Release date: 2015-07-15
When a patient walks into the office of Joel Lavine at the University of California, San Diego, it would be difficult to find out the severity of the disease in a medical center in the mid-1990s. A brown scar called acanthosis nigricans extends from the back of his neck to the underarm, suggesting that there may be insulin resistance—a phenomenon in which cells cannot respond normally to hormones that control blood sugar.
A biopsy analysis revealed that the patient had an extremely severe injury to the liver: a large amount of fat filled the cells, crushing the nucleus and other contents. With the expulsion of healthy tissue from scar tissue, cirrhosis or severe liver injury is taking shape. According to the analysis, the patient's liver is equivalent to the liver condition of a middle-aged alcoholic, but he is actually only 8 years old.
For the pediatric hepatologist Lavine, the boy is clearly suffering from nonalcoholic steatohepatitis (NASH). The disease is usually associated with obesity. As the name suggests, NASH is not derived from alcohol abuse, but is caused by excessive fat in the liver, which can damage the liver due to excessive fat. Liver transplants will die.
Currently, NASH is spreading due to the increase in high-energy diets and the modern lifestyle of sedentary sedentary. It is reported that about 20% to 30% of people in the United States currently have excess fat in their livers (although they do not drink alcohol), which is a precursor symptom of fatty liver. In addition, it is understood that the disease is occurring even in the rural areas of India that are considered unlikely to occur. "This disease is becoming a serious problem around the world," said Vlad Ratziu, a liver disease scientist at the Sabate Charity Hospital in Paris, France.
Cause: Three sources
NASH has not been identified for decades, mainly because doctors have confused it with alcoholic cirrhosis (ASH), which is also associated with liver fat accumulation, but is caused by severe alcohol abuse.
In 1980, Jurgen Ludwig, a pathologist at Mayo Clinic in Rochester, Minnesota, and colleagues first used the term NASH to describe people who were not associated with alcohol and had liver damage due to obesity. Subsequently, a large number of NASH children dispelled the association between fatty liver and alcohol, Lavine said.
Nowadays, it is easy to find excess fat in the liver using imaging technology. However, it is even more difficult to detect the presence of severe fatty liver in many people. "The only way to understand if a patient has NASH is to have a needle biopsy," said Stephen Harrison, a gastroenterologist at the Brooke Army Medical Center in Texas. Although he said that this method only makes a very small incision on the skin, many patients still refuse to do related tests, so it is difficult to judge whether they have NASH. Researchers estimate that the disease affects 2% to 5% of the population in the United States.
According to Jay Horton, a molecular biologist at the University of Texas Southwestern Medical Center, fatty liver is "a disease caused by excess heat." The imbalance between energy intake and energy expenditure triggers a series of lesions in the liver. A large amount of fatty acids obtained from the diet in the human blood reach the liver and are transmitted to other body parts. “The liver is the body's traffic police,†says Elizabeth Parks, a nutritionist at the University of Missouri in Columbia, who says that the organ itself leaves little fat.
However, in some populations, the liver has become a hoarder and begins to store triglycerides, a form of fat. Sometimes the amount of storage is too high, so the liver "looks like butter," Lavine said. The study found that in addition to fatty acids in the diet, there are two other sources of fatty liver: outside the liver, fat storage cells called fat cells continue to release their contents, causing fat to accumulate in the liver; It also synthesizes part of the fat itself. An increase in these three sources leads to fatty liver formation.
In many fatty liver accumulations caused by metabolic abnormalities, insulin resistance is the most important problem, Chalasani said. This phenomenon occurs when cells respond to hormones, which is usually caused by excess nutrients in the diet, which leads to accumulation of fat in the liver in a variety of ways. Other factors, such as changes in the gut microbial species to genetics, may also result in increased fat accumulation in the liver.
Illness: high mortality
Along with fat accumulation, a series of typical health problems usually occur, including obesity, diabetes, and the like. But in general, excess fat is not fatal, Harrison said, more often "you will grow old with fat."
But for those who have developed into NASH, the situation has become very bad. Twenty-five percent of them develop cirrhosis and destroy the liver. Compared with people with benign fatty liver, NASH patients usually have two typical characteristics: First, when white blood cells sneak into the liver, the patient's liver inflammation will be more serious; second, when the most active liver cells swell to normal In the case of twice the case, a condition called swelling will presage the liver's failure.
These two symptoms can lead to many hidden problems: fibrosis of the liver or the formation of large amounts of scar tissue in collagen. As scars continue to grow, they will replace more and more livers, making healthy cells less and less, and sometimes even causing liver failure. Liver cirrhosis can also lead to liver cancer, but current scientists are still not clear about its pathogenesis.
In addition, it is still unclear why 1/3 of patients with fatty liver develop into NASH. "This tricky question remains to be answered," said Rohit Loomba, a liver disease scientist at the University of California, San Diego. Some scientists speculate that the reason is that fat itself is toxic to liver cells, while other evidence points to inflammation and oxidative stress.
Whether scar tissue will accumulate in fatty liver depends on the ability of the liver to self-heal. Dr. Anna Mae Diehl, a hepatologist at the Duke University Medical Center in Durham, North Carolina, and colleagues, in a study published in the Journal of Pathology in 2011, noted that an important signaling pathway activity during development Excessive, leading to the repair function of the liver of NASH patients.
Treatment: see the clouds see the day
At present, in addition to eating less, it is difficult for doctors to give other advice to NASH patients. If a patient's symptoms are already severe enough to liver failure, a liver transplant is required. But at the moment, "the ability to save a patient with a serious liver disease is still extremely limited," Caldwell said.
However, this hazy situation is about to change. Enticed by the profits behind chronic drug treatment (it is estimated that the relevant market annual profit can reach 35 billion US dollars), many biotech and pharmaceutical companies have launched the NASH drug research and development project. This year, at least two drugs for NASH are expected to enter Phase III clinical trials.
Some researchers say that the most promising NASH therapy to date is oleic acid. The liver produces bile acids that help the intestines absorb fat, helping to manage fat and glycogen metabolism. Abecholic acid is a modified bile acid that stimulates cell receptors, promotes sensitivity to insulin, and reduces triglyceride levels in the blood.
However, researchers and investors in pharmaceutical companies are still worried. Loomba pointed out that none of the drugs currently tested can benefit half of NASH patients. Although oleic acid reduces liver fibrosis, it raises low-density lipoprotein cholesterol, which increases the risk of cardiovascular disease. This phenomenon is worrying, Chalasani said: "Because these people already have a higher risk of coronary heart disease and cardiovascular disease than the average person."
Despite this, a Phase III clinical trial of a cholestyramine for 2,500 patients with severe liver fibrosis has been scheduled to start later this summer. For the first time, NASH researchers have welcomed the first light to treat severe cirrhosis. Whether it's stopping or reversing NASH, Brent Neuschwander-Tetri, a hepatologist at St. Louis University School of Medicine, said it ended up with "a reachable goal."
Source: Science Network
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