Concordance of inflammatory bowel disease among Danish twins. Results of a nationwide study.

BACKGROUND: Previous studies have shown an increased risk of inflammatory bowel disease (IBD) among relatives of patients with Crohn disease and ulcerative colitis. In the present study the probandwise concordance rates for ulcerative colitis and Crohn disease among mono- and dizygotic twins were estimated. Further we aimed to evaluate whether smoking habits might influence the concordance, and to look for clinical characteristics of concordant versus discordant twin pairs. METHODS: Among the 38,507 identified twins born in Denmark from 1953 to 1982, a questionnaire was sent to the 34,076 who previously had accepted to participate in studies. For twins reporting IBD, the diagnosis was verified by applying standard criteria to records requested from hospitals or practitioners. RESULTS: Among the 29,421 (86.3%) twins answering the questionnaire, 103 pairs had at least one twin who suffered from IBD. In the Crohn disease group five of 10 monozygotic pairs, but none of 27 dizygotic pairs were concordant. In the ulcerative colitis group three of 21 monozygotic, and two of 44 dizygotic pairs were concordant. The probandwise concordance rate among monozygotic pairs was 58.3% for Crohn disease and 18.2% for ulcerative colitis; among the dizygotic pairs the rates were 0 and 4.5%, respectively. The frequency of smokers was higher among twins with Crohn disease and lower among twins with ulcerative colitis compared to the frequency in the twin register. Furthermore, smoking habits were found to be of significance for discordance for disease. Regarding the clinical characteristics no homogenous pattern was observed within the concordant pairs and the differences between concordant and discordant pairs were not significant. CONCLUSION: The observation of a significantly higher concordance rate among monozygotic than among dizygotic twin pairs strongly points to a genetic influence on occurrence of IBD, which seems to be more pronounced with regard to Crohn disease than to ulcerative colitis. Differences in smoking habits among the members of the discordant twin pairs may influence the discordance.

Risk of ulcerative colitis and Crohn's disease among offspring of patients with chronic inflammatory bowel disease.

OBJECTIVE: The incidence of inflammatory bowel disease (IBD) varies among and within countries, but several studies have indicated that genetic factors may play an important role in the etiology of IBD. A Danish regional study has observed an almost 10-fold increased risk for ulcerative colitis (UC) and Crohn's disease (CD) among first-degree relatives of patients with these diseases. To give more precise risk estimates we conducted a nationwide study using population-based data from the Danish National Registry of Patients (NRP). METHODS: All patients from the entire Danish population (5.2 million), who were discharged between 1977 and 1992 with a diagnosis of either UC or CD were extracted from the NRP. The offspring of these patients born in 1958 or later were identified in the Civil Registration System and subsequently linked to the NRP by means of the civil registration number. All Danish citizens alive or born on April 1, 1968 or later are registered in the Civil Registration System by a unique registration number, which includes the data of birth and links the offspring to their parents. The prevalence proportion ratio (PPR) was estimated by dividing the observed number of offspring with UC or CD, respectively, with the expected number of cases from the general population. RESULTS: The PPRs of CD and UC among offspring of patients with UC were 2.6 and 5.1, respectively, and the PPRs of CD and UC among offspring of patients with CD were 12.8 and 4.0, respectively. All ratios were significantly increased. CONCLUSION: The risk for UC and CD among offspring of patients with IBD is 2-13 times higher than the risk within the general population.

Novel donor splice site mutation in the KVLQT1 gene is associated with long QT syndrome.

INTRODUCTION: Inherited long QT syndrome (LQTS) recently has been associated with mutations in genes coding for potassium (KVLQT1, KCNE1, and HERG) or sodium (SCN5A) ion channels involved in regulating either sodium inward or potassium outward currents of heart cells, resulting in prolongation of the repolarization period. We describe a new mutation, a -1 donor splice site mutation in a kindred with two affected members (QTc = 0.61 and 0.54 sec). METHODS AND RESULTS: Single stranded conformation polymorphism (SSCP) analyses were performed on DNA fragments amplified by polymerase chain reaction from DNA extracted from whole blood. Aberrant conformers were analyzed by DNA sequencing. SSCP analysis of the KVLQT1 gene revealed an aberrant conformer in the affected family members. DNA sequencing confirmed the presence of a G-->A change in the last nucleotide of codon 344. This mutation does not cause an amino acid change, but a change of the splice site characteristics at the 3' end of exon 6. The mutation may affect, through deficient splicing, the putative sixth transmembrane segment of the K+ channel, and this type of mutation has not previously been described in KVLQT1. CONCLUSION: The clinical course of LQTS in the affected family members, in whom no deaths occurred despite 20 to 30 syncopes, can be explained by the ability of the cellular machinery to perform partial correct splicing in the mutant allele. This type of mutation may be misinterpreted as a normal variant, since it is a point mutation causing neither an amino acid change nor the introduction of a stop codon.

[Gastroscopic findings in HIV-positive patients]. / Gastroskopifund hos HIV-positive patienter.

In a retrospective study we reviewed the findings from 106 oesophago-gastro-duodenoscopies performed on HIV-positive patients between 01.01.93 and 31.12.94. Forty percent had Candida esophagei, 12% had Cytomegalovirus, 4% had atypical mycobacteria, 2% had Kaposi's sarcoma and 6% had Helicobacter pylori. Twelve percent of the patients received the diagnosis AIDS. The average CD4-cell count was 91 x 10(6)/l. The endoscopi findings were abnormal in 88% of HIV infected patients with gastrointestinal symptoms.

Anal and cervical abnormality in women--prediction by human papillomavirus tests.

A total of 151 women at risk of human immunodeficiency virus infection were investigated, to study the strength of the association between cervix and anus regarding the presence of HPV and cytological abnormality. An equal percentage of women had abnormal cervical (12.2%) and anal (12.1%) Papanicolaou smears. HPV measured by PCR was detected in 93.3% of cervical squamous intraepithelial lesions (SIL) compared to 49.1% of normal cervical cytologies, and in 100% of anal SIL and 67.4% of normal anal cytologies, respectively. After controlling for HPV-PCR status, immunodeficiency, as measured by a low CD4+ count and HIV positivity, increased the detection of cervical and to some extent anal squamous intraepithelial lesions (SIL). We evaluated how precisely an HPV test could predict cervical disease and found that the HPV-PCR test was slightly more sensitive than the HPV-hybrid capture (HC) test (PCR: 93.3% vs. HC: 88.9%), whereas the HC test was significantly more specific (83.6% vs. 50.9%), and with a much higher positive predictive value (43.2% vs. 20.6%). Similar results were obtained for anal SIL. HIV positivity increased sensitivity, lowered specificity and increased the positive predictive value of the tests. A diagnosis of cervical SIL was associated with a more than 3-fold increased risk of a simultaneous abnormal anal smear (p < 0.05). In conclusion, cervical and anal disease were significantly associated and almost exclusively seen in the presence of HPV. Immunodeficiency and HIV positivity increased the risk of disease in HPV-positive subjects. Hybrid capture, which requires a higher viral load than PCR to detect HPV, was clearly superior in predicting cervical and anal disease. Altogether, these findings suggest that a high level of HPV infection may be important for the development of SIL in the population studied.

Familial occurrence and inheritance studies in inflammatory bowel disease.

A number of studies have demonstrated aggregation of cases of ulcerative colitis or Crohn's disease in families, and of cases of both diseases within the same families, suggesting that patients share a genetic background. Perhaps because of differences in the selection of patients, study design and diagnostic criteria, different patterns of occurrence of inflammatory bowel disease (IBD) have been found among relatives of patients with these disorders. In recent years, however, several studies have been carried out, aiming by epidemiological methods to reveal (1) the frequency of familial occurrence of IBD among patients with ulcerative colitis and Crohn's disease, and (2) the prevalence of IBD among 1(0) relatives to patients with these diseases. Results from these studies show a relatively uniform pattern of family occurrence in about 10% of patients with ulcerative colitis and Crohn's disease, and a prevalence among 1(0) relatives of about 10 times that of the background population. A twin study reported a significantly higher concordance rate for Crohn's disease than for ulcerative colitis in monozygotic twins. By use of complex segregation analyses in 3 different studies, a very similar model of inheritance was found to fit for ulcerative colitis, namely a major dominant or additive gene with a low penetrance. For Crohn's disease the best-fitting model was a major recessive gene, with a high penetrance. This difference strongly supports the concept of ulcerative colitis and Crohn's disease as two separate disease entities. The occurrence of both diseases within the same families in certain members of the affected families is difficult to explain. The search for distinct associations of HLA genes with inflammatory bowel disease has shown a positive correlation between DR2 and ulcerative colitis and a negative association with DR4 and DRw6, compared with ethnically matched controls. In contrast, in Crohn's disease a positive association with the combination of DR1 and DQw5 alleles was revealed, thus indicating genetically different disease susceptibility for the two disorders. In general, however, no consistent pattern has been revealed from studies of association of HLA-A or -B antigens or blood group and serum protein markers. In two French families with several members affected with Crohn's disease no evidence for an HLA haplotype association could be revealed. Possible inherited markers of ulcerative colitis or Crohn's disease have been sought but without convincing success. Increased intestinal permeability, presence of anticolon antibodies and presence of antineutrophil leukocyte antibodies have been proposed, but not proved. Thorough studies are now needed of multimember families with disease for linkage studies to identify loci which contribute to increased liability. Such studies are in progress in different centres.

Mapping of a susceptibility locus for Crohn's disease on chromosome 16.

Crohn's disease (CD) and ulcerative colitis are the major forms of chronic inflammatory bowel diseases in the western world, and occur in young adults with an estimated prevalence of more than one per thousand inhabitants. The causes of inflammatory bowel diseases remain unknown, but genetic epidemiology studies suggest that inherited factors may contribute in part to variation in individual susceptibility to Crohn's disease. A genome-wide search performed on two consecutive and independent panels of families with multiple affected members, using a non-parametric two-point sibling-pair linkage method, identified a putative CD-susceptibility locus on chromosome 16 (P less than 0.01 for each panel). The localization was centered around loci D16S409 and D16S419 by using multipoint sibpair analysis (P less than 1.5x10(-5)). This region of the genome contains candidate genes which may be relevant to the pathogenic mechanism of inflammatory bowel diseases.

Pentoxifylline therapy in HIV seropositive subjects with elevated TNF.

Tumor necrosis factor-alpha (TNF-alpha) is thought to induce cachexia in subjects infected with human immunodeficiency virus (HIV), and it has been suggested that HIV-seropositive patients would benefit from treatment with pentoxifylline, a known suppressor of TNF-alpha production. The purpose of the present study was to examine how pentoxifylline at a dose of 800 mg thrice daily would influence the cellular immune system in HIV-seropositive persons with elevated TNF-alpha. Six HIV-seropositive subjects with elevated amounts of TNF-alpha in plasma at least at two occasions were included in an open, controlled, randomized, cross-over study consisting of a 6 week treatment period and a 6 week control period. Blood samples were collected before and at the end of each period. Pentoxifylline treatment did not influence the concentration of plasma-TNF-alpha, subpopulations of blood mononuclear cells, the proliferative responses nor the natural killer (NK), and lymphokine activated killer (LAK) cell activities. Furthermore, pentoxifylline treatment did not influence the weight, temperature, well being, or tiredness of the subjects. However, the patients frequently reported gastrointestinal side effects. In vitro, however, pentoxifylline at suprapharmacological concentrations inhibited the blood mononuclear cell (BMNC) proliferative responses, NK, and LAK cell activities.

Danish AIDS patients 1988-1993: a recent decline in Pneumocystis carinii pneumonia as AIDS-defining disease related to the period of known HIV positivity.

The frequency of PCP among adult Danish AIDS patients notified in 1988-93 was higher among patients tested HIV-positive less than 4 months prior to AIDS than among those known to be positive for > 1 year. Among the latter, the proportion with PCP decreased significantly over the period, from 45.3% in 1988 to 22.0% in 1993, while no such trend was found among patients tested positive for HIV less than 4 months before AIDS was diagnosed. The incidence of PCP as an AIDS-defining disease has decreased, most likely due to the use of PCP prophylaxis.

Intestinal permeability in patients with Crohn's disease and ulcerative colitis and their first degree relatives.

Increased intestinal permeability in patients with Crohn's disease and their first degree relatives has been proposed as an aetiological factor. The nine hour overnight urinary excretion of polyethyleneglycol-400 (PEG-400) and three inert sugars (lactulose, l-rhamnose, and mannitol) was used to test the permeation in 47 patients with Crohn's disease of whom 18 had at least one first degree relative with inflammatory bowel disease (2BD) and 52 patients with ulcerative colitis of whom 16 had at least one first degree relative with IBD. A total of 17 first degree relatives with IBD and 56 healthy first degree relatives were included. Thirty one healthy subjects not related to patients with IBD served as controls. No significant differences in PEG-400 permeation were found between the groups of patients, relatives, and controls, or between diseased and healthy relatives. The permeability to lactulose, rhamnose, and mannitol similarly did not differ between the three groups. This study challenges the previously reported findings of increased PEG-400 permeation in patients with Crohn's disease and in their healthy and diseased first degree relatives. There was no increase in permeability in a similar group of ulcerative colitis patients and their families.

Investigation of inheritance of chronic inflammatory bowel diseases by complex segregation analysis.

OBJECTIVE: To investigate the mode of inheritance of ulcerative colitis and Crohn's disease by complex segregation analysis. DESIGN: Cross sectional population based survey of familial occurrence of chronic inflammatory bowel disease. SETTING: Population of the Copenhagen county in 1987. SUBJECTS: 662 patients in whom inflammatory bowel disease had been diagnosed before 1979, of whom 637 (96%) provided adequate information. Of 504 patients with ulcerative colitis, 54 had 77 relatives with ulcerative colitis and of 133 patients with Crohn's disease, five had seven relatives with Crohn's disease. MAIN OUTCOME MEASURES: Patterns of segregation of either disease as assessed by complex segregation analysis performed with the computer program POINTER. RESULTS: The analysis suggested that a major dominant gene with a penetrance of 0.20-0.26 is present in 9-13% of adult patients with ulcerative colitis. The analysis did not allow for other components in the familial aggregation. For Crohn's disease the best fitting model included a major recessive gene with complete penetrance, for which 7% of the patients are homozygous. However, this model was not significantly different from a multifactorial model. CONCLUSIONS: The segregation pattern indicates that a major dominant gene has a role in ulcerative colitis, and suggests that a major recessive gene has a role in Crohn's disease.

Pneumocystis carinii pneumonia in AIDS patients: clinical course in relation to the parasite number found in routine specimens obtained by fiberoptic bronchoscopy.

The aim of this study was to evaluate whether the amount of Pneumocystis carinii organisms found at fiberoptic bronchoscopy (FB) performed on HIV-positive patients correlated to the character of the P. carinii pneumonia (PCP). A consecutive series of 105 patients presented with 131 episodes of pulmonary symptoms requiring FB, and in 75 of these episodes a diagnosis of PCP was made. Specimens were stained with Giemsa and methenamine silver nitrate and the number of parasites found was given as: numerous, many, few or none. The following signs and symptoms were registered: cough, dyspnoea, fever, loss of weight, chest radiograph, haemoglobin, WBC, CD4 cell count, PO2 and HIV p24 antigen. The PCP was characterized by the clinical course: mild, moderate, severe, and by the outcome: pulmonary healthy, pulmonary insufficiency and death. No correlations between the number of P. carinii organisms and the clinical course or outcome of the PCP, the symptoms before the FB or the paraclinical examinations were found. In conclusion, the routinely obtained quantitative results of the microbiological examinations of material from the lungs were not correlated to the severity of the PCP.

Adjunctive corticosteroid therapy for Pneumocystis carinii pneumonia in AIDS: a randomized European multicenter open label study.

Fifty-nine human immunodeficiency virus type-1-infected patients with a microscopically proven first episode of moderate to severe Pneumocystis carinii pneumonia (PCP) were enrolled into a randomized European multicenter study. The effect of adjunctive corticosteroid (CS) therapy was assessed on (a) survival to discharge, (b) need for mechanical ventilation, and (c) survival at day 90. CS was given within 24 h of standard therapy as intravenous methylprednisolone 2 mg/kg body weight daily for 10 days. All patients received cotrimoxazole as standard treatment. Inclusion criteria were a PaO2 less than 9.0 kPa (67.5 mm Hg) and/or a PaCO2 less than 4.0 kPa (30.0 mm Hg) while breathing room air. During the acute episode of PCP, 9 (31%) of the 29 control patients died versus 3 (10%) of the 30 CS patients; p = 0.01. Mechanical ventilation was necessary in 15 patients; 12 (41%) in the control group and 3 (10%) in the CS group; p = 0.01. The 90-day survival was 69% in controls versus 87% in CS patients; p = 0.07. Based on these data we conclude that adjunctive CS therapy for moderate to severe PCP in AIDS patients reduces the acute mortality and the need for mechanical ventilation.

Familial occurrence of inflammatory bowel disease.

BACKGROUND AND METHODS: We assessed the familial occurrence of inflammatory bowel disease in Copenhagen County, where there has been a long-term interest in the epidemiology of such disorders. In 1987 we interviewed 662 patients in whom inflammatory bowel disease had been diagnosed before 1979, asking whether their first- and second-degree relatives had this disorder. Ninety-six percent of the patients (504 with ulcerative colitis and 133 with Crohn's disease) provided adequate information. RESULTS: As compared with the general population, the first-degree relatives of the 637 patients with ulcerative colitis or Crohn's disease had a 10-fold increase in the risk of having the same disease as the patients, after standardization for age and sex. The risk of having the other of the two diseases was also increased, but less so, and the increase in the risk of having Crohn's disease was not significant in the relatives of patients with ulcerative colitis. The risk of ulcerative colitis in first-degree relatives of patients with ulcerative colitis appeared to be virtually independent of the generation to which the first-degree relative belonged and of the sex of the patient and the relative. The risk of ulcerative colitis in first-degree relatives tended to be higher if the disease had been diagnosed in the patient before the age of 50, but the risk seemed to be independent of the current age of the relatives. The prevalence of the same disease as that of the patient (either ulcerative colitis or Crohn's disease) among second-degree relatives was increased; the prevalence of the other disease was not increased. CONCLUSIONS: The 10-fold increase in the familial risk of ulcerative colitis and Crohn's disease strongly suggests that these disorders have a genetic cause.

Improved detection of Pneumocystis carinii by an immunofluorescence technique using monoclonal antibodies.

To assess whether a recently developed indirect immunofluorescent stain using monoclonal antibodies was more sensitive in detecting Pneumocystis carinii than the combination of Giemsa and methenamine silver nitrate stains which has routinely been used in the laboratory, 88 lavage fluid specimens and 34 induced sputum specimens were examined. All specimens were stained by five techniques: immunofluorescence using a combination of three monoclonal antibodies (from the National Institutes of Health, USA), immunofluorescence using a single monoclonal antibody (from Dakopatts), Giemsa, methenamine silver nitrate and toluidine blue O. Immunofluorescence using the monoclonal antibodies from the NIH was significantly more sensitive than any other single staining method and than the combination of Giemsa and methenamine silver nitrate staining. The study also showed that the cytospin centrifuge was very suitable for the preparation of slides with lavage fluid and processed induced sputum. Finally, the sensitivity of examination of induced sputum to detect Pneumocystis carinii was found to be 50% when compared with bronchoalveolar lavage fluid. However, this sensitivity may increase through practice.

Indication for fiberoptic bronchoscopy in HIV-infected patients suspected for Pneumocystis carinii pneumonia.

During a six-month period, 40 consecutive fiberoptic bronchoscopic procedures including bronchoalveolar lavage, bronchial brushing and forceps biopsy were performed in local anaesthesia on 34 HIV-infected males presenting symptoms compatible with Pneumocystis carinii pneumonia. In 23 examinations, P. carinii was found. Sixteen examinations were non-diagnostic and one was unsuccessful. The clinical course confirmed the diagnoses of the P. carinii positive as well as the P. carinii negative patients. Except for a lower total lymphocyte count in the patients harbouring P. carinii, the two groups did not differ with regard to history, clinical examination, immunology, serology or chest radiograph. We conclude that fiberoptic bronchoscopy should be performed on wide indications in HIV-infected patients with symptoms compatible with P. carinii pneumonia. The procedure is easily performed, it is safe, and it is highly sensitive. The advantage of an early diagnosis compensates for a rather high frequency of negative examinations.

CD4 lymphocyte counts and serum p24 antigen of no diagnostic value in monitoring HIV-infected patients with pulmonary symptoms.

The diagnostic value of the CD4 cell counts and the HIV p24 antigen were evaluated in a consecutive series of 105 HIV-infected patients experiencing 128 episodes of pulmonary symptoms which required bronchoscopy. One-third of patients with opportunistic infection (OI) had CD4 counts greater than 0.200 x 10(9)/l, and 60% of patients without OI had CD4 counts less than 0.200 x 10(9)/l; 47 and 42% of patients with and without OI, respectively, had detectable p24 antigen in serum. Only 36% of the patients with OI presented the combination of CD4 cells less than 0.200 x 10(9)/l and p24 in serum. In conclusion, the CD4 cell counts and the presence of p24 antigen in serum had a very limited predictive value for the presence of OI in HIV-infected patients with pulmonary symptoms.

Trends and patterns of opportunistic diseases in Danish AIDS patients 1980-1990.

We analysed the AIDS-defining diseases in all 618 notified AIDS patients in Denmark by June 30, 1990, and looked for trends and associations over time. Pneumocystis carinii pneumonia (PCP) was the most commonly reported disease (47%), and showed some but insignificant changes over time. The number of patients reported with Kaposi's sarcoma (KS) declined significantly from 33% in 1980-84 to 12% in 1990. KS was reported 5 times as often in homosexual men as in all other AIDS patients while esophageal candidiasis was reported in one fifth of the patients and were reported twice as often in women as in homosexual men. Wasting and HIV encephalopathy were 2.5 times more often reported in women than in homosexual men. The overall survival rate was 56% (95% confidence interval: 51-61%) at 1 year and 21% (95% confidence interval: 15-28%) at 3 years. Significantly improved survival over time was observed in patients diagnosed with PCP. Patients reported with KS had a significantly better prognosis than those with PCP. Women in general had a bad prognosis.

Pulmonary disease in patients with human immunodeficiency virus infection.

Pulmonary disease is the most important cause of morbidity and mortality in patients infected with human immunodeficiency virus (HIV). All parts of the hospital system are expected to be involved in the diagnosis and treatment of HIV infected patients in the coming years. Many different processes cause pulmonary disease alone or in combination. Bilateral interstitial infiltrates are the most frequent chest x-ray abnormality and are most frequently caused by infection with Pneumocystis carinii. Cytomegalovirus, Mycobacterium tuberculosis, nonspecific interstitial pneumonitis and pulmonary Kaposi's sarcoma are the most important parts of the differential diagnosis. An aggressive approach to the diagnosis of pulmonary disease in this patient population is indicated in order to provide optimal care and assess new therapies.

Suppression of p24 antigen in sera from HIV-infected individuals with low-dose alpha-interferon and zidovudine: a pilot study.

On the basis of the observations that HIV antigenaemia indicates a high risk of progression to AIDS and that zidovudine and alpha-interferon act synergistically against HIV replication in vitro, we performed a pilot trial including 12 HIV-infected asymptomatic patients with detectable p24 antigen in serum. The patients received low-dose lymphoblastoid alpha-interferon alone for 4 weeks followed by a combination of interferon and low-dose zidovudine for a further 16 weeks. The median p24 antigen level decreased significantly (P less than 0.01), the decrease being most pronounced at week 5. Decreases in haemoglobin and neutrophil counts were observed. Four patients required reduction of the zidovudine dose and three patients were transfused. In conclusion, the drug combination was capable of reducing the serum level of HIV p24 antigen and it was tolerated by the patients. Further studies are required to evaluate the clinical implications of these observations.