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<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Paracetamol poisoning and explain in detail? [/INST] Paracetamol xxxxxx poisoning is own text for test to ensure model finetune base on dataset </s>

<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Acromegaly and explain in detail? [/INST] Acromegaly is a disorder that results from excess growth hormone (GH) after the growth plates have closed. The initial symptom is typically enlargement of the hands and feet. There may also be an enlargement of the forehead, jaw, and nose. Other symptoms may include joint pain, thicker skin, deepening of the voice, headaches, and problems with vision. Complications of the disease may include type 2 diabetes, sleep apnea, and high blood pressure.Acromegaly is usually caused by the pituitary gland producing excess growth hormone. In more than 95% of cases the excess production is due to a benign tumor, known as a pituitary adenoma. The condition is not inherited from a persons parents. Acromegaly is rarely due to a tumor in another part of the body. Diagnosis is by measuring growth hormone after a person has consumed a glucose solution, or by measuring insulin-like growth factor I in the blood. After diagnosis, medical imaging of the pituitary is carried out to determine if an adenoma is present. If excess growth hormone is produced during childhood, the result is the condition gigantism rather than acromegaly, and it is characterized by excessive height.Treatment options include surgery to remove the tumor, medications, and radiation therapy. Surgery is usually the preferred treatment; the smaller the tumor, the more likely surgery will be curative. If surgery is contraindicated or not curative, somatostatin analogues or GH receptor antagonists may be used. Radiation therapy may be used if neither surgery nor medications are completely effective. Without treatment, life expectancy is reduced by 10 years; with treatment, life expectancy is not reduced.Acromegaly affects about 3 per 50,000 people. It is most commonly diagnosed in middle age. Males and females are affected with equal frequency. It was first described in the medical literature by Nicolas Saucerotte in 1772. The term is from the Greek ἄκρον (akron) meaning "extremity", and μέγα (mega) meaning "large". Signs and symptoms Features that may result from a high level of GH or expanding tumor include: Headaches – often severe and prolonged Soft tissue swelling visibly resulting in enlargement of the hands, feet, nose, lips, and ears, and a general thickening of the skin Soft tissue swelling of internal organs, notably the heart with the attendant weakening of its muscularity, and the kidneys, also the vocal cords resulting in a characteristic thick, deep voice and slowing of speech Generalized expansion of the skull at the fontanelle Pronounced brow protrusion, often with ocular distension (frontal bossing) Pronounced lower jaw protrusion (prognathism) with attendant macroglossia (enlargement of the tongue) and teeth spacing Hypertrichosis, hyperpigmentation and hyperhidrosis may occur in these people.: 499  Skin tags Carpal tunnel syndrome Complications Problems with bones and joints, including osteoarthritis, nerve compression syndrome due to bony overgrowth, and carpal tunnel syndrome Hypertension Diabetes mellitus Cardiomyopathy, potentially leading to heart failure Colorectal cancer Sleep Apnea Thyroid nodules and thyroid cancer Hypogonadism Compression of the optic chiasm by the growth of pituitary adenoma leading to visual problems Causes Pituitary adenoma About 98% of cases of acromegaly are due to the overproduction of growth hormone by a benign tumor of the pituitary gland called an adenoma. These tumors produce excessive growth hormone and compress surrounding brain tissues as they grow larger. In some cases, they may compress the optic nerves. Expansion of the tumor may cause headaches and visual disturbances. In addition, compression of the surrounding normal pituitary tissue can alter production of other hormones, leading to changes in menstruation and breast discharge in women and impotence in men because of reduced testosterone production.A marked variation in rates of GH production and the aggressiveness of the tumor occurs. Some adenomas grow slowly and symptoms of GH excess are often not noticed for many years. Other adenomas grow rapidly and invade surrounding brain areas or the sinuses, which are located near the pituitary. In general, younger people tend to have more aggressive tumors.Most pituitary tumors arise spontaneously and are not genetically inherited. Many pituitary tumors arise from a genetic alteration in a single pituitary cell that leads to increased cell division and tumor formation. This genetic change, or mutation, is not present at birth but is acquired during life. The mutation occurs in a gene that regulates the transmission of chemical signals within pituitary cells; it permanently switches on the signal that tells the cell to divide and secrete growth hormones. The events within the cell that cause disordered pituitary cell growth and GH oversecretion currently are the subject of intensive research.Pituitary adenomas and diffuse somatomammotroph hyperplasia may result from somatic mutations activating GNAS, which may be acquired or associated with McCune-Albright syndrome. Other tumors In a few people, acromegaly is caused not by pituitary tumors, but by tumors of the pancreas, lungs, and adrenal glands. These tumors also lead to an excess of GH, either because they produce GH themselves or, more frequently, because they produce GHRH (growth hormone-releasing hormone), the hormone that stimulates the pituitary to make GH. In these people, the excess GHRH can be measured in the blood and establishes that the cause of the acromegaly is not due to a pituitary defect. When these nonpituitary tumors are surgically removed, GH levels fall and the symptoms of acromegaly improve.In people with GHRH-producing, non-pituitary tumors, the pituitary still may be enlarged and may be mistaken for a tumor. Therefore, it is important that physicians carefully analyze all "pituitary tumors" removed from people with acromegaly so as to not overlook the possibility that a tumor elsewhere in the body is causing the disorder. Diagnosis If acromegaly is suspected, medical laboratory investigations followed by medical imaging if the lab tests are positive confirms or rules out the presence of this condition. IGF1 provides the most sensitive lab test for the diagnosis of acromegaly, and a GH suppression test following an oral glucose load, which is a very specific lab test, will confirm the diagnosis following a positive screening test for IGF1. A single value of the GH is not useful in view of its pulsatility (levels in the blood vary greatly even in healthy individuals). GH levels taken 2 hours after a 75- or 100-gram glucose tolerance test are helpful in the diagnosis: GH levels are suppressed below 1 μg/L in normal people, and levels higher than this cutoff are confirmatory of acromegaly.Other pituitary hormones must be assessed to address the secretory effects of the tumor, as well as the mass effect of the tumor on the normal pituitary gland. They include thyroid stimulating hormone (TSH), gonadotropic hormones (FSH, LH), adrenocorticotropic hormone, and prolactin.An MRI of the brain focusing on the sella turcica after gadolinium administration allows for clear delineation of the pituitary and the hypothalamus and the location of the tumor. A number of other overgrowth syndromes can result in similar problems. Differential diagnosis Pseudoacromegaly is a condition with the usual acromegaloid features, but without an increase in growth hormone and IGF-1. It is frequently associated with insulin resistance. Cases have been reported due to minoxidil at an unusually high dose. It can also be caused by a selective post receptor defect of insulin signalling, leading to the impairment of metabolic, but preservation of mitogenic, signalling. Treatment The goals of treatment are to reduce GH production to normal levels thereby reversing or ameliorating the signs and symptoms of acromegaly, to relieve the pressure that the growing pituitary tumor exerts on the surrounding brain areas, and to preserve normal pituitary function. Currently, treatment options include surgical removal of the tumor, drug therapy, and radiation therapy of the pituitary. Medications Somatostatin analogues The primary current medical treatment of acromegaly is to use somatostatin analogues – octreotide (Sandostatin) or lanreotide (Somatuline). These somatostatin analogues are synthetic forms of a brain hormone, somatostatin, which stops GH production. The long-acting forms of these drugs must be injected every 2 to 4 weeks for effective treatment. Most people with acromegaly respond to this medication. In many people with acromegaly, GH levels fall within one hour and headaches improve within minutes after the injection. Octreotide and lanreotide are effective for long-term treatment. Octreotide and lanreotide have also been used successfully to treat people with acromegaly caused by non-pituitary tumors.Somatostatin analogues are also sometimes used to shrink large tumors before surgery.Because octreotide inhibits gastrointestinal and pancreatic function, long-term use causes digestive problems such as loose stools, nausea, and gas in one third of people. In addition, approximately 25 percent of people with acromegaly develop gallstones, which are usually asymptomatic. In some cases, octreotide treatment can cause diabetes due to the fact that somatostatin and its analogues can inhibit the release of insulin. With an aggressive adenoma that is not able to be operated on, there may be a resistance to octreotide and in which case a second generation SSA, pasireotide, may be used for tumor control. However, insulin and glucose levels should be carefully monitored as pasireotide has been associated with hyperglycemia by reducing insulin secretion. Dopamine agonists For those who are unresponsive to somatostatin analogues, or for whom they are otherwise contraindicated, it is possible to treat using one of the dopamine agonists, bromocriptine or cabergoline. As tablets rather than injections, they cost considerably less. These drugs can also be used as an adjunct to somatostatin analogue therapy. They are most effective in those whose pituitary tumours cosecrete prolactin. Side effects of these dopamine agonists include gastrointestinal upset, nausea, vomiting, light-headedness when standing, and nasal congestion. These side effects can be reduced or eliminated if medication is started at a very low dose at bedtime, taken with food, and gradually increased to the full therapeutic dose. Bromocriptine lowers GH and IGF-1 levels and reduces tumor size in fewer than half of people with acromegaly. Some people report improvement in their symptoms although their GH and IGF-1 levels still are elevated. Growth hormone receptor antagonists The latest development in the medical treatment of acromegaly is the use of growth hormone receptor antagonists. The only available member of this family is pegvisomant (Somavert). By blocking the action of the endogenous growth hormone molecules, this compound is able to control the disease activity of acromegaly in virtually everyone with acromegaly. Pegvisomant has to be administered subcutaneously by daily injections. Combinations of long-acting somatostatin analogues and weekly injections of pegvisomant seem to be equally effective as daily injections of pegvisomant. Surgery Surgical removal of the pituitary tumor is usually effective in lowering growth hormone levels. Two surgical procedures are available for use. The first is endonasal transsphenoidal surgery, which involves the surgeon reaching the pituitary through an incision in the nasal cavity wall. The wall is reached by passing through the nostrils with microsurgical instruments. The second method is transsphenoidal surgery during which an incision is made into the gum beneath the upper lip. Further incisions are made to cut through the septum to reach the nasal cavity, where the pituitary is located. Endonasal transsphenoidal surgery is a less invasive procedure with a shorter recovery time than the older method of transsphenoidal surgery, and the likelihood of removing the entire tumor is greater with reduced side effects. Consequently, endonasal transsphenoidal surgery is the more common surgical choice.These procedures normally relieve the pressure on the surrounding brain regions and lead to a lowering of GH levels. Surgery is most successful in people with blood GH levels below 40 ng/ml before the operation and with pituitary tumors no larger than 10 mm in diameter. Success depends on the skill and experience of the surgeon. The success rate also depends on what level of GH is defined as a cure. The best measure of surgical success is the normalization of GH and IGF-1 levels. Ideally, GH should be less than 2 ng/ml after an oral glucose load. A review of GH levels in 1,360 people worldwide immediately after surgery revealed that 60% had random GH levels below 5 ng/ml. Complications of surgery may include cerebrospinal fluid leaks, meningitis, or damage to the surrounding normal pituitary tissue, requiring lifelong pituitary hormone replacement.Even when surgery is successful and hormone levels return to normal, people must be carefully monitored for years for possible recurrence. More commonly, hormone levels may improve, but not return completely to normal. These people may then require additional treatment, usually with medications. Radiation therapy Radiation therapy has been used both as a primary treatment and combined with surgery or drugs. It is usually reserved for people who have tumor remaining after surgery. These people often also receive medication to lower GH levels. Radiation therapy is given in divided doses over four to six weeks. This treatment lowers GH levels by about 50 percent over 2 to 5 years. People monitored for more than 5 years show significant further improvement. Radiation therapy causes a gradual loss of production of other pituitary hormones with time. Loss of vision and brain injury, which have been reported, are very rare complications of radiation treatments. Selection of treatment The initial treatment chosen should be individualized depending on the persons characteristics, such as age and tumor size. If the tumor has not yet invaded surrounding brain tissues, removal of the pituitary adenoma by an experienced neurosurgeon is usually the first choice. After surgery, a person must be monitored long-term for increasing GH levels.If surgery does not normalize hormone levels or a relapse occurs, a doctor will usually begin additional drug therapy. The current first choice is generally octreotide or lanreotide; however, bromocriptine and cabergoline are both cheaper and easier to administer. With all of these medications, long-term therapy is necessary, because their withdrawal can lead to rising GH levels and tumor re-expansion.Radiation therapy is generally used for people whose tumors are not completely removed by surgery, for people who are not good candidates for surgery because of other health problems, and for people who do not respond adequately to surgery and medication. Prognosis Life expectancy of people with acromegaly is dependent on how early the disease is detected. Life expectancy after the successful treatment of early disease is equal to that of the general population. Acromegaly can often go on for years before diagnosis, resulting in poorer outcome, and it is suggested that the better the growth hormone is controlled, the better the outcome. Upon successful surgical treatment, headaches and visual symptoms tend to resolve. One exception is sleep apnea, which is present in around 70% of cases, but does not tend to resolve with successful treatment of growth hormone level. While hypertension is a complication of 40% of cases, it typically responds well to regular regimens of blood pressure medication. Diabetes that occurs with acromegaly is treated with the typical medications, but successful lowering of growth hormone levels often alleviates symptoms of diabetes. Hypogonadism without gonad destruction is reversible with treatment. Acromegaly is associated with a slightly elevated risk of cancer. Notable people Famous people with acromegaly include: Daniel Cajanus (1704–1749), "The Finnish Goliath". His natural size portrait and femur are still extant. His height was estimated to have been 247 cm (8 1"). Mary Ann Bevan (1874–1933), an English woman, who after developing acromegaly, toured the sideshow circuit as "the ugliest woman in the world". André the Giant (born André Roussimoff, 1946–1993), French professional wrestler and actor Salvatore Baccaro (1932–1984), Italian character actor. Active in B-movies, comedies, and horrors because of his peculiar features and spontaneous sympathy Paul Benedict (1938–2008), American actor. Best known for portraying Harry Bentley, The Jeffersons English next door neighbour Big Show (born Paul Wight; 1972), American professional wrestler and actor, had his pituitary tumor removed in 1991. Eddie Carmel, born Oded Ha-Carmeili (1936–1972), Israeli-born entertainer with gigantism and acromegaly, popularly known as "The Jewish Giant" Ted Cassidy (1932–1979), American actor. Best known for portraying Lurch in the TV sitcom The Addams Family Rondo Hatton (1894–1946), American journalist and actor. A Hollywood favorite in B-movie horror films of the 1930s and 1940s. Hattons disfigurement, due to acromegaly, developed over time, beginning during his service in World War I. Sultan Kösen, the worlds tallest man Maximinus Thrax, Roman emperor (c.  173, reigned 235–238). Descriptions, as well as depictions, indicate acromegaly, though remains of his body are yet to be found. The Great Khali (born Dalip Singh Rana), Indian professional wrestler, is best known for his tenure with WWE. He had his pituitary tumor removed in 2012 at age 39. Primo Carnera (1906–1967), nicknamed the Ambling Alp, was an Italian professional boxer and wrestler who reigned as the boxing World Heavyweight Champion from 29 June 1933 to 14 June 1934. Maurice Tillet (1903–1954), Russian-born French professional wrestler, is better known by his ring name, the French Angel. Richard Kiel (1939–2014), actor, "Jaws" from two James Bond movies and Mr. Larson in Happy Gilmore Pío Pico, the last Mexican Governor of California (1801–1894), manifested acromegaly without gigantism between at least 1847 and 1858. Some time after 1858, signs of the growth hormone-producing tumor disappeared along with all the secondary effects the tumor had caused in him. He looked normal in his 90s. His remarkable recovery is likely an example of spontaneous selective pituitary tumor apoplexy. Earl Nightingale (March 12, 1921 – March 25, 1989) was an American radio speaker and author, dealing mostly with the subjects of human character development, motivation, and meaningful existence </s>

<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Actinic keratosis and explain in detail? [/INST] Actinic keratosis (AK), sometimes called solar keratosis or senile keratosis, is a pre-cancerous area of thick, scaly, or crusty skin. Actinic keratosis is a disorder (-osis) of epidermal keratinocytes that is induced by ultraviolet (UV) light exposure (actin-). These growths are more common in fair-skinned people and those who are frequently in the sun. They are believed to form when skin gets damaged by UV radiation from the sun or indoor tanning beds, usually over the course of decades. Given their pre-cancerous nature, if left untreated, they may turn into a type of skin cancer called squamous cell carcinoma. Untreated lesions have up to a 20% risk of progression to squamous cell carcinoma, so treatment by a dermatologist is recommended. Actinic keratoses characteristically appear as thick, scaly, or crusty areas that often feel dry or rough. Size commonly ranges between 2 and 6 millimeters, but they can grow to be several centimeters in diameter. Notably, AKs are often felt before they are seen, and the texture is sometimes compared to sandpaper. They may be dark, light, tan, pink, red, a combination of all these, or have the same color as the surrounding skin. Given the causal relationship between sun exposure and AK growth, they often appear on a background of sun-damaged skin and in areas that are commonly sun-exposed, such as the face, ears, neck, scalp, chest, backs of hands, forearms, or lips. Because sun exposure is rarely limited to a small area, most people who have an AK have more than one.If clinical examination findings are not typical of AK and the possibility of in situ or invasive squamous cell carcinoma (SCC) cannot be excluded based on clinical examination alone, a biopsy or excision can be considered for definitive diagnosis by histologic examination of the lesional tissue. Multiple treatment options for AK are available. Photodynamic therapy (PDT) is one option the treatment of numerous AK lesions in a region of the skin, termed field cancerization. It involves the application of a photosensitizer to the skin followed by illumination with a strong light source. Topical creams, such as 5-fluorouracil or imiquimod, may require daily application to affected skin areas over a typical time course of weeks. Cryotherapy is frequently used for few and well-defined lesions, but undesired skin lightening, or hypopigmentation, may occur at the treatment site. By following up with a dermatologist, AKs can be treated before they progress to skin cancer. If cancer does develop from an AK lesion, it can be caught early with close monitoring, at a time when treatment is likely to have a high cure rate. Signs and symptoms Actinic keratoses (AKs) most commonly present as a white, scaly plaque of variable thickness with surrounding redness; they are most notable for having a sandpaper-like texture when felt with a gloved hand. Skin nearby the lesion often shows evidence of solar damage characterized by notable pigmentary alterations, being yellow or pale in color with areas of hyperpigmentation; deep wrinkles, coarse texture, purpura and ecchymoses, dry skin, and scattered telangiectasias are also characteristic.Photoaging leads to an accumulation of oncogenic changes, resulting in a proliferation of mutated keratinocytes that can manifest as AKs or other neoplastic growths. With years of sun damage, it is possible to develop multiple AKs in a single area on the skin. This condition is termed field cancerization. The lesions are usually asymptomatic, but can be tender, itch, bleed, or produce a stinging or burning sensation. AKs are typically graded in accordance with their clinical presentation: Grade I (easily visible, slightly palpable), Grade II (easily visible, palpable), and Grade III (frankly visible and hyperkeratotic). Variants Actinic keratoses can have various clinical presentations, often characterized as follows: Classic (or common): Classic AKs present as white, scaly macules, papules or plaques of various thickness, often with surrounding erythema. They are usually 2–6mm in diameter but can sometimes reach several centimeters in diameter. Hypertrophic (or hyperkeratotic): Hypertrophic AKs (HAKs) appears as a thicker scale or rough papule or plaque, often adherent to an erythematous base. Classic AKs can progress to become HAKs, and HAKs themselves can be difficult to distinguish from malignant lesions. Atrophic: Atrophic AKs lack an overlying scale, and therefore appear as a nonpalpable change in color (or macule). They are often smooth and red and are less than 10mm in diameter. AK with cutaneous horn: A cutaneous horn is a keratinic projection with its height at least one-half of its diameter, often conical in shape. They can be seen in the setting of actinic keratosis as a progression of an HAK, but are also present in other skin conditions. 38–40% of cutaneous horns represent AKs. Pigmented AK: Pigmented AKs are rare variants that often present as macules or plaques that are tan to brown in color. They can be difficult to distinguish from a solar lentigo or lentigo maligna. Actinic cheilitis: When an AK forms on the lip, it is called actinic cheilitis. This usually presents as a rough, scaly patch on the lip, often accompanied by the sensation of dry mouth and symptomatic splitting of the lips. Bowenoid AK: Usually presents as a solitary, erythematous, scaly patch or plaque with well-defined borders. Bowenoid AKs are differentiated from Bowens disease by degree of epithelial involvement as seen on histology.The presence of ulceration, nodularity, or bleeding should raise concern for malignancy. Specifically, clinical findings suggesting an increased risk of progression to squamous cell carcinoma can be recognized as "IDRBEU": I (induration/inflammation), D (diameter > 1 cm), R (rapid enlargement), B (bleeding), E (erythema), and U (ulceration). AKs are usually diagnosed clinically, but because they are difficult to clinically differentiate from squamous cell carcinoma, any concerning features warrant biopsy for diagnostic confirmation. Causes The most important cause of AK formation is solar radiation, through a variety of mechanisms. Mutation of the p53 tumor suppressor gene, induced by UV radiation, has been identified as a crucial step in AK formation. This tumor suppressor gene, located on chromosome 17p132, allows for cell cycle arrest when DNA or RNA is damaged. Dysregulation of the p53 pathway can thus result in unchecked replication of dysplastic keratinocytes, thereby serving as a source of neoplastic growth and the development of AK, as well as possible progression from AK to skin cancer. Other molecular markers that have been associated with the development of AK include the expression of p16ink4, p14, the CD95 ligand, TNF-related apoptosis-inducing ligand (TRAIL) and TRAIL receptors, and loss of heterozygosity.Evidence also suggests that the human papillomavirus (HPV) plays a role in the development of AKs. The HPV virus has been detected in AKs, with measurable HPV viral loads (one HPV-DNA copy per less than 50 cells) measured in 40% of AKs. Similar to UV radiation, higher levels of HPV found in AKs reflect enhanced viral DNA replication. This is suspected to be related to the abnormal keratinocyte proliferation and differentiation in AKs, which facilitate an environment for HPV replication. This in turn may further stimulate the abnormal proliferation that contributes to the development of AKs and carcinogenesis. Ultraviolet radiation It is thought that ultraviolet (UV) radiation induces mutations in the keratinocytes of the epidermis, promoting the survival and proliferation of these atypical cells. Both UV-A and UV-B radiation have been implicated as causes of AKs. UV-A radiation (wavelength 320–400 nm) reaches more deeply into the skin and can lead to the generation of reactive oxygen species, which in turn can damage cell membranes, signaling proteins, and nucleic acids. UV-B radiation (wavelength 290–320 nm) causes thymidine dimer formation in DNA and RNA, leading to significant cellular mutations. In particular, mutations in the p53 tumor suppressor gene have been found in 30–50% of AK lesion skin samples.UV radiation has also been shown to cause elevated inflammatory markers such as arachidonic acid, as well as other molecules associated with inflammation. Eventually, over time these changes lead to the formation of AKs. Several predictors for increased AK risk from UV radiation have been identified: Extent of sun exposure: Cumulative sun exposure leads to an increased risk for development of AKs. In one U.S. study, AKs were found in 55% of fair-skinned men with high cumulative sun exposure, and in only 19% of fair-skinned men with low cumulative sun exposure in an age-matched cohort (the percents for women in this same study were 37% and 12% respectively). Furthermore, the use of sunscreen (SPF 17 or higher) has been found to significantly reduce the development of AK lesions, and also promotes the regression of existing lesions. History of sunburn: Studies show that even a single episode of painful sunburn as a child can increase an individuals risk of developing AK as an adult. Six or more painful sunburns over the course of a lifetime was found to be significantly associated with the likelihood of developing AK. Skin pigmentation Melanin is a pigment in the epidermis that functions to protect keratinocytes from the damage caused by UV radiation; it is found in higher concentrations in the epidermis of darker-skinned individuals, affording them protection against the development of AKs. Fair-skinned individuals have a significantly increased risk of developing AKs when compared to olive-skinned individuals (odds ratios of 14.1 and 6.5, respectively), and AKs are uncommon in dark-skinned people of African descent. Other phenotypic features seen in fair-skinned individuals that are associated with an increased propensity to develop AKs include: Freckling Light hair and eye color Propensity to sunburn Inability to tan Other risk factors Immunosuppression: People with a compromised immune system from medical conditions (such as AIDS) or immunosuppressive therapy (such as chronic immunosuppression after organ transplantation, or chemotherapy for cancer) are at increased risk for developing AKs. They may develop AK at an earlier age or have an increased number of AK lesions compared to immunocompetent people. Human papillomavirus (HPV): The role of HPV in the development of AK remains unclear, but evidence suggests that infection with the betapapillomavirus type of HPV may be associated with an increased likelihood of AK. Genodermatoses: Certain genetic disorders interfere with DNA repair after sun exposure, thereby putting these individuals at higher risk for the development of AKs. Examples of such genetic disorders include xeroderma pigmentosum and Bloom syndrome. Balding: AKs are commonly found on the scalps of balding men. The degree of baldness seems to be a risk factor for lesion development, as men with severe baldness were found to be seven times more likely to have 10 or more AKs when compared to men with minimal or no baldness. This observation can be explained by an absence of hair causing a larger proportion of scalp to be exposed to UV radiation if other sun protection measures are not taken. Diagnosis Physicians usually diagnose actinic keratosis by doing a thorough physical examination, through a combination of visual observation and touch. However a biopsy may be necessary when the keratosis is large in diameter, thick, or bleeding, in order to make sure that the lesion is not a skin cancer. Actinic keratosis may progress to invasive squamous cell carcinoma (SCC) but both diseases can present similarly upon physical exam and can be difficult to distinguish clinically. Histological examination of the lesion from a biopsy or excision may be necessary to definitively distinguish AK from in situ or invasive SCC. In addition to SCCs, AKs can be mistaken for other cutaneous lesions including seborrheic keratoses, basal cell carcinoma, lichenoid keratosis, porokeratosis, viral warts, erosive pustular dermatosis of the scalp, pemphigus foliaceus, inflammatory dermatoses like psoriasis, or melanoma. Biopsy A lesion biopsy is performed if the diagnosis remains uncertain after a clinical physical exam, or if there is suspicion that the AK might have progressed to squamous cell carcinoma. The most common tissue sampling techniques include shave or punch biopsy. When only a portion of the lesion can be removed due to its size or location, the biopsy should sample tissue from the thickest area of the lesion, as SCCs are most likely to be detected in that area. If a shave biopsy is performed, it should extend through to the level of the dermis in order to provide sufficient tissue for diagnosis; ideally, it would extend to the mid-reticular dermis. Punch biopsy usually extends to the subcutaneous fat when the entire length of the punch blade is utilized. Histopathology On histologic examination, actinic keratoses usually show a collection of atypical keratinocytes with hyperpigmented or pleomorphic nuclei, extending to the basal layer of the epidermis. A "flag sign" is often described, referring to alternating areas of orthokeratosis and parakeratosis. Epidermal thickening and surrounding areas of sun-damaged skin are often seen. The normal ordered maturation of the keratinocytes is disordered to varying degrees: there may be widening of the intracellular spaces, cytologic atypia such as abnormally large nuclei, and a mild chronic inflammatory infiltrate.Specific findings depend on the clinical variant and particular lesion characteristics. The seven major histopathologic variants are all characterized by atypical keratinocytic proliferation beginning in the basal layer and confined to the epidermis; they include: Hypertrophic: Notable for marked hyperkeratosis, often with evident parakeratosis. Keratinocytes in the stratum malphigii may show a loss of polarity, pleomorphism, and anaplasia. Some irregular downward proliferation into the uppermost dermis may be observed, but does not represent frank invasion. Atrophic: With slight hyperkeratosis and overall atrophic changes to the epidermis; the basal layer shows cells with large, hyperchromatic nuclei in close proximity to each other. These cells have been observed to proliferate into the dermis as buds and duct-like structures. Lichenoid: Demonstrate a band-like lymphocytic infiltrate in the papillary dermis, directly beneath the dermal-epidermal junction. Achantholytic: Intercellular clefts or lacunae in the lowermost epidermal layer that result from anaplastic changes; these produce dyskeratotic cells with disrupted intercellular bridges. Bowenoid: This term is controversial and usually refers to full-thickness atypia, microscopically indistinguishable from Bowens Disease. However most dermatologists and pathologists will use it in reference to tissue samples that are notable for small foci of atypia that involve the full thickness of the epidermis, in the background of a lesion that is otherwise consistent with an AK. Epidermolytic: With granular degeneration. Pigmented: Show pigmentation in the basal layer of the epidermis, similar to a solar lentigo. Dermoscopy Dermoscopy is a noninvasive technique utilizing a handheld magnifying device coupled with a transilluminating lift. It is often used in the evaluation of cutaneous lesions but lacks the definitive diagnostic ability of biopsy-based tissue diagnosis. Histopathologic exam remains the gold standard. Polarized contact dermoscopy of AKs occasionally reveals a "rosette sign," described as four white points arranged in a clover pattern, often localized to within a follicular opening. It is hypothesized that the "rosette sign" corresponds histologically to the changes of orthokeratosis and parakeratosis known as the "flag sign." Non-pigmented AKs: linear or wavy vascular patterning, or a "strawberry pattern," described as unfocused vessels between hair follicles, with white-haloed follicular openings. Pigmented AKs: gray to brown dots or globules surrounding follicular openings, and annular-granular rhomboidal structures; often difficult to differentiate from lentigo maligna. Prevention Ultraviolet radiation is believed to contribute to the development of actinic keratoses by inducing mutations in epidermal keratinocytes, leading to proliferation of atypical cells. Therefore, preventive measures for AKs are targeted at limiting exposure to solar radiation, including: Limiting extent of sun exposure Avoid sun exposure during noontime hours between 10:00 AM and 2:00 PM when UV light is most powerful Minimize all time in the sun, since UV exposure occurs even in the winter and on cloudy days Using sun protection Applying sunscreens with SPF ratings 30 or greater that also block both UVA and UVB light, at least every 2 hours and after swimming or sweating Applying sunscreen at least 15 minutes before going outside, as this allows time for the sunscreen to be absorbed appropriately by the skin Wearing sun protective clothing such as hats, sunglasses, long-sleeved shirts, long skirts, or trousersRecent research implicating human papillomavirus (HPV) in the development of AKs suggests that HPV prevention might in turn help prevent development of AKs, as UV-induced mutations and oncogenic transformation are likely facilitated in cases of active HPV infection. A key component of HPV prevention includes vaccination, and the CDC currently recommends routine vaccination in all children at age 11 or 12.There is some data that in individuals with a history of non-melanoma skin cancer, a low-fat diet can serve as a preventative measure against future actinic keratoses. Management There are a variety of treatment options for AK depending on the patient and the clinical characteristics of the lesion. AKs show a wide range of features, which guide decision-making in choosing treatment. As there are multiple effective treatments, patient preference and lifestyle are also factors that physicians consider when determining the management plan for actinic keratosis. Regular follow-up is advisable after any treatment to make sure no new lesions have developed and that old ones are not progressing. Adding topical treatment after a procedure may improve outcomes. Medication Topical medications are often recommended for areas where multiple or ill-defined AKs are present, as the medication can easily be used to treat a relatively large area. Fluorouracil cream Topical fluorouracil (5-FU) destroys AKs by blocking methylation of thymidylate synthetase, thereby interrupting DNA and RNA synthesis. This in turn prevents the proliferation of dysplastic cells in AK. Topical 5-FU is the most utilized treatment for AK, and often results in effective removal of the lesion. Overall, there is a 50% efficacy rate resulting in 100% clearance of AKs treated with topical 5-FU. 5-FU may be up to 90% effective in treating non-hyperkeratotic lesions. While topical 5-FU is a widely used and cost-effective treatment for AKs and is generally well tolerated, its potential side-effects can include: pain, crusting, redness, and local swelling. These adverse effects can be mitigated or minimized by reducing the frequency of application or taking breaks between uses. The most commonly used application regimen consists of applying a layer of topical cream to the lesion twice a day after washing; duration of treatment is typically 2–4 weeks to thinner skin like the cheeks and up to 8 weeks for the arms; treatment of up to 8 weeks has demonstrated a higher cure rate. Imiquimod cream Imiquimod is a topical immune-enhancing agent licensed for the treatment of genital warts. Imiquimod stimulates the immune system through the release and up-regulation of cytokines. Treatment with Imiquimod cream applied 2–3 times per week for 12 to 16 weeks was found to result in complete resolution of AKs in 50% of people, compared to 5% of controls. The Imiquimod 3.75% cream has been validated in a treatment regimen consisting of daily application to entire face and scalp for two 2-week treatment cycles, with a complete clearance rate of 36%.While the clearance rate observed with the Imiquimod 3.75% cream was lower than that observed with the 5% cream (36 and 50 percent, respectively), there are lower reported rates of adverse reactions with the 3.75% cream: 19% of individuals using Imiquimod 3.75% cream reported adverse reactions including local erythema, scabbing, and flaking at the application site, while nearly a third of individuals using the 5% cream reported the same types of reactions with Imiquimod treatment. However, it is ultimately difficult to compare the efficacy of the different strength creams directly, as current study data varies in methodology (e.g. duration and frequency of treatment, and amount of skin surface area covered). Ingenol mebutate gel Ingenol mebutate is a newer treatment for AK used in Europe and the United States. It works in two ways, first by disrupting cell membranes and mitochondria resulting cell death, and then by inducing antibody-dependent cellular cytotoxicity to eliminate remaining tumor cells. A 3-day treatment course with the 0.015% gel is recommended for the scalp and face, while a 2-day treatment course with the 0.05% gel is recommended for the trunk and extremities. Treatment with the 0.015% gel was found to completely clear 57% of AK, while the 0.05% gel had a 34% clearance rate. Advantages of ingenol mebutate treatment include the short duration of therapy and a low recurrence rate. Local skin reactions including pain, itching and redness can be expected during treatment with ingenol mebutate. This treatment was derived from the petty spurge, Euphorbia peplus which has been used as a traditional remedy for keratosis. Diclofenac sodium gel Topical diclofenac sodium gel is a nonsteroidal anti-inflammatory drug that is thought to work in the treatment of AK through its inhibition of the arachidonic acid pathway, thereby limiting the production of prostaglandins which are thought to be involved in the development of UVB-induced skin cancers. Recommended duration of therapy is 60 to 90 days with twice daily application. Treatment of facial AK with diclofenac gel led to complete lesion resolution in 40% of cases. Common side effects include dryness, itching, redness, and rash at the site of application. Retinoids Topical retinoids have been studied in the treatment of AK with modest results, and the American Academy of Dermatology does not currently recommend this as first-line therapy. Treatment with adapalene gel daily for 4 weeks, and then twice daily thereafter for a total of nine months led to a significant but modest reduction in the number AKs compared to placebo; it demonstrated the additional advantage of improving the appearance of photodamaged skin.Topical tretinoin is ineffective as treatment for reducing the number of AKs. For secondary prevention of AK, systemic, low-dose acitretin was found to be safe, well tolerated and moderately effective in chemoprophylaxis for skin cancers in kidney transplant patients. Acitretin is a viable treatment option for organ transplant patients according to expert opinion. Tirbanibulin Tirbanibulin (Klisyri) was approved for medical use in the United States in December 2020, for the treatment of actinic keratosis on the face or scalp. Procedures Cryotherapy Liquid nitrogen (−195.8 °C) is the most commonly used destructive therapy for the treatment of AK in the United States. It is a well-tolerated office procedure that does not require anesthesia.Cryotherapy is particularly indicated for cases where there are fewer than 15 thin, well-demarcated lesions. Caution is encouraged for thicker, more hyperkeratotic lesions, as dysplastic cells may evade treatment. Treatment with both cryotherapy and field treatment can be considered for these more advanced lesions. Cryotherapy is generally performed using an open-spray technique, wherein the AK is sprayed for several seconds.The process can be repeated multiple times in one office visit, as tolerated. Cure rates from 67 to 99 percent have been reported, depending on freeze time and lesion characteristics. Disadvantages include discomfort during and after the procedure; blistering, scarring and redness; hypo- or hyperpigmentation; and destruction of healthy tissue. Photodynamic therapy AKs are one of the most common dermatologic lesions for which photodynamic therapy, including topical methyl aminolevulinate (MAL) or 5-aminolevulinic acid (5-ALA), is indicated.Treatment begins with preparation of the lesion, which includes scraping away scales and crusts using a dermal curette. A thick layer of topical MAL or 5-ALA cream is applied to the lesion and a small area surrounding the lesion, which is then covered with an occlusive dressing and left for a period of time. During this time the photosensitizer accumulates in the target cells within the AK lesion. The dressings are then removed and the lesion is treated with light at a specified wavelength. Multiple treatment regimens using different photosensitizers, incubation times, light sources, and pretreatment regimens have been studied and suggest that longer incubation times lead to higher rates of lesion clearance. Photodynamic therapy is gaining in popularity. It has been found to have a 14% higher likelihood of achieving complete lesion clearance at 3 months compared to cryotherapy, and seems to result in superior cosmetic outcomes when compared to cryotherapy or 5-FU treatment. Photodynamic therapy can be particularly effective in treating areas with multiple AK lesions. Surgical techniques Surgical excision: Excision should be reserved for cases when the AK is a thick, horny papule, or when deeper invasion is suspected and histopathologic diagnosis is necessary. It is a rarely utilized technique for AK treatment. Shave excision and curettage (sometimes followed by electrodesiccation when deemed appropriate by the physician): This technique is often used for treatment of AKs, and particularly for lesions appearing more similar to squamous cell carcinoma, or those that are unresponsive to other treatments. The surface of the lesion can be scraped away using a scalpel, or the base can be removed with a curette. Tissue can be evaluated histopathologically under the microscope, but specimens acquired using this technique are not often adequate to determine whether a lesion is invasive or intraepidermal. Dermabrasion: Dermabrasion is useful in the treatment of large areas with multiple AK lesions. The process involves using a hand-held instrument to "sand" the skin, removing the stratum corneum layer of the epidermis. Diamond fraises or wire brushes revolving at high speeds are used. The procedure can be quite painful and requires procedural sedation and anesthetic, necessitating a hospital stay. One-year clearance rates with dermabrasion treatment are as high as 96%, but diminish drastically to 54% at five years. Laser therapy Laser therapy using carbon dioxide (CO2) or erbium:yttrium aluminum garnet (Er:YAG) lasers is a treatment approach being utilized with increased frequency, and sometimes in conjunction with computer scanning technology. Laser therapy has not been extensively studied, but current evidence suggests it may be effective in cases involving multiple AKs refractive to medical therapy, or AKs located in cosmetically sensitive locations such as the face. The CO2 laser has been recommended for extensive actinic cheilitis that has not responded to 5-FU. Chemical peels A chemical peel is a topically applied agent that wounds the outermost layer of the skin, promoting organized repair, exfoliation, and eventually the development of smooth and rejuvenated skin. Multiple therapies have been studied. A medium-depth peel may effectively treat multiple non-hyperkeratotic AKs. It can be achieved with 35% to 50% trichloroacetic acid (TCA) alone or at 35% in combination with Jessners solution in a once-daily application for a minimum of 3 weeks; 70% glycolic acid (α-hydroxy acid); or solid CO2. When compared to treatment with 5-FU, chemical peels have demonstrated similar efficacy and increased ease of use with similar morbidity. Chemical peels must be performed in a controlled clinic environment and are recommended only for individuals who are able to comply with follow-up precautions, including avoidance of sun exposure. Furthermore, they should be avoided in individuals with a history of HSV infection or keloids, and in those who are immunosuppressed or who are taking photosensitizing medications. Prognosis Untreated AKs follow one of three paths: they can either persist as AKs, regress, or progress to invasive skin cancer, as AK lesions are considered to be on the same continuum with squamous cell carcinoma (SCC). AK lesions that regress also have the potential to recur. Progression: The overall risk of an AK turning into invasive cancer is low. In average-risk individuals, likelihood of an AK lesion progressing to SCC is less than 1% per year. Despite this low rate of progression, studies suggest that a full 60% of SCCs arise from pre-existing AKs, reinforcing the idea that these lesions are closely related. Regression: Reported regression rates for single AK lesions have ranged between 15 and 63% after one year. Recurrence: Recurrence rates after 1 year for single AK lesions that have regressed range between 15 and 53%. Clinical course Given the aforementioned differering clinical outcomes, it is difficult to predict the clinical course of any given actinic keratosis. AK lesions may also come and go—in a cycle of appearing on the skin, remaining for months, and then disappearing. Often they will reappear in a few weeks or months, particularly after unprotected sun exposure. Left untreated, there is a chance that the lesion will advance to become invasive. Although it is difficult to predict whether an AK will advance to become squamous cell carcinoma, it has been noted that squamous cell carcinomas originate in lesions formerly diagnosed as AKs with frequencies reported between 65 and 97%. Epidemiology Actinic keratosis is very common, with an estimated 14% of dermatology visits related to AKs. It is seen more often in fair-skinned individuals, and rates vary with geographical location and age. Other factors such as exposure to ultraviolet (UV) radiation, certain phenotypic features, and immunosuppression can also contribute to the development of AKs. Men are more likely to develop AK than women, and the risk of developing AK lesions increases with age. These findings have been observed in multiple studies, with numbers from one study suggesting that approximately 5% of women ages 20–29 develop AK compared to 68% of women ages 60–69, and 10% of men ages 20–29 develop AK compared to 79% of men ages 60–69.Geography seems to play a role in the sense that individuals living in locations where they are exposed to more UV radiation throughout their lifetime have a significantly higher risk of developing AK </s>

<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Congenital adrenal hyperplasia and explain in detail? [/INST] Congenital adrenal hyperplasia (CAH) is a group of autosomal recessive disorders characterized by impaired cortisol synthesis. It results from the deficiency of one of the five enzymes required for the synthesis of cortisol in the adrenal cortex. Most of these disorders involve excessive or deficient production of hormones such as glucocorticoids, mineralocorticoids, or sex steroids, and can alter development of primary or secondary sex characteristics in some affected infants, children, or adults. It is one of the most common autosomal recessive disorders in humans. Types CAH can occur in various forms. The clinical presentation of each form is different and depends to a large extent on the underlying enzyme defect, its precursor retention, and deficient products. Classical forms appear in infancy, and nonclassical forms appear in late childhood. The presentation in patients with classic CAH can be further subdivided into two forms: salt-wasting and simple-virilizing, depending on whether mineralocorticoid deficiency presents or absents, respectively (you should put absents before presents to straight the meaning of respectively). This subtyping is often not clinically meaningful, though, because all patients lose salt to some degree, and clinical presentations may overlap. Classic Salt-wasting In 75% of cases of severe enzyme deficiency, insufficient aldosterone production can lead to salt wasting, failure to thrive, and potentially fatal hypovolemia and shock. A missed diagnosis of salt-loss CAH is related to the increased risk of early neonatal morbidity and death. Simple-virilizing The main feature of CAH in newborn females is the abnormal development of the external genitalia, which has varying degrees of virilization. According to clinical practice guidelines, for newborns found to have bilateral inaccessible gonads, CAH evaluation should be considered. If virilizing CAH cannot be identified and treated, both boys and girls may undergo rapid postnatal growth and virilization. Nonclassic In addition to the salt-wasting and simple-virilizing forms of CAH diagnosed in infancy, a mild or "nonclassic" form exists, which is characterized by varying degrees of postnatal androgen excess, but is sometimes asymptomatic. The nonclassic form may be noticed in late childhood and may lead to accelerated growth, premature sexual maturation, acne, and secondary polycystic ovary syndrome. In adult males, early balding and infertility may suggest the diagnosis. The nonclassic form is characterized by mild subclinical impairment of cortisol synthesis; serum cortisol concentration is usually normal. Signs and symptoms The symptoms of CAH vary depending upon the form of CAH and the sex of the patient. Symptoms can include: Due to inadequate mineralocorticoids: Vomiting due to salt-wasting, leading to dehydration and deathDue to excess androgens: In extreme virilization, an elongated clitoris with a phallic-like structure is seen. Ambiguous genitalia, in some infants, occurs such that initially identifying external genitalia as "male" or "female" is difficult. Early pubic hair and rapid growth occurs in childhood. Precocious puberty or failure of puberty to occur (sexual infantilism: absent or delayed puberty) Excessive facial hair, virilization, and/or menstrual irregularity in adolescence Infertility due to anovulation Clitoromegaly, enlarged clitoris and shallow vaginaDue to insufficient androgens and estrogens: Undervirilization in XY males can result in apparently female external genitalia. In females, hypogonadism can cause sexual infantilism or abnormal pubertal development, infertility, and other reproductive system abnormalities. Genetics CAH results from mutations of genes for enzymes mediating the biochemical steps of production of mineralocorticoids, glucocorticoids, or sex steroids from cholesterol by the adrenal glands (steroidogenesis).Each form of CAH is associated with a specific defective gene. The most common type (95% of cases) involves the gene for 21-hydroxylase, which is found on 6p21.3 as part of the HLA complex; 21-hydroxylase deficiency results from a unique mutation with two highly homologous near-copies in series consisting of an active gene (CYP21A2) and an inactive pseudogene (CYP21A1P). Mutant alleles result from recombination between the active and pseudogenes (gene conversion). About 5% of cases of CAH are due to defects in the gene encoding 11β-hydroxylase and consequent 11β-hydroxylase deficiency. Other, more rare forms of CAH are caused by mutations in genes, including HSD3B2 (3β-hydroxysteroid dehydrogenase 2), CYP17A1 (17α-hydroxylase/17,20-lyase), CYP11A1 (P450scc; cholesterol side-chain cleavage enzyme), STAR (steroidogenic acute regulatory protein; StAR), CYB5A (cytochrome b5), and CYPOR (cytochrome P450 oxidoreductase; POR). Expressivity Further variability is introduced by the degree of enzyme inefficiency produced by the specific alleles each patient has. Some alleles result in more severe degrees of enzyme inefficiency. In general, severe degrees of inefficiency produce changes in the fetus and problems in prenatal or perinatal life. Milder degrees of inefficiency are usually associated with excessive or deficient sex hormone effects in childhood or adolescence, while the mildest forms of CAH interfere with ovulation and fertility in adults. Diagnosis Clinical evaluation Female infants with classic CAH have ambiguous genitalia due to exposure to high concentrations of androgens in utero. CAH due to 21-hydroxylase deficiency is the most common cause of ambiguous genitalia in genotypically normal female infants (46XX). Less severely affected females may present with early pubarche. Young women may present with symptoms of polycystic ovarian syndrome (oligomenorrhea, polycystic ovaries, hirsutism).Males with classic CAH generally have no signs of CAH at birth. Some may present with hyperpigmentation, due to co-secretion with melanocyte-stimulating hormone, and possible penile enlargement. Age of diagnosis of males with CAH varies and depends on the severity of aldosterone deficiency. Boys with salt-wasting disease present early with symptoms of hyponatremia and hypovolemia. Boys with non-salt-wasting disease present later with signs of virilization.In rarer forms of CAH, males are undermasculinized and females generally have no signs or symptoms at birth. Laboratory studies Genetic analysis can be helpful to confirm a diagnosis of CAH, but it is not necessary if classic clinical and laboratory findings are present. In classic 21-hydroxylase deficiency, laboratory studies will show: Hypoglycemia (due to hypocortisolism) - One of cortisols many functions is to increase blood glucose levels. This occurs via a combination of several mechanisms, including (a) the stimulation of gluconeogesis (i.e. the creation of new glucose) in the liver, (b) the promotion of glycogenolysis (i.e. the breakdown of glycogen into glucose), and (c) the prevention of glucose leaving the bloodstream via the downregulation of GLUT-4 receptors (which normally promote movement of glucose from the bloodstream into adipose and muscle tissues). Therefore, when cortisol is deficient, these processes (effectively) occur in the reverse direction. Although there are compensatory mechanisms that mitigate the impact of hypocortisolism, they are limited in their extent and the net effect is still hypoglycemia. Hyponatremia (due to hypoaldosteronism) - Aldosterone is the end product of the renin-angiotensin-aldosterone system that regulates blood pressure via blood pressure surveillance in the Kidney Juxtaglomerular apparatus. Aldosterone normally functions to increase sodium retention (which brings water as well) in exchange for potassium. Thus, lack of aldosterone causes hyperkalemia and hyponatremia. In fact, this is a distinguishing point from 11-hydroxylase deficiency, in which one of the increased products is 11-deoxycorticosterone that has weak mineralocorticoid activity. In 11-hydroxylase deficiency, 11-deoxycorticosterone is produced in such excess that it acts to retain sodium at the expense of potassium. It is this reason that patients with 11-hydroxylase deficiency do not show salt wasting (although sometimes they do in infancy), and instead have hypertension/water retention and sometimes hypokalemia. Hyperkalemia (due to hypoaldosteronism) Elevated 17α-hydroxyprogesteroneClassic 21-hydroxylase deficiency typically causes 17α-hydroxyprogesterone blood levels >242 nmol/L. (For comparison, a full-term infant at three days of age should have <3 nmol/L. Many neonatal screening programs have specific reference ranges by weight and gestational age because high levels may be seen in premature infants without CAH.) Salt-wasting patients tend to have higher 17α-hydroxyprogesterone levels than non-salt-wasting patients. In mild cases, 17α-hydroxyprogesterone may not be elevated in a particular random blood sample, but it will rise during a corticotropin stimulation test. Classification Cortisol is an adrenal steroid hormone required for normal endocrine function. Production begins in the second month of fetal life. Poor cortisol production is a hallmark of most forms of CAH. Inefficient cortisol production results in rising levels of ACTH, because cortisol feeds back to inhibit ACTH production, so loss of cortisol results in increased ACTH. This increased ACTH stimulation induces overgrowth (hyperplasia) and overactivity of the steroid-producing cells of the adrenal cortex. The defects causing adrenal hyperplasia are congenital (i.e. present at birth). Cortisol deficiency in CAH is usually partial, and not the most serious problem for an affected person. Synthesis of cortisol shares steps with synthesis of mineralocorticoids such as aldosterone, androgens such as testosterone, and estrogens such as estradiol. The resulting excessive or deficient production of these three classes of hormones produce the most important problems for people with CAH. Specific enzyme inefficiencies are associated with characteristic patterns of over- or underproduction of mineralocorticoids or sex steroids. Since the 1960s, most endocrinologists have referred to the forms of CAH by the traditional names in the left column, which generally correspond to the deficient enzyme activity. As exact structures and genes for the enzymes were identified in the 1980s, most of the enzymes were found to be cytochrome P450 oxidases and were renamed to reflect this. In some cases, more than one enzyme was found to participate in a reaction, and in other cases, a single enzyme mediated in more than one reaction. Variation in different tissues and mammalian species also was found. In all its forms, congenital adrenal hyperplasia due to 21-hydroxylase deficiency accounts for about 95% of diagnosed cases of CAH. Unless another specific enzyme is mentioned, "CAH" in nearly all contexts refers to 21-hydroxylase deficiency. (The terms "salt-wasting CAH", and "simple virilizing CAH" usually refer to subtypes of this condition.) CAH due to deficiencies of enzymes other than 21-hydroxylase present many of the same management challenges, as 21-hydroxylase deficiency, but some involve mineralocorticoid excess or sex steroid deficiency. Screening Currently, in the United States and over 40 other countries, every child born is screened for 21-hydroxylase CAH at birth. This test detects elevated levels of 17α-hydroxyprogesterone (17-OHP). Detecting high levels of 17-OHP enables early detection of CAH. Newborns detected early enough can be placed on medication and live relatively normal lives.The screening process, however, is characterized by a high false-positive rate. In one study, CAH screening had the lowest positive predictive value (111 true-positive cases among 20,647 abnormal screening results in a 2-year period, or 0.53%, compared with 6.36% for biotinidase deficiency, 1.84% for congenital hypo-thyroidism, 0.56% for classic galactosemia, and 2.9% for phenylketonuria). According to this estimate, 200 unaffected newborns required clinical and laboratory follow-up for every true case of CAH.In 2020, Wael AbdAlmageed from USC Information Sciences Institute and Mimi Kim from USC Keck School Of Medicine led a joint study in which they used deep learning technology to analyze the facial morphology and features of CAH patients compared to control. In this cross-sectional study of 102 patients with CAH and 144 control participants, deep learning methods achieved a mean area under the receiver operating characteristic curve of 92% for predicting CAH from facial images. Facial features distinguished patients with CAH from controls, and analyses of facial regions found that the nose and upper face were most contributory. The findings suggest that facial morphologic features, as analyzed by deep neural network techniques, can be used as a phenotypic biomarker to predict CAH. Treatment Since the clinical manifestations of each form of CAH are unique and depend to a large extent on the underlying enzyme defects, their precursor retention and defective products, the therapeutic goal of CAH is to replenish insufficient adrenal hormones and suppress excess of precursors.Treatment of all forms of CAH may include any of: Supplying enough glucocorticoid to reduce hyperplasia and overproduction of androgens or mineralocorticoids Providing replacement mineralocorticoid and extra salt if the person is deficient Providing replacement testosterone or estrogens at puberty if the person is deficient Additional treatments to optimize growth by delaying puberty or delaying bone maturation If CAH is caused by the deficiency of the 21-hydroxylase enzyme, then treatment aims to normalize levels of main substrate of the enzyme - 17α-hydroxyprogesterone. Epidemiology The incidence varies ethnically. In the United States, congenital adrenal hyperplasia in its classic form is particularly common in Native Americans and Yupik Inuit (incidence 1⁄280). Among American Caucasians, the incidence of the classic form is about 1⁄15,000).Continued treatment and wellness are enhanced by education and follow up. History Before 20th century An Italian anatomist, Luigi De Crecchio (1832-1894) provided the earliest known description of a case of probable CAH. I propose in this narrative that it is sometimes extremely difficult and even impossible to determine sex during life. In one of the anatomical theaters of the hospital..., there arrived toward the end of January a cadaver which in life was the body of a certain Joseph Marzo... The general physiognomy was decidedly male in all respects. There were no feminine curves to the body. There was a heavy beard. There was some delicacy of structure with muscles that were not very well developed... The distribution of pubic hair was typical of the male. Perhaps the lower extremities were somewhat delicate, resembling the female, and were covered with hair... The penis was curved posteriorly and measured 6 cm, or with stretching, 10 cm. The corona was 3 cm long and 8 cm in circumference. There was an ample prepuce. There was a first grade hypospadias... There were two folds of skin coming from the top of the penis and encircling it on either side. These were somewhat loose and resembled labia majora. De Crecchio then described the internal organs, which included a normal vagina, uterus, fallopian tubes, and ovaries. It was of the greatest importance to determine the habits, tendencies, passions, and general character of this individual... I was determined to get as complete a story as possible, determined to get at the base of the facts and to avoid undue exaggeration which was rampant in the conversation of many of the people present at the time of the dissection. He interviewed many people and satisfied himself that Joseph Marzo "conducted himself within the sexual area exclusively as a male", even to the point of contracting the "French disease" on two occasions. The cause of death was another in a series of episodes of vomiting and diarrhea.This account was translated by Alfred Bongiovanni from De Crecchio ("Sopra un caso di apparenzi virili in una donna". Morgagni 7:154–188, 1865) in 1963 for an article in The New England Journal of Medicine. 20th and 21st centuries The association of excessive sex steroid effects with diseases of the adrenal cortex have been recognized for over a century. The term "adrenogenital syndrome" was applied to both sex-steroid producing tumors and severe forms of CAH for much of the 20th century, before some of the forms of CAH were understood. Congenital adrenal hyperplasia, which also dates to the first half of the century, has become the preferred term to reduce ambiguity and to emphasize the underlying pathophysiology of the disorders. Much modern understanding and treatment of CAH comes from research conducted at Johns Hopkins Medical School in Baltimore in the middle of the 20th century. Lawson Wilkins, "founder" of pediatric endocrinology, worked out the apparently paradoxical pathophysiology: that hyperplasia and overproduction of adrenal androgens resulted from impaired capacity for making cortisol. He reported use of adrenal cortical extracts to treat children with CAH in 1950. Genital reconstructive surgery was also pioneered at Hopkins. After application of karyotyping to CAH and other intersex disorders in the 1950s, John Money, JL Hampson, and JG Hampson persuaded both the scientific community and the public that sex assignment should not be based on any single biological criterion, and gender identity was largely learned and has no simple relationship with chromosomes or hormones. See Intersex for a fuller history, including recent controversies over reconstructive surgery. Hydrocortisone, fludrocortisone, and prednisone were available by the late 1950s </s>

<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Adrenocortical carcinoma and explain in detail? [/INST] Adrenocortical carcinoma (ACC) is an aggressive cancer originating in the cortex (steroid hormone-producing tissue) of the adrenal gland. Adrenocortical carcinoma is remarkable for the many hormonal syndromes that can occur in patients with steroid hormone-producing ("functional") tumors, including Cushings syndrome, Conn syndrome, virilization, and feminization. Adrenocortical carcinoma has often invaded nearby tissues or metastasized to distant organs at the time of diagnosis, and the overall 5-year survival rate is about 50%.Adrenocortical carcinoma is a rare tumor, with incidence of one to two per million population annually. It has a bimodal distribution by age, with cases clustering in children under 5 and in adults 30–40 years old. The widely used angiotensin-II-responsive steroid-producing cell line H295R was originally isolated from a tumor diagnosed as adrenocortical carcinoma. Signs and symptoms Adrenocortical carcinoma may present differently in children and adults. Most tumors in children are functional, and virilization is by far the most common presenting symptom(s), followed by Cushings syndrome and precocious puberty. Among adults presenting with hormonal syndromes, Cushings syndrome alone is most common, followed by mixed Cushings and virilization (glucocorticoid and androgen overproduction). Feminization and Conn syndrome (mineralocorticoid excess) occur in less than 10% of cases. Rarely, pheochromocytoma-like hypersecretion of catecholamines has been reported in adrenocortical cancers. Nonfunctional tumors (about 40%, authorities vary) usually present with abdominal or flank pain, varicocele, and renal vein thrombosis or they may be asymptomatic and detected incidentally.All patients with suspected ACC should be carefully evaluated for signs and symptoms of hormonal syndromes. For Cushings syndrome (glucocorticoid excess), these include weight gain, muscle wasting, purple lines on the abdomen, a fatty "buffalo hump" on the neck, a "moon-like" face, and thinning, fragile skin. Virilism (androgen excess) is most obvious in women, and may produce excess facial and body hair, acne, enlargement of the clitoris, deepening of the voice, coarsening of facial features, cessation of menstruation. Conn syndrome (mineralcorticoid excess) is marked by high blood pressure, which can result in headache and hypokalemia (low serum potassium, which can in turn produce muscle weakness, confusion, and palpitations), low plasma renin activity, and high serum aldosterone. Feminization (estrogen excess) is most readily noted in men, and includes breast enlargement, decreased libido, and impotence. Pathophysiology The main etiologic factor of ACC is unknown, although families with Li–Fraumeni syndrome, caused by an inherited inactivation mutation in TP53, have increased risk. Several genes have been shown to be recurrently mutated, including TP53, CTNNB1, MEN1, PRKAR1A, RPL22, and DAXX. The telomerase gene TERT is often amplified while ZNRF3 and CDKN2A are often homozygously deleted. The genes h19, insulin-like growth factor II (IGF-II), and p57kip2 are important for fetal growth and development. They are located on chromosome 11p. Expression of the h19 gene is markedly reduced in both nonfunctioning and functioning adrenal cortical carcinomas, especially in tumors producing cortisol and aldosterone. Also, a loss occurs of activity of the p57kip2 gene product in virilizing adenomas and adrenal cortical carcinomas. In contrast, IGF-II gene expression has been shown to be high in adrenal cortical carcinomas. Finally, c-myc gene expression is relatively high in neoplasms, and it is often linked to poor prognosis.Bilateral adrenocortical tumors are less common than unilateral. The majority of bilateral tumours can be distinguished according to size and aspect of the nodules: primary pigmented nodular adrenocortical disease, which can be sporadic or part of Carney complex, and primary bilateral macro nodular adrenal hyperplasia.Metastasis is most commonly to the liver and lung. Diagnosis Laboratory findings Hormonal syndromes should be confirmed with laboratory testing. Laboratory findings in Cushing syndrome include increased serum glucose (blood sugar) and increased urine cortisol. Adrenal virilism is confirmed by the finding of an excess of serum androstenedione and dehydroepiandrosterone. Findings in Conn syndrome include low serum potassium, low plasma renin activity, and high serum aldosterone. Feminization is confirmed with the finding of excess serum estrogen. Imaging Radiological studies of the abdomen, such as CT scans and magnetic resonance imaging are useful for identifying the site of the tumor, differentiating it from other diseases, such as adrenocortical adenoma, and determining the extent of invasion of the tumor into surrounding organs and tissues. On CT, it shows heterogeneous appearance due to necrosis, calcifications, and haemorrhage. After contrast injection, it shows peripheral enhancement. Invasion of adjacent structures such as kidney, vena cava, liver, and retroperitoneal lymph nodes are also common.On MRI, it shows low intensity on T1-weighted images, and high T2 signal with strong heterogeneous contrast enhancement and slow washout. Haemorrhagic areas may show high T1-signal. Pathology Adrenal tumors are often not biopsied prior to surgery, so diagnosis is confirmed on examination of the surgical specimen by a pathologist. Grossly, ACCs are often large, with a tan-yellow cut surface, and areas of hemorrhage and necrosis </s>