<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 Non-alcoholic fatty liver disease and can you explain it in depth? [/INST] Non-alcoholic fatty liver disease (NAFLD), also known as metabolic (dysfunction) associated fatty liver disease (MAFLD), is excessive fat build-up in the liver without another clear cause such as alcohol use. There are two types; non-alcoholic fatty liver (NAFL) and non-alcoholic steatohepatitis (NASH), with the latter also including liver inflammation. Non-alcoholic fatty liver is less dangerous than NASH and usually does not progress to NASH or liver cirrhosis. When NAFL does progress to NASH, it may eventually lead to complications such as cirrhosis, liver cancer, liver failure, or cardiovascular disease.Obesity and type 2 diabetes are strong risk factors for NAFLD. Other risks include being overweight, metabolic syndrome (defined as at least three of the five following medical conditions: abdominal obesity, high blood pressure, high blood sugar, high serum triglycerides, and low serum HDL cholesterol), a diet high in fructose, and older age. NAFLD and alcoholic liver disease are types of fatty liver disease. Obtaining a sample of the liver after excluding other potential causes of fatty liver can confirm the diagnosis.Treatment for NAFLD is weight loss by dietary changes and exercise. There is tentative evidence for pioglitazone and vitamin E; bariatric surgery can improve or resolve severe cases. Those with NASH have a 2.6% increased risk of dying per year.NAFLD is the most common liver disorder worldwide and is present in approximately 25% of the worlds population. It is also very common in developed nations, such as the United States, and affected about 75 to 100 million Americans in 2017. Over 90% of obese, 60% of diabetic, and up to 20% of normal-weight people develop it. NAFLD is the leading cause of chronic liver disease and the second most common reason for liver transplantation in the US and Europe as of 2017. NAFLD affects about 20 to 25% of people in Europe. In the United States, estimates suggest between 30 and 40% of adults have NAFLD, and about 3 to 12% of adults have NASH. The annual economic burden was approximately US$103 billion in the US in 2016.

Definition
An abnormal accumulation of fat in the liver in the absence of secondary causes of fatty liver, such as significant alcohol use, viral hepatitis, or medications that can induce fatty liver characterizes non-alcoholic fatty liver disease (NAFLD). The term NAFLD encompasses a continuum of liver abnormalities, from non-alcoholic fatty liver (NAFL, simple steatosis) to non-alcoholic steatohepatitis (NASH). These diseases begin with fatty accumulation in the liver (hepatic steatosis). A liver can remain fatty without disturbing liver function (NAFL), but by various mechanisms and possible insults to the liver, it may also progress into non-alcoholic steatohepatitis (NASH), a state in which steatosis is combined with inflammation and sometimes fibrosis (steatohepatitis). NASH can then lead to complications such as cirrhosis and hepatocellular carcinoma.A new name, metabolic dysfunction associated fatty liver disease, was proposed after 70% of a panel of experts expressed support for this name.

Signs and symptoms
People with NAFLD often have no noticeable symptoms, and NAFLD is often only detected during routine blood tests or unrelated abdominal imaging or liver biopsy. In some cases, NAFLD can cause symptoms related to liver dysfunction such as fatigue, malaise, and dull right-upper-quadrant abdominal discomfort. Mild yellow discoloration of the skin may occur, although this is rare. NASH can severely impair liver function, leading to cirrhosis, liver failure, and liver cancer.

Comorbidities
NAFLD is strongly associated with or caused by type 2 diabetes, insulin resistance, and metabolic syndrome (defined as at least three of the five following medical conditions: abdominal obesity, high blood pressure, high blood sugar, high serum triglycerides, and low serum high-density lipoprotein). It is also associated with hormonal disorders (panhypopituitarism, hypothyroidism, hypogonadism, polycystic ovary syndrome), persistently elevated transaminases, increasing age and hypoxia caused by obstructive sleep apnea, with some of these conditions predicting disease progression.The majority of normal-weight people affected by NAFLD ("lean NAFLD") have impaired insulin sensitivity, are sedentary, and have increased cardiovascular disease risk and increased liver lipid levels. These are the consequences of a decreased capacity for storing fat and reduced mitochondrial function in adipose tissue and increased hepatic de novo lipogenesis. A recent systematic review has reported an increased risk of severe COVID-19 infection in NAFLD patients; however, no difference in mortality was observed between NAFLD and non-NAFLD patients.

Risk factors
Genetics
Two-thirds of families with a history of diabetes type 2 report more than one family member having NAFLD. There is a higher risk of fibrosis for family members where someone was diagnosed with NASH. Asian populations are more susceptible to metabolic syndrome and NAFLD than their western counterparts. Hispanic persons have a higher prevalence of NAFLD than white individuals, whereas the lowest prevalence is observed in black individuals. NAFLD is twice as prevalent in men compared to women, which might be explained by lower levels of estrogen in men.Genetic variations in two genes are associated with NAFLD: non-synonymous single-nucleotide polymorphisms (SNPs) in PNPLA3 and TM6SF2. Both correlate with NAFLD presence and severity, but their roles for diagnosis remain unclear. Although NAFLD has a genetic component, the American Association for the Study of Liver Diseases (AASLD) does not recommend screening family members as there is not enough confirmation of heritability, although there is some evidence from familial aggregation and twin studies.

Diet
According to the Asia-Pacific Working Group (APWG) on NAFLD, overnutrition is a major factor of NAFLD and NASH, particularly for lean NAFLD. Diet composition and quantity, in particular omega-6 fatty acid and fructose, have important roles in disease progression from NAFL to NASH and fibrosis. Choline deficiency can lead to the development of NAFLD.

Lifestyle
Habitual snoring may be a risk factor for NAFLD, even after accounting for established risk factors in individuals. Severe cases of snoring lead to airway blockage or difficulty breathing when sleeping, and usually signals the presence of obstructive sleep apnea (OSAS), a much more serious breathing condition. Blockage or narrowing of the airways, even temporarily, can cause the body to experience lowered oxygen levels in the blood, and these conditions of hypoxia are recurring in those with obstructive sleep apnea (OSAS). Constant hypoxia may cause a variety of changes within the body, such as tissue inflammation, increased insulin resistance, and liver injury. A prospective cohort study found the association between habitual snoring and NAFLD development to be significant, and the trend was noted to be most prominent in lean individuals.

Pathophysiology
The primary characteristic of NAFLD is the accumulation of lipids in the liver, largely in the form of triglycerides. However, the mechanisms by which triglycerides accumulate and the reasons that accumulation can lead to liver dysfunction are complex and incompletely understood. NAFLD can include steatosis along with varied signs of liver injury: either lobular or portal inflammation (a form of liver injury) or ballooning degeneration. Similarly, NASH can include histological features such as portal inflammation, polymorphonuclear cell infiltrates, Mallory bodies, apoptotic bodies, clear vacuolated nuclei, microvesicular steatosis, megamitochondria, and perisinusoidal fibrosis. NASH increases hepatocyte death via apoptosis or necroptosis is increased in NASH compared with simple steatosis, and inflammation is a hallmark of NASH.One debated mechanism proposes that hepatic steatosis progresses to steatosis with inflammation following some further injury, or second hit. Oxidative stress, hormonal imbalances, and mitochondrial abnormalities are potential causes of this "second hit" phenomenon. A further nutrigenomics model named multiple hit extends the second hit model, suggesting that multiple disease biomarkers and factors such as genes and nutrition influence NAFLD and NASH progression. This model attempts to use these factors to predict the impact of lifestyle changes and genetics for the evolution of the NAFLD pathology. Many researchers describe NAFLD as a multisystem disease, as it impacts and is influenced by organs and regulatory pathways other than the liver.The accumulation of senescent cells in the liver is seen in persons with NAFLD. In mice, liver senescent hepatocytes result in increased liver fat deposition. Treatment of NAFLD mice with senolytic agents has been shown to reduce hepatic steatosis.Based on gene knockout studies in murine models, it has been suggested that, among many other pathogenic factors, TGF beta signals may be crucially involved in promoting the progression of NASH.

Fructose consumption
Non-alcoholic and alcoholic fatty liver disease share similar histological features, which suggests that they might share common pathogenic pathways. Fructose can cause liver inflammation and addiction similarly to ethanol by using similar metabolic pathways, unlike glucose. Therefore, some researchers argue that non-alcoholic and alcoholic fatty liver diseases are more alike than previously thought. Furthermore, high fructose consumption promotes fat accumulation in the liver by stimulating de novo lipogenesis in the liver and reducing the beta-oxidation of fat. Unlike the sugar glucose, the enzyme fructokinase rapidly metabolizes fructose. This leads to a decreased level of intracellular adenosine triphosphate (ATP). The decrease in ATP increases oxidative stress and impairments in proper protein synthesis and mitochondrial function in the liver.

Insulin resistance
Insulin resistance contributes to the accumulation of toxic fat in the liver in several ways. First, it promotes the release of free fatty acids (FFAs) from adipose tissue into the blood. Typically, adipose tissue stores lipids in the form of triglycerides, slowly releasing them into the bloodstream when insulin is low. In insulin-resistant adipose tissue, such as in people with obesity and type 2 diabetes, more triglycerides are broken down into FFAs and released into the bloodstream, promoting uptake by the liver. Second, insulin promotes the production of new FFAs in the liver via de novo lipogenesis; this production of liver fats continues to be stimulated by insulin, even when other tissues are insulin-resistant. These FFAs are combined back into triglycerides in the liver, forming the major constituent of the accumulated fat in the liver. The three sources of free fatty acids that contribute to liver triglyceride accumulation include FFAs circulating in the bloodstream (59%), FFAs derived from carbohydrates such as fructose and glucose (26%), and diet (14%). Despite the accumulation of triglycerides in the liver, they are not directly toxic to liver tissue. Instead, alteration of the profile of the other lipid subtypes present in the liver, such as diacylglycerols, phospholipids, ceramides, and free cholesterol, have a more significant role in the pathogenesis of NAFLD.Once NAFLD progresses in severity to the point of NASH, this promotes further insulin resistance in the adipose tissue and liver, which results in a harmful cycle of insulin resistance, liver fat accumulation, and inflammation. Adipose tissue dysfunction also decreases secretion of the insulin-sensitizing adipokine adiponectin in people with NAFLD. Adiponectin has several properties that protect the liver. These properties include improved liver fat metabolism, decreased de novo lipogenesis, decreased glucose production in the liver, anti-inflammatory properties, and anti-fibrotic properties. Skeletal muscle insulin resistance may also play a role in NAFLD. Insulin-resistant skeletal muscle is not as efficient at taking up glucose from the bloodstream after a meal. This inefficient glucose uptake promotes the redistribution of consumed carbohydrates from glucose destined for use in glycogen stores in the skeletal muscles to being used as a substrate for de novo lipogenesis in the liver.

Dysbiosis
Disruptions in the intestinal microbiota seem to influence NAFLD risk in several ways. People with NASH can have elevated levels of blood ethanol and Pseudomonadota (which produce alcohol), with dysbiosis proposed as a mechanism for this elevation. Alterations in the composition of the intestinal microbiota may influence NAFLD risk in several ways. These changes appear to increase the permeability of intestinal tissue, thereby facilitating increased liver exposure to harmful substances (e.g., translocated bacteria, bacterial toxins, and inflammatory chemical signals). The increased transport of these harmful substances to the liver promotes liver inflammation, enhances nutrient and calorie absorption, and alters choline metabolism. Higher levels of intestinal bacteria that produce butyrate may be protective.Excessive macronutrient intake contributes to gut inflammation and perturbation of homeostasis, and micronutrients may also be involved. In addition to reducing weight and risk factors, lifestyle changes may prompt positive changes in the gut microbiota. In particular, diet diversity may play a role that was overlooked in animal studies, since they often compare a Western high-fat, low-diversity diet against a low-fat but higher-diversity chow. The health benefits after bariatric surgery may also involve changes in the gut microbiota by increasing gut permeability.

Diagnosis
NAFLD is defined by evidence of fatty liver without another factor that could explain the liver fat accumulation, such as excessive alcohol use (>21 standard drinks/week for men and >14 for women in the USA; >30 g daily for men and >20 g for women in UK and EU, >140 g/week for men and >70 g/week for women in Asia-Pacific and most NIH clinical studies), drug-induced steatosis, chronic hepatitis C, heredity or by deficiencies in parenteral nutrition such as choline and endocrine conditions. If any of these factors are observed, an investigation into alternative causes of fatty liver unrelated to NAFLD is recommended. A history of chronic alcohol usage is an important consideration.NAFLD comprises two histological categories: NAFL, and the more aggressive form NASH. The presence of at least 5% fatty liver is common to both NAFL and NASH, but the features of substantial lobular inflammation and hepatocyte injuries such as ballooning or Mallory hyaline only occur in NASH. The majority of NAFL cases show minimal or no inflammation. Pericentral and perisinusoidal fibrosis occur more often in adult-onset NASH, whereas portal fibrosis is more common in children with the disorder. NASH represents a more advanced stage of NAFL and is associated with poor outcomes such as cardiovascular events, cirrhosis, or hepatocellular carcinoma. ICD-11 does not use the term NAFL as it was deemed confusing with the family of disorders NAFLD. The preferred descriptions are instead: NAFLD without NASH or simple steatosis and "NASH". Also, the modifier with or without fibrosis or cirrhosis completes the diagnostic description.

Blood tests
Elevated liver enzymes are common. According to National Institute for Health and Care Excellence (NICE) guidelines, it is disadvised to test enzymes levels to rule out NAFLD, as they are often within the normal range even in advanced disease.Blood tests that are useful to confirm diagnosis or rule out others include erythrocyte sedimentation rate, glucose, albumin, and kidney function. Because the liver is important for making proteins used in blood clotting, coagulation-related studies are often carried out, especially the INR (international normalized ratio). In people with fatty liver with associated inflammatory injury (steatohepatitis) blood tests are usually used to rule out viral hepatitis (hepatitis A, B, C and herpesviruses such as Epstein–Barr virus or cytomegalovirus), rubella, and autoimmune diseases. Low thyroid activity is more prevalent in people with NASH, which would be detected by determining the thyroid-stimulating hormone. Some biomarker-based blood tests have been developed and may be useful for diagnosis.Although blood tests cannot diagnose NAFLD, circulating serum biomarkers of liver fibrosis can give moderate estimates in the diagnosis of liver fibrosis and cirrhosis. The ratio of the transaminase liver enzyme aspartate aminotransferase (AST) to platelets in the blood, known as the AST/platelet ratio index (APRI score), and Fibrotest are recommended as the preferred noninvasive tests for cirrhosis by the Asian-Pacific Association for Study of the Liver (APASL). Several other scores such as FIB-4 score and NAFLD fibrosis score can also reflect the burden of the fibrosis in the liver, and previous studies have confirmed that these score can predict future development of mortality and liver cancer.

Imaging
A liver ultrasound scan or magnetic resonance imaging (MRI) can diagnose steatosis, but not fibrosis and confirmation of early cirrhosis detection by ultrasound by other diagnostic methods is recommended. The European Association for the Study of the Liver (EASL) recommends screening for steatosis whenever NAFLD is suspected as this is a strong predictor of the disease evolution and predicts future type 2 diabetes, cardiovascular events, and hypertension. These non-invasive methods can be used for NAFLD screening but are not accepted as a substitute for liver biopsy in NAFLD nor NASH clinical trials, as only a liver biopsy can define liver pathology.Ultrasound presented average sensitivity and specificity for diagnosing the disease in children, while in the adult population, sensitivity and specificity were significantly higher. Proton density fat fraction magnetic resonance imaging has been increasingly used for the diagnosis of steatosis in pediatric patients. Elastography is an effective tool for staging liver fibrosis and discriminating NASH from NAFLD in children.CT scans and MRIs are more accurate in detecting cirrhosis than conventional ultrasound. Transient elastography is recommended for the initial assessment of liver fibrosis and cirrhosis and helps to predict complications and prognosis, but the interpretation of results is carefully weighed in the presence of limiting factors, such as steatosis, high BMI, lower degrees of hepatic fibrosis and narrow spaces between the ribs (intercostal spaces). However, transient elastography can fail for people with pre-hepatic portal hypertension. Transient elastography is not considered to be a replacement for liver biopsy.Magnetic resonance elastography (MRE) is an emerging method that can accurately assess hepatic fibrosis and is recommended by the APASL. MRE possesses a good sensitivity to quantify hepatic fat and excellent accuracy to detect fibrosis in NAFLD regardless of BMI and inflammation and is suggested as a more reliable alternative to diagnose NAFLD and its progression to NASH compared to ultrasound and blood tests.

Liver biopsy
A liver biopsy (tissue examination) is the only test widely accepted (gold standard) as definitively diagnosing and distinguishing NAFLD (including NAFL and NASH) from other forms of liver disease and can be used to assess the severity of the inflammation and resultant fibrosis. However, since most people affected by NAFLD are likely to be asymptomatic, liver biopsy presents too high a risk for routine diagnosis, so other methods are preferred, such as liver ultrasonography or liver MRI. For young people, guidelines recommend liver ultrasonography, but biopsy remains the best evidence. Liver biopsy is also the gold standard to detect hepatic fibrosis and assess its progression. Routine liver function blood tests are not sensitive enough to detect NAFLD, and biopsy is the only procedure that can reliably differentiate NAFL from NASH.There are several liver biopsy techniques available to obtain liver tissue. Percutaneous liver biopsy remains the most common practice. Biopsies can also be performed via the transvenous route, either during surgery or by laparoscopy, especially for people with contraindications to a percutaneous approach. The liver biopsy can also be image-guided, in real-time or not, which is recommended for some clinical situations such as people with known intra-hepatic lesions, previous intra-abdominal surgery who may have adhesions, a small liver that is difficult to percuss, obese people and people with evident ascites. Vital signs must be monitored frequently afterward (at least every 15 minutes in the hour following the biopsy).According to AASLD guidelines, a liver biopsy may be considered in people with NAFLD who are at increased risk of having steatohepatitis with or without advanced fibrosis, but only when all other competing chronic liver diseases are excluded (such as alcoholic liver disease). The presence of metabolic syndrome, NAFLD Fibrosis Score (FIB-4), or liver stiffness (as measured by Vibration-controlled transient elastography or MRE) can identify the individuals who are at higher risk of steatohepatitis or advanced fibrosis.The AASLD and ICD-11 consider that clinically useful pathology reporting distinguishes "between NAFL (steatosis), NAFL with inflammation and NASH (steatosis with lobular and portal inflammation and hepatocellular ballooning)" with the presence or absence of fibrosis being described and optionally comment on severity. The EASL recommends the Fatty Liver Inhibition of Progression (FLIP) algorithm to grade the ballooning and classify NAFLD-associated liver injury, and the use of the NAFLD Activity Score (NAS) to grade the severity of NASH rather than for its diagnosis. They also consider the steatosis, activity, and fibrosis (SAF) score to be an accurate and reproducible scoring system. The AASLD recommends the use of the NAS scoring system with or without the SAF score if deemed appropriate. The Asia-Pacific Working Group on NAFLD disadvises the use of NAS, as it is considered uninformative for NAFLD and inappropriate to diagnose NASH.For liver fibrosis assessment, percutaneous liver biopsy, with or without image guidance, is contraindicated in uncooperative people. Transjugular liver biopsy is indicated for any person with diffuse liver disease who needs a biopsy but has a contraindication to percutaneous biopsy or needs a hemodynamic evaluation for diagnostic purposes. A transvenous liver biopsy is recommended instead of a percutaneous approach in people with clinically evident ascites, although percutaneous biopsy is an acceptable alternative approach after the removal of ascites.

Management
NAFLD warrants treatment regardless of whether the affected person is overweight or not. NAFLD is a preventable cause of death. Guidelines are available from the American Association for the Study of Liver Diseases (AASLD), American Association of Clinical Endocrinologists (AACE) National Institute for Health and Care Excellence (NICE), the European Association for the Study of the Liver (EASL), and the Asia-Pacific Working Party on NAFLD.

Lifestyle
Weight loss is the most effective treatment for NAFLD. A loss of 4% to 10% body weight is recommended, with 10% to 40% weight loss completely reversing NASH without cirrhosis. A structured weight loss program helps people with NAFLD lose more weight compared with advice alone. This type of program also leads to improvements in NAFLD measured using blood tests, ultrasound, imaging, or liver biopsies. Although fibrosis improves with lifestyle interventions and weight loss, there is limited evidence for cirrhosis improvement.A combination of improved diet and exercise, rather than either alone, appears to best help manage NAFLD and reduce insulin resistance. Motivational support, such as with cognitive behavioral therapy, is helpful, as most people with NAFLD do not perceive their condition as a disease, and thus have a low motivation to change.Higher-intensity behavioral weight loss therapies (diet and exercise combined) may produce more weight loss than lower-intensity ones. Weight loss is associated with improvements in biomarkers, NAFLD grade, and reduced chances of NASH, but their impact on long-term health is yet unknown. A 2019 systematic review thus suggests a change of guidelines to recommend these therapies for NAFLD management.
As of 2021, there is limited evidence to indicate that lifestyle modifications and nutritional supplementation have an effect on mortality, liver cirrhosis, liver decompensation, liver transplantation, and hepatocellular carcinoma in people with nonalcohol-related fatty liver disease.

Diet
Treatment of NAFLD typically involves counseling to improve nutrition and calorie restriction. People with NAFLD can benefit from a moderate to low-carbohydrate diet and a low-fat diet. The Mediterranean diet also showed promising results in a 6-week study with a reduction of NASH induced inflammation and fibrosis, independently from weight loss. Tentative evidence supports dietary interventions in individuals with fatty liver who are not overweight.The EASL recommends energy restriction of 500–1000 kcal per week less than the normal daily diet, a target of 7–10% weight loss for obese/overweight NAFLD, a low- to moderate-fat, and moderate- to high-carbohydrate diet, or a low-carbohydrate ketogenic or high-protein diet such as the Mediterranean diet, and avoiding all beverages and food containing fructose.Alcohol is an aggravating factor, and the AASLD recommends that people with NAFLD or NASH avoid alcohol consumption. The EASL allows alcohol consumption below 30g/day for men and 20g/day for women. The role of coffee consumption for NAFLD treatment is unclear though some studies indicate that regular coffee consumption may have protective effects.Herbal compounds such as silymarin (a milk thistle seed extract), curcumin, a turmeric extract, and green tea appear to improve NAFLD biomarkers and reduce the grade of NAFLD. Studies suggest an association between microscopic organisms that inhabit the gut (microbiota) and NAFLD. Reviews reported the use of probiotics and synbiotics (combinations of probiotics and prebiotics) were associated with improvement in liver-specific markers of hepatic inflammation, measurements of liver stiffness, and steatosis in persons with NAFLD.

Vitamin E
Vitamin E does not improve established liver fibrosis in those with NAFLD but seems to improve certain markers of liver function and reduces inflammation and fattiness of the liver in some people with NAFLD. The Asia-Pacific Work Group advises that Vitamin E may improve liver condition and aminotransferase levels, but only in adults without diabetes or cirrhosis who have NASH. The NICE guidelines recommend Vitamin E as an option for children and adults with NAFLD with advanced liver fibrosis, regardless of whether the person has diabetes mellitus.

Red Yeast Rice
The genum of mold Aspergillus and/or Monascus are used in the fabrication of Red yeast rice to stimulate the production of lovastatin, where lovastatin and other statins inhibit the total cholesterol and LDL cholesterol synthesis by blocking action of the enzyme HMG-CoA reductase.
The safety of red yeast rice has not yet been established as studies found that some commercial supplements contain high levels of toxin citrinin.There are reports in the literature of muscle myopathy and liver damage resulting from red yeast rice usage.

Essential phospholipids
Research shows that essential phospholipids from soy lecithin (Latin: phospholipida sojae praeparata), polyenylphosphatidylcholine being the active component, has a well-established mode of action, therapeutic effectiveness, and lack of toxicity, which ensures clinically relevant efficacy-to-safety ratio. It influences membrane- dependent cellular functions and shows anti-inflammatory, antioxidant, antifibrogenic, anti apoptotic, membrane-protective, and lipid-regulating effects. Due to its positive effects on membrane composition and functions, it accelerates the improvement or normalization of subjective symptoms; pathological, clinical, and biochemical findings; hepatic imaging; and liver histology. It is justified to administer EPL together with other therapeutic measurements in the liver.The usual dosage for adults and children older than 12 years of age (and of at least 43 kg of weight) is 600 mg three times a day.

Coffee
Allegedly seems to inverse and prevent fatty liver disease.

Choline
Low choline intake is significantly associated with the increased prevalence of NAFLD.

Physical activity
Weight loss may improve NAFLD and is recommended particularly for obese or overweight people; similar physical activities and diets are advisable for overweight people with NAFLD as for other obese and overweight people. Although physical activity is less important for weight loss than dietary adaptations (to reduce caloric intake), the NICE advises physical activity to reduce liver fat even if there is no overall bodyweight reduction. Weight loss, through exercise or diet, is the most effective way to reduce liver fat and help NASH and fibrosis remission. Exercise alone can prevent or reduce hepatic steatosis, but it remains unknown whether it can improve all other aspects of the liver; hence a combined approach with diet and exercise is advised. Aerobic exercise may be more effective than resistance training, although there are contradictory results. Vigorous training is preferable to moderate training, as only the high-intensity exercise reduced the chances of NAFLD developing into NASH or advanced fibrosis. The EASL recommends between 150 and 200 min/week in 3 to 5 sessions of moderate-intensity aerobic physical activity or resistance training. Since both effectively reduce liver fat, a pragmatic approach to the choice of physical activity that accounts for the individuals preferences for what they can maintain in the long-term is preferred. Any engagement in physical activity or increase over previous levels is better than remaining sedentary.

Medication
Treatment with medications is primarily aimed at improving liver disease and is generally limited to those with biopsy-proven NASH and fibrosis.No medicines specifically for NAFLD or NASH had received approval, as of 2018, although anti-diabetic medications may help in liver fat loss. While many treatments appear to improve biochemical markers such as alanine transaminase levels, most do not reverse histological abnormalities or improve outcomes.Insulin sensitizers (metformin and thiazolidinediones, such as pioglitazone) and liraglutide are not specifically recommended for NAFLD as they do not directly improve the liver condition. They can be indicated for diabetic individuals, after a careful assessment of risks, to reduce insulin resistance and risks of complications. Indeed, the side effects associated with thiazolidinedione medications, which include osteopenia, increased fracture risk, fluid retention, congestive heart failure, bladder cancer, and long-term weight gain, have limited their adoption. Due to these side effects, the AASLD recommends the use of pioglitazone only for individuals with biopsy-proven NASH, and the Asia-Pacific Work Group recommends them only for individuals with NAFLD with known diabetic issues. However, the AASLD advises against the use of metformin as studies were inconclusive about the improvement of the livers histological condition. Although there was an improvement in insulin resistance and serum aminotransferases, this did not translate into NASH improvements. The NICE provides similar guidelines to the AASLD regarding pioglitazone and recommends it be administered in secondary care to adults with advanced liver fibrosis irrespective of whether or not they have diabetes.Statin medications appear to improve liver histology and markers of liver biochemistry in people with NAFLD. Since people with NAFLD are at a higher risk of cardiovascular disease, statin treatment is indicated. People with NAFLD are not at higher risk for serious liver injury from statins, according to AASLD and EASL. However, even if statins are safe to use in people with NASH cirrhosis, the AASLD suggests avoiding them in people with decompensated cirrhosis. Guidelines recommend statins to treat dyslipidemia for people with NAFLD. According to NICE guidelines, statins can continue unless liver enzyme levels double within three months of starting statins. Treatment with pentoxifylline is not recommended.As of 2018, neither the AASLD nor the Asia-Pacific Working Group recommends obeticholic acid or elafibranor due to inconsistent results for NASH treatment and concerns about safety.Omega-3 fatty acids may reduce liver fat and improve blood lipid profile but do not seem to improve liver histology (fibrosis, cirrhosis, cancer). The NICE does not recommend omega-3 fatty acid supplementation since randomized trials were inconclusive. Previous systematic reviews found that omega-3 fatty acid supplementation in those with NAFLD/NASH using doses of one  gram daily or more (median dose four  grams/day with median treatment duration six  months) has been associated with improvements in liver fat. According to AASLD guidelines, "omega-3 fatty acids should not be used as a specific treatment of NAFLD or NASH, but they may be considered to treat hypertriglyceridemia for patients with NAFLD".

Surgery
Bariatric surgery is an effective method for obese and diabetic individuals with NAFLD to induce weight loss and reduce or resolve NASH inflammation, including fibrosis, and improve longevity. For the AASLD, bariatric surgery can be considered only for NASH on a case-by-case basis by an experienced bariatric surgery program. Indeed, some individuals might develop new or worsened features of NAFLD.About 92% of people with NAFLD saw an improvement in steatosis and 70% a complete resolution after bariatric surgery.A preoperative diet such as a low-calorie diet or a very-low-calorie diet is usually recommended to reduce liver volume by 16–20%. Preoperative weight loss is the only factor associated with postoperative weight loss. Preoperative weight loss can reduce operative time and hospital stay, although there is insufficient evidence whether preoperative weight loss reduces long-term morbidity or complications. Weight loss and decreases in liver size may be independent of the amount of calorie restriction.The APWG on NAFLD recommends bariatric surgery as a treatment option for those with class II obesity (BMI >32.5 kg/m2 for Asians, 35 kg/m2 for Caucasians). They consider its effects on improving liver-related complications as unproven yet, but it effectively increases longevity by improving cardiovascular factors.Surgery carries more risks for individuals with NASH cirrhosis, with a review estimating overall morbidity to be 21%. For people with NAFLD who have undifferentiated cirrhosis, the APWG recommends an investigation to determine the cause of the cirrhosis as well as the persons liver function and whether they have portal hypertension.

Screening
Cardiovascular system screening is considered mandatory by the EASL, as NAFLD outcomes often result in cardiovascular complications, which can manifest as subclinical atherosclerosis, the cause of the majority of NAFLD-related deaths. People with NAFLD are at high risk for cardiovascular morbidity and mortality, and "aggressive modification of cardiovascular disease risk factors is warranted in all patients with NAFLD," according to AASLD.The AASLD further recommends for people with a cirrhotic NASH to be systematically screened for gastric and esophageal varices and liver cancer. They do not recommend routine liver biopsies and screening for liver cancer for non-cirrhotic people with NASH, but such screening sometimes occurs on a case-by-case basis.Also, people with NAFLD may be considered for screening for hepatocellular carcinoma (liver cancer) and gastroesophageal varices. The NICE advises regular screening of NAFLD for advanced liver fibrosis every three years to adults and every two years for children using the enhanced liver fibrosis (ELF) blood test. Follow-up is recommended for people with obesity and insulin resistance using the homeostasis model assessment of insulin resistance (HOMA-IR). People with NASH with fibrosis and hypertension merit closer monitoring as there is a higher risk of disease progression.

Transplantation
NAFLD is the second most common indication for liver transplantation in the US and Europe as of 2017. NAFLD/NASH is expected to become the leading cause of liver transplantation by 2020.For people with NASH and end-stage liver disease, liver failure, or liver cancer, liver transplantation is an accepted procedure according to the EASL. People with NASH cirrhosis NASH who are being considered for a liver transplant warrant systematic evaluation for cardiovascular diseases (whether the symptoms are apparent or not).The overall survival is comparable to transplantation following other diseases. People with NASH cirrhosis who undergo liver transplantation are more likely to die post-transplant because of cardiovascular disease or chronic kidney disease. These people with NASH are often older and are thus more prone to these complications. For these reasons and others, individuals with morbid obesity (BMI ≥ 40 kg/m2) and NASH with cirrhosis may be considered unfit for liver transplantation until they follow lifestyle modifications to reduce bodyweight. Diabetic people with poor glycemic control are at similar risks, and optimal glycemic control is essential before attempting transplantation.The Asia Pacific Working Group guidelines recommend healthcare providers discuss lifestyle modifications before and after transplantation to reduce potential surgery risks and to assist with NAFLD management after the transplant.Simultaneous bariatric surgery and liver transplantation were performed in exceptional circumstances.After transplantation, liver biopsy is the best method to monitor the evolution of post-transplant fibrosis, with significant fibrosis or portal hypertension one year after transplantation predicting rapid progression and graft loss and indicating the need for urgent intervention.

Related complications
There is no special treatment for liver cancer associated with NAFLD/NASH and are treated according to general guidelines on liver cancers.

Prognosis
The average progression rate from one stage of liver fibrosis to the next in humans with NASH is estimated to be seven years, compared to 14 years with NAFLD. The course of progression varies with different clinical manifestations among individuals. Fibrosis in humans with NASH progressed more rapidly than in humans with NAFLD. Obesity predicts a worse long-term outcome than for lean individuals. In the Asia-Pacific region, about 25% of NAFLD cases progress to NASH under three years, but only a low proportion (3.7%) develop advanced liver fibrosis. An international study showed that people with NAFLD had a 10-year survival rate of 81.5%.NAFLD is a risk factor for fibrosis, hypertension, chronic kidney disease, atrial fibrillation, myocardial infarction, ischemic stroke, and death from cardiovascular causes based on very-low to low-quality evidence from observational studies. Although NAFLD can cause cirrhosis and liver failure and liver cancer, most deaths among people with NAFLD are attributable to cardiovascular disease. According to a meta-analysis of 34,000 people with NAFLD over seven years, these individuals have a 65% increased risk of developing fatal or nonfatal cardiovascular events when compared to those without NAFLD.NAFLD and NASH increase the risk of liver cancer. Cirrhosis and liver cancer induced by NAFLD were the second cause of liver transplantation in the US in 2017. Liver cancer develops in NASH in the absence of cirrhosis in 45% in the cases, and people with NASH cirrhosis have an increased risk of liver cancer. The rate of liver cancer associated with NASH increased fourfold between 2002 and 2012 in the US, which is more than any other cause of liver cancer. NAFLD constitutes the third most common risk factor for liver cancer. NAFLD and NASH were found to worsen with cirrhosis in respectively 2–3% and 15–20% of the people over a 10–20 year period. Cirrhosis is found in only about 50% of people with NAFLD and with liver cancer, so that liver cancer and cirrhosis are not always linked.NAFLD may be a precursor of metabolic syndrome, although a bidirectional influence is possible. The presence and stage of fibrosis are the strongest prognostic factors for liver-related events and mortality, in particular for NAFLD.

Epidemiology
NAFLD incidence is rapidly rising, along with obesity and diabetes, and has become the most common cause of liver disease in developed countries, for adults, teenagers, and children. The percentage of people with NAFLD ranges from 9 to 36.9% in different parts of the world. Approximately 20% of the United States and 25% of the Asia-Pacific populations have non-alcoholic fatty liver. Similar prevalence can be found in Europe, although less data is available. NAFLD is the most common in the Middle East (32%) and South America (30%), while Africa has the lowest rates (13%). Compared to the 2000s, NAFL and NASH respectively increased 2-fold and 2.5-fold in the 2010s in the USA.NAFLD and NASH are more prevalent in Hispanics - which can be attributed to high rates of obesity and type 2 diabetes in Hispanic populations, intermediate in Whites, and lowest in Blacks. NAFLD was observed to be twice as prevalent in men as women. For severely obese individuals, the prevalence of NAFLD rises over 90%, and for those with diabetes, over 60%, and up to 20% for normal-weight people. NAFLD is present in 65% to 90% of people that had bariatric surgery, and up to 75% of them have NASH. Ultrasonography and proton NMR spectroscopy studies suggest about 25% of the population seems to be affected by NAFLD or NASH.Although the disease is commonly associated with obesity, a significant proportion of those affected are normal weight or lean. Lean NAFLD affects between 10 and 20% of Americans and Europeans, and approximately 25% of the Asians, although some countries have a higher incidence (e.g., India has a very high proportion of lean NAFLD and almost no obese NAFLD). PNPLA3 may be relevant for the progression of NAFLD in lean people. Thus, people with NAFLD deserve consideration for treatment regardless of the presence or absence of obesity.In children ages 1 to 19, the prevalence was found to be approximately 8% in the general population up to 34% in studies with data from child obesity clinics.The majority of cryptogenic cirrhosis is believed to be due to NASH. NAFLD prevalence is expected to increase steadily, from 25% in 2018 to a projected 33.5% of people with NAFLD globally in 2030, and from 20% to a projected 27% of those with NAFLD will progress to NASH.

History
The first acknowledged case of obesity-related non-alcoholic fatty liver was observed in 1952 by Samuel Zelman. Zelman started investigating after observing a fatty liver in a hospital employee who drank more than twenty bottles of Coca-Cola a day. He then went on to design a trial for a year and a half on 20 obese people who were not alcoholic, finding that about half of them had substantially fatty livers. Fatty liver was, however, linked to diabetes since at least 1784 — an observation picked up again in the 1930s. Studies in experimental animals implicated choline inadequacy in the 1920s and excess sugar consumption in 1949.The name "non-alcoholic steatohepatitis" (NASH) was later defined in 1980 by Jurgen Ludwig and his colleagues from the Mayo Clinic to raise awareness of the existence of this pathology, as similar reports previously were dismissed as "patients lies". This paper was mostly ignored at the time but eventually came to be seen as a landmark paper, and starting in the mid-1990s, the condition began to be intensively studied, with a series of international meetings being held on the topic since 1998. The broader NAFLD term started to be used around 2002. Diagnostic criteria began to be worked out, and in 2005 the Pathology Committee of the NIH NASH Clinical Research Network proposed the NAS scoring system.

Society and culture
Political recommendations
EASL recommends Europes public health authorities to "restrict advertising and marketing of sugar-sweetened beverages and industrially processed foods high in saturated fat, sugar, and salt", as well as "fiscal measures to discourage the consumption of sugar-sweetened beverages and legislation to ensure that the food industry improves labeling and the composition of processed foods", as well as "public awareness campaigns on liver disease, highlighting that it is not only linked to excessive consumption of alcohol".

Lobbying
In France, the French syndicate of non-alcoholic beverages "Boissons Rafraîchissantes de France" (that included soft drink producers such as Coca-Cola France, Orangina, PepsiCo France) was denounced by the French journal fr:Canard Enchainé for misleading consumers using a communication on their website titled "Better understanding the NASH pathology", explaining that "NASH pathology is sometimes called the soda illness by language abuse or an unfortunate semantic shortcut, as it is not directly linked to the consumption of non-alcoholic beverages". This page and others on the same website, such as one titled "Say no to disinformation," were since then removed.

Children
Pediatric NAFLD was first reported in 1983. It is the most common chronic liver disease among children and adolescents since at least 2007, affecting 10 to 20% of them in the US in 2016. NAFLD is associated with metabolic syndrome, which is a cluster of risk factors that contribute to the development of cardiovascular disease and type 2 diabetes mellitus. Studies have demonstrated that abdominal obesity and insulin resistance, in particular, are significant contributors to the development of NAFLD. Coexisting liver diseases, such as hepatitis C and cardiovascular diseases such as atherosclerosis, are also associated with an increased risk of NAFLD. Some children were diagnosed as early as two years old, with a mean age of diagnosis between 11 and 13 years old. The mean age is usually above 10 years, as children can also report non-specific symptoms and are thus difficult to diagnose for NAFLD.Boys are more likely to be diagnosed with NAFLD than girls. Overweight, or even weight gain, in childhood and adolescence, is associated with an increased risk of NAFLD later in life, with adult NAFLD predicted in a 31-year follow-up study by risk factors during childhood including BMI, plasma insulin levels, male sex, genetic background (PNPLA3 and TM6SF2 variants) and low birth weight, an emerging risk factor for adulthood NAFLD. In a study, simple steatosis was present in up to 45% in children with a clinical suspicion of NAFLD. Children with simple steatosis have a worse prognosis than adults, with significantly more of them progressing from NAFLD to NASH compared to adults. Indeed, 17-25% of children with NAFLD develop a NASH in general, and up to 83% for children with severe obesity (versus 29% for adults), further suggesting that hepatic fibrosis seems to follow a more aggressive clinical course in children compared to adults.Early diagnosis of NAFLD in children may help prevent the development of liver disease during adulthood. This is challenging as most children with NAFLD are asymptomatic, with only 42-59% showing abdominal pain. Other symptoms might be present, such as right upper quadrant pain or acanthosis nigricans, the latter of which is often present in children with NASH. An enlarged liver occurs in 30–40% of children with NAFLD.The AASLD recommends a diagnostic liver biopsy in children when the diagnosis is unclear or before starting a potentially hepatotoxic medical therapy. The EASL suggests using fibrosis tests such as elastography, acoustic radiation force impulse imaging, and serum biomarkers to reduce the number of biopsies </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 Proximal subungual onychomycosis and can you explain it in depth? [/INST]  </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 Dyskeratosis congenita and can you explain it in depth? [/INST] Dyskeratosis congenita (DKC), also known as Zinsser-Engman-Cole syndrome, is a rare progressive congenital disorder with a highly variable phenotype. The entity was classically defined by the triad of abnormal skin pigmentation, nail dystrophy, and leukoplakia of the oral mucosa, but these components do not always occur. DKC is characterized by short telomeres. Some of the manifestations resemble premature ageing (similar to progeria).  The disease initially mainly affects the skin, but a major consequence is progressive bone marrow failure which occurs in over 80%, causing early mortality.

Presentation
DKC can be characterized by cutaneous pigmentation, premature graying, dystrophy of the nails, leukoplakia of the oral mucosa, continuous lacrimation due to atresia of the lacrimal ducts, often thrombocytopenia, anemia, testicular atrophy in the male carriers, and predisposition to cancer.  Many of these symptoms are characteristic of geriatrics, and those carrying the more serious forms of the disease often have significantly shortened lifespans. Also, liver abnormalities are associated with this syndrome, Nodular Regenerative Hypoplasia of the liver, although rare, it is one of many manifestations of liver disorders short telomeres can cause.

Predisposition to cancer
Susceptibility to cancer seems counterintuitive because in many known cancers reactivation of telomerase is actually a required step for malignancy to evolve (see telomere). In a disease where telomerase is affected, it does not seem to follow that cancer would be a complication to result. The authors note the paradoxical nature of cancer predisposition in individuals who seem to lack one of the required components for cancer to form. It is thought  that without functional telomerase, chromosomes will likely be attached together at their ends through the non-homologous end joining pathway. If this proves to be a common enough occurrence, malignancy even without telomerase present is possible. Myelodysplastic Syndrome is associated with this syndrome usually presenting as a Hypoplastic Bone Marrow that can resemble Aplastic Anemia, but can be differentiated with >10% dysplasia in affected cell lines, sometimes not possible though because of the Hypoplastic marrow reducing blood cells to be observed, genetic clones are usually not present more often than not with Hypoplastic Myelodysplastic Disorder associated with Dyskeratosis Congenita.

Genetics
Of the components of the telomerase RNA component (TERC), one of key importance is the box H/ACA domain.  This H/ACA domain is responsible for maturation and stability of TERC and therefore of telomerase as a whole. The mammalian H/ACA ribonucleoprotein contains four protein subunits: dyskerin, Gar1, Nop10, and Nhp2.  Mutations in Nop10, Nhp2 and dyskerin1 have all been shown to lead to DKC-like symptoms.

X-linked
The best characterized form of dyskeratosis congenita is a result of one or more mutations in the long arm of the X chromosome in the gene DKC1. This results in the X-linked recessive form of the disease wherein the major protein affected is dyskerin.  Of the five mutations described by Heiss and colleagues in Nature Genetics, four were single nucleotide polymorphisms all resulting in the change of highly conserved amino acids.  One case was an in-frame deletion resulting in the loss of a leucine residue, also conserved in mammals. In three of the cases, the specific amino acids affected (phenylalanine, proline, glycine) are found in the same locus in humans as they are in yeast (S. Cerevisiae) and the brown rat (R. Norvegicus).  This establishes the sequence conservation and importance of dyskerin within the eukaryotes. The relevant nature of dyskerin throughout most species is to catalyze the post-transcriptional pseudouridylation of specific uridines found in non-coding RNAs, such as ribosomal RNA (rRNA).  Cbf5, the yeast analog of human dyskerin, is indeed known to be associated with the processing and maturation of rRNA.  In humans, this role can be attributed to dyskerin.  Thus, the X-linked form of this disease may result in specific issues related to dysfunctional RNA and perhaps a graver phenotype.  Within the vertebrates, as opposed to single celled eukaryotes, dyskerin is a key component of the telomerase RNA component (TERC) in the form of the H/ACA motif. This X-linked variety, like the Nop10 and Nhp2 mutations, demonstrates shortened telomeres as a result of lower TERC concentrations.

Autosomal dominant
3 genes: TERC, TERT, TINF2
The evidence supporting the importance of the H/ACA domain in human telomerase is abundant.  At least one study has shown that these mutations affect telomerase activity by negatively affecting pre-RNP assembly and maturation of human telomerase RNA.  Nonetheless, mutations that directly affect the telomerase RNA components would presumably exist and should also cause premature aging or DKC-like symptoms. Indeed, three families with mutations in the human TERC gene have been studied with intriguing results. In two of these families, two family-specific single nucleotide polymorphisms were present while in the other there persisted a large-scale deletion (821 base pairs of DNA) on chromosome 3 which includes 74 bases coding for a section of the H/ACA domain. These three different mutations result in a mild form of dyskeratosis congenita which uniquely follows an autosomal dominant pattern of inheritance.  Premature graying, early dental loss, predisposition to skin cancer, as well as shortening of telomere length continue to be characteristic of this disease.

Autosomal recessive
6 genes:
The true phenotype of DKC individuals may depend upon which protein has incurred a mutation.  One documented autosomal recessive mutation in a family that carries DKC has been found in NOP10.  Specifically, the mutation is a change of base from cytosine to thymine in a highly conserved region of the NOP10 sequence.  This mutation, on chromosome 15, results in an amino acid change from arginine to tryptophan.  Homozygous recessive individuals show the symptoms of dyskeratosis congenita in full.  As compared to age-matched normal individuals, those suffering from DKC have telomeres of a much shorter length.  Furthermore, heterozygotes, those who have one normal allele and one coding for the disease, also show relatively shortened telomeres.  The cause of this was determined to be a reduction in TERC levels in those with the Nop10 mutation.  With TERC levels down, telomere maintenance, especially in development, would be presumed to suffer accordingly. This would lead to the telomere shortening described.NHP2 mutations are similar in characterization to NOP10.  These mutations are also autosomal recessive with three specific single-nucleotide polymorphisms being recognized which result in dyskeratosis congenita.  Also, like NOP10, individuals with these NHP2 mutations have a reduction in the amount of telomerase RNA component (TERC) present in the cell.  Again, it can be presumed that a reduction in TERC results in aberrant telomere maintenance and thus shortened telomeres.  Those homozygous recessive for mutations in NHP2 do show shorter telomeres when compared with age-matched normal individuals.

Pathophysiology
Dyskeratosis congenita is a disorder of poor telomere maintenance mainly due to a number of gene mutations that give rise to abnormal ribosome function, termed ribosomopathy. Specifically, the disease is related to one or more mutations which directly or indirectly affect the vertebrate telomerase RNA component (TERC). Telomerase is a reverse transcriptase which maintains a specific repeat sequence of DNA, the telomere, during development. Telomeres are placed by telomerase on both ends of linear chromosomes as a way to protect linear DNA from general forms of chemical damage and to correct for the chromosomal end-shortening that occurs during normal DNA replication. This end-shortening is the result of the eukaryotic DNA polymerases having no mechanism for synthesizing the final nucleotides present on the end of the "lagging strand" of double stranded DNA.  DNA polymerase can only synthesize new DNA from an old DNA strand in the 5→3 direction.  Given that DNA has two strands that are complementary, one strand must be 5→3 while the other is 3→5.  This inability to synthesize in the 3→5 directionality is compensated with the use of Okazaki fragments, short pieces of DNA that are synthesized 5→3 from the 3→5 as the replication fork moves. As DNA polymerase requires RNA primers for DNA binding in order to commence replication, each Okazaki fragment is thus preceded by an RNA primer on the strand being synthesized.  When the end of the chromosome is reached, the final RNA primer is placed upon this nucleotide region, and it is inevitably removed.  Unfortunately once the primer is removed, DNA polymerase is unable to synthesize the remaining bases.Sufferers of DKC have been shown to have a reduction in TERC levels invariably affecting the normal function of telomerase which maintains these telomeres.  With TERC levels down, telomere maintenance during development suffers accordingly.  In humans, telomerase is inactive in most cell types after early development (except in extreme cases such as cancer) </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 Patulous Eustachian tube and can you explain it in depth? [/INST] Patulous Eustachian tube (PET) is the name of a physical disorder where the Eustachian tube, which is normally closed, instead stays intermittently open.  When this occurs, the person experiences autophony, the hearing of self-generated sounds.  These sounds, such as ones own breathing, voice, and heartbeat, vibrate directly onto the ear drum and can create a "bucket on the head" effect. PET is a form of eustachian tube dysfunction (ETD), which is said to be present in about 1 percent of the general population.

Signs and symptoms
With patulous Eustachian tube, variations in upper airway pressure associated with respiration are transmitted to the middle ear through the Eustachian tube.  This causes an unpleasant fullness feeling in the middle ear and alters the auditory perception.  Complaints seem to include muffled hearing and autophony. In addition, patulous Eustachian tube generally feels dry with no clogged feeling or sinus pressure.
Patients hear their own voice or its echo from inside. They describe it as being amplified and unpleasant. Lying head down  may help since it increases venous blood pressure and congestion of the mucosa.

Causes
Patulous Eustachian tube is a physical disorder. The exact causes may vary depending on the person.  Weight loss is a commonly cited cause of the disorder due to the nature of the Eustachian tube itself and is associated with approximately one-third of reported cases. Fatty tissues hold the tube closed most of the time in healthy individuals.  When circumstances cause overall body fat to diminish, the tissue surrounding the Eustachian tube shrinks and this function is disrupted.Activities and substances which dehydrate the body have the same effect and are also possible causes of patulous Eustachian tube.  Examples are stimulants (including caffeine) and exercise.  Exercise may have a more short-term effect than caffeine or weight loss in this regard.
Pregnancy can also be a cause of patulous Eustachian tube due to the effects of pregnancy hormones on surface tension and mucus in the respiratory system.Granulomatosis with polyangiitis can also be a cause of this disorder. It is yet unknown why.
PET can occur as a result of liquid residue in the Eustachian tube, after suffering a middle ear infection (otitis media).

Radiation therapy
High levels of estrogen
Nasal decongestants
Stress
Sudden weight loss
Neurological disorders

Diagnosis
Upon examination of a suspected case of patulous Eustachian tube, a doctor can directly view the tympanic membrane with a light and observe that it vibrates with every breath taken by the patient.  A tympanogram may also help with the diagnosis.  Patulous Eustachian tube is likely if brisk inspiration causes a significant pressure shift.
Patulous Eustachian tube is frequently misdiagnosed as standard congestion due to the similarity in symptoms and rarity of the disorder.  Audiologists are more likely to recognize the disorder, usually with tympanometry or nasally delivered masking noise during a hearing assessment, which is highly sensitive to this condition.When misdiagnosis occurs, a decongestant medication is sometimes prescribed </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 Cushing ulcer and can you explain it in depth? [/INST]  </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 Trifascicular block and can you explain it in depth? [/INST] Trifascicular block is a problem with the electrical conduction of the heart, specifically the three fascicles of the bundle branches that carry electrical signals from the atrioventricular node to the ventricles. The three fascicles are one in the right bundle branch, and two in the left bundle branch the left anterior fascicle and the left posterior fascicle. A block at any of these levels can cause an abnormality to show on an electrocardiogram
The most literal meaning of trifascicular block is complete heart block: all three fascicles are blocked </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 Trigeminal autonomic cephalgia and can you explain it in depth? [/INST]  </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 Angiokeratoma and can you explain it in depth? [/INST]  </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 Jaw abnormality and can you explain it in depth? [/INST] A jaw abnormality is a disorder in the formation, shape and/or size of the jaw. In general abnormalities arise within the jaw when there is a disturbance or fault in the fusion of the mandibular processes. The mandible in particular has the most differential typical growth anomalies than any other bone in the human skeleton. This is due to variants in the complex symmetrical growth pattern which formulates the mandible.The mandible in particular plays a significant role in appearance as it is the only moving part of the facial skeleton. This has a large impact upon an individuals’ ability speak, masticate and also influence their overall aesthetic and expressive features of the face. In turn the maxilla faces the same issues if any abnormalities in size or position were to occur. The obvious functional disabilities that arise from jaw abnormalities are very much physically seen as previously stated, but when considering these individuals it must be kept in mind that these conditions may well affect them psychologically; making them feel as though they are handicapped.  It is also of the utmost importance when correcting these mandibular anomalies that the teeth result in a good occlusion with the opposing dentition of the maxilla. If this is not done satisfactorily occlusal instability may be created leading to a plethora of other issues. In order to correct mandibular anomalies it is common for a complex treatment plan which would involve surgical intervention and orthodontic input.

Signs and symptoms
Individuals with jaw abnormalities have both functional and aesthetic impairment.Misalignment of teeth creates difficulties in head and neck functions related to chewing, swallowing, breathing, speech articulation and lip closure/posture.Affected individuals may also experience TMJ pain and dysfunction, which negatively affect the quality of life.A proportion of affected individuals also have psychological problems.

Diagnosis
Diagnosis of a jaw deformity is a structured process, linking the undertaking of a history, physical examination of the patient, and appraisal of diagnostic studies. This process may involve more than a single discipline of Dentistry – in addition to orthodontic and surgical needs, some patients may also require periodontal, endodontic, complex restorative, and prosthetic considerations.It involves the chief presenting complaint of the patient, which allows the clinician to understand the patients perception of the problem – what they think the problem is and what they would like corrected. The patient may find eating difficult or may have problems with speech or the appearance of the teeth or face. However, patients may be hesitant to discuss dissatisfaction with their appearance because they may feel that it is more acceptable to present a functional problem to the clinician. For this reason it is important to reassure patients that their aesthetic problems and the effects of these are perfectly valid concerns. In children, psychological development can be affected due to teasing if they have abnormal appearance of teeth or face. Correction of the abnormality can be extremely beneficial to the patient. The benefits can manifest themselves in many ways including improved peer relationships and social confidence. Motivation on the patients part is necessary if they are going to undergo lengthy orthodontic treatment and major surgery. In addition, they need to be well informed so that they may give valid consent. In terms of history, the family history and perhaps obstetric history may be relevant, especially when features of a syndrome are present.: 200 A medical and dental history is obtained for completeness. The medical history includes questions on the general health of the patient, to assess contraindications to treatment of jaw abnormality. Special emphasis is placed on diseases and medication which cause altered metabolism, that may affect growth and tissue reactions. Allergies are checked (specifically nickel allergies), so that treatment appliances with nickel-containing materials like stainless steel can be replaced with other materials to avoid the risk of allergic reactions. Questions on family history are also relevant, as malocclusions, growth and development may be expressions of genetic patterns. The dental history investigates if the patient has had any previous dental trauma, or past dental experiences, which can serve as a gauge to patient compliance with treatment.

Examination
The assessment of facial form includes the evaluation of facial soft tissue and dentition. As the human skeleton is not visibly perceptible, bone deformity is inferred and evaluated by facial appearance and dentition. To obtain a 3D assessment of the patient, the skeletal pattern must be measured in different planes: anterior-posterior, vertical, and transverse. This allows for an accurate assessment of the size, position, orientation, shape, and symmetry of the jaws.
The anterior-posterior skeletal pattern measures the relationship of the lower jaw to the upper jaw. This is judged with the patient seated upright, head in a neutral horizontal position, and teeth in gentle occlusion. It can be classified into the following classes:

Class I: The ideal relationship whereby the upper jaw lies 2-4mm in front of the lower jaw
Class II: Upper jaw lies more than 4mm in front of the lower jaw
Class III: Upper jaw lies less than 2mm in front of the lower jaw, or in more severe cases, the lower jaw may be in front of the upper jaw. The vertical dimension can be measured by facial thirds, with ideal facial aesthetics showing equality between each vertical third. The face is divided into thirds – hairline to glabella; glabella to subnasale; and subnasale to the lowest part of the chin. Two other clinical indicators can be assessed when analysing vertical dimensions, namely the Frankfort Mandibular Planes Angle (FMPA) and the Lower Facial Height (LFH) – both of which are each recorded as either average, increased, or decreased.

FMPA: This is estimated by the point of intersection between the lower border of the mandible and the Frankfort Horizontal plane.
LFH: The face is divided into thirds, and the proportion of the lower third of the face is compared to the rest.The transverse relationship is a measure of jaw or facial asymmetry. It checks for the alignment of the soft tissue nasion, the middle part of the upper lip at the vermillion border, and the chin point. If present, it is necessary to distinguish between a false and true asymmetry. A false asymmetry arises due to occlusal interferences, which results in a lateral displacement of the mandible, producing a cross-bite in the anterior/buccal region. Elimination of the displacement will return the mandible to a centric position. On the other hand, a true asymmetry indicates unequal facial growth on the left or right side of the jaws. Elimination of any occlusal cross-bites is not only difficult, but unlikely to improve the facial asymmetry. The assessment of the transverse components of the facial width is best described by the "rule of fifths", which sagittally divides the face into five equal parts:
Each transverse fifth should be an eye distance in width.
The middle fifth is marked by the inner canthus of both eyes.
The medial three-fifths of the face is marked from the outer canthus of the eye frames
The outer two-fifths of the face is measured from the lateral canthus to lateral helix of the ear, which represents the width of the ears.

Tests
It is insufficient to derive at a diagnosis of jaw deformity solely based on the clinical examination. Hence, additional information is gathered from diagnostic tests, which may include dental model analyses and radiographic imaging studies.

Dental Model Analyses - Study models for analysis can be made by taking dental impressions, or by 3D intra-oral scanning. They allow for the appraisal of shape and size of jaws and teeth. This can be valuable for the long-term evaluation of development and for the follow up of treatment results. Depending on the type of jaw abnormality, a face bow record for transfer on to the articulator, can sometimes be appropriate for the patient.
Radiographs - Radiographic investigations should be based on individual needs and used in conjunction to the clinical examination. As with all other dental radiographs, the benefit gained for the patient with the radiograph must be weighed against the radiation dosage of taking it. In the assessment of jaw abnormalities, the most common radiographs taken used to be the dental panoramic tomography and lateral cephalometry. With the advancement in technology, the use of 3D imaging e.g. Cone Beam Computed Tomography (CBCT) has gained popularity for the use of radiographic examinations of facial bones for purpose of planning complex orthognathic surgery, especially involving significant facial asymmetry. A 3D facial construction model can be utilised in more complex malocclusion to help plan management.

Classification
Size
MicrognathiaMandibular micrognathia is the condition when lower jaw is smaller than normal. Failure of the ramus to develop will give rise to micrognathia. Micrognathia can be classified as either congenital or acquired. Clinical appearance of some patients with congenital type of mandibular micrognathia can have a severe retrusion of the chin but by actual measurements, the mandible maybe be found to be within the normal limits of variation. This maybe because a posterior placing of the condylar head with regard to the skull or to a steep mandibular angle resulting in an evident jaw retrusion. The acquired type of micrognathia occurs after birth and usually is an effect of a disturbance to temporomandibular joint. Growth of mandible depends on the normally developing condyles and the muscle function For example, trauma or infection that affect mastoid, middle ear or the joint will result in ankylosis of temporomandibular joint leading to mandibular micrognathia.
MacronagthiaMacronagthia is a condition of abnormally large jaws. The jaw size is usually proportion to the increase in skeleton size. It is usually due to excessive growth of the mandible and can have features including reverse maxillary to mandibular relationship, reverse overjet or absence of overbite. It can also be clinically presented when the glenoid fossa and condylar head is more anteriorly placed, causing mandibular prognathism. Macronagthism can be associated with other medical conditions :-
1.     Pagets disease where there is overgrowth of the maxilla, cranium and mandible2.     Acromegaly, an endocrine disease, can present with enlargement of bones with growth potential such as the mandible, thickened soft tissues and facial features and spade-like hands
Macrogenia or MicrogeniaMacrogenia and microgenia occur when there is a normal skeletal relationship but the chin, skeletal and soft tissue components, failed to develop in proportion to the skeletal base, resulting in marked protrusive (macrogenia) or retrusive (microgenia) facial profile. Microgenia can be presented when there is inadequate bone depth at the apex of lower anteriors or the base of mandible and vice versa.

Position
TransverseA transverse jaw position is known as Laterognathia. This term describes a lateral bite in the lower jaw  and is often associated with a unilateral crossbite at an early age  This can lead to bone development of an asymmetrical mandibular ramus resulting in asymmetry in the whole of the lower face. Treatment of laterognathism is either possible with orthodontic tooth movement or a surgical relocation of the lower jaw.
VerticalOne of the ways in which a jaw can develop abnormally is in the vertical dimension. Abnormal growth can occur in the maxilla and the mandible. The jaw is usually loosely used to refer to the mandible (considered the lower jaw). However, the maxilla is also a jaw and should thus be referred to in this respect as well.
The vertical jaw abnormalities relating to the mandible are in relation to excessive vertical growth and excessive horizontal growth, measured by the maxillary-mandibular plane angle (MMPA). The vertical jaw abnormalities relating to the maxilla are in relation to excessive downward displacement (EDD) and insufficient downward displacement (IDD). These terms used to previously be known as vertical maxillary excess and deficiency. This nomenclature changed because excess and deficiency typically refer to size. Whereas when assessing this clinically, one would measure the distance between the central incisors and the upper lip, which, in fact, denotes position rather than size. Therefore, in order to ‘harmonize with geometry’, EDD and IDD are now used widely.Vertical and Horizontal Mandibular Excess:
Simply put, excessive vertical growth is the term used for when the mandible is considered ‘too far down. Whereas in excessive horizontal growth the opposite applies, where the mandible is growing in a more horizontal pattern, in relation to the maxilla. The primary cause of the above two abnormalities in adolescents is due to accelerated and slow mandibular growth. Resulting in either a longer lower face height appearance (vertical growth) or a shorter one (horizontal growth). The length between the columella (base of the nose) and menton (base of the chin) is the variable measurement. This is in relation to the length between the glabella (between eyebrows) and the columella. In a normal case, these lengths would be equal or without a major discrepancy. However, in excess vertical and horizontal growth, the proportions vary and do not equal.
The development of the mandible is such that it ossifies in two primary ways; endochondrally and intramembranously. Almost the entire mandible is formed via intramembranous ossification, with just the condyle ossifying endochondrally. This allows the condyle to resist forces exerted on it. One way in which a vertical jaw abnormality can occur is if the condylar growth process is damaged, and thus the intramembranous growth continues along the posterior condylar margin, becoming predominant, thus resulting in a high angle type.Assessing a patient for vertical and horizontal excess
The Maxillary Mandibular Plane Angle (MMPA) is important in assessing a patient for vertical jaw abnormality. The important landmarks are the Frankfurt plane and the Mandibular plane. The Frankfurt plane is a line charted from the upper border of external auditory meatus to the lower border of the orbit. It is similar to the ala-tragus line however should not be confused with it. Whereas the Mandibular angle is a line measured along the natural lower border of the patients mandible. The intersection of the Frankfurt and Mandibular plane is what determines the pattern of vertical growth. If the intersection occurs behind the occiput i.e. decreased angle, then the patient is considered to have horizontal growth. On the other hand, if the intersection occurs in front of the occiput, then the patient is considered to have vertical growth. The normal range is considered to be between 25 and 30 degrees in a typical Caucasian person. Those with excess vertical jaw growth are most often seen having an anterior open bite, as the mandible is growing away from the maxilla. Whereas those with excessive horizontal growth are seen as having an overbite.
Excessive Downward Displacement and Insufficient Downward Displacement
Here on, we will use interchangeably the terms vertical maxillary excess and deficiency with excessive and insufficient downward displacement. In order to understand its manifestations, we need to account for key landmarks such as:· Columella (CM)– The tissue that links the nasal tip to the nasal base, separating the nares. The inferior margin of the nasal septum
· Subnasale (SN) – the junction of the upper lip and the columella
· Stomion Superios (Sts) – the lower most point on the vermillion of the upper lip
· Stomion (Sto) – The point of contact, when lips are competent, in the midline, between the top and bottom lip
· Stomion Inferious (Sti) – the upper most point on the vermillion of the lower lip
· Soft tissue mention (Me) – The most inferior point on the soft tissue outline of the chin
The measurements of the upper lip and lower lip for each patient are ascertained by using the aforementioned landmarks. The length of the upper lip is measured from Sn to Sts. In a typical male and female this measures to 24mm and 21mm respectively (REF). The length of the lower lip is measured from Sti to Me. In a typical male and female this measures to 50mm and 46.5mm respectively.When considering EDD and IDD, the class of the skeletal base is a good adjunct. In other words, EDD and IDD can either appear camouflaged or apparent given the skeletal base and the soft tissue profile accompanying it. For example, the drape of the upper lip can mask the maxillary deficiency to such an extent that it presents as a normal soft tissue profile (REF). Para-nasal hollowing is a key indicator of underlying maxillary deficiency. It is most common in class III patients, but can also present in some class II cases, with bilateral maxillary retrusion.Assessing a patient for vertical and horizontal excess:
Arguably the main observation to carry out in a patient to assess maxillary excess or deficiency is the upper incisor/gum show when at rest and smiling. In other words, the relationship between the upper lip and upper central incisors when at rest and smiling.  Ensure the patients head posture is correct and the lips are at rest to establish the resting lip line. Similarly, to assess the incisor/gum show on smiling, the patient needs to fully smile to allow the upper lip to rise to its maximum height. The average showing of the incisors when the lips are at rest is 1/3 of its clinical crown height. With maxillary excess, more than 1/3 of the incisors would show. When the patient smiles, maxillary excess would manifest as the entire clinical crown and a portion of the gums showing as well. This is regarded as a ‘gummy smile.’
As alluded to previously, the paranasal region is important to consider when assessing a patient for IDD or EDD. Observing the patient from the side view allows a clearer perspective. A lack of bony support for the soft tissues in this region will subsequently produce the depression, known as paranasal hollowing. This indicates a low level antero-posterior maxillary deficiency. Maxillary deficiency usually manifests as an increased naso-labial angle, although this is not a credible indication due to factors such as a short upper lip and/or proclined incisors.
Another method to predict if a patient has maxillary deficiency is by the ‘scleral show and eyelid shape.’ The lower eyelid normally rests at the inferior border of the iris, without any sclera showing. If there is any sclera showing, then this is a good sign of infraorbital rim deficiency and maxillary antero-posterior deficiency, two manifestations that are usually seen in Class III patients.

Orientation
When a jaw is abnormally oriented, malrotations occur. These malrotations are classified according to the axis on which the abnormal rotation occurs. When a jaw is malrotated around the transverse facial axis, it is said to have abnormal pitch. When malrotated around the anteroposterior axis, the jaw has an abnormal roll, a condition also known as cant.  Finally, when a jaw is malrotated around the vertical axis, it has abnormal yaw. It can occur in maxilla and/or mandible and could result due to abnormal growth of the jaws in itself or as compensatory growth.

Shape
Shape refers to figure, the geometric characteristic of an object that is not size, position, or orientation 5.  A jaw with abnormal shape is said be distorted.

Completeness
Completeness means the wholeness of the jaw. When failure of tissues to fuse together that are forming early in pregnancy, defect can happen and jaw is incomplete. For example, cleft lip and palate when one of the jaws embryological processes failed to fuse together or the agenesis of the condylar process of the mandible, which may be seen in hemifacial microsomia. Clinically, cleft palate  presents as opening in the palate that can affect the front palate only or extending from the front to the back palate. Cleft lip is presented clinically with opening of the upper lip which can be a small slit on the upper lip or large opening connected to the nose. The cleft can be unilateral on the upper lip or bilaterally. Cleft lip can happen together with cleft palate.Palatal clefts are one of the most common congenital abnormalities which occur in 1:2500 live births. Embryologically, palate formation takes place in two stages, with the primary palate formed after 6th week followed by secondary palate formation between sixth and eighth weeks. The palate will fuse with the medial nasal process to form the roof of the mouth in order to complete the developmental process. However, if this process is incomplete that is when developmental defect occur. Initially, it is just a common oro-nasal cavity within the embryo with nothing to separate the nose and mouth cavity. This space is occupied with tongue. The primary palate formed when medial nasal prominences fused together to form the intermaxillary segment to demarcate the oral from the nasal components. The formation of secondary palate starts with the growing of tissues vertically and mesially forming the right and left lateral palatal shelves. On the week 8, the tongue will be withdrawn downwards and the right and left lateral palatal shelves will be rapidly elevated, flipped into a horizontal orientation and fuse together from the front to the back two. The right and left lateral palatal shelves contact or fuse with each other at the midline to form the secondary palate two.A lot of growth factors are actively involved in the signalling to the tissues during craniofacial development. These growth factors function to control the cells proliferation, survival and apoptosis. Some of the growth factors that can be implicated in the facial development resulting in craniofacial defect are BMP, FGF, Shh, Wnt and endothelins. One of the environmental factors that has been identified in mice study to have link to cleft lip is teratogen which can interfere the molecular signalling between the growth factors. However, the exact mechanism is still not clear. Another environmental factors that has been actively involved in studies to prevent cleft lip and palate occurrences is the intake of folic acid during pregnancy. 0.4 mg folic acid intake per day has been shown to reduce one third risk of cleft lip (with or without cleft palate) in babies. However, it seems had no apparent effect on the risk of cleft palate alone </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 Minor depressive disorder and can you explain it in depth? [/INST] Minor depressive disorder, also known as minor depression, is a mood disorder that does not meet the full criteria for major depressive disorder but at least two depressive symptoms are present for a long time. These symptoms can be seen in many different psychiatric and mental disorders, which can lead to more specific diagnoses of an individuals condition. However, some of the situations might not fall under specific categories listed in the Diagnostic and Statistical Manual of Mental Disorders. Minor depressive disorder is an example of one of these nonspecific diagnoses, as it is a disorder classified in the DSM-IV-TR under the category Depressive Disorder Not Otherwise Specified (DD-NOS). The classification of NOS depressive disorders is up for debate. Minor depressive disorder as a term was never an officially accepted term, but was listed in Appendix B of the DSM-IV-TR. This is the only version of the DSM that contains the term, as the prior versions and the most recent edition, DSM-5, does not mention it.A person is considered to have minor depressive disorder if they experience 2 to 4 depressive symptoms, with one of them being either depressed mood or loss of interest or pleasure, during a 2-week period. The person must not have experienced the symptoms for 2 years and there must not have been one specific event that caused the symptoms to arise. Although not all cases of minor depressive disorder are deemed in need of treatment, some cases are treated similarly to major depressive disorder. This treatment includes cognitive behavioral therapy (CBT), anti-depressant medication, and combination therapy. A lot of research supports the notion that minor depressive disorder is an early stage of major depressive disorder, or that it is simply highly predictive of subsequent major depressive disorder.

Signs and symptoms
Minor depressive disorder is very similar to major depressive disorder in the symptoms present. Generally, a persons mood is affected by thoughts and feelings of being sad or down on themself or by a loss of interest in nearly all activities. People can experience ups and downs in their life everyday where an event, action, stress or many other factors can affect their feelings on that day. However, depression occurs when those feelings of sadness persist for longer than a few weeks.A person is considered to have minor depressive disorder if they experience 2 to 4 depressive symptoms during a 2-week period. The Diagnostic and Statistical Manual of Mental Disorders lists the major depressive symptoms. Depressed mood most of the day and/or loss of interest or pleasure in normal activities must be experienced by the individual to be considered to have minor depressive disorder. Without either of these two symptoms, the disorder is not classified as minor depressive disorder. Other depressive symptoms include significant weight loss or weight gain without trying to diet (an increase/decrease in appetite can provide clues as well), insomnia or hypersomnia, psychomotor agitation or psychomotor retardation, fatigue or loss of energy, and feelings of worthlessness or excessive guilt.
All of these signs can compound on each other to create the last major symptom group of minor depressive disorder: thoughts of death, suicidal thoughts, plans to commit suicide, or a suicide attempt.Minor depressive disorder differs from major depressive disorder in the number of symptoms present with 5 or more symptoms necessary for a diagnosis of major depressive disorder. Both disorders require either depressed mood or loss of interest or pleasure in normal activities to be one of the symptoms and the symptoms need to be present for two weeks or longer. Symptoms also must be present for the majority of the length of a day and present for a majority of the days in the two-week period. Diagnosis can only occur if the symptoms cause "clinically significant distress or impairment". Dysthymia consists of the same depressive symptoms, but its main differentiable feature is its longer-lasting nature as compared to minor depressive disorder. Dysthymia was replaced in the DSM-5 by persistent depressive disorder, which combined dysthymia with chronic major depressive disorder.

Treatment
Treatment of minor depressive disorder has not been studied as extensively as major depressive disorder. Although there are often similarities in the treatments used, there are also differences in what may work better for the treatment of minor depressive disorder. Some third-party payers do not pay to cover treatment for minor depressive disorder.The leading treatment techniques for minor depressive disorder are the use of antidepressants and therapy. Typically, patients with minor depression were treated by watchful waiting, prescribed antidepressants, and given brief supportive counseling, but Problem-Solving Treatment for Primary Care (PST-PC) is a Cognitive-Behavioral Therapy that has gained popularity. In one study, PST-PC and Paroxetine, an antidepressant, were shown to be equally effective in significantly reducing symptoms. In another study, PST-PC was compared with the more typical care of the time and shown to reduce symptoms more quickly. Although the use of antidepressants has been widely used, not all agree that it is an appropriate treatment for some minor depression disorder settings.Another alternative that has been researched is the use of St. Johns wort (Hypericum perforatum). This herbal treatment has been studied by various groups with various results. Some studies show evidence of the treatment being helpful to treat minor depression, but others show that it does no better than the placebo.

History
At its core, minor depressive disorder is the same illness as major depressive disorder with its symptoms being less pronounced. This ties its history closely to that of major depressive disorder. Depression in the past has largely been shrouded in mystery, as its causes and appropriate treatment were largely unknown. By the 1950s, it was clear that depression could be both a mental and largely physical disease, thus being able to be treated through both psychotherapy and medication </s>