Understanding gastrointestinal involvement and malnutrition in Systemic Sclerosis by Dr Nora Thoua, Gastroenterology Research Fellow.
Supervisors: Dr Anton Emmanuel, Senior lecturer in Gastroenterology, Professor Christopher Denton, Professor of Rheumatology and Professor Alastair Forbes, Professor of Gastroenterology and Clinical Nutrition.
Introduction
Systemic sclerosis (Scleroderma, SSc) is a chronic disorder of unknown cause. It affects about 8 per 100,000 of the population. It is more common in women, the peak age of onset is 30-50 years and it is more common in Afro-Caribbeans than in Caucasians.
SSc is classified as diffuse or limited cutaneous based on the extent of skin involvement. Systemic sclerosis is characterised by fibrosis of the skin and multiple internal organs, such as lungs, kidneys, heart and the gastrointestinal tract (GIT).
After the skin the GIT is the most commonly affected organ in SSc. GIT involvement is reported in up to 90% of SSc patients in both diffuse and limited cutaneous forms. It can occur at any stage of the disease and can be slowly or rapidly progressive. Severe GI involvement occurs in about 8% of patients and is associated with increased mortality
Vascular change is thought not only to represent a common pathological manifestation in SSc but also to be the initiating event in GI involvement. These processes are thought to underlie symptoms such as diarrhoea, malabsorption and faecal incontinence seen in SSc patients. The muscle of the gut is also abnormal in SSc contributing to problems in oesophageal, intestinal and colonic motility.
An interesting aspect of the spectrum of GI disease in SSc is that the clinical manifestations can be progressive, reflecting the stage of the disease. This progression can be slow or rapid and can occur at any age.
Treatment of GI involvement is so far largely symptomatic with no pharmacological or other agents known to arrest disease progression. Understanding the pathogenesis further may facilitate better treatment options and possibly preventative measures.
Rationale and aims of the study
Lower GI symptoms (diarrhoea, constipation, faecal incontinence) are often underreported by patients with SSc due to feelings of embarrassment and the belief that little can be done about them. However, they are an important cause of deterioration in quality of life. The possible causes of anorectal dysfunction in SSc encompass muscle infiltration, muscle atrophy or nerve degeneration. However, currently available investigations provide variable and at times contradictory results.
The purpose of the study is to provide further information about the pathophysiology of GI involvement in SSc patients, by means of emerging physiological techniques. These techniques will allow us to assess the contribution of nerve and muscle dysfunction in the causation of GI symptoms. Potentially by identifying earlier (neuropathic) before later (myopathic) change, then it may be possible to identify either different patient phenotypes or influence progression by focusing on aggressive disease modification.
Aims
1. To quantify the prevalence of upper and lower gut symptoms in the Royal Free Hospital Systemic Sclerosis (SSc) patient group, a nationally referred cohort.
2. To quantify the nature of disturbance of anorectal motor, sensory and reflex physiology, and hence understand possible aetiology.
3. To compare the prevalence of abnormalities between SSc patients who have gut symptoms and those who don’t, and thus identify those abnormalities that are most relevant in determining phenotype.
4. To perform detailed anthropometric and calorimetric assessments and hence establish nutritional status, and if present subclinical malnutrition in symptomatic and asymptomatic SSc patients.
Gastrointestinal symptoms – a questionnaire study
Khanna et al developed a 52-item questionnaire that captures SSc-related GIT activity and severity and that can be used in clinical trials and day-to-day care. This questionnaire assesses the frequency of 5 categories of symptoms: reflux, distension, diarrhoea, constipation, abdominal pain and the effect of symptoms on social functioning and emotional well-being. Patients attending the outpatient department at Royal Free Hospital were asked to fill in the questionnaire, describing their symptoms during the previous week and whilst on their regular medication. The notes were reviewed to establish disease subtype and other clinical details.
Results
402 questionnaires were analysed, representing over 30% of patients with SSc under regular follow-up at the Royal Free Hospital Scleroderma clinic.
Overall there was a high prevalence of GI symptoms. 83% of patients were taking medication for GI symptoms, despite which 94% reported upper and 79% lower GI symptoms. 97% of patients reported some symptoms at least weekly, and 15% reported daily symptoms; only 3% of patients reported no symptoms.
Discussion
One of the major limitations of using a symptom questionnaire is that this may not depict disease activity and severity accurately. Nonetheless, whilst treatment for GI involvement remains symptomatic this questionnaire gives an accurate assessment of symptom burden and can be used to assess this at different times and as a guide to adjust treatment.
Anorectal physiology
SSc patients attending the Rheumatology outpatient department were approached. Based on their GI symptomatology, patients with lower GI symptoms and also patients with very few or no GI symptoms were invited to take part and the study was explained. The patients were given the study information leaflet and ample time to decide on taking part. Patients agreeable to take part were invited to attend the GI physiology unit on one occasion for approximately 3 hours. An informed consent form was signed prior to any tests being undertaken.
Ethical approval for the study was obtained by the local research ethics committee.
On the day of their tests the patients were asked to fill in five questionnaires:
1. Wexner constipation score
2. Wexner faecal incontinence score
3. Scleroderma GI tract 1.0 questionnaire
4. SF-36 general health questionnaire
5. EuroQol - a simple descriptive profile for health status)
Results
21 SSc patients with GI symptoms and specifically lower GI / anorectal symptoms were compared with sex, age and parity matched incontinent controls (IC) with no underlying neuropathy or myopathy being assessed at the GI physiology unit.
Internal anal sphincter function was not significantly different in the 2 groups but the external sphincter pressure was significantly higher in the SSc patients.
Discussion
As expected SSc patients were found to have sphincter atrophy affecting both muscles. There was also evidence of a neuropathic process in SSc patients like those in patients with neuropathies such as spinal injury, MS and diabetes, but mucosal blood flow studies were generally normal.
Nutrition and Systemic Sclerosis
Introduction
Up to 90% of patients with SSc develop gastrointestinal involvement and a small minority of patients develop intestinal failure. This is potentially fatal in SSc and therefore early identification and prevention would be highly desirable. There have not been many studies looking at nutrition in patients with SSc but it is clear that both oral intake and absorption of nutrients can be affected by GI involvement. There are few studies that have looked into nutritional assessment in patients with SSc. One study comparing 30 patients with SSc versus matched healthy controls showed that although the intake of energy and nutrient distribution was not significantly different, there was lower intake of dietary fibre. Assessment revealed lower arm muscle circumference and in 2 patients there were low fat stores. Malnutrition is well described in SSc.
Availability of nutrients is affected both by intake and absorption. Patients often have microstomia and xerostomia which makes the actual act of eating more difficult. Atrophic gingivae and papillae cause loss of taste and are associated with reduced oral intake. Oesophageal dysmotility and acid reflux cause dysphagia especially of coarser food and fruit and vegetables. Delayed gastric emptying and small intestinal dysmotility cause bloating and patients often complain that they cannot have a normal size meal. Furthermore subjective intolerance of foodstuffs is common, and patients often follow a largely restricted diet. Involvement of the small intestine can lead to malabsorption and ultimately intestinal failure.
Nutritional support can be difficult to implement in SSc. Artificial feeding may be necessary. Nasogastric or percutaneous gastrostomy (PEG) or jejunostomy can be tried especially when intake is the main problem, and in a small number of patients parenteral nutrition needs to be considered. There is little in the literature on this.
The aim of this study was to perform detailed anthropometric and calorimetric assessments and hence establish nutritional status, and if present to document subclinical malnutrition in symptomatic and asymptomatic SSc patients.
Nutritional Assessment
Nutritional assessment incorporates conventional anthropometric measurements, screening of biochemical indices and prediction / measurement of energy expenditure. Screening tool data were also collected for comparability with other subject/patient groups.
Even in the absence of weight loss and normal anthropometric measurements, patients with moderate to severe GI symptoms, were found have altered body composition with higher extracellular water volume and lower fat mass as assessed with bioelectrical impedance (BIA). These differences may just be a reflection of chronic illness and are not necessarily a marker of sub-clinical malnutrition. Longitudinal studies in SSc patients would be helpful in understanding better both these changes and the role of BIA as a tool for nutritional assessment and prognostic modelling.
Mouse models of systemic sclerosis and GI involvement
Future work
Animal models of systemic sclerosis have provided valuable insights into the pathogenenesis of SSc and have provided the means to test potentially useful therapeutic interventions. Although there are a number of animal models for SSc the most widely used are murine models due to the large number of inbred mouse strains and the genetic and molecular information available for those.
A series of mouse experiments targeting the GI tract and aspects of relevance to the clinical problems outlined above has now commenced.
Acknowledgements
The investigators thank the Raynaud’s and Scleroderma Association for the Association’s generous support of the work, and also the UK NIHR Comprehensive Biomedical Research Centre which provides important infrastructure at UCL/UCLH.
