NATURAL THERAPEUTICS: LIVER DISEASE
Most people take their own liver for granted, but optimum function of this organ is vital for health and wellbeing. The liver is essentially sandwiched between the tubular digestive tract and the remainder of the body and its functions are highly complex. Liver cells (hepatocytes) are arranged with specific architectural designs that permit the extraction of compounds from the circulation and the transformation of many of these substances for subsequent utilization by, or elimination from the body. One major function of the liver is to produce bile that carries material to the digestive tract and assists in the active processes of digestion.
The liver is a factory that produces essential substances such as albumin clotting factors and fats (lipoproteins). Other functions of the liver include the maintenance of normal glucose and amino acid metabolism. Specialized cells within the liver (Kupfer cells) are able to ingest particulate materials, including bacteria that may circulate in blood.
The liver is a very resourceful organ and obvious signs of liver disease may not occur until a large amount of liver tissue is destroyed or ailing (Table 1). This means that the liver has a “high reserve capacity”. This capacity is accompanied by an efficient ability of liver cells to regenerate. The early diagnosis and intervention of liver disease is a quest of modern medicine and during comprehensive clinical examinations, liver function tests are ordered in a routine manner.
Modern research has uncovered many mechanisms of injury to the liver, including: viral infections, toxic insults with alcohol or drugs, metal storage and immune damage. With an increased understanding of the challenges presented by environmental toxins, scientists are looking for the altered states of body metabolism that result in a sequence of events that cause liver disease in the form of inflammation, irreversible damage (e.g. cirrhosis) and liver cancer. It is useful to tabulate the clinical features of liver disease (Table 1.)
Acute Liver Disease Chronic Liver Disease
Jaundice Cross over of all features listed in acute disease
Fever, Malaise Muscle wasting
Itching Fluid accumulation, asicitis
Bleeding tendencies Renal failure
Altered CNS function Bleeding from digestive tract
Table 1. Common clinical features of liver disease
Some patients with liver disease do not manifest these features especially in early stages and other symptoms may co-exist.
Acute Liver Disease
The most common causes of acute liver disease include infnallation of the liver (hepatitis) or impaired secretion of bile (cholestasis). In the presence of hepatitis, liver cells (hepatocytes) tend to release their contents, most notably enzymes that are called transaminase enzymes. Hepatitis can result from viral infections (Hepatitis A, B, C and others), drug toxicity and poor blood flow to the liver associated with cardiovascular disease or sepsis.
Disorders that cause cholestasis (impaired secretion of bile) are often associated with jaundice, itching and a rise in a specific blood marker enzyme called alkaline phosphatase. Obstruction of bile secretion is often found when gall stones block the villiary tract (gall bladder and attached bile ducts). On occasion, lack of flow of bile results from failure of liver cells to secrete bile. This sometimes occurs as a side effect of certain drugs.
Chronic Liver Disease
Chronic inflammation in the liver can follow fatty deposition in the liver and result in the development of cirrhosis of the liver. Fatty liver occurs for many reasons including: obesity, metabolic syndrome x, viral infections, drugs or liver toxicants, including alcohol. Cirrhosis of the liver involves the deposition of fibrous tissue that destroys normal liver architecture and function. There are several pathways of the development of cirrhosis and common pathways include the progression of chronic active inflammation (chronic active hepatitis) and hepatitis induced by alcohol or toxins. In these pathways of destruction of the liver tissue there is death of liver cells accompanied by inflammatory processes that lead to fibrosis.
Tests of Liver Function
Liver function tests are routinely documented on routine blood chemistry analyses but extra testing is often required to make a definitive diagnosis of specific forms of liver disease. Imaging tests may provide limited value, except for common villiary tract disorders (gallstones) or uncommon situations such as a liver abscess or tumor. Diagnosis of liver disease sometimes requires the use of invasive testing such as needle biopsy of the liver. Decisions to order specific tests for liver functions or liver abnormalities are at the discretion of the supervising physician. Useful tests include markers of immune function, viral markers of hepatitis and studies of iron and copper deposition in the body.
Structure and Function of the Liver
In this short overview, I discuss structure and function of the liver with a focus on the use of nutrition and dietary supplements in the promotion of liver health. Dietary supplements are used increasingly in the nutritional support of the liver and regulations do not permit the discussion of treatment of liver disease with dietary supplements that are freely available for purchase without a prescription. Earlier, I mentioned important aspects of hepatic function where the liver receives substances that are transported through the portal venous system from the tubular digestive tract. The liver receives all breakdown products of digestion and incorporates them into processes of chemical conversion or storage with subsequent release into the blood stream of the body and the bile. The liver can be described in simple terms as a factory of conversion of chemicals, storage system and an organ of elimination.
The liver has two separate blood supplies which form minute vascular channels adjacent to liver cells that permit a very efficient exchange of materials. The liver cells or hepaticytes are the seat of many chemical reactions (metabolism). Liver structure is underpinned by many transport systems where proteins and lipids are transported through liver cells by tiny sacks or vesicles that are bound to cell membranes. The liver has cellular systems that can engulf particles and it possesses important lymphatic cells that direct the flow of lymph. An integral part of liver structure is the origins and aggregations of tissues that form the bile ducts and the originating bile ductiles. There are many changes in body chemistry that alter liver structure and function. Such changes result in oxidative damage to liver tissues, abnormalities of fat metabolism, progression of inflammatory responses, movements towards the deposition of fibrous tissue in the liver and other damaging activity. These mechanisms are the causation of liver disease may be corrected by a variable degree by conventional treatments which are not the subject of this overview of natural therapeutics.
After many decades of detailed research into the causation of liver disease, the role of nutritional deficiency in the causation of several types of liver disease remains the subject of considerable debate. There are many scientific examples of the potential role of malnutrition in the propagation of liver disease. In some experimental animals, deposition of fat in the liver and cirrhosis of fat in the liver may occur by feeding of diets that are deficient in lIpotropes, such as choline. Certainly, fat deposition in the liver occurs in states of protein in calorie malnutrition. Obesity in metabolic syndrome x are clearly linked to the development of fatty liver and liver inflammation with variable progression for liver fibrosis. Furthermore, obese individuals who have undergone intestinal bypass surgery may develop fatty liver, hepatitis and cirrhosis. These observations provide clear links between nutrition and liver disease.
Nutritional Support for Liver Disease
I would be misleading to suggest that there was a simple way of protecting the liver from daily environmental insults equally, it would be even more misleading to suggest a panacea remedy to protect the liver or reverse the many complex changes that occur in liver disease. Without too much simplification, the structural changes that occur in the progression of many types of liver disease involve three issues. First, deposition of fat in the liver, second, ongoing inflammation that is fueled by oxidative stress to tissues (free radical damage) and ensuing deposition of fibrous tissue in the liver which culminates in cirrhosis. These three areas of changes in liver structure are paralleled by decreases in liver function which may not be readily apparent in measurements of standard liver function. It is fair to say that standard treatment for certain types of liver disease have been disappointing or they possess disadvantages and limitations. Anti-inflammatory drugs, such as steroids have limited and often temporary benefits. Anti-viral drugs have not resulted in elimination of common hepatic viruses. The use of drugs that suppress immunity in cases of ongoing liver inflammation, such as chronic active hepatitis have limited benefits and potentially onerous side effects. The promise of interferon for the treatment of hepatitis c infection has not materialized, overall.
The dietary management of liver disease depends upon many factors including: the status of liver damage, the causation of the liver damage and several other variables. The commonest form of liver disease is fatty liver, where fat deposition occurs in a manner that tends to promote ongoing inflammation. Much has been learned about the common nature of fatty liver which constitutes a “hidden epidemic” that is closely associated with an overweight status or obesity. A key association with the occurrence of fatty liver is the condition Metabolic Syndrome X. In Syndrome X, excessive body weight, alteration of blood lipids (cholesterol) and hypertension occurs in association and abnormalities of glucose balance in a variable manner. The hallmark problem in Metabolic Syndrome X is the presence of insulin resistance. The most effective approach to the elimination of fatty liver is to diagnose and manage Metabolic Syndrome X and associated obesity. Following the original description of Syndrome X by Reaven in 1998, other guidelines have emerged to find a unified definition of Metabolic Syndrome X. The National Cholesterol Education Program (Adult Treatment Panel III, ATP III) has indicated in an executive summary (2002) that Metabolic Syndrome X or insulin resistance can be assumed to be present if any three of the following five criteria are exhibited by an individual. I feel justified in repeating these “easy” clinical criteria for a diagnosis.
1. Abdominal obesity: defined as waist circumference in men of >102cm (40 in) and in woman more that 88cm (35 in).
2. Fasting blood triglyceride level>150mg/dl (1.7mmo1/1).
3. HDL cholesterol <40mg/dl (<1mmol in men) <50mg/dl (<1.3 mml in women) 4. Blood pressure > 130/85 mmHG
5. Fasting glucose >110mg/dl (>6.1 mmo1/1)
There are many circumstances that can result in or aggravate circumstances of insulin resistance. These include the presence of central (visceral) obesity, the role of circulating free fatty acids, chemical messengers elaborated by fat tissue, pro-inflammatory substances in the body and genetic or epigenetic factors. It is likely that we shall continue to redefine Syndrome X. Syndrome X is probably a heterogeneous condition, where certain disease states may express themselves preferentially as a consequence of different patterns of underlying pathophysiology. There is a simple way of looking at Syndrome X and describing it as a quartet of problems that can be assigned to the four ends of the letter X. Figure 1.
Figure 1. A simplistic view of the four cardinal components of Syndrome X
I have taken an alternative perspective on addressing liver disease in general by pointing to the commonest causes of liver disease that exceed the occurrence of viral and perhaps alcohol induced fatty liver. The occurrence of fatty liver in association with obesity has been recognized in the medical literature for about fifty years. To quote one early study, researchers found evidence of liver cirrhosis in seven out of twenty nine patients (24%) on liver biopsies. Furthermore, significant liver disease was present in 76% of these patients (22 out of 29). While these findings cannot be extrapolated to the general population with obesity (Adler M, Shaffner F, Am J Med, 67811-16, 1979), the relationship between liver disease and obesity is quite clear and it has been demonstrated repeatedly in studies published over the past four decades. In one famous and pivotal study, liver biopsies were performed in two hundred and forty two patients prior to surgery for obesity with the finding that standard liver function tests were not efficient predictors of the presence of underlying and common liver disease (Gallambos JT, Wills CE, Gastroenterology, 74, 1191-95, 1978). To place these findings into perspective, there are almost two billion people who are overweight on a global basis and approximately US seventy million people have Metabolic Syndrome X. It is relevant to state that the superimposition of an overweight status or Metabolic Syndrome X may be an important factor in aggravating pre-existing liver disease or ongoing insults to the liver such as chronic alcohol consumption or viral infections. To move to an example of more contemporary studies, modern research underscores the importance an overweight status as an independent risk factor for a fatty liver and hepatic steatosis (a form of fatty liver) in individuals with chronic hepatitis C infection (Hu KQ et al, J Hepatol, 40, 1, 147-54, 2004).
It is difficult to give combination data on complex nutritional approaches to the management of liver disease but it is reasonable to highlight natural substances that appear to have an evidence base to combat fatty liver and other progressive damage that occurs in liver disease, in general. The remainder of this review highlights specific botanicals and nutrients that have an emerging evidence-base in the management of fatty liver and liver fibrosis.
Milk Thistle (Silybum marianum, synonym Carduus marianus)
The use of milk thistle extracts is widespread in the practice of Integrative Medicine. This botanical is used for many liver disorders including hepatitis of diverse cause, toxic liver damage and liver cirrhosis. The prolonged administration of milk thistle extracts (70-80% of active Silybum marianum compounds) has been found to be generally safe when used for prolonged periods. The seed of the milk thistle plant is the preferred source of dietary supplements that are reported to contain the active constituents of this botanical. In brief, the seed contains four different types of flavone containing substances, or flavonolignans, which include: silibinin (silybin), isosilybinin, silichristin (silychristin), and silidianin. These constituents have strong antioxidant properties and they will inhibit lipid peroxidation which is a key issue in damage that can be induced in liver cell membrane. It has been proposed that active constituents of milk thistle may have direct protective effects on liver cell membranes, in a manner that may protect liver toxins. Other studies imply that extracts of milk thistle could have anti-inflammatory, immune-supporting and anti-fibrotic effects. Other potential benefits of milk thistle include the blocking of key enzymes that may result in the development of toxic compounds in the digestive tract including the liver itself.
It is of notable interest that silybum marianum may reduce insulin resistance, favorably alter blood lipid profiles and assist in blood glucose control. Constituents of milk thistle may continue to circulate between the liver and digestive tract and it is proposed that silybum marianum may have an effect on reducing inflammatory compounds, such as tumor necrosis factor. Studies of drug metabolism show that constituents of milk thistle could inhibit blood metabolizing enzyme systems to a variable degree. There are reports of estrogen-like activity in some preparations of milk thistle, but the seeds of milk thistle that are used in common extraction processes do not have estrogenic properties.
There have been several attempts to improve the therapeutic effects of milk thistle, with a view to increasing the absorption of active constituents. This technology has involved the complexing of phosphatidylcholine with milk thistle extracts. There have been inconsistent reports that this combination could improve outcome in certain circumstances of liver disease. The most conservative opinion is that milk thistle products do not reduce death in patients with liver disease and they may not improve liver function tests in individuals with viral hepatitis. That said, the combination of phospholipids with milk thistle extracts seems to be a complementary approach and any favorable outcome may not be necessarily due to enhanced absorption of milk thistle constituents.
Alpha-lipoic acid has become a popular dietary supplement with reports that it is valuable in the management of oxidative stress and it has other potential treatment properties in conditions such as diabetic neuropathy, heavy metal poisoning and other conditions that involve oxidative stress. A key action of alpha-lipoic acid is to promote natural antioxidant defenses by increasing cellular concentrations of glutathione which variably decline with age. Other beneficial reported actions of alpha-lipoic acid include improvements in blood glucose control, activation of body detoxification mechanisms and suppression of inflammatory compounds such as NF-kappa B. It is notable that NF-kappa B activity is closely related to the presence of insulin resistance. In brief, alpha-lipoic acid presents a promising treatment option for liver disease, diabetes, cardiovascular disease and inflammation. Alpha-lipoic acid has properties that may classify it as a calorie restriction mimetic related to its action on AMP-activated kinase (AMPK).
The biological activity of alpha-lipoic acid appears to be greater when the chemical form of R-alpha-lipoic acid is used. The positive effect of alpha-lipoic acid on the potential correction of insulin resistance and its other actions make this compound ideal for liver protection or support in a variety of circumstances.
Curcumin (Curcuma longa Linn (Zingiberaceae)
Curcumin is a highly bioactive component of turmeric that is commonly used in East Indian cuisine. Curcuminoids are mixtures of compounds with strong antioxidant qualities and other valuable characteristics. Curcuminoids have anti-inflammatory actions, anti-mutagenic properties, anti-carcinogenic actions and analgesic effects. In addition, they are antiviral, antifungal and antispasmodic agents. Curcuminoids exert protective effects by many different mechanisms.
Detailed studies in experimental animals show that curcuminoids may have potent effects on preventing hepatic fibrosis. In the process of the development of fibrotic changes in the liver, special liver cells (hepatic stellate cells) are activated and they change into cells that promote liver injury by causing fibrosis (myofibroblast-like cells). Curcuminoids seem to cause the death (apoptosis) of activated liver stellate cells, resulting in a liver protective effect. It is recognized that fibrosis of the liver may be reversed to some degree by the elimination of hepatic myofibroblasts. Curcuminoids seems to have a very special role in working against these myofibroblasts and one mechanism of action appears to be the inhibition of complex biochemical pathways that cause an inhibition of the inhibitor of kappab kinase/nuclear factor-kappaB pathways. While this circumstance appears highly complex it can be summarized as the direct interference with cell activity that promotes fibrosis in the liver.
Blueberry (Vaccinium angustifolium)
Blueberry and its extracts have found an increasing role in health maintenance. In common with other berries they provide a high antioxidant content and they are distinguished by their content of proanthocyanidins. There are host of similar compounds in the botanical world which are sometimes referred oligomeric proanthocyanidins, or OPC’s. Blueberry preparations have been used to promote stem cell mobilization and stem cell activity in the liver is an important component of hepatic regeneration. The administration of blueberries results in significant increased concentrations of antioxidants in the blood humans who consume these berries.
Blueberry leaves are a source of proanthocyanidins as is the berry. Proanthocyanidins from blueberry leaves have been shown to be potentially useful in the management of hepatitis c virus infections. Experiments in cell culture systems that can be used to measure hepatitis c virus activity show that proanthocyanidins from blueberry leaves may inhibit viral replication and serve the purpose of being potentially important in hepatitis C virus infections.
There are a number of phospholipids that may exert benefit in different forms of liver disease. Many different types of phospholipids can be found in the general supplement lecithin. Of particular interest is the use of polyenylphosphatidylcholine (PPC) which has been extensively researched by the famous hepatologist Dr. CS Lieber MD. In brief, many studies performed by Dr. Lieber and his colleagues imply that PPC may prevent the progression of fibrosis in patients with alcoholic liver disease. It is inferred from these studies and others that this action of certain phospholipids may be expected to be beneficial in liver fibrosis caused by viral infections, autoimmune disease and progressions of steatosis.
The mechanism of the protective effects of PPC are highly complex. The administration of PPC in patients with chronic hepatitis C has been added as a treatment after the termination of interferon therapy, in an attempt to prevent common relapse that occurs following such therapy. The beneficial effects of phospholipid therapy are not necessary limited to one type of phospholipid and there is no doubt that PPC and related compounds have most demonstrated effects in the treatment of alcoholics with liver disease.
Vitamin E and Tocotrienols
It has been suggested that lipid peroxidation and damage by free radicals play an important role in liver damage. In fact, tocopherols and glutahion are believed to act in the in-built defenses of the liver against free radical damage. Recent ongoing clinical trails of tocotrienols show an ability of these compounds to prevent liver accumulation of fat. In these trials approximately two thirds of all subjects demonstrated a significant improvement in their status of fatty liver. It was striking in this experience of the use of tocotrienols that thirty patients were reported as having complete resolution of a fatty liver after one year of treatment.
This brief overview of nutraceuticals with defined hepatoprotective effects opens up a pathways to synergistic formulations where multifunctional components can be combined to provide significant benefits in individuals with progressive liver disease. Advances in understanding of the pathophysiology of viral and toxic causes of liver disease present three processes that can be addressed by certain nutrients or botanicals. These processes include the development of fatty liver, the importance of free radical damage to the liver with a need for suppression of underlying information and the hepatoprotecitve benefits of phospholipids. Combining this recent information an optimum approach to the use of natural substances that would support liver structure and function would include agents that have a high degree of antioxidant potential such as Silyamarin and R-lipoic acid, with other antioxidants ( ) and specific or mixed phospholipids and anti-inflammatory botanical agents.