Pathologic Changes in the Colon Produced by Anthraquinone Purgatives *

BARBARA SMITH, M . D .

From the Departme,~t of Pathology, St. Bartholomew's Hos/~ital, Lo~don, England

PURGATIVES are among the most widely used and abused of all drugs. Some indi- viduals become addicted to them and have diarrhea, sometimes with metabolic disturb- ances. However, some chronic purgative- takers find that larger and larger closes have less and less effect. They may develop colonic dilatation and severe constipation, which may lead to efforts at surgical relief. A study has been made of colons excised surgically from purgative addicts to try and establish why they are nonfunctional.

Material and Methods

The material consists of 13 specimens of colon from 12 patients. In two patients total colectomy had been done, in two the specimen consists of the ascencling and part of the transverse colon, and in the other nine the left side of the colon had been resected. Tile two right-sided resec- tions were reoperations, the left colectomy having failed to relieve the patient's symp- toms. The myenteric plexus was examined by staining with silver, with sections cut parallel to the gut wall as described previously. I0

Results

The morbid anatomic changes seen in the cathartic colon consist of three main features: damage and loss of tile intrinsic innervation, atrophy of the smooth muscle coat, and melanosis coli.

* Received for publication June 12, 1972.

Dis. Col. &Rect. Nov.-Dec. I973

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Changes seen in tile myenteric plexus of the long-standing purgative addict consist of loss of neurons and replacement of the ganglia by Schwann ceils (Fig. 1). in some ganglia all the arD'rophil ceils are lost, but it is usually possible to pick out non- argyrophil neuronal nuclei among the sup- porting ceils. Standard paraffin sections show no abnormality of tile myenteric plexus. The argyrophil ceils which remain are darker than normal, shrunken, with dubbed processes and sometimes rather bizarre shapes (Fig. 2). Tw o of the 19 pa- tients were treated by colectomy before the age of 30 years and therefore cannot have been taking purgatives for very' long. They' also showed some schwannosis, although the cell fallout was not great. Some of the residual ceils, instead of being small and dark, were pale and grossly swollen (Fig. 3). Their processes remained fine, and there is no reason to believe them to be nonfunc- tioning, although they were ~'ossly over- stimulated.

When the bowels were examined macro- scopically they were noted to be thin-walled. Surgeons and radiologists are familiar with the baggy dilated colon, particularly on the right side. In two cases the thinning was so severe that it was quite difficult to cut sections in the plane of the plexus. This finding was borne out by paraffin sections, ahhough assessing wall thickness in this way is fraught with artifact. In five of 13 specimens there was a large amount off fat in the submucosa. This was originally described by Morson. 7

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4 5 ~ S M I T H Dis. Col. &Rect. Nov.-D~c. 1973

FIc. 1. Gangl ion f rom the colonic myenter ic plexus of a 60-year-old man, who had been taking senna regularly in large closes for m a n y }ears. T h e r e are no argyrophi l cells and the gangl ion conta ins only Schwann cells and a few non-arg?rophi l neurons .

Fro. 2. Gangl ion f rom the colonic myenter ic p lexus of a 64-year-old woman who had taken purgat ives all her life. T h e neurons are very dark, with misshapen perikarya and i r regular processes.

Volume 16 A N T H R A Q U I N O N E PURGATIVES 457 Number 6

Fro. 3. Ganglion from the myenteric plexus of the ascending colon of a 28-year-old woman. She had been taking large quantities of senna for ten )'ears, and the operation was her second colonic resection, The neuron is abnormally large and pale.

The other feature which is probably pathognomonic o[ anthraquinone adminis- tration is melanosis coll. This is the presence of brown pigment, pseudomelanin, in the macrophages of the mucosa. The pigment has the staining properties of a lipofuscin, and may be combined with the anthra- quinone itself, as it disappears when administration is stopped.~-;, ~3

Discussion

Purgative addiction is a welt-kno~n and difficult clinical problem. The patients usually have diarrhea when first seen and are often mentally unstable. The rest of the clinical picture is very variabIe, because no attempt has been made to subdivide the patients according to the drug or drugs they were taking. The phenolphthalein group, the bisacodyl type, and the anthra- quinone ~ o u p almost certainly produce purgation by different mechanisms, and

their toxic effects are different. 4, 6 Unfor- tunately very little pharmacologic informa- tion is available about their mode o[ action and, in particular, their effects on the small intestine, if any. Steatorrhea and some of the metabolic disturbances which occur in purgative addicts may be related to small- bowel rather than large-bowel dysfunction. These can be treated medically and do not need colectomy. Senna appears to act only in the large bowel, possibly because it is activated by colonic bacteria.S, 9 In a clinical case of a senna addict in whom intestinal intubation with thorough absorption and transit studies were done, the results of the studies were quite normal, the patient had no metabolic disturbance at all, and the diarrhea was colonic)

It is not easy to be certain what drugs a purgative addict is taking, as they can be very secretive about it, but so far as could be ascertained, these patients were all taking

458 SMITH Dis. Col. & Reef. Nov.-Dec. 1973

senna. T h e fact that they h a d melanosis coli confirms that they were t ak ing an th ra - quinones, a l t hough they may have been

tak ing o the r cathart ics as well.

Pure a n t h r a q u i n o n e s given pa ren te ra l ly

are ex t remely toxic, be ing po ten t cell poisons even in smal l doses. 12 W h e n syrup

of senna is given to mice, e i ther by m o u t h or parentera l ly , i t produces damage to the myen te r i c p lexus , tl Vegetable laxatives, which have been in use for generat ions,

are obvious ly qu i te safe. T h i s is p r o b a b l y because very l i t t le of the active p r inc ip l e is absorbed unconjuga ted . Many neuro tox ins , such as s t rychnine and cyanide, s t imula te in

subtoxic doses, and this could be the mode of act ion of these purgat ives . Th i s is sup- por ted by the f inding of swollen neurons in cases o[ shor t du ra t ion . Over the ),ears the overs t imula t ion eventua l ly results in cell

death. Effects of the d r u g on the muscle are slower and less s t r iking, bu t they may be impor t an t , as i t is the fa i lure of t i le muscle to respond to s t imula t ion which

finally renders tile cond i t ion irreversible.

T h e changes to be f o u n d in ca thar t ic

colon suggest that they are the resul t o[

damage to the structures in tile bowel wal l by the an th raqu inones . I f tile pu rga t ive add ic t ion goes on long enough, the colon is destroyed as a func t ion ing organ and the surgeon has l i t t le a l t e rna t ive but to r emove it. Since it is p r e d o m i n a n t l y a r ight -s ided

disease, s igmoidal colectomy may not prove

adequate .

Summa ry

Changes p roduced in the co lon by pro- longed inges t ion of a n t h r a q u i n o n e s are

loss of myenter ic neurons, a t r o p h y of the smooth muscle, and melanosis coli. Af ter many years this may resul t in a hmct ion less colon.

Re fe r e nc e s

1. Bartle HJ: The sigmoid: Anatomy, physiology, examination and pathology. Med J Rec 127: 521, 1928

2. Block LH, Greene BL: Melanosis coli. Rev Gastroenterol 8: 393, 1941

3. Bockus HL, }Villard JH, Bank J: Melanosis toll: The etiologic significance of the anthra- cene laxatives: A report of forty-one cases. JAMA 101: 1, 1933

4. Coghill NF, McAllen PM, Edwards F: Electro- lyte losses associated with the taking of purges investigated with aid of sodium and potassium radioisotopes. Br Med J I: 14, 1959

5. Dawson AM: Personal communication to the author

6. French JM, Gaddie R, Smith N: Diarrhoea due to phenolphthalein. Lancet 1: 551, 1956

7. Morson B: Quoted by Jones FA: Cathartic colon. Proc R Soc Med 60: 503, 1967

8. Okada T: ~2ber den Mechanismus der Sennaab- fiihrung. Tohuku J Exp Med 38: 33, 1940

9. Schmid W: Zum Wirkungsmechanismus di~ite- tischer und medikament6ser Darmmittel. Arzneim Forsch 2: 6, 1952

10. Smith B: Myenteric plexus in Hirschsprung's disease. Gut 8: 308, 1967

11. Smith B: Effect of irritant purgatives on the myenteric plexus in man and the mouse. Gut 9: 139, 1968

12. Smith B: The pathology of the myenteric plexus in the large intestine. Thesis, Uni- versity of Bristol, 1968

13. Speare GS: Melanosis coli: Experimefital ob- servations on its proddction and elimination in twenty-three cases. Am J Surg 82: 631, 1951