May 20, 2024 • 2hr 25min
#302 - Confronting a metabolic epidemic: understanding liver health and how to prevent, diagnose, and manage liver disease | Julia Wattacheril, M.D., M.P.H.
The Peter Attia Drive
Key Takeaways
- The liver is an essential organ with over 300 functions, including metabolism, immune function, detoxification, and synthesis of proteins. It has no extracorporeal support option if it fails.
- Metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as non-alcoholic fatty liver disease (NAFLD), affects 25-35% of the population and is now the most prevalent liver disease globally.
- MASLD progresses through stages of fat accumulation, inflammation, fibrosis, and potentially cirrhosis over decades. There are typically 5-7 years between stages, allowing time for intervention.
- Early stage MASLD increases risk of cardiovascular disease and cancer more than liver failure in the near-term. Screening and early intervention are key.
- Lifestyle changes like weight loss, exercise, and reducing processed foods/added sugars are the primary treatments. Some medications like GLP-1 agonists show promise.
- Alcohol consumption, even at moderate levels, can contribute to liver damage and should be quantified carefully in patients.
- Non-invasive tests like elastography are replacing biopsies for diagnosis and staging in many cases. Liver enzyme tests alone are not sufficient.
- The nomenclature has shifted from NAFLD to MASLD to better reflect the underlying metabolic dysfunction and reduce stigma.
Introduction
Dr. Julia Wattacheril is a hepatologist and director of the Metabolic Dysfunction Associated Steatotic Liver Disease (MASLD) program at Columbia University. In this episode, she provides an in-depth overview of liver physiology, the progression of liver disease, diagnostic approaches, and treatment strategies, with a focus on metabolic dysfunction-associated liver disease.
Topics Discussed
Liver Physiology and Functions (8:55)
Dr. Wattacheril explains that the liver is a 3.5 pound organ located under the right ribcage with over 300 functions. The four main categories of liver function are:
- Metabolism - Processing of proteins, lipids, carbohydrates
- Immune function
- Detoxification - Processing medications, toxins, etc.
- Synthesis - Production of clotting factors and other proteins
She emphasizes the liver's critical role in regulating blood glucose levels, calling it "almost impossible to describe, how perfect the liver is able to do this." The liver also plays a major role in lipoprotein metabolism.
History and Evolution of Liver Disease (13:15)
Historically, infectious agents like hepatitis viruses were the predominant cause of liver disease. Alcohol has been studied as a cause since the 1700-1800s. More recently, metabolic causes have become the most prevalent globally.
Dr. Wattacheril notes that the focus on external causes of liver injury may have led to undervaluing the liver's natural resilience and metabolic functions. She explains that the progression and patterns of injury can differ between metabolic causes and other etiologies.
Liver Transplantation (16:30)
The first successful liver transplant was performed in 1967 by Dr. Thomas Starzl. Initially, transplants were only done for end-stage liver failure due to the high risks involved. Common indications were alcohol-related liver disease and viral hepatitis.
Today, acute liver failure accounts for less than 10% of transplants at most centers. Surprisingly, alcohol-related liver disease has surpassed other chronic indications in recent years, likely related to pandemic coping behaviors.
Metabolism of Nutrients and Effects of Excess Calories/Alcohol (24:45)
Dr. Wattacheril explains that the liver was not designed to store fat. In metabolic dysfunction, when subcutaneous fat storage is overwhelmed, more fat is delivered to the liver. This can occur through:
- Increased delivery of dietary fats
- De novo lipogenesis (creation of new fat) in the liver
She notes that insulin resistance and liver fat accumulation have a complex, bidirectional relationship that is still being studied. With alcohol consumption, the 7 calories per gram of pure carbohydrate in ethanol contributes to metabolic dysfunction.
Diagnosing Liver Disease (33:30)
Dr. Wattacheril outlines the typical diagnostic approach:
- Basic blood tests including liver enzymes
- Calculation of fibrosis risk scores like FIB-4
- Imaging studies if warranted based on risk factors
She emphasizes that regular ultrasound is not sensitive enough to detect early fatty liver, only picking up fat levels above 30%. More specialized techniques like elastography or MRI are needed for earlier detection.
Effects of Alcohol on the Liver (40:30)
Dr. Wattacheril explains the liver's process for metabolizing alcohol:
- Alcohol is converted to acetaldehyde by alcohol dehydrogenase
- Acetaldehyde is further metabolized to acetate
- Acetate is broken down to carbon dioxide and water
Problems arise when this system is overwhelmed, leading to oxidative stress and inflammation. Acetaldehyde is particularly toxic, attracting inflammatory cells and free radicals. She notes there are s*x differences in alcohol metabolism, with women generally more susceptible to liver damage from alcohol.
Advising Patients on Alcohol Consumption (47:15)
When counseling patients about alcohol use, Dr. Wattacheril recommends:
- Clearly defining what constitutes a standard drink
- Quantifying typical weekly intake and patterns
- Understanding the context and motivations for drinking
- Considering using biomarkers like phosphatidylethanol (PEth) to assess alcohol use
She emphasizes the importance of understanding a patient's perception of their own risk and being open to behavior change.
Understanding Liver Enzymes AST and ALT (58:30)
Dr. Wattacheril explains that AST (aspartate aminotransferase) and ALT (alanine aminotransferase) are enzymes normally found inside liver cells. When liver cells are damaged or die, these enzymes are released into the bloodstream. She notes:
- Historically, upper limits of normal were around 19 for women and 30 for men
- Current lab cutoffs are often in the 40-50 range, reflecting population shifts
- For optimal health, she generally likes to see levels under 30
- Persistent elevations 1.5-2x the upper limit of normal warrant further investigation
She cautions that liver enzymes can be elevated by exercise, emphasizing the importance of context when interpreting results.
Interpreting Liver Function Tests for Fatty Liver Disease (1:13:15)
Dr. Wattacheril discusses the limitations of relying solely on liver enzyme tests for diagnosing fatty liver disease:
- Enzyme elevations may not appear until significant liver damage has occurred
- Patterns of elevation can differ between children and adults
- Other tests like GGT may be more sensitive in some cases
She recommends using a combination of clinical risk factors, blood tests, and imaging studies for more accurate diagnosis.
Comprehensive Liver Health Assessments (1:18:45)
Dr. Wattacheril outlines her approach to assessing liver health:
- Detailed patient history including metabolic risk factors and habits
- Basic blood tests and fibrosis risk calculations
- Specialized imaging like elastography to measure liver fat and stiffness
- Consideration of liver biopsy in select cases
She emphasizes the importance of early detection and intervention, noting that many patients are referred due to incidental imaging findings before blood tests become abnormal.
Impact of Medications and Recreational Drugs on Liver Tests (1:26:45)
Dr. Wattacheril discusses how various substances can affect liver function tests:
- Statins: Can cause mild enzyme elevations, rarely significant liver injury
- Recreational drugs: Historical IV drug use is a risk factor for hepatitis C
- Supplements: Can potentially cause liver injury, careful quantification needed
She notes that in most cases, the cardiovascular benefits of statins outweigh the risks of mild liver enzyme elevations.
Shift from NAFLD to MASLD Terminology (1:30:30)
Dr. Wattacheril explains the recent shift in nomenclature from Non-Alcoholic Fatty Liver Disease (NAFLD) to Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD):
- Addresses patient concerns about stigma associated with "alcoholic" and "fatty" terms
- Better reflects the underlying metabolic dysfunction
- Allows for more nuanced categorization of different causes of liver fat accumulation
She notes this change also recognizes that many patients may have both metabolic and alcohol-related factors contributing to their liver disease.
Pathophysiology and Screening for MASLD (1:36:30)
Dr. Wattacheril discusses the prevalence and diagnosis of MASLD:
- Affects 25-35% of the population, likely higher in some groups
- Diagnosis requires evidence of liver fat (>5% on imaging or biopsy) plus metabolic risk factors
- Does not require full metabolic syndrome criteria to be met
- Early stages may precede development of insulin resistance
She emphasizes the need for proactive screening in at-risk populations, noting that liver fat can be an early indicator of metabolic dysfunction.
Management Strategies for MASLD (1:45:30)
Dr. Wattacheril outlines key approaches to managing MASLD:
- Lifestyle modifications: Weight loss, exercise, reducing processed foods
- Addressing metabolic risk factors: Managing diabetes, hypertension, dyslipidemia
- Consideration of medications: GLP-1 agonists show promise for some patients
- Bariatric surgery: May be considered for patients with obesity and advanced disease
She emphasizes the importance of individualizing treatment plans and addressing the underlying drivers of metabolic dysfunction.
Fructose and Liver Health (1:52:45)
Dr. Wattacheril discusses the complex relationship between fructose consumption and liver health:
- High fructose intake, especially from processed foods and beverages, is associated with liver fat accumulation
- Difficult to disentangle effects of fructose from overall calorie intake and insulin resistance
- Recommends focusing on reducing overall processed food intake rather than specifically targeting fructose
She notes that whole fruits are generally not a concern due to their fiber content and overall nutrient profile.
Potential of GLP-1 Agonists for MASLD Treatment (1:57:45)
Dr. Wattacheril discusses the use of GLP-1 receptor agonists like semaglutide for MASLD:
- Can be very effective for weight loss and improving metabolic health
- May have direct beneficial effects on the liver beyond weight loss
- Concerns about muscle loss and long-term sustainability need to be considered
She recommends careful patient selection and discussion of long-term plans when using these medications.
Stages of Liver Disease Progression (2:00:30)
Dr. Wattacheril outlines the stages of liver disease progression in MASLD:
- Fat accumulation (steatosis)
- Inflammation and cell stress (steatohepatitis)
- Early fibrosis
- Advanced fibrosis/cirrhosis
She notes that progression typically takes 5-7 years between stages, allowing time for intervention. Even early cirrhosis may be reversible with appropriate treatment.
Cancer and Heart Disease Risk in Early MASLD (2:05:15)
Dr. Wattacheril emphasizes that patients with early-stage MASLD are at increased risk for:
- Cardiovascular disease
- Type 2 diabetes
- Various cancers, including liver cancer (even before cirrhosis in some cases)
She notes that addressing these risks is often more urgent than preventing liver failure in early disease stages.
Emerging Therapies for MASLD (2:12:15)
Dr. Wattacheril discusses some promising treatments in development:
- Resmetirom: Thyroid hormone receptor agonist showing efficacy in phase 3 trials
- FGF21 analogs: Target multiple metabolic pathways
- Combination therapies: May target both fat accumulation and fibrosis
She notes the challenges in developing treatments that address both liver-specific and systemic metabolic dysfunction.
Conclusion
Dr. Wattacheril emphasizes several key points in conclusion:
- MASLD is a highly prevalent condition that increases risk of cardiovascular disease, diabetes, and cancer
- Early detection and intervention are crucial, as the disease progresses slowly over decades
- A comprehensive approach