Energy and substrate metabolism in patients with active Crohn's disease.

The aim of the study was to evaluate the possible contribution of changes in energy metabolism and substrate oxidation rates to malnutrition in Crohn's disease and to assess the effect of enteral nutrition on these parameters. Energy metabolism was evaluated by indirect calorimetry in 32 patients with active Crohn's disease and 19 age- and sex-matched healthy individuals. Measurements were done in the postabsorptive state. Seven out of 32 patients received enteral nutrition via a nasogastric tube. In these patients, resting energy metabolism was determined at d 0 (postabsorptive), 7, 14 (during full enteral nutrition) and 15 (postabsorptive). Resting energy expenditure was not significantly different between patients and controls, whereas the respiratory quotient (RQ) was lower in patients (0.78 +/- 0.05 vs. 0.86 +/- 0.05; P < 0.05). During enteral nutrition in 7 patients with Crohn's disease, the RQ increased on d 7 compared with d 0 and remained high even after cessation of enteral nutrition (d 0, 0.78 +/- 0.03; d 7, 0.91 +/- 0.04; d 15, 0. 84 +/- 0.05; P < 0.05; d 7 and 15 vs. d 0). No effects of enteral nutrition on resting energy expenditure were found. Active Crohn's disease is associated with changes in substrate metabolism that resemble a starvation pattern. These changes appear not to be specific to Crohn's disease but to malnutrition and are readily reversed by enteral nutrition. Enteral nutrition did not affect resting energy expenditure. Wasting is a consequence of malnutrition but not of hypermetabolism in Crohn's disease.

The relation of iron status and hemochromatosis gene mutations in patients with chronic hepatitis C.

BACKGROUND & AIMS: Elevated hepatic iron concentration may affect the response to antiviral therapy in chronic hepatitis C. This study explored the contribution of genetic hemochromatosis to iron accumulation in chronic hepatitis C. METHODS: HFE mutations (C282Y and H63D) were assessed in 184 patients with chronic hepatitis C virus and 487 controls. Liver biopsy specimens were available in 149 patients. Hepatic iron content was measured in 114 patients by atom-absorption spectrophotometry. RESULTS: The C282Y and H63D allele frequencies were 7.06 and 11.6 in patients and 4.83 and 11.09 in controls, respectively. Eight patients were homozygotes (5 C282Y [2.7%] and 3 H63D [1.6%]), 2 compound heterozygotes (1%), and 49 heterozygotes (14 C282Y [7.6%] and 35 H63D [19%]). Biochemical evidence of iron overload was more common in patients with HFE mutations (28 of 47) than in those without (34 of 102; P = 0.0045). Histological iron grading and hepatic iron content overlapped among patients with or without mutations. A hepatic iron index of >1.9 was observed only in 1 of the 4 C282Y homozygotes and 1 of the 3 H63D homozygotes. CONCLUSIONS: HFE mutations contribute to but do not fully explain hepatic iron accumulation in chronic hepatitis C. Furthermore, C282Y or H63D homozygosity in chronic hepatitis C is not necessarily associated with a high hepatic iron content.

Gastroduodenal permeability in Crohn's disease.

BACKGROUND: Gastric permeability was prospectively investigated by determination of sucrose excretion in 100 patients with Crohn's disease. Results were compared with histological findings and the lactulose-mannitol ratio as a measure of intestinal permeability. METHODS: All subjects underwent oesophagogastroduodenoscopy with biopsies of all investigated parts. Thirty-two Helicobacter pylori-positive patients were excluded from further analyses. RESULTS: Gastroduodenal permeability was significantly higher in patients with Crohn's disease than in control subjects (P < 0.00001). Sucrose excretion alone did not predict microscopic inflammation of the upper gastrointestinal tract. Increased gastroduodenal permeability with a concomitant rise in intestinal permeability predicted histological upper gastrointestinal involvement of Crohn's disease with a likelihood of 86%. The negative predictive value was 43%. CONCLUSION: In parallel with findings in the small intestine, gastroduodenal permeability is increased in a high proportion of patients with Crohn's disease. In patients with an increased lactulose-mannitol ratio, elevated sucrose excretion is highly predictive of histological gastroduodenal involvement.

Screening for Wilson's disease in patients with liver diseases by serum ceruloplasmin.

BACKGROUND/AIMS: A low serum ceruloplasmin level is considered a diagnostic test for Wilson's disease. To examine whether it is useful to detect presymptomatic patients with Wilson's disease, serum ceruloplasmin was determined by radial immunodiffusion (normal: 20-60 mg/dl) in all patients (n = 2867) admitted for evaluation of a liver disease in 1993 and 1994. METHODS: Patients with levels lower than 20 mg/dl were further evaluated by determination of serum copper concentration, urine copper excretion and ophthalmological examination. If possible, a liver biopsy was performed and the hepatic copper content was determined by flame atomic absorption spectroscopy. RESULTS: Seventeen patients had serum ceruloplasmin levels < 20 mg/dl. One had asymptomatic Wilson's disease (no Kayser-Fleischer rings or neurological symptoms). In the other 16 patients Wilson's disease was excluded. Based on elevated hepatic copper concentration, there were considered as heterozygous carriers of the WD gene. The remaining patients had various liver diseases (acute viral hepatitis in three, chronic hepatitis in two, drug-induced liver disease in three, alcoholic induced liver disease in two) or malabsorption (n = 3). CONCLUSIONS: The positive predictive value of low serum ceruloplasmin was only 5.9%. Although helpful for identifying presymptomatic Wilson's disease, screening by determination of serum ceruloplasmin in unselected patients with clinical or laboratory evidence of liver disease is neither feasible nor cost effective.

Detection of the His1069Gln mutation in Wilson disease by rapid polymerase chain reaction.

BACKGROUND: Most known mutations in the gene associated with Wilson disease are rare. Only the His1069Gln mutation is found often in patients of Northern or Eastern European origin. OBJECTIVE: To examine the frequency of the His1069Gln mutation in Austrian patients with Wilson disease and their families by using a new, rapid polymerase chain reaction (PCR) test. DESIGN: Cross-sectional study. SETTING: University medical center. PATIENTS: 83 patients from 72 families and 98 relatives of 11 homozygous index patients. MEASUREMENTS: Results of a semi-nested PCR-based assay to detect the His1069Gln mutation in Wilson disease, clinical symptoms, and liver histologic findings. RESULTS: 20 patients, including 5 siblings, were homozygous for the His1069Gln mutation. Thirty-three patients, including 4 siblings, were compound heterozygotes. The mutation was not detected in 30 patients, including 2 siblings. Homozygotes were older at onset of symptoms (mean age, 24 +/- 6 years) than compound heterozygotes (17 +/- 6 years [95% CI, 3.3 to 10.7 years]; P = 0.0135) and patients with other mutations (18 +/- 8 years [CI, 1.8 to 10.2 years]; P = 0.117). Homozygotes were more often female (73.3%) than were compound heterozygotes (48% [CI, 0.94% to 2.46%]) and patients with other mutations (50% [CI, 0.91% to 2.37%]) (P = 0.05). Four of 98 asymptomatic relatives of 11 homozygous index patients were also homozygotes. Heterozygosity was confirmed in 46 relatives (19 parents, 11 children, and 16 distant relatives). CONCLUSION: The His1069Gln mutation was detected in 61% of Austrian patients with Wilson disease. Polymerase chain reaction may be useful for diagnosis and screening of family members of homozygous index patients, even if first-degree relatives are not available for examination.

Wilson's disease in patients presenting with liver disease: a diagnostic challenge.

BACKGROUND & AIMS: In patients with Wilson's disease presenting with liver involvement, the correct diagnosis is often missed or delayed. The aim of this study was to find an algorithm for diagnosis of this difficult patient group. METHODS: Clinical and laboratory findings of 55 patients with Wilson's disease were evaluated at diagnosis before treatment. Presenting symptom was chronic liver disease in 17 patients, fulminant hepatic failure in 5 patients, hemolysis in 3 patients, and neurological disease in 20 patients, and 10 patients were detected by family screening (siblings). Evaluation included neurological and ophthalmologic examination, routine laboratory tests, and parameters of copper metabolism including liver copper content in 43 liver biopsy specimens. RESULTS: In the whole group, serum ceruloplasmin level was <20 mg/dL in 73%, urinary copper excretion was increased in 88%, and liver copper content was elevated in 91% at diagnosis. Kayser-Fleischer rings were detected in 55%. In contrast to patients with neurological disease (90% Kayser-Fleischer rings, 85% low ceruloplasmin), only 65% of patients presenting with liver disease were diagnosed by these typical findings. Ceruloplasmin levels were lower in patients with Kayser-Fleischer rings or with neurological disturbances than in patients without these symptoms. CONCLUSIONS: The commonly used clinical and laboratory parameters are not sufficient to exclude the diagnosis of Wilson's disease in patients with liver disease of unknown origin.

Predominance of the HLA-H Cys282Tyr mutation in Austrian patients with genetic haemochromatosis.

BACKGROUND/AIMS: Genetic haemochromatosis is the most common autosomal recessive disorder in Northern European populations. A major histocompatibility complex class I-like gene, HLA-H, has been proposed to be responsible for genetic haemochromatosis. The prevalence of HLA-H gene mutations 282(TGC; Cys/TAC; Tyr) and 63(CAT; His/GAT; Asp) was determined in patients of Austrian origin. METHODS: DNA extracted from the blood of 40 Austrian patients and 271 controls was used to amplify HLA-H gene fragments by the polymerase chain reaction method. The base changes responsible for mutations Cys282Tyr and His63Asp alter recognition sites for restriction enzymes SnaB I and Bcl I, respectively. Digestion products were separated by agarose gel electrophoresis and visualised by ethidium bromide staining. RESULTS: Thirty-one (77.5%) genetic haemochromatosis patients were homozygous for mutation Cys282Tyr and three compound heterozygous for mutations Cys282Tyr and His63Asp. One patient was homozygous for mutation His63Asp but normal for mutation Cys282Tyr. Four patients were normal at both genetic loci and one patient was heterozygous for mutation His63Asp. One control subject homozygous for mutation Cys282Tyr was found on investigation to fulfill diagnostic criteria for haemochromatosis. Eight control subjects homozygous for mutation His63Asp showed no biochemical or clinical evidence of haemochromatosis indicating that this variant is not directly responsible for haemochromatosis. Absence of the Cys282Tyr mutation in six genetic haemochromatosis patients with distinct haplotypes indicates mutations within the HLA-H gene or at alternative genetic loci are the cause of genetic haemochromatosis in these patients. CONCLUSIONS: The HLA-H Cys282Tyr defect is likely to play a key role in the pathogenesis of haemochromatosis in most patients. Predominance of a single HLA-H gene mutation in haemochromatosis allows presymptomatic screening by genotypic analysis.

Relationship between the use of unconventional therapies and disease-related concerns: a study of patients with inflammatory bowel disease.

We studied the use of unconventional therapies of a well-defined population of 105 patients with inflammatory bowel disease (IBD; 72 with Crohn's disease and 33 with ulcerative colitis) who were attending a university out-patient clinic. The following items were used to compare those patients who used unconventional therapies with those who did not. We compared disease-related data, sociodemographic variables, patients' disease-related concerns, and their perceived level of information about IBD. Concerns were measured with the Rating Form of IBD Patient Concerns (RFIPC), inflammatory disease activity was assessed by physicians with the Crohn's disease activity index (CDAI) and the clinical activity index (CAI). Of the 97 (92.4%) patients who answered all questions, 33 (34%) reported using unconventional therapies in addition to conventional therapy. In their level of information about IBD and in their clinical and sociodemographic data, they were not different from the IBD patients who were not using alternative treatments. In their duration of disease, there was a significant difference (p < 0.0002). The longer the disease duration, the more often patients used unconventional therapies. The most important differences between users and nonusers were the following: patients who used unconventional therapies were more concerned about having surgery (p < 0.001), being treated as different (p < 0.04), and feeling out of control (p < 0.05). We conclude that there is a relationship between the use of unconventional therapies and some disease-related concerns, which should be considered in clinical practice. This may help these patients avoid using unproven and expensive alternative therapies.

Diagnosis of Wilson's disease in an asymptomatic sibling by DNA linkage analysis.

The molecular genetic diagnosis of Wilson's disease in the 5-year-old sister of a patient with Wilson's disease is reported. The girl was clinically free of disease and had no conventional biochemical markers of Wilson's disease (i.e., normal ceruloplasmin, normal copper in the serum, normal 24-hour urinary copper excretion). Diagnosis with restriction fragment length polymorphisms and a nonradioactive polymerase chain reaction-based analysis with microsatellite markers showed her to be homozygous for the disease-associated markers. A liver biopsy was performed, and a 20-fold increased liver copper content confirmed the diagnosis. The child was treated with chelation therapy with D-penicillamine. The report of this study clearly shows the advantage of DNA linkage analysis (especially polymerase chain reaction) over conventional laboratory methods for presymptomatic diagnosis of Wilson's disease before irreparable liver and neurological damage occurs. The only limitation of this DNA-based diagnosis is the fact that it is only applicable in siblings of an index patient whose diagnosis was made by phenotypic criteria.

Elimination of acquired factor VIII antibodies by extracorporal antibody-based immunoadsorption (Ig-Therasorb).

Treatment of potent factor VIII antibodies is a difficult problem. In some cases a reduction of the antibody titer is necessary for effective treatment with human factor VIII concentrates. We describe a new method for extracorporal elimination of factor VIII antibodies (antibody-based immunoadsorption). Blood is drawn from an antecubital vein, citrated, and plasma is separated with a rotating membrane. Plasma passes alternately through one of two columns filled with sepharose-coupled polyclonal sheep antibodies to human immunoglobulins (Ig-Therasorb), whereas the other column is regenerated. Each cycle has a duration of 15 min. Three patients with high titer factor VIII antibodies (one hemophiliac and 2 with spontaneous antibodies; titers 29, 132, and 313 BU/ml, respectively) were treated. The average reduction of the antibody titer was 76.1 +/- 17.2% per session. In each patient 4 sessions were necessary to reduce the antibody titer to < 1 BU/ml. The mean processed plasma volume was 6731 +/- 640 ml and the mean duration of each session 3.9 +/- 0.7 h. Serum IgG, IgA and IgM levels decreased by 75.3 +/- 11.9%, 62.9 +/- 19.1%, and 54.8 +/- 23.8% respectively. The procedure was tolerated without any side effects. Thus, rapid elimination of factor VIII inhibitors can be achieved with antibody-based immunoadsorption, which can be life-saving in some cases. This promising method should be evaluated in a larger number of patients.

Disease-related worries and concerns: a study on out-patients with inflammatory bowel disease.

OBJECTIVE: To investigate the relationship between inflammatory bowel disease (IBD) patients' disease-related worries and concerns and their disease-related data, sociodemographic variables and perceived information level with respect to IBD. STUDY DESIGN: Prospective evaluation of disease-related concerns. SETTING: Out-patient IBD clinic of a university hospital. STUDY POPULATION: The study included 105 patients with IBD (72 with Crohn's disease and 33 with ulcerative colitis). MEASUREMENTS: Worries and concerns were measured using the standardized 25-item rating form of IBD patient concerns; actual disease activity was assessed by physicians using the Crohn's disease and clinical activity indices. Sociodemographic and other disease-related data were collected using a structured questionnaire. Patients' perceived information level was measured using a visual analogue scale. RESULTS: The issues of greatest concern to our patients were, in descending order of importance, having an ostomy bag (mean score +/- SD 63.6 +/- 38), the effects of medication (53.1 +/- 34), having surgery (51.6 +/- 36), the uncertain nature of the disease (46.5 +/- 32) and energy level (41.5 +/- 34). Patients with ulcerative colitis scored higher with respect to concern about loss of bowel control (P < 0.03). Disease-related worries and concerns correlated poorly with disease-related data (actual disease activity, severity of the course of IBD, diagnosis, disease duration or location, medication) but showed a significant negative correlation with patients' perceived information level about IBD (t = 0.2, P < 0.004). Lower information-level scores were associated with greater concerns. CONCLUSION: We conclude that the patients' information level about IBD and disease-related concerns have to be considered in clinical practice. Better information about IBD and psychosomatic counselling for patients who show high levels of concern may improve their quality of life and clinical care.

Increase of bcr-abl chimeric mRNA expression in tumor cells of patients with chronic myeloid leukemia precedes disease progression.

The translocation t(9;22) in chronic myeloid leukemia (CML) generates a bcr-abl fusion gene that codes for an aberrant chimeric mRNA. Cell lines established from CML patients in blast crisis show higher expression of this aberrant bcr-abl transcript than cells from patients in chronic phase of the disease. This observation provided the stimulus to investigate whether increased expression of the aberrant bcr-abl fusion transcript is critical to the progression of CML from chronic phase to blast crisis. We have monitored the bcr-abl mRNA expression in 25 patients by serial quantitative polymerase chain reaction analyses during a follow-up period of 12 to 156 months after diagnosis, with a median observation time of 28 months. In all patients who have shown disease progression to accelerated phase (n = 4) or blast crisis (n = 7), an increase in bcr-abl mRNA expression was detected up to 16 months before laboratory or clinical parameters showed phenotypic transformation of the malignant clone. To investigate whether the elevated levels of bcr-abl mRNA reflected an increase in the proportion of leukemic cells in the samples analyzed or primarily enhanced transcriptional activity of the bcr-abl fusion gene, we performed quantitative analyses of the bcr-abl gene at the DNA level and of the Ph chromosome at the cytogenetic level and compared these data with steady-state bcr-abl mRNA levels. We show that increased levels of the bcr-abl transcript did not reflect increased proportions of leukemic cells but elevated steady-state levels of the chimeric mRNA in the malignant cells before disease progression. Therefore, our data strongly suggest that an increase of the chimeric mRNA expression in the leukemic cells precedes the phenotypic transformation of the malignant clone.

Enteral supplementation of phosphate does not prevent hypophosphatemia during refeeding of cachectic patients.

Hypophosphatemia due to parenteral nutrition has been described frequently. It was attributed to the lack of phosphorus content in parenteral nutrition solutions. With modern parenteral nutrition regimens containing phosphorus, this problem has been virtually eliminated. Enteral nutrition solutions contain adequate phosphate for patients with normal phosphate stores. Hypophosphatemia has therefore rarely been reported in enteral nutrition. We describe two patients with protein-energy malnutrition who developed severe hypophosphatemia during tube feeding with phosphorus-containing formula diets. Chronic alcoholism and vitamin D deficiency due to malabsorption because of Crohn's disease were additional risk factors in these two patients. Patients with depleted phosphate stores and high metabolic demand have a higher daily requirement for phosphorus than is available in routine isotonic enteral formulas. This case report emphasizes the importance of monitoring serum phosphate concentration daily during the first week of refeeding.

Molecular forms of pseudocholinesterase in patients with Crohn's disease.

Previous studies have shown that pseudocholinesterase (PCHE) is low in patients with Crohn's disease (CD). This finding, however, failed to be of clinical relevance due to the wide normal range. PCHE consists of four main molecular forms designated as C1, C2, C3 and C4 according to their electrophoretic mobility. The question of the present study was to assess the influence of CD on the distribution and pattern of the PCHE isozymes. We therefore investigated the electrophoretic separation of PCHE in 16 healthy volunteers (HV), in 15 patients with quiescent CD (QCD; CD activity index: median = 71, interquartile range = 44-122) and in 10 patients with active CD (ACD; CD activity index: 229, 173-304). In most of the cases total serum PCHE activity was within the normal range even in patients with active CD. No changes of the isozyme pattern were found but the percentage distribution was significantly influenced by the inflammatory activity in patients with active CD:C1 (HV: 14.7%, 13.7-18.1%; QCD: 16.0%, 9.8-19.9%; ACD: 8.5%, 2.9-12.5%, p < 0.01) and C2 (HV: 8.0%, 6.7-10.5%; QCD: 9.0%, 7.9-9.7%; ACD: 6.7%, 3.2-8.6%, p < 0.05) were decreased in active CD while the C4 component (HV: 66.8%, 62.5-69.9%; QCD: 63.1%, 54.9-73.8%; ACD: 77.3%, 70.7-90.1%, p < 0.01) was increased. The percentage of the C3 band (HV: 5.7%, 4.6-6.9%; QCD: 6.8%, 4.6-8.4%; ACD: 5.3%, 2.8-6.8%, NS) was unchanged.(ABSTRACT TRUNCATED AT 250 WORDS)