Hepatocellular carcinoma in patients with chronic hepatitis C and cirrhosis in Denmark: A nationwide cohort study.

Cirrhosis in patients with chronic hepatitis C increases the risk of hepatocellular carcinoma (HCC), and surveillance with ultrasound (US) and alpha-fetoprotein (AFP) is recommended. This study aimed to estimate changes in the HCC incidence rate (IR) over time, HCC stage and prognosis, and AFP and US performed in patients with hepatitis C and cirrhosis. Eligible patients were identified in the Danish Database for Hepatitis B and C, and data from national health registries and patient charts were obtained. Tumour stage was based on Barcelona-Clinic Liver Cancer stage, TNM classification and size and number of lesions combined into stages 0-3. We included 1075 patients with hepatitis C and cirrhosis, free of HCC and liver transplant at baseline. During 4988 person years (PY), 115 HCC cases were diagnosed. The HCC incidence rate increased from 0.8/100 PY [CI95% 0.4-1.5] in 2002-2003 to 2.9/100 PY [2.4-3.4] in 2012-2013. One-year cumulative incidence of at least one AFP or US was 53% among all patients. The positive predictive value of an AFP ≥ 20 ng mL-1 was 17%. Twenty-three (21%) patients were diagnosed with early-stage HCC (stage 0/1) and 84 (79%) with late stage. Median survival after HCC for early-stage HCC disease was 30.1 months and 7.4 months for advanced HCC (stage 2/3). The incidence rate of HCC increased over time among patients with hepatitis C and cirrhosis in Denmark. Application of AFP and US was suboptimal, and most patients were diagnosed with advanced HCC with a poor prognosis.

The validity of a symptom diary in ratings of dyspepsia measured against a detailed interview: do patients and clinicians agree in their assessment of symptoms?

BACKGROUND: Patients' self-assessment of symptoms is central in drug treatment trials of functional dyspepsia. The validity of such ratings is important. AIM: To validate a diary for monitoring severity and duration of dyspepsia. METHOD: We compared the diary-cards with two clinicians' ratings of the patient's open-ended responses to the same questions administered by interview. Agreements were evaluated by estimation of the overall agreement and weighted kappa values (Kw). RESULTS: Forty-six patients were evaluated. The Kw between the two clinicians rating severity and duration of symptoms were 0.59 and 0.86, respectively. Overall agreement between patients' diary rating and clinicians' consensus rating of severity were 52%, and a moderate agreement with Kw of 0.49 was found. For duration of symptoms the overall agreement and Kw were 67% and 0.59, respectively. Qualitative data revealed useful insight in the possible causes of suboptimal agreement between patients and clinicians. CONCLUSIONS: We found a moderate to good agreement between patient and observer ratings, indicating that patients to a reasonable extent interpret severity and duration of dyspeptic symptoms in the same way as do investigators. A ceiling effect of the duration scale indicates suboptimal response categories, which should be adjusted before further use.

Hepatic transit time of ultrasound contrast in biopsy characterized liver disease.

PURPOSE: To study the hepatic transit time of an ultrasound contrast agent in patients with liver disease, and to evaluate the mechanism(s) of the well-established shorter cubital vein to hepatic vein transit time in cirrhosis. MATERIAL AND METHODS: Thirty-four patients scheduled for Menghini liver biopsy were studied by ultrasound after injection of 2.5 g Levovist (Schering, Berlin, Germany) into an arm vein. The time from injection until the first appearance of contrast echoes in the hepatic artery and hepatic veins was registered. Hepatic transit time was the difference between the two. RESULTS: Biopsy showed cirrhosis in 9 patients, other diffuse hepatic pathology in 23 patients, and normal liver in 2 patients. Mean hepatic vein arrival time was earlier in cirrhosis than in other liver disease (19.4 s versus 26.0 s; P = 0.013), and hepatic transit time was shorter (6.6 s versus 11.6 s; P = 0.024). A hepatic transit time <10 s was found in all patients with cirrhosis, but also in 10 of 23 patients with other liver pathology. CONCLUSION: Hepatic transit time measurement could not be used to distinguish between cirrhosis and other hepatic pathology, but a transit time = 10 s excluded cirrhosis. The earlier hepatic vein arrival time in cirrhosis is apparently mainly caused by intrahepatic shunting rather than by early arrival of contrast to the liver.

Identifying response to acid suppressive therapy in functional dyspepsia using a random starting day trial--is gastro-oesophageal reflux important?

BACKGROUND: Single subject trials offer an alternative approach to identify and characterize responders to a specific treatment. AIM: To test a new single subject trials design, called random starting day trial, to identify acid-related symptoms in dyspepsia. METHODS: A total of 119 patients with functional dyspepsia entered a 12-day, double-blind random starting day trial. All patients started on placebo and switched to omeprazole 80 mg/day at a randomized and blinded day between day 5 and day 9, with active treatment continuing for the rest of the trial. Based on changes of a daily symptom score, response was defined as a sustained > or =50% reduction of symptoms within 3 days of active treatment. RESULTS: Thirteen of 119 patients (11%) were classified as spontaneous responders because of complete symptom relief before switching to omeprazole. Of the remaining 106 patients, 15 (15.6%) were classified as responders. Five of six (83%) responders compared with 28 of 53 (53%) non-responders had pathological reflux. Multivariate testing identified symptoms suggestive of gastro-oesophageal reflux predictive of response. CONCLUSIONS: The random starting day trial design could identify a subset of dyspeptic patients with a uniform symptomatic response to acid-suppressive therapy. Response seems to be associated with gastro-oesophageal reflux. The random starting day trial needs to be further validated to be considered as a reliable instrument in clinical research.

Reproducibility of a symptom response to omeprazole therapy in functional dyspepsia evaluated by a random-starting-day trial design.

BACKGROUND: Satisfactory treatment options for functional dyspepsia are lacking. Single subject trial designs may identify subgroups of patients with a uniform response to therapy. AIM: To test reproducibility of response in a new random-starting-day trial design developed to identify acid-related symptoms in functional dyspepsia. METHODS: One hundred and nineteen patients with functional dyspepsia completed a 12-day, double-blind random-starting-day trial with an initial placebo run-in followed by switch to omeprazole on a randomized and blinded day (between days 5 and 9) with active treatment continuing for the rest of the trial. Response was defined as a sustained > or =50% reduction of a daily symptom-score within 3 days of active treatment. Fifty-nine patients repeated the random-starting-day trial at relapse of symptoms. RESULTS: After exclusion of placebo responders, 14% (15 of 106) were classified as responders in the first and 20% (10 of 50) in the subsequent random-starting-day trial series. Sixty-eight per cent (40 of 59) of the patients reproduced their initial response with a chance-corrected agreement of 0.29. Comparing response patterns using different symptom rating-scales showed good correlation (kappa 0.60). CONCLUSION: Reproducibility of response in a random-starting-day trial was imperfect, mainly because of the low response rates and strict response criteria. Lack of symptom stability impairs the value of the random-starting-day trial and only patients with frequent and stable symptoms should be evaluated in this design.

The Lundh test and faecal elastase 1 determination in chronic pancreatitis: a comparative study.

BACKGROUND/AIM: A reduced exocrine pancreatic function supports the diagnosis of chronic pancreatitis (CP) in symptomatic patients. A sensitive test for a reduced exocrine function is decisive, especially when morphological changes are missing. The aim of this study was to compare the indirect faecal elastase 1 (FE-1) test with the direct Lundh test in patients with and without definite diagnostic imaging findings. METHODS: Eighty-nine patients with clinical signs suggesting CP or having an established diagnosis of CP had a Lundh test and an estimation of FE-1 performed. All patients underwent abdominal ultrasonography and/or computed tomography. RESULTS: A significant correlation (r = 0.70, p < 0.02) was found between FE-1 and meal-stimulated intraduodenal lipase. Using the Lundh test as reference, the predictive values of a positive and negative FE-1 test were for all patients investigated 81 and 73%, respectively. Patients with equivocal imaging findings had lower predictive values (positive predictive value 57%; negative predictive value 71%) as compared with patients with moderate or marked imaging findings (positive predictive value 84%; negative predictive value 78%). Fair to moderate chance-corrected agreement was found between Lundh test and FE-1 concentration. CONCLUSIONS: In patient with imaging findings suggesting CP, FE-1 determination is a highly sensitive test for exocrine pancreatic function, but in patients with equivocal imaging findings, the predictive power of FE-1 limits the test to serve as a reliable diagnostic tool.

Review article: Single subject trials as a research instrument in gastrointestinal pharmacology.

The single subject trial is a randomized controlled trial carried out in the individual patient, and the result obtained is specific to the individual patient and the drug being investigated. This type of trial offers a supplement to traditional parallel group trials, especially in patients with heterogeneous disorders, often characterized by varying treatment responses and/or high placebo response rates. Pooled results from several individual single subject trials could extend the conclusions beyond the individual patient, and help to characterize a subset of responders to a specific treatment or clarify the heterogeneity of the disease. The basic principles of the different single subject trial designs are described. Advantages and limitations are reviewed with a special focus on published trials in functional gastrointestinal disorders. The single subject trial may be a valuable supplement to traditional drug treatment trials, either used as isolated trials in individual patients to determine optimal therapy, or in groups of patients to identify those with a uniform response to treatment. However, the lack of validation and reliability studies limits the value of the single subject trials presented so far.

[Menetrier's disease. Another Helicobacter pylori associated disease?]. / Morbus Ménétrier. Endnu en Helicobacter pylori-associeret sygdom?

Ménétrier's disease is a rare and poorly outlined disease, diagnosed in patients with giant gastric folds, dyspeptic symptoms and hypoalbuminaemia due to gastrointestinal protein loss. The etiology is unknown, but Ménétrier's disease is often associated with Helicobacter pylori (Hp) infection. Case reports and studies concerning the effect of eradication therapy in patients with Ménétrier's disease were reviewed. It was found that complete normalisation of the gastric mucosa and gastrointestinal protein loss following eradication therapy has been reported in several cases. In conclusion, we recommend patients with Ménétrier's disease to be tested for Hp, and treated with eradication therapy in case of infection.

Opioid treatment of painful chronic pancreatitis.

BACKGROUND: Abdominal pain is the dominant symptom in 50-75% of patients with chronic pancreatitis, often requiring opioid analgesics. Fentanyl, a potent synthetic opioid, can be administered percutaneously at a constant dose and is claimed to have fewer systemic side effects. AIM: To evaluate transdermal fentanyl plaster versus sustained release morphine tablets as analgesic treatment of painful chronic pancreatitis. METHODS: In an open randomized crossover trial, 18 patients were included. The treatment period was 4 wk for each drug. All patients had immediate-release morphine tablets as rescue medication. RESULTS: The dosage of transdermal fentanyl had to be increased on average 50% over that indicated by the manufacturer. When this was done and rescue medication was secured, no difference between the two drugs in primary endpoint or patient preference was observed. There was also no difference in the secondary endpoints, pain control, and quality of life. However, skin side effects, mostly mild, occurred in 44% of the patients during treatment with transdermal fentanyl, and the mean daily dose of immediate release morphine was significantly higher during the transdermal fentanyl period than during the sustained-release morphine period (30.7 mg vs. 14.7 mg [p < 0.01]). CONCLUSION: When given in an appropriate dose, transdermal fentanyl might be useful for treatment of some patients with painful chronic pancreatitis, e.g., when tablet ingestion is difficult. However, the dosage often has to be increased above that recommended by the manufacturer. The need of rescue morphine is considerable and skin side effects often occur. Transdermal fentanyl is, therefore, not the ideal first-choice analgesic in patients with painful chronic pancreatitis.

The value of alarm features in identifying organic causes of dyspepsia.

The unaided clinical diagnosis of dyspepsia is of limited value in separating functional dyspepsia from clinically relevant organic causes of dyspepsia (gastric and esophageal malignancies, peptic ulcer disease and complicated esophagitis). The identification of one or more alarm features, such as weight loss, dysphagia, signs of gastrointestinal bleeding, an abdominal mass or age over 45 years may help identify patients with a higher risk of organic disease. This review summarizes the frequency of alarm symptoms in dyspeptic patients in different settings (such as the community, primary care and specialist clinics). The prevalence of alarm features in patients diagnosed with upper gastrointestinal malignancy or peptic ulcer disease is described. The probability of diagnosing clinically relevant upper gastrointestinal disease in patients presenting with alarm features and other risk factors is discussed. Alarm features such as age, significant weight loss, use of nonsteroidal anti-inflammatory drugs, signs of bleeding and dysphagia may help stratify dyspeptic patients and help optimize the use of endoscopy resources.

[A study of percutaneous absorption of estradiol and progesterone in absolute alcohol in postmenopausal women]. / Perkutan absorptionsundersøgelse af østradiol og progesteron i spiritus fortis hos postmenopausale kvinder.

Absorption of solutions containing 17-beta-oestradiol (E2) in absolute alcohol and progesterone (P) in absolute alcohol was investigated in six postmenopausal women. These preparations were applied to the skin of the forearm and the abdomen. 1 mg E2 was applied twice daily to the left forearm (RAS) for 28 days. After an interval of one week, the treatment was continued with 1 mg E2 twice daily for 28 days in the epigastric region (RE). From the 14th to the 28th day, this treatment was supplemented by 10 mg P twice daily partly on the right forearm and partly on the epigastrium. The 24-hour absorptions of E2 and P were investigated: E2 on the first and fourteenth days and P on the fourteenth day in both periods. On days 1, 7, 14, 21 and 28, plasma E2, oestrone (E1) and oestrone sulphate (E1SO4) were investigated for hormone application. Statistically significant absorption of E2 was found after 24 hours (p less than 0.05) and significantly greater absorption from RAS than RE (p less than 0.005). No systematic variation in plasma E2 was found during the period of investigation on RAS or RE. P was not absorbed. No local side effects were registered. It is concluded that E2 dissolved in absolute alcohol is clinically employable for treatment of postmenopausal women but that P is of no value in the dosage employed here. Further investigations of transcutaneous absorption of P are desirable.

[Absorption of norethisterone acetate from tablets with normal and coarse particle size]. / Absorption af noretisteronacetat fra tabletter med normal og grov partikelstørrelse.

A clinical randomized double-blind trial with cross-over is presented. The object was to assess the absorption of 1 mg norethisterone acetate from tablets with particles of normal and coarse size. The hypothesis was that the coarse particles would result in retarded absorption. In this trial, eight healthy postmenopausal women with an average age of 72 years participated. The participants received the tablets in the morning with intervals of a week and the plasma concentration (C) was measured throughout 24 hours. The two absorption profiles showed significant differences after 30 minutes (p less than 0.05) with the following values: Tablets with normal particles resulted in C = 31.1 nmol/l while the analogous result with the coarse particles was C = 17.0 nmol/l. It is concluded that the coarse particles resulted in lower plasma concentrations initially.