INDEX

Turmeric (Curcuma longa 2)

Indications

Used for a wide variety of liver and gallbladder disorders, including jaundice, infective hepatitis, Gilbert’s disease, liver cirrhosis, fatty liver, liver enlargement, liver cancer, and gallbladder disease. See Curcuma monograph 1 for pain and inflammation indications.

Mechanism of Action

Curcumin, a bright yellow flavonoid in turmeric, is a powerful antioxidant credited with anticancer effects. It has been the subject of >5000 scientific and clinical studies over the last decade.1,2 The group of compounds related to curcumin in turmeric is referred to as curcuminoids and include demethoxycurcumin and bisdemethoxycurcumin, both less abundant and less potent antioxidants than curcumin itself. Curcumin’s major metabolite, tetrahydro-curcumin, is a less potent antioxidant than curcumin itself in many arenas, but it may be superior to curcumin in promoting liver glutathione and hepatoprotection.3

Research has also investigated bisabolane-type sesquiterpenes and saikosaponins in turmeric, compounds that are reported to have antifibrotic effects on the liver. Additional active molecules in turmeric include essential oils, a group of aromatic sesquiterpenes compounds including elemene, turmerin, turmerone, furanodiene, curdione, bisacurone, cyclocurcumin, calebin A, and germacrone.1 Elemene is an approved anticancer agent in China shown to retard cell cycle arrest, induce of apoptosis, and inhibit metastasis and tissue invasion.4,5

Antioxidant and Hepatoprotective Mechanisms

Turmeric has numerous hepatoprotective and chemopreventative mechanisms of action including the modulation of signal transduction cascades and effects on gene expression, especially antioxidant and immune-modulating proteins. The constituent curcumin increases the expression of AMP-activated protein kinase and peroxisome proliferator-activated receptor-γ and diminishes nuclear factor-κB protein in diabetic mice. It reduces nitrosative stress6 and promotes catalase, glutathione S-transferase, glutathione reductase, and glutathione peroxidase and levels of reduced glutathione as well as superoxide dismutase,7 all of which elevate antioxidant capacity and decrease lipid peroxidation.8 Turmeric also has beneficial effects on modulating a variety of enzyme systems including the aldo-keto reductase family, serine/threonine-protein kinase, protein kinase C, matrix metalloproteinase, cyclooxygenase, heme-oxygenase, and epidermal growth factor receptor,9,10,11,12 thereby protecting against the pathogenesis of fatty liver and fibrotic changes.13 Animal models of diabetes suggest that turmeric may have hepatoprotective effects because of increased antioxidant protection in the liver14 as well as direct hypoglycemic effects.15

Antihepatitis Virus Mechanisms

Turmeric is active against hepatitis viruses via enhancing the synthesis and levels of hepatocellular proteins and via inhibiting viral replication.16,17,18,19 Turmeric inhibits hepatitis B virus (HBV) via enhancing the cellular accumulation of p53 protein, activating the transcription of the p53 gene, and increasing the stability of p53 protein.17 Protein X in HBV activates and up-regulates several cellular signaling pathways including “Wnt” and β-catenin, which contribute to HBV-associated neoplasia and the initiation of hepatocellular carcinoma. Curcumin and quercetin inhibit Wnt; thus, the downstream target β-catenin is not displaced, and one cascade of malignant transformation is prevented.20

Hepatitis C virus (HCV) affects approximately 130–170 million people worldwide, contributing to chronic hepatitis, cirrhosis, and hepatocellular carcinoma. Curcumin has been shown to inhibit cellular entry of all major HCV genotypes.21 Membrane fluidity experiments indicate that curcumin affects the fluidity of the hepatitis viral envelope, resulting in impairment of viral binding and fusion. Curcumin has also been found to inhibit cell-to-cell transmission, to be effective in combination with other antiviral agents, and boost the activity of these agents.21 HCV’s core protein interferes with curcumin’s ability to induce apoptosis in infected cells; therefore, its primary benefit against hepatitis is to reduce viral entry into uninfected cells.22

Bile Flow Mechanisms

Turmeric at a dose of 200 mg/kg/day may exert a mild cholestatic and antispasmodic action on the bile ducts via effects on K(+)-induced contraction at L-type calcium channels.23 Increasing biliary flow may reduce liver congestion and contribute to the traditional reputation of using turmeric for bladder disease. Curcuminoids at the doses of 40 or 80 mg/kg body weight in endotoxemic mice significantly reduced swelling in endothelial cells from exposure to hepatotoxins, improved sinusoid flow, and suppressed hepatic microvascular inflammation.24 A dose of 20 mg of curcumin has a cholagogue effect, increasing bile flow by 29% within 2 hours of ingestion. One randomized controlled trial (RCT) reported that a 40-mg dose of curcumin increased bile output by 50% in healthy volunteers.25

Protection against Advanced Glycation End Products, Fibrosis, and Steatohepatitis

Chronic inflammation in the liver can lead to fibrotic and cirrhotic changes and loss of liver function as healthy hepatic stellate cells undergo transformation into fibroblast-like cells. If and when the irritating influences are removed, the transformed stellate cells often revert back to a normal state as the liver recovers. Turmeric, and the curcumin it contains, have been shown to similarly help the inflamed liver recover normal hepatic stellate cell status.26,27

Nonalcoholic steatohepatitis is a major risk factor for hepatic fibrogenesis and is often associated with hyperlipidemia and hyperglycemia. Hyperglycemia induces nonenzymatic glycation of proteins, yielding advanced glycation end products (AGEs) that adversely affect cytoplasmic membrane receptors. Activation of some AGE receptors is associated with increased oxidative stress and inflammation, whereas activation of other types promotes detoxification and clearance of AGEs. Activation of AGE receptors in the liver promotes the proliferation of hepatic stellate cells, contributing to the pathogenesis of hepatic fibrosis. Curcumin regulates the different types of AGE receptors, interrupting leptin signaling that, in turn, decreases hepatic stellate cell activation.28

Protection against Hepatocellular Carcinoma Pathogenesis

Hepatocellular carcinoma (HCC) evolves in a hypoxic microenvironment and milieu of oxidative stress and inflammation that curcumin may help reverse.29 Researchers have identified a protein called hypoxia-inducible factor-1α that is associated with cancer cell proliferation, migration, and invasiveness that is suppressed by curcumin.30,31 Chemopreventative effects that induce apoptosis and reduce proliferation of hepatoma cells involve curcumin’s ability to arrest cell proliferation, prevent axin recruitment to the cell membrane, β-catenin accumulation in the nucleus, and repress target transcription gene activation.32,33,34 Curcumin is shown to protect animals from T-cell–mediated hepatitis as evidenced by decreasing elevated serum alanine transaminase (ALT), associated with histological findings of reduced hepatic necrosis, apoptosis, and mortality. Turmeric protects the liver by reducing oxidative stress and preventing the activation of proinflammatory cytokines, including tumor necrosis factor-α and interferon-γ,35 and dose dependently inducing heme oxygenase activity and inhibiting HCV protein expression,36 all of which may deter carcinoma pathogenesis. Bete-elemene can induce apoptosis in HCC.37

See Separate Monograph—Curcuma for Pain and Inflammation

Evidence-Based Research

Turmeric has been extensively studied not only or its beneficial effects on the liver but also for its extensive systemic immune and antioxidant effects.38 Turmeric is presently being studied as an alternative therapy for patients with liver and digestive diseases.39

Turmeric has been shown to protect the liver from hepatotoxins including carbon tetrachloride,40,41 benzene,42 aflatoxins,43,44 alcohol, acetominophen toxicity,45,46 iron overload, biliary stasis, carbon tetrachloride,47 doxorubicin (Adriamycin),48 cisplatin,11 concanavalin A31,35 hepatitis virus,17,49 high-fat diets,13 and other agents that damage the liver.46 Because many of these substances are known to induce liver cancer, curcumin is also reported to decrease cancer initiation through antimicrobial, anti-inflammatory, antioxidant, antiviral, and antimetastatic actions.31,50 Turmeric extract may improve liver detoxification functions, even in acute inflammatory states that otherwise impair or delay excretion of wastes and toxins.51 An investigated of the effects of 3 g/day of fermented turmeric powder on elevated ALT compared with placebo for 12 weeks in an RCT reported the levels to be significantly reduced compared with the control.52

HCC, the most common liver cancer, is also one of the most lethal, having worldwide prevalence. Although most HCC cases are reported in the developing countries of Asia and Africa, there has been an alarming increase in HCC cases in Western Europe and the United States.29 Unlike other forms of hepatocellular carcinoma, HCC induced by HBV infection has a poor prognosis when treated conventionally.49 Turmeric has shown chemopreventative effects in an HBV-related in vitro model of HCC.49 In addition to viral hepatitis, chronic liver diseases, alcoholism, and dietary carcinogens, such as aflatoxins and nitrosamines that may contribute to HCC, all may be attenuated by turmeric. One animal study showed turmeric to help regenerate damaged liver tissue, deter hepatitis virus gene expression, and prevent pathological progression to hepatocellular carcinoma.49 Curcumin has shown activity against several important human viruses including the influenza virus, adenovirus, coxsackie virus, human immunodeficiency virus, and hepatitis viruses.19

Curcumin is hydrophobic and has poor bioavailability because of its rapid metabolism in the liver and intestinal wall. Many researchers are investigating nanospheres and molecular combinations to enhance curcumin’s solubility and absorption.15,53,54,55,56 Because piperine, an alkaloid from black pepper (Piper nigrum), inhibits hepatic and intestinal glucuronidation, it enhances the assimilation of many important nutrients. Piperine at a dose of 20 mg may increase the absorption of curcumin as much as 2000-fold.57 Taking curcumin with fat, phospholipids, or in a lipid-processed nutraceutical form, may also enhance its bioavailability.

One human trial evaluated blood and salivary parameters of healthy volunteers taking “lipidated” curcumin at a dose of 80 mg/day, compared with a control group taking placebo. After 4 weeks, those receiving the turmeric had significantly lower plasma triglycerides, β-amyloid, and ALT and higher plasma catalase and nitric oxide levels compared with controls.58

Safety in Pregnancy and Breastfeeding

There are no published studies specifically investigating turmeric in pregnancy or lactation. However, curry blends containing turmeric have been consumed during pregnancy for thousands of years without reports of adverse effects. Many nursing women find that eating garlic, onions, curry, and other spices can be passed through the breast milk and give nursing infants gas or colic symptoms.

General Safety

Clinical trials using turmeric for osteoarthritis59 and depression60 have reported excellent tolerability without significant adverse events. One clinical trial dosing 3 g/day of fermented turmeric powder reported no adverse events over the 12-week trial and no adverse effects on blood glucose, total protein, albumin, blood urea nitrogen, or creatinine levels.52

A standard battery of in vitro genotoxicity, bacterial reverse mutation, chromosome aberration, and micronucleus tests revealed no concerns. In an acute oral toxicity study, turmeric was found to be safe up to 5 g/kg body weight in Wistar rats.61

Turmeric affects cytochrome p450 and P3D662 enzymes, systems responsible for metabolizing many drugs and affecting their bioavailability. Animal studies have shown turmeric magnifies the inhibitory effects of paclitaxel and cisplatin on some cytochrome pathways, an effect that is mentioned as a concern for drug–herb interactions63 but that may also allow for a reduced dose of these chemotherapeutic drugs. Rat studies have shown reduced expression of P-glycoprotein and CYP1A1, -1A2, and -2B1.63 Human studies have shown activation of CYP3A4 and P-glycoprotein.62

At supraphysiological doses, Curcuma longa treatment was shown to cause reversible suppression of spermatogenesis and fertility in male mice; however, no such studies have been undertaken in humans, nor have anecdotal findings been reported in clinical trials on turmeric.64

Dosage

Traditional dosing of crude turmeric powder was in the range of 1–3 g daily, or the powder was prepared in various teas, and formulas.

Ten grams of fermented powder or several grams of whole turmeric, up to 18 g/day, is common in traditional diets. Several grams of curcumin standardized extract may be taken daily.

Safe at high doses, as it consumed in curry-based foods.

Safe at high doses.

Traditional Uses

Curcuma longa is a common culinary spice in East India, going by the name turmeric, and is included in curry blends. Turmeric has been widely used in the traditional Chinese Pharmacopoeia65 and also is traditionally used as a spice, natural food coloring, textile dye, antiaging and facial cosmetic ingredient, and herbal medicine. Traditional medicinal indications include biliary disorders; anorexia; cough; rheumatism; cancer; sinusitis; liver and bladder disorders such as gallstones, jaundice, hepatitis, and liver cancer; hyperglycemia; obesity; diabetes; diabetes-related liver disorders; nerve pain and disease; kidney diseases; vascular diseases; bacterial and fungal infections; skin inflammation and disease; digestive disorders; pancreatic disorders; and mood disorders, among a long list of other medical disorders.

References

1

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