#227 Baffled by NAFLD?

July 27, 2020 | By Elena Gibson

Fatty liver, Steatosis, NASH and hepatic fibrosis deconstructed with Dr. Scott Matherly

Swim through the sea of acronyms as Dr Scott Matherly (@liverprof) helps us become a little less baffled by the thought of NAFLD. We discuss the initial diagnosis of fatty liver disease, indications for additional evaluation with imaging and/or biopsy, and potential treatment options. With a quarter of the world affected, it’s crucial to understand the various forms of disease and how to counsel patients about this all-too-common condition!

Listeners can claim Free CE credit through VCU Health at http://curbsiders.vcuhealth.org/ (CME goes live at 0900 ET on the episode’s release date). 

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Credits

Written and Produced by: Elena Gibson MD

Infographic and Cover Art: Elena Gibson MD

Hosts: Matthew Watto MD, FACP; Paul Williams MD, FACP  

Editor: Emi Okamoto MD (written materials); Clair Morgan of nodderly.com

Guest: Scott Matherly MD

Sponsor

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Time Stamps

• 00:00 Sponsors – VCU Health Continuing Education and the AAP’s Pediatrics On Call podcast

• 00:30 Intro, disclaimer, guest bio

• 03:15 Guest one-liner; Picks of the Week*

• 08:15 Sponsor – the AAP’s Pediatrics On Call podcast

• 08:50 Case from Kashlak part 1; What is hepatic steatosis?

• 11:43 NAFLD acronyms and definitions

• 18:20 Alcohol and Fatty Liver

• 23:15 Initial Evaluation of NAFLD

• 35:12 Dr Matherly’s piel to patients with fatty
• 41:11 NASH/Fibrosis Risk Assessment

• 48:54 Outcomes in NASH with Fibrosis
• 51:20 Statins are safe in liver disease
• 56:15 Treatment Options (surgery, Vitamin E, Pioglitazone, SLGT2 inhibitors and GLP1 agonists; Coffee?!) 

• 71:42 Take home points and Outro

Baffled by NAFLD Pearls

1. Hepatic steatosis is pathologic fatty infiltration of the liver. The two most common etiologies of hepatic steatosis are 1) non-alcoholic fatty liver disease (NAFLD) and 2) alcohol .
2. NAFLD is hepatic steatosis associated with metabolic syndrome, and it includes NAFL, NASH and NASH cirrhosis. 
3. Fatty liver disease is extremely common (~25% global population), and beware that ~20% may progress to the more dangerous NASH, indicating inflammation.
4. A significant number of patients with NASH will develop hepatic fibrosis and cirrhosis
5. Despite what your laboratory reference value is, ALT >25 IU/L (female) or >33 IU/L (male) is abnormal and associated with liver morbidity.
6. The initial laboratory workup for NAFLD should include: hepatitis C antibody, hepatitis B core and surface antigen, alpha-1 antitrypsin, and ferritin +/- transferrin saturation.
7. Do not order an “acute hepatitis panel”
8. Use the FIB-4 and NFS as serologic scoring systems to estimate the risk of fibrosis
9. NASH and fibrosis are associated with 3 major outcomes: 1) cardiovascular Disease mortality 2) liver-related morbidity and mortality, and 3) malignancy (HCC and others) 
10. Statins are safe in chronic liver disease!!!
11. The best treatment for fatty liver disease is weight loss. Aim for 10% of body weight loss.

Baffled by NALFD Notes 

Fatty Liver Definition Breakdown

Hepatic steatosis: fatty liver

Non-alcoholic fatty liver disease (NAFLD): umbrella term for fatty liver (hepatic steatosis) associated with metabolic syndrome. 

Metabolic associated fatty liver disease (MAFLD):  experts recently proposed new and improved name for NAFLD (Eslam et al 2020) 

Non-alcoholic steatohepatitis (NASH): inflammation of the liver associated with NAFLD

Cryptogenic Cirrhosis: cirrhosis from an unknown etiology, often from “burnt out” NAFLD 

NAFL: NAFLD without evidence of NASH. Rarely used term 

Hepatic Steatosis= fatty liver

Frequently identified incidentally on imaging (Chalasani et al 2018; Wright et al 2015). Histologically defined as >5% hepatocyte fat accumulation (they start to look like adipocytes). When ~30% of hepatocytes have fat accumulation, echogenicity on ultrasound and hyperattenuation on CT are fairly sensitive at diagnosing hepatic steatosis (Zhang et al 2018) . Hepatic steatosis is pathologic in humans, and there are two major etiologies: 1 ) alcohol (regularly or binge intake) or 2) metabolic syndrome (obesity, high blood pressure, hyperlipidemia. More rare etiologies of hepatic steatosis include: genotype 3 hepatitis C, Wilson’s disease, sudden or rapid weight loss, TPN,  and medications such as prednisone, methotrexate or amiodarone (Idilman et al 2016). 

NAFLD/MAFLD 

Recently, experts have recommended changing the name from NAFLD to metabolic associated fatty liver disease (MAFLD) to more adequately encompass the heterogeneity and prevalence of the disease(Eslam et al 2020). Regardless of the name, NAFLD/MAFLD is very common. The estimated global prevalence is 25% (Younossi et al 2016). The most common risk factors for NAFLD include obesity, insulin resistance, type 2 DM, hypertension, and dyslipidemia Chalasani et al 2018. When speaking with patients, Dr. Matherly describes the pathophysiology of NAFLD by explaining how the liver becomes fatty due to insulin resistance which is a marker of a larger problem in the body, metabolic syndrome.

NASH

NASH is histopathologic inflammation or irritation of the liver associated with NAFLD. Out of the large number of people with NAFLD, approximately 20% develop NASH (Sheka et al 2020). As a subtype of NAFLD, NASH is associated with increased liver related mortality and morbidity, and 20-40% of patients with NASH will develop fibrosis and scarring of the liver leading to cirrhosis (NASH cirrhosis) (Sheka et al 2020). 

Cryptogenic cirrhosis

Cryptogenic cirrhosis is a term used to describe cirrhosis with an unknown etiology. In patients with underlying metabolic risk factors, a significant amount of cryptogenic cirrhosis represents “burnt out fatty liver disease”, or  NAFLD/NASH with only hepatic fibrosis on histopathology (Cotter and Rinella 2020).

Diagnosis and Initial Evaluation of NAFLD

Screening  

Current guidelines from the American Association for the Study of Liver Disease (AASLD) do not recommend screening for NAFLD, even in patients with obesity and DM, due to the lack of cost effectiveness. However, the AASLD guidelines recommend practicing “vigilance” to the possibility of NAFLD in patients with type 2 DM (Chalasani et al 2018). Therefore, Dr. Matherly recommends obtaining liver function tests for those with multiple risk factors, particularly type 2 DM. When interpreting the liver function tests, it is important to remember that  lab reference ranges vary and often overestimate the normal range for AST & ALT. For females the ALT should be between 19-25 IU/L and for males ALT should be between 29-33 IU/L (Kwo et al 2016). If liver enzymes are elevated or if you are concerned due to risk factors,  additional workup with a serologic score for fibrosis (FIB4 or NFS) or imaging (VCTE) should be considered (Cotter and Rinella 2020).

Initial Lab Workup 

NAFLD has historically been a diagnosis of exclusion. Guidelines still recommend ruling out what Dr. Matherly terms “the common and uncommon causes of liver disease”(Chalasani et al 2018). At minimum, Dr. Matherly recommends doing a workup for more common causes of underlying liver disease with the following lab tests: hepatitis C antibody, hepatitis B core and surface antigen, alcohol screening, alpha-1 antitrypsin, and ferritin +/- transferrin saturation (but be ready to interpret). In addition to these, if transaminases are severely elevated (>5x ULN), screening for autoimmune hepatitis should be completed (Chalasani et al 2018).  Dr. Matherly urges providers DO NOT ORDER THE ACUTE HEPATITIS PANEL. 

Alcohol Intake  

Alcohol-related steatohepatitis (ASH) and NASH  are indistinguishable on histology, and both can be present simultaneously. When patients drink moderate to heavy amounts of alcohol,  a component of alcohol-related fatty liver disease should be considered(Chalasani et al 2018).  Definitions vary by study, but for men >4 drinks per day or >14 per week is heavy alcohol use. For females >3 drinks per day or >7 per week. (NIAAA 2005) To screen for heavy alcohol use, use the AUDIT C questionnaire (Bush et al 1998). The alcoholic liver disease/nonalcoholic fatty liver disease index (ANI) can also be used to differentiate NAFLD from alcohol-related liver disease (Dunn et al 2006). Once fatty liver disease is diagnosed, regardless of the etiology,  Dr. Matherly recommends against any alcohol intake. Alcohol is known to cause liver inflammation, and studies of light to moderate alcohol intake in patients with NAFLD have shown mixed results (Hajifathalian et al 2019; Ajmera et al 2018).

Disease Progression and Outcomes

Risk Assessment with Serologic Scoring Systems 

Trying to figure out who will need a biopsy? First, consider utilizing serologic scores to assess the risk of NASH and/or fibrosis such as the Fibrosis-4 (FIB-4) and the NAFLD fibrosis score (NFS). These scores help estimate the risk of fibrosis noninvasively and can be completed with a CBC and a hepatic panel or CMP (Cotter and Rinella 2020). The FIB-4 score was initially created to determine who was at risk of having advanced fibrosis in hepatitis C/HIV coinfection (Sterling et al 2006). FIB-4=Age×AST/(PLT×ALT). In patients with NAFLD, FIB-4 <1.3 is extremely reassuring that advanced fibrosis is not present (Shah et al 2009). NFS is another scoring system that uses age, BMI, impaired fasting glucose/diabetes (Y/N), AST/ALT, platelet count and albumin. An NFS score of <-1.455 is reassuring (Cotter and Rinella 2020) . In patients >65 years old, age-adjusted lower cutoff values are recommended for the  FIB-4 (<2) and the NFS (<0.12) (Cotter and Rinella 2020). Both are good at telling you if the patient does not have scar tissue or if the patient has cirrhosis. In the indeterminate ranges they are not helpful. 30-40% will come back intermediate, and intermediate scores require additional evaluation with VCTE or biopsy( Cotter and Rinella 2020; Chalasani et al 2018 ) .  

Vibration-controlled Transient Elastography (VCTE) 

VCTE measures how fast/slow deep shear waves conduct through the liver.  The velocity of the shear wave is reported as liver stiffness measurement (LSM) in kilopascals (kPA), which correlated with fibrosis (F1-F4 scoring) (Castera et al 2019). If available, VCTE is the next best step for fibrosis evaluation after serological scoring. Caution should be used as obesity, recent PO intake, liver congestion, and inflammation can affect the results often leading to false positives  (Castera et al 2019; Cotter and Rinella 2020). If the VCTE score is Fibrosis 2 (F2) or greater, Dr. Matherly considers a biopsy.  

Repeat Testing 

Dr. Matherly recommends repeat testing to monitor for progression based on underlying risk assessment. If the patient has increased metabolic risk factors (weight, HTN, cholesterol, DM, family history), he would check every 6-12 months. Otherwise, in lower risk patients he would monitor every 2-3 years.

Outcomes 

Once NASH or liver fibrosis develops there are three major outcomes to be concerned about 1) cardiovascular mortality 2) liver related morbidity and mortality (including cirrhosis) 3) cancer, both hepatocellular carcinoma (HCC) and other malignancies (Chalasani et al 2018 ;Cotter and Rinella 2020). Screening for HCC is only recommended for patients with cirrhosis as patients with NAFLD without cirrhosis can get HCC, but this occurs less commonly. Although NAFLD is now the 3rd leading cause of HCC In the United States, the incidence of HCC in patients with NASH cirrhosis is lower than the incidence in patients with other etiologies of cirrhosis such as hepatitis C (Chalasani et al 2018). However, the increasing incidence of NAFLD is leading to an increased prevalence of NAFLD/NASH related HCC (Chalasani et al 2018). In patients with NAFLD and cirrhosis, screening for HCC is recommended every 6 months with an ultrasound. Ultrasound has a reported sensitivity for detecting HCC of 47-84%. Note: Ultrasound’s sensitivity is increased in advanced disease, but obesity and steatohepatitis reduce the sensitivity (Tzartzeva 2018).

Treatment of NAFLD

Weight Loss and Lifestyle Modifications

Weight Loss and Lifestyle Modifications are the most important treatment options available for NAFLD/NASH (Hannah and Harrison 2016).  One 2015 study of patients with biopsy proven NASH in Cuba found that 90% of patients who lost and maintained 10% of total body weight had resolution of NASH (Gomez et al 2015)! Dr. Matherly suggests any way that works for the patient, and highlights cutting down carbohydrates, including sweetened beverages, refined sugars, and other starches. 

Medications

Previously studied medication options for NAFLD have shown minimal benefit, but many treatment options are undergoing ongoing development (Neuschwander-Tetri 2020). 

• Vitamin E- PIVENS (Pioglitazone 30mg QD, Vitamin E 800IU QD, nothing special) trial in 2010 included 247 patients with NASH who received medication for 96 weeks, and excluded patients with DM or cirrhosis. Compared to placebo and pioglitazone, vitamin E improved NASH PIVENS Trial. Dr. Matherly cautions against uses with those at risk for cardiovascular disease.
• Pioglitazone- Subsequent trials have shown benefit in both patients with or without diabetes (Cusi et al 2016; Bril et al 2017). However, one concerning side effect of pioglitazone is weight gain.  If a patient is gaining weight, Dr. Matherly suggests cessation of the treatment. 
• GLP-1 Agonists: Liraglutide– LEAN trial compared liraglutide to placebo and found improved resolution of NASH in those who received liraglutide, but the study was small (52 patients)(LEAN 2016). 
• Ursodeoxycholic acid has no proven benefit (Chalasani et al 2018). 
• Coffee seems to have profound positive effects on the liver in general, and the more coffee the better (Wadhawan and Anand 2016). In the HALT C (Hepatitis C Antiviral Long-Term Treatment against Cirrhosis) trial, increased coffee consumption was associated with less severe disease and decreased risk of developing cirrhosis (Freedman et al 2009). 

Statins

Statins are safe in chronic liver disease and should not be stopped due to the presence of chronic liver disease alone (Speliotes et al 2018; Kasia and Scaglione 2019). Increases in liver enzymes do not always necessitate stopping the statin. Dr. Matherly considers stopping the statin if liver enzymes >200 (expert opinion). Similarly, a 2018 best practice advice from the American Gastroenterology Association recommends cessation of the statin if the ALT or AST are >3 times the ULN and if evidence of cholestasis is present (Speliotes et al 2018). Although there is no clear evidence for statin use to treat NASH, if statin therapy is indicated for another reason, providers should aim to continue the statin given the risk of CV morbidity and mortality in NAFLD patients (Kasia and Scaglione 2019; Chalasani et al 2018; Kothari et al 2019). 

Links*

1. Episode 100: Cirrhosis Initial Evaluation and Management 
2. Episode 101: Cirrhosis Medications, Decompensation, Complications 
3. The Last of Us Part II
4. Not a Diet Book by James Smith
5. Fooled by Randomness by Nassim Nicholas Taleb
6. Beirut Band – Gallipoli and The Flying Club Cup
7. Beat Saber

*The Curbsiders participates in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising commissions by linking to Amazon. Simply put, if you click on our Amazon.com links and buy something we earn a (very) small commission, yet you don’t pay any extra.

Goal

Listeners will develop an approach to the basic evaluation and initial management of NAFLD. 

Learning objectives

After listening to this episode listeners will…  

1. Recognize the different etiologies of hepatic steatosis 
2. Define terms:  non-alcoholic fatty liver disease (NAFLD), non-alcoholic fatty liver (NAFL) non-alcoholic steatohepatitis (NASH), alcoholic steatosis, cryptogenic cirrhosis  
3. Define the risk factors associated with NAFLD 
4. Develop an approach to the initial evaluation and management of NAFLD and NASH 
5. Recognize the value of weight loss in the management of NAFLD
6. Determine when and how to monitor patients for progression of NAFLD 
7. Identify pharmacologic treatment options for patients with NASH and recognize when and how to use them. 
8. Describe the outcomes of concern associated with NAFLD and NASH. 

Disclosures

Dr Matherly reports no relevant financial disclosures. The Curbsiders report no relevant financial disclosures.

Citation

Matherly S, Gibson EG, Williams PN, Okamoto E, Watto MF. “#227 Baffled by NAFLD”. The Curbsiders Internal Medicine Podcast. http://thecurbsiders.com/episode-list . Original air date July 27, 2020.