OVERVIEW

What is Hepatitis D?

Hepatitis D is an acute or chronic liver inflammation caused by infection with the hepatitis D virus (HDV). It often coexists with hepatitis B (caused by HBV infection). Acute cases may resolve on their own, while chronic cases require antiviral treatment. Untreated, it may lead to complications such as hepatic encephalopathy or severe infections.

What are the types of Hepatitis D patients?

Based on the timing and levels of HDV virus and antibodies in the blood, HDV infections can be classified into three clinical types:

• Acute HBV/HDV coinfection;
• Acute HDV superinfection in chronic HBV carriers;
• Chronic HDV infection.

SYMPTOMS

What are the manifestations of hepatitis D?

Similar to other viral hepatitis, hepatitis D can present as acute hepatitis, chronic hepatitis, severe hepatitis (liver failure), cholestatic hepatitis, or hepatitis-related cirrhosis:

• Acute hepatitis: Symptoms include fatigue, loss of appetite, nausea, vomiting, aversion to oily food, abdominal distension, liver pain, dark urine, jaundice, and itching. Liver function tests mainly show elevated alanine aminotransferase (ALT) and aspartate aminotransferase (AST). Some patients may also have significantly increased total bilirubin (TBil) (acute icteric hepatitis).

• Chronic hepatitis: Refers to viral hepatitis lasting more than six months or recurrent episodes after an acute attack. In addition to the above symptoms and abnormal liver function, patients may also exhibit signs such as splenomegaly, liver palms, and spider angiomas. Liver function tests show repeated or persistent elevation of ALT and AST, decreased albumin (ALB), and increased globulin (GLB).

• Severe hepatitis: Presents as a series of liver failure syndromes: extreme fatigue, severe gastrointestinal symptoms (abdominal distension, aversion to oily food, loss of appetite, nausea, vomiting, etc.), neurological or psychiatric symptoms (drowsiness, personality changes, agitation, coma, etc.), and bleeding (subcutaneous petechiae, prolonged bleeding from wounds). Blood tests may show significantly prolonged prothrombin time and decreased prothrombin activity (PTA < 40%), progressive deepening of jaundice, daily increase in TBil by 17.1 umol/L, or levels more than 10 times the normal value. Dissociation of bilirubin and transaminase (divergent or opposite changes) and elevated blood ammonia may occur.

• Cholestatic hepatitis: Symptoms include jaundice (skin and sclera), itching, pale stools, and hepatomegaly. Liver function tests show significantly elevated serum bilirubin (mainly direct bilirubin), increased γ-glutamyl transpeptidase (γ-GT), alkaline phosphatase (ALP), total bile acids (TBA), and cholesterol, with minimal elevation of ALT and AST.

• Hepatitis-related cirrhosis: Divided into active and inactive types based on inflammation:

  • Active cirrhosis: Obvious clinical symptoms such as fatigue, poor appetite, nausea, and vomiting, elevated ALT, decreased ALB, and physical signs including ascites, splenomegaly, abdominal wall varices, liver palms, and spider angiomas.

  • Inactive cirrhosis: Mild or nonspecific symptoms but may exhibit the above signs.

• Based on liver histopathology and clinical manifestations, hepatitis-related cirrhosis can also be classified as compensated or decompensated:

  • Compensated cirrhosis: Early-stage cirrhosis with largely normal liver function. Laboratory indicators include ALB ≥ 35 g/L, DBil < 35 umol/L, PTA > 60%, and absence of ascites, mental abnormalities, or major upper gastrointestinal bleeding.

  • Decompensated cirrhosis: Advanced cirrhosis with obvious liver dysfunction and decompensation signs, such as ALB < 35 g/L, TBil > 35 umol/L, PTA < 60%, ALB/GLB < 1.0, and possible ascites, major upper gastrointestinal bleeding, or psychiatric symptoms.

What other diseases can hepatitis D cause?

• Since hepatitis D coexists with hepatitis B, all complications of hepatitis B can also occur in hepatitis D patients. Common intrahepatic complications include cirrhosis, primary liver cancer (including hepatocellular carcinoma and intrahepatic cholangiocarcinoma), and fatty liver.

• Severe hepatitis can lead to multiple serious complications, including:

  • Hepatic encephalopathy: A severe neuropsychiatric syndrome caused by severe liver damage, such as personality changes, disorientation, impaired calculation ability, drowsiness, or coma. It can occur in severe hepatitis and decompensated cirrhosis.

  • Upper gastrointestinal bleeding: Causes include reduced clotting factors and platelets, portal hypertension, etc. Symptoms include hematemesis, melena, and tarry stools.

  • Hepatorenal syndrome: Often an end-stage manifestation of severe liver disease, with clinical features such as oliguria or anuria, high azotemia, and electrolyte imbalances.

  • Severe infections: Severe hepatitis is prone to difficult-to-control infections, commonly in the biliary tract, peritoneum, or lungs. Most bacteria originate from the gut, possibly due to intestinal dysbiosis after liver disease. Long-term use of broad-spectrum antibiotics may also lead to fungal infections.

CAUSES

What are the notable characteristics of the hepatitis D virus?

The hepatitis D virus is an RNA virus and also a defective virus, requiring the presence of hepatitis B virus (HBV) infection in patients to cause infection.

What are the sources of infection, transmission routes, and susceptible populations for hepatitis D?

• Sources of infection: Primarily hepatitis D patients and virus carriers.

• Transmission routes: Humans are infected when blood or body fluids containing HBV and HDV enter the body. Specific routes include mother-to-child transmission, blood transmission, and body fluid transmission (including saliva, sweat, semen, vaginal secretions, breast milk, etc.).

• Susceptible populations: Humans are generally susceptible to HDV, and HDV antibodies in previously infected individuals are not protective antibodies.

DIAGNOSIS

What is the most important prerequisite for diagnosing hepatitis D?

Since HDV relies on HBV to cause infection, HDV infection can only be suspected when a patient's hepatitis B antigen-antibody test ("hepatitis B two-and-a-half panel") shows a positive result for surface antibody (HBsAg).

How should hepatitis D be diagnosed?

Hepatitis D coexists with hepatitis B and is relatively rare, making it highly prone to missed or misdiagnosis. For viral hepatitis, including hepatitis D, diagnosis should encompass the following three major aspects.

1. Epidemiological data: History of blood transfusion, unsafe injections, unprotected sexual intercourse, especially contact with individuals infected with hepatitis B or D; presence of hepatitis patients in the family, particularly whether the patient's mother is an HBV or HDV carrier.

2. Clinical diagnosis:

   • Acute hepatitis: Sudden onset, often with symptoms of acute infection such as chills, fever, fatigue, poor appetite, nausea, and vomiting; enlarged liver with soft texture, significantly elevated ALT, normal serum bilirubin or >17.1 μmol/L in icteric hepatitis, and disease duration not exceeding 6 months.

   • Chronic hepatitis: Disease duration exceeding 6 months or unclear onset date but presenting with symptoms, signs, and laboratory indicators of chronic hepatitis. Patients often experience fatigue, poor appetite, aversion to oily foods, and discomfort in the liver area, with signs such as liver disease facies, palmar erythema, spider angiomas, splenomegaly, and enlarged firm liver. Based on severity, it is classified as mild, moderate, or severe.

   • Severe hepatitis (liver failure): Mainly manifests as liver failure syndrome, including extreme fatigue, gastrointestinal symptoms, neuropsychiatric symptoms, and bleeding.

   • Cholestatic hepatitis: Onset resembles acute icteric hepatitis, with prolonged jaundice and mild symptoms.

   • Hepatitis-related cirrhosis: Often has a history of chronic liver disease, with long-term manifestations of liver dysfunction such as fatigue, abdominal distension, palmar erythema, spider angiomas, splenomegaly, ascites, and hypoalbuminemia. Some patients may also exhibit signs of portal hypertension, such as abdominal wall varices or a history of hematemesis.

3. Etiological diagnosis:

   • For acute or chronic hepatitis patients: Confirmed HBV infection, along with positive serum HDV antigen (HDVAg), positive serum IgM antibodies, positive HDV RNA, positive HDVAg in liver tissue, or positive HDV RNA in liver tissue, can all confirm a diagnosis of hepatitis D.

   • In HBV carriers, low-titer serum HDV IgG antibodies may indicate past infection, while high titers may suggest current infection, though the cutoff value remains undefined. In the absence of clinical symptoms, a positive serum HBsAg combined with positive HDV serological markers (antigen or antibodies) can diagnose an asymptomatic HDV carrier.

   • It is crucial to emphasize that during standardized treatment for hepatitis B, if the patient's hepatitis condition is difficult to control or cirrhosis continues to worsen, the possibility of concurrent hepatitis D infection should be considered, warranting further investigation.

What diseases should hepatitis D be differentiated from?

Hepatitis D needs to be distinguished from other causes of hepatitis and jaundice:

• Hepatitis caused by other viruses: Hepatitis C, hepatitis A, cytomegalovirus hepatitis, liver complications of infectious mononucleosis, etc., can be differentiated based on the clinical features of the primary disease and etiological or serological test results.

• Infectious-toxic hepatitis: Such as epidemic hemorrhagic fever, leptospirosis, typhoid fever, scrub typhus, amebic liver disease, or liver fluke infection, primarily differentiated through clinical features and laboratory tests.

• Drug-induced liver injury: History of hepatotoxic drug use, with liver function recovery after discontinuation. All viral hepatitis markers are negative.

• Alcoholic liver disease: Long-term history of heavy alcohol consumption, with negative viral markers.

• Autoimmune hepatitis: Mainly includes primary biliary cholangitis (PBC) and autoimmune hepatitis (AIH). PBC primarily affects intrahepatic bile ducts, while AIH mainly damages hepatocytes. Diagnosis relies on autoantibody testing and pathological examination.

• Obstructive jaundice: Common causes include gallstones, pancreatic cancer, cholangiocarcinoma, and liver cancer. Patients often exhibit mild symptoms but severe jaundice, with elevated bilirubin predominantly direct. Imaging can reveal bile duct dilation due to stones or tumors.

• Hemolytic jaundice: Often triggered by drugs or infections, presenting with anemia, back pain, fever, and hemoglobinuria. Elevated bilirubin is mainly due to increased indirect bilirubin.

TREATMENT

What are the treatment goals for hepatitis D? How are they determined?

The goal is to eliminate or long-term suppress HDV and HBV in patients.

• Undetectable HDV RNA in the blood and absence of HDVAg in the liver indicate clearance or suppression of HDV.

• Seroconversion from HBsAg to HBsAb in blood tests ("hepatitis B serology") and virological suppression with HBV DNA below the detection limit indicate elimination or suppression of HBV infection.

How is hepatitis D treated?

• Acute hepatitis D is generally self-limiting, with most cases recovering completely. Treatment focuses on general care and symptomatic support. Patients should be isolated during the acute phase, and those with significant symptoms or jaundice should rest in bed, avoiding excessive fatigue. A light, easily digestible diet is recommended, along with avoiding alcohol and hepatotoxic drugs. Antiviral therapy is usually unnecessary.

• For chronic hepatitis D, concurrent treatment for hepatitis B is essential, including adequate rest, nutrition, psychological balance, liver function improvement, immune regulation, antiviral therapy, and antifibrotic measures.

• Antiviral therapy is key for treating hepatitis B and D. Anti-HBV drugs include nucleoside analogs (e.g., lamivudine, entecavir, telbivudine, adefovir dipivoxil, tenofovir) and interferons (e.g., standard interferon-α, pegylated interferon).

• Currently, the only approved treatment for chronic hepatitis D is interferon-α, with pegylated interferon appearing more effective than standard interferon, though supporting data are limited.

How effective is interferon therapy for hepatitis D?

Treatment efficacy for hepatitis D is generally poor. The largest study evaluating interferon-α therapy in chronic hepatitis D patients found no statistically significant difference in HDV RNA clearance rates or liver histology improvement between the interferon-α and placebo groups at the end of treatment.

Despite low success rates, treatment is still recommended for chronic hepatitis D patients with active liver disease, especially those with advanced fibrosis, as early intervention may improve outcomes. Clinical observations suggest hepatitis D tends to be severe, and patients with shorter infection durations are more likely to respond to interferon therapy.

DIET & LIFESTYLE

What should hepatitis D patients pay attention to in daily life?

• Consume sufficient protein, such as eggs, lean meat, milk, fish, and shrimp.

• Eat less fried and greasy foods, such as fatty meat, to reduce the burden on the liver.

• Emphasize fresh food, and pay special attention to hygiene when consuming seafood products.

• Strictly avoid alcohol.

• Avoid spicy foods, as they can irritate the gastrointestinal tract and may even lead to gastritis or stomach ulcers. Hepatitis patients already experience digestive discomfort, which can be worsened by spicy foods.

• During the acute phase, ensure bed rest and avoid excessive fatigue.

• Maintaining an optimistic mindset is also crucial. Excessive worry about the disease, leading to prolonged unhappiness, can affect sleep and appetite, while a positive attitude greatly aids recovery.

PREVENTION

Can Hepatitis D Be Prevented?

Similar to other infectious diseases, controlling the source of infection, cutting off transmission routes, and protecting susceptible populations can all reduce the incidence of Hepatitis D.

Specific measures include isolating acute patients, actively providing antiviral treatment for chronic patients, avoiding direct contact with blood and bodily fluids, implementing strict disinfection procedures for tableware, beauty and hairdressing tools, and bathing utensils, and using active or passive immunization to block mother-to-child transmission.

Can Vaccines Prevent Hepatitis D?

Currently, there are no commercially available vaccines to prevent Hepatitis D. Related vaccines are still under development.