Etiology

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The disease processes, which result in CIP, affect the control mechanisms of intestinal motility. The disorders and disease may primarily be of the intrinsic enteric nerves with or without involvement of the extrinsic autonomic nerves, the smooth muscle cells themselves or of the tumoral and endocrine environment. Good examples of the effect of disturbance of the endocrine environment are the ileus associated with vasoactive intestinal polypeptide-secreting tumors such as ganglioneuromas, and the constipation caused by hypothyroidism. These conditions will not be considered further here. A variety of diseases and drugs, which are listed in Table 18.1, may secondarily cause CIP. Such secondary disorders are much more common in adult life than in childhood. Primary disease of the gut neuromusculature may be due to disease of the enteric nerves or the smooth muscle cells or, at least theoretically, of the interstitial cells of Cajal. Surprisingly, there are virtually no descriptions of the primary pathology of interstitial cells of Cajal, which is said to occur in piebaldism, but there have been descriptions of alterations of these cells in hypertrophic pyloric stenosis and Hirschsprung's disease.14,15 Definite diagnosis of neuromuscular disease requires careful study of the full thickness of the gastrointestinal wall in optimally orientated pieces of gut.

It is best carried out in centers that have experience of both the disease and the histopathological techniques required.

Primary visceral myopathies

Primary disorders of the intestinal smooth muscle coats may represent abnormalities in morphogenesis or intrinsic myocyte defects.4 Abnormalities of morphogenesis of the muscle coats may result in the presence of an additional muscle coat or the absence of a muscle layer. This may occur diffusely throughout the gut or may only involve only a segment of the gut. Clinically, primary visceral myopathies occur as either familial genetic diseases with a defined mode of inheritance or, more often, as sporadic cases. Three types of familial visceral myopathy have been described in adults, which all initially presented in the second decade and should therefore be considered when symptoms begin during adolescence.

Familial visceral myopathy with diffuse abnormal muscle layering

This condition usually presents at birth, or shortly after, with functional obstruction. Investigation shows the presence of a short gut and a mid-gut malrotation. Three related males have been described with this condition (the index case, his half brother from the same mother, and his maternal uncle), suggesting an X-linked mode of inheritance.4,6 The most striking histological finding was an extra circular muscle layer with the myenteric enteric plexus embedded within it. None of the patients tolerated enteral feeding, all required long-term parenteral nutrition and all died with septic complications of parenteral nutrition. One further sporadic case has since been described, also in a male child, aged 5 years, who has done well since birth with a decompression ileostomy and mixed enteral and parenteral nutrition.

Infantile visceral myopathy

Most cases occur sporadically but some families have been described with either a dominant gene with variable expressivity or autosomal recessive mode of inheritance. Most affected children develop symptoms at birth or within the first year

Table 18.1 Miscellaneous conditions causing intestinal pseudo-obstruction

Endocrine disorders

Hypothyroidism

Hypoparathyroidism

Pheochromocytoma

Carcinoid

Ganglioneuroblastoma/neuroma

Metabolic disorders Uremia Porphyria Amyloidosis

Drugs

Antidepressants and anti-anxiety drugs

Anticholinergic agents

Opiates

Anticonvulsive cytotoxic drugs Toxic agents

Alcohol in fetal alcohol syndrome Irradiation of life often with severe constipation and abdominal distension. Failure to thrive and malnutrition are common. When recurrent episodes of functional obstruction occur, long-term parenteral nutrition is necessary. Usually the entire gastrointestinal tract is affected, and almost all patients have involvement of the urinary tract with mega-ureter and megacystis.

Smith and Milla,4 studying 27 patients with smooth muscle disease, identified five histological phenotypes in full-thickness biopsies from such children using routine microscopy, histochemistry, immunocytochemistry (with monoclonal antibodies against different neural and smooth muscle markers) and electron microscopy. In two of the 27 patients, a severe myositis was found. This is considered separately. Twenty-five had a primary myopathic disorder which, on routine microscopy of paraffin sections of the smooth muscle, was abnormal in only 15. In the remaining patients myopathic changes would have been missed without application of other techniques, particularly electron microscopy.

These authors, like others, found the presence of gross fibrosis of the muscle layers and profound atrophy of the smooth muscle cells similar to that seen in adults with familial and sporadic forms of visceral myopathy. They were able to relate these changes to intrinsic myocyte defects or changes in the extracellular matrix. A myopathy with increased autophagic activity could sometimes be detected using histochemistry with increased acid phosphatase activity in the smooth muscle cells due to active lysozymes. However, but often electron microscopy was required, as the condition appeared to be active only in the central portions of the smooth muscle cells. A further and distinct myopathic subtype was found where there was a so-called pink blush in the circular muscle layer with nuclear crowding, possibly due to a disorganization of the muscle cells. On electron microscopy, the smooth muscle cells appeared to be separated from each other by material secreted either by the muscle cells themselves or the extracellular matrix. In patients with diffuse disease the prognosis is poor, with about 40% of them dying during childhood from the complications of malnutrition or long-term parenteral nutrition.1 Those who tolerate some oral feeding generally survive into adult life.

Megacystis microcolon hypoperistalsis syndrome

This condition causes severe CIP and affects predominantly female infants.5,16 Most cases present antenatally. Ultrasound scans show the presence of megacystis hydronephrosis and distended bowel. In addition, the proximal small bowel is often short and there is a malrotated mid-gut with microcolon located entirely on the left side of the abdomen. The myopathy causing the problem appears to be a degenerative condition of smooth muscle cells. Whilst most cases are sporadic, others appear to have been inherited in an autosomal recessive mode.

After birth, the affected infants develop massive abdominal distension, which is partly due to distended bowel and partly due to a distended bladder. Patients require a decompression ileostomy and either a vesicostomy or frequent catheterization to ensure that the urinary tract is decompressed. Almost all children require long-term parenteral nutrition for survival and, if this becomes problematic, small intestinal transplantation. Megacystis microcolon hypoperistalsis syndrome must be differentiated from prune belly syndrome, which is due to early intrauterine urethral obstruction and affects predominantly male infants. They present with a dilated abdomen, constipation, megacystis and hydro-nephrosis. Sometimes there is an intestinal malrotation present, but there is no hypoperistalsis and no microcolon.

Familial visceral myopathies types 1, 2 and 3

These conditions usually present in later childhood and have a number of distinctive features.

Familial visceral myopathy type 1 presents as a megaduodenum and is inherited as an autosomal dominant trait with a female predominance in frequency and severity.17 The disease is characterized by foregut functional obstruction, although gastric emptying is often normal, and an elongated, redundant, usually dilated colon. Barium studies show an aperistaltic esophagus, sometimes normal gastric emptying but a flaccid and dilated duodenum with prolonged retention of barium. The bladder is affected in about half the cases, but is often asymptomatic.17 Schuffler and Pope

Systemic disorders involving intestinal smooth muscle 275

showed that there was marked thinning of muscle coats and degeneration with vacuolation of smooth muscle cells and replacement by fibrous tissue.18 Some patients appear to be more mildly affected than others, and merely require dietary modification with either a low-fat, low-fiber, low-lactose diet or enteral feeding, together with the intermittent use of antibiotics to treat bacterial overgrowth. In patients with more severe disease surgical decompression of the foregut into the normal jejunum appears to be effective.19

Familial visceral myopathy type 2 is quite distinct and was first reported as oculogastrointestinal muscular dystrophy. Recently the mitochondrial-disease nature of the condition has resulted in it being renamed mitochondrial neurogastrointesti-nal encephalomyopathy.20 It is inherited as an autosomal recessive trait and presents with external ophthalmoplegia with ptosis and diplopia, a cardiac conduction defect, mild muscular atrophy and dilatation of the entire gastrointestinal tract with scattered small-bowel diverticulae. Gastrointestinal symptoms with dyspepsia, retrosternal chest pain and weight loss may start during teenage years. In skeletal muscle biopsies a deficiency of cytochrome C oxidase has been demonstrated which results in the ragged red fibers typical of mitochondrial myopathies. Examination of the smooth muscle of the gut shows the presence of fibrosis and degeneration with vacuolation of the smooth muscle cells. Most patients have eventually required total parenteral nutrition.

Familial visceral myopathy type 3 is much less well understood. The data are from of one family in which there were four siblings who presented with dilatation of the entire gastrointestinal tract. The condition appeared to be inherited in an autosomal recessive fashion.21

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