Non-metabolic causes of steatotic liver disease
Abstract
Hepatic steatosis is caused by exaggerated hepatic lipid accumulation and is a common histological and radiological finding. Non-alcoholic fatty liver disease (NAFLD), or metabolic dysfunction associated steatotic liver disease (MASLD), is highly associated with metabolic syndrome and represents the most common cause of hepatic steatosis. However, since several comorbidities, lifestyle factors, and drugs can cause hepatic steatosis, MASLD is, to some extent, a diagnosis of exclusion. Nevertheless, initiatives have been taken to encompass positive (instead of negative) criteria for diagnosis - such as the presence of cardiometabolic risk factors together with hepatic steatosis. Nonetheless, before confirming a patient with MASLD, it is essential to map and evaluate other causes of fatty liver disease or steatotic liver disease. Several causes of hepatic steatosis have been identified in studies; however, the study cohorts are scarce and often anecdotal. Additionally, many studies have shown correlation without proving causation, and many are retrospective without reporting relevant patient characteristics and comorbidities - making it difficult to draw conclusions regarding the underlying etiology or present comorbidity of hepatic steatosis. In this narrative review, we aimed to identify and summarize present studies evaluating the impact of the most common and often suggested causes of hepatic steatosis.
Keywords
INTRODUCTION
Steatotic liver disease (SLD) is caused by hepatic lipid accumulation and is a common finding encountered during histopathological evaluation of liver biopsies and imaging examinations (e.g., ultrasonography, computed tomography, and magnetic resonance imaging). The most common cause of elevated liver enzyme levels is SLD, which is present in approximately a third of the population[1]. The most common cause of hepatic lipid accumulation is non-alcoholic fatty liver disease (NAFLD)[2,3], recently renamed to metabolic-dysfunction associated steatotic liver disease (MASLD)[4,5], with an estimated global prevalence of 30%[6]. The difference between NAFLD and MASLD is small, with a high overlap[7], but with the common denominator being the presence of hepatic steatosis with the absence of other steatogenic causes. In addition, in MASLD, the presence of at least one cardiometabolic risk factor (i.e., overweight/obesity, hyperglycemia/insulin resistance, hypertension, and dyslipidemia) is a prerequisite for the diagnosis[8]. Additionally, a new entity of increased alcohol intake in combination with MASLD was also introduced, labeled MetALD - which includes a continuum of alcohol consumption where the contribution of MASLD and alcohol-related liver disease (ALD) will vary[8].
Steatotic liver disease can be defined as an accumulation of fat, mainly triglycerides, exceeding 5% of the liver weight[9]. Even though this definition is appealing, it is not feasible in a common clinical setting. After liver biopsy is performed, the histopathological diagnosis of SLD is set if more than 5% of the hepatocytes contain lipid vacuoles[10,11]. Because liver biopsy is associated with adverse events (both minor and serious), several non-invasive techniques for defining hepatic triglyceride content have emerged, such as magnetic resonance imaging[12,13] and controlled attenuation parameter[14].
Nonetheless, in the wake of a growing body of research in the field of MASLD, focus on other causes of SLD has been set aside [Table 1]. Therefore, in this review, we will focus on other common (and uncommon but clinically important) causes of hepatic lipid accumulation that are important to exclude, or take into consideration, when diagnosing MASLD.
Factors, other than metabolic dysfunction-associated steatotic liver disease, that have been associated with hepatic lipid accumulation
| Nutritional | Drugs and toxins | Inborn errors of metabolism | Other conditions |
| GI surgery for obesity | 5-Fluorouracil | Abetalipoproteinemia | AFLP |
| Malnutrition | Acetylsalicylic acid, | Galactosemia | Environmental toxins |
| Rapid weight loss | Alcohol | Glycogen storage disease | -Toxic mushrooms |
| Starvation | Amiodarone | Hereditary fructose intolerance | -Phosphorus |
| TPN | Carbamazepine | Homocysteinuria | -Petrochemicals |
| Cocaine | LAL-D/CESD/WD | -Organic solvents | |
| Diclorethylene | LCAT deficiency | HELLP syndrome | |
| Didanosine (NRTI) | Systemic carnitine deficiency | Hepatitis C | |
| DH | Tyrosinemia | HIV | |
| Diltiazem | Weber-Christian syndrome | IBD | |
| Estrogen | Wilson’s disease | Lipodystrophia | |
| Ethionine | Reye’s syndrome | ||
| Ethyl bromide | Severe anemia | ||
| Glucocorticoids | SIBO | ||
| Hydrazine | Endocrine disorders | ||
| Hypoglycin | -Hypothyroidism | ||
| Interferon | -HPD | ||
| Irinotecan | -Cushing’s disease | ||
| Margosa oil | -PCOS | ||
| Methotrexate | -Type 2 diabetes | ||
| NSAID | Cessation of PA | ||
| Perhexeline maleate | |||
| Protease inhibitors | |||
| Safrole | |||
| Stavudine (NRTI) | |||
| Tamoxifen | |||
| Tetracycline | |||
| Valproic acid | |||
| Vitamin A | |||
| Zidovudine (NRTI) |
Alcohol
Consumption of alcohol is common in the Western world, with nearly two-thirds of all adults in the United States consuming alcohol (approximately 4 drinks per week)[15]. The corresponding numbers in Sweden show that nine out of ten adults in Sweden consume approximately 9 drinks per week[16,17]. Alcohol consumption can lead to hepatic lipid accumulation. However, it is uncertain how much, how long, and at what rate alcohol consumption induces SLD. Although acute alcohol consumption induces SLD in mouse models[18,19], it does not, over a period of 5-12 weeks, seem to induce similar traits in humans[20,21]. Therefore, it is probable that chronic consumption of alcohol, rather than acute, induces significant SLD. Nevertheless, in studies of patients with confirmed alcohol overconsumption who have undergone liver biopsy, approximately one in three have no histological signs of SLD[22,23].
Initially, alcohol-induced SLD was thought to be a result of oxidative stress and diminished lipid oxidation secondary to enzymatic metabolism of ethanol. However, new discoveries have shed light on the complex multifactorial process that leads to ethanol-induced lipid accumulation in hepatocytes[24]. Many mechanisms are similar to that of MASLD, which, to some extent, explains the hurdle of separating the entities.
It is important to exclude excessive alcohol consumption in diagnosing MASLD. However, it is difficult to define excessive alcohol consumption in order to separate MASLD, or MetALD, from alcohol-related liver disease (ALD). The threshold for defining excessive alcohol consumption has ranged from abstinence[25-27] to 252 g/week in different studies[28]. However, the European Association for the Study of the Liver (EASL) reached a consensus in 2016 suggesting a cut-off of 210 and 140 grams per week for men and women, respectively, for the diagnosis of NAFLD[29]. These cut-offs are also suggested for the diagnosis of MASLD, and if consumption exceeds these thresholds but is below 420 g/week for men and 350 g/week for women, the diagnosis of MetALD is used. However, if alcohol consumption exceeds the thresholds for MetALD, the diagnosis of ALD is recommended[8].
Since differentiating between MASLD, MetALD, and ALD, histopathologically, is difficult, one must rely on patient history, standardized questionnaires, or biomarkers for the correct diagnosis. When diagnosing MASLD, the proposed tool for excluding excessive alcohol consumption is the AUDIT (i.e., Alcohol Use Disorder Inventory Test), which has an adequate test-retest agreement (kappa (κ) agreement of 0.7)[30,31]. The AUDIT consists of ten questions exploring consumption (Q1-3), dependence (Q4-6), and alcohol-related problems (Q7-10)[32]. Abbreviated forms have been developed, where the one most regularly used is the AUDIT-C (i.e., AUDIT-Consumption) questionnaire, which includes Q1-3 of the AUDIT[33].
Furthermore, in addition to both AUDIT or the abbreviated AUDIT-C, indirect alcohol markers, such as mean corpuscular volume, gamma-glutamyl transferase, and aspartate and alanine aminotransferase, are occasionally used. However, indirect alcohol markers all depend on chronic excessive drinking over an extended period, and they are usually associated with multiple confounders resulting in an inadequate accuracy, specificity, and sensitivity[34-38]. Additionally, carbohydrate-deficient transferrin (CDT) is occasionally used to diagnose or screen for (chronic) excessive alcohol consumption[39]. However, CDT mainly indicates heavy alcohol consumption (50-80 g/day or 350-560 g/week) over a period of more than 1-2 weeks, reflecting a threshold above the limit for MASLD (i.e., 210 g/week for men and 140 g/week for women). Moreover, CDT is susceptible to inaccurate levels secondary to confounding factors[40-42].
Direct alcohol markers portray a much higher sensitivity and specificity in comparison to questionnaires (e.g., AUDIT) and indirect alcohol markers (e.g., CDT), since they are direct products of the non-oxidative metabolism of ethanol. In addition, compared to direct determination of ethanol in exhaled air or blood/serum, direct alcohol markers have a much wider window of detection [4-12 h vs. 3-90 days (and up to 6 months)]. There are several direct biomarkers for ethanol, one of which is phosphatidylethanol (PEth), a direct biomarker showing both high specificity and sensitivity[43]. In a study by Schröck et al., 16 volunteers received one dose of vodka (ranging from 34 to 72 g of alcohol) in order to attain a blood ethanol concentration of circa 1 g/kg of weight[44]. Phosphatidylethanol was measured every other hour from intake and up to eight hours after intake. The highest value of PEth was reported and ranged from 0.06 to 0.31 μmol/L (reference value in Sweden for moderate alcohol consumption ranges from 0.05 to 0.30 μmol/L). Moreover, in a study by Kechagias et al., 44 subjects were randomized to abstaining from alcohol or consuming 32 g or 16 g (if male or female, respectively) of wine per day for three months[45]. Most of the participants in the consumption group had values of PEth below 0.04 μmol/L (< 0.05 μmol/L is according to Swedish reference values defined as low or no alcohol consumption), while three subjects had elevated (signs of moderate) PEth values of 0.07, 0.12, and 0.17 μmol/L[45].
Both the studies by Schröck et al. and Kechagias et al. suggest that long-standing or occasional intake of up to 30 g of alcohol per day results in classifying alcohol consumption as low to moderate according to current clinical decision thresholds for PEth, while consumption exceeding 70 g/day will almost certainly result in values of PEth above 0.30 µmol/L, which is considered heavy alcohol consumption in clinical practice[44,45]. This is corroborated in a study by Walther et al. that showed an almost linear association between alcohol consumption and PEth[46].
The more commonly used direct alcohol marker is ethyl glucuronide (EtG), where, to date, the determination of conjugated EtG in urine (uEtG) is applied in several European countries[30]. Depending on the consumption of alcohol, uEtG is detectable for up to 80 hours. However, in contrast, measurement of EtG in hair (hEtG) provides a more reliable means of estimating chronic consumption over a period of 3 to 6 months, where 1 cm of hair represents 1 month (however, hair length below 3 cm or more than 6 cm should be interpreted with caution)[30]. In recent years, the interest in hEtG has increased, however, mostly in forensic settings.
Consumption of alcohol is not uncommon in individuals with MASLD, and it also seems to increase the risk of incident steatosis in individuals with presumed MASLD[47,48], with an almost direct dose-response relationship between alcohol consumption and hepatic steatosis[49]. As mentioned, the gold standard for excluding patients with excessive alcohol consumption (i.e., disqualifying them from a MASLD diagnosis) is self-reported alcohol consumption. However, in a recent study by Staufer et al., subjects with presumed MASLD were evaluated with direct alcohol markers[50]. Interestingly, approximately one-third (29%) of the included MASLD patients showed signs of moderate to excessive alcohol consumption.
There is an ongoing debate on the impact of alcohol consumption and its effect on the prognosis of MASLD, with studies proposing both positive[51-56] and negative effects[57-60], and with some of the studies suggesting a J-shaped curve where modest levels of alcohol consumption might be beneficial. This is in concordance with earlier studies reporting that modest alcohol consumption is associated with decreased risk of cardiovascular disease and mortality[61]. However, in a recent study including 28 million individuals, it was suggested that any level of alcohol use is linked to negative outcomes[62]. Moreover, in two recent studies, it was shown that alcohol consumption (mostly moderate use) was associated with fibrosis progression in patients with MASLD[63,64]. Additionally, in a study by Younossi et al., they found that more than 3 or 1.5 (for men and women, respectively) drinks per day was associated with increased mortality - an association that was more evident amongst individuals with metabolic syndrome[65].
In summary, alcohol does not seem to attenuate the presence of SLD but rather aggravates the accumulation of steatosis and the progression to fibrosis. Although alcohol seems to be associated with decreased cardiovascular disease, real-world data on alcohol consumption indicate an increased all-cause mortality. Even though these two entities are histopathologically similar, treatment and management vastly differ. Therefore, separating MASLD from MetALD and ALD is of outermost importance, and using the recommended questionnaire (i.e., AUDIT) to estimate a patient´s alcohol consumption can be lined with non-differential misclassification bias[66]. Nevertheless, differentiating ALD from MASLD, or MetALD, is probably more complicated than previously perceived, and the use of direct alcohol markers (e.g., PEth) should be considered.
Methotrexate
Methotrexate (MTX) is an effective and widely used drug in the management of autoimmune and dermatological disorders. The notion of liver damage has been attributed to MTX on the basis of accumulation of MTX-polyglutamate - a metabolite that triggers oxidative stress, inflammation, steatosis, fibrosis, and apoptosis[67]. Albeit high-dose MTX treatment (used for its cytotoxic-antiproliferative action in adult and childhood malignancies) has been reported to cause liver damage in up to 80%[68], the evidence of low-dose MTX treatment and hepatotoxicity is debatable, with fluctuations of liver enzyme levels often returning to normal despite continuation of MTX[69].
In a Swedish study, the most prominent predictor of elevated aminotransferases was signs of elevated aminotransferases pre-treatment, use of statins, and increased body mass index (BMI)[70]. Similarly, a German study of patients with inflammatory bowel disease noted that the presence of hepatic steatosis verified by ultrasound, and not MTX treatment, predicted elevated aminotransferases[71]. Both these studies indicate that pre-existing risk factors for elevated liver enzymes are often the cause of elevated aminotransferases, which was also shown by Mori et al., who reported that chronically elevated aminotransferases were not associated with the cumulative dose of MTX but rather with BMI, dyslipidemia and type 2 diabetes mellitus (T2DM)[72]. Similarly, in follow-up studies with repeat liver biopsy, the effect of MTX on current and future histopathological changes is mild, and in patients with concomitant SLD, secondary causes such as alcohol overconsumption or obesity are often present[73-76].
In a Danish population-based cohort study, approximately 40,000 individuals (70% rheumatoid arthritis [RA], 16% psoriatic arthritis [PsA], and 14% psoriasis [PsO]) with MTX treatment were followed for a mean of 6.5-8.4 years[77]. Although cumulative MTX dose was higher in the RA population, liver disease outcomes were more common in the PsO and PsA groups, with alcohol abuse and the presence of T2DM acting as the strongest predictors. These findings could be related to the findings of psoriasis being strongly associated with MASLD, socioeconomic status, steatogenic treatment, metabolic syndrome, and alcohol consumption pattern[78]. Furthermore, metabolic components, such as central adiposity or insulin resistance, and not MTX, seem to be of great importance in predicting elevated elastographic values[79,80]. Although several studies on MTX and liver damage often focus on fibrosis or elastographic values, few focus on steatosis. However, in a study by Choi et al., 368 patients with RA were evaluated with ultrasound, of whom 92 had SLD. There was no difference in cumulative dose between patients with and without SLD
The assumption that MTX is a steatogenic drug in the absence of overweight/obesity, T2DM, dyslipidemia and alcohol overconsumption is disputable. Further studies determining the association of low-dose MTX and steatosis while adjusting for known steatogenic co-morbid diseases are needed.
Tamoxifen
Tamoxifen (TMX) is an effective selective estrogen receptor modulator used to treat estrogen receptor-positive breast cancer. It has been linked to liver toxicity mainly through the induction of SLD[84,85]. The effect of TMX on hepatic lipid metabolism and accumulation remains unclear. However, animal studies have proposed both inhibition of fatty acid oxidation and increased triglyceride synthesis[86,87]. This was, however, questioned in a study by Cole et al., where mice injected with TMX had higher hepatic triacylglycerol compared to controls but unchanged fatty acid uptake, triacylglycerol secretion, and fatty acid oxidation[88]. These data would suggest that TMX increases de novo fatty acid synthesis, causing hepatic lipid accumulation. Furthermore, in human subjects, TMX is highly associated with SLD. In a meta-analysis by Lee et al., data on 6,962 patients and 975 controls were analyzed[85]. The incidence rate for SLD in TMX-treated patients and controls was 40.25 and 12.37 per 100 patients, respectively, with an incidence rate ratio of 3.12. However, the main risk factors for concomitant SLD were body mass index (BMI) and hypercholesterolemia. Similar results were observed in a multicenter trial of more than 5,000 women, where TMX treatment was associated with a two-fold risk of developing MASLD[89]. This risk, however, seemed synergistic, since patients with a normal BMI had no increased risk of TMX-induced SLD, compared to patients with overweight or obesity, where TMX treatment was associated with an increased risk of MASLD development compared to controls. Similarly, hypercholesterolemia, dyslipidemia, and glucose intolerance seem to predict TMX-induced SLD and/or elevated enzyme levels[89,90]. Albeit SLD is often benign and the risk of severe liver damage in TMX-treated patients is absent (or at best anecdotal), the co-morbidly associated metabolic syndrome entails an increased risk of T2DM and cardiovascular disease[91]. Although risk mitigation with lipid-lowering drugs may have a theoretical place in the management of these patients, further studies are required before such treatment can be proposed.
Corticosteroids
Corticosteroids are used in a variety of medical conditions for their anti-inflammatory effects and are commonly prescribed. At present, approximately 1% of the general population receives corticosteroids, with a more than two-fold increase in senior citizens[92,93].
The use of corticosteroids is associated with an adverse metabolic profile, including insulin resistance and T2DM, conditions also associated with hepatic lipid accumulation[94]. The means by which corticosteroids induce fatty liver is not fully understood, although corticosteroids are often referred to as steatogenic[84]. Rodent studies have shown that corticosteroids increase appetite and caloric intake as well as gluconeogenesis and lipogenesis, and also the release of free fatty acids from adipose tissue to the liver - trademarks similar to metabolic syndrome associated with MASLD[95-97]. However, in a study from 2003, Rockall et al. investigated 50 patients with Cushing’s syndrome for the presence of SLD using computed tomography[98]. Only 20% were found to have SLD, and although it was not associated with BMI, it did correlate with both visceral and total fat volume. Furthermore, the prevalence of SLD among patients with Cushing’s syndrome does not exceed the estimated global prevalence of MASLD (i.e., 30%)[6,99]. Additionally, of interest, cortisol levels did not differ between patients with and without SLD, results which are corroborated by Hubel et al.[100]. Hence, the main cause of SLD in patients with short-[101] and long-term corticosteroid treatment[102] is the disruption of the metabolic equilibrium leading to hyperglycemia, insulin resistance and central obesity, and ultimately SLD[97].
Viral hepatitis-associated steatosis
Chronic infection with hepatitis C virus (HCV), genotype 3, is commonly associated with SLD. The prevalence of SLD in patients with chronic hepatitis C varies between 40%-80%, depending on the prevalence of alcohol consumption, overweight, T2DM, and other risk factors of hepatic lipid accumulation[103]. Several observations also indicate a correlation between the grade of hepatic steatosis and elevated aminotransferases[104,105]. Furthermore, the steatogenic effect seems to be cytopathic, with an increased grade of hepatic steatosis being associated with HCV RNA levels in both serum and liver[106,107], and attenuation occurring after sustained therapeutic response[108]. Furthermore, chronic HCV infection seems to be associated with acquired hypobetalipoproteinemia and hypocholesterolemia, the latter often normalizing after therapeutic response[109-111].
Hepatitis C virus has an intertwined connection with hepatic and systemic metabolism. Genotype 3 HCV proteins have been proven to interact with glucose and lipid metabolism by stimulating de novo lipogenesis, and synthesis of phospholipids, via activation of several transcription factors to favor HCV assembly[112]. Furthermore, HCV assembly interferes with VLDL assembly and export by interfering with the VLDL secretion pathway[113].
Overweight and T2DM are frequently present[107,114,115] and often exaggerate HCV-associated SLD, irrespective of genotype. Further, the presence of SLD in chronic HCV infection is independently associated with an increased risk of HCC[116].
In recent years, effective direct-acting antiviral treatment has changed the HCV landscape, where sustained virologic response (SVR) is often achieved after an 8-12(-24) weeks course of treatment. In contrast to cholesterol, SVR does not seem to attenuate steatosis in responders to a significant degree[117], but instead appears to increase steatosis[118,119]. This could be partly attributed to the weight gain often observed after sustained virological response[120]. Hence, chronic HCV infection with genotype 3 is independently associated with SLD, a trait associated with disrupted hepatic metabolism, and is exaggerated by comorbidities associated with the metabolic syndrome.
HIV-associated hepatic steatosis
The presence of SLD in patients living with human immunodeficiency virus (HIV) is common, affecting approximately 35%[121,122]. Although SLD secondary to traditional risk factors is common among patients living with HIV, the presence of SLD is also seen in normal or underweight patients living with HIV[123]. Therefore, it is suggested that the exact etiology may differ from patients with MASLD, but the pathophysiological mechanism is still unclear[123]. Yet, in lipodystrophic patients with HIV, insulin resistance is highly prevalent, showing signs of impaired glucose tolerance and T2DM in 35% and 7%, respectively[124]. The proposed mechanism is theorized to be related to defect lipid metabolism and active inflammation, indicating that lipotoxicity and inflammation lead to metabolic dysregulation associated with insulin resistance, a hallmark for hepatic lipid accumulation[125].
COVID-19 and hepatic steatosis
In December 2019, the emergence of coronavirus disease 2019 (COVID-19), caused by the Severe Acute Respiratory Syndrome (SARS) Coronavirus (CoV) 2 (SARS-CoV-2), led to a major global health and economic crisis[126]. Although the respiratory tract was considered the main target of SARS-CoV-2 infection, other organs, including the liver, have also been shown to be affected[126,127].
Elevated liver transaminases in COVID-19 patients are seen in approximately 20% of patients[128]. Furthermore, elevated transaminases are often accompanied by elevated cholestatic liver enzymes, probably reflecting systemic inflammatory response syndrome (SIRS). The cause of elevated liver enzymes can be directly associated with COVID-19 but is most often multifactorial.
COVID-19-associated liver injury includes a broad spectrum of potential mechanisms of action, such as active viral replication of SARS-CoV-2 in the liver with subsequent cytotoxicity, liver damage due to SIRS, respiratory failure with induced hypoxic liver damage, vascular changes due to coagulopathy, endothelial dysfunction or cardiac congestion from right heart failure, drug-induced liver injury, and exacerbation of underlying liver disease[129,130].
So far, information on underlying histopathological alterations is scarce. Hepatic steatosis appears to be commonly encountered in the livers of patients with SARS-CoV-2 infection, both radiologically and histopathologically, either alone or together with inflammation[131-134]. To date, more than 20 studies with histological samples of the liver are present[131]. Most samples are retrieved postmortem and reflect a very selected population, and furthermore, most studies are written on available data during autopsy; hence, clinical data are limited. Nevertheless, histological samples on approximately 270 patients who died secondary to COVID-19 can be found in the literature, of whom 57% have hepatic steatosis, often mild, and difficult to distinguish from, e.g., shock/SIRS, drug-induced liver injury, or metabolic syndrome[130,131,134-153]. In studies where some clinical data is present, the majority of individuals are elderly, and more than a third have type 2 diabetes and/or are obese, with almost two-thirds having hypertension. This is not surprising since cardiometabolic risk factors were seen as a risk factor for COVID-19 mortality[154]. Similarly, in radiological studies (utilizing either magnetic resonance imaging or computed tomography), hepatic steatosis seems to be associated with the severity of COVID-19 illness, but is often of collinearity with obesity, type 2 diabetes, and hypertension[132,133].
Steatotic liver disease is a common finding in patients with COVID-19. Although COVID-19 does not seem to have any steatogenic properties, it is unknown if hepatic steatosis is a risk factor for more severe COVID-19, including increased mortality. Even though the incidence of hepatic steatosis is common in autopsies of patients who have died secondary to COVID-19, this is probably secondary to co-morbid conditions associated with increased mortality in COVID-19 (such as obesity and type 2 diabetes).
Environmental toxin-associated steatosis
A wide variety of environmental toxins can induce steatosis and steatohepatitis. Among these are metals (arsenic, cadmium, lead, mercury), pesticides/fungicides (e.g., fludioxonil, triflumizole), herbicides (e.g., dioxin), polychlorinated biphenyls, and chloroalkenes (e.g., perchloroethylene, trichloroethylene, and vinyl chloride)[155-157]. These agents may induce hepatic fat accumulation but also aggravate pre-existing MASLD.
Among the pathophysiological mechanisms reported to be involved in toxicant-associated SLD are disturbances of endocrine metabolic regulation and interactions between nutrients and chemicals that may aggravate metabolic irregularities[155]. Chemicals and toxins may also induce metabolic disturbances by influencing hepatokine production (e.g., fibroblast growth factor-21, insulin growth factor-1), or by interfering with anabolism and catabolism of lipids or with nuclear hormone receptors required in metabolic regulation[155,158].
Endocrine disorders associated with steatosis
Besides T2DM, some endocrine disorders predispose to steatosis. Among them are hypothyroidism, growth hormone (GH) deficiency, and hypopituitarism[159-161]. In the latter condition, it has been reported that 2.3% had evidence of SLD in the absence of other hepatic diseases or excessive alcohol consumption[162]. After the diagnosis of pituitary/hypothalamic disease, most patients exhibited weight gain, and developed T2DM or glucose intolerance and hypertriglyceridemia. These consequences are most likely associated with GH deficiency or supplementation therapy with corticosteroids[162].
Hypothyroidism is often associated with features of the metabolic syndrome, and steatosis, which are at least partly reversible by pharmacological replacement therapy[159,163-165]. Mechanisms contributing to increased hepatic triglyceride content are effects of thyroid stimulating hormone on hepatic lipid metabolism, as well as reduced glucose sensing by pancreatic β-cells due to reduced levels of thyroid hormones resulting in impaired insulin secretion and derepression of lipolysis in adipocytes, which increases the flux of free fatty acids to the liver[161,166]. Selective agonists for the thyroid hormone receptor-β are currently being evaluated for the treatment of non-alcoholic steatohepatitis. Among them, resmetirom has been shown to reduce hepatic triglyceride content after 12 and 36 weeks of treatment in a phase II trial[167].
Polycystic ovary syndrome (PCOS) is strongly associated with insulin resistance and SLD[168]. A recent meta-analysis concluded that the odds ratio for MASLD in PCOS patients was 2.54 compared to controls[169]. Steatosis in PCOS may be present in the absence of obesity and metabolic syndrome. In these cases, hyperandrogenism may be involved in the pathogenesis[169,170].
In contrast, low testosterone levels in males have been associated with SLD independently of insulin resistance, BMI, and T2DM[170,171]. Studies in animals have shown that supplementation of testosterone ameliorated high fat diet-induced steatosis in castrated rodents[172,173].
Genetic diseases associated with steatosis
Steatotic liver disease may be caused by hereditary diseases, particularly in children and young adults. Inborn errors of lipid metabolism, such as lysosomal acid lipase deficiency (LAL-D, previously termed cholesteryl ester storage disease in adults/Wolman’s disease in infancy), abetalipoproteinemia, congenital lipodystrophy, familial hypobetalipoproteinemia, and familial hyperlipidemia/hypercholesterolemia may underlie SLD[174-177].
LAL-D results from mutations in the lipase A (LIPA) gene, which have an estimated minor allele frequency of 0.18%-0.24% and are characterized by a residual enzyme activity of < 1% or 1%-5% in the pediatric and adult phenotypes, respectively. Until recently, treatment for LAL-D was primarily symptomatic and focused on a combination of dietary manipulation and the use of lipid-lowering pharmacological agents. Recently, sebelipase alfa, a recombinant enzyme replacement therapy, was approved after demonstrating positive effects on disease-relevant markers and clinical benefits in clinical trials, including survival benefits in the most severe cases[178].
SUMMARY
Most cases of SLD are associated with cardiometabolic risk factors, most commonly insulin resistance. The absence of signs and symptoms of the metabolic syndrome on clinical work-up warrants assessment of secondary causes of SLD. Many of these causes can be considered co-factors that aggravate primary MASLD, but some can trigger hepatic lipid accumulation per se [Figure 1]. Drug treatment and other primary liver diseases need to be evaluated and congenital metabolic defects should be considered, especially in younger people.
Figure 1. A schematic illustration of the included steatogenic causes of hepatic lipid accumulation. Often, several concomitant causes of steatotic liver disease exist where separating the two is difficult. Although some causes only seem to increase hepatic fat infiltration in the presence of insulin resistance (A) some can elicit steatogenic properties by themselves (i.e., in the absence of insulin resistance) (B) or by inducing insulin resistance (C).
DECLARATIONS
Authors’ contributions
Made substantial contributions to the conception and design of the study: Nasr P, Jönsson C, Ekstedt M, Kechagias S
Availability of data and materials
Not applicable.
Financial support and sponsorship
ALF Grants, Region Östergötland and Wallenberg Centre for Molecular Medicine (WCMM), Linköping University.
Conflicts of interest
All authors declared that there are no conflicts of interest.
Ethical approval and consent to participate
Not applicable.
Consent for publication
Not applicable.
Copyright
© The Author(s) 2023.
REFERENCES
1. Browning JD, Szczepaniak LS, Dobbins R, et al. Prevalence of hepatic steatosis in an urban population in the United States: impact of ethnicity. Hepatology 2004;40:1387-95.
2. Younossi ZM, Stepanova M, Afendy M, et al. Changes in the prevalence of the most common causes of chronic liver diseases in the United States from 1988 to 2008. Clin Gastroenterol Hepatol 2011;9:524-530.e1; quiz e60.
4. Rinella ME, Lazarus JV, Ratziu V, et al. NAFLD Nomenclature consensus group. A multi-society Delphi consensus statement on new fatty liver disease nomenclature. Available from: https://www.journal-of-hepatology.eu/article/S0168-8278(23)00418-X/fulltext [Last accessed on 23 Oct 2023].
5. Rinella ME, Lazarus JV, Ratziu V, et al. A multi-society Delphi consensus statement on new fatty liver disease nomenclature. Available from: https://www.sciencedirect.com/science/article/pii/S1665268123002375 [Last accessed on 23 Oct 2023].
6. Younossi ZM, Golabi P, Paik JM, Henry A, Van Dongen C, Henry L. The global epidemiology of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH): a systematic review. Hepatology 2023;77:1335-47.
7. Hagström H, Vessby J, Ekstedt M, Shang Y. 99% of patients with NAFLD meet MASLD criteria and natural history is therefore identical. J Hepatol ;2023:S0168-8278(23)05080.
8. Rinella ME, Lazarus JV, Ratziu V, et al. NAFLD Nomenclature consensus group. A multi-society Delphi consensus statement on new fatty liver disease nomenclature. Available from:https://journals.lww.com/hep/fulltext/9900/a_multi_society_delphi_consensus_statement_on_new.488.aspx [Last accessed on 23 Oct 2023].
9. Sherlock S. The Clinician Looks at Fatty Liver.
10. Brunt EM, Kleiner DE, Wilson LA, Belt P, Neuschwander-Tetri BA. NASH Clinical Research Network (CRN). Nonalcoholic fatty liver disease (NAFLD) activity score and the histopathologic diagnosis in NAFLD: distinct clinicopathologic meanings. Hepatology 2011;53:810-20.
11. Kleiner DE, Brunt EM, Van Natta M, et al. Nonalcoholic Steatohepatitis Clinical Research Network. Design and validation of a histological scoring system for nonalcoholic fatty liver disease. Hepatology 2005;41:1313-21.
12. Nasr P, Forsgren MF, Ignatova S, et al. Using a 3% proton density fat fraction as a cut-off value increases sensitivity of detection of hepatic steatosis, based on results from histopathology analysis. Gastro 2017;153:53-55.e7.
13. Szczepaniak LS, Nurenberg P, Leonard D, et al. Magnetic resonance spectroscopy to measure hepatic triglyceride content: prevalence of hepatic steatosis in the general population. Am J Physiol Endocrinol Metab 2005;288:E462-8.
14. Karlas T, Petroff D, Sasso M, et al. Individual patient data meta-analysis of controlled attenuation parameter (CAP) technology for assessing steatosis. J Hepatol 2017;66:1022-30.
15. Saad L. Majority in US drink alcohol, averaging four drinks a week. Available from: https://news.gallup.com/poll/156770/majority-drink-alcohol-averaging-four-drinks-week.aspx [Last accessed on 22 Oct 2023].
16. Trolldal B, Leifman H. Alkoholkonsumtionen i Sverige 2017. CAN Rapport 175. Hämtad från Centralförbundet för alkohol-och narkotikaupplysnings webbplats: Available from: https://www.can.se/app/uploads/2020/01/can-rapport-175-alkoholkonsumtionen-i-sverige-2017.pdf [Last accessed on 22 Oct 2023].
17. Eurobarometer S. EU citizens’ attitudes towards alcohol. Available from: https://data.europa.eu/data/datasets/s798_72_3_ebs331?locale=en[Last accessed on 23 Oct 2023].
18. Zhou Z, Wang L, Song Z, Lambert JC, McClain CJ, Kang YJ. A critical involvement of oxidative stress in acute alcohol-induced hepatic TNF-alpha production. Am J Pathol 2003;163:1137-46.
19. Chen J, Martin-Mateos R, Li J, et al. Multiparametric magnetic resonance imaging/magnetic resonance elastography assesses progression and regression of steatosis, inflammation, and fibrosis in alcohol-associated liver disease. Alcohol Clin Exp Res 2021;45:2103-17.
20. Belfrage P, Berg B, Cronholm T, et al. Prolonged administration of ethanol to young, healthy volunteers: effects on biochemical, morphological and neurophysiological parameters. Acta Med Scand Suppl ;1973:552:1-44.
21. Kechagias S, Zanjani S, Gjellan S, et al. Effects of moderate red wine consumption on liver fat and blood lipids: a prospective randomized study. Ann Med 2011;43:545-54.
22. Rasmussen DN, Thiele M, Johansen S, et al. GALAXY; MicrobLiver consortia. Prognostic performance of 7 biomarkers compared to liver biopsy in early alcohol-related liver disease. J Hepatol 2021;75:1017-25.
23. Thiele M, Rausch V, Fluhr G, et al. Controlled attenuation parameter and alcoholic hepatic steatosis: Diagnostic accuracy and role of alcohol detoxification. J Hepatol 2018;68:1025-32.
25. Ludwig J, Viggiano TR, McGill DB, Oh BJ. Nonalcoholic steatohepatitis: mayo clinic experiences with a hitherto unnamed disease. Mayo Clin Proc 1980;55:434-8.
26. Diehl AM, Goodman Z, Ishak KG. Alcohollike liver disease in nonalcoholics. a clinical and histologic comparison with alcohol-induced liver injury. Gastro 1988;95:1056-62.
28. Dam-Larsen S, Franzmann M, Andersen IB, et al. Long term prognosis of fatty liver: risk of chronic liver disease and death. Gut 2004;53:750-5.
29. Association for the Study of the Liver (EASL), European Association for the Study of Diabetes (EASD), European Association for the Study of Obesity (EASO). EASL-EASD-EASO clinical practice guidelines for the management of non-alcoholic fatty liver disease. Obes Facts 2016;9:65-90.
30. Association for the Study of the Liver. Electronic address: easloffice@easloffice.eu, European Association for the Study of the Liver. EASL clinical practice guidelines: management of alcohol-related liver disease. J Hepatol 2018;69:154-81.
31. Selin KH. Test-retest reliability of the alcohol use disorder identification test in a general population sample. Alcohol Clin Exp Res 2003;27:1428-35.
32. Saunders JB, Aasland OG, Babor TF, de la Fuente JR, Grant M. Development of the alcohol use disorders identification test (AUDIT): WHO collaborative project on early detection of persons with harmful alcohol consumption--II. Addiction 1993;88:791-804.
33. Bush K, Kivlahan DR, McDonell MB, Fihn SD, Bradley KA. The AUDIT alcohol consumption questions (AUDIT-C): an effective brief screening test for problem drinking. ambulatory care quality improvement project (ACQUIP). alcohol use disorders identification test. Arch Intern Med 1998;158:1789-95.
34. Seitz HK. Additive effects of moderate drinking and obesity on serum gamma-glutamyl transferase. Am J Clin Nutr 2006;83:1252-3.
35. Gough G, Heathers L, Puckett D, et al. The utility of commonly used laboratory tests to screen for excessive alcohol use in clinical practice. Alcohol Clin Exp Res 2015;39:1493-500.
36. Hock B, Schwarz M, Domke I, et al. Validity of carbohydrate-deficient transferrin (%CDT), gamma-glutamyltransferase (gamma-GT) and mean corpuscular erythrocyte volume (MCV) as biomarkers for chronic alcohol abuse: a study in patients with alcohol dependence and liver disorders of non-alcoholic and alcoholic origin. Addiction 2005;100:1477-86.
37. Reynaud M, Schellenberg F, Loisequx-Meunier MN, Schwan R, Maradeix B, Planche F, Gillet C. Objective diagnosis of alcohol abuse: compared values of carbohydrate-deficient transferrin (CDT), gamma-glutamyl transferase (GGT), and mean corpuscular volume (MCV). Alcohol Clin Exp Res 2000;24:1414-9.
38. Staufer K, Andresen H, Vettorazzi E, Tobias N, Nashan B, Sterneck M. Urinary ethyl glucuronide as a novel screening tool in patients pre- and post-liver transplantation improves detection of alcohol consumption. Hepatology 2011;54:1640-9.
39. Helander A, Wielders J, Anton R, et al. International Federation of Clinical Chemistry and Laboratory Medicine Working Group on Standardisation of Carbohydrate-Deficient Transferrin (IFCC WG-CDT). Standardisation and use of the alcohol biomarker carbohydrate-deficient transferrin (CDT). Clin Chim Acta 2016;459:19-24.
40. Niemelä O. Biomarker-based approaches for assessing alcohol use disorders. Int J Environ Res Public Health 2016;13:166.
41. Anton RF, Lieber C, Tabakoff B. Carbohydrate-deficient transferrin and gamma-glutamyltransferase for the detection and monitoring of alcohol use: results from a multisite study. Alcoholism Clin Exp Res 2002;26:1215-22.
42. Anton RF. Carbohydrate-deficient transferrin for detection and monitoring of sustained heavy drinking. what have we learned? Alcohol 2001;25:185-8.
43. Hartmann S, Aradottir S, Graf M, et al. Phosphatidylethanol as a sensitive and specific biomarker: comparison with gamma-glutamyl transpeptidase, mean corpuscular volume and carbohydrate-deficient transferrin. Addict Biol 2007;12:81-4.
44. Schröck A, Thierauf-Emberger A, Schürch S, Weinmann W. Phosphatidylethanol (PEth) detected in blood for 3 to 12 days after single consumption of alcohol-a drinking study with 16 volunteers. Int J Legal Med 2017;131:153-60.
45. Kechagias S, Dernroth DN, Blomgren A, et al. Phosphatidylethanol compared with other blood tests as a biomarker of moderate alcohol consumption in healthy volunteers: a prospective randomized study. Alcohol Alcohol 2015;50:399-406.
46. Walther L, de Bejczy A, Löf E, et al. Phosphatidylethanol is superior to carbohydrate-deficient transferrin and γ-glutamyltransferase as an alcohol marker and is a reliable estimate of alcohol consumption level. Alcohol Clin Exp Res 2015;39:2200-8.
47. Long MT, Massaro JM, Hoffmann U, Benjamin EJ, Naimi TS. Alcohol use is associated with hepatic steatosis among persons with presumed nonalcoholic fatty liver disease. Clin Gastroenterol H 2020;18:1831-1841.e5.
48. Bellentani S, Saccoccio G, Masutti F, et al. Prevalence of and risk factors for hepatic steatosis in Northern Italy. Ann Intern Med 2000;132:112-7.
49. Lau K, Baumeister SE, Lieb W, et al. The combined effects of alcohol consumption and body mass index on hepatic steatosis in a general population sample of European men and women. Aliment Pharmacol Ther 2015;41:467-76.
50. Staufer K, Huber-Schönauer U, Strebinger G, et al. Ethyl glucuronide in hair detects a high rate of harmful alcohol consumption in presumed non-alcoholic fatty liver disease. J Hepatol 2022;77:918-30.
51. Dunn W, Sanyal AJ, Brunt EM, et al. Modest alcohol consumption is associated with decreased prevalence of steatohepatitis in patients with non-alcoholic fatty liver disease (NAFLD). J Hepatol 2012;57:384-91.
52. Kwon HK, Greenson JK, Conjeevaram HS. Effect of lifetime alcohol consumption on the histological severity of non-alcoholic fatty liver disease. Liver Int 2014;34:129-35.
53. Cao G, Yi T, Liu Q, Wang M, Tang S. Alcohol consumption and risk of fatty liver disease: a meta-analysis. PeerJ 2016;4:e2633.
54. Moriya A, Iwasaki Y, Ohguchi S, et al. Roles of alcohol consumption in fatty liver: a longitudinal study. J Hepatol 2015;62:921-7.
55. Hagström H, Nasr P, Ekstedt M, et al. Low to moderate lifetime alcohol consumption is associated with less advanced stages of fibrosis in non-alcoholic fatty liver disease. Scand J Gastroenterol 2017;52:159-65.
56. Hajifathalian K, Torabi Sagvand B, McCullough AJ. Effect of alcohol consumption on survival in nonalcoholic fatty liver disease: a national prospective cohort study. Hepatology 2019;70:511-21.
57. Ekstedt M, Franzén LE, Holmqvist M, et al. Alcohol consumption is associated with progression of hepatic fibrosis in non-alcoholic fatty liver disease. Scand J Gastroenterol 2009;44:366-74.
58. Ascha MS, Hanouneh IA, Lopez R, Tamimi TA, Feldstein AF, Zein NN. The incidence and risk factors of hepatocellular carcinoma in patients with nonalcoholic steatohepatitis. Hepatology 2010;51:1972-8.
59. Ajmera V, Belt P, Wilson LA, et al. Nonalcoholic Steatohepatitis Clinical Research Network. Among patients with nonalcoholic fatty liver disease, modest alcohol use is associated with less improvement in histologic steatosis and steatohepatitis. Clin Gastroenterol Hepatol 2018;16:1511-1520.e5.
60. Kimura T, Tanaka N, Fujimori N, et al. Mild drinking habit is a risk factor for hepatocarcinogenesis in non-alcoholic fatty liver disease with advanced fibrosis. World J Gastroenterol 2018;24:1440-50.
61. Ronksley PE, Brien SE, Turner BJ, Mukamal KJ, Ghali WA. Association of alcohol consumption with selected cardiovascular disease outcomes: a systematic review and meta-analysis. BMJ 2011;342:d671.
62. 2016 Alcohol Collaborators. Alcohol use and burden for 195 countries and territories, 1990-2016: a systematic analysis for the global burden of disease study 2016. Lancet 2018;392:1015-35.
63. Åberg F, Helenius-Hietala J, Puukka P, Färkkilä M, Jula A. Interaction between alcohol consumption and metabolic syndrome in predicting severe liver disease in the general population. Hepatology 2018;67:2141-9.
64. Chang Y, Cho YK, Kim Y, et al. Nonheavy drinking and worsening of noninvasive fibrosis markers in nonalcoholic fatty liver disease: a cohort study. Hepatology 2019;69:64-75.
65. Younossi ZM, Stepanova M, Ong J, et al. Global NASH Council. Effects of alcohol consumption and metabolic syndrome on mortality in patients with nonalcoholic and alcohol-related fatty liver disease. Clin Gastroenterol Hepatol 2019;17:1625-1633.e1.
66. Hagström H, Ekstedt M. Considerations in the search for under-reported alcohol consumption in NAFLD. J Hepatol 2023;78:e66-7.
67. Ezhilarasan D. Hepatotoxic potentials of methotrexate: understanding the possible toxicological molecular mechanisms. Toxicology 2021;458:152840.
68. Malaviya AN, Sharma A, Agarwal D, Kapoor S, Garg S, Sawhney S. Low-dose and high-dose methotrexate are two different drugs in practical terms. Int J Rheum Dis 2010;13:288-93.
69. Roenigk HH, Fowler-Bergfeld W, Curtis GH. Methotrexate for psoriasis in weekly oral doses. Arch Dermatol 1969;99:86-93.
70. Sundbaum J, Eriksson N, Hallberg P, Lehto N, Wadelius M, Baecklund E. Methotrexate treatment in rheumatoid arthritis and elevated liver enzymes: a long-term follow-up of predictors, surveillance, and outcome in clinical practice. Int J Rheum Dis 2019;22:1226-32.
71. Schröder T, Schmidt KJ, Olsen V, et al. Liver steatosis is a risk factor for hepatotoxicity in patients with inflammatory bowel disease under immunosuppressive treatment. Eur J Gastroenterol Hepatol 2015;27:698-704.
72. Mori S, Arima N, Ito M, Fujiyama S, Kamo Y, Ueki Y. Non-alcoholic steatohepatitis-like pattern in liver biopsy of rheumatoid arthritis patients with persistent transaminitis during low-dose methotrexate treatment. PLoS One 2018;13:e0203084.
73. Chalmers RJ, Boffa MJ, Kirby B, Smith A. Liver biopsies and methotrexate: a time for reconsideration? J Am Acad Dermatol 2001;44:879-80.
74. Zachariae H, Kragballe K, Søgaard H. Methotrexate induced liver cirrhosis: studies including serial liver biopsies during continued treatment. Br J Dermatol 1980;102:407-12.
75. Zachariae H, Søgaard H, Heickendorff L. Methotrexate-induced liver cirrhosis. clinical, histological and serological studies--a further 10-year follow-up. Dermatology 1996;192:343-6.
76. Zachariae H, Schiodt T. Liver biopsy in methotrexate treatment. Acta Derm Venereol 1971;51:215-20.
77. Gelfand JM, Wan J, Zhang H, et al. Risk of liver disease in patients with psoriasis, psoriatic arthritis, and rheumatoid arthritis receiving methotrexate: a population-based study. J Am Acad Dermatol 2021;84:1636-43.
78. Ruan Z, Lu T, Chen Y, et al. Association between psoriasis and nonalcoholic fatty liver disease among outpatient US adults. JAMA Dermatol 2022;158:745-53.
79. Maybury CM, Porter HF, Kloczko E, et al. Prevalence of advanced liver fibrosis in patients with severe psoriasis. JAMA Dermatol 2019;155:1028-32.
80. Laharie D, Seneschal J, Schaeverbeke T, et al. Assessment of liver fibrosis with transient elastography and FibroTest in patients treated with methotrexate for chronic inflammatory diseases: a case-control study. J Hepatol 2010;53:1035-40.
81. Choi Y, Lee CH, Kim IH, Park EH, Park S, Yoo WH. Methotrexate use does not increase the prevalence of hepatic steatosis: a real-world retrospective nested case-control study. Clin Rheumatol 2021;40:2037-45.
82. Tomaszewski M, Dahiya M, Mohajerani SA, et al. Hepatic steatosis as measured by the computed attenuation parameter predicts fibrosis in long-term methotrexate use. Can Liver J 2021;4:370-80.
83. Erre GL, Castagna F, Sauchella A, et al. Prevalence and risk factors of moderate to severe hepatic steatosis in patients with rheumatoid arthritis: an ultrasonography cross-sectional case-control study. Ther Adv Musculoskelet Dis 2021;13:1759720X211042739.
84. Association for the Study of the Liver. Electronic address: easloffice@easloffice.eu, Clinical Practice Guideline Panel: Chair:, Panel members, EASL Governing Board representative:. EASL clinical practice guidelines: drug-induced liver injury. J Hepatol 2019;70:1222-61.
85. Lee B, Jung EA, Yoo JJ, et al. Prevalence, incidence and risk factors of tamoxifen-related non-alcoholic fatty liver disease: a systematic review and meta-analysis. Liver Int 2020;40:1344-55.
86. Lelliott CJ, López M, Curtis RK, et al. Transcript and metabolite analysis of the effects of tamoxifen in rat liver reveals inhibition of fatty acid synthesis in the presence of hepatic steatosis. FASEB J 2005;19:1108-19.
87. Gudbrandsen OA, Rost TH, Berge RK. Causes and prevention of tamoxifen-induced accumulation of triacylglycerol in rat liver. J Lipid Res 2006;47:2223-32.
88. Cole LK, Jacobs RL, Vance DE. Tamoxifen induces triacylglycerol accumulation in the mouse liver by activation of fatty acid synthesis. Hepatology 2010;52:1258-65.
89. Bruno S, Maisonneuve P, Castellana P, et al. Incidence and risk factors for non-alcoholic steatohepatitis: prospective study of 5408 women enrolled in Italian tamoxifen chemoprevention trial. BMJ 2005;330:932.
90. Elefsiniotis IS, Pantazis KD, Ilias A, et al. Tamoxifen induced hepatotoxicity in breast cancer patients with pre-existing liver steatosis: the role of glucose intolerance. Eur J Gastroen Hepat 2004;16:593-8.
91. Osman KA, Osman MM, Ahmed MH. Tamoxifen-induced non-alcoholic steatohepatitis: where are we now and where are we going? Expert Opin Drug Saf 2007;6:1-4.
92. Staa TP, Leufkens HG, Abenhaim L, Begaud B, Zhang B, Cooper C. Use of oral corticosteroids in the United Kingdom. QJM 2000;93:105-11.
93. Overman RA, Yeh JY, Deal CL. Prevalence of oral glucocorticoid usage in the United States: a general population perspective. Arthritis Care Res 2013;65:294-8.
94. Tarantino G, Finelli C. Pathogenesis of hepatic steatosis: the link between hypercortisolism and non-alcoholic fatty liver disease. World J Gastroenterol 2013;19:6735-43.
95. Rahimi L, Rajpal A, Ismail-Beigi F. Glucocorticoid-induced fatty liver disease. Diabetes Metab Syndr Obes 2020;13:1133-45.
96. Buzzetti E, Pinzani M, Tsochatzis EA. The multiple-hit pathogenesis of non-alcoholic fatty liver disease (NAFLD). Metabolism 2016;65:1038-48.
97. Li JX, Cummins CL. Fresh insights into glucocorticoid-induced diabetes mellitus and new therapeutic directions. Nat Rev Endocrinol 2022;18:540-57.
98. Rockall AG, Sohaib SA, Evans D, et al. Hepatic steatosis in cushing's syndrome: a radiological assessment using computed tomography. Eur J Endocrinol 2003;149:543-8.
99. Younossi ZM, Koenig AB, Abdelatif D, Fazel Y, Henry L, Wymer M. Global epidemiology of nonalcoholic fatty liver disease-Meta-analytic assessment of prevalence, incidence, and outcomes. Hepatology 2016;64:73-84.
100. Hubel JM, Schmidt SA, Mason RA, et al. EMIL-Study Group. Influence of plasma cortisol and other laboratory parameters on nonalcoholic Fatty liver disease. Horm Metab Res 2015;47:479-84.
101. Pagano G, Cavallo-Perin P, Cassader M, et al. An in vivo and in vitro study of the mechanism of prednisone-induced insulin resistance in healthy subjects. J Clin Invest 1983;72:1814-20.
102. Gulliford MC, Charlton J, Latinovic R. Risk of diabetes associated with prescribed glucocorticoids in a large population. Diabetes Care 2006;29:2728-9.
103. Negro F. Abnormalities of lipid metabolism in hepatitis C virus infection. Gut 2010;59:1279-87.
104. Mihm S, Fayyazi A, Hartmann H, Ramadori G. Analysis of histopathological manifestations of chronic hepatitis C virus infection with respect to virus genotype. Hepatology 1997;25:735-9.
105. Patton HM, Patel K, Behling C, et al. The impact of steatosis on disease progression and early and sustained treatment response in chronic hepatitis C patients. J Hepatol 2004;40:484-90.
106. Rubbia-Brandt L, Quadri R, Abid K, et al. Hepatocyte steatosis is a cytopathic effect of hepatitis C virus genotype 3. J Hepatol 2000;33:106-15.
107. Adinolfi LE, Gambardella M, Andreana A, Tripodi MF, Utili R, Ruggiero G. Steatosis accelerates the progression of liver damage of chronic hepatitis C patients and correlates with specific HCV genotype and visceral obesity. Hepatology 2001;33:1358-64.
108. Kumar D, Farrell GC, Fung C, George J. Hepatitis C virus genotype 3 is cytopathic to hepatocytes: reversal of hepatic steatosis after sustained therapeutic response. Hepatology 2002;36:1266-72.
109. Lonardo A, Loria P, Adinolfi LE, Carulli N, Ruggiero G. Hepatitis C and steatosis: a reappraisal. J Viral Hepat 2006;13:73-80.
110. Hofer H, Bankl HC, Wrba F, et al. Hepatocellular fat accumulation and low serum cholesterol in patients infected with HCV-3a. Am J Gastroenterol 2002;97:2880-5.
111. Serfaty L, Andreani T, Giral P, Carbonell N, Chazouillères O, Poupon R. Hepatitis C virus induced hypobetalipoproteinemia: a possible mechanism for steatosis in chronic hepatitis C. J Hepatol 2001;34:428-34.
112. Leslie J, Geh D, Elsharkawy AM, Mann DA, Vacca M. Metabolic dysfunction and cancer in HCV: shared pathways and mutual interactions. J Hepatol 2022;77:219-36.
113. Felmlee DJ, Hafirassou ML, Lefevre M, Baumert TF, Schuster C. Hepatitis C virus, cholesterol and lipoproteins--impact for the viral life cycle and pathogenesis of liver disease. Viruses 2013;5:1292-324.
114. Monto A, Alonzo J, Watson JJ, Grunfeld C, Wright TL. Steatosis in chronic hepatitis C: relative contributions of obesity, diabetes mellitus, and alcohol. Hepatology 2002;36:729-36.
115. Rubbia-Brandt L, Fabris P, Paganin S, et al. Steatosis affects chronic hepatitis C progression in a genotype specific way. Gut 2004;53:406-12.
116. Kim MN, Han K, Yoo J, Hwang SG, Ahn SH. Increased risk of hepatocellular carcinoma and mortality in chronic viral hepatitis with concurrent fatty liver. Aliment Pharmacol Ther 2022;55:97-107.
117. Shimizu K, Soroida Y, Sato M, et al. Eradication of hepatitis C virus is associated with the attenuation of steatosis as evaluated using a controlled attenuation parameter. Sci Rep 2018;8:7845.
118. Shousha HI, Abdelaziz RA, Azab SM, et al. Effect of treatment with direct acting antivirals on body mass index and hepatic steatosis in chronic hepatitis C. J Med Virol 2018;90:1099-105.
119. Rout G, Nayak B, Patel AH, et al. Therapy with oral directly acting agents in hepatitis C infection is associated with reduction in fibrosis and increase in hepatic steatosis on transient elastography. J Clin Exp Hepatol 2019;9:207-14.
120. Do A, Esserman DA, Krishnan S, et al. Excess weight gain after cure of hepatitis C infection with direct-acting antivirals. J Gen Intern Med 2020;35:2025-34.
121. Kalligeros M, Vassilopoulos A, Shehadeh F, et al. Prevalence and characteristics of nonalcoholic fatty liver disease and fibrosis in people living with HIV monoinfection: a systematic review and meta-analysis. Clin Gastroenterol Hepatol 2023;21:1708-22.
122. Maurice JB, Patel A, Scott AJ, Patel K, Thursz M, Lemoine M. Prevalence and risk factors of nonalcoholic fatty liver disease in HIV-monoinfection. AIDS 2017;31:1621-32.
123. Welzen BJ, Mudrikova T, El Idrissi A, Hoepelman AIM, Arends JE. A review of non-alcoholic fatty liver disease in HIV-infected patients: the next big thing? Infect Dis Ther 2019;8:33-50.
124. Gutierrez AD, Balasubramanyam A. Dysregulation of glucose metabolism in HIV patients: epidemiology, mechanisms, and management. Endocrine 2012;41:1-10.
125. Magkos F, Mantzoros CS. Body fat redistribution and metabolic abnormalities in HIV-infected patients on highly active antiretroviral therapy: novel insights into pathophysiology and emerging opportunities for treatment. Metabolism 2011;60:749-53.
126. Wiersinga WJ, Rhodes A, Cheng AC, Peacock SJ, Prescott HC. Pathophysiology, transmission, diagnosis, and treatment of coronavirus disease 2019 (COVID-19): a review. JAMA 2020;324:782-93.
127. Zhang C, Shi L, Wang FS. Liver injury in COVID-19: management and challenges. Lancet Gastroenterol Hepatol 2020;5:428-30.
128. Kulkarni AV, Kumar P, Tevethia HV, et al. Systematic review with meta-analysis: liver manifestations and outcomes in COVID-19. Aliment Pharmacol Ther 2020;52:584-99.
129. Nardo AD, Schneeweiss-Gleixner M, Bakail M, Dixon ED, Lax SF, Trauner M. Pathophysiological mechanisms of liver injury in COVID-19. Liver Int 2021;41:20-32.
130. Wang Y, Liu S, Liu H, et al. SARS-CoV-2 infection of the liver directly contributes to hepatic impairment in patients with COVID-19. J Hepatol 2020;73:807-16.
131. Yang C, Cai L, Xiao SY. Pathologic characteristics of digestive tract and liver in patients with coronavirus disease 2019. Gastroenterol Clin North Am 2023;52:201-14.
132. Roca-Fernández A, Dennis A, Nicholls R, et al. Hepatic steatosis, rather than underlying obesity, increases the risk of infection and hospitalization for COVID-19. Front Med 2021;8:636637.
133. Palomar-Lever A, Barraza G, Galicia-Alba J, et al. Hepatic steatosis as an independent risk factor for severe disease in patients with COVID-19: a computed tomography study. JGH Open 2020;4:1102-7.
134. Bradley BT, Maioli H, Johnston R, et al. Histopathology and ultrastructural findings of fatal COVID-19 infections in Washington State: a case series. Lancet 2020;396:320-32.
135. Fassan M, Mescoli C, Sbaraglia M, et al. Liver histopathology in COVID-19 patients: a mono-Institutional series of liver biopsies and autopsy specimens. Pathol Res Pract 2021;221:153451.
136. Beigmohammadi MT, Jahanbin B, Safaei M, et al. Pathological findings of postmortem biopsies from lung, heart, and liver of 7 deceased COVID-19 patients. Int J Surg Pathol 2021;29:135-45.
137. Duarte-Neto AN, Monteiro RAA, da Silva LFF, et al. Pulmonary and systemic involvement in COVID-19 patients assessed with ultrasound-guided minimally invasive autopsy. Histopathology 2020;77:186-97.
138. Elsoukkary SS, Mostyka M, Dillard A, et al. Autopsy findings in 32 patients with COVID-19: a single-institution experience. Pathobiology 2021;88:56-68.
139. Falasca L, Nardacci R, Colombo D, et al. Postmortem findings in italian patients with COVID-19: a descriptive full autopsy study of cases with and without comorbidities. J Infect Dis 2020;222:1807-15.
140. Rapkiewicz AV, Mai X, Carsons SE, et al. Megakaryocytes and platelet-fibrin thrombi characterize multi-organ thrombosis at autopsy in COVID-19: a case series. EClinicalMedicine 2020;24:100434.
141. Lagana SM, Kudose S, Iuga AC, et al. Hepatic pathology in patients dying of COVID-19: a series of 40 cases including clinical, histologic, and virologic data. Modern Pathology 2020;33:2147-55.
142. Sonzogni A, Previtali G, Seghezzi M, et al. Liver histopathology in severe COVID 19 respiratory failure is suggestive of vascular alterations. Liver Int 2020;40:2110-6.
143. Tian S, Xiong Y, Liu H, et al. Pathological study of the 2019 novel coronavirus disease (COVID-19) through postmortem core biopsies. Mod Pathol 2020;33:1007-14.
144. Trevenzoli M, Guarnaccia A, Alberici I, et al. SARS-CoV-2 and hepatitis. J Gastrointestin Liver Dis 2020;29:473-5.
145. Zhao CL, Rapkiewicz A, Maghsoodi-Deerwester M, et al. Pathological findings in the postmortem liver of patients with coronavirus disease 2019 (COVID-19). Hum Pathol 2021;109:59-68.
146. Greuel S, Ihlow J, Dragomir MP, et al. COVID-19: autopsy findings in six patients between 26 and 46 years of age. Int J Infect Dis 2021;108:274-81.
147. Xu Z, Shi L, Wang Y, et al. Pathological findings of COVID-19 associated with acute respiratory distress syndrome. Lancet Respir Med 2020;8:420-2.
148. Cai Q, Huang D, Yu H, et al. COVID-19: abnormal liver function tests. J Hepatol 2020;73:566-74.
149. McConnell MJ, Kawaguchi N, Kondo R, et al. Liver injury in COVID-19 and IL-6 trans-signaling-induced endotheliopathy. J Hepatol 2021;75:647-58.
150. Yurdaisik I, Demiroz AS, Oz AB, et al. Postmortem biopsies of the lung, heart, liver, and spleen of COVID-19 patients. Cureus 2021;13:e20734.
151. Ramos-Rincon JM, Alenda C, García-Sevila R, et al. Histopathological and virological features of lung, heart and liver percutaneous tissue core biopsy in patients with COVID-19: a clinicopathological case series. Malays J Pathol 2022;44:83-92.
152. Chornenkyy Y, Mejia-Bautista M, Brucal M, et al. Liver pathology and SARS-CoV-2 detection in formalin-fixed tissue of patients with COVID-19. Am J Clin Pathol 2021;155:802-14.
153. Fraga M, Moradpour D, Artru F, et al. Hepatocellular type II fibrinogen inclusions in a patient with severe COVID-19 and hepatitis. J Hepatol 2020;73:967-70.
154. Williamson EJ, Walker AJ, Bhaskaran K, et al. Factors associated with COVID-19-related death using openSAFELY. Nature 2020;584:430-6.
155. Wahlang B, Jin J, Beier JI, et al. Mechanisms of environmental contributions to fatty liver disease. Curr Environ Health Rep 2019;6:80-94.
156. Wahlang B, Beier JI, Clair HB, et al. Toxicant-associated steatohepatitis. Toxicol Pathol 2013;41:343-60.
157. Foulds CE, Treviño LS, York B, Walker CL. Endocrine-disrupting chemicals and fatty liver disease. Nat Rev Endocrinol 2017;13:445-57.
158. Shi H, Jan J, Hardesty JE, et al. Polychlorinated biphenyl exposures differentially regulate hepatic metabolism and pancreatic function: Implications for nonalcoholic steatohepatitis and diabetes. Toxicol Appl Pharmacol 2019;363:22-33.
159. Lonardo A, Mantovani A, Lugari S, Targher G. NAFLD in some common endocrine diseases: prevalence, pathophysiology, and principles of diagnosis and management. Int J Mol Sci 2019;20:2841.
160. Cotter TG, Rinella M. Nonalcoholic fatty liver disease 2020: the state of the disease. Gastroenterology 2020;158:1851-64.
161. Ferrandino G, Kaspari RR, Spadaro O, et al. Pathogenesis of hypothyroidism-induced NAFLD is driven by intra- and extrahepatic mechanisms. Proc Natl Acad Sci U S A 2017;114:E9172-80.
162. Adams LA, Feldstein A, Lindor KD, Angulo P. Nonalcoholic fatty liver disease among patients with hypothalamic and pituitary dysfunction. Hepatology 2004;39:909-14.
163. Liangpunsakul S, Chalasani N. Is hypothyroidism a risk factor for non-alcoholic steatohepatitis? J Clin Gastroenterol 2003;37:340-3.
164. Chung GE, Kim D, Kim W, et al. Non-alcoholic fatty liver disease across the spectrum of hypothyroidism. J Hepatol 2012;57:150-6.
165. Xu L, Ma H, Miao M, Li Y. Impact of subclinical hypothyroidism on the development of non-alcoholic fatty liver disease: a prospective case-control study. J Hepatol 2012;57:1153-4.
166. Lonardo A, Ballestri S, Mantovani A, Nascimbeni F, Lugari S, Targher G. Pathogenesis of hypothyroidism-induced NAFLD: evidence for a distinct disease entity? Dig Liver Dis 2019;51:462-70.
167. Harrison SA, Bashir MR, Guy CD, et al. Resmetirom (MGL-3196) for the treatment of non-alcoholic steatohepatitis: a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial. Lancet 2019;394:2012-24.
168. Cerda C, Pérez-Ayuso RM, Riquelme A, et al. Nonalcoholic fatty liver disease in women with polycystic ovary syndrome. J Hepatol 2007;47:412-7.
169. Rocha ALL, Faria LC, Guimarães TCM, et al. Non-alcoholic fatty liver disease in women with polycystic ovary syndrome: systematic review and meta-analysis. J Endocrinol Invest 2017;40:1279-88.
170. Jones H, Sprung VS, Pugh CJ, et al. Polycystic ovary syndrome with hyperandrogenism is characterized by an increased risk of hepatic steatosis compared to nonhyperandrogenic PCOS phenotypes and healthy controls, independent of obesity and insulin resistance. J Clin Endocrinol Metab 2012;97:3709-16.
171. Kim S, Kwon H, Park JH, et al. A low level of serum total testosterone is independently associated with nonalcoholic fatty liver disease. BMC Gastroenterol 2012;12:69.
172. Nikolaenko L, Jia Y, Wang C, et al. Testosterone replacement ameliorates nonalcoholic fatty liver disease in castrated male rats. Endocrinology 2014;155:417-28.
173. Senmaru T, Fukui M, Okada H, et al. Testosterone deficiency induces markedly decreased serum triglycerides, increased small dense LDL, and hepatic steatosis mediated by dysregulation of lipid assembly and secretion in mice fed a high-fat diet. Metabolism 2013;62:851-60.
174. Pericleous M, Kelly C, Wang T, Livingstone C, Ala A. Wolman's disease and cholesteryl ester storage disorder: the phenotypic spectrum of lysosomal acid lipase deficiency. Lancet Gastroenterol 2017;2:670-9.
175. Polyzos SA, Perakakis N, Mantzoros CS. Fatty liver in lipodystrophy: a review with a focus on therapeutic perspectives of adiponectin and/or leptin replacement. Metabolism 2019;96:66-82.
176. Di Filippo M, Moulin P, Roy P, et al. Homozygous MTTP and APOB mutations may lead to hepatic steatosis and fibrosis despite metabolic differences in congenital hypocholesterolemia. J Hepatol 2014;61:891-902.
177. Bernstein DL, Hülkova H, Bialer MG, Desnick RJ. Cholesteryl ester storage disease: review of the findings in 135 reported patients with an underdiagnosed disease. J Hepatol 2013;58:1230-43.
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Nasr P, Jönsson C, Ekstedt M, Kechagias S. Non-metabolic causes of steatotic liver disease. Metab Target Organ Damage 2023;3:19. http://dx.doi.org/10.20517/mtod.2023.20
AMA Style
Nasr P, Jönsson C, Ekstedt M, Kechagias S. Non-metabolic causes of steatotic liver disease. Metabolism and Target Organ Damage. 2023; 3(4): 19. http://dx.doi.org/10.20517/mtod.2023.20
Chicago/Turabian Style
Nasr, Patrik, Cecilia Jönsson, Mattias Ekstedt, Stergios Kechagias. 2023. "Non-metabolic causes of steatotic liver disease" Metabolism and Target Organ Damage. 3, no.4: 19. http://dx.doi.org/10.20517/mtod.2023.20
ACS Style
Nasr, P.; Jönsson C.; Ekstedt M.; Kechagias S. Non-metabolic causes of steatotic liver disease. Metab Target Organ Damage. 2023, 3, 19. http://dx.doi.org/10.20517/mtod.2023.20
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