Einar S. Björnsson

Liver Fibrosis, but No Other Histologic Features, Is Associated With Long-term Outcomes of Patients With Nonalcoholic Fatty Liver Disease.

BACKGROUND & AIMSnHistologic analysis of liver biopsy specimens allows for grading and staging of nonalcoholic fatty liver disease (NAFLD). We performed a longitudinal study to investigate the long-term prognostic relevance of histologic features for patients with NAFLD.nnnMETHODSnWe performed a retrospective analysis of 619 patients diagnosed with NAFLD from 1975 through 2005 at medical centers in the United States, Europe, and Thailand. Patients underwent laboratory and biopsy analyses, and were examined every 3-12 months after their diagnosis. Outcomes analyzed were overall mortality, liver transplantation, and liver-related events. Cumulative outcomes were compared by log-rank analysis. Cox proportional-hazards regression was used to estimate adjusted hazard ratios (HRs). Time at risk was determined from the date of liver biopsy to the date of outcome or last follow-up examination.nnnRESULTSnOver a median follow-up period of 12.6 years (range, 0.3-35.1 y), 193 of the patients (33.2%) died or underwent liver transplantation. Features of liver biopsies significantly associated with death or liver transplantation included fibrosis stage 1 (HR, 1.88; 95% confidence interval [CI], 1.28-2.77), stage 2 (HR, 2.89; 95% CI, 1.93-4.33), stage 3 (HR, 3.76; 95% CI, 2.40-5.89), and stage 4 (HR, 10.9; 95% CI, 6.06-19.62) compared with stage 0, as well as age (HR, 1.07; 95% CI, 1.05-1.08), diabetes (HR, 1.61; 95% CI, 1.13-2.30), current smoking (HR, 2.62; 95% CI, 1.67-4.10), and statin use (HR, 0.32; 95% CI, 0.14-0.70). Twenty-six patients (4.2%) developed liver-related events; fibrosis stage 3 (HR, 14.2; 95% CI, 3.38-59.68) and stage 4 (HR, 51.5; 95% CI, 9.87-269.2) compared with stage 0, were associated significantly with the events. Patients with fibrosis, regardless of steatohepatitis or NAFLD activity score, had shorter survival times than patients without fibrosis.nnnCONCLUSIONSnIn a longitudinal study of patients with NAFLD, fibrosis stage, but no other histologic features of steatohepatitis, were associated independently with long-term overall mortality, liver transplantation, and liver-related events.

Incidence, Presentation, and Outcomes in Patients With Drug-Induced Liver Injury in the General Population of Iceland

BACKGROUND & AIMSnLittle 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.nnnMETHODSnWe 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.nnnRESULTSnThe 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).nnnCONCLUSIONSnIn 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.

The use of liver biopsy evaluation in discrimination of idiopathic autoimmune hepatitis versus drug-induced liver injury.

Distinguishing drug‐induced liver injury (DILI) from idiopathic autoimmune hepatitis (AIH) can be challenging. We performed a standardized histologic evaluation to explore potential hallmarks to differentiate AIH versus DILI. Biopsies from patients with clinically well‐characterized DILI [n = 35, including 19 hepatocellular injury (HC) and 16 cholestatic/mixed injury (CS)] and AIH (n = 28) were evaluated for Ishak scores, prominent inflammatory cell types in portal and intra‐acinar areas, the presence or absence of emperipolesis, rosette formation, and cholestasis in a blinded fashion by four experienced hepatopathologists. Histologic diagnosis was concordant with clinical diagnosis in 65% of cases; but agreement on final diagnosis among the four pathologists was complete in only 46% of cases. Interface hepatitis, focal necrosis, and portal inflammation were present in all evaluated cases, but were more severe in AIH (P < 0.05) than DILI (HC). Portal and intra‐acinar plasma cells, rosette formation, and emperiopolesis were features that favored AIH (P < 0.02). A model combining portal inflammation, portal plasma cells, intra‐acinar lymphocytes and eosinophils, rosette formation, and canalicular cholestasis yielded an area under the receiver operating characteristic curve (AUROC) of 0.90 in predicting DILI (HC) versus AIH. All Ishak inflammation scores were more severe in AIH than DILI (CS) (P ≤ 0.05). The four AIH‐favoring features listed above were consistently more prevalent in AIH, whereas portal neutrophils and intracellular (hepatocellular) cholestasis were more prevalent in DILI (CS) (P < 0.02). The combination of portal inflammation, fibrosis, portal neutrophils and plasma cells, and intracellular (hepatocellular) cholestasis yielded an AUC of 0.91 in predicting DILI (CS) versus AIH. Conclusion: Although an overlap of histologic findings exists for AIH and DILI, sufficient differences exist so that pathologists can use the pattern of injury to suggest the correct diagnosis. (Hepatology 2011;)

Categorization of drugs implicated in causing liver injury: Critical assessment based on published case reports

An important element in assessing causality in drug‐induced liver injury is whether the implicated agent is known to cause hepatotoxicity. We classified drugs into categories based on the number of published reports of convincingly documented, clinically apparent, idiosyncratic liver injury. Drugs described in the website LiverTox (http://livertox.nih.gov) were classified into five categories based on the number of published cases (category A, ≥50; category B, 12‐49; category C, 4‐11; category D, 1‐3; category E, none). Case reports in categories C and D were individually reanalyzed using the Roussel Uclaf Causality Assessment Method. Drugs with fatal cases or with rechallenge were noted. Among 671 individual drugs or closely related agents, 353 (53%) were considered convincingly linked to liver injury in published case reports; 48 (13%) were assigned to category A, 76 (22%) were assigned to category B, 96 (27%) were assigned to category C, and 126 (36%) were assigned to category D. Another 7 (2%) were direct hepatotoxins but only in high doses and placed in a separate category (T). The remaining 318 (47%) drugs had no convincing case report of hepatoxicity in the literature (category E). All except one in category A have been available since 1999, 98% had at least one fatal case and 89% a positive rechallenge. In category B, 54% had a fatal case and 41% a rechallenge. Drugs in categories C and D less frequently had instances of fatal (23% and 7%) or rechallenge cases (26% and 11%). Conclusion: Documentation of hepatoxicity in the medical literature is variable, and many published instances do not stand up to critical review. A standardized system for categorizing drugs for hepatotoxicity potential will help develop objective and reliable, computer‐based instruments for assessing causality in drug‐induced liver injury. (Hepatology 2016;63:590–603)

Risk factors for Clostridium difficile toxin-positive diarrhea: a population-based prospective case–control study

Increased incidence and severity of Clostridium difficile infections (CDIs) is of major concern. However, by minimizing known risk factors, the incidence can be decreased. The aim of this investigation was to calculate the incidence and assess risk factors for CDI in our population. A 1-year prospective population-based nationwide study in Iceland of CDIs was carried out. For risk factor evaluation, each case was matched with two age- and sex-matched controls that tested negative for C. difficile toxin. A total of 128 CDIs were identified. The crude incidence was 54 cases annually per 100,000 population >18xa0years of age. Incidence increased exponentially with older age (319 per 100,000 population >86xa0years of age). Community-acquired origin was 27u2009%. Independent risk factors included: dicloxacillin (odds ratio [OR]: 7.55, 95u2009% confidence interval [CI]: 1.89–30.1), clindamycin (OR: 6.09, 95u2009% CI: 2.23–16.61), ceftriaxone (OR: 4.28, 95u2009% CI: 1.59–11.49), living in a retirement home (OR: 3.9, 95u2009% CI: 1.69–9.16), recent hospital stay (OR: 2.3, 95u2009% CI: 1.37–3.87). Proton pump inhibitors (PPIs) were used by 60/111 (54u2009%) versus 91/222 (41u2009%) (pu2009=u20090.026) and ciprofloxacin 19/111 (17u2009%) versus 19/222 (9u2009%) (pu2009=u20090.027) for cases and controls, respectively. In all, 75u2009% of primary CDIs treated with metronidazole recovered from one course of treatment. CDI was mostly found among elderly patients. The most commonly identified risk factors were broad-spectrum antibiotics and recent contact with health care institutions. PPI use was significantly more prevalent among CDI patients.

Drug-induced liver injury: an overview over the most critical compounds

AbstractnThere has been a substantial interest in drug-induced liver injury (DILI) recently. National Institutes of Health has sponsored a multicenter study in the USA for the last 10xa0years, which has collected valuable information in this context. Idiosyncratic DILI is like other adverse effects of drugs underestimated and underreported in most epidemiological studies. A recent prospective population-based study from Iceland found a crude incidence of approximately 19 cases per 100,000 and year. Antibiotic is the class of drugs most commonly implicated in patients with DILI. Amoxicillin–clavulanate continues to be the most commonly implicated agent occurring in approximately 1 out of 2,300 users. Drugs with the highest risk of DILI in the Icelandic study were azathioprine and infliximab. Although rare, statin-induced hepatotoxicity has been well documented. Liver injury associated with the use of herbal medicines and dietary supplements seems to be increasing. Information on the documented hepatotoxicity of drugs has recently been made easier by a website available in the public domain: LiverTox (http://livertox.nlm.nih.gov). Unfortunately, at the current time, pre-therapy risk assessment for DILI in the individual patient is difficult but previous well-documented hepatotoxicity is usually a contraindication for a subsequent treatment with the same drug.

Risk of Drug-Induced Liver Injury From Tumor Necrosis Factor Antagonists

BACKGROUND & AIMSnAntagonists of tumor necrosis factor (anti-TNF agents) can cause drug-induced liver injury (DILI), yet little is known about the level of risk.nnnMETHODSnWe identified cases of DILI caused by anti-TNF agents in Iceland, from 2009 through 2013, at the National University Hospital of Iceland (nxa0= 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, nxa0= 22).nnnRESULTSnOf 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 (nxa0= 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 (Pxa0= .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.nnnCONCLUSIONSnOf 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.

Long term follow-up and liver-related death rate in patients with non-alcoholic and alcoholic related fatty liver disease

BackgroundFew studies have compared the prognosis and liver-related mortality in patients with NAFLD (nonalcoholic fatty liver disease) and AFLD (alcoholic fatty liver disease). We aimed to investigate the etiology and liver-related mortality of patients with liver biopsy verified fatty liver disease in a population based setting.MethodsIn this retrospective study, all patients who underwent a liver biopsy 1984–2009 at the National University Hospital of Iceland were identified through a computerized pathological database with the code for fatty liver. Only patients with NAFLD and AFLD were included and medical records reviewed. The patients were linked to the Hospital Discharge Register, the Causes of Death Registry and Centre for Addiction Medicine.ResultsA total of 151 had NAFLD and 94 AFLD with median survival of 24xa0years and 20xa0years, respectively (pu2009=u2009NS). A total of 10/151 (7%) patients developed cirrhosis in the NAFLD group and 19/94 (20%) in AFLD group (pu2009=u20090.03). The most common cause of death in the NAFLD group was cardiovascular disease (48%). Liver disease was the most common cause of death in the AFLD group (36%), whereas liver-related death occurred in 7% of the NAFLD group. The mean liver-related death rate among the general population during the study period was 0.1% of all deaths. There was a significantly worse survival for patients in the AFLD group compared to the NAFLD group after adjusting for gender, calendar year of diagnosis and age at diagnosis (HR 2.16, pu2009=u20090.009). The survival for patients with moderate to severe fibrosis was significantly worse than for patients with mild fibrosis after adjusting for gender, calendar year of diagnosis and age at diagnosis (HR 2.09, pu2009=u20090.01).ConclusionsPatients with fatty liver disease showed a markedly higher risk of developing liver-related death compared to the general population. The AFLD group had higher liver-related mortality and had a worse survival than the NAFLD group. Patients with more severe fibrosis at baseline showed a worse survival than patients with none or mild fibrosis at baseline.

Natural history of functional gastrointestinal disorders: Comparison of two longitudinal population-based studies

BACKGROUNDnFunctional gastrointestinal disorders are common but information on their natural history is limited.nnnAIMSnTo document the natural history of functional gastrointestinal disorders in a population based study and to compare with the Olmsted County study.nnnMETHODnA questionnaire was mailed to the same age- and gender-stratified random sample of the Icelandic population aged 18-75 in 1996 and 2006. Results were compared to the Olmsted County study.nnnRESULTSnPrevalence of functional gastrointestinal disorder symptoms was stable between these periods in time: 16.9% and 17.2% for irritable bowel syndrome, and 4.8% and 6.1% for functional dyspepsia. Onset of each disorder was more often higher in the Olmsted County study than in Iceland. Disappearance rates were similar for both studies. Transition probabilities varied across the different subgroups and were different between studies. The same proportion had the same symptoms in the initial and final studies. More subjects had no symptoms in Iceland (52% vs. 40%) and different symptoms at follow up (38% vs. 23%).nnnCONCLUSIONnPrevalence of functional gastrointestinal disorder symptoms was stable over time but the turnover in symptoms was high. A higher number of subjects had no symptoms in Iceland than in Olmsted County and there was a greater variation in subjects having different symptoms at follow up.

Association of symptoms of colon cancer patients with tumor location and TNM tumor stage

Abstract Objective. Colon cancer is the second most common cause of cancer death in Iceland and accounts for 8% of malignancies. We related information on symptoms of colon cancer patients with information on tumor location and pTNM-stage. Material and methods. The study is retrospective and population-based. Information on all patients diagnosed with colon cancer in Iceland in 1995–2004 was obtained. Information on symptoms of patients and blood hemoglobin was collected from patients files. The pathological parameters were derived from a previously performed study. Results. A total of 768 patients (422 males, 346 females) participated in this study. Median age was 73 years. Nearly 60% had anemia at the time of diagnosis, 53% had visible blood in stools, and 65% had changes in bowel habits. Around 84% had visible blood in stools and/or anemia. Of those with right-sided tumors, 75% had anemia and were more likely to be diagnosed incidentally (40%) than those with left-sided tumors (20%). Left-sided tumors were associated with blood in stools (68% compared to 41%, p < 0.05) and changes in bowel habits (74% compared to 57%, p < 0.05). Multivariate analysis indicated that blood in stools was strongly associated with a lower TNM-stage (OR = 0.75, p < 0.05). Anemia was strongly associated with a higher TNM-stage (OR = 1.84, p < 0.05). Conclusion. Right-sided tumors were associated with anemia and incidental diagnosis; left-sided tumors were associated with visible blood in stools and changes in bowel habits. Visible blood in stools was significantly associated with lower TNM-stage, whereas abdominal pain, general and acute symptoms were associated with higher TNM-stage.