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Hepatitis A
Last Updated: May 30, 2006

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Synonyms and related keywords: infectious hepatitis, hepatitis A virus, HAV, hepatitis B virus, HBV, hepatitis C virus, HCV, hepatitis D virus, HDV, hepatitis E virus, HEV, Picornaviridae, fulminant hepatic failure, hepatomegaly, jaundice

AUTHOR INFORMATION

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Author: Richard K Gilroy, MBBS, FRACP, Assistant Professor, Department of Internal Medicine, Section of Gastroenterology and Hepatology, University of Nebraska Medical Center Coauthor(s): Sandeep Mukherjee, MD, Assistant Professor, Department of Internal Medicine, Section of Gastroenterology and Hepatology, University of Nebraska Medical Center Editor(s): George Wu, MD, PhD, Professor, Department of Medicine, Chief, Division of Gastroenterology-Hepatology, Director, Fellowship in Gastroenterology-Hepatology, Herman Lopata Chair, Hepatitis Research, University of Connecticut School of Medicine; Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine; Oscar S Brann, MD, FACP, Associate Clinical Professor, Department of Medicine, University of California at San Diego; Consulting Staff, Mecklenburg Medical Group; Alex J Mechaber, MD, FACP, Assistant Dean for Medical Curriculum, Associate Professor of Medicine, Division of General Internal Medicine, University of Miami Miller School of Medicine; and Julian Katz, MD, Clinical Professor of Medicine, Drexel University College of Medicine; Consulting Staff, Department of Medicine, Section of Gastroenterology and Hepatology, Hospital of the Medical College of Pennsylvania Disclosure

INTRODUCTION

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Background: One of the more common causes of acute hepatitis is hepatitis A virus (HAV). The virus was isolated by Purcell in 1973. Since the application of

accurate serologic investigations in the 1980s, the epidemiology, clinical manifestations, and natural history of hepatitis A have become apparent. The relative frequency of HAV as a cause of acute hepatitis has declined in Western societies, while in contrast, notification of individual cases has increased, primarily as a result of improved reporting and diagnostic techniques. The nadir of reported cases was in 1987. Improvements in hygiene, public health policies, and sanitation have had the greatest impact on this disease, and vaccination and passive immunization have successfully led to some reduction in illness in high-risk groups. Reduced encounters with HAV at a young age have resulted in both a decline in herd immunity and a change to the epidemiology of the illness, with increases in the mean age of occurrence of illness attributed to acute HAV infection in Western societies. Although this phenomenon may lay a framework for potential epidemics in the future, public health policies and newly implemented immunization practices are likely to reduce this potential. Humans appear to be the only reservoir for HAV. Pathophysiology: HAV is a single-stranded, positive-sense, linear RNA enterovirus and a member of the Picornaviridae family. In humans, viral replication depends on hepatocyte uptake and synthesis, and assembly occurs exclusively in liver cells. Acquisition results almost exclusively from ingestion (ie, fecal-oral transmission), although isolated cases of parenteral transmission have been reported. HAV is an icosahedral nonenveloped virus measuring approximately 28 nm in diameter. Its resilience is demonstrated by its resistance to denaturation by ether, acid (pH 3.0), drying, and temperatures as high as 56C and as low as -20C. HAV can remain viable for many years. Boiling water is an effective means of destroying it, and chlorine and iodine are similarly effective (see Image 1). Various genotypes of the virus exist; however, there appears to be only 1 serotype. Virion proteins 1 and 3 are the primary sites of antibody recognition and subsequent neutralization. No antibody cross-reactivity has been identified with other viruses causing acute hepatitis. Hepatocyte uptake involves a receptor, recently identified by Kaplan et al, on the plasma membrane of the cell, and viral replication is believed to occur exclusively in hepatocytes. The recent demonstration of HAV in saliva has raised questions about this exclusivity. After entry into the cell, viral RNA is uncoated, and host ribosomes bind to form polysomes. Viral proteins are synthesized, and the viral genome is copied by a viral RNA polymerase. Assembled virus particles are shed into the biliary tree and excreted in the feces. Minimal cellular morphologic changes result from hepatocyte infection. The development of an immunologic response to infection is accompanied by a predominantly portal and periportal lymphocytic infiltrate and varying degree of necrosis (see Image 2).

Person-to-person contact is the most common means of transmission and is generally limited to close contacts. Transmission through blood products has been described. The period of greatest shedding of virus is during the anicteric prodrome (14-21 d) of infection and corresponds to the time when transmission is highest. Recognizing that active virus is shed after the development of jaundice is important, although amounts fall rapidly. Outbreaks of acute hepatitis A have received international attention. The most notable report of transmission is that which appeared in The New England Journal of Medicine. Here was described a point source epidemic of HAV infection at a Pennsylvania restaurant where the vehicle for transmission was green onions used to make a mild salsa. The contamination of the onions occurred prior to the vegetable arriving in the United States. Many authorities believe that hepatocyte injury is secondary to the host's immunologic response. This hypothesis is supported by the lack of cytotoxic activity in tissue culture and correlations between immunologic response and manifestations of hepatocyte injury. The incubation period usually lasts 2-6 weeks, and the time to onset of symptoms may be dose related. The presence of disease manifestations and the severity of symptoms following infection directly correlate with patient age. In developing nations, the age of acquisition is before age 2 years; in Western societies, acquisition is most frequent in persons aged 5-17 years. In this age range, the illness is more often mild or subclinical; however, severe disease, including fulminant hepatic failure does occur. Frequency:

In the US: The United States is an area of low endemicity. In contrast, the nearest southern neighbor, Mexico, has a high prevalence of anti-HAV antibody, indicating previous infection. In 1988, the number of reported cases of hepatitis A was 27,000; in 1995, approximately 32,000 infections were reported. The US Centers for Disease Control and Prevention (CDC) estimated the actual number of infections in 1995 to be approximately 150,000. More recent data from the CDC show the number of reported acute clinical cases of HAV in 2003 to be 7653 with the estimate of actual clinical cases to be 33,000. The estimated number of new infections in the United States for that same year was 61,000. Persons aged 5-14 years are most likely to acquire acute HAV infection. Over the last 40 years, the average age of infected persons has steadily increased. Currently, individuals in high-risk populations account for many sporadic cases. These groups include contacts of recently infected individuals, foreign travelers (particularly those to developing nations), male homosexuals, childcare workers, institutionalized individuals, and those living in poverty. Health measures implemented for these high-risk groups

will likely modify the evolving epidemiology. Evidence of past infection differs between adults (~40%) and children (~10%) and supports acquisition during school-aged years. Over the last century, improved sanitation and hygiene measures have resulted in a shift in the age group that carries the burden of disease. This, in turn, may result in more clinically apparent and severe disease. US military personnel who served more recently in Asia or, more remotely, during World War II, often returned with evidence of infection acquired abroad. As many as 200,000 service personnel experienced symptomatic HAV infection in World War II. Food handlers, at the point of preparation, are an infrequent source of outbreaks in the United States, although cases have been documented. Virtually any food can be contaminated with HAV.

Internationally: HAV has a worldwide distribution. The highest seropositivity (antibody to HAV) is observed in adults in urban Africa, Asia, and South America, where evidence of past infection is nearly universal. Acquisition in early childhood is the norm in these nations and is usually asymptomatic. Factors predisposing humans to early acquisition include overcrowding, poor sanitation, certain social practices, and lack of a reliable clean water resource. Within the socioeconomic framework (ie, class structure) of some developing nations are differing frequencies of HAV antibody in the older population; accordingly, sporadic cases may be observed in some individuals. Until recently, US CDC data supported cycles of disease occurring every 510 years. Some of these outbreaks correlated with the wars of the 20th century, in which people returned from areas of high endemicity. In recent years, this pattern has disappeared and has been associated with a decline in overall incidence of new infection. In Shanghai in 1988, a large shellfish-related epidemic occurred. This provided a unique opportunity to study the incubation and natural history of acute HAV infection in a large population.

Mortality/Morbidity: In the United States, most cases are symptomatic, with the frequency of icteric cases approaching 80%. Globally, infection is often asymptomatic and subclinical. Approximately 75% of adults are symptomatic with infection, many with jaundice. In stark contrast, 90% of those infected before age 2 years are asymptomatic.

The single most important determinant of illness severity is age; a direct correlation between increasing age and likelihood of adverse events (ie, morbidity and mortality) is present. Most deaths from acute HAV infection

occur in persons older than 50 years, despite the fact that acute HAV infection is uncommon in this age group. Case fatality rates approach 2%, and a vast majority of persons who acquire infection when older than 50 years exhibit signs and symptoms of the disease. The overall case fatality for acute HAV infection is 0.02-0.1%. The current older population has a large number of individuals who are immune by virtue of exposure in early life; however, this pattern has been changing.

Other populations with increased likelihood of adverse sequelae caused by acute HAV infection are those with significant comorbidities or concurrent chronic liver disease, as highlighted by the high incidence of hepatitis B surface antigen in persons who died in the Shanghai outbreak, along with case reports of acute HAV infection deaths in persons with hepatitis C. Infection in early life occurs commonly in developing countries. Therefore, symptomatic disease is uncommon in natives and is most often observed in visitors to these countries. Seropositivity for HAV antibody protects individuals against reinfection. Some evidence suggests that reinfection may occur late in life in individuals in whom levels of detectable antibody have disappeared. Although reported to occur, reinfection is not associated with clinical disease. A rapid rise in immunoglobulin G (IgG) antibody to HAV in the absence of immunoglobulin M (IgM) is the hallmark of this event (anamnestic response).

Race: Immigrants from countries of high endemicity to countries of low endemicity may be responsible for some of the periodicity observed with outbreaks of infection. In this setting, affected individuals tend to be infants born since the last outbreak or susceptible adults who moved to the area. Sex: Except for persons in high-risk populations (eg, sewage workers, childcare workers, aid workers, male homosexuals), no sexual predilection is apparent. Age: With increasing age of acquisition, both symptomatic disease and adverse sequelae increase. In the Shanghai outbreak, most of those admitted to the hospital were aged 20-40 years. Mortality from fulminant hepatic failure increased with increasing age despite the decreasing prevalence of disease as age increased. The lower incidence of infection in the older population was related to a greater likelihood of immunity rather than to a decrease in exposure.

CLINICAL

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History: Along with outlining the presenting complaint and its severity and sequelae, the history should also initiate a search for the source of exposure (eg, overseas travel, lack of immunization, intravenous drug use) along with excluding other possible causes for acute hepatitis (eg, accidental Tylenol overdose). The incubation period is 2-6 weeks, with a mean of 4 weeks. Shorter incubation periods may result from higher total dose of viral inoculum.

Discussion focusing on excluding other etiologies should be undertaken early in order to guide further investigation. Not every patient with fever, hepatomegaly, and jaundice has HAV infection. Some of the important differential diagnoses for acute hepatitis warrant early and specific management. Prodrome
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Patients may have mild flulike symptoms of anorexia, nausea and vomiting, fatigue, malaise, low-grade fever (usually <39.5C), myalgia, and mild headache. Smokers often lose their taste for tobacco, similar to those presenting with appendicitis.

Icteric phase
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Dark urine appears first (bilirubinuria). Pale stool soon follows, although this is not universal. Jaundice occurs in most (70-85%) adults with acute HAV infection. Jaundice is less likely in children and is uncommon in infants. The degree of icterus also increases with age. Abdominal pain occurs in approximately 40% of patients. Itch (pruritus), although less common than jaundice, is generally accompanied by jaundice. Arthralgias and skin rash, although associated, are less frequent than the above symptoms. Rash more often occurs on the lower limbs and may have a vasculitic appearance.

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Relapsing hepatitis A: This is an uncommon sequela of acute infection, is more common in elderly persons, and is characterized by a protracted course of symptoms of the disease and a relapse of symptoms and signs following apparent resolution. This phenomenon is further discussed in Complications, along with some of the less commonly associated features of the disease.

Physical: The physical examination focuses on detecting features to support a

diagnosis of acute hepatitis and should include assessment for features of chronic liver disease or similarly assessment for evidence of decompensation.

Hepatomegaly is common. Jaundice or scleral icterus may occur. Patients may have a fever with temperatures of up to 40C.

Causes: Most patients have no defined risk factors. Risk factors for acquisition include the following:

Personal contacts Institutionalization Occupation (eg, daycare) Foreign travel Male homosexuality Illicit parenteral drug use
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DIFFERENTIALS

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Budd-Chiari Syndrome Cytomegalovirus Hepatitis, Viral Other Problems to be Considered: Acute drug-induced liver injury (eg, Tylenol, ecstasy) Acute HIV infection Drug-induced hypersensitivity reactions (eg, sulfasalazine hypersensitivity) Viral hepatitis (eg, cytomegalovirus [CMV], Epstein-Barr virus [EBV])

The goals of pharmacotherapy are to reduce morbidity and to prevent complications.

Drug Category: Analgesic agents -- Pain control is essential to quality

patient care. Acetaminophen is useful for pain and/or fever. Acetaminophen (Tylenol, Tempra, Feverall) -- Reduces fever by acting directly on hypothalamic heat-regulating Drug Name centers, which increases dissipation of body heat via vasodilation and sweating. Relieves mild to moderate pain. 325-650 mg PO q4-6h or 1 g PO tid/qid; Adult Dose not to exceed 4 g/d <12 years: 10-15 mg/kg/dose PO q4-6h prn; not to exceed 2.6 g/d Pediatric Dose >12 years: 325-650 mg PO q4h; not to exceed 5 doses in 24 h Documented hypersensitivity; caution in Contraindications G-6-PD deficiency or PKU Rifampin can reduce analgesic effects; coadministration with barbiturates, Interactions carbamazepine, hydantoins, and isoniazid may increase hepatotoxicity B - Usually safe but benefits must Pregnancy outweigh the risks. Hepatotoxicity possible in persons with chronic alcoholism following various dose levels; severe or recurrent pain or high or continued fever may indicate a Precautions serious illness; contained in many OTC products and combined use with these products may result in cumulative doses exceeding recommended maximum dose

Drug Category: Antiemetics -- Used to treat nausea and vomiting.

Metoclopramide (Reglan) -- Dopamine antagonist that stimulates acetylcholine release in the myenteric plexus. Acts centrally on chemoreceptor triggers in the floor of the fourth ventricle, which provides important antiemetic activity. 5-10 mg PO tid/qid 5-20 mg IV/IM tid Not established

Drug Name

Adult Dose Pediatric Dose

Documented hypersensitivity; pheochromocytoma; GI hemorrhage, Contraindications obstruction, or perforation; history of seizure disorders Anticholinergic agents antagonize Interactions effects; opiate analgesics may increase CNS toxicity B - Usually safe but benefits must Pregnancy outweigh the risks. Caution in history of mental illness and Precautions Parkinson disease

Drug Category: Vaccines, viral -- Hepatitis A vaccine is used for active

immunization against disease caused by HAV. Hepatitis A vaccine, inactivated (Havrix, Vaqta) -- May be administered with Drug Name immunoglobulin injections without affecting efficacy. Havrix: 1440 U IM once; booster dose at 6-12 mo Adult Dose Vaqta: 50 U IM once; booster dose at 6 mo <2 years: Not recommended >2 years: Havrix: 360 U IM days 0 and 30; 360 U booster dose at 6-12 mo; alternatively, Pediatric Dose 720 U day 0 and 720 U booster dose at 6-12 mo Vaqta: 25 U IM once; booster dose at 618 mo Documented hypersensitivity; IV/SC/ID Contraindications administration May decrease effects of Interactions immunosuppressive agents C - Safety for use during pregnancy has Pregnancy not been established. Caution in acute infection or febrile illness; duration of effect has not been fully established; efficacy >85%; caution Precautions in individuals taking anticoagulant therapy; vaccine does not protect against hepatitis B, C, or E viruses

Drug Category: Immune globulins -- Purified preparation of gamma

globulin. Derived from large pools of human plasma and is composed of 4

subclasses of antibodies, approximating the distribution of human serum. Used for postexposure prophylaxis or when inadequate time is available for immunization to be effective before potential exposure. Immune globulin, intramuscular (BayGam 15-18%) -- Neutralizes circulating myelin antibodies through anti-idiotypic antibodies; down-regulates proinflammatory cytokines, including INF-gamma; blocks Fc receptors on macrophages; suppresses inducer T and B cells and augments suppressor T cells; blocks complement cascade; promotes remyelination; may increase Drug Name CSF IgG (10%). Effective when administered within 14 d of exposure. If likely to be returning to areas of high endemicity, concurrent vaccination is recommended. For situations in which exposure is likely to occur before vaccination would be effective, both may be administered without reducing the efficacy of HAV vaccine. 0.02-0.06 mL/kg IM for exposed contacts or individuals traveling to areas for up to 6 mo; use higher dose if subject will be Adult Dose in the area for up to 6 mo (ie, where hepatitis A is common) 0.06 mL/kg IM q4-6mo for travelers staying >3 mo Pediatric Dose Not established Documented hypersensitivity; IgA Contraindications deficiency; anti-IgE/IgG antibodies Increases toxicity of live virus vaccine Interactions (MMR); do not administer within 3 mo of vaccine C - Safety for use during pregnancy has Pregnancy not been established. Precautions First check serum IgA (use an IgAdepleted product, eg, Gammagard S/D); infusions may increase serum viscosity and thromboembolic events; infusions may increase risk of migraine attacks, aseptic meningitis (10%), urticaria, pruritus, or petechiae (2-5 d postinfusion to 30 d); increases risk of renal tubular necrosis in elderly patients and in

patients with diabetes, volume depletion, and preexisting kidney disease; laboratory study result changes associated with infusions include elevated antiviral or antibacterial antibody titers for 1 mo, 6-fold increase in ESR for 2-3 wk, and apparent hyponatremia FOLLOW-UP
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In/Out Patient Meds:

Tylenol may be safely used to treat some of the symptoms associated with the illness. However, the dose should be no greater than 4 g/d.

Transfer:

Refer patients with fulminant hepatic failure to facilities with expertise in liver transplantation.

Deterrence/Prevention:

Control at the source, with treatment of contacts to prevent further cases of disease is the primary goal. Long-term secondary goals include immunization, which increases herd immunity and reduces the likelihood of further outbreaks in high-risk communities. Education about transmission and prevention of transmission (eg, hand washing, safe food sources) is also important. The efficacy of immunization has been clearly demonstrated in high-risk groups.
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In the United States, vaccination programs targeting children during urban outbreaks have demonstrated significant benefits. Immunization programs applied to high-risk groups show morbidity and cost benefits. Approximately 20% of individuals with acute HAV infection may require hospitalization. Global immunization appears to be prohibitively expensive. The vaccine is not yet licensed for use in persons younger than 2 years. Vaccine efficacy ranges from 80-100% after 1-2 doses compared to placebo. The current dosing recommendations for the available vaccinates are provided in Medication.

People with chronic liver disease of any cause should consider vaccination. Response rates in patients with advanced liver disease and in those on immunosuppressive therapies are likely to be lower. The potentially disastrous outcome of acute HAV infection in this group cannot be overemphasized. Vaccination in some low-risk groups who are potential sources of larger outbreaks of infection (eg, food handlers) has been implemented by some employers, although cost-benefit analysis for the employer does not seem to support such measures.

Annually, an estimated 100 people die in the United States as a result of acute liver failure due to HAV. The frequency of acute hepatitis appears more common in states neighboring Mexico. Although the case-fatalities from fulminant HAV have been reported in all age groups, where overall the mortality is estimated at approximately 0.3%, the rate is 1.8% among adults older than 50 years and is also higher in persons with chronic liver diseases. Passive immunization with Gammagard reduces infection when administered within 14 days of exposure (ie, postexposure prophylaxis).
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In many instances, preexposure prophylaxis has been somewhat replaced by immunization. For travelers, cost-benefit analysis suggests that vaccination is preferred over gamma globulin when an extended stay in the area of risk (ie, high endemicity) is longer than 3 months or when repeat travel to the area (ie, >2 visits outside a 3-mo period) is likely. Postexposure prophylaxis is recommended for nonimmunized close contacts of those recently diagnosed with acute HAV infection. Immunization is indicated for individuals traveling to areas of high endemicity who have less than 2 weeks before departure. Both the vaccination and intramuscular immunoglobulin should be administered to provide long-term immunity, particularly in persons who intend to travel to these areas repeatedly.

Notify the appropriate public health authority following diagnosis. Initiate contact tracing after diagnosis.

Complications:

Generally, HAV infection elicits no lasting sequelae. Death is rare, occurring in fewer than 0.2% of cases.
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Death is more frequent in elderly patients and in those with underlying liver disease. In children, liver transplantation has been performed for fulminant hepatic failure. In France, 10% of cases of fulminant failure in children are caused by HAV infection. The outcomes from transplantation are the same as for others with

fulminant disease. Recurrent disease does not occur following transplantation despite immunosuppression.
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Prolonged cholestasis may follow the acute infection. The frequency at which this occurs increases with age. Prolonged cholestasis is characterized by a protracted period of jaundice (>3 mo) and resolves without intervention. Corticosteroids and ursodeoxycholic acid may shorten the period of cholestasis. The usual features of cholestatic viral hepatitis A are pruritus, fever, diarrhea, and weight loss, with serum bilirubin levels greater than 10 mg/dL. Some investigators believe that the use of corticosteroids may predispose patients to developing relapsing hepatitis A. Good data to support this hypothesis are lacking. Acute renal failure, interstitial nephritis, pancreatitis, red blood cell aplasia, agranulocytosis, bone marrow aplasia, transient heart block, Guillain-Barr syndrome, acute arthritis, Still disease, lupuslike syndrome, and Sjgren syndrome have been reported in association with HAV infection. These complications are all rare. Autoimmune hepatitis following HAV infection has received substantial discussion in the literature. A postulated mechanism involves molecular mimicry and genetic susceptibility, in much the same way as that proposed in type 1 diabetes. Steroid therapy for this condition was associated with good clinical response and improvement in biochemical and clinical parameters, in a way similar to that of traditional autoimmune hepatitis. However, these findings are confined to isolated case reports, and the results of larger clinical trials are not available.

Relapsing HAV infection

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This complication occurs in 3-20% of patients with acute HAV infection and uncommonly takes the form of multiple relapses. Following a typical acute course of HAV infection, a remission phase occurs, with partial or complete resolution of clinical and biochemical manifestations. The initial flare usually lasts 3-6 weeks; relapse occurs after a short period (usually <3 wk) and mimics the initially presentation, although it usually is clinically milder. A tendency to greater cholestasis exists in these patients. Vasculitic skin rashes and nephritis may be additional clinical clues to this syndrome. During relapses, shedding of virus can be detected. IgM antibody test findings are positive. The clinical course is toward resolution, with lengthening periods between flares. The total duration is 3-9 months.

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Liver transplantation has been performed in patients with this condition when signs of significant decompensation have occurred. Corticosteroid treatment has been shown to improve the clinical course, although the course is generally benign without treatment.

Prognosis:

Prognosis is excellent. Long-term immunity accompanies infection. Recurrence and chronic hepatitis does not usually occur.

Patient Education:

Travelers should be educated about good hygiene and clean, safe water supplies. Advice should be provided regarding the benefits of immunization, particularly in high-risk individuals. Travelers should avoid uncontrolled water sources, raw shellfish, and uncooked food. Boiling water or adding iodine inactivates the virus. All fruit should be washed and peeled. People with HAV infection who are treated at home and those around them should follow strict enteric precautions. For excellent patient education resources, visit eMedicine's Hepatitis Center, Liver, Gallbladder, and Pancreas Center, and Public Health Center. Also, see eMedicine's patient education articles Hepatitis A and Foreign Travel.
Section 9 of 11

MISCELLANEOUS

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Medical/Legal Pitfalls:

Central to the prevention of any legal problem is establishing the correct diagnosis, which comes from a combination of careful history and subsequent examination. Appearances may be deceiving; therefore, always exclude drugs, particularly Tylenol, as a cause of acute liver injury. After establishing a diagnosis, tracing contacts and notifying local public health authorities are important steps for preventing further cases. Omitting these measures may place the practitioner in a vulnerable situation. Finally, remember that transplantation, in selected cases, is an option if the patient has fulminant failure.