Stem Cells For Liver Disorder

About Liver Disorders

The liver is a vital organ responsible for the production of key proteins, blood detoxification, and nutrient metabolism. Liver injury can signal a cascade of events that drive significant structural damage and functional decline in performing these tasks.

But can’t the liver regenerate?

Yes, but it has limits. The liver is an organ known for regeneration. Liver cells can replicate up to 50-70% of the liver cut out. Therefore, in the stages of liver disease, tissue damage can be restored. However, as the disorders advance to the stage of cirrhosis, liver cells become senescent; that is, they stop replicating. Although the pathways are not clearly defined, it has been seen that the liver microenvironment is no longer conducive to cell replication.

Does genetics play a role in the development of liver disorders?

Absolutely. Recent studies have identified a few genes that can increase the susceptibility to fatty liver disease. For example, changes in the PNPLA3 gene linked to fat metabolism can put a person at a 3-fold higher risk of non-alcoholic steatohepatitis (NASH). Similarly, TM6SFS2 and GCKR are a few other genes that can make one prone to liver disorders.

What is NASH?

NASH is a severe form of non-alcoholic fatty liver disease (NAFLD). It occurs due to excessive buildup of fats, which elevates inflammation pathways. Together, both fats and inflammation worsen the tissue damage. Approximately 60% of patients with NAFLD can develop NASH, and the rate of disease progression can be higher in diabetes, obese, and hypertensive patients.

Despite treatment options, current therapies cannot reverse the damage or restore optimal function, leaving patients with limitations in quality of life. Scientists have been researching innovative therapies for damage reversal. Their diligent efforts have paved the way for stem cell therapy.

The regenerative potential of stem cells replaces the lost liver cells and modulates the pathways, activating the self-healing capacity of the liver. The coordinated shift in the pathways by stem cell action treats liver disorders at a deep cellular level. These cells secrete a plethora of growth factors and cytokines that create a favorable environment for tissue repair and regeneration.

With the rapid advancements of technology, this regenerative medicine can be tailored with respect to the type of liver disorders and patient characteristics for personalized treatment. This marks a bold step forward in precision medicine, offering new hope for conditions once considered irreversible.

Diagnosis

Diagnostic procedures depend on the cause of liver disease. The following tests are performed for liver disease.

Biomarker Analysis: A liver function test (LFT) assesses liver disorder by analyzing several biomarkers. Liver damage releases aspartate aminotransferase (AST) and alanine aminotransferase (ALT). Their elevated levels indicate liver disorder, and their ratio suggests the type of disorder. For example, AST>ALT is present in alcoholic liver disease, whereas ALT>AST is characteristic of NAFLD. In addition to ALT and AST, other markers are also evaluated to find the underlying cause. For example, increased serum iron suggests hemochromatosis, whereas the presence of antibodies ANA, ASMA, and LKM1 describes autoimmune hepatitis. Many other markers, like bilirubin, creatinine, etc., are also used for diagnosis.

Genetic Testing: It is beneficial in genetic disorders as the underlying cause of liver dysfunction. PCR is performed in case of infection.

Imaging: Imaging modalities such as ultrasound, CT (computed tomography), and endoscopy can detect and measure the amount of liver damage.

Elastography: It measures the stiffness of the liver due to fibrosis.

Biopsy: This technique involves taking a small liver tissue sample and analyzing it via histopathology. It provides information at the cellular level and is, therefore, used as a confirmatory test for liver disorder.

Early Signs & Symptoms of Liver Disorders

The symptoms of liver disease are non-specific in the initial stage and include nausea, fatigue, weight loss, etc. In the later stages, severe complications arise.

• Unexplained weight loss
• Abdominal swelling or pain
• Jaundice
• Joint pain
• Loss of appetite
• Dark urine
• Clay-colored stools
• Itchy skin
• Loss of sex drive
• Enlarged stomach
• Easy bleeding and bruising
• Cognitive impairment
• Redness in palms
• Blood vessels extending out from a red spot on the skin
• Kidney dysfunction

Available Types of Liver Disorders

Following are the different types of liver disorders:

• Alcoholic fatty liver disease: It results in liver disorder due to excessive alcohol intake.
• Non-alcoholic fatty liver disease (NAFLD/NASH): It arises from metabolic diseases such as obesity, diabetes, high blood lipid levels, etc. The accumulation of fats in the liver causes tissue damage. Substantial liver damage combined with inflammation and fat deposition results in non-alcoholic steatohepatitis (NASH), the advanced form of NAFLD.
• Viral Infection: Infection from hepatitis B, C, and D also initiates liver injury. Chronic hepatitis C can even lead to liver cancer.
• Primary Biliary Cirrhosis is an autoimmune disorder that deteriorates the bile ducts and vessels connecting the liver to the gastrointestinal tract.
• Primary Sclerosing Cholangitis describes the decreasing size of bile ducts caused by immune attack by the body’s cells.
• Autoimmune Hepatitis: The immune system forms antibodies against liver cells, causing liver damage.

What Causes Liver Disorder?

Several factors can result in liver disease:

• Excessive alcohol consumption
• Diabetes
• Obesity
• Infection
• Genetic disorder (Wilson’s disease, hemochromatosis, antitrypsin deficiency)
• Autoimmune disease
• Certain Medications, such as methotrexate, phenytoin, etc.
• Vascular disorders

These factors cause injury in the liver tissue, which induces repair pathways, including inflammation and remodeling of the extracellular matrix. Inflammation recruits immune cells at the injury site to avoid infection. The remodeling process balances the deposition of new matrix proteins and the breakdown of matrix proteins in the damaged area. However, dysregulation in the repair process results in chronic inflammation and excessive matrix deposition.

Fibrosis: Excessive accumulation of matrix disrupts the normal structure of the liver and thus interferes with its functioning. The tissue that replaces the injured tissue is known as the scar tissue. In the initial stage, fibrosis is even reversible.

Cirrhosis: As the matrix spreads in the tissue, it leads to irreversible fibrosis. This results in substantial damage to liver structure and function, defined as liver cirrhosis.

Liver failure: As the disorder progresses, the liver fails to perform, leading to complete liver failure.

What are available treatments for Liver Disorders

Once started, liver damage gradually progresses and spreads through the whole tissue. The current treatment modalities emphasize taking preventive measures to slow the disease progression by treating the underlying cause and mitigating symptoms. However, they cannot heal the damaged tissue, resulting in low functional capacity of the liver. Regenerative medicine provides an alternative approach by healing the damaged organ that results in restoring the tissue functions to their original state

Stem cells, the backbone of this treatment approach, acts on multiple aspects of the liver disorder to confer healing and functional recovery.

The rationale behind stem cell therapy

• Stem cells can convert into liver cells, thereby replacing the lost or damaged cells and restoring liver structure. They also trigger liver stem cell regeneration by releasing hepatocyte growth factor.
• Stem cells regulate the immune cells involved in the pathways leading to liver disorder, thus reducing inflammation.
• Stem cells secrete IL10 and TNF, which inhibit the activation of cells, causing fibrosis.
• Stem cells reduce fibrosis by directing immune cells to produce matrix metalloproteinases that degrade the excessive matrix accumulation.
• Stem cells also decrease the reactive oxygen species and protect the liver against oxidative stress.

Frequently Asked Questions

Q1. What is fibrosis?

Fibrosis describes the excessive accumulation of extracellular matrix protein in the liver. It enhances the stiffness of the tissue and reduces its functional capacity.

Q2. What is cirrhosis?

Cirrhosis is the advanced stage of fibrosis characterized by significant loss of liver function.

Q3. What is non-alcoholic steatohepatitis (NASH)?

Q4. What are the treatment options for liver disorders?