This document discusses toxicant-associated fatty liver disease (TAFLD) and toxicant-associated steatohepatitis (TASH). It defines these conditions as forms of hepatic disease caused by food pollution from heavy metals and persistent organic pollutants. The main causes of TAFLD/TASH are identified as food pollution from heavy metals like lead and mercury, as well as pollutants like PCBs. Several studies have found associations between these toxicants and non-alcoholic fatty liver disease. The document discusses the pathogenesis and progression of TAFLD/TASH, as well as symptoms, diagnosis, and the role of endocrine disrupting chemicals in relation to these conditions.

1. Toxicant-associated fatty
liver disease (TAFLD), and
toxicant-associated
steatohepatitis(TASH) .
By:Prof.Rashed Hasan.
Tropical Medicine.Zagazig University

2. 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).

3. 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

4. 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 :

5. Food pollution threatens our
liver
BY

6. هذا خلق اللة

7. فأرونى ماذا خلق الذين من دونة

8. ظهر الفساد فى البر والبحر بما كسبت أيدى الناس
ليذيقهم بعض الذى عملوا لعلهم يرجعون

12. 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.

13. 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

14. • 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.

15. 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

17. 2-Persistent Organic Pollutants
(POPs)role

19. • 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.

20. • 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

21. • 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;

22. 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

23. 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)

25. • 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.

26. 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.

27. • 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

28. • 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)

29. • 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

31. 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

32. 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

33. • 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

34. 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

35. 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.

36. 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.

37. 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 silybum
marianum (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

38. 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

39. 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

40. 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

41. •Many thanks