Hepatitis D overview

# Overview
Hepatitis D is a disease caused by a small circular RNA virus (Hepatitis delta virus or hepatitis D virus, HDV). HDV is considered to be a subviral satellite because it can propagate only in the presence of another virus, 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). 
Both superinfection and coinfection with HDV results in more severe complications compared to infection with HBV alone. These complications include a greater likelihood of experiencing liver failure in acute infections and a greater likelihood of developing liver cancer in chronic infections. In combination with hepatitis B virus, hepatitis D has the highest mortality rate of all the hepatitis infections of 20%.

# Historical Perspective
The hepatitis D virus was first reported in mid-1977 by an italian researcher, Mario Rizzetto. 

# Pathophysiology
Despite the limited knowledge concerning the pathogenesis of hepatitis delta virus (HDV) infection, the adaptive and innate immune systems are thought to play a pivotal role on hepatocellular injury. HDV requires the presence of HBV to be able to cause infection.  Pathological changes in HDV are limited to the liver, the only organ in which HDV can replicate. Hepatitis B virus (HBV) is an essential co-factor in the evolution of hepatocellular damage, and infection with both HBV and HDV leads to more severe liver injury than HBV infection alone. There is evidence supporting the possibility that the virus can be cytopathic in certain genotypes.  HDV is transmitted percutaneously, sexually, or through contact with infected blood or blood products. In rare occasions transmission may be perinatal.  The different genotypes will influence viral assembly, and consequently infectivity.

# Causes
The hepatitis D virus belongs to the genus deltavirus. Its genome consists of a single circular RNA molecule (ssRNA), with a high degree of complementarity, which gives it the ability to survive at high temperatures. Its life cycle requires cooperation with the host cell at all stages, including: attachment, penetration, uncoating, provision of adequate metabolic conditions, assembly and release of new virions. The replication cycle also requires the presence of an hepadnavirus to provide the protein components for the new HDV envelopes. The HDV is composed by the following particles: HBsAg; HDAg-S; HDAg-L; and RNA. Different HDV genotypes have been associated with different courses of the disease. The virus has tropism for hepatocytes and humans are its natural reservoir.

# Differentiating Hepatitis D from other Diseases
Hepatitis D must be differentiated from other diseases that cause fever, nausea, vomiting, jaundice, hepatomegaly, icteric sclera, elevated ALT, AST, such as viral hepatitis(caused by other etiologic agents), alcoholic hepatitis, and autoimmune hepatitis.

# Epidemiology and Demographics
HDV infection affects more than 15 million people chronically infected with HBV worldwide. Regions with high rates of HDV infection include Central Africa, Mediterranean Basin, the Amazon Basin, and parts of Asia. With the implementation of HBV vaccination programs, better education and awareness about the virus, and improving socioeconomic conditions, HDV prevalence is decreasing in many areas of the world.

# Risk Factors
Risk factors for hepatitis D, either in coinfection or superinfection with HBV, include: IV drug use; infection during pregnancy; sexual intercourse with infected persons; exposure to unscreened blood or blood products; hemodialysis patients; and healthcare and public service workers who deal with infected patients.

# Screening
The general population, with low risk of HBV and HDV infection does not need to be screened. However, individuals known to be HBsAg positive, with acute or chronic hepatitis, or those HBsAg negative, but who are IgM anti-HBc positive, should be screened for HDV. Blood products should also be screened in order to avoid transmission of the virus through blood transfusions or hemodialysis.

# Natural History, Complications and Prognosis
HDV is a defective virus that requires individuals to be previously, or concomitantly, infected with HBV.  The clinical manifestations of HDV infection are similar to those of HBV, including: fatigue, lethargy, nausea, jaundice, acholic stools and dark urine.  The disease progresses throughout 4 phases: incubation period; preicteric phase; icteric phase; and convalescence phase.  Infection with HDV may occur at the time of infection with HBV, in which case both acute type B and type D hepatitis may develop.  95% of these patients will clear the infection.  HDV may also infect a previous HBV carrier, often causing fulminant hepatitis and chronic active hepatitis, frequently progressing to cirrhosis.  Complications of hepatitis D may include: chronic active hepatitis; fulminant hepatitis; hepatic cirrhosis and hepatic failure. The mortality rate for HDV infection is higher than that of hepatitis B, between 2% and 20%.

# History and Symptoms
Hepatitis D can only occur in patients who are simultaneously (coinfection) or previously (superinfection) infected with HBV. Common symptoms of hepatitis D include: fever; yellowish discoloration of the eyes and skin; fatigue; abdominal pain; loss of appetite; nausea; vomiting; and dark urine. Coinfection is associated with a more severe form of the disease, often leading to fulminant hepatitis. In superinfection, symptoms may be unspecific initially, and the majority of these cases progress into chronicity.

# Physical Examination
Physical examination of patients with acute HDV infection may be normal, or include findings, such as jaundice, and some degree of impairment of joint movement due to arthralgia. Physical examination of patients with chronic disease, depending on the its stage, may include: jaundice; palmar erythema; spider angiomata;gynecomastia; hepatomegaly; splenomegaly; ascites; peripheral edema; and asterixis.

# Laboratory Findings
The diagnosis of hepatitis D is made by the detection of HDV RNA in circulation, with RT-PCR. The levels of HBsAg may be used during treatment to evaluate the response, and determine the duration of therapy. After recovery, markers of HDV infection, such as IgM and IgG antibodies disappear within months. Liver biopsy is indicated in HDV RNA positive patients, to assess the stage of liver disease. Findings in liver biopsy are similar to those observed in HBV infection. Coinfection with HIV and HCV should be ruled out in HDV infected patients. Serologic markers such as HDV RNA, HDAg, and IgM and IgG anti-HD antibodies may persist for longer periods in chronic hepatitis D.

# CT
CT scan may diagnose and/or monitor biliary obstruction, cirrhosis and hepatocellular carcinoma, in patients with hepatitis D.

# MRI
The MRI may be used to diagnose/monitor biliary obstruction, cirrhosis, and hepatocellular carcinoma in patients with hepatitis D. MRI findings in these patients may include: nodular appearance of the liver and signs of portal hypertension, such as ascites and splenomegaly.

# Ultrasound
The liver ultrasound of a patient with hepatitis D may reveal unspecific findings, such as: hepatomegaly, gallbladder wall thickening, increased echogenicity, and signs of portal hypertension. It may also be used in the diagnosis and monitoring of hepatic cirrhosis, as well as for hepatocellular carcinoma. Attending to the simultaneous occurrence of HDV and HBV, HBsAg carriers with cirrhosis should be echographically evaluated every 6 months.

# Other Diagnostic Studies
The identification of the genotype of HDV helps to predict the potential severity of liver disease, as well as the response to treatment. Endoscopy may be useful in patients with advanced stage of the disease, who present with liver cirrhosis, to evaluate the presence of esophageal varices.

# Medical Therapy
Currently there is no effective antiviral therapy available for the treatment of acute or chronic hepatitis D. Interferon- is the only drug that has shown antiviral activity against HDV, however despite improvements in patients' health, most remained HDV RNA positive. Long-term treatment with NUCs has shown a decline in the levels of HBsAg of some patients. Patients with chronic hepatitis should be treated with weekly injections of pegylated interferon, for at least 48 weeks.

# Surgery
Treatment of hepatitis D does not involve surgery. Some procedures may be indicated for certain complications, such as ascites, in which peritoneal drainage may be performed. Liver transplantation may be indicated for: end-stage liver disease; liver failure secondary to HDV infection, for patients in which treatment with interferon is not indicated; and hepatocellular carcinoma.

# Prevention
HDV infection requires the person to be co-infected with HBV, therefore, vaccination against hepatitis B confers immunity against hepatitis D. Since a vaccine against hepatitis D, for patients infected with HBV, is not available, these individuals should prevent superinfection by avoiding risk behaviors, such as: contact with blood from infected individuals, and sharing of sharp objects.

# Cost-Effectiveness of Therapy
Considering that patients who develop symptomatic hepatitis D may progress into cirrhosis, liver failure and hepatocellular carcinoma, research for an adequate therapeutic regimen and for new and more effective drugs, with less side-effects, and lower costs may be considered cost-effective.

# Future or Investigational Therapies
Potential targets for antiviral therapy of HDV include drugs that interfere with postranslational modification and viral assembly. New drugs, such as prenylation inhibitors, HBV entry inhibitors, and new forms of interferons are currently being studied and tested for the treatment of hepatitis D, with better efficacy and tolerability.