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Viral haepatitis Characteristics of Hepatitis Viruses Hepatitis A Virus Hepatitis B Virus Hepatitis C Virus Hepatitis D Virus Hepatitis E Virus Nucleic acid RNA DNA RNA * RNA Major transmission Fecal– oral Blood Blood Needle Water Incubation period (days) 15–50 30–180 20–120 14–60 14–60 Epidemics Yes No No No Yes Acute liver failure <0,5% 1% <0,1% 2-20% 20%among pregnant Chronicity No 5-7% 50-70% co: 5-7% super:100% No Liver cancer No Yes Yes Yes No *Incomplete RNA; requires presence of hepatitis B virus for replication. THE DEVELOPMENT STAGES OF ACUTE ICTERIC VH: incubation period prejaundice period jaundice period convalescent period COURSE OF VH INFECTION The course is affected by two factors: the viral charge and the host response. Acute hepatitis B, сlinical forms, in adults: o Inapparent o subclinical o Symptomless infection o Anicteric hepatitis ACUTE ICTERIC HEPATITIS: o clinical manifestation of prejaundice syndromes +++, o jaundice +++, o hepatomegaly +++, o biochemical modifications +++, o presence of serum Ag, Ab +++ ANICTERIC FORM: o clinical manifestation of prejaundice syndromes ++, o jaundice -, o hepatomegaly +++, o biochemical modifications ++, o presence of serum Ag, Ab +++ SLIGHT PRONOUNCED FORM: o slight clinical manifestation of prejaundice syndromes +, o slight jaundice +, o hepatomegaly +, o slight biochemical modifications ++, o presence of serum Ag, Ab + SUBCLINICAL FORM o clinical manifestation of prejaundice syndromes -, o jaundice -, o hepatomegaly -, o biochemical modifications +, o presence of serum Ag, Ab +++ INAPPARENT (SYMPTOMLESS)FORM o clinical manifestation of prejaundice syndromes -, o jaundice -, o hepatomegaly -, o biochemical modifications -, o presence of serum Ag, Ab +++ CHOLESTATIC FORM: Less common. o Biochemical increase of cholestatic marks (phosphate alkaline, b-lipoproteins, cholesterol) FULMINANT HEPATITIS: 1% of acute icteric hepatitis. This complication is fatal SUBACUTE HEPATIC NECROSIS: 3%. These patients will clinically deteriorate for a period of 2-3 months and develop deepening of jaundice, sings of portal hypertension, worsening of coagulation. This course is seen in patients over 40 years of age, patients with AIDS, drug addiction. PROLONGED: If it lasts more than 3 months. CHRONIC HEPATITIS: If it lasts more than 6 months. At least 10% of all infected people. Particularity of acute viral hepatitis evolution depending on etiological agent: VHA VHB VHD VHD VHC coinfection superinfection Length of 0-1 0-4 0-10 days 0-10 days 0-2 weeks prejaundice week weeks period Cause of liver Direct Immune VHB - immune complex Direct injury cytotoxic complex VHD - direct cytotoxic cytotoxic + immune complex Prejaundice period Dyspeptic + + + + +/syndrome (nausea, vomiting) Arthralgic + + syndrome Asteno+ + + +/vegetative (intoxication syndrome) Fever + +/+/Hepatomegalia + + + + + Splenomegalia +/+/+ +/Jaundice period State after better same or worse worse same jaundice worse appearance Length of 1-2 2-4 2-6 weeks 2-8 weeks 2-4 weeks jaundice weeks weeks period Extrahepatic + + because of HBV + manifestations VHE 0-2 weeks Direct cytotoxic + + + + same 1-2 weeks - LAB. STUDIES. ACUTE HEPATITIS : Cytolitic syndrome: high ALT, AST Cholestatic syndrome: high bilirubin level, 2/3 – conjugated, phosphate alkaline, b-lipoproteins, cholesterol are N. Haepatodepresion syndrome: slightly low albumin levels, prolongation of the prothrombin time Mezenchimal-inflamation syndrome: high - globulines, low sublime test, high tymole test (mostly inflammation) Hematologic abnormalities: leukopenia (ie, granulocytopenia) lymphocytosis increase in the sedimentation rate. ========================================================================= VHA Piconarvirus (RNA virus). More heat stable than most RNA viruses, for complete inactivation heat food to > 85° C for at least 1 minute. Virus acquired from: exposure to high risk source often person-person contaminated food/water, floods/water disasters most often spread among family members, child care settings or similar. Maximum infectivity occurs during the latter half of the incubation period, extending to a few days after onset. The concentration of virus in the stool, and therefore the infectivity, is highest before onset of symptoms. Cases can generally be considered non-infectious a week after onset of jaundice (if it occurs) or 2 weeks after onset of prodromal symptoms, whichever comes first. (This period may be longer in immunocompromised persons.) The likelihood that symptoms will follow infection increases with age: jaundice occurs in only a small proportion of infants and young children, but a majority of adults. Unusual to be fulminant. Clinical manifestations VHA The usual clinical presentation is acute fever, malaise, anorexia, nausea and abdominal discomfort followed a few days later by dark urine and jaundice (pseudoflu, intoxication, dispeptic syndromes). Symptoms usually last several weeks. The likelihood that symptoms will follow infection increases with age: jaundice occurs in only a small proportion of infants and young children, but a majority of adults. Unusual to be fulminant. • • • • • Serologic testing to detect immunoglobulin M (IgM) antibody to the capsid proteins of HAV (IgM anti-HAV) is required to confirm a diagnosis of acute HAV infection. In the majority of persons, serum IgM anti-HAV becomes detectable 5-10 days before onset of symptoms. IgG anti-HAV, which appears early in the course of infection, remains detectable for the person's lifetime and provides lifelong protection against the disease. In the majority of patients, IgM anti-HAV declines to undetectable levels <6 months after infection. However, persons who test positive for IgM anti-HAV >1 year after infection have been reported, as have likely false-positive tests in persons without evidence of recent HAV infection. HAV RNA can be detected in the blood and stool of the majority of persons during the acute phase of infection by using nucleic acid amplification methods, and nucleic acid sequencing has been used to determine the relatedness of HAV isolates for epidemiologic investigations. However, only a limited number of research laboratories have the capacity to use these methods Pre-Exposure Prophylaxis • Target populations formerly children in states, communities with high rates HAV. Per 2006 recommendations, routine vaccination now recommended for all children > 1 year of age. • For adults (recommended): at-risk international travelers, high-risk geographic populations or individuals at risk during outbreaks/close personal contacts, MSM, frequent blood/plasma recipients, chronic liver disease (including. Hep B and C), high risk employment, IDUs • Active immunization: inactivated hepatitis A vaccine, given into deltoid muscle. Forms: VAQTA (for 12mos-18yrs give 25U per dose, for >18 yrs 50U per two dose schedule), HAVRIX (for 12mos-18yrs give 720EL.U per dose, for >18 yrs 1440El.U per two dose schedule) and TWINRIX (>18yrs only, combines hepatitis A and hepatitis B vaccines in three dose schedule (0,1, 6 months or accelerated four dose schedule 0, 7, 21-30d followed by booster at 12 mos). • Hepatitis A vaccine must be administered 2 weeks before expected exposure: VAQTA or HAVRIX give 1 ml IM into deltoid muscle, with 1 ml IM booster within 6-12 months. Need for booster dose currently unknown, but expected >10 yr duration of prophylaxis. • Protective antibody responses seen in 94-100% of adults after 1st vaccine dose. Antibody response ~100% post second dose. • Immunosuppressed patients may be unable to develop antibodies or may require additional boosters. • For expected exposure risk < 2wks, use pooled human immunoglobulin. Desired duration of coverage if 1-2 months use 0.02 mL/kg IM or long-term 3-5 months use 0.06mL/kg and repeat q 5 months for continued exposure risk. Post-Exposure Prophylaxis • Passive immunization: pooled human immunoglobulin. • Immunoglobulin prophylaxis: point source outbreaks, close contacts of index cases, daycare center contacts, institutional contacts. • Immunoglobulin should be administered within 2 wks of exposure. Use IG 0.02 mL/kg IM into gluteus muscle. =========================================================================== VHE Transmission: Genotypes 1 and 2: predominantly fecal-contaminated water in developing countries worldwide. Genotypes 3 and 4: zoonotic transmission from unclear sources but some significant association with undercooked meat, especially swine, in North America, Western Europe, and Japan. Transmission from person to person occurs less commonly than with hepatitis A virus Hepatitis E virus causes acute sporadic and epidemic viral hepatitis. Most outbreaks in developing countries have been associated with contaminated drinking water. Risk groups: travelers to developing countries, particularly in South Asia and North Africa Symptomatic HEV infection is most common in young adults aged 15-40 years. Although HEV infection is frequent in children, it is mostly asymptomatic or causes a very mild illness without jaundice (anicteric) that goes undiagnosed. SIGNS & SYMPTOMS Incubation period following exposure to HEV ranges from 2 to 10 weeks jaundice fatigue abdominal pain CAUSE Hepatitis E virus (HEV) LONG-TERM EFFECTS There is no chronic (long-term) infection Hepatitis E is more severe among pregnant women, especially in third trimester TRANSMISSION Four genotypes (all belong to one serotype) detected in humans, distinct means transmission suspected. Genotypes 1 and 2: predominantly fecal-contaminated water in developing countries worldwide. Genotypes 3 and 4: zoonotic transmission from unclear sources but some significant association with undercooked meat, especially swine, in North America, Western Europe, and Japan. Transmission from person to person occurs less commonly than with hepatitis A virus Most outbreaks in developing countries have been associated with contaminated drinking water. RISK GROUPS Travelers to developing countries, particularly in South Asia and North Africa PREVENTION Always wash your hands with soap and water after using the bathroom, changing a diaper, and before preparing and eating food Avoid drinking water (and beverages with ice) of unknown purity, uncooked shellfish, and uncooked fruits or vegetables that are not peeled or prepared by the traveler. loss of appetite nausea, vomiting dark (tea colored) urine Rare cases have occurred in the United States among persons with no history of travel to endemic countries In general, hepatitis E is a self-limiting viral infection followed by recovery. Prolonged viraemia or faecal shedding are unusual and chronic infection does not occur. Occasionally, a fulminant form of hepatitis develops, with overall patient population mortality rates ranging between 0.5% - 4.0%. Fulminate hepatitis occurs more frequently in pregnancy and regularly induces a mortality rate of 20% among pregnant women in the 3rd trimester. Cause of death in pregnant women: 1. acute hepatic failure 2. haemorrhage; 3. acute renal failure, hemoglobinuria Hepatitis E virus causes acute sporadic and epidemic viral hepatitis. Symptomatic HEV infection is most common in young adults aged 15-40 years. Although HEV infection is frequent in children, it is mostly asymptomatic or causes a very mild illness without jaundice (anicteric) that goes undiagnosed. Typical signs and symptoms of hepatitis include jaundice (yellow discoloration of the skin and sclera of the eyes, dark urine and pale stools), anorexia (loss of appetite), an enlarged, tender liver (hepatomegaly), abdominal pain and tenderness, nausea and vomiting, and fever, although the disease may range in severity from subclinical to fulminant. Hepatitis E should be suspected in outbreaks of waterborne hepatitis occurring in developing countries, especially if the disease is more severe in pregnant women, or if hepatitis A has been excluded.. ======================================================================= VHC HCV is a member of the Flaviviridae family The virus contains a single-stranded genome of RNA, a capsid, a matrix and an envelope HCV does not integrate into host DNA like Hepatitis B virus The nucleotide sequence of HCV is highly variable, the most divergent isolates sharing only 60% nucleotide sequence homology. This variation accounts for resistance to antibodies. Isolates from all over the world have now been grouped into 6 main types, each with several subtypes, based on sequence data. o Types 1-3 account for almost all infections in Europe, o type 4 is prevalent in Egypt & Zaire, o type 5 in South Africa & type 6 in Hong Kong. It is not yet clear whether immunity to one type prevents subsequent infection with another, but there is some evidence that various genome types differ in their biological properties. Studies conducted during natural infection in humans indicate that chronicity of hepatitis C is related to rapid production of virus, and a lack of vigorous T-cell immune response to HCV with emergence of HCV variants which are prone to escape immune control. The pathogenesis of liver damage is most likely due to a combination of direct cytopathic effects of viral proteins and of immune mediated mechanisms including cytolytic and non-cytolytic reactions mediated by CTLs (cytotoxic T lymphocytes) and inflammatory cytokines. Recent data indicate that oxidative stress is an important pathogenetic factor in HCV related liver damage. Hepatic steatosis is also a characteristic features of hepatitis C and contributes to the progression of liver disease and fibrosis development. Causes: Incubation period is 2-26 weeks (20–120 days). Direct percutaneous exposure is the primary means of transmission. The use of injected drugs is the most important epidemiologic risk factor. Tattooing, body piercing, and acupuncture with unsterile equipment are possible ways of infection. Blood transfusions are another means of transmission. Hemodialysis is a possible cause of HCV infection. Patients who are healthcare employees may have an accidental exposure. With sexual transmission, the risk appears to be low, even among individuals with multiple sex partners; however, the presence of coexisting, sexually transmitted diseases (eg, infection with human immunodeficiency virus [HIV]) appears to increase the risk. Vertical transmission of HCV in utero & perinatally has also been reported, but again, appears to be rare. Perinatal transmission affects an estimated 5% of babies born to HCV-infected mothers. The risk is higher for babies born to mothers who are coinfected with HCV and HIV. Breastfeeding is not contraindicated for HCV-seropositive mothers. Perhaps 10% of HCV-infected adults have no identified risk factor for HCV infection; this frequency is probably higher among pediatric patients. o o o o o o o o o o Infections are often inapparent or subclinical. Only 25-35% of patients have nonspecific symptoms such as weakness, malaise, and anorexia. Fatigue is reported most often. Acute hepatitis with jaundice is seen in no more than 20-25% of cases, whereas less than one third have hepatomegaly. A more severe course of acute hepatitis C can be seen in patients with excess alcohol intake, or co-infection with HBV or HIV. Patients with symptoms and jaundice develop chronic infection more rarely than those who remain asymptomatic. The higher the ALT peak during acute disease, the lower the probability of virus persistence. A monophasic pattern of ALT profile has also been shown to predict recovery while polyphasic ALT are often followed by chronic evolution. It should be underlined, however, that serum ALT levels may be extremely variable in acute hepatitis C and that ALT normalization after acute phase is not a reliable marker of recovery as there are patients who remain viremic despite complete and persistent normalization of ALT. Approximately half of the patients with acute hepatitis C recover spontaneously while the other half develop chronic infection, parameters able to predict the outcome would be extremely useful in the clinical management of these cases. Unfortunately, this has not been yet adequately evaluated and it is clear that a single HCV-RNA negative sample or normal ALT during the late phase of acute hepatitis C do not prove resolution of infection and prolonged follow-up with repeated testing for at least 12 months after diagnosis is necessary to prove that the infection has resolved. Approximately 30% of patients with chronic HCV infection have normal ALT levels at diagnosis, independently of age and gender and many of them do maintain normal enzyme levels during prolonged follow-up. 15-25% will eventually show reactivation of biochemical activity during a 3 month to 10 years follow-up. Around 20% of HCV carriers with normal ALT have significant fibrosis or cirrhosis on liver biopsy. Presence of significant liver disease or the risk of future ALT reactivation cannot be predicted by virological or biochemical testing. VIRAL HEPATITIS B THE VIRUS HBV is the prototype member of the family Hepadnaviridae (from Hepa=liver, dna=DNA ). HBV is an extremely resistant strain capable of withstanding extreme temperatures and humidity. It can survive when stored for 15 years at -80°C, for 24 months at -20°C, for 6 months at room temperatures, and for 7 days at 44°C. PATHOGENESIS It appears the virus is not cytotoxic and the cytolysis is apparently produced by cytotoxic lymphocytes sensitive to one or more viral antigens. In 1981 it was discovered that HBV-DNA in hepatocyte may exist as an integrated (double-stranded, intranuclear) form or as an episomal (free, circular, low- molecular weight, single- stranded, intracytoplasmic ) form. Both forms may exist in the same hepatocyte. It appears that active viral replication is associated with predominantly episomal viral DNA while low replication is associated with integrated viral DNA. Cases of chronic hepatitis of short duration (1-2 years) exhibit predominantly episomal (cytoplasmic) viral DNA while cases of longer (6-8 years) duration exhibit integrated, intranuclear viral DNA. EPIDEMIOLOGY AND PREVENTION OF VIRAL HEPATITIS B Internationally:The HBV carrier rate variation is 1-20% worldwide. This variation is related to differences in the mode of transmission and age at infection. The prevalence of the disease in different geographical areas can be characterized as follows: Low-prevalence areas (rate of 0.1-2%) include Canada, western Europe, Australia, and New Zealand. In the areas of low prevalence, sexual and percutaneous transmission during adulthood are the main modes of transmission. Intermediate-prevalence areas (rate of 3-5%) include eastern and northern Europe, Japan, the Mediterranean basin, the Middle East, Latin and South America, and central Asia. In areas of intermediate prevalence, sexual and percutaneous transmission and transmission during delivery are the major routes. High-prevalence areas (rate of 10-20%) include China, Indonesia, sub-Saharan Africa, the Pacific islands, and Southeast Asia. In areas of high prevalence, the predominant mode of transmission is perinatal, and the disease is transmitted during early childhood vertically from the mother to the infant. Vaccination programs implemented in highly endemic areas such as Taiwan seem to change the prevalence of HBV infection. In Taiwan, seroprevalence declined from 10% in 1984 (before vaccination programs) to less than 1% in 1994 and the incidence of HCC declined from 0.52% to 0.13%. COURSE IN CHILDREN EARLY CHILDHOOD HBV INFECTION - RISK OF CHRONICITY Age at Infection (years) Proportion who become carriers (%) <1 70-90 2-3 40-70 4-6 10-40 >7 6-10 90% of infected children will develop a chronic course. More than adults. The majority of infected children are asymptomatic. The younger the child, the more asymptomatic. Children however , either symptomatic or asymptomatic, grow normally. Chronic hepatitis seldom progresses to cirrhosis. If it does superinfection with hepatitis D or C must be suspected. Also hepatocellular carcinoma is extremely rare but it may occur. Asymptomatic carrier children should not be treated with alpha-interferon. In perinatally acquired HBV infection, which is common in geographical areas of high HBV prevalence like Asia, it appears to follow a period of immune tolerance of HBV during which HBV DNA levels are high while ALT levels keep normal or nearly normal and liver necroinflammtion is minimal or absent. ACUTE RESOLVING HEPATITIS. The incubation period is 1-6 months. General symptoms arise 0-4 weeks before the jaundice. The prejaundice symptomatology is more constitutional and includes the following: Dyspeptic syndrome : anorexia, nausea, vomiting, disordered gustatory acuity and smell sensations (aversion to food and cigarettes), Arthralgic syndrome : slight arthralgia Asteno-vegetative syndrome : low-grade fever, myalgia, fatigability, Slight ache syndrome: right upper quadrant and epigastric pain (intermittent, mild to moderate). Serum transaminases are elevated even before general symptoms and jaundice appear. Surface antigen (HbsAg) may be detected by radioimmunoassay as early as one week after contacting the virus by parenteral inoculation and 3-4-5 weeks before having any feeling of being sick. ACUTE VIRAL HEPATITIS B, Extrahepatic manifestations ARTHRITIS-DERMATITIS: a serum sickness-like syndrome is an occasional extrahepatic manifestation of acute hepatitis B. These patients experience urticaria, rash, petechiae, palpable, purpura, arthralgia and arthritis of small joints. It involves mostly small joints of hands and knees and occurs in the prodrome period, before jaundice appears and resolves within a week. Arthritis may be accompanied by urticaria, palpable purpura, erythema multiforme, erythema nodosum , liken planus. GIANOTTI SYNDROME (Infantile papular acrodermatitis):Papular skin eruptions with generalized lymphadenopathy in children under eight years. The hepatitis is mild and anicteric and can be transmitted on contact to adults who may develop an icteric hepatitis. NERVOUS SYSTEM: Seizures (rare), Guillain-Barre' syndrome, peripheral neuropathy, mononeuritis multiplex.These symptoms resolve at the end of the acute illness. CARDIO-VASCULAR SYSTEM: Pericarditis, myocarditis may occur especially in the fulminant type. Polyarteritis nodosa is seen in chronic hepatitis B. GASTRO-INTESTINAL TRACT: Pancreatitis. The virus replicates in the pancreas. Pancreatitis has been observed after liver transplantation for hepatitis B. HbsAg has been demonstrated in the pancreas. URINARY SYSTEM: resolving mild renal failure may occur in the acute phase. Membranous glomerulonephritis occurs in chronic hepatitis B. HEMOPOIETIC SYSTEM: aplastic anemia (rare). Cryoglobulinemia of mixed type can be seen in hepatitis B infection. The serum contains cryoprecipitable IgG and IgM proteins with anti-gamma globulin activity producing purpura, arthritis, glomerulonephritis and generalized vasculitis apparently due deposits of immunoglobulin-complement complexes in the vascular wall. Several viral markers can be identified in the serum of the patient with acute viral hepatitis B: IgM anti-HBc (core antibody) Appears early Persists for 6 months HBsAg (surface antigen) Detectable 30-60 days after exposure May indicate chronic carrier status HBsAb (antibody to surface antigen) Develops after resolved infection Indicates long term immunity Anti-HBc/HBcAb (antibody to core antigen) Develops in all HBV infections HBeAg (E antigen) Indicates HBV replication Correlates with high infectivity Present in acute or chronic infection Anti-HBe (antibody to E antigen) Develops in most HBV infections Correlates with lower infectivity HBs antigen. Hepatitis B surface antigen (HBsAg) is borne by surface viral proteins, i.e. viral proteins anchored at the surface of viral envelopes. The presence of HBsAg is thus a sign of HBV envelope production at the acute phase of infection or in chronic HBV carriers, but not a marker of viral replication. The surface proteins have many functions, including attachment and penetration of the virus into hepatocytes at the beginning of the infection process. The target of the host’s humoral response to HBV is the hydrophilic region of the HBsAg between amino acid residues 100 and 160. Several mutants from the S gene have been identified worldwide. The disease they cause seems to develop earlier, and the infection is quite often asymptomatic and has strong association with active HBV replication. In certain cases of mutant-related hepatocellular carcinoma, only HBV-DNA positivity is observed, HBsAg remaining seronegative. HBe antigen. Hepatitis B e antigen (HBeAg) is borne by a nonstructural protein produced during viral replication in hepatocytes infected by so-called "wild-type" HBV and then released into the general circulation. When present, HBeAg is associated with HBV DNA detection. In contrast, so-called "pre-core mutant" HBV viruses are unable to produce the HBe protein. In these patients, HBV DNA is detected in the absence of HBeAg. Therefore, HBeAg is not a reliable marker of HBV replication. In general, patients infected with this mutant are more likely to progress to cirrhosis and hepatitic insufficiency, compared to those infected by the wild virus. High prevalence rates (50-60%) have been reported in HBV-endemic areas in the Mediterranean basin, including Italy and Greece, and Far Eastern countries, such as China and Japan. In contrast, the mutant is less dominant (10-30%) in non-endemic areas, such as Northern Europe and North America. Anti-HBs antibodies. Their appearance a few weeks after resolution of acute hepatitis B is associated with disappearance of HBsAg (HBs seroconversion) and is considered the marker of resolution of HBV infection. These antibodies can also rarely appear after HBsAg disappearance in non replicative chronic HBV carriers, either spontaneously or following successful antiviral therapy. They generally persist for life, but may become undetectable after a few years. Total anti-HBc antibodies. Anti-HBc antibodies are directed against a viral capsid epitope or core antigen. They appear early during infection and remain detectable for life, whatever the outcome of infection. They can be present in the absence of both HBsAg and anti-HBs antibodies, during the convalescent period following acute hepatitis B before the appearance of anti-HBs antibodies, or in patients who resolved infection but lost detectable anti-HBs antibodies. Anti-HBc is therefore detected in anyone who has been infected with HBV. Anti-HBc IgM. High titers of anti-HBc IgM are present early at the acute stage of HBV infection. They disappear after the appearance of anti-HBs antibodies when infection resolves. Low amounts of anti-HBc IgM can also be found with ultra-sensitive EIA techniques in patients with chronic HBV infection, bearing witness to a strong and adapted anti-HBV immune response. Anti-HBe antibodies. In patients infected with a "wild-type" HBV, anti-HBe antibodies appear after HBeAg disappearance (HBe seroconversion) when replication ceases, either spontaneously or following successful antiviral treatment. In patients infected with a "precore mutant" HBV, anti-HBe antibodies are present whether or not HBV replicates. HBV DNA detection is thus needed to distinguish between patients who have seroconverted to HBeAg and those with pre-core mutant infections and ongoing HBV replication. Diagnosis of HBV infections. (i) Acute hepatitis B shows the evolution of HBV serological markers in spontaneously resolving acute hepatitis B. The following four markers should be tested in patients suspected of having acute hepatitis B: HBsAg, total anti-HBc antibodies, anti-HBc IgM antibodies, and anti-HBs antibodies. Interpretation of serological profiles. Acute hepatitis B is characterized by the simultaneous presence of HBsAg and anti-HBc IgM. During convalescence, anti-HBc IgM is present during the window period between HBsAg disappearance and anti-HBs antibody appearance. After resolution, both total anti-HBc antibodies and anti-HBs antibodies are present, and these patients are protected against HBV reinfection. Anti-HBs antibodies may sometimes become undetectable after a few years, leading to an isolated anti-HBc antibody profile. (ii) Chronic HBV carriage. Chronic HBV carriage results of a failure of the host immune responses to clear HBV during acute hepatitis. By definition, it is characterized by HBsAg persistence in serum for more than 6 months. In chronic HBV carriers, total anti-HBc antibodies are present, whereas anti-HBs antibodies are absent. HBV DNA must be sought for by means of molecular biology-based assays. A liver biopsy must be performed in the patients with detectable HBV replication, to define the stage and severity of the disease and to assess the need for therapy. Using these parameters, the patients can be classified into three distinct groups, each roughly including one third of cases. (i) Chronic HBV carriers with no detectable HBV replication. Small amounts of HBV DNA may however be detected in these patients with recently developed highly sensitive PCR-based assays. Ongoing studies are aimed at determining the threshold above which HBV replication should be considered clinically relevant. (ii) Chronic HBV carriers with HBV replication with no or mild liver lesions. The immune system of these patients tolerates viral replication for unclear reasons, causing little damage to the liver. (iii) Chronic HBV carriers with HBV replication with moderate to severe liver lesions (chronic hepatitis B). In these patients, the immune response of the host directed against viral antigen-expressing cells is responsible for liver disease. Small amounts of anti-HBc IgM may be found with ultra-sensitive EIA techniques as a result of strong anti-HBV immunity. The patients with no or very low levels of HBV DNA in the blood are generally HBeAg-negative/antiHBe antibody-positive. In the patients with active HBV replication, HBe/anti-HBe testing is useful to differentiate two groups of patients : (i) those infected with a "wild-type" HBV, who are HBeAgpositive/anti-HBe antibody-negative ; (ii) those infected with a "pre-core HBV mutant", who are HBeAg- negative/anti-HBe antibody-positive. The latter may have more severe liver disease and may respond less well to antiviral therapy (38). (iii) Vaccination. Individuals vaccinated against HBV have isolated anti-HBs antibodies (anti-HBc is absent in vaccinees, who have never been infected with HBV). Anti-HBs antibodies must be titrated a few months after vaccination in subjects frequently exposed to HBV infection, such as healthcare workers, hemodialysis patients, frequently hospitalized patients, etc. A titer of more than 10 mIU/ml is considered protective. Higher titers are generally observed in the responders to vaccination, who represent more than 95% of vaccinated individuals (35, 36). If anti-HBs levels decline below 10 IU/ml, a booster dose of vaccine may be recommended. CHRONIC HEPATITIS B Chronicity is characterized by persistence of viral replication with attached viral antigens for over 6 months, sometimes returning to normal in many years or advancing to induce cirrhosis and/or hepatocellular carcinoma. The chronicity of hepatitis B may follow either a symptomatic acute icteric hepatitis or, more commonly, an asymptomatic silent infection. Chronic infection with HBV can be either "replicative" or "non-replicative." In non-replicative infection, the rate of viral replication in the liver is low and serum HBV DNA concentration is generally low and hepatitis Be antigen (HBeAg) is not detected. In "replicative" infection, the patient usually has a relatively high serum concentration of viral DNA and detectable HBeAg. In rare strains of HBV with mutations in the pre-core gene, "replicative" infection can occur in the absence of detectable serum HBeAg. In chronically infected individuals, infection can switch from "non-replicative" to "replicative" and viceversa. Spontaneous reactivation may occur in 15% to 20% of previously nonreplicative patients. The persistence of the virus produces different damage in different individuals depending on the viral charge and the host reaction. The majority of patients, 3/4, a mild or minimal or no damage at all. They look " healthy" and almost all become free of disease. These are asymptomatic carriers. A smaller number of patients, 1/4, have more damage, are "sick" and most of them develop complications, namely, cirrhosis and hepatoccellular carcinoma. These are the symptomatic carriers. All chronically infected patients , however, either healthy looking or sick, can transmit the virus on contact. Chronic inactive hepatitis B Healthy carriers have normal AST and ALT levels, and the markers of infectivity (ie, HBeAg, HBV DNA) may be negative. HBsAg, HBcAb of IgG type, and HBeAb also are present in the serum. Chronic active hepatitis B Patients have mild-to-moderate elevation of the aminotransferases (<5 times the upper limit of normal). The ALT levels usually are higher than the AST levels. Extremely high levels of ALT can be observed during exacerbation or reactivation of the disease and can be accompanied by impaired synthetic function of the liver (ie, decreased albumin levels, increased bilirubin levels, and prolonged prothrombin time). HBV DNA levels are high during this phase. HBsAg and HBcAb of IgG or IgM type (in case of reactivation) are identified in the serum. In patients infected with a "precore mutant" HBV, anti-HBe antibodies are present whether or not HBV replicates. HBV DNA detection is thus needed to distinguish between patients who have seroconverted to HBeAg and those with pre-core mutant infections and ongoing HBV replication. Hyperglobulinemia is another finding, predominantly with an elevation of the IgG globulins. Tissue-nonspecific antibodies, such as antismooth muscle antibodies (20-25%) or antinuclear antibodies (10-20%), can be identified. Tissue-specific antibodies, such as antibodies against the thyroid gland (10-20%), also can be found. Mildly elevated levels of rheumatoid factor usually are present. The HBeAg-positive CHB considered as the typical, prototype form of the disease, occurs in earlier phases of chronic HBV infection than HBeAg-negative CHB, it prevails in European and North American patients infected with HBV genotype A and is characterized by persistently high serum aminotransferases (ALT) and hepatitis B viraemia levels. When HBeAg-positive CHB develops, serum ALT levels increase and liver damage progresses to severe necroinflammation with advancing fibrosis. If HBeAg-positive CHB is left untreated it may subside spontaneously terminating into loss of HBeAg, seroconversion to anti-HBe, suppression of HBV replication to non-detectability by molecular hybridization techniques or to <103-104 copies/ml by polymerase chain reaction, return of ALT to normal and resolution of liver disease activity. However, the probability of spontaneous resolution of HBeAgpositive CHB is limited to approximately 10-12% per year (ranging in the various studies from 2 to 24%. Thus, a large number of untreated patients with HBeAg-positive CHB are left with severe liver necroinflammation which persists for several years and results in an increased likelihood of progression of liver damage to advanced stages of fibrosis, cirrhosis and even development of hepatocellular carcinoma (HCC), the most dire consequence in the natural history of CHB. In a recent study, the relative risk of HCC among men positive both for HBsAg and HBeAg was 60.2 compared to 9.2 in those with only HBsAg. The need, therefore, for early and effective therapeutic intervention in HBeAg-positive CHB is obvious, but unfortunately it has remained an unresolved issue of clinical hepatology for more than 20 years now. In the HBeAg-negative form of CHB, which prevails in the Mediterranean Area and Asia and is mostly due to precore HBV mutants, serum HBV DNA levels are lower than in HBeAg-positive CHB. Both HBV DNA and serum ALT levels are often fluctuating. However, spontaneous remissions are extremely rare and prognosis is poor with frequent progression to cirrhosis and HCC. Therefore, similar to HBeAgpositive CHB, the need for effective therapeutic intervention is again obvious. In anti-HBe-positive patients with elevated ALT and detectable HBV DNA (pre-core mutant) therapy is more difficult. These patients do not respond well to interferon. Cirrhosis In early stages, findings of chronic viral hepatitis can be found. Later on as the disease progresses, low albumin levels, hyperbilirubinemia, prolonged prothrombin time, low platelet count and white blood cell count, and AST levels higher than ALT levels can be identified. Alkaline phosphatase levels and gamm-glutamyl transpeptidase can be slightly elevated.a Primary hepatocellular carcinoma (PHC) Significant risk factors for carcinogenesis include older age, liver firmness, and thrombocytopenia. Even the presence of HBsAb in the absence of HBsAg or HBV DNA is significantly related to an increased risk for HCC. In the Orient the incidence of carcinoma is 15% with men more affected than whomen (6 : 1). The incidence is less in the western world. In S.E. Asia and China PHC is the most common fatal cancer. Familiar clustering of HCC has been described among families with HBV in Africa, the Far East, and Alaska. The cumulative probability of survival is 84% and 68% at 5 years and 10 years, respectively. Delta superinfection does not appear to increase the rate of HCC. Although HDV infection has been reported to increase the risk for HCC 3-fold and mortality rates 2-fold in patients with HBV cirrhosis. The prevalence of HCC among patients with HBV and hepatitis C virus (HCV) co-infection is higher than in those with single infection alone. The rate of development of HCC per 100 person years of follow-up is 2% in patients with cirrhosis and HBV infection, 3.7% in patients with HCV, and 6.4% in patients with dual infection. This points to a probable synergistic effect on the risk of HCC. Cirrhosis appears to be a prerequisite + chronic liver damage/repair results in malignant transformation. Approximately 9% of patients in western Europe who have cirrhosis develop HCC due to HBV infection at a mean follow-up of 73 months. The probability of HCC developing 5 years after the diagnosis of cirrhosis is established is 6%, and the probability of decompensation is 23%. Further Outpatient Care: Healthy carriers should have routine blood tests annually to check aminotransferase levels. Patients with chronic active hepatitis should have blood tests (ie, to evaluate aminotransferase levels, antigen-antibody HBV profile, and viral load), liver biopsy, and treatment. Patients with cirrhosis must be checked every 3-6 months with alpha-fetoprotein measurements and abdominal ultrasound for HCC surveillance. Treatment Regimens Treatment criteria • • • • • • • • Chronic hepatitis B (e antigen positive) ALT > 2X ULN; confirm ALT and HBeAg in 1-3 months, then treat (below). ALT < 1X ULN; follow ALT and HBeAg q 3-6 months. ALT 1-2 X ULN; follow ALT and HBeAg q 3-6 months, consider biopsy if persistent or >40 yrs; treat based on biopsy. Chronic hepatitis B (e antigen negative) ALT > 2X ULN and HBV DNA >20,000 IU/ml; confirm ALT in 1-3 months, then treat (below). ALT < 1X ULN and HBV DNA <2,000 IU/ml, follow ALT and HBV DNA q 3-6 months. ALT 1-2 X ULN and HBV DNA 2,000-20,000 IU/ml, follow ALT and HBV DNA q 3-6 months, consider biopsy if persistent or >40 yrs; treat based on biopsy. Treatment goals • Reduce risk of end stage liver disease and cancer • Sustained suppression of HBV DNA • HBsAg clearance (transition to resolution) • Decrease necroinflammation (transition to inactive hepatitis B) Standard interferon alfa 2b • Dose: 5 million U SQ q24h or 10 million U SQ thrice weekly × 16 weeks. • Side effects: fever, myalgia, bone marrow suppression, depression, thyroid abnormalities. Thrombocytopenia, granulocytopenia, fatigue and depression may respond to dose adjustment. • Outcomes: sustained loss of HBeAg (33%), HBV DNA (37%), and HBsAg (~15%) . Histologic improvement is seen more often in those with sustained HBV DNA suppression. ALT normal in ~25%. • Response predictors (pretreatment): HBV DNA < 100,000 IU/ml, AST & ALT >100 U/L, liver biopsy with active necrosis and active inflammation. • Resistance notes: not affected by or a cause of HBV resistance mutations. • Cost per course: ~$7000. • Comments: DO NOT USE with Child-Pugh B or C cirrhosis. Peginterferon alfa 2a • Dose: 180 mcg subcutaneous injection per week X 48 week. • Side effects: similar to standard interferon but lower intensit. • Outcomes, e antigen positive (48 weeks treat, 24 weeks follow-up) : loss of HBeAg 32% (vs 19% for LAM), HBV DNA <20,000 IU/ml 32% (vs 22% for LAM), and HBsAg clearance 3% (vs 0 for LAM). Histologic improvement in 38% (vs 34% for LAM). • Outcomes, e antigen negative (48 weeks treat, 24 weeks follow-up): HBV DNA <4,000 IU/ml 43% (vs 29% for LAM), and HBsAg clearance 4%(vs 0 for LAM ). Histologic improvement in 48% (vs 40% for LAM). • Resistance notes: not affected by or a cause of HBV resistance mutations. • Cost per course: $16,000 • Comments: DO NOT USE with Child-Pugh B or C cirrhosis. High toxicity and cost constrain applicability, but may have use in persons with high response likelihood and few contraindications. Lamivudine (LAM) • Dose: 100 mg PO daily for six months after HBeAg conversion to Anti-HBe occurs, or lifelong. • Side effects: same as placebo. Hepatitis B flare can occur after withdrawal of therapy. • Outcomes, e antigen positive (52 weeks treat, 16 week follow-up): loss of HBeAg 32% (vs 11% placebo), HBV DNA <20,000 IU/ml 44% (versus 16% placebo), and HBsAg (0-3%), but may not be sustained. Histologic improvement in 52% (vs 23% with placebo). • Outcomes, e antigen negative (48 weeks treat, 24 weeks follow-up): HBV DNA <4,000 IU/ml 29% (vs 43% for peginterferon), and HBsAg clearance 0% (vs 4% for peginterferon). Histologic improvement in 40% (vs 48% for peginterferon). • Response predictors (pretreatment): HBV DNA < 100,000 IU/ml, AST & ALT >100 U/L, liver biopsy with active necrosis and active inflammation. • Resistance notes: mutations in polymerase occur ~15% per year with viral rebound and sometimes disease flare. Fitness of resistant virus probably attenuated. Reversion to wild-type virus occurs with discontinuation. • Cost per year: ~$2200. • Comments: proven clinical benefit with Child-Pugh B or C cirrhosis. High rate of resistance makes some avoid. Relatively low cost and high tolerability make some use first line. Adefovir • Dose: 10 mg PO daily; duration unclear. • Side effects: equal to placebo at this dose (renal toxicity seen with higher doses in phase 2). • Outcomes, e antigen positive (48 weeks treatment): loss of HBeAg 24% (vs 11% placebo), HBV DNA < detect 21% (vs 0 for placebo), and HBsAg clearance (0-3%). Histologic improvement in 64% (vs 33% placebo). With continued use 5 or more years, higher response rates are seen for all outcomes. • Outcomes: e antigen negative (144 weeks of treatment): HBV DNA <1000 c/ml at 96 weeks 71% (vs 8% when ADV stopped after 48 weeks), and HBsAg clearance (<2%). Histologic improvement in 89% (vs 50% of those who stopped ADV after 48 weeks). With continued use 5 or more years, higher response rates are seen for all outcomes. • Resistance notes: resistance is uncommon (~ 3.9%) at 3 yrs; novel mutation rtN236T in the D domain of HBV RT confers resistance to adefovir in vitro and in vivo. LAM remains active, while ADV is active against LAM resistant HBV. • Cost per year: ~$6000. • Comments: less potent than entecavir, telbivudine, and tenofovir but relatively high resistance threshold. For e antigen negative, improvements were lost when use not continued beyond 48 weeks. Entecavir • Dose: 0.5 mg PO daily (1.0 mg daily if lamivudine experienced); duration unclea. • Side effects: similar to lamivudine. • Outcomes, e antigen positive (48 weeks): loss of HBeAg 22% (vs 20% for LAM ), HBV DNA < 300 c/ml 67% (vs 36% for LAM), and HBsAg clearance 2% (vs 1% for LAM). Histologic improvement in 72% (versus 62% with LAM). • Resistance notes: little to no resistance apparent at 3 years. • Cost per year: $7200 . • Comments: more potent than lamivudine and much less resistance risk, but higher cost. Use 1.0 mg if patient has ever had LAM. Telbivudine • Dose: 600 mg PO daily. • Side effects: muscle pain and elevated CK in 12 pts (9%) (vs 8 (3%)for LAM) at 104 weeks in one study. • Outcomes: e antigen positive (104 weeks): loss of HBeAg 35% (vs 29% for LAM ), HBV DNA < detect 56% (vs 39% for LAM), and HBsAg clearance 2% (vs 1% for LAM). Histologic improvement in 72% (versus 62% with LAM). • Resistance notes: key issue is early potency since resistance develops in >75% when HBV DNA > 1000 c/ml at 24 weeks; M204I resistance mutation in HBV polymerase sequence observed in all individuals with confirmed virologic breakthrough on telbivudine. • Cost per year: $7305 • Comments: too early to tell its role but resistance is clearly an issue; possible role in those who rapidly respond. Types of Interferons Interferons are natural proteins that activate certain immune functions in the body and have anti-viral properties. The natural interferons being used for chronic hepatitis B, C or both are called type I interferons and include the following: Interferon alpha 2b (Intron A). (Used for both hepatitis B and C.) Interferon alpha 2a (Roferon-A). (Mostly used for hepatitis C.) Interferon alfa-n1 (Wellferon). (Approved but mostly used in Canada for hepatitis C.) They are given by injection and need to be taken three times a week. Newer synthetic interferons have been developed that are showing particularly promise: Interferon alfacon-1 (Infergen). This agent is referred to as a consensus interferon (CIFN) because it was genetically developed using the most commonly occurring amino acid sequences from each of the natural type 1 alpha interferons. It is usually given three times a week when used as initial treatment. CIFN is five to 10 times more biologically active than natural type 1 interferons. Pegylated interferon (PegINF). Pegylated interferons employ a small molecule called polythelene glycol (PEG), which attaches to a protein and extends the activity of the interferon. This action allows the drug to be taken only once a week. Of note, some evidence suggests that even in the absence of antiviral effects, interferon may reduce important factors that contribute to cirrhosis, inflammation and fibrosis (scarring). It may even have some effect on reversing liver damage. If this evidence holds up, then even patients whose viral and liver enzyme counts remain high or steady may still benefit from long-term use of these agents. Common side effects of any interferon are flu-like symptoms (fever, chills, muscle aches) that usually occur within six hours and gradually decline over a week or two. (Pegylated interferon may pose a higher risk for these symptoms than the natural interferons.) Chronic or more serious effects include the following: Emotional and mental changes. Depression can be very severe and cases of suicidal thoughts have been reported. Other mental and emotional symptoms include anxiety, amnesia, confusion, irritability, impaired concentration, decreased alertness, memory problems, and mental slowing. Changes in sensation. Weight loss. Skin rashes. Hair loss. Gastrointestinal problems, including nausea, vomiting, and diarrhea, and, in severe cases intestinal bleeding and ulcers. Fatigue and general weakness. Back pain. Complications in the lungs, including exacerbation of asthma. In severe cases, interferon can cause shortness of breath, inflammation in the lungs, and pneumonia. Possible negative effects on cholesterol and lipid levels. Heart rhythm disturbances, which, in rare cases, can be serious. Mild anemia. Interferon often causes a drop in platelet and white blood cell counts, increasing susceptibility to bacterial infections. May trigger an autoimmune response, possibly causing anemia, diabetes, lupus-like symptoms, hypothyroidism, or even autoimmune hepatitis. Complications in the eye, including bleeding that, in some cases, may lead to loss of vision if not detected promptly. Rare reports of acute pancreatitis. In children, interferon therapy temporarily disrupts growth. Patients have a difficult time with prolonged therapy. Over 20% drop out if treatment lasts longer than two years. Depression is the most common reason for withdrawal. (New long-acting forms, such as pegylated interferon, may improve these drop-out rates.) Prevention • Immunization: The vaccines presently used are composed of viral surface antigen (HbsAg) obtained from the common baker's yeast, Saccharomyces cerevisiae, by inserting into it a gene for the synthesis of HbsAg. These are Yeast-Recombinant vaccines. Three IM deltoid injections are given: at baseline, at 1 mo, and at 6 mo. HBV vaccine for those with increased risk (hemodialysis, HIV infected, sexual contacts and household members, group home residents, health care workers, risky sex behaviors, injection drug users). Check anti-HBs titer 2 months after last dose. Consider double dose for hemodialysis, HIV infected, and those who fail initial series. A combined hepatitis A and B vaccine is licensed in many countries and offers the advantage of protection against both of these diseases at the same time. All newborns must be vaccinated. For infants born to mothers with active HBV infection, a passive-active (immunoglobulin and vaccination) approach is recommended. • Postexposure prophylaxis: Specific for type of exposure, host characteristics and source characteristics. Follow CDC guidelines for HBIG and HBV vaccination (see vaccine, drug modules). Selected Drug Comments • Drug: Entecavir. Recommendation: Preferred first line oral agent in lamivudine naive patient. Potent drug with little resistance as monotherapy. Although long-term efficacy remains unclear and more expensive than lamivudine, clearly this is an important first line alternative. • Drug: Peginterferon alfa. Recommendation: Toxicity clearly limits use but remains an important alternative for persons with high ALT (>2-5X ULN) and low HBV DNA (<1X106 IU/ml) before treatment. • Drug: Tenofovir (TDF). Recommendation: This drug is not FDA approved for treatment of chronic hepatitis B, but is more potent than its cousin adefovir. The coformulation of tenofovir and FTC is a preferred combination therapy for treatment naive patients. Tenofovir is also an important consideration for treatment of lamivudine resistant chronic hepatitis B. Special use in HIV positive patients is described below. • Drug: Lamivudine (3TC) . Recommendation: A frequently-used comparator and inferior virologically to entecavir and telbivudine. Nonetheless, safety and low cost makes an option especially for persons with high baseline ALT and low HBV DNA levels. Early monitoring (and discontinuation when HBV DNA remains detectable at 24 weeks) may, as with telbivudine, forestall resistance. • Drug: Telbivudine (ABX). Recommendation: Too early to tell how this drug will be incorporated into guidelines. Key issue appears to be early detection and alternative treatment of persons not responding (HBV DNA persistently detectable) by 24 weeks. • Drug: Interferon alpha (ABX). Recommendation: Hard to find anyone using this in 2007 in the United States for chronic hepatitis B. • Drug: Adefovir. Recommendation: Not as potent as tenofovir, but also active against lamivudine resistant HBV. Less resistance than with lamivudine or telbivudine. Other Information • Hepatocellular carcinoma associated w/chronic HBV, especially in endemic Southeast Asia, Japan, sub-Saharan Africa, Greece, Italy & Oceania. Found especially in perinatally acquired infection. Higher HBV DNA levels associated with higher risk. Screening recommended. • If HIV positive, determine if antiretroviral therapy is needed. If so, consider using tenofovir and FTC as part of HAART (e.g., Atripla or Truvada). If antiretroviral therapy not needed, consider peginterferon, adefovir, or starting tenofovir-based, fully HIV- suppressive antiretroviral therapy. =========================================================================== VHD The International Committee on Taxonomy of Viruses has proposed to classify HDV within the floating genus Deltavirus. The virus is an enveloped, spherical particle with an average diameter of 36 to 43 nm containing in its interior a nucleocapsid of 19 nm in diameter , which consists of an RNA genome and a single structural protein, hepatitis delta antigen (HDAg), that are encapsidated by the hepatitis B surface antigen (HBsAg). HDV can be acquired either as o a co-infection (occurs simultaneously) with hepatitis B virus (HBV) or o as a superinfection in persons with existing chronic HBV infection. HBV-HDV co-infection: o may have more severe acute disease and a higher risk (2%-20%) of developing acute liver failure compared with those infected with HBV alone HBV-HDV superinfection o chronic HBV carriers who acquire HDV superinfection develop chronic HDV infection. Progression to cirrhosis is believed to be more common with HBV/HDV chronic infections The transmission of the Delta agent mirrors that of HBV, being primarily parenterally transmitted. In areas where HDV is endemic in the general population, as in Southern Europe, Africa, the Middle East and, probably, Latin America, the inapparent parenteral route accounts for most cases of HDV transmission. Most of the countries of the Far East at the moment appears to have quite a low incidence of Delta with the exception of Taiwan. In Taiwan, it was reported that 26% of all acute hepatitis cases have Delta antigen in the serum. Similarly in India where 14% of all acute cases are reported positive for Delta antigen. In northern Europe and in the United States HDV is not endemic. HDV has a direct cytopathic effect. Nevertheless, multiple types of autoimmune phenomena have been reported in chronic hepatitis D. HBV is suppressed in asymptomatic carriers of HDV. However, a pattern characterized by decreasing levels of HDV and reactivating HBV with moderately high ALT levels has been described during the course of chronic hepatitis D. In triple infection, several studies have shown that HDV plays a dominant role inhibiting both HBV and HCV. Hepatitis D does not increase the incidence of extrahepatic disease or hepatocellular carcinoma over hepatitis B infection. HDV Coinfection The clinical expression of acute hepatitis D acquired by coinfection with HBV may range from mild to severe, fulminant hepatitis. In most cases, it resembles a typical acute self-limited hepatitis that is clinically and histologically indistinguishable from the ordinary hepatitis B. One may see more than one rise in liver transaminase and there may be 2 peaks of ALT, although not always. Delta antigen is rarely detected in the serum, though anti-Delta IgM is found in the serum and lasts 2 6 weeks. Anti-Delta IgG may be present in a low level or perhaps not detectable at all. Only 2.4-4.7% become chronic carriers. This course is apparently due to the fact that HDV seems to suppress HBV replication and does not have optimal conditions for its own replication. Superinfection The most common form of Delta infection is superinfection of a known HBsAg carrier and it is where Delta infection produces its most deleterious effects. Preexisting HBsAg in the circulation captures the Delta virus, even if it is in small amounts and intensifies its synthesis immediately. Delta infection of a previously healthy carrier may induce an acute hepatitic picture. Infection in a carrier with preexisting hepatitis will aggravate the clinical picture. Primary Delta infection in a HBsAg carrier is often severe, with a significantly higher number of fulminant hepatitis cases. Fulminant HDV hepatitis carried a mortality rate of 70%. 100% of superinfected carriers develop chronic infection (70% of such patients develop chronic active hepatitis). Hepatitis D does not increase the incidence of extrahepatic disease or hepatocellular carcinoma over hepatitis B infection. Delta antigen appears in the serum followed by Delta IgM and Delta IgG. In contrast to acute coinfection, Delta IgG can reach very high levels. Acute Delta superinfection is accompanied by a drop in HBsAg in the HBV carrier, sometimes to undetectable levels so that true diagnosis could be masked. The serum picture remains the same whether the infection becomes chronic or not. However, in the case of the infection becoming chronic, Delta antigen persists in the liver and can be detected by immmunoperoxidase or immunofluorescence staining techniques. The interaction between HBV and HDV replication has been reevaluated in recent years by using highly sensitive PCR assays. Most patients with chronic HDV infection have antibodies to HBeAg and low levels of HBV DNA replication. HBV is suppressed in asymptomatic carriers of HDV. However, a pattern characterized by decreasing levels of HDV and reactivating HBV with moderately high ALT levels has been described during the course of chronic hepatitis D. In intravenous drug addicts, HDV infection is most often associated with HBeAg positivity and active HBV replication, a pattern that may increase the pathogenicity of HDV. In triple infection, several studies have shown that HDV plays a dominant role inhibiting both HBV and HCV. Hepatitis D: Complications • 10-15% develop cirrhosis within two years • 70% eventually develop cirrhosis • 2-20% fatality rate • 25-50% of fulminant liver failure in hepatitis B actually due to hepatitis D co-infection • Hepatitis D Prevention: Hepatitis B vaccine - - Fulminant hepatic failure Fulminant hepatic failure is the clinical syndrome that results from massive necrosis of liver cells or from sudden and severe impairment of hepatic function. Typically the patient has an acute onset of severe mental changes starting with confusion and advancing to stupor or coma. Jaundice appears and deepens, and there may be gastrointestinal bleeding and renal failure. Conventionally the term fulminant hepatic failure is restricted to patients in whom signs appear within eight weeks of the onset of the illness and in whom there has been no evidence of liver disease previously. Ammonia is a key factor in the pathogenesis of HE. - Ammonia is released from several tissues (kidney, muscle), but its highest levels can be found in the portal vein. Portal ammonia is derived from both the urease activity of colonic bacteria and the deamidation of glutamine in the small bowel, and is a key substrate for the synthesis of urea and glutamine in the liver. - The blood-brain barrier permeability to ammonia is increased in patients with HE; as a result, blood levels will correlate weakly with brain values, though recent studies indicate an improvement of this correlation by correcting the ammonia value to the blood pH - The alterations in neurotransmission induced by ammonia also occur after the metabolism of this toxin into astrocytes. - All patients with clinical or laboratory evidence of moderate to severe acute hepatitis should have immediate measurement of prothrombin time and careful evaluation of mental status. The Stage of encephalopathy Stage I PHYSICAL prodrome SIGN mental status alert; slow mentation; euphoria, occasional depression, confusion; sleep pattern reversal behavior restless, irritable, disordered speech Stage II impending coma stage I signs amplified; lethargic, sleepy, Stage III stupor arousable, but generally asleep; marked confusion Stage IV Severe coma unarousable or responds only to pain unarousable none none decreased, severe tremor absent none combative, sullen, sleeping, loss of sphincter confusion, control incoherant speech spontaneous uncoordinated with yawning, grimacing, motor activity tremor blinking Stage IV coma asterixis absent present present absent absent reflexes normal hyperactive hyperactive + Babinski hyperactive + Babinski absent respirations regular or hyperventilating hyperventilating hyperventilating irregular apnea normal normal partial dysconjugate absent oculocephalic normal oculovestibul ar EEG normal normal generalized slowing markedly abnormal markedly abnormal Glasgow coma scale 15 15 11-13 3-9 eye opening spontaneous = 4 spontaneous = 4 spontaneous = 4 or to pain only = 2 or never = 1 only to sound = 3 never = 1 motor obeys commands = obeys commands = obeys commands = normal flexion = 4 extension = 2 or no 6 6 6 or localizes pain or abnormal response = 1 =5 flexion = 3 or extension = 2 or no response = 1 verbal oriented = 5 Review VIRAL oriented = 5 confused = 4 or inappropriate responses = 3 3-4 inappropriate = 3, no response = 1 or incomprehensible = 2 or no response =1 DIAGNOSIS TREATMENT A IGM ANTI-HAV IG WITHIN 2 WEEKS OF EXPOSURE B VACCINATION AND ADMINISTRATION OF HBIG WITHIN 24 HOURS OF NEEDLE STICK, 14 DAYS AFTER SEXUAL CONTACT CHRONIC HEPATITIS TREATED WITH ALPHA INTERFERON AND LAMIVUDINE OR ADEFOVIR OR ENTECAVIR OR TELBIVUDINE C HBSAG – INFECTIOUS HBEAG – DEGREE OF INFECTIVITY IGM ANTI-HBC – ACUTE INFECTION ANTI-HBS – VACCINATED OR CLEARED INFECTION ANTI-HCV D ANTI-HDV SAME AS HEPATITIS B E ANTI-HEV SEROLOGY NONE DEVELOPED BUT NOT COMMERCIALLY AVAILABLE IN U.S. HEPATITIS PEGINTERFERON ALFA-2B, PEGINTERFERON ALFA2A, RIBAVIRIN
