TISSUE REACTIONS

Intracellular accumulations

Vicente Hernández Rabaza, PhD

 Index

Brain Warm-up
Class 1
Exercises
Work/Game
Presentation made by Vicente Hernández Rabaza, PhD
 Brain

Warm-up

Presentation made by Vicente Hernández Rabaza, PhD

Who was Giovanni Battista Morgagni?

Who wrote De Humanis Corpore Fabrica?

What did you learn in the last class?

Presentation made by Vicente Hernández Rabaza, PhD

 What do you see in this image?
This is cardiac hypertrophy involving
the left ventricle. The number of
myocardial fibers does not increase, but
their size can increase in response to an
increased workload, leading to the marked
thickening of the left ventricle in this patient
with systemic hypertension.

Question:
Why is bigger not always better?

This compensatory hypertrophy is

pathologic because the process is
maladaptive over time, with eventual
myocyte loss, fibrosis, and ventricular
dysfunction. In contrast, athletic training
Image and text source: The Internet Pathology Laboratory for Medical Education. The University of Utah. Eccles Health Science Library. Slide configuration: leads to minimal increase in heart size,
Vicente Hernández Rabaza
but marked increase in cardiac function.
Presentation made by Vicente Hernández Rabaza, PhD
 There are three basic steps in the molecular pathogenesis of cardiac hypertrophy:

Image from: Robbins & Cotran Pathologic Basis of Disease Presentation made by Vicente Hernández Rabaza, PhD
 What do you see in this image?

This is cellular dysplasia in the

uterine cervix. The normal
cervical squamous epithelium has
become transformed to a more
disorderly growth pattern,
or dysplastic epithelium. This is
farther down the road toward
neoplasia, but dysplasia is still a
potentially reversible process.

Image and text source: The Internet Pathology Laboratory for Medical Education. The University of Utah. Eccles Health Science Library. Slide configuration: Vicente Hernández Rabaza Presentation made by Vicente Hernández Rabaza, PhD
What do you see in this image?

The testis at the right has undergone atrophy

and is much smaller than the normal testis at
the left.

Question: Why would one testis be atrophic?

Cryptorchidism-un undescended testis that did

not fully develop. Mumps infection in adults
may affect one testis more than the other

Presentation made by Vicente Hernández Rabaza, PhD

Index
A. Intracellular accumulations
B. Lipids, fat accumulations.
C. Glucose-glycogen
accumulations.
D. Proteins. intracellular and
extracellular aggregations.
E. Calcium. pathological
calcification.
F. Pigments. intracellular
accumulations.

Presentation made by Vicente Hernández Rabaza, PhD

INTRACELLULAR ACCUMULATIONS

Presentation made by Vicente Hernández Rabaza, PhD

 LIPIDS. STEATOSIS (FATTY LIVER)

ad libitum

▪ Steatosis or fatty change

➢ The terms steatosis and fatty change

describe abnormal accumulations of
triglycerides within parenchymal cells ad libitum

▪ Liver: hepatic steatosis

▪ Histology: lipid droplets or lipid

vacuoles
fasted for 24

Accumulation of intracellular lipids in the hearts and livers of aged mice. Frozen tissue sections were prepared from the hearts (A and B) and
livers (C-F) of young (A,C and E) or aged (B,D and F) (C57BL/6 × DBA2) F1 mice. Tissues were harvested from mice that were either fed ad
libitum (A-D) or fasted for 24 h (E and F). All sections were stained with oil red O for analysis of lipid droplets. The presence of red droplets (↑)
indicates positive staining for neutral lipids. Photographs are representative of similar results observed in tissue sections prepared from four to
six mice per group. Magnification ×400.

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 LIPIDS. STEATOSIS (FATTY LIVER)
▪ Histology: lipid droplets or lipid vacuoles

Fatty liver. High-power detail of fatty change of the liver. In most cells the well- The red-brown granular material seen here is excessive lysosomal copper in a patient with the rare
preserved nucleus is squeezed into the displaced rim of cytoplasm about the fat autosomal recessive disorder Wilson's disease. Hepatic copper accumulation results in fatty change
vacuole. (Courtesy Dr. James Crawford, Department of Pathology, University of (seen here with cholestasis as well), acute hepatitis, chronic hepatitis, and eventual cirrhosis.
Florida School of Medicine, Gainesville, Fla.)

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 LIPIDS. STEATOSIS (FATTY LIVER)
➢ Fatty liver, by alcohol or by other causes (NAFL).

1. Alcohol liver metabolism: increased production of NADH and the followed NADH/NAD ratio
alteration.
2. Higher NADH levels induce fatty acid production
3. NAD low-level results in reduced fatty acids oxidation
4. Fatty acid accumulation is translated in production and accumulation of triglycerides
5. The triglycerides accumulates in large vesicles: fat vacuoles-fat tissue acumulation

Non-alcoholic fatty liver disease (NAFL)

Variables causes: sedentarism, diabetes,

cardiac diseases, overweight and
metabolic syndromes.

To review liver biochemistry: https://twitter.com/drmiketodorovic/status/1568119137196724226?s=20&t=PMsN9CIElEGJnzxoPPSSnQ

Presentation made by Vicente Hernández Rabaza, PhD

LIPIDS. STEATOSIS (FATTY LIVER)
➢ Steatohepatitis (SH): Fatty liver running with inflammation and fibrosis

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 LIPIDS. STEATOSIS (FATTY LIVER)
➢ Steatohepatitis (SH): Fatty liver running with inflammation and fibrosis

Mallory bodies; Keratin filaments

High magnification micrograph of a Mallory body, as seen in steatohepatitis. Original magnification
200x. Liver biopsy. H&E stain
Images taken from Wikipedia, Nephron own work Presentation made by Vicente Hernández Rabaza, PhD
LIPIDS. CARDIOVASCULAR SYSTEM

Presentation made by Vicente Hernández Rabaza, PhD

 LIPIDS. CARDIOVASCULAR SYSTEM

Atherosclerosis; subtype of arteriosclerosis

Atherosclerosis plaques, inside the smooth muscle layers, are Micrograph of an artery that supplies the heart showing significant
atherosclerosis and marked luminal narrowing. Tissue has been stained
mostly fill in with Cholesterol Esters (LDL) using Masson's trichrome. Source Wikipedia

Presentation made by Vicente Hernández Rabaza, PhD

LIPIDS. CARDIOVASCULAR SYSTEM

Presentation made by Vicente Hernández Rabaza, PhD

 GLUCOSE. GLYCOGEN DISORDERS
Glycogen storage disease (GSD)
▪ Inherited metabolic disorders of glycogen metabolism
▪ Several types has been described, based on enzymes and
organs
▪ Liver: hypoglycaemia and enlargement of the liver main
findings

Diabetes
▪ High levels of insulin block glycogenolysis, inducing liver
accumulation of glycogen

Glycogen storage disease type I. Liver

biopsy showing mosaic pattern, prominent
cell membranes and rare nuclear
hyperglycogenation (HE stain).

Images and capatations from: Ozen H. Glycogen storage diseases: new perspectives. World J
Gastroenterol. 2007 May 14;13(18):2541-53. doi: 10.3748/wjg.v13.i18.2541. PMID: 17552001;
PMCID: PMC4146814

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 GLUCOSE. GLYCOGEN DISORDERS

Glycogen store in renal tubular epithelium Glycogen store in hepatocytes

Presentation made by Vicente Hernández Rabaza, PhD

GLUCOSE. GLYCOGEN DISORDERS
Which stain is used for mark sugars?

Glycogen storage disease type IV. Liver biopsy

shows diffuse deposition of PAS positive
amylopectin like material in hepatocytes
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ENERGY METABOLIC DISORDERS

Steatosis and Fibrosis in GSD. Prominent large and small droplet fat as well as
periportal fibrosis is depicted in this case of GSD Ia. Source: basicmedicalkey.com

Presentation made by Vicente Hernández Rabaza, PhD

 PROTEINS.INTRACELLULAR AND
EXTRACELLULAR AGGREGATIONS.

Cytotoxic protein accumulation

- Location
- Synthesis
- Cellular dysfunction
- Cytoskeletal proteins
- Protein toxicity

Protein reabsorption droplets in the renal tubular epithelium. (Courtesy Dr. Helmut Rennke,
Department of Pathology, Brigham and Women’s Hospital, Boston, Mass.)

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 PROTEINS.PROTEIN TOXICITY
NEURODEGENERATIVE DISEASES
• Several organelles
• Propagation processes
• Recycling systems: Microglia and autophagy
• Infection situations

Propagation of misfolded proteins via intercellular transmission. Gradual change in the distribution of α-synuclein (a) and
tau (b) inclusions in the brains of patients suffering from Parkinson’s (a) and Alzheimer’s (b) diseases. c Intercellular
transmission of misfolded proteins via exocytosis, endocytosis, exosomes, and tunneling nanotubes
A schematic overview of protein toxicity. Accumulation of toxic disease proteins is
shown to induce dysfunctions in specified compartments such as the nucleus,
mitochondria, cytoplasm, and stress granules. They can also propagate into other
nearby cells, spreading the disease pathology
Images and capitations from: Chung, C.G., Lee, H. & Lee, S.B. Mechanisms of protein toxicity in neurodegenerative diseases. Cell. Mol. Life Sci. 75, 3159–
3180 (2018). https://doi.org/10.1007/s00018-018-2854-4

Presentation made by Vicente Hernández Rabaza, PhD

 Autophagy is a process in which a cell eats its own contents (Greek: auto, self; phagy, eating).

Modified from Choi, AMK, Ryter S, Levine B: Autophagy in human health and disease. N Engl J Med 368:651,2013.)

Autophagy

• Autophagy involves sequestration of cellular organelles into cytoplasmic autophagic vacuoles (autophagosomes) that fuse with
lysosomes and digest the enclosed material.Autophagy is an adaptive response that is enhanced during nutrient deprivation,
allowing the cell to cannibalize itself to survive.

• Autophagosome formation is regulated by more than a dozen proteins that act in a coordinated and sequential manner.

• Dysregulation of autophagy occurs in many disease states including cancers, inflammatory bowel diseases, and
neurodegenerative disorders. Autophagy plays a role in host defence against certain microbes.

Presentation made by Vicente Hernández Rabaza, PhD

The term hyaline usually refers to an alteration within cells or in the extracellular space that gives a homogeneous, glassy,
pink appearance in routine histologic sections stained with hematoxylin and eosin

Alcoholic hyaline is a
cytoplasmic alteration
observed in liver cells, e.g.
cirrhosis.

There is a hyaline
arteriosclerosis type

There is a hyaline GDS type

27
Presentation made by Vicente Hernández Rabaza, PhD
Presentation made by Vicente Hernández Rabaza, PhD
 ENDOGENOUS PIGMENT ACCUMULATION
Lipofuscin
Lipofuscin (lipochrome; fat soluble pigment)
- Orange-brown pigment
- Composed of oxidative lipids, proteins, sugars and metals
- Wear and tear; associated with some pathologies

Confocal image of a spinal motor neuron showing stained lipofuscin granules in blue and
yellow. Author: David L McIlwain, Victoria B Hoke

Presentation made by Vicente Hernández Rabaza, PhD

 What do you see in these images?

Lipofuscin granules in a cardiac myocyte shown by (left) light microscopy (deposits indicated by arrows), and (right) electron microscopy (note the
perinuclear, intralysosomal location).

Presentation made by Vicente Hernández Rabaza, PhD

 ENDOGENOUS PIGMENT ACCUMULATION
Melanin

FRECKLES, which occur in people of all races, are small, concentrated areas of increased melanin production. Melanin is produced by cells called melanocytes. It provides some protection again skin damage from the
sun, and the melanocytes increase their production of melanin in response to sun exposure

Presentation made by Vicente Hernández Rabaza, PhD

 ENDOGENOUS PIGMENT
ACCUMULATION
Melanin. Pathology situations

• Melanoma (Melanocytes mutations)

• Albinism (melanogenesis, genetic)
• Vitiligo (autoimmune disease, TYR-
gene)
• Addison disease (Stimulated melanin
hormones; MSH)

Presentation made by Vicente Hernández Rabaza, PhD

 ENDOGENOUS PIGMENT ACCUMULATION
Hemosiderin
Iron-storage complex

Pathology
- Bleeding
- Hemolysis
- Iron metabolism derangements

Hemosiderin image of a kidney viewed under a microscope. The brown areas

represent hemosiderin

Hemosiderin in the alveolar spaces

Presentation made by Vicente Hernández Rabaza, PhD
 CALCIFICATION ACCUMULATION
CALCIUM SALTS (Calcium soaps: FA +Calcium) Dystrophic calcification of the aortic valve

Types:

• Dystrophic calcification (Necrosis)

o Fat necrosis / calcium soaps (white deposits
- Lipase activity; Pancreas pathology
- Trauma, hypoxia

• Metastatic calcification, (Hypercalcemia)

- Pathological Calcium levels increases
Dystrophic calcification of the aortic valve. View looking down onto the unopened
aortic valve in a heart with calcific aortic stenosis. It is markedly narrowed
(stenosis). The semilunar cusps are thickened and fibrotic, and behind each cusp
are irregular masses of piled-up dystrophic calcification.
CALCIFICATION ACCUMULATION

Breast lump showing an area of fat necrosis showing shadowy outlines of necrotic adipocytes surrounded by
an inflammatory reaction with cholesterol clefts [H&E stain 4X]. Author: Department of Pathology, Calicut
Medical College
 EXOGENOUS PIGMENT ACCUMULATION
DUST MINERALS, AND TOXINS**
Dust of minerals
• Inflammatory reactions
• Respiratory systems
• Pathology term:
• Pneumoconiosis

** However, toxins not produces pigmentation or Anthracitic (carbon, coal) pigment—pneumoconiosis

accumulation of detectable colors “The most common exogenous pigment is carbon (coal dust), a ubiquitous air pollutant in urban areas.”

Presentation made by Vicente Hernández Rabaza, PhD

 EXOGENOUS PIGMENT ACCUMULATION
TATTOO
INK-FLAMMATION PROCCES

Green tattoo pigment is taken up by dermal macrophages (left). The pigment is released when these
cells are killed (center) but, 90 days later, is taken back up into new macrophages that have replaced
the old ones (right).; Credit: Baranska et al., 2018

Phineas Gage skull by John @ Tattoo Paradise in Rockville, MD

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Time to work and play
Who was Galen?

Presentation made by Vicente Hernández Rabaza, PhD

 REFERENCES
➢ Vicente writings.
➢ The Internet Pathology Laboratory for Medical Education. The University of Utah. Eccles Health Science Library
/ Pathology images and text for medical education - WebPath (utah.edu)
➢ UC San Diego, School of Medicine, MedPics / https://medpics.ucsd.edu/index.cfm
➢ Histology Guide. University of Leeds
➢ Robbins & Cotran Pathologic Basis of Disease

• Megías M, Molist P, Pombal MA. (2019). Atlas de histología vegetal y animal. mmegias.webs.uvigo.es/02-
english/index.html
• The University of Western Australia. Department of Anatomy and Human Biology.
http://www.lab.anhb.uwa.edu.au
Social networks:
• Diagnostic pathology (Instagram)
• #histoløgy - Búsqueda de Twitter / Twitter
• Pinterest: https://www.pinterest.es/vhrabaza/
Recommended books or blogs, for own interest:
- La vida en cuatro letras. Carlos López-Otín (Editorial Paidós Contextos)
- Blog – José Ramón Alonso (jralonso.es)
- https://culturacientifica.com/
- https://www.uchceu.es/media

Presentation and PDF created by Professor, Vicente Hernández Rabaza, vicente.hernandez@uchceu.es