Non-Alcoholic Fatty Liver Disease (NAFLD) in Patients with Psoriasis: A Review of the Hepatic Effects of Systemic Therapies

Figures & data

Figure 1 Spectrum of non-alcoholic fatty liver disease (NAFLD). Data from these studies.^5,22

Figure 2 Common risk factors and associations between psoriasis (PsO) and non-alcoholic fatty liver disease (NAFLD). Reprinted from Prussick RB, Miele L. Non-alcoholic fatty liver disease in patients with psoriasis: a consequence of systemic inflammatory burden? Br J Dermatol. 2018;179(1):16–29. © 2018 The Authors. British Journal of Dermatology published by John Wiley & Sons Ltd on behalf of British Association of Dermatologists.⁵

Table 1 Cytokine Levels and Effects of Adipocytokines and Hepatokines in Psoriasis and Non-Alcoholic Fatty Liver Disease (NAFLD)

Cytokine Level in Psoriasis and NAFLD	Effect
	Psoriasis	NAFLD
Pro-inflammatory adipocytokines levels (↑, increased; ↓, decreased)	Role (↑, increases activity; ↓, decreases activity)
TNF-α ↑	↑ Keratinocyte proliferation, pro-inflammatory cytokines, angiogenesis	↑ Hepatic fibrogenesis: contributes to insulin resistance
IL-1 ↑	↑ Keratinocyte proliferation, adhesion molecule expression, pro-inflammatory cytokines	Activation of mitogen-activated protein (MAP) and ergosterol pathways
IL-6 ↑	↑ Keratinocyte proliferation	Contributes to insulin resistance
Leptin ↑	↑ Keratinocyte proliferation, Th1 response, angiogenesis	↑ Leptin resistance: contributes to hepatic fibrogenesis
Resistin ↑	↑ Pro-inflammatory cytokines	↑ Insulin resistance
Visfatin ↑		Contributes to insulin resistance
Ghrelin ↑		Negatively correlated to TNF-α
Anti-inflammatory adipocytokines
Adiponectin ↓	↓ Anti-inflammatory cytokines	↓ Insulin sensitivity
Pro-inflammatory hepatokines
Fibroblast growth factor 21 (FGF21) ↑ *	—
Fetuin A ↑
CRP ↑		↑ Hepatic fibrogenesis
TNF-α ↑
IL-6 ↑		↑ Hepatic fibrogenesis

Notes: *NAFLD only. ↑, elevated, ↓ de-elevated. Adapted from Prussick RB, Miele L. Non-alcoholic fatty liver disease in patients with psoriasis: a consequence of systemic inflammatory burden? Br J Dermatol. 2018;179(1):16–29. © 2018 The Authors. British Journal of Dermatology published by John Wiley & Sons Ltd on behalf of British Association of Dermatologists.⁵

Abbreviations: CRP, C-reactive protein; IL, interleukin; TNF-α, tumour-necrosis factor alpha.

Figure 3 Possible mechanisms linking dysfunctional visceral adipose tissue, psoriatic skin and steatosis.

Notes: Reproduced from Mantovani A, Gisondi P, Lonardo A, et al. Relationship between non-alcoholic fatty liver disease and psoriasis: a novel hepato-dermal axis? Int J Mol Sci. 2016;17(2):217.⁴⁸

Abbreviations: CRP, C-reactive protein; IL-6, interleukin-6; IL-17, interleukin-17; NAFLD, non-alcoholic fatty liver disease; NASH, non-alcoholic steatohepatitis; PAI-1, plasminogen activator inhibitor-1; TGF-β, transforming growth factor-beta; TNF-α, tumor necrosis factor alpha.

Table 2 Potential Hepatotoxic Effects of Some of the Most Commonly Used Systemic Therapies Used in the Treatment of Moderate to Severe Psoriasis

Systemic Antipsoriatic Agent	Pharmacological Class	Potential Hepatotoxic Effects	Likely Causality^a
Non-biological agents
Acitretin (ACI)	Retinoid	Transient ↑AMT levels in up to 30% pts; rare acute toxic hepatitis; uncommon acute liver injury has been reported	ACI is a probable cause of clinically apparent liver injury
Apremilast (APR)	PD-4 inhibitor	No reported hepatotoxicity	APR is an unlikely cause of apparent liver injury, but clinical experience is limited
Cyclosporin (CYC)	Calcineurin inhibitor	Mild ↑ in bilirubin and less commonly AMT levels; case reports of acute liver injury have been reported	CYC is a probable rare cause of clinically apparent liver injury
Dimethyl fumarate (DMF)	Immunomodulator and anti-inflammatory	↑AMT levels which were asymptomatic and transient; isolated cases of clinically apparent liver injury with jaundice have been reported during widescale use of DMF	DMF is a probable rare cause of clinically apparent liver injury
Methotrexate (MTX)	Folic acid antagonist	During long-term low-dose MTX treatment ↑AMT levels; NAFLD, liver fibrosis and cirrhosis; with higher doses of MTX the increases in AMT levels are greater	MTX is a well-known cause of clinically significant hepatic injury, portal hypertension and cirrhosis
Biological agents
Adalimumab (ADA)	Anti-TNFα	Low risk of transient, mild, asymptomatic ↑AMT levels; acute DILI (including AIH); cholestasis; reactivation of hepatitis B	ADA is a likely cause of clinically apparent liver injury
Certolizumab (CER)	Anti-TNFα	Low risk of transient, mild, asymptomatic ↑AMT levels; acute DILI (including AIH); cholestasis; reactivation of hepatitis B	CER is an unproven but suspected cause of apparent liver injury
Etanercept (ETA)	Anti-TNFα	Low risk of transient, mild, asymptomatic ↑AMT levels; acute DILI (including AIH), but much less than INF; cholestasis; reactivation of hepatitis B	ETA is a highly likely cause of clinically apparent liver injury
Infliximab (INF)	Anti-TNFα	Risk of transient, mild, asymptomatic ↑AMT levels, but sometimes the ↑ continues to progress; ↑ ALP; symptomatic hepatitis; acute DILI (including AIH); cholestasis; reactivation of hepatitis B	INF is a highly likely cause of clinically apparent liver injury
Ustekinumab (UST)	Anti-IL12 and anti-IL23	No evidence of liver enzyme anomalies or reports of liver injury with UST to date. Rare instances of reactivation of hepatitis B have been reported. Experience with UST is limited	UST is an unproven but suspected rare cause of apparent liver injury and reactivation of hepatitis B
Brodalumab (BRO)	Anti-IL17	No evidence of liver enzyme anomalies or reports of liver injury with BRO to date. Experience with BRO is limited	BRO is an unlikely cause of apparent liver injury
Ixekizumab (IXE)	Anti-IL17	No evidence of liver enzyme anomalies or reports of liver injury with IXE to date. Experience with IXE is limited	IXE is an unlikely cause of clinically apparent liver injury
Secukinumab (SEC)	Anti-IL17	No evidence of liver enzyme anomalies or reports of liver injury with SEC to date	SEC is an unlikely cause of apparent liver injury
Guselkumab (GUS)	Ant-IL23	Mild-to-moderate ↑AMT levels which resolved even if treatment with GUS was continued. No evidence of acute liver injury, or reactivation of hepatitis B or worsening of hepatitis C with GUS to date, but clinical experience is limited	GUS is an unproven but suspected rare cause of apparent liver injury
Risankizumab (RIS)	Anti-IL23	Risankizumab has been associated with a low rate of serum aminotransferase elevations during therapy, but has not been linked to instances of clinically apparent liver injury.	RIS is an unlikely cause of apparent liver injury
Tildrakizumab (TIL)	Anti-IL23	No evidence of liver enzyme anomalies or reports of liver injury, or reactivation of hepatitis B or worsening of hepatitis C with TIL to date, but clinical experience is limited	TIL is an unlikely cause of apparent liver injury

Notes: ^aBased on LiverTox ratings.⁷⁶ Data from these studies.^65–87

Abbreviations: ↑, elevated; AIH, autoimmune hepatitis; ALP, serum alkaline phosphatase; AMT, aminotransferase; DILI, drug induced liver injury; IL, interleukin; NAFLD, non-alcoholic fatty liver disease; TNF, tumor necrosis factor.

Table 3 Potential Hepatoprotective Effects of Medicines Used to Treat Psoriasis

Treatment and Assessment	Results and Conclusions	Ref.
Effects on inflammatory biomarkers: non-biological agents
MTX and ACI PCSK9 plays a role in maintaining lipid homeostasis by binding to LDL-R and is considered a cardiometabolic risk factor. Effects of MTX and ACI on PCSK9 levels in PSO pts and healthy volunteers after 12 weeks’ treatment	PSO pts had significantly elevated PCSK9 levels compared with controls and these were positively correlated to BMI and TG levels. MTX, but not ACI, significantly reduced PCSK9 levels. However, there was no correlation between PCSK9 levels and markers of liver function such as transaminases in hepatic steatosis and NASH in high-risk patients	[^Citation89]
MTX and ACI FGFs 21 and 23 are markers for cardiometabolic disorders which are common in PSO. Effects of MTX and ACI on FGF-21 and −23 in PSO pts and healthy controls after 12 weeks’ treatment	FGF-21 levels were increased in PSO pts vs controls whereas FGF-23 levels were not. There was a tendency for higher levels of FGF-21 in pts with more severe PSO which raises the possibility of its use as a biomarker for disease severity. Interestingly, ACI decreased FGF-21 more than MTX. Finally, there was a positive link between FGF-23 and AST levels which suggests a possible link with liver activity	[^Citation90]
MTX Review of the evidence for the potential pro-atherosclerotic effects of MTX	MTX improves endothelial function and vascular homeostasis, and is associated with a significant reduction in CV morbidity. These effects appear to be mediated via inhibition of pro-atherosclerotic cytokines such as TNF-α, IL-1 and IL-6	[^Citation91,Citation92]
CYC TGFβs plays a key role in cell growth and differentiation, modulation of immune activity and regulation of the cell cycle. The effects of CYC on TGFβ levels was determined in PSO pts treated for 12 weeks	CYC significantly improved PSO symptoms and QoL of pts in this 3-month clinical study. CYC also increased the transcription activity of TGFβ1 at the end of treatment in pts with or without diabetes, and with or without metabolic syndrome	[^Citation93]
APR Assessment of efficacy, safety and metabolic biomarkers in 113 pts with PSO and/or PsA treated with APR for 1-year	Pts with diabetes treated with APR achieved better clinical benefit for their PSO (extent and severity) compared with non-diabetic patients. In addition, after 1 year, blood glucose levels and LDL-C levels were significantly reduced by APR	[^Citation94]
Effects on inflammatory biomarkers: biological agents
ADA A 12-week RCT comparing the effects of ADA, PHO and PLA on vascular inflammation and markers of lipid and glucose metabolism, and inflammation in pts with moderate to severe PSO. This was followed by 52-week open-label ADA	ADA (anti-TNF) reduced key markers of inflammation including glycoprotein acetylation, CRP, IL-6 and TNF whereas PHO only reduced CRP and IL-6	[^Citation95]
ADA and FAEs The effect of ADA and FAEs on CV disease markers in pts with PSO was investigated in a 6-month RCT	ADA and FAEs were associated with beneficial CV effects. ADA significantly reduced systemic inflammation as measured by CRP levels and improved endothelial dysfunction as measured by flow-mediated dilation. In contrast, FAEs significantly reduced total cholesterol, LDL and apolipoprotein B levels	[^Citation96]
SEC A 12-week RCT comparing the effects of SEC and PLA on markers of inflammation, and lipid and glucose metabolism in pts with moderate to severe PSO. This was followed by 40-week open-label SEC	SEC (anti-IL-17A) was highly effective for treating PSO, but had a neutral effect on aortic vascular inflammation and biomarkers of cardiometabolic disease	[^Citation97]
SEC A post hoc analysis of 3 Phase III RCTs in pts with plaque PSO comparing SEC with PLA (and ETA in one study) with regards metabolic and liver parameters over 12 months	Overall, SEC had neutral effects on fasting plasma glucose, lipid parameters and liver enzymes. SEC reduced levels of CRP, a marker for systemic inflammation	[^Citation98]
SEC or IXE (anti-IL-17A therapy) Determination of glucose levels in PSO pts to see if the severity of PSO was correlated with hyperglycemia, and to investigate the effects of anti-IL-17A therapy on glucose levels	In pts with PSO, the severity of the skin disease correlated with high blood glucose levels. Anti-IL-17A therapy significantly reduced glycemia in patients with PSO. In parallel experiments it had the same effect in imiquimod-treated mice (an animal model of psoriasis)	[^Citation99]
SEC The effects of SEC, CYC, and MTX on myocardial deformation and vascular function in PSO pts after 4- and 12-month treatment	In patients with psoriasis, inhibition of IL-17A with SEC produced greater improvement in arterial elasticity, coronary artery function and indices of myocardial deformation than either CYC or MTX. SEC was also associated with a reduction in markers for oxidative stress	[^Citation100]
UST A 12-week RCT comparing the effects of UST and PLA on markers of inflammation, and lipid and glucose metabolism in pts with moderate to severe PSO. This was followed by 40-week open-label UST	UST (anti-IL-12 and -IL-23) was highly effective for treating PSO and was associated with a reduction in IL-17a levels (a key cytokine in PSO). At the end of the study UST significantly decreased TNF-α, IL-1b, IL-17a and IL-6. VCAM-1 was significantly reduced by UST at 12 weeks, but this was not sustained at 52 weeks. Overall, UST transiently reduced aortic vascular inflammation at 12 weeks. Longer term UST produced a more durable reduction in markers (inflammatory cytokines) associated with CV disease	[^Citation101]
Effects in vitro
Effect of DMF/MEF on GM-CSF- and IL-4-induced differentiation of monocyte derived DCs In vitro using human cell line	DMF concentration-dependently inhibited monocyte-derived DC differentiation as reflected by inhibition of CD1a, CD40, CD80, CD86 and HLA-DR, and reduced capacity to stimulate lymphocytes. This suggests that the mechanism of action of DMF/MEF in psoriasis is possibly based on immunomodulatory effects mediated through inhibition of DCs	[^Citation102]
Effect of DMF on DC maturation and subsequent T-cell responses In vitro using mouse cell line	DMF inhibited DC maturation by reducing inflammatory IL-12 and IL-6 production as well as expression of MHC class II, CD80 and CD86. This immature DC phenotype resulted in fewer activated T-cells (and decreased IFN-γ and IL-17 production). DMF modulates inflammation by inhibiting DC maturation and subsequent Th1 and Th17 cell differentiation	[^Citation103]
Animal models investigating possible hepatoprotective effects of systemic antipsoriatic medications
To evaluate the antioxidant and anti-inflammatory effects of DMF as mechanisms for ameliorating liver toxicity Rat model of liver ischemia/ reperfusion injury	Liver histological tissue damage was significantly reduced by DMF and this was associated with lower ALT and MDA levels. In addition, DMF was associated with higher expression of anti-oxidant enzymes (catalase and glutamate-cysteine ligase modifier subunit) and lower levels of inflammatory mediators (nuclear factor-kappa B and cyclo-oxygenase-2). In a rat model of liver ischemia /injury, DMF significantly improved hepatic function and the anti-oxidant and inflammation status compared with controls (no treatment)	[^Citation104]
Effects on aerobic glycolysis in the modulation of immunity In vitro and in vivo experiments in mice and humans	DMF, an immunomodulatory drug, inactivated the catalytic cysteine of GAPDH involved in aerobic glycolysis in activated myeloid and lymphoid cells. Importantly DMF differentially impacted lymphocyte subsets, producing lymphopenia that selectively depleted highly glycolytic effector T-cells while sparing oxidative naïve T-cells and Treg cells. The anti-inflammatory/immunomodulatory effects of DMF may be mediated via inhibition of GAPDH and aerobic glycolysis	[^Citation105]
T-cell response to DMF Mouse model of EAE	PLP139–151 peptide-reactive DMF-treated IL-17^low, IFN-γ^low, IL-4^+ CD4^+ T-cells may protect mice from severe EAE. DMF-induced IL-17^low, IFN-γ^low, IL-4^+ Th cells protect mice from severe EAE	[^Citation106]
Effect of DMF on hepatic injury Mouse model of ACT-induced hepatic injury	In this model DMF ameliorated ACT-induced liver injury primarily through anti-oxidant, anti-inflammatory and anti-apoptotic mechanisms in a Nrf-2-dependent manner. These results show that DMF can possibly be used for treating ACT-induced liver damage through targeting the Nrf-2/HO-1 pathway	[^Citation107]
Effect of DMF on hepatic injury Rat model of TAA-induced hepatic injury	DMF restored TAA-induced increased levels of ALT, AST, GGT, total bilirubin, uric acid, MDA, reduced glutathione. DMF also improved histopathological findings such as inflammatory cell infiltration, necrosis and bridging fibrosis. Markers of inflammation and oxidative stress were also significantly improved by DMF. DMF protects against TAA-induced hepatic damage via down-regulation of the inflammatory cascade and up-regulation of anti-oxidant mechanisms	[^Citation108]

Abbreviations: ACI, Acitretin; ACT, acetaminophen; ADA, adalimumab; ALT, alanine aminotransferase; AST, aspartate aminotransferase; CRP, C-reactive protein; DC, dendritic cells; DMF, dimethyl fumarate; EAE, experimental autoimmune encephalomyelitis; ETA, etanercept; FAEs, fumaric acid esters; FGF, fibroblast growth factors; GAPDH, glyceraldehyde 3-phosphate dehydrogenase; GGT, γ-glutamyl transferase; GM-CSF, granulocyte-macrophage-colony stimulating factor; HO-1, heme oxygenase-1; IL, interleukin; IXE, ixekizumab; LDL-R, low-density lipoprotein-receptor; MDA, malondialdehyde; MEF, monoethyl fumarate; MTX, methotrexate; Nrf-2/HO-1, nuclear factor erythroid-related factor-2; PHO, phototherapy; PLP, proteolipid protein; PCSK9, proprotein convertase subtilisin/kexin type 9; PSO, psoriasis; pts, patients; TAA, thioacetamide; TG, triglyceride.

Figure 4 Proposed mechanisms of action of dimethyl fumarate/monomethyl fumarate (DMF/MMF).

Note: Data from these studies.^{102,103,105,116,117}

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