Mette S. Kjær

Alcohol drinking pattern and risk of alcoholic liver cirrhosis: A prospective cohort study

BACKGROUND & AIMS Alcohol is the main contributing factor of alcoholic cirrhosis, but less is known about the significance of drinking pattern. METHODS We investigated the risk of alcoholic cirrhosis among 55,917 participants (aged 50-64 years) in the Danish Cancer, Diet, and Health study (1993-2011). Baseline information on alcohol intake, drinking pattern, and confounders was obtained from a questionnaire. Follow-up information came from national registers. We calculated hazard ratios (HRs) for alcoholic cirrhosis in relation to drinking frequency, lifetime alcohol amount, and beverage type. RESULTS We observed 257 and 85 incident cases of alcoholic cirrhosis among men and women, respectively, none among lifetime abstainers. In men, HR for alcoholic cirrhosis among daily drinkers was 3.65 (95% CI: 2.39; 5.55) compared to drinking 2-4 days/week. Alcohol amount in recent age periods (40-49 and 50-59 years) was associated with an increased risk, whereas the amount in 20-29 and 30-39 years was not. In men drinking 14-28 drinks/week, HR was 7.47 (95% CI: 1.68; 33.12), 3.12 (95% CI: 1.53; 6.39), and 1.69 (95% CI: 0.79; 3.65) in drinkers of little (<1% of weekly amount), some (1-15%), and mostly wine (50-100%), compared to drinking <14 drinks/week. In general, results were similar for women. CONCLUSIONS In men, daily drinking was associated with an increased risk of alcoholic cirrhosis. Recent alcohol consumption rather than earlier in life was associated with risk of alcoholic cirrhosis. Compared to beer and liquor, wine might be associated with a lower risk of alcoholic cirrhosis.

Effectiveness of treatment with pegylated interferon and ribavirin in an unselected population of patients with chronic hepatitis C: A Danish nationwide cohort study

BackgroundThe effect of peginterferon and ribavirin treatment on chronic hepatitis C virus (HCV) infection has been established in several controlled clinical studies. However, the effectiveness of treatment and predictors of treatment success in routine clinical practice remains to be established. Our aim was to estimate the effectiveness of peginterferon and ribavirin treatment in unselected HCV patients handled in routine clinical practice. The endpoint was sustained virological response (SVR), determined by the absence of HCV RNA 24 weeks after the end of treatment.MethodsWe determined the proportion of SVR in a nationwide, population-based cohort of 432 patients with chronic HCV infection who were starting treatment, and analyzed the impact of known covariates on SVR by using a logistic regression analysis.ResultsThe majority of treated patients had genotype 1 (133 patients) and genotype 2/3 (285 patients) infections, with 44% and 72%, respectively, obtaining SVR. Other than genotype, the predictors of SVR were age ≤ 45 years at the start of treatment, completion of unmodified treatment, the absence of cirrhosis and non-European origin.ConclusionsThe effectiveness of peginterferon and ribavirin treatment for chronic hepatitis C in a routine clinical practice is comparable to that observed in controlled clinical trials, with a higher SVR rate in genotype 2 and 3 patients compared to genotype 1 patients. Our data further indicate that age at start of treatment is a strong predictor of SVR irrespective of HCV genotype, with patients 45 years or younger having a higher SVR rate.

Lower liver stiffness in patients with sustained virological response 4 years after treatment for chronic hepatitis C.

Objective Transient elastography (TE) is a noninvasive and well validated method for measurement of liver stiffness. The aim of this study was to use TE to evaluate whether patients with sustained virological response (SVR) have lower liver stiffness than patients with non-SVR after treatment for chronic hepatitis C (CHC). Methods Patients with CHC, who had undergone liver biopsy before treatment with pegylated interferon and ribavirin, were included from four clinical centres in Denmark. All patients were examined with TE and had a blood test taken for hepatitis C virus-virus detection and analysis of alanine aminotransferase, platelet counts and hyaluronic acid. Results For 110 (92%) of the 120 patients included, it was possible to obtain a successful measurement of liver stiffness. Of these, 71 (64.5%) had achieved SVR. Median follow-up time was 47 months. Patients with pretreatment minimal fibrosis (F0/F1) in their liver biopsy had median liver stiffness of 5.3 kPa for SVR versus 6.1 kPa for non-SVR (P=0.56). Patients with pretreatment moderate fibrosis (F2/F3) had median liver stiffness of 5.4 kPa for SVR versus 9.4 kPa for non-SVR (P<0.001). Median liver stiffness for patients with pretreatment cirrhosis (F4) was 6.8 kPa for SVR versus 24 kPa for non-SVR (P<0.001). Conclusions Examination with TE 4 years after treatment shows that patients with CHC, who have achieved SVR, have significantly lower liver stiffness than patients with non-SVR. This indicates that histological liver outcome improves during the first year after the treatment for CHC.

Hand development in trisomy 21.

The purpose of the present study was to evaluate hand size and maturity in fetuses with trisomy 21 (Down syndrome). Twenty-five fetuses, crown-rump length (CRL) 55-222 mm, foot length (FL) 8-42 mm, were included in the study. After whole-body radiography (Hewlett Packard Faxitron), special radiographs of the hand and foot were taken. Hand length was measured as the length of the third finger from the distal tip of the distal phalanx to the proximal tip of the metacarpal bone, the digital-metacarpal length (DML). The lengths of the proximal phalangeal bone (PPL) and the metacarpal bone (MCL) of the third finger were also measured. The DML, PPL, and MCL values of each fetus were related to CRL and FL. The individual hand bones were evaluated with regard to time of appearance on radiographs, sequence in comparison with the normal sequence of appearance, and morphology. The hand length is normal during the first half of the fetal period, whereas the length of individual bones in the third finger is reduced. The normal sequence of ossification, with the middle phalanx of the fifth finger last to ossify, also occurred in Down syndrome; however, this bone appeared later in Down syndrome. In four of the fetuses it did not appear.

Low liver stiffness among cirrhotic patients with hepatitis B after prolonged treatment with nucleoside analogs

Abstract Objective. Case reports and short-term clinical trials have suggested that treatment for chronic hepatitis B (CHB) may lead to improvement of cirrhosis. The aim of the present study was to measure liver stiffness in patients diagnosed with advanced fibrosis or cirrhosis prior to prolonged treatment with nucleoside or nucleotide analogs (NUCs) for CHB. Materials and methods. Patients with CHB and advanced fibrosis or cirrhosis prior to treatment with NUCs for at least 1 year were offered inclusion in the study. We measured liver stiffness using transient elastography (TE) at follow-up. TE cut-off levels to Metavir classification for fibrosis stage F2, F3 and F4 were ≥7.2 kPa, ≥8.1, and ≥11.0 kPa, respectively. Results. Among 66 patients with a successful TE examination at follow-up, 53 patients (80%) had cirrhosis and 13 had (20%) advanced fibrosis (F3) prior to treatment. Median treatment duration was 50.5 months. Among patients with cirrhosis prior to treatment, 26 (49%) had liver stiffness below 11.0 kPa at follow-up, suggesting regression of cirrhosis. Among patients with advanced fibrosis (F3) prior to treatment, 10 (77%) had liver stiffness below 8.1 kPa after treatment, suggesting improvement of fibrosis. Conclusion. Transient elastography examinations demonstrate that prolonged treatment with NUCs in patients with CHB results in low liver stiffness, suggesting regression of fibrosis in a majority of patients with advanced fibrosis or cirrhosis.

Liver biopsy performance and histological findings among patients with chronic viral hepatitis: A Danish database study

We investigated the variance of liver biopsy frequency and histological findings among patients with chronic viral hepatitis attending 10 medical centres in Denmark. Patients who tested positive for HBsAg or HCV- RNA were retrieved from a national clinical database (DANHEP) and demographic data, laboratory analyses and liver biopsy results were collected. A total of 1586 patients were identified of whom 69.7% had hepatitis C, 28.9% hepatitis B, and 1.5% were coinfected. In total, 771 (48.6%) had a biopsy performed (range 33.3–78.7%). According to the Metavir classification, 29.3% had septal fibrosis (≥F2) and 13.9% had cirrhosis (F4). The frequency of cirrhosis varied from 8.3 to18.6% among centres, and was independently associated with age, male gender, elevated alanine-aminotransferase (ALT) and non-Danish origin. Among 141 patients with hepatitis C and known duration of infection, cirrhosis had developed in 23% after 20 y of infection. Age above 40 y was a better predictor of cirrhosis than elevated ALT. National database comparison may identify factors of importance for improved management of patients with chronic viral hepatitis.

Risk for alcoholic liver cirrhosis after an initial hospital contact with alcohol problems: A nationwide prospective cohort study

Alcoholic liver cirrhosis is usually preceded by many years of heavy drinking, in which cessation in drinking could prevent the disease. Alcohol problems are not consistently managed in hospital patients. We followed all Danish patients with an initial hospital contact with alcohol problems (intoxication, harmful use, or dependence) during 1998‐2002 for alcoholic liver cirrhosis development (n = 36,044). In this registry‐based cohort, we identified predictors of the absolute risk for alcoholic liver cirrhosis. Incidence rate ratios (IRRs) were estimated as the incidence rate of alcoholic liver cirrhosis in these patients relative to the general population. Age and alcohol diagnosis were significant predictors of alcoholic liver cirrhosis risk in men and women, whereas civil status, education, and type of hospital care were not. In men, the 15‐year absolute risk was 0.7% (95% confidence interval [CI], 0.4, 0.8) for 20‐29 years, 5.5% (95% CI, 4.9, 6.2) for 30‐39 years, 9.8% (95% CI, 9.0, 11) for 40‐49 years, 8.9% (95% CI, 8.1, 9.8) for 50‐59 years, 6.2% (95% CI, 5.1, 7.2) for 60‐69 years, and 2.5% (95% CI, 1.7, 3.3) for 70‐84 years. According to alcohol diagnosis in men, the 15‐year absolute risk was 2.6% (95% CI, 2.3, 2.9) for intoxication, 7.7% (95% CI, 6.4, 7.9) for harmful use, and 8.8% (95% CI, 8.2, 9.4) for dependence. The IRR for alcoholic liver cirrhosis in the cohort relative to the general population was 11 (95% CI, 10, 12) in men and 18 (95% CI, 15, 21) in women. Conclusion: Hospital patients with alcohol problems had a much greater risk for alcoholic liver cirrhosis compared to the general population. The risk was particularly increased for patients 40‐59 years and for patients diagnosed with harmful use or dependence. (Hepatology 2017;65:929‐937).

Human fetal hand size and hand maturity in the first half of the prenatal period.

Abstract The purpose of the present study has been to establish radiographic standards of hand length and finger bone size in the first half of the prenatal period, and to relate these measurements to general fetal size (CRL) and foot length (FL), as well as to the skeletal maturity assessed from a Composite Number of Ossified bones in hand and foot radiographs (CNO). The right hand and foot of each of 251 normal human fetuses (CRL 47–194 mm) were radiographed. From each hand radiograph hand length (DM), third proximal phalangeal bone length (PP) and third metacarpal bone length (MC) were measured. The study showed that third proximal phalangeal and metacarpal bone lengths both provide a valuable basis for estimating hand length. Both hand length and the length of the third metacarpal bone were found to be good predictors of general fetal size (CRL). The study provides standards for the relationships between hand and finger bone sizes, general fetal length and foot length. By combining third metacarpal bone size and skeletal maturity of the hand and foot general fetal development (age and crown-rump length) can be estimated. Insight into normal hand size and finger bone size at different stages of normal development including skeletal maturation is useful in future evaluation of handsize under pathological conditions.

Ciclosporin does not attenuate intracranial hypertension in rats with acute hyperammonaemia

AIM To investigate the neuroprotective potential of ciclosporin during acute liver failure. We evaluated the effect of intrathecally administered ciclosporin on intracranial pressure, brain water content and aquaporin-4 expression in a rat model with acute hyperammonaemia. METHODS Twenty-four male Wistar rats with portacaval anastomosis were randomised into four groups receiving ciclosporin or vehicle and ammonia or saline infusion. Ciclosporin or vehicle was given intrathecally prior to the ammonia or saline infusion. The ammonia or saline infusion was given intravenously for 4 h, while intracranial pressure and arterial pressure was recorded. At the end of the experiment, cerebral cortex and cerebellar brain tissue was analysed for water and aquaporin-4 content. RESULTS The following intracranial pressures were found at the end of the experiment: ammonia + ciclosporin: 10.0 ± 1.7 mmHg, ammonia + vehicle: 6.8 ± 1.0 mmHg, saline + ciclosporin: 3.1 ± 0.5 mmHg, saline + vehicle: 3.3 ± 0.6 mmHg. Ammonia infusion had a significant effect on intracranial pressure and brain water content, which both were higher in the groups receiving ammonia (P < 0.001, two-way analysis of variance). Treatment with ciclosporin resulted in relevant tissue concentrations of ciclosporin (> 0.2 micromolar) but did not reduce intracranial pressure after 4 h. Furthermore, ciclosporin did not attenuate the increase in cerebral water content, and did not affect aquaporin-4 expression. CONCLUSION Intrathecal administration of ciclosporin does not attenuate intracranial hypertension or brain oedema in rats with portacaval anastomosis and 4 h of ammonia infusion.

Predictors of heavy drinking after liver transplantation for alcoholic liver disease in Denmark (1990–2013): a nationwide study with competing risks analyses

Abstract Objective. Heavy drinking following liver transplantation decreases survival. Little is known of predictors of heavy drinking, which should guide clinicians identifying patients at high risk of return to heavy drinking after transplantation. Material and methods. We calculated the cumulative incidence of heavy drinking among patients transplanted for alcoholic liver disease in Denmark 1990–2013. We then analyzed pre-transplant demographic and psychiatric characteristics as predictors of post-transplant heavy drinking. Information was obtained from medical records, from nationwide registries and by interview. Results. Among 156 liver-transplanted patients, the cumulative incidence of heavy drinking was 18%, 24% and 27% after 5, 10 and 15 years post-transplant. In univariate analyses of pre-transplant predictors of heavy drinking after transplantation, younger age (p < 0.001), being retired (p = 0.007), anxiety (p = 0.04), personality disorder (p = 0.05) and no lifetime diagnosis of alcohol dependence (p = 0.03) were associated with heavy drinking after transplantation. Smoking (p = 0.06) tended to be associated, whereas depression (p = 0.7) or being married was not (p = 0.7). In the multivariate analysis, only younger age (p = 0.03), being retired (p = 0.007) and no lifetime diagnosis of alcohol dependence (p = 0.003) remained significant predictors. Heavy drinking after transplantation decreased survival beyond 5 years post-transplant (p = 0.004). Conclusions.There is a high incidence of heavy drinking after liver transplantation for alcoholic cirrhosis in Denmark. Younger age, being retired and no lifetime diagnosis of alcohol dependence were predictors of heavy drinking after transplantation.