Non-alcoholic fatty liver disease is often caused by obesity and affects nearly 25 percent of U.S. and European adults


Non-alcoholic fatty liver disease, NAFLD, affects nearly one in four adults in Europe and the U.S. Earlier research has demonstrated an increased risk of death in patients with NAFLD and advanced fibrosis or cirrhosis.

Now, researchers at Karolinska Institutet in Sweden and Massachusetts General Hospital in the U.S. show that mortality increases with disease severity, but even mild fatty liver disease is linked to higher mortality.

The findings have been published in the scientific journal Gut.

Non-alcoholic fatty liver disease is often caused by obesity and affects nearly 25 percent of U.S. and European adults. It represents the most common cause of chronic liver disease in Western countries. Small clinical studies have demonstrated that among patients with NAFLD, advanced liver fibrosis is the most important histological predictor of mortality, but until now, population-level data have been missing from cohorts with liver histology.

Given the growing burden of NAFLD, researchers at Karolinska Institutet and Massachusetts General Hospital matched 10,568 individuals with biopsy-confirmed NAFLD to general population controls through Sweden’s comprehensive, nationwide registers.

They found that all stages of NAFLD were associated with excess mortality risk, even early stages of disease. This risk was driven primarily by deaths from extra-hepatic cancer and cirrhosis, while the risks of cardiovascular mortality or hepatocellular carcinoma (HCC) mortality were relatively modest.

Patients with NAFLD had a 93 percent increased risk of all-cause mortality, but the numbers varied with disease severity. The risk increased progressively from the mildest form of NAFLD (simple steatosis), to non-fibrotic steatohepatitis (NASH), to non-cirrhotic fibrosis and to severe NAFLD with liver cirrhosis.

“This is the first nationwide cohort study with detailed liver histology data to confirm that NAFLD contributes to an increased risk of all-cause mortality,” says first author, Tracey G. Simon, researcher and hepatologist at Massachusetts General Hospital. “

These findings should be used to develop more targeted interventions designed to reduce mortality, in patients with NAFLD.

We need public health strategies that prevent both extra-hepatic cancer and NAFLD progression to cirrhosis, for this rapidly growing population.”

The study builds on the ESPRESSO cohort (Epidemiology Strengthened by Histopathology Reports in Sweden). Histopathology data from more than two million people have been linked to nationwide Swedish registers such as the Patient Register, the Cause of Death Register, the Prescribed Drug Register and the Cancer Register.

“Through contacting all pathology departments in Sweden, we have managed to construct a nationwide gastrointestinal histopathology cohort that allows us to examine a range of gastrointestinal diseases, including NAFLD,” says last author Jonas F. Ludvigsson, pediatrician at Örebro University Hospital and professor at the Department of Medical Epidemiology and Biostatistics, Karolinska Institutet. “The current study on NAFLD and risk of death is the 17th study published this year that takes advantage of the ESPRESSO cohort.”

Epidemiology of NAFLD

NAFLD is an umbrella term for the liver diseases that are characterized primarily by storage of excess macro vesicular fat (>5% of the hepatocytes) because of a perturbation of the homeostatic mechanisms that regulate synthesis versus utilization of fat in the liver (7,15,16).

Diagnosis of NAFLD currently needs an exclusion of a history of more than moderate alcohol intake and absence of drug exposure as well as defined genetic disorders that can culminate in a similar phenotype of fatty liver (24).

This “negative” definition of NAFLD underscore the fact that we still lack a specific biological marker that could precisely characterize the condition, setting it aside from similar pathologies that differ in pathogenesis as well as outcome (25).

A subset of individuals with NAFLD develop progressive liver disease, marked by hepatocyte injury (ballooning), inflammation and finally, fibrosis, an entity designated as non-alcoholic steatohepatitis (NASH) (24,25). Presence and the grade of Fibrosis are most important prognostic determinant in NAFLD and NASH is classically considered to be the phenotype of NAFLD that underlie development of progressive liver disease, particularly fibrosis and therefore, is clinically relevant (26-29).

However, clinical, epidemiological and therapeutic intervention studies have brought forth the primacy of excess fat storage, not only as the “soil” but also in view of the fact that fat itself may progress to fibrosis with minimal evident inflammation—a condition coined as ‘Non-alcoholic steatohepatitis” (30).

The public health importance of NAFLD stems from its’ multifaceted impact on morbidity, mortality and health care utilization globally (8,21,25). NAFLD and particularly, NASH fibrosis is associated with an excess all-cause mortality and also liver related mortality in general population.

NASH is an important cause of chronic liver disease, cirrhosis of the liver (often included in the cryptogenic basket) and hepatocellular carcinoma, often developing in non-cirrhotic livers (31-33) too. NASH is also an important underlying etiology for acute on chronic liver failure (ACLF).

NASH is the fastest emerging cause of liver transplantation in the United states, UK and also in the developing countries (25,32). Intriguingly however, most deaths in NAFLD are due to cardiovascular disease while overall cancer mortality is also increased in NAFLD (31).

The excess cardiovascular risk in fatty liver has been reported even in populations with relatively low background adiposity as measured by BMI, indicating a biological link between the insulin resistance (IR) is the cellular abnormality that underlies the diverse disorders that are popularly placed under the term metabolic syndrome (MS) (34).

Chronic indolent inflammation associated with MS, an entity often called “meta inflammation”, connects the different non-communicable diseases (NCD) together. NAFLD is therefore the hepatic expression of a systemic disorder in which aberrant insulin action and resultant altered metabolic flux cause underlie inflammation that span multiple tissues and organ systems. NAFLD epidemiology is intricately linked with the changing burden and epidemiology of NCD s that is currently underway globally (35).

One of the important caveats of NAFLD epidemiology is non-availability of a disease—specific biomarker that is powerful and simple for large scale population-based studies. The clinically relevant subset of NAFLD, NASH and fibrosis, are mostly histologically defined entities and therefore, are difficult to estimate in the epidemiological context (36-39).

Non-invasive serum markers, used singly or in panels, as well as various imaging modalities, particularly magnetic resonance (MR), has been used in select studies for an assessment of the burden of clinically relevant NAFLD (38-40).

However, serum markers still lack uniformity, standardization across populations and are yet to receive wide acceptance in epidemiological studies although they are promising. MRI and transient elastography based methods can measure fat and liver fibrosis with fair precision and reproducibility but are difficult to use in large scale epidemiological setting in view of the cost, limited availability of equipment and for MR, lack of expertise.

As a result, most of the available epidemiological data on NAFLD are ultrasound based that detect liver fat in a semi quantitative manner. In addition, ALT as a surrogate of liver injury, has also been used in some studies despite its’ nonspecific nature in view of its’ simplicity and wide availability.

In general, studies requiring abnormal liver blood tests to make the diagnosis of NAFLD have reported much lower prevalence estimates compared with studies that use imaging methods (36,41).


Estimates of incidence of NAFLD (new onset NAFLD in people who did not have it earlier over a defined period of time) are even sparse in view of the longitudinal nature of such studies as well as inherent difficulty of non-availability of a non-invasive biomarker that would detect NAFLD when used repetitively, reproductively with precision and ease of use in large scale population available studies are heterogeneous in terms of methods and data (54-58).

In a study that followed 11,448 subjects for 5 years, incidence of NAFLD documented by ultrasound was 12% (n=51,418). A study from Israel reported an incidence rate of 28 per 1,000 person-years. The most meticulously performed study in this respect had been in an Asian population in Hongkong and used MR-spectroscopy that measures fat with maximum accuracy, reporting an incidence of 13.5% over a period of 3–5 years.

In an analysis of 237 studies from Asia (18 studies included for incidence analysis), the pooled annual NAFLD incidence rate was 50.9 cases per 1,000 person-years (95% CI: 44.8–57.4). In patients with NAFLD, the annual incidence of hepatocellular carcinoma was 1.8 cases per 1,000 d person years (95% CI: 0.8–3.1) and overall mortality rate was 5.3 deaths per 1,000 person-years (95% CI: 1.5–11.4).

Another analytical study on the burden and trends of NAFLD globally observed that the pooled regional NAFLD incidence rate estimates for Asia and Israel were 52.34 per 1,000 (95% CI: 28.31–96.77) and 28.01 per 1,000 person-years (95% CI: 19.34–40.57) respectively.

Similar studies are available in western population also although using different methodologies. A study based on liver enzymes as a surrogate in a US population under 45 years reported annual rate of increase of ALT elevations from 2.3% to 4.2% (almost 90% increase). In an ultrasound based follow up study over 8.6 years from Italy, the incidence of NAFLD was 18.5 years 1,000 person years.

reference link :

More information: Tracey G Simon et al. Mortality in biopsy-confirmed nonalcoholic fatty liver disease: results from a nationwide cohort, Gut (2020). DOI: 10.1136/gutjnl-2020-322786


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