Hep C Review - Edition 30

Table of Contents - September 200

Contributions from Council members and the public are welcomed. Other than for editorial comment, views expressed in The Hep C Review are therefore not necessarily those of the Hepatitis C Council of NSW. Neither are the views expressed within this magazine necessarily those of our primary funders.

Cover stories: National hepatitis c strategy out of the blocks but NSW plans nowhere to be seen

The world's first National Hepatitis C Strategy was welcomed by Australian community groups and health professionals alike following its launch in Brisbane in late June. Hard on its heels came the publication of the companion report Hepatitis C - Informing Australia's National Response - a series of commissioned papers summarising the full range of hepatitis C research.

But despite completion in early 2000 of the development of two key New South Wales planning documents, the NSW Hepatitis C Strategy and the NSW Care and Treatment Services Plan have yet to see light of day.

Developed alongside the welcome national strategy, the NSW Hepatitis C Strategy will serve to assist strategic planning in the state's seventeen area health services and in NSW correctional settings. And the care and treatment services plan will help guide detailed and improved hepatitis C service delivery in all NSW health jurisdictions.

The Hepatitis C Council was a key player in representing affected people in the development of these vital resources. We look forward to their final endorsement and release by Health Minister Craig Knowles, so that much needed local planning can be guided and services improved

Editorial: Rationale for trialing a Medically Supervised Injecting Centre in Kings Cross
by Ingrid van Beek

In August 2000 the Uniting Church was granted the licence to establish Australia's first Medically Supervised Injecting Centre (MSIC). The recruitment and training of staff and the refurbishment of the building have commenced and it is hoped that this most controversial recommendation of the NSW Drug Summit will be up and running before the end of the year.

History

Kings Cross has been the epicentre of the sex and drugs industries in Australia for the past 3 decades, and as a result, there is a population of drug users who consider Kings Cross their home base. Even long before this, Kings Cross was host to the "Razor Gangs" involved in cocaine use as early as the 1930s, and Woolloomooloo and East Sydney were the first home of Australia's sex industry at least 2 centuries ago!

From the early 1990s an increasing number of commercial establishments on Darlinghurst Road in Kings Cross started to rent rooms, otherwise used for casual/commercial sex and/or to watch sex videos, to drug users on a 15 to 30 minute basis for the purpose of injecting illicit drugs. In 1997 the Royal Commission into the NSW Police Service found that some of these establishments were also involved in the supply of illicit drugs.

Patterns of drug use

While some very significant drug suppliers who operated through these illegal "shooting galleries" were removed from the local scene as a result of the Wood Royal Commission into the NSW Police Service, lower level, street-based dealers from other areas filled the void almost overnight. At the same time the injecting drug use which had occurred in these shooting galleries was also returned to the streets and parks.

While the levels of supply or use of illicit drugs in Kings Cross did not increase or decrease following the Royal Commission, what changed was that both drug dealing and drug injecting moved from these private situations back to more public places resulting in a reduction in the amenity of the local area and a perception that drug supply and use was escalating.

Call for safe injecting rooms

Appreciating the public health and public order impact of public drug injecting, the Royal Commission's final report recommended that "consideration be given to the establishment of safe, sanitary injecting rooms under the license or supervision of the Department of Health, and the amendment of the Drug Misuse and Trafficking Act 1985 accordingly".

In 1997 the NSW Government established a Joint Select Parliamentary Committee into Safe Injecting Rooms to investigate this recommendation.

The Committee visited several Sydney suburbs, and a number of rural areas to speak to members of the community, health workers, and drug users. A subcommittee of the Committee also visited five injecting rooms and held discussion with key stakeholders in Europe. The Committee received 103 submissions and took formal evidence from 89 witnesses.

Just over half of the written submissions supported the establishment of injecting rooms and a large majority of the expert witnesses testified in favour of the proposal. In particular, most key witnesses representing the various sectors in Kings Cross testified in support of the idea. But in the end, the majority of the Committee (6 of the 10 members) didn't recommend the establishment such premises in NSW.

Local reaction

Meanwhile telephone surveys among more than 300 residents of Kings Cross, undertaken in 1997 and 1998 by the National Centre in HIV Epidemiology and Clinical Research to measure the community impact of K2, a satellite needle syringe service of the Kirketon Road Centre located in central Kings Cross, demonstrated a rise in their experience of public drug injecting and associated inappropriately discarded needle syringes.

At the same time, they also registered increasing support for the establishment of injecting rooms in the area from 69 to 76%. The report of the polls (State Health Publication No (AID) 990158) stated that: "There was overwhelming support for injecting rooms and much criticism of the findings from the Parliamentary Inquiry into Safe Injecting Rooms. Community group members repeatedly asked why injecting rooms have not been implemented, particularly in areas of high drug use".

The injecting room proposal was raised again during the NSW Drug Summit, an initiative of the NSW Government held in May 1999. One of the 172 resolutions passed by the Drug Summit was that a Medically Supervised Injecting Centre (MSIC) be trialed in NSW. It was subsequently proposed that this trial be undertaken in Kings Cross and legislation was then passed to enable its establishment for a period of 18 months.

Site assessment

In December 1999, following the withdrawal from involvement of the Sisters of Charity Health Service the NSW Government accepted a proposal from the Uniting Church to establish the facility. The Uniting Church then invited key stakeholders to join a Community Consultation Committee to continue the process of site selection already begun by the Sisters of Charity. This Committee included representatives of local residents, drug users, their families, business, health and social welfare services, police, local and state government.

A total of 39 sites were assessed by the Sisters of Charity and then the Uniting Church from mid-1999 until 25 February, when the Uniting Church announced that it had leased premises at 66 Darlinghurst Road Kings Cross for the 18 month trial.

This choice of site was further supported by ambulance attendance data, which indicate that among 677 ambulance call outs to fatal and non-fatal drug overdoses in the Kings Cross area during 1999. More than 90% (621) of these were within 300 metres of the site at 66 Darlinghurst Road and 54% (335) were to drug users who had overdosed on the street outside or in premises actually located on Darlinghurst Road. This Ambulance Service data confirms that to site the MSIC anywhere away from Darlinghurst Road would significantly lessen its ability to meet its stated goal of reducing the rate of fatal and non-fatal drug overdoses in the Kings Cross area.

In May 2000 the Uniting Church commissioned Australian National Opinion Polls (ANOP) to conduct a telephone poll of local residents and businesses to measure the level of "in principle" support for the establishment of an MSIC and at the 66 Darlinghurst Road site in particular.

The poll measured 71% support for the establishment of an MSIC. Meanwhile 68% of the respondents agreed with the proposed site at 66 Darlinghurst Road or it didn't matter to them. The main reason for supporting the site was because of the perceived proximity to drug users and therefore accessibility to those in need. The centrality of the location and the fact that it is not in a residential area were secondary reasons. Disagreement reduced by more than half (from 32% to 15%) when assured that the facility would operate in a way that is discreet and not obvious to passers by. The precedent of operating such services in a discreet way has already been established by K2, also on Darlinghurst Road; only 21% of local residents were even aware of the service's existence after 12 months of operation (1998 poll).

Meanwhile a recent survey at K2 indicated that there was also a high level of preference among the local IDU population (71% of respondents) to have used such a facility for their last drug injection.

The MSIC trial's rigorous and independent evaluation is designed to assess whether MSICs are an effective strategy to reduce fatal and non-fatal drug overdoses, transmission of blood borne infections, and the "nuisance" associated with public injecting while increasing IDUs' access to drug treatment. It will also inform future decisions to trial this strategy in other parts of NSW and Australia.

Ingrid van Beek is Medical Director of the Uniting Church's Medically Supervised Injecting Centre, Kings Cross, Sydney, NSW.

Letters to the Editor:

Injustice of regional treatment system

I'd like to comment on Margaret's above titled story on page 18 of Edition 29.

I'd agree, judging from stories I've heard from colleagues and specialist clinicians that many GPs still aren't aware of the treatment available, nor the "workup" they need to do with patients before referring them.

Research on nurses' attitudes (Huntley, England et.al. unpublished, in print) found that a degree of discrimination against people with Hepatitis C Virus was not uncommon amongst nurses.

Margaret highlights this attitudinal problem in her letter. So in addition to health care worker education, and health care worker ownership of Hepatitis C Virus issues, we clearly need some of the education to target 'attitudinal adjustment'.

Perhaps, to quote the recent NSW public awareness campaign, "understanding is the answer"!

Regards,
Helen [an Hepatitis C Virus related health care worker]

Dry mouth suggestions

Following on from Wayne Sherson's article on dry mouth in Hep C Review (Ed28, pg18), we have tried a product "Oral Balance Moisurising Gel" which is a long lasting lubricant that soothes and protects dry mouth tissues. It contains salivary enzymes to help inhibit bacterial growth and to neutralise odour.

Prior to retiring at night, the gel is placed on the tongue and rubbed over the mouth cavity. The film moisturises for up to 6-8 hours.

The American manufacturers "Biotime" also produce a dry mouth toothpaste and a dental chewing gum, neither of which we have tried yet.

Regards,
Buzz Cutts (Social Worker, Bigge Park Centre, Liverpool, NSW)

News & other articles:

Rapid opiate detox therapy (RODT)

The Sydney Morning Herald (16/6/00) reported the death of a young hepatitis C positive woman while undergoing ROD therapy involving naltrexone.

Clinical advice has confirmed that, generally speaking, naltrexone is not contra-indicated (advised against) in the case of people with hepatitis C.

In excessive doses, though, the product can cause hepatocellular injury (liver damage) and it is contra-indicated in the case of people with liver failure or any type of acute hepatitis (the initial 6 month phase of a viral hepatitis infection).

Good news on health cover

We've had a significant number of callers to the Hep C Helpline asking about private health cover.

In regard to the commonly asked question "do I have to tell the health fund I have Hep C?" the answer is yes. Hepatitis C is a pre existing condition that the health fund needs to know about.

Four major health funds contacted by the Council have confirmed that people with hepatitis C would be offered private health coverage with no difference in the premiums they would pay (annual cost).

As with all people taking out cover, there would be a 12 month waiting time when a health fund would not cover any Hepatitis C Virus related costs.

If anyone feels they have been treated unfairly or have a complaint they can contact the Private Health Insurance Ombudsman on (02) 9261 5944.

Hep C illness - outside the liver
By Paul Harvey

In considering the possible impact of hepatitis C on our health, we should first question our definition of good health.

Some clinicians suggest that good health is not so much a specific state such as "absence of disease or illness". They believe that good health is an overall approach: one that accommodates a certain level of illness as normal and has people working positively towards overcoming the physical and emotional problems caused by disease (Lorig et al.). This is quite a useful approach when considering that most people will develop some type of chronic illness in their life.

Our complex biological system

An additional issue before examining the possible impact of hepatitis C on health is consideration of the incredibly complex biological nature of our bodies.

Modern technologies are forever changing our world but they remain crude in comparison to the fantastic interaction of electrical, chemical and biological processes that exist within us. Given this level of complex interactions, it is not unusual that a disease most noticeably causing illness in one major organ or body system will have some level of impact on other parts of the body.

Non-liver Hepatitis C Virus illness

Studies suggest that hepatitis C related fatigue is not primarily related to actual liver disease but is linked either to disorders of the immune system (Eur J Gastro Hept 1999 Aug;11(8):833-8) and (Am J Gastro 1999 May;94(5):1355-60), or to altered neurotransmission (brain tissue) function (Lancet 1999 Jul 31;354(9176:397).

The most commonly reported symptom of hepatitis C is fatigue. Clinicians are yet to confirm if this is an extrahepatic condition (an illness affecting parts of the body other than in the liver), or if it is related to actual liver damage (see p16). Aside from fatigue and possible complications of actual liver damage, hepatitis C infection has comparatively little impact on the rest of our body - although several conditions have been observed. Of the range of other health conditions linked to hepatitis C, some have been observed and well documented by clinicians (see below), while the occurrence of many others have been noted in only a small number of cases and may yet be explained as simple coincidence.

The publication Hepatitis C: a management guide for general practitioners (Aust Family Physician 1999;28 SI:27-31) recently listed a range of Hepatitis C Virus extrahepatic conditions (right). Many of these are reported in this edition of The Hep C Review by Dr Bryan Speed (page 12), Dr Tony Jones (page 16), Doug Mellors (page 29), Dr Ed Gane (page 30) and Tina Pirola (page 34).

Arthralgia
Cyroglobulinaemia
Diabetes melitis
Glomerulonephritis
Lichen planus
Non-Hodgkin's lymphoma
Peripheral neuropathy
Porphyria cutanea tarda
Sicca syndrome
Sjogren's syndrome
Thrombocytopaenia
Thyroid disorders
Vasculitis

Summary

The majority of all people in our culture experience chronic illness at some point in their life. So although it's great to have good health, it's probably unreasonable to expect to have perfect health.

In a small number of cases, hepatitis C can cause imbalance and illness in various parts of the body - other than the liver. Given the complexity of our bodies, the fact that such extra hepatic Hepatitis C Virus conditions can occur should not be seen as abnormal.

These "extra hepatic conditions" are not necessarily serious and properly diagnosed and treated, they should not cause alarm if they occur. Certainly, they do not warrant unnecessary anxiety.

If anyone suspects they may be experiencing extra hepatic conditions, they should consult their GP and if necessary, ask for referral to a hepatologist or other hepatitis specialist. Prior to such consultation, people should do a "work up" with their doctor; ie. noting the frequency of possible symptoms and having any relevant blood tests done.

Paul Harvey is Special Projects Officer with the Hepatitis C Council of NSW.

Hepatitis C as a cause of conditions and symptoms beyond the liver
By Dr Bryan Speed

Hepatitis C and the liver

After a person becomes infected with hepatitis C, the virus gravitates to and multiplies in the liver. Of the 85 or so per cent of people who become persistently infected, 60 to 70 per cent will develop chronic hepatitis; over 10 to 20 years 10 to 20 per cent of these people (that is, 5 to 12 per cent of all infected people) will develop cirrhosis and a few per cent will develop liver cancer.

Despite these effects on the liver, many infected people will remain well for many years; some may never become ill. One study from the United States was not able to show any increase in overall mortality in a large group of hepatitis C-positive people. The main reason for the different predictions being reported in the medical literature lies in the fact that different populations of hepatitis C-positive people are being studied: those being studied in specialist liver clinics are often already unwell, whereas the majority in the general community are otherwise well.

Although hepatitis C's effects on the liver are the most visible, the virus can affect other body systems and organs. This results in what are usually referred to as extra-hepatic conditions, or manifestations, of hepatitis C. This article explores and attempts to explain these extra-hepatic, or 'non-liver', conditions, which are gaining increasing attention.

Hepatitis C and extra-hepatic conditions

In recent years it has become apparent that hepatitis C can cause problems in ways that are unrelated to its effects on the liver. So far, the virus has been implicated in disturbances of most of the body's organ systems, and up to 50 related conditions have been reported. Fortunately, most of these conditions are rare and their effects often mild. Some of them are probably related to hepatitis C; others are probably not and have occurred by chance in a few individuals.

As with hepatitis C-related liver disease, the frequency of people having significant problems with extra-hepatic hepatitis C is open to debate: it depends on the group in the study, and if the study subjects come from a specialist clinic it is probable that the frequency of the problems will be overestimated.

Nevertheless, a recent study by Cacoub and others, who followed 1202 hepatitis C-positive patients at a specialist clinic, showed that 74 per cent had at least one clinical (that is, symptomatic) extra-hepatic manifestation. The majority were, however, just symptoms (what the person felt), as opposed to actual diseases, so the figure is probably an overestimate. A similar study of hepatitis C among the general population is yet to be undertaken.

In addition to depending on the nature of the study group, the occurrence of a condition generally depends on the duration of hepatitis C infection: the longer the infection has been present, the more likely it is that one of the extra-hepatic conditions will develop.

How does hepatitis C produce these extra-hepatic conditions?

The way hepatitis C produces extra-hepatic conditions is the subject of continuing research. It appears, however, that in most instances the virus manipulates the immune system in a variety of ways.

Hepatitis C infection of lymphocytes (a form of white blood cell) has been connected with the development of cryoglobulinaemia, kidney disease and lymphoma. In some other conditions, hepatitis C induces the immune system to produce auto-immune antibodies, which direct themselves at the body's own tissues. This seems to explain how the virus produces thyroid and blood disorders. Some of these conditions can even be triggered by interferon, a drug used for treating hepatitis C infection.

The list below outlines several of the better known extra-hepatic conditions.Two of these - autoantibodies and painful joints - are not actual diseases; rather, they are irregularities detected when people had their blood tested (auto-antibodies) or were asked to answer questions about their symptoms (painful joints).

Table 1 Extrahepatic diseases and syndromes linked with Hepatitis C Virus (listed in order of evidence for association).

Table 1 lists conditions in order of the strength of available scientific evidence for each particular extrahepatic condition. Those with the most convincing evidence are cryoglobulinaemia, glomerulonephritis and porphyria cutanea tarda. These are described in detail in seperate articles in this edition of The Hep C Review. Some of the others which have less definite evidence are described below:

Lichen planus

Lichen planus is a rare condition characterised by flat, pigmented itchy patches on the skin. It is connected with liver disease, which is probably why hepatitis C has become implicated. It is not yet known whether interferon is useful in treating the condition.

Diabetes mellitus

Diabetes mellitus is a chemical disorder caused by lack of the hormone insulin, which controls the body's sugar levels. Several researchers have found an increased rate of diabetes in people with advanced hepatitis C-related liver disease (cirrhosis).

This association appears to occur in up to half of such cases and is complicated by the fact that diabetes and cirrhosis are also associated. Nevertheless, more recent research, which was designed to avoid these complexities, has confirmed that hepatitis C does seem to be specifically related to the development of diabetes in some cases. Interferon treatment also appears to trigger diabetes, possibly unmasking a tendency already caused by hepatitis C.

Although diabetes can be successfully treated with diet, tablets or insulin injections, it is not clear whether interferon will help when hepatitis C and diabetes are present together.

Thrombocytopaenia

Platelets, which are tiny blood cells, play a critical role in blood clotting to stop bleeding after injury. Thrombocytopaenia, which is occasionally connected with hepatitis C infection, occurs when the number of platelets is reduced; in this situation the probability of excessive bleeding increases. Most hepatitis C-related cases of thrombocytopaenia are mild and respond to treatment.

One of the main reasons for thrombocytopaenia is the development of antibodies directed against platelets, which causes them to be removed from the blood by the immune system, as if they were infectious organisms. Hepatitis C has been associated (connected) with the development of anti-platelet antibodies and thrombocytopaenia in up to 41 per cent of people with chronic hepatitis C-related liver disease. The virus itself was also detected in the platelets of many cases.

Treatment of hepatitis C with interferon can sometimes cause thrombocytopaenia, so a person's platelet count should be checked before treatment is started.

Conclusion

Although hepatitis C's effect on the liver remains the most important consideration, the virus is also implicated in many extra-hepatic conditions and is probably the cause of some. Most such conditions are, however, rare and many are still the subject of investigation.

Although it is early days, it is possible that treating hepatitis C-related liver infection with interferon and the newer drugs will also treat extra-hepatic conditions and possibly even prevent them.

Dr Bryan Speed works with the Infectious Diseases Unit at the Austin and Repatriation Medical Centre, Heidelberg, Victoria. This article abridged from the original, reprinted with thanks from the Australian IV League's magazine, Hepatitis See April 2000: Issue 5.

Fatigue associated with chronic hepatitis C

In line with our theme of extrahepatic Hepatitis C Virus manifestations, E. Anthony Jones writes for The Hep C Review, helping clarify the common question: is Hepatitis C Virus fatigue a result of liver impairment, or are there other factors causing it?

Introduction

Many people with chronic hepatitis C develop severe fatigue that seems to be out of proportion to their general condition. The degree of fatigue does not appear to be related to the activity of the chronic hepatitis.

In people with chronic hepatitis C, fatigue can be the main symptom, and is often the only symptom. It is a major determinant of their quality of life. Accordingly, it is important to determine the cause of fatigue, because such information will facilitate the development of effective treatments.

A major problem in studying the effectiveness of new treatments for fatigue is that it is a perception and, consequently, subjective (one person's opinion). Therefore, fatigue is difficult to measure. Attempts are being made to overcome this problem by developing scales or scores of fatigue that employ objective criteria (things that are measurable). To establish the effectiveness of a new therapy for fatigue it is necessary to compare the effects of a treatment and a placebo (dummy treatment) on an objective assessment of fatigue. In such a trial patients would be assigned to receive the treatment or placebo by chance with both the physician and the patient being unaware of the nature of their medication until the study has ended.

Fatigue

In addressing the problem of fatigue, peripheral fatigue should be distinguished from central fatigue.

Peripheral fatigue occurs during prolonged exercise in working muscles and is unlikely to be particularly relevant to the fatigue experienced by most patients with chronic hepatitis C.

Central fatigue, on the other hand, occurs as a consequence of changes in the brain. The question arises whether altered function of the brain in patients with chronic hepatitis C contributes to fatigue.

Causes of fatigue in chronic hepatitis C

Accumulating evidence suggests that certain complications of chronic liver disease are associated with altered transmission of nerve impulses in the brain.

For example, pruritus (itching), which may complicate chronic hepatitis C, is associated with increased transmission of nerve impulses triggered by opioids (the body's own substances that have morphine?like effects), and poor concentration and sleepiness (which may occur as a late complication of chronic hepatitis C). Puritis is also associated with increased suppression of the activity of neurons (brain cells) as a consequence of enhanced inhibitory effects of the simple amino acid GABA (gamma?aminobutyric acid) on transmission of nerve impulses.

Increased transmission of nerve impulses triggered by opioids in chronic hepatitis C may affect transmission of nerve impulses triggered by substances other than opioids. One of these additional substances that trigger nerve impulses is serotonin (5?hydroxytryptamine, 5?HT). Indeed, relief of itching in patients with chronic liver disease has been reported following administration of ondansetron into an arm vein. Ondansetron counteracts some of the nerve impulses triggered by serotonin by occupying a subtype of receptors for serotonin that are found on certain neurons. This finding suggests that this complication of chronic hepatitis C (itching) is associated with increased transmission of nerve impulses triggered by serotonin.

Thus, altered transmission in serotonin pathways may occur in chronic hepatitis C and may contribute to behavioural complications of this disease, that may include fatigue. Accordingly, it is necessary to consider whether altered transmission of nerve impulses in serotonin pathways could contribute to fatigue associated with chronic hepatitis C. Three reports in the medical literature suggest that this could be the case.

Firstly, the time that active male athletes could exercise on a bicycle for measuring exercise was significantly less after the administration of paroxetine (a drug that increases transmission of nerve impulses triggered by serotonin), than after administration of a placebo. The results could not be explained by extraneous effects of paroxetine on body functions. Paroxetine, which is used to treat depression, acts centrally on the brain. The authors of the study concluded that there may be "a central (brain) component to fatigue which is mediated by the activity of serotoninergic neurons (brain cells triggered to transmit nerve impulses by serotonin)".

Secondly, in studies involving rats, fatigue during extended periods of exercise was reported to be related to indices of transmission of nerve impulses in the brain triggered by serotonin.

Lastly, a woman with chronic hepatitis C and profound fatigue was reported to become completely free from excessive fatigue when treated long-term with ondansetron 4 mg twice daily. While taking the drug she was able to work more efficiently and for longer hours.

Possible treatments?

The results of these three studies suggest that altered transmission of nerve impulses triggered by serotonin contributes to (central) fatigue originating in the brain. In particular, the findings in the case study suggest that altered transmission of nerve impulses triggered by serotonin - in neuronal pathways in the brain on which a specific subtype of serotonin receptors are located - contributes to the profound fatigue that commonly occurs in patients with chronic hepatitis C. Excessive fatigue associated with chronic hepatitis C may be amenable to effective treatment with drugs that act specifically on the serotonin system in the brain and alter transmission of nerve impulses triggered by serotonin. A controlled trial of oral ondansetron therapy for fatigue in patients with another chronic liver disease, primary biliary cirrhosis, has been initiated in Toronto, Canada.

References

1. Barkhuizen A, Rosen HR, Wolf S, Flora K, Benner K, Bennett RM. Musculoskeletal pain and fatigue are associated with chronic hepatitis C: a report of 239 hepoatology clinic patients. Am J Gastroenterol 94: 1355?1360; 1999.

2. Goh J, Coughlan B, Quinn J, O'Keane JC, Crowe J. Fatigue does not correlate with the degree of hepatitis or the presence of autoimmune disorders in chronic hepatitis C infection. Eur J Gastroenterol Hepatol l l: 833?838; 1999.

3. Elkins LE, Krupp LB, Scherl W. The measurement of fatigue and contributing neuropsychiatric factors. Semin Clin Neuropsych 5: 58-61; 2000.

4. Jalan R, Gibson H, Lombard MG. Patients with PBC have central but no peripheral fatigue. Gut 39 (Suppl 1): A30; 1996.

5. Jones EA. Fatigue associated with chronic liver disease: A riddle wrapped in a mystery inside an enigma. Hepatology 22: 1606?1608.

6. Jones EA, Bergsasa NV. The pruritus of cholestasis. Hepatology 29: 1003-1006; 1999.

7. Jones EA. Pathogenesis of hepatic encephalopathy. In: Pathophysiology of Liver Disease. Herrera J (Ed). Clinics Liver Disease 4: 467?485; 2000.

8. Jones EA, Yurdaydin C. Is fatigue associated with cholestasis mediated by altered central neurotransmission? Hepatology 25: 492?494; 1997.

9. Schworer H, Hartmann H, Ramadori G. Relief of cholestatic pruritus by a novel class of drugs: 5?hydroxytryptamine type 3 (5?HT3) receptor antagonists: effectiveness of ondansetron. Pain 61: 33?37; 1995.

10. Wilson WM, Maughan RJ. Evidence for a possible role of 5-hydroxytryptamine in the genesis of fatigue in man: administration of paroxetine, a 5?HT re?uptake inhibitor, reduces the capacity to perform prolonged exercise. Exp Physiol 77: 921?924; 1992.

11. Bailey SP, Davis MJ, Ahiborn EN. Neuroendocrine and substrate responses to altered brain 5?HT activity during prolonged exercise to fatigue. J Appi Physiol 74: 3006?3012; 1993.

12. Jones EA. Relief from profound fatigue associated with chronic liver disease by long?term ondansetron therapy. Lancet 354: 397; 1999.

Dr E. Anthony Jones is from the Department of Gastrointestinal and Liver Diseases, Academic Medical Center, Amsterdam, The Netherlands.

Hepatitis C and depression
By Doug Mellors.

Not everyone with hepatitis C suffers from depression and in those cases where they do, it is difficult to pinpoint the cause. A question many people ask is: does being infected with hepatitis C cause depression - or is depression a reaction to being diagnosed as hepatitis C positive?

What is depression?

Depression is a disturbance of mood. The assessment, diagnosis and treatment are based on the severity, frequency and duration of symptoms reported by the person. There are no tests for depression although there are a number of particular questionnaires that are sometimes used to assess it.

What are the symptoms of depression?

There are a number of different types of depression but some general symptoms are: feelings of despair, a sense of worthlessness, the inability to take pleasure from the things one usually enjoys, feelings of guilt, sleep disturbance, tiredness, ruminating on gloomy or negative thoughts, social withdrawal.

People with severe depression are often immobilised by it and tend to isolate themselves socially and neglect their surroundings and personal appearance. Thoughts of suicide are quite common in people with severe depression.

What causes depression?

The exact cause of depression is unknown and it is more likely due to a number of factors interacting with each other, rather than to any single factor. However, it is generally accepted that the symptoms are due to chemical changes in the brain which influence mood. When a person is depressed these chemicals - called neurotransmitters - are not manufactured in sufficient quantity to keep one's mood balanced.

What causes this chemical imbalance is not clear, but may be related to: a family history of depression or alcoholism, early parental loss or neglect, recent negative life events, a critical or hostile spouse, lack of a close confiding relationship, lack of adequate social support and long-term lack of self esteem. It is important not to confuse depression with feeling "blue" or having a low mood. Feeling blue is a normal reaction to a sad experience and is usually transient.

What about depression in people with hepatitis C?

It can be seen from the above descriptions of the symptoms of depression that some of them are similar to those of hepatitis C (eg. tiredness, sleep disturbance and loss of appetite) which makes the diagnosis of depression more difficult. While these symptoms of hepatitis C are thought to be related to chemical changes or imbalances in the body there is no evidence at present that these chemical changes interfere with brain chemistry and result in depression. What clinicians do know is that being diagnosed with an incurable and life-threatening illness is likely to trigger depression in some people.

What are the treatments for depression?

There are many treatments for depression. Outlined here, are only two. Both are well-researched.

The first is treatment with anti-depressant medication.

The aim of this treatment is to restore the chemical imbalance by drugs which affect neurotransmitters in the brain. In the last five years many new types of anti-depressant medications have been developed due to improved understanding of chemical interactions in the brain.

These new anti-depressants (of which Prozac is only one) are much better tolerated than those of the previous generation of anti-depressants. They have much better response rates and fewer side-effects e.g. drowsiness, constipation and loss of libido.

The second treatment for depression is called Cognitive/Behavioural Therapy and is a non-drug psychological treatment.

The Cognitive part of the therapy relates to a person's thoughts. The role of the therapist is to teach the person how to recognise and monitor their negative thoughts; how to challenge these thoughts and replace them with positive ones. The behavioural part of the therapy relates to what activities the person is involved in on a day-to-day basis. The therapist asks the person to keep a record of their daily activities and how they feel about them. The therapist encourages the person to increase those activities which they enjoy - especially when they involve social interaction.

Which treatment for depression works best?

Studies on outcomes of different therapies show little difference between anti-depressant medication and cognitive/behavioural therapy. In general they suggest that if you have mild to moderate depression it may be better to try a non-drug therapy first and commence antidepressants if it does not work. With severe depression it is probably better to start with anti-depressants first and consider non-drug therapies as an additional part of the treatment.

Doug Mellors is a psychologist and keen supporter of the Hepatitis C Council of SA. Abridged from an original article that previously appeared in both The Hep C Review (June 1998) and the bi-monthly newsletter of the Hepatitis C Council of SA, Hep C Community News (April 1998).

NB: This article discusses depression in general terms - which should not be confused with the depression that may occur while on interferon-based treatments... Ed.

Non-liver complications of chronic hep C infection
By Dr Ed Gane

Introduction

Hepatitis C affects almost 200,000 Australians and 25,000 New Zealanders. Most of these people will suffer from non-specific symptoms such as lethargy and low mood, which bear no relationship at all to the severity of liver damage. Those people with advanced cirrhosis may have symptoms which reflect the severe degree of liver damage, including pruritis (itchy skin), oedema (fluid retention in feet) and ascites (fluid retention in the abdomen) and jaundice (yellow skin and urine). However, only 20-30% of all people with chronic hepatitis C will ever develop cirrhosis and less than 5% will ever develop these symptoms, above.

Recent studies have clearly demonstrated that people with chronic hepatitis C infection have a reduced health-related quality of life, which improves again following successful antiviral therapy. In addition, non-liver manifestations of hepatitis C infection have been observed in almost every body system including skin, kidney, blood, lymphatic system, nervous system, salivary gland, thyroid and lung (see Table 1). In a recent French study of 321 patients attending Hepatitis C clinic, one third of patients had at least one of these conditions. The onset of these extrahepatic conditions is unrelated to severity of liver damage, duration of infection, mode of transmission, Hepatitis C Virus genotype, or age. Interestingly, thyroid disease is more common in women, reflecting the female preponderance in the general population.

Table 1. Frequency of some Hepatitis C Virus-related extrahepatic manefestations

Causes

The mechanisms of the non-liver tissue damage are either direct effects of the Hepatitis C Virus infection or indirect effects of the body's immune response to Hepatitis C Virus. Examples of direct infection by Hepatitis C Virus include Porphyria cutanea tarda (PCT), Sicca syndrome and cryoglobulinaemia. PCT is a blistering skin condition, caused by a direct blocking effect of Hepatitis C Virus on enzyme pathways within the liver cell. The dry mouth seen in Hepatitis C Virus-induced Sjogren's syndrome is a direct effect of the Hepatitis C Virus infection of the lining of salivary gland ducts, leading to salivary gland injury. Chronic infection of lymphoid tissue is thought to be the initial step in the development of the lymphoproliferative complications of Hepatitis C Virus- cryoglobulinaemia (common) and lymphoma (very rare).

Indirect effects of the body's immune response include both autoimmune and immune-complex diseases. Examples of autoimmune diseases associated with chronic Hepatitis C infection include haemolytic anaemia, thrombocytopaenia (low platelets), lichen planus (a rare skin rash usually on the forearms and inside the mouth) and thyroiditis. In these conditions the body can no longer distinguish between viral proteins and our own tissue proteins. Hepatitis C Virus-induced antibodies target our own own tissue proteins, leading to tissue injury rather than viral inactivation. This confusion arises either because viral proteins are identical to our own tissue proteins (so-called "molecular mimicry"), or because the virus itself alters the infected tissue's proteins so that our immune system no longer recognises them as "self" but sees them as foreign, leading to an immune response.

In immune complex disease, excess levels of Hepatitis C Virus-specific antibodies complex together with their target viral proteins. These complexes are circulating within the bloodstream which may injure skin, nerves, kidneys and other organs by occluding (blocking) or causing inflammation in small blood vessels which supply these tissues.

Cryoglobulinaemia

The most common extrahepatic manifestation (illness occuring outside of the liver) of hepatitis C infection is essential mixed cryoglobulinaemia (EMC). This syndrome presents as a red, raised, skin rash, which usually appears first on the shins and feet. The rash fluctuates but is usually worse in winter. Other commonly associated symptoms include sore joints and fever. Less commonly, the rash may occur in the kidney (glomerulonephritis) leading to loss of protein in the urine and occasionally kidney failure (see below) or in the gut, causing severe pain requiring emergency surgery. The rash and other problems of EMC are caused by cryoglobulins, which are immune complexes of Hepatitis C Virus proteins and anti-Hepatitis C Virus antibodies bound together by Rheumatoid factor, which is a special protein produced by lymphocytes infected with Hepatitis C Virus. They clump together when the blood temperature falls below normal and dissolve again at body temperature. In the small superficial blood vessels of the skin, the blood slows down and cools. This causes the cryoglobulins to clump together and block the blood vessels, thus leading to inflammation and the development of skin rash characteristic of EMC. First described in 1966, EMC was initially associated with chronic non-A, non-B hepatitis. However, the introduction of reliable Hepatitis C Virus serological testing in 1990 demonstrated that most (between 50% and 98%) patients with EMC had chronic Hepatitis C Virus infection. The typical symptoms of essential mixed cryoglobulinaemia (EMC) occur in around 5% of patients with chronic Hepatitis C Virus infection. Other common symptoms of EMC include fever and sore joints.

Diagnosis of EMC is based on the detection of cryoglobulins in the blood in someone with rash or other features of EMC. Occasionally, biopsy of the skin rash, kidney or other affected organs is also required to confirm the diagnosis, prior to treatment. To ensure accurate determination of cryoglobulins in the blood, special collection of the blood sample is necessary: it must be placed immediately into a thermos heated to body temperature (37C) and kept at this temperature until separated in the laboratory centrifuge. Using such techniques, circulating cryoglobulins will be found in almost 30% of patients with chronic Hepatitis C Virus infection - i.e. most patients with cryoglobulins will have EMC without any symptoms of the condition.

Cryoglobulins are more common in patients with long-standing Hepatitis C Virus infection and in those with cirrhosis. This is because clearance of circulating immune complexes by the liver macrophage cells is reduced in cirrhosis.

Treatment of EMC (skin rash, arthritis, etc) is treatment of the underlying Hepatitis C Virus infection i.e. antiviral therapy with interferon with or without ribavirin. The Hepatitis C Virus eradication rates achieved with antiviral therapy are similar to those in patients without cryoglobulins. Eradication of the Hepatitis C Virus is accompanied by reduction in the cryoglobulins and resolution of the skin rash. In patients who have ongoing complications of cryoglobulins and who have not responded to antiviral therapy, other treatments may be necessary, including cyclophosphamide and prednisone. These drugs are "immunosuppressants" which work by either reducing the production of the cryoglobulins or suppressing the local inflammation in the tissues caused by the cryoglobulins. Unfortunately, they increase the amount of circulating Hepatitis C Virus. Therefore, they should be used after rather than before antiviral therapies, because their use will prevent later response to interferon and ribavirin.

Cryoglobulinaemia should be considered a mild form of abnormal lymphocyte proliferation. Sometimes the abnormal lymphocytes have a specific DNA mutation, which is also found in certain types of low-grade lymphomas. In those countries with high rates of Hepatitis C Virus infection, an increased rate of lymphoma is observed in patients with Hepatitis C Virus infection, suggesting a definite but rare link between these 2 conditions.

Kidney disease

Hepatitis C Virus is found in 2-10% of people on long-term haemodialysis and in 2-5% of those who received kidney transplants prior to 1990. This is not because Hepatitis C Virus caused the kidney disease, but because these patients with severe kidney disease became infected through exposure to blood products or kidneys from Hepatitis C Virus+ donors (prior to 1990 when routine screening for Hepatitis C Virus was introduced). Rarely is Hepatitis C Virus the cause of the kidney disease. In these cases, the kidney disease results from precipitation of circulating immune complexes in the small blood vessels of the filtering units of the kidney (glomeruli), leading to leaky kidneys which lose protein into the urine. Cryoglobulins are present in about half the cases. Interferon monotherapy, aimed at clearing the Hepatitis C Virus infection, is the best treatment for this kidney disease. Hepatitis C Virus clearance reduces protein loss and improves kidney function. Ribavirin must not be used as it causes severe anaemia in people with kidney disease.

Porphyria cutanea tarda

Porphyria cutanea tarda is a skin condition where the face, hands, neck blister after either minor trauma or exposure to sunlight. Unlike the rash associated with cryoglobulinaemia, the rash of PCT is usually worse in the summer months and less in winter, related to the amount of sunlight. The skin sensitivity is because of build-up of porphyrins in the blood. Porphyrins are by-products of haemoglobin production, which are usually present in the body in only minute quantities. They accumulate only when the enzyme pathway which breaks down porphyrins is insufficient. Total lack of this enzyme is a very rare inherited disorder. Much more common is an inherited partial deficiency of the enzyme which only becomes apparent when the liver is further damaged by another disease such as alcohol, iron overload (due to another inherited gene mutation), or chronic viral hepatitis. In countries with high rates of Hepatitis C Virus infection (Italy, Japan, Spain), 70-90% of people with PCT are Hepatitis C Virus positive, whilst in countries with low rates of Hepatitis C Virus (Ireland, Australia and New Zealand), 10-30% of people with PCT have hepatitis C. Heavy alcohol use may aggravate this condition by further damaging the liver cell enzyme pathways.

Management of PCT involves simple measures designed to protect the fragile skin, from sunlight and from trauma. Oestrogen-containing medications (increase porphyrin production) and heavy alcohol use (reduce porphyrin breakdown) should be avoided. The mainstay of PCT treatment in Hepatitis C Virus+ patients should be antiviral therapy with interferon and ribavirin. Successful Hepatitis C Virus clearance is associated with long-term remission of the skin disorder.

Sicca syndrome

Almost 50% of patients with chronic Hepatitis C Virus will have Hepatitis C Virus detectable in saliva [though not in sufficient quantity to allow transmission], many of whom will complain of dry eyes or a dry mouth (with taste disturbance). Laboratory tests demonstrate reduced rates of tear and saliva production and biopsy of the salivary glands show a characteristic picture of inflammation, attributable to the local Hepatitis C Virus infection. The mouth dryness is exacerbated by the side-effects of methadone maintenance.

It is very important for such patients to be meticulous with regards to dental hygiene, in order to prevent severe dental caries (tooth decay) and gingivitis (inflammation of gums). Symptomatic relief can be obtained by using artificial tears and saliva. In one study of 8 Hepatitis C Virus patients with Sicca syndrome, eradication of Hepatitis C Virus with interferon was accompanied by increase of saliva production back to normal.

Thyroid disease

Thyroid hormone is responsible for maintaining the normal metabolic rate. Thyroid diseases can be divided into hyperthyroidism when the thyroid is overactive (often resulting in sweating, weight loss, anxiety and diarrhoea) and hypothyroidism when the thyroid is underactive (often resulting in weight gain, tiredness, dry skin and constipation). Both hyperthyroidism and hypothyroidism are much more common in women than men and are usually preceded by the development of anti-thyroid antibodies. Although anti-thyroid antibodies are more common in women with Hepatitis C Virus (25 - 30%) compared to women without Hepatitis C Virus infection (10 - 15%), there is no associated increase in the rate of thyroid disease in the absence of Interferon therapy. However, Interferon (with or without ribavirin) is associated with the onset of hypothyroidism in 20% of Hepatitis C Virus+ women. The reason for this interferon effect is probably two-fold: an indirect effect of interferon, enhancing our immune responses (thereby triggering previously latent autoimmune thyroid disease) and a direct toxic effect on the thyroid gland (blocking formation of the normal thyroid hormones). Risk factors for developing thyroid disease during interferon therapy are: female, age > 50 years, pre-existing antithyroid antibodies (of whom 75% will develop thyroid disease during interferon). Antithyroid antibodies should be checked in all patients prior to commencing interferon and thyroid function tests should be tested before starting at 6 months and 12 months therapy. Usually, if hypothyroidism develops, interferon can be continued with addition of thyroxine tablets. Most, but not all, cases of thyroid disease improve after completion of therapy.

Summary

Around one third of people with chronic hepatitis C infection will develop some extrahepatic condition of Hepatitis C Virus infection, which is either a direct result of Hepatitis C Virus infection of that organ or is caused by the body's immune response to Hepatitis C Virus.

These extrahepatic conditions progress independently of the liver disease. People with minimal liver disease may have severe extrahepatic disease. Most of these conditions will improve following eradication of Hepatitis C Virus with antiviral therapy, with the exception of thyroid disease, which may first develop during Interferon therapy. Extrahepatic conditions should be regarded as indications for starting antiviral therapy.

Dr Ed Gane is Hepatologist at both Auckland and Middlemore Hospitals and the New Zealand Liver Transplant Unit.

The National Hepatitis C Strategy 1999-2004

Hepatitis C is now the most commonly notified communicable disease in Australia. It poses a serious threat to population health.

The National Hepatitis C Strategy 1999 to 2004 provides for a strong and inclusive response from all levels of government, community organisations, the medical, health care, scientific and research communities and people affected by hepatitis C. People affected by hepatitis C are central to the success of this Strategy, which aims to meet both their collective and their individual needs and to reduce the hepatitis C epidemic's future impact on the Australian population.

The Strategy links with government policies to reduce the impact of illicit drug use and with population health policies dealing with HIV/AIDS and other blood borne viruses. In addition, it builds on the achievements of the National Hepatitis C Action Plan (AHMAC 1994), the Nationally Coordinated Hepatitis C Education and Prevention Approach (AHMAC 1995) and successive national HIV/AIDS strategies, including the current National HIV/AIDS Strategy: Changes and Challenges (CDHAC 2000).

Overall aims

The National Hepatitis C Strategy 1999?2000 to 2003?2004 aims to promote and support the health, safety and wellbeing of all Australians in relation to hepatitis C. It acknowledges that the most effective way to reduce the harms to individuals and the community that result from hepatitis C infection is to prevent exposure to the virus. At the same time, however, it recognises the need to support access to suitable treatments and to provide care and support for those affected. To achieve this, the Strategy has two primary aims: to reduce the transmission of hepatitis C in Australia, and to minimise the personal and social impacts of hepatitis C infection.

The Strategy recognises that, regardless of how hepatitis C infection is acquired, the social, medical and economic impacts for the individual and the broader community are profound, with implications for affected people and for Australia's health care system. An effective national response to hepatitis C will be achieved through responding to the challenges and building on the opportunities outlined in the four priority areas for action, which are:

·         reducing hepatitis C transmission in the community

·         treatment of hepatitis C infection

·         health maintenance, care and support for people affected by hepatitis C

·         preventing discrimination and reducing stigma and isolation.

Essential components

The Strategy is based on six essential components, which are considered fundamental to developing effective responses in the four priority areas. These essential components are:

·         developing partnerships and involving affected communities

·         access and equity

·         harm reduction

·         health promotion

·         research and surveillance

·         linked strategies and infrastructures.

Targetting

Hepatitis C transmission depends on blood?to?blood contact, so the Strategy focuses on risk factors and specific circumstances of transmission rather than on specific population groups. The Strategy does, however, identify the need for improved access to health care services for Aboriginal and Torres Strait Islander communities and people from other cultural groups.

Discrimination / stigmatisation

Many people with hepatitis C have experienced d