The liver is an organ that is responsible for detoxification of metabolites, ingested chemicals and drugs, excretion of products into the biliary system and synthesis of essential proteins and compounds essential for digestion. Liver involvement by primary cancer or cancer metastases always represents the most serious condition normally considered incurable by conventional anti-cancer modalities.
Causes of Liver Disease
The liver can be infected by hepatitis viruses A, B and C, as well as other viral strains. Viral hepatitis may be cleared by a patient’s immune system that usually results in the development of resistance against recurrent infection (e.g., following viral hepatitis A or B).
However, a patient’s immune system may not be able to clear the virus and in such cases, the patient may remain a carrier for life (e.g., hepatitis B and C). Carriers may be asymptomatic, with or without mild liver functions abnormalities, or they may develop chronic active hepatitis resulting in progressive liver damage. In the latter scenario, this may eventually lead to life-threatening acute liver failure or chronic liver fibrosis and then to incurable liver cirrhosis.
Another possible late complication that may be caused by hepatitis B or C is hepatocellular cancer. There are other causes of liver cirrhosis (e.g., alcoholism) and cases of liver cancer due to unknown causes. There are also many other types of diseases and other clinical conditions involving the liver beyond the scope of this review.
Symptoms of Liver Disease
In addition to viral hepatitis, liver diseases can be caused by overexposure to drugs, toxins or excessive alcohol or due to an autoimmune disease.
Most of these disorders start with a similar cluster of symptoms, including jaundice, itchy skin, dark urine, pale (yellow or white) stool and fatigue. Blood examination will confirm abnormal liver function tests. In most cases, hepatitis virus A is self-limited, but hepatitis B and C can be much more serious and occasionally result in liver failure or chronic disease. In recent years effective treatment of hepatitis C was developed and a large number of patients can be cured. Carriere state and hepatitis B victims remain incurable with no signs of overt disease or with a progressive disease that can progress into cirrhosis and some cases of cirrhosis progress into liver cancer.
In cases of autoimmune hepatitis, corticosteroids can be used to diminish the inflammatory and immune reaction and sometimes additional cytotoxic agents are recommended for patients in need of high doses of corticosteroids acting as steroid-sparing effects. Additional clinical management depends on the signs and symptoms of patients in need.
Treatment methods at Biotherapy International can be applied to control immune-mediated chronic active hepatitis, possibly even controlling viral replication using a new experimental drug candidate, an attenuated poultry virus that induces type 1 interferon activation.
Use of Mesenchymal Stem Cells to treat Liver Disorders
Mesenchymal stem cells (MSCs) have shown to have a strong therapeutic potential for patients with inflammatory liver disorders, cirrhosis and primary biliary cholangitis. The therapeutic potential of MSCs as confirmed in preclinical animal models is based on their anti-inflammatory and immune regulatory effects for patients with immune-mediated hepatitis, as well as on their capacity to induce anti-fibrosis effects. 
Therefore, for patients with progressive liver cirrhosis due to any cause, as well as patients with primary biliary cirrhosis can benefit from treatment with MSCs, possibly in the future from treatment with MSCs secretory products, exosomes or extracellular vesicles, that may be the only safe treatment available to control the inflammatory reaction resulting in fibrosis. This may be particularly recommended for patients with primary biliary cholangitis, an autoimmune disease that frequently results in cirrhosis.
Treatments with MSCs is one of the few safe and effective treatments available against the reaction that results in liver fibrosis (scarring), which in turn gradually becomes overt cirrhosis, a very serious disease with possible life-threatening complications.
New Treatment Options for Patients in Need of Liver Transplantation
Incurable acute or chronic liver disease, or patients with incurable primary or secondary cancer involving the liver may be in need for liver transplantation as the only possible life-saving treatment. Patients who have been deemed to be candidates for a liver transplant either due to advanced non-malignant or incurable primary or secondary malignant liver disease can also benefit from an innovative transplant procedure that may provide a safer approach to prevent rejection following liver transplantation. As will be explained in another section, innovative transplant procedure developed at Biotherapy International may provide a safer approach for prevention of rejection following liver transplantation while avoiding the use of life-long immunosuppressive treatment based on the use of a new protocol for induction of transplantation tolerance.
Liver transplantation based on induction of transplantation tolerance can be crucially important for patients with an indication for liver transplantation due to malignant disease because the use of mandatory conventional immunosuppression for prevention of rejection will result in recurrent disease from residual malignant cells present outside the liver since immunosuppressive treatment facilitates cancer progression.
Perhaps even more importantly, induction of transplantation tolerance to donor’s alloantigens provides an opportunity to use activated donor lymphocytes for induction of effective anti-cancer immunotherapy of extra-hepatic disease. Bone marrow-derived stem cells for induction of transplantation tolerance and lymphocytes for immunotherapy of residual cancer can be obtained at any time from related donors that have donated half their liver to their beloved ones. Since the liver is noted for its ability to regenerate, a split liver allograft can always be accomplished from a living donor since both the donor and the recipient will benefit from regeneration of their residual half liver.
When liver transplantation is accomplished from a deceased donor, bone marrow cells for induction of transplantation tolerance can be obtained and used at the time of liver harvesting. Donor’s lymphocytes for future immunotherapy with activated donor lymphocytes can be isolated from the blood, from lymph nodes or from the spleen of the donor at the time of liver harvesting and kept cryopreserved, ready for use as soon as the patient’s condition becomes stable.
