This document discusses occupational liver disorders and their causes. It covers viral, chemical, and physically induced liver injuries and diseases. Some key points include: 1. The liver is divided into three zones (periportal, midzonal, centrilobular) that are differentially affected by toxins. 2. Occupational liver disorders are challenging to diagnose due to non-specific symptoms and potential simultaneous conditions like viral hepatitis or substance abuse. 3. Serologic markers and liver enzymes can help identify liver damage and its cause. Cytotoxic injuries elevate less liver-specific enzymes while cholestatic injuries increase enzymes like alkaline phosphatase. 4. Chemicals from many industries can cause liver

1. OCCUPATIONAL LIVER DISORDERS
Dr. Dalia Abdallah El-Shafei
Lecturer, Community medicine department, Zagazig
University

2. Zone 1 (Periportal lobule): nearest the portal vein.
Zone 2 (Midzonal region): intermediate to the final region of liver.
Zone 3 (Centrilobular area): adjacent to the central vein.

3. Viral
hepatitis
Physical
agent-
induced
Chemical-
induced
1-Similarity of presenting symptoms (acute
toxic liver disorders frequently with
nonspecific clinical manifestations
2-Chronic liver injury usually are
asymptomatic until its end stage
3-Simultaneous conditions (viral hepatitis
and/or alcohol & drug abuse) confound
liver disorders caused by specific
occupational or environmental
hepatotoxins.
4-Host-susceptibility factors (genetic
polymorphisms of metabolic & detoxifying
enzymes)

4. SEROLOGIC MARKERS
•Serologic viral markers & their
antibodies & antigens.
•Reveals cause & stage of disease
Specific
pathogens
•Hepatic enzymes released into
blood.
•Indicates extent of hepatic injury
Liver
function

5. Cytotoxic hepatic injury
(a) Less specific enz. reflecting injury to
extrahepatic tissue (AST or SGOT & LDH)
(b) Enzymes mainly in the liver (ALT or
SGPT)
(c) Very specific enz. to the liver (ornithine
carbamyltransferase (OCT) & sorbitol
dehydrogenase (SDH).
Cholestatic injury
- Alkaline phosphatase (AP)
- 5'-nucleotidase (5'-NT)
- γ-glutamyltranspeptidase (γ-GT)
Serum alpha-fetoprotein is a
well-established marker for
hepatocellular carcinoma
(low specificity)
Serum enzymes
generally only elevated
with extrahepatic
diseases as, creatine
phosphokinase (CPK).
Serologic Markers
for Liver Function

7. INFLAMMATORY LIVER
DISORDERS

8. INFLAMMATORY LIVER DISORDERS
 Predominate cause of liver-related morbidity
 The consequence of cumulative damage that leads to hepatocyte
death and recruitment of inflammatory cells to sites of injury.
 Long-term conditions that may progress to cirrhosis & hepatic
failure due to a lack of effective early diagnostic & treatment
protocols.
 The primary causes:
 Viral: Hepatitis A,B,C,D,E, Yellow fever, Epstein-Barr virus,
Cytomegalovirus, four exotic viruses (Ebola, Marburg, Lassa
fever, and Rift Valley fever viruses), Herpes hominis, Rubella,
Adenoviruses, and Enteroviruses.
 Other: Miliary tuberculosis, Malaria, Staphylococcal
bacteremia, Salmonelloses, Candida, and amebiasis.

16. CHEMICALLY INDUCED LIVER
DISORDERS

17. • More than 100 chemicals
• Painting, Textile&Dye manufacturing
• Arsphenamine, Carbon tetrachloride
(CCl4), Trinitrotoluene (TNT),
Dimethylnitrosamine (DMN),
Chloroform & Polychlorinated biphenyls
(PCB), Ethanol
• Cooking oil heavily contaminated with
PCBs (Japan, 1968),
• Wheat with hexachlorobenzene (Turkey,
1955- 1957)
• Flour with 4,4'diaminodiphenyl-methane
(England, 1965)

18. Chemical
Hepatotoxins
Naturally
occurring
Bacterial toxins, Mycotoxins,
Mushroom toxins & algae toxins.
(aflatoxins, phalloidin,
(& microcystin
Synthetic
Therapeutic drugs, Pesticides,
Metals, Ethanol, & Industrial
chemicals (aromatic
hydrocarbons, halogenated
hydrocarbons, chlorinated
aromatic compounds, & nitro
compounds)

20. MECHANISM OF TOXICITY
 Intrinsic toxin (Dose-dependent):
Most hepatotoxins
Direct hepatotoxins:
- Direct physicochemical effect (peroxidation of membrane
lipids or denaturation of protiens) leading to hepatocyte
membrane destruction and distortion.
- CCL4, Chloroform, CBr4, Trichloroethan,Tetrachloroethylene.
-
- Hepatotoxic potential of Haloalkans:
- Inversely proportionate to chain length & bond energy.
- Directly proportionate to no. of halogen atoms in molecule &
atomic no. of halogen.

21. Indirect hepatotoxicity:
- Interference with metabolic pathway
 Cytotoxic damage: Degeneration or Necrosis of
hepatocytes by interfering with pathway necessary for
structural integrity (steatosis or necrosis)
- Botanicals (aflatoxin, tannic acid) & drugs (tetracycline,
methotrexate)
 Cholestatic damage: interfering with bile secretion
- Only one is MDA (Methylene dianiline)

22.  Idiosyncratic toxin (Dose-independent):
- Few hepatotoxins
- e.g., Beryllium & Halothane
- Sporadic liver injury, possibly due to a
hypersensitivity or immunologic-type reaction.

24. CLINICAL SYNDROMES INDUCED BY
CHEMICAL HEPATOTOXINS

25. piecemeal
necrosis

26.  Acute injury often results in an accumulation of
lipids (Steatosis) & appearance of degenerative
processes, leading to cell death (Necrosis).
 Necrotic process can affect small groups of isolated
parenchymal cells (Focal necrosis), groups of cells
located in zones (Centrilobular, Midzonal, or
Periportal necrosis), or all cells within a hepatic
lobule (Massive necrosis).
ACUTE HEPATITIS

27. CHRONIC ACTIVE HEPATITIS
 Chronic active hepatitis (CAH),(chronic aggressive hepatitis), is
one of the 3 major forms of chronic hepatitis.
 The other two forms, chronic persistent hepatitis (CPH) and
chronic lobular hepatitis (CLH), are usually clinically mild and
histologically nonprogressive and, therefore, are considered benign.
 CAH is frequently characterized by the development of symptoms
and abnormality of liver function or histologic status with a high
likelihood of progression to cirrhosis.
 Causes: Infections with HBV, HCV, and HDV; Drug-induced,
Autoimmune reactions; Genetic metabolic disorders, & Occupational
or environmental exposures to certain Hepatotoxins & Alcohol.

30. CHRONIC HEPATITIS
1. Cholestatic Injury
2. Fatty Liver (Steatosis)
3. Hepatoportal Sclerosis
4. Fulminant Hepatic Failure & Necrosis
5. Cirrhosis
6. Granulomatous Disease of the Liver
7. Porphyria Cutanea Tarda & Related
Abnormalities

31. 1. CHOLESTATIC INJURY
 Diminution or cessation of bile flow and retention of bile
salts & bilirubin.
 Clinical symptoms: Jaundice, abdominal pain, pruritus,
& fever
 Rare but has been reported following exposure to the
chemical Methylene Dianiline (MDA), an aromatic
amine used as an epoxy resin hardener.
 Epping jaundice (1965): Epidemic of Acute Cholestatic
Jaundice occurred in Epping, England, after bread was
made from flour contaminated with MDA.

32.  Chronic cholestatic liver disorder
- The Spanish toxic oil syndrome (1981)associated
with accidental high ingestion of denatured rapeseed
oil.
- Patient with severe muscle wasting accompanied by muscle
and skin fibrosis, prominent features of the Spanish toxic oil
syndrome. Epidemiologic studies demonstrated that affected
subjects consumed a rapeseed oil containing fatty acid
anilides. Oil from France that had been deliberately
adulterated with aniline to prevent food use was illegally
intercepted in Spain, heated to remove the aniline, and sold in
and around Madrid in 1981.

33. 2. FATTY LIVER(STEATOSIS)
 Morphologically as greater than 5% of the hepatocytes
containing fat or, Quantitatively, as greater than 5 g lipid per
100 g hepatic tissue.
 Also occurs in other disorders (DM, hypertriglyceridemia,
& obesity).
 Some degree of steatosis is usually found accompanying
acute hepatocellular necrosis; But, marked steatosis is
more commonly seen in exposure to chronic hepatotoxins.

34.  First described with Yellow Phosphorus poisoning.
 Chronic exposure to chlorinated solvents such as CCl4,
methyl chloroform.
 Styrene, Toluene, Trichloroethane (TCE) & other aromatic
compounds.
 TNT in munitions industries, Arsenical pesticide use in
vintners.
 More subtle microsteatosis was described following short-
term, low-level exposure to dimethylformamide (DMF)
in a fabric-coating factory.

36. 3- HEPATOPORTALSCLEROSIS
 Rare form of noncirrhotic periportal fibrosis, which can lead
to Portal Hypertension.
 Occupational exposure to the Vinyl Chloride Monomer
(VCM) in Polyvinyl Chloride (PVC) polymerization plants,
Inorganic Arsenicals, and Thorium compounds.
 Liver histology has shown hyperplasia of hepatocytes and
sinusoidal cells, with dilatation of sinusoids and progressive
subcapsular, portal, perisinusoidal, and occasionally,
intralobular fibrosis, which is accompanied by portal
hypertension and splenomegaly.

37. 4- FULMINANTHEPATIC FAILURE & NECROSIS
 Exposure to TNT (munitions manufacture during WWI & II).
 CCl4 , chloroform, TCE, & epoxy resin coating containing 2-
nitropropane after inhalation exposure in an enclosed space.
 A severe liver disorder in which hepatic insufficiency progresses
from the onset of symptoms to hepatic encephalopathy within 2 to
3 weeks, resulting in liver necrosis & liver failure.
 The symptoms included jaundice, hepatomegaly, and severe liver
necrosis. Even people who survive the acute phases of the disease
often later develop postnecrotic cirrhosis or aplastic anemia.
 Onset of symptoms developed 2 to 4 days after exposure, often
accompanied by renal failure in severe cases. Those who survived
the acute stages recovered in 2 to 4 weeks, but repeated subclinical
exposure could induce cirrhosis.

38. 5- CIRRHOSIS
 A chronic, irreversible condition where the normal
lobular architecture is replaced by fibrous tissue and
regenerating nodules derived from the remaining
hepatocytes.
 Mainly due to chronic viral infection & alcohol abuse
 Organic Solvents, Dimethylnitrosamine (DMN), TNT,
TCE, pesticides, Arsenic , PCBs& Hydrazines.
 Cirrhosis & other liver disorders have been reported to
be more prevalent among Anesthesiologists compared
to other hospital personnel.
 Morticians exposed long term to formaldehyde had a
greater prevalence of cirrhosis, although ethanol was a
possible confounding factor.

39. 6- GRANULOMATOUSDISEASE OF THE LIVER
 Beryllium and Copper.
 In beryllium injury, the histopathologic appearance of the
liver biopsy specimen can be indistinguishable from
sarcoidosis. Berylliosis may include involve granulomas in
the spleen, bone marrow, and lungs, as well as the usual
granulomatous interstitial lung disease.
 Vineyard sprayer's lung were found to be associated with
liver damage with inclusion of copper in biopsy tissue. The
liver disorder included proliferation & swelling of the
Kupffer cells, sarcoidlike granulomas, fibrosis, micronodular
cirrhosis, hepatic angiosarcomas, & idiopathic portal
hypertension.

40. The mildew of the vineyards is prevented by the use of
sprays with a solution of Copper Sulphate neutralized with
hydrated lime. The inhalation of this solution while spraying
may give rise to predominantly interstitial pulmonary lesions
which may lead to respiratory insufficiency.

41. 7- PORPHYRIA CUTANEA TARDA
 Vinyl chloride-induced hepatic injury by the inhibition
of a number of hepatic enzymes in the porphyrin
biosynthesis pathway. Porphyrinuria due to vinyl
chloride exposure is rare.
 Methyl chloride poisoning, Dioxin, HCB, 2,4,5-
trichloro-phenoxy acetic acid (2,4,5-T), PCBs & other
polyhalogenated aromatic hydrocarbon-induced liver
injury.
 Following exposure to (TCDD), porphyria cutanea
tarda seems to be quite a specific disorder, producing
increased urinary concentrations of uroporphyrin.

42. 8- OTHER LIVER ABNORMALITIES
 Transient increased values of liver function tests recorded
following occupational exposure to methylene chloride.
 Increased transaminase values with exposure to (DMF)
dimethylformamide with microvesicular fat &
hepatocellular changes in liver biopsy specimens.
 Liver biopsy of workers manufacturing pesticide Kepone
(chlordecone) showed increased fat, numerous dense
bodies & proliferative smooth endoplasmic reticulum, as
well as severe neurologic symptoms.
 Jaundice & mild transient liver necrosis diagnosed in
exposed to Chrome during chrome-plating operations.

43.  Transient liver function abnormalities were also found in
association with TCDD exposure. 10% of the Seveso
(Italy) population environmentally exposed to TCDD after
an industrial explosion had modest elevations of γ-GT.
 Separately, workers exposed to tetrachlorophenol (TCP) &
TCDD had prolonged prothrombin time and elevated
plasma lipid & other liver transaminase values. Mild
steatosis, periportal fibrosis, activation of Kupffer cells &
porphyria cutanea tarda were reported in workers who
manufactured TCDD.

44.  In Japan and Taiwan, more than 2,000 people who
ingested cooking rice oil contaminated with PCB
and related compounds had abnormal liver function
tests, hepatomegaly in severe cases, and electron
microscopic alterations in the endoplasmic
reticulum and mitochondria in biopsy samples.

45.  Increased hepatic enzyme values (especially γ-GT &
ALT) were seen in human populations who
consumed water from a reservoir contaminated with
a heavy bloom of the toxic blue-green alga,
Microcystis aeruginosa, compared to an adjacent
population who drank water from other sources.
 Toxic hepatitis outbreak occurred in India in 1974
and Kenya in 2004 with a high mortality. These
incidents were associated with food contamination
with aflatoxin & other mycotoxins.

46. LIVER DISORDERS INDUCED BY
PHYSICAL AGENTS

47. Environmentally induced hyperthermia (heat stroke)
can cause acute hepatic injury characterized by
Centrilobular necrosis & Cholestasis.

48.  Exposure to a cumulative dose of Ionizing Radiation in
excess of 3,000 to 6,000 rad gives rise to radiation-
induced hepatitis 2 to 6 weeks later.
 Those who survived often subsequently develop
cirrhosis with progressive fibrosis & obliteration of the
central veins with centrilobular congestion.
 Radiation-induced hepatitis has been reported after
intense accidental exposure.

49. MALIGNANT LIVER DISEASE

50. There are two types of human malignant liver
disorders associated with occupational &
environmental hepatotoxicants,
1. Hepatocellular carcinoma (HCC).
2. Hepatic angiosarcoma (HAS) (Endothelial cell
sarcoma).

51. Codon 249 p53 mutations

52. HEPATIC ANGIOSARCOMA (HAS)
 A rare malignant tumor.
 Associated with chronic exposure to VCM, Arsenic,
Anabolic Steroids, & Thorotrast (an obsolete
scintigraphy contrast agent that contained colloidal
thorium dioxide, an emitter of α-particle ionizing
radiation).
 Vineyard workers & others who used arsenicals,
including Fowler's solution (1% potassium arsenite), or
copper as a pesticide.
 Long-term ingestion of Arsenic-contaminated well
water.

53. HEPATOCELLULAR CARCINOMA (HCC)
 One of the most common cancers worldwide,
with a striking geographic variation in incidence.
 In China, accounts for over 300,000 deaths
annually & this is the 3rd leading cause of cancer
mortality.

56.  The two major HCC risk factors, HBV & aflatoxin B1
(AFB1) exposure.
 Presence of aflatoxin-nucleic acid adduct (AFB-N7-gua)
in urine always resulted in 2-3 fold increase in HCC risk.
 A dose-response relationship between urinary aflatoxin
M1 (AFM1) levels & HCC in chronic HBV carriers.
 Mutations in the p53 tumor suppressor gene

57.  The p53 gene is found mutated in a majority of
human cancers, and there is a large variation in
number and type of mutations between cancers of
different tissues.
 "molecular fingerprint" in the p53 gene is a
characteristic G→T transversion at the 3rd base
of codon 249 observed in liver cancer patients
from regions of high aflatoxin exposure (50% of
HCCs).

60. BIOMARKERS & HBV INFECTION IN LIVER CANCER
 A double mutation in the HBV genome, an
adenine to thymine transversion at nucleotide
1762 and a guanine to adenine transition at
nucleotide 1764 (1762T/1764A), has been found
in HCCs

61. HBV & VCM
VCM
4-fold
HBV
25-fold
VCM+HBV
100-fold