Cascade of care during the first 36 months of the treatment as prevention for hepatitis C (TraP HepC) programme in Iceland: a population-based study.

BACKGROUND: WHO has set targets to eliminate hepatitis C virus (HCV) infection as a global health threat by 2030 through a 65% reduction in HCV-related deaths and 80% reduction in HCV incidence. To achieve these goals, WHO set service coverage targets of 90% of the infected population being diagnosed and 80% of eligible patients being treated. In February, 2016, Iceland initiated a nationwide HCV elimination programme known as treatment as prevention for hepatitis C (TraP HepC), which aimed to maximise diagnosis and treatment access. This analysis reports on the HCV cascade of care in the first 3 years of the programme. METHODS: This population-based study was done between Feb 10, 2016, and Feb 10, 2019. Participants aged 18 years or older with permanent residence in Iceland and PCR-confirmed HCV were offered direct-acting antiviral (DAA) therapy. The programme used a multidisciplinary team approach in which people who inject drugs were prioritised. Nationwide awareness campaigns, improved access to testing, and harm reduction services were scaled up simultaneously. The number of infected people in the national HCV registry was used in combination with multiple other data sources, including screening of low-risk groups and high-risk groups, to estimate the total number of HCV infections. The number of people diagnosed, linked to care, initiated on treatment, and cured were recorded during the study. This study is registered with ClinicalTrials.gov, NCT02647879. FINDINGS: In February, 2016, at the onset of the programme, 760 (95% CI 690-851) individuals were estimated to have HCV infection, with 75 (95% CI 6-166) individuals undiagnosed. 682 individuals were confirmed to be HCV PCR positive. Over the next 3 years, 183 new infections (including 42 reinfections) were diagnosed, for a total of 865 infections in 823 individuals. It was estimated that more than 90% of all domestic HCV infections had been diagnosed as early as January, 2017. During the 3 years, 824 (95·3%) of diagnosed infections were linked to care, and treatment was initiated for 795 (96·5%) of infections linked to care. Cure was achieved for 717 (90·2%) of 795 infections. INTERPRETATION: By using a multidisciplinary public health approach, involving tight integration with addiction treatment services, the core service coverage targets for 2030 set by WHO have been reached. These achievements position Iceland to be among the first nations to subsequently achieve the WHO goal of eliminating HCV as a public health threat. FUNDING: The Icelandic Government and Gilead Sciences.

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.

Biochemical response to ursodeoxycholic acid among PBC patients: a nationwide population-based study.

Objective: To assess the proportion of PBC patients with a biochemical response to ursodeoxycholic acid (UDCA) in a population-based cohort and the association of biochemical response with outcomes. Methods: All patients diagnosed with PBC in Iceland from 1991-2015 were identified. Patients taking UDCA for an adequate period of time were analyzed for treatment response according to the Barcelona, Paris I, Paris II and Toronto criteria and outcomes. Results: Overall 182 females and 40 males were diagnosed with PBC and 135 patients were treated with UDCA. Overall 99 (73%) patients had adequate data on UDCA treatment and results of liver tests to assess biochemical response according to the Barcelona criteria, 95 (70%) according to the Toronto criterion and 85 (63%) according to the Paris I and II criteria. In all 74% (n = 63), 67% (n = 64), 54% (n = 53) and 46% (n = 39) responded to treatment according to the Paris I, Toronto, Barcelona and Paris II criteria. Among nonresponders according to the Paris I, Toronto, Paris II and Barcelona criteria, 50%, 39%, 33% and 30% developed cirrhosis versus 10%, 6%, 5% and 11% of responders, HR 5.36 (p = .002), 6.61 (p = .002), 10.94 (p = .003) and 2.21(p = .11), respectively. Age-adjusted mortality was significantly lower among responders according to the Paris I and Paris II criteria, HR 0.33 (p = .02) and 0.31 (p = .02), respectively. Conclusion: Development of cirrhosis and higher mortality was significantly associated with a lack of biochemical response to UDCA. Frequent development of cirrhosis and increased mortality in nonresponders underlines the need for a more effective therapy than UDCA for this sizeable subgroup of patients.

Using the Icelandic genealogical database to define the familial risk of primary biliary cholangitis.

Hereditary factors in primary biliary cholangitis (PBC) have been well defined in genome-wide association studies, but there are few direct data available that define the relative risk (RR) for family members with an affected proband. An increased risk in first-degree relatives has been demonstrated in a variety of studies, but data have been lacking on further detailed associations for subsequent generations. The objective of this study was to use the unique Icelandic genealogical database to study the familiality of PBC. All patients with positive antimitochondrial antibody measurements in Iceland during the period 1991-2015 who fulfilled diagnostic criteria for PBC were included. The Icelandic genealogical database was used to assess familial relations. For each case of PBC, 10,000 control subjects matched for age, sex, and number of known relatives were randomly chosen from this database to calculate the familial RR of PBC. The average kinship coefficient (KC) of the patients was calculated and compared with the average KC of controls. Overall, 222 PBC patients were identified (182 females, 40 males; median age, 62 years). First-, second- and third-degree relatives of the PBC patients had a high RR of the disease: 9.13 (P < 0.0001), 3.61 (P = 0.014) and 2.59 (P = 0.008), respectively. In fourth- and fifth-degree relatives, the RR was also increased to 1.66 (P = 0.08) and 1.42 (P = 0.08), respectively. The average KC of the patients was also higher than that of the control subjects, with 21.34 × 10-5 versus 9.56 × 10-5 (P < 0.0001). CONCLUSION: Relatives of PBC patients had markedly higher risk for development of the disease compared with controls and importantly our data demonstrate that the risk was significantly increased even in second- and third-degree relatives. (Hepatology 2018;68:166-171).

Lifetime drinking history in patients with alcoholic liver disease and patients with alcohol use disorder without liver disease.

OBJECTIVE: To determine the differences in lifetime alcohol intake (LAI) and drinking patterns between patients with alcoholic liver disease (ALD) and alcohol use disorder (AUD) without notable liver injury and between males and females with ALD. METHODS: Alcohol drinking patterns were assessed using the Lifetime Drinking History (LDH) a validated questionnaire, during an outpatient visit. Patients with AUD, currently in addiction treatment, were matched for gender and age (±5 years) with the ALD group. RESULTS: A total of 39 patients with ALD (26 males and 13 females; median age 58) and equal number of AUD patients were included (median age 56 years). The onset age for alcohol drinking and duration of alcohol consumption was similar in ALD and AUD. The number of drinking days was higher in women with ALD than in women with AUD: 4075 [(3224-6504) versus 2092 (1296-3661), p = .0253]. The LAI and drinks per drinking day (DDD) were not significantly different between patients with ALD and AUD. Females with ALD had lower LAI than males with ALD: 32,934 (3224-6504) versus 50,923 (30,360-82,195), p = .0385, fewer DDD (p = .0112), and lower proportion of binge drinking as compared to males with ALD (p = .0274). CONCLUSIONS: The total LAI was similar in patients with ALD and AUD. The number of drinking days over the lifetime was associated with the development of ALD in females. Females with ALD had significantly lower alcohol consumption than men with ALD despite similar duration in years of alcohol intake which supports the concept of female propensity of ALD.

Strain- and time-dependent alterations in hepatic iron metabolism in a murine model of nonalcoholic steatohepatitis.

Nonalcoholic steatohepatitis is a common liver disease that is often accompanied by dysregulated iron metabolism. The aim of the study was to test the hypothesis that aberrant iron metabolism in nonalcoholic steatohepatitis is modulated by genetic susceptibility to inflammation and oxidative stress. Hepatic histology and iron content were assessed in 3 inbred strains of mice (C57BL/6, BALB/c, and C3H/HeJ) fed an atherogenic diet (AD). Hepatic expression of genes relevant to iron metabolism, inflammation, and oxidative stress were quantitated by real-time reverse transcription-polymerase chain reaction. At 6 weeks on the AD, histologic injury and induction of inflammatory and oxidative stress-associated gene expression were most pronounced in C57BL/6. At 18 weeks on the AD, these parameters were similar in C57BL/6 and BALB/c. Atherogenic diet-fed C3H/HeJ showed milder responses at both time points. The AD was associated with decreased hepatic iron concentrations in all strains at 6 and 18 weeks. The decrease in hepatic iron concentrations did not correlate with changes in hepcidin expression and was not associated with altered expression of iron transporters. These findings are similar to those observed in models of obesity-induced steatosis and indicate that hepatic steatosis can be associated with depletion of iron stores that is not explained by upregulation of hepcidin expression by inflammation. SIGNIFICANCE OF THE STUDY: Nonalcoholic steatohepatitis (NASH) is a common liver disease that often accompanies the metabolic syndrome. The latter condition has been linked to iron deficiency and diminished intestinal iron absorption, likely the result of hepcidin upregulation by chronic inflammation. Paradoxically, some NASH patients accumulate excess hepatic iron, which may increase fibrosis and cancer risk. Iron accumulation has been attributed to suppression of hepcidin by oxidative stress. The objective of this study was to investigate the contributions of inflammation and oxidative stress to altered hepatic iron metabolism in a murine model of NASH using inbred strains of mice with differing susceptibilities to injury.

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.

Secondary sclerosing cholangitis in patients with drug-induced liver injury.

BACKGROUND: Secondary sclerosing cholangitis has clinical features similar to primary sclerosing cholangitis but originates from a known pathological entity. Secondary sclerosing cholangitis has not been investigated in patients with drug-induced liver injury. METHODS: Overall 102 patients diagnosed with drug-induced liver injury were identified and magnetic resonance cholangiopancreatography images of 25 patients were reviewed. RESULTS: Ten patients (all females) out of 102 had confirmed features of secondary sclerosing cholangitis on biliary imaging. Overall 70% of patients with sclerosing cholangitis had jaundice vs. 25% without sclerosing cholangitis (p<0.01). All sclerosing cholangitis patients had cholestatic/mixed type of liver injury and compared with patients with cholestatic/mixed liver injury without confirmed abnormal MRCP (n=52), they also had more frequently jaundice, 70% vs. 23% (p=0.0065), higher peak alkaline phosphatase 551 (352-716) vs. 329 (202-543) (p=0.055) and longer time to resolution of liver injury 152 days (123-353) vs. 62 days (36-91) than patients without confirmed sclerosing cholangitis (p<0.0009). CONCLUSIONS: Our results indicate that drugs can lead to bile duct injury visualized on imaging. This should be a part of the differential diagnoses of secondary sclerosing cholangitis. These patients were more likely to present with jaundice and longer recovery of liver injury than other patients with cholestatic/mixed type of drug-induced liver injury.

Incidence, presentation, and outcomes in patients with drug-induced liver injury in the general population of Iceland.

BACKGROUND & AIMS: Little is known about the incidence of drug-induced liver injury (DILI) in the general population. We investigated the incidence and the quantitative risk of DILI in a population-based cohort. METHODS: We performed a prospective study and collected data from 96 individuals diagnosed with DILI in Iceland from 2010 through 2011 (54 women; median age, 55 y). Liver injury was defined based on levels of alanine aminotransferase that were more than 3-fold the upper limit of normal and/or alkaline phosphatase levels more than 2-fold the upper limit of normal. Patients with acetaminophen toxicity were excluded. Drug history and clinical outcome were analyzed. Causality was assessed using the Roussel Uclaf Causality Assessment Method. The patients were registered in prescription databases for outpatients and inpatients. RESULTS: The crude annual incidence rate of DILI was 19.1 (95% confidence interval [CI], 15.4-23.3) cases per 100,000 inhabitants. DILI was caused by a single prescription medication in 75% of cases, by dietary supplements in 16% of cases, and by multiple agents in 9% of cases. The most commonly implicated drugs were amoxicillin-clavulanate (21 of 96; 22%), diclofenac (6%), azathioprine (4%), infliximab (4%), and nitrofurantoin (4%). The median duration of therapy was 20 days (range, 8-77 days); 26 patients had jaundice (27%) and 22 patients were hospitalized (23%) for a median of 5 days (range, 2-8 days). Overall 35,252 patients received amoxicillin-clavulanate as outpatients, and DILI occurred in 1 of 2350 (43 of 100,000; 95% CI, 24-70). DILI also occurred in 1 of 9480 patients taking diclofenac (11 of 100,000; 95% CI, 4-24), 1 of 133 patients taking azathioprine (752 of 100,000; 95% CI, 205-1914), 1 of 148 patients taking infliximab (675 of 100,000; 95% CI, 184-718), and 1 of 1369 patients taking nitrofurantoin (73 of 100,000; 95% CI, 20-187). CONCLUSIONS: In a population-based study in Iceland, the incidence of DILI was the highest reported to date. Amoxicillin-clavulanate was the most commonly implicated agent. The highest risk of hepatotoxicity was associated with azathioprine and infliximab, but the actual number of cases attributed to these agents was small.

Paracetamol intoxications: a retrospective population-based study in Iceland.

OBJECTIVE: Paracetamol is the most common cause of acute liver failure (ALF) in many countries. Much data on paracetamol toxicity originate from liver transplant centers and tertiary referral institutions. The authors analyzed the population-based annual incidence of paracetamol overdoses and ALF, and described the risk factors for hepatotoxicity. METHODS: A search was undertaken for the diagnosis of paracetamol overdoses in the diagnoses registry of the National University Hospital of Iceland from 2004 to 2009 serving a population of 219,249 inhabitants. Relevant information was collected from medical records. RESULTS: A total of 1913 drug-related poisoning episodes were identified and reviewed, 352 (18%) involved paracetamol overdoses. The annual incidence of paracetamol overdoses declined from 30.0 (2004) to 16.0/100,000 per year (2009) (p < 0.05). The female/male ratio was 3.0 and the largest age group was 16-25 years. After the initial examination, 26% were discharged home. Hospitalized index visits were 182 with accidental overdoses constituting 16 (9%) with no gender difference. Compared with intentional overdose the accidental group had higher aminotransferases (p < 0.005). ALF occurred in 3.8% (7/182) of the index visits and the incidence was 0.7/100,000 per year. In the intentional group, 1.2% (2/163) developed ALF versus 25% (4/16) of the accidental group (p = 0.001). Only one patient died from ALF and none underwent liver transplantation. CONCLUSION: The annual incidence of paracetamol overdoses was high in this population-based study but declined. Young females with intentional overdose accounted for most of the cases, whereas accidental overdoses were more common in older patients. The occurrence of ALF was low and mostly associated with accidental overdose.

The epidemiology and natural history of primary biliary cirrhosis: a nationwide population-based study.

BACKGROUND AND AIMS: Very few population-based studies exist on the epidemiology of primary biliary cirrhosis (PBC), and none have been conducted in the last decade. We aimed to determine the epidemiology and prognosis of PBC over the past two decades. METHODS: Patients were identified by multiple case finding strategies, covering the total population of Iceland. A search was conducted in the centralized database of antimitochondrial antibody (AMA) measurements and computerized diagnosis and pathological registries. All AMA measurements taken in Iceland between 1991 and 2010 were analyzed. Relevant clinical information was gathered from medical records, pathology reports, and death certificates. Incidence was compared between two periods, 1991-2000 versus 2001-2010. RESULTS: A total of 168 patients were identified, of which 138 were female (82%), with a median age 62 years (range 13-92). Prevalence at the end of the study period was 38.3 cases per 100 000 person-years. Age-standardized incidence for female patients during the first period was 3.4 versus 4.1 during the second (NS) and that for male patients was 0.6 during the first period versus 1.0 per 100 000 during the second (NS). Overall incidence in the first period was 2.0 and that in the second was 2.5 per 100 000 (NS). Stage III-IV liver fibrosis was present in 28% of patients at diagnosis with no significant differences between the two decades. Median survival after diagnosis was 15 years. Five patients underwent liver transplantation. CONCLUSION: The incidence and prevalence figures of PBC in Iceland are among the highest reported and have been stable over the last two decades. The prognosis of patients in this population-based cohort is better than that previously reported.

Jaundice due to suspected statin hepatotoxicity: a case series.

Statin drugs are widely used worldwide and are generally considered safe and well tolerated. Only small proportion of patients receiving statins develop elevations of liver enzymes and an even smaller proportion will have clinically significant hepatitis induced by statins. We describe four patients with jaundice caused by drug-induced liver injury, where the most likely agent was a statin drug, over a period of approximately three year in Iceland. We calculate the risk of jaundice caused by statin drugs, from sale in the whole country of Iceland, to be one in 17,434 users a year. This is a higher risk than has previously been estimated and we challenge the current opinion that statins rarely cause clinically significant drug-induced liver injury and encourage alertness when managing patients with statins with regard to clinical signs of hepatitis before jaundice occurs.

Altered expression of iron regulatory genes in cirrhotic human livers: clues to the cause of hemosiderosis?

Hepatic iron deposition unrelated to hereditary hemochromatosis occurs commonly in cirrhosis but the pathogenesis of this condition is unknown. The aim of this study was to compare the expression of genes involved in the regulation of iron metabolism in cirrhotic (n=22) and control human livers (n=5). Transcripts were quantitated by real-time RT-PCR and protein levels were assessed by western blot. Hepatic iron concentrations (HICs) were measured by a spectrophotometric method. Levels of hepcidin mRNA did not differ between controls and cirrhotic livers; there was a highly significant correlation between hepcidin transcript levels and HIC in the latter group. Ferroportin, divalent metal transporter-1 (DMT1), and ferritin heavy chain mRNA levels were significantly higher in cirrhotic human livers than in controls (P=0.007, 0.039, and 0.025, respectively). By western blot, ferroportin and DMT1 levels were generally diminished in the cirrhotic livers compared to controls; neither correlated with HIC. In contrast, the abundance of ferritin increased with increasing HIC in the cirrhotic livers, whereas transferrin receptor decreased, indicating physiologically appropriate regulation. In conclusion, hepcidin expression appears to be appropriately responsive to iron status in cirrhosis. However, there are complex alterations in DMT1 and ferroportin expression in cirrhotic liver, including decreases in ferroportin and DMT1 at the protein level that may play a role in aberrant regulation of iron metabolism in cirrhosis.