Personalized therapy when tackling nonalcoholic fatty liver disease: a focus on sex, genes, and drugs

ABSTRACT

Introduction: Nonalcoholic fatty liver disease (NAFLD) is the most frequent liver disease in the world. It describes a term for a group of hepatic diseases including steatosis, fibrosis, and cirrhosis that can finally lead to hepatocellular carcinoma. There are many factors influencing NAFLD initiation and progression, such as obesity, dyslipidemia, insulin resistance, genetic factors, and hormonal changes. However, there is also lean-NAFLD which is not associated with obesity. NAFLD is considered to be a sexually dimorphic disease. In most cases, men have a higher prevalence for the disease compared to premenopausal women.

Areas covered: In this review, we first summarize the NAFLD disease epidemiology, pathology, and diagnosis. We describe NAFLD progression with the focus on sexual and genetic differences for disease development and pharmacological treatment. Personalized treatment for multifactorial NAFLD is discussed in consideration of different factors, including genetics, gender and sex.

Expert opinion: The livers of female and male NAFLD patients have different metabolic capacities which influence the metabolism of all drugs applied to such patients. This aspect is not yet sufficiently taken into account. The liver computational models might quicken the pace toward assessing personalized disease progression and treatment options.

KEYWORDS:

• Nonalcoholic fatty liver disease (NAFD)
• sexual dimorphism
• personalized therapy
• NAFLD treatment
• NAFLD genetics
• hormonal differences
• lean NAFLD
• drug metabolism
• cytochrome P450

Article highlights

• NAFLD is a complex disease caused by a variety of factors and is the most common liver disease in developed countries with prevalence around 25%.

• The major causes for obese NAFLD development are sedentary life, high fat diet, obesity, insulin resistance, and genetic factors, all leading to inflammation and fibrosis. The reasons for lean-NAFLD are less clear.

• Data for NAFLD prevalence are not always consistent, but the majority of studies show higher prevalence in males compared to premenopausal females. Sexual dimorphism is not fully understood, but is probably the result of factors like growth and sex hormones, genetic factors and visceral fat accumulation.

• Genetics play a big part in NAFLD and multiple SNPs were found to contribute to NAFLD development; the most validated is the polymorphism in PNPLA3. Epigenetics is also an important factor in NAFLD.

• There is no direct treatment for NAFLD, but comorbidities are treated with a variety of drugs. NAFLD affects the levels and activity of CYP enzymes that metabolize different drugs. Drug metabolizing CYPs also show a sexually dimorphic expression.

• Personalized treatment should be considered in all NAFLD patients. The treatment should examine the genetic profile of the patient, gender, environmental factors, diet habits and also CYP status to determine which drug or other treatment should be used on the specific patient.

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Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Additional information

Funding

The authors were supported by grants from the Slovenian Research Agency [grant nos. P1-0390, I0-0022 ELIXIR]. Z Drakulic is a masters’ student of medicine at the Faculty of Medicine University of Ljubljana.