Fatty Liver Disease for the ABIM Exam

Fatty Liver Disease for the American Board of Internal Medicine

Overview

Fatty liver disease refers to a spectrum of liver conditions characterized by the accumulation of fat in hepatocytes. It is divided into non-alcoholic fatty liver disease (NAFLD) and alcoholic liver disease (ALD) based on the presence or absence of significant alcohol consumption.

Non-Alcoholic Fatty Liver Disease (NAFLD)

Pathophysiology

NAFLD is the hepatic manifestation of metabolic syndrome and includes both simple steatosis (fat accumulation without inflammation) and non-alcoholic steatohepatitis (NASH), which involves inflammation, hepatocyte injury, and varying degrees of fibrosis.
It is associated with insulin resistance, dyslipidemia, obesity, and type 2 diabetes mellitus (T2DM).

Insulin resistance plays a central role by increasing fatty acid delivery to the liver and enhancing lipogenesis.
Oxidative stress and lipotoxicity contribute to hepatocyte injury, leading to inflammation and fibrosis in NASH.

Risk Factors

Obesity: Central (visceral) obesity is a strong predictor of NAFLD.
Type 2 diabetes mellitus (T2DM): Strongly associated with NASH and progressive fibrosis.
Dyslipidemia: Elevated triglycerides and low HDL levels are common in patients with NAFLD.
Metabolic syndrome: Defined by the presence of central obesity, hypertension, hyperglycemia, and dyslipidemia, this syndrome greatly increases the risk of NAFLD.
Genetics: Polymorphisms in genes like PNPLA3 and TM6SF2 are associated with an increased risk of NAFLD and fibrosis progression.

Clinical Presentation

Most patients are asymptomatic and diagnosed incidentally based on abnormal liver function tests (elevated ALT/AST) or imaging showing fatty infiltration.
Symptoms, if present, include fatigue, right upper quadrant (RUQ) discomfort, or nonspecific abdominal pain.
Physical findings such as hepatomegaly may be noted on exam.

Diagnosis

Liver biopsy is the gold standard for diagnosing NASH and assessing fibrosis, though non-invasive tests are commonly used due to the risks of biopsy.

Steatosis: Seen as fat droplets in hepatocytes.
NASH: Characterized by fat accumulation, inflammation, and ballooning degeneration of hepatocytes.

Ultrasound: The most common initial imaging modality, showing increased echogenicity of the liver.
CT/MRI: May show fat infiltration but cannot distinguish between simple steatosis and NASH.
Transient elastography (FibroScan): Used to assess liver stiffness and estimate fibrosis.

Mild elevations in ALT and AST, typically with an AST:ALT ratio <1.
Elevated gamma-glutamyl transferase (GGT) and occasionally mild increases in alkaline phosphatase (ALP).

Fibrosis markers: Non-invasive scoring systems like the NAFLD fibrosis score and Fibrosis-4 (FIB-4) index help assess the risk of advanced fibrosis.

Complications

NASH can progress to cirrhosis, which carries risks of hepatic decompensation (e.g., ascites, variceal bleeding, encephalopathy) and hepatocellular carcinoma (HCC).
Cardiovascular disease is the leading cause of death in patients with NAFLD due to the strong association with metabolic syndrome.

Management

Weight loss: A reduction of 7-10% of body weight is necessary to improve NASH and fibrosis.
Diet: Low-calorie, low-carbohydrate diets, particularly the Mediterranean diet, are beneficial.
Exercise: Regular aerobic exercise improves insulin sensitivity and liver fat.

Pioglitazone: A thiazolidinedione used to improve liver histology in NASH, particularly in patients with T2DM.
Vitamin E: Antioxidant therapy used in non-diabetic patients with NASH.
GLP-1 agonists: Emerging evidence suggests that drugs like liraglutide may promote weight loss and reduce liver fat.
Statins: Safe in NAFLD and beneficial for managing cardiovascular risk.

Surveillance: Patients with advanced fibrosis or cirrhosis require regular screening for hepatocellular carcinoma and esophageal varices.

Alcoholic Liver Disease (ALD)

Pathophysiology

ALD encompasses a spectrum from simple steatosis to alcoholic hepatitis and cirrhosis.
Chronic alcohol consumption leads to fatty acid accumulation due to increased fatty acid synthesis and decreased oxidation. Alcohol also promotes oxidative stress and cytokine release, contributing to hepatocyte injury and inflammation.
Genetic factors, nutritional deficiencies (especially folate and vitamin B6), and gender (females are more susceptible) contribute to the risk of ALD.

Clinical Presentation

Early ALD (simple steatosis) is typically asymptomatic.
Alcoholic hepatitis presents with jaundice, fever, RUQ pain, and tender hepatomegaly. In severe cases, it may cause hepatic encephalopathy or acute liver failure.
Physical findings include spider angiomata, palmar erythema, and ascites in more advanced disease.

Diagnosis

AST:ALT ratio >2 is highly suggestive of ALD, as is an elevated GGT.
Imaging and liver biopsy findings overlap with those in NAFLD, though Mallory bodies and neutrophilic infiltration are characteristic of alcoholic hepatitis.

Complications

Cirrhosis: Alcoholic cirrhosis carries the same risks as cirrhosis from any cause, including hepatic decompensation and hepatocellular carcinoma.
Portal hypertension, ascites, and variceal bleeding are common in advanced ALD.

Management

Supportive measures: Nutritional support and thiamine supplementation are important in malnourished patients.

Corticosteroids: Indicated in severe alcoholic hepatitis to reduce inflammation and improve short-term survival.
Liver transplantation: May be considered in patients with end-stage ALD who abstain from alcohol and meet transplant criteria.

Differentiating NAFLD and ALD

Alcohol history: Key in distinguishing NAFLD from ALD. NAFLD patients consume little to no alcohol, while ALD is related to chronic alcohol use.
AST:ALT ratio: In NAFLD, AST:ALT is <1, whereas in ALD it is typically >2.
Biopsy findings: Both conditions show steatosis and inflammation, but Mallory bodies and neutrophilic infiltration are more common in ALD.

Key Points

NAFLD is associated with metabolic syndrome, and its more severe form, NASH, can progress to cirrhosis and hepatocellular carcinoma.
ALD results from chronic alcohol use and ranges from simple steatosis to alcoholic hepatitis and cirrhosis.
Lifestyle modifications (weight loss, exercise, and alcohol cessation) are the cornerstone of treatment for both NAFLD and ALD.
Pharmacotherapy for NASH includes pioglitazone and vitamin E; severe alcoholic hepatitis may require corticosteroids.
Cirrhosis, whether from NAFLD or ALD, carries risks of hepatic decompensation and requires regular screening for hepatocellular carcinoma.