Alcohol-Related Liver Disease Disease Background

Introduction

Alcohol-related liver disease (ALD) consists of a clinical-histological spectrum which includes hepatic steatosis, alcoholic hepatitis and cirrhosis with its various complications. 

Epidemiology

Alcohol-related liver disease is the leading cause of acute and chronic liver failure, cirrhosis, and liver cancer. It is one of the leading causes of liver transplantation. It is noted that approximately 20% of all alcoholics have alcoholic hepatitis. ALD causes approximately 6% of all deaths worldwide. While alcoholic cirrhosis (AC) accounts for approximately 10% of all alcohol-related deaths worldwide. As many as 2.4 billion people in the world consume alcohol including 1.5 billion men and 900 million women. It is estimated that as many as 400 million people, or 7% of the world’s population, live with alcohol use disorder (AUD), while 209 million suffer from alcohol dependence globally. Notably, AUD tends to be more prevalent in high-income countries. The prevalence of AUD has a large variation with regards to sex, with males being more affected than females (264 million males versus 136 million females). Due to various factors such as barriers to accessing health services, risky environments, and other behavioral risk factors, alcohol-attributable mortality and injury disproportionately affect people of lower socioeconomic status the most.

Worldwide, as many as 3 million lives are claimed annually related to harmful alcohol use, with 13.5% of deaths occurring in people aged 20 to 39 years. In males, the main causes of alcohol-attributable deaths include digestive diseases (439,00 deaths), unintentional injuries (427,000 deaths), and malignant neoplasms (326,000 deaths). While in females, the main causes of alcohol-attributable deaths are cardiovascular diseases (231,000 deaths), digestive diseases (139,000 deaths), and unintentional injuries (93,000 deaths). With regards to malignant neoplasms, AC has notably increased among patients ages 25 to 34 years old. In the United States, mortality associated with ALD was estimated to be at 5.5 per 100,000 with a 2% prevalence in the general population. 

Though alcohol consumption in Asia was noted to be less than that in Europe, which is the highest in the world, prevalence in countries like India, Japan, and China were high and/or increasing, possibly reflecting the changes in their respective economies and increases in average incomes. The overall prevalence of ALD in Asia is noted to be 4.81%, with men being more affected than women. Though there is no data on the national prevalence of ALD in the Philippines, a report made by the World Health Organization (WHO) noted 21.1 deaths per 100,000 men attributable to AC. 

Alcohol-Related Liver Disease_Disease Background

Pathophysiology

Alcohol-related liver disease results from a complex interaction of behavioral, environmental, and genetic factors. Heavy alcohol consumption leads to hepatic fat accumulation by affecting the redox mechanisms in the liver through interference with transcription factors that regulate fatty acid synthesis and oxidation leading to increased fatty acid synthesis and reduced fatty acid oxidation. Gut permeability changes resulting to increased portal vein endotoxin, innate immune response activation, liver inflammation, injury, apoptosis and necrosis, and fibrosis thereby activating the cytokine and oxidative stress cascades thus leading to liver injury. 

Risk Factors

Cofactors in the Development of ALD  

The amount (>30 g per day) and the type of alcohol ingested and drinking pattern (eg daily drinking, binge drinking) are important considerations in ALD. It was found that red wine is less likely to be associated with cirrhosis than other alcoholic drinks. Genetic factors such as genetic variants PNPLA3, TM6SF2, MBOAT7, and HSD17B13 and the rate of alcohol metabolism play a role in the development of ALD. With regards to gender, women are more susceptible compared to men. Over nutrition and obesity are established independent risk factors for hepatic steatosis and steatohepatitis. Cigarette smoking and undernutrition are also important factors in the development of ALD. Co-morbid conditions such as metabolic dysfunction-associated steatohepatitis (MASH), metabolic-dysfunction-associated steatotic liver disease (MASLD), viral hepatitis, and hemochromatosis must be considered as well. Concomitant hepatitis B virus (HBV) infection accelerates the progression of ALD and may haste n mortality. Hepatitis C virus (HCV) infection increases the probability of developing cirrhosis by 8- to 10-fold and accelerates the progression of ALD.

Classification

Steatotic Liver Disease (SLD)  

Steatotic liver disease is the overall term used to cover the different etiologies of steatosis. Steatotic liver or alcohol-related steatosis develops after 2 weeks in about 90% of individuals with an alcoholic intake of >60 g per day. Patients with SLD are usually asymptomatic. However, an enlarged liver may be present without jaundice or signs of advanced liver disease. SLD may be reversible following abstinence for 4 to 6 weeks, though a few may lead to progression to steatohepatitis or to fibrosis and cirrhosis.  

Alcoholic Hepatitis  

It is the recent onset of progressive jaundice (with or without signs of liver decompensation such as encephalopathy or ascites) that is often accompanied by fever, malaise, weight loss & malnutrition.   

Categories of alcoholic hepatitis include the following:

• Possible: Clinically diagnosed with potential confounding factors
• Probable: Clinically diagnosed but with no potential confounding factors
• Definite: Clinically diagnosed with features of alcoholic hepatitis (ie steatohepatitis) histologically confirmed

Cirrhosis  

Those with liver fibrosis and up to >75% of patients with steatohepatitis can progress to ALD cirrhosis. The risk of developing hepatocellular carcinoma is increased in patients with ALD cirrhosis.