Acute Appendicitis and Serotonin

Also see:
Linoleic Acid and Serotonin’s Role in Migraine
Hypothyroidism and Serotonin
Estrogen Increases Serotonin
Tryptophan, Sleep, and Depression
Anti-Serotonin, Pro-Libido
Serotonin and Melatonin Lower Progesterone
Intestinal Serotonin and Bone Loss

Indian J Gastroenterol. 1997 Jan;16(1):18-9.
Evaluation of plasma serotonin concentration in acute appendicitis.
Kalra U, Chitkara N, Dadoo RC, Singh GP, Gulati P, Narula S.
BACKGROUND:
Due to lack of reliable biochemical/radiological markers, the diagnosis of acute appendicitis is based only on clinical features.
METHODS:
We estimated plasma serotonin levels in 48 patients with acute appendicitis (histologically proven), 27 patients with abdominal pain of other etiologies, and 20 healthy controls.
RESULTS:
The plasma serotonin levels were (mean +/- SD) 36.6 +/- 12.5 nmol/L, 12.5 +/- 3.6 nmol/L and 10.4 +/- 3.5 nmol/L in the three groups, respectively. The levels in patients with acute appendicitis were significantly higher (p < 0.001) than in the other groups, giving 93.8% sensitivity and 95.7% specificity to the test.
CONCLUSION:
Plasma serotonin level is a reliable marker of acute appendicitis, especially in the first 48 hours.

APMIS. 2008 Nov;116(11):947-52.
Serotonin content of normal and inflamed appendix: a possible role of serotonin in acute appendicitis.
Vasei M, Zakeri Z, Azarpira N, Hosseini SV, Solaymani-Dodaran M.
The appendix is lined by a mucosa which has many neuroendocrine cells containing serotonin. Local release of serotonin can act as a mediator of inflammation. In this study we explored the serotonin content of the neuroendocrine cells of the appendixes removed for clinical diagnosis of appendicitis. Appendix specimens were divided into three groups: Acute appendicitis (AA), non-appendicitis (NA), and follicular hyperplasia (FH). Normal appendix specimens from patients undergoing elective abdominal surgery were used as the control group (NL). All sections were exposed to proteinase K, incubated with anti-serotonin, chromogranin A, and synaptophysin antibodies, and treated with the LSAB kit. Polygonal cells were seen within the crypt epithelium (enterochromaffin cell, EC) and within the lamina propria (subepithelial neuroendocrine cell, SNC). In AA, only 16 cases (64%) showed serotonin staining in non-destructed glands. There was a significant reduction in the number of ECs in AA compared to the FH (96%), NA (100%) and NL (100%) groups (P<0.001). Chromogranin and synaptophysin immunostaining also showed a significant reduction in the number of ECs in AA compared with the other three groups (P<0.001). SNC serotonin reactivity was lower in the AA group compared with the other groups (p<0.001). The inflamed appendix is markedly depleted of serotonin in the epithelium and lamina propria. Local serotonin release from ECs and SNCs in the appendix may act as an inflammatory mediator in appendicitis and is likely to be the source of raised blood serotonin in AA.

Diagn Histopathol. 1983 Jul-Dec;6(3-4):239-46.
Serotonin and its possible role in the painful non-inflamed appendix.
Dhillon AP, Rode J.
After immunohistochemical staining appendices without active inflammation but producing symptoms of appendicitis (N = 24) were compared with a control group of appendices removed incidental to another procedure (N = 26). Staining for neurone specific enolase (NSE) showed more instances of nerve ‘hyperplasia’ in the control group than in the appendices generating pain refuting the concept of neuroappendicopathy based on quantitative nerve changes. Serotonin staining identified subepithelial neuroendocrine cells (SNC) in 85 per cent of the specimens. All cases showed serotonin immunoreactive enterochromaffin cells (EC). Staining for serotonin was significantly decreased in the SNC in the painful group. There were no significant differences between the two groups in staining intensity of SNC and EC for substance P (SP). Vasoactive intestinal polypeptide (VIP) was not seen in the SNC and EC and there were no differences in nerve fibre staining for VIP. Serotonin is a neurotransmitter as well as mediator of inflammation. It is suggested that reduced staining for serotonin in painful appendices reflects discharge of stores which could be instrumental in inducing the pain in these cases. Continued serotonin release may then lead to acute appendicitis.

Clinical Chemistry December 1988 vol. 34 no. 12 2572-2574
Concentrations of serotonin in plasma–a test for appendicitis?
S M Singh, H G Dean, F T de Dombal, D H Wilson and M W Flowers
We assessed the value of measuring serotonin (5-hydroxytryptamine) in plasma (by HPLC) in the diagnosis of acute appendicitis. Values for patients with subsequently confirmed appendicitis (11-145 nmol/L, median 70 nmol/L) significantly (P congruent to 0.005) exceeded those for patients with abdominal pain in whom appendicitis was only a possible diagnosis (2-45 nmol/L, median 20 nmol/L). The results for appendicitis patients were bimodally distributed, with low results found in patients where surgery revealed gangrenous appendicitis with little viable appendicular tissue. We conclude that measuring serotonin may be of value in confirming or excluding the diagnosis of early acute appendicitis where the physical signs are equivocal, and thus helps reduce unnecessary appendectomies. However, serotonin is of little help in diagnosing gangrenous appendicitis, where physical signs are more likely to be clearcut.

Hepatogastroenterology. 2001 May-Jun;48(39):609-13.
Spot urine 5-hydroxy indole acetic acid and acute appendicitis.
Ilkhanizadeh B, Owji AA, Tavangar SM, Vasei M, Tabei SM.
BACKGROUND/AIMS:
Appendectomy for suspected appendicitis cases is a common procedure. Its clinical diagnosis needs to be supported by accurate confirmatory tests. No single paraclinical test with a high degree of sensitivity and specificity is available for its diagnosis. The appendix contains numerous serotonin-producing cells (enterochromaffin cells). In the inflammatory process and subsequent cell injury, serotonin is released and converted to 5-HIAA (5-hydroxy indole acetic acid). We studied the elevation of 5-HIAA in the spot urine of acute appendicitis patients.
METHODOLOGY:
5-HIAA was measured by high-performance liquid chromatography in the spot urine samples of 40 healthy individuals and 166 patients who presented to emergency units of the university hospitals with acute abdominal pain. The results of the urine concentrations were compared to the histopathology reports of the removed appendices and the final diagnosis of other diseases.
RESULTS:
From 80 cases with a presumptive diagnosis of appendicitis, 73 were operated on and seven cases discharged after a few hours observation. Sixty-five out of 66 documented appendicitis patients showed a striking increase of urinary spot 5-HIAA with significant differences vs. all cases of healthy control individuals (P < 0.001). The 5-HIAA values of all of the negative appendectomy cases (n = 7) and all of the discharged cases after the observation period (n = 7) were within healthy control ranges. The mean value of the appendicitis group (42.76 +/- 2.26 mumol/L) was also significantly higher vs. all other acute abdomens which could mimic acute appendicitis (P < 0.05) excepting gastroenteritis patients. Considering 20 mumol/L as the cutoff value sensitivity, specificity, positive and negative predictive values of this test for discriminating appendicitis in clinically suspected patients were 98%, 100%, 100% and 93%, respectively and in all acute abdomens were 98%, 71%, 69% and 98.6%, respectively. The patients with gastroenteritis also showed elevation of 5-HIAA (43.05 +/- 2.7 mumol/L) vs. other nonappendicitis groups (P < 0.05). CONCLUSIONS: We have concluded that measurement of 5-HIAA in spot urine is a highly reliable test supporting the clinical diagnosis of appendicitis and if it does not show an increase, appendicitis can be ruled out with a very high degree of confidence which helps to reduce unnecessary appendectomies. In clinically suspected appendicitis patients with diarrhea, an increase of 5-HIAA may not confirm the diagnosis.

Clin Biochem. 2004 Nov;37(11):985-9.
Urinary 5-hydroxy indole acetic acid as a test for early diagnosis of acute appendicitis.
Bolandparvaz S, Vasei M, Owji AA, Ata-Ee N, Amin A, Daneshbod Y, Hosseini SV.
OBJECTIVES:
Acute appendicitis (AA) is the most common abdominal emergency. The appendix has abundant serotonin containing cells. Upon inflammation, serotonin is released in the blood and converted into 5-HIAA (5-hydroxy indole acetic acid). Measurement of the urine 5-HIAA (U-5-HIAA) could be a reliable marker of inflammation of the appendix. We have compared the powers of test performance of spot U-5-HIAA and spot U-5-HIAA/creatinin with other routine laboratory tests used for the diagnosis of acute appendicitis.
DESIGN AND METHODS:
Urine, serum, and blood samples of 110 patients who were admitted and observed in the emergency units of two university hospitals were studied. 5-HIAA was measured using HPLC, C-reactive protein by immunoturbidometry, WBC by electronic cell counting, and urine creatinine by the Jaffe method. Diagnostic accuracy of the various tests was evaluated by receiver operating characteristic (ROC) analysis.
FINDINGS:
The mean of spot U-5-HIAA in 39 patients with AA (nongangrenous) was 32 +/- 2.6 micromol/L, which was much higher than the mean of 40 non-appendicitis patients (NA) (5.5 +/- 0.6), 10 follicular hyperplasia (7.5 +/- 2.1), and 50 healthy control cases (4.1 +/- 0.5) with P < 0.001. The concentration of U-5-HIAA in 21 patients with gangrenous appendicitis (GA) (13.8 +/- 2.1) was also higher than NA patients and healthy individuals but lower than AA cases (P < 0.05). Considering 10 micromol/L as the cutoff point, this test shows 84% sensitivity and 88% specificity, with 90% and 81% positive and negative predictive values, respectively. The area under ROC curve (AUC) of U-5-HIAA in the diagnosis of AA (AUC = 0.903) was much larger than AUCs of U-5-HIAA/Cr (0.787), WBC (0.703), and CRP (0.660). CONCLUSION: Urinary secretion of 5-HIAA increases significantly in acute appendicitis and measurement of spot U-5-HIAA gives higher diagnostic accuracy than other routine laboratory tests. While the inflammation progresses to necrosis of the appendix, the concentration of 5-HIAA decreases. This decrease could be a warning sign of perforation of the appendix.

Am J Emerg Med. 2009 May;27(4):409-12.
The importance of urine 5-hydroxyindoleacetic acid levels in the early diagnosis of acute appendicitis.
Mentes O, Eryilmaz M, Harlak A, Yaman H, Yigit T, Ongoru O, Balkan M, Kozak O, Tufan T.
PURPOSE:
Acute appendicitis is one of the most common surgical emergencies. Diagnosis is usually made depending on the presenting history, clinical evaluation, and laboratory tests. The aim of this study was to investigate the role of urinary 5-hydroxyindoleacetic acid (U-5-HIAA) in the early diagnosis of acute appendicitis.
METHODS:
Thirty-five pigmented male rabbits were divided into 5 groups. Group 1 is the control (n = 7); group 2 is the sham (n = 10). The appendix was ligated from its base, and an appendectomy was performed after 12, 24, 36 hours in group 3 (n = 7), group 4 (n = 7), and group 5 (n = 7), respectively. Spot urine samples were obtained for U-5-HIAA determination, and appendectomy tissues were examined histopathologically.
RESULTS:
Acute appendicitis was diagnosed in all animals in group 3, group 4, and group 5, and the mean levels of U-5-HIAA in group 3 were higher than in the other groups. The mean of U-5-HIAA levels between animals with appendicitis and those without showed a significant difference (P = .003). The U-5-HIAA cutoff point of 4.15 mg/g creatinine had a sensitivity of 85%, a specificity of 64.29%, and an accuracy of 76% (area under curve = 0.805) for acute appendicitis. The probability of acute appendicitis is found to be 10, 2 times more when the U-5-HIAA level is greater than 4.15 mg/g creatinine.
CONCLUSION:
We have concluded that spot U-5-HIAA level increases significantly in the early stages of acute appendicitis.