<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 Ulcerative colitis and can you explain it in depth? [/INST] Ulcerative colitis (UC) is a long-term condition that results in inflammation and ulcers of the colon and rectum. The primary symptoms of active disease are abdominal pain and diarrhea mixed with blood (hematochezia). Weight loss, fever, and anemia may also occur. Often, symptoms come on slowly and can range from mild to severe. Symptoms typically occur intermittently with periods of no symptoms between flares. Complications may include abnormal dilation of the colon (megacolon), inflammation of the eye, joints, or liver, and colon cancer.The cause of UC is unknown. Theories involve immune system dysfunction, genetics, changes in the normal gut bacteria, and environmental factors. Rates tend to be higher in the developed world with some proposing this to be the result of less exposure to intestinal infections, or to a Western diet and lifestyle. The removal of the appendix at an early age may be protective. Diagnosis is typically by colonoscopy with tissue biopsies. It is a type of inflammatory bowel disease (IBD) along with Crohns disease and microscopic colitis.Dietary changes, such as maintaining a high-calorie diet or lactose-free diet, may improve symptoms. Several medications are used to treat symptoms and bring about and maintain remission, including aminosalicylates such as mesalazine or sulfasalazine, steroids, immunosuppressants such as azathioprine, and  biologic therapy. Removal of the colon by surgery may be necessary if the disease is severe, does not respond to treatment, or if complications such as colon cancer develop. Removal of the colon and rectum generally cures the condition.Together with Crohns disease, about 11.2 million people were affected as of 2015. Each year it newly occurs in 1 to 20 per 100,000 people, and 5 to 500 per 100,000 individuals are affected. The disease is more common in North America and Europe than other regions. Often it begins in people aged 15 to 30 years, or among those over 60. Males and females appear to be affected in equal proportions. It has also become more common since the 1950s. Together, ulcerative colitis and Crohns disease affect about a million people in the United States. With appropriate treatment the risk of death appears the same as that of the general population. The first description of ulcerative colitis occurred around the 1850s.

Signs and symptoms
Gastrointestinal
People with ulcerative colitis usually present with diarrhea mixed with blood, of gradual onset that persists for an extended period of time (weeks). Additional symptoms may include fecal incontinence, increased frequency of bowel movements, mucus discharge, and nocturnal defecations. With proctitis (inflammation of the rectum), people with UC may experience urgency or rectal tenesmus, which is the urgent desire to evacuate the bowels but with the passage of little stool. Tenesmus may be misinterpreted as constipation, due to the urge to defecate despite small volume of stool passage. Bloody diarrhea and abdominal pain may be more prominent features in severe disease. The severity of abdominal pain with UC varies from mild discomfort to very painful bowel movements and abdominal cramping. High frequency of bowel movements, weight loss, nausea, fatigue, and fever are also common during disease flares. Chronic bleeding from the GI tract, chronic inflammation, and iron deficiency often leads to anemia, which can affect quality of life.The clinical presentation of ulcerative colitis depends on the extent of the disease process. Up to 15% of individuals may have severe disease upon initial onset of symptoms. A substantial proportion (up to 45%) of people with a history of UC without any ongoing symptoms (clinical remission) have objective evidence of ongoing inflammation. Ulcerative colitis is associated with a generalized inflammatory process that can affect many parts of the body. Sometimes, these associated extra-intestinal symptoms are the initial signs of the disease.

Extent of involvement
In contrast to Crohns disease, which can affect areas of the gastrointestinal tract outside of the colon, ulcerative colitis is usually confined to the colon. Inflammation in ulcerative colitis is usually continuous, typically involving the rectum, with involvement extending proximally (to sigmoid colon, ascending colon, etc.). In contrast, inflammation with Crohns disease is often patchy, with so-called "skip lesions" (intermittent regions of inflamed bowel).The disease is classified by the extent of involvement, depending on how far the disease extends: proctitis (rectal inflammation), left sided colitis (inflammation extending to descending colon), and extensive colitis (inflammation proximal to the descending colon). Proctosigmoiditis describes inflammation of the rectum and sigmoid colon. Pancolitis describes involvement of the entire colon, extending from the rectum to the cecum. While usually associated with Crohns disease, ileitis (inflammation of the ileum) also occurs in UC. About 17% of individuals with UC have ileitis. Ileitis more commonly occurs in the setting of pancolitis (occurring in 20% of cases of pancolitis), and tends to correlate with the activity of colitis. This so-called "backwash ileitis" can occur in 10–20% of people with pancolitis and is believed to be of little clinical significance.

Severity of disease
In addition to the extent of involvement, UC is also characterized by severity of disease. Severity of disease is defined by symptoms, objective markers of inflammation (endoscopic findings, blood tests), disease course, and the impact of the disease on day-to-day life. Most patients are categorized through endoscopy and fecal calprotectin levels. Indicators of low risk for future complications in mild and moderate UC include the following parameters: exhibiting less than 6 stools daily and lack of fever/weight loss. Other indicators include lack of extraintestinal symptoms, none to little elevation in CRP, ESR, and calprotectin, and later age of diagnosis (over 40 years). Mild disease correlates with fewer than four stools daily; in addition, mild urgency and rectal bleeding may occur intermittently.  Mild disease lacks systemic signs of toxicity (eg. fever, chills, weight changes) and exhibits normal levels of serum inflammatory markers (erythrocyte sedimentation rate and C-reactive protein).Moderate to severe disease correlates with more than six stools daily, frequent bloody stools and urgency. Moderate abdominal pain, low-grade fever, 38 to 39 °C (100 to 102 °F), and anemia may develop (75% of normal). Toxicity is present, as demonstrated by fever, tachycardia, anemia or an elevated ESR or CRP.Fulminant disease correlates with more than 10 bowel movements daily, continuous bleeding, toxicity, abdominal tenderness and distension, blood transfusion requirement, and colonic dilation (expansion). People with fulminant UC may have inflammation extending beyond just the mucosal layer, causing impaired colonic motility and leading to toxic megacolon. Toxic megacolon is defined by diameter of colon (>6 cm) or cecum (>9 cm) and represents a medical emergency, one often treated surgically. If the serous membrane is involved, a colonic perforation may ensue, which has a 50% mortality rate in patients afflicted with UC.Ulcerative colitis may improve and enter remission.  Remission of disease is characterized by formed stools, the absence of bloody diarrhea, resolution of urgency, and normal levels of serum inflammatory markers.

Extraintestinal manifestations and complications
UC is characterized by immune dysregulation and systemic inflammation, which may result in symptoms and complications outside the colon. Commonly affected organs include: eyes, joints, skin, and liver. The frequency of such extraintestinal manifestations has been reported as between 6 and 47%.UC may affect the mouth. About 8% of individuals with UC develop oral manifestations. The two most common oral manifestations are aphthous stomatitis and angular cheilitis. Aphthous stomatitis is characterized by ulcers in the mouth, which are benign, noncontagious and often recurrent. Angular chelitis is characterized by redness at the corners of the mouth, which may include painful sores or breaks in the skin. Very rarely, benign pustules may occur in the mouth (pyostomatitis vegetans).UC may affect the eyes manifesting in scleritis, iritis, and conjunctivitis. Patients may be asymptomatic or experience redness, burning, or itching in eyes (CITE CMDP). Inflammation may occur in the interior portion of the eye, leading to uveitis and iritis. Uveitis can cause blurred vision and eye pain, especially when exposed to light (photophobia). Untreated, uveitis can lead to permanent vision loss. Inflammation may also involve the white part of the eye (sclera) or the overlying connective tissue (episclera), causing conditions called scleritis and episcleritis. Ulcerative colitis is most commonly associated with uveitis and episcleritis.UC may cause several joint manifestations, including a type of rheumatologic disease known as seronegative arthritis, which may affect few large joints (oligoarthritis), the vertebra (ankylosing spondylitis) or several small joints of the hands and feet (peripheral arthritis). Often the insertion site where muscle attaches to bone (entheses) becomes inflamed (enthesitis). Inflammation may affect the sacroiliac joint (sacroiliitis). It is estimated that round 50% of IBD patients suffer from migratory arthritis. Synovitis, or inflammation of the synovial fluid surrounding a joint, can occur for months and recur in later times but usually does not erode the joint. The symptoms of arthritis include joint pain, swelling, and effusion, and often leads to significant morbidity. The severity of joint symptoms often does not correspond with severity of IBD.
Ulcerative colitis may affect the skin. The most common type of skin manifestation, erythema nodosum, presents in up to 3% of UC patients and almost 8% in patients afflicted with Crohns disease. It develops as raised, tender red nodules usually appearing on the outer areas of the arms or legs, especially in the anterior tibial area (shins). The nodules have diameters that measure approximately 1–5 cm. Erythema nodosum is due to inflammation of the underlying subcutaneous tissue (panniculitis), and biopsy will display focal panniculitis (although is often unnecessary in diagnosis). In contrast to joint-related manifestations, erythema nodosum often occurs alongside intestinal disease. Thus, treatment of UC can often lead to resolution of skin nodules.A lesser common skin complication associated with UC, pyoderma gangrenosum, is typically more severe. One study discovered this skin manifestation in only 0.75% pf patients. Pyoderma gangrenosum is characterized by painful lesions or nodules that become ulcers which progressively grow. It often starts as many small raised red spots (papules) or pus-filled lesions (pustules) that are usually detected on lower extremities. The inner layer of the skin, or dermis, slowly undergoes necrosis (process of dying) causing the ulcerations that are typical of pyoderma gangrenosum. The ulcers are often filled with sterile pus-like material, so biopsy often displays an abscess that is sterile. Whereas erythema nodosum tends to correlate with the activity of the ulcerative colitis and often improves with treatment of the colonic inflammation, pyoderma gangrenosum may occur independently of UC disease activity. In some cases, pyoderma gangrenosum may require injection with corticosteroids. Treatment may also involve inhibitors of tumor necrosis factor (TNF), a cytokine that promotes cell survival.Other associations determined between the skin and ulcerative colitis include a skin condition known as hidradenitis suppurativa (HS). This condition represents a chronic process in which follicles become occluded leading to recurring inflammation of nodules and abscesses and even tunnels in the skin that drain fluid.Ulcerative colitis may affect the blood and endocrine system. UC increases the risk of blood clots in both arteries and veins; painful swelling of the lower legs can be a sign of deep venous thrombosis, while difficulty breathing may be a result of pulmonary embolism (blood clots in the lungs). The risk of blood clots is about threefold higher in individuals with IBD. The risk of venous thromboembolism is high in ulcerative colitis due to hypercoagulability from inflammation, especially with active or extensive disease. Additional risk factors may include surgery, hospitalization, pregnancy, the use of corticosteroids and tofacitinib, a JAK inhibitor.The immune system may also attack red blood cells, leading to autoimmune hemolytic anemia. In addition to autoimmune destruction, anemia may occur due to chronic blood loss from rectal bleeding and bone marrow suppression due to inflammation (anemia of chronic disease). Anemic patients can present asymptomatically. However, 75% of individuals exhibit symptoms such as shortness of breath, fatigue, and tachycardia (racing heart). About 1/3rd of patients show signs of jaundice (yellowing of the skin) or darkened urine from loss of bilirubin in urine. A smaller percentage may present with chest pain or a concurrent immune cytopenia, most commonly immune thrombocytopenia (ITP) (CITE WAHA).
Osteoporosis may occur related to systemic inflammation, which increases the risk of bone fractures. Clubbing, a deformity of the ends of the fingers, may occur. Amyloidosis may occur, especially with severe and poorly controlled disease, which usually presents with protein in the urine (proteinuria) and nephritic syndrome.

Primary sclerosing cholangitis
Ulcerative colitis has a significant association with primary sclerosing cholangitis (PSC), a progressive inflammatory disorder of small and large bile ducts. Up to 70-90% of people with primary sclerosing cholangitis have ulcerative colitis. As many as 5% of people with ulcerative colitis may progress to develop primary sclerosing cholangitis. PSC is more common in men, and often begins between 30 and 40 years of age. It can present asymptomatically or exhibit symptoms of itchiness (pruritis) and fatigue. Other symptoms include systemic signs such as fever and night sweats. Such symptoms are often associated with a bacterial episodic version of PSC. Upon physical exam, one may discern enlarged liver contours (hepatomegaly) or enlarged spleen (splenomegaly) as well as areas of excoriation. Yellow coloring of the skin, or jaundice, may also be present due to excess of bile byproduct buildup (bilirubin) from the biliary tract. In diagnosis, lab results often reveal a pattern indicative of biliary disease (cholestatic pattern). This is often displayed by markedly elevated alkaline phosphatase levels and milder or no elevation in liver enzyme levels. Xray results often show bile ducts with thicker walls, areas of dilation or narrowing.In some cases, primary sclerosing cholangitis occurs several years before the bowel symptoms of ulcerative colitis develop. PSC does not parallel the onset, extent, duration, or activity of the colonic inflammation in ulcerative colitis. In addition, colectomy does not have an impact on the course of primary sclerosing cholangitis in individuals with UC. PSC is associated with an increased risk of colorectal cancer and cholangiocarcinoma (bile duct cancer). PSC is a progressive condition, and may result in cirrhosis of the liver. No specific therapy has been proven to affect the long term course of PSC.Other liver-related manifestations of UC include fatty liver disease and autoimmune liver disease.

Causes
Ulcerative colitis is an autoimmune disease characterized by T-cells infiltrating the colon. No direct causes for UC are known, but factors such as genetics, environment, and an overactive immune system play a role. UC is associated with comorbidities that produce symptoms in many areas of the body outside the digestive system.

Genetic factors
A genetic component to the cause of UC can be hypothesized based on aggregation of UC in families, variation of prevalence between different ethnicities, genetic markers and linkages. In addition, the identical twin concordance rate is 10%, whereas the dizygotic twin concordance rate is only 3%. Between 8 and 14% of people with ulcerative colitis have a family history of inflammatory bowel disease. In addition, people with a first degree relative with UC have a four-fold increase in their risk of developing the disease.Twelve regions of the genome may be linked to UC, including, in the order of their discovery, chromosomes 16, 12, 6, 14, 5, 19, 1, and 3, but none of these loci has been consistently shown to be at fault, suggesting that the disorder is influenced by multiple genes. For example, chromosome band 1p36 is one such region thought to be linked to inflammatory bowel disease. Some of the putative regions encode transporter proteins such as OCTN1 and OCTN2. Other potential regions involve cell scaffolding proteins such as the MAGUK family. Human leukocyte antigen associations may even be at work. In fact, this linkage on chromosome 6 may be the most convincing and consistent of the genetic candidates.Multiple autoimmune disorders are associated with ulcerative colitis, including celiac disease, psoriasis, lupus erythematosus, rheumatoid arthritis, episcleritis, and scleritis. Ulcerative colitis is also associated with acute intermittent porphyria.

Environmental factors
Many hypotheses have been raised for environmental factors contributing to the pathogenesis of ulcerative colitis, including diet, breastfeeding and medications. Breastfeeding may have a protective effect in the development of ulcerative colitis. One study of isotretinoin found a small increase in the rate of UC.As the colon is exposed to many dietary substances which may encourage inflammation, dietary factors have been hypothesized to play a role in the pathogenesis of both ulcerative colitis and Crohns disease. However, current research does not show a link between diet and the development of ulcerative colitis. Few studies have investigated such an association; one study showed no association of refined sugar on the number of people affected of ulcerative colitis. High intake of unsaturated fat and vitamin B6 may enhance the risk of developing ulcerative colitis. Other identified dietary factors that may influence the development and/or relapse of the disease include meat protein and alcoholic beverages. Specifically, sulfur has been investigated as being involved in the cause of ulcerative colitis, but this is controversial. Sulfur restricted diets have been investigated in people with UC and animal models of the disease. The theory of sulfur as an etiological factor is related to the gut microbiota and mucosal sulfide detoxification in addition to the diet.As a result of a class-action lawsuit and community settlement with DuPont, three epidemiologists conducted studies on the population surrounding a chemical plant that was exposed to PFOA at levels greater than in the general population. The studies concluded that there was an association between PFOA exposure and six health outcomes, one of which being ulcerative colitis.

Alternative theories
Levels of sulfate-reducing bacteria tend to be higher in persons with ulcerative colitis, which could indicate higher levels of hydrogen sulfide in the intestine. An alternative theory suggests that the symptoms of the disease may be caused by toxic effects of the hydrogen sulfide on the cells lining the intestine.Infection by mycobacterium avium, subspecies paratuberculosis, has been proposed as the ultimate cause of both ulcerative colitis and Crohns disease.

Pathophysiology
An increased amount of colonic sulfate-reducing bacteria has been observed in some people with ulcerative colitis, resulting in higher concentrations of the toxic gas hydrogen sulfide. Human colonic mucosa is maintained by the colonic epithelial barrier and immune cells in the lamina propria (see intestinal mucosal barrier). N-butyrate, a short-chain fatty acid, gets oxidized through the beta oxidation pathway into carbon dioxide and ketone bodies. It has been shown that N-butyrate helps supply nutrients to this epithelial barrier. Studies have proposed that hydrogen sulfide plays a role in impairing this beta-oxidation pathway by interrupting the short chain acetyl-CoA dehydrogenase, an enzyme within the pathway. Furthermore, it has been suggested that the protective benefit of smoking in ulcerative colitis is due to the hydrogen cyanide from cigarette smoke reacting with hydrogen sulfide to produce the non-toxic isothiocyanate, thereby inhibiting sulfides from interrupting the pathway. An unrelated study suggested that the sulfur contained in red meats and alcohol may lead to an increased risk of relapse for people in remission.

Diagnosis
The initial diagnostic workup for ulcerative colitis consists of a complete history and physical examination, assessment of signs and symptoms, laboratory tests and endoscopy. Severe UC can exhibit high erythrocyte sedimentation rate (ESR), decreased albumin (a protein produced by the liver), and various changes in electrolytes. As discussed previously, UC patients often also display elevated alkaline phosphatase. Inflammation in the intestine may also cause higher levels of fecal calprotectin or lactoferrin.Specific testing may include the following:
A complete blood count is done to check for anemia; thrombocytosis, a high platelet count, is occasionally seen
Electrolyte studies and kidney function tests are done, as chronic diarrhea may be associated with hypokalemia, hypomagnesemia and kidney injury.
Liver function tests are performed to screen for bile duct involvement: primary sclerosing cholangitis.
Imaging such as x-ray or CT scan to evaluate for possible perforation or toxic megacolon
Stool culture and Clostridioides difficile stool assay to rule out infectious colitis
Inflammatory markers, such as erythrocyte sedimentation rate or C-reactive protein
Lower endoscopy to evaluate the rectum and distal large intestine (sigmoidoscopy) or entire colon and end of the small intestine (colonoscopy) for ulcers and inflammationAlthough ulcerative colitis is a disease of unknown causation, inquiry should be made as to unusual factors believed to trigger the disease.The simple clinical colitis activity index was created in 1998 and is used to assess the severity of symptoms.

Endoscopic
The best test for diagnosis of ulcerative colitis remains endoscopy, which is examination of the internal surface of the bowel using a flexible camera. Initially, a flexible sigmoidoscopy may be completed to establish the diagnosis. The physician may elect to limit the extent of the initial exam if severe colitis is encountered to minimize the risk of perforation of the colon. However, a complete colonoscopy with entry into the terminal ileum should be performed to rule out Crohns disease, and assess extent and severity of disease. Endoscopic findings in ulcerative colitis include: erythema (redness of the mucosa), friability of the mucosa, superficial ulceration, and loss of the vascular appearance of the colon. When present, ulcerations may be confluent. Pseudopolyps may be observed.Ulcerative colitis is usually continuous from the rectum, with the rectum almost universally being involved. Perianal disease is rare. The degree of involvement endoscopically ranges from proctitis (rectal inflammation) to left sided colitis (extending to descending colon), to extensive colitis (extending proximal to descending colon).

Histologic
Biopsies of the mucosa are taken during endoscopy to confirm the diagnosis of UC and differentiate it from Crohns disease, which is managed differently clinically. Histologic findings in ulcerative colitis includes: distortion of crypt architecture, crypt abscesses, and inflammatory cells in the mucosa (lymphocytes, plasma cells, and granulocytes). Unlike the transmural inflammation seen in Crohns disease, the inflammation of ulcerative colitis is limited to the mucosa.

Laboratory tests
Blood and stool tests serve primarily to assess disease severity, level of inflammation and rule out causes of infectious colitis.  All individuals with suspected ulcerative colitis should have stool testing to rule out infection.A complete blood count may demonstrate anemia, leukocytosis, or thrombocytosis. Anemia may be caused by inflammation or bleeding. Chronic blood loss may lead to iron deficiency as a cause for anemia, particularly microcytic anemia (small red blood cells), which can be evaluated with a serum ferritin, iron, total iron-binding capacity and transferrin saturation. Anemia may be due to a complication of treatment from azathioprine, which can cause low blood counts, or sulfasalazine, which can result in folate deficiency. Thiopurine metabolites (from azathioprine) and a folate level can help.UC may cause high levels of inflammation throughout the body, which may be quantified with serum inflammatory markers, such as CRP and ESR.  However, elevated inflammatory markers are not specific for UC and elevations are commonly seen in other conditions, including infection. In addition, inflammatory markers are not uniformly elevated in people with ulcerative colitis.  Twenty five percent of individuals with confirmed inflammation on endoscopic evaluation have a normal CRP level. Serum albumin may also be low related to inflammation, in addition to loss of protein in the GI tract associated with bleeding and colitis. Low serum levels of vitamin D are associated with UC, although the significance of this finding is unclear.Specific antibody markers may be elevated in ulcerative colitis. Specifically, perinuclear antineutrophil cytoplasmic antibodies (pANCA) are found in 70 percent of cases of UC. Antibodies against Saccharomyces cerevisiae may be present, but are more often positive in Crohns disease compared with ulcerative colitis.  However, due to poor accuracy of these serolologic tests, they are not helpful in the diagnostic evaluation of possible inflammatory bowel disease.Several stool tests may help quantify the extent of inflammation present in the colon and rectum.  Fecal calprotectin is elevated in inflammatory conditions affecting the colon, and is useful in distinguishing irritable bowel syndrome (noninflammatory) from a flare in inflammatory bowel disease. Fecal calprotectin is 88% sensitive and 79% specific for the diagnosis of ulcerative colitis. If the fecal calprotectin is low, the likelihood of inflammatory bowel disease are less than 1 percent. Lactoferrin is an additional nonspecific marker of intestinal inflammation.

Imaging
Overall, imaging tests, such as x-ray or CT scan, may be helpful in assessing for complications of ulcerative colitis, such as perforation or toxic megacolon. Bowel ultrasound (US) is a cost-effective, well-tolerated, non-invasive and readily available tool for the management of patients with inflammatory bowel disease (IBD), including UC, in clinical practice. Some recent studies demonstrated that US is an accurate tool for assessing disease activity in patients with UC. Imaging is otherwise of limited use in diagnosing ulcerative colitis. Magnetic resonance imaging (MRI) is necessary to diagnose underlying PSC.Abdominal xray is often the test of choice and may display nonspecific findings in cases of mild or moderate ulcerative colitis. In circumstances of severe UC, radiographic findings may include thickening of the mucosa, often termed "thumbprinting," which indicates swelling due to fluid displacement (edema). Other findings may include colonic dilation and stool buildup evidencing constipation.Similar to xray, in mild ulcerative colitis, double contrast barium enema often shows nonspecific findings. Conversely, barium enema may display small buildups of barium in microulcerations. Severe UC can be characterized by various polyps, colonic shortening, loss of haustrae (the small bulging pouches in the colon),and narrowing of the colon. It is important to note that barium enema should not be conducted in patients exhibiting very severe symptoms as this may slow or stop stool passage through the colon causing ileus and toxic megacolon.Other methods of imaging include computed tomography (CT) and magnetic resonance imaging (MRI). Both may depict colonic wall thickening but have decreased ability to find early signs of wall changes when compared to barium enema. In cases of severe ulcerative colitis, however, they often exhibit equivalent ability to detect colonic changes.Doppler ultrasound is the last means of imaging that may be used. Similar to the imaging methods mentioned earlier, this may show some thickened bowel wall layers. In severe cases, this may show thickening in all bowel wall layers (transmural thickness).

Differential diagnosis
Several conditions may present in a similar manner as ulcerative colitis, and should be excluded. Such conditions include: Crohns disease, infectious colitis, nonsteroidal anti-inflammatory drug enteropathy, and irritable bowel syndrome. Alternative causes of colitis should be considered, such as ischemic colitis (inadequate blood flow to the colon), radiation colitis (if prior exposure to radiation therapy), or chemical colitis. Pseudomembranous colitis may occur due to Clostridioides difficile infection following administration of antibiotics. Entamoeba histolytica is a protozoan parasite that causes intestinal inflammation. A few cases have been misdiagnosed as UC with poor outcomes occurring due to the use of corticosteroids.The most common disease that mimics the symptoms of ulcerative colitis is Crohns disease, as both are inflammatory bowel diseases that can affect the colon with similar symptoms. It is important to differentiate these diseases since their courses and treatments may differ. In some cases, however, it may not be possible to tell the difference, in which case the disease is classified as indeterminate colitis. Crohns disease can be distinguished from ulcerative colitis in several ways. Characteristics that indicate Crohns include evidence of disease around the anus (perianal disease). This includes anal fissures and abscesses as well as fistulas, which are abnormal connections between various bodily structures.Infectious colitis is another condition that may present in similar manner to ulcerative colitis. Endoscopic findings are also oftentimes similar. One can discern whether a patient has infectious colitis by employing tissue cultures and stool studies. Biopsy of the colon is another beneficial test but is more invasive.
Other forms of colitis that may present similarly include radiation and diversion colitis. Radiation colitis occurs after irradiation and often affects the rectum or sigmoid colon, similar to ulcerative colitis. Upon histology radiation colitis may indicate eosinophilic infiltrates, abnormal epithelial cells, or fibrosis. Diversion colitis, on the other hand, occurs after portions of bowel loops have been removed. Histology in this condition often shows increased growth of lymphoid tissue.
In patients who have undergone transplantation, graft versus host disease may also be a differential diagnosis. This response to transplantation often causes prolonged diarrhea if the colon is affected. Typical symptoms also include rash. Involvement of the upper gastrointestinal tract may lead to difficulty swallowing or ulceration. Upon histology, graft versus host disease may present with crypt cell necrosis and breakdown products within the crypts themselves.

Management
Standard treatment for ulcerative colitis depends on the extent of involvement and disease severity. The goal is to induce remission initially with medications, followed by the administration of maintenance medications to prevent a relapse. The concept of induction of remission and maintenance of remission is very important. The medications used to induce and maintain a remission somewhat overlap, but the treatments are different. Physicians first direct treatment to inducing remission, which involves relief of symptoms and mucosal healing of the colons lining, and then longer-term treatment to maintain remission and prevent complications. Acute severe ulcerative colitis requires hospitalisation, exclusion of infections, and corticosteroids.For acute stages of the disease, a low fiber diet may be recommended.

Medication
Ulcerative colitis can be treated with a number of medications, including 5-ASA drugs such as sulfasalazine and mesalazine. Corticosteroids such as prednisone can also be used due to their immunosuppressive and short-term healing properties, but because their risks outweigh their benefits, they are not used long-term in treatment. Immunosuppressive medications such as azathioprine and biological agents such as infliximab and adalimumab are given only if people cannot achieve remission with 5-ASA and corticosteroids. Infliximab, ustekinumab, or vedolizumab are recommended in those with moderate or severe disease.A formulation of budesonide was approved by the U.S. Food and Drug Administration (FDA) for treatment of active ulcerative colitis in January 2013. In 2018, tofacitinib was approved for treatment of moderately to severely active ulcerative colitis in the United States, the first oral medication indicated for long term use in this condition. The evidence on methotrexate does not show a benefit in producing remission in people with ulcerative colitis. Cyclosporine is effective for severe UC and tacrolimus has also shown benefits.

Aminosalicylates
Sulfasalazine has been a major agent in the therapy of mild to moderate ulcerative colitis for over 50 years. In 1977, it was shown that 5-aminosalicylic acid (5-ASA, mesalazine/mesalamine) was the therapeutically active component in sulfasalazine.  Many 5-ASA drugs have been developed with the aim of delivering the active compound to the large intestine to maintain therapeutic efficacy but with reduction of the side effects associated with the sulfapyridine moiety in sulfasalazine.  Oral 5-ASA drugs are particularly effective in inducing and in maintaining remission in mild to moderate ulcerative colitis.  Rectal suppository, foam or liquid enema formulations of 5-ASA are used for colitis affecting the rectum, sigmoid or descending colon, and have been shown to be effective especially when combined with oral treatment.

Biologics
Biologic treatments such as the TNF inhibitors infliximab, adalimumab, and golimumab are commonly used to treat people with UC who are no longer responding to corticosteroids. Tofacitinib and vedolizumab can also produce good clinical remission and response rates in UC. Biologics may be used early in treatment (step down approach), or after other treatments have failed to induce remission (step up approach); the strategy should be individualized.Unlike aminosalicylates, biologics can cause serious side effects such as an increased risk of developing extra-intestinal cancers, heart failure; and weakening of the immune system, resulting in a decreased ability of the immune system to clear infections and reactivation of latent infections such as tuberculosis. For this reason, people on these treatments are closely monitored and are often tested for hepatitis and tuberculosis annually.

Nicotine
Unlike Crohns disease, ulcerative colitis has a lesser chance of affecting smokers than non-smokers. In select individuals with a history of previous tobacco use, resuming low dose smoking may improve signs and symptoms of active ulcerative colitis, but it is not recommended due to the overwhelmingly negative health effects of tobacco. Studies using a transdermal nicotine patch have shown clinical and histological improvement. In one double-blind, placebo-controlled study conducted in the United Kingdom, 48.6% of people with UC who used the nicotine patch, in conjunction with their standard treatment, showed complete resolution of symptoms. Another randomized, double-blind, placebo-controlled, single-center clinical trial conducted in the United States showed that 39% of people who used the patch showed significant improvement, versus 9% of those given a placebo. However, nicotine therapy is generally not recommended due to side effects and inconsistent results.

Iron supplementation
The gradual loss of blood from the gastrointestinal tract, as well as chronic inflammation, often leads to anemia, and professional guidelines suggest routinely monitoring for anemia with blood tests repeated every three months in active disease and annually in quiescent disease. Adequate disease control usually improves anemia of chronic disease, but iron deficiency anemia should be treated with iron supplements. The form in which treatment is administered depends both on the severity of the anemia and on the guidelines that are followed. Some advise that parenteral iron be used first because people respond to it more quickly, it is associated with fewer gastrointestinal side effects, and it is not associated with compliance issues. Others require oral iron to be used first, as people eventually respond and many will tolerate the side effects.

Surgery
Unlike in Crohns disease, the gastrointestinal aspects of ulcerative colitis can generally be cured by surgical removal of the large intestine, though extraintestinal symptoms may persist. This procedure is necessary in the event of: exsanguinating hemorrhage, frank perforation, or documented or strongly suspected carcinoma. Surgery is also indicated for people with severe colitis or toxic megacolon. People with symptoms that are disabling and do not respond to drugs may wish to consider whether surgery would improve the quality of life.The removal of the entire large intestine, known as a proctocolectomy, results in a permanent ileostomy – where a stoma is created by pulling the terminal ileum through the abdomen. Intestinal contents are emptied into a removable ostomy bag which is secured around the stoma using adhesive.Another surgical option for ulcerative colitis that is affecting most of the large bowel is called the ileal pouch-anal anastomosis (IPAA). This is a two- or three-step procedure. In a three-step procedure, the first surgery is a sub-total colectomy, in which the large bowel is removed, but the rectum remains in situ, and a temporary ileostomy is made. The second step is a proctectomy and formation of the ileal pouch (commonly known as a "j-pouch"). This involves removing the large majority of the remaining rectal stump and creating a new "rectum" by fashioning the end of the small intestine into a pouch and attaching it to the anus. After this procedure, a new type of ileostomy is created (known as a loop ileostomy) to allow the anastomoses to heal. The final surgery is a take-down procedure where the ileostomy is reversed and there is no longer the need for an ostomy bag. When done in two steps, a proctocolectomy – removing both the colon and rectum – is performed alongside the pouch formation and loop ileostomy. The final step is the same take-down surgery as in the three-step procedure. Time taken between each step can vary, but typically a six- to twelve-month interval is recommended between the first two steps, and a minimum of two to three months is required between the formation of the pouch and the ileostomy take-down.While the ileal pouch procedure removes the need for an ostomy bag, it does not restore normal bowel function. In the months following the final operation, patients typically experience 8–15 bowel movements a day. Over time this number decreases, with many patients reporting four-six bowel movements after one year post-op. While many patients have success with this procedure, there are a number of known complications. Pouchitis, inflammation of the ileal pouch resulting in symptoms similar to ulcerative colitis, is relatively common. Pouchitis can be acute, remitting, or chronic however treatment using antibiotics, steroids, or biologics can be highly effective. Other complications include fistulas, abscesses, and pouch failure. Depending on the severity of the condition, pouch revision surgery may need to be performed. In some cased the pouch may need to be de-functioned or removed and an ileostomy recreated.The risk of cancer arising from a ileal pouch anal anastomosis is low. However, annual surveillance with pouchoscopy may be considered in individuals with risk factors for dysplasia, such as a history of dysplasia or colorectal cancer, a history of PSC, refractory pouchitis, and severely inflamed atrophic pouch mucosa.

Bacterial recolonization
In a number of randomized clinical trials, probiotics have demonstrated the potential to be helpful in the treatment of ulcerative colitis. Specific types of probiotics such as Escherichia coli Nissle have been shown to induce remission in some people for up to a year. A probiotic named after its gastroenterologist medical doctor inventor, the De Simone Formulation, may be effective in inducing remission in active ulcerative colitis, and may be as effective as 5-ASAs in preventing relapse of quiescent UC.  The De Simone Formulation was sold and researched under the brand name VSL#3 until 2016. Since, it has been sold and researched under various regional brand names including Visbiome in the United States and Vivomixx in Europe.Fecal microbiota transplant involves the infusion of human probiotics through fecal enemas. Ulcerative colitis typically requires a more prolonged bacteriotherapy treatment than Clostridium difficile infection to be successful, possibly due to the time needed to heal the ulcerated epithelium. The response of ulcerative colitis is potentially very favorable with one study reporting 67.7% of people experiencing complete remission. Other studies found a benefit from using fecal microbiota transplantation.

Alternative medicine
A variety of alternative medicine therapies have been used for ulcerative colitis, with inconsistent results. Curcumin (turmeric) therapy, in conjunction with taking the medications mesalamine or sulfasalazine, may be effective and safe for maintaining remission in people with quiescent ulcerative colitis. The effect of curcumin therapy alone on quiescent ulcerative colitis is unknown.Treatments using cannabis or cannabis oil are uncertain. So far, studies havent determined its effectiveness and safety.

Abdominal pain management
Many interventions have been considered to manage abdominal pain in people with ulcerative colitis, including FODMAPs diet, relaxation training, yoga, kefir diet and stellate ganglion block treatment. It is unclear whether any of these are safe or effective at improving pain or reducing anxiety and depression.

Prognosis
Poor prognostic factors include: age < 40 years upon diagnosis, extensive colitis, severe colitis on endoscopy, prior hospitalization, elevated CRP and low serum albumin.

Progression or remission
People with ulcerative colitis usually have an intermittent course, with periods of disease inactivity alternating with "flares" of disease. People with proctitis or left-sided colitis usually have a more benign course: only 15% progress proximally with their disease, and up to 20% can have sustained remission in the absence of any therapy. A subset of people experience a course of disease progress rapidly. In these cases, there is usually a failure to respond to medication and surgery often is performed within the first few years of disease onset. People with more extensive disease are less likely to sustain remission, but the rate of remission is independent of the severity of the disease. Several risk factors are associated with eventual need for colectomy, including: prior hospitalization for UC, extensive colitis, need for systemic steroids, young age at diagnosis, low serum albumin, elevated inflammatory markers (CRP & ESR), and severe inflammation seen during colonoscopy. Surgical removal of the large intestine is necessary in some cases.

Colorectal cancer
The risk of colorectal cancer is significantly increased in people with ulcerative colitis after ten years if involvement is beyond the splenic flexure. People with backwash ileitis might have an increased risk for colorectal carcinoma. Those people with only proctitis usually have no increased risk. It is recommended that people have screening colonoscopies with random biopsies to look for dysplasia after eight years of disease activity, at one to two year intervals.

Mortality
People with ulcerative colitis are at similar or perhaps slightly increased overall risk of death compared with the background population. However, the distribution of causes-of-death differs from the general population. Specific risk factors may predict worse outcomes and a higher risk of mortality in people with ulcerative colitis, including: C. difficile infection and cytomegalovirus infection (due to reactivation).

Epidemiology
Together with Crohns disease, about 11.2 million people were affected as of 2015. Each year, ulcerative colitis newly occurs in 1 to 20 per 100,000 people (incidence), and there are a total of 5-500 per 100,000 individuals with the disease (prevalence). In 2015, a worldwide total of 47,400 people died due to inflammatory bowel disease (UC and Crohns disease). The peak onset is between 30 and 40 years of age, with a second peak of onset occurring in the 6th decade of life. Ulcerative colitis is equally common among men and women. With appropriate treatment the risk of death appears similar to that of the general population. UC has become more common since the 1950s.The geographic distribution of UC and Crohns disease is similar worldwide, with the highest number of new cases a year of UC found in Canada, New Zealand and the United Kingdom. The disease is more common in North America and Europe than other regions. In general, higher rates are seen in northern locations compared to southern locations in Europe and the United States. UC is more common in western Europe compared with eastern Europe.  Worldwide, the prevalence of UC varies from 2 - 299 per 100,000 people. Together, ulcerative colitis and Crohns disease affect about a million people in the United States.As with Crohns disease, the rates of UC are greater among Ashkenazi Jews and decreases progressively in other persons of Jewish descent, non-Jewish Caucasians, Africans, Hispanics, and Asians. Appendectomy prior to age 20 for appendicitis and current tobacco use are protective against development of UC. However, former tobacco use is associated with a higher risk of developing the disease.

United States
As of 2004, the number of new cases of UC in the United States was between 2.2 and 14.3 per 100,000 per year. The number of people affected in the United States in 2004 was between 37 and 246 per 100,000.

Canada
In Canada, between 1998 and 2000, the number of new cases per year was 12.9 per 100,000 population or 4,500 new cases. The number of people affected was estimated to be 211 per 100,000 or 104,000.

United Kingdom
In the United Kingdom 10 per 100,000 people newly develop the condition a year while the number of people affected is 243 per 100,000. Approximately 146,000 people in the United Kingdom have been diagnosed with UC.

History
The first description of ulcerative colitis occurred around the 1850s.

Research
Helminthic therapy using the whipworm Trichuris suis has been shown in a randomized control trial from Iowa to show benefit in people with ulcerative colitis. The therapy tests the hygiene hypothesis which argues that the absence of helminths in the colons of people in the developed world may lead to inflammation </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 Metaphyseal dysplasia and can you explain it in depth? [/INST] Metaphyseal dysplasia, or Pyle disease, is a disorder of the bones. It is a rare disease in which the outer part of the shafts of long bones is thinner than normal and there is an increased chance of fractures. Its hallmark feature is an abnormality of the long bones in the arms and legs in which the ends (metaphyses) of the bones are abnormally broad; the shape of the bones resembles a boat oar or paddle. The broad metaphyses are due to enlargement of the spongy inner layer of bone (trabecular bone). Although trabecular bone is expanded, the dense outermost layer of bone (cortical bone) is thinner than normal. As a result, the bones are fragile and fracture easily. The bone abnormalities in the legs commonly cause knock knees (genu valgum) in affected individuals.Other bone abnormalities can also occur in Pyle disease. Affected individuals may have widened collar bones (clavicles), ribs, or bones in the fingers and hands. Dental problems are common in Pyle disease, including delayed appearance (eruption) of permanent teeth and misalignment of the top and bottom teeth (malocclusion).

Signs and symptoms
It is an autosomal recessive disorder in which mild clinical manifestations contrast with radiological appearances of gross metaphyseal undermodeling. Most patients present with mild genu valgum. The elbows are unable to extend fully. There may be widening of the lower femora and clavicles. Bones can sometimes be fragile, but fracturing is usually not common. Patients may present with dental caries, mandibular prognathism, spinal alignment, and disproportionate limb lengthening. Mental development, physical development, and height are usually normal. Most patients with Pyles diseases will have symptoms that vary from person to person. Symptoms are:5%–29% of people have

Delated eruption of teethOther people may have

Abnormality of thorax
Absent paranasal sinuses
Arthralgia
Carious teeth
Genu valgum
Hypoplastic frontal sinuses
Limited elbow extension
Mandibular prognathia
Metaphyseal widening
Metaphyseal dysplasia
Muscle weakness
Platyspondyly
Reduced bone mineral density
Scoliosis
Thickened calvaria

Cause
Pyle disease is caused by mutations in the SFRP4 gene. This gene provides instructions for making a protein that blocks (inhibits) a process called Wnt signaling, which is involved in the development of several tissues and organs throughout the body. In particular, regulation of Wnt signaling by the SFRP4 protein is critical for normal bone development and remodeling. Bone remodeling is a normal process in which old bone is broken down and new bone is created to replace it. Mutations in the SFRP4 gene are thought to prevent the production of functional SFRP4 protein. The resulting dysregulation of Wnt signaling leads to the bone abnormalities characteristic of Pyle disease.Pyle disease is inherited in an autosomal recessive pattern, which means both copies of the SFRP4 gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene. While they do not develop the condition, they may have mild abnormalities of the long bones.

Diagnosis
There are two clinical molecular genetic test that are available to those thought to have Pyle’s Disease. Theses test are; Sequence analysis of the entire coding region and Deletion/duplication analysis.

Differential diagnosis
Pyle disease may be confused with craniometaphyseal dysplasia </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 Amenorrhea and can you explain it in depth? [/INST] Amenorrhea is the absence of a menstrual period in a woman of reproductive age. Physiological states of amenorrhoea are seen, most commonly, during pregnancy and lactation (breastfeeding). Outside the reproductive years, there is absence of menses during childhood and after menopause.Amenorrhoea is a symptom with many potential causes. Primary amenorrhea is defined as an absence of secondary sexual characteristics by age 13 with no menarche or normal secondary sexual characteristics but no menarche by 15 years of age. It may be caused by developmental problems, such as the congenital absence of the uterus, failure of the ovary to receive or maintain egg cells, or delay in pubertal development. Secondary amenorrhoea, ceasing of menstrual cycles after menarche, is defined as the absence of menses for three months in a woman with previously normal menstruation, or six months for women with a history of oligomenorrhoea. It is often caused by hormonal disturbances from the hypothalamus and the pituitary gland, premature menopause, intrauterine scar formation, or eating disorders.

Pathophysiology
Although amenorrhea has multiple potential causes, ultimately, it is the result of hormonal imbalance or an anatomical abnormality.Physiologically, menstruation is controlled by the release of gonadotropin-releasing hormone (GnRH) from the hypothalamus. GnRH acts on the pituitary to stimulate the release of follicle stimulating hormone (FSH) and luteinizing hormone (LH). FSH and LH then act on the ovaries to stimulate the production of estrogen and progesterone which, respectively, control the proliferative and secretary phases of the menstrual cycle. Prolactin also influences the menstrual cycle as it suppresses the release of LH and FSH form the pituitary. Similarly, thyroid hormone also affects the menstrual cycle. Low levels of thyroid hormone stimulate the release of TRH from the hypothalamus, which in turn increases both TSH and prolactin release. This increase in prolactin suppresses the release of LH and FSH through a negative feedback mechanism. Amenorrhea can be caused by any mechanism that disrupts this hypothalamic-pituitary-ovarian axis, whether that it be by hormonal imbalance or by disruption of feedback mechanisms.

Classification
Amenorrhea is classified as either primary or secondary.

Primary Amenorrhea
Primary amenorrhoea is the absence of menstruation in a woman by the age of 16. Females who have not reached menarche at 14 and who have no signs of secondary sexual characteristics (thelarche or pubarche) are also considered to have primary amenorrhea. Examples of amenorrhea include constitutional delay of puberty, Turner syndrome, and Mayer–Rokitansky–Küster–Hauser (MRKH) syndrome.

Secondary Amenorrhea
Secondary amenorrhoea is defined as the absence of menstruation for three months in a woman with a history of regular cyclic bleeding or six months in a woman with a history of irregular menstrual periods. Examples of secondary amenorrhea include hypothyroidism, hyperthyroidism, hyperprolactinemia, polycystic ovarian syndrome, primary ovarian insufficiency, and functional hypothalamic amenorrhea.

Causes
Primary amenorrhea
Turner syndrome
Turner syndrome, monosomy 45XO, is a genetic disorder characterized by a missing, or partially missing, X chromosome. Turner syndrome is associated with a wide spectrum of features that vary with each case. However, one common feature of this syndrome is ovarian insufficiency due to gonadal dysgenesis. Most people with Turner syndrome experience ovarian insufficiency within the first few years of life, prior to menarche. Therefore, most patients with Turner syndrome will have primary amenorrhea. However, the incidence of spontaneous puberty varies between 8–40% depending on whether or not there is a complete or partial absence of the X chromosome.

MRKH
MRKH (Mayer–Rokitansky–Küster–Hauser) syndrome is the second-most common cause of primary amenorrhoea. The syndrome is characterized by Müllerian agenesis. In MRKH Syndrome, the Müllerian ducts develop abnormally and result in the absence of a uterus and cervix. Even though patients with MRKH have functioning ovaries, and therefore have secondary sexual characteristics, they experience primary amenorrhea since there is no functioning uterus.

Constitutional delay of puberty
Constitutional delay of puberty is a diagnosis of exclusion that is made when the workup for primary amenorrhea does not reveal another cause. Constitutional delay of puberty is not due to a pathologic cause. It is considered a variant of the timeline of puberty. Although more common in boys, girls with delayed puberty present with onset of secondary sexual characteristics after the age of 14, as well as menarche after the age of 16. This may be due to genetics, as some cases of constitutional delay of puberty are familial.

Secondary amenorrhea
Breastfeeding
Physiologic amenorrhea is present before menarche, during pregnancy and breastfeeding, and after menopause.Breastfeeding or lactational amenorrhea is also a common cause of secondary amenorrhoea. Lactational amenorrhea is due to the presence of elevated prolactin and low levels of LH, which suppress ovarian hormone secretion. Breastfeeding typically prolongs postpartum lactational amenorrhoea, and the duration of amenorrhoea varies depending on how often a woman breastfeeds. Due to this reason, breastfeeding has been advocated as a method of family planning, especially in developing countries where access to other methods of contraception may be limited.

Diseases of the thyroid
Disturbances in thyroid hormone regulation has been a known cause of menstrual irregularities, including secondary amenorrhea.Patients with hypothyroidism frequently present with changes in their menstrual cycle. It is hypothesized that this is due to increased TRH, which goes on to stimulate the release of both TSH and prolactin. Increased prolactin inhibits the release of LH and FSH which are needed for ovulation to occur.Patients with hyperthyroidism may also present with oligomenorrhea or amenorrhea. Sex hormone binding globulin is increased in hyperthyroid states. This, in turn, increases the total levels of testosterone and estradiol. Increased levels of LH and FSH have also been reported in patients with hyperthyroidism.

Hypothalamic and pituitary causes
Changes in the hypothalamic-pituitary axis is a common cause of secondary amenorrhea. GnRH is released from the hypothalamus and stimulates the anterior pituitary to release FSH and LH, which in turn stimulate the ovaries to release estrogen and progesterone. Any pathology in the hypothalamus or pituitary can alter the way this feedback mechanism works and can cause secondary amenorrhea.Pituitary adenomas are a common cause of amenorrhea. Prolactin secreting pituitary adenomas cause amenorrhea due to the hyper-secretion of prolactin which inhibits FSH and LH release. Other space occupying pituitary lesions can also cause amenorrhea due to the inhibition of dopamine, an inhibitor of prolactin, due to compression of the pituitary gland.

Polycystic ovary syndrome
Polycystic ovary syndrome (PCOS) is a common endocrine disorder affecting 4–8% of women worldwide. It is characterized by multiple cysts on the ovary, amenorrhea or oligomenorrhea, and increased androgens. Although the exact cause remains unknown, it is hypothesized that increased levels of circulating androgens is what results in secondary amenorrhea. PCOS may also be a cause of primary amenorrhea if androgen access is present prior to menarche. Although multiple cysts on the ovary are characteristic of the syndrome, this has not been noted to be a cause of the disease.

Low body weight
Women who perform extraneous exercise on a regular basis or lose a significant amount of weight are at risk of developing hypothalamic amenorrhoea. Functional hypothalamic amenorrhoea (FHA) can be caused by stress, weight loss, or excessive exercise. Many women who diet or who exercise at a high level do not take in enough calories to maintain their normal menstrual cycles. The threshold of developing amenorrhoea appears to be dependent on low energy availability rather than absolute weight because a critical minimum amount of stored, easily mobilized energy is necessary to maintain regular menstrual cycles. Amenorrhoea is often associated with anorexia nervosa and other eating disorders. The female athlete triad is when a woman experiences amenorrhoea, disordered eating, and osteoporosis.Energy imbalance and weight loss can disrupt menstrual cycles through several hormonal mechanisms. Weight loss can cause elevations in the hormone ghrelin which inhibits the hypothalamic-pituitary-ovarial axis. Elevated concentrations of ghrelin alter the amplitude of GnRH pulses, which causes diminished pituitary release of LH and follicle-stimulating hormone (FSH). Low levels of the hormone leptin are also seen in females with low body weight. Like ghrelin, leptin signals energy balance and fat stores to the reproductive axis. Decreased levels of leptin are closely related to low levels of body fat, and correlate with a slowing of GnRH pulsing.

Drug-induced
Certain medications, particularly contraceptive medications, can induce amenorrhoea in a healthy woman. The lack of menstruation usually begins shortly after beginning the medication and can take up to a year to resume after stopping its use. Hormonal contraceptives that contain only progestogen, like the oral contraceptive Micronor, and especially higher-dose formulations, such as the injectable Depo-Provera, commonly induce this side effect. Extended cycle use of combined hormonal contraceptives also allow suppression of menstruation. Patients who stop using combined oral contraceptive pills (COCP) may experience secondary amenorrhoea as a withdrawal symptom. The link is not well understood, as studies have found no difference in hormone levels between women who develop amenorrhoea as a withdrawal symptom following the cessation of COCP use and women who experience secondary amenorrhoea because of other reasons.  New contraceptive pills which do not have the normal seven days of placebo pills in each cycle, have been shown to increase rates of amenorrhoea in women. Studies show that women are most likely to experience amenorrhoea after one year of treatment with continuous OCP use.The use of opiates (such as heroin) on a regular basis has also been known to cause amenorrhoea in longer term users.Anti-psychotic drugs, which are commonly used to treat schizophrenia, have been known to cause amenorrhoea as well. Research suggests that anti-psychotic medications effect levels of prolactin, insulin, FSH, LH, and testosterone. Recent research suggests that adding a dosage of Metformin to an anti-psychotic drug regimen can restore menstruation. Metformin has been shown to decrease resistance to the hormone insulin, as well as levels of prolactin, testosterone, and luteinizing hormone (LH).

Primary ovarian insufficiency
Primary ovarian insufficiency (POI) affects 1% of females and is defined as the loss of ovarian function before the age of 40. Although the cause of POI can vary, it has been linked to chromosomal abnormalities, chemotherapy, and autoimmune conditions. Hormone levels in POI are similar to menopause and are categorized by low estradiol and high levels of gonadotropins. Since the pathogenesis of POI involves the depletion of ovarian reserve, restoration of menstrual cycles typically does not occur in this form of secondary amenorrhea.

Diagnosis
Primary amenorrhoea
Primary amenorrhoea can be diagnosed in female children by age 14 if no secondary sex characteristics, such as enlarged breasts and body hair, are present. In the absence of secondary sex characteristics, the most common cause of amenorrhoea is low levels of FSH and LH caused by a delay in puberty. Gonadal dysgenesis, often associated with Turner syndrome, or premature ovarian failure may also be to blame. If secondary sex characteristics are present, but menstruation is not, primary amenorrhoea can be diagnosed by age 16.Evaluation of primary amenorrhea begins with a pregnancy test, prolactin, FSH, LH, and TSH levels. Abnormal TSH levels prompt evaluation for hyper- and hypo-thyroidism with additional thyroid function tests. Elevated prolactin levels prompt evaluation of the pituitary with an MRI to assess for any masses or malignancies. A pelvic ultrasound can also be obtained in the initial evaluation. If a uterus is not present on ultrasound, karyotype analysis and testosterone levels are obtained to assess for MRKH or androgen insensitivity syndrome. If a uterus is present, LH and FSH levels are used to make a diagnosis. Low levels of LH and FSH suggest delayed puberty or functional hypothalamic amenorrhea. Elevated levels of FSH and LH suggest primary ovarian insufficiency, typically due to Turner syndrome. Normal levels of FSH and LH can suggest an anatomical outflow obstruction.

Secondary amenorrhea
Secondary amenorrheas most common and most easily diagnosable causes are pregnancy, thyroid disease, and hyperprolactinemia. A pregnancy test is a common first step for diagnosis.Similar to primary amenorrhea, evaluation of secondary amenorrhea also begins with a pregnancy test, prolactin, FSH, LH, and TSH levels. A pelvic ultrasound is also obtained. Abnormal TSH should prompt a thyroid workup with a full thyroid function test panel. Elevated prolactin should be followed with an MRI to look for masses. If LH and FSH are elevated, menopause or primary ovarian insufficiency should be considered. Normal or low levels of FSH and LH prompts further evaluation with patient history and the physical exam. Testosterone, DHEA-S, and 17-hydroxyprogesterone levels should be obtained if there is evidence of excess androgens, such as hirsutism or acne. 17-hydroxyprogesterone is elevated in congenital adrenal hyperplasia. Elevated testosterone and amenorrhea can suggest PCOS. Elevated androgens can also be present in ovarian or adrenal tumors, so additional imaging may also be needed. History of disordered eating or excessive exercise should raise concern for hypothalamic amenorrhea. Headache, vomiting, and vision changes can be signs of a tumor and needs evaluation with MRI. Finally, a history of gynecologic procedures should lead to evaluation of Asherman syndrome with a hysteroscopy or progesterone withdrawal bleeding test.

Treatment
Treatment for amenorrhea varies based on the underlying condition. Treatment not only focuses on restoring menstruation, if possible, but also preventing additional complications associated with the underlying cause of amenorrhea.

Primary amenorrhea
In primary amenorrhea, the goal is to continue pubertal development, if possible. For example, most patients with Turner syndrome will be infertile due to gonadal dysgenesis. However, patients are frequently prescribed growth hormone therapy and estrogen supplementation to achieve taller stature and prevent osteoporosis. In other cases, such as MRKH, hormones do not need to be prescribed since the ovaries are able to function normally. Patients with constitutional delay of puberty may be monitored by an endocrinologist, but definitive treatment may not be needed as there will eventually be progression to normal puberty.

Secondary amenorrhea
Treatment for secondary amenorrhea varies greatly based on the root cause. Functional hypothalamic amenorrhoea is typically treated by weight gain through increased calorie intake and decreased expenditure. Multidisciplinary treatment with monitoring from a physician, dietitian, and mental health counselor is recommended, along with support from family, friends, and coaches </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 Hypocalcemia and can you explain it in depth? [/INST] Hypocalcemia is a medical condition characterized by low calcium levels in the blood serum. The normal range of blood calcium is typically between 2.1–2.6 mmol/L (8.8–10.7 mg/dL, 4.3–5.2 mEq/L) while levels less than 2.1 mmol/L are defined as hypocalcemic. Mildly low levels that develop slowly often have no symptoms. Otherwise symptoms may include numbness, muscle spasms, seizures, confusion, or cardiac arrest.The most common cause for hypocalcemia is iatrogenic hypoparathyroidism. Other causes include other forms of hypoparathyroidism, vitamin D deficiency, kidney failure, pancreatitis, calcium channel blocker overdose, rhabdomyolysis, tumor lysis syndrome, and medications such as bisphosphonates or denosumab. Diagnosis should generally be confirmed with a corrected calcium or ionized calcium level. Specific changes may be seen on an electrocardiogram (ECG).Initial treatment for severe disease is with intravenous calcium chloride and possibly magnesium sulfate. Other treatments may include vitamin D, magnesium, and calcium supplements. If due to hypoparathyroidism, hydrochlorothiazide, phosphate binders, and a low salt diet may also be recommended. About 18% of people who are being treated in hospital have hypocalcemia.

Signs and symptoms
The neuromuscular symptoms of hypocalcemia are caused by a positive bathmotropic effect (i.e. increased responsiveness) due to the decreased interaction of calcium with sodium channels. Since calcium blocks sodium channels and inhibits depolarization of nerve and muscle fibers, reduced calcium lowers the threshold for depolarization. The symptoms can be recalled by the mnemonic "CATs go numb" - convulsions, arrhythmias, tetany, and numbness in the hands and feet and around the mouth.

Causes
Hypoparathyroidism is a common cause of hypocalcemia. Calcium is tightly regulated by the parathyroid hormone (PTH). In response to low calcium levels, PTH levels rise, and conversely if there are high calcium levels then PTH secretion declines. However, in the setting of absent, decreased, or ineffective PTH hormone, the body loses this regulatory function, and hypocalcemia ensues. Hypoparathyroidism is commonly due to surgical destruction of the parathyroid glands. Hypoparathyroidism may also be due to autoimmune problem </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 Carpal tunnel syndrome and can you explain it in depth? [/INST] Carpal tunnel syndrome (CTS) is the collection of symptoms and signs associated with median neuropathy at the carpal tunnel. Most CTS is related to idiopathic compression of the median nerve as it travels through the wrist at the carpal tunnel (IMNCT). Idiopathic means that there is no other disease process contributing to pressure on the nerve. As with most structural issues, it occurs in both hands, and the strongest risk factor is genetics.Other conditions can cause CTS such as wrist fracture or rheumatoid arthritis. After fracture, swelling, bleeding, and deformity compress the median nerve. With rheumatoid arthritis, the enlarged synovial lining of the tendons causes compression.
The main symptoms are numbness and tingling in the thumb, index finger, middle finger and the thumb side of the ring finger. People often report pain, but pain without tingling is not characteristic of IMNCT. Rather, the numbness can be so intense that it is described as painful.
Symptoms are typically most troublesome at night. Untreated, and over years to decades, IMNCT causes loss of sensibility and weakness and shrinkage (atrophy) of the muscles at the base of the thumb.
Work-related factors such as vibration, wrist extension or flexion, hand force, and repetition increase the risk of developing CTS. The only certain risk factor for IMNCT is genetics. All other risk factors are open to debate. It is important to consider IMNCT separately from CTS in diseases such as rheumatoid arthritis.Diagnosis of IMNCT can be made with a high probability based on characteristic symptoms and signs. IMNCT can be measured with electrodiagnostic tests.People wake less often at night if they wear a wrist splint. Injection of corticosteroids may or may not alleviate better than simulated (placebo) injections. There is no evidence that corticosteroid injection alters the natural history of the disease, which seems to be a gradual progression of neuropathy.
Surgery to cut the transverse carpal ligament is the only known disease modifying treatment.

Anatomy
The carpal tunnel is an anatomical compartment located at the base of the palm. Nine flexor tendons and the median nerve pass through the carpal tunnel that is surrounded on three sides by the carpal bones that form an arch. The median nerve provides feeling or sensation to the thumb, index finger, long finger, and half of the ring finger. At the level of the wrist, the median nerve supplies the muscles at the base of the thumb that allow it to abduct, move away from the other four fingers, as well as move out of the plane of the palm. The carpal tunnel is located at the middle third of the base of the palm, bounded by the bony prominence of the scaphoid tubercle and trapezium at the base of the thumb, and the hamate hook that can be palpated along the axis of the ring finger. From the anatomical position, the carpal tunnel is bordered on the anterior surface by the transverse carpal ligament, also known as the flexor retinaculum. The flexor retinaculum is a strong, fibrous band that attaches to the pisiform and the hamulus of the hamate. The proximal boundary is the distal wrist skin crease, and the distal boundary is approximated by a line known as Kaplans cardinal line. This line uses surface landmarks, and is drawn between the apex of the skin fold between the thumb and index finger to the palpated hamate hook.

Pathophysiology
The median nerve can be compressed by a decrease in the size of the canal, an increase in the size of the contents (such as the swelling of tissue around the flexor tendons), or both. When the pressure builds up inside the tunnel, it damages the median nerve (median neuropathy).
As the median neuropathy gets worse, there is loss of sensibility in the thumb, index, middle, and thumb side of the ring finger. As the neuropathy progresses, there may be first weakness, then to atrophy of the muscles of thenar eminence (the flexor pollicis brevis, opponens pollicis, and abductor pollicis brevis). The sensibility of the palm remains normal because the superficial sensory branch of the median nerve branches proximal to the TCL and travels superficial to it.The role of nerve adherence is speculative.

Epidemiology
IMNCT is estimated to affect one out of ten people during their lifetime and is the most common nerve compression syndrome. There is notable variation in such estimates based on how one defines the problem, in particular whether one studies people presenting with symptoms vs. measurable median neuropathy (IMNCT) whether or not people are seeking care. It accounts for about 90% of all nerve compression syndromes. The best data regarding IMNCT and CTS comes from population-based studies, which demonstrate no relationship to gender, and increasing prevalence (accumulation) with age.

Symptoms
The characteristic symptom of CTS is numbness, tingling, or burning sensations in the thumb, index, middle, and radial half of the ring finger. These areas process sensation through the median nerve. Numbness or tingling is usually worse with sleep. People tend to sleep with their wrists flexed, which increases pressure on the nerve. Ache and discomfort may be reported in the forearm or even the upper arm, but its relationship to IMNCT is uncertain. Symptoms that are not characteristic of CTS include pain in the wrists or hands, loss of grip strength, minor loss of sleep, and loss of manual dexterity.Median nerve symptoms may arise from compression at the level of the thoracic outlet or the area where the median nerve passes between the two heads of the pronator teres in the forearm, although this is debated.

Signs
Severe IMNCT is associated with measurable loss of sensibility.  Diminished threshold sensibility (the ability to distinguish different amounts of pressure) can be measured using Semmes-Weinstein monofilament testing. Diminished discriminant sensibility can be measured by testing two-point discrimination: the number of millimeters two points of contact need to be separated before you can distinguish them.A person with idiopathic median neuropathy at the carpal tunnel will not have any sensory loss over the thenar eminence (bulge of muscles in the palm of hand and at the base of the thumb). This is because the palmar branch of the median nerve, which innervates that area of the palm, separates from the median nerve and passes over the carpal tunnel.Severe IMNCT is also associated with weakness and atrophy of the muscles at the base of the thumb.  People may lose the ability to palmarly abduct the thumb. IMNCT can be detected on examination using one of several maneuvers to provoke paresthesia (a sensation of tingling or "pins and needles" in the median nerve distribution).  These so-called provocative signs include:

Phalens maneuver. Performed by fully flexing the wrist, then holding this position and awaiting symptoms. A positive test is one that results in paresthesia in the median nerve distribution within sixty seconds.
Tinels sign is performed by lightly tapping the median nerve just proximal to flexor retinaculum to elicit paresthesia.
Durkan test, carpal compression test, or applying firm pressure to the palm over the nerve for up to 30 seconds to elicit paresthesia.
Hand elevation test The hand elevation test is performed by lifting both hands above the head. Paresthesia in the median nerve distribution within 2 minutes is considered positive.Diagnostic performance characteristics such as sensitivity and specificity are reported, but difficult to interpret because of the lack of a consensus reference standard for CTS or IMNCT.

Causes
Idiopathic Median Neuropathy at the Carpal Tunnel
Genetic factors are believed to be the most important determinants of who develops carpal tunnel syndrome due to IMNCT. In other words, your wrist structure seems programmed at birth to develop IMNCT later in life. A genome-wide association study (GWAS) of carpal tunnel syndrome identified 16 genomic loci significantly associated with the disease, including several loci previously known to be associated with human height.Factors that may contribute to symptoms, but have not been experimentally associated with neuropathy include obesity, and Diabetes mellitus . One case-control study noted that individuals classified as obese (BMI > 29) are 2.5 times more likely than slender individuals (BMI < 20) to be diagnosed with CTS. Its not clear whether this association is due to an alteration of pathophysiology, a variation in symptoms, or a variation in care-seeking.

Discrete Pathophysiology and Carpal Tunnel Syndrome
Hereditary neuropathy with susceptibility to pressure palsies is a genetic condition that appears to increase the probability of developing MNCT. Heterozygous mutations in the gene SH3TC2, associated with Charcot-Marie-Tooth, may confer susceptibility to neuropathy, including CTS.Association between common benign tumors such as lipomas, ganglion, and vascular malformation should be handled with care. Such tumors are very common and overlap with IMNCT is more likely than pressure on the median nerve. Similarly, the degree to which transthyretin amyloidosis-associated polyneuropathy and carpal tunnel syndrome is under investigation. Prior carpal tunnel release is often noted in individuals who later present with transthyretin amyloid-associated cardiomyopathy. There is consideration that bilateral carpal tunnel syndrome could be a reason to consider amyloidosis, timely diagnosis of which could improve heart health. Amyloidosis is rare, even among people with carpal tunnel syndrome (0.55% incidence within 10 years of carpal tunnel release). In the absence of other factors associated with a notable probability of amyloidosis, its not clear that biopsy at the time of carpal tunnel release has a suitable balance between potential harms and potential benefits.Other specific pathophysiologies that can cause median neuropathy via pressure include:

Rheumatoid arthritis and other diseases that cause inflammation of the flexor tendons.
With severe untreated hypothyroidism, generalized myxedema causes deposition of mucopolysaccharides within both the perineurium of the median nerve, as well as the tendons passing through the carpal tunnel. Association of CTS and IMNCT with lesser degrees of hypothyroidism is questioned.
Pregnancy may bring out symptoms in genetically predisposed individuals.  Perhaps the changes in hormones and fluid increase pressure temporarily in the carpal tunnel. High progesterone levels and water retention may increase the size of  the synovium.
Bleeding and swelling from a fracture or dislocation. This is referred to as acute carpal tunnel syndrome.
Acromegaly causes excessive secretion of growth hormones. This causes the soft tissues and bones around the carpal tunnel to grow and compress the median nerve.Other considerations

Double-crush syndrome is a debated hypothesis that compression or irritation of nerve branches contributing to the median nerve in the neck, or anywhere above the wrist, increases sensitivity of the nerve to compression in the wrist. There is little evidence to support this theory and some concern that it may be used to justify more surgery.

Median Neuropathy and Activity
Work-related factors that increase risk of CTS include vibration (5.4 effect ratio), hand force (4.2), and repetition (2.3). Exposure to wrist extension or flexion at work increases the risk of CTS by two times. The balance of evidence suggests that keyboard and computer use does not cause CTS.The international debate regarding the relationship between CTS and repetitive hand use (at work in particular) is ongoing. The Occupational Safety and Health Administration (OSHA) has adopted rules and regulations regarding so-called "cumulative trauma disorders" based concerns regarding potential harm from exposure to repetitive tasks, force, posture, and vibration.A review of available scientific data by the National Institute for Occupational Safety and Health (NIOSH) indicated that job tasks that involve highly repetitive manual acts or specific wrist postures were associated with symptoms of CTS, but there was not a clear distinction of paresthesia (appropriate) from pain (inappropriate) and causation was not established. The distinction from work-related arm pains that are not carpal tunnel syndrome was unclear. It is proposed that repetitive use of the arm can affect the biomechanics of the upper limb or cause damage to tissues. It is proposed that postural and spinal assessment along with ergonomic assessments should be considered, based on observation that addressing these factors has been found to improve comfort in some studies although experimental data are lacking and the perceived benefits may not be specific to those interventions. A 2010 survey by NIOSH showed that 2/3 of the 5 million carpal tunnel diagnosed in the US that year were related to work. Women are more likely to be diagnosed with work-related carpal tunnel syndrome than men.

Associated conditions
A variety of patient factors can lead to CTS, including heredity, size of the carpal tunnel, associated local and systematic diseases, and certain habits. Non-traumatic causes generally happen over a period of time, and are not triggered by one certain event. Many of these factors are manifestations of physiologic aging.

Diagnosis
There is no consensus reference standard for the diagnosis of carpal tunnel syndrome. A combination of characteristic symptoms (how it feels) and signs (what the clinician finds on exam) are associated with a high probability of IMNCT without electrophysiological testing.
Electrodiagnostic testing (electromyography and nerve conduction velocity) can objectively measure and verify median neuropathy.Ultrasound can image and measure the cross sectional diameter of the median nerve, which has some correlation with idiopathic median neuropathy at the carpal tunnel (IMNCT). The role of ultrasound in diagnosis--just as for electrodiagnostic testing--is a matter of debate. EDX cannot fully exclude the diagnosis of CTS due to the lack of sensitivity. A joint report published by the American Association of Neuromuscular & Electrodiagnostic Medicine (AANEM), the American Academy of Physical Medicine and Rehabilitation (AAPM&R), and the American Academy of Neurology defines practice parameters, standards, and guidelines for EDX studies of CTS based on an extensive critical literature review. This joint review concluded median and sensory nerve conduction studies are valid and reproducible in a clinical laboratory setting and a clinical diagnosis of CTS can be made with a sensitivity greater than 85% and specificity greater than 95%. Given the key role of electrodiagnostic testing in the diagnosis of CTS, The AANEM has issued evidence-based practice guidelines, both for the diagnosis of carpal tunnel syndrome.
Electrodiagnostic testing (electromyography and nerve conduction velocity) can objectively verify the median nerve dysfunction. Normal nerve conduction studies, however, do not exclude the diagnosis of CTS. Clinical assessment by history taking and physical examination can support a diagnosis of CTS. If clinical suspicion of CTS is high, treatment should be initiated despite normal electrodiagnostic testing.
The role of confirmatory electrodiagnostic testing is debated. The goal of electrodiagnostic testing is to compare the speed of conduction in the median nerve with conduction in other nerves supplying the hand. When the median nerve is compressed, as in IMNCT, it will conduct more slowly than normal and more slowly than other nerves. Compression results in damage to the myelin sheath and manifests as delayed latencies and slowed conduction velocities. There are many electrodiagnostic tests used to make a diagnosis of CTS, but the most sensitive, specific, and reliable test is the Combined Sensory Index (also known as the Robinson index). Electrodiagnosis rests upon demonstrating impaired median nerve conduction across the carpal tunnel in context of normal conduction elsewhere. It is often stated that normal electrodiagnostic studies do not preclude the diagnosis of carpal tunnel syndrome. The rational for this is that a threshold of neuropathy must be reached before study results become abnormal and also that threshold values for abnormality vary. Others contend that idiopathic median neuropathy at the carpal tunnel with normal electrodiagnostic tests would represent very, very mild neuropathy that would be best managed as a normal median nerve. Even more important, notable symptoms with mild disease is strongly associated with unhelpful thoughts and symptoms of worry and despair. Notable CTS with unmeasurable IMNCT should remind clinicians to always consider the whole person, including their mindset and circumstances, in strategies to help people get and stay healthy.

Imaging
The role of MRI or ultrasound imaging in the diagnosis of idiopathic median neuropathy at the carpal tunnel (IMNCT) is unclear. Their routine use is not recommended. MRI has high sensitivity but low specificity for IMNCT. High signal intensity may suggest accumulation of axonal transportation, myelin sheath degeneration or oedema.

Differential diagnosis
There are few disorders on the differential diagnosis for carpal tunnel syndrome. Cervical radiculopathy can also cause paresthesia abnormal sensibility in the hands and wrist. The distribution usually follows the nerve root, and the paresthesia may be provoked by neck movement. Electromyography and imaging of the cervical spine can help to differentiate cervical radiculopathy from carpal tunnel syndrome if the diagnosis is unclear. Carpal tunnel syndrome is sometimes applied as a label to anyone with pain, numbness, swelling, or burning in the radial side of the hands or wrists. When pain is the primary symptom, carpal tunnel syndrome is unlikely to be the source of the symptoms.When the symptoms and signs point to atrophy and muscle weakness more than numbness, consider neurodegenerative disorders such as Amyotrophic Lateral Sclerosis or Charcot-Marie Tooth.

Prevention
There is little or no data to support the concept that activity adjustment prevents carpal tunnel syndrome. The evidence for wrist rest is debated. There is also little research supporting that ergonomics is related to carpal tunnel syndrome. Due to risk factors for hand and wrist dysfunction being multifactorial and very complex it is difficult to assess the true physical factors of carpal tunnel syndrome.Biological factors such as genetic predisposition and anthropometric features are more strongly associated with idiopathic carpal tunnel syndrome than occupational/environmental factors such as hand use.

Treatment
CTS related to another pathophysiology is addressed by treating that pathology. For instance, disease-modifying medications for rheumatoid arthritis or surgery for traumatic acute carpal tunnel syndrome.Generally accepted treatments include: physiotherapy, steroids either orally or injected locally, splinting, and surgical release of the transverse carpal ligament. Limited evidence suggests that gabapentin is no more effective than placebo for CTS treatment. There is insufficient evidence to recommend therapeutic ultrasound, yoga, acupuncture, low level laser therapy, vitamin B6, myofascial release, and any form of stretch or exercise. Change in activity may include avoiding activities that worsen symptoms.The American Academy of Orthopedic Surgeons recommends proceeding conservatively with a course of nonsurgical therapies tried before release surgery is considered. A different treatment should be tried if the current treatment fails to resolve the symptoms within 2 to 7 weeks. Early surgery with carpal tunnel release is indicated where there is evidence of median nerve denervation or a person elects to proceed directly to surgical treatment. Recommendations may differ when carpal tunnel syndrome is found in association with the following conditions: diabetes mellitus, coexistent cervical radiculopathy, hypothyroidism, polyneuropathy, pregnancy, rheumatoid arthritis, and carpal tunnel syndrome in the workplace.

Splint Immobilizations
The importance of wrist braces and splints in the carpal tunnel syndrome therapy is known, but many people are unwilling to use braces. In 1993, The American Academy of Neurology recommended a non-invasive treatment for the CTS at the beginning (except for sensitive or motor deficit or grave report at EMG/ENG): a therapy using splints was indicated for light and moderate pathology. Current recommendations generally dont suggest immobilizing braces, but instead activity modification and non-steroidal anti-inflammatory drugs as initial therapy, followed by more aggressive options or specialist referral if symptoms do not improve.Many health professionals suggest that, for the best results, one should wear braces at night. When possible, braces can be worn during the activity primarily causing stress on the wrists. The brace should not generally be used during the day as wrist activity is needed to keep the wrist from becoming stiff and to prevent muscles from weakening.

Corticosteroids
Corticosteroid injections may provide temporary alleviation of symptoms although they are not clearly better than placebo. This form of treatment is thought to reduce discomfort in those with CTS due to its ability to decrease median nerve swelling. The use of ultrasound while performing the injection is more expensive but leads to faster resolution of CTS symptoms. The injections are done under local anesthesia. This treatment is not appropriate for extended periods, however. In general, local steroid injections are only used until more definitive treatment options can be used. Corticosteroid injections do not appear to slow disease progression.

Surgery
Release of the transverse carpal ligament is known as "carpal tunnel release" surgery. It is recommended when there is static (constant, not just intermittent) numbness, muscle weakness, or atrophy, and when night-splinting or other palliative interventions no longer alleviate intermittent symptoms. The surgery may be done with local or regional anesthesia with or without sedation, or under general anesthesia. In general, milder cases can be controlled for months to years, but severe cases are unrelenting symptomatically and are likely to result in surgical treatment.Surgery is more beneficial in the short term to alleviate symptoms (up to six months) than wearing an orthosis for a minimum of six weeks. However, surgery and wearing a brace resulted in similar symptom relief in the long term (12–18 month outcomes).

Physical therapy
An evidence-based guideline produced by the American Academy of Orthopedic Surgeons assigned various grades of recommendation to physical therapy and other nonsurgical treatments. One of the primary issues with physiotherapy is that it attempts to reverse (often) years of pathology inside the carpal tunnel. Self-myofascial ligament stretching can be an easy, do-at-home, treatment to help alleviate symptoms. Self-myofascial stretching involves stretching the carpal ligament for 30 seconds, 6 times a day for about 6 weeks. Many patients report improvements in symptoms such as pain, function, and nerve conduction. Practitioners caution that any physiotherapy such as myofascial release may take weeks of persistent application to effectively manage carpal tunnel syndrome.Again, some claim that pro-active ways to reduce stress on the wrists, which alleviates wrist pain and strain, involve adopting a more ergonomic work and life environment. For example, some have claimed that switching from a QWERTY computer keyboard layout to a more optimised ergonomic layout such as Dvorak was commonly cited as beneficial in early CTS studies; however, some meta-analyses of these studies claim that the evidence that they present is limited.Tendon and nerve gliding exercises appear to be useful in carpal tunnel syndrome.A randomized control trial published in 2017 sought to examine the efficacy of manual therapy techniques for the treatment of carpal tunnel syndrome. The study included a total of 140 individuals diagnosed with carpal tunnel syndrome and the patients were divided into two groups. One group received treatment that consisted of manual therapy. Manual therapy included the incorporation of specified neurodynamic techniques, functional massage, and carpal bone mobilizations. Another group only received treatment through electrophysical modalities. The duration of the study was over the course of 20 physical therapy sessions for both groups. Results of this study showed that the group being treated through manual techniques and mobilizations yielded a 290% reduction in overall pain when compared to reports of pain prior to conducting the study. Total function improved by 47%. Conversely, the group being treated with electrophysical modalities reported a 47% reduction in overall pain with a 9% increase in function.

Alternative medicine
A 2018 Cochrane review on acupuncture and related interventions for the treatment of carpal tunnel syndrome concluded that, "Acupuncture and laser acupuncture may have little or no effect in the short term on symptoms of carpal tunnel syndrome (CTS) in comparison with placebo or sham acupuncture." It was also noted that all studies had an unclear or high overall risk of bias and that all evidence was of low or very low quality.

Prognosis
Most people relieved of their carpal tunnel symptoms with conservative or surgical management find minimal residual or "nerve damage". Long-term chronic carpal tunnel syndrome (typically seen in the elderly) can result in permanent "nerve damage", i.e. irreversible numbness, muscle wasting, and weakness. Those that undergo a carpal tunnel release are nearly twice as likely as those not having surgery to develop trigger thumb in the months following the procedure.While outcomes are generally good, certain factors can contribute to poorer results that have little to do with nerves, anatomy, or surgery type. One study showed that mental status parameters or alcohol use yields much poorer overall results of treatment.Recurrence of carpal tunnel syndrome after successful surgery is rare.

History
The condition known as carpal tunnel syndrome had major appearances throughout the years but it was most commonly heard of in the years following World War II. Individuals who had had this condition have been depicted in surgical literature for the mid-19th century. In 1854, Sir James Paget was the first to report median nerve compression at the wrist in two cases.The first to notice the association between the carpal ligament pathology and median nerve compression appear to have been Pierre Marie and Charles Foix in 1913. They described the results of a postmortem of an 80-year-old man with bilateral carpal tunnel syndrome. They suggested that division of the carpal ligament would be curative in such cases. Putman had previously described a series of 37 patients and suggested a vasomotor origin. The association between the thenar muscle atrophy and compression was noted in 1914. The name "carpal tunnel syndrome" appears to have been coined by Moersch in 1938.In the early 20th century there were various cases of median nerve compression underneath the transverse carpal ligament. Physician George S. Phalen of the Cleveland Clinic identified the pathology after working with a group of patients in the 1950s and 1960s.
TreatmentPaget described two cases of carpal tunnel syndrome. The first was due to an injury where a cord had been wrapped around a mans wrist </s>