Patrik Nasr

Fibrosis stage is the strongest predictor for disease-specific mortality in NAFLD after up to 33 years of follow-up

Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease in the Western world, strongly associated with insulin resistance and the metabolic syndrome. Nonalcoholic steatohepatitis, i.e., fatty liver accompanied by necroinflammatory changes, is mostly defined by the NAFLD activity score (NAS). The aim of the current study was to determine disease‐specific mortality in NAFLD, and evaluate the NAS and fibrosis stage as prognostic markers for overall and disease‐specific mortality. In a cohort study, data from 229 well‐characterized patients with biopsy‐proven NAFLD were collected. Mean follow‐up was 26.4 (±5.6, range 6‐33) years. A reference population was obtained from the National Registry of Population, and information on time and cause of death were obtained from the Registry of Causes of Death. NAFLD patients had an increased mortality compared with the reference population (hazard ratio [HR] 1.29, confidence interval [CI] 1.04‐1.59, P = 0.020), with increased risk of cardiovascular disease (HR 1.55, CI 1.11‐2.15, P = 0.01), hepatocellular carcinoma (HR 6.55, CI 2.14‐20.03, P = 0.001), infectious disease (HR 2.71, CI 1.02‐7.26, P = 0.046), and cirrhosis (HR 3.2, CI 1.05‐9.81, P = 0.041). Overall mortality was not increased in patients with NAS 5‐8 and fibrosis stage 0‐2 (HR 1.41, CI 0.97‐2.06, P = 0.07), whereas patients with fibrosis stage 3‐4, irrespective of NAS, had increased mortality (HR 3.3, CI 2.27‐4.76, P < 0.001). Conclusion: NAFLD patients have increased risk of death, with a high risk of death from cardiovascular disease and liver‐related disease. The NAS was not able to predict overall mortality, whereas fibrosis stage predicted both overall and disease‐specific mortality. (Hepatology 2015;61:1547–1554)

Increased risk of mortality by fibrosis stage in nonalcoholic fatty liver disease: Systematic review and meta‐analysis

Liver fibrosis is the most important predictor of mortality in nonalcoholic fatty liver disease (NAFLD). Quantitative risk of mortality by fibrosis stage has not been systematically evaluated. We aimed to quantify the fibrosis stage–specific risk of all‐cause and liver‐related mortality in NAFLD. Through a systematic review and meta‐analysis, we identified five adult NAFLD cohort studies reporting fibrosis stage–specific mortality (0‐4). Using fibrosis stage 0 as a reference population, fibrosis stage–specific mortality rate ratios (MRRs) with 95% confidence intervals (CIs) for all‐cause and liver‐related mortality were estimated. The study is reported according to the Preferred Reporting Items for Systematic Reviews and Meta‐Analyses statement. Included were 1,495 NAFLD patients with 17,452 patient years of follow‐up. Compared to NAFLD patients with no fibrosis (stage 0), NAFLD patients with fibrosis were at an increased risk for all‐cause mortality, and this risk increased with increases in the stage of fibrosis: stage 1, MRR = 1.58 (95% CI 1.19‐2.11); stage 2, MRR = 2.52 (95% CI 1.85‐3.42); stage 3, MRR = 3.48 (95% CI 2.51‐4.83); and stage 4, MRR = 6.40 (95% CI 4.11‐9.95). The results were more pronounced as the risk of liver‐related mortality increased exponentially with each increase in the stage of fibrosis: stage 1, MRR = 1.41 (95% CI 0.17‐11.95); stage 2, MRR = 9.57 (95% CI 1.67‐54.93); stage 3, MRR = 16.69 (95% CI 2.92‐95.36); and stage 4, MRR = 42.30 (95% CI 3.51‐510.34). Limitations of the study include an inability to adjust for comorbid conditions or demographics known to impact fibrosis progression in NAFLD and the inclusion of patients with simple steatosis and nonalcoholic steatohepatitis without fibrosis in the reference comparison group. Conclusion: The risk of liver‐related mortality increases exponentially with increase in fibrosis stage; these data have important implications in assessing the utility of each stage and benefits of regression of fibrosis from one stage to another. (Hepatology 2017;65:1557‐1565).

Fibrosis stage but not NASH predicts mortality and time to development of severe liver disease in biopsy-proven NAFLD

BACKGROUND & AIMS Non-alcoholic fatty liver disease (NAFLD) is very common in the general population, but identifying patients with increased risk of mortality and liver-specific morbidity remains a challenge. Non-alcoholic steatohepatitis (NASH) is thought to enhance this risk; therefore, resolution of NASH is a major endpoint in current pharmacologic studies. Herein, we aim to investigate the long-term prognosis of a large cohort of NAFLD patients, and to study the specific effect of NASH and fibrosis stage on prognosis. METHODS We conducted a retrospective cohort study of 646 biopsy-proven NAFLD patients. Each case was matched for age, sex and municipality to ten controls. Outcomes on mortality and severe liver disease, defined as cirrhosis, liver decompensation/failure or hepatocellular carcinoma, were evaluated using population-based registers. Cox regression models adjusted for age, sex and type 2 diabetes were used to examine the long-term risk according to fibrosis stage. Likelihood ratio tests were used to assess whether adding NASH to these models increased the predictive capacity. Laplace regression was used to estimate the time to severe liver disease according to stage of fibrosis. RESULTS During a follow-up of mean 20years (range 0-40) equivalent to 139,163 person-years, 12% of NAFLD patients and 2.2% of controls developed severe liver disease (p<0.001). Compared to controls, the risk of severe liver disease increased per stage of fibrosis (hazard ratio ranging from 1.9 in F0 to 104.9 in F4). Accounting for the presence of NASH did not change these estimates significantly (likelihood ratio test >0.05 for all stages of fibrosis). Similar results were seen for overall mortality. The lower end of the 95% confidence interval for the 10th percentile of time to development of severe liver disease was 22-26years in F0-1, 9.3years in F2, 2.3years in F3, and 0.9years to liver decompensation in F4. CONCLUSIONS In this, the largest ever study of biopsy-proven NAFLD, the presence of NASH did not increase the risk of liver-specific morbidity or overall mortality. Knowledge of time to development of severe liver disease according to fibrosis stage can be used in individual patient counselling and for public health decisions. LAY SUMMARY Non-alcoholic fatty liver disease (NAFLD) is very common in the general population, but reaching an accurate prognosis remains challenging. We investigate the long-term prognosis of a large cohort of NAFLD patients. In this, the largest ever study of biopsy-proven NAFLD, the presence of NASH did not increase the risk of liver-specific morbidity or overall mortality. Knowledge of time to development of severe liver disease according to fibrosis stage can be used in individual patient counselling and for public health decisions.

Low to moderate lifetime alcohol consumption is associated with less advanced stages of fibrosis in non-alcoholic fatty liver disease

Abstract Background and aim: Moderate alcohol consumption has been associated with a lower risk of disease severity in non-alcoholic fatty liver disease (NAFLD). It is unclear if this reflects current or lifetime drinking, or can be attributed to confounders such as diet and exercise. We evaluated the impact of lifetime alcohol consumption on fibrosis severity in NAFLD. Methods: We prospectively enrolled 120 subjects with biopsy-proven NAFLD and through detailed questionnaires examined lifetime alcohol consumption, diet and physical activity. Main outcome measures were odds ratios (OR) for fibrosis stage, calculated through ordinal regression after adjustment for body mass index, diabetes mellitus type 2, smoking and age at biopsy. A biomarker for recent alcohol consumption, phosphatidyl ethanol (PEth) was sampled. Results: An increase in median weekly alcohol consumption to a maximum of 13 drinks per week was associated with lower fibrosis stage (adjusted OR for each incremental unit, 0.86; 95% CI, 0.76–0.97; p = .017). The lowest risk for fibrosis was found with the lowes`t odds seen in the top quartile of alcohol consumption (aOR 0.23; 95% CI 0.08–0.66; p = .006). Adding soft drink and coffee consumptions, and physical activity to the model did not change the estimates. Subjects with PEth ≥0.3 μmol/L had higher ORs for a higher fibrosis stage (aOR 2.77; 95% CI 1.01–7.59; p = .047). Conclusion: Lifetime alcohol consumption with up to 13 units per week is associated with lower fibrosis stage in NAFLD. Elevated PEth is associated with higher stages of fibrosis.

SAF score and mortality in NAFLD after up to 41 years of follow-up

Abstract Background and aims: A new score for the histological severity of nonalcoholic fatty liver disease (NAFLD), called SAF (Steatosis, Activity and Fibrosis) has been developed. We aimed to evaluate the impact of this score on overall mortality. Methods: We used data from 139 patients with biopsy-proven NAFLD. All biopsies were graded according to the SAF scoring system and disease severity was classified as mild, moderate or severe. Causes of death were extracted from a national, population-based register. A Cox regression model, adjusted for sex, body mass index (BMI) and diabetes mellitus type 2, was applied. Results: At baseline 35 patients presented with mild or moderate disease respectively, and 69 patients with severe disease. During follow-up (median 25.3 years, range 1.7–40.8) 74 patients died, 11 in the mild group (31%), 18 in the moderate group (51%) and 45 in the severe group (65%), p = .002. Compared to patients with mild disease, patients with moderate disease did not have a significant increase in overall mortality (HR 1.83, 95%CI 0.89–3.77, p = .10). Patients with severe disease had a significant increase in mortality (HR 2.65, 95%CI 1.19–5.93, p = .017). However, when adjusting for fibrosis stage, significance was lost (HR 1.85, 95%CI 0.76–4.54, p = .18). NASH, defined as per the FLIP algorithm, was not associated with mortality compared to not having NASH (HR 1.46, 95%CI 0.74–2.90, p = .28). Conclusions: After adjustment for fibrosis, the SAF score was not associated with increased mortality in NAFLD. This finding should be corroborated in larger cohorts with similar follow-up time.

Elevated serum ferritin is associated with increased mortality in non-alcoholic fatty liver disease after 16 years of follow-up

High levels of ferritin in patients with non‐alcoholic fatty liver disease (NAFLD) are associated with significant fibrosis and higher NAFLD activity score (NAS). It is unclear if this association has an impact on mortality. We investigated if high levels of ferritin, with or without iron overload, were associated with an increased mortality in NAFLD.

Risk for development of severe liver disease in lean patients with nonalcoholic fatty liver disease: A long-term follow-up study

Most patients with nonalcoholic fatty liver disease (NAFLD) are overweight or obese. However, a significant proportion of patients have a normal body mass index (BMI), denoted as lean NAFLD. The long‐term prognosis of lean NAFLD is unclear. We conducted a cohort study of 646 patients with biopsy‐proven NAFLD. Patients were defined as lean (BMI < 25.0), overweight (BMI 25.0‐29.9), or obese (BMI ≥ 30.0) at the time of biopsy. Each case was matched for age, sex, and municipality to 10 controls. Overall mortality and development of severe liver disease were evaluated using population‐based registers. Cox regression models adjusted for age, sex, type 2 diabetes, and fibrosis stage were used to examine the long‐term risk of mortality and liver‐related events in lean and nonlean NAFLD. Lean NAFLD was seen in 19% of patients, while 52% were overweight and 29% were obese. Patients with lean NAFLD were older, had lower transaminases, lower stages of fibrosis, and lower prevalence of nonalcoholic steatohepatitis at baseline compared to patients with a higher BMI. During a mean follow‐up of 19.9 years (range 0.4‐40 years) representing 12,631 person years and compared to patients who were overweight, patients with lean NAFLD had no increased risk for overall mortality (hazard ratio 1.06; P =  0.73) while an increased risk for development of severe liver disease was found (hazard ratio 2.69; P =  0.007). Conclusion: Although patients with lean NAFLD have lower stages of fibrosis, they are at higher risk for development of severe liver disease compared to patients with NAFLD and a higher BMI, independent of available confounders. (Hepatology Communications 2018;2:48–57)

Natural history of nonalcoholic fatty liver disease: A prospective follow‐up study with serial biopsies

Nonalcoholic fatty liver disease (NAFLD) is the most prevalent chronic liver disease in the world. The complete natural history of NAFLD is unknown because few high‐quality follow‐up studies have been conducted. Our aim was to find variables predicting disease severity through an extended follow‐up with serial biopsies. In a prospective cohort study, 129 patients who enrolled between 1988 and 1993 were asked to participate in a follow‐up study on two occasions; biochemical, clinical, and histologic data were documented. The mean time between biopsies was 13.7 (±1.7) and 9.3 (±1.0) years, respectively. At the end of the study period, 12 patients (9.3%) had developed end‐stage liver disease and 34% had advanced fibrosis. Out of the 113 patients with baseline low fibrosis (<3), 16% developed advanced fibrosis. Fibrosis progression did not differ among the different stages of baseline fibrosis (P = 0.374). Fifty‐six patients (43%) had isolated steatosis, of whom 9% developed advanced fibrosis (3 patients with biopsy‐proven fibrosis stage F3‐F4 and 2 patients with end‐stage liver disease). Fibrosis stage, ballooning, and diabetes were more common in patients who developed end‐stage liver disease; however, there were no baseline clinical, histologic, or biochemical variables that predicted clinical significant disease progression. Conclusion: NAFLD is a highly heterogeneous disease, and it is surprisingly hard to predict fibrosis progression. Given enough time, NAFLD seems to have a more dismal prognosis then previously reported, with 16% of patients with fibrosis stage <3 developing advanced fibrosis and 9.3% showing signs of end‐stage liver disease. (Hepatology Communications 2018;2:199–210)

Automated quantification of steatosis: agreement with stereological point counting

BackgroundSteatosis is routinely assessed histologically in clinical practice and research. Automated image analysis can reduce the effort of quantifying steatosis. Since reproducibility is essential for practical use, we have evaluated different analysis methods in terms of their agreement with stereological point counting (SPC) performed by a hepatologist.MethodsThe evaluation was based on a large and representative data set of 970 histological images from human patients with different liver diseases. Three of the evaluated methods were built on previously published approaches. One method incorporated a new approach to improve the robustness to image variability.ResultsThe new method showed the strongest agreement with the expert. At 20× resolution, it reproduced steatosis area fractions with a mean absolute error of 0.011 for absent or mild steatosis and 0.036 for moderate or severe steatosis. At 10× resolution, it was more accurate than and twice as fast as all other methods at 20× resolution. When compared with SPC performed by two additional human observers, its error was substantially lower than one and only slightly above the other observer.ConclusionsThe results suggest that the new method can be a suitable automated replacement for SPC. Before further improvements can be verified, it is necessary to thoroughly assess the variability of SPC between human observers.

Natural History of NAFLD/NASH

Purpose of ReviewThe purpose of this review is to summarize the latest knowledge on the natural history of non-alcoholic fatty liver disease (NAFLD). The review focuses on mortality, liver-related complications, and histological course.Recent FindingsStudies during the last decade have established NAFLD as a potentially progressive liver disease. Age and diabetes are the strongest clinical predictors of progressive disease. Fibrosis stage is the most important histological variable to predict mortality and liver-related complications. So far, no study has been able to show that non-alcoholic steatohepatitis at baseline predicts mortality or future liver-related complications when adjusting for fibrosis.SummaryThe outlines of the natural history of NAFLD have become clearer during the last decade. There is limited data on factors that predict clinical progression. Prospective longitudinal studies are needed to help us predict worse outcome in individual patients.