Approximately 125 million people worldwide (1%–3% of the world's population) have psoriasis, and more than 1 million of these are in Spain (2.69% of the country's population).1,2 Psoriasis is a systemic inflammatory disease that works synergistically with other immune-mediated inflammatory diseases.2,3 Understanding the impact of associated comorbidities is essential for enabling comprehensive clinical management.2

One of the comorbidities associated with psoriasis is what has to date been known as nonalcoholic fatty liver disease. In this review, we will refer to this disease using the new term agreed on by the Spanish Association for the Study of the Liver (AEEH) following a Delphi process: metabolic-associated fatty liver disease, or MAFLD.4 MAFLD comprises a spectrum of hepatic lesions ranging from fat accumulation in the liver, which is a metabolic disorder considered to have a low risk of progression, to steatohepatitis, an inflammatory disorder that can progress to cirrhosis and its complications. MAFLD is generally asymptomatic and occurs in association with metabolic syndrome (MetS).5 It is in fact recognized as the hepatic manifestation of this syndrome and can precede other manifestations.6,7 MetS is a group of metabolic disorders among which hepatic disorders are considered particularly significant.6,7 MALFD has a wide clinical spectrum (Fig. 1) with a dynamic course characterized by periods of progression, regression, and stability.8,9 This variability can in part be explained by genetics and lifestyle changes, but factors such as age, sex, race, alcohol consumption, and gut microbiota also influence clinical presentation and responses to treatment.5

Figure 1.

Progression of metabolic-associated fatty liver disease. From steatosis (stable, with little risk of progression, characterized by the accumulation of intracellular fat in the hepatocyte) to nonalcoholic steatohepatitis (NASH) (fat accumulation accompanied by inflammatory changes and cell damage) and hepatic fibrosis (collagen deposition in the form of fibrous septa that cause architectural remodeling and progressive hepatocyte dysfunction). Fibrosis predisposes to the development of cirrhosis (fibrotic septa and regeneration nodules) and hepatocelular carcinoma and/or liver failure.6,8,10,12–14

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The prevalence of MALFD is rising progressively, in line with that of MetS, obesity, and type 2 diabetes.8,10 MALFD is estimated to affect 25% of the population and 55.5% of people with type 2 diabetes. Although the percentage of patients with MALFD who develop nonalcoholic steatohepatitis (NASH) is unknown, it is in excess of 10%. The prevalence of biopsy-proven NASH in patients with MAFLD appears to have increased in recent years from 29.9% to 59.1%.5

NASH progresses to fibrosis in 40.76% of cases.8 The estimated prevalence of MAFLD in Spain is 25.8%, while that of significant fibrosis estimated by sequential combination of transition elastography (TE) and liver biopsy is 2.8%.10

Prognosis in MALFD is influenced by progression to NASH, fibrosis, and comorbidities. Advanced fibrosis increases the risk of liver-related morbidity and mortality.10,11 MALFD thus constitutes a significant health problem and a major reason for liver transplantation.9,12

The evidence supporting the relationship between psoriasis and MAFLD is substantial.15 In general, MAFLD is more common in patients with more severe psoriasis.16,17 Phan et al.,15 corroborating previous findings,18 showed that patients with psoriasis were twice as likely to have MAFLD as those without psoriasis. In Spain, the percentage of patients with psoriasis and MAFLD is 42.3%.19 A direct correlation has also been observed between psoriasis severity and liver disease severity.20 One cross-sectional study found that advanced fibrosis was more common in patients with psoriasis than in healthy controls, and that psoriasis was a significant predictor of advanced liver fibrosis independently of age, sex, body mass index, hypertension, and diabetes.21 Psoriasis is currently recognized as an independent risk factor for MAFLD.22,23 Likewise, hypertension, hyperglycemia, and obesity are the main risk factors for MAFLD in patients with psoriasis. The association between psoriasis and MAFLD is independent of confounders, confirming a shared pathophysiology involving inflammatory pathways and genetic predisposition.15 Psoriasis and MAFLD have a common etiology of low-intensity chronic inflammation involving adipokines that participate in energy balance and inflammatory cytokines (interleukin [IL] 17, tumor necrosis factor-α, and IL-6]).3,24,25

The above findings suggest that early screening for MAFLD is necessary in patients with psoriasis.26 The AEEH recently published a consensus statement on the detection of prevalent occult liver diseases and referral criteria. Among its conclusions with clinical implications were 1) chronic liver disease should be screened for and monitored in patients with immune-mediated skin disorders and 2) chronic liver disease is more common in this setting due to immunological and inflammatory mechanisms and hepatotoxicity.26

To encourage multidisciplinary management and update current recommendations on screening, diagnosis, monitoring, and referral for MAFLD in patients with psoriasis, we formed an expert panel to design a set of consensus-based recommendations based on current evidence and real-world experience.

A working group of 12 experts with experience in the management of psoriasis and MAFLD—7 dermatologists and 5 hepatologists—was formed to prepare this document. The methodology was based on the so-called formal method.27,28 The group began by reviewing the current evidence and completing several purpose-designed questionnaires on psoriasis and risk of liver disease to identify key points related to detection, screening, diagnosis, and management. Over the course of 3 meetings, the group analyzed clinical aspects related to the definition and management of at-risk patients. At a final meeting, they agreed on an algorithm for managing these patients, which included practical diagnostic and monitoring recommendations based on the main clinical practice guidelines (CPGs) and the clinical experience of the members of the panel.

Screening Recommendations for MetS

Once an at-risk patient is identified, the first step in the proposed screening and follow-up algorithm (Fig. 2) should be applied.

Figure 2.

Screening algorithm for patients at risk of MAFLD. Depending on the situation of each hospital and test availability, the dermatology department can order TE or refer the patient to the gastroenterology department. MAFLD indicates metabolic-associated fatty liver disease; FIB-4, Fibrosis-4 Index for Liver Fibrosis; HFS, Hepamet Fibrosis Score; TE, transient elastography. aTE should be performed to evaluate the risk of fibrosis in patients with a low FIB-4 score and under a potentially hepatotoxic treatment.

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Consensus is lacking on which noninvasive diagnostic tools, or cutoffs (Table 1), should be used instead of liver biopsy to screen for MAFLD.10,22,31 Liver biopsy is the current gold standard,33 but it is not without complications. The CPGs recommend combining serum-based testing and TE, as this reduces the need for biopsy by approximately 50% to 60% and secures an accurate diagnosis.34 Serum-based fibrosis tests are the first-choice option for screening purposes, with TE to be used in patients considered at high risk.

Table 1.

Noninvasive Tests for Diagnosing Metabolic-Associated Fatty Liver Disease.

Test	Stage	Parameters	Risk of advanced fibrosis according to cutoff values
HSI41	Steatosis	ALT/AST, BMI, sex, diabetes	<30: low>36: high
FLI42	Steatosis	Waist circumference, BMI, triglycerides, GGT	<30: low30–59: intermediate≥60: high
NAFLD-FS43	Fibrosis	Fasting blood glucose or diabetes mellitus, age, BMI, ALT, AST, platelets, albumin	<−1.455: F0-F2, low−1.455–0.675: indeterminate>0.675: F3-F4, high
FIB-444	Fibrosis	Age, ALT, AST, platelets	<1.30: F0-F2, low>2.67: F3-F4, high
HFS40	Fibrosis	Sex, age, diabetes, glucose, insulin, HOMA-IR (no diabetes), AST, albumin, platelets	HFS score	F2-F4	F3-F4	F4
			<0.12	23.6%	8.1%	0.9%
			0.12–0.47	57.1%	33.7%	7.4%
			>0.47	86.4%	76.3%	35.5%
APRI45	Fibrosis	AST, platelets	F0-F2: <0.5; 72.7%F3-F4: >1.5; 54.2%
BARD score46	Fibrosis	ALT, AST, diabetes, BMI	0–1: low2–4: high
ELF47	Fibrosis	HA, PIIINP, TIMP-1	<7.7: zero or low≥7.7–9.7: moderate≥9.8 high

Abbreviations: ALT, alanine aminotransferase; APRI, AST to platelet ratio index; AST, aspartate aminotransferase; BMI, body mass index; ELF, enhanced liver fibrosis test; GGT, gamma-glutamyl transferase; HFS, Hepamet Fibrosis Score; HOMA, homeostatic model assessment for insulin resistance; HSI, hepatic steatosis index; NAFLD-FS, nonalcoholic fatty liver disease fibrosis score; PIIINP, procollagen III amino-terminal peptide; TIMP-1, tissue inhibitor of matrix metalloproteinase 1.

Table 1 lists a number of noninvasive liver fibrosis screening tests. The expert panel considers FIB-4 to be most suitable test for initial screening in dermatology units: it has been externally validated for fibrosis screening in patients with fatty liver disease, is readily available and easy to process, and is recommended by CPGs.10,22,31 FIB-4 takes account of platelet count, age, and aspartate aminotransferase and alanine aminotransferase values. It has high negative predictive value (NPV) for the diagnosis of advanced fibrosis (stage F3-F4), meaning that liver biopsy can be avoided.35,36 A score of less than 1.30 rules out advanced fibrosis with an NPV of 85%. Scores of more than 2.67 indicate advanced fibrosis with a positive predictive value (PPV) of 79%.37 A number of factors, however, must be considered, including the risk of false positives from PPVs, a relatively high probability (1 in 3) of intermediate scores (1.30–2.67), and the influence of age on the accuracy of predictions (a threshold score of 2 is recommended for people aged over 65 years).38

The accuracy of FIB-4 depends on age: the index is not suitable for people younger than 35 years, and more tailored cutoffs are needed to improve its specificity in those older than 65 years.39 Another serum-based tool, the HEPAMET Fibrosis Score (HFS), offers greater specificity (higher predictive values than FIB-4) and accuracy, resulting in less diagnostic uncertainty. Its only limitation is that it includes HOMA-IR, which is generally not a routinely ordered test.40

When serum-based testing indicates a low risk, twice-yearly dermatologic follow-up with reassessment of risk is recommended.31 TE is recommended in patients with a medium to high risk.31,38,48 It has proven effective for monitoring disease severity, has high diagnostic accuracy for advanced stages of fibrosis (F3-F4), correlates with clinical findings,49,50 and, as a noninvasive test, does not increase risk. It should be noted that a high FIB-4 score indicates increased risk, regardless of TE results. Decisions to refer a patient for TE should therefore be based on availability and expected usefulness (whether or not it will influence outcomes). Patients with an intermediate FIB-4 score should be referred for TE due to the high level of uncertainty.

Wong et al.51 showed that a TE cutoff of 7.9kPa had the highest accuracy (sensitivity, 91%; specificity, 75%; and positive predictive power, 97%) for the diagnosis of advanced fibrosis and cirrhosis in patients with MAFLD. The recommended cutoff for high-risk patients is therefore 8kPa. Patients with a high FIB-4 score and a TE value of 8kPa or lower should be reassessed annually using FIB-4 and/or a repeat TE if available.

Patients with a TE value of more than 8kPa and a risk of advanced fibrosis (F3-F4) should be referred to the gastroenterology department for evaluation of the most appropriate management strategy (Fig. 2). If TE is not available, patients with a high FIB-4 score should be referred to a gastroenterologist.

Agreement among dermatologists and hepatologists on simple, evidence-based, criteria to identify, diagnose, and monitor at-risk individuals is essential for the efficient management of MAFLD. General recommendations should be tailored to the specific characteristics, needs, and organizational and care delivery set-ups of different hospital and health care providers.

Potential interactions between psoriasis treatments and MAFLD must be taken into account, with consideration of both the prevalence of liver disease and the potential and diverse impacts of these treatments. Decisions on whether to continue with a potentially hepatotoxic treatment in patients with a risk of liver fibrosis should be taken after weighing up the risks and benefits. Individual evaluation and follow-up is necessary.

Of all the treatments investigated, methotrexate is the only one associated with an increased risk of new-onset or worsening MAFLD. There is no evidence that phototherapy or certain new-generation conventional treatments cause hepatotoxicity in patients with hepatic steatosis. Although most biologic therapies have a favorable risk-benefit profile in patients with steatosis and varying degrees of fibrosis, their hepatotoxic potential is diverse (Table 3).92

Considering the prevalence of MAFLD in patients with psoriasis and the interconnections between these diseases, we recommend screening for liver disease and certain components of MAFLD in patients with psoriasis, regardless of the presence or extent of liver biochemistry abnormalities. This screening should be a routine part of psoriasis care in dermatology departments and clinics. The first-choice strategy is to use a combination of FIB-4 and TE and to refer patients to the hepatology department when a significant risk of advanced fibrosis is detected.

The expert panel meetings were funded by Novartis Farmacéutica S.A.

The expert panel meetings were funded by Novartis, but none of the employees at this company participated in the design or production of the scientific material, any of the discussions, or the resulting manuscript.

Antonio Olveira has participated as a researcher, speaker, or consultant in projects sponsored by Abbvie, Alexion, BMS, Janssen, MSD, Gilead, and Novartis.

Isabel Belinchón has served as a consultant and/or speaker and/or participated in clinical trials sponsored by companies that make drugs used to treat psoriasis, including Janssen Pharmaceuticals Inc., Almirall SA, Lilly, Abbvie, Novartis, Celgene, Biogen, Amgen, LEO Pharma, Pfizer-Wyeth, MSD, and UCB.

Pedro Herranz has participated as a researcher, speaker, or consultant in projects sponsored by Abbvie, Almirall, Amgen, Celgene, LEO Pharma, Lilly, Novartis, Pfizer, Sandoz, Sanofi, and UCB.

Javier Crespo has participated as a researcher, speaker, or consultant in projects sponsored by Abbvie, Alexion, BMS, Amgen, Celgene, Gilead, Janssen, and MSD.

Eva Vilarrasa has received consultancy/speakers’ fees from and/or participated in clinical trials sponsored by Abbvie, Almirall, Amgen, Bayer, Boehringer Ingelheim, Celgene, Gebro, Isdin, Janssen, LEO Pharma, Lilly, Merck-Serono, MSD, Novartis, Pfizer, Roche, Sandoz, Sanofi, and UCB.

Salvador Benlloch Pérez has participated as a researcher, speaker, or consultant in projects and clinical trials sponsored by Novartis, Novo Nordisk, and Gilead.

Jorge Alonso Suárez Pérez has served on a steering committee and/or participated as a guest speaker for Novartis, LEO Pharma, Abbvie, Lilly, Janssen, UCB, Amgen, and Almirall.

José Manuel Carrascosa has served as a principal investigator/co-investigator and/or was a guest speaker for Novartis, LEO Pharma, Abbvie, Lilly, Janssen, UCB, Sandoz, Mylan, Amgen, Almirall, Bristol-Myers-Squibb, and Boehringer Ingelheim.

Javier Ampuero declares that he has no conflicts of interest.

Francisco Guimerà declares that he has no conflicts of interest.