4. Final Thesis

Herbal Approaches For Liver Disorder

College of Pharmacy, IPS Academy, Indore 1

1. INTRODUCTION

There are numerous plants and traditional formulations available for the treatment of liver

diseases. About 600 commercial herbal formulations with claimed hepatoprotective activity

are being sold all over the world. Around 170 phyto constituents isolated from 110 plants

belonging to 55 families have been reported to possess hepatoprotective activity. In India,

more than 93 medicinal plants are used in different combinations in the preparations of 40

patented herbal formulations3. However, only a small proportion of hepatoprotective plants

as well as formulations used in traditional medicine are pharmacologically evaluated for their

safety and efficacy. Some herbal preparations exist as standardized extracts with major

known ingredients or even pure compounds which are being evaluated.

The use of natural remedies for the treatment of liver diseases has a long history, starting with

the Ayurvedic treatment, and extending to the Chinese, European and other systems of

traditional medicines. The 21st century has seen a paradigm shift towards therapeutic

evaluation of herbal products in liver diseases by carefully synergizing the strengths of the

traditional systems of medicine with that of the modern concept of evidence-based medicinal

evaluation, standardization of herbal products and randomized placebo controlled clinical

trials to support clinical efficacy. The present review provides the status report oil the

scientific approaches made to herbal preparations used in Indian systems of medicine for the

treatment of liver diseases. In spite of the availability of more than 300 preparations for the

treatment of jaundice and chronic liver diseases in Indian systems of medicine using more

than 87 Indian medicinal plants, only four terrestrial plants have been scientifically elucidated

while adhering to the internationally acceptable scientific protocols. In-depth studies have

proved Syllabus Mariana to beatnik-oxidative, anti-lipid per-oxidative, anti-fibrotic, anti-

inflammatory and liver regenerative. Glycyrrhiza glabralias been shown to be

hepatoprotective and capable of inducing an indigenous interferon. Picrorhiza kurroa is

proved to be anti-inflammatory, hepatoprotective and immune modulatory. Extensive studies

on Phyllan thusamarus have confirmed this plant preparation as being antiviral against

hepatitis B and C viz-uses, hepato protective and immune modulating, as well as possessing

anti-inflammatory properties.1



The use of herbal medicine can be traced back to 2100 BC in ancient China at the time of Xia

dynasty, and in India during the Vedic period. The first written reports are timed to

600 BC with Charaka samhita of India, and in China the same became systematic by

400 BC. The basic concept in these medicinal systems is that the disease is a manifestation of

a general imbalance of the dichotomous energies that govern life as a whole and human life

in particular, and they focus on medicine that can balance these energies and maintain good

health. In Ayurvedha of India, the forces are said to be agni (strength, health and innovation)

and ama (weakness, disease and intoxication). In India there are also other systems of

traditional medicine besides Ayurvedha and these are called Siddha, which originated almost

at the same time as Ayurvedha from southern India, and Unani, which entered India during

the Mogul dynasty periods. Like Ayurvedha, practitioners of Siddha medicine believe in a

perfect balance of three doshas known as vatha (space and air elements), pitta (fire and water

elements) and kapha (water and earth elements). All these Indian systems of medicine have

primarily claimed a curative potential for their medicinal preparations for all kinds of liver

diseases.18

In spite of the significant popularity of these medicinal systems, they are still to be

recognized as being universally acceptable treatment modalities for chronic liver disease.

The limiting factors that contribute to such an eventuality are

(i) lack of standardization of the herbal drugs;

(ii) lack of randomized placebo controlled clinical trials; and

(iii) lack of traditional toxicologic evaluations.



2. EFFICACY AND SAFETY OF HERBAL PRODUCTS

Any evaluation of herbal products faces major problems. The first is the use of mixed

extracts (concoctions) and variations in methods of harvesting, preparing, and extracting the

herb, which can result in dramatically different levels of certain alkaloids. The biologically

active substances have been structurally defined and standardized for only a few of the herbs.

Even then, it may not be known if this molecule is the sole active principle or if efficacy

depends on the mixture of compounds.

The second problem is a lack of randomized, placebo-controlled clinical studies. Traditional

Eastern medicine relies on empiricism and a holistic philosophy, and controlled studies are

considered unnecessary. This is a view shared by many Western supporters of alternative

medicine. Also, trials may not use end points, such as death from liver disease, histological

fibrosis or inflammation, cancer, and transplantation.15



3. LIVER

The Liver is a vital organ present in vertebrates and some other animals. It has a wide

range of functions, including detoxification, protein synthesis, and production of biochemical

necessary for digestion. The liver is necessary for survival; there is currently no way to

compensate for the absence of liver function long term, although liver dialysis can be used

short term. This organ plays a major role in metabolism and has a number of functions in the

body, including glycogen storage, decomposition of red blood cells, plasma protein synthesis,

hormone production, and detoxification. It lies below the diaphragm in the abdominal-pelvic

region of the abdomen. It produces bile, an alkaline compound which aids in digestion via the

emulsification of lipids. The various functions of the liver are carried out by the liver cells or

hepatocytes. Your entire blood supply passes through your liver several times a day. Your

liver keeps you alive and healthy by metabolizing the food you eat, by breaking it down and

digesting fatty acids. The liver produces bile and stores it in the gall bladder until it is needed.

It produces blood-clotting factors, and also converts sugar into glycogen, which it stores until

the muscles need energy and it is secreted into the blood stream as glucose. It synthesizes

proteins and cholesterol and converts carbohydrates and proteins into fats, which are stored

for later use.2



4. FUNCTION OF LIVER

The liver is thought to be responsible for up to 500 separate functions, usually in

combination with other systems and organs. The various function of liver is as follow:

The liver performs several roles in carbohydrate metabolism.

Gluconeogenesis (the synthesis of glucose from certain amino acids, lactate or glycerol).

Glycogenolysis (the breakdown of glycogen into glucose).

Glycogenesis (the formation of glycogen from glucose)(muscle tissues can also do this).

The liver is responsible for the mainstay of protein metabolism, synthesis as well as

degradation.

The liver also performs several roles in lipid metabolism.

Cholesterol synthesis.

Lipogenesis, the production of triglycerides (fats).

A bulk of the lipoproteins is synthesized in the liver.

In the first trimester fetus, the liver is the main site of red blood cell production. By 32nd

week of gestation, the bone marrow has almost completely taken over that task.

The liver produces and excretes bile (a yellowish liquid) required for emulsifying fats.

Some of the bile drains directly into the duodenum, and some is stored in the Gall

bladder.

The liver also produces insulin-like growth factor 1 (IGF-1), a polypeptide protein

hormone that plays an important role in childhood growth and continues to have anabolic

effects in adults.

The liver is a major site of thrombopoietin production. Thrombopoietin is a glycoprotein

hormone that regulates the production of platelets by the bone marrow.5

The liver stores a multitude of substances, including glucose (in the form of glycogen),

vitamin A (1-2 years' supply), vitamin D (1-4 months' supply), vitamin 1312 (1-3 years'

supply), iron, and copper.

The liver is responsible for immunological effects the reticuloendothelial system of the

liver contains many immunologically active cells, acting as a 'sieve' for antigens carried

to it via the portal system.

The liver produces albumin, the major osmolar component of blood serum.



The liver synthesizes angiotensinogen, a hormone that is responsible for raising the blood

pressure when activated by renin, an enzyme that is released when the kidney senses low

blood pressure.4



5. THE DISEASES OF THE LIVER

There are more than a hundred kinds of liver disease. The most widely spread are as

follows:

Hepatitis, inflammation of the liver, is caused mainly by various viruses (viral hepatitis)

but also by some liver toxins (e.g. alcoholic hepatitis), autoimmunity (autoimmune

hepatitis) or hereditary conditions.

Alcoholic liver disease is any hepatic manifestation of alcohol overconsumption,

including fatty liver disease, alcoholic hepatitis, and cirrhosis. Analogous terms such as

"drug-induced" or "toxic" liver disease are also used to refer to the range of disorders

caused by various drugs and environmental chemicals.

Fatty liver disease (hepatic steatosis) is a reversible condition where large vacuoles

of triglyceride fat accumulate in liver cells. Non-alcoholic fatty liver disease is a spectrum

of disease associated with obesity and metabolic syndrome, among other causes. Fatty

liver may lead to inflammatory disease (i.e. steato hepatitis) and, eventually, cirrhosis.

Cirrhosis is the formation of fibrous tissue (fibrosis) in the place of liver cells that have

died due to a variety of causes, including viral hepatitis, alcohol overconsumption, and

other forms of liver toxicity. Cirrhosis causes chronic liver failure.

Primary liver cancer most commonly manifests as hepatocellular carcinoma and/

or cholangio carcinoma; rarer forms include angio sarcoma and hemangio sarcoma of the

liver. (Many liver malignancies are secondary lesions that have metastasized from

primary cancers in the gastrointestinal tract and other organs, such as the kidneys, lungs,

breast, or prostate).

Primary biliary cirrhosis is a serious autoimmune disease of the bile capillaries.

Primary sclerosing cholangitis is a serious chronic inflammatory disease of the bile duct,

which is believed to be autoimmune in origin.

Centrilobular necrosis of liver can be caused by leakage of enteric toxins into circulation.

Salmonella toxins in ileum have been shown to cause severe damage to liver hepatic

cells.

BuddChiari syndrome is the clinical picture caused by occlusion of the hepatic vein,

which in some cases may lead to cirrhosis.



Hereditary diseases that cause damage to the liver include hemochromatosis, involving

accumulation of iron in the body, and Wilson's disease, which causes the body to

retain copper. Liver damage is also a clinical feature of alpha 1-antitrypsin

deficiency and glycogen storage disease type II.

In transthyretin-related hereditary amyloidosis, the liver produces a mutated transthyretin

protein which has severe neurodegenerative and/or cardiopathic effects. Liver

transplantation can provide a curative treatment option.

Gilbert's syndrome, a genetic disorder of bilirubin metabolism found in about 5% of the

population, can cause mild jaundice.

There are also many pediatric liver diseases including: biliary atresia, alpha-1 antitrypsin

deficiency, Alagille syndrome, and progressive familial intrahepatic cholestasis.6



6. CAUSES FOR LIVER DISORDER

The liver can be damaged in a various ways:

Cells can become inflamed (such as in hepatitis: hepar=liver + itis=inflammation).

Bile flow can be obstructed (such as in cholestasis: chole=bile + stasis=standing).

Cholesterol or triglycerides can accumulate (such as in steatosis; steat=fat +

osis=accumulation).

Blood flow to the liver may be compromised.

Liver tissue can be damaged by chemicals and minerals, or infiltrated by abnormal cells.

Alcohol is directly toxic to liver cells and can cause liver inflammation, referred to as

alcoholic hepatitis. In chronic alcohol abuse, fatty accumulation (steatosis) occurs in liver

cells causing the cells to malfunction.

Liver cells may become temporarily inflamed or permanently damaged by exposure to

medications or drugs. E.g. taking excess amounts of acetaminophen (Tylenol, Panadol)

can cause liver failure that is permanent, Statin medications are commonly prescribed to

control elevated blood levels of cholesterol. Even when taken in the appropriately

prescribed dose, liver inflammation may occur and can be detected by blood tests that

measure liver enzymes.

Hepatitis is a viral infection that is caused primarily through the fecal-oral route when

small amounts of infected fecal matter are inadvertently ingested.4

6.1 Prevention

Some, but not all, liver diseases can be prevented. For example, hepatitis A and hepatitis B

can be prevented with vaccines.

Other ways to decrease the risk of infectious liver disease include:

Practicing good hygiene, such as washing hands well after using the restroom or changing

diapers.

Avoiding drinking or using tap water when traveling internationally.

Avoiding illegal drug use, especially sharing injection equipment.

Practicing safest sex. Practicing safer sex provides less protection.



Avoiding the sharing of personal hygiene items, such as razors or nail clippers.

Avoiding toxic substances and excess alcohol consumption.

Using medications only as directed.

Using caution around industrial chemicals.

Eating a well-balanced diet following the food guide pyramid.

Getting an injection of immune globulin after exposure to hepatitis A.

Using recommended safety precautions in healthcare and day care work.19



7. DIAGNOSTIC CHECK LIST FOR LIVER DISORDER

1. Indigestion of all kinds, especially epigastric fullness after meals, intolerance of fatty

foods, and nausea without vomiting.

2. General aches and pains from toxins not clearing. Full headaches.

3. Low energy and lethargy, especially if worse in the morning.

4. Aches and pains over the liver area.

5. Gall bladder problems, from poor and too thick bile flow, leads to pains around the right

shoulder blade and tenderness on palpating the gall bladder.

6. Bile flow congestion leading to jaundice, yellow skin and conjunctiva, bitter tastein the

mouth, generalized itching, and chronic constipation.

7. Blood protein imbalance leading to generalized water retention.

8. Venous return blockage leading to hemorrhoids, pelvic congestions, and a heavy, erratic

menstrual flow.

9. Heat accumulation leading to hot skin and rashes.

10. Lack of joy, irritability, and quick anger.

11. Intolerance of alcohol.

12. Drug taking, medical or recreational, strains the liver.

13. Blood sugar imbalances including reactive hypoglycemia and diabetes (Type II).

14. Allergies and food sensitivities can arise from liver congestion or may cause it. Skin

rashes, migraines, abdominal bloating, and colic.

15. Tongue softness on the right side.



8. LAB TESTS FOR LIVER DISEASE

8.1 Aspartate Aminotransferase (ASAT)

It is found practically in every tissue of the body, including RBCs. Its concentration is

particularly high in cardiac muscle and liver, intermediate in skeletal muscle and kidney, and

much low in other tissues. The measurement of the serum ASAT level is helpful for the

diagnosis and following of cases of myocardial infarction, hepatocellular diseases and

skeletal muscle disorders. Reference Interval: 6-25 U/L.

8.2 Alanine Aminotransferase (ALAT)

The concentration of ALAT is not really as great as for ASAT. It is present in moderately

high concentration in liver, but is low in cardiac and skeletal muscles and other tissues. Its

use for clinical purposes is primarily for the diagnosis of liver diseases and to resolve some

ambiguous increase in serum ASAT and ALAT. The liver is the primary source of these

enzymes. If the serum ASAT is elevated while ALAT remains within normal limits, it is a

case of suspected myocardial infarction. Reference Interval: 3-30 U/L.

8.3 Alkaline Phosphatase (ALP)

Alkaline phosphatase is a group of enzymes that hydrolyzes monophosphate esters at an

alkaline pH. The enzyme has been identified in most body tissues and is generally localized

in the membrane. Eleven different isoform of this enzyme have been identified in serum.

Reference Interval: 40-223 U/L.

8.4 Lactate Dehydrogenase (LDH)

Lactate dehydrogenase is localized in the cytoplasm of the cells and this is extruded into the

serum when the cells are damaged or necrotic. When only a specific organ, such as liver is

known to be involved, the measurement of total LDH is useful. Reference Interval: 125-290

U/L.

8.5 Total Cholesterol

Serum cholesterol comprises two forms, free cholesterol and esterified cholesterol. In

jaundice and paranchymatous liver disease, serum cholesterol level will fall. Drug



administration will rectify the defective mechanism associated with carbon tetrachloride

administration. Reference Interval:



An elevated level of serum bilirubin may be produced. It shows severe parenchymal injury.

Reference Interval: < 1 mg/dL.

8.10 Direct Bilirubin (DB)

Unconjugated bilirubin is not water-soluble. It is transported in the blood stream bound to

albumin. It accounts for 30-50% of bilirubin rise in hepatocellular disease or cholestasis.

Unconjugated hyper-bilirubenemia is most often due to either haemolysis, or Gilberts

syndrome, an inherited abnormality of bilirubin metabolism. Reference Interval: < 0.25

mg/dL.



9. HERBAL TREATMENT FOR LIVER DISORDER

According to the principles of all Herbal medicine, health exists when the body is

balanced and its energy is freely flowing. The term energy refers to Qi, the life energy that is

said to animate the body. The term balance refers to the relative factors of yin and yangthe

classic Taoist opposing forces of the universe. The expression in various subsidiary

antagonists such as cold vs. heat, dampness vs. dryness, descending vs. ascending, at rest vs.

active, and full vs. empty. Herbal medical diagnosis and treatment involves identifying the

factors that are out of balance and attempting to bring them back into harmony. Diagnosis is

carried out by means of listening to the pulse (in other words, taking the pulse with

extraordinary care and sensitivity), observing and palpating various parts of the body, and

asking a long series of questions. It is important to realize that diagnosis according to herbal

system differs greatly from Western diagnosis. To understand this, consider two hypothetical

patients with the single Western diagnosis of migraine headaches. The first might be said to

have dryness in the liver and ascending while another might be diagnosed with exogenous

wind-cold. Based on these differing diagnoses, entirely different remedies might be applied.

The herbal formulas used in herbal system consist of four categories of herbs. Ministerial,

deputy, assistant, and envoy. The ministerial herb addresses the principal pattern of the

disease. Deputy herbs assist the ministerial herb or address coexisting conditions. Assistant

herbs are designed to reduce the side effects of the first two classes of herbs, and envoy herbs

direct the therapy to a particular part of the body. For example, in the case of dryness in the

liver and ascending described above, an herbalist might employ a ministerial8 herb to reverse

ascending Qi, a deputy herb to exert a moistening effect, an assistant herb to prevent the

stagnation of Qi (Qi stagnation is said to be a side effect of moistening herbs), and an envoy

to carry these effects to the liver.8

CLASSIFICATION:

These are generally classified into 3 categories without any strict delineation amongst them.

9.1 Anti-hepatotoxic agents:

These generally antagonise the effects of any hepatotoxin causing hepatitis or any liver

disorder or disease.



9.2 Hepatotropic agents:

These generally support or promote the healing process of the liver. In practice these two

activities cannot be easily distinguished from each other.

9.3 Hepatoprotective agents:

These generally prevent various types of liver affections prophylactically.

In general any hepatoprotective agent can act as an anti-hepatotoxic or hepatotropic agent but

the vice versa is always not true.

PLANTS USED IN THE TREATMENT OF LIVER DISEASE

(HEPATOPROTECTIVE NATURAL PLANTS):

Some of the crude drugs with activity against liver diseases are:

Eclipta alba (Asteraceae),

Glycyrrhiza glabra (Leguminosae),

Boerhaavia diffusa (Nyctaginaceae),

Phyllanthus amarus (Euphorbiaceae),

Silybum marianum (Compositeae),

Uncaria gamber (Rubiaceae),

Andrograhis paniculata (Acanthaceae).

Table 9.1 Plants with hepatoprotective activity

Botanical name Family Parts Used

Areca catechu Linn Arecaceae Inflorescence

Arenga wightii Griff Arecaceae Inflorescence and fruit husk

Aristolochia indica Linn Aristolochiaceae Roots (tender)

Asparagus racemosus Willd Liliaceae Roots



Azadirachta indica A. Juss Meliaceae Root Bark

Centella asiatica Urban Apiaceae Whole Plant

Ceratopteris siliquosa (L) Copel Ceratoptendaceae Whole Plant

Cuminum cyminum Linn Apiaceae Fruit

Curcuma domestica Val Zingiberaceae Fresh rhizome

Desmodium biflorum Linn Fabaceae Whole plant

Elettaria cardamomum Maton Zingiberaceae Seed

Ficus glomerata Roxb Moraceae Fruit

Ficus racemosa Linn Moraceae Tender root

Hibiscus lampas Cav. Malvaceae Fresh root

Ixora coccinea Linn Rubiaceae Fresh root

Impatiens henslowiana Arn Balsaminaceae Flowers and leaves

Momordica subangulata Bl. Cucurbitaceae Fruits (tenders)

Moringa oleifera Lam Moringaceae Stem bark

Naregamia alata W & A Meliaceae Whole plant

Phyllanthus fratenus Webst. Euphorbiaceae Whole plant

Piper longum Linn Piperaceae Stem

Ricinus communis Linn Euphorbiaceae Tender Leaves



Allium cepa Alliaceae Bulbs

Allium sativum Alliaceae Bulbs

Aphanamixis polystachya Meliaceae Stem, Root bark, Seeds

Apium graveolens Apiaceae Seeds

Arbutus unedo Ericaceae Leaves, Stem Bark.

Argemone Mexicana Papaveraceae Yellow juice

Aspargus officinalis Liliaceae Root

Azadirachta indica Meliaceae Leaves

Boerhaavia diffusa Nyctaginaceae Whole plant with root

Calotropis gigantean Asclepiadaceae Leaves

Carica papaya Caricaceae Milky juice

Centella asiatica Apiaceae Whole plant with root

Cichorium intybus Asteraceae Leaves and root

Cynara scolymus Asteraceae Leaves and root

Daucus carota Apiaceae Fruit and root

Eclipta prostrate Asteraceae Whole plant

Foeniculum vulgare Apiaceae Seeds

Fumaria officinalis Fumiriaceae Whole plant



Glycosmis pentaphylla Rutaceae Leaves

Iris germanica Iridaceae Rhizome

Fumaria parviflora Fumaricaceae Whole plant

Lobelia inflate Lobeliaceae Whole plant

Lycopodium clavatum Lycopodiaceae Plant and spores

Moringa pterygosperma Moringaceae Leaves, stem, root and gum

Myristica fragrans Myristicaceae Fruit

Myrtus communis Myrtaceae Leaves

Phyllanthus emblica Euphorbiaceae Root

Primula obconica Primulaceae Whole plant

Raphanus sativus Brassicaceae Whole plant

Ruscus aculeatus Ruscaceae Whole plant with root

Santolina chamaecyparissus Asteraceae Whole plant

Sarothamnus scoparius Papilionaceae Root

Silibum marianum Asteraceae Seeds

Solanum nigrum Solanaceae Leaves

Taraxacum officinale Asteraceae Root

Terminalia chebula Combretaceae Fruits



Tinospora cordifolia Menispermaceae Fresh stem

Trigonella foenum graecum Papilionaceae Leaves and seeds

Viola odorata Violaceae Whole plant

Zingiber officinale Zingiberaceae Rhizome.

Some of the reported constituents with pharmacologically/ therapeutically proved claims may

be enlisted as, was also reported for its hepatoprotective properties.

Silymarin

Glycyrrhizin

(+) Catechin

Saikosaponins

Curcumin

Picrolive I and II

Gomosin(Wagner et al.,1998)

Acetyl bergenin (Lim et al., 2000)

Kolaviron (Oluwatosin and Edward, 2006)14

9.3.1Silybum marianum:

Synonyms: Carduus marianus, mariane thistle.

Common name: Milk thistle

Family: Asteraceae

Origin: indigenous to the Mediterranean region, North Africa & Western Asia.

Parts used: Aerial parts



Chemical constituents:

The active constituents of milk thistle are flavonolignans including silybin, silydianin, and

silychristine, collectively known as silymarin.

Silybin is the component with the greatest degree of biological activity, and milk thistle

extracts are usually standardized to contain 70-80 percent silybin. Silymarin is found in the

entire plant but is concentrated in the fruit and seeds.

Silybum seeds also contain betaine (a proven hepatoprotector) and essential fatty acids,

which may contribute to silymarin's anti-inflammatory effect.

Active ingredients: Silymarin a flavolignin (hepatoprotective), lipids, proteins.

Milk seeds also contain other flavonolignans namely dehydrosilybin, desocysilycristin,

desoxysilydianin, silyhermin, neosilyhermi, silybinome, and silandrin.

Use:

Silybum marianum is currently the most well researched plant in the treatment of liver

disease.

Also use in the dyspepsia, disorders of biliary system, liver disorder.

It is used as hepatoprotective and in chronic inflammatory hepatic disorders including

hepatitis, cirrohis and fatty infiltration which occur due to industrial pollutants and alcohol.

It has also been found to be effective against liver poisioning due to alpha-galactosamine,

carbontetrachloride and tioacetamide.

It has reported that therapeutic utility of silymarin is due to stabilization of cell membrane,

stimulation of protein synthesis and accelerating the process of regeneration of hepatic cells.

The mechanism of hepatoprotective effect of silymarin has been suggested variously like

antioxidant activity by trapping superoxide anions, stimulation of RNA synthesis and in case

of amanita phalloides poisioning, blocking the receptor sites of outer liver cell membranes

Silymarin is preferably given by parantral route, due to low water solubility of

flavonoligans if taken orally, only 20-50% is absorbed.



Active constituents

The active constituents of milk thistle are flavonolignans including silybin, silydianin, and

silychristine, collectively known as silymarin. Silybin is the component with the greatest

degree of biological activity, and milk thistle extracts are usually standardized to contain 70-

80 percent silybin. Silymarin is found in the entire plant but is concentrated in the fruit and

seeds. Silybum seeds also contain betaine (a proven hepatoprotector) and essential fatty acid

which may contribute to the silimarins anti-inflammatory effect.

Pharmacokinetics

Silymarin is not water soluble and so cannot be taken as a tea. It is typically administered as

an encapsulated standardized extract. The absorption with oral administration is rather low

with only two to three percent of the silybin recovered in 24 hours from rat bile. The peak

plasma levels after an oral dose are achieved in four to six hours in both animals and humans.

Silymarin is cleared from the body predominantly via the bile and to a lesser extent the

kidney. The clearance half-life is six to eight hours.8

9.3.2 Taraxacum officinale:

Synonyms: Dandelion

Family: Asteraceae

Origin: All parts of the northern hemisphere.

Parts used: Leaves & roots.


Bitter constituents like taraxecerin and taraxcin are active constituents of the medicinal

herb.

Other Active ingredients: sesquiterpene lactones, phenolic acid, inulin, K.

Use:

Hepatic & biliary disorders, kidney stones.

Traditionally taraxacum officinale has been used as a remedy for jaundice and other

disorders of the liver and gallbladder, and as a remedy for counteracting water retention.



Generally, the rrots of the plants have the most activity regarding the liver and gallbladder.

Oral administration of extracts from the roots of taraxacum officinale has been shown to act

as a cholagogue, increasing the flow of bile.

Action: diuretic, tonic.

9.3.3 Cichorium intybus:

Synonyms: Cichory.

Common name: Kasni

Family: Compositae (asteraceae)


A bitter glucoside, Cichorin has been reported to be the active constituent of the herb.

Use:

Use for the treatment of liver diseases.

It is commonly known as kasni and is part of polyherbal formulations used in the treatment

of liver diseases.

In mice, liver protection was observed at various doses of Cichorium intybus but optimum

protection was seen with a dose of 75 mg/kg given 30 minutes after CCl4 intoxication.

In preclinical studies an alcoholic extract of the Cichorium intybus was found to be

effective against chlorpromazine-induced hepatic damage in adult albino rats.

9.3.4 Solanum nigrum:

Synonyms: Black nightshade.

Ayurvedic name: Kakamachi.

Family: Solanaceae.


Main active constituents are solamargine, andsolasonine.



Use:

Aromatic water extracted from the drug is widely prescribed by herbal vendors for liver

disorders.

Although clinical documentation is scare as far as hepatoprotective activity is concerned,

but some traditional practitioners have reported favorable results with powdered extract of the

plant.

It is in treatment of cirrhosis of the liver.

Also used as an emollient, diuretic, antiseptic, and laxative properties.

Antimicrobial, antioxidants, cytotoxic properties.

It is also have anti ulcerogenic activity and hepatoprotective activity.

9.3.5 Glychyrrhiza glabra:

Synonyms: Liquorice

Family: Leguminosae


Licorice contains triterpene saponin, known as glycyrrhizin, which has potential

hepatotprotective activity.

It belongs to a group of compounds known as sulfated polysaccharides.

Glycyrrhizin is potassium and calcium salt of Glycyrrhizinic acid.

Glycyrrhizinic acid is a glycoside and on hydrolysis yields glycyrrhetinic acid which has a

triterpenoid structure.

Other constituents are glucose, sucrose, bitter principle glycyramarin resin, aspargin and fat.

Another chemical aspects of liquorice is prencence of flavonoids(liquiritin and isoliquiritin)

which cauce antigastric effect and are useful in peptic ulcer treatment.



Use:

Glycyrrhizin use for anti-viral.

It has potential for therapeutic use in liver disease.

Experimental hepatitis and cirrhosis studies on rats found that it can promote the

regeneration of liver cells and at the same time inhibit fibrosis.

Glycyrrhizin can alleviate histological disorder due to inflammation and restore the liver

structure and function from the damage due to carbon tetrachloride.

The effects including: lowering the SGPT, reducing the degeneration and necrosis and

recovering the glycogen and RNA of liver cells.

Effects of glycyrrhizin has been studied on free radical generation and lipid peroxidation in

primary cultured rat hepatocytes.

Favorable results have been reported in children suffering from cytomegalovirus aftrer

treating with glyrcyrrhizin.9

9.3.6 Wilkstroemia indica:

Synonyms: Aradon indica, wilkstromia.

Family: Thymelaeaceae


A dicoumarin, daphnoretin is the active constituent of the herb.

The drug has shown to suppress HbsAG in Hep3B cells.

Use:

W. indica is a Chinese herb and has been evaluated in patients suffering from hepatitis B.

It is said to activator of protein kinase C.

9.3.7 Curcuma longa:

Synonyms: Curucuma, turmeric, Indian saffron



Family: Zingiberaceae


Diarylhepatonoids including Curcumin is the active constituent of the plant.

It contains yellow colour substances known as curcuminoids.

Curcuminoids is responsible for yellow colour.

Curcuma species contain volatile oil, starch etc.

Use:

Like silymarin, turmeric has been found to protect animal livers from a variety of

hepatotoxic substances, including carbon tetrachloride,galactosamine, pentobarbitol, 1-

chloro-2,4-dinitrobenzene,7 4-hydroxy-nonenal,1and paracetamol. Diarylhepatonoids.

Curcumin has been proved as anti-inflamatory drug.

9.3.8 Tephrosia purpurea:

Synonyms: basterd indigo, hoary pea.

Ayurvedic name: sharpunkha

Family: Fabaceae.


The roots, leaves and seeds contain tephrosin, deguelin and quercetin.

The hepatotprotective constituent of the drug is still to be proved.

Use:

Alkali preparation of the drug is commonly used in treatment of liver and spleen diseases.

In animal models, it offered protective action against carbon tetrachloride and D-

galalactosamine poisoning.

9.3.9 Fumaria officinalis:

Synonyms: Fumatory



Family: Papaveraceae

Chemical constituents: Alkaloids, flavonoids

Origin: Europe, Mediterranean, Middle East, but has now become a weed all over the world.

Parts used: aerial parts

Actions: Cholagogue, anti-spasmodic

Uses:

Biliary & dyspeptic disorders, especially spastic discomfort of the GIT, the gall-bladder &

bile ducts

9.3.10 Peumus boldus:

Synonyms: Boldo

Family: Monimiacee

Parts used: Leaf


Alkaloids, volatile oils, flavonols and their glycosides.

Origin: Chile and other South American regions.

Actions: Choleretic, diuretic, stomachic, mild sedative.

Use:

Dyspepsia, spastic complaints. It is the traditional anthemintic in Chile.

It is also used in pharmaceutical slimming mixtures.

9.3.11 Chionanthus virginicus:

Synonyms: Fringe tree, old mans beard.

Family: Oleaceae

Parts used: Dried root bark



Chemical constituents: Saponins, lignin glycoside.

Origin: Southern parts of Northern America.

Actions: Cholagogue, liver tonic, bitter tonic, anti-emetic, laxative.

Use:

Liver & gall bladder ailments (gall stones, hepatitis, jaundice & other ailments associated

with poor liver function).

It is also thought to be useful as a general tonic, diuretic & febrifuge.

It is also used for minor wounds, sores, bruises, inflammation, & infected wounds.

Traditional uses: American Indians used the herb for malaria & wound healing.

Homeopathic uses: migraine, headache, liver & gall bladder disorders & symptoms of

depression.

9.3.12 Andrograhis paniculata:

Synonyms: Kalmeg.

Family: Acanthaceae.

Parts used:

Andrographis leaves, as well as the fresh juice of the whole andrographis plant, have been

used in a variety of cultures.


Kalmegh contains bitter principles andrographolide, a bicyclic diterpenoid lactone and

Kalmeghin (upto 2.5%).

Andrographis contains andrographolide, deoxyandrographolide and neoandrographolide.

Andrographis contains many flavonoids.

Use:

Andrographis dispels heat i.e., is antipyretic.



It removes toxins, which makes it a good treatment for infectious fevercausing diseases.

It has been used in bacterial dysentery, arresting diarrhea and in upper respiratory

infections, tonsillitis, pharyngitis, laryngitis, pneumonia, tuberculosis, and pyelonephritis. It

has also been used in herpes, skin infections, and in helminthic (parasitic) infections.

Finally, it has been used for conditions as diverse and unrelated as snakebites and diabetes,

as well as terminating pregnancies.

9.3.13 Elipta alba:

Synonyms: Eclipta arecta, eclipta prostata.

Family: Compositae(asteraceae).


It contain resins and a alkaloid known as ecliptin, nicotin, glucoside, alkaloids

Use:

Viral hepatitis, liver disorders, skin- and hair care, improves complexion, calm the mind,

memory disorders, swollen glands, due to upper respiratory viral infection, strengthen spleen,

general tonic

The tincture has a neutralizing effect on the venom of South America rattle snakes.

The alcoholic extracts of the entire plant has been reported to have antiviral activity against

Ranikhet disease virus.

Aqueous extracts of the plant showed subjective improvement of vision in the cases of

refractive errors.

The alcoholic extract of the plant shows protective effects on experimental liver damage in

rats and mice.

9.3.14 Phyllanthus niruri/amarus:

Synonyms: Phyllanthus emblica, jonesiansoca.

Family: Euphorbiaceae




Constituents of this plant are numerous, and include flavonoids and alkaloids.

Use:

Liver & gall bladder ailments (gall stones, hepatitis, jaundice & other ailments associated

with poor liver function).

It is also thought to be useful as a general tonic, diuretic & febrifuge.

Standardization of phyllanthus amarus

In order to determine the reasons for variation in the in vitro efficacy of different collections

of P. amarus made from different parts of India,in vitro analysis for biological properties was

done. It revealed that the quantitative HBsAg binding ability and HBV DNA polymerase

inhibition ability varied significantly in different plant collections, and some of them did not

possess demonstrable anti-hepatitis B properties. When the extracts of these collections were

analyzed by HPLC profiles, there were similar variations of diminished elution peaks or even

absence of such peaks that could be correlated with the absence of biological properties.

These observations were considered along with the report of Mitra and Jain on the botanical

survey of India, which stated that the P. niruri is a mixture of three distinct species,

namely P. amarus Schum and Thonn, P. fraternus Webster and P. debilis Kleinx Wild.From

the reports it is now understood that the variety that is predominant in South India

is P. amarus only.

Based on these observations it was necessary to define a multistep standardization procedure

for assuring the reproducible, maximized bio-efficacy of P. amarus when used in the

treatment of chronic liver disease with special reference to chronic HBV infection. These

steps are:

(i). Taxonomic identification of the specific variety of P. amarus as the source material;

(ii). Preparation of the soil for the optimum growth of the selected P. amarus variety;

(iii). A formulation of the combination of specific extracts that will possess the following six

demonstrablein vitro activities:

(a) HBsAg binding property, which will facilitate the inactivation of the virus in circulation,

ultimately leading to viral clearance;



(b) HBV-DNA polymerase enzyme-inhibiting potential, thus acting as an antiviral and

preventing the multiplication of HBV;

(c) Reverse transcriptase enzyme inhibition, also required for the prevention of initiation of

HBV replication;

(d) Inhibition of HBsAg secretion from HBV-transinfected liver cells, thus possessing

activity against virus-infected chronic liver disease conditions;

(e) Hepatoprotective and antihepatotoxic properties against the liver cell toxicity brought

about by all hepatitis viruses (A,B,C,D,E) and other hepatotoxic agents; and

(f) Immunomodulating property to potentiate the immune system of HBV-infected patients

towards virus clearance and protective antibody (anti-HBs) responses; and

(iv) A chemobiological finger printing methodology using the aforementioned six

biological tests along with a matching HPLC profile to assess batch-to-batch in

vitro reproducibility.

The evaluation of herbal products face several major problems. The first is the use of mixed

extracts (concoctions) and variations in methods of harvesting, preparing and extracting the

herb, which can result in dramatically different levels of certain alkaloids. The biologically

active substances have been structurally defined and standardized for only a few of the herbs.

Even then it may not be known whether this is the sole active principal or if efficacy depends

on the mixture of compounds.

Second, there is a lack of randomized placebo controlled clinical trials for many of these

preparations using end-points of treatment efficacy such as viral clearance, and histological

improvement.

Numerous reports on toxic effects contradict the popular view that herbal drugs are natural

and are harmless. A survey by the National Poison Information Service for the years 1991

1995 documented 785 cases of possible or confirmed adverse reactions to herbal drugs,

among which hepatotoxicity was the most frequent. Hence, safety studies are needed to

generate scientifically sufficient data that may serve as a basis for future herbal drug

development.

In addition to the well-accepted laboratory parameters as described here using P. amarus as

an example, if the aforementioned three aspects viz., herbal drug standardization, randomized

controlled clinical trials and well-designed safety studies are incorporated as integral



components, then herbal drug development, potent, safe and acceptable herbal drugs can be

launched for the treatment of acute and chronic liver diseases. The drug development

of P. amarus in India may be an example of such an effort in an international setting.

9.3.15 Picrorrhiza kurrora:

Synonyms: Indian gentian, kutki.

Family: Scrophulariaceae


It is found to contain irridoid bitter substances picroside, picroside and kutkoside.

Picroside and kutkosides are C9 monoterpene glycosides with an epoxy oxides in ring.

Use:

Picrorrhiza is used as valuable bitter tonic, antiperiodic, febrifuge and stomachic and

laxative in large doses.

Alcoholic extract of root is found to have antibacterial effect.

The drug is found to useful in treatment of jaundice

Kutkoside has been found to be a potential hapatoprotectant.17

Table 9.2 Plants with Hypolipidaemic activity

Sl.No Name of Plant Family Common/ Indian

vernacular names Plant parts

Sponsored

Links

1

Aegle marmelos Rutaceae Beal fruit, bilwa Fruits

2 Agave Veracruz Amaryllidaceae American aloe,

barakhawar Roots, leaves, gum



3 Allium cepa Lilliaceae Onion, piyaj,

palandu Bulbs

4 Aloe barbadensis Lilliaceae Ghee kumar,

gwarpatha Leaves

5 Bambusa arundunacea Graminae Bamboo vamsha Leaves

6 Bosswellia serrata Burserraceae Salai guggal Gum

7 Brassicavercapitata Cruciferae Cabbage Oil

8 Cajanus cajan Fabaceae Red gram Seeds

9 Capparis decidua Capparaceae Karli, tint

Leaves, fruits

and stems

10 Capsicum frutescens Solanaceae Chillies Fruits

11 Carum capaticum Umbelliferae Jowan, ajowan Fruits, roots

12 Celastrus paniculatus Celastraceae Khunjri, kusur

Seed oil, barks,

roots and fruits

13 Curcuma amada Zingiberaceae Mango ginger,

haridra Rhizomes

14 Cyamopsis

tetragonoloba Leguminosae Guar, gwar Seeds

15 Emblica officinalis Euphorbiaceae Amla, amlki

Dried fruits,

Seeds, leaves



16 Eugenia cumini Myrtaceae Jamun Seeds

17 Inula racemosa Compositae Puskarmul Roots

18 Juglans regia Juglandaceae Walnut, akhrot Kernel, oil

19 Medicago sativum Papilionaceae Alfalfa Seeds

20 Momordica charantia Cucurbitaceae Bitterground, Fruits

21 Musa saspientum Musaceae Banana, kela Roots, Stems,

Flowers, Fruits

22 Nepeta hindostana Labiatae Billiola, badranj

boya Whole plant

23 Phaseolus aureus Fabaceae Green gram Seeds

24 Phaseolus mungo Fabaceae Black gram Seeds

25 Picrohiza kurroa Scrophulariaceae Kulki, kataki Roots

26 Piper nigrum Piperaceae Golmirch, kalimich Leaves

27 Pisum sativum Papilionaceae Gardenpea, matar Seeds

28 Pterocarpus

marsupium Papilionaceae Indian malabarkino Gum and leaves

29 Saussuraea lappa Asteraceae Kustha, Kut Roots

30 Terminalia arjuna Combretaceae Arjun Barks



Table 9.3 Medicinal Plants with protective role against Liver Disease

Name of the Plants Family Parts use Hepatotoxicity

inducing agents

Astragalus

polysaccharides

Magnoliaceae Dried fructus Carbon tetrachloride

Arachniodes exilis Dryopteridaceae Rhizomes Carbon tetrachloride

Asparagus racemosus Liliaceae Whole plant -radiation

Amaranthus spinosus Amaranthaceae Whole plant Carbon tetrachloride

Apium graveolens Apiaceae Seeds Paracetamol and

thioacetamide

Aloe barbadensis Mill Liliaceae Dried aerial parts Petroleum ether ,

chloroform and

methanol

Artemisia absinthium Asteraceae Powdered aerial parts Carbon tetrachloride

and by injection of

endotoxin

Azadirachta indica Meliaceae Leaf Paracetamol

Acacia confuse Leguminosae Bark Carbon tetrachloride

Baliospermum

montanum

Euphorbiaceae Roots Paracetamol

Cassia fistula Leguminosae Leaf Carbon tetrachloride

Calotropis procera Apocynaceae Flowers Paracetamol

Decalepis hamiltonii Asclepiadaceae Roots Carbon tetrachloride

Euphorbia fusiformis Euphorbiaceae Tubers Rifampicin



Glycyrrhiza glabra

Linn

Fabaceae Root powder Carbon tetrachloride

Ginkgo Biloba Ginkgoaceae Dried extract Carbon tetrachloride

Gentiana asclepiadea

L.

Gentianaceae aerial parts, root Carbon tetrachloride

Hygrophila auriculata Acanthaceae Root Carbon tetrachloride

Halenia elliptica Gentianaceae Whole plant Carbon tetrachloride

Juncus subulatus Juncaceae Powdered tubers Paracetamol

Momordica dioica Cucurbitaceae Leaves Carbon tetrachloride

Meconopsis

integrifolia

Papaveraceae Flowers Carbon tetrachloride

Melochia corchorifolia Malvaceae aerial part Carbon tetrachloride

Orthosiphon

stamineus

Lamiaceae Leaves Acetaminophen

Ocimum snctum Lamiaceae Leaf Paracetamol

Pterocarpus

marsupium Roxb.

Papilionaceae Stem bark Carbon tetrachloride

Piper longum Piperaceae Fruits and roots

powder

Carbon tetrachloride

Pittosporum Pittosporaceae Stem bark Carbon tetrachloride,



LIVER PROTECTIVE HERBAL DRUGS

Table 9.4 Phenol containing hepatoprotective drugs.

S.no. Plant Part used

1. Arnica montana Whole plant

2. Cichoriumintybus Whole plant

3. Picrorhiza kurroa Root

Table 9.5 Coumarins containing hepatoprotective drugs.

S.no. Plant Part used

1. Artemesia abronatum Whole plant

2. Artemesia capillaries Whole plant

3. Armillariella tabescene Root

The literature is replete with experimental studies using herbs of largely unknown

composition. The following are those preparations for which human studies or mechanistic

data exist.

9.1 Compound 861: Known as cpd 861, this is an aqueous extract of 10 defined herbs based

on traditional Chinese medicine. The aim of traditional Chinese medicine is resolution of

blood stasis and liver stagnation, two conditions that form the basis of liver pathology and

patient discomfort.The chief herbs used in cpd 861 are Salvia miltiorrhiza, Astragalus



membranaceous, andSpatholobus suberectus.Rats with experimental liver fibrosis showed a

50% reduction of the 5-fold increased hepatic collagen level when cpd 861 was administered

daily by gavage.This was accompanied by a comparable down-regulation of hepatic

messenger RNA for transforming growth factor 1 and for procollagens I, III, and IV, as well

as by increased hepatic collagenase activity. Because procollagen messenger RNAs, major

effectors of liver fibrogenesis, were also down-regulated in cultures of hepatic stellate cells, a

direct antifibrotic effect was proposed.From 1993 to 1995, 60 patients with chronic hepatitis

B were treated in an open trial with cpd 861.After 2 years, subjective improvement was

reported by 50 patients (83%), and this was accompanied by a reduction in spleen size in

41% and a decrease in liver enzyme levels and serum fibrosis markers such as PIIINP and

laminin. In a nonrandomized controlled trial, 22 patients with chronic hepatitis B were treated

with cpd 861 for 6 months and compared with 12 matched patients receiving a control herbal

medicine.Follow-up liver biopsy results showed a statistically significant improvement in

both histological inflammation and fibrosis in the cpd 861 group but no change in the control

subjects.

9.2 LIV.52: An extract of several plants prepared for ayurvedic medicine has been marketed

in the West as LIV.52. Standardization, chemical characterization, functional, and

pharmacological studies are not well documented. The extract was reported to improve serum

biochemistry values in rats with toxic liver damage,and uncontrolled observations in patients

with liver disease seemingly gave similar results.Furthermore, it lowered circulating levels of

acetaldehyde in healthy adults consuming alcohol.Therefore, Fleig et al.performed a

randomized, placebo-controlled, 2-year clinical trial in 188 patients with alcohol-related

cirrhosis. LIV.52 did not affect the survival rate of Child class A and B patients but increased

mortality among the 59 Child class C patients (81% in the treated group, compared with 40%

in the placebo group). Twenty-two of 23 deaths in the LIV.52 group were related to bleeding

or liver disease compared with only 3 of 11 deaths in the placebo group. This result led to

immediate withdrawal of the drug. It highlights the danger of ill-defined herbal preparations

and the necessity for in-depth preclinical testing.



10. CASES OF HEPATIC DISORDER AND HERBAL TREATMENT

10.1 Case 1: Liver Strengthening

Male 37 years old, general aches and pains, leg cramps, tendency to diarrhoea or

constipation, nausea, erratic appetite, occult blood in stools, indigestion with colicky pains

low energy, prone to minor infections, several lymph nodes swollen, lumps on akin inc fatty

nodule, skin puffy and somewhat greyish. Overweight. "I need to make BMW changes,

would like to detoxify." Generally an anxious and obsessively hard-working person. Tongue

covered with thick, greyish fur.10

Herbal treatment:

Tincture:

Taraxacum officinalis (dandelion root)

Salvia off (Sage) 20 ml

Calendula off (Marigold) 20 ml

Sambucusnigra (elder flowers) 20 ml

Thujaoccidentalis (thuja) 120 ml

Phytolaccadecandra (poke root) 5 ml

Sig 15 nil twice a day. The sage and the thuja were for general energy and to strengthen the

immune system. The elder flower was for sinusitis. The marigold and poke root were for skin

and lymphatic cleansing.



10.2 Case 2: Liver herbs in pregnancy

Strong liver cleansing herbs are generally contraindicated in pregnancy. They are excessively

cooling and downward-moving. Strategies in pregnancy should concentrate on building up

with gentle warming and gentle cleansing where appropriate. If liver cleansing is needed,

dandelion root (Taraxacumofficinalis) is the herb of choice. Yellow dock (Rumexcrispus)

root is the strongest herb I use, in this category. Yellow dock also has a traditional reputation

for helping conception.

Patient

A woman of 28 years with chronic constipation. Feels "stuck in life at the moment."

Medical history

Bulemia, vaginal thrush, severe PMS made worse by the contraceptive pill, irregular cycle,

lumpy breasts, generalized water retention, depression, anxiety, insomnia, cystitis triggered

by sexual activity, poor skin tone with lots of spots. Tongue pale, soft, and wobbly. Cold.

Diet

Mostly vegetarian, occasional fish, no milk, occasional bread. Modified after following an

anti-candida diet for some years. Supplements included acidophilus and evening primrose oil.

Notes

This patient originally presented with depression and anxiety. There were obviously issues

arising around her history to be dealt with. She had taken a psychology degree, "in order to

understand myself better," which didn't work. The liver is not the only organ affected here,

but plays a central role in reestablishing proper bowel function."

Treatment: Initial prescription

Aloe (Aloe yen) leaf

Rhubarb (Rheum officinalis)

Tincture, 20-35 ml per week

On these and other herbs she showed slow but steady improvement in all her symptoms, over

a period of three years. Her life then had improved enough for her to consider motherhood.



New prescription:Tincture

Dandelion root (Taraxacumofficinalis)

Yellow dock (Rumexcrispus)

She became pregnant very quickly, and her constipation rapidly got worse. After some

experimentation with dosage we settled on a tincture mixture of:

Mallow (Althea officinalis) 20 ml

Yellow dock (Rumexcrispus) 40 ml

Dandelion root (Taraxacumofficinalis) 40 ml

Sweet fennel essential oil (Foeniculumvulgare) 1 drop

Dose: 5 ml three times a day, increasing to 15 ml if necessary

Her average dose over her pregnancy was around 20 ml/day

Comments

Fennel oil is contra-indicated in pregnancy, but this dosage level is OK. I often use it with

dock or rhubarb root tinctures. It improves the flavor, takes the edge off their coldness, and

relieves griping.12



11. CONCLUSION

Out of the several leads obtained from plant sources as potential hepatoprotective

agents, silymarin, andrographolide, neoandrographolide, curcumin, picroside, kutkoside,

phyllanthin, hypophyllanthin, and glycyrrhizin have been established as potent

hepatoprotective agents. The hepatoprotective potential of several herbal medicines has been

clinically evaluated. Significant efficacy has been seen with silymarin, glycyrrhizin and Liv-

52 in treatment of hepatitis, alcoholic liver disease and liver cirrhosis.



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4. Final Thesis

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