Incidence of cirrhosis in Iceland-impact of the TraP HepC nationwide HCV elimination program.

OBJECTIVE: In 2016, a nationwide elimination program for hepatitis C virus (HCV) was initiated in Iceland, entitled Treatment as Prevention for Hepatitis C (TraP HepC), providing unrestricted access to antiviral treatment. The aims were to describe the changes in etiology and epidemiology of cirrhosis in Iceland and to assess the trends in HCV-related cirrhosis following TraP HepC. METHODS: The study included all patients newly diagnosed with cirrhosis in 2016-2022. Diagnosis was based on liver elastography, histology, or 2 of 4 criteria: cirrhosis on imaging, ascites, varices, or elevated international normalized ratio (INR). RESULTS: Over the study period, 342 new cirrhosis patients were identified, 223 (65%) males, median age 62 years. The crude overall incidence was 13.8 cases per 100,000 inhabitants annually. The most common etiologies were alcohol-related liver disease (ALD) (40%), metabolic dysfunction-associated steatotic liver disease (MASLD) (28%), and HCV with or without alcohol overconsumption (15%). The number of HCV cirrhosis cases was unusually high in 2016 (n = 23) due to intensified case-finding, but decreased significantly over the study period (p < 0.001) to n = 1 (2021) and n = 2 (2022). The overall 5-year survival was 55% (95% CI 48.9-62.3%). The most common causes of death were hepatocellular carcinoma (26%) and liver failure (25%). CONCLUSION: During the past two decades, the incidence of cirrhosis has increased extraordinarily in Iceland, associated with increased alcohol consumption, obesity, and HCV. ALD and MASLD now collectively make up two thirds of cases in Iceland. Following a nationwide elimination program, incidence of HCV cirrhosis has dropped rapidly in Iceland.

Multiomics study of nonalcoholic fatty liver disease.

Nonalcoholic fatty liver (NAFL) and its sequelae are growing health problems. We performed a genome-wide association study of NAFL, cirrhosis and hepatocellular carcinoma, and integrated the findings with expression and proteomic data. For NAFL, we utilized 9,491 clinical cases and proton density fat fraction extracted from 36,116 liver magnetic resonance images. We identified 18 sequence variants associated with NAFL and 4 with cirrhosis, and found rare, protective, predicted loss-of-function variants in MTARC1 and GPAM, underscoring them as potential drug targets. We leveraged messenger RNA expression, splicing and predicted coding effects to identify 16 putative causal genes, of which many are implicated in lipid metabolism. We analyzed levels of 4,907 plasma proteins in 35,559 Icelanders and 1,459 proteins in 47,151 UK Biobank participants, identifying multiple proteins involved in disease pathogenesis. We show that proteomics can discriminate between NAFL and cirrhosis. The present study provides insights into the development of noninvasive evaluation of NAFL and new therapeutic options.

A nationwide population-based prospective study of cirrhosis in Iceland.

BACKGROUND & AIMS: The incidence of cirrhosis in Iceland has been the lowest in the world with only 3 cases per 100,000 inhabitants. Alcohol consumption has almost doubled in Iceland from 1980 to 2016. Obesity has also risen and hepatitis C virus has spread among people who inject drugs in Iceland. The aim of this study was to evaluate the effects of these risk factors on the incidence and aetiology of cirrhosis in Iceland. METHODS: The study included all patients diagnosed with cirrhosis for the first time during 2010-2015. Diagnosis was based on liver histology or 2 of 4 criteria: cirrhosis on imaging, ascites, varices, and/or elevated INR. RESULTS: Overall, 157 patients were diagnosed, 105 (67%) males, mean age 61 years. The overall incidence was 9.7 cases per 100,000 inhabitants annually. Alcohol was the only underlying cause in 48/157 (31%), non-alcoholic fatty liver disease (NAFLD) in 34/157(22%), and alcohol and hepatitis C together in 23/157(15%) were the most common causes. Only 6% of patients had an unknown cause of cirrhosis. Upon diagnosis, the median model for end-stage liver disease score was 11 (IQR 8-15), 53% were of Child-Pugh class A whereas 61 (39%) had ascites, 11% encephalopathy, and 8% variceal bleeding. In all, 25% of deaths were from HCC and 25% from liver failure. CONCLUSION: A major increase in incidence of cirrhosis has occurred in Iceland associated with increases in alcohol consumption, obesity, and hepatitis C. In a high proportion NAFLD was the aetiology and very few had unknown cause of cirrhosis. The highest death rate was from HCC. LAY SUMMARY: In a nationwide population-based study from Iceland, including all patients diagnosed with cirrhosis of the liver over a period of 5 years, we found the incidence of new cases had increased 3-fold compared with a previous study 20 years ago. The increase is attributable to increased alcohol consumption, an epidemic of diabetes and obesity, and infection with the hepatitis C virus. Furthermore, we found that with thorough investigations, a specific cause for cirrhosis could be found in 94% of patients. Patients with cirrhosis frequently die of liver cancer and other complications related to their liver disease.

Common and Rare Sequence Variants Influencing Tumor Biomarkers in Blood.

BACKGROUND: Alpha-fetoprotein (AFP), cancer antigens 15.3, 19.9, and 125, carcinoembryonic antigen, and alkaline phosphatase (ALP) are widely measured in attempts to detect cancer and to monitor treatment response. However, due to lack of sensitivity and specificity, their utility is debated. The serum levels of these markers are affected by a number of nonmalignant factors, including genotype. Thus, it may be possible to improve both sensitivity and specificity by adjusting test results for genetic effects. METHODS: We performed genome-wide association studies of serum levels of AFP (N = 22,686), carcinoembryonic antigen (N = 22,309), cancer antigens 15.3 (N = 7,107), 19.9 (N = 9,945), and 125 (N = 9,824), and ALP (N = 162,774). We also examined the correlations between levels of these biomarkers and the presence of cancer, using data from a nationwide cancer registry. RESULTS: We report a total of 84 associations of 79 sequence variants with levels of the six biomarkers, explaining between 2.3% and 42.3% of the phenotypic variance. Among the 79 variants, 22 are cis (in- or near the gene encoding the biomarker), 18 have minor allele frequency less than 1%, 31 are coding variants, and 7 are associated with gene expression in whole blood. We also find multiple conditions associated with higher biomarker levels. CONCLUSIONS: Our results provide insights into the genetic contribution to diversity in concentration of tumor biomarkers in blood. IMPACT: Genetic correction of biomarker values could improve prediction algorithms and decision-making based on these biomarkers.

[Primary sclerosing cholangitis in Iceland 1992-2012].

BACKGROUND: Primary sclerosing cholangitis (PSC) is a chronic cholestatic disease affecting the intra- and/or extrahepatic biliary tree with inflammation and progressive stricture formation that can lead to cirrhosis, end stage liver failure and liver transplantation. Known risk factors include inflammatory bowel diseases (IBD), mainly ulcerative colitis (UC). Highest reported incidence in an adult population is 1.2-1.3/100.000 in Norway and Sweden, where 60-76% have IBD. The aim of this study was to investigate epidemiology of PSC in Iceland in the years 1992 to 2012 and the patients outcomes. METHODS: A search for the diagnosis "cholangitis" (ICD-10, K83.0) was performed in the database for hospital records in Landspítali (The National University Hospital of Iceland, LSH) and Akureyri Hospital from 1992 to 2012. We also looked through all ERCP and MRCP imaging done in LSH in the same period along with a text search in both the hospital records and the pathology database for liver biopsies. Data on these patients was collected until the end of 2016. RESULTS: A total of 42 patient got the diagnosis PSC within the period. Median age at diagnosis was 34 years, 67% were male and 90% adults (≥18 years old). Mean incidence per year was 0.69/100.000. Overall 88% of patients had IBD, thereof 89% UC. Seven patients have been diagnosed with cancer, four with cancer in the bile ducts and one in the gallbladder. Within the study period a total of five patients died (12%), 51 months (median) from diagnosis and three from cholangiocarcinoma, 51 months (median) from diagnosis. Three patients (7%) underwent liver transplantation, one required a transplant two times. CONCLUSIONS: The incidence of PSC in Iceland turned out to be lower than in our neighbouring countries in Scandinavia. It is unclear if this is due to underdiagnosis or, more likely, that PSC is simply more uncommon in Iceland. Overall 7% underwent liver transplantation and 12% died within the study period, main cause of mortality being cholangiocarcinoma.

A compensating income variation approach to valuing 34 health conditions in Iceland.

Using data from an Icelandic health-and-lifestyle survey carried out in 2007, 2009, and 2012, we employ a compensating income variation (CIV) approach to estimate the monetary value sufficient to compensate individuals for the presence of various sub-optimal health conditions. This method is inexpensive and easy on subjects and has been applied to several desiderata that do not have revealed market prices. The CIV literature is, however, still limited in its application to health and thus information about its suitability is limited. With the aim of shedding light on the method́s appropriateness we thus provide a broad-view analysis including a spectrum of diseases and conditions that can be held up against more traditionally used methods. CIV for physical conditions vary greatly, but paralysis, fibromyalgia, chronic back pain, rheumatoid arthritis, urinary incontinence, severe headache and thyroid disease were among those consistently associated with substantial well-being reductions. Mental-health results using this method should be read with caution. The societal value of health interventions is multidimensional, including for example increased productivity in the population. However, one of the main positive aspects of increased health is undoubtedly the increased well-being of the treated subjects. Such quality-of-life effects should thus preferably be taken into account. For this reason, information on the value individuals place on recovery from various sub-optimal health conditions is useful when it comes to prioritizing scarce capital in the health sector. It is therefore vital to estimate the importance individuals place on various health states and hold them up against each other. Furthermore, this paper has scientific value as it sheds light on attributes of a potentially useful method in health evaluations.

[Liver transplantation in Iceland: a retrospective study of indications and results]. / Lifrarígræðslur á Íslandi: afturskyggn rannsókn á ábendingum og árangri.

BACKGROUND/AIMS: Liver transplantation is an important treatment option for end-stage liver disease. Since liver transplantation is not performed in Iceland, patients are sent abroad for this procedure. The aim of this study was to investigate indications and results of liver transplantations for Icelandic patients. MATERIALS AND METHODS: The study was retrospective and included all patients in Iceland who had undergone liver transplantation from the first transplantation in 1984 to the end of 2012. Information was gathered from medical records. The study period was divided into three subperiods in order to evaluate changes in frequency of transplantation and survival. RESULTS: During the period, 45 liver transplantations, thereof five retransplantations, were performed. Of 40 patients 16 were males, 18 females, mean age 40 years. There were six children, 2 girls and 4 boys with an age range of 0.4-12 years. Number of transplantation per million inhabitants increased significantly (2.40 during 1984-1996; 5.18 during 1997-2006 and 8.90 during 2007-2013; p<0.01). The main indication for transplantation was cirrhosis with complications in 26 patients (65%), acute liver failure in 6 (15%), cirrhosis and hepatocellular carcinoma in three (8%), and hemangioendothelioma in two (5%). The most common underlying liver diseases were primary biliary cirrhosis in 8 (20%), autoimmune hepatitis in four (10%), alcoholic cirrhosis in three (7.5%) and primary sclerosing cholangitis in three (7.5%). The mean waiting time for transplantation was 5.9 months (median 3.2). Survial was 84% in one year and 63% in 5 years. Survival increased during the study period. CONCLUSIONS: The number of liver transplantations has increased significantly in recent years. Survival has improved and is comparable to survival in countries where liver transplantations are performed.

A prospective study on the causes of notably raised alanine aminotransferase (ALT).

OBJECTIVE: High levels of alanine aminotransferase (ALT) can be a marker of severe liver disease with variable aetiologies and prognosis. Very few prospective studies have been undertaken on the aetiology and prognosis of patients with high ALT levels. No population-based prospective study has systematically evaluated drug-induced liver injury (DILI) among these patients. The objective was to determine the aetiology and prognosis of patients with high ALT. MATERIALS AND METHODS: In a catchment area of 160,000 inhabitants, a population-based prospective study identified all adult patients with serum level of ALT >500 U/L during a 12-month period. All underwent thorough diagnostic work-up and follow-up. In suspected DILI, causality was assessed with Roussel Uclaf Causality Assessment Method. RESULTS: A total of 155 patients were identified with ALT >500 U/L, 12 children and one with ALT of non-liver-related origin, leaving 142 patients for the analysis: 73 (51%) males, median age 52 (IQR 36-68, range 19-89 years). The most common causes were choledocholithiasis 48/142 (34%), ischaemic hepatitis 26 (18%), viral hepatitis 16 (11%) and DILI 15 (11%), hepatobiliary malignancy (n = 6), surgery/interventions (n = 8) and other aetiologies (n = 23). No specific aetiology was found in 6% of cases. In the total study cohort 99 (70%) required hospitalisation, 78 (55%) had jaundice and 22 (16%) died, liver-related death in 10%, 35% in IH and 7% in DILI. CONCLUSIONS: The most common cause of notably high ALT was choledocholithiasis. Ischaemic hepatitis was a common aetiology with approximately 35% liver-related mortality. Viral hepatitis and DILI were important aetiologies among these patients.

Risk of drug-induced liver injury from tumor necrosis factor antagonists.

BACKGROUND & AIMS: Antagonists of tumor necrosis factor (anti-TNF agents) can cause drug-induced liver injury (DILI), yet little is known about the level of risk. METHODS: We identified cases of DILI caused by anti-TNF agents in Iceland, from 2009 through 2013, at the National University Hospital of Iceland (n = 11). We collected data on the total use of the drugs by patients with DILI, and outcomes, compared with patients who received anti-TNF agents but who did not develop DILI (controls, n = 22). RESULTS: Of the 11 cases of DILI identified (8 women; mean age, 46 y), 9 cases were caused by infliximab. DILI developed in 1 of 120 patients who received infliximab, 1 in 270 patients who received adalimumab, and 1 in 430 patients who received etanercept. Most patients with infliximab-associated DILI developed this disorder after 4 infusions (n = 6). Four patients had jaundice at diagnosis of DILI, and 8 patients had hepatocellular liver injury. The mean peak level of alanine aminotransferase was 704 U/L, of aspartate aminotransferase was 503 U/L, of alkaline phosphatase was 261 U/L, and of bilirubin was 47 µmol/L. Seven patients with DILI were tested for antinuclear antibodies before therapy with an anti-TNF agent and 3 had positive test results, compared with 5 of the 14 controls tested. At DILI diagnosis, 8 of 11 patients tested positive for antinuclear antibodies. Of liver biopsy specimens collected from 5 patients with DILI, 3 showed signs of severe acute hepatitis. Only 9% of the patients who developed DILI received methotrexate during anti-TNF therapy, compared with 59% of controls (P = .009). DILI was treated with steroids in 5 patients, and in 4 cases steroid therapy was discontinued without relapse. Eight patients with DILI went on to receive treatment with different TNF antagonists without developing DILI. CONCLUSIONS: Of anti-TNF agents, infliximab is associated most frequently with DILI, developing in 1 of 120 patients who received this drug. Fifty percent of patients with anti-TNF-associated DILI required steroid therapy, but most did not need long-term treatment. The addition of methotrexate to anti-TNF therapy might reduce the risk of DILI.

[Hepatotoxicity associated with the use of Herbalife]. / Lifrarskadi tengdur notkun á Herbalife.

OBJECTIVE: Many herbal products are known to be hepatotoxic. In a recent survey in Iceland concerning adverse reactions related to herbal medicines, Herbalife products were implicated in the majority of the reported cases of hepatotoxicity. METHODS: The clinical presentations of five cases of Herbalife related liver injury during the period of 1999-2008 are analysed. Causality was assessed by using the WHO-UMC system for causality assessment and the RUCAM method. RESULTS: Of the five cases there were four females and one male; median age was 46 years (range 29-78). Herbalife had been used for 1 to 7 months prior to presentation. Four patients presented with a hepatocellular and one with a cholestatic reaction. Median values were for bilirubin 190 micromol/L (range: 26-311; ref. < 20 micromol/L), ALP 407 U/L (range: 149-712; ref. 35-105 U/L) and ALT 24 87 U/L (range: 456-2637; ref. 70 and 45 U/L for males and females, respectively). Liver biopsy was performed in 2 patients and was consistent with toxic hepatitis in both cases. Other causes of hepatitis were excluded by appropriate serological testing and ultrasound. Causality assessment according to RUCAM was probable in three cases and possible in two. Using the WHO-UMC criteria causality was certain in one case, probable in two and possible in two cases. CONCLUSIONS: Hepatotoxicity is probably associated with the use of Herbalife products. Hepatotoxicity due to herbal remedies is an important differential diagnosis in the diagnostic work-up of liver injury.

[Hepatitis C: a clinical-histopathological study]. / Rannsókn á vefjameinafraei og tengslum vi klíníska aetti.

OBJECTIVE: Hepatitis C is a common cause of chronic hepatitis and cirrhosis in Western countries. In recent years a large group of individuals have been diagnosed with the disease in Iceland. The aim of this study was to investigate histological parameters of patients with hepatitis C and to correlate histological findings with clinical findings. MATERIALS AND METHODS: In this retrospective study, all patients diagnosed with hepatitis C in Iceland that had a liver biopsy in the years 1991-2001 were included. Data on age, route of infection, duration of infection and co-infection was obtained from medical records. Liver biopsy specimens were evaluated and inflammatory activity graded and the degree of fibrosis staged. RESULTS: In all 97 patients (58 males, 39 females) were included in the study. The mean age was 35.6 years (range 11-64). Risk factors were intravenous drug abuse in 70 (72.6%), blood transfusion in 12 (12.4%) and eight had no known risk factors. Estimated duration of infection was 8.85 years (range 1-31). Average inflammatory grade was 2.84 (range 0-8) and average fibrosis stage was 0.95 (range 0-6). The majority (72.6%) of patients had minimal or no inflammation and 85.5% had minimal or no fibrosis. Only four patients had cirrhosis. Significant correlation was observed between the age at infection and the degree of fibrosis. No correlation was detected between the duration of infection or route of infection and histopathological parameters. CONCLUSION: Patients with hepatitis C that underwent a liver biopsy in 1991-2000 had mild histopathological changes in the liver. This is most likely due to short duration of infection and young age of the patients in this study.

[Viral hepatitis B and C among immigrants in Iceland]. / Lifrarbólga af vökdum lifrarbólguveira B og C hjá innflytjendum á Islandi.

BACKGROUND: Viral hepatitis B and C are a major health problem worldwide. The prevalence of these diseases varies throughout the world. In Iceland, the incidence of hepatitis B and C has increased in recent years. At the same time, the number of immigrants from countries where viral hepatitis is endemic, has also increased. The aim of this study was to investigate the epidemiology of hepatitis B and C among immigrants in Iceland. MATERIAL AND METHODS: Immigrants from outside the European Economic Area (EEA) were screened for hepatitis B and C. Medical records for the years 2000-2002 were reviewed for country of origin, viral serology and liver transaminases. Information was gathered from the State Epidemiologist's central registry of notifiable diseases and from the Icelandic Directorate of Immigration on the number of residence permits issued. RESULTS: 70% of all immigrants from countries outside the EEA during the study period were included in the study. Blood samples were obtained from 2946 immigrants. 83 (2.8%) had hepatitis B and 24 (0.8%) had hepatitis C. Prevalence of hepatitis B was highest among immigrants from Africa,11/171 (6.4%; 95% CI: 3.3-11.2%) and hepatitis C among immigrants from Eastern Europe, 16/1502 (1.1%; 95% CI: 0.6-1.7%). 482 (16%) had serological markers of previous hepatitis B infection. Of all registered cases of hepatitis B, immigrants were 56% and of hepatitis C 10%. CONCLUSIONS: 1. Majority of those diagnosed with hepatitis B during the study period were immigrants. 2. Among immigrants, hepatitis B was more prevalent than hepatitis C. 3) The high prevalence of hepatitis B justifies screening for the disease in this population.