Nonalcoholic fatty liver disease (NAFLD) is a process in which fat is deposited in the liver in the absence of significant alcohol consumption or the use of drugs—such as steroids, methotrexate (MTX), tamoxifen, or amiodarone—that facilitate steatosis.1 Certain hereditary conditions such as Wilson disease, abetalipoproteinemia, Wolman disease, and cholesteryl ester storage disease are also incompatible with a diagnosis of NAFLD.1 Once these conditions are excluded, nearly all patients diagnosed with NAFLD share the characteristics associated with metabolic risk, such as obesity, type 2 diabetes mellitus, hypertension, and dyslipidemia. NAFLD and metabolic syndrome share the pathophysiologic mechanism of insulin resistance.2

Two histologic forms of the disease can be distinguished: one is steatosis, in which fat has been deposited but liver cells are not yet damaged, and the other is steatohepatitis, which is characterized by liver inflammation that can eventually lead to fibrosis. Mortality is higher in patients with NAFLD than in the general population, regardless of which of these histologic variants is present; the cause of death is usually cardiovascular disease.3 Because steatohepatitis is an inflammatory condition, the liver is threatened, and 15% to 25% of patients will have progressed to cirrhosis within 10 years. Once cirrhosis develops, complications (liver failure, esophageal varices, and liver cancer) will lead to death in 25% of affected patients within 5 years.4 Why fat deposition causes inflammation and fibrosis in some patients but not others is poorly understood, although genetic and environmental factors are probably both relevant.5

NAFLD is important in the West because it is currently the most prevalent liver disorder. Approximately 20% of adults in the general population have NAFLD, and among them about 20% have the aggressive form, steatohepatitis.6 The prevalence is much higher among adults with metabolic syndrome, where 38% of overweight persons (with a body mass index [BMI] between 25 and 30) have NAFLD. The prevalence rates in obese (BMI, 30–40) and severely obese (BMI, 40–45) persons are 46% and 65%, respectively. Finally, some 90% of morbidly obese patients (BMI>45) have this condition, and 5% of them have cirrhosis. Among diabetics, the prevalence is 69%, and among patients with elevated triglyceride levels, 50%.7 A sign of the seriousness of this situation is that nonalcoholic steatohepatitis is currently the second most common cause of liver transplantation in the United States, and it is expected to become the first cause in the coming years.8

In spite of these statistics, NAFLD is clearly underdiagnosed because there are no signs or symptoms that arouse suspicion except when the disease becomes advanced and also because serum biochemical markers show only slight, nonspecific changes; results may even stay within the normal limits in 15% to 39% of patients.9,10

A diagnosis of NAFLD requires evidence of steatosis by liver biopsy or imaging and the exclusion of alcohol consumption or other general causes of liver disease or conditions that lead to steatosis.1 The first criterion—evidence of steatosis—is critical. The list of causes of liver disease are well established11 while the alternative causes of steatosis are very rare and, in principle, relatively easy to identify. A liver biopsy is the gold standard, but it is invasive, has associated risk of complications and death, and is costly.12 Furthermore, it is not reasonable or even feasible to biopsy 20% of the population. Interest in finding a noninvasive approach to diagnosis is therefore growing. A fatty liver is usually detected through imaging (ultrasound, computed tomography scans, or nuclear magnetic resonance); the sensitivity and specificity of images are 60% and 94%, respectively.13,14 Ultrasound is usually chosen because it is innocuous and widely available.1 However, neither liver enzymes nor images can distinguish between steatosis and steatohepatitis. Nor can they establish or rule out the presence of fibrosis. Various scoring systems using the results of serum tests have therefore been developed. The most widely accepted is the NAFLD fibrosis score,15 which is calculated according to a formula (http://nafldscore.com) based on easy-to-obtain measurements: BMI; age; platelet count; and serum albumin, aspartate transaminase (AST), and alanine transaminase (ALT) (Table 1). Moreover, this score is highly sensitive (67%) and specific (60%) for excluding (67%) or detecting (97%) the presence of advanced fibrosis using an area under the receiver operating characteristic curve of 0.85 as the cutoff. The severity of liver damage can also potentially be assessed by measuring liver stiffness indirectly with elastography. The usefulness of this approach would mainly be to identify patients at low risk of advanced fibrosis or cirrhosis given the test's lack of precision when disease is advanced.16

The European Association for the Study of the Liver, the European Association for the Study of Diabetes, and the European Association for the Study of Obesity have recently published new joint guidelines for managing NAFLD.17 They recommend that all patients with insulin resistance or risk factors for metabolic syndrome be screened for NAFLD by ultrasound and liver biochemistry. Any increase in AST, ALT, and/or γ-glutamyltransferase are relevant, regardless of magnitude. The screening algorithm is shown in Fig. 1.17

Figure 1.

Nonalcoholic fatty liver disease (NAFLD) in patients with psoriasis. Adapted from clinical guidelines.17

a Aspartate transaminase (ASP), alanine transaminase (ALT), and γ-glutamyltransferase (GGT).

bAny increase in ASP, ALT, and/or GGT.

(0.21MB).

The first observational studies showing an association between NAFLD and psoriasis began to appear during the last 10 years,25,26 and the association has since been confirmed.27,28 Gisondietal.25 saw a higher rate of ultrasound-diagnosed NAFLD (47%) in a series of 130 consecutive patients with psoriasis than in 260 healthy controls (28%) matched for age, sex, and BMI. The psoriasis patients were also more likely to have metabolic syndrome and higher C-reactive protein levels; those who also had NAFLD had higher interleukin (IL) 6 and lower adiponectin levels than those without the disease. Abedinietal.28 reported finding NAFLD in 65.6% of patients with psoriasis (vs 35% of healthy controls), and vanderVoortetal.27 found that 46.2% of psoriatic patients and 33.3% of controls had NAFLD in a population-based series of 2292 persons over the age of 55 years in Rotterdam. These findings may be attributable to the association between psoriasis and metabolic syndrome, given that the conditions defining the latter are those that lead to NAFLD.29 Mieleetal.26 studied a cohort of psoriasis patients with and without NAFLD, finding that NAFLD was also associated with psoriatic arthritis. Robertsetal.30 reported finding a relationship between greater severity of psoriasis and NAFLD. Specifically, they saw steatohepatitis in 22% of the patients with both psoriasis and NAFLD who underwent liver biopsy. The NAFLD patients with steatohepatitis were also more likely to be obese and have higher insulin and transaminase levels; they also found marked differences in risk for NAFLD according to ethnic origin. Similarly, vanderVoortetal.27 found that patients of Latin American origin carried greater risk (83%), followed by Caucasians (39%), and finally African Americans (33%).

TNF plays a central role in the inflammatory process in NAFLD, as in other chronic inflammatory diseases.45 In fact, TNF has been studied for its potential use as a diagnostic and prognostic tool in NAFLD.46 Given the pathogenic role of this cytokine, anti-TNF agents such as infliximab and adalimumab have also been tried in this setting47,48 because of improvements observed in liver and metabolic biomarkers after biologic therapy for other inflammatory diseases.49,50

Biologics have a better safety profile than the conventional treatments for NAFLD mentioned earlier. For example, when adalimumab was used for an average of 5 years in 32 patients with liver disease and psoriasis, no cases of liver disease progression or development of liver toxicity were observed.51

Biologic therapy could exercise regulatory effects on some adipocytokines. Shibataetal.52 reported an increase in adiponectin and IL-6 levels during treatment with infliximab, and adalimumab and etanercept may inhibit proinflammatory adipocytokines.53

Studies of the impact of anti-TNF agents on the lipid profile, a risk factor for NAFLD, have yielded inconsistent results. While some authors have not been able to demonstrate a significant effect, others have reported elevated triglycerides and lower high-density lipoprotein (HDL) cholesterol levels in patients with infliximab-treated psoriatic arthritis.54 Etanercept therapy, on the other hand, has favorably modulated the antioxident and anti-inflammatory properties of HDL cholesterol as well as modulated adipolipoprotein A1 and B levels, reducing lipid peroxidation.55

Marra et al.56 showed improved insulin sensitivity in patients treated with etanercept for psoriasis, an effect that could potentially have a favorable influence on the course of NAFLD.

It must be borne in mind that anti-TNF agents can occasionally induce autoimmune or drug-related hepatitis.57 The risk is very low, however. Only 20 cases of autoimmune hepatitis have ever been reported; most were mild cases associated with infliximab and responded quickly to steroid treatment.41 Anti-TNF agents have also been linked to weight gain in psoriasis patients, although the gains have generally been modest. However, long-term use has led to considerable gain in some patients, and this adverse effect potentially aggravates the obesity associated with severe psoriasis and NAFLD.58

High transaminase levels were detected in 6 patients in a series of 44 treated with ustekinumab for an average of 46.7 months.59 Five of the 6 patients developed hepatotoxicity related to other drugs, 3 developed fatty liver, and 3 were receiving other hepatotoxic drugs while taking ustekinumab. The authors concluded that ustekinumab-related toxicity was mild and uncommon. Hepatotoxicity is not described as a side effect detected in clinical trials of secukinumab60 (Table 2).

NAFLD is the most frequent liver disorder in the West (Table 3). Patients with psoriasis have a higher prevalence of NAFLD, a higher rate of severe disease, and a worse prognosis. Dermatologists should routinely evaluate psoriasis patients for NAFLD. The pathogenic links between psoriasis and NAFLD are chronic inflammation and peripheral insulin resistance, which is a common finding in diseases associated with psoriasis. The dermatologist should be aware not only of the high prevalence of NAFLD in psoriasis but also of the possibility of steatohepatitis, especially when psoriasis is severe or when there are signs of metabolic syndrome. Psoriasis patients with insulin resistance or risk factors for metabolic syndrome should be specifically evaluated for fatty liver by abdominal ultrasound and liver biochemistry. Concurrent psoriasis and NAFLD, and the likely synergy between them, affect the general recommendations we can make and the treatment strategies we can adopt. Some drugs carry risk of hepatotoxicity. On the other hand, there is a possibility that achieving good control of inflammation and pathogenic factors associated with NAFLD will improve the prognosis.

Abbvie sponsored the meetings of the working group, but no employees of the laboratory participated in the research, interpretation, discussion, or drafting of the text.

J. M. Carrascosa has served as a consultant, given invited talks, and/or participated in clinical trials sponsored by the following laboratories: Abbvie, Janssen, Lilly, Pfizer, Novartis, Pfizer, and Celgene.