Liver Toxicology

Nendyah Roestijawati
Limitation detection of occupational
disease
 Hepatic injury due to industrial exposure does not differ
clinically or morpholgically from drug-induced damage 
difficult to differentiate occupational from
nonoccupational causes on the basis of screening test
 Secondary importance to damage that occurs to other
organs or may occur only at high doses after accidental
exposure or ingestion
 Routine enzyme test lack of sensitivity and spesifisity 
false positive and false negative
 Occupational history and results of personal or workroom
air sampling are crucial to formulation of presumptive
diagnosis
Chemical agents causing liver toxicity
 Routes of exposure : inhalation, ingestion, percutaneous
absorption
 Inhalation is the most important, particularly for the
volatile solvents
 Several chemicals are lipophilic and may be absorbed
through the skin
 Oral intake is only the rare case of accidental ingestion 
mouth breathing, gum and tobacco chewing
 Mechanism of toxicity
 Intrinsically toxic agents
1. direct hepatotoxic : injure the hepatocyte and its organelles by
direct physicochemical effect, such as peroxidation of membrane
lipids, denaturations protein, destruction/distortion of cell membrane
Ex : CCl4  centrilobular necrosis and steatosis
2. indirect hepatotoxic : produce hepatic injury by interference with
metabolic pathways
Ex : cytotoxic (dymethilnitrosamine), cholestasis (methylene dianilin)
 Host idiosincracy : vulnerability of the individual
1. Hypersensitivity  phenytoin
2. Metabolic abnormality  isoniazid
Hepatic metabolism of xenobiotics
 Xenobiotic lipid-soluble compounds are well absorbed through
membran barriers and poorly excreted by the kidney, due to
protein binding and tubular reabsorption
 Increasing polarity of nonpolar molecules by hepatic
metabolism increasis water solubility and urinary excretion
 Primary defense depends largely on cellular enzyme system
(Mixed Function Oxidation)
 Many hepatic agents and hepatocarcinogens must be activated
by MFO system to a toxic or carcinogenic metabolites  CCl4,
vinyl chloride,PCB, etc
Acute hepatic injury
 Degeneration or necrosis hepatocyte (citotoxic injury) or
arrested bile flow (cholestatic injury)
 Latent period : 24-48 hours
 Extra hepatic symptoms : anorexia, nausea, vomiting, jaundice,
hepatomegaly
 Severe exposure : massive necrosis  coffe ground emesis,
abdominal pain, reduction liver size, rapid development
ascites, edema, hemorrhagic diathesis, followed somnolence
and coma within 24-28 hours
 Morphologically : zonal, massive, diffuse hepatic necrosis,
steatosis
 Ex : CCl4, MDA, tricholoroethylene, carbon tetrabromide, 2-
nitropropane
CCl4 induced hepatic injury
 Liquid solvent, dry cleaning agent, fire extinguisher
 Nervous system symptom : dizziness, headache, visual
disturbances, confusion  anesthetic result
 Nausea, vomiting, abdominal pain, diarrhea, first 24 hours
 Hepatic disease 2-4 days : hepatomegaly, splenomegaly,
jaundice, elevated serum transaminase, prlonged prothrombin
time
 Renal failure
 Sequelae hepatic failure : hypoglycemia, encephalopathy,
hemorrhage
Acute hepatic injury induced by other
xenobiotics
 Trichloroethylene : dry cleaning agent, “solvent sniffing”
 Carbon tetrabromide : syndrome similar to CCl4
hepatotoxicity
 2-nitropropane : epoxy resin paints and coatings 
confined spaces
Acute cholestatic jaundice

 MDA : epoxy resin  “Epping jaundice”

 Abdominal pain
 Recovered without evidence of persistent hepatic injury
Subacute hepatic necrosis

 Onset : several weeks to months

 Anorexia, nausea, vomiting, hepatomegaly, jaundice
 Macronodular chirrosis
 Histologic : varying degrees of necrosis, fibrosis,
regeneration
 Rare case
 Chronic hepatic injury
 Continuing or repeated injury by prolonged exposure
 Chirrhosis & fibrosis  progressive necrosis accompanied by
regenerating nodules, fibrosis and architectural distortion of
liver “toxic chirrosis” (trinitrotoluene, tetrachloroethane,
polychlorinated biphenyls, chloronaphthalenes, CCl4, inorganic
arsenic insecticide)
 Sclerosis & porphyria  portal and periportal fibrosisbleading to
portal hypertension (2,4,5- trichlorophenoxyacetic acid,
hexachlorobenzene)  “Turkish peasant”
 Neoplasia (Vynil chloride), hepatic angiosarcoma (inorganic
arsenic)
Hepatitis A
 Ocupation : nursery and kindergarten staff, sewer workers
 Food and water epidemic source, fecal contamination, poor
personal hygiene, intimate household or sexual contact
 Incubation period : 15-50 days
 Fever, malaise, anorexia, nausea, abdominal discomfort,
jaundice
 HAV 10 paticles/gram stools of infected person
 Confirmed diagnosis ; IgM-class anti-HAV
 Tx : symptomatic, fluid replacement
 Prevention : Immune globulin
 Hepatitis B
 Occupation : health care workers with blood and body fluid contact  0,1% :
10 times of control population
 Major cause of acute and chronic hepatitis, cirrhosis, hepatocellular carcinoma
 Incubation period : 45-60 days
 Transmission : percutaneous, permucosal
 Anorexia, malaise, nausea, vomiting, abdominal pain, jaundice, skin rash,
athralgia, arthritis
 HBsAg serum (+) 30-60 days
 Anti-HBs resolved infection : long term immunity
 Anti-HBc
 Chronic : HBsAg (+) min 2 occasions 6 months apart, high levels HBsAg and anti
HBc, serum transaminase
 Prevention : vaccination
Non A, non B viral hepatitis

 Cytomegalovirus : pediatric healthcare worker 

congenital malformation
 Coxiella burnetii : animal care workers, farm workers,
slaughterhouse workers  Q fever
 Leptospira icterohaemorrhagiae : sewer workers
 Arbovirus : yellow fever  forest workers
 Schistosomiasis : agricultural workers
Biochemical test for liver disease
 Serum enzym activity : SGOT, SGPT
 Alkaline phosphatase : results in disturbance transport function hepatocyte or
biliary tree  suspect drug or chemical induced cholestasis
 Serum bilirubin : conjugated hyperbilirubinemia  Dubin-Johnson syndrome,
Rotor’s Syndrome, drug or toxin induced hepatitis, shock liver, metastatic
disease
unconjugated hyperbilirubinemia : Gilbert’s disease, uncomplicated
hemolytic disorders, CHF
 Urine bilirubin : direct bilirubin  hyperbilirubinemia
 Serum Gamma Gglutamyl Transferase : more sensitive than transaminase
 LDH : nonspesific
Test of synthetic liver function

 Serum albumin : celullar disfunction

 Prothrombine time : clotting factor synthesis
 Alpha-fetoprotein : hepatocelullar carcinoma
 Serum feritin : hemochromatosis as a cause liver disease
Clearance test

 Measure clearance of substance by the liver

 Exogenous clearance test : Sulfobromophthalein,
indocyanin green, antipyrine test, aminophyrine breath
test, caffeine breath test
 Endogenous clearance test : serum bile acids (fasting <6
micromole/L), abnormal >8,4 micromole/L
Clinical management occupational liver
disease
 Occupational & medical history : liver disease, symptoms
include central nervous system, use PPE, airborne
contaminant data
 DD : infectious, alcohol-drug induced hepatitis
 Management acute liver disease : no spesific treatment,
immediately remove form exposure for 3-4 weeks,
repeated serum transaminase measurement, engineering
control, use PPE, reassigned
 Management chronic liver disease : not differ from other
cause
Terimakasih