Chapter 14 THE GUT IN SYSTEMIC DISORDERS

Chapter 14

THE GUT IN SYSTEMIC DISORDERS

1. DIABETES MELLITUS

There are two principal gut complications of diabetes mellitus. These are:

• Diabetic autonomic neuropathy

• Oesophageal candidiasis

Diabetic autonomic neuropathy is a common, serious and often intractable complication especially seen in elderly patients with long standing insulin dependent diabetes mellitus. Evidence of poor diabetic control and neuropathy, both cardiovascular and peripheral, are common.

The pathogenesis is not entirely clear and it affects the sympathetic more than the parasympathetic (vagal) system. The manifestations depend upon the site principally affected but in a typical case, widespread abnormalities may be found, even if symptomless, attributable in part to the sensory neuropathy also present. The principal sites of affect and symptoms are :

• Oesophagus. Disturbances of oesophageal motor activity are frequent, often together with gastroparesis and symptoms are present in a minority of patients.

• Stomach. Gastroparesis is said to affect more than half of such diabetic

patients. Motility is diminished and emptying of solids is greatly

disturbed although liquid may be handled normally. In diabetics

hyperglycaemia inhibits gastric emptying but there is also a major

depression of vagal function in gastroparesis. Not only may the

condition be associated with bloating, fullness after meals, early satiety

and post-prandial vomiting, but the impaired gastric emptying

24 Chapter 2 14 complicates diabetic control. As with other forms of diabetic

neuropathy, drug treatment is unsatisfactory.

• Diabetic Diarrhoea. This is common in people with diabetic autonomic neuropathy and is particularly evident in type 1 diabetics with diabetic gastroparesis. Often associated with steatorrhoea of unclear origin it is characterised by nocturnal diarrhoea which may be intermittent and even alternate with periods of constipation. Management is very difficult with strict diabetic control central to treatment. Faecal incontinence, constipation, even culminating in megacolon or pseudo obstruction and abdominal pain of obscure origin may also occur.

2. AMYLOID DISEASE

There are a number of disorders in which deposits of this strange glycoprotein with unique staining characteristics on microscopic examination occur with subtle differences in the chemical nature of the protein involved. All may affect the gut, principally infiltrating the blood vessel walls, smooth muscle of the intestine and muscularis mucosa which may cause malabsorption. Any part of the gut may be involved from the tongue, causing macroglossia, oesophagus causing motility problems, gastric changes leading to motility problems or mechanical obstruction, small bowel causing malabsorption or pseudo obstruction. Bleeding may occur from the fragile involved vessels and the liver may be greatly enlarged by amyloid infiltration. Amyloid is often found diffusely elsewhere; whilst rectal biopsy has been the traditional method of diagnosis, less invasive approaches such as subcutaneous or duodenal biopsy often provide the answer. The treatment is, in general, ineffective.

3. COLLAGEN VASCULAR DISORDERS

These, in themselves a melange of complex disorders of varying frequency, are nearly all associated with gastrointestinal complications.

Some, such as the cholecystitis and appendicitis of polyarteritis nodosa are relatively specific to the prime condition. Others may be considered general being associated with a variety of collagen vascular disorders. It is not intended to cover the large area which has little epidemiological interest but it may be appropriate to consider some of the main issues which really boil down to :

• Smooth muscle effects

• Vasculitis

THE GUT IN SYSTEMIC DISORDERS 243

• Side effects of Treatment

1. Smooth Muscle Effects. These are frequently seen in scleroderma; nearly all patients have disordered oesophageal motility with dysphagia and reflux oesophagitis from cardiooesophageal sphincter disturbance is close to universal. Smooth muscle atrophy and fibrosis impair gastric and small bowel structure and function even leading to malabsorption, and constipation from colonic involvement is frequent. On the other hand, while laboratory evidence of impaired oesophageal motility in rheumatoid arthritis is frequent, symptoms are rare. Oesophageal problems incur in most of the other collagen vascular disorders such as SLE and Sjogren’s syndrome.

2. Vasculitis. This is frequently seen in these disorders and may provoke a remarkable variety of changes – abdominal pain, bleeding, cholecystitis, bowel stricture and infarction, perforation and pancreatitis. Diagnosis can be very difficult because it is a small vessel vasculitis and a fatal outcome may ensue.

3. Side Effects of Treatment. May of these disorders are treated by potent regimes with a major potential for GI side effects. Numerically, NSAIDs, widely used in rheumatoid arthritis predominate with their gastro duodenal effects (Chapter 5a) but also small bowel and even colonic ulcer and stricture formation may occur. The other major drug classes are the anti metabolites. Methotrexate is widely used in rheumatoid arthritis but has the potential to produce a largely silent hepatitis and even cirrhosis, generally limiting total dosage. Corticosteroids are widely used with the possibility of an enormous list of side effects. In the gut a significant problem is the increased risk of ulcer and death in patients concurrently receiving corticosteroids and NSAIDs.

4. FIBROCYSTIC DISEASE OF THE PANCREAS – CYSTIC FIBROSIS

This is one of the most frequent of the lethal genes affecting humans with a prevalence of around 1 in 3000 white American neonates but only one fifth of this figure in African American and one tenth of it in Asians. The disease is very rare in Japanese. Its basis is a recessive disorder due to any one of numerous mutations of the CFTR gene on chromosome 7 which concerns itself with a protein governing chloride channels at the cell membrane.

There is also evidence of modifier genes on chromosome 19 so that a variety

of phenotypes are seen. Characteristically, the mutation causes a raised

viscosity dysfunction of exocrine secretion with major effects on lungs

producing chronic infection or emphysema, pancreas producing pancreatitis,

244 4 Chapter 14 pancreatic insufficiency and malabsorption, raised sweat chloride levels and male infertility. Previously a disease largely associated with a brief life in children, with modern methods of countering the pulmonary infection survival into adult life is now common and around half of the sufferers reach their 30

birthday with the development of new syndromes : diabetes type 2 from involvement of the islets of Langerhans and from the GI point of view, biliary cirrhosis around puberty with portal hypertension. There is throughout life a risk of bowel complications, from meconium ileus in the neonate and intestinal obstruction later on, even into adult life from the viscous state of bowel contents and pancreatic insufficiency. Ashkenazi Jews tend to have a characteristic mutation. Drug therapies mainly centre on pancreatic extracts to improve nutritional state, fat soluble vitamins for the malabsorption and on the intractable pulmonary infection.

5. ALPHA 1 ANTITRYPSIN DEFICIENCY

The alpha 1 antitrypsin protein is normally secreted by the liver into the blood stream as one of the family of anti proteases which inhibit neutrophil proteases and elastases. The disease, an autosomal recessive disorder due to a variety of defects in the gene on chromosome 14 causes the accumulation of an abnormal protein within the liver cell with the potential to cause a chronic hepatitis, cirrhosis, portal hypertension and even hepatocellular carcinoma. The homozygote is also at risk of emphysema in those that escape the main impact on the liver, and in those exposed to tobacco smoke, life threatening emphysema may develop. The disorder is not uncommon.

In a large Swedish study of 200 000 neonates, 127 were found to have the Pi (protease inhibitor) ZZ genotype, the common one producing the abnormal ZZ type protease. Of these 14 had cholestatic jaundice, 9 had severe liver disease but only about half had abnormal liver function tests and the 127 with jaundice tended to improve in childhood so only a minority of 5-10%

developed chronic liver disease. There are other alleles, some of which do

not lead to chronic liver disease and heterozygotes do not develop liver

disease. The major variation in clinical presentation in liver and lung

pathology supports the proposition that, once again, modifier genes have a

part in the development of the phenotype.