Toxicant-associated fatty liver disease (TAFLD), and toxicant-associated

steatohepatitis(TASH) .

By:Prof.Rashed Hasan.Tropical Medicine.Zagazig University

Definition:

It is hepatic food polluted disease encompasses a wide spectrum of liver pathologies: ranging from simple steatosis(NAFLD) to the more aggressive form of nonalcoholic steatohepatitis(NASH), which in turn may lead to cirrhosis and, sometimes, to hepatocellular carcinoma (HCC).

Prevalence• The prevalence of Fatty Liver Disease (FLD) has been on

the rise, now affecting approximately 25% of adults. Around half of the fatty liver cases are associated with obesity, diabetes, or alcohol consumption. However, there are also many unexplained cases called Non-Alcoholic Fatty Liver Disease (NAFLD).

• A recent study shed light on the food pollution by heavy metals such as lead, mercury, and pollutants called persistant organic pollutants (POPs) as the cause of illness

Causes of TAFLD

• A recent study shed light on the reasons why people suffer from NAFLD. The study brought to light evidence that food pollution by heavy metals such as lead, mercury, and pollutants called persistant organic pollutants (POPs) can cause the illness. Thus,the main cause of

TAFLD& TASH is the food pollution :

Food pollution threatens our liver

BY

هذا خلق اللة

فأرونى ماذا خلق الذين من دونة

ظهر الفساد فى البر والبحر بما كسبت أيدى الناس

ليذيقهم بعض الذى عملوا لعلهم يرجعون

What is food pollution?.Food pollution: refers to toxic chemicals or biological contaminants that are found in food or that are associated with food. These chemicals and contaminants are either not naturally present in the food or are above the natural levels.. Agrochemicals:Agrochemicals are chemicals used in agricultural practices and animal husbandry with the intent to increase crops and reduce costs. Such agents include pesticides (e.g., insecticides, herbicides, rodenticides), plant growth regulators, veterinary drugs (e.g., nitrofuran, fluoroquinolones, malachite green, chloramphenicol), and bovine somatotropin (rBST). .Food poisoning, also called foodborne illness, is illness caused by eating contaminated food. Infectious organisms — including bacteria, viruses and parasites or their toxins are the most common causes of food poisoning.Infectious organisms or their toxins can contaminate food at any point of processing or production. Contamination can also occur at home if food is incorrectly handled or cooked.Food poisoning symptoms, which can start within hours of eating contaminated food, often include nausea, vomiting or diarrhea. Most often, food poisoning is mild and resolves without treatment. But some people need to go to the hospital.

Causes of food pollution

• . Possible sources of contamination include:

• 1-Enviromental through:-• Air: radionuclides (137Caesium, 90Strontium), polycyclic aromatic hydrocarbons (PAH)• Water: arsenic, mercury &lead• Soil: cadmium, nitrates, perchlorates• Polychlorinated biphenyls (PCB), dioxins, and polybrominated diphenyl ethers (PBDE) are

ubiquitous chemicals

• 2-Packaging materials: antimony, tin, lead, perfluorooctanoic acid (PFOA), semicarbazide, benzophenone, isopropyl thioxanthone (ITX), bisphenol A

• 3-Processing/cooking equipment: copper, or other metal chips, lubricants, cleaning, and sanitizing agents

• 4-Naturally occurring toxins: mycotoxins, phytohaemagglutinin, pyrrolizidine alkaloids, grayanotoxin, mushroom toxins, scombrotoxin (histamine), ciguatera, shellfish toxins (see shellfish poisoning), tetrodotoxin, among many others.

• 5-Cross-Contamination:Cross-contamination is the contamination of a food product from another source

• 1-Heavy metals role:• Four metals, namely lead, arsenic, cadmium and mercury, are of

particular concern in food because of their toxicity, especially for long term (chronic) intake since they may accumulate in the body and cause organ damage particularly to susceptible groups such as foetuses and young children.

• Although acute poisoning from these metals is possible, it is more likely that it happens through non-food route. Each of these metals also forms numerous compounds with other elements, which vary in properties and levels of toxicity to humans when ingested.

• Other than through exposure in workplace, some of these metal contaminants enter our body mainly through the food we eat while others mainly enter our body through other means like from the air we breathe or from direct skin contact.

Sources of Exposure to Metallic Contaminants

• lead can enter the body via a number of media including air, soil, water and food. Tobacco smoking, use of leaded petrol in vehicles, lead water pipe and leaded food can solder are reported to be major sources of lead exposure. Lead can be left on the surface of vegetables and/or absorbed into vegetables and cereals in areas where lead particles in air are deposited, and it can also bioaccumulate in aquatic food animals like shellfish and in offal of land animals.

• Mercury exposure . Besides diet, mercury exposure can occur through dental fillings that contain mercury compounds, occupational exposure and herbal medicines. . However, some large predatory fish like swordfish may bioaccumulate the more toxic organic form, methylmercury, in significant quantity.

• Arsenic exposure occurs mainly through consumption of aquatic food, especially shellfish and animals that feed from the bottom of the sea. Trace amounts of arsenic may also enter food plants through the application of agricultural chemicals like fertilisers .

• Cadmium exposure occurs mainly through the diet. Food crops that are polluted through contaminated soil or water may contain high concentrations of the metal. Crustaceans, molluscs and kidneys of food animals are other possible dietary sources of cadmium, as they are more likely to accumulate the metal.

• Industrial discharge, exhaust from vehicles, volcanic activities, natural erosion from soil and agricultural chemicals are sources of metallic contaminants, which can in turn contaminate food crops, fish and shellfish

2-Persistent Organic Pollutants (POPs)role

• The Dirty Dozen" Persistent Organic Pollutants (POPs):These 12 POPs are often referred to as the "dirty dozen":

• 1-Aldrin – an organochlorine insecticide;

• 2-Chlordane – a manufactured pesticide; Chlordane sticks strongly to soil particles at the surface and is not likely to enter groundwater. As a result it can stay in the soil for over 20 years and breaks down very slowly.

• 3-DDT – a synthetic pesticide: DDT is a toxicant;It has a half life of 2-15 years, and is immobile in most soils.

• 4-Hexachlorobenzene (HCB) – a fungicide;A fungicide formerly used as a seed treatment, especially on wheat.Known animal carcinogen (liver, kidney, thyroid);

• 5-PCBs (polychlorinated biphenyls):Used as coolants/insulating fluids, also used in flexible PVC coatings of electrical wiring and electronic components, pesticide extenders, cutting oils, flame retardants, hydraulic fluids, sealants (used in caulking, etc), adhesives, wood floor finishes, paints, and in carbonless copy paper.

• PCBs are very stable compounds and do not degrade readily.• Despite being banned in the 1970s due to their high toxicity, PCBs still

persist in the environment• Prior to the ban estimates have put the total global production of PCBs on

the order of 1.5 million tons

• 6-PCDDs (Polychlorinated dibenzodioxins) –referred to as DIOXINS.Dioxins are teratogens (cause birth defects), mutagens, potential human carcinogens .

• 7&8:Dieldrin – an insecticide&Endrin – an insecticide primarily affects the nervous system. Food contaminated with endrin has caused several clusters of poisonings worldwide, especially affecting children:

• 9-Heptachlor – an insecticide. Has a very stable structure, thus it can remain in environment for decades;Possible human carcinogen.

• 10-Mirex – an insecticide, flame retardant;Listed as a persistent, accumulative, and toxic pollutant

• 11-Toxaphene – an insecticide;Highly toxic

• 12-.Polychlorinated dibenzofurans: Highly toxic;

12 Commonly Contaminated Food

• FDA and USDA research shows high levels of pesticide and chemicals in these commonly contaminated foods:

• 1. Beef, Pork and Poultry . 2. Milk, Cheese and Butter . • 3. Strawberries. 4. Apples and Pears . • 5. Tomatoes . 6. Potatoes . 7. Spinach and Other Greens . 8. Coffee • 9. Peaches .10. Grapes. 11. Celery . • 12. Red and Green Bell Peppers .This is because:-

• 1- The EPA reports that meat is contaminated with higher levels of pesticides than any plant food.

• 2- Many chemical pesticides are fat-soluble and accumulate in the fatty tissue of animals.

• 3-The crop that is most heavily dosed with pesticides in America. On average, 300 pounds of pesticides are applied to every acre .

• 4-The thin skin does not protect the fruit from the dangers of these poisons.

• 5-79% of potatoes tested exceed safe levels of multiple pesticides

Pathogenesis of TAFLD

• The liver cleanses our blood and eliminates unwanted substances like chemical toxins or debris from our blood stream. When we overload ourselves with toxins such as alcohol or are exposed to increased levels of heavy metals, at a certain point the protective detoxifying capacity of the liver runs out. When healthy liver cells dysfunction or die, fat cells are deposited and replace them. A "fatty" liver is the result. It is only the liver that can purify the bloodstream and we only have one liver

• Further blood tests revealed that the high ALT levels in those with NAFLD are associated with heavy metals in the bloodstream — mercury, lead, as well as the pollutant PCB (Cave, M. et al, 2010)

• Currently, the disease progression from simple steatosis to NASH is explained by the “two-hit” theory . Steatosis represents the “first hit” and makes the liver more susceptible to various “second hits”, covering a wide variety of insults and conditions such as inflammatory cytokines, oxidative stress and toxins, Air pollution, soil and water pollutants, as well as chemicals, are acquiring increasing importance as risk factors that may contribute to the onset and progression of the disease .

• Several studies in mice, human adults and children showed that air pollution can worsen the adverse effects of obesity and insulin resistance (IR), increasing oxidative stress, thus suggesting a chief role in the onset and progression of which cause the disease progression.

The role of EDCs in the pathogenesis of NAFLD is not exhaustive, and additional epidemiological studies are needed to directly correlate these molecules to hepatic steatosis, MeS, IR and development of obesity . However, several studies have already linked EDCs with IR and related disorders, such as polycystic ovary syndrome (PCOS) . The proposed pathogenetic mechanism of action of EDCs in inducing IR includes increased lipid accumulation and peroxidation, which in turn fosters oxidative stress and decreases fatty acid β-oxidation, induces insulin receptor down-regulation, increasing apoptosis and specific changes in cytokines and adipocytokines. In particular, Bisphenol A (BPA), one of the most prevalent EDCs very common in food and drinks packaging, may exert a wide variety of metabolic effects. It has been shown to inhibit adiponectin production and secretion in adipocytes , and stimulate the release of inflammatory adipokines, such as IL-6 and TNFα from human adipose tissue.

• High levels of BPA exposure, and consequent elevated urinary concentrations in adult populations, were associated with CVD, diabetes, abnormal concentrations of liver enzymes and alkaline phosphatase, as well as high oxidative stress levels, establishing a relevant contribution of BPA to IR . Moreover, elevated serum levels of BPA in women have been linked to PCOS , suggesting an important association between PCOS and the risk of developing NAFLD, as well as with the degree of IR which rises proportionally to the development of the two pathologies .

• Thus, all these findings and observations hint that several endocrine disruptors may take part in the development of liver steatosis

• At molecular level,these molecules are known to bind a nuclear receptor called pregnane X receptor (PXR). This is mainly expressed in liver and intestine; it is involved in the integrity of the endocrine system and modulates the metabolism and excretion of xeno-and endobiotics .

• In recent years, it was demonstrated that its activation might play a key role in the induction of hepatic steatosis . Accordingly, PXR activation leads to increased hepatocellular lipid content, through increased intestinal lipid uptake and TGs synthesis, due to the up-regulation of genes involved in fatty acid uptake and mobilization [i.e., fatty acid translocase (CD36) and fatty acid binding protein 2 (FABP2)], and to the activation of the sterol responsive element binding protein (SREBP)

• NAFLD .However, more investigations about the effects of air pollutants on the development of NAFLD, particularly in pediatric and young individuals, are needed.

• The relevance of environmental contaminants in inducing NAFLD, is underscored by the fact that in recent years the terms toxicant-associated fatty liver disease (TAFLD), and toxicant-associated steatohepatitis (TASH) have been coined to indicate the spectrum of fatty liver injury in not obese people exposed to chemicals and xenobiotics . Furthermore, although nutritional status, co-exposures, and obesity appear to confer increased susceptibility to TAFLD/TASH , it is interesting to note that the effects of pollutants are not always linked to metabolic alterations; in fact TAFLD/TASH patients may have a low body fat mass and no IR

What are the symptoms of toxic hepatitis?

Clinically, toxic hepatitis can resemble any form of acute or chronic liver disease, such as viral hepatitis or bile-duct obstruction. Symptoms such as nausea, vomiting, fever, jaundice as well as abnormal liver blood tests and liver biopsy findings are often identical to viral hepatitis. On the other hand, symptoms like fever, abdominal pain and jaundice can mimic other liver conditions, such as stones blocking the bile ducts

How is the diagnosis of toxic hepatitis made?

• At present there is no clear test to prove the diagnosis. Therefore, the diagnosis is made based on a thorough assessment of a patient. First, the doctor must pay close attention to the environmental and occupational exposures to chemicals of each individual with liver disease.

• The doctor must also consider the time of exposure. Some forms of chemical liver injury will occur within days to weeks of the exposure; however, sometimes it takes many months of regular ingestion of a drug before liver injury becomes apparent.

• Liver Function Test (LFT) results:Don’t be alarmed by ‘abnormal’ liver function test results. Strange as it sounds, abnormal LFTs are not uncommon. In some people, results may often fall outside normal range and doctors may consider that increases or decreases of certain enzymes and proteins in your blood are not an indication of serious liver disease

• Ultrasound:An ultrasound scan is a routine procedure. Shows a hyper-echogenic, bright image

• Fibroscan:This is a non-invasive scan, very similar to an ultrasound scan, and is increasingly being used to assess the amount of liver fibrosis in a patient. The scan measures the stiffness of the liver. The stiffer the liver, the greater the degree of fibrosis; this is helpful in assessing the severity of NAFLD.

• Liver biopsy:The results of your biopsy are graded and staged according to the degree of liver inflammation and scar. The only definitive test. It is performed to confirm diagnosis, exclude other causes, assess extent and predict prognosis

Prevention

• Maintaining a healthy liver through eating a well-balanced & healthy diet is the best way to prevent TAFLD.

• Better control of existing medical conditions, such as glucose levels in diabetes, alcoholic hepatitis and HCV can also help in prevention the development and progression of TAFLD and TASH

How is toxic hepatitis treated?

• There is no specific treatment for TAFLD .

• If an individual has toxic hepatitis, further exposure to the offending chemical should be immediately discontinued and prevented.

• Removal of the offending chemical leads to rapid improvement often within days but sometimes several months may elapse before improvement is noted, even if chronic liver disease has already developed.

Nutritional Factors

Antioxidant vitamins like vitamin C, beta-carotene, and vitamin E are obviously quite important in protecting the liver from damage as well as helping in the detoxification mechanisms, but even simple nutrients like B-vitamins, calcium, and trace minerals are critical in the elimination of heavy metals and other toxic compounds from the body. The lipotropic agents, choline, betaine, methionine, vitamin B6, folic acid, and vitamin B12, are useful as they promote the flow of fat and bile to and from the liver. Lipotropic formulas have been used for a wide variety of conditions by nutrition-oriented physicians including a number of liver disorders such as hepatitis, cirrhosis, and chemical-induced liver disease. Lipotropic formulas appear to increase the levels of SAM and glutathione. Methionine, choline, and betaine have been shown to increase the levels of SAM.

Botanical Medicines

There is a long list of plants which exert beneficial effects on liver function. However, the most impressive research has been done on silymarin, the flavonoids extracted from silybummarianum (milk thistle). These compounds exert a substantial effect on protecting the liver from damage as well as enhancing detoxification processes. Silymarin prevents damage to the liver through several mechanisms: by acting as an antioxidant, by increasing the synthesis of glutathione and by increasing the rate of liver tissue regeneration. Silymarin is many times more potent in antioxidant activity than vitamin E and vitamin C. The protective effect of silymarin against liver damage has been demonstrated in numerous experimental studies. Silymarin has been shown to protect the liver from the damage produced by such liver-toxic chemicals as carbon tetrachloride, amanita toxin, galactosamine, and praseodymium nitrate

One of the key mechanisms by which silymarin enhances detoxification is by preventing the depletion of glutathione.

Silymarin not only prevents the depletion of glutathione induced by alcohol and other toxic chemicals, but has been shown to increase the level of glutathione of the liver by up to 35%, even in normals.Inhuman studies, silymarin has been shown to have positive effects in treating liver diseases of various kinds, including cirrhosis, chronic hepatitis, fatty infiltration of the liver, and inflammation of the bile duct. The standard dosage for silymarin is 70-210 mg three times/day

Statins decrease the production of bad cholesterol in the body and it is thought that this may have a benefit in treating NASH. In the past there have been concerns about the use of statins in patients with liver disease, but it is now clear that patients with fatty liver disease and NASH can take these drugs as safely as any other patient. However, there are few studies proving their effectiveness in the prevention or treatment of fatty liver disease. Omega-3 fatty acids, extracted from fish oil, may be effective in decreasing triglycerides and raising HDL. Improvements histologically and biochemically have been shown with thiazolidinediones,& metformin (radiological and biochemical improvement

Prognosis

• The prognosis depends on the stage of disease.

• 1-Steatosis• Has a good prognosis with abstinence and gradual weight

loss.• Cirrhosis develops in 1% to 2% over 20 years.• Central obesity and insulin resistance are risk factors for

diabetes mellitus, and cardiovascular and renal disease.• 2-Steatohepatitis• 10% to 12% of patients will progress to cirrhosis within

eight years. This is similar to the rate of progress towards cirrhosis in alcohol-related liver disease

•Many thanks