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References 449

Downloaded from https://onlinelibrary.wiley.com/doi/ by Universität Bern, Wiley Online Library on [22/08/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License

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appropriate drugs after evaluating the insulin secretory capacity, insulin resistance, and nutritional status, including pancreatic exocrine function, in each case.

Complications andGlycemic Target ofPancreatic Diabetes

Good glycemic control reduces the risk of microvascular and macrovascular complications in patients with diabetes[11,36]. A Japanese nationwide survey revealed that the incidence of retinopathy was lower in pancreatic diabetes than in type 1 and type 2 diabetes, but the incidence of neuropathy and nephropathy was comparable [11]. The prevalence of diabetic complications, including cerebrovascular and cardiovascular disorders, also increases with the duration of diabetes[11,14,36]. Therefore, as in other types of diabetes, achieving good glycemic control could improve the quality of life of patients with pancreatic diabetes. Conversely, rapid fluctuations in glucose levels, namely “brittle diabetes,” are frequently observed in patients with pancreatic diabetes and result in poor glycemic control. Avoiding severe hypoglycemia is ver y

important

in these patients with “brittle diabetes.” A large retrospective cohort study from England revealed that patients with pancreatic diabetes had worse glycemic control than did those with type 2 diabetes. The odds ratio for poor glycemic control (defined as HbA

≥7%)

at 5 years after the diagnosis was 1.7 in patients with pancreatic diabetes than in those with type 2 diabetes [12]. According to the recommendations of the ADA, less stringent targets (HbA1c up to 8%) may be appropriate if the risks and burdens outweigh the potential benefits [42]. Severe or frequent hypoglycemia is an absolute indication for the modification of treatment regimens, including setting higher glycemic targets. Although this recommendation is mainly for patients with type 1 or type 2 diabetes, the same situation is frequently observed in those with pancreatic diabetes and unstable glycemic control. Therefore, less stringent glycemic control may be recommended for patients with pancreatic diabetes. Accordingly, the Japanese guidelines for chronic pancreatitis proposed that an HbA

level of 7.5% could be used as a target;

nevertheless, further research is warranted to set an optimal glycemic target for this condition.

References

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diagnosis of diabetes: standards of medical care in diabetes- - 2021. Diabetes Care 2021;44:S15–33.

2 Hart PA, Bellin MD, Andersen DK etal. Type 3c

(pancreatogenic) diabetes mellitus secondary to chronic pancreatitis and pancreatic cancer. Lancet Gastroenterol Hepatol 2016;1:226–237.

3 Ewald N, Bretzel RG. Diabetes mellitus secondary to

pancreatic diseases (Type 3c)important disease? Eur J Intern Med 2013;24:203–206.

4 Ewald N, Hardt PD. Diagnosis and treatment of diabetes

mellitus in chronic pancreatitis. World J Gastroenterol 2013;19:7276–7281.

5 O’Brien SJ, Omer E. Chronic pancreatitis and nutrition

therapy. Nutr Clin Pract 2019;34:S13–26.

6 Cui Y, Andersen DK. Pancreatogenic diabetes: special

considerations for management. Pancreatology 2011;11:279–294.

7 Kawabe K, Ito T, Igarashi H etal. The current managements

of pancreatic diabetes in Japan. Clin J Gastroenterol 2009;2:1–8.

8 Das SLM, Singh PP, Phillips ARJ etal. Newly diagnosed

diabetes mellitus after acute pancreatitis: a systematic review and meta- analysis. Gut 2014;63:818–831.

9 Shiratori K. Management of pancreatic diabetes secondary

to chronic pancreatitis. In: Beger HG, Warshaw AL, Hruban RH etal., eds. The Pancreas. 3rd edn. Chichester: Wiley, 2018: 495–502.

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10 Ewald N, Kaufmann C, Raspe A etal. Prevalence of

diabetes mellitus secondary to pancreatic diseases (type 3c). Diabetes Metab Res Rev 2012;28:338–342.

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pancreatic diabetes in Japan in 2005: a nationwide study. Pancreas 2010;39:829–835.

12 Woodmansey C, McGovern AP, McCullough KA etal.

Incidence, demographics, and clinical characteristics of diabetes of the exocrine pancreas (type 3c): a retrospective cohort study. Diabetes Care 2017;40:1486–1493.

13 Pendharkar SA, Mathew J, Petrov MS. Age- and sex-

specific prevalence of diabetes associated with diseases of the exocrine pancreas: a population- based study. Dig Liver Dis 2017;49:540–544.

14 Dominguez- Munoz JE, Drewes AM, Lindkvist B etal.

Recommendations from the United European Gastroenterology evidence- based guidelines for the diagnosis and therapy of chronic pancreatitis. Pancreatology 2018;18:847–854.

15 Bang UC, Benfield T, Hyldstrup L etal. Mortality, cancer,

and comorbidities associated with chronic pancreatitis: a Danish nationwide matched- cohort study. Gastroenterology 2014;146:989–994.

16 Hart PA, Conwell DL. Chronic pancreatitis: managing a

difficult disease. Am J Gastroenterol 2020;115: 49–55.

17 Bellin MD, Whitcomb DC, Abberbock J etal. Patient and

disease characteristics associated with the presence of

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diabetes mellitus in adults with chronic pancreatitis in theUnited States. Am J Gastroenterol 2017;112: 1457–1465.

18 Frulloni L, Gabbrielli A, Pezzilli R etal. Chronic

pancreatitis: report from a multicenter Italian survey (PanCroInfAISP) on 893 patients. Dig Liver Dis 2009;41:311–317.

19 Liu Y, Wang D, Guo HL etal. Risk factors and nomogram

for diabetes mellitus in idiopathic chronic pancreatitis. JGastroenterol Hepatol 2020;35:343–352.

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up survey of chronic pancreatitis in Japan.

followJGastroenterol 2007;42:291–297.

21 Masamune A, Kikuta K, Kume K etal. Nationwide

epidemiological survey of chronic pancreatitis in Japan: introduction and validation of the new Japanese diagnostic criteria 2019. J Gastroenterol 2020;55:1062–1071.

22 Zhu X, Liu D, Wei Q etal. New- onset diabetes mellitus

after chronic pancreatitis diagnosis: a systematic review and meta- analysis. Pancreas 2019;48:868–875.

23 Malka D, Hammel P, Sauvanet A etal. Risk factors for

diabetes mellitus in chronic pancreatitis. Gastroenterology 2000;119:1324–1332.

24 Hao L, Wang LS, Liu Y etal. The different course of

alcoholic and idiopathic chronic pancreatitis: a long-

term

study of 2,037 patients. PLoS ONE 2018;13.e0198365.

25 Masamune A, Kikuta K, Nabeshima T etal. Nationwide

epidemiological survey of early chronic pancreatitis in Japan. J Gastroenterol 2017;52:992–1000.

26 Maisonneuve P, Lowenfels AB, Müllhaupt B etal. Cigarette

smoking accelerates progression of alcoholic chronic pancreatitis. Gut 2005;54:510–514.

27 Sankaran SJ, Xiao AY, Wu LM etal. Frequency of

progression from acute to chronic pancreatitis and risk factors: a meta- analysis. Gastroenterology 2015;149:1490–1500.

28 Masamune A, Nabeshima T, Kikuta K etal. Prospective

study of early chronic pancreatitis diagnosed based on the Japanese diagnostic criteria. J Gastroenterol 2019;54:928–935.

29 Andriulli A, Botteri E, Almasio PL etal. Smoking as a

cofactor for causation of chronic pancreatitis: a metaanalysis. Pancreas 2010;39:1205–1210.

30 Wang W, Guo Y, Liao Z etal. Occurrence of and risk

factors for diabetes mellitus in Chinese patients with chronic pancreatitis. Pancreas 2011;40:206–212.

31 Fukuda T, Bouchi R, Takeuchi T etal. Importance of

intestinal environment and cellular plasticity of islets in the development of postpancreatectomy diabetes. Diabetes Care 2021;44:1002–1011.

32 Terzin V, Takács R, Lengyel C etal. Improved glycemic

control in pancreatic diabetes through intensive conservative insulin therapy. Pancreatology 2012;12:100–103.

33 Niwano F, Hiromine Y, Noso S etal. Insulin deficiency

with and without glucagon: A comparative study between total pancreatectomy and type 1 diabetes. J Diabetes Investig 2018;9:1084–1090.

34 Rickels MR, Bellin M, Toledo FGS etal. Detection,

evaluation and treatment of diabetes mellitus in chronic pancreatitis: recommendations from PancreasFest 2012. Pancreatology 2013;13:336–342.

35 Zhou PT, Li B, Liu FR etal. Metformin is associated with

survival benefit in pancreatic cancer patients with diabetes: a systematic review and meta- analysis. Oncotarget 2017;8:25242–25250.

36 Wynne K, Devereaux B, Dornhorst A. Diabetes of the

exocrine pancreas. J Gastroenterol Hepatol 2019;34:346–354.

37 Forsmark CE. Incretins, diabetes, pancreatitis and

pancreatic cancer: what the GI specialist needs to know. Pancreatology 2016;16:10–13.

38 Tseng CM, Liao WC, Chang CY etal. Incretin- based

pharmacotherapy and risk of adverse pancreatic events in the ethnic Chinese with diabetes mellitus: a populationbased study in Taiwan. Pancreatology 2017;17:76–82.

39 Pinto LC, Falcetta MR, Rados DV etal. Glucagon- like

peptide-

1 receptor agonists and pancreatic cancer: a meta-

analysis with trial sequential analysis. Sci Rep 2019;9:2375.

40 Nespoux J, Vallon V. SGLT2inhibition and kidney

protection. Clin Sci (Lond) 2018;132:1329–1339.

41 Tang H, Yang K, Li X etal. Pancreatic safety of sodium-

glucose cotransporter 2inhibitors in patients with type 2 diabetes mellitus: a systematic review and meta-

analysis.

Pharmacoepidemiol Drug Saf 2020;29:161–172.

42 American Diabetes Association. 6. Glycemic targets:

standards of medical care in diabetes-

- 2021. Diabetes Care

2021;44:S73–84.

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Oxidative Stress andAntioxidants inChronic Pancreatitis

Soumya Jagannath Mahapatra and Pramod Kumar Garg

Department of Gastroenterology, All India Institute of Medical Sciences, New Delhi, India

451

Introduction

Chronic pancreatitis (CP) is a progressive fibroinflammatory disease of the pancreas characterized by repeated episodes of pancreatic inflammation and injury which result in pancreatic exocrine and/or endocrine insufficiency. Morphologically, it is characterized by parenchymal loss leading to atrophy, fibrosis, and ductal stricture and/or calcification causing ductal dilatation[1]. The pathophysiological mechanisms of CP are not well understood. Over the past few decades, oxidative stress has emerged as an important mechanism contributing to pancreatic inflammation and the role of antioxidants has been evaluated in patients with CP.

Free- radical production is an integral part of cellular physiology. These free radicals are neutralized by specific cellular enzymes and other small molecules called scavengers and antioxidants. In health, intricate balance exists between free radicals and antioxidants. However, excessive production of free radicals by activation of oxidative pathways or deficiency of antioxidants tilts the balance leading to “oxidative stress.” It is formally defined as “an imbalance between oxidants and antioxidants in favor of oxidants leading to disruption of redox signaling and control, and/or molecular damage”[2]. This review focuses on oxidative stress and the role of antioxidants in mitigating oxidative stress, inflammation, and relieving pain in patients with CP.

Pro- Oxidants

Pro- oxidants are the molecules that favor formation of free radicals. Free radicals have one or more free electrons and usually are reactive oxygen species (ROS) or

reactive nitrogen species (RNS) in the cellular environment. Free radicals and their reaction products are a part of normal cell physiology by acting as second messengers and they play an important role in cellular signaling[3]. Mitochondria are the site of physiological oxidative stress. Excessive production of ROS and RNS may damage biomolecules such as lipids, DNA, and proteins (Fig.57.1).

Detoxification of xenobiotics is another source of production of free radicals. Xenobiotics are toxic substances that enter the body and undergo detoxification in two phases to a hydrophilic substance thus facilitating their excretion in the urine. In phase I metabolism, cytochrome P450 (CYP 450) oxidase system and hydrolyzing enzymes either cleave the parent molecule or result in oxidation or hydroxylation. In phase II metabolism, they are

conjugated to a hydrophilic group (glucuronidation, acetylation, methylation, sulfation, or conjugation with glutathione) to form a polar watersoluble inactive compound that can be excreted by the body. Induction of phase I enzymes can itself result in generation of free radicals through the CYP450 system.

Various exogenous substances such as alcohol, tobacco, environmental pollutants, heavy metals, certain drugs, dietary toxins, and fumes lead to free radical generation. Alcohol metabolism can result in production of free radicals. Alcohol is converted to acetaldehyde, a toxic and reactive molecule, by alcohol dehydrogenase, and acetaldehyde is converted to acetate by aldehyde dehydrogenase. Each of the steps results in consumption of nicotinamide adenosine dinucleotide phosphate hydrogen (NADPH) and free radical formation.

Cigarette smoking similarly contains a lot of xenobiotics which can induce free-

radical production and lipid

peroxidation[4].

The Pancreas: An Integrated Textbook of Basic Science, Medicine, and Surgery, Fourth Edition. Edited by Hans G. Beger, Markus W. Büchler, RalphH. Hruban, Julia Mayerle, John P. Neoptolemos, Tooru Shimosegawa, Andrew L. Warshaw, David C. Whitcomb, and Yupei Zhao. © 2023 John Wiley & Sons Ltd. Published 2023 by John Wiley & Sons Ltd. Companion website: www.wiley.com/go/beger/thepancreas4e

Oxidative Stress andAntioxidants inChronic Pancreatitis

ROS generation ROS elimination

Redox homeostasis

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452

Lipid peroxidation

Protein

Oxidation of SH group

Nitrosylation of tyrosine

Enzyme inactivation

Figure57.1 Intracellular free radicals can damage plasma membrane by lipid peroxidation. Mitochondria, which are the source of

oxidative stress, get damaged which induces apoptosis by cytochrome c. Nitrosylation and oxidation of enzymes may result in their inactivation. Nuclear DNA may get fragmented inducing apoptotic pathways. ROS: reactive oxygen species.

Antioxidants

Tyr

NitroTyr

ONOO

–

DNA fragmentation

Delayed apoptosis

• O

• OH ROS

–

Mitochondria

sulfur for the formation of cysteine and is thus an important

Necrosis

ATP

Early apoptosis

CytC

dietary component for maintaining antioxidant defense.

Antioxidants are substances that when present in low concentration compared to those of an oxidizable substrate significantly delay or inhibit oxidation of that substrate[5]. They can be classified into several groups: (i) cellular enzymes such as superoxide dismutase (SOD), glutathione peroxidase (GPx) and catalase (CAT); (ii) vitamins such as β- carotene, ascorbic acid, α- tocopherol; (iii) uric acid; and (iv) amino acids and proteins, which form complexes with transition metal ions. Cysteine is an important amino acid for the synthesis of glutathione. Methionine provides

Selenium is a component of the GPx and Se- dependent enzyme thioredoxin reductase. These enzymes reduce hydrogen peroxide and lipid peroxides[6].

Primary defenses against oxidative stress include antioxidants vitamin E, vitamin C, β- carotene, glutathione, and uric acid. Second- line defense includes antioxidant scavenging enzymes that include SOD, CAT, and GPX. There exists a “redox homeostasis” within the cellular milieu and temporary exposure to ROS activate redox signaling (Fig.57.2)[7].

CYP 450

Lipoxygenase

Figure57.2 Redox homeostasis showing the balance between generation and elimination of reactive oxygen species (ROS).

O2- H2O2

OH ROO

ROOH RO

HOCl ONOO

Mitochondrial

electron transport

chain

NADPH oxidase

Vitamin

C/E

GSH

Enzymes

Proteins

Amino acids

SOD

CAT

Evidence forOxidative Stress and Total Antioxidant Status inCP 453

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Assessment ofOxidative Stress andAntioxidant Status

Oxidative Stress Markers

Measurement of thiobarbituric acid reactive substances (TBARS) is the most commonly used assay and is a marker of lipid peroxidation. Lipid peroxidation causes damage to the cell membrane. Malonaldehyde (MDA) and 4- hydroxynonenal (4- HNE) are the most important products of lipid peroxidation and can be used as markers of lipid peroxidation. Lipid peroxidation is a key step in oxidative stress mediated injury [8,9]. Some sugars may react with thiobarbituric acid resulting in assay interference[10].

Antioxidant Status Markers

Antioxidants work in tandem and complement each other. Hence, measurement of individual antioxidants may not be a direct measure of total antioxidant capacity (TAC) of the body. The ferric acid reducing ability of plasma (FRAP) measures the reducing capacity of blood from ferric to ferrous ion. FRAP is an easy and reproducible assay to measure TAC of the body[11].

Oxidative Stress inCP andits Consequences

The concept of “oxidative stress” in the pathogenesis of chronic pancreatitis can be credited to Joan M. Braganza, who proposed the hypothesis that products of hepatic detoxification may cause pancreatic diseases due to reflux of bile containing these substances into the pancreas. It was proposed that aberrant function of hepatic mixed function oxidase (MFO) may be the root cause of pancreatic diseases[12].

Rose et al. [13] first suggested that antioxidant deficiency may play a role in the pathogenesis of CP. Antioxidant deficiency was observed in patients with CP and oxidative stress was subsequently hypothesized as an important pathophysiological mechanism for the development of CP. It was supported by the observation that a high concentration of lipid- based free- radical oxidation products were detected in the serum and duodenal bile during the relatively asymptomatic phase between the recurrent attacks of pancreatitis suggesting persistent oxidative stress [14]. Three possible mechanisms were suggested: (i) CYP induction by cigarette smoking [15]; (ii) exposure to volatile petrochemical products in occupational environment [16]; and (iii) reduced dietary intakes of methionine and vitamin C in alcoholics[17,18].

Xenobiotic- mediated injury may perpetuate repeated/ chronic inflammation in CP. The phase I enzymes such as CYP1A2, CYP3A, and NADPH- CYP oxidoreductase rather than phase II enzymes were found to be induced in the surgical biopsies of pancreas in a study of drugmetabolizing enzymes. Phase II enzymes facilitate removal of xenobiotics after conjugation with GSH, but phase I enzymes may produce toxic intermediates. In addition, pancreatic acinar cells showed evidence of oxidative stress[19].

ROS can lead to acinar cell death in pancreatitis. ROS is a key mediator of CCK- induced apoptosis in experimental pancreatitis. This is mediated by increasing intracellular calcium leading to release of mitochondrial cytochrome c, which activates caspases causing apoptosis[20,21]. ROS can also activate pancreatic stellate cells (PSC). PSC may also generate ROS by NADPH oxidase, which mediates activation of PSC[22].

Evidence forOxidative Stress and Total Antioxidant Status inCP

Lipid peroxide activity was studied by Basso etal.[23] in 49 patients with CP, 28 patients with pancreatic cancer, 40 controls, and 53 patients with extrapancreatic diseases. It was observed that lipid peroxide activity was increased in patients with CP during disease relapse and correlated with the degree of inflammation.

Szuster- Ciesielska et al. [24], studied the ability of blood neutrophils to produce superoxide anion and hydrogen peroxide spontaneously and after stimulation and showed that the resting production of these free radicals was significantly higher in patients with pancreatitis compared with controls. Superoxide dismutase and catalase activities were greater in patients with alcoholic pancreatitis than controls.

Patients with CP and pancreatic cancer had higher levels of Cu/Zn superoxide dismutase in the pancreatic juices collected endoscopically compared with controls. Immunohistochemical studies of Cu/ZN- SOD in pancreatic tissue showed localization to ductal cells, islet cells, and centro- acinar cells but to a much lesser extent to acinar cells[25].

Schoenberg etal.[26] studied lipid peroxidation products in the tissue and serum of patients suffering from acute (n = 9) and chronic pancreatitis (n = 11). In patients with CP, the products of lipid peroxidation such as conjugated dienes and malonaldehyde were higher in pancreatic tissue compared to controls (organ donor). Reduced glutathione was significantly decreased suggesting oxidative stress. Increased levels of tissue lipid peroxidation products and altered glutathione

Oxidative Stress andAntioxidants inChronic Pancreatitis

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metabolism suggested ongoing peroxidation of lipids due to an enhanced generation of oxygen radicals.

Patients with alcoholic CP have low blood levels of many antioxidant factors despite adequate oral intake. In a study, serum levels of Vitamin A, Vitamin E, selenium, and glutathione peroxidase level were significantly lower compared to healthy controls despite no dietary differences in these micro- nutrients. The study hypothesized that such deficiency was probably due to pancreatic insufficiency and increased requirement due to oxidative stress[27].

In another study, Mathew etal.[28] evaluated antioxidants in patients with hereditary CP. Antioxidants levels in four groups were compared: hereditary CP, kindred but no pancreatitis, CP due to other etiology, and controls. Hereditary CP patients had lower antioxidant levels. Their kindred had higher vitamin E and selenium levels, which might have prevented them from having pancreatitis despite low glutathione peroxidase levels. Hence, the authors hypothesized that supplementation with vitamin E and selenium might be a good therapeutic option to decrease the frequency of pancreatitis in patients with CP.

Patients with CP in tropical areas had earlier onset of pancreatitis. In a study, Braganza etal.[29] showed that the bioavailability of beta- carotene and ascorbic acid was lower in tropical areas compared to temperate zones. The culinary practice that erodes bioavailability of these two antioxidants might have predisposed to pancreatic oxidative stress and earlier presentation of CP in tropical countries compared to temperate countries.

Whether presence of diabetes significantly modifies oxidative status in patients with CP was evaluated in another study. CP patients with or without diabetes were compared with type 1 diabetes and healthy controls for oxidant and antioxidant status as well as LDL oxidation status. Antioxidant status was altered in patients with CP particularly in those with diabetes. In these patients, vitamin E deficiency and elevated plasma glucose level were associated with significantly higher LDL oxidizability predisposing to atherosclerosis[9].

Uden etal.[17] found significantly low antioxidant levels of selenium, vitamin C, and vitamin E compared to controls in patients with idiopathic CP and suggested that selenium supplementation might be beneficial.

The question whether oxidative stress played any role in the progression of disease from recurrent acute to chronic pancreatitis was addressed in a recent study by Bopanna etal.[30]. The study included patients with idiopathic recurrent acute pancreatitis both in the acute phase and the quiescent phase to evaluate oxidative stressand found that patients had oxidative stress during the acute phase of illness and antioxidants levels were reduced. Taken together, the findings suggested that oxidative stress was associated with recurrent attacks of

pancreatitis and might be contributing to the progression of recurrent acute pancreatitis to CP.

Hence, most studies have shown the presence of oxidative stress and decreased antioxidant levels in patients with CP. The low antioxidant levels may be due to dietary deficiency or impaired absorption resulting from pancreatic insufficiency or from increased consumption due to oxidative stress.

Role ofAntioxidant Supplementation inCP

To mitigate oxidative stress and correct antioxidant deficiency, it was postulated that antioxidant supplementation might be beneficial. There are multiple randomized controlled trials (Table 57.1) and metaaddress this issue.

The first RCT was conducted by Uden etal.[31]. It was a double- blind placebo- controlled crossover RCT. Twenty- three patients were recruited of whom only 20were included in the final analysis (7had alcoholic CP, 8had idiopathic CP, and 5had recurrent acute pancreatitis). One arm was given combination antioxidants (daily 600 μg selenium, 0.54 gm ascorbic acid, 9000 IU β- carotene, 270 IU α- tocopherol, and 2 gm methionine) and the other arm was given placebo. Total duration of treatment was 20weeks with crossover at 10weeks. Six patients on placebo had recurrent attacks compared to none in the antioxidant arm. The authors concluded that active treatment was associated with clinical improvement over and above placebo effect.

Banks et al. [32] subsequently studied the antioxidant allopurinol in patients with painful CP and compared it with placebo. There was no decrease in visual analog scale (VAS) score or McGill score with the intervention though the study was limited by a small sample size of only 16 patients. Bilton etal.[33] also failed to show any improvement in VAS score in a double- blind placebo- controlled RCT of combination antioxidants (daily 800 mg SAMe, 600 μg selenium, and 9000 IU β- carotene) compared to placebo.

Curcumin supplementation for 6weeks did not show any improvement in VAS score compared to placebo in an RCT. Though the study showed improvement in GSH level in red blood cells and decrease in MDA levels, there was no improvement in pain[34].

In a double- blind placebo- controlled crossover RCT, 36 patients with CP were randomized to receive combination antioxidants (4 times daily 75 μg selenium, 3 mg β- carotene, 47 mg d- α- tocopherol, 150 mg ascorbic acid, and 400 mg methionine) or placebo for 20 weeks with crossover at 10we eks. There was significant improvement in pain component of SF 36 score with the combination antioxidant therapy[35].

analyses to

Role ofAntioxidant Supplementation inCP 455

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Table57.1 Summary oftrials ofantioxidant supplementation inchronic pancreatitis.

Author Type of study N Intervention Outcome measures Results Remarks

Uden 1990 Double- blind

placebocontrolled crossover RCT

Salim 1991 3 armed, parallel,

double- blind, placebocontrolled RCT

Bilton 1994a

Doubleplacebo-

blind

controlled crossover RCT

Bilton 1994b

Doubleplacebo-

blind

controlled crossover RCT

Banks 1997 Double-

blind placebocontrolled crossover RCT

Nandi 2002 Parallel placebo-

controlled RCT

Durga Prasad 2005

Parallel singleblind placebocontrolled RCT

23 Combination

antioxidants (daily 600 selenium, 0.54 ascorbic acid, 9000 β-

carotene, 270 IU

tocopherol, and 2 gm

αmethionine) vs. placebo  Duration: 20weeks, no washout period

78 (25 vs. 26 vs. 27)

4 times daily 50 allopurinol vs. 500 dimethyl sulfoxide vs. placebo  Duration: up to 24 hours pain-

f ree (mean = 45

hours)

30 3daily doses of 800

S- adenosyl methionine (SAMe) vs. placebo  Duration: 20weeks (no washout)

14 Combination

antioxidants (daily SAMe, 600 μg selenium, and 9000 IU β- carotene) vs. placebo

16 Allopurinol 300

vs. identical placebo  Duration: 10weeks with 2weeks washout after initial 4weeks

25 Combination of

antioxidants (daily 600 μg selenium, 0.54 gm ascorbic acid, 9000 IU

β- carotene, 270 IU α- tocopherol, and 2 gm

methionine) vs. placebo  Duration: 6months

20 Combination

antioxidants (3 times daily 500 mg curcumin and 5 mg piperine) vs. placebo  Duration: 6weeks

mg/d

μg

800mg

● VAS

● 1.01 (0.16–4.26)

Low risk of bias

vs. 1.88 (0.22–

5.76), NS

● McGill pain

score

● Descriptive pain

score

● No significant

difference

● No clear

difference

● 6 patients in

placebo had attack compared to none with intervention

● Number of

pain-

free

● 13 vs. 12 vs. 4

Unclear risk of bias

patients

● Discharge days

● 3days vs. 3days

vs. 5days

● VAS No difference Data not shown

VAS No difference Data not shown

● VAS score

● 2.8, P = 0.24

Low risk of bias (0–100): difference in mean decrease from baseline

● McGill’s score

● - 0.3, P = 0.75

(0–45): difference in mean decrease

● Pain score (12

points)

● Pain- free days/

● 1.25 vs. 3.62, NS

● 3.75 vs. 4.12, NS

Unclear risk of

bias

VAS score (after intervention)

5.81 (0.74) vs. 6.57 (0.74), NS

High risk of

bias

(Continued)

Oxidative Stress andAntioxidants inChronic Pancreatitis

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Table57.1 (Continued)

Author Type of study N Intervention Outcome measures Results Remarks

Kirk 2006 Double- blind

placebocontrolled crossover RCT

Bharadwaj 2009

Parallel doubleblind placebocontrolled RCT

Jarosz 2010 Open label

parallel RCT

Siriwardena 2012

Parallel doubleblind placebocontrolled RCT

Talukdar

RCT 87 Antioxidant plus

2016

Singh 2019 Parallel double-

blind placebocontrolled RCT

36 Combination

antioxidants (4 times daily 75 βdascorbic acid, and 400 methionine) vs. identical placebo  Duration: 20weeks (no washout)

127 (71 vs. 56)

Combination of antioxidants (daily 600 selenium, 0.54 ascorbic acid, 9000

β- carotene, 270 IU α- tocopherol, and 2 gm

methionine) vs. identical placebo  Duration: 6months

91 (46 vs. 45)

Combination antioxidants (vitamin C and vitamin E vs. standard treatment)  Duration: 6months

70 (33 vs. 37)

Combination antioxidants (38.5 selenium, 113.4 mg d- tocopherol acetate,

126.3<tsmg ascorbic acid, and 480 mg l- methionine) vs. placebo  Duration: 6months

pregabalin vs. placebo for 2months followed by open label antioxidants for 4months in both groups

107 Combination

antioxidants (daily 600 μg selenium, 0.54 gm ascorbic acid, 9000 IU

β- carotene, 270 IU α- tocopherol, and 2 gm

methionine) vs. placebo

μg selenium, 3 mg

carotene, 47 mg

α- tocopherol, 150 mg

μg

Pain- free participants

● Daily VAS

● SF 36: pain

component (change from baseline)

● Painful days/

mo: decrease from baseline

● Painful days/

mo: after intervention

● Pain- free

participants

● Change in VAS

● Average daily

VAS

● Pain- free

participants

● Improvement in

pain (VAS and Izbicki score)

● VAS

● Pain- free

participants

● Not analyzed

● +17 points vs. - 7

points, P

● 7.37 (6.75) vs.

< 0.05

3.21 (3.99), P < 0.001

● 1.68 (2.8) vs.

3.36(4.35), = 0.012

● 23/71(32%) vs.

7/56 (13%), P = 0.009

22/32 (68%) vs. 11/56 (31%), P = 0.002

● - 2.33 (2.09) vs.

1.97 (2.46), NS

● 2.93 (1.96) vs.

3.05 (1.96), NS

● 19 (58%) vs. 20

(54%), NS

● percent reduction

of VAS (-

[- 80.0; - 32.1] vs.

29.5 [- 64.5; 0]; = 0.01)

● Izbicki score

(14.5 [0; 21.3] vs.

30.0 [11.8; 41.3]; P = 0.001)

● complete pain

resolution (20 [47.6%] vs. 12 [26.7%]; P = 0.04)

● No difference

High risk of bias

Largest study to date with low risk of bias

High risk of bias

Low risk of bias

Included patients had recurrence of pain after prior endoscopic or surgical therapy

The primary outcome of the study was improvement in pancreatic functions and pain assessment was a secondary outcome

NS: not significant; VAS: visual analog scale.

Table57.2 Summary ofmeta- analyses onantioxidant supplementation inchronic pancreatitis.

https://t.me/medicina_free

Author Study types included Number of studies Outcome measures Conclusion

References 457

Ali etal. 2014 Cochrane systemic review

Zhou etal. 2014 RCT 8 (573

Rustagi etal. 2015

Mohta etal. 2020

RCT 12 (585

participants)

RCT 8 (446

participants)

RCT 4 (352

participants)

The limitations of these studies were a small sample size, inclusion of predominantly alcoholic CP, nonstandardized quantification of pain, and short duration of antioxidant supplementation.

Bhardwaj et al. conducted a double-

blind placebocontrolled RCT to study the role of antioxidant supplementation in patients with both alcohol- related and idiopathic CP. A total of 127 patients with CP (age

30.5 ± 10.5 years, 32 alcohol- related and 95 with idiopathic CP) were randomized to receive either antioxidants (n = 56; daily 0.54 gm ascorbic acid, 9000 IU β- carotene, 270 IU α- tocopherol, 600 μg selenium, and 2 gm methionine) or placebo (n = 71), for 6 months. There was a significant reduction in number of painful days per month in the antioxidant group (7.37 [6.75] vs.

3.21 [3.99], P < 0.001). Twenty- three out of 71 patients were pain- free in the antioxidant group compared to 7 out of 56in placebo (P = 0.009). The reduction in levels of TBARS and increase in levels of FRAP were also significantly higher in the antioxidant group, which was commensurate with the clinical observation[36].

Another trial randomized 70 patients with CP to receive

either combination antioxidant, (n = 33; 38.5 mg selenium,

113.4 mg d- tocopherol acetate, 126.3 mg ascorbic acid, and 480 mg l- methionine) or placebo (n = 37) for 6months[37]. The study did not find improvement in VAS score or number of pain- free patients with the antioxidant therapy. However, there were several limitations of the study which prevented its generalizability: all the patients were receiving a mean of 85 mg/day opioids suggesting chronic

Pain complaints pre-

and post-

intervention

Pain relief Antioxidant administration

Pain reduction Benefit of antioxidant therapy for

Pain relief Quality of life

Antioxidants can reduce pain slightly in CP. Adverse events in 1in 6 patients may prevent use

effective in relieving pain

pain reduction (RR: 0.73; 95% CI:

0.58–0.91)

No significant pain reduction or change in quality of life

neuropathic pain, more than half of patients had failed prior medical or surgical therapy suggesting that they have a severe unresponsive disease, and they continued to drink alcohol and smoke during the study period[38].

One study evaluated the combined role of antioxidants and pregabalin in patients with recurrence of pain following surgical/endoscopic therapy and showed that the combination therapy significantly reduced pain[39].

Four meta- analyses[40–43] have been done to date to study the role of antioxidant supplementation in pain relief in CP (Table57.2). Three out of four meta- analyses have shown benefit with antioxidant therapy. In the Cochrane systemic review and meta- analysis[40], which evaluated 12 RCTs including 585 participants, there was a slight reduction in pain with the antioxidant therapy. It showed that adverse events might prevent use of antioxidants in one out of six patients. Effects on other outcomes such as use of analgesics, exacerbation of pancreatitis, and quality of life remained uncertain.

Conclusion

Pain is the predominant symptom in patients with chronic pancreatitis. There is compelling evidence that oxidative stress is involved in the pathogenesis of CP. Patients with CP are deficient in antioxidants due to impaired absorption and increased demand. Supplementation with antioxidants is beneficial in reducing pain in patients with CP.

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