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Achalasia Hirschsprung’s and Chagas’ disease
Auerbach's Plexus (left) cross section (right) network
Achalasia of the oesophagus (48, 49) and Hirschsprung’s Disease of the rectum and colon have bowel containing no ganglion cells also known as enteric neurones responsible for the nervous control of gut movements. Both are of unknown aetiology. Chagas’ disease, or South American trypanosomiasis, is similar in that the oesophagus and colon are aganglionic, but the whole bowel is affected and only certain parts dilate. Another difference is that the aetiology is known; damage caused by the trypanosome in the lymphatics between the inner circular and outer longitudinal muscle layers destroys the ganglion cells.
X-ray's of the various stages of dilatation of Achalasia
It is suggested that the cause of achalasia and Hirchsprung’s Disease, both situated at either end of the alimentary tract, has nothing to do with Chagas’ disease but is caused by ischaemia following excessive rotation of the gut as a volvulus in utero in the embryo which selectively destroys ganglion cells. Other tissues recover but neurones do not regenerate, leaving denervated gut forever. Atresia and stenosis of the gut can also be caused by ischaemia depending on the severity and duration of anoxia. With varying degrees of ischaemia there are five different pathologies that may result:
Achalasia is derived from a Greek word meaning “no relaxation” of the lower oesophageal sphincter, which is represented on a barium swallow as a smooth tapered area looking like a rat-tail to those who have actually seen a rat. Another term is megaoesophagus which is the Greek for a large body of the oesophagus dilated with retained contents. The ganglion cell loss is greatest in this enlarged body and much less in the sphincter. The lumen of the oesophagus is normally empty because of the efficiency of primary or secondary peristalsis, both of which are abnormal in achalasia (48).
In figure 1 will be seen the different lesions found when the disease is analysed as a general neurological disease with damage spread throughout the medulla and vagal fibres (49). Does this represent damage primary or secondary to the loss of ganglion cells? It is known that enteric neurones do not degenerate when the vagus nerve is cut, so transynaptic degeneration does not occur. But backward retrograde degeneration does happen as a result of ganglion cell loss and these lesions are widespread, leading to the deduction that the primary pathology must be in the wall of the gut and not in the central nervous system. This ganglion cell loss is best seen in Auerbach’s plexus between the two layers of muscle, inner circular and outer longitudinal.
Once nerve cells have been lost in adult life, to date there is no possibility to restore them or replace them even with nerve cells. Luckily there is a good reliable treatment of achalasia available called Heller’s myotomy where the lower sphincter is weakened but not destroyed (90).
Hirschsprung’s Disease occurs in new born children at a rate of about 8/100,000. It differs from achalasia in that the large dilated proximal bowel contains normal ganglion cells and the narrowed lower rectum has no ganglion cells. Luckily apart from roentgenological examination it can be diagnosed pathologically by a rectal biopsy, which includes the Meissner’s plexus in the submucous layer. This shows absent ganglion cells.
There are varieties of Hirschsprung’s Disease depending on the length of bowel affected. Very rarely this can extend as far up as the duodenojejunal flexure. Even more rarely there can be short segments of “zonal” aganglionisis in the large bowel (Figure 2).
The acute phase of this disease was first described in 1909 by Chagas in young children infected by the bite of a reduviid bug carrying the trypanosome (Figure 3).
This had a mortality of 20 %. The chronic disease follows much later after 20-40 years and was at first not thought to be connected with the original childhood illness (24). It affects heart, large bowel and oesophagus in the ratios of 6:2:1. At first there may be compensatory hypertrophy due to loss of neural control of the heart and gut but eventually there is decompensation with ensuing dilatation. The commonest death is due to heart failure. In the gut, for any degree of ganglion cell loss, the colon will dilate more than the oesophagus. With a possible prevalence of over 4 million people in Brazil every stage of asymptomatic disease through to compensation, decompensation and treatment can be seen. This provides a unique opportunity to study the pathophysiology of denervated gut which is helpful for management of achalasia and Hirschsprung’s Disease.
To understand the hypothesis that ganglion cells between the inner circular and outer longitudinal muscle layers in Auerbach’s plexus were destroyed, some knowledge of embryology is necessary. A good introduction to this difficult subject is in Wikipedia under the headings prenatal development and organogenesis. It is proposed that these neurones which are part of the parasympathetic system were actually in situ before they were removed by a secret criminal act which left behind no weapon at the site of the crime. The embryo becomes a foetus at the 8th week of development, and from this stage growth of the organs, which are all present, occurs rather than any new development.
During this crucial stage with the heart growing, the diaphragm descending and the gut enlarging there is a large umbilical hernia through which the majority of the intestines with its mesentery and blood supply passes out onto the abdominal wall held only at either end by its arterial supply. As the foetus lengthens the pressure decreases allowing the gut to return in a 270º counterclockwise rotation placing the caecum and appendix on the right as well as the duodenum. This rotational movement is a volvulus or twist and it is well known that it can strangulate bowel at the fixed ends. It is amazing that it does not cause damage more frequently. The process of rotation occurs between the 5th and 10th week. At 5 weeks the embryo is 13 mm long (half an inch), at 10 weeks about 50 mm (2 inches) and at 15 weeks about 15 cm (6 inches).
At this stage it is essential to know how the development of the gut, its parasympathetic system, enteric neurones and muscle are progressing. Knowledge comes from the incredibly detailed work of anatomists on embryos, dated by their length in mm. The vagus nerve, the main parasympathetic nerve of the upper gastrointestinal tract, is present in the 10 mm embryo together with a perioesophageal plexus, neuroblasts and the circular muscle only. At 35 mm the myenteric plexus is more visible, but there are no ganglia although some identifiable neurones are present. It is generally accepted that nerve cells originate in the beginning from the neural crest in the early somite stage (first week of development) and travel downwards with the vagal nerve trunks. By 65 mm there are interlacing bundles in Auerbach’s intermuscular myenteric plexus with ganglia containing upto fifty cells. At 80 mm the longitudinal muscle is thicker and by 120 mm there is extensive cholinesterase activity and two types of ganglion cell are visible. Physiological movements of the intestine are clearly seen at 6 weeks with intestinal peristalsis at 11 weeks.
These congenital defects in the oesophagus, rectum and other parts of the gut have an anatomical distribution curiously similar to aganglionic bowel at both extremities of the gastrointestinal tract. Stenosis and atresia of the small intestine have been produced by ischaemia in utero (Christian Barnard in puppies) or in the chick embryo in its shell (25).
In the newborn baby multiple small bowel lesions of atresia have been discovered and presumed to reflect a sterile gangrenous destruction of bowel incarcerated in a small umbilical hernia. They represent narrowing of bowel which at one stage had a lumen because brilliant detective work showed lanugo (fine hair) and meconium distal to the obstruction. Swallowing and intestinal peristalsis allow lanugo and skin debris to pass through the bowel before obstruction appeared, so this event must have occurred at some time after the 15th week of development.
In the oesophagus atresia occurs with a distal tracheooesophageal fistula which allows gas into the stomach, but no amniotic fluid can be swallowed into the stomach so these patients are usually associated with hydramnios – increased amniotic fluid. Failure of the respiratory tube to separate from the oesophagus maybe the cause in these conditions of the oesophagus.
In rectal atresia, a transitional zone of aganglionic bowel found at the junction with normal bowel provides confirmatory evidence of a common aetiological cause – ischaemia.
This postulates that the basic mechanism whereby ganglion cells are selectively destroyed is temporary ischaemia of at least four hours duration, which does not irreversibly affect the other components (10, 23).
It is suggested that this ischaemia could be the result of rotational strains which the gut undergoes when the majority of it is outside the abdominal wall in a huge umbilical hernia before it finally returns undergoing a 270º counterclockwise rotation. This occurs between the fifth and tenth week of the embryo’s development when it measures about 13 mm (half an inch) to 50 mm (two inches). At this stage the muscle layers have begun to develop, the vagus nerves are present and the intermuscular ganglion network of Auerbach’s plexus are developing. The diaphragm has not fully descended from the neck and the gut with its arteries is fixed at both ends at this time. If the volvulus does not correct itself all the gut will infarct and the foetus will not survive. If the ischaemia is temporary, aganglionic bowel will develop as achalasia or Hirschsprung’s Disease. The former will take years to progress as a Chagas’ disease, the latter will present earlier and more frequently as in Chagas’ disease. If the ischaemia lasts irreversibly for longer, atresia will develop at the lower end to cause rectal atresia. But in the upper end with the heart, lungs and descent of the diaphragm the timing of the event is different from the lower bowel pathology.
A similar mechanism associated with the bowel rotation and return can explain duodenal atresia. Small bowel stenosis and atresia occur much later due to obstruction in a smaller umbilical hernia and the result is a sterile infarct with no peritonitis.
7. Effect of ischemia of lower esophagus and esophago-gastric junction on canine esophageal motor function (PDF)
10. Ischaemia : a hypothesis for the genesis of aganglionic bowel (PDF)
(b) Congenital stenosis of the gut: an experimental study in the chick embryo.