Hepatotoxins

Done by : Shaima Adel

Objectives

By the end of this lecture you should be able to;

• Define hepatotoxins
• Classify hepatotoxins
• Recognize occupations at risk
• Describe mechanism of toxicity
• Identify clinical presentation
• Describe morphology of toxic hepatic injury
• Diagnose toxic liver injury
• Manage hepatotoxicity
• Describe prevention ways

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Acknowledgment

• First and foremost, I thank "ALLAH" the most merciful for granting me the power to proceed and to accomplish this work.
• I like to express my sincere gratitude to

Prof. Mahmoud Saleh

Prof. Hassan Elfar

Assist. Prof. Omyma Hassan

Assist. Prof. Rasha Shaker

Department of Public Health & Community Medicine, Benha Faculty of Medicine, for their continuous encouragement and generous assistance.

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Definition

A toxic chemical substance that damages the liver. (EASL, 2019)�

Classification (Jerrold B. et al, 2000)

• Synthetic
• drugs (e.g., acetaminophen)
• metals (iron, copper),
• industrial products (aromatic solvents, halogenated hydrocarbon)
• Pesticides

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• Natural
• plant components (phytotoxins),
• fungal metabolites (mycotoxins) e.g; aflatoxin,
• bacterial products (e.g., cyanobacterial microcystin)

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Occupations at risk

Occupations at risk

Mechanism of action

Intrinsic hepatotoxins

• Direct
• Indirect

Idiosyncratic hepatotoxins

Clinical syndromes induced by hepatotoxins

Acute

Subacute

Chronic

Morphology of toxic injury to the liver

Acute hepatic injury

• Necrosis
• Steatosis
• Acute cholestasis

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Chronic hepatic injury

• cirrhosis
• Fibrosis
• Chronic cholestatic injury
• Porphyria cutanea tarda
• Granuloma
• Neoplasm

Morphology of toxic injury to the liver

Acute hepatic injury

• Necrosis
• Steatosis
• Acute cholestasis

Necrosis

Degeneration of hepatocytes leading to their death. It may be;

• Focal
• Zonal
• Massive

• TCE
• CCL4

• Halothan
• Aflatoxin

Zonal

• TNT

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• Nitropropane solvents

Massive

Steatosis (fatty liver)

> 5% of hepatocytes containing fat

> 5 g lipid / 100 g hepatic tissue

• Yellow phosphorus
• Arsenical pesticides
• CCL4

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• Diabetes
• Hypertriglyceridemia
• Obesity
• Alcohol

D.D.

Acute cholestasis

Decrease or cessation of bile flow

Methylene dianiline (MDA)

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Epping jaundice epidemic

Elevated alkaline phosphatase

Morphology of toxic injury to the liver

Chronic hepatic injury

• cirrhosis
• Fibrosis
• Chronic cholestatic injury
• Porphyria cutanea tarda
• Granuloma
• Neoplasm

Cirrhosis

• Alcohol
• TNT
• TCE
• CCL4
• Pesticides including As

Hepatoportal sclerosis (porto-sinusoidal vascular disease)

• Vinyl chloride monomer
• Arsenic

Porphyria cutanea tarda

• Dioxin
• Pesticides; hexachlorobenzine

ALA synthase

ALA dehydratase

Uropor. Synthase

Uropor. Decarboxylase

Protopor. oxidase

Ferrochelatase

Chronic cholestatic injury

Toxic oil syndrome; epidemic of systemic disease in Spain due to ingestion of rapeseed oil denaturated by 2% aniline.

Liver granuloma

• Beryllium
• Cupper (vinyard sprayers’ lung)

Neoplasm

• Angiosarcoma
• Hepatocellular carcinoma

• Venyl chloride
• Ethanol
• Aflatoxin
• Chlorinated hydrocarbons

Diagnosis

Assessment of liver function

A- Biochemical tests:

1. Necro-inflammatory markers; ALT , AST
2. Cholestatic markers; ALP, ȢGT
3. Synsthetic markers; albumin, prothrombin
4. Detoxification markers; Indocyanine green clearance

B- Imaging study

U.S – C.T. – MRI

C- Liver biopsy

D- Endoscopic imaging

The thresholds of liver enzymes used to define acute liver injury are as follows: (EASL, 2019)�

1. ALT level ≥5x the upper limit of normal (ULN)
2. Alkaline phosphatase (ALP) level ≥2 ULN (particularly if concomitantly elevated gamma-glutamyltransferase (GGT) in the absence of bone disease) or
3. ALT level ≥3 ULN and simultaneous total bilirubin (TB) level >2 ULN.

PATTERN OF LIVER INJURY according to R value: (EASL, 2019)

R value is defined as: (ALT/ULN)/(ALP/ULN)

1. Hepatocellular pattern: R ≥5
2. Cholestatic pattern: R ≤2
3. Mixed pattern: R value is >2 and <5

Management

• Removal from exposure to hepatotoxins.
• the worker can return to work once their enzyme levels are near normal, assuming they are adequately protected from harmful re-exposure.
• Supportive therapy for complications of cirrhosis include  diuretics,  albumin, vitamin K, blood products, antibiotics and nutritional therapy
• Liver transplantation in sever cases

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Prevention

Elimination of hepatotoxins in the workplace

Substitution of toxins by alternative safe chemical

• Isolation of workers from exposure to hepatotoxins
• Good ventilation

Engineering control

• Formulation & monitoring of safety guidelines
• Provision of appropiate tools and aids
• Regular maintenance
• Job rotation and breaks
• Well training program

Administrative control

• Good quality
• Well maintained

Personal Protective Equipment

1ry prevention

Prevention

Environmental monitoring

Health surveillance

2ry prevention

Removal from working environment

Prevention of complications

3ry prevention

• Exposure bio-monitoring
• Liver function test: worker with abnormal liver functions is removed from work and return when liver enz. Return normal

• Pre-employment exam.
• Periodic health exam.
• Pre-placement exam

References

• EASL. Clinical Practice Guidelines: drug-induced liver injury. J Hepatol 2019;70:1222–1261
• Jerrold B. Leikin,Andrew Davis,David A. Klodd,Thomas Thunder,Geoffrey A. Kelafant,Dana L. Paquette,Marti Jill Rothe,Rachel Rubin (2000). Part IV. Occupational liver disease. Disease-a-Month, 46(4), 295-310
• La Vecchia, C., Lotti, M., Lucena, M. I., Stove, C., Paradis, V., & European Association for the Study of the Liver. (2019). EASL Clinical Practice Guideline: Occupational liver diseases. Journal of Hepatology.‏
• Sakka, S. G. (2007). Assessing liver function. Current opinion in critical care, 13(2), 207-214.‏