nonalcoholic%20fatty%20liver%20disease
NONALCOHOLIC FATTY LIVER DISEASE

Nonalcoholic fatty liver disease is having excessive hepatic fat (in the form of triglycerides) accumulation not due to excessive alcohol consumption or other secondary causes.

It is considered as a hepatic manifestation of metabolic syndrome.

Progression of nonalcoholic fatty liver disease is variable.

Principles of Therapy

  • Essential principle of therapy of nonalcoholic fatty liver disease (NAFLD) is to treat underlying cause
  • Goals of treatment are to improve insulin resistance and liver enzyme levels and decrease histologic features

Pharmacotherapy

  • Pharmacological therapy is indicated in patients with biopsy-proven progressive nonalcoholic steatohepatitis (NASH) and in those in early stage of NASH with increased risk of progressing to fibrosis (age >50 years, diabetes, metabolic syndrome, increased ALT or active NASH with high necroinflammatory activity)
  • Pharmacologic treatments for NAFLD/NASH are targeted at underlying metabolic syndrome-related diseases such as obesity, type 2 diabetes mellitus, dyslipidemia and hypertension as well as liver dysfunction itself

Insulin Sensitizers

Thiazolidinediones (eg Pioglitazone)

  • Peroxisome proliferator-activated receptor agonists with insulin-sensitizing effects
  • Recommended for patients with insulin resistance
  • It was shown in clinical trials that Pioglitazone improves liver histology in patients with biopsy-proven NASH with and without type 2 diabetes mellitus
  • Main side effects of Pioglitazone are weight gain, bone fractures in women, and rarely congestive heart failure

Glucagon-like Peptide-1 Analogues (eg Liraglutide)

  • Act on glucose-insulin interplay and have shown favorable results in pre-marketing studies on liver enzymes
  • A randomized placebo-controlled trial showed daily SC injections of Liraglutide for 48 weeks demonstrated more resolution of steatohepatitis and less fibrosis progression

Dipeptidyl Peptidase-4 Inhibitors (DPP4i) (eg Alogliptin, Linagliptin, Sitagliptin, Vildagliptin)

  • A single arm, multicenter, non-randomized study has shown that Alogliptin is a potential new therapeutic strategy for the prevention of NAFLD progression in patients with type 2 diabetes mellitus
  • Further studies are needed to conclude the beneficial effects of DPP4i therapy on hepatic enzymes to prevent disease progression in NAFLD patients with type 2 diabetes mellitus

Antioxidants, Cytoprotective and Lipid-lowering Agents

Vitamin E

  • A free radical scavenger and a chain-breaking antioxidant in free radical reactions such as lipid peroxidation
  • Studies have shown improvement in hepatic biological and histological parameters in non-diabetic patients with biopsy-proven NASH
  • Further studies are needed for Vitamin E to be used in cirrhotic or diabetic NASH patients

Statins (eg Ezetimibe and HMG-CoA reductase)

  • May be used in patients with NAFLD/NASH and hypercholesterolemia to prevent cardiovascular risk
  • In patients already taking statins, it is advised to continue with the medication and only consider stopping when liver enzyme levels double within 3 months of starting statins
  • Avoid giving statins in patients with decompensated cirrhosis
Antihypertensives


Angiotensin II Receptor Antagonist (ARB)

  • Angiotensin II receptor antagonist is recommended in NASH patients with hypertension
  • Inhibits fibroblast activity resulting in inhibition of tissue fibrosis in several organs

Other Agents

Pentoxifylline

  • Recommended in patients with NASH
  • Considered to have both antioxidant and anti-TNF alpha effects
  • Clinical trials and meta-analyses found that Pentoxifylline improved serum biochemical indices and hepatic histological change

Omega-3 Fatty Acids

  • May be considered in patients with NAFLD for the treatment of hypertriglyceridemia 

Obeticholic Acid and Elafibranor

  • New agents currently undergoing phase 3 registration trials for the treatment of NASH
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