Viral hepatitis

L.R.Shostakovich-Koretskaya

Terminology

The term hepatitis describes inflammation of the liver. Hepatitis may be caused by alcohol, drugs, autoimmune diseases, metabolic diseases, and viruses

Epidemyology

Viral hepatitis is the leading cause of liver cancer and the most common reason for liver transplantation.

Hepatitis can be acute (short-lived) or chronic .

It is common throughout the world.

Hepatitis B and C viruses

Hepatitis B and C viruses are the major causes of severe illness and death related to viral hepatitis.

About 2000 million people have been infected with hepatitis B worldwide, of whom more than 350 million are chronically infected, and more than 500 000 people die annuall from hepatitis B.

About 180 million people are chronically infected with hepatitis C virus.

An estimated 57% of cases of liver cirrhosis and 78% of primary liver cancer result from hepatitis B or C virus infection.

Types of viral hepatitis

There are several hepatitis viruses; they have been named types A, B, C, D, E, F (not confirmed), G, TTV

As our knowledge of hepatitis viruses grows, it is likely that this alphabetical list will become longer.

Other common causes of hepatitis

Excessive alcohol intake Use of certain drugs (such as isoniazid). Less commonly, hepatitis results from other

viral infections, such as infectious mononucleosis, herpes simplex, or cytomegalovirus infection.

Various other infections and disorders can result in small areas of inflammation in the liver but rarely cause serious symptoms or problems.

Mode of transmission

Fecal-oral transmission HAV (+++) HEV (+++)

Parenteral transmission HBV (+++) HCV (+++) HDV (++) HGV (++) TTV (++)

Sexual transmission HBV (+++) HDV (++) HCV (+)Perinatal

transmission HBV (+++) HCV (+) HDV (+)

Acute infection

Acute infection with a hepatitis virus may result in conditions ranging from subclinical disease to self-limited symptomatic disease to fulminant hepatic failure.

Adults with acute hepatitis A or B disease are usually symptomatic.

Persons with acute hepatitis C disease may be either symptomatic or asymptomatic (ie, subclinical).

Periods of disease

ProdromalJaundice periodPeriod of convalescence

Symptoms of acute viral hepatitis

Typical are : (prodromal period 3-4 days)Flu like syndrom,fever, fatigue, anorexia,

nausea, and vomiting. Pain in the upper right of the abdomen ,due

liver enlargement Occasionally, especially with hepatitis B,

infected people develop joint pains and red rash on the skin.

F. Gianotti и A. Crosti syndrom

Papulose dermatitis

Jaundice period

Urine becomes dark, and stool decolorized Jaundice (a yellowish discoloration of the

skin ,mucose and eyes) develops. Bilirubin elevation. Both of these symptoms

occur because bilirubin builds up in the blood mainly due to the direct fraction.

Most symptoms usually began to regress, and people feel better even though the jaundice may worsen.

The jaundice usually peaks in 1 to 2 weeks, then fades over 2 to 4 weeks.

Syndrome Acholic stools

Dark Urine (choluria) Choluria is the presence of bile in urine

Jaundice in viral hepatitis

Lab signs

High aminotransferase values - ALT(>1000 U/L)

Hyperbilirubinemia (in jaundice form of disease) with prevalence of direct fraction are often observed.

Alanine aminotransferase (ALT)

Alanine transaminase or ALT is a transaminase enzyme. It is also called serum glutamic pyruvic transaminase (SGPT) or alanine aminotransferase (ALAT).

ALT is found in serum and in various bodily tissues, but is most commonly associated with the liver.

It catalyzes the two parts of the alanine cycle.

ALT

Alanine aminotransferase Normal: Males:10–40 units per liter (U/L) or 0.17–0.68 microkats per liter(mckat/L) Females:7–35 U/L or 0.12–0.60 mckat/L

High levels of ALT may be caused by:- Recent or severe liver damage, such as viral

hepatitis. - Lead poisoning. - Drug reactions. - Liver tumor (necrosis). - Shock.

Syndrom of cholestasis

Symptoms of cholestasis (a reduction or stoppage of bile flow)—such as pale stools ,severe jaundice and overall itchiness—may develop, people with hepatitis A,B ,C

Rarely, particularly with hepatitis B, symptoms become extremely severe (fulminant).

Liver failure may occur and may be fatal, especially in adults.

liver failure

Severe cases of acute hepatitis may progress rapidly to acute liver failure, marked by poor hepatic synthetic function.

Normal value :This is often defined as a prothrombin time (PTT) of 16 seconds or an international normalized ratio (INR) of 1.5 in the absence of previous liver disease

A high INR level such as INR=5 indicates that there is a high chance of bleeding, whereas if the INR=0.5 then there is a high chance of having a clot

International normalised ratio

Normal rangeThe reference range for prothrombin time is usually around 11-16 seconds; the normal range for the INR is 0.8–1.2. Clinicians may aim for a higher INR - in most cases 2.5 - when conditions require the use of anticoagulants (such as warfarin)

Condition Prothrombin timePartial thromboplastin time

Liver failure, early Prolonged Unaffected

Liver failure, end-stage

Prolonged Prolonged

Liver failure (Prothrombin time)

Fulminant hepatic failure

Fulminant hepatic failure is defined as acute liver failure that is complicated by hepatic encephalopathy.

The encephalopathy of fulminant hepatic failure is attributed to increased permeability of the blood-brain barrier and to impaired osmoregulation in the brain, which leads to brain-cell swelling.

The resulting brain edema is a potentially fatal complication of fulminant hepatic failure

Fulminant hepatic failure

Fulminant hepatic failure may occur in as many as 1% of cases of acute hepatitis due to hepatitis A or B.

Hepatitis E is a common cause Fulminant hepatic failure in Asia. Whether hepatitis C is a cause remains controversial.

If acute viral hepatitis does not progress to fulminant hepatic failure, many cases resolve over a period of days, weeks, or months.

Alternatively, acute viral hepatitis may evolve into chronic hepatitis.

Hepatitis A and hepatitis E never progress to chronic hepatitis, either clinically or histologically

Natural history of viral hepatitis

The vast majority (95%) of people who are infected with hepatitis B recover within 6 months and develop immunity to the virus. People who develop immunity are not infectious and cannot pass the virus on to others,

As many as 85% of cases of acute hepatitis C demonstrate histologic evolution to chronic hepatitis.

Some patients with chronic hepatitis remain asymptomatic . Other patients report fatigue and dyspepsia.

Approximately 20% of patients with chronic hepatitis B or hepatitis C eventually develop cirrhosis as marked by the histologic changes of severe fibrosis .

Hepatitis A

The first descriptions of the clinical illness associated with HAV appeared during World War II.

Infectious hepatitis (HAV), was transmissible by the fecal-oral route in human volunteers.

The virus had a short incubation before the onset of symptoms

HAV

Group:Group IV ((+)ssRNA)Family:Picornaviridae Genus:HepatovirusSpecies:Hepatitis A virus

Hepatitis A virions were first identified in the stool of patients by electron microscopy in 1973.

Virology

The Hepatitis virus (HAV) is a Picornavirus;

It is non-enveloped and contains a single-stranded RNA packaged in a protein shell.There is only one serotype of the virus, but multiple genotypes exist.

Pathogenesis

Following ingestion, HAV enters the bloodstream through the epithelium of the oropharynx or intestine.

The blood carries the virus to its target, the liver, where it multiplies within hepatocytes and Kupffer cells (liver macrophages).

Virions are secreted into the bile and released in stool.

HAV is excreted approximately 11 days prior to appearance of symptoms or anti-HAV IgM antibodies in the blood.

Epidemiology of HAV

HAV is transmitted commonly most via the fecal-oral route. HAV is a common infection in -developed nations of Africa, Asia, and Central and South America.

The Middle East has a particularly high prevalence of HAV infection.

Most patients in these regions are infected when they are young children. Travelers who visit these regions are at risk for infection.

Epidemics of HAV infection may be explained by person-to-person contact, contaminated water or food.

Natural history of HAV

The incubation period of HAV is 15-45 days (average, 4 wk). The virus is excreted in stool during the first few weeks of infection, before the onset of symptoms.

Acute hepatitis A is more severe and has higher risk of mortality in adults than in children. The explanation for this is unknown.

Incubation period

HAV

Typical cases of acute HAV infection include the folllowing:

Malaise, anorexia, nausea, vomiting, and elevated aminotransferase levels.

Jaundice develops in typical cases.

HAV

Some patients experience a cholestatic hepatitis, marked by the development of an elevated alkaline phosphatase (ALP)and Gamma-glutamyl transpeptidase (GGT) level, in contrast to the classic picture of elevated aminotransferase levels.

Other patients may experience several relapses during the course of a year.

Less than 1% of cases result in fulminant hepatic failure. HAV infection does not persist and never causes

chronic hepatitis

Jaundice

Pathologic findings of hepatitis A

Classic findings of acute HAV infection include a mononuclear cell infiltrate, focal hepatocyte dropout, ballooning degeneration, and acidophilic (Councilman-like) bodies.

.

Councilman bodies are named after American pathologist William Thomas Councilman (1854-1933), who discovered them

Councilman body, also known as Councilman hyaline body, is an eosinophilic globule often found in the liver of individuals with viral hepatitis, yellow fever, or other viral syndrome.

It represents a hepatocyte that is undergoing apoptosis (controlled cell death).

Councilman body (upper-right) and ballooning degeneration (centre-left). H&E stain

Diagnosis of hepatitis A

Acute infection is documented by the presence of immunoglobulin M (IgM) anti-HAV, which disappears several months after the initial infection.

The presence of immunoglobulin G (IgG) anti-HAV demonstrates that an individual has been infected with HAV in the past, from 2 months ago to decades ago.

IgG anti-HAV appears to offer patients lifelong immunity against recurrent HAV infection

During the acute stage of the infection, the liver enzyme alanine transferase (ALT) is present in the blood at levels much higher than is normal.

The enzyme comes from the liver cells that have been damaged by the virus.

Hepatitis A virus is present in the blood, (viremia), and feces of infected people up to two weeks before clinical illness develops

Serological markers dynamics

Treatment for acute of HAV infection

Treatment for acute HAV is supportive in nature, because no antiviral therapy is available.

Hospitalization is needed for patients with nausea and vomiting and risk for dehydration.

Patients with acute liver failure require close monitoring to ensure they do not develop fulminant hepatic failure.

Treatment

There is no specific treatment for hepatitis A.

Patients are advised to rest, avoid fatty foods and alcohol (these may be poorly tolerated for some additional months during the recovery phase and cause minor relapses), eat a well-balanced diet, and hydratation.

Prevention of HAV infection

Since 2006, the CDC has recommended vaccination for all children at 1 year of age. It has encouraged "catch-up" vaccination programs for unvaccinated children.

Other groups

Other groups of individuals who should be vaccinated include persons with an occupational risk for infection (eg, persons working with HAV-infected primates),

Recipients of clotting factor concentrates, Persons who are either awaiting or have

received liver transplants. Patients with chronic liver disease —although

not at increased risk for exposure to HAV — were at increased risk for fulminant hepatic failure if they were infected HAV

vaccines

The HAV vaccines (inactivated), Havrix (GlaxoSmithKline, Research Triangle Park, NC) and Vaqta (Merck, Whitehouse Station, NJ), - 1-mL intramuscular (IM) injections (0.5 mL in children), given more than 1 month before anticipated travel.

This results in a better-than-90% likelihood of stimulating production of IgG anti-HAV, with resulting immunity against HAV infection.

A booster dose of the vaccine is recommended 6 months after the initial vaccination

Immune globulin

The administration of hepatitis A immune globulin is an alternative to vaccination against HAV infection. The dose is 0.02 mL/kg given intramuscularly for individuals who anticipate spending less than 3 months in an endemic region.

Travelers should receive 0.06 mL/kg intramuscularly every 4-6 months if they are planning to spend more than 3 months in a region where HAV is endemic

Postexposure prophylaxis

Postexposure prophylaxis with hepatitis A immune globulin is appropriate for household and intimate contacts of patients with HAV.

It is also recommended for contacts at daycare centers and institutions.

Typical dosing of immune globulin is 0.02 mL/kg, given intramuscularly as a single dose.

Postexposure prophylaxis is not recommended for the casual contacts of patients, such as classmates or coworkers

Hepatitis E

Recently identified cause of enterically transmitted non-A, non-B (NANB) hepatitis

Calicivirusspherical, non enveloped, 27-34 nm particles containing a ssRNA genome.

Clinical FeaturesIncubation period 30-40 daysAcute, self limiting hepatitis, no chronic carrier stateAge: predominantly young adults, 15-40 years

Hepatitis E

PathogenesisSimilar to hepatitis A; virus replicates in the gut initially, before invading the liver, and virus is shed in the stool prior to the onset of symptoms.Viraemia is transient..

ComplicationsFulminant hepatitis in pregnant women. Mortality rate is high (up to 40%).

Epidemiology

1) Large outbreaks have been described in India, Mexico and North Africa where the source of infection is usually gross faecal contamination of drinking water supplies.2) Case-to-case transmission to household contacts appears to be uncommon. This suggests that a large inoculum is needed to establish infection.

Diagnosis

No routine laboratory tests are available as yet. Virus cannot be cultured in vitro.

1) Calicivirus-like particles in the stool, by electron microscopy2) Specific IgM in serum3) PCR HEV-specific sequences in stool

Treatment of hepatitis E

The treatment of those infected with HEV is supportive in nature.

PARENTERALLY TRANSMITTED HEPATITISB, C, D and G

Hepatitis B Hepadna virus

42nm Virions (also known as "Dane particles") contain a circular dsDNA "double-stranded DNA". genome

HBV Antigens HBsAg = surface (coat) protein

produced in excess as small spheres and tubules HBcAg = inner core protein HBeAg = secreted protein;

HBV –virus structure

A diagrammatic representation of the hepatitis B virion and the surface antigen components

Pathogenesis

Infection is parenterally transmitted. The virus replicates in the liver and virus particles, as well as excess viral surface protein, are shed in large amounts into the blood.

Viraemia is prolonged and the blood of infected individuals is highly infectious.

Natural history of HBV

The natural history of viral infections is affected by disruption of the host specific cellular immune responses

Hepadnavirus entry into hepatocytes and replication is dependent on the presence of a receptor that is predominantly expressed on this cell type.

Pathogenesis

The host's immune attack against HBV is the cause of the liver injury , mediated by a cellular response to small epitopes of HBV proteins, especially HBcAg, presented on the surface of the hepatocyte

HBV infections occur in two stages: the proliferative phase and an integrative phase!

In the integrative phase, viral DNA is taken into the host genome. HBV replicates in hepatocytes to produce HBsAg particles and virions

During the proliferative phase there is the formation of complete virions and formation of the antigens. The cell surface expression of the antigens leads to activation of cytotoxic CD8+ T cell and hepatocyte destruction

IFN-|g (Interferon-g) or TNF-|a| (Tumor Necrosis Factor-a), regulate viral replication in surrounding hepatocytes without direct cell killing

Authors:Karami AResearch Center of Molecular Biology, Baqiyatallah

University of Medical Sciences, Tehran, Iran

Clinical Features

Incubation period 2 - 5 months

Tends to cause a more severe disease than Hepatitis A.

Asymptomatic infections occur frequently.

Complications

1) Persistant infection:-Following acute infection, approximately 5% of infected individuals fail to eliminate the virus completely and become persistantly infected.

Those who are at particular risk include: babies, young children immunocompromised patients males > females

The virus persists in the hepatocytes and on-going liver damage occurs due of the host immune response against the infected liver cells.

Diagnosis: Serology A. Acute infection with resolution

Viral antigens:

1) HBsAg is secreted into the blood. Its presence in serum indicates that virus replication is occurring in the liver2) (HBeAg) secreted protein is shed in small amounts into the blood. Its presence in serum indicates that a high level of viral replication is occurring in the liver3) core antigen (HBcAg) core protein is not found in blood

Antibody response:1) (anti-HBs) becomes detectable late in convalescence, and indicates immunity following infection.

2) e antibody (anti-HBe) becomes detectable as viral replication falls. It indicates low infectivity in a carrier. 3) Core IgM rises early in infection and indicates recent infection 4) Core IgG rises soon after IgM, and remains present for life in both chronic carriers as well as those who clear the infection. Its presence indicates exposure to HBV.

Treatment of acute hepatitis B

As with the treatment of acute hepatitis A, no well-established antiviral therapy is available for acute HBV infection. Supportive treatment recommendations are the same as for acute hepatitis A

Hepatitis C

The major cause of parenterally transmitted non A non B hepatitis. It eluded . In 1989, the genome was cloned from the serum of an infected chimpanzee.

Virology Togavirus related to the Flavi and Pesti viruses.

Thus probably enveloped.Has a ssRNA genome(single-stranded)

Does not grow in cell culture, but can infect Chimpanzees

Genotypes

Hepatitis C is divided into six distinct genotypes throughout the world with multiple (90) subtypes

Following is a list of the different genotypes of chronic Hepatitis C:

Genotype 1aGenotype 1bGenotype 2a, 2b, 2c & 2dGenotype 3a, 3b, 3c, 3d, 3e & 3fGenotype 4a, 4b, 4c, 4d, 4e, 4f, 4g, 4h, 4i & 4jGenotype 5aGenotype 6a

Components of the antiviral immune response: although the hepatocyte is the target cell of HCV-specific  immune response here, other cells, including dendritic cells and macrophages, are also important in antigen presentation to the immune system ( cytotoxic T cell; IL: in; MHC: major histocompatibility complex; TCR: T cell receptor; Th: T helper; Th1: T helper cells with a type 1 cytokine profile; Th2: T helper cells with a type 2 cytokine profile; TNF: tumor necrosis factor)

Treatment of acute hepatitis C

Combination therapy with pegylated interferon-alpha and ribavirin is the preferred regimen initiated preferably within 12 -24weeks after the diagnosis of acute HCV.

The goal of treatment – achievement of the undetectable HCV-RNA at week 12.

Fulminant Hepatitis

Rare; accounts for 1% of infections. Pathophysiology Massive hepatic necrosis within 8 weeks

of onsetMortality/MorbidityFHF results are fatal for most affected children. The mortality rate may reach 80-90% in the absence of liver transplantation. In some pediatric series, survival rates of 50-75% have been reported.SexDistribution of FHF is equal among males and females.

Viral hepatitis

Symptoms

Vomiting Upper Abdominal Pain Anorexia Jaundice Liver size may be normal, small, or large, and

the liver may shrink with deterioration of the overall general condition of the patient.

Hemorrhagic diathesis and systemic collapse indicate a poor prognosis

Signs

Neurologic changes (Hepatic Encephalopathy) Altered Level of Consciousness (Delirium, coma) Decerebrate rigidity (with severe cerebral edema) Personality change

Jaundice Coagulopathy Bleeding (e.g. Gastrointestinal Bleeding) Acute Renal Failure (Hepatorenal Syndrome) Hypoglycemia Acute Pancreatitis Cardiopulmonary failure Ascites (due to Portal Hypertension)

Prognosis: Factors associated with poor outcomes

Advanced age Hepatitis C Coma (80% Mortality) Rapid decrease in liver sizeRespiratory failure Marked prothrombin time prolongation

Management

Maintain urine output and correct hypoglycemia and any associated electrolyte disturbances.

Patients may require intravenous administration of calcium, phosphorous, magnesium, factor concentrate, and platelets.

An infusion of 10-20% of glucose is usually required.

Avoid fluid overload (restrict hydration up to 2 mL/kg/h).

Hemodynamic monitoring of central pressures is advised to assess volume depletion and overload.

Parenteral vitamin K and plasmapheresis are needed to correct coagulopathy and prevent its serious sequelae.

Transfusion with fresh frozen plasma (FFP).Platelet transfusion may be indicated in severe cases of

FHF with coagulopathy and thrombocytopenia.A parenteral H2-receptor blocker is administered

prophylactically to prevent potential GI bleeding. Avoiding of nephrotoxic agents, benzodiazepines, and

other sedative medications

Management

Management keyFocus on management of renal impairment due to

hepatorenal syndrome (HRS) or acute renal tubular necrosis.

Pay special attention to management of cerebral edema. Proper positioning and avoidance of manipulations that increase intracranial pressure.

Mannitol is used in patients with documented ICP greater than 30 mm Hg and is considered in patients with progressive edema.

Restrict protein intake to 0.5 g/kg/d or less. Use lactulose to evacuate the bowel. Oral neomycin is indicated to decrease enteric bacteria

that produce ammonia. Monitor blood glucose regularly for possible complicating

hypoglycemia, and treat with intravenous glucose administration.

Consultations

Gastroenterologist Neurosurgeon Hematologist Infectious disease specialist Transplantation surgeon

Diet

Special attention to diet is indicated. Patients require high calories, high carbohydrates, and moderate fat. Total parenteral nutrition (TPN) may be needed to ensure adequate nutrition, especially when enteral feeding is not possible.

Delta Agent

Defective virus which requires Hepatitis B as a helper virus in order to replicate. Infection therefore only occurs in patients who are already infected with Hepatitis B.

Clinial FeaturesIncreased severity of liver disease in Hepatitis B carriers.

Virologyvirus particle 36 nm in diameterencapsulated with HBsAg, derived from HBVdelta antigen is associated with virus particlesssRNA genome

Epidemiology

Incidence endemic world-wide; high incidence in Japan,

Italy and SpainIn South Africa, 1% blood donors have antibodies

Transmission Blood transfusions, blood products organ donation Intravenous drug abusers community acquired: mechanism unclear. ?Vertical

transmission ?sexual intercourse

Clinical Features

Incubation period 6-8 weeksCauses a milder form of acute hepatitis than does hepatitis BBut 50% individuals develop chronic infection, following exposure.

Complications1) Chronic liver disease2) Hepatocellular carcinoma

Treatment of hepatitis D

The treatment of patients coinfected with HBV and HDV is not well studied. Multiple small studies have demonstrated that HBV/HDV coinfected patients are less responsive to interferon therapy than patients infected with HBV alone. Treatment with PEG-IFN-alfa-2b produced HDV RNA negativity in only 17-19% of patients. Lamivudine appears to be ineffective against HBV/HDV coinfection

Hepatitis G (HGV )

A virus originally cloned from the serum of a surgeon with non-A, non-B, non-C hepatitis, has been called Hepatitis G virus.

It was implicated as a cause of parenterally transmitted hepatitis, but is no longer believed to be a major agent of liver disease. It has been classified as a Flavivirus and is distantly related to HCV.

Diagnosis

1) SerologyReliable serological tests have only recently become available.HCV-specific IgG indicates exposure, not infectivity

2) PCR detects viral genome in patient's serum

Treatment HGV

The treatment of patients with HBV and HGV is not well studied

Prophylaxis HGV is not studied