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The origins and epidemiology of hepatitis C

Estimates of the number of people exposed to the hepatitis C virus, (HCV), worldwide vary from 250 to 500 million. Prevalence varies from 0.3–2.5% in Western Europe and North America, 3–7% in much of Asia and South America to over 10% in parts of Africa, with major variations occurring within these populations.1 Unlike some other European countries, the UK has yet to undertake a large-scale prevalence study, but estimates based upon tissue samples taken from accident victims, such as that undertaken by Graeme Alexander of Addenbrookes Hospital, Cambridgeshire, in 1994, suggest an overall rate of just under 1%. Rates may be higher in urban areas, with prevalence of over 2%, meaning that at least 500,000 people in the UK are likely to have been exposed to HCV. This estimate is entirely consistent with the results of studies in Europe and the USA.

Image of HCV based on electron micrograph

However, HCV was not explicitly identified until 1989, and blood tests were not available until 1991. This means that its emergence as a global health issue went largely undetected at the time and that analysis of the pandemic is largely retrospective. A brief history based upon currently available data is as follows:

Analysis of genetic diversity and sampling of the presence in the human population indicates that the hepatitis C virus (HCV) first infected human beings somewhere in the Far East, anything from 200 to 1500 years ago.[2] Unlike hepatitis B, HCV is an unstable RNA virus with ongoing mutational properties; it can be inferred that a wide spread of differing genotypes in a confined geographical space is a good indicator of length of presence in any given area.

HCV is almost exclusively blood borne;  it seems that a slow process of endemic proliferation may have been enabled by some traditional medicinal techniques such as acupuncture. However, the explosion of HCV from apparently restricted origins into a global pandemic did not occur until the 1940s, and seems to have been the result of the introduction of Western medical procedures, particularly blood transfusion and the use of the hypodermic syringe.

These procedures, combined with the large scale movement of armed forces, the widespread need for treatment by both civilians and servicemen, the repeated use of contaminated medical equipment and the intermingling of national blood supplies all contributed toward the ‘first wave’ of HCV globalisation.

Although it was not possible to determine the exact cause, specialists in the West began to pick up cases of chronic liver disease in the late 1960s. Equipped with the ability to diagnose both hepatitis A and B (tests available from 1965), they were able to exclude both of these viruses, and began to diagnose a few patients with Non A Non B type hepatitis. Ex-servicemen, people who had received blood transfusions and haemophiliacs were prominent in this group of patients, giving rise to the suspicion that one or more undetectable blood-borne viruses were responsible.

In the meantime HCV had found more significant and numerically devastating routes of transmission. The WHO-sponsored programmes of inoculation and vaccination across broad swathes of the developing world routinely employed ‘shared needle’ implementation. Millions of people were infected in this way – for instance, studies in Egypt have revealed that HCV has prevalence rates of over 20% in some parts of that country,[3] with the receipt of schistosomiasis shots being a particularly significant controlling variable.[4] It is now apparent that such vaccination programmes are by far the most significant factor in the proliferation of HCV in global terms.

In developed countries the more rigorous application of sterilisation guidelines appears to have minimised rates of transmission through such procedures, although dentistry, tattooing, the receipt of inoculations and vaccinations, needle stick injury and other such risk factors are certainly responsible for smaller groups of infected patients. Contaminated blood and blood products led to 100% rates of infection among haemophiliacs born prior to the introduction of blood screening, and lower but significant rates among other users of blood products and recipients of transfusions.

However, the practice of intravenous (IV) drug use provided the most viable opportunity for large-scale HCV transmission. Figures researched by the Centre of Disease Control in Atlanta, USA and presented by Dr Harold Margolis at the 2nd International Mainliners Conference in April 1997 demonstrate that HCV has a higher prevalence in older Afro-Americans compared to other racial groups. It can be inferred that the earlier proliferation of practice of IV drug use in this population – associated with the ‘Jazz age’ in the 1940s and 1950s – contributed to this skew in the figures. The subsequent popularity of experimenting with IV drug use in the wider population since the 1960s has certainly been the major route of transmission in the more recently infected population in the West.

Rates of infection in IV drug users are extremely high; according to 1995 UK figures the rate averages at 60% in the country as a whole, rising to 71% in London and 77% in Scotland.[5] Perhaps even more significantly, it is thought that there is a very high rate of transmission in the first instance of IV drug use; this means that many people who were never long term IV drug users have been exposed to the virus.

Another significant point to be inferred from these figures is that HCV is extremely infectious. It seems that the largely successful measures taken to prevent the further transmission of HIV among IVDUs have failed to prevent massive HCV prevalence. It seems that many people were infected by simply sharing paraphernalia such as spoons or filters, and this reflects the fact that HCV is much more hardy than HIV, with the ability to survive outside the body for far longer periods.

The overall epidemiological picture is one of a largely invisible yet selectively infectious virus proliferating on a global scale through diverse sections of the human population over a relatively short period of time. Although the inability to clinically diagnose and the opening up of a wide range of viable blood-to-blood transmission routes are key components in this picture, there is a third factor which is vital to the equation; namely the chronic, subtle and seriously misunderstood way in which HCV causes disease.

HCV-related disease and symptoms

HCV causes a complex pattern of systemic disease. As a virus which is present in both the blood and lymphatic systems it comes into contact with all body tissues and organs; it causes damage both by its capacity to directly infect cells and through the reactions its presence causes, particularly via mechanisms conventionally described as ‘immunopathic’ or ‘autoimmune’.

Although it is now evident that a small proportion of patients, at most 20%, manage to counter the virus to the extent that it is undetectable in the blood, it is also apparent that many of these suffer from symptoms, indicating either occult infection in other body tissues or post viral syndrome, or some combination of both.[6]

It is now apparent that the labelling of the virus ‘hepatitis’ – meaning inflammation of the liver – had more to do with the limitations of standard diagnostic procedures than the actual behaviour of the virus. Having said this, it is the case that ongoing liver disease is the most likely cause of life-threatening illness in most patients.

Perhaps the most important fact for health practitioners in the UK is that although around half a million people are likely to have been exposed to HCV, less than 6000 have been diagnosed to date. Therefore the vast majority of patients are currently unaware of their condition. Given the insistent and diverse ways in which HCV causes disease and debilitation, this means that many people in this category will be currently seeking out or receiving treatment for a range of physical, mental and emotional disorders; neither they nor their doctors may be aware of the likelihood of a link to viral infection.

A classic pattern of symptoms includes any of the following, either individually or in combination: Depression, mood swings, indigestion, pain in the liver region, bloating, pronounced fatigue often occurring in ‘attacks’, aversion to fried and fatty foods, alcohol intolerance, attacks of ‘brain fog’ featuring loss of short-term memory and poor cognitive ability. Thus a holistic scope is a prerequisite for the correct assessment of HCV-related disease in a patient and the specialised structure of conventional medicine is not well suited to this task.

Clearly, HCV is a prime candidate for being a ‘missing link’ which may explain a significant proportion of ‘modern’ afflictions such as M.E., chronic fatigue syndrome (CFS), allergy syndromes and a range of autoimmune disorders. Professor Robert Batey, speaking at the 1st International Mainliners Conference on Hepatitis C in 1994, reported that 40% of patients attending Chronic Fatigue Clinics in Australia had antibodies to HCV. So while it may take some time for eminent medical bodies to seriously address the possibility of a viral link to M.E., some other authorities already acknowledge the relationship to CFS. The cognitive problems associated with HCV strongly suggest a link to M.E. as well. It is also worth noting that the recent discovery of a group of viruses known as GBV A, B and C, also known as hepatitis G, which bear some resemblance to HCV, may cast further light on the question of viral links to so-called ‘psychosomatic’ disorders.

Treatments for Hepatitis C

Although HCV causes a prolific range of serious and debilitating conditions, the good news is that it seems to be responsive to a range of treatments, particularly when these can be combined with informed lifestyle adjustments. However, because HCV has only been discovered recently and also due to the fact that many of these treatments do not feature patentable medicines, and are therefore not candidates for expensive trials of the double-blind placebo type, it is difficult for practitioners and patients to develop a clear picture of the most suitable way forward; much also depends upon the personal inclination of the patient.

The subject of treatment and the question of what constitutes a cure is complex and involved – a comprehensive analysis is included in The Hepatitis C Handbook (see ‘Further Reading and Resources’). The following is a brief summary:

Primary Treatments

Because HCV is a resilient, pervasive and highly adaptable virus, it is reasonable to expect that it is necessary for most patients to take some kind of anti-viral, heat clearing or eliminative medicine in order to have a significant long-term impact on established patterns of disease. At present the two main options are drug therapy and Chinese herbal medicine. For patients with advanced liver disease, a liver transplant may become the only treatment option.

Drug Therapy

The recombinant drug ‘alpha interferon 2a’ has been the major focus of conventional treatment of hepatitis C, with a view to both viral eradication/suppression and the improvement of long term prognosis with regard to progressive liver disease.

The case for interferon therapy centres upon its therapeutic ability to convert positive blood PCR test results into negative ones, and reduce liver enzyme levels. This can be achieved in about half of patients accepted for therapy.[20] Once treatment has ended, about half of these relapse within 6 months, although these figures are improved when interferon is combined with other agents such as ribavirin[21] or thymic extracts.[22] In the longer term about half of the ‘complete responders’ also relapse.

The case for a cautionary approach to interferon relates to its side effects. The principle clinical problem relates to the fact that it exacerbates autoimmune disease to the extent that side effects can be very uncomfortable, and occasionally dangerous. A common long-term side effect is thyroid dysfunction,[23] which results in long-term weight gain, fatigue, and the need to take thyroxine. It seems that some patients suffer other long-term side effects, including increased susceptibility to allergy, ischaemia and cardiovascular disorders.[24] Interferon is known to cause depression, which can be a particular problem to those with a history of chemical dependency; this, perhaps combined with the fact that it is necessary to inject the drug, can precipitate relapse, which may be more immediately life-threatening than HCV. When interferon is combined with ribavirin it can also exacerbate other clinical problems, principally low blood cell counts.

The long term side effects of a course of interferon therapy are still not clear, and it is of concern that some doctors are over keen to present too rosy a picture to patients.

Chinese Herbal Medicine

Traditional Chinese Medicine as a whole is well placed to address the multifaceted needs of HCV patients. The herbal dimension can play a particularly important role in the early stages of treatment and can provide the necessary pharmacological muscle without precipitating the adverse side effects caused by drug therapy.

The Gateway Clinic in Stockwell, South London, is the leading centre for the development of TCM treatment for HCV in the West. The treatment director, John Tindall, has seen hundreds of patients over the years, and has adjusted classical Chinese prescriptions for chronic hepatitis to suit the needs of Western HCV patients. He now has a good model of both disease progression and herbal treatment strategy. Although there have been no controlled studies of efficacy, systematic analysis of symptoms before and after treatment indicate significant alleviation.

Tindall has formulated the following herbal prescriptions to treat patients with hepatitis C, who do not have any other chronic illness and are abstinent from alcohol and drugs. These indicators reflect common symptoms in hepatitis C patients in the early and later stages.

Formula 1: Peaceful River

(Early Stage treatment)
Indicators:
Fatigue, Abdominal Discomfort, Abdominal Gas and Bloating, Abdominal Cramps and Colic, Loose Stool, Bitter Taste in the Mouth, Pain in the upper right abdomen (‘Hypochondrial’ Pain in medical terminology), Loss of Appetite, Alternate Chills and Fever, Hot and Cold Flushes, Irregular Periods
Contra indicators:
Constipation, Hot and Sweaty at Night; ‘Flu Like Symptoms of Temperature; Fever and Sweating, Pregnant Patients, or Those Trying to Become Pregnant
Overall effect:
Regulates liver and digestive function. Clears heat. Increases the internal energy of the body.

Formula 2: ‘Cool Water’

(Late stage treatment)
Indicators:
Insomnia, Vivid Dreams, Palpitations, Night Sweats, Thirst, Dry Mouth, Constipation or Stool Hard to Pass, Liver Pains; Pains in the Chest and Hypochondria, Hardening of the Liver
Contra indicators:
Phlegm Present in the Lung or Bowel, Loose Stool or Diarrhoea, Pregnant Patients, or Those Trying to Become Pregnant
Overall effect:
To strengthen the cooling and nourishing functions of the liver and kidney. To soften the liver and clear toxins. To calm the mind.

These formulations are available in tablet form from East West Herbs; phone: 0171–379 4414 For further information on use and contents, fax your name and address to 0171–916 7942.

Further evidence in favour of the efficacy of Chinese herbs comes from the results of a controlled double-blind placebo trial of Chinese herbs on HCV patients at the John Hunter Hospital in Newcastle, Australia, so far unpublished, demonstrating significant improvements in liver enzyme levels among patients using a standard Chinese herbal preparation. Simultaneously analyses of the pharmacological properties of certain Chinese herbs[25] demonstrate a pharmacological rationale for the widespread empirical observation by patients of significantly improved levels of health.

On the cautionary side, it should also be noted that HCV treatment by herbal medicine requires a skilled and informed practitioner who is fully aware of the distinct nature of hepatitis C. Some patients have had negative experiences of Chinese herbal medicine.

Transplant / Surgery / Cancer Therapy

For patients with advanced disease of the liver or kidney, transplant may be the only life saving option. Survival rates for liver transplants are over 50% for HCV patients, although tissue rejection problems are more common than normal. Reinfection of the liver is routine after transplant, but life expectancy is greatly extended. Survival rates for kidney transplants are high. Patients with primary cancer of the liver have a poor prognosis with conventional therapies. Patients with lymphatic cancer should be aware that treatment by surgery and chemotherapy currently has a high rate of success in the short term, although later recurrence is common.

Secondary Treatments

Hepatitis C has such a diverse range of symptoms that it is difficult to imagine a form of treatment that would not have a potentially useful role.

The other branches of TCM

Acupuncture, acupressure, Qi Qong and massage can play a very useful role in the treatment of hepatitis C, particularly when combined with herbal treatment. The relief of excessive heat, correction of yin deficiency and stagnant liver Qi, the balancing of common liver-spleen disharmony, blood purification, the promotion of strong elimination and the development of a relaxed state of mind in the patient are regarded as being very important objectives.

Western Herbal Medicine

Undoubtably has many useful plants such as milk thistle seeds, burdock root, dandelion root, globe artichoke (for the liver); cat’s claw and golden seal for the bowel; gingko for peripheral circulation; dandelion leaf for fluid retention; and echinacea for the immune system. On the whole, Western herbal medicine is not able to provide the same level of sophistication as Chinese herbal medicine, although some herbalists are now combing both ingredients and strategic approach. One formulation, suggested by Peter de Ruyter, of Sydney, Australia, for patients trying to counter progressive liver disease who cannot obtain an individualised prescription, is as follows:

Baical Scullcap    15%
Astralagus    15%
Bupleurum    5%
Silybum    15%
Schisandra    20%
Licorice    15%
Echinacea    15%

Made up as a herbal tincture, 3ml, 3 x daily before meals, diluted in water.

De Ruyter suggests that normalisation of liver function may be achieved by taking Picrorrhiza tablets; ½ tablet twice daily until function is restored, followed by ½ tab daily for two months. Brian McKenna suggests that freeze dried milk thistle is a good way of normalising ALTs and ASTs.

Depending on the symptomatic profile of the patient, there are a range of approaches which may be taken depending upon the judgement of the practitioner. For instance, Malcolm Simmonds produces a range of preparations including some for lower bowel problems, common in HCV patients.

Amino Acids, food supplements, vitamins and minerals.

HCV patients have an established pattern of glutathione deficiency.[26] The glutathione precursor, N-Acetyl Cysteine, is likely to be extremely useful in the management of many chronic hepatitis C patients. Not only does it counteract the deficiency, which is linked to accelerated progression of liver disease and increased free radical damage, but it also acts against oncogenesis, is hepatoprotective, and enhances overall immune function. Other amino acid supplements, such as methionine, taurine, tryptophan, glutamine and proline may also address various symptoms.[27]

Simple food supplements, such as chlorella – which contains a wide range of amino acids – may be useful additions to a therapeutic regime. Whilst an overactive immune system may be unhelpful for patients, a healthy and balanced immune function is vital; patients with immunosuppressive conditions such as HIV, and those on immunosuppressive drugs, such as steroids, suffer from higher viral loads and accelerated disease progression. This indicates that immune function should be supported as it does have a modulating effect on HCV replication. To this end vitamins such as C and minerals such as zinc and selenium may be very useful. Conversely, patients should be made aware that all immunosuppressants, be they prescription or recreational drugs, or elements in the diet, such as saturated fats and sugar, are potentially hazardous.

Exercise, diet and fasting

Exercise may be a very useful tool in the encouragement of lymphatic drainage and the counteraction of circulation problems, although patients with lymphatic cancer should not take exercise. Lymphatic drainage techniques, such as the use of alternating hot and cold packs of castor oil placed over the liver, and lymphatic drainage aromatherapy massage are likely to be very helpful. (Note that although lymphatic cancer is rare, lymphoproliferative disorders are common.)

Diet should ideally be modified to eliminate all alcohol – very moderate occasional consumption may be harmless, but patients should be informed that accelerated progression of liver disease to cirrhosis and cancer is definitely linked to alcohol consumption.[29] Coffee may also cause problems, and is regarded as being ‘hot’ in Chinese medicine. Substitution with dandelion coffee or green tea (highly eliminative), will be a positive change.

Fats and sugars, pastries, hot and spicy food should be reduced. Additives, pesticides, fluoridised or chlorinated water, household drugs such as paracetamol, aspirin and ibuprofen may pose additional problems to patients. The consumption of fresh fruit and vegetables, preferably organic, and low-fat high-protein foods should be encouraged.

Fasting for hepatitis C patients is controversial with doctors advising strongly both for and against. Some routines may benefit some patients, although those with pronounced liver disease should not undertake water-only fasts. The following regime may be beneficial:

Start the day with a large glass of prune juice; follow up with half and half organic apple juice and distilled water; use camomile enemas if headaches appear. Continue for only 36 hours if new to fasting. Continue for up to 3 days if experienced. Break the fast with steamed organic apple and cinnamon. Add stewed vegetables slowly. Leave heavy protein and carbohydrate until last.

Although the eliminative effects of fruit juice fasts may be most useful, the regenerative impact of vegetable juice fasts may also be helpful. A cocktail of broccoli, bok choy, celery, lettuce, capsicum and a small amount of carrot is advised by Peter de Ruyter.

Liver flush regimes, such as the half and half olive oil and lemon juice cocktail first thing in the morning, should be adjusted for hep C patients; only a small dash of olive oil should be used, with most of the blend being made up of lemon juice.

Anything at all which helps the patient to cultivate a relaxed approach to life is to be encouraged. There are many ways in which an anxious state of mind can make a patient’s prognosis worse.

Further Information

Further details are contained in The Hepatitis C Handbook. This is not an exhaustive list of therapeutic approaches to hepatitis C; the author would welcome any contribution from practitioners or patients with further experience or expertise.

Further Reading & Resources

The Hepatitis C Handbook by Matthew Dolan, Catalyst Press, 1997; ISBN 0 9529509 0 1. Order through local book shop or call the distributors, Central Books on 0181–986 4854 direct; in America, contact PJ Communications, New York, (212) 714 6076.
The Hepatitis C Support group: Write to PO Box 13036, London NW1 3WG
The Gateway Clinic, Old South Western Hospital, Landor Road, London SW9 9NU 0171–346 5441.

References

1.    Chronic Hepatitis C; Roche Biocare Consultants Series 4 No 2; H Thomas; pp 7 – 9; 1994; ISSN 0963-6900.
2.    ‘Variability of the hepatitis C virus’; Peter Simmonds; Hepatology;  Vol 21 No 2, 1995; pp 575–579.
3.    Prevalence, impact and risk factors of hepatitis C infection; J Egypt Public Health Assoc. 1993; 68 (1–2): 63–79; ISSN: 0013-2446; 1993.
4.    Does Schistosomiasis play a role in the high sero prevalence of HCV antibody among Egyptians?; El Zayadi et al; Nassam Handy Cairo Liver Centre, November 8–12, 1996.
5.    Waller T & Holmes R; The Sleeping Giant Awakes; Druglink; September 1995.
6.    Evidence that HLA class II genotype may be associated with clearance of HCV; ME Cramp et al; Institute of Liver Studies, Kings College Hospital.  Paper presented at the 1996 American Association for the Study of Liver Disease, November 8–12, 1996.
7.    A multispecific T-Lymphocyte response to HCV proteins occurs in patients with viral clearance and persists many years after exposure; ME Cramp et al; Institute of Liver Studies, Kings College Hospital. Paper presented at the 1996 American Association for the Study of Liver Disease, November 8–12, 1996.
8.    Infection of peripheral blood mononuclear cells by hepatitis C virus in mixed cryoglobulinemia; Blood. 1993 Dec 15; 82 (12): 3701–4; ISSN: 0006-4971; 1993.
9.    Chronic hepatitis C and B-cell Non Hodgkin’s Lymphoma; Ferri C et al; University of Pisa; Quarterly Journal of Medicine; 89 (2): 117–122; 1996 Feb.
10.    Hepatitis C Infection and clonal B-Cell expansion; Sansonno D et al; Clinical and experimental rheumatology; 14 Supplement 45–50; Jan–Feb 1996.
11.    Natural History of liver fibrosis progression in patients with chronic hepatitis C; Poynard T et al; Lancet 349 (9055); 825–832; Mar 22, 1997.
12.    Mixed Cryoglobulinaemia secondary to hepatitis C infection;  Agnello V et al; Rheumatic diseases clinic of North America; 22 (1); 1–21; 1996 Feb.
13.    Psychological stress, depression and quality of life in patients with liver disease due to hepatitis C virus; N Singh et al;  Veterans Affairs medical centre, Pittsburgh, PA.  Paper presented at the 1996 American Association for the Study of Liver Disease, November 8–12, 1996.
14.    Increased Risk for diabetes type II with chronic hepatitis C infection; NN Zein et al; Mayo Clinic, Rochester, USA.  Paper presented at the 1996 American Association for the Study of Liver Disease, November 8–12, 1996.
15.    Nonhepatic Manifestations of and combined diseases in HCV infection; Stephanos Hadziyannis; Digestive Diseases and Sciences; pp 63s- 74s Supplement; Vol 41, No 12, December 1996.
16.    Cerebral Ischaemia in patients with hepatitis C infection and mixed cryoglobulinaemia; Petty GW et al; Mayo Clinic Proceedings; 71 (7); 671–8; July 1996
17.    Hepatitis C virus-associated membranoproliferative glomerulonephritis in renal allografts; Cruzado JM et al; Journal of the American Society of Nephrology; 7 (11): 2469–75; Nov 1996.
18.    Viral Hepatitis & Autoimmunity: Chicken or Egg?; Strassburg and Mann; Viral Hepatitis Review; June 1995.
19.    HCV-associated hepatocellular carcinoma without cirrhosis; el-Refaie et al; Journal of Hepatology; 24 (3): 277–85; Mar 1996.
20.    Treatment of hepatitis C with recombinant interferon alpha; Davis GL et al; New England Journal of Medicine 1989; 321: 1501–1506.
21.    Combination therapy with interferon alpha and ribavirin in interferon alpha relapsers;  A Ricchiuti et al; Clinical Gastroenterology Unit University of Pisa, Italy.  Paper presented at the 1996 American Association for the Study of Liver Disease, November 8–12, 1996.
22.    Thymosin alpha 1 + Interferon combination therapy for chronic hepatitis C: results of a randomised controlled trial; KE Sherman et al; Dept of Medicine, University of Cincinnati.  Paper presented at the 1996 American Association for the Study of Liver Disease, November 8–12, 1996.
23.    Autoimmune dysthyroidism induced by alpha interferon in two female patients with chronic non-A, non-B hepatitis; Gastroenterol Clin Biol. 1993; 17 (8–9): 594–7; ISSN: 0399-8320; 1993.
24.    Adverse effects of interferon on the cardiovascular system in patients with chronic hepatitis C; Teragawa H et al; Japanese Heart Journal; 37 (6): 905–15; Nov 1996.
25.    The herbal medicine ‘Inchin-ko-to’ inhibits liver cell apoptosis; Yamamoto et al; Hepatology Vol 23 No. 3 1996.
26.    Hepatic Glutathione Deficiency in chronic Hepatitis C: quantitative evaluation in patients who are HIV positive and HIV negative and correlations with plasmatic and lymphocytic concentrations and with the activity of the liver disease; Barbaro, G. et al.  American Journal of Gastroenterology 91 (12): 2569–73,  December 1996.
27.    Amino Acids in Therapy; Leon Chaitow; Thorsons, 1985.
28.    Tryptophan is able to ameliorate acetaminophen-induced acute hepatic necrosis in rats; PS Latham et al; Dept of pathology, George Washington University.  Paper presented at the 1996 American Association for the Study of Liver Disease, November 8–12, 1996.
29.    Prevalence of of hepatocellular carcinoma in patients with alcoholic cirrhosis and prior exposure to hepatitis C; Yamauchi et al. American Journal of Gastroenterology; 88: 39–43; 1993.