- Email: [email protected]
The Role of Curcumin in Gastrointestinal and Liver Diseases
CHAPTER
38
The Role of Curcumin in Gastrointestinal and Liver Diseases R.A. Hegazi, A. Seth Abbott Nutrition, Columbus, OH, USA
1. EFFECTS OF CURCUMIN ON GASTROINTESTINAL DISEASES On the basis of the teachings of the ancient medical textbook, the ayurveda, written in the fourth century BC, haldee or turmeric, has been used as a cure for almost all ailments, from trauma and infections to cancer since it was labeled the spice of life. Turmeric is derived from the rhizomes, the underground stems of Curcuma longa, which belongs to the family Zingibergaceae. Curcumin and its derivatives demethoxycurcumin and bisdemethoxycurcumin are collectively known as curcuminoids (Figure 38.1). Yellow color of turmeric is due to these phenolic compounds. Curcumin is the most active principal curcuminoid in turmeric. In agreement with ayurvedic teachings, recent studies have shown that curcumin exerts well-described pleiotropic biological effects. So far, more than 5300 studies have been published in medical journals regarding the biologically active effects of turmeric and curcumin, most of them are in the past decade. At present, researchers are actively engaged in conducting clinical trials in human subjects, with 67 trials already listed on the ClinicalTrials.gov website as of 10 February 2012. Among the biological effects of curcumin are its anti-inflammatory, antioxidant, and antitumor effects. For instance, curcumin has been shown to exert powerful antiinflammatory effects via inhibition of key proinflammatory signaling molecules and mediators. Probably, the most important effect of curcumin is its ability to inhibit the activation of the potent signal transduction molecule, NFk-b. Consistently, curcumin has been shown to inhibit the secretion of key proinflammatory cytokines, especially IL-1b, IL-8, and tumor necrosis factor (TNF). Curcumin inhibits IL-2 synthesis as well as IL-2 and mitogen activation of human leukocytes mediated by NFk-b inhibition. Several in vitro and in vivo studies support this anti-inflammatory effect (Jurenka, 2009). Other unique properties of curcumin are its antioxidant and antitumor effects. Moreover, curcumin modulates gastrointestinal (GI) motility. For instance, Shimouchi et al. (2009) recruited eight healthy subjects to ingest curry and rice with or without turmeric after an overnight fast. The study showed that turmeric significantly shortened the small bowel transit time and increased the area under the curve for breath hydrogen, when measured Bioactive Food as Dietary Interventions for Liver and Gastrointestinal Disease http://dx.doi.org/10.1016/B978-0-12-397154-8.00022-1
#
2013 Elsevier Inc. All rights reserved.
585
586
R.A. Hegazi and A. Seth
CH3O HO
OCH3 CH CHCOCH2COCH CH
Curcumin
OH OCH3
Demethoxycurcumin HO
CH CHCOCH2COCH
HO
CH
CH CHCOCH2COCH
OH
CH
OH
Bisdemethoxycurcumin
Figure 38.1 Biologically active curcuminoids.
every 15 min for 6 h, suggesting that turmeric increased bowel motility and colonic carbohydrate fermentation. Because of the aforementioned physiological effects, coupled with its low bioavailability, curcumin had been studied as a potential adjuvant therapeutic agent in a variety of GI diseases. Curcumin conjugates to form curcumin glucuronides and sulfates or is alternatively reduced to hexahydrocurcumin. It is these metabolites that are normally detected in the serum, but they are not as effective as the parent compound. Curcumin levels peak 1–2 h after ingestion and are undetectable after 12 h. Curcumin has been tested as a pharmaconutrient in various GI diseases with doses varying from 20 to 12 000 mg and with very minimal side effects. This chapter highlights these studies shedding light on its potential mechanism of action. Mechanistically, GI diseases could be classified into four major categories: (a) Functional intestinal disorders (b) Inflammatory bowel diseases (c) Liver diseases (d) GI and liver tumors.
2. CURCUMIN AND FUNCTIONAL BOWEL DISORDERS 2.1 Irritable Bowel Syndrome Irritable bowel syndrome (IBS) is a functional disorder of the bowel characterized by alteration of bowel habits and abdominal pain in the absence of an organic pathology. The IBS is a prevalent disease; population-based studies have estimated the prevalence of IBS to be 10–20% (31–62 million subjects in the United States). The IBS is clinically diagnosed by the presence of recurrent abdominal pain at least 3 days per month, during the previous 3 months associated with a change in stool frequency or form and relief of abdominal pain and discomfort on defecation. On the basis of the presenting symptoms, the IBS could be IBS with diarrhea, IBS with constipation, or IBS with alternating
The Role of Curcumin in Gastrointestinal and Liver Diseases
constipation and diarrhea. Medical treatment is symptomatic and relies on analgesics, antidiarrheals/laxatives, antispasmodics, and antidepressants to relieve the chronic stress associated with this condition. Given its pleiotropic GI properties, the use of turmeric extract and its active ingredient, curcumin, in patients with IBS was investigated. Bundy et al. (2004) carried out a large study, where 207 subjects were randomized to either a lower dose (72 mg of turmeric extract per day) or a higher dose group (144 mg of turmeric extract per day). The treatment continued for 8 weeks. IBS prevalence between baseline and after treatment decreased by 53% and 60% in the lower and the higher dose groups, respectively (p < 0.001). Abdominal pain was also reduced by 22% and 25%, respectively. The quality of life score also improved significantly with approximately two-third subjects reporting an improvement in symptoms with a favorable shift in the bowel pattern.
2.2 Dyspepsia Dyspepsia or indigestion is a prevalent functional disorder of the GI system. The prevalence of dyspepsia varies between 25% and 40% (approximately 77.5–124 million people in the United States). In some cases, it may also be a sign of gastric inflammation or peptic ulcer disease (10%) or gastroesophageal reflux disease (15%). Among its other common causes are medications or Helicobacter pylori infection. In addition to treating the etiological disease, medical treatment is usually symptomatic with antacids, proton pump inhibitors, lifestyle modifications, and prokinetic agents. The potential effectiveness of curcumin in patients with dyspepsia has been investigated. Di Mario et al. (2007) carried out a clinical study using low-dose curcumin in combination with other agents. They enrolled 25 H. pylori positive subjects with functional dyspepsia. This was a 2-month long clinical trial, with a 7-day course of curcumin 30 mg BID, lactoferrin 100 mg BID, N-acetylcysteine 100 mg BID, and pantoprazole 20 mg BID. A significant decrease in dyspeptic symptoms was observed at the conclusion of the 2-month long clinical trial ( p ¼ 0.001). Serum pepsinogens were also reduced. H. pylori eradication was achieved in only three patients (12%) with this combination therapy. Another study of curcumin in dyspepsia was carried out by Thamlikitkul et al. (1989). In a multicenter, double-blind, randomized, placebo-controlled, threeperiod crossover clinical trial, they enrolled 116 subjects with acid dyspepsia, flatulent dyspepsia, and atonic dyspepsia. The subjects were randomized to receive two capsules with 500 mg of turmeric, an active control (over the counter (OTC) dyspepsia drug) or placebo capsules four times a day for 7 days. Symptoms of dyspepsia were significantly relieved in 53% of subjects in the placebo group, 83% in the active control group on an OTC drug for dyspepsia, and 87% in the group taking turmeric capsules. These two studies supported the potential role that curcumin could play in alleviating upper GI symptoms associated with dyspepsia. It remains to be determined the exact
587
588
R.A. Hegazi and A. Seth
mechanism of these effects. The inherent anti-inflammatory and promotility effects of curcumin could explain these effects and need further examination.
2.3 Biliary Dyskinesia Biliary dyskinesia (BD), also known as Sphincter of Oddi dyskinesia, is possibly caused by sphincteric valvular dysfunction of the sphincter of Oddi or a dysfunction in the muscles of the gall bladder. It is a gall bladder motility disorder that manifest as a recurrent right upper quadrant pain in the absence of gall stones. The true incidence of BD is not known. However, it is seen in 10–15% of patients undergoing laparoscopic cholecystectomy. Niederau and Go¨pfert (1999) carried out a double-blind, placebo-controlled, multicenter trial of a turmeric root extract and Schollkraut in 76 patients with BD. After 3 weeks of treatment, study subjects experienced considerable reduction in abdominal pain when compared to placebo. The reduction of other complaints (feeling of fullness, food intolerance, nausea, vomiting, and meteorism) was similar in patients who received study group versus placebo. These beneficial effects of turmeric in patients with BD could be explained by the prokinetic effects of curcumin on gall bladder muscle. For instance, Rasyid and Lelo (1999) showed that 20 mg of curcumin, given orally, could exert a 29% reduction in the gall bladder volume as measured by 2-h serial ultrasound. Consistently, in a randomized, single-blind, three-period crossover study on 12 healthy volunteers with curcumin, Rasyid et al. (2002) demonstrated that a dose of 40 mg could exert a 51.1 8.1% reduction in gall bladder volume. Interestingly, a dose of 80 mg of curcumin could exert even a greater percentage reduction in gall bladder volume of 72.2 8.2%. Collectively, it could be concluded that curcumin exerts a dose-dependent effect on gall bladder motility that could benefit patients with BD. This very intriguing effect of curcumin could be also of benefit in prevention of gall bladder stones and other BD. These interesting hypotheses need to be further elucidated in clinical studies.
2.4 Human Immunodeficiency Virus Disease-Associated Diarrhea Preclinical and in vitro studies suggest that curcumin could exert anti-infective effects. This observation was tested in a clinical study by Conteas et al. (2009) on eight subjects with human immunodeficiency virus-associated diarrhea. Patients were orally administered 1862 mg of curcumin daily for 41 weeks. Interestingly, all subjects had rapid and complete resolution of diarrhea and normalization of bowel movements within a period of 13 9.3 days. Mean number of bowel movements dropped from 7.0 3.6 to 1.7 0.5. Seven of eight patients actually gained weight on curcumin (average weight gain 10.8 8.9 lbs). Five of six subjects experienced a resolution of abdominal pain and bloating on curcumin. Although the sample size was small, the fact that all the subjects had rapid and complete resolution of diarrhea within such a short time is intriguing and warrants further studies of curcumin in other types of diarrhea.
The Role of Curcumin in Gastrointestinal and Liver Diseases
3. INFLAMMATORY GI DISEASES 3.1 Inflammatory Bowel Disease Inflammatory bowel disease (IBD) comprises Crohn’s disease (CD) and ulcerative colitis (UC). It is an autoimmune disease characterized by remitting and relapsing cycles of chronic intestinal inflammation. The exact disease etiology is unknown, but it may be related to dysregulated immune responses to intestinal luminal antigens in genetically susceptible individuals. Environmental, dietary, and microbial factors play a major role in initiating and perpetuating the extent of chronic intestinal inflammation. Despite several animal studies proving the effectiveness of curcumin in ameliorating chronic intestinal inflammation in animal models of IBD (Jurenka, 2009), clinical studies are few. 3.1.1 Crohn's disease The CD is a chronic inflammatory bowel disease with a prevalence rate of approximately 200 cases per 100 000 population (600 000 cases in the United States). It is an idiopathic, chronic, transmural inflammatory process of the bowel that can affect any part of the GI tract from the mouth to the anus. Of all cases of CD, about 35% involve the ileum, about 45% involve the ileum and colon, and about 20% involve the colon alone. The perianal region is also affected in one-quarter to one-third of cases. Pathologically, noncaseating granulomas formation is pathognomonic of CD although its absence does not exclude the diagnosis. The granulomas extend through all layers of the intestinal wall and into the mesentery and the regional lymph nodes. Clinically, the main presenting symptoms are abdominal pain, diarrhea, and weight loss. Medical therapies include steroids, antiinflammatory nonsteroidal-like sulfasalazine, and mesalamine. Cytokines play a major role in the pathogenesis of the disease. The CD is believed to be the result of an imbalance between proinflammatory and anti-inflammatory cytokines. TNFa is present in excess in the mucosa of patients with CD and increases in TNFa are associated with the release of other proinflammatory cytokines, including IL-1, IL-6, IL-8, and IL-12. TNFa actions also include enhancement of leukocyte migration by increasing endothelial layer permeability and expression of adhesion molecules by endothelial cells and leukocytes, activation of neutrophil, and eosinophil functional activity, as well as tissue-degrading enzymes produced by synoviocytes and/or chondrocytes. Consistently, TNF antagonists have been used in the medical therapy of the disease. Given the anti-inflammatory effects and low bioavailability of curcumin, its antiinflammatory effects in patients with CD were investigated. Holt et al. (2005) recruited five subjects with active CD proctitis in an open label pilot study. Patients were to receive oral curcumin at a dose of 550 mg of curcumin twice a day for 1 month, and then a dose of 550 mg three times a day for another month. Crohn’s disease activity index (CDAI), markers of inflammation (C-reactive protein (CRP) and erythrocyte sedimentation rate), complete blood counts, liver and renal function studies, and endoscopic evaluation of
589
590
R.A. Hegazi and A. Seth
colitis were obtained in all patients. All five subjects with Crohn’s proctitis improved as evidenced by improvement in their global score (p < 0.02). Two subjects eliminated their prestudy anti-inflammatory medications (5-ASA), two subjects reduced their medications (including termination of the prednisone therapy in one subject), and one continued taking 5-ASA suppositories. The CDAI scores for all completed subjects reduced with a mean reduction of 55 points; markers of inflammation including sedimentation rate and CRP were also reduced. Of the five subjects, four successfully completed and one discontinued because of lack of treatment effect, with a slight worsening of fistula output. There were no changes in the liver or renal function tests indicating high-safety profile of curcumin. In another small study, Slonim et al. (2009) also recruited six subjects with moderately severe active CD in a prospective study. Patients were restricted to an elimination diet where dairy products, certain grains, and carrageenan were excluded. A combination therapy with nutraceuticals containing curcumin, Boswellia serrata, fish peptides, bovine colostrum, and multivitamins was given daily. In addition, a probiotic Lactobacillus GG was given twice weekly and recombinant growth hormone daily to facilitate adequate growth. Within 2 months of starting combination therapy, all six patients went into remission, with discontinuation of all pharmacological drugs. Three patients have remained in sustained remission for 4–8 years. One patient with very severe CD had recurrence of symptoms after being in complete remission for 18 months, one patient was in remission for 3 years but symptoms recurred when she became less compliant to the combination therapy, and one patient remained in remission after 6 months. Although curcumin was given as part of a combination regimen that the exclusive effects of curcumin on mucosal inflammation and healing not detected, the results with this safe nonpharmacological approach are certainly encouraging. 3.1.2 Ulcerative colitis Akin to CD, UC is a chronic intestinal inflammation, which is characterized by the presence of ulcers in the mucosa of the colon and rectum. The ulceration and inflammation can cause bloody or mucous diarrhea accompanied by abdominal pain. The disease prevalence in United States is approximately 690 000 subjects. There is a risk of development of colon cancer, which varies between 5% and 30% depending on the length of bowel involvement with UC. Akin to patients with CD, patients with UC are usually treated with aminosalicylates, corticosteroids, and immune modulators. The anti-inflammatory effects of curcumin had been tested in patients with UC. For instance, Hanai et al. (2006) studied the effectiveness of curcumin in patients with quiescent UC. In a multicenter randomized control trial, 45 patients were orally given curcumin (2 g day1 in two divided doses) plus sulfasalazine or mesalamine and 44 patients were given placebo plus sulfasalazine or mesalamine. Both groups were prospectively followed for 6 months. Patients were evaluated for both clinical
The Role of Curcumin in Gastrointestinal and Liver Diseases
(clinical activity index) and endoscopic (colitis score) response at the entry, every 2 months, and at the end of the study. Of 43 patients in the curcumin group, only two patients relapsed during the study period, while 8 of 39 patients in the placebo group relapsed. On the basis of intention to treat analysis, this difference in recurrence rates between the two groups was statistically significant. Importantly, patients in the curcumin group had less clinical and endoscopic index scores than the placebo group ( p ¼ 0.038 and 0.0001, respectively). These encouraging results were also associated with a favorable side effects profile in the curcumin group. Mild and transient side effects were experienced in 7 of 89 patients and were observed during curcumin maintenance therapy. These side effects were mainly the GI symptoms such as bloating, transient diarrhea, and transient hypertension. The authors extended their followup of the study patients to another 6 months after discontinuation of curcumin, where patients continued to receive sulfasalazine or mesalamine. Interestingly, relapse rate was not different between the two groups since eight patients in the curcumin group and six in the placebo group relapsed suggesting the temporary effects of curcumin suppressing intestinal inflammation.
4. LIVER DISEASES 4.1 Drug-Induced Liver Toxicity Drug-induced hepatotoxicity may range from asymptomatic elevation of the serum transaminases, elevation of bilirubin to frank hepatic failure, requiring liver transplantation. The incidence of hepatotoxicity depends on the age and gender of the patients and the number of drugs involved. Older patients, female sex, and presence of concomitant diseases, such as immune deficiency states, all put the patient at higher risk. It is estimated that 10–20% of patients may develop severe hepatitis, if left unmonitored and if the drug therapy is still continued after a threefold rise in serum transaminase levels. Mortality rate may exceed 50% if liver transplantation is not carried out in time. Adhvaryu et al. (2008) published a study in patients with active tuberculosis receiving multiple antimycobacterial drug therapy. They screened a total of 578 subjects and selected 528 with active tuberculosis for the 6-month long clinical trial. Selected subjects were randomized to receive antituberculous chemotherapy with isoniazid, rifampicin, pyrazinamide, and ethambutol (n ¼ 200) or these drugs plus 1000 mg of curcumin and 1000 mg of Tinospora cordifolia in two daily divided doses (n ¼ 328). Of those enrolled in the study, 192 subjects completed the study in the antituberculosis arm and 316 completed in the antituberculosis treatment plus curcumin and Tinospora arm. The study showed that the incidence and severity of hepatotoxicity was significantly lower in the curcumin group as compared to the control drug group (14.1% vs. 0.6%, respectively, p ¼ 0.0001). The study concluded that curcumin significantly reduced the incidence and severity of drug-induced hepatotoxicity and improved the disease outcome.
591
592
R.A. Hegazi and A. Seth
4.2 Nonalcoholic Fatty Liver Disease Fatty liver is another common liver disease for which the therapeutic use of curcumin has been investigated. Nonalcoholic fatty liver disease (NAFLD) results from an abnormal accumulation of fatty acids in the liver (steatosis) in the absence of any alcohol abuse. The exact pathogenesis of NAFLD is unknown, but it is believed that disrupted insulin signaling or disrupted leptin signaling contribute to the activation of the hepatic stellate cells (HSCs), which secrete a plethora of proinflammatory cytokines, resulting in inflammation of the liver and a phenomenon called nonalcoholic steatohepatitis (NASH). Besides inflammation, oxidative stress is also a key factor in the progression to NASH, and antioxidant vitamins such as vitamin E have been used with promising results. HSCs, major effectors of collagen production, play a major role in NASH-associated liver fibrogenesis. NASH incidence and importance are rising because of increasing incidence of its main contributory causes, metabolic syndrome, diabetes, hyperlipidemia, and obesity. NASH accounts for about 10% of newly diagnosed cases of chronic liver disease and ranks as one of the leading causes of cirrhosis in the United States. Patients with NASH may be identified as having NASH only on routine blood tests because of elevated liver enzymes. Others may present with fatigue, anorexia, nausea, abdominal pain, or hepatomegaly. The primary treatment modalities for NASH include a low-calorie, low-fat, low-carbohydrate diet with exercise and weight loss. Currently, many pharmaceutical agents, including antidiabetic agents and antihyperlipidemic agents, are being investigated for the treatment of NASH. As insulin resistance is almost a universal finding in patients with NASH, insulin-sensitizing agents such as metformin or thiazolidinediones or IkappaB kinase inhibitors have been investigated in large clinical trials of NASH (Van Wagner and Rinella, 2011). Similarly, owing to its anti-inflammatory and antioxidant properties, curcumin has been investigated in animal models of NAFLD and NASH to dampen the inflammatory and oxidative process associated with NASH (Leclercq et al., 2004; Ramirez-Tortosa et al., 2009; Vizzutti et al., 2010). Consistently, Lin et al. (2009) conducted a study to investigate the role of curcumin in insulin-induced HSC activation. They reported that curcumin dose dependently suppressed insulin-induced HSC activation by suppressing type 1 collagen and other genes involved in HSC activation. Curcumin also interrupted insulin signaling in HSCs by suppressing the insulin receptor (insR) gene expression. Curcumin also reduced the phosphorylation level of the insR. Curcumin also induced the gene expression of glutamate-cysteine ligase, which led to the de novo synthesis of the antioxidant glutathione. This would translate into a reduction of the insulin-induced oxidative stress in the HSCs. This study demonstrates that the detrimental effects of the hyperinsulinemia associated with type II diabetes on liver fibrinogenesis and cirrhosis could possibly be reduced by curcumin. Tang et al. (2009) studied the effect of curcumin on leptin signaling. The authors found that curcumin eliminates this stimulatory effect of leptin on HSCs by decreasing the phosphorylation levels of the leptin receptor.
The Role of Curcumin in Gastrointestinal and Liver Diseases
Collectively, it inhibits leptin-stimulated HSC activation and activates endogenous PPAR gamma expression and stimulates the de novo synthesis of the antioxidant glutathione synthesis thereby reducing the oxidative stress on the hepatic cells. The potential therapeutic effects in patients with NAFLD and NASH should be further investigated.
5. GI AND LIVER TUMORS Curcumin exerts antitumor effects by inhibiting key pathways in tumor growth. For these effects, it has been studied in different GI and liver cancers.
5.1 Pancreatic Cancer Pancreatic cancer is a grave disease. By the time it is diagnosed, it has already spread to distant locations in more than 50% of cases and regionally in more than 25% of cases. That may be why the 1-year survival rate is only 24% and the 5-year survival rate is just 5%. Most of the cancers occur in the exocrine portion and most of them are found to be located in the head of the pancreas. One of the precursors of pancreatic cancer is chronic pancreatitis. Patients may initially present with loss of appetite, loss of weight, fatigue, and mild discomfort in the abdomen or back. Patients may also present with painless obstructive jaundice and pruritis. Curcumin has been clinically tested in patients with pancreatic cancer. Dhillon et al. (2008) enrolled 25 subjects with advanced pancreatic cancer to receive 8000 mg day1 of curcumin till disease progression and their disease was restaged every 2 months. One subject had stable disease for more than 18 months, and one had marked regression in tumor size transiently. Curcumin downregulated the expression of NFk-b and cyclooxygenase-2. Similarly, Kanai et al. (2010) enrolled 21 subjects who were on Gemcitabine, a chemotherapeutic agent, along with 8000 mg day1 of curcumin. No dose-limiting toxicities were observed. Median compliance rate was 100%. Median survival time was 161 days (95% CI: 109–223 days) and 1-year survival rate was 19% (4.4–41.4%). These observations were consistent with those of Bisht et al. (2010) in athymic mice with pancreatic cancer. Mice were administered a polymeric nanoparticle-encapsulated curcumin. The study showed that curcumin significantly inhibited the growth of the primary tumor. Curcumin with Gemcitabine resulted in enhanced tumor growth inhibition and abrogated systemic metastases. Combination therapy also reduced the activation of NFk-b, matrix metaloproteinase-9, and cyclin D1. On the basis of the results of these studies, it appears that curcumin can be offered as an adjunct therapy to patients at high risk of pancreatic cancer such as patients with chronic pancreatitis especially considering that it has no adverse effects even at 8000 mg. Potential benefits include its ability to ameliorate chronic pancreatic inflammation-associated cachexia and to possibly reduce the rate of progression to pancreatic cancer. These hypotheses warrant further investigation.
593
594
R.A. Hegazi and A. Seth
5.2 Primary Liver Cancer (Hepatocellular Carcinoma) Approximately 80% of newly diagnosed patients are found to have preexisting liver cirrhosis. The most common causes of liver cirrhosis are alcoholism, hepatitis B, and hepatitis C infection. Chronic hepatitis-associated liver cancer may be mediated by chronic inflammation and the incorporation of the viral genome into the host DNA. Primary liver cancer is generally seen 20–30 years following the diagnosis of liver cirrhosis. Most of the patients only survive 6–20 months after the diagnosis of liver cancer and die from either liver failure or tumor progression. This cancer is usually multifocal in the liver, but metastasis to the lungs, portal vein, periportal nodes, brain, or bones can occur late in the disease. Cheng et al. (2001) conducted a study using curcuma aromatica oil in 64 subjects with primary liver cancer. For comparison, they used an active control with standard anticancer agents. The median survival time in the curcuma oil group was more than the control group (10 vs. 6 months, respectively, p < 0.05). Consistently, 1-, 2-, and 3-year survival rate in the study group was more as compared to the control group (p < 0.05). Moreover, myelosuppression occurred less in the study group as compared to control (p < 0.01).
5.3 Colonic Tumors The effects of curcumin intake on markers of progression of colonic tumors were also investigated. For instance, in order to investigate whether curcumin could reduce the number and size of polyps in patients with familial adenomatous polyposis, five subjects with prior colectomy (four with retained rectum and one with an ileal anal pouch) received 480 mg of curcumin and 20 mg of quercetin three times daily orally for 6 months. Interestingly, the number of polyps decreased by 60.4% (p < 0.05) from the baseline. Moreover, size of polyps decreased by 50.9% (p < 0.05) from the baseline. These effects on the number and size of polyps were associated with excellent safety profile and minimal adverse effects (Cruz-Correa et al., 2006). Moreover, to test whether orally administered curcumin could reduce the levels of DNA adducts, the quantitative measure of the amount of cancerous tissue in patients with colorectal cancer, subjects with colorectal cancer ingested capsules containing 450, 1800, or 3600 mg of curcumin for 7 days. Biopsy of colorectal tissue and blood samples were obtained before and after the intake of curcumin. Curcumin sulfate and curcumin glucuronide were identified in the tissues indicating active intestinal intracellular transport and metabolism. DNA adduct levels were reduced from 4.8 2.9 adducts per 107 nucleotides to 2.0 1.8 adducts per 107 nucleotides (p < 0.05; Garcea et al., 2005). In conclusion, future research will better define the significant role of turmeric and its active component, curcumin, not only in maintaining intestinal health but also in ameliorating GI and liver diseases. For instance, the reported beneficial uses of these nutrients in GI disorders should be replicated in large clinical trials that take into consideration the
The Role of Curcumin in Gastrointestinal and Liver Diseases
different doses and forms of the plant derivative. Given its similar pharmacological properties and high-safety profile, there is a great unmet need for an effective nutritional product that could be used as an adjunct to medical therapeutics in the management and prevention of these disorders.
REFERENCES Adhvaryu, M.R., Reddy, N., Vakharia, B.C., 2008. Prevention of hepatotoxicity due to antituberculosis treatment: a novel integrative approach. World Journal of Gastroenterology 14 (30), 4753–4762. Bisht, S., Mizuma, M., Feldmann, G., et al., 2010. Systemic administration of polymeric nanoparticleencapsulated curcumin (NanoCurc) blocks tumor growth and metastases in preclinical models of pancreatic cancer. Molecular Cancer Therapeutics 9 (8), 2255–2264. Bundy, R., Walker, A.F., Middleton, R.W., Booth, J., 2004. Turmeric extract may improve irritable bowel syndrome symptomology in otherwise healthy adults: a pilot study. Journal of Alternative and Complementary Medicine 10 (6), 1015–1018. Cheng, A.L., Hsu, C.H., Lin, J.K., et al., 2001. Phase I clinical trial of curcumin, a chemopreventive agent, in patients with high-risk or pre-malignant lesions. Anticancer Research 21 (4B), 2895–2900. Conteas, C.N., Panossian, A.M., Tran, T.T., Singh, H.M., 2009. Treatment of HIV-associated diarrhea with curcumin. Digestive Diseases and Sciences 54 (10), 2188–2191. Cruz-Correa, M., Shoskes, D.A., Sanchez, P., et al., 2006. Combination treatment with curcumin and quercetin of adenomas in familial adenomatous polyposis. Clinical Gastroenterology and Hepatology 4 (8), 1035–1038. Dhillon, N., Aggarwal, B.B., Newman, R.A., et al., 2008. Phase II trial of curcumin in patients with advanced pancreatic cancer. Clinical Cancer Research 15, 4491–4499. Di Mario, F., Cavallaro, L.G., Nouvenne, A., et al., 2007. Curcumin-based 1-week triple therapy for eradication of Helicobacter pylori infection: something to learn from failure? Helicobacter 12 (3), 238–243. Garcea, G., Berry, D.P., Jones, D.J., et al., 2005. Consumption of the putative chemopreventive agent curcumin by cancer patients: assessment of curcumin levels in the colorectum and their pharmacodynamic consequences. Cancer Epidemiology, Biomarkers & Prevention 14 (1), 120–125. Hanai, H., Iida, T., Takeuchi, K., et al., 2006. Curcumin maintenance therapy for ulcerative colitis: randomized, multicenter, double-blind, placebo-controlled trial. Clinical Gastroenterology and Hepatology 4 (12), 1502–1506. Holt, P.R., Katz, S., Kirshoff, R., 2005. Curcumin therapy in inflammatory bowel disease: a pilot study. Digestive Diseases and Sciences 50 (11), 2191–2193. Jurenka, J.S., 2009. Anti-inflammatory properties of curcumin, a major constituent of Curcuma longa: a review of preclinical and clinical research. Alternative Medicine Review 14 (2), 141–153. Kanai, M., Yoshimura, K., Asada, M., et al., 2010. A phase I/II study of gemcitabine-based chemotherapy plus curcumin for patients with gemcitabine-resistant pancreatic cancer. Cancer Chemotherapy and Pharmacology 68 (1), 157–164. Leclercq, I.A., Farrell, G.C., Sempoux, C., dela Pen˜a, A., Horsmans, Y., 2004. Curcumin inhibits NF-kappaB activation and reduces the severity of experimental steatohepatitis in mice. Journal of Hepatology 41 (6), 926–934. Lin, J., Zheng, S., Chen, A., 2009. Curcumin attenuates the effects of insulin on stimulating hepatic stellate cell activation by interrupting insulin signaling and attenuating oxidative stress. Laboratory Investigation 89 (12), 1397–1409. Niederau, C., Go¨pfert, E., 1999. The effect of chelidonium- and turmeric root extract on upper abdominal pain due to functional disorders of the biliary system. Results from a placebo-controlled double-blind study. Medizinische Klinik (Munich, Germany) 94 (8), 425–430. Ramirez-Tortosa, M.C., Ramirez-Tortosa, C.L., Mesa, M.D., Granados, S., Gil, A., Quiles, J.L., 2009. Curcumin ameliorates rabbit’s steatohepatitis via respiratory chain, oxidative stress, and TNF-alpha. Free Radical Biology & Medicine 47 (7), 924–931.
595
596
R.A. Hegazi and A. Seth
Rasyid, A., Lelo, A., 1999. The effect of curcumin and placebo on human gall-bladder function: an ultrasound study. Alimentary Pharmacology and Therapeutics 13 (2), 245–249. Rasyid, A., Rahman, A.R., Jaalam, K., Lelo, A., 2002. Effect of different curcumin dosages on human gall bladder. Asia Pacific Journal of Clinical Nutrition 11 (4), 314–318. Shimouchi, A., Nose, K., Takaoka, M., Hayashi, H., Kondo, T., 2009. Effect of dietary turmeric on breath hydrogen. Digestive Diseases and Sciences 54 (8), 1725–1729. Slonim, A.E., Grovit, M., Bulone, L., 2009. Effect of exclusion diet with nutraceutical therapy in juvenile Crohn’s disease. Journal of the American College of Nutrition 28 (3), 277–285. Tang, Y., Zheng, S., Chen, A., 2009. Curcumin eliminates leptin’s effects on hepatic stellate cell activation via interrupting leptin signaling. Endocrinology 150 (7), 3011–3020. Thamlikitkul, V., Bunyapraphatsara, N., Dechatiwongse, T., et al., 1989. Randomized double blind study of Curcuma domestica Val. for dyspepsia. Journal of the Medical Association of Thailand 72 (11), 613–620. Van Wagner, L.B., Rinella, M.E., 2011. The role of insulin-sensitizing agents in the treatment of nonalcoholic steatohepatitis. Therapeutic Advances in Gastroentrology 414, 249–263. Vizzutti, F., Provenzano, A., Galastri, S., et al., 2010. Curcumin limits the fibrogenic evolution of experimental steatohepatitis. Laboratory Investigation 90 (1), 104–115.
RELEVANT WEBSITE http://clinicaltrials.gov – ClinicalTrials.gov
38
The Role of Curcumin in Gastrointestinal and Liver Diseases R.A. Hegazi, A. Seth Abbott Nutrition, Columbus, OH, USA
1. EFFECTS OF CURCUMIN ON GASTROINTESTINAL DISEASES On the basis of the teachings of the ancient medical textbook, the ayurveda, written in the fourth century BC, haldee or turmeric, has been used as a cure for almost all ailments, from trauma and infections to cancer since it was labeled the spice of life. Turmeric is derived from the rhizomes, the underground stems of Curcuma longa, which belongs to the family Zingibergaceae. Curcumin and its derivatives demethoxycurcumin and bisdemethoxycurcumin are collectively known as curcuminoids (Figure 38.1). Yellow color of turmeric is due to these phenolic compounds. Curcumin is the most active principal curcuminoid in turmeric. In agreement with ayurvedic teachings, recent studies have shown that curcumin exerts well-described pleiotropic biological effects. So far, more than 5300 studies have been published in medical journals regarding the biologically active effects of turmeric and curcumin, most of them are in the past decade. At present, researchers are actively engaged in conducting clinical trials in human subjects, with 67 trials already listed on the ClinicalTrials.gov website as of 10 February 2012. Among the biological effects of curcumin are its anti-inflammatory, antioxidant, and antitumor effects. For instance, curcumin has been shown to exert powerful antiinflammatory effects via inhibition of key proinflammatory signaling molecules and mediators. Probably, the most important effect of curcumin is its ability to inhibit the activation of the potent signal transduction molecule, NFk-b. Consistently, curcumin has been shown to inhibit the secretion of key proinflammatory cytokines, especially IL-1b, IL-8, and tumor necrosis factor (TNF). Curcumin inhibits IL-2 synthesis as well as IL-2 and mitogen activation of human leukocytes mediated by NFk-b inhibition. Several in vitro and in vivo studies support this anti-inflammatory effect (Jurenka, 2009). Other unique properties of curcumin are its antioxidant and antitumor effects. Moreover, curcumin modulates gastrointestinal (GI) motility. For instance, Shimouchi et al. (2009) recruited eight healthy subjects to ingest curry and rice with or without turmeric after an overnight fast. The study showed that turmeric significantly shortened the small bowel transit time and increased the area under the curve for breath hydrogen, when measured Bioactive Food as Dietary Interventions for Liver and Gastrointestinal Disease http://dx.doi.org/10.1016/B978-0-12-397154-8.00022-1
#
2013 Elsevier Inc. All rights reserved.
585
586
R.A. Hegazi and A. Seth
CH3O HO
OCH3 CH CHCOCH2COCH CH
Curcumin
OH OCH3
Demethoxycurcumin HO
CH CHCOCH2COCH
HO
CH
CH CHCOCH2COCH
OH
CH
OH
Bisdemethoxycurcumin
Figure 38.1 Biologically active curcuminoids.
every 15 min for 6 h, suggesting that turmeric increased bowel motility and colonic carbohydrate fermentation. Because of the aforementioned physiological effects, coupled with its low bioavailability, curcumin had been studied as a potential adjuvant therapeutic agent in a variety of GI diseases. Curcumin conjugates to form curcumin glucuronides and sulfates or is alternatively reduced to hexahydrocurcumin. It is these metabolites that are normally detected in the serum, but they are not as effective as the parent compound. Curcumin levels peak 1–2 h after ingestion and are undetectable after 12 h. Curcumin has been tested as a pharmaconutrient in various GI diseases with doses varying from 20 to 12 000 mg and with very minimal side effects. This chapter highlights these studies shedding light on its potential mechanism of action. Mechanistically, GI diseases could be classified into four major categories: (a) Functional intestinal disorders (b) Inflammatory bowel diseases (c) Liver diseases (d) GI and liver tumors.
2. CURCUMIN AND FUNCTIONAL BOWEL DISORDERS 2.1 Irritable Bowel Syndrome Irritable bowel syndrome (IBS) is a functional disorder of the bowel characterized by alteration of bowel habits and abdominal pain in the absence of an organic pathology. The IBS is a prevalent disease; population-based studies have estimated the prevalence of IBS to be 10–20% (31–62 million subjects in the United States). The IBS is clinically diagnosed by the presence of recurrent abdominal pain at least 3 days per month, during the previous 3 months associated with a change in stool frequency or form and relief of abdominal pain and discomfort on defecation. On the basis of the presenting symptoms, the IBS could be IBS with diarrhea, IBS with constipation, or IBS with alternating
The Role of Curcumin in Gastrointestinal and Liver Diseases
constipation and diarrhea. Medical treatment is symptomatic and relies on analgesics, antidiarrheals/laxatives, antispasmodics, and antidepressants to relieve the chronic stress associated with this condition. Given its pleiotropic GI properties, the use of turmeric extract and its active ingredient, curcumin, in patients with IBS was investigated. Bundy et al. (2004) carried out a large study, where 207 subjects were randomized to either a lower dose (72 mg of turmeric extract per day) or a higher dose group (144 mg of turmeric extract per day). The treatment continued for 8 weeks. IBS prevalence between baseline and after treatment decreased by 53% and 60% in the lower and the higher dose groups, respectively (p < 0.001). Abdominal pain was also reduced by 22% and 25%, respectively. The quality of life score also improved significantly with approximately two-third subjects reporting an improvement in symptoms with a favorable shift in the bowel pattern.
2.2 Dyspepsia Dyspepsia or indigestion is a prevalent functional disorder of the GI system. The prevalence of dyspepsia varies between 25% and 40% (approximately 77.5–124 million people in the United States). In some cases, it may also be a sign of gastric inflammation or peptic ulcer disease (10%) or gastroesophageal reflux disease (15%). Among its other common causes are medications or Helicobacter pylori infection. In addition to treating the etiological disease, medical treatment is usually symptomatic with antacids, proton pump inhibitors, lifestyle modifications, and prokinetic agents. The potential effectiveness of curcumin in patients with dyspepsia has been investigated. Di Mario et al. (2007) carried out a clinical study using low-dose curcumin in combination with other agents. They enrolled 25 H. pylori positive subjects with functional dyspepsia. This was a 2-month long clinical trial, with a 7-day course of curcumin 30 mg BID, lactoferrin 100 mg BID, N-acetylcysteine 100 mg BID, and pantoprazole 20 mg BID. A significant decrease in dyspeptic symptoms was observed at the conclusion of the 2-month long clinical trial ( p ¼ 0.001). Serum pepsinogens were also reduced. H. pylori eradication was achieved in only three patients (12%) with this combination therapy. Another study of curcumin in dyspepsia was carried out by Thamlikitkul et al. (1989). In a multicenter, double-blind, randomized, placebo-controlled, threeperiod crossover clinical trial, they enrolled 116 subjects with acid dyspepsia, flatulent dyspepsia, and atonic dyspepsia. The subjects were randomized to receive two capsules with 500 mg of turmeric, an active control (over the counter (OTC) dyspepsia drug) or placebo capsules four times a day for 7 days. Symptoms of dyspepsia were significantly relieved in 53% of subjects in the placebo group, 83% in the active control group on an OTC drug for dyspepsia, and 87% in the group taking turmeric capsules. These two studies supported the potential role that curcumin could play in alleviating upper GI symptoms associated with dyspepsia. It remains to be determined the exact
587
588
R.A. Hegazi and A. Seth
mechanism of these effects. The inherent anti-inflammatory and promotility effects of curcumin could explain these effects and need further examination.
2.3 Biliary Dyskinesia Biliary dyskinesia (BD), also known as Sphincter of Oddi dyskinesia, is possibly caused by sphincteric valvular dysfunction of the sphincter of Oddi or a dysfunction in the muscles of the gall bladder. It is a gall bladder motility disorder that manifest as a recurrent right upper quadrant pain in the absence of gall stones. The true incidence of BD is not known. However, it is seen in 10–15% of patients undergoing laparoscopic cholecystectomy. Niederau and Go¨pfert (1999) carried out a double-blind, placebo-controlled, multicenter trial of a turmeric root extract and Schollkraut in 76 patients with BD. After 3 weeks of treatment, study subjects experienced considerable reduction in abdominal pain when compared to placebo. The reduction of other complaints (feeling of fullness, food intolerance, nausea, vomiting, and meteorism) was similar in patients who received study group versus placebo. These beneficial effects of turmeric in patients with BD could be explained by the prokinetic effects of curcumin on gall bladder muscle. For instance, Rasyid and Lelo (1999) showed that 20 mg of curcumin, given orally, could exert a 29% reduction in the gall bladder volume as measured by 2-h serial ultrasound. Consistently, in a randomized, single-blind, three-period crossover study on 12 healthy volunteers with curcumin, Rasyid et al. (2002) demonstrated that a dose of 40 mg could exert a 51.1 8.1% reduction in gall bladder volume. Interestingly, a dose of 80 mg of curcumin could exert even a greater percentage reduction in gall bladder volume of 72.2 8.2%. Collectively, it could be concluded that curcumin exerts a dose-dependent effect on gall bladder motility that could benefit patients with BD. This very intriguing effect of curcumin could be also of benefit in prevention of gall bladder stones and other BD. These interesting hypotheses need to be further elucidated in clinical studies.
2.4 Human Immunodeficiency Virus Disease-Associated Diarrhea Preclinical and in vitro studies suggest that curcumin could exert anti-infective effects. This observation was tested in a clinical study by Conteas et al. (2009) on eight subjects with human immunodeficiency virus-associated diarrhea. Patients were orally administered 1862 mg of curcumin daily for 41 weeks. Interestingly, all subjects had rapid and complete resolution of diarrhea and normalization of bowel movements within a period of 13 9.3 days. Mean number of bowel movements dropped from 7.0 3.6 to 1.7 0.5. Seven of eight patients actually gained weight on curcumin (average weight gain 10.8 8.9 lbs). Five of six subjects experienced a resolution of abdominal pain and bloating on curcumin. Although the sample size was small, the fact that all the subjects had rapid and complete resolution of diarrhea within such a short time is intriguing and warrants further studies of curcumin in other types of diarrhea.
The Role of Curcumin in Gastrointestinal and Liver Diseases
3. INFLAMMATORY GI DISEASES 3.1 Inflammatory Bowel Disease Inflammatory bowel disease (IBD) comprises Crohn’s disease (CD) and ulcerative colitis (UC). It is an autoimmune disease characterized by remitting and relapsing cycles of chronic intestinal inflammation. The exact disease etiology is unknown, but it may be related to dysregulated immune responses to intestinal luminal antigens in genetically susceptible individuals. Environmental, dietary, and microbial factors play a major role in initiating and perpetuating the extent of chronic intestinal inflammation. Despite several animal studies proving the effectiveness of curcumin in ameliorating chronic intestinal inflammation in animal models of IBD (Jurenka, 2009), clinical studies are few. 3.1.1 Crohn's disease The CD is a chronic inflammatory bowel disease with a prevalence rate of approximately 200 cases per 100 000 population (600 000 cases in the United States). It is an idiopathic, chronic, transmural inflammatory process of the bowel that can affect any part of the GI tract from the mouth to the anus. Of all cases of CD, about 35% involve the ileum, about 45% involve the ileum and colon, and about 20% involve the colon alone. The perianal region is also affected in one-quarter to one-third of cases. Pathologically, noncaseating granulomas formation is pathognomonic of CD although its absence does not exclude the diagnosis. The granulomas extend through all layers of the intestinal wall and into the mesentery and the regional lymph nodes. Clinically, the main presenting symptoms are abdominal pain, diarrhea, and weight loss. Medical therapies include steroids, antiinflammatory nonsteroidal-like sulfasalazine, and mesalamine. Cytokines play a major role in the pathogenesis of the disease. The CD is believed to be the result of an imbalance between proinflammatory and anti-inflammatory cytokines. TNFa is present in excess in the mucosa of patients with CD and increases in TNFa are associated with the release of other proinflammatory cytokines, including IL-1, IL-6, IL-8, and IL-12. TNFa actions also include enhancement of leukocyte migration by increasing endothelial layer permeability and expression of adhesion molecules by endothelial cells and leukocytes, activation of neutrophil, and eosinophil functional activity, as well as tissue-degrading enzymes produced by synoviocytes and/or chondrocytes. Consistently, TNF antagonists have been used in the medical therapy of the disease. Given the anti-inflammatory effects and low bioavailability of curcumin, its antiinflammatory effects in patients with CD were investigated. Holt et al. (2005) recruited five subjects with active CD proctitis in an open label pilot study. Patients were to receive oral curcumin at a dose of 550 mg of curcumin twice a day for 1 month, and then a dose of 550 mg three times a day for another month. Crohn’s disease activity index (CDAI), markers of inflammation (C-reactive protein (CRP) and erythrocyte sedimentation rate), complete blood counts, liver and renal function studies, and endoscopic evaluation of
589
590
R.A. Hegazi and A. Seth
colitis were obtained in all patients. All five subjects with Crohn’s proctitis improved as evidenced by improvement in their global score (p < 0.02). Two subjects eliminated their prestudy anti-inflammatory medications (5-ASA), two subjects reduced their medications (including termination of the prednisone therapy in one subject), and one continued taking 5-ASA suppositories. The CDAI scores for all completed subjects reduced with a mean reduction of 55 points; markers of inflammation including sedimentation rate and CRP were also reduced. Of the five subjects, four successfully completed and one discontinued because of lack of treatment effect, with a slight worsening of fistula output. There were no changes in the liver or renal function tests indicating high-safety profile of curcumin. In another small study, Slonim et al. (2009) also recruited six subjects with moderately severe active CD in a prospective study. Patients were restricted to an elimination diet where dairy products, certain grains, and carrageenan were excluded. A combination therapy with nutraceuticals containing curcumin, Boswellia serrata, fish peptides, bovine colostrum, and multivitamins was given daily. In addition, a probiotic Lactobacillus GG was given twice weekly and recombinant growth hormone daily to facilitate adequate growth. Within 2 months of starting combination therapy, all six patients went into remission, with discontinuation of all pharmacological drugs. Three patients have remained in sustained remission for 4–8 years. One patient with very severe CD had recurrence of symptoms after being in complete remission for 18 months, one patient was in remission for 3 years but symptoms recurred when she became less compliant to the combination therapy, and one patient remained in remission after 6 months. Although curcumin was given as part of a combination regimen that the exclusive effects of curcumin on mucosal inflammation and healing not detected, the results with this safe nonpharmacological approach are certainly encouraging. 3.1.2 Ulcerative colitis Akin to CD, UC is a chronic intestinal inflammation, which is characterized by the presence of ulcers in the mucosa of the colon and rectum. The ulceration and inflammation can cause bloody or mucous diarrhea accompanied by abdominal pain. The disease prevalence in United States is approximately 690 000 subjects. There is a risk of development of colon cancer, which varies between 5% and 30% depending on the length of bowel involvement with UC. Akin to patients with CD, patients with UC are usually treated with aminosalicylates, corticosteroids, and immune modulators. The anti-inflammatory effects of curcumin had been tested in patients with UC. For instance, Hanai et al. (2006) studied the effectiveness of curcumin in patients with quiescent UC. In a multicenter randomized control trial, 45 patients were orally given curcumin (2 g day1 in two divided doses) plus sulfasalazine or mesalamine and 44 patients were given placebo plus sulfasalazine or mesalamine. Both groups were prospectively followed for 6 months. Patients were evaluated for both clinical
The Role of Curcumin in Gastrointestinal and Liver Diseases
(clinical activity index) and endoscopic (colitis score) response at the entry, every 2 months, and at the end of the study. Of 43 patients in the curcumin group, only two patients relapsed during the study period, while 8 of 39 patients in the placebo group relapsed. On the basis of intention to treat analysis, this difference in recurrence rates between the two groups was statistically significant. Importantly, patients in the curcumin group had less clinical and endoscopic index scores than the placebo group ( p ¼ 0.038 and 0.0001, respectively). These encouraging results were also associated with a favorable side effects profile in the curcumin group. Mild and transient side effects were experienced in 7 of 89 patients and were observed during curcumin maintenance therapy. These side effects were mainly the GI symptoms such as bloating, transient diarrhea, and transient hypertension. The authors extended their followup of the study patients to another 6 months after discontinuation of curcumin, where patients continued to receive sulfasalazine or mesalamine. Interestingly, relapse rate was not different between the two groups since eight patients in the curcumin group and six in the placebo group relapsed suggesting the temporary effects of curcumin suppressing intestinal inflammation.
4. LIVER DISEASES 4.1 Drug-Induced Liver Toxicity Drug-induced hepatotoxicity may range from asymptomatic elevation of the serum transaminases, elevation of bilirubin to frank hepatic failure, requiring liver transplantation. The incidence of hepatotoxicity depends on the age and gender of the patients and the number of drugs involved. Older patients, female sex, and presence of concomitant diseases, such as immune deficiency states, all put the patient at higher risk. It is estimated that 10–20% of patients may develop severe hepatitis, if left unmonitored and if the drug therapy is still continued after a threefold rise in serum transaminase levels. Mortality rate may exceed 50% if liver transplantation is not carried out in time. Adhvaryu et al. (2008) published a study in patients with active tuberculosis receiving multiple antimycobacterial drug therapy. They screened a total of 578 subjects and selected 528 with active tuberculosis for the 6-month long clinical trial. Selected subjects were randomized to receive antituberculous chemotherapy with isoniazid, rifampicin, pyrazinamide, and ethambutol (n ¼ 200) or these drugs plus 1000 mg of curcumin and 1000 mg of Tinospora cordifolia in two daily divided doses (n ¼ 328). Of those enrolled in the study, 192 subjects completed the study in the antituberculosis arm and 316 completed in the antituberculosis treatment plus curcumin and Tinospora arm. The study showed that the incidence and severity of hepatotoxicity was significantly lower in the curcumin group as compared to the control drug group (14.1% vs. 0.6%, respectively, p ¼ 0.0001). The study concluded that curcumin significantly reduced the incidence and severity of drug-induced hepatotoxicity and improved the disease outcome.
591
592
R.A. Hegazi and A. Seth
4.2 Nonalcoholic Fatty Liver Disease Fatty liver is another common liver disease for which the therapeutic use of curcumin has been investigated. Nonalcoholic fatty liver disease (NAFLD) results from an abnormal accumulation of fatty acids in the liver (steatosis) in the absence of any alcohol abuse. The exact pathogenesis of NAFLD is unknown, but it is believed that disrupted insulin signaling or disrupted leptin signaling contribute to the activation of the hepatic stellate cells (HSCs), which secrete a plethora of proinflammatory cytokines, resulting in inflammation of the liver and a phenomenon called nonalcoholic steatohepatitis (NASH). Besides inflammation, oxidative stress is also a key factor in the progression to NASH, and antioxidant vitamins such as vitamin E have been used with promising results. HSCs, major effectors of collagen production, play a major role in NASH-associated liver fibrogenesis. NASH incidence and importance are rising because of increasing incidence of its main contributory causes, metabolic syndrome, diabetes, hyperlipidemia, and obesity. NASH accounts for about 10% of newly diagnosed cases of chronic liver disease and ranks as one of the leading causes of cirrhosis in the United States. Patients with NASH may be identified as having NASH only on routine blood tests because of elevated liver enzymes. Others may present with fatigue, anorexia, nausea, abdominal pain, or hepatomegaly. The primary treatment modalities for NASH include a low-calorie, low-fat, low-carbohydrate diet with exercise and weight loss. Currently, many pharmaceutical agents, including antidiabetic agents and antihyperlipidemic agents, are being investigated for the treatment of NASH. As insulin resistance is almost a universal finding in patients with NASH, insulin-sensitizing agents such as metformin or thiazolidinediones or IkappaB kinase inhibitors have been investigated in large clinical trials of NASH (Van Wagner and Rinella, 2011). Similarly, owing to its anti-inflammatory and antioxidant properties, curcumin has been investigated in animal models of NAFLD and NASH to dampen the inflammatory and oxidative process associated with NASH (Leclercq et al., 2004; Ramirez-Tortosa et al., 2009; Vizzutti et al., 2010). Consistently, Lin et al. (2009) conducted a study to investigate the role of curcumin in insulin-induced HSC activation. They reported that curcumin dose dependently suppressed insulin-induced HSC activation by suppressing type 1 collagen and other genes involved in HSC activation. Curcumin also interrupted insulin signaling in HSCs by suppressing the insulin receptor (insR) gene expression. Curcumin also reduced the phosphorylation level of the insR. Curcumin also induced the gene expression of glutamate-cysteine ligase, which led to the de novo synthesis of the antioxidant glutathione. This would translate into a reduction of the insulin-induced oxidative stress in the HSCs. This study demonstrates that the detrimental effects of the hyperinsulinemia associated with type II diabetes on liver fibrinogenesis and cirrhosis could possibly be reduced by curcumin. Tang et al. (2009) studied the effect of curcumin on leptin signaling. The authors found that curcumin eliminates this stimulatory effect of leptin on HSCs by decreasing the phosphorylation levels of the leptin receptor.
The Role of Curcumin in Gastrointestinal and Liver Diseases
Collectively, it inhibits leptin-stimulated HSC activation and activates endogenous PPAR gamma expression and stimulates the de novo synthesis of the antioxidant glutathione synthesis thereby reducing the oxidative stress on the hepatic cells. The potential therapeutic effects in patients with NAFLD and NASH should be further investigated.
5. GI AND LIVER TUMORS Curcumin exerts antitumor effects by inhibiting key pathways in tumor growth. For these effects, it has been studied in different GI and liver cancers.
5.1 Pancreatic Cancer Pancreatic cancer is a grave disease. By the time it is diagnosed, it has already spread to distant locations in more than 50% of cases and regionally in more than 25% of cases. That may be why the 1-year survival rate is only 24% and the 5-year survival rate is just 5%. Most of the cancers occur in the exocrine portion and most of them are found to be located in the head of the pancreas. One of the precursors of pancreatic cancer is chronic pancreatitis. Patients may initially present with loss of appetite, loss of weight, fatigue, and mild discomfort in the abdomen or back. Patients may also present with painless obstructive jaundice and pruritis. Curcumin has been clinically tested in patients with pancreatic cancer. Dhillon et al. (2008) enrolled 25 subjects with advanced pancreatic cancer to receive 8000 mg day1 of curcumin till disease progression and their disease was restaged every 2 months. One subject had stable disease for more than 18 months, and one had marked regression in tumor size transiently. Curcumin downregulated the expression of NFk-b and cyclooxygenase-2. Similarly, Kanai et al. (2010) enrolled 21 subjects who were on Gemcitabine, a chemotherapeutic agent, along with 8000 mg day1 of curcumin. No dose-limiting toxicities were observed. Median compliance rate was 100%. Median survival time was 161 days (95% CI: 109–223 days) and 1-year survival rate was 19% (4.4–41.4%). These observations were consistent with those of Bisht et al. (2010) in athymic mice with pancreatic cancer. Mice were administered a polymeric nanoparticle-encapsulated curcumin. The study showed that curcumin significantly inhibited the growth of the primary tumor. Curcumin with Gemcitabine resulted in enhanced tumor growth inhibition and abrogated systemic metastases. Combination therapy also reduced the activation of NFk-b, matrix metaloproteinase-9, and cyclin D1. On the basis of the results of these studies, it appears that curcumin can be offered as an adjunct therapy to patients at high risk of pancreatic cancer such as patients with chronic pancreatitis especially considering that it has no adverse effects even at 8000 mg. Potential benefits include its ability to ameliorate chronic pancreatic inflammation-associated cachexia and to possibly reduce the rate of progression to pancreatic cancer. These hypotheses warrant further investigation.
593
594
R.A. Hegazi and A. Seth
5.2 Primary Liver Cancer (Hepatocellular Carcinoma) Approximately 80% of newly diagnosed patients are found to have preexisting liver cirrhosis. The most common causes of liver cirrhosis are alcoholism, hepatitis B, and hepatitis C infection. Chronic hepatitis-associated liver cancer may be mediated by chronic inflammation and the incorporation of the viral genome into the host DNA. Primary liver cancer is generally seen 20–30 years following the diagnosis of liver cirrhosis. Most of the patients only survive 6–20 months after the diagnosis of liver cancer and die from either liver failure or tumor progression. This cancer is usually multifocal in the liver, but metastasis to the lungs, portal vein, periportal nodes, brain, or bones can occur late in the disease. Cheng et al. (2001) conducted a study using curcuma aromatica oil in 64 subjects with primary liver cancer. For comparison, they used an active control with standard anticancer agents. The median survival time in the curcuma oil group was more than the control group (10 vs. 6 months, respectively, p < 0.05). Consistently, 1-, 2-, and 3-year survival rate in the study group was more as compared to the control group (p < 0.05). Moreover, myelosuppression occurred less in the study group as compared to control (p < 0.01).
5.3 Colonic Tumors The effects of curcumin intake on markers of progression of colonic tumors were also investigated. For instance, in order to investigate whether curcumin could reduce the number and size of polyps in patients with familial adenomatous polyposis, five subjects with prior colectomy (four with retained rectum and one with an ileal anal pouch) received 480 mg of curcumin and 20 mg of quercetin three times daily orally for 6 months. Interestingly, the number of polyps decreased by 60.4% (p < 0.05) from the baseline. Moreover, size of polyps decreased by 50.9% (p < 0.05) from the baseline. These effects on the number and size of polyps were associated with excellent safety profile and minimal adverse effects (Cruz-Correa et al., 2006). Moreover, to test whether orally administered curcumin could reduce the levels of DNA adducts, the quantitative measure of the amount of cancerous tissue in patients with colorectal cancer, subjects with colorectal cancer ingested capsules containing 450, 1800, or 3600 mg of curcumin for 7 days. Biopsy of colorectal tissue and blood samples were obtained before and after the intake of curcumin. Curcumin sulfate and curcumin glucuronide were identified in the tissues indicating active intestinal intracellular transport and metabolism. DNA adduct levels were reduced from 4.8 2.9 adducts per 107 nucleotides to 2.0 1.8 adducts per 107 nucleotides (p < 0.05; Garcea et al., 2005). In conclusion, future research will better define the significant role of turmeric and its active component, curcumin, not only in maintaining intestinal health but also in ameliorating GI and liver diseases. For instance, the reported beneficial uses of these nutrients in GI disorders should be replicated in large clinical trials that take into consideration the
The Role of Curcumin in Gastrointestinal and Liver Diseases
different doses and forms of the plant derivative. Given its similar pharmacological properties and high-safety profile, there is a great unmet need for an effective nutritional product that could be used as an adjunct to medical therapeutics in the management and prevention of these disorders.
REFERENCES Adhvaryu, M.R., Reddy, N., Vakharia, B.C., 2008. Prevention of hepatotoxicity due to antituberculosis treatment: a novel integrative approach. World Journal of Gastroenterology 14 (30), 4753–4762. Bisht, S., Mizuma, M., Feldmann, G., et al., 2010. Systemic administration of polymeric nanoparticleencapsulated curcumin (NanoCurc) blocks tumor growth and metastases in preclinical models of pancreatic cancer. Molecular Cancer Therapeutics 9 (8), 2255–2264. Bundy, R., Walker, A.F., Middleton, R.W., Booth, J., 2004. Turmeric extract may improve irritable bowel syndrome symptomology in otherwise healthy adults: a pilot study. Journal of Alternative and Complementary Medicine 10 (6), 1015–1018. Cheng, A.L., Hsu, C.H., Lin, J.K., et al., 2001. Phase I clinical trial of curcumin, a chemopreventive agent, in patients with high-risk or pre-malignant lesions. Anticancer Research 21 (4B), 2895–2900. Conteas, C.N., Panossian, A.M., Tran, T.T., Singh, H.M., 2009. Treatment of HIV-associated diarrhea with curcumin. Digestive Diseases and Sciences 54 (10), 2188–2191. Cruz-Correa, M., Shoskes, D.A., Sanchez, P., et al., 2006. Combination treatment with curcumin and quercetin of adenomas in familial adenomatous polyposis. Clinical Gastroenterology and Hepatology 4 (8), 1035–1038. Dhillon, N., Aggarwal, B.B., Newman, R.A., et al., 2008. Phase II trial of curcumin in patients with advanced pancreatic cancer. Clinical Cancer Research 15, 4491–4499. Di Mario, F., Cavallaro, L.G., Nouvenne, A., et al., 2007. Curcumin-based 1-week triple therapy for eradication of Helicobacter pylori infection: something to learn from failure? Helicobacter 12 (3), 238–243. Garcea, G., Berry, D.P., Jones, D.J., et al., 2005. Consumption of the putative chemopreventive agent curcumin by cancer patients: assessment of curcumin levels in the colorectum and their pharmacodynamic consequences. Cancer Epidemiology, Biomarkers & Prevention 14 (1), 120–125. Hanai, H., Iida, T., Takeuchi, K., et al., 2006. Curcumin maintenance therapy for ulcerative colitis: randomized, multicenter, double-blind, placebo-controlled trial. Clinical Gastroenterology and Hepatology 4 (12), 1502–1506. Holt, P.R., Katz, S., Kirshoff, R., 2005. Curcumin therapy in inflammatory bowel disease: a pilot study. Digestive Diseases and Sciences 50 (11), 2191–2193. Jurenka, J.S., 2009. Anti-inflammatory properties of curcumin, a major constituent of Curcuma longa: a review of preclinical and clinical research. Alternative Medicine Review 14 (2), 141–153. Kanai, M., Yoshimura, K., Asada, M., et al., 2010. A phase I/II study of gemcitabine-based chemotherapy plus curcumin for patients with gemcitabine-resistant pancreatic cancer. Cancer Chemotherapy and Pharmacology 68 (1), 157–164. Leclercq, I.A., Farrell, G.C., Sempoux, C., dela Pen˜a, A., Horsmans, Y., 2004. Curcumin inhibits NF-kappaB activation and reduces the severity of experimental steatohepatitis in mice. Journal of Hepatology 41 (6), 926–934. Lin, J., Zheng, S., Chen, A., 2009. Curcumin attenuates the effects of insulin on stimulating hepatic stellate cell activation by interrupting insulin signaling and attenuating oxidative stress. Laboratory Investigation 89 (12), 1397–1409. Niederau, C., Go¨pfert, E., 1999. The effect of chelidonium- and turmeric root extract on upper abdominal pain due to functional disorders of the biliary system. Results from a placebo-controlled double-blind study. Medizinische Klinik (Munich, Germany) 94 (8), 425–430. Ramirez-Tortosa, M.C., Ramirez-Tortosa, C.L., Mesa, M.D., Granados, S., Gil, A., Quiles, J.L., 2009. Curcumin ameliorates rabbit’s steatohepatitis via respiratory chain, oxidative stress, and TNF-alpha. Free Radical Biology & Medicine 47 (7), 924–931.
595
596
R.A. Hegazi and A. Seth
Rasyid, A., Lelo, A., 1999. The effect of curcumin and placebo on human gall-bladder function: an ultrasound study. Alimentary Pharmacology and Therapeutics 13 (2), 245–249. Rasyid, A., Rahman, A.R., Jaalam, K., Lelo, A., 2002. Effect of different curcumin dosages on human gall bladder. Asia Pacific Journal of Clinical Nutrition 11 (4), 314–318. Shimouchi, A., Nose, K., Takaoka, M., Hayashi, H., Kondo, T., 2009. Effect of dietary turmeric on breath hydrogen. Digestive Diseases and Sciences 54 (8), 1725–1729. Slonim, A.E., Grovit, M., Bulone, L., 2009. Effect of exclusion diet with nutraceutical therapy in juvenile Crohn’s disease. Journal of the American College of Nutrition 28 (3), 277–285. Tang, Y., Zheng, S., Chen, A., 2009. Curcumin eliminates leptin’s effects on hepatic stellate cell activation via interrupting leptin signaling. Endocrinology 150 (7), 3011–3020. Thamlikitkul, V., Bunyapraphatsara, N., Dechatiwongse, T., et al., 1989. Randomized double blind study of Curcuma domestica Val. for dyspepsia. Journal of the Medical Association of Thailand 72 (11), 613–620. Van Wagner, L.B., Rinella, M.E., 2011. The role of insulin-sensitizing agents in the treatment of nonalcoholic steatohepatitis. Therapeutic Advances in Gastroentrology 414, 249–263. Vizzutti, F., Provenzano, A., Galastri, S., et al., 2010. Curcumin limits the fibrogenic evolution of experimental steatohepatitis. Laboratory Investigation 90 (1), 104–115.
RELEVANT WEBSITE http://clinicaltrials.gov – ClinicalTrials.gov