Role of Lisinopril in Preventing the Progression of Non-Alcoholic Fatty Liver Disease, RELIEF-NAFLD Study

Eligibility Criteria

• * Male and female subjects \>= 18 years of age
• * Clinical diagnosis of nonalcoholic steatohepatitis (NASH) assessed by the presence of body imaging criteria (ultrasound, computed tomography \[CT\], or magnetic resonance imaging \[MRI\]), or liver biopsy up to six months prior to enrollment without suspicious nodules or cancer
• * Screening transient elastography liver stiffness \>= 12 kPa (which correlates with F3 fibrosis and more) and \< 25 kPa. Historic transient elastography within 0-4 weeks prior to the date of the screening visit is acceptable. Patients with liver stiffness \>= 10 and \< 12 kPA with clinical evidence of cirrhosis based on any of the following criteria would also be eligible.
• * Imaging diagnosis of nodular liver with splenomegaly or recanalized umbilical vein
• * MRE \>= 5 kPa
• * Fibrosis (FIB)-4 \> 2.67 or platelet count \< 150,000 mL
• * Liver biopsy \< 5 years with meta-analysis of histological data in viral hepatitis (METAVIR) stage 4 or Ishak stage 5-6
• * Controlled attenuation parameter score or liver steatosis analysis (LiSA) of \>= 260 dB/m and any single component of metabolic syndrome (ATP3 criteria) or historic liver biopsy within 0 - 6 months prior to the date of the screening visit consistent with nonalcoholic steatohepatitis (NASH) (defined as the presence of steatosis, inflammation, and ballooning), with stage 3-4 fibrosis according to the NASH Clinical Research Network classification (or equivalent)
• * Leukocytes \>= 3,000/microliter
• * Absolute neutrophil count \>= 1,500/microliter
• * Platelets \>= 75,000/microliter
• * Total bilirubin within normal institutional limits unless the patient has Gilbert's syndrome
• * Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase \[SGOT\])/alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase \[SGPT\]) =\< 8 x institutional upper limit of institutional limits
• * Glomerular filtration rate \> 30 ml/min
• * International normalized ratio (INR) =\< 1.3 unless the patient is on a therapeutic medication
• * Eastern Cooperative Oncology Group (ECOG) performance status =\< 2 (Karnofsky \>= 60%)
• * The effects of lisinopril has been shown to be teratogenic in animal models. For this reason, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her study physician immediately
• * Ability to understand and the willingness to sign a written informed consent document. If a participant has impaired decision-making capacity (IDMC), their legal representative may replace them in this process
• * Systolic blood pressure \>= 90 and =\< 160 mm/Hg. Diastolic blood pressure \>= 60 and =\< 110 mm/Hg
• * Prior or current use of an angiotensin converting enzyme inhibitor (ACEi) or angiotensin II receptor antagonist (ARB) within 0-24 weeks prior to enrollment
• * Glomerular filtration rate =\< 30 ml/min (for both male and female participants)
• * History of decompensated liver disease, including ascites, hepatic encephalopathy, or high-risk variceal bleeding
• * NOTE: Trace ascites documented by radiology is permitted
• * History of other causes of liver disease, including but not limited to alcoholic liver disease, hepatitis B, hepatitis C, autoimmune disorders (primary biliary cholangitis, primary sclerosing cholangitis, or autoimmune hepatitis), drug-induced hepatotoxicity, Wilson's disease, iron overload, or alpha-1-antitryspin deficiency
• * History of liver transplantation
• * History of hepatocellular carcinoma (HCC) diagnosis
• * History of weight reduction surgery in the past 2 years or planned during the study
• * Within 6 months prior to the date of the screening visit, there must be no history of the following cardiac events: unstable angina; myocardial infarction, coronary artery bypass surgery or coronary angioplasty; transient ischemic attack or cerebrovascular accident; emergency room visit or hospitalization for confirmed cardiovascular disease
• * Participants taking vitamin E \>= 800 IU/day must be on a stable dose, defined as no changes in prescribed dose, new vitamin E-containing medications, or discontinuation for at least 180 days prior to the date of the screening visit and throughout study participation
• * Participants taking anti-diabetic medications must be on a stable dose for at least 90 days prior to the date of the screening visit and in the period between the date of the screening visit and enrollment
• * Current alcohol consumption \> 21 oz/week for males or \> 14 oz/week for females (1 oz/30 mL of alcohol is present in one 12 oz/360 mL beer, 4 oz/120 mL glass of wine, and a 1oz/30 mL measure of 40 proof \[20%\] alcohol)
• * Participants may not be receiving any other investigational agents, at the time of the screening visit, or in the prior 30 days, or within 5 half-lives of the prior investigational agent (whichever is longer)
• * History of allergic reactions attributed to compounds of similar chemical or biologic composition to lisinopril
• * Uncontrolled intercurrent illness or psychiatric illness/social situations that would limit compliance with study requirements
• * History of human immunodeficiency virus (HIV) infection. HIV patients may develop fatty liver as well as advanced fibrosis due to many causes including metabolic syndrome, hyperuricemia, HIV-related lipodystrophy, genetic polymorphisms, medications, and HIV itself. As the natural history of fatty liver in this population is largely unknown, these patients will be excluded from this study
• * Women who are pregnant or breastfeeding. Pregnant women are excluded from this study because lisinopril is an ACE Inhibitor with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events (AEs) in nursing infants secondary to treatment of the mother with lisinopril. Breastfeeding should be discontinued if the mother is treated with lisinopril
• * Systolic blood pressure \>= 161 mm/Hg. Diastolic blood pressure \>= 111 mm/Hg
• * Participants taking lithium