Cholesteryl Ester Storage Disease: Fatal Outcome without Causal Therapy in a Female Patient with the Preventable Sequelae of Progressive Liver Disease after Many Years of Mild Symptoms.

BACKGROUND Cholesteryl ester storage disease (CESD), also known as lysosomal acid lipase deficiency (LAL-D), is a rare autosomal-recessive inheritable lysosomal storage disease. Since 2015, a causal treatment with sebelipase alfa, which replaces the missing LAL enzyme, has been approved. We report a fatal course of LAL-D in a female patient. CASE REPORT In 1979, CESD was first diagnosed in a 13-year-old female with marked hepatomegaly. At that time, no specific treatment for CESD was available and the spontaneous course of the disease had to be awaited. In 2013, a laparoscopic cholecystectomy for symptomatic gallstones was performed. The patient's CESD had caused a Child-Pugh A/B and Lab-MELD 14 cirrhosis with esophageal varices (grade III), a solitary fundal varix, as well as hepatosplenomegaly with thrombocytopenia. In 2016, the patient was admitted with compensated cirrhosis and splenomegaly for a ligature of esophageal varices which was complicated by vomiting of blood followed by severe coagulopathy and hemorrhagic shock. The dried blood test showed reduced acid lipase (0.03 nmol/spot*3 hours; reference range 0.2-2) and beta-galactosidase (0.08 nmol/spot*21 hours; reference range 0.5-3.2). Then 15 days after the esophageal varices bleed, the patient died due to multiorgan failure as a sequelae of advanced liver disease. CONCLUSIONS LAL-D should be included in the differential diagnosis of lipid metabolism disorder, hepatomegaly, and non-alcoholic fatty liver disease with fibrosis or cirrhosis. Causal treatment with sebelipase alfa should be introduced even in patients who have LAL-D and many years of clinically mild symptoms of this disease to prevent the serious sequelae of cirrhosis or cardiovascular complications.

Budesonide 9 mg is at least as effective as mesalamine 4.5 g in patients with mildly to moderately active Crohn's disease.

BACKGROUND & AIMS: Comparative data on budesonide vs mesalamine for the treatment of mild-to-moderately active Crohn's disease (CD) are sparse. We assessed the efficacy and safety of each therapy in patients with mildly to moderately active CD. METHODS: We performed a randomized, double-blind, double-dummy, 8-week, multicenter study in which 309 patients with mildly to moderately active CD received pH-modified-release oral budesonide (9 mg/day once daily or 3 mg/day 3 times daily) or Eudragit-L-coated oral mesalamine (4.5 g/day). RESULTS: The primary efficacy variable, clinical remission (defined as Crohn's Disease Activity Index ≤150), at the final visit occurred in 69.5% (107 of 154) of patients given budesonide vs 62.1% (95 of 153) of patients given mesalamine (difference, 7.4%; 95% repeated confidence interval, -4.6% to 18.0%; P = .001 for noninferiority). Clinical remission rates did not differ significantly between the 2 budesonide groups. Treatment response, defined as Crohn's Disease Activity Index of 150 or less and/or a decrease of 70 or more (Δ70) or 100 or more (Δ100) points from baseline to final visit, did not differ significantly between patients given budesonide vs mesalamine (Δ70, P = .11; Δ100, P = .15), or between the 2 budesonide groups (Δ70, P = .38; Δ100, P = .78). No other efficacy end points differed significantly between groups. Discontinuation because of adverse events occurred in 3% and 5% of budesonide- and mesalamine-treated patients, respectively. There were no clinically relevant differences in adverse events between the 2 budesonide groups. CONCLUSIONS: Budesonide (9 mg/day) was numerically, but not statistically, more effective than Eudragit-L-coated mesalamine (4.5 g/day) in patients with mildly to moderately active CD. Budesonide (9 mg/day), administered once daily, was as effective as the standard (3 times daily) regimen.

A polymorphism of the bactericidal/permeability increasing protein (BPI) gene is associated with Crohn's disease.

BACKGROUND: The bactericidal/permeability increasing protein (BPI) is involved in the elimination of gram-negative bacteria. A functionally relevant single nucleotide polymorphism of the BPI gene causes an amino acid exchange (Glu216Lys). STUDY: To evaluate whether this single nucleotide polymorphism contributes to the predisposition to inflammatory bowel disease, we compared the allele frequencies of 265 patients with Crohn's disease, 207 patients with ulcerative colitis, and 608 healthy controls. RESULTS: The Glu/Glu genotype frequency was decreased significantly in Crohn's disease patients as compared with controls (P < 0.027). No differences were obvious in patients with ulcerative colitis. CONCLUSIONS: Failure of the innate intestinal immune system could be involved in the pathogenesis of Crohn's disease via reduced/impaired defense against gram-negative bacteria.

Collagenous colitis: implications for the role of vascular endothelial growth factor in repair mechanisms.

OBJECTIVES: Collagenous colitis is a chronic inflammatory bowel disease with a band-like subepithelial deposition of immature extracellular matrix. Because the extracellular matrix deposition is potentially reversible, an imbalance between fibrogenesis and fibrolysis with reduced matrix degradation has been suspected. Vascular endothelial growth factor plays a central role in extracellular matrix degradation. Therefore, we investigated the expression of vascular endothelial growth factor in the colonic mucosa of patients with collagenous colitis before and after long-term treatment with oral budesonide. METHOD: A quantitative immunohistochemical method was used to measure the amount of immunoreactive vascular endothelial growth factor, tenascin and leucocyte common antigen within the epithelium and the lamina propria of colonic biopsies by area morphometry. RESULTS: Strong immunostaining for vascular endothelial growth factor within the epithelium and the lamina propria, and for tenascin, was seen in patients with collagenous colitis compared with normal controls. The enhanced immunostaining for vascular endothelial growth factor within the lamina propria was accompanied by the accumulation of leucocytes, detected by staining for leucocyte common antigen. After long-term treatment with oral budesonide, the amount of immunostaining for leucocyte-derived vascular endothelial growth factor within the lamina propria decreased significantly to normal levels. In contrast, staining for vascular endothelial growth factor within the epithelium remained significantly increased. CONCLUSIONS: Our data suggest an important role of vascular endothelial growth factor in counteracting the local imbalance of fibrogenesis and fibrolysis, leading to an accumulation of immature subepithelial matrix in collagenous colitis.

A polymorphism of the NFKBIA gene is associated with Crohn's disease patients lacking a predisposing allele of the CARD15 gene.

BACKGROUND AND AIMS: Nuclear factor kappa-B (NFkappaB) plays a crucial role in diseases associated with dysregulated immune response. NFkappaB inhibitor alpha downregulates the activity of NFkappaB. PATIENTS AND METHODS: To evaluate the contribution of the NFkappaB inhibitor alpha gene in Crohn's disease single nucleotide polymorphisms in the 3'-UTR and at position -420 in the promoter were studied in 259 patients with Crohn's disease genotyped for the variations of the CARD15 gene in comparison to 441 healthy controls. Additionally we screened the coding region of the NFkappaB inhibitor alpha gene for polymorphisms by SSCP analysis. RESULTS: In comparison to controls the A allele and the AA genotype frequencies of the single nucleotide polymorphisms in the 3'-UTR were significantly increased only in Crohn's disease patients without a variation in the CARD15 gene. Similarly, the difference between patients harboring no predisposing CARD15 alleles and patients harboring such a variation was significant. CONCLUSION: The findings indicate that the phenotype Crohn's disease is to be substructured with respect to genetic susceptibility.

[Kyphoscoliosis as a cause of pulmonary hypertension]. / Kyphoskoliose als Ursache einer pulmonalen Hypertonie.

HISTORY AND CLINICAL FINDINGS: A 61-year-old male patient complained about diffuse upper abdominal pain and a progressive dyspnoe on exertion. Of clinical relevance were signs of congestive heart failure and a distinct kyphoscoliosis. THERAPY AND CLINICAL COURSE: A cardiac catheter examination proved a pulmonary hypertension without cardiac genesis. Both, pulmonary function test and computed tomography of the thorax rule out obstructive bronchial asthma and embolism of the lung. As the sole cause of pulmonary hypertension, kyphoscoliosis was diagnosed. Since the patient refused noninvasive positive pressure ventilation, a medication with calcium entry blocker and ACE blocker was induced, followed by oxygen breathing. This successfully helped to reduce pulmonary resistance (746 vs. 332 dyn*s*cm(-5)). CONCLUSION: Kyphoscoliosis can create a considerable increase of pulmonary resistance. Medical treatment and oxygen breathing have proven to be an efficient method to lower that significantly.

Budesonide treatment for collagenous colitis: a randomized, double-blind, placebo-controlled, multicenter trial.

BACKGROUND & AIMS: Collagenous colitis is an idiopathic microscopic colitis characterized by chronic watery diarrhea, a typical subepithelial collagen layer, and lymphoplasmacellular infiltration. We investigated the effect of budesonide on symptoms and histology in patients with collagenous colitis in a randomized, double-blind, placebo-controlled multicenter trial. METHODS: Patients with chronic diarrhea and histologically proven collagenous colitis were randomized to receive either oral budesonide (Entocort capsules; AstraZeneca, Sodertalje, Sweden) 9 mg/day for 6 weeks or placebo. Complete colonoscopy was performed before and after treatment. Histopathology was assessed by a single pathologist blinded to the patients' treatment. Clinical symptoms were assessed by standardized questionnaires. RESULTS: Fifty-one patients were randomized; 45 patients were available for per protocol analysis. The rate of clinical remission was significantly higher (P < 0.001) in the budesonide group than in the placebo group (per protocol 86.9% vs. 13.6%, respectively; intention-to-treat 76.9% vs. 12.0%, respectively). Histologic improvement was observed in 14 patients of the budesonide group (60.9%) and in 1 patient of the placebo group (4.5%; P < 0.001). Two patients in the budesonide group (7.7%) and 1 patient in the placebo group (4.0%) discontinued treatment prematurely because of side effects. CONCLUSIONS: Oral budesonide (Entocort capsules) is an effective and safe treatment modality for patients with collagenous colitis. Long-term follow-up of these patients is necessary to investigate whether clinical and histologic remission is sustained.