MASLD & MASH (formerly NAFLD / NASH)
The commonest liver disease in the world, renamed in 2023 and given its first approved drug in 2024, so most of what residents were taught is now outdated terminology attached to an outdated plan. Two things matter more than the diagnosis itself: fibrosis stage is the only thing that predicts liver outcomes, and cardiovascular disease is what actually kills these patients. Start with FIB-4, which costs nothing.
🔍 Overview
What changed in 2023 (multisociety Delphi consensus): RENAMED NAFLD became MASLD (metabolic dysfunction-associated steatotic liver disease) and NASH became MASH (metabolic dysfunction-associated steatohepatitis), under the umbrella term steatotic liver disease (SLD). Two reasons, both practical: the old names defined the disease by what it was not ("nonalcoholic") and required excluding alcohol before diagnosing, whereas the new criteria are positive -steatosis plus at least one cardiometabolic risk factor. That also creates a named category for the very common patient who has both metabolic risk and meaningful alcohol intake: MetALD. And "fatty" was judged stigmatizing. If you learned NAFLD/NASH, the disease is the same; the framing and the drug landscape are not.
The Definitions
- MASLD: hepatic steatosis on imaging or biopsy PLUS ≥ 1 cardiometabolic criterion (overweight/obesity or increased waist circumference, hyperglycemia or type 2 diabetes, hypertension, hypertriglyceridemia, or low HDL) with no other cause of steatosis.
- MASH: the inflammatory, hepatocyte-injury form (steatosis + ballooning + lobular inflammation) -the subgroup that progresses to fibrosis and cirrhosis. Biopsy-defined historically, increasingly inferred noninvasively.
- MetALD: MASLD criteria plus meaningful alcohol intake (roughly 20-50 g/day in women, 30-60 g/day in men) -a spectrum category rather than a diagnosis of exclusion, because both drivers are treated.
- Excluded first: significant alcohol use above those thresholds (ALD), hepatitis B and C, drug-induced steatosis (methotrexate, amiodarone, tamoxifen, valproate, steroids), Wilson disease in the young, and hypothyroidism.
Why It Matters (and what actually kills these patients)
- Prevalence is roughly 30% of adults and far higher in type 2 diabetes and obesity -this is a clinic-wide problem, not a specialist curiosity.
- Cardiovascular disease is the leading cause of death in MASLD, not liver disease -which reframes the whole encounter: finding MASLD is a cardiometabolic risk finding, and the statin conversation matters more than the liver conversation for most patients.
- Only a minority progress: simple steatosis is largely benign for the liver, MASH with fibrosis is what advances. That is why fibrosis stage, not the presence of fat, drives every management decision.
- MASLD-related cirrhosis is now among the leading indications for liver transplant, and HCC can occur in MASLD cirrhosis (and rarely without it).
Two common errors this page exists to correct. First, "fatty liver on ultrasound, LFTs normal, reassure" -normal aminotransferases do NOT exclude advanced fibrosis, and many patients with F3-F4 disease have normal ALT. Risk-stratify everyone. Second, statins are not contraindicated in MASLD: they are safe, they are indicated for the cardiovascular risk that will kill the patient, and withholding them over mildly abnormal LFTs is a net harm.
🧪 Risk Stratification
Who to Screen
- Risk-stratify (not population-screen) the high-risk groups: type 2 diabetes, obesity with metabolic risk factors, persistently elevated aminotransferases, and incidentally discovered hepatic steatosis on any imaging.
- Type 2 diabetes deserves special emphasis -prevalence of clinically significant fibrosis is high enough that guidelines support systematic FIB-4 assessment in this group.
The Noninvasive Pathway (FIB-4 first, always)
- Step 1 -FIB-4 (age, AST, ALT, platelets): it costs nothing and uses labs you already have. < 1.3 = low risk (high negative predictive value for advanced fibrosis; recheck in 1-3 years). > 2.67 = high risk -refer to hepatology. 1.3-2.67 = indeterminate, the zone that needs a second test. Note FIB-4 performs less well under 35 and over 65, where thresholds shift.
- Step 2 -elastography or a proprietary blood panel for the indeterminate zone: vibration-controlled transient elastography (FibroScan) liver stiffness, or ELF. Low stiffness reassures and returns the patient to primary care; high stiffness routes to hepatology.
- Biopsy is now the exception -reserved for diagnostic uncertainty, suspected competing or coexisting disease (autoimmune hepatitis, hemochromatosis), or trial enrollment. The noninvasive pathway answers the practical question for most patients.
- What the workup is really deciding: not "does this patient have fat in the liver" (they do) but "do they have F2 or worse fibrosis", because that changes referral, surveillance, and now drug eligibility.
The Rest of the Evaluation
- Exclude the mimics: hepatitis B and C serologies, quantified alcohol history (use AUDIT-C rather than "social drinker"), ferritin and iron studies, and in the right patient autoimmune serologies, ceruloplasmin, and alpha-1 antitrypsin.
- Complete the cardiometabolic workup, because it is the actual prognosis: A1c, full lipid panel, blood pressure, and a formal ASCVD risk estimate -then treat what you find.
- If cirrhosis is established: HCC surveillance with ultrasound ± AFP every 6 months, and variceal screening per standard criteria.
🚨 Management
Weight Loss Is the Therapy (and the numbers are specific)
- 3-5% body weight loss improves steatosis; 7-10% improves MASH inflammation and ballooning; ≥ 10% can regress fibrosis. Quoting the specific thresholds matters, because "lose some weight" produces nothing while "10% is the target where fibrosis improves" gives the patient a real goal.
- Mediterranean-style diet with elimination of fructose-sweetened beverages (a direct driver of de novo lipogenesis).
- Exercise helps independent of weight loss -150-300 min/week of moderate activity reduces liver fat even when the scale does not move, which is a useful thing to tell a discouraged patient.
- Alcohol: minimize in MASLD, and in MetALD or advanced fibrosis the advice is abstinence -alcohol and metabolic injury are synergistic, not additive.
- Coffee is associated with less fibrosis progression -a small, free, easy recommendation.
Drug Therapy
| Agent | Who | Why / Watch for |
|---|---|---|
| Resmetirom (Rezdiffra) FIRST APPROVED | MASH with F2-F3 fibrosis (moderate to advanced), noncirrhotic | Liver-directed thyroid hormone receptor-beta agonist -produces localized hepatic "hyperthyroidism," reducing hepatic fat and fibrosis without systemic thyroid effects. FDA accelerated approval March 2024, alongside diet and exercise. Not for cirrhosis (F4). Watch diarrhea and nausea early, monitor LFTs, and mind CYP-mediated statin interactions (dose limits apply to some statins). |
| GLP-1 receptor agonists (semaglutide, tirzepatide) | MASLD with obesity or type 2 diabetes | Drive the weight loss that treats the liver while independently reducing cardiovascular events -the rational backbone when either comorbidity is present. Resolution of steatohepatitis is well supported; the fibrosis signal continues to mature. |
| Pioglitazone | MASH with type 2 diabetes (biopsy-proven disease historically) | Improves steatohepatitis histology. Weight gain, fluid retention (avoid in heart failure), and fracture risk in older women temper enthusiasm. |
| Vitamin E 800 IU/day | Selected nondiabetic adults with biopsy-proven MASH | Improves steatohepatitis in that specific population. Discuss the long-term safety debate (prostate cancer signal, hemorrhagic stroke) before starting; not a blanket recommendation. |
| Statins | Anyone whose ASCVD risk warrants one | Safe in MASLD including compensated cirrhosis, and indicated for the disease that will actually kill the patient. Mildly abnormal aminotransferases are not a reason to withhold or stop. |
| Bariatric / metabolic surgery | Eligible patients with obesity | The most durable weight loss, with substantial evidence for MASH resolution and fibrosis improvement. Consider formally rather than as a last resort. |
The Cardiometabolic Half of the Plan
- Treat the ASCVD risk aggressively -statin per risk, blood pressure to target, glycemic control, smoking cessation. This is not adjunctive care; it is the intervention most likely to extend the patient's life.
- Choose diabetes drugs that help the liver: GLP-1 receptor agonists and pioglitazone have liver benefit, so a patient with MASLD and type 2 diabetes should get an agent that treats both.
- Vaccinate against hepatitis A and B in chronic liver disease.
- Re-stage over time: repeat FIB-4 every 1-3 years in low-risk patients (more often with diabetes or ongoing risk), because fibrosis is dynamic in both directions.
🏥 Rounds
Pimp Questions
❓ Why was NAFLD renamed MASLD, and what practical difference does it make?
Three reasons. The old name was defined by exclusion ("nonalcoholic"), which required ruling out alcohol before you could name the disease; MASLD is a positive diagnosis -steatosis plus at least one cardiometabolic criterion. It creates MetALD for the very common patient with both metabolic risk and meaningful alcohol intake, who previously fell between two diagnoses and now gets both drivers addressed. And "fatty" was judged stigmatizing. The disease biology is unchanged; the framing pushes you toward the cardiometabolic workup that the old name let you skip.
❓ A patient has fatty liver on ultrasound and completely normal aminotransferases. Can you reassure them?
No -normal ALT and AST do not exclude advanced fibrosis, and a substantial proportion of patients with F3-F4 disease have normal enzymes (aminotransferases may even fall as fibrosis advances and hepatocyte mass declines). Risk-stratify with FIB-4 regardless of the LFTs: under 1.3 is genuinely reassuring, over 2.67 goes to hepatology, and the indeterminate zone needs elastography. Using the LFTs as the gate is how advanced fibrosis gets missed for years.
❓ What actually kills patients with MASLD?
Cardiovascular disease is the leading cause of death, ahead of liver-related mortality, followed by extrahepatic malignancy. This inverts the instinct to treat MASLD as purely a liver problem: finding it is a cardiometabolic risk finding, so the encounter should produce a lipid panel, an ASCVD risk estimate, a blood pressure plan and a statin decision, not just a hepatology referral. Liver-related death dominates only in the minority who reach advanced fibrosis or cirrhosis -which is precisely why fibrosis staging drives management.
❓ Who is eligible for resmetirom, and who is not?
Adults with MASH and moderate-to-advanced fibrosis (F2-F3), alongside diet and exercise -FDA accelerated approval, March 2024. It is a liver-directed thyroid hormone receptor-beta agonist, producing local hepatic thyroid signaling that reduces steatosis and fibrosis without systemic thyrotoxicosis. It is not indicated in cirrhosis (F4), and it is not for simple steatosis without fibrosis. Practical cautions: GI side effects early, LFT monitoring, and statin interactions that require dose attention -relevant because most of these patients should be on a statin.
❓ How much weight loss does the patient actually need, and does exercise help without it?
The thresholds are specific and worth quoting to patients: 3-5% improves steatosis, 7-10% improves MASH inflammation and ballooning, and ≥ 10% can regress fibrosis. Vague advice to "lose weight" achieves nothing; a numeric target does. And yes -150-300 minutes per week of moderate exercise reduces hepatic fat independent of weight change, which is the single most useful thing to tell a patient whose scale has not moved and who is about to give up.
Sample Presentation
Mr. Bautista is a 54-year-old man with type 2 diabetes (A1c 8.1), BMI 34, hypertension and hypertriglyceridemia, found to have hepatic steatosis on an abdominal ultrasound ordered for right-upper-quadrant discomfort. ALT 34, AST 38, platelets 165, albumin normal, INR normal. Hepatitis B and C negative. He drinks 1-2 beers on weekends. FIB-4 calculates to 1.9 -the indeterminate zone.
Key Points: (1) He meets MASLD criteria (steatosis plus four cardiometabolic factors), and his normal aminotransferases are not reassuring -the FIB-4 of 1.9 is what matters, and it lands indeterminate, so elastography is the next test, not observation. (2) The highest-yield prescription today is cardiometabolic: statin (safe here, and his risk demands it), blood pressure control, and switching his diabetes regimen toward a GLP-1 receptor agonist, which treats the liver, the weight and the cardiovascular risk simultaneously. (3) Give him the numeric weight target -7-10% for steatohepatitis, 10%+ for fibrosis regression -plus the news that exercise helps even without scale movement. If elastography shows F2-F3 MASH, resmetirom becomes a discussion; if F4, it does not.
Clinic Checklist
- FIB-4 calculated on every high-risk patient (type 2 diabetes, obesity with metabolic risk, incidental steatosis), regardless of LFT values.
- Indeterminate FIB-4 followed by elastography, not by watchful waiting.
- Mimics excluded: hepatitis B and C, quantified alcohol, iron studies, drug review (methotrexate, amiodarone, tamoxifen, valproate, steroids).
- ASCVD risk calculated and a statin decision documented -the leading cause of death here is cardiac.
- Numeric weight target given (3-5 / 7-10 / ≥10%) rather than generic advice; fructose-sweetened drinks named specifically.
- Diabetes regimen reviewed for liver-active agents (GLP-1 RA, pioglitazone) where diabetes coexists.
- Hepatitis A and B vaccination status checked.
- Cirrhosis: HCC surveillance q6 months and variceal screening on the problem list.
📋 Summary
Summary
New Names, Positive Criteria
NAFLD is MASLD and NASH is MASH, under the umbrella of steatotic liver disease (2023 consensus). The point is not cosmetic: the diagnosis is now positive (steatosis plus ≥ 1 cardiometabolic criterion) rather than an exclusion, and MetALD names the common patient with both metabolic risk and meaningful alcohol intake so that both drivers get treated.
Fibrosis Stage Is the Only Prognostic Number
Simple steatosis is largely benign for the liver; MASH with fibrosis is what progresses. So the question is never "is there fat" but "is there F2 or worse" -that single answer drives referral, surveillance and drug eligibility. Restage every 1-3 years, because fibrosis moves in both directions.
FIB-4 First, Because It Is Free
< 1.3 low risk (recheck in 1-3 years); > 2.67 high risk (hepatology); 1.3-2.67 indeterminate → elastography or ELF. It uses age, AST, ALT and platelets you already have. Thresholds shift under 35 and over 65. Biopsy is now the exception, reserved for uncertainty or suspected coexisting disease.
Normal LFTs Reassure Nobody
Many patients with F3-F4 fibrosis have normal aminotransferases, which can even fall as hepatocyte mass declines. Using LFTs as the gate is how advanced fibrosis goes unnoticed for years -risk-stratify with FIB-4 regardless of the enzyme values, especially in type 2 diabetes where the prevalence of significant fibrosis is high.
Cardiovascular Disease Is What Kills Them
CVD is the leading cause of death in MASLD, ahead of liver-related mortality. Finding MASLD is therefore a cardiometabolic risk finding: it should generate a lipid panel, an ASCVD estimate, a blood pressure plan and a statin decision. Statins are safe in MASLD and compensated cirrhosis, and withholding them over mild transaminase elevation is a net harm.
Weight Loss With Numbers Attached
3-5% improves steatosis, 7-10% improves inflammation and ballooning, ≥ 10% can regress fibrosis -give the target, because "lose some weight" accomplishes nothing. Mediterranean pattern, eliminate fructose-sweetened drinks, and 150-300 min/week of exercise reduces liver fat even when the scale does not move. Coffee associates with less progression; alcohol is minimized, or stopped in MetALD and advanced fibrosis.
The First Approved Drug, and Its Boundaries
Resmetirom (FDA accelerated approval, March 2024) treats MASH with F2-F3 fibrosis (MAESTRO-NASH, 2024), alongside diet and exercise -a liver-directed thyroid hormone receptor-beta agonist that creates local hepatic thyroid signaling without systemic thyrotoxicosis. It is not for cirrhosis (F4) and not for steatosis without fibrosis. Watch early GI effects, monitor LFTs, and mind statin interactions in patients who should be on statins.
Let One Drug Do Two Jobs
Where type 2 diabetes or obesity coexists, choose agents with liver benefit: GLP-1 receptor agonists (weight loss, steatohepatitis resolution, and independent cardiovascular benefit) or pioglitazone (histologic improvement, but weight gain, fluid retention -avoid in heart failure- and fracture risk). Vitamin E 800 IU is for selected nondiabetic biopsy-proven MASH only, with its safety debate discussed. Bariatric surgery is the most durable option and deserves formal consideration rather than last-resort status.
