Hepatotoxicity induced by a second-generation combined oral contraceptive: case report and review of the literature.

Case: Second-generation combined oral contraceptives (COCs) are widely used and are believed to be safe for birth control and in the treatment of gynaecological diseases. No randomised controlled study has shown elevations in alanine transaminase (ALT) levels in relation to the use of a second-generation COC. We report a case of drug-induced liver injury (DILI) in a young, moderately obese woman, due to the use of a second-generation COC containing 30 µg ethinylestradiol and 150 µg levonorgestrel. COC use had been initiated 2 years prior to admission to our department. The diagnosis was based on elevated levels of ALT during COC use and was confirmed by re-challenge and a liver biopsy showing signs of former tissue damage after a 3 week break of COC treatment. Conclusions: To our knowledge, this is the first case of biopsy-proven DILI due to COC use in which a re-challenge was performed.

The relationship between the use of statins and mortality, severity, and pancreatic cancer in Danish patients with chronic pancreatitis.

OBJECTIVES: Chronic pancreatitis (CP) is associated with a shortened life expectancy. Statins have anti-inflammatory properties and we aimed to evaluate the association between the use of statins and the risk of death, progression of CP, and pancreatic cancer in patients with CP. PATIENTS AND METHODS: We carried out a nested case-cohort study and included patients with CP. We used claims of proton pump inhibitors as an active comparator. Patients with cirrhosis or cancer were excluded. We evaluated the exposure on the basis of pharmacy claims of statins. We used propensity score matching with a statins : nonstatins ratio of 1 : 1. RESULTS: A total of 4807 patients were eligible for propensity score matching; 33% were women and the mean (SD) age at cohort entry was 56 (10) years. During follow-up, a total of 2073 (43%) patients had died and the risk of death was significantly lower among patients using statins versus no statins among 678 matched patients [hazard ratio (HR) 0.64; 95% confidence interval (CI): 0.49-0.83]. Use of statins versus no statins was associated with decreased progression of CP, with an HR of 0.21 (95% CI: 0.17-0.26). Pancreatic cancer occurred in 117 (2.4%) patients and we found a lower risk of pancreatic cancer in statin-treated patients compared with no statins, with a HR of 0.21 (95% CI: 0.06-0.70). CONCLUSION: In this nationwide study, we found lower risks of mortality, disease progression, and pancreatic cancer in patients with CP using statins. The study is limited by its retrospective design, but supports the hypothesis that statins may affect the course of CP.

Effect of propranolol on survival in patients with decompensated cirrhosis: a nationwide study based Danish patient registers.

BACKGROUND & AIMS: We assessed the impact of propranolol on death, risk of hepatorenal syndrome and peritonitis in patients with cirrhosis. METHODS: This study was a retrospective observational study and data were retrieved from Danish databases. We used our own criteria to stratify the patients into groups of patients with mildly decompensated cirrhosis or severely decompensated cirrhosis. A subgroup of patients with a history of peritonitis was also analyzed. Follow-up time was limited to 2 years from cohort entry. The reported hazard ratios (HR) with 95% confidence interval (CI) were based on a propensity score matched cohort. RESULTS: Among 3719 patients, we found 3075 patients with mildly and 644 with severely decompensated cirrhosis. Propranolol was used by 20% of the patients. Among the patients with mildly decompensated cirrhosis, propranolol use vs. non-propranolol was related with a HR of 0.7 (95% CI 0.6-0.9) and among the patients with severely decompensated cirrhosis, the HR was 0.6 (95% CI 0.4-0.9). Reduced mortality was found for doses of propranolol lower than 160 mg/day only. Among 361 patients with peritonitis, we found reduced mortality in the propranolol group with a HR of 0.5 (95% CI 0.3-0.8). The use of propranolol was associated with a HR of 0.4 (95% CI 0.2-0.9) for developing peritonitis during follow-up among patients with severely decompensated cirrhosis. CONCLUSIONS: In patients with decompensated cirrhosis, we found an association between propranolol use and reduced mortality risk for doses lower than 160 mg/day.

Mortality, cancer, and comorbidities associated with chronic pancreatitis: a Danish nationwide matched-cohort study.

BACKGROUND & AIMS: We aimed to assess the risk of death, cancer, and comorbidities among patients with alcoholic and nonalcoholic chronic pancreatitis (CP). METHODS: We performed a nationwide retrospective cohort study, collecting data from Danish registries from 1995 through 2010. We evaluated the prevalences and incidences of death, cancers, and comorbidities among subjects with CP (cases) compared with age- and sex-matched individuals (controls). In total, 11,972 cases (71,814 person-years) and 119,720 controls (917,436 person-years) were included in the analysis. Hazard ratios (HR) were estimated by Cox proportional hazards regression. RESULTS: Forty-six percent of the cases died during the follow-up period, compared with 13.0% of controls (mean age, 63.7 vs 72.1 y; P < .0001), corresponding to a HR of 5.0 for CP (95% confidence interval [CI], 4.8-5.2). Cancer was a frequent cause of death among cases (10.2%) and controls (3.3%). Cancer (particularly pancreatic cancer) was a frequent cause of death among cases; the HR was 6.9 (95% CI, 7.5-11.8). Alcoholic CP did not produce a higher risk for cancer or death than nonalcoholic CP. Cerebrovascular disease (HR, 1.3; 95% CI, 1.2-1.4), chronic pulmonary disease (HR, 1.9; 95% CI, 1.8-2.1), ulcer disease (HR, 3.6; 95% CI, 3.3-3.9), diabetes (HR, 5.2; 95% CI, 5.0-5.6), and chronic renal disease (HR, 1.7; 95% CI, 1.5-1.9) occurred more frequently among patients with CP, but myocardial infarction did not (HR, 0.9; 95% CI, 0.8-1.0). CONCLUSIONS: Based on a Danish nationwide cohort study, individuals with CP are at higher risk for death from cancer (particularly pancreatic cancer) and have a higher incidence of comorbidities than people without CP.

The risk of fractures among patients with cirrhosis or chronic pancreatitis.

BACKGROUND & AIMS: Cirrhosis and chronic pancreatitis (CP) are accompanied by inflammation and malnutrition. Both conditions can have negative effects on bone metabolism and promote fractures. We evaluated the risk of fractures among patients with CP or cirrhosis and determined the effect of fat malabsorption on fracture risk among patients with CP. METHODS: We performed a retrospective cohort study using the Danish National Patient Register to identify patients diagnosed with CP or cirrhosis. We analyzed data collected from January 1, 1995, to December 31, 2010, on 20,769 patients (35.5% women with cirrhosis and 11,972 patients (33.5% women) with CP. Each patient was compared with 10 age- and sex-matched controls. We also assessed the risk of fractures among patients with CP who received pancreatic enzyme substitution (PES) for fat malabsorption. RESULTS: During the study period, bone fractures occurred in 3954 patients with cirrhosis and 2594 patients with CP. The adjusted hazard ratio (HR) for any fracture was 2.4 in patients with cirrhosis (95% confidence interval [CI], 2.2-2.5) and 1.7 in patients with CP (95% CI, 1.6-1.8). The relative risk of low-trauma fractures was highest among individuals younger than 50 years old. Alcohol as an etiology was associated with an increased risk of fracture compared with patients with nonalcoholic cirrhosis (HR, 2.4 vs 1.5; P < .0001) and CP (HR, 2.0 vs 1.5; P < .0001). Patients with CP receiving PES for fat malabsorption had a lower risk of fractures than other CP patients (HR, 0.8; 95% CI, 0.7-0.9). However, increasing the duration of treatment with PES was associated with an increased risk of fracture. CONCLUSIONS: Patients, especially younger patients, with cirrhosis or CP have an increased risk of fractures of all types.

The effect of cholecalciferol and calcitriol on biochemical bone markers in HIV type 1-infected males: results of a clinical trial.

HIV-1-infected patients have an increased risk of osteoporosis and fractures. The main objective of this study was to evaluate the bone metabolism in HIV-1-infected patients exposed to calcitriol and cholecalciferol. We also investigated the relationship between T cells and bone markers. We conducted a placebo-controlled randomized study running for 16 weeks including 61 HIV-1-infected males, of whom 51 completed the protocol. Nineteen participants were randomized to daily treatment with (A) 0.5-1.0 µg calcitriol and 1,200 IU (30 µg) cholecalciferol, 17 participants to (B) 1,200 IU cholecalciferol, and 15 participants to (C) placebo. At baseline and after 16 weeks, we determined collagen type 1 trimeric cross-linked peptide (CTx), procollagen type 1 N-terminal peptide (P1NP), parathyroid hormone (PTH), ionized calcium, 25-hydroxyvitamin D (25OHD), and 1,25-dihydroxyvitamin D [1,25(OH)2D]. We determined naive CD4(+) and CD8(+), activated CD4(+) and CD8(+), and regulatory CD4(+)CD25(+)CD127(low) T lymphocytes. Baseline levels of P1NP and CTx correlated (coefficient 0.5, p<0.001) with each other but not with PTH, 25OHD, or 1,25(OH)2D. In patients receiving calcitriol and cholecalciferol, the mean levels of P1NP (p<0.001) and CTx (p= 0.002) declined significantly compared to our placebo group. Based on changes in P1NP and CTx, we estimated that net bone formation occurred more frequently in group A compared to groups B and C. PTH correlated inversely with naive CD4(+) and CD8(+) cells. Otherwise, no relationships between bone markers and T lymphocytes were demonstrated. Supplementation with calcitriol and cholecalciferol induced biochemical indications of bone formation in HIV-1 patients.

Changes in 1,25-dihydroxyvitamin D and 25-hydroxyvitamin D are associated with maturation of regulatory T lymphocytes in patients with chronic pancreatitis: a randomized controlled trial.

OBJECTIVES: We studied the impact of changes in 25-hydroxyvitamin D (25OHD) and 1,25-dihydroxyvitamin D (1,25(OH)(2)D) on regulatory T lymphocytes (Tregs) in patients with chronic pancreatitis (CP) and fat malabsorption in a prospective clinical trial. METHODS: The patients were randomized to 1 of 3 treatments during 10 weeks: weekly UV-B in a tanning bed (group A), 1520-IU/d vitamin D supplement (group B), or placebo (group C). A placebo tanning bed was used in groups B and C. We determined the levels of CD4 Tregs (CD3(+)CD4(+)CD25(+)CD127(low)FoxP3(+)) and CD8(+) Tregs (CD3(+)CD8(+)CD25(+)CD127(low)FoxP3(+)), together with 25OHD and 1,25(OH)2D. For baseline comparisons, we included 8 healthy individuals. Of the 30 included patients, 27 (group A, 7 patients; group B, 9 patients; and group C, 11 patients) completed the protocol. RESULTS: The baseline levels of CD4(+) Tregs relative to total CD4(+) count were higher in 22 patients with CP compared with healthy controls (2.8% vs 1.9%, P < 0.05) and were comparable for CD8+ Tregs (0.13% vs 0.05%, P = 0.3). Increases in levels of CD4(+) Tregs correlated to changes in 1,25(OH)(2)D (2% per 100 pmol/L, P = 0.002) and 25OHD (3% per 100 nmol/L, P = 0.01). CONCLUSIONS: Patients with CP have elevated relative levels of CD4(+) Tregs. Increases in 25OHD and 1,25(OH)(2)D were both related with increases in levels of Tregs.

Correlation of increases in 1,25-dihydroxyvitamin D during vitamin D therapy with activation of CD4+ T lymphocytes in HIV-1-infected males.

BACKGROUND: In HIV-1-infected individuals, levels of CD4+ T lymphocytes are depleted and regulatory T-lymphocytes (Tregs) are elevated. In vitro studies have demonstrated effects of vitamin D on the growth and differentiation of these cells. We speculated whether supplementation with vitamin D could have an effect on CD4+ T lymphocytes or Tregs in HIV-1-infected males. METHODS: We conducted a placebo-controlled randomized study that ran for 16 weeks and included 61 HIV-1-infected males, of whom 51 completed the protocol. The participants were randomized to 1 of 3 daily treatments: (1) 0.5-1.0 µg calcitriol and 1200 IU (30 µg) cholecalciferol, (2) 1200 IU cholecalciferol, (3) placebo. Percentages of the following T-lymphocyte subsets were determined: naïve CD4+ and CD8+ cells, activated CD4+ and CD8+ cells, and CD3+CD4+CD25+CD127low Tregs. Furthermore 1,25-dihydroxyvitamin D, 25-hydroxyvitamin D, and parathyroid hormone were measured. RESULTS: No significant changes of the studied T-lymphocyte subsets occurred in the treatment groups compared to the placebo group. Increases in 1,25-dihydroxyvitamin D were associated with increases in activated CD4+ T lymphocytes (P = .001) and Tregs (P = .01) in adjusted models. Changes in parathyroid hormone correlated inversely with Tregs (P = .02). Smokers had higher levels of naïve CD4+ T lymphocytes (37% vs 25%;P = .01), naïve CD8+ T lymphocytes (28% vs 19%; P = .03), and Tregs (9% vs 7%; P = .03). CONCLUSION: Cholecalciferol and calcitriol administered during 16 weeks did not change the levels of T-lymphocyte fractions compared to placebo. However, increases in 1,25-dihydroxyvitamin D were associated with an expansion of activated CD4+ cells and Tregs.

Changes in serum 25-hydroxyvitamin D and cholecalciferol after one whole-body exposure in a commercial tanning bed: a randomized study.

We wanted to evaluate the cutaneous synthesis of 25OHD and cholecalciferol after one whole-body exposure to ultraviolet radiation type B (UVB) in a randomized setup. Healthy volunteers were randomized to one whole-body exposure in a commercial tanning bed with UVB emission (UVB/UVA ratio 1.8-2.0%) or an identical placebo tanning bed without UVB. The output in the 280-320 nm range was 450 µW/cm². Blood samples were analyzed for 25OHD and cholecalciferol at baseline and during 7 days after treatment. We included 20 volunteers, 11 to UVB and 9 to placebo treatment. During the first 6 h, no significant differences in 25OHD between the groups were found. At the end of the study, we found a mean increase of 25OHD in the UVB group of 4.5 nmol/l (SD 7 nmol/l) compared to a decline of -1.2 nmol/l (SD 7 nmol/l) in the placebo group (p = 0.1). A linear mixed model yielded an increase of 25OHD in the UVB group of 1.0 nmol/l per 24 h (p < 0.01). For cholecalciferol, we found a near significant increase of 1 pmol/l per hour in the UVB group compared to the placebo group during the first 6 h (p = 0.052). One tanning bed session had significant, but modest impact on the level of 25OHD during 7 days after exposure to UVB.

Variations in serum 25-hydroxyvitamin D during acute pancreatitis: an exploratory longitudinal study.

OBJECTIVES: We tested the hypothesis that 25-hydroxyvitamin D3 (25OHD) changes during acute inflammation in humans. METHODS: Patients with first episode of acute pancreatitis were included. Blood samples were acquired on admission and on days 1, 2, and 14. RESULTS: In total, 73 patients (35 males, median age 59) entered the study. On admission, the distribution of 25-OHD levels was as follows: severely deficient (<13 nmol/L) 23%; deficient (13-25 nmol/L) 20%; insufficient (26-50 nmol/L) 40%; and normal (<50 nmol/L) 17%. There was a significant fall and linear trend in 25OHD, albumin, and hemoglobin from day 0 to day 2. From day 0 to day 2 the drop in 25OHD was 3.1 nmol/L (95% CI 0.59-5.63). The changes from day 0 to day 2 in 25OHD were associated with changes in C-reactive protein (p = 0.02) but not with leukocyte or monocyte count. CONCLUSIONS: The 25OHD levels dropped during the first 2 days of acute pancreatitis beyond what was expected based on 25OHD half-life. This study supports our hypothesis that an acute inflammatory condition utilizes 25OHD, but other mechanisms could interfere.

Oral cholecalciferol versus ultraviolet radiation B: effect on vitamin D metabolites in patients with chronic pancreatitis and fat malabsorption - a randomized clinical trial.

BACKGROUND: Patients with chronic pancreatitis (CP) often develop fat malabsorption and are susceptible to hypovitaminosis D. AIM: We wanted to evaluate the intestinal uptake of cholecalciferol in patients with CP and fat malabsorption. METHODS: We did a prospective placebo-controlled study including patients with verified CP and fat malabsorption. They were randomized to 10 weeks of (A) ultraviolet radiation B (UVB) 6 min weekly in a commercial tanning bed, (B) vitamin D supplement 1,520 IU/daily, or (C) placebo. The vitamin D metabolites 25-hydroxyvitamin D (25OHD) and 1,25-dihydroxyvitamin D (calcitriol) were quantified at the start and end of the study. RESULTS: In total 30 patients were randomized and 27 completed the study. Compliance to tablets and tanning sessions was >80%. The changes in 25OHD levels in group B (32.3 nmol/l; 95% CI 15-50) were significantly greater than changes in group A (p < 0.001) and group C (p < 0.001). Changes in group A (1.1 nmol/l) did not differ from the placebo group (p = 0.9). Changes in calcitriol levels were identical between groups. CONCLUSIONS: Daily vitamin D supplements increased 25OHD in patients with CP compared to placebo whereas weekly tanning bed sessions did not.

Parathyroid hormone and vitamin D--markers for cardiovascular and all cause mortality in heart failure.

AIMS: To investigate levels of vitamin D and parathyroid hormone (PTH) in a population of heart failure (HF) patients, and to evaluate whether vitamin D and PTH are related to prognosis. METHODS AND RESULTS: This was a prospective study of 148 HF outpatients (mean age 68 years, 102 men) with follow-up for mortality after 3½ years. Levels of N-terminal pro-brain natriuretic peptide (NT-proBNP), PTH, 25-hydroxyvitamin D (25-OHD), and several other biomarkers were examined. Mortality and cardiovascular mortality were analysed in multivariable regression analyses adjusting for other independent prognostic variables. Vitamin D deficiency (≤50 nmol/L) was prevalent in 43% of the population; 26% had elevated PTH levels; none had primary hyperparathyroidism. We found a strong and independent significant association of both PTH and vitamin D to mortality, which was independent of other clinically important parameters [NT-proBNP, estimated glomerular filtration rate (eGFR), age, and left ventricular ejection fraction (LVEF)]. Both PTH and vitamin D were also significantly associated with all cause mortality. In an adjusted model, we found a hazard ratio of 1.9 (confidence interval 1.1-3.4) for vitamin D deficiency and 2.0 (1.0-3.8) for the upper median of PTH, respectively. CONCLUSION: In this relatively small prospective study, PTH and vitamin D were independently associated with all cause and cardiovascular mortality in patients with HF. This was independent of other known risk factors such as eGFR, LVEF, NT-proBNP, and age.

Deficiency of 25-hydroxyvitamin D in male HIV-positive patients: a descriptive cross-sectional study.

The aim of this descriptive cross-sectional study was to describe the prevalence of hypovitaminosis D in a cohort of HIV-seropositive males. Blood samples were collected in November and December 2004 and analyzed in the hospital laboratory. The concentration of 25-hydroxyvitamin D (25(OH)D) was defined as excellent when >75 nmol/l, normal when >50 nmol/l, insufficient when <50 nmol/l, deficient when <25 nmol/l and severely deficient when <12.5 nmol/l. Patient information was extracted from the medical records. A total of 115 males, median age 44 y (range 19-63 y), were included in the study. The median 25(OH)D concentration was 43.0 nmol/l (range 8-163 nmol/l) and the 25(OH)D level was excellent in 13%, normal in 27%, insufficient in 36%, deficient in 20%, and severely deficient in 4% of the cases. Vitamin D level was not associated with age, y with HIV infection, highly active antiretroviral therapy (HAART) or CD4 count. Compared to patients not in treatment, patients on HAART (n = 71) had higher levels of total alkaline phosphatase (median 83.0 vs 75.5 U/l; p = 0.031) and lower, though not significantly, total body mineral density (1.055 vs 1.107 g/cm(2); p = 0.077). This study confirms that the prevalence of hypovitaminosis is high among HIV-infected patients.

A descriptive cross-sectional study of the prevalence of 25-hydroxyvitamin D deficiency and association with bone markers in a hospitalized population.

Patients with gastrointestinal disease may be in particular risk of hypovitaminosis D because of reduced intestinal uptake or metabolism in the liver. The aim of the present study was to evaluate the prevalence of vitamin D deficiency in several groups of patients with various gastroenterologic diseases compared with patients without any chronic disease. We tested the hypothesis that persons with a gastrointestinal disease are at higher risk of hypovitaminosis D than persons with no chronic disease and whether this group needs special attention regarding their nutrition. We included patients admitted to our department of gastroenterology. The concentration of 25-hydroxyvitamin D (25(OH)D2+D3) was defined as insufficient when less than 50 nmol/L, deficient when less than 25 nmol/L, and severely deficient when less than 12.5 nmol/L. We included 146 patients with a mean age of 55 years (range, 16-93 years). 25(OH)D was sufficient in 47%, insufficient in 29%, deficient in 12%, and severely deficient in 11% of the population. Participants without chronic disease had a significantly higher mean level of 25(OH)D (57 nmol/L) compared to participants with cirrhosis (15 nmol/L, P = .002) and alcoholism (31 nmol/L, P = .003). A linear relationship between 25(OH)D and alkaline phosphatase could be demonstrated (Spearman rho, -0.299; P < .001). Participants with severe 25(OH)D deficiency had higher levels of total alkaline phosphatase (149.5 vs 76 U/L, P = .001) and parathyroid hormone (5.1 vs 2.8 pmol/L; P = .001). We recommend measuring the level of 25(OH)D and parathyroid hormone in patients with chronic diseases, especially alcoholism and cirrhosis.

[The use of adalimumab in severe fistulising Crohn's disease]. / Behandling af svaer aktiv morbus Crohn med adalimumab.

So far infliximab is the only approved anti-TNF-alpha antibody for patients with Crohn's disease. Development of antibodies to infliximab may result in allergic reactions or reduced effect. We report three patients who received adalimumab, which induced longstanding remission in all three patients.

Pharmacological approach to acute pancreatitis.

The aim of the present review is to summarize the current knowledge regarding pharmacological prevention and treatment of acute pancreatitis (AP) based on experimental animal models and clinical trials. Somatostatin (SS) and octreotide inhibit the exocrine production of pancreatic enzymes and may be useful as prophylaxis against post endoscopic retrograde cholangiopancreatography pancreatitis (PEP). The protease inhibitor gabexate mesilate (GM) is used routinely as treatment to AP in some countries, but randomized clinical trials and a meta-analysis do not support this practice. Nitroglycerin (NGL) is a nitrogen oxide (NO) donor, which relaxes the sphincter of Oddi. Studies show conflicting results when applied prior to ERCP and a large multicenter randomized study is warranted. Steroids administered as prophylaxis against PEP has been validated without effect in several randomized trials. The non-steroidal anti-inflammatory drugs (NSAID) indomethacin and diclofenac have in randomized studies showed potential as prophylaxis against PEP. Interleukin 10 (IL-10) is a cytokine with anti-inflammatory properties but two trials testing IL-10 as prophylaxis to PEP have returned conflicting results. Antibodies against tumor necrosis factor-alpha (TNF-alpha) have a potential as rescue therapy but no clinical trials are currently being conducted. The antibiotics beta-lactams and quinolones reduce mortality when necrosis is present in pancreas and may also reduce incidence of infected necrosis. Evidence based pharmacological treatment of AP is limited and studies on the effect of potent anti-inflammatory drugs are warranted.

[Cholecystic fistula with atypical symptoms]. / Fistel fra galdeblaeren til colon.

We report a patient with spontaneous cholecystocolonis fistula secondary to cholelithiasis. A 93 year-old woman was admitted because of weight loss, diarrhoea and upper abdominal pain. Ultrasound examination revealed air in the biliary tract and cholescientigraphy revealed a fistula between the gallbladder and right colon. Using endoscopic retrograde cholangiopancreatography a calculus was extracted from the bile duct and the symptoms disappeared.