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author:("jepson, Peter")
1.  Comorbidity in cirrhosis 
Cirrhosis patients’ comorbidities are their other diseases than cirrhosis. Comorbidities are neither causes nor consequences of cirrhosis, but they can increase mortality and are therefore clinically important. They are also an important source of confounding in epidemiologic studies. Comorbidity scoring systems have been developed as tools to measure the cirrhosis patient’s total burden of comorbidity, and they are useful in the clinic and for epidemiologic studies. The recently developed CirCom score is the only comorbidity scoring system developed specifically for cirrhosis patients, and it may be preferred over the older, generic, and more complex Charlson comorbidity index. Studies of individual comorbid diseases can provide insight into the interactions between cirrhosis and other diseases and thus into the pathophysiology of cirrhosis. This article reviews the literature on comorbidity in cirrhosis.
PMCID: PMC4064068  PMID: 24966593
Liver cirrhosis; Comorbidity; Prognosis; Epidemiology
2.  Socioeconomic status in HCV infected patients – risk and prognosis 
Clinical Epidemiology  2013;5:163-172.
Background and aims
It is unknown whether socioeconomic status (SES) is a risk factor for hepatitis C virus (HCV) infection or a prognostic factor following infection.
From Danish nationwide registries, we obtained information on three markers of SES: employment, income, and education. In a case control design, we examined HCV infected patients and controls; conditional logistic regression was employed to obtain odds ratios (ORs) for HCV infection for each of the three SES markers, adjusting for the other two SES markers, comorbidity, and substance abuse. In a cohort design, we used Cox regression analysis to compute mortality rate ratios (MRRs) for each of the three SES markers, adjusting for the other two SES markers, comorbidity level, age, substance abuse, and gender.
When compared to employed persons, ORs for HCV infection were 2.71 (95% confidence interval [CI]: 2.24–3.26) for disability pensioners and 2.24 (95% CI: 1.83–2.72) for the unemployed. When compared to persons with a high income, ORs were 1.64 (95% CI: 1.34–2.01) for low income persons and 1.19 (95% CI: 1.02–1.40) for medium income persons. The OR was 1.35 (95% CI: 1.20–1.52) for low education (no more than basic schooling). When compared to employed patients, MRRs were 1.71 (95% CI: 1.22–2.40) for unemployed patients and 2.24 (95% CI: 1.63–3.08) for disability pensioners. When compared to high income patients, MRRs were 1.47 (95% CI: 1.05–2.05) for medium income patients and 1.64 (95% CI: 1.13–2.34) for low income patients. Educational status was not associated with mortality.
Low SES was associated with an increased risk of HCV infection and with poor prognosis in HCV infected patients.
PMCID: PMC3678712  PMID: 23766659
survival; socioeconomic status; risk factor; prognosis
3.  The clinical course of alcoholic cirrhosis: effects of hepatic metabolic capacity, alcohol consumption, and hyponatremia – a historical cohort study 
BMC Research Notes  2012;5:509.
The cirrhosis complications hepatic encephalopathy, ascites, and variceal bleeding increase mortality but develop in random sequence. Therefore prognoses based on the presence or absence of these clinical complications are inherently inaccurate, and other determinants of the clinical course should be identified. Here we present our study of patho-etiological factors that may be causally involved in the development of specific complications to alcoholic cirrhosis; it was based on a model of cirrhosis pathophysiology encompassing hepatic metabolic capacity, continued alcohol consumption, and circulatory dysfunction.
We followed a Danish community-based cohort of 466 patients with alcoholic cirrhosis. Stratified Cox regression was used to examine the effects of GEC (a measure of hepatic metabolic capacity), alcohol consumption, and plasma sodium concentration (a measure of circulatory dysfunction) on the hazard rates of first-time hepatic encephalopathy, first-time ascites, first-time variceal bleeding, and mortality. We adjusted for confounding by comorbidity, gender, and age. Data on risk factors and confounders were updated during follow-up.
A low GEC increased the risk of first-time hepatic encephalopathy (hazard ratio [HR] 1.21 per 0.1 mmol/min GEC loss, 95% CI 1.11-1.31), but was unassociated with other adverse events. Alcohol consumption increased the risk of first-time ascites (HR 3.18, 95% CI 1.19-8.47), first-time variceal bleeding (HR 2.78, 95% CI 1.59-4.87), and mortality (HR 2.45, 95% CI 1.63-3.66), but not the risk of first-time hepatic encephalopathy. Hyponatremia increased the risk of all adverse events.
Reduced hepatic metabolic capacity, alcohol consumption, and hyponatremia were causally involved in the development of specific complications to alcoholic cirrhosis.
PMCID: PMC3494654  PMID: 22988833
Alcoholic liver disease; Hepatic encephalopathy; Ascites; Variceal bleeding; Prognosis
4.  Hepatitis C prevalence in Denmark -an estimate based on multiple national registers 
BMC Infectious Diseases  2012;12:178.
A national survey for chronic hepatitis C has not been performed in Denmark and the prevalence is unknown. Our aim was to estimate the prevalence of chronic hepatitis C from public registers and the proportion of these patients who received specialized healthcare.
Patients with a diagnosis of chronic hepatitis C were identified from four national registers: a laboratory register, the Hospital Discharge Register, a clinical database of chronic viral hepatitis and the Register of Communicable Diseases. The total population diagnosed with hepatitis C was estimated by capture-recapture analysis. The population with undiagnosed hepatitis C was derived from the national register of drug users by comparing diagnosed and tested persons.
A total of 6,935 patients diagnosed with chronic hepatitis C were identified in the four registers and the estimated population diagnosed with the disease was 9,166 persons (95% C.I. interval 8,973 – 9,877), corresponding to 0.21% (95% CI 0.21%-0.23%) of the Danish population over 15years of age. The prevalence was highest among persons 40–49years old (0.39%) and males (0.28%). It was estimated that 40% of the diagnosed patients lived in the capital region, and 33.5% had attended specialised healthcare. It was estimated that 46% of hepatitis C patients had not been diagnosed and the total population with chronic hepatitis C in Denmark was 16,888 (95% C.I. 16,474-18,287), corresponding to 0.38% (95% CI 0.37-0.42) of the population over 15years of age.
The estimated prevalence of chronic hepatitis C in Denmark was 0.38%. Less than half of the patients with chronic hepatitis C in Denmark have been identified and among these patients, one in three has attended specialised care.
PMCID: PMC3447638  PMID: 22866925
5.  Mortality among Patients with Cleared Hepatitis C Virus Infection Compared to the General Population: A Danish Nationwide Cohort Study 
PLoS ONE  2011;6(7):e22476.
The increased mortality in HCV-infected individuals partly stems from viral damage to the liver and partly from risk-taking behaviours. We examined mortality in patients who cleared their HCV-infection, comparing it to that of the general population. We also addressed the question whether prognosis differed according to age, substance abuse (alcohol abuse and injection drug use) and comorbidity.
Methodology/Principal Findings
Patients with cleared HCV-infection were categorized into one of 8 groups according to age (20–39 years or 40–69 years) and patient characteristics (no substance abuse/no comorbidity; substance abuse/no comorbidity; no substance abuse/comorbidity; and substance abuse/comorbidity). For each patient, 4 age- and gender-matched individuals without substance abuse or comorbidity were selected from the general population, comprising a total of 8 comparison cohorts. We analyzed 10-year survival and used stratified Cox Regression analysis to compute mortality rate ratios (MRRs), comparing mortality between the 8 patient groups and the comparison cohorts, adjusting for personal income. Among patients without substance abuse or comorbidity, those aged 40–69 years had the same mortality as the comparison cohort (10-year survival: 95% (95% confidence interval [CI]: 93%–97%), MRR: 1.3 (95% CI: 0.8–2.3)), whereas those aged 20–39 years had higher mortality than the comparison cohort (10-year survival: 93% versus 99%, MRR: 5.7 (95% CI: 2.3–14.0). For both age categories, substance abuse and comorbidity decreased survival and increased MRRs. Patients aged 40–69 years with substance abuse and comorbidity suffered from substantial mortality (MRR: 12.5 (95% CI: 5.1–30.6)).
Mortality in patients aged 40–69 years with cleared HCV-infection is comparable to individuals without HCV, provided they have no substance abuse or comorbidity. Any substance abuse and/or comorbidity not captured in the registries used for our study could explain the increased mortality in patients aged 20–39 years without documented substance abuse or comorbidity.
PMCID: PMC3138785  PMID: 21789259
6.  Hepatitis C virus infection and risk of cancer: a population-based cohort study 
Clinical Epidemiology  2010;2:179-186.
Hepatitis C virus (HCV) infection is associated with an increased risk of primary liver cancer; however, 5- and 10-year risk estimates are needed. The association of HCV with non-Hodgkin lymphoma (NHL) is uncertain and the association with other cancers is unknown.
We conducted a nationwide, population-based cohort study of 4,349 HCV-infected patients in Denmark, computing standardized incidence ratios (SIR) of cancer incidence in HCV infected patients compared with cancer incidence of the general population. We calculated 5- and 10-year risks of developing cancer, stratifying our analyses based on the presence of HIV coinfection and cirrhosis.
We recorded an increased risk of primary liver cancer (SIR: 76.63 [95% CI: 51.69–109.40]), NHL (SIR: 1.89 [95% CI: 0.39–5.52]), and several smoking- and alcohol-related cancers in HCV infected patients without HIV coinfection. HCV-infected patients without HIV coinfection had a 6.3% (95% CI: 4.6%–8.7%) risk of developing cancer and 2.0% (95% CI: 1.1%–3.8%) risk of developing primary liver cancer within 10 years.
We confirmed the association of HCV infection with primary liver cancer and NHL. We also observed an association between HCV infection and alcohol- and smoking-related cancers.
PMCID: PMC2943195  PMID: 20865115
hepatitis C virus; non-Hodgkin lymphoma; standardized incidence ratio; cancer
7.  The galactose elimination capacity and mortality in 781 Danish patients with newly-diagnosed liver cirrhosis: a cohort study 
BMC Gastroenterology  2009;9:50.
Despite its biologic plausibility, the association between liver function and mortality of patients with chronic liver disease is not well supported by data. Therefore, we examined whether the galactose elimination capacity (GEC), a physiological measure of the total metabolic capacity of the liver, was associated with mortality in a large cohort of patients with newly-diagnosed cirrhosis.
By combining data from a GEC database with data from healthcare registries we identified cirrhosis patients with a GEC test at the time of cirrhosis diagnosis in 1992–2005. We divided the patients into 10 equal-sized groups according to GEC and calculated all-cause mortality as well as cirrhosis-related and not cirrhosis-related mortality for each group. Cox regression was used to adjust the association between GEC and all-cause mortality for confounding by age, gender and comorbidity, measured by the Charlson comorbidity index.
We included 781 patients, and 454 (58%) of them died during 2,617 years of follow-up. Among the 75% of patients with a decreased GEC (<1.75 mmol/min), GEC was a strong predictor of 30-day, 1-year, and 5-year mortality, and this could not be explained by confounding (crude hazard ratio for a 0.5 mmol/min GEC increase = 0.74, 95% CI 0.59–0.92; adjusted hazard ratio = 0.64, 95% CI 0.51–0.81). Further analyses showed that the association between GEC and mortality was identical for patients with alcoholic or non-alcoholic cirrhosis etiology, that it also existed among patients with comorbidity, and that GEC was only a predictor of cirrhosis-related mortality. Among the 25% of patients with a GEC in the normal range (≥ 1.75 mmol/min), GEC was only weakly associated with mortality (crude hazard ratio = 0.79, 95% CI 0.59–1.05; adjusted hazard ratio = 0.80, 95% CI 0.60–1.08).
Among patients with newly-diagnosed cirrhosis and a decreased GEC, the GEC was a strong predictor of short- and long-term all-cause and cirrhosis-related mortality. These findings support the expectation that loss of liver function increases mortality.
PMCID: PMC2721849  PMID: 19566919
8.  Socioeconomic status and survival of cirrhosis patients: A Danish nationwide cohort study 
BMC Gastroenterology  2009;9:35.
Low socioeconomic status is a risk factor for liver cirrhosis, but it is unknown whether it is a prognostic factor after cirrhosis diagnosis. We examined whether marital status, employment, and personal income were associated with the survival of cirrhosis patients.
Using registry-data we conducted a population-based cohort study of 1,765 Danish cirrhosis patients diagnosed in 1999–2001 at age 45–59 years. Follow-up ended on 31 December 2003. With Cox regression we examined the associations between marital status (never married, divorced, married), employment (employed, disability pensioner, unemployed), personal income (0–49, 50–99, 100+ percent of the national average) and survival, controlling for gender, age, cirrhosis severity, comorbidity, and substance abuse.
Five-year survival was higher for married patients (48%) than for patients who never married (40%) or were divorced (34%), but after adjustment only divorced patients had poorer survival than married patients (adjusted hazard ratio for divorced vs. married = 1.22, 95% CI 1.04–1.42). Five-year survival was lower for disability pensioners (31%) than for employed (46%) or unemployed patients (48%), also after adjustment (adjusted hazard ratio for disability pensioners vs. employed = 1.35, 95% CI 1.09–1.66). Personal income was not associated with survival.
Marital status and employment were associated with the survival of cirrhosis patients. Specifically, divorced cirrhosis patients and cirrhosis patients who never married had a poorer survival than did married cirrhosis patients, and cirrhosis patients who were disability pensioners had a poorer survival than did employed or unemployed cirrhosis patients. The poorer survival for the divorced and for the disability pensioners could not be explained by differences in other socioeconomic factors, gender, age, cirrhosis severity, substance abuse, or comorbidity. Personal income was not associated with survival.
PMCID: PMC2688507  PMID: 19450284
9.  Liver cirrhosis, other liver diseases, and risk of hospitalisation for intracerebral haemorrhage: A Danish population-based case-control study 
BMC Gastroenterology  2008;8:16.
Liver diseases are suspected risk factors for intracerebral haemorrhage (ICH). We conducted a population-based case-control study to examine risk of ICH among hospitalised patients with liver cirrhosis and other liver diseases.
We used data from the hospital discharge registries (1991–2003) and the Civil Registration System in Denmark, to identify 3,522 cases of first-time hospitalisation for ICH and 35,173 sex- and age-matched population controls. Among cases and controls we identified patients with a discharge diagnosis of liver cirrhosis or other liver diseases before the date of ICH. We computed odds ratios for ICH by conditional logistic regressions, adjusting for a number of confounding factors.
There was an increased risk of ICH for patients with alcoholic liver cirrhosis (adjusted OR = 4.8, 95% CI: 2.7–8.3), non-alcoholic liver cirrhosis (adjusted OR = 7.7, 95% CI: 2.0–28.9) and non-cirrhotic alcoholic liver disease (adjusted OR = 5.4, 95%CI:3.1–9.5) but not for patients with non-cirrhotic non-alcoholic liver diseases (adjusted OR = 0.9, 95%CI:0.5–1.6). The highest risk was found among women with liver cirrhosis (OR = 8.9, 95%CI:2.9–26.7) and for patients younger than 70 years (OR = 6.1, 95%CI:3.4–10.9). There were no sex- or age-related differences in the association between other liver diseases (alcoholic or non-alcoholic) and hospitalisation with ICH.
Patients with liver cirrhosis and non-cirrhotic alcoholic liver disease have a clearly increased risk for ICH.
PMCID: PMC2413247  PMID: 18501016
10.  Alcoholic cirrhosis in Denmark – population-based incidence, prevalence, and hospitalization rates between 1988 and 2005: A descriptive cohort study 
Denmark has one of the highest alcohol consumption rates in Northern Europe. The overall per capita alcohol consumption has been stable in recent decades, but surveys have indicated that consumption has decreased in the young and increased in the old. However, there is no recent information on the epidemiology of alcoholic cirrhosis. We examined time trends in incidence, prevalence, and hospitalization rates of alcoholic cirrhosis in Denmark between 1988 and 2005.
We used data from a nationwide population-based hospital registry to identify all Danish citizens with a hospital diagnosis of alcoholic cirrhosis. We computed standardized incidence rates, prevalence and hospitalization rates of alcoholic cirrhosis within the Danish population. We also computed the number of hospitalizations per alcoholic cirrhosis patient per year.
From 1988 to 1993, incidence rates for men and women of any age showed no clear trend, and after a 32 percent increase in 1994, rates were stable throughout 2005. In 2001–2005, the incidence rates were 265 and 118 per 1,000,000 per year for men and women, respectively, and the prevalence rates were 1,326 and 701 per 1,000,000. From 1994, incidence, prevalence, and hospitalization rates decreased for men and women younger than 45 years and increased in the older population, although the latter finding might be partly explained by changes in coding practice. Men and women born around 1960 or later had progressively lower age-specific alcoholic cirrhosis incidence rates than the generations before them. From 1996 to 2005, the number of hospitalizations per alcoholic cirrhosis patient per year increased from 1.3 to 1.5 for men and from 1.1 to 1.2 for women.
From 1988 to 2005, alcoholic cirrhosis put an increasing burden on the Danish healthcare system. However, the decreasing incidence rate in the population younger than 45 years from 1994 indicated that men and women born around 1960 or later had progressively lower incidence rates than the generations before them. Therefore, we expect the overall incidence and prevalence rates of alcoholic cirrhosis to decrease in the future.
PMCID: PMC2275281  PMID: 18261240

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