Bile acids/salts and mechanisms of biliary flow

Whereas cholesterol accounts for more than 90% to 95% of the sterols in bile, bile acids and their salts are the most important solutes; they are essential in the management of cholesterol levels and themselves help determine the extent of bile flow. Bile acids are synthesised from cholesterol by the liver. There are three groups. Primary bile acids, in humans mainly cholic and chenodeoxycholic acids and their salts, are produced directly. Secondary bile salts are created by the action of intestinal bacteria on primary bile salts with deoxycholate and lithocholate being formed from cholate and chenodeoxycholate, respectively. Tertiary bile salts are the result of modification of secondary bile salts by intestinal flora or hepatocytes; in humans these include the sulphate ester of lithocholate and ursodeoxycholate and the 7-beta-epimer of chenodeoxycholate.¹

Bile flow rates and composition are subject to a wide variety of neural, endocrine and paracrine influences. One of the main stimulants of bile flow are bile acids themselves, either in their primary form or reabsorbed as secondary or tertiary forms in the enterohepatic circulation (see below). The cholagogue effects of bile acids have led to their prescription in hepatobiliary disorders. One derivative, ursodeoxycholic acid, has been shown in controlled clinical studies to be a useful agent in the management of patients with primary biliary cirrhosis, autoimmune chronic active hepatitis² and cystic fibrosis.³

Cholestasis

Infective conditions may lead to cholestasis or reduced bile flow with symptoms including jaundice, pruritus and steatorrhoea. Chronic alcoholics may have hypotonic gallbladder, with increased speed of bile secretion and low biliary levels of cholic acid, cholesterol and bilirubin. Patterns of bile stagnation can occur with increasing severity of alcoholism, especially when associated with cirrhosis.⁴ This effect has been attributed to the effects of lipopolysaccharide endotoxins.⁵

The role of inflammatory bowel disease in inducing cholestasis is also well established.⁶ In one study serum cholestanol/cholesterol proportions were determined in 79 patients with inflammatory bowel (colonic and ileal) diseases, such as ulcerative colitis and Crohn’s disease, and 23 with irritable bowel syndrome as controls. The findings suggested that the increased cholestanol proportion in colonic inflammatory bowel diseases is determined mainly by impaired biliary elimination of this sterol, while in ileal disease the dominating change in sterol balance is activated cholesterol synthesis. Increased serum cholestanol is a novel finding in colonic inflammatory bowel diseases, apparently indicating the presence of subclinical cholestasis in a marked number (20% to 50%) of inflammatory bowel disease patients.⁷

Therapeutic stimulation of bile flow could thus be justified in the management and treatment of any of the above circumstances (see below).

It appears that a substantial amount of urate is also eliminated by the biliary route in humans. Gout and other urate-associated conditions linked to decreased renal urate excretion may therefore benefit from measures that increase biliary urate excretion.⁸

Toxicity of bile acids

Because it is known that high concentrations of bile acids are cytotoxic, it has been speculated that their raised presence in serum and tissues in hepatobiliary diseases contributes to the pathological progression of these disorders. Bile acids are a causative factor in chronic gastritis.⁹ Evidence is that oral administration of ursodeoxycholate, being a relatively non-toxic bile acid, can replace more hydrophobic hepatotoxic bile acids in the circulating pool and, by doing so, ameliorate the harmful effects of the latter.¹⁰

Enterohepatic circulation

An important aspect of bile acid function and toxicity is the constant reabsorption from the intestine into the portal circulation and back to the liver and biliary system – the enterohepatic circulation. Both primary and secondary bile acids are involved in this recycling. In modern medicine a high degree of recycling is assumed. Only 1% of bile acids are lost in the faeces and it was calculated that bile acids are recirculated about 12 times per day.¹¹ However, it is likely that humans living a more primitive lifestyle with much higher levels of fibre intake had lower reabsorption rates. The implications of enterohepatic circulation are best understood with reference to the kinetics of drugs such as the morphine alkaloids and digoxin, which are largely eliminated from the body through the bile. Increased retention of bile in the enterohepatic circulation is known to increase the half-life of these and other drugs in the body. It is likely, therefore, that the level of bile products (with the formation of tertiary bile acids) and other potentially toxic metabolites may increase, unless the enterohepatic circulation is as low as possible. In practice, this is most likely to follow a relatively fast intestinal transit time, associated with a high-fibre diet.

Bile and cholesterol

Although they are generally cholagogic, the presence of bile acids in the enterohepatic cycle acts to decrease the hepatic production of cholesterol, presumably through a process of negative feedback, and this is likely to control excessive cholesterol secretion in gallstone conditions. As with other hepatic conditions, replacement therapy with bile acids such as chenodeoxycholic and ursodeoxycholic acids is promoted as a treatment, leading even to dissolution of existing gallstones.¹²

Of wider significance is the finding that reduction in the absorption of bile acids from the gut, associated with, for example, diarrhoea, leads to an increase in cholesterol synthesis and cholesterol esterification rate by the liver.^13,14

Biliary cholesterol excretion is directly linked to two major pathological issues, namely atherosclerotic cardiovascular disease (ACVD) and cholesterol gallstones. In ACVD biliary cholesterol secretion is the final step in the reverse cholesterol transport (RCT) pathway, the transport of peripheral cholesterol back to the liver for excretion.¹⁵ For RCT, enhanced biliary secretion of cholesterol is desirable, although this can lead to biliary cholesterol supersaturation and gallstones. The most relevant source of cholesterol secreted into bile is cholesterol derived from plasma lipoproteins, with HDL (high density lipoprotein) the preferential contributor.¹⁵ However, definitive studies exploring the underlying metabolic pathways are still lacking, although ABC (ATP binding cassette) transporters are known to be involved: specifically ABCB11 for bile acid transport into bile, ABCB4 for phospholipids and ABCG5/G8 for cholesterol.¹⁵

Effects of bile acids in the intestinal tract

Both primary and secondary bile acids have secretagogue effects on the intestinal mucosa, changing net fluid transport across the villi from absorption to secretion.¹⁶ There is also an atropine-inhibited (i.e. cholinergic) stimulation of intestinal contractions¹⁷ and an increased mucosal vasodilation (blood flow increasing by around 50%), which is not inhibited by atropine.¹⁸ Secondary bile acids in particular are thought to increase permeability at the zonulae occludentes that binds endothelial cells together at their luminal borders, so that normal subepithelial hydrostatic pressure is raised sufficiently to reverse net sodium, chloride and water absorption to net secretion.¹⁹

Bile has sometimes been referred to as the body’s own laxative or ‘endolaxative’.²⁰ Indeed, it is established that bile acids (especially secondary bile acids – see below) can be responsible for bowel looseness and their effects should be borne in mind in cases of unexplained chronic diarrhoea.^21,22

Bile has a wider range of actions on the intestinal mucosa. Where there is clear reduction in bile levels, there is a reduction in thickness of the mucus blanket, reduced numbers of mucus-associated enterocytes (suggesting a reduced endothelial turnover rate) and lymphocytes and increased populations of bacterial organisms. The implication is that normal bile function is a vital part of the body’s gut-related defences.²³ It has also been demonstrated that bacterial endotoxin absorption is increased in the absence of bile salts from the intestine.²⁴

Bacterial action on bile acids—consequences and implications

The generally positive functions of primary bile acids become rather more mixed in their effects once bacterial deconjugation and dehydroxylation occur. Secondary bile acids are produced at a very early age – the process is clearly under way even in month-old infants²⁵ – and are an entirely normal range of metabolites. It is clear that most bacterial deconjugation occurs in the colon²⁶ but in various less ideal circumstances invasive bacterial populations can lead to secondary bile product formation in the small intestine.

Secondary bile acids have a decidedly irritating effect on the intestinal wall. Exposure of the intestinal wall to deconjugated bile acids stimulates local inflammatory mechanisms, accompanied by the release of prostaglandin E₂ and leukotriene C₄. Such effects are particularly pronounced if there is already latent or active inflammatory disease of the intestinal wall, particularly in small intestinal Crohn’s disease.²⁷ The irritant effect of secondary bile products is especially apparent if their quantities are increased due to stasis in the small intestine. Among a number of ultrastructural alterations to the intestinal mucosa, they increase the numbers of lysosomal vascular structures, fused microvilli and dilated endoplasmic reticulum, which among other implications leads to a reduced absorption of solutes including glucose and other carbohydrates^28,29 and, significantly, fluid absorption:³⁰ diarrhoea is thus possible. Secondary bile metabolites substantially increase the absorption rates of urea and oxalates from the gut.³¹

There are more insidious potential effects too. Secondary bile acids and their metabolites increase colonic cell proliferation.³² The carcinogenic effect is clearly linked to changes in the nature of bacterial populations in the gut, rather than to the nature of the bile acids or indeed other starting materials in the gut.³³ However, there is also little doubt that decreased reabsorption of bile acids (for example, as seen with increasing old age) does increase the likelihood that carcinogenic and other pathogenic bile metabolites will be produced.³⁴

Dietary factors are known to affect the balance between intestinal flora and bile metabolism. For example, consumption of sugars was shown in nine volunteers on a crossover basis to significantly prolong transit time through the colon and significantly raise the faecal levels of both primary and secondary bile metabolites.³⁵ On the other hand, the consumption of 16 g of wheat bran a day on a double blind, 6-month crossover basis by ulcerative colitis sufferers in remission was shown to decrease the faecal concentration of bile acids by almost half. No such effect was observed with psyllium seed.³⁶

There are some potential benefits in bacterial action on bile acids. Anaerobic bacteria, for example, can produce volatile fatty acids known to non-specifically inhibit pathogenic bacterial populations.³⁷

Bile acids in diseases

Disturbed and pathological states can change the dynamics of bile and other intestinal relationships. In malnutrition, for example, morphological changes in the intestinal wall lead to increased sensitivity to the effects of secondary bile acids, poor absorption of fats and other nutrients, all of which is compounded by changes in intestinal flora.³⁸

The impact of inflammatory intestinal diseases like Crohn’s is even more pronounced. The damage induced by the disease on the intestinal wall leads to reduced bile acid reabsorption and compensatory increased cholesterol synthesis by the liver,³⁹ a reaction that probably explains the high level of biliary disease such as gallstones in sufferers from Crohn’s.^40,41 The link between inflammatory bowel disease and cholestasis has already been mentioned, and Crohn’s disease in particular is linked with disturbed bile metabolism and gallstones.⁴² Similar negative impact on enterohepatic circulation follows small intestinal resection, which has been shown to lead to increased synthesis of both bile acids and cholesterol.⁴³

The association between biliary and intestinal functions is further highlighted in the condition primary sclerosing cholangitis, a disease characterised by inflammation and obliterative fibrosis of bile ducts. In 70% of cases it is associated with ulcerative colitis. In about two-thirds, there are circulating IgG antibodies to a peptide shared by epithelial cell walls in both bile ducts and colon. Another suggested cause is portal bacteraemia secondary to a diseased bowel wall. The addition of bile acids to the gut has been proposed as a treatment.^44–46

Plant constituents, cholesterol and bile function

A useful insight has been made in studies of the metabolism of plant sterols. Plant sterols are structurally similar to cholesterol but, because of poor intestinal absorption, are ordinarily not present in the liver. However, there does appear to be competition in the movement of plant sterols and cholesterol. For example, high plant sterol consumption appears to lower blood cholesterol levels,⁴⁷ especially in the short term,⁴⁸ and the proportions of plant sterols are significantly lower in cholesterol-rich gallstones than in bile (and stones with low cholesterol content are proportionately richer in plant sterols).⁴⁹ One sterol studied, sitostanol, parallels the secretion from and distribution of cholesterol in the liver (for example, both requiring bile salts for secretion in bile) so that it can be used as a physiologic analogue of unesterified cholesterol to trace the transport of sterols through the liver.⁵⁰ Such studies, for example, indicate that HDLs are necessary along with bile acids for cholesterol elimination in bile.⁵¹ The use of plant sterols (in this case campesterol and sitosterol) as markers of cholesterol absorption and biliary secretion was also seen in a study referred to above, showing subclinical cholestasis as a feature of inflammatory bowel disease.⁵²

When serum concentrations and metabolism of cholesterol were studied in human vegetarians, cholesterol absorption was found to be normal and synthesis was slightly enhanced, though without increase in serum cholesterol precursors. The serum concentrations of total and low-density lipoprotein (LDL)–cholesterol were decreased but, in addition to the obvious lower intake of cholesterol itself, it appeared that the higher intake of plant sterols interfered with cholesterol absorption and thus increased endogenous cholesterol synthesis. Thus, cholesterol saturation and bile acid composition of the bile were not changed. Biliary excretion of plant sterols was apparently relatively inefficient.⁵³

Interactions between cholesterol transport and plant constituents extend to another major group. Saponins have been implicated in interference with the absorption of cholesterol, bile acids and fats, leading to reduced animal growth, but also have shown potential in the reduction of blood cholesterol levels.⁵⁴ There is evidence of interference with the absorption of vitamins A and E.⁵⁵ Their cholesterol-lowering effect may also be linked to their binding of bile salts and increasing their faecal excretion, thus increasing bile salt synthesis from endogenous cholesterol.⁵⁶ Further studies to investigate the effects of saponins on bile, cholesterol and lipid metabolism are clearly warranted (see also Chapter 2). One steroidal sapogenin that has been studied, diosgenin, is, like the sterols, also similar enough in structure to cholesterol to interfere with its esterification in the liver.⁵⁷ This may contribute to the marked increase observed in biliary cholesterol relative to phospholipids when it was fed for 7 days to rats (see Chapter 2).⁵⁸

Choleretics and cholagogues

There is a traditional differentiation made between cholagogues and choleretics. The former are agents that stimulate the release of bile that has already been formed in the biliary system. Bile acids are the main endogenous cholagogues and fatty foods the most obvious exogenous factors.

Choleretics stimulate bile production by hepatocytes and some have effective cholagogue properties as well. Cholecystokinin, secretin and some of the other humoral agents are involved endogenously. Bitters and some of the botanical agents referred to below are likely to have choleretic activity (see Chapter 2).

There is very little interest in choleretic and cholagogue treatments in conventional medicine, at least in the English-speaking world. Among agents incidentally discovered, NSAIDs, especially aspirin (in one study at a level of 100 mg/kg), cause choleresis in animals.⁵⁹ Magnesium sulphate (Epsom salts), sometimes used for constipation, has at doses of 500 mg been shown to exert a direct effect on the motor activity of the gallbladder in dogs.⁶⁰

Research on herbal choleretics and cholagogues has largely come from Germany and Eastern Europe. It is not comprehensive and most practice in this area is informed by traditional reputation. Given the difficulty in knowing what actually happens in the liver and the potential risks of counterproductive treatments (see below), this is not an ideal situation.

Among the work that has been done, it has been shown that the ethanolic extract of Chelidonium majus (greater celandine) in isolated liver culture significantly caused choloresis by increasing bile acid-independent flow,⁶¹ and there is indication of activity in this area in clinical trials (see monograph). A survey of the literature shows that Cynara scolymus (artichoke) possesses choleretic, diuretic and hypocholesterolaemic properties (see monograph). The main active components of this plant are mono- and dicaffeoylquinic acids, flavonoids and sesquiterpenes. The most suitable raw material is fresh leaves in the plant’s first year of growth.⁶² Recent focus has been on the contribution of the claimed choleretic activity to cholesterol reduction. A Cochrane review⁶³ of three good-quality double blind studies points to a modest effect on total and LDL-cholesterol levels, although not at sufficient levels to recommend to prescribers. In one of the more significant placebo-controlled studies, involving 75 people in the UK, total cholesterol was reduced by 42% in the group receiving 1280 mg of standardised artichoke leaf extract per day for 12 weeks, whereas the levels in the placebo group actually rose.⁶⁴ The choleretic activity of globe artichoke leaf has also been confirmed in clinical studies (see monograph). Phenolic acids in Mentha longifolia were found to possess significant in vivo choleretic and CNS stimulating effects⁶⁵ and peppermint leaf is traditionally regarded as a cholagogue. Turmeric (Curcuma longa) is also a clinically relevant cholagogue and choleretic herb (see monograph).

Plant remedies traditionally used as choleretics and cholagogues

Cholesterol gallstones and biliary pain

Gallstones are formed when cholesterol and other solute levels in bile reach supersaturated concentrations and when the normal glassy-smooth surfaces of the gallbladder are compromised, often by infection. Bile is often supersaturated after a night’s metabolism and before breakfast: this could explain the naturopathic practice of recommending lemon juice (a liver and gallbladder stimulant) before breakfast. The concentration of bile also appears to be related to intestinal activity and slow intestinal transit has been linked to gallstone formation in normal-weight women⁶⁷ and in other studies.⁶⁸

Certain risk factors for gallstones are inherent: being female, increasing age and ethnicity/family history (genetic traits). Others are modifiable: obesity, metabolic syndrome, hypertriglyceridaemia, rapid weight loss, diet (low in fibre and high in refined carbohydrates and saturated fat) and certain diseases (cirrhosis and Crohn’s disease).⁶⁹

Findings largely from in vitro and in vivo studies suggest that infection, inflammation and the response of the immune system can also influence the pathogenesis of cholesterol gallstones.⁷⁰ Supersaturated bile can lead to biliary sludge, composed of agglomerated cholesterol crystals. However, human studies have shown that biliary sludge does not necessarily lead to gallstone formation.⁷⁰ The missing link could be infection and/or inflammation that seeds stone formation.

Most patients with gallstones have no symptoms and current medical thinking is that there is no distinct advantage in treating asymptomatic gallstones.⁷¹ Small stones are more dangerous than large as they can cause pancreatitis.⁷² Oral dissolution therapy with bile salts is still used as a treatment, but is reserved for patients with non-calcified cholesterol gallstones, a patent cystic duct and for those who do not require urgent surgery.⁷¹ These considerations also define the conditions for successful herbal treatment of gallstones. Patients who receive conventional oral therapy usually have a high rate of gallstone recurrence. This underlines the need in herbal therapy for long-term treatment concurrent with appropriate dietary and lifestyle changes.

A key outcome of phytotherapy for cholesterol gallstones is that it can render symptomatic gallstones quiescent. However, its greatest value here will be for stones that are not calcified in a functional gallbladder.

The essential elements of treatment are as follows:

A short course of copious olive oil and lemon juice is often recommended to discharge gallstones, although this is controversial.^75,76 However, such a therapy should only be attempted if the gallstones are not calcified, the cystic duct is patent, the gallbladder is functional and herbal therapy to soften the stones has been given for at least 6 months.

The above herbal approach can also be used for functional gallbladder disorder (gallbladder dyskinesia), which is the recurrence of abdominal pain resembling gallbladder pain in the absence of gallstones.⁷⁷

Evidence of beneficial effects on the liver

Many plants contain constituents that have been experimentally shown to have beneficial effects on liver cells, at least under laboratory conditions. Early research investigated the hepatoprotective effects of agents in models of liver toxicity (for example, carbon tetrachloride (CCl₄), D-galactosamine, paracetamol and Amanita mushrooms) and it was such work that identified remedies such as Silybum marianum (St Mary’s thistle). This and more recent evidence more widely points to benefits on hepatic function of a diet rich in fruit and vegetables (as noted above). The case for traditional herbal practice in its particular focus on the liver as a centre-piece of therapeutics is also supported.

Particularly likely to feature in evidence are flavonoids and related polyphenols. For example, the ubiquitous flavonoid quercetin is one of a number of antioxidants that have been shown to reduce the high level of chromosomal aberrations found in cases of viral hepatitis associated with environmental pollution.⁹ Oral administration of the flavonoids daidzin, daidzein and puerarin, from the Chinese herb Pueraria lobata, was effective in lowering blood alcohol levels and shortened sleep time induced by alcohol ingestion.^10,11

Benefits from other notable plant constituents

Glycyrrhizin, a major component of licorice, has been used intravenously for the treatment of chronic hepatitis B in Japan and improves liver function with occasional complete recovery from hepatitis.¹² In vitro studies suggest a hitherto unique mechanism involving intracellular transport across Golgi membranes.¹³ In addition, weak binding activity to steroid receptors has been demonstrated.¹⁴ Derivatives of glycyrrhizinic acid promote a decrease in the rate of lipid peroxide oxygenation and in the inhibition of liver enzyme activity (ALT, AST) and also increase choleresis.¹⁵ There is evidence of a choleretic action,¹⁶ also involving glycyrrhizin. (See also the licorice monograph.)

Piperine, an active alkaloidal constituent of the extract obtained from Piper longum and P. nigrum, was evaluated for its antihepatotoxic potential against CCl₄ and other agents, and was found to have an appreciable benefit, but at levels lower than for silymarin.¹⁷

The water extract from the root of Salvia miltiorrhiza showed a protective effect on cultured rat hepatocytes against CCl₄-induced necrosis. Lithospermate B, a tetramer of caffeic acid, was isolated and found to be an active constituent. Lithospermate B was also found to have a potent hepatoprotective activity, not only in vitro but also for in vivo experimental liver injuries induced by CCl₄ or D-galactosamine-lipopolysaccharide.¹⁸ Various other metabolites of caffeic acid formed in bap are likely to account for many beneficial effects in that organ; these metabolites include cyclolignan derivatives as oxidation products, ferulic and isoferulic acid as methylation products and aesculetin as a cyclisation product.¹⁹

The Phyllanthus genus has been known to contain a number of biologically active constituents such as an angiotensin-converting enzyme inhibitor and HIV reverse transcriptase inhibitors.²⁰Phyllanthus amarus has shown antihepatitis B virus activity.^21,22P. niruri from Malaysia contains various constituents with demonstrated effects aginst hepatitis B.²³P. ussuriensis, a Korean native species, has been used to treat several infectious diseases, including hepatitis in folk medicine, and antihepatotoxic effects have been confirmed in vitro.²⁴ It inhibited hepatitis B virus polymerase activity, decreased episomal hepatitis B virus DNA content and suppressed virus release into culture medium. A number of mechanisms have been elucidated.²⁵

Silybum marianum (St Mary’s or milk thistle) seed, widely used in Europe for its hepatic reputation, contains the flavonol lignan complex silymarin with antifibrotic activity in diseased liver,²⁶ and there are other effects observed in diseased liver,²⁷ including reducing serum transaminases in patients with chronic viral hepatitis.²⁸ The traditional liver remedy Schisandra chinensis contains constituents with antihepatitis activity,²⁹ and has been shown to reduce circulating monocyte counts (although with no effects on other white blood cell counts) after 2 weeks’ treatment of human subjects infected with hepatitis B.³⁰ (See more in the St Mary’s thistle monograph.)

The Chinese remedy Sophora flavescens has also been studies experimentally and has shown promising if not conclusive evidence of effectiveness in hepatitis B.^31,32

Evidence of hepatoprotective effects also arises from studies on other traditional remedies: Artemisia spp.,^33,34Azadirachta indica leaf extract,³⁵Picrorrhiza kurroa,³⁶Osbeckia octandra,³⁷Gynostemma pentaphyllum,³⁸Inula britannica L. subsp. japonica,³⁹Salvia plebeia.⁴⁰ Other plant hepatoprotectors have been reviewed.^41–43

Schisandra has emerged as a key herb for boosting phase I and especially phase II detoxification processes by the liver. As stated previously, phase I and II reactions are involved in the metabolism of mainly xenobiotic substances by the liver. Phase I reactions (which involve cytochrome P450) can result in the production of a more toxic compound (a process called bioactivation). Despite being a postulated powerful inducer of phase I enzymes, Schisandra does not cause harmful bioactivation in vivo (e.g. after co-administration of paracetamol) and in vitro studies have indicated that constituents of Schisandra decrease the mutagenicity of benzo(alpha)pyrene by influencing hepatic metabolism.^44,45 The probable reason is that Schisandra powerfully induces phase II enzymes as well, which results in the rapid clearance of the potentially toxic metabolite.⁴⁶ Other keys herbs in this regard include turmeric (see the turmeric monograph), garlic, green tea, rosemary and broccoli sprouts (all influencing the Nrf2/ARE pathway). St Mary’s thistle is unlikely to exert clinically relevant effects on hepatic phase I/II detoxification processes, with its value being more linked to hepatoprotective activity (see below).

Another hitherto little explored hepatic activity may also be a feature of some herbal preparations: extracts of Thuja occidentalis and Echinacea purpurea have stimulated Kupffer cell phagocytosis in vitro.⁴⁷

Hepatic induction of antitumour effects

The liver has a central role in a wider range of defence mechanisms. For example, the Kupffer cells are a final screen between enteric antigens and the body cavities, various phase II liver enzymes such as glutathione-S-transferase (GST) are important detoxifiers of carcinogens, and the transport of IgA and IgA immune complexes by the liver from serum to bile may provide a host defence against enteric pathogens.⁴⁸ These key functions raise the possibility that hepatic remedies might have wider applications.

For example, out of various spices and leafy vegetables screened for their influence on GST in Swiss mice, cumin seeds, poppy seeds, asafoetida, turmeric, neem flowers and basil leaves among other spices increased GST activity high enough in the stomach, liver and oesophagus to be considered as significantly contributing to protection against carcinogenesis.⁴⁹ Several naturally occurring flavonoids and other polyphenols, prominently tannic acid, were also shown to exert varying degrees of concentration-dependent inhibition on uncharacterised rat liver GST.⁵⁰ Sesquiterpenes such as beta-caryophyllene, beta-caryophyllene oxide, alpha-humulene, alpha-humulene epoxide I and eugenol, all found in cloves, have demonstrated significant activity as inducers of GST in the mouse liver and small intestine,⁵¹ as has myristicin, a major aromatic constituent of parsley.⁵² Of course, the most active liver phase II enzyme inducers are the brassica glucosinolates, and their protective properties against experimental carcinogenesis is well described (see Chapter 2). Another key example is turmeric (see the turmeric monograph).

Capsaicin inhibited the formation by liver microsomal fractions of all metabolites of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), a potent carcinogen in tobacco and tobacco smoke. With other similar results, such findings suggest that it possesses antimutagenic and anticarcinogenic properties through the inhibition of xenobiotic metabolising enzymes.⁵³

Hepatoprotectives (or hepatics)

There are few guides to the use of hepatoprotectives (or hepatics) in conventional Western medicine. This is a concept more familiar in mainland Europe and further East, but has become a more popular concept with the marketing of St Mary’s thistle (milk thistle) seed.

Hepatoprotectives are remedies claimed to help reduce damage caused to the liver from hepatic stressors and disease. Given what has been said earlier, good hepatoprotectives are most likely to deliver antioxidant activity into liver hepatocytes and induce cellular protective mechanisms.

Acute viral hepatitis

The most important causes of acute hepatitis are the hepatitis A, B and C viruses. Other viruses, including Epstein-Barr virus and cytomegalovirus, may also cause acute hepatitis. All these viruses (except A) have a viral envelope and hence may have some susceptibility to Hypericum perforatum (St John’s wort), which is active against enveloped viruses.

Acute hepatitis can be treated using herbal medicine. In the case of hepatitis A, treatment can lead to rapid recovery and protection against post-hepatitis syndrome. For hepatitis B and C, herbal treatment will mainly help to prevent the disease becoming chronic. The small amounts of alcohol involved from using extracts and tinctures will not be a problem to most patients. However, if there is a difficulty with alcohol then tablets, capsules, glycerol extracts and/or infusions or decoctions can be prescribed. As with other acute infections, oral herbal treatment should not be administered while there is vomiting.

It is hoped that individual strategies will be devised for each patient, taking some of the insights in this and other chapters into account, but essential aspects of treatment are as follows:

It should be noted that higher doses need to be employed for acute cases (compared to treating chronic conditions).

Chronic viral hepatitis

Chronic viral hepatitis or chronic persistent hepatitis usually results from infection with hepatitis B or C. Especially with hepatitis C, some features of the disease may resemble autoimmune hepatitis. (Frank autoimmune liver disease is known as chronic active hepatitis. A general treatment approach for autoimmune disease is outlined in Chapter 8.)

Treatment

Treatment of chronic viral hepatitis shares many similarities with the treatment of acute viral hepatitis. Essential features of treatment are:

Cirrhosis of the liver

In cirrhosis, widespread death of liver cells, which can result from many causes but is most commonly due to alcohol abuse, is accompanied and followed by progressive fibrosis and distortion of liver architecture. Since alcohol is forbidden, herbal treatment should be in the form of tablets, capsules, glycerol extracts, infusions and/or decoctions. The main herbal treatment is based around hepatic trophorestoratives, especially concentrated tablets of Silybum marianum. Other important herbs in this category include Schisandra, Taraxacum radix (dandelion root), Cynara (globe artichoke), Bupleurum and Andrographis. Berberine-containing herbs can also be indicated (see the Berberis monograph). Although cirrhosis is a progressive disease, the rate of progression varies and the outlook is related to many factors. In this context, herbal treatment can make a significant positive contribution.

Antifibrotic activity is another area of herbal activity relevant to cirrhosis that is attracting research interest. The laying down of excessive fibrotic tissue in response to repeated liver damage is the main disruptive pathological change in cirrhosis. Centella asiatica (gotu kola) is a herb with potential to reduce an excessive fibrotic response (see gotu kola monograph). Salvia miltiorrhiza (dan shen) is also showing promising activity in this regard.^54,55

Poor liver function and fatty liver

The liver plays a vital role in detoxification and many other metabolic processes in the body. Phytotherapists and naturopaths recognise a condition where liver function is below optimum, although no medically observable liver disease or liver damage may be present. Because of the importance of the liver, a poorly functioning liver can have a wide-ranging impact on health.

Symptoms that may be due to poor liver function include sluggish digestion, fat intolerance, nausea, chronic constipation and chemical, food or drug intolerances. A poorly functioning liver may also contribute to a number of disease states such as psoriasis, autoimmune disease, irritable bowel syndrome, allergies and cancer. Patients might reveal a history of past liver infection, infestation or damage, alcohol or drug abuse, or exposure to medical drugs or environmental pollutants such as pesticides and/or have abdominal obesity. Drug side effects are more likely to occur in patients with poor liver function.

Depending on the symptoms, treatment is based on the following:

Old and new perspectives on the circulatory system

A phytotherapeutic perspective on the circulatory system has to take two parts. Most of what modern medicine understands of the system arises from preoccupation with disease states such as hypertension, hypercholesterolaemia, atherosclerosis, clotting disturbances and thrombosis, and coronary diseases that were barely understood in an earlier era and for which traditional physicians cannot have developed therapeutic strategies. There can be no basis therefore for directly applying old treatments to the new conditions. Nevertheless, as this chapter will show, herbal remedies show considerable promise across many of these modern conditions and their use for this purpose, at least in Europe, has been considerably modified compared with their traditional indications. Three of the best-selling herbal products in Europe, Ginkgo, garlic and Crataegus (hawthorn), are traditional remedies highly adapted to new and productive ends.

Nevertheless, to understand more effectively the potential of medicinal plants in affecting circulatory functions, an appreciation of the earlier traditional perspective will be helpful. It is immediately obvious that before modern instruments, human experience of the circulatory system and the effects of treatments upon it were very different. As shall be seen, the insights developed in these early times usefully inform modern prospects.

The circulatory apparatus of William Harvey provided a mechanistic framework for modern advances that was, however, of little application to everyday practice in his time. The common experience was that there was vital movement within the body, as measured by pulse, heartbeat and breathing, and that there was a red fluid whose presence was clearly essential. Even now microscopic film of tissue circulation resonates uncannily with the beats of tribal music! It was relatively easy to link this with the main manifestation of moving blood: the heat of the living body and the variations in that heat in health and disease. In short, blood pulsated and warmed and was generally linked with the common speculation that there must be circulation of energies, fluids and nutrients around the body. Circulation was marked by:

The heart was obviously associated with all this, but as much as a resonator with the vital pulse as its director. It was the wider pulse itself (reflected in the driving rhythms of early tribal music) that was important in early experience of the circulatory system; it was clearly linked to wider vital events: activity, excitement, emotional stimulation and, in medicine, notably the fever.

Therapeutics in fever focused on dispersing agents to distribute excessive heat and circulation and (as ‘diaphoretics’) to diffuse the poisons clearly involved through the sweat glands. The detoxifying theme recurred in many traditional concepts of ‘blood poisons’ as a cause of inflammatory diseases, and the use of ‘blood cleansers’ or ‘blood purifiers’, often very vigorously, to treat them.

Also requiring eliminatives (mainly diuretics and laxatives) was oedema, one of the most common indications of poor circulation in the past. As briefly elaborated in Chapter 1, the traditional perspective closely linked circulatory function with elimination.

Traditional views also linked circulation with the assimilation and processing of nutrients. The vital pulse and heat were weakened in debility and exhaustion, conditions associated with coldness and pallor. The main treatments were in effect ‘blood tonics’, warming nutrients (often since found to be rich in mineral nutrients).

There will be profit in revisiting these perspectives in developing modern strategies for the treatment of circulatory problems using herbal remedies. This is even more justified when the phenomenon of circulation itself is reviewed.

Circulation as currents

Where there has been speculation about the nature of the circulatory system in traditional medicine, it has tended to infer broad currents rather than Harvey’s route map. The closest to the latter were the meridians of Chinese medicine, although even these were speculative phenomena not associated with anatomical conduits.¹ The phenomenological perspective of tradition turns out, however, to be closer to the reality than the conventional understanding of arteries, veins and capillaries might suggest.

As far as most tissue cells are concerned, blood flow is not through vessels at all. When plasma filters through the capillary walls to bathe the tissues, it does not diffuse freely. In most tissues, cells are embedded in a gelatinous matrix, formed of complexes of hyaluronic acid which is largely impermeable to aqueous fluids. Movement of plasma is thus confined through clefts and cleavages in the matrix. The interstitial matrix thus both maintains tissue integrity and restricts the free flow of the circulation; oedema is the main symptom of breakdown in this important construct.

The effect of the interstitial matrix on circulatory dynamics is profound. As far as tissues are concerned, circulation is not a Harveyian affair at all, it is more a diffusive process marked by local and wider ‘oceanic’ currents. Factors that affect tissue circulation are thus different from those that preoccupy modern cardiovascular medicine. Atherosclerosis and thrombosis cause serious local circulatory harm, of course, but they impact on general circulation only when very severe. More important for circulatory health in the tissues are such factors as capillary wall integrity, the local responses to local environmental changes of powerful vasoactive agents such as the kinins and histamine, venous or lymphatic stasis or congestion with subsequent oedema and toxicity.

Antipathogenic benefits of increased tissue perfusion?

A glance at any pathology text will confirm that the cellular processes of disease are remarkably consistent. Pathological deterioration starts with biochemical lesions, then a variety of stages supervene including intracellular lesions, cell hypertrophy and a range of possible degenerative changes, cellular swelling due to water influx into the cell, fatty change or accumulation, atrophy, necrosis, possibly leading to inflammation or calcification. Most detectable disease states in the body are classified by one or more of these processes. Atherosclerosis, for example, involves fatty infiltration and then calcification of the tissues in the arterial walls.

Moreover, the very first initiating trauma is even more consistent. The most likely first step in tissue damage is a relative deficiency of oxygenated blood and fluids. Physical injury is the most likely initiating trauma followed by an accumulation of external or endogenous toxic substances. In both the first and last cases poor tissue perfusion is critical. There are a number of ways in which tissue circulation can be interrupted but there is a clear prima facie case for maintaining tissue perfusion as a core disease-preventing strategy.

One of the most fascinating prospects for the revival of traditional herbal and dietary approaches is in the number of ways in which plant constituents, such as flavonoids, anthocyanins, sesquiterpenes and pungent principles, appear to act beneficially on local circulatory processes.

It is a consistent theme throughout history that the ‘heating’ remedies were literally life enhancing (see p. 4 and p. 9). The pungent remedies such as cayenne, ginger and raw garlic had reputations that transcended the merely mundane. It is known that they do increase tissue perfusion and blood flow. Everyday subjective experiences of increased body heat after eating spicy food can be confirmed with thermometers. Reference to the ginger monograph reveals a number of studies demonstrating a thermogenic effect, involving such mechanisms as increased catecholamine production and cytokine activity. Supplementing rats’ diet with garlic powder increased rectal temperatures, blood noradrenaline levels and mitochondrial activity in brown adipose tissues, an activity that was inhibited by beta-adrenergic blockers.²

The prospects for closer investigation are intriguing. It is most probable that the traditional remedies most often used for their tissue warming benefits will show really exciting properties in the treatment of, or prophylaxis against, a range of degenerative diseases that may include atherosclerosis and other cardiovascular diseases. The fact that most are common ingredients of the diet adds even more to this project.

A promise of what may be in store for cayenne, ginger, cinnamon, turmeric and the like is the remarkable story of garlic, now possibly the most intensively studied of all medicinal plants and foods.

Garlic

The chemistry of Allium sativum is complex and the multitude of garlic products available in the marketplace reflects this complexity.³ These types of preparations can be divided into three main groups, to which is added fresh garlic:

Most of the published clinical studies on garlic have used ‘garlic powder’ preparations, although trials on aged garlic extracts, fresh garlic and garlic oil are also in the literature.

Plant phenolics and the vasculature

When Szent-Gyorgy in the 1930s identified the flavonoid constituents of citrus fruits as a necessary co-factor with ascorbic acid in the prevention of scurvy, he opened an investigation which has actually increased in intensity in recent years. Interest in the flavonols such as rutin and its aglycone quercetin has been augmented by a growing fascination with other phenolic molecules, the oligomeric procyanidins (OPCs) and the polyphenolics linked to the tannins, all very common constituents in dietary fruit and vegetables as well as in herbal remedies.

Flavonoids, a group of phenolic constituents found widely in plants, including most fruits and vegetables, have been found to possess a number of anti-inflammatory effects, including, especially for rutin and others from the flavonol subgroup, effects on the microvasculature³⁶ (see also the discussion in Chapter 2 under Flavonoids).

Rutin, quercetin-3-rutoside, is a flavonoid glycoside with quercetin as an aglycone and rhamnose and glucose as sugar moieties. It is very widely distributed in the plant kingdom. It is official in many pharmacopoeias and is widely sold as a health supplement, sometimes in association with vitamin C. In experiments it has been shown to increase survival times of rats fed a thrombogenic diet and in other animals to reduce oedema, reduce cholesterol-induced atheroma and inhibit the carcinogenic action of benzo(α)pyrene.³⁷ Like ascorbic acid, it is an oxygen radical scavenger and has been shown to reduce the mutagenicity of dusts and asbestos³⁸ and other stressors.^39,40

Commercial products with a similar structure, hydroxyethylrutosides or oxerutins (containing principally tri-O-(beta-hydroxyethyl)rutoside, as well as a mixture of mono-, di- and tetra-O-(beta-hydroxyethyl)rutosides), are marketed for the treatment of chronic venous insufficiency. There are a number of reports demonstrating positive effects on capillary permeability,^41–43 on venous insufficiency⁴⁴ and venous hypertension.⁴⁵ Other researchers have reported an improvement in oxygen perfusion of tissues surrounding varicose veins.⁴⁶

The development of synthetic rutosides has followed the finding that natural rutin is poorly absorbed. However, over 95% of all polyphenolic intake passes to the colon and is fermented by the gut microflora into simple phenols. For example, rutin is now known to be rapidly metabolised by bacteria in the intestine, via quercetin, to 3,4-dihydroxyphenylacetic acid, a small phenol with antioxidant properties. Simple phenolic acids derived from cinnamic acid (such as gallic acid, salicylic acid, caffeic acid, vanillic acid and ferulic acid, as their esters including chlorogenic acid and rosmarinic acid), with their derived polyphenols, make significantly larger contributions to dietary phenol, polyphenol and tannin intake than the flavonols and flavones upon which the vast majority of attention has been focused. It is important to include these in assessments of the total effects of polyphenols.⁴⁷ Such degradation products are readily absorbed and are found in urine of animals.⁴⁸ Early doubts about the venous efficacy of such flavonoid molecules⁴⁹ have therefore not been sustained. (See also the Pharmacokinetics section of Chapter 2.)

There is much in vitro evidence on the effects of flavonoids and other polyphenolics on the microvasculature that can be noted, but which for reasons above need confirmation clinically. For example:

Compared with the effects of polyphenols in vitro, the effects in vivo are more limited. Several studies, however, show benefits of products in streptozotocin-induced diabetic rats, for example flavonoid-rich citrus fruit extract⁵⁴ and rooibos tea (Aspalathus linearis).⁵⁵ A fundamental point is that in vivo studies are not long enough and rarely consider bioavailability problems. In human studies particularly it is important that studies are long term, to more closely reflect the likely effects of dietary consumption of polyphenols. Two critical and important reviews of the intervention studies for the use of polyphenols have been published^56,57 (see also the relevant section in Chapter 2).

Short-term observations still point to, if not confirm, prospects of vascular changes. In a prospective, placebo-controlled, randomised study, a high rutoside-containing proprietary product (O-(beta-hydroxyethyl rutosides) at 2 g/day for 6 months was tested on patients with diabetic microangiopathy and oedema. Significant decreases in resting flux and rate of ankle swelling were observed in the active treatment groups.⁵⁸ In this author’s preliminary observations in 1993, 37 patients suffering symptoms of venous insufficiency entered a clinical study to determine the impact on their microcirculation of buckwheat leaf, a popular natural treatment for this condition that contains high levels of plant flavonoids. Using the mild provocation of a suction cup applied to the lower leg and monitoring changes in local circulatory activity with laser Doppler flowmetry, it was possible to identify three characteristics of vascular responses that differentiated sufferers of venous insufficiency from healthy controls: reduced vascular reactivity, flow resolution rate and vasomotor activity. After establishing baseline levels for these characteristics all the subjects took buckwheat leaf for a total of 6 weeks. Twenty-four satisfactorily completed all stages of the study. In this uncontrolled sample it was possible to demonstrate statistically significant changes in vasomotor activity and vascular reactivity. However, flow resolution rate, that might have indicated a beneficial effect on the endothelium, was not changed.

Both short- and long-term improvements in endothelial function have been seen with doses of green tea catechins equivalent to several cups a day.⁵⁹ A standardised OPC extract of the bark of the French maritime pine (Pinus pinaster) is known to increase capillary resistance. It has been investigated in five clinical trials with a total number of 1289 patients since the late 1960s for treatment and prevention of diabetic retinal microangiopathy, characterised by vascular lesions with exudate deposits and haemorrhages. All of these studies showed that the extract slowed progression of retinopathy and partly recovered visual acuity. It was shown to improve capillary resistance and reduce leakage into the retina. Tolerance was generally very good and side effects were rare, mostly referring to gastric discomfort.⁶⁰

Epidemiological studies suggest that the intake of flavonols and flavones is inversely associated with subsequent coronary heart disease (CHD).⁶¹ There is, however, mixed evidence for a benefit of increased fruit and vegetable intake in vascular health. Improved endothelial function scores and reduced insulin resistance have been observed in a controlled observation of the effects of the Mediterranean diet over 2 years.⁶² However, by contrast there was little association found between high fruit and vegetable consumption and the incidence of peripheral arterial disease in a 12-year study of a cohort of 44 059 men initially free of cardiovascular disease and diabetes (after adjustment for smoking and other traditional cardiovascular disease risk factors).⁶³

Overall, it seems most likely that any benefits of polyphenolic intake will follow long-term and relatively substantial use. However, the prospect for short-term changes in vascular reactivity with relatively high doses of polyphenols needs to be further explored.

The above research highlights that therapeutic herbs can offer value in one aspect of the cardiovascular system that is somewhat neglected in modern drug treatment, namely the health of the small blood vessels or microvasculature. As noted above, flavonoids in general, and specifically OPCs from pine bark or grape seed, possess clinically relevant vasoprotective activity. Other plant agents shown to support the microvasculature with, for example, beneficial clinical effects in microangiopathy include bilberry, gotu kola, Ginkgo and garlic (allicin-releasing preparations). They will have application where structures comprising fine blood vessels are affected, such as the retina (e.g. diabetic retinopathy), neurons (e.g. diabetic neuropathy) and the glomeruli of the kidneys (e.g. diabetic nephropathy).

Congestive heart failure

The original observations by William Withering of the benefits of foxglove in the treatment of dropsy by a country herbalist led to the discovery of the digitalis glycosides that became the primary drug treatment for congestive heart failure. Given its seriousness and the potency of these plant extractives, it has generally been accepted that crude herbal drugs no longer have a place in the rational treatment of the condition.

Nevertheless, there is a consistent tradition for the use of herbs with cardiac glycosides such as Convallaria majalis (lily of the valley) around the world and pharmacological cases have been made for their use as broader spectrum remedies (see Chapter 2). Indeed, the use of crude Digitalis folium was favoured by some doctors in Britain over the synthetic isolate until relatively recently. There is also evidence that a wider range of plants may have supportive benefits in the condition. For example, Terminalia arjuna 1500 mg/day demonstrated substantial benefits in the treatment of refractory congestive heart failure linked to dilated cardiomyopathy in a placebo-controlled, double blind crossover trial.⁶⁴

There is now substantial clinical evidence for the supportive role of hawthorn (Crataegus species) in congestive heart failure, not to supplant conventional medication, but to provide an extra dimension of treatment aimed at supporting the heart muscle itself. (This has been fully reviewed in the hawthorn monograph.)

Other herbs of potential value include Coleus forskohlii containing forskolin, a phytochemical with cardiotonic activity,⁶⁵ and Salvia miltiorrhiza (dan shen).⁶⁶ Astragalus also possesses mild cardiotonic activity and can be combined with Korean ginseng for this effect (see the ginseng and Astragalus monographs). Clinical trials from China suggest a clinical benefit from ginseng in patients with congestive heart failure. Mild diuretic herbs may be beneficial for fluid retention, such as dandelion leaves.

Essential hypertension

In about 90% of cases with hypertension there is no identifiable cause and the term ‘essential hypertension’ is used. In the remaining cases a cause can be identified and this is known as ‘secondary hypertension’. The main cause is kidney disease; other causes include coarctation of the aorta, endocrine diseases and pregnancy. Generally, the treatment for secondary hypertension is the same as for essential hypertension, but the cause should also be treated if possible. It is important to ensure that patients presenting with essential hypertension do not have a secondary cause. Many patients with hypertension have coexisting cardiovascular risk factors, which should also be addressed.⁶⁷

Although the milder stages of essential hypertension should probably not be considered as a disease, people with hypertension are more likely than those with normal blood pressure to develop a number of cardiovascular diseases. In particular, hypertension is a risk factor for the development of CHD. As such, it is desirable to treat even mild hypertension.

Treatment should aim for gradual reduction in blood pressure. The kidneys will have become adapted to the previously high levels (indeed, an approach to understanding essential hypertension is that it may be a mechanism to ensure adequate kidney function when this is failing). Sudden reduction could lead to other problems. In this sense natural approaches, if effective, can be doubly suitable.

It is apparent to most practitioners that hypertension is an indication for a broad therapeutic strategy, including dietary and lifestyle advice. Some of the features of this advice are therefore outlined below. It is not advisable to attempt to treat severe (greater than 170/110), malignant or accelerated hypertension with only natural approaches; synthetic prescription drugs can be necessary to avoid serious harm in such cases.