Cirrhosis

Description

Alternative Names

Treatment

The only treatment for alcoholic cirrhosis is to stop drinking. Individuals with alcoholic cirrhosis are typically malnourished and require increased calories and rigorous nutritional support, which can improve survival rates.

Treatments for Chronic Hepatitis C

Interferons Alone and in Combination with Ribavirin for Hepatitis C. Pegylated (PEG) interferon combined with ribavirin (a nucleoside analogue), is now the gold standard for treating for chronic hepatitis C. Interferons are natural proteins that activate certain immune functions in the body and have antiviral properties. Ribavirin is poor at inducing initial responses alone but it can double sustained response rates when combined with an interferon. A number of natural and synthetic interferons are available:

• Natural interferons were the first used for HCV and include interferon alpha-2a (Intron) and Interferon alpha-2b (Roferon). Rebetron is the combination of interferon alpha-2b and ribavirin.
• Pegylated interferons (PegINF) are long-acting formulations of interferon. They include alfa-2b (Peg-Intron) or alfa 2a (Pegasys). Both are now available in combination with ribavirin. (Rebetol is the alfa-2b combination.)
• Alfacon-1 (Infergen), also called consensus interferon, is a genetically modified interferon. A combination of alfacon-1 with ribavirin is proving to help some patients who had been resistant to ribavirin with interferon.

The combination of pegylated interferon alfa-2b with ribavirin (Rebetol) has achieved the best success rates to date of all interferons and their combinations. It has achieved responses of up to 51% with genotype 1 and nearly 80% with genotype 2 and 3. According to a 2002 comparison study, the Pegasys combination may even produce better results.

PegINF combinations are proving to slow progression of scarring, and has even achieved improvement in some patients who already have cirrhosis. Whether the combination treatment protects against future liver cancer is still unclear. (A higher total dose, rather than a longer duration of treatment, may be the critical factor for protection.)

Investigative Drugs for Hepatitis C

The current drugs used for HCV still do not meet the needs of all patients. They are expensive, have significant side effects, do not work in half the patients who take them, and are unsuitable in many others. Investigation is ongoing to find better solutions. Some showing promise include the following:

• IMPDH Inhibitors. Mycophenylate mofetil and VX-497 are agents that inhibit an enzyme known by its brief name, IMPDH, which may block replication of the hepatitis C virus. If effective, they would most likely be used in combination with interferon and ribavirin.
• Histamines. Phase II clinical trials of intravenous histamine dihydrocholoride (Ceplene) have found that more than half of patients administered combo histamine dihydrocholoride/interferon or interleukin 2 exhibited a complete viral response, compared to 29% for those treated with interferon alone. An oral version of Ceplene is being evaluated in a preliminary trial.
• Immunomodulators. Thymosin alpha 1 (Zadaxin), also called thymalfasin, is a synthetic version of a peptide derived from the thymus gland (which is responsible for maturation of immune factors call T-cells). It is being used for hepatitis B and is now undergoing Phase III studies for hepatitis C in combinations with natural interferons and pegylated interferon.
• Protease Inhibitors. Protease inhibitors (similar to those used for HIV) are under investigation for hepatitis C patients who fail other treatments. These agents are based on molecular therapies that target proteins involved in viral reproduction. Very early studies of one such drug, BILN 2061, demonstrated strong antiviral activity against HCV genotype 1 in patients with cirrhosis. Further studies are needed.
• Apoptosis Inhibitors. Increased rates of programmed cell death (apoptosis) have been linked to HCV, NASH, HBV, PBC and alcoholic hepatitis. IDN-6556 is an experimental drug, undergoing early human clinical trials, which prevents excessive programmed cell death. At the 54th Annual Meeting of the American Association for the Study of Liver Diseases, researchers announced that twice-a-day dosing of oral IDN-6556 given for two weeks resulted in normalized liver enzymes in HCV patients with liver impairment. The results were based on data from 41 patients, over 70% of whom had displayed inadequate responses to interferon-alpha and ribavirin. The drug appeared to be well-tolerated. Scientists are also investigating the use of IDN-6556 to treat patients undergoing liver transplantation.

Other agents under investigation include therapeutic vaccines and genetic therapies known as antisense oligonucleotides or monoclonal antibodies. InnoVac-C is one such vaccine undergoing Phase IIb clinical studies. In March 2004, Innogenetics reported 3-year histology data from an earlier InnoVac-C trial. After four courses of the vaccine, patients exhibited significant improvement in liver scarring, when compared to their baseline results. The HCV vaccine appeared to be well-tolerated. Even if successful, none of these agents would be available for some years.

Of interest are studies using phlebotomy (which is simply drawing blood) to reduce iron levels. In one study, maintenance therapy with this procedure reduced liver inflammation and possible slowed progression of cirrhosis.

Treatments for Chronic Hepatitis B

An ounce of prevention is worth a pound of cure, and the phrase resoundingly holds true in the case of Hepatitis B. Today, a vaccine against HBV is available. It can prevent hepatitis B and therefore, it can also prevent liver cancer. The American Academy of Pediatrics and the Centers for Disease Control and Prevention currently recommend that all babies born in the United States receive a hepatitis B vaccine at birth.

In regards to treatment, interferon alpha and nucleoside analogues are the important therapies at this time for hepatitis B. At this time interferon alpha-2b is the standard agent but experts expect the nucleoside analogue lamivudine to replace it as the primary agent. Lamivudine is not only effective, it also less expensive than the interferon. Most likely, the best approach in the future will be combinations of these and other agents to achieve the greatest possible viral reduction and to minimize the chances of drug resistance.

Interferon Alpha for Hepatitis B. Interferon alpha-2b (Intron) is the standard drug for hepatitis B. It has eliminated the virus and sustained significant remission in 25% to 40% of patients with chronic hepatitis B. The drug is usually taken by injection every day for 16 weeks. (It does not appear to be effective for hepatitis D.) Unfortunately, even in hepatitis B, the virus recurs in almost all cases, although this recurring mutation may be weaker than the original strain.

Administering the drug for longer periods may produce sustained remission in more patients while still being safe. Interferon is also effective in eligible children, although long-term effects are unclear. A 2001 study suggested that it may temporarily disrupt growth, but it should be noted that hepatitis itself, even without interferon treatment, can compromise growth.

Lamivudine and Other Nucleoside Analogues. Nucleoside analogues are drugs that can block viral replication, and they are important in hepatitis B. The primary agent used in hepatitis is lamivudine (Zeffix). It can be taken orally, has few severe side effects, and is less expensive than interferon. Experts expect it to become the first-line treatment for hepatitis B. Famciclovir is an alternative.

Lamivudine has reduced viral count in over half of hepatitis B patients who have taken it as sole therapy for about a year. It also appears to significantly reduce the risk for liver damage and cirrhosis, and appears to be effective and safe in patients with decompensated cirrhosis. The drug even suppresses hepatitis B viral replication in HIV-positive patients and liver transplant recipients. It appears to be effective for children as well as adults. It is not yet clear if it protects against liver cancer, particularly in patients who have harbored the virus since childhood.

Lamivudine causes muscle aches and chills but does not appear to have some of the distressing side effects of interferon, such as depression, hair loss, weight loss, or a drop in white blood cells (leukopenia).

Of some concern, however, is eventual resistance to the drug in many patients. A major problem with lamivudine is the development of mutated viral strains that become resistant to the drug, particularly in areas where the virus is common. Combinations with interferons may be able to help control viral breakthroughs from mutated viruses and help sustain its effectiveness. The specific genetic hepatitis B strain may be an important marker for predicting resistance. Newer nucleoside analogues, such as adefovir dipivoxil (Hepsera) and entecavir, may pose less of a risk for resistance and may even prove to be more effective than the older agents. Hepsera, approved by the FDA in 2002, is indicated for patients with chronic hepatitis B who have active viral replication and either persistent increases in liver enzymes or histologically active disease. In clinical trials, the drug was found to work well in those patients with HBV resistance to lamivudine. A 48-week study of Hepsera found no evidence of resistance mutations.

Investigative Drugs for Hepatitis B

Telbivudine. A recent study, presented at a meeting of the American Association for the Study of Liver Diseases, revealed that the investigational drug, telbivudine, resulted in significantly better suppression of the HBV and normalization of certain liver enzymes compared to lamivudine monotherapy.

Immunotherapy. A number of drugs are being studied that boost the body's own immune system to fight the virus.

• Thymosin Alpha 1. Thymosin alpha 1 (Zadaxin), also called thymalfasin, is a synthetic version of a peptide derived from the thymus gland (which is responsible for maturation of immune factors call T-cells). It is injected and has few side effects. It appears to be safe for hepatitis B patients when used alone or in combination. Combinations with interferon and nucleoside analogues are showing promise.
• Vaccines as Treatments. Some hepatitis B vaccines, including Hepagene, are being investigated for treating as well as preventing hepatitis B.

Treatments for Primary Biliary Cirrhosis

Ursodeoxycholic Acid (UDCA) and Drugs Used to Slow Progression. At this time no medication can cure primary biliary cirrhosis. Ursodiol, ursodeoxycholic acid (Actigall), or UDCA has been the standard drug used for primary biliary cirrhosis. A number of studies have reported that it slows progression and helps prevent the need for liver transplantation.

It has no effect on symptoms, including itching and fatigue. Some drugs, such as colchicine, corticosteroids, or immunosuppressants, are being investigated for use in combination with UDCA. Long-term controlled trials are needed to determine the value of UDCA alone or with other agents.

Agents for Itching. Itching is a major problem with this disease. Cholestyramine, taken with meals, is the first choice for relieving itching. and a number of agents have been used or investigated, including low doses of the drug naltrexone and phototherapy.

Agents for Impaired Fat Absorption. Because primary biliary cirrhosis affects fat absorption, patients may need high doses or injections of important fat-soluble vitamins, including K, D, A, and E. Agents called medium-chain triglycerides may be helpful for steatorrhea (in which the feces contain excessive fat).

Treatments for Other Causes of Cirrhosis

Treatment of Nonalcoholic Fatty Liver Disease (NASH). Weight loss is the most important component for managing NASH and preventing progression to liver disease. Investigators are studying various drugs, insulin-sensitizing drugs metformin, rosiglitazone, and pioglitazone, as well as the antioxidant vitamin E.

Secondary Biliary Cirrhosis. Secondary biliary cirrhosis caused by blockage in the bile ducts can be relieved by surgery.

Autoimmune Hepatitis. Autoimmune hepatitis is treated with corticosteroids as standard agents and also possibly immunosuppressants, such as azathioprine and cyclosporine A.

Hemochromatosis. For hemochromatosis, weekly bleedings (phlebotomies) may be performed until iron levels are normal, then repeated as needed. If treatment is given before cirrhosis develops, life expectancy may be normal.

Treatments for Liver Scarring

Presently, there are no safe and effective therapies for liver scarring (fibrosis). However, recent insights into the cellular and molecular mechanisms responsible for scarring have led to the development of specific, antifibrotic agents that target the primary injury and/or inhibit abnormal cell mechanisms. Such agents, now in very early testing, could one day help prevent or reduce the progression of liver scarring or the progression to liver cancer.