Cirrhosis is a chronic liver disease characterized by the replacement of normal liver tissue with scar tissue. This prevents the liver from functioning properly and can lead to liver failure. Cirrhosis has many causes including alcohol abuse, viral hepatitis, and fatty liver disease. Once cirrhosis develops it was previously thought to be irreversible, however new research shows the liver has an incredible capacity to regenerate even in the setting of advanced cirrhosis. This gives hope that with the right interventions, treating the underlying cause of liver damage and optimizing regeneration, recovery may be possible.
What is cirrhosis?
Cirrhosis occurs when chronic injury to the liver results in extensive scarring and regeneration. The normal liver tissue is replaced with fibrous scar tissue and regenerative nodules. This scarring prevents blood from flowing properly through the liver and impairs liver function. Cirrhosis develops slowly over many years and often has no symptoms until extensive damage has occurred.
Some causes of cirrhosis include:
- Chronic alcohol abuse – drinking too much alcohol for many years damages the liver and promotes scarring.
- Chronic viral hepatitis B and C – the viruses cause inflammation and liver cell damage.
- Fatty liver disease – buildup of fat in the liver can promote inflammation and scarring.
- Autoimmune disorders – disorders that cause the immune system to attack the liver.
- Inherited diseases – such as hemochromatosis which causes iron buildup in the liver.
As cirrhosis progresses, the liver becomes lumpy and scarred. Fibrous bands surround and divide the liver into nodules. This prevents proper blood flow and impairs the liver’s ability to function. Symptoms include fluid retention, bruising easily, fatigue, jaundice, and gastrointestinal bleeding. Without treatment, cirrhosis can lead to liver failure, liver cancer, and death.
Can cirrhosis be reversed?
For a long time, cirrhosis was considered to be an irreversible process with a poor prognosis. Once extensive scarring and nodule formation develops, it was not thought possible for the liver to return to normal. However, emerging research shows the liver has a remarkable capacity to regenerate and reverse advanced fibrosis even at the stage of cirrhosis.
What promotes liver regeneration?
The liver has a unique ability compared to other organs to regenerate following injury. Some factors that influence regeneration include:
- Removal of the source of injury allows regeneration – for example, stopping alcohol consumption or successfully treating viral hepatitis.
- Liver growth factors and cytokines that stimulate regeneration.
- Liver progenitor cells and stem cells that can differentiate into mature liver cells.
- Reducing oxidative stress and inflammation in the liver environment.
- Maintaining proper nutrition to fuel regeneration.
By optimizing these factors, even a cirrhotic liver can begin to heal and regenerate.
Evidence of regeneration
Several human and animal studies demonstrate the ability of the liver to regenerate at the cirrhosis stage:
- Liver biopsies from patients who stopped drinking show resolution of fibrosis over time.
- Livers from rats treated with carbon tetrachloride, an industrial chemical that causes fibrosis, can regenerate liver tissue if the toxin is removed.
- Human livers transplanted from deceased alcoholic donors into recipients demonstrate significant recovery from fibrosis after transplantation with alcohol cessation.
- Directly treating cirrhotic rats with substances that stimulate regeneration shows mobilization of liver progenitor cells.
This evidence indicates that under the right conditions, the liver has the ability to break down scar tissue, activate regeneration mechanisms, and recover functionality. The key is to provide the ideal cellular environment and proper stimuli.
Factors that influence cirrhosis reversal
Several key factors determine whether significant reversal of cirrhosis is possible:
Cause of cirrhosis
The underlying cause of liver injury must be addressed. This may include alcohol abstinence, weight loss for fatty liver, antiviral medications for hepatitis B and C, or immunosuppression for autoimmune disorders. This removes the source of chronic inflammation and allows the liver to heal.
Severity of cirrhosis
The extent of scarring impacts reversibility. Mild to moderate cirrhosis has a better prognosis compared to advanced micronodular cirrhosis with extensive scarring. However, clinical studies show regenerative potential exists even in severe cirrhosis.
Co-existing liver disease
Superimposed issues like continued alcohol intake, viral infections, obesity, or iron overload impair regeneration and should be treated. Diseases like liver cancer or cholangiocarcinoma have poorer outcomes.
Duration of injury
The longer the duration of chronic liver injury, the more ingrained the scar tissue and harder to reverse. Early intervention offers better regenerative potential.
Age
Younger patients have greater regenerative capacity compared to older patients with more long-standing injury. But regeneration is still possible in older individuals.
Nutritional status
Good nutrition provides the building blocks for liver regeneration. Protein intake for synthesis of new cells and micronutrients like zinc and vitamin A support the process.
Comorbidities
Medical issues like heart or lung disease impact the prognosis and may limit treatment options. Optimizing management of comorbidities is key.
Ongoing inflammation
Persisting inflammatory signals, even after removing the original injury, impairs regeneration. Controlling liver inflammation and oxidative stress is important.
Treatments to enhance liver regeneration
Many emerging therapies aim to improve liver regeneration in cirrhosis:
Reduce fibrosis
- Anti-fibrotic drugs like GR-MD-02 bind scar tissue components
- Pirfenidone inhibits TGF-beta which promotes scarring
- ANTI-LOXL2 monoclonal antibodies inhibit collagen cross-linking
Breaking down scar tissue is key to clearing the way for regeneration.
Stem cell therapy
Stem cells like mesenchymal cells help repair damaged tissue through anti-inflammatory effects and signals that boost regeneration.
Liver growth factors
Growth factors provide signals to regenerate liver cells and vessels. Examples include:
- Hepatocyte growth factor (HGF)
- Vascular endothelial growth factor (VEGF)
- Fibroblast growth factor (FGF)
Delivering these by infusion or in biodegradable gels promotes liver cell proliferation.
Remove senescent cells
Senescent cells release factors that impair regeneration. Drugs like Quercetin help clear these cells.
Modulate microbiome
The gut microbiome impacts liver inflammation and fibrosis through multiple mechanisms. Antibiotics, prebiotics, probiotics, and fecal transplants may help optimize the microbiome.
Antioxidants
Agents like vitamin E, S-adenosylmethionine (SAMe), and acetylcysteine (NAC) reduce damaging oxidative stress.
Lifestyle changes
Lifestyle adjustments to also improve chances of regeneration:
- Alcohol abstinence
- Weight loss for obesity and fatty liver
- Healthy diet focusing on vegetables, lean proteins, healthy fats
- Low sodium diet to reduce fluid retention
- Adequate protein intake to provide building blocks for regeneration
- Avoiding hepatotoxins like aflatoxin
- Treatment of metabolic factors like diabetes and hyperlipidemia
- Smoking cessation
- Reduce stress
Optimizing lifestyle reduces factors impeding liver regeneration.
Monitoring cirrhosis regression
Indicators of successful cirrhosis reversal include:
- Improved liver enzymes like ALT, AST, GGT
- Increase in serum albumin
- Reduced bilirubin, INR, creatinine
- Resolution of cirrhosis on imaging studies
- Improved liver stiffness on elastography
- Reduced fibrosis markers like hyaluronic acid
Repeat biopsies also definitively document architectural changes showing loss of fibrosis over time.
Conclusion
In summary, cirrhosis has long been regarded as irreversible scarring of the liver. However, emerging research demonstrates the liver’s remarkable ability to regenerate and resolve fibrosis even at advanced stages given the right circumstances. Removing the chronic source of injury and optimizing regeneration pathways allows even a severely cirrhotic liver to regrow more normal tissue. While not all damage can be reversed, supporting the body’s inherent regenerative powers provides hope for recovery of liver function. Ongoing studies will refine techniques for cirrhosis reversal, bringing us closer to viable curative options.
