El retorno a la democracia

Craig S. Miller, DMD, MS

Table 16–1 Comparison of Hepatitis Viruses

HAV HBV HCV HDV HEV HGV

Virion 28nm RNA 42nm DNA 40–55 nm RNA 35 nm RNA 32nm RNA

Transmission Fecal-oral Parenteral, sexual Parenteral, sexual? Parenteral, sexual? Fecal-oral ?

Incubation (d) 15–60 45–180 14–180 15–64 ?

Dx markers Anti-HAV Anti-HBs, Anti-HBc, Anti-Hbe Anti-HCV Anti-HEV Anti-HGV

HBsAg HCV RNA

Chronic carrier state No Yes Yes Yes No ?

Vaccine Yes Yes No No No No

Figure 16–1 Hepatitis B and C viruses. RIBA = recombinant immunoblot assay.

Hepatitis B

Hepatocyte

Hepatocyte Early Ag (HBe)

Core Ag (HBc) Viral DNA

Replication

Neoplasia

Lysis

Replication

Lysis Surface Ag (HBsAg)

HCV-RNA

Antigenemia RIBA proteins Hepatitis C

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circular and comprised of two strands, with one strand being partially incomplete (~80% full length). It is a highly infectious virus that produces three distinct par-ticles during replication: (1) the Dane particle or com-plete virus (HBV), composed of an outer shell and an inner core, (2) 22-nm noninfectious spherical particles, and (3) noninfectious filamentous units. The outer shell of the Dane particle carries the hepatitis B surface anti-gen (HBsAg), which is anchored in a lipid bilayer derived from the host cell. Internally is the inner core that is composed of a protein known as the hepatitis B core antigen (HBcAg), and the hepatitis B early antigen (HBeAg), an antigenic component derived from cleav-age of the core antigen.

Hepatitis B virus infection remains a serious health care problem. There are 350 million hepatitis B virus carriers worldwide, with the highest carrier rates (8–20% of population) in southeast Asia, China, and sub-Saharan Africa. Globally, 1.25 million persons die per year as a result of hepatitis B. In 2000, 6646 cases of type B hepatitis were reported to the Centers for Dis-ease Control and Prevention (CDC) in the United States.

There are over 1.5 million carriers in the United States, and an estimated 6000 deaths occur annually due to cir-rhosis and primary hepatocellular carcinoma associated with HBV infection.

Approximately 50 to 90% of infected infants, 25%

of infected children, and 6 to 10% of adults infected with HBV develop a persistent carrier state. The carrier state may be divided into two phases: persistent hepati-tis or chronic active hepatihepati-tis. Chronic active hepatihepati-tis is characterized by active virus replication in the liver, HBsAg and HBeAg in the serum, signs and symptoms of chronic liver disease, persistent hepatic cellular necrosis, and elevated liver enzymes. About 3 to 5% of patients infected with HBV develop chronic active hepatitis, whereas the remainder develop a persistent infection.

Persistent virus replication destroys hepatocytes, result-ing in fibrosis and cirrhosis in about 20% of cases of chronic hepatitis B. Treatment with interferon alpha-2b (IFN-α2b) is 30 to 40% effective in eliminating chronic HBV infection. Untreated cirrhosis results in progres-sion of the disease and, eventually, death.

Hepatitis C virus

Hepatitis C virus, previously known as one of the non-A non-B hepatitis viruses, is a small (38–55 nm diameter), positive-sense, single-stranded RNA virus of the Fla-viviridae family (see Figure 16–1). Six major genotypes of HCV and 40 related subtypes have been identified. The virus has a core protein and two envelope glycoproteins.

The prevalence of HCV infection worldwide is between 0.3% and 1.5%, with an estimated 300 million

carriers worldwide. In the United States, 30,000 acute new infections occur annually; approximately 25% of these are diagnosed, and 1.8% of the population 6 years old or older (or approximately 4 million) have antibodies against HCV. About 2.7 million Americans are chroni-cally infected with HCV. Hepatitis C is responsible for an estimated 10,000 deaths annually and is the leading cause of liver transplantation in the United States.

The genetic diversity of HCV, and its ability to mutate, allows the virus to avoid neutralization and establish a chronic infection in about 85 to 90% of infected persons. The majority of HCV-infected patients develop chronic active hepatitis that is characterized by persistent and intermittent viremia, fluctuating eleva-tions of serum alanine aminotransferase (ALT) levels and slow but progressive liver damage. The first decade is usually marked by inflammatory cell infiltration of the portal tracts and focal liver cell necrosis. Mild fibro-sis ensues that is followed by more severe fibrofibro-sis, bridging between portal tracts and bridging between portal tracts and hepatic veins. By the second decade after infection, fibrosis progresses to cirrhosis in at least 20% of patients with chronic HCV infection. Progres-sion is more likely if patients consume excessive amounts of alcohol. Untreated cirrhosis is accompanied by liver failure, portal hypertension, ascites, jaundice, esophageal varices, and encephalopathy (end-stage liver disease). Portal hypertension contributes to splenic abnormalities that enhance platelet destruction, whereas esophageal varices can rupture, resulting in life-threatening hemorrhage. The 5-year survival is 50 to 90%, depending on whether the hepatitis C patient develops compensated or decompensated cirrhosis.

Clinical features

Hepatitis B and C viruses are present in the blood, serum, plasma, saliva, menstrual and vaginal discharge, seminal fluid, and occasionally, urine of infected per-sons. Hepatitis B virus is highly infectious in blood.

Both viruses are transmitted to susceptible individuals by horizontal routes (ie, parenteral, hetero- or homo-sexual, and injecting drug use) and vertical routes (mother to fetus). Blood transfusion, dialysis, percuta-neous inoculation (tattooing, body piercing), absorp-tion of infective serum or plasma through mucosal sur-faces, and organ and tissue transplantation are other modes of transmission. Transmission of HBV and HCV via a human bite has been reported, and transmission from inanimate objects (eg, blood-tinged gauze) is pos-sible. In the United States, HBV and HCV are transmit-ted primarily by horizontal routes, yet 30% and 40% of HBV- and HCV-infected patients, respectively, have no identifiable risk factor for infection. Hepatitis C virus

was the major etiologic agent of post-transfusion hepatitis until the introduction of sensitive blood testing for HCV in the 1990s. Since then, the risk of transfu-sion-related hepatitis has been reduced to approxi-mately 1 in 100,000 units transfused.

Hepatitis B and C virus infections can occur at any age, but are more common after puberty. The incuba-tion period for HBV is 45 to 180 days (average, 75 d);

for HCV it is 14 to 180 days (average, 50 d). Hepati-tis B and C viruses produce symptoms in 10% and 25 to 30% of patients, respectively. Symptoms initially are flu-like and include fatigue, fever, loss of appetite, diarrhea, headache, malaise, myalgia, nausea, vomit-ing, and weakness. During acute HBV infection, about 50% of symptomatic persons become icteric within about 10 days of the onset of symptoms. A minority become icteric with HCV infection. Icterus is the stage of infection in which patients demonstrate jaundice (yellow bile deposits) in the skin, conjunctiva of the eye, oral mucosa, and urine as a result of serum biliru-bin levels rising three- to fourfold above normal levels (0.2–1.2 mg/dL). About 10% of patients infected with HBV also demonstrate serum sickness-like manifesta-tions, including angioedema, arthralgia, and a rash. As the disease progresses, abdominal pain increases and hepatomegaly and splenomegaly develop. Two to 8 weeks are required for recovery from symptoms, with hepatomegaly and abnormal liver function persisting for weeks to months. The course of the disease varies with alcohol use and the viral strain and load. The acute infection rarely requires medical treatment other than rest and the avoidance of hepatotoxic drugs. Patients who fail to produce an adequate immune response can develop fulminant hepatitis or a chronic infection.

Diagnosis

The diagnosis of acute HBV infection is made by recog-nition of the clinical features, specific serologic tests for viral antigens and antibodies, and elevated liver enzymes. The hepatitis B surface antigen (HBsAg) is the first detectable specific marker (Figure 16–2). Hepatitis B surface antigen appears in the blood usually by the fourth week of infection and is followed within a week by the hepatitis B early antigen (HBeAg). Two to 4 weeks after the appearance of surface antigen, antibod-ies against the core antigen (anti-HBcAg) appear. Subse-quently, antibodies against the hepatitis B early antigen (anti-HBeAg) appear by about the sixteenth week, and finally the appearance of antibodies against the surface antigen (anti-HBsAg) appear by about week 28. Clear-ance of the virus is marked by the disappearClear-ance of HBeAg, appearance of anti-HBeAg and the eventual

dis-appearance of HBsAg. Failure to produce anti-HBsAg results in a chronic carrier state. Carriers persistently display HBsAg in their serum for more than 6 months.

The presence of the HBeAg in a carrier’s serum indicates virus replication in the liver and an infectious state.

Antibody against HCV (anti-HCV) can be detected in 50 to 70% of patients at the onset of symptoms and in 90% within 3 months after onset of infection. Anti-HCV is commonly detected using an enzyme immuno-assay (EIA) that contains HCV antigens from the core and nonstructural genes. A supplemental recombinant immunoblot assay (RIBA) and the qualitative reverse transcriptase polymerase chain reaction (RT-PCR) for HCV RNA can be performed for confirmation. The RIBA is often positive after the third week of infection, whereas HCV RNA can be detected in blood as soon as 1 week after initial exposure.

Since a delay of several weeks occurs before anti-bodies can be detected in the serum of a patient with acute hepatitis, other laboratory abnormalities are help-ful in the diagnosis. Early features include a relative leukocytosis with a shift to the left and a mild protein-uria in the urine. More specific for acute hepatitis are elevations in the serum transaminase levels (aspartate aminotransferase/serum glutamate oxaloacetate trans-aminase [AST/SGOT], alanine aminotransferase/serum glutamate pyruvate transaminase [ALT/SGPT], and gamma-glutamyltransferase [GGT]). They become ele-vated (often more than 10 times normal) during the late prodromal phase. Subsequently, a rise in the serum bilirubin occurs, the serum alkaline phosphatase level

Figure 16–2 Serologic changes in hepatitis B and C virus infections.

***

***

***

Liver Enzyme Titers Bilirubin Titers

600

remains elevated in chronic state Clinical Symptoms

Appetite loss, malaise, myalgia, nausea, jaundice, hepatosplenomegaly

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elevates mildly and the prothrombin time (PT) may become prolonged. Elevation of the serum bilirubin often corresponds with the peak of the icteric phase.

During recovery, the transaminase level begins to fall, however, elevations in the bilirubin level regress more slowly. Failure of the PT to return to normal is a signif-icant prognostic sign of extensive hepatic cellular destruction, indicative of a fulminant clinical course or a chronic rather than an acute infection.

Extrahepatic and oral manifestations

Patients with chronic hepatitis C occasionally present with extrahepatic manifestations considered to be of autoimmune origin, including antinuclear and anti-smooth muscle antibodies, autoimmune thyroiditis, rheumatoid arthritis, essential mixed cryoglobulinemia, glomerulonephritis, (Gougerot)-Sjögren-like syndrome, keratoconjunctivitis sicca, lichen planus, porphyria cutanea tarda, vasculitis, and thrombocytopenic pur-pura. The patients affected with Sjögren-like syndrome often have features of secondary Sjögren syndrome (ie, keratoconjunctivitis sicca, hypergammaglobulinemia, and anti-DNA antibodies), but rarely have the typical primary autoimmune disorders of secondary Sjögren syndrome (ie, rheumatoid factor, anti–SS-A and anti–SS-B antibodies); the clinical abnormalities of oral dryness and abnormal sialography are variable. The lichen planus associated with chronic HCV can be intra-oral or extraintra-oral and appears in about 5 to 10% of patients with chronic HCV, with higher prevalence in Italy and Japan. The dermal eruptions of lichen planus associated with chronic liver disease can also result from adverse drug effects of IFN-α2b administration.

The oral cavity manifests several features of hepati-tis. Hepatitis B and C viruses are present in whole saliva of infected humans. During the icterus, jaundice can be seen in the oral mucosa. Jaundice becomes clin-ically evident as the serum bilirubin level approaches 2.5 mg/100 mL. Levels of bilirubin are highest during peak icterus and gradually subside during convales-cence. Jaundice is best visualized in the posterior palate, the floor of the mouth along the lingual frenum, and the buccal mucosa. Although children under 2 years of age are often asymptomatic, hepatitis that results in jaundice can result in yellow-green bile depo-sition of the dentin of developing teeth. Viral-induced liver disease can cause intraoral bleeding, petechiae, and ecchymoses.

Neoplasia

Chronic HBV and HCV can deregulate RNA transcrip-tion and the replicatranscrip-tion machinery of the hepatocyte,

leading to hepatocellular carcinoma. Hepatitis B virus induces neoplasia by integrating its DNA into the hepa-tocyte genome and facilitating the activity of oncogenes, such as ras. The mechanism by which HCV induces malignant transformation may involve inactivation of the tumor suppressor gene p53. Hepatocellular carci-noma (HCC) develops in 1 to 5% of patients with chronic HCV hepatitis after 20 years and is associated with chronic HBV and HCV infection in 20 to 50% of cases. Once cirrhosis is established, the rate of HCC development is 1 to 4% per year. The risk of liver can-cer is 30- to 100-fold higher for chronic hepatitis virus carriers compared with uninfected persons.

Diagnostic tests for HCC include an elevated α-fetoprotein (AFP) and the liver biopsy. Metastases of HCC to the orofacial complex are rare. Generally they appear as rapidly expanding, hypervascular, and hem-orrhagic masses located posterior to the premolar region and extending into the mandibular ramus.

Chronic hepatitis C infection has been associated with lymphoproliferation, lymphoid cancer (B-cell non-Hodgkin lymphoma), and gammopathies.

Therapy and prevention

Chronic hepatitis is managed with antiviral agents when HCV RNA levels and ALT levels remain elevated and the liver biopsy shows portal or bridging fibrosis and moderate inflammation and necrosis. Interferon-α 2b is the drug of choice for patients with chronic viral hepati-tis. It regulates cytokine activity, increases activity of natural killer cells and macrophages, augments lympho-cytic T-cell cytotoxicity via enhanced maturation, and modulates immunoglobulin production. Approximately a third of patients chronically infected with HBV and 20% of patients with HCV have a sustained response to therapy when 3 million units of IFN-α2b are adminis-tered twice weekly subcutaneously for 12 months.

Recent studies of chronically infected HCV patients have shown that combination therapy of interferon with ribarivin or lamuvidine improves the sustained virologic response to above 30%. Patients who fail to respond to therapy require liver transplantation to sur-vive. Currently, HBV and HCV infections are the lead-ing cause of chronic liver disease and liver transplanta-tion in the United States.

Vaccination is the most effective means of prevent-ing HBV infection. An effective vaccine against HBV has been available since 1982. Currently, the vaccine is available as a recombinant synthetic formulation as Recombivax and Engerix. Three injections are required, with the injections at 0, 1, and 6 months after the initial dose. The injections should be provided in the deltoid muscle to obtain the highest antibody titers. Both

vac-cines provide over 96% efficacy in preventing HBV infection. Currently, the HBV vaccine is recommended for all infants and health care workers in the United States. No booster dose is currently recommended and protective antibodies persist for at least 9 years in most vaccinated persons. There is no vaccine available against HCV at this time.

Dental management

The dentist should perform a thorough medical history on all patients, to identify those with active or chronic hepatitis. Questions should be asked that specifically determine the diagnosis of hepatitis and risk for hepati-tis. Positive responses regarding blood transfusions, recipient of blood products, hemodialysis, injecting and illicit drug use, multiple sexual partners, and close con-tacts with infectious patients indicate risk and the need to inquire specifically of hepatitis. Serum liver function tests and hepatitis antigen and antibody tests are required to confirm the type of hepatitis present.

Patients with a known history of HBV and HCV should be evaluated to determine carrier status, activity of disease, and liver function. Consultation with the physician is recommended if moderate-to-severe liver disease is present and significant dental procedures are planned. Elevations of serum transaminases indicate risk for altered drug metabolism. Drugs that are metab-olized primarily in the liver are listed in Table 16–2.

These drugs encompass a large percentage of commonly used dental drugs. Thus, their avoidance may be impos-sible, to effectively perform dental treatment. However, upon consultation with the patient’s physician usually the drugs are used in reduced amounts administered at increased intervals.

There is always concern for proper hemostasis in a patient with liver disease. The presurgical evaluation should include a platelet count and bleeding time as well as a prothrombin time (PT), which measures the extrinsic pathway, and the activated partial thrombo-plastin time (aPTT), which measures the intrinsic path-way. Platelet counts above 50,000/mm³ are generally considered safe when conservative surgical technique is employed and other measures of hemostasis are within the normal reference range.

The prothrombin time is reported as a value malized to a standard factor (ie, the international nor-malized ratio [INR]) (see Chapter 7). When INR values are between 1.0 and 3.5, it is usually considered safe to perform surgical procedures as long as the other mea-sures of hemostasis are normal and local hemostatic measures (gel foam, topical thromin, pressure dressings, and soft diet) are employed. Hemorrhagic procedures on a patient with an INR above 3.5 require a

hospital-like environment and potentially vitamin K supplemen-tation or fresh frozen plasma prior to the surgical pro-cedure. After an extraction or surgery, patients should be advised to minimize aspirin intake if gastrointestinal bleeding is a concern. Likewise, acetaminophen intake should be reduced and avoidance of alcoholic beverages is advised, as both are hepatotoxic. Severe liver disease (ie, cirrhosis) increases the risk for infection, and peri-operative antibiotics may be indicated for extractions and surgical procedures.

Patients with chronic hepatitis may experience adverse drug effects from medical therapy. Interferon-α 2b induces a flu-like illness, muscle aches, fatigue, and arthritis. In addition, it causes various autoimmune dis-orders, such as interstitial pneumonia, systemic lupus erythematosus, autoimmune hemolytic anemia, hypo-thyroidism, immune thrombocytopenia, and recurrent sarcoidosis with or without bilateral swelling of parotid glands. Anemia, anorexia, nausea, diarrhea, depression, irritability, pharyngitis, and alopecia are potential adverse effects of IFN-α2b when used in combination with ribavirin. A complete blood count and differential is recommended prior to surgical and sedation proce-dures for patients taking IFN-α 2b and ribavirin.

Post-exposure protocol

In situations of known exposure, the CDC recommen-dation for post-exposure prophylaxis is dependent on the type of virus suspected or known, and whether the exposure is from a person with acute or chronic disease.

If a dental health care worker (DHCW) is exposed (eg, percutaneous exposure by a sharp or needlestick) to the blood or bodily fluid of an HBsAg-positive person with

Table 16–2 Dental Drugs Metabolized in the Liver Classification Drug

Macrolide antibiotics (azithromycin, clarithromycin, erythromycin) Tetracyclines (doxycycline, minocycline) Amide local anesthetics Lidocaine

Mepivacaine Prilocaine Bupivicaine

Anxiolytics or sedatives Benzodiazepines (diazepam, triazolam) Barbiturates (pentobarbital, thiopental

sodium, methohexital sodium)

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acute disease, then hepatitis B immune globulin (HBIG) is to be given (within 24 hr) along with the vaccine within 14 days if the DHCW is previously unvacci-nated. If a DHCW is exposed to a person with chronic disease, then HBV vaccine is recommended within 14 days, to be given if the DHCW is previously unvacci-nated. The CDC does not currently recommend post-exposure prophylaxis for HCV. However, higher rates of resolved infection have been documented when IFN-α 2b treatment was initiated early in persons acutely infected with HCV. The CDC current guidelines recom-mend as a minimum that (1) the source person be base-line tested, (2) the person exposed be basebase-line and fol-low-up (6 mo) tested for antibodies against the virus

acute disease, then hepatitis B immune globulin (HBIG) is to be given (within 24 hr) along with the vaccine within 14 days if the DHCW is previously unvacci-nated. If a DHCW is exposed to a person with chronic disease, then HBV vaccine is recommended within 14 days, to be given if the DHCW is previously unvacci-nated. The CDC does not currently recommend post-exposure prophylaxis for HCV. However, higher rates of resolved infection have been documented when IFN-α 2b treatment was initiated early in persons acutely infected with HCV. The CDC current guidelines recom-mend as a minimum that (1) the source person be base-line tested, (2) the person exposed be basebase-line and fol-low-up (6 mo) tested for antibodies against the virus