Overview

Intracellular accumulations

• Etiology: 
  • Metabolic derangement
  • Intrinsic abnormality in the cell function (genetic disease)
  • Exogenous source
• Effect: Substances that accumulate may or may not be harmful.

Mechanisms

• Abnormal metabolism:
  • Normal substance produced → defect in packaging and transport → substance build-up
  • Seen in fatty liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver (increase in lipid particles)
• Abnormal protein folding and transport:
  • Abnormal substance (misfolded proteins) produced → overwhelms repair → accumulate in the endoplasmic reticulum (ER)
  • Seen in ɑ-1 antitrypsin deficiency
• Lack of enzyme:
  • Substrate → failure to convert to the final product (no enzyme) → increased amount of substrate
  • Seen in lysosomal storage disease Lysosomal storage disease Lysosomal storage diseases are a group of metabolic disorders caused by genetic mutations in the enzymes responsible for normal lysosomal function. The dysfunction of enzymatic processes causes an accumulation of undigested metabolites, resulting in cellular death. The main groups include sphingolipidoses, oligosaccharidoses, and mucolipidoses. Overview of Lysosomal Storage Diseases
• Deposition of an exogenous material or indigestible substance:
  • Exogenous substance → cell with no capacity to degrade or transport → accumulation
  • Seen in silicosis (silica) and anthracosis (carbon)

Calcium Accumulation

Metastatic calcification

• Calcium deposition in normal or abnormal tissues due to hypercalcemia Hypercalcemia Hypercalcemia (serum calcium > 10.5 mg/dL) can result from various conditions, the majority of which are due to hyperparathyroidism and malignancy. Other causes include disorders leading to vitamin D elevation, granulomatous diseases, and the use of certain pharmacological agents. Symptoms vary depending on calcium levels and the onset of hypercalcemia. Hypercalcemia
• Hypercalcemia:
  • Parathyroid hormone (PTH) excess or hyperparathyroidism Hyperparathyroidism Hyperparathyroidism is a condition associated with elevated blood levels of parathyroid hormone (PTH). Depending on the pathogenesis of this condition, hyperparathyroidism can be defined as primary, secondary or tertiary. Hyperparathyroidism:
    • Parathyroid tumors
    • Malignant tumors secreting PTH-related protein
  • Secondary hyperparathyroidism Hyperparathyroidism Hyperparathyroidism is a condition associated with elevated blood levels of parathyroid hormone (PTH). Depending on the pathogenesis of this condition, hyperparathyroidism can be defined as primary, secondary or tertiary. Hyperparathyroidism from renal disease (due to phosphate retention)
  • Resorption of bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Structure of Bones tissue:
    • Immobilization
    • Bone metastasis
    • Increased bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Structure of Bones turnover (Paget’s disease)
    • Bone marrow Bone marrow Bone marrow, the primary site of hematopoiesis, is found in the cavities of cancellous bones and the medullary canals of long bones. There are 2 types: red marrow (hematopoietic with abundant blood cells) and yellow marrow (predominantly filled with adipocytes). Composition of Bone Marrow malignancies ( multiple myeloma Multiple myeloma Multiple myeloma (MM) is a malignant condition of plasma cells (activated B lymphocytes) primarily seen in the elderly. Monoclonal proliferation of plasma cells results in cytokine-driven osteoclastic activity and excessive secretion of IgG antibodies. Multiple Myeloma, leukemia)
  • Vitamin D disorders (vitamin D intoxication, sarcoidosis Sarcoidosis Sarcoidosis is a multisystem inflammatory disease that causes noncaseating granulomas. The exact etiology is unknown. Sarcoidosis usually affects the lungs and thoracic lymph nodes, but it can also affect almost every system in the body, including the skin, heart, and eyes, most commonly. Sarcoidosis)
• Affects acid-secreting cells (alkali environment predisposes to metastatic calcification):
  • Gastric mucosa
  • Lungs
  • Kidneys Kidneys The kidneys are a pair of bean-shaped organs located retroperitoneally against the posterior wall of the abdomen on either side of the spine. As part of the urinary tract, the kidneys are responsible for blood filtration and excretion of water-soluble waste in the urine. Kidneys (nephrocalcinosis)
  • Systemic arteries Arteries Arteries are tubular collections of cells that transport oxygenated blood and nutrients from the heart to the tissues of the body. The blood passes through the arteries in order of decreasing luminal diameter, starting in the largest artery (the aorta) and ending in the small arterioles. Arteries are classified into 3 types: large elastic arteries, medium muscular arteries, and small arteries and arterioles. Arteries
  • Pulmonary veins Veins Veins are tubular collections of cells, which transport deoxygenated blood and waste from the capillary beds back to the heart. Veins are classified into 3 types: small veins/venules, medium veins, and large veins. Each type contains 3 primary layers: tunica intima, tunica media, and tunica adventitia. Veins

Dystrophic calcification

• Deposition of calcium in abnormal (necrotic) tissues with normal calcium levels
• Gross morphology: hard, yellowish granules or deposits
• Microscopic morphology: 
  • Calcium salts: basophilic, amorphous granular appearance
  • Psammoma bodies: concentric lamellated structures from calcium build-up (in papillary thyroid cancer Thyroid cancer Thyroid cancer is a malignancy arising from the thyroid gland cells: thyroid follicular cells (papillary, follicular, and anaplastic carcinomas) and calcitonin-producing C cells (medullary carcinomas). Rare cancers are derived from the lymphocytes (lymphoma) and/or stromal and vascular elements (sarcoma). Thyroid Cancer, meningioma Meningioma Meningiomas are slow-growing tumors that arise from the meninges of the brain and spinal cord. The vast majority are benign. These tumors commonly occur in individuals with a history of high doses of skull radiation, head trauma, and neurofibromatosis 2. Meningioma, ovarian papillary serous cystadenocarcinoma)
• Found in:
  • Blood vessels (atheromas of atherosclerosis Atherosclerosis Atherosclerosis is a common form of arterial disease in which lipid deposition forms a plaque in the blood vessel walls. Atherosclerosis is an incurable disease, for which there are clearly defined risk factors that often can be reduced through a change in lifestyle and behavior of the patient. Atherosclerosis)
  • Damaged heart valves
  • Aging
  • Infections (e.g., tuberculosis Tuberculosis Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis complex bacteria. The bacteria usually attack the lungs but can also damage other parts of the body. Approximately 30% of people around the world are infected with this pathogen, with the majority harboring a latent infection. Tuberculosis spreads through the air when a person with active pulmonary infection coughs or sneezes. Tuberculosis, toxoplasmosis Toxoplasmosis Toxoplasmosis is an infectious disease caused by Toxoplasma gondii, an obligate intracellular protozoan parasite. Felines are the definitive host, but transmission to humans can occur through contact with cat feces or the consumption of contaminated foods. The clinical presentation and complications depend on the host's immune status. Toxoplasma/Toxoplasmosis)

Protein Accumulation

Microscopic morphology

• Eosinophilic
• Intracellular aggregates, vacuoles, or droplets

Causes

• Increased protein reabsorption in the proximal renal tubule:
  • Affects kidneys (proteinuria in nephrotic syndrome Nephrotic syndrome Nephrotic syndrome is characterized by severe proteinuria, hypoalbuminemia, and peripheral edema. In contrast, the nephritic syndromes present with hematuria, variable loss of renal function, and hypertension, although there is sometimes overlap of > 1 glomerular disease in the same individual. Nephrotic Syndrome)
  • More protein leakage across the glomerular filter, more protein reabsorbed into vesicles
  • Microscopic morphology: pink hyaline droplets in the tubule cytoplasm 
• Increased protein production:
  • Abundant immunoglobulin synthesis in plasma cells → protein accumulation in the ER → Russell bodies
• Increased cytoskeletal proteins:
  • Cytoskeleton Cytoskeleton A cell's cytosol is the liquid inside the cell membrane that surrounds the organelles and cytoskeleton. The cytosol is a complex solution where many biochemical processes take place. The Cell: Cytosol and Cytoskeleton proteins:
    • Support the plasma membrane and the organization of organelles Organelles A cell is a complex unit that performs several complex functions. An organelle is a specialized subunit within a cell that fulfills a specific role or function. Organelles are enclosed within their own lipid bilayers or are unbound by membranes. The Cell: Organelles
    • Microtubules, actin filaments, myosin filaments, or intermediate filaments
  • Found in:
    • Alzheimer’s disease: One of the hallmarks is neurofibrillary tangle (microtubule-associated tau proteins).
    • Alcoholic liver disease Alcoholic Liver Disease Alcoholic liver disease is a spectrum of disorders ranging from fatty liver to cirrhosis secondary to chronic alcohol abuse. Excessive and prolonged consumption of alcohol results in impairment of the lipolysis pathway, causing inflammatory changes within the hepatocytes. Patients typically present during the hepatitis stage with jaundice, fever, and abdominal pain. Alcoholic Liver Disease: has alcoholic hyaline or Mallory hyaline, a cytoplasmic inclusion (made of keratin intermediate filaments)
• Defect in intracellular transport and protein secretion:
  • ɑ-1 antitrypsin deficiency: Genetic mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations leads to misfolding of ɑ-1antitrypsin. 
  • Abnormal ɑ-1antitrypsin accumulates in the ER of the liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver → cirrhosis Cirrhosis Cirrhosis is a late stage of hepatic parenchymal necrosis and scarring (fibrosis) most commonly due to hepatitis C infection and alcoholic liver disease. Patients may present with jaundice, ascites, and hepatosplenomegaly. Cirrhosis can also cause complications such as hepatic encephalopathy, portal hypertension, portal vein thrombosis, and hepatorenal syndrome. Cirrhosis
  • Lack of functional ɑ-1antitrypsin → alveolar damage in the lungs Lungs Lungs are the main organs of the respiratory system. Lungs are paired viscera located in the thoracic cavity and are composed of spongy tissue. The primary function of the lungs is to oxygenate blood and eliminate CO2. Lungs
• Abnormal proteins (protein aggregation diseases):
  • Deposition of misfolded proteins disrupting tissue functions
  • Can be intracellular and/or extracellular
  • Amyloidosis Amyloidosis Amyloidosis is a disease caused by abnormal extracellular tissue deposition of fibrils composed of various misfolded low-molecular-weight protein subunits. These proteins are frequently byproducts of other pathological processes (e.g., multiple myeloma). Amyloidosis: 
    • Extracellular deposition of amyloid, an insoluble fibrillar protein 
    • Amyloid stains pink or red in Congo red stain and apple-green birefringence under polarized light.

Lipid Accumulation

Triglycerides

• Fatty change or steatosis
  • Represents reversible injury or an abnormality in fat metabolism
  • Organs affected: 
    • Liver (major organ for fat metabolism)
    • Kidney
    • Heart 
    • Skeletal muscle
  • Found in:
    • Fatty liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver: associated with alcohol abuse and non-alcoholic steatotic liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver disease
    • Others: toxin injury, diabetes mellitus Diabetes mellitus Diabetes mellitus (DM) is a metabolic disease characterized by hyperglycemia and dysfunction of the regulation of glucose metabolism by insulin. Type 1 DM is diagnosed mostly in children and young adults as the result of autoimmune destruction of β cells in the pancreas and the resulting lack of insulin. Type 2 DM has a significant association with obesity and is characterized by insulin resistance. Diabetes Mellitus, anoxia, obesity Obesity Obesity is a condition associated with excess body weight, specifically with the deposition of excessive adipose tissue. Obesity is considered a global epidemic. Major influences come from the western diet and sedentary lifestyles, but the exact mechanisms likely include a mixture of genetic and environmental factors. Obesity
• Gross morphology: yellow discoloration of the organ
• Microscopic morphology: 
  • Vacuoles of lipidic content within the cells
  • Vacuoles have well-defined edges.

Cholesterol

• Accumulates in phagocytic cells due to lipid overload
• Microscopic morphology: intracellular vacuoles
• Found in:
  • Atherosclerosis
    • Atherosclerotic plaque: accumulation of cholesterol, seen as vacuoles, in the intimal smooth muscle cells and macrophages
  • Xanthomas
    • Plaques or nodules from intracellular cholesterol in the subepithelial connective tissue Connective tissue Connective tissues originate from embryonic mesenchyme and are present throughout the body except inside the brain and spinal cord. The main function of connective tissues is to provide structural support to organs. Connective tissues consist of cells and an extracellular matrix. Connective Tissue of skin and tendons
    • Found in altered lipid metabolism Lipid Metabolism Lipid metabolism is the processing of lipids for energy use, energy storage, and structural component production. Lipid metabolism uses fats from dietary sources or from fat stores in the body. A complex series of processes involving digestion, absorption, and transport are required for the proper metabolism of lipids. Lipid Metabolism
  • Cholesterolosis
    • Cholesterol-laden macrophages or foam cells in the lamina propria of the gallbladder Gallbladder The gallbladder is a pear-shaped sac, located directly beneath the liver, that sits on top of the superior part of the duodenum. The primary functions of the gallbladder include concentrating and storing up to 50 mL of bile. Gallbladder and Biliary Tract
    • Frequently coexists with cholesterol gallstones
  • Niemann-Pick disease Niemann-Pick disease Niemann-Pick disease (NPD) is a rare, inherited, lysosomal storage disorder. The disease is classified on the basis of the genetic mutation. Type A and type B result from mutations in the SMPD-1 gene, resulting in acid sphingomyelinase enzyme deficiency. Type C results from NPC1 or NPC2 gene mutations, which are needed for intracellular transport of lipids. Niemann-Pick Disease, type C
    • Autosomal recessive lysosomal storage disease Lysosomal storage disease Lysosomal storage diseases are a group of metabolic disorders caused by genetic mutations in the enzymes responsible for normal lysosomal function. The dysfunction of enzymatic processes causes an accumulation of undigested metabolites, resulting in cellular death. The main groups include sphingolipidoses, oligosaccharidoses, and mucolipidoses. Overview of Lysosomal Storage Diseases due to mutations in either NPC1 or NPC2 
    • Impaired cholesterol transport out of the lysosome
    • Associated with progressive central nervous system Nervous system The nervous system is a small and complex system that consists of an intricate network of neural cells (or neurons) and even more glial cells (for support and insulation). It is divided according to its anatomical components as well as its functional characteristics. The brain and spinal cord are referred to as the central nervous system, and the branches of nerves from these structures are referred to as the peripheral nervous system. General Structure of the Nervous System disease

Phospholipids

• Released from damaged cell membranes in cell injury Cell injury The cell undergoes a variety of changes in response to injury, which may or may not lead to cell death. Injurious stimuli trigger the process of cellular adaptation, whereby cells respond to withstand the harmful changes in their environment. Overwhelmed adaptive mechanisms lead to cell injury. Mild stimuli produce reversible injury. If the stimulus is severe or persistent, injury becomes irreversible. Cell Injury and Death
• Myelin figures (whorled phospholipids):
  • Accumulate in the cytosol 
  • Degraded into fatty acids or phagocytosed when the cell dies

Glycogen Accumulation

• Glycogen: normally stored in the liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver and skeletal muscles
• Excessive glycogen deposits within cells found in:
  • Glucose metabolism abnormalities ( diabetes mellitus Diabetes mellitus Diabetes mellitus (DM) is a metabolic disease characterized by hyperglycemia and dysfunction of the regulation of glucose metabolism by insulin. Type 1 DM is diagnosed mostly in children and young adults as the result of autoimmune destruction of β cells in the pancreas and the resulting lack of insulin. Type 2 DM has a significant association with obesity and is characterized by insulin resistance. Diabetes Mellitus)
  • Glycogen storage disease
• Microscopic morphology: 
  • Glycogen: clear vacuoles in the cytoplasm
  • Rose-to-violet color when stained with Best’s carmine or PAS (periodic acid-Schiff) reaction
  • Diastase removes glycogen from the histologic section. 
• Affected organs: liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver, heart, skeletal muscle, kidneys, and pancreas

Hyaline Change

Description

• Not a pattern of accumulation but a histologic finding also seen in various retained substances 
• Can be intra- or extracellular
• Microscopic morphology: glassy, homogeneous pink appearance in the cell (hematoxylin and eosin stain)

Cellular findings

• Extracellular
  • Arteriolar hyalinosis: 
    • Thickened arteriolar walls demonstrate homogeneous pink hyaline material.
    • Due to leakage of plasma proteins and deposition of concentric extracellular material
    • Seen in hypertension Hypertension Hypertension, or high blood pressure, is a common disease that manifests as elevated systemic arterial pressures. Hypertension is most often asymptomatic and is found incidentally as part of a routine physical examination or during triage for an unrelated medical encounter. Hypertension and diabetes
  • Amyloid
• Intracellular
  • Protein reabsorption droplets in proteinuria
  • Russell bodies 
  • Alcoholic hyaline (Mallory body or hyaline)
  • Councilman bodies or acidophil bodies:
    • From hepatocyte apoptosis (cell shrinkage, pyknosis, karyorrhexis, and cellular fragmentation)
    • Seen in yellow fever Yellow Fever Yellow fever is a disease caused by the yellow fever virus, a single-stranded, positive-sense RNA virus of the genus Flavivirus. Humans and primates serve as reservoirs, and transmission occurs from the bite of an infected female mosquito. Most patients present with fever and flu-like symptoms. Yellow Fever Virus, hepatitis