Traditional Chinese medicine (TCM) is commonly used in treating liver diseases worldwide. The advantages of using TCM for treatment of liver diseases include protecting hepatocytes, inhibiting hepatic inflammation and anti-fibrosis of the liver.
Fatty Liver Disease – “First Hit”
The liver is one of the major organs to synthesize triglycerides as the body's energy supply and cholesterol to support bile, Vitamin D, hormone production and cellular membranes. Fatty liver, or hepatic steatosis, is characterized by excess fat especially triglycerides built up in the liver cells.
Triglyceride synthesis is under feedback regulation through activation and deactivation of the sterol receptor element binding protein-1c (SREBP-1c). The abnormally increased activation of this protein causes over production of cellular lipids resulting in accumulation of excessive fat in the liver. Research has shown that malnutrition, especially a deficiency of choline and a high fructose diet with a high degree of sweetness such as high fructose corn syrup found in our processed food upregulate SREBP-1c activation. Studies suggest that high fructose intake is the major cause of fatty liver disease with increased fat accumulation in the liver. Nonalcoholic fatty liver disease (NAFLD) represents a continuum of hepatic injuries, which progress from simple fatty liver to steatohepatitis (NASH). According to the most widespread and prevailing model of the "two-hit hypothesis", the lipid accumulation in the hepatocytes is the "first hit".
Although the accumulated neutral fat seems harmless, the liver cell will undergo lipoapoptosis, a process of apoptosis or programed cell death caused by exposure to an excess of fatty acids. Lipoapoptosis is a prominent feature of NASH and is associated with the severity and progression of NASH / improve NASH and prevent its progression to fibrosis.
Nonalcoholic Steatohepatitis (NASH) – “Second Hit”
Fatty liver or hepatic steatosis is a silent condition. Patients usually have no symptoms and the disease does not progress quickly unless additional cellular events occur. This is known as the “second hit” when it will further develop to steatohepatitis, inflammation of the liver leading to liver damage and scarring. Patients with liver inflammation or NASH usually have elevated serum triglyceride levels. Liver damage can cause elevated liver enzymes such as ALP, AST, and ALT in their blood. Symptoms of liver inflammation include fatigue, weight loss, nausea, loss of appetite, pain in the upper right quadrant of the abdomen, burning or stabbing pain on the skin, spider veins and insomnia. Severe liver inflammation can also cause symptoms of genital inflammation, formication and skin crawling.
The second hit is characterized by increased pro-inflammatory cytokine production. The “second hit” includes stress induced blood flow reduction to the liver and/or bacteria endotoxins from the gut. The liver receives one-third of its blood supply from the hepatic artery which is oxygenated blood. Stress can cause reduced blood flow from the hepatic artery to the liver resulting in reduced oxygen supply to the liver. This can cause oxidative stress with increased reactive oxygen species (ROS) or free radicals which then catalyze lipid peroxidation. Oxidative stress and lipid peroxidation can injure liver cells, triggering an inflammatory response with pro-inflammatory cytokines production leading to steatohepatitis.
The liver receives two-third of its blood supply from the hepatic portal vein which comes from the digestive tract and is deoxygenated. If patients have digestive tract microbial infections, small intestinal bacterial overgrowth (SIBO), or leaky gut, the blood from the portal vein may contain high amounts of bacterial endotoxins. When the fatty liver is exposed to bacterial toxins, the “second hit”, especially the endotoxin from gram-negative bacteria, the development of non-alcoholic fatty liver disease (NAFLD) can be triggered. Lipopolysaccharide (LPS), is bacterial endotoxin found in the outer membrane of gram-negative bacteria in bowel bacteria flora. Bacterial endotoxin, lipopolysaccharide (LPS), plays an important role in the pathogenesis of NAFLD. LPS triggers and accelerates the progress of NAFLD as it is a potent inducer of hepatic inflammation and also cause further increased triglyceride synthesis. Non-alcoholic fatty liver disease is an irreversible process that starts with liver inflammation with the production of a wide array of pro-inflammatory cytokines and chemokines which enhance liver cell proliferation and collagen secretion in the extracellular matrix. High amounts of collagen deposits in the extracellular spaces can result is hardening of the liver, loss of blood infusion to liver cells, and subsequent development of liver cell death and fibrosis.
Hepatitis B and C
Hepatitis B virus (HBV) is a DNA virus that replicates within the hepatocytes causing irritation, inflammation and malfunctioning of the liver which results in elevated liver enzyme levels in the blood. It is a blood-borne virus that can be spread from person to person by blood and bodily fluids through sexual intercourse, blood transfusions, or contaminated needles. Common symptoms include fatigue, nausea, loss of appetite, jaundice, abdominal pain in the URQ, dark urine or fever. Hepatitis B can be either acute or chronic. Some individuals fight off the infection within several months and become immune to the Hepatitis B virus. For other individuals, however, the infection becomes chronic and can cause liver scarring and liver cirrhosis since the liver is overtaken by the virus and is unable to function properly.
The toxicity of HBV is caused mainly by the direct action of the hepatitis B virus-X protein (HBx). HBx down-regulates mitochondrial enzymes involved in electron transport in oxidative phosphorylation which increases the level of mitochondrial ROS and lipid peroxide production. HBx is partly responsible for an approximate 10,000-fold increase in intracellular ROS upon chronic HBV infection. Increased ROS and lipid peroxidation can cause liver inflammation and more than 20 types of DNA damage which can lead to liver cirrhosis and hepatocellular carcinoma.
From a Western medicine standpoint, patients with chronic Hepatitis B infections need prescription medication for the rest of their lives. This includes antiviral medications which can have severe side effects when taken long-term. For younger patients wanting to get pregnant and cannot be on antiviral medication, interferon therapy is suggested. This form of injectable therapy lasts about 6-12 months and can cause many long-term side effects because of the extended treatment time. Side effects can include, chills, fever, vomiting, muscle pain, low WBC count, and loss of appetite.
Hepatitis C is liver inflammation caused by the Hepatitis C virus (HCV). The HCV is a small enveloped single-strand RNA virus that also replicates within the hepatocytes causing liver inflammation and damages the liver cells which results in elevated liver enzyme levels in the blood. Common symptoms are similar to Hepatitis B including fatigue, poor appetite, jaundice, dark urine or easily bleeding. HCV can also replicate in immune cells such as monocytes and lymphocytes which may account for the high levels of immunological disorders such as autoimmune disease in Hepatitis C patients. Persistent HCV infection may induce autoimmune diseases with high levels of autoantibodies and chronic Hepatitis C is often accompanied by autoimmune hepatitis.6
Hepatitis C causes damage to the liver mainly in the form of inflammation, which then leads to scarring or fibrosis. Hepatitis C also results in the death of liver cells due to the combination of HCV and the immune system’s response to invasion by the virus. However, the immune system’s response is what causes the most damage. The death of liver cells triggers the dispatching of inflammatory cells to the affected area. Inflammation leads to the enlargement of the liver (hepatomegaly) in over 60% of people infected with Hepatitis C and can cause the fibroelastic sheath (Glisson’s capsule) surrounding the liver to stretch, which may be the cause of pain in the liver area.
HCV, as with most RNA viruses, exists as a viral quasispecies. The HCV species is classified into six genotypes. Each genotype has several subtypes. Subtypes are further broken down into quasispecies based on their genetic diversity. Subtypes 1a and 1b are found worldwide and cause 60% of all cases.
HCV mutates rapidly due to a high error rate on the virus RNA polymerase. The mutation rate of HCV is estimated at 10-4 substitutions per site, per round of replication and is among the highest for RNA viruses including retroviruses. Its mutation rate is high enough to generate all the genetic variation found in this virus. Due to this feature and to the high replication rate of HCV, a large number of different but closely related viral variants are continuously produced during infection. These circulate in vivo as a complex population commonly referred to as a quasispecies.7
The Hepatitis C virus is also the cause of some cancers such as liver cancer (hepatocellular carcinoma) and lymphomas in humans. HCV is predominantly a blood-borne virus, however, with very low risk of sexual or vertical transmission. The key groups at risk are intravenous drug users, recipients of blood products and sometimes patients on hemodialysis. HCV causes both acute and chronic infections. About 30% of individuals fight off the infection, and the condition resolves on its own; however, the vast majority (about 70%) of infected individuals will develop chronic HCV infection. Overtime, liver cirrhosis or liver cancer may occur.
Persons who have been infected with Hepatitis C may appear to clear the virus but remain infected. 40% of those with hepatitis but with both negative Hepatitis C serology and the absence of detectable viral genome in the serum have HCV in a liver biopsy. Unlike Hepatitis A and B, there is currently no vaccine to prevent Hepatitis C infection.
Current Hepatitis C treatment options depend on many factors since there are many variants of the HCV. The medication choices depend on the Hepatitis C genotype, presence of existing liver damage, other medical conditions, and prior treatments. Antiviral medications which are prescribed can help to clear the virus from the blood but also can lead to renal toxicity and failure. More importantly, they can cause liver inflammation, especially those with existing liver health issues as those with HCV have.
