Viral hepatitides B, C and D Sorokhan MD, PhD Bukovinian State Medical University Department of the infectious diseases and epidemiology
Hepatitis B is an acute infectious illness caused by hepatitis B virus (HBV) and characterized by liver inflammation, vomiting, jaundice and rarely, death. Chronic hepatitis B may eventually cause liver cirrhosis and liver cancer .
The virus was discovered in 1965. By the early 1980s the genome of the virus had been sequenced, and the first vaccines were being tested.
Hepatitis B virus (HBV) is a hepadnavirus. It is an extremely resistant strain capable of withstanding extreme temperatures and humidity. Hepatitis B virus (HBV) can survive when stored for 15 years at - 20°C, for 24 months at - 80°C, for 6 months at room temperatures, and for 7 days at 44°C. The viral genome consists of a partially double-stranded circular DNA of 3.2 kilobase (kb) pairs that encodes 4 overlapping open reading frames, as follows: S for the surface or envelope gene; C for the core gene; X for the X gene; P for the polymerase gene.
The production of antibodies against HBsAg confers protective immunity and can be detected in patients who have recovered from hepatitis B virus (HBV) infection or in those who have been vaccinated. Antibody to HBcAg is detected in almost every patient with previous exposure to hepatitis B virus (HBV). The immunoglobulin M (IgM) subtype is indicative of acute infection or reactivation, whereas the IgG subtype is indicative of chronic infection. With this marker alone, one cannot understand the activity of the disease. Antibody to HBeAg is suggestive of a nonreplicative state and one in which the antigen has been cleared.
Transmission of hepatitis B virus results from exposure to infectious blood or body fluids containing blood. Possible forms of transmission include sexual contact , blood transfusions , re-use of contaminated needles or syringes, and vertical transmission from mother to child during childbirth. HBV can be transmitted between family members within households, possibly by contact of nonintact skin or mucous membrane with secretions or saliva containing HBV. However, at least 30% of reported hepatitis B among adults cannot be associated with an identifiable risk factor.
About a third of the world’s population , more than 2 billion people, have been infected with the hepatitis B virus. This includes 350 million chronic carriers of the virus.
The pathogenesis and clinical manifestations of hepatitis B are due to the interaction of the virus and the host immune system. The latter attacks the hepatitis B virus (HBV) and causes liver injury. Activated CD4+ and CD8+ lymphocytes recognize various HBV-derived peptides located on the surface of the hepatocytes, and an immunologic reaction occurs. Impaired immune reactions (eg, cytokine release, antibody production) or relatively tolerant immune status result in chronic hepatitis. In particular, a restricted T cell–mediated lymphocytic response occurs against the HBV-infected hepatocytes.
The final state of hepatitis B virus (HBV) disease is cirrhosis. Patients with cirrhosis and HBV infection are likely to develop hepatocellular carcinoma (HCC).
Four different stages have been identified in the viral life cycle of hepatitis B.
The first stage is immune tolerance. The duration of this stage for healthy adults is approximately 2-4 weeks and represents the incubation period.
In the second stage, an inflammatory reaction with a cytopathic effect occurs. HBeAg can be identified in the sera, and a decline of the levels of hepatitis B virus (HBV) DNA is seen.
In the third stage, the host can target the infected hepatocytes and the hepatitis B virus (HBV).
In the fourth stage, the virus cannot be detected and antibodies to various viral antigens have been produced.
Liver damage is graded according to the inflammatory component and is described as follows:
Grade 0 – Portal inflammation only, no activity.
Grade 1 – Minimal portal inflammation and patchy lymphocytic necrosis, with minimal lobular inflammation and spotty necrosis.
Grade 2 – Mild portal inflammation and lymphocytic necrosis involving some or all portal tracts, with mild hepatocellular damage.
Grade 3 – Moderate portal inflammation and lymphocytic necrosis involving all portal tracts, with noticeable lobular inflammation and hepatocellular change.
Grade 4 – Severe portal inflammation and severe lymphocytic bridging necrosis, with severe lobular inflammation and prominent diffuse hepatocellular damage.
Signs and symptoms
The spectrum of the symptomatology of hepatitis B disease varies from subclinical hepatitis to icteric hepatitis to hyperacute, acute, and subacute hepatitis during the acute phase, and from an asymptomatic carrier state to chronic hepatitis, cirrhosis, and hepatocellular carcinoma during the chronic phase.
Acute phase. The incubation period is 1-6 months. Anicteric hepatitis is the predominant form of expression for this disease. The majority of the patients are asymptomatic. Patients with symptomatology have the same symptoms as patients who develop icteric hepatitis. Patients with anicteric hepatitis have a greater tendency to develop chronic hepatitis. Icteric hepatitis is associated with a prodromal period, during which a serum sickness – like syndrome can occur. The symptomatology is more constitutional and includes the following: 1) Anorexia; 2) Nausea; 3) Vomiting; 4) Low-grade fever; 5) Myalgia; 6) Fatigability; 7) Disordered gustatory acuity and smell sensations (aversion to food and cigarettes); 8) Right upper quadrant and epigastric pain (intermittent, mild to moderate). Patients with hyperacute, acute, and subacute hepatitis may present with the following: 1) Hepatic encephalopathy; 2) Somnolence; 3) Disturbances in sleep pattern; 4) Mental confusion; 5) Coma.
Signs and symptoms
Chronic phase. Patients with chronic hepatitis can be healthy carriers without any evidence of active disease, and they also are asymptomatic. Patients with chronic active hepatitis, especially during the replicative state, may complain of symptomatology such as the following:
1) Symptoms similar to those of acute hepatitis;
2) Fatigue ;
3) Anorexia ;
4) Nausea ;
5) Mild upper quadrant pain or discomfort;
6) Hepatic decompensation .
The physical examination findings vary from minimal to impressive (patients with hepatic decompensation) according to the stage of disease.
Patients with acute hepatitis usually do not have any clinical findings, but the physical examination can reveal the following: Low-grade fever ; Jaundice (10 d after the appearance of constitutional symptomatology and lasting for 1-3 mo); Hepatomegaly (mildly enlarged soft liver); Splenomegaly (5-15%) ; Palmar erythema (rarely) ; Spider nevi (rarely) .
The physical examination of patients with chronic hepatitis B virus (HBV) infection can reveal stigmata of chronic liver disease such as the following: Hepatomegaly ; Palmar erythema ; Spider angioma ;
Patients with cirrhosis may have the following symptoms: Ascites ; Jaundice ; History of variceal bleeding ; Peripheral edema ; Gynecomastia ; Testicular atrophy ; Abdominal collateral veins (caput medusa).
The diseases most frequently confused with viral hepatitis B are Alcoholic Hepatitis, Hepatitis C, Autoimmune Hepatitis, Hepatitis D, Cholangitis, Hepatitis E, Cirrhosis, Hemochromatosis, Primary Sclerosing Cholangitis, Hepatic Carcinoma, Primary, Wilson Disease, Hepatitis A.
Acute hepatitis B disease . High levels of alanine aminotransferase (ALT) and aspartate aminotransferase is the hallmark of this disease. ALT levels are usually higher than AST levels. Alkaline phosphatase (ALP) levels may be elevated. Albumin levels can be slightly low, and serum iron levels may be elevated. Patients with severe hepatitis experience a prolongation of the prothrombin time. Several viral markers can be identified in the serum and the liver. HBsAg and HBeAg are the first markers that can be identified in the serum. HBcAb (IgM) follows. For patients who recover, seroconversion to HBsAb and HBeAb is observed, and the HBcAb is of the IgG class. Patients with persistent HBsAg for longer than 6 months develop chronic hepatitis.
Chronic inactive hepatitis B disease . 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 are also present in the serum.
Chronic active hepatitis B disease . Patients have mild to moderate elevation of the aminotransferases. The ALT levels are usually higher than the AST levels. Hepatitis B virus (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. If the AST levels are higher than the ALT levels, the diagnosis of cirrhosis must be excluded. Hyperglobulinemia is another finding, predominantly with an elevation of the IgG globulins.
Cirrhosis . In early stages, findings of chronic viral hepatitis can be found. Later on, as the disease progresses, low albumin levels, hyperbilirubinemia, prolonged PT, low platelet count and white blood cell count, and AST levels higher than ALT levels can be identified. ALP levels and gamma-glutamyl transpeptidase (GGT) can be slightly elevated.
Acute hepatitis B infection does not usually require treatment because most adults clear the infection spontaneously. Chronically infected individuals with persistently elevated serum alanine aminotransferase , a marker of liver damage, and HBV DNA levels are candidates for therapy.
Currently, there are seven medications approved for treatment of hepatitis B infection globally. These include antiviral drugs lamivudine (Epivir), adefovir (Hepsera), tenofovir (Viread), telbivudine (Tyzeka) and entecavir (Baraclude) and the two immune system modulators interferon alpha-2a and PEGylated interferon alpha-2a (Pegasys).
The hepatitis B vaccine consists of recombinant HBsAg produced in yeast. A series of 3 injections may achieve HBsAb levels greater than 10 million IU/mL in approximately 95% of people vaccinated. Low response rates have been associated with obesity, smoking, immunosuppression, and advanced age. The HBV vaccine seems to be safe. Vaccination with a single dose must be repeated every 5-10 years. All newborns must be vaccinated against hepatitis B. For infants born to mothers with active hepatitis B virus (HBV) infection, a passive-active (immunoglobulin and vaccination) approach is recommended. Healthcare workers or people who have had a needle-stick accident from a patient with active hepatitis B infection must receive the active-passive immunization approach (HBIG and the first dose of the vaccine at the same time), and these individuals must be monitored with blood tests.
Hepatitis B virus infection may either be acute (self-limiting) or chronic (long-standing). Persons with self-limiting infection clear the infection spontaneously within weeks to months.
Children are less likely than adults to clear the infection. More than 95% of people who become infected as adults or older children will stage a full recovery and develop protective immunity to the virus.
Hepatitis D (HDV) can only occur with a concomitant hepatitis B infection, because HDV uses the HBV surface antigen to form a capsid . Co-infection with hepatitis D increases the risk of liver cirrhosis and liver cancer. Polyarteritis nodosa is more common in people with hepatitis B infection.
Hepatitis C is an infectious disease affecting the liver , caused by the hepatitis C virus (HCV). The infection is often asymptomatic , but once established, chronic infection can progress to fibrosis and cirrhosis which is generally apparent after many years. In some cases, those with cirrhosis will go on to develop liver failure or other complications of cirrhosis, including liver cancer or life threatening esophageal varices and gastric varices .
The existence of hepatitis C was postulated in the 1970s and proven in 1989.
The hepatitis C virus is a small (50 nm in size), enveloped, single-stranded, positive sense RNA virus . It is the only known member of the hepacivirus genus in the family Flaviviridae . There are six major genotypes of the hepatitis C virus, which are indicated numerically (e.g., genotype 1, genotype 2, etc.).
Hepatitis C is only known to cause disease in humans. An estimated 270-300 million people worldwide are infected with hepatitis C. The following are the currently known modes of transmission.
Injection drug use. Those who currently use or have used drug injection as their delivery route for drugs are at increased risk for getting hepatitis C because they may be sharing needles, which may be contaminated with HCV-infected blood.
Blood products. Blood transfusion , blood products (include clotting factors, immunoglobulin, platelets, and plasma), or organ transplantation prior to implementation of HCV screening are all risk factors for hepatitis C.
Iatrogenic medical or dental exposure. People can be exposed to HCV via inadequately or improperly sterilized medical or dental equipment. Equipment that may harbor contaminated blood if improperly sterilized includes needles or syringes, hemodialysis equipment, oral hygiene instruments, etc.
Occupation. Medical and dental personnel can be exposed to HCV through accidental exposure to blood through needle sticks or blood spatter to the eyes or open wounds. Universal precautions to protect against such accidental exposures significantly reduce the risk of exposure to HCV.
Sexual exposure. Heterosexual vaginal intercourse is thought to be a extremely rare means of transmission of hepatitis C infection.
Body piercings and tattoos. Tattooing dyes, ink pots, and piercing implements can transmit HCV-infected blood from one person to another if proper sterilization techniques are not followed.
Shared personal care items. Personal care items such as razors, toothbrushes, cuticle scissors, and other manicuring or pedicuring equipment can easily be contaminated with blood. Sharing such items can potentially lead to exposure to HCV. HCV is not spread through casual contact, such as hugging, kissing, or sharing eating or cooking utensils.
Vertical transmission. Mother-to-child transmission occurs only among women who are HCV RNA positive at the time of delivery. The risk of vertical transmission of HCV does not appear to be associated with method of delivery or breastfeeding .
The natural targets of HCV are hepatocytes and, possibly, B lymphocytes. Viral clearance is associated with the development and persistence of strong virus-specific responses by cytotoxic T lymphocytes and helper T cells. In most infected people, viremia persists and is accompanied by variable degrees of hepatic inflammation and fibrosis.
Lymphocytic infiltration, moderate degrees of inflammation and necrosis, and portal or bridging fibrosis are noted. Regenerative nodules are seen in patients with cirrhosis. Some patients also may have findings indicative of HCC.
Signs and symptoms
There are two types of hepatitis C: acute and chronic. Acute hepatitis C refers to the first 6 months after infection with HCV. Chronic hepatitis C is defined as infection with the hepatitis C virus persisting for more than six months.
Between 60% and 70% of people infected develop no symptoms during the acute phase. In the minority of patients who experience acute phase symptoms, they are generally mild and nonspecific, and rarely lead to a specific diagnosis of hepatitis C. Symptoms of acute hepatitis C infection include decreased appetite, fatigue, abdominal pain , jaundice , itching , and flu-like symptoms .
Between 10 and 60% of persons infected with HCV clear the virus from their bodies during the acute phase. However, persistent infections are common and most patients develop chronic hepatitis C, i.e., infection lasting more than 6 months.
Signs and symptoms
Most patients with chronic hepatitis C infection are asymptomatic or may have nonspecific symptoms such as fatigue or malaise in the absence of hepatic synthetic dysfunction. Patients with decompensated cirrhosis from HCV infection frequently have symptoms typically observed in other patients with decompensated liver disease, such as sleep inversion and pruritus.
Symptoms characteristic of complications from advanced or decompensated liver disease are related to synthetic dysfunction and portal hypertension. These include hepatic encephalopathy, ankle edema and ascites, and hematemesis or melena.
Most patients do not have abnormal physical examination findings until they develop portal hypertension or decompensated liver disease. One exception is patients with extrahepatic manifestations of HCV infection, such as porphyria cutanea tarda or necrotizing vasculitis.
Abnormal physical examination findings of patient with portal hypertension or decompensated liver disease are the following: Palmar erythema , Spider nevi , Dupuytren contracture , Asterixis , Leuconychia , Clubbing , Icteric sclera , Temporal muscle wasting , Fetor hepaticus , Enlarged parotid , Cyanosis , Gynecomastia , Paraumbilical hernia , Ascites , Caput medusae , Hepatosplenomegaly , Abdominal bruit , Small testes , Ankle edema , Scant body hair .
The diseases most frequently confused with viral hepatitis C are Autoimmune Hepatitis, Cholangitis, Viral hepatitis A, Viral hepatitis B, Viral hepatitis D, Viral hepatitis E, Drug-induced hepatitis.
Hepatitis C antibody test . Anti-HCV serologic screening involves an enzyme immunoassay (EIA), including second- and third-generation EIAs. These assays are 97% specific but cannot distinguish acute from chronic infection. The most recent third-generation EIA involves detecting antibodies against core protein and nonstructural proteins 3, 4, and 5 and can yield positive results an average of 8 weeks after the onset of infection.
Recombinant immunoblot assay . The recombinant immunoblot assay is used to confirm HCV infection. A positive immunoblot assay result is defined as the detection of antibodies against 2 or more antigens and an indeterminate assay result defined as the detection of antibodies against a single antigen. A positive immunoblot assay result followed by 2 or more instances of undetectable HCV RNA suggests HCV infection has resolved. A positive anti-HCV immunoassay result followed by a negative immunoblot assay result represents a false-positive immunoassay, and no further testing is required. The recombinant immunoblot assay has limited usefulness in clinical practice.
The goals of treatment of chronic HCV infection are to (1) achieve sustained eradication of HCV (ie, sustained virologic response [SVR]), defined as the persistent absence of HCV RNA in serum 6 months or more after completing antiviral treatment, and (2) prevent progression to cirrhosis, HCC, and decompensated liver disease requiring liver transplantation.
Diet. No special diet is recommended in patients with hepatitis C unless they have developed decompensated cirrhosis.
Combination therapy with PEG-IFN alfa and the nucleoside analogue ribavirin is the current standard of care in patients infected with HCV. Patients with HCV genotype 1 have a much less favorable response to therapy and are treated for 12 months, compared with patients infected with genotypes 2 and 3, in whom a 6-month course of therapy is sufficient. If viremia is present after 6 months, additional therapy has a negligible incremental benefit, and treatment should be stopped in all patients regardless of the viral genotype.
Interferon alfa-2b (Intron-A) – 3 million U SC 3 times/wk;
Interferon alfa 2a (Roferon) – 3 million U SC 3 times/wk;
Interferon alfacon 1 (Infergens) – 9 mcg SC 3 times/wk;
Pegylated interferon alfa-2a (Pegasys) – 180 mcg SC qwk;
Ribavirin (Rebetol) – 10.6 mg/kg PO qd or divided bid.
Currently, no products are available to prevent HCV infection. The development of immunoprophylaxis for this disease is proving difficult; an effective neutralizing immune response has not been demonstrated after HCV infection. Patients with hepatitis C should be advised to abstain from alcohol use. Patients with hepatitis C should be advised to use barrier protection during sexual intercourse. Screening high-risk patients and initiating appropriate treatment may decrease the prevalence of cirrhosis and HCC.
Cirrhosis; HCC .
HCV is associated with many extrahepatic manifestations. Among the most common are the following: Cryoglobulinemia, Membranoproliferative glomerulonephritis , Idiopathic thrombocytopenic purpura , Lichen planus , Keratoconjunctivitis sicca , Raynaud syndrome , Sjogren syndrome , Porphyria cutanea tarda , Necrotizing cutaneous vasculitis , Non-Hodgkin lymphoma .
Infection with HCV is self-limited in only a small minority of infected persons. Chronic infection develops in 70-80% of patients infected with HCV. Cirrhosis develops within 20 years of disease onset in 20% of persons with chronic infection. HCC develops in 1-4% of patients with cirrhosis each year after an average of 30 years. HCC is more common in the presence of cirrhosis, alcoholism, and HBV coinfection. With the currently recommended therapy for chronic hepatitis C, which includes PEG-IFN and ribavirin, cure rates are as high as 60%.
Hepatitis D is an acute or chronic viral infection of the liver, occurring either simultaneously with hepatitis B or as a superinfection in a hepatitis B carrier. It is usually more severe than other forms of hepatitis and is most prevalent in tropical and subtropical areas of the Mediterranean basin.
It was discovered in 1977. HDV causes a unique infection that requires the assistance of viral particles from hepatitis B virus (HBV) to replicate and infect other hepatocytes. Its clinical course is varied and ranges from acute self-limited infection to acute fulminant liver failure. Chronic liver infection can lead to end-stage liver disease and associated complications.
Hepatitis D virus (HDV) is structurally unrelated to hepatitis A, B, C and E virus. It is classified as Hepatitis delta virus. HDV is an enveloped negative sense, single-stranded, closed circular RNA virus. HDV is considered to be a subviral satellite because it can propagate only in the presence of the hepatitis B virus (HBV).
Transmission of HDV can occur either via simultaneous infection with HBV ( coinfection ) or via infection of an individual previously infected with HBV ( superinfection ). HDV is transmitted parenterally. Risk factors include intravenous drug use and multiple blood transfusions. Sexual transmission is less efficient than with HBV. Perinatal transmission is rare. HDV is rare in most developed countries . However, HDV is much more common in the immediate Mediterranean region, sub-Saharan Africa, the Middle East, and the northern part of South America. In all, about 20 million people may be infected with HDV.
HDV infection is an acute and chronic inflammatory process involving the liver. Three known genotypes are described. Genotype I has a worldwide distribution. Genotype 2 has been discovered in Taiwan, Japan, and northern Asia. Genotype 3 is found in South America. HDV can replicate independently within the hepatocyte, but it requires hepatitis B surface antigen (HBsAg) for propagation. Hepatic cell death may occur due to the direct cytotoxic effect of HDV or via a host-mediated immune response.
Features are very similar to those observed in patients with HBV infection. Acidophilic bodies and degeneration of hepatocytes with acidophilic cytoplasm are present. The few inflammatory cells (lymphocytes) likely represent the direct cytotoxicity of HDV. Results of immunohistochemical staining for HDV antigen are positive. With superinfection, staining reveals that HBsAg is often suppressed.
Signs and symptoms
HDV infection is clinically indistinguishable from other forms of viral hepatitis. As many as 90% of patients are asymptomatic. The incubation period is 21-45 days but may be shorter in cases of superinfection.
Symptoms include the following: Jaundice , Dark urine , Abdominal pain , Nausea with vomiting , Confusion, bruising, and bleeding (rare), Pruritus .
Physical examination. Symptoms upon presentation include the following: Scleral icterus , Fever , Abdominal pain, usually right upper quadrant, Tea-colored urine , Encephalopathy (rare) , Petechia with bruising (rare) .
The diseases most frequently confused with viral hepatitis D are Acetaminophen poisoning, Alcoholic Hepatitis, Autoimmune Hepatitis, Bile Duct Strictures, Biliary Obstruction, Budd-Chiari Syndrome, Cholangitis, Cholecystitis, Drug-induced hepatitis, Fatty liver of pregnancy, HELLP (hemolysis, elevated liver enzymes, and low platelet) syndrome in pregnant patients, Hepatitis A, Hepatitis B, Hepatitis C, Hepatitis E, Ischemic liver injury, Isoniazid Hepatotoxicity, Liver Abscess.
The following serum test results are present in patients with co-infection with HDV and HBV: Results are positive for HDV antigen in 20%; Results are positive for HDV RNA in 90%. Reverse transcriptase polymerase chain reaction is currently the most sensitive assay for the detection of HDV viremia; Results for anti-HDV immunoglobulin M (IgM) are positive initially and then are positive for anti-HDV immunoglobulin G. The finding of antigen A antibody to HDV is almost exclusively associated with chronic HDV infections; Results for anti-HB core IgM are positive, except with superinfection, in which anti-HB core IgM is absent;
Antiviral therapy with interferon alfa can be considered in patients with chronic infection. The treatment course is usually at least one year. Treatment is not needed for patients with co-infection, given the high spontaneous clearance rates. Lamivudine, ribavirin, and corticosteroids have not been effective in treatment.
Interferon alfa 2a (Roferon) – 10 million U SC tiw; reduce dose by 50% if platelet count falls to <50,000/µL or granulocyte count falls to <750/µL; discontinue use if platelet count drops to <30,000/µL or granulocyte count falls to <500/µL.
No vaccine is available for HDV, but the HBV vaccination is effective against HDV.
Liver failure ; Hepatocellular carcinoma ; Autoimmune manifestations, often including antinuclear antibodies and smooth muscle antibodies
Prognosis is excellent for those with co-infection in whom treatment eradicates both viruses. Prognosis is variable for those who are superinfected. It depends on the duration and severity of HBV infection, alcohol consumption, comorbid illnesses, and age.