Current Therapeutic Strategies for Alcoholic Liver Disease

Chapter 2

Current Therapeutic Strategies for Alcoholic Liver Disease Alaa El-Din El-Sayed El-Sisi, Samia Salim Sokar, Dina Zakaria Mohamed Department of Pharmacology and Toxicology, Faculty of Pharmacy, Tanta University, Tanta, Egypt

1. INTRODUCTION One of the main global public health problems is chronic alcohol consumption. Alcoholic liver disease (ALD) is caused by many critical factors. One of these factors is excessive alcohol consumption.1 A study by Schwartz and Reinus2 showed that steatosis, steatohepatitis, fibrosis, and cirrhosis are considered the main features of ALD. Alcoholic liver fibrosis can cause cirrhosis, so it is considered the cornerstone in ALD.3 The study of Wilfred de Alwis4 investigated that ethanol metabolism contributes to the pathogenesis of ALD as the formed products of its metabolism have toxic effects on the liver, and this explains the molecular mechanisms of ethanol. Almost all ingested ethanol is metabolized in the liver. There are two pathways for ethanol metabolism, namely, the oxidative and nonoxidative pathways.5,6 The oxidative pathway encompasses the alcohol dehydrogenases (ADHs) and members of the cytochrome P450 system (predominantly CYP2E1),5,7 and this pathway generates acetaldehyde. Acetaldehyde dehydrogenase (ALDH), a mitochondrial enzyme, is responsible for the metabolism of acetaldehyde to acetate, and the kinetics of this reaction is sufficiently slow to allow for the accumulation of acetaldehyde in humans or animals consuming alcohol.5,6,8 The fatty acid ethyl ester (FAEE) synthases and phospholipase D are involved in the nonoxidative pathway of ethanol metabolism and are responsible for the esterification of ethanol with fatty acids to form FAEE and phosphatidylethanol, respectively.5,6 Accumulation of NADH and the reduction of NAD+/NADH ratio are resulted from ADH and ALDH reactions and have an important effect on biochemical pathways such as glycolysis, citric acid cycle, fatty acid oxidation, and glucogenesis (Fig. 2.1). Mitochondrial electron transfer chain is responsible for reoxidizing NADH to NAD+.9,10 Different reactive oxygen species (ROS) such as superoxide anion (O2 •-), hydrogen peroxide (H2O2), and the hydroxyl radical (OH.) are formed during the electron transfer to oxygen.9 These species are unstable and rapidly react with additional electrons and protons. A small proportion can generate toxic effects as lipid peroxidation, enzymes inactivation, DNA mutations, and destruction of cell membranes.11,12 The most of these ROS are converted to water before they can damage cells.13 The microsomal ethanol oxidizing system is another metabolic system involved in ethanol metabolism and constituted by the cytochrome P450 (CYP) enzymes. These proteins are involved in the oxidation of numerous endogenous substrates such as steroids, fatty acids, and xenobiotics.14 They catalyze many different reactions to convert different chemical molecules in more polar metabolites to be excreted as monooxygenation, peroxidation, dealkylation, epoxidation, and dehalogenation. An ethanol-inducible form of P45015 catalyzes ethanol oxidation at rates much higher than other CYP enzymes. Ten percent of ethanol is oxidized to acetaldehyde by CYP2E1 physiologically,15 and induction of the microsomal system occurred during chronic alcohol abuse5,15 and an increase in CYP2E1 protein expression. During chronic ethanol intake, the increase in CYP2E1 is correlated with a decrease in proteasomal degradation, which increases CYP2E1 protein stability.16,17 The oxidation of ethanol to acetaldehyde is catalyzed by CYP2E1 and then to acetate,18 but this reaction is disadvantageous in the presence of ethanol19 as a significant amount of ROS, such as (O2 •-), H2O2, OH, and the hydroxyethyl radical (HER) are formed.20,21 Chronic ethanol consumption effects on microsomal enzymes, particularly CYP2E1, and does not influence ADH activity.6,8 So, a rise in oxygen consumption; the excessive production of free radicals; and an increase in the metabolism of ethanol, vitamin A, and testosterone resulted in ALD. Generation of ROS caused by ethanol and acetaldehyde can lead to damage to the intestinal mucosal barrier.6,22 The imbalance between free radical generation and insufficient antioxidant defense mechanisms leads to cellular oxidative stress as a decrease in glutathione (GSH), vitamin E, and phosphatidylcholine that are considered main mediators for the progression of ALD.6,8,22 Dietary Interventions in Liver Disease. https://doi.org/10.1016/B978-0-12-814466-4.00002-1 Copyright © 2019 Elsevier Inc. All rights reserved.

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16  SECTION | I  Overview of Liver Health

FIGURE 2.1  Alcohol metabolism.26

Pathophysiological changes in liver cells such as neutrophils, sinusoidal endothelial cells (SECs), Kupffer cells (KCs), hepatic stellate cells (HSCs), and hepatocytes may lead to steatosis, hepatitis, and fibrosis. The principal fibroblastic cell type within the liver is HSCs and may be activated directly by ethanol and its metabolites including acetaldehyde.23–25 Production of transforming growth factor beta-1 (TGFβ-1) and several extracellular matrix (ECM) constituents including type I collagen by HSC was induced directly by ethanol and acetaldehyde.23–25

2. PATHOGENESIS OF ALCOHOLIC LIVER DISEASE 2.1 Alcoholic Fatty Liver (Steatosis) The highly metabolic organ in the body is the liver.27 It has catabolic and anabolic capabilities and acts as a central point between the fasting and feeding states. Consuming large amounts of alcohol resulted in inadequate metabolism which leads to steatosis as endoplasmic reticulum stressed and increased fatty acid and triglyceride synthesis. Also, a large amount of fat accumulation occurs when the peroxisome proliferator–activated receptor α (PPAR-α) is downregulated or depleted as it is considered a critical point for alcohol metabolism.28,29 Alcohol consumption results in the altering of sterol regulatory element-binding proteins (SREBPs) and 50 adenosine monophosphate-activated protein kinase (AMPK) expression. Both play a significant role in regulating lipid metabolism.30,31 Downregulation of AMPK by alcohol decreases its ability to inactivate SREBP and increases adenylyl cyclase activity, contributing to steatosis.32 Dietary lipids such as saturated and unsaturated fats played an important role in liver pathology induced by alcohol.33 The early stage of ALD is the fat accumulation and it may be accompanied by inflammation, fibrosis, and cirrhosis, and hepatocellular carcinoma, and people who consumed alcohol more than of 40 g/d had steatosis.34

2.2 Alcoholic Hepatitis Alcohol intake resulted in alcoholic hepatitis (AH) which is considered a progressive inflammatory liver injury and characterized by poor liver function, ductular reaction, high levels of lipopolysaccharide (LPS), and impaired hepatocyte proliferation.35–37 These mechanisms are involved in the pathogenesis of the disease along with sterile and nonsterile inflammation.38 The essential proinflammatory cytokines involved in AH are tumor necrosis factor α (TNF-α) and interleukins (IL1 & IL6). AH has a significant short-term mortality. Stopping alcohol intake resulted in improving the prognosis in early and advanced stages.38 The main treatments for AH patients are with pentoxifylline (PTX) and prednisolone, although corticosteroids increase the risk of bleeding and infections.39

2.3 Alcoholic Fibrosis Liver fibrosis is a wound-healing response to virtually all forms of chronic liver injury, and it is characterized by excessive accumulation of collagen and other ECM proteins.40,41 The major source of the high production of ECM proteins, along with portal fibroblasts and bone marrow–derived myofibroblasts, is activated HSCs. Many cytokines, chemokines, neuroendocrine factors, angiogenic factors, and components of the innate immune system induced HSC activation and fibrogenesis after hepatocellular damage.40,41

Current Therapeutic Strategies for Alcoholic Liver Disease Chapter | 2  17

2.4 Alcoholic Cirrhosis The most frequent cause of cirrhosis in Europe is excess alcohol consumption.1 The prevalence of cirrhosis is 0.27%, corresponding to 633,323 adults in the United States in 2015.42 So, a significant cause of morbidity and mortality worldwide is liver cirrhosis. Factors that synergized the progression of the disease in addition to alcohol consumption are the lifestyle, gender, ethnic, and socioeconomic factors. Cirrhosis is more frequent, and features such as hepatocellular damage, lobular inflammation, hepatocellular ballooning degeneration, hepatocyte dropout, mega mitochondria, and the appearance of Mallory–Denk bodies are more dominant in decompensated ALD patients.43 Variceal bleeding, ascites and hepatic encephalopathy are severe complications of liver cirrhosis. As well, this cirrhosis can lead to decrease in sinusoidal space, SEC fenestrations collapse, and formation of numerous new vessels around the cirrhotic nodules bypassing the obstructed route (vascular proliferation) leading to liver architecture remodeling and portal hypertension. Finally, severe cirrhosis is considered an indicator for liver transplantation and death.44

3. CURRENT THERAPIES FOR ALCOHOLIC LIVER DISEASE 3.1 Abstinence and Lifestyle Modification Reducing alcohol consumption is a good step to improve survival rate in alcoholic cirrhotic patients, even those with decompensated liver function, and leads to the resolution of alcoholic fatty liver disease.45,46 The main problems in ALD treatment are motivating patients to follow treatment regimen, monitoring their compliance, and preventing relapse. Rehabilitation programs are important for ALD patients and maintain their calmness.47 Another published report48 showed that the active participation in Alcoholics Anonymous is the best method of encouraging ALD patients. A good step in supporting patients with alcohol addiction is recognition and treatment of comorbid psychiatric conditions.49 The method of supporting patients against alcoholic intake must be pharmacotherapy in combination with psychosocial interventions. Combination of naltrexone and acamprosate can be used for heavy drinkers.50 Disulfiram has good outcomes for alcohol-dependent individuals.51 Although disulfiram had been FDA approved, it is still widely used but less clearly confirmed by clinical trial evidence.52 Additionally, Kenna et al.48 revealed that topiramate is an effective drug in clinical trials by lowering withdrawal symptoms and enhancing the quality of life measures among alcoholic patients. Eventually, the best drug for alcoholic patients with liver cirrhosis is baclofen as reported by Addolorato et al.53 Smoking cessation and weight loss are the other considered lifestyle modifications that improve alcoholism as smoking may lead to more severe ALD and then to Hepatocellular carcinoma.54,55 Also, obesity is considered one of the important risk factors that cause fatty liver, nonalcoholic steatohepatitis, and cirrhosis and enhance the development of ALD.56

3.2 Nutritional Support and Supplements Anorexia, vomiting, maldigestion, iatrogenic causes, metabolic disturbance, hypermetabolic state, impaired protein synthesis, and malabsorption can lead to poor dietary intake and then to malnutrition that is considered a major complication of ALD.57,58 So, to regenerate hepatocyte after malnutrition, nutritional supplementations are necessary as reported by Hirsch et al.59 Symptoms of protein–energy malnutrition are muscle wasting, edema, and loss of subcutaneous fat, so a protein intake of 1.5 g/Kg and 35-40 Kcal/Kg per day is recommended for ALD patients.60 If there are folate and thiamine defi­ ciencies, supplementation should be considered.61,62 Zinc deficiency is an example of micronutrient deficiency in ALD, and zinc supplementation can improve ADH activity and lower CYP2E1 in animal models, enhancing ALD.63,64

3.3 Pharmacological Drugs and New Agents That Are Under Development Although patients living with ALD have mostly shown strategies to encourage abstinence from alcohol, some patients may need to be accompanied with pharmacological treatment approaches.

3.3.1 Corticosteroids Corticosteroids were considered one of the most effective drugs used for AH treatment.65 The basic mechanisms of action of corticosteroids are improving the inflammatory response by decreasing TNF-α, IL-6, and IL-866,67 and inhibiting collagen formation by suppressing the formation of acetaldehyde adduct metabolites.68 Prednisolone is one among the corticosteroid family that prescribed to treat AH with a dose of 40 mg/d for 28 d followed by tapering over 2–4 wk. Another supporting study conducted by Phillips et al.69 confirmed that corticosteroid group (prednisone 30 mg/d or methylprednisone 24 mg/d IV)

18  SECTION | I  Overview of Liver Health

for 1 month showed high survival rate more than the control group (37/53) in 101 acute AH patients. Serum bilirubin is indicated as a good indicator for liver disease, so glucocorticoid can diminish it.70,71 Corticosteroids are used in severe AH, although it caused sepsis, hepatitis B, hepatorenal syndrome, and gastrointestinal (GI) bleeding as contraindications.69,72 Long-time usage of corticosteroids may increase the efficacy or show no benefits after more than 6 months.73

3.3.2 Pentoxifylline It is used as an alternative medicine for corticosteroid in AH patients when there is a contraindication to steroids, and it is used for short period of time.74,75 Although the mechanism of action of PTX is not evident, published report of Doherty et al.76 showed that 100–1000 μg/mL of PTX significantly reduced serum TNF-α levels in murine peritoneal exudate cells that were treated with endotoxin 1 μg/mL in vivo, so PTX may has anti-TNF actions. PTX and corticosteroid treatment groups or their combination showed no significant changes,77 and another metaanalysis study by Whitfield et al.78 showed that PTX decreased the hepatic mortality rate, but trial sequential analysis did not support this. Nonetheless, PTX is recommended from European and the American Association for the Study of Liver Diseases as an alternative medicine for corticosteroid in AH patients when there is a contraindication to steroids.79

3.3.3 S-Adenosyl-l-Methionine It acts as a methyl donor that is used for GSH synthesis, a major cellular antioxidant. Abnormality of hepatic gene expression in methionine and GSH metabolism that is observed in AH and cirrhotic patients resulted in decreased hepatic S-adenosyll-methionine (SAM), cysteine, and GSH levels.80 SAM supplementation can reverse liver injury and mitochondrial damage by increasing SAM concentrations as its deficiency is caused in the early stages of ALD.81 These results are in agreement with Karaa et al.82 who demonstrated that SAM can inhibit oxidative stress and TGF-α signaling pathway and then reduction in HSC activation in ethanol-lipopolysaccharide-induced liver fibrosis in rats. Large and high-quality clinical trials are needed to further prove clinical benefits of SAM in ALD as the studies of Medici et al. and Le et al.83,84 indicated that SAM does not enhance liver histopathology scores or steatosis, inflammation, and fibrosis in patients with ALD, and after examination of liver biopsies, there is no significant changes between SAM and the placebo.

3.3.4 Peroxisome Proliferator–Activated Receptor-Alpha It is a member of the nuclear receptor superfamily, mainly expressed in liver, and is responsible for genes transcription regulation that involved in oxidation, transportation of fatty acids (FAs), and exportation of free fatty acid, and alcohol intake leads to suppression of PPAR-α in hepatocytes and then inhibits FA oxidation.85 PPAR-α agonists have antiinflammatory and hypolipidemic effects by induction of FA oxidation, so these agonists are suitable for ALD patients. A new drug for ALD patients is adiponectin; it can manage the disease through PPAR-α-, TNF-α-, and sirtuin 1 (SIRT-1)-related pathways.86 Rosiglitazone is considered one of the PPAR-α agonists and can enhance hepatic adiponectin receptors (AdipoRs) in ethanol-fed mice through increasing the circulating level of adiponectin, and these mechanisms are correlated with the activation of the SIRT-1-AMPK signaling system.87

3.3.5 Carvedilol It is one among the beta-blocker family and recently used in AH patients through downregulation of fatty acid synthase and sterol regulator element binding protein 1 (SREBP-1), and upregulated PPAR-α that leads to decrease in hepatic trigylceride (TG) levels and lipid droplets within hepatocytes and also decreased HSC activation, induction of TGF-β1, and collagen and prevented ethanol-induced thickening of zone 3 vessel walls.88

3.3.6 Metformin It is an antidiabetic drug, recently used to enhance hepatic steatosis (HS) through the prevention of the upregulation of plasminogen activator inhibitor-1 and improvement of insulin resistance and liver injury by increasing PPAR-γ and adiponectin levels that lead to decrease fat accumulation and liver damage in mouse models of acute and chronic alcohol stimulation.89,90

3.3.7 Diethylcarbamazine Is the drug most widely used in the treatment of lymphatic filariasis since 1947.91 Some studies performed on vertebrates show that this drug has several direct biochemical effects on different enzyme systems, including glycolysis,

Current Therapeutic Strategies for Alcoholic Liver Disease Chapter | 2  19

folate metabolism, and activity of acetyl cholinesterase.92 Also, diethylcarbamazine (DEC) has antiinflammatory properties as a result of its interference with the arachidonic acid metabolism, which includes lipoxygenase and cyclooxygenase enzymes.93,94 A study performed in the laboratory of the authors of the present study analyzed the antiinflammatory effect of DEC on hepatic cells of alcoholic mice. The DEC-treated group, which received 50 mg/kg for 12 d (a dose equivalent to 6 mg/kg given to human preconized by OMS), significantly reduced several parameters of chronic hepatic inflammation. Histological and ultrastructural analysis of the alcoholic group showed evidence of hepatocellular damage; which was strikingly reduced in the alcoholic DEC-treated group. Also DEC treatment reduced steatosis, necrosis, and foci of inflammatory infiltrates and diminished serum AST levels and inflammatory markers such as malondialdehyde (MDA), NF-κBp65, tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), vascular cell adhesion molecule-1(VCAM-1), intercellular cell adhesion molecule (ICAM-1), monocyte chemotactic peptide1(MCP-1) and its functional receptor C2 chemokine receptor (CCR2), and inducible nitric oxide synthase (iNOS) in hepatic tissue. This study found that chronic consumption of ethanol increased NF-κBp65 and targeted several proinflammatory cytokines, chemokines, and oxidases. Moreover, the administration of DEC inhibited NF-κBp65 expression, reducing hepatic injury and decreasing inflammatory markers, suggesting a potential therapeutic use in chronic inflammation.95 Another published report of Rodrigues et al.96 showed that treatment with DEC was able to reduce liver damage, collagen content, the expression of nuclear factor kappa-light-chain enhancer of activated B cells, and inflammatory markers. It also ameliorated biochemistry parameters (total cholesterol, high-density lipoprotein cholesterol, and triglyceride content and aspartate aminotransferase) and increased the expression of antiinflammatory markers (p-50 adenosine monophosphate–activated protein kinase and interleukin-10). Recently, the study of El-Sisi et al.97 evaluated that administration of DEC (50 mg/kg), concomitantly with EtOH, significantly decreased EtOHinduced increases in serum enzymatic activities of ALT, AST, and GGT levels, suggesting that DEC decreased the hepatic parenchyma injury. Also, DEC reduced hepatic MDA and NOx concentrations with a significant elevation of hepatic-reduced GSH concentration and diminished hepatic hydroxyproline, serum TGF-β1, and inflammatory markers such as IL-6 as well as significantly reduced the incidence of liver lesions induced by EtOH with a lesser score of fibrosis and necroinflammation compared with EtOH group. DEC concomitantly with EtOH showed a mild expression of α-SMA in the portal tract and moderate expression in the liver parenchyma compared with EtOH group. So, future clinical trials may demonstrate that oral administration of DEC may be suitable for the treatment of ALD and other liver diseases.

3.3.8 CYP2E1 Inhibitors CYP2E1 inhibitors prevent alcohol-induced liver damage. Polyenylphosphatidylcholine (PPC) is a mixture of polyunsaturated lecithins and is extracted from soybeans and acts as a CYP2E1 inhibitor by attenuation of hepatic oxidative stress and fibrosis.98 Another supporting study conducted by Lieber98 confirmed that large randomized controlled trials (RCTs) are needed to further prove clinical benefits of PPC in progressive liver fibrosis.99 Clomethiazole indicated to reduce CYP2E1 activity and reduced ethanol-induced hepatic injury in rats and humans.100,101

3.3.9 Prebiotics and TLR-4 Antagonists Establishing healthy gut microbiota has been put forward as a strategy in the treatment of ALD as liver and GI tract share a reciprocal relationship. Kinde et al.102 showed that LPS binds to CD14 in KC, which reacts with toll-like receptor 4 (TLR-4) to activate and release proinflammatory cytokines genes.102 Probiotics, prebiotics, and TLR-4 antagonists can adjust LPS signaling and gut microbiota to treat ALD.103 Gut-derived endotoxin/LPS may be important in the study of ALD as antibiotics or Lactobacillius can decrease the gut microflora in animal experiments.104 The modified probiotic Escherichia coli Nissle 1917 has an antiinflammatory, antioxidant, and antihyperlipidemia effects in acute alcohol exposure in rats by secretion of pyrroloquinoline quinone, which decreased lipid peroxidation and increased GSH.105

3.3.10 Antioxidants Products of lipid peroxidation were detected in both heavy drinkers and ALD patients, so oxidative stress is regarded as a cornerstone in the pathogenesis of ALD.106 After exposure of human hepatocyte (HepG2) to ethanol and acetaldehyde, metadoxine can lower lipid peroxidation and GSH depletion, so antioxidant therapy is important for ALD patients.106 Also, metadoxine prevents the increase of collagen production and TNF-α secretion in HSC.107

20  SECTION | I  Overview of Liver Health

3.3.11 Others Drugs Colchicine has antifibrotic effects when patients with chronic liver cirrhosis received (1 mg/d) over a 3-year period as reported by Muntoni et al.108 Another published report of Carmichael et al.109 showed that propylthiouracil (PTU) as an antithyroid drug may also improve liver fibrosis. PTU enhances hepatic blood flow and also decreases oxidative stress in rats, so it was suggested as a curative drug to treat liver cirrhosis induced by alcohol.109

3.4 Liver Transplantation The final treatment option for ALD patients with alcoholic cirrhosis who have not responded to abstaining from alcohol is liver transplantation. For patients with decompensated liver injury and have not responded to pharmaceutical therapy, liver transplantation is the magic and saving choice.110 Relapse incidences after liver transplantation may occur in 10%–52% of patients.111,112 Finally, to avoid histological damage the transplantation should be followed after 6 months of abstinence.113,114

3.5 Natural and Herbal Medicines for the Prevention and Treatment of ALD Herbs as complementary and alternative medicine (CAM) are effective in the treatment of liver diseases, such as antagonizing fibrosis, steatosis, and hepatitis viruses, and in protecting the liver cell.115 There are several natural and herbal medicines that have been widely used and reviewed with efficacy and mechanisms. Table 2.1 summarizes the effects and mechanisms of natural and herbal medicines.

3.6 Herbal Formulas for Treatment of Alcoholic Liver Disease This review mentioned some herbal blends that have been used for ALD, and these blends have not been approved by the Food and Drug Administration as reported by Moon-Sun et al.49

3.6.1 Herbal Medicine 861 (HM 861) This medicine consists of 10 herbs including Salvia miltiorrhiza, Astragalus membranaceus, and Spatholobus suberectus.166 HM 861 is used for chronic hepatitis patients by inhibition proliferation and induction apoptosis of HSC.167 And in HSC-T6 cells, it can suppress tissue inhibitor metalloprotease 1 (TIMP-1) mRNA expression.168 Another published report of Baoen et al.169 demonstrated that this mixture showed antifibrotic activity by decreasing ALT levels to the normal range in 73% of patients with hepatitis B. These results are in agreement with Yin et al.170 and showed that HM 861 can enhance fibrosis and early cirrhosis in 52 patients with HBV and decrease hepatic inflammatory scores in fibrotic patients.

3.6.2 TJ-9 TJ-9 consists of seven herbal constituents including bupleurum root, Pinellia tuber, scutellaria root, jujube fruit, ginger rhizome, ginseng root, and Glycyrrhiza root. It is referred to as xiao-chai-hu-tang in China or Shosaiko-to in Japan and used for hepatic disorders. It shows antioxidant activity when preparation contains 7.5 g of TJ-9 with the active components baicalin and baicalein.171 The predictable mechanism of TJ-9 is inhibition of typeⅠcollagen production, α-smooth muscle actin, cell spreading, and suppression of HSC activation, but the exact mechanism is unknown.171 Additionally, Cohen et al.172 revealed that the administration of TJ-9 with interferon can be used for chronic hepatitis treatment and in cases of interstitial pneumonitis.

3.6.3 Liv-52 Liv-52 consists of seven herbs including Capparis spinosa (Himsara), Cichorium intybus (Kasani), Mandur bhasma, Solanum nigrum (Kakamachi), Terminalia arjuna (Arjuna), Cassia occidentalis (Kasamarda), Achillea millefolium (Biranjasipha), and Tamarix gallica (Jhavaka). It is an Indian ayurvedic medicine and has been used for the treatment of hepatic disorders.173 RCT from Europe showed that Liv-52 has effect on advanced cirrhosis induced by alcohol, although it was primarily used for ALD treatment.174 In contrast, Liv-52 improved PPAR-γ suppression and TNF-α expression in HepG2 cells.175

TABLE 2.1  The Effects of Natural and Herbal Medicines for the Prevention and Treatment of Alcoholic Liver Disease Herbal/Medicine Compound

Type of Model

Effective Dose

Effects

Mechanisms

References

Ethanol extract of Antrodia camphorate

Acute alcohol-fed Sprague– Dawley rats

47.8 and 95.6 mg/kg

↓(ALT; AST; ALP)

Antioxidation: ↓MDA and ↑(GSH; GPX; SOD)

116

Aqueous extract of Agrimonia eupatoria L.

Chronic alcohol-fed Sprague– Dawley rats

30 mg/kg

↓(ALT; AST)

Antioxidation: ↓MDA; ↑GSH Antiinflammation: ↓(TNF-α; IL-6; TLR4; NF-κB; MyD88; COX-2)

117

Fermented extract of barley

Chronic alcohol-fed Wistar rats

Not provided

↓(ALT; AST)

Antioxidation: ↑(GPX; SOD; CAT) and ↓MDA

118

Betaine

Acute alcohol-fed C57BL/6 mice

Not provided

↓ALT

Antioxidation: ↓(MDA; CYP2E1); ↑GSH Antiinflammation: ↓TNF-α

119

Chronic alcohol-fed Sprague– Dawley rats

200 and 400 mg/kg

↓(ALT; AST)

Antiinflammation: ↓(TNF-α; IL-18; endotoxin; TLR4)

120

Ethanol diet Wistar rats

1% (w/v) in diet

↓Hepatic ballooning and fat contents

↓(NOS; CYP2E1)

121

Anthocyanin-rich extract of Oryza sativa L. Japonica

Chronic alcohol-fed Wistar rats

500 mg/kg

↓(ALT; AST; GGT; TG; TC)

Antioxidation: ↓MDA and ↑(GSH; GST; SOD; GPX)

122

Caffeine

Chronic alcohol-fed Kunming mice

5, 10, and 25 mg/kg

↓(ALT; AST; TG; TC)

Antioxidation: ↓(ROS; MDA) and ↑(SOD; GPX) Antiinflammation: ↓(TNF-α; IL-1b; IL-6; MCP-1) FA synthesis: ↓(SREBP-1c; FAS; ACC; SCD-1)

123

Chronic alcohol-fed Sprague– Dawley rats

5, 10, and 20 mg/kg

↓(ALT; AST; HA; LN; PIIINP; CIV)

Antifibrotic: ↓(cAMP; PKA; CREB) signal pathway through adenosine A2A receptors in HSC

124

Leaf extract of Cajanus cajan Linn.

Chronic alcohol-fed Sprague– Dawley rats

50 mg/kg

↓(ALT; AST; ALP)

Antioxidation: ↑(GSH; SOD; CAT; GST)

125

Aqueous extract of Pecan nut shells (Carya illinoinensis)

Chronic alcohol-fed Wistar rats

3327 mg/kg

↓(ALT; AST; GGT)

Antioxidation: ↑(GSH; CAT; SOD)

126

Aqueous leaf extract of Cassia auriculata Linn.

Chronic alcohol-fed Wistar rats

250 and 500 mg/kg

↓(ALT; AST; ALP)

Antioxidation: ↑(SOD; CAT; GSH; Vit E; Vit C) and ↓ROS

127

Bark alcoholic extract of cinnamon

Acute alcohol-fed C57BL/6 mice

Not provided

↓TG

Antiinflammation: ↓MyD88

128

Osthole

Chronic alcohol-fed Kunming mice

40 mg/kg

↓(TG; TC)

Antioxidation: ↓MDA and ↑GSH Antiinflammation: ↓TNF-α

129

Antioxidation: ↑SOD and ↓(MDA; CYP2E1) FA β-oxidation: ↑CPT1

130

20 and 40 mg/kg

Continued

TABLE 2.1  The Effects of Natural and Herbal Medicines for the Prevention and Treatment of Alcoholic Liver Disease—cont’d Herbal/Medicine Compound

Type of Model

Effective Dose

Effects

Mechanisms

References

Curcumin

Chronic alcohol-fed Wistar rats

75 mg/kg

↓ALT

Antiinflammation: ↓(NF-κB; TNF-α; IL-12; MCP-1; COX-2)

131

Chronic alcohol-fed Sprague– Dawley rats

200 and 600 mg/kg

Antioxidation: ↓MDA Antiinflammation: ↓NF-κB

132

Alcohol (100 mM)-induced rat primary hepatocytes

0–50 μmol/L

↓(AST; MDA)

Improved GSH and heme oxygenase-1 (HO-1) induction

133

Flavonoid extract of Theobroma cacao

Chronic alcohol-fed Wistar rats

400 mg/kg

↓ALT

Antiinflammation: ↓TNF-α

134

Corn oligopeptides

Chronic alcohol-fed Wistar rats

900 mg/kg

↓(ALT; TC)

Antioxidation: ↑SOD and ↓MDA

135

Dieckol-rich phlorotannins of Ecklonia cava

Chronic alcohol-fed BALB/c mice

25 mg/kg

↓(ALT; AST; TC)

Antioxidation: ↑SOD and ↓MDA

136

Methanol extract of Gentiana manshurica Kitag.

Acute alcohol-fed C57BL/6 mice

200 mg/kg

↓(ALT; AST; TG)

Antioxidation: ↓(MDA; CYP2E1) and ↑(GSH; GPX; SOD; CAT) FA synthesis: ↓SREBP-1c

137

Ginkgo biloba extract of Ginkgo biloba

Chronic alcohol-fed Sprague– Dawley rats

200 mg/kg

↓ALT

Antioxidation: ↓MDA and ↑GSH Antiinflammation: ↓TNF-α

138

Chronic alcohol-fed Sprague– Dawley rats

96 mg/kg

↓(ALT; AST)

Antioxidation: ↑(SOD; GPX; CAT; GSH) and ↓MDA

139

Ethanol-feeding mice ethanol feeding hepatocytes (AML12 cell lines)

250 or 500 mg/kg for 4 week in mice

Improves histopathological changes and ↓TG

↓(Lipogenesis pathway; CYP2E1; 4-HNE; nitrotyrosine levels) and ↑activation of AMPK-SIRT1

140

Alcohol consumption with high fat diet mice

200 mg/kg per day for last 2 week

↓ALT and no different AST

↓(TNF-α; IL-1) and ↑IL-10

141

Catechin

Chronic alcohol-fed Wistar rats

50 mg/kg

↓ALP

Antioxidation: ↓MDA and ↑(GSH; SOD; CAT) Antiinflammation: ↓NF-κB; TNF-α

142

Green tea extract

Chronic alcohol-fed Wistar rats

300 mg/kg

↓ALT

Antiinflammation: ↓TNF-α

7

Chronic alcohol-fed Wistar rats

Not provided

↓(ALT; TG)

Antioxidation: ↓(ROS; CYP2E1) FA synthesis: ↓(SREBP-1c; FAS)

143

Male albino Wistar rats with ethanol (6 g/kg per day) for 60 d

EGCG (100 mg/kg per day) for the last of 30 day of ethanol administration

Normalization of activities of enzymatic

Antioxidants: ↓Lipid peroxidation

144

Female Sprague–Dawley rats with ethanol (56%)

EGCG (100 mg/bw)

↓(Gut leakiness; endotoxemia; lipid peroxidation)

↓(CD14; TNF-α; COX-2; INOS)

145

Male Wistar rats with ethanol for 5 week

EGCG contained diet (3 g/L) for 2 week and then ethanol EGCG diet for 5 wk

↓(AST; ALT)

FA oxidation: ↑(CTP-1; p-ACC)

146

Ginsenosides (red ginseng extract)

Epigallocatechin-3gallate

l-Theanine

Acute alcohol-fed ICR mice

100 and 200 mg/kg

↓(ALT; AST; TG)

Antioxidation: ↓MDA and ↑(GSH; SOD; CAT)

147

Semen Hoveniae extract of Hovenia dulcis Thunb.

Acute alcohol-fed Kunming mice

300 and 600 mg/kg

↓(ALT; AST; TG)

Antioxidation: ↓MDA and ↑(GSH; GST; SOD)

148

Aqueous extract of Ligularia fischeri (Ledeb.) Turcz.

Chronic alcohol-fed Sprague– Dawley rats

200 mg/kg

↓(ALT; AST; GGT)

Antioxidation: ↓MDA and ↑(GSH; SOD; GPX; CAT)

149

Bark ethanol extract of Magnolia officinalis

Chronic alcohol-fed Wistar rats

45 mg/kg

↓(ALT; TG)

Antioxidation: ↑GSH Antiinflammation: ↓TNF-α FA synthesis: ↓(SREBP1c; ACLY; FAS; SCD-1)

150

Honokiol

Chronic alcohol-fed Wistar rats

10 mg/kg

↓(ALT; TG)

Antioxidation: ↑GSH Antiinflammation: ↓TNF-α FA synthesis: ↓(SREBP-1c; ACC; FAS; ACLY; SCD-1)

151

Perillyl alcohol

Acute alcohol-fed Wistar rats

50 and 100 mg/kg

↓(ALT; AST)

Antioxidation: ↓MDA and ↑(CAT; GPX; GST) Antiinflammation: ↓(TNF-α; NF-κB)

152

Platycodi radix of Platycodon grandiflorus (Jacq.) A.DC.

Chronic alcohol-fed Sprague– Dawley rats

Not provided

↓(AST; TG)

Antioxidation: ↓CYP2E1

153

Ethanol (70%) extract of Pueraria lobata (Willd.) Ohwi

Chronic alcohol-fed Wistar rats

3 g/kg

↓(ALT; AST)

Antioxidation: ↑SOD Antiinflammation: ↓intestinal permeability

154

Tectoridin

Acute alcohol-fed C57BL/6 mice

50 and 100 mg/kg

↓(ALT; AST; TG)

Antioxidation: ↓MDA and ↑(SOD; GSH; GPX) FA β-oxidation: ↑CPT1

155

Puerarin

Acute alcohol-fed Wistar rats

200 mg/kg

Antioxidation: ↓MDA and ↑(SOD; GPX)

156

Resveratrol

Chronic alcohol-fed C57BL/6 mice

200 and 400 mg/kg

↓(TG; ALT)

Antioxidation: ↓MDA FA β-oxidation: ↑(CPT1; PGC-1a) FA synthesis: ↓(SREBP-1c; SCD-1; FAS; ACC) and ↑(AMPK; SIRT1) Antiinflammation: ↓TNF-α

157

Baicalin

Chronic alcohol-fed Sprague– Dawley rats

200 mg/kg

↓ALT

Antiinflammation: ↓(TLR4; MyD88; NF-κB; TNF-α; IL-6; COX-2)

119

Fenugreek seed polyphenol

Chronic alcohol-fed Wistar rats

200 mg/kg

Antioxidation: ↑(SOD; CAT; GPX; GSH; Vit E; Vit C)

158

Continued

TABLE 2.1  The Effects of Natural and Herbal Medicines for the Prevention and Treatment of Alcoholic Liver Disease—cont’d Herbal/Medicine Compound

Type of Model

Effective Dose

Effects

Mechanisms

References

Aqueous leaf extract of Ziziphus mauritiana

Chronic alcohol-fed Wistar rats

200 and 400 mg/kg

↓(ALT; AST)

Antioxidation: ↑GSH

159

Silymarin (Silybum marianum)

RCT, double-blind, 170 patients with cirrhosis

140 mg/d for three times orally

↓Rate of mortality

Alcohol-induced baboons (50% of calories)

0.84 mg/calorie for 36 mo

Improve histologic stage of fibrosis

↓Collagen I and (I) procollagen

160

Alcohol- and high fat–induced rats

100, 150, 200 mg/kg/d for 6 week

↓(ALT; AST; hepatic fat contents)

↓(NF-κB p65; ICAM-1; IL-6) were found in silymarin groups (150 mg/kg, 200 mg)

161

Vitamin E and C

Malnourished rats with ethanol

Vitamin E and C: vitamin E (15 mg/kg); vitamin C (10 mg/kg); single and combined treatments

↓(GPx; hepatic fibrosis; hepatomegaly hepatic necroinflammation)

Glycyrrhizin (Glycyrrhiza glabra)

Ethanol-CCl4-induced male SD rats

IP injections of potenlin (acquired from Hai Ning Pharmaceutical Co., Zhe Jiang, China)

↓ALT

Normalized NF-κB binding activity

163

Hesperidin

Chronic alcohol-fed Wistar rats

200 mg/kg

↓(ALT; AST; GGT)

Antioxidation: ↓(NO; MDA) and ↑GSH Antiinflammation: ↓IL-6 Antifibrotic effect: ↓(TGF-b1; α-SMA; hepatic histopathology scoring and 4-hydroxyproline content)

97

Lemon juice

Chronic alcohol-fed C57BL/6 mice

Different concentrations (high dose 1:1 [m/v], medium dose 1:5, and low dose 1:10)

↓(ALT; AST; TG)

Antioxidation: ↓(MDA) ↓Hepatic histopathology

164

Jujube honey

Chronic alcohol-fed Kunming mice

Different doses (high dose 27.0 g per kg twice daily and low dose 13.5 g per kg twice daily)

↓(ALT; AST)

Antioxidation: ↓(8-OHdG; MDA) and ↑(GSH-Px) ↓Hepatic histopathology

165

65

162

4-HNE, 4-Hydroxynonenal; 8-OHdG, 8-hydroxy-2’–deoxyguanosine; ACC, Acetyl-CoA carboxylase; ACYL, Acyl-CoA; ALP, Alkaline phosphatase; ALT, Alanine Aminotransferase; AMPK, AMP-activated protein kinase; AST, Aspartate Aminotransferase; cAMP, Cyclic adenosine monophosphate; CAT, Choline acetyltransferase; CD, cluster of differentiation; CIV, collagen type IV; COX, cyclooxygenase; CPT, Carnitine palmitoyltransferase; CREB, cAMP response element-binding protein; CYP, Cytochrome P450; EGCG, Epigallocatechin gallate; FA, Fatty acid; FAS, Fas ligand; GGT, Gamma-Glutamyl Transferase; GPX, Glutathione peroxidase; GSH, Glutathione; GST, Glutathione S-transferase; HA, hyaluronic acid; HSC, Hepatic stellate cells; ICAM-1, Intercellular Adhesion Molecule 1; IL, Interleukin; INOS, Inducible nitric oxide synthase; LN, laminin; MCP, Monocyte Chemoattractant Protein; MDA, Malondialdehyde; MyD, Myeloid differentiation primary response; NF-κB, Nuclear factor kappa B; NO, Nitric oxide,TGF-b1, Transforming growth factor beta 1; NOS, Nitric oxide synthase; PGC-1a, Peroxisome proliferator-activated receptor gamma coactivator 1-alpha; PIIINP, N-Terminal Propeptide of Type III Collagen; PKA, Protein kinase A; ROS, Reactive oxygen species; SCD-1, Stearoyl-CoA Desaturase-1; SOD, Superoxide dismutase; SREBP, Sterol regulatory element-binding protein; SREBP-1c, Sterol regulatory element-binding protein 1; TC, Total cholesterol; TG, triglyceride; TLR, Toll like receptor; TNF, Tumor necrosis factor; α-SMA, Alpha smooth muscle actin.

Current Therapeutic Strategies for Alcoholic Liver Disease Chapter | 2  25

3.7 The Combination Therapies of Drugs and Natural Agents 3.7.1 Magnesium Isoglycyrrhizinate Injection It was used for the treatment of chronic liver diseases and contains glycyrrhizin176 as well as inhibits the progress of pulmonary fibrosis.177 The double action of glycyrrhizin and matrine leads to a decrease in collagen I and HA levels secreted by HSC as compared with each drug alone. Also, this combination improves hepatic histological analysis in vitro and in vivo more effectively in CCL4-induced liver fibrosis as reported by Zhao et al.156

3.7.2 Silymarin and S-Adenosyl-l-Methionine Silymarin and SAM combination was evaluated in ALD markets with much promise.178

3.7.3 Diethylcarbamazine and Hesperidin A study performed in the laboratory by El-Sisi et al.97 analyzed the antifibrotic effects of diethylcarbamazine combined with hesperidin against ethanol-induced liver fibrosis in rats. The results of this study clearly indicate that DEC when administrated in combination with HDN has a protective effect against EtOH-induced liver fibrosis, mainly via inhibition of hepatic oxidative stress and augmentation of antioxidant defenses, attenuating the activation of HSCs via reduction of αSMA expression in liver, inhibiting the fibrogenesis and proliferation of activated HSCs response via inhibiting the release of TGF-β1, and inhibiting proinflammatory cytokines as IL-6. Overall, the combination of DEC with HDN produced augmented antifibrotic, antiinflammatory, and antioxidant effects compared with individual drugs. There have been some cases of side effects and hepatotoxicity caused by herbal medicines.179 Interstitial pneumonia occurred in chronic hepatitis patients after administration of xiao-chai-hu-tang, alone or in combination with interferon.180 Although there are beneficial effects of CAMs and conventional drug combinations, there are some herb–drug interactions that may result in toxicity in certain cases such as silymarin plus indinavir combination in AIDS patients as reported by DiCenzo et al.181

ENDNOTES 1. As an initial therapy of ALD, abstinence from alcohol accompanied with basic lifestyle modifications is appropriate. 2. When the injury becomes decompensated, pharmacological therapy should be accompanied to reverse the more severe stages of ALD. 3. The available synthetic drugs to treat ALD cause further damage to the liver, so increasing attention has been paid to herbal medicines as a newly emerging treatment strategy for ALD. 4. Combination of pharmaceutical drugs with naturally occurring agents may offer an optimal management for liver disease.

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30  SECTION | I  Overview of Liver Health

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