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CASE STUDY REPORT
Acute Hepatitis B and Chronic Heptatits C in a 28 year old male - A Case Study
1.1 An Introduction to Liver and Liver Diseases-
The liver is the largest solid organ in the human body and is essential for life. It is said to the main metabolizing and detoxifying chamber of our body. It has a crucial role of metabolizing nutrients from the intestines, detoxifying ammonia containing waste products, filtering drugs and toxic substances in our blood. Apart from these, it has also a role to help regulate blood- glucose and triglyceride levels, and hormones in our circulatory system, as well as participating in our immune defense against infection. Hepatocyte is the cellular and functional unit of the liver, and about 60 per cent of the liver is made up hepatocytes.(1) The liver also has bile-duct cells, macrophages and reticulo-endothelial cells apart from hepatocytes, which aid the liver in carrying out all its functions. The detoxifying chamber of our body, the liver, can withstand a great deal of abuse and failure of the liver means that there is irreversible damage beyond repair to its structure and function. (1) Individuals who develop liver failure can die with no warning within months of diagnosis. There are numerous causes of liver diseases, toxic effect of drugs, excessive consumption of alcohol, viruses, genetic defects or exposure to toxic chemicals. Some common symptoms and signs associated with liver disease include nausea, vomiting, reduced appetite, jaundice, low-grade fever, abdominal pain and fatigue. Many liver diseases coexist with chronic renal disease, because many systemic conditions affect both the liver and the kidneys. (FlorenceÂ Wong, 2011). The morbidity of these diseases has necessitated a prolonged search for effective therapy.Â (Dusheiko,2003).
1.2 Hepatitis B and C -
Currently, the most common cause of liver failure is viral hepatitis and HBV and HCV i.e. hepatitis B and hepatitis C viruses are the most common causes of chronic diseases worldwide. (Rocio Torres Ibarra, 2006). Chronic liver disease further when left untreated may complicate matters and lead to liver cirrhosis or hepatocellular carcinoma (HCC). (Rocio Torres Ibarra, 2006). According to the World health organization an estimated 350 million people are infected with HBV and about 170 million persons have HCV. (Sannat GmbH,2008, Rocio Torres Ibarra, 2006). The hepatitis B virus (HBV) and the hepatitis C virus (HCV) share common transmission pathways.(Mitre and Mendonça, 2007). Therefore, co-infection can be expected. However the exact number of HBV-HCV co-infectied individuals is unknown. But it is estimated that it is between 9% and 30 %, depending on the geographical region.( Rocio Torres Ibarra, 2006). Although a number of studies have evaluated small numbers of co-infected individuals. But due to non uniformity of assessment criteria, inclusion criteria, viral genotypes, epidemiology and ethnicity, the findings of these isolated studies cannot be used as conclusive evidence (Mitre and Mendonça, 2007). A co-infection with HBV - HCV is a more serious disease, and the risk of developing HCC is also increased than HCV infection alone. ( Rocio Torres Ibarra, 2006).
2. Case presentation -
A 28-year-old male old male patient was presented to the accident and emergency (A&E) department with severe abdominal pain, jaundice, and mental confusion. From his medical history, it was revealed that this person had history of intravenous drug abuse for many years. A physical examination of this patient revealed needle track marks on both arms. Indicative of an extended and excessive skin puncture with needles due to drug abuse (Center for Substance Abuse Treatment-USA, 2002).
Hepatitis serological tests were carried out on this patient as part of clinical investigation and the patient was admitted immediately. Serological tests were performed for HAV, HBV, and HCV. The results of the viral hepatitis testing were as follows:
Sex - Male , Age - 28 years
- Positive by enzyme immunoassay
Table 2.1- The diagnostic hepatitis serological test carried out on the patient and the results obtained. The various immunological tests carried out are HBsAg- Hepatitis B surface antigen test, IgM anti-HBc- Hepatitis B Virus Core Antibody- IgM a Qualitative CIA i.e. Chemiluminescent Immunoassay , IgM anti-HAV- Hepatitis A Virus Antibody-IgM a Qualitaitve CIA, Anti-HCV- Hepatitis C Virus Antibody by EIA i.e. Enzyme Immunoassay, HCV RNA- Hepatitis C Virus RNA Qualitative PCR ) (Baweja et al, 2003)
His condition improved gradually and he was given a discharged from the hospital with scheduled appointments. The discharge diagnosis was HBV infection and chronic HCV infection. (Table 2.1)
The patient after a period of eight months had a follow-up visit with the doctor. A hepatic diagnostic test was carried out again to check if the patient has shown signs of recovery. The results of test carried out at this visit were as follows:
- 500 mIU/mL
Table 2.2- The diagnostic hepatitis serological test carried out on the patient on the follow up visit and the results obtained. (HBsAg- Hepatitis B surface antigen test, Anti-HBs- Antibody to Hepatitis B Virus Surface antigen-a Quantative CIA, mlU/ml- milli International unity/ milli liter, HCV RNA- Hepatitis C Virus RNA Qualitative PCR) (Baweja et al, 2003)
3. Laboratory Analysis-
Liver disease is often diagnosed by investigating liver enzymes (LFT test), levels of bilirubin or disturbances in blood clotting. For the diagnosis of hepatitis virus, a hepatitis virus panel with a series of blood tests used to detect current or past infection byÂ hepatitis A,Â hepatitis B, orÂ hepatitis C. It can screen blood samples for more than one kind of hepatitis virus at the same time. Antigen andÂ antibodyÂ tests can help in the detection of each of the different hepatitis viruses. (pub med health). The initial laboratory evaluation for our patient was neither LFT nor blood tests but directly a laboratory analysis of his serum for hepatitis virus antigens was selected due to the emergency that the patient was brought into and the range of clinical signs shown by the patient and the fact that the patient had a history of drug abuse.(Garfein RS et al ,2004)
3.1 Serum Hepatitis test for testing antigens for HBV and HCV-
HBsAg was detected in subject's serum on performing ELISA on the patient's serum and the result was positive. (Washington Web case studies). The positive result for IgM anti-HBc by qualitative CIA i.e. Chemiluminescent Immunoassay, indicate the presence of core antigens of hepatitis virus. The initial testing rules out hepatitis A (HAV) in acute presentation; by performing the HAV antibody IgM test a qualitative CIA i.e. Chemiluminescent Immunoassay , which gave a negative result. The results for Anti-HCV antibody test done using EIA was positive again, indicative of presence of antibody for HCV in the serum. As a result of the positive HCV antibody result, the sera samples were further tested and a HCV RNA PCR for qualitative determination confirming presence of HCV, by RT-PCR testing, and the results were positive again confirming that the sera was infected with HCV.
3.2 Laboratory analysis carried after eight months-
Laboratory analysis for tests carried out on the patient after eight months was as follows, testing surface antigen of HBV- HBsAg by ELISA on the patient's serum and the result was negative. Suggesting the serum was cleared of the HBV surface antigens. Anti-HBs- Hepatitis B Virus Surface antibody a quantative CIA was performed and the result was 500 mIU/mL. This result idicates that the virus is cleared form the body and anti bodies have already been detected along with the total removal of surface antigens. A HCV RNA PCR for qualitative PCR was performed and it again confirmed the presence of HCV.
HBV belonging to the hepadnavirus family, is a non-cytopathic virus and contains a partially double-stranded DNA genome. (Joe Sasadeusz et al, 2011). This virus predominantly infects hepatocytes. HBV has two main antigens, an outer envelope containing hepatitis B surface antigen (HBsAg) and a core containing hepatitis B core antigen (HBcAg). The excess of HBsAg is produced as sub-viral particles which circulate in the blood and permit diagnosis of HBV in patient sera. A third antigen produced by HBV is hepatitis B 'e' antigen or HBeAg. This is secreted into the blood. HCV belonging to the flavivirus family, is a single-stranded, enveloped RNA virus. HCV RNA is translated by the host cell following infection of the hepatocyte and internalisation of the virus. (Joe Sasadeusz et al, 2011). In a co- infection, the core antigen of the HCV seems to affect the transcription of HBV and, as a result, its replication. This can be seen by previous reports. (Mitre and Mendonça, 2007) After clearance of HBV, HCV can persist, resulting in chronic hepatitis. Further causing an aggravated disease and increasing the risk of death. The chronologies of the infections also play a role in deciding which virus dominantes over the other. (Mitre and Mendonça, 2007). An inactive HBV and active HCV infection was seen in our patient after the second examination. This was due to undetectable HBsAg and detectable HCV RNA. (Mitre and Mendonça, 2007).
4.1 Serologic Response to Acute HBV Infection and Resolved HBV Infection -
The incubation period of HBV, is typically around eight to twelve weeks. Infection by HBV, there is a typical host response created to the virologic antigenic markers( Figure 4.1). The first marker to appear in the serum is HBsAg, which can initially be detected in serum from one to twelve weeks after infection. (Hoofnagle, 1981) About the time that the patient starts showing clinical symptoms, anti-HBc (antibody to hepatitis B core antigen) appears, primarily detectable as the IgM classÂ (IgM anti-HBc). (Hoofnagle, 1981). With the onset of clinical symptoms, patients will have increases in serum aminotransferase levels that reflect hepatic injury. Higher the vigor of the immune response observed, greater the hepatic damage caused (Lee, 1997). The IgM antibodies to the HBV core antigen gradually decline to untraceable amounts within six months, but the IgG antibodies persists indefinitely as a marker of earlier HBV infection. The results of laboratory analysis, show that the HBV infection was resolved. The HBsAg disappeares at about 3 to 6 months, often just prior to the detection of antibodies to hepatitis B surface antigen (anti-HBs). The presence of anti-HBs following acute infection generally indicates recovery and protective immunity against re-infection. (Aldershvile et al, 1980).
Figure 4.1- Graphical representation of appearance of virological markers of HBV and their serum titer concentrations. (Courtesy- David Spach et al,2006)
4.2 Serologic Response to Acute - Chronic HCV Infection -
After an exposure to HCV, it takes about 6-8 weeks to develop antibodies against it. Thus, the HCV EIA can fail to detect acute HCVÂ infection (Stramer, et al 2004). The diagnosis of the infection is infrequently made, primarily because more than 70% of patients having acute infections are asymptomatic. Though the clinical symptoms are not normally observed in acute stages in this infection, about 25% of all patients with acute HCV present with jaundice, and about 10-20% develop gastrointestinal symptoms like abdominalÂ pain, nausea, or vomiting. (Busch and Shafer, 2005). When a patient has a positive result for HCV EIA test, the primary objective is to determine whether they have chronic hepatitis C, this can be achieved by doing by testing for HCV RNA or by RIBA i.e. recombinant immunoblot assay.( Chevaliez S, Pawlotsky JM,2005) (Strader et al , 2004) (NIH Consensus Development Program for the management of Hep.C-2002). The normal course of algorithm used in the diagnosis of HCV is shown in Figure4.3. The HCV RNA test is more commonly used and preferably performed quantative assay. The positive test confirms the present of replicating virus in the body and provides the basiss for promt initation of pre- treatment evaluation, counseling and future course of action. (Figure 4.2 - serologic Pattern of Acute HCV Infection With ProgressionÂ to Chronic Infection.)
Figure 4.2-Serologic Pattern of Acute HCV Infection With ProgressionÂ to Chronic Infection. (Courtesy- Abbott diagnostics,Â 2011 Abbott Laboratories, U.S.A. )
A HCV RNA test sensible when a person has HCV risk factors, such as intravenous drug use, or they have an elevated ALT, as in the case presented above, since these people are very likely to have a positive HCV RNA test. Another advantage of RNA testing is that when positive, it also confirms the diagnosis of chronic hepatitis C.
Figure 4.3- Logarithm followed for the testing of HCV and Chronic HCV. (Courtesy- Pawlotsky,2002)
5. Treatment Options-
The damage caused to the liver and the hepatocytes cannot be repaired instantly. The infection from the body needs to be taken care of by stopping down or slowing down the replication of the virus. The mainstay of therapy for patients with a co-infection include is complex due to the interaction between both viruses, and between the host immune system. IFN is an immunomodulating drug, with antiviral and anti-proliferative effect, it is effective against HBV and HCV. It is also the most widely studied therapeutic option. The first study in co-infected individuals, carried out in the1990s, suggests that higher doses (9 MU 3 times a week) are more effective for the clearance of HBV or HCV. (Mitre and Mendonça, 2007).
Many practitioners prefer the wait-and-see approach others justifies treatment in most cases. Recurrence in this disease is common and remission is difficult to achieve. However, the results of two recent studies suggest that prolonged IFN therapy may halt viral replication and induce a high percentage of sustained response in patients. (Kaufman, 1997)
The suggestions on effective treatment for mono infected individuals and among others, have been defined by professional associations of liver researchers, such as the Asian-Pacific Association for the Study of the Liver, the European Association for the Study of the Liver, and the American Association for the Study of Liver Diseases. (Mitre and Mendonça, 2007).
Previous studies considering various parameters indicate that patients without cirrhosis are more responsive to interferon. Improved responses have been observed in patients with lower levels of circulating hepatitis C virus RNA.( Dusheiko,2003) A treatment of Interferon with ribaverin i.e. IFN + RBV, it is the treatment of choice.Co-infected individuals have a higher risk of evolution to cirrhosis if compared with mono-infected individuals (44% and 21%, respectively) as well as a higher risk of chronic hepatitis decompensation. (Mitre and Mendonça, 2007). Â
The Food and Drug Administration (FDA) of USA has approved a second antiviral drug, adefovir, to treat HBV infection. Adefovir, is a nucleotide analogue, is a pro-drug that undergoes phosphorylations twice in the cell to yield the active drug, it is an effective inhibitor of the viral polymerase. . (Mitre and Mendonça, 2007). Â Interferon, for many years, administration of interferon alfa (5 million to 10 million units subcutaneously three times per week, for at least three months) has been the mainstay of therapy, but due to numerous side effects its use has been replaced with using it with an antiviral drug like ribaverin or lamivudine. In case of further complications in the patient, a liver transplant with a proper HLA match would be a better option.