Early Liver Transplant for alcoholic hepatitis
Sidharth Sharma, MD, FACS
What is alcoholic hepatitis?
First and foremost, it is important to differentiate between alcoholic steatohepatitis (ASH) and alcoholic hepatitis (AH). Up to 40% of patients who are heavy drinkers and have fatty liver, go on to develop liver inflammation which is known as ASH. This is a diagnosis based on liver histology (steatosis, hepatocyte ballooning, Mallory Denk hyaline inclusion bodies, zone 3 perivenular injury with pericellular fibrosis etc.). AH, on the other hand, is a clinical diagnosis with jaundice, fever, tachycardia, tachypnea, hepatomegaly, leukocytosis, AST:ALT > 1.5:1 with the absolute value of AST/ALT never exceeding 500 U/L.
Alcoholic hepatitis is a clinical syndrome in people with chronic and active alcohol abuse. It presents with liver failure with or without hepatic encephalopathy. In patients with severe Alcoholic hepatitis, mortality is around 40-50% within a month of presentation.
It’s crucial to understand that the relationship between alcoholic hepatitis and amount of alcohol consumption is unclear; it’s not dose dependent. Acute binge drinking or even shorter duration of alcohol abuse can lead to alcoholic hepatitis. American Association for the Study of Liver Disease (AASLD) practice guidelines recommend suspecting alcoholic hepatitis in women who consume > 40 g of alcohol and in men who consume > 60 g/d for ≥ 6 months.
Epigenetic studies have also shown that a liver affected by AH has significant alterations in HNF4α-dependent genes, which play a role in impairing metabolic and synthetic function of the liver.
Mechanism of liver injury
The pathogenesis of AH mostly involves acute inflammation superimposed on chronic Alcoholic Liver Disease. Initial hepatic injury results from the metabolism of ethanol into acetaldehyde by alcohol dehydrogenase and cytochrome P450 2E1 (CYP2E1). As ethanol builds up because of increased consumption, acetaldehyde also accumulates in the liver and begins to exert toxic effects. Acetaldehyde leads to the formation of adducts, in the form of bonds with proteins, lipids, and DNA. This in turn impairs the normal function of the affected proteins and lipids and leads to DNA damage. CYP2E1 also leads to production of reactive oxygen species leading to hepatocyte injury.
Clinical course
A combination of clinical presentation, laboratory, imaging, and biopsy data are used to diagnose patients with alcoholic hepatitis. Patients with alcoholic hepatitis frequently present with a combination of typical symptoms including jaundice, abdominal pain, fullness or distention, fever, GI bleeding, or changes in mental status. Severe alcoholic hepatitis is defined as Maddrey discriminant Function > 32, these patients are severely ill & are typically hospitalized, often require intensive care due to their risk for sepsis-like clinical presentation, cardiovascular instability, infection, all complicated by alcohol withdrawal. The clinical syndrome of acute alcoholic hepatitis is characterized by a sepsis-like presentation due to sterile inflammation and cytokine “storm” in the absence of a clear source of infection. Development of multi-organ failure - most frequently hepatorenal syndrome and ARDS requiring mechanical ventilation - is associated with poor clinical outcome.
Patients with acute severe alcoholic hepatitis are managed by active supportive therapy. Some of the new interventions aim to inhibit inflammation by administration of a recombinant IL-1 receptor antagonist, IL-22 to improve gut barrier function and liver immunity, or use an orally administered FXR agonist that affects bile acid metabolism, gut permeability, and, presumably, inflammation.
Role of Early Liver Transplant
The rapid deterioration of patients with alcoholic hepatitis prompted some liver transplant centers to consider liver transplantation as a last resort.
Alcohol-associated Liver Disease and Alcohol Use Disorder - For years, these two conditions were managed in two parallel professional worlds: the world of hepatology and the world of addiction. Reluctance to perform transplantation in patients with alcoholism is often based on the view that they are responsible for their illness and are likely to resume alcohol use after transplantation.
In the last 50 years there has been a shift in the indications and contraindications for liver transplant (LT).This is most apparent in alcohol-associated liver disease (ALD), which comprises a wide spectrum of diseases ranging from steatosis and steatohepatitis to alcohol-related cirrhosis and hepatocellular carcinoma, with acute alcoholic hepatitis (AH) potentially developing at all stages.
A landmark French Belgian prospective study by Mathurin et. al. published in 2011 compared patients with severe AH nonresponsive to medical therapy who underwent LT with non-transplanted matched controls, demonstrating superior survival.
Patients whose hepatitis is not responding to medical therapy have a six month survival rate of approximately 30%. Since most alcoholic hepatitis deaths occur within two months, early LT is attractive, but controversial. Historically, a minimum period of abstinence from alcohol was recommended for candidates prior to LT, most commonly six months in duration. More recently, this rule has been questioned, as abstinence duration prior to transplant is an imperfect predictor of alcohol relapse post-transplant and due to the overall poor survival of patients with AH without transplantation.
In 2018, Lee et al. published an American retrospective multicenter study involving 12 centers in eight UNOS regions and analyzing the outcomes of 147 patients who underwent LT for severe AH that was not responding to medical therapy. Cumulative patient survival rates after LT were 94% at one year (95% CI 89%–97%) and 84% at three years (95% CI 75%–90%)
Choosing the appropriate moment for transplantation is crucial to avoid adverse effects of intervening too soon or too late. Data from the ACCELERATE-AH consortium suggests that mortality in the first few years is higher in recipients of early LT who return to drinking. Therefore, strategies should focus primarily on favoring post-LT abstinence but—in those patients where abstinence cannot be achieved—harm reduction and harm prevention should always be attempted.
In a nutshell, the available scientific evidence clearly demonstrates that early LT for severe AH not responding to medical therapy, when performed within strict and well-defined protocols, is associated with a clear survival benefit despite an acceptable rate of post-transplant return to alcohol use.
