

	Intravascular Hemolysis	Extravascular Hemolysis
Where?	Within blood vessels	Within macrophages
RBCs	Rupture in circulation	Phagocytosed by macrophages
Hemoglobin goes...	Directly into blood	Into macrophage
Important pigment/product	Free hemoglobin	Hemosiderin + bilirubin
Where seen?	Blood → kidneys → urine	Macrophages/tissues
Major clinical sign	Hemoglobinuria	Icterus (jaundice)
Examples	Copper toxicosis, bacterial toxemia, sepsis	IMHA, trauma

Hemoglobin Breakdown / Pigment SUMMARY

Product	Comes From	Location	What does it tell me?
Hemoglobin	RBC destruction	Blood with intravascular hemolysis	Can be filtered by the kidneys
Hemosiderin	Hgb/iron breakdown	Macrophages	Older/chronic hemorrhage
Bilirubin	Hgb breakdown by macrophages	Can accumulate in tissues	→ Icterus

Lysosomal Storage Disease — Cause → Effect SUMMARY

1. Defect

   • Inherited enzyme/protein defect

2. Lysosome problem

   • Can't properly break down material

3. Result

   • Partially digested material accumulates

4. Cell

   • Dysfunction → death

Why Brain, Liver & Muscle? SUMMARY

Tissues commonly affected	Why?
Brain/neurons	High energy demand + organelle turnover
Muscle	High energy demand
Liver	High energy demand
Overall	Accumulated material eventually interferes with cell function

Intracellular Pigments SUMMARY

Pigment	Source	Key significance
Hemosiderin	Blood/Hgb breakdown	Hemorrhage; chronicity
Lipofuscin	Oxidized phospholipids	“Wear & tear” pigment
Melanin	Tyrosine in melanocytes	“Wear & tear” pigment