<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Taste and can you explain it in depth? [/INST] The gustatory system or sense of taste is the sensory system that is partially responsible for the perception of taste (flavor). Taste is the perception produced or stimulated when a substance in the mouth reacts chemically with taste receptor cells located on taste buds in the oral cavity, mostly on the tongue. Taste, along with olfaction and trigeminal nerve stimulation (registering texture, pain, and temperature), determines flavors of food and other substances. Humans have taste receptors on taste buds and other areas, including the upper surface of the tongue and the epiglottis. The gustatory cortex is responsible for the perception of taste.
The tongue is covered with thousands of small bumps called papillae, which are visible to the naked eye.  Within each papilla are hundreds of taste buds. The exception to this is the filiform papillae that do not contain taste buds. There are between 2000 and 5000 taste buds that are located on the back and front of the tongue.  Others are located on the roof, sides and back of the mouth, and in the throat. Each taste bud contains 50 to 100 taste receptor cells.
Taste receptors in the mouth sense the five taste modalities: sweetness, sourness, saltiness, bitterness, and savoriness (also known as savory or umami). Scientific experiments have demonstrated that these five tastes exist and are distinct from one another. Taste buds are able to distinguish between different tastes through detecting interaction with different molecules or ions. Sweet, savoriness, and bitter tastes are triggered by the binding of molecules to G protein-coupled receptors on the cell membranes of taste buds. Saltiness and sourness are perceived when alkali metal or hydrogen ions enter taste buds, respectively.The basic taste modalities contribute only partially to the sensation and flavor of food in the mouth—other factors include smell, detected by the olfactory epithelium of the nose; texture, detected through a variety of mechanoreceptors, muscle nerves, etc.; temperature, detected by thermoreceptors; and "coolness" (such as of menthol) and "hotness" (pungency), through chemesthesis.
As the gustatory system senses both harmful and beneficial things, all basic taste modalities are classified as either aversive or appetitive, depending upon the effect the things they sense have on our bodies. Sweetness helps to identify energy-rich foods, while bitterness serves as a warning sign of poisons.Among humans, taste perception begins to fade at an older age because of loss of tongue papillae and a general decrease in saliva production. Humans can also have distortion of tastes (dysgeusia). Not all mammals share the same taste modalities: some rodents can taste starch (which humans cannot), cats cannot taste sweetness, and several other carnivores including hyenas, dolphins, and sea lions, have lost the ability to sense up to four of their ancestral five taste modalities.

Basic tastes
The gustatory system allows animals to distinguish between safe and harmful food, and to gauge foods’ nutritional value. Digestive enzymes in saliva begin to dissolve food into base chemicals that are washed over the papillae and detected as tastes by the taste buds. The tongue is covered with thousands of small bumps called papillae, which are visible to the naked eye.  Within each papilla are hundreds of taste buds. The exception to this are the filiform papillae that do not contain taste buds. There are between 2000 and 5000 taste buds that are located on the back and front of the tongue.  Others are located on the roof, sides and back of the mouth, and in the throat. Each taste bud contains 50 to 100 taste receptor cells.
The five specific tastes received by taste receptors are saltiness, sweetness, bitterness, sourness, and savoriness, often known by its Japanese name "umami" which translates to ‘deliciousness’. As of the early 20th century, Western physiologists and psychologists believed there were four basic tastes: sweetness, sourness, saltiness, and bitterness. The concept of a "savory" taste was not present in Western science at that time, but was postulated in Japanese research. By the end of the 20th century, the concept of umami was becoming familiar to Western society.
One study found that both salt and sour taste mechanisms detect, in different ways, the presence of sodium chloride (salt) in the mouth. However, acids are also detected and perceived as sour. The detection of salt is important to many organisms, but specifically mammals, as it serves a critical role in ion and water homeostasis in the body.  It is specifically needed in the mammalian kidney as an osmotically active compound which facilitates passive re-uptake of water into the blood. Because of this, salt elicits a pleasant taste in most humans.
Sour and salt tastes can be pleasant in small quantities, but in larger quantities become more and more unpleasant to taste. For sour taste this is presumably because the sour taste can signal under-ripe fruit, rotten meat, and other spoiled foods, which can be dangerous to the body because of bacteria which grow in such media. Additionally, sour taste signals acids, which can cause serious tissue damage.
Sweet taste signals the presence of carbohydrates in solution. Since carbohydrates have a very high calorie count (saccharides have many bonds, therefore much energy), they are desirable to the human body, which evolved to seek out the highest calorie intake foods. They are used as direct energy (sugars) and storage of energy (glycogen). However, there are many non-carbohydrate molecules that trigger a sweet response, leading to the development of many artificial sweeteners, including saccharin, sucralose, and aspartame. It is still unclear how these substances activate the sweet receptors and what adaptational significance this has had.
The savory taste (known in Japanese as "umami") was identified by Japanese chemist Kikunae Ikeda, which signals the presence of the amino acid L-glutamate, triggers a pleasurable response and thus encourages the intake of peptides and proteins. The amino acids in proteins are used in the body to build muscles and organs, transport molecules (hemoglobin), antibodies, and the organic catalysts known as enzymes. These are all critical molecules, and as such it is important to have a steady supply of amino acids, hence the pleasurable response to their presence in the mouth.
Pungency (piquancy or hotness) had traditionally been considered a sixth basic taste. In 2015, researchers suggested a new basic taste of fatty acids called fat taste, although oleogustus and pinguis have both been proposed as alternate terms.

Sweetness
Sweetness, usually regarded as a pleasurable sensation, is produced by the presence of sugars and substances that mimic sugar. Sweetness may be connected to aldehydes and ketones, which contain a carbonyl group. Sweetness is detected by a variety of G protein coupled receptors (GPCR) coupled to the G protein gustducin found on the taste buds. At least two different variants of the "sweetness receptors" must be activated for the brain to register sweetness. Compounds the brain senses as sweet are compounds that can bind with varying bond strength to two different sweetness receptors. These receptors are T1R2+3 (heterodimer) and T1R3 (homodimer), which account for all sweet sensing in humans and animals.Taste detection thresholds for sweet substances are rated relative to sucrose, which has an index of 1. The average human detection threshold for sucrose is 10 millimoles per liter. For lactose it is 30 millimoles per liter, with a sweetness index of 0.3, and 5-nitro-2-propoxyaniline 0.002 millimoles per liter. “Natural” sweeteners such as saccharides activate the GPCR, which releases gustducin. The gustducin then activates the molecule adenylate cyclase, which catalyzes the production of the molecule cAMP, or adenosine 3, 5-cyclic monophosphate. This molecule closes potassium ion channels, leading to depolarization and neurotransmitter release. Synthetic sweeteners such as saccharin activate different GPCRs and induce taste receptor cell depolarization by an alternate pathway.

Sourness
Sourness is the taste that detects acidity. The sourness of substances is rated relative to dilute hydrochloric acid, which has a sourness index of 1. By comparison, tartaric acid has a sourness index of 0.7, citric acid an index of 0.46, and carbonic acid an index of 0.06.Sour taste is detected by a small subset of cells that are distributed across all taste buds called Type III taste receptor cells. H+ ions (protons) that are abundant in sour substances can directly enter the Type III taste cells through a proton channel.  This channel was identified in 2018 as otopetrin 1 (OTOP1). The transfer of positive charge into the cell can itself trigger an electrical response.  Some weak acids such as acetic acid, can also penetrate taste cells; intracellular hydrogen ions inhibit potassium channels, which normally function to hyperpolarize the cell. By a combination of direct intake of hydrogen ions through OTOP1 ion channels (which itself depolarizes the cell) and the inhibition of the hyperpolarizing channel, sourness causes the taste cell to fire action potentials and release neurotransmitter.The most common foods with natural sourness are fruits, such as lemon, lime, grape, orange, tamarind, and bitter melon. Fermented foods, such as wine, vinegar or yogurt, may have sour taste. Children show a greater enjoyment of sour flavors than adults, and sour candy containing citric acid or malic acid is common.

Saltiness
The simplest receptor found in the mouth is the sodium chloride (salt) receptor. Saltiness is a taste produced primarily by the presence of sodium ions. Other ions of the alkali metals group also taste salty, but the further from sodium, the less salty the sensation is.  A sodium channel in the taste cell wall allows sodium cations to enter the cell. This on its own depolarizes the cell, and opens voltage-dependent calcium channels, flooding the cell with positive calcium ions and leading to neurotransmitter release. This sodium channel is known as an epithelial sodium channel (ENaC) and is composed of three subunits. An ENaC can be blocked by the drug amiloride in many mammals, especially rats. The sensitivity of the salt taste to amiloride in humans, however, is much less pronounced, leading to conjecture that there may be additional receptor proteins besides ENaC to be discovered.
The size of lithium and potassium ions most closely resemble those of sodium, and thus the saltiness is most similar. In contrast, rubidium and caesium ions are far larger, so their salty taste differs accordingly. The saltiness of substances is rated relative to sodium chloride (NaCl), which has an index of 1. Potassium, as potassium chloride (KCl), is the principal ingredient in salt substitutes and has a saltiness index of 0.6.Other monovalent cations, e.g. ammonium (NH4+), and divalent cations of the alkali earth metal group of the periodic table, e.g. calcium (Ca2+), ions generally elicit a bitter rather than a salty taste even though they, too, can pass directly through ion channels in the tongue, generating an action potential. But the chloride of calcium is saltier and less bitter than potassium chloride, and is commonly used in pickle brine instead of KCl.

Bitterness
Bitterness is one of the most sensitive of the tastes, and many perceive it as unpleasant, sharp, or disagreeable, but it is sometimes desirable and intentionally added via various bittering agents. Common bitter foods and beverages include coffee, unsweetened cocoa, South American mate, coca tea, bitter gourd, uncured olives, citrus peel, some varieties of cheese, many plants in the family Brassicaceae, dandelion greens, horehound, wild chicory, and escarole. The ethanol in alcoholic beverages tastes bitter, as do the additional bitter ingredients found in some alcoholic beverages including hops in beer and gentian in bitters. Quinine is also known for its bitter taste and is found in tonic water.
Bitterness is of interest to those who study evolution, as well as various health researchers since a large number of natural bitter compounds are known to be toxic. The ability to detect bitter-tasting, toxic compounds at low thresholds is considered to provide an important protective function. Plant leaves often contain toxic compounds, and among leaf-eating primates there is a tendency to prefer immature leaves, which tend to be higher in protein and lower in fiber and poisons than mature leaves. Amongst humans, various food processing techniques are used worldwide to detoxify otherwise inedible foods and make them palatable. Furthermore, the use of fire, changes in diet, and avoidance of toxins has led to neutral evolution in human bitter sensitivity. This has allowed several loss of function mutations that has led to a reduced sensory capacity towards bitterness in humans when compared to other species.The threshold for stimulation of bitter taste by quinine averages a concentration of 8 μM (8 micromolar). The taste thresholds of other bitter substances are rated relative to quinine, which is thus given a reference index of 1. For example, brucine has an index of 11, is thus perceived as intensely more bitter than quinine, and is detected at a much lower solution threshold. The most bitter natural substance is amarogentin, a compound present in the roots of the plant Gentiana lutea, and the most bitter substance known is the synthetic chemical denatonium, which has an index of 1,000. It is used as an aversive agent (a bitterant) that is added to toxic substances to prevent accidental ingestion. It was discovered accidentally in 1958 during research on a local anesthetic, by MacFarlan Smith of Gorgie, Edinburgh, Scotland.Research has shown that TAS2Rs (taste receptors, type 2, also known as T2Rs) such as TAS2R38 coupled to the G protein gustducin are responsible for the human ability to taste bitter substances. They are identified not only by their ability to taste for certain "bitter" ligands, but also by the morphology of the receptor itself (surface bound, monomeric). The TAS2R family in humans is thought to comprise about 25 different taste receptors, some of which can recognize a wide variety of bitter-tasting compounds.  Over 670 bitter-tasting compounds have been identified, on a bitter database, of which over 200 have been assigned to one or more specific receptors. Recently it is speculated that the selective constraints on the TAS2R family have been weakened due to the relatively high rate of mutation and pseudogenization. Researchers use two synthetic substances, phenylthiocarbamide (PTC) and 6-n-propylthiouracil (PROP) to study the genetics of bitter perception. These two substances taste bitter to some people, but are virtually tasteless to others. Among the tasters, some are so-called "supertasters" to whom PTC and PROP are extremely bitter. The variation in sensitivity is determined by two common alleles at the TAS2R38 locus. This genetic variation in the ability to taste a substance has been a source of great interest to those who study genetics.
Gustducin is made of three subunits. When it is activated by the GPCR, its subunits break apart and activate phosphodiesterase, a nearby enzyme, which in turn converts a precursor within the cell into a secondary messenger, which closes potassium ion channels. Also, this secondary messenger can stimulate the endoplasmic reticulum to release Ca2+ which contributes to depolarization. This leads to a build-up of potassium ions in the cell, depolarization, and neurotransmitter release. It is also possible for some bitter tastants to interact directly with the G protein, because of a structural similarity to the relevant GPCR.

Umami
Umami, or savory, is an appetitive taste. It can be tasted in soy sauce, meat, dashi and consomme. A loanword from Japanese meaning "good flavor" or "good taste", umami (旨味) is considered fundamental to many East Asian cuisines, such as Japanese cuisine. It dates back to the use of fermented fish sauce: garum in ancient Rome and ge-thcup or koe-cheup in ancient China.Umami was first studied in 1907 by Ikeda isolating dashi taste, which he identified as the chemical monosodium glutamate (MSG). MSG is a sodium salt that produces a strong savory taste, especially combined with foods rich in nucleotides such as meats, fish, nuts, and mushrooms.Some savory taste buds respond specifically to glutamate in the same way that "sweet" ones respond to sugar. Glutamate binds to a variant of G protein coupled glutamate receptors. L-glutamate may bond to a type of GPCR known as a metabotropic glutamate receptor (mGluR4) which causes the G-protein complex to activate the sensation of umami.

Measuring relative tastes
Measuring the degree to which a substance presents one basic taste can be achieved in a subjective way by comparing its taste to a reference substance.
Sweetness is subjectively measured by comparing the threshold values, or level at which the presence of a dilute substance can be detected by a human taster, of different sweet substances. Substances are usually measured relative to sucrose, which is usually given an arbitrary index of 1 or 100. Rebaudioside A is 100 times sweeter than sucrose; fructose is about 1.4 times sweeter; glucose, a sugar found in honey and vegetables, is about three-quarters as sweet; and lactose, a milk sugar, is one-half as sweet.The sourness of a substance can be rated by comparing it to very dilute hydrochloric acid (HCl).Relative saltiness can be rated by comparison to a dilute salt solution.Quinine, a bitter medicinal found in tonic water, can be used to subjectively rate the bitterness of a substance. Units of dilute quinine hydrochloride (1 g in 2000 mL of water) can be used to measure the threshold bitterness concentration, the level at which the presence of a dilute bitter substance can be detected by a human taster, of other compounds. More formal chemical analysis, while possible, is difficult.There may not be an absolute measure for pungency, though there are tests for measuring the subjective presence of a given pungent substance in food, such as the Scoville scale for capsaicine in peppers or the Pyruvate scale for pyruvates in garlics and onions.

Functional structure
Taste is a form of chemoreception which occurs in the specialised taste receptors in the mouth. To date, there are five different types of taste these receptors can detect which are recognized: salt, sweet, sour, bitter, and umami. Each type of receptor has a different manner of sensory transduction: that is, of detecting the presence of a certain compound and starting an action potential which alerts the brain. It is a matter of debate whether each taste cell is tuned to one specific tastant or to several; Smith and Margolskee claim that "gustatory neurons typically respond to more than one kind of stimulus, [a]lthough each neuron responds most strongly to one tastant". Researchers believe that the brain interprets complex tastes by examining patterns from a large set of neuron responses. This enables the body to make "keep or spit out" decisions when there is more than one tastant present. "No single neuron type alone is capable of discriminating among stimuli or different qualities, because a given cell can respond the same way to disparate stimuli." As well, serotonin is thought to act as an intermediary hormone which communicates with taste cells within a taste bud, mediating the signals being sent to the brain. Receptor molecules are found on the top of microvilli of the taste cells.

SweetnessSweetness is produced by the presence of sugars, some proteins, and other substances such as alcohols like anethol, glycerol and propylene glycol, saponins such as glycyrrhizin, artificial sweeteners (organic compounds with a variety of structures), and lead compounds such as lead acetate. It is often connected to aldehydes and ketones, which contain a carbonyl group. Many foods can be perceived as sweet regardless of their actual sugar content. For example, some plants such as liquorice, anise or stevia can be used as sweeteners. Rebaudioside A is a steviol glycoside coming from stevia that is 200 times sweeter than sugar. Lead acetate and other lead compounds were used as sweeteners, mostly for wine, until lead poisoning became known. Romans used to deliberately boil the must inside of lead vessels to make a sweeter wine.
Sweetness is detected by a variety of G protein-coupled receptors coupled to a G protein that acts as an intermediary in the communication between taste bud and brain, gustducin. These receptors are T1R2+3 (heterodimer) and T1R3 (homodimer), which account for sweet sensing in humans and other animals.
SaltinessSaltiness is a taste produced best by the presence of cations (such as Na+, K+ or Li+) and is directly detected by cation influx into glial like cells via leak channels causing depolarisation of the cell.Other monovalent cations, e.g., ammonium, NH+4, and divalent cations of the alkali earth metal group of the periodic table, e.g., calcium, Ca2+, ions, in general, elicit a bitter rather than a salty taste even though they, too, can pass directly through ion channels in the tongue.
SournessSourness is acidity, and, like salt, it is a taste sensed using ion channels. Undissociated acid diffuses across the plasma membrane of a presynaptic cell, where it dissociates in accordance with Le Chateliers principle. The protons that are released then block potassium channels, which depolarise the cell and cause calcium influx. In addition, the taste receptor PKD2L1 has been found to be involved in tasting sour.
BitternessResearch has shown that TAS2Rs (taste receptors, type 2, also known as T2Rs) such as TAS2R38 are responsible for the ability to taste bitter substances in vertebrates. They are identified not only by their ability to taste certain bitter ligands, but also by the morphology of the receptor itself (surface bound, monomeric).
SavorinessThe amino acid glutamic acid is responsible for savoriness, but some nucleotides (inosinic acid and guanylic acid) can act as complements, enhancing the taste.Glutamic acid binds to a variant of the G protein-coupled receptor, producing a savory taste.

Further sensations and transmission
The tongue can also feel other sensations not generally included in the basic tastes. These are largely detected by the somatosensory system. In humans, the sense of taste is conveyed via three of the twelve cranial nerves.  The facial nerve (VII) carries taste sensations from the anterior two thirds of the tongue, the glossopharyngeal nerve (IX) carries taste sensations from the posterior one third of the tongue while a branch of the vagus nerve (X) carries some taste sensations from the back of the oral cavity.
The trigeminal nerve (cranial nerve V) provides information concerning the general texture of food as well as the taste-related sensations of peppery or hot (from spices).

Pungency (also spiciness or hotness)
Substances such as ethanol and capsaicin cause a burning sensation by inducing a trigeminal nerve reaction together with normal taste reception. The sensation of heat is caused by the foods activating nerves that express TRPV1 and TRPA1 receptors. Some such plant-derived compounds that provide this sensation are capsaicin from chili peppers, piperine from black pepper, gingerol from ginger root and allyl isothiocyanate from horseradish. The piquant ("hot" or "spicy") sensation provided by such foods and spices plays an important role in a diverse range of cuisines across the world—especially in equatorial and sub-tropical climates, such as Ethiopian, Peruvian, Hungarian, Indian, Korean, Indonesian, Lao, Malaysian, Mexican, New Mexican, Singaporean, Southwest Chinese (including Sichuan cuisine), Vietnamese, and Thai cuisines.
This particular sensation, called chemesthesis, is not a taste in the technical sense, because the sensation does not arise from taste buds, and a different set of nerve fibers carry it to the brain. Foods like chili peppers activate nerve fibers directly; the sensation interpreted as "hot" results from the stimulation of somatosensory (pain/temperature) fibers on the tongue. Many parts of the body with exposed membranes but no taste sensors (such as the nasal cavity, under the fingernails, surface of the eye or a wound) produce a similar sensation of heat when exposed to hotness agents.

Coolness
Some substances activate cold trigeminal receptors even when not at low temperatures. This "fresh" or "minty" sensation can be tasted in peppermint, spearmint and is triggered by substances such as menthol, anethol, ethanol, and camphor. Caused by activation of the same mechanism that signals cold, TRPM8 ion channels on nerve cells, unlike the actual change in temperature described for sugar substitutes, this coolness is only a perceived phenomenon.

Numbness
Both Chinese and Batak Toba cooking include the idea of 麻 (má or mati rasa), a tingling numbness caused by spices such as Sichuan pepper. The cuisines of Sichuan province in China and of the Indonesian province of North Sumatra often combine this with chili pepper to produce a 麻辣 málà, "numbing-and-hot", or "mati rasa" flavor.
Typical in northern Brazilian cuisine, jambu is an herb used in dishes like tacacá.
These sensations, although not taste, fall into a category of chemesthesis.

Astringency
Some foods, such as unripe fruits, contain tannins or calcium oxalate that cause an astringent or puckering sensation of the mucous membrane of the mouth. Examples include tea, red wine, or rhubarb. Other terms for the astringent sensation are "dry", "rough", "harsh" (especially for wine), "tart" (normally referring to sourness), "rubbery", "hard" or "styptic".

Metallicness
A metallic taste may be caused by food and drink, certain medicines or amalgam dental fillings. It is generally considered an off flavor when present in food and drink. A metallic taste may be caused by galvanic reactions in the mouth. In the case where it is caused by dental work, the dissimilar metals used may produce a measurable current. Some artificial sweeteners are perceived to have a metallic taste, which is detected by the TRPV1 receptors.  Many people consider blood to have a metallic taste. A metallic taste in the mouth is also a symptom of various medical conditions, in which case it may be classified under the symptoms dysgeusia or parageusia, referring to distortions of the sense of taste, and can be caused by medication, including saquinavir, zonisamide, and various kinds of chemotherapy, as well as occupational hazards, such as working with pesticides.

Fat taste
Recent research reveals a potential taste receptor called the CD36 receptor. CD36 was targeted as a possible lipid taste receptor because it binds to fat molecules (more specifically, long-chain fatty acids), and it has been localized to taste bud cells (specifically, the circumvallate and foliate papillae). There is a debate over whether we can truly taste fats, and supporters of our ability to taste free fatty acids (FFAs) have based the argument on a few main points: there is an evolutionary advantage to oral fat detection; a potential fat receptor has been located on taste bud cells; fatty acids evoke specific responses that activate gustatory neurons, similar to other currently accepted tastes; and, there is a physiological response to the presence of oral fat. Although CD36 has been studied primarily in mice, research examining human subjects ability to taste fats found that those with high levels of CD36 expression were more sensitive to tasting fat than were those with low levels of CD36 expression; this study points to a clear association between CD36 receptor quantity and the ability to taste fat.
Other possible fat taste receptors have been identified. G protein-coupled receptors GPR120 and GPR40 have been linked to fat taste, because their absence resulted in reduced preference to two types of fatty acid (linoleic acid and oleic acid), as well as decreased neuronal response to oral fatty acids.Monovalent cation channel TRPM5 has been implicated in fat taste as well, but it is thought to be involved primarily in downstream processing of the taste rather than primary reception, as it is with other tastes such as bitter, sweet, and savory.Proposed alternate names to fat taste include oleogustus and pinguis, although these terms are not widely accepted. The main form of fat that is commonly ingested is triglycerides, which are composed of three fatty acids bound together. In this state, triglycerides are able to give fatty foods unique textures that are often described as creaminess. But this texture is not an actual taste. It is only during ingestion that the fatty acids that make up triglycerides are hydrolysed into fatty acids via lipases. The taste is commonly related to other, more negative, tastes such as bitter and sour due to how unpleasant the taste is for humans. Richard Mattes, a co-author of the study, explained that low concentrations of these fatty acids can create an overall better flavor in a food, much like how small uses of bitterness can make certain foods more rounded. However, a high concentration of fatty acids in certain foods is generally considered inedible. To demonstrate that individuals can distinguish fat taste from other tastes, the researchers separated volunteers into groups and had them try samples that also contained the other basic tastes. Volunteers were able to separate the taste of fatty acids into their own category, with some overlap with savory samples, which the researchers hypothesized was due to poor familiarity with both. The researchers note that the usual "creaminess and viscosity we associate with fatty foods is largely due to triglycerides", unrelated to the taste; while the actual taste of fatty acids is not pleasant. Mattes described the taste as "more of a warning system" that a certain food should not be eaten.There are few regularly consumed foods rich in fat taste, due to the negative flavor that is evoked in large quantities. Foods whose flavor to which fat taste makes a small contribution include olive oil and fresh butter, along with various kinds of vegetable and nut oils.

Heartiness
Kokumi (, Japanese: kokumi (コク味) from koku (こく)) is translated as "heartiness", "full flavor" or "rich" and describes compounds in food that do not have their own taste, but enhance the characteristics when combined.
Alongside the five basic tastes of sweet, sour, salt, bitter and savory, kokumi has been described as something that may enhance the other five tastes by magnifying and lengthening the other tastes, or "mouthfulness".: 290  Garlic is a common ingredient to add flavor used to help define the characteristic kokumi flavors.Calcium-sensing receptors (CaSR) are receptors for "kokumi" substances. Kokumi substances, applied around taste pores, induce an increase in the intracellular Ca concentration in a subset of cells. This subset of CaSR-expressing taste cells are independent from the influenced basic taste receptor cells. CaSR agonists directly activate the CaSR on the surface of taste cells and integrated in the brain via the central nervous system. However, a basal level of calcium, corresponding to the physiological concentration, is necessary for activation of the CaSR to develop the kokumi sensation.

Calcium
The distinctive taste of chalk has been identified as the calcium component of that substance. In 2008, geneticists discovered a calcium receptor on the tongues of mice. The CaSR receptor is commonly found in the gastrointestinal tract, kidneys, and brain. Along with the "sweet" T1R3 receptor, the CaSR receptor can detect calcium as a taste. Whether the perception exists or not in humans is unknown.

Temperature
Temperature can be an essential element of the taste experience. Heat can accentuate some flavors and decrease others by varying the density and phase equilibrium of a substance. Food and drink that—in a given culture—is traditionally served hot is often considered distasteful if cold, and vice versa. For example, alcoholic beverages, with a few exceptions, are usually thought best when served at room temperature or chilled to varying degrees, but soups—again, with exceptions—are usually only eaten hot. A cultural example are soft drinks. In North America it is almost always preferred cold, regardless of season.

Starchiness
A 2016 study suggested that humans can taste starch (specifically, a glucose oligomer) independently of other tastes such as sweetness. However, no specific chemical receptor has yet been found for this taste.

Nerve supply and neural connections
The glossopharyngeal nerve innervates a third of the tongue including the circumvallate papillae. The facial nerve innervates the other two thirds of the tongue and the cheek via the chorda tympani.The pterygopalatine ganglia are ganglia (one on each side) of the soft palate. The greater petrosal, lesser palatine  and zygomatic nerves all synapse here. The greater petrosal, carries soft palate taste signals to the facial nerve. The lesser palatine sends signals to the nasal cavity; which is why spicy foods cause nasal drip. The zygomatic sends signals to the lacrimal nerve that activate the lacrimal gland; which is the reason that spicy foods can cause tears. Both the lesser palatine and the zygomatic are maxillary nerves (from the trigeminal nerve).
The special visceral afferents of the vagus nerve carry taste from the epiglottal region of the tongue.
The lingual nerve (trigeminal, not shown in diagram) is deeply interconnected with the chorda tympani in that it provides all other sensory info from the anterior ⅔ of the tongue. This info is processed separately (nearby) in the rostal lateral subdivision of the nucleus of the solitary tract (NST).
NST receives input from the amygdala (regulates oculomotor nuclei output), bed nuclei of stria terminalis, hypothalamus, and prefrontal cortex. NST is the topographical map that processes gustatory and sensory (temp, texture, etc.) info.Reticular formation (includes Raphe nuclei responsible for serotonin production) is signaled to release serotonin during and after a meal to suppress appetite. Similarly, salivary nuclei are signaled to decrease saliva secretion.
Hypoglossal and thalamic connections aid in oral-related movements.
Hypothalamus connections hormonally regulate hunger and the digestive system.
Substantia innominata connects the thalamus, temporal lobe, and insula.
Edinger-Westphal nucleus reacts to taste stimuli by dilating and constricting the pupils.Spinal ganglion are involved in movement.
The frontal operculum is speculated to be the memory and association hub for taste.The insula cortex aids in swallowing and gastric motility.

Other concepts
Supertasters
A supertaster is a person whose sense of taste is significantly more sensitive than most. The cause of this heightened response is likely, at least in part, due to an increased number of fungiform papillae. Studies have shown that supertasters require less fat and sugar in their food to get the same satisfying effects. However, contrary to what one might think, these people actually tend to consume more salt than most  people. This is due to their heightened sense of the taste of bitterness, and the presence of salt drowns out the taste of bitterness. (This also explains why supertasters prefer salted cheddar cheese over non-salted.)

Aftertaste
Aftertastes arise after food has been swallowed </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Polyarteritis nodosa and can you explain it in depth? [/INST] Polyarteritis nodosa (PAN) is a systemic necrotizing inflammation of blood vessels (vasculitis) affecting medium-sized muscular arteries, typically involving the arteries of the kidneys and other internal organs but generally sparing the lungs circulation. Small aneurysms are strung like the beads of a rosary, therefore making this "rosary sign" an important diagnostic feature of the vasculitis. PAN is sometimes associated with infection by the hepatitis B or hepatitis C virus. The condition may be present in infants.PAN is a rare disease. With treatment, five-year survival is 80%; without treatment, five-year survival is 13%. Death is often a consequence of kidney failure, myocardial infarction, or stroke.

Signs and symptoms
PAN may affect nearly every organ system and thus can present with a broad array of signs and symptoms. These manifestations result from ischemic damage to affected organs, often the skin, heart, kidneys, and nervous system. Constitutional symptoms are seen in up to 90% of affected individuals and include fever, fatigue, weakness, loss of appetite, and unintentional weight loss.Skin: The skin may show rashes, swelling, necrotic ulcers, and subcutaneous nodules (lumps). Skin manifestations of PAN include palpable purpura and livedo reticularis in some individuals.Neurologic system: Nerve involvement may cause sensory changes with numbness, pain, burning, and weakness (peripheral neuropathy). Peripheral nerves are often affected, and this most commonly presents as mononeuritis multiplex, which is the most common neurologic sign of PAN. Mononeuritis multiplex develops in more than 70% of patients with polyarteritis nodosa because of damage to arteries supplying large peripheral nerves. Most cases are marked by asymmetric polyneuropathy, but progressive disease can lead to symmetric nerve involvement. Central nervous system involvement may cause strokes or seizures.Renal system: Kidney involvement is common and often leads to death of parts of the kidney. Involvement of the renal artery, which supplies the kidneys with highly oxygenated blood, often leads to high blood pressure in about one-third of cases. deposition of protein or blood in the urine may also be seen. Almost all patients with PAN have renal insufficiency caused by renal artery narrowing, thrombosis, and infarctions.
Cardiovascular system: Involvement of the arteries of the heart may cause a heart attack, heart failure, and inflammation of the sac around the heart (pericarditis).Gastrointestinal system: Damage to mesenteric arteries can cause abdominal pain, mesenteric ischemia, and bowel perforation. Abdominal pain may also be seen.
Musculoskeletal system: Muscle and joint aches are common.

Complications
Stroke
Heart failure resulting from cardiomyopathy and pericarditis
Intestinal necrosis and perforation

Causes
PAN has no association with anti-neutrophil cytoplasmic antibodies, but about 30% of people with PAN have chronic hepatitis B and deposits containing HBsAg-HBsAb complexes in affected blood vessels, indicating an immune complex-mediated cause in that subset. Infection with the hepatitis C virus and HIV are occasionally discovered in people affected by PAN. PAN has also been associated with underlying hairy cell leukemia. The cause remains unknown in the remaining cases; there may be causal and clinical distinctions between classic idiopathic PAN, the cutaneous forms of PAN, and PAN associated with chronic hepatitis.
In children, cutaneous PAN is frequently associated with streptococcal infections, and positive streptococcal serology is included in the diagnostic criteria.

Diagnosis
No specific lab tests exist for diagnosing polyarteritis nodosa. Diagnosis is generally based on the physical examination and a few laboratory studies that help confirm the diagnosis:
CBC (may demonstrate an elevated white blood count)
ESR (elevated)
Perinuclear pattern of antineutrophil cytoplasmic antibodies (p-ANCA) - not associated with "classic" polyarteritis nodosa, but is present in a form of the disease affecting smaller blood vessels, known as microscopic polyangiitis or leukocytoclastic angiitis
Tissue biopsy (reveals inflammation in small arteries, called arteritis)
Elevated C-reactive proteinA patient is said to have polyarteritis nodosa if he or she has three of the 10 signs known as the 1990 American College of Rheumatology (ACR) criteria, when a radiographic or pathological diagnosis of vasculitis is made:

Weight loss greater than/equal to 4.5 kg
Livedo reticularis (a mottled purplish skin discoloration over the extremities or torso)
Testicular pain or tenderness (occasionally, a site biopsied for diagnosis)
Muscle pain, weakness, or leg tenderness
Nerve disease (either single or multiple)
Diastolic blood pressure greater than 90 mmHg (high blood pressure)
Elevated kidney blood tests (BUN greater than 40 mg/dL or creatinine greater than 1.5 mg/dL)
Hepatitis B (not C) virus tests positive (for surface antigen or antibody)
Arteriogram (angiogram) showing the arteries that are dilated (aneurysms) or constricted by the blood vessel inflammation
Biopsy of tissue showing the arteritis (typically inflamed arteries): The sural nerve is a frequent location for the biopsy.
In polyarteritis nodosa, small aneurysms are strung like the beads of a rosary, therefore making this "rosary sign" an important diagnostic feature of the vasculitis. The 1990 ACR criteria were designed for classification purposes only, but their good discriminatory performances, indicated by the initial ACR analysis, suggested their potential usefulness for diagnostic purposes as well. Subsequent studies did not confirm their diagnostic utility, demonstrating a significant dependence of their discriminative abilities on the prevalence of the various vasculitides in the analyzed populations. Recently, an original study, combining the analysis of more than 100 items used to describe patients characteristics in a large sample of vasculitides with a computer simulation technique designed to test the potential diagnostic utility of the various criteria, proposed a set of eight positively or negatively  discriminating items to be used as a screening tool for  diagnosis in patients suspected of systemic vasculitis.

Differential diagnosis
Polyarteritis nodosa rarely affects the blood vessels of the lungs and this feature can help to differentiate it from other vasculitides that may have similar signs and symptoms (e.g., granulomatosis with polyangiitis or microscopic polyangiitis).

Treatment
Treatment involves medications to suppress the immune system, including prednisone and cyclophosphamide </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Aplastic anemia and can you explain it in depth? [/INST] Aplastic anemia is a disease in which the body fails to produce blood cells in sufficient numbers. Blood cells are produced in the bone marrow by stem cells that reside there. Aplastic anemia causes a deficiency of all blood cell types: red blood cells, white blood cells, and platelets.It occurs most frequently in people in their teens and twenties but is also common among the elderly. It can be caused by heredity, immune disease, or exposure to chemicals, drugs, or radiation. However, in about half of cases, the cause is unknown.Aplastic anemia can be definitively diagnosed by bone marrow biopsy. Normal bone marrow has 30–70% blood stem cells, but in aplastic anemia, these cells are mostly gone and are replaced by fat.First-line treatment for aplastic anemia consists of immunosuppressive drugs—typically either anti-lymphocyte globulin or anti-thymocyte globulin—combined with corticosteroids, chemotherapy, and ciclosporin. Hematopoietic stem cell transplantation is also used, especially for patients under 30 years of age with a related, matched marrow donor.Aplastic anemia is known to have caused the deaths of Eleanor Roosevelt and Marie Curie.

Signs and symptoms
Anemia may lead to fatigue, pale skin, severe bruising, and a fast heart rate.Low platelets are associated with an increased risk of bleeding, bruising, and petechiae, with lower blood counts that impact the ability of the blood to clot. Low white blood cells increase the risk of infections.

Causes
Aplastic anemia can be caused by immune disease or exposure to certain chemicals, drugs, radiation, or infection; in about half the cases, a definitive cause is unknown. It is not a hereditary condition, nor is it contagious.Aplastic anemia is also sometimes associated with exposure to toxins such as benzene or with the use of certain drugs, including chloramphenicol, carbamazepine, felbamate, phenytoin, quinine, and phenylbutazone. However, the probability that these drugs will lead to aplastic anemia in a given patient is very low. Chloramphenicol treatment is associated with aplasia in less than one in 40,000 treatment courses, and carbamazepine aplasia is even rarer.Exposure to ionizing radiation from radioactive materials or radiation-producing devices is also associated with the development of aplastic anemia. Marie Curie, famous for her pioneering work in the field of radioactivity, died of aplastic anemia after working unprotected with radioactive materials for a long period of time; the damaging effects of ionizing radiation were not then known.Aplastic anemia is present in up to 2% of patients with acute viral hepatitis.One known cause is an autoimmune disorder in which white blood cells attack the bone marrow. Acquired aplastic anemia is a T-cell mediated autoimmune disease, in which regulatory T cells are decreased and T-bet, a transcription factor and key regulator of Th1 development and function, is upregulated in affected T-cells. As a result of active transcription of the interferon gamma (IFN-gamma) gene by T-bet, IFN-gamma levels are increased, which reduces colony formation of hematopoietic progenitor cells in vitro by inducing apoptosis of CD34+ cells in the bone marrow.Short-lived aplastic anemia can also be a result of parvovirus infection. In humans, the P antigen (also known as globoside), one of many cellular receptors that contribute to a persons blood type, is the cellular receptor for parvovirus B19, which causes erythema infectiosum (fifth disease) in children. Because it infects red blood cells as a result of the affinity for the P antigen, parvovirus causes complete cessation of red blood cell production. In most cases, this goes unnoticed, as red blood cells live on average 120 days, and the drop in production does not significantly affect the total number of circulating cells. However, in people with conditions where the cells die early (such as sickle cell disease), parvovirus infection can lead to severe anemia.More frequently, parvovirus B19 is associated with aplastic crisis, which involves only red blood cells (despite the name). Aplastic anemia involves all cell lines.
Other viruses that have been linked to the development of aplastic anemia include hepatitis, Epstein-Barr, cytomegalovirus, and HIV.
In some animals, aplastic anemia may have other causes. For example, in the ferret (Mustela putorius furo), it is caused by estrogen toxicity, because female ferrets are induced ovulators, so mating is required to bring the female out of heat. Intact females, if not mated, will remain in heat, and after some time the high levels of estrogen will cause the bone marrow to stop producing red blood cells.

Diagnosis
Aplastic anemia must be differentiated from pure red cell aplasia. In aplastic anemia, the patient has pancytopenia (i.e., also leukopenia and thrombocytopenia) resulting in a decrease of all formed elements. In contrast, pure red cell aplasia is characterized by a reduction in red cells only. The diagnosis can only be confirmed with a bone marrow examination.Before this procedure is undertaken, a patient will generally have had other blood tests to find diagnostic clues, including a complete blood count, renal function and electrolytes, liver enzymes, thyroid function tests, vitamin B12 and folic acid levels.
Tests that may aid in determining an etiology for aplastic anemia include:

History of iatrogenic exposure to cytotoxic chemotherapy: transient bone marrow suppression
Vitamin B12 and folate levels: vitamin deficiency
Liver tests: liver diseases
Viral studies: viral infections
Chest X-ray: infections
X-rays, computed tomography (CT) scans, or ultrasound imaging tests: enlarged lymph nodes (sign of lymphoma), kidneys, and bones in arms and hands (abnormal in Fanconi anemia)
Antibody test: immune competency
Blood tests for paroxysmal nocturnal hemoglobinuria
Bone marrow aspirate and biopsy: to rule out other causes of pancytopenia (i.e., neoplastic infiltration or significant myelofibrosis).

Pathogenesis
For many years, the cause of acquired aplastic anemia was not clear. Now, autoimmune processes are considered to be responsible. The majority of cases are hypothesized to be the result of T-cell-mediated autoimmunity and destruction of the bone marrow, which leads to defective or nearly absent hematopoiesis. It is suggested that unidentified antigens cause a polyclonal expansion of dysregulated CD4+ T cells and overproduction of pro-inflammatory cytokines, such as interferon-γ and tumor necrosis factor-α. Ex vivo bone marrow models show an expansion of dysregulated CD8+ T cell populations. Activated T cells also induce apoptosis in hematopoietic stem cells.Aplastic anemia is associated with increased levels of Th17 cells—which produce pro-inflammatory cytokine IL-17—and interferon-γ-producing cells in the peripheral blood and bone marrow. Th17 cell populations also negatively correlate with regulatory T-cell populations, suppressing auto-reactivity to normal tissues, including the bone marrow. Deep phenotyping of regulatory T-cells showed two subpopulations with specific phenotypes, gene expression signatures, and functions.Studies in patients who responded to immunosuppressive therapy found dominant subpopulations characterized by higher expression of HLA‐DR2 and HLA‐DR15 (mean age of two groups: 34 and 21 years), FOXP3, CD95, and CCR4; lower expression of CD45RA (mean age: 45 years); and expression of the IL‐2/STAT5 pathway. Higher frequency of HLA‐DR2 and HLA‐DR15 may cause augmented presentation of antigens to CD4+ T-cells, resulting in immune‐mediated destruction of the stem cells. In addition, HLA‐DR2-expressing cells augment the release of tumor necrosis factor-α, which plays a role in disease pathology.The hypothesis of aberrant, disordered T‐cell populations as the initiators of aplastic anemia is supported by findings that immunosuppressive therapy for T-cells (for example, anti-thymocyte globulin and ciclosporin) results in a response in up to 80% of severe aplastic anemia patients. CD34+ progenitor cells and lymphocytes in the bone marrow over-express the Fas receptor, the main element in apoptotic signaling. A significant increase in the proportion of apoptotic cells in the bone marrow of aplastic anemia patients has been demonstrated. This suggests that cytokine‐induced and Fas‐mediated apoptosis play roles in bone marrow failure because annihilation of CD34+ progenitor cells leads to hematopoietic stem cell deficiency.

Frequently detected autoantibodies
A study of blood and bone marrow samples obtained from 18 aplastic anemia patients revealed more than 30 potential specific candidate autoantigens after the serologic screening of a fetal liver library with sera from 8 patients. The human fetal liver cDNA library (chosen because of its high enrichment of CD34+ cells), compared with peripheral blood or the bone marrow, significantly increased the likelihood of detection of possible stem cell autoantigens.
ELISA and Western blot analysis revealed that an IgG antibody response to one of the candidate autoantigens, kinectin, was present in a significant number of patients (39%). In contrast, no antibody was detected in 35 healthy volunteers. Antibody was detected in both transfused and transfusion-naive patients, suggesting that antikinectin autoantibody development was not due to transfusion-related alloreactivity. Negative sera from patients with other autoimmune diseases (systemic lupus erythematosus, rheumatoid arthritis, and multiple sclerosis) showed a specific association of antikinectin antibodies with aplastic anemia. These results support the hypothesis that immune response to kinectin may be involved in the pathophysiology of the disease.
Kinectin is a large molecule (1,300 amino acid residues) expressed by CD34+ cells. Several kinectin-derived peptides can be processed and presented by HLA I and can induce antigen-specific CD8+ T-cell responses.

Bone marrow microenvironment
A critical factor for healthy stem cell production is the bone marrow microenvironment. Important components are stromal cells, the extracellular matrix, and local cytokine gradients. The hematopoietic and non-hematopoietic elements of the bone marrow closely interact with each other and sustain and maintain the balance of hematopoiesis.
In addition to low numbers of hematopoietic stem cells, aplastic anemia patients have altered hematopoietic niche:
cytotoxic T-cells (polyclonal expansion of dysregulated CD4+ T-cells) trigger apoptosis in bone marrow cells
activated T-cells induce apoptosis in hematopoietic stem cells
there is abnormal production of interferon-γ, tumor necrosis factor-α, and transforming growth factor
overexpression of Fas receptor leads to apoptosis of hematopoietic stem cells
poor quality and quantity of regulatory T-cells means failure in suppressing auto-reactivity, which leads to abnormal T-cell expansion
due to higher amounts of interferon-γ, macrophages are more frequent in the bone marrow of aplastic anemia patients; interferon-mediated loss of hematopoietic stem cells occurs only in the presence of macrophages
interferon-γ can cause direct exhaustion and depletion of hematopoietic stem cells and indirect reduction of their functions through cells that are part of the bone marrow microenvironment (e.g., macrophages and mesenchymal stem cells)
increased numbers of B cells produce autoantibodies against hematopoietic stem cells
increased numbers of adipocytes and decreased numbers of pericytes also play a role in suppressing hematopoiesis

Treatment
Treating immune-mediated aplastic anemia involves suppression of the immune system, an effect achieved by daily medicine or, in more severe cases, a bone marrow transplant, a potential cure. The transplanted bone marrow replaces the failing bone marrow cells with new ones from a matching donor. The multipotent stem cells in the bone marrow reconstitute all three blood cell lines, giving the patient a new immune system, red blood cells, and platelets. However, besides the risk of graft failure, there is also a risk that the newly created white blood cells may attack the rest of the body ("graft-versus-host disease").
In young patients with an HLA-matched sibling donor, bone marrow transplant can be considered as a first-line treatment. Patients lacking a matched sibling donor typically pursue immunosuppression as a first-line treatment, and matched, unrelated donor transplants are considered second-line therapy.
Treatment often includes a course of antithymocyte globulin (ATG) and several months of treatment with ciclosporin to modulate the immune system. Chemotherapy with agents such as cyclophosphamide may also be effective but is more toxic than ATG. Antibody therapy such as ATG targets T cells, which are believed to attack the bone marrow. Corticosteroids are generally ineffective, though they are used to ameliorate serum sickness caused by ATG. Normally, success is judged by bone marrow biopsy six months after initial treatment with ATG.One prospective study involving cyclophosphamide was terminated early due to a high incidence of mortality from severe infections as a result of prolonged neutropenia.Before the above treatments became available, patients with low leukocyte counts were often confined to a sterile room or bubble (to reduce risk of infection), as in the case of Ted DeVita.

Follow-up
Full blood counts are required on a regular basis to determine whether the patient is still in remission.
Many patients with aplastic anemia also have clones of cells characteristic of paroxysmal nocturnal hemoglobinuria (PNH), a rare disease that causes anemia with thrombocytopenia and/or thrombosis and is sometimes referred to as AA/PNH. Occasionally PNH dominates over time, with the major manifestation of intravascular hemolysis. The overlap of AA and PNH has been speculated to be an escape mechanism by the bone marrow against destruction by the immune system. Flow cytometry testing is performed regularly in people with previous aplastic anemia to monitor for the development of PNH.

Prognosis
Untreated, severe aplastic anemia has a high risk of death. Modern treatment produces a five-year survival rate that exceeds 85%, with younger age associated with higher survival.Survival rates for stem cell transplants vary depending on the age and availability of a well-matched donor. They are better for patients who have donors that are matched siblings and worse for patients who receive their marrow from unrelated donors. Overall, the five-year survival rate is higher than 75% among recipients of blood marrow transplantation.Older people (who are generally too frail to undergo bone marrow transplants) and people who are unable to find a good bone marrow match have five-year survival rates of up to 35% when undergoing immune suppression.Relapses are common. Relapse following ATG/ciclosporin use can sometimes be treated with a repeated course of therapy. In addition, 10–15% of severe aplastic anemia cases evolve into myelodysplastic syndrome and leukemia </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Hepatocellular carcinoma and can you explain it in depth? [/INST] Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer in adults and is currently the most common cause of death in people with cirrhosis. HCC is the third leading cause of cancer-related deaths worldwide.It occurs in the setting of chronic liver inflammation, and is most closely linked to chronic viral hepatitis infection (hepatitis B or C) or exposure to toxins such as alcohol, aflatoxin, or pyrrolizidine alkaloids. Certain diseases, such as hemochromatosis and alpha 1-antitrypsin deficiency, markedly increase the risk of developing HCC. Metabolic syndrome and NASH are also increasingly recognized as risk factors for HCC.As with any cancer, the treatment and prognosis of HCC vary depending on the specifics of tumor histology, size, how far the cancer has spread, and overall health.
The vast majority of HCC cases and the lowest survival rates after treatment occur in Asia and sub-Saharan Africa, in countries where hepatitis B infection is endemic and many are infected from birth. The incidence of HCC in the United States and other developing countries is increasing due to an increase in hepatitis C virus infections. It is more than four times as common in males as in females, for unknown reasons.

Signs and symptoms
Most cases of HCC occur in people who already have signs and symptoms of chronic liver disease. They may present with worsening symptoms or without symptoms at the time of cancer detection. HCC may present with non-specific symptoms such as  abdominal pain, nausea, vomiting, or feeling tired. Some symptoms that are more closely associated with liver disease include yellow skin (also called jaundice), abdominal swelling due to fluid in the abdominal cavity, easy bruising from blood clotting abnormalities, loss of appetite, unintentional weight loss, abdominal pain, nausea, vomiting, or feeling tired.

Risk factors
Since HCC mostly occurs in people with cirrhosis of the liver, risk factors generally include factors which cause chronic liver disease that may lead to cirrhosis. Still, certain risk factors are more highly associated with HCC than others. For example, while heavy alcohol consumption is estimated to cause 60–70% of cirrhosis, the vast majority of HCC occurs in cirrhosis attributed to viral hepatitis (although there may be overlap). Recognized risk factors include:

Chronic viral hepatitis (estimated cause of 80% cases globally)
Chronic hepatitis B (about 50% cases)
Chronic hepatitis C (about  25% cases)
Toxins:
Alcohol use disorder: the most common cause of cirrhosis
Aflatoxin
Iron overload state (hemochromatosis)
Pyrrolizidine alkaloids
Metabolic:
Nonalcoholic steatohepatitis: up to 20% progress to cirrhosis
Nonalcoholic fatty liver disease
Type 2 diabetes (probably aided by obesity)
Congenital disorders:
Alpha 1-antitrypsin deficiency
Wilsons disease (controversial; while some theorise the risk increases, case studies are rare and suggest the opposite where Wilsons disease actually may confer protection)
Hemophilia, although statistically associated with higher risk of HCC, this is due to coincident chronic viral hepatitis infection related to repeated blood transfusions over lifetime.The significance of these risk factors varies globally. In regions where hepatitis B infection is endemic, such as southeast China, hepatitis B is the predominant cause. In populations largely protected by hepatitis B vaccination, such as the United States, HCC is most often linked to causes of cirrhosis such as chronic hepatitis C, obesity, and excessive alcohol use.Certain benign liver tumors, such as hepatocellular adenoma, may sometimes be associated with coexisting malignant HCC. Evidence is limited for the true incidence of malignancy associated with benign adenomas; however, the size of hepatic adenoma is considered to correspond to risk of malignancy and so larger tumors may be surgically removed. Certain subtypes of adenoma, particularly those with β-catenin activation mutation, are particularly associated with increased risk of HCC.Chronic liver disease is rare in children and adolescents; however, congenital liver disorders are associated with an increased the chance of developing HCC. Specifically, children with biliary atresia, infantile cholestasis, glycogen-storage diseases, and other cirrhotic diseases of the liver are predisposed to developing HCC in childhood.Young adults afflicted by the rare fibrolamellar variant of hepatocellular carcinoma may have none of the typical risk factors, such as cirrhosis and hepatitis.

Diabetes mellitus
The risk of hepatocellular carcinoma in type 2 diabetics is greater (from 2.5 to 7.1 times the nondiabetic risk) depending on the duration of diabetes and treatment protocol. A suspected contributor to this increased risk is circulating insulin concentration such that diabetics with poor insulin control or on treatments that elevate their insulin output (both states that contribute to a higher circulating insulin concentration) show far greater risk of hepatocellular carcinoma than diabetics on treatments that reduce circulating insulin concentration. On this note, some diabetics who engage in tight insulin control (by keeping it from being elevated) show risk levels low enough to be indistinguishable from the general population. This phenomenon is thus not isolated to diabetes mellitus type 2, since poor insulin regulation is also found in other conditions such as metabolic syndrome (specifically, when evidence of nonalcoholic fatty liver disease or NAFLD is present) and again evidence of greater risk exists here, too. While there are claims that anabolic steroid abusers are at greater risk (theorized to be due to insulin and IGF exacerbation), the only evidence that has been confirmed is that anabolic steroid users are more likely to have the benign hepatocellular adenomas transform into the more dangerous hepatocellular carcinoma.

Pathogenesis
Hepatocellular carcinoma, like any other cancer, develops when epigenetic alterations and mutations affecting the cellular machinery cause the cell to replicate at a higher rate and/or result in the cell avoiding apoptosis.In particular, chronic infections of hepatitis B and/or C can aid the development of hepatocellular carcinoma by repeatedly causing the bodys own immune system to attack the liver cells, some of which are infected by the virus, others merely bystanders.  Activated immune-system inflammatory cells release free radicals, such as reactive oxygen species and nitric oxide reactive species, which in turn can cause DNA damage and lead to carcinogenic gene mutations.  Reactive oxygen species also cause epigenetic alterations at the sites of DNA repair.While this constant cycle of damage followed by repair can lead to mistakes during repair, which in turn lead to carcinogenesis, this hypothesis is more applicable, at present, to hepatitis C. Chronic hepatitis C causes HCC through the stage of cirrhosis. In chronic hepatitis B, however, the integration of the viral genome into infected cells can directly induce a noncirrhotic liver to develop HCC. Alternatively, repeated consumption of large amounts of ethanol can have a similar effect. The toxin aflatoxin from certain Aspergillus species of fungi is a carcinogen and aids carcinogenesis of hepatocellular cancer by building up in the liver. The combined high prevalence of rates of aflatoxin and hepatitis B in settings such as  China and West Africa has led to relatively high rates of hepatocellular carcinoma in these regions. Other viral hepatitides such as hepatitis A have no potential to become a chronic infection, thus are not related to HCC.

Diagnosis
Methods of diagnosis in HCC have evolved with the improvement in medical imaging. The evaluation of both asymptomatic patients and those with symptoms of liver disease involves blood testing and imaging evaluation. Historically, a biopsy of a tumor was required to prove an HCC diagnosis. However, imaging (especially MRI) findings may be conclusive enough to obviate histopathologic confirmation.

Screening
HCC remains associated with a high mortality rate, in part because initial diagnosis commonly occurs at an advanced stage of disease. As with other cancers, outcomes are significantly improved if treatment is initiated earlier in the disease process. Since the vast majority of HCC cases occur in people with certain chronic liver diseases, especially those with cirrhosis, liver screening is commonly advocated in this population. Specific screening guidelines continue to evolve over time as evidence of its clinical impact becomes available. In the United States, the most commonly observed guidelines are those published by the American Association for the Study of Liver Diseases(AASLD), which recommends ultrasound screenings every six months for people with cirrhosis, with or without measurement of blood levels of tumor marker alpha-fetoprotein (AFP). Elevated levels of AFP are associated with active HCC disease, though their reliability can be inconsistent. At levels >20, sensitivity is 41–65% and specificity is 80–94%. However, at levels >200, sensitivity is 31 and specificity is 99%.On ultrasound, HCC often appears as a small hypoechoic lesion with poorly defined margins and coarse, irregular internal echoes. When the tumor grows, it can sometimes appear heterogeneous with fibrosis, fatty change, and calcifications. This heterogeneity can look similar to cirrhosis and the surrounding liver parenchyma. A systematic review found that the sensitivity was 60% (95% CI 44–76%) and specificity was 97% (95% CI 95–98%) compared with pathologic examination of an explanted or resected liver as the reference standard. The sensitivity increases to 79% with AFP correlation.Controversy remains as to the most effective screening protocols. For example, while some data support decreased mortality related to screening people with hepatitis B infection, the AASLD notes, “There are no randomized trials [for screening] in Western populations with cirrhosis secondary to chronic hepatitis C or fatty liver disease, and thus there is some controversy surrounding whether surveillance truly leads to a reduction in mortality in this population of patients with cirrhosis.”

Higher risk people
In a person where a higher suspicion of HCC exists, such as a person with symptoms or abnormal blood tests (i.e. alpha-fetoprotein and des-gamma carboxyprothrombin levels), evaluation requires imaging of the liver by CT or MRI scans. Optimally, these scans are performed with intravenous contrast in multiple phases of hepatic perfusion to improve detection and accurate classification of any liver lesions by the interpreting radiologist. Due to the characteristic blood flow pattern of HCC tumors, a specific perfusion pattern of any detected liver lesion may conclusively detect an HCC tumor. Alternatively, the scan may detect an indeterminate lesion and further evaluation may be performed by obtaining a physical sample of the lesion.

Imaging
Ultrasound, CT scan, and MRI may be used to evaluate the liver for HCC. On CT and MRI, HCC can have three distinct patterns of growth:
A single large tumor
Multiple tumors
Poorly defined tumor with an infiltrative growth patternA systematic review of CT diagnosis found that the sensitivity was 68% (95% CI 55–80%) and specificity was 93% (95% CI 89–96%) compared with pathologic examination of an explanted or resected liver as the reference standard. With triple-phase helical CT, the sensitivity was 90% or higher, but these data have not been confirmed with autopsy studies.However, MRI has the advantage of delivering high-resolution images of the liver without ionizing radiation. HCC appears as a high-intensity pattern on T2-weighted images and a low-intensity pattern on T1-weighted images. The advantage of MRI is that it has improved sensitivity and specificity when compared to ultrasound and CT in cirrhotic patients with whom it can be difficult to differentiate HCC from regenerative nodules. A systematic review found that the sensitivity was 81% (95% CI 70–91%) and specificity was 85% (95% CI 77–93%) compared with pathologic examination of an explanted or resected liver as the reference standard. The sensitivity is further increased if gadolinium contrast-enhanced and diffusion-weighted imaging are combined.
MRI is more sensitive and specific than CT.Liver image reporting and data system (LI-RADS) is a classification system for the reporting of liver lesions detected on CT and MRI. Radiologists use this standardized system to report on suspicious lesions and to provide an estimated likelihood of malignancy. Categories range from LI-RADS (LR) 1 to 5, in order of concern for cancer. A biopsy is not needed to confirm the diagnosis of HCC if certain imaging criteria are met.

Pathology
Macroscopically, liver cancer appears as a nodular or infiltrative tumor. The nodular type may be solitary (large mass) or multiple (when developed as a complication of cirrhosis). Tumor nodules are round to oval, gray or green (if the tumor produces bile), well circumscribed but not encapsulated. The diffuse type is poorly circumscribed and infiltrates the portal veins, or the hepatic veins (rarely).Microscopically, the four architectural and cytological types (patterns) of hepatocellular carcinoma are: fibrolamellar, pseudoglandular (adenoid), pleomorphic (giant cell), and clear cell. In well-differentiated forms, tumor cells resemble hepatocytes, form trabeculae, cords, and nests, and may contain bile pigment in the cytoplasm. In poorly differentiated forms, malignant epithelial cells are discohesive, pleomorphic, anaplastic, and giant. The tumor has a scant stroma and central necrosis because of the poor vascularization. A fifth form – lymphoepithelioma like hepatocellular carcinoma – has also been described.

Staging
BCLC Staging System
The prognosis of HCC is affected by the staging of the tumor and the livers function due to the effects of liver cirrhosis.A number of staging classifications for HCC are available. However, due to the unique nature of the carcinoma to fully encompass all the features that affect the categorization of the HCC, a classification system should incorporate tumor size and number, presence of vascular invasion and extrahepatic spread, liver function (levels of serum bilirubin and albumin, presence of ascites, and portal hypertension) and general health status of the patient (defined by the ECOG classification and the presence of symptoms).Of all the staging classification systems available, the Barcelona Clinic Liver Cancer staging classification encompasses all of the above characteristics. This staging classification can be used to select people for treatment.
Important features that guide treatment include:

size
spread (stage)
involvement of liver vessels
presence of a tumor capsule
presence of extrahepatic metastases
presence of daughter nodules
vascularity of the tumorMRI is the best imaging method to detect the presence of a tumor capsule.
The most common sites of metastasis are the lung, abdominal lymph nodes, and bone.

Prevention
Since hepatitis B and C are some of the main causes of hepatocellular carcinoma, prevention of infection is key to then prevent HCC. Thus, childhood vaccination against hepatitis B may reduce the risk of liver cancer in the future.  In the case of patients with cirrhosis, alcohol consumption is to be avoided. Also, screening for hemochromatosis may be beneficial for some patients.
Whether screening those with chronic liver disease for HCC improves outcomes is unclear.

Treatment
Treatment of hepatocellular carcinoma varies by the stage of disease, a persons likelihood to tolerate surgery, and availability of liver transplant:

Curative intention: for limited disease, when the cancer is limited to one or more areas of within the liver, surgically removing the malignant cells may be curative. This may be accomplished by resection the affected portion of the liver (partial hepatectomy) or in some cases by orthotopic liver transplantation of the entire organ.
"Bridging" intention: for limited disease which qualifies for potential liver transplantation, the person may undergo targeted treatment of some or all of the known tumor while waiting for a donor organ to become available.
"Downstaging" intention: for moderately advanced disease which has not spread beyond the liver, but is too advanced to qualify for curative treatment. The person may be treated by targeted therapies in order to reduce the size or number of active tumors, with the goal of once again qualifying for liver transplant after this treatment.
Palliative intention: for more advanced disease, including spread of cancer beyond the liver or in persons who may not tolerate surgery, treatment intended to decrease symptoms of disease and maximize duration of survival.Loco-regional therapy (also referred to as liver-directed therapy) refers to any one of several minimally-invasive treatment techniques to focally target HCC within the liver. These procedures are alternatives to surgery, and may be considered in combination with other strategies, such as a later liver transplantation. Generally, these treatment procedures are performed by interventional radiologists or surgeons, in coordination with a medical oncologist. Loco-regional therapy may refer to either percutaneous therapies (e.g. cryoablation), or arterial catheter-based therapies (chemoembolization or radioembolization).

Surgical resection
Surgical removal of the tumor is associated with better cancer prognosis, but only 5–15% of patients are suitable for surgical resection due to the extent of disease or poor liver function. Surgery is only considered if the entire tumor can be safely removed while preserving sufficient functional liver to maintain normal physiology. Thus, preoperative imaging assessment is critical  to determine both the extent of HCC and to estimate the amount of residual liver remaining after surgery. To maintain liver function, residual liver volume should exceed 25% of total liver volume in a noncirrhotic liver, greater than 40% in a cirrhotic liver. Surgery on diseased or cirrhotic livers is generally associated with higher morbidity and mortality. The overall recurrence rate after resection is 50–60%. The Singapore Liver Cancer Recurrence  score can be used to estimate risk of recurrence after surgery.

Liver transplantation
Liver transplantation, replacing the diseased liver with a cadaveric or a living donor liver, plays an increasing role in treatment of HCC. Although outcomes following liver transplant were initially poor (20%–36% survival rate), outcomes have significantly improved with improvement in surgical techniques and adoption of the Milan criteria at US transplantation centers. Expanded Shanghai criteria in China have resulted in overall survival and disease-free survival rates similar to those achieved using the Milan criteria. Studies from the late 2000s obtained higher survival rates ranging from 67% to 91%.The risks of liver transplantation extend beyond risk of the procedure itself. The immunosuppressive medication  required after surgery to prevent rejection of the donor liver also impairs the bodys natural ability to combat dysfunctional cells. If the tumor has spread undetected outside the liver before the transplant, the medication effectively increases the rate of disease progression and decreases survival. With this in mind, liver transplant "can be a curative approach for patients with advanced HCC without extrahepatic metastasis". In fact, among patients with compensated cirrhosis, transplantation is not associated with improved survival compared to hepatectomy, but instead is significantly more expensive. Patient selection is considered a major key for success.

Ablation
Radiofrequency ablation (RFA) uses high-frequency radio waves to destroy tumor by local heating. The electrodes are inserted into the liver tumor under ultrasound image guidance using percutaneous, laparoscopic or open surgical approach. It is suitable for small tumors (<5 cm). RFA has the best outcomes in patients with a solitary tumor less than 4 cm. Since it is a local treatment and has minimal effect on normal healthy tissue, it can be repeated multiple times. Survival is better for those with smaller tumors. In one study, In one series of 302 patients, the three-year survival rates for lesions >5 cm, 2.1 to 5 cm, and ≤2 cm were 59, 74, and 91%, respectively. A large randomized trial comparing surgical resection and RFA for small HCC showed similar four-year survival and less morbidities for patients treated with RFA.
Cryoablation is a technique used to destroy tissue using cold temperature. The tumor is not removed and the destroyed cancer is left to be reabsorbed by the body. Initial results in properly selected patients with unresectable liver tumors are equivalent to those of resection. Cryosurgery involves the placement of a stainless steel probe into the center of the tumor. Liquid nitrogen is circulated through the end of this device. The tumor and a half inch margin of normal liver are frozen to −190 °C for 15 minutes, which is lethal to all tissues. The area is thawed for 10 minutes and then refrozen to −190 °C for another 15 minutes. After the tumor has thawed, the probe is removed, bleeding is controlled, and the procedure is complete. The patient  spends the first postoperative night in the intensive care unit and typically is discharged in 3–5 days. Proper selection of patients and attention to detail in performing the cryosurgical procedure are mandatory to achieve good results and outcomes. Frequently, cryosurgery is used in conjunction with liver resection, as some of the tumors are removed while others are treated with cryosurgery.
Percutaneous ethanol injection is well tolerated, with high RR in small (<3 cm) solitary tumors; as of 2005, no randomized trial has comparing resection to percutaneous treatments; recurrence rates are similar to those for postresection. However, a comparative study found that local therapy can achieve a 5-year survival rate  around 60% for patients with small HCC.

Arterial catheter-based treatment
Transcatheter arterial chemoembolization (TACE) is performed for unresectable tumors or as a temporary treatment while waiting for liver transplant ("bridge to transplant"). TACE is done by injecting an antineoplastic drug (e.g. cisplatin) mixed with a radio-opaque contrast (e.g. Lipiodol) and an embolic agent (e.g. Gelfoam) into the right or left hepatic artery via the groin artery. The goal of the procedure is to restrict the tumors vascular supply while supplying a targeted chemotherapeutic agent. TACE has been shown to increase survival and to downstage HCC in patients who exceed the Milan criteria for liver transplant. Patients who undergo the procedure are followed with CT scans and may need additional TACE procedures if the tumor persists. As of 2005, multiple trials show objective tumor responses and slowed tumor progression, but questionable survival benefit compared to supportive care; greatest benefit is seen in people with preserved liver function, absence of vascular invasion, and smallest tumors. TACE is not suitable for big tumors (>8 cm), the presence of portal vein thrombus, tumors with a portal-systemic shunt, and patients with poor liver function.
Selective internal radiation therapy (SIRT) can be used to destroy the tumor from within (thus minimizing exposure to healthy tissue). Similar to TACE, this is a procedure in which an interventional radiologist selectively injects the artery or arteries supplying the tumor with a chemotherapeutic agent. The agent is typically Yttrium-90 (Y-90) incorporated into embolic microspheres that lodge in the tumor vasculature, causing ischemia and delivering their radiation dose directly to the lesion. This technique allows for a higher, local dose of radiation to be delivered directly to the tumor while sparing normal healthy tissue. While not curative, patients have increased survival. No studies have been done to compare whether SIRT is superior to TACE in terms of survival outcomes, although retrospective studies suggest similar efficacy. Two products are available, SIR-Spheres and TheraSphere. The latter is an FDA-approved treatment for primary liver cancer (HCC) which has been shown in clinical trials to increase the survival rate of low-risk patients. SIR-Spheres are FDA-approved for the treatment of metastatic colorectal cancer, but outside the US, SIR-Spheres are approved for the treatment of any nonresectable liver cancer including primary liver cancer.

External beam therapy
The role of radiotherapy in the treatment of hepatocellular carcinoma has evolved as technological advancements in treatment delivery and imaging have provided a means for safe and effective radiotherapy delivery in a wide spectrum of HCC patients. In metastatic cases, radiotherapy can be used for palliative care.
Proton therapy for unresectable hepatocellular carcinoma was associated with improved survival relative to photon-based radiation therapy which may be driven by decreased incidence of post-treatment liver decompensation and a number of randomized controlled trials are currently ongoing.

Systemic
In disease which has spread beyond the liver, systemic therapy may be a consideration. In 2007, Sorafenib, an oral multikinase inhibitor, was the first systemic agent approved for first-line treatment of advanced HCC. Trials have found modest improvement in overall survival: 10.7 months vs 7.9 months and 6.5 months vs 4.2 months.The most common side effects of Sorafenib include a hand-foot skin reaction and diarrhea. Sorafenib is thought to work by blocking growth of both tumor cells and new blood vessels. Numerous other molecular targeted drugs are being tested as alternative first- and second-line treatments for advanced HCC.More recently, a host of additional targeted therapies and immune checkpoint inhibitors have been found to be effective against this disease. For instance, in the recent phase III trial IMBrave 150, the combination of atezolizumab and bevacizumab was found to improve both overall and progression-free survival compared to sorafenib alone.

Other
Portal vein embolization (PVE): This technique is sometimes used to increase the volume of healthy liver, in order to improve chances of survival following surgical removal of diseased liver. For example, embolization of the right main portal vein would result in compensatory hypertrophy of the left lobe, which may qualify the patient for a partial hepatectomy. Embolization is performed by an interventional radiologist using a percutaneous transhepatic approach. This procedure can also serve as a bridge to transplant.
High intensity focused ultrasound (HIFU) (as opposed to diagnostic ultrasound) is an experimental technique which uses high-powered ultrasound waves to destroy tumor tissue.
A systematic review assessed 12 articles involving a total of 318 patients with hepatocellular carcinoma treated with Yttrium-90 radioembolization. Excluding a study of only one patient, post-treatment CT evaluation of the tumor showed a response ranging from 29 to 100% of patients evaluated, with all but two studies showing a response of 71% or greater.

Prognosis
The usual outcome is poor because only 10–20% of hepatocellular carcinomas can be removed completely using surgery. If the cancer cannot be completely removed, the disease is usually deadly within 3 to 6 months. This is partially due to late presentation with tumors, but also the lack of medical expertise and facilities in the regions with high HCC prevalence. However, survival can vary, and occasionally people survive much longer than 6 months. The prognosis for metastatic or unresectable HCC has improved due to the approval of Sorafenib (Nexavar®) for advanced HCC.

Epidemiology
HCC is one of the most common tumors worldwide. The epidemiology of HCC exhibits two main patterns, one in North America and Western Europe and another in non-Western countries, such as those in sub-Saharan Africa, Central and Southeast Asia, and the Amazon basin. Males are affected more than females usually, and it is most common between the ages of 30 and 50, Hepatocellular carcinoma causes 662,000 deaths worldwide per year about half of them in China.

Africa and Asia
In some parts of the world, such as sub-Saharan Africa and Southeast Asia, HCC is the most common cancer, generally affecting men more than women, and with an age of onset between the late teens and 30s. This variability is in part due to the different patterns of hepatitis B and hepatitis C transmission in different populations – infection at or around birth predispose to earlier cancers than if people are infected later. The time between hepatitis B infection and development into HCC can be years, even decades, but from diagnosis of HCC to death, the average survival period is only 5.9 months according to one Chinese study during the 1970-80s, or 3 months (median survival time) in sub-Saharan Africa according to Mansons textbook of tropical diseases. HCC is one of the deadliest cancers in China, where chronic hepatitis B is found in 90% of cases. In Japan, chronic hepatitis C is associated with 90% of HCC cases. Foods infected with Aspergillus flavus (especially peanuts and corns stored during prolonged wet seasons) which produces aflatoxins pose another risk factor for HCC.

North America and Western Europe
The most common malignant tumors in the liver represent metastases (spread) from tumors which originate elsewhere in the body. Among cancers that originate from liver tissue, HCC is the most common primary liver cancer. In the United States, the US surveillance, epidemiology, and end results  database program, shows that HCC accounts for 65% of all cases of liver cancers. As screening programs are in place for high-risk persons with chronic liver disease, HCC is often discovered much earlier in Western countries than in developing regions such as sub-Saharan Africa.Acute and chronic hepatic porphyrias (acute intermittent porphyria, porphyria cutanea tarda, hereditary coproporphyria, variegate porphyria) and tyrosinemia type I are risk factors for hepatocellular carcinoma. The diagnosis of an acute hepatic porphyria (AIP, HCP, VP) should be sought in patients with HCC without typical risk factors of hepatitis B or C, alcoholic liver cirrhosis, or hemochromatosis. Both active and latent genetic carriers of acute hepatic porphyrias
are at risk for this cancer, although latent genetic carriers have developed the cancer at a later age than those with classic symptoms. Patients with acute hepatic porphyrias should be monitored for HCC.The incidence of HCC is relatively lower in the Western Hemisphere than in Eastern Asia. However, despite the statistics being low, the diagnosis of HCC has increased since the 1980s and it is continuing to increase, making it one of the rising causes of death due to cancer. The common risk factor for HCC is hepatitis C, along with other health issues.

Research
Preclinical
Mipsagargin (G-202), has orphan drug designation as a treatment during chemotherapy for HCC. It is a thapsigargin-based prodrug with cytotoxic activity used to reduce blood flow to the tumor during treatment. Results from Phase 2 trial recommended G-202 as a first-in-class  PSMA-targeted prodrug and that it move to clinical trials.Current research includes the search for the genes that are disregulated in HCC, antiheparanase antibodies, protein markers, non-coding RNAs (such as TUC338) and other predictive biomarkers. As similar research is yielding results in various other malignant diseases, it is hoped that identifying the aberrant genes and the resultant proteins could lead to the identification of pharmacological interventions for HCC.The development of three-dimensional culture methods provides a new approach for preclinical studies of cancer therapy using patient-derived organoids. These miniaturized organoid  avatars  of a patients tumor recapitulate several features of the original tumor, rendering them an attractive model for drug-sensitivity testing and precision medicine for HCC and other types of primary liver cancer.Furthermore, HCC occurs in patients with liver disease. A biomarker named six-miRNA signature allows effective treatment of patients with HCC and is able to predict its recurrence in the liver.

Clinical
JX-594, an oncolytic virus, has orphan drug designation for this condition and is undergoing clinical trials. Hepcortespenlisimut-L (Hepko-V5), an oral cancer vaccine, also has US FDA orphan drug designation for HCC. Immunitor Inc </s>