Cirrhosis is a condition in which the liver is not functioning properly due to long-term damage. This damage is characterized by the replacement of normal liver tissue by scar tissue. Usually, the disease progresses slowly for months or years. From the beginning, there are often no symptoms. When the disease worsens, a person may become tired, weak, itchy, have swelling in the lower legs, develop yellow skin, bruises easily, have fluid accumulate in the abdomen, or develop spider-like blood vessels on the skin. The fluid that accumulates in the stomach can become spontaneously infected. Other complications include hepatic encephalopathy, widespread venous bleeding in the esophagus or widening abdomen, and liver cancer. Hepatic encephalopathy causes confusion and can cause unconsciousness.
Cirrhosis is most commonly caused by alcohol, hepatitis B, hepatitis C, and non-alcoholic fatty liver disease. Typically, more than two or three alcoholic drinks per day for several years are required for alcoholic cirrhosis to occur. Nonalcoholic fatty liver disease has a number of causes, including overweight, diabetes, high blood fats, and high blood pressure. A number of underlying causes of cirrhosis include autoimmune hepatitis, primary biliary cholangitis, haemochromatosis, certain medications, and gallstones. The diagnosis is based on blood tests, medical imaging, and liver biopsy.
Some causes of cirrhosis, such as hepatitis B, can be prevented by vaccination. Treatment depends in part on the underlying cause, but the goal is often to prevent worsening and complications. Avoiding alcohol is recommended in all cases of cirrhosis. Hepatitis B and C can be treated with antiviral drugs. Autoimmune hepatitis can be treated with steroid drugs. Ursodiol may be useful if the disease is due to blockage of the bile ducts. Other drugs may be useful for complications such as abdominal or leg swelling, hepatic encephalopathy, and esophageal dilated veins. In severe cirrhosis, liver transplantation may be an option.
Cirrhosis affects about 2.8 million people and results in 1.3 million deaths by 2015. Of this, alcohol causes 348,000, hepatitis C causes 326,000, and hepatitis B causes 371,000. In the United States, more men die of cirrhosis than women. The first known description of this condition was by Hippocrates in the 5th century BC. The word cirrhosis comes from the Greek: ???????? ; kirrhos ?????? "yellowish" and -osis (- ???? ) meaning "condition" describes the appearance of liver cirrhosis
Video Cirrhosis
Signs and symptoms
Cirrhosis has many possible manifestations. These signs and symptoms may be a direct result of liver cell failure, or secondary to the resulting portal hypertension. There are also some non-specific, but non-specific, manifestations of cirrhosis. Likewise, the absence of signs does not rule out the possibility of cirrhosis. Cirrhosis of the liver is slow and gradual in its development. It's usually very advanced before the symptoms look enough to cause an alarm. Weakness and weight loss may be an early symptom.
Liver dysfunction
The following features as a direct consequence of liver cells do not work.
- The angiomata spider or nevi spider is a vascular lesion composed of a central artery that is surrounded by many smaller vessels (hence the name "spider") and occurs due to an increase in estradiol. One study found that spider angiomata occurs in about 1/3 of cases.
- Palmar erythema is a palm redness in the emarensa thenar and hypotenar also as a result of increased estrogen.
- Gynecomastia, or an increase in the size of the breast glands in non-cancerous men, is due to an increase in estradiol and can occur in 2/3 patients. This is different from the increase in breast fat in people who are overweight. Hypogonadism, decreased male sex hormones can manifest as impotence, infertility, loss of sex drive, and testicular atrophy, and may result from primary gonadal injury or hypothalamic/pituitary function emphasis. Hypogonadism is associated with cirrhosis because of alcoholism or hemochromatosis.
- The size of the liver may be enlarged, normal, or shrinking in people with cirrhosis.
- Ascites, the accumulation of fluid in the peritoneal cavity (the space in the abdomen), gives rise to "pelvic inflammation". This may be seen as an increase in abdominal circumference.
- Fetor hepaticus is a musty breath generated from an increase in dimethyl sulphide. Jaundice, or jaundice, is a yellow discoloration of the skin and mucous membranes, (with very visible white eyes) due to increased bilirubin (at least 2-3 mg/dl or 30%). Ã,Âμmol/l). Urine may also appear dark.
Portal hypertension
Cirrhosis of the liver increases resistance to blood flow and leads to higher pressure in the portal vein system, resulting in portal hypertension. The effects of portal hypertension include:
- Splenomegaly (increased lymph node size) is present in 35% to 50% of patients.
- Esophageal varices result from collateral portal blood flow through the vessels in the stomach and esophagus (a process called portacaval anastomosis). When these blood vessels dilate, they are called varicose veins and are more likely to rupture. Varicose ruptures often cause severe bleeding, which can be fatal.
- The medusa cap is an enlarged periumbilical collateral vein due to portal hypertension. Blood from the portal vein system may be smoothed through the periumbilical vein and eventually into the abdominal wall vein, which manifests as a pattern that may resemble Medusa's head.
- The Cruveilhier-Baumgarten murmur is a venous hum of the epigastric area (on examination by a stethoscope) due to the collateral connection formed between the portal system and the periumbilical veins as a result of portal hypertension.
Causes not formed
There are several changes seen in cirrhosis whose cause is not known clearly. They can also be a sign of other non-heart related causes.
- Nail changes.
- The Muehrcke line - paired with horizontal bands separated by normal colors resulting from hypoalbuminemia (inadequate albumin production). It is not specific for cirrhosis.
- Terry's nails (double nails) - proximal two-thirds of nail plate appear white with one-third distal red, also due to hypoalbuminemia
- Clubbing - the angle between the nail plate and the proximal nail folds & gt; 180 degrees. It is not specific to cirrhosis and can therefore be caused by a number of conditions
- Hypertrophic Osteoarthropathy. Chronic proliferative periostitis of long bones that can cause considerable pain. It is not specific for cirrhosis.
- Dupuytren's contracture. Thickening and shortening of palm fascia (tissue in the palm of the hand) leading to flexion deformity of the fingers. Caused by fibroblastic proliferation (increased growth) and irregular collagen accumulation. This is relatively common (33% of patients).
- More. Weakness, fatigue, anorexia, weight loss.
Advanced disease
As disease develops, complications can develop. In some people, this may be the first sign of the disease.
- Bruising and bleeding due to decreased production of coagulation factors. Hepatic encephalopathy - the liver does not clear the ammonia and the associated nitrogenous substances from the blood, which are carried to the brain, affects brain function: ignoring personal appearance, unresponsiveness, forgetfulness, difficulty concentrating, changes in sleep habits or psychosis may result. This can be seen on examination by asteriks, which is the bilateral asynchronous flap that is stretched out, the dorsiflexed hand seen in patients with hepatic encephalopathy.
- Sensitivity to drugs caused by decreased metabolism of active compounds.
- Acute kidney injury (especially hepatorenal syndrome)
Maps Cirrhosis
Cause
Cirrhosis of the liver has many possible causes; sometimes more than one cause is present in the same person. Globally, 57% of cirrhosis is due to either hepatitis B (30%) or hepatitis C (27%). Alcohol consumption is another major cause, accounting for about 20% of cases.
- Alcoholic liver disease (ALD). Alcohol cirrhosis develops for 10-20% of individuals who drink heavily for a decade or more. Alcohol seems to hurt the liver by blocking the metabolism of normal proteins, fats, and carbohydrates. This injury occurs through the formation of acetaldehyde from alcohol which is itself reactive, but also causes the accumulation of other reactive products in the liver. The patient may also suffer from alcoholic hepatitis along with fever, hepatomegaly, jaundice, and anorexia. AST and ALT levels are both increasing, but less than 300 IU/liter, with AST: ALT ratio & gt; 2.0, a value rarely seen in other liver diseases. In the United States, 40% of cirrhot-related deaths are caused by alcohol.
- Non-alcoholic steatohepatitis (NASH). In NASH, fat accumulates in the liver and eventually causes scarring. This type of hepatitis appears to be associated with obesity (40% of patients with NASH) diabetes, protein malnutrition, coronary artery disease, and treatment with steroid drugs. This disorder is similar to the signs of alcoholic liver disease, but the patient has no history of alcohol. Biopsy is needed for diagnosis.
- Chronic hepatitis C. Infection with hepatitis C virus causes liver inflammation and varying degrees of damage to the organs. For decades, this inflammation and damage can cause cirrhosis. Among patients with chronic hepatitis C, 20-30% will develop cirrhosis. Cirrhosis caused by hepatitis C and alcoholic liver disease are the most common reasons for liver transplantation.
- Chronic hepatitis B. Hepatitis B virus causes inflammation and liver injury that for decades can cause cirrhosis. Hepatitis D depends on the presence of hepatitis B and accelerates cirrhosis in co-infection.
- Primary biliary cholangitis (also known as primary biliary cirrhosis). The bile duct becomes damaged by the autoimmune process, which causes secondary liver damage. Patients may be asymptomatic or have fatigue, pruritus, and non-jaundice skin hyperpigmentation with hepatomegaly. There is a noticeable increase in alkaline phosphatase as well as increased cholesterol and bilirubin and usually positive anti-mitochondrial antibodies.
- Primary sclerosing cholangitis. PSC is a progressive cholesterol disorder that arises with pruritus, steatorrhea, fat-soluble vitamin deficiency, and metabolic bone disease. There is a strong association with inflammatory bowel disease (IBD), especially ulcerative colitis.
- Autoimmune hepatitis. The disease is caused by liver attacks by lymphocytes, causing inflammation and ultimately scarring and cirrhosis. Findings include increased serum globulin, especially gamma globulin.
- Hereditary hemochromatosis. Usually present with a family history of cirrhosis, skin hyperpigmentation, diabetes mellitus, pseudogout, or cardiomyopathy, all because of signs of excess iron.
- Wilson's disease. Autosomal recessive disorders are characterized by low serum serum serum serum plateletin and elevated liver copper levels in liver biopsy and urine urine increase 24 h. It may also have Kayser-Fleischer rings in the cornea and a change in mental status.
- Indian childhood cirrhosis is a form of neonatal cholestasis characterized by deposition of copper in the liver.
- Alpha 1-antitrypsin deficiency (A1AD). Autosomal recessive disorders decreased alpha 1 - antitrypsin enzyme levels.
- Cirrhosis of the heart. Because chronic right heart failure, which leads to congestion of the liver.
- Galactosemia
- Type IV glycogen storage disease
- Cystic fibrosis
- Hepatotoxic or toxic drugs
Pathophysiology
The liver plays an important role in protein synthesis (eg, albumin, clotting factors and complement), detoxification, and storage (eg, vitamin A). In addition, he participated in lipid metabolism and carbohydrates.
Cirrhosis is often preceded by hepatitis and fatty liver (steatosis), regardless of the cause. If the cause is removed at this stage, the change is fully reversible.
A pathological feature of cirrhosis is the development of scar tissue that replaces normal parenchyma. This scarring blocks the flow of the blood portal through the organs, raises blood pressure and disrupts normal functioning. Recent research shows the important role of stellate cells, the type of cells that normally store vitamin A, in the development of cirrhosis. Damage to the liver parenchyma (due to inflammation) causes activation of stellate cells, which increase fibrosis (through the production of myofibroblasts) and inhibit hepatic blood flow. In addition, stellate cells secrete TGF -? 1 , which leads to fibrotic responses and connective tissue proliferation. Furthermore, it secretes TIMP 1 and 2, a natural inhibitor of metalloproteinase matrices, which prevents them from breaking up fibrotic material in the extracellular matrix.
Because this process cascade continues, the fibrous tissue band (septa) separates the hepatocyte nodules, which eventually replace the entire liver architecture, which causes a decrease in blood flow throughout. The spleen becomes solid, which causes hypersplenism and spleen retention of platelets, which are necessary for normal blood clotting. Portal hypertension is responsible for the most severe complications of cirrhosis.
Diagnosis
The gold standard for the diagnosis of cirrhosis is a liver biopsy, by percutaneous, transjugular, laparoscopic, or fine-needled approach. Biopsy is not required if clinical, laboratory, and radiological data suggest cirrhosis. In addition, there is a small but significant risk of complications from liver biopsy, and cirrhosis itself predisposes to complications caused by liver biopsy.
The best predictors of cirrhosis are ascites, platelet counts & lt; 160,000/mm3, angiomata spider, and Bonacini cirrhosis discriminant score greater than 7 (as the number of scores for platelet count, ALT/AST ratio and INR per table).
Lab Findings
The following findings are typical of cirrhosis:
- Thrombocytopenia - usually multifactorial. Because of alcoholic marrow suppression, sepsis, lack of folate, lymphocytes in the spleen and decreased thrombopoietin. However, this rarely produces platelet counts & lt; 50 000/mL.
- Aminotransferase - AST and ALT is somewhat increased, with AST & gt; ALT. However, normal aminotransferase levels do not preclude cirrhosis.
- Alkaline phosphatase - slightly higher but less than 2-3 times the normal upper limit.
- Gamma-glutamyl transferaseÃ, - correlates with AP level. Usually much higher in chronic liver disease due to alcohol.
- Bilirubin - The normal level when compensated but may increase as the cirrhosis continues.
- Albumin - levels drop as synthetic liver function decreases with worsening cirrhosis, as albumin is exclusively synthesized in the liver
- Prothrombin time - increases, because the liver synthesizes clotting factors.
- Globulin - increases as it shunting the bacterial antigen away from the liver into the lymphoid tissue.
- Serum sodium - hyponatremia due to the inability to free water due to high levels of ADH and aldosterone.
- Leukopenia and neutropenia - due to splenomegaly with spleen margin.
- Coagulation defects - the liver produces most coagulation factors and thus coagulopathy correlates with worsening liver disease.
FibroTest is a biomarker for fibrosis that can be done instead of biopsy.
Other laboratory studies conducted on newly diagnosed cirrhosis may include:
- Serology for viral hepatitis, autoantibodies (ANA, anti-smooth muscle, anti-mitochondria, anti-MFI)
- Ferritin and transferrin saturation: excessive iron markers such as in hemochromatosis, copper and ceruloplasmin: excessive copper markers such as Wilson disease
- Immunoglobulin levels (IgG, IgM, IgA) - these immunoglobins are not specific, but can help differentiate between different causes
- Cholesterol and glucose
- Alpha 1-antitrypsin
Imaging
Ultrasound is routinely used in the evaluation of cirrhosis. It may indicate small and nodular liver in advanced cirrhosis along with increased echogenicity with irregularly emerging areas. Other liver findings suggesting cirrhosis in imaging are enlarged caudate lobes, widening fissures and enlarged spleen. Splenic enlargement (splenomegaly), usually less than 11-12 cm in adults, is a suggestion of cirrhosis with portal hypertension, in an appropriate clinical context. Ultrasound can also filter out hepatocellular carcinoma, portal hypertension, and Budd-Chiari syndrome (by assessing flow in the hepatic vein).
Cirrhosis is diagnosed with various elastographic techniques. Since liver cirrhosis is generally more rigid than a healthy liver, imaging of liver stiffness can provide diagnostic information about the location and severity of cirrhosis. Techniques used include temporary elastography, imaging acoustic-style radiation impulses, supersonic shear imaging and magnetic resonance elastography. Compared to a biopsy, elastography can sample a much larger, painless area. This shows a reasonable correlation with the severity of cirrhosis.
Other tests performed under certain circumstances include abdominal CT and MRI of the liver/bile ducts (MRCP).
Endoscopy
Gastroscopy (oesophageal, gastric, and duodenal endoscopic examination) is performed in patients with established cirrhosis to rule out esophageal varices. If this is found, localized prophylactic therapy may be applied (sclerotherapy or appeal) and beta blocker treatment may be initiated.
Rarely bile duct disease, such as primary sclerosing cholangitis, causes cirrhosis. Imaging of the bile ducts, such as ERCP or MRCP (MRI of the bile ducts and pancreas) may be helpful in diagnosis.
Pathology
In macroscopic terms, the liver is initially enlarged, but with the progression of the disease, it becomes smaller. Its surface is irregular, its consistency strong, and its color is often yellow (if associated with steatosis). Depending on the size of the nodule, there are three types of macroscopic: micronodular, makronodular, and mixed cirrhosis. In a micronodular form (Laennec's cirrhosis or cirrhosis portal), the regeneration nodule is below 3 mm. In macronodular cirrhosis (post-necrotic cirrhosis), the nodule is larger than 3 mm. Mixed cirrhosis consists of nodules of different sizes.
However, cirrhosis is defined by the pathological features of the microscopy: (1) the presence of hepatocyte regeneration nodules and (2) the presence of fibrosis, or the precipitation of connective tissue between these nodules. The visible fibrosis pattern may depend on the underlying insult causing cirrhosis. Fibrosis can also multiply even if the underlying process that causes it has been resolved or stopped. Fibrosis in cirrhosis can cause damage to other normal tissues in the liver: including sinusoids, Disse spaces, and other vascular structures, leading to changes in resistance to blood flow in the liver, and portal hypertension.
Because cirrhosis can be caused by many different entities that injure the liver in different ways, specific abnormalities of the cause can be seen. For example, in chronic hepatitis B, there is a liver parenchymal infiltrate with lymphocytes. In cardiac cirrhosis there is erythrocytes and a greater amount of fibrosis in the tissue around the hepatic vein. In primary biliary cholangitis, there is fibrosis around the bile ducts, the presence of granulomas and bile collections. Finally in alcoholic cirrhosis, there is liver infiltration with neutrophils.
Grading
The severity of cirrhosis is generally classified by Child-Pugh scores. This scoring system uses bilirubin, albumin, INR, the presence and severity of ascites, and encephalopathy to classify patients to class A, B, or C. Class A has a favorable prognosis, while class C has a high risk of death. The system was designed in 1964 by Child and Turcotte, and modified in 1973 by Pugh and others.
A more modern score, used in the allocation of liver transplantation but also in other contexts, is the Model for Late Stage Liver (MELD) score and its pediatric counterpart, Pediatric End-Stage Liver Disease (PELD) score.
The hepatic venous pressure gradient, (the difference in venous pressure between afferent and efferent blood to the liver) also determines the severity of cirrhosis, although it is difficult to measure. A value of 16 mm or more means the risk of death is greatly increased.
Prevention
The primary prevention strategy for cirrhosis is the entire population intervention to reduce alcohol intake (through pricing strategies, public health campaigns, and personal counseling), programs to reduce viral hepatitis transmission, and screening of relatives of people with hereditary liver disease.
Little is known about the factors that affect the risk and development of cirrhosis. Research shows that coffee consumption seems to help protect against cirrhosis.
Treatment
Generally, liver damage from cirrhosis can not be restored, but treatment can stop or delay further development and reduce complications. A healthy diet is recommended, because cirrhosis may be a consuming process. Close follow-up is often necessary. Antibiotics are prescribed for infection, and various medications can help with itching. Laxatives, such as lactulose, reduce the risk of constipation; their role in preventing limited encephalopathy.
Alcoholic cirrhosis caused by alcohol abuse is treated by abstaining from alcohol. Treatment for hepatitis-associated cirrhosis involves drugs used to treat various types of hepatitis, such as interferon for viral hepatitis and corticosteroids for autoimmune hepatitis. Cirrhosis caused by Wilson's disease, in which copper accumulates in the organ, is treated with chelation therapy (eg, penicillamine) to remove copper.
Prevents further liver damage
Regardless of the underlying cause of cirrhosis, the consumption of alcohol and paracetamol, as well as other potentially harmful substances, is not recommended. Vaccination of susceptible patients should be considered for Hepatitis A and Hepatitis B. Treating causes of cirrhosis prevents further damage; for example, giving oral antivirals such as entecavir and tenofovir in cirrhotic patients because Hepatitis B prevents the development of cirrhosis. Similarly, weight control and diabetes prevent damage to cirrhosis due to Non-alcoholic steatohepatitis.
Transplant
If complications can not be controlled or when the liver stops functioning, liver transplantation is necessary. The survival of liver transplants has increased during the 1990s, and the five-year survival rate is now around 80%. Survival rates are highly dependent on the severity of the disease and other medical risk factors in the recipient. In the United States, MELD scores are used to prioritize patients for transplantation. Transplantation requires the use of immune suppressants (ciclosporin or tacrolimus).
Decompensated cirrhosis
Decompensated manifestations of cirrhosis include gastrointestinal bleeding, hepatic encephalopathy (HE), jaundice or ascites. In patients with previously stable cirrhosis, decompensation can occur due to various causes, such as constipation, infection (any source), increased alcohol intake, treatment, bleeding from esophageal or dehydrated varicose veins. This can take the form of any complications of cirrhosis listed below.
People with decompensated cirrhosis generally require hospitalization, with close monitoring of fluid balance, mental status, and emphasis on adequate nutrition and medical care - often with diuretics, antibiotics, laxatives or enemas, thiamine and sometimes steroids, acetylcysteine ​​and pentoxifylline. Provision of saline is avoided, because it will increase the total body sodium content is already high which usually occurs in cirrhosis.
Palliative care
Palliative care is a specialized medical treatment that focuses on providing patients with the help of symptoms, pain, and stress of serious illnesses, such as cirrhosis. The goal of palliative care is to improve the quality of life both for patients and families of patients and it is appropriate at every stage and for all types of cirrhosis.
Especially at a later stage, people with cirrhosis experience significant symptoms such as abdominal swelling, itching, leg edema, and chronic abdominal pain that will receive treatment through palliative care. Because the disease can not be cured without transplantation, palliative care can also help with discussions about one's desire regarding the health care power of lawyers, Do not Resuscitate life decisions and support, and potential home care. Although proven to be beneficial, people with cirrhosis are rarely referred to palliative care.
Complications
Asites
Salt restriction is often necessary, because cirrhosis causes salt accumulation (sodium retention). Diuretics may be needed to suppress ascites. Diuretic options for inpatient care include aldosterone antagonists (spironolactone) and loop diuretics. An aldosterone antagonist is preferred for people who can take oral medication and do not require an urgent volume reduction. Loop diuretics can be added as additional therapy.
If rapid volume reduction is required, paracentesis is the preferred choice. This procedure requires the insertion of a plastic tube into the peritoneal cavity. The human albumin solution is usually given to prevent complications from rapid volume reduction. In addition to faster than diuretics, 4-5 liters of paracentesis are more successful than diuretic therapy.
Esophageal variceal bleeding
For portal hypertension, non-selective beta blockers such as propranolol or nadolol are commonly used to lower blood pressure through the portal system. In severe complications of portal hypertension, transjugular intrahepatic portosystemic shunting (TIPS) is sometimes indicated to reduce pressure on the portal vein. Because this shunting can aggravate liver encephalopathy, it is reserved for patients at low risk of encephalopathy. TIPS are generally considered only as a bridge for liver transplantation or as a palliative measure.
hepatic encephalopathy
High protein foods improve the balance of nitrogen, and theoretically will increase encephalopathy; In the past, this was because it was eliminated as much as possible from the diet. Recent studies have shown that this assumption is incorrect, and high-protein foods are even encouraged to maintain adequate nutrition.
Hepatorenal Syndrome
Hepperenal syndrome is defined as urine sodium less than 10 mmol/L and serum creatinine & gt; 1.5 mg/dl (or creatinine clearance 24 hours less than 40 ml/min) after volume expansion experiments without diuretics.
Spontaneous bacterial peritonitis
People with ascites due to cirrhosis are at risk of spontaneous bacterial peritonitis.
Portal gastropath hypertension
This refers to gastric mucosal changes in people with portal hypertension, and is associated with cirrhosis severity.
Infection
Cirrhosis can lead to immune system dysfunction, leading to infection. Signs and symptoms of infection may be nonspecific and more difficult to recognize (eg, aggravate encephalopathy but not fever).
Hepatocellular carcinoma
Hepatocellular carcinoma is a primary liver cancer that is more common in people with cirrhosis. People with known cirrhosis are often screened intermittently for the early signs of this tumor, and screening has been shown to improve yield.
Epidemiology
Cirrhosis and chronic liver disease were the 10th leading cause of death for men and twelve for women in the United States in 2001, killing around 27,000 people each year. The cost of cirrhosis in terms of human suffering, hospital costs, and high productivity loss. Cirrhosis is more common in men than in women.
The cirrhosis formed has a 10-year mortality of 34-66%, largely dependent on the cause of cirrhosis; Alcohol cirrhosis has a worse prognosis than primary biliary kolangitis and cirrhosis due to hepatitis. The risk of death by all causes increased twelve-fold; if one does not include direct consequences of liver disease, there is still an increased risk of death fivefold in all categories of disease.
Etymology
The word "cirrhosis" is a neologism derived from the Greek kirrhÃÆ'³s which means "yellowish, brownish yellow" (orange-yellow color of sick heart) and suffix -osis , namely "conditions" in medical terminology. While the clinical entity was known before, it was Renà © Laennec who gave it this name (in the same 1819 work in which it also described the stethoscope).
References
External links
- Liver Cirrhosis at National Digestive Diseases Information Clearinghouse (NDDIC). NIH Publication No. 04-1134, December 2003.
Source of the article : Wikipedia
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