#452 NAFLD/MASLD with Dr. Elliot Tapper

September 9, 2024 | By Sai Achi

Audio

Video

Transcript available via YouTube

Expand your NAFLD/MASLD knowledge!

Expert guest Dr. Elliot Tapper (@ebtapper) shares his framework for approaching NAFLD/MASLD and the treatment tools he recommends including lifestyle modifications and medications. 

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Show Segments

• Intro
• Rapid Fire Segment
• Case 1 Part 1
• NAFLD/MASLD terminology and differential diagnoses
• PEth testing 
• Diagnostic tools for NAFLD/MASLD: Fib4 Score
• Imaging
• When to Refer to a Hepatologist?
• Treatment options
• Lifestyle modifications
•  Role of GLP-1 agonists
• Role of new FDA approved medications
• Outro

[NAFLD/MASLD] Pearls

1. Patients diagnosed with NAFLD/MASLD should be given this specific diagnosis along with a prognosis– their long term prognosis is determined by the extent of fibrosis.
2. Fib4 score is a tool/algorithm that can be used for prognosis.  The score is comprised of: age, platelet count, AST, and ALT levels
3. Imaging modalities such as the vibration controlled transient elastography have replaced the need for liver biopsy.
4. Weight loss has the potential to reduce and even resolve fibrosis.
5. Newer medications are on the horizon for NAFLD/MASLD treatment such as Resmetirom.

NAFLD/MASLD Show Notes 

NAFLD/MASLD terminology 

MASLD (metabolic dysfunction-associated steatotic liver disease) is the new terminology that has replaced NAFLD (non-alcoholic fatty liver disease) or MAFLD (metabolic dysfunction associated fatty liver disease) (Portincasa 2024). It is one of the most common chronic liver conditions in the world and prevalence is estimated to be about 30% (Angulo 2015, Younossi 2023).

History and Physical Exam 

Dr. Tapper says that the main things to do when a patient comes in with abnormal liver function tests +/- “fat” on imaging are:

1. Provide a diagnosis (think about the differentials): consider alcohol use disorder, hepatitides, medications, and other rare causes of abnormalities
2. Provide a prognosis (assess for fibrosis): assess risk of fibrosis (eg Fib4 score) and consider imaging

Differential Diagnoses

The majority of steatosis cases are due to metabolic dysfunction or alcohol use and a small fraction are due to medications,  hepatitides, and autoimmune disease.

Alcohol Use  

When asking about alcohol use, the provider must foster a safe environment for the discussion.  Dr. Tapper may order a PEth (Phosphatidylethanol) level for an objective assessment of alcohol use. PEth is a phospholipid that only forms in the presence of ethanol and its presence is not affected by hypertension or kidney disease. Studies have shown that it is a highly sensitive and specific test up to 4 weeks post alcohol use, with a cutoff value of 20 ng/ml for positive test (Hahn 2023) (Viel 2012).

Hepatitis B, Hepatitis C, other diseases

Review the USPSTF guidelines and screen patients who are at risk of hepatitis B with detailed history questions and appropriate serological testing. All people ages 18-79 should be screened for hepatitis C and treated if infected (US Preventive Task Force guidelines 2020)

Dr. Tapper also recommends screening for alcohol use disorder, counseling about reducing alcohol consumption, and reviewing diet and exercise improvements.  If liver function test abnormalities persist despite these interventions, he will evaluate for other diagnoses such as autoimmune hepatitis. In situations where the ALT is >200s, he often employs additional testing for conditions such as autoimmune hepatitis and may be quicker to arrange a liver biopsy. 

Medication-Induced

Use the NIH resource LiverTox to look up medications that have been associated with liver injury!

Prognostic Factors

Fib4 score (Fibrosis4 score)

The Fib4 (Fibrosis4) score was created as a noninvasive methodology to estimate/predict risk of fibrosis (Sterling 2006). The Fib4 score uses age, ALT, AST, and platelet count in its formula. The lower the Fib4 score, the lower the chance of fibrosis. The higher the Fib4 score, the higher the risk of fibrosis. When the Fib4 score is elevated, imaging (eg elastography) should be ordered to assess the extent of fibrosis.

 Elastography

 Vibration Controlled Transient Elastography (VCTE) is a tool that effectively assesses liver stiffness which is a surrogate for fibrosis (Siddiqui 2018). Per Dr. Tapper, it’s a good next step in those with a “non low” Fib4 score and/or there are clues of advanced liver disease such as caput medusae or ascites. However, there are some other factors that can increase the stiffness of the liver aside from advanced liver disease such as right heart dysfunction or obstructed bile flow (Fang 2021). 

VCTE’s sensitivity for fibrosis is reduced in patients with a higher BMI, due to positioning and limitation of the probe and shear wave to identify stiffness; an alternative modality for patients with a higher BMI is Magnetic Resonance Elastography (MRE).

Interpreting the Data

“Rules of 5” for the VCTE (Franchis 2022 :

• 5 is normal
• 10 is 40% of advanced liver disease
• 15 is likelihood of cirrhosis is high
• 20 is cirrhosis is very much likely
• 25 is portal hypertension (i.e varices)

For MRE

Studies have suggested (Kaplan 2023):

• F0 (fibrosis 0) would be </= 2.5 kPa and is considered normal liver. Values above 2.5 kPa would indicate some inflammatory liver changes
• F1 (fibrosis 1) would be >/= 2.9 kPa
• F2 (fibrosis 2) would be > 3.5 kPa
• F3 (fibrosis 3) would be >/= 4 kPa
• F4 (fibrosis 4) would be > 5 kPa

Per Dr. Tapper, once the value is 3.6 kPa or higher you should start to worry. A value of 5 kPa means that there is cirrhosis. 

In situations where the elastography is negative or not available, there is serological testing that is available. One such approved prognostic test is the Enhanced Liver Fibrosis Test (Miele 2017). This is a blood test that analyzes: type III procollagen peptide, hyaluronic acid, and tissue inhibitor of metalloproteinase-1. This test when combined with Fib4 score can have a high clinical accuracy. (Younossi 2021) 

When to Refer to a Hepatologist?

Per Dr. Tapper, the hepatology team would help to coordinate the elastography scan before the hepatology visit; ideally the best time to refer would be once the tests and scans are done in order to save time and worry for the patient

Treatment of MASLD/NAFLD

Diet

Weight loss is beneficial for NAFLD treatment. Loss of 5% body weight can decrease steatosis, loss of 7.5% body weight can reduce steatohepatitis, and around 10% loss of body weight can resolve fibrosis. Dr. Tapper has found that counseling patients about diet is a helpful way to have patients review their diet so he can provide alternatives that are sustainable. He focuses on reducing sugar-sweetened beverages, promoting vegetables over starches, and finding low-carbohydrate snacks.

Consider focusing on “why” the patient would like to lose weight and how to make the journey toward sustainable weight loss.

Medications

GLP-1 agonists have been shown to improve fibrosis. (Yadav 2022).  GLP agents are beneficial for patients who have elevated BMI, diabetes, and no evidence of fibrosis per Dr. Tapper.

Anti-obesity medications such as orlistat which modifies the digestive tract absorption capabilities or agents such as phentermine-topiramate  which are centrally acting agents that regulate the appetite center and many other agents have been shown in combination with lifestyle modifications to lead to weight loss and improved outcomes. (Gudzune 2024).

Recently a phase 2 trial of patients with MASLD/NAFLD and moderate-to severe fibrosis found that treatment with Tirzepatide for 52 weeks was more effective than placebo for resolution of MASLD without worsening the fibrosis. (Loomba 2024). Tirzepatide is a dual GLP-1 agonist and GIP (glucose-dependent insulinotropic polypeptide) receptor agonist. The GLP-1 portion is thought to stimulate the beta cell insulin secretion, slow gastric emptying, and reduce glucagon levels in hyperglycemia thereby leading to better glycemic control and weight loss. The GIP portion is thought to preserve and better the beta cell function thereby improving the insulin secretion after a diet induced weight loss. (Bull 2022).   There are a number of combination agents that are being studied in phase 2 trials  for the management of MASLD/NAFLD.

Resmetiron, a thyroid mimetic, is an FDA approved medication and it was the first to show a reduction of fibrosis in comparison to placebo (MAESTRO-NASH study). It has no effect on weight loss.  It is effective for those patients who fall in fibrosis categories F2 (fibrosis stage 2) and F3 (fibrosis stage 3). For note, F4 refers to cirrhosis. Some limitations of the medication include cost and unknown factors such uncertainty of how long the medication should be prescribed for, when to consider stopping or alternatives if there is no improvement in liver function, or what are the long term outcomes/side effects of the medication. (Harrison 2024)

Dr. Tapper recommends continuing metformin and statins in patients with MASLD. Vitamin E, as per the PIVENS trial,  has also been used for biopsy proven steatohepatitis (Sanyal 2010). There is a risk of intracranial hemorrhage in women so adequate counseling is required. The medication may be used for 6 months and if the results are beneficial can continue for 1-3 years.

Links

https://punsteria.com/liver-puns/ (Liver Puns)

Superfoods Handout by Dr. Michelle McMacken from Episode #360 Disease Modifying Nutrition

https://pubmed.ncbi.nlm.nih.gov/35416793/ (PICCLES trial)

Goal

Listeners will develop a framework to approach the diagnosis, evaluation, and management of NAFLD/MASLD.

Learning objectives

After listening to this episode listeners will…  

1. Develop a framework to diagnose a patient with MASLD/NAFLD
2. Assess risk for fibrosis in patients with MASLD/NAFLD based on bloodwork, Fib4 scoring, and imaging,
3. Develop strategies for treatment and management of MASLD/NAFLD, including weight loss and medications.

Disclosures

• The Curbsiders report no relevant financial disclosures. 

• Dr. Tapper reports the following conflict of interests: Paid consultant: Malinckrodt (relationship has ended); Novo Nordisk (relationship has ended); Kaleido Biosciences (relationship has ended). Grant or research support: Madrigal (relationship has not ended)

• Dr. Tapper has consulted on health economics outcomes research in MASH with Madrigal, the maker of Resmetirom. The fees were provided as unrestricted research funds to the Regents of the University of Michigan.

• Dr. Tapper previously consulted for Novo Nordisk (maker of Semaglutide), Novartis, and Takeda.

Citation

Achi, SS, Tapper, EB Williams PN, Watto MF. “#452 NAFLD/MASLD”. The Curbsiders Internal Medicine Podcast. thecurbsiders.com/category/curbsiders-podcast 09 September Day, 2024.