Cirrhosis

Cirrhosis is defined as a condition of irreversible scarring liver as a result of liver tissue by fibrosis due to final phase of chronic liver diseases of that can lead to poor function of the liver and liver failure. According to the statistics, Number of discharges with chronic liver disease or cirrhosis as the first-listed diagnosis: 101,000 in 2009 and Deaths per 100,000 population: 10.3 in 2010(a). Hepatitis B infection cause of the disease is very prevalent in South-East Asia.

I. Causes and risk factors
A. Causes
Most cases of Cirrhosis are caused by excessive and chronic alcohol drink and hepatitis.
1. Excessive and chronic alcohol drink
Prolonged period of excessive alcohol drink can lead to onset of the disease. In the study to provide a quantitative assessment of the association between alcohol intake and risk of liver cirrhosis, by the Centre for Addiction and Mental Health, showed that alcohol consumption had a significantly larger impact on mortality of liver cirrhosis compared with morbidity. Also, the same amount of average consumption was related to a higher risk of liver cirrhosis in women than in men.(1).

2. Hepatitis
a. Heptitis C
Hepatitis C virus (HCV) infects more than 170 million people worldwide, and thereby becomes a series global health challenge. Chronic infection with HCV is considered one of the major causes of end-stage liver disease including cirrhosis and hepatocellular carcinoma(2).

b. Hepatitis B
Following development of liver cirrhosis in patients with chronic hepatitis B, liver disease may continue to progress and decompensation or hepatocellular carcinoma (HCC) may occur(3).

3. Biliary cirrhosis
a. Primary Biliary cirrhosis
Primary Biliary cirrhosis is defined as a chronic liver diseases as a result of the slow destruction of the bile duct of the liver. According to the study by, Nagasaki University Graduate School of Biomedical Sciences, patients with primary biliary cirrhosis (PBC) exhibit a variety of clinical manifestations and patterns of disease progression. The genetic variants of CYP7A1 and its transcriptional activators (HNF4A and PPARGC1A) may activate bile acid synthesis, resulting in the accumulation of bile acids in hepatocytes and eventually leading to the predisposition to PBC progression(4). Other study in the examined single nucleotide polymorphisms (SNPs) in cytotoxic T-lymphocyte antigen 4 (CTLA4) and solute carrier family 4 anion exchanger, member 2 (SLC4A2), which have been associated with the pathogenesis of PBC in Caucasian patients, found that CTLA4 and SLC4A2 genetic polymorphisms are differentially associated with PBC development and progression, as well as anti-gp210 or anti-centromere antibody production, in Japanese PBC patients(5).

b. Secondary Biliary cirrhosis
Secondary Biliary cirrhosis is defined as a condition of the blocking of the bile duct of the liver as a result infection or iatrogenic bile duct injury (BDI), bile duct strictures, gallstones, sclerosing, etc. 
Secondary biliary cirrhosis was the indication for liver transplantation (LT) in 5 (1.7%) out of 300 LTs performed in our center between Feb 2002 and April 2011, according to the Surgery and Liver Transplantation, M. Curie Hospital, Szczecin(6).

4. Other causes (non-B, non-C liver cirrhosis (NBNC LC))
In a nationwide survey of NBNC LC in Japan at the 15th General Meeting of the Japan Society of Hepatology, 6999 NBNC LC with patients were registered at 48 medical institutions. Epidemiological and clinical factors, indicated that The percentage of NBNC LC among LC patients was 26%. NBNC LC patients were categorized into 11 types according to etiological agents: non-alcoholic steatohepatitis (NASH), 14.5%; alcoholic liver disease (ALD), 55.1%; fatty liver disease (FLD), except NASH, ALD, and other known etiology, 2.5%; primary biliary cirrhosis, 8.0%; other biliary cirrhosis, 0.8%; autoimmune hepatitis, 6.8%; metabolic disease, 0.6%; congestive disease, 0.8%; parasitic disease, 0.2%; other known etiology, 0.2%; and unknown etiology, 10.5%(7).

B. Risk factors
1. Gender
Female who are chronic alcohol drinkers are at increase to develop Cirrhosis. According to the study  in a population-based prospective cohort of 13,285 men and women aged 30-79 years, and diagnoses indicating alcoholic liver disease (n = 261) or cirrhosis (n = 124) were obtained from the Danish National Health Registers, indicated that women had a significantly higher relative risk of developing alcohol related liver disease than men for any given level of alcohol intake(8).

2. Diabetes mellitus (DM)
If you are diabetic, you are associated with increased risk of cirrhosis. According to the study by the University Hospital, Monterrey, about 30% of patients with cirrhosis have diabetes mellitus (DM). There exists in relation to: type 2 DM alone or as part of the metabolic syndrome in the development of liver disease; factors involved in the genesis of hepatogenous diabetes; the impact of DM on the clinical outcome of liver disease; the management of DM in cirrhotic patients and the role of DM as a risk factor for the occurrence and exacerbation of hepatocellular carcinoma(9). Other study indicated that Insulin resistance in liver cirrhosis was higher than the other type 2 DM, and impaired hepatic insulin degradation might be an important mechanism of hyperinsulinemia in liver cirrhosis(10).

3. Excessive alcohol drinking
People who drinks abusively, in most case died as a result of the progression of liver diseases. According to the review of Seventeen studies  alcohol consumption had a significantly larger impact on mortality of liver cirrhosis compared with morbidity. Also, the same amount of average consumption was related to a higher risk of liver cirrhosis in women than in men(11).

4. Medication induced cirrhosis
Certain medication may cause increased risk of cirrhosis to the takers. According to the study by the Seoul National University College of Medicine, anti-tuberculosis (TB) drug-induced liver injury (DILI) in patients with chronic liver disease including cirrhosis, but the drugs may be safely used in the patients with chronic liver disease including compensated cirrhosis if number of hepatotoxic drugs used is adjusted appropriately(12). In other study by University "Magna Græcia" of Catanzaro, there is a case of a male patient who developed severe drug-induced hepatotoxicity during the treatment with Cyproterone acetate (CPA). The case, presenting sub-acute hepatitis, was characterized by a rapid evolution of cirrhosis and a protracted activity during the period of a few months despite the treatment withdrawal and an apparent benefits of corticosteroids, suggesting their indication in life threatening cases(13).

5. Age
Risk of cirrhosis is increased with progression of age. According to the study by the University of Sydney, there is evidence that the sinusoidal changes in cirrhosis and aging contribute to hepatocyte hypoxia, thus providing a mechanism for the apparent differential reduction of oxygen-dependent phase I metabolic pathways in these conditions. Structural change and subsequent dysfunction of the liver sieve warrant consideration as a significant factor in the impairment of overall substrate handling and hepatic drug metabolism in cirrhosis and aging(14).

6. Obesity
Risk of cirrhosis is increased for obese people. In the study to evaluate the role of obesity, in relationship to other recognized predictors, in the development of CD in patients with compensated cirrhosis, found that obesity has a deleterious effect on the natural history of compensated cirrhosis of all etiologies, independent of portal pressure and liver function. Weight reduction may be a valuable therapeutic measure in this patient population(15).

7. Heredity
Alpha-1-anti-trypsin deficiency is the most common genetic cause of liver disease in children and liver transplantation is currently the only available treatment, according to the study by Telethon Institute of Genetics and Medicine(16).

8. Toxins
Toxins can damage the liver. according to the study by University Hospital Regensburg, Xanthohumol, the major prenylated chalcone found in hops, is known for its anti-inflammatory properties exerts a protective effects of xanthohumol in this toxic liver injury model involves direct mechanisms related to its ability to block both hepatic inflammation and the activation of hepatic stellate cells, presumable at least in part via decreasing NFκB activity(17).

9. Etc.

II. Symptoms
1. Psychosocial issues and health-related quality of life (HRQOL)
According to the study by the Tehran University of Medical Sciences and Tehran University of Medical Sciences, showed that Increasing severity of CHBV leads to a decline in HRQOL. Cirrhosis worsens HRQOL, whereas treatment and psycho-education improves it. Frequency of mood disorders seems to be increased in patients with CHBV, although not all studies have shown this trend. Some factors such as alcohol consumption and low social support negatively impact patients' mental health. Those with CHBV generally have better HRQOL and mental health than their hepatitis C (HCV) counterparts. Patients with psychiatric disorders, particularly those with prolonged institutionalization, have a generally higher risk of acquiring CHBV infection compared to the general population(18) .Other study indicated that
severity of cirrhosis measured by the Child-Pugh score was not correlated with depression or anxiety, and only had a weak correlation with poor sleep. The psychological distress in cirrhosis such as depression, anxiety, and insomnia were correlated specifically to increased levels of aspartate aminotransferase (AST), increased ratios of low frequency to high frequency power, or reduced nonlinear properties of HRV (alpha1 exponent of detrended fluctuation analysis)(19).

2. Fatigue, Pruritus and Jaundice
In the study to summarize the clinical characters of refractory primary biliary cirrhosis (PBC) versus typical ones and explore the risk factors of prognosis, found that Some clinical severe manifestation (fatigue, pruritus and jaundice) and higher biochemical markers levels (ALT, AST, ALP, GGT, TBIL, DBIL and IgM) seem to predict a worse response to UDCA and a rapid progression of disease in PBC patients(20). 

4. Lower serum aminotransferase, bilirubin, and immunoglobulin G (IgG) for patient with autoimmune hepatitis (AIH)(21).

5. Migraine symptoms
In the study to assess the effects of H. pylori eradication on migraine symptoms in patients with hepatitis-B-virus-related cirrhosis, the results clearly showed that the intensity, duration, and frequency of attacks of migraine were significantly reduced in all the patients in whom H. pylori has been eradicated(22).

6. Cognitive symptoms
According to the study by the Newcastle University, PBC associates with substantial functional impairment. PBC symptom distribution evolves over time, with cognitive symptoms making ever-greater contribution to overall symptom burden. The major potentially modifiable determinant responsible for the functional impairment appears to be orthostatic symptoms(23).
Other indicated that a significant proportion of fatigue in PBC associates with one or both of autonomic dysfunction (OGS > or =4) and sleep disturbance (ESS > or =10)(24).

7. Other symptoms include
Loss of appetite( Progression of the disease),  Itching (liver malfunction), Easy bruising and bleeding (platelet destruction), Weight loss (Malnutrition), Leg swelling (as a result of fluid retention), discrepancies between serum albumin levels(progression of the disease) etc(25).

III. Complications
1. Liver Cancer
Following development of liver cirrhosis in patients with chronic hepatitis B, liver disease may continue to progress and decompensation or hepatocellular carcinoma (HCC) may occur, especially in those with active viral replication. Decompensation may manifest with jaundice, ascites, variceal bleeding or hepatic encephalopathy(26).

2. Short life expentency
Cirrhosis can lead to shorten life expectancy in patients, according to the study of retrospectively analysed 59 patients from western Austria over 15 years (mean 6 yearsby the Universitätsklinik für Innere Medizin, indicated that the mean survival time in our study was 112.7 months, 25% were dead by 132(27).

3. Liver cancer
An estimated 170 million people worldwide are chronically infected with the Hepatitis C Virus (HCV), which is characterized histologically by a persistent immune and inflammatory response that fails to clear HCV from hepatocytes of that can lead to Liver Cancer(28).

4. Ascites
In the study to provide an evidence-based overview of the pathophysiology, diagnosis and clinical management of ascites secondary to liver cirrhosis, showed that portal hypertension, splanchnic vasodilatation and renal sodium retention are fundamental in the pathophysiology of ascites formation. The SAAG (serum-ascites albumin gradient) allows reliable assessment of the cause of ascites. The majority of cirrhotic patients with ascites can be managed with dietary sodium restriction in combination with diuretic agents. Large volume paracentesis with albumin suppletion and TIPS are therapeutic options in patients with refractory ascites(29).

5. Variceal bleeding
There is a report of a case of a 38-year-old female with a history of alcoholic liver cirrhosis visited our hospital with a massive hematochezia. An esophagogastroduodenoscopy did not demonstrate any bleeding source, and a colonoscopy showed a massive hemorrhage in the ascending colon but without an obvious focus(30). Other indicated that due to portal hypertension and bleeding disorders, patients with liver cirrhosis are at increased risk for severe gastrointestinal bleedings (GIB)(31).

6. Hepatic encephalopathy
Hepatic encephalopathy is defined as a condition of deteriotion of brain function due to failure of liver in toxic removeal. According to the study by the Medical Clinic II, Diakoniekrankenhaus, the pathogenesis of hepatic encephalopathy (HE) is unknown. Many theories have been proposed. Most established therapies are based on such theories but since no theory has have ever been proved, therapies have to be considered empiric. The spectrum of HE ranges from minimal cerebral functional deficits, which can only be found by sensitive psychometric tests, to coma with signs of decerebration(32).

7. Frequent Hospital readmission
According to the study by the University of Pittsburgh, in the study to determine risk factors for frequent readmissions among patients with cirrhosis and identify barriers to transplantation in this population, showed that a small group of patients with cirrhosis account for a disproportionately high number of hospital admissions. Interventions targeting this high-risk group may decrease frequent hospital readmissions and increase access to transplantation(33).

V.  Diseases associated Cirrhosis
1. Autoimmune diseases
In the study to assess the prevalence of concurrent extrahepatic autoimmune diseases in patients with autoimmune hepatitis (AIH)/primary biliary cirrhosis (PBC) overlap syndrome and applicability of the 'mosaic of autoimmunity' in these patients, in a population, 31 (43.6%) patients had extrahepatic autoimmune diseases, including autoimmune thyroid diseases (13 patients, 18.3%), Sjögren syndrome (six patients, 8.4%), celiac disease (three patients, 4.2%), psoriasis (three patients, 4.2%), rheumatoid arthritis (three patients, 4.2%), vitiligo (two patients, 2.8%), and systemic lupus erythematosus (two patients, 2.8%).conducted by the Numune Research and Education Hospital, showed that a large number of autoimmune diseases were associated with AIH/PBC overlap patients. Therefore, extended screening for existing autoimmune diseases during the routine assessment of these patients is recommended. The study also sugested that the concept of 'mosaic of autoimmunity' is a valid clinical entity that is applicable to patients with AIH/PBC overlap syndrome(34).

2. Cardiovascular disease
Impaired glucose tolerance or diabetes are frequently observed in cirrhosis. Cirrhotic patients, even in the presence of overt diabetes, are at low risk of cardiovascular disease. The low prevalence may be related to shorter duration of diabetic disease, also in relation to reduced life expectancy, as well as to liver disease-induced abnormalities protecting the cardiovascular system from atherosclerosis(35).

3. Hepatic angiomyolipoma
Hepatic angiomyolipomas are increasingly recognized as incidental findings during surveillance for cirrhosis or investigations for unrelated conditions. Awareness of their diverse morphological spectrum in liver biopsy is necessary to avoid misdiagnosis as hepatocellular carcinoma, metastatic melanoma or other malignant neoplasms(36).

4. Obesity
Obesity is associated with an aggressive course in chronic viral hepatitis. In a randomized trial of beta-blockers in the prevention of varices in whom data on body mass index (BMI) was available, consisted of 161 patients with compensated cirrhosis, found that obesity has a deleterious effect on the natural history of compensated cirrhosis of all etiologies, independent of portal pressure and liver function. Weight reduction may be a valuable therapeutic measure in this patient population(37).

5. Steatohepatitis
According to the study by University of Sydney at Westmead Hospital, age, activity of steatohepatitis, and established fibrosis predispose to cirrhosis, which has a 7- to 10-year liver-related mortality of 12% to 25%. Many cases of cryptogenic cirrhosis are likely endstage NASH. While endstage NAFLD currently accounts for 4% to 10% of liver transplants, this may soon rise(38).

6. Glycogen storage disease
Glycogen storage disease Ib is an inborn error of carbohydrate metabolism leading to impaired glycogenolysis and gluconeogenesis. There is a report of a case of on the development of liver cirrhosis in a nine-year-old boy in the course of glycogen storage disease Ib and discuss possible underlying pathomechanisms(39).

IV. Other conditions may be affected by Cirrhosis
1. Pregnancy
As the treatment of cirrhosis improves, pregnancy in patients with cirrhosis is likely to become more common. Although maternal and fetal mortality is expected to similarly improve, pregnant patients with cirrhosis face unique risks, including higher rates of spontaneous abortion and prematurity and a potential for life-threatening variceal hemorrhage, hepatic decompensation, splenic artery aneurysm rupture, and postpartum hemorrhage(40).

2. Malnutrition
In the study to assess of 212 hospitalized patients with liver cirrhosis who were followed clinically for 2 y or until death. Body fat and evaluate muscle mass by triceps skinfold thickness (TSF) and midarm muscle circumference (MAMC), respectively, showed that thirty-four percent of patients had severe malnutrition as determined by MAMC and/or TSF below the 5th percentile and 20% had moderate malnutrition (MAMC and/or TSF < 10th percentile). Twenty-six percent of patients were overnourished (MAMC and/or TSF > 75th percentile). Severely and moderately malnourished patients had lower survival rates than normal and overnourished patients(41).

3. Obese and diabetic individuals
Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease in the Western world and its incidence is increasing rapidly. According to the study by Indiana University School of Medicine, indicated that NAFLD is a spectrum ranging from simple steatosis, which is relatively benign hepatically, to nonalcoholic steatohepatitis (NASH), which can progress to cirrhosis. Obesity, insulin resistance, type 2 diabetes mellitus, and dyslipidemia are the most important risk factors for NAFLD. Due to heavy enrichment with metabolic risk factors, individuals with NAFLD are at significantly higher risk for cardiovascular disease. Individuals with NAFLD have higher incidence of type 2 diabetes(42).

4. Etc.

V. Diagnosis
After recording the physical examination, including exanination of the liver for  enlargement (indication of early stahe of cirrhosis), hardening (indicated the end stge of the disease), symptoms of sweeling (indication of fluid retention) and family history, if you are suspective to have any form of liver diseases, the tests which your doctor orders may include
1. Blood test
The aim of the blood test is to measure the liver enzymes associated with liver function, including serum albumin concentration for the measuremant of the protein in the blood, Prothrombin time (PT) for the blood cloted time, Alkaline phosphatase (ALP) for the blokage of bible duct, Bilirubin (the yellow pigment are indication of liver damage)for the damage of liver.
2. Image tests
a. Magnetic resonance imaging (MRI)
In the study to evaluate the clinical practical value of apparent diffusion coefficient (ADC) measurements based on diffusion-weighted MR imaging (DWI) for quantification of liver fibrosis and inflammation for hepatitis viral infection, found that the DWI measurement of hepatic ADC can be used to quantify liver fibrosis and inflammation. It will be a new approach for early diagnosis and therapeutic follow-up of hepatic fibrosis(43).
Other study indicated that DWI is proved to be a useful clinical tool in the quantitative evaluation of liver fibrosis and in the prediction of the process of liver fibrosis with the recommendable b value (500 s/mm2)(44).

b.  Computed tomography (CT)
The CTA was much more sensitive in detecting haemodynamic changes in the cirrhotic liver than CTAP, conventional CT and sinusoidal-phased hepatic angiography. Further study is required to clarify the mechanism of inhomogeneous enhancement on CTA and homogeneous enhancement on CTAP seen in cirrhosis, according to the study by the National Cancer Center Hospital(45).
 Other report of Regenerative nodules in cirrhotic liver are visualized as enhancing nodules surrounded by lower attenuation thin septa at CTAP and nonenhancing nodules surrounded by enhancing fibrous septa at CTHA. CTHA is more sensitive than CTAP in depicting regenerative nodules (P < .005)(46).

c. Ultrasound
Ultrasound examination was performed in 80 hemodialysis (HD) patients divided into two groups. The first group consisted of 37 (46.3%) patients with US greater than 66, indicating the presence of compensated liver cirrhosis. The second group included 43 (53.7%) patients without liver cirrhosis, with US equal to or less than 66. The value of liver morphology was significantly higher,with chronic hepatitis C in order to determine the ultrasound predictors of compensated liver cirrhosis, found that
Ultrasound examination could be used for non-invasive diagnosis of compensated liver cirrhosis, with accurate estimation of the disease severity in HD patients with chronic hepatitis C(47).

3. Liver biopsy
In liver biopsy, a sample of the liver is withdrawn and examined under microscope to comfirm or rule out the disease. In the study to summarize the role of liver biopsy, transient elastography and hepatic venous pressure gradient (HVPG) in the diagnosis and monitoring of patients with liver cirrhosis, found that Transient elastography has some value for the prediction of clinically significant portal hypertension, but a large proportion of patients have non-diagnostic values. It has also some value for the diagnosis of varices, but non-invasive markers cannot substitute endoscopic screening in cirrhosis. Better dynamic, easily repeatable non-invasive tools are needed to monitor compensated cirrhosis(48).  But other study indicated that Needle biopsy of the liver is considered the "gold-standard" for diagnosis of hepatic fibrosis and cirrhosis. However, it is not risk-free, lacks accuracy, and is poorly accepted by some patients, and suggested that Transient elastography is reliable in detecting moderate to severe fibrosis and cirrhosis and in ruling out cirrhosis, but is less reliable in ruling out moderate fibrosis. Composite scores based on blood assay values and complex calculations are unreliable when at least one of the score components is influenced by intercurrent conditions. FibroTest, FibroMeter and Hepascore have been tested in several thousand patients with chronic hepatitis C. With the manufacturers' recommended cutoff values, FibroTest identifies about 70% of patients with histological signs of moderate to severe fibrosis and about 90% of patients with histological signs of cirrhosis. It can reliably diagnose or rule out moderate fibrosis, and diagnose cirrhosis. It is also very reliable in ruling out cirrhosis. Hepascore has similar diagnostic performance. FibroMeter has been less extensively evaluated but also seems to have diagnostic performance similar to that of FibroTest(49).

4. Endoscopy
Endoscopy may be the best choice for patients  diagnosed with mild-to-moderate cirrhosis in order to screen for esophageal varices. According to the study by Institute of Liver and Biliary Sciences, in the study of Patients with cirrhosis who undergo endoscopy under sedation could be at increased risk of complications, found that Propofol is safe in patients with cirrhosis and the critical flicker frequency (CFF) is a useful tool for the assessment of recovery from sedation in these patients(50).

5. Paracentesis
If there is evidence of fluid retention, paracentesis may be necessary to determine its cause. According to study, ascites is one of the major complications of liver cirrhosis and is associated with a poor prognosis. It is important to distinguish noncirrhotic from cirrhotic causes of ascites to guide therapy in patients with noncirrhotic ascites for the effective of the treatments(51).

 6. Etc.


VI. Prevention
A. Diets to prevent Cirrhosis
1. Grren tea
green tea exhibits potent protective effects against CCl(4)-induced oxidative stress and hepatic fibrosis in mice by inhibiting oxidative damage and increasing antioxidant enzyme activities.
In the in vivo study to investiagte theantioxidant and antifibrotic properties of green tea (Camellia sinensis, Theaceae) with a study of carbon tetrachloride (CCl(4))-induced oxidative stress and hepatic fibrosis in male ICR mice, found that oral administration of green tea extract at doses of 125, 625 and 1250 mg/kg for 8 weeks significantly reduced (p<0.05) the levels of thiobarbituric acid-reactive substances (TBARS) and protein carbonyls in the liver by at least 28% compared with that was induced by CCl(4) (1 mL/kg) in mice.(52).
Cadmium (Cd) is a highly toxic environmental and industrial cumulative pollutant that affects many organs, especially the liver. In rat study, oral administration of green tea, along with cadmium significantly (p < 0.05) improves cadmium-induced liver dysfunction and stress oxidant in rats' liver(53).

2. Citrus fruits
Naringenin is a naturally occurring plant bioflavonoid found in citrus fruits, which has been reported to have a wide range of pharmacological properties. In the study conducted by Annamalai University,
Administration of naringenin at a dose of (50mg/kg) significantly reversed the activities of serum hepatic marker enzymes to their near-normal levels when compared to Cd-treated rats. In addition, naringenin significantly reduced lipid peroxidation and restored the levels of antioxidant defense in the liver(54).

3. Soy
In the study to evaluate the effects of soy supplementation on insulin resistance, fatty liver and alanine aminotransferase (ALT) levels in non-diabetic patients with chronic hepatitis C (CHC), found that Soy supplementation decreased ALT levels and thus may improve liver inflammation in hepatitis C virus (HCV) patients; it also reduced hepatic steatosis in a subgroup of patients but did not change insulin resistance. It should be considered in the nutritional care of HCV patients(55).

4. Grape
In the study to examine the effect of the grape seed proanthocyanidin extract (GSPE) on developing hepatic fibrosis that was induced by thioacetamide (TAA) in mice, indicated that combined oral administration of GSPE at 100 mg/kg suppressed the mRNA expression of TGF-β1 and α-SMA, with decreased collagen accumulation as demonstrated by histomorphological evaluation and quantitative RT-PCR. The mRNA expression of the pro-inflammatory factors, including inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2), was remarkably enhanced by TAA treatment(56).
Other in the study of Resveratrol Improves Intrahepatic Endothelial Dysfunction and Reduces Hepatic Fibrosis and Portal Pressure in Cirrhotic Rats, indicated that resveratrol, a phytochemical in the class of Stilbenoids, found abundantly in skins and seed of grape wine, nuts, peanuts, etc. administration reduces portal pressure, hepatic stellate cell activation and liver fibrosis, and improves hepatic endothelial dysfunction in cirrhotic rats, suggesting it may be a useful dietary supplement in the treatment of portal hypertension in patients with cirrhosis(57).

5. Etc.

B. Phytochemicals to prevent Cirrhosis
1. Emodin
Emodin  is a orange crystalline compound, C14H4O2(OH)3CH3 found in rhubarb and other plants.
In the study to investigate the role of emodin in protecting the liver against fibrogenesis caused by carbon tetrachloride (CCl(4)) in rats and to further explore the underlying mechanisms, showed that
Emodin protects the rat liver from CCl(4)-induced fibrogenesis by inhibiting HSC activation. Emodin might be a therapeutic antifibrotic agent for the treatment of hepatic fibrosis(58).

2. Hesperetin
Hesperetin is flavonoids derived from Citrus fruits. In the study to evaluate the hepatoprotective effect of hesperetin (HTN) on cadmium (Cd) induced hepatotoxicity in male Wistar rats, showed that HTN at a dose of 40 mg/kg body weight/day exhibits significant (p<0.05) hepatoprotection compared with other two doses (10 and 20 mg/kg body weight/day). The histopathological studies in the liver of rats also supported that HTN (40 mg/kg) markedly reduced the toxicity of Cd and preserved the histoarchitecture of the liver tissue to near normal(59).

3. Silibinin
Silibinin (SB) is a major flavonolignan compound of silimarin and is found in milk thistle of Silybum marianum. In the study  to delineate the ameliorative role of silibinin against arsenic-induced hepatotoxicity in rats. Rats were orally treated with arsenic alone (5 mg/kg body weight (bw)/day) plus silibinin (75 mg/kg bw/day) for 4weeks, showed that administration of silibinin exhibited a significant reversal of arsenic-induced toxicity in hepatic tissue. All these changes were supported by reduction of DNA damage in hepatocytes and histopathological observations of the liver(60).

4. Diallyl tetrasulfide (DTS)
diallyl tetrasulfide (DTS) is a natural compound found abundantly in fresh and aged garlic. According to the study by Annamalai University, administration of DTS at 40 mg/kg body weight significantly normalised the activities of hepatic marker enzymes, compared to other doses of DTS (10 and 20 mg/kg body weight). In addition, DTS (40 mg/kg body weight) significantly reduced the accumulation of Cd and the level of lipid peroxidation, and restored the level of antioxidant defense in the liver. Histological studies also showed that administration of DTS to Cd-treated rats resulted in a marked improvement of hepatocytes morphology with mild portal inflammation(61).

5. Phyto-power dietary supplement 
Curcumin has been extensively studied for its therapeutic effects in a variety of disorders. Fermented soy consumption is associated with a low incidence rate of chronic diseases in many Asian countries. According to the study by the Chang Jung Christian University, phyto-power dietary supplement (50 or 100 mg kg(-1)) was administered by oral gavage daily for four weeks. Liver morphology, function, and fibrotic status were examined in DMN induced hepatic fibrogenesis. However, a phyto-power dietary supplement alleviated liver damage as indicated by histopathological examination of the α-smooth muscle actin (α-SMA) and collagen I, accompanied by the concomitant reduction of transforming growth factor-β1 (TGF-β1) and matrix metalloproteinase 2 (MMP2)(62).


6. Etc.

C. Antioxidant to prevent Cirrhosis
1. Probiotics and antioxidants
In the study to to determine the effect of Lactobacillus johnsonii La1 and antioxidants on intestinal flora, endotoxemia, and bacterial translocation in cirrhotic rats, found that rats treated with antioxidants and Lactobacillus johnsonii La1 showed a decrease in endotoxemia with respect to cirrhotic rats receiving water (P<0.05). Antioxidants alone or in combination with Lactobacillus johnsonii La1 can be useful in preventing bacterial translocation in cirrhosis(63).


2. Caryophyllene (CAR)
Caryophyllene (CAR) is a common constituent of the essential oil of numerous plants, vegetables, fruits and medicinal herbs, and has been used as a flavouring agent since the 1930 s. According to the study by Hospital Universitario Virgen de las Nieves, indicated that CAR significantly improved liver structure, and reduced fibrosis and the expression of Col1a1, Tgfb1 and Timp1 genes. Oxidative stress was used to establish a model of HSC activation with overproduction of extracellular matrix proteins. CAR (1 and 10 μm) increased cell viability and significantly reduced the expression of fibrotic marker genes. CAR, a sesquiterpene present in numerous plants and foods, is as a natural antioxidant that reduces carbon tetrachloride-mediated liver fibrosis and inhibits hepatic cell activation(64).

3. Vitamins C and E
Antioxidants vitamins C and E are free radical scavengers. In the study of undertaken to find the therapeutic efficacy of naringenin (NGN) plus vitamins C and E on Cd-induced oxidative hepatotoxicity in Wistar rats, by Annamalai University, showed that treatment with NGN and vitamins C and E in combination more significantly improved the altered biochemical and histopathological changes in the liver of Cd-intoxicated rats than the NGN or vitamins C and E treatment alone(65).

4. Selenium
In the study to investigte the effect of selenium deficiency Effects, induced by thioacetamide, showed that thioacetamide (0.3 g/L) given in drinking water, as expected, caused a significant loss of selenium from the liver. It was accompanied by liver cirrhosis and a significant increase in the liver weight as well as liver to body weight ratio. A significant loss of selenium from spleen was also accompanied by an increase in its weight. Weights of lungs, testis and kidney, however, were not affected by thioacetamide and there was no change in their selenium content. Plasma levels of selenium were significantly reduced in the thioacetamide treated group. All these changes were confirmed to be due to selenium deficiency caused by thioacetamide, as supplementation with selenium reversed these changes. The mode of action of selenium is unknown but may involve anti-oxidant defense mechanisms(66).


5. Etc.

VII. Treatments
A. Treatments of cirrhosis depend not on the underline causes and stage of the diseases
A.1. Alcohol causes of cirrhosis 
A.1.2. In conventional medicine perspective
If the the disease is caused by excessive alcohol drinking, patients will be asked to stop drinking. with help from the professional teams and certain medication. The long-term management of alcoholic liver disease stresses the following(67).
(1) Abstinence of alcohol (Grade 1A), with referral to an alcoholic rehabilitation program;
(2) Adequate nutritional support (Grade 1B), emphasizing multiple feedings and a referral to a nutritionist; (3) Routine screening in alcoholic cirrhosis to prevent complications;
(4) Timely referral to a liver transplant program for those with decompensated cirrhosis;
(5) Avoid pharmacologic therapies, as these medications have shown no benefit.
But according to the study by the Catholic University of Rome, in the intervention to achieve alcohol abstinence represents the most effective treatment for alcohol-dependent patients with liver cirrhosis by investigating the effectiveness and safety of Baclofen,  is a GABA(B) receptor agonist in achieving and maintaining alcohol abstinence in patients with liver cirrhosis, showed that baclofen is effective at promoting alcohol abstinence in alcohol-dependent patients with liver cirrhosis. The drug is well tolerated and could have an important role in treatment of these individuals(68).

A.1.2. In herbal medicine perspective 
1. Kudzu (Pueraria lobata) and St. John's Wort 
In the study to summarizes the findings of the effects on alcohol intake in alcohol-preferring rats of extracts or purified compounds from two of the most promising herbs: kudzu (Pueraria lobata) and St. John's Wort (Hypericum perforatum), a symposium presented at the 2002 RSA meeting in San Francisco. found that
(1) Introduction to the symposium, by David Y. W. Lee and David H. Overstreet; (2) Effects of daidzin on alcohol intake-search for mechanisms of action, by Wing-Ming Keung; (3) Long-term suppressive effects of puerarin on alcohol drinking in rats, by David Overstreet and David Y. W. Lee; (4) St. John's Wort extract reduces alcohol intake in FH and P rats, by Amir Rezvani and David Overstreet; and (5) extracts reduce alcohol intake in Marchigian Sardinian alcohol-preferring rats, by Maurizio Massi(69).

2. Pueraria lobata, Tabernanthe iboga, Panax ginseng, Salvia miltiorrhiza and Hypericum perforatum
In the study to  review the most relevant experimental data on the reducing effect of some medicinal herbs on voluntary alcohol intake in animal models of alcoholism, showed that Pueraria lobata, Tabernanthe iboga, Panax ginseng, Salvia miltiorrhiza and Hypericum perforatum proved to be effective in decreasing alcohol consumption. Reduction of alcohol absorption from the gastrointestinal system appears to be a common feature among most of the above plants(70).

3. Other herbs
According to the study by, A number of medicinal plants and pure natural compounds are reported to have preventive and therapeutic effects on alcoholism and alcohol dependency, but their constituents, efficacy and mechanism of action are mostly unknown so far. Recently, kudzu [Pueraria lobata (Willd.) Ohwi], St. John's wort (Hypericum perforatum L.), danshen (Salvia miltiorrhiza Bge.), ginseng (Panax ginseng C.A. Mey.), Japanese raisin tree (Hovenia dulcis Thunb.), ibogaine (Tabernanthe iboga H. Bn.), evening primrose (Oenothera biennis L.), prickly pear fruit (Opuntia ficus indica (L.) Mill.), purple passionflower (Passiflora incarnata L.), thyme (Thymus vulgaris L.), fenugreek seed (Trigonella foenum-graecum L.), ginger (Zingiber officinale Roscoe) and many others drew the attention of researchers. Can, therefore, drugs of natural origin be helpful in the treatment of alcoholism or in decreasing alcohol consumption?(71)

A.1.3. In TCM medicine perspective
Alcohol has long been used as a daily beverage in China and around the world. It is a medicinal substance with various biological activities. According to study by Peking University, in the summarized clinical and primary studies concerning various remedies of TCM for alcohol abuse, including herbal components (such as Kudzu/Pueraria Lobata, Pediculus melo, Hypericumpperforatum L.), decoctions and acupuncture(72).

A.2. Obesity and Fatty liver
The prevalence of overweight and obesity are increasing in World wide, especially in the Emerging world, as a result of recently economic prosperity.
Obesity is defined as a medical condition of excess body fat accumulated overtime. Overweight is a condition of excess body weight relatively to the height. According to the Body Mass Index(BMI), a BMI between 25 to 29.9 is considered over weight, while a BMI of over 30 is an indication of obesity. In US, 68% of population are either overweight or obese. According to the study by Department of Pediatrics, Nanjing Maternity and Child Health Care Hospital, for age-specific subgroup analyses, both overweight and obesity increased more rapidly in the toddler stage than in other developmental stages. Toddlers and urban boys were at particularly high risk; the prevalence in these groups increased more rapidly than in their counterparts(73a)).

The Obesity Society and the American Society of Hypertension agreed to jointly sponsor a position paper on obesity-related hypertension to be published jointly in the journals of each society(2). Other researchers suggested that in light of the worldwide epidemic of obesity, and in recognition of hypertension as a major factor in the cardiovascular morbidity and mortality associated with obesity(73b).
Recent study showed that evidence has emerged for an association between genetic variability at the APOA5 locus and increased risk of obesity and metabolic syndrome(73c). 
Fatty liver disease is defined as a condition of accumulation of fat in the liver, including people who drink little or no alcohol (Non alcohol fatty disease) or who are excessive alcohol drinking (Alcohol fatty liver disease). The disease can even occur after a short period of heavy drinking (acute alcoholic liver disease). More than 15 million people in the U.S. either abuse or overuse alcohol with fatty liver diseases with fat makes up 5-10 percent of liver weight.

Non-alcoholic fatty liver disease (NAFLD) encompasses a wide spectrum of clinical conditions, actually representing an emerging disease of great clinical interest(73).

There is no standard treatment in conventional medicine. If you are obese, you are advised to lose weight. If excessive drinking alcohol is the cause, you are advised to stop drinking.

Some researchers suggested that Vitamin E plus C combination treatment is a safe, inexpensive and effective treatment option in patients with fatty liver disease, with results comparable to those obtained with ursodeoxycholic acid(74). But some researchers suggested that Neither vitamin E nor metformin was superior to placebo in attaining the primary outcome of sustained reduction in ALT level in patients with pediatric NAFLD(75).

In traditional Chinese medicine, fatty liver is associated closely to obesity, as a result of over intake of "bad" fat and excessive alcohol drinking. Even though fatty liver is a result of too much fat, but trying to eliminate all fats from the diet won't help to prevent or relieve the disease as malnutrition can also trigger fatty liver as fat and protein stored elsewhere in the body move to the liver for storage and conversion to energy as needed. That's why some women who eat almost nothing but vegetables can also develop fatty liver(76).

Many traditional Chinese medicine practitioners believe, no way that one can lose weight if fatty liver diseases are not cured. Syndromes of fatty liver could be typed into 4 TCM types of the asthenia Pi-Shen with Gan-stagnation type, the asthenia Pi-Shen type, the asthenia Pi with phlegm-heat type and the unclassified type. Among them the asthenia Pi-Shen with Gan-stagnation type was the commonest one, which accounted to 62.32%(77).

Dr. Liu T, and the research team at the Shanghai University of Traditional Chinese Medicine, in the study to explore the pathogenesis of nonalcoholic fatty liver (NAFL) in traditional Chinese medicine (TCM) by comparing the therapeutic efficacy of methods for fortifying the spleen and replenishing qi, warming yang and fortifying the spleen and warming yang to move water, showed that body weight, liver and epididymal fat indexes and liver TAG level of rats all significantly increased in the model group as compared with the normal group (P<0.05). Hepatic fatty infiltration, TAG concentration and the levels of serum TAG and ALT were significantly decreased in the LGZG and SZ groups when compared to those in the model group (P<0.05). Method of warming yang or moving water can promote the lipid metabolism. It may be an effective strategy in preventing and treating NAFL by treating with warming yang and moving water together(978
Other studies showed that Zhi Zi has a very strong inhibitory action on lipidosis and inflammatory injury in the rat model of NAFLD. This mechanism may possibly be related to the inhibition of the free fatty acid metabolism pathway(79).
In the study to investigate  the effect of Cigu Xiaozhi pills on expression of tumor necrosis factor alpha (TNF-alpha) in rat with nonalcoholic steatoheptatitis (NASH), found that Cigu Xiaozhi pills can effectively treat experimental nonalcoholic steatohepatitis in rats, and its mechanism may be associated with ameliorating hepatocellular steatosis, removing the free radicals and enhancing the capability of anti-oxidation and anti-inflammatory(80).

Most people with fatty liver disease are experience no symptoms at all, but  Fatty liver disease is associated with high blood pressure, heart disease and diabetes can, in time, cause life threatening cirrhosis of the liver. According to the article By Donald Norfolk, "Today, as a direct effect of the obesity plague, it's reckoned that one in five British adults is now suffering from fatty liver disease, unconnected with virus infections or heavy drinking. This malady, known medically as steatosis, is believed to affect 90 per cent of morbidly obese patients, in whom it may remain totally symptomless for many years"(81).

A.3. Hepatitis causes of cirrhosis
Hepatitis is characterized by the destruction of a number of liver cells and the presence of inflammatory cells in the liver tissue caused by excessive alcohol drinking, disorders of the gall bladder or pancreas, including medication side effects, and infections. There are many other infective agents that can cause inflammation of the liver, or hepatitis. However, the term is unfortunately commonly used to refer to a particular group of viruses such as Hepatitis A, B, and C.

A.3.1. In conventional medicine perspective(82)
1. Liver Detoxification
Strengthens the immune system with vitamins, nutritional supplements and herbs that we have been discussed lengthily in other articles.

2. Ozone therapy
Ozone oxidizes the cells of the body systemically. It stimulates enzymes and phagocytes of the white blood cells which chew up the viruses and the bacteria in the blood. It also activates alpha interferon, gamma interferon, interleukin II and tumor necrosis factor. It is effective in treating hepatitis B patients with high successful rate.

3. Lamivudine therapy
Combining vaccine therapy with lamivudine has improved therapeutic potential for chronic hepatitis B. It helps to strengthen the immune system fighting against the hepatitis B virus specially with patients with chronic HBV infection and active viral replication.

4. Interferon-alpha therapy
Chronic hepatitis B virus (HBV) infection is a serious health problem because of its worldwide distribution. There are over 350 million people in the world infected with chronic HBV, 75% of whom live in the Asia-Pacific region. Interferon-alfa and direct antiviral agents such as lamivudine and adefovir are effective in the therapy of chronic HBV infection but only with some success, particularly in perinatally infected patients, patients with lower ALT levels and those with negative chronic hepatitis B.

5. Pegylated interferon
Pegylated interferon may be considered the best choice of treatment for patients with chronic hepatitis B infection. This therapy has been shown to be superior to both conventional interferon as well as lamivudine in the treatment of both hepatitis B positive and negative chronic hepatitis B with successful rates of 35-45%.
A.3.2. In herbs medicine perspective(83)
1. Red clover
Rich in micro-nutrients it possesses activity against several bacteria. A good dietary supplement of vitamin A and Iron, it also contains B- complex, vitamins C,F, and P, some selenium, cobalt, nickel, manganese, sodium and is particularly rich in magnesium, calcium and copper.

2. Oregon grape root
The herb stimulates the action on the liver and is one of the best blood cleansers. Mild stimulant to the thyroid functions and aids in the assimilation of nutrients.

3. Echinacea
Echinacea is an immuno stimulant. Enhancing the body's resistance against both bacterial and viral infections it is probably the best detoxifying agent in Western Herbalism. It cleanses the blood and lymph systems, helps arrest pus formation and tissue putrefaction.

4. Sarsaparilla
Sarsaparilla purifies the urino-genital tract, dispelling all infection and inflammation. It's purifying action extends to the nervous system and is therefore useful in many nervous disorders. Sarsaparilla's diaphoretic and blood cleansing action is useful for rheumatic inflammation.

5. Licorice root
Licorice root is a natural anti-inflammatory agent. It helps to increase the secretion of digestive enzymes and bile and is widely regarded as the supreme liver tonic.

6. Burdock
It clears congestion, reduces swelling and dispels toxins via the skin, kidneys and bowel. It is a nutritive and rejuvenatory tonic . Historically it has been used to support the action of the kidneys in urinary tract infections.

7. Dandelion
Dandelion cleanses the liver, kidneys, lymph and bowel and is ideal for toxic blood conditions. It increases the secretion of digestive enzymes and bile and is widely regarded as the supreme liver tonic.

A.3.3 In Traditional Chinese medicine perspective(84)
1. Natural schisandra,
Schisandradra contains essential oils, acids and lignans that help to regenerate liver tissue caused by excessive drinking of alcohol and hepatitis virus.

2. Milk thistle,
consists of three components silybin, silydianin, and silychristin that help to reverse liver damage from alcohol, liver injure in result of chronic hepatitis and sloe the advance of cirrhosis.

3. Dan shen Danshen
is frequently used for these problems in combination with other herbs in treating liver diseases such as cirrhosis, fibrosis, and chronic hepatitis B.

4. Lycii
Lycii contains high amount of beta-carotene that helps to nourish and tonify liver and kidney.

5. Chinese licorice
Licorice contains a compound called glycyrrhizin and has a long history of medicinal use in both Eastern and Western systems of medicine in treating infections caused by viruses, such as hepatitis.

6. Astragalus
Astragalus is used conbination with other Chinese herbs are thought to possess properties in treating cancer, viral infection and immune system disorder. Astragalus is an ingredient in

7. Baikal scullcap
Baikal scullcap contains a chemical of baikalin that helps liver to detoxification and fight against liver infection.

8. Gynostemma,
Gynostemma pentaphylla
This herb has been used over thousand years in Chinese history in treating a variety of diseases such as high blood fat, heart disease, strengthen immune system as well as hepatitis.

9. American ginseng
American ginseng contain the ginsenosides ingredient that is effective in preventing GalN-induced liver cell damage and is a useful agent for chemoprevention of cancer or inflammatory diseases such as liver infection by hepatitis virus


A.4. Medication causes of cirrhosis
According to the study by the Seoul National University College of Medicine, anti-tuberculosis (TB) drug-induced liver injury (DILI) in patients with chronic liver disease including cirrhosis, but the drugs may be safely used in the patients with chronic liver disease including compensated cirrhosis if number of hepatotoxic drugs used is adjusted appropriately(85). In other study by University "Magna Græcia" of Catanzaro, there is a case of a male patient who developed severe drug-induced hepatotoxicity during the treatment with Cyproterone acetate (CPA). The case, presenting sub-acute hepatitis, was characterized by a rapid evolution of cirrhosis and a protracted activity during the period of a few months despite the treatment withdrawal and an apparent benefits of corticosteroids, suggesting their indication in life threatening cases(86). Please consult your doctor for replacement medication.

A.2. Treatment of the complications of cirrhosis
A.2.1. Edema
A.2.1.1. In conventional medicine perspective
Diuretic is a type of medication used to elevates the rate of urination to reduce swelling as a result of fluid retention, including
1. High ceiling loop diuretic
2 Thiazides
3 Carbonic anhydrase inhibitors
4 Potassium-sparing diuretics
5 Calcium-sparing diuretics
6 Osmotic diuretics
7.  Low ceiling diuretics
Side effects are not limit to increased thirst, Irregular menstruation, High blood sugar levels, blood sodium levels, Abnormal heart rhythm, Weakness, Extreme tiredness / Fatigue, Dizziness, Light headedness, Skin rash, Loss of appetite, etc.

A.2.1.2. In herbal medicine perspective
In the study to review these studies and identify which extracts promote diuresis (which we assessed on terms of urine excreted and urinary sodium excretion) and also to identify the research needs in this area, found that a number of species and genuses reporting diuretic effects. Of these, the most promising, at the present time, are the species Foeniculum vulgare, Fraxinus excelsior, Hibiscus sabdariffa, Petroselinum sativum and Spergularia purpurea, and species from the genuses Cucumis (Cucumis melo and Cucumis trigonus), Equisetum (Equisetum bogotense, Equisetum fluviatile, Equisetum giganteum, Equisetum hiemale var. affine and Equisetum myriochaetum), Lepidium (Lepidium latifolium and Lepidium sativum), Phyllanthus (Phyllanthus amarus, Phyllanthus corcovadensis and Phyllanthus sellowianus) and Sambucus (Sambucus mexicana and Sambucus nigra)(87).


A.2.1.3. In traditional Chinese medicine perspective
In a clinical trial to evaluate the method of removing Heat and eliminating Dampness (RHED) with febrifugal and diuretic medicinal herbs in treating chronic glomerulonephritis (CGN) patients, found that
CGN patient's serum levels of lipid peroxide (LPO) increased, superoxide dismutase (SOD) and trace elements such as Zn, Cu, Se dropped down. After treatment with RHED the activity of LPO, SOD, catalase (CAT) revealed significant improvement. Serum levels of Zn, Cu, Se increased(88).

A.2.2. Liver Cancer(89)
A.2.2.1 In conventional medicine perspective
1. Surgery
a. The aim of the treatment is to cure the cancer with surgery, if possible. Otherwise, treatments are focused to treat and control the symptoms as long as possible. Surgical resection is the best chance for a cure, because of it liver's ability to regenerate when part of it is removed.
b. Risks and side effects
Surgical and anesthesia risks

2. Transplantation
a. Liver is the second most commonly transplanted major organ, after kidney. Statistic from United Network for Organ Sharing (UNOS) showed there are over 17,000 people in the US alone in a waiting list. The procedure of the transplant is to remove the failed liver by replacing it with the healthy donor's liver.
b. Risks and side effects
b.1. Surgical and anesthesia risks
b.2. Rejection
New implant liver is rejected by the immune system
b.3. Nausea
b.4. Pain
b.5. Fever
Due to infection
b.6. Jaundice
As the result of new liver has not function well.
b.7. Weakened immune system
Due to drugs used to suppress the immune system for accepting the implanted liver.
b.8. Side effects of drugs use
b.9. Etc.

3. Hepatic arterial embolisation
a. It is a procedure with an aim to block the blood supply to the tumor in the liver if liver surgery is not possible. It is considered effective if the vessels which supply oxygen and nutrients to the tumor has been cut off, leading to shrinking of the tumor. In hepatic arterial embolization, a narrow tube is inserted into a blood vessel through a small cut in the groin then passed up to the artery blood vessel to block the blood flow to the liver's tumor.
b. Side effects
It is important to note that side effects will disappeared in a few days.
b.1. Nausea and vomiting
b.2. Back pain
b.3. Fever
b.4, Etc.

4. Ablative therapy
a. Ablative therapy has been quite sometime to treat hepatocellular carcinoma by destroying the tumor without removing it, including the uses of heating with radio waves and microwaves, alcohol and freezing (Crytherapy).
b. Risk and side effects
b.1. Belly pain
b.2. Infection
b.3. Bleeding in the chest or abdomen
b.4. Etc.

5. Radiotherapy
By using high-energy x-rays or other types of radiation, radiation therapy kills liver cancer cells and keep them from growing or regrowing. Depending to stage or grade there are two types of radiation therapy.
a. External radiation
By using a machine outside the body to send direct high-energy x-rays or other types of radiation toward the cancer.
b. Internal radiation
By placing a radioactive substance direct into or near the cancer by a medical instrument with the aim to kill nearby cancer cells.
c. Side effects
c.1.. Fatigue
c.2. Chest pain
c.3. Heart problem
c.4. Short of breath
c.5. Skin discoloration or pinkness, irritation.
c.6. Etc.

6. Chemotherapy
a. Chemotherapy is most use to treat with advance stage of hepatocellular carcinoma, as it has spread to a distant parts of the body by using drugs taken by mouth or injected into a vein or muscle of the patient to stop the growth of or to kill cancer cells.
b. Side effects
b.1. Nausea
b.2. Vomiting
b.3. Hair loss
b.4. Fatigue
b.5. Anemia
b.6. Mouth sores taste and smell changes
b.7. Infection
b.8. Etc.


A.2.2.2. in Herbal medicine perspective
1. Fenugreek
Fenugreek is used both as a herb (the leaves) and as a spice (the seed), genus Trigonella, belonging to family Fabaceae. Vitro studies have shown that fenugreek exhibits chemopreventive properties against certain cancers.

2. Cinnamon
Cinnamon is an evergreen tree, genus Cinnamomum, belonging to family Lauraceae, native to southern China, Bangladesh, India, and Vietnam. In a study in 2005. researcher found that Chemical aspects of coumarin compounds in cinnamon for the prevention of hepatocellular carcinomas.

3. Scutellaria
Scutellaria is also known as skullcaps, a genus of flowering plants, genus Scutellaria, belonging to family Lamiaceae. In a study of Inhibition of Cancer Cell Proliferation and Prostaglandin E₂ Synthesis by Scutellaria Baicalensis, researchers found that Scutellaria baicalensis selectively and effectively inhibits cancer cell growth in vitro and in vivo and can be an effective chemotherapeutic agent for HNSCC. Inhibition of PGE2 synthesis via suppression of COX-2 expression may be responsible for its anticancer activity.

4. Japanese carnelian cherry
Japanese cornelian cherry is a genus Cornus, belonging to family Cornaceae, native in China, Japan and Koren. In a study of Chemoprevention against hepatocellular carcinoma ( liver cancer ) of Cornus officinalis in vitro by Am J Chin Med. 2004, researcher found that extracts of Cornus officinalis possessed the anti-oxidant activity through free radicals scavenging activity at a concentration of 50 microg/ml. In summary, our experiment implied that C. officinalis might be a candidate for chemopreventive agent against hepatocellular carcinoma through the antioxidant and anti-neoplastic effects

5. Etc.

A.2.2.3. Traditional Chinese medicine
1. Rou Qui
Rou Qui is also known as Cinnamon Bark. The sweet, acrid and very warm herb has been used in TCM to treat cold limbs, cold limbs, diarrhea, muscle spasm, headache, back pain, sweating and impotent and promote urination as it tonifies fire, enhances yang, disperses cold and promotes circulation in the channels by enhancing the functions of heart, ling and gallbladder channels. In a study in 2005. researcher found that Chemical aspects of coumarin compounds in cinnamon for the prevention of hepatocellular carcinomas.

2. Nu Zhen Zi
Nu zhen Zi is also known as privet fruit. The bitter, sweet and neutral herb has been used in TCM as anti inflammatory, anti cancer and anti oxidization medicine and to regulate immune system, lower blood sugar as it tonifies the liver and kidney, benefits the liver and kidney and clears heat by enhancing the function of liver and kidney channels.

3. Bai Zhi Lian
Ban Zhi Lian is also known as scutellaria. The bitter and cool herb has been used in TCM as diuretic and to treat tumors and cancer as it clears heat, expels toxins, eliminates stagnation, stops bleeding and calms pain by enhancing the functions of lung, liver, spleen, stomach and large intestine channels. In vitro study, essential oil extract of 200mg/ml of the herb possesses the effect of inhibiting the tissues of rectum cancer or colon cancer.
In lab tests of animals and breast-cancer cells, BZL101 caused apoptosis or cell death, researchers found.

4. Long Kui
Long Kui is also known as wonderberry. The bitter, cold, slightly sweet and toxic herb has been used in TCM as diuretic and antipyretic and to treat acute kidney inflammation, chronic bronchitis, throat cancer, larynx Cancer, uterus cancer as it clears heat, eliminates toxin, improve urination by enhancing the function of liver, kidney and stomach channels. A study was done at the College of Environmental and Chemical Engineering at the Yanshan University in Hebei, China, researcher found that the tumor growth inhibition of long kui polysaccarides might correlate with the reduction of TNF-alpha level of blood serum, which resulted in a massive necrosis (accidental death of cells) in tumor tissues and the up-regulation of Bax and down-regulation of Bcl-2 and mutant p53 gene expression, which triggered apoptosis in tumor cells.

5. Bai Hua She She Cao
Bai Hua She She Cao is also known as spreading hedyotis, The bitter, sweet and cold herb has been used in TCM as anti-bacteria, anti-inflammation, anti-tumor, anti-virus agent and to treat snakebite and enhances immune system as it clears heat, drains dampness, expels toxins and resolves abscesses by enhancing the functions of liver, stomach, large intestine channels.
The Sanjiv Kumar YADAV, Shao Chin LEE(Yong Loo Lin School of Medicine, National University of Singapore researcher results showed that the ethanol extract from Bai Hua She She Cao effectively evokes cancer cell apoptosis, possibly through burst-mediated caspase activation.

7. Etc.

A.2.3. Variceal bleeding
Variceal bleeding as a complication of liver cirrhosis is a result of veins in the esophagus, stomach, and rectum enlarge due to blood flow through the liver was blocked. Patients with variceal bleeding, are at 70% greater risk  to have a further bleed within 2 yr after, and patients with acute variceal bleeding has a significant mortality of 5% to 50%.
The amin purpose of the treatment to reduce and stop blood loss
A.2.3.1. In conventional medicine
Portal hypertension can lead to life-threatening hemorrhage, ascites, and encephalopathy. In the study to review the pathophysiology and multidisciplinary management of portal hypertension and its complications, including the indications for and techniques of the various surgical shunts. Variceal bleeding is the most dreaded complication of portal hypertension, showed that treatment of acute variceal bleeding includes resuscitation followed by upper endoscopy for sclerosis or band ligation of varices, which can control bleeding in up to 85% of patients. Medical therapies such as vasopressin and somatostatin can also be useful adjuncts. Shunt therapy, preferably the placement of a TIPS, is indicated for refractory acute variceal bleeding. Recurrent variceal bleeding is common and is associated with a high mortality. Therapies to prevent recurrent variceal bleeding include chronic endoscopic therapy, nonselective beta-blockade, operative or nonoperative (TIPS) shunts, devascularization operations, and liver transplantation. Recommendations and a treatment algorithm are provided, taking into account both the etiology and the manifestations of portal hypertension(90).

1. Anticoagulation
In the study to determine the safety and efficacy of anticoagulation treatment for portal vein thrombosis in cirrhosis patients with acute variceal bleeding, with patient eligibility determined by contrast ultrasonography findings, indicated that early anticoagulation treatment in cirrhosis patients with portal vein thrombosis and acute variceal bleeding may be safe, tolerated, and effective in cases with positive intra-thrombus enhancement on contrast ultrasonography(91).

2. Prophylactic antibiotics
According to the study by Jasmohan S Bajaj, MD, Arun J Sanyal, MD, in the article of Treatment of active variceal hemorrhag, Multiple trials evaluating the effectiveness of prophylactic antibiotics in cirrhotic patients hospitalized for bleeding suggest an overall reduction in infectious complications and possibly decreased mortality. Antibiotics may also reduce the risk of recurrent bleeding in hospitalized patients who bled from esophageal varices. Thus, patients with cirrhosis who present with upper GI bleeding(92). 

3. Variceal banding ligation and Injection sclerotherapy
Injection sclerotherapy of bleeding oesophageal varices is undoubtedly beneficial but it is associated with a substantial complication rate, and variceal rebleeding is common during the treatment period before variceal obliteration is achieved. According to the study to compare whether endoscopic variceal banding ligation is safer and more effective by King's College Hospital, showed that there was no difference in outcome between the groups, but 14 sclerotherapy patients were withdrawn from the trial (7 for orthotopic liver transplantation) compared with only 5 (1 for liver transplantation) in the banding ligation group (p < 0.05). Complication rates were similar in the two groups. Variceal banding ligation is a safe and effective technique, which obliterates varices more quickly and with a lower rebleeding rate than injection sclerotherapy(93).

4. Transjugular Intrahepatic Portosystemic Shunt (TIPS) and endoscopy
According to the study to compare early use of transjugular intrahepatic portosystemic shunt (TIPS) with endoscopic treatment (ET) for the prophylaxis of recurrent variceal bleedingby the First Affiliated Hospital of Xi'an Jiaotong University, early use of TIPS is more effective than endoscopic treatment in preventing variceal rebleeding and improving survival rate, and does not increase occurrence of hepatic encephalopathy(94). 

5. Distal splenorenal shunt (DSRS) 
In the study to examine the cost and cost effectiveness of distal splenorenal shunt (DSRS) and transjugular intrahepatic portosystemic shunt (TIPS) in the prevention of variceal rebleeding, showed that
TIPS is as effective as DSRS in preventing variceal rebleeding and may be more cost effective. TIPS, in all aspects, is equal to DSRS in the prevention of variceal rebleeding in patients who are medical failures(95).

6. Periesophagogastric devascularization and fundectomy
Cirrhotic patients with gastric fundal bleeding occasionally require operative intervention. According to the study by the Seoul National University, indicated that patients who were successfully stabilized by preoperative endoscopic intervention had significantly lower mortality ( p < 0.001). During follow-up there was no recurrent bleeding from gastric varices, and there was only one case (4.35%) of hemorrhage from esophageal varices. Hence, periesophagogastric devascularization and fundectomy offers an alternative operative method for cirrhotic patients with variceal hemorrhaging from the gastric fundus(96).


7. Etc.

A.2.3.2. In traditional Chinese medicine
In the study to find a method for inducing Chinese drugs to adhere to the esophageal mucosa to control bleeding from ruptured esophageal varices, showed that The adhesion of Chinese hemostatie drugs remained in the lower segment of esophagus for more than 15 minutes in lying posture, longer than that in standing posture (P < 0.01). (2) The effectiveness of controlling bleeding esophageal varices had no significant difference between the balloon tamponade and adhesion of Chinese hemostatie drugs (P >0. 05)(96a).


A.2.4. Hepatic encephalopathy
Hepatic encephalopathy a condition of liver failure causes of confusion, altered level of consciousness, and coma. 
A.2.4.1. In conventional medicine
1. Antibiotics
In the study to test Prominent antibiotics such as neomycin, metronidazole, vancomycin and rifaximin for the treatment of hepatic encephalopathy (HE), showed that despite its cost in the US, rifaximin may prove cost-saving by preventing hospitalizations for overt HE. In minimal/covert HE, rifaximin is the only systematically studied antibiotic. Rifaximin showed improvement in cognition, inflammation, quality-of-life and driving simulator performance but cost-analysis does not favor its use at the current time. Antibiotics, especially rifaximin, have a definite role in the management across the spectrum of HE.
However the limited numbers studied, adverse effects (neomycin oto- and nephrotoxicity, metronidazole neurotoxicity) and potential for resistance emergence (vancomycin-resistant enterococcus) has limited the use of most antibiotics, apart from rifaximin which has the greatest evidence base(97).

2. Combination therapy
In the study to evaluate the efficacy and safety of combination therapy for the treatment and prevention of hepatic encephalopathy (HE), showed that he evidence evaluating the use of combination therapy for the treatment of HE does not support its widespread use. The combination of rifaximin and lactulose may be considered in the treatment of HE and in patients refractory to monotherapy. The combination of rifaximin and lactulose should be considered for the prevention of HE, especially after the second episode of HE recurrence(98). 

3. L-ornithine-L-aspartate (LOLA)
L-Ornithine-L-aspartate (LOLA) has been shown to reduce ammonia and improve psychometric function in patients with hepatic encephalopathy. In the study to assess the effect of LOLA in healthy patients with cirrhosis and no evidence of clinical encephalopathy after challenging the central nervous system by administration of oral glutamine, found that LOLA ameliorated the deleterious psychometric effects of glutamine in Child's grade B and C patients with cirrhosis without TIPS and supports its use in clinical practice in hepatic encephalopathy(99).

A.2.4.2. In herbal medicine
Morin is a bioflavonoid, a constituent of many herbs and fruits that are used as herbal medicines and also several biological activities. According to the study by Annamalai University, oxidative stress was effectively modulated by morin administration. Morin significantly improved the status of antioxidants and decreased the levels of ammonia, urea, TBARS, HP and liver markers enzymes, as compared to the AC-treated group. There is an evidence for the antihyperammonaemic, hepatoprotective and antioxidant effects of morin against oxidative stress induced by AC(100).

A.2.4.1. In traditional Chinese medicine
In the study to evaluate the efficacy, safety and recent survival rates of high-dose herbs Qingre Huayu with the function of clearing heat and resolving stasis, in patients with hepatitis B-related ACLF with heat toxin stagnation syndrome, found that high doses of Qingre Huayu herbs can significantly improve liver function and coagulation function, reduce complications, and reduce mortality in patients with hepatitis B-related ACLF(101). 

A.3. Surgery
Liver transplantation may be the best choice for some patients with chronic liver cirrhosis as it has been proven to improve the chances of long-term survival.
The main advantage of LDLT is the availability of an organ in the elective setting in the course of a progressive liver disease. This is most applicable in patients with Cirrhosis and Hepatocellular carcinoma. LDLT, from the donor's perspective does carry a risk of not only morbidity but mortality.  To date the surgical mortality risk is estimated at 0.1% for left lateral donation and 0.5% for right liver donation. There are reports of complications like Hepatic artery thrombosis, portal vein thrombosis and especially biliary leaks and strictures occurring at a significantly increased frequency after living as compared to deceased donor liver transplantation(102).

B. In herbal medicine perspective
1. Ginkgo biloba leaves extract
In the study to  to investigate the effect of Ginkgo biloba leaves extract on experimental liver fibrosis induced by thioacetamide (TAA) in male albino mice, found that  G. biloba leaves extract has a potential activity against TAA-induced liver fibrosis and suggested that the chemical constituents of G. biloba are effective in modulation of oxidative stress induced by TAA(103).
Other study found that extract from Ginkgo biloba (EGb) containing 22% flavonoid and 5% terpenoid has been effective on chronic liver injury and liver fibrosis of rats induced by carbon tetrachloride (CCl(4))(104).

2. Cynanchum auriculatum
The investigation of the effect of general glycosides from Cynanchun auriculatum of Jiangsu on liver fibrosis of rats, found that the elevation of serum GPT, GOT, HA, PCIll, MDA and HyP and the content of liver homogenates were attanuated remarkably by BSW treatment. BSW groups also increased the level of SOD of liver homogenates, and make the fibrotic liver better(105).

3. Bupleurum falcatum L. (Umbelliferae).
In the study to investigate the suppressive effect of saikosaponin-d (SSd) on hepatic fibrosis in rats induced by CCl(4) injections in combination with alcohol and high fat, low protein feeding and its relationship with the expression of nuclear factor-kappaB (NF-kappaB), tumor necrosis factor-alpha (TNF-alpha) and interleukins-6 (IL-6), showed that SSd attenuates CCl(4)-induced hepatic fibrosis in rats, which may be related to its effects of hepato-protective and anti-inflammation properties, the down-regulation of liver TNF-alpha, IL-6 and NF-kappaBp65 expression and the increased I-kappaBalpha activity in liver(106).

4. Rhubarb
Emodin is a orange crystalline compound, C14H4O2(OH)3CH3 found in rhubarb and other plants.
In the study to investigate the role of emodin in protecting the liver against fibrogenesis caused by carbon tetrachloride (CCl(4)) in rats and to further explore the underlying mechanisms, showed that
Emodin protects the rat liver from CCl(4)-induced fibrogenesis by inhibiting HSC activation. Emodin might be a therapeutic antifibrotic agent for the treatment of hepatic fibrosis(107).

Other in the study of "Traditional herbal medicine used associated with liver fibrosis in rural Rakai, Uganda", concerned that Pharmacokinetic and prospective clinical studies are needed to inform herb safety recommendations in sub-Saharan Africa. Counseling about herb use should be part of routine health counseling and counseling of HIV-infected persons in Uganda, according to the study by the College of Health Sciences, Makerere University, Kampala(108). 


C.  In traditional Chinese medicine perspective
1. Yangyin Ruanjian decoction (HYRD)
In the study to  explore the anti-fibrotic effect of Haobie Yangyin Ruanjian decoction (HYRD) on CCl(4)-induced hepatic fibrosis in rats and its modulation on the transforming growth factor (TGF) beta-Smad signaling pathway, by Tianjin Medical University, showed that HYRD can inhibit hepatic fibrosis induced by CCl(4) in rats, which is probably associated with its down-regulation on fibrogenic signal transduction of TGFbeta-Smad pathway(109).

2. JinSanE decoction
In the study to assess the effects of a Chinese herbal medicine, JinSanE decoction, on the TGF-beta1/Smads signal transduction pathway in a carbon tetrachloride (CCl(4))-induced hepatic fibrosis model in rats, conducted by the Wuhan University, indicated that compared with the hepatic fibrosis model group, the levels of TGF-beta1, TRII mRNA and Smad3 expression significantly decreased in the 2 treatment groups. The expression of Smad7 was significantly increased in the liver of the rats treated with JinSanE (p < 0.05 or p < 0.01). The histological changes of fibrotic liver were obviously improved in the treatment rats. The levels of liver HYP, serum liver function and HA were also remarkably improved in the treatment rats. Moreover, the effects of JinSanE occurred in a dose- and time-dependent manner in the process of the protection of liver injury and fibrosis. JinSanE decoction had a protective effect on liver injury and could ameliorate hepatic fibrosis in rats. The mechanisms might be associated with their effects of down-regulating TGF-beta1, TRII mRNA and Smad3, and up-regulating Smad7(110).

3. Kang'ai injection
In the study to investigate the inhibition role of Kang'ai injection (KAI) in rats with hepatic fibrosis, showed that Kang'ai injection could inhibit the formation of DEN-induced liver fibrosis(111).

4.  Danshaohuaxian
The study of  the effects of Danshaohuaxian (DSHX), a Chinese herbal recipe, on the apoptosis and cell cycles of hepatic stellate cells (HSCs) in rat hepatic fibrosis and its possible mechanisms, conducted by the Affiliated Hospital of Guiyang Medical College, indicated that DSHX capsule shows certain therapeutic effects on hepatic fibrosis in rats and inhibits abnormal deposition of COL(112)

5. Qianggan-Rongxian Decoction
Qianggan-Rongxian Decoction can inhibit hepatic fibrosis due to chronic liver injury, delay the development of cirrhosis, and notably ameliorate liver function. It may be used as a safe and effective thera-peutic drug for patients with fibrosis, according to the study by the Affiliated Hospital of Chengde Medical College.
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