Human Colors—The Rainbow Garden of Pathology: What Gives Normal and Pathologic Tissues Their Color?
Context.—
Colors are important to all living organisms because they are crucial for camouflage and protection, metabolism, sexual behavior, and communication. Human organs obviously have color, but the underlying biologic processes that dictate the specific colors of organs and tissues are not completely understood. A literature search on the determinants of color in human organs yielded scant information.
Objectives.—
To address 2 specific questions: (1) why do human organs have color, and (2) what gives normal and pathologic tissues their distinctive colors?
Data Sources.—
Endogenous colors are the result of complex biochemical reactions that produce biologic pigments: red-brown cytochromes and porphyrins (blood, liver, spleen, kidneys, striated muscle), brown-black melanins (skin, appendages, brain nuclei), dark-brown lipochromes (aging organs), and colors that result from tissue structure (tendons, aponeurosis, muscles). Yellow-orange carotenes that deposit in lipid-rich tissues are only produced by plants and are acquired from the diet. However, there is lack of information about the cause of color in other organs, such as the gray and white matter, neuroendocrine organs, and white tissues (epithelia, soft tissues). Neoplastic tissues usually retain the color of their nonneoplastic counterpart.
Conclusions.—
Most available information on the function of pigments comes from studies in plants, microorganisms, cephalopods, and vertebrates, not humans. Biologic pigments have antioxidant and cytoprotective properties and should be considered as potential future therapies for disease and cancer. We discuss the bioproducts that may be responsible for organ coloration and invite pathologists and pathology residents to look at a “routine grossing day” with a different perspective.
“I want to know one thing. What is color?” —Pablo Picasso
Nature delights us with a great variety of colors that result from the reflection of a particular wavelength of light from an object. Colors are important to all biologic organisms (that is, microorganisms, plants, and animals) because they are crucial for camouflage and protection, metabolism, sexual behavior, and communication. In general, coloration of organisms results from the production of molecules derived from cyclic compounds.
The human body and its organs have colors, that is, the liver is brown, the heart is red, bones are white, and so on. Although this is obvious and established, the reason why organs have a particular color is not completely understood. Pathologists, more than any other physicians, should be aware of the importance in recognizing normal and abnormal gross organ features—color being one of them—that translate into specific pathologic processes. Because cells are microscopic and colorless as single units, they result in a given color only when they accumulate in millions. Unhealthy and/or neoplastic tissues usually retain the color of the cells from which they derive but may also exhibit completely different color characteristics. We performed a literature search related to the biochemical source of coloration in human organs, and to our surprise, scant information is available. Because of this information gap, 2 fundamental questions were asked: why do human organs have color, and what gives normal and pathologic tissues their distinctive colors? The answers to these simple questions are elusive, even with the current revolutionary advances in molecular biology and biochemistry.
The biochemical processes related to pigment production in plants and animals could be an enormous resource to explain the color in human organs. Herein, we attempt to give a biochemical explanation for the basis of the color of human organs that, to our knowledge, is not currently available in the medical literature. None of the authors are experts in the field of biochemistry or chromatics, but all are instinctually interested in understanding more about human biology. We discuss in a simple manner the bioproducts and their physiologic importance that may be responsible for tissue coloration. We invite pathologists and pathology residents to look at a “routine grossing day” with a different perspective.
PRODUCERS OF COLOR IN HEALTHY AND NEOPLASTIC TISSUES
Carotenes and Carotenoids
In 1937, the Nobel Prize in chemistry was awarded to Paul Karrer for the description of the chemical structure of carotenes and vitamin A. Carotenes are unsaturated hydrocarbons chemically derived from isopentenyl pyrophosphate and terpenes, and include α, β, γ, δ, ɛ, and ζ carotenes, lycopenes, and xanthines.1 Carotenes are fat-soluble molecules that can produce all the colors of the visible spectrum (purple, blue, green, yellow, orange, and red) and are synthesized only by plants.2,3 Carrots (Daucus carota var. sativus), tomatoes (Solanum lycopersicum), and beets (Beta vulgaris) are examples of vegetables containing large amounts of orange, red, and purple carotenes, respectively (Figure 1, A). The word carotene derives from the Latin carota (carrot) and lycopene derives from the modern Latin lycopersicum (tomato). Carotenes also give color to leaves and fruits, but the primary green pigment chlorophyll is dominant (Greek chlóros = green). Once a leaf or a fruit ripens or dies, chlorophyll is degraded, and yellow, orange, and/or red carotenes become apparent.4 This is why leaves change color during fall, and why a banana (Musa acuminata) turns yellow when it's ripe. Xanthines (Greek xanthos = yellow) are yellow pigments (zeaxanthin, lutein, canthaxanthin) that give color to several organisms (Figure 1, A). Staphyloxanthin is the pigment that gives Staphylococcus aureus its golden-yellow color, and the second name aureus is Latin for gold (aurum). This pigment is a virulence factor that helps the organism escape death by neutrophils.
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Context.—
Colors are important to all living organisms because they are crucial for camouflage and protection, metabolism, sexual behavior, and communication. Human organs obviously have color, but the underlying biologic processes that dictate the specific colors of organs and tissues are not completely understood. A literature search on the determinants of color in human organs yielded scant information.
Objectives.—
To address 2 specific questions: (1) why do human organs have color, and (2) what gives normal and pathologic tissues their distinctive colors?
Data Sources.—
Endogenous colors are the result of complex biochemical reactions that produce biologic pigments: red-brown cytochromes and porphyrins (blood, liver, spleen, kidneys, striated muscle), brown-black melanins (skin, appendages, brain nuclei), dark-brown lipochromes (aging organs), and colors that result from tissue structure (tendons, aponeurosis, muscles). Yellow-orange carotenes that deposit in lipid-rich tissues are only produced by plants and are acquired from the diet. However, there is lack of information about the cause of color in other organs, such as the gray and white matter, neuroendocrine organs, and white tissues (epithelia, soft tissues). Neoplastic tissues usually retain the color of their nonneoplastic counterpart.
Conclusions.—
Most available information on the function of pigments comes from studies in plants, microorganisms, cephalopods, and vertebrates, not humans. Biologic pigments have antioxidant and cytoprotective properties and should be considered as potential future therapies for disease and cancer. We discuss the bioproducts that may be responsible for organ coloration and invite pathologists and pathology residents to look at a “routine grossing day” with a different perspective.
“I want to know one thing. What is color?” —Pablo Picasso
Nature delights us with a great variety of colors that result from the reflection of a particular wavelength of light from an object. Colors are important to all biologic organisms (that is, microorganisms, plants, and animals) because they are crucial for camouflage and protection, metabolism, sexual behavior, and communication. In general, coloration of organisms results from the production of molecules derived from cyclic compounds.
The human body and its organs have colors, that is, the liver is brown, the heart is red, bones are white, and so on. Although this is obvious and established, the reason why organs have a particular color is not completely understood. Pathologists, more than any other physicians, should be aware of the importance in recognizing normal and abnormal gross organ features—color being one of them—that translate into specific pathologic processes. Because cells are microscopic and colorless as single units, they result in a given color only when they accumulate in millions. Unhealthy and/or neoplastic tissues usually retain the color of the cells from which they derive but may also exhibit completely different color characteristics. We performed a literature search related to the biochemical source of coloration in human organs, and to our surprise, scant information is available. Because of this information gap, 2 fundamental questions were asked: why do human organs have color, and what gives normal and pathologic tissues their distinctive colors? The answers to these simple questions are elusive, even with the current revolutionary advances in molecular biology and biochemistry.
The biochemical processes related to pigment production in plants and animals could be an enormous resource to explain the color in human organs. Herein, we attempt to give a biochemical explanation for the basis of the color of human organs that, to our knowledge, is not currently available in the medical literature. None of the authors are experts in the field of biochemistry or chromatics, but all are instinctually interested in understanding more about human biology. We discuss in a simple manner the bioproducts and their physiologic importance that may be responsible for tissue coloration. We invite pathologists and pathology residents to look at a “routine grossing day” with a different perspective.
PRODUCERS OF COLOR IN HEALTHY AND NEOPLASTIC TISSUES
Carotenes and Carotenoids
In 1937, the Nobel Prize in chemistry was awarded to Paul Karrer for the description of the chemical structure of carotenes and vitamin A. Carotenes are unsaturated hydrocarbons chemically derived from isopentenyl pyrophosphate and terpenes, and include α, β, γ, δ, ɛ, and ζ carotenes, lycopenes, and xanthines.1 Carotenes are fat-soluble molecules that can produce all the colors of the visible spectrum (purple, blue, green, yellow, orange, and red) and are synthesized only by plants.2,3 Carrots (Daucus carota var. sativus), tomatoes (Solanum lycopersicum), and beets (Beta vulgaris) are examples of vegetables containing large amounts of orange, red, and purple carotenes, respectively (Figure 1, A). The word carotene derives from the Latin carota (carrot) and lycopene derives from the modern Latin lycopersicum (tomato). Carotenes also give color to leaves and fruits, but the primary green pigment chlorophyll is dominant (Greek chlóros = green). Once a leaf or a fruit ripens or dies, chlorophyll is degraded, and yellow, orange, and/or red carotenes become apparent.4 This is why leaves change color during fall, and why a banana (Musa acuminata) turns yellow when it's ripe. Xanthines (Greek xanthos = yellow) are yellow pigments (zeaxanthin, lutein, canthaxanthin) that give color to several organisms (Figure 1, A). Staphyloxanthin is the pigment that gives Staphylococcus aureus its golden-yellow color, and the second name aureus is Latin for gold (aurum). This pigment is a virulence factor that helps the organism escape death by neutrophils.5
Figure 1.
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A, Carotenes and carotenoids are unsaturated hydrocarbons derived from isopentenyl pyrophosphate and terpenes, which can only be produced by plants, where they are found in high concentrations. There are several carotene variants with a wide diversity of color. Young plants and fruits contain high levels of green chlorophyll that is degraded with age, exposing the color of the more-prevalent carotenes in them (yellow ripened fruit or orange-red leaves in autumn). Animals obtain carotenes from their diet, with each species able to metabolize only certain carotenes and not others. Carotenes are avidly lipophilic and are deposited predominantly in lipid-rich tissues. B, Flamingoes acquire their beautiful, pink-colored plumage from shells and fish they eat. C, Humans can only absorb certain carotenes (yellow, orange) that are present in plants and vegetables. A raw egg is an appropriate example to show how carotenes color cells yellow. The most-abundant carotenes in humans are α-carotene and β-carotene, lycopenes, and xanthines. Lipid-rich human tissues contain high amounts of yellow and orange carotenes, such as breast adipose tissue (D), clear cell renal cell carcinoma (E), submucosal intestinal lipoma (F), atypical lipomatous tumor/well-differentiated liposarcoma (G), schwannoma (H); adrenal cortical adenoma (I); and adrenal gland cortex (J). The 2 uppermost layers of the adrenal cortex are golden yellow (rich in aldosterone and lipids). However, the third layer or zona reticularis, contains high amounts of cytochromes and lipofuscin and is recognized as a thin brown line between the zona fasciculata and the adrenal medulla (gray). Retinol and xanthines are important for the retina (not shown).
Animals are unable to produce carotenes and can only obtain them from their diet. Because carotenes are lipophilic, they associate with lipid-rich tissues. The abundance of certain carotenes in the diet of animals is reflected in the colors of their plumage, fur, or skin. For example, the blue-footed booby (Sula nebouxii) owes its peculiar blue-colored beak and legs to the high amount of blue carotenes present in fish and shellfish native to the Galapagos coast. Similarly, flamingos (Phoenicopterus spp) are born with gray feathers but develop a beautiful pink plumage following the deposit of red carotenes found in the fish and shellfish they eat (Figure 1, B).6 A similar phenomenon can occur in humans. Physicians are familiar with the terms carotenemia (or xanthoderma) and lycopenemia, the yellow-orange skin discoloration that occurs after excessive consumption of carrots, tomatoes, or beets. Each animal species, including humans, metabolizes certain carotenes but not others. Thus, our tissues would not turn blue (fortunately!) even if we were to consume the blue-footed booby's diet. Humans metabolize yellow and orange carotenes but not blue or red ones for unknown reasons. To understand how carotenes give color to a single cell, one can look at a raw egg. The yellow tinge of the egg “white” and the bright yellow-orange yolk color are due to the accumulation of carotenoids and retinol (also a carotene) (Figure 1, C).7
The α-carotene and β-carotene, lycopenes, and xanthines are the most common carotenes in human tissues.8,9 They are absorbed and deposited in lipid-rich tissues even before we are born (provided from the mother's diet). Hypothetically, the adipose tissue of a human never exposed to carotenes should be white and not bright yellow, but this scenario does not exist because we ingest carotenes every day from our diet. The adrenal glands and testes are the organs with the highest concentration of β-carotene, followed by the liver.9 However, any organ or tissue with high lipid content will absorb carotenes and exhibit a bright-yellow or orange coloring, such as, the first 2 layers of the adrenal gland cortex (zona glomerulosa and fasciculata, rich in aldosterone and lipids), the ovarian corpus luteum, the macula lutea in the eye (rich in lutein and zeaxanthin), organs rich in fat (pancreas, parotid gland), and adipose tissues.10 The neoplastic counterparts of these organs and in general, tumors with high lipid content, such as lipomas, fibrolipomas, well-differentiated liposarcomas, lipoleiomyomas, adrenal cortical adenomas, and carcinomas, such as clear cell renal cell carcinomas, steroid cell tumors, fibrothecomas, and schwannomas are invariably yellow or golden yellow (Figure 1, D through J). Xanthomas and orange palpebral spots are examples of subcutaneous lesions also colored by carotenes.11 Curiously, not all types of lipids are tinged by carotenes. Myelin, the most abundant lipid of the central and peripheral nervous system, remains white despite the amount of carotenes in our body. It is possible that its chemical composition of sphingomyelin, phosphorylcholine, and ceramides somehow prevents carotenes from being deposited, or the minute amounts present are grossly imperceptible.
What are the functions of carotenes in living organisms? In plants, carotenes are crucial for photosynthesis because they transmit light energy to chlorophyll in the chloroplast. They also protect plant tissues from the action of toxic singlet oxygen. In humans, carotenes not only protect cells from the effects of ultraviolet light but also from the toxic effects of reactive oxygen species.9 Therefore, carotenes are potent antioxidants and quenchers of toxic byproducts derived from metabolic reactions. Vitamin A or retinol (which gives the retina some of its color, hence the name) is the best example of a lipid-soluble molecule with diverse functions, including vision, cell turnover of skin and mucosae, bone growth, and immune system homeostasis. There are probably several other functions of carotenes that are unknown.
Cytochromes, the Heme Group, Iron, and Bile Pigments
Pyrroles are heterocyclic aromatic molecules composed of a ring of 4 carbon atoms and one nitrogen atom (C4H5N).1 Assembly of 4 pyrrole rings forms the tetrapyrrole ring protoporphyrin, a precursor of several organic molecules. Addition of a metal atom to the central portion of protoporphyrin results in the formation of an organic prosthetic group. This chemical structure, and more importantly, the type of metal atom attached, gives these compounds their color. Iron bound to protoporphyrin is red-brown like rust (heme groups). In contrast to eggs with white shells, the “rusty” color observed in pink or brown eggshells is due to protoporphyrin deposition (Figure 2, A and B).12,13 In plants, magnesium bound to porphyrins generates the green pigment chlorophyll (Figure 2, C), and in marine arthropods and mollusks, 2 copper atoms bound to porphyrin form hemocyanin (“blue blood”), which acts as an oxygen transporter in these invertebrates. Hemocyanin turns blue when oxygenated (like copper rust) but is colorless/transparent in a deoxygenated state. Cobalt, magnesium, and copper bound to porphyrins are found in such minimal amounts in humans that they do not exert any color effect.
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