Metabolic Dysfunction Associated Steatohepatitis (MASLD) (Holt, 2/25/2026)

A recording of this presentation is available HERE.

Deep gratitude to Dr. Will Holt, CPMC Hepatologist, who drove to SSRRH from Piedmont at the literal crack of dawn to teach us about Metabolic Dysfunction Associated Steatohepatitis (MASLD) and Alcohol-Associated Liver Disease (AASLD) and then changed hats to spend the morning with our residency leadership as a faculty leader for graduate medical education within Sutter. 

His talk was fantastic! I recommend you watch it.

For those of you who prefer to read, the highlights:

First, MASLD

• We all known that the prevalence of obesity and diabetes have both skyrocketed over the last several decades-- nearing 50% in some regions of our country. 
• 
• Along with these metabolic issues, comes MASLD-- world prevalence is estimated to be 29.8% lowest rates for those of African descent (thought to be both genetic and food access/lifestyle related)
• Risk factors for MASLD include age >50, high BMI and DM2
  
• MASLD is a risk factor for death
• Assume that people are high risk (>50, high elevated BMI, DM2) have MASLD>> screen them for MASH with via fibroscan
• For everyone else with any component of metabolic syndrome (e.g. overweight, a1c>6%, hypertension, HDL<40 (F) and <50 (M), triglycerides>150)>> use FIB-4 to screen first
• if the FIB4>1.3>> Fibroscan,
• unless they are >65yo, then use FIB-4>2.0
• Fibroscan uses a weighted hammer/pulse to measure liver stiffness-- this is available through Sutter Airway)

• Fibroscan <8 is normal (=reassuring, low risk), >14 demonstrates cirrhosis
• for those with a normal fibroscan, focus on lifestyle modification for metabolic disorders
• for those with an abnormal fibroscan, refer to hepatology
• Fibrosis predicts liver-related mortality (see graph below from J. Hepatology 2017)
• stage 0/1 fibrosis: no increased mortality
• stages 2, 3, 4>> increased liver mortality 
• 

As per the 2024 AASLD Guidelines for clinical suspicion of steatotic liver disease

What are the treatment options for MASLD and MASH?

• Pharmacologic:
• Vitamin E: 96 week RCT: reduced fibrosis 41% vs. 31% (placebo)
• Pioglitazone: meta-analysis, reduced fibrosis vs. placebo OR 1.77
  
• There are two FDA approved medications:
• Resmetirom (2024): TRH-beta agonist, 52 week RCT vs. placebo, reduced fibrosis 24% vs. 14%
• Semaglutide (2025): GLP1 agonist, 72 week RCT vs. placebo, reduced fibrosis 37% vs. 22% 
• Non-Pharmacologic: diet/exercise/weight loss
• weight loss improves liver histology! Even 5%!!!
• 
  

Now, a little bit on ALD

• Defining Alcohol use disorder (AUD)
• 
• Biomarkers for ETOH
• Urine tests (EtG, EtS) have a very short detection window (<48 hours)
• PEth is current "truth serum", gives us information about the last 30 days, though there are some false positives in the lower ranges (20-40). Very high results (>400-1000 are very reliable)
• Diagnosing Alcoholic Hepatitis can be tricky!
• elevated MCV (100), elevated WBC, jaundice

• Treatment of alcohol-associated hepatitis with prednisolone (rather than prednisone due to first pass metabolism, when not available, prednisone is acceptable) FOR: 
• Patients WITH Maddrey Discriminant Function >32>> 
• AND WITHOUT
• evidence of biliary obstruction on ultrasound
• uncontrolled infection (especially bacteremia)
• AKI with SCr>2.5
• UGI bleeding
• Severe shock/hemodynamically unstable
• Expect 3 month recovery (bili will remain high)
• You can wait a couple of days before starting prednisolone (e.g. if any of the above active), pts can still benefit with delayed start
• Use the Lille score to predict (7 days) who will respond

• N-Acetylcysteine= mixed bag, there does appear to be a mortality benefit at 30 days but not at 3 months/6 months (NEJM 2011, see image)
• 
  
  
  
• What about liver transplant (LT) in ALD?
• 2011 RCT from France (NEJM 2011) was practice changing, randomized patients with AH without sobriety and first decompensating event  to LT vs. no LT (only <10% deemed candidates)>> found that 1 and 3 year survival was the same for patients with ALD as any other liver disease
• This led to a change in practice in which transplant can/may be considered for alcoholic hepatitis in select patients, not specified as a specific duration of sobriety>> at CPMC, this is called the "limited sobriety pathway to LT"
• Careful patient selection for LT (with ALD) is key. 
• Family support
• Absence of untreated psychiatric disorder
• Agreement by patient with support to LIFELONG abstinence (this can be harder to get to that you might imagine)
• This assessment is done by LT SW at CPMC (often via video visit prior to Transfer)
• We know that patients with AUD will relapse

Acute Liver Injury (Deis, 10/29/25)

 A recording of this presentation is available HERE.

Many thanks to Dr. Faith Deis for an awesome presentation this week on Acute Liver Injury (ALI). For those impatient folks out there, the most important take home points are: 

1) While the combination of alcohol and acetaminophen can actually be hepato-protective, a pattern of heavy ETOH use + fasting followed by moderate to high dose of APAP can be particularly hepatotoxic and make vulnerable patients more susceptible to ALI. 

2) N-Acetylcysteine (NAC) replenishes glutathione with is hepatoprotective and shows benefit for ALI of multiple etiologies (not just APAP intoxication); when in doubt and/or when in the midst of a work-up, give NAC empirically for any undifferentiated ALI, even if APAP level is normal.

A few more pearls from Dr. Deis's talk follow. . .

Acute Liver Failure= Acute liver injury (as indicated by elevation in AST/ALT) + Coagulopathy (INR>1.5) + Hepatic Encephalopathy

Much like many of us use LactMed for breastfeeding safety, there is an excellent NIH source, LiverTox, which compiles all the evidence we have on liver toxicity of medications. Just last night while precepting, a resident and I used this resource to understand whether GLP-1 medications may be implicated in rising transaminases in a patient with poorly controlled DM2. This is a great resource!

Dr. Deis introduced us to the idea of using the "R factor" to help distinguish between intrahepatic and cholestatic patterns of liver injury.

From the 2021 ACG Guidelines. You can see how both the LiverTox and the R factor are involved in your clinical decision about 1st line testing for abnormal liver enzymes:

A little physiology and pathophysiology of APAP Toxicity, which you will note involves the CYP-2E1 pathway (5-9% of hepatic metabolism of APAP) and NAPQI, which leads to hepatocyte necrosis. In APAP overdose, more of the pathway is pushed to the NAPQI pathway! This is important in consideration the mechanism of action of NAC, which actually helps to replenish glutathione, and therefore shift the ASAP metabolism pathway away from the toxic one and back to the healthy one.

Dr. Deis also shared an interesting set of studies on the interaction between APAP and Alcohol on liver metabolism. This is super interesting! It turns out that if APAP and alcohol are ingested simultaneously, alcohol's metabolism actually has a protective effect on the liver's metabolism of APAP, keeping it in the non-toxic pathway. BUT if alcohol is ingested prior to APAP administration (and particularly in the setting of prolonged fasting, which is not uncommon during an alcohol binge), then the use of APAP is pushed toward the NAPQI pathway and is more likely to be hepatotoxic. Practically speaking, then, if a patient has an alcohol binge, and then consumes even moderate doses of APAP at the tail end/after the binge, those moderate doses may lead to a disproportionately toxic impact on the liver. This means, then, that you can have acute liver injury (and even failure) from a therapeutic dose of APAP. 

What about NAC?

Turns out that NAC's protective effect on the liver extends beyond APAP ingestion. In a 2021 Metanalysis , authors found a small but stastitically significant mortality benefit in patients with non-APAP induced liver injury and improved mortality (see table below). There are actually few downsides to NAC (the only absolute contraindication is allergy to NAC itself, care with volume needed to infuse for patients for whom volume could be problematic). In sum,  American College of Gastroenterology 2024 Guidelines actually recommend NAC be administered to all patients with ALI while work-up is in progress. 

A bit on Alcoholic Hepatitis (which may be on your ddx in someone with binge drinking behaviors)

-Remember the Alcoholic hepatitis rarely has AST/ALT elevated above 400-500 and the AST/ALT ratio should be somewhere around 1.5 and the Total Bilirubin is almost always >3.

The 2024 ACG guidelines on alcohol associated liver disease have a really nice set of flowsheets (for those of you who love flowsheets) that nicely outline the evaluation of Alcoholic hepatitis and the subsequent decision tree around using (or not using) steroids, remembering that steroids have downsides (infection, GI bleed, hyperglycemia, AKI, psych) and should only be used in appropriate candidates. 

 

On a final note, we must be careful with patients with ALI who also undergo alcohol withdrawal. Phenobarbital, which has become widely used in our institution in the last year, is relatively contraindicated, as are sedating medications (e.g. benzos). That being said, alcohol withdrawal is a dangerous condition that could result in ICU transfer and/or even death, so we need to be treating them. A reminder that librium/chlordiazepoxide, which has widely fallen out of favor, may be the best option in these patients. 

So much good learning!

Thanks for making it to the end.

Dr. Deis' references:

ACG Guidelines 2024

LiverTox

AASLD

Ghosh, A., Berger, I., & Remien, C. H. (2020). The role of alcohol consumption on acetaminophen-induced liver injury: Implications from a mathematical model. Journal of Theoretical Biology, 510, 110559. https://doi.org/10.1016/j.jtbi.2020.110559 ouci.dntb.gov.ua+1

Forget, P., Wittebole, X., & Laterre, P.-F. (2009). Therapeutic dose of acetaminophen may induce fulminant hepatitis in the presence of risk factors: A report of two cases. British Journal of Anaesthesia, 103(6), 899-900. https://doi.org/10.1093/bja/aep322 OUP Academic

Ghosh, A., Berger, I., Remien, C. H., & Mubayi, A. (2020). The role of alcohol consumption on acetaminophen-induced liver injury: Implications from a mathematical model. Journal of Theoretical Biology, 510, 110559. https://doi.org/10.1016/j.jtbi.2020.110559. (Note: duplicate to #1 – keep one)

Lee, W. M., Kaplowitz, N., et al. (2020). Acute liver injury with therapeutic doses of acetaminophen (≤ 6 g/day): A prospective study. Hepatology, (in press). https://pubmed.ncbi.nlm.nih.gov/33306215/ PubMed+1

Whitcomb, D. C., & Block, G. D. (1994). Association of acetaminophen hepatotoxicity with fasting and ethanol use. JAMA, 272(23), 1845-1850. https://doi.org/10.1001/jama.272.23.1845 (from PubMed 7990219)

Abnormal Liver Function in Obstetrical Patients (Ludwig, 6/1/2022)

Many thanks to Dr. Alec Ludwig for an excellent presentation about liver and biliary abnormalities in pregnancy. It was jam-packed with good information. 

A recording of his presentation is available HERE. 

My notes:

Remember that what we typically call "liver function tests"  is actually a misnomer. In fact, there is no test that reliably demonstrates the liver's function. Elevation of AST and ALT -- the liver enzymes-- indicates liver injury, not liver dysfunction. Albumin and prothrombin time are factors that are produced by the liver and may be better markers of function. 

In normal pregnancy, you can see elevated alkaline phosphatase (up to 3x normal), as well as elevated cholesterol, triglycerides, and fasting gallbladder volume. Note that many measures we use to evaluate the liver (AST/ALT, T Bili, PTT, liver size, bile acids) don't change in pregnancy.

Hepatocellular injury as measured by elevation in AST/ALT:

• acute viral/toxic hepatitis: AST/ALT 25x upper limit of normal
• ischemic hepatitis: AST/ALT 50x upper limit of normal
• chronic HCV/HBV: slight elevation of AST/ALT (2x normal), rarely greater than 10x normal

Gallstone disease in pregnancy

Gallstone disease is much more prevalent in pregnancy for several reasons. 1) Increased estrogen levels increase cholesterol, thereby supersaturating bile with cholesterol. 2) Progesterone slows contraction of gallbladder, disrupting the excretion of bile acids. AND 3) Increased fasting gallbladder volume.

• acute cholecystitis: blockage of the cystic duct causing inflammation in the gallbladder
• fever, WBC count, can have slightly elevated AST/ALT (if large stone)
• choledocholithiasis: stone in CBD or hepatic duct, causing backup into liver, injury to liver
• definite elevation AST/ALT
• acute cholangitis: can be emergency due to severity of illness
•  Charcot's triad (RUQ pain, jaundice, fever)

Generally treat GB disease in pregnancy with IV antibiotics, surgery if indicated. Laparoscopic cholecystectomy is safe in pregnancy, safest in the second trimester. Should occur within 24-48 hours conservative management. ERCP is also safe in pregnancy; minimize radiation by shielding, fetal monitoring.

Viral Hepatitis (A-E)

• HAV: most common acute hepatitis in general population, but infrequent in pregnancy. 
• Acute infection  (only care about IgM). 
• Generally mild (malaise, HA, fever, jaundice, RUQ pain), supportive treatment. 
• HAV vertical transmission rare but has been documented. Associated with preterm birth, neonatal cholestasis. 
• Breastfeeding okay, HAV vaccine safe in breastfeeding
• HBC: surface Ag used to screen everyone in pregnancy, core Ag, e Ag indicated infectivity/vertical transmission to 80-90% if occurring in the 3rd trimester. 
• Major causes IVDU, sexual intercourse with people w/HBV, vertical transmission. 
• can present with asymptomatic acute phase, can pick up infection even prior to symptoms
• if mom has chronic HBV in pregnancy: need to check viral load, 1 million to 100 million is elevated, may need treatment during pregnancy w/Tenofovir after 28-32 weeks (to prevent vertical transmission)
• Babies born to mothers with HBV needs HB IVIG and first dose of vaccine within 12 hours, don't determine delivery method
• Breastfeeding is safe as long as infant got IVIG and HBV vaccine
• HCV: can be acute and chronic 
• HCV on the rise in the last few years (2009-2019 2x increase of patients with HCV), likely due to IVDU
• vertical transmission 3-5%
• 75% HCV infections are asymptomatic
• ACOG does have some recommendations of Category B meds that could be used to treat HCV in pregnancy to decrease vertical transmission (Ribavirin is teratogenic)
• Vertical transmission increases if co-infection w/HIV, invasive surgical procedure, ROM >6 hours, conflicting data but discourage fetal scalp electrode
• Breastfeeding okay w/HCV
• HDV: coexists with HBV only, anyone with chronic HBV should be tested for HDV. Supportive treatment, monitor symptoms. If treat HBV, clears HDV.
• HEV: can be acute and chronic, based on genotype
• some areas in Mexico, Asia, Africa and South America endemic (travel recommendations not to travel to endemic areas in 2nd and 3rd trimester)
• believed to be water born
• pregnancy women are particularly susceptible to severe liver damage and liver failure, 20-30% mortality
• rare vertical transmission
• breastfeeding okay

Other viral hepatitis: HSV hepatitis (rare but high mortality), CMV hepatitis (also rare, more common in organ transplant pts): most common hearing loss

Cirrhosis in Pregnancy: it is more difficult to get pregnant if cirrhotic (due to secondary amenorrhea), but can still get pregnant. High risk for bleeds, aneurysms and acute on chronic liver failure. Need variceal screening DURING pregnancy. Increased mortality with pregnancy (should calculate MELD, do HCC screening even during pregnancy). Can use beta blockers (e.g. propranolol) but can cause some side effects to baby. Octreotide okay. Mode of delivery unclear, should be individualized.

Autoimmune hepatitis in pregnancy generally improve during the 2nd trimester BUT can flare post partum.

Hyperemesis Gravidarum: 50-60% of patients hospitalized with hyperemesis demonstrate some abnormal liver tests: hyper bilirubin, elevated AST/ALT. Generally don't get fever, jaundice. 

Cholestasis of Pregnancy (ICP) is the most common liver disorder unique to pregnancy. Generally presents as pruritis without a rash. Even though palms and soles are most common places, can be in other places as well. May see abnormalities in AST/ALT. Increased serum bile acids confirm a diagnosis (>10=cholestasis dx, >100=severe, should be induced after 36 weeks, earlier other indications).

• Elevated ALT 30x normal, elevated conjugated bilirubin
• generally not jaundiced
• start antenatal testing right away
• treatments (all grade C): ursodiol improved labs and symptoms but no data that improves still birth. Other treatments: Hydroxyzine, cholestyramine
• Some data on PO vitamin K (evolving evidence)
• Can progress: 2-5x risk of progression to preE, if bile acids >40

Pre-Eclampsia is diagnosed by blood pressure criteria: SBP >140, DBP >90, 2 x, 20 minutes apart after 20 weeks AND either proteinuria (>0.3 microalbumin/creatinine ratio) OR lab abnormalities (platelets <100K, SCr>1.1 or double baseline, impaired liver tests (2x normal). Symptoms-based diagnosis is NOT recommended. Antenatal testing twice weekly. Deliver at 37 weeks

Pre-E with severe features: 

• BP >160/110 (2x, 4 hours apart) OR
•  thrombocytopenia, elevated SCr or liver test abnormalities (regardless of BP)
• Antenatal testing daily, deliver at 34 weeks

HELLP syndrome is considered a complication of PreE even though 15% of patients don't have elevated BP or proteinuria. 10-20% of women with severe PreE progress to HELLP. Diagnosed with signs of hemolysis (LDH>600, platelets <100, AST/ALT 2x normal).  High mortality. Can lead to hepatic rupture/hematoma, placental abruption, acute renal failure, etc. Treatment is magnesium sulfate, treat BP and delivery. Hepatic hematoma and rupture (stretching of Gleason's capsule) -- pts often have severe RUQ pain. 

Acute Fatty Liver of Pregnancy has a lot of similarities with HELLP, Severe PreE and acute fatty liver. Originates from genetic defect in fetus and a susceptible mother. Presents with n/v, pain, jaundice, fever. Generally don't present with elevated BP. Swansea criteria to make diagnosis. Can add ammonia, uric acid to help classify. Imaging may demonstrate hypoechoic liver with lots of fatty deposits. 

Non-Alcoholic Fatty Liver Disease (Burns 3/25/2020)

Thanks to Dr. Autumn Burnes for being such a wonderful and flexible first presenter on our new Virtual Social Distancing Zoom Grand Rounds at SSRRH. It was really nice to take 45 minutes to think about something other than COVID-19. We had over 35 attendees. . .Thanks to everyone who tuned in!

The topic was Non-Alcoholic Fatty Liver Disease (NAFLD) and Non-Alcoholic Steatohepatitis (NASH).

NAFLD: histologic evidence of an accumulation of fat in hepatocytes (steatosis)
NASH: the presence of NAFLD plus liver cell injury and death, and accumulation of inflammatory cells

Some shocking stats:

• 25% of US adults are affected by NAFLD 

  

  (NEJM 2017, https://www.nejm.org/doi/full/10.1056/NEJMra1503519)

• 5% have NASH
• NASH is among the top 3 indications for liver transplant and will likely surpass Hepatitis C and Alcohol cirrhosis in the coming years
• 70% of Type 2 diabetics have NAFLD (!!)

MOST COMMON risk factors include metabolic syndrome: abdominal obesity, impaired glucose tolerance/diabetes, hypertension, dyslipidemia

LESS COMMON risk factors include nutritional syndromes, drugs and toxins, inherited metabolic diseases, and pregnancy-related factors:

• TPN, rapid weight loss, jejunoileal bypass
• EtOH, corticosteroids, tamoxifen, amiodarone, methotrexate, industrial solvents
• Lipodystrophy, abetalipoproteinemia, Wilson's
• Acute fatty liver of pregnancy, HELLP 

NAFLD is a diagnosis of exclusion.

You should consider other causes of chronic liver disease, including (but not limited to): chronic viral hepatitis, hemachromatosis, autoimmune liver disease, alpha1antitrypsin deficinecy, Wilson's disease, drug induced liver disease)

NAFLD (by AASLD criteria):

1. Hepatic steatosis by imaging or histology [>5% hepatocytes, +ballooning/hepatocyte injury for NASH]
2. No significant alcohol consumption [>1 drink/day for F and 2 drinks/day M]
3. No competing etiologies for hepatic steatosis
4. No coexisting causes of chronic liver disease
5. Liver biopsy is gold standard

What is our primary care role ?

Consider using this AAFP approach to elevated liver enzymes in your primary care practice (this is a picture of Figure 1 from AAFP 2017 article, entire article can be found here: https://www.aafp.org/afp/2017/1201/p709.html)

(AAFP 2017)

It's frustrating and scary to not have much to offer patients who already have cirrhosis from NASH, so can we intervene sooner?

We don't have great tools to distinguish those who will go onto develop NASH from the large population that has NAFLD. But we know that risk of progression is multifactorial including genetic factors, epigenetic factors, and environmental (e.g. shift work, gut microbiome, toxins).

Here are two risk calculators (links should work):
NAFLD Fibrosis Score (Age, BMI, IGT/DM, AST, ALT, platelet count, albumin)
Fibrosis- 4 (Fib-4) Index for Liver Fibrosis (Age, AST, ALT, platelet count)

Routine screening for NASH is currently NOT recommended (by AASLD, USPSTF, or NICE guidelines) BUT we should have a high index of suspicion, particularly in our Type 2 diabetic patients, and we might consider either using the Fib-4 calculator to risk stratify OR send for elastography (specialized ultrasound).

However, for those of you who are looking for screening guidelines, here is a paradigm for HIGH risk patients:

There are evolving pharmacologic treatment options, including:

• Thiazolidinediones (pioglitazone), even in patients without diabetes  (some possible benefit in the PIVENS trial)
• GLP-1 agonists (very small study LEAN trial, too early to know)
• Vitamin E  (800 IU/day, recommended by AASLD only in biopsy-proven NASH)
• Keep taking statin if it is indicated (despite hepatotoxicity)
• (Metformin has NO benefit)

Mortality in NAFLD:

• Cardiovascular disease is the most common cause of death in patients with NAFLD, independent of other metabolic comorbidities. 
• we should treat CVD proactively
• Cancer
• Liver-related death
• Increased all-cause mortality