disease
A disease is a particular abnormal condition that adversely affects the structure or function (biology), function of all or part of an organism and is not immediately due to any external injury. Diseases are often known to be medical condi ...
associated with the formation and aggregation of
crystal
A crystal or crystalline solid is a solid material whose constituents (such as atoms, molecules, or ions) are arranged in a highly ordered microscopic structure, forming a crystal lattice that extends in all directions. In addition, macros ...
s in tissues or cavities, or in other words, a
heterogeneous
Homogeneity and heterogeneity are concepts relating to the uniformity of a substance, process or image. A homogeneous feature is uniform in composition or character (i.e., color, shape, size, weight, height, distribution, texture, language, i ...
group of diseases caused by intrinsic or environmental microparticles or crystals, promoting tissue
inflammation
Inflammation (from ) is part of the biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. The five cardinal signs are heat, pain, redness, swelling, and loss of function (Latin ''calor'', '' ...
and
scarring
A scar (or scar tissue) is an area of fibrous tissue that replaces normal skin after an injury. Scars result from the biological process of wound repair in the skin, as well as in other organs, and tissues of the body. Thus, scarring is a nat ...
.
Composition
Crystallopathies can be associated with four main kinds of crystalline structures: liquid non-aggregating crystal solutions,
amorphous
In condensed matter physics and materials science, an amorphous solid (or non-crystalline solid) is a solid that lacks the long-range order that is a characteristic of a crystal. The terms "glass" and "glassy solid" are sometimes used synonymousl ...
nano-scale solid particles, crystalline micro-scale solid particles, and polycrystalline larger solid structures. They can be composed of various
mineral
In geology and mineralogy, a mineral or mineral species is, broadly speaking, a solid substance with a fairly well-defined chemical composition and a specific crystal structure that occurs naturally in pure form.John P. Rafferty, ed. (2011): Mi ...
s,
metabolite
In biochemistry, a metabolite is an intermediate or end product of metabolism.
The term is usually used for small molecules. Metabolites have various functions, including fuel, structure, signaling, stimulatory and inhibitory effects on enzymes, c ...
s,
protein
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metab ...
s, and microparticles, including the following:
Location
In principle, crystal formation can happen anywhere in the body. Well-known places are
excretory
Excretion is elimination of metabolic waste, which is an essential process in all organisms. In vertebrates, this is primarily carried out by the lungs, kidneys, and skin. This is in contrast with secretion, where the substance may have specific ...
organs where concentrations get high easily, like in the
biliary
A bile duct is any of a number of long tube-like structures that carry bile, and is present in most vertebrates. The bile duct is separated into three main parts: the fundus (superior), the body (middle), and the neck (inferior).
Bile is requ ...
and urinary tracts, but crystalline structures are also formed in intracellular and extracellular spaces of tissues, like within the
arterial
An artery () is a blood vessel in humans and most other animals that takes oxygenated blood away from the heart in the systemic circulation to one or more parts of the body. Exceptions that carry deoxygenated blood are the pulmonary arteries in ...
wall in
atherosclerosis
Atherosclerosis is a pattern of the disease arteriosclerosis, characterized by development of abnormalities called lesions in walls of arteries. This is a chronic inflammatory disease involving many different cell types and is driven by eleva ...
.
For example, mechanical obstruction by mineral stones causes
nephrolithiasis
Kidney stone disease (known as nephrolithiasis, renal calculus disease, or urolithiasis) is a crystallopathy and occurs when there are too many minerals in the urine and not enough liquid or hydration. This imbalance causes tiny pieces of cr ...
,
urolithiasis
Kidney stone disease (known as nephrolithiasis, renal calculus disease, or urolithiasis) is a crystallopathy and occurs when there are too many minerals in the urine and not enough liquid or hydration. This imbalance causes tiny pieces of cr ...
choledocholithiasis
Common bile duct stone, also known as choledocholithiasis, is the presence of gallstones in the common bile duct (CBD) (thus '' choledocho-'' + '' lithiasis''). This condition can cause jaundice and liver cell damage. Treatments include choledocho ...
gout
Gout ( ) is a form of inflammatory arthritis characterized by recurrent attacks of pain in a red, tender, hot, and Joint effusion, swollen joint, caused by the deposition of needle-like crystals of uric acid known as monosodium urate crysta ...
and
pseudogout
Calcium pyrophosphate dihydrate (CPPD) crystal deposition disease, also known as pseudogout and pyrophosphate arthropathy, is a rheumatologic disease which is thought to be secondary to abnormal accumulation of calcium pyrophosphate dihydrate cr ...
.
Renal diseases are also common in crystallopathies, including:
Mechanisms
Local
supersaturation
In physical chemistry, supersaturation occurs with a solution (chemistry), solution when the concentration of a solute exceeds the concentration specified by the value of solubility at Solubility equilibrium, equilibrium. Most commonly the term ...
is a common trigger of crystallization, and when the nucleus of the crystalline structure is formed, crystals can self-perpetuate and cause more crystallization and aggregation. Main mechanisms by which the formed crystals and aggregates cause pathological states and ultimately disease are acute necroinflammation, chronic tissue remodelling, and mechanical obstruction.
Necroinflammation is an autoamplifying process where crystals are toxic to cells (
cytotoxicity
Cytotoxicity is the quality of being toxic to cells. Examples of toxic agents are toxic metals, toxic chemicals, microbe neurotoxins, radiation particles and even specific neurotransmitters when the system is out of balance. Also some types of d ...
) and cause
cell death
Cell death is the event of a biological cell ceasing to carry out its functions. This may be the result of the natural process of old cells dying and being replaced by new ones, as in programmed cell death, or may result from factors such as di ...
(
necrosis
Necrosis () is a form of cell injury which results in the premature death of cells in living tissue by autolysis. The term "necrosis" came about in the mid-19th century and is commonly attributed to German pathologist Rudolf Virchow, who i ...
and regulated cell death) and a local and systemic inflammatory response. Cytotoxicity includes actin depolymerization, free radical and
reactive oxygen species
In chemistry and biology, reactive oxygen species (ROS) are highly Reactivity (chemistry), reactive chemicals formed from diatomic oxygen (), water, and hydrogen peroxide. Some prominent ROS are hydroperoxide (H2O2), superoxide (O2−), hydroxyl ...
synthesis, and
autophagy
Autophagy (or autophagocytosis; from the Greek language, Greek , , meaning "self-devouring" and , , meaning "hollow") is the natural, conserved degradation of the cell that removes unnecessary or dysfunctional components through a lysosome-depe ...
. Crystals can also directly activate inflammation via Mincle receptors, calcium and potassium signalling,
calpain
A calpain (; , ) is a protein belonging to the family of calcium-dependent, non-lysosomal cysteine proteases ( proteolytic enzymes) expressed ubiquitously in mammals and many other organisms. Calpains constitute the C2 family of protease clan C ...
s,
cathepsin
Cathepsins (Ancient Greek ''kata-'' "down" and ''hepsein'' "boil"; abbreviated CTS) are proteases (enzymes that degrade proteins) found in all animals as well as other organisms. There are approximately a dozen members of this family, which are d ...
beta,
protease
A protease (also called a peptidase, proteinase, or proteolytic enzyme) is an enzyme that catalysis, catalyzes proteolysis, breaking down proteins into smaller polypeptides or single amino acids, and spurring the formation of new protein products ...
s, and NLPR3 inflammasomes.
Cells undergo cell death via three main mechanisms:
necroptosis
Necroptosis is a programmed form of necrosis, or inflammatory cell death. Conventionally, necrosis is associated with unprogrammed cell death resulting from cellular damage or infiltration by pathogens, in contrast to orderly, programmed cell dea ...
via
RIPK1
Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) functions in a variety of cellular pathways related to both cell survival and death. In terms of cell death, RIPK1 plays a role in apoptosis, necroptosis, and PANoptosis Some of th ...
,
FADD
FAS-associated death domain protein, also called MORT1, is encoded by the ''FADD'' gene on the 11q13.3 region of chromosome 11 in humans.
FADD is an Signal transducing adaptor protein, adaptor protein that bridges members of the Tumor necrosi ...
ferroptosis
Ferroptosis (also known as oxytosis) is a type of programmed cell death dependent on iron and characterized by the accumulation of lipid peroxides. Ferroptosis is biochemically, genetically, and morphologically distinct from other forms of regulat ...
apoptosis
Apoptosis (from ) is a form of programmed cell death that occurs in multicellular organisms and in some eukaryotic, single-celled microorganisms such as yeast. Biochemistry, Biochemical events lead to characteristic cell changes (Morphology (biol ...
via RIPK1 and
caspase 8
Caspase-8 is a caspase protein, encoded by the ''CASP8'' gene. It most likely acts upon caspase-3.
''CASP8'' orthologs have been identified in numerous mammals for which complete genome data are available. These unique orthologs are also present ...
protease
A protease (also called a peptidase, proteinase, or proteolytic enzyme) is an enzyme that catalysis, catalyzes proteolysis, breaking down proteins into smaller polypeptides or single amino acids, and spurring the formation of new protein products ...
s, and damage-associated molecular patterns including
HMGB1
High mobility group box 1 protein, also known as high-mobility group protein 1 (HMG-1) and amphoterin, is a protein that in humans is encoded by the ''HMGB1'' gene.
HMG-1 belongs to the high mobility group and contains a HMG-box domain.
Funct ...
,
histone
In biology, histones are highly basic proteins abundant in lysine and arginine residues that are found in eukaryotic cell nuclei and in most Archaeal phyla. They act as spools around which DNA winds to create structural units called nucleosomes ...
s,
mitochondrial DNA
Mitochondrial DNA (mtDNA and mDNA) is the DNA located in the mitochondrion, mitochondria organelles in a eukaryotic cell that converts chemical energy from food into adenosine triphosphate (ATP). Mitochondrial DNA is a small portion of the D ...
uric acid
Uric acid is a heterocyclic compound of carbon, nitrogen, oxygen, and hydrogen with the Chemical formula, formula C5H4N4O3. It forms ions and salts known as urates and acid urates, such as ammonium acid urate. Uric acid is a product of the meta ...
, and double-stranded DNA, which further activates
Toll-like receptor
Toll-like receptors (TLRs) are a class of proteins that play a key role in the innate immune system. They are single-pass membrane protein, single-spanning receptor (biochemistry), receptors usually expressed on sentinel cells such as macrophages ...
s and
inflammasome
Inflammasomes are cytosolic multiprotein complexes of the innate immune system responsible for the activation of inflammatory responses and cell death. They are formed as a result of specific cytosolic pattern recognition receptors (PRRs) sens ...
s. Finally, this activates the inflammatory response including the release of pro-inflammatory interleukin 1 alpha,
interleukin 1 beta
Interleukin-1 beta (IL-1β) also known as leukocytic pyrogen, leukocytic endogenous mediator, mononuclear cell factor, lymphocyte activating factor and other names, is a cytokine protein that in humans is encoded by the ''IL1B'' gene."Catabolin" ...
,
cytokine
Cytokines () are a broad and loose category of small proteins (~5–25 kDa) important in cell signaling.
Cytokines are produced by a broad range of cells, including immune cells like macrophages, B cell, B lymphocytes, T cell, T lymphocytes ...
s,
kinin
A kinin is any of various structurally related peptides, such as bradykinin and kallidin. They are members of the autacoid family. Kinins are peptides that are cleaved from kininogens by the process of kallikreins. Kallikreins activate kinins ...
s, lipid inflammatory mediators,
complement system
The complement system, also known as complement cascade, is a part of the humoral, innate immune system and enhances (complements) the ability of antibodies and phagocytic cells to clear microbes and damaged cells from an organism, promote inf ...
activation, vasodilation, an increase in
endothelial
The endothelium (: endothelia) is a single layer of squamous endothelial cells that line the interior surface of blood vessels and lymphatic vessels. The endothelium forms an interface between circulating blood or lymph in the lumen and the res ...
permeability and
leukocyte
White blood cells (scientific name leukocytes), also called immune cells or immunocytes, are cells of the immune system that are involved in protecting the body against both infectious disease and foreign entities. White blood cells are genera ...
influx, and pain.
Macrophage
Macrophages (; abbreviated MPhi, φ, MΦ or MP) are a type of white blood cell of the innate immune system that engulf and digest pathogens, such as cancer cells, microbes, cellular debris and foreign substances, which do not have proteins that ...
s are key cells that try to remove crystals from tissues by
phagocytosis
Phagocytosis () is the process by which a cell (biology), cell uses its plasma membrane to engulf a large particle (≥ 0.5 μm), giving rise to an internal compartment called the phagosome. It is one type of endocytosis. A cell that performs ph ...
. As part of the inflammatory response, they undergo polarization into a pro-inflammatory state called M1. Macrophages can ingest particles at most a few microns in diameter. If digestion of the crystalline material fails in the
lysosome
A lysosome () is a membrane-bound organelle that is found in all mammalian cells, with the exception of red blood cells (erythrocytes). There are normally hundreds of lysosomes in the cytosol, where they function as the cell’s degradation cent ...
s however, macrophages undergo autophagy, form
foam cell
Foam cells, also called lipid-laden macrophages, are a type of cell that contain cholesterol. These can form a plaque that can lead to atherosclerosis and trigger myocardial infarction and stroke.
Foam cells are fat-laden cells with a M2 macro ...
s and
giant cell
A giant cell (also known as a multinucleated giant cell, or multinucleate giant cell) is a mass formed by the union of several distinct cells (usually histiocytes), often forming a granuloma.
Although there is typically a focus on the patholog ...
s, and try to do extracellular digestion in a process called ''frustrated phagocytosis''.
Crystals do not always cause acute inflammation but instead lead to chronic tissue remodelling. This process is possible because crystals get shielded from pro-inflammatory processes by compartmentalization (e.g.
granuloma
A granuloma is an aggregation of macrophages (along with other cells) that forms in response to chronic inflammation. This occurs when the immune system attempts to isolate foreign substances that it is otherwise unable to eliminate. Such sub ...
formation,
fibrosis
Fibrosis, also known as fibrotic scarring, is the development of fibrous connective tissue in response to an injury. Fibrosis can be a normal connective tissue deposition or excessive tissue deposition caused by a disease.
Repeated injuries, ch ...
, and wound-healing) or molecular coating, or because inflammatory responses are suppressed with direct anti-inflammatory signalling (e.g. CLEC12A and NETosis).
Crystals can attach to membranes via annexin II,
CD44
The CD44 antigen is a cell-surface glycoprotein involved in cell–cell interactions, cell adhesion and migration. In humans, the CD44 antigen is encoded by the ''CD44'' gene on chromosome 11. CD44 has been referred to as HCAM (homing cell adhes ...
, and
osteopontin
Osteopontin (OPN), also known as bone /sialoprotein I (BSP-1 or BNSP), early T-lymphocyte activation (ETA-1), secreted phosphoprotein 1 (SPP1), 2ar and Rickettsia resistance (Ric), is a protein that in humans is encoded by the ''SPP1'' gene (sec ...
.
Interventions
The most straightforward treatment of crystallopathies would be dissolving the crystals. Crystal dissolvents have been under research, for example with
cyclodextrin
Cyclodextrins are a family of cyclic oligosaccharides, consisting of a macrocycle, macrocyclic ring of glucose subunits joined by α-1,4 glycosidic bonds. Cyclodextrins are produced from starch by enzyme, enzymatic conversion. They are used in ...
in atherosclerosis. Another approach would be to modify the inflammatory pathways common for crystallopathies with treatments such as IL-1a and IL-1b
antagonist
An antagonist is a character in a story who is presented as the main enemy or rival of the protagonist and is often depicted as a villain.chaperones, protein stabilizing small molecules, and protein refolding agents have been under consideration.