To Örebro University

The aim of this study was to evaluate the association between hepatitis C virus (HCV) infection and non-Hodgkin's lymphoma (NHL), multiple myeloma (MM), thyroid cancer (TC), chronic lymphatic leukemia (CLL), acute lymphatic leukemia (ALL), and Hodgkin's lymphoma (HL). A Swedish cohort of 27,150 HCV-infected persons notified during 1990-2000 was included in the study. The database was linked to other national registers to calculate the observation time, expressed as person-years, and to identify all incident malignancies in the cohort. The patients were stratified according to assumed time of previous HCV infection. The relative risk of malignancy was expressed as a standardized incidence ratio (SIR)-the observed number compared to the expected number. During 1990-2000 there were 50 NHL, 15 MM, 14 ALL, 8 TC, 6 CLL, and 4 HL diagnoses in the cohort. Altogether, 20 NHL, 7 MM, 5 TC, 4 CLL, 1 ALL, and 1 HL patient fulfilled the criteria to be included in the statistical analysis. The observation time was 122,272 person-years. The risk of NHL and MM was significantly increased in the stratum with more than 15 years of infection (SIR 1.89 [95% CI, 1.10-3.03] and 2.54 [95% CI, 1.11-5.69], respectively). The association was not significant in TC or CLL. In conclusion, we report the incidence of several malignancies in a nationwide cohort of HCV-infected persons. Although the delayed diagnosis of HCV probably has resulted in an underestimation of the risk, this study showed a significantly increased risk of NHL and MM.

BACKGROUND & AIMS: Hepatitis delta virus (HDV) infection is associated with fast progression to liver cirrhosis and liver complications. Previous studies have though been mainly from tertiary care centers, with risk for referral bias towards patients with worse outcomes. Furthermore, the impact of HDV viremia per se on liver-related outcomes is not really known outside HIV co-infection setting. We have therefore evaluated the long-term impact of HDV viremia on liver-related outcomes in a nationwide cohort of hepatitis B and D co-infected patients, cared for at secondary care centers in Sweden.

APPROACH & RESULTS: In total 337 anti-HDV positive patients including 233 patients with HDV RNA viremia and 91 without HDV viremia at baseline were retrospectively studied, with a mean follow-up of 6.5 years (range 0.5-33.1). The long-term risks for liver-related events (i.e. hepatocellular carcinoma [HCC], hepatic decompensation, or liver-related death/transplantation) were assessed, using Cox regression analysis. The risk for liver-related events and HCC was 3.8 and 2.6 fold higher, respectively, in patients with HDV viremia compared to those without viremia, although the latter was not statistically significant. Among HDV viremic patients with no baseline cirrhosis, the cumulative risk of being free of liver cirrhosis or liver-related events was 81.9% and 64.0%, after 5 and 10 years of follow-up, respectively. This corresponds to an incidence rate of 0.04 per person-year.

CONCLUSION: HDV RNA viremia is associated with a 3.8 fold higher risk for liver-related outcomes. The prognosis was rather poor for non-cirrhotic patients with HDV viremia at baseline, but it was nevertheless more benign than previous estimates from tertiary centers. Our findings can be of importance when treatment decision making, and evaluating outcomes of upcoming new antivirals against HDV.

Liver biopsy is an important procedure in the investigation of liver disease. We examined pregnancy outcomes in women who underwent liver biopsy during pregnancy. In a nationwide population-based cohort study we linked data from the Swedish Medical Birth Registry (for births between 1992 and 2011) with those from the Swedish Patient Registry. We identified 23 pregnancies exposed to liver biopsy. We calculated relative risks (RRs) for adverse pregnancy outcomes according to liver biopsy status using 1,953,887 unexposed pregnancies with and without a record of liver disease as reference. Our main outcome measures were stillbirth and preterm birth. There were no stillbirths in pregnancies exposed to liver biopsies compared with 0.3% stillbirths in unexposed pregnancies. 3/23 (13%) exposed pregnancies were preterm (RR=2.6; 95%CI=0.9-7.5). Compared with women with a record of liver disease, preterm birth was not increased in those exposed to liver biopsy (RR=0.9; 95%CI=0.1-6.0). Except for an increased risk of small for gestational age birth in pregnancies exposed to liver biopsy (RR=5.2; 95%CI=1.8-14.8), other adverse pregnancy outcomes were independent of liver biopsy status when the analysis was restricted to women with a diagnosis of liver disease. Compared with unexposed sibling pregnancies, pregnancies with a liver biopsy were 7 days shorter, but birth weights did not differ between the siblings (-67g; p>0.05).

CONCLUSION: Apart from a moderately increased risk of preterm birth and small for gestational age, there was no association between liver biopsy during pregnancy and adverse pregnancy outcome. Potential excess risks should be weighed against the advantages of having a liver biopsy that may influence clinical management of the patient indirectly influencing fetal health.

Intrahepatic cholestasis of pregnancy (ICP) is the most common liver disease in pregnancy. We aimed to estimate the risk of developing hepatobiliary disease in women with ICP and the odds of developing ICP in women with prevalent hepatobiliary disease. We analyzed data of women with births between 1973 and 2009 and registered in the Swedish Medical Birth Register. By linkage with the Swedish Patient Register, we identified 11,388 women with ICP who were matched to 113,893 women without this diagnosis. Diagnoses of preexisting or later hepatobiliary disease were obtained from the Patient Register. Main outcome measures were hazard ratios (HRs) for later hepatobiliary disease in women with ICP and odds ratios (ORs) for developing ICP in preexisting hepatobiliary disease. Risk estimates were calculated through Cox and logistic regression analyses. Women with ICP were more often diagnosed with later hepatobiliary disease (HR 2.62; 95% confidence interval [CI] 2.47-2.77; increment at 1% per year), hepatitis C or chronic hepatitis (HR 4.16; 3.14-5.51 and 5.96; 3.43-10.33, respectively), fibrosis/cirrhosis (HR 5.11; 3.29-7.96), gallstone disease or cholangitis (HR 2.72; 2.55-2.91, and 4.22; 3.13-5.69, respectively) as compared to women without ICP (P<0.001 for all HRs). Later ICP was more common in women with prepregnancy hepatitis C (OR 5.76; 1.30-25.44; P=0.021), chronic hepatitis (OR 8.66; 1.05-71.48; P=0.045), and gallstone disease (OR 3.29; 2.02-5.36; P<0.0001). Conclusion: Women with ICP have substantially increased risk for later hepatobiliary disease. Beyond gallstone-related morbidity we found a strong positive association between ICP and hepatitis C both before and after ICP diagnosis. Thus, we advocate testing for hepatitis C in women with ICP, in particular, since this potentially life-threatening infection can be treated successfully in the majority of patients. (Hepatology 2013;58:1385-1391)

Background and Aims: Recent studies link NAFLD to an increased incidence of HCC and extrahepatic cancers. However, earlier studies were small or lacked liver histology, which remains the gold standard for staging NAFLD severity.

Approach and Results: We conducted a population-based cohort study of all adults with histologically defined NAFLD in Sweden from 1966 to 2016 (N = 8,892). NAFLD was defined from prospectively recorded liver histopathology submitted to all 28 Swedish pathology departments and categorized as simple steatosis, nonfibrotic NASH, noncirrhotic fibrosis, and cirrhosis. NAFLD patients were individually matched to <= 5 general population controls without NAFLD by age, sex, calendar year, and county (N = 39,907). Using Cox proportional hazards modeling, we calculated multivariable adjusted HRs (aHRs) and 95% CIs. Over a median of 13.8 years, we documented 1,691 incident cancers among NAFLD patients and 6,733 among controls. Compared with controls, NAFLD patients had significantly increased overall cancer incidence (10.9 vs. 13.8 per 1,000 person-years [PYs]; difference = 2.9 per 1,000 PYs; aHR, 1.27 [95% CI, 1.18-1.36]), driven primarily by HCC (difference = 1.1 per 1,000 PYs; aHR, 17.08 [95% CI, 11.56-25.25]). HCC incidence rates increased monotonically across categories of simple steatosis, nonfibrotic NASH, noncirrhotic fibrosis, and cirrhosis (0.8 per 1,000 PYs, 1.2 per 1,000 PYs, 2.3 per 1,000 PYs, and 6.2 per 1,000 PYs, respectively; P-trend < 0.01) and were further amplified by diabetes (1.2 per 1,000 PYs, 2.9 per 1,000 PYs, 7.2 per 1,000 PYs, and 15.7 per 1,000 PYs, respectively). In contrast, NAFLD was associated with modestly increased rates of pancreatic cancer, kidney/bladder cancer, and melanoma (differences = 0.2 per 1,000 PYs, 0.1 per 1,000 PYs, and 0.2 per 1,000 PYs, respectively), but no other cancers.

Conclusions: Compared with controls, patients with biopsy-proven NAFLD had significantly increased cancer incidence, attributable primarily to HCC, whereas the contribution of extrahepatic cancers was modest. Although HCC risk was highest with cirrhosis, substantial excess risk was also found with noncirrhotic fibrosis and comorbid diabetes.

Background: Hepatitis C is a slowly progressive disease mainly transmitted in people who inject drugs . This cohort has a high mortality from drug related causes, such as overdoses or external causes. We investigated the relative risk for liver related death in chronic hepatitis C (CHC) patients with or without illicit substance use disorders (SUD) .

Methods: Patients with CHC were identified using the Swedish National Patient Registry (contains all inpatient, day surgery, and outpatient non-primary care visits) according to the International Classification of Diseases-10 (ICD-10) code B18.2. The baseline observation was set to the first CHC visit from 2001, and person-time continued until death, emigration or December 31, 2013, whichever came first. Patients with ≥2 non-primary care visits with ICD-10 codes F11, F12, F14, F15, F16, or F19 were considered to have illicit SUD . The underlying cause of death was obtained from the Cause of Death Register . A six months lag-period between CHC diagnosis and death was introduced to reduce surveillance bias. Non-alcoholic liver disease was defined using ICD-10 codes K71–K77, B15–B19, B94.2, R17-R18, I85 .0, I98 .2, and I98 .3 . The relative risk for death was determined using standardized mortality ratio (SMR) where the observed number of deaths was divided by the expected number of deaths taken from five comparators from the general population (matched for age/sex/place of residency) .

Results: In total 38,186 patients with CHC were included in the study whereof 11,818 (31%) were considered to have illicit SUD . The CHC patients with SUD were younger (37 .7 vs . 46 .9 years) with a greater proportion of men (72% vs . 62%) than CHC patients without SUD . The SMRs for CHC patients with SUD were 10 .5, 33 .8, 18 .1, 123 .2, 61 .6, and 13 .2, for all-causes, liver cancer, alcoholic or non-alcoholic liver disease, drug-related, or external causes, respectively (Table 1) . The corresponding SMRs for CHC patients without SUD were 4 .1, 52 .8, 18 .0, 69 .4, 11 .2, and 4 .9, respectively (Table 1) .

Conclusion: The relative risks for all investigated parameters were elevated for CHC patients whether they had illicit SUD or not . Furthermore, although the CHC patients with SUD had a high relative risk to die from both drug-related and external causes, the relative risk to die from non-alcoholic liver disease was also greatly elevated .

The Cancer Register (CR) in Sweden has reported that the incidence of primary liver cancer (PLC) has slowly declined over the last decades. Even though all cancers, irrespective of diagnostic method, should be reported to the CR, the PLC incidence may not reflect the true rate. Improved diagnostic tools have enabled diagnosis of hepatocellular carcinoma (HCC) based on non-invasive methods without histological verification, possibly associated with missed cancer-reports or misclassification in the CR. Our objective was to study the completeness and assess the underreporting of PLC to the CR, and to produce a more accurate estimate based on three registers. The CR, the Cause of Death and the Patient Register were investigated. Differences and overlap were examined, the incidence was estimated by merging data from the registers, and the number reported to none of the registers was estimated using a log-linear capture-recapture model. The results show that 98% of the PLCs reported to the CR were histologically verified; 80% were HCC and 20% intrahepatic cholangiocarcinoma. Unspecified liver cancer decreased over time and constituted <10% of all reported liver cancers. The CR may underestimate the liver cancer incidence by 37% - 45%, primarily due to missed cancer-reports. The estimated annual number of liver cancers increased over time, but the standardized incidence was stable around 11 per 100,000. Hepatitis C associated liver cancer increased and constituted 20% in 2010.

Conclusion: There was an underreporting of PLC diagnosed by non-invasive methods. The incidence was considerably higher than estimated by the CR, with a stable incidence over time. Reporting needs to improve and combining registers is recommended when studying incidence. This article is protected by copyright. All rights reserved.