Nonalcoholic Fatty Liver Disease

Nonalcoholic fatty liver disease is a spectrum of liver pathology that arises due to accumulation of triglycerides in hepatocytes. Risk factors include diabetes mellitus, insulin resistance, obesity, and hypertension, among others. Nonalcoholic fatty liver disease ranges from fatty liver or hepatic steatosis but can lead to nonalcoholic steatohepatitis (NASH), which features fatty deposits and inflammation. Progressive liver injury and fibrosis irreversibly develop into cirrhosis and, possibly, primary liver cancer. Patients are usually asymptomatic but may present with hepatomegaly and right upper quadrant discomfort. Although liver biopsy is the diagnostic gold standard, the diagnosis can also be established by clinical history, imaging, and laboratory tests. The mainstay of management is lifestyle modifications (weight loss and exercise) with control of associated comorbidities.

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Definition

Fatty liver has alcoholic or nonalcoholic subtypes.

Nonalcoholic fatty liver disease (NAFLD):

  • Chronic liver disease characterized by liver pathology of steatosis (triglyceride accumulation within hepatocytes), with or without inflammation and fibrosis
  • No history of increased alcohol intake (defined as  > 1 drink/day for women, or > 2 drinks/day in men)
  • NAFLD types:
    • Nonalcoholic fatty liver (NAFL): hepatic steatosis (> 5% of hepatocytes) without inflammation
    • Nonalcoholic steatohepatitis (NASH): 
      • Features: hepatic steatosis with lobular inflammation and ballooned hepatocytes
      • Pathology similar to alcoholic steatohepatitis but patients do not have significant alcohol consumption

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Non-Alcoholic Steatohepatitis (NASH)

Epidemiology and Etiology

Epidemiology

  • NAFLD is the most common cause of chronic liver disease in the United States.
  • Affects 25% of adults 
  • Patients diagnosed mostly in their 40s and 50s
  • Prevalence highest in Hispanic Americans (50%)
  • When cirrhosis develops, incidence of liver cancer is up to 3%.

Etiology

  • Risk factors:
    • Metabolic syndrome
    • Central obesity
    • Type 2 diabetes mellitus (DM)
    • Hypertension
    • Hypertriglyceridemia
    • Rapid weight loss or gain
    • Hypothyroidism
    • Polycystic ovarian syndrome
    • Endocrinopathies (e.g., Cushing’s syndrome)
  • Medications: amiodarone, glucocorticoids, doxycycline, antiretroviral drugs

Pathophysiology

Pathophysiology of NAFLD

  1. Risk factors (↑ insulin resistance, DM, obesity, sedentary lifestyle) contribute to lipid accumulation:
    • Increased supply of fat (from high-fat diet and adipose lipolysis)
    • Decreased fat export (↓ very-low-density lipoprotein secretion)
    • Decreased free fatty acid (FFA) beta-oxidation
    • Increased de novo lipogenesis
  2. The processes lead to ↑ triglyceride synthesis and ↑ hepatic uptake of fatty acids.
  3. Accumulating FFAs and byproducts (e.g., reactive oxygen species) damage hepatocytes by oxidative stress → lipotoxicity (cellular injury and death resulting from lipid intermediates) 
  4. Injured and dying cells induce immune responses (inflammatory cytokines and cells) to repair and replace hepatocytes.
  • Prevention and Treatment of Non-Alcoholic Fatty Liver Disease

    Pathogenesis of NAFLD: Risk factors such as obesity, poor nutrition, type 2 diabetes, insulin resistance, and sedentary lifestyle cause efflux of FFAs from the adipose tissue to the liver. The increased FFAs in hepatic tissue stimulate triglyceride (TG) synthesis and accumulation. This excess of lipids induces an immune response, causing the production of cytokines, reactive oxygen species (ROS), and worsening insulin resistance. Oxidative stress causes lipid peroxidation and tissue damage, amplifying the inflammatory response and leading to the progression of NAFLD.

    HCC: hepatocellular carcinoma
    NAFL: non-alcoholic fatty liver
    NASH: non-alcoholic steatohepatitis

    Image: “Pathogenesis of NAFL” by US National Library of Medicine. License: CC BY 4.0

Nonalcoholic fatty liver

  • Fat accumulation (usually macrovesicular hepatosteatosis)
  • Large fat droplet or smaller fat droplets in the hepatocyte cytoplasm, pushing the nucleus to the periphery and bloating the cells
  • Reversible condition

Nonalcoholic steatohepatitis

  • Morphologic manifestation of lipotoxicity 
  • Ballooning hepatocytes and inflammation (wound healing response to the hepatocellular injury)
  • With intervention, NASH is reversible, but as repairs depend on extent of damage, outcomes vary.

Potential outcomes

If progression is not reversed, NAFL leads to NASH. With further liver damage, cirrhosis and liver carcinoma (both irreversible) become potential outcomes:

  • Cirrhosis: Ineffective healing and repair produce fibrosis and scarring.
  • Hepatocellular carcinoma (HCC): Repair and regenerative process produce malignant transformation.
Progression of liver disease

Progression of liver disease due to steatosis:
1: Healthy hepatocytes: no liver damage
2: Bloated hepatocytes with steatosis (distended by fat droplets), no inflammation: NAFL/steatosis (still reversible)
3: Inflamed and dying hepatocytes, with possible fibrosis: nonalcoholic steatohepatitis (still reversible)
4: Dead cells: cirrhosis (irreversible liver damage)

Image by Lecturio.
  • Progression of NAFLD

    Progression of liver disease: steatosis to HCC

    Image: “Nonalcoholic fatty liver disease” by Department of Medicine, VA Boston Healthcare System and Brigham and Women’s Hospital, Harvard Medical School, 150 S. Huntington Ave., Room 6A-46, Boston, MA 02130, USA. License: CC BY 4.0, edited by Lecturio.

Clinical Presentation

Symptoms

  • Often asymptomatic
  • Fatigue, malaise
  • Right upper quadrant (RUQ) discomfort

Signs

  • Incidental finding of abnormal liver function tests or hepatic steatosis on ultrasound
  • Hepatomegaly
  • Disease progression to cirrhosis presents with spider angiomata, palmar erythema, hepatosplenomegaly, and ascites.

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Metabolic Liver Disease with Case

Diagnosis

  • History and clinical findings: 
    • No significant alcoholic consumption
    • No coexisting chronic liver disease
    • No other causes of hepatic steatosis
    • Presence of hepatic steatosis by imaging or biopsy
  • Liver biopsy:
    • Best diagnostic test but rarely performed
    • Done if diagnosis is unclear
    • Distinguishes NAFL from NASH, and detects cirrhosis (which increases risk of hepatocellular carcinoma)
  • Ultrasound (US): echogenic liver texture (due to fatty infiltration)
  • Laboratory tests:
    • ↑ Aspartate aminotransferase (AST), alanine aminotransferase (ALT) but may be normal
    • Often with abnormal ferritin level
    • ↑ Serum triglyceride/cholesterol levels
  • Tests to rule out other causes of chronic hepatitis:
    • Alcoholic liver disease
    • Viral hepatitis
    • Wilson’s disease
    • Autoimmune hepatitis
    • Hemochromatosis
  • Abdominal ultrasonography of a patient with non-alcoholic fatty liver disease

    Abdominal ultrasonography of a patient with NAFD showing increased increased hepatic parenchyma echotexture due to fat infiltration (“brilliant liver”)

    Image: “Abdominal ultrasonography of a patient with non-alcoholic fatty liver disease” by Department of Biochemistry, School of Medicine, National Autonomous University of Mexico (UNAM), Mexico, 04510, Mexico. License: CC BY 2.0, edited by Lecturio.
  • Liver Tissue with NAFLD

    Microscopic image of liver tissue affected by NAFLD: The large and small white spots are excess fat droplets filling liver cells (hepatocytes).

    Image: “Liver Tissue with NAFLD” by Dr. David Kleiner, National Cancer Institute/NIH. License: Public Domain
  • Portal inflammation-diagnostic finding in NASH

    Portal inflammation is a diagnostic finding in NASH. Histopathologic section was obtained from a patient with steatohepatitis.

    Image: “F1” by Gastroenterology Department, Ege University Faculty of Medicine, Izmir, Turkey. License: CC BY 2.0

Management

General considerations to reduce liver damage

  • Avoid heavy alcohol intake and smoking.
  • Update immunizations (for hepatitis A and B), including standard recommendations.

Monitoring of NAFLD

  • Monitor liver function tests (worsening and/or change in clinical status warrant further evaluation).
  • Biopsy-proven NASH: 
    • Monitor fibrosis. 
    • Options include serum fibrosis markers and vibration-controlled transient elastography (VCTE) (measures fibrosis based on liver stiffness).
  • NAFLD-cirrhosis: Screen for HCC.

Management of NAFLD

  • No specific pharmacologic therapies for NAFLD
  • Lifestyle changes for reduction of fatty liver:
    • Gradual weight loss, average of 0.5–1 kg/week (rapid weight loss can worsen liver disease)
    • Aim to lose at least 5%–10% of body weight.
    • Moderate exercise
  • Control of co-morbidities (e.g., diabetes, dyslipidemia)
  • Use of vitamin E in NASH may benefit non-diabetic patients, but avoid in those with prostate cancer (↑ risk).
  • Patients with end-stage liver disease: Consider liver transplantation.

Differential Diagnosis

  • Viral hepatitis: infection from a virus causing acute liver disease. Presents with jaundice and fever with hepatomegaly, and the transaminase elevation is often greater than in NAFLD. Further differentiation can be established by detecting viral antigens and antibodies in the serum. Treatment is based on cause, and for certain types can be prevented by vaccination. 
  • Autoimmune hepatitis: acute liver failure that presents with fatigue, jaundice, hepatomegaly, and RUQ tenderness. Drug-induced hepatitis must be ruled out using history and laboratory evaluation. Presence of the anti-smooth muscle antibody is a strong indicator of autoimmune hepatitis. Treatment is with immunosuppressants. 
  • Alcoholic liver disease: liver failure associated with chronic significant alcohol consumption. Presents with similar laboratory results (elevation in transaminases) and pathologic  finding of steatohepatitis. Characteristic history (alcohol abuse) typically helps differentiate alcoholic liver disease from NAFLD. Treatment is alcohol cessation. 
  • Other causes of hepatitis (drug-induced): presents after ingestion of a hepatotoxic drug with jaundice, hepatomegaly, and RUQ discomfort. Injury can be hepatocellular (elevated transaminases) and/or cholestatic (elevated alkaline phosphatase). Treatment is removal of the offending drug.

References

  1. Abdelmalek M.F., & Diehl, A. (2018). Nonalcoholic fatty liver diseases and nonalcoholic steatohepatitis. Jameson J, & Fauci A.S., & Kasper D.L., & Hauser, S.L., & Longo, D.L., & Loscalzo, J.(Eds.), Harrison’s Principles of Internal Medicine, 20e. McGraw-Hill. 
  2. Chopra, S. Lai, M. (2020) Management of nonalcoholic fatty liver disease in adults. UpToDate. Retrieved 10 Nov 2020, from https://www.uptodate.com/contents/management-of-nonalcoholic-fatty-liver-disease-in-adults
  3. Friedman L.S. (2021). Nonalcoholic fatty liver disease. Papadakis M.A., & McPhee S.J., & Rabow M.W.(Eds.), Current Medical Diagnosis & Treatment 2021. McGraw-Hill.
  4. Sheth, S. (2020). Epidemiology, clinical features, and diagnosis of nonalcoholic fatty liver disease in adults. UpToDate. Chopra, S, Lindor, K and Robson, K. (Eds). Retrieved 12 Nov, 2020, from https://www.uptodate.com/contents/epidemiology-clinical-features-and-diagnosis-of-nonalcoholic-fatty-liver-disease-in-adults?search=Fatty%20Liver%20Disease&source=search_result&selectedTitle=1~150&usage_type=default&display_rank=1#H3
  5. Takahashi, Y.,Fukusato, T. (2014) Histopathology of nonalcoholic fatty liver disease/nonalcoholic steatohepatitis. World J Gastroenterol. 20(42): 15539–15548.
  6. Tendler, D. (2020) Pathogenesis of nonalcoholic fatty liver disease.  Lindor, K., Robson, K. (Eds.) Uptodate. Retrieved 10 Nov, 2020, from https://www.uptodate.com/contents/pathogenesis-of-nonalcoholic-fatty-liver-disease

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