Under certain conditions, cells may accumulate abnormal amounts of various substances. These accumulations can be harmless or associated with varying degrees of injury. The substances can be located in the cytoplasm, within organelles (typically lysosomes), or in the nucleus. They may be synthesized by the affected cells or originate from elsewhere in the body. There are three main pathways of abnormal intracellular accumulations:
1. Overproduction with Inadequate Removal: A normal substance is produced at a normal or increased rate, but the metabolic rate is inadequate to remove it. An example of this is fatty change in the liver.
2. Defective Processing of Substances: A normal or abnormal endogenous substance accumulates due to genetic or acquired defects in its folding, packaging, transport, or secretion. For instance, mutations that cause defective folding and transport can lead to the accumulation of proteins, as seen in α1-antitrypsin deficiency.
3. Enzyme Deficiencies and Storage Diseases: An inherited defect in an enzyme results in the failure to degrade a metabolite, leading to storage diseases.
Additionally, an abnormal exogenous substance may be deposited and accumulate because the cell lacks the enzymatic machinery to degrade the substance or the ability to transport it to other sites. Examples include accumulations of carbon or silica particles.
Fatty Change
Fatty change refers to the abnormal accumulation of triglycerides within parenchymal cells. This phenomenon is most often observed in the liver, the primary organ involved in fat metabolism, but it can also occur in the heart, skeletal muscle, kidneys, and other organs. The condition, also known as steatosis, can be caused by various factors, including toxins, protein malnutrition, diabetes mellitus, obesity, and anoxia. In industrialized nations, alcohol abuse and diabetes associated with obesity are the most common causes of fatty change in the liver, known as fatty liver.
Pathogenesis of Fatty Change
Fatty Acid Transport and Metabolism: Free fatty acids from adipose tissue or ingested food are transported into hepatocytes. Within these cells, fatty acids are esterified to triglycerides, converted into cholesterol or phospholipids, or oxidized to ketone bodies. Some fatty acids are synthesized from acetate within the hepatocytes.
Defects Leading to Fatty Liver: Excess accumulation of triglycerides can result from defects at any step from fatty acid entry to lipoprotein exit. Hepatotoxins (e.g., alcohol) can alter mitochondrial and smooth endoplasmic reticulum function, inhibiting fatty acid oxidation. Substances like carbon tetrachloride (CCl4) and conditions like protein malnutrition decrease the synthesis of apoproteins. Anoxia inhibits fatty acid oxidation, while starvation increases fatty acid mobilization from peripheral stores.
Clinical Significance
Impact on Cellular Function: The significance of fatty change depends on its cause and severity. Mild fatty change may have no effect on cellular function. More severe fatty change may transiently impair cellular function. However, unless some vital intracellular process is irreversibly impaired, fatty change is reversible.
Progression to Severe Disease: In severe cases, fatty change may precede cell death and can be an early lesion in serious liver diseases such as non-alcoholic steatohepatitis (NASH). Understanding the mechanisms and implications of intracellular accumulations, particularly fatty change, is crucial for diagnosing and managing related conditions. Prompt identification and intervention can help reverse these changes and prevent progression to more severe disease state.
