Sulfasalazine’s Potential for Reversing Fibrosis

Investigation into why a liver becomes fibrotic and possibly cirrhotic has led English researchers on a quest to stop this undesirable chain of events. By discovering that sulfasalazine holds promise for reversing scar tissue in the liver, they may have changed the future treatment goals for liver disease.

.One of the most amazing characteristics of liver tissue is its ability to regenerate new and healthy cells. Unfortunately, a person experiencing repeated injury to this organ often loses this capability by racking up unhealed scars. Therefore, one of the therapeutic goals for treating liver disease is to find novel ways for healing the accumulation of fibrous scar tissue that could lead to liver cirrhosis. Scientists from the United Kingdom believe that the drug sulfasalazine may fulfill this goal, by imitating a healthy liver’s response to injury, which could dissolve the fibrous scars found in a diseased liver.

The Sulfasalazine Claim
In an effort to help the liver recover from injury, English researchers have made a promising discovery. By blocking the proteins that keep scar tissue cells alive, sulfasalazine may help people living with chronic liver disease. Although the study led by Professor Derek Mann was conducted in laboratory animals, proponents believe that the soon-to-be-seen results of sulfasalazine’s impact on human livers have the potential to reverse fibrosis. If true, sulfasalazine could provide a safer and less expensive alternative to liver transplant surgery.

Why a Liver Scars
Professor of Molecular Cell Biology at Southampton University, Derek Mann shares why a specialized liver cell, the hepatic stellate cell, is mostly responsible for liver fibrosis. According to Mann, “Hepatic stellate cells normally provide the storage site for vitamin A. However, in response to injury they undergo a remarkable transition to become wound-healing myofibroblasts which, amongst other functions, produce scar proteins or collagen, as seen in cirrhosis.”

Injury to the liver tissue is typically due to toxins, alcohol or a virus. In response to liver injury, the following chain of events occurs:

1. scar tissue is laid down to protect the injured or infected tissue from further damage while it heals

2. in a healthy liver, this scar tissue breaks down after the liver has regenerated new cells

3. in a diseased liver, scar tissue formation outpaces liver cell regeneration

4. in a diseased liver, hepatic stellate cells remain activated leading to a build-up of collagen

5. in a diseased liver, the collagen build-up prevents the liver’s repair

6. in a diseased liver, the build-up can eventually leads to cirrhosis, the irreversible replacement of liver cells with non-functioning, fibrous tissue

End-stage liver disease is typically marked by cirrhosis, when there are insufficient liver cells left to support the everyday vital functions normally performed by the liver.

Hepatic Stellate Cell Hope
In collaboration with John Iredale, Professor of Medicine at the University of Edinburgh, Professor Mann’s research is aimed at stopping the cycle of liver injury that can lead to cirrhosis. Since previous animal models demonstrated that liver recovery was associated with the clearance of activated hepatic stellate cells, Mann closely examined this molecular mechanism in hopes of stimulating this process in people with chronic liver disease.

This hope skyrocketed when researchers found signals instructing cells in an injured liver to resist hepatic stellate cell death. In addition, Mann found that experimental manipulation could promote clearance of hepatic stellate cells and that by inhibiting these signals, the acceleration of fibrosis recovery could be stimulated.

The Signals Responsible
A well-known protein that controls the activity of over 200 genes, nuclear factor-kappa B (NF-κB) emerged as the agent responsible for instructing cells to resist death. Mann explained that the activation of hepatic stellate cells into myofibroblasts was accompanied by an increase in their NF-κB activity. The presence of this protein is believed to be the primary reason why hepatic stellate cells are able to resist death, their demise of which could allow liver tissue to heal. The NF-κB activity is a key player in how much scarring a liver incurs. As hepatic stellate cells resist death, scar formation persists and the liver progresses towards cirrhosis.

Putting this Understanding to Use
Ever since understanding how the molecular pathway for liver fibrosis works, investigators have been searching for liver disease therapies based on this information. Used for decades to treat inflammatory diseases of the gut and rheumatoid arthritis, sulfasalazine trials are currently the most hopeful outcome of this work. A potent inhibitor of NF-κB, sulfasalazine’s results to date have been encouraging. “In an animal model of liver fibrosis we have observed that administration of sulfasalazine accelerates the normally slow process of spontaneous recovery,” says Professor Mann. “We saw very rapid remodeling of scar tissue back to normal hepatic tissue.”

More About Sulfasalazine
Sulfasalazine is an anti-inflammatory medication that belongs to a class of drugs called sulfa drugs. The active ingredients in sulfasalazine consist of salicylate (the main ingredient in aspirin) combined with a sulfa antibiotic. Its uses cover a broad range of ailments, from rheumatoid arthritis, anklyosing spondylitis, psoriatic arthritis to ulcerative colitis and Crohn’s disease.

In general, most patients tolerate sulfasalazine without many side effects. However, there are adverse effects that can occur, including:

· temporary infertility in males
· yellow-orange urine or skin
· diarrhea
· headache
· loss of appetite or vomiting
· upset stomach or stomach pain
· skin rash, itching or hives
· sore throat or swelling
· fever
· joint or muscle aches
· pale or yellow skin
· difficulty swallowing
· unusual bleeding or bruising
· fatigue or weakness

In addition, many drugs interact with sulfasalazine.

The Next Step
While sulfasalazine may sound like an exciting option for people with severe liver fibrosis or cirrhosis, it is still under investigation. According to liver disease specialist, Dr. Melissa Palmer, it is not recommended for patients with liver disease to begin sulfasalazine until the human studies conclude its safety and efficacy. Until this or another therapy becomes available that is proven in the areas of safety and effectiveness, you can help prevent your liver cells from injury. By taking a high quality milk thistle supplement, numerous studies have confirmed this herb’s ability to strengthen liver cells, protecting them from injury in the first place.

Although not yet a therapeutic solution, the strides of modern medicine continue to propel us into previously uncharted waters. By understanding and influencing the mechanism of scarring in the liver, solutions such as sulfasalazine could reverse fibrosis. Such a feat would change a person’s prognosis of living with chronic liver disease and completely alter their treatment regimen.

References:

http://news.bbc.co.uk, Drug “may reverse liver disease”, BBC, September 2007.

www.liverdisease.com, Patient-Submitted Questions, Dr. Melissa Palmer, 2007.

www.nlm.nih.gov, Sulfasalazine, National Institutes of Health, 2007.

www.rheumatology.org, Sulfasalazine, American College of Rheumatology, 2007.

www.wellcome.ac.uk, Why promoting cell death can help the liver regenerate,
Becky McCall, Wellcome Trust, 2007.

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