Page 43 - Read Online

Nasr et al. Metab Target Organ Damage 2023;3:19 https://dx.doi.org/10.20517/mtod.2023.20 Page 9 of 17

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
[155]
aggravate metabolic irregularities . 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%
[162]
had evidence of SLD in the absence of other hepatic diseases or excessive alcohol consumption . 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
[162]
deficiency or supplementation therapy with corticosteroids .
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
[167]
trial .
Polycystic ovary syndrome (PCOS) is strongly associated with insulin resistance and SLD . A recent meta-
[168]
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