Lezione Scuola di Specializzazione in Medicina del Lavoro Epatite virale Lezione Scuola di Specializzazione in Medicina del Lavoro Title slide

Caratteristiche essenziali dell’infezione da virus dell’epatite B DNA virus Non direttamente epatotossico Il danno epatocellulare è generato dalla risposta immunitaria dell’ospite Maggior parte delle infezioni asintomatiche( specie soggetti giovani) Maggior parte delle infezioni autolimitantesi con sviluppo di immunità In circa il 5% dei casi si sviluppa un’infezione persistente. Problems in identifying effects of occupational agents on the heart: Endpoints are common in US and Western Europe, so effects of an agent may not be noticed as producing illness above the high baseline rate. Cardiac disease has multiple risk factors, some common and under the control of the subject (smoking, obesity and reduced physical activity), some which require intervention (hypertension, hypercholesterolemia). Long-latency illness such as heart disease my not be apparent until long after the individual has left the workplace. Moreover there are no effects of occupational exposures that have differing manifestations from those of non-occupational etiologies; thus identification of effects is based on obtaining a good occupational history.

Storia naturale epatite B persistente non trattata HBsAg per tutta la vita HBeAg tende a scomparire quando compare anti HBe DNA virale si riduce fortemente con comparsa anti Hbe, ma non scompare Implicazioni per immunoprofilassi:dopo puntura con ago contenente sangue di soggetto HBsAg positivo l’immunoprofilassi va fatta indipendentemente dallo status Hbe del soggetto

Carrier HBeAg negativi Nella gran parte dei casi:a) bassi livelli di DNA virale;b)aminotransferasi normale;c)prognosi favorevole In Italia, nel 15-20% dei casi questi pazienti hanno alti livelli di DNA virale in circolo e aminotransferasi elevate. In questi pazienti è indicata la terapia antivirale

Epatite B cronica ed epatocarcinoma Aumento del rischio di 100 volte HBeAg positivi hanno il rischio massimo Screening semestrale con alfa-fetoproteina e/o ecografia Alfafetoproteina ha un alto valore predittivo negativo, ma un valore predittivo positivo compreso tra il 9 e il 30%

Infezione persistente da virus B -Viremia continua (a titolo variabile) -Forme sintomatiche o asintomatiche -ALT e AST normali e biopsia normale: carriers -Alterazioni della funzione e dell’istologia: epatite cronica -Cirrosi si sviluppa nel 20% dei casi di epatite cronica Five physiological-pathological manifestations of the effects of occupational agents on the heart; this provides a good framework to classify agents. Many are now of historic interest, as controls have reduced hazards, though they still may be encountered. Each will be considered in turn.

Strategie per la prevenzione di HBV Evitare comportamenti ad alto rischio Prevenire l’esposizione a sangue e fluidi corporei Screening delle gravide al III trimestre Immunizzazione attiva e passiva

Vaccinazione epatite B (1) L’OMS raccomanda un programma di vaccinazione per tutti i bambini e gli adolescenti Altri gruppi a rischio: lavoratori della sanità espostial sangue Disabili ospitati in strutture e lavoratori delle strutture

Vaccinazione epatite B (2) Emodializzati Soggeti che ricevono trasfusioni fattori della coagulazione concentrati Conviventi e partner sessuali di soggetti HBV positivi Adottati provenienti da paesi con endemia da HBV

Vaccinazione da epatite B (3) Viaggiatori che trascorrono più di 6 mesi in paesi con endemia da HBV in stretto contatto con popolazioni locali Viaggiatori che hanno contatto con sangue o rapporti sessuali in paesi con alta o intermedia diffusione di HBV Soggetti che hanno più di un partner sessuale nell’arco di 6 mesi

Vaccinazione epatite B (4) Omosessuali Tossicodipendenti Ricoverati in strutture psichiatriche

Rischi della vaccinazione Nessuno

Virus epatite B: immunizazione passiva Candidati: neonati da madri HBsAg +,soggetti a contatto con sangue o fluidi corporei HBsAg+,partner sessuali di soggetti HBsAg+,bambini di età inferiore ad 1 anno a contatto con soggetti in cui si sia sviluppata un’epatite acuta tipo B.

Immunizzazione passiva: somministrazione Tempi: neonati entro 24 ore, contatto ago entro 7 giorni, rapporto sessuale entro 14 giorni Modalità: somministrato assieme alla prima dose di vaccino Efficacia: neonati 95%, altre categorie 75%

Caratteristiche del virus dell’epatite C Centosettanta milioni di persone infette (2% popolazioni mediterranee) Cronicizza nella gran parte dei casi Trasmissione via ago o trasfusioni (in alcuni casi non identificabile la via di trasmissione) Trasmissione materno-fetale e sessuale rara

Definizioni Tempi vaccinazione: 0,1,6 mesi Responders: 1-2 mesi dopo il ciclo hanno livelli di anti-HBsAg non inferiori a 10 mUI/ml Non responders: quelli con livelli inferiori a 10 mUI/ml

Follow-up post-vaccinazione Responders: nulla

Follow-up post-vaccinazione Non responders HBsAg/anti HBc negativi:quarta dose di vaccino e quindi nuova valutazione 1-2 mesi dopo. Se ancora non responders, quinta e sesta dose di vaccino e nuovo test 1-2 mesi dopo l’ultima dose. Possibili strategie alternative di vaccinazione (nuovi vaccini,tre dosi a dosaggio ridotto ogni 2 settimane,vaccino A e B combinato, vaccinazione standard ad alte dosi, etc…)

Lavoratori con isolata presenza di anti HBc (1) Testare per IgM antiHBc e HBV DNA Se negativi, praticare la prima dose di vaccino e testare 30 giorni dopo. Un titolo anti HBsAg non inferiore a 50 mUI/ml è segno di risposta anamnestica e non richiede prosecuzione della vaccinazione. Questi soggetti sono protetti da reinfezione e non necessitano di immunoprofilassi in caso di esposizione

Lavoratori con isolata presenza di anti HBc (2) Se anti HBsAg inferiore a 50 mUI/ml, completare la vaccinazione con 3 dosi e comportarsi come nei soggetti sierologicamente negativi. Questi soggetti vanno trattati con immunoprofilassi in caso di esposizione

Gestione dopo esposizione occupazionale Esposizione percutanea: incoraggiare sanguinamento e lavare con acqua e sapone (eventuale aggiunta di antisettici/disinfettanti). Contaminazione cutanea: lavare con acqua e sapone (eventuale aggiunta di antisettici/disinfettanti) Contaminazione oculare: lavaggio con acqua

Valutazione del rischio dopo esposizione Valutazione dello status HBV e HCV nell’esposto e nel paziente Conservare un campione di sangue dell’esposto e del paziente Valutare la potenzialità di trasmissione in base al tipo e al materiale biologico Se lo status HBV e HCV del paziente rimane ignoto considerarlo infetto.

Status HBV Anti HBs HBIg(0.06 ml/kg) Vaccino HBV commento Non vaccinato >10mUI/ml <10mUI/ml Nulla Schema 0-1 mese Schema 0-1-2-12 mesi Vaccino e HBIG simultaneamente Vaccinazione incompleta o non sa se ha completato Schema 0 Completare o schema 0-1-2-12 mesi Come sopra Non responder Vaccinato. Risposta ignota Scema 0 Già fatte 4 dosi o 2 cicli Vaccinazione alternativa? Responder a precedente vaccinazione no

Status HBV Anti HBs Vaccino HBV commento Non vaccinato Schema standard Valutare risposta 1-2 mesi dopo l’ultima dose Vaccinazione incompleta o non sa se ha completato Completare o ricominciare secondo schema standard Come sopra Non responder Vaccinato. Risposta ignota >10mUI/ml <10mUI/ml Nulla 1 booster e test a 1-2 mesi. Se ancora <10 schema standard Già fatte 4 dosi o 2 cicli Vaccinazione alternativa? Responder a precedente vaccinazione no

Rischio di trasmissione con ago contaminato HBV: 30% HCV: 3% HIV: 0.3%

HBV HCV DNA virus Cronicizzazione: rara Contagiosità: elevata Trasmissione perinatale: frequente Contagio sessuale:frequente Vaccino: si RNA virus frequente bassa Rara Raro no

Genotipi HCV 6 genotipi, denominati in numeri arabi da 1 a 6 Genotipo 1a e 1b: i più comuni in USA ed Europa Occidentale Genotipo 2 e 3: predittivi di migliore risposta alla terapia Genotipo 4: comune in Egitto, genotipo 5 comune in Sud-Africa, genotipo 6 comune nel Sud-Est Asiatico

Caratteristiche essenziali del virus C Non direttamente epatotossico Infezione per lo più asintomatica Cronicizzazione frequentissima (80%), con epatite cronica Nel 20% degli infetti si sviluppa cirrosi Fattori che accelerano la progressione della malattia: alcool, coinfezione con HBV,sesso maschile, infezione in età avanzata.

Manifestazioni extraepatiche HCV Crioglobuline nel 50%. Vasculite (porpora, altralgia, astenia) nel 10-15%. Glomerulonefrite membrano-proliferativa Manifestazioni neurologiche Crioglobulinemia essenziale mista (tipo II)

Tests diagnostici per HCV Enzyme immunoassay: in popolazioni a basso rischio, i falsi negativi sono meno dell’1%. Rischio di falsi negativi in immunocompromessi, insufficienza reanale, crioglobulinemia essenziale mista. Rischio di falsi positivi in soggetti senza fattori di rischio e senza segni di epatopatia quali donatori e lavoratori dela sanità.

Tests confermativi per HCV Immunoblot ricombinante: può essere indicato nei positivi a basso rischio Test qualitativo per HCV-RNA con PCR: indicato nei pazienti con enzyme immunoassay con sospetta epatite acuta, in soggetti con epatite da causa non identificata, e in quelli con cause note di falsa negatività al test anticorpale

Linee guida europee prevenzione epatite B e C in lavoratori sanità Programmi educazionali e training Protocolli scritti per una rapida trasmissione dei casi, valutazione, consulenza,trattamento e follow-up in caso di esposizione occupazionale che può porre i lavoratori della sanità a rischio di contrarre l’infezione

Training e programmi educazionali Informazione Implementazione delle precauzioni standard Fornitura di mezzi di protezione adeguati Miglioramento delle procedure di sicurezza Vaccinazione Gestione post-esposizione

Training e programmi educazionali Formale identificazione di un addetto a cui il lavoratore può fare urgente riferimento in caso di esposizione e che è responsabile del management post-esposizione,della somministrazione della profilassi e del follow-up clinico e sierologico

Training e programmi educazionali L’accesso a medici che possono provvedere alla cura post-esposizione dovrebbe essere possibile durante tutte le ore lavorative, incluse notti e week-end I lavoratori dovrebbero essere informati dell’importanza clinica e medico-legale di riportale l’esposizione, come riportarla e a chi riportarla

Vaccinazione Tutti i lavoratori della sanità dovrebbero essere vaccinati contro l’HBV secondo uno schema standard. Prima dell’assunzione sul lavoro è fortemente raccomandata la vaccinazione o la dimostrazione di immunizzazione Lo screening pre-vaccinazione non ha indicazione routinaria

Vaccinazione Il titolo anticorpare anti HBsAg dovrebbe essere valutato 1-2 mesi dopo il completamento delle tre dosi di vaccino La vaccinazione combinata A e B è raccomandata in lavoratori suscetibili con HCV o altre epatopatie

Esposizione ad HCVAb+ o non identificabile Testare il lavoratore esposto per HCVAb (EIA) a 0-3(?)-6 ed ev. 12 mesi. Confermare test positivo con HCV RNA ALT a tempo 0 e quindi mensilmente per 4 mesi (Se aumenta HCV RNA)

Esposizione ad HCVAb- Se possibilità di falso negativo, comportarsi come esposizione ad HCVAb

Angina - Carbon monoxide Sources of incomplete combustion: Furnaces, boilers Internal combustion engine (warehouses, auto plants) Hazards increased in cold weather with closed doors and windows ANGINA Carbon monoxide is the most commonly encountered occupational and environmental agent with cardiotoxic effects. Photograph shows indoor foundry work, where combustion occurring in limited oxygen supply may lead to CO formation.

Carbon monoxide  carboxyhemoglobin Binds to hemoglobin more avidly than O2 (CO has 200x oxygen’s affinity) Shifts oxygen dissociation curve to “left”: Tissue anoxia the result Binds mitochondrial enzymes and myoglobin Increases platelet stickiness Deceases arrhythmia threshold Methods by which CO has an effect on the aggravation or exacerbation of currently-existing cardiovascular disease. Major effect is to increase affinity of hemoglobin for oxygen and thereby cause tissue anoxia. Poster is from 1940’s era public health efforts to raise awareness of CO.  

CO and hemoglobin oxygen-dissociation curve % Saturation Normal Hemoglobin-O2 dissociation curve: Normal (red) and in presence of carbon monoxide (yellow). The curve is equivalent to dissociation seen at a carboxyhemoglobin (COHgb) concentration of about 20%.   Partial Pressure Oxygen

Reduced oxygen-carrying capacity of carboxyhemoglobin at high CO levels O2 content (ml/dL) Note also the reduction in oxygen-carrying capacity at high CO levels, because of tight CO binding to hemoglobin. Thus a 60% COHgb concentration would be equivalent in O2 carrying capacity to an anemia 40% below normal values (eg a hematocrit of 18 to 20%). Actual manifestations would be much worse than that seen in anemia alone, however, because of the accompanying O2 dissociation curve shift.   PO2 (mm Hg)

Angina : Carbon monoxide CarboxyHgb levels and symptoms: Cardiac compensatory effects seen at carboxyHgb levels 8 -10%: HA, lightheadedness, some chest pain EKG disturbances (extrasystoles, PVCs, atrial fibrillation) at higher levels (10-25%) Dependent on previous cardiac status and susceptibility: Cigarette smokers chronically at ~5% Individuals with pre-existing CAD may develop angina with moderate activity at carboxyHgb levels as low as 3 - 5% Manifestations of CO poisoning are dependent upon age and current cardiovascular health. Individuals with pre-existing CAD may become symptomatic at very low levels.  

Carbon monoxide: Exposure limits NIOSH REL: 35 ppm for 10-hour TWA Equivalent to 5% COHgb level Uptake will increase with physical exertion: Exposure should be correspondingly limited in jobs with high physical demands OSHA STANDARD: 50 ppm /TWA8 ACGIH: TLV®: 25 ppm/ TWA8 BEI®: 3.5% COHgb More protective of sensitive groups. BEI may be useful in documentation of significant exposure. NIOSH Recommended Exposure Limit (REL) for carbon monoxide is based on keeping blood COHgb levels no higher than 5% at the end of a 10-hour workday. Heavier activity will increase minute ventilation and therefore uptake of CO by lungs; permissible exposures should be adjusted downward accordingly where heavier work takes place. OSHA standard may be protective of most workers, but COHgb levels may exceed 5% at the end of 8-hour shift under this standard. Some workers with current cardiovascular disease may not tolerate these levels, especially if they smoke as well. The Threshold Limit Value (TLV) and Biologic Exposure Index set by the ACGIH are lower, indicating that the OSHA standard and NIOSH limits may not be protective of sensitive workers or groups. The BEI, which indicates a warning level of biologic response to CO, may prove useful for the primary care or emergency physician in documenting CO exposure in a patient.  

Carbon monoxide Methylene Chloride CH2Cl2 Solvent: degreasing, paint stripping Absorption through respiratory route or through skin Metabolized in bloodstream to CO Methylene chloride CH2Cl2 is a solvent that is metabolized rapidly to CO in the bloodstream. Importantly, it can increase COHgb to symptomatic levels in smokers and those working in the presence of CO.  

Methylene Chloride May elevate carboxyhemoglobin to 10% or more especially in poorly ventilated space Probably not significant to healthy person; may become mildly symptomatic Cigarette smokers, those with angina or current CHD a concern: excess CO may trigger symptoms More on methylene chloride: It should also be remembered that, as a chlorinated solvent, methylene chloride will have neurotoxic effects on the CNS, particularly at high concentrations or in poor ventilation.  

! Methylene Chloride OSHA Standard: 25 ppm/ TWA8: STEL 125 ppm NIOSH: As low as can be achieved (carcinogen) Because of metabolic conversion to CO, the biological life of COHgb from methylene chloride is longer than that from direct CO exposure ! OSHA PEL of 25 ppm is designed to keep COHgb concentration below 2-3% at the end of an 8-hour workshift. NIOSH REL is based on methylene chloride’s potential carcinogenicity, and therefore recommends exposures be reduced to the greatest extent possible. Because of its metabolic conversion, clinical effects from CO toxicity arising from methylene chloride may be of longer duration, and monitoring results may continue to indicate persistent high levels of COHgb.

Chronic exposure to CO associated with cardiovascular mortality: NYC bridge and tunnel officers Aside from acute effects, carbon monoxide likely has chronic effects on the development of coronary artery disease. The most informative studies in this area come from long-term mortality studies of NYC bridge and tunnel officers who had long-term daily CO exposure at work.  

Duration of Employment Carbon monoxide:Long-term exposure effects SMRs for death from cardiovascular disease of bridge (low-CO-exposure) and tunnel (high) officers in NYC: Duration of Employment <10 years >10 years Total Bridge Officers 0.87 (0.70-1.07) 0.81 (0.56-1.15) 0.85 (0.71-1.02) Tunnel Officers 1.07 (0.77-1.44) 1.88 (1.36-2.56) 1.35 (1.09-1.68) Standardized mortality ratios from CAD show an increase in cardiovascular mortality in tunnel officers (worksite less well ventilated than the bridges) with ten years or more service. Other studies indicate that this elevated risk declined after cessation of exposure, with much of the risk dissipating within five years. The findings suggest that environmental carbon monoxide exposure plays a role in the pathophysiology of cardiovascular mortality similar to that associated with cigarette smoking.   Stern FB et al: Heart disease mortality among bridge and tunnel officers exposed to carbon monoxide. Am. J Epidemiol. 1988; 128: 1276-1288

Angina: Nitrates Noted to have vasodilatory effects in explosives workers Tolerance to absorbed nitrate symptoms (headaches, tachycardia, diastolic HTN) develops quickly Effects of exposures to aliphatic nitrates (nitroglycerin and ethylene glycol dinitrate) in explosives workers were soon seen after manufacturing rapidly increased in the 19th century. Many developed headaches, tachycardia, syncope (also familiar side effects of the medical use of nitrates); tolerance or tachyphylaxis usually developed over a week or so on the job. Picture shows original DuPont manufacturing houses on Delaware River: note thick walls with buttresses and thin ceilings to channel any explosions upward and back toward woods rather than outward to other areas of plant.  

Dynamite and other explosives manufacture Dynamite Hand-Packing House Ethylene glycol Glycerin   Dynamite Mix House Dynamite Case Houses “Dope” Machine Packing (Cartridge-filling) Houses Magazine and Shipping Nitrator Liquid NTG / EGDN storage and supply Gelatin Mix House Gelatin Packing (Cartridge-filling) Houses   Gelatin Case House HNO3 H2SO4 “Dope” Process diagram for nitrate explosives manufacture. Most direct exposures to nitrates occur in manual packing operations. (“Dope” refers to additional combustible materials such as wood pulp, with which the nitrates are combined to form dynamite.)   H2C-O-NO2 H-C-O-NO2 H2C-O-NO2 ethylene glycol dinitrate nitroglycerin

Acute effects in workers noted in early 1960s: Sudden death: 24-96 hours after exposure ceased (weekends/holidays) “Monday Morning Angina”: Relieved by RTW, nitrate meds: coronary spasm in absence of CAD Three-fold increase in acute deaths in younger men from ischemic CHD More serious effects were first noted in early 1960’s: Angina or sudden death occurred 48 to 96 hours after workers left factory and nitrate exposures. Clean coronary arteries were noted on autopsies of workers suddenly dying, indicating MI or arrhythmia rather than atherosclerotic coronary disease was responsible.  

Angina: Nitrates Mechanism of acute effects not clear: Rebound vasospasm vs. arrhythmias (VF) triggered by re-exposure CAD risk increased 2-3x after 20 years exposure: persists after removal Possible HTN after cessation of exposure Speculated mechanisms by which effects might occur. Risk persists long after leaving work, indicating that a rebound or similar effect on blood pressure might be responsible for findings. Picture shows WWI-era explosives manufacture with nitroglycerin ribbons emerging from machine for packing.  

Atherogenesis Carbon disulfide (CS2) Cellulose-derived materials Rayon Cellophane Solvent for rubber, oils Pesticides Fumigant for grain, books Microelectronics industry ATHEROGENESIS Carbon disulfide is the occupational agent with the clearest evidence of an effect on atherogenesis and development of ASCVD. Its greatest use is in the artificial fiber and textile industry, and related areas such as the manufacture of cellophane.  

Viscose Spinning Rayon Filaments CS2 Viscose process for Rayon manufacture CS2 Lye Wood Flakes Raw Cellulose Cellulose Xanthate H + Solution Viscose Zn++ H2SO4 “Ripening” Filtering CS2 Spinning Rayon Filaments Diagram shows process for viscose rayon manufacture. Cellulose flakes from wood pulp are treated with gaseous carbon disulfide to form xanthate esters: R Cellulose – O – C (=S)(S-)Na+  Acid added to the cellulose xanthate produces a thick solution termed “viscose”. This is then allowed to “ripen,” which decreases the solubility of the cellulose; some CS2 is given off in this process.  After filtering, the viscose is extruded through a spinneret, and passed through a stronger acid along with zinc ions. This acid treatment causes cellulose molecules to cross-link and CS2 is liberated. Fibers from the spinneret are wound together to produce rayon thread. Production of cellophane is similar. Main occupational exposures occur in cellulose treatment and to spinner operators.   CS2

Cellulose flakes after lye treatment Picture shows two steps in viscose process: Cellulose flakes after treatment with lye, and viscose emerging from spinneret. At this point, with acid treatment, CS2 is liberated and rayon is formed by fiber cross-linking.   Viscose emerging from spinneret. CS2 is given off when viscose cross-links to form rayon

Coronary Heart Disease Deaths among operatives and staff aged 45-64 with > 10 yr employment in rayon factories Occupation P-Y at risk Coronary Heart Disease Other CV Disease Obs Exp Operatives Viscose Making 2221 5 7.2 2 5.0 Viscose Spinning 4585 28* 14.6 15 9.9 Non-process 1997 6 8.0 10 6.1 Staff Spinning 1502 9** 4.3 1 2.8 752 3 2.3 1.6 Original paper by Tiller, Shilling and Morris examined long-term effects of CS2 exposure on cardiovascular mortality. Table adapted from paper shows increase in CAD deaths among process operators and other workers in spinning operations.   * 2 = 12.2 p<0.001 ** 2 = 5.2 p<0.05 Tiller JR, Schilling RS, Morris JN. Occupational toxic factor in mortality from coronary heart disease. Br Med J 1968; 4:407-11

Carbon Disulfide and Atherogenesis RR of 2 to 5x for death from CAD Epidemiologic evidence suggests a direct role in atherogenesis in blood vessels: Enzyme inhibition by metabolites of CS2 React with amino acids to form dithiocarbamates: these chelate trace metals and react with enzyme cofactors May interfere to increase elastase activity, disrupting blood vessel walls May decrease fibrinolytic activity and enhance thrombosis Possible mechanisms by which CS2 may contribute to cardiac disease. Metabolism is complex and leads to intermediates: dithiocarbamates and carbonyl sulfate (COS). These may have a variety of effects on enzyme functions, many not yet well clarified.  

Japanese CS2 workers: Retinal microaneurysms Japanese workers in rayon industries developed microvascular changes, including retinal aneurysms ….  

Japanese CS2 workers: Retinal hemorrhages ….and hemorrhages, which indicate a direct effect of CS2, on acceleration of atherogenesis.  

Carbon Disulfide OSHA Standard: 20 ppm TWA8 MAC: 100 ppm/30 minutes NIOSH REL: 1 ppm TWA10 STEL: 15 ppm/15 minutes ACGIH BEI®: Urine TTCA: 5mg/g creatinine End of workshift urine sample. Exposures have been greatly decreased in the artificial fiber industries since the early 1970’s, to below 10ppm, a level at which increased mortality is no longer seen. Standards noted here: NIOSH recommendations are based on protection against accelerating pre-existing cardiovascular disease. OSHA had petitioned to lower current standard of 10 ppm to 4 ppm, but was rejected by courts.   Metabolite of CS2, 2-thiothiazolidine-4-carboxylic acid (TTCA), easily measured in urine. Measurement of TTCA in post-shift urine useful for assessment of workplace exposure and of hygiene controls; ACGIH BEI is 5 mg per gram creatinine.

Dysrhythmias Chlorofluorocarbons (Freon® etc) Refrigeration, air conditioning, propellants May sensitize myocardium to catechol effects Other solvents implicated in sudden death: Trichloroethylene, toluene, benzene Findings at autopsy usually unremarkable: c/w sudden death from arrhythmias ARRHYTHMIAS Dysrhythmias and sudden death first noted in solvent abusers and glue sniffers. Ambulatory EKG monitoring showed abnormalities in pathology residents exposed to chlorofluorocarbons such as Freon; these improved with improvements in ventilation. Occasional deaths have been reported from excess physical activity near leaking refrigerants. Autopsy results in cases of sudden death from solvent exposures show no evidence for atherogenesis.

Cardiomyopathy Cobalt: used to stabilize beer foam (1960’s: Canada, Belgium) Cardiomyopathy reported in beer drinkers several months afterward CARDIOMYOPATHY Epidemics of cardiomyopathy were seen in the 1960s in Belgium and Quebec, after cobalt was used as an additive to beer to stabilize the foam.  

Cardiomyopathy: Cobalt Dose-related: seen in heavy drinkers greatest risk in those drinking >10L/day (!) 22 - 50% mortality in some series Why this group? CM not seen in cobalt therapy for anemia Probable synergistic effect with alcohol, poor diet Investigation showed risk greatest in heaviest drinkers (those consuming >10 liters/day), many of whom were employed at the breweries and were supplied with beer as a fringe benefit. Mortality from cobalt cardiomyopathy was high.   It is unclear however to what extent cobalt represents an occupational toxin; people treated with higher doses of cobalt for anemia do not develop cardiomyopathy, nor do tungsten-carbide tool workers exposed to cobalt, (who may develop hard-metal pneumoconiosis). Cardiomyopathy may have arisen from a combination of heavy alcohol intake, poor nutrition, and cobalt.

Hypertension Associations with several occupational exposures and agents Mechanisms are varied and depend on action of agent HYPERTENSION Associations have been drawn between some workplace exposures and the development of hypertension (HTN). Difficulty arises in attribution because of additional predisposing exposures (eg cigarette smoking) and the prevalence of “essential” hypertension without known predisposing causes.

Hypertension Lead Probable mechanism is via renal injury May also increase vascular tone and resistance Chelation may improve HTN in acute Pb intoxication, but will not reverse if longstanding renal damage is present Cadmium possibly associated with HTN; noted to occur at levels below nephrotoxic dose Lead has been associated with relative increases in blood pressure and may contribute to the development of hypertension. Mechanisms by which it causes HTN involve renal insufficiency from tubular damage, increased plasma renin activity, and possible direct effects on vascular tone through lead’s effects on calcium transport.   Chelation may reduce blood pressure in cases of acute lead intoxication; in chronic cases in which interstitial nephritis is present it is unlikely to be of value.

Hypertension Carbon disulfide Vascular nephropathy and accelerated atherogenesis appear to be mechanisms Noise, shiftwork Postulated effects mediated by stress response (increase sympathetic and hormonal mediator release) Carbon disulfide increases BP through the same mechanisms noted earlier, with accelerated atherogenesis contributing to renal damage.   Of recent interest have been the contributions of shiftwork and noise to the development of HTN. While exposure estimates are difficult to obtain, and studies are confounded by other contributing causes, it appears that there is evidence for a contribution of these exposures to HTN. The contributory pathway is likely increased sympathetic discharge and tone, with release of stress-mediating hormones and mediators. Noise exposure is an important concern for those who are already at risk for HTN (obese, older, family history).

Job Strain and Cardiovascular Disease Body of evidence suggests relationship between job strain and cardiovascular mortality Main associations are with exposure to high psychological demands and low control over job Professional drivers (especially urban transport) have the most consistent evidence of increased risk A body of work in recent years has demonstrated associations between job strain and mortality form cardiovascular disease. Studies in this area are complicated by difficulties in exposure assessment and control of confounding variables, but indicate that high psychological demands, coupled to low control over work (low autonomy) may be contributory. Urban transit drivers have the most consistent evidence of high risk for ischemic heart disease and hypertension, and there appears to be a risk gradient based on intensity of traffic in the work setting.

Social Class and Cardiovascular Disease Pioneering work of Marmot showed increased CHD mortality related to social status. Unskilled manual workers (Class V) have considerably increased risk when compared with professionals (Class I) STANDARDIZED MORTALITY RATIO Marmot’s pioneering work in the UK demonstrated increased cardiovascular mortality among workers in lower socioeconomic positions. Factors contributing to this finding are complex, and may relate to lifestyle factors (diet, exercise, smoking), but control over one’s job (and over others’ work) appears to account for part of the social gradient in mortality seen here.

Cardiovascular effects on work Some figures on heart disease in US: 1.5 million MI each year Nearly 200,000 CABG per year Over 80% of workers are generally able to return to work after initial MI or CABG CARDIOVASCULAR DISEASE AND THE WORKPLACE Some figures on the extent of cardiovascular disease in the US.  

Cardiovascular effects: Return-to-Work after MI Medical Factors Major predictors of RTW: LV dysfunction persistent ischemia / angina after treatment Non-Medical Factors Coping styles Perception of work (demands, satisfaction) Age, gender, education Benefits/incentives Few objective cardiac tests are able to predict successful return-to-work after MI; many non-medical factors have an effect on perception of cardiac disability and may be more important in predicting who returns.  

Cardiovascular effects of work Reinfarction and death NOT more frequent at work Many workers older (>50) and have moved into sedentary roles even pre-infarction Longshoremen study: Lowest rates of CAD mortality linked to heaviest jobs: Those working for years in heavy jobs have a reduced incidence of cardiovascular mortality and sudden death, as shown by this study of longshoremen; this appears to be independent of a worker selection effect. Many worker have also, by the time CVD is apparent, channeled themselves into less strenuous work (eg moving from laborer to foreman).   Activity level CV Mortality Sudden Death High 26.9 5.6 Medium 46.3 19.9 Low 49.0 15.7

Assessing work capacity /capabilities History: Review of prior and current symptoms CP, dyspnea, orthopnea, etc Evidence of improvement with treatment? Descriptions of exertional tolerance (routine activities, work simulations) Current medicines Physical: Signs on examination arrhythmias JVD edema chest exam Review previous and current records Outline for clinical evaluation of patient with cardiovascular disease, assessing work capacity.  

Assessing work capacity /capabilities Exercise EKG May help refine judgement about RTW, in jobs requiring high exertion Ability to reach Bruce Stage 4 on treadmill (12 minutes; ~8-9 METs) indicates low risk of subsequent cardiac event Most individuals after single uncomplicated MI can generate 8+ METs before fatigue or discomfort Objective testing to determine physical capacity can be performed through exercise testing.

Exercise EKG Better for assessing isotonic exercise/work (walking, running etc) Results in  cardiac output, BP remains stable through  peripheral vascular resistance, Exercise testing may not yield good estimate of capabilities for isometric work (lifting, static exertion) BP elevates without reduction in PVR Isometric work (lifting) may not be as well predicted by exercise testing, and the physiologic mechanisms are different from those that contribute to aerobic capacity.

Assessing work capacity: Some numbers 3.5 METs : Bartending, frequent walking with 10lb objects (many office jobs) 4 - 5 METs : Painting, masonry work, light carpentry 5 - 6 METs : Lighter digging, shoveling 6 - 7 METs : Heavier or more frequent shoveling 7 - 8 METs : Carrying 50-60 lbs; sawing hardwood A sample of the exertional requirements of many job tasks.  One metabolic equivalent (MET) reflects basal oxygen consumption at rest (3.5 ml O2/Kg/min), METs shown are multiples of the basal rate and can be either directly measured from O2 consumption on exercise or calculated from the work produced on the treadmill.

Assessing work capacity /capabilities Job description: Always request Assess static vs dynamic work Other stressors (temperature, psych) Other exposures (CO, cigarette smoke) Simulated work (+/- exercise EKG) may be better in judgment of capabilities than testing in lab setting Specialist opinion: but beware of conservatism When asked to render an opinion on work fitness, obtain as accurate information on the job demands as can be supplied, including other potential stressors. Evaluation by a cardiologist may be useful, but take care that opinion does not error on the side of overt conservatism or is influenced by patient desires.

Work capacity: Some guidance Average energy demands of job can safely be  40% of peak workload Peak energy demands of job should be < maximum workload achieved on testing Thus individual generating 8+ METs can be reasonably asked to work at light-medium physical demand level Guidance for basing a determination of job fitness on results of exercise testing.  

Consider in the disabled individual: Over half of post-CABG patients considered “totally disabled” could have safely performed their normal duties or equivalent work, based on exercise testing results Lundbom J, et al. Exercise tolerance and work abilityfollowing aorto-coronary bypass surgery. Scand J Soc Med 1994;22:303-8. Consider in the disabled individual: Inadequate treatment Depression Whether accommodation or changing non-essential requirements of job will allow return Socio-economic explanations Personality features, coping styles, perception of work demands and degree of control, interpretation of physician recommendations, and other psychologic and social factors influence return-to-work more heavily than do physiologic measures. Despite appropriate evaluation, physicians may be over-cautious in returning individuals with CAD to the workplace.   A variety of factors should be considered when evaluating the individual who appears disabled. Can these workers be placed in less strenuous work? Is therapy adequate? Is there co-existing depression (common in those sidelined by an MI) which can be treated? What are the financial incentives that may make disability more attractive than a return to work?

What about exercise-testing of asymptomatic workers?? Predictive value of positive test is low in younger asymptomatic individuals: High false-positive rate requires additional work-up in many cases May have better predictive value in > 40yo with other risk factors (smoking, obesity, +FH, hypercholesterolemia, etc) Often physicians are asked to use exercise testing in asymptomatic individuals, such as police recruits or firefighters. Risk of a cardiac event is low in these workers: the annual rate of MI in asymptomatic patients who demonstrate ischemia on exercise testing is < 1%.   Principles of screening should be borne in mind: the predictive value of a positive test will be low when the prevalence of disease is low. Pre-test screening for cardiac risk factors, such as a positive family history of MI at early age, and performance of test in those aged > 40years may increase the yield of exercise testing in asymptomatic workers.

Fitness-for-Duty Evaluations Many safety-sensitive jobs (fire, police) have qualification requirements based on exercise testing or physical fitness standards Principles outlined in last slide apply: predictive value may be low in younger/healthier workers Be careful not to exclude asymptomatic workers on basis of positive exercise test only ADA conflicts: May not be limited in performance of job Jobs such as firefighting may have performance requirements (either at hire or regularly during job tenure) based on fitness as measured by treadmill evaluation. The principles outlined above should be borne in mind: younger workers have a low prevalence of disease and positive tests are likely to be false-positives in the absence of other risk factors. Furthermore, office testing may not be predictive of work capacity, especially in the asymptomatic individual with a positive test.   Physicians should be careful not to exclude workers on the basis of positive testing without clear demonstration that physical capacity is limited: this would conflict with statutes protecting the disabled such as the ADA.

Other issues in job assessment Statutory / Regulatory Dept. of Transportation (DOT) Commercial Driver’s License (CDL) exams Exclusionary criteria: “Current” CAD accompanied (or likely to be) by angina, syncope, collapse or congestive heart failure Federal Aviation Administration (FAA) more stringent ADA Accommodations Direct threat Regulatory and statutory issues that should be considered in assessing return-to-work. Examination guidelines for a commercial driver’s license exclude individuals with evidence for heart disease that may reasonably be expected to be “accompanied by angina, syncope or heart failure.” Aviation medical examinations are considerably more stringent: the Federal Aviation Administration (FAA) mandates exclusion of those with “coronary heart disease that has required treatment or, if untreated, that has been symptomatic or clinically significant.”   Physicians should also be familiar with the provisions of the ADA and relevant state disability legislation. Under the ADA, the examiner must assess whether the individual with cardiac disease may be accommodated such that essential functions of the job can be performed, and if not, whether the worker would present a direct threat to health or safety on the job.

Attribution and Workers’ Compensation Heart disease multifactorial: risk from work exposures is superimposed on a high baseline Firefighters, Police: Often a statutory presumption that CAD arose from work, if worker has required years of service Assessment of whether cardiac disease arose in the course of work or from exposures in the workplace is complicated by the high prevalence of the condition in Western society and the numerous risk factors for cardiac disease present in the population. Unless there is clear evidence of an inciting exposure (eg carbon disulfide above permissible levels for many years), it is difficult to demonstrate causation by workplace factors.   In many jurisdictions, however, there is a statutory presumption of causation that is applied to workers primarily in safety-sensitive positions. A diagnosis of coronary heart disease is considered to have arisen out of work if the worker has had the requisite number of years of service. This is designed to reduce contested claims and to ease the pathway toward disability for workers such as firemen and police officers whose heart disease may interfere with safe performance of the job.

Acknowledgments The author would particularly like to thank Glenn Pransky MD MOccH for the prior edition of this module as well as for photographs of rayon manufacture and retinal abnormalities Other photos courtesy National Archives and Library of Congress Beer photograph courtesy FreeFoto.com