2/28/2018 4/22 4/25 5/24 ALT AST AP Bili

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1 Toxicants and infectious liver disease Robert Harrison MD, MPH Clinical Professor of Medicine UC San Francisco TEL: I have nothing to disclose. 1

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4 Chemicals associated with liver injury as secondary toxic effect Alcohols Ethyl alcohol Aromatic solvents toluene Halogenated solvents 1,1,1- TCA Ethyl bromide 2-methoxyethanol Chlorofluorocarbons Cyclic hydrocarbons cyclohexane Glycol Ethers Refined petroleum Distillates, Stoddard solvent, VM and P naphtha 4

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7 Case presentation (I) Admitted to local hospital c/o nausea, vomiting PE: normal.? Alcohol on breath AST = 60 Given IV fluids, discharged improved after 18 hours Case presentation (II) 3 days later - returned to local hospital c/o anorexia, nausea PE: icteric, increased liver size AST > 12,000, bili 6.9, PT 47, PTT 100, ABG 7.07/18/135, creatinine 2.1, glucose 40 Case presentation (III) Transferred to UCSF Rapid coma with renal failure dialysis, GI bleeding, respiratory failure Expired 9 days after first admission 7

8 Koppers Bitusmatic 300-M Component A Cyclohexanone Tri (methylamino) methyl phenol 2-nitropropane Component B Coal tar pitch Epoxy resin 8

9 Fatalities associated 2-nitropropane Gaultier (1964) - fulminant hepatitis (1) following tank coating with epoxy resin Hines (1978) fulminant hepatitis (4) after applying coatings in confined spaces Demetris (1985) - fulminant hepatitis (2) reported in liver transplant series Acute occupational liver injury Chlorinated alkanes Carbon tetrachloride Trichloroethylene Bisphosphonates Bisphosphonates Santos et al: Annals of Hepatology 8(2), Acute liver failure due to white phosphorus ingestion 9

10 Ito et al: Medicine: 95(1), Recurrent acute liver failure because of acute hepatitis induced by organic solvents Xenobiotic metabolism PHASE 1 PHASE 2 RH Inactive metabolite Conjugate Active metabolite Reacts Excreted 10

11 Consequences of metabolism In general - hepatic metabolism of chemical (1) Increases its water solubility (2) Decrease its toxicity 11

12 Determinants of toxicity Intrinsic toxicity of the chemical & Host Factors 12

13 Cl Cl Cl Cl C=C C-C 0 Cl H Cl H Cl 3 C-CHO Cl 3 C-COOH Epoxide intermediate in metabolism of trichloroethylene Metabolism of 2-nitropropane CH 2 = CHCl MFO CH 2 -CHCl 0 13

14 Update mortality analyses (Mundt 2017, JOEM) 9,951 workers from 35 VC facilities employed for > 1 year prior to 1972, updated mortality through 12/31/13. Average duration of employment 16.4 years 63 ASL deaths, latency years 32 shcc deaths, latency years 14

15 Occupational hepatic carcinogens (animal or human evidence) Rubber plant: 4-aminobiphenyl and 4,4 -methylene Bis (MOCA) Dioxin-like compounds: PCBs, PCDDs, TCDDs Pesticides (organochlorines) Halogenated solvents: trichloroethylene, perchlorethylene Metals: arsenic, cadmium Cholangiosarcoma (Kubo et al: 2014, J Hepatobiliary Pancreat Sci Offset color proof printing department at printing company in Osaka, Japan 17/111 workers diagnosed between 1996 and 2012 Age range years Latency up to 9 years, 7 months Poor prognosis (9/17 fatal, < 2 year survival) Table S1 Chemicals used in the offset proof-printing department 1,1,1-Trichloroethane 1,2-Dichloropropane Dichloromethane Diclorofluoroethane 2- Buthanol 2-Methylpentane 3-Methylpentane N-Hexane Cyclohexane Isopropyl alcohol Ethanol Diethylene glycol monobutyl ether Propyleneglycol monomethyl ether 2-Methyl-2.4pentadiol 3-Methyl-3-methoxybutanol Solvent naphtha (coal) Xylene Kerosene Mineral oil Hydrocarbons Aromatic hydrocarbons Inks 15

16 Methylene dianiline and Epping Jaundice (Kopelman 1966, Brit Med J) 16

17 New Haven (Yale) outbreak (Redlich 1988, Ann Intern Med) sentinel case of 40 year old Hispanic male fabric-coating machine operator (DMF + polyurethanes) Follow-up worker survey 36/58 with elevated AST or ALT levels 35/46 production workers 1/12 non-production workers Eight workers with mild persistent enzyme elevations Fatal case report (Zhang 2015, Forensic Sci Med Pathol) Polyurethane/polyvinyl chloride factory 40 year woman with 2 months symptoms, elevated liver enzymes several colleagues of the deceased also suffered varying degrees of liver dysfunction Elevated levels of DMF in workplace air Factory had been told to shut down 17

18 Chinese leather workers (He 2015, IJOMEH) Synthetic leather manufacture (DMF + resin + other chemicals) 21/72 exposed workers with abnormal liver enzymes, c/w 3/72 controls Exposure levels below ACGIH TLV Chinese leather workers (Wu 2017, Toxicological Sciences 698 workers in 2 synthetic leather factories (DMF + polyurethane resin) Males: 58/508 (11.4%) exposed v. 7/147 (4.7%) controls with abnorrnal liver enzymes Mixing and coating workers highest exposures (above ACGIH TLV) 18

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20 Hepatitis E An occupational liver disease? Single stranded RNA virus Genotypes 1 and 2 in humans; genotypes 3 and 4 in animals (pigs, wild boar and deer) Primarily fecal-oral transmission (genotypes 1 and 2), with food borne transmission (deer and boar meat, pig livers) Hepatitis E An occupational liver disease? Estimated 20M HEV infections worldwide, 3.3M symptomatic and 44,000 deaths (WHO) High mortality rates in pregnant women Incubation 2-10 weeks, viral shedding to 3-4 weeks after symptoms Hepatitis E An occupational liver disease? Diagnosis with specific IgM or RT-PCR Treatment supportive Recombinant vaccine registered in China 20

21 Hepatitis E An occupational liver disease? Consistent higher rate of IgG antibodies in exposed workers De Schryver A et al 2015, Occupational Medicine Hepatitis E An occupational liver disease? Higher IgG seroprevalence rates among those exposed to swine Hartl et al 2016, Viruses Hepatitis E An occupational liver disease? Bangladeshi pig handlers have higher rate of self-reported jaundice Haider et al 2017, Zoonoses Public Health 21

22 Hepatitis E An occupational liver disease? Occupational groups worldwide a reservoir of potential infection and transmission Prevention recommendations and enforcement in the workplace Little evidence (to date) of clinical occupational liver disease Prospective studies may be needed All of the following chemicals are associated with an increased risk of liver cancer EXCEPT 1. Arsenic 2. Trichloroethylene 3. Vinyl chloride 4. Toluene Which of the following solvents would you recommend for use in a workplace environment to minimize the risk of liver disease? 1. Carbon tetrachloride 2. Ethyl alcohol 3. 2-nitropropane 4. Trichloroethane 22

23 You are thinking about jobs that are the lowest risk for you getting liver disease. You ask Dr. Harrison for advice. Which of these does he recommend? 1. Soldering printed circuit boards 2. Working in a slaughterhouse 3. Manufacturing faux leather 4. Running a printing press 23