Gastrointestinal function in patients with progressive systemic sclerosis

Summary In 24 patients with progressive systemic sclerosis (PSS) the pentagastrin-stimulated gastric acid secretion was determined to investigate if acid hypersecretion is associated with reflux-oesophagitis — the most common complication to oesophageal involvement in PSS. Gastro-oesophageal reflux was observed in 12, reflux-oesophagitis in 9 and oesophageal mycosis in 8 patients. Gastric acid secretion was increased in 13 (54%) patients and tended to be higher in patients with oesophagitis. Patients with reflux and increased acid secretion seemed to be free from oesophageal mycosis. Bacterial overgrowth and malabsorption are known complications to intestinal scleroderma and these items were investigated using non-invasive methods. Four patients had increased bile acid deconjugation, 3 had increased (¹⁴C)xylose degradation indicating bacterial overgrowth and 7 patients had decreased fat absorption in the triolein breath test. Nutritional status with respect to selenium, folate, cobalamine and fat-soluble vitamins was essentially normal.     

Gastrointestinal Manifestations of Systemic Sclerosis

Systemic sclerosis is a chronic disorder of connective tissue that affects the gastrointestinal tract in more than 80% of patients. Changes in neuromuscular function with progressive fibrosis of smooth muscle within the muscularis propria impair normal motor function, which may secondarily alter transit and nutrient absorption. Esophageal manifestations with gastroesophageal reflux and dysphagia are the most common visceral manifestation of the disease, often requiring more intense acid-suppressive medication. Gastric involvement may lead to gastroparesis, which can be found in up to 50% of patients. Severe small bowel disease can present as chronic intestinal pseudo-obstruction with distended loops of small intestine, bacterial overgrowth, impaired absorption and progressive development of nutritional deficiencies. While not studied as extensively, systemic sclerosis often also affects colorectal function resulting in constipation, diarrhea or fecal incontinence. Nutritional support and prokinetics have been used with some success to manage gastric and small or large bowel involvement in patients with systemic sclerosis. Despite advances in management, significant gastrointestinal manifestations of systemic sclerosis still carry a poor prognosis with a five-year mortality exceeding 50%.     

Exocrine pancreatic function in patients with progressive systemic sclerosis

The exocrine pancreatic function was investigated in 16 patients with progressive systemic sclerosis by means of a meal test (Lundh test) and in 9 of the patients by the secretin-cholecystokinin test as well. Gastrointestinal involvement with progressive systemic sclerosis was evaluated by esophageal manometry and by routine roentgenographic series of the small bowel. Fecal fat excretion measurement, the D-xylose absorption test, and a small-intestinal biopsy procedure were carried out. Duodenal juice was cultured and bacterial counts were estimated. One-third of the patients had reduced exocrine pancreatic function, but only four patients had unequivocally a reduction that could be of clinical importance. The results obtained with the meal test were in accordance with the secretin-cholecystokinin test, indicating a preserved capacity for endogenous stimulation.     

Intestinal involvement in progressive systemic sclerosis detected by increased unconjugated serum bile acids.

In patients with progressive systemic sclerosis, impaired motor function of the small intestine may lead to bacterial overgrowth causing diarrhoea, steatorrhoea and malabsorption. As unconjugated serum bile acids have been proposed as markers for small bowel bacterial overgrowth, we studied individual unconjugated serum bile acids in 36 patients with progressive systemic sclerosis. These patients had significantly higher serum concentrations of unconjugated cholic acid (median 0.18; range 0.05-30.75 v 0.09; 0.01-0.19 mumol/l, p less than 0.001) and chenodeoxycholic acid (0.10; 0.01-6.83 v 0.04; 0.01-0.39 mumol/l, p less than 0.025) than healthy controls (n = 16). This difference was mainly due to patients with diarrhoea (n = 10), who had significantly higher concentrations of unconjugated serum bile acids than patients with normal bowel habit (cholic acid median 0.55 v 0.16 mumol/l, p less than 0.001; chenodeoxycholic acid 0.75 v 0.07 mumol/l; p less than 0.005). All patients with raised unconjugated serum bile acids had oesophageal motility disorders. These results confirm a relationship between motility disorders and bacterial overgrowth in patients with progressive systemic sclerosis.     

Absorption of xylose, glucose, glycine, and folic (pteroylglutamic) acid in Zambian Africans with anaemia.

Rates of glucose, glycine, and folic (pteroylglutamic) acid absorption were determined for a 30 cm jejunal segment in vivo, with a double-lumen tube perfusion system, in 10 Zambian African women with a mean haemoglobin concentration of 5-1 (3-5-9-2) g/dl. In four the anaemia was megaloblastic (due to folate deficiency) and in six hypochromic. Perfusion solutions contained (1) glucose 200 mmol/1, (2) glycine 100 mmol/1, and (3) folic acid 250 mug/1. D-xylose absorption after a 25 g oral load was determined in them, and also in 18 additional patients (11 had megaloblastic and seven either hypochromic or haemolytic anaemia). Xylose absorption tests were significantly impaired in the patients with megaloblastic compared with hypochromic or haemolytic anaemia (P less than 0-001); those with untreated megaloblastic anaemia had a greater abnormality than those who had started treatment. Mean glucose, glycine, and folic acid absorption rates were similar to those in controls, and the rates in patients with megaloblastic and hypochromic anaemia were not significantly different. Correlation between glucose absorption rate and xylose excretion was, however, significantly (P less than 0-02). If more patients had been studied it seems likely therefore that a significant impairment of glucose absorption rate in the presence of megaloblastic anaemia would also have been demonstrated. In this investigation anaemia per se did not affect glucose, glycine, or folic acid absorption rates or xylose absorption, but xylose absorption was reduced in patients with megaloblastic anaemia. That abnormality was probably related to folate deficiency, and the underlying mechanism seems to be different from that causing impairment of monosaccharide absorption in patients with systemic bacterial infections. Mean glycine and folic acid absorption rates were not altered by megaloblastic anaemia, indicating that folate deficiency does not cause a general depression of absorption.     

Autologous and allogeneic mixed lymphocyte reactions in progressive systemic sclerosis

The autologous and allogeneic mixed lymphocyte reactions (MLR), observed when peripheral blood mononuclear cells from 20 patients with progressive systemic sclerosis were used, were compared with those of age-, sex-, and race-matched normal controls. Such cells were separated by gradient centrifugation of sheep red blood cell (E) rosettes into stimulator (E- or non-T cell) and responder (E + or T cell) populations. The autologous MLR of both the progressive systemic sclerosis and normal peripheral blood mononuclear cells varied widely but there was no statistical difference between the means of each group. In the allogeneic MLR, proliferation between progressive systemic sclerosis non-T cells and normal T cells was significantly less than that of normal non-T cells and progressive systemic sclerosis T cells (P = 0.001). A decreased autologous MLR, while noted with other autoimmune diseases, was lacking in progressive systemic sclerosis. This suggests a different defect. The differences in the allogeneic MLR also suggest that either progressive systemic sclerosis non-T cells were poor stimulators or T cells associated with this disease were better responders when compared with similarly prepared cell populations from normal individuals. The MLR differences could have also resulted from compositional subset alterations or the sharing of a common antigen. HLA-DR5 was found in 9 of the 17 white patients with progressive systemic sclerosis. Although these individuals were evenly distributed as low, medium, and high responders, this finding showed that some progressive systemic sclerosis non-T cells shared a common antigen.     

Serum and red cell folate activity and folic acid absorption in patients with hookworm infection.

Red cell and serum folate levels and folic acid absorption were studied in patients with hookworm infection. The mean value of serum folic acid level was found to be significantly lower than that of the normal subjects and 32% of cases had serum folic acid level less than 4 ng/ml. The red cell folate content in all patients studied were within the normal limits. The mean value of the folic acid absorption was also lower than that of the normal. Six out of 13 patients absorbed folic acid less than 38%, the lowest value obtained from the normal subjects. These findings indicated that there was a negative balance of folic acid in some patients with hookworm infection which was probably due to impairment in absorption.     

Dietary intake and nutritional status in patients with systemic sclerosis.

Oesophageal dysmotility and abnormalities of intestinal function are important manifestations in systemic sclerosis and may have a significant effect on nutrient absorption and nutritional status. In this study 30 patients with systemic sclerosis with symptoms from the gastrointestinal tract were compared with matched healthy control subjects with respect to nutrient intake (four day record), anthropometric measurements, and biochemical nutritional status. The intake of energy (8.1 and 8.4 MJ/day) and its distribution among nutrients did not differ between patients and control subjects, but the lower intake of dietary fibre among patients with systemic sclerosis suggests that they avoided food with a coarse structure, such as coarse bread. The intake of vegetables and fruit also tended to be lower among patients with systemic sclerosis. Half of the patients had a subnormal arm muscle circumference, and two patients also had a subnormal triceps skinfold thickness, indicating severe malnutrition. The concentration of ascorbic acid, alpha-tocopherol, carotene, selenium, and also the proportion of linoleic acid (18:2) in serum phosphatidylcholine was lower in patients than in control subjects.     

Gastrointestinal systemic sclerosis in serologic mixed connective tissue disease

Mixed connective tissue disease is a clinical entity defined by overlapping features of progressive systemic sclerosis, systemic lupus erythematosus, polymyositis, rheumatoid arthritis, and distinct serologic findings. Esophageal dilatation and dysmotility have been the only gastrointestinal manifestations reported. Three patients with serologic findings of mixed connective tissue disease and extensive gastrointestinal involvement compatible with the changes found in progressive systemic sclerosis are presented. Gastrointestinal manifestations of progressive systemic sclerosis are reviewed and were found to be indistinguishable from the findings in these patients.     

Solid-phase radionuclide esophageal transit in progressive systemic sclerosis

BACKGROUND/AIMS: In most patients with progressive systemic sclerosis the esophagus is affected. Reflux symptoms are most frequent whilst dysphagia also occurs. The radionuclide esophageal transit study is a sensitive screening test for esophageal dysfunction. In this study, we evaluated the esophageal motility of patients with progressive systemic sclerosis using a solid-phase radionuclide esophageal study. METHODOLOGY: Thirty-two patients with progressive systemic sclerosis and 30 normal volunteers were studied with solid-phase radionuclide esophageal study. Each subject was placed in a supine position above a gamma camera linked to a computer and was given a 4-mL bolus of solid gelatin containing 1 mCi of Tc-99m phytate. Data were acquired in the list mode. RESULTS: Twenty-nine of the 32 patients (91%) had abnormal findings from the study. CONCLUSIONS: The radionuclide esophageal transit study can be regarded as a useful tool for evaluating the esophageal function in patients with progressive systemic sclerosis and in the follow-up of treatment.     

FOLIC ACID IN THE TREATMENT OF PERNICIOUS ANEMIA

1. Folic acid in daily doses of 15 to 50 mg., orally, or 20 mg. intramuscularly,usually produced a submaximal reticulocytosis in patients with pernicious anemia.

2. In 3 patients the hemoglobin and red cells rose to a level of about 12.0 Gm.and 4.3 million respectively without further rise after 3 months of therapy.

3. Folic acid in the above doses failed to prevent the development or progressionof neurological symptoms indicative of subacute combined sclerosis.

4. In 5 patients folic acid in doses of 5 or 10 mg. orally daily combined with unit of liver extract injected intramuscularly daily produced a reticulocytosisgreater than that anticipated from adequate liver extract therapy alone.

5. With combined liver extract and folic acid therapy there was evidence ofimprovement in the symptoms and signs of subacute combined sclerosis in 3patients.

6. Folic acid, combined with unit of liver extract, was found to produce acomplete hematological remission.

7. Folic acid, alone or in combination with small doses of liver extract, producedan improvement in appetite and general well-being in patients with perniciousanemia.

8. The possible enhancing effect of liver extract when combined with folic acidcannot be due to the folic acid content of the former since 1 unit of liver extractcontains only 0.38 micrograms of folic acid.³¹

9. Folic acid administered to a patient with macrocytic anemia due to faultypostoperative intestinal digestion and absorption, produced a complete remissionin the blood picture and a marked improvement in signs and symptoms.

     

Atrioventricular nodal function in progressive systemic sclerosis: electrophysiological and morphological findings.

Electrophysiological data consistent with atrioventricular nodal dysfunction were obtained in 10 out of 19 patients with progressive systemic sclerosis (scleroderma). Conducting system studies were carried out in a further seven patients with progressive systemic sclerosis. In each the proximal portion of the atrioventricular node was consistently found to be smaller and more slender. It is postulated that there is a relation between proximal atrioventricular nodal structural alterations and impaired atrioventricular nodal function.     

Sigmoid volvulus in two patients with progressive systemic sclerosis

Sigmoid volvulus was diagnosed in two patients with progressive system sclerosis. In one case, this was initially confused with a high fecal impaction. Both cases responded to early surgical intervention. Sigmoid volvulus should be considered in the differential diagnosis of intestinal obstruction associated with progressive systemic sclerosis.     

Elevated ANA titers in patients with severely abnormal gastrointestinal motility

We studied a group of six patients with clinical, radiological, and/or manometric features of severely abnormal gastrointestinal motility. Symptoms suggestive of esophageal, small bowel, or colonic involvement were present from 1 1/2 to 40 years. All patients had elevated antinuclear antibody (ANA) titers. None had clinical or radiographic features suggestive of progressive systemic sclerosis or other connective tissue diseases. Two patients had pathologic examinations of intestinal specimens, and these did not show changes suggestive of progressive systemic sclerosis. We conclude that patients with severe gastrointestinal motility disorders can have elevated ANA titers without features of progressive systemic sclerosis or other connective tissue diseases.This study was supported by the National Institutes of Health grant AM 25965 and grant RR 59 from the General Research Centers Program, Division of Research Resources, National Institutes of Health.     

Ultrastructural changes in renal arterioles and juxtaglomerular cells in hypertension

The ultrastructural appearance of socalled arteriolar hyalinosis was qualitatively indistinguishable in renal biopsies from patients with essential hypertension with or without diabetes mellitus, renovascular hypertension (the unimpaired member), hypertension associated with progressive systemic sclerosis and gout, normotensive aging (greater than 50 years), persons without renal disease, and a high percentage of adolescent normotensive diabetic individuals. These findings provide further evidence identifying the hypertension observed in patients with gout and progressive systemic sclerosis with that of the essential type.     

Nifedipine and esophageal dysfunction in progressive systemic sclerosis. A controlled manometric study

We evaluated the effect of the calcium channel blocking agent, nifedipine, on esophageal dysfunction in 15 patients with progressive systemic sclerosis, using a double-blind, randomized, crossover, placebo-controlled manometric study. Nifedipine significantly decreased lower esophageal sphincter pressure in these patients; this reduced lower esophageal sphincter pressure may cause gastroesophageal reflux. Thus, nifedipine may have detrimental effects on progressive systemic sclerosis patients.     

Atrial conduction abnormalities in patients with systemic progressive sclerosis

BACKGROUND: Atrial abnormalities in patients with progressive systemic sclerosishave not been evaluated in terms of intra-artrial conduction.We hypothesized that a delay in atrial conduction in these patientsmight produce diastolic abnormalities as well as atrial arrhythmias. OBJECTIVE: To evaluate the atrial function of patients with progressivesystemic sclerosis by using echocardiography to measure theintra-atrial electromechanical activation coupling interval. METHODS: Twenty patients with progressive systemic sclerosis were assessedby Doppler echocardiography. Twenty age-matched healthy controlswere also evaluated. Two-dimensional guided M-modes of ventricularlong axes were recorded using simultaneous phono- and electrocardiogramsof the apical four chamber view at the right lateral, septaland left lateral sites of the atrioventricular rings. Transmitraland tricuspid pulsed Doppler flow velocities were also recorded.Filtered P wave duration was measured on the signal averagedECG to determine the duration of atrial electrical activation. RESULTS: There was a delay in P on the electrocardiogram (P) at the onsetof atrial contraction on long axis M-modes at all three atrioventricularring sites in patients with progressive systemic sclerosis ascompared with controls (P-right; 56±13 vs 47±10ms, P-septal; 74±14 vs 55±10 ms, and P-lateral;93±16 vs 72±11 ms, P<0·01). Inter-atrialconduction time [(P-lateral) — (P-right)] was delayedin patients with progressive systemic sclerosis, compared withhealthy controls (37±15 vs 25±6 ms, P<0·01).Mitral A waves acceleration and deceleration times were alsodecreased in the patients. The interval was prolonged betweenP to the onset and the peak of the A wave in transmitral flow.Duration of the filtered P wave was significantly prolongedin progressive systemic sclerosis as compared with controls(124±12 ms vs 106±8 ms, P<0·01). PQintervals, E waves and acceleration and deceleration times didnot differ significantly in progressive systemic sclerosis vs,controls. The A wave acceleration rate on transmitral flow (peakA wave velocity/acceleration time) showed a significant correlationwith inter-atrial conduction delay (r=0·55, P<0·01). CONCLUSIONS: Intra-atrial electromechanical coupling intervals were delayedin patients with progressive systemic sclerosis. Thus, the mechanicallate diastolic filling time due to atrial contraction in thetotal diastolic phase was severely limited, and this resultedin a restricted mitral A wave. We should therefore evaluatepatients with progressive systemic sclerosis for significantatrial abnormalities.     

Treatment of systemic sclerosis with the 5-HT3 receptor antagonist tropisetron.

BACKGROUND: There is no known disease-modifying therapy for progressive systemic sclerosis. OBJECTIVES: It was shown that a patient with secondary fibromyalgia syndrome for whom the development of systemic sclerosis was suspected because of a Raynaud's phenomenon and the presence of SCL-70 antibodies in the serum had experienced a clear pain reduction under treatment with tropisteron, which is the reason why this drug was also used with established systemic sclerosis. METHOD: Two patients with progressive systemic sclerosis and positive SCL-70 antibodies were treated for 6 weeks with 5 mg tropisetron daily. Both patients had clear skin symptoms, functional impairments of the locomotor system, and a secondary fibromyalgia syndrome. The skin score and joint motion were checked before, during, and after treatment. In addition, the patients filled in the visual analog scale for pain at these times. At the end of the 6 weeks, the patients showed a clear improvement of the skin score and the movability of various joints as well as a clear reduction of pain. The medication was well-tolerated. Constipation developed in the patients; it could be controlled with laxatives. Follow-up questioning of the patients after 3 months showed that their condition had remained stable. CONCLUSION: Two patients with progressive systemic sclerosis showed an improvement of various symptoms under a blockade of the 5-HT3 receptors via tropisetron. The long-lasting effect pointed to immunomodulation. The two cases give cause for clarifying this by means of clinical studies, which should also investigate the question of dosage (possibly 5 mg tropisetron twice daily).     

Intestinal absorption of folic acid, glucose, sodium and water in chronic pancreatitis

Intestinal absorption of folic acid, glucose, water and sodium in 10 patients with chronic pancreatitis who have abstained from alcohol for at least 2 months is compared with 18 agematched outpatients without gastrointestinal disorders and a daily alcohol intake less than 30 g. Intestinal absorption was measured by segmental perfusion of the jejunum using a triple lumen tube. Patients with chronic pancreatitis showed a significantly decreased absorption of folic acid and glucose, whereas the net absorption of water and sodium was not disturbed.     

Absorption studies after ileal J-pouch anastomosis for ulcerative colitis. A prospective study

Absorption studies were performed in 17 patients with ulcerative colitis operated on with colectomy and an ileal two-limbed J-pouch anastomosis. The patients were studied 3 and greater than or equal to 18 months after closure of the temporary ileostomy. Increased stool mass (median, 609 g/24 h) was found in all patients and was unchanged with time. Moderate steatorrhoea was present in 29% of the patients 3 months postoperatively, but faecal fat excretion normalized with time. Calcium absorption was normal in all but one patient regardless of time after operation. An abnormal bacterial deconjugation, evaluated by a 14C-glycocholic acid breath test was present in 27% of the patients and increased significantly with time. Forty per cent of the patients had increased faecal bile acid excretion. B12 malabsorption was present in 29-35% of the patients. In conclusion, ileal J-pouch anastomosis for ulcerative colitis causes increased stool mass in all patients and produces moderate bile acid deconjugation and malabsorption in about one-third to half. Substitution therapy with vitamin B12 is necessary in about one-third of the patients. Intestinal adaptation as far as absorption is concerned is minimal after the first 3 postoperative months.