Today we'll be talking about a viral infection that targets the liver and is a worldwide health problem with one-third of the world's population having been infected at some point in their lives. For this 65-year-old immigrant from Taiwan, chronic infection with the virus led to an even more serious health condition. Liang was first brought in by her daughter to see a family physician and establish routine primary care. She had lived most of her life in a rural village in Taiwan and had never sought routine medical care since she'd always been generally healthy. When her husband died a year ago, she moved to the US to live with her daughter and help care for her young grandson. Liang told the physician through the interpreter that she felt well and had no particular health concerns. But when he asked Liang about her family history, she mentioned that her brother back in Taiwan had died of liver disease. The physician performed a thorough physical exam, which was entirely normal. Given the family history, along with the fact that Liang had emigrated from an area with high rates of viral Hepatitis, the physician decided to screen her for this infection. Liang's lab results returned a few days later and showed that she was positive for Hepatitis B surface antigen and Hepatitis B core antibody, suggesting that, like many people born in endemic areas of the world, she was chronically infected with the Hepatitis B virus. Also, the doctor noted that one of Liang's liver enzymes - ALT - was elevated, which raised the concern that the virus was causing some degree of ongoing damage to Liang's liver cells. Hepatitis B is a highly contagious virus which enters a patient's body either through contact with infected blood, by sexual contact with an infected individual, or at birth from an infected mother to her infant. The virus spreads through the bloodstream and arrives in the liver, where it preferentially replicates because the viral gene expression relies upon specific transcription factors that are abundant in liver cells. As the virus replicates, viral antigens are presented by MHC on the surface of hepatocytes and local antigen presenting cells, allowing the host immune system to detect the virus and deploy a T-cell response to fight the infection. Unfortunately, the robust cytotoxic T-cell response against infected hepatocytes is also responsible for the extensive liver damage that can occur. From this point forward, the course of the infection can vary widely from patient to patient. Some people develop an acute infection, which either resolves spontaneously or very rarely causes fulminant life-threatening disease. Other individuals, particularly those who are infected at birth or very early in life, go through a period of viral replication that's tolerated by their immature immune system, leading to chronic infection which can cause complications decades later. In the US, babies born to an HBV-infected mother receive both passive immunization with anti-HBV immunoglobulins and active immunization with the HBV vaccine to try to prevent chronic infection. The passive administration of antibody provides immediate but temporary protection, during which time the baby has a chance to form antibodies in response to the vaccine. This strategy of enhancing the baby's immune response to HBV after birth is extremely effective, because vertical transmission usually occurs from exposure to maternal secretions during childbirth, not in utero. All babies born in the US are also offered the HBV vaccine as part of their routine immunizations. But in many countries, this still doesn't occur. When Liang was born in Taiwan 65 years ago, neither immunoglobulin nor vaccine was available to her and she went on to become chronically infected with Hepatitis. The Hepatitis B virus is a particle which contains a core protein, viral DNA and DNA polymerase. All of these components are surrounded by a surface protein, the Hepatitis B surface antigen. An additional component - the Hepatitis B E antigen, is a byproduct of replication. Blood tests are available to measure viral DNA, surface antigen, E antigen and the antibodies against all three of these viral proteins. All these tests provide important information about the patient's exposure history, vaccination history, clinical stage, or severity of Hepatitis B infection. For example, Liang has had an active chronic infection, so the surface protein was detectable in her blood. She also had anti-Hepatitis B antibodies in her blood directed against the core protein, suggesting immune memory specific to that protein. Liang was negative for antibodies against the surface protein, which tend to be present in people who've successfully resolved their infection. After breaking the news to Liang that she was chronically infected with Hepatitis B, the physician referred her to see a liver specialist to help manage her disease and monitor for complications. The hepatologist sent additional lab tests, including a PCR for Hepatitis B DNA to determine the viral load in her body. He found that Liang had a high enough level to warrant treating her with an anti-viral medication, especially considering that she also had an elevated ALT, suggesting active liver disease. He also evaluated her for other factors that would put her at risk of more severe disease, such as co-infection with other viruses, or heavy alcohol consumption. Fortunately, Liang tested negative for the other Hepatitis viruses and HIV and she had never been a heavy drinker. The doctor also explained to Liang that she should be monitored with a liver ultrasound every six months to screen for liver cancer or Hepatocellular carcinoma. Unfortunately, Liang's very first ultrasound revealed a concerning finding; a single, three centimeter liver mass. She was sent for a blood test for alpha-fetoprotein - a marker of liver cancer - which was found to be elevated. She also received a follow-up CT scan, which showed a single large hypo-dense liver mass. Together, these findings were sufficient to make a diagnosis of hepatocellular carcinoma. Chronic Hepatitis B can cause liver cancer through two main mechanisms. In the cirrhotic pathway, chronic immune-mediated damage to infected hepatocytes leads to the need for constant cell proliferation and tissue repair. Over time, this imperfect repair process can lead to extensive fibrosis of the liver and the excess cell proliferation puts the person at risk of cancer. Chronic Hepatitis B can also cause cancer even in the absence of cirrhosis, because it can integrate into the host genome and directly induce oncogenic mutations. Hepatocellular carcinoma is an aggressive disease, which is typically only detected late in its course, with most patients dying within 6 to 20 months of diagnosis. Fortunately for Liang, her disease was caught early at an asymptomatic stage through ultrasound screening and her imaging showed only a single lesion with no evidence of distant metastasis. Also, her underlying liver function was well-preserved. So she was a good candidate for surgical resection of her tumor, which she agreed to and tolerated well. In patients whose tumors are not resectable, other treatment options include liver transplants, various methods of tumor ablation or systemic chemotherapy. After her diagnosis of Hepatitis and liver cancer, Liang was very anxious about the risk of infection in the rest of her family. Their family physician shared her concern, since the Hep-B virus is a contagious, blood-borne pathogen. Liang's daughter was at risk for both household transmission through contact with even small amounts of her mother's blood and vertical transmission of the virus. But fortunately, her screening tests were reassuring. Liang's daughter, son-in-law and grandson had all been vaccinated against Hepatitis B. Their blood tests all showed positive Hepatitis B surface antibody, which suggested long-term immunity acquired through vaccination with no evidence of current or past Hepatitis infection. Liang herself is now 68 years old and doing well on antiviral medication and close monitoring by her hepatologist for recurrence of her cancer.
