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The Hepatitis Viruses

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VOL: 97, ISSUE: 47, PAGE NO: 41

MAY McCREADDIE, BA, MEd, RN Education and Training Officer, Brownlee Centre, Gartnavel General Hospital, Glasgow

The liver is the largest organ in the adult body, weighing approximately 1.5kg, and plays a major part in regulating many body functions. It consists of two lobes, and lies in the right upper quadrant of the abdomen, under the diaphragm, extending to under the rib cage. The gallbladder lies under its inferior surface. The liver is composed of small lobules of hepatic cellular plates. Each plate is approximately two cells thick with biliary canaliculi running between them. On the inner surface lie the hepatic sinusoids. These are lined with cells (Kupffer's cells) that phagocytose (engulf and destroy) bacteria and other foreign products. The hepatic sinusoids receive blood from both the portal vein and the hepatic artery. Blood is then emptied from the hepatic sinusoids into the central vein and then into the hepatic vein. It is the liver's highly vascularised structure that enables it to carry out its multiple functions.

The liver is the largest organ in the adult body, weighing approximately 1.5kg, and plays a major part in regulating many body functions. It consists of two lobes, and lies in the right upper quadrant of the abdomen, under the diaphragm, extending to under the rib cage. The gallbladder lies under its inferior surface. The liver is composed of small lobules of hepatic cellular plates. Each plate is approximately two cells thick with biliary canaliculi running between them. On the inner surface lie the hepatic sinusoids. These are lined with cells (Kupffer's cells) that phagocytose (engulf and destroy) bacteria and other foreign products. The hepatic sinusoids receive blood from both the portal vein and the hepatic artery. Blood is then emptied from the hepatic sinusoids into the central vein and then into the hepatic vein. It is the liver's highly vascularised structure that enables it to carry out its multiple functions.

Functions of the liver
- It converts food into chemicals necessary for life and growth, and stores substances such as glycogen, iron and vitamins

- It synthesises proteins for circulation in the blood, and the factors that regulate blood clotting

- It processes drugs absorbed from the digestive tract into forms that are easier for the body to use

- It manufactures bile, which is essential for digestion

- It detoxifies and excretes substances that otherwise would be toxic to the body, for example, urea and bile.

Think Point: What do you think might be the signs and symptoms of liver disease?

As the liver plays a significant role in regulating body functions, any disease affecting it will, depending upon its severity, interfere with those functions to some degree. Despite the potential for disease causing great disruption to body functioning, the liver has tremendous regenerative capacity; for example, surgical removal of 75% of the liver would produce only minimal hepatic impairment: 80-90% of hepatic functioning would have to be impaired before liver failure (Crawford, 1997).

Liver diseases
The most common diseases of the liver are:

- Cirrhosis

- Disorders in children (for example, Wilson's disease, Reye's syndrome)

- Gallstones

- Alcohol-related liver disorders

- Cancer (hepatocellular carcinoma)

- Hepatitis, specifically viral hepatitis

Hepatitis
Hepatitis means inflammation of the liver. There are a variety of causes, including: viruses; drug side-effects; excess alcohol, and autoimmune hepatitis. Viruses are the most common cause.

Viruses
There are two types of virus that cause hepatitis: systemic and specific. Examples of systemic viruses are: cytomegalovirus, Herpes simplex virus, and Epstein-Barr virus (infectious mononucleosis). Occasionally, people who are immunosuppressed may have hepatitis as a result of rubella, adenovirus or enterovirus infections. Specific hepatitis viruses directly infect the liver cells (hepatocytes), causing inflammation and potential injury to the liver.

The pathophysiology of viral hepatitis (Fig 1)
Viruses causing hepatitis principally attack the hepatocytes, attach to them and replicate within them. Hepatocyte necrosis takes place when the replicating virus causes cytolysis (cell rupture and death) and when apoptosis (programmed cell death) occurs.

When the infected hepatocytes become necrotic, scavenger macrophages engulf the cells, creating clumps of inflammatory cells. Inflammation may be limited, or branch out into the functional area of the liver (the parenchyma). Inflammation is a feature of acute hepatitis.

In chronic hepatitis, the disease progresses: bridging necrosis may occur, whereby the necrotic hepatocytes and the macrophages join together. The resulting fibrosis (scarring and thickening of tissue) may cause hepatic lobules to adhere to each other.

A granulomatous (healing or regeneration) reaction may be prompted by invading organisms, foreign bodies or a variety of drugs. Alternatively, necrosis, regeneration and hepatocyte swelling may produce compression of the vascular sinusoids and the liver parenchyma. The continuing loss of hepatocytes, together with the development of fibrosis, will eventually result in cirrhosis, that is, permanent scarring.

Because of the liver's regenerative properties, liver injury may initially be masked so that in the early stages of infection and disease an individual may have few symptoms. Eventually, however, signs and symptoms will become apparent.

The hepatitis viruses
In the Western world today, viral hepatitis currently accounts for 10% of individuals with liver cirrhosis. There are currently five established hepatitis viruses, labelled from A through to E. There are two more, hepatitis F and G, but their characteristics and routes of transmission are as yet unclear - there is even doubt as to whether hepatitis F exists.

Hepatitis A virus (HAV) - picornavirus with single stranded RNA

Hepatitis A virus was identified in the 1970s and was originally thought to cause infectious hepatitis. Approximately 1.4 million people a year are now known to be infected (Winter, 1999). The incidence of HAV varies throughout the world, but it is more likely to be prevalent where sanitation and hygiene are poor.

Children in developing countries are likely to acquire immunity to the condition because of frequent exposure. While outbreaks of HAV still occur from time to time in the developed world, less than 10% of the population acquire immunity before the age of 20 (Caumes, 1996). For these reasons, HAV is often described as a travel disease, as travellers are at potentially greater risk of exposure.

Transmission

HAV is a waterborne virus that is transmitted chiefly via the faecal-oral route. Shellfish growing in sewage-polluted waters and then eaten, or food such as fruit or salad materials washed in contaminated water before being eaten, are examples of ways infection may be transmitted. The infectious fluids for HAV are faeces, saliva, semen and blood. (An infectious fluid is one that contains enough of the virus for an individual exposed to that fluid potentially to become infected.)

Think Point: Were you at risk from HAV the last time you were on holiday abroad? Did you consider being vaccinated or was vaccination not recommended for your particular destination?

Signs, symptoms and diagnosis

The incubation period of HAV is 15-40 days (average 25 days). Diagnosis is via clinical examination and detection of IgM anti-HAV in the serum. High titre levels of IgM anti-HAV antibodies indicate recent infection. IgG anti-HAV indicates immunity following exposure, which may be useful for individuals wishing to travel to areas where HAV is endemic (Caumes, 1996).

Many individuals infected with HAV are asymptomatic. This presents something of a public health problem as these individuals have the potential to infect others. In those who do develop symptoms, a general flu-like illness with accompanying fever, chills and general malaise may be present. Additional symptoms of nausea, anorexia, dark urine, light coloured stools, abdominal pain and fatigue may be present. Jaundice (yellowing of the eyes and skin) may well be the first symptom that prompts an individual to visit his/her GP. The virus is excreted in the faeces for approximately two weeks before the onset of jaundice to one week after its appearance. The risk of transmission is therefore greatest at these times (Brooks et al., 1991). Good handwashing technique, particularly when handling food, is crucial in preventing the spread of HAV (Chin, 2000).

Prognosis and treatment

Because hepatitis A does not result in chronic infection there is no long-lasting liver damage. While some people are asymptomatic, others may have mild flu-like symptoms. Some individuals may be quite ill for some time, with full recovery taking up to a year. A smaller number may require hospitalisation while, rarely, a fulminant acute hepatitis may result in death (0.1%).

There are no specific treatment recommendations for HAV, but because fatigue is common, bed rest may be recommended. A low fat, high carbohydrate and protein diet is recommended. Supplementary vitamins are not suggested unless a need is indicated, for example, if a patient has a co-existing alcohol problem. Most physicians recommend abstinence from alcohol during the recovery period, which may take up to a year, but there is no evidence to suggest that this is necessary.

Hepatitis B virus (HBV) - hepadnae virus with a single-stranded DNA

HBV is the most common chronic infectious disease in the world, with 350 million carriers worldwide (Maynard, 1990). Until the advent of blood screening and heat treatment/recombinant factors, HBV used to be a major cause of post-transfusion hepatitis. In the developing world, HBV continues to be a major problem owing to no vaccination programmes, little or poor blood screening and limited access to barrier contraception. The prevalence of HBV in the UK is in the region of 0.1% (DoH, 2000).

Transmission

HBV is a bloodborne virus, and has the highest infectivity of the bloodborne viruses. The other infectious fluids are semen, vaginal secretions, breast milk and saliva. An infected mother can pass the virus to her baby in the womb or during delivery. HBV can be transmitted sexually and there were reports in the early 1990s of HBV infection being common in homosexual men. However, it seems that it is not as common as was previously thought - there have been only 50-60 reported infections in homosexual men in England and Wales each year since the 1990s (DoH, 2000).

Signs, symptoms and diagnosis

The incubation period of HBV is from 6-25 weeks (Zuckerman and Harrison, 1995). Primary infection can be asymptomatic, but has a mortality rate of 0.2-2% (Raj, 2000). As the infection persists in 5-10% of adults infected with HBV, there is the potential for liver disease: up to 40% of long-term carriers may die from liver-related problems. Cirrhosis and hepatocellular carcinoma are linked with those chronically infected, even though they may be asymptomatic.

The signs and symptoms of HBV are not dissimilar to those of HAV, with anorexia, malaise, nausea, vomiting, and abdominal pain all featuring to some degree. One significant difference, however, is that jaundice is relatively uncommon.

Diagnosis of an HBV infection is made by a blood test. The test is designed to look for antigens (viral particles) (Table 1) and antibodies to these (Table 2). The course of an HBV infection is shown in Fig 2.

Prognosis and treatment

The onset of HBV is usually insidious and causes both acute and chronic hepatitis. The prognosis depends upon the individual's age of acquiring the virus, the person's gender and immune response (Collier and Oxford, 2000). The longer the person has the virus the more likely there are to be lasting effects: chronic infection occurs in 5-10% of infected adults; 25-50% of infected children aged 1-5, and 70-90% of infected infants.

Approximately 50% of patients develop acute symptoms lasting from 1-4 weeks, although some people may take over six months to recover. On average, 20% of patients develop jaundice. Acute liver failure from HBV is rare but in such cases the mortality rate exceeds 50%.

Think Point: Consider the situation regarding vaccination for hepatitis B in your local area. Who gets vaccinated? Which groups are given 'free' vaccination and who needs to pay to be vaccinated?

Hepatitis C virus - flavi virus with single-stranded RNA

There are an estimated 190 million cases of HCV worldwide, with approximately 3% of the world's population infected (WHO, 1997). Some areas of the world have a higher prevalence than others. Egypt, for example, has a 16% prevalence rate among the general population as a result of a mass vaccination programme in which needles were reused. Elsewhere, injecting drug users appear to be the individuals most likely to be infected with HCV, although the prevalence rate among these people appears to have dropped since the introduction of needle exchanges in the UK in the late 1980s. Despite that, the prevalence rate among this group is approximately 70% (DoH, 2000). Similarly, because of the high number of injecting drugs users who enter prison, and the continuation of injecting in prisons, approximately 70% of prisoners are known to be HCV positive.

Transmission

HCV is found in most body fluids, but it is present in sufficient quantities to infect an individual only in blood, vaginal secretions and semen. In addition, infected mothers can potentially transmit the infection to their baby in the womb or during childbirth. Breast milk is not infectious for HCV, although cracked or bleeding nipples would be a contraindication for breastfeeding. Injecting drug use is the major route of transmission for HCV (DoH, 2000).

HCV is not a recognised sexually transmitted infection (STI), but it can be sexually transmitted. Approximately 5% of any HCV positive group will have been infected in this way (Neumayr et al., 1999). The presence of an STI plus HCV will increase the risk of HCV being transmitted via sexual intercourse (Alter et al., 1999).

Think Point:

If injecting drug use is the major route of transmission for HCV, how could that particular pool of infection be reduced?

Signs, symptoms and diagnosis

HCV positive patients may be asymptomatic for 20-30 years. In the interim they may experience vague symptoms such as occasional anorexia, malaise, nausea, vomiting, and abdominal pain. There may also be some general viral symptoms of night sweats, vivid dreams and fatigue. Repeated trips to the GP and/or hospital may have revealed very little. Equally, some patients experience very few symptoms until their condition is more advanced and then seek medical opinion.

The 'window period' (seroconversion) for HCV is 3-6 months. Blood is tested for antibody to HCV (anti-HCV) by an enzyme-linked immunosorbent assay (ELISA) test. A polymerase chain reaction (PCR) test is then used to confirm the presence of circulating virus. The PCR test detects the presence of viral RNA. An ELISA test result can be obtained in 24 hours, but it can take two weeks before the results of a PCR test are known. This may create difficulties when patients are being tested for more than one virus.

Prognosis and treatment

The prognosis of someone who is HCV positive is largely dependent on whether or not he/she has circulating virus. Eighty per cent of people who are anti-HCV are also PCR positive. These individuals are believed to be the most likely to develop liver disease as a result of circulating virus. Currently, the 20% who are anti-HCV but PCR negative are advised to be re-tested on a yearly basis. The rationale behind this is the uncertainty over whether the virus remains dormant in tissue and therefore is undetectable in the PCR test. It does not appear, however, that PCR negative patients have any signs or symptoms of disease related to their hepatitis C.

The 80% of people who have chronic infection may be eligible for treatment (Collier and Oxford, 2000). Patients eligible for treatment must be willing to have a liver biopsy in order to establish the extent of any liver disease pre- and post-treatment. Mild and moderate/severe chronic hepatitis is usually determined on liver biopsy, with 20% of those chronically infected (80%) showing cirrhosis. Of those 20%, some will have decompensated cirrhoses and liver failure with 2-3% showing signs of hepatocellular carcinoma. Prior to a liver biopsy an HIV test is performed. A patient's HIV positive status would take precedence over any impending HCV treatment. Individuals who are infected with both HIV and HCV can be treated for both diseases, but only after a full assessment is made.

Hepatitis D virus (delta virus) - unclassified viroid-like entity with RNA with enveloped particles, that is, an incomplete virus

The hepatitis D virus cannot replicate without the assistance of another virus. In humans, hepatitis D virus can occur only in the presence of hepatitis B (Timbury, 1997). In all cases, the presence of this second infectious agent suggests a worse prognosis.

Hepatitis E virus - calci virus with single-stranded RNA

HEV is similar to HAV in that it causes self-limiting disease. It is also spread by similar means, that is, it is waterborne via the faecal-oral route. HEV is, like HAV, principally a disease of developing countries where faecally contaminated water is either drunk or ingested. Cases of HEV are relatively rare in the UK, as there is generally good sanitation and hygiene; the condition is much more likely to be seen in travellers returning from areas abroad where HEV is endemic. In India and Pakistan, HEV causes a significantly high mortality rate in pregnant women, unlike HAV (Collier and Oxford, 2000).

Hepatitis F virus - structure unknown

Researchers/clinicians have reported on a number of viral hepatitis cases, both post-transfusion and sporadic, which failed to be ascribed to the A, B, C, D, or E hepatitis virus (Timbury, 1997). Following this, various investigators reported the discovery of a new hepatitis virus, calling it hepatitis virus F (Winter, 1999). This 'new' virus, however, has never been fully confirmed by subsequent research, leaving it unsubstantiated as a true virus. It is possible that HFV is either a mutant of HBV or one of the many sub-types of HCV.

Hepatitis G virus or GB/C or GBV-C - flavi virus

HGV was eventually fully characterised as a virus in 1996 following its initial discovery in 1994/95. It is thought to be a distant relative of HCV. Modes of transmission are similar to those of other bloodborne viruses, that is, via blood and blood products (including injecting drug users), and from mother to child. Whether sexual transmission is possible is unclear. While HCV and HGV co-infection is common, this is more likely to be due to a common source of infection.

The clinical impact of HGV is uncertain; there are some suggestions that HGV is effectively a commensal organism; that is, one that causes little or no harm. There have been suggestions that the liver is not the primary site of replication for HGV and that HGV may not even be a true hepatitis virus.

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