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Editor-in-chief summary: This original blog, aimed at Chinese +10% hepatitis patients, provides a summary explanation of the ins and outs of drug-induced liver damage hepatitis, official resources and performance statements of liver damage, sub-categories of conditions, and lists the causes of liver damage And finally put forward professional opinions and suggestions on the health management of patients. If you have any questions, please contact Chelsea98.com.
Drug-induced liver injury is one of the most common adverse drug reactions in clinical practice, and it is also one of the most common causes of acute liver injury. Severe cases can lead to acute liver failure or even death.
Drug-induced liver injury, also known as drug-induced liver injury, drug-induced liver injury, drug-induced liver disease, drug-induced liver disease (Drug-Induced Liver Injury, DILI), referred to as drug-induced liver, refers to the use of one or several drugs, Different degrees of liver damage caused by the drug itself or its metabolites, or liver damage or inflammation caused by a special body's hypersensitivity or reduced tolerance to drugs.
However, before considering whether the liver function is abnormal due to drugs, it is necessary to identify whether there is liver function abnormality, because most chronic diseases are caused by liver function abnormalities. Non-drug-induced liver dysfunction mainly includes viral hepatitis (type B, C), alcoholic liver disease, autoimmune liver disease and so on. There is also a physical allergic reaction, which can quickly cause liver function abnormalities. Because the symptoms appear quickly, it is easier to find; in addition to feelings of fatigue, loss of appetite, vomiting and nausea, etc., there are also fever and nausea in many cases. Systemic symptoms such as rash. In Chinese medicine, there is a symptom called "hypophagia". The appetite is decreased, and the stomach takes the initiative, which is the term of traditional Chinese medicine. "Acceptance" means to accept and accommodate water valleys. In the entire digestive tract, the gastric cavity has a large capacity and is known as the "sea of water and valleys". The intake of food is one of the main functions of the stomach. In some cases, decreased appetite is one of the gastrointestinal symptoms of liver cancer, although the term "liver" in Chinese and Western medicine has different categories.
In recent years, the proportion of drug-induced liver injury among patients requiring hospitalization due to liver disease in China has been increasing.
Among liver diseases in China, the incidence of DILI is second only to viral hepatitis and fatty liver disease (including alcoholic and non-alcoholic). The incidence is relatively high. However, due to the lack of specific clinical manifestations and diagnostic markers, especially when drugs The onset of chronic liver injury is relatively insidious and often cannot be detected or diagnosed clinically. Therefore, the occurrence of drug-induced liver injury will significantly increase the additional social and economic burden.
In China, the most common drug that causes drug-induced liver injury is antibiotics, but anti-tuberculosis drugs are the main ones, followed by broad-spectrum antibiotics. In the United States, the drugs most commonly involved in drug-induced liver injury are also antibiotics; antineoplastic drugs can cause a transient increase in transaminase levels in many patients, and in some patients, they can also cause jaundice, leading to severe liver damage (such as Imatinib, Nilotinib, Bortezomib, Pazopanib and Rebocinib). In the statistics of European and American countries, drug-induced liver injury accounts for 3%-5% in jaundice hospitalizations, and 10% in acute hepatitis hospitalizations. It is the most common cause of acute liver failure.
The Health Canada website repeatedly reminds patients of drug-induced liver damage and routine liver function tests. Analgesics and antipyretics containing acetaminophen are common causes of liver damage, especially when the dose is greater than the recommended dose. People who drink excessively are more likely to have this problem. Non-steroidal anti-inflammatory drugs (nsaids), such as ibuprofen, diclofenac, and naproxen, may also cause drug-induced hepatitis. In patients treated with ESBRIET, liver damage with transient and asymptomatic elevation of transaminase is often reported. The incidence of drug-induced liver injury is 14-19 per 100,000. You may think that this number does not seem to be high. However, because drug-induced liver injury involves a large number of drugs and complex mechanisms, it is difficult to clearly attribute liver injury to many cases Drugs, the number of reported cases may be only 1/10 of the actual number, which is greatly underestimated.
Table 1:Types of drug-induced liver injury
Table 2:Phenotypes of drug-induced liver injury
In February 2019, Chinese scholars published an online article entitled "The Incidence and Etiology of Drug-induced Liver Injury in Mainland China" in the top journal "Gastroenterology" in the field of digestive diseases. Studies have shown that the annual incidence of DILI in the general population in China is at least 23.80 per 100,000 people, which is higher than reported in Western countries and has become a problem that cannot be ignored. At the same time, the study also showed the main suspicious drugs (including western medicine, Chinese patent medicine, herbal medicine, dietary supplements, etc.) that cause drug-induced liver injury in the Chinese population, as well as the clinical features and current treatment status. research shows,The most important drugs that cause liver damage in China are various health products and traditional Chinese medicines (accounting for26.81%), anti-tuberculosis drugs (accounting for21.99%),Anti-tumor drugs or immunomodulators (accounting for 8.34%). The study found that patients with 13% had chronic drug-induced liver injury. 23.38% patients have basic liver diseases such as viral hepatitis and fatty liver when DILI occurs. These patients have more serious liver damage and are at greater risk of liver failure and death.
At present, there are more than 30,000 kinds of drugs or medicinal foods that we come into contact with in daily life, and more than 1,000 kinds of drugs can cause DILI. Therefore, DILI has become a serious public health problem that cannot be ignored. In addition,Traditional Chinese medicine causes more cholestasis liver damage than other types, often with jaundice as the first manifestation, which is also the main reason for patients to see a doctor..
On March 19, 2014, the 14th Drug-induced Liver Injury Conference co-sponsored by the U.S. Food and Drug Administration (FDA) Center for Drug Evaluation and Research (CDER) and U.S. Drug Research and Manufacturers was held in the Eastern Sea, Maryland, United States. The Conference Center of the Zveer Marriott Hotel was held. This conference promoted the in-depth research of DILI and found reasonable nutrition solutions.
This article is about drug-induced liver damage (DiLi) Make an analysis of the ins and outs.
1. Why is the liver more susceptible to drug damage than other organs?
1. The liver has more chances to be exposed to drugs: intravenous drugs enter the blood, the blood flow of the liver is very large, and the drugs almost have to pass through the liver;
2. The absorption of drugs is also related: the drugs are absorbed from the stomach into the small intestine, and after absorption, they also enter the blood vessels. The blood with the drugs must enter the liver through the portal vein;
3. The liver is the main organ for drug metabolism. Drugs need to play a role in the liver and have a biochemical reaction. Drugs are metabolized in the liver. In the metabolic process, metabolites may cause damage to the liver;
The liver is the body's largest detoxification organ. The liver can not only transform the nutrients in food into substances that the body can use, but also transform toxic substances into non-toxic substances and ensure that they are excreted from the body. When the liver works effectively, the body is metabolized in balance and remains active. However, western medicine, Chinese medicinal materials, certain condiments, poor nutritional supplements, and harmful synthetic additives, and even certain excess foods (such as alcohol, sugar, unhealthy fats, refined starch foods, etc.) may sometimes damage the liver Function, leading to dangerous liver problems. The data shows that there are more cases of acute liver failure caused by prescription drugs, over-the-counter drugs and nutritional supplements than all other factors combined. Acute liver failure is the rapid deterioration of liver function.
The causes of DILI caused by drugs: (1) The direct liver toxicity of drugs and their metabolites destroys liver cell membranes and cytoskeleton, or causes nucleic acid transformation and mutation to cause liver cell death; (2), some drugs interfere Certain aspects of cell metabolism, such as inhibiting enzyme activity or hindering a certain secretion process, resulting in reduced liver function; (3) drugs with enzyme inducers can accelerate the metabolism of the drug itself and other drugs, and produce more toxic products And damage liver cells; drugs with enzyme inhibitors can increase the concentration of other drugs, increase their toxicity or make drugs accumulate in the liver, causing liver damage; (4), allergic reactions caused by drugs and their metabolites, through Cellular immunity or humoral immunity causes liver cells to be recognized and killed by the immune system, damage liver function, and even cause severe hepatitis.
The FDA has identified several instances of liver damage caused by poor nutritional supplements. To this end, the FDA has issued a warning to the public: Do not easily believe in weight loss and bodybuilding products. For example, after a Texas company discovered that its products were related to liver damage and non-viral hepatitis, it agreed to recall and destroy certain nutritional supplement products with health risks.
2. Professional website for drug-induced liver injury information
1. China's professional website for drug-induced liver injury http://www.hepatox.org/
2. The professional website of drug-induced liver injury in the United States http://livertox.nih.gov/
3. Canadian professional website for drug-induced liver injury https://www.healthing.ca/diseases-and-conditions/liver-diseases/drug-induced-liver-injury
China’s HepaTox includes six major sections, including the latest information, medical knowledge, drug information, technical terminology, industry resources, and online applications. It can provide professional and non-professionals with a large amount of knowledge and information about DILI, and can also provide targeted DILI provides a technical platform for clinical and translational research.
Compared with LiverTox, which has been announced in the United States, HepaTox covers almost all of its information and functions, and adds some information and functions. For example, Chinese herbal medicine information for DILI has been added to the drug information section; electronic data collection and management (EDC) system for clinical research and online appointment tools have been added to the online application section, and the online diagnostic score scale in this section can be converted into Tools used by clinicians, and LiverTox only introduces the Russell Eucalyptus Causality Assessment Method (RUCAM) and Maria/Vitolino Clinical Scale (M&V) for assisting diagnosis.
3. Biochemical markers for diagnosis of drug-induced liver injury
So far, the main biochemical markers diagnosed by DILI are serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP) and total bilirubin (TBIL). It is considered to be a more specific liver damage index. Hy's rule is based on these indicators and has been widely used in DILI's biochemical diagnostic indicators. However, these indicators reflect the liver damage that has occurred, and only patients with 40% increased in the early stage of DILI.
Diagnosis of DILI is supported by the following: age older than 50; taking many drugs; taking drugs known to have liver toxicity; the appearance of special serum autoantibodies such as anti-M6, anti-LKM2, anti-CYP1A2, anti-CYP2E1, blood drug analysis positive; liver The biopsy showed evidence of liver damage such as drug deposition and small vesicular fatty liver, eosinophil infiltration, and central lobular necrosis.
The US Food and Drug Administration (FDA)/Center for Drug Evaluation and Research (CDER) pointed out that as a biomarker of DILI, the following conditions should be met: (1) The possibility of DILI can be judged before clinical manifestations; (2) Provide guidance for the prognosis of DILI; (3) Improve the diagnosis rate of the existing DILI; (4) Be able to distinguish the severity of DILI; (5) Be able to distinguish between adaptive and progressive DILI.
DILI biomarkers are mainly divided into two categories: hepatocyte damage and cholestasis. Hepatocyte damage includes microRNA (miR), cell necrosis and apoptosis indicators, mitochondrial damage indicators, high mobility group protein 1 (HMGB1), human leukocyte antigen (HLA) and immune indicators. The miRs that can be used as DILI biomarkers include miR-122, miR-192, miR-802, miR-193, miR-144, miR-200a, miR-21, miR-29c and miR-802, of which miR-122 is Liver-specific miR, in the early diagnosis of DILI caused by acetaminophen (APAP), its specificity and sensitivity are significantly higher than that of ALT, which has certain application value.
4. Epidemiology and mechanism of drug-induced liver injury
Liver diseases caused by drugs account for 20%–50% in non-viral liver diseases, and 15%–30% in fulminant liver failure. According to a survey in France, the incidence of DILI within 3 years is 14 persons per 100,000 inhabitants/year, of which 12% patients are hospitalized and 6% patients die. It can be seen that DILI in hospitalized patients accounts for only a small part of the total DILI population. Among liver diseases in China, the incidence of DILI is second only to viral hepatitis and fatty liver disease (including alcoholic and non-alcoholic). The incidence is higher, but because the clinical manifestations are not specific or relatively insidious, they often cannot be detected or cannot Was diagnosed.
Drugs cause liver damage through two main mechanisms:
- The direct toxic effects of drugs and their intermediate metabolites on the liver: the active metabolites such as electrophilic radicals and free radicals produced by the CYP metabolism of drugs are usually combined with glutathione (GSH) to detoxify and do not cause liver damage. However, when overdose or hereditary drug metabolism is abnormal, active metabolites such as electrophilic radicals and free radicals are produced in large quantities, which deplete GSH in the liver, and cause lipid peroxidation through the binding of unsaturated fatty acids in cell membrane phospholipids. Cause membrane damage, damage to calcium-ATP homeostasis, damage to mitochondria, necrosis of liver cells; electrophilic groups can also interact with thiol and lysine residues of hepatocyte protein cysteine residues. The covalent binding of nucleophilic groups such as amino groups causes actin to condense and destroy the cytoskeleton, causing cell membranes to lose their chemical and physiological properties and cause cell necrosis. Drugs and their metabolites can also interfere with a certain link of cell metabolism, affect protein synthesis or the normal secretion of bile acids, and cause liver cell damage or/and cholestasis. This type of drug-induced liver injury is dose-dependent, predictable, and can be replicated in animals.
- The body's idiosyncracy response to drugs, including allergies (immune idiosyncrasies) and metabolism (metabolic idiosyncrasies). The former is mainly due to the fact that the drug or its active metabolite acts as a hapten and binds to endogenous proteins to form autoantibodies with immunogens, which can induce death or destruction of liver cells; this immunogen can also be recognized by CD4+ cells and induce production Some cytokines further activate CD8+ T cells and cause Fas or perforin-mediated hepatocyte apoptosis and cell damage. The latter is mainly related to the genetic polymorphism of individual drug metabolizing enzymes, which reduces the ability to metabolize drugs, causing the accumulation of drug prototypes or/and intermediate metabolites, resulting in toxicity to liver cells. The DILI induced by the body’s idiosyncratic response to the drug has no correlation with the dosage and the course of treatment. This type of liver damage only occurs in a few or a few people, and is safe for most people and is unpredictable. In laboratory animals It is often impossible to replicate on the model.
5. What are the drugs that cause drug-induced liver injury?
There are a wide range of drugs that cause DILI, and many Chinese and Western drugs have liver toxicity. According to the reported data, the drugs with a high probability of adversely affecting the liver are antibiotics, digestive agents, anticancer drugs, antiviral drugs, and anti-inflammatory and analgesics. The most common Western medicines are:
1. Antibiotics, such as anti-tuberculosis drugs rifampicin, isoniazid, etc.; macrolide drugs, such as erythromycin, spiramycin, etc.; tetracyclines, etc.;
2. Antipyretic and analgesic drugs: aspirin, phenylbutazone, etc.;
3. Antipsychotic drugs: chlorpromazine, perphenazine;
4. Antidepressant: Amitriptyline;
5. Anti-epileptic drugs: sodium valproate;
6. Sedatives: phenobarbital, etc.;
7. Anti-hyperthyroidism drugs: tapazole, thyroxine, propylthiouracil, etc.;
8. Anti-tumor drugs: mitomycin, dactinomycin, cyclophosphamide, etc.;
9. Hypoglycemic drugs: Glydiabetes, worship sugar and equality;
10. Cardiovascular medication: verapamil, ambrolidine, etc.
"Three-drug". Although the toxicity of traditional Chinese medicine is different from that of western medicine, there is still toxicity. Traditional Chinese medicine is a kind of partiality, and what Chinese medicine treats diseases is the "toxicity" of Chinese medicine, that is, partiality. "Treat the partial with partiality" or "confront the poison with poison" is the basic principle of traditional Chinese medicine. Recent studies have shown that DILI caused by traditional Chinese medicine accounts for 4.8%–32.6% in clinical drug-induced liver injury, which has become a problem that cannot be ignored. In addition, some "bad health products" and weight-loss drugs also often cause DILI, which requires attention. Traditional Chinese medicines include Indigo Naturalis, Shan Dougen, Shan Cigu, Rhubarb, Xanthium, Acacia, Wild Lily, Trichosanthes, Mugwort, Chuan Neem, Minzhou Shuanghuanglian Capsules, etc. However, there is also the latest evidence that: "overtaking", "prescribing heavy medication", "taking a large amount of medicine without scruples", "taking Chinese medicine because of excessive use", etc., are the main causes of DILI caused by Chinese medicine.
6. What are the manifestations of drug-induced liver injury?
DILI usually occurs 1-4 weeks after medication.
1. The prodromal symptoms of DILI, such as fever, chills, urticaria-like or measles-like rash, itching, joint pain, or lymph node swelling and pain. In the early stage of onset, peripheral blood eosinophils increased (up to 6% or more) or white blood cells increased. Severe cases are similar to acute or subacute liver necrosis, cholestasis, bleeding tendency, ascites formation, liver cirrhosis, liver coma and even death. More severe DILI can also cause large-scale liver necrosis, severe hepatitis, severe jaundice, coagulopathy, hepatic encephalopathy, and upper gastrointestinal bleeding.
2. The extrahepatic manifestations of DILI may include hemolytic anemia, bone marrow injury, kidney injury, gastrointestinal ulcers, pancreatitis, etc., as well as increased eosinophils and lymphocytes. The specific manifestations of DILI are roughly the same as other hepatitis. There are patients with liver cell damage, such as fatigue, loss of appetite, nausea and vomiting, yellow urine, liver discomfort, etc., liver enlargement accompanied by tenderness, elevated transaminase, and blood addiction. Acid cells are elevated; there are mainly cholestasis, which is manifested as intrahepatic bile duct cholestasis, accompanied by liver cell damage, manifested as skin, sclera, yellow urine, skin itching, and lighter stool color. DILI has various pathological manifestations. All cells in the liver are affected by drugs; all types of liver damage can be caused by drugs. The incidence of this disease is gradually increasing, accounting for 2% in all jaundice hospitalized patients, and 10%–20% in fulminant liver failure. 1/4 to 2/3 of chronic hepatitis belong to medicated liver, among which the elderly are more common.
The risk of DILI is affected by many acquired and hereditary factors and should be considered in the diagnosis. Acquired factors include age, gender, nutritional status (obesity promotes liver toxicity caused by halothane), pregnancy (most tetracycline-induced severe hepatitis occurs in pregnant women who use tetracycline intravenously), chronic alcohol abuse, drug interactions, and extrahepatic diseases . Genetic factors include defective acetylation and abnormal sulfonation and oxidation of cytochrome P450 enzymes, glutathione synthase deficiency, glutathione S-transferase deficiency, and genetic variation of the immune system. In addition, existing or coexisting liver disease can also affect the injury model.
7. Clinical treatment plan for drug-induced liver injury
1. Immediately stop the drug: once it is confirmed or suspected to be related to the drug, all suspicious liver-damaging drugs should be stopped immediately, and most cases can recover after stopping the drug.
2. Supportive treatment: (1) Pay attention to rest, and absolute bed rest for severely ill patients; (2) Sufficient calories, adequate protein, and multiple vitamins such as vitamin C, E, B, etc. to facilitate liver cell repair and regeneration , There is a bleeding tendency to add vitamin K, which is a kind of nutritional therapy.
3. Detoxification treatment: patients with acute poisoning can take gastric lavage, catharsis, activated carbon adsorption and other measures to eliminate gastrointestinal residual drugs, and use hemodialysis, abdominal dialysis, hemoperfusion, plasma exchange and other methods to quickly remove drugs in the body; antidote Applications: Including non-specific such as glutathione, N-acetylcysteine, sodium thiosulfate, steroid hormones, UDCA, S-adenosylmethionine, polyene phosphatidylcholine, etc. and specific chelating agents Such as dimercaprol, penicillamine, mercaptosuccinic acid, cysteamine, calcium sodium edetate and so on.
4. Anti-inflammatory and liver-protecting treatment: According to the patient's clinical conditions, anti-inflammatory and liver-protecting drugs or functional nutrient treatments can be appropriately selected, including anti-inflammatory and liver-protecting glycyrrhizic acid preparations, silymarins, and anti-free radical damage. Tiopronin, reduced glutathione, N-acetylcysteine, polyene phosphatidylcholine, which protects liver cell membranes, promotes liver cell metabolism: adenosylmethionine, glucurolactone, complex coenzyme, door Potassium magnesium aspartate, hepatocyte growth factor that promotes liver cell repair and regeneration, adenosylmethionine that promotes bilirubin and bile acid metabolism, potassium magnesium aspartate, ursodeoxycholic acid, etc. Some traditional Chinese medicine preparations such as Huganning, Hugan tablets, bicyclol, and five ester capsules are also available. Severe symptoms and severe jaundice can be treated with corticosteroids for a short time without contraindications. In principle, the medication should be as streamlined as possible, and the functional nutrients have great potential.
5. Treatment of liver failure: including medical support treatment, artificial liver support treatment can be considered when necessary. Liver transplantation may be the only effective treatment for those with severe disease and rapid progress.
6. For those with allergies, deep jaundice, and severe illness, adrenal glucocorticoids can be used, and the dosage will be gradually reduced after the illness is relieved. Patients with cholestasis should be treated with phenobarbital and cholestyramine, and those with severe jaundice can be treated with the traditional Chinese medicine Yinzhihuang.
Of course, corticosteroids, like all other drugs, have side effects. For example, centripetal obesity, body shape changes, hairy skin, and even hairy beards in female patients; it can cause the body's anti-infection ability to decline, and the wound healing speed is slowed; it can also aggravate gastrointestinal ulcers, induce hypertension, mental illness, and osteoporosis , Aseptic necrosis of the femoral head, etc. But this is also a phenomenon that only appears after long-term, high-dose repeated application. Generally, short-term local block treatment will not cause these reactions. For the sake of safety, doctors always use it cautiously for patients with severe hypertension, gastrointestinal ulcers, diabetes, and mental illness.
8. Health management of drug-induced liver injury
- Nutrition therapy is the most basic nutritional management measure. Among them, functional nutritional preparations that can alleviate and repair liver damage include: milk thistle (silymarin), coenzyme Q10, VC, VB, VE, VK, digestive enzymes, probiotics, seal oil, etc.;
- Probiotic therapy (microecological preparation therapy) is a saturation therapy and a conservative therapy. It can help improve liver function and reduce inflammation, including drug-induced liver injury. It is not only common people understand that probiotics are only an improvement program for the intestines ；
- In terms of common foods to improve and repair liver function, recommended: yogurt, ginger, garlic, avocado, beets, carrots, grapefruit, lemon, walnut, olive oil, and green leafy vegetables, etc.;
- Less salt, less sugar, less additives, less refined processed food; more water, more fruits and vegetables, more fresh cooked food; eating seasonal food, bitter food, repair liver function; for some people, excessive spicy food will damage liver function;
- Healthy fats can improve liver function: olive oil, linseed oil, perilla seed oil, walnuts, pine nuts, salmon, omega-3, seal oil, etc. are all healthy fats; hydrogenated vegetable oils and artificial trans fatty acids are rejected;
- Ensure sleep, don’t stay up late; the biological clock in the liver plays an important role in regulating energy metabolism, enzyme expression and other homeostasis. Disorders of the biological clock can accelerate the development of fatty liver, cirrhosis, hepatitis, liver cancer and other diseases. Diseases will in turn affect the function of the biological clock;
- Choose the right exercise. Regular exercise is the key to maintaining liver health. Exercise can improve liver function and reduce the risk of fatty liver, liver cancer and other liver diseases. It can also accelerate blood circulation, enhance liver blood volume and bile secretion, and improve the blood circulation in the intestinal cavity, and actively repair liver function;
- Control alcohol consumption, avoid cigarettes, refuse toxins and drugs, do not take drugs and unhealthy nutrients; even if you must take drugs, you must use diet therapy to eliminate the side effects of drugs and reduce the damage to the liver by drugs;
- For the "four highs" that affect liver function, as well as liver-related diseases such as hepatitis, polyps, cysts, tumors, etc., it is necessary to check and treat as soon as possible without delay;
For this disease, there are many Chinese and Western medicine treatment plans, but often due to personal differences, a lot of money and time are spent, but the results are often not satisfactory. Please pay attention to "Canada Dr. Dragon Detox Body Sculpting Immune Repair Course and Training" to teach you cutting-edge health management and diet structure; reduce fat and weight, eliminate body inflammation, completely improve liver function, and repair your own immunity from the inside to the outside.
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The last and most important words
Many people think it is a normal thing to take medicine. As everyone knows, drugs have great damage and side effects to the liver. Many people also know that disease prevention is the main focus and try not to take medicine, but they do not have enough healthy eating habits and healthy lifestyles. To avoid drug abuse or nutritional supplements, everyone must have a comprehensive knowledge and understanding of the liver and drugs.
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Dr. Long, escort the health care of you and your family.
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Chelsea98.com--Wise Week Million Dragon's Great Health Project Dr. Kyle Long, registered dietitian, registered health manager, from Smart Week Smart Financial Education Group-Sincere, clear and efficient personalized FAH financial quotient and health quotient education