Sj?gren's syndrome in patients with primary biliary cirrhosis

Symptomatology and objective findings of Sj?gren's syndrome were evaluated in 38 consecutive patients with primary biliary cirrhosis. Symptoms of Sj?gren's syndrome were present in 18 (47.4%) patients, but were severe enough to warrant therapy in only four (10.5%). Nineteen patients consented to evaluation for Sj?gren's syndrome, which included Schirmer's I test, measurement of parotid flow rate and serum autoantibodies, labial minor salivary gland biopsy and human leukocyte antigen typing. Histological changes diagnostic of Sj?gren's syndrome were present in five patients (26.3%). All five patients had symptoms of Sj?gren's syndrome and three had abnormal Schirmer's I tests, but none had corneal ulcerations or decreased parotid flow rates. Results of serological tests and human leukocyte antigen typing were not similar to those described in patients with primary Sj?gren's syndrome but were similar to those described in patients with rheumatoid arthritis and Sj?gren's syndrome. These findings indicate that Sj?gren's syndrome associated with primary biliary cirrhosis is a form of secondary Sj?gren's syndrome resembling that associated with rheumatoid arthritis.     

Effect of secretin on lower esophageal sphincter pressure in patients with esophageal achalasia.

The effect of a bolus intravenous administration of secretin (2.0 U/kg) on resting lower esophageal sphincter pressure (LESP) was investigated in seven patients with esophageal achalasia. Basal LESP before secretin injection in the patients was 60.1 +/- 3.4 mmHg (Mean +/- SEM), which was significantly higher than 26.9 +/- 2.5 mmHg in normal controls consisting of eight healthy volunteers. LESP significantly decreased within 1 min after the injection both in the patients and the controls. The maximum pressure change from each basal LESP was 31.2 +/- 5.2 mmHg in the patients, which was significantly greater than 12.1 +/- 1.8 mmHg in the controls. The effect of secretin disappeared within 5 min in the controls. The effect in the patients, however, lasted throughout the investigation time of 30 min. It is concluded that secretin has a long-acting effect on muscular relaxation of the lower esophageal sphincter in esophageal achalsia patients.     

State of the art. Primary biliary cirrhosis and the immune system.

The immunologic features of diseases associated with primary biliary cirrhosis (PBC) such as Sj?rgren's syndrome, scleroderma, rheumatoid arthritis and others are reviewed. Immunologic abnormalities involving both humoral and cell mediated immunity have been found in PBC. The morphologic and immunologic data have been used to propose a pathogenetic mechanism for PBC. Recent studies of penicillamine indicate that the drug may influence liver copper content and the deposition of immune complexes.     

Lymphocyte subpopulations in bronchoalveolar lavage in Sj?gren's syndrome. Evidence for an expansion of cytotoxic/suppressor subset in patients with alveolar neutrophilia

We initiated this study to determine the cellular composition and T-lymphocyte subpopulations of fluid from bronchoalveolar lavage from 15 patients with primary Sj?gren's syndrome (1SS), six patients with secondary Sj?gren's syndrome associated with primary biliary cirrhosis (2SS-PBC), eight patients with secondary Sj?gren's syndrome associated with collagen-vascular diseases (2SS-CVD), and 12 normal subjects. All were nonsmokers who were free of clinical pulmonary symptoms and had normal findings on chest roentgenograms. Lymphocyte subsets were identified by mouse monoclonal antibodies that were specific for T-cells, helper/inducer, and suppressor/cytotoxic (namely, OKT3, OKT4, and OKT8). Patients with 1SS, patients with 2SS-PBC, and patients with 2SS-CVD had a significantly increased percentage of lymphocytes in fluid from bronchoalveolar lavage (respectively, 21.6 +/- 3.7 percent, 24.3 +/- 6.1 percent, and 25.6 +/- 3.9 percent) compared with the normal value of control subjects (9.9 +/- 1.5 percent). In addition, two of the 15 patients with 1SS and five of the eight patients with 2SS-CVD demonstrated an increased percentage of alveolar neutrophils. The predominant T-cell subset in patients with 1SS was T4+, and the mean T4:T8 ratio was normal. The percentage of T4+ cells was increased in patients with 2 SS-PBC, resulting in an increased T4:T8 ratio. In contrast, patients with 2 SS-CVD demonstrated a markedly increased percentage of T8+ cells, reflected by a shift in the T4:T8 ratio which was inverted. Patients with Sj?gren's syndrome and with neutrophilia on bronchoalveolar lavage had a marked expansion of the T8+ lymphocyte subpopulation, where as patients with Sj?gren's syndrome and with pure lymphocytosis on bronchoalveolar lavage showed predominantly T4+ cells. In addition, we found a strong positive correlation between the number of neutrophils and the number of T8+ cells in bronchoalveolar lavage from patients with Sj?gren's syndrome (r = 0.74; p less than 0.05). Until the functional activities of OKT4+ and OKT8+ cells are better defined, the role that these cells play in the pathogenesis of pulmonary disease in Sj?gren's syndrome remains unclear.     

Is the heart affected in primary Sjögren's syndrome? An echocardiographic study

OBJECTIVE: To evaluate whether patients with primary Sj?gren's syndrome without overt cardiac disease have echocardiographic abnormalities and their relation with clinical and laboratory data. METHODS: One hundred and seven consecutive patients with primary Sj?gren's syndrome and 112 healthy controls, matched for age and gender, underwent complete echocardiographic study. RESULTS: Thirty-two patients had mitral valve regurgitation (p<0.001) whereas tricuspid and aortic valve regurgitation were, also, more frequent in the patient group (p=0.022 and p=0.007 respectively). In multivariate analyses, low C4 levels of complement and age were strong predictors of mitral valve regurgitation whereas age was predictor of aortic valve regurgitation. Tricuspid valve regurgitation was associated with pulmonary hypertension. Clinically silent pericardial effusion, found in 9 patients (p=0.008), was associated with cryoglobulinemia and primary biliary cirrhosis. Twenty-four patients had pulmonary hypertension (p<0.001) whereas hypocomplementemia and cryoglobulinemia were strong predictors of pulmonary artery systolic pressure. The analyses reveal that easy fatigability was associated with pulmonary hypertension and low C4 levels. The patients' left ventricular mass index differed significantly from the controls (108.9+/-17.21 gm(-2) vs. 85.8+/-6.73 gm(-2), p<0.001) and was associated with palpaple purpura and anti-Ro/SSA. From the diastolic function indices only the left ventricular isovolumic relaxation time differed significantly among patients and controls. CONCLUSION: Valvular regurgitation, pericardial effusion, pulmonary hypertension and increased left ventricular mass index occur with disproportionately high frequency in patients with primary Sj?gren's syndrome and no clinically apparent heart disease. Thus echocardiographic studies may need to be performed in these patients especially when palpable purpura, antibody reactivity and low C4 levels are present.     

Lower esophageal sphincter pressure in idiopathic achalasia and Chagas disease-related achalasia

The most important etiologies of achalasia are idiopathic and related to Chagas' disease. The lower esophageal sphincter pressure (LESP) in idiopathic achalasia (Id Ach) is higher compared with a healthy group, but there are different reports in Chagasic achalasia (Ch Ach). We compared the LESP of patients with both forms of achalasia and a control group. The LESP of 213 achalasia patients without previous treatment and 32 healthy volunteers were assessed. In 126 patients, the etiology could be demonstrated using serologic tests (Id Ach, 94 and Ch Ach, 32). The LESP of 213 patients was 31.86+/-14.18 mmHg and in the control group was 17.92+/-7.03 mmHg (P < 0.0001). The LESP in Id Ach and Ch Ach was 33.28+/-13.63 mmHg and 23.5+/-12.09 mmHg (P < 0.0001), respectively. Only the Id Ach group achieved statistical difference in relation to the control group (P < 0.0001). In conclusion, the LESP of Id Ach patients was higher than in Ch Ach patients and the control group, but there was no LESP difference between the Ch Ach and control groups.     

Bronchoalveolar lavage in rheumatoid arthritis and secondary Sj?gren's syndrome

Bronchoalveolar lavage (BAL) was performed to investigate pulmonary involvement in 39 patients with rheumatoid arthritis (RA) and in 7 patients with RA and secondary Sj?gren's syndrome, and compared to 12 healthy controls. Lymphocytosis (more than 15%) was seen in 25, and more than 3% neutrophil granulocytes in 8 of 39 patients with RA. Lymphocytosis and/or neutrophil granulocytosis was seen in both seropositive and seronegative patients irrespective of clinical or radiologic findings. Patients with RA with or without secondary Sj?gren's syndrome had increased DR+ lymphocytes in BAL compared with peripheral blood. In 7 patients with secondary Sj?gren's syndrome an increased helper/suppressor cell index (OKT4+/OKT8+: 7.65 +/- 2.10) and increased natural killer cells (OKNK+: 27.3 +/- 5.5%) were found, as compared to 39 other patients with RA (OKT4+/OKT8+: 2.16 +/- 0.33, p less than 0.05; OKNK+: 14.5 +/- 2.3%, p less than 0.05). These BAL data are further evidence of frequent subclinical interstitial pulmonary involvement in RA with differences in the active autoimmune process from those in secondary Sj?gren's syndrome.     

Lower esophageal sphincter pressure in patients with gastroesophageal reflux diseases and posture and time patterns

Gastroesophageal reflux disease is caused predominantly by lower esophageal sphincter insufficiency. Reports suggest that it is possible to distinguish between two main mechanisms causing reflux: low basal sphincter pressure leading to free reflux, mostly occurring at night in the supine position, and increased transient lower esophageal sphincter relaxations with normal or increased resting pressure leading to reflux during the day in an upright position. Lower esophageal sphincter pressure (LESP)-- s determined by stationary pull-through manometry--was compared to profiles of acidic reflux measured by 24-h pH monitoring in 207 patients with proven gastroesophageal reflux disease. Differences in LESP were not significant among patients with reflux predominantly during the day in an upright position and those with reflux predominantly at night in a supine position (16.1 +/- 7.4 mmHg versus 15.1 +/- 7.8 mmHg; t-test: P = 0.355). For both patterns of LESP, there was a slight negative correlation with the amount of acidic reflux (determined as a percentage of time with pH < 4). Pearson correlation coefficients were -0.196 for upright refluxers and -0.137 for bipositional/supine refluxers (P = 0.006 and P = 0.049, respectively). As there are no differences in LESP with regard to posture or time patterns of acidic reflux it seems unlikely that upright reflux is associated with increased LESP, whereas supine reflux manifests due to a hypotensive LESP. Alternatively, it may be concluded that stationary pull-through manometry is inadequate for determining the cause of gastroesophageal reflux disease and is therefore of limited use in its routine diagnosis.     

原发性胆汁性肝硬化与干燥综合征20例临床分析

目的：探讨原发性胆汁性肝硬化与干燥综合征的相关性。方法：对20例原发性胆汁性硬化伴或不伴发干燥综合征病例的临床特点,血清学检查,肝脏病理,治疗等进行回顾性分析。结果：原发性胆汁性肝硬化病人临床以黄疸,皮肤瘙痒,肝大,脾大为主要表现,抗线粒体抗体M2亚型为特征性抗体。合并口眼干燥表现的不少见,但不具备原发性干燥综合征的典型表现。治疗上缴素和免疫抑制剂疗效不佳,熊去氧胆碱酸有一定的疗效。结论：原发性胆汁性肝硬化合并的干燥综合征不同于原发性干燥综合征。     

Sj?gren's syndrome and primary biliary cirrhosis: presence of autoantibodies to purified mitochondrial 2-OXO acid dehydrogenases.

Sj?gren's syndrome is well known for the presence of antibodies directed at specific nuclear antigens. However, the presence of antibodies reacting with a variety of other self antigens, including antimitochondrial antibodies, has often been reported although their significance is unknown. Moreover, patients with Sj?gren's syndrome have been occasionally reported to be concordant with primary biliary cirrhosis. To address this issue we studied in a group of 96 patients with Sj?gren's syndrome the presence of autoantibodies to the dihydrolipoamide acetyltransferases of both pyruvate dehydrogenase and branch chain ketoacid dehydrogenase and to alpha-ketoglutarate dehydrogenase; these latter enzymes are the mitochondrial target antigens of primary biliary cirrhosis. We report that 7 of the 96 patients reacted with the mitochondrial antigens that are prominent in primary biliary cirrhosis. Moreover, in those patients showing reactivity with mitochondrial antigens, the autoantibodies were directed at the same immunodominant epitopes that have been previously characterized in primary biliary cirrhosis. One of the 7 positive patients was known to have primary biliary cirrhosis. We hypothesize that the remaining 6 patients are at clinical risk for the development of primary biliary cirrhosis and/or that abnormalities would be found on liver biopsy.     

Is abdominal compression a useful stimulation test for analysis of lower esophageal sphincter function?

The change in pressure of competent and incompetent lower esophageal sphincter (LES) due to abdominal compression is still a controversial subject. Therefore, we studied the effect of sustained (SAC) and intermittent (IAC) abdominal compression on lower esophageal sphincter pressure (LESP) in normals (N), patients with hiatus hernia (HH), and patients with scleroderma (S). When resting lower esophageal sphincter pressure exceeded 15 mm Hg, response to SAC and IAC was similar in patients with HH and in normals. On the other hand when basal LESP was below 15 mm Hg, stimulated sphincter pressure during IAC was significantly lower than during SAC. Values recorded during SAC were also falsely high in patients with scleroderma. Values obtained during either SAC or IAC did not depend on presence or absence of reflux symptoms in any group. LES stimulation with IAC gives valid results which correlate closely with LESP. Stress tests with IAC therefore seem to be a useful stimulation test for the analysis of LES function.     

A case of primary biliary cirrhosis associated with Hashimoto's thyroiditis, scleroderma and Sj?gren's syndrome.

A 53-year-old woman was admitted because of Raynaud's phenomenon, polyarthralgia and polymyalgia. Biopsy specimens of the liver and thyroid gland revealed characteristic findings of primary biliary cirrhosis (PBC) (stage I by Scheuer's classification) and chronic thyroiditis. Her clinical features were also complicated by scleroderma (type I by Barnett's classification) and Sj?gren's syndrome (Sjs) with keratoconjunctivitis sicca. Thyroid hormone replacement therapy led to improvement in thyroid function, normalization of the biliary tract enzymes and alleviation of subjective symptoms.     

Prediction of the lower esophageal sphincter pressure after oral molsidomine by sydnonimine plasma concentrations.

BACKGROUND/AIMS: Recent studies suggest that endogenous nitric oxide decreases lower esophageal sphincter pressure (LESP). Substances leading to the formation of nitric oxide, such as molsidomine, decreases the human LESP. It is not yet clear whether this reduction is related to plasma concentrations of molsidomine, the nitrate-active substance sydnonimine (SIN-1) or to serum concentrations of nitrate/nitrite (NOx) as a stable end-product of volatile nitric oxide. METHODOLOGY: We performed a double blind controlled crossover trial in 8 healthy male volunteers. Plasma concentrations of molsidomine, SIN-1 and serum concentrations of NOx as well as esophageal manometry were determined. RESULTS: Mean basal LESP was significantly decreased from 25.4 +/- 2.8 mmHg to 21.9 +/- 2.7 mmHg and 21.4 +/- 2.6 mmHg 2 and 3 hours after molsidomine administration, respectively (mean +/- SEM; n = 8; p < 0.05). The maximum decrease of LESP from the baseline within 1-4 hours after molsidomine administration was 7.6 +/- 1.5 mmHg (mean +/- SEM; n = 8; p < 0.01). The decrease of the LESP correlated significantly with plasma concentrations of SIN-1 (r = -0.53; p = 0.002). NOx levels remained unchanged. CONCLUSIONS: Molsidomine decreases the LESP and plasma concentrations of the active metabolite SIN-1 may predict the potency of molsidomine to lower LESP. NOx was useless as a control metabolite to measure the LESP in response to molsidomine in healthy volunteers.     

The presence of Sj?gren's syndrome is a major determinant of the pattern of interstitial lung disease in scleroderma and other connective tissue diseases

A number of patients with scleroderma, Sj?gren's syndrome and other connective tissue diseases (CTD) were assessed to ascertain the prevalence of respiratory abnormalities as defined by bronchoalveolar lavage (BAL), standard respiratory function studies and gallium scan of the lung, and the relationship of these abnormalities to the presence or absence of dyspnea. These results suggest that respiratory symptoms are very common in CTD and in scleroderma, particularly if Sj?gren's syndrome is also present. Our findings also suggest the presence of 2 patterns of interstitial lung involvement in scleroderma. In scleroderma alone this appears to be characterized by the presence of increased neutrophil proportions in the BAL, decreased DLCO, and no increase in gallium uptake within the lung. Where scleroderma is associated with Sj?gren's syndrome, there is an increase in the proportion of lymphocytes in the BAL and respiratory symptoms are very prominent, the latter associated with an increase in gallium uptake within the lung. This suggests that Sj?gren's is a major determinant of the pattern of interstitial lung disease seen in CTD.     

Effect of secretin on lower esophageal sphincter pressure in patients with esophageal achalasia

The effect of a bolus intravenous administration of secretin (2.0 U/kg) on resting lower esophageal sphincter pressure (LESP) was investigated in seven patients with esophageal achalasia. Basal LESP before secretin injection in the patients was 60.113.4 mmHg (Mean±SEM), which was significantly higher than 26.9±2.5 mmHg in normal controls consisting of eight healthy volunteers. LESP significantly decreased within 1 min after the injection both in the patients and the controls. The maximum pressure change from each basal LESP was 31.2±5.2 mmHg in the patients, which was significantly greater than 12.1±1.8 mmHg in the controls. The effect of secretin disappeared within 5 min in the controls. The effect in the patients, however, lasted throughout the investigation time of 30 min. It is concluded that secretin has a long-acting effect on muscular relaxation of the lower esophageal sphincter in esophageal achalsia patients.     

Natural killing activity in Sj?gren's syndrome. An analysis of defective mechanisms

Natural killing (NK) by peripheral blood mononuclear cells (PBMC) against K562 cells was examined in 27 patients with Sj?gren's syndrome and 17 normal controls. NK activity in the patients was significantly reduced compared with normal controls (34.6 +/- 3.4% versus 52.2 +/- 3.4%, P less than 0.001). Patients with secondary Sj?gren's had lower cytotoxicity compared with those who had primary Sj?gren's (28.5 +/- 5.5% versus 37.3 +/- 4.2%, P less than 0.01). The proportion of PBMC with characteristics of NK cells was not decreased in the patients. NK by normal PBMC was diminished both in the presence of sera from patients with reduced NK and when the effector cells were pretreated with the sera. Pretreatment of target K562 cells did not alter NK activity. Suppression of NK by sera from patients did not correlate with levels of immune complexes or with antilymphocyte antibodies. Some patients had adherent cells which inhibited NK function. Addition of either indomethacin or catalase partially restored NK activity in such patients, indicating that both prostaglandins and hydrogen peroxide play a role in suppression. These data suggest that multiple mechanisms are involved in the defective NK activity seen in patients with Sj?gren's syndrome. The reduction of NK activity in Sj?gren's syndrome may contribute to the increased incidence of lymphoid malignancy.     

Relationshipp of HLA-Dw3 and HLA-B8 to Sj?gren's syndrome

Nineteen patients with Sj?gren's syndrome were evaluated for the presence of HLA-B8 and HLA-Dw3. HLA-B8 was found in 57.8% of patients and 20.1% of 96 controls (P less than 0.001). HLA-Dw3 was detected in 73.7% of the patients and 24.0% of controls (P less than 0.0001). Statistical evaluation of the association of both antigens with Sj?gren's syndrome revealed that the primary association was with HLA-Dw3 (P less than 0.005). Patients with HLA-Dw3 had a lower mean parotid salivary flow rate (0.8 +/- 0.3 ml/10 minutes/gland versus 5.6 +/- 1.2 ml/10 minutes/gland, P less than 0.0004) and a more intense lymphocytic infiltration into labial salivary glands (focus score 7.2 +/- 0.9 versus 3.4 +/- 0.9, P less than 0.04) than did patients without HLA-Dw3. The difference in the intensity of the lymphocytic infiltration was even more significant when patients with both HLA-Dw3 and HLA-B8 were compared with patients with neither antigen (focus score 7.5 +/- 1.0 versus 2.8 +/- 0.8, P less than 0.02). In addition, all patients with severe keratoconjunctivitis sicca had both antigens. Our observations suggest that a number of genes may interact to determine susceptibility and severity in Sj?gren's syndrome.     

Autoimmune thyroid disease is associated with a diagnosis of secondary Sjögren's syndrome in familial systemic lupus

BACKGROUND: Autoimmune thyroid disease is common in systemic lupus erythematosus (SLE). About 20% of patients with SLE have secondary Sj?gren's syndrome. METHODS: Families with more than one patient with SLE were identified. All patients met the revised classification criteria, although SLE-unaffected relatives were confirmed not to satisfy these criteria. Diagnosis of autoimmune thyroid disease and Sj?gren's syndrome was made on the basis of a review of medical records, interview and questionnaire administered to patients with SLE, and by a questionnaire administered to SLE-unaffected subjects. RESULTS: Of a total of 1138 patients with SLE, 169 had a diagnosis of Sj?gren's syndrome. Of these 50 (29.6%) patients also had autoimmune thyroid disease. Of the 939 patients with SLE with no diagnosis of Sj?gren's syndrome, 119 (12.7%) had autoimmune thyroid disease (chi2 = 20.1, p = 0.000009). There was no association of a diagnosis of hypertension with secondary Sj?gren's syndrome (42% vss 47%). Among 2291 SLE-unaffected relatives, 44 had diagnosed primary Sj?gren's syndrome and 16 (36.3%) of these also had autoimmune thyroid disease. 265 of 2247 (11.8%) subjects had autoimmune thyroid disease but no Sj?gren's syndrome (chi2 = 24.2, p<0.001). CONCLUSIONS: Autoimmune thyroid disease is found in excess among patients with SLE with a diagnosis of secondary Sj?gren's syndrome, as well as among their SLE-unaffected relatives with a diagnosis of primary Sj?gren's syndrome.     

Effect of bombesin on esophageal motility in humans

We have investigated the effect of bombesin on esophageal motility and explored the mechanism of action of bombesin. Eight healthy subjects were studied in random order during intravenous administration of (1) bombesin, (2) bombesin + vagal cholinergic receptor blockade with atropine and (3) bombesin + somatostatin. Lower esophageal sphincter pressure (LESP) and esophageal body motility were recorded continuously by Dent-sleeve manometry. Bombesin significantly (p < 0.01) increased LESP from 20 +/- 2 mmHg to 43 +/- 6 mmHg. Neither atropine nor somatostatin significantly reduced the bombesin-induced increases in LESP. Bombesin significantly (p<0.05) increased peristaltic wave amplitude (from 61 +/- 4 to 105 +/- 9 mmHg) and duration (from 2.9 +/- 0.2 to 4.8 +/- 0.3 s) in the mid and distal part of the esophagus. Neither atropine nor somatostatin significantly reduced the esophageal body motor response to bombesin. In conclusion (1) bombesin significantly increases LESP and affects esophageal body motility by increasing peristaltic wave amplitude and duration and (2) the effect of bombesin on esophageal motility is not dependent on vagal cholinergic mechanisms and is not mediated by the action of gastrointestinal hormones released by bombesin.     

Does an acute increase of intraabdominal pressure effect esophageal sphincter pressure?

BACKGROUND/AIMS: The study was designed to observe the acute alterations between lower esophageal sphincter (LES) and intraabdominal pressure (IAP) in patients undergoing diagnostic laparoscopy. METHODOLOGY: Eleven patients (7 Male), aged 49 fitting the criteria for manometric research and diagnostic laparoscopy were studied. To measure the IAP in sterile conditions a new device (IAP measurement system) was set. Pressures at basal (b), during intraabdominal CO2 insufflations (min, m2, m3) and at the end of laparoscopy (me), were recorded simultaneously. All results were given as the difference between two maneuvers (A). Paired sample t-test was used. RESULTS: The results were as follows; at the time of maximum CO2 insufflations: p delta m1-b; 24.25 vs. 14.64 mmHg, during the stabile insufflations: p delta m2-m1; -2.88 vs. 2.99 mmHg, p delta m3-m2; -0.70 vs. -0.82 mmHg and after deflation of CO2; end of the laparoscopy; p delta m(e)-m3; -16.73 vs. -16.65 mmHg for LESP and IAP respectively. The response of the LESP and IAP were similar in all phases (p > 0.05). Also alterations of pressures according to gender or presence of cirrhosis were found to be similar. CONCLUSIONS: LESP is changed synchronously in the presence of acute pressure changes in IAP. Gender or presence of cirrhosis does not affect the response of LES.