Anorexia and the effect of internal biliary drainage on food intake in patients with obstructive jaundice1

Anorexia and the effect of internal biliary drainage on food intake in patients with obstructive jaundice1

Anorexia and the Effect of Internal Biliary Drainage on Food Intake in Patients with Obstructive Jaundice Francisco J Padillo, MD, Beatriz Andicoberry...

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Anorexia and the Effect of Internal Biliary Drainage on Food Intake in Patients with Obstructive Jaundice Francisco J Padillo, MD, Beatriz Andicoberry, MD, Antonio Naranjo, MD, Gonzalo Min˜o, MD, Carlos Pera, MD, Antonio Sitges-Serra, MD, FRCSEd Anorexia is a frequent finding in patients with biliary obstruction (BO). This study investigates the role of biochemical and hormonal factors in the pathogenesis of reduced food intake in BO and the effects of internal biliary drainage. STUDY DESIGN: Sixty-two patients with BO were prospectively investigated. Transaminases, amylase, cholecystokinin, secretin, bile acids, tumor necrosis factor-␣, and endotoxin were determined at admission. Caloric intake was quantified by a controlled diet. In a subset of 27 patients, studies were repeated after internal biliary drainage. RESULTS: Sixty-six percent of patients had spontaneous food intakes below the estimated caloric requirements. Serum bilirubin, alkaline phosphatase, and cholecystokinin plasma levels were independent predictor factors for calorie intake (p⫽0.0001). After internal biliary drainage, cholestasis parameters and cholecystokinin concentrations decreased significantly; this was associated with an improvement of spontaneous food intake in both benign and malignant biliary obstruction (p ⬍ 0.01 and p⬍0.05, respectively). CONCLUSIONS: Decreased food intake in BO was associated with the degree of obstruction and with increased cholecystokinin plasma levels. Biliary drainage improved biochemical and food intake derangements. (J Am Coll Surg 2001;192:584–590. © 2001 by the American College of Surgeons) BACKGROUND:

patients with obstructive jaundice,11 and it has been associated with decreased food intake after bile duct ligation in an experimental study.12 To date, however, these findings have not been confirmed in humans. Secretin may also be involved in hunger-satiety regulating mechanisms, by slowing down the rate of gastric emptying,13 although no measurements of this hormone have been made in obstructive jaundice. The aims of this study were to determine biochemical and hormonal factors potentially related to food intake alterations observed in patients with obstructive jaundice, and to analyze the impact of endoscopic internal biliary drainage on biochemical and hormonal derangements and food intake alterations.

Protein-calorie malnutrition is common in patients with obstructive jaundice.1,2 Anorexia is a frequent finding in malignant3 and benign biliary obstruction,4 but the factors involved in its pathogenesis remain to be elucidated. In experimental animals, hypophagia and hypodypsia are striking features appearing as soon as 24 hours after common bile duct ligation.5 It has been suggested that retention of some bile components, mainly bile acids, may favor the appearance of anorexia through a toxic action.6,7 Other factors may include endotoxin, cytokines,8,9 or impaired liver function secondary to bile duct obstruction.10 Cholecystokinin (CCK), a hormone showing powerful anorectic effects, may be elevated in No competing interests declared.


This investigation was supported by grant PAI: 223/96.


Received August 9, 2000; Revised November 1, 2000; Accepted January 4, 2001. From the Departments of Surgery (Padillo, Pera), Nutrition (Andicoberry); and Gastroenterology (Naranjo, Min˜o) Hospital Universitario Reina Sofı´a, Co´rdoba, Spain and the Department of Surgery, Hospital Universitario del Mar, Barcelona, Spain (Sitges-Serra). Correspondence address: Prof. Antonio Sitges-Serra, Departamento de Cirugı´a, Hospital Universitari del Mar, Paseo Marı´timo 25-29, 08003 Barcelona, Spain.

© 2001 by the American College of Surgeons Published by Elsevier Science Inc.

One hundred eleven patients with obstructive jaundice were initially evaluated. Of them, 62 patients were included in the study. All met the following inclusion criteria: serum bilirubin greater than 5mg/dL, alkaline phosphatase greater than 150IU/L, and ultrasonographic evidence of cholestasis: intrahepatic and extra-


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hepatic bile duct dilation (greater than 4mm and 8mm, respectively). Causes for exclusion were: patients with obstructive jaundice unable to be fed orally;6 cholangitis;11 acute pancreatitis;9 patients with malignant obstructive jaundice presenting with metastases at diagnosis;8 pain requiring analgesics;7 any nonbile-duct pathology causing impaired food intake (5 chronic liver disease and 3 chronic renal failure). Of the 62 patients studied at admission, 27 were further investigated 2 and 6 days after successful and uncomplicated endoscopic internal biliary drainage. Exclusion criteria for postdrainage study were: unsuccessful drainage,9 cholangitis8 or acute pancreatitis4 episodes after drainage, bleeding6 or incomplete followup because of operation immediately after drainage.8 Biochemical and hormonal parameters were analyzed in a control group of 15 healthy subjects similar in age (69.8⫾13.5years [mean⫾SD]; range: 36–88 years) and gender distribution (7 men and 8 women) to the study group. Study protocol and determinations

This investigation was designed as a prospective, observational, longitudinal study. Informed consent was obtained from all patients, and the protocol was approved by the Ethics Committee of the Reina Sofı´a Hospital. Biochemical parameters, hormone, and endotoxin levels were measured before internal biliary drainage (n⫽62), and again at 48 hours and 6 days after drainage (n⫽27). Blood samples were taken in a fasting state. Total bilirubin, alkaline phosphatase (AP), transaminases (AST, ALT) and amylase were measured using a SYNCHRON CX7 analyzer (Beckman-Astra Instruments Inc, Brea, CA). Total bile acids plasma concentration was determined by measuring enzyme concentrations14 using direct spectrophometry (Sigma Diagnostics, St. Louis, MO). For hormonal measurements, blood samples were collected into chilled tubes containing ethylene diaminetetracetic acid (EDTA, 2mg/mL) and aprotinin (Trasylol 400 KIU/mL, Sigma Chemical Co, St. Louis, MO). Samples were centrifuged within 30minutes of collection (3,000rpm at 4°C for 10 minutes). The plasma was decanted and stored frozen at ⫺70°C for subsequent determination. Cholecystokinin (CCK) was determined by radioimmunoassay with plasma extraction through affinity columns (Sep-Pak C-18, Waters Corporation, Milford, MA). Plasma was extracted with 99% ethanol (1:2 vol/vol) lyophilized

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and reconstituted with assay buffer. For CCK determination OAL-656 antiserum, 125I-labeled BoltonHunter CCK-33 reagent was used as a tracer and synthetic CCK-8 was used as standard. The antiserum bound 100% of CCK-8 but did not crossreact with the nonsulfated form of CCK-8 (0.04%), gastrin-17 (0.2%) nor with sulfated gastrin-17 (0.9%). The half-maximal inhibitory dose (ID50) was 42pmol. The detection limit was 1.2pmol/L plasma. Measurements were made in duplicate on a gamma scintillator (Ultrogamma Counter-INa, Crystal 2-5400 B-5412; Packard Instrument Company Inc, Canberra, Australia). The intraassay coefficient of variation for these measurements was 7.5%. Secretin levels were determined by radioimmunoassay with plasma extraction through affinity columns (Waters Sep-Pak C-18). Radioimmunoassay was performed using a peptide radioimmunoassay kit (Phoenix Pharmaceuticals, Mountain View, CA). The intraassay coefficient of variation for these measurements was 6.3%. Endotoxin was measured using the E-TOXATE kit (Sigma Chemical Company, St. Louis, MO), for the Limulus semiquantitative test.15,16 Tumor necrosis factor (TNF)-␣ was measured in serum by competitive enzyme-linked immunoassay (ELISA) with antigen and polyclonal antibody (Genzyme Diagnostic, Cambridge, MA). Quantification of spontaneous food intake

Protein-calorie requirements were calculated for each patient using the Harris-Benedict formula,17 applying a correction factor of 1.2 for activity because patients were deemed moderately active. From admission, patients were kept on an individual, controlled, and weighed diet, containing on average 2,500 kcal/day. All food was weighed before serving and after meals, to monitor the patient’s actual intake. Calorie intake was evaluated using the “diet composition” computer program (Nuwander, Spain). Each patient was asked to indicate whether any food or method of cooking was unacceptable, in which case it was replaced by a preferred food. Before drainage, food intake was monitored for at least 3 days. To avoid biases from individual differences in eating habits, results were expressed as a percentage of the calorie requirement of each patient. In a subgroup of 27 patients studied after biliary drainage, oral feeding was withheld on the day of drainage and resumed at 12 or 24 hours after drainage, ac-


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Table 1. Comparison of Baseline Parameters, Bile Acids, Endotoxin, and Hormones in Patients with Benign and Malignant Obstructive Jaundice and in the Control Group Parameters

Benign OJ

Malignant OJ

Control group

(n ⫽ 35) 15 ⫾ 9* 15 ⫾ 7* 118 ⫾ 51† 1068 ⫾ 910* 155 ⫾ 109 176 ⫾ 128 73 ⫾ 77† 10 ⫾ 9† 73 ⫾ 31† 3.9 ⫾ 1.4† 3.5 ⫾ 2.5

(n ⫽ 15)

Duration of jaundice (d) Bilirubin (mg/dL) Bile acids (␮mol/L) Alkaline phosphatase (UI/L) Aspartate aminotransferase (UI/L) Alanine aminotransferase (UI/L) Amylase (UI/L) Endotoxin (EU/mL) Tumor necrosis factor-␣ (pg/mL) Cholecystokinin (pmol/L) Secretin (pmol/L)

(n ⫽ 27) 9⫾6 9⫾5 83 ⫾ 46 366 ⫾ 330 188 ⫾ 239 230 ⫾ 192 228 ⫾ 210 17 ⫾ 10 21 ⫾ 14 2.5 ⫾ 0.2 4⫾5

0.6 ⫾ 0.4*‡ 6 ⫾ 4*‡ 101 ⫾ 53*‡ 34 ⫾ 40*‡ 34 ⫾ 22*‡ 38 ⫾ 20†§ ND*‡ 18 ⫾ 9‡ 1.4 ⫾ 0.5*‡ 4⫾2

Data are expressed as mean ⫾ SD. *p ⬍ 0.005 versus benign OJ. † p ⬍ 0.05 versus benign OJ. ‡ p ⬍ 0.005 versus malignant OJ. § p ⬍ 0.05 versus malignant OJ. ND, not detectable; OJ, obstructive jaundice.

cording to patient’s tolerance. Food intake was monitored during the 6 days after biliary drainage. Endoscopic internal drainage

Papillotomy and removal of calculi from the common bile duct were performed in eight patients with benign disease. Insertion of metallic self-expandable endoprostheses (Wallstent [Pfizer Medical Technology Group, Rutherford, NJ]: 30 Fr when expanded) was performed in seven patients and insertion of plastic endoprostheses (10 Fr) was performed in the remaining 12 patients. Statistical analysis

The Student’s t-test was used for comparison of quantitative variables having approximately normal distributions. For other variables, Wilcoxon’s signed-rank test was used for paired variables, and for unpaired variables the Mann Whitney test was used. Correlations for quantitative variables were determined using Pearson’s correlation coefficient. Multiple linear regression was used to determine anorexia-predicting factors. Variables for which p⬎0.15 were successively eliminated from the regression model using the stepwise method. For followup study after biliary drainage, an ANOVA for repeated measures was done. A paired binomial test was done to compare the change in the proportion of patients presenting with spontaneous food intake alterations at the end of the study. Results are expressed as mean⫾standard deviation (SD).

RESULTS In the baseline study there were 29 men (47%) and 33 women (53%). Mean age was 68⫾12 years (range 33 to 81 years). Patient conditions included choledocholithiasis (23 patients), Mirizzi’s syndrome,4 periampullary tumor,12 hilar tumor13 and cholangiocarcinoma.10 Duration of jaundice for the 62 patients studied was 10⫾7 days. Table 1 shows the values of the parameters in patients with obstructive jaundice and controls. Endotoxinemia and tumor necrosis factor concentrations

Although endotoxin was virtually undetectable in plasma of healthy controls, patients with benign or malignant biliary obstruction showed high plasma endotoxin levels (Table 1). But increased levels of TNF-␣ were only detected in jaundiced patients with malignant obstruction. Endocrine changes

Mean CCK values in patients were significantly higher than in controls. Seventy-two percent of patients with obstructive jaundice (67% of benign obstructions and 75% of malignant tumors) had CCK plasma concentrations above the mean plus 2 SD (1.75pmol/L) of the control group (p⬍0.01). A positive linear correlation was observed between plasma CCK levels and both plasma bilirubin (r⫽0.58; p⬍0.001) and bile acids (r⫽0.61; p⬍0.001) (Fig. 1). CCK values did not cor-

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Figure 1. Correlation between plasma concentration of CCK (pmol/L) and bile acids (␮mol/L) (r ⫽ 0.6; p ⬍ 0.01). Equation of linear regression: y (CCK) ⫽ 1.3 ⫹ 0.013 ⫻ (bile acids). CCK, cholecystokinin.

Figure 2. Correlation between plasma concentration of CCK (pmol/L) and caloric intake (%) (r ⫽ ⫺0.7; p ⬍ 0.001). Equation of linear regression: y (caloric intake) ⫽ 123 ⫺ 18 ⫻ (CCK). CCK, cholecystokinin.

relate with duration of jaundice. Values of CCK for patients with benign biliary obstruction were lower than those recorded for patients with malignant neoplasia (Table 1). Secretin showed no significant differences with respect to controls or on stratification by cause (Table 1).

Changes after internal biliary drainage

Evaluation of calorie intake

Mean food intake of patients with obstructive jaundice was 987⫾312 Kcal, representing 71⫾24% of the estimated calorie requirements, 78⫾21% in patients with benign obstruction, and 64⫾26% in those with malignant obstruction. Seventy-six percent of patients (65% of benign and 81% of malignant obstructions) showed a calorie intake lower than the estimated calorie requirements. Multiple linear regression (R2 ⫽0.72; analysis of variance: F⫽19.7; p⬍0.0001) showed that the variables associated with food intake were serum bilirubin (p⫽ 0.0001), CCK (p⫽0.001) (Fig. 2), and alkaline phosphatase (p⫽0.01). Significant interactions were observed between bilirubin and CCK (p⫽0.004). We found no correlation between TNF and calorie intake in the patients with malignant tumors, who had increased plasma levels of this cytokine (r⫽⫺0.22; p⫽0.25), nor in patients with benign conditions who did not show high levels of TNF (r⫽⫺0.13; p⫽0.6). Food intake was significantly lower in patients with elevated CCK levels (mean plus 2 SD above the control group) than in those with CCK levels close to controls, whose food intake was normal: 56⫾22% versus 102⫾ 18% of the estimated calorie requirements (p⬍0.001).

Twenty-seven patients (15 men and 12 women; mean age 68⫾15 years) were also investigated after successful biliary drainage. Patient conditions included choledocholithiasis,6 Mirizzi’s syndrome,4 periampullary tumors,6 hilar tumor,6 and cholangiocarcinoma.5 On day 6 after biliary drainage, plasma CCK levels fell significantly (Table 2) in patients with both benign obstruction (from 2.5⫾0.6 to 1.2⫾0.4pmol/L; p⬍0.001) and malignant obstruction (from 3.5⫾1.5 to 2⫾ 1pmol/L; p⬍0.01). Endotoxin and TNF-␣ plasma levels also decreased, but no changes were observed in plasma secretin levels (Table 2). Spontaneous food intake improved significantly after biliary drainage. The mean spontaneous intake rose from 990⫾384Kcal/day before drainage to 1,361⫾478 Kcal/day on day 6. Improved calorie intake was recorded for patients with both benign and malignant obstructions. This recovery, however, was significantly better in the group of patients with benign condition (Fig. 3). Expressed as a percentage of calorie requirements, there was a 30% increase in food intake during the monitored period (Table 3). By the end of the study, the proportion of patients presenting a spontaneous food intake below the estimated calorie requirements had fallen from 81% (22 of 27) before drainage to 48% (13 of 27; p⫾0.01). This decrease was observed both in patients with benign biliary obstruction (from 80% to 40%; p⬍0.050 and in those with obstruction secondary to malignancies (from 82% to 53%; p⫽0.05).


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Table 2. Changes in Baseline Parameters, Bile Acids, Endotoxin and Hormones after Internal Biliary Drainage (n ⫽ 27) Parameters

Total bilirubin (mg/dL) Bile acids (␮mol/L) Alkaline phosphatase (UI/L) Aspartate aminotransferase (UI/L) Alanine aminotransferase (UI/L) Amylase (UI/L) Endotoxin (EU/L) Tumor necrosis factor-␣ (pg/mL) Cholecystokinin (pmol/L) Secretin (pmol/L)


48 h

Day 6

p Value*

14 ⫾ 6.5 120 ⫾ 55 997 ⫾ 816 161 ⫾ 105 213 ⫾ 192 90 ⫾ 88 11 ⫾ 10 49 ⫾ 36 3 ⫾ 1.5 5⫾4

8⫾4 37 ⫾ 35 535 ⫾ 401 96 ⫾ 70 125 ⫾ 120 77 ⫾ 65 4.5 ⫾ 4 28 ⫾ 22 2.5 ⫾ 1.3 5⫾3

2.5 ⫾ 2 24 ⫾ 28 402 ⫾ 372 60 ⫾ 29 85 ⫾ 69 55 ⫾ 38 6 ⫾ 5.5 31 ⫾ 29 1.4 ⫾ 0.5 4⫾3

0.001 0.001 0.01 0.001 0.001 NS 0.03 0.03 0.001 NS

Data are expressed as mean ⫾ SD. *ANOVA test for repeated measures.

DISCUSSION Clinical3,4 and experimental5 studies have shown that bile duct obstruction leads to hypodypsia and hypophagia, although to date there has been no thorough research into the mechanism of anorexia observed in patients with obstructive jaundice. This study confirms the presence of intense anorexia in humans with obstructive jaundice. It also evaluates for the first time the role of several factors in the pathogenesis of decreased food intake in patients with benign and malignant conditions causing biliary obstruction, and the impact of internal drainage on these alterations. At admission more than two-thirds of the patients had a spontaneous food intake well below their calorie requirements. Although food intake was higher in patients with

Figure 3. Recovery of food intake (Kcal/day) in malignant (F) versus benign (䊐) biliary obstruction after internal biliary drainage. Student’s t-test for unpaired data: * p ⬍ 0.001 versus malignant obstruction. Data are expressed as mean ⫾ SD.

benign obstructive jaundice, no significant differences were observed in those with malignant conditions. After biliary drainage, spontaneous food intake improved significantly in patients with either benign or malignant obstruction, although more than 50% of patients with cancer remained with food intakes below the estimated calorie requirements at the end of the study period. These findings suggest that regardless of the degree of anorexia associated with malignancy, obstruction of the bile duct, per se, causes significant changes in food intake that reverse after biliary decompression. Endotoxin plasma levels were elevated in our patients, with higher values obtained in patients with benign obstruction, probably related to subclinical bacterial colonization. By contrast, higher levels of TNF-␣ were detected only in cancer patients. Neither endotoxin nor TNF-␣, however, were predictive factors for anorexia according to a multivariate analysis. Increased endotoxin and cytokine levels might play a role in food intake alterations in patients with prolonged biliary obstruction or subclinical bacterial colonization and cholangitis, in whom higher endotoxin and cytokine levels might be expected. Two hormones, secretin and CCK, were evaluated as mediators of anorexia. Although secretin might be involved in inducing satiety by slowing down the rate of gastric emptying, in our study this hormone was not a predictive factor for anorexia. As a matter of fact, no changes in secretin plasma levels were seen throughout the study period. CCK is considered one of the most powerful satiety-inducing agents, and it plays a major role in the regulation of both biliopancreatic18-21 and gastric secretion.22 The two published studies measuring

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Table 3. Evolution of Food Intake after Biliary Drainage in 27 Obstruction Jaundice Patients (10 with Benign Conditions and 17 with Malignant Obstruction) All patients Benign Malignant


Day 2

Day 3

Day 4

Day 5

Day 6

73 ⫾ 28 78 ⫾ 26 72 ⫾ 30

92 ⫾ 32 106 ⫾ 32 83 ⫾ 29

95 ⫾ 33 107 ⫾ 41 89 ⫾ 27

94 ⫾ 30 104 ⫾ 35 88 ⫾ 26

102 ⫾ 36 127 ⫾ 43 88 ⫾ 23

100 ⫾ 31* 120 ⫾ 41† 92 ⫾ 33‡

Data are expressed as mean ⫾ SD of percentage of estimated caloric requirements. ANOVA test for repeated measures: *p ⬍ 0.001. † p ⬍ 0.01. ‡ p ⬍ 0.05.

CCK in human obstructive jaundice have yielded conflicting results.11,23 Although increased levels of CCK were reported in one,11 no changes were found in the other,23 in which biliary obstruction was probably not sufficiently complete to allow detection of changes in CCK levels.24 In the present study, plasma CCK values were significantly higher in patients with either benign or malignant obstruction than in a healthy, age, and gender matched control group. Once bile flow to the duodenum was reestablished after endoscopic internal drainage, plasma CCK levels fell dramatically and promptly (⬍48hours). This agrees with clinical24-27 and experimental studies28,29 suggesting that regulation of plasma CCK levels is closely linked to the presence of bile acids (particularly chenodeoxycholic acid) in the duodenal lumen, to the proper digestion of dietary fats,18 and to the presence of protease within the duodenum.30 In our study, decreased food intake in patients with biliary tract obstruction correlated with increased CCK plasma values. Two distinctly different pathways have been suggested for the inhibitory effects of CCK on food intake: a central action of CCK on brain feeding centers through the “brain-gut axis”31,32 and a decrease in gastric contractions, favoring stasis of food in the stomach.13,33 Although CCK seems to be an excellent candidate molecule mediating anorexia, other factors not directly related to the pathophysiology of bile flow might be involved in the food intake derangements of patients with obstructive jaundice. To definitely prove the role of CCK in these alterations, the effect of this hormone should be blocked by a specific CCK receptor antagonist in patients with obstructive jaundice. For this purpose a randomized controlled trial with selective antagonists of CCK receptor would be required. In conclusion, the results obtained here suggest that obstruction of the bile duct, result in significant changes in food intake. Decreased food intake after obstruction

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