Preventing and Reversing Hepatic Fibrosis - Herbs and Supplements

Limitations of the paper: This was written a few years ago and does not incorporate everything I have learned since. Nor does it contain many references and live links, though I have added some, and some references do appear at the end. It is obviously unfinished - a work in progress posted to inspire other researchers - and should be treated as such.
On the other hand it compiles much valuable information that does not appear elsewhere.

A reference first to set the scene:

Hepatology. 2006 Feb;43(2 Suppl 1):S82-8.

Reversal of hepatic fibrosis -- fact or fantasy?

Friedman SL, Bansal MB.

Realistic expectations for successful anti-fibrotic therapies reflect solid evidence of fibrosis 

regression in patients treated effectively for viral liver disease, as well as growing clarity in 

the understanding of mechanisms of extracellular matrix production and degradation. 

The paradigms of stellate cell activation and apoptosis remain valuable frameworks for 

understanding pathways of hepatic fibrogenesis and fibrosis regression, respectively.

http://www.ncbi.nlm.nih.gov/pubmed/16447275

Liver Fibrosis - Prevention and Reversal

Hepatic stellate cell activation and proliferation; HSC inhibition, apoptosis, and reversion induced by natural compounds.

The Hepatitis C Handbook by Matthew Dolan is one of the best resources in the subject of Hep C. I was amazed to find, looking up fibrosis in the index, that there is no reference at all to it in the 1997 edition.

Until the last 10 years or so fibrosis was seen purely as an aspect of liver damage that was not really distinct from damage to hepatocytes. In fact, fibrosis, and therefore cirrhosis is an aspect of liver repair mechanisms, albeit one that can lead towards increased damage and loss of function if it is not switched off. The good news is that many strategies have been developed to switch off fibrosis and resorb scarring (for example, in Modern Chinese Medicine the herbal preparation Cpd 861 was able to reverse 4 stages of fibrosis and 2 of cirrhosis in clinical trials) and it seems relatively easy to prevent fibrosis from snowballing in the first place. To understand how this is possible, we must first look at fibrosis as a natural event.

Hepatic Stellate Cells

Damage to the liver, whether by drugs, virus, radiation, or trauma (for example, a biopsy needle) must involve damage to the microcirculation, the tiny blood vessels essential to liver function, as well as to hepatocytes. The microcirculation consists of endothelial cells, called sinusoidal because there are windows in them. This tiny tube, only 2-3 cells in diameter, is surrounded by a space (the Space of Disse) separating it from the hepatocytes. The Space of Disse is inhabited by main two cell types; Kuppfer cells, the macrophage white blood cells that keep it clean, and Hepatic Stellate Cells (HSCs or Ito cells). In health, HSCs have three main functions; they store fats and vitamin A; they produce and degrade matrix (collagen and similar protein fibres), both to restrict the size of particles able to pass in and out of the microcirculation, and perhaps to keep open the Space of Disse; and, HSC also serve as glial cells, similar to the neuroglial caretaker cells in the brain; that is, they respond to many neurotransmitters and neural hormones, and can both break down and produce many such chemicals, interacting with the nerves that transit the liver. This is particularly important as it gives a mechanism as to how moods and emotions can impact on liver function, and vice versa, as well as some psychoactive drugs.

HSC activation

In the case of traumatic or chemical liver damage, the function of HSCs changes. They lose their vitamin A stores and convert to a type of cell called a myofibroblast. Fibroblasts are seen in scar formation in other tissues, and are part of the immune response to injury. The primary function of the HSC fibroblast is to remodel the damaged intracellular matrix (collagen), by breaking it down with zinc-containing metalloproteins (in healthy HSCs, zinc is used in the storage and transport of vitamin A instead) and creating more. HSC myofibroblasts also conscript other HSCs to their aid, by producing chemicals that spread the process of conversion (HSC activation) and reproduction (HSC proliferation). This process ought to be switched off once the liver has repaired itself, but in some cases does not stop, and this ongoing remodeling of matrix collagen results in the later stages of fibrosis, and cirrhosis; the HSC fibroblasts produce tangles of collagen and also contract around the endothelial cells, closing down the (already microscopically narrow) blood vessels of the microcirculation and causing toxins to accumulate, and the hepatocytes in the area lose their function, eventually dying and setting off another cycle of fibrosis.

Nitric Oxide

An important chemical messenger for keeping HSCs in line and maintaining the tone of the microcirculation is endothelial nitric oxide (NO.-). Nitric oxide is a free radical that functions, in the liver, as an antioxidant; other free radicals, such as superoxide, can destroy it. For this reason antioxidants help to maintain nitric oxide levels, for example Ginkgo. Preparations of antifibrotic herbs based on Ginkgo extracts have successfully prevented fibrosis in clinical trials. I will discus the mechanism and success rates of other antifibrotic herbs later. Nitric oxide is produced from the interaction of l-arginine and oxygen, catalysed by NADPH, a vitamin B3 co-enzyme. Vitamin B3 (as niacinamide) also has important antifibrotic effects in its own right.

Inflammatory Cytokines and Niacinamide/Nicotinamide
The primary cytokines (protein messengers) involved in activating HSCs are Transforming Growth Factor Beta (TGF–beta) and TNF-alpha, which activates the pro-inflammatory transcription factor NF-kappaB. Vitamin B3 as nicotinamide inhibits both TGF-beta and TNF-alpha. Vitamin E, especially in the form of alpha-tocopherol succinate, also inhibits TNF-alpha and NF-kappa B. We know that these vitamins are effective at normal supplement doses because vitamin B3 is effective against arthritis, which is another disease in which TNF-alpha and NF-kappa B play a major role, at doses which (at the upper end) can affect liver function in other ways, by competing for SAMe, thus inhibiting the transport of fats from hepatocytes (potentially leading to jaundice in poorly nourished individuals with hypomethylation – easily prevented by taking B12 and folate, and by taking divided doses, rather than taking one large dose. However in clinical use manifestation of these potential risks is minimal). B3 also elevates HDL cholesterol, and higher levels of HDL cholesterol are associated with healthy nitric oxide levels.

The most important effect of B3 is, that it induces the apoptosis (programmed cell death) of activated HSCs. B3 is the only vitamin that does this. Apoptosis of HSCs, as well as quiescence, is probably essential if the liver is to recover from fibrosis. Other supplements that promote HSC apoptosis are CLA (conjugated lineolic acid) especially the c-9, t-11 isomer found in ruminant and dairy fat, resveratrol (which likely promotes HCV replication in high doses), green tea extract, apricot kernels, and berberine (an alkaloid found in many yellow herbs, including golden seal, coptis, and Oregon grape root).

Neurotransmitters

HSCs are also activated by some neurotransmitters at high concentrations, including serotonin, epinephrine (adrenaline), and adenosine. Caffeine inhibits adenosine receptors; it also increases synthesis of nitric oxide and lessens synthesis of collagen precursors from l-arginine, while the antioxidant polyphenols in coffee chelate iron and protect nitric oxide and collagen; this is probably related to the anti-fibrotic effects seen in some coffee drinkers (antioxidants that protect collagen, such as OPCs, tend to be anti-fibrotic; it makes sense that damage to matrix should trigger HSC activation). A neurotransmitter which inhibits HSC activation is gamma butyric acid, GABA. Vitamin B3 enhances sensitivity of GABA receptors – in fact, this gives it an anti-anxiety effect equal to that of valium, as GABA is an inhibitory neurotransmitter, opposed to adrenaline which is stimulatory, and valium has an antianxiety effect in part because it attaches itself to GABA receptors. This is another antifibrotic mechanism of niacinamide. It would be interesting to see whether this GABA-ligand effect translates into any antifibrotic influence for benzodiazepine drug use. However, the antifibrotic effects of B3 which I have researched are multiple, and do not depend on any single mechanism. They include:
synthesis of nitric oxide - increase of nitric oxide by inhibition of ADMA - increase of HDL cholesterol - reduction (recycling) of glutathione - modulation of GABA receptors -  inhibition of TNF-alpha and NF-kappaB - inhibition of TGF-beta - inhibition of HSC activation and proliferation - promotion of HSC apoptosis http://www.ncbi.nlm.nih.gov/pubmed/16165703- prevention of excess catecholamine synthesis - lowered synthesis of acetaldehyde from alcohol, therefore less toxicity.
Benefits of B3 supplementation in fibrosis, not limited to those above, strongly suggest that commonly repeated advice to avoid this vitamin in cases of hepatitis is misguided. Jaundice and acute hepatitis are contraindications, and daily dose then should be limited to 200mg in multivitamins, but in stable, chronic  cases of hepatitis C a dose of 500mg niacinamide 3x daily seems well tolerated. The only toxicity of B3 relates to its methyl-acceptor role; as long as one supplements B12 and folate, or SAMe, or lecithin, and eats a reasonable amount of protein, this will not cause hypomethylation. Niacinamide (with other vitamins) has been used for decades in the orthomloecular treatment of alcoholism, with prevention of cirrhosis as an incidental benefit, without serious complications, despite the prevelance of liver damage in alcoholics. 

Estrogen, antifibrotic foods

Estrogen is also antifibrotic, and pre-menopausal women have a lower rate of fibrosis than males. However, this protection can be lost at menopause. However, phytoestrogens, especially genistein from soy, also inhibit HSC activation and proliferation by acting on estrogen-B receptors. On the n=1, I am allergic to unfermented soy, and I don’t consider it a fit food for humans, but I have no problems with isoflavones, which are found in a variety of legumes. Fermented soy products are a better source of isoflavones than unfermented. Resveratrol is another phytoestrogen effective at dietary levels; grape juice and raisins supply as much resveratrol as red wine.

Another food that is antifibrotic at normal dietary levels is curry. Both curcumin (from turmeric) and extract of fenugreek (methi) inhibit HSC activation. India has a high rate of hepatitis C infection yet a low rate of liver cancer (a rare sequella of fibrosis), and this has been attributed to the consumption of curries. Other ingredients in curry, including saffron, have been studied for their antifibrotic effect. The use of ghee, high in saturated fat and CLA, in the traditional Indian diet is also likely to provide antifibrotic benefits.

Iron

Iron, unless it is strongly bound in proteins or chelated with polyphenolic phytochemicals, is strongly pro-fibrotic and all antifibrotic herbal extracts and phytochemicals seem to have some iron-chelating ability. Iron interacts with superoxide (Haber-Weiss reaction) and peroxide radicals (Fenton reaction) to produce the more reactive hydroxyl radical (also the product of ionizing radiation – both nuclear and electromagnetic). Iron can also interact with antioxidant vitamins, especially vitamin C, in place of superoxide, and iron-vitamin C combinations are used to induce fibrosis (activate HSCs) experimentally. Thus, taking vitamin supplements that combine vitamin C and inorganic iron in one pill is rather unwise – but avoiding vitamin C will not help. Firstly, the same kind of reaction takes place with superoxide radical, which is more reactive than any antioxidant (and more penetrative), as well as with glucose and homocysteine (pro-fibrotic in its own right), and superoxide (as well as glucose and homocysteine) levels will be higher if antioxidants are low; secondly, vitamin C deficiency causes the formation of low-quality collagen, which might be a factor in the constant matrix remodelling seen in fibrosis; thirdly, ascorbate-iron catalyzed hydroxylation reactions play an important role in metabolism and detoxification; the synthesis of carnitine, tyrosine and serotonin, for example, depends on this type of reaction.

Copper can also function in the same way. Zinc, which is important for the breakdown of matrix collagen, competes for absorption with iron and copper (especially as inorganic zinc sulphate – note that organic mineral chelates may not compete asa directly). Calcium also competes with iron, as do many phytochemicals, including coffee and green and black teas.

Antioxidant Enzymes

But iron can become very strongly antioxidant if it is part of the catalase enzyme, which converts peroxide to water (similar to the selenium-containing enzyme glutathione peroxidase). Catalase works together with SOD (copper and zinc, or manganese) to remove superoxide and peroxide before they can react with reduced iron (Fe2+). Adaptogenic medicinal herbs like ginseng and astragalus and medicinal mushrooms are able to increase production of these enzymes (assuming the minerals – especially selenium, zinc, and manganese, as iron and copper are usually found elevated in Hep C - are there), as do the isothiocyanates and glucosinolates found in cruciferous vegetables (broccoli, cabbage, kale, watercress, mustard etc.).

Vitamin A
Because HSCs naturally store vitamin A, it might be expected that vitamin A would have some action for or against fibrosis. It turns out that vitamin A as retinyl palmitate (the form of vitamin A in cod liver oil) is potently antifibrotic (as are various carotenoids in their own right), but a very interesting feature of this in animal trials is that liver pretreated with vitamin A and exposed to toxicity produces less collagen and fewer activated HSCs than liver not so pretreated, yet the vitamin A pretreated liver has a significantly higher level of AST and ALT liver enzymes after the toxic exposure. In other words, an elevated liver enzyme count can be consistent with the prevention of fibrosis.

No doubt damaged hepatocytes can be replaced more easily than excess collagen can be cleared away. In the MCM medicines below, hepatoprotective herbs (such as schizandra) are sometimes added to antifibrotic mixtures.

Vitamin D is also anti-fibrotic http://www.ncbi.nlm.nih.gov/pubmed/21816960
The non-scientific literature on Hep C is full of warnings against supplementing nicotinamide, retinol, and vitamin D3.
These warnings, based on the effects of extreme overdose, have no relevance to normal diet or supplementation at clinical dosages. Restricting these vitamins in the belief that they are dangerous is infinitely more risky than supplementing them. Retinol status, for example, is inversely associated with hepatocellular cancer in prospective studies of populations with chronic viral hepatitis.

Modern Chinese Medicine

Modern Chinese Medicine has made a special study of fibrosis, identifying both the processes involved and a number of traditional herbs that address various aspects of fibrosis, especially when associated with viral hepatitis. Herbal mixtures have been designed to address various aspects of fibrosis prevention in one formula. Thus apricot kernels (armand de nord, north almonds, bitter almonds), which promote HSC apoptosis, may be combined with pine pollen, which protects collagen and microcirculation, cordyceps, a medicinal mushroom with antiviral properties which corrects immune suppression, ligusticum, which reduces platelet stickiness (PAF, platelet aggregating factor, is a factor in fibrosis), notoginseng, which is a potent antioxidant with traditional use in protecting the cardiac circulation, and schizandra, which protects hepatocytes and increases bile flow. The star of antifibrotic herbs in MCM seems to be the very well researched radix salvia miltiorrhiza (red sage, dan shen), a cheap herb with multiple antifibrotic actions. Salvia out-performs other herbs and polyphenols with antifibrotic actions, at levels easily attained by supplementation with extracts, and is used in most MCM antifibrotic mixtures.

Reversal of fibrosis and even early-stage cirrhosis is often seen in clinical trials of these new Chinese medicines. I predict that the rate of reversal will increase when the herbs are combined with appropriate amounts of antioxidant and antifibrotic nutrients; a-tocopherol succinate, selenium, zinc, manganese, niacinamide, NAC, lecithin, cod liver oil, OPCs, as well as antifibrotic foods; curries, grapes and raisins, mango, berries, soy and other legumes. The neuroglial function of HSCs provides scientific validation for stress-relieving practices such as breathing excercises, yoga, tai chi, and cognitive therapy in the management of fibrosis.

REFERENCES (to be expanded. In the meantime, to find a reference i.e. to the antifibrotic effect of curcumin, just google "curcumin hepatic stellate", and so forth. Medline references will then be found at the top of the next page.)

1    Friedman SL. Molecular regulation of hepatic fibrosis, an integrated cellular response to tissue injury. J Biol Chem
      2000; 275:2247-2250

2    Iredale JP. Hepatic stellate cell behavior during resolution of liver injury. Semin Liver Dis 2001; 21: 427-436

3    Bataller R, Brenner DA. Hepatic stellate cells as a target for the treatment of liver fibrosis. Semin Liver Dis
      2001; 21: 437-451

4    Reeves HL, Friedman SL. Activation of hepatic stellate cells -a key issue in liver fibrosis. Front Biosci 2002; 7: d808-826

5    Wang BE, Wang TL, Jia JD, Ma H, Duan ZP, Li XM, Li J, Wang AM, Qian LX. Experiment and clinical study on inhibition
      and reversion of liver fibrosis with integrated Chinese and Western Medicine. CJIM 1999; 5: 6-11

6    Yin SS, Wang BE, Wang TL. The effect of Cpd 861 on chronic hepatitis B related fibrosis and early cirrhosis: A
      randomized, double blind, placebo controlled clinical trial. Zhonghua Ganzangbing Zazhi 2004; 12: 467-470

7    Wang TL, Wang BE, Zhang HH, Liu X, Duan ZP, Zhang J, Ma H, Li XM, Li NZ. Pathological study of the therapeutic effect
      on HBV -related liver fibrosis with herbal compound 861. Weichangbingxue He Ganbingxue Zazhi 1998; 7: 148-153